FULL PAPER
DOI: 10.1002/chem.200801665
Selective Benzylic and Allylic Alkylation of Protic Nucleophiles with
Sulfonamides through Double Lewis Acid Catalyzed Cleavage of sp3 Carbon–
Nitrogen Bonds
Cong-Rong Liu, Man-Bo Li, Cui-Feng Yang, and Shi-Kai Tian*[a]
Abstract: The acid-catalyzed benzylic
and allylic alkylation of protic nucleo-
philes is fundamentally important for
of sp3 carbon–nitrogen bonds at room
temperature. In the presence of a cata-
lytic amount of inexpensive ZnCl2-
TMSCl (TMSCl: chlorotrimethylsi-
lane), 1,3-diketones, b-keto esters, b-
keto amides, malononitrile, aromatic
compounds, thiols, and thioacetic acid
can couple with a broad range of tosyl-
activated benzylic and allylic amines to
give diversely functionalized products
in good to excellent yields and with
high regioselectivity. Furthermore, the
cross-coupling reaction of 1,3-dicarbon-
yl compounds with benzylic propargylic
amine derivatives has been successfully
applied to the one-step synthesis of
polysubstituted furans and benzofur-
ans.
À
the formation of carbon carbon and
À
carbon heteroatom bonds, and it is a
formidable challenge for benzylic and
allylic amine derivatives to be used as
the alkylating agents. Herein we report
a highly efficient benzylic and allylic al-
kylation of protic carbon and sulfur nu-
cleophiles with sulfonamides through
double Lewis acid catalyzed cleavage
Keywords: allylic compounds · ben-
zylic compounds · carbon nucleo-
philes · oxygen heterocycles · sulfur
Introduction
results in the formation of hydrogen halides and sulfonic
acids, the strong acidity of which may lead to undesired side
reactions. One of the promising approaches to avoid this
problem is to explore benzylic and allylic amines or their de-
rivatives as alkylating agents, which can completely shut
down the formation of acidic by-products. However, it re-
mains a formidable challenge for benzylic and allylic amines
and their derivatives to be coupled with protic nucleophiles
through catalytic cleavage of sp3 carbon–nitrogen bonds
under acidic conditions.[2]
Although benzylic amine derivatives have been reported
to undergo Friedel–Crafts alkylation of aromatic com-
pounds, such an alkylation is restricted by the use of highly
activated substrates, a large excess of acids and/or elevated
temperature, and at times the formation of a multitude of
products.[3] Furthermore, the reaction conditions have not
been extended to the benzylic and allylic alkylation of other
important protic nucleophiles, such as active methylene
compounds, thiols, and thioacids. To explore benzylic and al-
lylic amines as useful alkylating agents, we planned to acti-
vate the amino groups with appropriate electron-withdraw-
ing groups (EWG) and Lewis acids (LA) to facilitate the
cleavage of benzylic and allylic sp3 carbon–nitrogen bonds
(Scheme 1). The cross-coupling reaction of benzylic and al-
The benzylic and allylic alkylation of protic nucleophiles is
fundamentally important for the formation of carbon
carbon and carbon heteroatom bonds, and benzylic and al-
À
À
lylic halides and the corresponding sulfonates are frequently
employed as the alkylating agents. In general, at least stoi-
chiometric amounts of bases are needed to activate protic
nucleophiles, such as active methylene compounds, alcohols
and thiols, to facilitate the corresponding alkylating reac-
tions. Alternatively, the alkylation of protic nucleophiles can
be catalyzed by Lewis or Brønsted acids, owing to the ready
cleavage of benzylic and allylic sp3 carbon-halogen and sp3
carbon-oxygen bonds under acidic conditions,[1] and the
scope of protic nucleophiles for the acid-catalyzed alkylation
has been successfully extended to aromatic compounds.
Nevertheless, the use of benzylic and allylic halides and the
corresponding sulfonates as alkylating agents in the reaction
[a] C.-R. Liu, M.-B. Li, C.-F. Yang, Prof. Dr. S.-K. Tian
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui, 230026 (China)
Fax : (+86)0551-3601592
À
lylic amine derivatives with protic nucleophiles (Nu H) re-
Supporting information for this article is available on the WWW
sults in the formation of ammonia derivatives, H2N
A
Chem. Eur. J. 2009, 15, 793 – 797
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
793