Synthesis of 3,6-Dibromopyrazine-2,5-dicarbonitrile [1]

Article abstract of DOI:10.1002/jhet.797

Symmetrically functionalized pyrazine of 3,6-dibromopyrazine-2,5- dicarbonitrile was synthesized in three or four steps from 3- aminopyrazinecarbonitrile or its 6-bromo derivatives.

Full text of DOI:10.1002/jhet.797

May 2012
Synthesis of 3,6-Dibromopyrazine-2,5-dicarbonitrile [1]
675
*
Nobuhiro Sato and Shunsuke Fukuya
Division of Organic Chemistry, Graduate School of Arts and Sciences, Yokohama City University,
Yokohama 236-0027, Japan
*
E-mail: nbsato@yokohama-cu.ac.jp
Received September 17, 2010
DOI 10.1002/jhet.797
View this article online at wileyonlinelibrary.com.
Symmetrically functionalized pyrazine of 3,6-dibromopyrazine-2,5-dicarbonitrile was syn-
thesized in three or four steps from 3-aminopyrazinecarbonitrile or its 6-bromo derivatives.
J. Heterocyclic Chem., 49, 675 (2012).
INTRODUCTION
of 3 to dicarbonitrile 4 should be prompted by elec-
tron-withdrawing effect of the existing cyano group
because it involves nucleophilic attack of cyanide
ion on the para carbon. In contrast, electrophilic bro-
mination of 4 was impeded by those cyano substitu-
ents, and purification of the desired product 5 from
unreacted precursor 4 is somewhat formidable. The
inverse reaction sequence via bromopyrazine N-oxide
6 was still suffered by far lower yield of 6. However,
synthesis of N-oxide 6 was efficiently achieved by
oxidation of 7 with 3-chloroperbenzoic acid in 83%
yield. Reaction of 6 with trimethylsilyl cyanide pro-
ceeded smoothly at room temperature to give a 76%
yield of the product 5, when the starting material 6
was completely consumed within 10 min. Nitrosation
of 5 followed by bromination was realized by treating
with t-butyl nitrite and copper(II) bromide in acetoni-
trile at room temperature to give an 80% yield of 1.
The IR spectrum for 1 has several prominent bands
because of symmetrical molecule, and the 13C-NMR
obviously shows three carbons.
A number of fully substituted pyrazines have received
significant attention due to their optical properties. As an
intermediate in synthesis of such molecules, symmetrically
functionalized pyrazines, for example, 3,6-diaminopyrazine-
2,5-dicarbonitrile [2], N,N′-di(t-butoxycarbonyl)-2,5-bis
(tri-n-butylstannyl)-3,6-diaminopyrazine, 2,5-diiodo-3,
6-dicarbonylpyrazine [3], 2,5-dibromo-3,6-dichloropyrazine,
and 3,6-dichloropyrazine-2,5-dicarbonitrile [4], have been
used. These highly functionalized compounds, with the
exception of the first one, have been conducted by multistep
sequence starting from less substituted pyrazines, and the
synthetic approaches are of great interest. In other words,
synthesis of pyrazines having two same functionalities at
the 2 and 5 carbons, including their 3,6-disubstituted
derivatives, has been known to be considerably daunting
project compared with that of the other 2,3- and 2,6-
isomers [5]. We now report synthetic pathway toward
3,6-dibromopyrazine-2,5-dicarbonitrile (1) which would
be expected as a versatile precursor for synthesis of other
highly functionalized pyrazines.
EXPERIMENTAL
RESULTS AND DISCUSSION
Melting points were determined with a Büchi capillary
apparatus and are uncorrected. IR spectra were recorded on
a Perkin Elmer Spectrum One. NMR spectra were obtained
with a Bruker Avance 600 (600 MHz 1H, 150.9 MHz 13C)
instrument using tetramethylsilane as internal standard.
The synthesis of 1 began with N-oxidation of 3-ami-
nopyrazinecarbonitrile (2), which has been readily
prepared by deoxidative cyanation of 3-aminopyrazine
1-oxide with trimethylsilyl cyanide [6]. Thus, the N-oxide
3 was obtained by treatment of 2 with 3-chloroperbenzoic
acid (Scheme 1) and has been also prepared by conden-
sation of aminomalononitrile with glyoxal and acetone
oxime [7], albeit in low yield. Deoxidative cyanation
2-Amino-3-cyanopyrazine 1-oxide (3). To a stirred mixture
of 2 (0.500 g, 4.16 mmol) in 1,2-dichloroethane (35 mL), 3-
chloroperbenzoic acid (70%, 1.99 g, 8.08 mmol) was added
portionwise, and the resulting mixture was refluxed for 4 h.
The hot mixture was filtered, and the insoluble matter was
© 2012 HeteroCorporation

676
N. Sato and S. Fukuya
Vol 49
Scheme 1
washed with 1,2-dichloroethane. The filtrate and washings were
concentrated to dryness in vacuo, and the residue was
recrystallized from ethanol (20 mL) containing several drops of
dimethylformamide to give 3 (0.420 g, 74%) as pale yellow
tiny prisms, mp 251–252ꢀC (lit. [7] mp 251–253ꢀC).
(0.800 g, 5.5 mmol) in wet acetic acid (acetic acid 10 mL and
water 1.0 mL) containing sodium acetate (1.3 g) in the dark,
and the mixture was stirred at room temperature for 24 h. Ice
water (50 mL) was added to quench the reaction, and the
mixture was extracted with ether (4 Â 30 mL). The combined
extracts were washed with saturated aqueous sodium hydrogen
carbonate followed by water, dried over magnesium sulfate,
filtered, and concentrated in vacuo to give powder (0.712 g),
which was recrystallized from hexane (100 mL) containing
several drops of 2-propanol to yield yellow prisms (0.580 g,
47%); mp > 280ꢀC.
IR (potassium bromide): 3355, 2245 (C[ꢁ]N), 1629, 1313,
1
1200, 869 cmÀ1; H-NMR (DMSO-d6): d 7.86 (d, J = 3.8 Hz,
1H, H-5), 7.98 (s, 2H, NH2), 8.48 (d, J = 3.8 Hz, 1H, H-6).
13C-NMR (DMSO-d6): d 112.0 (C-3), 114.9 (C[ꢁ]N), 134.0
(C-6), 134.3 (C-5), 150.8 (C-2).
3-Aminopyrazine-2,5-dicarbonitrile (4). A mixture of 3
(0.600 g, 4.4 mmol) in anhydrous acetonitrile (30 mL) containing
freshly distilled triethylamine (3.0 mL) was placed under argon,
and trimethylsilyl cyanide (2.6 mL, 21 mmol) was added
dropwise via a syringe. The mixture was refluxed with stirring for
45 min and then cooled to room temperature. The solvents were
removed in vacuo, and the residue was purified by
chromatography on silica gel (30 g) using hexane-ethyl acetate
(3:1) as eluent to afford dicarbonitrile 4 (0.481 g, 75%). The
analytical sample was obtained by recrystallization from benzene
as yellow tiny needles, mp 216–216.5ꢀC.
IR (potassium bromide): 3466, 3353, 2234 (C[ꢁ]N), 1627,
1544, 1386, 1214 cmÀ1 1H-NMR (DMSO-d6): d 8.09 (s, 2H,
;
NH2); 13C-NMR (DMSO-d6): d 113.9 (C-2), 114.6 (C[ꢁ]N),
114.7 (C[ꢁ]N), 124.1 (C-6), 132.5 (C-5), 154.9 (C-3); Anal.
Calcd. for C6H2N5Br: C, 32.17; H, 0.90; N, 31.26. Found: C,
32.41; H, 0.87; N, 31.14.
From N-oxide 6: A solution of 6 (0.432 g, 2.0 mmol) in anhydrous
acetonitrile (24 mL) containing distilled triethylamine (1.4 mL,
10 mmol) was placed in argon, and trimethylsilyl cyanide
(0.96 mL, 7.7 mmol) was added dropwise. The mixture was
stirred at room temperature for 15 min, and then ethanol (1 mL)
was added. After stirring for 15 min, the mixture was concentrated
to dryness in vacuo. The residue was purified by flash chromato-
graphy on silica gel (20 g) using hexane-ethyl acetate (3:1) to afford
5 (0.343 g, 76%).
IR (potassium bromide): 3383, 3180, 2237 (C[ꢁ]N), 1647,
1530, 1439, 1212 cmÀ1 1H-NMR (DMSO-d6): d 7.93 (s, 2H,
;
NH2), 8.38 (s, 1H, H-6); 13C-NMR (DMSO-d6): d 114.7 (C-2),
115.4 (C[ꢁ]N), 115.9 (C[ꢁ]N), 130.2 (C-5), 135.5 (C-6), 155.8
(C-3). Anal. Calcd. for C6H3N5: C, 49.66; H, 2.08; N, 48.26.
Found: C, 49.94; H, 2.08; N, 48.08.
2-Amino-5-bromo-3-cyanopyrazine 1-oxide (6).
From N-
3-Amino-6-bromopyrazine-2,5-dicarbonitrile (5).
pyrazinedicarbonitrile 4. A solution of Br2 (0.54 mL, 11 mmol)
in acetic acid (1.0 mL) was added to a stirred mixture of 4
From
oxide 3: A solution of Br2 (0.04 mL, 0.78 mol) in acetic acid
(0.2 mL) was added to a stirred mixture of 3 (0.068 g, 0.50 mmol)
in wet acetic acid (acetic acid 0.9 mL and water 0.08 mL) containing
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Synthesis of 3,6-Dibromopyrazine-2,5-dicarbonitrile
677
sodium acetate (0.123 g) in the dark, and the mixture was stirred at
room temperature for 24 h. Ice water (30 mL) was added, and the
mixture was extracted with dichloromethane (8 Â 10 mL). The
combined extracts were washed with saturated aqueous sodium
hydrogen carbonate followed by water, dried over magnesium sulfate,
filtered, and concentrated in vacuo. The residue was chromatographed
on silica gel (16 g) using with hexane-ethyl acetate (2:1) to give 6
(0.025 g, 23%). Further elution gave the starting material 3 (14 mg,
21%). The analytical sample of 6 was prepared by recrystallization
from 2-propanol to give yellow tiny needles, mp 216ꢀC.
concentrated to dryness in vacuo. The residue was purified by short
column chromatography on silica gel (20 g) using with hexane-ethyl
acetate (4:1) to give 1 (0.461 g, 80%). The analytical sample was
obtained by recrystallization from benzene as colorless tiny needles,
mp is not determined because of sublimation on heating.
IR (potassium bromide): 2236 (C[ꢁ]N), 1366, 1295, 1165,
1101 cmÀ1
;
13C-NMR (DMSO-d6): d 112.6 (C[ꢁ]N), 134.3
(C-2,5), 140.8 (C-3,6). Anal. Calcd. for C6N4Br2: C, 25.03; N,
19.46. Found: C, 24.57; N, 19.01.
IR (potassium bromide): 3291, 2235 (C[ꢁ]N), 1643, 1463, 1312,
1192, 1117, 890 cmÀ1; 1H-NMR (DMSO-d6): d 8.15 (s, 2H, NH2),
8.87 (s, 1H, H-6); 13C-NMR (DMSO-d6): d 109.7 (C-3), 114.2
(C[ꢁ]N), 122.2 (C-5), 135.7 (C-6), 150.9 (C-2). Anal. Calcd. for
C5H3N4OBr: C, 27.93; H, 1.41; N, 26.15. Found: C, 28.20; H, 1.30;
N, 26.13.
Acknowledgment. Partial financial support by the Nippon
Soda Co., Ltd., Tokyo, Japan, for this project is gratefully
acknowledged.
From 6-bromo-3-aminopyrazinecarbonitrile (7): A solution of 7
[8,9] (1.993 g, 10.0 mmol) and 3-chloroperbenzoic acid (70%,
3.88 g, 15.8 mmol) in acetone (100 mL) was stirred at 50ꢀC
(inner temperature), and after 24 h another portion of 3-chloro-
perbenzoic acid (1.94 g, 7.9 mmol) was added. The mixture
was further stirred at that temperature for 3 days, and then
concentrated to dryness in vacuo. The residue was purified by
flash-chromatography on silica gel (50 g) using with hexane-ethyl
acetate (3:1) to give 6 (1.783 g, 83%).
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3,6-Dibromopyrazine-2,5-dicarbonitrile (1). Conversion of 5
to 1 was carried out according to the procedure of Doyle et al. [10].
A solution of 5 (0.448 g, 2.0 mmol) in anhydrous acetonitrile (4 mL)
was added to a stirred mixture of CuBr2 (0.670 g, 3.0 mmol) and t-
BuONO (0.57 mL, 4.8 mmol) in anhydrous acetonitrile (10 mL)
under argon. The mixture was stirred at room temperature for 2
h and then poured into 3M hydrochloric acid (80 mL) containing
sulfamic acid (0.30 g). The resulting solution was extracted with
dichloromethane (3 Â 20 mL), and the combined extracts were
washed with brine, dried over magnesium sulfate, filtered, and
[8] Taylor, E. C.; Ray, P. S. J Org Chem 1987, 52, 3997.
[9] Sato, N.; Takeuchi, R. Synthesis 1990, 659.
[10] Doyle, M. P.; Siegfried, B.; Dellaria, J. F., Jr. J Org Chem
1977, 42, 2426.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet