An efficient and improved method for the preparation of nitriles from primary amides and aldoximes

Article abstract of DOI:10.1002/adsc.200404059

The pivaloyl chloride-pyridine system has been utilized as a novel and efficient reagent for the preparation of nitriles from primary amides and aldoximes. The reaction proceeds smoothly under mild reaction conditions and the products are obtained in excellent yields. This method is applicable to a wide range of substrates including aromatic, heterocyclic and aliphatic species. The dehydration takes place at room temperature in the case of primary amides and dichloromethane at reflux temperature is required for rapid conversion in the case of aldoximes.

Full text of DOI:10.1002/adsc.200404059

COMMUNICATIONS
An Efficient and Improved Method for the Preparation of
†
Nitriles from Primary Amides and Aldoximes
A. Venkat Narsaiah, K. Nagaiah*
Division of Organic Chemistry, Fine Chemicals Laboratory, Indian Institute of Chemical Technology,
Hyderabad – 500007, India
Fax: (þ91)-40-27160512; e-mail; nagaiah@iict.res.in
Received: March 1, 2004; Revised: July 20, 2004; Accepted: July 23, 2004
Abstract: The pivaloyl chloride-pyridine system has
been utilizedas a novel andefficient reagent for
the preparation of nitriles from primary amides and
aldoximes. The reaction proceeds smoothly under
mild reaction conditions and the products are ob-
tainedin excellent yiel ds . This methodis applicable
to a wide range of substrates including aromatic, het-
erocyclic and aliphatic species. The dehydration
takes place at room temperature in the case of pri-
mary amides and dichloromethane at reflux temper-
ature is requiredfor rapidconversion in the case of
aldoximes.
long-standing studies of their utilization in organic syn-
[
1]
thesis andcontinue to receive attention from the
chemists roundthe globe in search of new methodology.
In recent years, the potential utility of nitriles was also
demonstrated in the synthesis of thiazoles, 2-oxazolines,
tetrazoles, imidazoles, triazoles and benzamidines pos-
[
2]
sessing a broadspectrum of biological activities. Sever-
al methods are available in the literature to prepare ni-
[
3]
[4]
triles starting from aldehydes, aldoximes, primary
[
5]
[6]
amides, primary amines andalso by nucleophilic sub-
[
7]
stitution with the cyano group. However, many of
these methods are deficient in some respect or other.
Some are expensive, require vigorous reaction condi-
[
8]
Keywords: aldoximes; dehydration; nitriles; pivaloyl
chloride-pyridine reagent; primary amides
tions, others involve hazardous (selenium dioxide)
[9]
andcorrosive (formic acid) reagents, the work-up is te-
dious or perhaps, more importantly, the method is not
generally applicable to alkyl, aryl andheterocyclic com-
pounds. Hence, there is considerable interest in finding
convenient, less toxic, more affordable, universally ap-
Owing to the increasing demand for generic procedures plicable reagents with potential selectivity towards oth-
in solution-phase chemistry andthe broadrange of com-
mercial importance of nitriles, it has become desirable to
er protecting groups.
Trimethylacetyl chloride (pivaloyl chloride) is a re-
devise an improved protocol for the dehydration of pri- agent for the selective protection of less hindered pri-
mary amides and aldoximes. Although this reaction has mary alcohols andalso is able to activate heteroaromatic
[
10]
foundendless applications in synthetic organic chemis-
amines towards ring lithiation. It has not been usedfor
try over the years, most procedures involve the use of the synthesis of nitriles from aldoximes and primary
stoichiometric or excess amounts of highly reactive re- amides so far. As part of our ongoing program on the
agents or harsh conditions and hence suffer from a synthesis and development of new methodologies in or-
[
11]
lack of selectivity andgenerality.
ganic synthesis, we report here an efficient protocol
The most commonly desired conditions should be for the chemoselective transformation of primary
milder, involve easiertohandle reagents, and offer abet- amides and aldoximes into nitriles using pivaloyl chlor-
ter scope for functional group compatibility. Numerous ide and pyridine in dichloromethane at room tempera-
examples can be foundin the literature de monstrating
ture to 508C that furnishes the products in excellent
the enormous changes in this methodology. Due to the yields. Accordingly, treatment of 3,4,5-trimethoxybenz-
remarkable synthetic properties of the nitrile group as aldoxime (Table 1, entry 1) with pivaloyl chloride and
an intermediate for the preparation of carboxylic acids, pyridine afforded the corresponding 3,4,5-trimethoxy-
aldehydes, amides, amines and ketones, have undergone benzonitrile in 95% yield.
The dehydration is very clean and completed with in
3.0 h in dichloromethane at reflux temperature. In a sim-
ilar manner various aliphatic andaromatic al do ximes
underwent dehydration with pivaloyl chloride and pyri-
dine to give the corresponding nitriles in high yield. The
a,b-unsaturatedoxime (entry 2) also smoothly convert-
edto correspon di ng nitrile in 76% yieldandthe com-
Scheme 1.
Adv. Synth. Catal. 2004, 346, 1271–1274
DOI: 10.1002/adsc.200404059
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1271

COMMUNICATIONS
A. Venkat Narsaiah, K. Nagaiah
Table 1. Conversion of aldoximes to nitriles.
Table 2. Conversion of primary amides to nitriles.
[a]
All the products were characterised by comparison of their
m.p. IR and H NMR spectra with those of the authentic
1
[
[
a]
b]
All products were characterised by comparison of their
mp, IR and H NMR data with those of the authentic sam-
ples.
samples
Yields of isolated products.
1
[b]
Yields of isolated products.
pounds having halogen substituents (entries 6 and 8) proceeded smoothly at room temperature. The results
were convertedto the corresponding nitriles in excellent
yields. In all the cases reactions were completed 3 to
are summarizedin the Tables 1 and2, respectively.
Comparedto the other classical amide to nitrile meth-
ods, one advantageous feature of the present protocol is
5.5 h andthe yields were 76 to 95%.
In the same way, the treatment of benzamide (Table 2, demonstrated with various different functional groups
entry 11) with pivaloyl chloride and pyridine, afforded such as methoxy, allyloxy, halogens, andnitro; also ali-
the corresponding benzonitrile in 87% yield. The dehy- phatic andheterocylic substrates participatedin this re-
dration is very clean and completed within 4 h at room action, affording excellent yields and high purities. Fur-
temperature. In a similar manner various aromatic, het- thermore, in the case of 4-nitrobenzaldoxime (entry 3)
eroaromatic andaliphatic primary ami de s un de rwent
the dehydration takes place with in 5 h, the yield is
dehydration with pivaloly chloride and pyridine to 88% andin the same way, 4-methoxybenzaldoxime (en-
give the corresponding nitriles in very good yields. The try 4) yields the corresponding 4-methoxybenzonitrile
dehydration reaction with the heterocyclic system of 2- in 85%. From this observation, it appears that elec-
ethyl-4-pyridinamide (entry 9) proceeded smoothly, tron-withdrawing or electron-donating groups do not af-
without forming any side products, within 3.5 h at fect significantly the rate of reaction.
room temperature in 82% yield, whereas, the aliphatic
Among the bases investigatedfor this conversion, pyr-
amide (entry 10) required a little more time and the idine was found to be more effective than triethylamine
yieldwas also somewhat lower (75%) but the substrate
allyloxy andmethoxy (entry 12) groups also undergone
in terms of conversion andreaction time. Primary
amides were converted at room temperature, but aldox-
dehydration in excellent yield. In all cases the reaction imes require reflux temperature because the intermedi-
1272
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Adv. Synth. Catal. 2004, 346, 1271–1274

Preparation of Nitriles from Primary Amides and Aldoximes
COMMUNICATIONS
was dried over Na SO andconcentratedto give the crude
2
4
product, which was purified by column chromatography, using
0–120 mesh silica gel andeluting with a 9:1 hexane-ethyl ace-
tate.
,4,5-Trimethoxybenzonitrile (entry 1): Light coloured
6
[4g]
3
solid, mp 92–948C; IR (KBr): n¼3068, 2934, 2823, 2238,
ꢀ
1 1
1
(
1
605, 1550, 1456, 1130, 876 cm ; H NMR (CDCl ): d¼3.85
3
þ
s, 3H), 3.90 (s, 6H), 6.90 (s, 2H); EIMS: m/z (%)¼193 (M ,
00), 178, (62), 150 (46), 132 (24), 106 (12), 74 (27), 49 (19).
[
3e]
Cinnamonitrile (entry 2): Colourless liquid; IR (neat):
Scheme 2.
n¼3085, 2963, 2846, 2235, 1606, 1588, 1434, 1269, 1035, 864,
ꢀ
1
1
7
5
66 cm ; H NMR (CDCl ): d¼5.83 (d, 1H, J¼17.5 Hz),
3
.91 (d, 1H, J¼17.5 Hz), 7.32–7.63 (m, 5H); EIMS: m/z
þ
ate of pathway B is relatively stable. The formation of ni- (%)¼129 (M , 18), 103 (34), 77 (100), 51 (43).
[3e]
triles from aldoximes and primary amides can be ex-
plainedby the mechanism shown in Scheme 2.
4-Nitrobenzonitrile (entry 3): Colourless solid, mp 147–
1498C; IR (KBr): n¼3092, 2964, 2846, 2234, 1593, 1542,
ꢀ
1
1
In summary, we have demonstrated an efficient meth- 1400, 1336, 1084, 782 cm ; H NMR (CDCl ): d¼8.37 (d,
3
2
H, J¼8.5 Hz), 7.89 (d, 2H, J¼8.5 Hz): EIMS: m/z (%)¼148
od for the conversion of primary amides and aldoximes
to nitriles. The mildmethodoffers several a dv antages
over existing methods in terms of enhanced reaction
rates, high yields, easily handled reagent system, ambi-
ent temperature, cleaner products and wide applicabili-
ty for heterocyclic, aromatic as well as aliphatic com-
pounds.
þ
(
M , 69), 102 (100) 75 (32), 48 (23).
[3e]
4
-Methoxybenzonitrile (entry 4):
Colourless solid; mp
5
1
8
6–578C, IR (KBr): n¼3089, 2967, 2834, 2218, 1596, 1422,
ꢀ
1 1
306, 1285, 974 cm ; H NMR (CDCl ): d¼7.66 (d, 2H, J¼
3
.5 Hz), 6.97 (d, 2H, J¼8.5 Hz), 3.87 (S, 3H); EIMS: m/z
þ
(
%)¼133 (M , 100), 102 (42), 75 (26), 50 (18).
[5c]
Octanenitrile (entry 5): Syrup; IR (KBr): n¼2233, 1452,
ꢀ
1 1
1
7
3
366, 1238, 1059, 684 cm ; H NMR (CDCl ): d¼2.36 (t, J¼
3
.0 Hz, 2H), 1.76–1.57 (2H, m,), 1.43–1.12 (8H, m ) 0.94 (t,
þ
Experimental Section
H, J¼7.0 Hz); EIMS: m/z (%)¼125 (M , 25), 79 (6), 51 (4).
[4g]
4
-Chlorobenzonitrile (entry 6): Solid; mp 92–938C; IR
(
1
KBr): n¼3093, 2964, 2839, 2235, 1632, 1560, 1465, 1305,
General
ꢀ1
1
056, 865, 769 cm ; H NMR (CDCl ): d¼7.56 (d, 2H, J¼
3
þ
Melting points are uncorrected. TLC was performed using pre-
coatedsilica gel 60 F254 (0.25 mm) glass plates. Chromatogra-
phy was performedusing silica gel (60–120 mesh). IR spectra
6.0, Hz), 7.62 (d, 2H, J¼6.0 Hz); EIMS: m/z (%)¼139 (M
þ2, 81), 137 (100), 102 (32), 77 (21) 51 (28).
[4f]
Phenylpropionitrile (entry 7): Liquid; IR (neat): n¼3096,
ꢀ
1
were recorded neat and in KBr on a refractive spectrophotom-
2974, 2832, 2230, 1588, 1493, 1336, 1184, 1053, 935, 875 cm ;
1
1
eter. H NMR spectra were recorded in CDCl at 200 MHz.
H NMR (CDCl ): d¼7.13 (br s, 5H), 2.85 (t, 2H, J¼7.5 Hz),
3
3
þ
Chemical shifts are given in ppm with respect to internal
TMS, and J values are quotedin Hz. Mass spectra were record-
ed70 eV.
2.53 (t, 2H, J¼7.5 Hz); EIMS: m/z (%)¼131 (M , 11), 105
(62), 77 (100), 51 (32).
[4g]
4-Bromobenzonitrile (entry 8):
Colourless solid, mp
1
1
10–1128C, IR (KBr): n¼3100–2850, 2240, 1590, 1450,
ꢀ
1
1
260, 1040, 830, 670 cm ; H NMR (CDCl ): d¼7.60 (dd,
3
þ
General Procedure for Dehydration of Aldoximes
4H, J¼4.0 Hz, J¼1.5 Hz); EIMS: m/z (%)¼182 (M , 17),
1
02 (48), 76 (100), 50 (29).
-Ethyl-4-cyanopyridine (entry 9):
To a stirredmixture of the al do xime (5 mmol) andpivaloyl
chloride (5.5 mmol) in dichloromethane (10 mL) was added
pyridine (6 mmol) slowly and the reaction mixture was heated
at reflux for the specifiedtime (Table 1). Then, the reaction
mixture was diluted with dichloromethane and washed with
water (3Â25 mL). The organic layer was dried over Na SO
[5a]
2
Liquid: IR (neat):
n¼3096, 2968, 2837, 2234, 1608, 1559, 1405, 1400,1126, 1034,
ꢀ1
1
8
2
8
68, 764 cm ; H NMR (CDCl ): d¼1.31 (t, 3H, J¼8.5 Hz),
3
.90 (q, 2H, J¼8.5 Hz), 7.30 (s, 1H), 7.65 (d, 1H, J¼6.0 Hz),
þ
.66 (d, 1H, J ¼ 6.0 Hz); EIMS: m/z (%)¼132 (M , 24), 106
2
4
(
59), 80 (19), 66 (100), 41 (32).
and concentrated to yield the crude product, which was puri-
fiedby chromatography, eluting with a 9:1 hexane-ethyl ace-
tate mixture.
[4f]
Benzonitrile (entry 11): Liquid; IR (neat): n¼3069, 2934,
ꢀ
1
2
860, 2238, 1610, 1585, 1430, 1286, 1065, 976, 834, 769 cm ;
1
H NMR (CDCl ): d¼7.62–7,80 (m, 3H), 7.40–7.50 (d, 2H,
3
þ
J¼8.5 Hz, 2H); EIMS: m/z (%)¼103 (M , 36), 77 (100), 51
(
48).
3
General Procedure for Dehydration of Amides
[5a]
-Methoxy-4-allyloxybenzonitrile (entry 12): Solid; mp
5
9–608C; IR (KBr): n¼3069, 2938, 2842, 2239, 1608, 1552,
To a stirredmixture of the primary amide (5 mmol) andpiva-
loyl chloride (5.5 mmol) in dichloromethane (10 mL) was add-
edpyri di ne (6 mmol) at room temperature andstirring was
continuedfor 3–6 h. After complete conversion as in di cated
by TLC, the reaction mixture was diluted with dichlorome-
thane andwashedwith water (3 Â25 mL). The organic layer
ꢀ
1 1
1461, 1220, 864, 696 cm ; H NMR (CDCl
): d¼3.88 (s, 3H),
3
4.65 (dd, J¼5.4, 1.2 Hz, 2H), 5.33 (m, 1H), 5.42 (m, 1H,),
6.05 (m, 1H), 6.91 (d, J¼8.4 Hz, 1H), 7.12 (d, J
¼
2.0 Hz,
þ
1H), 7.3 (dd, J ¼ 8.4, 2.0 Hz, 1H); EIMS; m/z (%)¼189 (M ,
28), 148 (43), 133 (69), 117 (83), 91 (10), 75 (29), 49 (11).
Adv. Synth. Catal. 2004, 346, 1271–1274
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1273

COMMUNICATIONS
A. Venkat Narsaiah, K. Nagaiah
[
3e]
Naphthalene-2-carbonitrile (entry 13):
Solid; mp 66–
55, 13265; c) H. M. S. Kumar, B. V. S. Reddy, P. T. Reddy,
J. S. Yadav, Synthesis 1999, 586; d) I. R. Baxendale, S. V.
Ley, H. F. Sneddon, Synlett 2002,775; e) H. Sharghi,
M. H. Sarvari, Tetrahedron 2002, 58, 10323; f) F. E
Chen, G. Meng, Y. Cheng, Y. Xiang, Lu, Synthesis
6
1
3
1
88C, IR (KBr): n¼3086, 2961, 2842, 2230, 1604, 1558, 1383,
ꢀ
1
1
027, 834 cm ; H NMR (CDCl ): d¼8.26 (s, 1H) 7.9 (m,
3
þ
H), 7.64 (m, 3H); EIMS: m/z (%)¼153 (M , 41), 127 (69),
01 (22), 76 (100), 53 (32).
3
[
3g]
,4-Dimethoxybenzonitrile (entry 14): Colourless solid;
2
1
000, 1519; g) C. Patrice, L. Andre, M. Michael, Synthesis
989, 451.
mp 66–688C; IR (KBr): n¼3092, 2968, 2835, 2238, 1596,
ꢀ
1 1
1
3
8
437, 1254, 987, 673 cm ; H NMR (CDCl ): d¼3.8 (s, 3H),
3
[
4] a) H. M. Meshram, Synthesis 1992, 943; b) A. R. Katritz-
ky, G. F. Zhang, W. Q. Fan, Org. Prep. Proc. Int. 1993, 25,
.9 (s, 3H), 6.82 (d, J ¼ 8.0 Hz, 1H), 7.1 (s,1H), 7.25 (d, J ¼
þ
.0 Hz, 1H); EIMS; m/z (%)¼163 (M , 46), 101 (100), 75
3
7
15; c) M. Boruah, D. Konwar, J. Org. Chem. 2002, 67,
138; d) D. L. Luca, G. Giacomelli, A. Porcheddu, J.
(
38), 49 (23).
[4c]
Phenylacetonitrile (entry 15): Liquid; IR (neat): n¼3089,
ꢀ
1
1
Org. Chem. 2002, 67, 6272; e) K. Iashihara, Y. Furuya,
H. Yamamoto, Angew. Chem. Int. Ed. 2002, 41, 2983;
f) M. P. Heck, A. Wagner, C. Mioskowski, J. Org.
Chem. 1996, 61, 6486. g) M. Ghiaci, K. Bakhtiari, Synth.
Commun. 2001, 31, 1803.
5] a) D. S. Bose, A. V. Narsaiah, Synthesis 2001, 373;
b) D. S. Bose, P. R. Goud, Tetrahedron Lett. 1999, 40,
747; c) J. Correia, Synthesis 1994, 1127; d) C. R. Stephens,
E. J. Bianco, F. J. Pilgrim, J. Am. Chem. Soc. 1955, 77,
2
(
(
958, 2839, 2225, 1600, 1558, 1436, 1265, 968 cm ; H NMR
CDCl ): d¼7.35 (brs, 5H) 3.74 (s, 2H); EIMS: m/z (%)¼117
3
þ
M , 34), 91 (27), 77 (100), 51 (49).
[
5a]
2
,4-Dimethoxybenzonitrile (entry 16): Colourless solid;
mp 93–948C, IR (KBr): n¼3098, 2956, 2832, 2238, 1596,
ꢀ
1 1
[
1
7
(
(
468, 1310, 1266, 1049, 834, 675 cm ; H NMR (CDCl ): d¼
3
.42 (d, 1H, J¼8.5 Hz), 6.40–6.50 (m, 2H), 3.92 (s,3H), 3.80
þ
s,3H); EIMS: m/z (%)¼163 (M , 40), 133 (100), 107 (52), 76
34), 43 (25).
1
701; e) G. E. Ficken, H. France, R. P. Linstead, J.
Chem. Soc. 1954, 3730; f) T. M. Bagar, C. M. Riley,
Synth. Commun. 1980, 10, 479; g) S. Akbar, Synthesis
Acknowledgements
1
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The authors are grateful to the Director, Dr. J. S. Yadav, for his
support and encouragement.
hedron Lett. 1977, #18#1813; i) W. D. Ernest, J. H. Nich-
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8
3; k) D. S. Bose, B. Jayalaxmi, J. Org. Chem. 1999,
6
4,1713.
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ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1271–1274