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165

CHAPTER 4

Study on Lewis acid catalyzed cyanation

reactions:Zn(OTf)2 catalyzed cyanation

Part-1

Cyanation reactions in organic synthesis

166

4.1.1. Introduction

The Lewis acid catalyzed cyanation reactions play very important role in the

synthesis of nitriles via C-C bond formation. Nitriles are very important

intermediates in synthetic organic chemistry1

and are also of industrially important

as integral parts of dyes, herbicides, natural products, agrochemicals and new

biologically active agents.

4.1.1.1. Background history

Hydrogen cyanide was discovered in 1782 by Carl Scheele, who was

investigating the dye Prussian Blue or Berliner Blau, as it was known in the German-

speaking world. Mixing the dye with an acid and heating gave him a flammable gas

that dissolved well in water, producing an acidic solution. Logically enough, he called

his discovery Berlin Blausaure (Prussic acid). Scheele's death in 1786 is sometimes

attributed to accidental poisoning by hydrogen cyanide. J. L. Gay-Lussac was the first

to prepare the pure acid in 1811 and Friedrich Wohler and Justus von Liebig were the

first to prepare the first nitriles, benzoyl cyanide and benzonitrile in 1832.

4.1.1.2. Chemical & physical properties of nitriles

The cyanide ion CN - is isoelectronic with carbon monoxide and dinitrogen and,

because of the highly electronegative nitrogen, the C≡N bond is highly polar,

resulting in high molecular dipole moments.1a

Nitriles, therefore, have strong

permanent dipole-dipole attractions as well as van der Waals dispersion forces

between the molecules. Hence, nitriles have higher boiling points than would

otherwise be expected from their molecular weights. Alkane-nitriles with

α-hydrogens typically have pKa ~ 25, but the acidity increases if more than one

cyano group is present as seen in the case of the malononitrile (pKa 11.0).

167

Nitriles are important laboratory and industrial solvents because of

their characteristic physical properties. The common solvent acetonitrile

can be taken as an example. It has a high boiling point for a two-carbon

system (bp 81.6 °C/760 Torr), due to the above mentioned large dipole

moment (3.9 D) leading to intermolecular association. On account of their

σ-donating, π-accepting and potential π-donating properties, nitriles act as ligands

in coordination and organometallic compounds, besides the cyanide anion

(Figure 4.1).

N

LnM N R LnM

N MLn

R R

σ–bonding π-bonding σ- π-bonding

Figure 4.1: Ligand binding models of nitriles

The ability of the cyano group to act as a ligand has been exploited to form

liquid – crystalline metal complexes. These are found to enhance the electronic

polarizabilities2

(Figure 4.2).

Cl

N M N

Cl

Figure 4.2: Metal-complex liquid crystals with nitrile ligands

4.1.1.3. Reactivity of nitriles

The importance of nitriles as intermediates in organic synthesis is well

established.1b,3

However nitriles are relatively unreactive in comparison to other

unsaturated organo-nitrogen compounds. A classic example is acetonitrile,

commonly employed as a solvent in a variety of reactions. The low reactivity of

168

nitriles is attributed to the low basicity of the sp-hybridised nitrogen atom. Nitriles

typically undergo nucleophilic additions.

Hydration of nitriles to form primary amides

Nitriles can be converted to the corresponding primary amides.

Several methods have been developed that include the catalytic hydration

with manganese dioxide on silica gel,4a,4b

alkaline solution of peroxide, microwave

irradiation with sodium perborate tetrahydrate in a mixture of water/ethanol

and enzymatic reactions.4c

Nitriles are activated by low-valent ruthenium

complexes and undergo reactions with nucleophiles under neutral conditions

(Scheme 4.1). 3a,5

RCN + H2O

RuH2(PPh3)4 cat. O R NH2

Scheme 4.1: Catalytic hydration of nitriles under neutral conditions

Hydrolysis of nitriles to carboxylic acids

Carboxylic acids can be prepared by hydrolysis of nitriles. The reaction

requires strong acid (e.g. H2SO4) or strong base (e.g. NaOH) and heat.

Reduction of nitriles to primary amines

Nitriles can be converted to the corresponding primary amines by

hydrogenation. Several catalysts can be used including Rh-AlO3 in ammonia and

ethanol,6

nickel catalysts such as Raney Nickel, Ni-Al-NaOH, palladium catalysts,

BH3, NaBH4/AlCl3, LiAlH4 among others.

RCN

H2, cat RCH2NH2

Scheme 4.2: Reduction of nitriles to amines

169

Ritter reaction

Nitriles are converted to the corresponding N-alkyl amides via the Ritter

reaction using various alkylating reagents, for example, strong acid and

isobutylene.7a-7c

Tertiary alcohols, such as tert-butyl acetate,7d-7f

react with nitriles in

the presence of strong acids to form amides via a carbocation.

O

R N R N

H2SO4, H2O H

Pinner reaction

Scheme 4.3: Ritter reaction

The Pinner reaction is the partial solvolysis of a nitrile to yield an iminoether.

Treatment of the nitrile with gaseous HCl in a mixture of anhydrous chloro

form and an alcohol produces the imino ether hydrochloride. These salts are

known as Pinner salts and may react further with various nucleophiles

(Scheme 4.4).8

HCl R N

R N H Cl

R'OH

NH2 Cl K2CO3 NH R R

OR O R

Scheme 4.4: Synthesis of imino ethers

4.1.1.4. Biological activity

Although nitriles (organic cyanides) have sometimes been stigmatized as

poisonous, compared to simple cyanide salts such as sodium and potassium cyanide,

they are ordinarily much less toxic. The parent compound, hydrogen cyanide can

cause rapid death in humans due to metabolic asphyxiation. Death can occur within

seconds or minutes of the inhalation of high concentrations of hydrogen cyanide gas.

A recent study reports an estimated LC(50) in humans of 270 ppm for a 6-8 minutes

170

exposure.9

Organic compounds possessing a cyano group occur in nature, including

compound A, which has antibiotic activity and compound B which is an antiviral

agent isolated from a Verongida sponge (Figure 4.3).

OH

O H

O NC

HO H

O

CN

(A)

H (B)

Figure 4.3: Naturally occurring compounds containing a cyano group

Compounds containing a cyano group have applications in medicinal

chemistry and some of them are also available in the market. A selection of drugs is

given in Figure 4.4.

NC CN

N N

N

H3COC

H3COC

CH3

N

C

N

O CH3

O CH3

Letrozole Femara (Novartis) antineoplastic, aromatase

inhibitor

Verapamilanti-arrhythmic and vasodilatator agent

O H CN

H N N

O NC

N

Vildagliptin anti-diabetic agent

(Novartis)

Fadrozole Arensin (Ciba-Geigy) antineoplastic, non-steroidal

aromatase inhibitor

Figure 4.4: Selected cyano-substituted pharmaceuticals

171

4.1.2. Review of literature

Catalytic cyanation reactions are very powerful synthetic methods. Current

challenges focus on the development of simple and highly efficient methods for the

synthesis of nitriles using Lewis acids as catalysts and many methods have been

reported in literature for these transformations.

Yang, et al.(2011)10

: They have described the BF3·OEt2-catalyzed direct

cyanation of indoles and pyrroles using a less toxic, bench-stable, and easily

handled electrophilic cyanating agent N-cyano-N-phenyl-para-toluenesulfonamide

(NCTS) affording 3-cyanoindoles and 2-cyanopyrroles in good yields with

excellent regioselectivity. The substrate scope was broad with respect to indoles and

pyrroles.

H

3

N R

R1

R2

+

Ts CN

N

Ph

CN

BF3.OEt2

R2

DCE, 80°C, 12h N R3

R1

Scheme 4.5

Nakao, et al.(2007)11

: Lewis-acid catalysts such as AlMe3, AlMe2Cl, and

BPh3 significantly improve the efficiency of the nickel-catalyzed aryl- and

alkenylcyanation of alkynes. Electron-rich cyanides, which exhibit poor reactivity in

the absence of Lewis acids, readily undergo the arylcyanation reaction under the

newly disclosed conditions.

Ar CN + Pr Pr

1 mol % Ni(cod)2

2 mol % PPh2Me

Ar CN

4 mol% AlMe2Cl Pr Pr Toluene, 80°C,

Scheme 4.6

172

Han et al. (2009)12

: Iron(II) and iron(III) salts catalyze the oxidative α-cyanation

of tertiary amines by trimethylsilyl cyanide in the presence of tert-butyl

hydroperoxide under acid-free conditions at room temperature.

R2

N R1

+ Me3Si CN

X

10 mol% FeCl2

tert -BuO OH MeO H, Rt X

R2

N R1

CN

Scheme 4.7

Dohi et al.(2007)13

: Hypervalent iodine(III) reagents mediate the direct cyanating

reaction of a wide range of electron-rich heteroaromatic compounds such as

pyrroles, thiophenes, and indoles under mild conditions (ambient temperature),

without the need for any prefunctionalization. Commercially available

trimethylsilylcyanide is usable as a stable and effective cyanide source, and the

reaction proceeds in a homogeneous system. The N-substituent of pyrroles is crucial

to avoid the undesired oxidative bipyrrole coupling process, and thus a cyano group

was introduced selectively at the 2-position of N-tosylpyrroles in good yields using

the combination of phenyliodine bis(trifluoroacetate) (PIFA), TMSCN, and

BF3·Et2O at room temperature.

R

X

(X= NTs, S)

PIFA-BF3.Et2O

TMSCN

in situ

PhI(CN)Y-BF3. Et2O

CH2Cl2,r.t

(Y=CN or OCOCF3)

Scheme 4.8

R

X

CN

Reetz et al.(1986)14

: They have described the first example of the enantioselective

addition of trimethylsilyl cyanide to aldehydes catalyzed by a chiral Lewis acid.

173

Thus, in the presence of boron-containing heterocycles A (10 mol %) or B (20 mol

%), isobutanal reacted with trimethylsilyl cyanide, to give, after hydrolysis,

2-hydroxy-4-methylpentanonitrile in 45-55% yield. The reaction was conducted

at -78 °C for 140 h and showed some stereoselectivity (12-16% asymmetric induction).

CHO + M e3SiCN

A (10 mol%) B (20 mol%)

CN

-78°C O H

Ph B Ph

O Me

Ph B Ph

Cl

(A) (B)

Scheme 4.9

Zieger et al.(1994)15

: Six sterically hindered benzylic chlorides have been

substituted with cyano group in excellent yields with trimethylsilyl cyanide and

titanium tetrachloride in methylene chloride.

Cl Cl

Ph Ph

T MS-CN

T iCl

Cl CN

Ph Ph

T MS-CN

CN CN

Ph Ph

Ph Ph 4

Ph Ph

Scheme 4.10

T iCl4 Ph Ph

Saidi et al. (2004)16

: Iodine, was found to be a practical and novel catalyst for the

reaction of aminal and trimethylsilyl cyanide under mild and neutral reaction

condition to afford the corresponding α-aminonitriles in high yields and short

reaction times. Trimethylsilyl iodide derived in situ from elemental iodine and

trimethylsilyl cyanide catalyzed this conversion.

R2'N NR2' + (CH3)3SiCN

I2 (ca t), 5 min

CH Cl , rt

R2'N

CN + T MSNR2'

2 2 R R

Scheme 4.11

174

N

CN

Karrer et al. (1920)17

: They had investigated the direct electrophilic cyanation of

aromatic systems using cyanogen chloride using Lewis-acids.

X-CN CN

AlCl3 RT R R

R=alkyl,aryl X=Cl

Scheme 4.12

4.1.3. General mechanism of Lewis acid catalyzed cyanation

reactions

Classically, nitriles have been prepared in S 2-displacements of either active

halides or sulphonate esters by cyanide anion. Cyanotrimethylsilane and Lewis acids

have been shown to be effective in the cyanation of alkyl halides. Organic

compounds with a halogen atom attached to an aromatic carbon are very different

from those compounds where the halogen is attached to an aliphatic compound.

While the aliphatic compounds readily undergo nucleophilic substitution (such as

Cyanation etc.) and elimination reactions, the aromatic compounds resist

nucleophilic substitution, only reacting under severe conditions or when strongly

electron withdrawing groups are present ortho/para to the halogen.

TMSCN

Lewis acid

1 ) X CN

+ CN X

2) CN + :X

X

X=Cl, Br, I

Scheme 4.13: Mechanism of Lewis acid catalyzed cyanation

175

N N

In alcohol or carbonyl compounds, the mechanistic steps are: (1) Lewis acid

forming a polar coordinate with a basic site on the reactant (such as an O or N). (2)

Its electrons are drawn towards the catalyst, thus activating the reactant. (3) The

reactant is then able to be transformed by a substitution reaction. (4) The product

dissociates and catalyst is regenerated.

Example: Lewis acid catalyzed Cyanation of carbonyl compound

O TiCl4

TiCl

O

4

TMSCN

TiCl4

O O TMS

H3O

TMSO H OH

R H R H

R H -TiCl4

R C

H R C

H

CN

Scheme 4.14: Cyanation of carbonyl compounds

176

CHAPTER 4

Study on Lewis acid catalyzed cyanation reactions

Part-2

Zn(OTf)2–Catalyzed direct cyanation of alcohols

177

4.2.1. Introduction

Lewis acid catalyzed cyanation reaction for the synthesis of nitrile is one of the

most powerful and useful methodologies for the formation of carbon-carbon bonds. The

preparation of nitriles by nucleophilic substitution of alkyl or aryl halides and sulfonates

with inorganic cyanides are common and well known procedures. Few other procedures

for the nitrile synthesis involve hydrogen cyanide as the cyanide source where, the

volatility and extreme toxicity of this reagent cause obvious difficulties. Direct

cyanation of alcohols constitutes an attractive synthetic route to nitriles in terms of both

starting material accessibility and economy concerns. In addition, it is desirable to have

an alternative cyanide source to HCN. Among the alternative cyanide sources,

trimethylsilylcyanide (TMSCN) seems to be one of the most effective and safer one for

cyanation of alcohols and carbonyl compounds. In recent years, more attention has been

paid to new synthetic methods using triflates as Lewis acid catalysts due to their unique

chemical and physical properties such as, excellent chemical and thermal stability with

ease of reuse. Triflates have emerged as powerful Lewis acid catalysts in the

performance of many useful organic transformations under mild reaction conditions.

Unlike other Lewis acids like SnCl4 and AlCl3, triflates are stable in air and also act as

Lewis acids even in the presence of water. In almost all cases, catalytic use, recovery,

and reuse of the triflates are possible.

4.2.2. Review of literature

Chen et al. (2008)

18: A convenient and efficient synthesis of α-aryl nitriles was

developed by direct cyanation of alcohols with TMSCN under the catalysis of Lewis

acid. Using 5−10 mol % of InBr3 as the catalyst, a variety of benzylic alcohols can

be converted to the corresponding nitriles in 5−30 min with yields of 46−99%.

178

OH

Ar R2

+TMSCN

InX3

(5-10 mol %) CN

2

R1

R1= alkyl, Ar

R2= H, alkyl

CH2Cl2, rt, 0.1-10h Ar R R1

Scheme 4.15

Rajagopal et al. (2009) 19

: Various α-aryl nitriles have been prepared in excellent

yields from the corresponding α-aryl alcohols employing 3 mol % of B(C6F5)3 as

Lewis acid catalyst and TMSCN as cyanide source. Cyano transfer from TMSCN to

alcohol proceeds within short reaction time at rt. α-Aryl thiols also produce

corresponding nitriles in good to excellent yield at reflux condition.

MeO

OH

+ (CH3)3SiCN

B(C6F5)3

Rt

CN MeO

Scheme 4.16

Wang et al. (2011)20

: They have reported a simple protocol for nitrile synthesis by

the direct cyanation of various secondary/tertiary benzylic and allylic alcohols with

trialkylsilyl cyanide (TASCN) with moderate to excellent yields as well as high

regioselectivities catalyzed by solid Brønsted acids of metal ion-exchanged

montmorillonites (M-Mont; M = Sn and Ti).

OH

R1 R3

TAS-CN TAS-OH

CN

R2 R1 R3 Brønsted montmorillonite

R2 Catalyst. Rt, CH2Cl2, 0.1-10h TAS =Trialkylsilyl

Scheme 4.17

Tsunoda et al. (1999)21

: Some new Mitsunobu reagents, especially N,N,N′,N′-

tetramethylazodicarboxamide(TMAD)-tributylphosphine(TBP) and cyanomethylene

179

trimethyl phosphorane (CMMP), mediated the direct transformation of primary and

secondary alcohols into the corresponding nitriles in the presence of acetone

cyanohydrin. This type of cyanation process can convert 3β-cholestanol to 3α-

cyanocholestane in high yield with complete Walden inversion.

NC OH Me O

O Me

R OH T MAD-PPh3 or CMMP

R CN N C

Me

N N C N

Me

NC PMe3

T MAD CMMP

Scheme 4.18

Rad et al. (2007)22

: A convenient and efficient one-pot preparation of nitriles from

alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method,

treatment of alcohols with a mixture of NaCN, TsIm and triethylamine in the

presence of catalytic amounts of tetra-n-butylammonium iodide (TBAI) in refluxing

DMF furnishes the corresponding alkyl nitriles in good yields.

R OH + NaCN TsIm/TBAI/TEA

DMF, reflux, 3 -6 h R CN

O N

R= 1°, 2°and 3°alkyl TsIm: H3C S N O

Scheme 4.19

Iranpoor et al. (2004)23

: Triphenylphosphine and 2,3-dichloro-5,6-

dicyanobenzoquinone afford an adduct which in the presence of n-Bu4NCN

converts alcohols, thiols, and trimethylsilyl ethers into their corresponding alkyl

cyanides in good to excellent yields at room temperature. This method is highly

selective for the conversion of 1° alcohols (in the presence of 2° and 3° ones), thiols

and silyl ethers.

180

R Y

PPh3 /DDQ/n-Bu4NCN R

CN

CH3CN, rt

R= 1°, 2°and 3°alkyl

Y= OH, SH, OSiMe3

Scheme 4.20

Chen et al. (2002)24

: A facile nickel-catalyzed oxidation of primary alcohols with

tetrabutylammonium peroxydisulfate in the presence of ammonium hydrogen

carbonate under basic aqueous conditions provides access to various aliphatic,

aromatic and heterocyclic nitriles in excellent yields with very high purity.

1.1 eq.NH4HCO3, 1eq. (Bu4N)2S2O8

3 mol% Cu(HCO2)2 .Ni(HCO2)2

R O H R CN

1 e q.KOH, iPrO H/H2O(1:1) 25°C, 1.5-2 h

R= Aryl, Alkyl,

Vinyl

Scheme 4.21

Ghorbani-Vaghei et al. (2009)25

: The reagents poly(N,N'-dichloro-N-ethylbenzene-

1,3-disulfonamide) (PCBS) and N,N,N',N'-tetrachlorobenzene-1,3-disulfonamide

(TCBDA) allow the preparation of N,N-dichloroamines, nitriles, and aldehydes from

primary amines. A direct oxidative conversion of primary alcohols into nitriles was

successfully carried out in aqueous ammonia.

1.1 eq. T CBDA

R O H R CN

30%, aq. NH3

TCBDA:

Cl2N

S S NCl2

R=alkyl, Ar 25° C, 1.5 - 5 h O O O O

Scheme 4.22

Iida et al. (2007)26

: Various primary alcohols, and primary, secondary, and

tertiary amines were efficiently converted into the corresponding nitriles in good

yields by oxidation with 1,3-diiodo-5,5-dimethylhydantoin (DIH) in aqueous

ammonia at 60 °C.

181

1 .5 - 2 eq. DIH

O I

DIH: N R OH R CN

30%, aq. NH3 N O

R=alkyl, Ar dark, 60°C, 3 - 32 h I

4.2.3. Objective Scheme 4.23

Many of these reported methods suffered from drawbacks such as harsh

reaction conditions (or) tedious work-up procedures, unsatisfactory yields,

prolonged reaction times, and often-expensive catalysts. Therefore, development of

a more practical and economical method for direct cyanation of alcohols using

TMSCN as cyanating agent may be highly desirable. Seeking to broaden the scope

of Lewis acid catalysts for the cyanation of alcohols with TMSCN, we are interested

in establishing a method using Zn(OTf)2 as a reusable catalyst.

4.2.4. Present work

Herein, we have described the use of Zn(OTf)2 as a versatile catalyst for the

direct cyanation of secondary benzylic alcohols with TMSCN, allowing the easy

preparation of useful synthetic intermediates for various applications and

representing the first example of triflates-catalyzed direct cyanation of alcohols.

As the first attempt, the reaction of benzhydrol (1) with trimethylsilyl

cyanide (1a) in the presence of 15 mol % Zn(OTf)2 was selected as a prototype

reaction to develop the optimum reaction conditions.

OH

+ (CH3)3SiCN

CN

1 5 mol % Zn(OTf)2

CH3NO 2, 100 oC

1 1a 1b

Scheme 4.24: Zn(OTf)2-Catalyzed direct cyanation of benzhydrol with TMSCN.

182

4.2.5. Results and discussion

The effect of solvent was also investigated and the yield was observed to be

highly dependent on the nature of the solvent. The reaction did not proceed at

all in coordinating solvents (Table 4.1, entries 1, 7 and 8) like, tetrahydrofuran

and dioxane, as well as in dimethylformamide. However, 40% yield was obtained

in acetonitrile (Table 4.1, entry 2). Hydrocarbon solvents such as toluene gave

a mixture of products and the desired product was obtained in trace amount

(Table 4.1, entry 3). Dichloromethane gave only 50% of the desired product.

Among the various solvents studied, nitromethane was the most effective, and

afforded the desired product in higher yield (Table 4.1, entry 6).

Table 4.1. Optimizing the reaction conditions for the direct cyanation of benzylic

alcoholsa

Entry

Solvent

T (ºC)

Time (h) Yield (%)b

1 DMF 100 24 -

2 CH3CN 80 8 40

3 Toluene 100 24 25

4 CH2Cl2 45 12 50

5 CH3NO2 25 24 30

6 CH3NO2 100 6.0 90

7 THF 70 24 -

8 Dioxane 100 24 -

aAll reactions were performed with benzylic alcohol (1 mmol), TMSCN (1.2 mmol), and 15

mol % of Zn(OTf)2 in the indicated solvent (10 vol). bIsolated yield after flash column

chromatography.

When the two reactants were mixed with zinc triflate in nitromethane at room

temperature, only a trace amount of product was observed even after 24 h (Table 4.1,

entry 5). Elevating the reaction temperature increased the yield considerably and the

183

reaction proceeded with the highest efficiency at 100 ºC in a sealed tube affording the

product (1b) in 90% yield with shorter reaction time (Table 4.1, entry 6).

In addition, the efficiency of similar other catalysts have also been screened

for the conversion of benzhydrol to the nitrile under the same conditions (Table 4.2)

and it was observed that the target α-aryl nitriles were formed in low yield (20%)

with anhydrous FeCl3 (20 mol %) in nitromethane at 100 ºC (Table 4.2, entry 7).

Table 4.2. Reaction of benzhydrol and TMSCN with different catalysts.a

Entry Catalyst Catalyst loading

Time (h) Yield

(mol %) (%)[b]

1 Sc(OTf)3 10 8.0 50

2 Sc(OTf)3 15 6.0 70

3 Zn(OTf)2 10 8.0 55

4 Zn(OTf)2 15 6.0 90

5 TMSOTf 10 8.0 55

6 TMSOTf 15 6.0 75

7 FeCl3 20 8.0 20

a Reaction condition: Benzhydrol (1 mmol), TMSCN (1.2 mmol), nitromethane 10 volume)

at 100 °C in sealed tube. b

Isolated yield after column chromatography.

The other catalysts employed [Sc(OTf)3, TMSOTf] can also activate

benzylic alcohols, but in these cases, the desired product was obtained in good to

moderate yield (Table 4.2 entries 1,2 and 5,6). We found that the reaction proceeded

to give excellent yield when 15 mol% of Zn(OTf)2 has been used whereas, the

conversion was very slow under similar condition when 5-10 mol % of Zn(OTf)2

was used, revealing that 15 mol% of Zn(OTf)2 was optimum amount for this

transformation.

184

Using the optimized conditions, the present reaction was further extended to a

broad range of benzylic alcohols to evaluate the scope and limitations of the

method. The results are listed in Table 4.3.

Table 4.3. Zn(OTf)2 -Catalyzed direct cyanation of benzylic alcohols under the

optimized conditionsa

OH Z n(OTf)2

CN

R1 R2 + (CH3)3SiCN CH NO ,100 °C R1 R2

3 2

Entry Alcohol Time (h) Product Yield (%)b

OH

5.5 1

CN

9019

1 b

OH Cl

2

6.0

CN Cl 82

27

2b

OH

3 6.0

Me

CN

3b Me

91

28

OH

4 6.0

F

CN

80

4b F

OH

5 Br 6.0

CN

Br 83

5b

OH

6

Br

6.0

C N

6b

B r

88

28

O H

7

OMe

6.0

CN

7b

OMe

78

28

185

O H

8

MeO OMe

OH

9

5.0

6.0

CN

MeO

8 b

CN

OMe

9529

8619

F F F

9b F

OH

10 Cl 6.0

Cl

CN

Cl 89

10b Cl

OH C N

11 5.0 85

11 b

O H

8.0

12

CN 12b

4319

OH

13 8.0

Cl

O H

14 6.0

CN

Cl

1 3b

CN

14b

48

19

5419

O H

15

M eO

OH

16

8.0

6.0

M eO

C N

1 5b

C N

5219

77

1 6b

aAll reactions were performed with benzylic alcohol (1 mmol), TMSCN (1.2 mmol), and 15

mol % of Zn(OTf)2 in nitromethane (10 volume) at 100 °C in seald tube. bIsolated yield after

flash column chromatography.

As can be observed in Table 4.3, the reaction of TMSCN with benzylic alcohols

possessing various substituents on the aromatic ring were examined in the presence of

Zn(OTf)2. Electron-rich benzylic alcohols reacted with TMSCN to give 54-95% yield,

and electron-deficient alcohols gave the desired product in 52-85 % yield. Similarly,

186

the reactions of 1- phenyl ethanols with TMSCN proceeded smoothly and afforded the

corresponding products in moderate yields (Table 4.3. entry 12–15).

4.2.6. Plausible mechanism:

A possible mechanism may be discussed (Scheme 4.25) based on the

experimental observations. Mechanistic investigations revealed that the cyanation

system soon attained equilibrium with alcohol, symmetrical ether, and water via the

benzylic carbocation. The benzylic cation formed by the heterolytic cleavage of the

C–O bond of the alcohols with the assistance of Lewis acidic Zn(OTf)2 might have

reacted with the nucleophile (cyanide anion) to give the corresponding product. The

formation and stability of benzylic carbocations is well documented.30

Moreover,

support for this mechanism could be observed in the reaction of substrate a with

Zn(OTf)2 as catalyst in nitromethane at room temperature, where, dimerization

giving the symmetric ether b was observed. The formation of the ether has been

confirmed by its isolation in one of this experiments and its characterization by

NMR. In addition, reaction of isolated b with trimethyl silylcyanide at 100 oC in the

presence of a catalytic amount of the zinc triflate under similar reaction conditions

led to the corresponding aryl nitrile in almost quantitative yield.

R

Ar O H a

(CH3)3SiCN (CH3)3Si(OH)

R

Ar + H2O

Ar CN

R R

Ar O

b

c d

OH

Ar Ar R

Scheme 4.25: Possible mechanism for the cyanation

187

4.2.7. Conclusion

In summary, we have developed a very simple and highly efficient

methodology for the direct cyanation of benzylic alcohols with TMSCN

(Trimethylsilyl cyanide) as cyanating agent catalyzed by Zn(OTf)2. Using the

present procedure, a variety of α-aryl alcohols can be converted to the corresponding

nitriles within shorter reaction time in good to excellent yields under mild reaction

conditions. This method provides a clean, efficient, synthetically competitive, and

cheap alternative to the existing catalytic systems.

4.2.8. Experimental Section

General procedure for the cyanation of secondary alcohols with TMSCN:

A mixture of alcohol (1 mmol), trimethylsilyl cyanide (1.2 mmol) and zinc

triflate (15 mol%) were placed in a 50 ml sealed tube and heated to 100 ºC for the

appropriate time mentioned in Table 4.3. After completion of the reaction

(monitored by TLC), the reaction mixture was diluted with 30 ml of water

and extracted with dichloromethane (2x50 ml). The organic layer was separated

and washed with water, brine and dried over sodium sulfate, concentrated to

furnish the desired α-aryl nitriles. When necessary, the obtained nitriles

were purified by column chromatography (silica gel; petroleum ether/ethyl

acetate 8:2).

4.2.9. Characterization of the products

The melting points, IR, LC-MS and

1H,

13C, NMR, data of some unknown

compounds are given below. All other known compound’s data were cross checked

with reported data in literature.

188

2,2-Diphenylacetonitrile (1b): White solid; mp 73–75 ºC;

1H NMR (400 MHz,

CDCl3) δ = 7.30–7.40 (m, 10 H, ArH), 5.14 (s, 1 H, CH) ppm. 13

C NMR (100 MHz,

CDCl3) δ 135.95, 129.24, 128.42, 128.29, 127.77, 119.73, 42.62 ppm. IR (neat):

ν = 2357, 2243, 1596, 1491 cm-1

. GC-MS: m/z cacld. for C11H14N 193.24; found

193.1.

2-(2-Chlorophenyl)-2-phenylacetonitrile (2b): Pale yellow oil; 1H NMR (400

MHz, CDCl3) δ = 7.51–7.53 (m, 1 H, ArH), 7.25–7.44 (m, 8 H, ArH), 5.66 (s, 1 H,

CH) ppm. 13

C NMR (100 MHz, CDCl3): δ 134.55, 133.74, 133.26, 130.19, 129.89,

129.86, 129.20, 128.41, 127.78, 119.09, 39.5 ppm. IR (neat): ν = 2245, 1494, 1471.

GC-MS: m/z cacld. for C14H10ClN 227.69; found 227.1.

2-Phenyl-2-p-tolylacetonitrile (3b): White solid; mp 62–64 ºC;

1H NMR (400

MHz, CDCl3): δ = 7.31–7.40 (m, 5H, ArH), 7.23–7.27 (m, 2 H, ArH), 7.18–7.20 (m,

2 H, ArH), 5.11 (s, 1 H, CH), 2.35 (s, 3 H, CH3) ppm. 13

C NMR (100 MHz, CDCl3)

δ 138.11, 136.22, 133.04, 129.89, 129.19, 128.18, 127.71, 127.64, 119.88, 42.27,

21.08 ppm. IR (neat): ν = 2246, 1510, 1494, 1452. GC-MS: m/z cacld. for

C15H13N 207.21; found 207.1.

2-(4-Fluorophenyl)-2-phenylacetonitrile (4b): White solid; mp 43–45 ºC;

1H NMR

(400 MHz, CDCl3) δ = 7.30–7.41 (m, 7 H, ArH), 7.04–7.08 (m, 2 H, ArH), 5.13 (s,

1 H, CH) ppm. 13

C NMR (100 MHz, CDCl3) δ 163.73, 161.27, 135.75, 131.88,

129.49, 128.44, 127.69, 119.58, 116.31, 41.86 ppm. IR (neat): ν = 2246, 1604, 1507,

1495, 1231. GC-MS: m/z cacld for C14H10FN 211.23; found 211.1.

2-(3-Bromophenyl)-2-phenylacetonitrile (5b): Pale yellow oil.; 1H NMR (400


CH) ppm. 13

C NMR (100 MHz, CDCl3) δ 138.04, 135.15, 131.54, 130.79, 130.74,

189

129.40, 128.59, 127.73, 126.40, 123.22, 119.07, 42.17 ppm. IR (neat): ν = 2245,

1603, 1504, 1238. GC-MS: m/z cacld. for C14H10BrN 271.0; found 271.0.

2-(4-Bromophenyl)-2-phenylacetonitrile (6b): White solid; mp 82–83 ºC.

1H NMR

(400 MHz, CDCl3) δ = 7.50–7.52 (m, 2 H, ArH), 7.32–7.41 (m, 5 H, ArH), 7.22–

7.27 (m, 2 H, ArH), 5.10 (s, 1 H, CH) ppm. 13

C NMR (100 MHz, CDCl3) δ 135.32,

134.98, 132.365, 129.40, 129.34, 128.51, 127.68, 122.47, 119.15, 42.09 ppm. IR

(neat): ν = 2246, 1600, 1494, 1450 cm-1

. GC-MS: m/z cacld for C14H10BrN 271.0;

found 271.0.

2-(4-Methoxyphenyl)-2-phenylacetonitrile (7b): White solid; mp 129–131 ºC;

1H

NMR (400 MHz, CDCl3) δ = 7.31–7.37 (m, 5 H, ArH), 7.23–7.26 (m, 2 H, ArH),

6.87–6.90 (m, 2 H, ArH), 5.09 (s, 1 H, CH), 3.79 (s, 3 H, OCH3) ppm. 13

C NMR

(100 MHz, CDCl3) δ 159.49, 136.28, 129.17, 128.93, 128.17, 127.99, 127.65,

119.93, 114.57, 55.36, 41.84 ppm. IR (neat): ν = 2244, 1738, 1610, 1493, 1250 cm-

1. GC-MS: m/z cacld. for C15H13NO 223.27; found 223.1.

2,2-Bis(4-methoxyphenyl)acetonitrile (8b): White solid; mp 145–146 ºC;

1H NMR

(400 MHz, CDCl3) δ = 7.22–7.25 (dd, 4 H, ArH), 6.87–6.89 (dd, 4 H, ArH), 5.04 (s, 1

H, CH), 3.79 (s, 6 H, OCH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 159.42, 129.74,

128.82, 128.32, 120.14, 114.51, 113.87, 55.35, 41.06 ppm. IR (neat): ν = 2245, 1738,

1608, 1507, 1458, 1246 cm-1

. GC-MS: m/z cacld for C16H15NO2 253.3; found 253.1.

2,2-Bis(4-fluorophenyl)acetonitrile (9b): Pale yellow solid; mp 59–61 ºC;

1H

NMR (400 MHz, CDCl3) δ = 7.25–7.32 (m, 4 H, ArH), 7.02–7.10 (m, 4 H, ArH),

5.12 (s, 1 H, CH) ppm. 13

C NMR (100 MHz, CDCl3) δ 159.04, 156.575, 126.79,

124.73, 114.54, 111.65, 36.38 ppm. IR (neat): ν = 2245, 1603, 1504, 1233 cm-1

. GC-

MS: m/z cacld. for C14H9 F2N 229.2.3; found 229.1.

190

2-(3,4-Dichlorophenyl)-2-phenylacetonitrile (10b): Colorless oil; 1H NMR (400


CH) ppm. 13

C NMR (100 MHz, CDCl3) δ 135.80, 134.57, 133.28, 132.65, 130.97,

129.51, 129.31, 128.57, 127.49, 126.81, 118.53, 41.57 ppm. IR (neat): ν = 2245,

1494, 1470, 1396 cm-1

. GC-MS: m/z cacld for C14H9 Cl2N 261.13; found 261.1.

2-(3,4-Dimethylphenyl)-2-phenylacetonitrile(11b): Colorless oil; 1H NMR (400


CH), 2.25 (d, J=2.0 Hz, 3 H, CH3) ppm. 13

C NMR (100 MHz, CDCl3) δ 137.2,

133.36, 132.85, 132.00, 131.52, 130.58, 128.55, 127.32, 126.44, 125.58, 124.37,

123.34, 122.9, 120.34, 115.17, 37.50, 15.25,14.66 ppm. IR (neat): ν = 2243, 1652,

1495, 1448, 1270 cm-1

. GC-MS: m/z cacld. for C16H15 N 221.3; found 221.

2-Phenylpropanenitrile (12b): Colorless oil; 1H NMR (400 MHz, CDCl3) δ =

7.31–7.40 (m, 5 H, ArH), 4.29 (q, 1 H, CH), 1.41 (d, J= 6.4 Hz, 3 H, CH3) ppm. 13

C

NMR (100 MHz, CDCl3) δ 137.21, 128.52, 127.44, 126.38, 31.6, 24.7, 22.73 ppm.

IR (neat): ν = 3061, 3019, 2236, 1866, 1607, 1493, 1075 cm-1

. GC-MS: m/z cacld

for C16H15 N 131.14; found 131.1.

2-(4-Chlorophenyl)propanenitrile (13b): Colorless oil; 1H NMR (400 MHz,

CDCl3) δ = 7.38 (d, J= 8.4 Hz, 2 H, ArH), 7.31 (d, J= 8.4 Hz, 2 H, ArH), 3.91 (q,

J= 7.2 Hz, 1 H, CH), 1.64 (d, J= 7.2 Hz, 3 H, CH3) ppm. 13

C NMR (100 MHz,

CDCl3) δ 135.55, 134.08, 129.33, 128.10, 121.09, 30.72, 21.34 ppm. GC-MS: m/z

cacld. for C9H8ClN 165.0; found 165.1.

2-p-Tolylpropanenitrile (14b): Colorless oil; 1H NMR (400 MHz, CDCl3) δ =

7.28 (d, J= 8.0 Hz, 2 H, ArH), 7.22 (d, J= 8.0 Hz, 2 H, ArH), 3.91 (q, J= 7.2 Hz, 1

H, CH), 2.38 (s, 3 H, Ar-CH3), 1.65 (d, J= 7.6 Hz, 3 H, CH3) ppm. 13

C NMR (100

191

MHz, CDCl3) δ 137.21, 128.52, 127.44, 126.38, 31.6, 24.7, 22.73 ppm. IR (neat): ν

=3025, 2986, 2877, 2243, 1515, 1453, 1084 cm-1

. GC-MS: m/z cacld for C10H11 N

145.0; found 145.1.

2-(4-Methoxyphenyl)propanenitrile (15b): Colorless oil; 1H NMR (400 MHz,

CDCl3) δ = 7.26 (d, J= 8.7 Hz, 2 H, ArH), 6.91 (d, J= 8.7 Hz, 2 H, ArH), 3.18 (q, J=

4.5 Hz, 1 H, CH), 3.81 (s, 3 H, OCH3), 1.61 (d, J= 4.5 Hz, 3 H, CH3) ppm. 13

C NMR

(100 MHz, CDCl3) δ 159.22, 129.13, 127.84, 121.92, 114.41, 55.32, 36.44, 21.37

ppm. IR (neat): ν = 2954, 2869, 2241, 1610, 1460, 1249, 1034, 828 cm-1

. GC-MS:

m/z cacld. for C10H11 NO 161.2; found 161.1.

(E)-2,4-diphenylbut-3-enenitrile (16b): White solid; mp 72–74 ºC;

1H NMR (400

MHz, CDCl3) δ = 7.27–7.45 (m, 10 H, ArH), 6.86 (d, J= 16.0 Hz, 1 H, –CH= ), 6.24

(dd, J= 16.0 Hz, 1 H, =CH–) 4.72 (d, J = 6.0 Hz, 1 H, –CH) ppm. 13

C NMR (100

MHz, CDCl3): 135.53, 134.62, 133.6, 129.33, 128.75, 127.61, 126.75, 123.33,

118.82, 40.06 ppm. IR (neat): ν = 3061, 3028, 2908, 2243, 1494, 1451, 968 cm-1

.

LC-MS: m/z cacld. for C16H13 N [M]- 218.2; found 218.1.

192

4.2.9.1. Spectras

CN

1H NMR (400 MHz, CDCl3) of compound 1b

CN

13C NMR (100 MHz, CDCl3) of compound 1b

193

CN Cl


CN Cl


194

CN

Me


CN

Me


195

CN

F


CN

F


196

CN

Br


CN

Br

13

C NMR (100 MHz, CDCl3) of compound 5b

197

CN

Br


CN

Br


198

CN

OMe


CN

OMe


199

CN

MeO OMe


CN

MeO OMe


200

C N

F F


C N

F F

13

C NMR (100 MHz, CDCl3) of compound 9b

201

CN

Cl

Cl


CN

Cl

Cl


202

CN


CN


203

CN

Cl


CN

Cl


204

CN


CN


205

CN


206

CN

207

CN

208

4.3. References

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