Rhodium enalcarbenoids: Direct synthesis of indoles by rhodium(II)- catalyzed [4+2] benzannulation of pyrroles

Article abstract of DOI:10.1002/anie.201400161

Disclosed herein is the design of an unprecedented electrophilic rhodium enalcarbenoid which results from rhodium(II)-catalyzed decomposition of a new class of enaldiazo compounds. The synthetic utility of these enalcarbenoids has been successfully demonstrated in the first transition-metal-catalyzed [4+2] benzannulation of pyrroles, thus leading to substituted indoles. The new benzannulation has been applied to the efficient synthesis of the natural product leiocarpone as well as a potent adipocyte fatty-acid binding protein inhibitor. Fat cat: A new class of enaldiazo compounds resulted in the first transition-metal-catalyzed [4+2] benzannulation of pyrroles to deliver indoles. The benzannulation is proposed to involve an unprecedented diacceptor rhodium enalcarbenoid. The reaction was used in the highly efficient synthesis of the natural product leiocarpone and a potent adipocyte fatty-acid binding protein inhibitor.

Full text of DOI:10.1002/anie.201400161

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Angewandte
Communications
DOI: 10.1002/anie.201400161
Heterocycle Synthesis
Rhodium Enalcarbenoids: Direct Synthesis of Indoles by
Rhodium(II)-Catalyzed [4+2] Benzannulation of
Pyrroles**
Sudam Ganpat Dawande, Vinaykumar Kanchupalli, Jagadeesh Kalepu,
Haribabu Chennamsetti, Bapurao Sudam Lad, and Sreenivas Katukojvala*
Dedicated to Professor Sukh Dev on the occasion of his 90th birthday
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Abstract: Disclosed herein is the design of an unprecedented
electrophilic rhodium enalcarbenoid which results from rho-
dium(II)-catalyzed decomposition of a new class of enaldiazo
compounds. The synthetic utility of these enalcarbenoids has
been successfully demonstrated in the first transition-metal-
catalyzed [4+2] benzannulation of pyrroles, thus leading to
substituted indoles. The new benzannulation has been applied
to the efficient synthesis of the natural product leiocarpone as
well as a potent adipocyte fatty-acid binding protein inhibitor.
I
ndoles are a very important structural motifs which are
present in diverse natural products, pharmaceuticals, fine-
chemicals, and materials.[1,2] Hence, development of new
methodologies for functionalized indoles continues to be an
active research area.[3] The classical methods include Fischer,
Bartoli, and Larock syntheses.[4] The majority of the recent
methodologies involve transition-metal-catalyzed annula-
tions onto an appropriately functionalized benzene ring.[5]
In contrast, transition-metal-catalyzed annulations onto pyr-
role rings are scarce, not general, or can consist of a multistep
synthesis.[6] Hence, development of efficient catalytic meth-
odologies for the direct benzannulation of pyrroles would be
highly valuable.
Scheme 1. Benzannulation of carbene complexes. EWG=electron-with-
drawing group.
Benzannulation is a fundamentally significant reaction for
the formation of substituted benzenes. For the past few
decades, several elegant benzannulation strategies, including
transition-metal-mediated reactions, have been developed for
functionalized benzene and fused benzene derivatives.[7,8]
Among these strategies, the Dçtz [3+2+1] benzannulation
of alkenyl Fischer carbene complexes (1) with alkynes is
a highly versatile method for the functionalized 4-alkoxy
phenol derivatives 2 and 3 (Scheme 1a).[9,10] In contrast, the
complementary Wulff and Merlic [5+1] orthobenzannulation
of the dienyl Fischer carbene complexes 4 and 5 delivers
valuable o-alkoxy phenol derivatives (6; Scheme 1b).[11,12]
Despite their great synthetic utility, these benzannulations
are not catalytic, involve stoichiometric chromium carbene
complexes, and require carbon monoxide as one-carbon
reactant from either a metal template or as a reagent. Thus,
development of catalytic versions of these benzannulations, in
which the use of stoichiometric carbene complexes and
carbon monoxide are avoided, would be highly useful. In
this context we have designed a conceptually new class of
enaldiazo compounds (7) consisting of a four-carbon unit
embedded within an alkenyl and carbonyl moiety (Sche-
me 1c). We envisioned that the electrophilic diacceptor[13]
enalcarbenoid 8, generated by transition-metal-catalyzed
decomposition of the diazo compound 7, would serve as
a four-carbon reacting partner for unique catalytic annulation
reactions. Herein, we report the realization of the first
catalytic [4+2] benzannulation of rhodium enalcarbenoids
(8; M = Rh2L4) with the pyrroles 9, thus leading to the direct
synthesis of valuable substituted indoles (10).[14]
As shown in Scheme 2, a variety of enaldiazo ketones
(7a–g) and esters (7h–j) were prepared.[15] Enaldiazo ketones
were obtained in three steps from the aryl enones 11 and
involved diazotransfer, deprotection, and oxidation reactions.
In contrast, the enaldiazo esters 7h–j were prepared by
formylation of the known vinyldiazo esters 12[16] using the
Vilsmeier reagent.
Our studies on the enaldiazo compounds 7 were initiated
by rhodium(II)-catalyzed reactions with pyrroles.[17,18] To our
[*] S. G. Dawande, V. Kanchupalli, J. Kalepu, H. Chennamsetti,
B. S. Lad, Dr. S. Katukojvala
Department of Chemistry
Indian Institute of Science Education & Research
Bhopal, Madhya Pradesh 462066 (India)
E-mail: sk@iiserb.ac.in
Homepage: http://home.iiserbhopal.ac.in/~sk/
[**] We are grateful for the financial support from IISER Bhopal and the
Department of Science and Technology. We thank Dr. S. Konar and
P. Srinivasulu for X-ray crystal structure determination.
Scheme 2. Design and synthesis of new enaldiazo compounds.[15]
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMF=N,N-dimethylforma-
mide, DMSO=dimethylsulfoxide, IBX=2-iodoxybenzoic acid, TBAF=
tetra-n-butylammonium fluoride, THF=tetrahydrofuran.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400161.
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Table 2: Rhodium(II)-catalyzed [4+2] benzannulation of enaldiazo
delight, when a 0.1m solution of 7a (0.1 mmol, 1 equiv) in
dichloromethane (CH2Cl2) was added slowly over a 1 hour
period to a CH2Cl2 solution (1 mL) of pyrrole (0.15 mmol)
and 1 mol% [Rh2(OAc)4] at room temperature, the indole 13
was obtained in 62% yield. The yield was improved to 71%
with 1:1 ratio of pyrrole and diazo substrate. Use of slight
excess of the aldehyde (1.2 equiv) gave an optimum yield of
89%. Interestingly, the benzannulation proceeded with
complete regioselectivity, thus leading to 7-substituted
indole.[15] Encouraged by this exciting result we screened
several rhodium(II) catalysts and solvents for the reaction
(Table 1). All rhodium(II) catalysts tested are effective, but
the best results were obtained with 1 mol% [Rh2(OAc)4] in
CH2Cl2. It is noteworthy that even 0.1 mol% [Rh2(OAc)4]
was sufficient for the efficient benzannulation at larger scale
(entry 11).
ketones with pyrroles.[a]
Table 1: Optimization of benzannulation.[a]
Entry
[Rh2L4]
Mol%
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
[Rh2(OAc)4]
[Rh2(Oct)4]
[Rh2(esp)4]
1
1
1
1
1
1
1
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Toluene
C2H4Cl2
CH2Cl2
CH2Cl2
CH2Cl2
89
68
58
48
61
80
62
64
81
72
87[c]
[Rh2(TFA)4]
[Rh2{(R)-dosp)}4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
[Rh2(OAc)4]
9
10
11
0.1
1.5
0.1
[a] Reaction conditions: 7a/pyrrole=0.12:0.1 mmol; a solution of 7a
(1 mL) was added over 1 h to a solution of pyrrole and rhodium(II)
catalyst (1 mL) at RT, and stirred for an additional 2 h. [b] Yield of
isolated product. [c] Reaction carried out with 1 mmol of pyrrole.
dosp=(N-dodecylbenzenesulfonyl)prolinate, esp=a,a,a’,a’-tetra-
methyl-1,3-benzenedipropionic acid, TFA=trifluoroacetate.
With the optimized reaction conditions, the generality of
the benzannulation was tested with various enaldiazo ketones
(7a–g) and pyrroles (Table 2). Pyrrole gave excellent yields of
the indole products 14–19[19] (87–92%) with the enaldiazo
ketones 7a–g, thus indicating that the electronic and steric
nature of the aryl group in diazo ketones did not have
a noticeable impact on the benzannulation. Both 2- and 3-
alkyl-substituted pyrroles participated efficiently in the
benzannulation, thus leading to the 2-methyl indoles 20–22
in 81–90% yield and 3-benzyl indole 23 in 58% yield.[19] The
electron-deficient 3-acyl pyrroles smoothly gave high yields of
the biologically relevant 3-acylindoles derivatives 24–26 in
81–85% yield.[20,21] Even 2,3-disubstitution on pyrrole facili-
tated the benzannulation, thus resulting in very good yields of
the densely functionalized indoles 27 (83%) and 28 (80%).
When the benzannulation was protected from light, the highly
unstable 3-chloropyrrole gave good yields of the 3-chloroin-
dole derivatives 29 (68%) and 30 (65%), which are suitable
À
[a] 0.24 mmol of 7 in CH2Cl2 was added over 2 h to a solution of N H
pyrrole and [Rh2(OAc)4] (0.2:0.002 mmol), and was then stirred for an
additional 2 h. [b] 0.6 mmol of 7 added over 5 h. Cbz=benzyloxycar-
bonyl.
substrates for cross-coupling reactions. The N-substituted
pyrroles required longer reaction times and an excess amount
of the diazo partner (3 equiv) to give good yields of the
indoles 31–34 (65–71%). This outcome could be attributed to
the steric hindrance at the 2-position of the pyrrole ring. An
interesting example is the preferential benzannulation over
N H insertion of 2-(pyrrol-2-yl)ethanaminecarbamates,
a reaction which gave good yields of the valuable isotrypt-
amine derivatives 35 (72%) and 36 (65%).
À
In contrast to the enaldiazo ketones 7a–g, benzannulation
reaction with the enaldiazo esters 7h–j was sluggish at room
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temperature as they proceeded via an unstable intermedi-
ate.[15] However, the reaction was efficient with excess diazo
substrate (2.5 equiv) at reflux conditions in CH2Cl2, and gave
the indoles 37–42 in 52–70% yield (Table 3). To our delight
the reaction tolerated methyl substitution on the enaldiazo
ester 7i, which gave decent yields of the valuable 6-methyl
indole derivatives 41 (52%) and 42 (56%) when using an
excess of diazo substrate (4 equiv).
Table 3: Rhodium(II)-catalyzed [4+2] benzannulation of enaldiazo
esters with pyrroles.[a]
Scheme 4. Proposed mechanism of [4+2] benzannulation.
48 via 49[24] or 50 delivers the alcohol 51. Subsequent
dehydration of 51 results in the formation of the indole 52.
In summary we have designed a new class of enaldiazo
ketones and esters. The unprecedented rhodium enalcarbe-
noids derived from these diazo compounds have been
employed in the first direct catalytic [4+2] benzannulation
of pyrroles, thus leading to substituted indoles. In contrast to
the Dçtz, Wulff, and Merlic benzannulations, which uses
stoichiometric Fischer carbenes, our new benzannulation
involves catalytically generated rhodium enalcarbenoids.
The synthetic utility of the benzannulation was demonstrated
with the highly efficient one step synthesis of leiocarpone as
well as a short synthesis of a potent and selective adipocyte
fatty-acid binding protein (A-FABP) inhibitor. Studies are
ongoing with regard to the mechanistic aspects of the
benzannulation and its applications. We hope that the new
class of enaldiazo compounds, enalcarbenoids, and the
benzannulation reaction will find wide applications in syn-
thetic chemistry.
[a] 0.5 mmol of 7 in CH2Cl2 was added over 4 h to a refluxing solution of
pyrrole and [Rh2(OAc)4] (0.2:0.002 mmol) in CH2Cl2 and stirred for
additional 2 h. [b] 0.8 mmol of 7 added over 7 h.
The synthetic utility of benzannulation was demonstrated
with a short synthesis of the 7-substituted indole natural
product leiocarpone (43),[22] as well as a potent and selective
adipocyte fatty-acid binding protein (A-FABP) inhibitor (44;
Scheme 3).[23] Thus, direct benzannulation of pyrrole with the
Received: January 7, 2014
Published online: March 3, 2014
Keywords: annulation · carbenes · diazo compounds ·
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heterocycles · rhodium
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