Indian Journal of Chemistry Vol. 40B, October 2001 , pp. 1 000- 1 006

Note

A simple and highly efficient one-pot chemoselective synthesis of nitriles from

aldehydes: Mechanistic insight and selectivity control through modulation

of electronic and steric factors t+

Asit K Chakraborti*·t.t, Gurmeet Kaurt & Susmita Roy (nee Bhattacharya)t

t Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research

"(NIPER), Sector 67, S. A. S. Nagar 1 60 062, India and +Department of Chemistry, The University of Burdwan,

Burdwan 7 1 3 1 04, India

Received 30 January 2001 .. accepted (revised) 23 May 2001

Aldehydes are converted into nitriles in a one-pot reaction by treatment with H2NOHHCI in dipolar aprotic solvents under heating. Amongst various solvents NMP offers the best results. No competitive ether cleavage (e.g. methoxy, benzyloxy) or aro­matic nucleophilic substitution (e.g. nitro or chloro) takes place for substrates bearing such functionalities. Electronic and steric factors around the aldehyde carbon affect the rate of nitrile for­mation. Excellent to moderate selectivity is observed during in­termolecular competition between pair of aldehydes with varying electronic and steric requirements.

Functional group interconversion is an important arti­fice in organic synthesis of any length and in this context transformation of aldehyde functionality into nitrile is highly demanded because nitriles are versa­tile reagents for organic synthesis as exemplified in their applications in the preparation of thiazoles as inhibitors of superoxide l , chiral 2-oxazolines as FLC dopants2, tetrazoles as antipicornaviral agents3, 1 ,2-diarylimidazoles as potent · antiinflammatory agents4, triazolo[ I ,5-c]pyrimidines with potential antiasthma activity5, and benzamidines as fibrinogen antago­nists

6. The various methods available for conversion

of aldehyde to nitrile include (i) dehydration of al­doximes7, (ii) elimination of oxime ethers8 or oxime esters9 and (iii) elimination of quaternary hydra-

. 1 10 'd ' I I & • zomum sa ts or OXI ahve translormahon of N,N-

dimethylhydrazones. Although a direct conversion from aldehyde would have been an attractive ap­proach the examples are rather limitedl2 and recent developments in this regard include treatment of alde-

: Dedicated to Prof. U. R. Ghatak on his 70th birthday. + NIPER communication no. 26.

hydes with CU(N03h/N�OHlK2S2081 3, NaN3/

AICh 14, CISi(N3h 15, H2NOHHCUphthalic anhy­dridelEt3Nl6, H2NOHHCI under microwave irradia-. 1 7 hon , and NHiKI under electrochemical conditionl 8.

A critical survey of these procedures reveal the fol­lowing limitations: (a) involvement of two step reac­tions needing isolation and purification of the product in each stage, (b) use of costly reagents and/or harsh reaction condition, (c) need of special apparatus and (d) in many cases the methods are applicable to aro­matic aldehydes only. Thus there is a need to develop a convenient and easily operative method for this coveted transformation.

We thought that the direct conversion of aldehyde to nitrile in a one-pot reaction may be made feasible through in situ generation of the oxime and subse­quent activation of the oxime hydroxyl group for elimination. However, formation of oxime by the treatment of aldehyde with H2NOHHCl requires a base thereby making the separate formation inevita­ble. We thought that use of dipolar aprotic solventl9

such as I-methyl 2-pyrrolidinone (NMP) may serve the purpose of base in trapping the H+ due to their cation specific solvation property. Subsequently there might be proton exchange between the intermittently formed oxime and the protonated solvent to activate the oxime hydroxyl . The role of the dipolar aprotic solvent may further be realised in the fact that the 'naked' cr should attack the methine hydrogen for eliminating the activated hydroxyl group (Scheme I).

We report herein an efficient protocol for chemo­selective transformation of aldehyde functionality into nitrile by the treatment of the aldehyde with H2NOHHCl in dipolar aprotic solvents under heating in a one-pot reaction20. Amongst the various solvents employed (Table I) NMP offered the best results.

The intermediacy of oxime was established by its detection while monitoring the progress of the reac­tions by GCMS. The overall transformation may be realised as (i) trapping of H+ (from H2NOHHC1) by NMP, due to its cation (proton) specific solvation property, enabling the condensation of aldehyde with H2NOH generating the oxime without the necessity of base, (ii) activation of the oxime OH group (for elimination) through coordination with the protonated NMP and (iii) abstraction of the methine hydrogen of the complexed oxime by naked cr leading to elimi-

NOTES 1001

(Step 1 ) R · H2NOH HCI �R f\ cr f\ cr j >= 0 � F NOH + t... + � --- t... + 9-.. H f\ H , N.. 0 � OH t... N �O Me H Me �e l (Step 2)

R = N (Step 3)� � RrCb.� + .� � r H -'" � 0

\. cr Me Scheme I

Table I-The effect of solvent, temperature and time on nitrile formation. a.b.c

Entry Solvent Temp. Time Yield (DC) (min) (%) d

1 NMP Reflux 30 80" 2 NMP 1 00 30 1 00 3 DMF 1 00 30 30 4 Sulpholane 1 00 30 75 5 DMEU 1 00 30 85 6 DMPU 100 30 70 7 HMPA 1 00 30 65 8 NMP 100 60 1 3f.8 9 NMP 1 00 30 76 10 NMP 1 00 30 70 1 1 NMP 1 00 30 3h

1 2 NMP 1 00 30 4h

"In case of entries 1 -7 , 4-methoxybenzaldehyde was treated with 1 .5 eq. of H1NORHCl. bIn case of entries 9 and 1 0, 4-methoxybenzaldoxime was treated with 1 eq. of HCl and NaHS04 respectively. cIn case of entries 1 1 and 1 2, 4-methoxybenzaldoxime was treated with 1 eq. of NaCI and Na1S04 respectively. dGCMS yields. "4-Cyanophenol was also formed ( 1 5%). fBlank experiment with 4-methoxybenz­aldoxime. gThe oxime was recovered (80 %). h The oxime was recovered (-95 %)

nation of H20 producing the nitrile (Scheme I). The importance of activation of the oxime OH group, prior to elimination, (Step 2) was substantiated by the lack of formation of significant amount of nitrile when 4-methoxybenzaldoxime was heated at 100°C for 60 min in NMP (Table I, entry 8) and was further sup­ported by the nitrile formation in good yields during the treatment of 4-methoxybenzaldoxime with stoi­chiometric amount of HCl or NaHS04 at 100°C for 30 min in NMP (Table I, entries 9 , 10). The synchronous roles of nucleophilic attack by cr and activation of oxime through interaction with the protonated NMP is further supported by the lack of nitrile formation

when 4-methoxybenzaldoxime was treated separately with NaCI and Na2S04 (Table I, entries 1 1 , 1 2) .

The efficiency of this protocol was put to test for various aldehydes. The reactions were carried out by heating the mixture in NMP either at 100°C (Method A) for 5 - 60 min or under reflux (Method B) for 5 min and the results are summarised in Table II. Ex­cellent chemoselectivity was observed in that meth­oxy (Table II, entries 1 -4) and benzyloxy (Table II, entry 5) groups did not experience any ether cleavage despite the known a-nucleophilicity2 1 of the intermit­tently formed oxime and the ability of cr to cleave aryl alkyl ethers22. Substrates containing nitro (Table II, entries 1 3 , 14) and halo (Table II, entries 6,7) groups also remain unaffected for competitive aro­matic nucleophilic substitution23• However, the mechanistic course of the reaction (Scheme I, Step 3) demands that the nitrile formation should be affected by the electronic and steric factors around the methine hydrogen. Thus, the aromatic aldehydes bearing strong electron withdrawing group, such as F and N02, require higher temperature for complete conver­sion to nitrile to take place (Table II, entries 7, 13 and 14) as the extent of leaving group departure decreases with the electron withdrawing ability of the {3-aryl substituent9• The elevated temperature required for naphthyl aldehydes (Table II, entries 15 , 16) is a re­sult of bulkiness of the aryl group offering steric hin­drance for approach of the cr towards the (3-hydrogen. Similar steric hindrance was realised for substrates bearing ortho substituent(s) as exemplified by the requirement of longer reaction time (Table II, entries 3, 1 1 ). The slower reactivity in case of pyri­dinecarboxaldehydes (Table II, entries 17- 1 9) may be explained as arising from the competition between the nitrogen atom of the heterocycle and the oxime hy­droxyl group for protonation whereas the slow rate of nitrile formation with furan-2-carboxaldehyde and thiophene-2-carboxaldehyde (Table II, entries 20,2 1 ) could be the result of electrostatic repulsion between the respective heteroatoms and the approaching Cr. Aliphatic aldehydes (Table II, entries 22-24) react at a much faster rate than that of aromatic aldehydes because of less steric crowding at the aliphatic alde­hyde carbon. In case of citral (Table II, entry 24) an 1 : 1 cis/trans mixture of the aldehyde resulted in the corresponding nitriles in 1 : 1 ratio indicating that no olefin isomerisation takes place under the experi­mental condition further exemplifying the chemose­lectivity of the process.

1 002

Entry

2

3

4

5

6

7 8

9 10

1 1

1 2

13

14

1 5 16

17 1 8

1 9

20 2 1

2 2 23 24

INDIAN J. CHEM., SEC. B, OCTOBER 2001

Table II---Chemoselective transformation of aldehydes to nitriles

Aldehyde

Rl O"c=<:( RS h- R3 R4 R I = R2 = R4 = R5 = H; R3 = OMe R I = R5 = H; R2 = R3 = R4 = OMe R I = R3 = R5 = OMe; R2 = R3 = H

R I = R4 = R5 = H; R2 = OMe; R3 = OH

R I = R4 = R5 = H; R2 = R3 = OCH2Ph

R I = R2 = R4 = R5 = H; R3 = CI

R I = R2 = R4 = R5 = H; R3 = F R I = R3 = R4 = R5 = H; R2 = OH

R I = R2 = R4 = R5 = H; R3 = OH

R I = R4 = R5 = H; R2 = R3 = OH

R I = R3 = OH; R2 = R4 = R5 = H

R I = R2 = R4 = R5 = H; R3 = NMe2

R I = R2 = R4 = R5 = H; R3 = N02 R I = R3 = R4 = R5 = H; R2 = NOz

00 I -R � h-

R = I -CHO R = 2-CHO

OR -:? N

R = 2-CHO

R = 3-CHO

R = 4-CHO

� X CHO

X = O X = S

o-X-CHO X = trans-CH = CH

X = CH2 Citral (cis and trails)

Method

A A A A A A A A A A A A B

B

B B

B

B

B

B B

A A A

Time Yield (min) (%)"

30 100

30 1 00

60 79 45 8 1

1 5 90

30 88

30 50b

1 5 97 1 5 84

30 100

60 57 1 5 90

1 5 90c

1 5 98c

5 98d

5 99d

5 76e

5 70e

5 80e

5 80f

5 92g

5 1 00

5 1 00

1 5 8 0

"Isolated yields. "The oxime was recovered in 48 % yield. c60-70 % yield in 3 0 min via Method A. d50 % yield in 3 0 min via. Method A. e20 % yield in 60 min via. Method A. f30 % yield in 60 min via. Method A. g75 % yield in 30 min via. Method A.

NOTES 1003 NOH

¢+ e

HO eN Q eN GNOH NH2OH.HCl ¢ I � + I � � + +

NMP � � OMe OMe OMe II III IV V VI

Scheme II

Table III--Intermolecular competition between 4-methoxybenzaldehyde and phenylacetaldehyde during the nitrile formation."

Entry NH20HHClb Temp. Time Yield (%) of the ProductsC (0C) (min)

II III IV V VI

1 1 .5 100 5 73.5 0 26.5 0 1 3 87 2 3 100 5 1 6 2.5 63 2 1 26.5 70 3 3d 1 00 5 8 0 74 1 8 1 4 86

'I mmole of each aldehyde was used. �olar equivalent with respect to one aldehyde. cGCMS yields. �e aldehyde mixture was stirred with H2NORHCI for 15 min at room temperature prior to heating.

Being encouraged by the effect of electronic and steric factors on the relative rates of formation of ni­triles we planned to test the selectivity of nitrile for­mation during intermolecular competitions between different aldehydes. The overall rate of nitrile forma­tion should be dependent on (i) the ease of formation of the oxime (Scheme I, Step 1 ) and (ii) the ease of attack at the J3-hydrogen by the cr (Scheme I, Step 3). As expected, the oxime formation should be faster for aldehydes wherein the carbonyl carbon is more electrophilic. Therefore aliphatic aldehydes should form oxime in preference to the aromatic aldehydes and amongst aromatic aldehydes the presence of electron withdrawing substituent should make oxime formation more favourable. Nitrile formation from the intermediate oxime should be affected by both steric and electronic factors. The relatively less steric crowding around the J3-hydrogen in aliphatic alde­hydes compared to that of aromatic aldehydes should · make the elimination (Scheme I, Step 3) more facile in the case of use of aliphatic substrates. The influ­ence of the electronic effect during the nitrile forma­tion from the intermediate oxime may be realised in the fact that with aromatic aldehydes as substrates, the presence of electron withdrawing group should retard the rate of elimination9. In order to justify these hy­potheses, studies involving intermolecular competi­tion between (i) an aromatic aldehyde and an aliphatic aldehyde (ii) an electron rich aromatic aldehyde and

an electron deficient aromatic aldehyde and (iii) be­tween aromatic aldehydes of varying size of aromatic moiety were undertaken.

An equimolar mixture of 4-methoxybenzaldehyde and phenyl acetaldehyde was subjected to nitrile for­mation under different conditions (Scheme II) and the results are summarised in Table III. In all of the cases the aliphatic aldehyde is selectively converted to the nitrile referring to the importance of steric control at the elimination step.

The influence of electronic effect on selectivity was demonstrated by the competitive nitrile formation during the reaction of an equimolar mixture of 4-methoxybenzaldehyde and 4-nitrobenzaldehyde (Scheme III) and the results are summarised in Table IV. Thus although the oxime formation takes place preferentially with 4-nitrobenzaldehyde the influence of the electron withdrawing substituent at the elimi­nation step is reflected in the lack of nitrile formation from 4-nitrobenzaldehyde (compare entries 1 and 2, Table IV). Preferential nitrile formation as a factor of rate of elimination (Scheme I, Step 3) due to elec­tronic effect is further exemplified by Entry 4 (Table IV). The results in entry 3 (Table IV) demonsn;ate that even under conditions favouring oxime formation from both aldehydes, a 5 : 1 selectivity in the nitrile formation was observed in favour of 4-methoxybenzaldehyde highlighting the influence of the electron withdrawing substituent in the J3-aryl

1004 INDIAN J. CHEM., SEC. B, OCTOBER 2001

NOH

QOH

CHO CHO Q CN CN

¢ ¢ NHpH.HCI ¢ I � + ¢ + .. + + NMP �

OMe N02 OMe OMe N02 N02

II III IV V VI

Scheme III

NOH NOH S CHO 02Nn CHO NHpH.HCl

V + NMP ... d S

CN

� Ii + V + O,N,(} 01' "V CN

� Ii + � Ii II III IV V VI

Scheme IV

Table IV-Intermolecular competition between 4-methoxybenzaldehyde and 4-nitrobenzaldehyde during the nitrile formation."

Entry NH20H HClb Temp. Time Yield (%) of the ProductsC (OC) (min)

II III IV V VI

I Id

1 00 1 5 89 20 1 1 0 80 0 2 I

d Reflux 5 73 0 0 27 0 1 00 3 3d

1 00 30 0 0 39 6 1 8 8 1 2 4 3d Reflux 5 0 0 9 9 1 0 100

" I mmole of each aldehyde was used. b Molar equivalent with respect to one aldehyde. C GCMS yields. d The aldehyde mixture was stirred with H2NOHHCI for 15 min at room temperature prior to heating.

moiety of the intermediate oxime on the rate of elimi­nation during nitrile formation.

Excellent selectivities were observed during the competitive nitrile formation from an equimolar mixture of thiophene-2-carboxaldehyde and 5-nitrothiophene-2-carboxaldehyde (Scheme IV, Table V).

The effect of steric factor during the elimination step influencing the overall selectivity in nitrile for­mation was elaborated by the competitive reaction of an equimolar mixture of 4-methoxybenzaldehyde and I -naphthaldehyde (Scheme V, Table VI). Selective nitrile formation from 4-methoxybenzaldehyde (Ta­ble VI, entry 2) justifies the significance of steric control at the elimination step.

In conclusion, we have achieved an efficient method for one-pot conversion of aldehydes to ni­triles. The advantages of this protocol over the exist­ing methods are: (a) chemoselectivity, (b) wide appli­cation - suitable for aromatic as well as aliphatic al-

dehydes, (c) replacement of a two stage operation by one-pot reaction, (d) shorter reaction time (e) high yield of product formation, (f) ease of operation -simple workup and no need of special equipment, (g) requirement of no additional agents such as base, electrophilicloxidising agents, metal catalysts and (h) excellent to moderate selectivity in intermolecular competition.

Experimental Section General. The aldehydes are available commer­

cially. H2NOHHCI was purchased from S. d. fine chemicals, India.

General procedure for nitrile formation: Repre­sentative procedure. 4-Methoxybenzaldehyde (340.37 mg, 2.5 mmole) was heated at l OODC with H2NOHHCl (260.58 mg, 3.75 mmole) in NMP (2.5 mL) under nitrogen. After the reaction was over (30 min, monitored by GCMS) the cooled reaction mix­ture was diluted with water (25 mL) and extracted with Et20 (3 x 1 5 mL). The combined ether extracts

NOTES 1005

CHO � VV

NHpH.HCI NMP OMe

II

.. OMe III

OMe IV

cONOH ::?' I � + � ...:;;

V VI

Scheme V

Table V-Intennolecular competition between thiophene-2-carboxaldehyde and 5-nitrothiophene-2-carboxaldehyde during the nitrile fonnationa

Entry NH2OH"HClb Temp. Time Yield (%) of the ProductsC (0C) (min)

II III IV V VI

I 1 .5 100 30 79 3.5 2 1 0 67.5 29 2 1 d 100 60 97.5 24 0 2.5 0 76 3 I d Reflux 20 9 1 0 0 9 0 100

" I mmole of each aldehyde was used. �olar equivalent with respect to one aldehyde. cGCMS yields. 'The aldehyde mixture was stirred with H2NOH"HCI for 25 min at room temperature prior to heating.

Table VI-Intennolecular competition between 4-methoxybenzaldehyde and I -naphthaldehyde during the nitrile fonnation:

Entry NH2OH"HClb Temp. Time Yield (%) of the ProductsC (0C) (min)

I ' II III IV V VI

I 1 .5 100 25 39 39 14 47.5 40.5 20.5 2 2.5 100 45 0 0 14 86 47 53

"1 mmole of each aldehyde was used. bMolar equivalent with respect to one aldehyde. cGCMS yields.

were washed with brine ( 1 5 mL), dried (Na2S04) and concentrated under vacuo to furnish pure (NMR, GCMS) 4-methoxybenzonitrile (332.87 mg, 1 00 %).

Reactions with other aldehydes were carried out in a similar fashion following methods A or B (Table II). In most of the cases the products were obtained in sufficient purity (GCMS, NMR) and were purified, wherever applicable, by passing through a column of silica gel and elution with 5 - 30 % EtOAc-hexane.

All the products are known compounds and are easily identified by comparison of their spectra with those of authentic samples24 .

Selective nitrile formation in intermolecular competition: Representative procedure. A mixture of thiophene-2-carboxaldehyde ( 1 1 2 mg, 1 mmole) and 5-nitro thiophene-2-carboxaldehyde ( 1 57 mg, 1 mmole) in NMP (2 mL) was stirred with H2NOHHCI (69 mg, 1 mmole) at room temperature for 25 min under nitrogen and heated under reflux for 20 min. The cooled reaction mixture was worked up as above

and the product on being subjected to GCMS analysis was found to contain 9 1 % of unreacted thiophene-2-carboxaldehyde, 9% thiophene-2-carbonitrile and 1 00% 5-nitro thiophene-2-carbonitrile.

Acknowledgement One of the authors (G.K.) thanks CSIR, New Delhi

for award of research associateship.

References Chichiro M, Nagamoto H, Takemura I, Kitano K, Komatsu H, Sekiguchi K, Tabusa F, Mori T, Tomonnaga M & Yabuuchi Y, J Med Chern, 38, 1995, 353.

2 Serrano J L, Sierra T, Gonzalez y, Bolm C, Weickhardt K, Magnus A & Moll G, J Arn Chem Soc, 1 1 7, 1995, 832 1 .

3 Diana G D, Cutcliffe D, Volkots D L, Mallamo J P, Bailey T R, Vesico N, Oglesby R C, Nitz T J, Wetzel J, Giranda V, Pevear D C & Dutko F J, J Med Chern, 36, 1993, 3240.

4 Khanna I K, Weier R M, Yu Y, Xu X D, Koszyk F J, Collins P W, Koboldt C M, Veenhuizen A W, Perkins W E, Casler J J, Masferrer J L, Zhang Y Y, Gregory S A, Seibert K & Isak­son P C, J Med Chern, 40, 1997, 1 634.

1006 INDIAN J. CHEM., SEC. B, OCTOBER 2001

5 Medwid J B, Paul R, Baker J S, Brockman J A, Du M T, Hallet W A, Hanifin J W, Hardy R A, Tarrant M E, Torley I W & Wrenn S, J Med Chem, 26, 1990, 435 1 .

6 Judkins B D, Allen D G, Cook T A, Evans B & SardharwaJa T E, Synth Commun, 26, 1996, 435 1 .

7 (a) March J Advanced Organic Chemistry; Wiley: New York, 1 992; p 1038. (b) Meshram H M Synthesis, 1992, 943. (c) Bandgar B P, Jagtap S R, Ghodeshwar S B & Wad­gaonkar P P, Synth Commun, 25, 1995, 2993. (d) Fukuzawa S, Yamaishi Y, Furuya H, Terao K & Iwasaki, F, Tetrahedron Lett, 38, 1997, 7203. (e) Sampath Kumar H M, Mohanty P K, Suresh Kumar M & Yadav J S, Synth Commun, 28, 1998, 1 327.

8 (a) Cho B R, Yoon C -0 M & Song K S, Tetrahedron Leu, 36, 1995, 3 193 . (b) Ortiz-Marciales M, Pinero L, Ultret M de L, Algarin W & Morales J, Synth Commun, 28, 1998, 2807.

9 Cho B R, Chung H S & Cho N S, J Org Chem, 63, 1998, 4685.

10 March 1 . Advanced Organic Chemistry; Wiley: New York, 1 992; p 1 039.

I I (a) Said S B, Skarzewski J & Mlochowski J, Synthesis, 1989, 223. (b) Altamura A, D' Accolti L, Detomaso A, Dino A, Fioren­tino M, Fusco C & Curci R, Tetrahedron Leu, 39, 1998, 2009.

(c) Stankovic S & Espenson J H, J Chem Soc Chem Com­mun, 1998, 1579.

1 2 March J , Advanced Organic Chemistry; Wiley: New York, 1992; p 907.

1 3 Arora P K & Sayre L M, Tetrahedron Leu, 32, 1991, 1007. 14 Suzuki H & Nakaya C, Synthesis, 1992, 641 . 1 5 Elmorsy S S , El-Ahl A - A S , Soliman H & Amer F A , Tetra­

hedron Lett, 36, 1995, 2639. 16 Wang E -C & Lin G -J, Tetrahedron Lett, 39, 1998, 4047. 17 (a) Chakraborti A K & Kaur G Tetrahedron, 55, 1999,

1 3265. (b) Bose D S & Narsaiah A V, Tetrahedron Leu, 39, 1998, 6533.

1 8 Okimoto M & Chiba T, J Org Chem, 53, 1988, 218 . 19 Audoye P, Gaset A & Gorrichon J P, Chimia, 36, 1982, 4. 20 After the completion of this work a similar report appeared in

the literature: Sampath Kumar H M, Subbha Reddy B V, Tirupathi Reddy P & Yadav Y S, Synthesis, 1999, 586.

2 1 March J , Advanced Organic Chemistry (Wiley: New York), 1992, p35 1 .

22 Bernard A M, Ghiani M R, Piras P P & Rivoldini A, Synthe­sis, 1989, 287.

23 Khudsen R D & Snyder H R, J Org Chem, 39, 1974, 3343. 24 Pouchert C J, The Aldrich Library of NMR Spectra, Vols. I

and 2, 2nd Edn (Aldrich Chemical Co., Inc. : Milwaukee), 1983.