Stereomeric studies on the oxidation and alkylation of 4-thiazolidinones

Article abstract of DOI:10.1016/j.tetlet.2008.01.038

Diastereoselectivity in the oxidation of different 4-thiazolidinones was discussed. Alkylation of these compounds with benzyl bromide was also studied. The stereoselectivity obtained was interpreted by the presence of the sulfoxide.

Full text of DOI:10.1016/j.tetlet.2008.01.038

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1569–1572
Stereomeric studies on the oxidation and alkylation of 4-thiazolidinones
a
a
b
a
`
´
Aina Colombo , Joan Carles Fernandez , Dolors Fernandez-Forner , Natalia de la Figuera ,
c,
a,
*
*
Fernando Albericio , Pilar Forns
a Almirall-Barcelona Science Park Unit, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
b
`
´
Laboratorios Almirall, S.A., Research Center, Crta. Laurea Miro 390, 08980 Sant Feliu de Llobregat, Spain
c Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
Received 11 November 2007; revised 24 December 2007; accepted 8 January 2008
Available online 12 January 2008
Abstract
Diastereoselectivity in the oxidation of different 4-thiazolidinones was discussed. Alkylation of these compounds with benzyl bromide
was also studied. The stereoselectivity obtained was interpreted by the presence of the sulfoxide.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Reaction mechanism; Stereoselectivity; Sulfone; Sulfoxide
4-Thiazolidinones are important cores in the structures
of biologically active compounds. In this sense, different
4-thiazolidinones with anti-inflammatory,1 antibacterial,2
or anticancer3 activity have been reported. Their activity
as calcium agonists4 and HIV-RT inhibitors has also been
described.5 For this reason, the solid-phase6 and solution7
synthesis of 4-thiazolidinones has been widely described
usually in a one-pot reaction involving an amine, an alde-
hyde, and an a-mercapto acid. If carbon 5 of the 4-thiazol-
idinone has to be substituted, the a-mercapto acid has to be
previously synthesized8 because only very few a-mercapto
acids are commercially available. An alternative to the
use of a-mercapto acids is via a Mannich reaction with
formaldehyde and an amine.9 Lastly, it is worth pointing
out that sometimes the most potent compounds have the
sulfide of the heterocycle oxidized into sulfoxide or even
into sulfone.3b
R∗1
R∗1
R1-CHO
COOH
∗
R2
R2
O
+
N
S
N
S
∗
NH2-R2
SH
O
O
R3
Fig. 1. Synthetic scheme for 4-thiazolidinones.
To identify the best conditions for this manipulation, a
parallel strategy was used.10
Initially, five different 4-thiazolidinones (Fig. 2) were
synthesized from five different aldehydes, benzylamine,
and mercaptoacetic acid using a strategy modified from
the one described in the literature.7a Yields and purities
are outlined in Table 1. For 1–4, the two enantiomers of
each 4-thiazolidinone were obtained showing total absence
of stereoselectivity (5 does not present a chiral center).
Then, 4-thiazolidinone 1 was used as a model to find the
best conditions for each reaction step as well as the best
way to determine the stereoselectivity of the reactions.
First of all and taking as model 1, a broad range of con-
ditions were tested to find the best conditions for the oxida-
tion into sulfoxide (Fig. 3). The best yield and total absence
of overoxidation to sulfone were obtained when 1 equiv of
AcOOH was used (Table 2, entry 11).
Having this in mind, we decided to further investigate
the oxidation of the sulfide of these compounds into sulf-
oxide and then to carry out the alkylation at carbon 5 of
the heterocycle to obtain compounds with the general
structure presented in Figure 1.
*
Corresponding authors.
Next, a study of the diastereoselectivity for the 3-benzyl-
2-(4-methoxyphenyl)thiazolidin-4-one-1-oxide (6) was car-
E-mail addresses: albericio@pcb.ub.es (F. Albericio), pforns@pcb.
ub.es (P. Forns).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.038

1570
A. Colombo et al. / Tetrahedron Letters 49 (2008) 1569–1572
O
S
S
N
N
S
N
S
N
S
N
O
O
O
O
O
1
4
5
2
3
Fig. 2. 4-Thiazolidinones synthesized for this study.
Table 1
Purities and yields of the 4-thiazolidinones synthesized
4-Thiazolidinones
% Yield
% Puritya
1
2
3
4
5
89
92
78
95
48
97
99
94
99
96
a
% Purity by HPLC at 210 nm.
O
O
O
Fig. 4. X-ray structure of trans-3-benzyl-2-(4-methoxyphenyl)thiazolidin-
4-one-1-oxide (trans-6).
O
*
*
*
O
O
N
* S
N
S
S
N
O
O
O
after different trials with the chiral column AD-H and the
X-Terra column, the conditions to separate both diastereo-
mers were not found and the study was carried out by H
7
6
1
1
Fig. 3. sulfide oxidation of 1.
NMR. Table 3 shows that, as expected, the diastereoselec-
tivity depends on the steric hindrance at carbon 2.
Finally, alkylation of 4-thiazolidinone-1-oxide at C-5
with benzyl bromide using various bases, various reaction
times, and various temperatures was performed (Fig. 5).
Table 2
Conditions tested for the oxidation of 1 into sulfoxide
Entry
Oxidant (equiv)
Time (h)
1a
6a
7a
1
2
3
4
5
6
7
8
9
TBHP (1)
TBHP (5)
UHP (1)
UHP (5)
H2O2 (1)
H2O2 (5)
CHP (1)
CHP (5)
20
20
20
20
20
20
20
20
20
3.5
3.5
99
99
97
86
79
85
51
29
37
10
—
—
—
3
—
—
—
2
—
—
—
3
Table 3
11
21
15
48
68
63
89
99
Diastereoselectivity of the oxidation of 2–4
4-Thiazolidinones
4-Thiazolidinone-1-oxidea
Yield (%)
drb
2
3
4
a
8
9
78
93
81
142:1
49:1
3:1
MCPBA (1)
MCPBA (5)
AcOOH (1)
—
—
—
10
10
11
a
Oxidation conditions: 1 equiv of AcOH during 3.5 h in DCM.
As determined by 1H NMR.
b
% Purity by HPLC at 210 nm.
R1
R1
ried out by HPLC with an X-Terra column and with the
chiral column AD-H, observing a diastereomeric ratio, dr
of 9:1 for the titled compound. The diastereomers of 6 were
then separated by silica column and the major one was
crystallized and analyzed by X-ray, obtaining a trans dia-
stereoselectivity for this compound, as shown in Figure 4.
Next, the oxidation of the other 4-thiazolidinones was
carried out under optimized conditions and each product
was analyzed by HPLC to find the dr (except for the oxida-
tion of 5 where 2 enantiomers were obtained). However,
*
*
O
*
O
N
S
∗
S
N
O
O
6
8
9
10
R1:p-OMe-Phe
R1: tBu
12 R1:p-OMe-Phe
13 R1: tBu
R1: iPr
14 R1: iPr
R1: Me
15
16
R1: Me
R1: H
11 R1: H
Fig. 5. Alkylation of the 4-thiazolidinones-1-oxide 6–11.

A. Colombo et al. / Tetrahedron Letters 49 (2008) 1569–1572
1571
Table 5
Table 4 shows that the best results for the alkylation of 6
Yields and purities of the alkylation of 8–11
were obtained by using NaH as a base for 4 h at 4 °C
(Table 4, entry 11) in THF.
Entry 4-Thiazolidinone- 5-Benzyl-4-
% Yield % Purityb
1-oxidea
thiazolidinone-1-oxide
Once the best alkylating conditions were determined,
the diastereoselectivity of the reaction was investigated.
Since the separation of the 8 possible stereoisomers of 12
was not possible using HPLC, the alkylation of the trans-
3-benzyl-2-(4-methoxyphenyl)thiazolidin-4-one-1-oxide
(trans-6) was carried out instead, rendering 4 different
stereoisomers only. After the reaction, the dr was calcu-
lated by HPLC obtaining a dr of 19:1. Furthermore, both
diastereomers were separated by silica column and the
major diastereomer was crystallized and analyzed by
X-ray spectroscopy, which indicated that the substituent
of carbon 5 and the sulfoxide were in a cis conformation
(Fig. 6).
1
2
3
4
8
9
13
14
15
16
60
22
59
34
88
98
97
81
10
11
a
Reaction conditions: 1 equiv of NaH, 1.1 equiv of benzyl bromide, 4 h,
at 4 °C.
b
% Purity by HPLC at 210 nm.
O
S
N
O
O
Table 4
Optimized alkylation of 6
Fig. 7. Key intermediate in the alkylation step of 6.
Entry Base
Base Temperature Time
%
%
%
equiv (°C)
(h)
6a 12a Bisalkylated
Finally, the same conditions used for the alkylation of 6
(1 equiv of NaH, 1.1 equiv of benzyl bromide, 4 h at 4 °C)
were applied to the other racemic 4-thiazolidinone-1-oxides
(8–11) to give 13–16 (Fig. 5). Table 5 shows yields and puri-
ties obtained for these reactions.
It was only possible to separate diastereomers of 16
showing a dr of 6:1. Comparing with the selectivity
obtained during the alkylation of 6, this result indicates
that the selectivity is induced by the sulfoxide group and
depends on the steric hindrance at carbon 2. To confirm
this, sulfone 7 of the model compound 1 was first synthe-
sized11and then alkylated12 obtaining a dr of 2:1, which
confirms the importance of having a sulfoxide for good dia-
stereoselectivity in the alkylation process.
proda
1
2
3
4
5
6
7
8
9
LHMDS 1.05
LHMDS 1.1
LHMDS 1.05
À78
6
3
24
3
89
88
32 28
91
87
56 17
23 73
80 18
—
7
—
—
—
—
—
—
7
À60
rt
LDA
LDA
LDA
LDA
nBuLi
NaH
NaH
NaH
1.1
1.1
1.1
1.1
1.05
1.05
1.05
1.00
À78
À30
4
—
4
4
24
48
3
4
4
rt
À60
—
—
0
41
3
10
11
a
10
4
10 61 21
87
4
2
8
% Purity by HPLC at 210 nm.
These results match with those reported in the literature
for the oxidation and alkylation of a thiazoloisoquinoline13
and allow us to postulate that the sulfoxide attacks the
benzyl group before the nucleophile (carbon 5) does
(Fig. 7), allowing the cis orientation between the sulfoxide
and the benzylic group.
Acknowledgments
This work was partially supported by funds from CI-
CYT (CTQ2006-03794/BQU), Almirall Laboratories, and
the Barcelona Science Park. A.C. thanks Almirall Labora-
tories for providing a predoctoral fellowship. We also wish
to thank Dr. Rick Roberts for his help on the synthesis of
4-thiazolidinones and Dr. Rodolfo Lavilla for the discus-
sion on the alkylation mechanism.
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Fig. 6. X-ray structure of the major enantiomer of 12 after alkylation of
trans-6.

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