Synthesis of new 1H-indazoles through Diels-Alder transformations of 4-styrylpyrazoles under microwave irradiation conditions

Article abstract of DOI:10.1002/ejoc.200900513

Microwave irradiation under solvent-free conditions induces 1-acetyl-4-styrylpyrazoles to undergo Diels-Alder cycloaddition reactions with N-methyl- or N-phenylmaleimide to give tetrahydroindazoles in good yields and with high selectivities, With conventi

Full text of DOI:10.1002/ejoc.200900513

FULL PAPER
DOI: 10.1002/ejoc.200900513
Synthesis of New 1H-Indazoles through Diels–Alder Transformations of
4-Styrylpyrazoles under Microwave Irradiation Conditions
Vera L. M. Silva,[a] Artur M. S. Silva,*[a] Diana C. G. A. Pinto,[a] José Elguero,[b] and
José A. S. Cavaleiro[a]
Keywords: Diels–Alder reaction / Microwave irradiation / Indazoles / Cycloaddition / Nitrogen heterocycles / Dehydrogena-
tion
Microwave irradiation under solvent-free conditions induces
1-acetyl-4-styrylpyrazoles to undergo Diels–Alder cycload-
dition reactions with N-methyl- or N-phenylmaleimide to
give tetrahydroindazoles in good yields and with high selec-
tivities. With conventional heating, these reactions either do
not occur or afford only traces of the cycloadducts. These cy-
cloadducts were then converted into the corresponding 1H-
indazoles by dehydrogenation with DDQ in dry 1,2,4-tri-
chlorobenzene under microwave irradiation or classical heat-
ing conditions. The structures of all new derivatives and the
stereochemistries of the cycloadducts were assigned by NMR
spectroscopy.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
graphic materials and as components of adhesives, with ap-
plications in polyimide films and as corrosion inhibitors.[7]
There are several methods for the synthesis of ind-
azoles;[8,9,35] most of them start from benzene derivatives,
with the pyrazole ring being formed by ring closure. Most
indazole ring-closure procedures involve bond formation
between the two nitrogen atoms (N–N) as the last step;[36]
nevertheless, ring-closure through N–C bond formation
through the creation of N2–C3[37] or N1–C7a bonds[38]
[numbering of 1H-indazole (1); Figure 1] is also common.
A few examples involving C3–C3a ring-closure have also
been reported.[39] There are also, however, some examples
that start from pyrazoles, involving cycloaddition reactions
between 1-phenyl-5-vinylpyrazole,[40] 1-aryl-3-phenyl-1,6-
dihydropyrano[2,3-c]pyrazoles[41] or N-unsubstituted pyr-
azole ortho-quinodimethanes[42] and several dienophiles. As
part of our continuing work on the synthesis and transfor-
mation of styrylpyrazoles we have studied Diels–Alder reac-
tions between 1-acetyl-4-styrylpyrazoles and (mainly) N-
methylmaleimide, as well as the oxidation of the obtained
cycloadducts, thus developing a method for the synthesis of
fused 1H-indazoles.
Introduction
Natural products containing indazole moieties are rare
and at present only three examples are known: nigellicine,
nigeglanine and nigellidine.[1–6] Many synthetic indazoles,
however, are known and recognized by their pharmaceuti-
cal activity, which has inspired the development of a
number of new syntheses for the indazole ring system.[7–10]
Certain indazoles act as dopamine D2 receptor antago-
nists,[11–13] antipyretic and anti-inflammatory agents
(bendazac and benzidamine),[14] analgesics[15,16] or anti-
HIV protease[17,18] and Rho kinase inhibitors[19,20] and are
used in the treatment of diabetes[7,21,22] and obesity.[23]
Other derivatives exhibit antitumour (combretastatin),[24–28]
CNS (granisetron),[8] bronchodilatory, vasodilatory or neu-
roprotectant activities.[29] 1-Benzyl-1H-indazole-3-carbox-
ylic acids display antispermatogenetic[30] and anticancer ac-
tivity,[24,28] whereas 4-(indazol-3-yl)phenols behave as anti-
arthritic drugs.[31,32] Indazoles also have agrochemical ap-
plications as herbicides, bactericides, fungicides (flucon-
azole)[33] and plant growth inhibitors.[7] In the food industry
they (mainly guanidino-1H-indazoles) are used as sweeten-
ers.[7] Indazole-type compounds also have a wide range of
applications in analytical determinations and in industry.
Arylazoindazoles are used as reagents for the determination
of vanadium,[7,34] whereas others are formulated in photo-
[a] Chemistry Department and QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
Fax: +351-234-370-084
E-mail: artur.silva@ua.pt
[b] Instituto de Química Médica (CSIC),
Juan de la Cierva 3, 28006 Madrid, Spain
E-mail: iqmbe17@iqm.csic.es
Figure 1. Structures of 1H- and 2H-indazoles.
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2009, 4468–4479
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1H-Indazoles by Diels–Alder Reactions
Results and Discussion
Chemistry
Vinylpyrazoles are very reluctant to participate as dienes
in cycloaddition reactions involving their pyrazole rings,
owing to the loss of aromaticity involved in these reac-
tions.[40] Cycloaddition reactions of vinylpyrazoles require
very reactive dienophiles and high temperatures and pres-
sures (120–140 °C and 8–10 atm) and are usually slow reac-
tions giving rise to adducts in moderate to low yields.[40,43]
Obviously these conditions are not compatible with sensi-
tive or unstable compounds, and retro Diels–Alder reac-
tions can occur when the cycloadditions require long reac-
tion times. In spite of vinylpyrazoles being very unreactive
we decided to study the reactivities of styrylpyrazoles as
dienes under classical heating or microwave irradiation con-
Scheme 1. Acetylation of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-
styrylpyrazoles 3a–e and 4a–c.
ditions, following our previous work with compounds of Table 1. Results and conditions for N-acetylation of (E)- and (Z)-
this type.[44]
3-(2-hydroxyphenyl)-4-styrylpyrazoles 3a–e and 4a–c.
All attempts to achieve reactions between (E)-5(3)-(2-hy-
droxyphenyl)-3(5)-styrylpyrazoles or their N-methyl deriva-
tives and either electron-rich or electron-poor dienophiles
R
AcCl (mo- Reaction Yield of 5/6 Yield of 7/
lar equiv.)
time [h]
(%)
8 (%)
3a
H
H
3b Cl
3b Cl
3c OC2H5
3d NO2
3d NO2
3e CF3
H
4b Cl
1.1
3.5
1.1
3.2
3
70
24
24
24
70
24
66
24
24
24
48
72
5a (75)
–
–
in 1,2,4-trichlorobenzene at reflux or under microwave irra- 3a
7a (79)
5b (77)
–
diation conditions, in solvent or under solvent-free condi-
tions, had previously been unsuccessful; the expected ad-
ducts either were obtained only in small yields or were not
obtained at all.[45] In that prior study, however, we also
showed that (E)-1-acetyl-3-(2-hydroxyphenyl)-5-styrylpyr-
azole can react with N-methylmaleimide to give the ex-
pected cycloadduct, though in less than 20% yield, together
with other products.[45]
–
7b (80)
5c (72)
5d (45)
–
–
–
1.1
3.2
1.1
1.5
1.5
2.4
3.0
7d (92)
5e (60)
6a (59)
6b (62)
6c (70)
6c (56)
–
4a
–
–
–
4c OC2H5
4c OC2H5
8c (28)
In our ongoing research into the synthesis and transfor-
mation of (E)- and (Z)-3-styrylchromones[46] we have syn-
thesized several (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-sty-
In continuation of our previous work on microwave-
rylpyrazoles 3a–e and 4a–c[47] (Scheme 1) in order to study assisted Diels–Alder cycloaddition reactions under solvent-
their reactivities in cycloaddition reactions. As we have pre- free conditions,[49] mixtures of each one of the 1-acetyl-4-
viously shown in the Diels–Alder reactions of (E)-5(3)-(2- styrylpyrazoles 5a–e or 6a–c and N-methylmaleimide were
hydroxyphenyl)-3(5)-styrylpyrazoles, it is necessary to carry subjected to microwave irradiation under solvent-free con-
out N-derivatisation to avoid conjugate additions to dieno- ditions[45] (Scheme 2) and the desired cycloadducts 9a–e or
philes,[45] so the 4-styrylpyrazoles 3a–e and 4a–c were acety- 10a–c were obtained in moderate to very good yields (9a–
lated with acetyl chloride in dry pyridine (Scheme 1). These e, 68–95%; 10a–c, 54–60%).
acetylation reactions are dependent on the substituents on
We tried to improve the yield of cycloadduct 9a by
the aryl rings of the styryl groups and on the stereochemis- changing the reaction time. The reaction between 5a and
tries of the styryl groups (Table 1). Acetylation of the (E)- N-methylmaleimide in a shorter reaction time (20 min) af-
styrylpyrazoles 3a–e with excess acetyl chloride led to the forded 9a in 12% yield, whereas a longer reaction time (1 h)
diacetylated pyrazoles 7a, 7b and 7d, except in the case of gives 9a in 34% yield with the recovery of starting material
the compound bearing an electron-donating group on the 5a (17%), probably due to a retro-Diels–Alder reaction. We
aryl ring of the styryl group (derivative 3c), which also re- thus concluded that the best yield was achieved after 40 min
quires an excess of acetylation agent to yield the monoacetyl of irradiation, and therefore all the cycloaddition reactions
derivative 5c. The (Z)-4-styrylpyrazoles 4a–c seem to be were conducted with this period of time. The Z isomers 6a–
more reactive than the corresponding diastereomers 3a–c, c seem to be less reactive than the corresponding E isomers
because smaller amounts of acetylating agent or shorter re- 5a–c, because the adducts 10a–c were obtained in lower
action times are required to provide similar results (Table 1). yields (54–60% for 10a–c, in comparison with 68–95% for
Although some indication about the acetylation sites of 9a–c) under the same experimental conditions (800 W for
some asymmetric pyrazoles can be found in the literature, 40 min).
acetylation generally occurs at N-1 in the starting material
In the reactions between N-methylmaleimide and 5b or
because the resulting product is the less hindered one;[48] in 5d, another compound besides the expected adducts 9b and
the present case N1-acetylation is probably reinforced by the 9d was isolated in each case (7–10%). The formation of this
hydrogen bond between the 2Ј-hydroxy proton and N-2.
compound can be explained by partial oxidation of the
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A. M. S. Silva et al.
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Scheme 3. Synthesis of compounds 12b and 12d.
Table 2. Results and conditions for the dehydrogenation of adducts
9a–e and 10a–c with DDQ under microwave and conventional
heating conditions.[a]
Microwave/conventional heating conditions
Reaction
time [h]
Yield of 13 Yield of
Yield of
15 (%)
R
(%)
14 (%)
9a
H
Cl
OC2H5
NO2
CF3
H
6
4
6
4
4
4
3
8
3
85/31
32/60
36/36
13/–
–/–
–/–
–/20
–/–
–/–
–/–
–/–
–/–
–/–
13/–
4/–
20/–
6/–
25/–
–/–
–/–
9b
Scheme 2. Synthesis of indazoles 13a–e.
9c
9d
34/73
9e
11*/68
22**/56
6***/55
31/36
10a
10b
10c
formed adducts 9b or 9d in the reaction medium, giving
the intermediates 11b or 11d. Cycloadditions between the
formed diene moieties in these intermediates with another
molecule of N-methylmaleimide, which was used in excess,
afforded compounds 12b or 12d (Scheme 3). Probably the
presence of a 5-aryl ring bearing electron-withdrawing sub-
stituents increases the acidity of proton H-5, facilitating the
Cl
OC2H5
–/49
–/–
[a] Recovered starting material: * 7%, ** 25%, *** 18%.
These results indicate that the dehydrogenation was ac-
oxidation of 9b and 9d into 11b and 11d, which further companied by N-deacetylation.[51] The yields, however, were
react with the excess N-methylmaleimide to give 12b and low to moderate, due to extensive degradation occurring in
12d (Scheme 3). The literature reports the formation of the reaction mixtures. In some cases we also recovered small
compounds of this type in the reactions between vinylic de- amounts of the starting cycloadducts and we isolated the
rivatives of [1]benzothieno[3,2-b]furan and DMAD.[50]
partially oxidised compounds 15a–e (Figure 2, Table 2). By
In order to determine the scope of these reactions and dehydrogenation of tetrahydro-1H-pyrrolo[3,4-g]indazole
their utility as a new synthetic methodology for the synthe- 9a we obtained 14a (13%), whereas from the dehydrogena-
sis of novel indazole-type compounds, with complete and tion of adducts 9b–e and 10a we also isolated the partially
extended aromatic structures, we studied the oxidation of oxidised compounds 15a–e. From the dehydrogenation of
the cycloadducts by our recently published methodology adduct 9d under conventional heating conditions we also
using DDQ as dehydrogenation agent and microwave irra- isolated 14d (20%). In order to improve the yields of com-
diation as an alternative to conventional heating pounds 13a–e we studied the dehydrogenation of 9b over a
(Scheme 2).[49] The 1-acetyl-5-aryl-3-(2-hydroxyphenyl)-7- longer reaction time (1 h) but we only obtained unknown
methyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]- compounds (decomposition products).
indazoles 9a–e and 10a–c were oxidised with DDQ (3 molar
Because the above results were not satisfactory we de-
equiv., excess) in 1,2,4-trichlorobenzene under microwave cided to investigate the dehydrogenation of the 1-acetyl-5-
irradiation at 170 °C for 30 min, and the 5-aryl-3-(2- aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxo-5,5a,8a,8b-
hydroxyphenyl)-7-methyl-6,8-dioxo-1H-pyrrolo[3,4-g]ind- tetrahydro-1H-pyrrolo[3,4-g]indazoles 9a–e and 10a–c un-
azoles 13a–e (Scheme 2) were obtained in moderate to low der classical heating conditions. The dehydrogenation of ad-
yields (Table 2).[45]
ducts 9a–e and 10a–c in the presence of DDQ (3 molar
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Eur. J. Org. Chem. 2009, 4468–4479

1H-Indazoles by Diels–Alder Reactions
It was also decided to study cycloadditions between the
(E)-1-acetyl-4-nitrostyrylpyrazole 5d and the other electron-
deficient dienophiles N-phenylmaleimide and dimethyl ace-
tylenedicarboxylate (DMAD) (Scheme 4). Treatment of 5d
with an excess of N-phenylmaleimide (3 molar equiv.) under
microwave irradiation and solvent-free conditions for
40 min led to the formation of the cycloadduct 16d in 49%
yield and to the oxidised indazole 17d in 5% yield, without
recovery of any starting material. We examined the cycload-
dition reaction between 5d and N-phenylmaleimide in a
shorter reaction time (20 min) in an attempt to improve the
yield of the adduct 16d and to avoid its oxidation, but a
mixture of compounds that was difficult to separate was
obtained and no pure compound was isolated or identified.
The cycloaddition reaction between 5d and an excess of
DMAD (3 molar equiv.) under microwave irradiation in
solvent-free conditions for 40 min yielded traces of com-
pound 18d, obtained from the conjugate addition of the
pyrazole nitrogen of 5d to DMAD (Scheme 4).[52]
Figure 2. Structures of compounds 14a, 14d and 15a–e.
equiv., excess) in dry 1,2,4-trichlorobenzene at 170 °C, until
the consumption of the starting material, gave the expected
indazoles 13a–e in moderate to good yields (Table 2).
In an attempt to improve the yields we investigated the
dehydrogenation of cycloadduct 9b under classical heating
conditions in the presence of chloranil instead of DDQ, ex-
pecting to minimize the degradation of the reaction mix-
ture. The reaction between 9b and chloranil (3 molar equiv.)
in dry 1,2,4-trichlorobenzene at 170 °C over 17 h led to the
corresponding indazole 13b in 27% yield and to decomposi-
tion products. These results suggested that the best condi-
tions for the dehydrogenation under classical heating condi-
tions involve the use of a stronger oxidant such as DDQ
during a short period of time.
Indazoles 13a–e were obtained in better yields when the
dehydrogenation of adducts 9a–e and 10a–c was performed
under classical heating conditions; probably the hard condi-
tions used under microwave irradiation are responsible for
the observed radical degradation and consequently for the
low obtained yields. Our results also suggested that the de-
hydrogenation of the cycloadducts 9a–e and 10a–c is easy
to perform when there is an electron-withdrawing substitu-
ent in the 5-aryl ring.
Nuclear Magnetic Resonance
The 1H NMR spectra of the 1-acetyl-3-(2-hy-
droxyphenyl)-4-styryl-1H-pyrazoles 5a–e and 6a–c each
show a singlet at δ = 2.71–2.78 ppm corresponding to the
COCH3 protons and a deshielded singlet at δ = 9.66–
10.32 ppm due to the resonance of the 2Ј-OH proton. The
high frequency value of this proton is due to the intramo-
lecular hydrogen bond with N-2. Other important features
of the NMR spectra of pyrazoles 5a–e and 6a–c are the
presence in each of a singlet due to the resonance of 5-H (δ
= 8.00–8.55 ppm) and doublets due to the resonances of H-
α and H-β. Protons 5-H and H-α can appear as a doublet
and a double doublet, respectively, when they are coupled
to each other (J = 0.6–1.2 Hz). The coupling constant val-
3
ues of JHα,Hβ are the main criteria to distinguish between
3
pyrazoles 5a–e and 6a–c: JHα,Hβ ≈ 16–18 Hz indicates a
trans configuration of the vinylic moiety whereas a value of
3JHα,Hβ ≈ 11–12 Hz indicates a cis configuration. Because
of the non-coplanarity between ring B and the rest of the
structure in the cases of pyrazoles 6a–c the resonances of
the 5-H, H-α and H-β protons appear at lower frequencies
than in the cases of pyrazoles 5a–e.
The 13C NMR spectra of pyrazoles 5a–e and 6a–c each
presented two characteristic signals at δ = 21.6 and 167.8–
168.1 ppm due to the resonance of methyl and carbonyl
group, respectively. The identification of the other carbons
was done on the basis of two-dimensional HSQC and
HMBC spectroscopic experiments [the main connectivities
of the HMBC spectra are (CH3ǞC=O); (H-αǞC-3, C-4, C-
5, C-1ЈЈ, C-β); (H-βǞC-α, C-4, C-2ЈЈ,6ЈЈ, C-1ЈЈ); (5-HǞC-3,
C-4, C-α); (6Ј-HǞC-2Ј, C-3, C-4Ј); (3Ј-HǞC-2Ј, C-1Ј, C-4Ј
e C-5Ј); (2ЈЈ,6ЈЈ-HǞC-4ЈЈ); (3ЈЈ,5ЈЈ-HǞC-1ЈЈ)].
In the spectra of the diacetylated pyrazoles 7a, 7b, 7d
and 8c one can in each case observe the singlet due to the
resonance of the methyl protons of the O-acetyl group
(CO2CH3) at δ = 2.07–2.20 ppm and the singlet due to the
Scheme 4. Reactions of (E)-1-acetyl-3-(2-hydroxyphenyl)-4-(4-ni-
trostyryl)-1H-pyrazole (5d) with N-phenylmaleimide and DMAD.
Eur. J. Org. Chem. 2009, 4468–4479
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A. M. S. Silva et al.
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resonance of the methyl protons of the N-acetyl group and at δ = 2.71 ppm, due to the resonance of the six protons
(NCOCH3) at a higher frequency (δ = 2.68–2.75 ppm). Also of the two NCH3 groups, ii) pairs of doublets at δ = 3.52
characteristic of these compounds are the signals observed and 4.34 ppm, due to the resonance of two protons from
in the 13C NMR spectra corresponding to the resonance of sp3 carbons from two N-methylmaleimide units, and iii) sin-
two CO2CH3 groups (at δ = 20.8–21.1 and 21.4–21.6 ppm glets at δ = 7.21 ppm, due to the resonance of 4-H.
and also at δ = 168.9–169.1 and 169.2–169.4 ppm).
The NMR spectroscopic data for cycloadducts 16d and
1
The main feature in each of the H NMR spectra of cy- 17d are similar to those for 9d and 13d, except for the pres-
cloadducts 9a–e and 10a–c is the presence in the aliphatic ence in each case of an extra multiplet due to the resonance
region of signals due to the proton resonances of the tetra- of the phenyl ring of the N-phenylmaleimide unit in the
hydro-aromatic ring and the absence of H-α and H-β reso- aromatic region. The structure 18d is supported by the pres-
nances. Other spectroscopic characteristics are: i) the pres- ence in the 1H NMR spectrum of two singlets at δ =
ence of the hydroxy group involved in a hydrogen bond (δH 3.85 ppm and 4.10 ppm, due to the resonance of the meth-
= 9.73–9.85 ppm), ii) the presence of the acetyl group, ap- oxy groups (CO2CH3) of the dienophile, the absence of the
1
parent in the H NMR spectra from the signal correspond- singlet characteristic of the acetyl group resonance and the
ing to the methyl group (δH = 2.46–2.55 ppm) and in the presence of a singlet due to the resonance of H-3ЈЈЈ. We
13C NMR spectra due to the signals corresponding to the also observed some typical signals of compound 18d in the
methyl group at (δC = 21.4–21.5 ppm) and the carbonyl 13C NMR spectrum, such as i) the signals due to the reso-
group at (δC = 168.4–168.6 ppm), and iii) the presence of an nance of the methoxy groups of DMAD at δ = 52.4 and
N-methyl group (δH = 2.76–2.77 ppm; δC = 25.0–25.4 ppm). 53.9 ppm, ii) the signals due to the resonance of vinylic car-
These data are consistent with the proposed cycloadduct bons at δ = 105.9 ppm (C-3ЈЈЈ) and δ = 141.8 ppm (C-2ЈЈЈ),
structures 9a–e and 10a–c.[45] The cis configurations of pro- and iii) the signals due to the resonances of the DMAD
tons 5-H, 5a-H, 8a-H and 8b-H in adducts 9a–e and of carbonyl groups at δ = 162.7 and 165.0 ppm.
protons 5a-H, 8a-H and 8b-H in adducts 10a–c, confirmed
by NOE cross peaks observed in the NOESY spectra[45] and
Conclusions
also by detailed analysis of the coupling constants of some
protons (JH8a,H8b ≈ 7–8 Hz for both isomers; JH5,H5a ≈ 8 Hz
for 9a–e; JH5,H5a ≈ 0 Hz for 10a–c) indicate that the reaction
selectively afforded the endo adduct in both cases. No traces
of the exo adduct were detected.
We have established a new and efficient methodology for
the synthesis of novel indazole-type compounds. Our results
indicate that the (Z)-1-acetyl-3-(2-hydroxyphenyl)-4-styryl-
pyrazoles 6a–c are less reactive than the (E)-1-acetyl-3-(2-
hydroxyphenyl)-4-styrylpyrazoles 5a–e, probably due to the
steric hindrance caused by the phenyl ring at the β position.
The Diels–Alder cycloadditions described here were stereo-
selective and gave the expected endo cycloadducts, which
were dehydrogenated to the indazole-type compounds 13a–
e. Under microwave conditions, however, indazoles 13a–e
were obtained in better yields by the dehydrogenation of
cycloadducts 9a–c. This result can be explained by con-
sidering the dehydrogenation mechanism and the structures
of the isomer cycloadducts, because the DDQ-mediated de-
hydrogenation of hydroaromatic compounds involves the
parallel approach of the DDQ to the cyclohexene moiety
of the cycloadduct in order to produce a 1,4-cis elimi-
nation.[53] This kind of elimination is easier for cycload-
ducts 9a–c, in which the protons 5-H and 8b-H are in a cis
configuration, because in the isomers 10a–c there is higher
steric hindrance and the protons 5-H and 8b-H are in a
trans configuration.
In the aliphatic region of the 13C NMR spectra, several
signals due to the newly formed tetrahydro-aromatic ring
are observed at δ = 40.3–57.6 ppm. The signals due to the
carbonyl groups of the N-methylmaleimide moiety in these
compounds were assigned at δ = 172.9–173.9 ppm (C-6)
and δ = 174.1–174.7 ppm (C-8). Another characteristic sig-
nal is the resonance of C-4 appearing at δ = 123.3–
126.2 ppm. Unambiguous assignment of the carbons was
carried out on the basis of the correlations observed in
HSQC and HMBC spectra [the main connectivities of the
HMBC spectra are (COCH3ǞCOCH3); (NCH3ǞC-6 and
C-8); (2Ј-OHǞC-2Ј and C-1Ј); (6Ј-HǞC-2Ј, C-3 and C-4Ј);
(5a-HǞC-8a, C-8); (8a-HǞC-3a, C-6); (3Ј-H and 5Ј-HǞC-
1Ј); (3ЈЈ,5ЈЈ-HǞC-1ЈЈ); (2ЈЈ,6ЈЈ-HǞC-4ЈЈ)].
The main features of the 1H NMR spectra of compounds
13a–e are the singlets at δ = 8.40–8.44 ppm, each corre-
sponding to the resonance of proton 4-H, and δ = 10.33–
10.50 ppm, due to the resonance of the NH proton and
confirming the absence of the acetyl group. The signal due
to the resonance of 2Ј-OH proton appears in each case as
a broad singlet, which means that the hydrogen bond be-
tween the 2Ј-OH proton and N-2 is less strong in these oxi-
dised derivatives due to the possible prototropy. The 1H
NMR spectra of 14a and 14d are similar to those of 13a
and 13d, save for the singlets due to the resonance of the
NCOCH3 protons at δ ≈ 2.10 ppm.
Experimental Section
General Remarks: Melting points were measured in a Reichert
Thermovar apparatus fitted with a microscope and are uncor-
rected. NMR spectra were recorded on a Bruker Avance 300 spec-
trometer (300.13 MHz for 1H and 75.47 MHz for 13C), with CDCl3
used as solvent if not stated otherwise. Chemical shifts (δ) are re-
ported in ppm values and coupling constants (J) in Hz. The in-
ternal standard was TMS. 1H assignments were made by use of 2D
The structures of compounds 12b and 12d are supported
1
by the presence in their H NMR spectra of: i) singlets at δ
= 2.64 ppm, due to the resonance of the COCH3 protons, gCOSY spectra, whereas unequivocal 13C assignments were made
4472
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4468–4479

1H-Indazoles by Diels–Alder Reactions
with the aid of 2D gHSQC (or HETCOR) and gHMBC experi-
ments (delays for one-bond and long-range J C/H couplings were
optimised for 145 and 7 Hz, respectively). Mass spectra (EI, 70 eV)
were measured on VG Autospec Q and M mass spectrometers,
whereas mass spectra (ESI+) were measured on a Micromass Q-
TOF-2TH spectrometer [dilution of 1 µL of the sample chloroform
solution (≈ 10–5 ) in 200 µL of 0.1% trifluoroacetic acid/methanol
solution; nitrogen was used as nebulizer gas and argon as collision
gas; the needle voltage was set at 3000 V, with the ion source set at
80 °C and desolvation temperature at 150 °C; cone voltage was
35 V]. Mass spectra (MALDI TOF/TOF) were measured on a 4800
MALDI TOF/TOF Analyzer, MDS (Applied Biosystems) with α-
cyano-4-hydroxycinnamic acid as matrix. Elemental analyses were
obtained with Carlo Erba 1108 and LECO 932 instruments. Pre-
parative thin-layer chromatography was carried out with Merck sil-
ica gel (60 DGF254) and column chromatography with Merck silica
gel 60 (70–230 mesh). All other chemicals and solvents used were
obtained from commercial sources and were either used as received
or dried by standard procedures.
1 H, 6Ј-H), 8.43 (s, 1 H, 5-H), 9.91 (s, 1 H, 2Ј-OH) ppm. 13C NMR:
δ = 14.8 (4ЈЈ-OCH2CH3), 21.6 (1-COCH3), 63.5 (4ЈЈ-OCH2CH3),
114.7 (C-3ЈЈ,-5ЈЈ), 114.9 (C-α), 116.0 (C-1Ј), 117.2 (C-3Ј), 119.7 (C-
5Ј), 123.5 (C-4), 125.7 (C-5), 127.9 (C-2ЈЈ,-6ЈЈ), 128.9 (C-6Ј), 129.1
(C-1ЈЈ), 130.8 (C-4Ј), 132.3 (C-β), 152.3 (C-3), 156.0 (C-2Ј), 159.1
(C-4ЈЈ), 168.1 (1-COCH3) ppm. EI-MS: m/z (%) = 349 (75) [M]+·,
319 (5) [M – C2H5]+, 307 (91), 290 (12), 260 (31), 247 (8), 185 (19),
171 (100), 115 (8), 91 (11), 77 (4), 65 (3). C21H20N2O3 (348.4):
calcd. C 72.40, H 5.79, N 8.04; found C 72.20, H 6.14, N 7.68.
(E)-1-Acetyl-3-(2-hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazole
1
(5d): M.p. 178–180 °C (recrystallized from ethanol). H NMR: δ =
2.78 (s, 3 H, 1-COCH3), 7.02 (ddd, J = 7.5, 7.7, 1.1 Hz, 1 H, 5Ј-
H), 7.05 (d, J = 16.0 Hz, 1 H, Hβ), 7.13 (dd, J = 8.1, 1.1 Hz, 3Ј-
H), 7.25 (dd, J = 16.0, 0.6 Hz, 1 H, Hα), 7.38 (ddd, J = 8.1, 7.5,
1.6 Hz, 1 H, 4Ј-H), 7.57 (dd, J = 7.7, 1.6 Hz, 1 H, 6Ј-H), 7.62 (d,
J = 8.8 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 8.25 (d, J = 8.8 Hz, 2 H, 3ЈЈ-,5ЈЈ-H),
8.55 (d, J = 0.6 Hz, 1 H, 5-H), 9.66 (s, 1 H, 2Ј-OH) ppm. 13C NMR:
δ = 21.6 (1-COCH3), 115.7 (C-1Ј), 117.5 (C-3Ј), 119.9 (C-5Ј), 121.9
(C-α), 122.2 (C-4), 124.3 (C-3ЈЈ,-5ЈЈ), 126.6 (C-5), 127.0 (C-2ЈЈ,-6ЈЈ),
128.8 (C-6Ј), 130.1 (C-β), 131.2 (C-4Ј), 142.8 (C-1ЈЈ), 147.2 (C-4ЈЈ),
152.5 (C-3), 156.0 (C-2Ј), 168.1 (1-COCH3) ppm. EI-MS: m/z (%)
= 349 (86) [M]+·, 319 (4) [M – NO]+, 307 (100) [M – C2H2O]+, 290
(21), 260 (43), 231 (8), 185 (30), 171 (98), 115 (13), 102 (6), 91 (3),
77 (5); 65 (4). C19H15N3O4 (349.3): calcd. C 65.32, H 4.33, N 12.03;
found C 64.97, H 4.23, N 11.86.
Syntheses of the (E)- and (Z)-1-Acetyl-3-(2-hydroxyphenyl)-4-styryl-
pyrazoles 5a–e and 6a–c: An appropriate amount of acetyl chloride
was added to a stirred solution of the (E)- or (Z)-3-(2-hy-
droxyphenyl)-4-styrylpyrazole 3a–e or 4a–c (0.76 mmol) in dry pyr-
idine (20 mL). The mixture was stirred at room temperature under
nitrogen until complete consumption of the starting material 3a–e
or 4a–c. The reaction mixture was then poured onto ice and water
and acidified to pH 2–3 with hydrochloric acid (20%). The re-
sulting mixture was extracted with chloroform and dried with anhy-
drous sodium sulfate. The solvent was evaporated to dryness and
the residue was purified by thin layer chromatography with CH2Cl2
as eluent, giving the expected (E)- or (Z)-1-acetyl-3-(2-hy-
droxyphenyl)-4-styrylpyrazole [5a 173 mg (75%), 5b 198 mg (77%),
5c 191 mg (72%), 5d 119 mg (45%), 5e 170 mg (60%), 6a 136 mg
(59%), 6b 160 mg (62%), 6c 185 mg (70%)]. Compounds 5a–c, 5e
and 6a–c were obtained as white solids and compound 5d was ob-
tained as a yellow solid, all of them recrystallized from ethanol.
(E)-1-Acetyl-3-(2-hydroxyphenyl)-4-(4-trifluoromethylstyryl)-1H-
pyrazole (5e): M.p. 164–166 °C (recrystallized from ethanol). 1H
NMR: δ = 2.77 (s, 3 H, 1-COCH3), 7.00 (ddd, J = 7.8, 7.4, 1.1 Hz,
1 H, 5Ј-H), 7.02 (d, J = 16.3 Hz, 1 H, Hβ), 7.13 (dd, J = 8.0,
1.1 Hz, 1 H, 3Ј-H), 7.17 (d, J = 16.3 Hz, 1 H, Hα), 7.36 (ddd, J =
8.0, 7.8, 1.7 Hz, 4Ј-H), 7.58 (d, J = 8.2 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.60
(dd, J = 7.4, 1.7 Hz, 1 H, 6Ј-H), 7.64 (d, J = 8.2 Hz, 2 H, 3ЈЈ-,5ЈЈ-
H), 8.51 (s, 1 H, 5-H), 9.76 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ =
21.6 (1-COCH3), 115.8 (C-1Ј), 117.4 (C-3Ј), 119.8 (C-5Ј), 119.9 (C-
α), 122.5 (C-4), 123.6 (q, J = 273.5 Hz, 4ЈЈ-CF3), 125.8 (q, J =
3.8 Hz, C-3ЈЈ,-5ЈЈ), 126.7 (C-5), 128.9 (C-2ЈЈ,-6ЈЈ), 129.9 (q, J =
32.4 Hz, C-4ЈЈ), 130.1 (C-6Ј), 131.0 (C-4Ј,-β), 139.9 (C-1ЈЈ), 152.5
(C-3), 156.0 (C-2Ј), 168.1 (1-COCH3) ppm. EI-MS: m/z (%) = 372
(66) [M]+·, 353 (8), 330 (73), 185 (24), 171 (100), 115 (10), 102 (5),
91 (3), 77 (5). C20H15F3N2O2 (372.3): calcd. C 64.51, H 4.06, N
7.52; found C 64.89, H 4.18, N 7.25.
(E)-1-Acetyl-3-(2-hydroxyphenyl)-4-styryl-1H-pyrazole (5a): M.p.
1
124–126 °C (recrystallized from ethanol). H NMR: δ = 2.75 (s, 3
H, 1-COCH3), 6.98 (ddd, J = 7.5, 7.7, 1.3 Hz, 1 H, 5Ј-H), 6.98 (d,
J = 16.8 Hz, 1 H, Hβ), 7.07 (dd, J = 16.8, 0.4 Hz, 1 H, Hα), 7.11
(dd, J = 8.2, 1.3 Hz, 3Ј-H), 7.28–7.34 (m, 4Ј-,4ЈЈ-H), 7.39 (dt, J =
7.0, 7.5 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.49 (dd, J = 7.0, 1.6 Hz, 2 H, 2ЈЈ-
,6ЈЈ-H), 7.66 (dd, J = 7.7, 1.6 Hz, 1 H, 6Ј-H), 8.47 (s, 1 H, 5-H),
9.87 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 21.6 (1-COCH3), 115.9
(C-1Ј), 117.3 (C-α,3Ј), 119.8 (C-5Ј), 123.2 (C-4), 126.1 (C-5), 126.6
(C-2ЈЈ,-6ЈЈ), 128.3 (C-4ЈЈ), 128.85 (C-3ЈЈ,-5ЈЈ), 128.99 (C-6Ј), 130.9
(C-4Ј), 132.7 (C-β), 136.5 (C-1ЈЈ), 152.5 (C-3), 156.1 (C-2Ј), 168.1
(1-COCH3) ppm. EI-MS: m/z (%) = 304 (80) [M]+·, 262 (73), 202
(6), 185 (21), 171 (100), 115 (23), 89 (5), 77 (8), 65 (4). C19H16N2O2
(304.3): calcd. C 74.98, H 5.30, N 9.20; found C 75.01, H 5.26, N
9.05.
(Z)-1-Acetyl-3-(2-hydroxyphenyl)-4-styryl-1H-pyrazole (6a): M.p.
1
151–153 °C (recrystallized from ethanol). H NMR: δ = 2.71 (s, 3
H, 1-COCH3), 6.48 (dd, J = 11.9, 1.2 Hz, 1 H, Hα), 6.81 (d, J =
11.9 Hz, 1 H, Hβ), 6.96 (ddd, J = 7.9, 7.5, 1.2 Hz, 1 H, 5Ј-H), 7.09
(dd, J = 8.2, 1.2 Hz, 1 H, 3Ј-H), 7.21–7.39 (m, 5 H, 2ЈЈ-,3ЈЈ-,4Ј-,5ЈЈ-
,6ЈЈ-H), 7.33 (tt, J = 7.8, 1.6 Hz, 1 H, 4ЈЈ-H), 7.91 (dd, J = 7.9,
1.6 Hz, 1 H, 6Ј-H), 8.00 (d, J = 1.2 Hz, 1 H, 5-H), 10.26 (s, 1 H,
2Ј-OH) ppm. 13C NMR: δ = 21.6 (1-COCH3), 115.9 (C-1Ј), 117.2
(C-3Ј), 119.2 (C-α), 119.6 (C-5Ј), 120.4 (C-4), 127.6 (C-5), 128.3 (C-
4ЈЈ), 128.5 (C-2ЈЈ,-6ЈЈ,-3ЈЈ,-5ЈЈ), 128.7 (C-6Ј), 130.9 (C-4Ј), 133.7 (C-
β), 136.0 (C-1ЈЈ), 153.2 (C-3), 156.3 (C-2Ј), 167.9 (1-COCH3) ppm.
MALDI TOF/TOF-MS: m/z (%) = 304.3 (23) [M + H]+.
C19H16N2O2 (304.3): calcd. C 74.98, H 5.30, N 9.20; found C 74.76,
H 5.38, N 8.97.
(E)-1-Acetyl-4-(4-chlorostyryl)-3-(2-hydroxyphenyl)-1H-pyrazole
(5b): This compound was shown to possess spectroscopic and ana-
lytical data identical to those previously reported.[45]
(E)-1-Acetyl-4-(4-ethoxystyryl)-3-(2-hydroxyphenyl)-1H-pyrazole
(Z)-1-Acetyl-4-(4-chlorostyryl)-3-(2-hydroxyphenyl)-1H-pyrazole
(6b): This compound was shown to possess spectroscopic and ana-
lytical data identical to those previously reported.[45]
1
(5c): M.p. 138–139 °C (recrystallized from ethanol). H NMR: δ =
1.44 (t, J = 7.0 Hz, 3 H, 4ЈЈ-OCH2CH3), 2.75 (s, 3 H, 1-COCH3),
4.07 (q, J = 7.0 Hz, 2 H, 4ЈЈ-OCH2CH3), 6.89 (d, J = 16.4 Hz, 1
H, Hβ), 6.91 (d, J = 8.6 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 6.95 (d, J = 16.4 Hz, (Z)-1-Acetyl-4-(4-ethoxystyryl)-3-(2-hydroxyphenyl)-1H-pyrazole
1
1 H, Hα), 6.98 (ddd, J = 7.4, 7.7, 1.2 Hz, 1 H, 5Ј-H), 7.10 (dd, J
= 8.3, 1.2 Hz, 1 H, 3Ј-H), 7.34 (ddd, J = 8.3, 7.4, 1.6 Hz, 1 H, 4Ј-
(6c): M.p. 132–133 °C (recrystallized from ethanol). H NMR: δ =
1.39 (t, J = 7.0 Hz, 3 H, 4ЈЈ-OCH2CH3), 2.72 (s, 3 H, 1-COCH3),
H), 7.42 (d, J = 8.6 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.68 (dd, J = 7.7, 1.6 Hz, 4.00 (q, J = 7.0 Hz, 2 H, 4ЈЈ-OCH2CH3), 6.35 (dd, J = 11.8, 1.2 Hz,
Eur. J. Org. Chem. 2009, 4468–4479
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4473

A. M. S. Silva et al.
FULL PAPER
Hα), 6.73 (d, J = 11.8 Hz, 1 H, Hβ), 6.75 (d, J = 8.7 Hz, 2 H, 3ЈЈ-
,5ЈЈ-H), 6.94 (ddd, J = 7.9, 7.2, 1.2 Hz, 1 H, 5Ј-H), 7.08 (dd, J =
7.0 Hz, 3 H, 4ЈЈ-OCH2CH3), 2.20 (s, 3 H, OCOCH3), 2.68 (s, 3 H,
NCOCH3), 4.04 (q, J = 7.0 Hz, 2 H, 4ЈЈ-OCH2CH3), 6.03 (dd, J =
7.9, 1.2 Hz, 1 H, 3Ј-H), 7.19 (d, J = 8.7 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.32 12.1, 0.7 Hz, 1 H, Hα), 6.52 (d, J = 12.1 Hz, 1 H, Hβ), 6.81 (d, J
(ddd, J = 7.9, 7.2, 1.6 Hz, 1 H, 4Ј-H), 7.94 (dd, J = 7.9, 1.6 Hz, 1 = 8.8 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.22 (d, J = 8.8 Hz, 2 H, 2ЈЈ-,6ЈЈ-H),
H, 6Ј-H), 8.06 (d, J = 1.2 Hz, 1 H, 5-H), 10.32 (s, 1 H, 2Ј-OH) ppm. 7.22 (dd, J = 7.8, 1.1 Hz, 1 H, 3Ј-H), 7.31 (dt, J = 7.6, 1.1 Hz, 1
13C NMR: δ = 14.8 (4ЈЈ-OCH2CH3), 21.6 (1-COCH3), 63.4 (4ЈЈ-
OCH2CH3), 114.4 (C-3ЈЈ,-5ЈЈ), 116.0 (C-1Ј), 117.16 (C-3Ј), 117.18
(C-α), 119.5 (C-5Ј), 120.7 (C-4), 127.6 (C-5), 128.3 (C-1ЈЈ), 128.7
H, 5Ј-H), 7.46 (ddd, J = 7.6, 7.8, 1.7 Hz, 1 H, 4Ј-H), 7.56 (dd, J =
7.6, 1.7 Hz, 1 H, 6Ј-H), 8.12 (d, J = 0.7 Hz, 1 H, 5-H) ppm. 13C
NMR: δ = 14.8 (4ЈЈ-OCH2CH3), 21.1 (OCOCH3), 21.6 (NCOCH3),
(C-6Ј), 129.9 (C-2ЈЈ,-6ЈЈ), 130.8 (C-4Ј), 133.3 (C-β), 153.2 (C-3), 63.4 (4ЈЈ-OCH2CH3), 114.5 (C-3ЈЈ,-5ЈЈ), 117.2 (C-α), 121.0 (C-4),
156.3 (C-2Ј), 158.5 (C-4ЈЈ), 167.8 (1-COCH3) ppm. EI-MS: m/z (%)
123.1 (C-3Ј), 124.6 (C-1Ј), 125.96 (C-5Ј), 126.04 (C-5), 129.0 (C-
1ЈЈ), 129.4 (C-2ЈЈ,-6ЈЈ), 130.2 (C-4Ј), 131.4 (C-6Ј), 131.6 (C-β), 148.4
= 348 (100) [M]+·, 320 (2), 306 (73), 291 (3), 277 (27), 260 (3), 247
(6), 185 (8), 171 (59), 155 (5), 131 (7), 115 (8), 102 (7), 91 (4), 77 (C-2Ј), 152.5 (C-3), 158.4 (C-4ЈЈ), 169.1 (OCOCH3), 169.2
(8), 65 (5). C21H20N2O3 (348.4): calcd. C 72.40, H 5.79, N 8.04;
found C 72.21, H 5.75, N 7.65.
(NCOCH3) ppm. EI-MS: m/z (%) = 390 (16) [M]+·, 348 (100) [M –
C2H2O]+, 319 (1), 306 (99), 291 (3), 277 (42), 260 (3), 247 (8), 229
(1), 222 (3), 205 (4), 185 (8), 171 (69), 155 (5), 139 (3), 131 (7), 115
(7), 102 (5), 89 (2), 77 (6), 65 (3). HRMS (ESI+ ): calcd.
(C23H22N2O4Na) 413.14718; found 413.14685.
(E)-1-Acetyl-3-(2-acetyloxyphenyl)-4-styryl-1H-pyrazole (7a): Yield
1
621 mg (79%), yellow oil. H NMR: δ = 2.07 (s, 3 H, OCOCH3),
2.71 (s, 3 H, NCOCH3), 6.72 (d, J = 16.4 Hz, 1 H, Hα), 6.93 (d, J
= 16.4 Hz, 1 H, Hβ), 7.21–7.23 (m, 1 H, 4ЈЈ-H), 7.26 (dd, J = 8.0,
1.0 Hz, 1 H, 3Ј-H), 7.30 (dd, J = 7.3, 7.6 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.34–
7.38 (m, 1 H, 5Ј-H), 7.37 (d, J = 7.3 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.49 (ddd,
J = 7.7, 8.0, 1.7 Hz, 1 H, 4Ј-H), 7.57 (dd, J = 7.5, 1.7 Hz, 1 H, 6Ј-
H), 8.49 (s, 1 H, 5-H) ppm. 13C NMR: δ = 20.8 (OCOCH3), 21.4
(NCOCH3), 116.9 (C-α), 123.1 (C-3Ј), 123.2 (C-4), 124.1 (C-5),
124.7 (C-1Ј), 126.1 (C-5Ј), 126.2 (C-2ЈЈ,-6ЈЈ), 127.8 (C-4ЈЈ), 128.5
(C-3ЈЈ,-5ЈЈ), 130.2 (C-4Ј), 130.7 (C-β), 131.3 (C-6Ј), 136.5 (C-1ЈЈ),
148.4 (C-2Ј), 151.3 (C-3), 168.9 (OCOCH3), 169.2 (NCOCH3) ppm.
ESI+-MS: m/z (%) = 369.1 (37) [M + Na+]. HRMS (ESI+): calcd.
(C21H18N2O3Na) 369.12096; found 369.12072.
Synthesis of endo-1-Acetyl-5-aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-
dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]indazoles 9a-e and
10a-c: A mixture of each one of the (E or Z)-1-acetyl-3-(2-hy-
droxyphenyl)-4-styrylpyrazoles 5a–e or 6a–c (0.16 mmol) and N-
methylmaleimide (0.11 g, 0.96 mmol) was irradiated at atmospheric
pressure in an Ethos SYNTH microwave (Milestone Inc.) at 802 W
for 40 min. The crude product was dissolved in chloroform and
purified by thin layer chromatography with a mixture of CHCl3/
EtOAc (8:2) as eluent. The residue was crystallised from ethanol
to give the endo-1-acetyl-5-aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-
dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]indazole [9a 58.5 mg
(88%), 9b 49.0 mg (68%), 9c 69.8 mg (95%), 9d 62.6 mg (85%), 9e
60.3 mg (78 %), 10a 40.0 mg (60 %), 10b 38.9 mg (54 %), 10c
39.7 mg (54%)]. Compounds 9a–c, 9e and 10a–c were obtained as
white solids and compound 9d was obtained as a yellow solid.
(E)-1-Acetyl-3-(2-acetyloxyphenyl)-4-(4-chlorostyryl)-1H-pyrazole
(7b): Yield 1.10 g (80 %), M.p. 124–126 °C, yellow solid (recrys-
1
tallized from ethanol). H NMR: δ = 2.08 (s, 3 H, OCOCH3), 2.74
(s, 3 H, NCOCH3), 6.69 (dd, J = 16.6, 0.5 Hz, 1 H, Hα), 6.87 (d,
J = 16.6 Hz, 1 H, Hβ), 7.27–7.33 (m, 4 H, 2ЈЈ-,3ЈЈ-,5ЈЈ-,6ЈЈ-H), 7.34
(dd, J = 7.7, 1.2 Hz, 1 H, 3Ј-H), 7.38 (ddd, J = 7.2, 7.6, 1.2 Hz, 1
H, 5Ј-H), 7.52 (ddd, J = 7.2, 7.7, 1.8 Hz, 1 H, 4Ј-H), 7.57 (dd, J =
7.6, 1.8 Hz, 1 H, 6Ј-H), 8.49 (s, 1 H, 5-H) ppm. 13C NMR: δ = 21.0
(OCOCH3), 21.6 (NCOCH3), 117.7 (C-α), 123.1 (C-4), 123.2 (C-
3Ј), 124.3 (C-5), 124.7 (C-1Ј), 126.3 (C-5Ј), 127.5 (C-2ЈЈ,-6ЈЈ), 128.9
(C-3ЈЈ,-5ЈЈ), 129.5 (C-β), 130.5 (C-4Ј), 131.4 (C-6Ј), 133.5 (C-4ЈЈ),
135.1 (C-1ЈЈ), 148.6 (C-3), 151.5 (C-2Ј), 169.1 (OCOCH3), 169.4
(NCOCH3) ppm. ESI+-MS: m/z (%) = 403.1 (100) [M + Na+],
381.1 (5) [M + H+]. C21H17ClN2O3 (380.8): calcd. C 66.23, H 4.50,
N 7.36; found C 66.21, H 4.66, N 7.26.
(5S*,5aS*,8aS*,8bS*)-1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-
phenyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]indazole
(9a): M.p. 227–229 °C (recrystallized from ethanol). 1H NMR: δ =
2.54 (s, 3 H, 1-COCH3), 2.76 (s, 3 H, 7-NCH3), 3.42 (dd, J = 7.1,
7.9 Hz, 1 H, 5a-H), 3.59 (ddd, J = 7.1, 4.0, 3.6 Hz, 1 H, 5-H), 4.48
(dd, J = 7.2, 7.9 Hz, 1 H, 8a-H), 4.98 (ddd, J = 7.2, 3.6, 3.7 Hz, 1
H, 8b-H), 6.94–7.00 (m, 1 H, 5Ј-H), 6.99 (dd, J = 4.0, 3.7 Hz, 1 H,
4-H), 7.11 (dd, J = 8.3, 1.1 Hz, 1 H, 3Ј-H), 7.26 (d, J = 8.5 Hz, 2
H, 2ЈЈ-,6ЈЈ-H), 7.31–7.49 (m, 1 H, 4Ј-H), 7.38–7.42 (m, 1 H, 4ЈЈ-H),
7.42 (t, J = 8.5 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.65 (dd, J = 7.9, 1.6 Hz, 1 H,
6Ј-H), 9.80 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 21.5 (1-COCH3),
25.0 (7-NCH3), 40.6 (C-8a), 42.0 (C-5a), 45.0 (C-5), 57.6 (C-8b),
114.4 (C-1Ј), 117.7 (C-3Ј), 119.7 (C-5Ј), 125.6 (C-4), 127.5 (C-6Ј),
127.9 (C-4ЈЈ), 128.6 (C-3ЈЈ,-5ЈЈ), 128.8 (C-2ЈЈ,-6ЈЈ), 131.9 (C-4Ј),
137.2 (C-1ЈЈ), 138.0 (C-3a), 149.2 (C-3), 157.1 (C-2Ј), 168.6 (1-
COCH3), 173.4 (C-6), 174.4 (C-8) ppm. EI-MS: m/z (%) = 415 (70)
[M]+·, 373 (42), 304 (47), 286 (15), 262 (100), 202 (7), 185 (16), 171
(91), 149 (14), 128 (8), 115 (19), 91 (40), 83 (66), 69 (11), 57 (17).
C24H21N3O4 (415.4): calcd. C 69.39, H 5.10, N 10.11; found C
68.98, H 4.92, N 10.39.
(E)-1-Acetyl-3-(2-acetyloxyphenyl)-4-(4-nitrostyryl)-1H-pyrazole
(7d): Yield 844 mg (92%), M.p. 171–174 °C, yellow solid (recrys-
1
tallized from ethanol). H NMR: δ = 2.08 (s, 3 H, OCOCH3), 2.75
(s, 3 H, NCOCH3), 6.90 (d, J = 16.5 Hz, 1 H, Hα), 6.97 (d, J =
16.5 Hz, 1 H, Hβ), 7.29 (dd, J = 8.0, 0.6 Hz, 1 H, 3Ј-H), 7.40 (ddd,
J = 7.5, 7.8, 0.6 Hz, 1 H, 5Ј-H), 7.51 (d, J = 8.9 Hz, 2 H, 3ЈЈ-,5ЈЈ-
H), 7.55 (ddd, J = 7.5, 8.0, 1.7 Hz, 1 H, 4Ј-H), 7.57 (dd, J = 7.8,
1.7 Hz, 1 H, 6Ј-H), 8.18 (d, J = 8.9 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 8.56 (s, 1
H, 5-H) ppm. 13C NMR: δ = 21.0 (OCOCH3), 21.6 (NCOCH3),
121.8 (C-α), 122.4 (C-4), 123.3 (C-3Ј), 124.2 (C-3ЈЈ,-5ЈЈ), 124.6 (C-
1Ј), 125.1 (C-5), 126.4 (C-5Ј), 126.8 (C-2ЈЈ,-6ЈЈ), 128.3 (C-β), 130.7
(C-4Ј), 131.4 (C-6Ј), 143.1 (C-1ЈЈ), 146.9 (C-4ЈЈ), 148.6 (C-2Ј), 151.6
(C-3), 169.0 (OCOCH3), 169.4 (NCOCH3) ppm. EI-MS: m/z (%)
= 391 (57) [M]+·, 361 (2) [M – NO]+, 349 (73), 307 (100), 290 (16),
277 (49), 260 (33), 231 (5), 202 (6), 185 (16), 171 (75), 155 (2), 140
(2), 115 (6), 102 (2), 91 (2), 77 (2). C21H17N3O5 (391.4): calcd. C
64.45, H 4.38, N 10.74; found C 64.85, H 4.50, N 10.80.
(5S*,5aS*,8aS*,8bS*)-1-Acetyl-5-(4-chlorophenyl)-3-(2-hydroxy-
phenyl)-7-methyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]-
indazole (9b): M.p. 209–210 °C (recrystallized from ethanol). 1H
NMR: δ = 2.54 (s, 3 H, 1-COCH3), 2.76 (s, 3 H, 7-NCH3), 3.39
(dd, J = 6.9, 8.0 Hz, 1 H, 5a-H), 3.59 (ddd, J = 6.9, 4.0, 3.4 Hz, 1
H, 5-H), 4.48 (dd, J = 8.0, 7.1 Hz, 1 H, 8a-H), 4.97 (ddd, J = 7.1,
3.9, 3.4 Hz, 1 H, 8b-H), 6.90 (dd, J = 4.0, 3.9 Hz, 1 H, 4-H), 6.98
(ddd, J = 7.9, 7.4, 1.1 Hz, 5Ј-H), 7.11 (dd, J = 8.1, 1.1 Hz, 1 H, 3Ј-
(Z)-1-Acetyl-3-(2-acetyloxyphenyl)-4-(4-ethoxystyryl)-1H-pyrazole H), 7.26 (d, J = 8.5 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.38 (ddd, J = 8.1, 7.4,
(8c): Yield 590 mg (92%), yellow oil. 1H NMR: δ = 1.43 (t, J =
1.6 Hz, 1 H, 4Ј-H), 7.42 (d, J = 8.5 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.65 (dd,
4474
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Eur. J. Org. Chem. 2009, 4468–4479

1H-Indazoles by Diels–Alder Reactions
J = 7.9, 1.6 Hz, 1 H, 6Ј-H), 9.80 (s, 1 H, 2Ј-OH) ppm. 13C NMR: (dd, J = 8.2, 2.8 Hz, 1 H, 5-H), 4.79 (ddd, J = 8.2, 3.2, 2.8 Hz, 1
δ = 21.5 (1-COCH3), 25.0 (7-NCH3), 40.4 (C-8a), 41.8 (C-5a), 44.4
(C-5), 57.5 (C-8b), 114.3 (C-1Ј), 117.7 (C-3Ј), 119.8 (C-5Ј), 124.9
H, 8b-H), 6.96 (dd, J = 3.2, 1.3 Hz, 1 H, 4-H), 6.98 (ddd, J = 7.9,
7.8, 1.2 Hz, 1 H, 5Ј-H), 7.09 (dd, J = 8.3, 1.2 Hz, 1 H, 3Ј-H), 7.31–
(C-4), 127.4 (C-6Ј), 128.8 (C-3ЈЈ,-5ЈЈ), 130.1 (C-2ЈЈ,-6ЈЈ), 131.9 (C- 7.39 (m, 6 H, 2ЈЈ-,3ЈЈ-,4ЈЈ-,5ЈЈ-,6ЈЈ-,4Ј-H), 7.70 (dd, J = 7.9, 1.6 Hz,
4Ј), 133.8 (C-4ЈЈ), 135.8 (C-1ЈЈ), 138.3 (C-3a), 149.1 (C-3), 157.0 1 H, 6Ј-H), 9.79 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 21.4 (1-
(C-2Ј), 168.6 (1-COCH3), 173.2 (C-6), 174.3 (C-8) ppm. EI-MS: COCH3), 25.4 (7-NCH3), 41.5 (C-8a), 42.5 (C-5), 42.8 (C-5a), 55.6
m/z (%) = 451 (29) [M]+· (37Cl), 449 (75) [M]+· (35Cl), 407 (64), 338 (C-8b), 114.2 (C-1Ј), 117.6 (C-3Ј), 119.7 (C-5Ј), 125.4 (C-4), 126.8
(34), 321 (10), 296 (91), 257 (7), 202 (16), 188 (14), 171 (100), 160
(C-2ЈЈ,-6ЈЈ), 127.5 (C-6Ј), 127.7 (C-4Ј), 129.3 (C-3ЈЈ,-5ЈЈ), 131.8 (C-
(35), 152 (11), 131 (10), 115 (16), 102 (6), 78 (8); 55 (4). HRMS 4ЈЈ), 136.8 (C-1ЈЈ), 138.4 (C-3a), 149.5 (C-3), 157.0 (C-2Ј), 168.4 (1-
(FAB+-LR): calcd. (C24H21N3O435Cl) 450.1221; found 450.1220.
COCH3), 173.8 (C-6), 177.6 (C-8) ppm. EI-MS: m/z (%) = 415 (93)
[M]+·, 373 (100) [M – CH2CO]+, 304 (24), 296 (8), 282 (46), 262
(88), 239 (6), 231 (6), 210 (7), 202 (9), 185 (16), 171 (90), 160 (7),
152 (11), 141 (6), 131 (8), 128 (10), 115 (24), 102 (8), 91 (11), 77
(14), 63 (10). HRMS (FAB+-LR) (C24H22N3O4): calcd. 416.1610;
found 416.1617.
(5S*,5aS*,8aS*,8bS*)-1-Acetyl-5-(4-ethoxyphenyl)-3-(2-hydroxy-
phenyl)-7-methyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]-
indazole (9c): This compound was shown to possess spectroscopic
and analytical data identical to those previously reported.[45]
(5S*,5aS*,8aS*,8bS*)-1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-(4-
nitrophenyl)-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]ind-
azole (9d): M.p. 229–231 °C (recrystallized from ethanol). 1H
NMR: δ = 2.55 (s, 3 H, 1-COCH3), 2.77 (s, 3 H, 7-NCH3), 3.47
(dd, J = 8.6, 6.9 Hz, 1 H, 5a-H), 3.68 (ddd, J = 6.9, 4.0, 3.6 Hz, 1
H, 5-H), 4.53 (dd, J = 8.6, 7.3 Hz, 1 H, 8a-H), 5.00 (ddd, J = 7.3,
4.0, 3.6 Hz, 1 H, 8b-H), 6.94 (t, J = 4.0 Hz, 1 H, 4-H), 7.00 (ddd,
J = 7.5, 7.8, 1.0 Hz, 1 H, 5Ј-H), 7.12 (dd, J = 8.1, 1.0 Hz, 1 H, 3Ј-
H), 7.40 (ddd, J = 8.1, 7.5, 1.5 Hz, 1 H, 4Ј-H), 7.52 (d, J = 8.7 Hz,
2 H, 2ЈЈ-,6ЈЈ-H), 7.65 (d, J = 7.8 Hz, 1 H, 6Ј-H), 8.32 (d, J = 8.7 Hz,
2 H, 3ЈЈ-,5ЈЈ-H), 9.73 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 21.5 (1-
COCH3), 25.1 (7-NCH3), 40.3 (C-8a), 41.8 (C-5a), 44.5 (C-5), 57.6
(C-8b), 114.2 (C-1Ј), 117.8 (C-3Ј), 119.8 (C-5Ј), 123.3 (C-4), 123.8
(C-3ЈЈ,-5ЈЈ), 127.3 (C-6Ј), 129.8 (C-2ЈЈ,-6ЈЈ), 132.1 (C-4Ј), 138.8 (C-
3a), 144.7 (C-1ЈЈ), 147.5 (C-4ЈЈ), 148.9 (C-3), 157.0 (C-2Ј), 168.6 (1-
COCH3), 172.9 (C-6), 174.1 (C-8) ppm. EI-MS: m/z (%) = 460 (54)
[M]+·, 430 (9), 418 (61), 386 (17), 349 (26), 331 (16), 319 (19), 307
(81), 296 (11), 277 (21), 255 (24), 220 (13), 205 (36), 185 (20), 171
(100), 160 (19), 149 (22), 137 (12), 123 (16), 109 (38), 97 (68), 65
(63), 57 (71). C24H20N4O6 (460.4): calcd. C 62.60, H 4.38, N 12.17;
found C 62.96, H 4.50, N 12.43.
(5R*,5aS*,8aS*,8bS*)-1-Acetyl-5-(4-chlorophenyl)-3-(2-hydroxy-
phenyl)-7-methyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo-
[3,4-g]indazole (10b): M.p. 136–137 °C (recrystallized from etha-
nol). 1H NMR: δ = 2.46 (s, 3 H, 1-COCH3), 2.88 (s, 3 H, 7-NCH3),
3.55 (d, J = 8.6 Hz, 5a-H), 4.43 (dd, J = 8.1, 8.6 Hz, 1 H, 8a-H),
4.72 (d, J = 7.7 Hz, 1 H, 5-H), 4.73 (ddd, J = 8.1, 3.9, 3.9 Hz, 1
H, 8b-H), 6.93 (dd, J = 3.9, 4.1 Hz, 1 H, 4-H), 6.98 (ddd, J = 7.5,
7.7, 0.9 Hz, 1 H, 5Ј-H), 7.09 (dd, J = 8.6, 0.9 Hz, 1 H, 3Ј-H), 7.35
(d, J = 8.6 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.37 (ddd, J = 8.6, 7.5, 1.5 Hz, 1
H, 4Ј-H), 7.68 (dd, J = 7.7, 1.5 Hz, 1 H, 6Ј-H), 8.63 (d, J = 8.6 Hz,
2 H, 3ЈЈ-,5ЈЈ-H), 9.74 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 21.4 (1-
COCH3), 25.4 (7-NCH3), 41.4 (C-8a), 41.9 (C-5), 42.7 (C-5a), 55.6
(C-8b), 114.1 (C-1Ј), 117.7 (C-3Ј), 119.7 (C-5Ј), 124.8 (C-4), 127.5
(C-6Ј), 128.2 (C-3ЈЈ,-5ЈЈ), 129.4 (C-2ЈЈ,-6ЈЈ), 131.9 (C-4Ј), 133.6 (C-
4ЈЈ), 135.3 (C-1ЈЈ), 138.8 (C-3a), 149.4 (C-3), 157.0 (C-2Ј), 168.4 (1-
COCH3), 173.6 (C-6), 177.3 (C-8) ppm. EI-MS: m/z (%) = 449 (91)
[M]+·, 407 (100), 338 (17), 321 (15), 296 (92), 282 (41), 257 (7), 239
(6), 228 (6), 213 (5), 211 (8), 202 (9), 185 (15), 171 (84), 160 (5),
152 (9), 127 (5), 115 (14), 102 (6), 77 (6). HRMS (FAB+-LR)
(C24H21N3O435Cl): calcd. 450.1221; found 450.1201.
(5R*,5aS*,8aS*,8bS*)-1-Acetyl-5-(4-ethoxyphenyl)-3-(2-hydroxy-
phenyl)-7-methyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo-
[3,4-g]indazole (10c): This compound was shown to possess spectro-
scopic and analytical data identical to those previously reported.[45]
(5S*,5aS*,8aS*,8bS*)-1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-(4-
trifluoromethylphenyl)-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo-
[3,4-g]indazole (9e): M.p. 208–209 °C (recrystallized from ethanol).
1H NMR: δ = 2.54 (s, 3 H, 1-COCH3), 2.77 (s, 3 H, 7-NCH3), 3.45
(broad dd, J = 8.0, 7.3 Hz, 1 H, 5a-H), 3.63 (ddd, J = 7.3, 4.0,
3.6 Hz, 5-H), 4.50 (dd, J = 8.0, 7.5 Hz, 1 H, 8a-H), 4.98 (ddd, J =
7.5, 3.9, 3.6 Hz, 8b-H), 6.94 (dd, J = 4.0, 3.9 Hz, 4-H), 6.98 (ddd,
1-Acetyl-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-7-methyl-5,8b-(1-
methylsuccinimido)-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo-
[3,4-g]indazole (12b): M.p. 222–223 °C (10%), white solid (recrys-
J = 7.9, 7.5, 1.0 Hz, 1 H, 5Ј-H), 7.11 (dd, J = 8.1, 1.0 Hz, 1 H, 3Ј- tallized from ethanol). 1H NMR: δ = 2.64 (s, 3 H, 1-COCH3), 2.71
H), 7.39 (ddd, J = 8.1, 7.5, 1.5 Hz, 1 H, 4Ј-H), 7.46 (d, J = 8.2 Hz,
2 H, 2ЈЈ-,6ЈЈ-H), 7.65 (dd, J = 7.9, 1.5 Hz, 1 H, 6Ј-H), 7.71 (d, J =
(s, 6 H, 2ϫNCH3), 3.52 (d, J = 8.5 Hz, 2 H, 8a-,8aЈ-H), 4.34 (d,
J = 8.5 Hz, 2 H, 5a-,5aЈ-H), 7.00 (ddd, J = 8.1, 7.7, 1.1 Hz, 1 H,
8.2 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 9.78 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 5Ј-H), 7.10 (dd, J = 8.1, 1.1 Hz, 1 H, 3Ј-H), 7.21 (s, 1 H, 4-H), 7.40
21.5 (1-COCH3), 25.0 (7-NCH3), 40.4 (C-8a), 41.7 (C-5a), 44.7 (C- (ddd, J = 8.1, 7.7, 2.0 Hz, 1 H, 4Ј-H), 7.47–7.57 (m, 4 H, 2ЈЈ-,3ЈЈ-,
5), 57.6 (C-8b), 114.2 (C-1Ј), 117.7 (C-3Ј), 119.8 (C-5Ј), 123.9 (q, J
5ЈЈ-,6ЈЈ-H), 7.67 (dd, J = 8.1, 2.0 Hz, 6Ј-H), 9.75 (s, 1 H, 2Ј-
= 270.0 Hz, CF3), 124.3 (C-4), 125.6 (q, J = 3.7 Hz, C-3ЈЈ,-5ЈЈ), OH) ppm. 13C NMR: δ = 22.2 (1-COCH3), 25.0 (2ϫNCH3), 29.2
127.4 (C-6Ј), 129.2 (C-2ЈЈ,-6ЈЈ), 130.0 (q, J = 32.4 Hz, C-4ЈЈ), 132.0 (C-5), 43.0 (C-5a,-5aЈ), 46.1 (C-8a,-8aЈ), 66.4 (C-8b), 114.0 (C-1Ј),
(C-4Ј), 138.5 (C-3a), 141.3 (C-1ЈЈ), 149.0 (C-3), 157.0 (C-2Ј), 168.6 118.0 (C-3Ј), 119.8 (C-5Ј), 121.8 (C-4), 126.7 and 128.6 (C-3ЈЈ and
(1-COCH3), 173.1 (C-6), 174.2 (C-8) ppm. 19F NMR (300.13 MHz, C-5ЈЈ), 128.1 (C-6Ј), 128.9 and 129.5 (C-2ЈЈ and C-6ЈЈ), 132.3 (C-
CDCl3, ref. C6F6): δ = –85.5 (s, CF3) ppm. EI-MS: m/z (%) = 483
4Ј), 134.36 (C-4ЈЈ), 134.40 (C-3a), 139.4 (C-1ЈЈ), 146.4 (C-3), 157.1
(C-2Ј), 169.6 (1-COCH3), 171.6 (C-6,6Ј), 172.8 (C-8,8Ј) ppm.
(71) [M]+·, 441 (65) [M – C2H2O]+, 372 (22), 354 (11), 330 (100),
211 (6), 185 (15), 171 (81), 160 (23), 115 (6), 77 (5). C25H20F3N3O4 FAB+-MS: m/z (%) = 559 (8) [M + H]+, 558 (16), 460 (4), 452 (6),
(483.4): calcd. C 62.11, H 4.17, N 8.69; found C 62.31, H 4.17, N
8.85.
406 (4), 307 (30), 289 (17), 288 (10), 244 (7), 219 (6), 176 (6), 155
(31), 154 (100). HRMS (FAB+-LR) (C29H24N4O635Cl): calcd.
559.1384; found 559.1364.
(5R*,5aS*,8aS*,8bS*)-1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-
phenyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]indazole
1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5,8b-(1-methylsuccinimido)-
5-(4-nitrophenyl)-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]-
1
(10a): M.p. 223–224 °C (recrystallized from ethanol). H NMR: δ
= 2.46 (s, 3 H, 1-COCH3), 2.88 (s, 3 H, 7-NCH3), 3.60 (dd, J = indazole (12d): 7%, oil. 1H NMR: δ = 2.64 (s, 3 H, 1-COCH3), 2.71
8.7, 1.3 Hz, 1 H, 5a-H), 4.43 (dd, J = 8.2, 8.7 Hz, 1 H, 8a-H), 4.76 (s, 6 H, 2ϫNCH3), 3.61 (d, J = 8.5 Hz, 2 H, 8a-,8aЈ-H), 4.38 (d,
Eur. J. Org. Chem. 2009, 4468–4479
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4475

A. M. S. Silva et al.
FULL PAPER
J = 8.5 Hz, 2 H, 5a-,5aЈ-H), 7.02 (ddd, J = 8.1, 7.5, 0.8 Hz, 1 H,
5-(4-Chlorophenyl)-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxo-1H-pyr-
5Ј-H), 7.11 (dd, J = 7.9, 0.8 Hz, 1 H, 3Ј-H), 7.24 (s, 1 H, 4-H), 7.42 rolo[3,4-g]indazole (13b): M.p. Ͼ 275 °C (recrystallized from etha-
1
(ddd, J = 7.9, 7.5, 1.4 Hz, 4Ј-H), 7.52 (dd, J = 8.1, 1.4 Hz, 1 H, 6Ј-
nol). H NMR: δ = 3.21 (s, 3 H, 7-NCH3), 7.06 (ddd, J = 7.8, 7.4,
H), 7.75 (dd, J = 8.2, 1.8 Hz, 1 H, 2ЈЈ-H), 7.94 (dd, J = 8.3, 1.8 Hz, 1.0 Hz, 1 H, 5Ј-H), 7.17 (dd, J = 8.1, 1.0 Hz, 1 H, 3Ј-H), 7.37 (ddd,
1 H, 6ЈЈ-H), 8.40 (dd, J = 8.3, 2.3 Hz, 1 H, 5ЈЈ-H), 8.45 (dd, J = J = 8.1, 7.4, 1.5 Hz, 1 H, 4Ј-H), 7.47–7.57 (m, 4 H, 2ЈЈ-,3ЈЈ-,
8.2, 2.3 Hz, 1 H, 3ЈЈ-H), 9.67 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ =
22.2 (1-COCH3), 25.1 (2ϫNCH3), 29.2 (C-5), 42.9 (C-5a,-5aЈ),
46.1 (C-8a,-8aЈ), 66.5 (C-8b), 113.9 (C-1Ј), 118.0 (C-3Ј), 120.0 (C-
5ЈЈ-,6ЈЈ-H), 7.99 (dd, J = 7.8, 1.5 Hz, 1 H, 6Ј-H), 8.40 (s, 1 H, 4-
H), 10.43 (s, 1 H, NH), 11.37 (brs, 1 H, 2Ј-OH) ppm. 13C NMR:
δ = 24.0 (7-NCH3), 115.5 (C-8a), 116.1 (C-1Ј), 117.7 (C-3Ј), 119.8
5Ј), 120.8 (C-4), 123.6 and 124.2 (C-3ЈЈ,-5ЈЈ), 126.7 (C-6Ј), 127.9 (C-5Ј), 126.1 (C-5a), 127.2 (C-6Ј), 128.4 (C-3ЈЈ,-5ЈЈ), 130.0 (C-4),
and 128.7 (C-2ЈЈ,-6ЈЈ), 132.4 (C-4Ј), 139.9 (C-1ЈЈ), 143.5 (C-4ЈЈ), 130.6 (C-4Ј), 131.0 (C-2ЈЈ,-6ЈЈ), 132.7 (C-8b), 133.2 (C-5), 133.5 (C-
146.3 (C-3a), 147.5 (C-3), 157.1 (C-2Ј), 169.7 (1-COCH3), 171.4 (C-
6,6Ј), 172.7 (C-8,8Ј) ppm. HRMS (ESI+) (C29H23N5O8Na): calcd.
592.1418; found 592.1436.
3a), 134.7 (C-4ЈЈ), 135.0 (C-1ЈЈ), 145.7 (C-3), 156.2 (C-2Ј), 167.6
(C-6,-8) ppm. FAB+-MS: m/z (%) = 404 (13), 338 (11), 289 (16),
273 (3), 242 (2), 212 (7), 195 (3), 165 (6). (FAB+-LR)-HRMS:
(C22H15N3O335Cl): calcd. 404.0802; found 404.0813.
Synthesis of 5-Aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxo-1H-pyr-
rolo[3,4-g]indazoles 13a–e under Microwave Irradiation Conditions:
A mixture of each of the appropriate endo-1-acetyl-3-(2-hy-
droxyphenyl)-7-methyl-5-phenyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-
1H-pyrrolo[3,4-g]indazoles 9a–e or 10a–c (0.12 mmol) and DDQ
(0.082 g, 0.36 mmol) in 1,2,4-trichlorobenzene (20 mL) was irradi-
ated at atmospheric pressure and 170 °C in an Ethos SYNTH mi-
crowave (Milestone Inc.) at 800 W for 30 min. The crude product
was purified by column chromatography, with light petroleum as
eluent, to remove the 1,2,4-trichlorobenzene, followed by ethyl ace-
tate to remove the reaction product, which was further purified by
thin layer chromatography with a mixture of CHCl3/EtOAc (9:1)
as eluent. The residue was recrystallized from ethanol to give the
5-aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxo-1H-pyrrolo[3,4-g]-
indazole [13a from 9a, 37.6 mg (85%); 13b from 9b, 15.5 mg (32%);
13c from 9c, 17.9 mg (36%), 13d from 9d, 16.9 mg (34%), 13e from
9e, 5.8 mg (11 %); 13a from 10a, 9.7 mg (22 %); 13b from 10b,
2.9 mg (6%); 13c from 10c, 15.4 mg (31%)]. In the purification of
compound 13a obtained from 9a we also isolated a spot with lower
Rf value that was identified as compound 14a, obtained as a yellow
residue (6.42 mg, 13%). Compounds 15a–e were identified, in each
case, as a spot with a lower Rf value than the indazole 13a–e (15b–
e from the dehydrogenation of 9b–e and 15a from 10a): 15a 12.4 mg
(25%), 15b 7.0 mg (13%), 15c 2.2 mg (4%), 15d 11.0 mg (20%),
15e 3.5 mg (6%).
5-(4-Ethoxyphenyl)-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxo-1H-pyr-
rolo[3,4-g]indazole (13c): M.p. 258–260 °C (recrystallized from eth-
anol). 1H NMR: δ = 1.47 (t, J = 7.0 Hz, 3 H, 4ЈЈ-OCH2CH3), 3.20
(s, 3 H, 7-NCH3), 4.13 (q, J = 7.0 Hz, 2 H, 4ЈЈ-OCH2CH3), 7.03
(d, J = 8.7 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.05 (ddd, J = 7.8, 7.3, 1.2 Hz, 1
H, 5Ј-H), 7.16 (dd, J = 8.3, 1.2 Hz, 1 H, 3Ј-H), 7.35 (ddd, J = 8.3,
7.3, 1.6 Hz, 1 H, 4Ј-H), 7.50 (d, J = 8.7 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 8.01
(dd, J = 7.8, 1.6 Hz, 1 H, 6Ј-H), 8.41 (s, 1 H, 4-H), 10.50 (s, 1
H, NH), 11.34 (brs, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 14.9 (4ЈЈ-
OCH2CH3), 24.0 (7-NCH3), 63.5 (4ЈЈ-OCH2CH3), 114.1 (C-3ЈЈ,
-5ЈЈ), 115.3 (C-8a), 116.2 (C-1Ј), 117.6 (C-3Ј), 119.8 (C-5Ј), 127.3
(C-6Ј), 128.1 (C-5a), 128.7 (C-1ЈЈ), 130.0 (C-4), 130.4 (C-4Ј), 130.9
(C-2ЈЈ,-6ЈЈ), 133.0 (C-8b,-3a), 134.0 (C-5), 145.5 (C-3), 156.2 (C-2Ј),
159.3 (C-4ЈЈ), 168.2 (C-6,-8) ppm. EI-MS: m/z (%) = 413 (100)
[M]+·, 385 (22) [M – CO]+, 356 (5), 300 (3), 271 (2), 119 (1), 69 (5).
(FAB+-LR)-HRMS: (C24H20N3O4): calcd. 414.1454; found
414.1462.
3-(2-Hydroxyphenyl)-7-methyl-5-(4-nitrophenyl)-6,8-dioxo-1H-pyr-
rolo[3,4-g]indazole (13d): M.p. Ͼ275 °C (recrystallized from etha-
1
nol). H NMR: δ = 3.20 (s, 3 H, 7-NCH3), 7.07 (ddd, J = 7.8, 7.5,
1.1 Hz, 5Ј-H), 7.18 (dd, J = 8.3, 1.1 Hz, 1 H, 3Ј-H), 7.38 (ddd, J =
8.3, 7.8, 1.5 Hz, 1 H, 4Ј-H), 7.76 (d, J = 8.8 Hz, 2 H, 2ЈЈ-,6ЈЈ-H),
7.98 (dd, J = 7.5, 1.5 Hz, 1 H, 6Ј-H), 8.38 (d, J = 8.8 Hz, 2 H, 3ЈЈ-,
5ЈЈ-H), 8.44 (s, 1 H, 4-H), 10.33 (s, 1 H, NH), 11.30 (brs, 1 H, 2Ј-
OH) ppm. 13C NMR: δ = 24.1 (7-NCH3), 117.9 (C-3Ј), 120.0 (C-
5Ј), 123.4 (C-3ЈЈ,-5ЈЈ), 127.3 (C-6Ј), 128.8 (C-5a), 130.1 (C-4), 130.7
(C-4Ј,-2ЈЈ,-6ЈЈ), 133.3 (C-8b), 133.5 (C-3a), 134.7 (C-5), 137.1 (C-
1ЈЈ), 142.3 (C-4ЈЈ), 143.4 (C-3), 156.0 (C-2Ј), 167.8 (C-6,-8) ppm.
FAB+-MS: m/z (%) = 415 (5) [M + H]+, 391 (12), 355 (2), 338 (14),
242 (3), 212 (7), 195 (5), 180 (10), 123 (17). (FAB+-LR)-HRMS:
(C22H15N4O5): calcd. 415.1042; found 415.1049.
Synthesis of 5-Aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxo-1H-pyr-
rolo[3,4-g]indazoles 13a–e under Classical Heating Conditions: A
mixture of each one of the appropriate endo-1-acetyl-3-(2-hy-
droxyphenyl)-7-methyl-5-phenyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-
1H-pyrrolo[3,4-g]indazoles 9a–e or 10a–c (0.12 mmol) and DDQ
(0.082 g, 0.36 mmol) in 1,2,4-trichlorobenzene (20 mL) was heated
at 170 °C until the consumption of the starting material. The reac-
tion progress was monitored by tlc. After that, the crude product
was purified by column chromatography, with light petroleum as
eluent to remove the 1,2,4-trichlorobenzene, followed by elution
with a mixture of ethyl acetate/light petroleum (3:2) to remove the
reaction product, which in some cases was further purified by thin
layer chromatography with the same mixture of ethyl acetate/light
petroleum (3:2) as eluent. The residue was recrystallized from etha-
nol to give the 5-aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxo-1H-
pyrrolo[3,4-g]indazole [13a from 9a (13.7 mg, 31%), 13b from 9b
(29.1 mg, 60%), 13c from 9c (17.8 mg, 36%), 13d from 9d (36.3 mg,
73%), 13e from 9e (35.7 mg, 68%), 13a from 10a (24.8 mg, 56%),
13b from 10b (26.6 mg, 55%), 13c from 10c (24.3 mg, 49%)]. In
the dehydrogenation of compound 9d into 13d we also isolated a
compound 14d (10.9 mg, 20%) with a lower Rf value than 13d.
3-(2-Hydroxyphenyl)-7-methyl-5-(4-trifluoromethylphenyl)-6,8-di-
oxo-1H-pyrrolo[3,4-g]indazole (13e): M.p. Ͼ275 °C (recrystallized
1
from ethanol). H NMR: δ = 3.07 (s, 3 H, 7-NCH3), 6.98 (dd, J =
8.0, 7.2 Hz, 1 H, 5Ј-H), 7.06 (d, J = 8.0 Hz, 1 H, 3Ј-H), 7.25–7.38
(m, 1 H, 4Ј-H), 7.59 (dd, J = 8.0, 1.5 Hz, 1 H, 6Ј-H), 7.68 (d, J =
8.5 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.73 (d, J = 8.5 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 8.43
(s, 1 H, 4-H), 9.95 (brs, 1 H, NH) ppm. 13C NMR: δ = 24.5 (7-
NCH3), 117.3 (C-3Ј), 119.8 (C-5Ј), 127.5 (C-6Ј), 125.6 (C-3ЈЈ,-5ЈЈ),
126.6 (C-2ЈЈ,-6ЈЈ), 130.0 (C-4Ј), 133.4 (C-8b), 133.9 (C-3a), 134.4
(C-5), 143.0 (C-3), 152.0 (C-2Ј), 162.6 (C-6,-8) ppm. MS
(ESI +): m/z (%) = 438.1 (6) [M + H]+. C23H14F3N3O3 (437.4):
calcd. C 63.16, H 3.23; N 9.61: found C 62.91, H 3.45, N 9.11.
1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-phenyl-6,8-dioxo-1H-pyr-
rolo[3,4-g]indazole (14a): 1H NMR: δ = 2.10 (s, 3 H, 1-COCH3),
3-(2-Hydroxyphenyl)-7-methyl-5-phenyl-6,8-dioxo-1H-pyrrolo[3,4-g]- 3.20 (s, 3 H, NCH3), 7.39–7.54 (m, 8 H, 3Ј-,4Ј-,5Ј-,2ЈЈ-,3ЈЈ-,4ЈЈ-,
indazole (13a): This compound was shown to possess spectroscopic
5ЈЈ-,6ЈЈ-H), 7.78 (dd, J = 7.5, 1.6 Hz, 1 H, 6Ј-H), 8.07 (s, 1 H, 4-
and analytical data identical to those previously reported.[45]
H), 11.23 (s, 1 H, 2Ј-OH) ppm. 13C NMR: δ = 20.9 (1-COCH3),
4476
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4468–4479

1H-Indazoles by Diels–Alder Reactions
23.9 (NCH3), 127.2 (C-5a), 128.1 (C-2ЈЈ,-6ЈЈ), 128.3 (C-6Ј), 129.3
(C-4ЈЈ), 129.5 (C-3ЈЈ,-5ЈЈ), 130.2 (C-4), 131.0 (C-4Ј), 133.3 (C-5),
thin layer chromatography with a mixture of CHCl3/EtOAc (9:1)
as eluent. The residue was crystallised from ethanol to give endo-
133.6 (C-3a), 136.7 (C-1ЈЈ), 155.0 (C-2Ј), 168.0 (1-COCH3), 168.4 1-acetyl-3-(2-hydroxyphenyl)-5-(4-nitrophenyl)-7-phenyl-6,8-dioxo-
(C-6), 169.3 (C-8) ppm.
5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]indazole (16d), obtained as
a yellow solid (49%, 29.2 mg).
1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-(4-nitrophenyl)-6,8-dioxo-
1H-pyrrolo[3,4-g]indazole (14d): 1H NMR: δ = 2.09 (s, 3 H, 1-
(5S*,5aS*,8aS*,8bS*)-1-Acetyl-3-(2-hydroxyphenyl)-5-(4-ni-
COCH3), 3.21 (s, 3 H, NCH3), 7.16–7.26 (m, 1 H, 5Ј-H), 7.29 (d, trophenyl)-7-phenyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo-
J = 8.1, 1.1 Hz, 1 H, 3Ј-H), 7.36–7.54 (m, 2 H, 4Ј,6Ј-H), 7.70 (d, J
= 8.8 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 8.07 (s, 1 H, 4-H), 8.33 (d, J = 8.8 Hz,
2 H, 3ЈЈ-,5ЈЈ-H) ppm.
[3,4-g]indazole (16d): M.p. 229–231 °C (recrystallized from etha-
nol). 1H NMR: δ = 2.48 (s, 3 H, 1-COCH3), 3.61 (dd, J = 7.5,
5.3 Hz, 1 H, 5a-H), 3.73 (ddd, J = 2.8, 3.2, 5.3 Hz, 1 H, 5-H), 4.63
(dd, J = 7.5, 7.8 Hz, 1 H, 8a-H), 5.09 (ddd, J = 2.8, 3.9, 7.8 Hz, 1
H, 8b-H), 6.54 (dd, J = 3.2, 3.9 Hz, 1 H, 4-H), 7.10 (dd, J = 7.9,
1.6 Hz, 2 H, 2ЈЈЈ-,6ЈЈЈ-H), 7.24 (dd, J = 8.6, 1.6 Hz, 1 H, 3Ј-H),
7.31–7.39 (m, 4 H, 5Ј-,3ЈЈЈ-,4ЈЈЈ-,5ЈЈЈ-H), 7.48–7.56 (m, 4 H, 4Ј-,2ЈЈ-
,6ЈЈ-,6Ј-H), 8.22 (d, J = 8.7 Hz, 2 H, 3ЈЈ-,5ЈЈ-H) ppm. 13C NMR: δ
= 21.2 (1-COCH3), 40.4 (C-8a), 42.6 (C-5a), 44.3 (C-5), 58.3 (C-
8b), 120.0 (C-4), 122.8 (C-1Ј), 123.6 (C-3ЈЈ,-5ЈЈ), 123.9 (C-3Ј), 126.4
(C-5Ј), 126.5 (C-2ЈЈЈ,-6ЈЈЈ), 128.7 (C-4ЈЈЈ), 128.9 (C-3ЈЈЈ,-5ЈЈЈ), 129.7
(C-2ЈЈ,-6ЈЈ), 129.8 (C-4Ј), 131.3 (C-6Ј), 140.1 (C-3a), 144.9 (C-1ЈЈ),
147.2 (C-4ЈЈ), 147.7 (C-3), 148.5 (C-2Ј), 169.5 (1-COCH3), 172.0
(C-6), 173.4 (C-8) ppm. FAB+-MS: m/z (%) = 523 (30) [M + H]+,
522 (10), 479 (7), 391 (7), 349 (6), 307 (32), 289 (16), 273 (7), 219
(7), 174 (10), 155 (30), 154 (100). HRMS (FAB+ -LR)
(C29H23N4O6): calcd. 523.1618; found 523.1618.
(5aR*,8aS*)-1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-phenyl-6,8-di-
oxo-5a,8a-dihydro-1H-pyrrolo[3,4-g]indazole (15a): 1H NMR: δ =
2.83 (s, 3 H, 1-COCH3), 2.98 (s, 3 H, NCH3), 4.71 (dd, J = 11.3,
2.2 Hz, 1 H, 5a-H), 5.51 (d, J = 11.3 Hz, 1 H, 8a-H), 6.91 (d, J =
2.2 Hz, 1 H, 4-H), 6.97 (ddd, J = 7.7, 7.4, 1.2 Hz, 1 H, 5Ј-H), 7.09
(dd, J = 8.3, 1.2 Hz, 1 H, 3Ј-H), 7.33 (ddd, J = 8.3, 7.4, 1.6 Hz, 1
H, 4Ј-H), 7.38–7.52 (m, 5 H, 2ЈЈ-, 3ЈЈ-,4ЈЈ-,5ЈЈ-,6ЈЈ-H), 7.60 (dd, J
= 7.7, 1.6 Hz, 1 H, 6Ј-H), 9.90 (s, 1 H, 2Ј-OH) ppm.
(5aR*,8aS*)-1-Acetyl-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-7-
methyl-6,8-dioxo-5a,8a-dihydro-1H-pyrrolo[3,4-g]indazole (15b): 1H
NMR: δ = 2.83 (s, 3 H, 1-COCH3), 2.98 (s, 3 H, NCH3), 4.66 (dd,
J = 11.3, 2.0 Hz, 1 H, 5a-H), 5.51 (d, J = 11.3 Hz, 1 H, 8a-H), 6.89
(d, J = 2.0 Hz, 4-H), 6.98 (ddd, J = 7.8, 7.4, 1.0 Hz, 1 H, 5Ј-H),
7.10 (dd, J = 8.3, 1.0 Hz, 3Ј-H), 7.34 (ddd, J = 8.3, 7.4, 1.5 Hz, 1
H, 4Ј-H), 7.39 (d, J = 8.6 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.44 (d, J = 8.6 Hz,
2 H, 3ЈЈ-,5ЈЈ-H), 7.58 (dd, J = 7.8, 1.5 Hz, 1 H, 6Ј-H), 9.85 (s, 1 H,
2Ј-OH) ppm.
1-Acetyl-3-(2-hydroxyphenyl)-5-(4-nitrophenyl)-7-phenyl-6,8-dioxo-
1H-pyrrolo[3,4-g]indazole (17d): Yellow oil (5%). 1H NMR: δ =
2.75 (s, 3 H, 1-COCH3), 6.98–6.95 (m, 2 H, 3Ј-,5Ј-H), 7.20–7.61
(m, 6 H, NC6H5, 4Ј-H), 7.51 (d, J = 8.8 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.97
(d, J = 8.7 Hz, 1 H, 6Ј-H), 8.18 (d, J = 8.8 Hz, 2 H, 3ЈЈ-,5ЈЈ-H),
8.56 (s, 1 H, 4-H) ppm. MS (ESI+): m/z (%) = 478.1 (20) [M +
H]+, 500.1 (73) [M + Na]+.
(5aR*,8aS*)-1-Acetyl-5-(4-ethoxyphenyl)-3-(2-hydroxyphenyl)-7-
methyl-6,8-dioxo-5a,8a-dihydro-1H-pyrrolo[3,4-g]indazole (15c): 1H
NMR: δ = 1.44 (t, J = 7.0 Hz, 3 H, 4ЈЈ-OCH2CH3), 2.83 (s, 3 H,
1-COCH3), 2.98 (s, 3 H, NCH3), 4.09 (q, J = 7.0 Hz, 2 H, 4ЈЈ-
OCH2CH3), 4.66 (dd, J = 11.4, 2.1 Hz, 1 H, 5a-H), 5.49 (d, J =
11.4 Hz, 1 H, 8a-H), 6.84 (d, J = 2.1 Hz, 1 H, 4-H), 6.92–7.10 (m,
2 H, 3Ј-,5Ј-H), 7.03 (d, J = 8.7 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 7.33 (ddd, J =
7.8, 7.7, 1.5 Hz, 1 H, 4Ј-H), 7.44 (d, J = 8.7 Hz, 2 H, 2ЈЈ-,6ЈЈ-H),
7.61 (dd, J = 7.9, 1.5 Hz, 1 H, 6Ј-H), 9.92 (s, 1 H, 2Ј-OH) ppm.
Synthesis of 1-[1,2-Bis(methoxycarbonyl)ethenyl]-3-(2-hydroxy-
phenyl)-4-(4-nitrostyryl)-1H-pyrazole (18d): A mixture of (E)-1-ace-
tyl-3-(2-hydroxyphenyl)-4-(4-nitrostyryl)-1H-pyrazole (5d, 0.040 g;
0.11 mmol) and DMAD (0.049 g, 0.33 mmol) was irradiated at at-
mospheric pressure in an Ethos SYNTH microwave (Mile-
stone Inc.) at 802 W for 40 min. The crude product was dissolved
in chloroform and purified by thin layer chromatography with chlo-
roform as eluent. The residue was isolated in a trace amount and
identified by NMR as 18d. 1H NMR: δ = 3.85 (s, 3 H, 1ЈЈЈ-
CO2CH3), 4.10 (s, 3 H, 4ЈЈЈ-CO2CH3), 6.48 (s, 1 H, 3ЈЈЈ-H), 6.51
(s, 1 H, 4-H), 7.02 (dd, J = 7.0, 7.8 Hz, 1 H, 5Ј-H), 7.03 (d, J =
16.4 Hz, 1 H, Hβ), 7.12 (d, J = 8.0 Hz, 1 H, 3Ј-H), 7.26 (d, J =
16.4 Hz, 1 H, Hα), 7.38 (ddd, J = 8.0, 7.0, 1.4 Hz, 1 H, 4Ј-H), 7.55
(d, J = 7.8 Hz, 1 H, 6Ј-H), 7.63 (d, J = 8.8 Hz, 2 H, 2ЈЈ-,6ЈЈ-H),
7.96 (s, 1 H, 5-H), 8.27 (d, J = 8.8 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 9.45 (s, 1
H, 2Ј-OH) ppm. 13C NMR: δ = 52.4 (1ЈЈЈ-CO2CH3), 53.9 (4ЈЈЈ-
CO2CH3), 105.9 (C-3ЈЈЈ), 115.6 (C-1Ј), 117.6 (C-3Ј), 119.8 (C-5Ј),
121.8 (C-α), 124.3 (C-3ЈЈ,-5ЈЈ), 127.0 (C-2ЈЈ,-6ЈЈ), 127.2 (C-5), 128.7
(C-6Ј), 129.6 (C-β), 131.1 (C-4Ј), 141.8 (C-2ЈЈЈ), 142.9 (C-1ЈЈ), 147.2
(C-3), 152.1 (C-4ЈЈ), 155.9 (C-2Ј), 162.7 (1ЈЈЈ-CO2CH3), 165.0 (4ЈЈЈ-
CO2CH3) ppm. FAB+-MS: m/z (%) = 451 (5) [M + H]+, 450 (18),
391 (29), 313 (13), 307 (20), 289 (15), 259 (10), 219 (17), 203 (8),
191 (9), 176 (9), 167 (18), 165 (12), 163 (10), 156 (10). HRMS
(FAB+-LR) (C23H20N3O7): calcd. 450.1301; found 450.1292.
(5aR*,8aS*)-1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-(4-nitrophen-
yl)-6,8-dioxo-5a,8a-dihydro-1H-pyrrolo[3,4-g]indazole (15d): 1H
NMR: δ = 2.85 (s, 3 H, 1-COCH3), 3.00 (s, 3 H, NCH3), 4.74 (dd,
J = 11.4, 2.0 Hz, 1 H, 5a-H), 5.58 (d, J = 11.4 Hz, 1 H, 8a-H), 7.03
(ddd, J = 7.8, 7.5, 1.0 Hz, 1 H, 5Ј-H), 7.04 (d, J = 2.0 Hz, 1 H, 4-
H), 7.11 (dd, J = 8.2, 1.0 Hz, 1 H, 3Ј-H), 7.35 (ddd, J = 8.2, 7.5,
1.5 Hz, 4Ј-H), 7.58 (dd, J = 7.8, 1.5 Hz, 6Ј-H), 7.67 (d, J = 8.6 Hz,
2 H, 2ЈЈ-,6ЈЈ-H), 8.29 (d, J = 8.6 Hz, 2 H, 3ЈЈ-,5ЈЈ-H), 9.74 (s, 1 H,
2Ј-OH) ppm.
(5aR*,8aS*)-1-Acetyl-3-(2-hydroxyphenyl)-7-methyl-5-(4-trifluoro-
methylphenyl)-6,8-dioxo-5a,8a-dihydro-1H-pyrrolo[3,4-g]indazole
(15e): 1H NMR: δ = 2.84 (s, 3 H, 1-COCH3), 2.99 (s, 3 H, NCH3),
4.72 (dd, J = 11.4, 2.3 Hz, 1 H, 5a-H), 5.55 (d, J = 11.4 Hz, 1 H,
8a-H), 6.96 (d, J = 2.3 Hz, 1 H, 4-H), 6.98 (ddd, J = 8.1, 7.4,
1.4 Hz, 1 H, 5Ј-H), 7.10 (dd, J = 8.1, 1.4 Hz, 1 H, 3Ј-H), 7.34 (ddd,
J = 8.1, 7.4, 1.6 Hz, 1 H, 4Ј-H), 7.57 (dd, J = 8.1, 1.6 Hz, 1 H, 6Ј-
H), 7.61 (d, J = 8.2 Hz, 2 H, 2ЈЈ-,6ЈЈ-H), 7.68 (d, J = 8.2 Hz, 2 H,
3ЈЈ-,5ЈЈ-H), 9.81 (s, 1 H, 2Ј-OH) ppm.
Synthesis of endo-1-Acetyl-3-(2-hydroxyphenyl)-5-(4-nitrophenyl)-7-
phenyl-6,8-dioxo-5,5a,8a,8b-tetrahydro-1H-pyrrolo[3,4-g]indazole
(16d): A mixture of (E)-1-acetyl-3-(2-hydroxyphenyl)-4-(4-nitrosty-
ryl)-1H-pyrazole (5d, 0.040 g; 0.11 mmol) and N-phenylmaleimide
(0.060 g, 0.33 mmol) was irradiated at atmospheric pressure in a
Acknowledgments
Thanks are due to the University of Aveiro, to the Fundação para
a Ciência e a Tecnologia (FCT) and to the Fundo Europeu de
Ethos SYNTH microwave (Milestone Inc.) at 802 W for 40 min. Desenvolvimento Regional (FEDER) for funding the Organic
The crude product was dissolved in chloroform and purified by Chemistry Research Unit. V. L. M. S is also thankful to the FCT
Eur. J. Org. Chem. 2009, 4468–4479
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4477

A. M. S. Silva et al.
FULL PAPER
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and to the Fundo Social Europeu (FSE) for her PhD Grant
(SFRH/BD/6647/2001). Financial support from the Fundação para
a Ciência e a Tecnologia and the Consejo Superior de Investiga-
ciones Científicas (FCT-CSIC) bilateral convention (26/CSIC/08)
is also acknowledged.
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Received: May 8, 2009
Published Online: July 29, 2009
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