Stereochemical studies of 5-methyl-3-(substituted phenyl)-5-[(substituted phenyl) hydroxy methyl]-2-thiooxazolidin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2010.05.027

The synthesis and stereochemical aspects of the aldol products, 5-methyl-3-(substituted phenyl)-5-[(substituted phenyl) hydroxy methyl]-2-thiooxazolidin-4-ones, are discussed.

Full text of DOI:10.1016/j.tetlet.2010.05.027

Tetrahedron Letters 51 (2010) 3654–3657
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Tetrahedron Letters
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Stereochemical studies of 5-methyl-3-(substituted phenyl)-5-[(substituted
phenyl) hydroxy methyl]-2-thiooxazolidin-4-ones
Gopal L. Khatik a, Anang Pal a, Shaikh M. Mobin b, Vipin A. Nair a,
*
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
b National Single Crystal X-ray Diffraction Facility, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 January 2010
Revised 6 May 2010
Accepted 7 May 2010
Available online 12 May 2010
The synthesis and stereochemical aspects of the aldol products, 5-methyl-3-(substituted phenyl)-5-
[(substituted phenyl) hydroxy methyl]-2-thiooxazolidin-4-ones, are discussed.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
5(a)(iv) for which the methyl protons appeared shielded would
be the anti isomer, where the methyl shares a syn relation with
Many drugs/intermediates contain oxazolidinones and thi-
ooxazolidinones as an integral part of their skeleton.1,2 Thiooxazo-
lidinone scaffolds are known for various biological activities, such
as antidiabetics,2 potassium channel openers,3 and anticonvul-
sants.4 They are also employed as chiral directing agents in asym-
metric synthesis.5,6 Our investigations on these substrates were
mainly directed to study the aldol reactions, ascertain the extent
of diastereoselectivity, and determine the stereochemical configu-
rations at the newly generated chiral centers.
Aryl isothiocyanates 2(a–e), prepared by treating various ani-
lines 1(a–e) with thiophosgene and sodium hydrogen carbonate
in dichloromethane-water medium,7 were converted into 5-
methyl-3-aryl-2-thiooxazolidin-4-ones 3(a–e) by treating with
ethyl lactate and LiClO4 in DIPEA-mediated cyclization.8 The 3-
aryl-2-thiooxazolidin-4-ones were subjected to aldol reactions
with 4-halobenzaldehydes 4(i–iii) by in situ generation of enolates
using LHMDS to obtain 5-methyl-3-(substituted phenyl)-5-
[(substituted phenyl) hydroxy methyl]-2-thiooxazolidin-4-ones
5(a–e)(i–iii) (Scheme 1).
As a model reaction, 5-methyl-3-(4-fluorophenyl)-2-thiooxaz-
olidin-4-one 3(a) when subjected to aldol reaction with benzalde-
hyde 4(iv) afforded the diastereomers of the aldol product in the
ratio of 60:40 as determined from 1H NMR by comparing the inte-
gration values of characteristic methyl protons.9 Further examina-
tion of the 1H NMR spectra of isolated diastereomers revealed that
in the case of one diastereomer 5(a)(iv) the methyl protons at C5
appeared shielded as indicated by the relative upfield signal at
1.54 ppm, whereas for the other isomer 50(a)(iv) the methyl pro-
tons were deshielded and appeared downfield at 1.88 ppm
(Scheme 2). Therefore it may be assumed that the diastereomer
the phenyl group and anti relation with the hydroxy group, while
the diastereomer 50(a)(iv) with methyl protons deshielded would
be the syn isomer with the phenyl and the hydroxy groups oriented
anti and syn, respectively. This assumption was further supported
by the observance of spatial interaction between the hydroxy
and methyl groups in the syn isomer as revealed by the ROESY
spectra (Fig. 1) and its absence in the anti isomer. A similar differ-
ence in chemical shifts of the methyl protons was observed for the
syn and anti diastereomers in the case of other aldol adducts also
(Table 1). Thus the aldol reactions of 2-thiooxazolidin-4-ones with
4-halobenzaldehydes afforded anti isomer as the major product
(Table 2), which is widely the case observed with enolates of cyclic
and acyclic systems with E-geometry.9,10
To obtain a better perspective on the stereochemical orienta-
tion, computational studies11 were carried out. The most stable
conformations of the anti and syn aldol isomers were identified
R2
R1
NCS
R2
R1
NH2
Cl2CS, NaHCO3
DCM:H2O
2(a-e)
1(a-e)
LiClO4, DIPEA
reflux
Ethyl lactate
S
O
H
S
LHMDS,
THF, -78 C
O
O
R3
º
CH3
OH
R2
R1
N
CH3
R2
R1
N
CHO
O
anti/syn
5(a-e)(i-iii)
R3
3(a-e)
4(i-iii)
* Corresponding author. Tel.: +91 172 2292045; fax: +91 1722214692.
E-mail addresses: vnair@niper.ac.in, vn74nr@yahoo.com (V.A. Nair).
Scheme 1. Synthesis of 5-methyl-3-(substituted phenyl)-5-[(substituted phenyl)
hydroxy methyl]-2-thiooxazolidin-4-ones.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.027

G. L. Khatik et al. / Tetrahedron Letters 51 (2010) 3654–3657
3655
Table 1
S
F
Chemical shift (ppm) comparison of aldol diastereomers
O
N
Entry
Product
Me
1.54 ppm
CH3
O
S
HO
F
CHO
O
N
O
S
5(a)(iv); ( ) anti, 60%
CH3
4(iv)
LHMDS, THF
O
1
1.54
1.88
1.52
F
N
+
HO
S
CH3
F
O
5(a)(iv); ( ) anti
O
N
O
3(a)
1.88 ppm
CH3
OH
S
F
O
N
O
CH3
OH
2
5'(a)(iv); ( ) syn, 40%
Scheme 2. Anti and syn isomers of 5-methyl-3-(4-fluorophenyl)-5-(phenyl hydroxy
methyl)-2-thiooxazolidine-4-one.
5'(a)(iv); ( ) syn
S
F
F
O
N
O
CH3
3
HO
F
5(a)(i); ( ) anti
S
O
N
O
CH3
OH
4
1.83
F
5'(a)(i); ( ) syn
Table 2
Synthesis of 5-methyl-3-(substituted phenyl)-5-[(substituted phenyl) hydroxy
methyl]-2-thiooxazolidin-4-ones
Entry
R1
R2
R3
Isolated yielda (5) (%)
Anti/syn ratiob (5) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
F
F
F
Cl
Cl
Cl
F
F
F
Cl
Cl
Cl
Me
Me
Me
H
H
H
H
H
H
Cl
Cl
Cl
CF3
CF3
CF3
H
F
65
63
67
70
75
62
59
55
58
56
54
59
70
68
66
90:10
82:18
85:15
85:15
86:14
88:12
69:31
66:34
67:33
74:26
66:34
71:29
80:20
77:23
92:08
Cl
Br
F
Cl
Br
F
Cl
Br
F
Cl
Br
F
Figure 1. Expanded ROESY spectrum of 50(a)(iv) indicating hydroxy and methyl
interactions.
(Fig. 2), and transition state models12 corresponding to these con-
formers were proposed as illustrated in Figure 3. In the transition
state TS-I, the phenyl and methyl groups are in a diequatorial con-
formation and this is possible only if they are trans to each other.
Energetically this would be the most stable conformation, and
the diaxial trans conformer would be much less favored. The tran-
sition state TS-II with the methyl group oriented axial and the phe-
nyl group disposed equatorial represents the cis isomer and is less
stable when compared to the diequatorial trans conformer. The
most stable diequatorial conformation would thus lead to an anti
diastereoselectivity in product formation. An assignment of the
stereochemistry would indicate that the transition state TS-I
would lead to (S,R) configurations at C5 and C6 for the anti aldol
and (R,S) for its enantiomer, whereas the syn aldol arising from
the transition state TS-II will have the configurations (R,R), and
(S,S) for its enantiomer. To prove our assumptions and further to
determine the stereochemistry, the anti aldol of 5(a)(i) was chosen
and chiral derivatization method was employed to separate the
two enantiomers from the racemic mixture.13,14
H
H
Cl
Br
a
The isolated yield is given as a total of anti and syn isomers after chromato-
graphic purification.
b
The anti/syn ratio was determined from 1H NMR of the crude product.
Figure 2. Most stable conformations of the anti and syn aldols.

3656
G. L. Khatik et al. / Tetrahedron Letters 51 (2010) 3654–3657
S
S
O
O
Ar
N
Ar
O
N
CH3
Ph
CH3
H
(S)
Ph
Ph
O
HO
O
S
Li
(R)
Ph
H
H
Ar
O
anti aldol
N
O
O
TS-I
CH3
LHMDS
CH3
O
O
CH3
(R)
HO
O
Ph
O
O
Li
(R)
N
N
Ar
Ar
H
S
H
S
TS-II
syn aldol
Figure 3. Transition state models for the formation of anti and syn aldol diastereomers.
S
A suitable crystal of 6(a)(i)-II was subjected to single crystal X-
ray analysis15 and a perspective view of the diastereomer with the
atom numbering is given in Figure 4. The crystal structure shows
that the stereochemistry at C5 and C6 is (R,S) for the diastereomer
6(a)(i)-II of the anti aldol MPA ester, which validates the stereo-
chemistry predicted. Consequently the diastereomer 6(a)(i)-I
should have the opposite configuration (S,R) at the chiral centers;
it being the other enantiomer of the anti aldol.
O
N
O
F
(S)
CH3
F
Ph
H
O
(R)
S
(R)
MeO
F
O
H
O
(R)-MPA, EDC-HCl
N
O
6(a)(i)-I
DMAP, DCM
CH3
H
(S)
To conclude, we have described herein the aldol reactions of 5-
methyl-3-(substituted phenyl)-2-thiooxazolidin-4-ones which
gave the anti aldol isomer as the major product. The stereochemis-
try at the two chiral centers was predicted with the help of transi-
tion state models and further confirmed by single crystal X-ray
diffraction study.
O
HO
OMe
(R)
F
O
F
O
N
Ph
H
5(a)(i); ( ) anti
H3C
(R)
F
O
S
6(a)(i)-II
2. X-ray crystallographic data
Scheme 3. Chiral derivatization of secondary alcohol with (R)-MPA.
Crystallographic data for compound 6(a)(i)-II have been depos-
ited with the Cambridge Crystallographic Data Centre, CCDC No.
761988. Copies of the data can be obtained free of charge on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44
(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
The compound 5(a)(i) was subjected to reaction with (R)-a-
methoxyphenylacetic acid (MPA) using N-(3-dimethylaminopro-
pyl)-N0-ethylcarbodiimide hydrochloride (EDCꢀHCl) and DMAP in
DCM (Scheme 3), and a third chiral center of known and fixed con-
figuration was incorporated thereby converting the two enantio-
mers into diastereomers 6(a)(i)-I (Rf 0.53; EtOAc/hexane, 3:7; mp
78–81 °C) and 6(a)(i)-II (Rf 0.40; EtOAc/hexane, 3:7; mp 72–
75 °C), which were conveniently separated using preparative thin
layer chromatography and characterized by 1H NMR.
Acknowledgments
We are thankful to the Department of Science and Technology,
Government of India for the research funding and the National Sin-
gle Crystal X-Ray Diffraction Facility (NSCXRD), Indian Institute of
Technology, Bombay, for the crystallographic study.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.027.
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