Enantioselective bromocyclization of allylic amides catalyzed by BINAP derivatives

Article abstract of DOI:10.1021/acs.orglett.5b00220

A highly enantioselective bromocyclization of allylic amides with N-bromosuccinimide (NBS) was developed with DTBM-BINAP as a catalyst, affording chiral oxazolines with a tetrasubstituted carbon center in high yield with up to 99% ee. By utilizing the bro

Full text of DOI:10.1021/acs.orglett.5b00220

Letter
pubs.acs.org/OrgLett
Enantioselective Bromocyclization of Allylic Amides Catalyzed by
BINAP Derivatives
Yuji Kawato, Akino Kubota, Hiromi Ono, Hiromichi Egami, and Yoshitaka Hamashima*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
S
* Supporting Information
ABSTRACT: A highly enantioselective bromocyclization of allylic amides with N-bromosuccinimide (NBS) was developed with
DTBM-BINAP as a catalyst, affording chiral oxazolines with a tetrasubstituted carbon center in high yield with up to 99% ee. By
utilizing the bromo substituent as a handle, the obtained compounds were converted to synthetically useful chiral building blocks.
example of asymmetric halofunctionalization of olefins
catalyzed by chiral phosphine compounds.
Bearing in mind that a chiral bromophosphonium ion is an
active species, we aimed to develop an asymmetric bromocyc-
lization of allylic amides 1 (Scheme 1). This reaction would
lectrophilic halofunctionalization of alkenes is a syntheti-
Ecally useful transformation, allowing for simultaneous
incorporation of two heteroatom functionalities across non-
activated C−C double bonds. Further, stereodefined halo-
genated compounds are widely found among naturally
occurring compounds and can serve as versatile chiral building
blocks. Therefore, development of an asymmetric version of
this reaction is of great interest,1 and in recent years, there has
been remarkable progress in catalytic asymmetric halogenation
reactions using so-called intelligent chiral catalysts.2−8 Among
them, Lewis base catalysis is a straightforward approach for the
generation of chiral halogenating agents, but is relatively
underdeveloped, probably because racemization of halonium
ion intermediates via olefin−olefin exchange reaction is
considered to be rapid.1d,9 In addition, soft Lewis bases (P, S,
Se, etc.) are generally unstable under halogenation conditions.
The application of Lewis base activation of a halogen to
asymmetric reactions has been thought to be difficult, and such
failures led to the development of bifunctional catalysts with a
secondary interaction. Nonetheless, Yeung and co-workers
recently developed optically active dialkyl sulfide and selenide
as single-site Lewis base catalysts for asymmetric bromination
of olefins with an alcohol or tosyl amide as a pendant
nucleophile.10 Also, Ishihara and co-workers used a chiral
phosphoramidite as a stoichiometric promoter in a highly
enantioselective iodocyclization of polyprenoids.11 While
phosphines (PR3) and related compounds are potential
promoters of electrophilic halogenation reactions,11,12 their
use in asymmetric catalysis has been less well studied. During
our investigations on halogenation reactions,13 we found that
chiral phosphine compounds can catalyze the enantioselective
delivery of halogen atoms. In this letter, we report a successful
Scheme 1. Catalytic Asymmetric Bromocyclization of Allylic
Amides
furnish chiral oxazoline compounds 2 with a tetrasubstituted
stereogenic carbon center and was expected to be useful for
synthesizing bioactive compounds. Also, these compounds
would be useful as precursors to chiral 1,2-amino alcohols.
Borhan and co-workers previously reported a chlorocyclization
reaction with DCDPH (1,3-dichloro-5,5-diphenylhydantoin)
catalyzed by (DHQD)2PHAL, but their system was not
applicable to the corresponding bromination reaction.2c Indeed,
there is no precedent for such a bromination reaction in the
literature, even though brominated products are amenable to
various transformations. We initially designed quinine-triphe-
nylphosphine conjugate 3, since cinchona alkaloids were good
catalysts for our asymmetric bromolactonization of prochiral
cyclic dienes.13 The chiral phosphine 3 promoted the reaction
smoothly to give the product 2a with appreciable enantiose-
lectivity (Table 1, entry 1). This contrasted with the negligible
Received: January 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00220
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Optimization of the Reaction Conditions
Scheme 2. Effect of Brominating Reagents on
Enantioselectivity
a
bc
,
entry
cat.
solvent
temp (°C)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
3
4
5
6
7
7
7
7
7
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
0
0
99
99
99
92
99
95
99
99
99
19
5
Table 2. Scope of the Bromocyclization of Allylic Amides
0
39
38
66
73
95
99
0
0
−60
−60
−78
−78
a
b
entry
1
R
2
time (h)
yield (%)
ee (%)
4-MeC6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-naphthyl
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
3-F3CC6H4
3-NCC6H4
4-NCC6H4
3-pyridyl
3-thienyl
c-hexyl
2b
2c
2d
2e
2f
12
24
12
12
12
12
12
12
12
12
12
24
24
24
24
12
12
24
12
24
92
91
99
85
99
81
90
73
99
99
94
89
95
84
97
91
85
90
92
99
80
95
7
d
c
9
99
c
2
a
b
Isolated yield. The ee was determined by chiral HPLC analysis. The
absolute configuration of 2a was determined to be R after conversion
(vide infra). 12 h. NBS = N-bromosuccinimide.
3
4
93
90
86
99
95
97
98
99
97
98
90
91
86
60
39
99
d
5
6
2g
2h
2i
asymmetric induction observed with commercially available
cinchona alkaloids as catalysts under identical conditions,14
suggesting that the phosphine moiety has an important role in
this reaction. Among various chiral phosphine compounds
examined, only BINAPs showed promising asymmetric
induction.14 Since MOP (4) was totally ineffective for chirality
control, the bisphosphine structure with axial chirality is likely
essential for achieving high enantioselectivity. As shown in
entries 3−5, DTBM-BINAP (7)15 was found to be the best
catalyst. While lowering the reaction temperature had little
influence on the reaction efficiency, a change in solvent caused
marked improvement of the ee without reducing the reaction
rate (entries 6, 7). When the reaction was conducted in CH2Cl2
at −78 °C, the reaction was complete within 12 h, affording 2a
quantitatively with 99% ee (entry 9). As described later, the
absolute stereochemistry of 2a was determined to be R after the
conversion.
7
8
9
2j
10
11
12
13
14
2k
2l
2m
2n
2o
2p
2q
2r
2s
2a
2a
c
15
c
16
c
17
n-octyl
c
18
d
H
19
Ph
e
20
Ph
96
a
b
c
Isolated yield. The ee was determined by chiral HPLC analysis. The
d
Ph group of 1 was replaced with 4-BrC6H4 group. 1 mmol of 1a was
used. 5 mol % of 7 was used.
e
It should be noted that other brominating reagents gave
comparable enantioselectivity, regardless of their different
structural and electronic properties (Scheme 2). This is distinct
from other reported reactions, as the choice of halogenating
reagent is generally crucial for high enantioselectivity. These
results are suggestive of the generation of a similar chiral
brominating species in all cases.
Having established the optimum reaction conditions, we next
examined the scope of the reaction (Table 2). Our reaction
displayed broad generality with respect to the R group, and
various oxazoline compounds were accessible in high yield with
excellent enantioselectivity.16 Though the reaction of 1b was
less enantioselective, the ee was improved to 95% when the
amino group was protected with a 4-bromobenzoyl group
(entries 1, 2).17 In line with previous reports, the reaction of an
electron-rich 4-methoxyphenyl-substituted substrate gave an
almost racemic mixture, probably because a carbocation
intermediate would be generated (entry 3). In contrast, 1e
with a MeO group at the meta position underwent the desired
reaction in a highly enantioselective manner (entry 4). A
bulkier naphthyl-substituted amide was also a good substrate
(entry 5). As for electron-withdrawing groups, any halogen
group was tolerated, affording products with up to 99% ee
(entries 6−11). Regardless of possible steric repulsion, a 2-
chlorophenyl-substituted amide reacted without difficulty to
give 2g in good yield with 86% ee. Additionally, 3- and 4-cyano-
substituted substrates were converted to the desired oxazoline
compounds with 97 and 98% ee, respectively (entries 12, 13).
Notably, our reaction was compatible with medicinally
important heteroaromatic substructures such as a pyridine
ring and a thiophene ring, and high enantioselectivity was
observed in both cases (entries 14, 15). Alkyl-substituted
amides 1q and 1r were also available for this reaction, affording
the corresponding products with reasonably high enantiose-
B
DOI: 10.1021/acs.orglett.5b00220
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
lectivity (entries 16, 17). However, terminal olefin 1s was a
difficult substrate, giving lower enantioselectivity (entry 18).
Our reaction was easy to scale up, and 2a was obtained in 92%
yield with 99% ee on a 1 mmol scale (entry 19). Finally, the
amount of the catalyst could be reduced to 5 mol % (entry 20).
Although a longer reaction time was required, comparable
results were obtained (24 h, 99%, 96% ee).
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” and a grant for Platform for
Drug Discovery, Informatics, and Structural Life Science from
The Ministry of Education, Culture, Sports, Science and
Technology, Japan.
To confirm the synthetic utility of the reaction, we next
examined the conversion of 2a (Scheme 3). First, radical
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In summary, we have developed a highly enantioselective
bromocyclization of allylic amides. This reaction provides chiral
brominated oxazoline compounds, which can be converted to
synthetically useful chiral building blocks. As mentioned above,
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been thought to be difficult. Therefore, we believe that our
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ASSOCIATED CONTENT
* Supporting Information
■
S
Typical experimental procedure and characterization for all new
products are presented in the Supporting Information. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hamashima@u-shizuoka-ken.ac.jp.
Notes
(7) For phase transfer catalysts, see: (a) Rauniyar, V.; Lackner, A. D.;
The authors declare no competing financial interest.
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(15) DTBM-BINAP was purchased from WAKO Pure Chemical
Industries Ltd. and used as received.
(16) The use of substrates with other substitution patterns such as
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reaction system. See Supporting Information.
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D
DOI: 10.1021/acs.orglett.5b00220
Org. Lett. XXXX, XXX, XXX−XXX