An efficient approach to 1,2,3-trisubstituted indole via rhodium catalyzed carbene Csp3-H bond insertion

Article abstract of DOI:10.1039/c5ob00085h

A method for convenient synthesis of N-alkyl-2-aryl-indole-3-carbaldehyde has been described. A variety of highly valuable indolyl aldehydes have been prepared through this method. Electron donating groups on both aromatic rings (anilinyl and benzyl) facilitate the formation of the desired products. A benzylic C-H insertion by rhodium carbene is the key step for this transformation. This journal is

Full text of DOI:10.1039/c5ob00085h

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An efficient approach to 1,2,3-trisubstituted indole
via rhodium catalyzed carbene Csp3–H bond
insertion†
Cite this: DOI: 10.1039/c5ob00085h
Received 15th January 2015,
Accepted 23rd March 2015
Mei-Hua Shen,* Ying-Peng Pan, Zhi-Hong Jia, Xin-Tao Ren, Ping Zhang and
Hua-Dong Xu*
DOI: 10.1039/c5ob00085h
www.rsc.org/obc
A method for convenient synthesis of N-alkyl-2-aryl-indole-3-carb-
aldehyde has been described. A variety of highly valuable indolyl
aldehydes have been prepared through this method. Electron
donating groups on both aromatic rings (anilinyl and benzyl) facili-
tate the formation of the desired products. A benzylic C–H insertion
by rhodium carbene is the key step for this transformation.
A 1,2,3-trisubstituted indole moiety constitutes a large number
of natural and synthetic biologically active molecules and func-
tional materials. 3-Formyl indole is a versatile intermediate for
the synthesis of indole derivatives due to the diverse trans-
formations in which the aldehyde functional group could par-
ticipate.1 Conventionally, direct formylation of the
corresponding parent indole is the choice for the preparation
of this class of molecule, such as Vilsmeier–Haack formyla-
tion,2 Reimer–Tiemann–Gattermann reaction,3 and recently
reported protocols for direct indole formylation.4 On the other
hand, several de novo methods for the construction of 3-formyl
indole from non-indole precursors have also appeared in the
literature which possess some merits devoid in the direct
approach.5
Since they were discovered as convenient 2-azavinyl carbene
progenitors in 2008,6 1-sulfonyl 1,2,3-triazoles have been
applied with great success in a variety of efficient transform-
ations7 leading to the construction of unique frameworks
otherwise hardly accessible.8 Our interest in this research area
has led to the discovery of several practical reactions,9 and par-
ticularly relevant to the current report is rhodium catalyzed
3-formyl indole synthesis from triazole 1 (Scheme 1, eqn (a)).9a
A key event in this process is the (formal) insertion of the
in situ generated metal carbene into the ortho anilinyl Csp2–H
bond.8h,l,m Here we wish to report a complementary strategy
which employed N-benzyl anilinyl triazole 3 as the starting
Scheme 1 Complementary de novo 3-formyl indole synthesis using
sulfonyl triazoles.
material for a facile entry into 1-alkyl-2-aromatic-3-formyl
indole 4 (Scheme 1, eqn (b)).
Initially, N,N-bisallyl-anilinyl triazole 3a was treated with a
catalytic amount of Rh2(OAc)4 in hot toluene under nitrogen
and tricyclic aldehyde 7a was isolated in 60% yield after hydro-
lysis in an open flask. Efforts to expand this reaction to other
close analogues have encountered unexpected difficulties as
triazoles 3b and 3c, with one allyl group replaced by the
methyl or tosyl group respectively, delivered complex reaction
mixtures. However, when substrate 3d, carrying an N-benzyl
group instead, was subjected to the identical reaction con-
ditions, 1-allyl-2-phenyl-3-formyl indole 4d was, interestingly,
isolated in 47% yield. The divergence in reaction behaviours of
3a–3d was really intriguing giving the subtle structural discre-
pancies among these molecules. Even though the exact reason
for the substituent sensitive selectivity is not clear at the
present stage, it can be deduced that the azavinyl carbenoid 5a
derived from 3a reacted with one pendent allyl double bond to
give cyclopropane 6a (Scheme 2a); while in intermediate 5d,
the allyl group was out-competed by the neighbouring benzylic
C
sp3–H for the rhodium carbene,10 the resulting indoline inter-
School of Pharmaceutical Engineering and Life Science, Changzhou University,
Changzhou, Jiangsu Province 213164, China. E-mail: meihuashen@gmail.com,
mediate underwent in situ dehydrogenative aromatization to
give 6d (Scheme 2c). On the other hand, reactive carbenoids
5b and 5c may undergo multiple pathways leading to various
products each in small quantities (Scheme 2b).
huadongxu@gmail.com
†Electronic supplementary information (ESI) available: The details of experi-
ments, compound characterization and spectroscopic data. See DOI: 10.1039/
c5ob00085h
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We were interested in the C–H insertion pathway as it could
serve as a complementary method for our prior de novo
3-formyl indole synthesis (Scheme 1a). A range of N-benzyl-ani-
linyl sulfonyl triazoles have been prepared and subjected to
the rhodium catalyzed reactions. The data are shown in
Table 1. For the N,N-bisbenzyl series (3e–3i), the electronic
impact on the reaction is prominent, as evidenced by the 74%
and 72% yields of 4g and 4f bearing methoxyl and methyl
groups at the 6-position respectively, and the decreased yields
of chlorinated 4h (54%) and fluorinated 4i (52%). The trend
that the electron donating group facilitates the indole for-
mation also holds for the substituent effect on the N-benzyl
moiety. In N-benzyl-N-methyl series (3j–3o), the yield increased
from 25% for 4-CO2Me-benzyl anilinyl triazole 3o to 55% for
Scheme 2 The divergent outcomes affected by subtle N-substituent
variations.
Table 1 Preparation of 3-formyl indoles from sulfonyl triazolesa
Substrate
Product, yieldb
Substrate
Product, yieldb
a Reaction conditions: step (1) 3 (0.4 mmol), Rh2(OAc)4 (2.0 mol %), tol (4 mL), 85 °C, under N2 for 2 h, then volatiles removed under vacuum;
step (2) K2CO3 (1.6 mmol), MeOH (4 mL), rt, in air overnight. b Isolated yield.
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The authors wish to thank the Natural Science Foundation
of China (21402014 and 21272077), the Natural Science Foun-
dation of Jiangsu Province (BK20131143), the Priority Aca-
demic Program Development of Jiangsu Higher Education
Institutions (PADA), and Jiangsu Key Laboratory of Advanced
Catalytic Materials and Technology (BM2012110).
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