Preparation of cyanopyridines by direct cyanation

Article abstract of DOI:10.1055/s-2005-861849

After pretreatment with nitric acid and trifluoroacetic anhydride, aqueous potassium cyanide converted pyridines 1a-1 into their corresponding 2-cyano derivatives 4a-1 in an average yield of 52%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-861849

PAPER
993
Preparation of Cyanopyridines by Direct Cyanation
Preparation of
C
ya
l
nopyrid
a
ines by Di
n
rec
t
Cyanation R. Katritzky,*a Eric F. V. Scriven,a Suman Majumder,a Hongbin Tu,a Anatoliy V. Vakulenko,a
Novruz G. Akhmedov,a Ramiah Muruganb
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
E-mail: katritzky@chem.ufl.edu
Reilly Industries, Inc, 1500 South Tibbs Avenue, P.O. Box 42912, Indianapolis, IN 46242-0912, USA
b
E-mail: rmurugan@reillyind.com
Received 22 October 2004; revised 17 December 2004
i) Ammoxidation of A) 2-methylpyridines;7,10 B) pyridine
Abstract: After pretreatment with nitric acid and trifluoroacetic an-
hydride, aqueous potassium cyanide converted pyridines 1a–l into
their corresponding 2-cyano derivatives 4a–l in an average yield of
52%.
2-aldehydes.11–13
ii) Reactions of cyanide ion with: A) activated pyridine N-
oxides;14–18 B) N-alkyl;19 C) N-acyl-pyridinium cations;14
Key words: pyridines cyanation, concd nitric acid, TFAA, potassi- D) N-aminopyridinium cations;20 E) 2-halopyridines.21
um cyanide
iii) Dehydration, decarboxylation and/or oxidation of: A)
primary amides;22,23 B) primary alcohols;24,25 C) 2-pyri-
dylacetic esters, oximinocarbonates and carbamates;26 D)
Cyanopyridines are widely used in the preparation of the
pyridine-2-aldehyde and 2-acylpyridine N,N-dimethylhy-
corresponding acids,1,2 aldehydes,3,4 ketones,5 and as im-
portant synthetic intermediates for the synthesis of herbi-
cides, pesticides, fungicides,6 and pharmaceuticals.7
Some substituted cyanopyridines are themselves biologi-
cally active.6 2-Cyanopyridine is also useful as starting
material for complex heterocyclic compounds.8,9
drazones;27 E) dehydration of pyridine-2-oximes.28–33
The parent 2-, 3- and 4-cyanopyridines are themselves
each produced on an industrial scale in large quantities by
ammoxidation of the corresponding picolines. However,
this method shows poor selectivity with respect to a par-
ticular methyl group when applied to lutidines and it is not
applicable to most functionalized methylpyridines.
Three main approaches are currently available for the
preparation of 2-cyanopyridines (Scheme 1):
Scheme 1
SYNTHESIS 2005, No. 6, pp 0993–0997
x
x
.
x
x
.2
0
0
5
Advanced online publication: 10.03.2005
DOI: 10.1055/s-2005-861849; Art ID: M08404SS
© Georg Thieme Verlag Stuttgart · New York

994
A. R. Katritzky et al.
PAPER
On a laboratory scale, a cyano group is frequently intro- tinic acid ester, to afford one-pot syntheses of the corre-
duced into the 2- and/or 4- position of a pyridine ring by a sponding 2-cyanopyridine (Table 1). All the products
variant of method (ii), i.e., treatment of an activated pyri- were characterized by comparison with melting points of
dine ring with cyanide ion and the cyanopyridines formed the known compounds (wherever data is available) and by
result from an addition-elimination process. Commonly elemental analysis. The structures of all compounds were
this has been achieved by treatment of pyridine-1-oxides confirmed using 1D NOE difference, proton-coupled 13
with an alkylating or acylating agent plus a source of cya- NMR, gHMQC and gHMBC experiments.
nide ions.
C
No direct cyanation of the pyridines (4a–l) has been re-
Recently methods have been reported for the one-pot con- ported. All previous methods used have involved multiple
version of pyridines to the 2-cyanopyridines by in situ ac- steps, with detriment to the final yield (see Table 1). For
tivation: direct cyanation of pyridine with dicyanogen example, the reported syntheses of 3-chloro-2-cyanopyri-
gives a mixture of 2-, 3- and 4-cyanopyridines.34 Direct dine start with either (i) 2,3-dichloropyridine, not easily
conversion of pyridine to 2-cyanopyridine in 27% yield prepared in the laboratory from 3-chloropyridine or (ii) 3-
was reported in a recent patent.6
chloropyridine N-oxide and which gives the desired 2,3-
isomer in 45% yield mixed with the 3,5-isomer.
The present research started with the objective of activat-
ing the pyridine nitrogen to generate a pyridinium species We consider a plausible mechanism for this reaction to in-
in situ, to promote subsequent nucleophilic attack by cya- volve initial formation of an N-nitropyridinium salt 1,
nide ion to produce cyanopyridines. Bakke and cowork- which is known to be formed in similar reactions of py-
ers,35 have described N-nitropyridinium ions as ridines with dinitrogen pentoxide as shown by Bakke.37
intermediates for the direct nitration of pyridines in ni- The N-nitropyridinium salt then undergoes a 1,2-addition
tromethane or sulfur dioxide to afford nitropyridines us- of cyanide ion to give ‘pseudocyanide’ 2. Intermediate 2
ing dinitrogen pentoxide as the nitrating agent. While readily undergoes elimination with the formal loss of ni-
dinitrogen pentoxide, is difficult to prepare and unstable, trous acid to form the cyanopyridine 3. This mechanism is
it does ionize in organic solvents like CCl4.
closely analogous to that of the Reissert–Henze reaction.38
The NO2 moiety is remarkable in that it as the nitronium
ion attacks as an excellent electrophile, and departs as ni-
trite, a good leaving group.
We sought to generate dinitrogen pentoxide in situ, under
conditions in which it would react readily with a pyridine
to give the corresponding N-nitropyridinium salt as an in-
termediate. This intermediate could then be treated with
KCN to form the corresponding cyanopyridines
(Scheme 2).
We now report a general one-pot conversion of a series of
pyridines to 2-cyanopyridines, which avoids the prepara-
tion of N-oxides or isolation of any other intermediate.
Moreover, the 2-cyanoderivatives are formed regioselec-
tively. The conversion of pyridines 1a–l with KCN to 2-
cyanopyridines 4a–l, pre-treated with nitric acid and in
trifluoroacetic anhydride, were achieved in an average
yield of 52%.
Scheme 2
Dinitrogen pentoxide can be produced by removing one
mole of water from two moles of nitric acid.36 This
prompted us to carry out the reaction in trifluoroacetic an-
hydride, which could act as a solvent and dehydrating
agent. Indeed this sequence succeeds.
Scheme 3
Thus pyridines 1a–l, pretreated with nitric acid and tri-
fluoroacetic anhydride, were added to potassium cyanide–
NaOAc buffer solution to give the corresponding 2-cyan-
opyridines 4a–l in an average yield of 52%.
By standardizing with pyridine as substrate, it was found
optimum to first dissolve the pyridine in trifluoroacetic
anhydride under chilled conditions followed by slow ad-
dition of concentrated nitric acid to the mixture. This so-
lution was then added dropwise to aqueous KCN buffered
with NaOAc at 0 °C to give 2-cyanopyridine (Scheme 3).
Melting points are uncorrected. H NMR and 13C NMR spectra in
1
CDCl3 (TMS as internal standard) were recorded on a Varian Mer-
cury 300 MHz NMR. The gHMQC and gHMBC experiments were
performed without spinning and acquired with several spectral
widths. The GARP pulse sequence was used for decoupling. The
FID’s were processed using Gauss and Gauss-shifted weighting
functions before Fourier transformation.
The optimum reaction time was also standardized at 3
hours for the nitric acid treatment and the reaction mixture
was allowed to stand at room temperature for 18 hours af-
ter addition to buffered KCN.
Cyanations, under the optimized reaction conditions,
were carried out on picolines, lutidines, halopyridines,
acylpyridines and even acid sensitive substrates like nico-
Preparation of 2-Cyanopyridines; General Procedure
Trifluoroacetic anhydride (10 mL, 42 mmol) was chilled in an ice
bath and the pyridine or substituted pyridine (17 mmol) was slowly
Synthesis 2005, No. 6, 993–997 © Thieme Stuttgart · New York

PAPER
Preparation of Cyanopyridines by Direct Cyanation
995
Anal. Calcd for C6H4N2: C, 69.22; H, 3.87; N, 26.92. Found: C,
68.83; H, 3.80; N, 26.89.
Table 1 Preparation of Cyanopyridines 4a–l and Previous Litera-
ture
Product
R
Yield (%) Literature
Yield Method
3-Methyl-2-pyridinecarbonitrile (4b)
Yield: 75%; yellow prisms; mp 83.5 °C (Lit.15 mp 84.0–86.0 °C).
Ref.
(%)
(Scheme 1)
(ii)-A
(ii)-A
(ii)-A
(ii)-A
(ii)-A
(ii)-E
1H NMR: d = 2.58 (s, 3 H), 7.43 (dd, J = 4.8, 8.0 Hz, 1 H), 7.69 (dd,
J = 1.6, 8.0 Hz, 1 H), 8.55 (d, J = 4.8 Hz, 1 H).
13C NMR: d = 18.6, 116.3, 126.5, 134.0, 138.0, 138.4, 148.4.
f
39
40
41
39
15
40
42
39
40
43
44
41
41
45
41
46
47
4a
4b
H
72
75
f
c
f
f
f
f
f
f
f
f
d
Anal. Calcd for C7H6N2: C, 71.19; H, 5.12; N, 23.73. Found: C,
71.41; H, 5.11; N, 23.76.
3-CH3
4-Methyl-2-pyridinecarbonitrile (4c)
Yield: 42%; yellow prisms; mp 87.0 °C.
1H NMR: d = 2.44 (s, 3 H), 7.34 (d, J = 4.9 Hz, 1 H), 7.53 (br s, 1
H), 8.57 (d, J = 4.9 Hz, 1 H).
13C NMR: d = 20.8, 117.3, 127.8, 129.3, 133.7, 148.7, 150.7.
(ii)-A
(ii)-A
(ii)-A
Anal. Calcd for C7H6N2: C, 71.19; H, 5.12; N, 23.73. Found: C,
71.41; H, 5.15; N, 23.81.
4c
4-CH3
42
3,5-Dimethyl-2-pyridinecarbonitrile (4d)
Yield: 82%; yellow prisms; mp 61.5 °C.
1H NMR: d = 2.39 (s, 3 H), 2.52 (s, 3 H), 7.48 (dq, J = 1.3, 0.7 Hz,
1 H), 8.35 (dq, J = 1.3, 0.7 Hz, 1 H).
13C NMR: d = 18.4, 18.5, 116.5, 131.0, 137.2, 137.8, 138.3, 149.0.
4d
4e
4f
3,5-di-CH3
3,6-di-CH3
3-C2H5
82
45
78
55
(ii)-A
a
(ii)-A
(ii)-A
(ii)-A
(ii)-A
Anal. Calcd for C8H8N2: C, 72.68; H, 6.10; N, 21.20. Found: C,
72.11; H, 6.03; N, 21.21.
4g
3-Cl
85g
47g
86
3,6-Dimethyl-2-pyridinecarbonitrile (4e)
Yield: 45%; yellow oil.
1H NMR: d = 2.52 (s, 3 H), 2.56 (s, 3 H), 7.29 (br d, J = 7.9 Hz, 1
H), 7.57 (br d, J = 7.9 Hz, 1 H).
13C NMR: d = 18.0, 23.7, 116.5, 126.6, 132.8, 135.3, 138.2, 145.2,
157.5.
4h
4i
3-Br
81
10
53
22e
20
5-COCH3
4-COCH3
25
(ii)-A
b
4j
26
4j¢
4k
4l
Anal. Calcd for C8H8N2: C, 72.68; H, 6.10; N, 21.20. Found: C,
72.80; H, 6.10; N, 21.23.
41
48
5-CO2C2H5
51g
90g
(ii)-A
(ii)-A
4-(4¢-pyridyl) 20
3-Ethyl-2-pyridinecarbonitrile (4f)
Yield: 78%; yellow oil.
1H NMR: d = 1.33 (t, J = 7.6 Hz, 3 H), 2.90 (q, J = 7.9 Hz, 2 H), 7.47
(dd, J = 7.9, 4.6 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 8.55 (d, J = 4.6
Hz, 1 H).
13C NMR: d = 14.8, 26.1, 116.2, 127.1, 133.6, 136.9, 144.5, 148.7.
a Prepared by ring cyclization.
b Prepared from dicyanopyridines.
c 93% Crude yield of mixture of isomers reported to be inseparable.
d 94% Crude yield of mixture of isomers reported to be inseparable.
e The product is a cyanohydrin.
f No yield quoted in the original reference.
Anal. Calcd for C8H8N2: C, 72.68; H, 6.10; N, 21.20. Found: C,
72.13; H, 6.15; N, 21.30.
g The reported yield is starting from pyridine-N-oxides, the overall
yield from pyridine itself being comparable to our method.
3-Chloro-2-pyridinecarbonitrile (4g)
Yield: 55%; yellow prisms; mp 83.0–84.0 °C (Lit.49 mp 83.0–84.0
°C).
1H NMR: d = 7.53 (dd, J = 8.2, 4.6 Hz, 1 H), 7.90 (dd, J = 1.2, 8.2
Hz, 1 H), 8.63 (dd, J = 1.2, 4.6 Hz, 1 H).
added. After 1 h, concd nitric acid (1.9 mL, 36 mmol) was added
dropwise under cooling. After stirring for 2–3 h at r.t., the solution
was dripped slowly into chilled aq solution of KCN (8.4 g) and
NaOAc (8.1 g). After 12 h, the pH of the solution was checked to be
6–7 and extracted with CH2Cl2 to give the pure cyanopyridines 4a–
l. All the compounds have been purified by column chromatogra-
phy on silica gel using EtOAc–hexane (1:1).
13C NMR: d = 114.5, 127.5, 133.1, 135.9, 137.6, 148.7.
Anal. Calcd for C6H3ClN2: C, 52.01; H, 2.18; N, 20.22. Found: C,
52.09; H, 2.02; N, 20.02.
2-Pyridinecarbonitrile (4a)
Yield: 72%; yellow oil.
1H NMR: d = 7.63 (dd, J = 7.7, 1.3 Hz, 1 H), 7.78 (ddd, J = 7.7, 1.3,
0.9 Hz, 1 H), 7.95 (td, J = 7.7 Hz, 1.8 Hz, 1 H), 8.76 (ddd, J = 4.9,
1.8, 0.9 Hz, 1 H).
3-Bromo-2-pyridinecarbonitrile (4h)
Yield: 81%; yellow prisms; bp 119.5 °C/3 Torr (Lit.41 bp 120.0 °C/
3 Torr).
1H NMR: d = 7.43 (dd, J = 8.2, 4.5 Hz, 1 H), 8.04 (d, J = 8.2 Hz, 1
H), 8.66 (d, J = 4.5 Hz, 1 H).
13C NMR: d = 117.0, 126.8, 128.2, 133.3, 137.0, 151.0.
13C NMR: d = 115.6, 124.5, 127.6, 135.2, 140.6, 149.0.
Synthesis 2005, No. 6, 993–997 © Thieme Stuttgart · New York

996
A. R. Katritzky et al.
PAPER
Anal. Calcd for C6H3BrN2: C, 39.38; H, 1.46; N, 15.07. Found: C,
39.56; H, 6.15; N, 21.30.
(6) Murugan, R.; Scriven, E. F. V.; Hillstrom, G. F.; Ghoshal, P.
K. Int. Patent, WO 2002090328, 2002; Chem. Abstr. 2002,
137, 352895.
5-Acetyl-2-pyridinecarbonitrile (4i)
(7) Verma, P. K.; Agarwal, A. Int. Patent, WO 2003022819,
2003; Chem. Abstr. 2003, 138, 239701.
Yield: 10%; yellow prisms; mp 54.5 °C (Lit.46 mp 55.0–56.0 °C).
(8) Abarca, B.; Ballesteros, R.; Chadlaoui, M. ARKIVOC 2002,
1H NMR: d = 2.70 (s, 3 H), 7.83 (d, J = 8.1 Hz, 1 H), 8.36 (dd, J =
8.1, 2.2 Hz, 1 H), 9.23 (dd, J = 2.2, 1.1 Hz, 1 H).
13C NMR: d = 26.9, 116.5, 128.4, 133.8, 136.5, 136.8, 150.7, 195.1.
x, 52.
(9) Brun, E. M.; Gil, S.; Parra, M. ARKIVOC 2002, x, 80.
(10) Luecke, B.; Martin, A.; Seeboth, H.; Ladwig, G.; Parlitz, B.;
French, J. German (East) Patent, DD 241903, 1987; Chem.
Abstr. 1987, 107, 175674.
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Synthesis 2000, 1519.
(12) Ikeda, I.; Machh, Y.; Okahara, M. Synthesis 1978, 301.
(13) Talukdar, S.; Hsu, J.-L.; Chou, T.-C.; Fang, J.-M.
Tetrahedron Lett. 2001, 42, 1103.
(14) Fife, W. K.; Scriven, E. F. V. Heterocycles 1984, 22, 2375.
(15) Vorbrüggen, H.; Krolikiewicz, K. Synthesis 1983, 316.
(16) Fife, W. K. J. Org. Chem. 1983, 48, 1375.
(17) Katritzky, A. R.; Sammes, M. P. J. Chem. Soc., Chem.
Commun. 1975, 247.
(18) Morita, T.; Kuroda, K.; Okamoto, Y.; Sakurai, H. Chem.
Lett. 1981, 921.
(19) Fife, W. K.; Boyer, B. D. Heterocycles 1984, 22, 1121.
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Perkin Trans. 1 1977, 327.
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(23) Katritzky, A. R.; Lapucha, A. R.; Siskin, M. Energy Fuels
1990, 4, 555.
Anal. Calcd for C8H6N2O: C, 65.75; H, 4.14; N, 19.17. Found: C,
65.37; H, 4.05; N, 19.03.
4-Acetyl-2-pyridinecarbonitrile (4j)
Yield: 53%; yellow prisms; mp 101.5 °C (Lit.47 mp 101.0–102.0
°C).
1H NMR: d = 2.68 (s, 3 H), 7.95 (dd, J = 5.1, 1.7 Hz, 1 H), 8.13 (dd,
J = 1.7, 0.8 Hz, 1 H), 8.94 (dd, J = 5.1, 0.8 Hz 1 H).
13C NMR: d = 26.6, 116.6, 124.4, 126.1, 143.6, 152.4, 194.9.
Anal. Calcd for C8H6N2O: C, 65.75; H, 4.14; N, 19.17. Found: C,
65.75; H, 4.03; N, 18.99.
4-Pyridineglycolonitrile, a-Methyl (4j¢)
Yield: 22%; white prisms; mp 121.0 °C.
1H NMR: d = 1.86 (s, 3 H), 7.51 (br s, OH, 1 H), 7.53 (AA¢BB¢,
JAB = 6.1 Hz, 2 H), 8.42 (AA¢BB¢, JAB = 6.1 Hz, 2 H).
13C NMR: d = 31.0, 69.1, 119.9, 120.9, 149.1, 151.8.
Anal. Calcd for C8H8N2O: C, 64.83; H, 5.44; N, 18.91. Found: C,
64.89; H, 5.35; N, 18.82.
5-Ethoxycarbonyl-2-pyridinecarbonitrile (4k)
Yield: 20%; yellow prisms; mp 47.0 °C.
1H NMR: d = 1.44 (t, J = 7.1 Hz, 3 H), 4.47 (q, J = 7.1 Hz, 2 H), 7.81
(d, J = 8.0 Hz, 1 H), 8.45 (dd, J = 8.0, 2.1 Hz, 1 H), 9.29 (dd, J =
2.1, 1.1 Hz, 1 H).
(24) Chen, F.-E.; Li, Y.-Y.; Xu, M.; Jia, H.-Q. Synthesis 2002,
1804.
(25) McAllister, G. D.; Wilfred, C. D.; Taylor, R. J. K. Synlett
2002, 1291.
(26) Kim, H. Y.; Lantrip, D. A.; Fuchs, P. L. Org. Lett. 2001, 3,
13C NMR: d = 14.1, 62.3, 116.5, 128.0, 128.9, 136.8, 138.0, 151.8,
2137.
(27) Rudler, H.; Denise, B.; Masi, S. C. R. Acad. Sci., Ser. IIc:
Chim. 2000, 3, 793.
(28) Barman, D. C.; Thakur, A. J.; Prajapati, D.; Sandhu, J. S.
Chem. Lett. 2000, 1196.
163.6.
Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.58; N, 15.90. Found: C,
61.31; H, 4.55; N, 15.78.
(29) Tamami, B.; Kiasat, A. R. Synth. Commun. 2000, 30, 235.
(30) Jose, B.; Sulatha, M. S.; Pillai, P. M.; Prathapan, S. Synth.
Commun. 2000, 30, 1509.
(31) Iranpoor, N.; Zeynizadeh, B. Synth. Commun. 1999, 29,
2747.
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4-(4¢-Pyridyl)-2-pyridinecarbonitrile (4l)
Yield: 20%; yellow prisms; mp 238.5 °C (Lit.48 mp 238.0–240.0
°C).
1H NMR: d = 7.55 (AA¢BB¢, JAB = 6.0 Hz, 2 H), 7.77 (dd, J = 8.2,
5.2 Hz, 1 H), 7.95 (s, 1 H), 8.82 (AA¢BB¢, JAB = 6.0 Hz, 2 H), 8.86
(d, J = 5.2 Hz, 1 H).
(34) So, Y.-H.; Miller, L. L. J. Am. Chem. Soc. 1980, 102, 7119.
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Paul, N. C.; Sanderson, A. J.; Stewart, M. J. Phil. Trans. R.
Soc. Lond. A 1992, 339, 305.
13C NMR: d = 116.9, 121.2, 124.5, 126.2, 135.0, 143.3, 147.2,
151.0, 151.9.
Anal. Calcd for C11H7N3: C, 72.91; H, 3.90; N, 23.19. Found: C,
72.04; H, 3.90; N, 22.86.
(37) Bakke, J. M.; Riha, J. Acta Chem. Scand. 1999, 53, 356.
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S.; Sano, H. Int. Patent, WO 9902518, 1999; Chem. Abstr.
1999, 130, 95555.
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Preparation of Cyanopyridines by Direct Cyanation
997
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