A simple procedure for the preparation of 2-cyano-4-chloropyridines

Article abstract of DOI:10.1002/jhet.643

Figure represented. 4-Nitro-pyridine-N-oxides are reacted with ethylchloroformate and trimethylsilyl cyanide to give 4-chloro-2-cyanopyridine.

Full text of DOI:10.1002/jhet.643

July 2011
A Simple Procedure for the Preparation of
2-Cyano-4-chloropyridines
961
Arava Veerareddy,a* Gogireddy Surendrareddy,a and P. K. Dubeyb
aR&D Centre, Suven Life Sciences Ltd, Plot No. 18, Phase-III, Jeedimetla, Hyderabad 500055,
India
bDepartment of Chemistry, J.N.T. University, Hyderabad 500072, India
*E-mail: reddyvenis@rediffmail.com
Received April 25, 2010
DOI 10.1002/jhet.643
Published online 12 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
4-Nitro-pyridine-N-oxides are reacted with ethylchloroformate and trimethylsilyl cyanide to give
4-chloro-2-cyanopyridine.
J. Heterocyclic Chem., 48, 961 (2011).
INTRODUCTION
The chloro-N-oxide pyridines 8 are usually prepared
from 4-nitro-N-oxide pyridines 4 in the presence of acid
chlorides such as acetyl chloride and chloroformate
esters.
Among many heterocyclic compounds, pyridine and
its derivatives are important compounds and are present
in many biological systems [1,2]. Substituted pyridines,
among the different applications, the pharmaceutical [3]
and agrochemical [3] applications are more important.
Extensive studies have been carried out on the synthesis
of substituted pyridine compounds owing to their wide
importance as drugs, biologically active natural prod-
ucts, and for other applications. Preparation of 2-cyano-
pyridine derivatives is an important activity because of
the versatility of the group for further conversions [4] to
acids [5,6], aldehydes [7,8], ketones [9], and amines.
Some substituted cyanopyridines are themselves biologi-
cally active [10].
RESULTS AND DISCUSSION
In our medicinal chemistry program, we were in need
of several 4-chloro-2-cyanopyridine building blocks. We
hereby report our serendipitous discovery of preparing 4-
chloro-2-cyanopyridines 9, from 4-nitropyridine-N-oxide
8, in a one-step process. In our interest to replace dime-
thylcarbamoyl chloride reagent with ethylchloroformate
in conversion of 4-nitropyridine-N-oxide 4 to 4-nitro-2-
cyanopyridine 11, surprisingly we found that 4-chloro-2-
cyanopyridine 12 is the major product. The ethyl chloro
formate not only served as a reagent to replace dimethyl-
carbamoyl chloride in cyanation but also converted the
4-nitro to chloro compounds (Scheme 5).
4-Substituted 2-cyanopyridines are prepared by differ-
ent methods. Japanese [11] team prepared 2-cyano-4-
substituted pyridine oxides 2 from picoline oxides 1,
with acetyl chloride. Compound 2 is deoxygenated with
PCl3 to give 4-chloro-2-cyanopyridines 3 with overall
yields of 31.5% (Scheme 1).
To see the generality of this reaction, we studied
number of substituted derivatives of nitropyridine-N-
oxides and found that the reaction is a general one. The
best results were obtained when pyridine ring is substi-
tuted with benzyl ester (Entry 10). The results are tabu-
lated in Table 1.
Matsumura et al. [12c] prepared 2-cyano-4-substituted
pyridines 7, using the Reissert–Kaufmann-type reaction
on 4-nitropyridine-N-oxide 4 (Scheme 2).
Later, Yamanaka and coworkers [12b,d–g] reported
trimethylsilylcyanide as a versatile reagent for convert-
ing pyridine-N-oxides to 2-cyanopyridine derivatives
(Scheme 3).
In conclusion, we have developed a simple and con-
venient method for the preparation of 2-cyano-4-
chloropyridines.
Desjardins et al. [12a] and Hiroshi et al. [12h]
reported trimethylsilylcyanide in combination with
dimethylcarbamoyl chloride to convert substituted pyri-
dines-N-oxides to 2-cyanopyridine derivatives at room
temperature (Scheme 4).
EXPERIMENTAL
All reagents were obtained commercially and were of the
highest commercial quality and used without further
C
V
2011 HeteroCorporation

962
A. Veerareddy, G. Surendrareddy, and P. K. Dubey
Vol 48
Scheme 1
Scheme 4
4-Chloro-3-methyl-2-cyanopyridine (14). mp 70–72ꢀC; IR
(KBr): 3068.24, 2925.79, 2222.89 (CN), 1562.57, 1545.56,
1
1389.87, 1222.53, 1222.53, 1015.37, 858.18, 804.61 cmꢁ1; H-
purification. Solvents were freshly distilled and used. Melting
points were determined in open capillaries and are uncorrected.
The purity of all compounds was routinely checked by TLC
on silica gel-coated plates. IR spectra were recorded on a Per-
kin-Elmer model 2000 instrument in KBr phase. 1H-NMR
(400 MHz) and 13C-NMR (100 MHz) spectra were recorded in
CDCl3 using Brucker instrument, and mass spectra were
recorded on a Perkin-Elmer mass spectrometer operating at 70
eV.
NMR (CDCl3): d 2.62 (s, 3H), 7.5 (d, J ¼ 5.16 Hz, 1H), 8.44
(d, J ¼ 5.12 Hz, 1H); 13C-NMR (CDCl3): d 16.61, 115.70
(CN), 127.32, 135.11, 137.11, 145.42, 148.80; ms: m/z 153.0
(Mþ) and 154.7 (Mþ2).
4-Chloro-3,5-dimethyl-2-cyanopyridine (15). mp 70–72ꢀC;
IR (KBr): 3427.14, 2925.13, 2231.98 (CN), 1544.76, 1452.53,
1213.25, 1017.33, 809.01 cmꢁ1; H-NMR (CDCl3): d 2.48 (s,
1
1H), 2.60 (s, 1H), 8.37 (s, 1H); 13C-NMR (CDCl3): d 16.99,
17.70, 116.04 (CN), 132.40, 136.28, 136.62, 145.13, 149.63;
ms: m/z 166.8 (Mþ) and 169.1 (Mþ2).
General procedure for the preparation of 4-chloro-2-
cyanopyridines. To a solution of 5.0 g (0.032 mol) of 4-nitro-
pyridine-N-oxide and 7.0 g of (0.064 mol) ethylchloroformate
in 20 mL of 1,2-dichloroethane (EDC)/acetonitrile (CH3CN)
was added 3.17 g (0.032 mol) of trimethylsilylcyanide at 40–
45ꢀC over a period of 30 min, and then the reaction mixture
was stirred at 60–65ꢀC for 1 h. After the completion of reac-
tion, the reaction mixture was cooled to 10ꢀC, and the chilled
DM water was added (10 mL) at 10–20ꢀC over a period of 15
min and stirred for 30 min at 25–30ꢀC. The separated organic
layer was dried over sodium sulfate, and the solvent was
removed in vacuo to get the crude product, which was purified
by column chromatography or by recrystallization to yield
1.44 g (32%), mp 82–85ꢀC.
4-Chloro-6-methyl-2-cyanopyridine (16). mp 78–79ꢀC; IR
(KBr): 3444.58, 3072.65, 2927.37, 2242.75 (CN), 1573.30,
1411.00, 1261.54, 1114.42, 881.88, 849.45 cmꢁ1 1H-NMR
;
(CDCl3): d 2.60 (s, 3H), 7.39, (s, 1H), 7.5 (s, 1H); 13C-NMR
(CDCl3): d 24.15, 116.22 (CN), 125.83, 126.98, 133.98,
144.93, 161.92; ms: m/z 153.0 (Mþ) and 155.0 (Mþ2).
4-Chloro-3,5,6-trimethyl-2-cyanopyridine (17). mp 47–
49ꢀC; IR (KBr): 2926.90, 2229.31 (CN), 1571.10, 1539.48,
1440.93, 1410.32, 1235.65, 1012.47, 815.63 cmꢁ1 1H-NMR
;
(CDCl3): d 2.46 (s, 3H), 2.56 (s, 3H), 2.56 (s, 3H); 13C-NMR
(CDCl3): d 16.55, 17.19, 23.34, 116.29 (CN), 130.69, 134.45,
134.53, 144.94, 157.56; ms: m/z 180.9 (M)þ and 183.11 (Mþ2).
4-Chloro-5,6-dimethyl-2-cyanopyridine (18). IR (KBr):
2985.24, 2928.64, 2241.58 (CN), 1557.70, 1372.09, 1242.38,
4-Chloro-2-cyanopyridine (13). mp 82–85ꢀC; IR (KBr):
3086.38, 2467.90, 2239.82 (CN), 1963.38, 1547.75, 1380.86,
1214.74, 885.96, 846.76 cmꢁ1 1H-NMR (CDCl3): d 8.6 (s,
;
1126.41, 1023.70, 758.23 cmꢁ1; H-NMR (CDCl3): d 7.56 (s,
1
1H), 7.7 (d, J ¼ 5.3 Hz, 1H), 7.3 (d, J ¼ 6.8 Hz, 1H); 13C-
NMR (CDCl3): d 116.06 (CN), 127.4, 128.68, 134.75, 145.18,
1 51.78; ms: m/z 139.0 (Mþ) and 141.0 (Mþ2).
1H), 2.43 (s, 3H), 2.61 (s, 3H); 13C-NMR (CDCl3): d 13.95,
15.92, 116.45 (CN), 126.75, 130.03, 134.89, 148.3, 151.98.
6-Bromo-4-chloro-2-cyanopyridine (19). mp 80–84ꢀC;
IR (KBr): 3064.30, 1560.38, 1382.0, 1163.23, 980.71, 889.58,
817.98 cmꢁ1; H-NMR (CDCl3): d 7.65 (s, 1H), 7.76 (s, 1H);
1
13C-NMR (CDCl3): d 114.9 (CN), 127.56, 128.20, 133.94,
146.91, 153.3.
Scheme 2
3-Bromo-4-chloro-6-methyl-2-cyaonopyridine (20). mp
83–85ꢀC; IR (KBr): 067.58, 2242.25 (CN), 1561.51, 1407.17,
1340.85, 1037.9, 875.65, 849.23 cmꢁ1 1H-NMR (CDCl3): d
;
7.47 (s, 1H), 2.56 (s, 3H); 13C-NMR (CDCl3): d 23.58, 115.47
(CN), 122.17, 127.911, 135.89, 145.68, 159.70; ms: m/z 233.2
(Mþ) and 235.1 (Mþ2).
6-Bromo-4-chloro-3-methyl-2-cyaonopyridine (21). IR
(KBr): 3072.82, 2242.57 (CN), 1560.87, 1417.46, 1227.32,
1
1101.18, 1026.83, 833.84 cmꢁ1; H-NMR (CDCl3): d 7.58 (s,
1H), 2.63, (s, 3H); 13C-NMR (CDCl3): d 2.59, 114.64 (CN),
Scheme 5
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
A Simple Procedure for the Preparation of 2-Cyano-4-chloropyridines
963
Table 1
Preparation of 2-cyano-4-chloropyridine.
Reaction conditions
Temp
(ꢀC)
Time
(h)
Entry
Nitro compound
Entry
Product
Solvent
EDC
mp (ꢀC)
Yield (%)
1
13
60–65
25–30
1
82–85 (84–85) [13]
32
2
3
14
15
EDC
EDC
3
70–72
47–49
30
25–30
25–30
3
3
30
10
4
16
EDC
78–80 (NR) [11h]
5
6
17
18
EDC
EDC
5–10
2
1
74–78
18
18
–5 to 10
NR
7
8
19
20
EDC
60–65
80–83
5
6
80–84
83–85
19
17
CH3CN
9
21
CH3CN
80–83
6
NR
15
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

964
A. Veerareddy, G. Surendrareddy, and P. K. Dubey
Vol 48
Table 1
(Continued)
Reaction conditions
Temp
(ꢀC)
Time
(h)
Entry
Nitro compound
Entry
Product
Solvent
EDC
mp (ꢀC)
88–93
Yield (%)
10
22
60–65
60–65
2
48
11
23
24
EDC
1
106–108 (109) [13a,b]
25
12
CH3CN
80–83
6
101–103
31
EDC, ethylene dichloride; CH3CN, acetonitrile; NR, mp not reported.
127.93, 133.92, 136.32, 147.27, 150.01; ms: m/z 232.2 (Mþ)
and 234.2 (Mþ2).
[3] (a) Gavin, D. H. Tetrahedron 2004, 60, 6043; (b) Baily, T.
D.; Geo, G. L.; Scriven, E. F. V. Chem Heterocycl Compd 1984, 14,
1; (c) Thummel, R. P. Chem Heterocycl Compd 1984, 14, 253; (d)
Kumar, R.; Chandra, R. Adv Heterocycl Chem 2001, 78, 269; (e) Han-
ket, T.; Brunne, R. M.; Miller, H.; Rechel, F. Angew Chem Int Ed
1999, 38, 643; (e) Lukevits, E. Chem Heterocycl Compd 1995, 31,
639.
4-Chloro-6-cyano-5-methylnicotinic acid-4-cyano-2-fluro
benzyl ester (22). mp 88–93ꢀC; IR (KBr): 2928.35, 2238.01
(CN), 1575.69, 1418.35, 1294.55, 1215.83, 1150.25, 757.59
1
cmꢁ1; H-NMR (CDCl3): d 8.9 (s, 1H), 7.95 (d, J ¼ 9.94 Hz,
1H), 7.88 (d, J ¼ 7.5 Hz, 1H), 7.75 (t, J ¼ 8.56 Hz, 1H), 5.5
(s, 2H), 2.49 (s, 3H); 13C-NMR (CDCl3): d 17.19, 61.16,
114.29 (CN), 115.17, 116.93, 119.3, 127.5, 128.34, 131.33,
136.88, 138.34, 145.11, 149.61, 158.96, 161.48, 162.52.
[4] (a) Katrizky, A. R.; Scriven, E. F. V.; Majumdar, S.; Tu,
H.; Vakulenko, A. V.; Akhmedov, N. Z.; Murugan, R. Synthesis 2005,
993; (b) Abraca, B.; Ballesteros, R.; Chadlaoui, M. ARKIVOV 2002,
10, 52; (c) Brun, E. M.; Gil, S.; Parra, M. ARKIVOC 2002, 10, 80.
[5] Werstiuk, N. H.; Ju, C. Can J Chem 1989, 67, 5.
[6] Belokon, Y. N.; Tararov, V. I.; Savel’eva, T. F.; Vitt, S. V.;
Paskonova, E. A.; Dotdayev, S. C.; Borisov, Y. A.; Struchkov, Y. T.;
Batasanor, A. S.; Balikov, V. M. Inorg Chem 1988, 27, 4046.
[7] Cha, J. S.; Yoon, M. S. Tetrahedron Lett 1989, 30, 3677.
[8] Uno, T. Jpn Pat. 10259180 (1988); Chem Abstr 1998, 129,
260349.
4-Chloro-2-cyanoquinoline (23). mp 106–108ꢀC; IR (KBr):
3093.86, 2344.01, 2239.84 (CN), 1570.54, 1491.74, 1402.69,
;
1292.47, 1023.82, 907.86, 853.94 cmꢁ1 1H-NMR (CDCl3): d
8.28 (d, J ¼ 8.6 Hz, 1H), 8.19 (d, J ¼ 8.44 Hz, 1H), 7.92 (t, J ¼
7.48 Hz, 1H,), 7.82 (t, 7.76 Hz, 1H), 7.78 (s, 1H); 13C-NMR
(CDCl3): d 116.53 (CN), 123.17, 124.1, 127.04, 130.41, 131.97,
133.12, 144.0, 148.65; ms: m/z 189.1 (M)þ and 191.2 (Mþ2).
3,6-Dibromo-4-chloro-pyridine-2-carbonitrile (24). mp
101–103ꢀC; IR (KBr): 3092.448, 3051.8, 2245.1 (CN),
1524.00, 1537.81, 1385.75, 1210.82, 1137.60, 885.88, 836.98,
[9] Reimann, E.; Ziegon, H.-L. Liebigs Ann Chem 1976, 1351.
[10] Murugan, R.; Scriven, E. F. V.; Hillstrom, G. F.; Ghoshal,
P. K. PCT WO Pat. 2002090328 (2002); Chem Abstr 2002, 137,
352895.
817.79 cmꢁ1 1H-NMR (400 MHz, CDCl3): d 7.66 (s, 1H);
;
13C-NMR (400 MHz, CDCl3): d 114.31 (CN), 124.48, 128.74,
35.71, 147.84, 151.09.
[11] (a) Hamano, M.; Saeki, S.; Hatano, Y.; Nagakura, M. Yaku-
gaku Zasshi 1963, 83, 348; (b) Kato, T.; Hayashi, H. Yakugaku Zasshi
1963, 83, 352.
Acknowledgments. The authors are grateful to Suven Life Sci-
ences management for allowing them to publish these results.
[12] (a) Desjardins, S. Y.; Cavell, K. J.; Hoare, J. L.; Skelton, B.
W.; Sobolev, A. N.; White, A. M.; Keim, W. J Organomet Chem 1997,
544, 163; (b) Sakamato, T., Kaneda, S.; Nishimura, S.; Yamanaka, H.
Chem Pharm Bull 1985, 33, 565; (c) Matsumura, E.; Agira, M.; Ohfuji,
T. Bull Chem Soc Jpn 1970, 43, 3210; (d) Vorbruggen, H.; Krolikie-
wicz, K. Synthesis 1983, 316; (e) Fife, W. K. J Org Chem 1983, 48,
1375; (f) Fife, W. K. Heterocycles 1984, 22, 93; (g) Fife, W. K.; Boyer,
R. Heterocycles 1984, 22, 1211; (h) Hiroshi, S.; Tadashi, N.; Hiroshi,
H.; Akira, M.; Takahiro, A. Eur Pat. 1,236,717 (2002).
REFERENCES AND NOTES
[1] Jones, G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, p 167.
[2] Balasubrahmanian, M.; Keay, J. G. In Comprehensive Het-
erocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon Press: Oxford, 1996; Vol. 5, p 245.
[13] Bisagni, E.; Rautureau, M.; Huel, C. Heterocycles 1989, 29,
1815.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet