Synthesis of 5-(1,2,5-oxadiazol-3-yl)-1H-etrazoles from 3-cyano-1,2,5-oxadiazoles

Article abstract of DOI:10.1007/s11172-010-0023-5

A number of 5-(1,2,5-oxadiazol-3-yl)-1H-tetrazoles were obtained in high yields by reactions of 3-cyano-1,2,5-oxadiazoles with sodium azide or by nitrosation of furazan-based amidrazones, which are easily prepared from the same starting reagents.

Full text of DOI:10.1007/s11172-010-0023-5

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 406—409, February, 2009
406
Synthesis of 5ꢀ(1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1Hꢀtetrazoles
from 3ꢀcyanoꢀ1,2,5ꢀoxadiazoles*
T. I. Godovikova, S. K. Vorontsova, L. D. Konyushkin, S. I. Firgang, and O. A. Rakitin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: orakitin@ioc.ac.ru
A number of 5ꢀ(1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1Hꢀtetrazoles were obtained in high yields by reacꢀ
tions of 3ꢀcyanoꢀ1,2,5ꢀoxadiazoles with sodium azide or by nitrosation of furazanꢀbased
amidrazones, which are easily prepared from the same starting reagents.
Key words: synthesis, 1,2,5ꢀoxadiazoles, 1Hꢀtetrazoles, amidrazones, cyclization, sodium
azide.
Earlier,1 we have reported on the synthesis of 1,2,5ꢀoxaꢀ
Scheme 1
diazole (furazan) derivatives containing a 1,2,4ꢀoxadiazole
substituent from appropriate amide oximes and carboxyꢀ
lic acid anhydrides. In turn, amide oximes of the furazan
series can be easily obtained from 3ꢀcyanofurazans. It is
known2 that aromatic and heterocyclic nitriles are conveꢀ
nient starting materials for the synthesis of other heteroꢀ
cyclic compounds (e.g., 1Hꢀtetrazoles). However, although
furazans containing various heterocyclic substituents are
of constant chemical interest as biologically active comꢀ
pounds with different activities,3 only one representative
of this class (viz., 3ꢀaminoꢀ4ꢀ(1Hꢀtetrazolꢀ5ꢀyl)ꢀ1,2,5ꢀ
oxadiazole) has been documented.4
In our continued investigations of the reactivity of
4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile (1), we studied
the possibility of its transformation into oxadiazolylꢀ
tetrazole 2 in two ways: (1) a reaction of nitrile 1 with
sodium azide and (2) a transformation of nitrile 1 into
amidrazone 3 followed by its nitrosation with HNO2
(Scheme 1). We found that a reaction of nitrile 1 with
NaN3 in DMF gives tetrazole 2 in 80% yield. Alternaꢀ
tively, treatment of nitrile 1 with hydrazine hydrate in
isopropyl alcohol leads to the corresponding amidrazone
3 (78% yield), which reacts with NaNO2 and HCl to give
tetrazole 2.
The singleꢀstep synthesis of tetrazole 2 immediately
from nitrile 1 and NaN3 seems to be more attractive for
both the higher yield of the final product (80% versus
55%) and its easy isolation (see Experimental).
For further investigations of the synthesis of tetrazolylꢀ
furazans, we used 1,2,5ꢀoxadiazoleꢀ3,4ꢀdicarbonitrile (4)
as the most attractive starting reagent. Having two reacꢀ
tive cyano groups, this compound seems to be a valuable
starting material for the synthesis of 1,2,5ꢀoxadiazoles
containing various heterocyclic substituents in positions
3 and 4. This would substantially extend the range of
3,4ꢀbis(heteryl)ꢀ1,2,5ꢀoxadiazoles for their biological
tests. The only documented5 method for the preparation
of dinitrile 4 involves reduction of not easily accessible
furoxandicarbonitrile with triethyl phosphite (74% yield);
however, neither spectroscopic nor physicochemical charꢀ
acteristics of dinitrile 4 have been cited. Later, its physical
characteristics have been examined in two more studies.6
In an attempt to make compound 4 more accessible and
increase its yield, we developed a method for its synthesis
from 1,2,5ꢀoxadiazoleꢀ3,4ꢀdicarboxamide 5 with P2O5 as
a dehydrating agent (see Ref. 5). Under the conditions
described for 4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamide,1
the yield of dinitrile 4 approximated to 100% (Scheme 2).
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 400—403, February, 2009.
1066ꢀ5285/09/5802ꢀ0406 © 2009 Springer Science+Business Media, Inc.

5ꢀ(1,2,5ꢀOxadiazolꢀ3ꢀyl)ꢀ1Hꢀtetrazoles
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
407
Scheme 2
Scheme 5
1,2,5ꢀOxadiazoleꢀ3,4ꢀdicarbonitrile (4) is a colorless
and highly volatile compound with a low melting point;
its structure was proved by elemental analysis, mass specꢀ
trometry, and 1H and 13C NMR and IR spectroscopy. We
studied reactions of dinitrile 4 with hydrazine hydrate and
hydroxylamine for selective involvement of only one
cyano group. Both reactions gave monocyanofurazans 6
and 7 in high yields (Scheme 3).
Scheme 3
Scheme 6
Nitriles 4, 6, and 7 were used in reactions with NaN3
in DMF. It turned out that mononitriles 6 and 7 successꢀ
fully yield tetrazoles 8 and 9, respectively, with retention
of the reactive amidrazone and amide oxime groups
(Scheme 4).
Scheme 4
R = C(NH)NHNH2 (6, 8), C(NH2)NOH (7, 9)
R = CN (4, 6, 10), C(NH2)NOH (7, 9, 12)

408
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Godovikova et al.
m/z (Irel (%)): 141 [M+] (100), 84 (74), 57 (91). IR, ν/cm–1
3400—3200 (C—H, N—H), 1630 (C=N).
:
The reaction of dinitrile 4 with NaN3 selectively gives
monoꢀ (10) and bistetrazoles (11) in good yields for the
ratios 4 : NaN3 = 1 : 1 and 1 : 2, respectively (Scheme 5).
Bistetrazole 11 may be a potential explosive and should
be handled with due caution.
Alternatively, tetrazolylfurazans 9—11 can be obtained
from nitriles 4 and 7 in two steps through intermediate
amidrazones 6, 12, and 13. As in previous transformaꢀ
tions, their total yields are somewhat lower than those
achieved with the use of sodium azide (Scheme 6).
4ꢀCyanoꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbohydrazonamide (6). The
yield was 2.30 g (84%), yellow crystals, m.p. 142 °C (decomp.,
from methanol). Found (%): C, 31.73; H, 2.57; N, 55.39.
C4H4N6O. Calculated (%): C, 31.58; H, 2.65; N, 55.25. 1H NMR
(DMSOꢀd6), δ: 6.00 (s, 2 H, NH2); 6.40 (s, 2 H, NH2). MS,
m/z (Irel (%)): 152 [M+] (58), 84 (100), 67 (31). IR, ν/cm–1
:
3460, 3370, 3170 (NH2), 1650 (C=N).
4ꢀ[Amino(hydrazono)methyl]ꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboꢀ
hydroximamide (12). The yield was 2.40 g (72%), colorless
crystals, m.p. 185 °C (from methanol). Found (%): C, 25.97;
H, 3.83; N, 52.45. C4H7N7O2. Calculated (%): C, 25.81; H,
Experimental
1
3.79; N, 52.67. H NMR (DMSOꢀd6), δ: 5.62 (s, 2 H, NH2);
5.92 (s, 2 H, NH2); 6.35 (s, 2 H, NH2); 10.15 (s, 1 H, OH). MS,
m/z (Irel (%)): 185 [M+] (69), 153 (100), 138 (72), 112 (33), 101
(41). IR, ν/cm–1: 3420, 3340, 3220 (OH, NH2), 1650 (C=N).
1,2,5ꢀOxadiazoleꢀ3,4ꢀdicarbohydrazonamide (13). The yield
was 2.88 g (87%), yellow crystals, m.p. 160 °C (from methanol).
Found (%): C, 26.15; H, 4.41; N, 60.97. C4H8N8O. Calcuꢀ
lated (%): C, 26.09; H, 4.38; N, 60.84. 1H NMR (DMSOꢀd6), δ:
5.85 (s, 2 H, NH2); 6.35 (s, 2 H, NH2). MS, m/z (Irel (%)): 184
[M+] (63), 1543 (25), 138 (100), 68 (50). IR, ν/cm–1: 3450,
3350, 3140 (NH2), 1650 (C=N).
Synthesis of furazanyltetrazoles from cyanofurazans (general
procedure). Sodium azide (4.03 g, 62 mmol) (or 8.06 g, 124 mmol
for tetrazole 11) was added to a solution of 3ꢀcyanofurazan 1, 4,
6, or 7 (50 mmol) in DMF (10 mL). The reaction mixture was
heated at 80—90 °C for 30 min, cooled to room temperature,
poured into water (70 mL), and acidified with 2% HCl to
pH 3—4. The product was extracted with ether (2×100 mL), the
solvent was removed, and the residue was recrystallized.
Synthesis of furazanyltetrazoles from amidrazones (general
procedure). A solution of NaNO2 (0.5 g, 7.2 mmol) (or 1.0 g,
14.4 mmol for tetrazole 11) in water (4 mL) was added dropꢀ
wise at 0 °C to a stirred solution of amidrazone 3, 6, 12, or 13
(7 mmol) in 2% HCl (20 mL). After 2 h, the precipitate that
formed was filtered off, washed with water, and dried in air. An
additional crop was obtained by extracting organic materials
from the filtrate with ether (2×15 mL). The solvent was removed
in vacuo. The residue was combined with the precipitate and
recrystallized.
1H NMR spectra were recorded on a Bruker DRXꢀ500 inꢀ
strument (500 MHz) in CDCl3. Chemical shifts are given on the
δ scale with reference to Me4Si. Melting points were determined
on a Kofler instrument and are given uncorrected. Mass spectra
were measured on a Finnigan MAT INCOS 50 instrument (EI,
70 eV). IR spectra were recorded on a Specord M80 instrument
in KBr pellets.
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile 1 (see Ref. 1)
and 1,2,5ꢀoxadiazoleꢀ3,4ꢀdicarboxamide 5 were prepared as
described earlier;5 their properties agree with the literature data.
1,2,5ꢀOxadiazoleꢀ3,4ꢀdicarbonitrile (4). A Claisen flask fitted
with an airꢀcooled condenser was charged with a finely divided
mixture of amide 5 (1.00 g, 6.4 mmol) and P2O5 (3 g). The
mixture was heated at 180 °C in vacuo (20 Torr) on an oil bath
and a receiving flask was cooled with dry ice. The yield of dinitrile
4 was 0.75 g (97%), colorless crystals, m.p. 42 °C (cf. Ref. 5:
m.p. 37 °C; Ref. 6: m.p. 42 °C), b.p. 60 °C (20 Torr). Found (%):
C, 39.85; N, 47.03. C4N4O. Calculated (%): C, 40.00; N, 46.66.
13C NMR (DMSOꢀd6), δ: 106.4 (CN), 135.9 (Cquat). MS, m/z
(Irel (%)): 120 [M+] (14), 97 (5), 90 (15), 68 (100), 57 (38). IR,
ν/cm–1: 2220 (CN), 1570 (C=N).
4ꢀCyanoꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbohydroximamide (7).
Sodium carbonate (2.5 g, 24 mmol) was added at 0—5 °C to a
stirred solution of dinitrile 4 (5.0 g, 47 mmol) and NH2OH•HCl
(3.3 g, 47 mmol) in a mixture of water (40 mL) and isopropyl
alcohol (20 mL). The reaction mixture was kept at 0—5 °C for
15 min, warmed to room temperature, and stirred for an addiꢀ
tional 1 h. The precipitate that formed was filtered off, washed
with water, dried in air, and recrystallized from methanol. The
yield was 5.4 g (85%), colorless crystals, m.p. 180 °C. Found (%):
C, 31.50; H, 2.03; N, 45.94. C4H3N5O2. Calculated (%):
5ꢀ(4ꢀMethylꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1Hꢀtetrazole (2). The
yield was 80% from cyanofurazan and 70% from amidrazone,
colorless crystals, m.p. 50 °C (from EtOH—H2O). Found (%):
C, 31.80; H, 2.73; N, 55.45. C4H4N6O. Calculated (%):
1
1
C, 31.58; H, 2.65; N, 55.25. H NMR (DMSOꢀd6), δ: 2.68 (s,
C, 31.38; H, 1.98; N, 45.75. H NMR (DMSOꢀd6), δ: 2.52 (s,
3 H, CH3); 6.90 (br.s, 1 H, NH). MS, m/z (Irel (%)): 152 [M+]
(8), 124 (84), 96 (74), 83 (100). IR, ν/cm–1: 3560 (N—H), 1630
(C=N).
3 H, CH3); 6.15 (s, 2 H, NH2); 10.50 (s, 1 H, OH). MS, m/z
(Irel (%)): 153 [M+] (100), 149 (10), 123 (60), 101 (22), 85 (53).
IR, ν/cm–1: 3400—3200 (C—H), 1630 (C=N).
4ꢀ(1HꢀTetrazolꢀ5ꢀyl)ꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbohydrazonamide
(8). The yield was 74% from cyanofurazan and 62% from
amidrazone, colorless crystals, m.p. 148 °C (from MeOH—H2O).
Found (%): C, 24.93; H, 2.71; N, 64.85. C4H5N9O. Calculated
(%): C, 24.62; H, 2.58; N, 64.60. 1H NMR (DMSOꢀd6), δ: 6.80
(br.s, 4 H, NH, NH2). MS, m/z (Irel (%)): 195 [M+] (43), 153
(93), 124 (30), 83 (39), 67 (100). IR, ν/cm–1: 3340, 3310, 3260,
3140, 2890, 2810 (OH, NH2), 1660 (C=N).
Synthesis of furazanylamidrazones (general procedure).
Hydrazine hydrate (1 mL) (or 2 mL for amidrazone 13) was
added to a stirred solution of 3ꢀcyanofurazan derivative 1, 4, or
7 (18 mmol) in isopropyl alcohol (15 mL). The precipitate that
formed was filtered off, washed with isopropyl alcohol (2 mL),
dried in air, and recrystallized.
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbohydrazonamide (3). The
yield was 1.82 g (78%), yellow crystals, m.p. 135 °C (from
acetonitrile). Found (%): C, 34.15; H, 5.09; N, 49.87. C4H7N5O.
Calculated (%): C, 34.04; H, 5.00; N, 49.63. 1H NMR (DMSOꢀd6),
δ: 2.38 (s, 3 H, CH3); 5.45, 5.52 (both s, 4 H each, 2 NH2). MS,
4ꢀ(1HꢀTetrazolꢀ5ꢀyl)ꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbohydroximꢀ
amide (9). The yield was 76% from cyanofurazan and 70%
from amidrazone, colorless crystals, m.p. 150 °C (from H2O).

5ꢀ(1,2,5ꢀOxadiazolꢀ3ꢀyl)ꢀ1Hꢀtetrazoles
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
409
Found (%): C, 24.61; H, 2.09; N, 57.28. C4H4N8O2. Calcuꢀ
lated (%): C, 24.49; H, 2.06; N, 57.13. 1H NMR (DMSOꢀd6), δ:
7.60 (br.s, 3 H, NH, NH2); 10.55 (s, 1 H, OH). MS, m/z
(Irel (%)): 196 [M+] (45), 171 (10), 138 (25), 67 (100). IR,
ν/cm–1: 3480, 3370, 3240, 3140 (NH2), 1650 (C=N).
2. R. N. Butler, Adv. Heterocycl. Chem., 1977, 21, 323; R. N.
Butler, in Comprehensive Heterocyclic Chemistry II, 1996, 4,
621; V. A. Ostrovskii, G. I. Koldobskii, R. E. Trifonov, in
Comprehensive Heterocyclic Chemistry III, 2008, 6, 257.
3. R. M. Paton, in Comprehensive Heterocyclic Chemistry II, 1996,
4, 229; G. Nikonov, S. Bobrov, in Comprehensive Heterocyclic
Chemistry III, 2008, 5, 315.
4. V. G. Andrianov, A. V. Eremeev, Khim. Geterotsikl. Soedin.,
1994, 693 [Chem. Heterocycl. Compd. (Engl. Transl.), 1994].
5. C. Grundmann, Chem. Ber., 1964, 97, 575.
4ꢀ(1HꢀTetrazolꢀ5ꢀyl)ꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile (10).
The yield was 74% from cyanofurazan and 62% from amidrazone,
colorless crystals, m.p. 45 °C (from MeOH—H2O). Found (%):
C, 29.58; H, 0.69; N, 60.23. C4HN7O. Calculated (%): C, 29.45;
1
H, 0.62; N, 60.12. H NMR (DMSOꢀd6), δ: 3.90 (br.s, 1 H,
NH). 13C NMR (DMSOꢀd6), δ: 107.6 (CN), 132.8, 146.1, 148.7
(3 C quat.). MS, m/z (Irel (%)): 163 [M+] (1), 135 (80), 107
(56), 82 (100), 76 (88), 68 (84). IR, ν/cm–1: 3580 (N—H), 2270
(CN), 1610 (C=N).
6. (a) E. C. Lupton, Jr., G. Hess, J. Chem. Eng. Data, 1975, 20,
135; (b) V. V. Zverev, I. Sh. Saifullin, G. P. Sharnin, Izv.
Akad. Nauk SSSR, Ser. Khim., 1978, 313 [Bull. Acad. Sci.
USSR, Div. Chem. Sci. (Engl. Transl.), 1978, 27].
3,4ꢀBis(1Hꢀtetrazolꢀ5ꢀyl)ꢀ1,2,5ꢀoxadiazole (11). The yield
was 82% from cyanofurazan and 78% from amidrazone, colorꢀ
less crystals, m.p. 202 °C (decomp. explosively at 273 °C) (from
H2O). Found (%): C, 21.53; H, 1.80; N, 62.71. C4H2N10O•H2O.
Calculated (%): C, 21.43; H, 1.80; N, 62.49. 13C NMR
(DMSOꢀd6), δ: 144.7, 147.5 (2 Cquat). IR, ν/cm–1: 3570, 3350,
2920 (NH), 1660, 1630 (C=N).
References
1. T. I. Godovikova, S. K. Vorontsova, L. D. Konyushkin, S. I.
Firgang, O. A. Rakitin, Izv. Akad. Nauk, Ser. Khim., 2008,
2389 [Russ. Chem. Bull., Int. Ed., 2008, 57, 11].
Received October 30, 2008;
in revised form January 29, 2009