A New Synthetic Approach to Pyrazolo[3,4-c]-1,2,5-oxadiazoles

Article abstract of DOI:10.1055/s-2000-6231

4-Aryl-substituted-6-methyl-4H-pyrazolo[3,4-c]-1,2,5-oxadiazoles 15-21 were easily obtained through the oxidation reaction mediated by lead(IV) acetate of 5-methyl-4-nitroso-2-phenyl-2H-pyrazol-3-ylamines 8-14 in 88-97 percent yields.

Full text of DOI:10.1055/s-2000-6231

72
SHORT PAPER
A New Synthetic Approach to Pyrazolo[3,4-c]-1,2,5-oxadiazoles
Pier Giovanni Baraldi,* Maria J. Pineda de las Infantas,1 Stefano Manfredini, Romeo Romagnoli
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, I-44100, Ferrara, Italy
Fax:+39(532)291296; E-mail: pgb@dns.unife.it
Received 28 May 1999; revised 16 August 1999
dride. We envisaged that the pyrazolo[3,4-c]-1,2,5 oxadi-
azole nucleus could be generated through a single step and
with a minimal work-up by oxidation, mediated by
lead(IV) acetate, of 5-methyl-4-nitroso-2-phenyl-substi-
tuted-2H-pyrazol-3-ylamine, 8-14. The latter compounds
are obtainable in large quantities by published proce-
dures,10 through nitrosation with ethyl nitrite of the corre-
sponding 5-methyl-2-phenyl-substituted-2H-pyrazol-3-
ylamine 1-7. Moreover, compounds 8-14 are easily acces-
sible and versatile synthetic precursors which have
proven useful in the preparation of 1-phenyl-substitut-
ed-3-methyl-1H-pyrazolo[3,4-b]pyrazine-5,6-dicarboxy-
lic acid diethyl esters.11
Abstract: 4-aryl-substituted-6-methyl-4H-pyrazolo[3,4-c]-1,2,5-
oxadiazoles 15-21 were easily obtained through the oxidation reac-
tion mediated by lead(IV) acetate of 5-methyl-4-nitroso-2-phenyl-
2H-pyrazol-3-ylamines 8-14 in 88-97% yields.
Key words: lead(IV) acetate, 4-nitroso-5-aminopyrazoles, intramo-
lecular cyclization, fluorescent dyes, purine receptor antagonists
1,2,5-Oxadiazoles (furazanes) and their derivatives are a
class of interesting heterocycles, which have been the sub-
ject of intensive investigations since their discovery in the
late nineteenth century.2 The main reasons for these stud-
ies reside in the interest for their particular structure and
reactivity.3 More recently, their particular susceptibility to
give rise to fluorescent compounds has gained further in-
terest in view of their applications as reagents for biolog-
ical assays, and fluorescent probes in studies of ligand-
receptor interactions by fluorescence microscopy.4
H3C
H3C
NO
N
EtONO
EtOH
R = H, 8
NH2
N
N
NH2
N
o-nitro, 9
m-nitro, 10
p-nitro, 11
m-chloro, 12
3,4-dichloro, 13
2,5-dichloro, 14
(67-78%)
R
Our continuous interest in the reactivity of substituted
pyrazole derivatives and the above illustrated importance
of 1,2,5-oxadiazoles, prompted us to develop a simple and
efficient entry to pyrazolo[3,4-c]-1,2,5-oxadiazoles. For
the synthesis of this latter class of compounds, we consid-
ered taking advantage of the use of lead(IV) acetate
(LTA), which is a versatile and efficient oxidizing agent
that has been widely used in organic synthesis, and its use
has been published in several interesting reviews.5 The
oxidation of aromatic nitroso amines with LTA has been
described in the literature,6 but in most cases relatively
poor yields of the corresponding 1,2,5-oxadiazoles were
obtained. As an example, the treatment of 6-amino-1,3-
dimethyl-5-nitrosouracil with LTA is reported to give
only low yields of the corresponding furazan.7
R
R = H, 1
o-nitro, 2
Pb(OAc)4
CH3CO2H
m-nitro, 3
p-nitro, 4
m-chloro, 5
3,4-dichloro, 6
2,5-dichloro, 7
(88-97%)
H3C
N
N
N
O
R = H, 15
N
o-nitro, 16
m-nitro, 17
p-nitro, 18
m-chloro, 19
3,4-dichloro, 20
2,5-dichloro, 21
R
Scheme 1
In this paper, we wish to report a general, one pot-synthe-
sis of a novel series of 4-aryl-substituted-6-methylpyrazo-
lo[3,4-c]-1,2,5-oxadiazoles using this commercially
available reagent. It must be outlined that, to the best of
our knowledge, only two syntheses of pyrazolo[3,4-c]-
1,2,5-oxadiazoles, starting with the pyrazoline ring and
with varying degrees of success and convenience, have
been reported. Namely, the Mohr’s methodology8 which
involves the preparation of 6-methyl-4-phenyl-4H-pyra-
zolo[3,4-c]-1,2,5-oxadiazole by oxidation of 5-methyl-4-
nitroso-2-phenyl-2H-pyrazol-3-ylamine with an alkaline
aqueous solution of potassium hypochlorite. Whereas,
Bertelson9 et al. reported the synthesis of 4,6-diphenyl-
4H-pyrazolo [3,4-c]-1,2,5-oxadiazole from 1,3-diphenyl-
4,5-dioximino-2-pyrazoline by heating in acetic anhy-
As one may expect, the lead(IV) acetate mediated oxida-
tion, was not inhibited by the presence of an electron-
withdrawing group (e.g. nitro or halogens) at position-1
on the aryl group of the pyrazole moiety. As a general pro-
cedure, the nitroso amines 8-14 were dissolved in glacial
acetic acid and to the resulting red solution an equimolar
quantity of lead(IV) acetate trihydrate was added. The
mixture became intensely green colored and after two
hours at room temperature was diluted with water to pre-
cipitate the reaction products 15-21, which were collected
by filtration and crystallized from ethanol. Our results on
the series of nitroso-amino pyrazoles 8-14 are shown in
the Table, the yields refer to purified products 15-21. The
Synthesis 2000, No. 1, 72–74 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A New Synthetic Approach to Pyrazolo[3,4-c]-1,2,5-oxadiazoles
73
Table 4-Aryl-substituted-6-methyl-4H-pyrazolo[3,4-c]-1,2,5-oxadiazoles 15-21 Prepared
Compound
R
Yielda
(%)
Mp
(°C)
1H NMR (CDCl3)
d
IR (KBr)
cm-1
158
16
H
78
92-95
2.66 (s, 3H), 7.23 (d, 1H, J = 7.80 Hz), 7.48 (t,
2H, J = 8.60 Hz), 7.77 (d, 2H, J = 8.22 Hz).
1606, 1529, 1383, 1350,
1288, 1020, 777, 745.
o-nitro
83
65-70
2.64 (s, 3H), 7.52 (t, 1H, J = 7.68 Hz), 7.76 (dd,
1H, J = 7.80, 1.22 Hz), 7.83 (t, 1H, J = 8.02 Hz),
7.93 (dd, 1H, J = 8.20, 1.22 Hz).
1598, 1548, 1507, 1457,
1281, 1123, 843, 751.
17
18
19
20
21
m-nitro
80
85
75
90
82
190-194
120-125
100-103
160-165
160-162
2.71 (s, 3H), 7.78 (t, 1H, J = 8.02 Hz), 7.96 (d,
1H, J = 7.88 Hz), 8.23 (d, 1H, J = 7.86 Hz), 8.31
(s, 1H).
1645, 1531, 1474, 1353,
1289, 1082, 986, 717, 679.
p-nitro
2.68 (s, 3H), 7.85 (d, 2H, J = 8.04 Hz), 8.33 (d,
2H, J = 7.28 Hz).
1647, 1594, 1519, 1470,
1343, 1259, 1093, 849, 780,
687.
m-chloro
3,4-dichloro
2,5-dichloro
2.67 (s, 3H), 7.21 (dd, 1H, J = 8.22, 2.02 Hz),
7.41 (t, 1H, J = 8.20 Hz), 7.65 (dd, 1H, J = 8.04,
2.02 Hz), 7.81 (d, 1H, J = 2.20 Hz).
1616, 1599, 1497, 1385,
1055, 777, 740.
2.68 (s, 3H), 7.32 (dd, 1H, J = 8.82, 2.20 Hz),
7.48 (d, 1H, J = 8.62 Hz), 7.58 (d, 1H, J = 2.42
Hz).
1616, 1599, 1546, 1493,
1405, 1294, 1120, 818, 787.
2.67 (s, 3H), 7.34 (d, 1H, J = 7.82 Hz), 7.46 (d,
1H, J = 7.80 H), 7.56 (s, 1H).
1611, 1544, 1478, 1386,
1071, 865, 811, 635.
a Yield of isolated products after crystallization.
structures of compounds 15-21 were attributed on the ba- In conclusion, we have developed an efficient and versa-
sis of their spectroscopic data.
tile method for the preparation of a new series of pyrazo-
lo[3,4-c]-1,2,5-oxadiazoles which takes advantage of
easily accessible precursors and commercial reagents.
The extension of this procedure to heterocyclic ring sys-
tems other than pyrazoles, is currently being evaluated
and, moreover, compounds 15-21 are currently being in-
vestigated in our laboratories, as potential fluorescent
dyes and antagonists of the purine P2Z receptor.12
As a possible mechanism for the conversion of 8-14 to 15-
21, we may advance the hypothesis that LTA reacts with
the oxygen of the nitroso group at position-4 of the pyra-
zole ring to yield the general adduct 22. This in turn un-
dergoes intramolecular cyclisation with a concomitant
release of lead(II) acetate and formation of the expected
products 15-21.
Reaction courses and product mixtures were routinely monitored by
TLC on silica gel (pre-coated F254 Merck plates) and visualized with
aq KMnO4. 1H NMR spectra were obtained in CDCl3 solutions with
a Bruker AC 200 spectrometer. Chemical shifts (d) are given in ppm
downfield from TMS. All products reported showed 1H NMR spec-
tra in agreement with the assigned structures. Mps were determined
on a Buchi-Tottoli apparatus and are uncorrected. Elemental analy-
ses were effected at the microanalytical laboratory of Dipartimento
di Chimica, University of Ferrara. Lead tetraacetate trihydrate
(A.C.S. reagent) was purchased from Aldrich.
H3C
N
O
H3C
N
O
OAc
Pb
OAc
AcO Pb
- AcOH
OAc
OAc
OAc
OAc
N
N
NH
NH2
N
N
R
R
22
8-14
- AcOH
-Pb (OAc)2
5-Methyl-2-phenyl-substituted-4-nitroso-2H-pyrazol-3-
ylamines (8-14); General Procedure
N
O
H3C
N
N
A stream of ethyl nitrite was bubbled through a solution of 1-7 (5
mmol) dissolved in EtOH (20 mL) for 10 min. After this time, the
solution was cooled and 10% HCl (0.5 mL) was added and the bub-
bling of ethyl nitrite was continued (15 min.). The red crystals were
collected and recrystallized from dioxane (15 mL), to give 8-14 as
pure products.
N
R
15-21
Scheme 2
5-Methyl-2-(2-nitro-phenyl)-4-nitroso-2H-pyrazol-3-ylamine
(9)
5-Methyl-2-(2-nitro-phenyl)-2H-pyrazol-3-ylamine 213 (2.18 g., 10
mmol) dissolved in EtOH (20 mL) was used. After the workup,
Synthesis 2000, No. 1, 72–74 ISSN 0039-7881 © Thieme Stuttgart · New York

74
P. G. Baraldi et al.
SHORT PAPER
compound 9 was obtained as a red solid. Yield: 1.8 g (73%); mp:
102 °C.
IR (KBr): n = 3360, 1647, 1531, 1474, 1352, 1290, 1080, 718 cm-1.
1H NMR (CDCl3): d = 2.78 (s, 3H), 7.68 (t, 1H, J = 7.8 Hz), 7.76 (t,
1H, J = 8 Hz), 7.92 (d, 1H, J = 8.2 Hz), 8.37 (d, 1H, J = 8.2 Hz),
8.50 (br s, 2H).
b) Bradshaw, C. G.; Ceszkowski, K.; Turcatti, G.; Beresford,
I. J. M.; Chollet, A. J. Med. Chem. 1994, 37, 1991.
c) Lampe, D.; Potter, B. V. L. J. Chem. Soc., Chem. Comm.
1990, 1500.
(5) a) Mihailovic, M. L.; Cekovic, Z. In Encyclopedia of Reagents
for Organic Synthesis, Vol. 5; Paquette, L. A., Ed.; Wiley:
Chichester, 1995; p. 2949.
b) Butler, R. N. In Synthetic Reagents, Vol. 3; Pizey J. S., Ed.;
Wiley: New York, 1977, p. 277.
c) Butler, R. N.; Scott, F. L.; O'Mahony, T. A. F. Chem. Rev.
1973, 73, 93.
d) For a recent publication related to the oxidation by lead
tetraacetate see: Paredes, M. D.; Alonso, R. Tetrahedron Lett..
1999, 40, 3973.
5-Methyl-2-(3-nitro-phenyl)-4-nitroso-2H-pyrazol-3-ylamine
(10)
5-Methyl-2-(3-nitro-phenyl)-2H-pyrazol-3-ylamine 313 (2.18 g., 10
mmol) dissolved in EtOH (20 mL) was used. After the workup,
compound 10 was obtained as a red solid. Yield: 1.7 g (69%), mp:
135 °C.
(6) Taylor, E. C.; Beardsley, G. P.; Maki, Y. J. Org. Chem. 1971,
36, 3211.
(7) Taylor, E. C.; Maki, Y.; McKillop, A. J. Org. Chem. 1972, 37,
1601.
IR (KBr): n = 3358, 1642, 1531, 1476, 1350, 1238, 1070, 988, 739
cm-1.
1H NMR (CDCl3): d = 2.77 (s, 3H), 7.72 (t, 1H, J = 8 Hz), 7.92 (d,
1H, J = 8 Hz), 8.22 (d, 1H, J = 8.4 Hz), 8.38 (s, 1H), 8.50 (br s, 2H).
(8) Mohr, E. J. Prakt. Chem. 1909, 79, 45.
(9) Bertelson, R. C.; Glanz, K. D.; McQuain, D. B. J. Heterocycl.
Chem. 1969, 6, 317.
Pyrazolo[3,4-c]-1,2,5-oxadiazoles (15-21); General Procedure
The appropriate nitroso-amine pyrazole 8-14 (10 mmol) was dis-
solved in glacial HOAc (10 mL) at r.t.. Then, an equimolar amount
of Pb(OAc)4•3H2O (3.89 g., 10 mmol) was added in small portions
over 10 min and the disappearance of the starting material was ob-
served by TLC over 2 h. The solution was slowly diluted with H2O
(5 mL) and the resulting mixture, containing a yellow solid, was
cooled on ice-bath and the solid filtered off. The solid, washed with
H2O (20 mL), vacuum dried, and recrystallized from EtOH (15
mL), furnished 15-21 with excellent yields (88-97%).
(10) a) For the synthesis of the compound 11 see: Guarneri, M.;
Ferroni, R.; Fiorini, F. Gazz. Chim. Ital. 1968, 98, 569.
b) For the synthesis of the compound 12 see: Giori, P.;
Mazzotta, D.; Vertuani, G.; Guarneri, M.; Pancaldi, D.;
Brunelli, A. Il Farmaco Ed. Sci. 1981, 36, 1019.
c) For the synthesis of compounds 13 and 14 see: Ferroni, R.;
Milani, L.; Simoni, D.; Orlandini, P.; Poli. T.; Guarneri, M.;
Taddeo, U. Il Farmaco Ed. Sci. 1988, 43, 891.
(11) Baraldi, P. G.; Simoni, D.; Periotto, V.; Manfredini, S.;
Guarneri, M. Synthesis 1984, 148.
References
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Article Identifier:
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Synthesis 2000, No. 1, 72–74 ISSN 0039-7881 © Thieme Stuttgart · New York