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Sodium Borohydride Digest Copyright: October 2003

Rohm and Haas… Quality, Service and Innovation in Borohydride Products

Rohm and Haas (formerly Metal Hydrides Inc.) broke ground on the world’s first large-scale sodium borohydride plant in 1956, making possible the widespread use of this important chemical. Four and a half decades later, we have two world-class plants (USA and NL), a wide variety of product forms (Powder, Granular, Caplets, Aqueous Solutions and Organic Solutions) and a worldwide comprehensive customer support. While we are proud of our role as innovator in the sodium borohydride market, we understand that continued success depends on giving our customers the tools they need to move from concept to finished product. The Sodium Borohydride Digest is an important part of our efforts to help users understand the wide utility of sodium borohydride reductions in organic Organic Synthesis. For example, sodium borohydride has long been the reagent of choice for reducing aldehydes and ketones to alcohols. It has also become well known for situations where selective reductions are needed. However, many organic chemist may be less familiar with the facts that successful reduction are also possible with acid chlorides, imines, esters, carboxylic acids, unsaturated cyclic quaternary compounds and many other functional groups. The Digest is designed to allow readers to survey the entire spectrum of sodium borohydride chemistry and to obtain more details on reactions of interest. Illustrations of reductive chemistry are followed wherever possible, by the corresponding Chemical Abstracts references, which are collected at the end of each section. In addition when ever possible reference to Alembic will be sited. The Alembic is a publication that intends to highlight one specific chemical topic with possible interest for Organic Synthesis on industrial scale.



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In addition, the Sodium Borohydride Digest is a guide to sodium borohydride’s relative position among reducing reagents.

We include table showing common functional groups and their general reducibility by sodium borohydride, sodium borohydride derivatives and by some analogous aluminohydride reducing agents. Within the market of chemical reducing agents in organic synthesis, NaBH4 is the primary reductant used on industrial scale, with a estimated (equivalent) market share greater than 50%. Some of the benefits of using borohydride chemistry include : - the least expensive metal hydride commercially available (on a hydride equivalent basis) - safe with regards to storage and use & handling - industrial implementation requires no or limited equipment investment - ease of work-up (water soluble boron salts) - ubiquitous solvents such as water and methanol are typically employed - unique and versatile as a hydride reducing agent for both chemo- and diastereo-selectivity Rohm and Haas welcomes request for additional information and will gladly provide technical assistance to those interested in developing or optimizing sodium borohydride applications. Our research and technical service groups can provide assistance by telephone or, if appropriate, by visiting your facility. We can furnish technical literature on a wide variety of applications. Finally, Rohm and Haas, as a subscriber to the Responsible Care® Codes, is committed to the safe use of our products. We have wide variety of information and presentations on safety and handling. John Yamamoto, Ph.D Editor Rohm and Haas Company Synthesis & ProcessApplications

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TABLE OF CONTENTS I. Properties Page #

A. Physical and Thermodynamic 6 B. Solubility 7 C. Stability 9

II. Organic Reductions A. Theory 14 B. Practice 16 C. Carbonyl groups 28

Aldehydes 28 Ketones 35 Acids 51 Amides 55 Anhydrides 57 Acid Halides 59 Esters 63 Enol Esters 71 Imides 72 Lactone 74

D. Carbon-Nitrogen Compounds Reductive Amination 77 Azides 82 Deamination 85 Diazonium Salts 86

Heterocyclic C=N Bonds 87 Hydrazones 92 Imines 97 Nitriles 98 Nitro 101 Nitroso 105 Oximes 107 Quaternary Compounds 110

E. Miscellaneous Organic Reductions Carbonium Ions 114 Reductive Cleavage 116 Reductive Cyclization 119 Dehalogenantions 122 Demercurations 125 Double bonds 128 Epoxides 133 Organo Calcogen Compounds 135 Ozonides 140 Peroxides and Hydroperoxide 141

III. Inorganic Applications A. Inorganic Reductions 143

Metal Cation Reduction 143 Metal Anion Reduction 145

B. Organometallic 155 C. NaBH4 Derivatives 160



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Sodium Cyanoborohydride 160 Polymer Bound borohydrides 161 Other Solid Supports 162 NaBH2S3 Lanacett’s Reagent 162 NaBH(OR)3 Sodium Hydridotrialkoxyborates

163 NaBH4 Polyamine Polymer 163 Lithium Borohydride 164 Potassium Borohydride 164 Calcium Borohydride 164 Zinc Borohydride 164 Mixed Hydrides 165 Esters and Acids 165 Acetals and Ketals 165 Hydroboration with NaBH4 166 Other Derivatives 167

IV/ Analytical Procedures A. Assay Methods 179

Trace Methods for Borohydrides 180 NaBH4 Assay- Hydrogen Evolution Method 182 Iodate Method 185 Trace NaBH4 Assay-

Hydrogen evolution 188 Iodate Method 191 NBC Method 193

Crystal Violet Method 195

V. Availability 198 VI. Personal Protective Equipment 199 VII. First Aid 200 VIII. Reactivity 202 IX. Fire Fighting/ Flammability 204 X. Spill And Waste Disposal 205 XI. Toxicity 207 XII. Storage And Handling 208 XIII. Shipping 210



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I. PROPERTIES A. Physical and Thermodynamic Properties These properties are listed in the following two tables. Infrared and Raman spectra of both sodium and potassium borohydrides have been reported (1). Table I Selected Physical Properties of Sodium Borohydride Properties Formula NaBH4 Molecular Weight 37.84 Purity >98.5% Color WhiteCrystalline Form(anhydrous)

Face Centered cubic a= 6.15 Å

(dihydrate)Existsbelow 36.5

oC

Melting Point 505 oC (10 atms H2) Decomposes above 400 oC In Vacuum

Thermal Stability Will not ignite above 400 oC on a hot plate Ignites from free flame in air, Burning quietly

Density 1.074g/cm3 Apparent Bulk Density 5lb/gal

Table II Thermodynamic Properties of Sodium Borohydride Function Value Ref Free Energies of Formation Heat of Formation Entropy Heat Capacity Free Energy of Ionization NaBH4(s)= Na+ + BH4

-

∆Fo298

∆Ho298

So Co

p ∆Fo

298

-30.1 kcal/mol -45.53 kcal/mol +24.26 cal/omol +20.67 cal/omol -5660 cal/mol

3 2 5 3 4

Borohydride ion BH4- (aq.)

Free Energy of Formation Heat of Formation Entropy Hydrolysis BH4

- + H+ + 3 H2O (liq)= H3BO3 + 4 H2(g) Oxidation BH4

- + 8 OH- = B(OH)4- + 4

H2O + 8e-

∆Fo

298 ∆Ho

298 So

298 ∆Fo

298 ∆Fo

298 Eo

298

+28.6 kcal/mol +12.4 kcal/mol +25.5 cal/omol -88.8 kcal/mol -228.9 kcal/mol +1.24 V

4 4 4 4 4 4

Roh

m and Haas : the Sodium Borohydride Digest press <CTRL>-F for Searching

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2. Nonaqueous Solvents B. Solubility The solubility of sodium borohydride in different solvents has been determined accurately at different temperatures for many alcohols, amines, and glycol ethers. In general, sodium borohydride is soluble in polar compounds containing a hydroxyl or amine group. A point to note is the glycol ethers differ from most solvent in that their ability to solubilize sodium borohydride decreases as solvent temperature increases. See table III.

1. Water The solubility of sodium borohydride in water, the most commonly used solvent, has been accurately measured at the different temperatures by Jensen (6). The data presented in the following graph shows the equilibrium temperature of the two crystal forms NaBH4 and NaBH4•2 H2O. The curve below 36.4oC represents the solubility of the dihydrate, and above 36.4oC, the solubility of anhydrous NaBH4.

25

30

35

40

45

50

55

0 20 40 60

Temperature o C

gm. N

aBH

4 in

100

g s

atur

ated

so

lutio

n

Figure 1at diffe

. The solubility of sodium borohydride in water rent temperatures.




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Table III NaBH4 Solubility in Various Solvents (g/100g of solvent)

Solvent Temp(oC) Solubility0 25.0 25 55.0

Water

60 88.5Liquid Ammonia 25 104.0 Methylamine -22.0 27.6Ethylamine 17 20.9N-Propylamine 28 9.6Iso-Propylamine 28 6N-Butylamine 28 4.9Cyclohexylamine 28 1.8

25 1.4Morpholine 75 2.5

Aniline 75 0.625 3.1Pyridine 75 3.4

Monoethanolamine 25 7.7Ethylenediamine 75 22.0Methanol 20 16.4 (reacts) Ethanol 20 4.0 (reacts

slowly) 25 0.37Iso- Propanol 60 0.88

Tert-Butanol 25 0.11

60 01.82-Ethylhexanol 25 0.01Tetrahydrofurfuryl Alcohol

20 14.0 (reacts slowly

0 2.6Ethylene glycol dimethyl ether 20 0.8

0 1.725 5.545 8.0

Diethylene glycol dimethyl ether

75 0.00 8.425 8.750 8.5

Triethylene glycol dimethyl ether

100 6.70 8.725 9.150 8.475 8.5

Tetraethylene glycol dimethyl ether

100 4.2Dimethylformamide 20 18.0Dimethylacetamide 20 14.0Dimethylsulfoxide 25 5.8Acetonitrile 28 2.0Tetrahydrofuran 20 0.1



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3. Non-Solvents In cases where sodium borohydride is not soluble, traces amounts of water or low molecular weight alcohols can be added to the organic solvent to effect reduction. In general, two moles of water are needed for every mole of sodium borohydride. This procedure has proven effective with very high molecular weight alcohols. In some cases, however, an organic borohydride such as tetraethylammonium borohydride will be more effective because of its greater solubility. The use of NaBH4 on solid supports such as silica gel, alumina, and zeolites in nonpolar solvents has been published (See section IIIC). C. Stability Sodium borohydride is very stable thermally. It decomposes slowly at temperatures above 400oC in vacuum or under a hydrogen atmosphere. Sodium borohydride absorbs water rapidly from moist air to form the dihydrate complex, which decomposes slowly forming hydrogen and sodium metaborate. Decomposition in air is therefore a function of both temperature and humidity. Generally higher reaction temperatures favor borohydride reductive chemistries.

1. Aqueous Solutions The stability of sodium borohydride in water is dependent upon the temperature and the pH. Increasing the temperature and lowering the pH accelerates the hydrolysis reaction.

NaBH4 + 4 H2O NaB(OH)4 + 4 H2 As the borohydrides are alkaline, the higher the concentration, the more stable the resulting solutions. See Table IV.

Table IV pH of Solutions of NaBH4 at 24oC

Concentration of NaBH4

pH

1.000M 10.48 ± 0.02 0.100M 10.05 ± 0.02 0.010M 9.56 ± 0.02

The kinetics of the hydrolysis reaction has been studied by Gardiner and Collat (7,8), Wang and Jolly (9), and by Kreevoy (10,12). The reaction is pseudo-first order and is subject to general acid catalysis. First order kinetics also applies in strongly alkaline solution (13). The decomposition rate of aqueous NaBH4 solutions can be estimated conveniently (14) using equation

Log10t1/2(mins)= pH-(0.034T-1.92)


10

where t1/2 is the half-life in minutes and T is the temperature (kelvin scale). Table V. numerically shows the relationship between pH and the half-life of NaBH4 at 25 oC in an aqueous solution.

(a) Effect of pH It is obvious, therefore, that the addition of sodium hydroxide will stabilize aqueous sodium borohydride solutions. This was demonstrated by Jensen (6) over a pH range of 12.9 to 13.8 (calc.)

Table V: pH Vs Half life of SBH

At higher pH values there is essentially no decomposition during storage. pH NaBH4 Half life

4.0 0.0037 sec. 5.0 0.037 sec5.5 0.12 sec6.0 0.37 sec7.0 3.7 sec.8.0 36.8 sec.9.0 6.1 mins

10.0 61.4 mins11.0 10.2 hours12.0 4.3 days13.0 42.6 days14.0 426.2 days

86889092949698

100

0 50 100 150

Time (hours)

% N

aBH

4 0.10 N NaOH0.25 N NaOH1.00N NaOH

Figure 2. Effect of pH on stability of NaBH4 solutions. The hydrolysis of sodium borohydride in water causes a rise in pH value, and the rate of decomposition therefore decreases. For example, a 0.01 M solution of NaBH4 has an initial pH of 9. 6 that changes during hydrolysis to 9.9.

(b) Effect of Temperature If the temperature is increased, the stability decreases

as shown in Fig.1. This can be compensated for, by adding more caustic or increasing the sodium borohydride concentration.



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Figure 3. Stability of an alkaline solution (1.00 N NaOH) of sodium borohydride (0.10 M NaBH4) at 24o C and 46o C (c) Effect of catalysts Noble metals, copper, nickel and cobalt borides (15-23) catalyze the hydrolysis of the borohydride ion; the catalyst is frequently formed by borohydride reduction of the corresponding metal salts in solution. 2. Aqueous solutions (VenPure) VenPure Solution is a stabilized water solution of sodium borohydride in caustic soda. Such a solution containing 12% NaBH4 and 40% NaOH, decomposes at

a rate of only 5x10-6% per day at 21oC and at 4x10-5% per day at 54oC.

40

50

60

70

80

90

100

0 50 100

Time (hour)

% N

aBH

4

24.0 oC47.0o C

3. Tetraglyme solutions (Venpure OGS) Venpure OGS is a tetraglyme solution of 8.5 % sodium borohydride. This solution is to be used when sodium borohydride is needed in an aprotic solvent. The stability of the sodium borohydride in this solvent is very good, no decomposition of the NaBH4 occurs after 336 hour at either 24 or 60 oC. 4. Alcohol Solutions. NaBH4 is unstable in acidic alcohols (e.g. phenol) and low molecular weight primary alcohols such as methanol, ethanol and ethylene glycol due to solvolysis but is stable in secondary and tertiary alcohols such as isopropanol, t-butanol and 2-ethylhexanol, even at elevated temperatures (24,25). It reacts with higher molecular weight primary alcohols. The instability in lower alcohols can be overcome by the addition of base, as in aqueous solutions. For example, Jensen (6) has reported that ethanol only 5.7% of the sodium borohydride is lost in 144 hours at 24oC in the presence of 2 N sodium hydroxide. Studies undertake at Rohm and Haas have demonstrated that the addition of as little as 0.01 N MeONa to a methanol solution or 0.01N NaOEt to an Ethanol solution of

Rohm and Haas : the Sodiu F for Searching

m Borohydride Digest press <CTRL>-


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Figure 4 NaB

sodium borohydride can substantially suppress the hydrolysis of NaBH4 as shown in the graphs below.

05

1015202530

0 2Time, Hours

% N

aBH

4 C

onsu

med

0.001 NaOEt

0.1 NaOEt

No NaOEt

Figure 5. Effect of the addition of NaOEt on the solvolysis of sodium borohydride in ethanol at 30 oC. . Effect of the addition of NaOMe on solvolysis

of H4 in methanol over a short period of time.

020406080

100

0 200Ti me ( M i nut e s)

0.1N NaOMe 30oC

0.1N at 50 oC

0

20

40

60

80

100

0 10 2

T

% N

aBH

4 co

nsum

ed

0 30 40

ime (minutes)

No NaOMeadded0.010 NNaOMe

Figure 6. Effect of Temperature on the solvolysis of NaBH4 in methanol with NaOMe.


13

00,5

11,5

22,5

3

0 0,5 1Ti me ( hour s)

0.01 NaOEt at 50°C

0.01 NaOEt at 30°C


Figure 7. Effect of Temperature on the solvolysis of SBH in ethanol with NaOEt. 5. Other Solvents The stability of sodium borohydride solutions in organic solvents is dependent upon the amount of hydrolysis that can occur. In solvents such as Glymes, DMAC, NMP, pyridine and dioxane, where there is no chance of hydrolysis, sodium borohydride is stable indefinitely. As soon as water is present in significant amounts, hydrolysis can occur and affect the stability. While dilute solutions of NaBH4 in dimethlyformamide (DMF) have been used many times without incident, a violent exothermic reaction was reported (26) involving

a saturated (4.7M) solution and resulting in spontaneous ignition of the flammable gases evolved. Laboratory investigation at Rohm and Haas showed that after a temperature-dependent induction period, a runaway reaction occurs in concentrated (>2M) NaBH4-DMF solutions in which DMF is reduced to trimethyl amine. The reaction is accelerated by small amounts of carboxylic acids. Formic acid is known to be present in commercial DMF in ppm quantities as a result of slight hydrolysis. Dimethylacetamide (DMAC), which is also a good solvent for NaBH4, does not react violently with NaBH4 under similar conditions. In view of the above findings, we strongly advise caution in working with NaBH4 in DMF. We recommend substitution of dimethylacetamide as safer solvent especially if the use of concentrated solutions or elevated temperatures is contemplated.



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II. ORGANIC REDUCTIONS A. Theory

0

10

20

30

40

50

60

70

80

90

100

0 50 100

Time (minutes)

% R

educ

tion Benzaldehyde

Salicyladehyde

m-hydroxybenzaldehyde

p-hydroxybenzaldehyde

b-Resorcylaldehyde

The rate of addition of sodium borohydride to a ketoneic carbon is directly related to the magnitude of the charge on that carbon.

O

D D R R

O

W W

O

δ- δ+ Least reactive Most reactive

Because of this, any substituent that increases the fractional positive charge on the carbonyl carbon atom will increase the rate of reduction. If the fractional positive charge is decreased by substituents, then the rate is slowed. Jensen (6), for example, has shown that the rate of reduction for substituted benzaldehyde derivatives is as shown in Figure 8.

Figure 8. Rate of reduction of benzaldehyde and a few hydroxybenzaldehydes. With perfluoro compounds, however, the inductive effect is clearly shown, and it has been demonstrated (27) that fluorinated esters are reducible by NaBH4 in nonaqueous systems in good yield.

In this case, the inductive effect leading to a greater positive charge is overcome by the resonance effect.

R-CF2-COOEt R-CF2CH2-OH

The presence of metal ions, either as a catalyst (28, 29), or to form other more powerful or stereo selective borohydrides, and solvents (24) can influence reductions with NaBH4.




15

The mechanism of borohydride reductions of aldehydes or ketones in the presence of alcohols was initially thought to proceed by a stepwise hydride ion transfer to the carbonyl carbon, resulting in formation of a tetraalkoxyborate containing the substrate being reduced. Subsequent hydrolysis of the complex, during work up, generated the product alcohol.

The first model to predict the stereoselectivity of hydride reductions of carbonyl groups was proposed by cram in 1952 (35-36). This model proposed that the hydride atom attacks the carbonyl group form the direction of the smallest substituent as shown in figure 10.

O

R R

+

NaBH4

+

R'OH

K1

R

RO

H

BH H

H

R'O

HK2

R R

OHH

+

NaBH3OR'

Various aspects of the relatively few

mechanistic studies reported in ensuing years served only to cloud the issue. These included solvent and cation effects (24,25), Kinetic observations (30) that suggested complete disproportionation of alkoxyborohydride intermediates to regenerate BH4

- as the actual reducing agent, and questions on the origin of stereoselectivity. Detailed studies by Wigfield (31-34) indicate that during carbonyl reductions in alcohol solvents, the alkoxyborate anion intermediate contains the solvent alkoxy rather than that of the product. (Figure 9) Isotope studies show that disproportionation of the intermediate back to BH4- does not occur.

Figure 9

In any case, kinetic studies show that the first

step in the process must be rate controlling.


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ohydride Digest press <CTRL>-


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H-

H-

103o

H

SM

P,L

HO R

SM

P,L

RO

SM

P,L

OR H

SM

P,L

R OH

Figure 10

In 1968 Felkin improved on Cram's model by

proposing that the bulkiest substituent could also be the most electron-withdrawing group regardless of steric size. (37) These new conclusions were later substantiated by the theoretical calculations of Ahn. (38-40) The theoretical calculations also showed that the hydride attacking the carbonyl group approaches at a 103o angle instead of 90o. Another model set forth by Cram in 1952 proposed that substrates containing a chelating group in the α or β position will chelate with a metal cation to form a five or six membered ring. (41) The chelating

cation adds steric bulk to the molecule, which will increase the specificity of the attack of the hydride.

H-

ROS

LM Metal

R

OHS

LM

H

See the section on ketones for further details. B. Practice Sodium borohydride is an attractive reducing agent for organic substrates because of its convenience as well as its selectivity and efficiency. The general techniques of its use are by now well known to the practitioners of organic synthesis, who also knows that modifications are sometimes dictated by the properties (solubility, thermal stability, pH sensitivity) of the materials being reduced. Nevertheless, a few comments are in order, to ensure the reagent’s effective use.

Part of the convenience associated with sodium borohydride reductions lies in the fact that, unlike most other complex hydrides, it is not necessary to exclude moisture and atmospheric oxygen from the reaction mixture. While some of



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the borohydride will be consumed by reaction with any water present, this will not have any adverse effect on the desired reduction, provided that sufficient borohydride is present. This is the main reason why hydride reductions customarily use a slight excess of reducing agent. The selection of a solvent for a NaBH4 reduction can influence the results. Water and lower alcohols are most commonly used, but the solubility characteristics of the material being reduced may dictate selection of a different solvent (see Table III for NaBH4 solubility information.) It is important to note that while the literature containing numerous references to borohydride reductions in methanol, NaBH4 is not stable in this solvent, especially at elevated temperatures. Interaction of NaBH4 and methanol, analogous to hydrolysis, takes place readily unless the reducing agent solution is stabilized by the addition of alkali. Ethanol and isopropanol, in which NaBH4 is less soluble, are preferable because of their much slower rates of solvolytic reaction with NaBH4. Water is a good solvent for NaBH4 and is recommended for water-soluble compounds. As is true with methanol, however, addition of alkali to stabilize the borohydride solution may be warranted.

In simple ketone reductions, as well as in many other cases, the order of addition has no effect on the course of the reaction and the yields obtained. The conversion in complex hydride reductions is analogous to that of Grignard reactions in that addition of substrate to the reducing solution is considered the normal method. This order of addition is used even with alkali-sensitive compounds, such as aldehydes or aminoketones, since only a small amount of starting material at a time is subjected to the alkaline conditions of the reducing agent and this is rapidly reduced.

After completing the reduction reaction, destruction of any unreacted borohydride is recommended before attempting product isolation or workup. This can be accomplished by addition of excess acetone that rapidly consumes borohydride. Alternatively, dilute aqueous base or dilute mineral acids can be added for the same purpose. Note that concentrated acids must never be used because of the potential for formation of hazardous boranes, which may also cause undesired reduction of other functional groups present. Provision should be made to vent safely any hydrogen gas formed during destruction of unreacted borohydride. See section VI for additional details. 1) Phase Transfer Catalysis

This general discussion of the practical aspects of applying sodium borohydride as a reducing agent would not be complete without mentioning the increasing use of phase



18

transfer catalysis (PTC) as a means of overcoming solvent incompatibilities between the borohydride and the substrate to be reduces (42-45). Quaternary ammonium salts, such as tetrbutylammonium ion, are the most commonly used catalysts. In fact, preformed tetrabutyl ammonium borohydride has also been used for reductions in aprotic solvents such as ethylene chloride (38). Crepitates (39) and chiral functional polymers (40-43) have also been applied in PTC reductions with sodium borohydride. Continuing interest in stereospecific reductions has resulted in the use of chiral quaternary ammonium salts as phase transfer catalysts. Asymmetric induction has been demonstrated to occur when ephedrinium salts are used in PTC reductions with sodium borohydride (44-46). 2) Chemically Modified Borohydride Anion

Modifying the chemo and/or enantio-selective reductive properties of NaBH4 with the addition of either an organic or inorganic modifier has opened areas of reductive chemistry that were normally considered inaccessible to NaBH4. Two classes of reagent that have been used to modify sodium borohydride are carboxylic acids (55-56), chiral alcohols (57), sugars (58-62), tartaric acid (63) and lactic acid (64-65).

The reaction of carboxylic acids with NaBH4 forms either mono or tris-substituted acyloxyborohydrides, which have unique reactive properties depending on the quantity of acid, added to the reaction. The true strength of this system is realized with the reduction of nitrogen containing organic molecules such as immines, oximes, enamines, iminium salts and heterocyclic compounds. Reductive aminations can be done efficiently using this system. Two reviews exploring the vast chemistry of this methodology has been published recently (55-56).

Finally, chiral alcohols have been added to the NaBH4 reducing system to induce selective enantiomeric reduction of organic functional groups. This selectivity is induced by asymmetric induction. Chiral alcohols such as amino alcohols, sugars and tartaric acid have been used to accomplish these selective reductions (55-65). 3) Changing of the Cation

Many different metal salts have been used with sodium borohydride to form new more powerful and selective reducing reagents. The most common metals to be added are LiCl (66), ZnCl2 (67-79), TiCl4(80-82), Ti(Isopropoxide)4 (83-85), Cp2TiCl2 (87), CeCl3 (88-89), CaCl2 (90-92) and lanthanide salts (93). The use of these metal salts to modify the chemo, stereoslectivity and the reductive strength of the NaBH4 towards organic functional groups have been and are


19

currently being studied. A review has recently been written on this subject.

5) Co-catalyst: The use of catalysts to increase the chemo and stereo selectivity of sodium borohydride has been demonstrated recently. Adiminato Co(II) complexes have reduced ketones as well as carboxyamides and imines functional groups stereoselectively (102-106). Other inorganic and organic catalysts have been reported (107).

4) Modification of the substrate. Recently cynuric acid (94) and BOP (95) have been added to solutions of carboxylic acids prior to treatment with sodium borohydride, to help the reduction of carboxylic acid groups under mild conditions. This methodology makes it possible to convert amino acid to amino achohols under very mild conditions.

6) Supported borohydrides

The impregnation of organic and inorganic polymers such as ion exchange resins, zeolites, silica gel, alumina or aluminophosphates with sodium borohydride or derivative has been used to stereoselectively and chemoselectively reduce organic functional groups. Depending on the nature of the support, the type of borohydride reagent used and the type of co-reagent are used, different chemo and stereoselectivities can be achieved. These reductive systems have advantages such as with the exchange resins, the spent borohydride are easily separated from the product by filtration and with silica gel and alumina reactions can be done in aprotic solvents such as hexane.

R OH

O N

N

N

Cl

Cl Cl

NMM, DME

3h, RT+

R

O N

N

N

Cl

Cl

NaBH4, H2O

0 oCR OH

Cyclodextrin have recently been used as an additive to help induce stereoselectrive reduction of carbonyl groups. This reagent works by forming an inclusion complex with the substrate to be reduced in such a way as to allow the addition of hydride to the functional group from one direction only (96-101).

7) In situ or ex situ production of diborane. Diborane, B2H6 can be synthesized directly from borohydride in high yields using many different reagents. Reagents that can accomplish this transform are H2SO4 (108-




20

111), I2 (112-120), Me3SiCl (121-122), TiCl4 (123-124), BF3 (125-128) and others. These reaction can be done either in situ where the compound to be reduced and the reagents to generate diborane are placed in to the same reaction flask or the diborane which is a gas at room temperature can be transferred from the diborane generation flask to a new flask which contains the molecule to be reduced. Both of these methods are a very economical way of generating diborane. Diborane will form stable complexes with Lewis bases such as ethers, thioethers, and amines to form borane Lewis acid base complexes. The chemistry of these complexes has been published and is outside of the scope of this digest. Precaution: Diborane is a highly toxic gas at room temperature and should be handled with appropriate care. 8) Enantioselective reduction using sodium borohydrides Normally alkali and alkaline earth borohydrides by them self cannot enantioselectively reduce organic functional groups. There are a few exceptions to this rule where the alkali or alkaline earth cation complexes with the compound in such a manner as to stericlly direct the approach of the borohydride to

the functional group to be reduced therefore forming only one conformer. (129) Another method that works on the premise of controlling the steric availability of functional group to the reducing agent is the use of molecules that associates with the substrate in such a manner as to sterically direct the borohydride to react with only one face of the reducible functional group. A prime example of this technique is cyclodextrin. The molecule of interest can enter the cavity of the cyclodextrin molecule and due to steric restraints imposed by the cyclodextrin molecule only one face of the reducible functional group is accessible to the borohydride reducing agent. (130-131)

Enantioselective reductions can be achieved using sodium borohydride by adding chiral modifying reagents such as enantiomerically pure; chiral alcohols, chiral carboxylic acids, sugars, tartaric acids and other chiral organic compounds to the borohydride prior to reaction with the substrate. These reagents have been shown to give high ee’s. (55-65)

Chiral transition metal catalyst such as the cobalt catalyst developed by Yamada et al. can catalytically reduce functional groups such as ketones, imines and oximes by using the sodium borohydride as a source of hydride. (102-106)

Many borane based chiral reducing reagents and catalyst that are formed from and use diborane as a source of



21

hydrides are synthesized from borohydrides (see above). Many reviews using these reagents have been published. (132-138) 9) Chemoselectivity As a general rule the reactivity of sodium borohydride towards organic functional groups at room temperature is as follows:

Easily reduced Aldehydes>> Ketones> Acid Chlorides = Imines =

>C=N+< Moderately reduced

Esters, Epoxides, Lactones Difficult to reduce:

Carboxylic Acids, Amides, Imides, Carbinol, Nitrile, Nitro Dehalogenantion, Tosylehydrazone,

Hydroboration and C-Calcogen Bond Cleavage

The selectivity of sodium borohydride can be attributed to the inherent reductive strength of sodium borohydride itself. This reductive strength can be modified by adding co-reagents that either transforms or modify the boron hydride bond or by changing the kinetic properties of the reductive system, such as temperature or time of reaction.

Modifiers which increase the reductive strength of sodium borohydride by decreasing the bond strength between boron and hydrogen while the borohydride keeps all four of it’s hydrides are metal salts such as LiCl, ZnCl2, CaCl2, AlCl3 , N(Bu)4 and others. (66-82, 90-92)

Sodium borohydride can be transformed into a stronger reducing agent by adding modifiers that cause the sodium borohydride to loss between 1 and three hydrogens to form NaBH3OR or NaBH(OR)3. These modifiers are usually small molecular weight alcohols and carboxylic acids. (55-56)

Another method of increasing the reductive strength of sodium borohydride is to increase the temperature of the reaction. This accomplishes two things it increases the rate of the reaction and also adds energy to system to overcome the ∆ G of the reaction. These different methods of increasing the reactivity of sodium borohydride can be and are usually used in combination to accomplish many reductions that are not possible with sodium borohydride alone.



22

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1996, 96, 835



28

C. Carbonyl Coumpounds

ALDEHYDES Alembic 18, 32, 48, 50, 52, 55, 58 The use of NaBH4 for the reduction of aldehydes to the corresponding primary alcohol is well known. The reductions proceed rapidly, and in most cases quantitatively in water, lower alcohols, amines and a variety of other organic solvents :

4 RCHO + NaBH4 NaB(OCH2R)4 4 RCH2OH Jensen (1) has shown that NaBH4 can quantitatively reduce the following aldehydes in a water/dioxane solvent system within two minutes at room temperature. Formaldehyde Aldol Acetaldehyde benzaldehyde Paraformaldehyde phenylacetaldehyde propionaldehyde 4-tolualdehyde butylradehyde naphthaldehyde isobutyraldehyde 2-ethoxybenaldehyde isovaleraldehyde 2-chlorobenzaldehyde 4- chlorobenzaldehyde hexanal Crotonaldehyde methacrylaldehyde anisaldehyde glyceraldehyde

While NaBH4 can reduce nearly all aldehydes the reduction rate depends upon the concentration of the solvent used and the reaction temperature. Reduction is generally rapid and quantitative in aqueous media. Kinetic studies of carbonyl compounds reduction in water DMSO and water/DMSO mixtures indicate that the reaction obeyed second order kinetics and that the rate constants increased with increasing water contents (2). Room temperature reductions of aldehydes (and ketones) in two-phase systems, i.e. Et2O/aq. NaBH4, have resulted in excellent yields of the corresponding alcohol (3). Water-soluble bisulfite adducts of aldehydes can be formed to facilitate NaBH4 reduction in aqueous media (4). Electron-Withdrawing substituents that increase the fractional positive charge on the carbonyl carbon accelerate the reduction rate while electron- donating substituents have the opposite effect. This high reactivity with NaBH4 enables one to selectively reduce aldehydes in the presence of other functional groups that are reducible under more vigorous reaction conditions. For example, the reactivity of aldehydes with NaBH4 is considerably greater than that of ketones. Because of this difference in reactivity of the two carbonyl groups, it is possible to carry out the selective reduction of


29

aldehyde groups in the presence of keto groups, providing a micromethod for distinguishing between these two types of carbonyl compounds (5). Luche demonstrated an example of the reverse selectivity, that the use of 1 mole equivalence of CeCl3 will retard the reduction of an aldehyde group in the presents of both cyclic and acyclic ketone. (6)

NaBH4 reduction of aldehydes has been used as a “blocking” technique to prevent Schiff base staining in histology work (11). Chemoselective reduction of aldehydes in the presence of ketones is greatly enhanced by employing acyloxyborohydrides formed from sodium borohydride and a lower aliphatic carboxylic acid, as reported by Gribble and coworkers. The reagent, e.g. NaBH(OAc)3, can either be formed in situ or prepared separately before use (12). The corresponding tetrabutylammonium salt, Bu4NBH(OAc)3 that can be made readily at room temperature, has also been reported (13).

Competitive reaction studies of aldehyde-ketone mixtures with NaBH4 have demonstrated the enhanced reactivity with both aliphatic and aromatic aldehydes with respect to the corresponding ketone (7). The addition of thiol compounds can further enhance the selectivity (8). The selectivity of NaBH4 for aldehydes over ketones was utilized to reduce aldehydic substituents on benzopyranopuyridines to the corresponding alkanols without affecting the keto group (9) and the synthesis of hycanthone (10).

O NH(CH2)2NEt2

C

O

H

O NH(CH2)2NEt2

C HH

OH

NaBH4




30

The specificity of NaBH4 for carbonyl groups makes it possible to reduce aldehydes in the presence of the following functional groups: Functional group References carbonyl 14,15 ester 16-21 lactone 22-24 lactam 25 imide 26-27 acetate 22,28 nitrile 17,24,29 nitro 30. 31 amine oxide 32 olefin 17,18,27,32-36, epoxy 28,34 tosyl ester 38 haloalkyl or aryl 18,39-41 thiocarbonyl 40 amide 42 acetylenes 43-48

Because of its selectivity and rapidity in

aldehyde reductions, NaBH4 has been used extensively in the synthesis of steroids (37), carbohydrate derivatives (49-53), insecticides (54,55), perfume

ingredients (56-58), in the reduction of Vitamin A aldehyde (59) and in the production of other pharmaceuticals such as dihydrostreptomycin (60-63), antihypertensives (65), antiviral (66) and antithrombotic (67) drugs. The mild reaction conditions employed in NaBH4 reduction of aldehydes favor retention of stereochemical configuration (65,68). In some instances, lactones can be formed during NaBH4 reduction of aldehydes located α or β to carboxylate groups (69,70). Similarly, ozonolysis of unsaturated ketones followed by NaBH4 reduction can lead to formation of δ-lactones (71).

Periodate cleavage of vicinyl diols followed by NaBH4 reduction of the resulting dialdehyde has been utilized to characterize polysaccharides and in the preparation of lividomycin B derivatives (72). A related cleavage/reduction reaction, ozonolysis followed by NaBH4 reduction, was employed in the total synthesis of camptothecin from acridine (73).

The use of aprotic solvents such as hexane as a reaction solvent for the sodium borohydride reduction of aldehydes has recently been demonstrated. Either aromatic or aliphatic aldehydes were combined with hexane in the presents of silica gel and sodium borohydride to give the corresponding alcohols in high yield. (74) The use of tetraalkyl ammonium chloride (75) or crown ethers for the reduction of aldehydes with sodium



31

borohydride in phase transfer catalysis systems is a well established technique. (76) (Alembic 52, 55) Recently polyethylene gycol has been used as a phase transfer reagent in the reduction aldehydes with sodium borohydride. This methodology has the advantage over previous phase transfer reagent in that PEG is relatively cheap reagent in comparison to traditional phase transfer reagents such as crown ethers, polyethers or onium salts. (77). (Alembic 56)

A very important technique for the reduction of aldehydes with sodium borohydride is the impregnation of solid supports such as polymer (78), ion exchange resins (78, 79) (Alembic 52) and zeolite (80) with borohydrides. (Alembic 58) Many different metal borohydrides such as Zn (77, 81) and Cu (79) have also been used in cooperation with solid supports to achieve high yield reductions of aldehydes to alcohols and alkanes.

Polymeric zinc borohydride with organic nitrogen compounds will reduce aldehydes selectively. (82) References: 1) Jensen, E.H. “A Study on Sodium Borohydride”,

Ny Nordisk, Forlag, Arnold Busck, Copenhagen 1954 (out of Print.)

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32

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22) Golab, T.; Trabert, C.H.; Jaeger, H.; Reichstein, T. Helv. Chim. Acta 1959, 42, 2418; Chem. Abstr. 55, 27407a

23) Chernobai, V.T.; Kolesnikov, D.G. Proc. Acad. Sci. USSr (Engl. Trans.) 1959, 127, Chem. Abstr. 53,20696c

24) Ger. Offen. 2,142,842; Chem. Abstr. 77, 48245a 25) Fall, H.H.; Petering, H.G.; J. Am. Chem. Soc. 1956,

78, 377; Chem. Abstr. 50, 13038i 26) Schoeberl, A; Pape, C.V. Chem. Ber. 1965, 98,

1688; Chem. Abstr. 63, 4383c

27) Danishefsky, S.; McKee, R.; Singn, R.K. J. Am. Chem. Soc. 1977, 99, 4783; Chem. Abstr. 87, 184743v

28) Moreau, S.; Cacan, M.; Lablanche-Combier, A.; J. Org. Chem. 1977, 42, 2632; Chem. Abstr. 87, 65069s

29) Milijkovic, D.; Petrovic, J. J. Org. Chem. 1977, 42, 2101; Chem. Abstr. 87, 23595h

30) Schechter, H.; Ley, D.E.; Zeldin, H. J. Am. Chem. Soc. 1952, 74, 3664; Chem Abstr. 47, 5885c

31) Salgado, A.; Huybrechts, T.; De Buyck, L.; Czombos, J.; Tkachev, A.; De Kimpe, N. Synth. Commun. 1999, 29, 57-63

32) Dirlam, J.P.; McFarland, J.W. J. Org. Chem. 1977, 42, 1360; Chem. Abstr. 86, 155694z

33) Eldelson, J. Et. Al. J. Am. Chem. Soc. 1959, 81, 5150; Chem. Abstr. 54, 7548b

34) Klein, E.; Rojahn, W.; Henneberg, D. Tetrahedron 1964, 20, 2025; Chem. Abstr. 61, 14716h

35) Ger. Ofen. 2,513,996 1976; Chem. Abstr. 86, 16353d 36) Ger. Offen. 2,559,433 1976; Chem. Abstr. 86, 55066g 37) U.S. 4,544,555 1985; Chem. Abstr. 105, 43157k 38) Dale, W.J.; Hennis, H.E.; J. Am. Chem. Soc. 1956, 78,

2543; Che. Abstr. 51, 1080a 39) Brink, M. Acta Chem. Scand. 1965, 19, 255; Chem. Abstr.

62, 14544d 40) Hull, R.; Van der Brock, P.J.; Swain, M.L. J. Chem. Soc.

Perkin 1 1975, 2271; Chem. Abstr. 84, 89960t



33

41) Ger. Offen. 2,064,106 1972; Chem. Abstr. 77, 101126r

42) Fr. Demande 2,260,332 1971; Chem Abstr. 84, 89999n

43) Ger. Offen. 2,065,014 1971; Chem. Abstr. 76, 59435t

44) Jpn. 72,03,342 1972; Chem. Abstr. 76, 126766s 45) Jpn. 73,32,108 1973; Chem. Abstr. 80, 47827s 46) Jpn. 74 13 778 1974; Chem. Abstr. 81, 151982v 47) Jpn. Kokai 75 25, 539 1975; Chem. Abstr. 83,

131442g 48) Parry, R.J.; Kunitani, M.G. J. Am. Chem. Soc.

1976, 98, 4024; Chem. Abstr. 85, 89917e 49) Wolfrom, M.L.; Anno, K. J. Am. Chem. Soc. 1952,

74, 5583; Chem. Abstr. 101, 73033b 50) Morin, C. Carbohydr. Res. 1984, 128, 345;

Chem.Abstr. 101, 73033b 51) Sinhabau, A.K.; Barle, R.l.; Pochopin, N.;

Borchardt, R.T. J. Am. Chem. Soc. 1985, 107, 7628; Chem. Abstr. 013, 209794b

52) Usuki, S.; Nagai, Y Anal. Biochem. 1986, 152; Chem. Abstr. 014, 48213q

53) Williams, A.G.; Withers,S.E. J. Microbiol. Methods 1986, 4, 277; Chem. Abstr. 105, 75147y

54) Eur. Pat. Appl. 50,857 1982; Chem. Abstr. 97, 144560h

55) Ger. Offen. 3,402,483 1984; Chem. Abstr. 102, 24273s 56) Eur. Pat. Appl. 53, 716 1982; Chem. Abstr. 97, 216516y 57) U.S. 4,521,634 1985; Chem. Abstr. 104, 6053g 58) Eur. Pat. Appl. 184, 7078 1986; Chem. Abstr. 105,

178244g 59) Brit. 778,753 1957; Chem. Abstr. 52,2077I 60) U.S. 3,397,197, 1968; corresponds to Brit 1,063,450

1967; Chem. Abstr. 68, 22212b 61) Kaplan, M.A.; Fardig, O.B.; Hopper, I.R. J. Am. Chem.

Soc. 1954, 76, 5161; Chem. Abstr 49, 20876I 62) U.S. 2,790,792 1957; Chem. Abstr. 51, 15561d 63) U.S.; 2,945,850 1960; Chem. Abstr. 54, 23211I 64) Jpn. Kokai Tokkyo Koho 83, 140,032 1983; Chem. Abstr.

100, 22323t 65) Arigoni, D.; Battagila, R.; Akhtar, M.; Smith, T. J. Chem.,

Chem. Commun. 1975, 185; Chem. Abstr. 83, 2961b 66) U.S. 5,233,041 1993 67) U.S. 5,767,269 1998 68) Jpn. Kokai Tokkyo Koho 85, 146,840 1985; Chem. Abstr.

104, 33760s 69) Spry, D.O. J. Org. Chem. 1975, 40, 2411; Chem. Abstr.

83, 97171f 70) Bowen, D.H.; Cloke, C.; Harrison, D.M.; MacMillan, J.

H. J. Chem. Soc., Perkin 1 1975, 83; Chem. Abstr. 82, 140326d



34

71) Chavdarian, C.G.; Heathcock, C.H. J. Org. Chem. 1975, 40, 2970; Chem. Abstr. 83, 179317x

72) Jpn. 76,11,611 1976; Chem. Abstr. 86, 5774r 73) Corey, E.J.; Crouse, D.N.; Anderson, J.E. J. Org.

Chem. 1975, 40, 2140; Chem. Abstr. 83, 79450s 74) Yakabe, S.; Hirano, M.; Morimoto, T. Synth.

Commun. 1999, 29, 295 75) Stark, C.M.; Liotta, C.L.; Halpern, M. Phase

Transfer Catalysis: Fundamentals, Applications and industrial Perspectives; Chapman and Hall; New York, 1994

76) Blanton, J.R. Synth. Commun. 1997, 27, 2093 77) Tamami, N.; Goudarzian, N.; Kiasat, A.R. Eur.

Polym. J. 1997, 33, 977 78) Bandgar, B.P.; Kshirsagar, .N.; Wadgaonkar, P.P.

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70, 1101 80) Sreekumar, R.; Padmakumar, R.; Rugmini, P.

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1995, 25, 1089 82) Firouzabadi, F.; Zeynizadeh, B. Bull. Chem. Soc.

Jpn. 1997, 155



35

KETONES

Alembic: 7, 18, 21, 26, 31, 48, 50, 52, 55, 58, 62 Under normal conditions, NaBH4 reduces ketones at a slower rate than aldehydes. While in most cases aldehydes undergo reactions within a few minutes, the reduction of ketones usually takes 30-90 minutes. A few examples of ketones that are reduced at least 90 % at room temperature are: Time required for 90 % Reduction Ketone (min) Acetone 40 3-hydroxy-2-butanone 2 acetophenone 100 benzophenone 130 benzoin 6 cyclopentanone 90 cyclohexanone 4 2-methylcyclohexanone 7 menthone 90 isatin 2 furoin 12 As indicated in the table, α-substituents which increase the fractional positive charge on the carbonyl

carbon enhance the rate of BH4- attack. Of course, many other

factors play a part in the rate of reduction. Ring strain and steric effects are also important. Five and six membered cyclic ketones are reduced much more rapidly than more highly strained cyclic(1-4) ketones. The influence of steric effects has been correlated with reduction rates(5). Physico-chemical factors in ketone reductions by NaBH4 are reported by other investigators for unbranched aliphatic ketones (6), cycloalkyl phenyl ketones (7), substituted acetophenones (8), and substituted fluorenones (9,10). The heats of reduction for simple ketones are reported (11).

The mechanism and kinetics of ketone reduction by sodium borohydride have been topics of extensive study in recent years, particularly in view of the striking stereochemical control that can be achieved with sodium borohydride. (Alembic 11, 24) Wigfield et. al. (12-18), in a series of elegant studies, have provided a better insight into the mechanisms and transition state in this reaction and a rationale for prediction of stereodirection. It has generally been assumed that the product of ketone reduction is a tetraalkoxyborate formed according to the equation:

4 R2C=O + BH4- (R2CHO)4B-



36

However, Wigfield has clearly shown (12,13) that during ketone reduction in alcoholic solvents, the alcohol plays a crucial role, and that the alkoxy groups are derived from the solvent and not the ketone. Further work (18) using mixtures of NaBH4 and NaBD4 in ketone reductions demonstrated that disproportionation of the monoalkoxy borohydride intermediate does not occur, thus raising doubts as to the validity of the previously proposed (19) completely disproportionation mechanism. Similarly, the evidence for solvent participation and the determination (6) of a kinetic order of 3/2 with respect to 2-propanol in reduction would rule out 4 center and 6 center transition states which have been advocated in the literature, and favor a linear acyclic transition state (20,21) which is product-like in nature. Thus, a stepwise mechanism as previously proposed (22,23), but modified to incorporate the solvent alkoxy group (12,13) has been suggested (18).

BH4- + >C=O (RO)BH3

- + >CHOH (RO)BH3

- + >C=O (RO)2BH2- + >CHOH

(RO)2BH2- + >C=O (RO)3BH- + >CHOH

(RO)3BH- + >C=O (RO)4B- + >CHOH Measurements of activation parameters in

cyclohexanone reductions (15,16) have led to a simple

formula for calculating and predicting stereochemical product ratios (17). Additional work by Wigfield and other on the kinetics of ketone reduction (24-27), transition state analysis (28-32), and steric effects (33-36) have contributed greatly to the current understanding and utility of NaBH4 reductions in organic synthesis. While the rate of ketone reduction is influenced by the solvent, ketone reductions are routinely conducted in a wide variety of organic media as well as in water. Comparative reduction rates for acetone in three solvents are shown below (37)

Rate of acetone Reduction in Water, Ethanol and Isopropanol at 0 oC

Solvent k2x104

(L mol-1 sec-1) Water 93

Ethanol 97Isopropanol 15.1



37

Among the many classes of solvents used for sodium borohydride reductions of ketone are:

Alkanes Sulfoxides Aromatics Amines Alcohols Carboxylic Acids Ethers Nitroalkanes Nitriles Phosphoramides Amides Water Halocarbons

Phase Transfer Catalysis techniques have been applied successfully to the reduction of ketones with sodium borohydride. (Alembic 55, 56) Several authors (38,40, 40a) have described the asymmetric reductions of ketones using ephedrinium bromides as stereoregulating phase transfer agents. Others have employed lecithin (41), crown ethers (42), and phosphonium salts on silica gel (43) as phase transfer catalysts for ketone reductions. Tetrabutylammonium salts are common phase transfer catalysts (44). Microemulsions have also been used as an alternative to phase transfer catalysis (45). Reduction rate is also influenced by temperature as demonstrated by the following data:

Rate of Reduction of Acetone with Increasing Temperature in Isopropanol

Temperature oC k2 x104

(L mol-1 sec-1) 0 15.1

15 36.125 6335 105.0

Raising the temperature from 0o C to 35o C in isopropanol increases the rate sufficiently so reduction can be accomplished as rapidly in isopropanol at 35o C as in water at 0o C. NaBH4 reduces a wide variety of aliphatic, alicyclic, aromatic and heterocyclic ketones to their secondary alcohol. Thioketones reduced to thiols. Diketones are reduced to diols (46,47); this effect has recently been used in the synthesis of cyclophanes (48). This reduction of quinones to hydroquinones was first published in 1949 (49) and rapidly followed by similar reports (50-53). Sodium borohydride has been used in ketone reductions raging from conversion of anthraquinones to anthracenes (54), to the synthesis of codeine (54), the preparation of vitamin A esters (56), quinuclidines (57), and prostaglandins (58-60).


38

This remarkable utility is the result of the ease of handling and use of NaBH4, its selectivity for ketones and its stereospecificity. The value of selective reduction with sodium borohydride becomes obvious in compounds containing other functional groups, such as amido (61,62), epoxy (63-65), mercapto (66-67), carboxyl lactone (68), nitrile (69-70), nitro (71), ester (72-73) and many unsaturated CC bonds (74-78). This property has been utilized in the synthesis of tetracyclines (79,80) and prostaglandins (58-60, 81,82). Ketone reductions have recently been employed in the stereospecific conversion of carbonyl compounds to olefins, by NaBH4 reduction of ketophosphonamides (83) and in transposition of ketones via reduction of nitro ketones (84), e.g., cholestan-3-one to the 2-one. The recent growth in importance of aminoalcohols, resulting from the synthesis of chloramphenicol analogues and phenothiazines, is an example of the general utility of NaBH4. These are readily available by reduction of the corresponding amino ketone (85-91). The selectivity of NaBH4 is also used beneficially in converting keto acids to hydroxyacids (92-95). The sodium salt of the acid is used because the borohydrides are decomposed by organic acids. The reduction of γ− and δ- keto acids and esters leads directly to lactone formation (96-101). Normally,

unsaturated keto acids give the unsaturated hydroxy-acids (102-104).

O

OH

O

PhO

O

Ph

NaBH4

Similarly, ketoesters are reduced to the hydroxyester (105-107) and unsaturated ketoesters to unsaturated hydroxyesters (108,109). In the case of diketones, diols (110-112) or ketoalcohols (113-116) can be obtained with NaBH4, depending on the reactivity of the two carbonyl groups. Complete reduction to the diol has been employed in the synthesis of cyclophanes (117). A variety of additives or cation modifications have been employed to enhance the selectivity or reactivity of sodium borohydride in ketone reductions. Luche (118-121) has demonstrated that lanthanides promote the selective 1,2 reduction of conjugated enones to form the allylic alcohol. The use of PdCl2-NaBH4 to enhance selectivity in the reduction of oxonaphthoic acids has been reported (122). This area of chemistry has been topic of a review article. (123)




39

Enhanced stereo- and chemoselectivity has been achieved by the use of the cations such as zinc (124-136), titanium (137- 142), zirconium (143,144), lanthanide metals (123,145), Copper (146-148) and calcium (149-156), chiral alcohols (157), chiral carboxylic acids (158-165), sugars (166-170) and macrocyclic ligands such as cyclodexstan (171-180). (Alembic 17, 21, 26, 33, 57, 53) The importance of ketone reduction with NaBH4 is shown by its innumerable applications in many fields of organic chemistry. Some of the diverse applications where the chemo- and stereoselectivity of sodium borohydride have been utilized in ketone reduction are tabulated below.

Class of compounds ref Steroid ketones 181-187 Amino ketones 85-91 Prostaglandines 58-60,

188-192 Menthanones 193 CNS suppressants 194- 197 Synthetic juvenile hormones 198- 201 Gibberellic acids 201, 202 Antibiotics 203-210 Artificial flavors and coloring 211- 214 Triterpenoids 113, 215 Flavanoids 216- 218 Adamantanone 219- 221 Methadones 222- 224 Epoxy ketones 225 Polymeric ketones 226 -228 Antiinflammatories 229- 231 Beta-Blockers 232- 234 Antiulcer compounds 235, 236 Antihypertensives 237- 239 Fungicides/herbicides 240- 143 Anti HIV 244- 247 Antipsychotic 248 Anti viral 249 Taxol 250



40

One of the most important applications of sodium borohydride is the stereospecific and selective reduction of steroid ketones. Meteos (251) has established the following sequence for the reactivity of NaBH4 for most of the ketones in the steroid molecule: ∆5-3Keto > ∆8(14)-3 keto > 3 keto A/B cis > 3 Keto A/B trans > 6 keto > 7 keto > ∆4-3 keto > 12 keto > 17 keto

> 20 keto >11 keto Due to the differences in the reactivity of the keto groups in the individual positions of the steroid ring, certain keto groups can be reduced simply and selectively by using stoichiometric quantities of borohydride or by blocking individual positions. In steroid chemistry and in prostaglandin synthesis (252), it has been possible to reduce the keto group with zinc borohydride made from ZnCl2 and NaBH4 without attacking activated olefinic bonds.

Recently the addition of a catalytic amount of a Co (II) complex has shown very good yields and enantiomeric excess for the synthesis of chiral alcohols from the reduction of ketones. (253- 255)

The use of nonpolar solvents such as hexane are normally not considered for use with sodium borohydride reductions of ketones because of the solubility of SBH in this solvent. A unquie solution to this problem is the use of solid supports such as silica

gel (256, 257) or alumina (258- 260) which helps to catalyze the reduction of ketones in hexanes. Luche has demonstrated that ketones can be reduced selectively in the presence of aldehydes by using NaBH4 with CeCl3 (261). References: 1) Brown, H.C.; Ichikawa, K. Tetrahedron 1957, 1, 221;

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Chem. Abstr. 63, 17823a



41

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42

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2,130,654 1971; Chem. Abstr. 76, 140041h



43

59) Jpn. Kokai Tokkyo Koho 84, 134, 787 1984; Chem. Abstr. 102, 45692t

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51

CARBOXYLIC ACIDS O

OH

CF3

ONaBH4 O

H

CF3

OHHAlembic: 48, 49, 55, 61, 62

Carboxylic acids are not normally reduced with sodium borohydride in protic solvents. However, there are a few techniques that permit the direct borohydride reduction of carboxylic acids or their easily prepared derivatives.

Carboxylic acids can be reacted with ethyl chloroformate to form the mixed anhydrides, in situ, which are then reduced in aqueous tetrahydrofuran to the corresponding alcohols (5). A number of aromatic and aliphatic carboxylic

acids (and esters) have been reduced to their corresponding alcohol using sodium borohydride at high temperatures (300o C) in the presence or absence of any solvent (1,2).

R OH

O

Cl OEt

O+

NaBH4

R

O

EtO

O

O R H

OH

H C5H11COOH + NaBH4 C6H13OH Other reagents such as cyanuric chloride, tosyl chloride and

BOP (6, 7, 8) have reduced amino acids to their corresponding chiral alcohol in high yield. This technique is very cost effective as well as very mild. One problem with this methodology is that all carboxylic acid and alcohol groups will react with these reagents. Therefore all hydroxy group that are not to be reduced must be protected prier to treatment.

Using a 0.25 mole equivalent of borohydride to acid, the hexyl caproate was obtained. Enol esters derived from the reaction of carboxylic acids with N-ethyl-5-phenylisoxazolium-3’-sulfoxate can be reduced with sodium borohydride in water to the alcohols (3). A series of perfluorinated acids were reduced to the alcohols with NaBH4 (4): This technique has been applied in a number of

syntheses of complex materials (9- 13) The reductive system of NaBH4/metal chloride/diglyme is effective for reducing carboxylic acids.




52

2)

3)

4) 5)

AlCl3 has been used successfully, but will also reduce other functional groups if they are present (14,15).

Zinc borohydride will reduce both aliphatic and aromatic carboxylic acids under reflux conditions in THF in high yields, amino acids have also been reduced to chiral amino alcohols with this methodology. (16,17) Cuprous halide/NaBH4/diglyme gives a reducing system which is specific for carboxylic acids while TeCl4 or ThCl4 renders it specific for reduction of esters and acids (18). Zirconium tetrachloride with sodium borohydride will also reduce carboxylic acids to their corresponding alcohols. (19) NaBH4 has been used with TiCl4 to reduce both a carboxylic acid to the alcohol and a nitro group to the amine, in a single step, during the synthesis of the alkaloid ismine (20). Ti(OiPr)3 with Sodium borohydride also reduces aliphatic and aromatic carboxylic acids as well as amino acids to their corresponding alcohol in high yields. (21)

Reagents such as I2, Me3SiCl, BF3, MeSO2OH and H2SO4 are combined with borohydrides to form borane, which is a very active component for the reduction of carboxylic acids.(22-28) These combinations of reagents have reduced both aliphatic and aromatic carboxylic acid as well as amino acids to their corresponding alcohols.

Thioacids are also rapidly reduced to high yields of the thiol, with small amounts of alcohols, by the system AlCl3/NaBH4/diglyme (29). Sodium borohydride alone normally does not reduce carboxylic acid but the addition of triphenylborate reduces both aromatic and aliphatic acids.(30) Other reagents which can be used are dimethyl sulfate (31). The addition of trifluoro acetic acid and catechol to sodium borohydride in THF at room temperature will reduce both aliphatic and aromatic carboxylic acids. (32)

The combination of Amberlist-15, LiCl and sodium borohydride in methanol will reduce amino acids in high yields. (33) Borohydride exchange resins with chloroformate have reduced both aliphatic and aromatic carboxylic groups at RT. (34) References: 1) Nose, A.; Kudo, T. Yakugaku Zasshi 1976, 96, 1401;

Chem. Abstr. 86, 139533y Yang, C.; Pittman, C.U. Synthetic Commun. 1998, 28, 2027 Hall, P.L.; Perfeti, R.B. J. Org. Chem. 1974, 39, 11; Chem. Abstr. 80, 96354 U.S. 3,752,847 1973; Chem.Abstr. 79, 91611v Ishizumi, K.; Koga, K.; Yamada, S. Chem. Pharm. Bull. 1968, 16, 492; Chem. Abstr. 69, 58805g



53

6)

7) 8) 9)

10)

11)

12)

13) 14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28) 29)

30)

31)

32) 33)

Faloprni, M; Porcheddu, A.; Taddei, M. Tettrahedron Lett. 1999, 40, 4395 Kokotos, G.; Noula, C. J. Org. Chem. 1996, 6994 McGreary, R.P. Tetrahedron Lett. 1998, 39, 3319 Ger. Offen. ,007,366 1981; Chem. Abstr. 95, 2033633t Jpn. Tokkoyo Koho 83 33,866 1983; Chem. Abstr. 100, 68730b Olsen, R.K.; Ramasamy, K.; Emery, T J. Org. Chem. 1984, 49, 3527; Chem. Abstr. 101, 131063z Jpn. Kokai Tokkyo Koho 85, 174,769 1985; Chem. Abstr. 104, 88456c U.S. 4,760,196 1988 Brown, H.C.; Subba Rao, B.C. J. Am. Chem. Soc. 1955, 77, 3164; Chem. Abstr. 50, 3995c

Blawood, R.K.; Hess, G.B.; Larrabee, C.E.; Pilgrim, F.J. J. Am. Chem. Soc. 1958, 80, 6244; Chem. Abstr. 53, 11373e Narasimhan, S.; Madhavan, S.; Prasad, K.G. J. Org. Chem. 1995, 60, 5314 Narasimhan, S.; Madhavan, S.; Prasad, K.G. Synth. Commun. 1996, 26, 703 Subba Rao, B.C.; Thakar, G.P. J. Sci. Indust. Res. 1961, 20b, 317 Itsuno, S.; Sukurai, Y.; Ito, K. Synthesis 1988, 995

Prabhakar, S.; Lobo, AM.; Marques, M.M.; Tavares, M.R. J Chem. Research (s) 1985, 394; Chem. Abstr. 104, 225068u Ravikumar, K.S.; Chanderasekaran, S. J. Org. Chem. 1996, 61, 826 Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M. Tetrahedron 1992, 48, 4623 Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl. 1989, 28, 218 Sengupta, S.; Sahu, D.P.; Chatterjee, S.K. Indian J. Chem. 1994, 33b, 285 Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem. 1981, 46, 2579 Boesten, W.H.; Schepers, C.H.M.; Roberts, M.J.A. EPO 322982 A2 1989 Abiko, A.; Masamiune, S. Tetrahedron Lett. 1992, 33, 5517 U.S. 5,744,611 1998 Heasly, G.E. J. Org. Chem. 1971, 36, 3235; Chem. Abstr. 13524f Yoon, N.M.; Chho, B.T.; Yoo, J.U.; Kim, G.P.. J. Korean Chem. Soc. 1983, 27, 434 Cho, B.T.; Yoon, N.M. Bull. Korean Chem. Soc. 1982, 3, 149 Suseele, Y.; Periasamy, M. Tetrahedron 1992, 42, 371 Anand, R.C.; Vimal Tetrahedron Lett. 1998, 39, 917



54

34) Bandger, B.P.; Modhave, R.K.; Wadgaonkar, P.P.; Sande, A.R. J. Chem. Soc., Perkin Trans 1 1996, 1993



55

AMIDES Alembic: 9, 47, 50, 61, 62 Amides were once considered to be not reducible by NaBH4. Attempts to reduce primary amides in boiling diglyme led to the formation of nitriles with the elimination of water (1). In refluxing pyridine, primary amides form the nitrile, secondary amides do not react and tertiary amides are slowly reduced to amine (2,3). When catalyzed by salts of transition metals, such as cobalt, nickel and zirconium, NaBH4 has been shown to reduce primary and secondary amides to the amine. (4, 5) Zn(BH4)2 can reduce both aromatic and aliphatic amides to amines in high yields in refluxing THF. (6) A cobalt complex recently developed will reduce amides using NaBH4 as the hydride source (7) A number of useful techniques to accomplish amides reductions are now known. These include reduction with TiCl4/NaBH4 (8,9) reduction with Bu4NBH4 in dichloromethane (10), reduction with NaBH4 via imino derivatives using POCl3 (11), and reduction via thioamides and (alkylthio) methyleniminium salts (12). The asymmetric reduction of pyruvamides has also been reported

(13), using NaBH4 in conjunction with chiral amines. 1o, 2o and 3o aromatic and aliphatic amides are reduced using a combination of NaBH4 with reagents such as I2, Me3SiCl, BF3, MeSO2OH and R2SeBr2 at RT. (14, 15, 16, 17, 18) These combination of reagents form borane in-situ which is the ingredient which reduce the amide group. B(OPh)3 is another reagent that is used catalytically with NaBH4 to reduce amides in high yields.(19) The reduction of amides with NaBH4 in ether solvents is accomplished by the addition of 1 molar equivalent (based on NaBH4) of glacial acetic acid to the stirred amide-NaBH4-solvent mixture. For the preparation of tertiary amines from disubstituted amides, trifluoroacetic is substituted for acetic acid (20,21). A very similar technique where DMSO was the solvent gave good yields of a wide variety of primary, secondary and tertiary amines (22). The activation of NaBH4 with ethanedithiol or benzenethiol in boiling THF permitted the reduction of certain amides and imides to the corresponding amines (23). It has recently been shown that cyclic secondary amides can be selectively reduced to an alcohol in the presence of tertiary amide by chemically activating the secondary amine with BOC or Cbz. (24)



56

References: 1) Elzey, S.E. Jr.; Mack, C.H.; Connick, W.J. Jr. J.

Org. Chem. 1967, 32, 846; Chem. Abstr. 67, 2860n 2) Kikugawa, Y.; Ikegami, S.; Yamada, S. Chem.

Pharm. Bull 1969, 17, 98; Chem. Abstr. 70, 97491 3) Saito, I.; Kiugawa, Y.; Yamada, S. Chem. Pharm.

Bull. 1970, 18, 1731; Chem. Abstr. 73, 110093x 4) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai,

Z. Tetrahedron Lett. 1969, 4555; Chem. Abstr.94, 1499e

5) Itsuno, S.; Sukurai, Y.; Ito, K. Synthesis 1988, 995 6) Narasimhan, S.; Madhavan, S.; Balakumar, R.;

Swarnalakshmi, S. Synth. Commun. 1997, 27, 391 7) Yamada, T.; Ohtsauka, Y.; Ikeno, T. Chem. Lett.

1998, 1129 8) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S.

Synthesis 1980, 695; Chem. Abstr. 94, 14599e 9) Jp. Okai Tokkyo Koho 80, 162, 756 1980; Chem.

Abstr. 95, 62023e 10) Wakamatu, T.; Inaki, H.; Ogawa, A.; Watanabe, M.

Ban, Y. Heterocycles 1980, 14, 1437; Chem. Abstr. 94, 3027a

11) Kuehne, M.E. Shannon, P.J. J. Org. Chem. 1977, 42, 2082; Chem. Abstr. 87, 22928g

12) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21, 4061; Chem. Abstr. 94, 156223b

13) Munegumi, T.; Harada, K. Bull Chem. Soc. Jpn. 1983, 56, 298; Chem. Abstr. 99, 53287z

14) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M. Tetrahedron, 1992, 48, 4623

15) Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl. 1989, 28, 218

16) Sengupta, S.; Sahu, D.P.; Chatterjee, S.K. Indian J. Chem. 1994, 33b, 285

17) Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem. 1981, 46, 2579

18) Akabori, S.; Takanohashi, Y. J. Chem. Soc.; Perkin Trans 1, 1991, 479

19) Yoon, N.M.; Chho, B.T.; Yoo, J.U.; Kim, G.P.. J. Korean Chem. Soc. 1983, 27, 434

20) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976, 763; Chem. Abstr. 85, 20719z

21) Malawska, B.; Gorczyca, M. Pol. J. Chem. 1985, 59, 811; Chem. Abstr. 105, 226250e

22) Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem. 1981, 46, 2579; Chem. Abstr. 95, 5881j

23) Maki, Y.; Kikuchi, K.; Sugiyama, H.; Seto, S. Chem. Ind. 1976, 322; Chem. Abstr. 85, 62767u

24) Lee, B.H.; Clothier M.F. Tetrahedron Lett. 1999, 40, 643



57

ACID ANHYDRIDES Alembic: 50 Because of their chemical nature, acid anhydrides cannot be reduced by borohydride in aqueous solvents. Early literature reports only a few instances of carboxylic anhydrides reductions with NaBH4 in ether solvents, The products being either lactones (1-4), diols (5), or alcohols (6). Cyclic anhydrides are readily reduced by NaBH4 to γ and δ-lactones in very good yields (7-13) to form antibiotics, (14) growth factors (15) and β-amino acids (16,17) . Additional reports of the use of NaBH4 for reducing anhydrides have appeared in the literature (18- 21) Mixed carboxylic-diphenylphosphoric acid and diphenylphosphorochloridate in the presence of triethylamine, were reduced with excess NaBH4 to the corresponding primary alcohols in fair yield. Nitro, ester, amides groups and conjugated double bonds were not affected (22). The NaBH4/TiCl4 (4:1) system in diglyme has been reported to reduce acid anhydrides to diols (23).

The reduction of a series of substituted phthalic anhydrides to phthalides with sodium borohydride has been reported (24). Preferential reduction of the carbonyl function adjacent to the 3- substituent was observed. In the 4- substituted analogous, selectivity of reduction was found only when, the substituent is electron donating. Acid anhydrides formed from amino acids and isobutyl chloroformate are reducible with sodium borohydride to form chiral amino alcohols in high yields. (25,26)

References: 1) Vaughn, W.R.; Goetschel, C.T.; Goodow, M.H.; Warren,

C.L. J. Am. Chem. Soc. 1963, 85, 2282; Chem. Abstr. 59, 6443c

2) Cross, B.E.; Galt, R.H.B.; Hanson, J.R. J. Chem. Soc. 1963, 5052; Chem. Abstr. 60, 566f

3) Birckelbaw, M.E.; LeQuesne, P.W.; Wocholski, C.K. J. Org. Chem. 1970, 35, 588; Chem. Abstr. 72, 100989j

4) Longlois, N.; Gastambide, B. C. Acad. Sci. Paris, Ser, C 1967, 264, 1878; Chem. Abstr. 67, 90956b

5) Longlois, N.; Gastambide, B. C. Helv. Chim. Acta 1968, 51. 2048; Chem. Abstr. 70, 29097t

6) Perron, Y.G. et. al. J. Med. Chem. 1964, 7, 483; Chem. Abstr. 61, 5631a

7) Bailey, D.M.; Johnson, R.E. J. Org. Chem. 1970, 35, 3574; Chem. Abstr. 73, 120261q



58

8) Jefford, C.W.; Wang, J. Tetrahedron Lett. 1993, 34, 1111

9) Jefford, C.W.; Wang, J.B.; Lu, Z.H. Tetrahedron Lett. 1993, 34, 7557

10) Patterson, J.W. J. Org. Chem. 1995, 60, 560 11) Kinoshita, Y.; Watanabe, H.; Kitahara, T.; Mori, K.

Synlett. 1995, 186 12) Patterson, J.W. J. Org. Chem. 1995, 60, 560 13) Miki, Y.; Hachiken, H. Synlett 1993, 333 14) Roa, A.V.R.; Reddy, D.R.; Annapurna, G.S.;

Deshpande, V.H. Tetrahedron Lett. 1987, 28, 451 15) Roa, A.V.R.; Reddy, R.G. Tetrahedron Lett. 1992,

33, 4061 16) Jefford, C.W.; Wang, J. Tetrahedron Lett. 1993, 34,

1111 17) Jefford, C.W.; Wang, J.B.; Lu, Z.H. Tetrahedron

Lett. 1993, 34, 7557 18) Brooks, C.J.W.; Ekhato, I.V. J. Chem. Soc., Chem.

Commun. 1982, 943; Chem. Abstr. 98, 34839u 19) U.S. 4,473,700 1984; Chem. Abstr. 102, 9487w 20) Jpn. Kokai Tokkyo Koho 85,156,691 1985; Chem.

Abstr. 104, 207262y 21) Zhidkova, T.A. et. al. Khim. 1985, 21, 1653;

Chem. Abstr. 105, 43108v

22) Koizumi, T.; Yamamoto, N.; Yoshii, E. Chem. Pharm. Bull. 1973, 21, 312; Chem. Abstr. 78, 135830b

23) Subba Roa, B.C. Curr. Sci. 1961, 30, 218; Chem. Abstr. 56, 3326c

24) McAlees, A.J.; Mc Crindle, R.; Sneddon, D. J. Chem. Soc., Perkin Trans 1 1977, 2038; Chem. Abstr. 88, 50432e

25) Rodriques, M.; Llinares, M.; Doulut, S. Heitz, A.; Martinez, J. Tetrahedron Lett. 1991, 32, 923

26) Ho, M.; Chung, J.K.K.; Tang, N. Tetrahedron Lett. 1993, 34, 6513

Roh

m and Haas : the Sodiu F for Searching m Borohydride Digest press <CTRL>-

59

ACID HALIDES

N

N

Cl

O

O

H

NaBH4

N

N

H

O

OH

H

H

(9)

Alembic: 50, 58 NaBH4 reduction of acids chlorides in inert solvents (generally ethers) is a generally accepted synthetic procedure (1-6). NaBH4 reduction of various acid chlorides from hydantoic peptides has been report (7).

N

OR

H

O

Cl

O NaBH4

NH

O

H

OH

H

OR

OEt

ClO

O

NaBH4

OEt

HHO

O

H

(10)

Cl

Cl

O

O

(OC)3FeH

H

OH

OH

(OC)3Fe

NaBH4H

H (11)

This reduction has been applied to synthesis of oxazoles having anti-inflammatory activity (8).

N

OAr

NaBH4Cl

O

N

OAr

H

OH

H

The following acid chloride reductions have been reported:




60

O

HOCl

O

O

HOH

HO H

NaBH4

(12)

The reduction of acid chlorides with tetrabutylammonium borohydride in dichloromethane provides instantaneous reactions and nearly quantitative yields (13). Similar reactions of quaternary borohydrides in binary solvents or the use of NaBH4 with a phase transfer catalyst, have been reported (14). Phosphonium borohydride can reduce acid chlorides to alcohols in high yields in aprotic solvents at RT. (15) The Luche method, using CeCl3 with NaBH4, has been applied to the reduction of conjugated unsaturated acid chlorides to the corresponding unsaturated alcohol (16). NaBH4 reduces acid chlorides to aldehydes in good yield in the presence of cadmium chloride and DMF (17,18). The reagent bis-(triphenylphosphine) copper (1) borohydride, easily prepared from NaBH4, also gives high yields of aldehydes from acid chlorides (19-22). Reduction to aldehydes by NaBH4 without added metal salts has been studied (23). Careful control of the ratio of NaBH4 to acid chloride, operation at –

70oC in dimethylformamide-tetrahydrofuran solvent and strict attention to the method of quenching the reaction minimized overreduction to the alcohol. Aromatic and aliphatic acid chlorides are reduced to alcohols with SBH in MeOH.(24) Acid chlorides can be reduced to aldehydes with SBH in the presence of pyridine as a borane scavenger to stop over reduction to the alcohol. (25)

Zinc borohydride can reduce acid chlorides to their corresponding alcohols in high yield in ether type solvents. (26,27) The addition of organic nitrogen containing bases such as DABCO and pyrazine have been added to zinc borohydride to reduce acid chlorides to alcohols (28,29)

The addition of titanium tetraisopropoxide to NaBH4 has been shown to reduce acid chlorides to alcohols in 5 to 10 mins. (30) Cyanoborohydride has also been shown to reduce acid chloride to alcohols in high yields. (31) References: 1) Chaikin, S.W.; Brown, W.G. J. Am. Chem. Soc. 1949, 71,

122; Chem. Abstr. 43, 2570d 2) Walton, E. Et. Al. J. Am. Chem. Soc. 1955, 77, 5144;

Chem. Abst. 50, 8452h 3) Tomita, M; Hirai, K. J. Pharm. Soc. Japan. 1958, 78, 798;

Chem. Abstr. 52, 1875g 4) Vecchi, A.; Melone, G. J. Org. Chem. 1959, 24, 109;

Chem. Abstr. 54, 6627f



61

5) Endres, G.F.; Epstein, J. J. Org. Chem. 1959, 24, 1497; Chem. Abstr. 54, 4379h

6) Sato, S.; Ono, Y.; Tatsumi, S.; Wakamatsu, H.; Nippon Kagaku Zasshi 1971, 92, 178; Chem. Abstra. 76, 33755x

7) Wessey, F. Schloegl, K.; Korger, G. Nature 1952, 169, 708; Chem. Abstr. 47, 2700f

8) Brit. 1,139,940 1969; Chem. Abstr. 70, 106494z 9) Ger, Offen. 2,237,832 1973; Chem. Abstr. 78,

111342t 10) Hudrilik, P.F.; Rudnik, L.R.; Korzenowski, S.H. J.

Am. Chem. Soc. 1973, 95, 6848; Chem. Abstr. 80, 3149t

11) Berens, G. et. al. J. Am. Chem. Soc. 1975, 97, 7076; Chem. Abstr. 83, 206405h

12) Paul, K.G.; Johnson, F.; Favara, D.; J. Am. Chem. Soc. 1976, 41, 690; Chem. Abstr. 84, 135153g

13) Raber, D.J. Guida, W.C. J. Org. Chem. 1976, 41, 690; Chem. Abstr. 84, 88901n

14) Brit. Pat. Appl 2,1544 1985; Chem. Abstr. 104, 168107e

15) Firouazbadi, H.; Adibi, M. Synth. Commun. 1996, 26, 2429

16) Lakshmy, K.V.; Mehta, P.G.; Seth, J.P.; Trivedi, G.K. Org. Prep. Proced. Int. 1985, 17, 251; Chem Abstr. 104, 88199w

17) Johnstone, R.A.W.; Telford, R. J. Chem. Soc., Chem. Commun. 1978, 354; Chem. Abstr. 89, 16547t

18) U.S. 4,211,727 1980; Chem. Abstr. 93, 203401b 19) Fleet, G.W.; Fller, C.J. Harding, P.J.C. Tetrahedron Lett.

1978, 1437; Chem Abstr. 89, 108495s 20) Barlett, P.A.; Johnson, C.R. J. Am. Chem. Soc. 1985, 107,

7792; Chem. Abstr. 104, 50753j 21) Sorrell, T.N.; Pearlman, P.S. J. Org. Chem. 1980, 45,

3449 22) Paquette, LA.; Teleha, C.A.; Taylor, R.T.; Maynard, G.D.;

Rogers, R.D.; Gallucci, J.C.; Springer, J.P. J. am. Chem. Soc. 1990, 112, 265

23) 23)Babler, J.H.; Invergo, B.J. Tetrahedron Lett. 1981, 21, 11; Chem. Abstr. 94, 174230f

24) Kang, S.K.; Lee., D.H. Bull. Korean Chem. Soc. 1988, 9, 402

25) Babler, J.H. Synth. Commun. 1982, 12, 839 26) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J. J. Org.

Chem. 1985, 50, 1927 27) Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M. Bull.

Chem. Soc. Jpn. 1988, 61, 2684 28) Firouzabadi, H.; Zeynizadeh, B. Bull. Chem. Soc. Jpn.

1997, 70, 155 29) Tamami, B.; Lakouraj, M.M. Synth. Commun. 1995, 25,

3089



62

30) Ravikumar, K.S.; Chanderasekaran, S. J. Org. Chem. 1996, 61, 826

31) Hui, B.C Inorg. Chem. 1980, 19, 3185


63

ESTERS OO

OEt

ONaBH4 OO

H

OH

HpH 2-3

Alembic: 10, 36, 48, 50, 55, 57, 60, 61

Traditionally the reduction of simple aliphatic esters with sodium borohydride in protolytic solvents is extremely slow and therefore not practical for industrial processes. In aprotic solvents such as dichloromethane, the reduction of ethyl laurate with the soluble tetrabutylammonium borohydride is only 25% complete after 4 days at 25oC (1). In comparison tetrabutylammonium borohydride in CCl3H at reflux temperatures will reduce aliphatic esters to alcohols in 70 % yields after 5h (2).

In the case of ket-esters, both keto and ester groups are reduced to give a diol (8-11). The reduction of alpha-amino esters gives optically active alpha amino alcohols (12,13). Alpha chloroamines also activate esters for borohydride reduction (14).

NH3+Cl-

OCH3

O

NH3+Cl-

H

OH

H

NaBH4 A large number of “activated” esters can be reduced directly with sodium borohydride in protolytic solvents. Electron withdrawing groups alpha to the ester carbonyl group increase the positive charge on the carbonyl carbon making it much more susceptible to attack by the borohydride ion (3).

Amido and thioamido groups residing on the carbon next to ester group activates the ester group so that it can be reduced with sodium borohydride at R.T. (15)

Examples of electron withdrawing groups and their borohydride reduction products are: Hydroxyl-Sugar Esters Primary alcohols (4-7). Alpha epoxy esters are reduced to epoxy alcohols (16,17) in

the presence of nitrile groups. and Lactones



64

OOCH3

O

OH

HNaBH4

OH

Similarly, the following reduction in anhydrous solvents using potassium borohydride has been reported (21).

EtO2C(CF2)3CO2Et HOC(CF2)3COH Very rapid reductions of alpha-chloroesters to their corresponding alcohols have been reported as part of the amine ester study mentioned above (12,18). Similarly, the following reduction is reported (19).

Processes have been patented (22,23) for the reduction of perfluoroesters and acids with NaBH4 to the corresponding alcohol.

N

N

OCH3

ClO

CH

N

N3

H

ClHO

CH3

NaBH4

H

Cyano- Like the halogens, the alpha-cyano group is a powerful electron withdrawing group and activates borohydride reduction of the ester group as illustrated below: (24- 26)

O N

OCH3

Ph

O

O N

H

Ph

OH

HNaBH4 (24)

A series of fluoronitroesters have been reduced to the corresponding alcohols with sodium borohydride in water (20).

OEt

CNPh

PhO

H

CNPh

PhHO

H

NaBH4 (25)diglyme15-20 oC

O2NOR

O

F R

O2NH

OH

F R

H

NaBH4

H2O




65

OEt

CNR

RO

NaBH4 (26)

EtOH H

CNR

RHO

H

NaBH4H

H

OEt

CNR

RO

HH The acyl groups in lecithin and monogalactosyl diglycerides

were reduced by sodium borohydride to fatty alcohols with no detectable reduction or isomerization of double bonds in 94 and 64% yield, respectively (31) Changing the alcohol portion of the ester group can facilitate the borohydride reduction of the ester. It has been reported (32) that the reduction of esters of alcohols more electronegative than methyl, such as phenol and other acidic alcohols, can increase reduction rates by 300-fold.

The ester groups of a series of triglycerides from virgin olive oil can be selectively reduced with sodium borohydride to form their corresponding alcohols in high yields. (27) Miscellaneous: Examples of other activated esters, which have been reduced with sodium borohydride, are (28-30)

Another technique that is effective to reduce esters is to modify the cation associated with the borohydride anion. Lithium borohydride will reduce most esters quite easily (33). The enhanced reduction effect of the lithium ion is greatest in solvents of low dielectric constants. In such solvents, the reaction presumably proceeds through the ion-pair (Li+BH4

-) rather than through the completely dissociated ions. Magnesium borohydride and calcium borohydride probably behave in a similar manner. The reactions of sodium or potassium borohydride with lithium chloride, magnesium chloride or calcium chloride in tetrahydrofuran, diglyme or ethanol give the corresponding lithium, magnesium or calcium borohydrides by metathesis. Reducing systems based on these reactions can be used for ester reductions by in situ preparative techniques without removal of the by-product alkali metal chloride (34-41 ). Olefins have been demonstrated to increases the reactivity of calcium borohydride towards the reduction of

(28)OCH3H3CO

O O

NaBH4

EtOH

HH

OH OH

HH

(29)N

NH2N NH2

NH2

OCH3O

NaBH4 N

NH2N NH2

NH2

HHOH

N-Acyldipeptide ester Amino Alcohol (30)



66

esters group.(42) This technique works for reducing aromatic and aliphatic esters to alcohols. The addition of olefins to Zn(BH4)2 also increase the reactivity of the Zn(BH4)2 towards the reduction of esters.(43) Other catalyst which have demonstrated to increase reactivity of metal borohydride towards the reduction of esters are trialkyl borates and amines. (44-46)


Clear diglyme solutions of aluminum chloride and sodium borohydride (molar ratio 1:3) easily reduce esters to alcohols, but other functional groups and double bonds are also reduced (47-48). A study on the effect of metal halides on the reducing properties of sodium borohydride in aprotic solvents has been published (49). Cuprous halide gave a reagent specific for the reduction of carboxylic acids, and TeCl4or ThCl4 gave systems specific for the reduction of esters and acids. Zirconium tetrahalides produced a very strong reducing system that attacked all functional groups including reduction of nitro groups at room temperature. An extensive evaluation of cation and solvent effects on the borohydride reduction of carboxylic esters has been published (50). It is also possible to modify the BH4

- anion to greatly enhance its reactivity. Many esters have been reduced with large excesses of sodium borohydride in

refluxing methanol (51-52). It is believed now that the active reducing species was sodium trimethoxyborohydride which was formed in situ. Sodium acetanilidoborohydride has been synthesized by the reaction of acetamilide (or benzanilide) in α-picoline. This reagent reduced methyl esters in good yields without affecting other functional groups (amide, nitro and isopropyl ester) (53-54).

H3C NH

Ph

O

H3C NPh

OBH3

-Na+

+ H2+

NaBH4

Another system involves refluxing sodium borohydride with ethanedithiol in dry THF along with the ester has been described (55-56). Benzoate and aliphatic esters were reduced and methyl cinnamate was reduced to 3-phenyl propanol. A large number of aliphatic and aromatic acids and esters have been reduced by sodium borohydride in the presence or absence of a solvent at high temperatures. Reductions using 1 equivalent of NaBH4 gave the corresponding alcohols (57).



67

A novel approach to ester reductions is the slow addition of methanol to a refluxing mixture of the ester and NaBH4 in tert-butanol or tetrahydrofuran (58-59), resulting chemoselectively in high yields of primary alcohols. This system has been applied successfully to the preparation of N-protected amino alcohols and N-protected peptide alcohols.

NaBH4 in diglyme at elevated temperatures reduces aromatic ester to alcohols while at RT no reaction occurs. (60) Both aromatic and aliphatic esters are reduced to alcohols with NaBH4 in water or a 1:1 mixture of water and dioxane at RT. ( 61)

Sodium borohydride when combined with reagents such as Me3SiCl or I2 form borane BH3, which will reduce both aromatic and aliphatic esters chemoselectively. (62-63)

Esters can be converted to aldehydes by oxidizing the borate ester intermediate formed from the reduction of esters with calcium borohydride ( 64).

References: 1) Raber, D.J.; Guida, W.C. J. Org. Chem. 1976, 41 690;

Chem. Abstr. 84 880n 2) Narasimhan, S.; Swarnlakshmi, S.; Balakumar, R.;

Velmathi, S. Synlett. 1998. 1321 3) Schenker, E. "Newer Methods of Preparative Organic

Chemisty", Vol IV, 1968, 196, Verlang, Chemie, Weinheim

4) Wolfrom, M.L.; Anno, K. J. Am. Chem. Soc. 1952, 74, 5583; Chem. Abstr. 8, 134e

5) Wolfrom, M.L.; Wood, H.B. J. Am. Chem. Soc. 1951, 73, 2933; Chem. Abstr. 46, 3961a

6) Barton, D.H.R. et. al. J. Chem. Soc. Perkin Trans. 1 1975, 2069; Chem. Abstr. 84, 31342b

7) Ger. Offern. 2,911,377, 1980; Chem. Abstr. 94, 121935h 8) Heymann, H.; Fiesser, L.F. J. Am. Chem. Soc. 1951, 73,

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Abstr. 63, 14971d



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13) Mandal, S.B.; Achari, B.; Chattopadyay, S. Tetrahedron Lett. 1992, 33, 1647

14) Macmillan, J.G. et. al. J. Am. Chem. Soc. 1976, 98, 246; Chem. Abstr. 84, 90114b

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17) Mauger, J.; Robert, A. J. Chem. Soc.; Chem. Commun. 1986, 395

18) Seki, H.; Koga, K.; Yamada, S. Chem. Pharm. Bull. 1967, 15, 1948; Chem. Abstr. 69, 107039w

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Abstr. 99,104774r 24) Paul, R.; Williams, R.P.; Cohen, E. J.Org. Chem.

1975, 40, 1653; Chem. Abstr. 83, 192471n 25) Meschino, J.A.; Bond, C.H.; J. Org. Chem. 1963,

28, 3129; Chem. Abstr. 59, 15280f

26) Marshall, J.A.; Caroll, R.D. J. Org. Chem. 1965, 30, 2748; Chem. Abstr. 63, 11387d

27) Giumanini, A.G.; Tubaro, F. J. Prakt. Chemie. Band 1990, 332, 755

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30) Yonemitsu, O.; Hamada, .; Kanaoka, Y. Tetrahedron Lett. 1968, 3575; Chem. Abstr. 69, 87454x

31) Nichols, B.W.; Safford, R. Chem. Phys. Lipids 1973, 11, 222 Chem. Abstr. 80, 47412

32) Takahashi, S.; Cohen, L.A. J. Org. Chem. 1970, 35, 1505; Chem. Abstr. 73, 3270f

33) Nystrom, R.F.; Chaikin, S.W.; Brown, W.G. J. Am. Chem. Soc. 1949, 71, 3245; Chem. Abstr. 44, 1017e

34) Paul, R.; Joseph, N. Bull. Soc. Chim. France 1952, 550; Chem. Abstr. 47, 32651

35) Kollonitsch, J. Fuchs, O.; Gabor, V Nature 1955, 175, 346; Chem. Abstr. 50, 1774d

36) Brown, H.C.; Mead, E.J.; Subba Rao, B.C.; J. Am. Chem. Soc. 1955, 77, 6209; Chem. Abstr. 50, 8529h

37) Jpn. Kokai Tokkyo Koho 80, 133,369, 1980; Chem. Abstr. 94, 174915h

38) U.S.; 4512,991 1985; Chem. Abstr. 103, 71338x



69

39) Jpn. Kokai, Tokkyo Koho 85, 178,845 1985; Chem. Abstr. 104 88116s

40) Brisse, F.; Durocher, G. et.al. J. Am. Chem. Soc. 1986, 108, 6579

41) Dieks, H.; Senge, M.O.; Kirste, B.; Kurreck, H. J. Org. Chem. 1997, 62, 8666

42) Narasimhan, S.; Prasad, G.; Madhavan, S. Synth. Commun. 1995, 25, 1689

43) Narashhan, S.; Madhavan,S.; Prasad, K. Synth. Commun. 1997, 27, 385

44) Brown, H.C.; Narasimhan, S. J. Org. Chem. 1982, 47, 1604

45) Yamakawa, T. Masaki, M.; Nohira, H. Bull. Chem. Soc. Jpn. 1991, 64, 2730

46) Ranu, B.C.; Basu, M.K. Tetrahedron Lett. 1991, 32, 3243

47) Brown, H.C.; Subba Rao J. Am. Chem. Soc. 1956, 78, 2582; Chem. Abstr. 51, 1077c

48) U.S. 4,842,775 1989 49) Subba Rao, B.C.; Thakar, G.P.; J. Sci. Industr. Res.

1961, 0b, 317; Chem. Abstr. 56, 6881h 50) Brown, H.C.; Narasimhan, S; Choi, Y.M. J. Org.

Chem. 1982, 47, 4702; Chem. Abstr. 97, 197647y 51) Brown, M.S.; Rapoport, H. J. Org. Chem. 1963, 28,

3261; Chem. Abstr. 60, 2924d

52) Zanka, A.; Ohmori, H.; Okamoto, T. Synlett 1999, 10, 1636

53) Kikugawa, Y. Chem. Lett. 1975, 1029; Chem. Abstr. 83, 192759n

54) Kikugawa, Y. Chem. Pharm. Bull. 1976, 24, 1059; Chem. Abstr. 85, 108365s

55) Maki, Y.; Kikuchi, K.; Sugiyama, H. Set, S. Tetrahedron Lett. 1975, 3295; Chem. Abstr. 83, 192758m

56) Guida, W.C.; Entreken, E.E.; Guida, A.R.; J Org. Chem. 1984, 40, 3024; Chem. Abstr. 101, 72355w

57) Nose, A.; Kudo, T.; Yakugaku Zasshi 1976, 96, 1401; Chem. Abstr. 86, 139533v

58) Soai, K.; Oyamada, H.; Takase,M.; Ookawa, A. Bull. Chem. Soc. Jpn. 1984, 57, 1948; Chem. Abstr. 101, 230087s

59) Soai, K.; Oyamada, H.; Takase, M. Bull. Chem. Soc. Jpn. 1984, 57, 2327; Chem. Abstr. 101, 192464c

60) Yang, C.; Pittman, C.U. Synthetic Commun. 1998, 28, 2027

61) Binco, A.; Passacantilli, P. Righi, G. Synth. Commun. 1988, 18, 1765


63) Giannis, A.; Sandhoff, K. Angew. Chem. Int. Ed. Engl. 1989, 28, 218



70

64) Narasimhan, S.; Ganeshwar, K.; Madhavan, S. Synth. Commun. 1995, 25, 1689

Roh


71

ENOL ESTERS In mixed solvent systems containing water, NaBH4 reduces enol esters to the alcohol. The enol ester is first hydrolyzed to the ketone, which is reduced by the borohydride:

References: 1) Belleau, B.; Gallagher, T.F. J. Am. Chem. Soc. 1951, 73,

4458; Chem. Abstr. 47, 138I 2) Kurath, P.; Capezzuto, M. J. Am. Chem. Soc. 1956, 78,

3527; Chem. Abstr. 51, 1229h 3) Djerassi, C. et. al. J. Am. Chem. Soc. 1958, 80, 2596;

Chem. Abstr. 52, 20262a H2O

Aco HO HO

NaBH4

4) Smith, S.H.; Turner, A.B. J. Chem. Soc. Perkin 1 1975, 1751; Chem. Abstr. 84 5241y Cholestenone has been reduced to cholesterol in good

yield via the enol ester route (1). Enol ester reductions are applied most frequently in steroid synthesis (2-6).

5) Gruenke, L.D.; Craig, J.C. J. Labeled Compd. Radiopharm. 1979, 16, 495; Chem. Abstr. 92, 59077h

6) Fendrich, G.; Abeles, R.H. Biochemistry 1982, 21, 6685; Chem. Abstr. 98, 2166f




72

IMIDES

N

O

O

CH3

NaBH4

Me

N

O

OH

CH3Me

N

OH

O

CH3Me

(84%)

(16%)

While broadly definitive papers on the imide reductions by NaBH4 have not appeared in the literature, many specific reductions have been described and the products obtained vary with starting imide. In some cases, carbonyl reductions accompanied by ring opening are obtained. For example, several cyclic imides have been reduced by sodium borohydride in methanol as shown below(1).

Tetrahydrothalimide derivatives have been reduced with sodium borohydride in ethanol (7). Various other imide reductions are cited in the literature (8-15).

N

O

O

Ph

R

Me NaBH4

HO

HN Ph

R Me O

HO

HN Ph

O

R Me

Imidic ethers have been reduced with the system NaBH4/SnCl4 dietherate in gylme at 0 oC (16).

NaBH4NH

OEt

NH2

HH

SnCl4

Examples of reduction of substituted succinimides, glutarimides and 3-nitrophthalimide by sodium borohydride in isopropanol have also been reported (2,3). The acid catalyzed borohydride reduction of imides also has been described (4-6).

Stereoselective reduction of imides to hydroxy lactam can be achieved by reacting imides with tetramethylammonium triacetoxy borohydride, NaBH4 with magnesium perchlorate and NaBH4 with CeCl3. (17-19)




73

Cyclic Imides can be deoxygenated to form cyclic amines in high yields using NaBH4 with I2 or H2SO4. (20) References: 1) Ohki, S. et. al Yakugaku Zasshi 1973, 93, 841;

Chem. Abstr. 79, 91872f 2) Watanabe, T.; Hamaguchi, F.; Ohki, S. Yakugaku

Zasshi 1973, 93, 845; Chem. Abstr. 79, 78328p 3) Watanabe T. Hamaguchi, F.; Ohki, S.; Chem.

Pharm. Bull. 1972, 20, 2123; Chem. Abstr. 78, 4058h

4) Wijnberg, J.; Speckamp, W. Tetrahedron 1975, 31, 1437; Chem. Abstr. 84, 59813e

5) Wijnberg, J.; Speckamp, W. Tetrahedron 1975, 31, 4035; Chem. Abstr. 84, 74482q

6) Hubert, J.C.; Wijnberg, J.; Speckamp, W. Tetrahedron 1975, 31, 1437; Chem. Abstr. 83, 147364u

7) Zielinski, T.; Esztajn, J.Jatczak, M. Rocz. Chem. 1975, 49, 1671; Chem. Abstr. 84, 150433s

8) Iida, H.; Takahaski, K.; Kikuchi, T; Heterocycles 1976, 4, 1497; Chem. Abstr. 86, 29596k

9) Newman, H. J. Org. Chem. 1974, 39, 100; Chem. Abstr. 80, 95165w

10) Martin, M.G.; Ganem, B. Tetrahedron Lett. 1984, 25, 2093; Chem. Abstr. 101, 131057a

11) Burnett, D.A.; Choi, J.-K., hart, D.J.; Tsai, Y.M. J. Am. Chem. Soc. 1984, 106, 8201; Chem. Abstr. 012, 79186w

12) Trehan, I.R.; Kad, G.L.; Rani, S.; Bala, R. Inidian J. Chem, Sec B 1985, 24B, 659; Chem. Abstr. 104, 225089b

13) Ger. Offen. 3,446,303 1986; Chem. Abstr. 105, 153331v 14) Koot, W.J.; VanGinkel, R.; Kraneburg, M.; Hiemstra, H.;

Louwier, S.; Moolemaar, M.J.; Speckamp, W.N. Tetrahedron Lett. 1991, 32, 401

15) Leban, J.J.; Colson, K.L. J. Org. Chem. 1996, 61, 228 16) Tsuda, Y.; Sano, T.; Watanabe, H. Synthesis 1977, 652;

Chem. Abstr. 88, 36668e 17) Miller, S.A.; Chamberlin, A.R. J. Org. Chem. 1989, 54,

2502 18) Konopikova, M.; Fisera, L.; Pronayova, N.; Ertl, P.

Liebigs, Amn. Chem. 1993, 1047 19) Deprez, P.; Royer, J.; Husson, H.P. Tetrahedron 1993, 49,

3781 20) U.S. 5585500 1996



74

LACTONES Glycidic lactones glycidol loactols (10) Alembic: 50

O O

O

O O O

O

OH

NaBH4 Sodium borohydride has been used extensively for the reduction of lactones mainly in the synthesis of complex organic fine chemicals and pharmaceuticals. Reductions are best carried out in water, alcohols or mixtures of these solvents. Yields are generally acceptable but may require use of an excess of sodium borohydride. Lactones that resist reduction with sodium borohydride in protic solvents usually can be reduced with NaBH4 and AlCl3 in diglyme (1).

ON

OH3C

H3C

Ph

HN

OHH3C

H3C

Ph

NaBH4(11)

But recently it has been demonstrated that sodium borohydride in MeOH can reduce lactones (2)

Lithocarpic lactone

No definitive study of borohydride reduction of lactones has been published. Nevertheless, the application is well established (3-5). Some selected examples are:

O

O

H H

H

HO

HO

H H

H

NaBH4

O

O

XR

RO

O

XR

RNaBH4

PGF2

polysaccharides loactones aldose (6-9)


Roh



75

OO

OO

OO

HOHO

NaBH4 (13)

Aflatoxins B1 and B2

O

OO

O O

OCH3

OH

OO

OH O

OCH3

NaBH4(14)

Production of N-(dihydroxyalkyl) uracils

(15,16)

N

N

O

O

OO

N

N

O

O

HOHO

NaBH4

The use of lanthanide metal salts with sodium borohydride has been shown to reduce lactone efficiently. (17) Stereoselective reduction of a lactone to α-hydroxy cyclic ether has been accomplished by

using cyclodextrans as a template. (18) Sodium borohydride has been shown to also convert lactones to α-hydroxy cyclic ether in high yield (19) References: 1) 1)Brown, H.C.; Subba Rao, B.C.; J. Am. Chem. Soc.

1956, 78, 2582; Chem. Abstr. 51, 1077c 2) Di Nardo, C.; Jerancic, L.O. de Lederkremer, R.M.;

Varela, O. J. Org. Chem. 1996, 61, 4007 3) Hsu, C.T.; Wang, N.Y.; Latimer, L.H.; Shih, C.J. J. Am.

Chem. Soc. 1983, 105, 593; Chem. Abstr. 98, 107052u 4) Kametani, T.; Tsubuki, M.; Furuyama, H.; Honda, T.J. J.

chem. Soc. Perkin 1 1985, 557; Chem. Abstr. 103, 6604s 5) Jpn. Kokai Tokkyo Koho 85,224,684 1985; Chem. Abstr.

104, 109358q 6) Wolfrom, M.L.; Wood, H.B. J. Am. Chem. Soc. 1951; 73;

2933; Chem. Abstr. 46, 3961a 7) Wolfom, M.L.; Anno, K. J. Am. Chem. Soc. 1952, 74,

5583; Chem. Abstr. 48, 134e 8) Frush, H.L.; Isbell, H.S. J. Am. Chem. Soc. 1956, 78,

2844; Chem. Abstr. 14533h 9) Shenai, V.A.; Sdudan, R.K. J. Appl. Polym. Sci. 1972, 16,

545; Chem. Abstr. 76, 155353k 10) Corsano, S.; Piancatelli, G. J. Chem. Soc., Chem.

Commun. 1971, 1106; Chem. Abstr. 75, 151935h



76

11) Truitt, P.; Chakravarty, J. J. Org. Chem. 1970, 35, 864; Chem. Abstr. 72, 100568w

12) Hui, W.H.; Moon, L.M.; Lee, L.C. J. Chem. Soc., Perkin Trans 1 1975, 617; Chem. Avstr. 83, 10489u

13) Woodward, R.B. et. al. J. Am. Chem. Soc. 1973, 95, 6853; Chem. Abstr. 809, 3140h

14) Ashoor, S.H.; Chu, F.S. J. Assoc. Off. Anal. Chem. 1975, 58, 492; Chem. Abstr. 83, 109529u

15) Brit. 1,393,863 1975; Chem. Abstr. 84, 4991f 16) Hillers, S.; Zhuk, R.A.; Berzina,A.; Kaulina, L.

Khim. Geterotsikl. Soedin. 1975, 694; Chem. Abstr. 83, 114332d

17) Masaguer, C.F.; Bleriot, Y.; Charlwood, J.; Winchester, B.G.; Fleet, G.W.J. Tetrahedron 1997, 44, 15147

18) Pitchumani, K.; Velusamy, P.; Srinivsan, C. Tetrahedron 1994, 50, 12979

19) Wu, H.J.; Tsai, S..; Chern, J.H.; Lin, H.C. J. Org. Chem. 1997, 62, 6367


77

D. Carbon Nitrogen Compounds

NH

NCH3

NaBH4

CH2=O

REDUCTIVE AMINATION

Alembic: 6, 7, 28, 52, 55 The little known reaction of N-ethylation of amines by a combination of formaldehyde and sodium borohydride involves the sequential treatment of a primary or secondary amine with the reagents.

Two additional references (8,9) report the methylation of tetrahydropteridines in similar fashion. These are especially noteworthy because the pteridine nucleus is selectively methylated at the N-5 position.

It is analogous to the Eschweiler-Clarke reaction, except that reduction of the imine or immonium intermediate with sodium borohydride occurs at room temperature, instead of requiring reflux conditions on the steam bath.

N

NN

N

H

H

N

NN

N

H

CH3

NaBH4

CH2=O

This reaction has found most frequent us in alkaloid synthesis, to convert cyclic amines to their N-methyl derivatives, the tetrahydroisoquinoline nucleus being the most common substrate (1-5)

NH

NCH3

NaBH4

CH2=O

The utility of this reaction is by no means limited to heterocyclic amines. Conversions to methyl tertiary amino substituents in steroid systems have been reported (10-12). Numerous other systems (13) have been described including dibenzoxepis (14), Biological species (15), Amnonucleosides

Closely related structures in aporphines have also been methylated with fomaldeyde- NaBH4 (6,7). *For Online Consulting Only



78

(16) and β-alkanolamines- via the readily formed oxazolidins (17). The methylation reaction has been applied to organometallic specifically α-ferrocenylethylamine (18) and α-ferrocenylbenzylamine (19). Alkylation using NaBH4 in the presence of lower aliphatic carboxylic acids have been investigate extensively by Gribble (20-24) and exploited by others (25-33). Giumanini has shown that the combination of carboxylic acid and sodium borohydride can N-alkylate hydrazides in high yields. (34)

Formaldehyde can be replaced by a number of reagents in this reaction, e.g. ClCOOMe (to give N-COOMe) (35,36), other aldehydes (37) and aryl halides (38). Sodium cyanoborohydride has become a popular alternative reducing agent for reductive alkylations. (39-48)

Metal modifiers such as TiCl4, Ti(OiPr)4 and ZnCl2 with borohydrides can reductively aminate ketones and aldehydes to form 2o and 3o amines.(49-58) The use of aprotic solvents such as hexane as a reaction medium with solid supports such as silica gel and clays for the reductive amination of aldehydes and ketones by borohydride have been demonstrated to be highly efficient.(59,60) Borohydride exchange resins can also

induce reductive amination of aldehydes and ketones in high yields in methanolic solutions. (61,62)

Reductive amination of ketones and aldehydes can be accomplished in high yields using sodium borohydride with sulfuric acid.(63-67). References: 1) Konda, M.; Ohishi, T.; Yamada, S. Chem. Pahrm. Bull.

1977, 25, 69; Chem. Abstr. 86, 171684f 2) Kupchan, S.M.; Leipa, A.;J. Baxter, R.L.; Hintz, H.P. J.

Org. Chem. 1973, 38, 1846; Chem. Abstr. 790, 5482z 3) Dwama-Badu, D. et al. Experientia 1975, 31, 1251;

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1967, 120, 712; Chem. Abstr. 67, 100112q 9) Whiteley, J.M.; Drais, J.H.; Huennekens, F.M. Arch.

Biochem. Biophys. 1969, 133, 436; Chem. Abstr. 71, 101824t



79

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12) Sondengam, B.L. Hemo, J.H.; Charles, G. Tetrahedron. Lett. 1973, 261; Chem. Abstr. 78, 124800r

13) Ger. Offen. 3,405,334 1985; Chem. Abstr. 104, 129795h

14) Bickelhaupt, F.; Stach, K.; Thiel, M. Monatsh. 1965, 95, 485; Chem. Abstr. 61, 5575h

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16) Morr, M.; Ernest, L. J. Chem. Res. (S) 1981, 90; Chem. Abstr. 95, 98193z

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19) Allenmark, S; Kalen, K Tetrahedron Lett. 1975, 3175; Chem. Abstr. 83, 206401d

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21) Gribble, G.N.; Wright, S.W.; Hetercycles 1982, 19, 229; Chem. Abstr. 96, 162482t

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Chem. 1985, 50, 1927 58) Ranu, B.C.; Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63,

370 59) Varma, R.S.; Dahiya, R. Tetrahedron, 1998, 54, 6293 60) Nah, J.H.; Kim, S.Y.; Yoon, N.M. Bull. Korean, Chem.

Soc. 1998, 19, 269 61) Yoon, N.M.; Kim, E.G.; Son, H.S.; Choi, J. Synth.

Commun. 1993, 23, 1595



81

62) Verardo, G.; Giumanini, A.G.; Strazzolini, P.; Poiana, M. Synthesis 1993, 121

63) Verardo, G.; Giumanini, A.G.; Strazzolini, P. Synth. Commun. 1994, 24, 609

64) Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, H.; Kocovsky, P. J. Org. Chem. 1998, 63, 7738

65) Giumanini, A.G.; Verardo, G. Gei, M.H.; Lassiani, L. J. Labelled Compd. Radiopharm. 1987, 24, 255

66) Verardo, G.; Giumanini, A.G. Strazzolini, P.; Poiana, M. Synthesis 1991, 6, 447

Rohm and Haas : the Sodium F for Searching

Borohydride Digest press <CTRL>-

82

AZIDES

NaBH4HO

O

N3OH

HHHH

HN

N

O

OHO

O

NH2OH

HHHH

HN

N

O

O

Alembic: 50, 52, 55, 58 Acyl and aromatic azides (but not monofunctional aliphatic azides) are reduced to the corresponding primary amine as reported by Boyer and Elizer (1).

4 RN3 + NaBH4 4 RNH2 R = acyl, aryl or sulfonly group.

N3NH

OH

Cl2HCO

2N OHNH

OH

Cl2HCO

O2N

O

NaBH4

Highest yields were achieved when caustic was added to stabilize the borohydride in an aqueous dioxane solvent system.

O

The conversion of azides to amines by conventional methods cannot be employed if sulfur is present in the compound. NaBH4 in isopropanol is effective if no other easily

This reduction has been applied to chloramphenicol synthesis (7).

reducible group is present, and is useful for acid-sensitive compounds (2-6).

S

N

"RR'N

O

CH3

CH3

N3O

S

N

"RR'N

O

CH3

CH3

HHO H

NaBH4

NaBH4

N

N3

Ac

XX N

NH2

Ac

XX




83

And to the acyl azides of N-substituted, 6-aminopenicilanic acids, to give the corresponding penicillanyl alcohols (8). It has been used in the synthesis of antidepressant aryloxyphenylpropylamines (9) and antigenic glycopeptides (10). Azide reductions with bis(triphenylphosphine) copper (1) borohydride (11) and with NaBH4 under phase transfer conditions (12,13) have also been reported.

Alky and aromatic azides can be reduced to amines with transition metals and sodium borohydride under mild reaction conditions. (14,15, 16) Some of these reactions are also catalytic. Zinc borohydride formed in situ or complexed with DABCO can reduce alkyl and aromatic azides to amines in high yield. (17,18)

Reaction of sodium borohydride with 1,3 dithiolethane forms a reactive species which will reduce azides easily.(19) Methanol is another reagent when added to a solution of sodium borohydride will reduce both aromatic and aliphatic azides. (20,21) Trifluoro actic acid with sodium borohydride will n-alkylate azide groups. (22)

Borohydride exchange resin with and with out nickel acetate in methanol at RT will reduce aromatic

and aliphatic azides to their corresponding primary amine in high yields. (23,24)

References: 1) Boyer, J.H.; Ellzey, S.E. J. Org. Chem. 1958, 23, 127;

Chem. Abstr. 52, 18276f 2) Smith, P.A.; Hall, J.H.; Kan, R.O. J. Am. Chem. Soc.

1962, 84, 485; Chem. Abstr. 56,14129g 3) Woodward, R.W. et. al. J. Med. Chem. 1970, 13, 979;

Chem. Abstr. 73, 87769m 4) Verheyden, J.P.H.; Wanger, D.; Moffatt, J.G. J. Org.

Chem. 1971, 36, 250; Chem. Abstr. 74, 54139y 5) Sztaricskai, F.; Pelyvas, I.; Bognar, R.; Tamas, J. Acta,

Chim, Hung. 1983, 112, 275; Chem. Abst. 99, 2212852y 6) Kirk, D.N.; Wilson, M.A.; J. Chem. Soc. (C) 1971, 414;

Chem. Abstr. 74, 112291e 7) Ehrart, G.; Siedel, W.; Nahm, H. Chem. Ber. 1957, 90,

2088; Chem. Abstr. 53, 276h 8) Perron, Y.G. et. al. J. Med. Chem. 1964, 7, 483; Chem.

Abstr. 61, 5631a 9) U.S. 4,313,896 1982; Chem. Abstr. 96, 142447g 10) Ferrari, B.; Pavai, A.A. Tetrahedron 1985, 41, 1939;

Chem. Abstr. 103, 160841y 11) Clarke, S.J.; Fleet, G.W.; Irving, E.WM. J. Chem. Res. (s)

1981, 17; Chem. Abstr. 94, 208452x



84

12) Rolla, F. J. Org. Chem. 1982, 47, 4327; Chem. Abstr. 97, 161849b

13) Vlassa, M.; Kezdi, M. Pol. J. Chem. 1984, 58, 611; Chem. Abstr. 103, 87759w

14) Rao, H.S.P.; Siva, P. Synth. Commun. 1994, 24, 549

15) Rao, H.S.P.; Reddy, K.S.; Turnbull, K.; Borchers, V. Synth. Commun. 1992, 22, 1339

16) Tschaen, D.M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.H.; Frey, L.; Karadty, S.; Shi, Y.ZJ.; Verhoeven, T.R. J. Org. Chem. 1995, 60, 4324

17) Ranu, B.; Sarkar, A.; Chakraborty, R. J. Org. Chem. 1994, 59, 4114; Chem. Abstr. 121 82111

18) Firouzabadi, H.; Adibi, M.; Zeynizadeh, B. Synth. Commun. 1998, 28, 1257

19) Pei, Y.; Wickham, B.O.S. Tetrahedron Lett. 1993, 34, 7509

20) Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis 1987, 48

21) Krein, D.M.; Sullivan, P.J.; Turnbull, K. Tetrahedron Lett. 1996, 7213

22) U.S. 5,012,000 1991 23) Yoon, N.M.; Choi, J.; Shon, Y.S. Synth. Commun.

1993, 23, 3047 24) Kabalka, G.W.; Wadgonkar, P.P.; Chatla, N. Synth.

Commun. 1990, 20, 293



85

REDUCTIVE DEAMINATION The alkaline cleavage of compounds of the type RN(NO)ONH2 with NaBH4 has been reported (1) to give the hydrocarbon RH. The reaction proceeds via an intermediate cabonium ion, similar to dehalogenantion with NaBH4. In hexameylphosphoraide, N,N-disulfonimides of primary amines, e.g. RN(SO2C6H4Me-p)2 where R= decyl, or 2,5-Me2C4H3CH2 are reduced to the hydrocarbon RH by NaBH4 in good yield. Other deamination, e.g. of amidines (3), have been reported. References: 1) Kimse, W.; Shuette, H. Liegig, Ann. Chem. 1968,

718, 86; Chem. Abstr. 70, 36855s 2) Hutchns, R.O.; Cistone, F.; Goldsmith, B.;

Heuman, P. J. Org. Chem. 1975, 40, 2018; Chem. Abstr. 83, 58333r

3) Okamoto, Y.; Kinoshita, T. Chem. Pharm. Bull 1981, 29, 1165; Chem. Abstr. 95, 97752u


86

DIAZONIUM SALTS References: 1) Hendrickson, J.B. J. Am. Chem. Soc. 1961, 83, 1251;

Chem. Abstr. 55, 13345c

NaBH4 has been reported to reduce diazonium fluoroborates in high yields (1,2) using either methanol or dimethylformamide as solvent. This is a reliable means of replacing diazonium groups by hydrogen, and thus of removing from aromatic rings groups easily converted to the diazonium salts, such as nitro, amino, and carbonyl groups.

2) Xu, G; Shi, X; Liu, M. Lanzhou Daxue Xueao, Ziran Kexueban 1983, 19, 112; Chem. Abstr. 99, 21739g

3) Traylor, T.G.; McKenna, C.E. J. Am. Chem. Soc. 1971, 93, 2323; Chem. Abstr. 75, 5372f

4) Koenig, E.; Musso, H; Zahorszky, U.I. Angew Chem, Int. Ed. Engl. 1972, 11, 45; Chem. Abstr. 76, 85126h

5) Bandgar, B. P.; Thite, C. S. Synth. Commun. 1997, 27, 635-639; Chem. Abstr. 126211857

R

N2+ BF4

-

R

H

NaBH4 6) HU 50108, 1989; Chem. Abstr. 113 5904

The use of a solvent that does not interact with borohydride, such as higher alcohols, amines and glycol ethers, is preferred. Phenyldiimine (R-N=NH) has been suggested to be the intermediate in the NaBH4 reduction of benzenadiazonium salts, and under anaerobic conditions has been detected in this reaction (3,4) Diazonium groups can be reduced to their corresponding hydrazine efficiently with sodium borohydride or borohydride exchange resins. (5,6)



87

HETEROCYCLIC C=N BONDS

N

CO2RRO2CNH

CO2RRO2C

NH

CO2RRO2C

NaBH4

Alembic: 7,12 Numerous examples of heterocyclic C=N reductions by NaBH4 have appeared in the literature in the last 20 years. NaBH4 has found wide application in this area, mainly because the work-up is much easier and the products are of high purity. NaBH4 selectively reduces the C=N bond in a number of heterocycles, such as 7-aminofurazone[3,4-d] pyrimidines (1).

Quinoxalines (3),

N

N NO

N

NH

Ph

O

N

N

RNH

HN

RNaBH4

AcOH, 5oC

Pyracrimycin A (4),

NH

CONH2HNH

H

CONH2H

NaBH43,5 substituted pyridines (2).

in which neither the C=C bond nor the amide group is reduced.


Roh


88

NaBH4 is also a versatile reagent for heterocyclic C=N bond reduction in alkaloid synthesis, e.g., in the synthesis of veracintine (5),


NMe

Me

HO

Me

HO

NaBH

N

Me

MeH H

Me

4

N* HCl

RO

RO

CO2Me

HOOH

N

RO

RO

CO2Me

HOOH

HNaBH4

Reserpine (7,8) and analogs (9-11), and dihydrovasicnone

N

N

O

N

N

O

H

NaBH4

In which the either group is unreactive (12). Other areas of application also involve the synthesis of vitamins, e.g. pteridine derivatives (13,14) and tetrahydrofolic acid (15),

Tetrahydroisoquiniline derivatives (6).

HN

N N

N

O

H2N

ClHN

N N

N

O

H2N

Cl

H

NaBH4


89

References: 1) Maki, Y. Chem. Pharm. Bull. 1976, 24, 234; Chem. Abstr.

84, 180161u Amino acids (16)

2) Booker, E.; Eisner, U. J. Chem. Soc., Perkin Trans 1 1975, 929; Chem. Abstr. 83, 79041j

NHO

HO

H

CO2H3) Rao, K.V.; Jackman, D. J. Heterocycl. Chem. 1973, 10,

213; Chem. Abstr. 79, 18669r 4) Coronelli, C.; Vigevani, A.; Cavalleri, B.; Gallo, G.G. J.

Antibiot. 1971, 24, 495; Chem. Abstr. 76, 140387a

5) Vassova, A Voticky, Z.; Tomko, J.; Ahond, A. Collect.

Czech. Chem. Commun. 1976, 41, 2964; Chem. Abstr. 86, 90128a

and pyrines (17, 18) Recent applications include the conversion of

pyrroline carboxylates to proline (19), the reduction of benzoxazepines (20), stereoselective synthesis of cis tetrahydropyrimidines (21) and N-norreticuline (22), and the formation of tetrahydrocarbolines (23) and dihydrondoloquinazolines (24).

6) Dornyei, G.; Szantay, C. Acta Chim. Acad. Sci. Hung. 1976, 89, 161; Chem. Abstr. 86, 29595j

7) Woodward, R.B. et. al. J. Am. Chem. Soc. 1956, 78, 2023; Chem. Abstr. 50, 13967b

8) Woodward, R.B. et. al. Tetrahedron, 1958, 2, 1; Chem. Abstr. 52, 11870f

Sodium borohydride with carboxylic acid forms trialkoxyborohydrides which have been demonstrated to be a general method to chemoselectively reduce cyclic imines to cyclic amines. (25-36)

9) Velluz, L. et. al. Bull. Soc. Chim. France 1958, 673; Chem. Abstr. 52, 18478d

10) Protiva, M.; Novak, L. Naturwiss. 1959, 46, 579; Chem. Abstr. 54, 6775I Sodium borohydride with NiCl2 have also been

used to reduce cyclic imine to their corresponding amines. (37)

11) Protiva, M.; Ernest, I. Naturwiss. 1960, 47, 156; Chem. Abstr. 54, 19746e




90

12) Zharekeev, B.K.; Telezhenetskaya, M.V.; Khashimov, K.; Tunusov, S.Y. Khim, Prir. Soedin. 1974, 679; Chem. Abstr. 82, 73290x

13) Taylor, E.C.; Kobylecki, R. J. Org. Chem. 1978, 43, 680; Chem. Abstr. 88, 89628y

14) Pendergast, W.; Hall, W.R. J. Org. Chem. 1985, 50, 388; Chem. Abstr. 102, 78834u

15) Boyle, P.H.; Keating, M.T.; J. Chem. Soc. Chem. Commun. 1974, 375; Chem. Abstr. 81, 105452z

16) Ramaswamy, S.G.; Adams, E. J. Org. Chem. 1977, 42, 3440; Chem. Abstr. 87, 184925f

17) Maki, Y.; Suzuki, M.; Ozeki, K. Tetrahedron Lett. 1976, 1199; Chem. Abstr. 85, 94314j

18) Beisler,J.A.; Abbai, M.M.; Driscoll, J.S. U.S. Pat. Appl. 712, 854 (Aug. 8, 1976); Chem. Abstr. 87, 62862n

19) Smith, R.J. Enzyme 1984, 31, 115; Chem. Abstr. 101, 2755c

20) Levkovskaya, L.G.; Sazanov, N.V. et. al. Khim. Geterotsiki. Soedin. 1985, 122; Chem. Abstr. 103, 37460w

21) Cho, H.; Shima, K. et. al. J. Org. Chem. 1985, 50, 4227; Chem. Abstr. 103, 178228p

22) Hung. Teljes 30,591 1984; Chem. Abstr. 101, 152163x

23) Nakamura, T.; Ishida, A.; Irie, K.; Oshishi, T. Chem. Pharm. Bull. 1984, 32, 2859; Chem. Abstr. 102, 6239

24) U.S.S.R. 816,116 1985; Chem. Abstr. 105, 208906u 25) Viagante, B.A.; Ozols, Y.Y.; Durbur, G. Y. Khim. Geter.

Soed. 1991, 1680 26) Carling R.W.; Leeson, P.D.; Moseley, A.M.; Baker, R.;

Foster, A.C.; Grimwood, S.; Kemp, J.A. Marshall, G.R. J. Med. Chem. 1992, 35, 1942

27) Brown, D.W.; Mahon, M.F.; Hihan, A.; Sainbury, M. J. Chem. Soc. Perkin Trans. 1 1995, 3117

28) Yadagiri, B.; Lown, J.W. Synth. Commun. 1990, 20, 175 29) Bock, M.G.; DiPardo, R.M.; Rittle, K.E.; Evans, B.E.;

Freidinger, R.M.; Veber, D.F.; Chang, R.S.L.; Chen, T.; Keegen, M.E.; Lotti, V.J. J. Med.. Chem. 1986, 29, 1941

30) Ishii, H.; Ishikawa, T.; Ichikawas, Y.; Sakamoto, M.; Ishikawa, M.; Takahashi, T. Chem. Pharm. Bull. Jpn. 1984, 32, 2984

31) Uchida, M.; Chihiro, M.; Morita, S.; Yamashita, H.; Yamasaki, K.; Kanbe, T.; Yabuuchi, Y.; Nakagawa, K. Chem. Pharm. Bull Jpn. 1990, 38, 534

32) Bergman, J.; Tilstam, U.; Tonroos, K.W. J. Chem. Soc., Perkin Trans. 1 1987, 519

33) Moody, C.J.; Warrellow, G.J. Tetrahedron Lett. 1987, 28, 6089

34) Bleicher, L.S.; Cosford, N.D.P.; Herbaut, A.; McCallum, J.S.; McDonald, I.A. J. Org. Chem. 1998, 63, 1109



91

35) Evans, B.E., et. al. J. Med. Chem. 1987, 30, 1229 36) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda,

M.; Suginome, H. J. Org. Chem. 1999, 64, 6583 37) Roberts, D.; Jopule, J.A.; Bos, M.A.; Alvarez, M. J.

Org. Chem. 1997, 62, 568



92

HYDRAZONES Alembic 12 p-Tosyl hydrazone of conjugated olefinic or aromatic

carbonyl compounds (e.g. carvone) undergo elimination reaction in preference to reduction with NaBH4, NaOR or K2CO3 in methanol to yield methyl ethers instead of hydrocarbon (11).

The reduction of hydrazones (R-CH=NNHR') to either hydrocarbon or hydrazides has been reported. (1-3) Tris 2,4-methanoprotoadamantane is synthesized by reducing the tosylhydrazone derivative in EtOH(4).

NNHTs OMe

NaBH4

MeOH

N NH Ts

NaBH4

The hydrocarbon can, however, be obtained by changing solvents (12).

This has also been applied to the synthesis of 1-methyl-1-dihalomethyl cyclohexane derivatives (5).

Recent applications include the synthesis of phoracatholide (13) and steroid derivatives (14,15) and the labeling of glycoproteins (16).

A number of hydrazides have been prepared by NaBH4 reduction of the hydrazones (6,9). The hydrazones C=N bond is selectively reduced e.g. in the synthesis of 3,4,5-trimethxybenzol hydrazides (10) . Zinc cyanoborohydride can reduce hydrazones to

hydrocarbons in high yields. (17,18) A mechanistic study on the reductive pathway of cyanoborohydride has been completed. (19)

MeO

MeO

MeO NN R

O

H R'

MeO

MeO

MeO NN R

O

H R'

H

H

NaBH4

Bis-triphenyl phosphine copper (I) borohydride can reduce hydrazones to alkanes in high yields.(20) Sodium




93

borohydride in the presence of CeCl3 in MeOH at RT will also reduce hydrazones to alkanes in high yield. (21)

Acetoxy borohydrides have also been demonstrated to reduce hydroazones to alkanes (22)

References: 1) Kabalka, G.W.; Baker, J.D. J. Org. Chem. 1975,

40, 1834 2) Kabalka, G.W.; Summer, S.T. J. Org. Chem. 1981,

46, 1217 3) Eycken, E.V.D.; Wilde, H.D.; Deprez, L.;

Wandewalle, M. Tetrahedron Lett. 1987, 28, 4759 4) Sasaki T.; Eguchi, S.; Hirako, Y. J. Org. Chem.

1977, 42, 2981; Chem. Abstr. 87, 117621r 5) Wenkert, E.; Wovkulick, P.; Pellicciari, P.;

Ceccherelli, P. J. Org. Chem. 1977, 42, 1105; Chem. Abtr. 86, 120829z

6) Claudi, F.; Grifantini, M.; Guilni, U.; Martelli, S.; Natalini, P.J. Pharm. Sci. 1977, 66, 1355; Chem. Abstr. 87, 167827h

7) Mazone, G.; Arrigo-Reina, R.; Amico-Roxas, M. Farmaco, E.D. Sci. 1976, 31, 517; Chem. Abstr. 85, 142768k

8) Ger. Offen. 2,305,972 1973; Chem. Abstr. 79, 115602w

9) Vartanyan, S.A.; Vartanyan, R.S. et. al. Khim. Farm. Zh. 1985, 19, 821; Chem. Abstr. 105, 42705a

10) Mazzone, G.; Arrigo, R.R. Boll. Sedute Accad. Gioenia Sci. Natur. Catania 1971, 41, 1755; Chem. Abstr. 78, 15733a

11) Grandi, R.; Marchesini, A.; Pagnonic, U.M.; Trave, R. J. Org. Chem. 1976, 41, 1755; Chem. Abstr. 84, 180401x

12) Silvestri, M.G.; Bednarski, P.J.; Kho, E. J. Org. Chem. 1985, 50, 2798; Chem. Abstr. 103, 54313t

13) Mahanjan, R.J.; DeAraujo, H.C. Synthesis 1981, 46, 2786; Chem. Abstr. 94, 208686b

14) Iida, T.; Chang, F.C. J. Org. Chem. 1981, 46, 2786; Chem. Abstr. 95, 25399m

15) Iida, T.; Tamura, R.; Matumoto, T.; Chang, F.C. Synthesis 1984, 957; Chem. Abstr. 102, 221092h

16) Estep, T.N.; Miller, T.J. Anal. Biochem. 1985, 157, 100; Chem. Abstr. 105, 168335y

17) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J. J. Org. Chem. 1985, 50, 1927

18) Paquette, L.A.; Wang, T.Z.; Vo, N.H. J. Am. Chem. Soc. 1993, 115, 1677

19) Miller, V.P.; Yang, D.Y.; Weigel, T.M.; Han, O.; Liu, H.W. J. Org. Chem. 1989, 54, 4175

20) Fleet, G.W.J.; Harding, P.J.C. Tetrahedron Letter. 1980, 4031



94

21) Fleet, G.W.J.; Harding, P.J.C.; Whitcombe, M.J. Tetrahedron Lett. 1980, 21, 4031

22) Maryanoff, B.E.; McComsey, D.F.; Nortey, S.O. J. Org. Chem. 1981, 46, 255



95

IMINES Alembic 23, 33, 43, 62

RH

NH2

O+

N

OHHO

Me

HO

N

OHHO

Me

NOH

RO

H

NaBH4 readily reduces imines to their corresponding secondary amines in good yield under mild condition (1-6).

RN

Cl

Me

NO2R

N

Cl

Me

NO2

H

HNaBH4

AcOH

which is then reduced to the pyridoxylamino acid with sodium borohydride. The individual acids are separated by column chromatography, followed by radiochemical determination. In this way, quantities of amino acids as small as 10-12 mmol can be detected.

Allylic imines have been reduced to allylic amines in high yield with sodium borohydride.(7,8) A large number of Schiff bases have also been reduced to the amine utilizing NaBH4 (9-12). The selective reduction of imines has made NaBH4 a versatile

reagent n the synthesis of antibacterial such as alkylaminoerythromycins (14), fungicides (15), 8-aminogibbanes (16), N-alkyamino pivalates (17) and antiinflammatory hydroxybenzylamines (18).

NHC

R

R'

R"

CO2H

N

R

R'

R"

CO2H

H

H

H

NaBH4

Sodium cyanoborohydride is also used frequently for

imine reductions (19-23). Zinc borohydride can reduce imines to secondary amines in high yields (24-26)

This type of reduction has been shown to provide the most sensitive method of determining amino acids (13) The amino acids are condensed with pyridoxal under alkaline condition to form the Schiff base,




96

Triacetoxy borohydride have been shown to reduce imines formed from the reductive amination of aldehydes and ketones with amines.(27) Stereospecific reduction of imines has been reported (28-30), including the chiral synthesis of doxpicomine (31), in which an imine is reduced with 88% enantiomeric excess. Sodium borohydride with amino acids have been shown to steroselctively reduce imines in high ee.(32) Stereoselctive reduction of imines can be accomplished catalytically with a cobalt catalyst. (33) Zinc borohydride can also reduce imines steroselectively.(34)

References: 1) Haire, M.J. J. Org. Chem. 1977, 42, 3446; Chem.

Abstr. 87, 183524n 2) Zhang, Z.; Martell, A.E.; Motekataitis, R.J.; Fu, L.

Tetrahedron. Lett. 1999, 40, 4615 3) Effenberger, F.; Jager, J. J. Org. Chem. 1997, 62,

3867 4) Froelich, O,.; Desos, P.; Bonin, M.; Quirion, J.C.;

Hussan, H.P J. Org. Chem. 1996, 61, 6700 5) Roberts, D.; Jopule, J.A.; Bos, M.A.; Alvarez, M.

J. Org. Chem. 1997, 62, 568 6) Krepski, L.R.; Jensen, K.M.; Heilmann, S.M.;

Rasmussen, J.K. Synthesis 1986, 301

7) Shin, W.S.; Lee, K.; Oh, D.Y. Tetrahedron Lett. 1995, 36, 281

8) De Kimpe, N.; Stanoeva, E.; Verhe, R.; Schamp, N. Synthesis 1988, 587

9) Lakhani, B.B.; Merchant, J.R. J. Inst. Chem. 1977, 49, 172; Chem. Abstr. 87, 167668g

10) Ger. Offen. 3,034,664 1982; Chem. Abstr. 97, 55815c 11) U.S. 4,454,226 1984; Chem. Abstr. 101, 70879w 12) Merrettt, M.; Stammers, D.K.; White, R.D.; Wootton, R.;

Kneen, G. Biochem. J. 1986, 239, 387; Chem. Abstr. 105, 218622n

13) Lustenberger, N.; Lange, H.; Hempel, K. Angew. Chem. Int. Ed. Engl. 1972, 11, 227; Chem. Abstr. 76, 148553x

14) Ger. Offen 2,606,662 1977; Chem. Abstr. 88, 23335u 15) Eur. Pat. Appl. 129,433 1984; Chem. Abstr. 103,6367s 16) Hung, P.D.; Adam, G.J. Prakt. Chem. 1984, 326, 253;

Chem. Abstr. 101, 38694w 17) Coatwes, R.M.; Cummins, C.H. J. Org. Chem. 1986, 51,

1383; Chem. Abstr. 104, 186037m 18) U.S. 4,578,290 1986; Chem. Abstr. 105, 97344n 19) Oveman, L.E.; Mendelson, L.T.; Jacobsen, E.J. J. Am.

Chem. Soc. 1983, 105, 6629; Chem. Abstr. 99, 176116a 20) Borne, R.F.; Fifer, E.K.; Waters, I.W. J. Med. Chem.

1984, 27, 1271; Chem. Abstr. 101, 1306113s 21) W.S. 4,537,885 1985; Chem. Abstr. 104, 155969n 22) S. Aferican 83 08,227 1985; Chem. Abstr. 105, 114934z



97

23) Cox, E.D.; Hamaker, L.K.; Li, J.; Yu, P.; Czerwinski, K.M.; Deng, L.; Bennett, D.W.; Cook, J.M.; Watson, W.H.; Krawiec, M. J. Org. Chem. 1997, 62, 44

24) Ranu, B.C.; Sarkar, A.; Majee, A. J. Org. Chem. 1997, 62, 1841

25) Uneyama, K.; Hao, J.A.; Amii, H. Tetrahedron Lett. 1998, 39, 4079

26) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M. Synlett, 1990, 401

27) Ryglowski, A.; Kafarski, P. Tetrahedron 1996, 52, 10685

28) Wrobel, J.E.; Ganem, B. Tetrahedron Lett. 1981, 22, 3447; Chem. Abstr. 96, 51861w

29) Czarnocki, Z; Mieczko, J.B. Pol. J. Chem. 1995, 69, 1447; Chem. Abstr. 124 9059

30) Zhu, J.Z.; Quirion, J.C.; Husson, H.P. Tetrahedron Lett. 1989, 30, 5137

31) Farkas, E.; Sunman, C.J. J. Org. Chem. 1985, 50, 1110; Chem. Abstr. 102, 149194y

32) Hajipour, A.R.; Hantehzadeh, M. J. Org. Chem. 1999 64, 8475


34) Jackson, W.R.; Jacobs, H.A.; Matthews, B.R.; Jayatilake, G.S.; Watson, K.G. Tetrahedron. Lett. 1990, 31, 1447

Roh


98

NITRILES Alembic 50, 55, 60 Examples of nitrile reduction by NaBH4 are limited to few heterocyclic compounds in which the –CN groups are activated by the heteroatom ring, e.g., the indole derivative (1) and some pyridine, quinoline (2) and napthalene (3) derivatives.


N

H

PhC N

H

N

H

Ph H

NaBH4NH2

Recently, NaBH4 has been reported to reduce effectively a number of aromatic nitriles to the amines in the presence of trifluoroacetic acid (4,5). The active species is believed to be sodium trifluoroacetoxyborohydride, was first formed by reacting an equimolar CF3COOH with NaBH4 in THF for 10 mins at 20 oC. In a series of studies involving nitrogenase reactions, Schrauzer has reported the NaBH4 reduction of isocyanide (6) and cyanides (7), catalyzed by

molybdenum complexes, to the amines and a number of other products. The CN groups are activated by coordinating to a metal atom rendering the carbon center more electropositive and therefore, more easily attacked by BH4

-. Similarly, perfuoroalkylnitirle are reduced to the amines (8). In the presence of a catalyst, e.g. Raney nickel, nickel or cobalt boride the nitrile groups can be effectively reduced, and this approach has found extensive applications in the reduction of aromatic nitrile compounds (9), alkaloids (10), amino acids and their derivatives (11), and biogenic polyamines derivatives (12). The combination of CoCl2 and sodium borohydride produces a reductive system that converts nitriles to either alkanes or amines.(13,14) Reaction of nitrile groups with girngard reagents to form imine groups, which are subsequently selectively reduced with zinc borohydride or sodium borohydride with trimethyl silane chloride have been demonstrated.(15,16)

Lithium or sodium borohydride with trimethylsilane chloride have reduced nitrile groups to amines in high yields.(17)

Borohydride exchange resin spiked with copper sulfate in MeOH at RT can reduce aromatic and aliphatic nitriles to their corresponding amines.(18) Lithium borohydride in a solvent mixture of MeOH and diglyme has demonstrated the same reactivity but at only moderate yields of the desired amine.(19)



99

Nitriles can be removed as a cyanide group to leave an alkane group by using sodium borohydride or cyanoborohydride in low molecular weight alcohols at both RT and at elevated temperatures.(20-26) zinc borohydride has also shown similar reactively towards nitrile groups.(27) Publications include a patent on selective nitrile reduction (28), and a proposed mechanism and optimized procedure for cobalt boride catalyzed nitrile reduction have been reported. (29). References: 1) Rusinova, V.N. et. al. Khim. Geterotsikl. Soedin.

1974, 211; Chem. Abstr. 81, 37455a 2) Kikugawa, Y.; Kuramoto, M.; Saito, I.; Yamada, S.

Chem. Pharm. Bull. 1973, 21, 1927; Chem. Abstr. 79, 145754q

3) Jpn. Kokai Tokkyo Koho 85, 100,542 1985; Chem. Abstr. 103, 123196w

4) Umino, N.; Iwaakuma, T.; Itoh, N. Tetrahedron Lett. 1976, 2875; Chem. Abstr. 86, 16375m

5) Beugelmans, R.; Singh, .P.; Bois-Choussy, M.; Chastanet, J.; Zhu, J. J. Org. Chem. 1994, 59, 5535

6) Schrauzer, G.N.; Doemeny, R.A.; Kiefer, G.W.; Frazier,R.H. J. Am. Chem. Soc. 1972, 94, 3604; Chem. Abstr. 77, 15965g

7) Schrauzer, G.N.; Doemeny, R.A.; Kiefer, G.W.; Frazier,R.H. J. Am. Chem. Soc. 1972, 94, 7378; Chem. Abstr. 77, 161531d

8) Ellzey, S.E.; Wittman, J.S.; Connick, W.J. J. Org. Chem. 1965, 30, 3945; Chem. Abstr. 64, 6490b

9) Wade, R.C.; Holah, .G.; Hughes, A.N.; Hui, B.C. Catal. Rev. Sci. Eng. 1976, 14, 211; Chem. Abstr. 86, 22275w

10) Harayama, T.; Ohtani, M.; Oki, M.; Inubushi, Y. Chem. Pharm. Bull. 1975, 23, 1511; Chem. Abstr. 83, 131793x

11) Mezo, I.; Havanek, M.; Tepan, I.; Benes, J.; Tanaces, B. Acta. Chim. Acas. Sci. Hung. 1975, 23, 1511; Chem. Abstr. 83, 59244z

12) Ger. Offen. 3,506,330 1985; Chem. Abstr. 104, 168275h 13) Williams, J.P.; Laurewnt, D.R.; Friedrich, D.; Pinard, E.;

Roden, B.A.; Paquette, L.A. J. Am. Chem. Soc. 1994, 116, 4689

14) Backvall, J.E.; Plobeck, N.A. J. Org. Chem. 1990, 55, 4528

15) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M. Synthesis 1990, 401

16) Urabe, H.; Aoyama, Y.; Sato, F. J. Org. Chem. 1992, 57, 5056

17) Giannis, A.; Snadhoff, K. Angew. Chem. Int. Ed. Engl. 1989, 28, 218

18) Sim, T.B.; Yoon, N.M. Bull. Chem. Soc. Jpn. 1997, 70, 1101



100

19) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000 20) Mitch, C.H. Tetrahedron Lett. 1988, 29, 6831 21) Hui, B.C Inorg. Chem. 1980, 19, 3185 22) Guerrier, L.; Royer, J.; Grierson, D.S.; Husson,

H.P. J. Am. Chem. Soc. 1983, 105, 7754 23) Yue, C.; Royer, J.; .; Husson, H.P. J. Org. Chem.

1990, 55, 1140 24) Grierson, D.S.; Royer, J.; Gruerrier, L.; Husson,

H.P. J. Org. Chem. 1986, 51, 4475 25) Marco, J.L.; Royer, J.; Husson, H.P. Synth.

Commun. 1987, 17, 669 26) Polniaszek, R.P.; Belmont, S.E. J. Org. Chem.

1990, 55, 4688 27) Vidal, L.; Royer, J.; Husson, H.P. Tetrahedron Lett.

1995, 36, 2991 28) PCT Int. Appl. 85, 00,605 1985; Chem. Abstr. 104,

110018k 29) Osby, J.O.; Heinzman, S.W.; Ganem, B. J. Am.

Chem. Soc. 1986, 108, 67; Chem. Abstr. 104, 50458s



101

NITRO COMPOUNDS Alembic: 4, 6, 9, 48, 51, 52, 61 Under normal conditions, NaBH4 does not reduce the nitro group, except in a few aromatic nitro compounds. For example, nitroanthraquinones are reduced to the corresponding amines in 65 to 100 % yield (1) in H2O, alcohols, aqueous DMF and THF. Reduction to the amine has also been reported for the 2-carbenthoxyindole derivatives (2). Ordinarily, aliphatic nitro compounds are not reactive with NaBH4, and the reduction of nitrobenzene generally results in a number of products, e.g. azo, azoxy, hydrazo derivatives and aniline (3,4). In the presence of thiols, NaBH4 reduces nitro groups to amine, hydroxylamines, azo and azoxy compounds, and the activity is attributed to the thiolate derivatives (5). A number of transition metal complexes have been reported to catalyze the borohydride reduction of nitro compounds, e.g., PdCl2(N-methylpyrrolidinone)2 (6), K2Ni(CN)4 (7), NiX2P2(8), and Co(NH3)6 3+ (9), MoO3 (10). NaBH4 can also convert a number of aromatic nitro compounds to the amines in the presence of palladium on charcoal (11-16). Cobalt and nickel borides, generated from Co(II) and Ni(II) salts and

NaBH4 are extremely effective in catalyzing the reduction of nitro compounds to amines (17-20).

It has been reported that copper (I) acetate will reduce aromatic nitro compounds in ethanol. (21) Other copper (I) complex such as CuBr•SMe2 in methanol at RT have also been demonstrated to reduce aromatic nitro compounds in the presence of halides, alkoxides and amines. (22) Potassium borohydride with CuCl will reduce aromatic nitro compounds to amines at RT. (23) Aromatic nitro groups can also be selectively reduced to amino compounds by sulfurated sodium borohydride, NaBH2S3, prepared by the reaction between sulfur and NaBH4 in dry THF (24,25)

Sato has found (26) that SnCl2•2 H2O and NaBH4 in ethanol reduces aromatic nitro compounds selectively in the presence of other functional groups, such as ester, chloro, nitrile and olefinic bonds.

Bismuth trichloride or SbCl3 with either sodium or potassium borohydride will reduce both aromatic and aliphatic nitro compounds to their corresponding amine in the presence of nitrile, chloride amine, hydroxy and alkoxy groups at elevated temperatures.( 27,28,29,30) The use of bismuth trichloride as a catalytic crosscoupling reagent of two aromatic nitro molecules to a azobenzene compound at RT has been demonstrated. This reaction will not effect ester, nitrile, chloride, hydroxy and alkoxy groups. (31)



102

The addition of selenium metal to sodium borohydride to form a Lancette type reagent that reduces aromatic nitro compounds to aromatic amines. (32)

Sodium borohydride with catalytic amounts of sodium methoxide will reduce nitro groups on imidazoles, pyrazoles or pyridine rings at RT. (33)

α−β unsaturated nitroalkenes can be reduced to a ketone group with NaBH4 and hydrogen peroxide at RT. Under these reaction conditions will not effect acetal, ester or olefinic groups. (34)

Sodium borohydride with ammonium sulfate in ethanol will reduce aromatic nitro compounds in less then an hour. This methodology is chemoselective and will not reduce nitrile, ester, carboxylic acid, halide and olefinic groups. (35 )

Borohydride exchange resins spiked with Ni acetate will reduce aliphatic and aromatic nitro compounds at RT in MeOH. (36) The nickel complexes anchored to a polymer backbone with NaBH4 can reduce nitrobenzene to analine. (37).

It has been demonstrated that sodium borohydride in refluxing diglyme can reduce nitrobenzene to analine in quantitative yields if

ammonium chloride is added to the reaction as a proton donor.(38) References: 1) Morley, J.O. Synthesis 1976, 8, 528; Chem. Abstr. 85,

177120v 2) Nantko-Namirski, P.; Ozdowska, Z. Acta Pol Pharm.

1975, 32, 273; Chem. Abstr. 84, 17065g 3) Panson, G.S.; Weill, C.E. J. Org. Chem. 1956, 21, 803;

Chem. Abstr. 51, 7320a 4) Nose, A.; Kudo, T. Yakugaku Zasshi 1977, 97, 116;

Chem. Abstr. 86, 170979u 5) Maki, Y.; Sugiyama, H.; Kikucki, K.; Seto, S. Chem. Lett.

1975, 1093; Chem. Abstr. 83, 192711r 6) Nazarova, N.M.; Opyttsev, Y.A.; Shcherbakova, S.I.;

Freidlin, L. K. Izv. Akad. Nauk SSSR, Ser. Khim. 1975, 2589; Chem. Abstr. 84, 43501r

7) Hanaya, K.; Kudo, H.; Hara, T.; Fujita, N.; Iwase, A. Yamagata Daigaku Kiyo Shizen Kagaku 1974, 8, 397; Chem. Abstr. 81, 169229q

8) Hanaaya, K.; Fujita, N.; Kudoi, H. Chem. Ind. 1973, 794; Chem. Abstr. 79, 125994q

9) Arai, Y. et. al. Nippon Kagaku Kaishi 1972, 194; Chem. Abstr. 76, 85484c

10) Yanada, K.; Yanada, R.; Meguri, H. Tetrahedron Lett. 1992, 1463



103

11) Neilson, T.; Wood, H.C.S.; Wylie, A.G. J. Chem. Soc. 1962, 371; Chem. Abstr. 56, 15391b

12) Hahn, R.C.; Johnson, R.P. J. Am. Chem. Soc. 1977, 99, 1508; Chem. Abstr. 86, 170495h

13) Billing, M.J.; Baker, E.W. Chem. Ind. 1969, 654; Chem. Abstr. 71, 22123k

14) Coutts, R.T.; El-Hawari, A.M. Can. J. Chem. 1975, 53, 3637; Chem. Absrt. 84, 105464s

15) Numazawa, M.;Kimura, K. Steriods 1983, 41, 675; Chem. Abstr. 100, 68583f

16) Walker, T.E.; Matheny, C.; Storm, C.B.; Hayden, H. J. Org. Chem. 1986, 51, 1175; Chem. Abstr. 104, 168804e

17) Wade, R.C.; Holah, D.G.; Hughes, A.N.; Hui, B.C. Catal. Rev. Sci. Eng. 1976, 14, 211; Chem. Abstr. 86, 22275w

18) Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159; Chem. Abstr. 95, 132421j

19) Ger. Offen. 3,309,493 1984; Chem. Abstr. 102, 95892d

20) Osby, J.O.; Ganem, B. Tetrahedron Lett. 1986, 27, 1205; Chem. Abstr. 105, 23917e

21) Drouin, J.; Gauthier, S.; Patricola, O.; Lanteri, P.; Longeray, R. Synlett 1993, 791

22) Patel, H.V.; Vayas, K.A. Org. Prep. Proc. Int. 1995, 27, 81

23) He, Y.; Zhao, H.; Pan, X.; Wang, S. Synth. Commun. 1989, 19, 3047

24) Lalancette, J.M.; Brindle, J.R. Can. J. Chem. 1971, 49, Chem. Abstr. 151488q

25) Jpn. Kokai Tokkyo Koho 85, 152, 497 1985; Chem. Abstr. 104, 69119d

26) Satoh, T.; Mitsuo, N.; Nishiki, M; Inoue, Y.; Ooi, Y. Chem. Pharm. Bull. 1981, 29, 1443; Chem. Abstr. 95, 97224y

27) Ren, P.; Pan, S.F.; Dong, T.W.; Wu, S.H. Chin. Chem. Lett. 1995, 6, 553; Chem. Abstr 123 313453

28) Ren, P.; Pan, S.F.; Dong, T.W.; Wu, S.H. Synth. Commun. 1995, 25, 3799

29) Borah, H.N.; Prajapati, D.; Sandhu, J.S. J. Chem. Res. (s) 1994, 228

30) Pan, S.F.; Ren, P.D.; Dong, T.W. Chinese Chem. Lett. 1996, 7, 981

31) Ren, P.; Pan, S.; Dong, T.; Wu, S. Synth. Commun. 1996, 26, 3903

32) Shao, J.G.; Wang, L.C.; Zheng, M.; Zhong, Q. Chinese Chem Lett. 1997, 8, 683

33) Suwinski, J.; Wagner, P.; Holt, E.M. Tetrahedron 1996, 52, 9541

34) Ballini, R.; Bosica, G. Synthesis 1994, 723 35) Gohain, S.; Prajapati, D.; Sandhu, J.S. Chem. Lett. 1995,

72



104

36) Yoon, N.M.; Choi, J. Synlett 1993, 135 37) Loubinoux, B.; Chanot, J.J.; Caubere, P. J.

Organomet. Chem. 1975, 88, C4; Chem. Abstr. 83, 27763b

38) Yang, C.M.; Pittman, Jr. C.U. Synth. Commun. 1998, 28, 2027

Roh


105

NITROSO COMPOUNDS

NO NH2

NaBH4

Pd/C

NMe2 NMe2

The conversion of the nitroso group to the hydroxylamine has been reported with NaBH4 in the absence of a catalyst (1).

ON N

NaBH4

OHH

Nitroso reduction to the corresponding amine has been reported in the case of the anticancer drug methyl CCNU, in which a nitrourea is reduced to a semicarbazide by NaBH4 (5).

Transition metal complexes also catalyze the reduction, e.g. bis(dimethylglyoximato)cobalt(2), or palladium on charcoal (3,4).

The reduction of nitrosamine amine can be accomplished in high yields using borohydride exchange resins spiked with CuI- sulfate in methanol at 0oC. (6)

NO

N N

O

N N

NH2

47 %

41 %

12 %

NaBH4

Co(DMGH)2

References: 1) Patrick, T.B.; Schield, J.A.; Kirchner, D.G. J. Org. Chem.

1974, 39, 1758; Chem. Abstr. 81, 25235r 2) Green, M.; Swinden, G. Inorg. Chim. Acta. 1971, 5, 49;

Chem. Abstr. 75, 34882c 3) Neilson, T.; Wood, H.C.S.; Wylie, A.G. J. Chem. Soc.

1962, 371; Chem. Abstr. 56, 15391b 4) Goodman, M.M.; Knapp, F.F. J. Org. Chem. 1982, 47,

3004; Chem. Abstr. 97, 38614u 5) Caddy, B.; Idowu, O.R. Analyst 1982, 107, 550; Chem.

Abstr. 97, 103741z




106

6) Lee, S.Y.; Sim, T.B.; Yoon, N.M. Bull. Korean Chem. Soc. 1997, 18, 1127

Rohm and Haas : the Sodium Borohydr press <CTRL>-F for Searching

ide Digest

107

OXIMES Partial reduction of an oxime may also afford a hydroxylamine; this can be achieved effectively by using NaBH4 in carboxylic acid (4).

Alembic 8, 50 The reduction of oximes may give amines, hydroxylamines or alcohols. Thus, ketoximes are reduced to the primary amines (1).

R R'

N

OH

R R'

NHO

R"NaBH4

R"CO2H

NaBH4RN

OOH

Me

RN

OH

Me

H

H

N

OHN

HOR"NaBH4

R"CO2H

Reductive hydrolysis of oximes generally produces the corresponding alcohols (2,3).

SS

NOH

NHBz HONHBz

OH

O

SS

OH

NHBz HONHBz

OH

O

NaBH4

The reaction appears to be general for aldoximes and ketoximes, except for bezophenone oxime and bibenzyl ketoxime, among a number of compounds studied. An interesting report shows that NaBH4 absorbed on Al2O3 or silica gel effectively reduces oximes to hydroxylamines in benzene (5). Sulfurated sodium borohydride, NaBH2S3 (6-8) and NaBH4 in the presence of NiCl2 or MoO3 (9) have been used to reduce oximes to the amine. Sodium cyanoborohydride is often used to reduce oximes to hydroxylamines (10-12).




108

Borohydride exchange resins spiked with nickel acetate have reduced aromatic oximes to amines in MeOH at RT. (13) Borane produced by the reaction of sodium borohydride with I2 or H2SO4 in THF at 0o C to reduce o-acyl oximes to amines. (14,15) Metal complexes such as ZrCl4, FeCl3 and SnCl4 have been shown to reduce asymmetric o-oximes to amines in high yields under mild reaction conditions. (16,17) Lithium borohydride as been shown to reduce oximes to hydroxy amines at RT in THF. (18) While amino oximes have been reduced to amino nitriles in refluxing acetonitrile. (19) References: 1) Seelkopt, C. Rev. Fac. Farm. Univ. Los Andes

1974, 15, 157; Chem. Abstr. 83, 78998q 2) Mikhno, S.D.; et. al. Zh. Org. Khim. 1977, 13, 175;

Chem. Abstr. 86, 171291a 3) Nazir, M.; Kreiser, W.; Inhoffen, H.H. Synthesis

1977, 466; Chem. Abstr. 87, 133228y 4) Gribble, G.W.; Leiby, R.W.; Sheehan, M.N.

Synthesis 1977, 856; Chem. Abstr. 88, 89018z 5) Ciurdaru, V.; Hodosan, F. Rev. Roum. Chim. 1977,

22, 1027; Chem. Abstr. 87, 201881h

6) Lalancette, J.M.; Brindle, J.R. Can. J. Chem. 1970, 48, 735; Chem. Abstr. 72, 110402b

7) Jpn. Kokai Tokkyo Koho 79 119,485 1979; Chem. Abstr. 92, 128979t

8) Jpn. Kokai Tokkyo Koho 81, 122,386 1981; Chem. Abstr. 96, 122832a

9) Ipaktschi, J. Chem. Ber. 1984, 117, 856; Chem. Abstr. 101, 22611f

10) Baldwin, J.WE.; Kruse, L.I.; Cha, J.K. J. Am. Chem. Soc. 1981, 103, 942; Chem. Abstr. 94, 121385d

11) U.S. 4,312,887 1982; Chem. Abstr. 96, 142446f 12) Tsuchiya, T.; Nakano, M.; Torii, T.; Suzuki, Y.;

Umezawa, S. Carbohydrate. Res. 1985, 136, 195; Chem. Abstr. 103, 123834c

13) Badgar, B.P.; Nikat, S.M.; Wadgaonkar, P.P. Synth. Commun. 1995, 25, 863

14) Barby, D.; Champagne, P. Synth. Commun. 1995, 25, 3503

15) U.S. 5,200,561 1993 16) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J. Chem. Soc.,

Perkin Trans. 1 1990, 1859 17) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J. Chem. Soc.,

Perkin Trans. 1 1989, 1548 18) Cho, B.T.; Seong, S.Y. Bull. Korean Chem. Soc. 1988, 9,

322



109

19) Petukhov, P.A.; Tkachev, A.V. Tetrahedron 1997, 53, 2535


110

QUATERNARY COMPOUNDS

N+

N

O

Me

NaBH4

MeN

N

OH

Me

Me

Alembic: 15, 28

A wide variety of cyclic quaternary ammonium salts containing >C=N+< unsaturations have been reduced with NaBH4, including pyridinum (1-7) pyrazinium (8,9), pyrazolium (10,11), isoquinolinium (12,13,14), quinolium (15,16), pyroliumum (17), Pyoladine (18), oxazolium(19,20,21), thiazolium (22,23), and indoloquinolizium (24,25) in these the >C=N+< is effectively hydrogenated to the amine. One of the most interesting reactions of this type is the complete reduction of quaternized 4-aminopyridines to the 4-aminopiperidines (26), and the reduction of oxidopyrazinium iodides to 1-hydroxypiperazines (8),

Similar results are reported for ternary oxonium salts, e.g., substituted are reported for tenary oxonium salts, e.g. 2-substituted 1,3-benzoathiolylium salts (27), and pyrylium salts (28,29).

O+

R

R'O

R

R'

O

R

R'

NaBH4

N+

NH2

R

NaBH4

N

NH2

R a reduction impossible to carry out by catalytic hydrogenantion.

Thiopyrylium salts (solfonium compounds) (30) are reduced in a similar manner.




111

S S+

NO2

S S

NO2NaBH4

Alkaloids have been synthesized by reducing quarternary ammonium salts with sodium borohydride. (37) References: 1) Knaus, E.E.; Redda, K. J. Heterocycl. Chem. 1976, 13,

1237; Chem. Abstr. 86, 155471d 2) Boulton, A.J.; Epsztajn, J.; Katritzky A.R.; Nie, P.

Tetrahedron Lett. 1976, 2689; Chem. Abstr. 86, 55248t 3) Lyle, R.E.; Krueger, W.E; Gunn, V.E. J. Org. Chem.

1983, 48, 3574; Chem. Abstr. 99, 139723a 4) Gessner, W.; Brossi, A.; Chen, R.S.; Fritz, R.R.; Abell,

C.W. Helv. Chim. Acta 1984, 67, 2037; Chem. Abstr. 102, 166584t

Even nitrilium salts (-C+N-R), by way of imino ester [-C(OR’)=N-R], are reduced in good yield to the secondary amine (31).

5) Jpn. Kokai Tokkyo Koho 85, 228,460 1985; Chem. Abstr. 104, 148756n

6) Park, K.K.; Han, D.; Shin, D. Bull. Korean Chem. Soc. 1986, 7, 201

Iminium salts have been reduced stereoselectively with sodium borohydride. (32,33,34) Trimethyl propogyl ammonium iodide can be reduced with sodium borohydride to an alkene and isopropyl alcohol in high yield (35)

7) Burge, J.R.; Prey, P.A. J. Org. Chem. 1996, 61, 530 8) Ohta, A.; Matsunaga, M.; Iwata, N.; Watanabe, T.

Heterocycles 1977, 8, 351; Chem. Abstr. 88, 74373n 9) Bryce, M.R.; Eaves, J.G.; Parker, D.; Howard, J.A.K.;

Johnson, O. J. Chem. Soc., Perkin Trans 2 1985, 433; Chem. Abstr. 103, 5770f

Nickel (II) chloride with sodium borohydride can reduce quartarnary ammonium salts in high yields (36).

10) Omar, N.M.; Bayomi, S.M. Egypt. J. Pharm. Sci. 1975, 16, 49; Chem. Abstr. 87, 682226e



112

11) Elguero, J.; Jacquier, R.; Mignonac-Mondon, S. Bull. Soc. Chim. Fr. 1972, 2807; Chem. Bastr. 78, 29668v

12) Kasmetani, RT.; Okawara, T. J. Chem. Soc. Perkin Trans. 1 1977, 579; Chem. Abstr. 87, 39710c

13) Sigh, H.; Kumar, K.S. J. Chem. Sci. 1975, 1, 18; Chem. Abstr. 85, 192683z

14) Ger. Offen. 3,244,594 1984; Chem. Abstr. 101, 151766j

15) Sharma, N.D.; Goyal, V.K.; Joshi, B.C. Croat. Chem. Acta 1976, 48, 317; Chem. Abstr. 86, 106326b

16) Verma, P.N.; Sharma, N.D.; Goyal, V.K.; Joshi, B.C. Acta Cienc. Indica Chem. 1980, 6, 213; Chem. Abstr. 95, 80686c

17) Zoltewicz, J.A.; Dill, C.D.; Abboud, K.A. J. Org. Chem. 1997, 62, 6760

18) Seeman, J. Synthesis 1977, 498; Chem. Abstr. 87, 151934e

19) Zoretic, P.A.; Branchaud,B.; Sinha, N.D. J. Org. Chem. 1977, 42, 3201; Chem. Abstr. 87, 151923a

20) Leed, A.R.; Boettger, S.D.; Ganem, B. J. Org. Chem. 1980, 45, 1098; Chem. Abstr. 92, 198143q

21) Alberola, A.; Gonzalez,A.M.; Laguna, M.A.; Pulido, F. J. Synthesis 1982, 1067; Chem. Abstr. 98, 179256m

22) Hori, M.; Kataoka, T.; Shimizu, H.; Imai, Y. Fujimura, H. Yakugaku Zasshi 1975, 95, 634; Chem. Abstr. 83, 193149a

23) Calrke, G.M.; Sykes, P. J. Chem. Soc. (C) 1967, 1269; Chem. Abstr. 67, 72972z

24) Oehl, R.; Lenzer, G.; Rosenmund, P. Chem. Ber. 1976, 109, 705; Chem. Abstr. 84, 121687x

25) Hung. Teljes 27,692 1983; Chem. Abstr. 100, 192140y 26) Walker, G.N. J. Org. Chem. 1961, 26,2740; Chem. Abstr.

55, 27301I 27) Degani, I; Fichi, R J. Chem. Soc., Perkin Trans 1 1976,

323; Chem. Abstr. 84, 121361m 28) Safieddine, A.; Royer,J.; Dreux, J. Bull. Soc. Chim. Fr.

1972, 2510; Chem. Abstr. 77, 151294q 29) Muljiani, Z; Talik, B.D. Indian J. Chem. 1969, 7, 28;

Chem. Abstr. 70, 87449v 30) Iddon, B.; Suschitzky, H.; Taylor, D.S.; Chippendale, K.E.

J. Chem. Soc., Perkin Trans 1 1974, 2500; Chem. Abstr. 82, 111966g

31) Borch, R.F. J. Org. Chem. 1969, 34, 627; Chem. Abstr. 70, 106088v

32) Poliaszek, R.P.; Kaufman, C.R. J. Am. Chem. Soc. 1989, 111, 4849

33) Sassaman, Tetrahedron, 1996, 52, 10835 34) Pewarson, W.; Fang, W.K. J. Org. Chem. 1995, 60, 4960;

Chem. Abstr. 123 313721



113

35) Gupton, J.T., Layman, W.J. J. Org. Chem. 1987, 52, 3683

36) Roberts, D.; Jopule, J.A.; Bos, M.A.; Alvarez, M. J. Org. Chem. 1997, 62, 568


114

E. Miscellaneous Organic Reductions


CARBONIUM IONS Alembic: 6 A variety of carbonium ions (R3C+) including aryl carbonium (1-6). Cyclopropenium (7-10), vinyl carbonium (>C=C-R2) (11-13) and heteroatoms stabilized carbonium ions (14-18) have been reduced with sodium borohydride to the parent hydrocarbons (R3CH):

(C6H5)3C+Cl- + NaBH4 (C6H5)3CH

NaBH4C+

R' R

H ClO4-

C

R' R

HH

"R CH

H+C

R

R'

"R CH

CR

R' H HNaBH4

This reduction has been useful for preparation of specific pharmacologically interesting molecules

(including several cyclopropenyl derivatives) (7-14) as well as the synthesis of specific isotopically labeled compounds:

NaBT4C+

R' R

H ClO4-

C

R' R

HT

Via reduction of carbonium ion intermediates, several workers have been able to trap these intermediates thus substantiating specific reaction paths (11). In systems where other nucleophiles are absent, intensely colored carbonium ions such as malachite green (2) and crystal violet (19) are rapidly reduced allowing their use for determination of low concentrations of sodium borohydride. References: 1) Olkah, G.A. Svobada, J.J. J. Am. Chem. Soc. 1973, 95,

3794; Chem. Abstr. 97, 31150j 2) Bunton, C.A.; Huang, S.K.; Paik, C.H. J. Am. Chem. Soc.

1975, 97, 6262; Chem. Abstr. 83, 192173s 3) Bunton, C.A.; Huang, S.K.; Paik, C.H Tetrahedron Lett.

1976, 1445; Chem. Abstr. 85, 108063s 4) Gribble, G.W.; Leese, R.M.; Evan, B.E. Synthesis 1977,

172; Chem. Abstr. 86, 170986u



115

5) Fry, A.J. et. al. Tetrahedron Lett. 1976, 4803; Chem. Abstr. 87, 5056d

6) Buton, C.A.; Carrasco, N. Watts, W.E. J. Chem. Soc., Chem. Commun. 1977, 529; Chem. Abstr. 87, 200400p

7) U.S. 3,654,324 1972; Chem. Abstr. 76, 153229a 8) Pawlowski, N.E.; Lee D.J.; Sinnhuber, R.O. J. Org.

Chem. 1972, 37, 3245; Chem. Abstr. 77, 164069 9) U.S. 3,699,146 1972; Chem. Abstr. 78, 57859b 10) Mata-Segreda, K.J.F.; Schowen, R.L. J. Org.

Chem. 1981, 46, 644; Chem. Abstr. 94, 833332z 11) Wigfield, D.C.; Feiner, S.; Taymaz, K. Tetrahedron

Lett. 1972, 895; Chem. Abstr. 76, 126140h 12) Hrazdina, G. Phytochemistry 1972, 11, 3491;

Chem. Abstr. 78, 43208b 13) Creary, X. J. Org. Chem. 1976, 41, 3734; Chem.

Abstr. 85, 176498n 14) Greenberg, S.; Moffatt, J.G. J. Am. Chem. Soc.

1973, 95, 4016; Chem. Abstr. 79, 42796a 15) Wudl, F. et. al. J. Org. Chem. 1974, 39, 3608;

Chem. Abstr. 82, 16720po 16) Stahl, I. Chem. Ber. 1985, 118, 3166; Chem. Abstr.

103, 215243n 17) Hirai, K.; Sugimoto, H.; Ishiba, T. J. Org. Chem.

1977, 42, 1543; Chem. Abstr. 86, 188865p

18) Tobia, D.; Rickborn, B. J. Org. Chem. 1986, 51, 3849; Chem. Abstr. 105, 208214s

19) Rudie, C.N.; Demko, P.R. J. Am. Oil Chem. Soc. 1979, 56, 520; Chem. Abstr. 90, 214801u



116

REDUCTIVE CLEAVAGES


Sodium borohydride reductive cleavages or hydride displacements, are known in several classes of compounds. The most commonly employed reaction involves the reductive cleavage of N, N’- N,O-, O,O’-, N,S- linked alkylidene compounds:

NaBH4

X Y

R' R" R' R"

X or Y

X HEtOH

= NR2, OR, SR

NaBH4

N

N N

N

N

NH

R

O

H2N

OH

H

N

N N

N

NCH3

NH

R

O

H2N

OH

H

H(2)

HO N HO HNaBH4

(3)

Reductive cleavage of one of the two alkylidene carbonheteroatom bonds is generally effected in this reduction. In many of the examples reported, the functional groups containing the heteroatoms are part of the same molecule (1), allowing for ring opening under mild conditions, so as not to effect other functional groups in the compound.

Reductive cleavages of imides (4-6) and decyanation (7,8) have been reported:

NHR

O

O

O

O OR

O

NH2NaBH4 (5)


117

References: 1) Shimizu, K.; Ito, K.; Sekiya, M. Chem. Pharm. Bull. 1974,

22, 1256; Chem. Abstr. 81, 120403c PhN

CNPh

N

H

NaBH4 (7)

2) U.S. 3,983,118 1976 3) U.S. 3,714,186 1973; Chem. Asbstr. 82, 170620m

4) Rautio, M. Farm. Aikak. 1974, 83, 131; Chem. Abstr. 82, 170620m Reductive cleavage with NaBH4 is a commonly used

method in the study of glycoproteins and related compounds (9,12). IT has frequently been applied to ring opening reactions of barituric acids (13,14), furans (15,16), pyrans (17), oxazines (18), benzothiazoles (19) and cyclic α-nitroketones (20). It also finds uses in cleaving side chains of azeidine compounds (21,22).

5) Parker, W.L.; Johnson, F. J. Org. Chem. 1973, 38, 2489; Chem. Abstr. 79, 53201d

6) Jpn. Kokai Tokkyo Koho 84, 161,3445 1984; Chem. Abstr. 102, 149102s

7) Jpn. 74 19,243 1974; Chem. Abstr. 82, 97816z 8) Takahashi, K.; Kurita, H.; Ogura, K.; Ida, H. J. Org.

Chem. 1985, 50, 4368; Chem.Abstr. 103, 178145j Cyanoborohydride has been used to reductively cleave N-O bonds (23) , while lithium borohydride (24) and sodium borohydride (25) have been used to cleave C-N bonds in high yields. Silicon oxygen bonds have been reductively cleaved with tetrabutyl ammonium borohydride (26) and C-O have been reduced to a methyl and hydoxy group with sodium borohydride. (27)

9) Liao, M.J.; Huang, K.S.; Khorana, H.G. J. Biol. Chem. 1984, 259, 4200; Chem. Abstr. 100, 187575h

10) Sahimamura, M.; Inoue, Y., S. Arch. Biochem.. Biophys. 1984, 232, 699; Chem. Abstr. 101, 106875h

11) Ud-Din, N.; Jeanloz, R.W. et. al. J. Biol. Chem. 1986, 261, 1992; Chem. Abstr. 104, 166504h

12) Mawhinney, T.P. J. Chromatog. 1986, 351, 91; Chem. Abstr. 104, 65133f Sulfur Nitrogen bounds have been reductively

cleaved to form amine and thioketone groups. (28) 13) Rautio, M. Acta Chem. Scand. Ser. B. 1979, B33, 770; Chem. Abstr. 93, 71685h

14) Rautio, M.; Heeso, A.; Rahkamaa, E. Arch. Pharm. (weinheim) 1981, 314, 622; Chem. Abstr. 95, 114299w




118

15) Jpn. Kokai Tokkyo Koho 79,109,972 1979; Chem. Abstr. 92, 164251h

16) Eur. Pat. Appl. 153, 890 1985; Chem. Abstr. 104, 224716s

17) U.S. 4,199,515 1980; Chem. Abstr. 93, 95129f 18) Marco, J.L. Royer, J.; Husson, H.P. Tetrahedron

Lett. 1985, 26, 6345; Chem. Abstr. 105, 78464k 19) Liso, G.; Trapani, G.; Reho, A.; Latofa, A.

Synthesis 1985, 288; Chem. Abstr. 104, 88471d 20) U.S. 4,554,387 1985; Chem.Abstr. 104, 185986h 21) Eur. Pat. Appl. 62,876 1982; Chem. Abstr. 98,

107072e 22) Ger. Offen. 3,229,439 1983; Chem. Abstr. 99,

5435z 23) Wade, P.A.; Tao, J.A.; Bereznak, J.F.; Yuan, C.K.

Tetrahedron Lett. 1989, 30, 5969 24) Gupta, R.B.; Franck, R.W. J. Am. Chem. Soc. 1989,

111, 7668 25) Barluenga, J.; Kouznetsov, V.; Rubio, E.; Tomas,

M. Tetrahedron Lett. 1993, 34, 1981 26) Micouin, L.; Quirion, J.C.; Husson, H.P.

Tetrahedron Lett. 1996, 37, 849 27) Firouzabadi, H.; Afsharifar, G.R Synth. Commun.

1996, 26, 1065 28) Kim, H.K..; Lee, Y.Y.; Kim, K.; Kim, J.H. Bull.

Korean Chem. Soc. 1994, 15, 273

Roh


119

REDUCTIVE CYCLIZATION Several interesting reductive cyclization involving sodium borohydride have been reported. For instance, NaBH4 reduction of beta and gamma keto (aldehydro) esters (or acids) yields lactone derivatives in good yields (1-8):


R

O

O

OH

O OR

NaBH4

Reduction of aromatic beta and gamma keto acids leads directly to lactone formation (9-12).

R

OH

O

O

R'

"R

O

O

R

R'

"R

NaBH4

Similarly, quinazoline derivatives, many showing anti-inflammatory and analgesic activities,

have been prepared by NaBH4 reductive cyclization of imines (13-16).

N

NR'

R"

H

O N

N

R"

H

O

R'

CCl3

NaBH4

In contrast to the above, where only sodium borohydride was employed to effect the reductive cyclization, Coutts has used NaBH4 catalyzed by palladized charcoal to prepare heterocyclic hydroamic acids, such as quinolones and hydroxyquinolones (17,18) from o-nitro esters,

NO2

CN N

CN

O

H

N

CN

O

OH

CO2Et

NaBH4

Pd/C


120

and bezothiazine hydroamic acids and their lactams from a-(o-nitrophenylthio) esters, acids and cinnamates (19-21)


NO2

S R'

N

S R"

O

OH

CO2R

NaBH4

"R

R'

Pd/C

Recent publications include reductive

cyclization of gamma imino compounds (22,23) photocatalyzed NaBH4 cyclizations (24-27) and even cyclization to form epoxides (28,29)

Organic compounds containing alkenes and halides, tin trichlorides or hydrazones are reductively cyclized with sodium borohydride or cyanoborohydride to from cyclic hydrocarbons. (30,31,32 ) Cyclic amines can be formed by the reductive amination/cyclization of ketones with amines or azides with borohydrides.(33,34) The five membered rings contained in Protocin C and D can be synthesized the same methodology. (35). It has been demonstrated that imines and O-mesty groups can be reductively cycilized to form cyclic amines in high yields with NaBH in MeOH (36). Other functional groups that have been

used to form cyclic amines are amides and aldehydes. (37,38). References: 1) Brownbridge, P.; Warren, S. J. Chem. Soc., Chem.

Commun. 1977, 465; Chem. Abstr. 88, 37213q 2) U.S. 4,031,113 1977; Chem. Abstr. 87, 135031c 3) Spry, D.O. J. Org. Chem. 1975, 40, 2411; Chem. Abstr.

83, 97171f 4) Jpn. Kokai Tokkyo Koho 83 13,572 1983; Chem. Abstr.

99, 38365e 5) Bates, H.A.; Deng, P-N. J. Org. Chem. 1983, 48, 4479;

Chem. Abstr. 99, 212331c 6) Jpn. Kokai Tokkyo Koho 83, 154,572 1983; Chem. Abstr.

100, 66612r 7) Rao, A.V.R.; Sreenivasan, N.; Reddy, D.R.; Deshpande,

V.H. Tetrahedron Lett. 1987, 27, 455 8) Lange, G.L.; Organ, M.G. J. Org. Chem. 1996, 61, 5358 9) Meyer , W.L.; Vaughn, W.R. J. Org. Chem. 1957, 22, 98;

Chem. Abstr. 51, 11316g 10) Cava, M.P.; Van Meter, J. P. J. Org. Chem. 1969, 34, 538;

Chem. Abstr. 70, 106288k 11) Oren, J.; Schleifer, L.; Shmueli, U.; Fuchs, B.

Tetrahedron Lett. 1984, 25, 981; Chem. Abstr. 101, 37932k

12) Newman, M.S.; Dhawan, B.; Khanna, V.K. J. Org. Chem. 1986, 51, 1631; Chem. Abstr. 104, 206875p



121

13) Jpn. Kokai 72 14,183 1972; Chem. Abstr. 77, 140123g

14) Ger.Offen 2,166327 1973; Chem. Abstr. 84, 180271e

15) Walser, A. et. al. J. Org. Chem. 1978, 43, 936; Chem. Abstr. 88, 12122s

16) U.S. 3,895,032 1975; Chem. Abstr. 83, 193094d 17) Coutts, R.T.; Wibberley, D.G.; J. Chem. Soc. 1963,

4610; Chem. Abstr. 59, 12799e 18) Coutts, R.T. J. Chem. Soc. C 1969, 713; Chem.

Abstr. 70, 96351j 19) Coutts, R.T. et. al. Can. J. Chem. 1965, 43, 3221;

Chem. Abstr. 64, 5083b 20) Coutts, R.T. et. al. Can. J. Chem. 1966, 44, 1733;

Chem. Abstr. 65, 8810d 21) Coutts, R.T. et. al. Can. J. Chem. 1967, 45, 975;

Chem. Abstr. 67, 11467s 22) U.S. 4,229,455 1980; Chem. Abstr. 94, 156906b 23) Jpn. Kokai Tokkyo Koho 83 41,864 1983; Chem.

Abstr. 101, 91321y 24) Ninomyia, I.; Hashimoto, C.; Kiguchi, T.; Naito, T.

J. Chem. Soc., Perkin Trans. 1 1985, 941; Chem. Abstr. 103, 160747x

25) Jpn. Kokai Tokkyo Koho 84, 53, 485 1984; Chem. Abstr. 101, 91321y

26) Jpn. Kokai Tokkyo Koho 85 56,978 1985; Chem. Abstr. 103, 160753w

27) Naito, T.; Kojima, N.; Miyata, O.; Ninomiya, I. J. Chem. Soc., Chem. Commun. 1985, 1611; Chem. Abstr. 104, 225079y

28) Zhao, D.; Zhong, J. et. al. Yaoxue Xuebao 1982, 17, 28; Chem. Abstr. 96, 199248x

29) Ger. Offen. 3,426,906 1986; Chem. Abstr. 105, 97473d 30) Stork, G.; Sher, P.M. J. Am. Chem. Soc. 1986, 108, 303 31) Hanessian, S.; Leger, R. J. Am. Chem. Soc. 1992, 114,

3115 32) Taber, D.F.; Wang, Y.; Stachel, S.J. Tetrahedron Lett.

1993, 34, 6209 33) Manescalchi, F.; Nardi, A.R.; Savoia, D. Tetrahedron

Lett. 1994, 35, 2775 34) McClure, C.K.; Mishra, P.K.; Grote, C.W. J. Org. Chem.

1997, 62, 2437 35) Heathcock, C.H.; Brown, R.C.D.; Norman, T.C. J. Org.

Chem. 1998, 63, 5013 36) Aelterman, W.; De Kiompe, N.; Declercg, J. Org. Chem.

1998, 63, 6 37) Wang, X.; De Silva, S.O.; Reed, J.N.; Billadeau, R.;

Griffen, E.J.; Chan, A.; Snieckus, V. Org. Synth. 1993, 72, 163

38) Dinsmore, C.J.; Ingman, J.M. J. Org. Chem. 1998, 63, 4131



122

DEHALOGENANTIONS Alembic: 9, 52, 55, 61 Under normal reaction conditions, alkyl and aryl halides are inert to NaBH4. Under solvolytic conditions, however, secondary and tertiary alkyl halides which are capable of forming stable carbonium ions are reducible to the corresponding hydrocarbon (1-3). Good to excellent yields are reported in dehalogenantion of bezhydril chloride to diphenyl methane, t-cumyl chloride to cumene and triphenyl methyl chloride to triphenylmethane. (See also section on carbonium ion reductions.) In addition, several authors have reported dehalogenantion of gem-dihalo compounds with sodium borohydride (4,5). New developments in the catalyzed NaBH4 reduction of halo compounds have broaden the applicability of this reaction.(6-8) Photo-catalyzed reduction of halogenated aromatic hydrocarbons has been reported (9-11). Inorganic catalysts such as palladium chloride or nickel chloride (in situ nickel boride) have proven effective for site specific deuteration of aryl halides (12,13), for dechlorination of various pesticides and PCB’s (14-17) and for analytical determination of organic solids bound halides (18,19).

Dicyclopentadienyltitanium dichloride has also been used to catalyze NaBH4 dehalogenantions (20). The combination of triakly tin halides with NaBH4, in which the dehaolganting agent is R3SnH has been used to advantage (21-23). Other main group alkyl reagents can catalytically dehalogenate aromatic and aliphatic halides with sodium borohydride. (24) Tetrabutylamonnium borohydride can reduce aromatic and aliphatic halogenated compounds in THF in high yields. (25). PCB’s can be reduced in diglyme at elevated temperatures with NaBH4 or NaBH4 and LiCl (26). LiBH4 can dehalogenate both aromatic and aliphatic halides chemoselectively. (27)

Alkyl halides are reduced with borohydride exchange resins spiked with Ni(OAc)2 at room temperature.(28) Zinc cyanoborohydride can dehalogenate both aromatic and aliphatic halides at the reflux temperature of methanol. (29)

γ-Lindene and α-chlorotolulene can be completely dehalogenated with NaBH2(OCH2CH2OCH3)2 at elevated temperatures. (30) The addition of transition metal chlorides to the above stated reagent such as PdCl2 and NiCl2 have dehalogenated chlorophenols and chlorobenzenes. (31) Other alkoxy borohydrides have declorinated PCB’s at the reflux temperature of THF (32) Recent applications include the preparation of tritium labeled retinoic acid (33) CNS-active 2,3-dihydroergolines (34) and triabicycloheptane substituted prostaglandin



123

analogues (35), which are cardiovascular agents useful in treating thrombotic disease. Allylic chlorides have been dechlorinated with sodium borohydride to form bucky ball type structures. (36) References: 1) Brown, H.C.; Bell, H.M.; J. Org. Chem. 1962, 27,

1928; Chem. Abstr. 57, 12353g 2) Bell, H.M.; Brown, H.C. J. Am. Chem. Soc. 1966,

88, 1473; Chem. Abstr. 64, 15695c 3) St. Clair, T.L.; Diss Abstr. Int. B 1972, 33, 200;

Chem. Abstr. 78, 57424f 4) Groves, J.T.; MA. K.W. J. Am. Chem. Soc.; 1974,

96, 6527; Chem. Abstr. 81, 151239h 5) Levitin, I.Y.; Dvoletski, M.; Volpin, M.E. Kinet.

Katal. 1972, 13, 690; Chem. Abstr. 77, 100449m 6) Schwartz, J.; Liu, Y.; J. Org. Chem. 1994, 59, 940 7) Schwartz, J.; Liu, Y. Tetrahedron 1995, 51, 4471 8) Cavallaro, C.L.; Liu, Y.; Schwartz, J.; Smith, P.

New J. Chem. 1996, 20, 253 9) Barltrop, J.A.; Bradbury, D. J. Am. Chem. Soc.

1973, 95, 5086; Chem. Abstr. 79, 85589c 10) Tsuijmoto, K.; Tasaka, S.; Ohashi, M. J. Chem.

Soc., Chem. Commun. 1975, 758; Chem. Abstr. 83, 192246t

11) Abeywickrema, A.N.; Beckewith, A.L. J. Tetrahedron Lett. 1986, 27, 109; Chem. Abstr. 105, 171926x

12) Bosin, T.R.; Raymond, M.G.; Buckpitt, A.R.; Tetrahedron Lett. 1973, 4699; Chem. Abstr. 80, 120462a

13) Stiles, M. J. Org. Chem. 1994, 59, 5381 14) Dennis, W.H.; Cooper, W. J. Bull. Environ. Contam.

Toxicol. 1975, 14, 738; Chem. Abstr. 84, 100851f 15) Dennis, W.H.; Cooper, W. J. Bull. Environ. Contam.

Tpoxicaol. 1976, 16, 425; Chem. Abstr. 86, 66792s 16) U.S. Pat. Appl. 794,928 1986; Chem. Abstr. 104,229975k 17) Kozloski, R.J. J. Chromatr. 1985, 318, 211; Chem. Abstr.

102, 124849c 18) Lassova, L.; Lee, H.K.; Hor, T.S.A. J. Org. Chem. 1998,

63, 3538 18) Egil, R.A. Helv. Chim. Acta 1968, 51, 2090; Chem. Abstr.

70, 28501h 19) Egli, R.A. Z. Anal. Chem. 1969, 247, 39; Chem. Abstr. 71,

131377s 20) Meunier, B. J. Organomet. Chem. 1980, 204, 345; Chem.

Abstr. 94, 191816u 21) Parnes, H.; Pease, J. J. Porg. Chem. 1979, 44, 151; Chem.

Abstr. 90, 55156u 22) Corey, E.J.; Marfat, A.; Hoover, D. J. Tetrahedron Lett.

1981, 22, 1587; Chem. Abstr. 95, 114733h



124

23) Gurjar, M.K.; Yadav, J.S.; Rama Rao, A.V. Indian J. Chem. Sect. B 1983, 22b, 1139; Chem. Abstr. 101, 91377w

24) Nakamura, T.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 1999, 1415

25) Narasimhan, S.; Swamalakshmi, S.; Balakumar, R.; Velmathi, S. Synth. Commun. 1999, 29, 685

26) Yang, C.; Pittman, C.U. Tetrahedron Lett. 1997, 38, 6561

27) Cho, B.T.; Yoon, N.M. J. Korean Chem. Soc. 1983, 27, 46

28) Yoon, N.M.; Lee, H.J.; Ahn, J.H.; Choi, J. J. Org. Chem. 1994, 59, 4687

29) Kim, S.; Kim, Y.J.; Ahn, K.H. Tetrahedron Lett. 1983, 24, 3369

30) Tabaei, S.M.H.; Pittman, C.U. Haz. Waste Haz. Mater. 1993, 10, 431

31) Tabaei, S.M.H.; Pittman, C.U. Tetrahedron Lett. 1993, 34, 3263

32) Tabaei, S.M.H.; Pittman, C.U.; Mead, K.T. J. Org. Chem. 1992, 57, 6669

33) Ger Offen. 3,142,975 1983; Chem. Abstr. 99, 71034u

34) Ger Offen. 3,411,981 1985; Chem. Abstr. 105, 43137d

33) U.S. 4,588,742 1986; Chem. Abstr. 105, 78746d

34) Zhang, H.R.; Wang, K.K. J. Org. Chem. 1999, 64, 7996

Roh


125

DEMERCURATIONS The oxymercuration of olefinic bonds, followed by reductive demercuartion with sodium borohydride, is an extremely efficient method for the stereoselective, high yield Markownikov hydration of olefins: (1)


R CH2

Hg(OAc)2

THF/H2OR

HgOAc

OHNaBH4

NaOHR

H

OH

HH

This procedure originally developed by H.C. Brown et. al. (2) has been the subject of two review articles (3,4). The mechanism (5-8) and stereochemical implication (9-12) of this reaction have been investigated extensively. From extensions of this basic reaction, new synthetic methods have been developed to provide alkylation (13-16) and cyclization (17-20) reactions, peroxymercuration (21,22), aminomercuration (23-25) and azidomercuration (26). Phase transfer catalysis (27-28) and micelle mediation (29-30) have been applied to oxymercuration demercuration reactions. Demercuration with NaBH4 has found practical applications in the synthesis of juvenile hormones (31-

33), prostaglandin derivatives (19, 20,34,35), porphyrins (36,37) and avermectins (38). References: 1) Russell, G.A.; Jiang, W.; Hu, S.S.; Khanna. R.K. J. Org.

Chem. 1986, 51, 5499 2) Brown, H.C.; Geoghegan, P. J. Am. Chem. Soc. 1967, 89,

1522; Chem. Abstr. 67, 99540u 3) Lorock, C. Angew. Chem. Int. Ed. Engl. 1978, 17, 27 4) Seyferth, D. Organomet. Chem. Rev., Sec. B, Ann. Rev.

1971, 8, 425; Chem. Abstr. 76, 59682w 5) Quirk, R.P.; Lea, R.E. J. Am. Chem. Soc. 1976, 98, 5973;

Chem. Abstr. 85, 191940u 6) Pasto, D.J.; Gontarz, J. A. J. Am. Chem. Soc. 1971, 93,

6902; Chem. Abstr. 76, 33692z 7) Pasto, D.J.; Gontarz, J. A. J. Am. Chem. Soc. 1969, 91,

719; Chem. Abstr. 70, 67337d 8) Giese, B.; Kretzschmar, G. Chem. Ber. 1984, 117, 3175;

Chem. Abstr. 102, 61581m 9) Jasseerand, D. et. al. Tetrahedron 1976, 32, 1535; Chem.

Abstr. 86, 43091y 10) Kitching, W.; Atkins, A.R.; Wickham, G.; Albert, V. J.

Org. Chem. 1981, 46, 563; Chem. Abstr. 94, 83505h 11) Harding, K.E.; Marman, T.H. J. Org. Chem. 1984, 49,

2838; Chem. Abstr. 101, 72865n



126

12) Gouzoules, F.H.; Whitney, R.A. J. Org. Chem. 1986, 51, 2024

13) Giese, B.; Meister, J. Chem. Ber. 1977, 110, 2588; Chem. Abstr. 87, 133845x

14) Henning, R.; Uraback, H. Tetrahedron Lett. 1983, 24, 5343; Chem. Abstr. 100, 139572q

15) Barluenga, J.; Campos, P.J.; Lopez-Padro, J.; Asensio, G. Synthesis 1985, 1985, 1125; Chem. Abstr. 105, 171935z

16) Bellec, N.; Guillemin, J.C. Tetrahedron Lett. 1995, 36, 6883 17) Harding, K.E.; Burks, S.R. J. Org. Chem. 1981, 46,

3920; Chem. Abstr. 95,115183r 18) Carruthers, W.; Williams, M.J.; Cox, M.T. J. Chem.

Soc., Chem. Commun. 1984, 1235; Chem. Abstr. 102, 131883n

19) Jpn. Kokai Tokkyo Koho 84 10,577 1984; Chem. Abstr. 101, 90657a

20) Jpn. Kokai9 Tokkyo Koho 85, 243,079 1985; Chem. Abstr. 104, 207038e

21) Bloodworth, A.J.; Courtneidge, J.L. J. Chem. Soc., Perkin Trans. 1 1982, 1807; Chem. Abstr. 97, 198305x

22) Corey, E.J.; Schmidt, G.; Shimoji, K. Tetrahedron Lett. 1983, 24, 3169; Chem. Abstr. 100, 34340j

23) Barluenga, J.; Perez-Prieto, J. Bayon, A.M.; Asensio, G. Tetrahedron 1984, 40, 1199; Chem. Abstr. 101, 171056f

24) Davtyan, S.Z.; Badanyan, S.O. Arm. Khim. Zh. 1983, 36, 508; Chem. Abstr. 100, 67447c

25) Roubaud,V.; Le Moigne, F.E.; Mercier, A.; Mordo, P. Synth. Commun. 1996, 26, 1507

26) Grunewald, G.L.; Bartlett, W.J. et. al. J. Med. Chem. 1986, 29, 1972; Chem. Abstr. 105, 225990j

27) Rolla, F. J. Org. Chem. 1981, 46, 3909; Chem. Abstr. 95, 114927z

28) Barluenga, J.; Lopez-Prado, J.; Campos, P.J.; Asensio G. Tetrahedron 1983, 39, 2863; Chem. Abstr. 100, 68122e

29) Link, C.M.; Jansen, D.K.; Sukenik, C.N. J. Am. Chem. Soc. 1980, 102, 7798; Chem. Abstr. 94, 30237r

30) Sutter, J.K.; Sukenik, C.N. J. Org. Chem. 1984, 49, 1295; Chem. Abstr. 100, 138928y

31) U.S. 3,923,868 1975; Chem. Abstr. 84, 58672w 32) Camps, F.; Coll, J.; Seba, M.E. An. Quim. 1979, 75, 401;

Chem. Abstr. 91, 210947u 33) Tolstikov, G.A.; Rozenstsvet, O.A. Izv, Akad. Nauk SSSR,

Ser. Khim. 1984, 816; Chem. Abstr. 101, 170676w 34) Corey, E.J.; Kewck, G.E.; Szekely, I J. Am. Chem. Soc.

1977, 99, 2006; Chem. Abstr. 86, 189264d 35) Suzuki, M.; Yanagisawa,A.; Noyori, R. Tetrahedron Lett.

1983, 24, 1187; Chem. Abstr. 99, 70430h



127

36) Smith, K.M.; Langry, K.C. J. Org. Chem. 1983, 48, 500; Chem. Abstr. 98, 89036k

37) Smith, K.M.; Langry, K.C.; Minnetian, O.M. J. Org. Chem. 1984, 49, 4602; Chem. Abstr. 101, 230212d

38) U.S. 4,423,209 1983; Chem. Abstr. 100, 175208j



128

DOUBLE BONDS

N

N

N

R

R'

R"

N

N

N

R

R'

R"

NaBH4

(17)

Olefinic bonds are reducible by sodium borohydride only when activated. Any functional group which sufficiently polarizes the double bond can activate this group for borohydride reduction. Several classes of activated double bonds have been reported including: α−β unsaturated nitriles (1-4), aldehydes, ketones (5), nitro (6,8), esters (9-11) and lactones (12,13): carbon-carbon double bonds alpha to an aryl ring (14,15); unsaturated amines (e.g. enamines 16-21). Several examples where activated double bonds have been reduced are shown below:

O

O

O

OO

AcO

O

O

O

OO

AcO

NaBH4

(20)

NaBH4

NMe

HN

NMe

HN

(16)

HC

OCO2R

O2N C

OCO2R

O2NH H

NaBH4 (22)


Roh

m and Haas : the Sodium Borohydr press <CTRL>-F for Searching ide Digest


129

O

OH

HO

O

O

OH

HHO

NaBH4

(23) OH

RNaBH4

hυOH

R

OH

R

Catalyzed NaBH4 reduction of acetylenes to olefins

has also been reported (27-29). This type of reaction is used to convert a dihydropyridine to the tetrahydro from in the manufacture of the substituted benzazocines (24) which are used as analgesic agents.

Metal salt such as BiCl3, Cu2+, NiCl2 and CoCl2 have been used to modify the reactivity of sodium borohydride so that it can easily reduce olefins to alkanes. (30-35).

Several authors have recently reported the use of sodium borohydride for reduction of photo excited aromatic compounds (25,26):

The use of low molecular weight alcohols and acetic acids with sodium borohydride to promote the reduction of alkenes to alkanes has been demonstrated. (36-38)

Zinc borohydride has been shown to reduce primary nitroalkenes to nitroalkanes while converting disubstituted nitroalkenes to oximes. (39,40) Borohydride exchange resins in MeOH at RT have reduced α−β unsaturated nitroalkenes to nitroalkanes in high yields. (41). CuSO4 and borohydride exchange resins in MeOH at RT reduces α−β unsaturated esters, amides, and cyanides to their corresponding alkane.(42) Nickel chloride



130

and borohydride exchange resins can reduce electron deficient alkenes to alkanes in high yields.(43) Zinc borohydride supported on aluminophosphates have hydrogenated both aromatic alkenes and alkynes. (44) Selective reduction of terminal over substituted alkenes has been accomplished using calcium borohydride and MeOH in THF at reflux temperatures. (45) The use of borane generated in situ using sodium borohydride and I2 at 0o C has been shown to reduce α−β keto alkenes to alkanes. (46) References: 1) Pepin, Y.; Nazemi, H.; Payette, D. Can. J. Chem.

1978, 56, 41; Chem. Abstr. 89, 41994h 2) Toda, F.; Kanno, M. Bull. Chem. Soc. Jpn. 1976,

49, 2643; Chem. Abstr. 86, 55130y 3) Jung, M.E.; Lam, P.; Mansuri, M.M.; Speltz, L.M.

J. Org. Chem. 1985, 50, 1087; Chem. Abstr. 102, 148972p

4) Vartanyan, R.S.; Shaginyan, R.S. et. al. Arm. Khim. Zh. 1985, 38, 304; Chem. Abstr. 105, 78803v

5) Formasier, R.; Lucchini, V.; Scrimin, P.; Tonellato, U. J. Org. Chem. 1986, 51, 1769; Chem.Abstr. 104, 206747y

6) Backman, G.B.; Maleski, R.J. J. Org. Chem. 1972, 37, 2810; Chem. Abstr. 104, 206747y

7) Varma, R.S.; Kabalka, G.W. Synth. Commun. 1985, 15, 151; Chem. Abstr. 103, 53338t

8) Bhattacharjya, A.; Mukhopasdhyay, R.; Pakrashi,S.C. Synthesis 1985, 886; Chem. Abstr. 015, 42400x

9) Setoi, H.; Takeno, H.; Hashimoto, M. J. Org. Chem. 1985, 50, 3948; Chem. Abstr. 103, 1607842s

10) Wiunterfeldt, E.; Freund, R. Liebigs Ann. Chem. 1986, 1262; Chem. Abstr. 105, 60796k

11) Eur. Pat. Appl. 156,261 1985; Chem. Abstr. 104, 148757p 12) Chhowdhury, P.K.; Barua, N.C. et. al. J. Org. Chem.

1983, 48, 732; Chem. Abstr. 98, 143670c 13) El-Feraly, F.; Benigni, D.A.; McPhail, A.T. J. Chem. Soc.,

Perkin Trans 1 1983, 355; Chem. Abstr. 98, 215814c 14) Dauzonne, D.; Royer, R. Synthesis 1984, 1054; Chem.

Abstr. 103, 5956w 15) Kametani, T.; Yukawa, H.; Suzuki, Y.; Honda, T. J.

Chem. Soc., Perkin Trams. 1 1985, 2151; Chem. Abstr. 104,186682t

16) Kudo, T.; Nose, A.; Yakugaku Zasshiu 1974, 94, 1475; Chem. Abstr. 82, 125255m

17) Swiss 593,965 1977; Chem. Abstr. 88, 105181e 18) Bata, I.; Heja, G.; Kiss, P.; Korbonits, D. J. Chem. Soc.,

Perkin Trans 1 1986, 9; Chem. Abstr. 105, 225559a 19) Eur. Pat. Appl. 80,847 1983; Chem. Abstr. 99, 1094979p



131

20) U.S. 3,641,005 1972; Chem. Abstr. 76, 141213c 21) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T.

J. Org. Chem. 1999, 64, 4914 22) Chandrasekaran, S.; Kluge, A.F.; Edwards, J.A. J.

Org. Chem. 1977, 42, 3972; Chem. Abstr. 88, 6819n

23) Chan, W.R.; Gibbs, J.A.; Taylor, D.R. J. Chem. Soc., Perkin Trans. 1 1973, 1047; Chem. Abstr. 79, 18886j

24) U.S. 3,250,678 1966; Chem. Abstr. 65, 7157g 25) Bradbury, D.; Barltrop, J. J. Chem. Soc. Chem.

Commun. 1975, 842; Chem. Abstr. 84, 42863y 26) Nishiki, M.; Miyataka, H. et. al. Tetrahedron Lett.

1982, 23, 193; Chem. Abstr. 96, 217296t 27) Suzuki, N.; Tsukanaka, T. et. al. J. Chem. Soc.,

Chem. Commun. 1983, 515; Chem. Abstr. 99, 157759w

28) Kijuma, M.; Nambu, Y.; Endo, T. Chem. Lett. 1985, 1851; Chem. Abstr. 105, 114651e

29) Jpn. Kokai Tokkyo Koho 84 33,300 1984; Chem. Abstr. 101, 111269t

30) Narasimhan, S.; Prasad, K.G.; Madhavan, S. Tetrahedron Lett. 1995, 36, 1141

31) Cowan, J.A. Tetrahedron Lett. 1986, 27, 1205

32) Roush, W.R.; Kageyama, M.; Riva, R.; Brown, B.B.; Warmus, J.S. Moriarty, K.J. J. Org. Chem. 1991, 56, 1192

33) Ihara, M; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1990, 55, 4497

34) Dondoni, A.; Perrone, D.; Semola, M.T. J. Org. Chem. 1995, 60, 7929

35) Morimoto, Y.; Iwahashi, M. Synlett 1995, 1221 36) Varma, R.S.; Kabalka, G.W. Synth. Commun. 1985, 15,

151 37) Hanessian, S.; Roy P.J.; Petrini, M.; Hodges, P.J.; Di

Fabio, R.; Carganico, G. J. Org. Chem. 1990, 55, 5766 38) Rao, C.S.; Chakrasali, R.T.; Ila, H.; Junjappa, H.

Tetrahedron 1990, 46, 2195 39) Ranu, B.C.; Chakraborty, R. Tetrahedron 1992, 48, 5317 40) Ranu, B.C.; Chakraborty, R. Tetrahedron Lett. 1991, 32,

3579 41) Goudgaon, N.M.; Wadgaonkar, P.P.; Kabalka, G.W.

Synth. Commun. 1989, 19, 805 42) Sim, T.B.; Yoon, N.M. Synlett 1995, 726 43) Sim, T.B.; Choi, J.; Joung, M.J.; Yoon, N.M. J. Org.

Chem. 1997, 62, 2357 44) Campelo, J.M.; Chakraborty, R.; Marinas, J.M. Synth.

Commun. 1996, 26, 1639 45) Narasimhan, S.; Prasad, K.G.; Madhavan, S. Tetrahedron

Lett. 1995, 36, 1141



132




133

EPOXIDES Alembic 48, 50, 55 Sodium borohydride is generally unreactive toward any epoxide groups and ahs been effectively to remove impurities in materials such as ethylene oxides (1), propylene oxide (2), and glycidylmethacrylate (3). However, some authors have reported the use of sodium borohydride for selective opening of strained or activated epoxides (4-8). In some instances it is not clear whether the borohydride ion BH4

- or an in situ generated derivative e.g. B(OR)3H- was actually responsible for the ring opening reaction. In sodium borohydride reduction of vicinal epoxy alcohols, only the trans epoxy alcohol and not the corresponding cis compound was reduced (9). This selective reactivity should be extremely useful in the synthesis of pharmaceutical compounds. The use of supported borohydride reagents has gained popularity in reducing many functional groups including epoxides. The use of zinc borohydride on zeolites, aluminophosphates and silica gel has been demonstrated to ring open epoxides. (10-12) Sodium borohydride in low molecular weight alcohols have been shown to reduce epoxy esters to

diols (13) and cyclic epoxides in diglyme to mono alcohols. (14) Reduction of epoxides with cyanoborohydride and BF3•Et2O in refluxing THF has been used to synthesis natural product compounds (15,16). Lithium borohydride with titanium tetraisopropoxide has reduced epoxides to alcohols. (17). Solid state reactions of lithium borohydride in hexane and epoxides have formed the corresponding alcohols in high yield (18). The reaction of NaBH4 and PhSeSePh has been used to ring open epoxide esters at RT (19). Cyclodextrin has been used to directionlize the ring opening of styrene oxides with sodium borohydride. (20) References: 1) U.S. 3,213,113 1965; Chem. Abstr. 64, 3482g 2) Ger. 1,144,704 1963; Chem. Abstr. 59, 6367d 3) Jpn 70 17,661 1970; Chem. Abstr. 73, 87776m 4) Stevens, C.L. et. al. J. Org. Chem. 1972, 37, 3130; Chem.

Abstr. 77, 151756p 5) Yoneta, T.; Matuno, T.; Nanahoshi, H.; Fukatsu, S. Chem.

Pharm. Bull. 1981, 29, 3469; Chem. Abstr. 96, 143219w 6) Soai, K.; Ookawa, A.; Oyamada, H.; Takase, M.

Heterocycles 1982, 19, 1371; Chem. Abstr. 97, 144694e



134

7) Steliou, K.; Poupart, M.A. J. Am. Chem. Soc. 1983, 105, 7130; Chem. Abstr. 99, 212319e

8) Falck, J.R.; Manna, S. et. al. Tetrahedron. Lett. 1983, 24, 5715; Chem. Abstr. 100, 138804e

9) Weissenbergf, M.; Krinsky, P.; Glotter, E. J. Chem. Soc., Perkin Trans 1 1978, 565; Chem. Abstr. 89, 147129v

10) Sreekumar, R.; Padmakumar, R.; Rugmini, P. Tetrahedron Lett. 1998, 39, 5151

11) Campelo, J.M.; Chakraborty, R.; Marinas, J.M. Synth. Commun. 1996, 26, 415

12) Ranu, B.C.; Das, A.R. J. Chem. Soc., Chem. Commun. 1990, 1334

13) Lanier, M.; Pastor, R. Tetrahedron Lett. 1995, 36, 2491

14) Huwe, C.M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621

15) Tone, H.; Nishi, T.; Oikawa, Y.; Hikota, M.; Yonemitsu, O. Tetrahedron Lett. 1987, 28, 4569

16) Taber, D.F.; Houze, J.B. J. Org. Chem. 1994, 59, 4004

17) Dai, L.X.; Lou, B.L.; Zhang, Y.Z.; Guo, G.Z. Tetrahedron Lett. 1986, 27, 4343

18) Sugita, K.; Onaka, M.; Izumi, Y. Tetrahedron Lett. 1990, 31, 7467

19) Miyashita, M, Hoshino, M.; Suzuki, T.; Yoshikoshi, A. Chem. Lett. 1988, 507

20) Ravichandran, R.; Divakar, S. J. Mol. Catal. A 1999, 137, 31


135

ORGANO CALCOGEN COMPOUNDS Alembic: 58 And to the resolution of racemic cyclic disulfides (17). The combination of sodium borohydride and NiCl2 or

CoCl2 has been demonstrated to desulfurize thiols, thioethers, sulfons and sulfonates in high yield. (18,19)

A number of workers have reported the reduction of organic disulfides to thiols (1-5) and of diselenides to the corresponding selenol (6) or organoselenides anions (7-9). This reduction has been developed into a method of disulfides analysis (10) since sulfides and mercaptans do not interfere (11), and has been used to measure naturally occurring urinary disulfides in cystinuric patients (12). NaBH4 has been used to distinguished organic polysulfides from disulfides (13); in addition to thiol formation, hydrogen sulfides is produced from polysulfides, but not from disulfides. Di and polysulfide reductions have been applied to the study of trypsinogens (14), the modification of sporidesmin-type antibiotics which contain the epithiodioxopiperazine system (I) common to a number of fungal metabolites (15), the preparation of rubber crosslinking agents (16),

Sodium borohydride has been demonstrated to have the ability to reduce sulfonyl chlorides to disulfides or completely remove the group with the addition of pyridine. (20-22) Borohydride exchange resins has been used to form symmetrical and unsymmetrical thioether from thiols or disulfides with organic halides in high yields. (23-25) While xanthates in general are not reduced (26), phenyl xanthates can be reduced to thiophenols (27).

R'SRO

O

R'HSNaBH4

A number of recent publications show the general applicability of NaBH4 to the reduction of cationic sulfur heterocycles (28) such as benzoxathiolium (II) (29) to the corresponding thiole,

N

NRSS

O

O

(1)


Roh



136

X= OX=

X

HS

R+NaBH4

X

SR

S

NMe

R1

R2

R3

R4

Benzodithiolium (III) (30) and thiopyrilium to the thiopyran (31).

SS+

NO2

SS

NO2

NaBH4

V R1=R2= OCH3; R3,R4=H R1=OCH3;R2=OH;R3=R4=H VI R1=R2= H; R3,R4= OCH3 R1;R2=H;R3=OH, R4=OCH3

Reduction of o-nitrophenylslenocyanate provides the arylselenium anion which was used in a synthetic sequence resulting in (a)-deoxyvernolepin (33). Aryl selenium anions produced by NaBH4

reduction are proving to be synthetically useful reagents. Sodium benzylselenolate, (IV) has been used for regioselective o-demethylation of aporphine alkaloids (32)

NO2

SeCN

NO2

Se-

NaBH4

High purity symmetrical diselenides has been

synthesized in excellent yield form both aliphatic and aromatic aldehydes (34) by NaBH4 reduction of a mixture of aldehyde, sodium hydrogen selenide and an amine catalyst such as piperidine or morpholine.

Ph SeSe Ph

NaBH4Ph SeNa2

such as nuciferine (V), and apomorphine dimethyl ether, (IV).



137

R H

O+2 2 NaHSe

NaBH4

Amine R SeSe R

Use of 0.25 molar equivalent of borohydride results in maximum diselenide yield with little selenol contamination. The NaHSe is conveniently prepared by NaBH4 reduction of elemental selenium in absolute ethanol (35). NaBH4, and more recently NaBH3CN, are being applied with increasing frequency to the desulfonation of p-toluene- and methanesulfonates. This reaction is often used to convert alcohols to the corresponding hydrocarbon (36-41). The selective reduction of a mesylate in the presence of a tosylate has been reported in studies elucidating the chirality in tetrahydroquinoxalines (42).

N

NCH2OMs

HOTs

H

N

NCH3

HOTs

H

NaBH4

Selenoether compounds synthesized by reducing Se metal or Alkyl dibromoselenide and

halocarbons with borohydride exchange resins or sodium borohydride. (43-45) It has been demonstrated that aryl nitriles can be reduced with NaBH4 in the presence of Se metal to form seleno amides in high yield (46) Both seleno ethers and diselenides can be reduced to selenols in high yielded with sodium borohydride. (47- 49) Telluerium ether compounds can be synthesized in high yield from the reduction of ArTeCl3 with sodium borohydride and a organic halide in THF at 0o C. (50) Di tellurides has been reduced to telluriol in high yielded using sodium borohydride. (51,52) References: 1) Bosman, W.P.; Van der Linen, H.G.M. J. Chem. Soc.,

Chem. Commun. 1977, 714; Chem. Abstr. 88, 145344s 2) Belg. 866,910 1978; Chem. Abstr. 90, 137816y 3) Ookawa, A.; Yokoyama, S.; Soai, K. Synth. Commun.

1986, 819; Chem. Abstr. 105, 208549e 4) Fr. Demande 2,566,400 1985; Chem. Abstr. 105, 152688e 5) Jpn. Kokai Tokkyo Koho 85, 2222, 485 1985; Chem.

Abstr. 105, 78751b 6) Rinaldi, A.; Dernini, S. Dessy, M.R.; DeMarco, C. Anal.

Biochem. 1975, 69, 289; Chem. Abstr. 84, 432242g



138

7) Entwistle, I.D.; Johnstone, R.A.W.; Varley, J.H. J. Chem. Soc., Chem. Commun. 1976, 61; Chem. Abstr. 84, 121363p

8) Liotta, D.; Sunay, U.,; Santiesteban, H.; Markiewicz, W. J. Org. Chem. 1981, 46, 2605; Chem. Bastr. 95, 41572t

9) Kuroda, C.; Theramongkol, P.; Engebrecht, J.R.; White, J.D. J. Org. Chem. 1986, 51, 957; Chem. Abstr. 104, 186207s

10) Stahl, C.R.; Siggia, S. Anal. Chem. 1957, 29, 154; Chem. Abstr. 51, 17611a

11) Sjoeberg, B.; Herdevall, S. Acta Chem. Scand. 1958, 12, 1347; Chem. Abstr. 54, 2281I

12) Bir, K.; Crawhall, J.C.; Mauldin, D. Clin, Chem. Acta 1970, 30, 183; Chem. Abstr. 73, 32989t

13) Klayman, D.L.; Griffin, T.S.; Woods, T.S. Int. J. Sulfur Chem. 1973, 8, 53; Chem. Abstr. 81, 32989t

14) Sondack, D.L.; Light, A. J. Biol. Chem. 1971, 246, 1630; Chem. Abstr. 74, 107621t

15) Ottenheijm, H.C.; Herscheid, J.D.M.; Kerkhoff, G.P.C.; Spande, T.F. J. Org. Chem. 1976, 41, 3433; Chem. Abstr. 85, 160025v

16) PCT Int. Appl 84 04,921 1984; Chem. Abstr. 102, 185115g

17) Ottenheijm, H.C.J.; Herscheid, J.D.M.; Nivard, R.J.F. J. Org. Chem. 1977, 42, 925; Chem. Abstr. 86, 140001b

18) Back, T.G.; Baron, D.L.; Yang, K. J. Org. Chem. 1993, 58, 2407

19) Alcaide, B.; Casarrubios, L.; Dominguesz, G.; Sierra, M.A. J. Org. Chem. 1994, 59, 7934

20) Suzuki, H.; Nakamura, T.; Yoshikawa, M. J. Chem. Research (S) 1994, 70

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22) Zhang, M.H.; Zheng, M.; Cheng, T.; Wang, S.X. Organic Prep. Proc. Int. 1996, 28, 467

23) Yoon, N.M.; Choi, J.; Ahn, J.H. J. Org. Chem. 1994, 59, 3490

24) Choi, J.; Yoon, N.M. Synth. Commun. 1995, 25, 2655 25) Nah. J. H.; Choi, J.; Yoon, N.M. Bull. Korean Chem. Soc.

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86, 139900n



139

30) Nakayama, J.; Fugiwaw, K.; Hishoni, M. Bull. Chem. Soc. Jpn. 1976, 49, 3567; Chem. Abstr. 86, 155545f

31) Iddon, B.; Suschitzky, H.; Taylor, D.S.; Chippendale, K.E. J. Chem. Soc., Perkin Trans 1 1974, 2500; Chem. Abstr. 82, 111966g

32) Ahmad, R.; Saa, J.M.; Cava, M.P. J. Org. Chem. 1977, 42, 1228; Chem. Abstr. 86, 155837c

33) Grieco, P.A.; Noguez, J.A.; Masaki, Y. J. Org. Chem. 1977, 42, 1228; Chem. Abstr. 86, 72908a

34) Lewicki, J.W.; Guenther, W.H.H.; Chu, J.Y.C. J. Org. Chem. 1978, 43, 2672; Chem. Abstr. 89, 59740g

35) Klayman, D.L.; Griffin, T.S. J. Am. Chem. Soc. 1973, 95, 197; Chem. Abstr. 78, 110774y

36) Marshall, J.A.; Wuts, P.G.M. J. Am. Chem. Soc. 1978, 100, 1627; Chem. Abstr. 88, 170333v

37) Agosta, W.C.; Wolff, S. J. Am. Chem. Soc. 1977, 99, 3355; Chem. Abstr. 87, 67743j

38) Grethe, G.; Mitt, T.; Williams, T.H.; Uskokovic, M.R. J. Org. Chem. 1983, 48, 5309; Chem. Abstr. 100 7015a

39) Barrette, E.P.; Goodman, L. J. Org. Chem. 1984, 49, 176; Chem. Abstr. 100, 34748y

40) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986, 108, 140; Chem. Abstr. 104, 51101g

41) Eur. Pat. Appl. 165,595 1985; Chem. Abstr. 104, 168761p 42) Fisher, G.H.; Schultz, H.P. J. Org. Chem. 1974, 39, 635;

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Synthesis 1984, 1044 45) Yamada, K.; Fujita, T.; Yamada, R. Synlett 1998, 971 46) Zhao, X.R.; Ruan, M.D.; Fan, W.Q.; Zhou, X.J. Synth.

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140

OZONIDES Ozonides are reduced by NaBH4 to the corresponding alcohol. The reduction of the ozonides of indene (1), 3-acetyl-digitoxigenin (2), cytochlasin E (3), and a number of other compounds (4-6) have been reported. Sousa and Bluhm (7) have used this reduction to cleave olefins to alcohols in good yields, with out the necessity of isolating the ozonide. When the ozonides of branched olefins are reduced with NaBH4, a mixture of alcohols is obtained which correctly, and without by products, locates the double bond position (8). Ozonide reduction with NaBH4 has been used on making anti-inflammatory derivatives of 6-oxo-1-a-naphthoic acid (9) and hydroxyl-terminated low molecular weight polymers for subsequent condensation with anhydrides to form polyesters (10). The reduction of ozonides can be accomplished with sodium borohydride to form compounds such as sugars(11), Triquinane type skeleton (12) and Zaragoic Acid (13). Ozononolyis of lactams and subsequent reduction with SBH forms allylic ethers. (14) References: 1) Warnell, J.L.; Shriner, R.L. J. Am. Chem. Soc.

1957, 79, 3165; Chem. Abstr. 51, 15509f

2) Boutagy, J.S.; Thomas, R.E. Aust. J. Chem. 1971, 24, 2723; Chem. Abstr. 76, 141179w

3) Aldridge, D.C.; Greatbanks, D.D; Turner, W.B.N. J. Chem. Soc., Chem. Commun. 1973, 551; Chem. Abstr. 79, 126471d

4) Sundaraaraman, P.; Barth, G.; Djerassi, C. J. Org. Chem. 1980, 45, 5231; Chem. Abstr. 94, 83490z

5) Arffin, A.A.B. J. Rubber Res. Inst. Malays. 1981, 29, 96; Chem. Abstr. 96, 2011035w

6) Takatsuko, S.; Ikekawa, N. Tetrahedron Lett. 1983, 24, 773; Chem. Abstr. 99, 54059p

7) Sousa, J.A.; Bluhm, A.L. J. Org. Chem. 1960, 25, 108; Chem. Abstr. 54, 15286f

8) Hoffman, J.; Smidova, J.; Landa, S. Collect. Czech. Chem. Commun. 1970, 35, 2174; Chem. Abstr. 73, 65937n

9) U.S. 3,644,500 1972; Chem. Abstr. 76, 140060p 10) Japan. 73 11,235 1973; Chem. Abstr. 80, 121713v 11) Lautens, M.; de Frutos, O.; Stammers, T.A. Tetrahedron

Lett. 1999, 40, 8317 12) Kocovsky, P.; Dunn, V.; Gogoll, A.; Langer, V. J. Org.

Chem. 1999, 64, 101 13) Maezaki, N.; Gijsen, H.J.M.; Suna, L.Q.; Paquette, L.A.

J. Org. Chem. 1996, 61, 6685 14) Alcaide, B.; Casarrubios, L.; Dominguesz, G.; Sierra,

M.A. J. Org. Chem. 1995, 60, 6012


141

PEROXIDES AND HYDROPEROXIDES Jensen (1) has reported the NaBH4 reduction of some organic peroxides to be extremely rapid at room temperature. Organic peracids and peroxides formed in most ethers are also reduced. Hydrogen peroxide can react violently with sodium borohydride. Reactions with concentrated solutions have resulted in explosions.


The literature describes the NaBH4 reduction of cholesterol hydroperoxide to the alcohol (2), naturally occuring terpene hydroperoxide such as neoconcinndiol hydroperoxide (3) and peroxyferolide (4), and numerous other (5-8). Rapid selective hydroperoxide reduction in the presence of keto and iodo functionalities has been reported for the 1-phenylhexanone derivative formed by hydrolysis of a benziodolium cation (9).

OBu OOH

Ph

OBu OH

Ph

NaBH4

I I Peroxides formed in photosensitized oxidations of homosemibullvalene (10), stilbene derivatives (11), cyclobutane dioxetanes (12), The natural sesquiterpene

valencene (13) and dienes of norbornane (14) have been reduced to the corresponding alcohol. Allylic hydroperoxides formed by autoxidation of methyl oleate are reduced to the corresponding allylic alcohols (15), Permitting accurate quantitative determination of their composition; previous methods were subject to significant errors. Hydroperoxides reduction has been reported in one synthetic route to the prostaglandines PGE1 and PGF1a (16). The reduction of a hydroperoxide group in an intermediate towards the synthesis of dihydroxyvitamin D3 has been accomplished with sodium borohydride. (17)

Sodium borohydride in MeOH have reduced peroxides to diols. (18) References: 1) Jensen, E.H. “ A Study on Sodium Borohydride”, Nyt.

Nordisk Forlag Arnold Busck, Copenagen 1954 (out of print); Chem. Abstr. 49, 13010a

2) Kulig, M.J.; Smith, L.L. J. Org. Chem. 1974, 39, 3398; Chem. Abstr. 82, 53949r

3) Howard, B.M.; Fennical, W.; Finer, J.; Hirotsu, K.; Clardy, J. J Am. Chem. Soc. 1977, 99, 6440; Chem. Abstr. 87, 184722n



142

4) Doskotch, R.W.; El-Feraly, F.S.; Fairchild, E.H.; Haung, C.T. J. Org. Chem. 1977, 42, 3614; Chem. Abstr. 87, 180643q

5) Johnson, W.S.; Dumas, D.J.; Berner, D. J. Am. Chem. Soc. 1982, 104, 3510; Chem. Abstr. 97, 24076h

6) Adam, W.; Hannemann, K.; Wilson, R.M. J. Am. Chem. Soc. 1984, 106, 7646; Chem. Abstr. 102, 5437g

7) Bull, A.; Nigro, N.D. et al. Cancer Res. 1984, 44, 4924; Chem. Abstr. 102, 19325f

8) Van Kuijk, F.J.G.M.; Thomas, D.W.; Stephens, R.J.; Dratz, E.A.; J. Free Radicals Biol. Med. 1985, 1, 215; Chem. Abstr. 104, 48268m

9) Beringer, F.M.; Ganis, P.; Avitabile, G.; Jaffe, H. J. Org. Chem. 1972, 37, 879; Chem. Abstr. 76, 126504e

10) Sakai, M.; Harris, D.L.; Winstein, S. J. Org. Chem. 1972, 37, 2631; Chem. Abstr. 77, 100898g

11) Saito, I.; Matsuura, T. Chem. Lett. 1972, 1169; Chem. Abstr. 78, 83937v

12) Rigaudy, J.; Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1972, 4997; Chem. Abstr. 78, 123619b

13) Schaffer, G.W.; Eschinasi, E.H.; Purzycki, K.L.; Doerr, A.B. J. Org. Chem. 1975, 40, 2181; Chem. Abstr. 83, 97599b

14) Jefford, C.W.; Rimbault, C.G. J. Org. Chem. 1978, 43, 1908; Chem. Abstr. 88, 189637u

15) Garwood, R.F.; Khambay, B.P.S.; Weedon, B.C.L.; Frankel, E.N. J. Chem. Soc., Chem. Commun. 1977, 364; Chem. Abstr. 87, 183915r

16) U.S. 3,953,499 1976; Chem. Abstr. 86, 16342z 17) Linker, T.; Frohlich, L. J. Am. Chem. Soc. 1995, 117,

2694 18) Carless, H.A.J.; Oak, O.Z. Tetrahedron Lett. 1989, 30,

1719



143

III. INORGANIC APPLICATIONS A. Inorganic Reductions Alembic: 6 Sodium borohydride is a tremendously versatile reducing agent and ligand for inorganic reactions, as shown by the wealth of literature which as appeared in the last 50 years. Some excellent reviews have appeared in the literature and are recommended (1-6). In addition Rohm and Haas over the past 30 years has complied and regularly updates a full bibliographic database pertaining to the reduction of metals. We are prepared to answer all questions relating to the application of borohydrides and amine boranes for the reduction of metals.

METAL CATION REDUCTIONS Alembic: 6 A substantial number of metal cations are reduced by borohydride in protic or aprotic solvent. Reduction can be classified according to the product obtained. The products may be a lower valence compound, the free element, a volatile hydride or a

metal “boride’. These reductions are summarized in Periodic Table form in Figure 11. In addition to a references cited in this table, the following publications are significant: - “Catalytically Active Borohydride-Reduced Nickel and

Cobalt Systems” (7), - “Reactions of Sodium Tetrahydroborate and

Cyanotrihydroborate with Divalent Cobalt, Nickel, Copper, Palladium and Platinum in the Presence of Triphenyl Phosphines” (8)

- Hydride Complexes of iron (II) and ruthenium (II)” (9) - The Mechanism of the reduction of the Inorganic

compounds with alkali Metal Borohydride” (10), - “Sodium tetrahydroborate as a new reagent in the

Systematic Course of Qualitative Analysis I. Reduction of Sodium Tetrahydroborate with metal cations” (11).

Reduction of toxic or valuable heavy metals in process waste streams is an important industrial application for sodium borohydride.(12-14). Quantitative reduction and recovery of mercury (15- 18), lead (19), silver (20, 21), gold (22, 23), copper (13,14), and platinum group metals (24-26) can be accomplished.

The use of NaBH4 in the development process for color reversal photographic film is well documented (27-29)



144

Cation reductions with NaBH4 are being used commercially in the area of electroless plating, particularly of nickel, on both metallic and non-metallic substrates. Practical aspects of this application have been published (30, 31), and extended plating bath life and ease of regeneration have been cited as advantages. These coatings contain up to 5% boron and, when annealed, consist of a dispersion of Ni3B in a nickel matrix (32) which provides a wear resistant finish of superior hardness. Cobalt (33, 34), gold (35,36), copper (37, 38) and iridium (39) have also been plated by NaBH4 reduction. The copper deposits, on plating glass, are used in solar control windows having reflective bronze finish. Russian publications report NaBH4 reduction of electroless plating of silver (40), iron (41), palladium (42), platinum (43), and ruthenium (44). NaBH4 is also reported to be effect in pretreating or sensitizing non-catalytic substrates for subsequent electroless plating (45, 46, 47). A recent patent has been issued for a process for electroless plating of polymer or resins with Ag, Co, Ru, Ce, Fe, Mn, Ni, Rh, and/or V. (48) Several metal compounds such as cobalt chloride (49) chromium oxide, Cr2O3 (50 44), molybdenum and tungsten oxides (51 45) and molybdenum chloride (52 46), have been reduced by

heating these compounds together with sodium borohydride in the absence of any solvent to produce metal powders. NaBH4 reduction has also been applied to the manufacturing of amorphous metal alloy (53), extremely fine metal powders of copper (54 55), silver (56), ruthenium (57), gold (58, 59), Pt (60), Fe (61) and nickel or cobalt (62), and magnetic metal powders for tape recording media (63, 64, 65, 66). Other recent applications include boiler scale removal (67), the preparation of methanol reforming catalysts (68), The preparation of a cobalt catalyst for the hydrogenantion of glucose to sorbetol (69) and of catalytic converters for automobile exhausts gases (70). Reacting metal salts and sodium borohydride at elevated temperatures have formed mixed metal alloys. (71- 80) The kinetics of the reaction of the ammonium ion with the borohydride anion in liquid ammonia to produce ammonia-borane, NH3BH3, has been reported (81). The borohydride reduction of nanogram quantities of arsenic (82-87), antimony (82-84, 87), bismuth (82, 83), tin (82-87), germanium (84) mercury (86), tellurium (86), selenium (82, 83), indium and thallium (88) and lead (86, 89) to produce volatile hydrides for detection by atomic absorption, gas chromatography and emission spectroscopy has been widely reported and is extensively used by analysts. Elemental powered selenium and sodium borohydride react rapidly in water or ethanol to give either NaHSe or



145

Na2Se2 (90). The reduction of Sb2O3 with sodium borohydride in ethylene glycol produces a finely divided antimony powder useful as a catalyst for polyester manufacture (91). The mechanism of the reduction of arsenic (III) chloride and oxide and the preparation of arsine by the borohydride reduction of these compounds has been reported (92).

METAL ANION REDUCTIONS Alembic: 6 An Important industrial use of sodium borohydride is the reduction of the bisulfite anion to produce dithionite (hydrosulfite) anion (93, 94):

BH4- + 8 HSO3

- + H+ 4 S2O42- + H3BO3 + 5 H2O

Hydrosulfite (S2O4)2- generated by NaBH4 reduction of tetravalent sulfur species is widely applied industrially in bleaching mechanical pulps (95, 96). Other anions which have been studied systematically, mainly in the USSR, include Rhenium dioxide and perrhenate to Re (V), (III), or (II) (97,98); Osmium tetraoxide to Os (VII), (VI), and (IV) (99); Pertechneate to Tc. Figure 11 : Studies of Na BH4 Reductive Strength


146




147

(0) (100); Vanadate to V (III) and (IV) (101,102); Molybdate to Mo (V) and “molybdenum blue” (103, 104); Tungstate to W (IV) and tungsten blue (105, 106); Permanganate to MnO2 and Mn (II) (107); hexacyanoferrate to Fe (II) (108, 109); and iodine (in DMF) to NaI = B2H6, BH2I, BH2I2 and B2H5I (110, 111).

The utilization of sodium borohydride as an efficient energy storage media has been demonstrated. The 8 electron electrochemical oxidation of sodium borohydride in aqueous alkaline solution produced specific energies of greater then 180 Wh/kg (based on total fuel wt.) and power densities greater then 20mW/cm2 at room temp and greater then 60mW/cm2 at 70 degree C. (112) References: 1) James, D.B. Wallbridge, M.G.H. Prog. Inorg.

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111) Khain, V.S.; Val’kova, V.P. Zh. Obshch. Khim 1977, 47, 961; Chem. Abstr. 87, 29619r

112) Amendola, S. C.; Onnerud, P.; Kelly, M. T.; Petillo, P. J.; Binder, M. Proc. - Electrochem. Soc., 1999, 98 , 47

113) Gardiner, J.A. Collat, J.W. J. Am. Chem. Soc. 1965, 87, 1692; Chem. Abstr. 62, 13899b

114) Gardiner, J.A. Collat, J.W Inorg. Chem. 1965, 4, 1208; Chem. Abstr. 63, 6610e

115) Jolly, W.L.; J. Am. Chem. Soc. 1961, 83, 335; Chem. Abstr. 55, 12126c

116) Waller, Sr. M.C. “Inorganic Chemistry of borohydride” Metal hydride inc.

117) Warburton, C.D.; Przbylowicz, E.P. Phot. SSCci. Eng. 1966, 10, 86; Chem. Abstr. 64, 15226e

118) Shah, A.R.; Padma, D.K.; Murthy, A.R.V. Indian J. Chem. 1971, 9, 885; Chem. Abstr. 75, 136669f

119) Castellani-Bisi, C. Ann. Chim. 1959, 49, 2057; Chem. Abstr. 54, 17137b

120) Chaikin, S.W. Anal. Chem. 1953, 25, 831; Chem. Abstr. 47, 7371g

121) Andreev, F.I.; Tsivelev, R.P.; Khain, V.S. Zh. Neorg. Khim. 1978, 23, 2847; Chem. Abstr. 89, 225385s

122) Sterlyadkina, Z.K.; Alekseeva, L.S.; Mikheeva, V.I. Zh. Neorg. Khim. 1969, 14, 2677; Chem. Abstr. 72, 38350p

123) Alekseeva, L.S. Zh. Neorg. Khim. 1975, 20, 2339; Chem. Abstr. 83, 201393t

124) Freund, T.; Neunkle, N. J. Am. Chem. Soc. 1961, 83, 3378; Chem. Abstr. 56, 1125d

125) Freund, T. J. Inorg. Nucl. Chem. 1959, 9, 246; Chem. Abstr. 53, 16665h

126) Mochalov, K.N.; Khain, V.S. Zh. Fiz. Khim. 1965, 39, 1960; Chem. Abstr. 63, 15846b



153

127) Freitag, W.O.; Sharp, T.A.; Baltz, A.; Suchodolski, V. J. Applied Phys. 1979, 50, 7801; Chem. Abstr. 92, 87038q

128) Schlesinger, H.I. et al. J. Am. Chem. Soc. 1953, 75, 199; Chem. Abstr. 47, 3741h

129) McBride, D.G.; Vlasak, G.P. J. Electrochem. Soc. 1971, 118, 2055; Chem. Abstr. 76, 62788r

130) Pratt, J.M.; Swinden, G. J. Chem. Soc., Chem. Commun. 1969, 1321; Chem. Abstr. 72, 47951

131) Paul, R.; Buisson, P.; Joseph, N. Ind. And Eng. Chem. 1952, 44, 1006; Chem. Abstr. 46, 9960e

132) Thonnart, P. Lenfart, P.; Legas, C.C. R. Acad. Sci. Paris 1964, 258, 5207

133) Hofer, L.J.E.; Shultz, J.F.; Panson, R.D.; Anderson, R.B. Inorg. Chem. 1964, 3, 1783; Chem. Abstr. 62, 4886b

134) Brown, C.A. J. Org. Chem. 1970, 35, 1900; Chem. Abstr. 73, 29374t

135) Waller, M.C.; Miniatas, B.O.; Hohnstedt, L.F. Anal. Chem. 1965, 37, 1163; Chem. Abstr. 10641c

136) Mochalov, K.N.; Bashkirova, T.I. Zavod. Lab. 1969, 35, 795; Chem. Abstr. 72, 74415x

137) Prokopoikas, A.; Sakalauskiene, J. Liet. Tsr Mokslu Akad. Darb., Ser B. 1971, 117; Chem. Abstr. 76, 63968m

138) Rozovskis, G. Issled. Obl. Osazhdeniya Metal., Mater. Respub. Konf. Electrokhim., Litov SSR, 11th 1971, 133; Chem. Abstr. 77, 23789t

139) Piper, T.S.; Wilson, K.M. J. Inorg. Nucl. Chem. 1957, 4, 22; Chem. Abstr. 51, 7924e

140) Maklen, E.D. J. Chem. Soc. 1959, 1989; Chem. Abstr. 53, 14805g

141) Jolly, W.L. et. al. J. Inorg. Nucl. Chem. 1960, 14, 190 142) Gunn, S.R.; Jollly, WL.; Green, L.G. J. Phys. Chem.

1960, 64, 1334; Chem. Abstr. 55, 8026f 143) Mochalov, K.N. et. al. Dokl. Akad. Nauk. SSSR 1966,

64, 1334; Chem. Abstr. 64, 17009f 144) Mochalov, K.N.; Polovnyak,V.K.; Groisberg, A. T. Izv.

Vyssh. Ucheb. Zaved., Khim,. Khim. Tekhnol. 1973, 16, 1115; Chem. Abstr. 79, 111314f

145) Alekseeva, L.S. et. al. Zh. Neorg.Khim. 1976, 21, 277; Chem. Abstr. 84, 115375c

146) Brown, H.C.; Brown, C.A. J. Am. Chem. Soc. 1962, 84, 1493; Chem. Abstr. 57, 111b



154

147) Mochalov, K.N.; Ostryakova, T.A.; Tremasov, N.V. Tr. Kazan. Khim. Teknol. Inst. 1969, 40, 186; Chem. Abstr. 75, 44502t

148) Khain, V.S.; Volkov, A.A. Zh. Prikl. Khim. 1983, 56, 663; Chem. Abstr. 98, 226838q

149) Borgonostesev, A.S.; Timofeeva, G.P. Tr. Kazan. Inzh. Stroit. Inst. 1967, 142; Chem. Abstr. 74, 37951q

150) Svata, M..; Jindra, J. Colllect. Czech. Chem. Commun. 1970, 35, 692; Chem. Abstr. 72, 95972s

151) U.S.S.R. 269, 670 1970; Chem. Abstr. 73, 58794k

152) Schaeffer, G.W.; Emilius, M. J. Am. Chem. Soc. 1954, 76, 1203; Chem. Abstr. 48, 6303h

153) Evans, D.H. Anal. Chem. 1964, 36, 2435; Chem. Abstr. 62, 3399f

154) Zorin, A.D.; Frolov, I.A.; Morozova, T.V. Sh. Obshch. Chim. 1972, 42, 900; Chem. Abstr. 77, 83043e

155) Khain, V.S.; Kotelevets, E.S. Zh. Neorg. Khim. 1982, 27, 1199; Chem. Abstr. 97, 32674s

156) Lyttle, D.A.; Jensen, E.H.; Struck, W.A. Anal. Chem. 1952, 24, 1843; Chem. Abstr. 47, 1005h

157) Mochalov, K.N.; Gilmanashin, G.G.; Giniyatullinm, N.G.; Polovnyak, V.K. Tr. Kazan. Khim. Tekhnol. Inst. 1969, 40, 143; Chem. Abstyr. 75, 14489b

158) Khain, V.S.; Zhomova, M.I.; Andreev, F.I. Zh. Neorg. Khim. 1985, 30, 360; Chem. Abstr. 102, 142133u

159) Khain, V.S. Zh. Prikl. Khim. 1980, 53, 2745; Chem. Abstr. 94, 149364v

160) Volkov, A.A.; Khain, V.S. Zh. Anal. Khim. 1982, 37, 876; Chem. Abstr. 97, 103483s

161) Marshall, E.D.; Widing, R.A. U.S.A.E.C. Report AECD-2914 1950

162) Romain, P.; Merland, R. Laubie, H. Bull. Soc. Pharm. Bordeaux 1954, 92, 131; Chem. Abstr. 50, 722e



155

B. Organometallic The rapid growth of organometallic chemistry in recent years has given rise to numerous applications of sodium borohydride’s reducing capabilities. From a survey of literature citations using NaBH4 in this specialized field, it quickly becomes apparent that, in general, five major types of reactions are involved: initial formation of organometallic compounds and complexes, reduction to lower valent metal compounds, demetallation or cleavage or organometallics to the metal and organic species, conversion of organometallic halides to the corresponding hydride or hydride halide, and reduction of organometallic cations to neutral species.

The formation of organometallics via NaBH4 reduction is typified by the formation of cobalt (II) thiol complex catalysts where the thiol ligands are derived from amino acids such as serine, cysteine and cysteamine (1); these catalysts are effective in the reduction of acetylene. The use of NaBH4 in the synthesis of hydridometal complexes with

organophosphorus ligands has been reported for iron (2-4), ruthenium (2) and cobalt (5). Examples of NaBH4 reduction to lower valent metal complexes are the octaethylporphyrin complexes of Rh (I) (6) and Fe (II) (7,8) made from the corresponding M(III) complex chlorides, and the bis-dehyrocorrin complex of Co(I) made from the corresponding dicyanocobalt (III) complex (9). The most familiar type of demetallation or cleavage of organometallics by NaBH4, is demercuration, which is covered in a separate section. The analogous reduction of organothallium compounds has also been reported (10,11). Other cleavages include those of serinato copper (II) complexes (12), a tetracarbonylallyliron cation (13), dimeric cienyl rhodium complexes (14), and cephem-π-allyl palladium dichloride (15). Complex formation and reduction in the last instance is utilized to isomerize 2-cephenms to 3-cephems. Published examples involve cleavage of magnesium and lead macrocycles (16), a palladium pyrazinoindole complex (17), silver and copper porphyrins (18), and heterocyclic amino acid complexes of copper and nickel (19). The conversion of organometallic halides to the corresponding hydride or hydride halide, by reduction with NaBH4 is widely used and has been applied to complexes of



156

chromium (20), iron (21), cobalt (22), nickel (23,24), molybdenum (25), tungsten (25), tin (26,27), ruthenium (28), rhodium (29,30) palladium (23), osmium (31,32), platinum (29,33,34), and iridium (35). The generation of organometallic hydrides has also been used on the analytical determination of organometallic species in various matrices, e.g. Ge (36), Sn (37) and Pb (38). Organometallic cations are often reduced by NaBH4 to give neutral organometallic compounds, as in the cases of Mo (39), Mn (40), Re (41), Ru (42), Co (43), and Fe (44). The preparation of several hydrogenantion catalysts bound to polymers has been reported, including palladium (45), rhodium (45,46), iridium (47), and others (48).

NaBH4 reduction of metal carbonyls, followed by acidification, has been used as a general synthetic method for transition metal hydrido carbonyl clusters (49).

Other used include a commercial nickel phosphine catalyst for ethylene oligomerization to linear alpha-olefins (50-53), the reduction of optically

pure deuterated amino acid complexes of Co (III) to provide optically pure amino acids without loss of deuterium (54), an active homogeneous molybdenum carbonyl catalyst for the water gas shift reaction (55), and the generation of spent hydroformylation catalysts (56). References: 1) Sugiura, Y.; Kikuchi, T.; Tanaka, H. J. Chem. Soc., Chem.

Commun. 1977, 795 2) Gerlach, D.H.; Peet, W.G.; Muetterties, E.L. J. Am. Chem.

Soc. 1972, 94, 4545; Chem. Abstr. 77, 62114p 3) Dapporto, P.; Fallani, G.; Midollini, S.; Sacconi, L. J. Am.

Chem. Soc. 1973, 95, 2021; Chem. Abstr. 78, 13154k 4) Giannoccaro, P.; Sacco, A. Inorg. Synth. 1977, 17, 69;

Chem. Abstr. 88, 12113d 5) Carriedo, C.; Gomez-Sal, P. et. al. J. Organomet. Chem.

1986, 301, 79; Chem. Abstr. 104, 179029g 6) Ogoshi, H.; Sntsune, J.; Tyoshida, Z. J. Am. Chem. Soc.

1977, 99, 3869; Chem. Abstr. 887, 135837v 7) Dolphin, D.; Sams, J.R.; Tsin, T.B.; Wong, K.L. J. Am.

Chem. Soc. 1976, 98, 6970 8) Jpn. Kokai Tokkyo Koho 78, 112, 900 1978; Chem.

Abstr. 90, 121679v



157

9) Murakami, Y.; Aoyama, Y.; Nakanishi, S.; Chem. Lett. 1977, 991;Chem. Abstr. 87, 126495e

10) Bach, R.D.; Holubka, J.W. J. Am. Chem. Soc. 1974, 96, 7814; Chem. Abstr. 82, 16203x

11) Uemura, S.; Miyoshi, M.: Tara, H.; Okano, M.; Ichikawa, K. J. Chem. Soc., Chem. Commun. 1976, 218; Chem. Abstr. 85, 46802w

12) O’Conner, M.J.; Smith, J.F.; Teo, S. Aust. J. Chem. 1976, 29, 375; Chem. Abstr. 84, 180114f

13) Pearson, A.J. Aust. J. Chem. 1976, 29, 1841; Chem. Abstr. 86, 16771p

14) Eaton, P.E.; Patterson, D.R. J. Am. Chem. Soc. 1978, 100, 2573; Chem. Abstr. 89, 43537k

15) Jpn. Kokai 77 105,192 1977; Chem. Abstr. 88, 105372t

16) Mandal, S.K.; Nag, K.J. J. Org. Chem. 1986, 51, 3900; Chem. Abstr. 105, 1724435y

17) Hegedus, L.S.; Mulhern, T.A.; Asada, H. J. Am. Chem. Soc. 1986, 108, 6224; Chem. Abstr. 105, 172406q

18) Cowen, J.A/; Sanders, J.K.M. Tetrahedron Lett. 1986, 27, 1202; Chem. Abstr. 105, 90145q

19) Teo, S.B.; Tech, S.G. Inorg. Chem. Acta 1985, 107, 35; Chem. Abstr. 103, 63855y

20) Koola, J.D.; Brintzinger, H.H. J. Chem. Soc., Chem. Commun. 1976, 388; Chem. Abstr. 85, 124088j

21) Nesmeyanov, A.N.; Chapovskii, Y.A.; Ustynyuk, Y.A. Izv. Akad. Nauk SSSR, Ser. Khim. 1966, 1871; Chem. Abstr. 66, 64860a

22) Chao, T.; Epsenson. J.H. J. Am. Chem. Soc. 1987, 100, 129; Chem. Abstr. 88, 111148r

23) Saito, T.; Munakata, H.; Imoto, H. Inorg. Synth. 1977, 17, 83; Chem. Abstr. 88, 121313e

24) Takagi, K. Chem. Lett. 1986, 265; Chem. Abstr. 105, 208796h

25) Meakin, P.; Guggenberg, L.J.; Peet. W.G.; Muetterties, E.L.; Jesson, J.P. J. Am. Chem.Soc. 1973, 95, 1467; Chem. Abstr. 78, 101033c

26) Corey, E.J.; Suggs, J.W. J. Org. Chem. 1975, 40, 2554; Chem. Abstr. 83, 130658v

27) Birnbaum, E.R.; Javora, P.H. J. Organomet. Chem. 1967, 9, 379; Chem. Abstr. 68, 22026u

28) Young, R.; Wilkinson, G. Inorg. Synth. 1977, 17, 75; Chem. Abstr. 88, 105484f



158

29) Empsail, H.D.; Hyde, E.M.; Pawson, D.; Shaw, B.L. J. Chem. Soc., Dalton Trans 1977, 1292; Chem. Abstr. 87, 168176g

30) Eur. Pat. Appl. 55, 487 1982; Chem. Abstr. 98, 4675v

31) Bell, B.; Chatt, J.; Lkeigh, G.J. J. Chem. Soc., Dalton Trans. 1973, 997; Chem. Abstr. 78, 154371u

32) Werner, H.; Zenkert, K. J. Chem. Soc., Chem. Commun. 1985, 1607; Chem. Abstr. 105, 97654p

33) Moulton, C.J.; Shaw, B.L. J. Chem. Soc., Chem. Commun. 1976, 365; Chem. Abstr. 85, 136363h

34) Meyer, W.R.: Venanzi, L.M. Angew, Chem. 1984, 96, 505; Chem. Abstr. 101, 64917r

35) Greene, T.R.; Roper, W.R. J. Organomet. Chem. 1986, 299, 245; Chem. Abstr. 105, 226938k

36) Hambrick, G.A.; Froelich, P.N.; Andreae, M.O.; Lewis, B.L. Anal. Chem. 1984, 56, 421; Chem. Abstr. 100, 90972d

37) Hattori, Y.; Kobayashi, A. et. al. J. Chromatogr. 1984, 315; 341; Chem. Abstr. 102, 100497k

38) D’Uliva, A.; Fouco, R.; Papoff, P. Talanta 1986, 33, 401; Chem. Abstr. 105, 90513h

39) Brunner, H.; Watchter, J. J. Organomet. Chem. 1980, 201, 453; Chem. Abstr. 94, 102685k

40) Brookhart, M.; Lukacs, A. J. Am. Chem. Soc. 1984, 106, 4161; Chem. Abstr. 101, 91137t

41) Sullivan, B.P.; Meyer, T.J. J. Chem. Soc., Chem. Commun. 1984, 1244; Chem. Abstr. 102, 55034u

42) Davies, D.L.; Knox, S.A.R. et. al. J. Chem. Soc., Dalton Trans. 1984, 2293; Chem. Abstr. 102, 113688y

43) Jacobsen, E.N.; Bergman, R.G. J. Am. Chem. Soc. 1985, 107, 2023; Chem. Abstr. 102, 149512a

44) Catheline, D.; Lapinte, C.; Astruc, D.C. R. Acad. Sci., Ser 2 1985, 301, 479; Chem. Abstr. 104, 186591n

45) Latov, V.K.; Belikov, V.M.; Belyaeva, T.A.; Vinogradova, A.I.; Soinov, S.I. Izv. Akad. Nauk SSR, Ser. Khim. 1977, 2481; Chem. Abstr. 88, 104852n

46) Holy, N.L. Tetrahedron Lett. 1977, 3703; Chem. Abstr. 88, 104735b

47) U.S. 4,062,803 1977 Corresponds to Ger. Offen. 2,600,634 1976; Chem. Abstr. 85, 198875k

48) U.S. 4,313,018 1982; Chem. Abstr. 96, 141870c 49) Kaesz. H.D. Chem. Brit. 1973, 9, 344; Chem. Abstr. 79,

86879j 50) U.S. 3,676, 523 1972; Chem. Abstr. 77, 100710q



159

51) U.S. 3,686, 351 1972; Chem. Abstr. 77, 151422e 52) U.S. 3,737, 475 1973; Chem. Abstr. 79, 31448n 53) U.S. 3,825,615 1974; Chem. Abstr. 81, 119895h 54) Keyes, W.E.; Legg, J.I. J. Am. Chem. Soc. 1976,

98, 4970; Chem. Abstr. 85, 108969s 55) King, R.B.; Frazier, C.C.; Hanes, R.M.; King,

A.D. J. Am. Chem. Soc. 1978, 100 2925; Chem. Abstr. 88, 198376k

56) Jpn. Kokai Tokkyo Koho 84, 115,752 1984; Chem. Abstr. 101, 213057q


160

C. NaBH4 Derivatives

NaBH3CN


Alembic 1, 3, 7, 8, 15, 18, 23, 44, 46 Sodium cyanoborohydride, which is soluble in a wide variety of solvents and is hydrolytically stable to a pH of approximately 3, has extremely interesting properties (1-4). Under neutral conditions in water and methanol, the reduction of aldehydes and ketones is insignificant; however, at pH 3-4, rapid reduction to the alcohol occurs (5,6). The imine group, >C=N-, is reduced by cyanoborohydride much more rapidly than carbonyls, providing a convenient and efficient route to the reductive amination of aldehydes and ketones (5,7-10). RR’C=O + R”NH2 + NaBH3CN RR’CHNHR” The reaction is general for ammonia, primary and secondary amines, all aldehydes and unhindered ketones. Smooth reductions of acid chlorides and enamines are also possible with NaBH3CN, the latter

via rapid and reversible protonation of the β-carbon generating a readily reducible imminium salt:

N H+ N+

HH

H

BH3CN- N

HHH

The versatility of this reagent is further demonstrated in a number of selective reductions of a variety of organic functional groups, for example, in the selective reduction of aldehydes and ketones to hydrocarbons via their tosy hydrazones (11-14), selective reduction of alkyl bromides, iodides and tosylates to hydrocarbon (15,16), reductive alkylation of amines and hydrazines (17,18) and of amides (19). NaBH3CN has also been applied in some interesting synthetic reactions, e.g. synthesis of N-labeled alkaloids (20), and amino acids (5), reduction of pyridines exclusively to the 1,4 dihydro derivatives (21), and synthesis of epoxy-N-nitrocarbamates (22). An excellent review article on the utility and applications of cyanoborohydride has been published (23).



161

Polymer bound borohydride reducing reagents (borohydride exchange resins)

0

20

40

60

80

100

0 50 100

Ti me M i nut e s

BER in MeOH

NaBH4 in MeoH

BER in 95% Et OH

NaBH4 in95%Et OH

Alembic 13, 52 Polymeric-bound borohydride (24,25), P-NR3

+BH4-, (borohydride exchange resins) offer several

advantages over sodium borohydride. The primary advantage are the convenience of use of these materials and the minimal introduction of ionic species or organic by products into the treated bulk media. The reactivity of these borohydride exchange resins depends on the skeletal structure/pore size of the resins, the nature of the solvents, the nature of the reducing reagent and the type of co reagent used.(26)

Borohydride exchange resins have been shown to be an effective reducing agents for the reduction of many functional groups such as aldehyde and ketones (27-34), azides (35,36), reductive amination (37-39), synthesis of thioethers (40-43), thiols (44) and disulfides (45,46), hydroboration of alkenes (47,49) and alkynes (50,51), dehalogenantion (52-55), carboxylic acids (56-57), nitro (58), anhydrides (59), hydrazones (60), cyanides (61), oximes (62), deoxygenantion of amine N-oxides (63-65) and the coupling of alkenes and halides (66-69). Chiral reductions of ketones have been achieved using chiral polymers as support. (70-71)

Fig. 12 Stability of Borohydride Exchange Resins in Alcohols

The combination of sodium borohydride and ion exchange resins stabilize the borohydride towards solvolysis with protic solvents such as methanol and ethanol. The graphs




162

which follows demonstrate the stability that can be achieved by combing ion exchange resins with sodium borohydride.

Other applications in which borohydride exchange resins have been used for are; purification of solvents, generation of volatile hydrides and reduction of metal ions. The anion exchange resins are generally of the styrene/divinylbenzene gel and macroreticular types such as Amberlitetm 400, although the triethylmethyl ammonium cellulose anion exchange has been reported (72-73) Anion exchange resin supported cyanoborohydride (styrene/divinylbenzene macroreticular type) has been utilized in a variety of reductions previously developed for the sodium salt (23). While the reductions are slower with resin, selectivity is retained.

Other Solid Supports for Borohydrides It has been demonstrated that silica gel

impregnated with NaBH4 or Zn(BH4)2 can selectively reduce ketones and aldehydes in nonpolars such as hexane, and other functional groups such as epoxides,

alkenes, alkynes, imines, nitro, esters, and reductive amination of aldehydes and ketones in high yields and under mild reaction conditions in polar solvents such as tetrahydrofuran.. (74-83) This technique has been extended to other solid supports such as alumina (84-86), zeolites (87) and alumino phosphates (88,89).

NaBH2S3 (Lalancette’s Reagent)

Alembic: 4

When sodium borohydride and sulfur are allowed to react at room temperature in THF (90) there is a rapid evolution of hydrogen, and sulfurated sodium borohydride NaBH2S3 is formed: 8 NaBH4 + 3 S8 8 NaBH2S3 + 8 H2. This reagent reduces aldehydes to the alcohols at low temperatures (91,92) and form sulfides and thiols at about 60o C (93). The reagent has also been used to prepared thioacetals in quantitative yields (94). The reduction of ketones (95,96), oximes (97-99), epoxides (100) and episulfides (101) has also been reported. NaBH2S3 is intermediate in reducing potential between LiAlH4 and NaBH4 and reductions of functional groups containing nitrogen are particularly facile (97-105). Aromatic nitro



163

compounds are reduced to amines selectively; halogen, ether olefin nitriles, ester, acid groups are inert to the sulfurated borohydride. Primary aliphatic nitro groups are converted to the nitrile and secondary to a mixture of ketones and the corresponding oxime, amides and nitroso compounds are reduced to amines, as are aromatic nitriles when the reducing agent is present in excess. When excess nitrile is present, the corresponding thioamide is formed.

NaBH(OR)3, Sodium Hydridotrialkoxyborates Alembic: 14, 25, 31, 33

Over the years many papers relating to the reduction of many functional groups such as indoles, imines, enamines, oximes, amides, nitriles, alcohols to hydrocarbon, ketones to hydrocarbon, acetals, ketals, ethers, aldehydes, ketones, and alkenes or reductive amination of ketones and aldehydes have been published. Summaries of these works have been published in a few informative reviews. (106-109) Examples of these reactions are shown below.

A number of trialkoxy derivatives have been reported, including R= Me, Et, CH(CH3)2, CHEtMe (110-112) and CH2CH2OCH3 (2-methoxyethoxy) (113). Trialkoxyhydridoborates reduce aldehydes, ketones, acid chlorides, and acid anhydrides. At low temperatures acid chlorides are reduced to aldehydes. Ester and nitriles are slowly reduced at elevated temperatures. The bulky sec-butoxy derivatives, NaBH(OCHEtMe)3, have been used in the stereoselective reduction of steroidal ketones (114). Reductive amination of aldehydes and ketones with amines have been demonstrated in high yields using alkoxy borohydrides.

Many examples of nitrogen – carbon double bonds have been reduced to amines in high yields using this reagent.

Bis and tris aryl methanol can be reduced to alkanes using trialkoxy borohydrides.

NaBH4 Polyamine polymers

By chelating the sodium ion with polyamine, PMDT (N,N,N’,N’,N’-pentamethyldiethylenetriamine), CH3N[CH2CH2NCH3)2]2, NaBH4 becomes solubulized in hydrocarbon solvents (115). Many reductions can be carried out in non-polar solvents.(116)



164

The multi amine containing organic molecules, DABCO (117,118) and polyvinyl pyridine (119,120), polypyrazine (121, 122) can complex to sodium and zinc borohydride to form very efficient reducing reagents.

Lithium Borohydride (LiBH4) Alembic 52 Lithium borohydride (LBH) is a stronger reducing agent then either potassium or sodium borohydrides. LBH will reduce aldehydes, ketones, acid chlorides, esters, epoxides, lactones and nitriles. It can be formed in situ by reacting either sodium or potassium borohydride with lithium chloride in an ether solvent or liquid ammonia. (123-125)

Potassium Borohydride (KBH4) Alembic 53 Potassium borohydride (KBH) has the same solubility and reductive power as sodium borohydride. KBH will reduce aldehydes, ketones, acid chlorides and epoxides, and lactones that contain α-withdrawing

group. A major use of potassium borohydride is in the synthesis of lithium borohydride. Potassium borohydride is synthesized by the reaction of sodium borohydride with potassium hydroxide in water. The potassium borohydride drops out of solution and is isolated as a white solid in high yield and purity. (126-127)

Calcium Borohydride (Ca(BH4)2) Calcium borohydride (CaBH) has similar solubility

and reductive power as lithium borohydride. CaBH will reduce aldehydes, ketones, acid chlorides, esters and epoxide. Calcium borohydrides is used to synthesize lactones from hemiesters and to stereoselectively reduce ketones by forming a sterically hindering metal complex. CaBH is synthesized by combining CaCl2 and sodium borohydride in either THF or methanol. Solid Ca(BH4)2•6THF is isolated when THF is used as the reaction solvent. (128, 129)

Zinc Borohydride (Zn(BH4)2 Alembic 48, 58 Zinc borohydride is a strong reducing agent that will reduce aldehydes, ketones, acid chlorides, esters, epoxide, azides, α,β ethylenic ketones to allylic alcohols, and



165

carboxylic acids. Zinc borohydride can selectively reduce aldehydes in the presence of ketones and aliphatic ketones in the presence of aromatic ketones. Reviews on the use of this reagent have been published. (130,131) This reagent has been combined with solid supports such as silica gel and ion exchange resins to make a more robust reducing reagent.(132-137) Polypyrazine and DABCO have been combined with zinc borohydride to form a polymeric solid reducing reagent. Zinc borohydride can exist as a dimeric compound when synthesized from LBH and ZnCl2 in diethyl ether. A more complex solution of zinc borohydrides are formed when prepared from SBH and ZnCl2 in THF or DME. In most cases this reagent is formed in situ and used as a freshly made before each use. (138-144)

Mixed Hydrides Several systems have been devised, adding to the number of functional groups that can be reduced effectively with NaBH4. In these, the reducing power of NaBH4 is enhanced to differing degrees.

Esters and Acids The system using NaBH4 and AlCl3 in dyglme, reported by brown and co-workers (145,146) gives good yields in the reduction of saturated acids and esters to alcohol at Room temperature. Unsaturated esters, diesters and diacids are also reduced, but the reaction is complicated by formation of difficulty hydrolyzed boron complexes. LiCl and NaBH4 in THF (147-149) also reduce esters readily to alcohols; LiBH4 is formed and consumed in situ. NaBH4 and CaCl2 in ethanol also effectively reduce esters (150-15). Enhanced reduction efficiency of NaBH4 has been reported in the presence of TiCl4 (153). Not only are esters reduced, but also many other functional groups causing problems with NaBH4 and AlCl3 are smoothly reduced using a 4 to 1 molar ratio of NaBH4 to TiCl4 in diglyme. This system reduces diesters and anhydrides to diols.

Acetals and ketals NaBH4 in combination with either AlCl3 or BF3 in diglyme reduces acetals and ketals to their corresponding ether (154).



166

Hydroboration Alembic 60 Diborane, prepared from NaBH4 and I2, BF3, Me3SlCl, TiCl4 or H2SO4 reacts rapidly and quantitatively in ether solvents with organic unsaturation to form organoboranes (155,156),

>B-H + CH2=CHR B-CH2CH2R which can serve as reactive intermediates in organic synthesis. This methodology is also capable of reducing the following functional groups: nitrile (157,158), epoxides (159,160), carboxylic acids (161-171), amides (172-176), esters (177), oximes (178), nitro (179,180), olefinic bonds (181, 182) as well as reductive amination of ketones and aldehydes (183-186). Stereoconfiguration is retained and, in contrast with Grignard reagents, the reagent is compatible with most functional groups.

The intermediates organoboranes undergo a wide variety of reactions, as shown in Table VI, including isomerization (187,188), displacement (189,

190), cyclization (188, 191), protonolysis to hydrocarbons (192), oxidation to alcohols (193), ketones (194 ), and carboxylic acids (195) (depending on the reagents used), amination (196, 197), metallation (198), coupling (199, 200) and 1, 2, 3 and 4 carbon homoolgations, alkylation and arylation (201) and conjugated addition (202). Carbonlyation of organoboranes at low pressures provides a route to primary, secondary and tertiary alcohols (203-205), aldehyde (206) and ketones, methanol derivatives and polycyclics (207).



167

Table VI Organoborane Reactions

Reaction Reactants Means ProdcdutAmination C-B H2NOSO3H C-NH2 Coupling 2 (C-B) Alk. AgNO3 C-CCyclization C-C H-B heat C-B

Displacment R-C-C-B R’CH=CH2 RCH=CH2 Homologation 1C C-B CO C-C-B2C α-haloester

(+ KOtBu) C-CH2CO2R

3C CH2=CHCHO CCH2CH2- CHO

4C CH2=CHC(O)CH3 CCH2CH2- C(O)CH3

Isomerization C-C-CB

heat C-C-C-B

Metalation C-B Alk. M salt C-M Oxidation Alk. H 2O2 C-OH

To alcohols H2CrO4 C=OTo Ketones 1. H2CrO4 C-CO2H To Acids 2. RCOOOH

Protonation RCOOH + heat C-H

Other Derivatives The reducing power of sodium borohydride can further be enhanced in the presence of a reagent such as carboxylic acid, thiol compounds or anilide. Such systems are becoming more important and have greatly extended the scope of this reagent. The active species in these systems have not been isolated and the reducing agent are prepared and used in-situ. Table VII summarizes the results.



168

Table VII Alkoxyborohydrides Reagent (mole

ratio) Proposed

intermediate Reduction ref

NaBH4/ CH3CO2H (1:3.25)

STAB Reduction ofaldehydes Reductive

alkylation of quinoline and isoquinoline

208 209

NaBH4./ CH3CO2H

(1:1)

SMAB Reduction ofamides and

amines

210

NaBH4/ CH3CO2H (excess)

STAB N-alkylation ofaromatic amines

and indoles Reductive

deoxygenantion of carbonyl tosyl

hydrazones

211 212 213

NaBH4/ CH3CO2H

(6.5:1)

Reduction ofnitrimines to nitramines

214

NaBH4/ RCO2H (excess)

STRB Reductivealkylation of

oximes

216

NaBH4./ CF3CO2H (excess)

STFAB Reduction ofcarbonols and

ketones to alkanes

215

NaBH4 /CF3CO2H (1:1)

SMFAB Reduction ofnitriles to amines

217

NaBH4/phthalic acid (1:1)

NaH2B (phthalato)

Reduction of nitriles to amines

218

NaBH4/thiol Reduction of nitro compounds,

esters, amides and imide

219 220 221

NaBH4/anilide (1:1)

NaH3B anilido)

Reduction of esters, aldehydes and ketones, acid

chlorides

222223224

NaBH4/ NaOH) NaH3BOH Reduction ofesters, nitriles and nitro compounds

225226

STAB= NaBH(O2CCH3)3 SMAB= NaBH3(O2CCH3) STRB= NaBH(O2CR)3 STFAB=NaBH(O2CCF3)3 SMFAB=NaBH3(O2CCF3)



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187) Brown, H. C.; Subba, Rao, B.C. J. Org. Chem. 1957, 22, 1136; Chem. Abstr. 52, 7136c

188) Koester, R. Ann. Chem. 1958, 618, 31; Chem. Abstr. 53, 10014g

189) Koester, R. Angew. Chem. Int. Ed. Engl. 1964, 3, 174 190) Brown, H.C.; Murray, K.J. J. Am. Chem. Soc. 1959, 81,

4108; Chem. Abstr. 54, 5435f



177

191) Zweifel, G; Brown, H.C.; “Organic Reactions” 1963, 13, 22 J. Wiley and Sons; Chem. Abstr. 60, 7881a

192) Brown, H.C.; Garg, C.P. J. Am. Chem. Soc. 1961, 83, 2951; Chem. Abstr. 56, 9983e

193) Brown, H.C.; Kabalka, G.W.; Rathke, M.W. J. Am. Chem. Soc. 1967, 89, 4530; Chem. Abstr. 67, 99594q

194) Brown, H.C et. al. J. Am. Chem. Soc. 1964, 86, 35654; Chem. Abstr. 61, 11886c

195) Rathke, M.W. et. al. J. Am. Chem. Soc. 1966, 88, 2870; Chem. Abstr. 65, 7072e

196) Honeycutt, Jr. J.B. Riddle, J.M. J. Am. Chem. Soc. 1960, 82, 3051; Chem. Abstr. 55, 5330b

197) Brown, H.C.; Snyder, C.H. J. Am. Chem. Soc. 1961, 83, 1001; Chem. Abstr. 55, 14283e

198) Brown, H.C.; Verbrugge, C.; Synder, C.H. J. Am. Chem. Soc. 1961, 83, 1001; Chem. Abstr. 55, 16392b

199) Brown, H.C.; Rogic, M.M. Organomet. Chem. Syn. 1972, 1, 305; Chem. Abstr. 77, 75239h

200) Brown, H.C.; Midland, M.M. Angew. Chem. Int. Ed. Engl. 1972, 11, 692; Chem. Abstr. 77, 75239h

201) Brown, H.C.; Rathke, M.W. J. Am. Chem. Soc. 1967, 89, 2737; Chem. Abstr. 67, 99562c

202) Brown, H.C.; Rathke, M.W. J. Am. Chem. Soc. 1967, 89, 2738; Chem. Abstr. 67, 99566g

203) Brown, H.C.; Rathke, M.W. J. Am. Chem. Soc. 1967, 89, 2740; Chem. Abstr. 67, 54196v

204) Brown, H.C.; Colman, R.A.; Rathke, M.W. J. Am. Chem. Soc. 1968, 90, 499; Chem. Abstr. 68, 104335h

205) Brown, H.C.; Negishi, E. J. Am. Chem. Soc. 1967, 89, 5478; Chem. Abstr. 68, 21596t

206) Gribble, G.W.; Ferguson, D.C. J. Chem. Soc., Chem. Commun. 1975, 535; Chem. Abstr. 83, 131278h

207) Gribble, G.W.; Heald, P.W. Synthesis 1975, 650; Chem. Abstr. 84, 43791k

208) Umino, N.; Iwakuma, T. Itoh, N. Tetrahedron Lett. 1976, 763; Chem. Abstr. 85, 20719z

209) Gribble, G.W. et. al. J. Am. Chem. Soc. 1974, 96, 7812; Chem. Abstr. 82, 16650r

210) Marchini, P. et. al. J. Org. Chem. 1975, 40, 3453; Chem. Abstr. 83, 20861s



178

211) Hutchiuns, R.O.; Natale, N.R. J. Org. Chem. 1978, 43, 2299; Chem. Abstr. 89, 5969v

212) Gribble, G.W.; Leiby, R. W.; Sheehan, M.N. Synthesis 1977, 856; Chem. Abstr. 88, 89018z

213) Haire, M.J. J. Org. Chem. 1977, 42, 3446; Chem. Abstr. 87, 183524n

214) Gribble, G.W.; Leese, R.M.; Evans, B.E. Synthesis 1977, 172; Chem. Abstr. 86, 170986u

215) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976, 2875; Chem. Abstr. 86, 16375n

216) Ger. Offen. 2,701,888; Chem. Abstr. 87, 1284194s

217) Maki, Y. et. al. Chem. Lett. 1975, 1093; Chem. Abstr. 83, 192711r

218) Maki, Y. et. al Tetrahedron Lett. 1975, 3295; Chem. Abstr. 83,192758m

219) Maki, Y. et. al Chem. Ind. 1976, 332; Chem. Abstr. 85, 62767u

220) Kikugawa, Y. Chem. Lett. 1975, 1029; Chem. Abstr. 83, 192759n

221) Kikugawa, Y. Chem. Pharm. Bull. 1976, 24, 1059; Chem. Abstr. 85, 108365s

222) Kikugawa, Y.; Yokayama, Y. Chem. Pharm. Bull. 1976, 24, 1939; Chem. Abstr. 86, 43522q

223) Reed, J.W.; Ho, H.H.; Jolly, W.L. J. Am. Chem. Soc. 1974, 96, 1248; Chem. Abstr. 80, 103345x

224) Reed, J.W.; Jolly, W.L. J. Org. Chem. 1977, 42, 3963; Chem. Abstr. 88, 6495d



179

IV. ANALYTICAL PROCEDURES FOR BOROHYDRIDES Disclaimer: These methods were developed for internal use by Rohm and Haas and are provided as an aid to our customers and other interested parties. While we believe the information contained herein to be reliable, we assume no liability for its use. It is suggested that the user validate these procedures for his/her own specific needs and samples. Assay Methods Sodium borohydride may be determined gasometically, the hydrogen evolution method (1-5), or volumetrically (6-9). Jensen (8) lists four volumetric methods of assay: acid and base titration (1), the iodate method (7), a hypochlorite method (6), and a potentiometric titration with permanganate. Sodium borohydride has also been determined volumetrically by an iodine method (2,10), a Chloramine T method (11) and the argentimetric method of Brown and Boyd (12). Other methods that have been reported to be successful include an indirect spectrophotometric

method based on the reduction of acetone to isopropyl alcohol (13), a gas chromatographic method based on the reduction of isobutyaldehyde to isobutyl alcohol (2), and a polarographic method (14, 15) Of the above methods, the gasometric or hydrogen evolution method is reported to be the most accurate (13,16, 17). In the volumetric methods, especially those involving oxidation-reductions in acid media, there are two competing reactions: the oxidation-reduction reaction, involving sodium borohydride and the oxidizing species; and the hydrolysis reaction. Harzdoff (9) reports that, in some cases, upon acidification of the alkaline iodate-sodium borohydride solution, gas evolution was observed. For quantitative results using iodometric methods, the borohydride must react with iodine or an iodine complex at a much faster rate than the rate of hydrolysis. The mechanism is reported to be most complicated (18). Lichtenstein (13) reports that results from his indirect spectrophotometric method agree with the hydrogen evolution method. He also reports that the iodate results vary with the concentration of the iodate used. In a Rohm and Haas study (16), the results from the hydrogen evolution technique agreed well with those obtained by the gas



180

chromatographic method. The iodate results were 1 to 2 % lower. The method most commonly used at Rohm and Haas for assays are the hydrogen evolution and iodate methods. The hydrogen evolution method is used for finished goods where high accuracy and precision is required. The iodate method is used for in-process control, in kinetic studies and by customers who do not want to use the hydrogen evolution method since it requires more specialized equipment than is usually available in the laboratory. Trace Methods for Borohydride The hydrogen evolution and iodate methods are both useful for the determination of small amounts of sodium borohydride (2). In the hydrogen evolution method, the 2000-mL reservoir used in the assay method is replaced with a 100-mL gas burette. A confining solution designed to dissolve only small amounts of gas (19) is used in place of water. This method will easily detect 100 ppm NaBH4. In the iodate method, 0.025 N iodate and 0.01 N thiosulfate solutions are used in place of the more concentrated

solutions used in the assay method. This method will detect as low as 20 ppm of NaBH4. Other methods used successfully for trace borohydride determinations include the NAD+ method (20,21), the crystal violet method (22, 23), the phosphomolybdic acid method (24) and the NBC+ method (25,26) In the NAD+ method, NaBH4 reduces nicotinamide adenine dinucleotide to a UV absorbing species, and the NADH is detected spectrophotometrically at 340 nm. In the crystal violet method, a solution of crystal violet in DMF is employed to titrate an organic solution containing borohydride to a purple end point. In the colorimetric method, phosphomolybdic acid is reduced with sodium borohydride to a blue color. The color can be measured at 665 nm. Table VIII lists the advantages and disadvantages of the various methods used at Rohm and Haas Company.



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Table VIII Analytical Methods for NaBH4

Test Method Advantages DisadvantagesAssay Hydrogen

evolution A highly

accurate absolute method based on gas laws.

Requires specialized glassware and close temperature control

Assay Iodate Rapidmethod Glassware readily available

Results are about 1 to 2% low due to a slight hydrolysis side reaction in the acidification step.

Trace 30-300 ppm

Hydrogen Evolution

Simple, Fast

Requires specialized glassware.

Trace 20-200 ppm

Iodate Rapidmethod Glassware

Other oxidants and reductants

readily available

interfere.

Trace 1-200 ppm

NAD+ Rapid,simple method applicable over a wide pH range

Reagent is expensive and unstable. Must be done in aqueous solution.

Trace 1-2000 ppm

Crystal Violet

Rapid, simple method

Not applicable to caustic solutions or where strong nucleophiles are present. Has been applied to aqueous and non-aqueous systems.



182

NaBH4 Assay-Hydrogen Evolution Method A. Apparatus

See Figure 13. B. Reagents

1) Distilled Water 2) Hydrochloric Acid (6 N)- Mix equal amounts

of concentrated HCl and distilled water. C. Procedure

1) Weigh a 3 to 4 g sample of a stabilized water solution of sodium borohydride, or a 0.5 g sample of the dry product to the nearest 0.0001g, into flask F, which is fitted with a rubber stopper.

2) Rinse down column C with a stream of distilled water to remove any acid from a previous run. Dry the inner glass tubing (8 mm O.D. tubing shown in the diagram just below the inner seal of column C) with a paper towel.

3) Fill the 2000-mL bulb G with distilled water through the 20 mL bulb H and then adjust the height of the H-shaped tube until the water level is the same at A and B.

4) Remove the rubber stopper and immediately attach flask F to the apparatus and secure it with a strong rubber band.

5) Being sure that column C and tubing below the inner seal are dry, vent flask F to the atmosphere by opening and closing the 2 mm stopcock. The water level at A and B should not change. NOTE: If the water level at B drops, add more water through the bulb H. If water overflows at E discard the water.

6) Place a tared 2-liter beaker under E and lower the H-shaped tube until B is at a level with D. No water should overflow at E if the system is airtight and properly adjusted

7) Slowly add through C and the 2 mm stopcock: 10 mL of water, 10 mL of HCl (1:1) and 10m mL of concentrated HCl. Cool flask F momentarily in a water bath whenever the reaction is too vigorous. Do not allow any air into the system through C. Rock the apparatus back and forth to insure completeness of reaction.

8) When gas evolution has ceased, cool flask F to room temperature in a water bath. This will pull water from B back into G. Take enough water from the 2-liter


183

beaker and adjust the height of the H-shaped tube so that the water level in B is the same as the water level in the 2000-mL bulb G.

P = Barometric pressure correction in millimeters of Hg due to the vapor pressure of water at temperature t. A 3 millimeter correction is added to the vapor pressure of water to correct for the difference in expansion of the mercury and the brass scale of the barometer (see Table IX).

9) Record the temperature of the water in the 2-liter beaker. Record the barometer pressure. Record the weight of the water and the 2-liter beaker. The net weight of the water is the weight of water displaced by the hydrogen evolved.

W = Sample weight in grams Table IX Hydrogen evolution procedure for the determination of NaBH4.

Water Temperature

(oC)

Barometric Pressure

Correction (-)

Density of Water (g/mL)

15.0 15.8 0.999115.5 16.216.0 16.6 0.999016.5 17.117.0 17.5 0.998817.5 18.018.0 18.5 0.998618.5 19.019.0 19.5 0.998419.5 20.020.0 20.5 0.9982


W2 = Weight of beaker and contents in grams W1 = Weight of empty beaker in grams D = Density of water at temperature t in grams/mL. V = Volume of water and acid added to flask in mL. t = Temperature of the water in the 2-liter beaker in oC. This should represent the temperature of the system. B = Barometric pressure in millimeters of Hg.

% NaBH4 =W2-W1

D-V

B-P

273 + t

15.17

W(1000)



184

20.5 21.021.0 21.6 0.998021.5 22.222.0 22.8 0.997822.5 23.423.0 24.1 0.997623.5 24.724.0 25.4 0.997324.5 26.025.0 26.7 0.997125.5 27.526.0 28.2 0.996826.5 29.027.0 29.7 0.996527.5 30.528.0 31.3 0.996328.5 32.229.0 33.0 0.996029.5 33.930.0 34.8 0.995730.5 35.731.0 36.7 0.9954

31.5 37.732.0 38.7 0.995132.5 39.733.0 40.0 0.994733.5 41.834.0 42.9 0.994434.5 44.035.0 45.2 0.9941

Figure 13



185

NaBH Assay- Iodate Method 4Warning: Chloroform is a cancer suspect

agent A. Generation of iodine in situ:

IO + 5 I + 6 H+ 3 I + 3 H O 3- -

2 2 Reaction with sodium borohydride: BH + 4 I + 10 H O B(OH) + 8 I + 7 H 0

4-

2 2 3-

3+

Titration of excess iodine with thiosulfate: I + 2 S O S O + 2 I2 2 3

-24 6

-2 -

B. Reagents

1. 6N H SO , Cautiously add 100 mL of concentrated H SO to 500 mL of distilled water while stirring. Mix and cool.

2 4

2 4

2. Starch Indicator Solution. Mix 4 grams of soluble starch and 10 milligrams of HgI with

40 mL of distilled water. Add the starch paste, with stirring, to 1000 mL of boiling distilled water. Allow to cool and settle. Use the supernatant liquid. Alternately, 1 mL of chloroform may be used in place of the HgI .

2

23. Potassium Iodide. Free Flowing. The highest purity

reagent should be used. It should be checked before using, for iodate as follows: dissolve 1g in 25 mL of water; add 2 mL of starch solution and 1 mL of 6 N H SO . There should be no immediate appearance of a blue color. If there is the bottle should be rejected.

2 4

4. Sodium Hydroxide (1N). Dissolve 40 grams of high purity NaOH pellets in 500 mL of distilled water. Cool. Dilute to one liter.

5. Potassium Iodate (0.25N). Dissolve 8.9173 grams of primary standard KIO in freshly boiled and cooled water. Dilute to one liter.

3

6. Sodium Thiosulfate (0.1N) Dissolve 25 grams of Na S O • 5H O in one liter of freshly boiled and cooled water. Add 0.1 gram of Na CO to the solution and allow the solution to stand for a day before standardizing. Standardize as follows: Transfer 15 to 18 mL of the standard iodate solution

2 2 3 2

2 3



186

to a 250-mL glass stoppered iodine flask. Add 50 mL of distilled water and 2 grams of KI. When the KI has dissolved, add 10 mL of 6 N H SO . Titrate with the Na S O solution to a faint yellow. Add starch indicator solution and continue the titration to the disappearance of the blue color. Calculate the normality for the Na S O solution as follows. Record to four places behind the decimal.

2 4 2 2 3

2 2 3

N = Volume of KIO3, mL x N

Volume of Na2S O , mL 2 3 Alternately, this solution may be standardized against a potassium iodate “standardette” available from Chemical Services Laboratories, P.O. Box 281, Largo, Florida 33540



187

1. Procedure for Dry NaBH 4• Weigh a 0.5-gram sample, to the nearest 0.0001g

into a stoppered vial and quantitatively transfer to a 250-mL volumetric flask with 1 N NaOH.

• Dilute to the mark with 1 N NaOH and mix well. • Pipette a 10.0 mL aliquot into a clean iodine flask

and immediately add 35.0 mL of 0.25 N KIO solution.

3

• Transfer the iodine flask to a top loading balance and add 2g of KI crystals. Swirl to dissolve KI.

• Add 10 mL of 6N H SO , stopper, swirl to mix and allow to stand in a cool, dark place for 2 to 3 minutes.

2 4

• Wash down the stopper and the sides of the flasks with distilled water. Titrate with 0.1 N Na S O , using starch indicator, to a colorless end point.

2 2 3

% NaBH = 4 (XN1-YN2) x 11.83

W X = Volume of KIO , mL 3N = Normality KIO 1 3Y = Volume of Na S O , mL 2 2 3

N = Normality Na S O 2 2 2 3W = Sample weight in grams

2. Procedure for aqueous NaBH 4• Weigh a 0.2 to 0.3 gram sample to the nearest 0.0001g into a

clean dry stoppered iodine flask containing 10 mL of 1N NaOH

• Add 0.25 N KIO solution according to the following table: 3

Sample size, Grams Volume of iodate to be added (mL)

0.15 300.20 350.25 400.30 45

• Transfer the iodine flask to a top loading balance and add 2

grams of KI crystals. Swirl to dissolve the KI. • Add 10 mL of 6N H SO , stopper, swirl to mix, and allow to

stand in a cool, dark place for 2-3 minutes. 2 4

• Wash down the stopper and the sides of the flask with distilled water. Titrate with 0.1N Na S O , using starch indicator, to a colorless end point.

2 2 3



188

% NaBH4 = (XN1-YN2) x 0.4731 W

Legend of symbols : see dry NaBH 4

Trace NaBH Assay-Hydrogen Evolution 4

Apparatus

See Figure 14

Reagents and Solutions 1. Confining solution: Dissolve 200 g of

Na SO in a solution composed of 800 mL of water and 40 mL of concentrated H SO

2 4

2 42. Concentrated H SO 2 4

Procedure:

1. In order to expel all the air from measuring burette (B)- the leveling bulb is raised while stopcock is open. A small amount of confining liquid is expelled to insure absence of air, and stopcock S is then closed. The

level in measuring burette should remain constant when leveling bulb is lowered.

2. Weigh a 100 g sample to the nearest 0.0001 g into a 250-mL evolution flask F.

3. Attach the evolution flask F to apparatus with stopcock E open. Close stopcock E and open S to evolution flask.

4. Add 20 mL of concentrated H SO through dropping column D while magnetic stirrer is stirring solution. NOTE: Strength of acid depends on material to be decomposed and hydride to be determined.

2 4

5. Keep solution in evolution flask at the same temperature as confining liquid.

6. Read the volume of evolved hydrogen by raising and lowering leveling bulb until its level is the same as the level inside the burette (V ). 2

7. Record temperature (t) of confining liquid and barometric pressure (B).

8. Run blank on NaBH free sample. Record volume displaced, (V ).

4

1



189

Figure 14 Calculation % NaBH = (V2-V1) x (B-3-P)* x 15.17 4

1000 x (273+t) x W

ppm NaBH = % NaBH x 10 44 4

V = The volume of gas evolved when sample is reacted, mL 2

V = The volume of gas evolved when blank is used, mL 1 B = Recorded barometric pressure in mm of Hg. P = The vapor pressure in mm of the confining solution at the temperature t. See Figure 15. t = Recorded room temperature in C o

W = Sample weight in grams. *3 mm are subtracted from the observed barometric pressure to correct for the difference in expansion of the mercury and the brass scale at different temperatures. Exact corrections can be found in any chemical handbook.



190

Figure 15




191

Trace NaBH Assay- Iodate Method 4

Generation of iodine in situ:

IO + 5 I + 6 H+ 3 I + 3 H O 3- -

2 2

Reaction with sodium borohydride:

BH + 4 I + 10 H O B(OH) + 8 I + 7 H 0 4-

2 2 3-

3+

Titration of excess iodine with thiosulfate:

I + 2 S O S O + 2 I2 2 3

-24 6

-2 -

A. Reagents and Solutions

1. 0.025 M Potassium Iodate 0.8917g/L 2. 0.01N Sodium Thiosulfate –2.5g/L

(NaS O •5 H 0) 2 3 23. Starch solution 4g of soluble starch per

liter of boiling distilled water. Use HgI or chloroform as a preservative.

2

4. 6N H SO - 100 mL of concentrated H SO in 500mL of H O.

2 4 2 4

25. 1N NaOH –40g/L

B. Procedures: 1. Weigh a 100-gram sample to the nearest 0.0001 g

and transfer it to a 500 mL iodine flask with 1N NaOH

2. Add 50-75 mL of H O (two layers develop-organic and an aqueous layer if the sample is organic).

2

3. Add equivalent amount of 0.025 N KIO (1 mL 0.025 N= 0.00012 g NaBH ) plus 10 mL in excess.

3

4

4. Add 2 g of potassium iodide and 10 mL of 6N H SO for every 10 mL of 1N NaOH present. 2 4

5. Titrate to yellow end point with 0.01 N Na S O , shaking vigorously while titrating.

2 2 3

6. Add 5 mL of starch and continue titration to clear end point.

7. Calculation:



192

g NaBH4 =[(V1 x N1) – (V2 x N2)] x 0.004731 g sample Weight of the sample

V = Volume of KIO1 3, mL N1= Concentration of KIO3 solution V2= Volume of Na2S2O3, mL N2= Concentration of Na2S2O3 solution ppm NaBH4 = (g NaBH4/ g sample) x 106



193

NaBH4 Trace Assay -NBC (Nicotinamide Benzyl Chloride)

A. Reagents and Solutions 1. KOH (0.5M)- Prepared by dissolving 3.27

grams of 85 % KOH in water and diluting to one liter.

2. HNO3 (4N, 25 %) 3. Tris(hydroxymethyl)aminomethane

(THAM®)-99.9 min 4. Trisbuffer (0.5M)-Prepared by dissolving

6.06 grams of THAM in water and diluting to one liter. The pH is adjusted to 8.5 with 4N HNO3 using a pH meter.

5. Nicotinamide benzyl chloride (NBC)- see section B for synthesis.

6. NBC solution (0.5M) – prepared by dissolving 0.62 grams of NBC in 50 mL of water.

7. NaBH4- high purity (99%). Rohm and Haas Product

8. NaBH4 stock solution (200 µg/mL)- prepared by weighing 20 mg of NaBH4 to the nearest

0.0001g into a 100-mL volumetric flask and diluting to the mark with 0.5 M KOH. This solution should be made freshly daily.

9. NaBH4 working solution (20 µg/mL)-Prepared by pipeting 10 mL of the NaBH4 stock solution into a 100 mL volumetric flask and diluting to the mark with 0.5M KOH. This solution should be prepared freshly daily.

B. Synthesis of Nicotinamide Benzyl Chloride (26)

1. Charge a 250-mL round bottom flask, fitted with a drying tube and reflux condenser, with 12.2 g of nicotinamide and 100 mL of methanol (spectrophotometric grade).

2. Dissolve 12.6 g of benzyl chloride in 20 mL of methanol and add to the flask in step 1.

3. Heat the solution under reflux conditions for eighteen hours.

4. Cool the reaction flask to ambient temperature and collect the crystalline salt, which precipitates, on a filter paper.



194

5. Wash the crystals with three 1.5 mL portions of cold (0 oC) methanol and dry to constant weight in a vacuum oven (0.5 mm Hg and 25 oC)

C. Calibration

1. Immediately before use, prepare a reagent mixture of 50 mL of 0.05M NBC and 850 mL of 0.05 THAM buffer. Dispense 85 mL of this mixture into each of six 100-mL volumetric flask.

2. Add 8 mL of 0.05M KOH to each flask. 3. Add 0.0, 1.0, 2.0, 3.0, 4.0 and 5.0 mL of the

NaBH4 working solution (20, 40, 60, 80, 100 µg NaBH4) to each flask, dilute to volume with 0.05 M KOH and mix well.

4. Zero the spectrophotometer at 360 nm using the blank (no NaBH4) solution in the 1.0 cm reference and sample cells.

5. After 10 minutes measure the absorbance of each of the standards at 360 nm.

6. Prepare a calibration curve by plotting absorbance versus amount of NaBH4.

D. Procedure 1. Dispense 85 mL of the THAM/NBC mixture (see C

1) into each of two 100 mL volumetric flasks. 2. Add 8 mL of 0.05 M KOH to each flask. 3. Add up to 5 mL of the sample containing NaBH4 to a

100-mL volumetric flask. Add 5 mL of sample matrix containing no NaBH4 (blank sample) to a second 100-mL flask.

4. Dilute the contents of the flasks to 100 mL with 0.05 M KOH.

5. Measure the absorbance of each solution at 360 nm after 10 minutes.

E. Calculations NaBH4 concentration (ppm) = (S-B)( C )(D) W S = absorbance of NaBH4 – treated sample B = absorbance of blank C= slope of calibration curve, µg NaBH4/ absorbance unit D = dilution factor, if any W = Weight of sample in g



195

NaBH4 Trace Assay – Crystal Violet Method A. Reagents and solutions

1. Crystal Violet (CV+)- Aldrich 22,928-8, 95 % or equivalent

2. N,N dimethylformamide (DMF)- must be specto -grade.

3. NaBH4- high purity (99 %) Rohm and Haas

B. Procedures: 1.Prepare a solution of CV+ in DMF using the

following guidelines: Exempted NaBH4 Recommended concentration Concentration, ppm of Crystal Violet Solution 0.019 g CV+ dye diluted to 1.0 L with DMF 200-2000 0.19 g CV+ dye diluted to 1.0 L with DMF NOTE: DMF is a toxic solvent and should be handled with gloves in the hood. Crystal violet is a suspected cancer agent.

2. Prepare a standard solution of NaBH4 by dissolving approximately 0.02 g 99% NaBH4 weighed to the nearest 0.0001g in a 100-mL volumetric flask with DMF. Use this solution to standardize the less concentrated CV+ solution. Prepare a more dilute NaBH4 solution by transferring a 10-mL aliquot of the original NaBH4 standard into a 100-mL volumetric flask and diluting to the mark with DMF.

3. Standardize the CV+ solution by titrating a 2.0mL aliquot of each NaBH4 standard with the appropriate CV+ solution to the purple endpoint.

4. Accurately weigh a sample, to the nearest 0.0001g into Erlenmeyer flasks according to the guidelines (see table X)

F= wt of SBH, g x dilution x 2 mL aliquot x 106 µg/g

100 mL (if any) vol of CV+

titrated, mL 5. Add DMF to solubilize sample (if solid) or to bring

total sample and DMF volume to approximately 2-5 mL. Titrate with the appropriate CV+ solution to the first purple endpoint which remains for 60 sec.



196

C. Calculations 1. Calculate the concentration of SBH in the

sample as follows:

ppm NaBH4 = F Volume of CV+, Sample wt, g ml used for

sample titration

Where: F = Titer value of the appropriate CV+ titrant, previously calculated in step B 3. Table X Expected NaBH4 Concentration in ppm

Suggested Sample Weight, g

Expected Volume of Titrant, mL

Recommended CV+

Concentration

0-25 3 Up to 42.6 25-50 1.5 21.3-42.650-100 0.75 21.3-42.6 0.019g CV+/L 100-200 0.4 22.7-45.4 200-500 1.5 17.0-42.6500-1000 0.75 21.3-42.6 0.19g CV+/L 1000-2000 0.4 22.7-45.4

References: 1) Davis, W.D.; Mason, L.S.; Stegeman, G. J. Am.

Chem. Soc. 1949, 71, 2775; Chem. Abstr. 43, 7805d 2) Morton Thiokol, inc. Ventron Products, Unpublished

standard methods 3) Krynitsky, J.A.; Johnson, J.E.; Carhart, H.W. Anal.

Chem. 1948, 20, 311; Chem. Abtsr. 42, 40941 4) Fatt, I.; Tashima, M. “Alkai Metal Dispersions”,

D.Van Nostrand Co. , Inc., Princeton, Newy Jersey, 1961, 98

5) Jensen, E.H. “A Study on Sodium Borohydride” Nyt Nordisk Forlag Arnold Busck, Copenhagen 1954, 49

6) Chaikin, S.W. Anal. Chem. 1953, 25, 831; Chem. Abstr. 47, 7371g

7) Lyttle, D.A.; Jensen, E.H.; Struck, W.A. Anal. Chem. 1953, 24, 1843

8) Jensen, E.H. “A Study on Sodium Borohydride” Nyt Nordisk Forlag Arnold Busck, Copenhagen 1954, 49

9) Harzdorf, C.F. Anal. Chem. 1965, 210, 12; Chem. Abstr. 63, 16f

10) Skoblionok, R.F.; Mochalov, K.N.; Berner, B.G. Zh. Anal. Khim. 1968, 23, 1518; Chem. Abstr. 70, 16832d



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11) Shah, A.R.; Padma, D.K.; Murthy, A.R.V. Analyst (London) 1972, 97, 17; Chem. Abstr. 76, 94184g

12) Brown, H.C.; Boyd Jr., A.C. Anal. Chem. 1955, 27, 156; Chem. Abstr. 49, 6031e

13) Lichtenstein, I.E.; Mras, J.S.; J. Fanklin Institute 1966, 281, 481; Chem. Abstr. 65, 6300f

14) Pecsok, R.L. J. Am. Chem. Soc. 1953, 75, 2862; Chem. Abstr. 47, 9817e

15) Gardiner, J.A.; Collat, J. J. Am. Chem. Soc. 1965, 87, 1692; Chem. Abstr. 62, 13899b

16) Morton Thiokol, inc. Ventron Products, Unpublished Report 1967

17) Novakova, A.; Hanovsek, F.; Stuchlik, J. Chem. Prum. 1977, 27, 293; Chem. Abstr. 88, 83074t

18) Freund, T. J. Inorg. Nucl. Chem. 1959, 9, 246; Chem. Abstr. 53, 16665h

19) Kobe, K.A.; Kenton, F.H. Ind. Eng. Chem. Anal. Ed. 1938, 10, 76; Chem. Abstr. 32, 2459

20) Werner, D.A.; Huang, C.C.; Aminoff, D. Anal. Biochem. 1973, 54, 554; Chem. Abstr. 79, 61169q


22) Bunton, C.A.; Huang, S.K.; Paik, C.H. Tetrahedron Lett. 1976, 1445; Chem. Abstr. 85, 108063s

23) Rudie, C.N.; Demko, P.R. J. Am. Oil Chem. Soc. 1979, 56, 520; Chem. Abstr. 90, 214801u

24) Hill, W.H.; Merrill, J.M.; Larsen, R.H.; Hill, D.L.; Heacock, J.F. Amer. Ind. Hyg. Assoc. J. 1959, 20, 5; Chem. Abstr. 54, 13965h


26) Beillmann, J.F.; Challot, H.J. Bull. Soc. Chim. Fr. 1968; Chem. Abstr. 69, 59060x



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V. AVAILABILITY Sodium borohydride is available in different forms to satisfy a variety of process needs. VenPure SF powder is a formulation of NaBH4 designed for usage in solvents, like THF, which require a large active surface. A proprietary anti-caking agent is used to increase the product’s flowing characteristics. VenPure AF caplets is a NaBH4 product designed to be dissolved in solvents like water and methanol. The caplets are bean-shaped pellets are about 1 cm long, which allow for a dust-free, straightforward use & handling. It does not contain an anti-caking agent. VenPure SF granules is an NaBH4 product designed for large scale usage in solvents such as ethanol and glymes. The particle size is comparable to table sugar (> 0.5mm), with only small amounts of fines (typically < 3%), which allows for a straightforward use and handling. A proprietary anti-caking agent is used to increase the product’s flowing characteristics.

As compared to VenPure SF granules, VenPure AF granules do not contain an anti-caking agent, which adds to its high purity. VenPure 20/20 solution is an aqueous formulation of NaBH4. It is a pumpable liquid, that contains 20% NaOH to assure transport-stability. VenPure solution is an aqueous formulation containing 40% NaOH, which makes it extremely stable, and suitable for high temperature chemistry. Sodium borohydride dry forms (powder, granules and caplets) are shipped in polyethylene bags packed in metal containers. They are classified by DOT regulations as dangerous when wet. Motor freight and or boxcar can ship unlimited quantities. Sodium borohydride solution is classified as a corrosive liquid under DOT regulations. The material is packaged in 5-gallon pails and 55-gallon drums containing 10% free space. Bulk quantities are shipped via tank truck or tank car.



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VI. PERSONAL PROTECTIVE EQUIPMENT

Dry Dry borohydride products are corrosive to eyes,

skin and respiratory tract. They will cause irritation or chemical burns if left in contact with moist skin or respiratory tract. Therefore, the use of personal protective equipment is required upon handling. The level of equipment required can vary depending on the expected level of exposure. We recommend : • Chemical goggles • Dust mask and/or a full face shield • Rubber gloves • Coveralls • Rubber boots or closed leather footwear

When the potential for exposure is significant, we

recommend wearing in addition to the above: • Apron or chemical resistant suit • A NIOSH-approved respirator for corrosive dusts

in place of dusk mask

Borohydride dust can contaminate personal protective equipment and result in chemical burns -care must be taken to keep equipment clean and serviced

Solution

Sodium borohydride solutions contain sodium borohydride stabilized with sodium hydroxide. These products are strongly alkaline and corrosive. They can be handled with the same personal protective equipment used when handling 50 % caustic. We recommend the following personal protective equipment when handling the solution form: • Chemical splash goggles and a full face shield • Impervious rubber gloves • Coveralls • Rubber boots with pants over boots (Note : Sodium borohydride solutions are very corrosive to leather)

When handling larger amounts, or when the potential

for exposure is greater, a rubber apron or chemical resistant suit can also be worn. If mist is expected, wear a NIOSH –approved respirator for corrosive mists.



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VII. FIRST AID Dry

Eye contact Immediately flush eyes with copious amounts of water for at least 15 minutes, including under the eyelids. Then seek immediate medical attention.

Skin Contact Immediately flush affected area with copious amounts of water for at least 15 minutes. For larger exposures, use an emergency shower. Remove contaminated clothing and shoe. Cleanse skin with soap and water, including hair and under fingernails. Then seek immediate medical attention.

Inhalation Remove to fresh air. If symptoms develop, seek immediate medical attention. If not breathing, give artificial respiration.

Ingestion Powder/Granules: Rinse mouth with water and give another cupful of water to drink. Do not give carbonated

drinks. Do NOT induce vomiting unless directed by medical personnel. Seek immediate medical attention. Caplets: Give several glasses of water to drink and induce vomiting as directed by medical personnel. Seek immediate medical attention. Solution

Eye Contact Immediately flush eyes with copious amounts of water for at least 15 minutes, including under the eyelids. Then seek immediate medical attention.

Skin Contact Immediately flush affected areas with copious amounts of water for at least 15 minutes. For large exposure, use an emergency shower. Remove contaminated clothing and shoes. Cleanse skin with soap and water, including hair and under fingernails. Seek immediate medical attention. Professionally wash clothing before re-use.

Inhalation If mist is inhaled, move to fresh air. Rinse mouth with water. If symptoms develop, seek immediate medical attention. If not breathing, give artificial respiration.



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Ingestion Give several glasses of water to drink. Do not give carbonated drinks. Do not induce vomiting, seek immediate medical attention.

Note to physician: Highly alkaline materials can cause extensive and deep penetrating tissue damage. There is danger of hemorrhage and perforation if lavage is performed. No attempt should be made to neutralize the base with a weak acid.



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VIII REACTIVITY Dry

Dry borohydride products will react violently or explosively in contact with concentrated oxidizers. They will also react vigorously in contact with concentrated acids or under acidic conditions, generating heat and hydrogen gas. Solutions containing borohydride will also react to release hydrogen in the presence of transition metal salts or finely divided metallic precipitates. Dry borohydride products will ignite from a free flame due to hydrogen formation formed by decomposition and will continue to burn as hydrogen is evolved. Dry borohydride products also react with moisture in the air, leading to caking. The moisture will slowly react with the borohydride to liberate hydrogen gas. Some organic solvents, such as acetone and methanol, will react vigorously with borohydride. Other materials can generate heat and liberate hydrogen when high concentrations of borohydride are dissolved or slurried in these materials. Some known

examples are polyglycols (2-5% NaBH4) and Dimethyl formamide (over 7% NaBH4)

Solution NaBH4 solutions will react violently or explosively in contact with concentrated oxidizers. They will also react vigorously in contact with strong acids or under acidic conditions, generating heat and hydrogen gas. Solutions containing borohydride will also react to release hydrogen in contact with transition metal salts or finely divided metallic precipitates. Sodium borohydride solution will also react violently with aluminum due to the sodium hydroxide present in the solution. In addition, material as sensitive polymerization under alkaline conditions, such as acrylonitirle and ethylene oxide, may polymerize upon contact with sodium borohydride solution. This solution is also incompatible with ammonia also.

General Consideration In all cases where borohydride products are used, some H2 generation is expected. In many cases, H2 can be safely vented to the outside of the building. H2 should not be allowed to collect in a closed area.



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For reaction vessels, use N2 blanking to prevent an explosive atmosphere from forming. Under ambient temperature and pressure, N2 will prevent such conditions, as long as O2 concentration is below 5%. The use of explosion proof equipment is recommended.


Once the fire is extinguished, add additional smothering agents such as dolomite, dry sand or lime. Allow the material to cool before disturbing the

surface. Disturbing the surface too soon can cause the hot material to reignite.


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IX. FIRE FIGHTING/ FLAMMABILITY Dry Dry borohydride products are flammable solids and are classified by the U.S. DOT as Division 4.3- Dangerous when wet and the NFPA as a class 1 dust.

Fires involving dry sodium borohydride products should be controlled with dry chemical extinguishers: recommended dry chemical agents are sodium bicarbonate based, monoammonium phosphate based or equivalent. Do not use water, carbon dioxide or halogen type fire extinguishers. Sand, dolomite or lime should also be available in case the dry chemical agent is insufficient or in windy conditions.

Firefighters and others who may be exposed to the products of combustion should be equipped with NIOSH-approved positive pressure self-contained breathing apparatus (SCBS) and full protective clothing.

Solution Sodium borohydride solution is nonflammable. Any flammability is due to hydrogen generation upon decomposition. Under normal storage conditions, it is extremely stable, decomposing less than 0.01% per year. To prevent pressure buildup, 10% free volume is required for all closed containers, under these conditions, containers will normally generate less then 1 psig per year.



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X. SPILL AND WASTE DISPOSAL Dry In the U.S., spills and wastes of dry sodium borohydride products are regulated by the U.S. EPA’s Resource Conservation and Recovery ACT (RCRA) as a hazardous waste with the code D003-reactive and D001-Ignitable. Check with local regulations and guidelines for additional requirements. When dry borohydride products are spilled, clean-up personnel must wear appropriate personal protective equipment. Use non-sparking tools or explosion proof equipment to shovel or vacuum material into an appropriate container for disposal as hazardous waste. After removing the spill from the floor, the area should be rinsed with water, and the rinse water collected for disposal. Solution In the U.S. spills and wastes of borohydride solution products are regulated by the U.S. EPA’s Resource Conservation and Recovery Act (RCRA) as a

hazardous waste with the code D002-corrosive. Check with local regulations and guidelines for additional requirements. In the event of an accidental spill, immediate steps should be taken to :

1.) contain the spill, 2.) absorb the spill using an absorbent 3.) remove the spilled material for disposal.

Proper procedures and protective equipment should by employed as outlined in the section “Personal Protective Equipment.” Spills of solution should be prevented from entering any sewer or streams. Dams can be constructed by using sand, dolomite, or other absorbent material. Solution spills can be transferred to a container for disposal. All remaining liquids should be absorbed using the material mentioned above and then placed in a container for disposal. If permitted by regulatory authorities borohydride wastes, spills and rinse water streams can be neutralized and hydrolyzed on site prior to discharge. This can be



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accomplished by adding the borohydride to a large excess of water followed by the slow addition of dilute acid to a neutral pH. Hydrogen gas will evolve, therefore be sure the area is well ventilated and all sources of ignition are eliminated. If the spill occurs indoors, adequate ventilation should be maintained prior to proceeding with containment, cleaning and disposal. After removing the spill, the area should be rinsed with water and the rinse water collected for disposal. If the spill occurs outdoors, any contaminated soil should be removed and placed into a container for proper disposal. Empty drums and lines should be disposed of as industrial waste in accordance with local regulations.



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XI. TOXICITY Dry

Dry sodium borohydride powder and caplets have an acute dermal LD50 on dry skin of 4000 –8000 mg /kg and are not skin sensitizers. Toxicity is increased in the presence of moisture and can result in severe irritation and skin burns.

The acute oral LD50 of sodium borohydride powder or caplets is 69-mg/kg. This product is considered toxic under FHSA classifications.

The acute oral LD50 of potassium borohydride powder is 160-mg/kg. This product is considered toxic under FHSA classifications.

Solution

Solution of sodium borohydride in 50 % caustic has a dermal LD50 of 100-500 mg/Kg and is considered moderately toxic. This is primarily attributed to caustic soda, which can cause skin burns and irritation.

The acute oral LD50 of the SWS solution is 500-1000 mg/kg. This product is considered toxic under FHSA classifications.

Sodium borate, the product form the reaction or decomposition of sodium borohydride, is considered slightly toxic orally (LD50; 2000-4000mg /kg) and nontoxic dermally (LD50 8000 mg/kg).



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XII. STORAGE AND HANDLING Dry

Dry borohydrides products are hydroscopic and should not be unnecessarily exposed to moisture. Any contact with moisture will result in hydrogen evolution. They will remain stable indefinitely in dry air or sealed containers. Dry borohydride products should be stored in closed containers in a dry, cool, well ventilated area and kept separated from oxidizers, acids and other incompatible materials.

Store only in original containers as received or in properly marked plastic bottles, do not store in glass due to the potential for pressure buildup and rupture. Also do not store in aluminum containers. This applies to the product as received or any make-up thereof.

Empty containers can be hazardous, following label warnings even after container is emptied since they may retain product residues. Do not re-use empty container without professional cleaning for food, clothing, or product for human or animal consumption or where skin contact can occur.

Solution

Sodium borohydride solution can be stored and handled in the same manner as 50 % caustic. Sodium borohydride solution may be stored in adequately ventilated mild steel, stainless steel, polyethylene or fiberglass vessels suitable for caustic storage. As with caustic, Aluminum equipment must not be used with sodium borohydride solutions. Store only in original containers as received or in properly marked plastic bottles. Do not store in glass due to the potential for pressure buildup and rupture and the corrosive nature of sodium hydroxide on glass. This applies to the product as received or any make-of thereof.

Under normal conditions storage, the decomposition of sodium borohydride solutions is less then 0.01% per year. One of the decomposition products is hydrogen. All closed containers of sodium borohydride solution should have at least 10% free volume and should be checked periodically. If this is followed, pressure buildup will be less then 1 psig per year at normal storage temperatures.



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Sodium borohydride solution can be stored in stainless steel, mild steel, and approved fiberglass vessels. Stainless (316 SS or 304 SS) is recommended for piping, valves, pumps, etc. Sodium borohydride solution must not be stored in vessels that react with caustic soda, such as aluminum.

Sodium borohydride solution should be stored at temperatures between 65o F (18o C) and 100o F (37o C) for ease of handling. Below 65o F the solution viscosity increases rapidly, and at temperatures below 55o F (13o C), crystallization can occur. If crystallization occurs, liquefy by slowly warming to 70-90o F (21-32o C) while venting. Do not use live steam. Heating above 100o F is not recommended due to the increased decomposition at these temperatures.

Transfer piping exposed to cold temperature should be heat traced and/or insulated. Precaution should be taken to avoid overheating the piping, as excessive line pressure and/ or product decomposition may result.



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XIII. SHIPPING Dry For transport purpose, dry borohydride products are designated as hazardous material under U.S. DOT, IATA/ICAO and IMO as follows: Proper Shipping Name: Sodium Borohydride (Potassium Borohydride) Hazard Class/ ID Number: 4.3/UN 1426 for NaBH4 (4.3/ UN 1870 for KBH4) Packing Group:I Label: Dangerous when wet

Solution For transport purposes sodium borohydride solutions are designated as a hazardous material under U.S. DOT, IATA/ICAO and IMO as follows: Proper Shipping Name: For less then 1000 lb. (454 kg) of NaOH: Sodium borohydride and Sodium Hydroxide solution For 1000 lb. (454 kg) or more of NaOH: RQ, Sodium borohydride and Sodium Hydroxide Solution Hazard Class/ Id Number: 8/ UN3320 Packaging Group: II Label: Corrosive



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Disclaimer: To the best of our knowledge the information contained herein is correct. All products may present unknown health hazards and should be used with caution. Although certain hazards are described herein, we cannot guarantee that these are the only hazards which exists. Final determination of suitability of the product is the sole responsibility of the user. Users of the products should satisfy themselves that thee conditions and methods of use assure that the product is used safely. NO REPRESENTAIONS OR WARRANTIES, EITHER EXPRESSED OR IMPLIED, OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE OR ANY OTHER NATURE ARE MADE HERE UNDER WITH REPECT TO THE NFORMATION CONTAINED HEREIN OR THE PRODUCT TO WHICH THE INFROMATION REFERS. Nothing herein is intended as a recommendation to use our products so as to infringe any patents. We assume no liability for customer’s violation of patents or other rights. The customer

should make his own patent investigation relative to his proposed use.


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Please feel free to send us your questions via [email protected], or contact one of our offices :

in America: in Asia: in Europe: Rohm and Haas Company Rohm and Haas China, Inc. Rohm and Haas France S.A. S&PA 23rd Floor, Hitech Plaza la tour de Lyon 60 Willow Street No. 488 S. Wu Ning Road 185, rue de Bercy Phone: 1-978-557-1832 Shanghai, China F-75579 Paris Fax: 1-978-557-1879 Phone: +86 21 6230 6366 Phone: +33-1 4002 5210 Fax: +86 21 6230 6377 Fax : +33-1 4002 5441

Updated information can be found at : http://www.hydridesolutions.com/


mailto:[email protected]

http://www.hydridesolutions.com/

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Ethan Frome - The Dow Chemical Company