Nef-isocyanide adducts as useful synthons in a novel synthesis of functionalized 5-imino-2-thioxothiazolidines

Article abstract of DOI:10.1016/j.tetlet.2013.03.041

An efficient synthesis of alkyl 3-alkyl-5-(alkylimino)-4-hydroxy-2- thioxothiazolidine-4-carboxylates via a novel sequential four-component reaction between alkyl amines, CS₂, and Nef-isocyanide adducts, under basic conditions, is described.

Full text of DOI:10.1016/j.tetlet.2013.03.041

Tetrahedron Letters 54 (2013) 2785–2787
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nef-isocyanide adducts as useful synthons in a novel synthesis
of functionalized 5-imino-2-thioxothiazolidines
⇑
Issa Yavari , Ramin Pashazadeh, Reza Hosseinpour, Ehsan Ghanbari
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:
An efficient synthesis of alkyl 3-alkyl-5-(alkylimino)-4-hydroxy-2-thioxothiazolidine-4-carboxylates via
a novel sequential four-component reaction between alkyl amines, CS2, and Nef-isocyanide adducts,
under basic conditions, is described.
Received 26 December 2012
Revised 26 February 2013
Accepted 8 March 2013
Available online 16 March 2013
Ó 2013 Published by Elsevier Ltd.
Keywords:
Thioxothiazolidine
Nef-isocyanide adduct
Isocyanide
Acyl chloride
CS2
The unique properties of the isocyano group, which can func-
tion as both an electrophile and a nucleophile, have made com-
pounds containing this moiety useful reagents in organic
synthesis.1 Apart from their role in multicomponent reactions,2
the most important applications of isocyanides are in the synthesis
of various heterocycles.3 A number of isocyanide reactions have
seen their potential largely unexplored, for example, the Nef reac-
of primary amines, carbon disulfide, and ethyl bromopyruvate,
has been described previously,12 there are no published examples
of 5-imino-2-thioxothiazolidines.
Initially, we examined the reaction of benzyl amine (4a), CS2,
and ethyl 3-chloro-3-(cyclohexylimino)-2-oxopropanoate (3a) [it-
self obtained from ethyl(chlorocarbonyl)formate (1a) and cyclo-
hexyl isocyanide (2a)], in MeCN:EtOH (4:1), in the presence of
various bases. As shown in Table 1, the best result was obtained
with K2CO3. Other bases, including KOH, DBU, DABCO, iPr2NEt,
and Et3N gave lower yields.
tion, which involves the a-addition of acyl chlorides to isocyanides
forming imidoyl chlorides.4 Intramolecular trapping of Nef adducts
with various nucleophiles has been reported.5–7
One of the main problems of the Nef isocyanide reaction is the
selectivity of the nucleophilic attack on the Nef adducts: either
the imidoyl or the carbonyl function which may lead to isocyanide
Under the optimized conditions a range of 5-imino-2-thioxo-
thiazolidines 7 was synthesized (Scheme 1).15 The structures of
all products 7 were characterized by IR, mass, 1H NMR, and 13C
NMR spectral data. For example, the 1H NMR spectrum of 7a in
CDCl3 exhibited signals for the NCH of the cyclohexyl moiety
(d = 2.84–2.88), hydroxy (d = 5.20), and aromatic (d = 7.25–7.42)
protons. The 1H-decoupled 13C NMR spectrum of 7a exhibited 17
signals in agreement with the proposed structure.
A plausible pathway may be advanced to rationalize the prod-
uct formation (Scheme 2). Presumably, the Nef-isocyanide adduct
3, formed from acid chloride 1 and isocyanide 2, is attacked by ad-
duct 6 to furnish intermediate 8, which undergoes intramolecular
cyclization to afford 5-imino-2-thioxothiazolidines 7.
elimination. We anticipated that the use of an a-carboalkoxy substi-
tuent would make the ketone more electrophilic and would proba-
bly lower the potential for elimination of isocyanide leading to
acylation derivatives. This modification was found to be successful.
Thus, as part of our studies on the development of new routes to het-
erocyclic systems,8–10 we report a simple synthesis of alkyl 3-alkyl-
5-(alkylimino)-4-hydroxy-2-thioxothiazolidine-4-carboxylates
7
in 70–87% yields, via sequential four-component reactions between
alkyl amines, CS2, and the Nef-isocyanide adducts 3, obtained from
alkyl chloroglyoxalates 1 and alkyl isocyanides 2, under basic condi-
tions at room temperature in dry MeCN (Scheme 1).11 Although, a
synthesis of functionalized 2-thioxo-1,3-thiazolanes via reaction
In summary, we have developed a simple, one-pot synthesis of
functionalized 5-imino-2-thioxothiazolidines by treatment of Nef-
isocyanide adducts with amines and CS2 in MeCN–EtOH. Short
reaction times and readily available starting materials are the main
advantages of this methodology.
⇑
Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.03.041

2786
I. Yavari et al. / Tetrahedron Letters 54 (2013) 2785–2787
R'
O
O
N
neat
10 min
Cl
R'
N
C
+
RO
RO
R"
Cl
K
OH
R"
O
_
O
CO2R
NR'
KCl
N
2
1
3
S
S
S
MeCN:EtOH
K2CO3
R" NH2
+ CS2
7
N
H
S
4
5
6
7
1-4,6,7
Yield (%) of
R
R"
R'
Cy
Cy
Cy
Cy
t-Bu
Cy
Cy
Cy
Cy
a
b
c
d
e
f
g
h
i
Bn
Bn
Et
Me
Et
Et
Me
Et
Et
Et
Et
87
85
76
73
72
78
72
70
74
4-Cl-C6H4CH2
2-Cl-C6H4CH2
4-MeO-C6H4
4-MeO-C6H4
Me
Et
allyl
Scheme 1. Four-component synthesis of 5-imino-2-thioxothiazolidines 7 via the Nef-isocyanide protocol.
Table 1
Optimization of the reaction conditions for the synthesis of 5-imino-2-thioxothiazolidine 7aa
Cy
O
N
O
neat
10 min
Cl
+
Cy
N
C
EtO
EtO
Bn
Cl
M
OH
Bn
O
O
3a
_
CO2Et
NCy
MCl
N
2a
1a
S
S
S
base
Bn NH2
CS2
+
7a
N
H
S
solvent
4a
5
6a
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
KOH
DBU
Et3N
i-Pr2NEt
DABCO
K2CO3
K2CO3
K2CO3
—
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
73
68
24
35
79
82
54
88
0
MeCN:EtOH (4:1)
EtOH
a
All reactions were carried out with 1 mmol of each substrate and base (1 mmol) at room temperature.
Isolated yield.
b
5
4
+
S
S
R"
R'
Cl
N
S
K
R"
O
N
H
N
H
O
S
cyclization
6
+
7
1
2
R'
RO
N
O
RO
O
3
8
Scheme 2. Plausible mechanism for the generation of 5-imino-2-thioxothiazolidines 7.

I. Yavari et al. / Tetrahedron Letters 54 (2013) 2785–2787
2787
11. General procedure for the synthesis of compounds 7: To a magnetically stirred
solution of amine 4 (1 mmol) in 1 mL of dry MeCN:EtOH (4:1) and CS2 (5)
(1 mmol) was added K2CO3 (1 mmol). After 30 min, a solution of imidoyl
chloride 3 [obtained from alkyl oxalyl choride 1 (1 mmol) and alkyl isocyanide
2 (1 mmol) at room temperature, 10 min] in CH2Cl2 (1 mL) was added. The
mixture was stirred for 3 h at room temperature and then concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography (5:1 hexane–EtOAc) to give the product.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.03.041.
Ethyl 3-benzyl-5-(cyclohexylimino)-4-hydroxy-2-thioxothiazolidine-4-carboxylate
(7a): Yellow oil, 0.34 g, yield 87%. IR (KBr): 3446 (OH), 1748 (C@O), 1654
(C@N), 1204 (C–O). 1H NMR (500 MHz, CDCl3): d 0.97 (3H, t, 3J = 7.1, Me), 1.21–
1.79 (10H, m, 5 CH2), 2.84-2.88 (1H, m, CH), 3.31–3.38 (1H, m, CH2O), 3.87–
3.94 (1H, m, CH2O), 4.55 (1 H, d, 2J = 15.0, CH2N), 5.20 (1H, br s, OH), 5.73 (1H,
d, 2J = 15.0, CH2N), 7.25 (2H, t, 3J = 7.1, CH), 7.28 (1H, t, 3J = 7.2, CH), 7.42 (2H, d,
3J = 7.4, CH). 13C NMR (125 MHz, CDCl3): d 14.8 (Me), 25.4, 25.5, 26.4, 33.2, 33.6
(cyclohexyl), 49.1 (NCH), 65.1 (CH2O), 69.1 (NCH2), 94.8 (C), 129.4 (CH), 129.6
(CH), 130.6 (CH), 135.9 (C), 158.6 (C@N), 168.9 (C@O), 194.0 (C@S). MS: m/z
(%) = 392 (M+, 29), 319 (90), 244 (45), 229 (9), 159 (19), 142 (59), 129 (26), 91
(100), 83 (95), 55 (78). Anal. Calcd for C19H24N2O3S2 (392.12): C, 58.14; H, 6.16;
N, 7.14. Found: C, 58.41; H, 6.04; N, 7.21.
References and notes
1. Suginome, M.; Ito, Y. In Science of Synthesis; Murahashi, S.-I., Ed.; Thieme:
Stuttgart, 2004; Vol. 19, p 445.
2. Dömling, A. Chem. Rev. 2006, 106, 17; Ramon, D. J.; Yus, M. Angew. Chem., Int.
Ed. 2005, 44, 1602.
3. Lygin, A. V.; Meiere, A. D. Angew. Chem., Int. Ed. 2010, 49, 9094.
4. Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267.
5. Coffinier, D.; El Kaim, L.; Grimaud, L. Org. Lett. 2009, 11, 1825.
6. Coffinier, D.; El Kaim, L.; Grimaud, L. Synlett 2010, 2474.
7. Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010, 12, 820.
8. Yavari, I.; Pashazadeh, R.; Hosseinpour, R. Helv. Chim. Acta 2012, 95, 169.
9. Yavari, I.; Khalili, G.; Mirzaei, A. Tetrahedron Lett. 2010, 51, 1190.
10. Yavari, I.; Khalili, G.; Sadeghizadeh, F. Synlett 2012, 24, 557.
12. Yavari, I.; Seyfi, S.; Hossaini, Z.; Sabbaghan, M.; Shirgahi-Talari, F. Monatsh.
Chem. 2008, 139, 1479.