Chiral phosphoric acid catalyzed enantioselective sulfamination of amino-alkenes

Article abstract of DOI:10.1039/c3ra40307f

This paper describes a chiral phosphoric acid-catalyzed sulfamination of amino-alkenes to form optically active 2-substituted pyrrolidines and piperidines in up to 86% ee.

Full text of DOI:10.1039/c3ra40307f

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Chiral phosphoric acid catalyzed enantioselective
sulfamination of amino-alkenes3
Cite this: RSC Advances, 2013, 3, 4523
Lijun Li,a Zequan Li,a Deshun Huang,a Haining Wanga and Yian Shi*ab
Received 4th December 2012,
Accepted 1st February 2013
DOI: 10.1039/c3ra40307f
www.rsc.org/advances
This paper describes a chiral phosphoric acid-catalyzed sulfamina-
tion of amino-alkenes to form optically active 2-substituted
pyrrolidines and piperidines in up to 86% ee.
Electrophilic sulfur additions to olefins provide an effective
approach to introduce two heteroatoms onto C–C double bonds.1
The development of corresponding asymmetric processes would
further enhance the synthetic values of these transformations.
Significant progress has been made in asymmetric sulfenylations
of olefins using chiral sulfur reagents.2 Very recently, catalytic
enantioselective sulfenylations have also appeared. Up to 92% ee
has been achieved for a Lewis base catalyzed-sulfetherification by
Denmark and coworkers.3–5 In our studies on acid-catalyzed
electrophilic sulfur additions to olefins (Scheme 1),6–8 we have
found that chiral acid-catalyzed asymmetric sulfenylation is
feasible and up to 63% ee is obtained for sulfetherification with
a dibenzoyl-D-tartaric acid derivative as the catalyst.9 Recently, we
have also shown that pyrrolidines can be efficiently synthesized by
the acid catalyzed-sulfamination of amino-alkenes with
PhSOMe.10 Herein, we wish to report our preliminary studies on
the asymmetric process of this transformation with chiral
phosphoric acid as the catalyst.
Scheme 1
carried out at 0 uC (Table 1, entry 10). Higher yields were obtained
at higher temperature and the ee remained almost the same
within the range of 25 uC to 70 uC (Table 1, entries 9 and 11–13).
Table 1 Studies on reaction conditionsa
Our initial studies were carried out with cis-c-amino–alkene 1a
as a test substrate (Table 1). Pyrrolidine 4a was obtained in 72%
yield and 70% ee when 1a was treated with benzenesulfenate
(2)10–12 and 10 mol% (S)-3,39-bis-(2,4,6-triisopropylphenyl)-BINOL
phosphoric acid (3c)13 in CH2Cl2 at 25 uC (Table 1, entry 3). Among
the solvents examined (Table 1, entries 3–9), the highest ee (77%)
was obtained with 1,1,1-trichloroethane (Table 1, entry 9).
Interestingly, the ee decreased to 70% when the reaction was
Entry
Acid (3)
Solvent
T (uC)
Yield (%)d
Ee (%)e
1
2
3
4
5
6
7
8
3a
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
PhMe
THF
CH3CN
Hexane
CH3CCl3
CH3CCl3
CH3CCl3
CH3CCl3
CH3CCl3
CH3CCl3
CH3CCl3
25
25
25
25
25
25
25
25
25
0
35
50
70
35
35
80
19
72
61
55
6
70
81
63
34
78
92
99
82
74
23
41
70
72
74
43
9
19
77
70
79
79
78
81
86
9
10
11
12
13
14b
15c
aBeijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
bDepartment of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States. E-mail: yian@lamar.colostate.edu; Fax: 001-970-4911801;
Tel: 001-970-4917424
a
The reactions were carried out with 1a (0.20 mmol), 2 (0.24 mmol),
and 3 (0.02 mmol) in solvent (2.0 mL) for 24 h unless otherwise
Electronic supplementary information (ESI) available: Experimental procedures,
3
b
c
d
stated. In 4.0 mL solvent. In 10.0 mL solvent. Isolated yield.
characterization data, HPLC data for determination of enantiomeric excesses, and
NMR spectra. See DOI: 10.1039/c3ra40307f
e
Determined by chiral HPLC analysis.
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Table 2 Asymmetric sulfamination of amino-alkenesa
e
g
Entry Substrates
Products
Yield (%)f Ee (%)
Scheme 2 a) PhSH, K2CO3, CH3CN/DMSO, 50 uC. b) (Boc)2O, DMAP, THF, rt. c)
RANEY1 Ni, EtOH, 80 uC. d) Pd–C, H2, EtOH, rt.
1
2
3
4
R = n-C5H11, 1a
R = CH3, 1b
R = C2H5, 1c
R = n-C9H19, 1d
R = CH2Bn, 1e
R= (CH2)3OTBDPS, 1f 4f
R = (CH2)3OAc, 1g
R = i-Bu, 1h
4a
4b
4c
4d
4e
80
78
82
79
64
77
64
76
62
86
78
84
85
83
83
80
85
85
5
6b
7b
8b
9b
10c
4g
4h
4i
R = t-Bu, 1i
1j
4j
85
71
11d
12d
R = Ph, 1k
R = 1-Naphth, 1l
5k
5l
50
62
44
55
Fig. 1 Proposed transition state model for sulfamination of cis-c-amino-alkenes.
a
The reactions were carried out with 1 (0.30 mmol), PhSOMe (0.36
mmol), and 3c (0.03 mmol) in CH3CCl3 (15.0 mL) at 35 uC for 72 h
b
c
unless otherwise stated. Ns = 4-nitrobenzenesulfonyl. At 50 uC. In
d
e
desulphurisation17,18 (Scheme 2). The absolute configurations of
piperidines 4j19 and 5k20 were determined in a similar manner
CH3CCl3 (6.0 mL) at 70 uC. In CH3CCl3 (6.0 mL) at 50 uC. For
entries 3, 10, and 11, the absolute configurations were determined
by comparing the optical rotations with corresponding N-Boc
pyrrolidine or piperidine after removal of the Ns group, protection
with the Boc group, and reductive desulphurisation. For entries 1, 2,
4–9, and 12, the absolute configurations were tentatively proposed
(see supporting information ).
3
A precise understanding of the origin of the enantioselectivity
awaits further study. A plausible transition state model is proposed
in Fig. 1.21 It is likely that the phosphoric acid forms hydrogen
bonds with PhSOMe and the sulfonamide of the substrate to
facilitate the reaction. Based on the determined absolute
configuration of pyrrolidine 4c, the cyclization of cis-c-amino-
alkenes likely proceeds mainly via transition state A. Transition
state B is disfavored due to the steric interaction between the
triisopropylphenyl group of the catalyst and the sulfonamide
group of the substrate (Fig. 1).
f
g
by analogy. Isolated yield. Determined by chiral HPLC analysis.
The ee further increased to 86% at a lower reaction concentration
(Table 1, entry 15).
Various substrates were subsequently investigated with
PhSOMe (2) as the sulfur reagent and chiral phosphoric acid 3c
as the catalyst in 1,1,1-trichloroethane. As shown in Table 2, a
variety of cis-c-amino-alkenes regioselectively cyclized to give the
corresponding pyrrolidines in 62–82% yield and 78–86% ee
(Table 2, entries 1–9). When cis-d-amino-alkene 1j was subjected
to the reaction conditions, piperidine 4j was obtained regioselec-
tively in 85% yield and 71% ee (Table 2, entry 10). trans-c-Amino-
alkenes were also investigated. A mixture including 5-exo and 6-
endo products was obtained for an alkyl substituted substrate [(E)-
N-(dec-4-en-1-yl)-4-nitrobenzene-sulfonamide]. For aryl substituted
olefins, the cyclization occurred regioselectively to give 6-endo
products in 50–62% yield and 44–55% ee (Table 2, entries 11 and
12). The absolute configuration of 4c was determined by
comparing the optical rotation with N-Boc-pyrrolidine 7c14 after
removal of the Ns group,15 protection with the Boc group,16 and
Conclusion
In summary, chiral Brønsted acid-catalyzed sulfamination of
amino-alkenes has been investigated. A variety of enantiomerically
enriched pyrrolidines and piperidines can be obtained in good
yield and up to 86% ee with benzenesulfenate (PhSOMe) as the
sulfur source and chiral phosphoric acid as the catalyst. The
results could provide useful insights for further development of
asymmetric sulfenylation and related electrophilic addition
reactions of olefins. Such studies are currently underway.
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8 For leading references on acid-promoted addition of RS or RSe
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Acknowledgements
We gratefully acknowledge the National Basic Research
Program of China (973 program, 2011CB808600), the
National Natural Science Foundation of China (21172221),
and the Chinese Academy of Sciences for the financial
support.
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This journal is ß The Royal Society of Chemistry 2013
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