Chapter 2

21

2.1. Introduction to Catalytic Transfer Hydrogenation

Organic synthesis is more complicated than discovering and using

reagents that will accomplish desired transformations. This is because

synthetic intermediates and targets are usually polyfunctional molecules,

and a reagent may react with more functional groups in a substrate than

were intended by the chemist. Therefore, a significant effort by chemists

are spent developing new methods and finding new reagents that will be

chemoselective or able to transform one functional group in a

polyfunctional molecule and leave the remaining ones intact.

Reduction of organic compounds is synthetically important process

in laboratories, chemical and pharmaceutical industries. There are many

methods of effecting reduction which may or may not lead to

hydrogenation. Reduction of organic functional groups can be

categorized into (i) addition of hydrogen to unsaturated groups, for

example, in the reduction of ketones to alcohols and (ii) addition of

hydrogen across single bonds leading to cleavage of functional groups. In

all the methods available for addition of hydrogen to organic compounds,

heterogeneous catalytic transfer hydrogenation reactions have been

relatively underutilized. This lack of popularity can be traced to the

relatively meager success of much of the earlier research, which

suggested that the technique was of only limited scope and could provide

only modest yields of products.

The first catalytic hydrogenation recorded in the literature is

reduction of acetylene and ethylene in the presence of platinum black in

1874 by von Wilde1. However, the widespread use of catalytic

hydrogenation did not start until 1897, when Sabatier2 developed the

reaction between hydrogen and organic compounds to a universal

reduction methods and he received Nobel prize for his work in 1912.

Chapter 2

22

In the original work, hydrogen and vapour of organic compounds

were passed at 100-300oC over copper or nickel catalyst. This method of

carrying out the hydrogenation has been now almost completely

abandoned, and only instance of hydrogenation still carried out by

passing hydrogen through a solution of a compound to be reduced is the

Rosenmund reduction3. The early pioneering work by Braude4 in 1954 largely ignored because of poor yields and long reaction times but the

situation has changed considerably following the introduction of greater

catalyst loadings and different hydrogen donors5. Another reason for the

underutilization of transfer reduction has been the very successful

exploitation of molecular hydrogen and hydrides for reduction of organic

compounds.

In comparison with catalytic reduction using molecular hydrogen,

transfer reduction using hydrogen donors has real and potential

advantages. Molecular hydrogen is a gas of low molecular weight and

therefore high diffusibility, easily ignited and presents considerable

hazards, particularly on the large scale. The use of hydrogen donors

obviates these difficulties in that no gas usage is necessary, no pressure

vessels are needed and simple stirring of solutions is usually all that is

required. Potentially, transfer methods could afford enhanced selectivity

in reduction. With a catalyst and molecular hydrogen, change of catalyst,

solvent, and temperature are possible variations in reaction conditions

but, with hydrogen donors, a new dimension opened up because the

choice of hydrogen donor can affect the reaction through its competitive

adsorption onto the catalyst surface. Thus, rate and specificity of

reduction are amenable to control through choice of hydrogen donors.

In terms of electronegativity, hydrogen occupies a central position

in the periodic table. With Pauling’s definition of electronegativity6,

hydrogen, having a value of 2.1 lies between fluoride (4.0) and many

metals which typically have values of about 0.9-1.5. Therefore, in

Chapter 2

23

reactions involving its transfer, hydrogen may appear as a proton, atom

or hydride depending on reagents and conditions. On dissolving gaseous

HCl in water, hydrogen is transferred as a proton to water, the reaction

of lithium tetrahydroaluminate to a carbonyl group effectively involves

the addition of hydride to carbon of the carbonyl.

Many catalytic hydrogenations with molecular hydrogen actually

involve atomic hydrogen dispersed in and over the catalyst. In many

reductions with hydrogen donors, it may not be easy to decide just how

hydrogen transferred. For example, formic acid may be regarded as

providing a proton and a hydride or two hydrogen atoms. However, for

suitable hydrogen donor properties, it seems clear that compounds

containing hydrogen bonded to elements or groups with similar

electronegativity to that of hydrogen itself provide the best hydrogen

donors. In this respect formic acid, ammonium formate,

triethylammonium formate, hydrazinium monoformate, phosphinic acid

and phosphinates, phosphorus acid and phosphites, hydrazine, alcohols,

amines, hydrocarbons, hydrides of boron, aluminium, silicon and tin are

all hydrogen donors to catalytic transfer reductions. An added advantage

gained when the products of the decomposing donors have large negative

enthalpies of formation. Thus, CO2 from formic acid provide added

driving force to the reactivity of these substances as hydrogen donors.

2.1.1. Hydrogen Donors Virtually any compound with a low oxidation potential can serve as

a useful hydrogen donor. The low oxidation potential enables the transfer

of hydrogen(s) from the donor to the substrate under mild reaction

conditions. The choice of donor is based on the nature of the reaction, its

availability and solubility in the reaction medium. Alcohols, hydrazine,

cyclic olefins and hydroaromatics have been employed as hydrogen

donors for the transfer hydrogenation of various functional groups.

Formic acid and its salts occupy a special place as hydrogen donors

Chapter 2

24

because the ease of hydrogen donation is higher than the other donors.

This results from the fact that a stable molecule such as CO2, which has

a very large negative enthalpy of formation released from the hydrogen

donor during the transfer hydrogenation reaction. Simply stated, the

hydrogen donation is irreversible. This is one of the major driving forces

for the high reactivity of formates.

As previously stated, nature of the hydrogen donor influences the

selectivity and activity of the reduction. This additional flexibility can be

illustrated with an aromatic substrate possessing nitro and halo

functionalities. While the palladium coupled with a formate salt is a

remarkably effective reagent to remove halogens from an aromatic

nucleus and to reduce a nitro to an amino group, the same catalyst with

phosphinic acid as hydrogen donor can reduce the nitro group without

affecting halogen7.

Although homogeneous and heterogeneous catalysts can utilize

common types of compounds as hydrogen donors, it is more often the

case that different types of compounds are favored in the two systems.

The more active hydrogen donors for homogeneous catalysis appear to be

principally alcohols, hydroaromatics, cyclic ethers and occasionally

formic and ascorbic acids whereas for heterogeneous catalysis, the more

widely used donors tend to be hydrazine, formic acid and formates,

phosphinic acid and phosphinates, indoline and cyclohexene. There is no

clear division between the two types, but some of the hydrogen donors

which are active for heterogeneous catalysts are water-soluble inorganic

salts and cannot be used with many homogeneous catalysts. More

recently, trialkylsilanes and trialkylstannanes have proved to be good

hydrogen donors in both homogeneous and heterogeneous catalysis8.

Whereas tri-n-butylstannane reduced α,β-unsaturated aldehydes in

methanol under fairly drastic conditions9 in the presence of Pd(PPh3)4

and a promoter, the reduction can be achieved in 10 min at RT.

Chapter 2

25

2.1.2. Catalysts Both homogeneous and heterogeneous catalysts have been

employed for transfer hydrogenation reactions. The homogeneous

catalysts are more selective and active under moderate reaction

conditions. Heterogeneous catalysts, on the other hand, are less selective

and not all the catalytic material participates in the reaction. Inspite of

this, the ease of separation of the catalyst from the reaction products

favours the use of heterogeneous catalysts. However, homogeneous

catalysts are preferred for reactions such as asymmetric hydrogenation

or transfer hydrogenation.

2.1.2a. Homogeneous Catalysts Most homogeneous hydrogenation catalysts are soluble complexes

of noble metals. Those, which are active for hydrogenation are equally

active for transfer hydrogenation. Literature10 abounds with the

applications of RuCl2(PPh3)3, RhCl(PPh3)3, PdCl2(PPh3)2 and IrCl(PPh3)3.

As most of these complexes are insoluble in water, these reactions are

carried out in non-aqueous media. Metal complexes having water-soluble

ligands for example m-sulphophenyl biphenylphosphine, have been

designed for reactions that demand an aqueous or a biphasic medium.

The homogeneous catalysts are often anchored to an insoluble polymer

to surmount the product isolation difficulty while retaining the

advantages of homogeneous catalysts.

The catalytic activity of the transition metal salts and complexes is

the result of a delicate balance of valence states and strengths of

chemical bonds. Too strong a bond between hydrogen donor and the

transition metal results in stable compounds showing no catalytic

activity. Similarly, there is no catalytic activity, if there is no interaction

between hydrogen donor and the transition element. Not only must the

hydrogen source accommodated by the transition metal, but also the

Chapter 2

26

organic substrate must be able to bond if transfer of hydrogen to the

substrate is to occur.

Operational temperatures for catalytic hydrogenation using

homogeneous catalysts are rarely low (~ 20-80 ºC) and usually require

moderate to high temperatures in the range of 100-200 ºC. Another

problem associated with homogeneous catalysts has been the difficulty of

their recovery from reaction products. Unfortunately, many of these

catalysts appear to be unstable and lose the complexed metal to the

reaction medium or the complex salt is reduced to the metallic state.

2.1.2b. Heterogeneous Catalysts Heterogeneous hydrogenation catalysts, similar to their

homogeneous counter parts, are transition metal elements but differ in

their zero oxidation state. While this is possible in the case of base

metals, the use of platinum metals in the bulk form is not cost effective.

For this reason, supported catalysts are preferred because they are

economical and are also more efficient on a metal weight basis as they

increase the availability of metal atoms for the catalysis. Catalyst

supports commonly employed are activated carbon, alumina, silica,

amorphous silica-alumina, zeolites, BaSO4 and CaCO3. The crystalline

size and hence dispersion of the supported metal depends on the method

of preparation and subsequent treatments. For 10% palladium on carbon

(Pd-C), the Pd crystalline size is estimated to be 3.5 – 5.0 nm11.

Activated carbon is the most widely used catalyst carrier for liquid-

phase hydrogenation reactions. This preference is for the following

reasons:

(1) Activated carbon can be synthesized with high purity and possesses

large surface area (~1000 m2/g).

Chapter 2

27

(2) The metal support interaction is the least among the various

common catalyst carriers and thus the electronic properties of the

active material are not modified.

(3) Activated carbon, being a good adsorbent for organic compounds,

can facilitate the reaction by aiding the migration of the adsorbate to

the active sites of the catalyst.

Although palladium is an excellent metal of choice for most of the

common reactions, platinum, ruthenium and rhodium are useful

complementary candidates when selectivity is crucial. For instance, a

ruthenium complex can be used to selectively transfer hydrogenate the

carbonyl group to a carbinol in α,β-unsaturated carbonyl compounds12,

while Pd/C is used to selectively reduce the C=C double bond13.

Similarly, in halo-nitro aromatics, platinum on carbon (Pt/C) can be

employed to reduce nitro groups without eliminating halogen

functionality while Pd/C may be utilized to remove halogens with

simultaneous reduction of nitro groups to amines14.

2.1.3. Reaction Conditions

a. Influence of Temperature: In homogeneous systems, at equilibrium

or under steady-state conditions15-20, normal solution kinetics can be

applied and energies of activation and enthalpies have been determined

experimentally for several systems. In a practical sense, increase in

temperature will lead usually to a faster overall rate of reaction i.e., faster

reduction, but for equilibria, the change in position of equilibrium with

increasing temperature is not easy to predict. In many reductions, a

linear increase in rate of reduction with increase in temperature has

been observed21.

Often, where comparative reactions can be studied, the transfer of

hydrogen from a donor to an acceptor with a homogeneous catalyst

requires a higher temperature than with heterogeneous catalysts using

Chapter 2

28

the same metal. However, increase in temperature has attendant

difficulties in that unwanted reactions may be encouraged as with over

reduction and isomerization22-24. Where these side reactions are

unimportant, increase in temperature of reaction can afford higher yields

of product for a given time of reaction. Different hydrogen donors may

require different optimum temperatures. Similarly, variation in the

hydrogen acceptor will afford various optimum temperatures for any one

hydrogen donor. As mentioned above, the effect of temperature on

equilibria is unpredictable without experimental data.

b. Influence of Solvent: A correct choice of solvent is an important

factor governing the activity of a soluble catalyst in transfer reduction. As

with the homogeneous catalyst systems, coordination of solvent to the

catalyst in heterogeneous systems must be competitive with binding of

hydrogen donors and hydrogen acceptors. If the coordinate link between

solvent and catalyst is stronger than the binding of donor or acceptor,

then transfer reduction is inhibited or stopped altogether. Several

examples emphasize this solvent effect and serve as a reminder that, in

seeking optimum conditions for any attempted transfer reduction, a trial

of a range of solvents should be a prime consideration.

The most common solvents for these reactions are alcohols,

particularly methyl or ethyl alcohol. Dimethylformamide and

dimethylacetamide are useful for reactants that are less soluble in

alcoholic solvents. Acetic acid is very effective as a solvent medium when

acidic conditions are demanded.

The efficiency of heterogeneously catalyzed reactions is influenced

by the rate of mixing. Increased mixing improves the contact between the

catalyst and the reactants and therefore has a beneficial effect on the

reaction rate. In addition to the familiar process parameters such as

temperature and pressure, ultrasound is found to promote the Pd-

catalyzed reduction of olefins using HCO2H in alcohols25.

Chapter 2

29

2.1.4. Mechanism of Transfer Hydrogenation

Pd/C emerges as the catalyst of choice in most of the transfer

reduction reactions. It is also apparent that the formate anion is a

prerequisite for the reactions. The following postulate is advanced to

rationalize the various literature observations that have been made.

The first step in these reactions is the chemisorption of formate

salts that may decompose into CO2 and H- ions on the metal surface. The

adsorbed hydrogen can exhibit H-, H or H+ behavior depending on the

environment. There is some evidence that hydrogen exhibits either H- or

H+ character on palladium in the liquid phase. For example, in the case

of dehalogenation, it is most likely that the hydride-like behavior is

predominant. In the case of coupling reactions performed in the presence

of a strong base such as NaOH, the chemisorbed hydrogen on Pd may

exhibit H+ character; the abstraction of this H+ by OH- would leave two

electrons on the surface of the metal cluster. These electrons may be

responsible for the radical chemistry witnessed in the coupling reaction

of bromobenzene to biphenyls. The H-D exchange reactions also support

the H+ nature of PdH- species. For example, the deuterium of PdD- can

exchange freely with H2O, alcohols, benzylic protons, organic acids and

NH4+.

2.1.5. Reactions Involving Various Functional Groups

The many reactions that can be accomplished by transfer

hydrogenation or hydrogenolysis is proliferating at a remarkable pace. In

all cases, the advantages of transfer hydrogenation over conventional

hydrogenation are obvious. A wide range of donors and catalysts has

been deployed in various combinations to carry out heterogeneous

hydrogen transfer reduction of most of the major functional groups

attached to or part of both aromatic and aliphatic structures. The most

important functional groups reduced by CTH include alkenes26,

Chapter 2

30

alkynes27, arenes28, nitro alkanes29, nitro arenes30-32, azo compounds32,

aldehydes34, ketones35, oximes36, imines37, nitriles38, azides39, epoxides40,

deoxygenation of N-oxides41, hydrodehalogenation42, β-lactam ring

opening43, reductive N-alkylation44, reductive dimerization45 of

nitroarenes, homo-coupling of aryl halides46, reductive N-formylation47,

reductive cyclization48 and N- and O-debenzylation49.

2.1.6. Ammonium Formate: A green reagent for catalytic transfer hydrogenation

The catalytic transfer hydrogenation has become one of the reliable

methodologies for reduction in organic synthesis. The lower solubility of

hydrogen gas in organic solvent made a limitation to gaseous

hydrogenation and to overcome these problems catalytic transfer

hydrogenation has been developed. In addition catalytic transfer

hydrogenation may be performed at atmospheric pressure and ambient

temperature without the additional restriction phase boundaries between

hydrogen gas and solvent or catalyst in the conventional methods.

There are many organic and inorganic compounds which have been used

as hydrogen source for reduction of organic compounds viz.,

cyclohexene50, cyclohexadiene51, limonene52, ethanol53, sugars54,

pyrollidine55, propanol56, benzyl alcohol57, benzhydrol58, hydroquinone59,

indole60, formic acid61 and inorganic compounds such as ammonium

formate62, hydrazine63, sodiumtetra hydroborate64, phosphinic acid65,

ammonium chloride66, sodium hydrogen sulphide67 etc. Among all,

ammonium formate is the widely used hydrogen source in catalytic

transfer hydrogenation for the purpose of reduction and functional group

transformation68.

In comparison with catalytic hydrogenation or with other methods

of reduction, CTH using ammonium formate in conjunction with a

suitable metal catalyst has real and potential advantages. The utility of

stable ammonium formate as hydrogen source makes the CTH process

simple, rapid, mild, chemo-selective and environmentally benign.

Chapter 2

31

Groschuff69 described preparation of ammonium formate in 1903

and it has been used for precipitation of base metals from the salts of the

Noble metals. The first use of ammonium formate in organic synthesis

was illustrated by Rudolf Leuckart70 in which various carbonyl

compounds were reacted with ammonium formate to give corresponding

amines. This process was later named as the “Leuckart reaction”.

Ammonium formate can be used as a source of non-volatile

ammonia71 but much of its use is as a hydrogen transfer agent in

conjunction with heterogeneous or homogeneous catalysts.

Regioselective stepwise debenzylation of 1,3-dibenzyluracils was

observed with this catalytic transfer hydrogenation system. Functional

groups such as esters, alcohols, non-benzylic ketones or ethers,

carboxylic acids, amides, acetals, and nitriles are stable under the

reaction conditions72.

Aryl ketones are selectively reduced to the secondary alcohols73 or

hydrocarbons by careful selection of the reaction temperature and

solvent. The reduced alcohol is formed in methanol at RT and the

hydrogenolysis product is formed at 110 oC in acetic acid. Diaryl ketones

also provided diarylmethanes under the latter reaction conditions74.

Raney Ni can also participate in the catalytic transfer hydrogenation

reaction. The combination of Raney-Ni and ammonium formate reduces

aryl alkyl ketones to alcohols at RT in >90% yield75.

Azides and pyridine-N-oxides are reduced to amines76 and

pyridines77, respectively with this reaction system. Allyl β-keto

carboxylates are decarboxylated to form ketones and propene78. Alk-2-

ynyl carbonates are hydrogenolyzed to 1,2-dienes79. Selective reduction

of quinoline, isoquinoline and acridine has been reported80.

Palladium on charcoal-catalyzed transfer hydrogenation using

ammonium formate is superior to other catalytic hydrogenation for the

Chapter 2

32

removal of O-benzyl protecting groups81. Ammonium formate is widely

employed for the removal of protecting groups in peptide synthesis82. The

commonly used protecting groups such as benzyloxycarbonyl (Z), 2-

chlorobenzyloxycarbonyl (2-ClZ), bromobenzyloxycarbonyl (BrZ), benzyl

esters (OBzl),O-benzyl ethers, nitro, and benzyloxymethyl (Bom) can be

conveniently removed under mild conditions using Pd-C or magnesium

without affecting the Boc and Fmoc groups.

The selective reduction of nitro compounds to the corresponding

amines via catalytic transfer hydrogenation using ammonium formate

has been extensively studied83-87. The reduction can also be performed

conveniently using ionic liquids as safe and recyclable media88. The use

of mesoporous PdMCM-41 as catalyst is advantageous as it is relatively

stable, non-hazardous and possesses high surface area89. Selective

reduction of aromatic and aliphatic nitro compounds in presence of

several other sensitive functionalities such as halogen, alkene, nitrile,

carbonyl and ester using inexpensive zinc90 or magnesium91 afforded

high yields of amines in short time. Attempted reduction of aromatic

nitro groups in presence of aliphatic nitro groups using Pd-C and

ammonium formate gave mixture of products92.

The direct conversion of aromatic nitro compounds93 and azides94

to formanilides can be achieved by the appropriate selection of catalyst,

solvent and reaction conditions. For example, Zn/HCO2NH4 system

reduced nitro compounds and azides95 to amines at RT but yielded

formanilides under microwave irradiation. Reductive N-alkylation of

aromatic and aliphatic nitro compounds and corresponding amines with

nitriles using Pd-C and ammonium formate gave high yields of secondary

amines96. Both symmetrical and unsymmetrical azo compounds can

easily reduced to their respective amines without formation of the

intermediate hydrazo compounds via metal-catalyzed transfer

hydrogenation using ammonium formate97. Reductive cleavage of N–N

Chapter 2

33

bonds is also reported98. The reduction of oximes using ammonium

formate produced different products depending on the reaction

conditions employed. Transfer hydrogenation of oximes catalyzed by Pd-

C99, Zn100 or Mg101 furnished the corresponding amines at reflux.

Ammonium formate and Pd-C forms an excellent reagent system for the

convenient catalytic transfer hydrogenation of carbon-carbon double

bonds. A wide variety of olefins and α,β-unsaturated carbonyls were

reduced to the corresponding alkanes and saturated carbonyls102.

The Pd-C/HCOONH4 reagent system is highly competent for the

rapid microwave assisted removal of N-benzyl and N-benzyl carbamate

protecting groups103. Rapid hydrogenolysis of N-benzyl amino derivatives

to the corresponding amines can also be performed using low cost and

non-hazardous catalysts such as zinc104 and magnesium105 in presence

of ammonium formate.

Catalytic transfer hydrogenation of N-benzyl protecting groups

using 10% palladium on carbon as the catalyst and ammonium formate

as the hydrogen source generally gives primary amines in excellent

yields106.

Chapter 2

34

2.2. Present Work 2.2.1. Synthesis and Applications of N-Benzyl amines

The benzyl group is commonly employed for the protection of

amino, hydroxyl groups and as handles for amine introduction in organic

synthesis107. This N-benzyl group has found wide application in

synthesis because of its remarkable stability towards acidic and basic

conditions. N-Benzyl amines are key components in peptide synthesis

and general organic synthesis108. Many other functional groups can be

easily deprotected keeping the benzyl group intact. Monobenzyl amine

has got wide scope in the synthesis of asymmetric N-substituted amines,

peptide mimetic, heterocyclic synthesis and homochiral β-amino acid

derivatives over the dibenzyl amines which have valuable therapeutic

applications109-110.

Generally dibenzyl amines were prepared by alkylation of amine

with excess of benzyl halide111. There were many attempts and methods

employed to prepare monobenzyl amines and benzylated amino acids

were acknowledged in literature. The preparation of monobenzylated

amines and amino acids are obtained by either one of the methods;

direct alkylation of amine with benzyl halide112, most commonly benzyl

bromide or benzyl chloride and the other method involves the formation

of a Schiff base followed by reduction with a hydride or catalytic

hydrogenation. These Schiff bases may also be reduced using Zn

reagents113.

In 1954, Heymes114 et.al. attempt to prepare selective monobenzyl

amino acids by treating amino acids with benzyl chloride in presence of

aqueous potassium carbonate, the reaction is represented in the Scheme 2.1. Heymes was able to achieve only 70% yield of monobenzyl derivative

along with dibenzylated product.

Chapter 2

35

Scheme 2.1. Heymes method for the preparation of monobenzyl amino

acids

In 1987, B.D. Gray115 and in 1989, Yamazaki116 groups prepared

benzylated derivatives of amino acids by treating amino acids with benzyl

bromide in presence of sodium carbonate or triethyl amine. They failed to

achieve selectivity but were able to get maximum yield of dibenzylated

product and benzyl esters as byproduct, as shown below in Scheme 2.2.

Scheme 2.2. Gray’s method for the preparation of dibenzyl amino acids

Cho and Kim117 prepared N-benzyl derivative of methyl ester of L-

phenylalanine by reacting methyl ester of phenylalanine with benzyl

bromide in presence of aqueous lithium hydroxide in DMF. The

developed methodology limited only to esterified amino acids. The

methodology was not able to reach the goal of synthesis, when same

method applied to free amino acids, with the developed conditions amino

acids yield benzylated ester as byproduct.

Methodology developed by Lorris118 in 2004 to prepare benzyl

amines by reacting dibenzyl carbonate with amine in presence of

tetraphenylphosphonium bromide as catalyst. The developed

methodology was able to produce dibenzyl product along with formation

of N-carbamates as shown in the Scheme 2.3.

R

H2N COOH

Bn-Cl, K2CO3

H2O, reflux

R

NH

COOHBnR

N COOHBn

Bn

+

R

H2N COOH

Bn-Br, Na2CO3/ TEA

H2O, reflux

R

N COOHBn

Bn

R

N COOBn

Bn

+ Bn

Chapter 2

36

Scheme 2.3. Lorris method for preparation of benzyl amines

Other methods applied to prepare N-benzyl amines are reductive

alkylation of amines. The methods involve formation of imines from

aldehyde or ketone with amine followed by hydride reduction. In 1990,

Cain119 et.al., developed a reductive alkylation of amines to prepare

benzyl amines as shown in the Scheme 2.4. Cain reacted amines with

benzaldehyde to form Schiff base, then obtained imine was reduced with

sodium cyanoborohydride to yield N-benzylated product.

Scheme 2.4. Reductive alkylation of benzyl amines

Reductive alkylation tremendously expanded to explore new

reagents and methodologies to reduce imines. In 1992, Guy120 and in

1996 Sclafani121 developed methods for reducing imines by using sodium

borohydride as hydride transfer agent. Other reagents such as N-

iodosuccinamide (NIS)122 and diisopropyl azodicarboxylate (DIAD)123 have

also been employed for selective debenzylation of dibenzyl amines.

Debenzylation of N-benzyl amine derivatives by catalytic transfer

hydrogenation to corresponding amines under drastic condition are also

reported in literature124. Partial debenzylation of tertiary and dibenzyl

amines can also be achieved by oxidising agent such as ceric ammonium

nitrate125.

R NH2 Ph4PBr

OO

O

O

O

RHNR N

Bn

Bn+

R NH2NaCNBH3

O

NR N

HR

Chapter 2

37

Both the methodologies suffer from drawbacks such as direct

alkylation yield mixture of mono, dibenzylated and esterified products126,

separation of these byproducts leads to cost effectiveness and time

consuming. On the other hand, condensation and reduction requires

additional workup and involve expensive reagents or a special apparatus

like autoclaves or high pressure apparatus.

After complete literature assessment, the partial debenzylation of

dibenzyl amines to corresponding monobenzyl amines is still emerging

methods, and more attention to be taken to develop a methodology where

the concern involves selectivity and practicality because of more

synthetic applicability of N-benzyl amines, amino acids as chiron and

synthons as building blocks in biologically active compounds.

In this context, we have developed a selective, simple and practical

methodology to synthesize monobenzyl amines from its dibenzyl amine.

The methodology involves partial debenzylation of dibenzyl amines using

catalytic transfer hydrogenation. Ammonium formate is used as

hydrogen source and 10% palladium on carbon as catalyst. The

developed methodology is as shown in the Scheme 2.5.

where, R = Various substituents

Scheme 2.5. Mono debenzylation of dibenzyl amines

NR

HCOONH4/ 10% Pd-CRT

NHR

Chapter 2

38

2.3. Experimental

2.3.1. Materials

All the amino acids were of L-configuration, unless it is mentioned

and were purchased from Advance Chem Tech, USA. Thin Layer

Chromatography was carried on silica gel coated plates obtained from

Merck, Darmstadt, Germany and for column chromatography 60-120

mesh silica gel was used obtained from Avra Research laboratories. IR

spectra were recorded on Shimadzu FTIR-9300 Spectrometer with KBr

and only significant absorption levels are listed. The melting points were

determined by using Thomas-Hoover apparatus and are uncorrected. 1H

and 13C NMR spectra were recorded at 400 and 100 MHz respectively

using Bruker FT-NMR spectrometer and the chemical shifts are reported

in ppm using DMSO, singlet at 2.5 ppm as the reference. Ammonium

formate was purchased from Sigma-Aldrich, Bangalore. 10% palladium

on carbon is purchased from Hindusthan Platinum Private Limited, Navi

Mumbai. All the solvents and reagents used were of analytical grade and

were distilled and purified prior to use wherever necessary. Distilled

water was used in the workup. The reaction was monitored by TLC,

visualized in UV chamber and ethanolic ninhydrin.

2.3.2. Method

All dibenzyl amines were synthesized by well established method

reported by Goff111 et.al. In the method, amino acids were treated with

2.2 equivalent of benzyl bromide in presence of aqueous potassium

carbonate under reflux condition and the reaction is as shown in the

Scheme 2.6. Obtained dibenzyl derivatives are tabulated in Table 2.1 along with their physical data. Melting points of all the dibenzyl products

were compared with standard values as reported in the literature.

Chapter 2

39

Scheme 2.6. General method for preparation of dibenzyl amines

2.3.2a. General Procedure for the Synthesis of Dibenzyl amines:

Amine or amino acid (10 mmol) was taken in a round bottom flask

and 50ml of aqueous solution of potassium carbonate (20 mmol) was

added and stirred for 5min. The solution of benzyl bromide (22 mmol) in

50ml of chloroform was added slowly and the reaction mass was heated

to reflux for 6hrs. After completion of reaction showed by absence of

starting material on TLC, reaction mass was neutralized with dil HCl,

then product was extracted in to MTBE. Organic phase was washed with

water followed by brine and organic phase was dried over sodium sulfate.

Solvent was removed under vacuum to yield desired dibenzyl products.

Products were recrystalised using ether.

Table 2.1. Physical data for dibenzyl amines

Entry Dibenzyl amine M.P in °C

Observed Literature

2a.

87-88

88-90127

2b.

187-188

190-192128

NR

H2N R

Br

K2CO3, H2O, CHCl3

NO

OH

O

ON

Chapter 2

40

2c. 75-77 89-91129

2d. 80-83 84-88130

2e.

85-88

90-92131

2f.

Oil

Oil

2g.

269-272

273-275132

2h.

249-251

253-254130

2i.

211-213

214-215130

NO

OH

NO

OH

NO

OH

NO

OHS

NO

OH

NO

OH

N

OOH

OOH

Chapter 2

41

In order to establish an optimum reaction condition for the mono

debenzylation choice of solvent, catalyst loading and temperature are

critical parameters where it demands more attention to establish liable

method. N,N-Dibenzyl glycine (2b) was chosen as the model substrate to

optimize reaction conditions as shown in Scheme 2.7.

2j.

39-40

42-43133

2k.

91-92

91-94134

2l.

132-133

136-138135

2m.

67-69

67-70136

2n.

Oil

Oil137

2o.

Oil

Oil138

OHN

N

N

N

N

N

Chapter 2

42

Scheme 2.7. Selective mono debenzylation of dibenzyl glycine

Initially several solvents were chosen for reaction, methanol &

ethanol were found to be the best among the solvents employed and the

obtained data are tabulated in Table 2.2. On other hand, effect of

catalyst loading on rate of reaction was also investigated. Initially,

reaction was carried out with 5% palladium on carbon and the reaction

became slow in the consumption of starting material. When 10%

palladium on carbon was used reaction went out smoothly and

completed within the 15-20 min. When the reaction was carried out

using 30 % palladium on carbon reaction got completed within 10-15

min with yield of di-debenzylated products as major byproduct.

Table 2.2. Screening Solvent for CTH

ayields were ascertained on the basis of starting material recovery, reaction was

conducted for 30 min at RT.

Entry Solvent Yield in %a

1. MTBE 71

2. Ethyl acetate 82

3. Methanol 93

4. Ethanol 93

5. Diethyl ether 90

6. THF 78

NO

OHHN

O

OH

2a IIa

Pd/ C

Ammonium formate

Chapter 2

43

Temperature is one of the critical parameters in the organic

synthesis. Temperature may increase the driving force of reaction by

increasing molecular movement in the reaction. In the previous report by

Rama47 et.al., complete debenzylation of dibenzyl amines to

corresponding amine was achieved by catalytic transfer hydrogenation

under reflux condition. In keeping this in mind, we conducted

temperature study of reaction. We have got surprising results by varying

temperature of the reaction and keeping all other parameters identical,

obtained data’s are tabulated in Table 2.3.

Table 2.3. Debenzylation at different temperatures

Entry Temperature in OC

Conversion in %b

Mono-debenzylated product

Di-debenzylated product

1. 0 25 Nil

2. 10 81 Nil

3. 20 90 Nil

4. RT 94 Nil

5. 40 66 30

6. 50 12 80

bratio of products were compared by 1H spectral data.

When the reaction was conducted at 0 oC, the reaction did not go

to completion even after 4hrs. At 10 and 20 oC, reaction took 100 min

and 40 min to complete respectively and when the reaction was carried

out at RT (25-28 oC), reaction completed within 20-25 min, without any

di-debenzylated product. When reaction temperature was increased to 40 oC, reaction got completed within 20 min which also yielded of di-

debenzylated product. At 50 oC, surprisingly reaction completed within

15 min, with major yield being di-debenzylated product as pictorised in

the Chart 2.1.

Chapter 2

44

Chart 2.1. Debenzylation at different temperature

After the optimization of reaction conditions, several examples

such as dibenzyl amino acids and other dibenzylated products were

subjected to explore the scope and limitation of this developed protocol.

Under the standard reaction conditions, different dibenzyl amines were

converted into corresponding monobenzyl amines and the results are

presented in Table 2.4.

Table 2.4. Conversion of dibenzyl amine to monobenzyl amine

0102030405060708090

100

0 10 20 25 40 50

Debenzylation at different temperature

monodebenzyl product

Debenzyl product

Yield in %

Temperature in oC

Sl.No. Substrate (2a-2o)

Time in

min

Products (IIa- IIo)

M.P in °C Observed Literature

2a.

20 Oil Oil139

Temperature in oC

O

ON

O

ONH

Chapter 2

45

2b.

18

195-196 196-198140

2c.

16 249-251 258-259141

2d.

17 251-253 253-255113

2e.

20

244-246 251-255113

2f.

20 220-221 228-230142

2g. 20 245-249 245-255113

2h.

20 145-148 156-157113

NO

OH

NO

OH

NO

OH

NO

OH

NO

OHS

NO

OH

NO

OH

HN

O

OH

NH

O

OH

NH

OOH

HNO

HO

HN

SO

OH

HNO

OH

HNO

OH

Chapter 2

46

2i.

20 Oil Oil142

2j.

20 Oil Oil143

2k.

10 Oil Oil144

2l.

16 Oil Oil145

2m.

15 80-82 83-85146

2n.

18 Oil Oil138

2o.

19 Oil Oil138

OHN

N

N

N

N

N

HN

OOH

OHO

OHNH

HN

NH

HN

HN

HN

N

OOH

OOH

Chapter 2

47

2.3.2b. General Procedure for Selective Mono debenzylation of Dibenbenzyl amines

The substrate dibenzyl compounds (1 mmol), ammonium formate

(3 mmol), 10% Pd/C (100 mg) and methanol (20 mL) were charged in to a

50 ml flask. Reaction was stirred for 10-20 min at RT under nitrogen.

Reaction was monitored by TLC using solvent system 9:2::

chlorofrom:methanol, mono debenzylated products were visualized in UV

and answered for ninhydrin. After completion of reaction as confirmed by

absence of starting materials, catalyst was removed by filtration of

reaction mass through celite, catalyst was washed with 5ml of methanol.

The combined filtrate was concentrated to dryness. Then the residue was

stirred with methyl tert- butyl ether and filtered to yield desired products.

Products were purified by column chromatography using 10% ethyl

acetate in hexane as eluent.

Chapter 2

48

2.4. Analytical data of synthesized compounds (Ia-IIo) IIa. N-Benzyl gamma-aminobutyric acid ethyl ester 1H NMR: 1.16(t, J = 7.0Hz, 3H), 1.91(t, J = 7.2Hz, 2H), 2.40(t, J = 7.1Hz,

2H), 2.88(t, J = 7.3Hz, 2H), 3.36(s, 2H), 4.08(m, 2H), 7.38-7.57(m, 5H),

9.54(brs, 1H).

IIb. N-Benzyl -glycine 3.16(s, 2H), 3.74(s, 2H), 7.23-7.36(m, 5H), 12.19(brs, 1H).

IIc. N-Benzyl-L-isoleucine 0.89(t, J = 7.1Hz, 3H), 1.09(d, J = 7.1Hz, 3H), 1.48(m,2H), 1.78(m, 1H),

3.44(d, J = 7.2Hz, 1H), 3.74(s, 2H), 5.97(brs, 1H), 7.26-7.34(m, 5H).

IId. N-Benzyl-L-leucine 0.95(d, J = 4.4Hz, 6H), 1.70(m, 1H), 1.83(t, J = 5.5Hz, 2H), 3.39(t, J =

6.5Hz, 1H), 3.65(s, 2H), 5.89(brs, 1H), 7.41-7.49(m, 5H).

IIe. N-Benzyl-L-alanine 1.48(d, J = 7.3Hz, 3H), 3.44(q, J = 7.3Hz, 1H), 3.69(s, 2H), 6.41(brs, 1H),

7.41-7.43(m, 5H).

IIf. N-Benzyl-L-methionine 1.82(m, 2H), 2.51(t, J=8.8Hz, 2H), 2.19(s, 2H), 3.33(m, 1H), 3.89(s, 2H),

7.21-7.38(m, 5H).

IIg. N-Benzyl-L-valine 0.82(d, J = 6.8Hz, 6H), 1.85(m, 1H), 3.45(d, J = 4.9Hz, 1H), 3.67(s, 2H),

6.17(brs, 1H), 7.33-7.22(m, 5H).

IIh. N-Benzyl-L-phenylalanine 3.11(d, J = 13.2Hz, 2H), 3.42(t, J = 13.2Hz, 1H), 3.71(s, 2H), 7.20-

7.45(m, 10H).

Chapter 2

49

IIi. N-Benzyl-L-glutamic acid 1.68-1.78(m, 2H), 1.92-1.97(m, 1H), 2.21-2.24(m, 2H), 3-94-4.01(m, 1H),

5.01(s, 2H), 7.20-7.36(m, 5H).

IIj. N-Benzyl-amino ethanol 2.61(t, J = 6.7Hz, 2H), 3.51(t, J = 6.7Hz, 2H), 3.65(s, 2H), 7.24-7.36(m,

5H).

Ik. N-Benzyl-benzyl amine 2.49(brs, 1H), 3.67(s, 4H), 7.19-7.39(m, 10H).

IIl. N-Benzyl-3-pentanamine 0.89(t, J= 7.2Hz, 6H), 1.47(m, 4H), 2.44(q, 1H), 3.76(s, 2h), 7.22-7.33(m,

5H)

IIm. N-Benzyl-aniline 4.28(s, 2H), 6.88-7.38(m, 10H).

IIn. N-Benzyl-hexylamine 0.92(t, J= 12Hz, 3H), 1.32-1.93(m, 8H), 2.66(t, J= 12Hz, 2H), 3.82 (s, 2H),

7.28-7.36(m, 5H).

IIo. N-Benzyl-octylamine 0.88(t, J= 12Hz, 3H), 1.26-1.82(m, 12H), 2.53(t, J= 12Hz, 2H), 3.79 (s,

2H), 7.25-7.32(m, 5H).

Chapter 2

50

2.5. Results and Discussion

The developed reaction conditions are quite mild, all the reactions

were carried out at RT and the reactions are fairly fast, lies less than 20

min, the obtained yields were moderate to excellent. The products have

been isolated in all cases except the entry IIa and IIk by simple filtration

of the catalyst followed by concentration. The residue was stirred in

MTBE and again filtered. In the case of entry IIa and IIk, the products

were purified and isolated by column chromatography. All the isolated

products were characterized by 1H and 13C NMR spectroscopic

techniques. Stereochemistry of compounds also retained in the developed

protocol. Entry IIk, IIm and IIn were monobenzylated in less reaction

time than other dibenzylated products it could be because of electron

density and bulkiness of the starting materials.

The developed methodology can be applied to chemo-selective

debenzylation to corresponding mono benzyl products of amines or

amino acids under laboratory conditions. The developed methodology is

replaces the gaseous hydrogen by solid and recoverable green reagent

ammonium formate. Recovery of reagents and solvents also lead to cost

effectiveness in the process.

A control experiment was carried out using dibenzyl amine with

ammonium formate but without palladium carbon, which did not yield

the desired product. This clearly indicated the requirement of palladium

carbon to catalyze the reaction. Further, mono debenzyaltion of dibenzyl

amine was also attempted with palladium carbon and methanol but

without ammonium formate. Even after long duration we could not

obtain any debenzylated product. This confirms that methanol serves

only as solvent and not as hydrogen source.

Chapter 2

51

2.6. Conclusion

A simple and practical method for selective mono debenzylation of

dibenzylamines to corresponding monobenylamines was developed.

Physical and Spectral data of the prepared compounds were well

matched with their literature values. Monobenzyl amino acids can be

used as key intermediates in the synthesis of trisubstituted asymmetric

amines. The critical parameters study towards temperature, solvent

effect and catalyst loading on debenzylation were conducted and

interesting results were obtained. Developed method is very simple,

clean, practical and replaced the gaseous hydrogen by solid ammonium

formate.

Chapter 2

52

2.7. 1H and 13C NMR Spectra of Representative Compounds

1H NMR Spectrum of IIa

13C NMR Spectrum of IIa

Chapter 2

53

1H NMR Spectrum of IIb

DEPT Spectrum of IIb

Chapter 2

54

1H NMR Spectrum of IIi

1H NMR Spectrum of IIk

Chapter 2

55

1H NMR Spectrum of IIl

13C NMR Spectrum of IIl1H NMR Spectrum of IIn

Chapter 2

56

HPLC Chromatogram of IIb

HPLC Chromatogram of IId

HPLC Chromatogram of IIg

Chapter 2

57

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