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Stereoselective Alkylations
fter more than 125 years, the FriedelCrafts alkylation is still one of
the most studied and most utilized reactions in organic synthesis. What
is the secret of this astonishing success? Perhaps the great versatility in
scope and applicability continues to justify its crucial role in the
synthesis of more and more complex molecules. However, it has taken
more than a century for asymmetric catalytic versions of this reaction
to be developed and subsequently extended to a range of aromatic
compounds and alkylating agents. Herein we review recent developments in the design and use of catalytic and stereoselective strategies
for the alkylation of aromatic systems and synthesis of a wide range of
polyfunctionalized enantiomerically enriched compounds.
1. Introduction
The FriedelCrafts (FC) reaction is one of the oldest
organic transformations to employ Lewis acids as promoters,
and since the pioneering study by Charles Friedel and
James M. Crafts[1] it has been one of the most powerful C C
bond-forming processes in organic synthesis.[2] The original
procedure (for which stoichiometric amounts of a Lewis acid
were required) has subsequently been replaced by milder and
more environmentally friendly conditions.[3] The ever-increasing number of catalytic procedures reported in the literature
over the past decade for the catalytic alkylation and acylation
of aromatic and heteroaromatic compounds is striking
(Figure 1).[4]
In the mid-1980s the first examples of the asymmetric
addition of aromatic C H bonds to carbonyl compounds
appeared in the literature.[5] Since then the synthetic relevance of the formation of benzylic carbon stereocenters
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DOI: 10.1002/anie.200301679
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FriedelCrafts Alkylations
additions of aromatic systems to carbonyl groups (Scheme 1 b), and 1,4-conjugate additions of aromatic systems to
a,b-unsaturated carbonyl compounds (Scheme 1 c).
oxophilicity[9] make them suitable candidates for the promotion of stereoselective alkylations of aromatic compounds by
the ring-opening of enantiomerically pure epoxides.
Our research group reported a highly stereoselective
alkylation of functionalized indoles with enantiomerically
pure aryl epoxides in the presence of anhydrous InBr3
(1 mol %).[10] The reaction, which proceeds exclusively
through a regio- and stereoselective SN2-type pathway at
the benzylic position of the epoxide, allows a number of b-3indolyl alcohols 3 to be isolated in high yields and with
99 % ee (Scheme 3).
As a natural extension of the ring-opening of enantiomerically pure epoxides, we recently developed the first catalytic
asymmetric resolution of racemic internal aromatic oxiranes
through a carboncarbon bond-forming reaction. It was found
that 2-methylindole reacts smoothly and regioselectively with
( )-styrene oxide (1) in the presence of a catalytic amount
(5 mol %) of the commercially available [Cr(salen)Cl] complex 4 a (salen = N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine) to afford both the unreacted styrene oxide
and the indolyl derivative 5 with moderate enantiomeric
excess (55 and 56 % ee, respectively, Scheme 4 a).[11] By careful tuning of the conversion of the kinetically controlled step,
the protocol allowed functionalized internal cis and trans
epoxides to be prepared in enantiomerically pure form (up to
99 % ee) and in moderate yields (Scheme 4 b). Moreover, the
[Cr(salen)Cl] 4 a was also found able to promote the
desymmetrization of meso stilbene oxide in the presence of
variously substituted indoles. The desired b-indolyl alcohols 5
were isolated in excellent chemical yields and optical purities
(up to 98 % yield, up to 98 % ee, Scheme 5).
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the intrinsic instability of many aminomethyl and hydroxymethyl aromatic systems, polysubstitution reactions to give
bisaryl compounds of the type 6 are commonly encountered
both under homogeneous and heterogeneous catalysis
(Scheme 6).[13] After the first catalytic asymmetric addition
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Scheme 8. Enantioselective FriedelCrafts alkylation of indoles catalyzed by the tol-binapCuI complex 10. Ts = p-toluenesulfonyl, tol-binap = bis[2,2-(di-p-tolylphosphanyl)-1,1-naphthyl].
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FriedelCrafts Alkylations
same levels of stereoselectivity (8292 % ee, 7277 % conversion) as observed in the homogeneous process
(86 % ee),[17a] and the heterogeneous catalysts could be
recovered easily by filtration. The reusability of the chiral
catalyst 21MCM-41 was also investigated, and the second
catalytic reaction afforded the same level of enantioselectivity
(84 % ee) and only a slight decrease in conversion (73 %).
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enantioselective catalytic 1,4-addition of electron-rich aromatic compounds to b,g-unsaturated-a-keto esters 22, in the
presence of the chiral box-copper(ii) complex 17, was
described by Jrgensen et al. (Scheme 13).[21] Later, Zhou
and Tang demonstrated the effectiveness of the pseudo-C3-
Scheme 13. Enantioselective conjugate addition of indoles to b,g-unsaturated a-ketoesters in the presence of the cationic tBu-boxcopper(ii)
complex 17.
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Scheme 18. Enantioselective Michael-type addition of indoles to a,bunsaturated aryl ketones catalyzed by an [Al(salen)Cl]/2,6-lutidine complex.
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