Axially chiral N-(o-aryl)-2-thioxo-oxazolidine-4-one and rhodanine derivatives: enantiomeric separation and determination of racemization barriers

Article abstract of DOI:10.1016/j.tetasy.2008.09.001

Axially chiral 5,5-dimethyl-3-(o-aryl)rhodanine, 3-(o-aryl)rhodanine and 5,5-dimethyl-3-(o-aryl)-2-thioxo-4-oxazolidinone derivatives have been synthesized as racemates and the energy barriers to enantiomerization have been determined by dynamic ¹

Full text of DOI:10.1016/j.tetasy.2008.09.001

Tetrahedron: Asymmetry 19 (2008) 2184–2191
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Tetrahedron: Asymmetry
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Axially chiral N-(o-aryl)-2-thioxo-oxazolidine-4-one and rhodanine
derivatives: enantiomeric separation and determination
of racemization barriers
_
*
Esra Müjde Yılmaz, Ilknur Dog˘an
_
Bog˘aziçi University, Chemistry Department, Bebek, 34342 Istanbul, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Axially chiral 5,5-dimethyl-3-(o-aryl)rhodanine, 3-(o-aryl)rhodanine and 5,5-dimethyl-3-(o-aryl)-2-thi-
oxo-4-oxazolidinone derivatives have been synthesized as racemates and the energy barriers to enantio-
merization have been determined by dynamic 1H NMR or by following the thermal equilibration of the
separated enantiomers using chiral HPLC. The barriers to rotation about the Nsp2–Caryl single bond were
found to be 82–129 kJ/mol. The racemization barriers in these compounds are affected by the size of the
ortho-substituent on the aryl ring. The magnitude of the barriers was found to change linearly with the
van der Waals radii of the ortho-halogen substituents.
Received 30 July 2008
Accepted 3 September 2008
Available online 9 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
R
R
X1
R
X1
R
5
4
5
4
Non-biaryl, axially chiral compounds have been receiving con-
siderable attention1–9 due to their interesting stereochemistries
and also due to their potential uses as catalysts and ligands for
asymmetric syntheses.10 Thus, the synthesis of such atropisomeric
compounds with high enantiomeric stability, their chiral separa-
tions and the determination of their barriers to enantiomerization
are of importance in chiral chemistry.
Based on our experiences with thermally interconvertible, axi-
ally chiral compounds,11–19 the synthesis of N-ortho-aryl-substi-
tuted heterocyclic compounds, as shown in Scheme 1, has been
planned.
2
2
3
N
3
O
N
S
H
O
S
Z
Z
H
M
P
( )-9 R= H; X= S Z= F
( )-10 R= H; X= S Z= Cl
1
( )- R= CH3; X= O Z= F
2
( )- R= CH3; X= O Z= Cl
11
12
( )-
( )-
R= H; X= S Z= Br
R= H; X= S Z= I
3
( )- R= CH3; X= O Z= Br
4
These compounds possess axial chirality because of the non-
planar ground states of the molecules caused by the restricted
rotation about the Nsp2–Caryl single bond, around which 180° rota-
tion forms M and P enantiomers. The racemic compounds shown in
Scheme 1 are expected to have thermally stable enantiomers at
room temperature which will, depending on the nature of the
ortho-substituent, become thermally interconvertible at higher
temperatures. We have recently reported20 the enantiodifferentia-
tion of some of these compounds ( )-1–4 and ( )-9–12, using 1H
and 13C NMR by applying the dirhodium method.21 Herein, we re-
port the synthesis of compounds ( )-1–12 as racemates, their res-
olutions via chiral HPLC and the determination of their activation
barriers to enantiomerization. Compounds ( )-1–4 and ( )-9–12
have been synthesized as racemates either by the reaction of o-ary-
( )- R= CH3; X= O Z= I
( )-5 R= CH3; X= S Z= F
( )-6 R= CH3; X= S Z= Cl
( )-7 R= CH3; X= S Z= Br
( )-8 R= CH3; X= S Z=
I
Scheme 1. The synthesized compounds.
o-arylisothiocyanates with the corresponding thioglycolic acid
ethyl ester.11 Compounds ( )-5–8 have been synthesized from
the corresponding dithiocarbamate salts, which have been pre-
pared according to a modified Kaluza synthesis.22
2. Results and discussion
2.1. NMR results
lisothiocyanates with
a
-hydroxyisobutyrate11 or by treatment of
The 1H and 13C NMR ( Tables 1 and 2, respectively) clearly dem-
onstrated the chirality of the compounds by the non-equivalence
* Corresponding author. Tel.: +90 212 359 6620; fax: +90 212287 2467.
E-mail address: dogan@boun.edu.tr (I. Dog˘an).
_
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.001

_
E. M. Yılmaz, Ilknur Dog˘an / Tetrahedron: Asymmetry 19 (2008) 2184–2191
2185
Table 1
400 MHz 1H NMR spectroscopic data for the compounds ( )-1–12 in CDCl3 at 30 °C
6 R
X1
R
5
4
7
2
3
N
O
S
H
Z
Compound no.
X
O
R
Z
F
d of 5-CH3 (ppm)
d of 5-CH2 (ppm)
d of aromatic (ppm)
( )-1
CH3
1.75a
—
7.25–7.53
6.60–7.20
7.26–7.62
7.30–7.76
7.20–8.20
7.34–7.59
7.49–7.68
7.25–7.57
7.43–7.81
7.25–7.74
7.23–7.98
7.25–7.50
7.09–7.20
7.15–7.40
6.50–6.90
7.22–7.76
6.37–7.01
7.20–8.10
6.13–7.23
1.14 and 1.16b,c
1.75 and 1.77b
1.76 and 1.79b
1.75 and 1.82b
1.72 and 1.76b,d
1.74 and 1.76b,d
1.80 and 1.84b
1.75 and 1.76b,d
1.80 and 1.85b
1.76 and 1.79b,d
—
( )-2
( )-3
( )-4
( )-5
( )-6
O
O
O
S
CH3
CH3
CH3
CH3
CH3
Cl
Br
I
F
Cl
—
—
—
—
—
S
( )-7
( )-8
S
S
CH3
CH3
Br
I
—
—
—
( )-9
S
S
S
S
H
H
H
H
F
dA ¼ 4:16, dB ¼ 4:27e
dA ¼ 2:79, dB ¼ 2:82c,e
dA ¼ 4:19, dB ¼ 4:25e
dA ¼ 2:75, dB ¼ 2:88f
dA ¼ 4:21, dB ¼ 4:27e
dA ¼ 2:69, dB ¼ 2:87f
dA ¼ 4:19, dB ¼ 4:26e
dA ¼ 2:70, dB ¼ 2:90f
( )-10
( )-11
( )-12
Cl
Br
I
—
—
—
—
—
—
a
Only one singlet was observed.
Diastereotopic methyl protons.
Solvent is toluene-d8.
Solvent is DMSO-d6.
AB type splitting.
b
c
d
e
f
Solvent is benzene-d6.
Table 2
100 MHz 13C NMR spectroscopic data for the compounds ( )-1–12 in CDCl3 at 30 °C
6 R
X 1
2
R
5
4
7
3
N
S
H
O
Z
Compound no.
X
R
Z
C-2
C-4
C-5
C-6,7
C-aromatic
( )-1
( )-2
( )-3
( )-4
( )-5
( )-6
( )-7
( )-8
( )-9
( )-10
( )-11
( )-12
O
O
O
O
S
S
S
S
S
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
F
188.0
187.8
188.0
187.4
197.0a
198.4
198.4
200.2b
200.0
198.0
199.5
197.6
173.6
174.9
175.8
174.6
177.3a
178.8
178.7
179.0b
173.6
172.6
171.9
172.6
87.5
87.4
88.0
87.6
54.1a
56.1
56.2
57.0b
37.0
36.6
35.6
36.9
22.3, 25.3
23.4, 24.1
23.2, 25.1
23.7, 24.1
24.8a, 25.9a
26.9, 28.3
27.0, 28.3
26.5b, 28.0b
—
128.3–158.
128.3, 132.2
123.3–136.2
98.1–140.4
123.5–158.1a
128.1–133.3
123.0–134.8
100.0–140.0b
117.3–160.2
128.2–133.0
128.5–135.8
98.4–140.3
Cl
Br
I
F
Cl
Br
I
F
S
S
S
H
H
H
Cl
Br
I
—
—
—
a
Solvent is benzene-d6.
Solvent is DMSO-d6.
b
of the protons or methyl groups present on C-5 of the heterocyclic
ring, which are diastereotopic owing to the stereostructures of the
compounds. The ground states of the compounds are non-planar
due to the restricted rotation about the Nsp2–Caryl bond, making
this bond a chiral axis. Figure 1 demonstrates a typical 1H NMR
spectrum showing the AB splittings of the diastereotopic methy-
lene protons. The chemical shift differences between the diastereo-
topic groups can be expected to be influenced by the anisotropic
influence of the substituent at the ortho-position, as well as by
the dihedral angles between the two rings, which in turn can be
determined largely by the size of the ortho-aryl substituents. The
magnitude of the chemical shift difference in every series was

_
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E. M. Yılmaz, Ilknur Dog˘an / Tetrahedron: Asymmetry 19 (2008) 2184–2191
diastereotopic
protons
diastereotopic
protons
H
H
S
H
S
H
N
O
N
S
O
S
H
I
I
H
M
P
Figure 1. The 400 MHz 1H NMR spectrum of compound ( )-12 in CDCl3.
found to increase from 0.02 ppm for o-fluoro derivatives to
0.07 ppm for the o-iodo compounds. The chemical shift difference
of the diastereotopic carbon atoms (Table 2), however, did not
seem to depend on the nature and size of the ortho-substituent.
Also, a strong solvent dependence of the C-5 hydrogens was ob-
served, which amounted to 1.5 ppm on going from aromatic sol-
vents (toluene-d8, benzene-d6) to polar solvents (CDCl3).
lic thiocarbamate structures. The enantiomers of compound ( )-1
could not be resolved due to its fast racemization. The 1H NMR
of this compound showed the diastereomeric methyl protons at
C-5; the energy barrier for this compound was therefore deter-
mined by temperature dependent NMR, as explained later in the
text.
It was observed that the rhodanine derivatives ( )-9–12, which
are unsubstituted at C-5, were better retained (Table 3) on a chir-
alpak AD-H column than the corresponding 5,5-dimethyl com-
pounds ( )-2–8.
2.2. Chiral chromatography
The enantiomers of compounds ( )-2–12 were resolved or en-
riched micropreparatively on analytical or semipreparative Chir-
alpak AD-H columns using hexane–ethanol mixtures as an eluent
(Table 3).
2.3. Barriers to racemization
After the enantiomers of ( )-2–12 were resolved by chiral chro-
matography, thermal racemizations were performed on the single
enantiomers, as has been described before,19 (Fig. 2) in order to
determine the activation energy barriers to racemization (Table 4).
The ortho-iodo compounds ( )-8 and ( )-12 could not be race-
mized at 78 °C using ethanol as solvent. The Chiralpak IB column
enabled the use of toluene as solvent for the racemization of these
compounds at 105 °C and 110 °C, respectively, for the determina-
tion of activation energies for enantiomeric interconversion. The
racemization barriers for these compounds were determined as
128.2 kJ/mol and 129.0 kJ/mol, respectively (Table 4).
The energy barrier for the racemization of compound ( )-10
was previously determined in diglyme at 387 K as 121.2 kJ/mol.12
The barrier for this compound in this work was found to be
119.5 kJ/mol when the racemization was carried out in ethanol
at 348 K. The difference appears more likely to be a temperature ef-
fect, rather than a solvent effect, when the activation barrier of the
structurally similar N-(o-tolyl)rhodanine determined at different
temperatures and solvents is compared. For this compound, an
activation barrier of 109.3 kJ/mol was found19 in ethanol at
333 K, whereas a value of 114.4 kJ/mol had been reported12 in
Table 3
Chromatographic data for the separation of enantiomers of ( )-2–12 on Chiralpak
AD-H columns
Compound
no.
Eluent (v/v) hexane/
ethanol
Flow rate (ml/
min)
k10
k20
a
( )-2a
( )-3a
( )-4a
( )-5b
( )-6a
( )-7b
( )-8b
( )-9b
( )-10b
( )-11a
( )-12a
95:5
95:5
95:5
95:5
0.8
0.8
0.8
2.5
0.6
3.0
3.0
3.5
4.5
0.6
0.6
2.09 2.56
2.12 2.47
2.54 2.99
2.11 2.43
1.65 2.77
0.88 1.27
1.14 1.31
8.16 13.5
1.22
1.16
1.18
1.15
1.67
1.44
1.15
1.65
95:5
90:10
90:10
90:10
95:5
50:50
50:50
6.49 10.12 1.56
3.64 4.34
3.19 4.51
1.19
1.41
a
Analytical Chiralpak AD-H column was used.
Semi-preparative Chiralpak AD-H column was used.
b
The cellulose- or amylose-based carbamate columns showed
good enantioselectivities for these N-ortho-phenyl-substituted cyc-

_
E. M. Yılmaz, Ilknur Dog˘an / Tetrahedron: Asymmetry 19 (2008) 2184–2191
2187
Figure 2. The plot of ln(([M]–[M]eq)/([M]o–[M]eq)) versus time at 353 K for the slope of which gives the rate of enantiomerization. (b) The liquid chromatograms taken to
follow the thermal racemization of the second eluted enantiomer of compound ( )-10 at 353 K. Column: Chiralpak AD-H. Eluent Hexane:Ethanol 90:10. Flow rate: 0.6
ml/min. UV detection at k = 240 nm.
diglyme at 348 K. When we repeated the same racemization in this
work at 348 K in ethanol, we found a barrier of 115.8 kJ/mol. Fur-
thermore, for compound 5,5-dimethyl-N-(o-tolyl)-2-thioxo-oxa-
zolidine-4-one, the barrier that was determined12 in diglyme
(104.3 kJ/mol) at 330 K was found to be quite close to the one
found in ethanol in this work as 103.8 kJ/mol at 328 K. Thus, the
temperature at which the racemization has been carried out
should be taken into consideration when comparing the energy
barriers of interconvertible enantiomers.
Compounds ( )-1–12 studied in this work are racemizing
through rotation around the Caryl–Nsp2 single bond. Therefore, the
molecules may in principle pass through two different planar tran-
sition states [Scheme 2, TS1 (X = S) and TS2 (X = S)].
Table 4
The activation barriers to racemization for the compounds ( )-1–12
Compound
Solvent
T (K)
k (sꢀ1
)
D )
G– (kJ molꢀ1
( )-1
DMSO-d6
Toluene-d8
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Toluene
Ethanol
Diglyme
Ethanol
2-Propanol
Toluene
386a
356a
343d
343d
348d
280d
348d
348d
378d
280d
387d
348d
351d
383d
61.9b
19.5b
82.0 0.5c
79.0 0.5c
112.6 0.7f
117.2 0.7f
124.0 0.7f
89.8 0.7f
( )-2
( )-3
( )-4
( )-5
( )-6
( )-7
( )-8
( )-9
( )-10
5.0 ꢁ 10ꢀ5e
1.0 ꢁ 10ꢀ5e
2.0 ꢁ 10ꢀ6e
1.0 ꢁ 10ꢀ4e
2.5 ꢁ 10ꢀ5e
4.0 ꢁ 10ꢀ6e
3.0 ꢁ 10ꢀ5e
5.0 ꢁ 10ꢀ5e
7.4 ꢁ 10ꢀ4e
1.5 ꢁ 10ꢀ5e
3.0 ꢁ 10ꢀ6e
2.0 ꢁ 10ꢀ5e
While TS2 (X = S), which has the sulfur passing the Z group,
might experience a higher steric hinderance than the one that
has the smaller-sized oxygen (TS1), both may in principle contrib-
ute to the racemization.
116.3 0.7f
121.6 0.7f
128.2 0.7f
91.0 0.7f
Comparing the energy barriers of 5,5-dimethyl-2-thioxo-4-oxa-
zolidinones ( )-1–4 determined in this work (despite different
temperatures of measurements), with the barrier of 5,5-di-
methyl-2,4-oxazolidinediones that have been reported earlier16
(Table 5) reveals that the former has barriers larger than 25 kJ/
mol for the o-fluoro derivative and 29, 29, 30, 30.5 kJ/mol for the
Cl, Br, I and CH3 derivatives, respectively. Thus, the 2-thioxo group
increased the barrier to rotation by about 30 kJ/mol when substi-
tuted for the carbonyl at the 2-position of the heterocyclic ring.
In the case of 5,5-dimethyl-oxazolidinediones, although the
bond lengths of the O–C and C–C bonds of the heterocyclic ring
121.2 0.2g
119.5 0.7f
123.6 0.7f
129.0 0.7f
( )-11
( )-12
a
The solvent in which the racemization took place.
Rate constant at the coalescence temperature.
b
c
d
e
f
Free energy of activation determined by 400 MHz temperature dependent NMR.
The temperature at which the thermal racemization has been performed.
The rate constant of interconversion between the enantiomers.
Free energy of activation determined by resolution-racemization via HPLC.
Value from Ref. 12.
g

_
2188
E. M. Yılmaz, Ilknur Dog˘an / Tetrahedron: Asymmetry 19 (2008) 2184–2191
CH3
CH3
CH3
CH3
CH3
CH3
X
CH3
O
O
O
CH3
N
N
N
O
O
O
N
X
X
X
O
X
Z
H
Z
H
H
Z
H
Z
or
P
TS1
TS2
M
X=S
X=O
Scheme 2. Rotational isomers of 5,5-dimethyl-3-(o-aryl)-2-thioxo-4-oxazolidinone (X = S) and 5,5-dimethyl-3-(o-aryl)-2,4-oxazolidinedione (X = O) derivatives.
Table 5
Comparison of the racemization barriers of 5,5-dimethyl-N-(o-aryl)-2-thioxo-4-oxazolidinone and the corresponding 2,4-oxazolidinedione derivatives
CH3
CH3
CH3
CH3
O
O
ΔG≠
82.0
112.6
117.2
124.0
103.8
ΔG≠*
57.3
83.2
86.6
94.2
73.5
Z
F
Cl
Br
I
T (K)
386
343
348
348
328
Z
F
Cl
Br
I
T (K)
247
377
395
293
321
N
N
O
O
O
H
S
H
Z
Z
CH3
CH3
*Values taken from reference 16
M and P
M and P
5,5-Dimethyl-N-(o-aryl)-2-thioxo-
4-oxazolidinone derivatives
5,5-Dimethyl-N-(o-aryl)-2,4-
oxazolidinedione derivatives
should be different, if the two transition states (Scheme 2, TS1 and
TS2, X = O) are assumed to be equally populated because the Z
group will pass through the oxygen atoms in both, the actual rate
constants for these compounds will be twice as low as the ob-
served ones.23 Taking this fact into account, the recalculated acti-
vation barriers for 5,5-dimethyl-N-(o-aryl)-2,4-oxazolidinediones
would have been 58.8, 85.4, 88.9, 95.8 and 75.3 kJ/mol for Z = F,
Cl, Br, I and CH3, respectively, which are still far smaller than the
observed barriers for 5,5-dimethyl-N-(o-aryl)-2-thioxo-4-oxazo-
lidinones (Table 5). Thus, it seems likely that both transition states,
TS1 and TS2 (Scheme 2, X = S), are contributing to the barrier rather
than TS1 (Scheme 2, X = S) predominantly.
It was found that for the halogen series, the barriers showed a
remarkable linearity with the van der Waals radii of the halogens24
(Fig. 3). Hence, it can be concluded that if the type of interactions
between the ortho-substituent and the exocyclic groups (C@O
and C@S in this case) are similar (mainly dipolar repulsions in
the planar transition state), the barrier observed is directly propor-
tional to the size of the substituent.
been determined by a temperature dependent NMR experiment
(Fig. 4).
At the probe temperature of 30 °C, diastereotopic 5,5-dimethyl
signals were observed at 1.72 and 1.65 ppm, respectively. At higher
temperatures, where the rotation became faster, the two singlets
slowly came to coalescence (Fig. 4) from which the first-order rate
constant for the interconversion of the M and P enantiomers was
determined25 and substitution of the rate constant in the Eyring
equation gave the
D
G value.25 The activation energy values deter-
mined by temperature dependent 1H NMR in DMSO-d6 were 3 kJ/
mol higher (82 kJ/mol) than the one determined in toluene-d8
(79 kJ/mol). The slightly higher value obtained in DMSO-d6 for this
o-fluoro-substituted compound may be due to the higher polarity
of this solvent compared to toluene-d8.
3. Conclusions
Axially chiral 5,5-dimethyl-3-(o-aryl)-2-thioxo-4-oxazolidinon-
es, ( )-1–4, 5,5-dimethyl-3-(o-aryl)-2-thioxo-4-thiazolidinones,
( )-5–8, and 3-(o-aryl)-2-thioxo-4-thiazolidinones, ( )-9–12, have
been synthesized as racemates.
The chirality of the compounds has been proven by the pres-
ence of diastereotopic protons or carbon atoms detected by 1H
NMR or 13C NMR spectroscopy. The chemical shift differences be-
tween the diastereotopic groups are affected by the anisotropic
influence of the substituent at the ortho-position as well as by
the dihedral angles between the two rings, which in turn will be
determined largely by the size of the ortho-aryl substituents.
The interconvertible enantiomers of compounds ( )-2–12 were
found to be thermally stable at 7 °C and their micropreparative
The oxazolidine–thiones ( )-1–4 have barriers to rotation that
are about 4 kJ/mol lower than that of the corresponding thiazoli-
dine–thiones ( )-5–8. The decrease in the bond length in going
from S–C to O–C should cause this difference. Comparing the bar-
riers of ( )-5–8 with ( )-9–12 shows that the 5,5-dimethyl substi-
tution decreases the barriers slightly (by about 2 kJ/mol).
2.4. Temperature dependent NMR
The activation energy for the racemization of compound ( )-1,
5,5-dimethyl-3-(o-fluorophenyl)-2-thioxo-4-oxazolidinone,
has

_
E. M. Yılmaz, Ilknur Dog˘an / Tetrahedron: Asymmetry 19 (2008) 2184–2191
2189
180
160
140
120
100
80
CH3
CH3
O
N
O
S
H
Z
60
40
20
Z = F, Cl, Br, I
0
1.2
1.4
1.6
1.8
2
van der Waals radii (Å)
180
160
140
120
100
80
CH3
CH3
S
N
O
S
H
Z
60
40
Z = F, Cl, Br, I
20
0
1.2
1.4
1.6
1.8
2
van der Waals radii (Å)
180
160
140
120
100
80
H
S
H
N
O
S
H
Z
60
40
Z = F, Cl, Br, I
20
0
1.2
1.4
1.6
1.8
2
van der Waals radii (Å)
Figure 3. The plot of activation barriers versus van der Waals radii of the o-substituted halogens for the series of 5,5-dimethyl-3-(o-aryl)-2-thioxo-4-oxazolidinones ( )-1–4,
5,5-dimethyl-3-(o-aryl)rhodanines ( )-5–8 and 3-(o-aryl)rhodanines ( )-9–12.
resolutions were achieved by HPLC on the chiralpak AD-H and IB
columns. The barriers to rotation around the CAryl–Nsp2 bond in
these compounds were determined by a subsequent thermal race-
mization as 90–129 kJ/mol. The energy barrier for the faster rotat-
ing o-fluoro derivative ( )-1 was determined by temperature
dependent 1H NMR and found to be 79 kJ/mol in toluene-d8 and
82 kJ/mol in DMSO-d6.
250 ꢁ 4.6 mm), Semi-preparative Chiralpak AD-H column (Daicel
Ltd, particle size: 5
m, column size: 250 ꢁ 10 mm) and Chiralpak
IB column (Daicel Ltd, particle size: m, column size:
250 ꢁ 4.6 mm). Thermohypersil-Keystone column pocket was
used for the temperature control of the chiral columns. Separations
were carried out at T = 280 K. Elemental analyses were performed
on a Thermo Scientific FlashEA 1112 elemental analyzer. Melting
points were recorded using an Electrothermal 9100 melting point
apparatus.
l
5
l
4. Experimental
The 1H NMR and 13C NMR spectra of all compounds were re-
corded on a Varian-Mercury VX-400 MHz and 100 MHz NMR spec-
trometer (T = 303 K). IR analyses were performed on a Mattson
Genesis II FTIR using KBr discs. Liquid chromatography analyses
with UV detector (k = 254 nm) were performed using Chiralpak
4.1. Syntheses
4.1.1. General procedure for the preparation of 5,5-dimethyl-3-
(o-aryl)-2-thioxo-4-oxazolidinones11
The 5,5-dimethyl-3-(o-aryl)-2-thioxo-4-oxazolidinones, com-
pounds ( )-1–4, were synthesized by the reaction of the
AD-H column (Daicel Ltd, particle size:
5 lm, column size:

_
2190
E. M. Yılmaz, Ilknur Dog˘an / Tetrahedron: Asymmetry 19 (2008) 2184–2191
44.35; H, 3.45; N, 4.77; S, 10.50. IR (KBr) 1785, 1269 cmꢀ1. UV–
vis (EtOH) kmax 206 (log 3.86), 272 (log 3.62), 335 (log 1.68) nm.
e
e
e
4.1.1.4. 5,5-Dimethyl-3-(o-iodophenyl)-2-thioxo-4-oxazolidi-
none ( )-4. The compound was synthesized according to the
general procedure using 5 g (0.019 mol) o-iodophenylisothiocya-
nate, 2.5 g (0.019 mol) -hydroxyisobutyrate, 0.043 g
a
(0.0019 mol) metallic sodium and 25 ml toluene. Yield: 3.1 g
(47%), mp: 152–154 °C. 1H NMR (400 MHz, CDCl3): d 8.20–7.20
(m, 4H), 1.82 (s, 3H), 1.75 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d
187.4, 174.6, 140.4–98.1, 87.6, 24.1, 23.7 ppm. Calcd for
C11H10O2NSI: C, 38.05; H, 2.90; N, 4.03; S, 9.24. Found: C, 38.27;
H, 2.99; N, 4.01; S, 9.53. IR (KBr) 1764, 1259 cmꢀ1. UV–vis (EtOH)
kmax 206 (loge 3.93), 272 (loge 3.69), 334 (loge 1.53) nm.
4.1.2. General procedure for the preparation of 5,5-dimethyl-3-
(o-aryl)rhodanines
The following is the generalized procedure used for the prepa-
ration of compounds ( )-5–8. The corresponding aryldithiocarba-
mates were synthesized according to
a
modified Kaluza
synthesis22 by using an amine, carbon disulfide and triethylamine.
At the first part of the procedure, the amine was dissolved in the
minimum amount of benzene and treated with carbon disulfide
and triethylamine as base. The solution was cooled to 0 °C. After
complete precipitation of the triethylammonium dithiocarbamate
salt, the solution was filtered. The solid was washed with anhy-
drous ether and air dried for about 15 min. Then, the salt was dis-
solved in chloroform, treated with triethylamine, and cooled again
Figure 4. Temperature dependent 1H NMR spectra of the diastereotopic C-5 methyl
groups of compound ( )-1 in DMSO-d6.
corresponding arylisothiocyanates with
a-hydroxy isobutyrate.
The appropriate arylisothiocyanate was mixed with
a
-hydroxyi-
sobutyrate in the presence of metallic sodium in toluene. The reac-
tion mixture was refluxed for 7 h. Toluene was distilled out and the
remaining crude product was purified by recrystallization from
ethanol.
to 0 °C. To this solution was added
a-bromoisobutyric acid ethyl
ester dropwise over a 20 min period with hand stirring. The result-
ing solution was stirred at 0 °C for 2 h and then heated at 50 °C for
4 h. Then, the chloroform solution was washed with 3 M HCl, twice
with water and then dried over calcium chloride. The chloroform
was evaporated in vacuo and the crude product was recrystallized
from ethanol.
4.1.1.1. 5,5-Dimethyl-3-(o-fluorophenyl)-2-thioxo-4-oxazolidi-
none ( )-1.
general procedure using 5 g (0.033 mol) o-fluorophenylisothiocya-
nate, 4.31 g (0.033 mol) -hydroxyisobutyrate, 0.075 g
The compound was synthesized according to the
a
(0.0033 mol) metallic sodium and 25 ml toluene. Yield: 1 g
(12.7%), mp: 82–84 °C. 1H NMR (400 MHz, toluene-d8): d 7.20–
6.60 (m, 4H), 1.16 (s, 3H), 1.14 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) : d 188.0, 173.6, 158.2–128.3, 87.5, 25.3, 22.3 ppm. Calcd
for C11H10O2NSF: C, 55.22; H, 4.21; N, 5.85; S, 13.40. Found: C,
55.06; H, 4.25; N, 5.77; S, 13.66. IR (KBr) 1775, 1269 cmꢀ1. UV–
4.1.2.1. 5,5-Dimethyl-3-(o-fluorophenyl)rhodanine ( )-5.
The
compound was synthesized according to the general procedure using
14.55 g (0.15 mol) o-fluoro aniline, 9.9 ml (0,15 mol) carbon disulfide
and 21 ml (0.15 mol, for the first part) triethylamine. 19.87 g
(0.069 mol) o-fluorophenyl dithiocarbamate was obtained. The dithio-
carbamate was dissolved in 60 ml CHCl3, treated with 13.4 g
vis (EtOH) kmax 206 (log
e 4.07), 272 (loge 3.86) nm, 336 (loge
1.71) nm.
(0.069 mol)
a-bromoisobutyric acid ethyl ester and 9.66 ml
(0.069 mol) triethylamine. Yield: 2 g (11.4%), mp: 70–72 °C. 1H NMR
(400 MHz, DMSO-d6): d 7.59–7.34 (m, 4H), 1.76 (s, 3H), 1.72 (s, 3H)
ppm. 13C NMR (100 MHz, benzene-d6): d 197.0, 177.3, 158.1–123.3,
54.1, 25.9, 24.8 ppm. Calcd for C11H10ONS2F: C, 51.74; H, 3.94; N,
5.48; S, 25.12. Found: C, 52.12; H, 3.91; N, 5.41; S, 25.09. IR (KBr)
4.1.1.2. 5,5-Dimethyl-3-(o-chlorophenyl)-2-thioxo-4-oxazolidi-
none ( )-2. The compound was synthesized according to the
general procedure using 6.78 g (0.040 mol) o-chlorophenylisothio-
cyanate, 5.28 g (0.040 mol) -hydroxyisobutyrate, 0.092 g
(0.0040 mol) metallic sodium and 25 ml toluene. Yield: 3.05 g
(29.8%), mp: 90 °C. 1H NMR (400 MHz, CDCl3): d 7.62–7.26 (m,
4H), d 1.77 (s, 3H), 1.75 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
a
1747, 1247 cmꢀ1. UV–vis (EtOH) kmax 300 (log
4.07), 398 (log 1.66) nm.
e
4.28), 205 (log
e
e
d
187.8, 174.9, 132.2–128.3, 87.4, 24.1, 23.4 ppm. Calcd for
4.1.2.2. 5,5-Dimethyl-3-(o-chlorophenyl)rhodanine ( )-6.
The
C11H10O2NSCl: C, 51.66; H, 3.94; N, 5.48; S, 12.54. Found: C,
compound was synthesized according to general procedure using
12.75 g (0.1 mol) o-chloro aniline, 7.6 ml (0.1 mol) carbon disulfide
and 14 ml (0.1 mol, for the first part) triethylamine. Next, 8.22 g
(0.027 mol) o-chlorophenyl dithiocarbamate was obtained. o-chloro-
phenyl dithiocarbamate was then dissolved in 25 ml CHCl3, and trea-
51.61; H, 3.95; N, 5.51; S, 12.89. IR (KBr) 1774, 1258 cmꢀ1. UV–
vis (EtOH) kmax 206 (loge 3.54), 273 (loge 3.49), 331 (loge 1.71) nm.
4.1.1.3. 5,5-Dimethyl-3-(o-bromophenyl)-2-thioxo-4-oxazolidi-
none ( )-3. The compound was synthesized according to the
general procedure using 2.17 g (0.01 mol) o-bromophenylisothio-
cyanate, 1.32 g (0.01 mol) -hydroxyisobutyrate, 0.023 g
ted with 5.27 g (0.027 mol)
a-bromoisobutyric acid ethyl ester and
3.85 ml (0.027 mol) triethylamine. Yield: 1.87 g (25.5%), mp: 74–
76 °C. 1H NMR (400 MHz, DMSO-d6): d 7.68–7.49 (m, 4H), 1.76 (s,
3H), 1.74 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): d 198.4, 178.8,
133.3–128.1, 56.1, 28.3, 26.9 ppm. Calcd for C11H10ONS2Cl: C, 48.61;
H, 3.71; N, 5.15; S, 23.59. Found: C, 48.56; H, 3.69; N, 5.31; S, 23.26.
a
(0.001 mol) metallic sodium and 25 ml toluene. Yield: 0.97 g
(32.3%), mp: 112 °C. 1H NMR (400 MHz, CDCl3): d 7.76–7.30 (m,
4H), 1.79 (s, 3H), 1.76 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): d
188.0, 175.8, 136.2–123.3, 88.0, 25.1, 23.2 ppm. Calcd for
C11H10O2NSBr: C, 44.01; H, 3.36; N, 4.67; S, 10.68. Found: C,
IR (KBr) 1725, 1263 cmꢀ1. UV–vis (EtOH) kmax 294 (log
(log 3.83), 336 (log 1.71) nm.
e 4.14), 205
e
e

_
E. M. Yılmaz, Ilknur Dog˘an / Tetrahedron: Asymmetry 19 (2008) 2184–2191
2191
4.1.2.3. 5,5-Dimethyl-3-(o-bromophenyl)rhodanine ( )-7.
The
sodium. Yield: 1.69 g (29.8%), mp: 142–146 °C. 1H NMR (400 MHz,
CDCl3): d 7.76–7.22 (m, 4H), 4.27 and 4.21 (AB quartet, 1H each,
JAB = 18.33 Hz) ppm 13C NMR (100 MHz, benzene-d6): d 199.5,
171.9, 135.8–128.5, 35.6 ppm. Calcd for C9H6ONS2Br: C, 37.51; H,
2.09; N, 4.86; S, 22.25. Found: C, 37.53; H, 2.05; N, 4.83; S, 22.12.
compound was synthesized according to the general procedure using
34.4 g (0.2 mol) o-bromoaniline, 13.2 ml (0.2 mol) carbon disulfide
and 28 ml (0.2 mol, for the first part) triethylamine. Next 42.87 g
(0.123 mol) o-bromophenyl dithiocarbamate was obtained. The dithio-
carbamate was then dissolved in 90 ml CHCl3, and treated with 23.9 g
IR (KBr) 1730, 1230 cmꢀ1. UV–vis (EtOH) kmax 301 (log
e
4.06) nm.
(0.123 mol)
a-bromoisobutyric acid ethyl ester and 17.22 ml
(0.123 mol) triethylamine. Yield: 11 g (25.6%), mp: 98–100 °C. 1H
NMR (400 MHz, CDCl3): 7.74–7.25 (m, 4H), 1.85 (s, 3H), 1.80 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3): d 198.4, 178.7, 134.8–123.0, 56.2,
28.3, 27.0 ppm. Calcd for C11H10ONS2Br: C, 41.78; H, 3.18; N, 4.43; S,
20.28. Found: C, 41.86; H, 3.19; N, 4.43; S, 20.67. IR (KBr) 1729,
4.1.3.4. 3-(o-Iodophenyl)rhodanine ( )-12.
The compound
was synthesized according to the general procedure using 5.22 g
(0.02 mol) o-iodophenyl isothiocyanate, 2.4 g (0.02 mol) thiogly-
colic acid ethyl ester and 0.046 g ( 0.002 mol) metallic sodium.
Yield: 3.45 g (54%), mp: 158–160 °C. 1H NMR (400 MHz, CDCl3): d
8.1–7.6 (m, 4H), 4.26 and 4.19 (AB quartet, 1H each, JAB = 18.33 Hz)
ppm. 13C NMR (100 MHz, CDCl3): d 197.6, 172.6, 140.3–98.4,
36.9 ppm. Calcd for C9H6ONS2I: C, 32.25; H, 1.80; N, 4.17; S,
19.13. Found: C, 32.49; H, 1.75; N, 4.14; S, 19.09. IR (KBr) 1736,
1245 cmꢀ1. UV–vis (EtOH) kmax 295 (log
e
4.16), 205 (log
e
3.92) nm.
4.1.2.4. 5,5-Dimethyl-3-(o-iodophenyl)rhodanine ( )-8.
The
compound was synthesized according to the general procedure using
10.95 g (0.05 mol) o-iodo aniline, 3.8 ml (0.05 mol) carbon disulfide
and 7 ml (0.05 mol, for the first part) triethylamine. Next, 8.48 g
(0.021 mol) o-iodophenyl dithiocarbamate was obtained. The dithio-
carbamate was then dissolved in 20 ml CHCl3, and treated with
1225 cmꢀ1. UV–vis (EtOH) kmax 296 (log
e 4.17) nm.
Acknowledgment
4.1 g (0.021 mol)
a-bromoisobutyric acid ethyl ester and 3 ml
This project has been supported by Bog˘aziçi University research
fund (BAP) with Project No. 08B506D.
(0.021 mol) triethylamine. Yield: 1 g (13.9%), mp: 130 °C. 1H NMR
(400 MHz, CDCl3): 7.98–7.23 (m, 4H), 1.79 (s, 3H), 1.76 (s, 3H) ppm.
13C NMR (100 MHz, DMSO-d6): d 200.2, 179.0, 140.0–100.0, 57.0,
28.0, 26.5 ppm. Calcd for C11H10ONS2I: C, 36.37; H, 2.77; N, 3.85; S,
17.65. Found: C, 36.54; H, 2.65; N, 3.78; S, 17.87. IR (KBr) 1734,
References
1. (a) Roussel, C.; Vanthuyne, N.; Bouchekara, M.; Djafri, A.; Elguero, J.; Alkorta, I.
J. Org. Chem. 2008, 73, 403; (b) Vanthuyne, N.; Andreoli, F.; Fernandez, S.;
Roman, M.; Roussel, C. Lett. Org. Chem. 2005, 2, 433.
1246 cmꢀ1. UV–vis (EtOH) kmax 295 (log
e 4.04), 205 (loge 3.88) nm.
2. (a) Betson, M. S.; Bracegirdle, A.; Clayden, J.; Helliwell, M.; Lund, A.; Pickworth,
M.; Snape, T. J.; Worrall, C. P. Chem. Commun. 2007, 754; (b) Betson, M. S.;
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4.1.3. General procedure for the preparation of 3-(o-aryl)rhod-
anine11
The 3-(o-aryl)rhodanines, compounds ( )-9–12, were synthe-
sized via the reaction of the corresponding aryl isothiocyanates
with thioglycolic acid ethyl ester in the presence of sodium metal
in toluene. In a 100 ml round-bottomed flask, aryl isothiocyanate
was mixed with thioglycolic acid ethyl ester in the presence of
the small pieces of sodium metal in toluene. The reaction was re-
fluxed for 7 h. The N-aryl rhodanine that formed at the end of this
period, and after distillation of toluene, was purified by recrystalli-
zation from ethanol.
´
424; (c) Adler, T.; Bonjoch, J.; Clayden, J.; Bardıa, M. F.; Pickworth, M.; Solans,
X.; Solé, D.; Vallverdú, L. Org. Biomol. Chem. 2005, 3, 3173; (d) Clayden, J.
Tetrahedron 2004, 60, 4335; (e) Clayden, J. Chem. Commun. 2004, 127; (f)
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3. (a) Lapierre, A. J. B.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc. 2007, 129, 494; (b)
Curran, D. P.; Chen, C. H. T.; Geib, S. J.; Lapierre, A. J. B. Tetrahedron 2004, 60,
4413; (c) Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001, 123, 5130; (d) Curran, D.
P.; Hale, G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandez, M. Z.;
Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8, 3955; (e) Curran, D. P.; Qi, H.;
Geib, S. J.; DeMello, C. J. Am. Chem. Soc. 1994, 116, 3131.
4. Marelli, C.; Monti, C.; Galli, S.; Masciocchi, N.; Piarulli, U. Tetrahedron 2006, 62,
8943.
5. (a) Koide, H.; Hata, T.; Yoshihara, K.; Kamikawa, K.; Uemura, M. Tetrahedron
2004, 60, 4527; (b) Koide, H.; Hata, T.; Uemura, M. J. Org. Chem. 2002, 67, 1929.
6. Kondo, K.; Iida, T.; Fujita, H.; Suzuki, T.; Wakabayashi, R.; Yamaguchi, K.;
Murakami, Y. Tetrahedron 2001, 57, 4115.
7. (a) Kitagawa, O.; Fujita, M.; Kohriyama, M.; Hasegawa, H.; Taguchi, T.
Tetrahedron Lett. 2000, 41, 8539; (b) Kitagawa, O.; Momose, S.; Taguchi, T.
Tetrahedron Lett. 1999, 40, 8827.
8. Kiefl, C.; Zinner, H.; Burgemeister, T.; Mannschreck, A. Recl. Trav. Chim. Pays-Bas
1996, 115, 125.
4.1.3.1. 3-(o-Fluorophenyl)rhodanine ( )-9.
The compound
was synthesized according to the general procedure using 3.06 g
(0.02 mol) o-fluorophenyl isothiocyanate, 2.4 g (0.02 mol) thiogly-
colic acid ethyl ester and 0.046 g ( 0.002 mol) metallic sodium.
Yield: 1.7 g (40%), mp: 103–104 °C. 1H NMR (400 MHz, toluene-
d8): d 7.2–7.09 (m, 4H), 2.82 and 2.79 (AB quartet, 1H each,
JAB = 18.33 Hz) ppm. 13C NMR (100 MHz, CDCl3): d 200.0, 173.6,
160.2–117.3, 37.0 ppm. Calcd for C9H6ONS2F: C, 47.56; H, 2.66;
N, 6.16; S, 28.21. Found: C, 47.71; H, 2.92; N, 6.44; S, 28.20 IR
9. Faigl, F.; Tarkanyi, G.; Fogassy, K.; Tepfenhardt, D.; Thurner, A. Tetrahedron
2008, 64, 1371.
10. Clayden, J. Angew. Chem., Int. Engl. 1997, 36, 949.
(KBr) 1727, 1238 cmꢀ1. UV–vis (EtOH) kmax 300 (log
e
4.11) nm.
_
_
_
11. Dog˘an, I.; Burgemeister, T.; Içli, S.; Mannschreck, A. Tetrahedron 1992, 48, 5157.
12. Dog˘an, I.; Pustet, N.; Mannschreck, A. J. Chem. Soc., Perkin Trans. 2 1993, 1557.
4.1.3.2. 3-(o-Chlorophenyl)rhodanine ( )-10.
The com-
_
13. Karatasß, M.; Koni, S.; Dog˘an, I. Can. J. Chem. 1998, 76, 254.
14. Demir, Ö.; Dog˘an, I. Chirality 2003, 15, 242.
15. Og˘uz, S. F.; Dog˘an, I. Tetrahedron: Asymmetry 2003, 14, 1857.
16. Ordu, Ö. D.; Dog˘an, I. Tetrahedron: Asymmetry 2004, 15, 925.
_
pound was synthesized according to the general procedure using
3.38 g (0.02 mol) o-chlorophenyl isothiocyanate, 2.4 g (0.02 mol)
thioglycolic acid ethyl ester and 0.046 g ( 0.002 mol) metallic so-
dium. Yield: 2.0 g (41.1%), mp: 112–113 °C. 1H NMR (400 MHz,
CDCl3): d 7.40–7.15 (m, 4H), 4.25 and 4.19 (AB quartet, 1H each,
JAB = 17.94 Hz) ppm. 13C NMR (100 MHz, CDCl3): d 198.0, 172.6,
133.0–128.2, 36.6 ppm. Calcd for C9H6ONS2Cl: C, 44.35; H, 2.48;
N, 5.47; S, 26.31. Found: C, 44.40; H, 2.43; N, 5.71; S, 25.99. IR
_
_
_
17. Aydeniz, Y.; Og˘uz, S. F.; Yaman, A.; Konuklar, A. S.; Dog˘an, I.; Aviyente, V.; Klein,
R. A. Org. Biomol. Chem. 2004, 2, 2426.
_
18. Ordu, Ö. D.; Yılmaz, E. M.; Dog˘an, I. Tetrahedron: Asymmetry 2005, 16, 3752.
_
19. Erol, Sß.; Dog˘an, I. J. Org. Chem. 2007, 72, 2494.
_
20. Gómez, E. D.; Dog˘an, I.; Yılmaz, E. M.; Ordu, Ö. D.; Albert, D.; Duddeck, H.
Chirality 2008, 20, 344.
21. (a) Boyar, E. B.; Robinson, S. D. Coord. Chem. Rev. 1983, 50, 109; (b) Multiple
bonds between metal atoms; Cotton, F. A., Walton, R. A., Eds., 2nd ed.;
Clarendon: Oxford, 1993.
(KBr) 1731, 1250 cmꢀ1. UV–vis (EtOH) kmax 300 (log
e
4.14) nm.
22. Hodgkins, J. E.; Reeves, W. P. J. Org. Chem. 1964, 29, 3098.
23. Roussel, C.; Djafri, A. New J. Chem. 1986, 10, 399.
24. Carey, A. F.; Sundberg, R. Advanced Organic Chemistry. Part-A: Structure and
Mechanism; Plenum Press: New York, London, 1990. p 120.
25. Friebolin, H. Basic One- and Two-dimensional NMR Spectroscopy, 3rd revised ed.;
Wiley-VCH, 1998. p 307.
4.1.3.3. 3-(o-Bromophenyl)rhodanine ( )-11.
The com-
pound was synthesized according to the general procedure using
4.28 g (0.02 mol) o-bromophenyl isothiocyanate, 2.4 g (0.02 mol)
thioglycolic acid ethyl ester and 0.046 g ( 0.002 mol) metallic