Efficient conversion of N-terminal of L-tyrosine, DL-phenyl alanine, and glycine to substituted 2-thioxo-thiazolidine-4-ones: A stereospecific synthesis

Article abstract of DOI:10.1080/00397911.2011.576322

We report facile and efficient conversion of the amino functional group of amino acids such a s L-tyrosine, DL-phenylalanine, and glycine to the corresponding (±)-2-thioxo-thiazolidine-4-ones (rhodanines). Stereospecific synthesis of amino acid-incorporated rhodanine is achieved in the case of L-tyrosine. Knoevenagel condensation over the active methylene group at the fifth position of the corresponding rhodanines is also described. The substituted rhodanine incorporated with tyrosine in the form of a dimer connected via two-carbon linker possesses significant anticancer activity against A549 cells (human lung cancer cells).

Full text of DOI:10.1080/00397911.2011.576322

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Efficient Conversion of N-Terminal of L-
Tyrosine, DL-Phenyl Alanine, and Glycine
to Substituted 2-Thioxo-thiazolidine-4-
ones: A Stereospecific Synthesis
B. R. Prashantha Kumar a , Prabudha Basu a , L. Adhikary a b & M. J.
Nanjan a
a TIFAC CORE, JSS College of Pharmacy, Ootacamund, India
b Bioanalytical Division, Biocon India Limited, Bangalore, India
Accepted author version posted online: 10 Jan 2012. Version of
record first published: 21 Jun 2012
To cite this article: B. R. Prashantha Kumar, Prabudha Basu, L. Adhikary & M. J. Nanjan (2012):
Efficient Conversion of N-Terminal of L-Tyrosine, DL-Phenyl Alanine, and Glycine to Substituted 2-
Thioxo-thiazolidine-4-ones: A Stereospecific Synthesis, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:20, 3089-3096
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Synthetic Communications1, 42: 3089–3096, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.576322
EFFICIENT CONVERSION OF N-TERMINAL
OF L-TYROSINE, DL-PHENYL ALANINE, AND GLYCINE
TO SUBSTITUTED 2-THIOXO-THIAZOLIDINE-4-ONES:
A STEREOSPECIFIC SYNTHESIS
B. R. Prashantha Kumar,1 Prabudha Basu,1 L. Adhikary,1,2
and M. J. Nanjan1
1TIFAC CORE, JSS College of Pharmacy, Ootacamund, India
2Bioanalytical Division, Biocon India Limited, Bangalore, India
GRAPHICAL ABSTRACT
Abstract We report facile and efficient conversion of the amino functional group of amino
acids such a s L-tyrosine, DL-phenylalanine, and glycine to the corresponding (ꢀ)-2-t-
hioxo-thiazolidine-4-ones (rhodanines). Stereospecific synthesis of amino acid–incorporated
rhodanine is achieved in the case of L-tyrosine. Knoevenagel condensation over the active
methylene group at the fifth position of the corresponding rhodanines is also described. The
substituted rhodanine incorporated with tyrosine in the form of a dimer connected via
two-carbon linker possesses significant anticancer activity against A549 cells (human lung
cancer cells).
Keywords A549 cells; anticancer activity; Knoevenagel condensation; rhodanine;
stereospecific synthesis; 2-thioxo-thiazolidine-4-one
INTRODUCTION
Thiazolidine heterocycles are of considerable interest from both synthetic and
biological points of view.[1] Thiazolidinone derivatives are reported to have anticon-
vulsant,[2] antibacterial,[3] and antiviral[4] properties. A thiazolidine-2,4-dione deriva-
tive, LY213829, used for the treatment of inflammatory bowel disease,[5] and
rosiglitazone,[6] used for non-insulin-dependant diabetes mellitus, contain the
thiazolidine-2,4-dione motif. The 2-thioxo-4-thiazolidinone (rhodanine) moiety,
being a bioisostere of thiazolidine-2,4-dione, is also known to have diverse pharma-
cological properties.[7,8] Rhodanine has been synthesized by various methods such as
Received October 11, 2010.
Address correspondence to M. J. Nanjan, TIFAC CORE, JSS College of Pharmacy, Ootacamund
643 001, India. E-mail: mjnanjan@gmail.com
3089

3090
B. R. PRASHANTHA KUMAR ET AL.
the addition of isothiocyanate to mercaptoacetic acid followed by acid cyclization or
the reaction of ammonia or primary amines with carbon disulfide and chloro-acetic
acid in the presence of a base.[9] Recently, Alizadeh et al. have reported
three-component coupling of carbon disulfide, primary amine, and acetylenic esters
to get rhodanine derivatives.[10] Rhodanines possess active CH2 groups and hence
condense with aldehydes, especially in the presence of basic catalysts. This
Knoevenagel condensation has been accomplished using piperidinium benzoate in
refluxing toluene using a Dean–Stark apparatus,[11] sodium acetate in refluxing gla-
cial acetic acid,[9] or piperidine and glacial acetic acid in refluxing toluene.[12] In con-
tinuation of our recent report on glitazones, we proposed to synthesize the
biologically active molecules by varying the existing protocols, which could allow
us access to amino acid–substituted rhodanines.[13] There are very few reports using
amino acids.[8] We, therefore, started the synthesis of the title compounds with
amino acids such as L-tyrosine, DL-phenylalanine, and glycine.
RESULTS AND DISCUSSION
The synthesis of the title compounds with amino acids such as L-tyrosine,
DL-phenylalanine, and glycine is shown in Scheme 1. Stereospecific synthesis is
demonstrated in the case of L-tyrosine by retaining the original configuration. In this
protocol, each amino acid was converted to the corresponding ammonium salt and
Scheme 1. Synthesis of 2-thioxo-thiazolidine-4-one derivatives incorporated with tyrosine, phenyl alanine,
and glycine residues: (a) H2O, 0–5 ꢁC, aqueous ammonia solution 25–30%, CS2, stir for 10 h; (b) 5–10 ꢁC,
sodium chloroacetate solution; (c) 6 N HCl, two drops POCl3, 50–60 ꢁC for 3 h; (d) toluene, dimeric
p-hydroxy benzaldehyde, N-methyl piperazine, ammonium acetate, molecular sieves, reflux for 15 h.

SYNTHESIS OF 2-THIOXO-THIAZOLIDINE-4-ONES
3091
Table 1. L-Tyrosine, DL-phenylalanine, and glycine incorporated 2-thioxo-thiazolidine-4-ones
a
Entry
R
CTC50 (mg)
7
3.6
8
9
>200
>200
aCTC50: Concentration that inhibited 50% growth of A549 cells.
then reacted with carbon disulfide using water as solvent to yield the corresponding
dithiocarbomates (1, 2, and 3). The reaction proceeded spontaneously and was
completed in 10 h. The dithiocarbamates formed were then reacted with sodium
chloroacetate and later cyclized under acidic conditions in the presence of phosphor-
ous oxychloride to yield products in which the N-terminal of amino acid is converted
to the corresponding 2-thioxo-thiazolidine-4-ones 4, 5, and 6 (77–86%). Compound
4 was found to be enantiomerically pure with the retention of original configuration.
Further, they were subjected to the Knoevenagel condensation with dimeric p-
hydroxy benzaldehyde (linked via two-carbon linker), using N-methyl piperazine
and ammonium acetate in refluxing toluene to yield 7, 8, and 9 (76–89%,
Table 1).[14] Knoevenagel condensation was performed on 4, 5, and 6 without the
aid of a Dean–Stark apparatus. Table 1 lists the substituted 2-thioxo-thiazolidine-
4-ones synthesized. Despite the heating in the Knoevenagel condensation, compound
7 was found to be enantiomerically pure with retention of the original configuration.
Apart from good yields, the advantages of the present protocol when com-
pared to the reported ones lie in the relative ease with which the ammonium salt
of dithiocarbamate is prepared rather than the sodium salt and completion of the
reaction at room temperature without the necessity for heating.[8] We also observed
that the dithiocarbamates are relatively more stable under cold conditions (<5 ꢁC).
The use of phosphorous oxychloride along with HCl was found to be useful in the

3092
B. R. PRASHANTHA KUMAR ET AL.
cyclization step for enhancing the yields. Apart from these advantages, another
advantage in using this protocol is the stereospecific synthesis. The rate of
Knoevenagel condensation with aldehydes over the active methylene group has been
shown to increase when N-methyl piperazine and ammonium acetate are used rather
than a piperidine and acetic acid mixture under similar conditions.[12]
The structures of the synthesized compounds were confirmed from infrared
(IR), mass, and NMR analysis. The cross peaks in heteronuclear correction
(HETCOR) spectrum for compound 7 helped us to identify protons attached to car-
bons (or vice versa) as shown in Fig. 1. Cross peaks for hydrogens at 3.43 d ppm in
1H NMR spectrum show that they are bonded to the carbon at 36.0 d ppm in 13C
NMR spectrum (b hydrogens attached to the b carbon of tyrosine structural part).
1
Cross peaks for hydrogens at 4.43 d ppm in H NMR spectrum are bonded to the
carbons at 67.08 d ppm in 13C NMR spectrum (methylene protons attached to the
methylene carbon atoms of two-carbon linker). Cross peaks for hydrogen at 5.62
1
d ppm in H NMR spectrum show that they are bonded to the carbon at 60.38
d ppm in 13C NMR spectrum (a hydrogen attached to the a carbon of tyrosine struc-
tural part). This indicates that the a-hydrogen becomes highly acidic after the amino
group is converted to the polar 2-thioxo-thiazolidine-4-one motif. Cross peaks for
1
hydrogen at 7.68 d ppm in H NMR spectrum show that they are bonded to the
carbon at 132.94 d ppm in 13C NMR spectrum (¼CH, at the fifth position of
thiazolidinedione ring system). The reason for this deshielding is attributed to the
Figure 1. 1H-13C HETCOR spectrum for compound 7 cross peaks are shown in different lines. (Figure is
provided in color online.)

SYNTHESIS OF 2-THIOXO-THIAZOLIDINE-4-ONES
3093
cis-position of the exocyclic carbonyl function of 2-thioxo-thiazolidine-4-one ring to
the ¼ CH and hence the Z configuration.[12–14] Similarly, other hydrogens and
carbon atoms are cross-correlated via cross peaks as shown in Fig. 1.
Compounds 7, 8, and 9 were subjected to in vitro cytotoxicity assay against
A549 cells (human lung cancer cells). The assay was performed by the sulforhoda-
mine B (SRB) method.[15] The results are given in Table 1. Surprisingly, compound
7 exhibits cytotoxicity with CTC50 of 3.6 mg (Table 1).
In summary, we report here a simple, efficient stereospecific method to synthe-
size some novel rhodanines of biological interest incorporated with amino acids such
a s L-tyrosine, DL-phenyl alanine, and glycine. Conditions for Knoevenagel conden-
sation reaction were also optimized. The results are encouraging us to extend this
protocol to the other amino acids.
EXPERIMENTAL
The infrared(IR) spectra of the compounds were recorded on Shimadzu and
Perkin-Elmer Fourior transform (FT)–IR spectrophotometer, using KBr pellet or
neat technique, and are expressed in centimeters ꢂ1. NMR spectra were recorded
on AV-400-and 500-MHz spectrometers using tetramethylsilane (TMS) as internal
standard and dimethylsulfoxide (DMSO-d6) as a solvent. The chemical shifts are
expressed in d ppm, and the following abbreviations are used: s, singlet; bs, broad
singlet; d, doublet; t, triplet; q, quartlet; and m, multiplet. The high-resolution mass
spectrometric (HRMS) analysis was done on a Perkin-Elmer Sciex API-150-EX by
electrospray (ESI) ionization and turnover frequency (TOF) detection techniques.
All the reactions were monitored using thin-layer chromatography. (TLC) per-
formed using 4% methanol in chloroform as mobile phase on aluminum plates that
were are precoated with silica gel GF. A Merck Microlab 200 autoanalyzer was used
for the estimation of glucose and triglycerides.
Preparation of Title Compounds
Water (10 ml) and ammonia solution (30 ml, 25–30%) were transferred into a
conical flask. The conical flask was placed in an ice bath, and the temperature was
maintained at 0–5 ꢁC. Carbon disulfide (0.0031 M) was then added. L-Tyrosine or
(ꢀ)-phenyl alanine or glycine (0.003 M) was added slowly to this solution for a per-
iod of 30 min with continuous stirring. A cotton plug was put to the flask, and the
reaction mixture was stirred for 10 h and allowed to stand for 2 h in a refrigerator
to yield dithiocarbamate of the corresponding amino acids (1, 2, and 3). Sodium
chloroacetate solution was prepared by dissolving chloroacetic acid (0.003 M) and
NaOH (0.003 M) each in 3 ml of water, separately. Then both were mixed and stirred
for 30 min. Solid sodium carbonate was then added slowly until the reaction mixture
became basic to litmus. Sodium chloroacetate solution was added into a flask con-
taining dithiocarbamate solution slowly at 5–10 ꢁC under stirring. The reaction mix-
ture was allowed to stir for 1 h. The uncyclized N-substituted rhodanine formed was
cyclized by adding 10 ml of 6 N HCl and two or three drops of phosphorous oxy-
chloride and heating at 60–70 ꢁC for about 3 h. All the reactions were monitored with
TLC using 20% methanol in chloroform as the mobile phase. The spots on TLC were

3094
B. R. PRASHANTHA KUMAR ET AL.
detected using alcoholic dodeca-phosphomolybdinum staining and heating, apart
from using ninhydrin reagent. The reaction mixture was allowed to cool. The solid
formed was filtered and recrystallized with diethyl ether to obtain 4, 5, and 6 (77–
86%). Compounds 7, 8, and 9 were prepared by subjecting 4, 5, and 6 to the
Knoevenagel condensation reaction with substituted aldehyde (76–89%).
Knoevenagel Condensation Reaction
Equimolar amounts of the substrate, 4 or 5 or 6 (0.002 M), and 20–30 ml of dry
toluene were transferred to a flat-bottomed flask. N-Methyl piperazine (0.0001 M),
ammonium acetate (0.0001 M), and molecular sieves (0.5 g) were then added. The
reaction mixture was stirred for 5 min and then heated under reflux at 110 ꢁC with
occasional stirring for about 15 h. After the completion of the reaction, the reaction
mixture was allowed to cool, and the precipitated solid was filtered and recrystallized
using methanol to obtain the pure compound.
Physical, Analytical, and Spectral Data of Compounds 7, 8, and 9
(ꢂ)-2-f5-[1-[4-(2-f4-[3-[(ꢂ)-1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-thia-
zolidin-(5)-ylidenemethyl]-phenoxyg-ethoxy)-phenyl]-meth-(Z)-ylidene]-thia-
zolidin-3-ylg-3-(4-hydroxy-phenyl)-propionic acid (7). Yellow crystals, mp
210–216 ꢁC, yield 65%. FTIR (KBr, cmꢂ1): 3500–2500 (O-H & N-H), 3000
(Ar-H), 2935 (AliC-H), 1697 (C¼O), 1508 (ArC¼C), 1242 (C¼S), 1172 (C-O),
1
1039 (C-N). HNMR (400 MHz, DMSO-d6, d ppm): 3.43 (bs, 4H, 2 ꢃ CH2), 4.43
(s, 4H, 2 ꢃ CH2), 5.62 (bs, 2H, 2 ꢃ CH), 6.55 (d, J ¼ 8.5 Hz, 4H, ArH), 6.87 (d,
J ¼ 8.5 Hz, 4H, ArH), 7.15 (d, J ¼ 8.5 Hz, 4H, ArH), 7.56 (d, J ¼ 8.5 Hz, 4H,
ArH), 7.68 (s, 2H, 2 ꢃ ¼ CH), 9.30 (bs, 2H, OH). 13C NMR (400 MHz, DMSO-
d6, d ppm): 36.0 (2 ꢃ CH2), 60.38 (2 ꢃ CH), 67.08 (2 ꢃ CH2), 115.51 (2 ꢃ ¼ C),
115.51 (6ArC), 116.15 (4ArC), 126.28 (2ArC), 128.57 (2ArC), 130.06 (4ArC),
132.94 (2 ꢃ ¼ CH), 133.35 (6ArC), 156.14 (2 ꢃ C¼O), 160.90 (2 ꢃ C¼O). HRMS
(ES-TOF) m=z found 851.4293 (M þ Na), calculated 851.0 (M þ Na).
(ꢀ)-2-f5-[1-[4-(2-f4-[3-((ꢂ)-1-Carboxy-2-phenyl)-ethyl]-thiazolidin-(5)-
ylidenemethyl]-phenoxyg-ethoxy)-phenyl]-meth-(Z)-ylidene]-thiazolidin-3-
ylg-3-phenyl propionic acid (8). Yellow crystals, mp 178–181 ꢁC, yield 71%.
FTIR (KBr, cmꢂ1): 3500–2500 (O-H & N-H), 3012 (Ar-H), 2958 (AliC-H), 1692
1
(C¼O), 1503 (ArC¼C), 1221 (C¼S), 1143 (C-O), 1007 (C-N). HNMR (400 MHz,
DMSO-d6, d ppm): 3.39 (bs, 4H, 2 ꢃ CH2), 4.40 (s, 4H, 2 ꢃ CH2), 5.63 (bs, 2H,
2 ꢃ CH), 6.82–7.38 (m, 10H, ArH), 7.21 (d, J ¼ 8.5 Hz, 4H, ArH), 7.58 (d, J ¼ 8.5 Hz,
Hz, 4H, ArH), 7.70 (s, 2H, 2 ꢃ ¼ CH). 13C NMR (400 MHz, DMSO-d6, d ppm):
36.11 (2 ꢃ CH2), 60.40 (2 ꢃ CH), 67.11 (2 ꢃ CH2), 115.62 (2 ꢃ ¼ C), 115.74 (6ArC),
116.23 (4ArC), 126.36 (2ArC), 128.69 (2ArC), 130.28 (4ArC), 132.45 (2 x ¼ CH),
133.71 (6ArC), 156.30 (2 ꢃ C¼O), 160.70 (2 x C¼O). HRMS (ES-TOF) m=z found
819.2173 (M þ Na), calculated 819.0 (M þ Na).
5-[3-(1-Carboxymethyl)-thiazolidin-(5)-ylidenemethyl]-phenoxy]-ethoxy)-
phenyl]-meth-(Z)-ylidene]-thiazolidin-3-yl-ethanoic acid (9). Cream-colored
crystals, mp 242–247 ꢁC, yield 78%. FTIR (KBr, cmꢂ1): 3500–2500 (O-H & N-H),

SYNTHESIS OF 2-THIOXO-THIAZOLIDINE-4-ONES
3095
3027 (Ar-H), 2971 (AliC-H), 1679 (C¼O), 1492 (ArC¼C), 1235(C¼S), 1149 (C-O),
1026 (C-N). 13C NMR (500 MHz, DMSO-d6, d ppm): 36.07 (2 ꢃ CH2), 71.43
(2 ꢃ CH2), 115.67 (2 ꢃ ¼ C), 115.81 (6ArC), 116.19 (4ArC), 126.30 (2ArC), 128.65
(2ArC), 130.14 (4ArC), 132.40 (2 ꢃ ¼ CH), 133.61 (6ArC), 156.30 (2 ꢃ C¼O),
162.70 (2 ꢃ C¼O), 197.30 (C¼S). HRMS (ES-TOF) m=z found 639.0819 (M þ Na),
), calculated 639.0 (M þ Na).
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