Halogen Bond Catalyzed Bromocarbocyclization
Yuk-Cheung Chan and Ying-Yeung Yeung*
Dedicated to Professor Elias J. Corey on the occasion of his 90th birthday
Abstract: Ahalogen bond catalyzed bromo-carbocyclization
of N-cinnamyl sulfonamides and O-cinnamyl phenyl ethers
has been developed. N-methyl 4-iodopyridinium triflate is used
as the halogen-bonding organocatalyst and the reaction is
highly chemoselective.This report represents the first proof-of-
concept for halogen-bonding organocatalyst-promoted elec-
trophilic halogenation. Mechanistic study suggests the auto-
catalytic nature of this reaction.
The halogen bond (XB) is defined as anoncovalent inter-
action between an electrophilic halogen substituent and
Key features of an XB include the high
directionality of the interaction (approximately 18088),
polarizable halogen atoms (Cl, Br,I),
and sufficiently high
bond strength (10 to 180 kJ mol
thus an XB is considered
ahydrophobic and soft analogue of ahydrogen bond.
Although the XB was discovered more than 150 years ago,
its applications are very concentrated in the fields of
supramolecular chemistry and crystal engineering.
In comparison, using an XB in organocatalysis remains
underexplored. In 2008, Bolm et al. reported an example of
using perfluoroiodoalkanes as an XB catalyst in the reduction
of quinolines by Hantzsch esters.
ing examples on the XB activation of either carbonyl or imine
functional groups in the classical and aza-Diels–Alder-type
reactions were reported by Huber et al. and Minakata et al.,
Another milestone was reported by Huber
et al. and involved amultidentate XB-donor-assisted C
Very recently,Takemoto et al. reported
two representative examples of XB-catalyzed Si
activation/benzylic carbon functionalization
ylide activation/cross-enolate coupling.
plications of an XB in organocatalysis are limited to afew
types of reactions and the scope remains limited when
compared to that of conventional hydrogen-bond catalysis.
Halofunctionalization of olefins is afundamental organic
transformation for furnishing various kinds of building blocks.
Among halofunctionalization reactions,halo-O-cyclizations
and halo-N-cyclizations are well-documented.
gous halo-C-cyclization, in particular the organocatalytic
version, is far less explored despite the fact that the resulting
cyclized products are valuable synthetic intermediates.
One of the challenges of halocarbocyclization is that the C-
nucleophiles might also react with the electrophilic halo-
and asuitable reaction protocol remains elusive.For
instance,electron-rich arenes are susceptible to aromatic
We hypothesize the XB catalyst could
activate an N-haloamide reagent to generate asoft electro-
philic halonium species for the halogenation of olefins.
Herein, we report the first case of using an XB as an
organocatalyst to catalyze bromo-carbocyclization of cin-
namyl substrates (Friedel–Crafts-type reaction;Scheme 1).
An inexpensive halogenating reagent is used and the reaction
conditions are mild. Theresulting halogenated tetrahydro-
are valuable drug cores and
natural products scaffolds.
At the outset of our investigation, bromo-carbocyclization
of the N-cinnamyl sulfonamide 4a was studied using 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) as the halogen
source in CH
(Table 1). In the absence of acatalyst, the
reaction was sluggish and low conversion was observed after
24 hours (entry 1). To our delight, the use of 10 mol %ofthe
iodine-containing XB organocatalyst 1a gave good yield of
the desired product 5a (85 %, d.r. > 99:1) and the reaction
was found to be readily scalable (entry 2). Thestructure of 5a
was confirmed by an X-ray crystallographic study.
comparison, replacing the iodine atom in 1a with either
abromine or chlorine atom (i.e.XBcatalysts 1b and 1c in
entries 3and 4) gradually decreased the catalytic perfor-
mance,and could be attributed to their weaker XB strength
Scheme 1. Halogen bond (XB) catalyzed bromo-carbocyclization.
Tf = trifluoromethanesulfonyl, Ts = 4-toluenesulfonyl.
[*] Y. -C. Chan, Prof. Dr.Y.-Y.Yeung
Department of Chemistry,The Chinese University of Hong Kong
Shatin, N.T., Hong Kong (China)
Supportinginformation and the ORCID identification number(s) for
the author(s) of this article can be found under:
3541Angew.Chem. 2018, 130,3541 –3545 2018 Wiley-VCH Verlag GmbH &Co. KGaA,Weinheim