Ionic diamine rhodium complex catalyzed reductive N-heterocyclization of N-(2-nitroarylidene)amines

Article abstract of DOI:10.1016/j.tetlet.2011.11.101

Ionic diamine rhodium complexes catalyze the reductive N-heterocyclization of N-(2-nitroarylidene)amines under carbon monoxide to afford the corresponding 2H-indazoles in up to 75% yields.

Full text of DOI:10.1016/j.tetlet.2011.11.101

Tetrahedron Letters 53 (2012) 620–622
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ionic diamine rhodium complex catalyzed reductive N-heterocyclization
of N-(2-nitroarylidene)amines
⇑
Kazumi Okuro, Joanna Gurnham, Howard Alper
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
Ionic diamine rhodium complexes catalyze the reductive N-heterocyclization of N-(2-nitroarylid-
ene)amines under carbon monoxide to afford the corresponding 2H-indazoles in up to 75% yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 October 2011
Revised 14 November 2011
Accepted 18 November 2011
Available online 25 November 2011
Keywords:
Rhodium
Heterocycles
2H-Indazole
Reductive N-heterocyclization
+
_
Indazoles, which are regarded as isoteres of indoles, are an
important class of heterocycles often occurring as constituents of
biologically active compounds. For example, it has been reported
that N-substituted indazoles exhibit high affinities for estrogen
receptor b, and exhibit analogestic and anti-angiogenic activities.1
Due to the pharmaceutical and agricultural importance of these
heterocyclic systems, it is somewhat surprising that the syntheses
of 2H-indazoles have been less explored than those of other hetero-
cycles including 1H-indazoles.2 Recent advances in organometallic
chemistry have provided several straightforward approaches to
2H-indazoles. Examples include the Pd/SnCl2 catalyzed reductive
N-heterocyclization of (2-nitroarylidene)amines,3 and the Pd
catalyzed domino reaction of 2-halophenylacetylenes with
phenylhydrazine.4
We have recently reported the synthesis of a novel, air stable
diamine rhodium complex, [Rh(CO)2(Me2NCH2CH2NMe2)]+[RhCl2
(CO)2]ꢀ (I).5 The complex is an excellent catalyst for the
regioselective hydroformylation of olefins,5 and for the inter- and
intra-molecular hydroaminomethylation of anilines containing an
olefinic unit.6 In further exploring the catalytic activity of I, we re-
cently found that I can catalyze reductive N-heterocyclization of 2-
nitroarenes under carbon monoxide affording indole derivatives.7
In this Letter, we describe the reductive N-heterocyclization of N-
(2-nitroarylidene)amines to give 2H-indazole derivatives, where
carbon monoxide is used as a reducing agent for the nitro group.
L
CO
CO
CO
CO
Cl
Cl
Rh
Rh
L
Ph
II
Ph
Ph
N
N
L
N
N
=
=
=
N
N
L
Ph
I
III
We initially employed N-(2-nitrobenzylidene)butylamine (1a)
to optimize the reaction conditions. When 1a was treated with
5 mol % of the complex I in THF at 100 °C for 24 h under CO
(100 psi), conditions used for the reductive N-heterocyclization of
2-nitroarenes affording indoles,7 2-butyl-2H-indazole (2a) was pro-
duced in a 56% yield (Table 1, entry 1). Performing the reaction in
toluene increased the yield to 75% (entry 2). Other solvents such
as CH2Cl2 and CH3CN were inferior to toluene. Decreasing the
temperature to 80 °C in toluene significantly reduced the conver-
sion of 1a (entry 6) and prolonged reaction time increased the yield
of 2a (entry 7). Higher (200 psi) or lower (42 psi) pressure of carbon
monoxide did not have a positive effect on the yield of 2a (entries 5
and 8). The effect of the diamine ligands was also examined. Use of
the rhodium complex with the diamines, N,N,N0,N0-tetrabenzyle-
thylenediamine(tipeda) (II)5 or trans-1,2-bis(dimethylamino)cycl-
ohexane (III)5 was evaluated, and although both complexes
catalyzed the reaction to some extent, they were not as effective
⇑
Corresponding author. Tel.: +1 613 562 5189; fax: +1 613 562 5871.
E-mail address: howard.alper@uottawa.ca (H. Alper).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.101

K. Okuro et al. / Tetrahedron Letters 53 (2012) 620–622
621
Table 1
Table 2
Reductive N-heterocyclization of 1a
Results of the Rh-catalyzed reductive N-cyclization of
a
variety of
Yield (%)
(2-nitroarylidene)aminea
+
_
Entry
1
Nitro compound
2H-indazole
But
CO
Rh
CO Cl
N
N
Rh
CO
Cl
CO
I
But
N
N
Bun
NO2
N
75
85
65
25
N
5 mol%
100 oC
NO2
N Bun
2b
1b
N
1a
Ph
N
N
2a
N
Ph
O
2
3
4
NO
2
Entry
Cat.
CO (psi)
Solvent
Yield (%)
1a
2c
1c
2a
O
N
NO2
1d
N
N
1
2
3
4
I
I
I
I
I
I
I
I
100
100
100
100
200
100
100
42
THF
56
75
43
58
65
42
64
29
11
46
0
0
Toluene
CH2Cl2
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
2d
Trace
0
0
39
11
42
83
Trace
Ph
N
2e
N
Ph
N
5
NO2
6a
7a,b
8
1e
N
NO2
1f
Ph
N
9
10
II
III
100
100
5
6
34(36)b
Trace
Ph
N
2f
a
Reaction at 80 °C.
Reaction for 48 h.
N
N
N
b
NO
2
2g
1g
Cl
Cl
as complex I (entries 9 and 10). When the reaction was carried out
using the catalyst system of [Rh(COD)Cl]2 and standard phosphines
such as PPh3, PCy3, dppe, dppp, dppb, and dppf, no reaction took
place at all, indicating that similar catalytic performance with I can-
not be obtained for the system with phosphine ligands.
n
Bu
N
N
n
N
N
Bu
7
8
32
65
NO
2
1h
1h
Bun
But
Cl
Cl
n
N
Bu
N
Having found the optimal conditions using 1a, the reaction was
applied to a variety of N-(2-nitroarylidene)amines. At first, the
effect of the substituents on nitrogen was examined. The reaction
of N-(2-nitrobenzylidene)-t-butylamine (1b), N-(2-nitrobenzyli-
dene)-2-phenylethylamine (1c), and N-(2-nitrobenzylidene)-2-
methoxyethylamine (1d) proceeded smoothly to afford the
corresponding 2-substituted 2H-indazoles in 65–85% yields (Table
2, entries 1–3). On the other hand, the substrate having phenyl-,
benzyl-, and allyl- substituted N-(2-nitrobenzylidene)amine deriv-
atives gave unsatisfactory results (entries 4–6). Several N-(2-nitro-
arylidene)amines having methoxy and chloro groups on the
aromatic ring were reacted under the optimal conditions to afford
the corresponding 2H-indazole derivatives in 32–65% yields. In
contrast, the ketimine 1o was totally unreactive, with 1o being
recovered unchanged. These results were comparable to those
reported using a Pd complex as the catalyst,3 except for N-(2-nitro-
benzylidene)arylamines (i.e., 1e). In the latter case, N-(2-nitroben-
zylidene)arylamine derivatives successfully reacted to afford the
corresponding N-aryl-2H-indazoles in moderate yields whereas
the present catalyst system resulted in a poor yield of 2e described
above.
The reaction mechanism is not known; however it would be
reasonable to consider the involvement of the nitrene-rhodium
intermediate, 33b,7,8 where carbon monoxide serves as a reducing
agent (Scheme 1). Thus, the diamine rhodium complex catalyzed
deoxygenation of the nitro group can give a nitrene-rhodium inter-
mediate of an electrophilic nature, and then the latter could under-
go intramolecular ring closure onto the imino nitrogen atom,
resulting in the formation of 2H-indazole. Considering that the nit-
rene would strongly coordinate to the metal, it is conceivable that
the reaction behavior of the nitrene intermediate is affected by the
nature of its metal species, depending on its coordination environ-
ment, which could lead to no comparable outcome for the reaction
of 1e using the Pd catalyst.
NO2
1i
2i
Cl
Cl
Cl
t
N
N
Bu
9
10
11
58
56
57
N
NO2
2j
1j
Cl
O
N
NO2
1k
N
N
O
2k
n
CH3O
CH O
3
Bu
Bun
N
2
N
N
NO
1l
2l
t
CH O
3
CH O
3
Bu
t
N
2
N Bu
12
13
14
50
47
0
N
NO
1m
2m
2n
CH3O
CH3O
O
N
N
NO2
O
N
1n
n
Bu
N
NO
2
1o
a
Conditions: 1 (1.0 mmol), I (0.05 mmol), toluene, 100 °C, CO 100 psi.
The yield in parenthesis at 80 °C.
b
the ionic diamine rhodium complex under carbon monoxide af-
fords 2H-indazole derivatives in up to 75% yields.
Acknowledgment
In conclusion, we have demonstrated that the reductive
N-heterocyclization of N-(2-nitroarylidene)amines catalyzed by
We are grateful to the Natural Sciences and Engineering Council
of Canada (NSERC) for the support of this research.

622
K. Okuro et al. / Tetrahedron Letters 53 (2012) 620–622
[Rh], 2CO
R
R
N
N
NO2
N R
N
[Rh]
N
3
2CO2
Scheme 1. Possible reaction mechanism for indazole formation.
4. Halland, N.; Nazare, M.; R’kyek, O.; Alonso, J.; Urmann, M.; Lindenschmidt, A.
Angew. Chem., Int. Ed. 2009, 48, 6879.
References and notes
5. Kim, J. J.; Alper, H. Chem. Commun. 2005, 3059.
1. (a) Cerecetto, A.; Gerpe, A.; González, V.; Arán, V. J.; Ochoa de Ocáriz, C. Mini-Rev.
Med. Chem. 2005, 5, 869; (b) Amgelis, M. D.; Stossi, F.; Carson, K. A.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2005, 48, 1132;
(c) Huang, L. J.; Shih, M. L.; Chen, H. S.; Pan, S. L.; Teng, C. M.; Lee, F. Y.; Kuo, S. C.
Bioorg. Med. Chem. 2006, 14, 528.
2. (a) Stadlbauer, W. Science of Synthesis 2002, 12, 227; (b) Elguero, J. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F.
C., Eds.; Pergamon: Oxford, 1996; Vol. 3, pp 1–75; (c) Elguero, J. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. C., Eds.;
Pergamon: Oxford, 1984; Vol. 3, pp 167–303; (d) Behr, L. C. In The Chemistry of
Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley-Interscience:
New York, 1967; Vol. 22, pp 289–382; (e) Schmidt, A.; Beutler, A.; Snovydovych,
B. Eur. J. Org. Chem. 2008, 4073; (f) Creencia, E. C.; Kosaka, M.; Muramatsu, T.;
Kobayashi, M.; Iizuka, T.; Horaguchi, T. J. Heterocycl. Chem. 2009, 46, 1309.
3. (a) Akazome, M.; Kondo, T.; Watanabe, Y. J. Chem. Soc., Chem. Commun. 1991,
1466; (b) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1995, 59, 3375.
6. (a) Vieira, T. O.; Alper, H. Chem. Commun. 2007, 2710; (b) Vieira, T. O.; Alper, H.
Org. Lett. 2008, 10, 485; (c) Okuro, K.; Alper, H. Tetrahedron Lett. 2010, 51, 4959.
7. Okuro, K.; Gurnham, J.; Alper, H. J. Org. Chem. 2011, 76, 4715.
8. (a) Abramovitch, R. A.; Davis, B. A. Chem. Rev. 1964, 64, 149; (b) Weigert, F. J. J.
Org. Chem. 1973, 38, 1316; (c) Dieck, H. A.; Laine, R. M.; Heck, R. F. J. Org. Chem.
1975, 40, 2819; (d) Watanabe, Y.; Tsuji, Y.; Takeuchi, R. Bull. Chem. Soc. Jpn. 1983,
56, 3343; (e) Cenini, S.; Pizzotti, M.; Crotti, C.; Porata, F.; La Monica, G. J. Chem.
Soc., Chem. Commun. 1984, 53, 1243; (f) Watanabe, Y.; Tsuji, Y.; Kondo, T.;
Takeuchi, R. J. Org. Chem. 1984, 49, 4451; (g) Watanabe, Y.; Tsuji, Y.; Takeuchi, R.
Bull. Chem. Soc. Jpn. 1984, 57, 3011; (h) Allessio, E.; Mestroni, G. J. Organomet.
Chem. 1985, 291, 117; (i) Tsuji, Y.; Takeuchi, R.; Watanabe, Y. J. Organomet. Chem.
1985, 290, 249; (j) Crotti, C.; Cenini, S.; Rindone, B.; Tollari, S.; Demartin, F. J.
Chem. Soc., Chem. Commun. 1986, 784; (k) Crotti, C.; Cenini, S.; Ragaini, F.; Porta,
F. J. Mol. Catal. 1992, 72, 283.