1298
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
Larionova et al.
Ethyl 3ꢀ{4ꢀcyanoꢀ3ꢀhydroxyꢀ5ꢀ[(2ꢀoxoꢀ2ꢀphenylethyl)sulfꢀ
anyl]ꢀ2ꢀthienyl}ꢀ3ꢀoxopropanoate (3a). The yield was 55%, m.p.
154—156 C. IR, /cm–1: 3435 (OH), 2221 (CN), 1742 (CO2Et),
Since the structure of the intermediately formed salt 5
does not have an amino group, the reaction stops at the
step of the thiophene ring closure and in contrast to the
reaction with malononitrile is not followed by the intraꢀ
molecular cyclization. Salt 5 is a convenient building block
and can be converted without isolation to the target comꢀ
pounds 3a—e by alkylation with halides 6a—e.
1
1677 (CO). H NMR, : 1.17 (t, 3 H, CH3, J = 7.1 Hz); 3.86
(s, 2 H, COCH2CO); 4.09 (q, 2 H, CH2CH3, J = 7.1 Hz); 5.17
(s, 2 H, SCH2); 7.58 (m, 2 H, C6H5); 7.72 (t, 1 H, C6H5, J = 7.3 Hz);
8.06 (d, 2 H, C6H5, J = 7.4 Hz). The signal for the OH group was
not found, probably, because of the exchange processes with the
solvent. MS ESI, found: m/z 390.0464 [M + H]+; C18H16NO5S2;
calculated: m/z 390.0470.
Ethyl 3ꢀ[5ꢀ(benzylsulfanyl)ꢀ4ꢀcyanoꢀ3ꢀhydroxyꢀ2ꢀthienyl]ꢀ3ꢀ
oxopropanoate (3b). The yield was 52%, m.p. 73—75 C. IR,
/cm–1: 3430 (OH), 2226 (CN), 1720 (CO2Et), 1686 (CO).
1H NMR, : 1.16 (t, 3 H, CH3, J = 7.1 Hz); 3.85 (s, 2 H,
COCH2CO); 4.08 (q, 2 H, CH2CH3, J = 7.1 Hz); 4.50 (s, 2 H,
SCH2); 7.25—7.50 (m, 5 H, C6H5), 8.09 (br.s, 1 H, OH). MS
ESI, found: m/z 362.0515 [M + H]+; C17H16NO4S2; calculated:
m/z 362.0521.
Ethyl 3ꢀ(4ꢀcyanoꢀ3ꢀhydroxyꢀ5ꢀ{[(4ꢀmethylphenyl)methyl]ꢀ
sulfanyl}ꢀ2ꢀthienyl)ꢀ3ꢀoxopropanoate (3c). The yield was 56%,
m.p. 80—82 C. IR, /cm–1: 3422 (OH), 2228 (CN), 1717
(CO2Et), 1681 (CO). 1H NMR, : 1.17 (t, 3 H, CH2CH3,
J = 7.1 Hz); 2.28 (s, 3 H, CH3); 3.85 (s, 2 H, COCH2CO); 4.08
(q, 2 H, CH2CH3, J = 7.1 Hz); 4.46 (s, 2 H, SCH2); 7.16 (d, 2 H,
C6H4, J = 7.7 Hz); 7.32 (d, 2 H, C6H4, J = 7.7 Hz); 8.12 (br.s,
1 H, OH). MS ESI, found: m/z 376.0672 [M + H]+; C18H18NO4S2;
calculated: m/z 376.0677.
Ethyl 3ꢀ{4ꢀcyanoꢀ3ꢀhydroxyꢀ5ꢀ[(2ꢀethoxyꢀ2ꢀoxoethyl)sulfꢀ
anyl]ꢀ2ꢀthienyl}ꢀ3ꢀoxopropanoate (3d). The yield was 58%, m.p.
82—84 C. IR, /cm–1: 3438 (OH), 2228 (CN), 1725 (CO2Et),
1691 (CO). 1H NMR, : 1.10—1.25 (m, 6 H, 2 CH3); 3.87 (s, 2 H,
COCH2CO); 4.05—4.20 (m, 4 H, 2 CH2CH3); 4.24 (s, 2 H,
SCH2); 7.30 (br.s, 1 H, OH). MS ESI, found: m/z 358.0414
[M + H]+, C14H16NO6S2; calculated: m/z 358.0419.
The structure of thiophenes 3a—e was confirmed by
1H NMR and IR spectroscopy and high resolution mass
spectrometry. The IR spectra of compounds 3 exhibit abꢀ
sorption bands of the carbonyl and ester groups of the
oxopropanoate fragment and the absorption band of the
nitrile group at 2220—2230 cm–1
.
In the 1H NMR spectra, the signals for the protons of
the ethyl group of one of the ester fragment are found at
1.16—1.17 and 4.08—4.09, and the signal for the two
protons of the methylene group is found as a singlet at
3.85—3.87.
In conclusion, we found that the reaction of ethyl
cyanoacetate (2), carbon disulfide, and ethyl 4ꢀchloroꢀ
acetoacetate selectively led to the formation of 3ꢀ(3ꢀhydrꢀ
oxyꢀ2ꢀthienyl)ꢀ3ꢀoxopropanoates 3a—e. After alkylation
of the intermediately formed dipotassium salt, the product
gives the Dieckmann reaction involving the ester group,
rather than the Thorpe—Ziegler cyclization.
Experimental
Melting points were determined on a Kofler heating stand.
IR spectra were recorded on a Bruker Alpha spectrophotometer
in KBr pellets, 1H NMR spectra were recorded on a Bruker
AM 300 spectrometer (300.13 MHz) in solutions in DMSOꢀd6,
using the residual signal of the solvent (H = 2.5) as a reference.
High resolution mass spectra were obtained on a Bruker
micrOTOF instrument.
Synthesis of substituted thiophenes 3a—e (general procedure).
Ethyl cyanoacetate (1) (2.82 g, 25 mmol) was added to a solution
of KOH (1.4 g, 25 mmol) in EtOH (50 mL) at 10 C, and the
mixture was stirred for 30 s, followed by a sequential addition of
CS2 (1.5 mL, 25 mmol) and KOH (1.4 g, 25 mmol) in EtOH
(50 mL). The reaction mixture was stirred for 60 min, diluted
with H2O (40 mL) until a precipitate formed was dissolved.
Ester 2 (3.4 mL, 25 mmol) was added dropwise to the solution
obtained over 30 min. After stirring for 10 min, a solution of
KOH (1.4 g, 25 mmol) in EtOH (50 mL) was added, and the
mixture was refluxed for 2 h. Then, the solution was cooled,
followed by the addition of concentrated HBr (2.8 mL, 25 mmol)
and stirring for 30 min. The thus obtained solution of salt 5 was
poured into five flasks (5 mmol of salt 5 each), added the correꢀ
sponding alkyl halide 6a—e (5 mmol), heated to reflux, and
cooled. A precipitate formed was filtered off to obtain thiophenes
3a—e in 52—58% yields.
Ethyl 3ꢀ{4ꢀcyanoꢀ5ꢀ[(2ꢀoxopropyl)sulfanyl]ꢀ3ꢀhydroxyꢀ2ꢀ
thienyl}ꢀ3ꢀoxopropanoate (3e). The yield was 53%, m.p. 97—99 C.
IR, /cm–1: 3432 (OH), 2229 (CN), 1722 (CO2Et), 1686 (CO).
1H NMR, : 1.17 (t, 3 H, CH2CH3, J = 7.1 Hz); 2.27 (s, 3 H,
CH3CO); 3.86 (s, 2 H, COCH2CO); 4.09 (q, 2 H, CH2CH3,
J = 7.1 Hz); 4.47 (s, 2 H, SCH2); 6.91 (br.s, 1 H, OH). MS ESI,
found: m/z 328.0308 [M + H]+, C13H14NO5S2; calculated: m/z
328.0313.
References
1. A. M. Shestopalov, L. A. Rodinovskaya, A. A. Shestopalov,
J. Comb. Chem., 2010, 12, 9.
2. T. Chiba, H. Sato, T. Kato, Chem. Pharm. Bull., 1983,
31, 2480.
Received January 10, 2013;
in revised form February 28, 2013