Isoquinoline synthesis via rhodium-catalyzed oxidative cross-coupling/ cyclization of aryl aldimines and alkynes

Article abstract of DOI:10.1021/ja904380q

(Chemical Equation Presented) A general rhodium-catalyzed oxidative coupling reaction between internal alkynes and aryl aldimines is described. This process affords 3,4-disubstituted isoquinolines in good yield and high regioselectivity. Preliminary mechanistic studies suggest that the C-N bond formation arises from the reductive elimination of a rhodium(III) species.

Full text of DOI:10.1021/ja904380q

Published on Web 08/05/2009
Isoquinoline Synthesis via Rhodium-Catalyzed Oxidative Cross-Coupling/
Cyclization of Aryl Aldimines and Alkynes
Nicolas Guimond and Keith Fagnou*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa,
10 Marie Curie, Ottawa, Canada K1N 6N5
Received May 29, 2009; E-mail: keith.fagnou@uottawa.ca
Recognizing the industrial value of nitrogen-containing hetero-
cyclic compounds,1 chemists continue to devise novel methods for
their synthesis.2 The preparative chemistry of isoquinolines is
illustrative, where traditional routes for azine ring fusion typically
involve intramolecular cyclizations of highly functionalized sub-
strates at elevated temperatures under strongly acidic reaction
conditions (Scheme 1).3 More recently, metal-catalyzed approaches4
have begun to address some of these issues, as exemplified by the
Larock isoquinoline synthesis that couples o-iodoaldimines and
alkynes in the presence of a palladium catalyst.5 Our interest in
the minimization of substrate preactivation in metal-catalyzed
processes led us to question whether a similar reaction mode in
which the aryl C-I functional group of the o-iodobenzimine is
replaced by a simple C-H bond might be possible.
conditions [83 °C, refluxing 1,2-dichloroethane (DCE)] with high
regioselectivity. We also present preliminary mechanistic studies
that point to the involvement of the rhodium catalyst in each of
the C-H bond-breaking and C-C/C-N bond-forming steps and
show that while a copper(II) terminal oxidant is employed, its use
is not a prerequisite for the C-N reductive elimination with these
substrates.10 In view of the importance of the isoquinoline motif,
particularly in medicinal chemistry, these results should find wide
use in the preparation of these compounds.
We found that treatment of a variety of N-tert-butylbenzaldi-
mines12 2 with an internal alkyne 3, 2.5 mol % 1, and 2.1 equiv of
Cu(OAc)2 ·H2O13 in refluxing DCE provides the corresponding
isoquinoline products 4 in good yield (Table 1). A variety of
substituents may be employed on the aldimine coupling partner,
including electron-donating and -withdrawing groups. An aryl
bromide substituent remains intact during the reaction (4e), provid-
ing a useful handle for further elaboration, and a phenolic OH group
does not need protection, as illustrated by the formation of 4g.
Scheme 1. Retrosynthetic Disconnections of the Isoquinoline Core
Table 1. Reaction Scopea b
,
A number of challenges are inherent in this approach. Colby,
Bergman, and Ellman6 have described a Rh(I)-catalyzed C-H
enimine vinylation that can be followed by electrocyclization/
oxidation steps to generate functionalized pyridines. However,
application of a similar approach in quinoline synthesis by Jun and
co-workers7 necessitated the use of highly elevated temperatures
(150 °C) because of the loss of aromaticity during the electrocy-
clization and resulted in product mixtures and diminished yields.
To avoid this unfavorable second step, we envisioned a catalytic
process where the metal catalyst would be involved in both the
C-C and C-N bond-forming steps.8,9 As a precedent, Jones and
co-workers10,11 recently reported that isoquinolinium salts can be
generated under mild conditions in three steps: (1) stoichiometric
Rh(III)-induced C-H bond cleavage of 2-phenylpyridine, benzo-
[h]quinoline, or N-benzilidenemethylamine; (2) alkyne carbometa-
lation; and (3) Cu(II)-induced C-N reductive elimination. In the
last step, the Cu(II) was proposed to engage in single-electron
transfer to form a Rh(IV) intermediate more pre-disposed to
reductive elimination.10
a Conditions: benzaldimine (1 equiv), alkyne (1.2 equiv), 1 (2.5 mol
%), and Cu(OAc)2 ·H2O (2.1 equiv) in DCE at 83 °C (reflux), 16 h.
b Isolated yields are reported. c Isolated as a 11:1 mixture of regio-
isomers.
Herein we describe the realization of this goal by showing that
[Cp*Rh(MeCN)3][SbF6]2 (1) catalyzes the formation of isoquinoline
compounds from readily available and minimally functionalized
starting materials. These reactions occur under mild reaction
When unsymmetrical alkynes are employed,14 the larger sub-
stituent is regioselectively placed at the benzylic position away from
9
12050 J. AM. CHEM. SOC. 2009, 131, 12050–12051
10.1021/ja904380q CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Proposed Mechanism
the nitrogen atom. For example, isoquinolines 4h-j are all formed
as the exclusive regioisomers. In the case of 4k, the two isomers
are produced in an 11:1 ratio.
Scheme 2. Potential Reaction Pathways
but also serve as a useful point of departure for the development
of other novel rhodium(III)-catalyzed transformations in heterocycle
synthesis.
Acknowledgment. We thank NSERC, the University of Ottawa,
Eli Lilly, Amgen, Astra Zeneca, and the Sloan Foundation
(fellowship to K.F.). N.G. thanks NSERC for a graduate student
scholarship.
In addition to the electrocyclization/oxidation6 and the Rh(IV)10
pathways described earlier and illustrated in Scheme 2, C-N
reductive elimination may also potentially occur directly from the
Rh(III) intermediate 5 (Scheme 3). To probe the nature of the reac-
tion mechanism, the reaction of 2a was performed in the presence
of 20 mol % 1 in the absence of added Cu(OAc)2 ·H2O. In this
case, 4a was obtained in 18% yield. Similarly, when the reaction
was performed with 2.5 mol % 1 without added Cu(OAc)2 ·H2O,
4a was generated in 2.2% GC-MS yield after 16 h. After this time,
addition of 2.1 equiv of Cu(OAc)2 ·H2O induced catalyst turnover,
resulting in a 79% GC-MS yield after 24 h. These results indicate
that Cu(II) is not essential for C-N bond formation (Scheme 2,
pathway A). Moreover, when aldimine 9 bearing an alkene
substituent was subjected to the standard reaction conditions, no
reaction was observed (eq 1).
Supporting Information Available: Detailed experimental proce-
dures and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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In a similar fashion, when 9 was reacted in the presence of alkyne
3c, the only product detected in the crude reaction mixture was 10
(eq 2). The absence of cyclization with the preinstalled olefinic
moiety in either the absence or the presence of added alkyne
strongly indicates that an electrocyclization/oxidation pathway does
not account for product formation (Scheme 2, pathway B). In light
of these studies, we currently favor the reaction pathway outlined
in Scheme 3, in which the rhodium catalyst is implicated in each
of the bond-breaking/bond-forming steps and C-N reductive
elimination may occur directly from Rh(III).
The ability of rhodium(III) to catalytically induce C-H bond
cleavage, C-C bond formation, and, importantly, C(sp2)-N(sp2)
bond reductive elimination under relatively mild reaction conditions
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