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

Article abstract of DOI:10.1016/j.tetasy.2010.06.034

A series of optically active cyclic trans-β-aryloxy alcohols have been obtained by non-enzymatic kinetic resolution of the corresponding racemic aryloxy cyclic alcohols using commercially available (S)-BINAP and NCS by S _N2 halogenation of a hydroxy group. The product, cis-β-aryloxy chlorides, was also obtained in optically active form with inversion of the stereochemistry.

Full text of DOI:10.1016/j.tetasy.2010.06.034

Tetrahedron: Asymmetry 21 (2010) 2177–2182
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Tetrahedron: Asymmetry
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Halogenative kinetic resolution of b-aryloxy cyclic alcohols: chiral
BINAP-mediated SN2 displacement of hydroxy groups by chlorides
with inversion of stereochemistry
*
E. A. Jaseer, I. Karthikeyan, 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-aryloxy alcohols have been obtained by non-enzymatic kinetic
resolution of the corresponding racemic aryloxy cyclic alcohols using commercially available (S)-BINAP
and NCS by SN2 halogenation of a hydroxy group. The product, cis-b-aryloxy chlorides, was also obtained
in optically active form with inversion of the stereochemistry.
Received 15 June 2010
Accepted 25 June 2010
Available online 23 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
a highly electron-withdrawing group such as a tosyl group on a
nitrogen or an electronegative oxygen atom instead of nitrogen
Enantiopure alcohols are very important structural units for the
synthesis of a wide range of natural products, chiral ligands, and
biologically active compounds.1 Recent efforts directed toward
the synthesis of biologically active molecules have pointed out
the need for a variety of chiral auxiliaries that are easy to synthe-
size. Among the various chiral auxiliaries, the cyclohexane-based
chiral auxiliaries2 such as (+) and (ꢀ)-menthol,3 (ꢀ)-8-phenylmen-
thol,4 (+) and (ꢀ)-trans-2-phenylcyclohexano15 are some of the
more commonly used chiral auxiliaries for asymmetric transforma-
tions. Since the structurally related trans-2-aryloxycyclohexan-1-ol
derivatives have also gained some interest as chiral auxiliaries in
organic synthesis, various methods have been developed for their
synthesis in enantiomerically pure form. Basavaiah et al. used pig
liver acetone powder (PLAP) for the enzymatic-enantioselective
hydrolysis of racemic trans-1-acetoxy-2-aryloxycyclohexanes to
produce the optically active trans-2-aryloxycyclohexan-1-ols and
their acetates in high enantiomeric purities.6 Non-enzymatic ki-
netic resolution (NKR) is a versatile and hence an attractive alterna-
tive for the enzymatic process. Herein, we report the first NKR of
racemic-2-aryloxy cyclic alcohols to produce both the optically ac-
tive recovered alcohol and the product chloride using chiral chlori-
nating agent.
at the b-position will provide cis-chloride with inversion of config-
uration.8 Herein, we report enantioselective non-enzymatic kinetic
resolution of b-aryloxy cyclic alcohols through SN2 displacement of
the hydroxy group by chlorides with commercially available chiral
BINAP and NCS, which produces both the optically active recovered
trans-aryloxy alcohols and cis-chloride with inversion of configura-
tion (Scheme 2).
2. Results and discussion
First, racemic trans-2-(4-chlorophenoxy)cyclohexanol ( )-trans-
1 was chosen as the model substrate and subjected to kinetic res-
olution with NCS and (S)-BINAP in CH2Cl2 at room temperature
(Scheme 3). After 24 h, 51% of optically active (ꢀ)-trans-b-2-
(4-chlorophenoxy) cyclohexanol (30% ee) and 18% of optically ac-
tive (ꢀ)-cis-b-1-chloro-4-(2-chlorocyclohexyloxy)benzene (35%
9
ee) were isolated. The selectivity factor s (k(fast)/k(slow)
)
is 2.7 at
46.2% conversion. The cis stereochemistry of the product (ꢀ)-
cis-2 was deduced from the coupling constant of the methine pro-
ton (dt, J = 8.0, 3.0 and 2.8 Hz) at 4.36 ppm (–CH–OAr) in the 1H
NMR spectrum. In this reaction, the slow reacting enantiomer
(ꢀ)-trans-1 was recovered with 30% ee. Here, the hydroxy group
of the (+)-enantiomer of the racemic aryloxy alcohol was selec-
tively replaced by a chloride ion through an SN2 reaction to
produce optically active cis-b-aryloxy chloride (ꢀ)-cis-2. The
trans-chloride was not observed in the reaction. During the reac-
tion and work-up procedure, the (S)-BINAP was converted to the
corresponding (S)-BINAPO and it was recovered in 92% yield with-
out any racemization,10 which can be reused after reduction.11
In order to improve the selectivity (s) of the kinetic resolution,
the reaction was screened with different solvents, temperatures,
Recently, we reported that the NKR of racemic trans-b-amino
alcohols by halogenation of a hydroxyl group using the chiral BIN-
AP and N-chlorosuccinimide (NCS) as the chlorinating agent.7 In
this kinetic resolution, the reaction produced racemic chloride
with trans stereochemistry through an aziridinium ion intermedi-
ate (through double SN2 reaction; Scheme 1). We found that having
* 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.2010.06.034

2178
E. A. Jaseer et al. / Tetrahedron: Asymmetry 21 (2010) 2177–2182
Cl
O
Cl
P
Cl
N
O
P
Me
Ph
N
SN2
(intramolecular)
2
SN
N
Me
Me
Ph
(intermolecular)
Ph
meso
( )-trans
( )-trans
Scheme 1. Halogenative kinetic resolution of ( )-b-amino alcohols with retention of configuration.
halogenative kinetic
resolution
OH
Cl
OH
+
OAr
OAr
inversion of configuration
through SN2 reaction
OAr
( )-trans
trans-recovered
cis-chloride
aryloxy alcohol
enantiomerically enriched
compounds
Scheme 2. Halogenative kinetic resolution of ( )-b-aryloxy cyclic alcohols with inversion of configuration.
(S)-BINAP (0.5 equiv.)
OH
Cl
Cl
Cl
+
OH
Cl
NCS (2 equiv.)
CH2Cl2, rt, 24h
O
O
O
( )-trans-1
(-)-cis-2
(-)-trans-1
18% yield
51% yield
35% ee
30% ee
s = 2.7 at C = 46.2%
recovery of (S)-BINAPO: 92% (>99.9% ee)
Scheme 3. HKR of trans-2-(4-chlorophenoxy)cyclohexanol ( )-trans-1.
and different ratios of (S)-BINAP and NCS; the results are summa-
rized in Table 1. Among the solvents examined, THF turned out to
be the solvent of choice as it provided a maximum of s = 2.9 at
C = 61.5% (entry 6). When the reaction temperature was increased
to 60 °C, the selectivity increased slightly to 3.0 (entry 7). Lowering
the temperature to 10 °C or ꢀ10 °C increased the selectivity to 3.7
and 3.6, respectively (entries 8 and 9). Next, the effect of the ratio
of chiral BINAP and NCS in the HKR of ( )-trans-2-(4-chlorophen-
oxy)cyclohexanol was carried out and it was observed that the
selectivity and conversion were highly dependent on the amount
of BINAP and NCS used. A maximum selectivity of 3.9 was obtained
when 0.4 equiv of (S)-BINAP and 0.9 equiv of NCS were used at
10 °C to room temperature (entry 14).
Using the optimized reaction conditions, a wide range of trans-
b-aryloxy-substituted cyclic alcohols were resolved and the results
are summarized in Table 2. trans-b-Aryloxy substituted- cyclohex-
anols with electron-withdrawing (entries 1–3 and 8) and electron-
releasing groups (entries 4–7) on the phenyl group were resolved
with moderate selectivities. The substrates with sensitive func-
tional groups, such as an acyl group at the para- and meta-positions
of the phenyl group, were resolved with selectivities of 4.6 and 3.7,
respectively. It was observed that when the substitution was a
methoxy group at the meta-position, the selectivity increased to
6.9 (entry 7). When the same methoxy group was present at the
para-position the selectivity was slightly reduced to s = 5.2 (entry
4). In all the reactions, the halogenative kinetic resolution provided
optically active cis-chloride (inversion of configuration) through
SN2 substitution reaction and in none of the cases was trans-
chloride (retention of configuration) isolated. In the cases of entries
2 and 4–7, the recovered trans-b-aryloxy cyclohexanols had
(1R,2R)-absolute stereochemistry.12 In these reactions, the (1S,2S)-
enantiomers of the racemates reacted faster than the (1R,2R)-enan-
tiomers and the (1R,2R)-enantiomers were recovered as unreacted
major enantiomers. Based on the same analogy, we assumed that
for entries 1, 3, and 8, the same (1S,2S)-enantiomers of the race-
mates reacted faster to give the corresponding cis-(1S,2R)-chlo-
rides as product.
3. Conclusion
In conclusion, we have demonstrated the enantioselective non-
enzymatic kinetic resolution of racemic trans-b-aryloxy cyclic alco-
hols using commercially available chiral BINAP and NCS. Using this
NKR, a wide range of trans-b-aryloxy-substituted cyclic alcohols
were resolved including trans-b-aryloxy alcohol having sensitive
groups such as acyl substitution. By substituting the electron-
withdrawing group such as aryloxy group instead of the elec-
tron-releasing amine, we were able to successfully prevent the
neighboring group participation to produce the optically active
cis-chlorides.
4. Experimental
4.1. General information
All the reactions were carried out in the reaction tubes under a
nitrogen atmosphere. All the solvents used in the experiments

E. A. Jaseer et al. / Tetrahedron: Asymmetry 21 (2010) 2177–2182
2179
Table 1
Optimization study of NKR of 2-(4-chlorophenoxy)cyclohexanol ( )-trans-1
OH
Cl
Cl
Cl
OH
Cl
(S)-BINAP, NCS
+
rt
O
O
O
( )-trans-1
(-)-cis-2
(-)-trans-1
Entry
Solvent
Molar ratio of
Time (h)
% eea
C (%)
s
alcohol/BINAP/NCS
Alcohol
Chloride
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DCM
Toluene
1,4-Dioxane
CHCl3
Benzene
THF
THF
THF
THF
THF
1:0.5:2
1:0.5:2
1:0.5:2
1:0.5:2
1:0.5:2
1:0.5:2
1:0.5:2
1:0.5:2
1:0.5:2
1:0.5:1
1:0.3:0.9
1:0.3:1
1:0.4:0.9
1:0.4:0.9
24
30
36
33
29
02
01
14
12
10
17
18
18
10
30
03
02
07
06
48
30
16
16
39
14
13
30
38
35
12
30
26
22
30
38
52
50
41
44
48
44
46
46.2
16.7
06.3
19.2
21.4
61.5
44.0
23.5
24.0
48.7
24.1
21.3
40.5
45.0
2.7
1.3
1.9
2.8
1.7
2.9
3.0b
3.7c
3.6d
3.4
3.0
3.2
3.4
3.9c
THF
THF
THF
THF
a
b
c
Determined by HPLC analysis using chiral columns.
Reaction temperature is 60 °C.
10 °C to rt.
ꢀ10 °C to rt.
d
were obtained from Merck, and dried by Vogel’s procedure. Reac-
tions were monitored by TLC plates (Silica Gel 60 F254, obtained
from Merck) using an appropriate mixture of ethyl acetate and
hexanes.
4.2.1. Spectroscopic data for recovered alcohol: 2-(4-
chlorophenoxy)cyclohexanol (Table 2, entry 1)
White solid; mp 84–86 °C; Rf 0.31 (10% ethyl acetate in hex-
anes); ½a 2D5
ꢁ
¼ ꢀ11:9 (c 0.5, CHCl3); IR (neat): 1237, 1488, 2861,
Product purification was done by using silica gel (100–
200 mesh) column chromatography using hexanes and ethyl
acetate mixture as eluent. (S)-BINAP and NCS were obtained from
Sigma-Aldrich company. Racemic aryloxy alcohols were synthe-
sized using the literature procedures.13 All the products were char-
acterized 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 melt-
ing point apparatus). 1H NMR spectra were reported relative to
Me4Si (d 0.0 ppm) or residual CHCl3 peak (d 7.26 ppm). 13C NMR
spectra were reported relative to CDCl3 (d 77.16 ppm). All yields
reported in this publication refer to isolated yields of com-
pounds. Enantioselectivities were determined by HPLC using JASCO
PU-2080 with Diacel chiral columns (ChiralPAK/Chiralcel AS-H,
OD-H, AD-H and OJ columns).
2935, 3414 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.22–1.46 (m,
;
4H), 1.70–1.81 (m, 2H), 2.05–2.15 (m, 2H), 2.58 (s, 1H), 3.66–3.74
(m, 1H), 3.94 (td, J = 9.2, 9.2, 4.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H),
7.22 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 24.0, 24.1,
29.2, 32.2, 73.5, 82.8, 117.8, 126.2, 129.5, 156.6; HRMS (ESI): m/z
calcd for C12H15O2NaCl [M+Na+]: 249.0658; found: 249.0652. The
enantiomeric excess (% ee) was determined to be 38% by HPLC
using Diacel Chiralcel OJ column (3% i-PrOH/hexanes, 1 mL/min,
220 nm). Retention time: 14.900 min (minor); 12.850 min (major).
4.2.2. Spectroscopic data for product: 1-chloro-4-(2-
chlorocyclohexyloxy)benzene (Table 2, entry 1)
Colorless viscous liquid; Rf 0.51 (5% ethyl acetate in hexanes);
½
a 2D5
ꢁ
¼ ꢀ10:2 (c 1.0, CHCl3); IR (neat): 823, 971, 1056, 1236,
1487, 1594, 2864, 2360 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.34–
;
1.51 (m, 2H), 1.65–1.93 (m, 4H), 1.98–2.09 (m, 1H), 2.10–2.21
(m, 1H), 4.29–4.34 (m, 1H), 4.36 (dt, J = 8.0, 3.0, 2.8 Hz, 1H), 6.91
(d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d 21.8, 22.2, 27.6, 32.1, 60.9, 77.7, 118.5, 126.6, 129.6,
156.2; HRMS (ESI): m/z calcd for C12H15OCl2 [M+H+]: 245.0500;
found: 245.0498. The enantiomeric excess (% ee) was determined
to be 46% by HPLC using Diacel Chiralcel OJ column (3% i-PrOH/
hexanes, 0.35 mL/min, 220 nm). Retention time: 19.967 min (min-
or); 22.100 min (major).
4.2. General procedure for the halogenative kinetic resolution
of racemic b-aryloxy cyclic alcohols
trans-2-(4-Chlorophenoxy)cyclohexanol ( )-trans-1 (56.7 mg,
0.25 mmol), N-chlorosuccinimide (30.0, 0.225 mmol), and (S)-
BINAP (62.3 mg, 0.1 mmol) were taken in a 10 mL reaction tube
capped with a septum. The tube was evacuated and back-filled
with nitrogen. Dry THF (2 mL) was added to the reaction mixture
at room temperature. The reaction mixture was stirred at 10 °C
to rt until 50–60% completion of the reaction had taken place
(monitored by TLC). After that, the solvent was evaporated by
rotary evaporator. The crude residue was purified by silica gel
column chromatography to provide the corresponding cis-chloride
(28.9 mg, 51%) and the recovered trans-alcohol (20.2 mg, 33%). The
enantiopurity of the product and recovered phenoxy alcohols was
measured by HPLC using chiral column.
4.2.3. 2-(4-Bromophenoxy)cyclohexanols6 (Table 2, entry 2)
White solid; mp 92–94 °C; Rf 0.58 (30% ethyl acetate in hexane);
½
a 2D5
ꢁ
¼ ꢀ7:4 (c 1.0, acetone); IR (neat): 1237, 1484, 2860, 2932,
3388 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.22–1.46 (m, 4H),
;
1.70–1.80 (m, 2H), 2.06–2.14 (m, 2H), 2.31 (br s, 1H), 3.67–3.74
(m, 1H), 3.91–3.98 (m, 1H), 6.83 (d, J = 9.2 Hz, 2H), 7.36 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 24.0, 24.1, 29.2,

2180
E. A. Jaseer et al. / Tetrahedron: Asymmetry 21 (2010) 2177–2182
Table 2
NKR of various ( )-trans-b-aryloxy cyclohexanols with (S)-BINAP and NCS
Cl
OH
OH
(S)-BINAP-NCSa
+
THF, 10 ºC-rt
OAr
( )-trans
OAr
OAr
(1S,2R)-cis
(1R,2R)-trans
Entry
Substrates
Time (h)
C (%)
Yieldb (%)
% eec
s
Alcohol
51
Chloride
Alcohol
38
Chloride
46
OH
Cl
Br
O
1
2
10
50
45.0
36.3
33
3.9
O
OH
59
67
35
18
26
14
46
60
3.5d,e
O
OH
3
20
19.0
4.6
O
O
OH
4
5
24
50
47.5
40.5
44
52
35
40
48
34
53
50
5.2e
O
OH
4.2d,e
O
OH
6
7
43
52
23.5
19.5
45
65
21
19
19
17
62
70
5.4e
6.9e
O
OH
O
O
OH
8
50
29.6
40
25
21
50
3.7d
O
O
a
b
c
Molar ratio of alcohol/BINAP/NCS = 1.0:0.4:0.9.
Isolated yield.
Determined by HPLC analysis using chiral columns.
Reaction carried out at room temperature.
d
e
Absolute configuration for recovered alcohol is determined as (1R,2R) by comparing its sign of specific rotation with the literature value.
32.2, 73.5, 82.8, 113.6, 118.3, 132.5, 157.2; HRMS (ESI): m/z calcd
for C12H15O2BrNa [M+Na+]: 293.0153; found: 293.0150. The enan-
tiomeric excess (% ee) was determined to be 26% by HPLC using
Diacel Chiralcel OJ column (3% i-PrOH/hexanes, 1 mL/min,
220 nm). Retention time: 17.350 min (minor); 14.758 min (major).
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 21.8, 22.2, 27.6, 32.1,
60.9, 77.4, 113.9, 118.9, 132.5, 156.7; HRMS (ESI): m/z calcd for
C
excess (% ee) was determined to be 46% by HPLC using Diacel Chiral-
cel OJ column (3% i-PrOH/hexanes, 0.2 mL/min, 220 nm). Retention
time: 37.567 min (minor); 40.333 min (major).
12H15BrClO [M+H+]: 287.9901; found: 287.9901. The enantiomeric
4.2.4. 1-Bromo-4-(2-chlorocyclohexyloxy)benzene (Table 2,
entry 2)
4.2.5. 1-(4-(2-Hydroxycyclohexyloxy)phenyl)ethanone (Table 2,
entry 3)
Pale yellowish viscous liquid; Rf 0.52 (5% ethyl acetate in hex-
anes); ½a 2D5
ꢁ
¼ ꢀ9:8 (c 1.0, acetone); IR (neat): 1487, 1594, 2864,
White solid; mp 125–126.5 °C ; Rf 0.32 (30% ethyl acetate in hex-
2360 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.35–1.51 (m, 2H), 1.65–
anes); IR (neat): 1259, 1597, 2935, 3434 cmꢀ1 1H NMR (400 MHz,
;
1.93 (m, 4H), 1.99–2.09 (m, 1H), 2.10–2.20 (m, 1H), 4.30–4.35 (m,
CDCl3):
d 1.27–1.49 (m, 4H), 1.73–1.82 (m, 2H), 2.07–2.20
1H), 4.37 (td, J = 8, 3.2, 3.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.38 (d,
(m, 2H), 2.53 (s, 1H), 2.55 (s, 3H), 3.71–3.79 (m, 1H), 4.08–4.16

E. A. Jaseer et al. / Tetrahedron: Asymmetry 21 (2010) 2177–2182
2181
(m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 9.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d 23.9, 24.0, 26.5, 29.2, 32.3, 73.3, 82.1, 115.5,
130.6, 130.8, 162.1, 196.9; HRMS (ESI): m/z calcd for C14H19O3
[M+H+]: 235.1334; found: 235.1330. The enantiomeric excess (%
ee) was determined to be 14% by HPLC using Diacel ChiralPAK AS-
H column (25% i-PrOH/hexanes, 1 mL/min, 220 nm). Retention time:
8.100 min (minor); 13.233 min (major).
2949 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.29 (s, 9H), 1.33–1.50
;
(m, 2H), 1.66–1.92 (m, 4H), 2.00–2.21 (m, 2H), 4.31–4.43 (m,
2H), 6.90 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d 22.0, 22.1, 27.7, 31.7, 32.2, 34.3, 61.2, 77.2,
116.5, 126.4, 144.4, 155.2; HRMS (ESI): m/z calcd for C16H23OClNa
[M+Na+]: 289.1335; found: 289.1340. The enantiomeric excess
(% ee) was determined to be 50% by HPLC using Diacel Chiralcel
OJ column (3% i-PrOH/hexanes, 0.35 mL/min, 220 nm). Retention
time: 17.733 min (minor); 25.567 min (major).
4.2.6. 1-(4-(2-Chlorocyclohexyloxy)phenyl)ethanone (Table 2,
entry 3)
White solid; mp 94.5 °C; Rf 0.48 (30% ethyl acetate in hexanes);
4.2.11. 2-(m-Tolyloxy)cyclohexanol6 (Table 2, entry 6)
IR (neat): 1254, 1601, 1659, 2860, 2942 cmꢀ1
;
1H NMR (400 MHz,
White solid; mp 69–70 °C; Rf 0.21 (5% ethyl acetate in hexanes);
CDCl3): d 1.38–1.53 (m, 2H), 1.69–1.98 (m, 4H), 2.04–2.24 (m, 2H),
2.55 (s, 3H), 4.32–4.38 (m, 1H), 4.56 (dt, J = 7.6, 2.8, 2.8 Hz, 1H),
6.99 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 9.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d 21.6, 22.4, 26.5, 27.7, 32.1, 60.7, 76.7, 115.9,
130.8, 130.9, 161.6, 196.8; HRMS (ESI): m/z calcd for C14H18O2Cl
[M+H+]: 253.0995; found: 253.0999. The enantiomeric excess (%
ee) was determined to be 60% by HPLC using Diacel ChiralPAK
AS-H (25% i-PrOH/hexanes, 0.5 mL/min, 220 nm). Retention time:
24.142 min (minor); 28.583 min (major).
½
a 2D5
ꢁ
¼ ꢀ10:4 (c 1.0, acetone); IR (neat): 1256, 1488, 1584, 1861,
3403, 2934 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.22–1.47 (m,
;
4H), 1.70–1.82 (m, 2H), 2.05–2.20 (m, 2H), 2.32 (s, 3H), 2.61 (s,
1H), 3.65–3.75 (m, 1H), 3.91–4.04 (m, 1H), 6.72–6.81 (m, 3H),
7.15 (t, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.6, 24.1,
24.2, 29.4, 32.2, 73.6, 82.3, 113.4, 117.4, 122.3, 129.4, 139.8,
158.1; HRMS (ESI): m/z calcd for C13H18O2Na [M+Na+]: 229.1204;
found: 229.1200. The enantiomeric excess (% ee) was determined
to be 19% by HPLC using Diacel Chiralcel OD-H column (3%
i-PrOH/hexanes, 1 mL/min, 220 nm). Retention time: 11.800 min
(minor); 8.383 min (major).
4.2.7. 2-(4-Methoxyphenoxy)cyclohexanols6 (Table 2, entry 4)
White solid; mp 78–80 °C; Rf 0.58 (30% ethyl acetate in hex-
anes); ½a 2D5
ꢁ
¼ ꢀ28:4 (c 1.0, MeOH); IR (neat): 1214, 1503, 2861,
4.2.12. 1-(2-Chlorocyclohexyloxy)-3-methylbenzene (Table 2,
entry 6)
2934, 3414 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.23–1.44 (m, 4H),
1.70–1.78 (m, 2H), 2.06–2.13 (m, 2H), 2.30 (br s, 1H), 3.65–3.73
(m, 1H), 3.77 (s, 3H), 3.80–3.88 (m, 1H), 6.82 (d, J = 9.2 Hz, 2H),
6.90 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 24.0, 24.1,
29.4, 32.2, 55.8, 73.6, 83.8, 114.8, 118.3, 151.9, 154.5; HRMS (ESI):
m/z calcd for C13H19O3 [M+H+]: 223.1334; found: 223.1336. The
enantiomeric excess (% ee) was determined to be 48% by HPLC using
Diacel Chiralcel OD-H column (3% i-PrOH/hexanes, 1 mL/min,
220 nm). Retention time: 15.033 min (minor); 13.350 min (major).
Colorless liquid; Rf 0.61 (5% ethyl acetate in hexanes);
½
a 2D5
ꢁ
¼ ꢀ7:4 (c 0.5, MeOH); IR (neat): 690, 770, 1059, 1154, 1256,
1447, 1487, 1583, 1601, 2861, 2940 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d 1.25–1.42 (m, 2H), 1.57–1.84 (m, 4H), 1.92–2.12 (m,
2H), 2.24 (s, 3H), 4.24–4.28 (m, 1H), 4.31 (dt, J = 8, 2.8, 2.8 Hz,
1H), 6.66–6.74 (m, 3H), 7.07 (t, J = 8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 21.6, 21.9, 22.1, 27.6, 32.1, 61.2, 76.9, 113.7, 118.0,
122.5, 129.3, 139.7, 157.5; HRMS (ESI): m/z calcd for C13H18OCl
[M+H+]: 225.1046; found: 225.1042. The enantiomeric excess (%
ee) was determined to be 62% by HPLC using Diacel Chiralcel OJ
column (3% i-PrOH/hexanes, 0.25 mL/min, 220 nm). Retention
time: 28.942 min (minor); 26.775 min (major).
4.2.8. 1-(2-Chlorocyclohexyloxy)-4-methoxybenzene (Table 2,
entry 4)
Pale yellowish liquid; Rf 0.38 (5% ethyl acetate in hexanes);
½
a 2D5
ꢁ
¼ ꢀ11:5 (c 1.0, MeOH); IR (neat): 1221, 1501, 2863,
2942 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.33–1.51 (m, 2H), 1.66–
;
4.2.13. 2-(3-Methoxyphenoxy)cyclohexanol6 (Table 2, entry 7)
1.91 (m, 4H), 1.97–2.16 (m, 2H), 3.77 (s, 3H), 4.24 (dt, J = 8.4, 3.2,
3 Hz, 1H), 4.31–4.38 (m, 1H), 6.82 (d, J = 9.2 Hz, 2H), 6.94 (d,
J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 22.0, 22.1, 27.7, 32.2,
55.8, 61.2, 78.8, 114.8, 119.1, 151.5, 154.8; HRMS (ESI): m/z calcd
for C13H18O2Cl [M+H+]: 241.0995; found: 241.0996. The enantio-
meric excess (% ee) was determined to be 53% by HPLC using Diacel
Chiralcel OJ column (3% i-PrOH/hexanes, 0.5 mL/min, 220 nm).
Retention time: 30.392 min (minor); 27.533 min (major).
White solid; mp 77–79 °C; Rf 0.32 (5% ethyl acetate in hexanes);
½
a 2D5
ꢁ
¼ ꢀ11:6 (c 1.2, MeOH); IR (neat): 1148, 1593, 2862, 2935,
3419 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.22–1.46 (m, 4H),
;
1.70–1.81 (m, 2H), 2.06–2.21 (m, 2H), 2.58 (d, J = 1.2 Hz, 1H),
3.66–3.75 (m, 1H), 3.79 (s, 3H), 3.93–4.04 (m, 1H), 6.51 (s, 1H),
6.52–6.57 (m, 2H), 7.17 (t, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 24.1, 24.1, 29.4, 32.2, 55.4, 73.6, 82.4, 103.0, 106.9,
108.6, 130.1, 159.3, 161.1; HRMS (ESI): m/z calcd for C13H18O3Na
[M+Na+]: 245.1154; found: 245.1151. The enantiomeric excess (%
ee) was determined to be 17% by HPLC using Diacel ChiralPAK
AS-H column (3% i-PrOH/hexanes, 1 mL/min, 220 nm). Retention
time: 13.217 min (minor); 14.442 min (major).
4.2.9. 2-(4-tert-Butylphenoxy)cyclohexanols6 (Table 2, entry 5)
White solid; mp 96–98 °C; Rf 0.20 (5% ethyl acetate in hexanes);
½
a 2D5
ꢁ
¼ ꢀ13:4 (c 1.0, acetone); IR (neat): 1244, 2859, 2941,
3302 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.23–1.49 (m, 13H),
;
1.70–1.82 (m, 2H), 2.06–2.23 (m, 2H), 2.30 (br s, 1H), 3.66–3.75
(m, 1H), 3.92–4.01 (m, 1H), 6.89 (d, J = 8.4 Hz, 2H), 7.29 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 24.1, 24.2, 29.5, 31.6,
32.2, 34.2, 73.7, 82.5, 116.0, 126.5, 144.2, 155.7; HRMS (ESI): m/z
calcd for C16H24O2Na [M+Na+]: 271.1674; found: 271.1669. The
enantiomeric excess (% ee) was determined to be 34% by HPLC using
Diacel ChiralPAK AS-H column (3% i-PrOH/hexanes, 0.4 mL/min,
220 nm). Retention time: 14.550 min (minor); 17.592 min (major).
4.2.14. 1-(2-Chlorocyclohexyloxy)-3-methoxybenzene (Table 2,
entry 7)
Colorless liquid; ½a D25
ꢁ
¼ ꢀ12:8 (c 1.0, MeOH); Rf 0.38 (5% ethyl
acetate in hexanes); IR (neat): 1148, 1593, 2862, 2941 cmꢀ1
;
1H
NMR (400 MHz, CDCl3): d 1.35–1.51 (m, 2H), 1.68–1.93 (m, 4H),
2.01–2.21 (m, 2H), 3.79 (s, 3H), 4.35–4.43 (m, 2H), 6.51–6.58 (m,
3H), 7.15–7.21 (m, 1H); 13C NMR (100 MHz, CDCl3): d 22.0, 22.1,
27.6, 32.2, 55.4, 61.1, 77.1, 103.5, 107.3, 108.9, 130.0, 158.8,
161.0; HRMS (ESI): m/z calcd for C13H18O2Cl [M+H+]: 241.0995;
found: 241.0996. The enantiomeric excess (% ee) was determined
to be 70% by HPLC using Diacel Chiralcel AD-H column (3%
i-PrOH/hexanes, 0.35 mL/min, 220 nm). Retention time: 15.083
min (minor); 15.975 min (major).
4.2.10. 1-tert-Butyl-4-(2-chlorocyclohexyloxy)benzene (Table 2,
entry 5)
Colorless liquid; Rf 0.64 (5% ethyl acetate in hexanes);
½
a 2D5
ꢁ
¼ ꢀ27:7 (c 1.2, acetone); IR (neat): 1238, 1507, 2865,

2182
E. A. Jaseer et al. / Tetrahedron: Asymmetry 21 (2010) 2177–2182
4.2.15. 1-(3-(2-Hydroxycyclohexyloxy)phenyl)ethanone
(Table 2, entry 8)
IIT-Madras, under the IRPHA scheme and ESI-MS facility under the
FIST programme.
Pale orange solid; mp 99.5–101.5 °C; Rf 0.38 (30% ethyl acetate
in hexanes); IR (neat): 1678, 1268, 2862, 2934, 3436 cmꢀ1 1H
;
References
NMR (400 MHz, CDCl3): d 1.25–1.49 (m, 4H), 1.72–1.81 (m, 2H),
2.07–2.19 (m, 2H), 2.59 (s, 3H), 2.62 (s, 1H), 3.70–3.79 (m, 1H),
4.03–4.13 (m, 1H), 7.12–7.17 (m, 1H), 7.36 (t, J = 8 Hz, 1H), 7.50–
7.56 (m, 2H); 13C NMR (100 MHz, CDCl3): d 24.0, 24.0, 26.8, 29.2,
32.3, 73.5, 82.5, 115.3, 121.5, 121.6, 129.8, 138.8, 158.3, 198.0;
HRMS (ESI): m/z calcd for C14H19O3 [M+H+]: 235.1334; found:
235.1336. The enantiomeric excess (% ee) was determined to be
21% by HPLC using Diacel ChiralPAK AS-H column (25% i-PrOH/
hexanes, 1 mL/min, 220 nm). Retention time: 5.750 min (minor);
6.942 min (major).
1. For the synthesis and application of enantiopure alcohols, see: (a) Ojima, I.
Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: NewYork, 2000; (b)
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.. In Comprehensive Asymmetric
Catalysis; Springer: Berlin, 1999; Vol. 1–3.
2. Whitesell, J. K. Chem. Rev. 1992, 92, 953–964.
3. Misumi, A.; Iwanaga, K.; Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107,
3343–3345.
4. Whitesell, J. K.; Bhattacharya, A.; Henke, K. J. Chem. Soc., Chem. Commun. 1982,
988–989.
5. (a) Whitesell, J. K.; Chenn, H. H.; Lawrence, R. M. J. Org. Chem. 1985, 50, 4663–
4664; (b) Greene, A. E.; Charbonnier, F.; Luche, M. J.; Moyano, A. J. Am. Chem.
Soc. 1987, 109, 4752–4753.
6. Basavaiah, D.; Krishna, P. R.; Bharathi, T. K. Tetrahedron: Asymmetry 1995, 6,
439–454.
7. Sekar, G.; Nishiyama, H. Chem. Commun. 2001, 1314–1315.
8. (a) Jaseer, E. A.; Naidu, A. B.; Kumar, S. S.; Rao, R. K.; Thakur, K. G.; Sekar, G.
Chem. Commun. 2007, 867–869; (b) Jaseer, E. A.; Sekar, G. Tetrahedron:
Asymmetry 2010, 21, 780–785.
4.2.16. 1-(3-(2-Chlorocyclohexyloxy)phenyl)ethanone (Table 2,
entry 8)
Colorless liquid; Rf 0.35 (5% ethyl acetate in hexanes); IR (neat):
1272, 1586, 1684, 2942 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.36–
;
1.54 (m, 2H), 1.69–1.97 (m, 4H), 2.02–2.23 (s, 2H), 2.59 (s, 1H),
4.32–4.38 (m, 1H), 4.51 (dt, J = 8, 2.8, 2.8 Hz, 1H), 7.16–7.21 (m,
1H), 7.35–7.43 (m, 1H), 7.52–7.58 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 21.8, 22.2, 26.9, 27.7, 32.2, 60.9, 77.2, 115.5, 122.0,
122.3, 129.9, 138.8, 157.9, 198.0; HRMS (ESI): m/z calcd for
9. Selectivity factor (s) = (rate of fast reacting enantiomer)/(rate of slow reacting
enantiomer).
(s) = kfast/kslow = ln[(1 ꢀ C)(1 ꢀ ee)]/ln[(1 ꢀ C)(1 + ee)]
Conversion % (C) = ee/(ee + ee0) ꢂ 100
ee = enantiomeric excess of the recovered amido alcohol.
ee0 = enantiomeric excess of the product chloride. For more information, see:
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–330.
10. (S)-BINAP bisoxide was recovered in 92% yield 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, 220 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.
C
14H17O2NaCl [M+Na+]: 275.0815; found: 275.0812. The enantio-
meric excess (% ee) was determined to be 50% by HPLC using Diacel
ChiralPAK AS-H (25% i-PrOH/hexanes, 0.5 mL/min, 220 nm). Reten-
tion time: 16.408 min (minor); 15.367 min (major).
Acknowledgments
11. 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.
12. Absolute configurations for the recovered alcohols were determined as (1R,2R)
by comparing their sign of its specific rotation with the literature values.
13. Tamami, B.; Iranpoor, N.; Rezaei, R. Synth. Commun. 2004, 34, 2789–2795.
We thank DST (Project No.: SR/S1/OC-06/2008) and CSIR, New
Delhi, for the financial support. E.A.J. and I.K. thank CSIR, New Delhi,
for the fellowship. We thank DST, New Delhi, for the funding to-
ward the 400 MHz NMR machine to the Department of Chemistry,