Reactive intermediates in the reaction of hydrazinecarbothioamides with 2-(bis(methylthio)methylene)malononitrile and ethyl 2-cyano-3,3-bis(methylthio)acrylate

Article abstract of DOI:10.1007/s11164-018-3633-4

Abstract: The reaction of N-substituted hydrazinecarbothioamides with both 2-(bis(methylthio)methylene)malononitrile and ethyl 2-cyano-3,3-bis(methylthio)acrylate afforded various heterocyclic rings such as 5-amino-4-cyano-3-(methylthio)-N-phenyl-1H-pyrazole-1-carbothioamide, 5-amino-3-(methylthio)-1H-pyrazole-4-carbonitrile, 4-substituted-3-(substituted amino)-1H-1,2,4-triazole-5(4H)-thione, ethyl 5-amino-3-(methylthio)-1-(substituted carbamothioyl)-1H-pyrazole-4-carboxylate, and (Z)-ethyl 2-cyano-2-(5-(substituted amino)-1,3,4-thiadiazol-2(3H)-ylidene)acetate. However, under gentle heating, the reaction of the same starting substances behaved differently. The structure of the obtained products was fully characterized using different spectral techniques including infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) together with elemental analyses as well as single-crystal X-ray diffraction analysis. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-018-3633-4

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-018-3633-4
Reactive intermediates in the reaction
of hydrazinecarbothioamides with 2‑(bis(methylthio)
methylene)malononitrile and ethyl
2‑cyano‑3,3‑bis(methylthio)acrylate
Ashraf A. Aly, et al. [full author details at the end of the article]
Received: 4 June 2018 / Accepted: 8 October 2018
© Springer Nature B.V. 2018
Abstract
The reaction of N-substituted hydrazinecarbothioamides with both 2-(bis(methylthio)
methylene)malononitrile and ethyl 2-cyano-3,3-bis(methylthio)acrylate aforded
various heterocyclic rings such as 5-amino-4-cyano-3-(methylthio)-N-phenyl-
1H-pyrazole-1-carbothioamide,
5-amino-3-(methylthio)-1H-pyrazole-4-carbonitrile,
4-substituted-3-(substituted amino)-1H-1,2,4-triazole-5(4H)-thione, ethyl 5-amino-3-
(methylthio)-1-(substituted carbamothioyl)-1H-pyrazole-4-carboxylate, and (Z)-ethyl
2-cyano-2-(5-(substituted amino)-1,3,4-thiadiazol-2(3H)-ylidene)acetate. However, under
gentle heating, the reaction of the same starting substances behaved diferently. The struc-
ture of the obtained products was fully characterized using diferent spectral techniques
including infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS)
together with elemental analyses as well as single-crystal X-ray difraction analysis.
Graphical abstract
Keywords N-substituted hydrazinecarbothioamides · 2-(Bis(methylthio)methylene)
malononitriles · Reactive intermediates · Various heterocycles · X-ray structure
analyses
Vol.:(0123456789)
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A. A. Aly et al.
Introduction
Hydrazinecarbothioamides are usually used as building blocks with several
π-defcient compounds for synthesis of diferent heterocycles such as 1,3,4-thiadia-
zoles and 1,3,4-thiadiazepines [1], pyridazinethiones and triazolopyridazine-thiones
[2], oxathiadiazoles and benzothiadiazines [3], and thiadiazepine, thiadiazole,
dithiadiazole, and oxathiadiazole derivatives [4]. Recently, spiro(indolone-3,2′-
[1,3,4-thiadiazol])-2-ones [5] and 1,2,4-triazepinethiones [6] were synthesized via
refuxing substituted hydrazinecarbothioamides with 3-(dicyanomethylene)-2-in-
dolone and dimethyl acetylenedicarboxylate or dibenzoylacetylene, respectively.
Aly et al. reported that the reaction of N,N-disubstituted hydrazinecarbothioamides
with 2-bromo-2-substituted acetophenones furnished thiazole, bis-thiazole, pyra-
zole, and 1,3,4-thiadiazole derivatives in good yield [7]. 2-(Bis(methylthio)meth-
ylene)malononitrile and ethyl 2-cyano-3,3-bis(methylthio)acrylate show diferent
reactivity, which is attributed to several electrophilic sites (C≡N, C=C, CO2Et),
towards diferent compounds, afording various heterocyclic compounds with bio-
logical activities [8–10]. Various mercaptopyrazoles were synthesized from the
reaction of ethyl bis(methylthio)-2-cyanoacrylate with amidrazones in dry etha-
nol and triethylamine [11]. On the other hand, 1,3,4-thiadiazoles and 1,3-thiazines
were obtained by reaction of 2-(bis(methylthio)methylene)malononitrile and ethyl
2-cyano-3,3-bis(methylthio)-acrylate with symmetrical N1,N2-disubstituted hydra-
zinecarbothioamides [12]. Pyrazoles are biologically active compounds that show
a broad spectrum of biological activities, involving antifungal, antitubercular, and
antiinfammatory activities [13, 14], analgesic efects [15], as well as antidepres-
sant and anticonvulsant activities [16]. Synthesis of 3-amino-5-(methylthio)-1-phe-
nyl-1H-pyrazole-4-carbonitrile [17] and ethyl-5-amino-3-(methylthio)-1-phenyl-
1H-pyrazole-4-carboxylate [17] was achieved by reaction of phenylhydrazine with
2-(bis(methylthio)methylene)malononitrile and ethyl 2-cyano-3,3-bis(methylthio)
acrylate, respectively. 1,2,4-Triazole-5-thiones were prepared by refuxing either
glycine hydrazide or hydrazine hydrate with diferent isothiocyanates in 10 %
K2CO3 [18]. The N2 of hydrazinecarbothioamides has greater nucleophilicity than
the terminal N1 [2, 6]. However, in the present investigation, all the nucleophilic
sites on the hydrazinecarbothioamides (SH, 1NH, 2NH, 3NH) play an important role
in the heterocyclization and formation of the fnal products.
Experimental
Melting points are uncorrected and were recorded on a Gallenkamp melting point
apparatus (Gallenkamp, UK) using open capillaries. NMR spectra were meas-
1
ured on a Bruker AV-400 spectrometer (400 MHz for H, 100 MHz for 13C, and
40.54 MHz for 15N). 1H and 13C chemical shifts are given relative to internal stand-
ard tetramethylsilane (TMS); 15N shifts are reported versus ammonia. For prepara-
tive thin-layer chromatography (PLC), glass plates (20 × 48 cm2) were covered
with a slurry of silica gel Merck PF254, air dried, and developed using the solvents
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Reactive intermediates in the reaction of…
listed. Zones were detected by quenching of indicator fuorescence upon exposure
to ultraviolet (UV) light at 254 nm. Elemental analyses were carried at Karlsruhe
Institut für Technologie (KIT), Institute of Organic Chemistry, Karlsruhe, Germany.
Mass spectra were recorded on a Varian MAT 312 instrument in electrospray ioniza-
tion (EI) mode (70 eV), at the Karlsruhe Institut für Technologie (KIT), Institute of
Organic Chemistry, Karlsruhe, Germany. IR spectra were obtained from KBr pellets
on a FT-IR (Bruker) at Minia University, El-Minia, Egypt.
Starting materials
N-Substituted hydrazinecarbothioamides 1a–d were prepared according to literature
procedures (1a [19], 1b [19, 20], 1c [21], and 1d [22]).
Reaction of N‑substituted hydrazinecarbothioamides 1a–d with 2a
General procedure
A solution of 1a–d (1.0 mmol) and 2a (1.0 mmol) was stirred with gentle heating
at 50 °C in dry ethanol containing 0.5 mL triethylamine till consumption of starting
materials. After reaction completion, the solvent was removed und vacuum and the
residue was subjected to PLC using toluene/EtOAc (10:1) to give diferent zones.
5‑Amino‑4‑cyano‑3‑(methylthio)‑N‑phenyl‑1H‑pyrazole‑1‑carbothioamide
(3) Yield: (0.187 g, 65 %); colorless crystals (EtOH); M.p.: 160–162 °C.
IR (KBr): ν = 3303-3251 (NH’s), 3090 (Ar–CH), 2215 (CN), 1633 (C=N), 1614
(Ar–C=C), 1358 (C=S) cm−1.
1H NMR (400 MHz, DMSO-d6): δH = 2.35 (s, 3H, SCH3), 6.01 (br. s, 2H, NH2),
6.91–6.94 (m, 3H, Ar–H), 6.98–7.00 (m, 2H, Ar–H), 11.55 (br. s, 1H, NH–Ph).
13C NMR (100 MHz, DMSO-d6): δC = 12.30 (SCH3), 62.00 (pyrazole-C-4),
114.22 (CN), 127.50, 128.30 (Ar-2CH), 129.42 (Ar–CH), 138.60 (Ar–C), 148.52
(pyrazole-C-3), 164.00 (pyrazole-C-5), 170.00 (C=S).
MS: m/z (%) = 289 (M.+, 14), 153 (100), 136 (70), 106 (17).
Anal. Calcd. for C12H11N5S2 (289.38): C, 49.81; H, 3.83; N, 24.20; S, 22.16.
Found: C, 49.83; H, 3.82; N, 24.18; S, 22.19.
5‑Amino‑3‑(methylthio)‑1H‑pyrazole‑4‑carbonitrile (4) Yield: (0.03 g, 20 %); color-
less crystals (EtOH); m.p.: 150-151 °C; Lit. ([23, 24] 152 °C).
13C NMR (100 MHz, DMSO-d6): δC = 12.60 (SCH3), 72.30 (pyrazole-C-4),
114.70 (CN), 147.60 (pyrazole-C-3), 154.30 (pyrazole-C-5).
4‑Phenyl‑3‑(phenylamino)‑1H‑1,2,4‑triazole‑5(4H)‑thione (5aa) Yield: (0.03 g,
20 %); colorless crystals (EtOH); M.p.: 204–206 °C; Lit. (201–203 °C [18]).
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A. A. Aly et al.
4‑(Pyridin‑3‑yl)‑3‑(pyridin‑3‑ylamino)‑1H‑1,2,4‑triazole‑5(4H)‑thione (5ba) Yield:
(0.175 g, 65 %); colorless crystals (EtOH); M.p.: 306–308 °C.
IR (KBr): ν = 3230 (NH), 3150 (Ar–CH), 1588 (Ar–C=C), 1315 (C=S) cm−1.
1H NMR (400 MHz, DMSO-d6): δH = 7.21–7.34 (m, 2H, Ar–H), 7.36–7.40 (m,
2H, Ar–H), 7.63–7.65 (m, 1H, Ar–H), 8.15–8.17 (m, 1H, Ar–H), 8.18–8.20 (m, 1H,
Ar–H), 8.75–8.77 (m, 1H, Ar–H), 10.19 (br. s, 1H, NH-pyridinyl), 13.53 (br. s, 1H,
NH-triazole).
13C NMR (100 MHz, DMSO-d6): δC = 129.50, 129.60, 130.40, 130.50, 137.10,
137.60, 141.90, 142.50 (Ar–CH), 147.90, 149.80 (Ar–C), 155.80 (C=N), 165.60
(C = S).
MS: m/z (%) = 270 (M.+) (17), 153 (100), 136 (67), 106 (17).
Anal. Calcd. for C12H10N6S (270.31): C, 53.32; H, 3.73; N, 31.09; S, 11.86.
Found: C, 53.28; H, 3.79; N, 31.15; S, 11.81.
5‑Amino‑4‑cyano‑2‑(2,2‑dicyano‑1,1‑bis(methylthio)ethyl)‑N‑ethyl‑3‑(methylthio
)‑2,3‑dihydro‑1H‑pyrazole‑1‑carbothioamide (12) Yield: (0.33 g, 80 %); colorless
crystals (EtOH); M.p.: 158–159 °C.
The IR spectrum of 12 showed absorptions at ν 3425–3231; 2211; 1608 and 1359
for (NH’s), C≡N, C=N and C=S, respectively.
1H NMR (400 MHz, DMSO-d6): δH = 1.10 (t, 3H, CH3, J = 7.0 Hz), 2.30 (s, 6H,
2SCH3), 2.40 (s, 3H, SCH3), 3.33 (s, 1H, CH(CN)2), 3.60 (q, CH2, 2H, J = 7.0 Hz),
8.79 (br. s, 1H, NH), 9.99 (br. s, 1H, NH-Et).
13C NMR (100 MHz, DMSO-d6): δC = 11.30 (CH3-Et), 12.50 (2SCH3), 12.70
(SCH3), 22.30 (CH(CN)2), 38.10 (CH2-Et), 65.00 (pyrazole-C-4), 78.00 [C(SCH3)2],
113.30 (2CN), 116.60 (CN), 163.30 (pyrazole-C-3), 169.00 (pyrazole-C-5), 184.00
(C=S).
MS: m/z (%) = 411 (M.+) (6), 391 (10); 166 (22), 148 (100), 108 (24), 94 (43).
Anal. Calcd. for C14H17N7S4 (411.59): C, 40.86; H, 4.16; N, 23.82; S, 31.16.
Found: C, 40.72; H, 4.18; N, 23.80; S, 31.19.
Reaction of N‑substituted hydrazinecarbothioamides 1a–d with 2b
General procedure
A mixture of N-substituted hydrazinecarbothioamides 1a–d (1 mmol) in abs. EtOH
(30 mL) was heated gently at 50 °C with 2-cyano-3,3-bis(methylthio)acrylate 2b
(1 mmol) followed by thin-layer chromatography (TLC) analysis. A colorless pre-
cipitate of 1,3,4-thiadiazole 13 was formed, and this was fltered and washed with a
small amount of EtOH. The fltrate was subjected to PLC [toluene:EtOAc (10:1)] to
give two zones 15 and 16.
(Z)‑Ethyl
2‑cyano‑2‑(5‑(phenylamino)‑1,3,4‑thiadiazol‑2(3H)‑ylidene)‑acetate
(13ab) Yield: (0.173 g, 60 %); colorless crystals (DMF/EtOH), M.p.: 280–282 °C.
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Reactive intermediates in the reaction of…
IR (KBr): ν = 3283 (NH’s), 3146 (Ar–CH), 2976 (Ali-CH), 2196 (CN), 1647
(C=O), 1623 (C=N), 1595 (Ar–C=C) cm−1.
NMR spectral data in Table 1.
MS: m/z (%) = 288 (M.+) (30), 153 (100), 135 (65), 106 (18), 76 (15).
Anal. Calcd. for C13H12N4O2S (288.32): C, 54.16; H, 4.20; N, 19.43; S, 11.12.
Found: C, 54.22; H, 4.27; N, 19.39; S, 11.07.
(Z)‑Ethyl
2‑cyano‑2‑(5‑(pyridin‑3‑ylamino)‑1,3,4‑thiadiazol‑2(3H)‑ylidene)acetate
(13bb) Yield: (0.13 g, 45 %); yellow crystals (DMF/EtOH); M.p.: 270-272 °C.
IR (KBr): ν = 3278 (NH), 3122 (Ar–CH), 2995 (Ali-CH), 2203 (CN), 1645
(C=O), 1622 (C=N), 1587 (Ar–C=C) cm−1.
1H NMR (400 MHz, DMSO-d6): δH = 1.21 (t, 3H, CH3, J = 6.8 Hz), 4.19 (q, 2H,
CH2, J = 7.0 Hz), 7.40–7.42 (m, 1H, Ar–H), 7.93–7.95 (m, 1H, Ar–H), 8.23–8.24
(m, 1H, Ar–H), 8.68–8.69 (m, 1H, Ar–H), 10.46 (br. s, 1H, NH-pyridyl), 13.81 (br.
s, 1H, thiadiazole-NH).
Table 1 NMR spectral data of 13ab
1H NMR
1H-1H COSY
Assignment
13.64 (b; 1H)
10.24 (bs; 1H)
NH-3
NH-5a
H–o
H-m
H-p
H-2c
H-2d
Assignment
7.48 (d, J = 7.7; 2H)
7.36 (“t”, J = 7.4; 2H)
7.02 (t, J = 7.1; 1H)
4.16 (q, J = 6.8; 2H)
1.23 (t, J = 6.8; 3H)
7.36, 7.02
7.48, 7.02
7.48, 7.36
1.23
4.16
HMBC
13C NMR
HSQC
166.42
162.94
155.52
139.88
129.15
122.12
117.32
116.68
60.03
4.16
C-2b
C-2/5
C-5/2
C-i
C-m
C-p
7.48, 7.36
7.36, 7.02
7.48
7.36
7.02
7.48
10.24, 7.48, 7.36, 7.02
C-o
C≡N
C-2c
C-2a
C-2d
4.16
1.23
1.23
58.69
14.52
15N NMR
4.16
HSQC
HMBC
Assignment
257.10
95.40
10.24
7.48
N-4
N-5a
10.24
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A. A. Aly et al.
13C NMR (100 MHz, DMSO-d6): δC = 14.70 (CH3), 59.10 (C-2a), 60.30 (CH2),
117.00 (CN), 124.20, 125.00, 137.00, 139.10 (Ar–CH), 142.90 (Ar–C), 156.20
(C=N), 163.50 (thiadiazole-C-2), 166.20 (CO).
MS: m/z (%) = 289 (M.+) (18), 153 (100); 135 (64), 106 (18).
Anal. Calcd. for C12H11N5O2S (289.31): C, 49.82; H, 3.83; N, 24.21; S, 11.08.
Found: C, 49.97; H, 3.89; N, 24.09; S, 11.20.
(Z)‑Ethyl
2‑(5‑(allylamino)‑1,3,4‑thiadiazol‑2(3H)‑ylidene)‑2‑cyanoacetate
(13cb) Yield: (0.151 g, 60 %); colorless crystals; M.p.: 242–244 °C.
IR (KBr): ν = 3291 (NH’s), 2970 (Ali-CH), 2192 (CN), 1644 (C=O), 1624
(C=N).
1H NMR (400 MHz, DMSO-d6): δH = 1.20 (t, 3H, CH3, J = 6.8 Hz), 4.12 (q, 2H,
CH2, J = 7.0 Hz), 5.14 (m, 2H, allyl-CH2), 5.22 (m. 2H, allyl-CH2N), 5.86 (m, 1H,
allyl-CH =), 7.70 (br. s, 1H, NH-allyl), 13.24 (br. s, 1H, thiadiazole-NH).
13C NMR (100 MHz, DMSO-d6): δC = 14.50 (CH3), 46.00 (allyl-CH2NH), 57.90
(C-2a), 59.70 (CH2), 116.30 (allyl-CH2=), 117.10 (CN), 134.00 (allyl-CH=), 159.50
(C=N), 163.20 (thiadiazole-C-2), 166.40 (CO).
MS: m/z (%) = 252 (M.+) (60), 153 (100); 136 (70), 106 (19), 92 (23).
Anal. Calcd. for C10H12N4O2S (252.29): C, 47.61; H, 4.79; N, 22.21; S, 12.71.
Found: C, 47.50; H, 4.94; N, 22.33; S, 12.60.
4‑Cyano‑3‑(methylthio)‑5‑oxo‑N‑phenyl‑2,5‑dihydro‑1H‑pyrazole‑1‑carbothioamide
(14ab) Yield: (0.058 g, 20 %); colorless crystals (EtOH); M.p.: 262–264 °C.
IR (KBr): ν = 3250 (NH’s), 3100 (Ar–CH), 2920 (Ali-CH), 2192 (CN), 1572
(CO), 1644 (C=O), 1494 (Ar–C=C), 1370 (C=S) cm−1.
1H NMR (400 MHz, DMSO-d6): δH = 2.50 (S, 3H, SCH3), 7.00–7.22 (m, 3H, Ph-H),
7.40–7.52 (m, 2H, Ph-H), 11.60 (br. s, 1H, NH–Ph), 13.22 (br. s, 1H, NH-pyrazole).
13C NMR (100 MHz, DMSO-d6): δC = 11.50 (SCH3), 73.40 (pyrazole-C-4),
115.00 (CN), 127.30, 128.40 (Ar-2CH), 128.80 (Ar–CH), 137.60 (Ar–C), 147.60
(pyrazole-C-3), 164.30 (CO), 173.50 (C=S).
MS: m/z (%) = 290 (M.+) (22), 153 (16), 131 (100), 91 (15).
Anal. Calcd. for C12H10N4OS2 (290.36): C, 49.64; H, 3.47; N, 19.30; S, 22.08.
Found: C, 49.49; H, 3.60; N, 19.42; S, 22.15.
Ethyl 5‑amino‑3‑(methylthio)‑1‑(phenylcarbamothioyl)‑1H‑pyrazole‑4‑carboxylate
(15ab) Yield: (0.04 g, 12 %); colorless crystals (EtOH); M.p.: 182–183 °C.
IR (KBr): ν = 3204 (NH’s), 3112 (Ar–CH), 2923 (Ali-CH), 1648 (CO), 1620
(C=N), 1559 (Ar–C=C), 1357 (C=S) cm−1.
1H NMR: (400 MHz, DMSO-d6): δH = 1.14 (t, 3H, CH3, J = 7.0 Hz), 2.50 (s, 3H,
SCH3), 4.16 (q, 2H, CH2, J = 6.8 Hz), 7.24–7.35 (m, 3H, Ar–H), 7.41–7.49 (m, 2H,
Ar–H), 6.17 (br. s, 2H, NH2), 11.70 (br. s, 1H, NH–Ph).
13C NMR (100 MHz, DMSO-d6): δC = 11.10 (CH3-Et), 11.40 (SCH3), 58.60
(CH2-Et), 92.50 (pyrazole-C-4), 127.50, 128.10 (Ar-2CH), 128.90 (Ar–CH), 130.03
(Ar-C), 140.70 (pyrazole-C-3), 149.80 (pyrazole-C-5), 155.50 (C=N), 163.30 (CO),
173.80 (C=S).
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Reactive intermediates in the reaction of…
MS: m/z (%) = 336 (M.+) (5 %), 201 (56), 153 (87), 148 (77), 135 (80), 116 (49),
90 (100).
Anal. Calcd. for C14H16N4O2S2 (336.43): C, 49.98; H, 4.79; N, 16.65; S, 19.06.
Found: C, 49.93; H, 4.90; N, 16.75; S, 19.15.
Ethyl
1‑(allylcarbamothioyl)‑5‑amino‑3‑(methylthio)‑1H‑pyrazole‑4‑carboxylate
(15cb) Yield: (0.06 g, 20 %); colorless crystals (EtOH); M.p.: 92 °C.
IR (KBr): ν = 3365-3338 (NH’s); 2920 (Ali-CH), 1671 (CO), 1615 (C=N), 1354
(C=S) cm−1.
NMR spectral data in Table 2.
MS: m/z (%) = 300 (M.+) (17), 252 (17), 201 (88), 155 (100), 90 (15).
Anal. Calcd. for C11H16N4O2S2 (300.07): C, 43.98; H, 5.37; N, 18.65; S, 21.35.
Found: C, 44.10; H, 5.42; N, 18.59; S, 21.46.
Ethyl
5‑amino‑1‑(ethylcarbamothioyl)‑3‑(methylthio)‑1H‑pyrazole‑4‑carboxylate
(15db) Yield: (0.158 g, 55 %); colorless crystals (EtOH); M.p.: 96 °C.
IR (KBr): ν = 3371–3336 (NH’s), 2986–2840 (Ali-CH), 1670 (CO), 1615 (C=N),
1354 (C=S) cm−1.
Table 2 NMR spectral data of 15cb
1H NMR
1H-1H COSY
4.26
Assignment
10.02 (bs; 1H)
NH-2b
NH-3a
H-2d
H-2e
H-2e
H-2c
H-4b
H-5a
H-4c
8.27 (b; 2H)
5.91 (ddt, Jd = 17.1, 10.4, Jt = 5.2; 1H)
5.21 (d, J = 16.6; 1H)
5.18 (d, J = 9.9; 1H)
4.26 (bm; 2H)
4.22 (q, J = 7.2; 2H)
2.51 (s; 3H)
5.21, 5.18, 4.26
5.91, 5.18, 4.26
5.91, 5.21, 4.26
10.02, 5.91, 5.21, 5.18
1.28
1.28 (t, J = 7.1; 3H)
13C NMR
4.22
HSQC
HMBC
Assignment
172.97
161.65
153.36
150.46
131.73
115.70
91.27
C-2a
C-4a
C-5
4.22
2.51
C-3
5.91
5.21, 5.18
4.26
C-2d
C-2e
C-4
58.46
44.54
13.33
11.46
4.22
4.26
1.28
2.51
1.28
4.22
C-4b
C-2c
C-4c
C-5a
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A. A. Aly et al.
1H NMR (400 MHz, DMSO-d6): δH = 0.87 (t, 3H, CH3, J = 7.0 Hz), 1.10 (t, 3H,
CH3, J = 6.8 Hz), 2.49 (S, 3H, SCH3), 3.64 (q, 2H, CH2, J = 7.0 Hz), 4.20 (q, 2H,
CH2, J = 7.0 Hz), 8.27 (br. s, 2H, NH2), 9.88 (br. s, 1H, NH-ethyl).
13C NMR (100 MHz, DMSO-d6): δC = 11.10 (CH3-Et), 11.60 (SCH3), 13.00
(CH3-Et), 42.50 59.40 (CH2-Et), 92.40 (pyrazole-C-4), 139.8 (pyrazole-C-3), 151.30
(pyrazole-C-5), 162.60 (CO), 173.40 (C=S).
MS: m/z (%) = 288 (M.+) (30), 201 (100), 200 (54), 154 (92), 147 (21).
Anal. Calcd. For C10H16N4O2S2 (288.38): C, 41.65; H, 5.59; N, 19.43; 10; S,
7.00. Found: C, 41.63; H, 5.60; N, 19.45; S, 6.91.
Ethyl 5‑amino‑3‑(methylthio)‑1‑(phenylcarbamothioyl)‑1H‑pyrazole‑4‑carboxylate
(16) Yield: (0.016 g, 8 %); colorless crystals (EtOH); M.p.: 136–137 °C; lit [25, 26]
135–136 °C.
13C NMR (100 MHz, DMSO-d6): δC = 11.40 (SCH3), 14.4 (CH3), 58.6 (OCH2),
91.5 (pyrazole-C-4), 149.5 (C=N), 152.9 (pyrazole-C-3), 163.3 (CO).
Crystal structure determination of 3, 4, and 15cb
Single-crystal X-ray difraction studies were carried out on a Bruker D8 Venture dif-
fractometer with Photon100 or PhotonII detector at 123(2) K using Cu Kα radiation
(λ = 1.54178 Å). Direct methods (SHELXS-97) or dual-space methods (SHELXT)
[27, 28] were used for structure solution, and refnement was carried out using
SHELXL-2014 (full-matrix least-squares on F2) [29]. Hydrogen atoms were local-
ized by diference electron density determination and refned using a riding model
H(N). Semiempirical absorption corrections were applied. Due to the poor quality
of the data and the (not to be resolved) disorder of the thiomethane substituents for
4, only the constitution could be determined. Therefor the data of 4 were not depos-
ited with The Cambridge Crystallographic Data Centre.
Compound 3: Colorless crystals, C12H11N5S2, Mr = 289.38, crystal size
0.22 × 0.16 × 0.10 mm, monoclinic, space group C2/c (no. 15), a = 22.0120(7) Å,
b = 19.5237(6) Å, c = 13.8667(5) Å, β = 118.775(1)°, V = 5223.4(3) Å3, Z = 16,
ρ = 1.472 Mg/m−3, µ(Cu Kα) = 3.642 mm−1, F(000) = 2400, 2θmax = 144.4°,
46,945 refections, of which 5138 were independent (Rint = 0.025), 363 parameters,
6 restraints, R1 = 0.028 [for 5056 I > 2σ(I)], wR2 = 0.075 (all data), S = 1.03, largest
dif. peak/hole = 0.416/−0.364 e Å−3.
Compound 4: Colorless crystals, C5H6N4S, Mr = 154.20, crystal size
0.26 × 0.14 × 0.12 mm, monoclinic, space group C2/c (no. 15), a = 30.5762(10) Å,
b = 11.7594(4) Å, c = 16.8216(5) Å, β = 107.038(2)°, V = 5782.9(3) Å3, Z = 32,
ρ = 1.417 Mg/m−3, µ(Cu Kα) = 3.384 mm−1, F(000) = 2560.
Compound 15cb: Colorless crystals, C11H16N4O2S2, Mr = 300.40, crystal size
0.16 × 0.10 × 0.04 mm, monoclinic, space group P21/c (no. 14), a = 9.3909(4) Å,
b = 19.3892(8) Å, c = 7.9959(4) Å, β = 98.096(2)°, V = 1441.40(11) Å3, Z = 4,
ρ = 1.384 Mg/m−3, µ(Cu Kα) = 3.397 mm−1, F(000) = 632, 2θmax = 144.4°, 11,575
refections, of which 2833 were independent (Rint = 0.033), 182 parameters, 3
1 3

Reactive intermediates in the reaction of…
restraints, R1 = 0.034 [for 2462 I > 2σ(I)], wR2 = 0.091 (all data), S = 1.05, largest
dif. peak/hole = 0.459/−0.282 e Å−3.
CCDC 1856010 (3) and 1840929 (15cb) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Due to their poor quality, the data for 4 were not deposited with The Cambridge
Crystallographic Data Centre.
Results and discussion
The reactions of diferent hydrazinecarbothioamides 1a–d with 2-(bis(methylthio)
methylene)malononitrile (2a) and ethyl 2-cyano-3,3-bis(methylthio)acrylate (2b)
were successfully achieved, giving diferent heterocyclic rings under reaction con-
ditions. The structures of the starting substances under investigation are shown in
Fig. 1.
Gentle heating (at 50 °C) of equimolar solutions of 1a and 2a in absolute etha-
nol containing 0.5 mL Et3N for 3 h gave compound 3 in 45 % yield together with
5-amino-3-(methylthio)-1H-pyrazole-4-carbonitrile (4) [23, 24] in 5 % yield and
4-phenyl-3-(phenylamino)1H-1,2,4-triazole-5(4H)-thione (5aa) [18] in 20 % yield
(Scheme 1). The side products 4 and 5aa were separated by preparative thin-layer
chromatography (PLC) using toluene/EtOAc (10:1). To optimize the yield of the
pyrazole derivative 3, we carried out the reaction between equal equivalents of
the two starting materials at room temperature. 5-Amino-4-cyano-3-(methylthio)-
N-phenyl-1H-pyrazole-1-carbothioamide (3) was successfully obtained as the major
product in 65 % yield (Scheme 1).
The IR spectrum of compound 3 showed absorptions at 3303–3251, 2215, 1633,
1
and 1358 due to (NH’s), (CN), (C=N), and C=S, respectively. In the H NMR
spectrum, a singlet appeared at δ = 2.35 due to methylthio protons, two broadened
singlets at δ = 6.01 and 11.55 related to NH2 and HN-Ph, respectively, in addition
to aromatic protons. The 13C NMR spectrum also supported the structure due to
δ = 12.30 (SCH3), 62.00 (pyrazole-C-4), 114.22 (CN), 148.52 (C=N), 164.00 (pyra-
zole-C-5), and 170.00 related to C=S. The mass spectrum also confrmed the result
of elemental analysis due to the appearance of a molecular ion peak at m/z = 289.
Fig. 1 Starting substances 1a–d
and 2a, b
1 3

A. A. Aly et al.
Scheme 1 Reaction of N-phenyl hydrazinecarbothioamide 1a with 2a
The structure of compound 3 was, ultimately, proved by X-ray structure analysis
(Fig. 2).
The formation of compound 3 can be explained due to nucleophilic attack of
the terminal N1 lone pair in 1a on the ethylenic carbon in 2a, to form interme-
diate 6a accompanied by elimination of methanethiol to form intermediate 6a
(Scheme 2). Nucleophilic addition of nitrogen lone pair-N2 on the nitrile car-
bon would lead to salt 7a. Subsequently, neutralization of 6a followed by aro-
matization would then give compound 3. Meanwhile, elimination of phenyl
Fig. 2 Molecular structure analysis of one of the crystallographic independent molecules of 3 (displace-
ment parameters drawn at 50 % probability level)
1 3

Reactive intermediates in the reaction of…
Scheme 2 Mechanism describing formation of compounds 3 and 4
isothiocyanate from 7a would give intermediate 8a (Scheme 2). Aromatization of
8 would directly give 4 (Scheme 2).
Meanwhile, the formation of the side product 4 can be explained as a result
of the loss of phenyl isothiocyanate molecule from compound 3 (Scheme 2).
The structure of 4 was elucidated by diferent spectral data (i.e., IR, NMR, and
mass spectra). In addition, single-crystal X-ray structure analysis of 4 was also
obtained (Fig. 3).
The formation of the product 5aa may be rationalized via tautomerism between
thione and thiol, followed by formation of salt 8. Elimination of hydrazine mol-
ecule from the Zwitter ion A would form isothiocyanate intermediate (Scheme 3).
Nucleophilic attack of the hydrazinyl-N lone pair of 1a on thiocarbonyl of isothi-
ocyanate intermediate would result in amidine-like reaction to the thione-C as in
9, accompanied by elimination of H2S molecule to give 5aa (Scheme 3). Such a
Fig. 3 Molecular structure of one of the four independent molecules of 4 (displacement parameters
drawn at 50 % probability level)
1 3

A. A. Aly et al.
Scheme 3 Plausible mechanism describing formation of 5aa and 5ba
route was also noted with pyridinyl substituent of hydrazinecarbothioamides, and
compound 5ba was also obtained.
In a diferent manner, reaction of compound 1b with 2a produced, either at
room temperature or in heating condition (50 °C), two products: 4 in 20 % yield
and 4-pyridyl-3-(pyridylamino)-1H-1,2,4-triazole-5(4H)-thione (5ba) in 65 % yield
(Scheme 4). The diferent behavior of 1a towards 2a compared with that between 1b
and 2a might be explained by the high reactivity of the 3-pyrindyl substituent and
the instability of its reaction products even at room temperature.
The molecular formula of 5ba (C12H10N6S) was confrmed from its mass spec-
trum due to the presence of a molecular ion peak at m/z = 270. The 1H NMR spec-
trum of compound 5ba showed two broad exchangeable (with D2O) singlets at
δ = 10.19 and 13.53 due to (NH-pyridyl) and (NH-triazole), respectively, as well as
aromatic protons in aromatic region. The 13C NMR spectrum showed the presence
of aromatic carbons at δ = 129.50, 129.60, 130.40, 130.50, 137.10, 137.60, 141.90,
142.50, 147.90, and 149.80 in addition to 155.80 and 165.60 due to carbon signals
of C=N and C=S, respectively.
In a diferent manner, N-ethyl hydrazinecarbothioamide (1c) reacted with 2a to
provide compound 12 in 80 % yield. The structure of 12 was confrmed by difer-
ent spectroscopic data and was identifed as 5-amino-4-cyano-2-(2,2-dicyano-1,1-
bis(methylthio)ethyl)-N-ethyl-3-(methylthio)-2,3-dihydro-1H-pyrazole-1-carbothio-
amide (Scheme 5). The mechanism could be explained as due to nucleophilic attack
of the hydrazine-lone pair in 1c on the electrophilic carbon in 2a. That was followed
by elimination of one molecule of methanethiol to give 6c. Thereafter, cyclization
would then occur due to another nucleophilic attack on the carbon of nitrile group
Scheme 4 Reaction of 3-N-pyridyl hydrazinecarbothioamide 1b with 2a
1 3

Reactive intermediates in the reaction of…
Scheme 5 Mechanism describing formation of compound 12
to give intermediate 7c. Addition of a second molecule of 2a to 7c would produce
compound 12 (Scheme 5).
1
The H NMR spectrum of compound 12 showed three singlets at δH = 2.30
(6H), 2.40 (3H), and 3.33 (1H) for 2SCH3, SCH3, and CH(CN)2, respectively (see
1
“Experimental” section). The N-ethyl protons resonated in the H NMR spectrum
as a quartet and triplet at δH = 3.60 (CH2, J = 7.0 Hz) and 1.10 (CH3, J = 7.0 Hz).
Two additional broad singlets were observed for NH and NHEt at δH = 8.79 and
9.99, respectively. The presence of methylthiol carbon signals was also confrmed
by 13C NMR at δC = 12.50 (2C) and 12.70 (C). respectively. Pyrazole C-5, C-4, and
C-3 resonated at δC = 169.00, 65.00, and 163.30. The low δ value of pyrazole-C-4 is
attributed to the presence of a push–pull system. In addition, the δC = 11.30, 22.30,
38.10, 78.00, and 184.00 ppm signals are attributed to CH3–Et, CH(CN)2, CH2–Et,
(C(SCH3)2), and C=S, respectively (see “Experimental” section). Finally, elemen-
tal analysis proved that compound 12 has molecular formula C14H17N7S4, as also
confrmed by the mass spectrum due to the appearance of the molecular ion peak at
m/z = 411. The aforementioned behavior between N-substituted hydrazinecarboth-
ioamides 1a–d with 2a encouraged us to study the behavior of 1a–d towards ethyl
2-cyano-3,3-bis(methylthio)acrylate (2b). Reaction of N-phenyl hydrazinecarboth-
ioamide 1a with 2b at room temperature in dry ethanol containing 0.5 mL trieth-
ylamine gave a colorless precipitate of (Z)-ethyl 2-cyano-2-(5-(phenylamino)-1,3,4-
thiadiazol-2(3H)-ylidene)-acetate (13ab) in 60 % yield, then the fltrate was
subjected to PLC to separate another zone, identifed as 4-cyano-3-(methylthio)-
5-oxo-N-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide (14ab), in 20 % yield
(Scheme 6). The structures of 13ab and 14ab were detected using various spectral
data (IR; 1H, 13C, and 2D NMR; MS) as well as elemental analyses.
In a diferent manner, reactions of 1a–d with 2b under heating at 50 °C in dry
ethanol containing 0.5 mL triethylamine yielded three structures 13, 15, and 16
(Scheme 7).
Compound 13 was separated as a precipitate, whereas the fltrate contained
the other two zones, which were separated out using PLC. The fast-migrating
1 3

A. A. Aly et al.
Scheme 6 Reaction of N-phenylhydrazinecarbothioamides 1a and 2b at room temperature
Scheme 7 Reaction of N-substituted hydrazinecarbothioamides 1a–d and 2b under gentle heating condi-
tion
Fig. 4 The distinctive carbons in
compound 13ab
zone contained 15 while the slowest-migrating zone contained ethyl 5-amino-
3-(methylthio)-1H-pyrazole-4-carboxylate 16 [25, 26] (Scheme 7).
1
Figure 4 shows distinctive carbon atoms in compound 13a, b. The H spectral
data of 13ab showed two broadened singlets downfeld, both having integrals of
1H, at δH = 13.64, 10.24 ppm due to thiadiazole NH and (NH–Ph), respectively
(Table 1). The methyl singlet is absent due to loss of two methanethiol molecules.
The ethoxy 3H triplet (H-2d) is distinctive at δH = 1.23; its attached carbon (C-2d)
appears at δC = 14.52; H-2d gives COSY correlation, and C-2d gives HMBC cor-
relation, with the 2H quartet at δH = 4.16, assigned as H-2c; the attached carbon
1 3

Reactive intermediates in the reaction of…
(C-2c) appears at δC = 60.03. The H-2c also gives HMBC correlation with a carbon
at δC = 166.42, assigned as the ester carbonyl C-2b (Fig. 4). The phenyl protons are
assigned straightforwardly as H-p (δ = 7.02), H-m (δH = 7.36), and H–o (δH = 7.48);
the attached carbons appear at δC = 122.12 (C-p), 129.15 (C-m), and 117.32 (C-o).
H-m and (weakly) H–o give HMBC correlation with a carbon at δC = 139.88,
assigned as C-i. H-o also gives HMBC correlation with a nitrogen at δN = 95.40,
assigned as N-5a; this nitrogen gives HSQC correlation with its attached proton at
δH = 10.24.
The H-5a gives HMBC correlation with C-o and with a nitrogen at δN = 257.10,
assigned as N-4 (Table 1). The carbon signal at δC = 116.68 is assigned as the nitrile
carbon, and the carbon signal at δC = 58.69 is assigned as C-2a, the upfeld shift
arising because of its position in a push–pull system. The carbons at δC = 162.94
and 155.52 must be C-2 and C-5.
The mass spectrum of 13ab also supported the proposed structure, showing a
molecular ion peak at (m/z = 288, 30 %) corresponding to the molecular formula
C13H12N4O2S.
The mechanism describing the formation of 13ab is presented in Scheme 8.
Nucleophilic attack of the thione lone pair 1a on C-2 of 2b accompanied by elimi-
nation of a molecule of methanethiol followed by another nucleophilic attack from
terminal hydrazine-NH2 on the same carbon leading to loss of another molecule of
methanethiol forms the target compounds 13ab (Scheme 8).
The mechanism for the formation of 14ab, 15, and 16 can be explained as nucleo-
philic attack of the more powerful terminal nitrogen N1 lone pair in 1a–d on C-3 of
2b accompanied by loss of a molecule of methanethiol giving intermediate 18, fol-
lowed by a second nucleophilic attack from N2 of hydrazinecarbothioamides on the
carbonitrile group, forming intermediate 19 (Scheme 9). Subsequently, nucleophilic
addition of N2-lone pair on the nitrile carbon would give zwitterion 19 (Scheme 9).
Neutralization of 19 followed by aromatization would give 15 (Scheme 9). Rear-
rangement to 19 accompanied by elimination of substituted isothiocyanate molecule
would give the pyrazole derivatives 16 (i.e., occurring easily under heating) [25,
26]. On the other hand, loss of ethanol molecule from 18a would occur at room tem-
perature due to nucleophilic attack from N2 of hydrazinecarbothioamide 1a on the
carbonyl of ester group to give 14ab (Scheme 9). Compound 14ab was identifed as
4-cyano-3-(methylthio)-5-oxo-N-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide
Scheme 8 Plausible mechanism for formation of 13ab
1 3

A. A. Aly et al.
Scheme 9 Rationale for the formation of products 14ab, 15, and 16
using diferent spectroscopic data. Formation of compound 16 was further con-
frmed from the reaction of 2b with hydrazine hydrate to give ethyl 5-amino-
3-(methylthio)-1H-pyrazole-4-carboxylate (16). Generally, the structure of ethyl
1-(allylcarbamothioyl)-5-amino-3-(methylthio)-1H-pyrazole-4-carboxylate (15cb)
was confrmed via diferent spectral data as follows: IR spectra of compound
15cb showed characteristic absorptions at ν = 3365–3338, 2920, 1671, 1615, and
1354 cm−1 relating to (NH’s), (Ali-CH), CO, C=N, and C=S. The ethoxy 3H triplet
(H-4c) is distinctive at δH = 1.28; its attached carbon (C-4c) appears at δC = 13.33.
The H-4c gives COSY correlation, and C-4c gives HBC correlation, with the
2H quartet at δH = 4.22, assigned as H-4b; the attached carbon (C-4b) appears at
δC = 58.46. The H-4b also gives HMBC correlation with a carbon at δC = 161.7,
assigned to the ester carbonyl C-4a. Distinctive carbon atoms of compound 15cb are
shown in Fig. 5.
The 1H double–double-triplet at δH = 5.91 is assigned as H-2d; the attached car-
bon C-2d appears at δC = 131.73. H-2d gives COSY correlation with the broad-
ened doublets at δH = 5.21 and 5.18, assigned to the terminal vinylic protons H-2e;
their attached carbon C-2e appears at δC = 115.70. Protons H-2e and H-2d all give
COSY correlation with a 2H broad multiplet at δH = 4.26, assigned as H-2c. The
fne structure of this signal is not resolved, even though the coupling constant with
H-2d is over 5 Hz; H-2c gives HSQC correlation with the carbon at δC = 44.54,
assigned as C-2c. H-2c also gives COSY correlation with the broad 1H singlet at
δH = 10.02, assigned as NH-2b. The broad 2H signal at δH = 8.27 is assigned as
1 3

Reactive intermediates in the reaction of…
Fig. 5 Distinctive carbons of
15cb
Fig. 6 Molecular structure analysis of 15cb (displacement parameters drawn at 50 % probability level)
NH-3a. The 13C spectrum has 11 signals; four are in the normal sp3 region upfeld
of δC = 58.46, while the other seven are downfeld of δC = 91.27 (Table 2). The car-
bon at δC = 11.46 gives HSQC correlation with a signal at δH = 2.51, which is not
resolved from the DMSO signal but must be a 3H singlet given by H-5a; the carbon
just mentioned is assigned as C-5a. H-5a gives HMBC correlation with a carbon at
δ = 153.36, assigned as C-5. The remaining three carbons at δC = 172.97, 150.46,
and 91.27 give no correlations; based on their chemical shifts, they are assigned
as C-2a, C-3, and C-4, respectively. The structure of 15cb was determined also by
single-crystal X-ray structure analysis, which confrmed the loss of a molecule of
methanethiol (Fig. 6). The bond lengths of C11–S11, N2–C3, C4–C5, and C41–O41
are 1.6727 (17) Å, 1.311 (2) Å, 1.395 (2) Å, and 1.219 (2) Å, respectively, relating
to C=S, C=N, C=C, and C=O double bond character, whereas the bond lengths of
N1–N2 [1.4105 (18) Å], N1-C11 [1.401 (2) Å], and C41-O42 [1.343(2) Å] suggest
that they have single bond character when compared with N–N, C–N, and C–O sin-
gle bonds.
Conclusions
Hydrazinecarbothioamides have attracted much attention due to the presence of
many active nucleophilic centers. The reactivity of substituents of hydrazinecarboth-
ioamides depends upon their electronic structure (i.e., aliphatic or aromatic), as well
1 3

A. A. Aly et al.
as their stability towards reaction with electrophiles. To date, many eforts have been
made in this feld, especially for construction of new simple classes of sulfur and/or
nitrogen heterocycles.
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Afliations
Ashraf A. Aly1 · Alaa A. Hassan1 · Nasr K. Mohamed1 · Kamal M. El‑Shaieb1 ·
Maysa M. Makhlouf1 · Stefan Bräse2 · Martin Nieger3
* Ashraf A. Aly
ashrafaly63@yahoo.com; minia.ashrafaly@gmail.com
1 3

Reactive intermediates in the reaction of…
1
Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt
2
Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6,
76131 Karlsruhe, Germany
3
Department of Chemistry, University of Helsinki, P.O. Box55, A. I. Virtasen Aukio 1,
00014 Helsinki, Finland
1 3