A Re-examination of the reaction of 3,4-diamino[1,2,5]oxadiazole with glyoxal

Article abstract of DOI:10.1002/jhet.1054

Reaction coordinate mapping was used to study the reaction of 3,4-diamino[1,2,5]oxadiazole (3,4-diaminofurazan) and 3,4-diamino[1,2,5] thiadiazole with glyoxal. The thiadiazole was known to give a good yield of [1,2,5]thiadiazolo[3,4-b]pyrazine, whereas the oxadiazole had not yielded, until now, [1,2,5]oxadiazolo[3,4-b]pyrazine (or furazano[2,3-b]pyrazine). The calculations suggested that the diols, 5,6-dihydroxy-4,5,6,7-tetrahydro[1,2,5] oxadiazolo[3,4-b]pyrazine and 5,6-dihydroxy-4,5,6,7-tetrahydro[1,2,5] thiadiazolo[3,4-b]pyrazine should be stable intermediates, and once formed, should provide a pathway to the target compounds via two dehydration steps, under forcing conditions. With this information in mind, the reactions of 3,4-diamino[1,2,5]oxadiazole with glyoxal and pyruvic aldehyde were re-examined. The reaction of 3,4-diamino[1,2,5]oxadiazole with glyoxal and pyruvic aldehyde produced, under slightly basic conditions, a near quantitative yield of the expected initial products, 5,6-dihydroxy-4,5,6,7-tetrahydro[1,2,5]oxadiazolo[3, 4-b]pyrazine and the 5-methyl analog, respectively. The diols were easily isolated by lyophilizing the aqueous reaction mixture. The diols were pyrolized on silica gel at 160°C to give the desired [1,2,5]oxadiazolo[3,4-b]pyrazine and the 5-methyl analog. Both compounds were easily reduced to the corresponding 4,5,6,7-tetrahydro-derivative using sodium borohydride in THF/methanol. The [1,2,5]oxadiazolo[3,4-b]pyrazine also displayed other interesting chemistry.

Full text of DOI:10.1002/jhet.1054

July 2012
A Re‐Examination of the Reaction of
919
3
,4‐Diamino[1,2,5]oxadiazole with Glyoxal
a
a
a
Rodney L. Willer, * Robson F. Storey, Christopher G. Campbell,
b
c
Steven W. Bunte, and Damon Parrish
a
School of Polymers and High Performance Materials, The University of Southern Mississippi
Hattiesburg, Mississippi 39406
b
U.S. Army Research Laboratory, Weapons and Materials Research Directorate, Aberdeen Proving Ground,
Maryland 21005
c
Code 6930, Naval Research Laboratory, Washington, District of Columbia 20375
*
E-mail: rodney.willer@usm.edu
Received April 19, 2011
DOI 10.1002/jhet.1054
View this article online at wileyonlinelibrary.com.
Reaction coordinate mapping was used to study the reaction of 3,4‐diamino[1,2,5]oxadiazole (3,4‐
diaminofurazan) and 3,4‐diamino[1,2,5]thiadiazole with glyoxal. The thiadiazole was known to give a
good yield of [1,2,5]thiadiazolo[3,4‐b]pyrazine, whereas the oxadiazole had not yielded, until now,
[
5
[
1,2,5]oxadiazolo[3,4‐b]pyrazine (or furazano[2,3‐b]pyrazine). The calculations suggested that the diols,
,6‐dihydroxy‐4,5,6,7‐tetrahydro[1,2,5]oxadiazolo[3,4‐b]pyrazine and 5,6‐dihydroxy‐4,5,6,7‐tetrahydro
1,2,5]thiadiazolo[3,4‐b]pyrazine should be stable intermediates, and once formed, should provide a path-
way to the target compounds via two dehydration steps, under forcing conditions. With this information
in mind, the reactions of 3,4‐diamino[1,2,5]oxadiazole with glyoxal and pyruvic aldehyde were re‐
examined. The reaction of 3,4‐diamino[1,2,5]oxadiazole with glyoxal and pyruvic aldehyde produced,
under slightly basic conditions, a near quantitative yield of the expected initial products, 5,6‐dihydroxy‐
4
,5,6,7‐tetrahydro[1,2,5]oxadiazolo[3,4‐b]pyrazine and the 5‐methyl analog, respectively. The diols were
easily isolated by lyophilizing the aqueous reaction mixture. The diols were pyrolized on silica gel at
60°C to give the desired [1,2,5]oxadiazolo[3,4‐b]pyrazine and the 5‐methyl analog. Both compounds were
1
easily reduced to the corresponding 4,5,6,7‐tetrahydro‐derivative using sodium borohydride in THF/
methanol. The [1,2,5]oxadiazolo[3,4‐b]pyrazine also displayed other interesting chemistry.
J. Heterocyclic Chem., 49, 919 (2012).
INTRODUCTION
reaction of 1 with glyoxal using hydrochloric acid as
the catalyst and found that when using a 2:1 stoichiom-
etry of 1 to glyoxal they could isolate an almost quan-
titative yield of the tetracyclo‐compound 3 [2].
These results stand in stark contrast to the results of
the reaction of the related 3,4‐diamino[1,2,5]thiadiazole,
4, with glyoxal. In 1976, Komin and Carmack reported
on the reaction of 4 with glyoxal and biacetyl [3]. They
found that 4 initially reacted with aqueous glyoxal at
100°C to produce a chloroform insoluble precipitate that
appeared to be the diol adduct, 5 (see Scheme 2).
The reaction of 3,4‐diamino[1,2,5]oxadiazole (3,4‐
diaminofurazan), 1, with glyoxal has been examined
several times in the past (see Scheme 1). In 1978, Sato
and Adachi investigated the reaction of 1 and aqueous
glyoxal at a 1:1 stoichiometry utilizing acetic acid as
the catalyst with the hopes of synthesizing [1,2,5]
oxadiazolo[3,4‐b]pyrazine (or furazano[3,4‐b]pyrazine),
2
[1]. They reported that the reaction produced no
product. In 1985, Willer and Moore re‐examined the
©
2012 HeteroCorporation

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R. L. Willer, R. F. Storey, C. G. Campbell, S. W. Bunte, and D. Parrish
Vol 49
Scheme 1. Reported reactions of 3,4-diamino[1,2,5]oxadiazole with glyoxal [1,2].
Scheme 2. Reaction of 3,4-diamino[1,2,5]thiadiazole with glyoxal [3].
Continued heating dissolved some of the precipitate. Ex-
traction of the reaction mixture with chloroform gave
the desired [1,2,5]thiadiazolo[3,4‐b]pyrazine, 6. Reheat-
ing the aqueous layer and re‐extracting with chloroform
gave a total yield of 6 of 81.5%.
details or properties of the compound were reported [4].
Compound 7 had been synthesized by the four‐step proce-
dure of Willer and Moore [2]. This overall very low yield,
five‐step synthesis of 2 is summarized in Scheme 3. These
results are important in that they show that 2 is a stable
molecule but they shed no light on why 2 could not be
directly synthesized from 1 and glyoxal.
An important question arises from an examination of
this literature. Is the failure to form [1,2,5]oxadiazolo
[
3,4‐b]pyrazine from the reaction of 1 with glyoxal simply
a result of not using the proper reaction conditions or is it
the result of the 1,2,5]oxadiazolo[3,4‐b]pyrazine being
unstable relative to the diol intermediate? It should be
noted that in a review in 2003, Sheremetev and Yudin
mentioned that the synthesis of 2 had been accom-
plished by the dehydrogenation of 4,5,6,7‐tetrahydro
RESULTS AND DISCUSSION
To understand why attempts to make 2 directly from 1
and glyoxal have been unsuccessful, reaction coordinate
mapping was used to examine the reaction of both 1 and
4 with glyoxal [5–7]. The results are shown in Figures 1
and 2.
[
1,2,5]oxadiazolo[3,4‐b]pyrazine, 7, but no experimental
Scheme 3. Literature synthesis of 2 [2,4].
Journal of Heterocyclic Chemistry
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July 2012
A Re‐Examination of the Reaction of 3,4‐Diamino[1,2,5]oxadiazole with Glyoxal
921
Figure 1. Reaction coordinate mapping of the reaction of 1 with glyoxal. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
First, both reactions appear to be exothermic, with the
thiadiazole reaction being the more exothermic of the
two. Second, both reactions occur via a similar mechanism,
namely, a carbonyl carbon on glyoxal is attacked by an
amine group on 1 or 4 followed by a similar attack on
the other glyoxal carbon by the remaining amine nitrogen
on 1 or 4, resulting in a diol intermediate, 5 or 8. The reac-
tion then proceeds to product via two dehydration steps.
Third, the energetics of the two reactions are qualitatively
similar. Fourth, the diol intermediates (5 and 8) appear to
be significantly more stable than the reactants, increasing
the chances that they could be isolated.
Given that the calculations on both reactions result in the
same qualitative picture, coupled with the fact that Komin
and Carmack produced [1,2,5]thiadiazolo[3,4‐b]pyrazine,
6, via the reaction of 4 with glyoxal, we believe that the
failure of the analogous reaction of 1 with glyoxal to give
[1,2,5]oxadiazolo[3,4‐b]pyrazine, 2, is most plausibly
ascribed to the use of improper reaction conditions rather
than instability of 2 relative to the diol intermediate. This
Figure 2. Reaction coordinate mapping of the reaction of 4 with glyoxal. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
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R. L. Willer, R. F. Storey, C. G. Campbell, S. W. Bunte, and D. Parrish
Vol 49
of a brown residue. The light‐yellow, crystalline material was
easily identified as the desired [1,2,5]oxadiazolo[3,4‐b]
pyrazine, 2, based on spectroscopic data. The brown residue
was very impure 8 based on standard spectroscopic data.
Repeating the pyrolysis at 160°C and 0.5 torr produced
similar results. It was theorized that the low yield of 2 might
be due to the molecules of 8 reacting with each other
in the “melt” phase. A significant improvement to the
yield was obtained, when the diol was deposited on
silica gel in a 1:10 ratio, and this material was
pyrolyzed at 160°C. The product was isolated in
ꢀ
30% yield by extracting the material on the silica
gel with hot anhydrous chloroform. The product could
Figure 3. DSC thermogram of 5,6‐dihydroxy‐4,5,6,7‐tetrahydro[1,2,5]
oxadiazolo[3,4‐b]pyrazine, 8. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
be purified by sublimation or column chromatography
(
CHCl , silica gel, R = 0.7).
3 f
Similar results were obtained when pyruvic aldehyde
was substituted for glyoxal. The diol, 9, was much less sta-
ble and could not be characterized except by NMR and IR.
Pyrolysis of the material on silica gel gave only a 10%
yield of 5‐methyl[1,2,5]oxadiazolo[3,4‐b]pyrazine, 10, which
is stable and was completely characterized (see Experimental
section). These results are summarized in Scheme 4.
The principal reason for the great interest in the
synthesis of 2 is that it might offer a shorter synthetic route
to 4,5,6,7‐tetrahydro[1,2,5]oxadiazolo[3,4‐b]pyrazine, 7.
Sato and Adachi had shown that more highly substituted
conclusion is further supported by the fact that Sato and
Adachi, rather than observing the diol intermediate, were
unable to isolate any product, whatsoever.
The prediction that the diol was a stable compound
prompted a search for better conditions for its synthesis
and isolation. An article by Vail etal. stressed the impor-
tance of keeping the reaction slightly basic and the reaction
temperature low in the reaction of amides with glyoxal to
give N,N′‐dihydroxylethylenebisamides [8]. The reaction
of 1 with glyoxal at 45°C under these conditions produced
1
3
[1,2,5]oxadiazolo[3,4‐b]pyrazines could be reduced to the
a clear solution that, when examined by C NMR, clearly
contained a single product. To isolate this product under
very mild conditions, the solution was frozen and the water
removed by lyophilization. The resulting white powder
was identified as the expected 5,6‐dihydroxy‐4,5,6,7‐
tetrahydro[1,2,5]oxadiazolo[3,4‐b]pyrazine, 8, based on
spectroscopic data, although we have yet been unable to
establish its stereochemistry. It was later found that if the
reaction temperature was lowered to 20°C, the product
would actually crystallize from the reaction mixture.
tetrahydro‐analogs using sodium borohydride or lithium
aluminum hydride [1]. Compound 7 is of interest, because
it is the precursor to 4,7‐dinitro‐4,5,6,7‐tetrahydro[1,2,5]
oxadiazolo[3,4‐b]pyrazine, 11, a well‐known energetic
material [2]. It has also shown interesting electronic prop-
erties [9–11]. The original four‐step synthesis of 7 is
shown in Scheme 3 [2]. We have indeed established that
Scheme 4. Synthesis of [1,2,5]oxadiazolo[3,4-b]pyrazine, 2, and its
The differential scanning calorimetry (DSC) and high
resolution mass spectrometry (HRMS) analyses of 8 were
extremely enlightening. The DSC thermogram is shown
in Figure 3. The two endotherms at 113 and 151°C were
very suggestive of a stepwise dehydration process leading
to the desired [1,2,5]oxadiazolo[3,4‐b]pyrazine, 2, which
is consistent with the theoretical prediction. In the mass
spectrum of 8, the molecular ion (158.0431) was relatively
weak. A peak of almost equal intensity was observed
5-methyl analog.
at 140.0334 Da (M‐H O), and a very strong peak was
2
observed at 122.0265 Da (M-2H O).
2
Both of these facts were very suggestive that pyrolysis of
8
might be a viable route to the desired [1,2,5]oxadiazolo
[
3,4‐b]pyrazine, 2. Komin and Carmack had used pyrolysis
of 1,2,3,4‐tetrahydro‐2,3‐dihydroxypyrazano[2,3‐b]quinoxaline
to give pyrazano[2,3‐b]quinoxaline [3]. Pyrolysis of 8 at 130°C
and 2 torr for 2 h produced a small amount of a light‐yellow,
crystalline material on the cold finger and a substantial amount
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
A Re‐Examination of the Reaction of 3,4‐Diamino[1,2,5]oxadiazole with Glyoxal
923
Scheme 5. Chemistry of [1,2,5]oxadiazolo[3,4-b]pyrazine and its
-methyl analog.
5
Figure 4. X-ray structure of [1,2,5]oxadiazolo[3,4-b]pyrazine, 2. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
both 2 and 10 can be reduced to 7 and 12 in very high yields
using sodium borohydride in methanol/THF (see Scheme 5).
pyrazine type carbons are shifted downfield from pyrazine
1
3
(145.7 ppm) by over 7 ppm. Unfortunately, the C NMR
chemical shifts for 6 were not reported.
In conclusion, a direct synthesis of [1,2,5]oxadiazolo
[3,4‐b]pyrazine, 2, from 3,4‐diamino[1,2,5]oxadiazole has
been developed. The compound exhibits interesting and
useful chemistry and studies to improve the yield and
explore its chemistry continue.
Reaction coordinate mapping calculations showed that
tetraaminoethane compounds, obtained by addition of
amines to 2, are significantly more stable than 2. This sug-
gested that 2 would readily react with amines. As an exam-
ple, the reaction of 2 with ethylene diamine was studied. A
vigorous reaction occurred, yielding 13 as the sole product.
The stereochemistry of the ring juncture appears to be cis,
Table 1
Crystal data and structure refinement for
1,2,5]oxadiazolo[3,4‐b]pyrazine, 2.
[
Empirical formula
Formula weight
Temperature
4 2 4
C H N O
122.10
100(2) K
0.71073 Å
Orthorhombic
Aba2
a = 6.395(8) Å, α = 90°
b = 6.179(8) Å, β = 90°
c = 12.669(16) Å, γ = 90°
Wavelength
Crystal system
Space group
1
based on the H NMR data. This assignment was made on
the following basis: the ethylene group protons appear as
Unit cell dimensions
two multiplets typical of a conformationally mobile AA′
1
3
BB′ system [12], and the C satellites for the bridgehead
protons show that there is a small coupling of 4.2 Hz be-
tween them which is consistent with the cis‐stereochemistry.
Compound 2 also reacts vigorously with other primary
amines and, at slightly elevated temperatures, primary alcohols.
These reactions can produce very interesting [1,2,5]oxadiazole
containing polymers, if difunctional or trifunctional amines
and alcohols are used. These results will be reported separately.
The X‐ray crystal structure of 2 was determined and is
shown in Figure 4; crystallographic data are listed in
3
Volume
Z
500.6(11) Å
4
1.620 mg m−
3
Density (−173°C)
Density (20°C)
Absorption coefficient
F(0 0 0)
−3
1.536 mg m
0.126 mm−
248
1
3
Crystal size
0.18 × 0.15 × 0.14 mm
4.86–26.52°
Theta range for data
collection
Index ranges
−8 ≤ h ≤ 7, −7 ≤ k ≤ 7, −15 ≤ l ≤13
1606
469 [Rint = 0.0413]
97.8%
Reflections collected
Independent reflections
Completeness to theta =
−
3
Table 1. The experimental density (1.536 g cm ) is very
close to that calculated by the “Energy” program (1.55 g
26.52°
−
3
1
cm ) [13]. The H NMR chemical shifts in both 2 and
the sulfur analog, 6, are very close (8.97 vs. 9.06 [3]) and
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness‐of‐fit on F
Final R indices [I > 2σ(I)]
R indices (all data)
Largest diff. peak and hole
Semiempirical from equivalents
0.9825 and 0.9776
Full‐matrix least‐squares on F
469/1/42
1.158
2
1
are shifted ∼0.5 ppm downfield from the H NMR chemi-
1
3
2
cal shifts in pyrazine. The C NMR chemical shifts for 2
are 152.03 and 153.04 ppm. They are easily assigned
because of the lack of a nuclear Overhauser effect (NOE)
enhancement for the oxadiazole carbons (152.03). The
R
R
1
= 0.0570, wR
= 0.0597, wR
2
= 0.1707
= 0.1751
1
2
−
3
0.493 and −0.788 e Å
Journal of Heterocyclic Chemistry
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R. L. Willer, R. F. Storey, C. G. Campbell, S. W. Bunte, and D. Parrish
Vol 49
EXPERIMENTAL
Reaction coordinate mapping. All calculations describing
70‐mL portions of chloroform. The chloroform extracts are combined
and stripped at reduced pressure. The yield of slightly impure product
1
was 0.20 g (1.6 mmol, 33%). H NMR(CDCl ): δ = 8.97 (s) ppm.
3
13
the potential energy surface (PES) were performed using the
Gaussian 09x quantum chemistry suite [14]. Critical points on
the PES were determined using the BHandHLYP functional and
the 6‐311++G(2df,2p) basis set. The gradients for all geometry
optimizations were converged to the default settings. Each
critical point on the PES was characterized through normal‐
mode analysis. All transition states reported here had one
imaginary frequency, and all minima had no imaginary
frequencies. The transition states were subjected to intrinsic
reaction coordinate (IRC) calculations (using the default step
size) to facilitate connection with minima along the reaction
path. Each IRC terminated upon reaching a minimum as defined
by the default criteria provided in G09. For those points that did
not terminate in this fashion, the last converged point on the
reaction path was used as the initial structure for a full geometry
optimization. For each instance in which such an optimization
was attempted, a local minimum was found. It is assumed that
this is the minimum to which the IRC would have converged, if
convergence problems had not been encountered.
3
C NMR(CDCl ): δ = 152.03, 153.04 ppm. FT‐IR(KBr) = 1984
(w), 1957 (w), 1716 (w), 1558 (m), 1524 (m), 1447 (m), 1390 (w),
1358 (m), 1344 (sh), 1270 (w), 1237 (m), 1024 (m), 980 (m), 946
−1
(m), 882 (m), 868 (m), 750 (m), 638 (w), 603 (m) cm .
5-Methyl[1,2,5]oxadiazolo[3,4-b]pyrazine, 10. Finely ground
(≈105–177 μm) 3,4‐diamino[1,2,5]oxadiazole (1.0 g, 10 mmol),
40% pyruvic aldehyde (1.85 g, 10.5 mmol), and sodium
bicarbonate (100 mg) are placed in a 20‐mL scintillation vial
equipped with a magnetic stirring bar. The mixture is stirred at
25°C for
1 h. The 3,4‐diamino[1,2,5]oxadiazole slowly
dissolves. The crude product is diluted with 10 mL of dry
acetonitrile, and the resulting solution is slowly added to a
mixture of 50 mL of acetone and 12 g of silica gel. The solvents
are then evaporated under reduced pressure. A reflux condenser
is attached to reduce the loss of the silica gel when a vacuum is
applied, and the mixture is placed under high vacuum at room
temperature to remove the remaining acetone and any water. The
apparatus is placed in a 50°C oil bath, and the contents are
stirred. After 20 min, the temperature is raised first to 120°C and
then to 160°C. The mixture darkens considerably, and the 5‐
methyl[1,2,5]oxadiazolo[3,4‐b]pyrazine starts to collect at the
top of the flask and in the condenser. After 1 h, the apparatus is
removed from the oil bath and allowed to cool. The product that
had sublimed is readsorbed onto the silica gel. Methylene
chloride (300 mL) is poured down the condenser, and the
mixture is stirred for 30 min. The silica gel is removed by
filtration and extracted with two 50‐mL portions of methylene
chloride. The methylene chloride extracts are combined and
stripped to give the crude product that is slightly red in color.
3
,4‐Diamino[1,2,5]oxadiazole (3,4‐diaminofurazan), 1.
This compound was made by the procedure of Visalok and
Ostrovskoya [15]. The melting point was 179–180°C (lit. [15] 180°C).
5
,6‐Dihydroxy‐4,5,6,7‐tetrahydro[1,2,5]oxadiazolo[3,4‐b]
pyrazine, 8. Finely ground (≈105–177 μm) 3,4‐diamino[1,2,5]
oxadiazole (2.0 g, 20 mmol), 40% aqueous glyoxal (3.0 g,
1 mmol) and sodium bicarbonate (25 mg) are placed in a 20‐mL
2
scintillation vial equipped with a magnetic stirring bar. The
mixture is stirred at 20°C for 1 h. The clear solution is frozen in
liquid nitrogen, and the water is removed by lyophilization. The
white product is slurried with acetonitrile and collected. The yield
is 3.05 g (19.2 mmol, 96%). The compound does not melt, but it
The yield of slightly impure product is 0.14 g (0.1 mmol, 10%).
1
The melting point is 57–58°C. H NMR(CDCl ): δ = 2.88 (s,
3
1
13
exhibits two decomposition endotherms at 113°C and 151°C. H
3H), 7.79 (s, 1H) ppm. C NMR(CDCl ): δ = 23.06, 149.97,
3
NMR(DMSO‐d
ppm. C NMR(DMSO‐d ): δ = 75.45, 146.52 ppm.
6
): δ = 4.65 (s, 1H), 5.92 (bs, 1H), 7.79 (s, 1H)
150.71, 154.51, 162.88 ppm. FT‐IR(KBr) = 3143 (vs), 1720
13
6
(sh), 1709 (vs), 1599 (m), 1532 (m), 1385 (vs), 1061 (s), 945
−
1
FT‐IR(KBr) = 3143 (vs), 1720 (sh), 1709 (vs), 1599 (m), 1532
(m), 828 (w), 770 (w), 765 (w), 715 (w), 601 (m) cm . HRMS
+
(
(
1
m), 1385 (vs), 1061 (s), 945 (m), 828 (w), 770 (w), 765 (w), 715
(EI); C H N O ; [M] : calcd. 136.0385; found 136.0382 amu.
4 6 4 3
−
1
+
w), 601 (m) cm . HRMS (EI); C H N O ; [M] : calcd.
1,4,5,6‐Tetrahydro[1,2,5]oxadiazolo[3,4‐b]pyrazine, 7.
[1,2,5]Oxadiazolo[3,4‐b]pyrazine (122 mg, 1.0 mmol) is placed
in a 50‐mL round‐bottom flask equipped with a magnetic
stirring bar. Anhydrous THF (10 mL) is added. Sodium
borohydride (80 mg, 2.1 mmol) is added as a solid. A dark
solution is obtained. The mixture is stirred for 1 h without
apparent reaction. Approximately 1 mL of methanol is added,
and the reaction becomes quite vigorous. It is stirred for an
additional 1 h. Two milliliters of water is added, and the
solution is stirred for 1 h. The solution is stripped to give a
solid. The crude product is taken up in 3 mL of acetonitrile, and
the solution is syringe filtered to give a clear solution. The
solution is evaporated under a stream of nitrogen to give 116
mg (0.92 mmol, 92%) of 1,4,5,6‐tetrahydro[1,2,5]oxadiazolo
[3,4‐b]pyrazine, 7, as colorless crystals. The melting point is
153–155°C (lit [2] 153–155°C).
5‐Methyl‐1,4,5,6‐tetrahydro[1,2,5]oxadiazolo[3,4‐b]pyrazine, 12.
5‐Methyl[1,2,5]oxadiazolo[3,4‐b]pyrazine (68 mg, 0.5 mmol) is placed in
a 25 mL round‐bottom flask equipped with a magnetic stirring bar.
Anhydrous THF (5 mL) is added. Sodium borohydride (38 mg, 1.0
mmol) is added as a solid. A dark solution is obtained. The mixture is
stirred for 1 h without apparent reaction. Approximately 0.5 mL of
methanol is added, and the reaction becomes quite vigorous. It is stirred
4
6 4 3
58.0440; found 158.0431 amu.
1,2,5]Oxadiazolo[3,4-b]pyrazine, 2 (method 1). 5,6-Dihydroxy-
,5,6,7-tetrahydro[1,2,5]oxadiazolo[3,4-b]pyrazine (0.79 g, 5 mmol)
[
4
is placed in a sublimation apparatus, which is then heated at 160°C
for 2 h at 0.5 mm. A yellow crystalline material deposits on the cold
finger. The apparatus is cooled, dried, and kept under vacuum. It is
transferred to a dry box and opened. The light yellow crystals are
collected and stored under nitrogen. The yield is 0.06 g (0.1 mmol,
1
0%). DSC shows that the compound melts at 89°C and undergoes a
very exothermic decomposition starting at 240°C with a maximum at
66°C.
1,2,5]Oxadiazole [3,4‐b]pyrazine, 2 (method 2). 5,6‐Dihydroxy‐
,5,6,7‐tetrahydro[1,2,5]oxadiazolo[3,4‐b]pyrazine (0.79 g, 5 mmol)
2
[
4
is dissolved in 10 mL of acetone, and the resulting solution is added
to a slurry of 8 g of silica gel and 30–40 mL of acetone in a 100 mL
round‐bottom flask. This mixture is stirred for 1 h; then, most of the
acetone is removed at reduced pressure. A tall condenser is attached,
and the mixture is stirred at room temperature under high vacuum
until frothing ceases. The mixture is slowly heated to 160°C under
high vacuum and held for 2 h. Yellow crystals deposit near the top
of the flask. The flask is allowed to cool, and the crystals apparently
are reabsorbed onto the silica gel. The silica gel is extracted with two
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
A Re‐Examination of the Reaction of 3,4‐Diamino[1,2,5]oxadiazole with Glyoxal
925
for an additional 1 h. Two milliliters of water is added, and the solution is
stirred for 1 h. The solution is stripped to give a solid. The crude product is
taken up in 3 mL of acetonitrile, and the solution is syringe filtered to give
a clear solution. The solution is evaporated under a stream of nitrogen to
give 65 mg (0.46 mmol, 92%) of 5‐methyl‐1,4,5,6‐tetrahydro[1,2,5]
Acknowledgments. This work was funded by grants N00014‐081006
(USM), N00014‐11‐AF‐0‐0002 (NRL), and N0001411MP20002
(ARL) from the Office of Naval Research (Dr. Clifford Bedford). The
3,4‐diamino[1,2,5]oxadiazole used was kindly supplied by Dr. Stephen
Palopoli and Robert Day of Alliant Tech Systems‐Elkton, MD. All
calculations were performed at the ARL DoD Supercomputing
Resource Center of the Department of Defense High Performance
Computing Modernization Program.
oxadiazolo[3,4‐b]pyrazine as colorless crystals, melting point 97–99°C.
1
H NMR(CD CN): δ = 1.90 (d, J = 6.3 Hz, 3H), 2.98 (d × d, J = 11.7
3
and 8.1 Hz, 1H), 3.33 (d × m, J = 11.7 Hz, 1H), 3.56 (m, 1H), 5.45 (bs,
1
3
2
H) ppm. C NMR(CD
ppm. FT‐IR(KBr) = 3274 (vs), 2972 (m), 2930 (m), 2871 (m), 1646
sh), 1598 (vs), 1343 (m), 1284 (w), 1170 (m), 1071 (m), 996 (m), 813
3
CN): δ = 18.38, 46.76, 47.07, 148.41, 148.93
(
(
1
‐1
m) cm . HRMS (EI); C
40.0698 amu.
,4,4a,5,6,7,8,8a‐Octahydro[1,2,5]oxadiazolo[3,4‐b]pyrazino
2,3‐e]pyrazine, 13. [1,2,5]Oxadiazolo[3,4‐b]pyrazine (61 mg, 0.5
4
H
6
N
4
O
3
; [M]+: calcd. 140.0698; found
REFERENCES AND NOTES
[
[
[
[
[
1] Sato, N.; Adachi, J. J Org Chem 1978, 43, 341.
1
2] Willer, R. L.; Moore, D.W. J Org Chem 1985, 50, 5123.
3] Komin, A. P.; Carmack, M. J Heterocycl Chem 1976, 13, 13.
4] Sheremetev, A. B.; Yudin, I. L. Russ Chem Rev 2003, 72, 87.
5] Bunte, S. W.; Rice, B. M.; Chabalowski, C. F. J Phys Chem A
[
mmol) is dissolved in 0.5 mL of CD CN in a small test tube
3
equipped with a small magnetic stirring bar. The solution is
stirred, and ethylene diamine (30 mg, 0.05 mmol) is added via a
microliter syringe. The solution gets very warm, and a white
1
997, 49, 9430.
6] Rice, B. M.; Cartland, H. E.; Chabalowski, C. F. Chem Phys
Lett 1993, 4–5, 283.
[7] Pai, S. V.; Chabalowski, C. F.; Rice, B. M. J. Phys Chem A
997, 18, 3400.
[8] Vail, S. L.; Moran, C. M.; Barker, R. H., J Org Chem 1965, 30,
[
precipitate forms almost immediately. The CD CN is evaporated
3
under a stream of nitrogen to give the product. The yield of 13 is
1
1
1
7
9
2
1 mg (0.5mmol, 100%). H NMR(DMSO‐d
6
): δ = 2.53 (m,1H),
13
.82 (m,1H), 2.93 (bs, 1H), 4.12 (s, 1H), 7.01 (bs, 1H) ppm.
): δ = 41.85, 63.18, 148.07 ppm. FT‐IR(KBr) =
377 (vs), 3316 (vs), 3001 (m), 2982 (m), 2934 (m), 2886 (m),
640 (sh), 1598 (vs), 720 (sh), 1463 (m), 1428 (m), 1404 (m),
331 (s), 1290 (m), 1222 (m), 1214 (m), 1140 (m), 1029 (s), 988
C
195.
NMR(DMSO‐d
6
[
9] Sharma, G. D.; Sangodkar, S. G.; Roy, M. S. Syn Met 1995,
5, 201.
10] Sharma, G. D.; Sangodkar, S. G.; Roy, M. S. Syn Met 1996,
80, 249.
[11] Roy, M. S.; Saxena, D.; Sharma, G. D.; Manmeeta, M. J.
Mater Sci: Mater Electron 2001, 12, 45.
12] Willer, R. L.; Moore, D. W.; Lowe‐Ma, C. K.; Vanderah, D. J.
J Org Chem 1985, 50, 2368.
3
1
1
[
−1
(
m), 945 (m), 824 (m), 767 (m), 740 (sh) cm . HRMS (EI);
C H N O; [M] : calcd. 182.0916; found 182.0910 amu.
+
6
10 6
[
Single‐crystal X‐ray diffraction analysis of [1,2,5]oxadiazolo
3,4‐b]pyrazine, 2. C O, FW = 122.10, orthorhombic, Aba2,
a = 6.395(8) Å, b = 6.179(8) Å, c = 12.669(16) Å, α = 90°, β = 90°,
[
4 2 4
H N
[13] Willer, R. L. J Mex Chem Soc 2009, 53, 107.
[14] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
3
−3
γ = 90°, V = 500.6(11) Å , Z = 4, dcalc = 1.620 mg m , μ = 0.126
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; P. Hratchian, H.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma,
K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.01; Gaussian, Inc.:
Wallingford, CT, 2009.
−1
mm , F(0 0 0) = 248, R = 0.0570 for 451 observed [I > 2σ(I)]
1
reflections and 0.0597 for all 1606 reflections, Goodness‐of‐fit =
1
.158, 42 parameters.
A yellow crystal of dimensions 0.18 × 0.15 × 0.14 mm was
3
mounted on a MiteGen MicroMesh using a small amount of
Cargille Immersion Oil. Data were collected on a Bruker three‐
circle platform diffractometer equipped with a SMART APEX
II CCD detector. The crystals were irradiated using graphite
monochromated MoK radiation (λ = 0.71073). An Oxford Cobra
α
low temperature device was used to keep the crystals at a constant
1
00(2) K during data collection.
Data collection was performed, and the unit cell was initially
refined using “APEX2” (v2010.3‐0; ref. 16). Data reduction was
performed using “SAINT” (v7.60A]; ref. 17) and “XPREP”
[15] Visalok, I. V.; Ostrovskoya, A. V. Khimiya, I. Tekhnol Ele-
mentoorgan Soedin 1978, 78, 48.
(
v2008/2; ref. 18). Corrections were applied for Lorentz, polariza-
[16] Bruker. APEX2 v2010.3‐0; Bruker AXS Inc.: Madison, WI,
tion, and absorption effects using “SADABS” (v2008/1; ref. 19).
The structure was solved and refined with the aid of the programs
in the “SHELXTL‐plus” [v2008/4] system of programs [20]. The
2010.
[17]
009.
[18] Bruker. XPREP v2008/2; Bruker AXS Inc.: Madison, WI,
008.
19] Bruker. SADABS v2008/1; Bruker AXS Inc.: Madison, WI,
008.
20] Bruker. SHELXTL v2008/4; Bruker AXS Inc.: Madison, WI,
2008.
Bruker. SAINT v7.68A; Bruker AXS Inc.: Madison, WI,
2
2
2
2
full‐matrix least‐squares refinement on F included atomic coor-
dinates and anisotropic thermal parameters for all non‐H atoms.
The H atoms were included using a riding model. The molecule
lies on a special position, with only half the molecule being crys-
tallographically unique.
[
[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet