Angewandte
Chemie
DOI: 10.1002/anie.200802889
Organocatalysis
Electrophilic Reactivities of a,b-Unsaturated Iminium Ions**
Sami Lakhdar, Takahiro Tokuyasu, and Herbert Mayr*
Dedicated to Professor Manfred T. Reetz on the occasion of his 65th birthday
During the last decade organocatalysis has become an
important branch of organic chemistry.[1] Secondary amines
have been demonstrated to activate carbonyl compounds
towards attack by electrophiles (enamine[2]) and nucleophiles
(iminium catalysis[3]). Scheme 1 illustrates the catalytic cycle
catalytic cycle separately, they concluded that the cyclo-
addition step is rate-determining under the specific reaction
conditions used.
The key step in Scheme 1, as in related organocatalytic
cycles employing iminium catalysis, is the reaction of an
iminium ion with a nucleophile. Because reactions of
carbocations and Michael acceptors with C, N, O, and P
nucleophiles have previously been reported to follow Equa-
tion (1),[5] where electrophiles are characterized by one
log kð20 ꢀCÞ ¼ sðN þ EÞ
ð1Þ
parameter (electrophilicity E) and nucleophiles are charac-
terized by two parameters (slope s and nucleophilicity N), we
assumed that the reactions of the iminium ions 3 with
nucleophiles also followed this correlation. We therefore
determined the electrophilicities of various iminium ions 3
(Scheme 2) derived from cinnamaldehyde (1) and secondary
amines by studying the kinetics of their reactions with the silyl
ketene acetals 2-(trimethylsiloxy)-5,6-dihydro-4H-pyran (4a)
and 2-(trimethylsiloxy)-4,5-dihydrofuran (4b), whose N and s
parameters are known.[5]
Scheme 1. Iminium catalysis in nucleophilic additions to cinnamalde-
hyde (1).
for amine-catalyzed additions of nucleophiles to cinnamalde-
hyde (1). The cycle is initiated by the condensation of the
catalyst 2 with the aldehyde 1 to produce the reactive iminium
ion intermediate 3, which is attacked by the nucleophile in the
second step. In the final step, the product is released, and the
catalyst is regenerated. Despite numerous applications of the
iminium ion catalysis in organic syntheses, mechanistic data,
which are needed to systematically optimize known processes
and explore the scope and limitations, are rare. During the
preparation of this manuscript, Platts, Tomkinson et al.
reported kinetic and theoretical investigations of the iminium
ion catalyzed Diels–Alder reaction of cinnamaldehyde with
cyclopentadiene, using 2-(trifluoromethyl)pyrrolidine as the
catalyst.[4] By studying the first two steps of the organo-
Scheme 2. Cinnamaldehyde-derived iminium ions 3a–g.
MM3[6] and DFT[7a] calculations indicate the E isomer of
iminium ion 3 f to be the more stable species because it avoids
nonbonding interactions between the geminal methyl groups
and the styryl group. This conclusion has so far not been
tested experimentally, because the reaction of 1 and 2 f-HCl in
CD3OD at room temperature gives 3 f-Cl in only low
conversion.[3f] As 3 f-OTf was synthesized as a pure crystalline
material in this work, NOE experiments could be performed
which showed strong correlations between the hydrogens as
indicated in Scheme 3(see the Supporting Information).
Weak correlations between the benzylic phenyl group and
one of the geminal methyl groups as well as the b-styryl
proton (dotted lines in structure (E)-3 f, Scheme 3) indicate
[*] Dr. S. Lakhdar, Dr. T. Tokuyasu,[+] Prof. Dr. H. Mayr
Department Chemie und Biochemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13 (Haus F), 81377 München (Germany)
Fax: (+49)89-2180-77717
E-mail: herbert.mayr@cup.uni-muenchen.de
[+] Current address: Hitachi Chemical Co. Ltd., Chiba (Japan)
[**] We thank the Alexander von Humboldt Foundation (research
fellowship for S.L.) and the Deutsche Forschungsgemeinschaft (Ma
673/21-2) for support of this work, as well as Dr. D. Stephenson and
Dr. A. R. Ofial for helpful discussions.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2008, 47, 8723 –8726
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8723