Facile ionic liquid-mediated protocol for the regioselective synthesis of 1,5-benzothiazepines

Article abstract of DOI:10.1080/00397911.2010.493626

An efficient one-step ionic liquid-mediated green protocol for the regioselective synthesis of (+)=(±)-cis-2-(4-methoxy/benzyloxyphenyl)-3- hydroxy-2,3-dihydro-1,5- benzothiazepin-4-[5H]-ones has been developed from the reaction between substituted 2-aminobenzenethiol and methyl-(±)-trans-3- (4-methoxy/benzyloxy phenyl)glycidate, under nitrogen atmosphere, at 60±2 °C. The reaction has been performed in ionic liquids (viz, 1-butyl-3-methylimidazolium bromide/hexafluorophosphate), and the yields of the 1,5-benzothiazepine derivatives were found to be excellent. The cis-stereoisomer was obtained as the major product along with a trans-isomer as minor product.

Full text of DOI:10.1080/00397911.2010.493626

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Facile Ionic Liquid–Mediated Protocol
for the Regioselective Synthesis of 1,5-
Benzothiazepines
Renuka Jain a , Tripti Yadav a , Manoj Kumar a & Ashok K. Yadav a
a Department of Chemistry, University of Rajasthan, Jaipur, India
Version of record first published: 02 May 2011.
To cite this article: Renuka Jain , Tripti Yadav , Manoj Kumar & Ashok K. Yadav (2011): Facile
Ionic Liquid–Mediated Protocol for the Regioselective Synthesis of 1,5-Benzothiazepines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 41: 1889–1900, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.493626
FACILE IONIC LIQUID–MEDIATED PROTOCOL FOR
THE REGIOSELECTIVE SYNTHESIS OF
1,5-BENZOTHIAZEPINES
Renuka Jain, Tripti Yadav, Manoj Kumar, and
Ashok K. Yadav
Department of Chemistry, University of Rajasthan, Jaipur, India
GRAPHICAL ABSTRACT
Abstract An efficient one-step ionic liquid–mediated green protocol for the regioselective
synthesis of (þ)=(ꢀ)-cis-2-(4-methoxy/benzyloxyphenyl)-3-hydroxy-2,3-dihydro-1,5-
benzothiazepin-4-[5H]-ones has been developed from the reaction between substituted
2-aminobenzenethiol and methyl-(ꢀ)-trans-3-(4-methoxy/benzyloxy phenyl)glycidate,
under nitrogen atmosphere, at 60 ꢀ 2 ꢁC. The reaction has been performed in ionic liquids
(viz, 1-butyl-3-methylimidazolium bromide/hexafluorophosphate), and the yields of the
1,5-benzothiazepine derivatives were found to be excellent. The cis-stereoisomer was
obtained as the major product along with a trans-isomer as minor product.
Keywords Benzothiazepines; glycidate; green chemistry; ionic liquids; regioselectivity
INTRODUCTION
1,5-Benzothiazepines constitute an important class of privileged scaffolds as a
result of their immense chemotherapeutic applications, such as antibacterial,[1] anti-
cancer,[2] antihypertensive,[3] antifeedant,[4] analgesic,[5] anticonvulsant,[6] coronary
vasodilatory,[7] antidepressant,[8] central nervous system stimulant,[9] calcium chan-
nel blocker,[10] and platelate aggregation,[11] activities. Some notable pharmacologi-
cally important patented 1,5-benzothiazepin-4-ones include diltiazem,[12]
thiazesim,[13] and clentiazem.[14] Owing to their remarkable pharmacological activi-
ties, several approaches have been reported for the synthesis of 1,5-benzothiazepines
such as the reactions between 2-aminothiophenol(s) with a,b-unsaturated ketones[15]
or x-bromoacetophenone and aromatic aldehyde[16] or chalcone in the presence of
Received August 22, 2009.
Address correspondence to Ashok K. Yadav, Department of Chemistry, University of Rajasthan,
Jaipur-302055, India. E-mail: drakyada@yahoo.co.in
1889

1890
R. JAIN ET AL.
[17]
SiO2 or chalcone analogs of dehydroacetic acid,[18] a,b-unsaturated ketones with
bis(2-nitrophenyl)disulfide in presence of TiClO4=Sm,[19] 2-aminophenyldisulfide
with itaconic anhydride and dimethylitacone,[20] photochemical reaction of
2-phenylbenzothiazole with ethoxyacetylene=ethoxy propyne,[21] and the microwave-
activated reaction between 3-(40-fluoro-20-methylbenzoyl)-2-propenoic acid with
2-aminothiolphenol.[22]
Most of these methods have some drawbacks, such as long reaction time, high
temperature, poor yields, and use of volatile organic compounds and environmen-
tally hazardous solvents. Inspired by the biological profile of 1,5-benzothiazepines,
the applications of ionic liquids as ecofriendly solvent=catalytic system, and our
interest in developing efficient green methodology,[20] we herein report, for the first
time, a convenient regioselective one-step synthesis of cis-1,5-benzothiazepines in
ionic liquids, namely 1-butyl-3-methylimidazolium bromide [BMIM]Br and 1-butyl-
3-methylimidazolium hexafluorophosphate [BMIM]PF6.
RESULTS AND DISCUSSION
In our strategy, we have carried out the reaction between substituted 2-amino-
benzenethiols (viz., 2-aminobenzenethiol, 4=5=6-chloro-2-amino-benzenethiol,
6-fluoro-2-aminobenzenethiol, and 4-trifluoromethyl-2-aminobenzenethiol) with
methyl-(ꢀ)-trans-3-(4-methoxyo=benzyloxy phenyl) glycidate in an ionic liquid
(viz., [BMIM]Br and [BMIM]PF6). The reaction has been performed under a
nitrogen environment at 60 ꢀ 2 ꢁC. The products obtained were (þ)-cis-(2S,3S)-
2,3-dihydro-3-hydroxy-2-(40-methoxyphenyl)-1,5-benzo-thiazepin-4-[5H]-one 3a, (þ)-
cis-(2S,3S)-7-chloro-2,3-dihydro-3-hydroxy-2-(40-methoxyphenyl)-1,5-benzothiazepin-
4-[5H]-one 3b, (þ)-cis-(2S,3S)-8-chloro-2,3-dihydro-3-hydroxy-2-(40-methoxyphenyl)-
1,5-benzothiazepin-4-[5H]-one 3c, (þ)-cis-(2S,3S)-9-chloro-2,3-dihydro-3-hydroxy-
2-(40-methoxyphenyl)-1,5-benzothiazepin-4-[5H]-one 3d, (ꢀ)-cis-(2S,3S)-9-fluoro-
2,3-dihydro-3-hydroxy-2-(40-methoxyphenyl)-1,5-benzothiazepin-4-[5H]-one 3e, (ꢀ)-
cis-(2S,3S)-7-trifluoromethyl-2,3-dihydro-3-hydroxy-2-(40-methoxyphenyl)-1,5-ben-
zothiazepin-4-[5H]-one 3f, (ꢀ)-cis-(2S,3S)-2-(40-benzyloxyphenyl)-2,3-dihydro-3-
hydroxy-1,5-benzothiazepin-4-[5H]-one 3g, (ꢀ)-cis-(2S,3S)-2-(40-benzyloxy phenyl)
8-chloro-2,3-dihydro-3-hydroxy-1,5-benzothiazepin-4-[5H]-one 3i, and (ꢀ)-cis-(2S,3S)-
2-(40-benzyloxyphenyl)-7-trifluoro-2,3-dihydro-3-hydroxy-1,5-benzo-thiazepin-4-[5H]-
one 3j, respectively, as major products. The corresponding trans-isomers 4a-j were
isolated as minor products in each case.
The progress of the reaction was monitored by thin-layer chromatography
60
(TLC; Merck silica gel
F
254
aluminium sheets) in petroleum ether–ethyl acetate
(4:1), and it reached completion in 6–8 h. The separation of cis- and trans-isomers
was accomplished in petroleum ether–ethyl acetate (4:1) on a column of silica gel
G (60–120 mesh), and the yields of the products are presented (Scheme 1, Table 1).
The stereochemistry (i.e., cis- and trans-) of compounds 3a–j and 4a–j was
1
deduced from the H NMR vicinal compling constant between Cꢂ2 and C3ꢂ methine
protons, which showed 2JHH ¼ 6.4–7.2 Hz and 2JHH ¼ 8.3–10.2 Hz for cis- and trans-
isomers, respectively.
The observation of data (Table 1) reveals that the cis-3a–j were obtained in
76–90% yield in [BBIM]Br and in 82–95% yield in [BBIM]PF6. The better yield in

IONIC LIQUID–MEDIATED SYNTHESIS
1891
Scheme 1. Synthesis of 1,5-benzothiazepine derivatives.
the latter ionic liquid is perhaps a result of the change in lipophilicity=hydrophilicity
of ionic liquid resulting from a change in anion as [BBIM]BF4 is miscible in water,
whereas [BBIM]PF6 is immiscible in water.
In our study, we were unable to isolate threo- and erythro-esters as has
been done by Hashiyama et al.[24] These authors studied the oxirane ring opening
with 2-=4-nitrophenol=2-aminophenol and obtained the corresponding threo- and
erythro-esters in benzene, dioxan, ButOH, hexamethyl phosphoramide (HMPA),
and CH3CN. The effects of various catalyst, such as ZnCl2, BF3-Et2O, SnX2, and
SnX4, on yields of threo- and erythro esters have been investigated. In our method,
the ring opening of methyl-(ꢀ)-trans-(4-methoxy)=4-benzyloxy phenyl) glycidate
with substituted 2-aminothiophenol in [BBIM]Br=PF6 gave directly cis-3a–j as major
products along with trans-4a–j as minor products. This observation suggests that in
the ionic liquid, the oxirane ring opens stereoselectively, followed by subsequent
cyclization. Also, the time to complete the reaction in our case is 6–8 h, far less than
reported earlier:[24] 18–48 h.
Effect of Substituent on the Benzene Ring of trans-Phenylglycidate 2
A careful look at the data of Table 1 reveals that with the glycidate 2b the over-
all yields of 3a–j and 4a–j and also the stereoselectivity for the cis-isomer is better

1892
R. JAIN ET AL.
Scheme 2. Plausible mechanism of the reaction process.
than with glycidate 2a. This is probably because of the better electron-donating abil-
ity of 2b (due to benzyloxy substituent), thereby resulting in increased carbocationic
character of the benzylic carbon in the transition state. This observation is in agree-
ment with an earlier report.[24]
Effect of Substituents on Thiolphenols
An observation of Table 1 suggests that the total yields of compounds 3 and 4
and the cis-=trans-ratio obtained were dependent upon the electron-withdrawing
effect of the substituents attached to 2-aminothiophenols; the total yields of com-
pounds 3 and 4 in both ionic liquids follow the order 7-CF3 > 9-F=9-Cl > 8-Cl > 7-
Cl > H and 7-CF3 > 8-Cl > 7-Cl > H when the reaction was carried out with the

IONIC LIQUID–MEDIATED SYNTHESIS
1893
Table 1. Yield of 1,5-benzothiozepine derivatives 3 and 4
[BMIM]Br
[BMIM]PF6
Entry
X
R
Yield (%)a=Time (h)
cis=trans
Yield (%)a=Time (h)
cis=trans
1
2
H
7-Cl
8-Cl
9-Cl
9-F
OMe
OMe
OMe
OMe
OMe
OMe
OBz
72=8.0
80=7.5
82=7.5
84=7.0
84=6.5
86=6.5
76=7.5
80=7.0
82=7.0
88=6.0
76=24
82=18
84=16
86=14
86=14
90=10
82=18
85=15
86=14
90=10
78=7.5
85=7.0
86=7.0
88=6.5
90=6.5
94=6.0
80=7.5
85=7.0
88=6.5
94=6.0
82=18
88=12
90=10
92=8
3
4
5
92=8
95=5
6
7-CF3
H
7
84=16
86=14
90=10
94=6
8
7-Cl
8-Cl
7-CF3
OBz
OBz
9
10
OBz
aTotal yield of cis and trans isomers (compounds 3 and 4).
Table 2. Recyclability data for products
Yield (%)=Time (h)
Products
Cycle
[BMIM]Br
[BMIM]PF6
3a þ 4a
3a þ 4a
3a þ 4a
3g þ 4g
3g þ 4g
3g þ 4g
0
1
2
0
1
2
72=8.0
70=8.0
68=8.0
76=7.5
72=7.5
70=7.5
78=7.5
75=7.5
72=7.5
80=7.5
78=7.5
75=7.5
corresponding substituted 2-aminothiophenol and glycidate 2a and 2b, respectively.
Furthermore, reaction between the 6-chloro=6-fluoro-2-aminothiophenol (entries 4
and 5 of Table 1) and glycidate 2a/2b gave better yields and stereoselectivity in com-
parison to the reaction between 4-chloro=5-chloro-2-aminothiophenol (entries 2 and
3 of Table 1) and glycidate 2a/2b, thereby indicating that no neighboring group
participation was involved in the reaction.
We have also investigated the recyclability of the ionic liquids for the overall
products (cis þ trans), and the results are presented in Table 2. These data clearly
suggest that the ionic liquids can be reused with significant success and thus offer
an attractive alternative methodology for the regioselective synthesis of 1,5-
benzothiazepines.
CONCLUSION
In conclusion, we have developed a regioselective one-pot synthesis of 1,5-
benzothiazepines at 60 ꢀ 2 ꢁC in environmentally friendly conditions in ionic liquids.
The simple experimental procedure, absence of catalyst, and the recyclability of
reaction media makes this procedure attractive for scale up.

1894
R. JAIN ET AL.
EXPERIMENTAL
Melting points of all the synthesized compounds were determined in open
capillary tubes and are uncorrected. Infrared (IR) spectra were recorded on a
1
Shimadzu Fourier transform (FT)–IR spectrometer using KBr pellets. H NMR
spectra were recorded on a Jeol AL 300-MHz NMR spectrometer in CDCl3 using
tetramethylsilane (TMS) as an internal standard (chemical shift in d ppm). 13C
NMR spectra were recorded on a Jeol AL 75.47-MHz NMR spectrometer in CDCl3
using TMS as an internal standard. The purity of each compound was checked by
60
TLC using silica-gel
F
254
aluminium sheets as adsorbent and visualization was
accomplished by iodine=ultraviolet light. Ionic liquids were prepared by a reported
method.[25] 2-Aminobenzenethiol, 2-amino-4-chlorobenzenethiol, and 2-amino-4-
trifluoromethylbenzenethiols were purchased from Sigma-Aldrich Co. Inc. Other
halogen substituted-2-aminobenzenethiols were synthesized according to the
reported method.[26] Methyl-(ꢀ)-trans-3-(4-methoxyphenyl)glycidate is commer-
cially available and purchased from Sigma-Aldrich Chemical Co. Inc., whereas
methyl-(ꢀ)-trans-3-(4-benzyloxyphenyl) glycidate was synthesized by the reaction
between 4-benzyloxybenzaldehyde and methyl chloroacetate in dioxane according
to the reported method.[27]
General Procedure for the Synthesis of 2,3-Dihydro-3-hydroxy-
2-(4’-methoxy/benzyloxyphenyl)-1,5-benzothiazepin-4-(5H)-one
(3 and 4)
Substituted 2-aminobenzenethiol (0.05 mol), methyl-(ꢀ)-trans-3-(4-methoxyl=
benzyloxyphenyl) glycidate (0.05 mol), and ionic liquid (5 mL) were taken in a
round-bottomed flask to carry out the reaction under a nitrogen atmosphere. The
contents of the flask were stirred magnetically at 60 ꢀ 2 ꢁC for 6–8 h. The progress
60
of the reaction was monitored by TLC plates (Merck silica-gel
F
aluminium
254
sheets) in petroleum ether–ethyl acetate (4:1), and visualization was accomplished
in iodine chamber=ultraviolet light. Upon completion of the reaction, water was
added to it and the organic mass was extracted with ethyl acetate (3 ꢃ 10 mL).
The combined organic layer was dried over anhydrous sodium sulfate and distilled
under reduced pressure (10 mm of Hg) to afford compounds 3 and 4. The organic
mixture was separated on a silica-gel column (60–120 mesh, 12’’) by eluting with
petroleum ether–ethyl acetate (4:1). Compound 3 (i.e., cis-isomer) was obtained first,
followed by compound 4 (i.e., trans-isomer). The ionic liquids were regenerated by
keeping then at 80 ꢀ 2 ꢁC (5 mm of Hg) and were reused for another cycle. The
characteristic data of the synthesized compounds are given.
Selected Data
(þ)-cis-(2S,3S)-2,3-Dihydro-3-hydroxy-2-(4’-methoxyphenyl)-1,5-benzo-
22
thiazepin-4-[5H]-one 3a. White solid, mp 200–202 ꢁC; ½aꢄD þ 116.6ꢁ (c 0.50 DMF);
IR (KBr, cmꢂ1) v: 3350, 3200, 3100, 1680, 1510, 1475; 1H NMR (CDCl3, 300 MHz) d
3.76 (s, 3H, –OCH3), 4.29 (dd, J ¼ 6.6 Hz and 6.4 Hz, 1H, C3-H), 4.74 (d, J ¼ 6.4 Hz,
1H, C2-H), 5.05 (d, J ¼ 6.6 Hz, 1H, -OH), 6.87–7.62 (m, 8H, Ar-H), 10.31 (s, 1H,

IONIC LIQUID–MEDIATED SYNTHESIS
1895
-NH); 13C NMR (CDCl3, 75.47 MHz) d 172.50, 160.25, 147.30, 136.10, 132.60,
132.04, 129.90, 128.60, 128.20, 126.40, 114.30, 70.40, 57.93, 55.50. Anal. calcd. for
C16H15NO3S: C, 63.75; H, 5.01; N, 4.64. Found: C, 63.90; H, 5.22, N, 4.52%.
22
(ꢂ)-trans-(2S,3R) Isomer 4a. Solid 196–198 ꢁC; ½aꢄD ꢂ 84.2ꢁ (c 1.0 DMF);
IR (KBr, cmꢂ1) v: 3500, 3160, 3030, 1690, 1515, 1475; 1H NMR (CDCl3,
300 MHz) d 3.72 (s, 3H, -OCH3), 4.07 (dd, J ¼ 10.2 Hz and 8.3 Hz, 1H, C3-H),
4.35 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.33 (d, J ¼ 8.3 Hz 1H, -OH), 6.83–7.56 (m, 8H,
Ar-H), 10.21 (s, 1H, -NH); 13C NMR (CDCl3, 75.47 MHz) d 173.20, 160.25,
147.45, 136.10, 132.45, 132.04, 129.80, 128.65, 128.20, 126.40, 114.25, 70.60, 57.93,
55.40. Anal. calcd. for C16H15NO3S: C, 63.75; H, 5.01; N, 4.64. Found: C, 63.85;
H, 5.28; N, 4.51%.
(þ)-cis-(2S,3S)-7-Chloro-2,3-dihydro-3-hydroxy-2-(4’-methoxyphenyl)-
22
1,5-benzothiazepin-4-[5H]-one 3b. Yellowish solid, mp 225–258 ꢁC; ½aꢄD þ 63.7ꢁ
1
(c 0.31 DMF); IR (KBr, cmꢂ1) v: 3350, 3170, 3100, 1680; H NMR (300 MHz,
CDCl3) d 3.79 (s, 3H, -OCH3), 4.32 (dd, J ¼ 6.6 Hz and 6.4 Hz, 1H, C3-H), 4.88 (b
d, J ¼ 6.6 Hz, 1H, -OH), 5.09 (d, J ¼ 6.4 Hz, 1H, C2-H), 6.80–7.60 (m, 7H, Ar-H),
10.25 (s, 1H, -NH); 13C NMR (CDCl3, 75.47 MHz) d 173.20, 160.30, 148.40,
137.40, 132.60, 132.40, 129.90, 128.90, 128.60, 126.50, 114.35, 72.40, 58.40, 55.50.
Anal. calcd. for C16H14ClNO3S: C, 57.20; H, 4.20; N, 4.17. Found: C, 57.42; H,
22
4.02; N, 4.35%. (–)-cis-(2R, 3R) Isomer 3b: ½aꢄD ꢂ 62.5 ꢁ (c 0.29 DMF), and other
data are identical with those of the (þ)-cis-(2S,3S) isomer.
(ꢀ)-trans-(2R,3S) Isomer 4b. Yellowish solid, mp 204–206 ꢁC; IR (KBr, cmꢂ1
)
v: 3480, 3190, 3090, 1685; 1H NMR (300 MHz, CDCl3) d 3.79 (s, 3H, -OCH3), 4.05 (dd,
J¼ 10.2 Hz and 8.3 Hz, 1H, C3-H), 4.74 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.29 (d, J ¼ 8.3 Hz,
1H, -OH), 6.78–7.55 (m, 7H, Ar-H), 10.15 (s, 1H, -NH); 13C NMR (CDCl3,
75.47 MHz) d 173.40, 160.20, 148.50, 137.45, 132.50, 132.30, 129.85, 128.90, 128.60,
126.50, 114.30, 72.45, 58.30, 55.50. Anal. calcd. for C16H14ClNO3S: C, 57.20; H,
4.20; N, 4.17. Found: C, 57.35; H, 4.01; N, 4.40.
(þ)-cis-(2S,3S)-8-Chloro-2,3-dihydro-3-hydroxy-2-(4’-methoxyphenyl)-
20
1,5-benzothiazepin-4-[5H]-one 3c. Yellowish solid, mp 232–234 ꢁC; ½aꢄD þ 91.1ꢁ (c
1
1.02 DMF); IR (KBr, cmꢂ1) v: 3350, 3180, 3100, 1680; EIMS m=z 335; H NMR
(300 MHz, CDCl3) d 3.78 (s, 3H, -OCH3), 4.37 (dd, J ¼ 6.6 Hz and 6.4 Hz, 1H,
C3-H), 4.90 (b d, J ¼ 6.6 Hz, 1H, -OH), 5.10 (d, J ¼ 6.4 Hz, 1H, C2-H), 6.80–7.58
(m, 7H, Ar-H), 10.21 (s, 1H, -NH); 13C NMR (CDCl3, 75.47 MHz) d 173.20,
160.30, 148.40, 140.62, 138.50, 134.40, 132.60, 129.90, 128.60, 126.50, 114.35,
72.40, 58.40, 55.50. Anal. calcd. for C16H14ClNO3S: C, 57.20; H, 4.20; N, 4.17%.
20
Found: C, 57.42; H, 4.36; N, 4.05. (–)-cis (2R,3R) Isomer (3c): ½aꢄD ꢂ 92 ꢁ (c 1.06
DMF), and other data are identical with those of the (þ)-cis-(2S, 3S) isomer 3c.
(ꢀ)-trans-(2R,3S) Isomer 4c. Yellowish solid, mp 184–185 ꢁC; IR (KBr, cmꢂ1
)
v: 3490, 3190, 3090, 1685; EIMS m=z 335; 1H NMR (300 MHz, CDCl3) d 3.78 (s, 3H,
-OCH3), 4.10 (dd, J ¼ 10.2 Hz and 8.3 Hz, 1H, C3-H), 4.60 (d, J ¼ 10.2 Hz, 1H, C2-
H), 5.33 (d, J ¼ 8.3 Hz, 1H, -OH), 6.78–7.86 (m, 7H, Ar-H), 10.11 (s, 1H, -NH); 13C
NMR (CDCl3, 75.47 MHz) d 173.40, 160.20, 148.50, 140.62, 138.40, 134.50, 132.50,

1896
R. JAIN ET AL.
129.90, 128.60, 126.50, 114.30, 72.40, 58.30, 55.50. Anal. calcd. for C16H14ClNO3S:
C, 57.20; H, 4.20; N, 4.17. Found: C, 57.30; H, 4.32; N, 4.02%.
(þ)-cis-(2S,3S)-9-Chloro-2,3-dihydro-3-hydroxy-2-(4’-methoxyphenyl)-
20
1,5-benzothiazepin-4-[5H]-one 3d. Yellowish solid, mp 188–190 ꢁC; ½aꢄD 0ꢁ (c
1
0.27 DMF); IR (KBr, cmꢂ1) v: 3350, 3160, 3100, 1680, 1630; H NMR (300 MHz,
CDCl3) d 3.79 (s, 3H, -OCH3), 4.32 (dd, J ¼ 6.6 Hz and 6.4 Hz, 1H, C3-H), 4.88 (b
d, J ¼ 6.6 Hz, 1H, -OH), 5.09 (d, J ¼ 6.4 Hz, 1H, C2-H), 6.80–7.62 (m, 7H, Ar-H),
10.21 (s, 1H, -NH); 13C NMR (CDCl3, 75.47 MHz) d 173.20, 160.30, 148.30,
138.40, 132.50, 132.20, 129.80, 128.60, 128.20, 126.60, 114.30, 72.40, 58.40, 55.50.
Anal. calcd. for C16H14ClNO3S: C, 57.20; H, 4.20; N, 4.17. Found: C, 57.04; H,
3.96; N, 4.38%.
22
(–)-cis-(2R,3R) Isomer 3d. ½aꢄD 0ꢁ (c 0.27 DMF), and other data are identical
with those of (þ)-cis-(2S,3S) isomer 3d.
(ꢀ)-trans-(2R,3S) Isomer 4d. Yellowish solid, mp 196–198 ꢁC; IR (KBr, cmꢂ1
)
v: 3480, 3170, 3110, 1685, 1640; 1H NMR (300 MHz, CDCl3) d 3.79 (s, 3H, -OCH3),
4.07 (dd, J ¼ 10.2 Hz and 8.3 Hz, 1H, C3-H), 4.70 (b d, J ¼ 10.2 Hz, 1H, C2-H), 5.30
(d, J ¼ 8.3 Hz, 1H, -OH), 6.75–7.62 (m, 7H, Ar-H), 10.15 (s, 1H, -NH); 13C NMR
(CDCl3, 75.47 MHz) d 173.30, 160.75, 148.45, 138.30, 132.60, 132.20, 129.85,
128.70, 128.20, 126.60, 114.30, 72.50, 58.35, 55.50. Anal. calcd. for C16H14ClNO3S:
C, 57.20; H, 4.20; N, 4.17. Found: C, 57.45; H, 3.98; N, 4.35%.
(ꢀ)-cis-(2S,3S)-9-Fluoro-2,3-dihydro-3-hydroxy-2-(4’-methoxyphenyl)-
1,5-benzothiazepin-4-[5H]-one 3e. White solid, mp 218–220 ꢁC; IR (KBr, cmꢂ1
)
v: 3380, 3230, 3100, 1680, 1610; 1H NMR (300 MHz, CDCl3) d 3.31 (s, 3H, -OCH3),
4.32 (t, J ¼ 7.0 Hz, 1H, C3-H), 4.70 (d, J ¼ 7.0 Hz, 1H, -OH), 4.78 (d, J ¼ 7.0 Hz, 1H,
C2-H), 6.85–7.85 (m, 7H, Ar-H), 10.31 (s, 1H, -NH); 13C NMR (CDCl3, 75.47 MHz)
d 173.30, 160.40, 148.50, 146.40, 132.20, 129.80, 129.30, 128.60, 128.20, 126.90,
114.20, 72.50, 58.45, 55.40. Anal. calcd. for C16H14FNO3S: C, 60.15; H, 4.42; N,
4.38. Found: C, 60.42; H, 4.10; N, 4.62%.
(ꢀ)-trans-(2R,3S) Isomer 4e. White solid, mp 226–228 ꢁC; IR (KBr, cmꢂ1) v:
3500, 3260, 1685, 1640; 1H NMR (300 MHz, CDCl3) d 3.31 (s, 3H, -OCH3), 4.05 (dd,
J ¼ 10.2 Hz and 8.3 Hz, 1H, C3-H), 4.65 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.10 (d,
J ¼ 8.3 Hz, 1H, -OH), 6.70–7.75 (m, 7H, Ar-H), 10.21 (s, 1H, -NH); 13C NMR
(CDCl3, 75.47 MHz) d 173.40, 160.30, 148.55, 146.25, 132.20, 129.90, 129.30,
128.60, 128.25, 126.90, 124.30, 72.55, 58.50, 55.40. Anal. calcd. for C16H14FNO3S:
C, 60.15; H, 4.42; N, 4.38. Found: C, 60.45; H, 4.20; N, 4.58%.
(ꢀ)-cis-(2S,3S)-7-Trifluoromethyl-2,3-dihydro-3-hydroxy-2-(4’-methoxy-
phenyl)-1,5-benzothiazepin-4-[5H]-one 3f. White solid, mp 244–246 ꢁC; IR
1
(KBr, cmꢂ1) v: 3400, 3250, 1680, 1590; H NMR (300 MHz, CDCl3) d 3.85 (s, 3H,
-OCH3), 4.35 (dd, J ¼ 6.6 Hz and 6.4 Hz, 1H, C3-H), 4.90 (b d, J ¼ 6.6 Hz, 1H, -
OH), 5.12 (d, J ¼ 6.4 Hz, 1H, C2-H), 6.85–7.70 (m, 7H, Ar-H), 10.31 (s, 1H, -NH);
13C NMR (CDCl3, 75.47 MHz) d 174.50, 162.40, 147.25, 142.60, 138.40, 132.80,
132.60, 129.90, 128.80, 126.40, 114.20, 78.40, 72.60, 58.30, 55.40. Anal. calcd. for
C17H14F3NO3S: C, 55.26; H, 3.82; N, 3.79. Found: C, 55.05; H, 3.98; N, 4.10%.

IONIC LIQUID–MEDIATED SYNTHESIS
1897
(ꢀ)-trans-(2R,3S) Isomer 4f. White solid, mp 255–257 ꢁC; IR (KBr, cmꢂ1) v:
3480, 3260, 1690, 1640; 1H NMR (300 MHz, CDCl3) d 3.85 (s, 3H, -OCH3), 4.08 (dd,
J ¼ 10.8 Hz and 8.3 Hz, 1H, C3-H), 4.76 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.35 (d,
J ¼ 8.3 Hz, 1H, -OH), 6.80–7.85 (m, 7H, Ar-H), 10.25 (s, 1H, -NH); 13C NMR
(CDCl3, 75.47 MHz) d 174.60, 162.50, 147.20, 142.55, 138.50, 132.95, 132.55,
129.90, 128.80, 126.50, 114.20, 78.40, 72.60, 58.20, 55.50. Anal. calcd. for
C17H14F3NO3S: C, 55.26; H, 3.82; N, 3.79. Found: C, 55.10; H, 3.85; N, 4.05%.
(ꢀ)-cis-(2S,3S)-2-(4’-Benzyloxyphenyl)-2,3-dihydro-3-hydroxy-1,5-benzo-
thiazepin-4-[5H]-one 3g. White solid, mp 145–146 ꢁC; IR (KBr, cmꢂ1) v: 3400,
1
3250, 1680, 1240; H NMR (300 MHz, CDCl3) d 4.31 (b t, J ¼ 7.2 Hz 1H, C3-H),
4.88 (b d, J ¼ 7.2 Hz, 1H, -OH), 4.92 (d, J ¼ 7.2 Hz, 1H, C2-H), 5.05 (s, 2H,
-OCH2 -OBz), 6.98–7.70 (m, 13H, Ar-H), 10.31 (s, 1H, -NH); 13C NMR (CDCl3,
75.47 MHz) d 173.50, 167.50, 165.35, 145.30, 142.40, 138.70, 136.60, 136.20,
132.60, 132.40, 131.50, 129.90, 128.50, 126.20, 118.30, 70.40, 67.50, 58.40. Anal.
calcd. for C23H19NO4S: C, 68.11; H, 4.72; N, 3.45. Found: C, 68.45; H, 4.42; N,
3.60%.
(ꢀ)-trans-(2S,3R) Isomer 4g. White solid, mp 158–160 ꢁC; IR (KBr, cmꢂ1) v:
1
3480, 3300, 1690, 1260; H NMR (300 MHz, CDCl3) d 4.05 (dd, J ¼ 10.2 Hz and
8.3 Hz, 1H, C3-H), 4.75 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.05 (s, 2H, -OCH2, OBz),
5.28 (d, J ¼ 8.3 Hz, 1H, -OH), 6.90–7.80 (m, 13H, Ar-H), 10.21 (s, 1H, -NH); 13C
NMR (CDCl3, 75.47 MHz) d 173.60, 167.40, 165.40, 147.35, 142.40, 138.65,
136.50, 136.20, 132.60, 132.20, 131.60, 130.40, 129.80, 128.60, 126.25, 118.30,
70.40, 67.50, 58.50. Anal. calcd. for C23H19NO4S: C, 68.11; H, 4.72; N, 3.45. Found:
C, 68.35; H, 4.55; N, 3.58%.
(ꢀ)-cis-(2S,3S)-2-(4’-Benzyloxyphenyl)-7-chloro-2,3-dihydro-3-hydroxy-
1,5-benzothiazepin-4-[5H]-one 3h. Yellowish solid, mp 172–174 ꢁC; IR (KBr,
cmꢂ1) v: 3420, 3260, 1685, 1250; 1H NMR (300 MHz, CDCl3) d 4.35 (b t, J ¼ 7.2 Hz
1H, C3-H), 4.92 (d, J ¼ 7.2 Hz, 1H, C2-H), 5.08 (s, 2H, -OCH2, OBz), 5.12 (d,
J ¼ 7.2 Hz, 1H, -OH), 6.95–7.80 (m, 13H, Ar-H), 10.35 (s, 1H, -NH); 13C NMR
(CDCl3, 75.47 MHz) d 174.20, 167.80, 165.40, 148.30, 140.30, 137.40, 136.40,
132.80, 132.60, 130.60, 130.20, 129.80, 128.40, 126.30, 124.30, 118.40, 72.50, 68.40,
58.30. Anal. calcd. for C23H18ClNO4S: C, 62.77; H, 4.12; N, 3.18. Found: C,
62.92; H, 3.90; N, 3.40%.
(ꢀ)-trans-(2S,3R) Isomer 4h. Yellowish solid, mp 186–188 ꢁC; IR (KBr,
cmꢂ1) v: 3500, 3320, 1690, 1240; 1H NMR (300 MHz, CDCl3) d 4.08 (d d, J ¼ 10.2 Hz
and 8.3 Hz, 1H, C3-H), 4.70 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.10 (s, 2H, -OCH2
-OBz), 5.28 (d, J ¼ 8.2 Hz, 1H, -OH), 6.90–7.85 (m, 13H, Ar-H), 10.31 (s, 1H,
-NH); 13C NMR (CDCl3, 75.47 MHz) d 174.40, 167.75, 165.50, 148.25, 140.40,
137.35, 136.40, 132.85, 132.55, 130.25, 129.70, 128.40, 126.25, 124.50, 118.40,
72.50, 68.40, 58.30. Anal. calcd. for C23H18ClNO4S: C, 62.77; H, 4.12; N, 3.18.
Found: C, 62.82; H, 3.95; N, 3.24%.
(ꢀ)-cis-(2S,3S)-2-(4’-Benzyloxyphenyl)-8-chloro-2,3-dihydro-3-hydroxy-
1,5-benzothiazepin-4-[5H]-one 3i. Yellowish solid, mp 176–178 ꢁC; IR (KBr,
cmꢂ1) v: 3420, 3250, 1680, 1240; 1H NMR (300 MHz, CDCl3) d 4.32 (b t, J ¼ 7.2 Hz

1898
R. JAIN ET AL.
1H, C3-H), 4.90 (d, J ¼ 7.2 Hz, 1H, C2-H), 5.10 (s, 2H, -OCH2 -OBz) 5.15 (d,
J ¼ 7.2 Hz, 1H, -OH) 6.92–7.85 (m, 13H, Ar-H), 10.31 (s, 1H, -NH); 13C NMR
(CDCl3, 75.47 MHz) d 174.20, 167.80, 165.40, 148.20, 140.30, 137.40, 136.30,
132.70, 132.40, 130.50, 130.20, 129.80, 128.40, 126.40, 124.60, 118.40, 72.60, 68.40,
58.30. Anal. calcd. for C23H18ClNO4S: C, 62.77; H, 4.12; N, 3.18. Found: C,
62.90; H, 4.30; N, 3.05%.
(ꢀ)-trans-(2S,3R) Isomer 4i. Yellowish solid, mp 188–189 ꢁC; IR (KBr, cmꢂ1
)
1
v: 3540, 3320, 1690, 1250; H NMR (300 MHz, CDCl3) d 4.05 (dd, J ¼ 10.2 Hz and
8.3 Hz, 1H, C3-H), 4.72 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.12 (s, 2H, -OCH2 -OBz), 5.32
(d, J ¼ 8.2 Hz, 1H, -OH), 6.90–7.85 (m, 13H, Ar-H), 10.25 (s, 1H, -NH); 13C NMR
(CDCl3, 75.47 MHz) d 174.40, 167.90, 165.40, 148.25, 140.30, 137.35, 136.45, 132.60,
132.40, 130.45, 130.25, 129.80, 128.50, 126.40, 124.50, 118.50, 72.50, 68.45, 58.30.
Anal. calcd. for C23H18ClNO4S: C, 62.77; H, 4.12; N, 3.18. Found: C, 62.80; H,
4.23; N, 3.12%.
(ꢀ)-cis-(2S,3S)-2-(4’-Benzyloxyphenyl)-7-trifluoromethyl-2,3-dihydro-3-
hydroxy-1,5-benzothiazepin-4-[5H]-one 3j. White solid, mp 195–196 ꢁC; IR
1
(KBr, cmꢂ1) v: 3450, 3280, 1690, 1260; H NMR (300 MHz, CDCl3) d 4.35 (b t,
J ¼ 7.2 Hz 1H, C3-H), 4.95 (d, J ¼ 7.2 Hz, 1H, C2-H), 5.10 (s, 2H, -OCH2 -OBz),
5.20 (d, J ¼ 7.2 Hz, 1H, -OH) 6.80–7.95 (m, 13H, Ar-H), 10.38 (s, 1H, -NH); 13C
NMR (CDCl3, 75.47 MHz) d 174.60, 168.20, 165.60, 148.20, 142.60, 138.60,
137.40, 136.70, 134.80, 132.90, 132.60, 131.60, 130.20, 129.65, 128.80, 126.70,
78.50, 72.50, 68.40, 58.30. Anal. calcd. for C24H18F3NO4S: C, 60.86; H, 3.83; N,
2.95. Found: C, 60.52; H, 3.60; N, 3.18%.
(ꢀ)-trans-(2S,3R) Isomer 4j. White solid, mp 202–204 ꢁC; IR (KBr, cmꢂ1) v:
1
3510, 3350, 1695, 1280; H NMR (300 MHz, CDCl3) d 4.05 (dd, J ¼ 10.2 Hz and
8.3 Hz, 1H, C3-H), 4.75 (d, J ¼ 10.2 Hz, 1H, C2-H), 5.08 (s, 2H, -OCH2 -OBz),
5.28 (d, J ¼ 8.2 Hz, 1H, -OH), 6.90–7.98 (m, 13H, Ar-H), 10.31 (s, 1H, -NH); 13C
NMR (CDCl3, 75.47 MHz) d 174.75, 168.30, 165.55, 148.30, 142.65, 138.60,
137.40, 136.75, 134.70, 132.95, 132.25, 131.60, 130.25, 129.70, 128.90, 126.75,
78.50, 72.60, 68.50, 58.40. Anal. calcd. for C24H18F3NO4S: C, 60.86; H, 3.83; N,
2.95. Found: C, 60.60; H, 3.72; N, 3.15%.
ACKNOWLEDGMENTS
We thank the head of the Department of Chemistry, University of Rajasthan,
Jaipur, for providing laboratory facilities. We are also grateful to Central Drug
Research Institute (CDRI), Lucknow, for some analytical data. Financial assistance
from the University Grants Commission, New Delhi, is thankfully acknowledged.
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