Enantioselective friedel-crafts alkylations with benzoylhydrazones promoted by a simple strained silacycle reagent

Article abstract of DOI:10.1021/ja042522a

The enantioselective Friedel-Crafts reaction of electron-rich arenes and heteroarenes with the benzoylhydrazone of isopropyl glyoxylate mediated by a simple chiral silane Lewis acid is described. The reactions are highly practical, as demonstrated by a la

Full text of DOI:10.1021/ja042522a

Published on Web 02/11/2005
Enantioselective Friedel-Crafts Alkylations with Benzoylhydrazones
Promoted by a Simple Strained Silacycle Reagent
Seiji Shirakawa, Richard Berger, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received December 13, 2004; E-mail: leighton@chem.columbia.edu
Scheme 2
Chemists have for decades been captivated by the notion that
chiral ligand/substituent-modified silanes might be used as Lewis
acids for asymmetric synthesis, due both to the significant practical
advantages that the use of silicon might offer and to the intellectual
challenge of rendering silicon Lewis acidic enough to mediate/
catalyze carbon-carbon bond forming reactions.1 To date, signifi-
cant success has been achieved by Denmark, who has developed
an elegant chiral Lewis base-modified silicon Lewis acid system
the arene (Table 1). Although it was found that a strongly activating
for enantioselective allylation,2 aldol,3 and Passerini4 reactions. Our
strategy for inducing Lewis acidity in silanes focuses on the use of
ring-strain,5,6 and we have documented that simply constraining
allyl- and crotylsilanes in a five-membered ring leads to enantio-
selective type I7 allylation reagents for both aldehydes and
acylhydrazones (Scheme 1).8 Seeking to harness this phenomenon
for the development of an effective and general chiral silane Lewis
acid, we wondered whether simple chiral silacycles could effectively
mediate carbon-carbon bond forming reactions. The enantiose-
lective Friedel-Crafts alkylation of arenes with imine derivatives9,10
is particularly attractive in this regard both because the nucleophiles
require no preactivation and because the products are chiral benzylic
amines, a substructure found in natural products and in many
medicinal chemistry programs. Herein, we report the development
of a simple chiral silane that mediates the enantioselective Friedel-
Crafts reaction of electron-rich arenes and heteroarenes with the
benzoylhydrazone of isopropyl glyoxylate, leading to a practical
synthesis of arylglycines.
amino group is required for the reaction to occur at a reasonable
rate, substitution on the arene ring was otherwise tolerated, notably,
at the position ortho to the site of alkylation.
Table 1. Enantioselective Friedel-Crafts Alkylations with Arenes
Scheme 1
Our studies began with the benzoylhydrazone of ethyl glyoxylate
and N,N-dimethylaniline (Scheme 2). The allyl group of the silane
was simply replaced with a presumably inert phenyl group, leading
to silanes 1, easily prepared (as a ∼2:1 mixture of diastereomers)
in a single step from pseudoephedrine and phenyltrichlorosilane.
An initial experiment in CH2Cl2 was highly encouraging, giving
the product in 80% yield and 71% ee. The use of toluene as solvent
led to a significantly more enantioselective (85% ee), albeit less
efficient, reaction. By switching to the isopropyl ester and lowering
the reaction temperature to -20 °C, we obtained the product in
95% ee. The tert-butyl glyoxylate-derived hydrazone was examined
as well, but led only to a very sluggish and inefficient reaction.
Having established the feasibility of and optimal conditions for
the reaction, we carried out a survey of the scope with respect to
a Determined by chiral HPLC. b Temperature ) -30 °C.
The reaction was investigated with heteroaromatic substrates as
well (Table 2). As shown, derivatives of several heterocyclic
systems (indole, pyrrole, and thiophene) gave results similar to those
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10.1021/ja042522a CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
of the aniline derivatives described in Table 1. Entry 1 is noteworthy
in demonstrating that an unprotected indole NH group is compatible
with the reaction. We note as well that indole itself provides the
corresponding product with significantly reduced enantioselectivity
(24% ee). At present, this surprisingly large drop in selectivity is
not well-understood, although the hypothesis that led us to employ
the 5-nitroindole is that a racemization pathway is kinetically
accessible with very reactive arenes and can be avoided by
attenuation of the reactivity of the arene.
reaction may be advanced. Thus, the pseudoephedrine determines
the placement of the phenyl group on the trigonal bipyramidal
silane, and in turn, this phenyl group blocks access to the back
(re) face of the silane-activated hydrazone. The arene preferentially
approaches from the exposed front (si) face, consistent with the
observed major enantiomer.
Scheme 4
Table 2. Enantioselective Friedel-Crafts Alkylations with
Heteroarenes
We have described a method for the synthesis of an array of
aryl- and heteroarylglycines mediated by an extraordinarily simple
chiral silane Lewis acid. Silanes 1 can be prepared in bulk in a
single step from (S,S or R,R) pseudoephedrine and PhSiCl3. The
former is trivially recoverable in near quantitative yield, and the
latter is available at a nominal cost.13 The process may thus lay a
formidable claim to a high degree of practicality despite the
requirement for a full equivalent of silanes 1. Current efforts are
focused on expanding the scope of this Friedel-Crafts reaction as
well as on the development of new reactions.
a Determined by chiral HPLC. b This reaction was run at -30 °C
Acknowledgment. S.S. is a recipient of a Japan Society for
the Promotion of Science Research Fellowship for Young Scientists.
We thank Merck Research Laboratories for fellowship support of
R.B. Generous support from Amgen and the Yamanouchi U.S.A.
Foundation is also gratefully acknowledged.
for 48 h.
To establish that the reaction is easily practicable on a larger
scale, the reaction of 3-methoxy-N,N-dimethylaniline was carried
out using 5 g of the hydrazone (Scheme 3). Employing only 1.2
equiv of both the arene and silanes 1, we obtained the product in
82% yield and 90% ee. In addition, it proved trivial to recover
pure pseudoephedrine in 99% yield by simple extraction during
the workup. Boc protection and hydrazide reduction11 were then
demonstrated to provide the protected amino acid in 83% overall
yield. Importantly, this two-step sequence was completely unac-
companied by racemization of these sensitive compounds.
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 3
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In a previous study, it was demonstrated that the reaction of
silanes 1 with the benzaldehyde-derived benzoylhydrazone leads
to structure 2 (Scheme 4).8d Notable features of this structure include
(1) the coalescence of both diastereomers of 1 into a single structure,
(2) the protonation of the pseudoephedrine amino group, presumably
leading to a significant increase in silane Lewis acidity,12 and (3)
the isomerization of the CdN bond from trans (in the hydrazone)
to cis (in the complex). Assuming the corresponding structure 3
obtains with the glyoxylate-derived hydrazone, a simple and
plausible model for the enantioselectivity of the Friedel-Crafts
JA042522A
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