Synthesis and reaction of 2-mercapto-3-arylpropanoic acids

Article abstract of DOI:10.1080/10426507.2011.649503

Two synthetic pathways for the preparation of 2-mercapto-3-arylpropanoic acids were developed. First, by the reaction of arenediazonium bromides with acrylic esters in the presence of CuBr, alkyl (2-bromo-3-aryl)propanoates were formed. Their cyclization with thiourea produced 5-(R-benzyl)-2-imino-4- thiazolidinones, which yielded 3-aryl-2-mercaptopropanoic acids by alkaline hydrolysis. Second, direct Meerwein arylation of acrylates in the presence of S-nucleophile (NaSH) allowed isolation of 3-phenyl-2-mercaptopropanoic acid in 8% yield. Such acids were used for cyclization with cyanoguanidine and phenyl isothiocyanate yielding 1-[5-(R-benzyl)-4-oxo-1,3-thiazolidin-2-ylidene] guanidines and new 5-(R-benzyl)-3-phenyl-2-thioxo-1,3-thiazolidin-4-one (rhodanine) derivatives correspondingly. Copyright Taylor and Francis Group, LLC 2012.

Full text of DOI:10.1080/10426507.2011.649503

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Phosphorus, Sulfur, and Silicon and the
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Synthesis and Reaction of 2-Mercapto-3-
Arylpropanoic Acids
Nazariy T. Pokhodylo a , Vasyl S. Matiychuk a & Mykola D. Obushak a
a Department of Organic Chemistry, Ivan Franko National University
of Lviv, Lviv, Ukraine
Version of record first published: 30 May 2012.
To cite this article: Nazariy T. Pokhodylo, Vasyl S. Matiychuk & Mykola D. Obushak (2012): Synthesis
and Reaction of 2-Mercapto-3-Arylpropanoic Acids, Phosphorus, Sulfur, and Silicon and the Related
Elements, 187:7, 850-858
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Phosphorus, Sulfur, and Silicon, 187:850–858, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.649503
SYNTHESIS AND REACTION
OF 2-MERCAPTO-3-ARYLPROPANOIC ACIDS
Nazariy T. Pokhodylo, Vasyl S. Matiychuk,
and Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv,
Lviv, Ukraine
GRAPHICAL ABSTRACT
OEt
O
O
O
3 b
NaNO2
HBr
H
(NH2)2CS
+ Br
OR2
NH2
N
N2
R1
Pyridine
EtOH
Br
NH
CuBr
Acetone
Path A
R1
S
R1
R1
5 a-i
1 a-i
2 a-i
4 a-i
OR2
O
NaOH
H2O
NaNO2
H2SO4
HBF4
OR2
SH
3 a, b
O
+ BF4
NaSH
-
NaOH
H2O
OH
SH
N2
O
CuSO4
Acetone
H2S
Path B
R1
6 j,k
6 a-i
2 j
1, 2, 5, 6: R = H (a), 2-Me (b), 3-Me (c), 2-Cl (d), 3-Cl (e), 4-Br (f), 3-CF3 (g), 3,4-Me2 (h), 2,5-Cl2 (i);
R2 = Me (3a,6j), Et (3b,6k).
Abstract Two synthetic pathways for the preparation of 2-mercapto-3-arylpropanoic acids
were developed. First, by the reaction of arenediazonium bromides with acrylic esters
in the presence of CuBr, alkyl (2-bromo-3-aryl)propanoates were formed. Their cycliza-
tion with thiourea produced 5-(R-benzyl)-2-imino-4-thiazolidinones, which yielded 3-aryl-2-
mercaptopropanoic acids by alkaline hydrolysis. Second, direct Meerwein arylation of acrylates
in the presence of S-nucleophile (NaSH) allowed isolation of 3-phenyl-2-mercaptopropanoic
acid in 8% yield. Such acids were used for cyclization with cyanoguanidine and phenyl isoth-
iocyanate yielding 1-[5-(R-benzyl)-4-oxo-1,3-thiazolidin-2-ylidene]guanidines and new 5-(R-
benzyl)-3-phenyl-2-thioxo-1,3-thiazolidin-4-one (rhodanine) derivatives correspondingly.
Keywords Mercapto acids; thiazolidinone derivatives; arylation; Meerwein reaction; cycliza-
tion; cyanoguanidine
INTRODUCTION
2-Mercapto-3-arylpropanoic acids have been the subjects of great interest due to
their application as close precursors of pharmaceutical substances. They are convenient
reagents in [2+3]-cyclocondensation for preparation of 4-thiazolidinones, among which
Received 8 November 2011; accepted 7 December 2011.
Address correspondence to Nazariy T. Pokhodylo, Department of Organic Chemistry, Ivan Franko National
University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine. E-mail: pokhodylo@gmail.com
850

SYNTHESIS AND REACTION OF 2-MERCAPTO-3-ARYLPROPANOIC ACIDS
851
Me
Me
S H
O
O
N
N
N
N
CO2H
H
H
SH
O
SH
O
CO2H
Gemopatrilat
Omapatrilat
O
O
Me
HS
N
N
H
O
N
HS
CO2H
N
H
CO2H
O
BMS-182657
SQ-26332
Me
O
Me
H
S
OH
SH
O
Me
N
NH
O
N
HO
Me
Me
O
Tazofelone
Me
I
Figure 1 Biologically active compounds containing fragments of 2-mercapto-3-arylpropanoic acids derivatives.
there are many compounds with a broad and potent biological activity.1 Compounds con-
taining the mercapto moiety often exhibit strong inhibitory effects on metal-containing
enzymes. For example, amides of 2-mercapto-3-phenylpropanoic acid Omapatrilat and
Gemopatrilat (Figure 1) were developed as vasopeptidase inhibitors for the treatment of
hypertension, congestive heart failure, and renal disease.2 α-Mercaptoacyl dipeptides SQ-
26332 and BMS-182657, shown in Figure 1, were demonstrated to be potent inhibitors
of angiotensin converting enzyme (ACE) and neutral endopeptidase.3 (S)-2-Mercapto-3-
phenylpropanoic acid was found as an effective competitive inhibitor of carboxypeptidase
A.4 A number of thioester derivatives of 2-mercapto-3-arylpropanoic acids were shown
as competitive inhibitors of IMP-1 metallo-L-lactamase.5 Furthermore, compound I (sub-
stituted α-mercapto-β-phenylpropanoic acid) was discovered to be an antihyperglycaemic
agent.6 Consequently, the development of methods of 2-mercapto-3-arylpropanoic acid
synthesis is an attractive target for researchers.
2-Mercapto-3-phenylpropanoic acid was first obtained by the sodium amalgam re-
duction of 3-phenyl-2-thioxo-propanoic acid.7 Currently, the synthesis of enantioenriched
α-mercapto carboxylic acids draws considerable attention.8 Several synthetic routes for
preparation of 2-mercapto-3-arylpropanoic acids have been recently proposed. For instance,
optically pure (S)-2-acetylthio-3-phenylpropanoic acid can be prepared in good yield from
inexpensive and commercially available L-phenylalanine via diazotization/bromination,
chiral inversion, and thioacetate substitution reactions.9 In addition, synthesis of enan-
tioenriched 4-thiazolidinone (-)-LY213829 (Tazofelone; Figure 1), which is used for the
treatment of inflammatory bowel disease, was performed from 3-(3,5-di-tert-butyl-4-
hydroxyphenyl)-2-sulfanylpropanoic acid10a or its amide,10b prepared by the rhodanine
ring opening with 2M NaOH or ammonia correspondingly.

852
N. T. POKHODYLO ET AL.
OEt
O
O
O
3 b
NaNO2
HBr
H
(NH2)2CS
NH2
+ Br
OR2
N
N2
R1
Pyridine
EtOH
Br
NH
CuBr
Acetone
R1
S
R1
Path A
R1
5 a-i
1 a-i
2 a-i
4 a-i
OR2
O
NaOH
H2O
NaNO2
H2SO4
HBF4
OR2
SH
3 a, b
O
+ BF4
NaSH
-
NaOH
H2O
OH
SH
N2
O
CuSO4
Acetone
H2S
Path B
R1
6 j,k
6 a-i
2 j
1, 2, 5, 6: R = H (a), 2-Me (b), 3-Me (c), 2-Cl (d), 3-Cl (e), 4-Br (f), 3-CF3 (g), 3,4-Me2 (h), 2,5-Cl2 (i);
R2 = Me (3a,6j), Et (3b,6k).
Scheme 1
RESULTS AND DISCUSSION
Herein, we suggest an approach to the synthesis of 2-mercapto-3-arylpropanoic
acids via the products of Meerwein arylation of acrylates. We selected alkyl 3-aryl-2-
bromopropanoates as precursors, which were previously used for preparation of target
mercapto acids.4,5b,8d We have reported the synthesis of alkyl 3-aryl-2-bromopropanoates 4
by the reaction of arenediazonium bromides 2 with ethyl acrylate in acetone in the presence
of CuBr earlier (Scheme 1, Path A).11 It is noteworthy that Meerwein arylation afforded alkyl
3-aryl-2-bromopropanoates from available anilines 1 in moderate yields (40%–60%) and
allowed slight variation of substituents in the aromatic fragment. Furthermore, it was shown
that esters 4a–i reacted with thiourea forming 5-(R1-benzyl)-2-imino-4-thiazolidinones 5
in high yields,11 while boiling in ethanol in the presence of pyridine. We also found that the
obtained compounds 5a–i could be readily transformed into the corresponding 2-mercapto-
3-arylpropanoic acids 6a–i via opening of the thiazolidine ring by alkaline hydrolyze. Acids
were isolated in approximately theoretical yields after the HCl addition.
During the last years, we have focused our research on the development of an effi-
cient methodology to Meerwein arylation of acrylates in the presence of S-nucleophile for
the one-step preparation of 2-mercapto-3-arylpropanoic acids from anilines and acrylates
(Scheme 1, Path B). Several experimental conditions were tested and finally 2-mercapto-
3-phenylpropanoic acid was isolated in 8% yield only. The reason is that a few concurrent
reactions occurred. When arenediazonium salts were decomposed in the presence of olefines
and sulfur compounds (H2S, NaSH), aryl radicals reacted more rapidly with S-nucleophile
than with the olefine. Newly formed arenesulfanyl radicals led to the formation of aryl-
sulfides and polysulfides. Moreover, the obtained 2-mercapto-3-phenylpropanoic acid, in
the reaction of phenyl radical with the acrylic substrate and SH anion, was disposed to
oxidation with arenediazonium salts and further radical reactions leading to formation of
tarry by-products.
The structure of acids 6 was confirmed by the 1Н NMR spectroscopy. As a result of
diastereotopic hydrogen atoms in a group CH2, the fragment of CH2CH appeared as a spin
system of ABX and observed in spectra as three doublet of doublets.

SYNTHESIS AND REACTION OF 2-MERCAPTO-3-ARYLPROPANOIC ACIDS
853
NH
N
N
NH2
H
PhNCS
O
O
O
OH
SH
7
H
HN
N
9
N
N
NH2
R
R
EtOH
S
S
NH3 H2O
R
S
10 a-d
6 a,b,e,g-i
8 a-f
8: R = H (a), 2-Me (b), 3-Cl (c), 3-CF3 (d),
3,4-Me2 (e), 2,5-Cl2 (f).
10: R = 4-Br (a), 3-CF3 (b),
3,4-Me2 (c), 2,5-Cl2 (d).
Scheme 2
The proposed synthetic route of preparation of 2-mercapto-3-arylpropanoic acids
in good general yields by a multi-step procedure enables creation of the library of such
compounds.
Additionally, two paths of subsequent cyclization of the obtained 2-mercapto-3-
arylpropanoic acids were studied. By the reaction of mercapto acids 6a,b,e,g–i with
cyanoguanidine 7 under base catalysis, 1-(5-aryl-4-oxo-1,3-thiazolidin-2-ylidene)guanidines
8a–f were prepared (Scheme 2). The isolated guanidines 8 were prospective reagents for
further modification12 and attractive from a biological viewpoint.13 In the 1H NMR spectra,
the guanidine fragment was identified by the presence of br.s signals at δ = 7.07 ppm for
the hydrogen bonded NH2 group and δ = 8.22 ppm identified as the C NH + C(O)NH. Si-
multaneously, the reactions of 2-mercapto-3-arylpropanoic acids with phenylisothiocyanate
were studied. Heating the mixture of compounds 6 and 9 in ethanol under reflux led to
formation of the rhodanine ring (10a–d, Scheme 2).
CONCLUSION
In conclusion, new synthetic paths for the synthesis of 2-mercapto-3-arylpropanoic
acids from simple, cheap, and commercially available anilines and acrylates, which rep-
resent a category of versatile synthetic building blocks and potent biologically active sub-
stances, were introduced. The prepared mercapto acids were used to synthesize a variety
of benzyl substituted 1-[4-oxo-1,3-thiazolidin-2-ylidene]guanidines and rhodanines.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury 400 (400 MHz) and Bruker
1
500 (500 MHz) instruments. The H chemical shifts were reported in parts per million
relative to tetramethylsilane or the deuterated solvent as an internal reference. Mass spectra
were run using Agilent 1100 series LC/MSD with an APCI ionization mode. Low-resolution
electron impact mass spectra (EIMS) were obtained on a 7683B LC/MS instrument (Agilent
Technology), m/z (rel intensity in %); ionization energy 70 eV. The evolution of the reactions
and purity of the synthesized compounds were monitored chromatographically on Silufol
UV-254 plates.
General Procedure for the Synthesis of 3-aryl-2-sulfanylpropanoic
Acids 6a–i
Path A. A solution of NaNO2 (16.6 g, 0.24 mol) in H2O (30 mL) was added dropwise
to a stirred, ice-cooled mixture of the substituted aniline 1 (0.22 mol), aqueous HBr (47%,

854
N. T. POKHODYLO ET AL.
◦
95 g, 0.55 mol), and water (30 mL) below 0–5 C. The cold diazonium salt solution was
slowly added to a vigorously stirred solution of CuBr (3 g, 21 mmol) and ethyl acrylate
◦
3b (22.0 g, 0.22 mol) in acetone (150 mL) at 40 C. The reaction was exothermic and
the dropping rate was adjusted at such a rate that nitrogen was evolved at 2–3 bubbles/sec
(0.5–1 h). The resulting homogeneous solution was stirred for 30 min at 40 ◦C and diluted
with H2O. The organic phase was dried with MgSO4 and concentrated. The residue was
purified by distillation under reduced pressure to give ethyl 3-aryl-2-bromopropanoates
4a–i (40%–60% yield).
The mixture of compounds 4a–i (4.1 mmol), pyridine (0.32 g, 4.1 mmol), thiourea
(0.31 g, 4.1 mmol), and ethanol (15 mL) was refluxed for 20–30 min. After cooling,
the crystals were collected by filtration and recrystallized from EtOH/DMF to yield 5-R-
benzyl-2-iminothiazolidin-4-ones 5a–i.
The solution of appropriate compound 5 (10 mmol) dissolved in 50% aqueous
NaOH/EtOH (1:1, 20 mL) was heated under reflux until the starting compound 5 was
completely consumed as indicated by reversed phase HPLC. The EtOH was removed in
vacuo; then the residue was diluted in water (10 mL), cooled to 0 ◦C, and acidified using
conc. HCl (pH ≈ 2). The solid was filtered, dried, and recrystallized from petroleum ether
to give acids 6a–i.
Path B. To the solution of aniline (1.84 g, 20 mmol) in H2O (5 mL) and HBF4
◦
(50% solution in Et2O, 5 mL) at 0 C, the solution of sodium nitrite (1.4 g, 20 mmol)
in H2O (5 mL) was added dropwise. The resulting heterogeneous mixture was stirred for
30 min at 0 ◦C, filtered, and washed with cold EtOH (5 mL) and Et2O (3 × 10 mL). The
diazonium salt and freshly prepared NaSH (1.51 g, 27 mmol) were subsequently slowly
added to a vigorously stirred solution of CuSO4 (0.3 g, 2.1 mmol) and methyl/ethyl acrylate
3a,b (22 mmol) in acetone (50 mL) at room temperature. The reaction was exothermic and
the dropping rate was adjusted at such a rate that nitrogen was evolved at 2–3 bubbles/sec
(0.5–1 h). The resulting homogeneous solution was stirred for 30 min at 40 ◦C and diluted
with H2O. The organic phase was separated and heated with 40% aqueous NaOH for
1 h. The water fraction was separated, acidified, and extracted with CH2Cl2. The crude
product was concentrated under reduced pressure and purified by flash chromatography
(15% EtOAc-petroleum ether) to give the target product 6a in 8% yield.
3-Phenyl-2-sulfanylpropanoic acid (6a). This compound w◦as isolated as a white
◦
1
powdered solid, mp 49–50 С (light petroleum; Ref.7 mp 49–50 С) in 95% yield. H
NMR ppm: δ 2.17 (d, J = 8.8 Hz, 1Н, SH), 3.01 (dd, J = 13.7, 6.8 Hz, 1Н, СН2), 3.25
(dd, J = 13.7, 8.8 Hz, 1Н, СН2), 3.62 (m, 1Н, СН), 7.19–7.33 (m, 5H, HPh), 10.55 (br.s,
1H, COOH). MS m/z: 182 (M+). Anal. requires for C9H10O2S (182.24) calcd./found: C,
59.32/59.70; H, 5.53/5.84; S, 17.59/17.11.
3-(2-Methylphenyl)-2-sulfanylpropanoic acid (6b). This compound was isolated
as a white powdered solid, mp 79–80 ◦С (light petroleum) in 93% yield. 1H NMR ppm: δ
2.32 (s, 3Н, СН3), 2.77 (d, J = 8.6 Hz, 1Н, SH), 2.89 (dd, J = 13.6, 6.8 Hz, 1Н, СН2),
3.16 (dd, J = 13.6, 7.8 Hz, 1Н, СН2), 3.51 (m, 1Н, СН), 7.07–7.15 (m, 4H, HAr), 12.54
(br.s, 1H, COOH). MS m/z: 196 (M+). Anal. requires for C10H12O2S (196.27) calcd./found:
C, 61.20/61.13; H, 6.16/5.81; S, 16.34/16.06.
3-(3-Methylphenyl)-2-sulfanylpropanoic acid (6c). This compound was isolated
◦
1
as a white powdered solid, mp 75–76 С (light petroleum) in 95% yield. H NMR ppm:
δ 2.30 (s, 3Н, СН3), 2.67 (d, J = 8.8 Hz, 1Н, SH), 2.84 (dd, J = 13.7, 6.8 Hz, 1Н,
СН2), 3.10 (dd, J = 13.7, 7.8 Hz, 1Н, СН2), 3.50 (m, СН), 6.96–7.03 (m, 3H, HAr),
7.14 (t, J = 7.5 Hz, 1H, HAr-5), 12.52 (br.s, 1H, COOH). MS m/z: 196 (M+). Anal.

SYNTHESIS AND REACTION OF 2-MERCAPTO-3-ARYLPROPANOIC ACIDS
855
requires for C10H12O2S (196.27) calcd./found: C, 61.20/60.82; H, 6.16/6.46; S, 16.34/
16.68.
3-(2-Chlorophenyl)-2-sulfanylpropanoic acid (6d). This compound was isolated
as a white powdered solid, mp 103–104 ◦С (light petroleum) in 95% yield. 1H NMR ppm:
δ 2.85 (d, J = 8.8 Hz, 1Н, SH), 3.02 (dd, J = 13.7, 6.8 Hz, 1Н, СН2), 3.25 (dd, J = 14.0,
8.2 Hz, 1Н, СН2), 3.58 (m, 1Н, СН), 7.21–7.26 (m, 2H, HAr-4,5), 7.29–7.33 (m, 1H,
HAr-6), 7.35–7.39 (m, 1H, HAr-3), 12.50 (br.s, 1H, COOH). MS m/z: 216 (M+). Anal. re-
quires for C9H9ClO2S (216.68) calcd./found: C, 49.89/49.62; H, 4.19/4.47; S, 14.80/14.61.
3-(3-Chlorophenyl)-2-sulfanylpropanoic acid (6e). This compound was isolated
◦
1
as a white powdered solid, mp 73–74 С (light petroleum) in 93% yield. H NMR ppm:
δ 2.78 (d, J = 8.9 Hz, 1Н, SH), 2.90 (dd, J = 13.8, 6.9 Hz, 1Н, СН2), 3.13 (dd, J =
13.8, 8.4 Hz, 1Н, СН2), 3.56 (m, 1Н, СН), 7.18 (t, J = 7.2 Hz, 1H, HAr-5), 7.21 (d, J =
6.81 Hz, 1H, HAr-6), 7.25–7.30 (m, 2H, HAr-2,4), 12.62 (br.s, 1H, COOH). MS m/z: 216
(M+). Anal. requires for C9H9ClO2S (216.68) calcd./found: C, 49.89/50.17; H, 4.19/3.90;
S, 14.80/14.70.
3-(4-Bromophenyl)-2-sulfanylpropanoic acid (6f). This compound was isolated as
◦
1
a white powdered solid, mp 98–99 С (light petroleum) in 96% yield. H NMR ppm: δ
2.77 (d, J = 9.0 Hz, 1Н, SH), 2.88 (dd, J = 14.0, 7.0 Hz, 1Н, СН2), 3.10 (dd, J = 14.0,
8.9 Hz, 1Н, СН2), 3.58 (dd, J = 14.6, 8.5 Hz, 1Н, СН), 7.02 (d, 2Н, J = 8.4 Hz, HAr-2,6),
7.24 (d, 2Н, J = 8.4 Hz, HAr-3,5). MS m/z: 260, 262 (M+). Anal. requires for C9H9BrO2S
(261.14) calcd./found: C, 41.40/41.18; H, 3.47/3.26; S, 12.28/12.36.
2-Sulfanyl-3-[3-(trifluoromethyl)phenyl]propanoic acid (6g). This compound was
isolated as an oil, bp 172 ◦С/5 mm Hg in 92% yield. 1H NMR ppm: δ 2.72 (d, J = 8.9 Hz,
1Н, SH), 2.84 (dd, J = 13.9, 7.0 Hz, 1Н, СН2), 3.17 (dd, J = 14.0, 8.5 Hz, 1Н, СН2), 3.74
(dd, J = 15.6, 8.5 Hz, 1Н, СН), 7.38–7.49 (m, 4Н, HAr). MS m/z: 250 (M+). Anal. requires
for C10H9F3O2S (250.24) calcd./found: C, 48.00/48.29; H, 3.63/3.37; S, 12.81/13.10.
3-(3,4-Dimethylphenyl)-2-sulfanylpropanoic acid (6h). This compound was iso-
◦
1
lated as a white powdered solid, mp 83–84 С (light petroleum) in 94% yield. H NMR
ppm: δ 2.21 (s, 6Н, СН3), 2.67 (d, J = 8.7 Hz, 1Н, SH), 2.87 (dd, J = 13.7, 6.7 Hz, 1Н,
СН2), 3.12 (dd, J = 13.7, 8.5 Hz, 1Н, СН2), 3.50 (dd, J = 15.4, 8.5 Hz, СН), 6.90 (d,
J = 7.8 Hz, 1H, HAr-5), 6.95 (s, 1H, HAr-2), 6.97 (d, J = 7.8 Hz, 1H, HAr-6). MS m/z: 210
(M+). Anal. requires for C11H14O2S (210.29) calcd./found: C, 62.83/62.57; H, 6.71/7.05;
S, 15.25/15.03.
3-(2,5-Dichlorophenyl)-2-sulfanylpropanoic acid (6i). This compound was isolated
as a white powdered solid, mp 116–117 ◦С (light petroleum) in 95% yield. 1H NMR ppm:
δ 2.82 (d, J = 9.2 Hz, 1Н, SH), 2.95 (dd, J = 14.2, 7.0 Hz, 1Н, СН2), 3.19 (dd, J = 14.2,
8.4 Hz, 1Н, СН2), 3.59 (dd, J = 15.6, 8.4 Hz, 1Н, СН), 7.18–7.36 (m, 3Н, HAr). MS m/z:
250, 252 (M+). Anal. requires for C9H8Cl2O2S (251.13) calcd./found: C, 43.05/43.30; H,
3.21/3.43; S, 12.77/12.60.
General Procedure for the Synthesis of 1-[5-(R-benzyl)-4-oxo-1,
3-thiazolidin-2-ylidene]guanidines 8a–f
The mixture of appropriate 3-aryl-2-sulfanylpropanoic acid 6 (10 mmol), cyanoguani-
dine (0.84 g, 10 mmol), and a few drops of conc. NH3 aqueous solution was dissolved in
ethanol, heated under reflux for 2 h, and cooled to room temperature. The precipitate was
filtered and successively washed with H2O (30 mL) and petroleum ether. The crude product
was purified by recrystallization (EtOH) to give pure compounds 8.

856
N. T. POKHODYLO ET AL.
1-[5-Benzyl-4-oxo-1,3-thiazolidin-2-ylidene]guanidine (8a). This compound was
isolated as a white powdered solid, mp 203–204 ◦С (ethanol) in 70% yield. 1H NMR ppm:
δ 2.80 (dd, J = 14.0, 10.4 Hz, 1Н, СН2), 3.44 (dd, J = 14.0, 3.7 Hz, 1Н, СН2), 4.23
(dd, J = 10.4, 3.7 Hz, 1Н, СН), 7.09 (br.s, 2Н, NH2), 7.18–7.30 (m, 5H, Ph), 8.21 (br.s,
2Н, C NH + C(O)NH). MS m/z: 248 (M+). Anal. requires for C11H12N4OS (248.30)
calcd./found: C, 53.21/53.56; H, 4.87/4.68; N, 22.56/22.44.
1-[5-(2-Methylbenzyl)-4-oxo-1,3-thiazolidin-2-ylidene]guanidine (8b). This com-
pound was isolated as a white powdered solid, mp 251–252 ◦С (ethanol) in 63% yield. 1H
NMR ppm: δ 2.33 (s, 3Н, СН3), 2.73 (dd, J = 14.3, 11.3 Hz, 1Н, СН2), 3.50 (dd, J = 14.3,
3.4 Hz, 1Н, СН2), 4.20 (dd, J = 11.3, 3.4 Hz, 1Н, СН), 7.08–7.16 (m, 6Н, HAr+NH2),
8.23 (br.s, 2Н, C NH + C(O)NH). MS m/z: 262 (M+). Anal. requires for C12H14N4OS
(262.33) calcd./found: C, 54.94/54.72; H, 5.38/5.21; N, 21.36/21.53.
1-[5-(3-Chlorobenzyl)-4-oxo-1,3-thiazolidin-2-ylidene]guanidine (8c). This com-
pound was isolated as a white powdered solid, mp 237–238 ◦С (ethanol) in 62% yield. 1H
NMR ppm: δ 2.85 (dd, J = 14.0, 10.0 Hz, 1Н, СН2), 3.40 (dd, J = 14.0, 4.0 Hz, 1Н,
СН2), 4.31 (dd, J = 9.7, 3.7 Hz, 1Н, СН), 7.16–7.30 (m, 6Н, HAr+NH2), 8.20 (br.s, 2Н,
C NH + C(O)NH). MS m/z: 282 (M+). Anal. requires for C11H11ClN4OS (282.75)
calcd./found: C, 46.73/46.54; H, 3.92/4.09; N, 19.82/19.67.
1-{4-Oxo-5-[3-(trifluoromethyl)benzyl]-1,3-thiazolidin-2-ylidene}guanidine (8d).
This compound was isolated as a white powdered solid, mp 196–197 ◦С (ethanol) in 67%
1
yield. H NMR ppm: δ 2.95 (dd, J = 14.0, 9.8 Hz, 1Н, СН2), 3.49 (dd, J = 14.0, 3.9
Hz, 1Н, СН2), 4.22 (dd, J = 9.8, 4.0 Hz, 1Н, СН), 7.07 (br.s, 2Н, NH2), 7.44–7.51
(m, 4Н, HAr), 8.16 (br.s, 2Н, C NH + C(O)NH). MS m/z: 316 (M+). Anal. requires for
C12H11F3N4OS (316.30) calcd./found: C, 45.57/45.77; H, 3.51/3.34; N, 17.71/17.90.
1-[5-(3,4-Dimethylbenzyl)-4-oxo-1,3-thiazolidin-2-ylidene]guanidine (8e). This
◦
compound was isolated as a white powdered solid, mp 240–241 С (ethanol) in 72%
yield. 1H NMR ppm: δ 2.20 (s, 3Н, СН3), 2.22 (s, 3Н, СН3), 2.67 (dd, J = 13.9, 10.9 Hz,
1Н, СН2), 3.39 (dd, J = 14.0, 3.5 Hz, 1Н, СН2), 4.09 (dd, J = 10.8, 3.6 Hz, 1Н, СН),
6.90 (d, J = 7.7 Hz, 1H, HAr-5), 6.95 (s, 1H, HAr-2), 6.97 (d, J = 7.9 Hz, 1H, HAr-6), 7.04
(br.s, 2H, NH2), 8.19 (br.s, 2Н, C NH + C(O)NH). MS m/z: 276 (M+). Anal. requires for
C13H16N4OS (276.36) calcd./found: C, 56.50/56.33; H, 5.84/5.67; N, 20.27/20.45.
1-[5-(2,5-Dichlorobenzyl)-4-oxo-1,3-thiazolidin-2-ylidene]guanidine (8f). This
compound was isolated as a white powdered solid, mp 261–262 ◦С (ethanol) in 71% yield.
1H NMR ppm: δ 2.85 (dd, J = 14.0, 11.0 Hz, 1Н, СН2), 3.67 (dd, J = 14.0, 3.5 Hz, 1Н,
СН2), 4.26 (dd, J = 11.0, 3.6 Hz, 1Н, СН), 6.96–7.38 (m, 5Н, HAr+NH2), 8.24 (br.s, 2Н,
C NH + C(O)NH). MS m/z: 316, 318 (M+). Anal. requires for C11H10Cl2N4OS (317.19)
calcd./found: C, 41.65/41.78; H, 3.18/3.03; N, 17.66/17.43.
General Procedure for the Synthesis of 5-(R-benzyl)-3-phenyl-2-thioxo-
1,3-thiazolidin-4-ones (9a–d)
The mixture of appropriate 3-aryl-2-sulfanylpropanoic acid 6 (10 mmol) and
phenylisothiocyanate (1.35 g, 10 mmol) was heated under reflux for 12 h. Then the mixture
was cooled and H2O was added dropwise until the solid started to precipitate. The product
was filtered and purified by recrystallization from diluted EtOH.
5-(4-Bromobenzyl)-3-phenyl-2-thioxo-1,3-thiazolidin-4-one (9a). This compound
◦
1
was isolated as light yellow crystals, mp 148–149 С (ethanol) in 84% yield. H NMR
ppm: δ 3.27 (dd, J = 14.2, 9.2 Hz, 1Н, СН2), 3.45 (dd, J = 14.2, 5.2 Hz, 1Н, СН2),

SYNTHESIS AND REACTION OF 2-MERCAPTO-3-ARYLPROPANOIC ACIDS
857
4.96 (dd, J = 9.2, 5.2 Hz, 1Н, СН), 7.04 (d, 2Н, J = 8.4 Hz, HAr-2,6), 7.27 (d, 2Н,
J = 8.4 Hz, HAr-3,5), 7.40–7.54 (m, 5Н, Ph). MS m/z: 377, 379 (M+). Anal. requires for
C16H12BrNOS2 (378.31) calcd./found: C, 50.80/50.59; H, 3.20/3.28; N, 3.70/3.87.
3-Phenyl-2-thioxo-5-[3-(trifluoromethyl)benzyl]-1,3-thiazolidin-4-one (9b). This
compound was isolated as light yellow crystals, mp 78–79 ◦С (ethanol) in 86% yield. 1H
NMR ppm: δ 3.44 (dd, J = 14.0, 8.1 Hz, 1Н, СН2), 3.58 (dd, J = 14.0, 4.5 Hz, 1Н, СН2),
5.01 (dd, J = 8.0, 4.6 Hz, 1Н, СН), 7.42–7.49 (m, 4Н, Ar), 7.51–7.59 (m, 5Н, Ph). MS
m/z: 367 (M+). Anal. requires for = C17H12F3NOS2 (367.41) calcd./found: C, 55.57/55.35;
H, 3.29/3.18; N, 3.81/3.65.
5-(3,4-Dimethylbenzyl)-3-phenyl-2-thioxo-1,3-thiazolidin-4-one (9c). This com-
pound was isolated as light yellow crystals, mp 77–78 ◦С (ethanol) in 75% yield. 1H NMR
ppm: δ 2.26 (s, 6Н, СН3), 3.20 (dd, J = 14.0, 9.0 Hz, 1Н, СН2), 3.43 (dd, J = 14.0, 4.0
Hz, 1Н, СН2), 4.87 (dd, J = 9.0, 4.0 Hz, 1Н, СН), 6.95–7.07 (m, 5Н, HPh), 7.43–7.51
(m, 3Н, HAr). MS m/z: 327 (M+). Anal. requires for C18H17NOS2 (327.46) calcd./found:
C, 66.02/66.14; H, 5.23/5.08; N, 4.28/4.16.
5-(2,5-Dichlorobenzyl)-3-phenyl-2-thioxo-1,3-thiazolidin-4-one (9d). This com-
◦
1
pound was isolated as light yellow crystals, mp 121–122 С (ethanol) in 83% yield. H
NMR ppm: δ 3.39 (dd, J = 14.2, 9.2 Hz, 1Н, СН2), 3.72 (dd, J = 14.2, 5.2 Hz, 1Н, СН2),
5.01 (dd, J = 9.2, 5.2 Hz, 1Н, СН), 7.18–7.36 (m, 3Н, HAr), 7.40–7.54 (m, 5Н, Ph). MS
m/z: 368 (M+). Anal. requires for C16H11Cl2NOS2 (368.30) calcd./found: C, 52.18/52.00;
H, 3.01/2.89; N, 3.80/3.99.
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