Heterocyclization of arylmethylidene derivatives of malononitrile dimer: Synthesis of 4-amino-6-aryl-2-halopyridine-3,5-dicarbonitriles

Article abstract of DOI:10.1016/j.tetlet.2012.10.015

The synthesis of 4-amino-6-aryl-2-halopyridine-3,5-dicarbonitriles from the reaction of arylmethylidene derivatives of malononitrile dimer with hydrohalic acid in the presence of an oxidizing agent is described.

Full text of DOI:10.1016/j.tetlet.2012.10.015

Tetrahedron Letters 54 (2013) 21–22
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Tetrahedron Letters
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Heterocyclization of arylmethylidene derivatives of malononitrile dimer:
synthesis of 4-amino-6-aryl-2-halopyridine-3,5-dicarbonitriles
⇑
Ivan N. Bardasov , Denis L. Mihailov, Anastasiya U. Alekseeva, Oleg V. Ershov, Oleg E. Nasakin
Ulyanov Chuvash State University, Cheboksary, Moskovsky pr. 15, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2012
Revised 22 September 2012
Accepted 4 October 2012
Available online 26 October 2012
The synthesis of 4-amino-6-aryl-2-halopyridine-3,5-dicarbonitriles from the reaction of arylmethylidene
derivatives of malononitrile dimer with hydrohalic acid in the presence of an oxidizing agent is described.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Heterocyclic compounds
Cyano compounds
Oxiranes
Pyridines
One-pot synthesis
Approaches to the synthesis of cyano-containing 4-amino-2-
halopyridines can be divided into two types. The first is a multi-
stage process that involves a phased introduction of functional
substituents to the pyridine ring.1 In these reactions there is usu-
ally a greater consumption of reagents, solvents, but only low total
yields of final products. The second variant of the synthesis of cya-
no-containing 4-amino-2-halopyridines is the use of cascade reac-
tions of poly- and heterofunctional compounds. The non-cyclic
cyano group of the substrate, in most cases, is involved in the con-
struction of the pyridine ring.2 This is due to its ability to form an
iminium anion during the attack of nucleophilic reagents, and the
imine anion then reacts with a spatially contiguous electrophilic
center of the molecule, forming an azaheterocycle. This strategy
follows the principles of ‘green chemistry’ in organic synthesis
since it allows the incorporation of most of the starting reagents
into the final product and reduces the number of steps, as well
as the reagents, thereby reducing the energy consumption and tox-
icity of the process. We have previously described convenient one-
step processes for the preparation of heterocyclic compounds from
non-cyclic cyano-containing precursors.3 In this paper, we describe
a new approach to 4-amino-2-halopyridines using arylmethyli-
dene derivatives 1a–e of malononitrile dimer as starting materi-
als.4 It was found that the reactions with hydrohalic acids in the
presence of an oxidant formed 4-amino-6-aryl-2-chloropyridine-
3,5-dicarbonitriles 2a–e5 in 76–89% yields and 4-amino-6-aryl-
2-bromopyridine-3,5-dicarbonitriles 2f–j6 in 78–89% yields
(Scheme 1 and Table 1).
The structures of compounds 2a–j were confirmed by IR, 1H,
and 13C NMR spectroscopy and by mass spectrometry. The infrared
spectra contained absorption bands due to the conjugated cyano
groups at 2222–2237 cmÀ1 and the amino group at 3216–
NH2
NH2
NC
Ar
CN
NC
Ar
CN
Hal
+HHal, [O]
CN
N
2
1
Scheme 1. Synthesis of pyridines 2a–j.
Table 1
Synthesis of 6-aryl-4-amino-2-halopyridine-3,5-dicarbonitriles 2a–j
Substrate Ar
Hal Product
Yielda (%)
SeO2 Br2 KMnO4 O2 TCEb
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
C6H5
3-ClC6H4
4-H3CC6H4 Cl
4-FC6H4
2-ClC6H4
C6H5
3-ClC6H4
4-H3CC6H4 Br
4-FC6H4
2-ClC6H4
Cl
Cl
2a
2b
2c
2d
2e
2f
2g
2h
2i
82
86
83
76
89
83
—
—
—
—
—
—
—
—
12
—
—
—
—
—
—
—
—
—
18 65
—
—
—
—
—
—
—
—
—
71
—
—
—
—
—
—
—
—
Cl
Cl
Br
Br
—
82
86
83
78
89
Br
Br
2j
a
Yield of the isolated product.
TCE = tetracyanoethylene.
⇑
Corresponding author. Tel.: +7 9083030163; fax: +7 8352770979.
E-mail address: bardasov.chem@mail.ru (I.N. Bardasov).
b
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.015

22
I. N. Bardasov et al. / Tetrahedron Letters 54 (2013) 21–22
NH2
NH2
NH2
N
NH2
NC
Ar
CN
Hal
NC
CN
Hal
NC
Ar
CN
Hal
NC
Ar
CN +HHal
[O]
CN
N
2
Ar HN
1
Scheme 2. Proposed mechanism for the synthesis of pyridines 2a–j.
3388 cmÀ1. The 1H NMR spectra of products 2a–j exhibited singlets
at 8.10–8.37 ppm for the amino group and resonances expected for
the aryl group and other substituents. The 13C NMR spectra of 2b
and 2f exhibited signals due to the carbon atoms of the benzene
ring, and the cyano groups at 113.19–114.89 ppm, and signals for
the pyridine ring at 91.74–92.02 ppm (C-3, C-5) and 147.65–
163.69 ppm (C-2, C-4 and C-6). The mass spectra of compounds
2a–j displayed molecular ion peaks and other fragmentations,
including peaks due to [MÀHal]+ fragments.
Thierrichter, B.; Wibmer, P. Monatsh. Chem. 1979, 110, 483–492; (e) Junek, H.;
Wolny, B. Monatsh. Chem. 1976, 107, 999–1006.
5. Typical procedure for the preparation of 4-amino-6-aryl-2-chloropyridine-3,5-
dicarbonitriles 2a–e:
A
solution of 2-amino-4-arylbuta-1,3-diene-1,1,3-
tricarbonitrile (1) (2.20 g, 10 mmol), SeO2 (1.2 g, 11 mmol) and concentrated
HCl (2 mL) in 1,4-dioxane (70 mL) was stirred at 70 °C for 6–8 h (TLC). After
neutralization with sat NaHCO3 solution, the resulting precipitate was filtered
and washed with 1,4-dioxane and H2O (40 mL) and, then recrystallized from
1,4-dioxane. Compound 2a: mp 247–249 °C; 1H NMR (500.13 MHz, DMSO-d6): d
7.54–7.61 (3H, m, C6H5), 7.79 (2H, d, J = 7.4 Hz, C6H5), 8.20 (2H, s, NH2). IR 3373,
3360, 3242 (NH2), 2234 (C„N). MS (EI, 70 eV): m/z (%) 256 [M+
[M+
(
37Cl), 16], 254
(
35Cl), 100), 219 ([C13H7N4]+, 38). Anal. Calcd for C13H7ClN4: C, 61.31; H,
The reaction apparently involves nucleophilic addition of the
halide to the electrophilic carbon atom of the cyano group in the
first stage Scheme 2. Subsequent cyclization of the imine on to
the spatially contiguous electrophilic carbon atom leads to forma-
tion of the dihydropyridine ring. Aromatization under the action of
an oxidizing agent completes the reaction.
2.77; N, 22.00. Found C, 61.42; H, 2.72; N, 21.94. Compound 2b: mp 237–239 °C;
1H NMR (500.13 MHz, DMSO-d6): d 7.59 (1H, t, J = 7.9 Hz, C6H4), 7.67 (1H, ddd,
3J = 8.0 Hz, 4J = 2.1 Hz, 4J = 1.0 Hz, C6H4), 7.76 (1H, dt, 3J = 7.8 Hz, 4J = 1.3 Hz,
C6H4), 7.81 (1H, t, J = 1.9 Hz, C6H4), 8.28 (2H, s, NH2). 13C NMR (125.76 MHz,
DMSO-d6): d 91.87, 92.02 (C-3, C-5), 113.19, 114.52 (CN), 127.61, 128.57, 130.53,
130.88, 133.21, 137.90 (C6H4), 155.35, 158.72, 162.22 (C-2, C-4, C-6). IR 3368,
3346, 3244 (NH2), 2233 (C„N). MS (EI, 70 eV): m/z (%) 290 [M+
[M+
54.07; H, 2.02; N, 19.39. Compound 2c: mp 264–266 °C; 1H NMR (500.13 MHz,
DMSO-d6): 2.40 (3H, s, CH3), 7.36 (2H, d, J = 8.1 Hz, C6H4), 7.71 (2H, d,
J = 8.2 Hz, C6H4), 8.16 (2H, s, NH2). IR 3387, 3338, 3237 (NH2), 2227 (C„N). MS
(EI, 70 eV): m/z (%) 270 [M+ 37Cl), 34], 268 [M+ 35Cl), 100]. Anal. Calcd for
(
37Cl), 70], 288
(
35Cl), 100]. Anal. Calcd for C13H6Cl2N4: C, 54.01; H, 2.09; N, 19.38. Found C,
In the absence of an oxidant, even after many days of heating at
reflux, only the parent compounds 1a–j remained in the reaction
mixture. This can be explained by the fact that the halide anion
addition and the formation of the dihydropyridine are likely to
be reversible, and their direction is strongly shifted toward the for-
mation of the parent compounds. The introduction of the oxidant
leads to irreversible aromatization and releases the final pyridines
2a–j. As oxidants we used tetracyanoethylene, potassium perman-
ganate, aerial oxygen, bromine, and selenium dioxide. The best re-
sults were obtained with selenium dioxide for compounds 2a–j
and bromine for compounds 2a–j.
In conclusion, functionally substituted 4-amino-2-halopyri-
dines are known to be precursors of pharmacologically active com-
pounds,7 and therefore our goal is further modification of the
substituents on the pyridine ring and the study of the biological
activity of these products.
d
(
(
C
14H9ClN4: C, 62.58; H, 3.38; N, 20.85. Found C, 62.68; H, 3.36; N, 20.89.
Compound 2d: mp 285–287 °C; 1H NMR (500.13 MHz, DMSO-d6): d 7.38–7.42
(2H, m, C6H4), 7.85–7.90 (2H, m, C6H4), 8.23 (2H, s, NH2). IR 3375, 3244 (NH2),
2232 (C„N). MS (EI, 70 eV): m/z (%) 274 [M+ 37Cl), 31], 272 [M+ 35Cl), 100], 237
( (
([C13H6FN4]+, 29). Anal. Calcd for C13H6ClFN4: C, 57.26; H, 2.22; N, 20.55. Found
57.36; H, 2.23; N, 20.44. Compound 2e: mp 206–208 °C; 1H NMR (500.13 MHz,
DMSO-d6): d 7.50–7.59 (3H, m, C6H4), 7.64 (1H, dd, 3J = 8.0 Hz, 4J = 0.9 Hz, C6H4),
8.37 (2H, s, NH2). IR 3369, 3233 (NH2), 2225 (C„N). MS (EI, 70 eV): m/z (%) 290
[M+ 37Cl), 66], 288 [M+ 35Cl), 100], 253 ([C13H6ClN4]+, 87). Anal. Calcd for
( (
C
13H6Cl2N4: C, 54.01; H, 2.09; N, 19.38. Found C, 54.13; H, 2.07; N, 19.28.
6. Typical procedure for the preparation of 4-amino-6-aryl-2-bromopyridine-3,5-
dicarbonitriles 2f–j: solution of 2-amino-4-arylbuta-1,3-diene-1,1,3-
A
tricarbonitrile (1) (2.20 g, 10 mmol), Br2 (0.88 g, 11 mmol) and concentrated
HBr (2 mL) in 1,4-dioxane (70 mL) was stirred at 70 °C for 6–8 h (TLC). After
neutralization with sat NaHCO3 solution, the resulting precipitate was filtered
and washed with 1,4-dioxane and H2O (40 mL) and, then recrystallized from
1,4-dioxane. Compound 2f: mp 285–286 °C; 1H NMR (500.13 MHz, DMSO-d6): d
7.54–7.61 (3H, m, C6H5), 7.79 (2H, d, J = 7.0 Hz, C6H5), 8.14 (2H, s, NH2). 13C NMR
(125.76 MHz, DMSO-d6): d 91.74, 94.72 (C-3, C-5), 114.57, 114.89 (CN), 128.54,
128.92, 131.12, 135.92 (C6H4), 147.65, 158.40, 163.69 (C-2, C-4, C-6). IR 3375,
Supplementary data
3344, 3245 (NH2), 2230 (C„N). MS (EI, 70 eV): m/z (%) 300 [M+
(
81Br), 12], 298
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
015. These data include MOL files and InChiKeys of the most
important compounds described in this article.
[M+ 79Br), 11], 219 ([C13H7N4]+, 100). Anal. Calcd for C13H7BrN4: C, 52.20; H,
(
2.36; N, 18.73. Found C, 52.30; H, 2.23; N, 18.76. Compound 2g: mp 252–253 °C;
1H NMR (500.13 MHz, DMSO-d6): d 7.59 (1H, t, J = 7.9 Hz, C6H4,), 7.67 (1H, ddd,
C6H4, 3J = 8.1 Hz, 4J = 2.1 Hz, 4J = 1.0 Hz), 7.75 (1H, dt, 3J = 7.7 Hz, 4J = 1.4 Hz,
C6H4), 7.80 (1H, t, J = 1.9 Hz, C6H4), 8.22 (2H, s, NH2). IR 3367, 3319, 3231 (NH2),
2215, 2237 (C„N). MS (EI, 70 eV): m/z (%) 334 [M+ 81Br), 2], 332 [M+ 79Br), 6],
( (
253 ([C13H6ClN4]+, 56). Anal. Calcd for C13H6BrClN4: C, 46.81; H, 1.81; N, 16.80.
Found C, 46.71; H, 1.90; N, 16.81. Compound 2h: mp 289–291 °C; 1H NMR
(500.13 MHz, DMSO-d6): d 2.40 (3H, s, CH3), 7.36 (2H, d, J = 8.1 Hz, C6H4), 7.70
(2H, d, J = 8.1 Hz, C6H4), 8.10 (2H, s, NH2). IR 3388, 3341, 3238 (NH2), 2228
References and notes
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115–116; (d) Eremkin, A. V.; Ershov, O. V.; Kayukov, Ya. S.; Sheverdov, V. P.;
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(C„N). MS (EI, 70 eV): m/z (%) 314 [M+ 81Br), 13], 312 [M+ 79Br), 19], 233
( (
([C14H9N4]+, 100). Anal. Calcd for C14H9BrN4: C, 53.70; H, 2.90; N, 17.89. Found C,
53.63; H, 2.90; N, 17.93. Compound 2i: mp 281–281 °C; 1H NMR (500.13 MHz,
DMSO-d6): d 7.38–7.42 (2H, m, C6H4), 7.86–7.89 (2H, m, C6H4), 8.18 (2H, s, NH2).
IR 3371, 3349, 3240 (NH2), 2230 (C„N). MS (EI, 70 eV): m/z (%) 318 [M+ 81Br),
(
95], 316 [M+ 79Br), 100], 237 ([C13H6FN4]+, 95). Anal. Calcd for C13H6BrFN4: C,
(
49.24; H, 1.91; N, 17.67. Found C, 49.34; H, 1.92; N, 17.56. Compound 2j: mp
208–210 °C; 1H NMR (500.13 MHz, DMSO-d6): d 7.49–7.59 (2H, m, C6H4), 7.64
(2H, dd, 3J = 8.0,4J = 0.8, C6H4), 8.31 (2H, s, NH2). IR 3378, 3216 (NH2), 2222
(C„N). MS (EI, 70 eV): m/z (%) 334 [M+ 81Br), 6), 332 [M+ 79Br), 1), 253
( (
([C13H6ClN4]+, 24). Anal. Calcd for C13H6BrClN4: C, 46.81; H, 1.8; N, 16.80. Found:
C, 46.71; H, 1.92; N, 16.78.
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