Synthesis of pyrazolo[3,4-b]pyridines by cycloaddition reactions under microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(00)00059-4

Microwave irradiation induces the cycloaddition of pyrazolylimines with aromatic and aliphatic nitroalkenes to afford pyrazolo[3,4-b]pyridines in 5- 20 min. Some of these reactions do not occur under classical heating. Tricyclic heterocycles can be synthesized from cycloalkenes. The reactivity and regiochemistry can be understood in terms of the energy and atomic coefficients of the frontier orbital, except in the case of compound 18. Calculations at the HF/3-21G level predict an asynchronous transition structure for this cycloaddition with regiocontrol determined by Coulombic interaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00059-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1569–1577
Synthesis of Pyrazolo[3,4-b]pyridines by Cycloaddition Reactions
under Microwave Irradiation
a,
a
b
a
*
´
´
´
´
´
´
Angel Dıaz-Ortiz, Jose Ramon Carrillo, Fernando P. Cossıo, Marıa J. Gomez-Escalonilla,
Antonio de la Hoz,a, Andres Moreno and Pilar Prieto
a
a
*
´
a
´
Facultad de Quımicas, Universidad de Castilla-La Mancha, 13071-Ciudad Real, Spain
b
´
´
´
Facultad de Quımica, Universidad del Paıs Vasco, Apdo 1072, 20080-San Sebastian, Spain
Received 28 October 1999; revised 20 December 1999; accepted 13 January 2000
´
Dedicated to Prof. Jose Elguero on the occasion of his 65th birthday
Abstract—Microwave irradiation induces the cycloaddition of pyrazolylimines with aromatic and aliphatic nitroalkenes to afford
pyrazolo[3,4-b]pyridines in 5–20 min. Some of these reactions do not occur under classical heating. Tricyclic heterocycles can be synthe-
sized from cycloalkenes. The reactivity and regiochemistry can be understood in terms of the energy and atomic coefficients of the frontier
orbital, except in the case of compound 18. Calculations at the HF/3-21G level predict an asynchronous transition structure for this
cycloaddition with regiocontrol determined by Coulombic interaction. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
through a Diels–Alder cycloaddition of pyrazolyl imines
with aromatic nitroalkenes under microwave irradiation.14
This is the first example of a [4ϩ2] cycloaddition of a
2-azadiene involving a pyrazole ring (Scheme 1).
Pyrazolo[3,4-b]pyridines are very interesting compounds
and have received considerable attention as a result of
their biological activity and structural relationship to
indoles. A number of pyrazolo[3,4-b]pyridines display
interesting anxiolytic activity1 (e.g. tracazolate2), are poten-
tially biologically active compounds as new inhibitors of
xantine oxidases,3 have proved to be active against Gram
positive and Gram negative bacteria4 and as cholesterol
formation-inhibiting compounds,5 and are also promising
for the treatment of cataracts associated with diabetes.6
The higher yields obtained and the mild reaction conditions
used with azadiene 2 can be justified, in part, by the HOMO
(diene)–LUMO (dienophile) energy gaps. These are 0.5 eV
lower than those relating to the cycloadditions of 1 (see
Table 1).
On the other hand, compounds 1 and 2 were modeled using
the Hyperchem program.15 The more stable conformation of
2-azadiene 2 has a torsion angle of 8.7Њ between the exocyclic
double bond and the pyrazole ring, while in azadiene 1 this
torsion angle has a value of 18.1Њ. This greater planarity in
compound 2 partly justifies its higher reactivity as a diene.
Pyrazolo[3,4-b]pyridines have been prepared generally by
cyclization reactions starting from different heterocyclic
reagents.7–11 Only two examples have been reported for
the preparation of these compounds by cycloaddition
reactions: in the first case, the title compounds were
obtained by [4ϩ2] cycloaddition of a 1,2,4-triazepine with
dimethyl acetylenedicarboxylate (DMAD) and subsequent
1,3-sigmatropic rearrangement;12 in the second case,
pyrazolo[3,4-b]pyridines were prepared by 1,3-dipolar
cycloaddition of cyclic ketene N,O-acetals with diphenyl-
nitrilimine.13
Results and Discussion
In order to determine the scope of this reaction and its
utility as a new synthetic approach to pyrazolo[3,4-
b]pyridines, we have studied the cycloaddition of 2-
azadienes 1 and 2 with aliphatic nitroalkenes and
other dienophiles under microwave irradiation. All the
cycloadditions were performed in the absence of solvent
at atmospheric pressure in a focused microwave reactor
with full control of the incident power and the reaction
temperature. The reaction mixture was irradiated until
complete consumption of the azadiene had been
achieved. The pyrazolopyridines were directly isolated
Recently, we have reported a new, interesting and versatile
approach to the preparation of pyrazolo[3,4-b]pyridines
Keywords: microwave heating; Diels–Alder reactions; nitrogen hetero-
cycles; computed-assisted methods.
* Corresponding author. Tel.: ϩ34-926-295300; fax: ϩ34-926-295318;
e-mail: adiaz@qino-cr.uclm.es
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00059-4

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A. Dıaz-Ortiz et al. / Tetrahedron 56 (2000) 1569–1577
1570
Scheme 1.
Table 1. HOMO–LUMO energies of Compounds 1–3 and energy gaps
Compound
E
HOMO (eV)
ELUMO (eV)
EHOMO 1ϪELUMO
EHOMO 2ϪELUMO
1
2
3a
3b
3c
Ϫ8.81
Ϫ8.61
Ϫ10.05
Ϫ8.68
Ϫ0.66
Ϫ0.13
Ϫ1.44
Ϫ1.29
Ϫ1.74
–
–
7.37
7.52
7.07
–
–
7.17
7.32
6.87
Ϫ10.09
Table 2. Diels–Alder cycloadditions of 2-azadienes 1 or 2 with electron-poor dienophiles 7–12
Diene
Dienophile
Reaction conditions
Product
Yield (%)
2
180 W, 10 min, 100ЊC
41
2
90 W, 10 min, 130ЊC
33

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A. Dıaz-Ortiz et al. / Tetrahedron 56 (2000) 1569–1577
1571
Table 2 (continued)
Diene
Dienophile
Reaction conditions
Product
Yield (%)
2
90 W, 10 min, 120ЊC
55
1
285 W, 15 min, 140ЊC
25
2
210 W, 15 min, 170ЊC
50
1
150 W, 20 min, 85ЊC
20
2
150 W, 20 min, 85ЊC
39
from the crude mixture by flash chromatography. Reac-
tion conditions, products and yields are summarized in
Table 2.
dienophiles in 10–20 min to give the corresponding pyra-
zolo[3,4-b]pyridines.
This is a versatile synthetic procedure that permits the
synthesis of several pyrazolopyridines by the introduction
of various different substituents in the heterocyclic ring and
Microwave irradiation induced pyrazolyl 2-azadienes to
undergo Diels–Alder cycloaddition with electron-poor

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A. Dıaz-Ortiz et al. / Tetrahedron 56 (2000) 1569–1577
1572
Figure 1. Selected NOEs for pyrazolopyridines 14–16.
even allows the preparation of tricyclic derivatives such as
13 or 17.
shows two doublets at 8.41 and 8.74 ppm (Jˆ1.9 Hz)
assigned to H-4 and H-6, respectively. In the case of 18, an
NOE (3%) between H-5 (d 8.11) and o-H of p-CH3OC6H4
(d 7.74) could be observed.
The moderate yields, in comparison with the results
obtained from aromatic nitroalkenes, can be explained in
terms of the LUMO energy of the dienophiles, ca. 1 eV
higher than in the aromatic nitroalkenes, and the ease of
polymerization of some of the reactants, such as 10 or 12.
In order to assess the efficiency of the microwave irradiation
in inducing these processes, we studied the reaction of 1 or 2
with 2-chloroacrylonitrile by classical heating in an oil bath
under the same reaction conditions (time and temperature).
However, in this case the adducts 18 or 19 were not obtained
and hydrolysis of the 2-azadiene took place.
In all the reactions with unsymmetrical dienophiles only one
regioisomer was obtained. The regiochemistry of the
adducts has been inferred by NOE difference experiments
(see Fig. 1).
The change in the regioselectivity of the cycloadditions of
acrylonitrile on using 1 or 2 as the substrate is remarkable.
Considering the LUMO of acrylonitrile, the atomic coeffi-
cient values could justify the regiochemistry of adduct 19
but not the regiochemistry of adduct 18.
Reaction of 2-azadiene 2 and aliphatic nitroalkenes 8 or 9
took place with loss of HNMe2 and oxidation to yield the
aromatic heterocycle. However, with 1-nitrocyclohexene
(7) aromatization is possible only through loss of HNO2.
In the case of 2-chloroacrylonitrile (12) aromatization took
place with loss of HCl, a less usual process in cyclo-
additions. Owing to the low boiling point of the 2-chloro-
acrylonitrile, these reactions were performed with a large
excess of dienophile (8 equiv.), in contrast with cyclo-
additions of the other dienophiles (only 2 equiv.).
Computational Studies
In order to understand the reasons underlying the regio-
divergent outcome of these cycloadditions, we performed
several calculations on the model structures depicted in
Scheme 2. Among the possible stereoisomers considered,
those possessing endo cyano groups proved to be more
stable and therefore only the corresponding reaction paths
will be discussed. Given the size of the structures, geometry
The regiochemistry of the adducts 18 and 19 was inferred by
1
spectroscopic experiments. The H NMR spectrum of 19
Scheme 2.

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A. Dıaz-Ortiz et al. / Tetrahedron 56 (2000) 1569–1577
1573
˚
Figure 2. Chief geometric features of the transition structures. Bond distances are given in A. Atoms are represented by increasing order of shading as follows:
H, C, N.
Table 3. Computed activation energiesa,b (DEa, kcal/mol) and reaction
optimizations were carried out at the relatively inexpensive
energiesa,c (DErxn, kcal/mol) for the transformations 20a–cϩ12!21a–c
and 20a,cϩ12!210a,c (see Scheme 2)
HF/3-21G level, since previous calculations on related
Diels–Alder reactions have shown that this level yields
sufficiently accurate geometries.16
Series
R
DEa
DErxn
eˆ36:64
eˆ1:00
eˆ36:64
eˆ1:00
The chief geometric features of the transition structures are
given in Fig. 2. It can be seen that the transition structures
Tsa–c are significantly more synchronous than their
regioisomeric analogues TS0a,c. In these latter transition
20a–cϩ12!21a–c
a
b
c
C6H5
39.31
40.62
41.33
47.51
Ϫ6.81
Ϫ5.72
ϩ3.71
Ϫ4.40
Ϫ2.43
ϩ8.97
p-CH3OC6H4 39.68
NMe2
45.17
˚
structures the C2···C3 bond distances are larger than 3 A,
20a,cϩ12!210a,c
whereas the C4···C5 bond distances lie in the normal range
for this kind of reaction.17,18
a
c
C6H5
34.54
29.69
43.73
32.17
Ϫ4.56
Ϫ5.11
Ϫ1.89
Ϫ10.27
NMe2
a Single-point energies computed at the B3LYP/G31Gء//HF/3-
21GءϩDZPVE and B3LYP(L1A1)/G-31Gء//HF/3-21GϩDZPVE
levels in the gas phase and in acetonitrile solution ꢀeˆ36:64†; respec-
tively.
Relative energies were computed by means of the three para-
meter hybrid functional B3LYP, since this method has proved
to yield accurate activation and reaction energies in thermal
conditions.19 Solvent effects were estimated by means of the
Onsager model,20,21 denoted as L1A1.22 The computed activa-
tion and reaction energies are reported in Table 3.
b Computed as DEa ˆ EꢀTS† Ϫ Eꢀ20† ϩ Eꢀ12†Š or DEaˆEꢀTS0†Ϫ
Eꢀ20†ϩEꢀ12†Š.
c Computed as DErxnˆEꢀ21†ϪEꢀ20†ϩEꢀ12†Š.

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A. Dıaz-Ortiz et al. / Tetrahedron 56 (2000) 1569–1577
1574
These results agree very well with our experimental find-
ings. However, it is noteworthy that this agreement is
obtained only if solvent effects are taken into account.
The explanation for this behavior can be found by examina-
tion of Fig. 3. In this figure we have included the frontier
molecular orbitals (FMOs) of reactants 12 and 20a,c, as well
as the electrostatic potentials mapped on the electron
density surfaces. From the shape of the FMOs it is clear
that in both cases the formation of cycloadducts 21a,c can
be expected if only orbital control is considered, and this is
in good agreement with our activation barriers computed in
vacuo. In contrast, the electrostatic interactions between the
reactants favor the formation of regioisomers 21a and 210c,
respectively. Therefore, if the electrostatic contribution of
the solution energy is considered, the regiocontrol of the
reaction is determined by Coulombic interaction rather
than by FMO overlap.
Conclusions
Cycloaddition of pyrazolyl imines with electron-poor dieno-
philes under microwave irradiation provides a general
procedure to synthesize substituted pyrazolo[3,4-b]pyri-
dines. The procedure has been extended to aromatic and
aliphatic nitroalkenes, cyclic electrondeficient dienophiles
and reagents with a high tendency to polymerize, such as
acrylonitrile. Some of these cycloadditions do not occur
under classical heating.
Experimental
Computational methods
All calculations reported in this study were performed using
the Gaussian 9423 program suite, with either the 3-21G24 or
6-31Gء25 basis sets. Electron correlation was partially taken
into account by using the B3LYP26–29 method. All station-
ary points were fully optimized with no symmetry
constraints using analytical gradient techniques. Transition
structures and local minima were conveniently character-
ized by harmonic analysis.30 Zero-point vibrational energies
(ZPVEs) computed at the HF/3-21G level were scaled by
0.92 as recommended.31 Solvent effects were estimated by
means of the Onsager model.20,21 Only the electrostatic
contribution was computed, since the cavitation and dis-
persion contributions are similar for stereoisomeric
structures.32 Electrostatic potentials were calculated by
means of the SPARTAN package.33
Figure 3. Frontier molecular orbitals (FMOs) of reactants 12, 20a and 20c,
respectively, as well as the electrostatic potentials mapped on the electron
density surfaces.
Our results indicate that formation of cycloadducts 21a,b is
exothermic. In contrast, formation of compound 21c is
endothermic, especially in acetonitrile solution. Cycloadduct
210a lies only 1.89 kcal/mol below the reactants, whereas the
energy of reaction for compound 210c is Ϫ10.27 kcal/mol in
acetonitrile solution, a value ca. 20 kcal/mol more exo-
thermic than for the formation of its analogue 21c.
General
Mp were determined on a Gallenkamp apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded at
With respect to the activation energies, our calculations
predict that formation of cycloadducts 210 is always favored
in the gas phase. However, the activation barriers computed
in solution give different results depending upon the nature
of the R group. If R is aromatic, virtually exclusive forma-
tion of cycloadducts 21 is predicted under kinetic control.
However, if R is an amino group only formation of cyclo-
adduct 210 should be expected under the same conditions.
299.94 and 75.429 MHz, respectively, on a Varian Unity
300 spectrometer. Chemical shifts are reported in ppm (d)
using Me4Si as the standard, and coupling constants J are
given in Hz. Percentage NOE enhancements were obtained
by integrating the affected resonance relative to the irra-
diated resonance in the difference spectrum in each case.
Column chromatography was carried out with SiO2 (silica
gel, Merck type 60 230–400 mesh). Microwave irradiations

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A. Dıaz-Ortiz et al. / Tetrahedron 56 (2000) 1569–1577
1575
were conducted in a focused microwave reactor (Prolabo
MX350) with measurement and control of power and
temperature by infrared detection. Elemental analyses
were determined on a Perkin–Elmer PE2400 CHN
apparatus. Mass spectra were obtained on a VG Autospec
instrument (70 eV).
Flash chromatography (hexane/ethyl acetate, 4:1) afforded
the pyrazolopyridine 4c (112 mg, 48%); H NMR (CDCl3)
1
d 1.60 (t, Jˆ7.3 Hz, 3H, CH3), 4.27 (q, Jˆ7.3 Hz, 2H, CH2),
7.04 (d, Jˆ8.8 Hz, 2H, m-H p- CH3OC6H4), 7.23 (dd, Jˆ3.7
and 5.1 Hz, 1H, H-40 thiophene), 7.52 (dd, Jˆ1.2 and
5.1 Hz, 1H, H-50 thiophene), 7.70 (s, 1H, H-5), 7.73 (dd,
Jˆ3.7 and 1.2 Hz, 1H, H-30 thiophene), 8.12 (d, Jˆ8.8 Hz,
2H, o-H p-CH3OC6H4), 8.29 (s, 1H, H-3); 13C NMR
(CDCl3) d 15.0 (CH3), 42.0 (CH2), 55.4 (OCH3), 110.9
(C-5), 114.1 (m-C p-CH3OC6H4), 127.1 (C-40 thiophene),
127.6 (C-30 thiophene), 128.3 (C-50 thiophene), 128.8
(o-C p-CH3OC6H4), 131.3 (C-3), 114.3, 131.9, 136.4,
140.4, 151.0, 156.4, 160.8 (other carbons). MS (EI) m/z
335 (Mϩ). Anal. calcd for C19H17N3OS: C, 68.0; H, 5.1;
N, 12.5. Found: C, 68.1; H, 5.05; N, 12.55%.
General procedure
A mixture of the 2-azadiene and the corresponding dieno-
phile (1:2 mole ratio) was irradiated at atmospheric pressure
in a focused microwave reactor (Prolabo MX350) for the
time and at the power indicated in Table 2. The crude
product was purified by flash chromatography on silica gel
(Merck type 60, 230–400 mesh).
1-Ethyl-5-nitro-4-phenylpyrazolo[3,4-b]pyridine
(5a)
1-Ethyl-6-(4-methoxyphenyl)-4-phenylpyrazolo[3,4-
b]pyridine (4a). From azadiene 1 (200 mg, 0.87 mmol)
and b-nitrostyrene (3a) (259 mg, 1.74 mmol) with irradia-
tion at 285 W for 7 min (final temperature 140ЊC). Flash
chromatography (hexane/ethyl acetate, 10:1) afforded the
pyrazolopyridine 4a (151 mg, 53%), mp 98–99ЊC (from
and 1-ethyl-4-phenylpyrazolo[3,4-b]pyridine (6a). From
azadiene 2 (200 mg, 1.2 mmol) and b-nitrostyrene (3a)
(358 mg, 2.4 mmol) with irradiation at 240 W for 5 min
(final temperature 130ЊC). Flash chromatography (hexane/
ethyl acetate, 5:1) gave pyrazolopyridines 5a (205 mg,
64%) and 6a (21 mg, 8%).
1
methanol); H NMR (CDCl3) d 1.61 (t, Jˆ7.3 Hz, 3H,
CH3), 3.88 (s, 1H, OCH3), 4.67 (q, Jˆ7.3 Hz, 2H, CH2),
7.03 (d, Jˆ8.8 Hz, 2H, m-H p-CH3OC6H4), 7.46–7.60 (m,
3H, p,m-H Ph), 7.63 (s, 1H, H-5), 7.79–7.82 (m, 2H, o-H
Ph), 8.13 (s, 1H, H-3), 8.15 (d, Jˆ8.8 Hz, 2H, o-H
p-CH3OC6H4); 13C NMR (CDCl3) d 15.0 (CH3), 42.0
(CH2), 55.4 (OCH3), 112.5 (C-5), 114.1 (m-C
p-CH3OC6H4), 128.3 (o-C Ph), 128.8 (o-C p-CH3OC6H4),
129.0 (m-C Ph), 129.1 (p-C Ph), 131.2 (C-3), 160.7
(C-OCH3), 112.4, 132.1, 137.9, 144.1, 150.9, 156.3 (other
carbons). MS (EI) m/z 329 (Mϩ). Anal. calcd for
C21H19N3O: C, 76.55; H, 5.8; N, 12.75. Found: C, 76.4; H,
5.9; N, 12.8%.
1
Data for 5a. Mp 103–104ЊC (from tert-butanol); H NMR
(CDCl3) d 1.57 (t, Jˆ7.3 Hz, 3H, CH3), 4.63 (q, Jˆ7.3 Hz,
2H, CH2), 7.43–7.46 (m, 2H, o-H Ph), 7.51–7.55 (m, 3H, m-
and p-H Ph), 7.96 (s, 1H, H-3), 9.12 (s, 1H, H-6); 13C NMR
(CDCl3) d 14.7 (CH3), 42.6 (CH2), 127.9 (o-C Ph), 128.8
(m-C Ph), 129.6 (p-C Ph), 134.1 (C-3), 145.3 (C-6), 115.2,
132.6, 138.9, 140.4, 149.5 (other carbons). MS (EI) m/z 268
(Mϩ). Anal. calcd for C14H12N4O2: C, 62.65; H, 4.5; N, 20.9.
Found: C, 62.7; H, 4.5; N, 20.95%.
Data for 6a. Yellow oil; 1H NMR (CDCl3) d 1.57 (t,
Jˆ7.3 Hz, 3H, CH3), 4.64 (q, Jˆ7.3 Hz, 2H, CH2), 7.22
(d, Jˆ4.9 Hz, 1H, H-5), 7.50–7.59 (m, 3H, m- and p-H
Ph), 7.75–7.78 (m, 2H, o-H Ph), 8.18 (s, 1H, H-3), 8.58
(d, Jˆ4.9 Hz, 1H, H-6); 13C NMR (CDCl3) d 15.0 (CH3),
42.3 (CH2), 115.2 (C-5), 128.4 (o-C Ph), 129.1 (m-C Ph),
129.3 (p-C Ph), 131.4 (C-3), 148.7 (C-6), 112.4, 137.4,
144.1, 150.3 (other carbons). Anal. calcd for C14H13N3:
C, 75.3; H, 5.85; N, 18.8. Found: C, 75.4; H, 5.9; N,
18.8%.
1-Ethyl-6-(4-methoxyphenyl)-4-(1-phenylindol-3-yl)pyra-
zolo[3,4-b]pyridine (4b). From azadiene 1 (200 mg,
0.87 mmol) and 3-(2-nitrovinyl)-1-phenylindole (3b)
(460 mg, 1.74 mmol) with irradiation at 285 W for 10 min
(final temperature 140ЊC). Flash chromatography (hexane/
ethyl acetate, 4:1) gave pyrazolopyridine 4b (120 mg, 32%),
1
mp 204–205ЊC (from methanol); H NMR (CDCl3) d 1.63
(t, Jˆ7.3 Hz, 3H, CH3), 3.90 (s, 3H, OCH3), 4.71 (q,
Jˆ7.3 Hz, 2H, CH2), 7.07 (d, Jˆ8.8 Hz, 2H, m-H
p-CH3OC6H4), 7.30–7.38 (m, 2H, H-50 and -60 indole),
7.59–7.61 (m, 5H, N–Ph), 7.63–7.67 (m, 1H, H-70 indole)
7.86 (s, 1H, H-20 indole), 7.89 (s, 1H, H-5), 8.06–8.09 (m,
1H, H-40 indole), 8.17 (s, 1H, H-3), 8.18 (d, Jˆ8.8 Hz, 2H,
o-H p-CH3OC6H4); 13C NMR (CDCl3) d 15.1 (CH3), 42.1
(CH2), 55.4 (OCH3), 111.2 (C-70 indole), 112.2 (C-5), 114.1
(m-C p-CH3OC6H4), 120.4 (C-40 indole), 121.6 (C-50
indole), 123.5 (C-60 indole), 124.7 (o-C N–Ph), 128.1
(C-20 indole), 128.9 (o-C p-CH3OC6H4), 129.8 (m- and
p-C N–Ph), 131.8 (C-3), 112.7, 115.4, 126.8, 136.9,
138.9, 156.4, 160.7 (other carbons). MS (EI) m/z 444
(Mϩ). Anal. calcd for C29H24N4O: C, 78.35; H, 5.45; N,
12.6. Found: C, 78.45; H, 5.45; N, 12.6%.
1-Ethyl-5-nitro-4-(1-phenylindol-3-yl)pyrazolo[3,4-
b]pyridine (5b) and 1-ethyl-4-(1-phenylindol-3-yl)pyra-
zolo[3,4-b]pyridine (6b). From azadiene 2 (200 mg,
1.2 mmol) and 3-(2-nitrovinyl)-1-phenylindole (3b)
(634 mg, 2.4 mmol) with irradiation at 240 W for 6 min
(final temperature 130ЊC). Flash chromatography (hexane/
ethyl acetate, 4:1) afforded the pyrazolopyridines 5b
(275 mg, 60%) and 6b (24 mg, 9%).
Data for 5b. Mp 138–139ЊC (from tert-butanol); 1H NMR
(CDCl3) d 1.57 (t, Jˆ7.3 Hz, 3H, CH3), 4.60 (q, Jˆ7.3 Hz,
2H, CH2), 7.21–7.26 (m, 1H, H-50 indole), 7.30–7.36 (m,
1H, H-60 indole), 7.43–7.48 (m, 2H, H-40 indole and p-H
N–Ph), 7.58–7.64 (m, 5H, o- and m-H N–Ph and H-70
indole), 7.80 (s, 1H, H-20 indole), 8.13 (s, 1H, H-3), 9.13
(s, 1H, H-6); 13C NMR (CDCl3) d 14.9 (CH3), 42.7 (CH2),
111.4 (C-70 indole), 119.7 (C-40 indole), 121.9 (C-50
indole), 123.7 (C-60 indole), 124.7 (o-C N–Ph), 127.6
1-Ethyl-6-(4-methoxyphenyl)-4-(2-thienyl)pyrazolo[3,4-
b]pyridine (4c). From azadiene 1 (160 mg, 0.7 mmol) and
2-(2-nitrovinyl)thiophene (3c) (218 mg, 1.4 mmol) with
irradiation at 285 W for 8 min (final temperature 140ЊC).

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(p-C N–Ph), 129.5 (C-20 indole), 129.9 (m-C N–Ph), 134.9
(C-3), 145.8 (C-6), 109.3, 115.1, 126.7, 133.7, 136.5, 138.5,
136.7, 149.7 (other carbons). MS (EI) m/z 383 (Mϩ). Anal.
calcd for C22H17N5O2: C, 68.9; H, 4.45; N, 18.25. Found: C,
68.8; H, 4.4; N, 18.25%.
H cyclohexyl), 3.35–3.45 (m, 1H, H-10 cyclohexyl), 4.59 (q,
Jˆ7.1 Hz, 2H, CH2CH3), 8.36 (s, 1H, H-3), 8.87 (s, 1H,
H-6); 13C NMR (CDCl3) d 14.7 (CH3), 25.9, 26.4, 32.9
(CH2 cyclohexyl), 40.2 (C-10 cyclohexyl), 42.5 (CH2),
134.1 (C-3), 144.9 (C-6), 113.4 (C-3a), 141.1, 147.2,
149.7 (C-4, -5 and -7a). Anal. calcd for C14H17N4O2: C,
61.5; H, 6.25; N, 20.5. Found: C, 61.6; H, 6.3; N, 20.5%.
1
Data for 6b. Mp 134–135ЊC (from methanol); H NMR
(CDCl3) d 1.59 (t, Jˆ7.3 Hz, 3H, CH3), 4.65 (q,
Jˆ7.3 Hz, 2H, CH2), 7.28–7.37 (m, 2H, H-50 and -60
indole), 7.41–7.48 (m, 1H, p-H N–Ph), 7.46 (d, Jˆ4.8 Hz,
1H, H-5), 7.57–7.64 (m, 5H, m- and o-H N–Ph and H-70
indole), 7.82 (s, 1H, H-20 indole), 8.02–8.05 (m, 1H, H-40
1-Ethyl-4-isobutyl-5-nitropyrazolo[3,4-b]pyridine (15).
From azadiene 2 (200 mg, 1.2 mmol) and 4-methyl-1-
nitro-1-pentene (9) (310 mg, 2.4 mmol) with irradiation
at 90 W for 10 min (final temperature 120ЊC). Flash
chromatography (hexane/ethyl acetate, 9:1) afforded the
indole), 8.21 (s, 1H, H-3), 8.59 (d, Jˆ4.8 Hz, 1H, H-6); 13
C
1
NMR (CDCl3) d 15.0 (CH3), 42.2 (CH2), 111.2 (C-70
indole), 114.8 (C-5), 120.3 (C-40 indole), 121.6 (C-50
indole), 123.5 (C-60 indole), 124.7 (o-C N–Ph), 127.4
(p-C N–Ph), 128.2 (C-20 indole), 129.8 (m-C N–Ph),
131.8 (C-3), 148.8 (C-6), 114.0, 114.9, 126.7, 136.9,
137.8, 138.9, 150.4 (other carbons). Anal. calcd for
C22H18N4: C, 78.1; H, 5.35; N, 16.55. Found: C, 78.2; H,
5.3; N, 16.6%.
pyrazolopyridine 15 (165 mg, 55%) as a yellow oil; H
NMR (CDCl3) d 0.99 (d, Jˆ7.1 Hz, 6H, 2×CH3CH), 1.56
(t, Jˆ7.1 Hz, 3H, CH3CH2), 2.12 (m, 1H, CH), 3.23 (d,
Jˆ7.1 Hz, 2H, CH2CH), 4.59 (q, Jˆ7.1 Hz, 2H, CH2CH3),
8.20 (s, 1H, H-3), 9.16 (s, 1H, H-6); 13C NMR (CDCl3) d
14.7 (CH3CH2), 22.8 (2×CH3), 30.0 (CH), 38.8 (CH2CH),
42.6 (CH2CH3), 133.8 (C-3), 146.3 (C-6), 116.6, 139.9
(C-3a and -7a), 143.5, 149.3 (C-4 and -5). Anal. calcd for
C12H14N4O2: C, 58.55; H, 5.75; N, 22.75. Found: C, 58.6; H,
5.8; N, 22.7%.
1-Ethyl-5-nitro-4-(2-thienyl)pyrazolo[3,4-b]pyridine
(5c). From azadiene 2 (200 mg, 1.2 mmol) and 2-(2-nitro-
vinyl)thiophene (3c) (374 mg, 2.4 mmol) with irradiation
at 240 W for 5 min (final temperature 110ЊC). Flash
chromatography (hexane/ethyl acetate, 4:1) gave the
pyrazolopyridine (278 mg, 84%), mp 79–80ЊC (from
Ethyl 1-ethyl-6-(4-methoxyphenyl)-4-phenylpyrazolo[3,4-
b]pyridine-5-carboxylate (16). From azadiene 1 (200 mg,
0.87 mmol) and ethyl phenylpropiolate (10) (454 mg,
2.61 mmol) with irradiation at 285 W for 15 min (final
temperature 140ЊC). Flash chromatography (hexane/ethyl
acetate, 15:1) gave pyrazolopyridine 16 as a yellow oil
1
methanol); H NMR (CDCl3) d 1.57 (t, Jˆ7.3 Hz, 3H,
CH3), 4.66 (q, Jˆ7.3 Hz, 2H, CH2), 7.24 (dd, Jˆ5.1 and
3.7 Hz, 1H, H-40 thiophene), 7.41 (dd, Jˆ3.7 and 1.2 Hz,
1H, H-30 thiophene), 7.67 (dd, Jˆ5.1 and 1.2 Hz, 1H, H-50
thiophene), 8.22 (s, 1H, H-3), 9.00 (s, 1H, H-6); 13C NMR
(CDCl3) d 14.8 (CH3), 42.7 (CH2), 128.1 (C-40 thiophene),
129.8 (C-50 thiophene), 130.1 (C-30 thiophene), 134.3 (C-3),
145.0 (C-6), 114.7, 131.9, 132.4, 139.4, 149.5 (other
carbons). MS (EI) m/z 274 (Mϩ). Anal. calcd for
C12H10N4O2S: C, 52.55; H, 3.65; N, 20.4. Found: C, 52.5;
H, 3.6; N, 20.5%.
1
(87 mg, 25%); H NMR (CDCl3) d 0.89 (t, Jˆ7.1 Hz, 3H,
CH3CH2), 1.56 (t, Jˆ7.2 Hz, 3H, CH3CH2O), 3.86 (s, 3H,
OCH3), 3.96 (q, Jˆ7.1 Hz, 2H, CH2N), 4.64 (q, Jˆ7.2 Hz,
2H, CH2O), 6.99 (d, Jˆ8.5 Hz, 2H, m-H p-CH3OC6H4),
7.48–7.53 (m, 5H, Ph), 7.67 (d, Jˆ8.5 Hz, 2H, o-H
p-CH3OC6H4), 7.90 (s, 1H, H-3); 13C NMR (CDCl3) d
13.5 (CH3CH2N), 15.0 (CH2O), 42.1 (CH3O), 55.3
(CH2N), 61.3 (CH2O), 113.3 (C-3a), 113.7 (m-C
p-CH3OC6H4), 128.4, 128.6, 128.9 (o-, m- and p-C Ph),
130.0 (o-C p-CH3OC6H4), 132.3 (C-3), 169.1 (COO),
122.3, 132.6, 135.9, 143.4, 149.2, 156.3, 160.2 (other
carbons). Anal. calcd for C24H23N3O3: C, 71.8; H, 5.8; N,
10.45. Found: C, 71.8; H, 5.8; N, 10.5%.
1-Ethyl-4,5,6,7-tetrahydropyrazolo[3,4-b]isoquinoline
(13). From azadiene 2 (200 mg, 1.2 mmol) and 1-nitro-
cyclohexene (7) (305 mg, 2.4 mmol) with irradiation
at 180 W for 10 min (final temperature 100ЊC). Flash
chromatography (hexane/ethyl acetate, 4:1) afforded the
tricyclic heterocycle 13 (97 mg, 41%), yellow oil; 1H
NMR (CDCl3), d 1.51 (t, Jˆ7.2 Hz, 3H, CH3), 1.88–1.92
(m, 4H, H-5 and -6), 2.84–2.87 (m, 2H, H-7), 2.99–3.04 (m,
2H, H-4), 4.55 (q, Jˆ7.2 Hz, 2H, CH2–CH3), 7.94 (s, 1H,
H-3), 8.28 (s, 1H, H-8); 13C NMR (CDCl3) d 15.0 (CH3),
21.9, 22.8 (C-5 and -6), 26.0, 26.1 (C-4 and -7), 42.1 (CH2–
CH3), 129.7 (C-3), 150.2 (C-8), 116.0, 125.1, 140.5 (other
carbons). Anal. calcd for C12H15N3: C, 71.6; H, 7.5; N,
20.85. Found: C, 71.55; H, 7.55; N, 20.9%.
1-Ethyl-5-methyl-1,2,5,8-tetraaza-1,4,5,6-tetrahydro-s-
indacene-4,6-dione (17). From azadiene 2 (120 mg,
0.74 mmol) and N-methylmaleimide (11) (165 mg,
1.48 mmol) with irradiation at 210 W for 15 min (final
temperature 170ЊC). Flash chromatography (hexane/ethyl
acetate, 4:1) afforded the tricyclic heterocycle 17 (143 mg,
50%), mp 143–135ЊC (from methanol); 1H NMR (CDCl3) d
1.58 (t, Jˆ7.3 Hz, 3H, CH3), 3.24 (s, 3H, NCH3), 4.67 (q,
Jˆ7.3 Hz, 2H, CH2), 8.43 (s, 1H, H-3), 8.99 (s, 1H, H-6);
13C NMR (CDCl3) d 14.7 (CH3), 24.1 (NCH3), 42.9 (CH2),
108.2 (C-3a), 120.0 (C-5), 131.3 (C-3), 134.3 (C-4), 142.6
(C-6), 152.6 (C-7a), 166.6, 167.8 (2×CO). MS (EI) m/z 230
(Mϩ). Anal. calcd for C11H10N4O2: C, 57.4; H, 4.4; N, 24.35.
Found: C, 57.4; H, 4.4; N, 24.4.
4-Cyclohexyl-1-ethyl-5-nitropyrazolo[3,4-b]pyridine
(14). From azadiene 2 (200 mg, 1.2 mmol) and 1-nitro-2-
cyclohexylethylene 34 (8) (372 mg, 2.4 mmol) with irradia-
tion at 90 W for 10 min (final temperature 130ЊC). Flash
chromatography (hexane/ethyl acetate, 9:1) gave pyrazo-
lopyridine 14 to be isolated (105 mg, 33%), mp 88–89ЊC
(from methanol); 1H NMR (CDCl3), d 1.25–1.51 (m, 3H, H
cyclohexyl), 1.55 (t, Jˆ7.1 Hz, 3H, CH3), 1.88–2.04 (m, 7H,
4-Cyano-1-ethyl-6-(4-methoxyphenyl)pyrazolo[3,4-
b]pyridine (18). From azadiene 1 (200 mg, 0.87 mmol) and
2-chloroacrylonitrile (12) (609 mg, 6.96 mmol) with
irradiation at 150 W for 20 min (final temperature 85ЊC).

´
A. Dıaz-Ortiz et al. / Tetrahedron 56 (2000) 1569–1577
1577
10. Bare, T. M.; McLaren, Ch. D.; Campbell, J. B.; Firor, J. W.;
Resch, J. F.; Walters, C. P.; Salama, A. I.; Meiners, B. A.; Patel,
J. B. J. Med. Chem. 1989, 32, 2561.
11. Sanghvi, Y. S.; Larson, S. B.; Robins, R. K.; Revankar, G. R.
J. Chem. Soc., Perkin Trans. 1 1990, 2943.
Flash chromatography (hexane/ethyl acetate, 9:1) gave
pyrazolopyridine 18 (44 mg, 20%), mp 93–94ЊC (from
1
methanol); H NMR (CDCl3) d 1.57 (t, Jˆ7.3 Hz, 3H,
CH3), 3.92 (s, 3H, OCH3), 4.62 (q, Jˆ7.3 Hz, 2H, CH2),
7.13 (d, Jˆ6.8 Hz, 2H, m-H p-CH3OC6H4), 7.74 (d,
Jˆ6.8 Hz, 2H, o-H p-CH3OC6H4), 8.11 (s, 1H, H-5), 8.77
(s, 1H, H-3); 13C NMR (CDCl3) d 14.9 (CH3), 42.6 (CH2),
55.5 (OCH3), 100.1 (C-3a), 114.2 (C-4), 114.7 (o-C
p-CH3OC6H4), 118.2 (CN), 125.8 (ipso-C), 130.7 (m-C
p-CH3OC6H4), 133.2 (C-5), 148.9 (C-7a), 149.9 (C-6),
151.9 (C-3), 161.5 (p-C p-CH3OC6H4). Anal. calcd for
C14H14ON4: C, 66.1; H, 5.55; N, 22.05. Found: C, 65.95;
H, 5.5; N, 22.05%.
12. Hasnaoui, A.; El Messaoudi, M.; Lavergne, J. P. J. Heterocycl.
Chem. 1985, 22, 25.
¨
13. Mohrle, H.; Dwuletzki, H. Chem. Ber. 1986, 119, 3591.
´
´
14. Dıaz-Ortiz, A.; Carrillo, J. R.; Gomez-Escalonilla, M. J.; de la
Hoz, A.; Moreno, A.; Prieto, P. Synlett 1998, 1069.
15. Hyperchem is a product of Autodesk Inc.
16. McCarrick, M. A.; Wu, Y.-D.; Houk, K. N. J. Org. Chem.
1993, 58, 3330.
17. Houk, K. N.; Li, Y.; Evanseck, J. D. Angew. Chem., Int. Ed.
Engl. 1992, 31, 682.
5-Cyano-1-ethylpyrazolo[3,4-b]pyridine (19). From
azadiene 2 (200 mg, 1.2 mmol) and 2-chloroacrylonitrile
(840 mg, 9.6 mmol) with irradiation at 150 W for 20 min
(final temperature 85ЊC). Flash chromatography (hexane/
ethyl acetate, 2:1) afforded the pyrazolopyridine 19
´
18. Houk, K. N.; Gonzalez, J.; Li, Y. Acc. Chem. Res. 1995, 28,
81.
19. Wiest, O.; Montiel, D. C.; Houk, K. N. J. Phys. Chem. A 1997,
101, 8378.
20. Onsager, L. J. Am. Chem. Soc. 1936, 58, 1486.
21. Wong, M. W.; Frisch, M. J.; Wiberg, K. B. J. Am. Chem. Soc.
1991, 113, 4776.
1
(79 mg, 39%), mp 93–94ЊC (from methanol); H NMR
(CDCl3) d 1.56 (t, Jˆ7.4 Hz, 3H, CH3), 4.62 (q,
Jˆ7.4 Hz, 2H, CH2), 8.15 (s, 1H, H-3), 8.41 (d, Jˆ1.9 Hz,
1H, H-4), 8.74 (d, Jˆ1.9 Hz, 1H, H-6); 13C NMR (CDCl3) d
14.8 (CH3), 42.6 (CH2), 132.9 (C-4), 135.0 (C-3), 150.2
(C-6), 102.1, 114.6, 117.7 (C-3a, -5 and CN), 136.1
(C-7a). Anal. calcd for C9H8N4: C, 62.75; H, 4.70; N,
32.55. Found: C, 62.65; H, 4.7; N, 32.5%.
22. Morao, I.; Lecea, B.; Arrieta, A.; Cossio, F. P. J. Am. Chem.
Soc. 1997, 119, 816.
23. Frisch, M. J.; Truck, G. W.; Schlegel, H. B.; Gill, P. M. W.;
Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.;
Peterson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham,
M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J. B.; Peng, C. Y.;
Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J. L.; Replogle,
E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.;
Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.;
Gonzalez, C.; Pople, J. A. Gaussian 94, Revision B.2; Gaussian
Inc.: Pittsburgh, PA, 1995.
Acknowledgements
´
Financial support by the Comision Interministerial de
´
Ciencia y Tecnologıa of Spain (DGICyT, PB97-0429) and
a grant (Junta de Comunidades de Castilla-La Mancha) are
gratefully acknowledged.
24. Binkley, J. S.; Pople, J. A.; Hehre, J. J. Am. Chem. Soc. 1980,
102, 939.
25. Hariharan, P. C.; Pople, J. A. Chem. Phys. Lett. 1972, 66, 217.
26. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1980, 37, 785.
27. Becke, A. D. Phys. Rev. A 1988, 38, 3098.
28. Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
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30. McIver, J. W.; Komornicki, A. K. J. Am. Chem. Soc. 1972, 94,
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