Halogenative kinetic resolution of β-amido alcohols: Chiral BINAP-mediated SN2 displacement of hydroxy groups by chlorides with inversion of stereochemistry

Article abstract of DOI:10.1016/j.tetasy.2010.04.011

A series of optically active cyclic trans-β-amido alcohols were obtained by the non-enzymatic kinetic resolution of the corresponding racemic amido alcohols using commercially available (S)-BINAP and NCS by S_N2 halogenation of the hydroxy group. The product, cis-β-amido chloride, was also obtained in optically active form with an inversion of stereochemistry.

Full text of DOI:10.1016/j.tetasy.2010.04.011

Tetrahedron: Asymmetry 21 (2010) 780–785
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Tetrahedron: Asymmetry
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Halogenative kinetic resolution of b-amido alcohols: chiral BINAP-mediated
SN2 displacement of hydroxy groups by chlorides with inversion of
stereochemistry
*
E. A. Jaseer, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of optically active cyclic trans-b-amido alcohols were obtained by the non-enzymatic kinetic res-
olution of the corresponding racemic amido alcohols using commercially available (S)-BINAP and NCS by
SN2 halogenation of the hydroxy group. The product, cis-b-amido chloride, was also obtained in optically
active form with an inversion of stereochemistry.
Received 4 February 2010
Accepted 1 April 2010
Available online 24 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
olution of racemic amino alcohols to produce optically active b-
amino chloride, we found that having a strong electron-withdraw-
Chiral b-amino alcohols are important structural elements for
the synthesis of a wide range of natural products, chiral ligands,
chiral auxiliaries and resolving reagents.1 It is evident from the bio-
logical study that chiral b-amino alcohol motifs are an ideal source
for a broad range of drug molecules used for the treatment of
numerous diseases such as hypertension, cardiac arrhythmia, angi-
na pectoris and open angle glaucoma.2 The most common methods
for the synthesis of this class of compounds are reduction of opti-
ing group on the amine will provide cis-chloride with inversion of
configuration.9 Herein, we report the enantioselective non-enzy-
matic kinetic resolution of amido alcohols through SN2 displace-
ment of the hydroxy group by halides with halogenating agents
in the presence of commercially available chiral diphosphine BIN-
AP and NCS which produces both optically active recovered trans-
amido alcohols and cis-chlorides with an inversion of configuration
(Scheme 2).
cally active
a
-amino acids3 and asymmetric ring-opening/amino-
lytic kinetic resolution of meso/racemic epoxides with amines.4
The kinetic resolution of b-amino alcohols through enzyme-cata-
lyzed acylation or deacylation is also one of the most efficient
methods for the synthesis of chiral b-amino alcohols.5 Non-enzy-
matic kinetic resolution (NKR) is an alternative for the enzymatic
process, which is particularly attractive and versatile. In contrast
to the large variety of enzymes and metallic catalysts reported
for the kinetic resolution (KR) of racemic amino alcohols over the
last decade,6 non-enzymatic kinetic resolution methods designed
for amino alcohols have rarely been reported. In recent years, some
effort has therefore been made to design non-enzymatic alterna-
tives and substantial progress has been made.7
Recently, we reported the NKR of racemic trans-b-amino alco-
hols by halogenation of the hydroxyl group using chiral BINAP
[(ꢀ)-2,20-bis(diphenylphosphino]-101-binaphthyl) and N-chloro-
succinimide (NCS) as the chlorinating agent.8 In this kinetic resolu-
tion, the reaction produces racemic chloride with trans
stereochemistry through an aziridinium ion intermediate (through
double SN2 reactions; Scheme 1). As part of our ongoing research
towards finding a suitable method for the halogenative kinetic res-
2. Results and discussion
First, we chose the racemic trans-N-(2-hydroxycyclohexyl)-4-
methylbenzenesulfonamide ( )-trans-1, as a model substrate and
subjected it to kinetic resolution with NCS and (S)-BINAP in CH2Cl2
at 60 °C (Scheme 3). After 4 h, 23% of optically active trans-b-amido
alcohol (30% ee) and 38% of optically active cis-b-amido chloride
(10% ee) were isolated. The selectivity factor s (k(fast)/k(slow)
10
)
is
1.5 at 75% conversion. In the reaction, the slow reacting enantio-
mer (1R,2R)-trans-1 was recovered with 30% ee.11 In this NKR,
the hydroxy group of the (S,S)-enantiomer of the racemic amido
alcohol was selectively replaced by a chloride ion through SN2
reaction to produce optically active cis-b-amido chloride, (1R,2S)-
cis-2. The cis-stereochemistry of the b-amido chloride (1R,2S)-cis-
2 was confirmed by comparing its 1H and 13C NMR values with
the literature reports.9,12 The trans-chloride was not observed
in the reaction. The strong electron-withdrawing nature of
sulfonamide group prevented the neighbouring group participa-
tion ability of the amino group which resulted in an optically active
cis-chloride with an inversion of stereochemistry. During the reac-
tion and work-up procedure, the (S)-BINAP was converted to the
corresponding (S)-BINAPO and was recovered in 94% yield without
any racemization13 which could be reused after reduction.14
* Corresponding author. Tel.: +91 44 2257 4229; fax: +91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.011

E. A. Jaseer, G. Sekar / Tetrahedron: Asymmetry 21 (2010) 780–785
781
Cl
O
Cl
P
Cl
N
O
P
Me
Ph
N
SN2
(intramolecular)
SN2
N
Me
Me
Ph
(intermolecular)
Ph
( )-trans
meso
( )-trans
Scheme 1. Halogenative kinetic resolution of ( )-b-amino alcohols with retention of configuration.
halogenating kinetic
OH
resolution
Cl
OH
+
inversion of configuration
through SN2 reaction
NHSO2Ar
( )-trans
n
NHSO2Ar
NHSO2Ar
n
n
trans-recovered
amido alcohol
cis-chloride
n = 0,1,2
enantiomerically enriched compounds
Scheme 2. Halogenative kinetic resolution of ( )-N-arylsulfonyl-substituted cyclic b-amino alcohols with an inversion of configuration.
DIOP, the selectivity dropped to 4.3 (entry 9). Next, we studied
the effect of the ratio of chiral BINAP and NCS in the NKR of racemic
trans-b-amido alcohol and we observed that the selectivity and
conversion were highly dependent on the amount of BINAP and
NCS used. Better selectivity was obtained when 0.75 equiv of (S)-
BINAP and 2 equiv of NCS were used (entry 4).
S)-BINAP (0.75 equiv.)
(
OH
Cl
NHTs
(1R,2S)-cis-2
38% yield
10% ee
OH
NCS (2 equiv.)
R
S
R
R
+
CH2Cl2, 60 o C, 4h
NHTs
NHTs
(1R,2R)-trans-1
23% yield
30% ee
(
)-trans -1
s = 1.5 at C = 75%
recovery of (S)-BINAPO = 94% (>99.9%ee)
Using the optimized reaction conditions, a wide range of trans-
b-N-arylsulfonyl-substituted cyclic alcohols was resolved and the
results are summarized in Table 2. trans-b-N-Arylsulfonyl-substi-
tuted cyclohexanols with electron-releasing groups (entries 2 and
3) and electron-withdrawing groups (entries 4–6) on the phenyl
group were resolved with moderate selectivities. Reducing the ring
size to a five-membered-alcohol or increasing the size to a seven-
membered ( )-trans-b-amido alcohol decreased the selectivity to
2.8 (entries 8 and 9). Racemic unsaturated cyclohexenol was also
resolved with s = 4.4 at C = 69.8% (60% ee for the recovered trans-
alcohol and 26% ee for the cis-chloride). In all of the reactions,
the halogenative kinetic resolution provided optically active cis-
chloride (inversion of configuration) through an SN2 substitution
Scheme 3.
In order to improve the selectivity (s) of the kinetic resolution,
the reaction was screened with different solvents, temperature
and different ratios of (S)-BINAP and NCS and the results are sum-
marized in Table 1. Among the solvents examined, THF turned out
to be the solvent of choice as it provided a maximum of s = 8.2 at
C = 58.5% (entry 4). Lowering the reaction temperature from
60 °C to room temperature caused the selectivity to decrease to
3.2 (entry 5). When the NKR was carried out with other commer-
cially available C2-symmetric diphosphine ligands such as (ꢀ)-
Table 1
Optimization study of NKR of N-(2-hydroxycyclohexyl)-4-methylbenzenesulfonamide ( )-trans-1
OH
Cl
OH
(S)-BINAP-NCS
+
NHTs
NHTs
NHTs
( )-trans-1
(1R,2S)-cis-2
(1R,2R)-trans-1
Entry
Solvent
Molar ratio of alcohol/BINAP/NCS
Temperature (°C)
Time (h)
C (%)
Yielda (%)
Alcohol Chloride
% eeb
Chloride
s
Alcohol
1
2
3
4
5
6
7
8
9
DCM
1,4-Dioxane
CHCl3
THF
THF
THF
THF
THF
THF
1:0.75:2
1:0.75:2
1:0.75:2
1:0.75:2
1:0.75:2
1:0.5:1
1:0.4:0.9
1:0.4:0.9
1:0.75:0.9
60
60
60
60
rt
60
60
rt
4
9
2
5
3
16
14
48
60
75.0
57.1
92.0
58.5
66.7
39.0
25.0
24.6
70.6
23
35
07
30
20
56
70
72
24
38
47
82
58
65
22
15
12
62
30
44
46
79
60
34
18
19
78
10
33
04
56
36
52
52
58
33
1.5
3.0
1.5
8.2
3.2
4.5
4.0
4.5
4.3c
60
a
b
c
Isolated yield.
Determined by HPLC analysis using chiral columns.
(ꢀ)-DIOP was used instead of (S)-BINAP.

782
E. A. Jaseer, G. Sekar / Tetrahedron: Asymmetry 21 (2010) 780–785
Table 2
NKR of various ( )-trans-N-arylsulfonyl cyclic b-amino alcohols with (S)-BINAP and NCSa
OH
OH
Cl
(S)-BINAP, NCS
+
º
THF, 60 C
NHSO2Ar
NHSO2Ar
NHSO2Ar
( )-trans
cis
trans
Entry
Substrate
Time (h)
C (%)
Yieldb (%)
Chloride
% eec
s
Alcohol
43
Alcohol
46
Chloride
36
OH
O
1
2
3
4
5
6
7
8
9
3
5
55.4
58.5
70.0
27.0
27.3
54.1
69.8
63.0
56.8
31
58
35
23
23
32
35
52
50
3.3
8.2
4.5
4.1
4.3
2.8
4.4
2.8
2.8
NHS
O
OH
O
30
29
71
69
45
29
36
36
79
63
20
21
38
60
29
42
56
27
54
56
32
26
17
32
NHS
O
OH
O
4
NHS
OMe
O
OH
O
10
10
2
NHS
Cl
O
OH
O
NHS
Br
O
OH
O
NHS
NO2
O
OH
O
2
NHS
O
OH
O
4
NHS
Br
O
OH
O
2
NHS
O
a
b
c
Molar ratio of alcohol/BINAP/NCS = 1.0:0.75:2.
Isolated yield.
Determined by HPLC analysis using chiral columns.
reaction and in none of the cases trans-chloride (retention of con-
figuration) was isolated.
we were able to successfully prevent neighbouring group partici-
pation ability of the amino group to produce optically active cis-
chlorides.
3. Conclusion
4. Experimental
In conclusion, we have demonstrated the enantioselective non-
enzymatic kinetic resolution of racemic trans-b-amido alcohols
using commercially available chiral BINAP and NCS. Using this
NKR, a wide range of trans-b-N-arylsulfonyl-substituted cyclic ami-
no alcohols was resolved including five-membered and seven-
membered trans-b-amino alcohol. By substituting a strong elec-
tron-withdrawing group such as a sulfonyl group on the amine,
4.1. General information
All reactions were carried out in reaction tubes under a nitrogen
atmosphere. All the solvents used in the experiments were ob-
tained from Merck and dried by Vogel’s procedure. Reactions were
monitored by TLC plates (Silica Gel 60 F254, obtained from Merck)

E. A. Jaseer, G. Sekar / Tetrahedron: Asymmetry 21 (2010) 780–785
783
using an appropriate mixture of ethyl acetate and hexanes. Product
4.2.3. N-(2-Hydroxycyclohexyl)benzenesulfonamide (Table 2,
entry 1)
purification was carried out by silica gel (100–200 mesh) column
chromatography using hexanes and ethyl acetate mixture as elu-
ent. (S)-BINAP, (ꢀ)-DIOP and NCS were obtained from the Sigma–
Aldrich company. Racemic amido alcohols were synthesized using
the literature procedures.15 All the products were characterized by
1H and 13C NMR (Bruker 400 MHz), FT-IR (Thermo Nicolet 6700),
mass spectra (Q-Tof micro hybrid quadruple time of flight mass
spectrometer) and melting points (Toshniwal melting point appa-
ratus). 1H NMR spectra were reported relative to Me4Si (d
0.0 ppm) or residual CHCl3 peak (d 7.26 ppm). 13C NMR were re-
ported relative to CDCl3 (d 77.16 ppm). All yields reported in this
publication refer to isolated yields of compounds. Enantioselectiv-
ities were determined by HPLC using JASCO PU-2080 with Diacel
chiral columns (ChiralPAK/Chiralcel AS-H, OD-H, AD-H and OJ
columns).
White solid, mp 80–82 °C; Rf 0.26 (in hexanes/ethyl acetate,
70:30 V/V); IR (neat): 3504, 3267, 2934, 2860, 1448, 1321, 1157,
1091, 689, 592 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.06–1.30 (m,
;
4H), 1.52–1.63 (m, 1H), 1.63–1.71 (m, 1H), 1.71–1.82 (m, 1H),
1.85–2.17 (m, 2H), 2.82–2.94 (m, 1H), 3.30 (td, J = 9.6, 9.2, 3.6 Hz,
1H), 4.70 (br s, 1H), 7.50–7.56 (m, 2H), 7.56–7.62 (m, 1H), 7.91
(d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 24.0, 24.8, 32.1,
33.6, 59.9, 73.5, 127.3, 129.3, 132.9, 140.6; HRMS (ESI): m/z calcd
for C12H18NO3S [M+H+]: 256.1007; found: 256.1006. The enantio-
meric excess (ee) was determined to be 46% by HPLC using Diacel
ChiralPAK AS-H column (30% i-PrOH/hexanes, 1 mL/min, 220 nm):
Retention time (minor, 14.108 min), Retention time (major,
11.950 min).
4.2.4. N-(2-Chlorocyclohexyl)benzenesulfonamide (Table 2,
entry 1)
4.2. General procedure for the halogenative kinetic resolution
of racemic amido alcohols
White solid, mp 110–111 °C; Rf 0.59 (in hexanes/ethyl acetate,
80:20 V/V); IR (neat): 3259, 3061, 2941, 2862, 1445, 1326, 1159,
trans-N-(2-Hydroxycyclohexyl)-4-methylbenzenesulfonamide
( )-trans-1 (67.3 mg, 0.25 mmol), N-chlorosuccinimide (66.8,
0.5 mmol) and (S)-BINAP (116.8 mg, 0.1875 mmol) were taken in
a 10 mL reaction tube capped with a septum. The tube was evacu-
ated and back-filled with nitrogen. Dry THF (2 mL) was added to
the reaction mixture at room temperature. The reaction mixture
was refluxed at 60 °C until 50–60% completion of the reaction
had taken place (monitored by TLC). The reaction mixture was then
allowed to cool to room temperature and the solvent was evapo-
rated by rotary evaporator. The crude residue was purified by silica
gel column chromatography to provide the corresponding cis-chlo-
ride (41.7 mg, 58%) and recovered trans-alcohol (20.2 mg, 30%).
The enantiopurity of the product and the recovered amido alcohols
were measured by HPLC using chiral column.
1091, 688 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.17–1.31 (m, 1H),
;
1.37–1.46 (m, 1H), 1.48–1.76 (m, 5H), 1.93–2.02 (m, 1H), 3.40–
3.51 (m, 1H), 4.12–4.21 (m, 1H), 4.96 (br s, 1H), 7.48–7.54 (m,
2H), 7.55–7.61 (m, 1H), 7.87–7.92 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 19.1, 24.4, 28.2, 33.2, 55.2, 64.1, 126.9, 129.3, 132.8,
141.6; HRMS (ESI): m/z calcd for
C
12H17NO2SCl [M+H+]:
274.0669; found: 274.0668. The enantiomeric excess (ee) was
determined to be 36% by HPLC using Diacel ChiralPAK AS-H col-
umn (30% i-PrOH/hexanes, 0.5 mL/min, 220 nm): Retention time
(minor, 20.008 min), Retention time (major, 17.083 min).
4.2.5. N-(2-Hydroxycyclohexyl)-4-methoxybenzenesulfonamide
(Table 2, entry 3)
Colourless viscous liquid; Rf 0.48 (50% ethyl acetate in hexane);
IR (neat): 3488, 3273, 2929, 2858, 1596, 1498, 1258, 1150, 834,
669 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.06–1.29 (m, 4H), 1.53–
;
4.2.1. Spectroscopic data for recovered alcohol: N-(2-hydroxycy-
clohexyl)-4-methylbenzenesulfonamide (Table 2, entry 2)
White solid, mp 121–122 °C (lit.11 120 °C); Rf 0.14 (in hexanes/
ethyl acetate, 80:20 V/V); IR (neat): 3481, 3273, 2934, 2861, 1519,
1.61 (m, 1H), 1.62–1.69 (m, 1H), 1.71–1.80 (m, 1H), 1.97–2.03
(m, 1H), 2.28 (s, 1H), 2.78–2.88 (m, 1H), 3.25–3.34 (m, 1H), 3.87
(s, 3H), 4.90 (s, 1H), 6.95–7.01 (m, 2H), 7.81–7.87 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 24.0, 24.8, 32.1, 33.6, 55.7, 59.8, 73.5,
114.5, 129.4, 132.1, 163.1; HRMS (ESI): m/z calcd for C13H20NO4S
[M+H+]: 286.1113; found: 286.1109. The enantiomeric excess
(ee) was determined to be 63% by HPLC using Diacel Chiralcel OJ
column (30% i-PrOH/hexanes, 1 mL/min, 220 nm): Retention time
(minor, 35.708 min), Retention time (major, 29.533 min).
1450, 1322, 1283, 1156, 1069, 912, 729 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d 1.03–1.28 (m, 4H), 1.48–1.57 (m, 1H), 1.58–1.71 (m,
2H), 1.94–2.03 (m, 1H), 2.40 (s, 3H), 2.80–2.89 (m, 1H), 3.01 (br
s, 1H), 3.31 (td, J = 9.6, 9.6, 4.4 Hz, 1H), 5.50 (br s, 1H), 7.29 (d,
J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d
21.6, 23.9, 24.7, 31.7, 33.4, 59.7, 73.2, 127.2, 129.8, 137.7, 143.6;
HRMS (ESI): m/z calcd for C13H20NO3S [M+H+]: 270.1164; found:
270.1172. The enantiomeric excess (% ee) was determined to be
79% by HPLC using Diacel Chiralcel OD-H column (10% i-PrOH/hex-
anes, 0.5 mL/min, 220 nm): retention time (minor, 21.842 min),
retention time (major, 25.942 min).
4.2.6. N-(2-Chlorocyclohexyl)-4-methoxybenzenesulfonamide
(Table 2, entry 3)
White solid, mp 99–100 °C; Rf 0.53 (in hexanes/ethyl acetate,
80:20 V/V); IR (neat): 3273, 2940, 2863, 1596, 1498, 1150 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.18–1.31 (m, 1H), 1.38–1.46 (m,
1H), 1.50–1.75 (m, 5H), 1.94–2.02 (m, 1H), 3.37–3.45 (m, 1H),
3.87 (s, 3H), 4.15–4.19 (m, 1H), 4.81 (d, J = 8.8 Hz, 1H), 6.96–7.00
(m, 2H), 7.80–7.84 (m, 2H); 13C NMR (100 MHz, CDCl3): d 19.2,
24.5, 28.3, 33.3, 55.1, 55.8, 64.1, 114.5, 129.2, 133.2, 163.1; HRMS
4.2.2. Spectroscopic data for product: N-(2-chlorocyclohexyl)-4-
methylbenzenesulfonamide (Table 2, entry 2)
White solid, mp 105–107 °C; Rf 0.66 (in hexanes/ethyl acetate,
80:20 V/V); IR (neat): 3273, 2940, 2863, 1150 cmꢀ1 1H NMR
;
(ESI): m/z calcd for
C
13H19NO3SCl [M+H+]: 304.0774; found:
(400 MHz, CDCl3): d 1.19–1.32 (m, 2H), 1.38–1.46 (m, 1H), 1.57–
1.60 (m, 1H), 1.60–1.64 (m, 1H), 1.64–1.76 (m, 2H), 1.94–2.03
(m, 1H), 2.43 (s, 3H), 3.38–3.48 (m, 1H), 4.13–4.19 (m, 1H), 4.80
(d, J = 9.2 Hz, 1H), 7.31 (d, J = 8 Hz, 2H), 7.76 (d, J = 8 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d 19.1, 21.7, 24.5, 28.3, 33.3, 55.1, 64.1,
127.0, 129.9, 138.6, 143.6; HRMS (ESI): m/z calcd for C13H19NO2SCl
[M+H+]: 288.0825; found: 288.0821. The enantiomeric excess (ee)
was determined to be 56% by HPLC using Diacel ChiralPAK AS-H
column (10% i-PrOH/hexanes, 1 mL/min, 220 nm): Retention time
(minor, 27.192 min), Retention time (major, 18.567 min).
304.0776. The enantiomeric excess (ee) was determined to be
27% by HPLC using Diacel ChiralPAK AS-H column (30% i-PrOH/
hexanes, 0.5 mL/min, 220 nm): Retention time (minor,
24.358 min), Retention time (major, 19.308 min).
4.2.7. 4-Chloro-N-(2-hydroxycyclohexyl)benzenesulfonamide
(Table 2, entry 4)
White solid, mp 138–140 °C; Rf 0.54 (in hexanes/ethyl acetate,
70:30 V/V); IR (neat): 3511, 3274, 2936, 2863, 1585, 1519, 1450,

784
E. A. Jaseer, G. Sekar / Tetrahedron: Asymmetry 21 (2010) 780–785
1159, 1085, 912, 735 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 1.07–1.32
(m, 4H), 1.53–1.79 (m, 3H), 1.96–2.05 (m, 1H), 2.69 (s, 1H), 2.83–
2.96 (m, 1H), 3.27–3.38 (m, 1H), 5.41 (br s, 1H), 7.48 (d,
J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 24.0, 24.7, 31.9, 33.7, 59.9, 73.2, 128.7, 129.5, 139.2, 139.4; HRMS
[M+Na+]: 323.0678; found: 323.0676. The enantiomeric excess
(ee) was determined to be 38% by HPLC using Diacel ChiralPAK
AS-H column (30% i-PrOH/hexanes, 0.7 mL/min, 220 nm): Reten-
tion time (minor, 21.325 min), Retention time (major, 23.258 min).
(ESI): m/z calcd for
C
12H17NO3SCl [M+H+]: 290.0618; found:
4.2.12. N-(2-Chlorocyclohexyl)-4-nitrobenzenesulfonamide
(Table 2, entry 6)
290.0616. The enantiomeric excess (ee) was determined to be
20% by HPLC using Diacel ChiralPAK AS-H column (30% i-PrOH/
hexanes, 1 mL/min, 220 nm): Retention time (minor, 12.583 min),
Retention time (major, 15.108 min).
White solid, mp 135–136 °C; Rf 0.73 (in hexanes/ethyl acetate,
80:20 V/V); IR (neat): 3297, 2942, 2866, 1529, 1349, 1165,
737 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.22–1.35 (m, 1H), 1.41–
;
1.49 (m, 1H), 1.50–1.62 (m, 2H), 1.66–1.77 (m, 3H), 1.97–2.06
(m, 1H), 3.49–3.59 (m, 1H), 4.18–4.24 (m, 1H), 5.13 (d, J = 8.8 Hz,
1H), 8.06–8.11 (m, 2H), 8.34–8.39 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 19.1, 24.3, 28.4, 33.2, 55.6, 63.8, 124.6, 128.2, 147.4,
150.2; HRMS (ESI): m/z calcd for C12H15N2O4SClNa [M+Na+]:
341.0339; found: 341.0334. The enantiomeric excess (ee) was
determined to be 32% by HPLC using Diacel ChiralPAK AS-H col-
umn (30% i-PrOH/hexanes, 1 mL/min, 220 nm): Retention time
(minor, 11.483 min), Retention time (major, 9.758 min).
4.2.8. 4-Chloro-N-(2-chlorocyclohexyl)benzenesulfonamide
(Table 2, entry 4)
White solid, mp 100–102 °C; Rf 0.56 (in hexanes/ethyl acetate,
80:20 V/V); IR (neat): 3278, 2939, 2864, 1330, 1160, 1083, 827,
752 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.12–1.26 (m, 1H), 1.32–
;
1.41 (m, 1H), 1.43–1.71 (m, 5H), 1.89–1.97 (m, 1H), 3.34–3.43
(m, 1H), 4.15–4.23 (m, 1H), 4.98 (s, 1H), 7.39–7.44 (m, 2H), 7.73–
7.78 (m, 2H); 13C NMR (100 MHz, CDCl3): d 19.1, 24.4, 28.3, 33.2,
55.3, 63.9, 128.4, 129.6, 139.3, 140.1; HRMS (ESI): m/z calcd for
C
12H16NO2SCl2 [M+H+]: 308.0279; found: 308.0276. The enantio-
4.2.13. N-(6-Hydroxycyclohex-3-enyl)-4-methylbenzenesulfon-
amide (Table 2, entry 7)
meric excess (ee) was determined to be 54% by HPLC using Diacel
ChiralPAK AS-H column (30% i-PrOH/hexanes, 0.5 mL/min,
220 nm): Retention time (minor, 18.658 min), Retention time (ma-
jor, 15.150 min).
Colourless viscous liquid; Rf 0.31 (30% ethyl acetate in hexane);
IR (neat): 3490, 3263, 3033, 2922, 1598, 1438, 1321, 1157, 1093,
664 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.86–1.97 (m, 1H), 1.99–
;
2.09 (m, 1H), 2.30–2.40 (m, 1H), 2.44 (s, 3H), 2.45–2.54 (m, 1H),
3.16–3.27 (m, 1H), 3.69 (td, J = 9.0, 8.8, 5.6 Hz, 1H), 4.75 (d,
J = 6 Hz, 1H), 5.42–5.48 (m, 1H), 5.51–5.57 (m, 1H), 7.32 (d,
J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 21.7, 31.9, 33.4, 55.5, 69.4, 124.1, 124.7, 127.3, 130.0, 137.5,
143.9; HRMS (ESI): m/z calcd for C13H18NO3S [M+H+]: 268.1007;
found: 268.1002. The enantiomeric excess (ee) was determined
to be 60% by HPLC using Diacel ChiralPAK AS-H column (30% i-
PrOH/hexanes, 1 mL/min, 220 nm): Retention time (minor,
9.883 min), Retention time (major, 11.775 min).
4.2.9. 4-Bromo-N-(2-hydroxycyclohexyl)benzenesulfonamide
(Table 2, entry 5)
White solid, mp 126–128 °C; Rf = 0.48 (in hexanes/ethyl acetate,
70:30 V/V); IR (neat): 3502, 3272, 2935, 2860, 1575, 1324, 1159,
1068, 739 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.08–1.35 (m, 4H),
;
1.56–1.65 (m, 1H), 1.65–1.73 (m, 1H), 1.77–1.86 (m, 1H), 1.97–
2.09 (m, 1H), 2.37 (s, 1H), 2.84–2.98 (m, 1H), 3.34 (td, J = 9.9, 9.8,
4.4 Hz, 1H), 5.18 (s, 1H), 7.66–7.70 (m, 2H), 7.78–7.82 (m, 2H);
13C NMR (100 MHz, CDCl3): d 24.0, 24.7, 32.1, 33.8, 60.0, 73.4,
127.9, 128.8, 132.6, 139.8; HRMS (ESI): m/z calcd for C12H17NO3SBr
[M+H+]: 334.0113; found: 334.0115. The enantiomeric excess (ee)
was determined to be 21% by HPLC using Diacel ChiralPAK AS-H
column (30% i-PrOH/hexanes, 1 mL/min, 220 nm): Retention time
(minor, 13.033 min), Retention time (major, 15.958 min).
4.2.14. N-(6-Chlorocyclohex-3-enyl)-4-methyl-benzenesulfon-
amide (Table 2, entry 7)
White solid, mp 100–101 °C; Rf 0.59 (in hexanes/ethyl acetate,
80:20 V/V); IR (neat): 3272, 3036, 2927, 1710, 1599, 1530, 1431,
1327, 1158, 1090, 913, 743 cmꢀ1 1H NMR (400 MHz, CDCl3): d
;
4.2.10. 4-Bromo-N-(2-chlorocyclohexyl)benzenesulfonamide
(Table 2, entry 5)
2.06–2.24 (m, 2H), 2.43 (s, 3H), 2.45–2.51 (m, 1H), 2.58–2.70 (m,
1H), 3.60–3.70 (m, 1H), 4.17–4.24 (m, 1H), 4.89 (d, J = 9.2 Hz,
1H), 5.46–5.53 (m, 1H), 5.53–5.61 (m, 1H), 7.31 (d, J = 8 Hz, 2H),
7.77 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 21.7, 28.8,
34.3, 52.3, 60.2, 122.4, 124.6, 127.1, 130.0, 138.4, 143.8; HRMS
(ESI): m/z calcd for C13H16NO2SClNa [M+Na+]: 308.0488; found:
308.0492. The enantiomeric excess (ee) was determined to be
26% by HPLC using Diacel ChiralPAK AS-H column (30% i-PrOH/
hexanes, 1 mL/min, 220 nm): Retention time (minor, 9.883 min),
Retention time (major, 11.775 min).
White solid, mp 120–122 °C; Rf = 0.79 (in hexanes/ethyl ace-
tate, 80:20 V/V); IR (neat): 3286, 2936, 2860, 1446, 1331, 1161,
1091, 826, 742 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.27–1.32
;
(m, 1H), 1.40–1.48 (m, 1H), 1.50–1.77 (m, 5H), 1.96–2.07 (m,
1H), 3.40–3.50 (m, 1H), 4.16–4.22 (m, 1H), 4.92 (d, J = 9.2 Hz,
1H), 7.63–7.67 (m, 2H), 7.73–7.77 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 19.1, 24.4, 28.3, 33.2, 55.3, 64.0, 127.8, 128.5, 132.6,
140.7; HRMS (ESI): m/z calcd for
C
12H16NO2SClBr [M+H+]:
351.9774; found: 351.9777. The enantiomeric excess (ee) was
determined to be 56% by HPLC using Diacel ChiralPAK AS-H col-
umn (30% i-PrOH/hexanes, 0.5 mL/min, 220 nm): Retention time
(minor, 19.250 min), Retention time (major, 15.658 min).
4.2.15. 4-Bromo-N-(2-hydroxycyclopentyl)benzenesulfonamide
(Table 2, entry 8)
Pale grey solid, mp 83–84 °C; Rf 0.33 (in hexanes/ethyl acetate,
70:30 V/V); IR (neat): 3490, 3263, 2957, 1575, 1470, 1324, 1154,
4.2.11. N-(2-Hydroxycyclohexyl)-4-nitrobenzenesulfonamide
(Table 2, entry 6)
1090, 1068, 738, 608 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.29–
;
1.42 (m, 1H), 1.49–1.73 (m, 3H), 1.86–2.05 (m, 2H), 2.39 (s, 1H),
3.21–3.30 (m, 1H), 4.04 (q, J = 6.8 Hz, 1H), 5.01 (s, 1H), 7.64–7.69
(m, 2H), 7.74–7.79 (m, 2H); 13C NMR (100 MHz, CDCl3): d 20.1,
30.1, 31.7, 62.1, 78.5, 128.0, 128.9, 132.6, 139.1; HRMS (ESI): m/z
calcd for C11H15NO3SBr [M+H+]: 319.9956; found: 319.9959. The
enantiomeric excess (ee) was determined to be 29% by HPLC using
Diacel ChiralPAK AS-H column (10% i-PrOH/hexanes, 0.4 mL/min,
220 nm): Retention time (minor, 63.800 min), Retention time (ma-
jor, 59.858 min).
White solid, mp 162–163 °C; Rf = 0.57 (in hexanes/ethyl acetate,
50:50 V/V); IR (neat): 3523, 3288, 3105, 2934, 2863, 1528, 1350,
1162, 737 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.14–1.31 (m, 4H),
;
1.62–1.66 (m, 1H), 1.66–1.73 (m, 1H), 1.87–1.94 (m, 1H), 1.98–
2.06 (m, 1H), 2.09 (s, 1H), 2.90–3.00 (m, 1H), 3.28–3.38 (m, 1H),
5.02 (d, J = 5.2 Hz, 1H), 8.08–8.13 (m, 2H), 8.34–8.39 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 24.0, 24.6, 32.4, 34.1, 60.2, 73.4, 124.5,
128.6, 146.7, 150.2; HRMS (ESI): m/z calcd for C12H16N2O5SNa

E. A. Jaseer, G. Sekar / Tetrahedron: Asymmetry 21 (2010) 780–785
785
4.2.16. 4-Bromo-N-(2-chlorocyclopentyl)benzenesulfonamide
(Table 2, entry 8)
fellowship. We thank DST, New Delhi, for funding towards the
400 MHz NMR machine to the Department of Chemistry, IIT-Ma-
dras, under the IRPHA scheme and ESI-MS facility under the FIST
programme.
White solid, mp 82–83 °C; Rf 0.62 (in hexanes/ethyl acetate,
80:20 V/V); IR (neat): 3274, 2956, 1574, 1343, 1323, 1160, 1091,
900, 822, 734, 608, 556 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.59–
;
1.68 (m, 2H), 1.82–1.96 (m, 2H), 1.98–2.04 (m, 2H), 3.72–3.82
(m, 1H), 4.07–4.12 (m, 1H), 4.94 (d, J = 9.2 Hz, 1H), 7.64–7.68 (m,
2H), 7.74–7.78 (m, 2H); 13C NMR (100 MHz, CDCl3): d 19.2, 28.5,
33.4, 58.1, 64.8, 127.9, 128.7, 132.5, 140.1; HRMS (ESI): m/z calcd
for C11H14NO2SBrCl [M+H+]: 337.9617; found: 337.9624. The enan-
tiomeric excess (ee) was determined to be 17% by HPLC using Dia-
cel ChiralPAK AS-H column (30% i-PrOH/hexanes, 0.5 mL/min,
220 nm): Retention time (minor, 19.967 min), Retention time (ma-
jor, 17.117 min).
References
1. For reviews on asymmetric synthesis and the use of vicinal amino alcohols, see:
(a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576; (b) Ager, D. J.; Prakash, I.;
Schaad, D. R. Chem. Rev. 1996, 96, 835–875; (c) Kolb, H. C.; Sharpless, K. B. In
Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 1998; p 243.
2. (a) Teerlink, J.; Massie, B. Am. J. Cardiol. 1999, 84, 94–102; (b) Messerli, F. H.;
Grossman, E. Drugs 2001, 61, 1531–1533; (c) Ellison, K. E.; Gandhi, G. Drugs
2005, 65, 787–797; (d) Baran, D.; Horn, E. M.; Hryniewicz, K.; Katz, S. D. Drugs
2000, 60, 997–1016.
3. McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568–3571.
4. (a) Arai, K.; Salter, M. M.; Yamashita, Y.; Kobayashi, S. Angew. Chem., Int. Ed.
2007, 46, 955–957; (b) Arai, K.; Lucarini, S.; Salter, M. M.; Ohta, K.; Yamashita,
Y.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 8103–8111.
5. Sekar, G.; Kamble, R. M.; Singh, V. K. Tetrahedron: Asymmetry 1999, 10, 3663–
3666.
6. (a) Chayaporn, R.; Darrell, A. P.; Andrew, G. L.; Paul, C. T.; Jacob, L. I.; Mark, R. P.
Chem. Commun. 2007, 3462–3463; (b) Juan, D.; Vicente, G. J. Org. Chem. 2002,
67, 6816–6819; (c) Hari, M. R. G.; Deendayal, M.; Philip, D. S.; Max, Y.; Yong, G.
Chem. Commun. 2005, 4432–4434; (d) Oscar, P.; Jan-E, B. J. Org. Chem. 2001, 66,
4022–4025; (e) Andrei, P.; Dirk, D. V.; Pierre, J. Chem. Commun. 2005, 5307–
5309.
7. (a) Rajender, R. L.; Bhanumathi, N.; Rama, R. K. Chem. Commun. 2000, 2321–
2322; (b) Govindasamy, S.; Hisao, N. J. Am. Chem. Soc. 2001, 123, 3603–3604; (c)
Wang, Y. J.; Shen, Z. X.; Li, B.; Zhang, Y.; Zhang, Y. W. Chem. Commun. 2007,
1284–1286; (d) Dong, Y. M.; Li, R.; Lu, J.; Xu, X. N.; Wang, X. Y.; Hu, Y. F. J. Org.
Chem. 2005, 70, 8617–8620; (e) Tom, G. D.; Jason, R. H.; Woerpel, K. A. J. Am.
Chem. Soc. 2007, 129, 3836–3837.
4.2.17. N-(2-Hydroxycycloheptyl)-4-methyl-benzenesulfona-
mide (Table 2, entry 9)
White solid, mp 79–81 °C; Rf 0.45 (in hexanes/ethyl acetate,
70:30 V/V); IR (neat): 3526, 3262, 2929, 2861, 1598, 1445, 1321,
1153, 1092, 729, 662 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.19–
;
1.65 (m, 9H), 1.75–1.85 (m, 1H), 2.40 (s, 3H), 2.91 (br s, 1H),
2.96–3.05 (m, 1H), 3.48 (td, J = 8.4, 8.3, 3.2 Hz, 1H), 5.47 (d,
J = 6.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d 21.6, 22.1, 23.7, 27.3, 31.1, 32.9, 62.3,
76.2, 127.3, 129.9, 137.4, 143.6; HRMS (ESI): m/z calcd for
C
14H22NO3S [M+H+]: 284.1320; found: 284.1318. The enantiomeric
excess (ee) was determined to be 42% by HPLC using Diacel Chiral-
cel OD-H column (30% i-PrOH/hexanes, 1 mL/min, 220 nm): Reten-
tion time (minor, 4.942 min), Retention time (major, 5.592 min).
8. Govindasamy, S.; Hisao, N. Chem. Commun. 2001, 1314–1315.
9. Jaseer, E. A.; Naidu, A. B.; Kumar, S. S.; Rao, R. K.; Thakur, K. G.; Sekar, G. Chem.
Commun. 2007, 867–869.
10. Selectivity factor (s) = (rate of fast reacting enantiomer)/(rate of slow reacting
enantiomer.
4.2.18. N-(2-Chlorocycloheptyl)-4-methylbenzenesulfonamide
(Table 2, entry 9)
(s) = kfast/kslow = ln[(1 ꢀ C)(1 ꢀ ee)]/ln[(1 ꢀ C)(1 + ee)]
White solid, mp 98–99 °C; Rf 0.30 (in hexanes/ethyl acetate,
90:10 V/V); IR (neat): 3268, 2933, 2864, 1428, 1330, 1275, 1159,
Conversion% (C) = ee/(ee + ee0) ꢁ 100
ee = enantiomeric excess of the recovered amido alcohol.
751 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.33–1.43 (m, 1H), 1.46–
;
ee0 = enantiomeric excess of the product chloride. For more information, see:
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–330.
11. The absolute configuration was confirmed by comparing its sign of specific
1.67 (m, 5H), 1.68–1.99 (m, 4H), 2.42 (s, 3H), 3.47–3.55 (m, 1H),
4.24–4.29 (m, 1H), 4.97 (d, J = 8.85 Hz, 1H), 7.30 (d, J = 8.0 Hz,
2H), 7.75 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 21.6,
22.1, 23.8, 26.3, 31.1, 33.8, 58.7, 67.5, 127.0, 129.9, 138.2, 143.6;
HRMS (ESI): m/z calcd for C14H21NO2SCl [M+H+]: 302.0982; found:
302.0980. The enantiomeric excess (ee) was determined to be 32%
by HPLC using Diacel ChiralPAK AS-H column (30% i-PrOH/hex-
anes, 1 mL/min, 220 nm): Retention time (minor, 9.808 min),
Retention time (major, 8.550 min).
rotation with
a literature report. Schiffers, I.; Rantanen, T.; Schmidt, F.;
Bergmans, W.; Zani, L.; Bolm, C. J. Org. Chem. 2006, 71, 2320–2331.
12. Bhuyan, R.; Nicholas, K. M. Org. Lett. 2007, 9, 3957–3959.
13. (S)-BINAP bisoxide was recovered quantitatively when the crude reaction
mixture was kept overnight before column chromatography purification. The
ee was determined to be >99% by HPLC analysis with ChiralPAK AD-H column
(25% i-PrOH/hexanes, 0.5 mL/min, 254 nm): Retention time: only one peak at
9.538 min for (S)-BINAPO and no peak was observed at 12.062 min for (R)-
BINAPO.
14. For the deoxygenation of chiral BINAP bisoxide to BINAP without loss of
enantiomeric excess, see: (a) Takaya, H.; Akutagawa, S.; Noyori, R. Org.
Synth. 1988, 67, 20; (b) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.;
Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986,
51, 629–635.
Acknowledgements
We thank DST (Project No.: SR/S1/OC-06/2008) and CSIR, New
Delhi, for the financial support. E.A.J. thanks CSIR, New Delhi, for
15. (a) Huang, J.; O’Brien, R. Synthesis 2006, 425–434; (b) Chandrasekhar, S.;
Narsihmulu, C.; Sultana, S. Tetrahedron Lett. 2002, 43, 7361–7363.