DOI: 10.1002/chem.201503153
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Bromocyclization
Highly Enantioselective Bromocyclization of Allylic Amides with
a P/P=O Double-Site Lewis Base Catalyst
Yuji Kawato, Hiromi Ono, Akino Kubota, Yoshihiro Nagao, Naoki Morita, Hiromichi Egami,
and Yoshitaka Hamashima*[a]
Abstract: The enantioselective bromocyclization of allylic
amides catalyzed by phosphorus-containing Lewis bases was
examined in detail. A series of control experiments and NMR
studies showed that a partially oxidized bis-phosphine gen-
erated in situ serves as the actual enantioselective catalyst.
The reaction mechanism involves distinct roles of two Lewis
basic sites, P and P=O, with P+Br serving as a fine-tuning
element for substrate fixation in the chiral environment, and
P+OBr as the Br+ transfer agent to the olefin. Catalyst load-
ing could be reduced to as little as 1 mol%, and the reaction
affords enantioenriched oxazolines with up to >99.5% ee.
Introduction
site Lewis base catalysts for asymmetric bromination of olefins
with alcohol or tosyl amide as pendant nucleophile.[8b,c] Con-
currently, during the course of our investigations of halogena-
tion reactions,[10] we found that chiral phosphine compounds
can catalyze the enantioselective delivery of halogen atoms,
and we achieved a highly enantioselective bromocyclization of
allylic amides 1 with DTBM-BINAP as a Lewis base catalyst,
obtaining chiral oxazolines 2 with a tetrasubstituted carbon
center (Scheme 1).[11]
Electrophilic halofunctionalization of olefins is commonly
employed to increase molecular complexity during organic
synthesis, since it enables double installation of heteroatoms
on a carbon–carbon double bond. Halocyclization by intra-
molecular attack of pendant nucleophiles, such as carboxylic
acid, alcohol, carbamate, and amide, proceeds in a highly ste-
reospecific manner under mild reaction conditions to afford
functionalized heterocyclic compounds. Since such reactions
have often been utilized as key steps in the synthesis of vari-
ous useful compounds, the development of catalytic asymmet-
ric variants is of continuing interest.[1] In this context, a wide
variety of catalysts have emerged, including chiral amine,[2]
Brønsted acid,[3] hydrogen-binding,[4] bifunctional,[5] Lewis
acid,[6] phase-transfer,[7] and Lewis base catalysts.[8] Complexa-
tion of chiral Lewis bases with haliranium ions would be the
most straightforward approach for the generation of chiral hal-
ogenating agents, but only a few monofunctional chiral Lewis
base catalysts have been identified, probably because soft
Lewis bases (P, S, Se, etc.) are generally unstable under halo-
genation conditions and they readily dissociate from the halira-
nium ions. In addition, even if a chiral halonium intermediate
is efficiently formed, the complex is considered to be race-
mized through halogen exchange with olefin prior to attack of
the pendant nucleophile.[1d,9]
Scheme 1. Enantioselective bromocyclization of allylic amides catalyzed by
DTBM-BINAP. DTBM=3,5-di-tert-butyl-4-methoxyphenyl, NBS=N-bromo-
succinimide.
This reaction is synthetically attractive, not only because the
oxazoline substructure frequently occurs in natural products
and biologically active compounds,[12] but also because enan-
tiomerically pure oxazolines can serve as useful chiral ligands
for asymmetric reactions.[13] Furthermore, oxazoline com-
pounds can be converted to synthetically useful 1,2-amino
alcohols under mild reaction conditions.[2c,11] We found that
a bis-phosphine structure with axial chirality was essential for
achieving high enantioselectivity, but the mechanism has
remained elusive.[11] Since this approach might be applicable
to other halogenation reactions, we set out to elucidate the re-
action mechanism in detail. Herein, we describe a comprehen-
Nevertheless, Yeung and co-workers recently developed
optically active dialkyl sulfide and selenide catalysts as single-
[a] Dr. Y. Kawato, H. Ono, A. Kubota, Y. Nagao, N. Morita, Dr. H. Egami,
Prof. Dr. Y. Hamashima
School of Pharmaceutical Sciences
University of Shizuoka
52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2016, 22, 2127 – 2133
2127
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