Intermolecular coupling of isomerizable alkenes to heterocycles via rhodium-catalyzed C-H bond activation

Article abstract of DOI:10.1021/ja0281129

This reports first intermolecular coupling of unactivated alkenes, including isomerizable alkenes, to a range of heterocycles using a Rh(I) catalyst. A variety of functional groups were incorporated, including esters, nitriles, and acetals. The intermolec

Full text of DOI:10.1021/ja0281129

Published on Web 11/05/2002
Intermolecular Coupling of Isomerizable Alkenes to Heterocycles via
Rhodium-Catalyzed C-H Bond Activation
Kian L. Tan, Robert G. Bergman,* and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California and DiVision of
Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California, 94720
Received August 12, 2002
Table 1. Additive Effectsa
Metal-mediated C-H bond activation reactions have become
important methods for the formation of carbon-carbon bonds.1 The
additive
% 1
% 2
additive
YCl3
Mg(OTf)3
MgI2
MgBr2
MgCl2
MgF2
% 1
% 2
selective functionalization of heterocycles is of particular importance
due to the ubiquity of these structures in natural products as well
as pharmaceutical agents. In the course of developing C-H
activation processes to reach this goal, our group has demonstrated
the intermediacy of an N-heterocyclic carbene2 Rh(I) complex in
the intramolecular coupling of an alkene to a benzimidazole core
(eq 1).3 We recognized from this intermediate that a broad range
of heterocycles could function under this mechanism, thereby
increasing the scope of the C-C bond-forming reaction dramati-
cally. However, the intramolecular system limits heterocycle
generality because it requires a tethered alkene proximal to the site
of C-H activation. Herein, we describe the first intermolecular
coupling of unactivated alkenes, including isomerizable alkenes,
to heterocycles.4 A wide range of heterocycles was employed in
the reaction, and a variety of functional groups can be incorporated,
including esters, nitriles, and acetals. The intermolecular coupling
became possible after it was discovered that weak acids dramatically
increase the rate of both the inter- and intramolecular reactions.
none
NH4Cl
77
66
32
50
70
72
72
76
44
<7
11
49
28
8
19
85
50
12
47
72
58
68
69
14
18
69
27
-
Lut.b Cl-
Lut.b pTSA
Bu4NCl
CuCl2
6
ZnCl2
Al(OTf)3
ScCl3
12
trace
33
LiBr
CaCl2
24
13
a Run at 0.15 M substrate; yields by H NMR. b Lut.)lutidinium.
1
With the increase in reactivity provided by the most effective
additives, intermolecular coupling of benzimidazole and neo-hexene
was explored in more detail. With addition of 5% MgBr2 the desired
linearly coupled product was isolated in 89% yield (eq 3).
However, when other heterocycles were used, incomplete conver-
sion occurred in many cases, presumably due to catalyst decom-
position. Further exploration of the effect of additives on the inter-
molecular coupling revealed that lutidinium chloride consistently
gave the highest yields. Using this additive, heterocycle generality
was expanded to include benzthiazole, benzoxazole, 4,5-dimeth-
ylthiazole, and purine (Table 2, entries 2-5). 1-Methylbenzimida-
zole also participated in the reaction, although higher catalyst load-
ing was required to obtain high conversion (Table 2, entry 6). The
success of the reaction with these substrates is consistent with the
formation of an N-heterocyclic carbene complex as a critical inter-
mediate on the catalytic cycle. No reaction was observed between
neo-hexene and either pyrimidine or indole, which is expected since
these compounds are not known to form N-heterocyclic carbenes.
Isoxazole and 1-phenylpyrazole also did not couple with neo-
hexene, even though they could form carbene complexes. Recently,
Herrmann and co-workers showed that in the formation of Rh(I)
carbene complexes with azolium salts the reaction rate decreased
in the order benzimidazole > triazole > imidazole > pyrazole,
which correlates to the decreasing acidity of the salt.6 We believe
this may also explain the lack of reactivity of 1-phenylpyrazole
and isoxazole. Interestingly, purine was found to undergo multiple
alkylations, unlike the other heterocycles tested.7 Monitoring the
Initial attempts to couple neo-hexene to benzimidazole, using
the optimized conditions previously reported, afforded low yields
of the desired product. In an effort to accelerate the rate of the
reaction, an additive screen was undertaken. The intramolecular
cyclization of compound 1 was used as the model substrate (eq 2).
The reaction was performed at 105 °C (55 °C lower than previously
reported). The initial screen provided the following information
(Table 1):5 (a) weak Brønsted acids have a dramatic impact on the
rate of the reaction; (b) the most effective additives are Lewis acids
such as MgBr2, which produce the highest conversions at 105 °C;
(c) noncoordinating anions for both Lewis and Brønsted acids led
to either low yields or decomposition of the starting material. Since
with both the Lewis and Brønsted acids the counterion had a
profound effect on the reactivity, we believe the reaction requires
a balance between acidity of the additive and Lewis basicity of the
X group. We are currently investigating the mechanism of the
additive effect more closely, to determine the origin of the rate
acceleration.
1
reaction by H NMR spectroscopy established that the reactions
proceed sequentially, with initial alkylation occurring at the 8
position, followed by reaction at the 6 position (Table 2, entry 5).
With these encouraging results, a survey of the alkene generality
was undertaken using benzimidazole as the model heterocycle. One
of the major hurdles in the C-H coupling to alkenes has been the
lack of success with isomerizable alkenes.8 We were delighted to
find that under the optimized conditions, 1-hexene reacts efficiently
with benzimidazole, giving the linearly coupled product 11 in 80%
* Corresponding authors. E-mail: jellman@uclink.berkeley.edu, bergman@
cchem.berkeley.edu.
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J. AM. CHEM. SOC. 2002, 124, 13964-13965
10.1021/ja0281129 CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Heterocycle Generality
acetals, such as acrolein dimethyl acetal and 2-vinyl-1,3-dioxolane,
led to decomposition or poor yields. We believe the steric bulk of
the pinacol hinders isomerization and provides a more robust
protecting group, thereby allowing the coupling to compete with
decomposition. A poor yield was observed when styrene was used
as the coupling partner (Table 3, entry 6).9 Polymerization of stryene
was observed under the conditions which may have accelerated
the catalyst decomposition.10 Since R,â-unsaturated esters reacted
with benzimidazole by hydroamination rather than by the desired
C-H coupling, we tested the Michael acceptors with 4,5-dimeth-
ylthiazole, which is unable to undergo the hydroamination reaction.
Acrylonitrile and tert-butyl acrylate both underwent coupling to
4,5-dimethylthiazole, showing that electron-deficient alkenes are
suitable substrates for the reaction (Table 3, entries 7 and 8). The
use of acrylonitrile gave mostly the linear isomer, but a smaller
amount of branched isomer was also observed (l:b ) 3.8:1).
In summary, the discovery of the profound effects of additives
on this reaction has led to (a) a significant lowering of the reaction
temperature required for the intramolecular cyclization of alkenes
with benzimidazole and (b) the first intermolecular coupling of
unactivated alkenes to heterocycles. The reaction functions with a
variety of heterocycles as well as alkenes. A large breadth of func-
tional groups can be introduced easily and from readily available
starting materials. The potential of this reaction in drug discovery
and process chemistry is evident. We are currently working on
improving the catalyst stability and performance.
a Reactions run with 5 mol % [RhCl(coe)2]2, 7.5 mol % PCy3, 5 mol %
lutidinium Cl-, and 5 equiv of neo-hexene, at 150 °C in THF. b Reaction
run with 10 mol % [RhCl(coe)2]2, 15 mol % PCy3, 5 mol % lutidinium
Cl-, and 5 equiv of neo-hexene at 150 °C in THF.
Table 3. Alkene Generality
Acknowledgment. This work was supported by a fellowship
(to K.L.T.) from Bristol-Myers Squibb, by the NIH Grant
GM5050353 (to J.A.E.), and by the Director, Office of Energy
Research, Office of Basic Energy Sciences, Chemical Sciences
Division, U.S. Department of Energy, under Contract No. DE-
AC03-76SF00098 (to R.G.B). Bristol-Myers Squibb is the founding
member of the UC Berkeley Center for New Directions in Synthesis.
Supporting Information Available: Experimental details, including
analytical data for all compounds described, X-ray diffraction data for
9, and a table of all additives screened (PDF/CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For recent reviews of C-H activation see: (a) Labinger, J. A.; Bercaw,
J. E. Nature 2002, 417, 507. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
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(5) Complete list of additives screened available in Supporting Information.
(6) Kocher, C.; Herrmann, W. A. J. Organomet. Chem. 1997, 532, 261.
(7) Regiochemistry of the bis-alkylated purine was determined by X-ray
crystallography. X-ray diffraction data are available in Supporting
Information.
(8) Kakiuchi, F.; Murai, S, Acc. Chem. Res. 2002, ASAP June 21, 2002.
(9) A small amount of the branched isomer was isolated from the reaction.
GC-MS analysis of the crude mixture showed a 25:1 linear:branched
ratio.
(10) At the reaction completion some styrene remains, indicating that poor
conversion did not simply result from consumption of styrene.
a Reactions run with 5 mol % [RhCl(coe)2]2, 7.5 mol % PCy3, 5 mol %
lutidinium Cl-, and 5 equiv of alkene at 150 °C, in THF. b Reactions run
with 10 mol % [RhCl(coe)2]2, 15 mol % PCy3, 5 mol % lutidinium Cl-,
and 5 equiv of alkene at 150 °C, in THF.
isolated yield (Table 3, entry 2). Attempts at coupling cyclohexene
with benzimidazole were unsuccessful, suggesting that highly
substituted alkenes are poor substrates. A silyl-protected alcohol
was stable under the C-H/alkene coupling conditions (Table 3,
entry 3). Ester 13 was synthesized by coupling a â,γ-unsaturated
ester to benzimidazole, although an increase in the catalyst loading
was necessary to obtain a high yield (Table 3, entry 4). This result
was surprising since the alkene could rearrange to its conjugated
isomer to shut down the reaction. The acetal of acrolein reacted
with benzimidazole to give the functionalized heterocycle 14 (Table
3, entry 5). The pinacol protecting group was used because other
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