COMMUNICATION
Asymmetric Friedel–Crafts reaction of N-heterocycles and nitroalkenes
catalyzed by imidazoline–aminophenol–Cu complexw
Naota Yokoyama and Takayoshi Arai*
Received (in Cambridge, UK) 2nd March 2009, Accepted 2nd April 2009
First published as an Advance Article on the web 24th April 2009
DOI: 10.1039/b904275j
Catalytic asymmetric Friedel–Crafts reaction of pyrrole with
nitroalkenes was smoothly catalyzed by newly synthesized
nitro-substituted imidazoline–aminophenol (1b)–Cu complex to
give the adduct with up to 92% ee.
One isolable by-product in entry 1 was a dialkylated adduct of
pyrrole, which was formed by dual Friedel–Crafts reaction at
both the 2- and 5-positions of pyrrole. An increase in the ratio
of pyrrole to nitrostyrene improved the chemical yield of 4a
without affecting the enantioselectivity (Table 1, entry 2). We
were impressed to note that, without use of HFIP, 4a was
obtained in 80% yield with a greatly improved selectivity of
80% ee (Table 1, entries 3 and 4). Other solvent systems
(xylene, CHCl3, AcOEt, THF) were not as effective as toluene
(Table 1, entries 5–8).
As symbolized by the potent alkaloid strychnine, various
highly functionalized N-heterocycles (e.g., indoles and/or
pyrroles) have been isolated from natural sources.1 Because
the structural complexity of these molecules is obviously
linked to their significant biological activity, the development
of an efficient method for the synthesis of N-heterocyclic
derivatives in an optically active form is currently in high
demand in organic chemistry. Moreover, a new class of
artificial N-heterocyclic derivatives having an array of
stereogenic centers would offer fascinating scaffolds for the
design and exploration of novel biologically active compounds
directed towards pharmaceutical research.
The catalytic asymmetric Friedel–Crafts reaction2 is one of
the most direct methods for introducing a new stereogenic
center on an N-heteroaromatic compound. In the last
few years, asymmetric Friedel–Crafts reaction employing a
nitroalkene as the electrophilic partner has attracted consider-
able attention because the installation of a nitro group allows
subsequent versatile transformations, and extensive progress
has been achieved in this direction. After pioneering work
which led to the SalenAlCl catalyst,3 successful catalytic
systems have since been reported for Friedel–Crafts reac-
tion of indole and nitroalkene by using bis-sulfonamides,4
thioureas,5 phosphoric acids,6 zinc,7 and copper catalysts.8
We have also succeeded in the development of an imidazoline–
aminophenol (1a)–Cu complex for the catalytic asymmetric
Friedel–Crafts reaction of indole (Scheme 1).9
In the 1a–Cu catalysis, a reduction in the temperature
lowered the chemical yield (Table 1, entries 9, 10). Because
the Lewis acidity of the 1a–CuOTf catalyst was not considered
to be high enough to effectively promote the Friedel–Crafts
reaction of pyrrole and nitroalkenes, we decided to modify the
structure of 1a. If the phenoxy functionality of the ligand
binds to the Cu atom, the substituent para to the phenoxy
group would significantly affect the Lewis acidity of the
resulting Cu complex. Based on this reasoning, we planned
to exchange the para-bromo functionality with an NO2 group.
DFT calculations based on the 1a–CuOTf model suggested
that the charge on the Cu-center would increase from +0.288
to +0.307 with a change in the ligand from 1a to 1b (see ESIw).
The synthesis of ligand 1b was readily accomplished using
a method similar to that used in the preparation of 1a
(see details in ESIw).
The newly developed nitro-functionalized ligand 1b–CuOTf
catalyst successfully catalyzed the Friedel–Crafts reaction of 2
and 3a at 0 1C, and 4a was obtained in 73% yield with 90% ee
after 27 h (other data shown in parentheses for comparison).
The scope and generality of the 1b–CuOTf catalyzed Friedel–
Crafts reaction of pyrrole (2) and nitroalkene (3) are shown in
Table 2.
Herein, we report on the application of an imidazoline–
aminophenol–Cu catalyst to the Friedel–Crafts reaction
of pyrrole, for which only a limited number of successful
examples have been reported.10
For aromatic nitroalkenes, attachment of an electron with-
drawing group at the 4-position on the phenyl ring gave the
adducts in good yields with high enantiomeric excesses
(Table 2, entries 2–6). The 4- and 3-substituted nitrostyrenes
The study began with an examination of the original
catalytic conditions required for the Friedel–Crafts reaction
of indole and nitroalkenes. When using the 1a–Cu catalyst in
combination with 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP),
conversion to the Friedel–Crafts adduct 4a occurred in low
yield with moderate enantiomeric excess (Table 1, entry 1).
Department of Chemistry, Graduate School of Science, Chiba
University, Inage, Chiba 263-8522, Japan.
E-mail: tarai@faculty.chiba-u.jp; Fax: +81-43-290-2889;
Tel: +81-43-290-2889
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization of new compounds, spectra and chiral
HPLC conditions. See DOI: 10.1039/b904275j
Scheme
1 Asymmetric Friedel–Crafts reaction of indole and
nitroalkenes catalyzed by imidazoline–aminophenol (1a)–CuOTf
complex.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3285–3287 | 3285
Yokoyama, Naota
