Efficient microwave-assisted synthesis of tetrahydroindazoles and their oxidation to indazoles

Article abstract of DOI:10.1055/s-2006-939715

N-Acetyl-styrylpyrazoles undergo Diels-Alder cycloaddition reactions with N-methylmaleimide under solvent-free conditions to give the corresponding tetrahydroindazoles in good yields and high selectivity. On heating, these reactions do not occur or afford

Full text of DOI:10.1055/s-2006-939715

LETTER
1369
Efficient Microwave-Assisted Synthesis of Tetrahydroindazoles and their
Oxidation to Indazoles
M
icrowave-Assist
e
e
d
Synthesi
r
s of Tetr
a
ahydroindazoles L. M. Silva, Artur M. S. Silva,* Diana C. G. A. Pinto, José A. S. Cavaleiro
Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: arturs@dq.ua.pt
Received 10 February 2006
4
4
5
5
3a
Abstract: N-Acetyl-styrylpyrazoles undergo Diels–Alder cyclo-
addition reactions with N-methylmaleimide under solvent-free con-
ditions to give the corresponding tetrahydroindazoles in good yields
3a
3
3
6
6
2
N
N
H
7a
7a
7
7
2
N
N1
1
H
and high selectivity. On heating, these reactions do not occur or
1H-indazole (1)
2H-indazole (2)
afford only traces of the cycloadducts. The stereochemistry of
obtained cycloadducts was assigned by NMR. Oxidation of the
tetrahydroindazoles with DDQ gave the expected indazoles and was
accompanied by N-deacylation.
Figure 1 Structure of 1H- and 2H-indazoles.
Key words: 4-styrylpyrazoles, Diels–Alder cycloadditions, micro-
wave irradiation, N-methylmaleimide, indazoles, dehydrogenation
tion of the cycloadducts thus obtained (Scheme 1). This
work led us to develop a novel and rapid method for the
synthesis of new classes of indazoles.
Although vinylpyrazole derivatives are very reluctant to
participate as dienes in cycloaddition reactions involving
the pyrazole ring, owing to the loss of its aromaticity in
the reaction,1b,12 we decided to study the reactivity of
styrylpyrazoles as dienes under classical heating condi-
tions or microwave irradiation following our ongoing
work with this type of compounds.15 The reaction of (E)-
5(3)-(2-hydroxyphenyl)-3(5)-styrylpyrazole (1a) with N-
methylmaleimide in refluxing 1,2,4-trichlorobenzene did
not afford the expected cycloadducts but yielded com-
pounds 1d16 resulting from a conjugate addition of the
pyrazole nitrogen to N-methylmaleimide (Figure 2). All
attempts to react (E)-3-(2-hydroxyphenyl)-1-methy-5-
styrylpyrazole (1b)17 with electron-rich or electron-poor
dienophiles in refluxing 1,2,4-trichlorobenzene were un-
successful. Following our work on microwave-assisted
reactions,18 we made several attempts to react (E)-3-(2-
hydroxyphenyl)-1-methyl-5-styrylpyrazole (1b) with N-
methylmaleimide under microwave irradiation, using sol-
vent or solvent-free conditions, different radiation power
and reaction time, but in all cases the starting pyrazole 1b
was recovered and no new products were detected. Our
next attempt was to study the reaction of (E)-1-acetyl-3-
(2-hydroxyphenyl)-5-styrylpyrazole19 (1c) with N-meth-
ylmaleimide under microwave irradiation, expecting that
a deactivating group would facilitate the Diels–Alder re-
action. This resulted in less than 20% of the (E)-1-acetyl-
3-(2-hydroxyphenyl)-5-styrylpyrazole (1c) being recov-
ered and (E)-3-(2-hydroxyphenyl)-5-styrylpyrazole (1a,
9%) could also be detected. Traces of the compound 1d16
obtained from the conjugate addition of the pyrazole
nitrogen of 1a to N-methylmaleimide and of the desired
cycloadduct 2c were observed (Figure 2). The structure of
the latter was supported by the absence of the double bond
and H-4 of the pyrazole ring and the presence of aliphatic
protons, characteristics of a newly formed cyclohexane
ring in the 1H NMR spectrum.
The indazole nucleus is an important pharmaceutical
structure and constitutes the key moiety of many drugs
with a broad range of pharmacological activities.1 Their
wide variety of applications in medicinal chemistry can be
illustrated by their use as pharmaceutical agents in fields
such as CNS disorders (e.g., granisetron),2 anti-inflamma-
tory (e.g., bendazac and benzydamine)2,3 and antimicrobi-
al agents,4 anti-HIV protease inhibition,5 anti-tumour6 and
nitric oxide synthase inhibitors7,8 and binding affinity of
non-steroidal progesterone receptor.9 Structural modifica-
tions of the anti-inflammatory agent bendazac have been
carried out and, in some cases, the synthesised compounds
showed analgesic effects along with anti-inflammatory
properties.10
There are several methods for the synthesis of inda-
zoles;1,11 most of them start from benzene derivatives,
where the pyrazole ring is formed by ring closure. The
major part of indazole ring-closure procedures involves
creating a bond between the two nitrogen atoms (N–N) as
the last step; nevertheless the ring closure by creation of a
N–C bond through the formation of N2–C3 or N1–C7a
bond is also common (according to the numbering of 1H-
indazole 1, Figure 1). A few examples involving a C3–
C3a ring closure are also reported. There are also some
examples starting from pyrazoles, involving the cyclo-
addition reactions of 1-phenyl-5-vinylpyrazole,12 1-aryl-
3-phenyl-1,6-dihydropyrano[2,3-c]pyrazoles13 and N-
unsubstituted pyrazole ortho-quinodimethanes14 with
several dienophiles. As part of our continuing work on
the synthesis and transformation of styrylpyrazoles,15
we have investigated the Diels–Alder reaction of 4-
styrylpyrazoles with N-methylmaleimide and the oxida-
SYNLETT 2006, No. 9, pp 1369–1373
0
1.
0
6.
2
0
0
6
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-939715; Art ID: D04006ST
© Georg Thieme Verlag Stuttgart · New York

1370
V. L. M. Silva et al.
LETTER
Table 1 Main Results Obtained from NOESY Spectra of Adducts
8a–d
Protons
H-5a
NOE cross-peaks with
H-8a and H-2¢¢,6¢¢
H-2¢¢,6¢¢
OH
N
OH
N
N
N
O
R
1a R = H
1b R = CH3
1c R = COCH3
N
H3C
1d
H-8a
CH3
O
N
O
O
Table 2 Main Results Obtained from NOESY Spectra of Adducts
7a–d
OH
N
N
Protons
H-5
NOE cross-peaks with
H-4 and H-8b
H-8b
COCH3
2c
Figure 2 Structures of 3-(2-hydroxyphenyl)-5-styrylpyrazoles
1a–d and cycloadduct 2c.
H-5a
H-8a
H-5a
As part of our ongoing research into the synthesis and
transformation of (E and Z)-3-styrylchromones we syn-
thesised several (E and Z)-3(5)-(2-hydroxyphenyl)-4-
styrylpyrazoles 3a–d and 4a–c,20 which were acetylated cycloadduct structures 7a–d and 8a–c.24,25 The cis-config-
with acetyl chloride in dry pyridine yielding in each case uration of protons H-5, H-5a, H-8a and H-8b in adducts
the corresponding (E and Z)-1-acetyl-3-(2-hydroxyphen- 7a–d and of protons H-5a, H-8a and H-8b in adducts
yl)-4-styrylpyrazoles 5a–d and 6a–c (Scheme 1).21,22 8a–c, was confirmed by NOE cross-peaks observed in
The mixture of each one of the 1-acetyl-4-styrylpyrazoles their NOESY spectra (Table 1 and Table 2) and was also
5a–d or 6a–c with N-methylmaleimide was submitted to supported by a detailed analysis of the coupling constants
microwave irradiation in solvent free conditions23 and the
desired cycloadducts 7a–d or 8a–c were obtained in mod-
erate to very good yields (7a–d, 68–95%; 8a–c, 32–54%).
The NMR spectroscopic characteristics of the products in
of some protons (JH8a–H8b ca. 7–8 Hz for both isomers;
J
H5–H5a ca. 8 Hz for 7a–d; JH5–H5a ca. 0 Hz for 8a–c). These
data indicate that the reaction selectively afforded the
endo adduct in both cases. No traces of the exo adduct
both cases are: (i) the presence of the hydroxyl group in- were detected.
volved in a hydrogen bond (dH ca. 10 ppm); (ii) the ab-
In order to determine the scope of this reaction and its
sence of double bonds; (iii) the presence of the acetyl
group noticed, in the 13C NMR spectra, by the signal cor-
responding to the carbonyl group (dC ca. 168 ppm); (iv)
the presence of an N-methyl group (dH ca. 2.5 ppm; dC ca.
22 ppm); (v) the presence of several signals in the aliphat-
ic region of the 1H NMR due to the newly formed cyclo-
hexene ring. These data are consistent with the proposed
utility as a new synthetic methodology to synthesise novel
indazole type-compounds, we extended our study to the
cycloadduct oxidation following our recently published
methodology using DDQ as an oxidant and microwave
irradiation as an alternative to conventional heating
(Scheme 1).18 Some of the 1-acetyl-3-(2-hydroxyphenyl)-
R
R
R
O
H
O
R
4''
5''
N
3''
CH3
6''
N
H
β
B
OH
N
H
2''
C
5'
5
O
4
COCH3
α
E-isomers
6'
5a
8a
6
4'
3'
A
7a–d
4
R
3
3a
N7
8
3
5
CH3
2'
N
N
8b
OH
N
OH
NH
N
Z-isomers
OH
NH
2
1
2
C
COCH3
O
1
B
E-isomers 3a–d
Z-isomers 4a–c
E-isomers 5a–d
Z-isomers 6a–c
9a–d
O
H
N
a R = H
b R = Cl
c R = OC2H5
d R = NO2
CH3
N
H
OH
N
H
O
COCH3
8a–c
Scheme 1 Reagents and conditions: (A) dry pyridine, CH3COCl, r.t.; (B) N-methylmaleimide (6 equiv), MW 800 W, 40 min; (C) 1,2,4-tri-
chlorobenzene, DDQ, MW 800 W, 30 min.
Synlett 2006, No. 9, 1369–1373 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Synthesis of Tetrahydroindazoles
1371
(6) Keppler, B. K.; Hartmann, M. Met.-Based Drugs 1994, 1,
145.
7-methy-5-phenyl-6,8-dioxopyrrolo[3,4-g]-5,5a,8a,8b-
tetrahydroindazoles 7a,b,d and 8c were oxidised26 and 3-
(2-hydroxyphenyl)-7-methyl-5-phenyl-6,8-dioxopyrro-
lo[3,4-g]indazoles 9a–d27 were the obtained products.
These results indicate that the oxidation was accompanied
by N-deacylation.28
(7) (a) Bland-Ward, P. A.; Moore, P. K. Life Sci. 1995, 57, 131.
(b) Mamiya, T.; Noda, Y.; Noda, A.; Hiramatsu, M.;
Karasawa, K.; Kameyama, T.; Furukawa, S.; Yamada, K.;
Nabeshima, T. Neuropharmacology 2000, 39, 2391.
(c) Schumann, P.; Collot, V.; Hommet, Y.; Gsell, W.;
Dauphin, F.; Sopkova, J.; MacKenzie, E. T.; Duval, D.;
Boulouard, M.; Rault, S. Bioorg. Med. Chem. Lett. 2001, 11,
1153.
(8) Raman, C. S.; Li, H.; Martásek, P.; Southan, G.; Masters, B.
S. S.; Poulos, T. L. Biochemistry 2001, 40, 13448.
(9) Connolly, P. J.; Wetter, S. K.; Beers, K. N.; Hamel, S. C.;
Haynes-Johnson, D.; Kiddoe, M.; Kraft, P.; Lai, M. T.;
Campen, C.; Palmer, S.; Phillips, A. Bioorg. Med. Chem.
Lett. 1997, 7, 2551.
(10) Mosti, L.; Menozzi, G.; Fossa, P.; Schenone, P.; Lampa, E.;
Parrillo, C.; Damico, M.; Rossi, F. Il Farmaco 1992, 47, 567.
(11) (a) Behr, L. C.; Fusco, R.; Jarboe, C. H. Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles and Condensed
Rings; Wiley, R. H., Ed.; Interscience Publishers: New
York, 1967. (b) Baiocchi, L.; Corsi, G.; Palazzo, G.
Synthesis 1978, 633.
In conclusion we have established a new efficient method-
ology for the synthesis of novel indazole-type com-
pounds. Our first results indicate that the (Z)-1-acetyl-3-
(2-hydroxyphenyl)-4-styrylpyrazoles 8a–c were less
reactive than the (E)-1-acetyl-3-(2-hydroxyphenyl)-4-
styrylpyrazoles 7a–d, probably due to the steric hindrance
caused by the phenyl ring at the b-position. We can also
conclude that electron-withdrawing substituents on the
para-position of the styryl group increase the reactivity of
the pyrazoles,23 therefore compound 7d is obtained in bet-
ter yield (95%). The Diels–Alder cycloadditions de-
scribed herein were stereoselective and gave the expected
endo-cycloadducts, which can be aromatised to indazole-
type compounds.
(12) (a) Medio-Simón, M.; Laviada, M. J. A.; Sepúlveda-Arques,
J. J. Chem. Soc., Perkin Trans. 1 1990, 2749.
Some aspects of this reaction are currently under active
investigation in our laboratory and results will be pub-
lished in due course.
(b) Sepúlveda-Arques, J.; Abarca-González, B.; Medio-
Simón, M. Adv. Heterocycl. Chem. 1995, 63, 339.
(13) Matsugo, S.; Takamizawa, A. Synthesis 1983, 852.
(14) Tomé, A. C.; Cavaleiro, J. A. S.; Storr, R. C. Synlett 1996,
531.
Acknowledgment
(15) (a) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.
Heterocycl. Commun. 1997, 3, 433. (b) Pinto, D. C. G. A.;
Silva, A. M. S.; Cavaleiro, J. A. S.; Foces-Foces, C.; Llamas-
Sainz, A. L.; Jagerovic, N.; Elguero, J. Tetrahedron 1999,
55, 10187. (c) Pinto, D. C. G. A.; Silva, A. M. S.; Lévai, A.;
Cavaleiro, J. A. S.; Patonay, T.; Elguero, J. Eur. J. Org.
Chem. 2000, 2593. (d) Pinto, D. C. G. A.; Silva, A. M. S.;
Cavaleiro, J. A. S. J. Heterocycl. Chem. 2000, 37, 1629.
(e) Lévai, A.; Patonay, T.; Silva, A. M. S.; Pinto, D. C. G.
A.; Cavaleiro, J. A. S. J. Heterocycl. Chem. 2002, 39, 751.
(f) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.;
Cavaleiro, J. A. S.; Elguero, J. Eur. J. Org. Chem. 2004,
4348.
Thanks are due to the University of Aveiro, ‘Fundação para a
Ciência e a Tecnologia’ and FEDER for funding the Organic
Chemistry Research Unit. V.L.M.S. is also thankful to FCT for her
fellowship (SFRH/BD/6647/2001).
References and Notes
(1) (a) Elguero, J. Pyrazoles and their Benzo Derivatives, In
Comprehensive Heterocyclic Chemistry, Vol. 5; Potts, K. T.;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984, 167–303. (b) Elguero, J. Pyrazoles, In
Comprehensive Heterocyclic Chemistry II, Vol. 3; Shinkai,
I.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 1–75.
(16) Physical Data of (E)-1-(1-Methyl-2,5-dioxo-3-pyrrol-
idinyl)-5-styryl-3-(2-hydroxyphenyl)pyrazole (1d).
Mp 234–236 °C. 1H NMR (300.13 MHz, CDCl3): d = 3.13
(s, 3 H, NCH3), 3.30 (dd, 1 H, J = 18.3, 9.1 Hz, 4¢¢¢-CH2),
3.45 (dd, 1 H, J = 18.3, 5.2 Hz, 4¢¢¢-CH2), 5.46 (dd, 1 H, J =
9.1, 5.2 Hz, 3¢¢¢-CH), 6.90 (s, 1 H, H-4), 6.96 (ddd, 1 H, J =
7.7, 7.3, 1.2 Hz, H-5¢), 7.00 (dd, 1 H, J = 8.4, 1.2 Hz, H-3¢),
7.01 (d, 1 H, J = 15.8 Hz, H-a), 7.22–7.27 (m, 1 H, H-4¢),
7.26 (d, 1 H, J = 15.8 Hz, H-b), 7.35–7.44 (m, 3 H, H-
3¢¢,5¢¢,4¢¢), 7.53 (dd, 2 H, J = 8.1, 1.5 Hz, H-2¢¢,6¢¢), 7.59 (dd,
1 H, J = 7.7, 1.7 Hz, H-6¢), 10.03 (s, 1 H, 2¢-OH). 13C NMR
(75.47 MHz, CDCl3): d = 25.5 (NCH3), 34.8 (4¢¢¢-CH2), 55.6
(3¢¢¢-CH), 100.8 (C-4), 112.6 (C-a), 115.8 (C-1¢), 117.1
(C-3¢), 119.5 (C-5¢), 126.6 (C-6¢), 126.9 (C-2¢¢,6¢¢), 128.9
(C-3¢¢,5¢¢), 129.1 (C-4¢¢), 129.9 (C-4¢), 135.6 (C-1¢¢), 136.1
(C-b), 143.9 (C-5), 152.5 (C-3), 155.7 (C-2¢), 173.3 (2¢¢¢-
C=O), 172.5 (5¢¢¢-C=O). MS (EI): m/z (rel. int.) = 374 (30),
373 (100) [M+•], 372 (25), 262 (39), 261 (67), 231 (11), 202
(10), 155 (5), 128 (6), 115 (16), 91 (29), 77 (9), 65 (9).
(17) Physical Data of (E)-3-(2-Hydroxyphenyl)-1-methyl-5-
styrylpyrazole (1b).
(2) O’Neil, M. J.; Smith, A. The 13th Merck Index; Merck
Research Laboratories Division of Merck & Co. Inc.:
Whitehouse Station, New York, 2001.
(3) (a) Bistocchi, G. A.; De Meo, G.; Pedini, M.; Ricci, A.;
Brouilhet, H.; Bucherie, S.; Rabaud, M.; Jacquignon, P.
Farmaco Ed. Sci. 1981, 36, 315. (b) Picciola, G.; Ravenna,
F.; Carenini, G.; Gentili, P.; Riva, M. Farmaco Ed. Sci.
1981, 36, 1037. (c) Mosti, L.; Sansebastiano, L.; Fossa, P.;
Schenone, P.; Mattioli, F. Il Farmaco 1992, 47, 357.
(d) Gordon, D. W. Synlett 1998, 1065. (e) Schindler, R.;
Hoefgen, N.; Heinecke, K.; Poppe, H.; Szelenyi, I.
Pharmazie 2000, 55, 857.
(4) (a) Lóránd, T.; Kocsis, B.; Emôdy, L.; Sohár, P. Eur. J. Med.
Chem. 1999, 1009. (b) Stefańska, J. Z.; Gralewska, R.;
Starościak, B. J.; Kazimierczuk, Z. Pharmazie 1999, 54,
879.
(5) (a) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.;
Nugiel, D. A. J. Org. Chem. 1997, 62, 5627. (b) Rodgers, J.
D.; Jonhson, B. L.; Wang, H.; Greenberg, R. A.; Erickson-
Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner, M. M.;
Lam, G. N.; Chang, C.-H. Bioorg. Med. Chem. Lett. 1996, 6,
2919.
Mp 159–161 °C. 1H NMR (300.13 MHz, CDCl3): d = 3.92
(s, 3 H, 1-CH3), 6.81 (s, 1 H, H-4), 6.89 (ddd, 1 H, J = 7.9,
7.3, 1.1 Hz, H-5¢), 6.91 (d, 1 H, J = 16.2 Hz, H-a), 7.02 (dd,
Synlett 2006, No. 9, 1369–1373 © Thieme Stuttgart · New York

1372
V. L. M. Silva et al.
LETTER
1 H, J = 8.0, 1.1 Hz, H-3¢), 7.13 (d, 1 H, J = 16.2 Hz, H-b),
7.21 (ddd, 1 H, J = 8.0, 7.3, 1.6 Hz, H-4¢), 7.32 (dd, 2 H, J =
7.6, 6.8 Hz, H-3¢¢,5¢¢), 7.39 (tt, 1 H, J = 7.6, 1.6 Hz, H-4¢¢),
7.51 (dd, 2 H, J = 6.8, 1.6 Hz, H-2¢¢,6¢¢), 7.57 (dd, 1 H, J =
7.9, 1.6 Hz, H-6¢), 10.82 (s, 1 H, 2¢-OH). 13C NMR (75.47
MHz, CDCl3): d = 36.6 (1-CH3), 98.9 (C-4), 113.7 (C-a),
116.5 (C-1¢), 117.0 (C-3¢), 119.2 (C-5¢), 126.1 (C-6¢), 126.7
(C-2¢¢,6¢¢), 128.6 (C-4¢¢), 128.8 (C-3¢¢,5¢¢), 129.0 (C-4¢),
133.5 (C-b), 136.0 (C-1¢¢), 141.8 (C-5), 150.2 (C-3), 155.8
(C-2¢). MS (EI): m/z (rel. int.) = 276 (100) [M+•], 275 (20),
231 (5), 202 (7), 185 (10), 144 (14), 128 (10), 115 (20), 102
(8), 91 (11), 77 (15). Anal. Calcd for C18H16N2O: C, 78.24;
H, 5.84; N, 10.14. Found:C, 77.84; H, 5.79; N, 10.02.
185 (20), 171 (100), 149 (5), 115 (14), 102 (6), 77 (4). Anal.
Calcd for C19H15ClN2O2: C, 67.36; H, 4.46; N, 8.27. Found:
C, 67.48; H, 4.73; N, 8.30.
(22) Physical Data of (Z)-1-Acetyl-4-(4-chlorostyryl)-3-(2-
hydroxyphenyl)pyrazole (6b).
Mp 141.8–143.6 °C. 1H NMR (300.13 MHz, CDCl3):
d = 2.72 (s, 3 H, 1-COCH3), 6.50 (dd, 1 H, J = 11.9, 1.1Hz,
H-a), 6.75 (d, 1 H, J = 11.9 Hz, H-b), 6.95 (ddd, 1 H, J = 7.2,
7.9, 1.2 Hz, H-5¢), 7.09 (dd, 1 H, J = 8.3, 1.2 Hz, H-3¢), 7.17–
7.23 (m, 4 H, H-2¢¢,3¢¢,5¢¢,6¢¢), 7.33 (ddd, 1 H, J = 7.2, 8.3, 1.6
Hz, H-4¢), 7.87 (dd, 1 H, J = 7.9, 1.6 Hz, H-6¢), 8.00 (d, 1 H,
J = 1.1 Hz, H-5), 10.23 (s, 1 H, 2¢-OH). 13C NMR (75.47
MHz, CDCl3): d = 21.6 (1-COCH3), 115.7 (C-1¢), 117.3 (C-
3¢), 119.6 (C-5¢), 119.9 (C-a), 120.0 (C-4), 127.6 (C-5),
128.5 (C-6¢), 128.7 (C-2¢¢,6¢¢), 129.8 (C-3¢¢,5¢¢), 131.0 (C-4¢),
132.4 (C-b), 133.5 (C-4¢¢), 134.4 (C-1¢¢), 153.1 (C-3), 156.3
(C-2¢), 167.8 (C=O). MS (EI): m/z (rel. int.) = 340 (31) [M+•,
37Cl], 338 (69) [M+•, 35Cl], 298 (32), 296 (71), 281 (5), 260
(8), 231 (7), 202 (8), 185 (22), 171 (100), 149 (6), 115 (17),
102 (8), 89 (5), 77 (7). Anal. Calcd for C19H15ClN2O2: C,
67.36; H, 4.46; N, 8.27. Found: C, 67.15; H, 4.37; N, 7.98.
(23) Optimised Experimental Procedure.
(18) (a) Pinto, D. C. G. A.; Silva, A. M. S.; Almeida, L. M. P. M.;
Carrillo, J. R.; Díaz-Ortiz, A.; de la Hoz, A.; Cavaleiro, J. A.
S. Synlett 2003, 1415. (b) Pinto, D. C. G. A.; Silva, A. M. S.;
Brito, C. M.; Sandulache, A.; Carrillo, J. R.; Prieto, P.; Díaz-
Ortiz, A.; de la Hoz, A.; Cavaleiro, J. A. S. Eur. J. Org.
Chem. 2005, 2973.
(19) Typical Experimental Procedure.
Acetyl chloride (1 mol equiv) was added to a stirred solution
of (E)-3-(2-hydroxyphenyl)-5-styrylpyrazole (1a) in dry
pyridine. The mixture was stirred at r.t. and under nitrogen
atmosphere until complete disappearance of the starting 5-
styrylpyrazole 1a. After that period the reaction mixture was
poured over ice and H2O, and acidified at pH 2 with a 10%
solution of HCl. The resulting mixture was extracted with
CHCl3 and dried over anhyd Na2SO4. The solvent was
evaporated to dryness and the residue purified by thin layer
chromatography with CH2Cl2 as eluent giving the expected
(E)-1-acetyl-3-(2-hydroxyphenyl)-5-styrylpyrazole (1c) in
moderate yield (44%). Mp 124.4–126.2 °C. 1H NMR
(300.13 MHz, CDCl3): d = 2.77 (s, 3 H, 1-COCH3), 6.98
(ddd, 1 H, J = 7.7, 7.5, 1.1 Hz, H-5¢), 7.06 (s, 1 H, H-4), 7.07
(dd, 1 H, J = 8.3, 1.1 Hz, H-3¢), 7.22 (d, 1 H, J = 16.5 Hz, H-
b), 7.30–7.43 (m, 4 H, H-4¢,3¢¢,4¢¢,5¢¢), 7.57 (d, 2 H, J = 7.7
Hz, H-2¢¢,6¢¢), 7.63 (dd, 1 H, J = 7.7, 1.6 Hz, H-6¢), 7.93 (d,
1 H, J = 16.5 Hz, H-a), 10.38 (s, 1 H, 2¢-OH). 13C NMR
(75.47 MHz, CDCl3): d = 24.0 (1-COCH3), 104.0 (C-4),
114.8 (C-1¢), 116.4 (C-a), 117.3 (C-3¢), 119.6 (C-5¢), 127.2
(C-2¢¢,6¢¢), 127.4 (C-6¢), 128.8 (C-3¢¢,5¢¢), 129.0 (C-4¢¢),
131.0 (C-4¢), 135.6 (C-b), 136.0 (C-1¢¢), 145.8 (C-5), 153.9
(C-3), 156.5 (C-2¢), 170.8 (1-COCH3). MS (EI): m/z (rel.
int.) = 304 (80) [M+•], 262 (73) [M – C2H2O]+, 245 (5), 233
(5), 216 (4), 202 (6) [M – C8H6]+, 191 (2), 185 (21) [M –
C7H5NO]+, 178 (4), 171 (100), 155 (3), 140 (4), 128 (5), 115
A mixture of (E or Z)-1-acetyl-3-(2-hydroxyphenyl)-4-
styrylpyrazoles 5a–d or 6a–c and N-methylmaleimide (1:6
mole ratio) was irradiated at atmospheric pressure in an
Ethos SYNTH microwave (Milestone Inc.), at 800 W for 40
min. The crude product was dissolved in CHCl3 and purified
by thin layer chromatography with a 8:2 mixture of CHCl3–
EtOAc as eluent. The residue was crystallised from EtOH to
give the expected 1-acetyl-3-(2-hydroxyphenyl)-7-methyl-
5-phenyl-6,8-dioxopyrrolo[3,4-g]-5,5a,8a,8b-tetrahydro-
indazoles (7a, 88%; 7b, 68%; 7c, 95%; 7d, 95%; 8a, 32%;
8b, 54%; 8c, 54%).
(24) Physical Data of 1-Acetyl-5-(4-ethoxyphenyl)-3-(2-
hydroxyphenyl)-7-methyl-6,8-dioxopyrrolo[3,4-g]-
5,5a,8a,8b-tetrahydroindazole (7c).
Mp 236–237 °C. 1H NMR (300.13 MHz, CDCl3): d = 1.44
(t, 3 H, J = 7.0 Hz, 4¢¢-OCH2CH3), 2.54 (s, 3 H, 1-COCH3),
2.76 (s, 3 H, 7-CH3), 3.37 (dd, 1 H, J = 8.5, 7.4 Hz, H-5a),
3.54 (br dd, 1 H, J = 7.4, 4.5 Hz, H-5), 4.07 (dq, 2 H, J = 7.0,
1.9 Hz, 4¢¢-OCH2CH3), 4.46 (dd, 1 H, J = 8.5, 7.1 Hz, H-8a),
4.97 (br dd, 1 H, J = 7.1, 3.6 Hz, H-8b), 6.94 (dd, 1 H, J =
4.5, 3.6 Hz, H-4), 6.96 (d, 2 H, J = 8.6 Hz, H-3¢¢,5¢¢), 6.97
(ddd, 1 H, J = 8.6, 7.2, 0.9 Hz, H-5¢), 7.10 (dd, 1 H, J = 8.0,
0.9 Hz, H-3¢), 7.21 (d, 2 H, J = 8.6 Hz, H-2¢¢,6¢¢), 7.38 (ddd,
1 H, J = 8.0, 7.2, 1.4 Hz, H-4¢), 7.66 (dd, 1 H, J = 8.6, 1.4 Hz,
H-6¢), 9.85 (s, 1 H, 2¢-OH). 13C NMR (75.47 MHz, CDCl3):
d = 14.9 (4¢¢-OCH2CH3), 21.5 (1-COCH3), 25.0 (7-CH3),
40.6 (C-8a), 42.1 (C-5a), 44.5 (C-5), 57.5 (C-8b), 63.5 (4¢¢-
OCH2CH3), 114.4 (C-1¢), 114.5 (C-3¢¢,5¢¢), 117.7 (C-3¢),
119.7 (C-5¢), 126.2 (C-4), 127.5 (C-6¢;), 129.0 (C-1¢¢), 129.8
(C-2¢¢,6¢¢), 131.9 (C-4¢), 137.8 (C-3a), 149.3 (C-3), 157.1 (C-
2¢), 158.5 (C-4¢¢), 168.6 (1-COCH3), 173.4 (C-6), 174.5 (C-
8). MS (EI): m/z (rel. int.) = 459 (52) [M+•], 417 (28), 348
(100), 306 (70), 277 (18), 257 (10), 171 (35), 160 (7), 91
(10). Anal. Calcd for C29H25N3O5: C, 67.96; H, 5.48; N, 9.14.
Found: C, 67.80; H, 5.49; N, 8.76.
+
(23), 102 (6), 89 (5), 77 (8) [C6H5 ], 65 (4). Anal. Calcd for
C19H16N2O2: C, 74.98; H, 5.30; N, 9.20. Found: C, 75.01; H,
5.26; N, 9.05.
(20) Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Lévai,
A.; Patonay, T. Arkivoc 2004, (vii), 106.
(21) Physical Data of (E)-1-Acetyl-4-(4-chlorostyryl)-3-(2-
hydroxyphenyl)pyrazole (5b).
Mp 169.1–169.9 °C. 1H NMR (300.13 MHz, CDCl3):
d = 2.76 (s, 3 H, 1-COCH3), 6.94 (AB, 1 H, J = 16.1 Hz, H-
b), 6.99 (dd, 1 H, J = 7.5, 6.9 Hz, H-5¢), 7.04 (AB, 1 H, J =
16.1 Hz, H-a), 7.12 (dd, 1 H, J = 8.3, 1.1 Hz, H-3¢), 7.33–
7.36 (m, 1 H, H-4¢), 7.36 (d, 2 H, J = 8.6 Hz, H-3¢¢5¢¢), 7.42
(d, 2 H, J = 8.6 Hz, H-2¢¢,6¢¢), 7.62 (dd, 1 H, J = 7.5, 1.6 Hz,
H-6¢), 8.47 (dd, 1 H, J = 0.7 Hz, H-5), 9.82 (s, 1 H, 2¢-OH).
13C NMR (75.47 MHz, CDCl3): d = 21.6 (1-COCH3), 115.9
(C-1¢), 117.4 (C-3¢), 117.9 (C-a), 119.8 (C-5¢), 122.9 (C-4),
126.2 (C-5), 127.8 (C-2¢¢,6¢¢), 128.9 (C-6¢), 129.0 (C-3¢¢,5¢¢),
130.9 (C-4¢), 131.3 (C-b), 133.9 (C-4¢¢), 135.0 (C-1¢¢), 152.4
(C-3), 156.0 (C-2¢), 168.1 (1-COCH3). MS (EI): m/z (rel.
int.) = 340 (36) [M+•, 37Cl], 338 (81) [M+•, 35Cl], 298 (35),
296 (81), 281 (5), 267 (4), 260 (8), 242 (4), 231 (6), 202 (8),
(25) Physical Data of 1-Acetyl-5-(4-ethoxyphenyl)-3-(2-
hydroxyphenyl)-7-methyl-6,8-dioxopyrrolo[3,4-g]-
5,5a,8a,8b-tetrahydroindazole (8c).
Mp 244–245 °C. 1H NMR (300.13 MHz, CDCl3): d = 1.42
(t, 3 H, J = 7.0 Hz, 4¢¢-OCH2CH3), 2.46 (s, 3 H, 1-COCH3),
2.89 (s, 3 H, 7-CH3), 3.56 (br d, 1 H, J = 8.6 Hz, H-5a), 4.70
(br d, 1 H, J = 7.6 Hz, H-5), 4.02 (dq, 2 H, J = 7.0 Hz, 4¢¢-
OCH2CH3), 4.42 (dd, 1 H, J = 8.6, 8.0 Hz, H-8a), 4.80 (dd,
1 H, J = 8.0, 3.8 Hz, H-8b), 6.96 (dd, 1 H, J = 7.6, 3.8 Hz, H-
4), 6.88 (d, 2 H, J = 8.7 Hz, H-3¢¢,5¢¢), 6.98 (ddd, 1 H, J = 7.6,
Synlett 2006, No. 9, 1369–1373 © Thieme Stuttgart · New York

LETTER
7.4, 1.0 Hz, H-5¢), 7.09 (dd, 1 H, J = 8.2, 1.0 Hz, H-3¢), 7.23
Microwave-Assisted Synthesis of Tetrahydroindazoles
1373
purified by TLC with a 9:1 mixture of CHCl3–EtOAc as
eluent. The residue was recrystallised from EtOH to give 5-
aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxopyrrolo[3,4-
g]indazoles (9a from 7a, 85%; 9b from 7b, 32%; 9c from 8c,
31%; 9d from 7d, 34%).
(d, 2 H, J = 8.7 Hz, H-2¢¢,6¢¢), 7.37 (ddd, 1 H, J = 8.2, 7.4, 1.5
Hz, H-4¢), 7.70 (dd, 1 H, J = 7.6, 1.5 Hz, H-6¢), 9.81 (s, 1 H,
2¢-OH). 13C NMR (75.47 MHz, CDCl3): d = 14.8 (4¢¢-
OCH2CH3), 21.5 (1-COCH3), 25.3 (7-CH3), 41.5 (C-8a),
41.8 (C-5), 43.0 (C-5a), 55.7 (C-8b), 63.6 (4¢¢-OCH2CH3),
114.3 (C-1¢), 115.2 (C-3¢¢,5¢¢), 117.6 (C-3¢), 119.7 (C-5¢),
125.9 (C-4), 127.6 (C-6¢), 127.9 (C-2¢¢,6¢¢), 128.2 (C-1¢¢),
131.8 (C-4¢), 138.2 (C-3a), 149.6 (C-3), 157.0 (C-2¢), 158.3
(C-4¢¢), 168.4 (1-COCH3), 173.9 (C-6), 177.7 (C-8). MS
(EI): m/z (rel. int.) = 459 (46) [M+•], 417 (29), 348 (14), 306
(42), 295 (100), 282 (14), 210 (21), 171 (36), 135 (16), 77
(5). Anal. Calcd for C29H25N3O5: C, 67.96; H, 5.48; N, 9.14.
Found: C, 67.91; H, 5.45; N, 9.16.
(27) Physical Data of 3-(2-Hydroxyphenyl)-7-methyl-5-
phenyl-6,8-dioxopyrrolo[3,4-g]indazole (9a).
Mp >275 °C. 1H NMR (300.13 MHz, CDCl3): d = 3.21 (s, 3
H, NCH3), 7.05 (ddd, 1 H, J = 7.7, 7.6, 1.2 Hz, H-5¢), 7.16
(dd, 1 H, J = 8.1, 1.2 Hz, H-3¢), 7.36 (ddd, 1 H, J = 7.6, 8.1,
1.6 Hz, H-4¢), 7.48–7.61 (m, 4 H, H-2¢¢,3¢¢,5¢¢,6¢¢), 8.02 (dd,
1 H, J = 7.7, 1.6 Hz, H-6¢), 8.44 (s, 1 H, H-4), 10.47 (s, 1 H,
NH), 11.27 (s, 1 H, 2¢-OH). 13C NMR (75.47 MHz, CDCl3):
d = 24.0 (NCH3), 116.2 (C-1¢), 117.7 (C-3¢), 119.8 (C-5¢),
130.2 (C-4), 127.3 (C-6¢), 128.2 (C-2¢¢,6¢¢), 129.7 (C-3¢¢,5¢¢),
130.5 (C-4¢), 128.5 (C-4¢¢), 133.1 (C-8b), 136.6 (C-5,1¢¢),
145.7 (C-3), 156.3 (C-2¢), 133.4 (C-3a), 128.2 (C-5a), 116.5
(C-8a), 167.9 (C-6,8). MS (EI): m/z (rel. int.) = 369 (100)
[M+•], 326 (3), 311 (3), 284 (5), 255 (5), 226 (4), 164 (3), 91
(2).
(26) Optimised Experimental Procedure.
A mixture of each of the appropriate 1-acetyl-3-(2-
hydroxyphenyl)-7-methyl-5-phenyl-6,8-dioxopyrrolo[3,4-
g]-5,5a,8a,8b-tetrahydroindazoles 7a,b,d or 8c and DDQ
(1:3 mol ratio) in 1,2,4-trichlorobenzene was irradiated at
atmospheric pressure in an Ethos SYNTH microwave
(Milestone Inc.), at 800 W for 30 min. The crude product
was purified by column chromatography, using light PE as
eluent, to remove the 1,2,4-trichlorobenzene, followed by
EtOAc to remove the reaction product, which was further
(28) Lévai, A.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J.
A. S.; Alkorta, I.; Elguero, J.; Jekö, J. Eur. J. Org. Chem.
2004, 4672.
Synlett 2006, No. 9, 1369–1373 © Thieme Stuttgart · New York