Convenient synthesis of pyrrolo[3,4-g]indazole

Article abstract of DOI:10.1016/j.tet.2013.09.003

The synthesis of a novel class of tetrahydropyrrolo[3,4-g]indazoles is reported, by annelation of the pyrazole ring on the isoindole moiety by means of 5-hydroxymethylene tetrahydroisoindole-4-ones key intermediates, with good regioselectivity. Dihydroderivatives were also obtained by oxidation with DDQ of the corresponding tetrahydropyrrolo[3,4-g]indazoles. The growth inhibitory effect was evaluated at the National Cancer Institute of Bethesda and some derivatives showed modest activity.

Full text of DOI:10.1016/j.tet.2013.09.003

Tetrahedron xxx (2013) 1e9
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Tetrahedron
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Convenient synthesis of pyrrolo[3,4-g]indazole
ꢀ
Virginia Spano, Alessandra Montalbano, Anna Carbone, Barbara Parrino, Patrizia Diana,
*
Girolamo Cirrincione, Paola Barraja
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Via Archirafi 32, 90123 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2013
Received in revised form 20 August 2013
Accepted 3 September 2013
Available online xxx
The synthesis of a novel class of tetrahydropyrrolo[3,4-g]indazoles is reported, by annelation of the
pyrazole ring on the isoindole moiety by means of 5-hydroxymethylene tetrahydroisoindole-4-ones key
intermediates, with good regioselectivity. Dihydroderivatives were also obtained by oxidation with DDQ
of the corresponding tetrahydropyrrolo[3,4-g]indazoles. The growth inhibitory effect was evaluated at
the National Cancer Institute of Bethesda and some derivatives showed modest activity.
ꢀ 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyrrolo[3,4-g]indazole
Hydroxymethyleneketones
Antiproliferative activity
Regioselectivity
1. Introduction
straightforward method to obtain pyrrolo[3,4-g]indazoles either as
tetrahydro- and as dihydro-derivatives with a variety of sub-
Due to their wide range of pharmacological applications, pyr-
azoles and their benzocondensed analogues, indazoles, have been
the focus of much synthetic purpose in the past decades.1 Fused
tricyclic systems containing the pyrazole moiety have recently
emerged as an important class of compounds with enhanced in-
hibitory activity targeting a variety of protein kinases, being thus
useful in the treatment of several cell proliferative disorders, such
as cancer, inflammatory, and autoimmune diseases.
stitution patterns at the pyrrole and at the pyrazole moieties. The
title ring system is not much represented in the literature, and in
fact pyrrolo[3,4-g]indazoles were a new ring system at the time we
started our synthetic work. Only two papers appeared in 2011 as
a
study of the 1,3-dipolar cycloaddition of an unstabilized
N-methylazomethine ylide to nitrosulfones. However, few de-
rivatives were prepared generally in modest yields by the ring
closure of a pyrroline system to an indazole moiety.21,22 Our
In particular, compounds 1e3, bearing the pyrazole ring con-
densed to dihydrobenzothiophene,2 dihydrobenzothiazole3 or
dihydroquinazoline4 are representative examples of potent kinase
inhibitors (Chart 1). Over the past decades we have devoted our
efforts to the study of pyrrole-containing ring systems some of
which showed very promising antitumor properties.5e10 Recently,
we have reported the synthesis of dihydroisoxazolo[5,4-e]inda-
R1
N
R1
R1
N
N
N
N
N
N
S
R
S
R
N
R
zoles of type 4 using pyrazolo a-enamino ketones as key synthons
N
for the annelation of the isoxazole moiety.11 Thus, in this paper we
focus our attention on the synthesis of the tetrahydropyrrolo[3,4-g]
indazole ring system 5, as part of our ongoing project aimed at
3
1
2
2
N
1
O
N
R1
N
exploring the versatility of a-substituted ketones of the pyrrole or
3
8
6
pyrrolo-fused series, which gave us the entry to tricyclic systems
with antitumor and/or photosensitizing properties.12e20 Our pur-
pose, in the present work, is the validation of a simple and
N
N R
7
N
4
R1
5
4
5
Chart 1. Structures of dihydrothieno[2,3-e]indazoles (1), dihydrothiazolo[4,5-g]in-
dazoles (2), dihydropyrazolo[4,3-h]quinazolines (3), dihydroisoxazolo[5,4-e]indazoles
(4), tetrahydropyrrolo[3,4-g]indazoles (5).
* Corresponding author. Tel.: þ39 091 6161606; fax: þ39 091 23860854; e-mail
address: paola.barraja@unipa.it (P. Barraja).
0040-4020/$ e see front matter ꢀ 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.003
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V. Spano et al. / Tetrahedron xxx (2013) 1e9
2
synthetic approach consists of the annelation of the pyrazole
moiety on an isoindole system.
group coupling with the adjacent CH (7.49 ppm for 7a and 7.76 for
7b); in one case (7b) the coupling constant is also observable.
Moreover, in the 13C NMR spectrum, the typical signal of an alde-
hyde is missing. The synthesis of the desired indazoles was readily
accomplished by boiling the proper hydroxymethyleneketone
precursor in ethanol with hydrazine hydrate, or an alkyl- or aryl-
substituted hydrazines.
In particular, when hydrazine hydrate was used as dinucleophile
in the reaction of hydroxymethyleneketones bearing 1,3-
disubstituted pyrroles (7a,b), tetrahydropyrrolo[3,4-g]indazoles 9
and 17 were obtained in 75% and 80% yields, respectively, as single
products, with an N(1) substituted structure as supported by pre-
vious studies.29e31 The same reaction carried out using other sub-
strates gave mixed results. In fact, reaction of hydrazine hydrate
with hydroxymethyleneketones 7c,e, bearing a methyl substituent
at the pyrrole nitrogen failed, giving a very complex mixture, from
which it was not possible to isolate the corresponding indazole
derivatives; the N-benzyl derivatives of the same series 7d,f fur-
nished compounds 27 and 29 in 68% and 80% yields, respectively, as
single NH substituted isomers.
Reactions between hydroxymethyleneketones and alkyl-
substituted hydrazines, could conceivably give a mixture of N(1)-
and N(2)-alkylsubstituted pyrazoles. Since the substituted nitrogen
in an alkylmonosubstituted hydrazine is the more nucleophilic of
the two, we expected to obtain a mixture of the N(1)- and N(2)-
substituted regioisomers with at least a preponderance of the
N(2)-substituted one. Among the alkyl-substituted hydrazines, we
investigated the reactivity toward methyl- and benzyl-hydrazines.
In particular, from the reaction of 7b with methylhydrazine, the
2. Results and discussion
Among the different methodologies used for the synthesis of
the pyrazole framework, we became interested in the pyrazole
ring closure on the isoindole moiety, by means of
5-hydroxymethyleneketones of type 7. In fact, the reactivity of
these type of intermediates is less investigated than that of
enaminoketones, which are generally used as key intermediates for
reaction with bidentate nucleophiles.11e13,23e25
Tetrahydroisoindole-4-ones 6, suitable substrates for our
purpose, were previously prepared by us decorated with various
substituents on the pyrrole moiety.26e29 Reaction of these latter
with ethylformate and potassium tert-butoxide in benzene,
under nitrogen atmosphere furnished in good yields hydrox-
ymethyleneketones 7 (52e92%) (Scheme 1).26 Spectroscopic data
for compounds 7a,b (see Supplementary data) are in agreement
with a hydroxymethylene structure, supporting the ketone form of
these compounds with respect to the possible enol form bearing
a vicinal aldehydic group. In fact, the H NMR spectra show the
signal at 14.41 (7a) and 14.66 (7b) ppm referring to the hydroxyl
O
O
R2
N R
R1
R2
N R
R1
HO
i
corresponding
ethyl
tetrahydropyrrolo[3,4-g]indazole-6-
carboxylate 18 was isolated, as a mixture of the N(1)- and N(2)-
regioisomers 18A (22%) and 18B (70%).
7a-f
6a-f
In the cases of 7a,c,d,f reacting with methylhydrazine a single
indazole derivative, namely 10 (ethyl 2,7,8-trimethyl-2,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate, 73%), 26 (2,7,8-
trimethyl-2,4,5,7-tetrahydropyrrolo[3,4-g]indazole, 40%), 28 (7-
benzyl-2,8-dimethyl-2,4,5,7-tetrahydropyrrolo[3,4-g]indazole, 45%),
a R= R2= Me, R1= CO2Et; b R = Bn, R1 = CO2Et,
R2= Me; c R= R2= Me, R1= H; d R= Bn, R1= H,
R2= Me; e R= Me, R1=R2= H; f R= Bn, R1= R2= H
ii
30
(7-benzyl-2-methyl-2,4,5,7-tetrahydropyrrolo[3,4-g]indazole,
v
70%) corresponding to the N(2) substituted isomers were, re-
spectively, isolated as expected. The hydroxymethyleneketone 7e,
bearing a methyl substituent at the pyrrole nitrogen, once again
reacted with methylhydrazine furnishing a very complex mixture,
from which it was not possible to isolate the corresponding indazole
derivativeasapurecompound. Themodestyieldof26and28 (from 7c
R3
O
O
2
1
N
N
MeO
R2
N R
R1
N R
8a,b
and 7d) and the unsuccessful ring closure of
a hydrox-
a R=Me; b R=Bn
ymethyleneketone bearing a methyl group at the pyrrole moiety 7e,
inducedusnottocarryonfurtherstudiesonthesesubstrates(Table 1).
Reaction of 7a with benzylhydrazine furnished in good yields
the desired tetrahydropyrrolo[3,4-g]indazole derivative 11 (72%) as
9-12,17-21,26-31
iii, for
9,17,29
13-16,22-25,32-35
vi
a single N(2) regioisomer, whereas the N-benzyl hydrox-
ymethyleneketone 7b furnished 19 as a mixture of the N(1)- and
N(2)-substituted tetrahydroindazoles 19A and 19B in 20 and 72%
yields, with a preponderance of the N(2) regioisomer as expected.
Moreover, reaction of 7f gave 31 as a single N(2) derivative (70%).
Considering that among the hydroxymethyleneketones, 7b was
the only one, which produced the two regioisomers in reactions
with alkyl hydrazines, we investigated its reactivity toward phe-
nylhydrazine to further confirm the previous assigned structures. In
this case, we expected to obtain just the N(1)regioisomer. In fact,
the experimental verification of this result can be found in the lit-
erature, in which it is demonstrated that, thanks to the higher
iv
R3
2
Me
N
N
1
N
O
N
R2
N
N R
R
43 R=Me
44 R=Bn
R1
36-42
(from 9,10,16-18B,23,30)
nucleophilicity of the nitrogen atom
b to the phenyl group of
phenylhydrazine, a single N(1)-substituted pyrazole derivative is
Scheme 1. Synthesis of compounds 9e44 (see also Table 1). Reagents: (i) HCOOEt, t-
BuOK, benzene, rt, 24 h, (52e92%); (ii); NH2NHR3, EtOH, 60 ꢀC, 4 h, 20e86%; (iii) NaH,
benzylchlorides, DMF, rt, 2e3 h, 12e98%; (iv) DDQ, benzene, rt, 4 h, 42e74%; (v)
(CH3O)2C]O, t-BuOK, reflux, 1 h, 65e68%; (vi) NH2NHMe, EtOH, reflux, 24 h, 38e45%.
generally obtained.29e31
In accordance with this expectation, we were able to isolate
from the above mentioned reaction of 7b with phenylhydrazine,
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V. Spano et al. / Tetrahedron xxx (2013) 1e9
3
Table 1
ethyl 7-benzyl-1-(3-chlorobenzyl)-8-dimethyl-1,4,5,7-tetrahydro
pyrrolo[3,4-g]indazole-6-carboxylate 24 (86%) were still iso-
lated in very good yields as the main component of the reaction
mixtures, despite TLC monitoring indicating the presence of
traces of a secondary product, suggesting that the preferred site
of alkylation was at the N(1). However, NMR studies indicated
that the N(2) regioisomers, which were never isolated as pure
compounds, were also formed in traces. A similar behavior was
observed in the reaction of 17 with 4-chloro- and 2,4-
dichlorobenzychlorides, giving the corresponding tetrahy-
droindazoles mainly as N(1)regioisomers 23 and 25 in 84% and
82%, respectively.
Tetrahydropyrrolo[3,4-g]indazoles 9e35 and dihydropyrrolo[3,4-g]indazoles 36e42
R
R1
R2
R3
Yields (%)
9
10
11
12
13
14
15
16
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Bn
Bn
Bn
Bn
Me
Bn
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
1-H
2-Me
2-Bn
1-(4-OMeeC6H4)
1-(4-OMeeBn)
1-(4-CleBn)
1-(3-Cl-Bn)
1-(2,4-diCleBn)
1-H
1-Me
2-Me
1-Bn
2-Bn
75
73
72
86
96
90
98
92
80
22
70
20
72
68
80
88
84
86
82
40
68
45
80
70
70
70
15
73
21
68
12
65
18
50
54
74
54
72
60
42
38
45
17
18A
18B
19A
19B
20
21
22
23
24
25
26
27
28
29
30
31
32A
32B
33A
33B
34A
34B
35A
35B
36
37
38
39
40
When 29, bearing a benzyl substituent at the pyrrole nitrogen,
was reacted with 4-methoxy-, 4-chloro-, 3-chloro-, and 2,4-
dichloro-benzychlorides, tetrahydropyrrolo[3,4-g]indazoles were
obtained as a mixture of the N(1) regioisomer 32Ae35A (65e73%),
as the major component and the N(2)ones 32Be35B (12e21%).
From an analysis of the results obtained, it can be observed that
the N-benzyl substitution at the pyrrole nitrogen, in many cases,
orients two possible ring closures yielding a mixture of N(1) and
N(2) regioisomers. Moreover, for what concerns the alkylation re-
actions of the pyrazole moiety, a different behavior was observed
depending on the substituent at the pyrrole nitrogen, influenced
also by the substituents on the adjacent carbon atoms. The N-
benzylsubstituted derivatives (17,29) produced two regioisomers
always in favor of the N(1) substitution, indicating a tautomeric
equilibrium in dimethylformamide between the two forms at var-
iance of the ethyl 7,8-dimethyl-1,4,5,7-tetrahydropyrrolo[3,4-g]
indazole-6-carboxylate 9, which produced single products.
Incorporation of the carbonyl functionality into the heterocyclic
system was also accomplished, through the preparation of pyr-
azolones 43 and 44. Thus, the ketoesters 8a,b (65e68 %) were
prepared by boiling the corresponding tetrahydroisoindole-4-ones
7e and 7f in dimethylcarbonate in the presence of potassium tert-
butoxide. Cyclization with methylhydrazine proceeded in moderate
yields furnishing 43 (38%) and 44 (45%). Tetrahydropyrrolo[3,4-g]
indazoles 9e17,18B,19B, 29e31, 32Ae35A, selected in terms of best
yields when the two regioisomeric structures were available, were
subjected to dehydrogenation to dihydropyrrolo[3,4-g]indazole by
treatment with dichlorodicyanobenzoquinone (DDQ) in boiling
benzene. Unfortunately only few aromatic compounds 36e42 in
yields from modest to good (42e74%), could be isolated from the
complex reaction mixtures, maintaining the regioisomeric struc-
ture of the starting tetrahydropyrroloindazoles.
Biological screenings on selected derivatives were performed at
the National Cancer Institute (Bethesda, MD), at one dose concen-
tration (10ꢁ5 M), for the in vitro disease-oriented antitumor
screenings against a panel of about 60 human tumor cell lines.32
Among all of the derivatives, three tetrahydropyrrolo[3,4-g]inda-
zoles 9, 13 (of the 8-methyl-6-carboxylate series) and 27 (of the 7-
benzyl-8-methyl series) showed modest activity. In particular,
compounds 9, 13 exhibited selectivity against the HOP-92 cell line
of the non-small cell lung cancer with a growth inhibitory per-
centage of 79 and 88, respectively, whereas 27 showed selectivity
against the MDA-MB-435 cell line of the melanoma sub-panel with
a growth inhibitory percentage of 73. Among the dihydroindazole
derivatives only compound 39 of the 8-methyl-6-carboxylate series
showed selectivity against the HOP-92 cell line of the non-small cell
lung cancer with growth inhibitory percentage of 82.
1-C6H5
1-(4-OMeeC6H4)
1-(4-OMeeBn)
1-(4-CleBn)
1-(3-CleBn)
1-(2,4-diCleBn)
2-Me
1-H
2-Me
1-H
2-Me
H
H
H
H
H
H
H
H
2-Bn
1-(4-OMeeBn)
2-(4-OMeeBn)
1-(4-CleBn)
2-(4-CleBn)
1-(3-CleBn)
2-(3-CleBn)
1-(2,4-diCleBn)
2-(2,4-diCleBn)
1-H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
Me
Me
Me
Me
Me
Me
H
2-Me
1-(2,4-diCleBn)
1-H
2-Me
41
42
43
44
1-(4-CleBn)
2-Me
d
H
H
H
H
d
ethyl 7-benzyl-8-methyl-1-phenyl-1,4,5,7-tetrahydropyrrolo[3,4-
g]indazole-6-carboxylate (20) in 68% yield.
In fact, the 1H NMR spectrum in CDCl3 solution of 20 shows the
signal for the H-3 proton at 7.59 ppm, which is in a typical range
(7.45e7.59 ppm) of an N(1) substitution in this solvent for tetra-
hydropyrrolo[3,4-g]indazoles, whereas the same signal is generally
found at higher field for an N(2) substitution (7.10e7.36 ppm).
Additionally
7a,b
were
reacted
with
4-
methoxyphenylhydrazine furnishing the tetrahydroindazoles 12
and 21 in 86% and 80%, respectively, maintaining an N(1) structure
confirmed by the slight variation of the H-3 chemical shift (com-
pare 20 with 21), attributable to the effect of the methoxy sub-
stituent at the phenyl ring.
Moreover, selected derivatives (9,17 and 29) bearing a free NH at
the pyrazole moiety were subjected to alkylation with several
benzylchlorides in anhydrous dimethylformamide in the presence
of sodium hydride as base.
The N-methyl substituted derivative, 9 reacted with 4-methoxy-
, 4-chloro-, 3-chloro-, and 2,4-dichloro-benzychlorides furnishing
the corresponding tetrahydroindazoles in excellent yields 13 (96%),
14 (90%), 15 (98%), and 16 (92%) as exclusive products with an N(1)
structure.
3. Conclusions
On the contrary, from the reaction of the N-benzyl
derivative 17 with 4-methoxy- and 3-chloro-benzylchlorides,
ethyl 7-benzyl-1-(4-methoxybenzyl)-8-methyl-1,4,5,7-tetrahy-
dro pyrrolo[3,4-g]indazole-6-carboxylate 22 (88%), and
In conclusion, we have established a new efficient and versatile
method for the synthesis of the tetrahydropyrrolo[3,4-g]indazole
ring system, by addition of substituted hydrazines to 5-
hydroxymethyleneketones. This kind of reactivity was never
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V. Spano et al. / Tetrahedron xxx (2013) 1e9
4
explored before in the isoindole series, and allowed the preparation
of several derivatives of the ring system in very good yields.
Moreover, our synthetic approach consisting of the annelation of
the pyrazole ring to the tetrahydroisoindole moiety demonstrated
a good regioselectivity. The antiproliferative activity shown in
particular by four derivatives, although modest, makes this class of
compounds interesting for further studies directed toward the
synthesis of new compounds with an improved growth inhibitory
effect.
Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.65; H,
6.52; N, 4.35.
4.3. General procedure for the preparation of methyl-4-oxo-
4,5,6,7-tetrahydro-2H-isoindole-5-carboxylates (8a,b)
Potassium tert-butoxide (2.69 g, 0.024 mol) was added to dry
dimethylcarbonate (10.11 mL, 0.12 mol) followed by the relevant
tetrahydroindol-4-one 6e,f (0.006 mol). The mixture was boiled for
1 h with stirring under nitrogen atmosphere and evaporated under
reduced pressure. Ice/water was added to the crude residue, made
slightly acidic with 6 M HCl, and extracted with dichloromethane.
Removing the organic solvent a crude residue formed, which was
recrystallized from ethanol or purified by chromatography column.
4. Experimental section
4.1. General
All melting points were taken on a Buchi-Tottoli capillary ap-
paratus and were uncorrected; IR spectra were determined in
CHBr3, with a Jasco FT/IR 5300 spectrophotometer; 1H and 13C NMR
spectra were measured in DMSO-d6 or CDCl3 solutions, at 200 and
50.3 MHz, respectively, using a Bruker Avance II series 200 MHz
spectrometer. Column chromatography was performed with Merck
silica gel 230e400 mesh ASTM or with a SEPACORE chromatogra-
4.3.1. Methyl 2-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindole-5-
carboxylate (8a). This product was obtained from 6e. Yellow oil;
Rf¼0.54 (CH2Cl2); yield 68%; IR cmꢁ1: 1780 (CO), 1661 (CO). 1H NMR
(CDCl3):
d
2.23e2.85 (4H, m, 2ꢃ CH2), 3.44e3.45 (1H, m, CH), 3.65
(3H, s, CH3), 3.75 (3H, s, CH3), 6.37 (1H, s, H-1), 7.21 (1H, s, H-3). 13
NMR (CDCl3): 20.2 (t), 28.9 (t), 37.1 (q), 52.5 (q), 54.9 (d), 118.5 (d),
121.0 (s), 124.3 (d), 127.0 (s), 171.9 (s), 189.6 (s). Anal. Calcd for
11H13NO3 (207.23): C, 63.76; H, 6.32; N, 6.76. Found: C, 63.44; H,
C
d
€
phy apparatus BUCHI. Elemental analyses (C, H, N) were within
C
ꢂ0.4% of the theoretical values and were performed with a VARIO
EL III elemental analyzer. Compounds 7cef were prepared as pre-
viously described.26
6.04; N, 7.02.
4.3.2. Methyl 2-benzyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindole-5-
carboxylate (8b). This product was obtained from 6f. White solid;
Rf¼0.52 (CH2Cl2); mp 228e229 ꢀC; yield 65%; IR cmꢁ1: 1782 (CO),
4.2. General procedure for the preparation of 5-(hydroxyl
methylidene)-2,5,6,7-tetrahydro-4H-isoindol-4-one (7a,b)
1682 (CO). 1H NMR (CDCl3):
d
2.21e2.78 (4H, m, 2ꢃ CH2), 3.44e3.45
(1H, m, CH), 3.74 (3H, s, CH3), 5.00 (2H, s, CH2), 6.41 (1H, s, H-1),
To a suspension of t-BuOK (36 mmol) in dry toluene (30 mL),
a solution of 6a,b (12 mmol) in dry toluene (40 mL) was added
dropwise under N2 at 0 ꢀC. After 3 h stirring at room temperature
the reaction was cooled at 0 ꢀC and a solution of ethylformate
(36 mmol) in toluene (20 mL) was added and the mixture was kept
stirring at room temperature for 24 h, then the solvent was re-
moved under vacuum. The residue was dissolved in water and the
solution was washed with diethyl ether. The aqueous solution was
then acidified with 6 M HCl and extracted with dichloromethane.
The organic extracts were dried (Na2SO4) and evaporated under
reduced pressure. The residue was purified by chromatography
using dichloromethane/ethyl acetate (95:5) as eluent.
7.14e7.31 (6H, m, Ar and H-3). 13C NMR (CDCl3):
d
20.3 (t), 28.9 (t),
52.5 (q), 54.4 (t), 55.0 (d),117.7 (d),121.1 (s),123.8 (d),127.1 (s),127.9
(2ꢃd), 128.7 (d), 129.3 (2ꢃd), 136.5 (s), 171.8 (s), 189.8 (s). Anal.
Calcd for C17H17NO3 (283.32): C, 72.07; H, 6.05; N, 4.94. Found: C,
72.45; H, 5.88; N, 5.10.
4.4. General procedure for the tetrahydropyrrolo[3,4-g]in-
dazoles (9e12, 17e21, 26e31)
To
a solution of the relevant hydroxymethyl derivative 7
(0.03 mol) in anhydrous methanol (100 mL), the proper hydrazine
(0.1 mol) was added dropwise at room temperature and under ni-
trogen atmosphere. The mixture was heated at 60 ꢀC for 4 h and,
upon cooling, evaporated to dryness. To the crude residue water was
added and the insoluble material was filtered off, dried, and purified
by chromatography column, to afford the desired compounds.
4.2.1. Ethyl 5-(hydroxymethylidene)-2,3-dimethyl-4-oxo-4,5,6,7-
tetrahydro-2H-isoindole-1-carboxylate (7a). This compound was
obtained from 6a. White solid; Rf¼0.66 (CH2Cl2); yield: 63%; mp:
63e65 ꢀC; %; IR cmꢁ1: 2976 (OH), 1689 (CO), 1635 (CO); 1H NMR
(CDCl3):
d
1.37 (3H, t, J¼7.3 Hz, CH3), 2.45 (2H, t, J¼6.3 Hz, CH2), 2.59
4.4.1. Ethyl 7,8-dimethyl-1,4,5,7-tetrahydropyrrolo[3,4-g]indazole-6-
carboxylate (9). This product was obtained from 7a. Yellow solid;
Rf¼0.39 (CH2Cl2/EtOAc 70:30); mp 105e106 ꢀC; yield: 75%; IR
(3H, s, CH3), 2.94 (2H, t, J¼6.3 Hz, CH2), 3.81 (3H, s, CH3), 4.30 (2H, q,
J¼7.3 Hz, CH2), 7.42 (1H, s, CH), 14.34 (1H, br s, OH); 13C NMR
(CDCl3):
d
11.3 (q), 14.3 (q), 22.6 (t), 25.0 (t), 32.5 (q), 59.8 (t), 109.1
cmꢁ1: 3210 (NH), 1685 (CO). 1H NMR (DMSO-d6):
d 1.29 (3H, t,
(s), 117.3 (s), 134.4 (s), 140.0 (s), 161.5 (s), 164.2 (d), 187.6 (s), 200.1
(s). Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.60; H, 6.78; N, 5.05.
J¼7.2 Hz, CH3), 2.49 (3H, s, CH3), 2.65 (2H, t, J¼7.0 Hz, CH2), 2.94
(2H, t, J¼7.0 Hz, CH2), 3.75 (3H, s, CH3), 4.21 (2H, q, J¼7.2 Hz, CH2),
7.44 (1H, s, H-3), 12.28 (1H, s, NH). 13C NMR (DMSO-d6):
d 11.1 (q),
14.4 (q), 19.4 (t), 22.3 (t), 32.3 (q), 59.1 (t), 113.0 (s), 117.1 (s), 118.9
(s), 124.3 (s), 128.3 (s), 130.6 (d), 144.4 (s), 161.2 (s). Anal. Calcd for
4.2.2. Ethyl
2-benzyl-5-(hydroxymethylidene)-3-methyl-4-oxo-
4,5,6,7-tetrahydro-2H-isoindole-1-carboxylate (7b). This compound
was obtained from 6b. White solid; Rf¼0.64 (CH2Cl2); yield: 80%;
mp: 78e79 ꢀC; %; IR cmꢁ1: 2981 (OH), 1691 (CO), 1635 (CO); 1H
C14H17N3O2 (259.31): C, 64.85; H, 6.61; N, 16.20. Found: C, 64.64; H,
6.78; N, 16.01.
NMR (CDCl3)
d
1.58 (3H, t, J¼7.2 Hz, CH3), 2.77 (2H, t, J¼6.9 Hz, CH2),
4.4.2. Ethyl 2,7,8-trimethyl-2,4,5,7-tetrahydropyrrolo[3,4-g]indazole-
6-carboxylate (10). This product was obtained from 7a. White
solid; Rf¼0.36 (CH2Cl2/EtOAc 70:30); mp 104e105 ꢀC; yield: 73%; IR
2.85 (3H, s, CH3), 3.31 (2H, t, J¼6.9 Hz, CH2), 4.52 (2H, q, J¼7.2 Hz,
CH2), 5.92 (2H, s, CH2), 7.24 (2H, d, J¼7.2 Hz, H-20 and H-60),
7.51e7.62 (3H, m, H-30, H-40 and H-50), 7.76 (1H, s, CH), 14.66 (1H, br
cmꢁ1: 1686 (CO). 1H NMR (CDCl3):
d
1.34 (3H, t, J¼7.0 Hz, CH3), 2.47
s, OH); 13C NMR (CDCl3):
d
11.5 (q),14.2 (q), 22.8 (t), 25.0 (t), 48.2 (t),
(3H, s, CH3), 2.59 (2H, t, J¼6.8 Hz, CH2), 2.93 (2H, t, J¼6.8 Hz, CH2),
60.0 (t), 109.3 (s), 117.7 (s), 125.7 (2ꢃd), 127.2 (d), 128.7 (2ꢃd), 134.9
3.86 (3H, s, CH3), 3.99 (3H, s, CH3), 4.31 (2H, q, J¼7.0 Hz, CH2), 7.30
(s), 137.1 (s), 140.4 (s), 161.3 (s), 164.8 (d), 187.7 (s), 201.2 (s). Anal.
(1H, s, H-3). 13C NMR (CDCl3):
d 13.5 (q), 14.4 (q), 21.1 (t), 23.2 (t),
ꢀ
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5
32.7 (q), 39.6 (q), 59.7 (t), 111.7 (s), 116.6 (s), 128.8 (d), 130.9 (s),
136.0 (s), 136.1 (s), 136.3 (s), 161.9 (s). Anal. Calcd for C15H19N3O2
(273.33): C, 65.91; H, 7.01; N, 15.37. Found: C, 65.72; H, 7.38; N,
15.18.
7.17e7.30 (3H, m, H-30, H-40 and H-50). 13C NMR (CDCl3):
d
11.6 (q),
14.4 (q), 19.9 (t), 22.7 (t), 38.7 (q), 48.1 (t), 59.6 (t), 113.9 (s), 115.4 (s),
117.6 (s), 125.7 (2ꢃd), 126.6 (d), 126.7 (d), 128.5 (2ꢃd), 130.2 (s), 131.1
(s), 138.7 (s), 145.8 (s), 161.8 (CO). Anal. Calcd for C21H23N3O2
(349.43): C, 72.18; H, 6.63; N,12.03. Found: C, 72.53; H, 6.42; N,12.22.
4.4.3. Ethyl 2-benzyl-7,8-dimethyl-2,4,5,7-tetrahydropyrrolo[3,4-g]
indazole-6-carboxylate (11). This product was obtained from 7a.
White solid; Rf¼0.66 (CH2Cl2/EtOAc 95:5); mp 127e128 ꢀC; yield:
4.4.8. Ethyl 1,7-dibenzyl-8-methyl-1,4,5,7-tetrahydropyrrolo[3,4-g]
indazole-6-carboxylate (19A). This product was obtained from 7b.
Brown oil; Rf¼0.43 (CH2Cl2); yield 20%; IR cmꢁ1: 1682 (CO). 1H NMR
72%; IR cmꢁ1: 1682 (CO). 1H NMR (CDCl3):
d
1.37 (3H, t, J¼7.1 Hz,
CH3), 2.58 (3H, s, CH3), 2.69 (2H, t, J¼7.2 Hz, CH2), 3.05 (2H, t,
J¼7.2 Hz, CH2), 3.82 (3H, s, CH3), 4.29 (2H, q, J¼7.1 Hz, CH2), 5.28
(2H, s, CH2), 7.10 (1H, s, H-3), 7.22e7.38 (5H, m, Ar). 13C NMR
(CDCl3): 11.7 (q), 14.5 (q), 20.0 (t), 22.5 (t), 32.6 (q), 55.7 (t), 59.5 (t),
113.4 (s), 115.7 (s), 117.8 (s), 125.6 (d), 127.6 (2ꢃd), 127.7 (d), 128.6
(2ꢃd), 129.5 (s),131.2 (s),137.4 (s),145.8 (s), 162.2 (s). Anal. Calcd for
(DMSO-d6):
d
1.21 (3H, t, J¼7.1 Hz, CH3), 2.40 (3H, s, CH3), 2.68 (2H,
t, J¼7.3 Hz, CH2), 3.00 (2H, t, J¼7.3 Hz, CH2), 4.14 (2H, q, J¼7.1 Hz,
CH2), 5.27 (2H, s, CH2), 5.60 (2H, s, CH2), 6.92 (2H, d, J¼6.7 Hz, H-20
and H-60), 7.20e7.38 (8H, m, 2ꢃ Ar), 7.57 (1H, s, H-3). 13C NMR
(DMSO-d6): d 11.1 (q), 14.1 (q), 19.4 (t), 22.4 (t), 47.4 (t), 54.6 (t), 59.2
(t), 113.7 (s), 114.4 (s), 117.0 (s), 125.5 (d), 125.6 (2ꢃd), 126.7 (d),
127.4 (2ꢃd), 127.5 (2ꢃd), 128.4 (s), 128.5 (2ꢃd), 129.0 (s), 130.7 (d),
138.1 (s), 138.7 (s), 144.7 (s), 161.9 (s). Anal. Calcd for C27H27N3O2
(425.52): C, 76.21; H, 6.40; N, 9.87. Found: C, 75.87; H, 6.67; N, 9.94.
C
21H23N3O2 (349.43): C, 72.18; H, 6.63; N, 12.03. Found: C, 71.87; H,
6.85; N, 11.78.
4.4.4. Ethyl 1-(4-methoxyphenyl)-7,8-dimethyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (12). This product
was obtained from 7a. Brown solid; Rf¼0.50 (CH2Cl2/EtOAc 95:5);
mp 119e120 ꢀC; yield: 86%; IR cmꢁ1: 1685 (CO). 1H NMR (DMSO-
4.4.9. Ethyl 2,7-dibenzyl-8-methyl-2,4,5,7-tetrahydropyrrolo[3,4-g]
indazole-6-carboxylate (19B). This product was obtained from 7b.
Brown oil; Rf¼0.25 (CH2Cl2); yield 72%; IR cmꢁ1: 1699 (CO). 1H NMR
d6):
d
1.30 (3H, t, J¼7.0 Hz, CH3), 1.51 (3H, s, CH3), 2.58 (2H, t,
(DMSO-d6):
d
1.21 (3H, t, J¼7.1 Hz, CH3), 2.22 (3H, s, CH3), 2.60 (2H,
J¼6.4 Hz, CH2), 2.96 (2H, t, J¼6.4 Hz, CH2), 3.65 (3H, s, CH3), 3.81
(3H, s, CH3), 4.24 (2H, q, J¼7.0 Hz, CH2), 7.04 (2H, d, J¼8.8 Hz, H-30
and H-50), 7.34 (2H, d, J¼8.8 Hz, H-20 and H-60), 7.51 (1H, s, H-3). 13C
t, J¼7.3 Hz, CH2), 2.91 (2H, t, J¼7.3 Hz, CH2), 4.15 (2H, q, J¼7.1 Hz,
CH2), 5.49 (2H, s, CH2), 5.58 (2H, s, CH2), 6.83 (2H, d, J¼6.8 Hz, H-20
and H-60), 6.96 (2H, d, J¼6.6 Hz, H-200 and H-600), 7.22e7.31 (6H, m,
NMR (DMSO-d6):
d
11.9 (q), 14.3 (q), 20.5 (t), 20.6 (t), 32.4 (q), 55.4
2ꢃ Ar), 7.35 (1H, s, H-3). 13C NMR (DMSO-d6):
d 12.8 (q), 14.1 (q),
(q), 59.4 (t), 110.6 (s), 114.2 (2ꢃd), 116.9 (s), 117.9 (s), 125.7 (2ꢃd),
129.5 (s), 130.0 (s), 134.8 (s), 135.4 (s), 137.5 (d), 158.3 (s), 161.0 (s).
Anal. Calcd for C21H23N3O3 (365.43): C, 69.02; H, 6.34; N, 11.50.
Found: C, 69.32; H, 6.02; N, 11.75.
20.6 (t), 23.1 (t), 47.5 (t), 54.3 (t), 59.6 (t), 111.7 (s), 116.5 (s), 117.8 (s),
125.5 (2ꢃd), 126.0 (2ꢃd), 126.8 (d), 127.0 (d), 128.4 (2ꢃd), 128.5
(2ꢃd), 129.7 (d), 130.7 (s), 136.0 (s), 136.7 (s), 138.2 (s), 138.4 (s),
160.8 (s). Anal. Calcd for C27H27N3O2 (425.52): C, 76.21; H, 6.40; N,
9.87. Found: C, 76.45; H, 6.17; N, 10.04.
4.4.5. Ethyl
7-benzyl-8-methyl-1,4,5,7-tetrahydropyrrolo[3,4-g]in-
dazole-6-carboxylate (17). This product was obtained from 7b.
4.4.10. Ethyl 7-benzyl-8-methyl-1-phenyl-1,4,5,7-tetrahydropyrrolo
[3,4-g]indazole-6-carboxylate (20). This product was obtained from
7b. Brown solid; Rf¼0.57 (CH2Cl2/EtOAc 95:5); mp 56e57 ꢀC; yield
Brown solid; Rf¼0.46 (CH2Cl2/EtOAc 70:30); mp 181e182 ꢀC; yield:
80%; IR cmꢁ1: 3210 (NH), 1683 (CO). 1H NMR (DMSO-d6):
d 1.22 (3H,
t, J¼7.3 Hz, CH3), 2.44 (3H, s, CH3), 2.71 (2H, t, J¼6.9 Hz, CH2), 3.03
(2H, t, J¼6.9 Hz, CH2), 4.16 (2H, q, J¼7.3 Hz, CH2), 5.61 (2H, s, CH2),
6.94 (2H, d, J¼6.9 Hz, H-20 and H-60), 7.20e7.30 (3H, m, H-30, H-40
and H-50), 7.44 (1H, s, H-3), 12.38 (1H, s, NH). 13C NMR (DMSO-d6):
68%; IR cmꢁ1: 1685 (CO). 1H NMR (CDCl3):
d
1.35 (3H, t, J¼7.1 Hz,
CH3), 1.45 (3H, s, CH3), 2.73 (2H, t, J¼6.6 Hz, CH2), 3.12 (2H, t,
J¼6.6 Hz, CH2), 4.24 (2H, q, J¼7.1 Hz, CH2), 5.52 (2H, s, CH2),
6.85e7.53 (10H, m, Ar), 7.59 (1H, s, H-3). 13C NMR (CDCl3):
d 12.4
d
11.1 (q),14.2 (q),19.4 (t), 22.4 (t), 47.4 (t), 59.2 (t),113.2 (s),117.0 (s),
(q), 14.4 (q), 21.2 (t), 23.2 (t), 48.2 (t), 59.9 (t), 100.3 (s), 112.0 (s),
118.4 (s), 124.4 (2ꢃd), 125.5 (2ꢃd), 126.9 (d), 127.4 (d), 128.6 (2ꢃd),
129.2 (2ꢃd), 130.5 (s), 136.0 (s), 138.3 (s), 138.4 (s), 138.5 (d), 142.0
(s), 161.6 (s). Anal. Calcd for C26H25N3O2 (411.50): C, 75.89; H, 6.12;
N, 10.21. Found: C, 75.94; H, 5.88; N, 10.44.
118.1 (s), 124.7 (s), 125.6 (2ꢃd), 126.7 (d), 128.4 (s), 128.5 (2ꢃd),
129.2 (s), 130.6 (d), 138.8 (s), 161.2 (s). Anal. Calcd for C20H21N3O2
(335.40): C, 71.62; H, 6.31; N, 12.53. Found: C, 71.90; H, 6.03; N,
12.75.
4.4.6. Ethyl 7-benzyl-1,8-dimethyl-1,4,5,7-tetrahydropyrrolo[3,4-g]
indazole-6-carboxylate (18A). This product was obtained from 7b.
Yellow oil; Rf¼0.67 (CH2Cl2/EtOAc 95:5); yield: 22%; IR cmꢁ1: 1686
4.4.11. Ethyl 7-benzyl-1-(4-methoxyphenyl)-8-methyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (21). This product
was obtained from 7b. Brown oil; Rf¼0.59 (CH2Cl2/EtOAc 95:5);
(CO). 1H NMR (CDCl3):
d
1.29 (3H, t, J¼6.9 Hz, CH3), 2.39 (3H, s, CH3),
yield 80%; IR cmꢁ1: 1693 (CO). 1H NMR (CDCl3):
d 1.31 (3H, t,
2.64 (2H, t, J¼6.9 Hz, CH2), 3.00 (2H, t, J¼6.9 Hz, CH2), 3.96 (3H, s,
CH3), 4.93 (2H, q, J¼6.9 Hz, CH2), 5.64 (2H, s, CH2), 6.94 (2H, d,
J¼6.9 Hz, H-20 and H-60), 7.19e7.31 (3H, m, H-30, H-40 and H-50), 7.45
J¼7.1 Hz, CH3), 1.49 (3H, s, CH3), 2.72 (2H, t, J¼6.6 Hz, CH2), 3.11 (2H,
t, J¼6.6 Hz, CH2), 3.81 (3H, s, CH3), 4.26 (2H, q, J¼7.1 Hz, CH2), 5.52
(2H, s, CH2), 6.85e6.91 (4H, m, H-20 and H-60, H-300 and H-500),
7.21e7.26 (3H, m, H-30, H-40 and H-50), 7.38e7.43 (2H, d, J¼6.9 Hz,
(1H, s, H-3). 13C NMR (CDCl3):
d 13.3 (q), 14.1 (q), 21.0 (t), 23.4 (t),
39.6 (q), 48.2 (t), 59.7 (t), 112.3 (s), 116.7 (s), 118.5 (s), 125.5 (2ꢃd),
126.8 (d), 128.5 (2ꢃd), 129.0 (s), 131.5 (s), 136.0 (d), 136.3 (s), 138.2
(s), 161.5 (s). Anal. Calcd for C21H23N3O2 (349.43): C, 72.18; H, 6.63;
N, 12.03. Found: C, 72.40; H, 6.34; N, 12.36.
H-200 and H-600), 7.56 (1H, s, H-3). 13C NMR (CDCl3):
d 12.2 (q), 14.4
(q), 21.1 (t), 23.3 (t), 48.2 (t), 55.5 (q), 59.9 (t), 112.0 (s), 114.3 (2ꢃd),
117.9 (s), 118.4 (s), 125.5 (2ꢃd), 125.9 (2ꢃd), 126.9 (d), 128.6 (2ꢃd),
130.5 (s), 131.4 (s), 135.4 (s), 136.1 (s), 137.9 (d), 138.3 (s), 158.8 (s),
161.6 (s). Anal. Calcd for C27H27N3O3 (441.52): C, 73.45; H, 6.16; N,
9.52. Found: C, 73.60; H, 5.96; N, 9.75.
4.4.7. Ethyl 7-benzyl-2,8-dimethyl-2,4,5,7-tetrahydropyrrolo[3,4-g]
indazole-6-carboxylate (18B). This product was obtained from 7b.
Brown solid; Rf¼0.37 (CH2Cl2/EtOAc 95:5); mp 150e151 ꢀC; yield:
4.4.12. 2,7,8-Trimethyl-2,4,5,7-tetrahydropyrrolo[3,4-g]indazole
(26). This product was obtained from 7c. Yellow solid; Rf¼0.22
(CH2Cl2/EtOAc 95:5); mp 143e144 ꢀC; yield: 40%. 1H NMR (DMSO-
70%; IR cmꢁ1: 1694 (CO). 1H NMR (CDCl3):
d
1.28 (3H, t, J¼7.1 Hz,
CH3), 2.52 (3H, s, CH3), 2.75 (2H, t, J¼7.3 Hz, CH2), 3.10 (2H, t,
J¼7.3 Hz, CH2), 3.86 (3H, s, CH3), 4.21 (2H, q, J¼7.1 Hz, CH2), 5.62 (2H,
s, CH2), 6.94 (2H, d, J¼7.0 Hz, H-20 and H-60), 7.10 (1H, s, H-3),
d6):
d
2.07 (3H, s, CH3), 2.38e2.49 (4H, m, 2ꢃ CH2), 3.48 (3H, s, CH3),
3.89 (3H, s, CH3), 6.55 (1H, s, H-6), 7.19 (1H, s, H-3). 13C NMR
ꢀ
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6
(DMSO-d6):
d
12.6 (q), 21.8 (t), 22.3 (t), 33.7 (q), 39.4 (q), 109.9 (s),
(0.06 g, 0.0025 mol) was added at 0 ꢀC and the reaction mixture
was stirred at room temperature. After 1 h the benzylchloride
(0.0025 mol) was added at 0 ꢀC and the reaction mixture was
stirred at room temperature for 2e3 h. Then, the reaction mixture
was poured onto crushed ice and the precipitate was filtered off.
The crude was purified by column chromatography of the residue,
using DCM as eluent, to give the expected product.
115.2 (s), 117.9 (d), 119.3 (s), 122.9 (d), 135.7 (s), 137.4 (s). Anal. Calcd
for C12H15N3 (201.27): C, 71.61; H, 7.51; N, 20.88. Found: C, 71.86; H,
7.32; N, 20.82.
4.4.13. 7-Benzyl-8-methyl-1,4,5,7-tetrahydropyrrolo[3,4-g]indazole
(27). This product was obtained from 7d. Yellow solid; Rf¼0.17
(CH2Cl2/EtOAc 95:5); mp 135e136 ꢀC; yield: 68%; IR cmꢁ1: 3176
(NH). 1H NMR (DMSO-d6):
d
2.20 (3H, s, CH3), 2.49e2.58 (4H, m, 2ꢃ
4.5.1. Ethyl 1-(4-methoxybenzyl)-7,8-dimethyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (13). This product
was obtained from 9. White solid; Rf¼0.21 (CH2Cl2/EtOAc 95:5); mp
74e75 ꢀC; yield: 96%; IR cmꢁ1: 1681 (CO). 1H NMR (DMSO-d6):
CH2), 5.02 (2H, s, CH2), 6.58 (1H, s, H-6), 7.07 (2H, d, J¼8.4 Hz, H-20
and H-60), 7.23e7.32 (3H, m, H-30, H-40 and H-50), 7.38 (1H, s, H-3),
12.20 (1H, s, NH). 13C NMR (DMSO-d6):
d 10.8 (q), 20.4 (t), 21.2 (t),
49.2 (t), 113.1 (s), 116.6 (d), 118.2 (s), 121.2 (s), 121.6 (s), 125.4 (s),
126.6 (2ꢃd), 127.1 (d), 128.5 (2ꢃd), 136.2 (d), 139.0 (s). Anal. Calcd
for C17H17N3 (263.34): C, 77.54; H, 6.51; N, 15.96. Found: C, 77.68; H,
6.64; N, 15.60.
d
1.28 (3H, t, J¼7.1 Hz, CH3), 2.47 (3H, s, CH3), 2.61 (2H, t, J¼7.3 Hz,
CH2), 2.92 (2H, t, J¼7.3 Hz, CH2), 3.72 (3H, s, CH3), 3.73 (3H, s, CH3),
4.20 (2H, q, J¼7.1 Hz, CH2), 5.17 (2H, s, CH2), 6.89 (2H, d, J¼8.7 Hz, H-
300 and H-500), 7.22 (2H, d, J¼8.7 Hz, H-200 and H-600), 7.46 (1H, s, H-3).
13C NMR (DMSO-d6):
d 11.2 (q), 14.3 (q), 19.3 (t), 22.1 (t), 32.2 (q),
4.4.14. 7-Benzyl-2,8-dimethyl-2,4,5,7-tetrahydropyrrolo[3,4-g]in-
dazole (28). This product was obtained from 7d. Yellow solid;
Rf¼0.24 (CH2Cl2/EtOAc 95:5); mp 102e103 ꢀC; yield: 45%. 1H NMR
54.1 (t), 55.0 (q), 59.1 (t), 113.1 (s), 113.8 (2ꢃd), 114.1 (s), 117.1 (s),
126.2 (s), 128.2 (s), 129.0 (2ꢃd), 130.0 (d), 130.6 (s), 144.7 (s), 158.6
(s), 161.1 (s). Anal. Calcd for C22H25N3O3 (379.45): C, 69.64; H, 6.64;
N, 11.07. Found: C, 69.40; H, 7.02; N, 10.94.
(DMSO-d6):
d
2.33 (3H, s, CH3), 2.46e2.57 (4H, m, 2ꢃ CH2), 3.88 (3H,
s, CH3), 5.09 (2H, s, CH2), 6.71 (1H, s, H-6), 7.09 (2H, d, J¼8.2 Hz, H-20
and H-60), 7.21 (1H, s, H-3), 7.25e7.37 (3H, m, H-30, H-40 and H-50).13C
4. 5. 2. Ethyl 1-(4-chlorobenzyl)-7, 8-dimethyl-1, 4, 5, 7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (14). This product
was obtained from 9. White solid; Rf¼0.67 (CH2Cl2/EtOAc 95:5); mp
100e101 ꢀC; yield: 90%; IR cmꢁ1: 1685 (CO). 1H NMR (DMSO-d6):
NMR (DMSO-d6): d 12.6 (q), 21.4 (t), 21.9 (t), 39.3 (q), 49.8 (t),110.1 (s),
115.1 (s), 117.6 (d), 119.6 (s), 121.3 (s), 126.5 (2ꢃd), 127.1 (d), 128.6
(2ꢃd),135.5 (d),136.8 (s),138.7 (s). Anal. Calcd for C18H19N3 (277.36):
C, 77.95; H, 6.90; N, 15.15. Found: C, 78.06; H, 6.52; N, 15.30.
d
1.29 (3H, t, J¼7.0 Hz, CH3), 2.46 (3H, s, CH3), 2.64 (2H, t, J¼6.9 Hz,
CH2), 2.93 (2H, t, J¼6.9 Hz, CH2), 3.73 (3H, s, CH3), 4.21 (2H, q,
J¼7.0 Hz, CH2), 5.27 (2H, s, CH2), 7.25 (2H, d, J¼8.2 Hz, H-200 and H-
600), 7.40 (2H, d, J¼8.2 Hz, H-300 and H-500), 7.53 (1H, s, H-3). 13C NMR
4.4.15. 7-Benzyl-1,4,5,7-tetrahydropyrrolo[3,4-g]indazole (29). This
product was obtained from 7f. Brown solid; Rf¼0.39 (CH2Cl2/EtOAc
70:30); mp 171e172 ꢀC; yield: 80%; IR cmꢁ1: 3128 (NH). 1H NMR
(DMSO-d6): d 11.2 (q),14.3 (q),19.3 (t), 22.0 (t), 32.3 (q), 53.7 (t), 59.1
(DMSO-d6):
(1H, s, H-6), 6.90 (1H, s, H-8), 7.22e7.38 (6H, m, Ar and H-3), 12.26
(1H, s, NH). 13C NMR (DMSO-d6):
20.2 (t), 21.0 (t), 52.3 (t),112.9 (s),
d
2.50e2.59 (4H, m, 2ꢃ CH2), 5.05 (2H, s, CH2), 6.64
(t),112.9 (s), 114.3 (s), 117.2 (s), 126.7 (s), 128.2 (s), 128.4 (2ꢃd), 129.2
(2ꢃd),130.7 (d), 132.0 (s), 137.2 (s), 145.1 (s), 161.1 (s). Anal. Calcd for
d
C21H22ClN3O2 (383.88): C, 65.71; H, 5.78; N, 10.95. Found: C, 65.56;
113.8 (d), 114.5 (s), 117.4 (d), 119.6 (s), 127.3 (2ꢃd), 127.4 (d), 128.5
(2ꢃd), 131.8 (s), 136.0 (d), 138.9 (s). Anal. Calcd for C16H15N3
(249.31): C, 77.08; H, 6.06; N, 16.85. Found: C, 77.30; H, 5.84; N,
17.05.
H, 5.94; N, 11.02.
4. 5. 3. Ethyl 1-(3-chlorobenzyl)-7, 8-dimethyl-1, 4, 5, 7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (15). This product
was obtained from 9. White solid; Rf¼0.53 (CH2Cl2); mp 98e99 ꢀC;
4.4.16. 7-Benzyl-2-methyl-2,4,5,7-tetrahydropyrrolo[3,4-g]indazole
(30). This product was obtained from 7f. White solid; Rf¼0.17
(CH2Cl2/EtOAc 95:5); mp 102e103 ꢀC; yield: 70%. 1H NMR (CDCl3):
yield: 98%; IR cmꢁ1: 1689 (CO). 1H NMR (DMSO-d6):
d 1.29 (3H, t,
J¼7.1 Hz, CH3), 2.46 (3H, s, CH3), 2.64 (2H, t, J¼6.9 Hz, CH2), 2.94
(2H, t, J¼6.9 Hz, CH2), 3.74 (3H, s, CH3), 4.21 (2H, q, J¼7.1 Hz, CH2),
5.29 (2H, s, CH2), 7.18e7.42 (4H, m, H-200, H-400, H-500and H-600),
d
2.66e2.74 (4H, m, 2ꢃ CH2), 3.90 (3H, s, CH3), 5.05 (2H, s, CH2), 6.53
(1H, s, H-6), 6.78 (1H, s, H-8), 7.14e7.35 (6H, m, Ar and H-3). 13C
NMR (CDCl3): 21.0 (t), 21.4 (t), 37.3 (q), 53.4 (t), 112.8 (s), 113.8 (d),
7.57 (1H, s, H-3). 13C NMR (DMSO-d6):
d 11.2 (q), 14.3 (q), 19.3 (t),
d
22.0 (t), 32.3 (q), 53.7 (t), 59.1 (t), 112.9 (s), 114.4 (s), 117.2 (s), 126.0
(d), 126.8 (d), 127.1 (d), 127.3 (d), 128.2 (s), 130.4 (d), 130.7 (s), 133.0
(s), 140.7 (s), 145.1 (s), 161.1 (s). Anal. Calcd for C21H22ClN3O2
(383.88): C, 65.71; H, 5.78; N, 10.95. Found: C, 65.85; H, 5.60; N,
10.80.
114.0 (s), 114.6 (s), 118.0 (d), 121.0 (s), 127.0 (2ꢃd), 127.8 (d), 128.8
(2ꢃd), 135.8 (d), 137.8 (s). Anal. Calcd for C17H17N3 (263.34): C,
77.54; H, 6.51; N, 15.96. Found: C, 77.40; H, 6.64; N, 15.80.
4.4.17. 2,7-Dibenzyl-2,4,5,7-tetrahydropyrrolo[3,4-g]indazole
(31). This product was obtained from 7f. Yellow oil; Rf¼0.33
4.5.4. Ethyl 1-(2,4-dichlorobenzyl)-7,8-dimethyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (16). This product
was obtained from 9. White solid; Rf¼0.20 (CH2Cl2); mp
151e152 ꢀC; yield: 92%; IR cmꢁ1: 1680 (CO). 1H NMR (DMSO-d6):
(CH2Cl2/EtOAc 95:5); yield: 70%. 1H NMR (CDCl3):
d 2.56e2.69 (4H,
m, 2ꢃ CH2), 4.87 (2H, s, CH2), 5.36 (2H, s, CH2), 6.45 (2H, d, J¼7.4 Hz,
Ar), 7.07e7.35 (11H, m, Ar and H-3). 13C NMR (CDCl3):
d
20.9 (t), 21.2
(t), 53.2 (t), 53.6 (t), 112.1 (s), 114.1 (d), 114.8 (s), 117.6 (d), 121.0 (s),
126.5 (2ꢃd), 126.9 (2ꢃd), 127.2 (d), 127.6 (d), 128.5 (2ꢃd), 128.6
(2ꢃd), 135.8 (s), 136.5 (d), 137.2 (s), 137.5 (s). Anal. Calcd for
d
1.29 (3H, t, J¼7.1 Hz, CH3), 2.44 (3H, s, CH3), 2.65 (2H, t, J¼7.3 Hz,
CH2), 2.94 (2H, t, J¼7.3 Hz, CH2), 3.74 (3H, s, CH3), 4.21 (2H, q,
J¼7.1 Hz, CH2), 5.35 (2H, s, CH2), 6.95 (1H, d, J¼8.3 Hz, H-600), 7.41
(1H, dd, J¼8.3 2.1 Hz, H-500), 7.55 (1H, s, H-3), 7.66 (1H, d, J¼2.1 Hz,
C
23H21N3 (339.43): C, 81.38; H, 6.24; N, 12.38. Found: C, 81.60; H,
6.02; N, 12.46.
H-300). 13C NMR (DMSO-d6):
d 11.2 (q), 14.3 (q), 19.3 (t), 22.0 (t), 32.3
(q), 51.6 (t), 59.1 (t), 112.8 (s), 114.4 (s), 117.2 (s), 127.2 (d), 127.6 (d),
128.2 (s), 128.7 (d), 130.6 (d), 130.8 (s), 132.7 (s), 132.8 (s), 134.8 (s),
145.4 (s), 161.1 (s). Anal. Calcd for C21H21Cl2N3O2 (418.32): C, 60.30;
H, 5.06; N, 10.05. Found: C, 59.97; H, 5.28; N, 9.83.
4.5. General procedure for the preparation of N-benzylsub-
stituted tetrahydropyrrolo[3,4-g]indazoles (13e16, 22e25,
32e35)
To a solution of the relevant tetrahydropyrrolo[3,4-g]indazole 9,
17, 29 (0.0025 mol) dissolved in anhydrous DMF (10 mL), NaH
4.5.5. Ethyl 7-benzyl-1-(4-methoxybenzyl)-8-methyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (22). This product
ꢀ
Please cite this article in press as: Spano, V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.003

ꢀ
V. Spano et al. / Tetrahedron xxx (2013) 1e9
7
was obtained from 17. Yellow oil; Rf¼0.11 (CH2Cl2); yield: 88%; IR
cmꢁ1: 1696 (CO). 1H NMR (CDCl3):
Anal. Calcd for C24H23N3O (369.46): C, 78.02; H, 6.27; N, 11.37.
Found: C, 77.84; H, 6.55; N, 11.46.
d
1.26 (3H, t, J¼7.1 Hz, CH3),
2.53 (3H, s, CH3), 2.72 (2H, t, J¼7.3 Hz, CH2), 3.09 (2H, t, J¼7.3 Hz,
CH2), 3.79 (3H, s, CH3), 4.18 (2H, q, J¼7.1 Hz, CH2), 5.21 (2H, s, CH2),
5.62 (2H, s, CH2), 6.84 (2H, d, J¼6.6 Hz, H-300 and H-500), 6.92 (2H, d,
J¼6.7 Hz, H-20 and H-60), 7.10e7.48 (6H, m, Ar and H-3). 13C NMR
4.5.10. 7-Benzyl-2-(4-methoxybenzyl)-2,4,5,7-tetrahydropyrrolo
[3,4-g]indazole (32B). This product was obtained from 29. Yellow
oil; Rf¼0.56 (CH2Cl2/EtOAc 95:5); yield: 15%. 1H NMR (DMSO-d6):
(DMSO-d6):
d
11.6 (q), 14.4 (q), 19.9 (t), 22.6 (t), 48.2 (t), 55.2 (t),
d
2.68e2.73 (4H, m, 2ꢃ CH2), 3.75 (3H, s, CH3), 4.96 (2H, s, CH2),
55.3 (q), 59.5 (t), 114.0 (s), 114.1 (2ꢃd), 115.7 (s), 117.6 (s), 125.4 (d),
125.8 (2ꢃd), 126.7 (s), 128.5 (2ꢃd), 129.2 (s), 129.3 (2ꢃd), 130.3 (d),
131.3 (s), 138.7 (s), 145.6 (s), 159.3 (s), 161.8 (s). Anal. Calcd for
5.32 (2H, s, CH2), 6.47 (1H, s, H-6), 6.54 (1H, s, H-8), 6.80 (2H, d,
J¼8.4 Hz, Ar), 7.03e7.12 (4H, m, Ar), 7.27e7.33 (3H, m, Ar), 7.35 (1H,
s, H-3). 13C NMR (DMSO-d6):
d 21.1 (t), 21.4 (t), 53.3 (t), 53.4 (t), 55.2
C
28H29N3O3 (455.56): C, 73.82; H, 6.42; N, 9.22. Found: C, 73.65; H,
(q), 112.4 (s), 114.1 (2ꢃd), 114.3 (d), 115.0 (s), 117.8 (d), 121.2 (s), 127.1
(2ꢃd), 127.8 (d), 128.0 (2ꢃd), 128.8 (2ꢃd), 129.5 (s), 135.7 (s), 136.6
(d), 137.6 (s), 158.8 (s). Anal. Calcd for C24H23N3O (369.46): C, 78.02;
H, 6.27; N, 11.37. Found: C, 78.38; H, 5.94; N, 10.98.
6.70; N, 9.05.
4.5.6. Ethyl 7-benzyl-1-(4-chlorobenzyl)-8-methyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (23). This product
was obtained from 17. White solid; Rf¼0.51 (CH2Cl2/EtOAc 95:5);
mp 75e76 ꢀC; yield: 84%; IR cmꢁ1: 1682 (CO). 1H NMR (DMSO-
4.5.11. 7-Benzyl-1-(4-chlorobenzyl)-1,4,5,7-tetrahydropyrrolo[3,4-g]
indazole (33A). This product was obtained from 29. White solid;
Rf¼0.62 (CH2Cl2/EtOAc 95:5); mp 126e127 ꢀC; yield: 73%. 1H NMR
d6):
d
1.22 (3H, t, J¼7.1 Hz, CH3), 2.39 (3H, s, CH3), 2.68 (2H, t,
J¼7.3 Hz, CH2), 3.00 (2H, t, J¼7.3 Hz, CH2), 4.14 (2H, q, J¼7.1 Hz,
CH2), 5.27 (2H, s, CH2), 5.60 (2H, s, CH2), 6.92 (2H, d, J¼6.7 Hz, H-
20 and H-60), 7.21e7.42 (7H, m, Ar), 7.58 (1H, s, H-3). 13C NMR
(CDCl3):
d
2.68e2.71 (4H, m, 2ꢃ CH2), 5.01 (2H, s, CH2), 5.22 (2H, s,
CH2), 6.48 (1H, s, H-6), 6.98 (1H, s, H-8), 7.18e7.48 (10H, m, Ar and
H-3). 13C NMR (CDCl3):
d
20.6 (t), 21.2 (t), 53.5 (t), 54.9 (t), 114.5 (d),
(DMSO-d6):
d
11.1 (q), 14.2 (q), 19.2 (t), 22.1 (t), 47.4 (t), 53.7 (t),
114.9 (s),116.2 (s),117.2 (d),121.2 (s),126.2 (d),127.4 (2ꢃd),127.7 (s),
128.7 (2ꢃd), 128.8 (2ꢃd), 128.9 (2ꢃd), 133.5 (s), 136.0 (d), 137.9 (s),
146.2 (s). Anal. Calcd for C23H20ClN3 (373.88): C, 73.89; H, 5.39; N,
11.24. Found: C, 74.01; H, 5.00; N, 11.58.
59.2 (t), 113.6 (s), 114.5 (s), 117.0 (s), 125.6 (2ꢃd), 126.7 (d), 128.4
(2ꢃd), 128.5 (2ꢃd), 129.0 (s), 129.3 (2ꢃd), 129.8 (d), 130.7 (s),
132.0 (s), 137.1 (s), 138.6 (s), 144.9 (s), 160.9 (s). Anal. Calcd for
C
27H26ClN3O2 (459.97): C, 70.50; H, 5.70; N, 9.14. Found: C, 70.28;
H, 6.03; N, 8.90.
4.5.12. 7-Benzyl-2-(4-chlorobenzyl)-2,4,5,7-tetrahydropyrrolo[3,4-g]
indazole (33B). This product was obtained from 29. Yellow oil;
Rf¼0.45 (CH2Cl2/EtOAc 95:5); yield: 21%. 1H NMR (CDCl3):
4.5.7. Ethyl 7-benzyl-1-(3-chlorobenzyl)-8-methyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (24). This product
was obtained from 17. Yellow oil; Rf¼0.33 (CH2Cl2); yield: 86%; IR
d
2.70e2.73 (4H, m, 2ꢃ CH2), 4.95 (2H, s, CH2), 5.35 (2H, s, CH2),
6.46 (1H, s, H-6), 6.48 (1H, s, H-8), 7.00e7.34 (9H, m, Ar), 7.36 (1H, s,
cmꢁ1: 1683 (CO). 1H NMR (DMSO-d6):
d
1.22 (3H, t, J¼7.1 Hz, CH3),
H-3). 13C NMR (CDCl3):
d
21.0 (t), 21.3 (t), 53.2 (t), 53.4 (t), 112.2 (s),
2.40 (3H, s, CH3), 2.69 (2H, t, J¼7.3 Hz, CH2), 3.00 (2H, t, J¼7.3 Hz,
CH2), 4.14 (2H, q, J¼7.1 Hz, CH2), 5.29 (2H, s, CH2), 5.60 (2H, s, CH2),
6.94 (2H, d, J¼7.4 Hz, H-20 and H-60), 7.18e7.39 (7H, m, Ar), 7.61 (1H,
114.0 (d), 115.2 (s), 117.9 (d), 121.1 (s), 127.1 (2ꢃd), 127.9 (d), 128.0
(2ꢃd), 128.8 (2ꢃd), 128.9 (2ꢃd), 133.2 (s), 135.8 (s), 135.9 (s), 136.9
(d), 137.5 (s). Anal. Calcd for C23H20ClN3 (373.88): C, 73.89; H, 5.39;
N, 11.24. Found: C, 73.60; H, 5.02; N, 11.46.
s, H-3). 13C NMR (DMSO-d6):
d 11.1 (q), 14.2 (q), 19.2 (t), 22.1 (t), 47.4
(t), 53.8 (t), 59.2 (t), 113.6 (s), 114.6 (s), 117.0 (s), 125.6 (2ꢃd), 126.1
(d), 126.7 (d), 126.9 (d), 127.2 (s), 127.3 (d), 127.4 (d), 128.5 (2ꢃd),
130.4 (d), 130.8 (s), 133.0 (s), 138.6 (s), 140.6 (s), 145.0 (s), 160.9 (s).
Anal. Calcd for C27H26ClN3O2 (459.97): C, 70.50; H, 5.70; N, 9.14.
Found: C, 70.73; H, 5.64; N, 9.30.
4.5.13. 7-Benzyl-1-(3-chlorobenzyl)-1,4,5,7-tetrahydropyrrolo[3,4-g]
indazole (34A). This product was obtained from 29. White solid;
Rf¼0.20 (CH2Cl2); mp 115e116 ꢀC; yield: 68%. 1H NMR (DMSO-d6):
d
2.50e2.58 (4H, m, 2ꢃ CH2), 5.03 (2H, s, CH2), 5.23 (2H, s, CH2),
6.63 (1H, s, H-6), 6.94 (1H, s, H-8), 7.16e7.36 (9H, m, Ar), 7.54 (1H, s,
4.5.8. Ethyl 7-benzyl-1-(2,4-dichlorobenzyl)-8-methyl-1,4,5,7-
tetrahydropyrrolo[3,4-g]indazole-6-carboxylate (25). This product
was obtained from 17. White solid; Rf¼0.44 (CH2Cl2); mp
107e108 ꢀC; yield: 82%; IR 1686 cmꢁ1: (CO). 1H NMR (DMSO-d6):
H-3). 13C NMR (DMSO-d6):
d
20.0 (t), 20.8 (t), 52.3 (t), 53.7 (t), 100.0
(s), 113.9 (d), 114.5 (s), 117.2 (d), 119.8 (s), 126.1 (d), 127.0 (d), 127.1
(d), 127.2 (2ꢃd), 127.3 (2ꢃd), 127.4 (d), 128.5 (d), 130.4 (d), 133.0 (s),
138.9 (s), 140.8 (s), 145.5 (s). Anal. Calcd for C23H20ClN3 (373.88): C,
73.89; H, 5.39; N, 11.24. Found: C, 73.70; H, 5.60; N, 11.46.
d
1.22 (3H, t, J¼7.1 Hz, CH3), 2.38 (3H, s, CH3), 2.70 (2H, t, J¼7.4 Hz,
CH2), 3.02 (2H, t, J¼7.4 Hz, CH2), 4.14 (2H, q, J¼7.1 Hz, CH2), 5.36 (2H,
s, CH2), 5.59 (2H, s, CH2), 6.92e7.01 (3H, m, Ar), 7.17e7.37 (3H, m,
Ar), 7.40 (1H, dd, J¼8.34, 2.14 Hz, H-500), 7.58 (1H, s, H-3), 7.64 (1H, d,
4.5.14. 7-Benzyl-2-(3-chlorobenzyl)-2,4,5,7-tetrahydropyrrolo[3,4-g]
indazole (34B). This product was obtained from 29. Brown oil;
Rf¼0.48 (CH2Cl2/EtOAc 95:5); yield: 12%. 1H NMR (DMSO-d6):
J¼2.12 Hz, H-300). 13C NMR (DMSO-d6):
d 11.1 (q), 14.2 (q), 19.2 (t),
22.1 (t), 47.4 (t), 51.6 (t), 59.2 (t), 113.5 (s), 114.4 (s), 117.1 (s), 125.6
(2ꢃd), 126.7 (d), 127.3 (d), 127.6 (d), 128.5 (2ꢃd), 128.7 (d), 129.1 (s),
130.7 (d), 130.8 (s), 132.7 (s), 132.9 (s), 134.7 (s), 138.6 (s), 145.2 (s),
160.9 (s). Anal. Calcd for C27H25Cl2N3O2 (494.41): C, 65.59; H, 5.10;
N, 8.50. Found: C, 65.29; H, 5.34; N, 8.28.
d
2.54e2.60 (4H, m, 2ꢃ CH2), 5.02 (2H, s, CH2), 5.41 (2H, s, CH2),
6.68 (1H, s, H-6), 7.11e7.33 (11H, m, H-8, Ar and H-3). 13C NMR
(DMSO-d6): 20.5 (t), 20.8 (t), 52.2 (t), 52.3 (t), 111.0 (s), 113.9 (s),
d
114.6 (d), 117.7 (d), 119.6 (s), 125.6 (d), 126.7 (d), 127.1 (d), 127.2
(2ꢃd), 127.4 (d), 128.5 (2ꢃd), 130.3 (d), 133.0 (s), 135.5 (s), 136.4 (d),
138.7 (s), 140.3 (s). Anal. Calcd for C23H20ClN3 (373.88): C, 73.89; H,
5.39; N, 11.24. Found: C, 74.04; H, 5.02; N, 11.10.
4.5.9. 7-Benzyl-1-(4-methoxybenzyl)-1,4,5,7-tetrahydropyrrolo[3,4-
g]indazole (32A). This product was obtained from 29. Yellow oil;
Rf¼0.67 (CH2Cl2/EtOAc 95:5); yield: 70%. 1H NMR (DMSO-d6):
4.5.15. 7-Benzyl-1-(2,4-dichlorobenzyl)-1,4,5,7-tetrahydropyrrolo
[3,4-g]indazole (35A). This product was obtained from 29. Yellow
oil; Rf¼0.67 (CH2Cl2/EtOAc 98:2); yield: 65%. 1H NMR (CDCl3):
d
2.52e2.58 (4H, m, 2ꢃ CH2), 3.71 (3H, s, CH3), 5.02 (2H, s, CH2), 5.12
(2H, s, CH2), 6.61 (1H, s, H-6), 6.86 (2H, d, J¼8.4 Hz, Ar), 6.92 (1H, s,
H-8), 7.14e7.33 (7H, m, Ar), 7.44 (1H, s, H-3). 13C NMR (DMSO-d6):
d
2.72e2.76 (4H, m, 2ꢃ CH2), 5.01 (2H, s, CH2), 5.32 (2H, s, CH2), 6.49
d
20.5 (t), 20.9 (t), 52.3 (t), 55.0 (t), 54.9 (q), 113.7 (2ꢃd), 113.8 (d),
(1H, s, H-6), 6.82 (1H, d, J¼8.3 Hz, H-600), 6.98 (1H, s, H-8), 7.12e7.48
114.3 (s),114.8 (s),117.2 (d),119.8 (s),126.4 (d),127.3 (s),127.4 (2ꢃd),
(7H, m, Ar and H-3), 7.58 (1H, d, J¼2.1 Hz, H-300). 13C NMR (CDCl3):
128.4 (2ꢃd), 128.9 (2ꢃd), 130.1 (d), 138.9 (s), 145.1 (s), 158.6 (s).
d
20.6 (t), 21.2 (t), 52.4 (t), 53.5 (t), 114.5 (d), 114.8 (s), 116.2 (s), 117.3
ꢀ
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8
(d), 121.2 (s), 126.8 (d), 127.4 (2ꢃd), 127.5 (d), 127.7 (d), 128.7 (2ꢃd),
129.1 (d), 130.2 (d), 133.0 (s), 134.0 (s), 134.2 (s), 137.8 (s), 146.6 (s).
Anal. Calcd for C23H19Cl2N3 (408.32): C, 67.65; H, 4.69; N, 10.29.
Found: C, 67.87; H, 4.40; N, 10.54.
Rf¼0.61 (CH2Cl2/EtOAc 70:30); mp 199e200 ꢀC; yield: 54%; IR
cmꢁ1: 3129 (NH), 1676 (CO). 1H NMR (DMSO-d6):
d 1.33 (3H, t,
J¼7.0 Hz, CH3), 2.77 (3H, s, CH3), 4.28 (2H, q, J¼7.0 Hz, CH2), 5.97
(2H, s, CH2), 6.93 (2H, d, J¼7.1 Hz, H-20 and H-60), 7.22e7.34 (3H, m,
H-30, H-40 and H-50), 7.47 (1H, d, J¼9.1 Hz, H-5), 7.72 (1H, d,
J¼9.1 Hz, H-4), 8.10 (1H, s, H-3), 13.47 (1H, s, NH). 13C NMR (DMSO-
d6): 11.9 (q), 14.3 (q), 48.3 (t), 59.3 (t), 111.8 (s), 115.2 (s), 116.9 (s),
119.2 (d), 125.7 (2ꢃd), 126.9 (d), 127.5 (s), 128.5 (s), 128.6 (2ꢃd),
129.5 (s), 134.4 (d), 135.4 (d), 137.8 (s), 161.1 (s). Anal. Calcd for
4.5.16. 7-Benzyl-2-(2,4-dichlorobenzyl)-2,4,5,7-tetrahydropyrrolo
[3,4-g]indazole (35B). This product was obtained from 29. Yellow
oil; Rf¼0.57 (CH2Cl2/EtOAc 98:2); yield: 18%. 1H NMR (CDCl3):
d
2.71e2.75 (4H, m, 2ꢃ CH2), 4.93 (2H, s, CH2), 5.43 (2H, s, CH2), 6.38
(1H, s, H-6), 6.47 (1H, s, H-8), 6.58 (1H, d, J¼8.4 Hz, H-600), 7.06e7.10
C20H19N3O2 (333.39): C, 72.05; H, 5.74; N, 12.60. Found: C, 72.32; H,
6.04; N, 12.43.
(3H, m, Ar), 7.29e7.36 (4H, m, Ar), 7.30 (1H, s, H-3). 13C NMR
(CDCl3): d 21.0 (t), 21.3 (t), 50.9 (t), 53.4 (t), 111.8 (s), 113.8 (d), 115.3
(s), 117.9 (d), 121.0 (s), 127.2 (2ꢃd), 127.6 (d), 127.9 (d), 128.8 (2ꢃd),
128.9 (d), 129.0 (d), 132.3 (s), 133.6 (s), 133.7 (s), 137.2 (d), 137.3 (s),
146.4 (s). Anal. Calcd for C23H19Cl2N3 (408.32): C, 67.65; H, 4.69; N,
10.29. Found: C, 67.38; H, 4.74; N, 10.02.
4.6.5. Ethyl
7-benzyl-2,8-dimethyl-2,7-dihydropyrrolo[3,4-g]in-
dazole-6-carboxylate (40). This product was obtained from 18B.
Yellow solid; Rf¼0.57 (CH2Cl2/EtOAc 95:5); mp 203e204 ꢀC; yield:
72%; IR cmꢁ1: 1676 (CO). 1H NMR (CDCl3):
d
1.41 (3H, t, J¼6.9 Hz,
CH3), 2.77 (3H, s, CH3), 4.36 (3H, s, CH3), 4.39 (2H, q, J¼6.9 Hz, CH2),
6.02 (2H, s, CH2), 6.90 (2H, d, J¼6.8 Hz, H-20 and H-60), 7.22e7.34
(3H, m, H-30, H-40, H-50), 7.42 (1H, d, J¼9.2 Hz, H-5), 7.90 (1H, s, H-
4.6. General procedure for the preparation of dihydropyrrolo
[3,4-g]indazoles (36e42)
3), 7.96 (1H, d, J¼9.2 Hz, H-4). 13C NMR (CDCl3):
d 14.4 (q), 14.5 (q),
To a solution of tetrahydroindazole (9e35) (0.03 mol) in dry
benzene (100 mL), DDQ (0.03 mol) was added. The mixture was
stirred at room temperature for 4 h, then the solvent was removed
under reduced pressure. The crude was purified by chromatogra-
phy column.
41.9 (q), 49.2 (t), 60.0 (t), 110.2 (s), 111.5 (s), 113.1 (s), 115.7 (d), 119.0
(d), 120.0 (s), 125.7 (2ꢃd), 127.2 (d), 128.7 (2ꢃd), 129.3 (s), 134.3 (s),
134.4 (d), 137.4 (s), 161.9 (s). Anal. Calcd for C21H21N3O2 (347.41): C,
72.60; H, 6.09; N, 12.10. Found: C, 72.65; H, 5.88; N, 11.86.
4.6.6. Ethyl 7-benzyl-1-(4-chlorobenzyl)-8-methyl-1,7-
dihydropyrrolo[3,4-g]indazole-6-carboxylate (41). This product was
obtained from 23. White solid; Rf¼0.33 (CH2Cl2); mp 139e140 ꢀC;
4.6.1. Ethyl 7,8-dimethyl-1,7-dihydropyrrolo[3,4-g]indazole-6-
carboxylate (36). This product was obtained from 9. White solꢁid1;
Rf¼0.58 (CH2Cl2/EtOAc 70:30); mp 151e152 ꢀC; yield: 50%; IR cm
:
yield: 60%; IR cmꢁ1: 1674 (CO). 1H NMR (DMSO-d6):
d 1.31 (3H, t,
3130 (NH), 1672 (CO). 1H NMR (DMSO-d6):
d
1.39 (3H, t, J¼6.9 Hz,
J¼7.1 Hz, CH3), 2.72 (3H, s, CH3), 4.26 (2H, q, J¼7.1 Hz, CH2), 5.59
(2H, s, CH2), 5.90 (2H, s, CH2), 6.92 (2H, d, J¼7.2 1.5 Hz, H-200 and H-
600), 7.21e7.44 (8H, m, H-5 and Ar), 7.68 (1H, d, J¼9.3 Hz, H-4), 8.34
CH3), 2.73 (3H, s, CH3), 4.04 (3H, s, CH3), 4.32 (2H, q, J¼6.9 Hz, CH2),
7.36 (1H, d, J¼9.2 Hz, H-5), 7.74 (1H, d, J¼9.2 Hz, H-4), 8.10 (1H, s, H-
3), 13.47 (1H, s, NH). 13C NMR (DMSO-d6):
d
13.7 (q), 14.4 (q), 33.5
(1H, s, H-3). 13C NMR (DMSO-d6):
d 11.9 (q),14.3 (q), 48.2 (t), 54.7 (t),
(q), 59.4 (t), 99.8 (s), 108.8 (s), 111.8 (s), 114.7 (s), 118.3 (d), 119.2 (s),
128.2 (s), 128.4 (d), 133.6 (d), 161.1 (s). Anal. Calcd for C14H15N3O2
(257.29): C, 65.35; H, 5.88; N, 16.33. Found: C, 65.02; H, 6.15; N,
16.50.
59.3 (t), 112.2 (s), 112.4 (s), 116.6 (d), 117.2 (s), 118.8 (d), 125.4 (d),
125.7 (2ꢃd), 126.9 (s), 128.5 (2ꢃd), 128.6 (2ꢃd), 129.3 (2ꢃd), 129.7
(s), 130.3 (s), 132.3 (s), 136.5 (d), 137.9 (s), 143.4 (s), 170.0 (s). Anal.
Calcd for C27H24ClN3O2 (457.95): C, 70.81; H, 5.28; N, 9.18. Found: C,
71.06; H, 4.98; N, 9.24.
4.6.2. Ethyl 2,7,8-trimethyl-2,7-dihydropyrrolo[3,4-g]indazole-6-
carboxylate (37). This product was obtained from 10. White solꢁid1;
4.6.7. 7-Benzyl-2-methyl-2,7-dihydropyrrolo[3,4-g]indazole
(42). This product was obtained from 30. Yellow solid; Rf¼0.37
(CH2Cl2/EtOAc 95:5); mp 107e108 ꢀC; yield: 42%; 1H NMR (CDCl3):
Rf¼0.33 (CH2Cl2/EtOAc 95:5); mp 168e169 ꢀC; yield: 54%; IR cm
:
1672 (CO). 1H NMR (DMSO-d6):
d
1.39 (3H, t, J¼7.0 Hz, CH3), 2.73
(3H, s, CH3), 4.03 (3H, s, CH3), 4.26 (3H, s, CH3), 4.34 (2H, q, J¼7.0 Hz,
d 4.35 (3H, s, CH3), 4.89 (2H, s, CH2), 7.14e7.30 (5H, m, Ar, H-6 and
CH2), 7.36 (1H, d, J¼9.2 Hz, H-5), 7.74 (1H, d, J¼9.2 Hz, H-4), 7.89
H-8), 7.47e7.53 (3H, m, Ar and H-5), 7.89 (1H, s, H-3), 7.99 (1H, d,
(1H, s, H-3). 13C NMR (DMSO-d6):
d
13.7 (q), 14.4 (q), 33.5 (q), 41.4
J¼9.3 Hz, H-4). 13C NMR (CDCl3):
d 41.3 (q), 41.4 (t), 114.6 (d), 125.4
(d), 127.1 (s), 127.4 (d), 127.5 (d), 127.7 (d), 128.6 (2ꢃd), 128.7 (d),
128.8 (2ꢃd), 132.2 (s), 136.7 (s), 141.5 (s), 169.3 (s). Anal. Calcd for
(q), 59.4 (t), 99.8 (s), 108.8 (s), 111.9 (s), 114.7 (s), 118.3 (d), 119.2 (s),
128.2 (d), 128.4 (s), 133.6 (d), 161.2 (s). Anal. Calcd for C15H17N3O2
(274.31): C, 66.40; H, 6.32; N, 15.49. Found: C, 66.63; H, 6.60; N,
15.24.
C17H15N3 (261.32): C, 78.13; H, 5.79; N, 16.08. Found: C, 78.46; H,
5.50; N, 16.04.
4.6.3. Ethyl 1-(2,4-dichlorobenzyl)-7,8-dimethyl-1,7-dihydropyrrolo
[3,4-g]indazole-6-carboxylate (38). This product was obtained
from 16. Yellow solid; mp 312e314 ꢀC; Rf¼0.19 (CH2Cl2/EtOAc
4.7. General procedure for the preparation of tetrahy-
dropyrrolo[3,4-g]indazol-3(2H)-ones (43,44)
95:5); yield: 74%; IR cmꢁ1: 1682 (CO). 1H NMR (DMSO-d6):
d
1.37
The relevant ketoester 8a,b (0.002 mol) was dissolved in an-
hydrous ethanol (12 mL) and methylhydrazine (1.05 mL, 0.02 mol)
was added. The reaction mixture was heated under reflux for 24 h.
Upon cooling the solvent was removed in vacuo and water was
added to the mixture. A solid precipitated, which was filtered,
dried, and recrystallized from ethanol.
(3H, t, J¼7.1 Hz, CH3), 2.77 (3H, s, CH3), 4.02 (3H, s, CH3), 4.32 (2H, q,
J¼7.1 Hz, CH2), 5.67 (2H, s, CH2), 7.00 (1H, d, J¼8.3 Hz, H-600), 7.32
(1H, d, J¼9.2 Hz, H-5), 7.41 (1H, d, J¼8.3 1.9 Hz, H-500), 7.62 (1H, d,
J¼9.2 Hz, H-4), 7.70 (1H, d, J¼1.9 Hz, H-300), 8.29 (1H, s, H-3). 13C
NMR (DMSO-d6): d 11.9 (q), 14.4 (q), 33.2 (q), 52.7 (t), 59.2 (t), 111.5
(s), 112.7 (s), 116.6 (d), 117.0 (s), 118.3 (d), 125.8 (d), 126.7 (s), 127.8
(d), 128.8 (s), 130.3 (d), 130.9 (d), 133.0 (s), 133.2 (s), 134.1 (s), 143.6
(s), 161.2 (s). Anal. Calcd for C21H19Cl2N3O2 (416.30): C, 60.59; H,
4.60; N, 10.09. Found: C, 60.63; H, 4.82; N, 9.94.
4.7.1. 2,7-Dimethyl-3a,4,5,7-tetrahydropyrrolo[3,4-g]indazol-3(2H)-
one (43). This product was obtained from 8a. White solid; Rf¼0.37
(CH2Cl2/EtOAc 95:5); mp 226e228 ꢀC; yield 38%; IR cmꢁ1: 1682
(CO). 1H NMR (CDCl3):
d
1.10e1.92 (2H, m, CH2), 2.30e3.14 (2H, m,
CH2), 3.29 (3H, s, CH3), 3.64 (3H, s, CH3), 4.17 (1H, s, CH), 6.43 (1H, s,
H-6), 6.98 (1H, s, H-8). 13C NMR (CDCl3):
17.0 (t), 31.1 (q), 32.0 (d),
4.6.4. Ethyl 7-benzyl-8-methyl-1,7-dihydropyrrolo[3,4-g]indazole-6-
carboxylate (39). This product was obtained from 17. Yellow solid;
d
ꢀ
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V. Spano et al. / Tetrahedron xxx (2013) 1e9
9
8. Barraja, P.; Diana, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.; Dattolo, G.;
Cirrincione, G. Bioorg. Med. Chem. 2004, 13, 295e300.
9. Viola, G.; Cecconet, L.; Leszl, A.; Basso, G.; Brun, P.; Salvador, A.; Dall’Acqua, F.;
Diana, P.; Barraja, P.; Cirrincione, G. Cancer Chemother. Pharmacol. 2009, 64,
1235e1251.
32.2 (t), 36.6 (q), 74.0 (s),110.4 (s),118.4 (d),118.8 (d),122.9 (s),173.3
(s). Anal. Calcd for C11H13N3O (203.24): C, 65.01; H, 6.45; N, 20.68.
Found: C, 65.30; H, 6.24; N, 20.78.
10. Diana, P.; Carbone, A.; Barraja, P.; Kelter, G.; Fiebig, H.-H.; Cirrincione, G. Bioorg.
4.7.2. 7-Benzyl-2-methyl-3a,4,5,7-tetrahydropyrrolo[3,4-g]indazol-
Med. Chem. 2010, 18, 4524e4529.
3(2H)-one (44). This product was obtained from 8b. White solꢁid1;
ꢀ
11. Barraja, P.; Spano, V.; Giallombardo, D.; Diana, P.; Montalbano, A.; Carbone, A.;
Rf¼0.49 (CH2Cl2/EtOAc 95:5); mp 112e114 ꢀC; yield 45%; IR cm
:
Parrino, B.; Cirrincione, G. Tetrahedron 2013, 69, 6474e6477.
1699 (CO). 1H NMR (CDCl3):
d
2.54e2.80 (4H, m, 2ꢃ CH2), 3.32 (3H,
ꢀ
12. Barraja, P.; Caracausi, L.; Diana, P.; Spano, V.; Montalbano, A.; Carbone, A.;
Parrino, B.; Cirrincione, G. ChemMedChem 2012, 7, 1901e1904.
13. Barraja, P.; Caracausi, L.; Diana, P.; Montalbano, A.; Carbone, A.; Salvador, A.;
Brun, P.; Castagliuolo, I.; Tisi, S.; Dall’Acqua, F.; Vedaldi, D.; Cirrincione, G.
ChemMedChem 2011, 6, 1238e1248.
s, CH3), 4.98 (1H, s, CH), 5.01 (2H, s, CH2), 6.48 (1H, s, H-6),
7.06e7.32 (6H, m, Ar and H-8). 13C NMR (CDCl3):
d
22.4 (t), 26.7 (t),
31.7 (q), 48.3 (d), 54.4 (t),113.5 (s),117.1 (d), 118.5 (d),123.9 (s), 127.9
(2ꢃd), 128.7 (d), 129.3 (2ꢃd), 137.2 (s), 156.3 (s), 173.8 (s). Anal.
Calcd for C17H17N3O (279.34): C, 73.10; H, 6.13; N, 15.04. Found: C,
73.40; H, 6.40; N, 14.86.
ꢀ
14. Barraja, P.; Diana, P.; Spano, V.; Montalbano, A.; Carbone, A.; Parrino, B.; Cir-
rincione, G. Tetrahedron 2012, 68, 5087e5094.
15. Barraja, P.; Caracausi, L.; Diana, P.; Carbone, A.; Montalbano, A.; Cirrincione, G.;
ꢀ
Brun, P.; Palu, G.; Castagliuolo, I.; Dall’Acqua, F.; Vedaldi, D.; Salvador, A. Bioorg.
Med. Chem. 2010, 18, 4830e4843.
16. Dall’Acqua, F.; Cirrincione, G.; Barraja, P.; Salvador, A. PCT Int. Appl. WO
Acknowledgements
2011013159; Chem. Abstr. 2011, 154, 182531.
17. Barraja, P.; Diana, P.; Montalbano, A.; Dattolo, G.; Cirrincione, G.; Viola, G.;
Vedaldi, D.; Dall’Acqua, F. Bioorg. Med. Chem. 2006, 14, 8712e8728.
18. Barraja, P.; Diana, P.; Montalbano, A.; Carbone, A.; Cirrincione, G.; Viola, G.;
Salvador, A.; Vedaldi, D.; Dall’Acqua, F. Bioorg. Med. Chem. 2008, 16, 9668e9683.
19. Barraja, P.; Sciabica, L.; Diana, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.;
Dattolo, G.; Cirrincione, G. Bioorg. Med. Chem. Lett. 2005, 15, 2291e2294.
20. Barraja, P.; Diana, P.; Lauria, A.; Montalbano, A.; Almerico, A. M.; Dattolo, G.;
Cirrincione, G. Bioorg. Med. Chem. Lett. 2003, 13, 2809e2811.
This work was financially supported by Ministero dell’Istruzione
ꢀ
dell’Universita e della Ricerca.
Supplementary data
21. Starosotnikov, A. M.; Khakimo, D. V.; Bastrakov, M. A.; Pechenkin, S. Y.; She-
velev, S. A.; Pivina, T. S. Chem. Heterocycl. Compd. 2011, 47, 215e221.
22. Starosotnikov, A. M.; Bastrakov, M. A.; Pechenkin, S. Y.; Leontieva, M. A.; Ka-
chala, V. V.; Shevelev, S. A. J. Heterocycl. Chem 2011, 48, 824e828.
23. Olivera, R.; SanMartin, P.; Dominguez, E. J. Org. Chem. 2000, 65, 7010e7019.
24. Olivera, R.; SanMartin, P.; Dominguez. Tetrahedron Lett. 2000, 41, 4353e4356.
25. Molteni, V.; Hamilton, M. M.; Mao, L.; Crane, C. M.; Termin, A. P.; Wilson, D. M.
Synthesis 2002, 1669e1674.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.003.
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Please cite this article in press as: Spano, V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.003