Catalytic asymmetric cleavage of sp3 C-N bonds for access to highly enantioenriched N-benzylic sulfonamides

Article abstract of DOI:10.1039/c1cc16630a

In the presence of 10 mol% of a chiral phosphoric acid, a variety of racemic N-benzylic sulfonamides having N-(3-indolyl)methyl groups smoothly undergo kinetic resolution with benzyl thiol at 0 °C or at room temperature and the remaining sulfonamides are recovered in moderate to excellent yields and with excellent ee.

Full text of DOI:10.1039/c1cc16630a

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 898–900
www.rsc.org/chemcomm
COMMUNICATION
Catalytic asymmetric cleavage of sp3 C–N bonds for access to highly
enantioenriched N-benzylic sulfonamidesw
Xue-Song Wu and Shi-Kai Tian*
Received 26th October 2011, Accepted 18th November 2011
DOI: 10.1039/c1cc16630a
In the presence of 10 mol% of a chiral phosphoric acid, a variety
of racemic N-benzylic sulfonamides having N-(3-indolyl)methyl
groups smoothly undergo kinetic resolution with benzyl thiol at
0 8C or at room temperature and the remaining sulfonamides are
recovered in moderate to excellent yields and with excellent ee.
having N-(3-indolyl)methyl groups with excellent ee through a
chiral phosphoric acid-catalyzed kinetic resolution of the
corresponding racemic compounds with benzyl thiol.8
Previously we found that thiols could serve as highly reactive
nucleophiles to couple with various N-benzylic sulfonamides in
the presence of TMSCl/ZnCl2 catalyst at room temperature.6a
Our continued studies showed that the alkylation of thiols with
N-benzylic sulfonamides having N-(3-indolyl)methyl groups
could be efficiently catalyzed by weaker acids such as organic
phosphoric acids. For example, the reaction of sulfonamide
1a with benzyl thiol (1.1 equiv.) proceeded smoothly in
the presence of 10 mol% of racemic phosphoric acid 3a
in 1,2-dichloroethane at room temperature to give thioether 2a
in 98% yield (eqn (1)). Consistent with an SN1 mechanism
proposed according to the stereochemical studies,6 kinetics studies
have shown that the reaction is first-order for both sulfonamide
1a and phosphoric acid 3a, and zero-order for benzyl thiol.9
Readily accessible N-benzylic sulfonamides are able to couple
with a range of nucleophiles, such as aromatics, active methylene
compounds, alkynes, thiols, sulfinic acids, and silanes, through
sp3 C–N bond cleavage under acidic conditions.1–6 The choice of
acidic catalyst highly depends on the nature of both N-benzylic
sulfonamides and nucleophiles. Stereochemical studies have
shown that the reaction proceeds in an SN1 manner and hence
requires sufficiently stable carbocations to be generated as
intermediates (Scheme 1).6 In addition, the acid-catalyzed sp3
C–N bond cleavage has been demonstrated to be reversible by the
fact that the optical purity of the remaining chiral sulfonamide
decreases during the reaction.6a
N-Benzylic sulfonamides having N-(3-indolyl)methyl groups
are highly reactive and their sp3 C–N bonds can be cleaved by
relatively weak acids.3,4 In 2008, Enders et al. reported a chiral
N-triflyl phosphoramide-catalyzed kinetic resolution of racemic
N-(3-indolyl)(aryl)methyl p-toluenesulfonamide with indole,
wherein the optical purity of the remaining sulfonamide was
found to be 66% ee when the conversion reached 55%.7 Later,
You et al. disclosed that a chiral phosphoric acid could catalyze
the kinetic resolution of racemic N-(3-indolyl)(phenyl)methyl
p-toluenesulfonamide with N-methyl indole and the sulfonamide
was recovered in 49% yield and with 35% ee.4b Based on the
mechanism depicted in Scheme 1, we envisioned that the
enantioselectivity could be improved by employing an appropriate
nucleophile, which was expected to reduce or even terminate the
reversible sp3 C–N bond cleavage by coupling quickly with
the carbocation once it was generated from the sulfonamide in
the presence of a chiral acid catalyst. Herein, we report a
convenient access to optically active N-benzylic sulfonamides
ð1Þ
Treatment of racemic sulfonamide 1a with benzyl thiol
(0.70 equiv.) and chiral phosphoric acid 3b (10 mol%) at
room temperature led to the formation of thioether 2a in
60% yield as a racemic form (Table 1, entry 1).10 Nevertheless,
remaining sulfonamide 1a was recovered in 36% yield and
with 98% ee.11 Encouraged by this result, a range of racemic
N-(3-indolyl)(phenyl)methyl sulfonamides were examined under
the same reaction conditions. Although the reaction rate was
significantly affected by the N-sulfonyl group, the remaining
Joint Laboratory of Green Synthetic Chemistry, Department of
Chemistry, University of Science and Technology of China,
Hefei, Anhui 230026, China. E-mail: tiansk@ustc.edu.cn;
Fax: +86 551-360-1592; Tel: +86 551-360-0871
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and copies of 1H NMR, 13C NMR,
and HPLC spectra for products. See DOI: 10.1039/c1cc16630a
Scheme 1 SN1 reaction of N-benzylic sulfonamides with nucleophiles.
c
898 Chem. Commun., 2012, 48, 898–900
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 1 Kinetic resolution of racemic N-(3-indolyl)(phenyl)methyl
sulfonamides with benzyl thiola,b
Table 2 Kinetic resolution of racemic N-benzylic sulfonamides with
benzyl thiola
Entry
R
1a–f*
Time/h
Yieldc (%)
eed (%)
1e
2
3
4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
2-MeC6H4
1-Naphthyl
Me
1a*
1b*
1c*
1d*
1e*
1f*
7.5
9
120
36
21
36
36
31
28
25
37
28
98
97
94
99
99
99
Temp/ Time/ Yieldb eec
Entry R1
R2
R3 1* 1C
h
(%)
(%)
5
6f
1d
2
Ph
H
H
H
H
H
H
H
H
H
H
5-MeO
5-Br
6-Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1e*
1g*
1h*
1i*
1j* 25
1k* 25
1l*
1m* 25
1n*
1o* 25
1p* 25
1q* 25
1r* 25
0
0
0
0
8
6
47
35
42
42
37
41
36
40
44
32
31
38
39
31
40
97
99
98
97
99
99
99
99
92
90
99
99
99
98
99
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-NCC6H4
4-O2NC6H4
2-MeC6H4
2-O2NC6H4
2-Thienyl
Cyclohexyl
Ph
a
Reaction conditions: racemic sulfonamide (0.10 mmol), benzyl thiol
(0.70 equiv.), phosphoric acid 3b (10 mol%), DCE (10 mL), rt.
3
4
26
55
11
16
19
16
14
3
3
9.5
9
5
8
b
5e
6e
7
Compounds 1a*, 1c*, and 1d* are known, and the absolute configuration
c
of the new products was assigned by analogy. Isolated yield.
d
e
Determined by chiral stationary phase HPLC analysis. Thioether
0
8e
9
f
2a was obtained in 60% yield as a racemic form. The reaction was
run in 4.0 mL of DCE at 0 1C.
0
10e
11
12
13
14f
15f
Ph
Ph
Ph
Ph
sulfonamides were recovered in moderate to good yields and
with excellent ee. Notably, the introduction of 1-naphthalene-
sulfonyl group to the substrate resulted in the best yield and
enantioselectivity (Table 1, entry 5, 37% yield and 99% ee).
The employment of phosphoric acid 3c instead of 3b as the
catalyst led to a faster kinetic resolution of racemic N-benzylic
sulfonamides having N-(3-indolyl)methyl groups. A range of
racemic N-(3-indolyl)methylic 1-naphthalenesulfonamides,
bearing a variety of functional groups such as alkoxy, halo,
cyano, and aromatic nitro, were subjected to the kinetic
resolution with benzyl thiol in the presence of 10 mol% of
phosphoric acid 3c at 0 1C or at room temperature, and the
remaining sulfonamides were recovered in good to excellent
yields and with excellent ee (Table 2). Notably, in the substrate
the R1 group could be an aryl, a heteroaryl, or an alkyl group,
the R2 group could be a hydrogen, a halo, or an alkoxy
group, and the R3 group could be a hydrogen or an alkyl
group. Although enantioenriched N-benzylic sulfonamides
having N-(3-indolyl)methyl groups have been reported to be
accessible through a chiral phosphoric acid-catalyzed Friedel–
Crafts alkylation of indoles with N-sulfonyl imines, the kinetic
resolution reaction affords higher ee when the R1 group in the
sulfonamide is an alkyl group.12 Moreover, our protocol is
unique in providing enantioenriched tertiary sulfonamides
(Table 2, entries 14 and 15).
Me 1s*
nPr 1t*
0
0
H
a
Reaction conditions: racemic sulfonamide (0.10 mmol), benzyl thiol
(0.70 equiv.), phosphoric acid 3c (10 mol%), DCE (6.7 mL), 0 1C or rt.
Isolated yield. Determined by chiral stationary phase HPLC
b
c
d
e
analysis. 10 mL of DCE was used. 2.0 mL of DCE was used.
f
20 mL of DCE was used.
to be recovered in a high yield and ee from the kinetic
resolution.13
ð2Þ
Our experimental results allow us to propose the transition
states shown in Fig. 1 to account for the stereochemical outcome,
though no direct evidence is available at present. The indole NH
moiety and the sulfonamide group of the substrate are tentatively
organized with the chiral phosphoric acid through hydrogen
bonding interactions,13 and hence the chiral phosphoric acid is
able to discriminate the two enantiomers of the substrate by
interacting with their R1 groups. In the case the R1 group suffers
steric repulsion from the chiral phosphoric acid (Fig. 1, TS2), the
corresponding sulfonamide enantiomer is subjected to slow sp3
C–N bond cleavage relative to the other enantiomer (Fig. 1, TS1)
and consequently can be recovered after the other enantiomer is
consumed by coupling with benzyl thiol.
To gain insight into the origin of enantioselectivity, the
reaction of racemic N-[3-(1-methylindolyl)](phenyl)methyl
p-toluenesulfonamide (1u) with benzyl thiol was carried out
in the presence of 10 mol% of phosphoric acid 3b at room
temperature (eqn (2)). In direct contrast to the reaction with
racemic sulfonamide 1a that bears an indole NH moiety
(Table 1, entry 1), this reaction proceeded much slower and
afforded very low enantioselectivity. This result clearly indicates
that the indole NH moiety is essential for the sulfonamide
In summary, we have provided a convenient access to highly
enantioenriched N-benzylic sulfonamides through catalytic
asymmetric cleavage of sp3 C–N bonds. In the presence of
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 898–900 899

View Article Online
4 (a) Q.-L. He, F.-L. Sun, X.-J. Zheng and S.-L. You, Synlett, 2009,
1111; (b) F.-L. Sun, X.-J. Zheng, Q. Gu, Q.-L. He and S.-L. You,
Eur. J. Org. Chem., 2010, 47.
5 Z.-Y. Jiang, C.-H. Zhang, F.-L. Gu, K.-F. Yang, G.-Q. Lai,
L.-W. Xu and C.-G. Xia, Synlett, 2010, 1251.
6 (a) C.-R. Liu, M.-B. Li, C.-F. Yang and S.-K. Tian, Chem.–Eur. J.,
2009, 15, 793; (b) C.-R. Liu, M.-B. Li, D.-J. Cheng, C.-F. Yang
and S.-K. Tian, Org. Lett., 2009, 11, 2543; (c) C.-R. Liu,
F.-L. Yang, Y.-Z. Jin, X.-T. Ma, D.-J. Cheng, N. Li and
S.-K. Tian, Org. Lett., 2010, 12, 3832; (d) B.-L. Yang and
S.-K. Tian, Chem. Commun., 2010, 46, 6180; (e) C.-F. Yang,
J.-Y. Wang and S.-K. Tian, Chem. Commun., 2011, 47, 8343;
(f) Z.-T. Weng, Y. Li and S.-K. Tian, J. Org. Chem., 2011,
76, 8095.
7 D. Enders, A. A. Narine, F. Toulgoat and T. Bisschops, Angew.
Chem., Int. Ed., 2008, 47, 5661.
8 Very few examples have been reported for the catalytic enantio-
selective stereoablative reactions that destroy stereogenic elements
of a molecule. For a review, see: J. T. Mohr, D. C. Ebner and
B. M. Stoltz, Org. Biomol. Chem., 2007, 5, 3571.
Fig. 1 Possible transition states for the chiral phosphoric acid-catalyzed
sp3 C–N bond cleavage.
10 mol% of a chiral phosphoric acid, a variety of racemic
N-benzylic sulfonamides having N-(3-indolyl)methyl groups
smoothly undergo kinetic resolution with benzyl thiol at 0 1C
or at room temperature and the remaining sulfonamides are
recovered in moderate to excellent yields and with excellent ee.
The reaction has been demonstrated to proceed in an SN1
manner on the basis of kinetics studies, which indicate that it is
first-order for both the sulfonamide and the phosphoric acid,
and zero-order for benzyl thiol.
9 For details, see the ESIw.
10 For reviews of asymmetric catalysis with chiral phosphoric acids,
see: (a) M. Terada, Synthesis, 2010, 1929; (b) M. Terada, Chem.
Commun., 2008, 4097; (c) T. Akiyama, Chem. Rev., 2007,
107, 5744. For pioneering reports, see: (d) T. Akiyama, J. Itoh,
K. Yokota and K. Fuchibe, Angew. Chem., Int. Ed., 2004, 43, 1566;
(e) D. Uraguchi and M. Terada, J. Am. Chem. Soc., 2004,
126, 5356.
11 Stereoselectivity factor (s = kfast/kslow) was not applied to evaluate
this reaction because it was found to vary with the conversion. For
reviews, see: (a) E. Vedejs and M. Jure, Angew. Chem., Int. Ed.,
2005, 44, 3974; (b) J. M. Keith, J. F. Larrow and E. N. Jacobsen,
Adv. Synth. Catal., 2001, 343, 5.
12 (a) Q. Kang, Z.-A. Zhao and S.-L. You, J. Am. Chem. Soc., 2007,
129, 1484; (b) F. Xu, D. Huang, C. Han, W. Shen, X. Lin and
Y. Wang, J. Org. Chem., 2010, 75, 8677; (c) C.-H. Xing,
Y.-X. Liao, J. Ng and Q.-S. Hu, J. Org. Chem., 2011, 76, 4125.
13 For related examples, see: (a) Y.-X. Jia, J. Zhong, S.-F. Zhu,
C.-M. Zhang and Q.-L. Zhou, Angew. Chem., Int. Ed., 2007,
46, 5565; (b) J.-H. Lin and J.-C. Xiao, Eur. J. Org. Chem., 2011,
4536; (c) D.-J. Cheng, H.-B. Wu and S.-K. Tian, Org. Lett., 2011,
13, 5636.
We are grateful for the financial support from the National
Natural Science Foundation of China (20972147 and
20732006) and the National Basic Research Program of China
(973 Program 2010CB833300).
Notes and references
1 H. Stamm, A. Onistschenko, B. Buchholz and T. Mall, J. Org.
Chem., 1989, 54, 193.
2 (a) K. H. Chung, J. N. Kim and E. K. Ryu, Tetrahedron Lett., 1994,
35, 2913; (b) M. R. Seong, H. J. Lee and J. N. Kim, Tetrahedron Lett.,
1998, 39, 6219; (c) H. J. Lee, M. R. Seong, H. N. Song and J. N. Kim,
Bull. Korean Chem. Soc., 1999, 20, 267; (d) K. Y. Lee, H. S. Lee,
H. S. Kim and J. N. Kim, Bull. Korean Chem. Soc., 2008, 29, 1441.
3 (a) J. Esquivias, R. Go
Chem., Int. Ed., 2006, 45, 629; (b) I. Alonso, J. Esquivias, R. Go
Arrayas and J. C. Carretero, J. Org. Chem., 2008, 73, 6401.
´
mez-Arraya
´
s and J. C. Carretero, Angew.
´
mez-
´
c
900 Chem. Commun., 2012, 48, 898–900
This journal is The Royal Society of Chemistry 2012