A highly enantioselective approach towards 2-substituted 3-bromopyrrolidines

Article abstract of DOI:10.1039/c2ob25327e

A facile and highly enantioselective approach towards 2-substituted 3-bromopyrrolidines has been developed. The process involves an amino-thiocarbamate catalyzed bromoaminocyclization of 1,2-disubstituted olefinic amides. The pyrrolidine products could re

Full text of DOI:10.1039/c2ob25327e

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Volume 10 | Number 19 | 21 May 2012 | Pages 3769–3956
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Ying-Yeung Yeung et al.
A highly enantioselective approach towards 2-substituted
3-bromopyrrolidines

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COMMUNICATION
A highly enantioselective approach towards 2-substituted
3-bromopyrrolidines†‡
Jie Chen, Ling Zhou and Ying-Yeung Yeung*
Received 14th February 2012, Accepted 6th March 2012
DOI: 10.1039/c2ob25327e
A facile and highly enantioselective approach towards 2-sub-
stituted 3-bromopyrrolidines has been developed. The
process involves an amino-thiocarbamate catalyzed bromo-
aminocyclization of 1,2-disubstituted olefinic amides. The
pyrrolidine products could readily be converted into other
useful building blocks including a dihydropyrrole and a
Fig. 1 2-Substituted pyrrolidines 1 and 2.
2-substituted pyrrolidine.
Substituted pyrrolidine is the fundamental unit of many pharma-
ceutically relevant molecules.1 For example, the synthesis of
polyhydroxylated pyrrolidines has attracted considerable atten-
tion since these compounds possess interesting biological
properties.2
Towards the synthesis of optically active substituted pyrroli-
dines, including polyhydroxylated pyrrolidines, 2-substituted 3-
halopyrrolidine 1 and 2-substituted dihydropyrrolidine 2 (Fig. 1)
appear to be attractive advanced intermediates. As a result, a
number of catalytic protocols such as olefin metathesis of chiral
allylic amines,3 Heck reaction of 2-pyrrolidines,4 and rhodium-
catalyzed arylation of N-tosylalkylaldimines,5 were reported on
the construction of enantioenriched pyrrolidines.6
Halocyclization is an effective method for the construction of
heterocyclic skeletons. For instance, cyclic amines can be syn-
thesized through the halocyclization of olefinic amides.7 As the
beneficiaries of the recent breakthrough of the catalytic enantio-
selective co-halogenation reactions, several enantioenriched
halo-heterocycles were prepared.8
Scheme 1 Enantioselective approaches toward pyrrolidines.
However, the asymmetric synthesis of cyclic amines through
catalytic halocyclization processes remains challenging. Very
recently, we reported the use of amino-thiocarbamate as the cata-
lyst in the asymmetric haloaminocyclization, resulting in the 1,1-
disubstituted pyrrolidines 4 (Scheme 1, eqn (1)).9 Shi and co-
workers also reported the use of BINOL-derived phosphoric acid
catalyst in the enantioselective synthesis of pyrrolidines 6
(Scheme 1, eqn (2)).10 Although these pyrrolidines were
achieved in high enantiopurity, further introduction of function-
alities into the pyrrolidine ring system may not be straightfor-
ward since the halogen handles sit at the exocyclic positions.
We reasoned that the synthesis of pyrrolidine that contains a
halogen in the pyrrolidine ring system should allow us to access
many useful substituted pyrrolidines such as dihydropyrrole 2.
Herein we report the first case of bromoaminocyclization of
trans-1,2-disubstituted olefinic amide 7, resulting in the syn-
thesis of 2-substituted 3-bromopyrrolidine 8.
Department of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore 117543. E-mail: chmyyy@nus.edu.sg; Fax: +65
6779 1691; Tel: +65 6516 7760
Initially, the cyclization of 7a was investigated using various
amino-thiocarbamate catalysts 9 (Table 1). After searching a
number of 2,4-dimethoxyphenyl thiocarbamate catalysts, cincho-
nine-derived thiocarbamate 9a gave the best ee of the desired
product 8a (Table 1, entries 1–4). Hence, the cinchonine core
†This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡Electronic supplementary information (ESI) available: NMR spectra,
physical data, and crystallographic data. CCDC 859894 and 859895. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25327e
3808 | Org. Biomol. Chem., 2012, 10, 3808–3811
This journal is © The Royal Society of Chemistry 2012

Table 1 Bromoaminocyclization of 7a using various catalysts
Table 2 Solvent screening of the bromoaminocyclization of 7a
Entrya
Solvent (ratio)
Temp (°C)
ee (%)
Entrya
Catalyst
Ar
R
ee (%)c
1
2
3
4
5
6
7
PhCH3
−62
−78
−78
−78
−78
−78
−78
30
48
68
74
86
88
90
PhCH3–CHCl3 (3 : 1)
PhCH3–CHCl3 (2 : 1)
PhCH3–CHCl3 (1.5 : 1)
PhCH3–CHCl3 (1 : 1)
PhCH3–CHCl3 (1 : 1.5)
n-hexane–CHCl3 (1 : 1)
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9f
9g
9h
9h
9i
2,4-(MeO)2-C6H3
2,4-(MeO)2-C6H3
2,4-(MeO)2-C6H3
2,4-(MeO)2-C6H3
C6H5
Cinchonine
Cinchonidine
Quinidine
37
−30
17
−18
35
50
74
81
Quinine
Cinchonine
Cinchonine
Cinchonine
Cinchonine
Cinchonine
Cinchonine
4-MeO-C6H4
a Reactions were carried out with olefinic amide 7a (0.1 mmol), catalyst
9h (0.01 mmol), and NBP (0.12 mmol) in solvent (3 mL) in the absence
of light. The reactions showed complete consumption of starting
materials.
2,4,6-(MeO)3-C6H2
2,6-(EtO)2-C6H3
2,6-(EtO)2-C6H3
2,6-(nPrO)2-C6H3
8
9b
10
84
70
a Reactions were carried out with olefinic amide 7a (0.1 mmol), catalyst
9 (0.01 mmol), and NBS (0.12 mmol) in CH2Cl2 (3 mL) in the absence
of light. The reactions showed complete consumption of starting
materials. b NBP was used instead of NBS. c The ee was determined by
chiral HPLC analysis with a UV detector. A isopropanol–hexane
mixture was used as the mobile phase and the UV wavelength was
254 nm or 230 nm.
Table 3 Substrate scope of the bromoaminocyclization of 7
was used for further optimization. Phenyl catalyst 9e gave a 35%
ee which was comparable to the 2,4-dimethoxyphenyl catalyst
9a (Table 1, entry 5). Unexpectedly, the 4-methoxyphenyl cata-
lyst 9f offered a higher ee value than 9a (Table 1, entry 6). A
dramatic increase in ee was observed when the bulkier phenyl
substituents were used. The use of catalyst 9h, which contains a
2,6-diethoxyphenyl group, afforded 8a in 81% ee (Table 1, entry
8). A slight improvement was observed when using N-bro-
mophthalimide (NBP) instead of NBS (Table 1, entry 9). The
use of a even bulkier 2,6-di-n-propoxyphenyl catalyst 9i,
however, gave a lower enantioselectivity (Table 1, entry 10).
Solvent screening was performed using the optimum catalyst
9h (Table 2). A sharp decrease in ee was observed when chan-
ging the solvent from chloroform to toluene (Table 2, entry 1).
In contrast, a toluene–chloroform solvent blend allowed us to
further improve the enantioselectivity, and an 88% ee was
obtained when using a toluene–chloroform (1 : 1.5) mixture
(Table 2, entry 6). A slight enhancement of ee was achieved
when using a n-hexane–chloroform co-solvent system (Table 2,
entry 7).
Entrya Substrate
R
Temp (°C) Yieldb (%) ee (%)
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
C6H5
−78
−50
−60
−50
−78
91
89
93
90
95
98
56
96
87
94
97
96
84
85
90
91
91
86
85
47
77
87
86
62
88
70
84
86
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4 −78
3-Cl-C6H4
3-Me-C6H4
7
8
9
7g
7h
7i
−50
−78
3-MeO-C6H4 −60
10
11
12
13
14
7j
7k
7l
7m
7n
2-Me-C6H4
2-Naphthyl
2-Thienyl
3-Thienyl
Et
−78
−50
−50
−50
−78
a Reactions were carried out with olefinic amide 7 (0.1 mmol), catalyst
9h (0.01 mmol), and NBP (0.12 mmol) in n-hexane–CHCl3 (1 : 1)
(3 mL) in the absence of light. b Isolated yield.
After identifying the optimized conditions, other substrates
were examined and the scope is indicated in Table 3. In general,
the desired 2-substituted 3-bromopyrrolidines 8 were obtained in
high reaction yields. Good to excellent ees were observed for
most of the 4-substituted and 3-substituted phenyl substrates 7
(Table 3, entries 2–5, 7–9). The deteriorating effect of the elec-
tron-rich 4-methoxyphenyl group on the enantioselectivity,
which has been observed in some studies, is also apparent for
this class of substrate (Table 3, entry 6).11 The sterically strained
2-methylphenyl substrate 7j gave a moderate ee (Table 3, entry
10). Good ees were achieved for other systems including 2-
naphthyl, 2-thienyl, and 3-thienyl substrates (Table 3, entries
11–13). Finally, alkyl substrate also worked well in this reaction
(Table 3, entry 14).
The absolute configuration of the products 8 were assigned
based on the X-ray crystallographic studies on pyrrolidines 8a
and 8m (Fig. 2 and 3). Based on our previous proposed working
model, a plausible transition state was showed in Fig. 4.
The mechanistic picture may involve a charge pair between
the quinuclidine and the sulfonamide, and a Lewis basic sulfur-
activated bromonium system (Fig. 4).12 The generally high enan-
tioselectivity can potentially be explained by less steric repulsion
that exists between the 2,6-diethoxyphenyl group and the R sub-
stituent of the substrate in TS-1 over TS-2.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3808–3811 | 3809

Fig. 2 X-ray structure of 8a.
Scheme 2 Enantioselective synthesis of 12.
Fig. 3 X-ray structure of 8m.
Acknowledgements
We thank the financial support from National University of
Singapore (grant no. 143-000-428-112).
Notes and references
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3808–3811 | 3811