Published on Web 07/12/2006
A General Process for the Haloamidation of Olefins. Scope and Mechanism
Ying-Yeung Yeung, Xuri Gao, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received May 25, 2006; E-mail: corey@chemistry.harvard.edu
Scheme 1. Haloamidation of Cyclohexene
An important step in a recently described synthesis of the antiflu
medicine oseltamivir (1, Tamiflu) was the bromoamidation of the
diene ester 2 to form the bromoamide derivative 3 regio- and
stereoselectively.1 The ready availability of 2 by a short enantio-
selective synthesis coupled with the effectiveness of the bromo-
amidation process was critical to the development of this short and
efficient (>30% overall yield) route to 1. In this paper, we provide
further evidence of the utility of this haloamidation reaction and
information regarding scope and mechanism. The results obtained
in this study can serve to guide the rational use of this process for
the elaboration of the core C d C functional group to a wide variety
of products having the amino function attached at one terminus.
chloroacetamide 8, but the reaction was slower and required 20 h.
The transformations outlined in Scheme 1 show that the amidation
process can function to give vicinal iodo-, bromo-, or chloroamides
in good yields, and that the reaction pathway from cyclohexene to
4 traverses the intermediates A, B, and C.
An initial study of bromoamidation was conducted with N-
bromoacetamide as the halogen source, acetonitrile as solvent,
cyclohexene as the olefinic substrate, and SnCl4 as the activating
Lewis acid. The previous work had established the superiority of
CH3CN in bromoamidation and the requirement of a Lewis acid to
activate the Br+ donor.1 Although the use of commercial reagent
grade CH3CN proved to be satisfactory in these initial studies, our
more recent experiments have demonstrated that the presence of
ca. 1 equiv of water in the reaction mixture is essential for optimum
yields. This fact and the observation that CH3CN was by far the
most efficacious solvent for the bromoamidation of olefins sug-
gested that CH3CN might participate in the reaction by nucleophilic
attack on an initial bromonium ion, in a fashion analogous to the
well-known Ritter reaction.2,3 Thus, reaction of cyclohexene, 1.2
equiv of N-bromoacetamide, 0.4 equiv of SnCl4, and 1.2 equiv of
H2O in CH3CN as solvent at 0 °C for 1 h produced the trans
bromoacetamide 4 stereoselectively in 91% yield, whereas the same
reaction in C2H5CN as solvent afforded the trans bromopropion-
amide 5 in 92% yield (see Scheme 1). Boron trifluoride etherate
(BF3‚Et2O) worked just as well as a catalyst for the conversion of
cyclohexene to 4 (91% yield) under the same conditions that were
used for SnCl4. The trans bromo urea derivative 6 was similarly
obtained from cyclohexene with N,N-dimethyl cyanamide (5 equiv)
as nucleophile (Scheme 1) in CH2Cl2 as solvent. Comparable results
were obtained for the bromoamidation of cyclohexene using
N-bromosuccinimide as Br+ donor instead of N-bromoacetamide,
but the process was somewhat more convenient with the latter
because the co-product acetamide is water soluble and more easily
removed than is succinimide. Treatment of cyclohexene with I2
using 1 equiv of SnCl4 as catalyst in CH3CN with 1.2 equiv of
H2O at 23 °C for 1 h gave the iodoacetamide derivative 7 (Scheme
1) in 98% yield. The corresponding reaction with N-chlorosuccin-
imide (NCS) under the same conditions gave a 90% yield of the
The scope of the bromoamidation process using N-bromoacet-
amide in CH3CN as solvent is indicated by the 11 examples listed
in Table 1. In the case of entry 1, the higher reactivity of the
intermediate trans bromoamide resulted in further conversion to
the oxazoline to produce the oxazoline 9, which was isolated in
75% yield. A similar result is documented in entries 3 and 5; the
intermediate in each case is a reactive trans 2-acetamido bromide
(isolable by rapid workup) that gives rise to the oxazolines 11 and
13. The formation of these oxazolines, precursors of the corre-
sponding cis amino alcohols, shows that the bromoamidation
reaction can be extended to constitute an olefinic amino hydroxyl-
ation process.
The examples given in entries 6-10 of Table 1 illustrate a very
useful selectivity aspect of the olefinic bromoamidation process
apart from the positional selectivity (Markovnikov-type) implied
by the cases shown in entries 3 and 5 for trisubstituted olefinic
substrates. The example in entry 6 is taken from the original
bromoamidation reaction that was employed in our recent synthesis
of oseltamivir (1). We rationalize the regio- and stereoselectivity
of the process by which 14 is formed as follows: (1) bromonium
ion complexation cis to the NHBoc group is favored by an attractive
interaction between the carbonyl oxygen of the Boc group (axially
located) and Br+; (2) preferential diaxial opening by CH3CN as
9
9644
J. AM. CHEM. SOC. 2006, 128, 9644-9645
10.1021/ja063675w CCC: $33.50 © 2006 American Chemical Society