Studies on Pyrazines. Part 33.1 Synthesis of 2,3-Diaminopyrazines via [1,2,5]Thiadiazolo[3,4-b] pyrazines

Article abstract of DOI:10.1039/a701579h

The syntheses of [1,2,5]thiadiazolo[3,4-b]pyrazine (3) and its methyl and/or phenyl derivatives as well as their reduction to 2,3-diaminopyrazines 4 are described.

Full text of DOI:10.1039/a701579h

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250 J. CHEM. RESEARCH (S), 1997
Studies on Pyrazines. Part 33.1 Synthesis of
2,3-Diaminopyrazines via [1,2,5]Thiadiazolo-
[3,4-b]pyrazines†
J. Chem. Research (S),
1997, 250–251†
Nobuhiro Sato* and Hajime Mizuno
Department of Chemistry, Yokohama City University, Yokohama 236, Japan
The syntheses of [1,2,5]thiadiazolo[3,4-b]pyrazine (3) and its methyl and/or phenyl derivatives as well as their reduction to
2,3-diaminopyrazines 4 are described.
The cleavage of fused pyrazines represents a useful method
for the synthesis of substituted pyrazines.2 We have pre-
viously reported the synthesis of 2,3-diaminopyrazines via
hydrogenolysis of furazano[3,4-b]pyrazines which were pre-
pared by the condensation of 3,4-diaminofurazan with
a-dicarbonyl compounds.3 Unfortunately, this methodology
was limited to the synthesis of diaminopyrazines having at
least one phenyl group, namely the diaminofurazan under-
went condensation with neither glyoxal, methylglyoxal nor
butane-2,3-dione. In contrast, 3,4-diamino-1,2,5-thiadiazole4
(1) was converted into a variety of [1,2,5]thiadiazolo[3,4-
b]pyrazines 3 including the parent and dimethyl deriva-
tives,4–6 which would be expected to form similarly 2,3-di-
aminopyrazines 4 by reductive desulfurization.
in the yield to 90% was achieved by a dropwise addition of 2
equiv. of 2c into a boiling mixture of 1 in ethanol followed by
refluxing. Similar treatment of 1 with 2e gave an excellent
yield of 3e, and the synthesis of 3b was best effected by
changing the solvent to methanol. This method, however, was
found to be of little value for the preparation of 3f because of
its low yield (24%). In comparison with the earlier synthetic
procedure4 for the parent thiadiazolopyrazine 3a, the con-
densation was notably improved by running the reaction in
ethanol at 55–60 °C, but a 42% yield of the desired product
was barely realized after purification by sublimation. Inci-
dentally, condensation of 1 with glyoxal–sodium bisulfite
addition compound did not proceed at all. The results are
summarized in Table 1.
Reductive desulfurization is usually accomplished by treat-
ment with Raney nickel or lithium aluminum hydride; use of
the former to reduce diphenylthiadiazolopyrazine 3f only
gave a 30% yield of the diaminopyrazine 4f and use of the
latter led to no formation of 4 at all. Recently, treatment with
tin powder in a mixture of concentrated hydrochloric acid
and dioxane was shown to convert benzobis[1,2,5]thiadia-
zoles into tetraaminobenzenes.7 A modified procedure using
tin(II) chloride in methanolic hydrochloric acid successfully
transformed 3 into 4 in excellent yields. With the exception of
4a, the cleavage was optimized by treating with 5 equiv. of tin
chloride at 60 °C (Table 2). Under the milder conditions of
using hydrochloric acid at room temperature, the parent di-
aminopyrazine 4a was formed in 83% yield. We have pre-
viously8 carried out the reduction with tin chloride with com-
plete conversion of azidopyrazines to aminopyrazines, in
which case some 2,3-diaminopyrazines 3 were obtained
from 2-amino-3-azidopyrazines. Compared with the existing
synthetic routes via 2-amino-3-halopyrazines9,10 or 1,4-dihy-
dropyrazine-2,3-diones,11 the current method provides a most
We report here the synthesis of the thiadiazolopyrazines 3
and their successful reduction to diaminopyrazines 4.
R1
R2
R1
R2
N
R1
R2
N
NH2
NH2
H2N
O
O
N
N
N
N
+
S
S
N
N
H2N
2a–f
1
3a–f
4a–f
a R1 = R2 = H; b R1 = Me, R2 = H; c R1 = R2 = Me; d R1= Ph, R2 =H;
e R1 = Ph, R2 = Me; f R1 = R2 = Ph
Scheme 1
The diaminothiazole 1 was conveniently prepared by
the hydrolysis of [1,2,5]thiadiazolo[3,4-c][1,2,5]thiadiazole
with ammonium hydroxide, in which the bicyclic compound
was produced by the cyclization of oxamide dioxime with an
excess of sulfur dichloride.6a Numerous thiadiazolopyrazines
3 have been synthesized mainly for use as agrochemicals, but
since most of them are patented procedures, only a few
preparations are available in the literature. Therefore, the
synthesis of 3 from 1 and the 1,2-diketones 2 was investigated
using a variety of solvents. Condensation of 1 with benzil 2f
easily proceeded in refluxing acetic acid and after 4 h gave
the thiadiazolopyrazine 3f in 85% yield. An almost equal
yield of 3f was obtained using a mixture of acetic acid and
ethanol (1:3 v/v)3 as the solvent for the same period, but
trifluoroacetic acid was found to be less practical (81% yield)
than the former acidic media. Treatment of 1 with phenyl-
glyoxal hydrate in refluxing acetic acid for 4 h afforded 3d in
excellent yield but treatment with 1-phenylpropane-
1,2-dione generated 3e in only 66% yield. Under identical
conditions, however, the aliphatic diketones 2a–c gave
modest yields (23–39%) of the corresponding products 3.
When ethanol was used as the solvent instead of acetic
acid, a better yield (60%) of 3c was obtained even after
shortening the reaction time to 1 h. An obvious improvement
Table 1 Synthesis of [1,2,5]thiadiazolo[3,4-b]pyrazines 3
Product 3
Solvent
Methoda
Yield (%)
a
b
c
d
e
f
EtOH
MeOH
EtOH
AcOH
EtOH
AcOH
A
A
A
B
A
B
42
77
90
90
85
85
aSee Experimental section.
Table 2 Reduction to 2,3-diaminopyrazines 4
Product 4
t/h
Yield (%)
a
b
c
d
e
f
1a
1
83
89
87
83
84
85
1
*To receive any correspondence (e-mail: nbsato@yokohama-cu.ac.jp).
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
3
2.5
3
aAt room temperature (see Experimental section).

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J. CHEM. RESEARCH (S), 1997 251
dmꢀ3 hydrochloric acid was used instead of the concentrated acid,
and the mixture was stirred at room temperature. The extent of the
reaction was monitored by TLC and the reaction was completed in
the time shown in Table 2. After being cooled to room tempera-
ture, the solution was basified with sodium carbonate at pH 8–9
and then evaporated to dryness under reduced pressure. The resi-
due was extracted with hot ethyl acetate (4Å15 cm3), and the
combined extracts were evaporated to dryness. Recrystallization of
the residue gave the following 2,3-diaminopyrazines 4a–f (Table
2). 2,3-Diaminopyrazine (4a), light tan microprisms, mp 200 °C
(MeOH) (lit.,8 207–209 °C); dH 4.23 (4 H, brs), 7.53 (2 H, s); dC
[(CD3)2SO] 129.0, 143.9. 2,3-Diamino-5-methylpyrazine (4b), light
tan needles, mp 176.5–177 °C (EtOAc) (lit.,8 176.5–178 °C); dH
2.29 (3 H, s), 4.05 and 4.21 (each 2 H, brs), 7.39 (1 H, s); dC 20.1,
130.8, 141.3, 141.5, 143.4. 2,3-Diamino-5,6-dimethylpyrazine (4c),
yellow needles, mp 214–215 °C (C6H6) (lit.,10 212–216 °C); dH 2.26
(6 H, s), 4.05 (4 H, brs); dC 20.2, 138.3, 141.1. 2,3-Diamino-5-phe-
nylpyrazine (4d), light tan needles, mp 172–173 °C (C6H6) (lit.,3
173 °C); dH 4.31 (4 H, brs), 7.34–7.46 (3 H, m), 7.84–7.86 (2 H, m),
7.99 (1 H, s); dC 125.8 (2 C), 127.9, 128.3, 128.7 (2 C), 129.5, 137.4,
142.8, 143.3. 2,3-Diamino-5-methyl-6-phenylpyrazine (4e), micro-
crystals, mp 168.5–169 °C (C6H6) (lit.,3 167–168 °C); dH 2.38 (3 H,
s), 4.16 and 4.26 (each 2 H, brs), 7.34–7.50 (5 H, m); dC 21.2, 127.4,
128.1 (2 C), 129.0 (2 C), 138.2, 139.4, 140.9, 141.1, 142.2. 2,3-Di-
amino-5,6-diphenylpyrazine (4f), light tan needles, mp 276–278 °C
(MeOH) (lit.,8 288.5–290 °C); dH 4.35 (4 H, brs) and 7.22–7.33
(10 H, m); dC 127.3, 128.0 (2 C), 129.6 (2 C), 132.7, 139.3, 142.0.
convenient route to 2,3-diaminopyrazines 3 in terms of the
accessibility of starting materials and the shorter reaction
sequence.
Experimental
Melting points were determined using a Bu¨chi 535 apparatus
and are uncorrected. 1H and 13C NMR spectra were obtained on a
JEOL JNM EX270 instrument at 270 and 67.8 MHz, respectively,
with solutions in CDCl3, unless otherwise stated, containing tetra-
methylsilane as internal standard.
General Procedure for Condensation of 3,4-Diamino-1,2,5-thia-
diazole 1 with 1,2-Diketones 2.sMethod A. Glyoxal (2a) and
methylglyoxal (2b) were used as 40% aqueous solutions. The
1,2-diketone solution (10 mmol for 2a–c, 6.0 mmol for 2e) was
added via syringe to a boiling solution of 3,4-diamino-1,2,5-thiadia-
zole (1) (0.571 g, 5.0 mmol) in alcohol (10 cm3) over 10 min, and
the resulting mixture was refluxed for 1 h. In the synthesis of 3a, the
reaction temperature was kept at 55–60 °C during the reaction.
After cooling, the reaction mixture was evaporated under vacuum,
and the residue was purified by column chromatography (silica gel,
30 g) using ethyl acetate–hexane (1:7 to 1:1) as eluent, and then
sublimed under reduced pressure. Analytical samples were
obtained by recrystallization.
Method B. A mixture of 3,4-diamino-1,2,5-thiadiazole (1)
(0.233 g, 2.0 mmol) and the diketone (2.1 mmol) in acetic acid
(4 cm3) was stirred and refluxed for 4 h. The reaction mixture was
cooled and concentrated under vacuum. Water was added to the
obtained residue, and the aqueous solution was extracted with
chloroform (3Å15 cm3). The extract was washed with water, dried
(MgSO4) and evaporated under vacuum. The residue was purified
as described above.
Received, 6th March 1997; Accepted, 13th March 1997
Paper E/7/01579H
The yields of [1,2,5]thiadiazolo[3,4-b]pyrazines 3a–f are sum-
marized in Table 1. The following compounds were obtained.
[1,2,5]Thiadiazolo[3,4-b]pyrazine (3a), Method A, yellow needles,
mp 166–168 °C (decomp.) (EtOH) [lit.,4 161–162 °C (decomp.)];
dH 9.05 (2 H, s); dC 149.2, 154.6. 5-Methyl[1,2,5]
thiadiazolo[3,4-b]pyrazine (3b), Method A, tiny yellow needles, mp
167.5–168 °C (decomp.) (EtOH) (Found: C, 39.7; H, 2.6; N, 37.1.
C5H4N4S requires C, 39.5; H, 2.65; N, 36.8%); dH 2.90 (3 H, s), 8.92
(1 H, s); dC 23.0, 150.9, 152.9, 154.1, 159.8. 5,6-Dimethyl-
[1,2,5]thiadiazolo[3,4-b]pyrazine (3c), Method A, yellow needles,
mp 125.5–126 °C (EtOH) (lit.,4 124–125 °C); dH 2.83 (6 H, s); dC
24.0, 153.2, 159.7. 5-Phenyl[1,2,5]thiadiazolo[3,4-b]pyrazine (3d),
Method B, yellow needles, mp 144.5–146 °C (EtOH) (lit.,5 115 °C)
(Found: C, 56.0; H, 2.7; N, 26.3. C10H6N4S requires C, 56.1; 2.8; N,
26.15%); dH 7.59–7.65 (3 H, m), 8.28–8.33 (2 H, m), 9.56 (1 H, s);
dC 128.4 (2 C), 129.5 (2 C), 131.9, 134.9, 148.5, 153.5, 154.5, 156.2.
5-Methyl-6-phenyl[1,2,5]thiadiazolo[3,4-b]pyrazine (3e), Method A,
yellow needles, mp 120.5–121 °C (EtOH) (Found: C, 58.0; H, 3.5;
N, 24.5. C11H8N4S requires C, 57.9; H, 3.5; N, 24.5%); dH 2.87 (3 H,
s), 7.56–7.69 (5 H, m); dC 25.6, 128.7 (2 C), 129.0 (2 C), 130.1,
137.5, 153.15, 153.19, 159.1, 159.9. 5,6-Diphenyl[1,2,5]thiadia-
zolo[3,4-b]pyrazine (3f), Method B, tiny yellow needles, mp
182–182.5 °C (EtOH) (Found: C, 66.2; H, 3.4; N, 19.3. C16H10N4S
requires C, 66.2; H, 3.5; N, 19.3%); dH 7.33–7.47 (6 H, m),
7.54–7.57 (4 H, m); dC 128.3 (2 C), 130.10, 130.14 (2 C), 137.7,
153.2, 158.7.
References
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General Procedure for the Reduction of [1,2,5]Thiadiazolo[3,4-
b]pyrazines 3.sA mixture of [1,2,5]thiadiazolo[3,4-b]pyrazines 3
(1.0 mmol) and tin(II) chloride (1.13 g, 5.0 mmol) in 12 mol dmꢀ3
hydrochloric acid (6 cm3) and methanol (6 cm3) was stirred and
heated at 60 °C (internal temperature). In the case of 3a, 1.5 mol