The reaction of N-R-2-cyanothioacetamides with ethyl[(aryl)hydrazono] chloroacetates

Article abstract of DOI:10.1007/s10593-007-0014-0

Depending on the nature of the substituents in the starting reagents and the basicity of the medium the cyclization of N-R-2-cyanothioacetamides with ethyl [(aryl)hydrazono]chloroacetates gives 3-aryl-2-cyanomethylidene-5- ethoxycarbonyl-1,3,4-thiadiazoles, 5-arylhydrazono-2-cyanomethylidene-3-phenyl- thiazolidin-4-ones, di[(aryl)hydrazono](ethoxycarbonylmethyl) sulfides, and 5-amino-3-cyano-2-phenyl-amino-4-(N-phenylaminothiocarbonyl)thiophene.

Full text of DOI:10.1007/s10593-007-0014-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 1, 2007
THE REACTION OF N-R-2-CYANOTHIOACETAMIDES
WITH ETHYL[(ARYL)HYDRAZONO]CHLOROACETATES
V. N. Britsun, V. N. Bodnar, and M. O. Lozinskii
Depending on the nature of the substituents in the starting reagents and the basicity of the medium the
cyclization of N-R-2-cyanothioacetamides with ethyl [(aryl)hydrazono]chloroacetates gives 3-aryl-2-
cyanomethylidene-5-ethoxycarbonyl-1,3,4-thiadiazoles, 5-arylhydrazono-2-cyanomethylidene-3-phenyl-
thiazolidin-4-ones, di[(aryl)hydrazono](ethoxycarbonylmethyl) sulfides, and 5-amino-3-cyano-2-phenyl-
amino-4-(N-phenylaminothiocarbonyl)thiophene.
Keywords: N-R-2-cyanothioacetamide, ethyl [(aryl)hydrazono]chloroacetate, 1,3,4-thiadiazole,
thiazolidin-4-one, thiophene, cyclization.
The chemistry of thioamides containing an active methylene group has been extensively developed over
the last 5 years [1-4]. These thioamides have four reactive centers and are ambident substrates which makes them
promising starting materials for the synthesis of the different five and six- membered heterocycles thiopyran-4-
ones [2, 3], piperidine-2-thiones [3, 4], pyrroles [5], 1,2,3-thiadiazoles [6], and thiazolines [7].
It is known that [(aryl)hydrazono]chloroacetate esters also show a dual reactivity and can react both with
dinucleophiles [8, 9] and with dipolarophiles [8, 10, 11].
Cl
Ar
N
N
Ph
Ar
H
COOEt
NC
N
NC
N
N
2a,d–f
S
S
O
2a–c
COOEt
3a–c
N
NH
Ar
Et3N
(EtONa)
Et3N
– PhNH2
S
NC
4a–d
HN
1a,b
R
2f
2a,d
; R = Ph
Et3N
Ar
N
S
N
CO2Et
Ph
H
Et3N
N
H
NC
S
(EtONa)
R = H
N
Ph
Ar
N
CO2Et
NH2
N
H
S
H
5a,b
6
1 a R = Ph; b R = H; 2a, 3а, 4c, 5a Ar = Ph; 2b, 3b Ar = 3-MeC6H4;
2c, 3c Ar = 4-FC6H4; 2d, 4a, 5b Ar = 3-CF3C6H4; 2e, 4b Ar = 4-CHF2SO2C6H4;
2f, 4d Ar = 4-MeOC6H4
__________________________________________________________________________________________
Organic Chemistry Institute, Ukraine National Academy of Sciences, Kiev 02660, e-mail:
ioch@bpci.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp 109-114, January,
2007. Original article submitted July 5, 2006.
0009-3122/07/4301-0093©2007 Springer Science+Business Media, Inc.
93

The aim of our work was to study the cyclocondensation of N-R-2-cyanothioacetamides 1a,b with the
ethyl [(aryl)hydrazono]chloroacetate 2a-f in the presence of base.
It was found that the course of this reaction depends both on the nature of the substituents found on the
N atom of the thioamides 1a,b and in the phenyl ring of the hydrazones 2a-f and on the strength of the base. The
reaction gives rise to 3-aryl-2-cyanomethylidene-5-ethoxycarbonyl-1,3,4-thiadiazoles 3a-c, 5-arylhydrazono-
2-cyanomethylidene-3-phenylthiazolidin-4-ones 4a-d, di[(aryl)hydrazono](ethoxycarbonylmethyl) sulfides 5a,b,
and 5-amino-3-cyano-2-phenylamino-4-(N-phenylaminothiocarbonyl)thiophene 6 (Tables 1 and 2).
Ar
HN
SNa
EtONa
–EtOH
2
NC
N
S
4
NH
NC
–NaCl
–EtOH
Ph
+
O
NH
EtO
Ph
7
8
+
H
–
Ar
N
N
+
S
CO2Et
CO2Et
–
S
CO2Et
NC
9
NC
Ph
NH
–
N
1a
N
NH
Ph
N
N
–
H
Ar
Ar
11
3
10
+
–PhNH2
H
1
The H NMR spectra of compounds 3a-c and 4a-d (Table 3) show characteristic methylidene and
1
aromatic proton signals at 4.57-4.84 and 7.16-7.56 ppm respectively. The H NMR spectra of the 1,3,4-
thiadiazoles 3a-c and the sulfides 5a,b also show signals for ethoxy group protons (as triplets and quartets at
1.20-1.32 and 4.19-4.37 ppm respectively) and the spectra of the thiazolidin-4-ones 4a-d, sulfides 5a,b, and
thiophene 6 show signals for the NH group protons at 10.47-11.32 ppm. The IR spectra of compounds 3a-c,
4a-d, and 6 shown absorption bands for Ar, C≡N, and C=C at 3100-3000, 2220-2200, and 1610-1570 cm-1
respectively. The IR spectra of products 3a-c, 4a-d, and 5a,b show the presence of C=O group stretching at
1720-1680 cm-1 and of 4a-d and 5 an NH group at 3400-3200 cm-1.
TABLE 1. Reaction Products of N-R-2-Cyanothioacetamides 1a,b
with Ethyl [(aryl)hydrazono]chloroacetates 2a-f in the Presence of Base
Thioa-
mide
Hydra-
zone
Yield,
%
Thio-
amide
Hydra-
zone
Base
Product
Base
Product Yield, %
52
1а
1а
1а
1а
1а
1b
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
2а
2b
2c
2d
2e
2а
3a
3b
3с
4a
4b
5a
53
57
62
65
63
60
1b
1а
1а
1а
1а
1b
Et3N
Et3N
2d
2f
5b
6
51
68
70
32
47
EtОNa
EtОNa
EtОNa
EtОNa
2а
2e
2f
4c
4b
4d
5a
2а
94

The formation of different products for the reaction of the thioacetamides 1a,b with the [(aryl)hydrazono]-
chloroacetates 2a-f is explained by the fact that the interaction is evidently brought about by a different mechanism.
TABLE 2. Parameters for the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
С
H
N
3a
3b
3c
4а
4b
4c
4d
5a
5b
6
C13H11N3O2S
56.92
57.13
58.80
58.52
53.81
53.60
55.90
55.67
49.95
49.77
63.49
63.74
61.82
61.70
58.24
57.96
3.81
4.06
4.87
4.56
3.27
3.46
3.04
2.85
3.05
2.78
3.54
3.78
4.22
4.03
5.12
5.35
15.20
15.37
14.35
14.62
14.22
14.43
14.65
14.43
13.02
12.90
17.72
17.49
16.19
15.99
13.77
13.52
127-128
122-124
148-150
295-296
278-280
265-267
238-240
135-137
108-110
255-258*
C14H13N3O2S
C13H10FN3O2S
C18H11F3N4OS
C18H12F2N4O3S2
C17H12N4OS
C18H14N4O2S
C20H22N4O4S
C22H20F6N4O4S
C18H14N4S2
47.88
48.00
61.90
61.69
3.42
3.66
3.84
4.03
9.91
10.18
16.24
15.99
TABLE 3. IR and 1H NMR Spectra of the Compounds Synthesized
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (SSCC, J,Hz)
3a
3080, 2210, 1700, 1580, 1530, 1.32 (3Н, t, J = 6.9, СН3СН2); 4.37 (2Н, q,
1500, 1450, 1410, 1395, 1360
J = 6.9, СН3СН2); 4.62 (1Н, s, NC−СН=);
7.56 (5Н, m, C6H5)
3b
3c
3050, 3000, 2200, 1710, 1610, 1.33 (3Н, t, J = 6.6, СН3СН2); 2.50 (3Н, s, СН3);
1565, 1490, 1450, 1400, 1380 4.39 (2Н, q, J = 6.6, СН3СН2); 4.62 (1Н, s,
NC−СН=); 7.35 (3Н, m, HAr); 7.46 (1Н, m, HAr)
3100, 3000, 2210, 1710, 1570, 1.33 (3Н, t, J = 6.9, СН3СН2); 4.38 (2Н, q,
1510, 1490, 1405, 1380, 1320
J = 6.9, СН3СН2); 4.57 (1Н, s, NC−СН=);
7.41 (2Н, m, 4-FC6H4); 7.61 (2Н, m, 4-FC6H4)
4a
4b
3230, 3100, 2220, 1720, 1590, 4.79 (1Н, s, NC−СН=); 7.27-7.72 (9Н, m, HAr);
1500, 1430, 1405, 1380, 1340 10.97 (1H, s, NH)
3230, 3190, 3100, 2220, 1720, 4.84 (1Н, s, NC−СН=); 7.14 (1H, t, J = 52.5, СНF2);
1590, 1490, 1420, 1380, 1350 7.45-7.61 (7Н, m, HAr); 7.85 (2Н, d, J = 8.7, 4-С6H4);
11.32 (1H, s, NH)
4c
4d
5a
5b
3250, 3100, 2200, 1720, 1580, 4.73 (1Н, s, NC−СН=); 6.99 (1H, m, НAr);
1500, 1450, 1380, 1320, 1280 7.29 (4Н, m, HAr); 7.41 (2Н, m, HAr); 7.58 (3Н, m, HAr);
10.74 (1H, s, NH)
3240, 3000, 2200, 1720, 1580, 3.73 (3Н, s, СН3О); 4.70 (1Н, s, NC−СН=);
1560, 1500, 1375, 1280, 1250 6.91 (2H, d, J = 8.5, 4-С6Н4); 7.22 (2Н, d, J = 8.5, 4-С6Н4);
7.40 (2Н, m, HAr); 7.59 (3Н, m, HAr); 10.65 (1H, s, NH)
3200, 3050, 3000, 1680, 1600, 1.23 (3Н, t, J = 6.9, СН3СН2); 4.21 (2Н, q,
1540, 1480, 1450, 1370, 1320 J = 6.9, СН3СН2); 7.04 (1Н, m, С6Н5);
7.36 (4Н, m, С6Н5); 10.86 (1H, s, NH)
3200, 3150, 3000, 1680, 1620, 1.20 (3Н, t, J = 6.6, СН3СН2); 4.19 (2Н, q,
J = 6.6, СН3СН2); 7.29 (1Н, d, J = 7.2, НAr);
7.55 (1Н, m, НAr); 7.65 (1Н, d, J = 8.7, НAr);
7.70 (1Н, s, НAr); 11.00 (1H, s, NH)
1600, 1550, 1500, 1420, 1340
6
3400, 3050, 2220, 1600, 1500, 7.16-7.37 (7Н, m, HAr + NH2); 7.57-7.72 (6Н, m, HAr);
10.47 (1H, s, NH)
1480, 1380, 1330, 1280
95

Treatment of the thioacetamide 1a with sodium acetate gives the thiolate 7 which reacts with the
chloroacetates 2a,e,f as with 1,2-dielectrophiles by a [3+2] type cyclocondensation. It is likely that the
intermediates in this reaction are the sulfides 8 which eliminate ethanol to give the thiazolidin-4-ones 4b-d. It
should be noted that, in this case, the substituent in the phenyl rings of the [(aryl)hydrazono]chloroacetates 2a,e,f
starting materials do not affect the course of the cyclocondensation.
As is known [8, 10, 12], the reaction of excess triethylamine with the [(aryl)hydrazono]chloroacetates 2
is a method for preparing nitrilimine 9 in situ which probably electrophilically attacks thioamide 1a to give the
intermediate product 10. The direction of the cyclization of sulfides 10 depends on the nature of the substituents
in the phenyl rings of the starting chloroacetates 2a-e. The presence of electron acceptor substituents lowers the
electron density on the negatively charged N atom of compound 10, deactivating it and leading to the formation
of the thiazolidin-4-ones 4a,b.
In the case of electron donor substituents (Ar = Ph, 3-MeC6H4) the intermediate 10 undergoes an
intramolecular nucleophilic attack at the activated double bond and is converted to the intermediate product 11.
Intermediate 11 adds a proton and eliminates arylamine to form the 1,3,4-thiadiazoles 3a-c.
The products of the reaction of thioamide 1b with the chloroacetates 2a,d in the presence of both
triethylamine and also of sodium ethylate are the sulfides 5a,b. This fact occurs because thioamide 1b in basic
medium can decompose to malonodinitrile and hydrogen sulfide [13]. Alkylation of the latter by the hydrazones
2a,b also leads to preparation of the sulfides 5a,b.
Formation of thiophene 6 is explained by the low reactivity of ethyl [(4-methoxyphenyl)hydrazono]-
chloroacetate 2f. Hence thioamide 1a is dimerized via a Gewald reaction [14] in triethylamine as was shown by
us earlier [15]. It should be noted that the chloroacetate 2f does not react with other dinucleophiles as has been
reported in [9].
Hence by variation of the substituent in the starting [(aryl)hydrazono]chloroacetates and the medium
basicity it is possible to target in preparative yields (51-70%) the synthesis of the heterocycles 3-aryl-
2-cyanomethylidene-5-ethoxycarbonyl-1,3,4-thiadiazoles and 5-arylhydrazono-2-cyanomethylidene-3-phenyl-
thiazolin-4-ones. The reaction of [(aryl)hydrazono]chloroacetates with 2-cyanothioacetamide is a method of
synthesizing di(carbethoxy[(aryl)hydrazono]methyl)sulfides in 52-60% yield.
EXPERIMENTAL
1H NMR Spectra were recorded on a Varian-300 (300 MHz) spectrometer using DMSO-d6 and with
TMS as internal standard. IR Spectra were taken on a UR-20 instrument for KBr tablets.
Reaction of N-R-2-cyanothioacetamides 1a,b with ethyl [(aryl)hydrazono]chloroacetates 2a-f in the
presence of triethylamine. A solution of the chloroacetate 2a-f (2 mmol) in ethanol (30 ml) was added
dropwise with stirring to a solution of the thioamide 1a,b (0.352 g, 2 mmol) and triethylamine (0.404 g, 4 mmol)
in ethanol (30 ml) at 0°C. The reaction product was stirred for 5-6 h at 0°C and 5-6 h at 20°C. Ethanol was
evaporated on a rotary evaporator and the crystalline residue was washed with water (5 x 40 ml), dried, and
recrystallized from ethanol.
Reaction of N-R-2-cyanothioacetamides 1a,b with ethyl [(aryl)hydrazono]chloroacetates 2a,e,f in
the presence of sodium ethylate. A solution of the chloroacetate 2a,e,f (2 mmol) in anhydrous ethanol (30 ml)
was added with stirring to a solution of the thioamide 1a,b (0.352 g, 2 mmol) and sodium ethylate (0.136 g, 2
mmol) in anhydrous ethanol (30 ml) at 0°C. The reaction product was stirred for 3-4 h at 20°C until the
crystallization had finished and the precipitated thiazolidin-4-one 4b-d (sulfide 5a) was filtered off, washed with
water (2×30 ml), dried, and recrystallized from ethanol.
96

Synthesis of 5-amino-3-cyano-2-phenylamino-4-(N-phenylaminothiocarbonyl)thiophene (6). A
solution of the chloroacetate 2f (0.513 g, 2 mmol) in ethanol (30 ml) was added with stirring to a solution of the
thioamide 1a (0.352 g, 2 mmol) and triethylamine (0.404 g, 4 mole) in ethanol (30 ml) at 0°C. The reaction
product was stirred for 5-6 h at 0°C and for 5-6 h at 20°C. The precipitate was washed with ether (2x5 ml), dried,
and recrystallized from ethanol.
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