A facile one-pot synthesis and heterocyclisation of (R)-2-amino-3- ((aroylcarbamothioyl)thio)propanoic acids

Article abstract of DOI:10.3184/174751914X13921421504937

A series of (R)-2-amino-3-((aroylcarbamothioyl)thio)propanoic acid derivatives have been synthesised by a one-pot, threecomponent reaction of L-cysteine with ammonium thiocyanate in the presence of various acid chlorides under solvent-free conditions in excellent yields. These compounds were converted to (R)-2-thioxothiazolidine-4-carboxylic acid in water under reflux conditions.

Full text of DOI:10.3184/174751914X13921421504937

172 RESEARCH PAPER
VOL. 38 MARCH, 172–174
JOURNAL OF CHEMICAL RESEARCH 2014
A facile one-pot synthesis and heterocyclisation of
(R)-2-amino-3-((aroylcarbamothioyl)thio)propanoic acids
Razieh Mohebat* and Elahe Kafrizi
Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
A series of (R)-2-amino-3-((aroylcarbamothioyl)thio)propanoic acid derivatives have been synthesised by a one-pot, three-
component reaction of L-cysteine with ammonium thiocyanate in the presence of various acid chlorides under solvent-free
conditions in excellent yields. These compounds were converted to (R)-2-thioxothiazolidine-4-carboxylic acid in water under
reflux conditions.
Keywords: (R)-2-amino-3-((aroylcarbamothioyl)thio)propanoic acid, (R)-2-thioxothiazolidine-4-carboxylic acid, acid chlorides,
L-cysteine, ammonium thiocyanate
L-Cysteine, a naturally occurring amino acid, has an
important role in many biological processes.1,2 Cysteine and its
derivatives are present in various cosmetic and pharmaceutical
preparations.3 Recently, the chemistry of isothiocyanates
has been studied, as these compounds are strong cancer
chemopreventors.4–6 Many different isothiocyanates (more than
25) block the carcinogenic effects of more than 12 chemically
different types of carcinogens in at least 10 different target
sites in three species of rodent7. Isothiocyanates are extremely
useful in organic synthesis.8,9 Several methods to prepare
isothiocyanates and the corresponding mercapturic acids have
been developed.10–15
Thiazolidine-2-thiones and their derivatives exhibit a range of
biological activities, such as hepatoprotective,16 antibacterial,17
antifungal,18 analgesic,19 insecticide,20 protein modification,21
antiinflammatory and immunosuppressive activities.22
As part of our current studies on the development of new
routes to sulfur-containing organic compounds synthesis,23–25 we
now describe a simple one-pot synthesis of six mercapturic acids
derived from aroyl isothiocyanates and L-cysteine under solvent-
free conditions. We have also converted these isothiocyanate-
derived mercapturic acids into (R)-2-thioxothiazolidine-4-
carboxylic acid in water under reflux conditions.
Results and discussion
(R)-2-amino-3-((aroylcarbamothioyl)thio)propanoic acids
4
were synthesised by the one-pot, three-component reaction
of L-cysteine with ammonium thiocyanate in the presence
of aroyl chlorides under solvent-free conditions in excellent
yields. The compounds 4 were then converted into (R)-2-
thioxothiazolidine-4-carboxylic acid
5 with high purity
(Scheme 1). The synthesis of compound 5 and compounds 6
has previously been described.26–31 The melting point and NMR
data were identical with those reported (see Table 1).
The structures of compounds 4a–f, 5, 6a–f were confirmed
1
by IR, H NMR, 13C NMR, LCMS, and elemental analysis.
For example, the 1H NMR spectrum of 4a showed two singlets
(δꢀ=7.20 and 9.02 ppm) assigned to the protons of the NH
groups with a singlet at δꢀ=11.14 for the COOH group. These
disappear after the addition of a few drops of D2O to DMSO
solution of 4a. The aromatic protons resonated between 8.12
and 8.34 ppm.
The 13C NMR spectrum of compound 4a shows nine distinct
signals, consistent with the proposed structure. The mass
spectrum of 4a displayed the molecular ion peak at m/z= 329.
The IR spectrum of compound 4a also supported the suggested
structure since strong absorption bands were observed at 3385,
3105 and 1670 cm–1 respectively for the NH and carbonyl groups.
O
COOH
solvent-free
HS
NH4SCN
Ar
Cl
O
r. t.
NH2
1
3
2
COOH
O
O
S
water
reflux
S
Ar
N
H
H
O
N
H
S
Ar
NH2
(76–94%)
NH2
S
5
6
4
20
([α]D –86.7 (c 0.25, H2O)
Lit. [α]D –88.7 (c 0.25, H2O)32)
16
Scheme 1 Synthesis and interconversion of (R)-2-amino-3-((aroylcarbamothioyl)thio)propanoic acids.
* Correspondent. E-mail: mohebat@iauyazd.ac.ir
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JOURNAL OF CHEMICAL RESEARCH 2014 173
Table 1 Yields of (R)-2-amino-3-((aroylcarbamothioyl)thio)propanoic acids 4a–f and benzamides 6a–f from the reaction
between L-cysteine and acid chlorides in the presence of ammonium thiocyanate (Scheme 1)
No.
1
Ar
4
Yield/%a
97
6
Yield/%a
94
M.p./°C
198–200
141–143
190–192
141–142
94–96
Lit.9 m.p./°C
4-NO2–C6H4
3-NO2–C6H4
4-Br–C6H4
2-CH3–C6H4
3-CH3–C6H4
C6H5
4a
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
201
142
189
143
95
2
93
91
3
91
87
4
80
76
5
83
78
6
88
84
127–129
129
aYields refer to the pure isolated products.
resulting precipitate was collected by filtration on a Buchner funnel
and recrystallised from EtOH to afford the pure title compounds.
A tentative mechanism for this transformation is shown in
Scheme 2.
It is conceivable that the aroyl chloride 1 reacts with
ammonium thiocyanate to form aroyl thiocyanate 2. The
addition of L-cysteine 3 generates 4 which is converted to
compound 5 by the elimination of benzamide.
In conclusion, we have developed a straightforward method
for the synthesis of isothiocyanate-derived mercapturic acids
under solvent-free conditions. (R)-2-Thioxothiazolidine-4-
carboxylic acid is formed in water under reflux conditions.
This procedure provides several advantages such as cleaner
reactions, shorter reaction times and affords excellent yields.
Synthesisꢀofꢀcompoundꢀ5ꢀandꢀbenzamides;ꢀgeneralꢀprocedure
The reaction mixture was stirred at room temperature for 2 h under
solvent-free conditions. The progress of the reaction was monitored
by TLC. After completion of the reaction, the resulting mixture
was refluxed in water (5 mL) for 1 h and extracted with ethyl acetate
(3×5 mL). After evaporation of the solvent, the resulting crude
material was purified by column chromatography on silica using
n-hexane/ethyl acetate (2:1) as eluent to give compound 5ꢀ and
benzamides.
(R)-2-Amino-3-(((4-nitrobenzoyl)carbamothioyl)thio)propanoicꢀ
acidꢀ(4a): White powder, yield (97%), m.p. 163–165 °C; [α]D21 –13.2 (c
1.00, DMSO); IR (KBr) (νmax): 3385, 3105, 2995, 1670, 1607, 1535, 1396,
Experimental
1
1348, 1297, 1204 cm–1; H NMR (500 MHz, DMSO-d6): δ 2.89 (1H,
Melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Costech ECS
4010 CHNS–O analyser at analytical laboratory of Islamic Azad
University Yazd branch. Optical rotations were determined at 589 nm
(sodium D line) using a Atago-Ap-300 digital polarimeter, products
were dissolved in DMSO (g 100 mL–1). Mass spectra were recorded on
a FINNIGAN-MAT 8430 mass spectrometer operating at an ionisation
potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470
spectrometer. 1H and 13C NMR spectra were recorded on Bruker
DRX-500 Avance spectrometer for solutions in d6-DMSO using TMS
as internal standard. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without further
purification.
dd, Jꢀ=13.8, 8.7, SCH2), 3.03 (1H,ꢀdd, Jꢀ=13.8, 3.8, SCH2), 4.54 (1H, m,
CHCOOH), 7.20 (2H, s, NH2), 8.12 (2 H, d, J=8.7 Hz, 2CHarom), 8.34 (2
H, d, J=8.7 Hz, 2CHarom), 9.02 (1H, s, NH), 11.14 (1H, s, COOH) ppm;
13C NMR (125 MHz, DMSO-d6): δ 34.2 (CH2), 53.2 (CH), 124.3, 131.4,
138.3 and 150.9 (carbons of aromatic), 166.9 and 170.1 (2C=O), 197.5
(C=S) ppm; MS (m/z, %): 329 (M+, 4). Anal. calcd for C11H11N3O5S2, C,
40.11; H, 3.37; N, 12.76; S, 19.47; found: C, 39.91; H, 3.40; N, 12.73; S,
19.37%;
(R)-2-Amino-3-(((3-nitrobenzoyl)carbamothioyl)thio)propanoicꢀ
21
acidꢀ(4b): White powder, yield (93%), m.p. 156–158 °C; [α]D –16.4
(c 1.01, DMSO); IR (KBr) (νmax): 3415, 3185, 2995, 1670, 1613, 1524,
1494, 1382, 1346, 1294, 1204 cm–1; 1H NMR (500 MHz, DMSO-d6): δ
2.92 (1H, dd, Jꢀ=14.1, 8.7, SCH2), 3.02 (1H,ꢀdd, Jꢀ=13.7, 4.1, SCH2), 4.56
(1H, m, CHCOOH), 7.15 (2H, s, NH2), 7.80 (1H, t, J=8.0 Hz, 1CHarom),
8.34 (1H, d, J=7.9 Hz, 1CHarom), 8.41 (1H, d, J=7.5 Hz, 1CHarom),
Synthesisꢀofꢀcompoundsꢀ4;ꢀgeneralꢀprocedure
Aroyl chloride (2 mmol) was added to ammonium thiocyanate
(2 mmol) in a 50 mL flask at room temperature. The reaction mixture
was stirred in a water bath at about 60 °C for 5 min. Then, L-cysteine 2
(2 mmol) was added slowly and the contents were stirred for 2 h at room
temperature under solvent-free conditions. The progress of the reaction
was monitored by TLC. After completion of the reaction, distilled
water (15 mL) was added over 5 min to the reaction mixture. The
8.74 (1H, s, 1CHarom), 9.09 (1H, s, NH), 11.30 (1H, s, COOH) ppm; 13
C
NMR (125 MHz, DMSO-d6): δ 33.3 (CH2), 51.9 (CH), 122.1, 126.2,
129.9, 131.3, 133.0 and 150.6 (carbons of aromatic), 166.5 and 170.1
(2C=O), 196.6 (C=S) ppm; MS (m/z, %): 329 (M+, 4). Anal. calcd for
C11H11N3O5S2, C, 40.11; H, 3.37; N, 12.76; S, 19.47; found: C, 39.94; H,
3.47; N, 12.74; S, 19.42%.
O
O
3
NH4SCN
r
A
N
C
Ar
S
Cl
7
2
1
COOH
NH
O
S
O
–
ArCONH2
S
Ar
N
H
O
S
H
NH2
S
5
4
Scheme 2 Suggested mechanism for formation compounds 4 and 5.
JCR1302297_FINAL.indd 173
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174 JOURNAL OF CHEMICAL RESEARCH 2014
(R)-2-Amino-3-(((4-bromobenzoyl)carbamothioyl)thio)propanoicꢀ
acidꢀ(4c): White powder, yield (91%), m.p. 136–144 °C; [α]D21 –20.6 (c
1.02, DMSO); IR (KBr) (νmax): 3400, 3185, 2925, 1675, 1617, 1589, 1484,
Receivedꢀ22ꢀNovemberꢀ2013;ꢀacceptedꢀ16ꢀJanuaryꢀ2014
Paperꢀ1302297ꢀdoi:ꢀ10.3184/174751914X13921421504937
Publishedꢀonline:ꢀ7ꢀMarchꢀ2014
1
1382, 1301, 1206 cm–1; H NMR (500 MHz, DMSO-d6): δ 2.95 (1H,
dd, Jꢀ=12.8, 8.5, SCH2), 3.08 (1H,ꢀdd, Jꢀ=12.8, 4.4, SCH2), 4.64 (1H, m,
CHCOOH), 7.24 (2H, s, NH2), 7.43 (2 H, d, J=8.4 Hz, 2CHarom), 7.58 (2
H, d, J=8.4 Hz, 2CHarom), 9.12 (1H, s, NH), 11.29 (1H, s, COOH) ppm;
13C NMR (125 MHz, DMSO-d6): δ 31.1 (CH2), 53.50 (CH), 125.0, 129.6,
131.3 and 133.3 (carbons of aromatic), 169.8 and 170.2 (2C=O), 195.0
(C=S) ppm; MS (m/z, %): 363 (M+, 2). Anal. calcd for C11H11BrN2O3S2,
C, 36.37; H, 3.05; N, 7.71; S, 17.65; found: C, C, 36.21; H, 3.11; N, 7.68;
S, 17.63%.
(R)-2-Amino-3-(((2-methylbenzoyl)carbamothioyl)thio)propanoicꢀ
acidꢀ(4d): White powder, yield (80%), m.p. 112–114 °C; [α]D21 –11.1 (c
1.00, DMSO); IR (KBr) (νmax): 3312, 3130, 2918, 1677, 1600, 1487, 1396,
1297, 1207 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.53 (3H, s, CH3),
2.93 (1H, dd, Jꢀ=13.9, 8.5, SCH2), 3.02 (1H,ꢀdd, Jꢀ=13.9, 4.4, SCH2), 4.55
(1H, m, CHCOOH), 7.12 (2H, s, NH2), 7.26 (1H, t, J=7.8 Hz, 1CHarom),
7.33 (1H, d, J=8.0 Hz, 1CHarom), 7.64 (1H, t, J=8.0 Hz, 1CHarom), 7.91
(1H, d, J=7.8 Hz, 1CHarom), 9.03 (1H, s, NH), 11.35 (1H, s, COOH) ppm;
13C NMR (125 MHz, DMSO-d6): δ 21.30 (CH3), 34.8 (CH2), 52.5 (CH),
126.1, 127.3, 131.9, 132.3, 134.7 and 138.4 (carbons of aromatic), 168.5
and 170.1 (2C=O), 190.6 (C=S) ppm; MS (m/z, %): 298 (M+, 5). Anal.
calcd for C12H14N2O3S2, C, 48.30; H, 4.73; N, 9.39; S, 21.49; found: C,
48.21; H, 4.63; N, 9.37; S, 21.46%.
(R)-2-Amino-3-(((3-methylbenzoyl)carbamothioyl)thio)propanoicꢀ
acidꢀ(4e): White powder, yield (83%), m.p. 118–120 °C; [α]D21 –12.4 (c
1.01, DMSO); IR (KBr) (νmax): 3345, 3150, 2909, 1675, 1598, 1485, 1396,
1295, 1204 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.45 (3H, s, CH3),
2.96 (1H, dd, Jꢀ=13.7, 8.7, SCH2), 3.06 (1H,ꢀdd, Jꢀ=13.7, 4.3, SCH2), 4.55
(1H, m, CHCOOH), 7.05 (2H, s, NH2), 7.34 (1H, d, J=7.8 Hz, 1CHarom),
7.40 (1H, t, J=8.0 Hz, 1CHarom), 7.67 (1H, d, J=8.0 Hz, 1CHarom), 7.85
(1H, s, 1CHarom), 9.05 (1H, s, NH), 11.34 (1H, s, COOH) ppm; 13C NMR
(125 MHz, DMSO-d6): δ 21.62 (CH3), 34.5 (CH2), 53.1 (CH), 126.3,
129.0, 130.8, 132.3, 134.9 and 138.8 (carbons of aromatic), 168.9 and
170.4 (2C=O), 190.4 (C=S) ppm; MS (m/z, %): 298 (M+, 5). Anal. calcd
for C12H14N2O3S2, C, 48.30; H, 4.73; N, 9.39; S, 21.49; found: C, 48.23;
H, 4.66; N, 9.35; S, 21.45%.
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(R)-2-Amino-3-((benzoylcarbamothioyl)thio)propanoicꢀ acid (4f):
White powder, yield (88%), m.p. 126–128 °C; [α]D –16.7 (c 1.04,
21
DMSO); IR (KBr) (νmax): 3315, 3110, 2915, 1665, 1600, 1489, 1380,
1292, 1206 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.90 (1H, dd,
Jꢀ=13.6, 8.4, SCH2), 3.01 (1H,ꢀdd, Jꢀ=13.6, 4.8, SCH2), 4.54 (1H, m,
CHCOOH), 7.20 (2H, s, NH2), 7.46–7.91 (m, 5CHarom), 9.02 (1H, s, NH),
11.40 (1H, s, COOH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 35.3
(CH2), 52.1 (CH), 127.3, 128.3, 132.2 and 133.6 (carbons of aromatic),
169.3 and 171.9 (2C=O), 191.0 (C=S) ppm. MS (m/z, %): 284 (M+, 6).
Anal. calcd for C11H12N2O3S2, C, 46.46; H, 4.25; N, 9.85; S, 22.55;
found: C, 46.31; H, 4.32; N, 9.80; S, 22.53%.
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We gratefully acknowledge financial support from the Research
Council of Islamic Azad University of Yazd of Iran.
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