A route to annulated indoles via a palladium-catalyzed tandem alkylation/direct arylation reaction

Article abstract of DOI:10.1021/ja054472v

A norbornene-mediated palladium-catalyzed tandem alkylation/C-H functionalization sequence is described, in which an alkyl-aryl bond and a heteroaryl-aryl bond are formed in one pot. A variety of highly substituted six- and seven-membered ring annulated i

Full text of DOI:10.1021/ja054472v

Published on Web 09/01/2005
A Route to Annulated Indoles via a Palladium-Catalyzed Tandem Alkylation/
Direct Arylation Reaction
Cyril Bressy, Dino Alberico, and Mark Lautens*
DaVenport Laboratories, Chemistry Department, UniVersity of Toronto, Toronto, Ontario, Canada M5S 3H6
Received July 6, 2005; E-mail: mlautens@chem.utoronto.ca
Table 1. Synthesis of Annulated Indoles via Palladium-Catalyzed
Traditionally, catalytic methods for biaryl formation involve
transition metal-catalyzed coupling between an organometallic
component with an aryl halide or pseudohalide.1 More recently,
considerable attention has been given to the direct arylation of
heteroarenes, achieved via cross-coupling of heteroaromatic sp2
C-H bonds and aryl halides.2 A direct arylation approach allows
for carbon-carbon bond formation without the need for prior
functionalization of the heteroarene via metalation. One important
application of direct arylation is the functionalization of indoles
since many biologically active natural products as well as phar-
maceutically important compounds contain this privileged motif.3
Although such an approach is highly desirable, few examples have
been reported for the direct arylation of indoles with aryl halides.4
We have reported a palladium-catalyzed reaction based on
modified Catellani conditions5 for the synthesis of carbocycles and
heterocycles from aryl iodides, alkyl halides, and Heck acceptors.6
This methodology is based on a norbornene-mediated tandem
aromatic alkylation/Heck reaction. Herein, we report a modification
of this sequence by using bromoalkyl indole 1, so that an
intramolecular direct arylation can follow the ortho alkylation. In
this highly efficient approach, two carbon-carbon bonds are created
from two carbon-hydrogen bonds in a one-pot process. In addition,
a wide range of functionalized annulated indoles 3 can be rapidly
synthesized in a convergent manner from relatively simple and
accessible starting materials (Scheme 1).
Tandem Alkylation/Direct Arylation Reactiona
Scheme 1. Synthesis of Annulated Indoles
Our initial attempts to effect a tandem alkylation/direct arylation
employed bromoalkyl indole 4. Use of aryl iodide 5 under the
optimized reaction conditions [iodoarene (1 equiv), Pd(OAc)2 (10
mol %), tri-2-furylphosphine (22 mol %), Cs2CO3 (2 equiv),
norbornene (2 equiv), and bromoalkyl indole (2 equiv) in acetonitrile
(0.1 M) at 90 °C in a sealed tube for 16 h] afforded the seven-
membered ring annulated indole 6 in 80% yield (entry 1, Table 1).
The generality of this reaction sequence was first demonstrated
for the seven-membered ring annulated indole by varying the
substituents on the bromoalkyl indole. Both electron-withdrawing
and electron-donating substituents are tolerated at various positions
on the bromoalkyl indole when reacted with aryl iodide 5. Reaction
of methoxy containing bromoalkyl indole 7 provided 8 in 83% yield
(entry 2). For bromoalkyl indole 9 containing an ester, 10 was
produced in 79% yield (entry 3). Substrate 11, bearing a chloro
substituent, gave a more modest yield of 12 (entry 4). Substituents
on the aryl iodide moiety were readily tolerated (entries 5 and 6).
Reaction of 1-iodo-2-methyl-3-nitrobenzene with 9 resulted in an
86% yield of 14 (entry 5). A N-methyl tosyl substituent at position
4 of the aryl iodide gave a similar yield of 16 (entry 6).
a All reactions were run under the following conditions: iodoarene (0.20
mmol, 1 equiv), Pd(OAc)2 (10 mol %), tri-2-furylphosphine (22 mol %),
Cs2CO3 (2 equiv), norbornene (2 equiv), and bromoalkyl indole (2 equiv)
in acetonitrile (2 mL) were heated in a sealed tube at 90 °C for 16 h.
b Isolated yield.
We next investigated the synthesis of six-membered ring
annulated indoles. A variety of polysubstituted aryl iodides were
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10.1021/ja054472v CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Proposed Mechanism for the Synthesis of Annulated
Indoles
bromoalkyl indole. We are currently exploring the application of
this methodology to the synthesis of other heterocyclic compounds.
Acknowledgment. We gratefully acknowledge the financial
support of the Natural Sciences and Engineering Research Council
(NSERC) of Canada, the Merck Frosst Centre for Therapeutic
Research for an Industrial Research Chair, and the University of
Toronto. C.B. thanks Le Ministe`re des Affaires Etrange`res Franc¸ais
for a Bourse Lavoisier postdoctoral fellowship.
Supporting Information Available: Experimental procedures and
spectroscopic characterization of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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reacted with bromoalkyl indole 17. Ester, nitro, and N-methyl tosyl
substituents gave good to excellent yields (entries 7-9). Having a
N-methyl tosyl substituent as the ortho blocking group afforded
22 in 76% yield (entry 10). However, when this substituent was
placed at position 5 of the aryl iodide, 24 was obtained in only
38% yield (entry 11), presumably due to steric effects.
The ortho alkylation likely proceeds through the mechanism
previously described by Catellani5a and is illustrated in Scheme 2.
Intermediate 27 arises from the reductive elimination of the
proposed Pd(IV) complex 25 to give 26, followed by expulsion of
norbornene. Heteroaryl-aryl coupling of 27 via C-H functional-
ization of the indole C-2 hydrogen follows to provide annulated
indole 6.
Several mechanisms have been suggested for C-H functional-
ization R to the heteroatom in heteroaromatic compounds.4c,7
Possible pathways for the intramolecular C-2 indole arylation
include (1) a Heck-type process4d,e involving a carbopalladation
followed by an atypical anti-â-hydride elimination,8 (2) a direct
C-2 palladation via a nonelectrophilic pathway,9 and (3) an
electrophilic substitution at the C-3 position, followed by a C-3 to
C-2 palladium migration and reductive elimination.4c Direct C-2
palladation via a nonelectrophilic pathway has been reported but
requires a coordinating heteroatom on the N- or C-3 substituent as
a directing group.9 Sames recently reported mechanistic investiga-
tions for the palladium-catalyzed intermolecular C-2 arylation of
indoles and concluded through kinetic studies and a Hammett plot
that the most likely pathway is an electrophilic substitution at the
C-3 position, followed by a C-3 to C-2 palladium migration.4c
Although this may be the most probable mechanism for the
intermolecular C-2 arylation, we cannot exclude a Heck-type
process for the intramolecular reaction.
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In summary, we have developed a new approach to highly
substituted six- and seven-membered ring annulated indoles, where
an alkyl-aryl bond and a heteroaryl-aryl bond are formed in one
pot. This process involves a norbornene-mediated tandem ortho
alkylation/C-H functionalization between an aryl iodide and a
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