Enantioselective Friedel-Crafts reaction of electron-rich alkenes catalyzed by chiral Bronsted acid

Article abstract of DOI:10.1021/ja0678166

We present the first enantioselective catalysis of the Friedel-Crafts reaction via activation of electron-rich multiple bonds by a chiral Bronsted acid. The reaction of various indole derivatives with a broad range of substituted enecarbamates affords the

Full text of DOI:10.1021/ja0678166

Published on Web 12/20/2006
Enantioselective Friedel-Crafts Reaction of Electron-Rich Alkenes Catalyzed
by Chiral Brønsted Acid
Masahiro Terada* and Keiichi Sorimachi
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received November 1, 2006; E-mail: mterada@mail.tains.tohoku.ac.jp
Table 1. Solvent Effect on the Enantioselective Friedel-Crafts
Reaction of 2a with 3a Catalyzed by 1 (eq 1)a
The Friedel-Crafts (F-C) reaction is one of the most powerful
methods for the formation of a new carbon-carbon bond and has
been widely utilized from benchtop experiments to industrial
processes.1 Enantioselective variants of this fundamental transfor-
mation have also been investigated using metal-based chiral
complex catalysts2 or chiral organocatalysts.3 These enantioselective
catalyses have been accomplished via activation of electron deficient
multiple bonds, such as CdO, CdNR, and CdC-X (X: electron-
withdrawing group), etc. Acid-catalyzed F-C reactions of arenes
with electron-rich alkenes are practical and atom-economical
methods for providing alkylated arenes and have been applied to
numerous industrial processes. However, to the best of our
knowledge, there have been no previous reports on enantioselective
catalysis of the F-C reaction initiated by an activation of electron-
rich multiple bonds. Herein we describe the first highly enantiose-
lective F-C reaction of electron-rich alkenes activated by a chiral
Brønsted acid catalyst.4-6 Thus, a BINOL-derived monophosphoric
acid (1)5,6 exhibited excellent performance for this activation mode,
in which the catalytic reaction of indoles (2) with enecarbamates
(3) as the electron-rich alkenes yielded the desired F-C products
(4) in high enantioselectivities as exemplified in eq 1.7 The method
provides easy and practical access to enantioenriched 1-indolyl-1-
alkylamine derivatives of pharmaceutical and biological importance.
entry
solvent
time
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
toluene
PhCF3
CH2Cl2
(CH2Cl)2
DMF
DMSO
CH3NO2
CH3CN
CH3CN
CH3CN
3 h
3 h
3 h
3 h
24 h
24 h
3 h
3 h
6 h
26
91
84
83
17
22
93
84
85
95
80
79
84
83
54
10
87
88
91
93
9c
10d
12 h
a Unless otherwise noted, all reactions were carried out with 0.002 mmol
of (R)-1 (2 mol %), 0.11 mmol of 2a, and 0.10 mmol of 3a in 0.5 mL of
the indicated solvent at room temperature. b Enantiomeric excess was
determined by chiral HPLC analysis. See Supporting Information for details.
c Reaction run at 0 °C. d Reaction run at -20 °C.
and DMSO (entries 5, 6). Among the solvents tested, the highly
polar but protophobic acetonitrile9 was found to be the best with
respect to the catalytic activity and the asymmetric induction (entry
8). As expected, enantiomeric excess increased with a decrease in
reaction temperature, reaching 93% ee at -20 °C (entries 9, 10).
In order to demonstrate the scope and potential of the present
enantioselective F-C reaction, we next examined a series of indole
derivatives (2) and substituted enecarbamates (3) (eq 2).
The proposed enantioselective F-C reaction was first examined
using indole (2a), N-Boc protected enamine (3a), and 2 mol % of
(R)-1 at room temperature in various organic solvents. As shown
in Table 1, it is noteworthy that not only the catalytic activity but also
the asymmetric induction were highly dependent on the solvents
employed. The less polar aromatic solvent, toluene, was useful for
a chiral monophosphoric acid-catalyzed F-C reaction via the acti-
vation of electron deficient double bond, CdNR,5b but in this acti-
vation mode 1 suffered from a marked retardation in the catalytic
activity (entry 1). Whereas, in the more polar aromatic solvent PhCF3,
1 exhibited high catalytic efficiency affording the F-C product
(4aa) in high chemical yield without notable loss of enantiomeric
excess (entry 2). Halogenated solvents possessing a similar polarity8
to PhCF3 were also tolerated by the reaction (entries 3, 4). However,
either the chemical yields or the enantioselectivities were seriously
diminished in highly polar and protophilic solvents9 such as DMF
Representative results are summarized in Table 2. The acid
catalyst 1 displayed excellent performance for the reaction of
various indole derivatives (2) with a broad range of substituted
enecarbamates (3). Uniformly high enantioselectivities and chemical
yields were obtained in the reaction of indole (2a) with 3 bearing
a linear or a branched alkyl group as well as an aromatic substituent
(entries 1-5). In addition, the sterically hindered disubstituted
enecarbamate (3g) was also applicable for the present enantiose-
lective F-C reaction (entry 6). Moreover, the enantioselectivities
were maintained at an equally high level for a wide variety of indole
derivatives (2), irrespective of their electronic properties (entries
7-11). It is noteworthy that the present catalytic system allows
for the reaction of indoles (2d-f) substituted by electron-withdraw-
ing groups affording the F-C product in high yield (entries 9-11).
As shown in eq 3, the geometric isomers (E)-3b and (Z)-3b gave
the product (4ab) with the same level of enantioselectivitiy.
9
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10.1021/ja0678166 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Freidel-Crafts Reaction of Indole
Derivatives (2) with Substituted Enecarbamates (3) Catalyzed by
(R)-1a
Acknowledgment. This work was supported by JSPS for a Grant-
in-Aid for Scientific Research (B) (Grant No. 17350042). We also
acknowledge The JSPS Research Fellowship for Young Scientists
(K.S.) from the Japan Society for the Promotion of Sciences.
Supporting Information Available: Representative experimental
procedure, spectroscopic data for enecarbamates (3) and Friedel-Crafts
products (4), and determination of absolute stereochemistry of 4ag.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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a Unless otherwise noted, all reactions were carried out with 0.005 mmol
of (R)-1 (5 mol %), 0.11 mmol of 2, and 0.10 mmol of 3 in 0.5 mL of
CH3CN at 0 °C for 36 h. b Isolated yield. c Enantiomeric excess was
determined by chiral HPLC analysis. d Reaction run at room temperature
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mol %), 0.10 mmol of 2a, and 0.15 mmol of 3. f Reaction run at 50 °C for
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determined to be S for 4ag. See Supporting Information for details.
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These results suggest that both reactions proceeded through the
common intermediate (A), composed of 1 and an imine, as it was
generated by the protonation of enecarbamates 3b. Hence the
present activation mode is regarded as an efficient alternative to
generating aliphatic imines,10 which are generally labile and difficult
to isolate.11 Furthermore, the reaction rate was dependent on the
geometry of the enecarbamate employed; (Z)-3b showed higher
reactivity than (E)-3b. It can be considered that the protonation of
3 by 1 via ionic transition states would be the rate-determining
step. This mechanistic assumption is strongly supported by the
solvent effect, in which a high catalytic efficiency was observed
in a highly polar but protophobic solvent.
(7) Presented at the 86th Annual Meeting of the Chemical Society of Japan,
March 27-30, 2006; Abstract No. 2H5-17.
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(10) During the preparation of this manuscript, Kobayashi, et al. reported the
metal salt-catalyzed Mannich reaction of 1,3-dicarbonyl compounds with
enecarbamates as an aliphatic imine surrogate, see: Kobayashi, S.;
Gustafsson, T.; Shimizu, Y.; Kiyohara, H.; Matsubara, R. Org. Lett. 2006,
8, 4923-4925.
(11) Imine (5) was completely isomerized to enecarbamate (3b) during
distillation, and hence it can be considered that enecarbametes (3) serve
as stable and useful precursors of aliphatic imines in the present activation
mode.
In conclusion, we have demonstrated the first enantioselective
Friedel-Crafts reaction catalyzed by a chiral monophosphoric acid
via activation of electron-rich alkenes. Further application of the
present method, a practical protocol for in situ generation of
aliphatic imines, is in progress with the aim of developing efficient
asymmetric organic transformations.
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