A regioselective synthesis of methyl 7-amino-3-phenylthieno-[2,3-b]pyrazine-6-carboxylate

Article abstract of DOI:10.1081/SCC-100103262

A practical synthesis of methyl 7-amino-3-phenylthieno [2,3-b]pyrazine-6-carboxylate (1) has been achieved via a regioselective synthesis of 3-cyano-5-phenyl-3-phenylthiopyrazine (5a), by condensing 1,1-diethoxyacetophenone with 2,3-diamino-3-phenylthioac

Full text of DOI:10.1081/SCC-100103262

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A REGIOSELECTIVE SYNTHESIS
OF METHYL 7-AMINO-3-
PHENYLTHIENO-[2,3-
b]PYRAZINE-6-CARBOXYLATE
Weijiang Zhang , Anthony R. Haight , Kelley L.
Ford & Shyamal I. Parekh
Published online: 16 Aug 2006.
To cite this article: Weijiang Zhang , Anthony R. Haight , Kelley L. Ford &
Shyamal I. Parekh (2001) A REGIOSELECTIVE SYNTHESIS OF METHYL 7-AMINO-3-
PHENYLTHIENO-[2,3-b]PYRAZINE-6-CARBOXYLATE, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:5, 725-730, DOI: 10.1081/SCC-100103262
To link to this article: http://dx.doi.org/10.1081/SCC-100103262
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SYNTHETIC COMMUNICATIONS, 31(5), 725–730 (2001)
A REGIOSELECTIVE SYNTHESIS OF
METHYL 7-AMINO-3-PHENYLTHIENO-
[2,3-b]PYRAZINE-6-CARBOXYLATE
Weijiang Zhang,* Anthony R. Haight, Kelley L. Ford, and
Shyamal I. Parekh
Chemical Process Research, D54P, Abbott Laboratories,
North Chicago, Illinois 60064, USA
ABSTRACT
A practical synthesis of methyl 7-amino-3-phenyl-
thieno[2,3-b]pyrazine-6-carboxylate (1) has been achieved via
a regioselective synthesis of 3-cyano-5-phenyl-3-phenylthio-
pyrazine (5a), bycondensing 1,1-diethoxyacetophenone with
2,3-diamino-3-phenylthioacrylonitrile.
Thieno[2,3-b]pyrazines and pyrazines have found wide uses in
pharmaceuticals and agrochemistry.1–5 To support the development of a
potential pharmaceutical candidate, a practical synthesis of the thieno
[2,3-b]pyrazine (1) was needed. The most general method of synthesizing
thieno[2,3-b]pyrazines has been to treat 3-cyano-2-halopyrazines with
thioglycolates, and base cyclization of the resulting 3-cyano-2-S-acyl-mer-
captopyrazines to yield the desired thieno[2,3-b]pyrazines.6–10 Retrosynthe-
tically, this approach required the preparation of pyrazine 2 where X was
either a halogen or a pseudohalogen (Scheme 1).
* Corresponding author.
725
Copyright & 2001 byMarcel Dekker, Inc.
www.dekker.com

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ZHANG ET AL.
Scheme 1.
The earlier work of the synthesis of pyrazine 2 was carried out by
using aminomalononitrile and an ꢀ-ketoaldoxime to make 2-amino-5-
phenyl-3-cyano-pyrazine11 followed bySandmeeyr reaction to give
2
(X ¼ Cl or Br). While this route appeared efficient, we had concerns about
the safe handling of aminomalononitrile after several episodes of allergic
reactions and skin rashes related to this reagent. We believed it would be
problematic to handle aminomalononitrile on a large scale. Herein we
would like to report an alternative synthesis of 2 byuse of 2,3-diamino-3-
phenylthioacrylonitrile13,14 (3) for the synthesis of pyrazine 5a and followed
byconversion of sulfide to sulfone (leaving group), which is also practical
for large scale preparation.
Sato reported the synthesis of 3-phenylthiopyrazinecarbonitrile by
condensing 3 with glyoxal.15 When phenylglyoxal was employed under
Sato’s conditions, it gave regioisomers 5a and 6a in 30–60% yield without
selectivity. No regioselectivity was achieved upon carrying the acids or the
solvents for the condensation. To overcome this, a protected ꢀ-ketoaldehyde
derivative, 2,2-diethoxyacetophenone 4a, was employed in condensation
(Scheme 2).
Scheme 2.
It was found that high selectivityfor 5a could be obtained byusing
4a stirred with 3 in the presence of excess trifluoroacetic acid (TFA) in
2-propanol. The selectivitywas lower in methanol or ethanol. Mineral
acids, such as hydrochloric or sulfuric acid, gave inferior selectivities and/
or yields. With a weaker acid, such as acetic acid, the reaction was slow and
the yield was poor due to the decomposition of the substrates. Increasing the
equivalents of TFA from 2 to 8.8 improved the selectivityof the condensa-
tion from 3.6:1, (5a:6a, Table entry1) to 13.1:1 (entry5) respectively. With

THIENO[2,3-b]PYRAZINES
727
Table. The Selectivityof Pyrazine 5a/6a from the Condensation of 3 and 4aa
EntryCF
3CO2H (eq.)
Ratio (5a/6a)b
Yield (%) (5a)c
1
2
3
4
5
6
2
2.6
4
3.6
5.3
41
45
55
73
67
86
4
6.5
8.8
17
11.8
13.1
15.5
aStandard conditions: 1 eq. 4a, 1.1 eq. 3, in 2-propanol(4a/2-propanol, 1/10, w/v)
at ambient temperature for 22–24 h.
bRatios of 5a:6a were of crude reaction mixtures. Reactions were monitored by
HPLC (Zorbax, SB-phenyl column, solvent: acetonitrile (50%) and 0.2% HClO4
(50%), 1.5 mL/min, ꢀ¼210 nm.
cYields are of isolated 5a.
17 eq. of TFA (entry6), the condensation of 3 with 4a resulted in a 15.5:1
ratio with an 86% isolated yield of 5a.
Presumably, an imine is first formed between 2-amino group of com-
pound 3 and the ketone carbonyl group of 4, subsequent cyclization then
gives pyrazine 5a. The formation of minor isomer 6a is due to the hydrolysis
of the acetal group of 4 under reaction conditions. Isolation of the product
was obtained bydilution of the reaction mixture with water to give the
desired product 5a as a filterable solid. If less TFA was used (entries 1–3),
5a could be further purified byrecrystallization from methanol to remove
the undesired isomer 6a.
We extended the cyclization to pyruvic aldehyde dimethyl acetal 4b
with 3 to yield 5b and 6b in an unexpected 1:6.8 mixture and 60% isolated
yield of 6b.14 This result might be due to rapid hydrolysis of dimethyl acetal
under the reaction conditions.
Activation of the phenylthio group in 5a as the sulfoxide 7 was accom-
plished bythe oxidation with sodium perborate in acetic acid at room
temperature (Scheme 3).16,17 Unfortunately, condensation of sulfoxide 7
with 1.1 eq. of methyl thioglycolate gave a low yield of thienopyrazine 1.
A competitive reduction of 7 to the sulfide 5a was a major side
reaction.18 Conversion of sulfide 5a to sulfone 8 is necessary. Oxidation of
ꢀ
5a bysodium perborate in acetic acid at 50 C provided a 1:3 mixture of
sulfoxide 7 to sulfone 8. With a catalytic amount of trifluoroacetic acid,
significant hydrolysis of the nitrile was observed.19 Oxidation of 3 eq.
of mCPBA in methylene chloride provided 82% sulfone 8,13 however,

728
ZHANG ET AL.
Scheme 3.
purification from the resulting meta-chlorobenzoic acid and methylene
chloride proved troublesome for large scale synthesis.
We found a 3:1 mixture of acetic acid and chloroacetic acid with 3.1
eq. sodium perborate to give an 1:7.3 ratio of sulfoxide 7 to sulfone 8 in a
95% overall yield after 16 hours at 50ꢀC. Presumably, the chloroacetic acid
creates a stronger peracid20 without causing the hydrolysis problems.
Treatment of the 1:7.3 mixture of 7:8 with 1.1 eq. of methyl thioglycolate
in ethanol with Hunig’s base yielded the title compound 1 in 93% yield.
In summary, an efficient synthesis of 2-phenylthio-3-cyano-5-phenyl-
pyrazine regioselectively has been developed. A convenient and inexpensive
oxidation method is described to convert sulfides to sulfones where the
substrate or product is sensitive to stronglyacidic conditions. This new
synthesis of methyl 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate 1
is suitable for large scale process. Further applications of this chemistryare
being studied.
SPECTRAL DATA FOR SOME SELECTED COMPOUNDS
Methyl 7-Amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate (1): mp:
198–199ꢀC(CHCl3); 1HNMR(CDCl3) ꢁ(ppm) 9.40(s, 1H), 8.06–8.03
(m, 2H), 7.60–7.48(m, 3H), 6.27(brs, 2H), 3.95(s, 3h); 13CNMR(CDCl3)
ꢁ(ppm) 201.1, 165.3, 149.2, 145.5, 142.3, 140.3, 136.1, 129.9, 129.1, 127.0,
51.9. MS(CI) m/z 286(Mþ1); Anal. Calc. for C14H11N3O2S: C, 58.94; H,
3.89; N, 14.73; Found: C, 58.47; H, 3.67; N, 14.66.
5-Phenyl-2-phenylthiopyrazine-3-carbonitrile (5a): mp: 133–135ꢀC
(EtOAc/Heptane); 1HNMR(CDCl3) ꢁ(ppm) 8.90(s, 1H), 8.00–7.90 (m, 2H),
7.70–7.60(m, 2H), 7.59–7.45(m, 6H). 13CNMR(CDCl3) ꢁ(ppm) 158.4,
149.1, 143.5, 135.4, 134.0, 130.6, 130.0, 129.6, 129.2, 127.1, 126.7, 126.6,

THIENO[2,3-b]PYRAZINES
729
114.6; Anal. Calc. for C17H11N3S: C, 70.57; H, 3.83; N, 14.73; Found: C,
70.35; H, 3.77; N, 14.60.
5-Methyl-2-phenylthiopyrazine-3-carbonitrile (5b): mp: 97–98ꢀC
(MeOH, lit.13 97–98.5ꢀC). HNMR(CDCl3) ꢁ(ppm) 8.31(s, 1H), 7.59–7.52
1
(m, 2H), 7.48–7.40(m, 2H), 2.53(s, 3H). 13CNMR(CDCl3) ꢁ(ppm) 159.7,
157.0, 140.7, 135.2, 129.7, 129.3, 127.1, 124.5, 114.7, 22.1.
6-Phenyl-2-phenylthipyrazine-3-carbonitrile (6a): mp: 133–134ꢀC
1
(EtOAc/heptane); HNMR(CDCl3) ꢁ(ppm) 8.80(s, 1H), 7.75–7.70(m, 2H),
7.65–7.60(m, 2H), 7.55–7.35(m, 6H); HRMS(FAB) Calc. m/z for (MþH)
C17H12N3S: 290.0752, Found: 290.0763; IR(KBr) 3060, 2210, 1520, 1509,
860(cmꢁ1). Anal. Calc. for C17H11N3S: C, 70.57; H, 3.83; N, 14.73; S, 11.08;
Found: C, 70.46; H, 3.68; N, 14.64; S, 11.09.
6-Methyl-2-phenylthiopyrazine-3-carbonitrile (6b): mp: 81–82ꢀC
(EtOAc/heptane, lit.13 82–82.5ꢀC). 1HNMR(CDCl3) ꢁ(ppm) 8.21(s, 1H),
7.59–7.52(m, 2H), 7.49–7.40(m, 2H), 2.44(s, 3H); 13CNMR(CDCl3)
ꢁ(ppm) 159.7, 157.0, 140.7, 135.3, 129.7, 129.3, 114.8, 90.4, 22.1; MS(CI)
m/z 228(Mþ1); IR(KBr) 3070, 3020, 2220, 1415, 1080, 750(cmꢁ1).
5-Phenyl-2-phenylsulfinylpyrazine-3-carbonitrile (7): mp: 173–174ꢀC
(toluene); 1HNMR (DMSO-d6) ꢁ(ppm) 9.67(s, 1H), 8.30–8.22(m, 2H),
7.99–7.93(m, 2H), 7.76–7.62(m, 6H); 13CNMR(CDCl3) ꢁ(ppm) 160.7,
152.9, 145.1, 142.1, 133.2, 132.2, 131.7, 129.8, 129.3, 127.6, 126.0, 125.3,
113.9; HRMS(FAB) Calc. m/z for (MþH) C17H12N3OS: 306.0701;
Found: m/z 306.0695. Anal. Calc. for C17H11N3OS: C, 66.87; H, 3.63; N,
13.76; S, 10.50; Found: C, 66.16; H, 3.50; N, 13.57; S, 10.75.
5-Phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (8): mp: 222–224ꢀC;
1HNMR(CDCl3) ꢁ(ppm) 9.19(s, 1H), 8.21(dd, 2H, J1 ¼ 8 Hz, J2 ¼ 2.5 Hz),
8.08(dd, 2H, J1 ¼ 8 Hz, J2 ¼ 3 Hz), 7.73(dt, 2H, J1 ¼ 8, J2 ¼ 2.5Hz), 7.60,
(m, 5H); IR(KBr) 3125, 3070, 2250, 1555, 1325, 1160, 730(cmꢁ1);
HRMS(FAB) Calc. m/z for (MþH) C17H12N3O2S: 322.0650, Found: m/z
322.0652. Anal. Calc. for C17H11N3O2S: C, 63.54; H, 3.45; N, 13.08; S, 9.98;
Found: C, 63.49; H, 3.37; N, 13.21; S, 9.98.
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Received in the U.S.A. June 1, 2000