Synthesis of 1,2,4-oxadiazole-, pyrrole- and 1,2,3-triazole-substituted (1,2,3-triazol-1-yl)furazans

Article abstract of DOI:10.1016/j.mencom.2008.05.017

The synthesis of tricyclic compounds with hitherto unknown combinations of heterocycles (1,2,3-triazol-1-yl)-1,2,5-oxadiazoles with 1,2,4-oxadiazol-3-yl, pyrrol-1-yl or 1,2,3-triazol-1-yl substituents at the furazan ring, was developed by interaction of c

Full text of DOI:10.1016/j.mencom.2008.05.017

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 161–163
Synthesis of 1,2,4-oxadiazole-, pyrrole- and
1,2,3-triazole-substituted (1,2,3-triazol-1-yl)furazans
Vladimir Yu. Rozhkov, Lyudmila V. Batog* and Marina I. Struchkova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: mnn@ioc.ac.ru
DOI: 10.1016/j.mencom.2008.05.017
The synthesis of tricyclic compounds with hitherto unknown combinations of heterocycles (1,2,3-triazol-1-yl)-1,2,5-oxadiazoles
with 1,2,4-oxadiazol-3-yl, pyrrol-1-yl or 1,2,3-triazol-1-yl substituents at the furazan ring, was developed by interaction of
corresponding substituted azidofurazans with 1,3-dicarbonyl compounds, and pyrrolyl derivatives were also synthesised by
condensation of amino(1,2,3-triazol-1-yl)furazans with 2,5-dimethoxytetrahydrofuran.
Previously,1–5 we have synthesised (1,2,3-triazol-1-yl)-1,2,5-oxa-
EtO2C
R
EtO2C
Ph
diazoles (triazolylfurazans) 1 with various substituents at both
rings by 1,3-dipolar cycloaddition of azidofurazans 2 to acety-
lenes,1 morpholinonitroethylene,2 1,3-dicarbonyl compounds3,4
and methylene-active nitriles.5 Azidofurazans with NH2, Me, OMe,
Ph and triazoloxadiazole substituents were used (Scheme 1).1–5
The synthesis of new triazolylfurazans based on reactions of
aminoazidofurazan 2a (R = NH2) with chloroacetoacetic ester
and studies on the chemical transformations4,6,7 of functional
groups in the resulting products expanded considerably the
range of these compounds. Studies on the biological activity of
triazolylfurazans revealed that some of the compounds have
a selective potentiating effect on the NO-dependent activation
of sGC (a soluble form of guanylate cyclase8) or can act as
selective inhibitors of glycogen-synthase kinase-3.6
Note that, of triazolylfurazans 1 (Scheme 1), only one com-
pound contains a heteroaromatic substituent at the furazan ring.
It was of interest to synthesise compounds of the triazolyl-
furazan series containing other aromatic heterocycles at the furazan
ring, e.g., 1,2,4-oxadiazole, pyrrole or 1,2,3-triazole, which occur
in various biologically active compounds. The compounds thus
obtained might be more promising as a result of acquiring a new
set of properties.
NH2
N3
N
N
N
N
i
N
N
N
N
N
N
O
O
9a R = Ph
9b R = CH2Cl
6a
O
O
R1
R2 ii
i
12a–c, iii
12a,b
EtO2C
Ph Me
COR2
EtO2C
CH2Cl
4''
5''
4'
5'
N
N
N
N
N3
N
N
N
N
N
3
4
N
N
N
N
O
O
3a R2 = Me
6b
3b R2 = OEt
12: a R1 = R2 = Me
b R1 = Me, R2 = OEt
c R1 = CH2Cl, R2 = OEt
Scheme 2 Reagents and conditions: i, NaNO2, H2SO4, 2–5 °C, H3PO4, 1 h,
NaN3, H2O; ii, 12a,b (1.2 equiv.), EtOH, EtOH–H2O (1:1), Et3N (2 equiv.),
20 °C, 1–8 h, H2O; iii, acetone–H2O (1:1), K2CO3 (0.6 equiv.), 20 °C.
R1
R2
containing a 1,2,3-triazole (6), 1,2,4-oxadiazole (7) or pyrrole
(8) ring as the second substituent to dipolarophiles, e.g. to
1,3-dicarbonyl compounds. With this in mind, we developed
methods to obtain the hitherto unknown (1,2,3-triazol-1-yl)-
(6a,b), (1,2,4-oxadiazol-3-yl)- (7) and (pyrrol-1-yl)- (8) azido-
furazans (Schemes 2–4).†
R
N3
N
R
N
N
N
N
N
N
O
O
2
1
Compounds 6a,b and 7 were synthesised under the condi-
tions used to obtain the known azidofurazans from amino-
furazans,9 namely, by diazotization of the appropriate amines
(9a,b and 10) with nitrosylsulfuric acid in a mixture of con-
centrated H2SO4 and H3PO4, followed by treatment of the
resulting diazonium ions with sodium azide (Schemes 2, 3).
To produce amine 10, amidoxime 11 was refluxed in AcOH.
Azidofurazan 8 was obtained by condensation of azidoamino-
furazan 2a with 2,5-dimethoxytetrahydrofuran (DMT) in refluxing
AcOH (Scheme 4). The condensation of primary amines with
DMT (Clauson–Kaas reaction10) that is successfully used to
N
N
R = NH2, Me, OMe, Ph,
N
O
N
N
Scheme 1
The purpose of this study was to synthesise new triazolyl-
furazan derivatives representing the following tricyclic struc-
tures: bis(1,2,3-triazol-1-yl)furazans 3, (1,2,4-oxadiazol-3-yl)- 4
and (pyrrol-1-yl)- 5 triazolylfurazans (Schemes 2–4). No com-
pounds with such a combination of heterocycles as in 3–5 have
been reported before.
By analogy with the methods we established previously for
the syntheses of triazolylfurazans,3,4 a possible way to synthesise
compounds 3–5 might involve cycloaddition of azidofurazans
†
The carbon atoms in compounds 3 (Scheme 2) and 4 (Scheme 3) are
numbered arbitrarily (see the signal assignments in the 13C NMR spectra
of these compounds).
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© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 161–163
The structures of the compounds synthesised were established
Me
Me
from the data of elemental analysis, IR, 1H and 13C NMR
spectroscopy, and mass spectrometry.‡ All target compounds
(3a,b, 4a,b and 5a,b) had molecular ions in mass spectra. The
attribution of carbon atom signals of furazan and triazole rings
in 13C NMR spectra was carried out based on previous data.1,3
The chemical shifts of the carbon atoms C(3) and C(4) of the
furazan ring in compounds 3a and 3b are at 145 ppm. The
chemical shifts of analogous carbon atoms in compounds 4a,b
and 5a,b are at 143 and 148 ppm, respectively. In the triazole
rings of compounds 3a,b, 4a,b and 5a,b the chemical shifts of
carbon atoms C(4'), C(4'') and C(5'), C(5'') occur at 136–142
and 141–143 ppm, respectively. The chemical shifts of carbon
atoms C(2'') and C(3'') of pyrrole ring in compounds 5a and 5b
are at 121 and 112 ppm, respectively, and those of carbon atoms
C(3'') and C(5'') of 1,2,4-oxadiazole ring in compounds 4a and
NH2
O
O
N
N
NH2
N3
NH2
HON
N
N
i
ii
N
N
N
N
N
N
O
O
O
11
10
7
COR2
4'
Me
Me
5''
5'
N
N
O
N
3''
N
3
12a,b, iii
N
4
N
N
O
4a R2 = Me
4b R2 = OEt
Scheme 3 Reagents and conditions: i, AcOH, 118 °C, 1 h, H2O; ii, NaNO2,
H2SO4, 2–5 °C, H3PO4, NaN3, H2O; iii, acetone–H2O (1:1, 2:1), K2CO3
(0.3–0.5 equiv.), 20 °C, 1–8 h, H2O.
‡
The 13C and 1H NMR spectra were measured in [2H6]DMSO in the pulse
mode on a Bruker AM-300 spectrometer (13C, 75.5 MHz; 1H, 300 MHz).
IR spectra were obtained on a Specord M-80 instrument in KBr pellets.
Chromatographic monitoring was carried out on Silufol UV-254 plates.
3a: yield 70%, mp 167–168 °C (EtOH–H2O, 1:2), Rf 0.55 (CHCl3–
AcOEt, 9:1). IR (KBr, nmax/cm–1): 2992, 1732 (CO), 1696 (CO), 1600,
1556, 1420, 1180, 980, 704. 1H NMR, d: 1.17 (t, 3H, Me, J 7.1 Hz), 2.43
(s, 3H, Me), 2.62 (s, 3H, Me), 4.26 (q, 2H, CH2, J 7.1 Hz), 7.36 (m, 5H,
Ph). 13C NMR, d: 9.3 (Me), 13.8 (CH2Me), 27.9 (COMe), 61.3 (CH2),
122.5 (Ph), 128.5 (Ph), 129.7 (Ph), 130.9 (Ph), 136.4 [C(4'')], 140.0 [C(4')],
142.8 [C(5')], 142.9 [C(5'')], 145.0 [C(3)], 145.3 [C(4)], 159.3 (CO), 192.5
(COMe). MS, m/z (%): 408 (M+, 8), 380 (M+ – N2, 2), 352 (M+ – 2N2, 2),
337 (M+ – N2 – COMe, 2), 43 (100). Found (%): C, 52.91; H, 4.04;
N, 27.61. Calc. for C18H16N8O4 (%): C, 52.94; H, 3.92; N, 27.45.
3b: yield 84%, mp 191–192 °C (EtOH–H2O, 1:2), Rf 0.61 (CHCl3–
AcOEt, 9:1). IR (KBr, nmax/cm–1): 2980, 1744 (CO), 1728 (CO), 1576,
1280, 1176, 980, 704. 1H NMR, d: 1.17 (t, 3H, Me, J 7.0 Hz), 1.34 (t, 3H,
Me, J 7.0 Hz), 2.45 (s, 3H, Me), 4.25 (q, 2H, CH2, J 7.0 Hz), 4.37 (q, 2H,
CH2, J 7.0 Hz), 7.38 (m, 5H, Ph). 13C NMR, d: 9.4 (Me), 13.7 (CH2Me),
14.0 (CH2Me), 61.2 (CH2), 61.3 (CH2), 122.6 (Ph), 128.4 (Ph), 129.7
(Ph), 130.9 (Ph), 136.4 [C(4')], 136.5 [C(4'')], 141.7 [C(5')], 142.9 [C(5'')],
145.1 [C(3)], 145.2 [C(4)], 159.3 (CO), 159.8 (CO). MS, m/z (%): 438
(M+, 10), 410 (M+ – N2, 2), 77 (45), 102 (100). Found (%): C, 51.69;
H, 4.18; N, 25.76. Calc. for C19H18N8O5 (%): C, 52.05; H, 4.11; N, 25.57.
4a: yield 72%, mp 135–136 °C (MeOH–H2O, 1:1), Rf 0.44 (CHCl3–
AcOEt, 9:1). IR (KBr, nmax/cm–1): 3020, 1688 (CO), 1584, 1564, 1552,
synthesise N-alkyl- and N-arylpyrroles was expanded for
3-amino-4-R-furazans.11 We have shown that this technique
is also suitable for synthesising azidopyrrolylfurazan 8 in
88% yield.
We have studied whether it is possible to synthesise com-
pounds 3–5 by the 1,3-dipolar cycloaddition of azidofurazans
6a,b, 7 and 8 to 1,3-dicarbonyl compounds 12a–c (Schemes 2–4).
The reactions were carried out in EtOH, EtOH–H2O or acetone–
H2O with a small excess of a dipolarophile 12 in the presence
of Et3N or K2CO3. We found that the interactions of azides 6a, 7
and 8 with acetylacetone 12a and acetoacetic ester 12b led to
target compounds 3a,b (Scheme 2), 4a,b and 5a,b in high yields
(Schemes 3, 4). Conversely, reactions of azide 6b with com-
pounds 12a–c gave amine 9b under the conditions studied
(Scheme 2). Examples are known12,13 where reactions of aromatic
azides, including azidofurazans,3 with 1,3-dicarbonyl compounds
gave products of formal reduction of azide groups into amino ones.
To synthesise pyrrole-containing compounds 5, we studied
the formation of a pyrrole ring at (1,2,3-triazol-1-yl)furazan by
condensation of aminotriazolylfurazans 9c,d with DMT, similarly
to the syntheses of (pyrrol-1-yl)furazans from aminofurazans.11
The study resulted in the high-yield production of target com-
pounds 5a,b (Scheme 4) that are identical to those obtained in
the reaction of azide 8 with compounds 12a,b (Scheme 4).
Both approaches were found to be acceptable for obtaining
compounds 5a,b.
1
1252, 1172, 952. H NMR, d: 2.64 (s, 3H, Me), 2.68 (s, 3H, Me), 2.72
(s, 3H, Me). 13C NMR, d: 9.1 [C(5')Me], 11.9 [C(5'')Me], 27.7 (COMe),
140.9 [C(5')], 142.0 [C(4')], 142.7 [C(3)], 148.2 [C(4)], 157.1 [C(3'')],
179.2 [C(5'')], 192.5 (COMe). MS, m/z (%): 275 (M+, 25), 247 (M+ – N2,
10), 205 (30), 190 (13), 172 (25), 43 (100). Found (%): C, 43.57; H, 3.38;
N, 35.44. Calc. for C10H9N7O3 (%): C, 43.64; H, 3.30; N, 35.62.
4b: yield 78%, mp 152–153 °C (EtOH–H2O, 1:1), Rf 0.53 (CHCl3–
AcOEt, 9:1). IR (KBr, nmax/cm–1): 3000, 1736 (CO), 1584, 1564, 1416,
1256, 1184, 884. 1H NMR, d: 1.37 (t, 3H, Me, J 7.0 Hz), 2.65 (s, 3H, Me),
2.72 (s, 3H, Me), 4.39 (q, 2H, CH2, J 7.0 Hz). 13C NMR, d: 9.3 (Me),
12.0 (Me), 14.0 (CH2Me), 61.0 (CH2), 136.2 [C(4')], 142.2 [C(3)], 142.6
[C(5')], 148.3 [C(4)], 157.2 [C(3'')], 160.1 (CO), 179.3 [C(5'')]. MS, m/z (%):
305 (M+, 2), 110 (10), 83 (10), 43 (100). Found (%): C, 43.21; H, 3.72;
N, 32.27. Calc. for C11H11N7O4 (%): C, 43.28; H, 3.83; N, 32.12.
5a: yield 74% (i), 55% (ii), mp 65–66 °C, Rf 0.71 (C6H6). IR (KBr,
N3
N
H2N
N3
i
+
N
N
N
N
MeO
Me
OMe
O
O
O
8
2a
DMT
12a,b, ii
COR2
n
max/cm–1): 3136, 1692 (CO), 1600, 1564, 1416, 1256, 1076, 752. 1H NMR,
COR2
N
d: 2.65 (s, 3H, Me), 2.67 (s, 3H, Me), 6.39 (br. s, 2H, 2CH), 7.05 (br. s, 2H,
2CH). 13C NMR, d: 9.3 (Me), 27.9 (MeCO), 112.8 (CH), 121.1 (CHNpyrr.),
141.3 [C(4')], 143.0 [C(5')], 143.5 [C(3)], 148.8 [C(4)], 192.8 [COMe].
MS, m/z (%): 258 (M+, 5), 230 (M+ – N2, 5), 43 (100). Found (%): C, 50.82;
H, 3.72; N, 32.40. Calc. for C11H10N6O2 (%): C, 51.16; H, 3.90; N, 32.54.
5b: yield 82% (i), 65% (ii), mp 74–75 °C, Rf 0.66 (C6H6). IR (KBr,
4'
Me
5'
N
H2N
N
N
4
N
N
N
DMT, i
3
N
N
N
N
O
O
n
max/cm–1): 3148, 2996, 1736 (CO), 1600, 1476, 1256, 1204, 752. 1H NMR,
9c R2 = Me
5a R2 = Me
9d R2 = OEt
5b R2 = OEt
d: 1.37 (t, 3H, Me, J 7.1 Hz), 2.64 (s, 3H, Me), 4.37 (q, 2H, CH2, J 7.1 Hz),
6.40 (br. s, 2H, 2CH), 7.03 (br. s, 2H, 2CH). 13C NMR, d: 9.3 (Me), 14.0
(CH2Me), 61.0 (CH2), 112.7 (CH), 121.0 (CHN), 136.5 [C(4')], 142.7 [C(3)],
143.5 [C(5')], 148.7 [C(4)], 160.1 (CO). Found (%): C, 49.62; H, 4.09;
N, 29.01. Calc. for C12H12N6O3 (%): C, 50.00; H, 4.16; N, 29.16.
Scheme 4 Reagents and conditions: i, DMT (1.2 equiv.), AcOH, 118 °C,
1 h, H2O; ii, 12a,b (1 equiv.), acetone–H2O (1:1, 2:1), K2CO3 (0.4 equiv.),
20 °C, 1–8 h, H2O.
– 162 –

Mendeleev Commun., 2008, 18, 161–163
3
4
5
6
7
8
L. V. Batog, V. Yu. Rozhkov and M. I. Struchkova, Mendeleev Commun.,
2002, 159.
4b, at 157 and 179 ppm, respectively, which are consistent with
published data.11,14
V. Yu. Rozhkov, L. V. Batog and M. I. Struchkova, Izv. Akad. Nauk,
Ser. Khim., 2005, 1866 (Russ. Chem. Bull., Int. Ed., 2005, 54, 1923).
V. Yu. Rozhkov, L. V. Batog, E. K. Shevtsova and M. I. Struchkova,
Mendeleev Commun., 2004, 76.
P. H. Olesen, A. R. Sorensen, B. Urso, P. Kurtzhals, A. N. Bowler,
U. Ehrbar and B. F. Hansen, J. Med. Chem., 2003, 46, 3333.
L. V. Batog, L. S. Konstantinova and V. Yu. Rozhkov, Izv. Akad. Nauk,
Ser. Khim., 2005, 1859 (Russ. Chem. Bull., Int. Ed., 2005, 54, 1915).
L. V. Batog, V. Yu. Rozhkov, Yu. V. Khropov, N. V. Pyatakova, O. G.
Busygina, I. S. Severina and N. N. Makhova, RF Patent 2158265, 2000
(Byul. Izobret., 2000, 30, 167) (in Russian).
Thus, we synthesised azidofurazans with 1,2,3-triazole,
1,2,4-oxadiazole and pyrrole rings as substituents, studied their
reactions with 1,3-dicarbonyl compounds (acetylacetone and
acetoacetic ester) and found methods to obtain tricyclic com-
pounds with hitherto unknown combinations of heterocycles.
In addition, a method for incorporating a pyrrole ring at a carbon
atom of the furazan ring in amino(1,2,3-triazol-1-yl)furazans by
condensation of the latter with DMT has been developed.
References
9
O. A. Rakitin, O. A. Zalesova, A. S. Kulikov, N. N. Makhova, T. I.
Godovikova and L. I. Khmel’nitskii, Izv. Akad. Nauk, Ser. Khim., 1993,
1949 (Russ. Chem. Bull., 1993, 42, 1865).
1 L. V. Batog, L. S. Konstantinova, V. Yu. Rozhkov, Yu. A. Strelenko,
O. V. Lebedev and L. I. Khmel’nitskii, Khim. Geterotsikl. Soedin., 2000,
100 [Chem. Heterocycl. Compd. (Engl. Transl.), 2000, 36, 91].
2 L. V. Batog, V. Yu. Rozhkov, Yu. A. Strelenko, O. V. Lebedev and L. I.
Khmel’nitskii, Khim. Geterotsikl. Soedin., 2000, 406 [Chem. Heterocycl.
Compd. (Engl. Transl.), 2000, 36, 343].
10 (a) N. Clauson-Kaas and Z. Tyle, Acta Chem. Scand., 1952, 6, 667;
(b) N. Elming and N. Clauson-Kaas, Acta Chem. Scand., 1952, 6, 867.
11 A. B. Sheremetev, S. M. Konkina, I. L. Yudin, D. E. Dmitriev, B. B.
Averkiev and M. Yu. Antipin, Izv. Akad. Nauk, Ser. Khim., 2003, 1337
(Russ. Chem. Bull., Int. Ed., 2003, 52, 1413).
12 B. Stanovnik, M. Tisler, S. Polanc and Ju. Žitnik, Synthesis, 1977, 491.
13 Yu. A. Azev, I. P. Loginova, O. L. Guzel’nikova, S. V. Shorshnev, V. L.
Rusinov and O. N. Chupakhin, Mendeleev Commun., 1994, 104.
14 J. C. Jochims and R. C. Storr, in Comprehensive Heterocyclic Chemistry II,
eds. A. K. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press,
Oxford, 1996, vol. 4, p. 179.
6a: yield 88%, mp 87–88 °C (EtOH–H2O, 1:1), Rf 0.27 (C6H6). IR (KBr,
n
max/cm–1): 2984, 2168 (N3), 2148 (N3), 1720 (CO), 1544, 1260, 1192,
1
1060, 984, 764, 696. H NMR, d: 1.15 (t, 3H, Me, J 6.9 Hz), 4.25 (q,
2H, CH2, J 6.9 Hz), 7.53 (s, 5H, Ph). 13C NMR, d: 13.8 (Me), 61.2 (CH2O),
123.6 (Cipso-Ph), 128.3 (Cm-Ph), 130.4 (Co-Ph), 130.9 (Cp-Ph), 136.8 [C(5')],
142.9 [C(4')], 143.8 (CN1tr), 150.3 (CN3), 159.4 (CO).
6b: yield 99%, oil. IR (KBr, nmax/cm–1): 2988, 2148 (N3), 1724 (CO),
1
1552, 1352, 1272, 1176, 1156, 992, 744. H NMR, d: 1.38 (t, 3H, Me,
J 7.1 Hz), 4.44 (q, 2H, CH2, J 7.1 Hz), 5.17 (s, 2H, CH2). 13C NMR, d: 14.9
(CH2Me), 32.4 (CH2Cl), 63.6 (CH2O), 139.1, 142.2, 145.2, 152.0, 161.5
(CO). MS, m/z (%): 298 (M+, 35), 253 (M+ – OEt, 25), 113 (50), 52 (100).
7: yield 81%, oil. IR (KBr, nmax/cm–1): 2160 (N3), 1588, 1528, 1456,
1264, 1200, 784.
8: yield 88%, mp 79–80 °C, Rf 0.85 (C6H6). IR (KBr, nmax/cm–1):
3144, 3124, 2148 (N3), 1596, 1556, 1532, 1336, 1068, 740. 1H NMR, d:
6.44 (s, 2H, 2CH), 7.38 (s, 2H, 2CH). 13C NMR, d: 112.7 (CH), 120.1
(CHN), 145.6 (CN3), 147.4 (CNpyrr.). Found (%): C, 41.04; H, 2.33;
N, 47.57. Calc. for C6H4N6O (%): C, 40.91; H, 2.27; N, 47.72.
Received: 16th November 2007; Com. 07/3042
– 163 –