Unprecedented SnCl2-mediated cyclization of nitro arenes via N-N bond formation

Article abstract of DOI:10.1021/ol053033y

A mild, efficient, one-pot protocol for the cyclization of nitro-aryl substrates using SnCl₂ has been described. The mechanistic course of the reaction suggests the involvement of a hydroxylamine intermediate leading to an intramolecular cyclization via N-N bond formation. The versatility of the methodology has been demonstrated by using two nitro-aryl substrates derived from dihydroisoquinolines and dihydro-β-carbolines. The intramolecular cyclization led to the formation of indazoles in high yields and purities.

Full text of DOI:10.1021/ol053033y

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1525-1528
Unprecedented SnCl2-Mediated
Cyclization of Nitro Arenes via N
Bond Formation†
−
N
Devesh Sawant,‡ Rishi Kumar,§ Prakas R. Maulik,§ and Bijoy Kundu*,‡
Medicinal Chemistry DiVision and Molecular and Structural Biology DiVision,
Central Drug Research Institute, Lucknow 226 001, India
bijoy_kundu@yahoo.com
Received December 14, 2005
ABSTRACT
A mild, efficient, one-pot protocol for the cyclization of nitro-aryl substrates using SnCl2 has been described. The mechanistic course of the
reaction suggests the involvement of a hydroxylamine intermediate leading to an intramolecular cyclization via N N bond formation. The
−
versatility of the methodology has been demonstrated by using two nitro-aryl substrates derived from dihydroisoquinolines and dihydro-
â-
carbolines. The intramolecular cyclization led to the formation of indazoles in high yields and purities.
Substituted heterocyclic compounds can offer a high degree
of structural diversity and have proven to be broadly useful
as therapeutic agents. Among the various heterocyclic
frameworks, benzoannelated nitrogen heterocycles are widely
used as biologically active compounds.1 One of the widely
acclaimed methods for the synthesis of benzoannelated
nitrogen heterocycles is via intramolecular cyclization of
ortho-nitro arene precursors. It generally involves reduction
of the nitro-aryl group followed by interaction of the reduced
intermediate with the functionality in an ortho-position
leading to heterocyclic compounds. The ring closure in these
precursors can be accomplished by two possible methods:
first, by the generation of an amino group from a nitro group
via reduction, which then participates in the cyclization, and
second, by direct involvement of intermediates generated in
situ from the nitro functionality during its reduction that leads
to the cyclization. Out of these two methods, the latter has
been utilized for the synthesis of N-rich heterocycles via an
intramolecular N-N bond formation. Reductive cyclizations
by direct involvement of aryl nitro compounds for N-N bond
formation are generally performed in the presence of tervalent
phosphorus reagents.2 It involves deoxygenation of the nitro
compounds by nucleophilic attack of tervalent phosphorus
reagents and subsequent cyclization to give heterocyclic
frameworks. Although a non-nitrene pathway was thought
to be the probable intermediate during the course of cycliza-
tion,3 subsequent studies in this area hinted at the possibility
of an arylnitrene pathway as well.4 The reactions are com-
monly carried out in an excess of triethyl phosphite, as both
the reductant and the reaction solvent at high temperatures.2b
However, this methodology suffers from the drawback that
the sensitive functional groups on heterocycles may undergo
alkylation leading to the formation of side products and a
decrease in yields.2b Additionally, intramolecular cyclizations
via N-N bond formation using methods other than tervalent
phosphorus reagents are rather scarce.5 During the course
of our studies on dihydroisoquinolines, we observed in-
(2) (a) Cadogan, J. I. G. Synthesis 1969, 11-17. (b) Cadogan, J. I. G.;
Cameron-Wood, M.; Mackie, R. K.; Searle, R. J. G. J. Chem. Soc. 1965,
4831-4837. (c) Freeman, A. W.; Urvoy, M.; Criswell, M. E. J. Org. Chem.
2005, 70, 5014-5019.
(3) (a) Brooke, P. K.; Herbert, R. B.; Holliman, F. G. Tetrahedron Lett.
1973, 14, 761-764. (b) Cadogan, J. I. G.; Kulik, S. J. Chem. Soc. C 1971,
2621-2632.
(4) Iddon, B.; Meth-Cohn, O.; Scriven, E. F. V.; Suschitzky, H.;
Gallagher, P. T. Angew. Chem., Int. Ed. Engl. 1979, 18, 900-917 and
references therein.
* To whom correspondence should be addressed. Phone: +91 522
2612411-18, ext. 4383. Fax: +91 522 2623405.
† CDRI communication number: 6896.
‡ Medicinal Chemistry Division.
§ Molecular and Structural Biology Division.
(1) For a review article: (a) Brase, S.; Gil, C.; Knepper, K. Bioorg. Med.
Chem. Lett. 2002, 10, 2415-2434. (b) Balaban, A. T.; Oniciu, D. C.;
Katritzky, A. R. Chem. ReV. 2004, 104, 2777-2812.
10.1021/ol053033y CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/21/2006

tramolecular cyclization of nitro compounds without involv-
ing the use of tervalent phosphorus reagents. In this
communication, we report an unprecedented SnCl2-mediated
cyclization via N-N bond formation in nitro arenes.
In our effort directed toward the reduction of the nitro
group of 1-(2-nitrophenyl)-3,4-dihydroisoquinoline (1a) using
SnCl2‚2H2O, we observed formation of an unusual side
product with a molecular weight of 280 Da in 3% isolated
yield along with the corresponding amine 2a in 85% isolated
yield (Scheme 1). Subjecting the byproduct to NMR and
cyclization (3a) as evident by HPLC. Similarly, treatment
of 1a with (EtO)3P also failed to yield the cyclized product
3a and led to the recovery of unconsumed starting material
(Scheme 1). This is the first example of a SnCl2-mediated
synthesis of 2H-indazole under mild conditions. It is quite
different from the transition-metal complexed-catalyzed
N-N bond formation via reductive carbonylation of N-(2-
nitrobenzylidene)amine performed under drastic conditions
(i.e., at 100 °C under 20 kg cm-2 of CO pressure).7 A careful
survey of the literature revealed three other methods5a,b,8 for
the intramolecular formation of a N-N bond leading to
indazole derivatives, but all of them involved harsh and
stringent reaction conditions (Scheme 2). Other syntheses
Scheme 1
Scheme 2
b
a Isolated yield. Recovered crude yield.
X-ray analysis revealed that an intramolecular cyclization
via N-N bond formation had occurred resulting in a novel
heterosystem 2,3-dimethoxy-5,6-dihydroindazolo[3,2-a]iso-
quinoline 3a. The ORTEP structure of the byproduct 3a has
been depicted in Figure 1. Interestingly, the catalytic reduc-
of indazole derivatives employ the thermal decomposition
of N-(2-azidobenzylidene)amines9a and oxidative cyclization
of acylhydrazones.9b
The indazole is one of the crucial heterocyclic skeletons
which is a part of various biologically active molecules, e.g.,
the marketed antiinflammatory drugs Bendazac10 and Ben-
zydamine.11
Armed with these observations, we set out to study the
course of cyclization that led to the formation of 3a from
(6) Crystal data for 3a: C17H16N2O2, M ) 280.32, monoclinic, P21/c,
a ) 11.438(1), b ) 7.421(1), c ) 16.332(1) Å, â ) 98.35(1)°, V ) 1371.6-
(2) Å3, T ) 293(2) K, Z ) 4, Dc) 1.357 g cm-3, µ ) 0.09 mm-1, λ(Mo
KR) ) 0.71073 Å, transparent block, crystal size ) 0.325 × 0.250 × 0.250
mm, R1 ) 0.0478 for 1681 Fo > 4σ(Fo) and 0.0740 for all 2411 data, 193
parameters. CCDC No. 299440. Crystal data for 14a: C17H13N3, M )
259.30, monoclinic, P21/n, a ) 12.167(1), b ) 17.406(3), c ) 12.419(1)
Å, â ) 93.74(1)°, V ) 2624.5(5) Å3, T ) 293(2) K, Z ) 8, Dc ) 1.313 g
cm-3, µ ) 0.08 mm-1, λ(Mo KR) ) 0.71073 Å, yellow block, crystal size
) 0.175 × 0.375 × 0.225 mm, R1 ) 0.0761 for 1929 Fo > 4σ(Fo) and
0.2041 for all 4604 data, 361 parameters. CCDC No. 299441. (For X-ray
queries: maulik_prakas@yahoo.com.)
Figure 1. ORTEP plot of the molecular structure of compound
3a and 14a in the crystal (at 50% probability level).6
tion using Pd-C of the nitro substrate 1a furnished amine
2a (Scheme 1) as the only product without any detectable
(7) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59,
3375-3380.
(8) Stanforth, S. P. J. Heterocycl. Chem. 1987, 24, 531-532.
(9) (a) Krbechek, L.; Takimoto, H. J. Org. Chem. 1964, 29, 1150-1152.
(b) Kotali, A.; Harris, P. A. J. Heterocycl. Chem. 1996, 33, 605-606.
(10) Guglielmotti, A.; Capezzone de Joannon, A.; Cazzolla, N.; Marchetti,
M.; Soldo, L.; Cavallo, G.; Pinza, M. Pharmacol. Res. 1995, 32, 369-
373.
(5) (a) Nyerges, M.; Somfai, B.; Toth, J.; Toke, L.; Dancso, A.; Blasko,
G. Synthesis 2005, 2039-2045. (b) Tima´ri, G.; Hajo´s, G.; Riedl, Z.; Be´res,
M.; Soo´s, T.; Messmer, A.; Gronowitz, S. Molecules 1996, 1, 236-241 (c)
Bates, D. K.; Kohrt, J. T.; Folk, H.; Xia, M. Heterocycl. Commun. 1997, 3,
201-206. (d) Gnichtel, H.; Moller, B. Liebigs Ann. Chem. 1981, 1751-
1759.
(11) Runti, C.; Baiocchi, L. Int. J. Tissue React. 1985, 7, 175-186.
1526
Org. Lett., Vol. 8, No. 8, 2006

substrate 1a under relatively mild conditions followed by
the development of a method for the quantitative synthesis
of dihydroindazoloisoquinolines 3. We envisaged that both
the products 2a and 3a were the outcome of a single
intermediate with the amine 2a having synthetic preference
over that of the cyclized product 3a when exposed to SnCl2‚
2H2O conditions. Reduction of the nitro group is generally
well-known to proceed through nitroso and hydroxylamine
intermediates.12 Although, Pd-catalyzed reduction (Pd/C) also
proceeds via the same intermediate, it is possible that
conversion of amines may be occurring on the catalyst’s
surface without the concomitant release of intermediates at
any stage,12 thus furnishing amine 2a without the cyclized
product 3a. To comprehend the mechanistic course for the
formation of dihydroindazoloisoquinoline 3a, the reduction
of the nitro group was abated at the hydroxylamine stage
with the view to examine its ability to undergo N-N
cyclization. Examples of cyclization involving the intramo-
lecular capture of an intermediate hydroxylamine are well-
documented in the literature.13 However, the role of hydroxy-
lamine as an intermediate in the formation of a N-N bond
has not yet been reported.
dual role by hindering the complete reduction of the nitro
group to amine 2a and by promoting the cyclization to
furnish product 3a, thus kinetically favoring formation of
3a over 2a. A closer look on the course of the cyclization
via hydroxylamine 11a to the cyclized product 3a revealed
that the cyclization may have occurred by the loss of a water
molecule, which in turn may have formed by the combination
of a proton obtained from the protonated base and the
hydroxyl anion departing from the hydroxylamine in 11a.
This gets support from the fact that the formation of cyclized
product 3a did occur, albeit in low yield (29%), because the
hydroxyl group is known to be a poor leaving group. Hence,
we decided to improve the leaving group tendency of the
hydroxyl group by derivatizing it with a tosyl group.15
Accordingly, we treated 11a with tosyl chloride, and after
15 min, we observed complete conversion to indazole 3a
(route II, Scheme 3). Next, the one-pot conversion of 1a to
3a was achieved by sequentially treating 1a with SnCl2‚
2H2O, PhSH, and Et3N for 15 min and then with tosyl
chloride for 15 min (route III, Scheme 3). The crude product
so obtained was purified by successively treating with water,
hexane, and methanol to yield the final product with >99%
purity.16 However, we further established the purity of 3a
by determining its melting point and HRMS, which matched
with the material obtained after passing through silica gel
column chromatography. A plausible mechanism for the
intramolecular cyclization of arylhydroxylamine 11a to
dihydroindazoloisoquinoline 3a could be via an electron-
deficient nitrene intermediate, as depicted in Scheme 4.
Recently, Lebel et al. demonstrated nitrene formation starting
from tosyloxy carbamates in the presence of potassium
carbonate as base.17 The scope and limitation of the strategy
was established by synthesizing three more congeners based
on 3 (route III, Scheme 3) by varying the phenethylamines
and o-nitro benzoic acids. The dihydroisoquinoline deriva-
tives 1a-d were synthesized by literature procedure using
For our studies, reduction of the nitro group to hydroxy-
lamine was achieved by treating substrate 1a with SnCl2‚
2H2O in the presence of PhSH and Et3N (route I, Scheme
3) as per literature procedure.14 The progress of the reduction
Scheme 3
(15) Stanetty, P.; Bahardoust, M. H.; Mihovilovic, M. D.; Mereiter, K.
Monatsh. Chem. 1999, 130, 1257-1268.
(16) General experimental procedure: Triethylamine (0.45 g, 3.20
mmol) was added dropwise to a stirred solution of SnCl2‚2H2O (0.22 g,
0.96 mmol) and PhSH (0.32 g, 2.90 mmol) in acetonitrile (5 mL) at room
temperature to generate yellow precipitate over a period of 5 min. Then,
1a (0.180 g, 0.64 mmol) was transferred to the suspension and stirred at
room temperature for 5 more min. After complete consumption of the nitro
substrate on TLC, TsCl (0.15 g, 0.83 mmol) was added to this solution and
monitoring of the reaction was done on TLC and HPLC. After completion
of the reaction, the solvent was evaporated and the resulting residue was
triturated with water (10 mL). The solid material was filtered and washed
extensively with water. It was dried in a desiccator in vacuo and then again
triturated with hexane. The solid was again filtered and washed extensively
with hexane and then dried in vacuo. The solid obtained was then dissolved
in methanol, and the insoluble material separated was removed by filtration.
The filtrate was finally evaporated, and the residue was crystallized from
EtOAc-hexane to give 2,3-dimethoxy-5,6-dihydroindazolo[3,2-a]isoquino-
line [3a]: white solid; yield ) 0.16 g (89%); mp 180-182 °C; tR ) 16.9
# Conversion was monitored by HPLC (%). $Isolated yield of 3
from 1.
was monitored by HPLC, and within 15 min, we were
pleased to observe the complete disappearance of 1a and
the formation of 3a (29%) along with the intermediate 11a
(71%). It appears that the basic condition probably played a
1
min; Rf ) 0.63 (2:3 EtOAc/hexane); H NMR (CDCl3, 300 MHz) δ 7.96
(d, 1H, J ) 8.4 Hz, ArH), 7.73 (d, 1H, J ) 8.7 Hz, ArH), 7.48 (s, 1H,
ArH), 7.32 (t, 1H, J ) 7.2 Hz, ArH), 7.16 (t, 1H, J ) 7.5 Hz, ArH), 6.85
(s, 1H, ArH), 4.62 (t, 2H, J ) 6.9 Hz, CH2), 4.02 (s, 3H, CH3), 3.94 (s,
(12) Enwistle, I. D.; Gilkerson, T. Tetrahedron 1978, 34, 213-215 and
references therein.
13
3H, CH3), 3.21 (t, 2H, J ) 6.9 Hz, CH2); C NMR (CDCl3, 50 MHz) δ
(13) (a) Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis
2005, 47-56. (b) Bates, D. K.; Li, K. J. Org. Chem. 2002, 67, 8662-
8665. (c) Sykes, B. M.; Atwell, G. J.; Denny, W. A.; O’Connor, C. J. J.
Phys. Org. Chem. 1995, 8, 587-596.
(14) Bartra, M.; Romea, P.; Urpi, F.; Vilarrasa, J. Tetrahedron 1990,
46, 587-594.
149.1, 148.8, 131.1, 126.4, 125.3, 122.3, 121.1, 120.5, 118.2, 117.9, 111.9,
107.7, 56.6, 56.5, 48.3, 29.1; IR (KBr) νmax 1603, 1696, 1217; MS (FAB)
281 for [M + 1]+; MS (HR EI) m/z calcd for [M]+ 280.12118, found
280.12300.
(17) Lebel, H.; Huard, S.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198-14199.
Org. Lett., Vol. 8, No. 8, 2006
1527

Scheme 4
Scheme 5
a Isolated yield of 14.
the conventional Bishler-Napieralski reaction.18 The cyclized
products dihydroindazoloisoquinolines 3b-d were obtained
in >85% isolated yields, and substitutions on either phen-
ethylamines or o-nitro benzoic acids had no effect on the
outcome of the reaction. The compounds were characterized
using NMR and HRMS. We next examined the versatility
of our strategy by replacing phenethylamines with tryptamines.
The synthetic strategy for synthesizing indole-based N-N
cyclized products triazaindeno[1,2-a]fluorenes 14a-c from
tryptamine has been depicted in Scheme 5. A literature
survey revealed 14 to be novel chemotypes whose synthesis
has not yet been reported. Our synthesis commenced with
the conversion of amide 12 derived by coupling tryptamine
with o-nitro benzoic acid derivatives to dihydro-â-carboline
13 by a modified Bishler-Napieralski reaction reported for
indoles.19 Our protocol involved the use of 5 equiv of POCl3
in the presence of 7 equiv of P2O5 in acetonitrile as solvent
under reflux which furnished 13 in moderate to good yields.
The dihydro-â-carboline 13 was finally subjected to one-
pot intramolecular cyclization by successively treating with
SnCl2‚2H2O/PhSH/Et3N in CH3CN for 15 min and then with
TsCl for 15 min at room temperature to give N-N cyclized
product 14. The scope and limitation of our strategy was
established by synthesizing three congeners based on 14
(Scheme 5), and in each case, the product was obtained in
>88% isolated yields. The compounds were characterized
using NMR, ESMS, and HPLC, and one of the derivatives
was characterized by X-ray crystallography. The ORTEP
structure of 14a has been depicted in Figure 1.
We have thus successfully developed a mild, efficient, and
one-pot protocol for the intramolecular cyclization of nitro
arene substrates. The mechanistic course of the reaction
suggests involvement of a hydroxylamine intermediate for
cyclization via N-N bond formation. The versatility of the
methodology has been demonstrated by using two nitro arene
substrates derived from dihydroisoquinolines and dihydro-
â-carbolines. The methodology may find application in
practicable heterocyclic syntheses using a suitable molecular
framework, and the results will be published shortly.
Acknowledgment. We thank one of the referees for his
valuable suggestion concerning the mechanistic aspect of the
reaction described in this paper. D.S. is thankful to CSIR,
New Delhi, India, for providing fellowship.
Supporting Information Available: Experimental de-
tails, spectroscopic characterization, and X-ray crystal-
lographic data of 3a and 14a. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Cortes, E. C.; Romere, E. C.; Ramirez, G. F. J. Heterocycl. Chem.
1994, 31, 1425-1427.
(19) (a) Sa´nchez-Sancho, F.; Mann, E.; Herrado´n, B. Synlett 2000, 509-
513. (b) Chern, M. S.; Shin, Y. K.; Dewang, p. M.; Li, W. R. J. Comb.
Chem. 2004, 6, 855-858. (c) Wang, X.-J.; Tan, J.; Grozinger, K.
Tetrahedron Lett. 1998, 39, 6609-6612. (d) Spaggiari, A.; Davoli, P.;
Blaszczak, L. C.; Prati, F. Synlett 2005, 661-663.
OL053033Y
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