Unexpected formation of bis-pyrazolyl derivatives by solid support coupled with microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(01)00604-4

Starting from 1,3-dimethyl-5-aminopyrazole 1 and p-substituted benzaldehydes 2 (R=H, CH₃, NO₂), four different compounds have been obtained: the Schiff bases 4, a bis-pyrazolyl Schiff base 6a (R=H), the expected bispyrazolo[3,4-b;4′,3′-e]pyridine 7b (R=CH₃) and the carbinol derived from the Schiff base 8c (R=NO₂). The products have been characterised by MS, NMR (¹H and ¹³C) and X-ray crystallography (in the case of 6a). A proposal for the relationships between the different compounds and a possible mechanism is presented.

Full text of DOI:10.1016/S0040-4020(01)00604-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 6147±6153
Unexpected formation of bis-pyrazolyl derivatives by solid
support coupled with microwave irradiation
a
Andressa Esteves-Souza, Aurea Echevarrõa, Ivo Vencato, Marõa Luisa Jimeno
a,p
Â
and Jose Elguero
b
c
Â
c
Â
a
 Ã
Departamento de Quõmica, Instituto de Ciencias Exatas, Universidade Federal Rural do Rio de Janeiro,
Â
23851-970 Seropedica, RJ, Brazil
b
 Â
Departamento de Quõmica, Universidade Federal de Santa Catarina, 88040-900 Florianopolis, SC, Brazil
c
 Â
Instituto de Quõmica Medica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain
Received 24 October 2000; accepted 29 May 2001
AbstractÐStarting from 1,3-dimethyl-5-aminopyrazole 1 and p-substituted benzaldehydes 2 (RˆH, CH3, NO2), four different compounds
have been obtained: the Schiff bases 4, a bis-pyrazolyl Schiff base 6a (RˆH), the expected bispyrazolo[3,4-b;40,30-e]pyridine 7b (RˆCH3)
and the carbinol derived from the Schiff base 8c (RˆNO2). The products have been characterised by MS, NMR (1H and 13C) and X-ray
crystallography (in the case of 6a). A proposal for the relationships between the different compounds and a possible mechanism is presented.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
the high yields and short reaction times are very attractive
for organic chemists.
Organic synthesis in dry media, eventually under micro-
wave (MW) irradiation is presently under extensive exam-
ination.1±4 The relatively low cost of modern domestic
microwave ovens makes them readily available to academic
and industrial chemists, and the use of such non-conven-
tional reaction conditions reveals several features such as:
a short reaction time compared to conventional heating,
reduction of the usual thermal degradation and better selec-
tivity.5±7 An attractive synthetic methodology is the possi-
bility of performing reactions in solvent-free conditions or
on solid inorganic supports. Indeed, in several cases, a solid-
state organic reaction occurs more ef®ciently and more
selectively than does its solution counterpart, since mole-
cules in a crystal are arranged tightly and regularly.8±12
Mineral oxides are very often poor conductors of heat but
behave as very ef®cient MW absorbents.11 This results in a
very rapid and homogeneous heating and, consequently,
reactions in solid supports under microwaves show strong
MW effects.12 Furthermore, solid-state reactions are very
convenient from a practical viewpoint since the reagents
and solid support are ef®ciently mixed in an appropriate
solvent which is then evaporated. After microwave irradia-
tion the products are simply extracted from the support by
washing and ®ltration. The absence of solvent coupled with
Pyrazoles are a class of heterocyclic compounds having
many derivatives with a wide range of interesting proper-
ties, such as drugs, pesticides, and new materials, amongst
others.13,14 Our interest in condensation reactions involving
pyrazole derivatives led us to apply MW assisted methodol-
ogy because several condensation reactions in solid support
and microwave conditions have been successfully reported
in the literature.15±17 Knowing that aminopyrazoles
condense with aromatic aldehydes to yield aldimines
(Schiff-bases),18,19 in the present work we describe the reac-
tivity of 1,3-dimethyl-5-aminopyrazole 1 towards three 4-
substituted benzaldehydes (a RˆH, b RˆCH3, c RˆNO2)
involving solid supports in dry conditions assisted by MW
irradiation. Two are the products expected from this reac-
tion. The most obvious are the Schiff-bases 4, but another
well documented reaction is the formation of bispyra-
zolo[3,4-b;40,30-e]pyridines 7 which implies an oxidation
step.20±29
2. Results and discussion
2.1. Synthesis
With the intention to prepare 1,3-dimethyl-5-(benzylidene-
amine)-pyrazoles 4, we applied initially a standard proce-
dure30 we had successfully used for Schiff bases derived
from piperonal.31 The method, described for benzylidene-
aniline, consists in mixing equimolar amounts of aniline and
Keywords: pyrazoles; imines; X-ray crystal structure; microwave irradia-
tion; solid support.
Corresponding author. Fax: 155-21-682-28-07;
e-mail: echevarr@ufrrj.br
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00604-4

6148
A. Esteves-Souza et al. / Tetrahedron 57 (2001) 6147±6153
Scheme 1.
benzaldehyde without solvent.30 However, when we applied
this procedure to 1 and 2a, we obtained the desired product
4a, but in very low yield (10%). Therefore, we decided, in
order to improve the yield and make the synthetic procedure
easier, to perform the reaction of benzaldehyde 2a and 1,3-
dimethyl-5-aminopyrazole 1 under different conditions.
quent evaporation, puri®ed. The reactions in the presence
of silica or sand as solid support provided the same yield
(85% of 6a), but the use of sand is preferable because it
makes possible a very easy isolation with a lower quantity of
solvent and a high purity of the product. In the same way, we
studied the reactivity of p-nitro and p-methylbenzaldehyde
(p-toluylaldehyde) (2b, 2c) that afforded compounds 7b and
8c instead of the Schiff bases 4b and 4c (Scheme 1). Consis-
tently which what happens with 2a, when reagents 1 and
2b,c were re¯uxed in ethanol during 5 h, the Schiff bases
4b,c were obtained in 30 and 10% yield, respectively.
Furthermore, we have checked that heating 6a in ethanol
during 10 h resulted in the tricyclic structure 7a in 67%
yield. Compound 7a has been obtained (mp 158±1598C,
yield 35%)18 by heating directly 1 and 2a in a 2:1 molar
ratio without solvent at 200±2408C.21,28
The ®rst method involved the reaction in solid state at room
temperature with silica gel 60 as catalyst, reaction that under
stirring conditions for 120 min, furnished compound 6a in
12% yield. Further experiments were carried out in solid
state conditions using silica or sand as dry support assisted
by MW irradiation. The experimental procedure was parti-
cularly simple: 1,3-dimethyl-5-aminopyrazole 1 was mixed
with benzaldehyde itself, 2a, the mixture adsorbed on the
solid support (silica or sand) and submitted to irradiation in
a domestic MW oven.32 The reactions were run in closed
Petri plates and the resulting products were treated with
methanol/dichloromethane (1:1), ®ltered and, after subse-
In MW assisted organic transformations, the effect of the
MW is mainly due to dielectric polarisation, although

A. Esteves-Souza et al. / Tetrahedron 57 (2001) 6147±6153
6149
bispyrazolo[3,4-b;40,30-e]pyridines related to 7, see Ref.
26). The unexpected structure of 6a was established de®-
nitely by X-ray crystallography. Thus, a single crystal
obtained by slow evaporation of an ethanol solution of 6a
was submitted to X-ray crystallography. Fig. 1 shows the
ZORTEP view of 6a.33
Table 1. Dry condensation reactions of 1 with p-substituted benzaldehydes
under microwave irradiation
Compound
Reaction conditions
Time (min) Yield (%) Mp (8C)
6a
6a
6a
7b
8c
Silica/room temperature 120
12
85
85
62
99
182±184
182±184
182±184
190±193
184±186
Silica/MW
Sand/MW
Sand/MW
Sand/MW
15
15
15
15
Bis-[5-(benzylideneamine)-1,3-dimethyl-4-pyrazolyl]-phenyl-
methane (6a).
We have used the atom numbering of the crystal structure
(Fig. 1) although it is not systematic. The NMR results are
reported in Table 2.
Figure 1. A ZORTEP plot of bis-[5-(benzylideneamine)-1,3-dimethyl-4-
pyrazolyl]-phenylmethane 6a, showing the atoms labelling scheme.
conduction losses can also be important, particularly at
higher temperatures.7 Furthermore, the reactions performed
using MW heating in sand or silica, possibly imply the
reactants adsorbed on the surface of the solid support,
which absorb the microwaves whereas the support does
not. Consequently, such supported reagents ef®ciently
induce reactions under safe and simple conditions affording
the desired products in high yields. In this manner, not only
are the yields better, indicative of a speci®c MW effect, but
also experiments are considerably easier to perform with a
very simpli®ed work-up. Table 1 shows the results obtained.
1,3,5,7-Tetramethyl-bispyrazolo-[3,4-b;40,30-e]-4-(p-methyl-
phenyl)pyridine (7b).
2.2. Identi®cation of the resulting compounds (6a, 7b, 8c)
Although mass spectrometry provided the ®rst indication
that the compounds were not the expected Schiff bases 4,
NMR spectroscopy (1H and 13C) proved the simplest way to
identify the compounds of Table 1 (for NMR spectroscopy
of Schiff bases related to 4, see Ref. 15 and for those of
1
Table 2. H and 13C NMR parameters of compound 6a. Chemical shifts in ppm. Solvent DMSO-d6
NMe (28,30)
3.58
CMe (29,31)
1.66
CHsp3 (21)
5.36
CHsp2 (4,14)
7.96
CHsp2 (Ph)
CHsp2 (Ph)
7.57 (o)
7.41 (m)
7.12 (o)
7.25 (m)
7.14 (p)
C3,13 142.50
C6,10,16,20 128.70
7.47 (p)
C21 37.31
C7,9,17,19 128.30
C28,30 34.72
C24,26 128.53
C29,31 13.17
C25 126.34
C1,11 145.08
C4,14 162.00
C2,12 107.73
C5,15 135.39
C22 145.56
C8,18 131.86
C23,27 128.37
The spectra shows the characteristic patterns of two identical pyrazole Schiff bases,18 as well as the presence of a CHsp3 group at position 21.

6150
A. Esteves-Souza et al. / Tetrahedron 57 (2001) 6147±6153
Table 3. 1H and 13C NMR parameters of compound 7b. Chemical shifts in ppm. Solvent DMSO-d6
NMe (15,17)
3.90
CMe (16,18)
1.86
CHsp2 (Ph)
CMe (19)
2.39
C11,13 128.42
C3,5
C3a,4a
110.85
C15,17 33.12
C7a,8a
151.22
C16,18 14.98
7.29 (10,14)
7.32 (11,13)
C10,14 128.75
140.94a
C4 140.90a
C9 131.07
C12 138.20
C19 20.89
a
The 1H and 13C NMR spectra of 7b are characterised by their simplicity and also by the quaternary carbons C3a and C4a near 110 ppm.21,26 Otherwise, the
spectra are very similar to those reported in Ref. 21 (NMe) and Ref. 26 (NPh).
Table 4. 1H and 13C NMR parameters of compound 8c. Chemical shifts in ppm. Solvent DMSO-d6
NMe (20)
3.74
Cme (21)
2.07
CHsp3 (6)
CHsp2 (13)
8.80
CHsp2 (Ph-8,9)
CHsp2 (Ph-15,16)
5.94
6.36 (OH)
7.55 (8,12)
8.07 (9,11)
8.03 (15,19)
8.28 (16,18)
JH6/OHˆ4.0 Hz
C3 145.64
C13 160.64
C4 110.48
C14 145.75
C5 140.96
C15,19 129.48
C6 64.58
C16,18 124.01
C7 148.99
C17 148.99
C8,12 126.95
C20 34.96
C9,11 122.90
C21 12.61
C10 146.10
The NMR data corresponding to 7b are reported in Table 3.
5-(p-Nitrobenzylideneamine)-1,3-dimethyl-4-pyrazolyl-(p-
nitrophenyl)-6-hydroxymethane (8c).
Compound 8c lacks the symmetry of the previous
compounds (6a Cs, 7b C2v). Consequently, it has been a
little more complicated to assign the NMR signals and
several two-dimensional techniques have been necessary
to complete the assignments of Table 4.
3. Conclusion
Our discussion is based on the argument that if the lone pair
on the amino group in 1 is able to activate the position 4
(formally an enamine behaviour), the lone pair in the imine
4 is not. The corresponding plausible intermediates, [10]
and [11], illustrate these differences.
Scheme 1 is not intended to be a reaction mechanism but
only a table of connectivities. We have selected bimolecular
reactions with the only exception of the transformation of
the intermediate [5] into 6, where two successive condensa-
tions with 2 are necessary. Therefore, the arrows in Scheme
1 only connect direct transformations. We have used brack-
ets for those compounds that have not been isolated, like the
carbinol [3] and the intermediate [5]. Pyrazolylalkanols,
related to [3] but without the 5-amino group, have been
described recently by Soai.34 The intermediate [5] has
been proposed by Brack.20 Some authors, have proposed
as intermediates the dehydrated derivative [8] and the
reduced precursor [9].24
We have summarised the experimental observations in
Table 5. Only the ®rst one is a simple process, all others
involve several intermediates. For instance, it is known that
Schiff bases 4 (in general, not only 1,3-dimethyl derivatives,
but those derived from N-phenyl pyrazoles) can be trans-
formed, on treatment with 5-aminopyrazoles 1, into the
tricyclic structures 7,21,24 to account for this reaction an
isomerization 4!6 has to be assumed (4!112![3]!

A. Esteves-Souza et al. / Tetrahedron 57 (2001) 6147±6153
Table 5. Experimental results related to Scheme 1 Table 6. Crystal data and structure re®nement for 6a
6151
General reaction
Speci®c reaction
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
C31H30N6
486.61
293(2) K
0.71073 A
Triclinic, P-1 (no. 2)
112!4
112a!4a,
112b!4b,
112c!4c
Ê
Ê
112!6
112!7
112a!6a
aˆ9.727(2) A aˆ69.12(3)8
Ê
Ê
112a!7a
bˆ11.719(2) A bˆ76.61(3)8
(Lit. Refs. 21,28),
112b!7b
112c!8c
cˆ13.857(2) A gˆ70.35(3)8
Ê 3
Volume
1375.0(5) A
Z, calculated density
Absorption coef®cient
F(000)
Crystal size
u range for data collection
Index ranges
2, 1.175 Mg m23
112!8
6!7
0.072 mm21
516
6a!7a
114!7
(Lit. Refs. 21,24)
0.56£0.50£0.10 mm
2.25±25.008
0 ^ h , 11; 212 % k % 13;
215 % 1 % 16
5101/4801 (R(int)ˆ0.0197)
99.0%
[5]!6). If 4 cannot be the direct precursor of 6, 7 and 8, then
the reactions starting from 1 and 2, must go through inter-
mediates like [3] and [5]. Compound 6a, isolated as inter-
mediate, under re¯ux in ethanol furnished also 7a. This
transformation 6!7 probably involves the hydrolysis of,
at least, one imine, i.e. 6![5]!7. Finally, the reaction
114!7, should proceed through 1 and 2.
Re¯ections collected/unique
Completeness to 2uˆ25.00
Re®nement method
Data/restraints/parameters
Goodness-of-®t on F2
Full-matrix least-squares on F2
4801/0/335
1.084
Final R indices ꢀI . 2sꢀI††
R1ˆ0.0629, wR2ˆ0.1657
Extinction coef®cient
Largest diff. peak and hole
0.045(5)
0.360 and 20.324e A
Ê 23
A last point that has to be discussed is the effect of the
substituent R in benzadehydes 2 on the course of the reac-
tions of Scheme 1. Especially, the fact that when 1 reacts
with 2, besides the imines 4, three different compounds are
obtained depending on the nature of R: RˆH 6a, RˆCH3 7b
and RˆNO2 8c. A possible explanation using the pivotal
intermediate [3] is that when RˆNO2, its electron withdraw-
ing effect make the carbinol less reactive and only the
formation of the imine 8c occurs. In the two other cases,
intermediate [5] is formed. When RˆCH3, the methyl group
would make [5b] more easily oxidized into 7b than [5a] into
7a (although 6a can be transformed into 7a). Finally, when
RˆH, 6a is isolated. The role of the silica could be related to
its acid catalytic properties, which could prevent the forma-
tion of 4. Another fact that must be considered is that under
MW irradiation, the temperature depends on the dielectric
constants (relative permittivities 1r) of the reagents and the
values of 1r for the three benzaldehydes should be different.
Monodimensional experiments were performed using stan-
dard conditions. 2D Inverse proton detected heteronuclear
shift correlation spectra, HMQC and HMBC, were obtained
with the following conditions: data were collected in a
4096£128 matrix with a spectral width of 8000 Hz in the
proton domain and 25,000 Hz in the carbon domain, and
processed in a 4096£512 matrix. The HMQC experiment
was optimised for one bond heteronuclear coupling constant
of 145 Hz and the HMBC experiment for long range
coupling constants of 8 Hz.
4.2. X-ray crystallography (see Table 6)
A yellow crystal was mounted on a glass ®ber and used to
collect data on a Nonius CAD-4 diffractometer36 with
graphite-monochromated MoKa radiation and v ±2u
scans. The structure was solved by means of direct methods
using shelxs9737 and re®ned by full-matrix least-squares
techniques using F2 with shelxl97.37
In conclusion, this work has shown that solid supported MW
irradiation not only affords better yields and cleaner reac-
tions than conventional heating,35 but even leads to different
compounds showing a change not only of reactivity but also
of selectivity. This is true, even if probably in all cases
mixtures of 4, 6 (6a 85%), 7 (7b 91%) and 8 (8c 99%) are
formed, because the major products are very abundant.
4.3. 5-Benzylideneamine-1,3-dimethyl-aminopyrazoles
Standard procedure: Benzaldehyde 2 (,0.5 mL, 4.5 mmol)
and 1,3-dimethyl-5-aminopyrazol 1 (0.5 g, 4.5 mmol) were
mixed in the presence of some drops of concentrated HCl in
30 mL of benzene as solvent. The mixture was re¯uxed
during 5 h and the water formed was collected in a Dean±
Stark trap. After cooling, the product was ®ltered and
recrystallised from ethanol.
4. Experimental
4.1. General procedures
The microwave assisted organic reactions were performed
in a Consul Pratice-Brastemp S.A./Model MU31AO, a
domestic oven. Melting points, uncorrected, were taken on
Mel-Temp II capillary apparatus. Infrared spectra were
obtained on a Perkin±Elmer FT 1640 spectrometer in KBr
pellets. Mass spectra were recorded using a MSD Hewlett
Packard Series 1100 spectrometer. 1H and 13C NMR spectra
were recorded on a Varian Unity-500 spectrometer operat-
ing at 499.88 and 125.71 MHz, respectively, using CD3OD
or DMSO-d6 as solvents and internal TMS as reference.
4.3.1. 5-Benzylideneamine-1,3-dimethyl-aminopyrazol
(4a). Yellow solid, 10% yield, mp 172±1748C. H NMR d
1.80 (3H, s), 3.70 (3H, s), 7.2 (1H, m), 7.3 (1H, m), 7.6 (1H,
m), and 7.8 (1H, s).
1
4.3.2. 5-(p-Methyl-benzilideneamine)-1,3-dimethylami-
nopyrazol (4b). White solid, 10% yield, mp 184±1868C.
1H NMR d 2.18 (3H, s), 2.63 (3H, s), 3.96 (3H, s), 7.28±
7.76 (1H, m), and 8.07 (1H, s).

6152
A. Esteves-Souza et al. / Tetrahedron 57 (2001) 6147±6153
Â
mento de Quõmica da Universidade Federal de Santa Catar-
ina, for personal assistance with mass spectra recording.
4.3.3. 5-(p-Nitro-benzilideneamine)-1,3-dimethylamino-
pyrazol (4c). Yellow solid, 30% yield, mp 185±1888C. H
1
NMR d 1.75 (3H, s), 1.97 (3H, s), 5.96 (1H, s), 7.38 (1H, d,
Jˆ8.68 Hz), 8.19 (1H, d, Jˆ8.68 Hz), and 8.40 (1H, s).
4.3.4. Bis-[5-(benzylideneamine)-1,3-dimethyl-4-pyrazo-
lyl]-phenyl-methane (6a). Method A: Using silica at ambi-
ent temperature. The mixture benzaldehyde (0.5 mL,
References
1. Bram, G.; Loupy, A.; Majdoub, M.; Gutterriez, E.; Ruiz-
Hitzky, E. Tetrahedron 1990, 45, 5167±5176.
2. Latouche, R.; Texier-Boullet, F.; Hamelin, J. Tetrahedron
Lett. 1991, 32, 1179±1182.
4.5 mmol),
1,3-dimethyl-5-aminopyrazole
(0.5 g,
4.5 mmol) and silica gel 60 (2 g) were stirred at room
temperature for 120 min. The product was extracted with
methanol/dichloromethane 1:1 (50 mL) after the excess of
solvent was evaporated and the product ®ltered. The recrys-
tallisation from hot ethanol gave 90 mg (12%) as a yellow
solid with mp 182±1848C; nmax 3059 (C±Harom), 2927
(CH3), 1617 (CvN), 1515 (CvCarom); MS, m/z (%): 486
(M1, 33).
 Â
3. Almena, I.; Dõez-Barra, E.; de la Hoz, A.; Ruiz, J.; Sanchez-
Â
Migallon, A.; Elguero, J. J. Heterocycl. Chem. 1998, 35,
1263±1267.
 Â
4. (a) Dõez-Barra, E.; de la Hoz, A.; Sanchez-Migallon, A. J.
Â
Â
Heterocycl. Chem. 1999, 36, 889±894. (b) Dõaz-Ortõz, A.;
Â
 Â
Carrillo, J. R.; Cossõo, F. P.; Gomez-Escalonilla, M. J.; de la
Hoz, A.; Moreno, A.; Prieto, P. Tetrahedron 2000, 56, 1569±
1577.
Method B: Using silica and microwave irradiation. Benzal-
dehyde (0.5 mL, 4.5 mmol), and 1,3-dimethyl-5-aminopyr-
azole (0.5 g, 4.5 mmol) in dried silica gel (2 g) were
submitted to microwave irradiation for 15 min. The product
was extracted with methanol/dichloromethane 1:1 (50 mL)
and after evaporation the product was ®ltered. The recrys-
tallisation from hot ethanol gave 625 mg (85% yield).
5. Bogdal, D.; Pielichowski, J.; Jaskot, K. Heterocycles 1997, 45,
715±722.
Â
6. Abehaim, D.; Dõez-Barra, E.; de la Hoz, A.; Loupy, A.;
Â
Sanchez-Migallon, A. Heterocycles 1994, 38, 793±801.
Â
7. Caddick, S. Tetrahedron 1995, 51, 10403±10432.
Â
8. Almena, I.; Carrillo, J. R.; de la Cruz, P.; Dõaz-Ortiz, A.;
Â
Gomez-Escalonilla, M. J.; de la Hoz, A.; Langa, F.; Prieto,
Method C: Using sand microwave irradiation. Benzalde-
hyde (0.5 mL, 4.5 mmol) and 1,3-dimethyl-5-amino-pyra-
zole (0.5 g, 4.5 mmol) in dry sand (5 g, Angra dos Reis,
RJ, Brazil) were submitted to microwave irradiation for
15 min. The product was extracted (using 30 mL of solvent
mixture), isolated and puri®ed in the same way above to
afford 625 mg (85%) of 6a.
Â
P.; Sanchez-Migallon, A. Targets Heterocycl. Syst. 1998, 2,
281±308.
9. Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025±1074.
10. Preparative Chemistry using Supported Reagents; Laszlo, P.,
Ed.; Academic: London, 1987; pp. 8±11.
11. Loupy, A. Solvent-free reactions. Top. Curr. Chem. 1999,
206, 155±207.
Â
Â
12. Langa, F.; de la Cruz, P.; de la Hoz, A.; Dõaz-Ortiz, A.; Dõez-
Barra, E. Contemp. Org. Synth. 1997, 373±386.
13. Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem. 1966, 6,
347±429.
4.3.5. 1,3,5,7-Tetramethyl-bispyrazolo-[3,4-b;40,30-e]-4-
(p-methylphenyl)pyridine
(0.53 mL, 4.5 mmol),
(7b). p-Tolualdehyde
1,3-dimethyl-5-aminopirazole
(0.5 g, 4.5 mmol) were added to dry sand (5 g), and
submitted to microwave irradiation for 15 min. The solid
obtained was treated in the same way to afford 425 mg
(91%) as a yellow solid with mp 184±1868C. nmax 3040
(C±Harom), 2923±2856 (CH3), 1605 (CvN), 1512
(CvCarom); MS, m/z (%): 307 (M1, 57).
14. (a) Elguero, J. In Pyrazoles and their Benzo Derivatives;
Katritzky, A. R., Rees, C. W., Eds.; Comprehensive Hetero-
cyclic Chemistry; Pergamon: Oxford, 1984; Vol. 5, pp. 167±
303. (b) Elguero, J. In Pyrazoles; Katritzky, A.R., Rees, C. W.,
Scriven, E. F., Eds.; Comprehensive Heterocyclic Chemistry;
Pergamon: Oxford, 1996; Vol. 2, pp. 1±75.
15. Rechsteiner, B.; Texier-Boullet, F.; Hamelin, J. Tetrahedron
Lett. 1993, 34, 5071±5074.
4.3.6. 5-(p-Nitrobenzylideneamine)-1,3-dimethyl-4-pyra-
zolyl-(p-nitrophenyl)-6-hydroxymethane (8c). A mixture
of p-nitro-benzaldehyde (0.7 g, 5.5 mmol), 1,3-dimethyl-5-
aminopirazole (0.5 g, 4.5 mmol) and dry sand (5 g) was
submitted to microwave irradiation for 15 min. The product
was extracted with methanol/dichloromethane 1:1 (25 mL),
®ltered and recrystallised from hot ethanol gave 880 mg
(99%) of a yellow solid with mp 190±1938C. nmax 3056
(C±Harom), 2931±2838 (CH3), 1600 (CvN), 1519 (C±
NO2), 1511 (CvCarom); MS, m/z (%): 395 (M1, 100).
16. Sarshar, S.; Siev, D.; Mjalli, A. M. M. Tetrahedron Lett. 1996,
37, 835±838.
17. Chemat, F.; Poux, M.; Berlan, J. J. Chem. Soc., Perkin Trans.
2 1994, 2597±2602.
18. Claramunt, R. M.; Forfar, I.; Cabildo, P.; Lafuente, J.;
Â
Barbera, J.; Gimenez, R.; Elguero, J. Heterocycles 1999, 51,
Â
751±762.
19. Echevarria, A.; Elguero, J.; Meutermans, W. J. Heterocycl.
Chem. 1993, 30, 957±960.
20. Brack, G. Ann. 1965, 681, 105±110.
21. Gonzalez, E.; Sarlin, R.; Elguero, J. Tetrahedron 1978, 34,
1175±1178.
Acknowledgements
22. Swett, L. R.; Ratajczyk, J. D.; Nordeen, C. W.; Aynilian, G. H.
J. Heterocycl. Chem. 1975, 12, 1137±1142.
23. Joshi, K. C.; Dubey, K.; Dandia, A. Pharmazie 1981, 36, 336±
337.
The authors wish to thank CNPq (Conselho Nacional de
Â
Desenvolvimento Cientõ®co e Tecnologico) and CAPES
(CoordenacËaÄo de AperfeicËoamento de Pessoal de Ensino
Â
Â
de Nõvel Superior) for ®nancial support and fellowships,
and Professor Maria da GracËa Nascimento, from Departa-
24. Hennig, L.; Hofmann, J.; Alva-Astudillo, M.; Mann, G. J.
Prakt. Chem. 1990, 332, 351±358.

A. Esteves-Souza et al. / Tetrahedron 57 (2001) 6147±6153
6153
Ã
25. Hennig, L.; MuÈller, T.; Grosche, M. J. Prakt. Chem. 1990,
332, 693±698.
31. Echevarria, A.; Nascimento, M. A.; Geronimo, V.; Miller, J.;
Giesbrecht, A. J. Brazilian Chem. Soc. 1999, 10, 60±64.
32. Consul Pratice-Brastemp S.A. Model MU31AO.
33. Zsolnai, L.; Pritzkow, H. zortep, ortep Program for PC;
University of Heidelberg: Germany, 1996.
26. Kolehmainen, E.; Laihia, K.; Rasala, D.; Puchala, A. Magn.
Reson. Chem. 1996, 34, 570±571.
27. Puchala, A.; Rasala, D.; Kolehmainen, E.; Prokesova, M. Org.
Prep. Proced. Int. 1997, 29, 212±216.
34. Tanji, S.; Aoyagi, H.; Tabira, H.; Satp, I.; Soai, K. Hetero-
cycles 2000, 53, 381±386.
28. He, Z.; Milburn, G. H. W.; Danel, A.; Puchala, A.; Tomasik,
P.; Rasala, D. J. Mater. Chem 1997, 7, 2323±2325.
29. Rechthaler, K.; Schamschule, R.; Parusel, A. B. J.; Rotkie-
wicz, K.; Piorun, D.; Kohler, G. Acta Phys. Pol., A 1999,
95, 321±334.
35. Santagada, V.; Perissutti, E.; Fiorino, F.; Vivenzio, B.;
Caliendo, G. Tetrahedron Lett. 2001, 42, 2397±2400.
36. Nonius. cad4-express, Version 1.1; Nonius, Delft: The Neth-
erlands, 1993.
37. Sheldrick, G.M. shelxs97. Program for the Solution of Crys-
È
tal Structures; University of Gottingen: Germany, 1997.
30. Bigelow, L. A.; Eatough, H. Organic Syntheses Collect;
Wiley: New York, 1941; Vol. 1, pp. 80±81.