Communications
DOI: 10.1002/anie.201102562
Organocatalysis
Highly Enantioselective a Alkylation of Aldehydes with 1,3-
Benzodithiolylium Tetrafluoroborate: A Formal Organocatalytic
a Alkylation of Aldehydes by the Carbenium Ion**
Andrea Gualandi, Enrico Emer, Montse Guiteras Capdevila, and Pier Giorgio Cozzi*
The benzodithiol heterocycle 1 (Scheme 1) is an interesting
and readily available synthon for organic synthesis.[1] The
application of the easily formed carbanion 2 and carbocation
alent, but the introduction of the 1,3-benzodithiol group in a
stereoselective fashion can also allow the generation of an
anionic (2) or cationic (3) equivalent. Furthermore, depro-
tection of 1,3-benzothiole with Raney Ni can give direct
access to a methyl group.[13] Herein we report the first
practical and highly organocatalytic stereoselective addition
of the commercially available cation 3a to various function-
alized aldehydes and the easy functionalization of the isolated
adducts.
Scheme 1. Benzodithiol as precursor of anionic 2 and cationic 3.
Formylation of aldehydes is of major importance in
synthesis,[14] and the cationic formylation of enolates has
also been studied.[15,16] Scolastico, Hopper, and their respec-
tive co-workers used ephedrine in the synthesis and use of
chiral formyl cations.[17] Furthermore, the diastereoselective
addition of an enamine to a chiral formyl cation was
reported.[18]
3 can give considerable advantages when designing complex
syntheses. The anion 2, which is a practical acyl anion
equivalent, can be easily generated by simple deprotonation
with strong bases such as nBuLi.[2] The carbenium ion 3 is also
a useful electrophile,[3] and can be easily prepared by hydride
exchange with triphenyl carbenium salts.[4] The stability of 3 is
between that of the tropylium and tritylium carbenium ions.[5]
The stable benzodithiolylium tetrafluoborate 3a is commer-
cially available and can be easily handled without any
precautions.
Several significant results in the field of a alkylation of
aldehydes were recently reported, in which attempts were
made to solve what is considered the “Holy Grail” of
organocatalysis.[6,7] We have recently contributed to this
field, and have focused our attention on the development of
new methodologies for the a alkylation of aldehydes[8] by SN1-
type reactions[9] with alcohols.[10,11] We have also found that
stable and isolable carbenium ions can be used in organo-
catalytic enantioselective a alkylation of aldehydes[12] by
using secondary amines (MacMillan catalyst).[7c] The stability
and reactivity of the versatile 1,3-benzodithiolylium cation
attracted our attention. Not only can the organocatalytic
a alkylation of 3 constitute the addition of a formyl equiv-
We have investigated the model reaction (Table 1) with
different bases and organocatalysts. In general, the reaction
was poorly promoted by proline derivatives. The presence of
the base was necessary to capture the HBF4 liberated by the
reaction of the carbenium ion. The nature of the base was
crucial for the reaction; organic bases such as 1,6-dimethyl-
pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or Et3N
resulted in poor yields because of side reactions of the 1,3-
benzodithiol unit.[19] Inorganic bases were more suitable for
the transformations; in terms of yield, NaH2PO4 was found to
be most suitable. Enantiomeric excesses and yields were
further optimized by screening different organocatalysts 5a–f
in different solvents and reaction conditions. The desired
product was produced with excellent enantioselectivity and
high yields in a 1:1 mixture of CH3CN and H2O after
reduction to the corresponding alcohol by NaBH4 in MeOH.
The use of the easily prepared and commercially available
catalysts 5a in the presence of water[20] gave excellent
enantiocontrol in the reaction with propanal. The stability
of the 1,3-benzodithiolylium carbenium is high in the
presence of water and no decomposition of the carbenium
ion occurs. The scope and limitations of this new formylation
reaction have been extensively investigated (Scheme 2).
Aldehydes bearing a variety of functional groups were
investigated by using the optimized protocol. Notably, a
wide array of aldehydes are applicable to this formylation
reaction. The reaction was quite tolerant of a large variety of
functional groups such as chloro and cyano groups, and
amides and acetals. The enantiomeric excesses obtained were
in the range 92–97% with different batches of MacMillan
catalyst and carbenium ions.[21] Remarkably, the formylation
provides straightforward access to a variety of valuable
[*] Dr. A. Gualandi, Dr. E. Emer, M. G. Capdevila, Prof. P. G. Cozzi
Dipartimento di Chimica “G. Ciamician”
ALMA MATER STUDIORUM Universitꢀ di Bologna
Via Selmi 2, 40126 Bologna (Italy)
E-mail: piergiorgio.cozzi@unibo.it
[**] PRIN (Progetto Nazionale Stereoselezioni in Chimica Organica:
Metodologie ed Applicazioni), Bologna University, Fondazione Del
Monte, and the European Commission through the project FP7-
201431 (CATAFLU.OR) are acknowledged for financial support.
Claire Margaret Wilson is acknowledged for proofreading the
manuscript.
Supporting information for this article is available on the WWW
7842
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 7842 –7846