Rhodium(III)-catalyzed synthesis of indoles from 1-alkylidene-2- arylhydrazines and alkynes via C-H and N-N bond cleavages

Article abstract of DOI:10.1016/j.tetlet.2014.04.016

1-Alkylidene-2-arylhydrazines undergo annulative coupling with internal alkynes in the presence of a rhodium(III) catalyst and a copper(II) salt. The reaction proceeds through cleavage of the C-H and N-N bonds of hydrazines to afford 1,2,3-trisubstituted indole derivatives.

Full text of DOI:10.1016/j.tetlet.2014.04.016

Accepted Manuscript
Rhodium(III)-catalyzed synthesis of indoles from 1-alkylidene-2-arylhydra-
zines and alkynes via C–H and N–N bond cleavages
Takanori Matsuda, Yuki Tomaru
PII:
S0040-4039(14)00613-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.016
TETL 44478
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
24 February 2014
2 April 2014
7 April 2014
Please cite this article as: Matsuda, T., Tomaru, Y., Rhodium(III)-catalyzed synthesis of indoles from 1-alkylidene-2-
arylhydrazines and alkynes via C–H and N–N bond cleavages, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.04.016
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Rhodium(III)-catalyzed synthesis of indoles
from 1-alkylidene-2-arylhydrazines and
alkynes via C–H and N–N bond cleavages
Leave this area blank for abstract info.
Takanori Matsuda, Yuki Tomaru

1
Tetrahedron Letters
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Rhodium(III)-catalyzed synthesis of indoles from 1-alkylidene-2-arylhydrazines and
alkynes via C–H and N–N bond cleavages
Takanori Matsuda * and Yuki Tomaru
Department of Applied Chemistry, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
1-Alkylidene-2-arylhydrazines undergo annulative coupling with internal alkynes in presence of
a rhodium(III) catalyst and a copper(II) salt. The reaction proceeds through cleavage of the C–H
and N–N bonds of the hydrazines to afford 1,2,3-trisubstituted indole derivatives.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Alkyne
Annulation
C–H bond functionalization
Hydrazine
Indole
Rhodium
Because of the importance of indoles as a privileged structure
in the manufacture of pharmaceuticals, agrochemicals, and
functional materials, the continued development of increasingly
efficient methods for the preparation of indoles has been a
pervasive topic in organic synthesis.1 The Fischer indole
cyclization (synthesis) has arguably become one of the most
studied and successful approaches to indole synthesis since its
discovery in 1883, and it remains under active development. The
vintage synthesis and its modern variants employ 1-alkylidene-2-
arylhydrazines or their tautomers, 1-alkenyl-2-arylhydrazines, as
substrates.
Figure 1. N–N Compounds used in rhodium(III)-catalyzed
annulation with alkynes to give indoles
Subjection of 1-ethylidene-2-methyl-2-phenylhydrazine (1a)
and diphenylacetylene (2a) to [Cp*RhCl2]2 (2.5 mol%, 5 mol%
Rh) and Cu(OAc)2 (2 equiv) in DMF at 120 °C under nitrogen
resulted in the formation of 1-methyl-2,3-diphenylindole (3a) in
34% yield through the annulative coupling involving cleavage of
the C–H and N–N bonds under rhodium(III)-catalyzed oxidative
conditions (Table 1, entry 1). Because a cationic system
([Cp*RhCl2]2/AgSbF6) proved to be more effective (entry 2), the
preformed
[Cp*Rh(MeCN)3](SbF6)2 was used; the reaction gave 3a in 58%
yield (entry 3). Furthermore, the addition of
cationic
rhodium(III)
catalyst
Transition-metal-catalyzed C−H bond functionalization has
witnessed tremendous growth in recent years because it offers an
innovative and elegant pathway for the construction of organic
molecules. As such, a wide variety of annulation and cyclization
reactions based on the functionalization of C–H bonds2 have been
devised for indole synthesis3,4 and have addressed some of the
issues pertaining to the traditional methods. Reports of a
rhodium(III)-catalyzed indole synthesis involving the cleavage of
N–N bonds appeared in succession last year (Figure 1).4,5 During
our ongoing investigation into transition-metal-catalyzed
reactions of hydrazine derivatives,6 we discovered an indole-
forming annulation reaction of alkylidenehydrazines with alkynes
under rhodium(III) catalysis, which we report herein.7
tetraphenylcyclopentadiene (C5H2Ph4) as the ligand boosted the
yield to 67% (entry 4).8 A control experiment revealed that the
use of an excess (1.5 equiv) of 2a was pivotal for obtaining the
product in good yield. The reaction performed at a lower
temperature (100 °C) led to a reduced yield (entry 5), and a
complex mixture of products was obtained when the reaction was
performed under air. Almost no indole formation was observed in
the absence of either the Rh(III) catalyst or the Cu(II) oxidant.
Table 1
Optimization of reaction conditionsa
———
* Corresponding author. Fax: +81 3 52614631.
E-mail address: mtd@rs.tus.ac.jp (T. Matsuda).

2
Entry Catalyst
Tetrahedron
Temp Time Yieldb
(PhMeN–NH2) under our reaction conditions afforded 3a in trace
amount, suggesting that a mechanism involving
hydrohydrazination of alkynes followed by the Fischer indole
cyclization10 is improbable in this case.
(°C)
120
120
(h)
3
(%)
34
1
2
2.5 mol% [Cp*RhCl2]2
The proposed mechanism for the rhodium(III)-catalyzed
indole-forming annulation reaction between 1c and 2a is shown
in Scheme 1. A rhodium(III) acetate species is presumably
generated from ligand exchange, and the nitrogen of the
hydrazine 1c directs the C–H bond cleavage event to generate
five-membered rhodacycle A with an accompanying loss of
acetic acid.11,12 Next, the C–C triple bond of 2a coordinates to the
rhodium, after which migratory insertion occurs to form seven-
membered rhodacycle B. The N–N bond in intermediate B is
then cleaved, and the amino group migrates to the rhodium to
forge six-membered rhodacycle C with the concomitant release
of acetic acid and isobutyronitrile.13 Finally, reductive
elimination of C furnishing indole 3a extrudes a rhodium(I)
species, which is oxidized by Cu(II) to restore the catalytically
active rhodium(III) complex. Under our oxidative conditions, the
putative byproduct, nitrile, was so unstable that its detection and
isolation were not possible.
2.5 mol% [Cp*RhCl2]2
20 mol% AgSbF6
3
46
3
4
5 mol% [Cp*Rh(MeCN)3](SbF6)2 120
5 mol% [Cp*Rh(MeCN)3](SbF6)2 120
20 mol% C5H2Ph4
1.5
1.5
58
67c
5
5 mol% [Cp*Rh(MeCN)3](SbF6)2 100
20 mol% C5H2Ph4
2
54
a
1a (0.20 mmol) and 2a (0.30 mmol) were reacted in the
presence of 5 mol% Rh(III) catalyst and 2 equiv Cu(OAc)2 in DMF
(1.0 mL) under nitrogen.
b Isolated yield.
c 50% yield with 1 equiv 2a.
We subsequently investigated the effect of the alkylidene
moieties of hydrazines 1 that are dismantled during the reaction
(Table 2).9 The reaction of N′-propylidene hydrazine 1b with 2a
resulted in a comparable yield (entry 1). N′-Isobutylidene
hydrazine 1c was among the most efficacious substrates for the
reaction, giving 90% yield of 3a (entry 2). However, the product
3a was not obtained with neopentylidene hydrazine 1d because
of the decomposition of the substrate (entry 3), and no reaction
was observed with benzylidene hydrazine 1e (entry 4). We also
examined ketone-derived substrates; the use of cyclohexylidene
derivative 1f led to the decomposition of the starting hydrazine
(entry 5).
Table 2
Screening of alkylidene substituents of 1a
Scheme 1. Proposed mechanism for the rhodium(III)-catalyzed
indole-forming annulation
Using N′-isobutylidene hydrazines as coupling partners of
choice, we subjected a range of alkynes to the optimized indole-
forming reaction conditions (Table 3).14 The reaction of 1c with
diaryl alkynes afforded the corresponding 2,3-diaryl indoles 3b–
f. A thienyl group was tolerated in this reaction to provide
dithienyl indole 3g. An aliphatic alkyne was also used that
resulted in 2,3-dipropylindole 3h being isolated in 54% yield. In
the case of the unsymmetrical alkyne 1-phenyl-1-propyne,
product 3i was obtained as an 80:20 mixture of regioisomers. In
addition to N-methylindoles, N-ethyl-, N-benzyl-, and N-
phenylindoles 3j–m were also prepared through the reaction. In
the reaction of 3-tolyl derivative, the C–H bond cleavage process
occurred at the more sterically accessible sites to give and 6-
methylindole 3o, respectively, as the exclusive products.
Entry
1
R, R´
Yieldb (%)
70
1
2
3
4
5
1b
1c
1d
1e
1f
Et, H
i-Pr, H
t-Bu, H
Ph, H
90
decomposition
no reaction
decomposition
(CH2)5
a 1 (0.20 mmol) and 2a (0.30 mmol) were reacted in the presence
of 5 mol% [Cp*Rh(MeCN)3](SbF6)2 and 2 equiv Cu(OAc)2 in DMF
(1.0 mL) under nitrogen.
b Isolated yield.
Some experiments were conducted to probe the mechanism of
the reaction. The reaction with 1-methyl-1-phenylhydrazine
Table 3
Substrate scope of the rhodium(III)-catalyzed annulative coupling of 1 with 2

3
3b 91%
3c 97%
3d 63%
3e 69%
3f 52%
3g 55%
3h 54%
3i 72% (80:20)
3j 73%
3k 41%
3l 92%
3m 61%
3n 88%
3o 89%
3p 74%
Chem. Soc. 2008, 130, 16474. (c) Tsuchikama, K.; Hashimoto, Y.-
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Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2009, 48, 4572. (e) Chen, J.; Song, G.;
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Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
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In conclusion, we developed a method for the synthesis of
indoles from alkylidenehydrazines and alkynes under
rhodium(III)-catalyzed oxidative conditions. This annulation
reaction proceeds via the cleavage of C–H and N–N bonds and
allows access to a range of 1,2,3-trisubstituted indoles.
Acknowledgments
This work was supported by JSPS, Japan (Grant-in-Aid for
Scientific Research (C) No. 25410054) and the Sumitomo
Foundation.
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11. Use of KOAc instead of Cu(OAc)2 as the source of acetate ion
was unsuccessful.
3. (a) Würtz, S.; Rakshit, S.; Neumann, J. J.; Dröge, T.; Glorius, F.
Angew. Chem., Int. Ed. 2008, 47, 7230. (b) Stuart, D. R.;
Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am.
12. When 1c was heated at 120 °C in DMF–CD3OD (5:1) in the
presence of [Cp*Rh(MeCN)3](SbF6)2 (5 mol%) and Cu(OAc)2 (50
mol%), deuteration at the ortho positions of 1c was observed.

4
Tetrahedron
13. For a similar acetate-induced C–H bond cleavage process via a
seven-membered intermediate, see: Nakamura, I.; Shiraiwa, N.;
Kanazawa, R.; Terada, M. Org. Lett. 2010, 12, 4198. See also ref
7.
14. Use of terminal alkynes resulted in homocoupling to yield 1,3-
diynes, and formation of indoles was not observed.