Synthesis of 3-methyl-4-(5-R-1H-1,2,4-triazol-3-yl)-1,2,5-oxadiazoles

Article abstract of DOI:10.1007/s11172-010-0108-1

A number of 3-methyl-4-(5-R-1H-1,2,4-triazol-3-yl)-1,2,5-oxadiazoles were obtained in high yields by thermal dehydration of acylated 4-methyl-1,2,5- oxadiazole-3-carboxamide hydrazones.

Full text of DOI:10.1007/s11172-010-0108-1

Russian Chemical Bulletin, International Edition, Vol. 59, No. 2, pp. 483—485, February, 2010
483
Synthesis of 3ꢀmethylꢀ4ꢀ(5ꢀRꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazoles
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 3ꢀmethylꢀ4ꢀ(5ꢀRꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazoles were obtained in high
yields by thermal dehydration of acylated 4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamide hydrazones.
Key words: synthesis, 1,2,5ꢀoxadiazoles, 1,2,4ꢀtriazoles, amidrazones, dehydration, cyꢀ
clization.
1,2,5ꢀOxadiazole (furazan) derivatives are of permaꢀ
nent interest for synthetic chemists as biologically active
compounds.1 Recently, furazans containing various hetꢀ
erocyclic substituents have attracted attention as AKT kiꢀ
nase inhibitors,2 antagonists of neurokininꢀ3 receptors
(NKꢀ3),3 antiarrhythmic agents,4 etc. Earlier, we have
published data on the synthesis of 1,2,5ꢀoxadiazole (furaꢀ
zan) derivatives with 1,2,4ꢀoxadiazole5 and tetrazole subꢀ
stituents6 at the C(4) atom of the furazan ring. In our
continued investigations of the synthesis of hetarylfuraꢀ
zans, we tried to obtain 1,2,4ꢀtriazolylfurazans.
Several examples of such structures with an amino
group in position 3 of the furazan ring have been docuꢀ
mented. Common routes to compounds 1 involve thermal
dehydration of acylamidrazones 2 (see Ref. 7) obtained
from aliphatic acid hydrazides containing various funcꢀ
tional substituents and methyl 3ꢀaminofurazanꢀ4ꢀcarboxꢀ
imidate (3), which is prepared from 3ꢀaminoꢀ1,2,5ꢀoxaꢀ
diazoleꢀ4ꢀcarbonitrile (4) (Scheme 1).8
This very advantageous synthetic approach has, howꢀ
ever, a drawback: aliphatic acid hydrazides are often not
commercially available and should be prepared from apꢀ
propriate acid chlorides, which increases the number of
steps in this process.
We developed, with 4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀ
carbonitrile (5) as an example, an alternative approach to
the synthesis of triazolyloxadiazoles. Previously,6 we demꢀ
onstrated that treatment of nitrile 5 with hydrazine hyꢀ
drate in isopropyl alcohol affords the corresponding
amidrazone 6 in 78% yield. A roomꢀtemperature reaction
of amidrazone 6 with commercial aliphatic acid chlorides
and benzoyl chloride in chloroform in the presence of
pyridine gave acylamidrazones 7 in high yields (Scheme 2).
Scheme 2
Scheme 1
7
a
b
c
R
Me
CH2Cl
Ph
Yield (%)
68
81
60
According to 1H NMR data, acyl derivatives 7a—c are
mixtures of two isomers with identical sets of signals for
the protons, as shown for other acylamidrazones of the
furazan series.7
i. MeONa, MeOH; ii. H2NNC(O)CH2R; iii. Heating.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 473—475, February, 2010.
1066ꢀ5285/10/5902ꢀ0483 © 2010 Springer Science+Business Media, Inc.

484
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 2, February, 2010
Godovikova et al.
N, 32.18, Cl, 16.29. 1H NMR, δ: 2.55 and 2.56 (both s, 3 H,
CH3), 4.13 and 4.62 (both s, 2 H, CH2), 6.73 and 6.90 (both s,
2 H, NH2), 10.40 and 10.55 (both s, H, NH). MS, m/z (Irel (%)):
We attempted to dehydrate acylamidrazones 7 by reꢀ
fluxing their solutions in toluene using a Dean—Stark trap
for removal of the resulting water. However, the reaction
proceeded slowly: even upon 20ꢀh reflux, a great deal of
the starting compound remained intact. That is why, we
heated acylamidrazones at temperatures above their meltꢀ
ing points by 2—3 °C.7 In this case, the reaction was comꢀ
pleted in 5—7 min, giving triazoles 8 in good yields
(Scheme 3).
217 [M+] (30), 200 (5), 168 (100), 141 (20), 110 (20). IR, ν/cm–1
:
3040 and 2960 (NH, NH2), 1700 (C=O), 1240, 800.
N´ꢀBenzoylꢀ4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamide hydrꢀ
azone (7c). Yield 147 mg (60%), colorless crystals, m.p. 170 °C
(from ethanol). Found (%): C, 54.01; H, 4.63; N, 28.72.
C11H11N5O2. Calculated (%): C, 53.87; H, 4.52; N, 28.56.
1H NMR, δ: 2.55 and 2.56 (both s, 3 H, CH3), 7.33 and 7.53
(both s, 2 H, NH2); 7.47—7.77 (m, 3 H, Ph); 7.63—7.90 (m, 2 H,
Ph); 10.53 and 11.02 (both s, H, NH). MS, m/z (Irel (%)): 245
[M+] (50), 168 (90), 125 (50), 83 (80). IR, ν/cm–1: 3040 and
2935 (C—H and N—H), 1700 (C=O), 1560 (C=N).
Scheme 3
Synthesis of triazolylfurazans 8 (general procedure). Acylꢀ
amidrazone 7 (2 mmol) was heated on an oil bath for 5—7 min at
a temperature above its melting point by 2—3 °C. On coolꢀ
ing to room temperature, the residue was recrystallized from
acetonitrile.
3ꢀMethylꢀ4ꢀ(5ꢀmethylꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiꢀ
azole (8a). Yield 72%, colorless crystals, m.p. 260 °C (from acetoꢀ
nitrile). Found (%): C, 43.87; H, 4.39; N, 42.63. C6H7N5O.
1
Calculated (%): C, 43.63; H, 4.27; N, 42.41. H NMR, δ: 2.45
8
a
b
c
R
Me
CH2Cl
Ph
Yield (%)
(s, 3 H, CH3), 2.69 (s, 3 H, CH3), 14.30 (br.s, 1 H, NH). MS,
m/z (Irel (%)): 165 [M+] (41), 148 (29), 124 (19), 109 (100), 56
(19). IR, ν/cm–1: 3100 (N—H), 2960 (C—H), 1460 (C=N),
1180, 990, 750.
72
84
64
4ꢀ(5ꢀChloromethylꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl)ꢀ3ꢀmethylꢀ1,2,5ꢀ
oxadiazole (8b). Yield 84%, colorless crystals, m.p. 200 °C (from
acetonitrile). Found (%): C, 36.23; H, 3.07; N, 35.19, Cl, 17.95.
C6H6ClN5O. Calculated (%): C, 36.10; H, 3.03; N, 35.39,
Experimental
H NMR spectra were recorded on Bruker WMꢀ250 and
Bruker AMꢀ300 instruments (250 and 300 MHz, respectively) in
DMSOꢀd6. Chemical shifts are expressed in terms of the δ scale
and referenced to SiMe4. Melting points were determined on
a Kofler hot stage 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 (KBr
pellets).
1
1
Cl, 17.76. H NMR, δ: 2.62 (s, 3 H, CH3), 5.00 (s, 2 H, CH2),
15.30 (br.s, 1 H, NH). MS, m/z (Irel (%)): 199 [M+] (30), 182
(26), 143 (100), 123 (34), 69 (36), 55 (58). IR, ν/cm–1: 3110
(N—H), 2930 (C—H), 1420 (C=N), 1040, 890.
3ꢀMethylꢀ4ꢀ(5ꢀphenylꢀ1Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiꢀ
azole (8c). Yield 64%, colorless crystals, m.p. 240 °C (from aceꢀ
tonitrile). Found (%): C, 58.14; H, 4.07; N, 31.13. C11H9N5O.
1
4ꢀMethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamide hydrazone 6 was
prepared as described earlier.6 Commercial acetyl, chloroacetyl,
and benzoyl chlorides were employed.
Calculated (%): C, 58.14; H, 3.99; N, 30.82. H NMR, δ: 2.70
(s, 3 H, CH3), 7.55 (m, 3 H, Ph), 8.08 (d, 2 H, Ph, J = 8.1 Hz),
15.15 (br.s, 1 H, NH). MS, m/z (Irel (%)): 227 [M]+ (56),
186 (53), 170 (45), 118 (69), 105 (80), 77 (100). IR, ν/cm–1
:
Synthesis of furazanylamidrazones 7 (general procedure). Pyꢀ
ridine (79 mg, 1 mmol) was added to a solution of amidrazone 6
(140 mg, 1 mmol) in dry chloroform (20 mL). Then a solution of
an appropriate acid chloride (1 mmol) in chloroform (10 mL)
was added with vigorous stirring. The reaction mixture was stirred
at room temperature for 2 h and left for 16 h. The precipitate that
formed was filtered off, washed with water, and dried in air.
N´ꢀAcetylꢀ4ꢀmethylꢀ1,2,5ꢀoxadiazoleꢀ3ꢀcarboxamide hydraꢀ
zone (7a). Yield 124 mg (68%), colorless crystals, m.p. 150 °C
(from PriOH). Found (%): C, 39.68; H, 5.00; N, 38.39. C6H9N5O2.
3000 (N—H), 2920 (C—H), 1490 (C=N), 1430, 1180, 980,
900, 700.
References
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1
Calculated (%): C, 39.34; H, 4.95; N, 38.24. H NMR, δ: 2.27
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6.70 and 6.95 (both s, 2 H, NH2), 10.35 and 10.50 (both s,
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83 (40). IR, ν/cm–1: 3030 and 2900 (C—H and N—H), 1700
(C=O), 1630 (C=N).
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hydrazone (7b). Yield 176 mg (81%), colorless crystals, m.p.
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4ꢀ(1Hꢀ1,2,4ꢀTriazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazoles
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Received December 4, 2008;
in revised form September 23, 2009