4-Methyl-1,2,5-oxadiazole-3-carbonitrile in the synthesis of 1,2,5-oxadiazolyl-1,2,4-oxadiazoles

Article abstract of DOI:10.1007/s11172-008-0349-4

4-Methyl-1,2,5-oxadiazole-3-carbonitrile reacts with hydroxylamine to form 4-methyl-1,2,5-oxadiazole-3-carboxamidoxime, which turned out to be the useful starting compound in the synthesis of 3-(1,2,5-oxadiazol-3-yl)-1,2,4- oxadiazoles.

Full text of DOI:10.1007/s11172-008-0349-4

Russian Chemical Bulletin, International Edition, Vol. 57, No. 11, pp. 2440—2442, November, 2008
2440
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile in the synthesis
of 1,2,5ꢀoxadiazolylꢀ1,2,4ꢀoxadiazoles
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. Еꢀmail: orakitin@ioc.ac.ru
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile reacts with hydroxylamine to form 4ꢀmethylꢀ
1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamidoxime, which turned out to be the useful starting compound in
the synthesis of 3ꢀ(1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,4ꢀoxadiazoles.
Key words: 1,2,5ꢀoxadiazoles, 1,2,4ꢀoxadiazoles, carboxylic anhydrides, cyclization.
Scheme 1
Compounds of the 1,2,5ꢀoxadiazole (furazan) series
are of constant interest for researchers as biologically
active substances.1 In recent years furazans containing
various heterocyclic substituents are attracting attention
as modulators of tyrosine kinase activity,2 antagonists of
NKꢀ3 receptors,3 compounds preventing heart arrhythꢀ
mia,4 etc. Compounds containing the substituted amiꢀ
doxime fragment seem to be especially promising as moduꢀ
lators of 2,3ꢀdioxygenase indolamine.5
Cyanosubstituted furazans and among them 4ꢀmethylꢀ
1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile (1) containing the chemiꢀ
cally inert methyl group could serve as important starting
compounds for the synthesis of the substances listed above.
However, although some spectral characteristics and
chemical transformations of compound 1 are described,6
data on the methods for the synthesis of this nitrile are
lacking. In the present work we describe the synthesis of
this compound and the transformation of its nitrile group
into the 1,2,4ꢀoxadiazole cycle.
We have chosen available 4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ
3ꢀcarboxamide 2 (see Ref. 7) as the starting compound for
the synthesis of nitrile 1. The transformations of furazanꢀ
carboxamides, in which trifluoroacetic anhydride was used
as a dehydrating agent, were described earlier.8 The yields
in these transformations reach 60—80%. We found that the
application of cheaper phosphorus pentaoxide provided
cyanofurazan 1 in 75% yield, which is not lower than the
yields obtained when trifluoroacetic anhydride is used in the
dehydration of other furazancarboxamides (Scheme 1).
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile (1) is a
labile, colorless, and highly volatile liquid. Its structure
was proved by the data of elemental analysis, mass specꢀ
trometry, and 1H and 13С NMR spectroscopy.
Scheme 2
It is known that aromatic and heterocyclic amidoximes
are the convenient starting compounds for the synthesis
of 1,2,4ꢀoxadiazoles.9 The synthesis of oxadiazolylfurazans
by the reaction of the corresponding amidoximes with
acetic10 and trichloroacetic11 anhydrides was described.
We showed that amidoxime 3 reacts on melting with cyꢀ
clic succinic, glutaric, and phthalic anhydrides to form
acids of the oxadiazole series 4а—с in moderate yields
(Scheme 3).
Melting of amidoxime 3 with chloroacetic anhydride
turned out to be inappropriate for the synthesis of chloroꢀ
methylꢀsubstituted compound 4d. Oxadiazole 4d began
to decompose intensely on heating of the reaction mixture
to 100 °C, and we failed to isolate 4d in significant amounts
from the reaction medium. Therefore, to obtain this comꢀ
pound, we used the twoꢀstep synthesis with the isolation
of intermediate Оꢀacyloxime 5. In the first step, the reacꢀ
tion of amidoxime 3 with chloroacetic anhydride (chloroꢀ
The reaction of nitrile 1 with hydroxylamine hydroꢀ
chloride affords the corresponding amidoxime 3 in 80%
yield (Scheme 2).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2390—2392, November, 2008.
1066ꢀ5285/08/5711ꢀ2440 © 2008 Springer Science+Business Media, Inc.

1,2,5ꢀOxadiazolylꢀ1,2,4ꢀoxadiazoles
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2441
the receiver was cooled with hard CO2. Nitrile 1 was obtained as
Scheme 3
20
20
a colorless liquid in a yield of 0.45 g (75%), nD 1.4342, d4
1.149; b.p. 158 °C. Found (%): C, 44.10; H, 2.80; N, 38.52.
C4H3N3O. Calculated (%): C, 44.04; H, 2.77; N, 38.62.
1H NMR (CDCl3), δ: 2.50 (s, 3 H, CH3). 13C NMR (CDCl3), δ:
8.07 (CH3); 107.5, 133.8, 152.5 (3 quaternary C atoms). MS,
m/z (Irel (%)): 109 [M]+ (64), 97 (16), 79 (100), 68 (57), 57 (95),
44 (54). IR, ν/cm–1: 3000 (C—H); 2250 (CN); 1430 (C=N).
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamidoxime (3). Sodium
carbonate (0.21 g, 2 mmol) was added with stirring to a solution
of nitrile 1 (0.33 g, 3 mmol) and hydroxylamine hydrochloride
(0.21 g, 3 mmol) in a mixture of water (10 mL) and isopropyl
alcohol (3 mL). The reaction mixture was kept at room temꢀ
perature for 1 h, and the precipitate was filtered off, washed with
water, dried in air, and recrystallized from methanol. The yield
was 0.34 g (80%), colorless crystals with m.p. 170—171 °C.
Found (%): C, 33.86; H, 4.30; N, 39.68. C4H6N4O2. Calculated
(%): C, 33.80; H, 4.26; N, 39.43. 1H NMR (DMSOꢀd6), δ: 2.52
(s, 3 H, CH3); 6.15 (s, 2 H, NH2); 10.50 (s, 1 H, OH). MS, m/z
(Irel (%)): 142 [M]+ (100), 125 (50), 110 (35), 86 (85), 69 (45),
55 (100). IR, ν/cm–1: 3400—3200 (C—H); 1630 (C=N).
Reactions of amidoxime 3 with acid anhydrides (general
procedure). A thoroughly triturated mixture of amidoxime 3
(2.84 g, 20 mmol) and an acid anhydride (20 mmol) was heated
in an oily bath to 130 °С and kept at this temperature for 40 min.
The reaction mixture was cooled to room temperature, and the
product was recrystallized from an appropriate solvent.
i, Reagent
Product
4a
4b
4c
R = (CH2)2CO2H (4a), (CH2)3CO2H (4b), C6H4CO2Hꢀo (4c)
Yield (%): 55 (4a), 60 (4b), 40 (4c)
acetic chloranhydride can be used instead of chloroacetic
anhydride, the yield of the target Oꢀacyl derivative deꢀ
creases noticeably) affords Oꢀacyloxime 5, which can be
isolated (60% yield) and then used in dehydration in toluꢀ
ene with the Dean—Stark receiver to form oxadiazole 4d.
However, it is not necessary to isolate acyloxime 5 from
the reaction mixture, but the both steps can be carried out
as one procedure with a slight decrease (to 48%) in the
yield of the target product (Scheme 4).
3ꢀ[3ꢀ(4ꢀMethylꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ5ꢀ
yl]propionic acid (4a). The yield was 2.46 g (55%), colorless
crystals, m.p. 105 °С (from benzene). Found (%): C, 42.91; H, 3.65,
N, 25.03. C8H8N4O4. Calculated (%): C, 42.86; H, 3.60, N, 24.99.
1H NMR (DMSOꢀd6), δ: 2.63 (s, 3 H, СН3); 2.87 (t, 2 H, СН2,
J = 6.7 Hz); 3.29 (t, 2 H, СН2, J = 6.7 Hz). MS, m/z (Irel (%)):
Experimental
224 [M]+ (5), 179 (100), 109 (67), 83 (61), 78 (79). IR, ν/cm–1
:
1Н NMR spectra (in CDCl3) were obtained on Bruker WMꢀ250
and Bruker AMꢀ300 instruments with working frequencies of
250 and 300 MHz, respectively. Chemical shifts in the NMR
spectra are given in the δ scale relative to SiMe4. Melting points
were determined on a Kofler heating stage and were not
corrected. Mass spectra (EI) were measured on a Finnigan MAT
INCOS 50 instrument with an ionization energy of 70 eV.
IR spectra were recorded for KBr pellets on a Specord Mꢀ80
instrument.
3450 (OH); 2900—2600 (CH); 1720 (C=O); 1600 (C=N).
4ꢀ[3ꢀ(4ꢀMethylꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ5ꢀ
yl]butyric acid (4b). The yield was 2.86 g (60%), colorless crystals,
m.p. 95 °C (from a benzene—hexane (1 : 1) mixture). Found
(%): C, 45.60; H, 4.01; N, 23.77. C9H10N4O4. Calculated (%):
1
C, 45.38; H, 4.23; N, 23.52. H NMR (DMSOꢀd6), δ: 2.02 (q,
2 H, СН2, J = 7.3 Hz); 2.40 (t, 2 H, СН2, J = 7.3 Hz); 2.63 (s,
3 H, СН3); 3.13 (t, 2 H, СН2, J = 7.3 Hz); 12.20 (s, H, ОН).
MS, m/z (Irel (%)): 238 [M]+ (2), 220 (71), 192 (18), 179 (91),
166 (15), 122 (23), 84 (50), 45(100). IR, ν/cm–1: 3100 (OH);
2900 (CH); 1700 (C=O); 1580 (C=N).
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamide (2) was synthesized
by a described procedure.7
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarbonitrile (1). A finely trituꢀ
rated mixture of amide 2 (0.76 g, 6 mmol) and P2O5 (3 g, 20 mmol)
was placed in a Claisen flask with an air condenser. The contents
of the flask was heated in an oily bath to 150 °C at 20 Torr, and
2ꢀ[3ꢀ(4ꢀMethylꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ
5ꢀyl]benzoic acid (4c). The yield was 2.18 g (40%), colorless
crystals, m.p. 100 °C (from benzene). Found (%): C, 53.15; H,
2.72; N, 20.70. C12H8N4O4. Calculated (%): C, 52.94; H, 2.96;
Scheme 4
i. ~20 °C, 24 h; ii. Δ, toluene.

2442
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Godovikova et al.
N, 20.58. 1H NMR (DMSOꢀd6), δ: 2.70 (s, 3 H, СН3); 7.82 (m,
2 H, Ar); 7.95 (m, 1 H, Ar); 8.05 (m, 1 H, Ar); 13.50 (s, H, ОН).
MS, m/z (Irel (%)): 272 [M]+ (4), 255 (12), 228 (13), 147 (7),
104 (48), 76 (67), 50 (100). IR, ν/cm–1: 3200 (OH); 2900 (CH);
1700 (C=O); 1560 (C=N).
2. W. B. Trotter, K. K. Nanda, S. Wolkenberg, B. M. Nolt,
P. Manley, N. R. Kett, M. T. Bilodeau, WO Pat. 2007050348
(2007); Chem. Abstr., 2007, 146, 481931.
3. A. V. Anikin, V. R. Gantla, V. E. Gregor, L. Jiang, Y. Liu,
D. P. C. Mcgee, C. C. Mikel, J. C. Pickens, T. R. Webb,
Y. Zheng, T. Zhu, A. Kadushkin, S. Zozulya, A. Chucholowski,
D. E. Mcgrath, S. Sviridov, WO Pat. 2007056155 (2007);
Chem. Abstr., 2007, 146, 521800.
4. O. Dirat, J. M. Elliott, A. P. Owens, D. E. Shaw, F. Sternfeld,
B. J. Williams, WO Pat. 2007003965 (2007); Chem. Abstr.,
2007, 146, 142372.
5. (а) A. P. Combs, A. Takvorian, W. Zhu, R. B. Sparks,
WO Pat. 2007075598 (2007); (b) A. P. Combs, E. W. Yue,
WO Pat. 200612215 (2006); Chem. Abstr., 2006, 145, 489247.
6. (а) T. Honma, Y. Tada, Heterocycles, 1977, 6, 1985;
(b) Y. Terui, M. Yamakawa, T. Honma, Y. Tada, K. Tori,
Heterocycles, 1982, 19, 221.
OꢀChloroacetylꢀ4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxꢀ
amidoxime (5). Chloroacetic anhydride (6.84 g, 0.04 mol) was
added to a solution of amidoxime 3 (5.68 g, 0.04 mol) in toluene
(50 mL). The reaction mixture was left for 16 h at room
temperature. The precipitate was filtered off, washed with water,
and dried in air. The yield was 2.46 g (55%), colorless crystals,
m.p. 100 °C (from toluene). Found (%): C, 33.01; H, 3.50, Cl,
16.28; N, 25.90. C6H7ClN4O3. Calculated (%): C, 32.96; H,
3.22; Cl, 16.22; N, 25.63. 1H NMR (DMSOꢀd6), δ: 2.56 (s, 3 H,
СН3); 4.62 (s, 2 H, СН2); 6.84 (s, 2 H, NН2). IR, ν/cm–1: 3440
(NH2); 2960 (CH); 1700 (C=O); 1660 (C=N); 800 (C—Cl).
5ꢀChloromethylꢀ3ꢀ(4ꢀmethylꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,4ꢀ
oxadiazole (4d). The reaction mixture obtained as described in
the previous experiment after addition of chloroacetic anhydride
(6.84 g, 0.04 mol) to a solution of amidoxime 3 (5.68 g, 0.04
mol) in toluene (50 mL) was left for 16 h. The contents of the
flask was refluxed with the Dean—Stark receiver until water
stopped to form (3 h). The organic layer was washed with a
saturated solution of soda and water and dried with MgSO4. The
solvent was distilled off in vacuo, and the residue was reꢀ
crystallized from CCl4. The yield of compound 4d was 3.84 g
(48%), colorless crystals, m.p. 35 °C (from CCl4). Found (%):
C, 36.01; H, 2.71; Cl, 17.59; N, 27.88. C6H5ClN4O2. Calculated
(%): C, 35.92; H, 2.51; Cl, 17.67; N, 27.93. 1H NMR
(DMSOꢀd6), δ: 2.65 (s, 3 H, СН3); 5.30 (s, 2 H, СН2). MS,
m/z (Irel (%)): 200 [M]+ (15), 170 (20), 159 (59), 125 (84), 93
(62), 83 (100), 76 (82). IR, ν/cm–1: 3050, 2950 (CH); 1550
(C=N); 800 (C—Cl).
7. A. Gasco, G. Rua, E. Menziani, V. Mortarini, A. Fundaro,
Farmaco Ed. Sci., 1971, 26, 241.
8. (а) A. Di Stilo, S. Visentin, C. Cena, A. M. Gasco,
G. Ermondi, A. Gasco, J. Med. Chem., 1998, 41, 5393;
(b) C. Cena, S. Visentin, A. Di Stilo, D. Boschi, R. Fruttero,
A. Gasco, Pharm. Res., 2001, 18, 157; (c) C. Cena, M. L.
Lolli, L. Lazzarato, E. Guaita, G. Morini, G. Coruzzi, S. P.
McElroy, I. L. Megson, R. Fruttero, A. Gasco, J. Med.
Chem., 2003, 46, 747.
9. J. C. Jochims, in Comprehensive Heterocyclic Chemistry II,
1996, 4, 179.
10. M. D. Coburn, J. Heterocycl. Chem., 1968, 5, 83.
11. R. Beaudegnies, S. Wendeborn, Heterocycles, 2003, 60,
2417.
References
Received April 16, 2008;
in revised form May 26, 2008
1. R. M. Paton, in Comprehensive Heterocyclic Chemistry II,
1996, 4, 229.