A simple and effective approach to the synthesis of rhodanine derivatives via three-component reactions in water

Article abstract of DOI:10.1016/j.tetlet.2008.12.107

A facile and direct synthetic entry to rhodanine derivatives via the three-component coupling of carbon disulfide, primary amines, and acetylenic esters under neutral conditions in water is reported.

Full text of DOI:10.1016/j.tetlet.2008.12.107

Tetrahedron Letters 50 (2009) 1533–1535
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Tetrahedron Letters
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A simple and effective approach to the synthesis of rhodanine derivatives
via three-component reactions in water
*
Abdolali Alizadeh , Sadegh Rostamnia, Nasrin Zohreh, Reza Hosseinpour
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and direct synthetic entry to rhodanine derivatives via the three-component coupling of carbon
disulfide, primary amines, and acetylenic esters under neutral conditions in water is reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 November 2008
Revised 14 December 2008
Accepted 22 December 2008
Available online 8 January 2009
Keywords:
Rhodanine
Primary amine
Carbon disulfide
Acetylenic ester
Three-component reaction
Water medium
Rhodanine-based molecules are biologically active and inhibit
numerous targets such as HCV NS3 protease,1 b-lactamase,2
PMT1 mannosyl transferase,3 and PRL-3 and JSP-1 phosphatases
(Fig. 1).4 Classical methods for their preparation require several
steps, and generally involve preparation of the rhodanine moiety
followed by a Knoevenagel condensation with aldehydes.5
OR
OR
R'
O
O
NH
NH
S
S
S
S
In our recent investigations,6 treatment of an amine or its deriv-
atives with dialkyl acetylenedicarboxylate and isocyanate (as a
substituted cumulene) at room temperature led to the formation
of maleimide derivatives.7 Thus, as part of a related study on mul-
ti-component reactions, we used carbon disulfide (as a cumulene)
under similar conditions for the synthesis of 5-oxo-2-thioxo-2,5-
dihydro-3-thiophenecarboxylate derivatives (Scheme 1), but in-
stead rhodanine derivatives were obtained in good yields.
5-Arylalkylidene rhodanines
(PRL-3 inhibitors)
Naphthylidene rhodanines
(PRL-3 inhibitors)
O
O
O2N
NH
N
S
S
S
HO
Water has many advantages over common organic solvents
when used as a solvent in chemical reactions. It is economical,
non-toxic, and environmentally friendly. hydrophobic reaction
products can be separated by extraction with an organic solvent.8
To our surprise, the one-pot reaction between amines and dialkyl
acetylenedicarboxylates (DAAD) in the presence of carbon disul-
fide in water as solvent gave several rhodanine derivatives (Table
1). It should be noted that the synthesis of arylidene rhodanine
derivatives reported earlier by Taran et al. proceeded via reaction
between dithiocarbamates and arylpropiolates in the presence of
S
S
OMe
5-Arylalkylidene rhodanine
( PDE4 inhibitors)
Cl
5-Arylalkylidene rhodanine
(UDP N-acetylmuramate/ L-alanine ligase)
Figure 1. Examples of biologically active rhodanine derivatives.
i
Bu3P as catalyst in PrOH.9
The reaction of carbon disulfide with amine 1 in the presence
of dialkyl acetylenedicarboxylate 2 proceeded spontaneously at
room temperature in water and was complete within a few
hours. Table 1 lists the products of our study. The structures of
* Corresponding author. Tel.: +98 21 8800663; fax: +98 21 88006544.
E-mail address: aalizadeh@modares.ac.ir (A. Alizadeh).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.107

1534
A. Alizadeh et al. / Tetrahedron Letters 50 (2009) 1533–1535
CO2R'
O
CO2R'
S
RHN
O
RHN
O
CO2R'
S
C
S
ArSO2
N
C
O
+
RNH2
references 6 and 7
N
H2O
S
CO2R'
SO2Ar
Scheme 1.
Table 1
Reaction of primary amine 1 with dialkyl acetylenedicarboxylate 2 in the presence of carbon disulfide
CHCO2R1
O
CO2R1
S
H2O
rt, 1 h
CS2
+
RNH2
+
S
N
R
3
CO2R1
2
1
Entry
1
Amine
R1
Rhodanine
Yield (%)
90
S
S
S
NH2
3a
N
Me
CHCO2Me
O
S
Me
Me
3b
N
2
3
4
5
6
7
Me
Me
Et
85
85
86
82
88
80
NH2
NH2
CHCO2Me
O
S
S
N
3c
Cl
Cl
CHCO2Me
Cl
Cl
O
S
S
NH2
N
3d
CHCO2Et
O
S
N
O
S
Me
Me
Me
NH2
3e
CHCO2Me
S
S
NH2
NH2
N
3f
CHCO2Me
O
S
S
N
3g
CHCO2Me
O
compounds 3 were deduced from their elemental analysis, mass
spectra, IR, and 1H and 13C NMR spectra. The mass spectrum of
3a displayed the molecular ion (M+) at m/z 293. The IR spectrum
of 3a exhibited absorption bands due to the carbonyl group at
1713 cmÀ1, the double bond at 1680 cmÀ1, and the C@S group
at 1342 and 1187 cmÀ1

A. Alizadeh et al. / Tetrahedron Letters 50 (2009) 1533–1535
1535
S
CHCO2R1
O
R
S
N
H
O
S
S
CS2
2
R
RNH2
-R1OH
N
S
CHCO2R1
S
H2
N
R
3
OR1
4
5
Scheme 2.
5CH of Ph). 13C NMR (125.7 MHz, CDCl3): dC = 47.38 (OMe), 52.86 (CH2Ph),
116.94 (C@CH), 128.33 (CH of Ph), 128.68 (2CH of Ph), 128.97 (2CH of Ph), 134.40
(Cipso), 142.06 (C@CH), 165.52 (CON), 166.54 (CO2Me), 195.49 (C@S). MS (EI), m/z
(%): 293 (M+, 19), 261 (9), 148 (22), 117 (9), 105 (9), 91 (100), 77 (8), 65 (26), 43
(15). Anal. Calcd for C13H11NO3S2 (293.35): C, 53.23; H, 3.78; N, 4.77. Found: C,
53.00; H, 3.75; N, 4.70. Compound 3b: methyl2-[3-(1-methyl-2-phenylethyl)-4-
oxo-2-thioxo-1,3-thiazolidin-5-yliden]ethanoate. Yield: 0.26 g (85%); yellow
The 1H NMR spectrum of 3a exhibited three sharp singlets read-
ily recognized as arising from the methoxy group (d = 3.89), meth-
ylene (d = 5.30) protons, and the vinylic CH at 6.86 ppm. The
phenyl moiety gave rise to characteristic signals in the aromatic re-
gion of the spectrum. The 1H-decoupled 13C NMR spectrum of 3a
showed 11 distinct resonances in agreement with the structure
of methyl 2-(4-oxo-3-(phenylmethyl)-2-thioxo-1,3-thiazolidin-5-
ylidene)ethanoate. The geometry of the exocyclic double bond
was not determined.
powder; mp = 89–91 °C. IR (KBr) (
m
max, cmÀ1): 1721 (C@O), 1689 (C@C), 1323
3
and 1196 (C@S). 1H NMR (500.13 MHz, CDCl3): dH = 1.94 (3H, d, JHH = 7.2 Hz,
CH3), 3.87 (3H, s, OMe), 6.50 (1H, q, 3JHH = 7.2 Hz, MeCH), 6.71 (1H, s, C@CH), 7.33
(1H, t, 3JHH = 6.3 Hz, CHpara of Ph), 7.36 (2H, t, 3JHH = 7.6 Hz, 2 CHmeta of Ph), 7.46
3
(2H, d, JHH = 7.5 Hz, 2CHortho of Ph). 13C NMR (125.7 MHz, CDCl3): dC = 15.39
Although we have not established the mechanism of the reac-
tion between the amines and carbon disulfide in the presence of
DAAD in an experimental manner, a possible explanation is pro-
posed in Scheme 2. Compound 3 could result from the initial addi-
tion of the amine to carbon disulfide and subsequent attack of the
resulting reactive alkylammoniumcarbodithioate 410 on the acety-
lenic ester to yield intermediate 5. Cyclization of the intermediate
5 and subsequent loss of R1OH lead to compound 3 (Scheme 2).
In summary, we have reported a one-pot method that is effec-
tive and simple for the synthesis of rhodanine derivatives of poten-
tial pharmacological and biological interest using commercially
available starting materials and water as the reaction medium.11
(CH3), 52.80 (phCH), 54.97(OMe), 116.37 (C@CH), 127.57(2CHof Ph), 128.09 (CH
of Ph), 128.46 (2CH of Ph), 137.8 (Cipso), 141.50 (C@CH), 165.56 (CON), 165.91
(CO2Me), 196.39 (C@S). MS (EI), m/z (%): 307 (M+, 59), 275 (18), 204 (2), 162 (28),
105 (100), 85 (4), 77 (8), 59 (7), 51 (3). Anal. Calcd for C14H13NO3S2 (307.38): C,
54.71; H, 4.26; N, 4.56. Found: C, 54.50; H, 4.30; N, 4.50. Compound 3c: methyl 2-
[3-((2-chlorophenyl)methyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-yliden]etha-
noate. Yield: 0.28 g (85%); yellow powder; mp = 112–114 °C. IR (KBr) (mmax
,
cmÀ1): 1716 (C@O), 1685 (C@C), 1330 and 1212 (C@S). 1H NMR (500.13 MHz,
CDCl3): dH = 3.90 (3H, s, OMe), 5.42 (2H, s, ArCH2), 6.90 (1H, s, C@CH), 6.92 (1H, t,
3
3JHH = 7.0 Hz, CH of Ar), 7.20 (1H, t, JHH = 6.6 Hz, CH of Ar), 7.23 (1H, d,
3JHH = 7.4 Hz, CH of Ar), 7.41 (1H, d, 3JHH = 7.4 Hz, CH of Ar). 13C NMR (125.7 MHz,
CDCl3): dC = 44.85 (OMe), 52.1 (ArCH2), 117.29 (C@CH), 126.98 (CH of Ar), 127.13
(CH of Ar), 129 (CH of Ar), 129.86 (CH of Ar), 131.45 (Cipso-Cl), 132.96 (Cipso-CH2),
141.86 (C@CH), 165.52 (CON), 166.29 (CO2Me), 195.14 (C@S). MS (EI), m/z (%):
327 (M+, 2), 292 (100), 264 (7), 182 (5), 148 (12), 125 (28), 105 (7), 89 (18), 77 (4),
59 (5), 45 (4). Anal. Calcd for C13H10ClNO3S2 (327.80): C, 47.63; H, 3.07; N, 4.27.
Found: C, 47.00; H, 3.10; N, 4.20. Compound 3d: ethyl 2-[3-((2-
chlorophenyl)methyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-yliden]ethanoate.
References and notes
Yield: 0.29 g (86%); yellow powder; mp = 104–106 °C. IR (KBr) (
m
max, cmÀ1):
1711 (C@O), 1683 (C@C), 1335 and 1192 (C@S). 1H NMR (500.13 MHz, CDCl3):
1. Sing, W. T.; Lee, C. L.; Yeo, S. L.; Lim, S. P.; Sim, M. M. Bioorg. Med. Chem. Lett.
2001, 11, 91–94.
3
3
dH = 1.37 (3H, t, JHH = 7.2 Hz, OCH2CH3), 4.34 (2H, q, JHH = 7.2 Hz, OCH2CH3),
5.41 (2H, s, ArCH2), 6.88(1H, s, C@CH), 6.90 (1H, d, 3JHH = 7.6 Hz, CH of Ar), 7.18
2. Grant, E. B.; Guiadeen, D.; Baum, E. Z.; Foleno, B. D.; Jin, H.; Montenegro, D. A.;
Nelson, E. A.; Bush, K.; Hlasta, D. J. Bioorg. Med. Chem. Lett. 2000, 10, 2179–2182.
3. Orchard, M. G.; Neuss, J. C.; Galley, C. M. S.; Carr, A.; Porter, D. W.; Smith, P.;
Scopes, D. I. C.; Haydon, D.; Vousden, K.; Stubberfield, C. R.; Young, K.; Page, M.
Bioorg. Med. Chem. Lett. 2004, 14, 3975–3978.
4. (a) Cutshall, N. S.; O’Day, C.; Prezhdo, M. Bioorg. Med. Chem. Lett. 2005, 15,
3374–3379; (b) Ahn, J. H.; Kim, S. J.; Park, W. S.; Cho, S. Y.; Ha, J. D.; Kim, S. S.;
Kang, S. K.; Jeong, D. G.; Jung, S.-K.; Lee, S.-H.; Kim, H. M.; Park, S. K.; Lee, K. H.;
Lee, C. W.; Ryu, S. E.; Choi, J.-K. Bioorg. Med. Chem. Lett. 2006, 16, 2996–2999.
5. (a) Lohray, B. B.; Bhushan, V.; Rao, P. B.; Madhavan, G. R.; Murali, N.; Rao, K. N.;
Reddy, K. A.; Rajesh, B. M.; Reddy, P. G.; Chakrabarti, R.; Rajagopalan, R. Bioorg.
Med. Chem. Lett. 1997, 7, 785–788; (b) Singh, S. P.; Parmar, S. S.; Raman, K.;
Stenberg, V. I. Chem. Rev. 1981, 81, 175–203; (c) Lee, C. L.; Sim, M. M.
Tetrahedron Lett. 2000, 41, 5729–5732; (d) Brown, F. C. Chem. Rev. 1961, 61,
463–521; (e) Rudorf, W.-D.; Schwarz, R. Heterocycles 1986, 24, 3459–3463; (f)
Khodair, A. I.; Nielsen, J. Heterocycles 2002, 57, 1017–1032.
6. (a) Alizadeh, A.; Rostamnia, S.; Zhu, L. G. Tetrahedron 2006, 62, 5641; (b)
Alizadeh, A.; Rostamnia, S.; Hu, M. L. Synlett 2006, 1592; (c) Alizadeh, A.;
Rostamnia, S.; Esmaili, A. A. Synthesis 2007, 709; (d) Alizadeh, A.; Oskueyan, Q.;
Rostamnia, S. Synthesis 2007, 2637.
7. (a) Alizadeh, A.; Movahedi, F.; Masrouri, H.; Zhu, L. G. Synthesis 2006, 3431; (b)
Alizadeh, A.; Movahedi, F.; Esmaili, A. A. Tetrahedron Lett. 2006, 47, 4469.
8. Liu, J.; Zhou, Y.; Wu, Y.; Li, X.; Chan, A. S. C. Tetrahedron: Asymmetry 2008, 19,
832–837.
3
3
(1H, t, JHH = 7.4 Hz, CH of Ar), 7.23 (1H, t, JHH = 7.7 Hz, CH of Ar), 7.4 (1H, d,
3JHH = 7.8 Hz, CH of Ar). 13C NMR (125.7 MHz, CDCl3): dC = 14.15 (OCH2CH3),
45.10 (OCH2CH3), 62.23 (ArCH2), 117.90 (C@CH), 126.97, 127.11, 128.98 and
129.86 (4 CH of Ar), 131.50 (Cipso-Cl), 132.98 (Cipso-CH2), 141.50 (C@CH), 165.04
(CON), 166.35 (CO2Et), 195.32 (C@S). MS (EI), m/z (%): 342 (M++1, 2), 341 (M+, 2),
306 (100), 278 (26), 182 (6), 148 (7), 125 (26), 89 (14), 63 (4), 53 (4). Anal. Calcd
for C14H12ClNO3S2 (341.83): C, 49.19; H, 3.54; N, 4.10. Found: C, 49.50; H, 3.50; N,
4.00. Compound 3e: methyl 2-[3-(1-methylethyl)-4-oxo-2-thioxo-1,3-
thiazolidin-5-yliden]ethanoate. Yield: 0.20 g (82%); yellow oil; IR (KBr) (mmax
,
cmÀ1): 1725 (C@O), 1670 (C@C), 1315 and 1196 (C@S). 1H NMR (500.13 MHz,
CDCl3): dH = 1.54 (6H, d, 3JHH = 7.0 Hz, CHMe2), 3.88 (3H, s, OMe), 5.20 (1H, sep,
3JHH = 7.0 Hz, CHMe2), 6.77 (1H, s, C@CH). 13C NMR (125.7 MHz, CDCl3):
dC = 18.47 (CHMe2), 46.31 (CHMe2), 50.10 (OMe), 115.93 (C@CH), 141.78
(C@CH), 165.62 (CON), 167.59 (CO2Me), 197.44 (C@S). MS (EI), m/z (%): 245
(M+, 76), 227 (15), 213 (26), 185 (14), 153 (22), 117 (100), 100 (78), 90 (42), 59
(40), 43 (42). Anal. Calcd for C9H11NO3S2 (245.31): C, 44.07; H, 4.52; N, 5.71.
Found: C, 44.00; H, 4.40; N, 5.75. Compound 3f: methyl 2-[3-(2-methylpropyl)-
4-oxo-2-thioxo-1,3-thiazolidin-5-yliden]ethanoate. Yield: 0.23 g (88%); yellow
powder; mp = 88–90 °C. IR (KBr) (
m
max, cmÀ1): 1715 (C@O), 1691 (C@C), 1325
and 1219 (C@S). 1H NMR (500.13 MHz, CDCl3): dH = 0.93 (6H, d, JHH = 6.7 Hz,
CH2CHMe2), 2.25–2.31 (1H, m, CH2CHMe2), 3.87 (3H, s, OMe), 3.93 (2H, d,
3JHH = 7.5 Hz, CH2CHMe2), 6.82 (1H, s, C@CH). 13C NMR (125.7 MHz, CDCl3):
dC = 20.06 (CH2CHMe2), 26.9 (CH2CHMe2), 51.29 (OMe), 52.78 (CH2CHMe2),
116.58 (C@CH), 142.03 (C@CH), 165.55 (CON), 166.89 (CO2Me), 196.11 (C@S).
MS (EI), m/z (%): 259 (M+, 2), 228 (14), 204 (48), 172 (16), 113 (18), 85 (38), 72
(34), 57 (86), 41 (100). Anal. Calcd for C10H13NO3S2 (259.34): C, 46.31; H, 5.05; N,
5.40. Found: C, 46.50; H, 5.00; N, 5.35. Compound3g:methyl2-[3-(3-butenyl)-4-
oxo-2-thioxo-1,3-thiazolidin-5-yliden]acetate. Yield: 0.19 g (80%); orange
3
9. Gabillet, S.; Lecercle, D.; Loreau, O.; Carboni, M.; Dezard, S.; Gomis, J.-M.; Taran,
F. Org. Lett. 2007, 9, 3925–3927.
10. (a) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem.
2006, 71, 3634; (b) Azizi, N.; Ebrahimi, F.; Aakbari, E.; Aryanasab, F.; Saidi, M. R.
Synlett 2007, 2797–2800; (c) Azizi, N.; Pourhasan, B.; Aryanasab, F.; Saidi, M. R.
Synlett 2007, 1239–1242.
powder; mp = 140–142 °C. IR (KBr) (m
max, cmÀ1): 1716 (C@O), 1683 (C@C),
1331 and 1199 (C@S). 1H NMR (500.13 MHz, CDCl3): dH = 3.88 (3 H, s, OMe),
4.71–4.72 (2H, m, CH2CH@CH2), 5.25–5.30 (2H, m, CH2CH@CH2), 5.75–5.90 (1H,
m, CH2CH@CH2), 6.84 (1H, s, C@CH). 13C NMR (125.7 MHz, CDCl3): dC = 46.19
(OMe), 52.83 (CH2CH@CH2), 116.84 (C@CHCO2Me), 119.78 (CH2CH@CH2), 129.2
(CH2CH@CH2), 142.08 (C@CHCO2Me), 165.52 (CON), 166.14 (CO2Me), 195.15
(C@S). MS (EI), m/z (%): 243 (M+, 47), 228 (100), 116 (28), 98 (25), 85 (79), 72 (32),
59 (26), 43 (61), 41 (79). Anal. Calcd for C9H9NO3S2 (243.29): C, 44.43; H, 3.73; N,
5.76. Found: C, 44.50; H, 3.60; N, 5.60.
11. Typical procedure for the preparation of methyl 2-[4-oxo-3-(phenylmethyl)-2-
thioxo-1,3-thiazolidin-5-yliden)ethanoate 3a: Benzylamine (1 mmol) was added
slowly to a mixture of CS2 (1.2 mmol) and dimethyl acetylenedicarboxylate
(1 mmol) in 3 ml of water at room temperature. The reaction mixture was stirred
for1 h. After completion ofthe reaction, theresulting solidwas filteredand dried.
Yield: 0.26 g (90%); orange powder; mp = 128–130 °C. IR (KBr) (m
max, cmÀ1):
1713 (C@O), 1680 (C@C), 1342 and 1187 (C@S). 1H NMR (500.13 MHz, CDCl3):
dH = 3.89 (3H, s, OMe), 5.30 (2H, s, CH2Ph), 6.86(1H, s, C@CH), 7.33–7.45 (5H, m,