Three-component synthesis of methyl 6-alkyl-3-cyano-2-halopyridine-4-carboxylates

Article abstract of DOI:10.1134/S1070428016070071

A procedure has been developed for the synthesis of methyl 6-alkyl-3-cyano-2-halopyridine-4-carboxylate by three-component reaction of 4-oxoalkane-1,1,2,2-tetracarbonitriles with hydrogen halides in methanol.

Full text of DOI:10.1134/S1070428016070071

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 7, pp. 970–973. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © O.V. Ershov, K.V. Lipin, O.E. Nasakin, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 7, pp. 977–980.
Three-Component Synthesis of Methyl
6
-Alkyl-3-cyano-2-halopyridine-4-carboxylates
O. V. Ershov, K. V. Lipin,* and O. E. Nasakin
I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
*
e-mail: lipinkost@mail.ru
Received March 9, 2016
Abstract—A procedure has been developed for the synthesis of methyl 6-alkyl-3-cyano-2-halopyridine-4-
carboxylate by three-component reaction of 4-oxoalkane-1,1,2,2-tetracarbonitriles with hydrogen halides in
methanol.
DOI: 10.1134/S1070428016070071
–
1
Isonicotinic acid derivatives are widely used in
practice, in particular as antitubercular drugs and anti-
depressants (monoamine oxidase inhibitors). There are
published data on bactericidal and other biological
activities of isonicotinic acid derivatives [1, 2]. There-
fore, development of new methods of synthesis of
diffucultly accessible compounds of this series is
an important problem. We previously reported that
carbonyl stretching bands at 1732‒1736 cm . Com-
1
pounds 2a–2c showed in the H NMR spectra a singlet
at 7.95‒7.97 ppm from the 3-H proton of the pyridine
ring, a singlet at δ 3.94‒3.96 ppm from the ester
methoxy group, and signals from protons of the
corresponding alkyl groups. The isotope ratios of the
molecular ion peaks in the mass spectra were 1:3 (2a,
2c) and 1:1 (2b).
4
-oxoalkane-1,1,2,2-tetracarbonitriles are convenient
1
13
However, the IR, H and C NMR, and mass spec-
tral data were insufficient to unambiguously determine
the position of the ester group in the pyridine ring of
2a–2c. Therefore, heteronuclear H– C correlation
study (HMBC) was performed for compound 2a
(see table). The HMBC spectrum of 2a displayed
a cross-peak between proton in the pyridine ring
(δ 7.95 ppm) and ester carbonyl carbon nucleus (C ,
δ 162.34 ppm), while no such correlation was
observed for the carbon atom of the cyano group (C ,
starting compounds for building up pyridine ring with
cyano groups in positions 3 and 4 [3–5].
1
13
We have developed a new method for the synthesis
of isonicotinic acid derivatives. Three-component
synthesis of methyl 6-alkyl-3-cyano-2-halopyridine-4-
carboxylates 2a–2c in 76–82% yield has been
accomplished by treatment of 4-oxoalkane-1,1,2,2-
tetracarbonitriles 1a and 1b with hydrogen halides in
methanol (Scheme 1).
7
C
9
δC 113.91 ppm). These findings indicated that the ester
The structure of 2a–2c was confirmed by IR,
1
13
H NMR, and mass spectra, as well as by C NMR
and heteronuclear two-dimensional HMBC spectra of
a. The IR spectra of 2a–2c contained strong absorp-
Correlations in the HMBC spectrum of compound 2a
O
7
O
8
2
CH
3
–
1
9
tion bands at 2231‒2235 cm due to stretching vibra-
4
H
3
CN
tions of the conjugated cyano group and strong ester
5
2
1
6
Scheme 1.
H
3
C
N
Cl
COOMe
O
1
13
NC
CN
CN
H, δ, ppm
C, δ
C
, ppm
HHlg/MeOH
CN
CN
2
7
5
R
7.95 (3-H)
164.68 (C ), 162.34 (C ), 105.51 (C ),
1
2
4.15 (C )
R
N
Hlg
8
7
3
2
.95 (OC H
3
)
162.34 (C )
1
a, 1b
2a–2c
1
2
3
.63 (C H
3
)
164.68 (C ), 122.89 (C )
R = Me, Hlg = Cl (a), Br (b); R = t-Bu, Hlg = Cl (c).
9
70

THREE-COMPONENT SYNTHESIS OF METHYL 6-ALKYL-3-CYANO-2-HALOPYRIDINE-...
971
Scheme 2.
HN
CN
NC
CN
CN
CN
NC
CN
Hlg
CN
Hlg
HHlg
R
O
1
O
Hlg
HO
H N
2
N
H
N
R
R
H
A
B
C
OMe
HN
OMe
CN
OMe
H N
2
CN
CN
HN
HO
MeOH
CN
Hlg
CN
Hlg
H O
2
2
O
–
H O, –HCN
2
–NH3
N
H
N
H
R
N
Hlg
R
R
D
E
F
group is located in position 4 of the pyridine ring.
In addition, the proton resonating at δ 7.95 ppm
step, hydrolysis of the imidic ester group in pyridine
derivative F yields methyl 6-alkyl-3-cyano-2-halopyri-
dine-4-carboxylate 2.
2
showed three more correlations, namely with C
5
(
(
δ 164.68 ppm), C (δ 105.51 ppm), and 2-CH
C
C
3
Alternative transformation sequences are also
possible. For example, methyl ester 2 could be formed
by reaction of 6-alkyl-2-halopyridine-3,4-dicarbonitrile
3 with methanol. In order to verify the proposed mech-
anism (Scheme 2) we performed additional studies.
For this purpose, 4-oxopentane-1,1,2,2-tetracarboni-
trile (1a) was reacted with hydrogen bromide and
aqueous HBr in 1,4-dioxane. We thus obtained
δC 24.15 ppm). The methyl protons displayed cou-
plings with the neighboring carbon atoms of the pyri-
2
3
dine ring, C and C (δ 122.89 ppm). Protons of the
C
7
ester methoxy group gave only one cross-peak with C .
Scheme 2 shows a probable mechanism of forma-
tion of compounds 2. In the first step, addition of
hydrogen halide to the terminal cyano group gives
intermediate A which undergoes cyclization to tetra-
hydropyridine structure B. We previously isolated
analogous hydroxytetrahydropyridine and determined
its structure by X-ray analysis [6]. When the reaction
was carried out in 1,4-dioxane or propan-2-ol, the next
step was dehydrocyanation and dehydration with
formation of 2-halopyridine-3,4-dicarbonitriles [3–5].
The use of methanol as solvent favors closure of
lactone imine ring (intermediate C) via intramolecular
interaction between spatially close hydroxy and cyano
groups. The subsequent addition of a methanol mole-
cule to C gives intermediate D. Analogous transforma-
tions were described previously for 3,3-diacetylcyclo-
propane-1,1,2,2-tetracarbonitrile [7]. Intermediate D is
unstable and is converted to imidic ester E which
undergoes aromatization as a result of elimination of
water and hydrogen cyanide molecules. In the final
2
3
-bromo-6-methylpyridine-3,4-dicarbonitrile (3) and
-bromo-1-methyl-6-oxo-2,7-diazabicyclo[3.2.1]oct-3-
ene-4,5-dicarbonitrile (4), respectively. No ester 2b
was detected in the reactions of 3 with methanol in the
presence of both dry hydrogen bromide and aqueous
HBr (Scheme 3). The formation of compound 4 in the
reaction of 1a with HBr/H O (Scheme 4) may be re-
2
garded as an indirect evidence in support of Scheme 2.
Intermediate C is converted to 4 via lactone imine–
lactam rearrangement [4, 8, 9]. It should also be noted
that the formation of methyl 6-alkyl-3-cyano-2-halo-
pyridine-4-carboxylates 2 and 3-bromo-1-methyl-6-
oxo-2,7-diazabicyclo[3.2.1]oct-3-ene-4,5-dicarboni-
trile (4) involves intramolecular interaction of one
cyano group with the carbonyl group [4].
The procedure proposed in this work for the syn-
thesis of methyl 2-chloro-3-cyano-6-methylpyridine-4-
Scheme 3.
O
CN
CN
CN
Br
CN MeOH, HBr
Br
HBr, H O
HBr
2
1
a
2b
HN
Me
N
H
Me
N
4
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

9
72
ERSHOV et al.
Scheme 4.
HN
O
CN
NC
CN
HBr
CN
Br
CN
Br
1
a
4
HO
Me
N
H
N
H
Me
B
C
+
carboxylate (2a) is more advantageous than those
described previously [10, 11] due to experimental sim-
plicity and low number of steps. Pyridine derivatives
m/z 254/256 (Irel 32/31%) [M] . Found, %: C 42.23;
H 2.76; N 11.05. C H BrN O . Calculated, %: C 42.38;
9
7
2
2
H 2.77; N 10.98. M 253.97.
2
a and 2b are convenient intermediate products for the
Methyl 6-tert-butyl-2-chloro-3-cyanopyridine-4-
carboxylate (2c). Yield 0.97 g (77%), mp 103‒104°C.
synthesis of pyridoxine.
–
1
IR spectrum, ν, cm : 2233 (C≡N), 1736 (C=O).
EXPERIMENTAL
1
H NMR spectrum, δ, ppm: 1.34 s (9H, t-Bu), 3.96 s
(
3H, OCH ), 7.97 s (1H, 5-H). Mass spectrum:
The purity of the isolated compounds was checked
by TLC on Sorbfil PTSKh-AF-A-UF plates; spots
were visualized under UV light, by treatment with
iodine vapor, or by thermal decomposition. The melt-
ing points were determined on an OptiMelt MPA100
melting point apparatus. The IR spectra were recorded
in mineral oil on an FSM-1202 spectrometer with
3
+
m/z 252/254 (Irel 11/3%) [M] . Found, %: C 57.09;
H 5.16; N 11.08. C H ClN O . Calculated, %:
12 13
2
2
C 57.04; H 5.19; N 11.09. M 252.07.
-Bromo-6-methylpyridine-3,4-dicarbonitrile
3). 1,4-Dioxane was saturated with dry hydrogen
2
(
bromide, 0.005 mol of 4-oxopentane-1,1,2,2-tetracar-
bonitrile was added, and the mixture was stirred for
1
1
Fourier transform. The H NMR spectra were
measured on a Bruker DRX-500 spectrometer at
.5–3 h at 50‒60°C. When the reaction was complete
5
00.13 MHz using DMSO-d as solvent and tetra-
6
(TLC), the mixture was cooled and diluted with a 4‒5-
fold volume of water. The precipitate was filtered off,
washed with water, and dried in air. The dry product
was dissolved in hot acetonitrile or ethyl acetate, the
solution was filtered from undissolved impurities, and
the filtrate was cooled and diluted with a 4‒5-fold
volume of water (acetonitrile solution) or with hexane
(ethyl acetate solution). The precipitate was filtered off
and washed with propan-2-ol. Yield 0.80 g (72%),
methylsilane as internal standard. The mass spectra
electron impact, 70 eV) were obtained on a Shimadzu
(
GCMS-QP 2010 SE instrument.
Methyl 2-chloro-3-cyano-6-methylpyridine-4-
carboxylate (2a). 4-Oxopentane-1,1,2,2-tetracarboni-
trile, 0.005 mol, was dissolved in 5 mL of methanol,
5
mL of concentrated aqueous HCl was added with
stirring, and the mixture was stirred for 1.5‒3 h at
0°C. When the reaction was complete (TLC), the
–
1
5
mp 56‒57°C. IR spectrum: ν 2230 cm (C≡N).
1
mixture was cooled and diluted with a 4‒5-fold
volume of water. The precipitate was filtered off and
washed with water and propan-2-ol. Yield 0.86 g
H NMR spectrum, δ, ppm: 2.63 s (3H, CH ), 8.02 s
3
(1H, 5-H). Mass spectrum: m/z 221/223 (I 54/55%)
[M] . Found, %: C 43.29; H 1.87; N 18.82. C H BrN .
rel
+
8
4
3
–
1
(
1
82%), mp 116°C. IR spectrum, ν, cm : 2235 (C≡N),
Calculated, %: C 43.27; H 1.82; N 18.92. M 220.96.
-Bromo-1-methyl-6-oxo-2,7-diazabicyclo[3.2.1]-
oct-3-ene-4,5-dicarbonitrile (4). 4-Oxopentane-
1
5
1
735 (C=O). H NMR spectrum, δ, ppm: 2.63 s (3H,
3
CH ), 3.95 s (3H, OCH ), 7.95 s (1H, 5-H). Mass
3
3
+
spectrum: m/z 210/212 (Irel 50/16%) [M] . Found, %:
,1,2,2-tetracarbonitrile, 0.005 mol, was dispersed in
mL of 1,4-dioxane, 5 mL of 40% aqueous HBr was
C 51.23; H 3.36; N 13.33. C H ClN O . Calculated, %:
9
7
2
2
C 51.32; H 3.35; N 13.30. M 210.02.
added with stirring, and the mixture was stirred for
.5–3 h at 70–80°C. When the reaction was complete
TLC), the mixture was cooled and diluted with a 4‒5-
Compounds 2b and 2c were synthesized in
a similar way.
1
(
Methyl 2-bromo-3-cyano-6-methylpyridine-4-
fold volume of water. The precipitate was filtered off
and washed with water and ethyl acetate. If necessary,
the product was recrystallized from ethyl acetate or
acetonitrile. Yield 1.05 g (79%), mp 256‒257°C. IR
carboxylate (2b). Yield 0.97 g (76%), mp 106‒107°C.
–
1
IR spectrum, ν, cm : 2231 (C≡N), 1732 (C=O).
1
H NMR spectrum, δ, ppm: 2.63 s (3H, CH ), 3.94 s
3
–
1
(
3H, OCH ), 7.96 s (1H, 5-H). Mass spectrum:
spectrum, ν, cm : 3223–3107 (NH), 2255 (C≡N),
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

THREE-COMPONENT SYNTHESIS OF METHYL 6-ALKYL-3-CYANO-2-HALOPYRIDINE-...
973
1
2
1
1
213 (C≡N), 1689 (C=O). H NMR spectrum, δ, ppm:
.48 s (3H, CH ), 2.15 d and 2.61 d (1H each, CH , J =
5. Ershov, O.V., Maksimova, V.N., Lipin, K.V., Beli-
kov, M.Y., Ievlev, M.Y., Tafeenko, V.A., and Nasa-
kin, O.E., Tetrahedron, 2015, vol. 71, no. 39, 7445.
3
2
0 Hz), 9.17 s (1H, NH), 9.53 s (1H, NH). Mass
spectrum: m/z 266/268 (Irel 11/12%) [M] . Found, %:
C 40.39; H 2.58; N 20.92. C H BrN O. Calculated, %:
C 40.47; H 2.64; N 20.98. M 265.98.
+
6
. Eremkin, A.V., Molkov, S.N., Ershov, O.V., Kayu-
kov, Y.S., Nasakin, O.E., Tafeenko, V.A., and Nuri-
eva, E.V., Mendeleev Commun., 2006, vol. 16, no. 2,
p. 115.
9
7
4
This study was performed under financial support
by President’s scholarship for young scientists and
post-graduate students (project no. SP-2782.2015.4).
7
. Yashkanova, O.V., Lukin, P.M, Nasakin, O.E.,
Urman, Ya.G., Khrustalev, V.N., Nesterov, V.N., Anti-
pin, M.Yu., and Vershinin, E.V., Russ. J. Org. Chem.,
1
997, vol. 33, p. 484.
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