Reactions of 5-amino-1,2-azoles with aromatic and heterocyclic o-chloroaldehydes: [1+1] versus [2+1] cyclocondensation

Article abstract of DOI:10.1016/S0040-4020(01)00917-6

5-Amino-1,2-azoles react with aromatic and heterocyclic aldehydes, having reactive halogen in ortho-position, and yield pyrazolo[3,4-b;2,3-b]quinolines, bispyrazolo[3,4-b;4′,3′-e]pyridines and their heterocyclic analogs, respectively as [1+1] or [2+1] con

Full text of DOI:10.1016/S0040-4020(01)00917-6

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 9123±9129
Reactions of 5-amino-1,2-azoles with aromatic and heterocyclic
o-chloroaldehydes: [111] versus [211] cyclocondensation
Michael A. Abramov, Erik Ceulemans, Carine Jackers, Mark Van der Auweraer
and Wim Dehaenp
Department of Chemistry, University of Leuven, Celestijnenlaan 200F, B-3001 Leuven ꢀHeverlee), Belgium
Received 30 November 2000; revised 13 June 2001; accepted 7 September 2001
AbstractÐ5-Amino-1,2-azoles react with aromatic and heterocyclic aldehydes, having reactive halogen in ortho-position, and yield
pyrazolo[3,4-b;2,3-b]quinolines, bispyrazolo[3,4-b;40,30-e]pyridines and their heterocyclic analogs, respectively as [111] or [211] conden-
sation products. The ¯uorescent properties of the synthesized compounds are discussed. q 2001 Elsevier Science Ltd. All rights reserved.
It has been shown in the literature that anilines react at
elevated temperature with arylaldehydes yielding 4-aryl
substituted acridines as a result of [211]-condensation.1
5-Aminopyrazoles with arylaldehydes by the same way
gave 4-aryl substituted bispyrazolo[3,4-b;40,30-e]pyridines
1.2 The resulting products have antibacterial properties2a
and their large conjugated p-systems are highly ¯uorescent
and of potential use in photophysical processes and devices,
such as photo-induced transfer reactions, pyrazole-based
electroluminescent compounds and polymers.3 The reaction
is thought to occur via a bis75-aminopyrazol-4-yl)phenyl-
methane intermediate, followed by the loss of ammonia
with subsequent oxidative aromatization to the pyridine
ring3b 7Scheme 1).
is known in the literature as a synthetic method for 7fused)
quinolines from anilines.4 Here the intermediate is thought
to be an ortho-amino imine A, which undergoes thermal or
acid-catalyzed ring closure 7Scheme 2).
Joshi et al. reported on the basis of elemental analysis, IR,
1H NMR and 19F NMR spectroscopy that the reaction
product of penta¯uorobenzaldehyde and 1,3-diphenyl-5-
aminopyrazole 2e was bispyrazolo [3,4-b;40,30-e]pyridine
Table 1. Reactions of 5-amino-1,2-azoles 2a±h with penta¯uorobenzalde-
hyde
5-Amino-1,2-azole
X
R1
Product
Yield 7%)
2a
2b
2c
2d
2e
2f
NMe
NMe
NMe
NPh
NPh
O
Me
t-Bu
Ph
Me
Ph
Me
Ph
Me
3a
3b
3c
3d
3e
3f
52
74
75
80
87
53
61
58
To get access to analogs of bispyrazolo[3,4-b; 40,30-e]pyri-
dines 1 we have studied the reactions of 5-amino-1,2-azoles
2 with the very reactive penta¯uorobenzaldehyde. In this
case we found that the result was a [111]-condensation
and 1,2-azolo[3,4-b;40,30-e]tetra¯uoroquinolines 3a±h
were formed in 52±87% yield 7Table 1). Also this reaction
2g
2h
O
S
3g
3h
Scheme 1.
Keywords: pyrazoles; aldehydes; cyclization; pyridines; ¯uorescence.
Corresponding author. Tel.: 132-16-32-74-39; fax: 132-16-32-79-90; e-mail: wim.dehaen@chem.kuleuven.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00917-6

9124
M. A. Abramov et al. / Tetrahedron 57 ꢀ2001)9123±9129
Scheme 2.
Scheme 3. 7a) R1ˆR2ˆF; 7b) R1ˆCl, R2ˆNO2.
Scheme 4.
5-nitrobenzaldehyde, an additional amount 73%) of pyra-
zolo[3,4-b;2,3-b]quinoline 3i was separated. In fact, this is
the only case reported so far where the two types of products
1 and 3 are obtained from the same reaction. 5-Amino-3-
methylisoxazole 2f and -isothiazole 2h did not form the
analogs of bispyrazolo[3,4-b;40,30-e]pyridines 1 and no
de®ned products were isolated from the reaction mixture.
Apparently, the thermally labile isoxazole and isothiazole
ring systems did not survive the rather drastic reaction
conditions 7Scheme 3).
Table 2. Reactions of azoles 2c,d,f,h with heterocyclic o-chlorocarbalde-
hydes 4a±c
Azole
R1
X
Aldehyde
R2
R3
Product Yield 7%)
2d
2d
2f
Me NPh
Me NPh
4a
4b
4a
4b
4a
Me
Ph
Me
Ph
Me
Ph
Ph
5a
5b
5c
5d
5e
5f
34
36
64
87
71
25
48
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
O
O
S
2f
2h
2c
2f
NMe 4c
O
Me
2-chloro-1-phenyl-3-
indolecarbaldehyde
5g
To show the scope and limitations of the [111] conden-
sation of heterocyclic a-chloroaldehydes with amines we
have studied the reaction of 5-amino-1,2-azoles 2 with the
reactive heterocyclic 5-chloropyrazole-4-carbaldehydes
4a±c 7Scheme 4 and Table 2).5 It should be mentioned
that in the literature only one example of the [111] conden-
sation reaction of 5-chloro-3-methyl-1-phenylpyrazole-4-
carbaldehyde 4a and 5-aminopyrazole 2a to give bispyra-
zolo[3,4-b;40,30-e]pyridine 5a was found.6
1 7ArˆC6F5).2a Comparing the MS 7m/eˆ393), 1H- and 13C
NMR data of the product we obtained under their conditions
with the spectral data of compounds 3a±d, we now showed
beyond doubt that this compound was the 1,2,3,4-tetra¯uor-
opyrazolo[3,4-b; 40,30-e]quinoline 3e. Furthermore, the less
reactive o-halosubstituted benzaldehydes 2,5-di¯uoroben-
zaldehyde and 2-chloro-5-nitrobenzaldehyde yielded the
[211]-condensation products when reacted with 5-amino-
pyrazoles. From the NMR and mass spectroscopic data we
could decide that these were the symmetrical bispyra-
zolo[3,4-b;40,30-e]pyridines 1a,b. In the case of 2-chloro-
As expected, the reaction goes the same way as in the reac-
tions leading to 3a±e and only the [111]-condensation
products 5a±e form. Further examples were the tricyclic

M. A. Abramov et al. / Tetrahedron 57 ꢀ2001)9123±9129
Table 3. Selected data from absorption and emission spectra of pyridines
3a±h and 5e,f
9125
Compound
Absorptiona lmax 7nm)
Emission lmax 7nm)
7e, M21 cm21
)
7e, M21 cm21
)
Ethanol
Toluene
Ethanol
Toluene
3a
3b
3c
3d
3e
3f
3g
3h
5e
5f
38274310)
38474510)
39875720)
39573180)
40975660)
33573400)
34275230)
36373520)
34273850)
37577940)
38675220)
38674890)
40175820)
43571.00)
43471.00)
48570.73)
49570.16)
50570.47)
40870.14)
41570.11)
41870.15)
44570.08)
44070.36)
41970.79)
42170.81)
46170.74)
41574910)
49170.61)
37777260)
41970.21)
Figure 2. Absorption spectrum of a 1.08£1024 M solution of compound 3a
I toluene 7left); ¯uorescence spectrum 7excitation at 386 nm) of compound
3a in toluene 7right).
a
Range reported: 300±450 nm.
pyridine 5f, and the tetracyclic indolopyridine 5g, which
were smoothly prepared from the corresponding o-chloro-
aldehyde and 5-amino-3-methylisoxazole.
excitation is apparently not accompanied with a change in
the dihedral angle between the phenyl and the heterocycle.
While the emission spectra of the compounds 3a and 3b
with an alkyl substituent in the 3 position show a vibrational
structure in toluene the latter is blurred in compounds 3c, 3e
and 5f. In ethanol, all vibrational structures of the emission
bands disappear, indicating a difference in dipole moment
for the ground and excited state. The small bathochromic
shift observed for the emission spectra between toluene and
ethanol indicates that the excited state dipole moment is
larger than the ground state dipole moment. The difference
will however not be very large, as for solvent probes with
strongly polar excited states, shifts up to 100 or 200 nm are
observed.7±14 The small hypsochromic shift of the absorp-
tion spectra observed between toluene and ethanol can be
attributed to a decreased polarizability of the solvent.15±18
The long wavelength of absorption and emission maxima,
the high ¯uorescence quantum yield, and the independence
of the photophysical properties upon the polarity and hydro-
gen donor properties of the environment make 3c, 3e and 5f
interesting as ¯uorescent labels. The last two properties
make them potentially interesting scintillators in electro-
luminescent devices.19±21 Furthermore, the non-planarity
indicated by the structureless spectra of compounds 3c, 3e
and 5f will probably reduce the aggregation which is an
advantage to use them at high concentration in a polymer
matrix or glass.22 For a possible use as probe and/or scintil-
lator compounds 3d and 3f, 3g and 3h are less interesting
due to a shorter excitation and emission wavelength and a
lower ¯uorescence quantum yield.
All of the compounds obtained 71a,b, 3a±i, 5a±g) are
highly ¯uorescent. In Table 3 are shown the selected data
from absorption and emission spectra of fused pyridines
3a±h and 5e,f and on Fig. 1 absorption and ¯uorescence
spectra of compound 3c are drawn.
The strong ¯uorescent properties of some of the compounds
makes them interesting as potential 7electro)luminescent
dye or scintillator or ¯uorescent probe. In compounds 3
the presence of the N-alkyl or N-aryl group in the pyrazine
ring is necessary for an absorption maximum above 380 nm
and a ¯uorescent quantum yield larger than 0.3. The long
wavelength absorption band is structureless in toluene or
both solvents 7toluene, ethanol) for compounds 3c, 3e and
5f, while it shows some vibrational ®ne structure in 3a
7Fig. 2) and 3b. This may indicate that the dihedral angle
between the heterocycle and the phenyl substituents in
position 3 changes upon excitation in compounds 3c, 3e
and 5f. Besides the long wavelength absorption band of
which the data are shown in Table 3 the compounds 3
with an N-alkyl or N-aryl moiety in the pyrazole ring
show a structured absorption band below 350 nm. This
1. Experimental
Mps were determined using a Reichert Thermovar appa-
ratus. NMR spectra were acquired on commercial instru-
mentation 7Bruker Avance 300 MHz or Bruker AMX
400 MHz) and chemical shifts are reported in ppm 7d)
referenced to internal residual solvent protons 71H) or
the carbon signal of deuterated solvents 713C). Mass spectro-
metry data were obtained with a HP MS-engine 5989A
7EIˆelectron impact, 70 eV). 5-Amino-1,2-azoles were
obtained from Maybridge Chemical and benzaldehydes
Figure 1. Absorption spectrum of a 1.147£1024 M solution of compound
3c in toluene 7left); ¯uorescence spectrum 7excitation at 401 nm) of
compound 3c in toluene 7right).

9126
M. A. Abramov et al. / Tetrahedron 57 ꢀ2001)9123±9129
from Aldrich. Heterocyclic o-chlorobenzaldehydes were
synthesized by known procedures.5
71.56 g, 7.9 mmol) and 5-amino-3-methyl-1-phenyl-1H-
pyrazole 2d 72.3 g, 13.3 mmol). Yield 2.1 g 780%), mp
1
179±1808C. H NMR 7CDCl3, d, ppm): 9.04 7s, 1H, C4H),
8.44 7d, 2H, ortho-Ph) 7.55 7t, 2H, meta-Ph), 7.30 7t, 1H,
1.1. General procedure for synthesis of fused pyridines
para-Ph), 2.77 7s, 3H, CH3C3). 13C NMR 7CDCl3, d, ppm):
2
13.6 7CH3C3), 112.3 7d, C4a, JCFˆ14.3 Hz), 119.9 7ortho-
In a typical experimental procedure 30 mL of acetic acid
were added at room temperature to a mixture of 5-amino-
pyrazole 2a±h 75 mmol) and aldehyde 73 mmol) in toluene
73 mL) and p-xylene 77 mL) and re¯uxed while removing
water azeotropically. The xylene solution obtained was
re¯uxed for 6±24 h 7monitoring with TLC), and allowed
to cool to room temperature. Then, methanol 710 mL) was
added, the crystalline solid was ®ltered off and washed with
methanol. The ®ltrate was evaporated to dryness under
reduced pressure and the residue was washed with water
and dried. The precipitates were combined and the reaction
product was puri®ed by column chromatography on silica
gel.
Ph), 125.0 7C4), 127.6 7para-Ph), 129.0 7meta-Ph), 134.7
2
1
7d£m, C8a, JCFˆ14.8 Hz), 135.6 7d£m, CF, JCFˆ
251 Hz), 139.9 7C3 and ipso-Ph), 142.2 7d£m, 3£CF,
1JCFˆ251 Hz), 150.6 7C9a). Mass spectrum, m/z 7EI, %):
331 7M1, 100). Found, %: C 61.38; H 2.73; N 12.53.
C17H9F4N3. Calcd, %: C 61.64; H 2.74; N 12.68.
1.1.5.
5,6,7,8-Tetra¯uoro-1,3-diphenyl-1H-pyrazolo-
[3,4-b]quinoline 3e. From penta¯uorobenzaldehyde
70.39 g, 2mmol) and 5-amino-1,3-diphenyl-1 H-pyrazole
2e 70.94 g, 4 mmol). Yield 0.69 g 787%), mp 207±2088C.
1H NMR 7CDCl3, d, ppm): 9.11 7s, 1H, C4H), 8.56 7d, 2H,
ortho-PhN1), 8.10 7d, 2H, ortho-PhC3), 7.56 7m, 5H, meta-
PhN1, meta-PhC3, and para-PhC3), 7.34 7t, 1H, para-PhN1).
1.1.1. 5,6,7,8-Tetra¯uoro-1,3-dimethyl-1H-pyrazolo[3,4-b]-
quinoline 3a. From penta¯uorobenzaldehyde 74.2g, 21.7
mmol) and 5-amino-1,3-dimethyl-1H-pyrazole 2a 74.0 g,
2
13C NMR 7CDCl3, d, ppm): 112.2 7d, C4a, JCFˆ15 Hz),
116.9 7C3a), 120.4 7ortho-PhN1), 124.7 7C4), 126.0 7para-
PhC3 and para-PhN1), 127.5 7ortho-PhC3), 129.1 7meta-
PhN1), 129.2 7meta-PhC3), 131.6 7ipso-PhC3), 134.1 d
1
36.1 mmol). Yield 3.0 g 752%), mp 155±68C. H NMR
7CDCl3, d, ppm): 8.71 7s, 1H, C4H), 4.13 7s, 3H, CH3N1),
2.69 7s, 3H, CH3C3). 13C NMR 7CDCl3, d, ppm): 12.5
2
1
7C8a, JCFˆ15 Hz), 135.6 7d£m, CF, JCFˆ252 Hz), 139.2
7ipso-PhN1), 141.6 7d£m, 3£CF, JCFˆ252 Hz), 144.7,
2
7CH3±C3), 33.77CH3±N1), 111.27d £m, C4a, JCFˆ
2
150.3 7C9a). Mass spectrum, m/z 7EI, %): 393 7M1, 100).
Found, %: C 67.22; H 2.80; N 10.59. C22H11F4N3. Calcd, %:
C 67.18; H 2.82; N 10.68.
14.3 Hz), 117.0 7br s, C3a), 123.2 7C4), 134.7 7d, C8a,
1
2JCFˆ14.3 Hz), 135.3 7d£m, CF, JCFˆ251 Hz), 141.5
2
7C3), 141.8 7d£m, 3£CF, JCFˆ251 Hz), 150.8 7C9a). Mass
spectrum, m/z 7EI, %): 269 7M1, 100). Found, %: C 53.51; H
2.87; N 15.47. C12H7F4N3. Calcd, %: C 53.54; H 2.62; N
15.61.
1.1.6. 5,6,7,8-Tetra¯uoro-3-methyl-isoxazolo[5,4-b]quino-
line 3f. From penta¯uorobenzaldehyde 71.20 g, 6.1 mmol)
and 5-amino-3-methylisoxazole 2f 70.69 g, 7.0 mmol).
1
Yield 0.83 g 753%), mp 142±1438C. H NMR 7CDCl3, d,
1.1.2. 5,6,7,8-Tetra¯uoro-3-tert-butyl-1-methyl-1H-pyra-
zolo[3,4-b]quinoline 3b. From penta¯uorobenzaldehyde
74.0 g, 20.4 mmol) and 5-amino-3-tert-butyl-1-methyl-1H-
pyrazole 2b 75.0 g, 32.7 mmol). Yield 4.7 g 774%), mp
ppm): 8.83 7s, 1H, C4H), 2.73 7s, 3H, CH3C3). 13C NMR
2
7CDCl3, d, ppm): 12.57CH3C3), 113.6 7d, C4a, JCFˆ
2
14.4 Hz), 116.57C3a), 126.6 7C4), 135.7 7d, C8a, JCFˆ
1
1
177±1788C. H NMR 7CDCl3, d, ppm): 8.91 7s, 1H, C4H),
14.4 Hz), 137.3 7d£m, CF, JCFˆ252 Hz), 142.0 7d£m,
2
3£CF, JCFˆ252 Hz), 156.2 7C3), 167.6 7C9a). Mass
4.18 7s, 3H, CH3N1), 1.59 7s, 9H, CH3). 13C NMR 7CDCl3,
d, ppm): 30.0 7CH3C), 33.7 7CH3CC3), 34.5 7CH3N1), 110.9
spectrum, m/z 7EI, %): 256 7M1, 100). Found, %: C
51.41; H 1.58; N 10.71. C11H4F4N2O. Calcd, %: C 51.58;
H 1.57; N 10.94.
2
7d, C4a, JCFˆ15.7 Hz), 115.0 7br s, C3a), 124.8 7C4), 134.1
7d£m, C4a, 2JCFˆ15.7 Hz), 135.6 7d£m, CF, 1JCFˆ250 Hz),
1
141.7 7d£m, 3£CF, JCFˆ250 Hz), 151.2 7C9a), 152.77C3).
Mass spectrum, m/z 7EI, %): 311 7M1, 100). Found, %: C
57.74; H 4.16; N 13.45. C15H13F4N3. Calcd, %: C 57.88; H
4.21; N 13.50.
1.1.7. 5,6,7,8-Tetra¯uoro-3-phenyl-isoxazolo[5,4-b]quino-
line 3g. From penta¯uorobenzaldehyde 71.0 g, 5.1 mmol)
and 5-amino-3-methylisoxazole 2g 71.0 g, 6.25 mmol).
1
Yield 0.98 g 761%), mp 189±1908C. H NMR 7CDCl3, d,
ppm): 9.09 7s, 1H, C4H), 8.05±8.027m, 2H, meta-PhC3),
7.67±7.64 7m, 3H, ortho-PhC3 and para-PhC3). 13C NMR
7CDCl3, d, ppm): 113.6 7d, C4a, 2JCFˆ14.0 Hz), 114.5 7C3a),
127.4 7C4 and ipso-PhC3), 127.8 7ortho-PhC3), 129.6 7meta-
1.1.3. 5,6,7,8-Tetra¯uoro-1-methyl-3-phenyl-1H-pyra-
zolo[3,4-b]quinoline 3c. From penta¯uorobenzaldehyde
74.25 g, 21.7 mmol) and 5-amino-1-methyl-3-phenyl-1H-
pyrazole 2c 76.25 g, 36.1 mmol). Yield 5.4 g 775%), mp
2
PhC3), 131.6 7para-PhC3), 134.5 7m, C8a, JCFˆ14.0 Hz),
1
157±1588C. H NMR 7CDCl3, d, ppm): 9.05 7s, 1H, C4H),
1
2
137.1 7d£m, CF, JCFˆ254 Hz), 142.0 7d£m, 2£CF, JCFˆ
254 Hz), 142.7 7d£m, CF, 2JCFˆ254 Hz), 157.4 7C3), 167.7
7C9a). Mass spectrum, m/z 7EI, %): 256 7M1, 100). Found,
%: C 51.41; H 1.58; N 10.71. C11H4F4N2O. Calcd, %: C
51.58; H 1.57; N 10.94.
8.027d, 2H, ortho-Ph), 7.56 7t, 2H, meta-Ph), 7.48 7t, 1H,
para-Ph), 2.77 7s, 3H, CH3N1). 13C NMR 7CDCl3, d, ppm):
2
34.9 7CH3±N1), 112.0 7d, C4a, JCFˆ14.8 Hz), 115.27C 3a),
2
124.5 7C4), 127.1, 129.1, 129.2, 134.4 7d, C8a, JCFˆ
1
14.8 Hz), 135.9 7d£m, CF, JCFˆ253 Hz), 141.7 7d£m,
2
3£CF, JCFˆ253 Hz), 151.17C9a). Mass spectrum, m/z 7EI,
%): 331 7M1, 100). Found, %: C 61.61; H 2.76; N 12.62.
C17H9F4N3. Calcd, %: C 61.64; H 2.74; N 12.68.
1.1.8.
5,6,7,8-Tetra¯uoro-3-methyl-isothiazolo[5,4-b]-
quinoline 3h. From penta¯uorobenzaldehyde 71.20 g,
6.1 mmol) and 5-amino-3-methylisothiazole 2h hydro-
chloride 71.05 g, 7.0 mmol) and triethylamine 71 mL).
1.1.4. 5,6,7,8-Tetra¯uoro-3-methyl-1-phenyl-1H-pyra-
zolo[3,4-b]quinoline 3d. From penta¯uorobenzaldehyde
1
Yield 0.96 g 758%), mp 139±1408C. H NMR 7CDCl3, d,

M. A. Abramov et al. / Tetrahedron 57 ꢀ2001)9123±9129
9127
ppm): 8.99 7s, 1H, C4H), 2.90 7s, 3H, CH3C3). 13C NMR
phenylpyrazole 4a 70.50 g, 2.27 mmol) and 5-amino-3-
methyl-1-phenylpyrazole 2d 70.40 g, 2.27mmol). Yield
0.26 g, 34%, mp 217±2188C. H NMR 7CDCl3, d): 8.27
2
7CDCl3, d, ppm): 18.3 7CH3C3), 112.7 7d, C4a, JCFˆ
2
1
14.5 Hz), 125.6 7C4a), 127.1 7C4), 134.5 7d, C8a, JCFˆ
1
14.5 Hz), 137.4 7d£m, CF, JCFˆ255 Hz), 141.8 7d£m,
7s, 1H, C4H), 8.40 7d, 4H, ortho-PhN1 and ortho-PhN7),
7.53 7t, 4H, meta-PhN1 and meta-PhN7), 7.27 7t, 2H, meta-
PhN1 and meta-PhN7) and 2.70 7s, 6H, CH3C3 and CH3C5).
13C NMR 7CDCl3, d): 12.6 7CH3C3 and CH3C5), 114.9 7C3a),
122.8 7C4), 120.1 7meta-PhN1 and meta-PhN7), 125.1 7para-
PhN1 and para-PhN7), 129.0 7ortho-PhN1 and ortho-PhN7),
139.7 7ipso-PhN1 and ipso-PhN7), 144.1 7C3) and 150.5
7C8a). Mass spectrum, m/z 7EI, %): 340 7M11H, 100),
339 7M1, 21). HRMS: 399.1487. C21H17N5. Calcd:
339.1484.
2
3£CF, JCFˆ252 Hz), 161.8 7C3a), 172.2 7C9a). Mass
spectrum, m/z 7EI, %): 272 7M1, 100). Found, %: C
48.58; H 1.58; N 10.11. C11H4F4N2S. Calcd, %: C 48.53;
H 1.48; N 10.29.
1.1.9. 4-12,5-Di¯uorophenyl)-3,5-dimethyl-1,7-diphenyl-
1,7-dihydro-dipyrazolo[3,4-b;40,30-e]pyridine 1a. From
penta¯uorobenzaldehyde 71.0 g, 7.0 mmol) and 5-amino-
3-methyl-1-phenylpyrazole 2g 71.60 g, 9.1 mmol) and
1
triethylamine 71 mL). Yield 0.75 g 738%), mp 2778C. H
NMR 7CDCl3, d, ppm): 8.39 7d, 4H, ortho-PhN1 and
ortho-PhN7), 8.54 7t, 4H, meta-PhN1 and meta-PhN7),
7.51±7.25 7m, 3H, arom), 7.17 7t, 2H, para-PhN1 and
para-PhN7), 2.21 7s, 6H, CH3C3 and CH3C5). 13C NMR
7CDCl3, d, ppm): 14.4 7CH3C3 and CH3C5), 113.4 7C3a
1.1.12. 3-Methyl-1,5,7-triphenyl-1,7-dihydro-dipyrazolo-
[3,4-b;40,30-e]pyridine 5b. From 5-chloro-1,3-diphenyl-
1H-pyrazole 4b 70.50 g, 1.77 mmol) and 5-amino-3-methyl-
1-phenylpyrazole 2d 70.30 g, 1.77 mmol). Yield 0.25 g,
1
36%, mp 209±2108C. H NMR 7CDCl3, d): 8.49 7s, 1H,
2
3
and C4a), 116.9±118.1 7m, JCFˆ14 Hz, JCFˆ8 Hz, ortho-
C4H), 8.45 and 8.36 72£d, 4H, ortho-PhN1 and ortho-
PhN7), 7.56±7.47 7m, 7H, meta-PhN1 and meta-PhN7,
meta-PhC5, para-PhC5), 7.31±7.23 72 t, 2H, para-PhN1
and para-PhN7), 8.01 7d, 2H, ortho-PhC5), and 2.65 7s,
3H, CH3C3). 13C NMR 7CDCl3, d): 12.6 7CH3C3), 113.0
7C4H), 115.6 7C3a), 123.8 7C4a), 119.9, 120.5, 125.0,
125.5, 127.5, 128.9, 129.0 and 128.92 7Ph), 139.62 and
139.64 7ipso-PhN1 and ipso-PhN7), 132.5 7ipso-PhC5),
1
CFarom), 118.8 7d, JCFˆ240 Hz, ipso-CFarom), 120.3 7meta-
PhN1 and meta-PhN7), 121.6 7d, 1JCFˆ240 Hz, ipso-CFarom),
125.3 7para-PhN1 and para-PhN7), 128.9 7ortho-PhN1 and
ortho-PhN7), 132.5 and 139.5 7C4, ipso-PhN1 and ipso-
PhN7), 143.7 7C3 and C5), 150.5 7C7a and C8a). Mass
spectrum, m/z 7EI, %): 272 7M1, 100). Found, %: C
48.58; H 1.58; N 10.11. C11H4F4N2S. Calcd, %: C 48.53;
H 1.48; N 10.29.
3
144.27C ), 145.4 7C5), 150.1 7C8a), and 150.7 7C7a). Mass
spectrum, m/z 7EI, %): 4027M 11H, 100), 401 7M1, 25).
HRMS: 401.1651. C26H19N5. Calcd: 401.1640.
1.1.10. 4-12-Chloro-5-nitrophenyl)-3,5-dimethyl-1,7-di-
phenyl-1,7-dihydro-dipyrazolo[3,4-b;40,30-e]pyridine 1b
and 3-methyl-6-nitro-1-phenyl-1H-pyrazolo[3,4-b]quino-
line 3i. From 2-chloro-5-nitrobenzaldehyde 71.0 g, 5.4
mmol) and 5-amino-3-methyl-1-phenyl-1H-pyrazole 2d
71.0 g, 5.8 mmol). After column chromatography a mixture
of two compounds was obtained. This mixture was
suspended in chloroform 73 mL), the suspension was ®ltered
and precipitate was washed again with chloroform 71 mL).
The ®ltrates were evaporated under reduced pressure and
4-72-chloro-5-nitrophenyl)-3,5-dimethyl-1,7-diphenyl-1,7-
dihydro-dipyrazolo[3,4-b;40,30-e]pyridine 70.56 g, 39%)
1.1.13. 3,5-Dimethyl-7-phenyl-1H-pyrazolo[40,30-b;5,4-e]-
isoxazolopyridine 5c. From 5-chloro-3-methyl-1-phenyl-
1H-pyrazole-4-carbaldehyde 4a 70.20 g, 0.91 mmol) and
5-amino-3-methyl-isoxazole 2f 70.09 g, 0.91 mmol). Yield
1
0.15 g, 64%, mp 1938C. H NMR 7CDCl3, d): 8.27 7d, 2H,
ortho-PhN7), 8.19 7s, 1H, C4H), 7.51 7d, 2H, meta-PhN7),
7.29 7t, 1H, para-PhN7), 2.64 7s, 3H, CH3C5) and 2.59 7s,
3H, CH3C3). 13C NMR 7CDCl3, d): 10.7 7CH3C3), 12.5
7CH3C5), 110.1 7C3), 116.0 7C4a), 120.6 7ortho-PhN7),
124.4 7C4), 125.8 7para-PhN7), 129.0 7meta-PhN7), 139.0
7ipso-PhN7), 144.1 7C5), 150.5 7C7a), 156.1 7C5), and 168.9
7C8a). Mass spectrum, m/z 7EI, %): 264 7M1, 100). HRMS:
264.1013. C15H12N4O. Calcd: 264.1011.
1
was isolated as crystals with mp 2158C. H NMR 7CDCl3,
d, ppm): 8.47 7s, 1H, ortho-NO2), 8.35±8.43 7m, 5H, arom),
7.80 7d, 1H, ortho-NO2), 7.527t, 4H, meta-PhN1 and meta-
PhN7), 7.29 7t, 2H, para-PhN1 and para-PhN7), 2.00 7s, 6H,
CH3C3 and CH3C5). 13C NMR 7CDCl3, d, ppm): 14.1
7CH3C3 and CH3C5), 112.8 7C3a and C4a), 120.1 7meta-
PhN1 and meta-PhN7), 125.3 7para-PhN1 and para-PhN7),
125.5, 128.9 7ortho-PhN1 and ortho-PhN7), 130.6, 134.1,
1.1.14. 3-Methyl-5,7-diphenyl-1H-pyrazolo[40,30-b;5,4-e]-
isoxazolopyridine 5d. From 5-chloro-1,3-diphenyl-1H-
pyrazole-4-carbaldehyde 4b 70.21 mg, 0.75 mmol) and
5-amino-3-methylisoxazole 2f 773 mg, 0.74 mmol). Yield
4
1
135.0, 139.3 7ipso-PhN1 and ipso-PhN7), 140.27C ), 143.1
214 mg, 87%, mp 208±2098C. H NMR 7CDCl3, d): 8.55
7C3 and C5), 146.1, 150.3 7C7a and C8a). Mass spectrum, m/z
7EI, %): 494 7M1, 100). Found, %: C 65.65; H 3.92; N
16.67. C27H19ClN6O2. Calcd, %: C 65.52; H 3.87; N
16.98. The precipitate from the chloroform suspension
77 mg) was identi®ed as 3-methyl-6-nitro-1-phenyl-1H-
7s, 1H, C4H), 8.36 7d, 2H ortho-PhN7), 8.00 7d, 2H ortho-
PhC5), 7.58±7.49 7m, 5H, Ph), 7.35±7.327t, 1H, para-
PhCN7) and 2.65 7s, 3H, CH3). 13C NMR 7100 MHz,
CDCl3, d): 10.9 7CH3C3), 111.1 7C3a), 114.3 7C4a), 121.2
7ortho-PhN7), 125.6 7C4H), 126.3 7para-PhN7), 127.6,
129.1 and 129.3 7Ph), 132.0 7ipso-PhC5), 138.9 7ipso-
PhN7), 145.7 7C4a), 151.1 7C7a), 156.27C 3), and 168.7
7C8a). Mass spectrum, m/z 7EI, %): 327 7M1, 100). Found,
%: C 73.4; H 4.6. C20H15N4O. Calcd: C 73.42; H 4.41.
1
pyrazolo[3,4-b]quinoline. H NMR 7CDCl3, d, ppm): 9.00
7s, 1H, C4H), 8.75 7s, 1H, ortho-NO2), 8.55±8.34 7m, 3H,
arom), 8.25 7d, 1H, ortho-NO2), 7.57 7m, 2H, meta-PhN1),
7.327t, 1H, para-PhN1), 2.80 7s, 3H, CH3C3). Mass
spectrum, m/z 7EI, %): 304 7M1, 100).
1.1.15. 3,5-Dimethyl-7-phenyl-1H-pyrazolo[40,30-b;5,4-e]-
isothiazolopyridine 5e. From 5-chloro-3-methyl-1-phenyl-
1H-pyrazole-1-4-carbaldehyde 4a 70.66 g, 3 mmol) and
1.1.11. 3,5-Dimethyl-1,7-diphenyl-1,7-dihydro-dipyra-
zolo[3,4-b;40,30-e]pyridine 5a. From 4-chloro-3-methyl-1-

9128
M. A. Abramov et al. / Tetrahedron 57 ꢀ2001)9123±9129
5-amino-3-methyl-isothiazole 2h hydrochloride 70.75 g,
5 mmol) and triethylamine 70.6 g). Yield 0.6 g 771%), mp
Acknowledgements
1
4
157±1598C. H NMR 7CDCl3, d, ppm): 8.427s, 1H, C H),
8.327d, 2H, ortho-PhN7), 7.527t, 2H, meta-PhN7) 7.29 7t,
1H, para-PhN7), 2.70 7s, 3H, CH3C3), 2.67 7s, 3H, CH3C5).
13C NMR 7CDCl3, d, ppm): 12.5 7CH3C5), 18.0 7CH3±C3),
115.9 7C4a), 120.4 7ortho-PhN7), 124.7 7C4), 125.6 7para-
PhN7), 129.0 7meta-PhN7), 139.0 7ipso-PhN7), 144.1 7C5a),
150.4 7C7a), 161.9 7C3a), and 172.5 7C8a). Mass spectrum,
m/z 7EI, %): 280 7M1, 100). Found, %: C 63.82; H 4.40; N
19.46. C15H12N4S. Calcd, %: C 64.26; H 4.31; N 19.98.
We thank the Ministerie voor Wetenschapsbeleid 7IUAP IV/
11), the FWO-Vlaanderen and the Katholieke Universiteit
Leuven for their ®nancial support.
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1
6 mmol). Yield 0.25 g 725%), mp 185±1868C. H NMR
7CDCl3, d, ppm): 8.86 7s, 1H, C4H), 7.96 7d, 4H, ortho-
PhC3 and ortho-PhC5), 7.54 7t, 4H, meta-PhC3 and meta-
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CH3N1 and CH3N7). 13C NMR 7CDCl3, d, ppm): 33.9
7CH3N1), 112.1 7C3a and C4a), 124.6 7C4), 127.3 7ortho-
PhC3 and ortho-PhC5), 128.5 7para-PhC3 and para-PhC5),
129.0 7meta-PhC3 and meta-PhC5), 133.1 7ipso-PhC3 and
ipso-PhC5), 144.0 7C3 and C5), 152.0 7C7a and C8a). Mass
spectrum, m/z 7EI, %): 339 7M1, 100). Found, %: C 74.13; H
5.14; N 20.47. C21H17N5. Calcd, %: C 74.32; H 5.05; N
20.63.
1.1.17. 3-Methyl-9-phenyl-1H-indolo[20,30-b;5,4-e]isoxa-
zolopyridine 5g. From 2-chloro-1-phenyl-1H-indole-3-
carbaldehyde 70.51 g, 2.0 mmol) and 5-amino-3-methyl-
isoxazole 2f 70.20 g, 2.0 mmol). Yield 285 mg, 48%, mp
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1
1978C. H NMR 7CDCl3, d): 8.58 7s, 1H, C4H) 8.15±8.13
7d, 1H, C5H, indole), 7.63 and 7.49 72£m, 7H, PhN9, C6H
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8a
PhN7), 135.4 and 141.27C and ipso-PhN7), 153.27C 9a),
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299 7M1, 100).
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