Efficient synthesis of some new functionalized 3-amino- and 5-aminopyrazoles derivatives

Article abstract of DOI:10.1007/s11164-014-1551-7

Cyanoacetic acid hydrazide derivatives were utilized as key intermediates for the synthesis of some new 3-amino- and 5-aminopyrazole derivatives. Coupling of N′-phenylsulfonyl-2-cyanoacetohydrazide (1) and 1-(2-cyanoacetyl)-4-phenyl thiosemicarbazide (4)

Full text of DOI:10.1007/s11164-014-1551-7

Res Chem Intermed
DOI 10.1007/s11164-014-1551-7
Efficient synthesis of some new functionalized
3-amino- and 5-aminopyrazoles derivatives
•
Ehab Abdel-Latif Abdel-Galil M. Khalil
Received: 14 November 2013 / Accepted: 30 January 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Cyanoacetic acid hydrazide derivatives were utilized as key interme-
diates for the synthesis of some new 3-amino- and 5-aminopyrazole derivatives.
Coupling of N0-phenylsulfonyl-2-cyanoacetohydrazide (1) and 1-(2-cyanoacetyl)-4-
phenyl thiosemicarbazide (4) with different aryl diazonium chlorides afforded the
corresponding 5-amino-1-substituted-4-pyrazolin-3-one derivatives
3 and 6,
respectively. Treatment of ketene dithioacetal 9 and ketene-N,S-acetal 13 with
hydrazine and/or benzenesulfonyl hydrazide furnished the corresponding 3-amino-
5-1H-pyrazole-4-carbohydrazide derivatives 10, 11, and 14. The structures of the
new synthesized compounds were elucidated and confirmed by elemental analyses
and spectral data.
Keywords Hydrazides ꢀ Benzenesulphonyl chloride ꢀ Carbon disulfide ꢀ
Ketene dithioacetal ꢀ 5-Aminopyrazole
Introduction
Pyrazole and its derivatives are very interesting heterocyclic compounds with wide-
ranging biological activities [1, 2]. In particular, 3-aminopyrazole derivatives have
been reported as protein b-sheet stabilizers [3] and are much used as ideal
precursors for the synthesis of biologically active fused heterocyclic compounds
[4–7]. Some of the 3-aminopyrazole analogues (e.g., H30935) are used as building
blocks to more complex moieties, such as potential drug candidates [8–11] and
others (e.g., H32918) as selective-based MK2-inhibitors [12]. Moreover, they are
used as intermediates in the dyestuff industry [13–17].
E. Abdel-Latif (&) ꢀ A.-G. M. Khalil
Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
e-mail: ehabattia00@gmx.net
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E. Abdel-Latif, A.-G. M. Khalil
The chemistry of 3(5)-aminopyrazoles has been recently reviewed and has
received considerable attention not only from the point of pharmaceutical and
medicinal applications but also because of their synthetic importance as versatile
precursors for the synthesis of azoloazines [18–21]. A literature survey revealed that
the synthetic strategy required to prepare 3(5)-aminopyrazoles involves either the
reactions of hydrazine hydrate with each of the a,b-unsaturated nitriles [22–25] and
3-oxoalkanenitriles [26–29], or the reactions of hydrazonyl halides with active
methylene nitriles [30]. In the light of these facts, we report here an efficient
synthesis of novel substituted 3-amino- and 5-aminopyazole derivatives, which have
not previously been reported.
Experimental
The chemicals used for the synthesis of the compounds were obtained from Aldrich
and Sigma Chemical without further purification. The solvents used were of
analytical grade. Melting points were measured on an electrothermal Gallenkamp
melting point apparatus. Elemental analyses were carried out at the Microanalytical
Unit, Cairo University, Giza, Egypt; the results were in satisfactory agreement with
the calculated values. The IR spectra were recorded in KBr disks on a Mattson 5000
FTIR spectrometer (not all frequencies are reported). The NMR spectra were
acquired using a Bruker WP 300 spectrometer at 300 MHz using TMS as an internal
standard and CDCl3 and/or DMSO-d6 as solvent. The mass spectra were performed
using a Varian MAT 311 mass spectrometer at 70 eV.
Synthesis of N0-phenylsulfonyl-2-cyanoacetohydrazide (1), 1-cyanoacetyl-4-
phenylthiosemicarbazide (4) and N0-arylidene-2-cyanoacetohydrazides 7
The starting materials N0-phenylsulfonyl-2-cyanoacetohydrazide (1) [31], 1-cya-
noacetyl-4-phenylthiosemicarbazide (4) [35], and N0-arylidene-2-cyanoacetohydra-
zide derivatives 7 [36] were prepared according to the previous literature.
General synthesis of 5-amino-4-arylazo-1-phenylsulfonyl-4-pyrazolin-3-ones
3a–c and 5-amino-4-arylazo-1-phenylthiocarbamoyl-4-pyrazolin-3-ones 6a–c
A cold solution of sodium nitrite (5 mmol) in 30 mL of water was added gradually
to a cold suspension of desired aromatic amine (5 mmol) in 1.5 mL of concentrated
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Efficient synthesis of some new functionalized pyrazole derivatives
HCl. The diazonium salt thus obtained was added by continuous stirring to a cold
solution of compound 1 and/or compound 4 (5 mmol) in 20 mL of pyridine. The
reaction mixture was stirred at 0–5 °C for 2 h and diluted with water. The solid was
then filtered, dried, and recrystallized from ethanol to afford the corresponding
pyrazoline derivatives 3 and/or 6, respectively.
5-Amino-4-phenylazo-1-phenylsulfonyl-4-pyrazoline-3-one (3a)
Yield 67 %, m.p. 220–221 °C. IR (KBr, cm-1): 3,307, 3,190 (NH2 and NH), 1,624
(C=O). 1H NMR (DMSO-d6, d ppm): 7.25–7.75 (m, 10H, Ar–H), 8.20 (s, 2H, NH2),
10.45 (s, 1H, NH). Anal. Calcd. for C15H13N5O3S (343.36): C, 52.47; H, 3.82; N,
20.40. Found: C, 52.58; H, 3.76; N, 20.51.
5-Amino-1-phenylsulfonyl-4-(p-tolylazo)-4-pyrazoline-3-one (3b)
Yield 78 %, m.p. 241–241 °C. IR (KBr, cm-1): 3,316, 3,233, 3,193 (NH2 and NH),
1
1,629 (C=O). H NMR (DMSO-d6, d ppm): 2.40 (s, 3H, CH3), 7.10–7.85 (m, 9H,
Ar–H), 8.78 (s, 2H, NH2), 11.25 (s, 1H, NH). 13C NMR (DMSO-d6, d ppm): 21.52,
105.28, 116.88, 122.65, 128.82 (2C), 129.68 (2C), 132.41 (2C), 133.16 (2C),
139.30, 141.08, 142.92, 161.62. MS (m/z, relative intensity): 358 (M??1, 100).
Anal. Calcd. for C16H15N5O3S (357.39): C, 53.77; H, 4.23; N, 19.60. Found: C,
53.96; H, 4.29; N, 19.51.
5-Amino-4-(p-anisylazo)-1-phenylsulfonyl-4-pyrazoline-3-one (3c)
Yield 58 %, m.p. 234–235 °C. IR (KBr, cm-1): 3,442, 3,335, 3,208 (NH2 and NH),
1,638 (C=O). 1H NMR (DMSO-d6, d ppm): 3.85 (s, 3H, OCH3), 6.90 (d, 1H, Ar–H),
7.20–7.75 (m, 7H, Ar–H), 8.55 (s, 2H, NH2), 10.85 (s, 1H, NH). Anal. Calcd. for
C16H15N5O4S (373.39): C, 51.47; H, 4.05; N, 18.76. Found: C, 51.39; H, 4.11; N, 18.84.
5-Amino-4-phenylazo-1-phenylthiocarbamoyl-4-pyrazolin-3-one (6a)
Yield 64 %, m.p. 181–182 °C. IR (KBr, cm-1): 3,382, 3,344, 3,268 (NH2 and NH),
1,634 (C=O). 1H NMR (CDCl3/DMSO-d6, d ppm): 6.85.7.60 (m, 10H, Ar–H), 8.85
(s, 2H, NH2), 10.70 (s, 1H, NH), 12.15 (s, 1H, NH). Anal. Calcd. for C16H14N6OS
(338.39): C, 56.79; H, 4.17; N, 24.84. Found: C, 56.63; H, 4.22; N, 24.76.
5-Amino-1-phenylthiocarbamoyl-4-(p-tolylazo)-4-pyrazolin-3-one (6b)
Yield 71 %, m.p. 208–209 °C. IR (KBr, cm-1): 3,417, 3,366, 3,305, 3,186 (NH2 and
NH), 1,631 (C=O). 1H NMR (CDCl3/DMSO-d6, d ppm): 2.35 (s, 3H, CH3),
6.75–7.40 (m, 9H, Ar–H), 9.05 (s, 2H, NH2), 11.10 (s, 1H, NH), 13.15 (s, 1H, NH).
13C NMR (DMSO-d6, d ppm): 21.65, 104.05, 118.96, 124.32, 128.37 (2C), 130.23
(2C), 132.69 (2C), 133.52 (2C), 139.75, 141.51, 143.55, 162.14, 184.15. MS (m/z,
relative intensity): 353 (M??1, 100). Anal. Calcd. for C17H16N6OS (352.41): C,
57.94; H, 4.58; N, 23.85. Found: C, 57.82; H, 4.50; N, 23.77.
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E. Abdel-Latif, A.-G. M. Khalil
5-Amino-4-(p-anisylazo)-1-phenylthiocarbamoyl-4-pyrazolin-3-one (6c)
Yield 66 %, m.p. 214–216 °C. IR (KBr, cm-1): 3,405, 3,374, 3,272, 3,218 (NH2 and
NH), 1,636 (C=O). 1H NMR (CDCl3/DMSO-d6, d ppm): 3.90 (s, 3H, OCH3),
6.80–7.70 (m, 9H, Ar–H), 8.90 (s, 2H, NH2), 10.80 (s, 1H, NH), 12.65 (s, 1H, NH).
Anal. Calcd. for C17H16N6O2S (368.41): C, 55.42; H, 4.38; N, 22.8. Found: C,
55.64; H, 4.33; N, 22.70.
General synthesis of N0-arylidene-2-cyano-3,3-bis-(methylthio)-
acrylohydrazides 9a–c
To a stirred suspension of finely powdered potassium hydroxide (20 mmol) in dry
dimethyl formamide (20 mL) cooled to 0 °C, first the cyanoacetic acid arylidene-
hydrazide 7 (10 mmol) and then carbon disulfide (10 mmol) were added gradually.
The reaction mixture was stirred at room temperature for 3 h, treated with methyl
iodide, and stirred at room temperature for an additional 6 h. Then, it was poured
into ice-water; the resulting precipitate was filtered off, dried, and recrystallized
from ethanol to give 9.
N0-Benzylidene-2-cyano-3,3-bis-(methylthio)-acrylohydrazide (9a)
Yield 54 %, m.p. 176–177 °C. IR (KBr, cm-1): 3,163 (NH), 2,111 (C:N), 1,640
1
(C=O). H NMR (CDCl3/DMSO-d6, d ppm): 2.45 (s, 3H, SCH3), 2.55 (s, 3H,
SCH3), 7.25–7.60 (m, 5H, Ar–H), 8.15 (s, 1H, CH=N), 10.65 (s, 1H, NH). Anal.
Calcd. for C13H13N3OS2 (291.39): C, 53.58; H, 4.50; N, 14.42. Found: C, 53.47; H,
4.53; N, 14.49.
2-Cyano-N0-(p-methylbenzylidene)-3,3-bis-(methylthio)-acrylohydrazide (9b)
Yield 66 %, m.p. 193–194 °C. IR (KBr, cm-1): 3,178 (NH), 2,110 (C:N), 1,638
(C=O). 1H NMR (DMSO-d6, d ppm): 2.40 (s, 6H, Ar–CH3 and SCH3), 2.55 (s, 3H,
SCH3), 7.20 (d, 2H, Ar–H), 7.50 (d, 2H, Ar–H), 8.20 (s, 1H, CH=N), 11.20 (s, 1H,
NH). Anal. Calcd. for C14H15N3OS2 (305.42): C, 55.06; H, 4.95; N, 13.76. Found:
C, 55.14; H, 4.98; N, 13.68.
2-Cyano-N0-(p-methoxybenzylidene)-3,3-bis-(methylthio)-acrylohydrazide (9c)
Yield 62 %, m.p. 198–200 °C. IR (KBr, cm-1): 3,183 (NH), 2,108 (C:N), 1,641
(C=O). 1H NMR (DMSO-d6, d ppm): 2.45 (s, 3H, SCH3), 2.55 (s, 3H, SCH3), 3.85
(s, 3H, OCH3), 6.90 (d, 2H, Ar–H), 7.50 (d, 2H, Ar–H), 8.20 (s, 1H, CH=N), 11.35
(s, 1H, NH). 13C NMR (DMSO-d6, d ppm): 16.35 (2C), 55.48, 78.66, 116.66,
126.86 (2C), 130.24 (2C), 132.18, 153.90, 158.62, 163.08, 179.95. MS (m/z, relative
intensity): 322 (M?, 52.4 %). Anal. Calcd. for C14H15N3O2S2 (321.42): C, 52.32; H,
4.70; N, 13.07. Found: C, 52.15; H, 4.76; N, 13.18.
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Efficient synthesis of some new functionalized pyrazole derivatives
General synthesis of 3-amino-N0-arylidene-5-methylthio-1H-pyrazole-4-
carbohydrazides 10a–c
A mixture of ketene dithioacetal 9 (3 mmol) and hydrazine hydrate 80 % (6 mmol)
in ethanol (25 mL) was heated under reflux for 2 h, then left to cool to room
temperature and further left overnight. The precipitated solid was filtered off and
dried, and then recrystallized from ethanol/DMF mixture (3:1) to yield compounds
10a–c as yellow crystals.
3-Amino-N0-benzylidene-5-methylthio-1H-pyrazole-4-carbohydrazide (10a)
Yield 67 %, m.p. 223–224 °C. IR (KBr, cm-1): 3,342, 3,227, 3,155 (NH2 and NH),
1,648 (C=O). 1H NMR (DMSO-d6, d ppm): 2.50 (s, 3H, SCH3), 7.30–7.70 (m, 5H,
Ar–H), 8.10 (s, 2H, NH2), 8.25 (s, 1H, CH=N), 10.30 (s, 1H, NH), 12.45 (s, 1H,
NH). Anal. Calcd. for C12H13N5OS (275.33): C, 52.35; H, 4.76; N, 25.44. Found: C,
52.56; H, 4.84; N, 25.33.
3-Amino-N0-(p-methylbenzylidene)-5-methylthio-1H-pyrazole-4-
carbohydrazide (10b)
Yield 73 %, m.p. 246–247 °C. IR (KBr, cm-1): 3,368, 3,212 (NH2 and NH), 1,652
1
(C=O). H NMR (DMSO-d6, d ppm): 2.40 (s, 3H, CH3), 2.50 (s, 3H, SCH3),
7.30–7.60 (m, 4H, Ar–H), 8.05 (s, 2H, NH2), 8.20 (s, 1H, CH=N), 9.80 (s, 1H, NH),
12.30 (s, 1H, NH). Anal. Calcd. for C13H15N5OS (289.36): C, 53.96; H, 5.23; N,
24.20. Found: C, 53.84; H, 5.31; N, 24.27.
3-Amino-N0-(p-methoxybenzylidene)-5-methylthio-1H-pyrazole-4-
carbohydrazide (10c)
Yield 71 %, m.p. 236–237 °C. IR (KBr, cm-1): 3,320, 3,276, 3,192 (NH2 and NH),
1,650 (C=O). 1H NMR (DMSO-d6, d ppm): 2.50 (s, 3H, SCH3), 3.90 (s, 3H, OCH3),
7.00 (d, 2H, Ar–H), 7.60 (d, 2H, Ar–H), 8.05 (s, 2H, NH2), 8.20 (s, 1H, CH=N),
10.15 (s, 1H, NH), 12.60 (s, 1H, NH). 13C NMR (DMSO-d6, d ppm): 18.22, 55.95,
88.74, 126.70 (2C), 130.04 (2C), 132.18, 134.48, 151.35, 154.45, 158.14, 163.65.
MS (m/z, relative intensity): 305 (M?, 100 %). Anal. Calcd. for C13H15N5O2S
(305.36): C, 51.13; H, 4.95; N, 22.94. Found: C, 51.29; H, 4.98; N, 23.03.
General synthesis of 3-amino-N0-arylidene-5-methylthio-1-phenylsulfonyl-1H-
pyrazole-4-carbohydrazides 11a–c
To the solution of 9 (3 mmol) in DMF (20 mL), benezenesulfonyl hydrazide
(3 mmol) and anhydrous potassium carbonate (0.42 g) were added. The reaction
mixture was heated under reflux for 4 h and then left to cool. The reaction mixture
was poured onto ice-cold water (100 mL) and the resulting solid was filtered off,
dried well, and re-crystallized from ethanol to yield compounds 11a–c as yellow
crystals.
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E. Abdel-Latif, A.-G. M. Khalil
3-Amino-N0-benzylidene-5-methylthio-1-phenylsulfonyl-1H-pyrazole-4-
carbohydrazide (11a)
Yield 48 %, m.p. 211–212 °C. IR (KBr, cm-1): ,3344, 3,282, 3,191 (NH2 and NH),
1
1,642 (C=O). H NMR (CDCl3, d ppm): 2.50 (s, 3H, SCH3), 7.40–7.80 (m, 10H,
Ar–H), 8.25 (s, 1H, CH=N), 9.05 (s, 2H, NH2), 11.15 (s, 1H, NH). Anal. Calcd. for
C18H17N5O3S2 (415.49): C, 52.03; H, 4.12; N, 16.86. Found: C, 52.16; H, 4.08; N,
16.91.
3-Amino-N0-(p-methylbenzylidene)-5-methylthio-1-phenylsulfonyl-1H-
pyrazole-4-carbohydrazide (11b)
Yield 61 %, m.p. 224–225 °C. IR (KBr, cm-1): 3,367, 3,275, 3,182 (NH2 and NH),
1
1,650 (C=O). H NMR (CDCl3/DMSO-d6, d ppm): 2.40 (s, 3H, CH3), 2.55 (s, 3H,
SCH3), 7.20–7.80 (m, 9H, Ar–H), 8.30 (s, 1H, CH=N), 9.20 (s, 2H, NH2), 12.05 (s,
1H, NH). Anal. Calcd. for C19H19N5O3S2 (429.52): C, 53.13; H, 4.46; N, 16.31.
Found: C, 53.04; H, 4.48; N, 16.36.
3-Amino-N0-(p-methoxybenzylidene)-5-methylthio-1-phenylsulfonyl-1H-
pyrazole-4-carbohydrazide (11c)
Yield 56 %, m.p. 218–219 °C. IR (KBr, cm-1): 3,411, 3,356, 3,282 (NH2 and NH),
1,648 (C=O). 1H NMR (CDCl3/DMSO-d6, d ppm): 2.55 (s, 3H, SCH3), 3.85 (s, 3H,
OCH3), 7.00 (d, 2H, Ar–H), 7.40–7.80 (m, 7H, Ar–H), 8.30 (s, 1H, CH = N), 9.30
(s, 2H, NH2), 12.15 (s, 1H, NH). 13C NMR (DMSO-d6, d ppm): 18.08, 55.95, 88.46,
123.04, 126.28 (2C), 128.62 (2C), 129.40 (2C), 130.12 (2C), 133.22, 134.82,
138.36, 152.34, 154.50, 158.04, 163.54. MS (m/z, relative intensity): 446 (M??1,
67 %). Anal. Calcd. for C19H19N5O4S2 (445.52): C, 51.22; H, 4.30; N, 15.72.
Found: C, 51.13; H, 4.34; N, 15.66.
General synthesis of N0-arylidene-2-cyano-3-methylthio-3-phenylamino-
acrylohydrazides 13a–c
To a stirred suspension of finely powdered potassium hydroxide (10 mmol) in dry
dimethyl formamide (20 mL), first N0-arylidene-2-cyanoacetohydrazides
7
(10 mmol) and then phenyl isothiocyanate (10 mmol) were added gradually. The
reaction mixture was stirred at room temperature for 3 h, treated with methyl iodide
(10 mmol), and stirred at room temperature for an additional 6 h. Then, it was
poured into ice-water; the resulting precipitate was filtered off, dried, and
recrystallized from ethanol to give 13.
N0-benzylidene-2-cyano-3-methylthio-3-phenylamino-acrylohydrazide (13a)
Yield 58 %, m.p. 162–163 °C. IR (KBr, cm-1): 32,13, 3,144 (2NH), 2,120 (C:N),
1
1,655 (C=O). H NMR (CDCl3, d ppm): 2.50 (s, 3H, SCH3), 6.70–7.60 (m, 10H,
Ar–H), 8.30 (s, 1H, CH=N), 9.20 (s, 1H, NH), 10.25 (s, 1H, NH). Anal. Calcd. for
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Efficient synthesis of some new functionalized pyrazole derivatives
C18H16N4OS (336.41): C, 64.26; H, 4.79; N, 16.65. Found: C, 64.36; H, 4.86; N,
16.74.
2-Cyano-N0-(p-methylbenzylidene)-3-methylthio-3-phenylamino-
acrylohydrazide (13b)
Yield 65 %, m.p. 155–156 °C. IR (KBr, cm-1): 3,189, 3,152 (2NH), 2,125 (C:N),
1,648 (C=O). 1H NMR (CDCl3, d ppm): 2.40 (s, 3H, Ar–CH3), 2.50 (s, 3H, SCH3),
6.80–7.60 (m, 9H, Ar–H), 8.30 (s, 1H, CH=N), 9.30 (s, 1H, NH), 10.45 (s, 1H, NH).
13C NMR (DMSO-d6, d ppm): 18.78, 21.29, 98.28, 114.92, 126.18 (2C), 128.39
(3C), 129.30 (2C), 130.08 (2C), 132.62, 135.53, 140.59, 155.28, 162.86, 179.74. MS
(m/z, relative intensity): 351 (M??1, 77 %). Anal. Calcd. for C19H18N4OS
(350.44): C, 65.12; H, 5.18; N, 15.99. Found: C, 65.28; H, 5.23; N, 15.91.
2-Cyano-N0-(p-methoxybenzylidene)-3-methylthio-3-phenylamino-
acrylohydrazide (13c)
Yield 54 %, m.p. 180–182 °C. IR (KBr, cm-1): 3,231, 3,177 (2NH), 2,124 (C:N),
1
1,651 (C=O). H NMR (CDCl3, d ppm): 2.50 (s, 3H, SCH3), 3.90 (s, 3H, OCH3),
6.80–7.80 (m, 9H, Ar–H), 8.35 (s, 1H, CH=N), 9.35 (s, 1H, NH), 10.30 (s, 1H, NH).
Anal. Calcd. for C19H18N4O2S (366.44): C, 62.28; H, 4.95; N, 15.29. Found: C,
62.19; H, 4.90; N, 15.37.
General synthesis of 3-amino-N0-arylidene-5-phenylamino-1H-pyrazole-4-
carbohydrazides 14a–c
A mixture of ketene-N,S-acetal 13 (3 mmol) and hydrazine hydrate 80 % (9 mmol)
was heated on a steam bath for 1 h and left to cool. The reaction mixture was
triturated with ethanol and the resulting solid was filtered off and recrystallized from
ethanol to give compounds 14a–c as white crystals.
3-Amino-N0-benzylidene-5-phenylamino-1H-pyrazole-4-carbohydrazide (14a)
Yield 76 %, m.p. 272–273 °C. IR (KBr, cm-1): 3,372, 3,311, 3,263, 3,177 (NH2 and
1
NH), 1,655 (C=O). H NMR (DMSO-d6, d ppm): 6.90–7.80 (m, 10H, Ar–H), 8.25
(s, 1H, CH=N), 8.90 (s, 2H, NH2), 10.20 (s, 1H, NH), 11.05 (s, 1H, NH), 12.50 (s,
1H, NH). Anal. Calcd. for C17H16N6O (320.35): C, 63.74; H, 5.03; N, 26.23. Found:
C, 63.82; H, 5.08; N, 26.18.
3-Amino-N0-(p-methylbenzylidene)-5-phenylamino-1H-pyrazole-4-
carbohydrazide (14b)
Yield 80 %, m.p. 250–251 °C. IR (KBr, cm-1): 3,358, 3,272, 3,194 (NH2 and NH),
1
1,654 (C=O). H NMR (DMSO-d6, d ppm): 2.40 (s, 3H, CH3), 6.90–7.70 (m, 9H,
Ar–H), 8.25 (s, 1H, CH=N), 8.85 (s, 2H, NH2), 9.75 (s, 1H, NH), 10.75 (s, 1H, NH),
12.60 (s, 1H, NH). 13C NMR (DMSO-d6, d ppm): 21.54, 97.23, 127.08 (2C), 128.63
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E. Abdel-Latif, A.-G. M. Khalil
(3C), 129.15 (2C), 130.26 (2C), 132.74, 135.96, 141.37, 146.41, 153.40, 156.24,
163.11. MS (m/z, relative intensity): 335 (M??1, 100 %). Anal. Calcd. for
C18H18N6O (334.38): C, 64.66; H, 5.43; N, 25.13. Found: C, 64.47; H, 5.37; N,
25.21.
3-Amino-N0-(p-methoxybenzylidene)-5-phenylamino-1H-pyrazole-4-
carbohydrazide (14c)
Yield 74 %, m.p. 285–286 °C. IR (KBr, cm-1): 3,412, 3,283, 3,247, 3,165 (NH2 and
NH), 1,657 (C=O). 1H NMR (DMSO-d6, d ppm): 3.85 (s, 3H, OCH3), 6.90–7.80 (m,
9H, Ar–H), 8.20 (s, 1H, CH=N), 9.10 (s, 2H, NH2), 9.85 (s, 1H, NH), 10.80 (s, 1H,
NH), 12.45 (s, 1H, NH). Anal. Calcd. for C18H18N6O2 (350.37): C, 61.70; H, 5.18;
N, 23.99. Found: C, 61.82; H, 5.22; N, 23.91.
Results and discussion
The N0-phenylsulfonyl-2-cyanoacetohydrazide (1) was prepared by the reaction of
2-cyanoacetohydrazide with benzenesulfonyl chloride according to the literature
procedure [31]. Coupling of compound 1 with a variety of aryl diazonium chlorides
afforded the corresponding cyanoaceto-N-phenylsulfonyl hydrazide intermediates 2
which underwent intramolecular cyclization to give the 5-amino-4-arylazo-1-
phenylsulfonyl-4-pyrazolin-3-ones 3a–c (Scheme 1).
O
O
H
N
H
N
NC
HN
Ph
NC
Ph
Pyridine
N
H
S
ArN2 Cl
N
H
S
+
O
O
N
O
O
O
1
Ar
2
Ar
Ar
HN
Ar
Ar
HN
N
O
N
OH
N
O
OH
N
O
O
N
N
NH
O
N
N
NH
O
H2N
HN
H2N
HN
N
S
N
S
N
S
N
S
O
O
O
Ph
Ph
Ph
Ph
enol-hydrazone (D)
3a: Ar = C6H5,
enol-azo (C)
keto-hydrazone (B)
keto-azo (A)
3b: Ar = 4-MeC6H4,
3c: Ar = 4-MeOC6H4
Scheme 1 Synthetic route to 5-amino-4-arylazo-1-phenylsulfonyl-4-pyrazolin-3-ones 3a–c and their
possible tautomeric structures
123

Efficient synthesis of some new functionalized pyrazole derivatives
Pyrazoles 3a–c can be formulated in four different possible tautomeric structures,
namely keto-azo (A), keto-hydrazone (B), enol-azo (C), and enol-hydrazone
tautomer (D) (Scheme 1). The tautomeric structures (B) and (D) were excluded
1
from the H NMR spectra of the studied compounds as they lacked signals in the
region of d = 13.83–13.92 ppm assignable to the hydrazone proton (–CH = N–
NH–) [32]. The enol-azo form (C) was also ruled out due to the presence of the
pyrazole-NH signal at 11.27 ppm [33] in 1H NMR spectra and the absence of an OH
group at 3,445 cm-1 in their IR spectra. The 13C NMR spectra of 3b revealed a
characteristic peak in the region d = 161.62 ppm due to a carbonyl carbon and
validated tautomeric structure (A). It is worth mentioning that the predominant
formation of the keto-azo form (A) is also in the line with similar structures reported
earlier by Morkovnik and coworkers [34].
Coupling of 1-cyanoacetyl-4-phenyl-thiosemicarbazide (4) [35] with a variety of
aryl diazonium chlorides afforded the corresponding 5-amino-4-arylazo-1-phe-
nylthiocarbamoyl-4-pyrazolin-3-ones 6a–c via intramolecular cyclization of cyano-
aceto-N-phenylthiocarbamoyl hydrazide intermediates 5 (Scheme 2). Spectral
studies indicated the superiority of the keto-azo structure 6 rather than other
tautomeric structures. The IR spectrum of the representative example 6b exhibited
absorption bands at 3,417, 3,366, 3,305, and 3,186 cm-1 attributed to NH2 and NH
vibrations, respectively, while the C=O vibration was observed at 1,631 cm-1. Its
1H NMR spectrum showed the methyl protons as a singlet signal at d 2.35 ppm. The
aromatic protons resonated at d 6.75–7.40 ppm. The NH2 protons appeared as a
singlet signal at d 9.05, and the protons of the NH groups appeared as two singlet
signals at d 11.10 and 13.15 ppm. Moreover, the mass spectrum of 6b clearly
showed the molecular ion peak at m/z 353 corresponding to the molecular weight of
the molecular formula (C17H16N6OS)?1.
O
O
H
N
H
N
NC
HN
NHPh
Pyridine
NC
NHPh
N
H
ArN2 Cl
+
N
H
N
S
S
4
Ar
5
Ar
N
O
N
NH
a: Ar = C6H5
b: Ar = 4-MeC6H4
c: Ar = 4-MeOC6H4
H2N
N
S
NHPh
6
Scheme 2 Synthetic route to 5-amino-4-arylazo-1-phenylthiocarbamoyl-4-pyrazolin-3-ones 6a–c
123

E. Abdel-Latif, A.-G. M. Khalil
Furthermore, the reaction of N0-arylidene-2-cyanoacetohydrazides 7 [36] with
carbon disulfide in dimethyl formamide, in the presence of potassium hydroxide,
gave the non-isolable intermediate 8. The latter was converted into the correspond-
ing ketene dithioacetal 9 by treatment with methyl iodide at room temperature in a
moderate yield (Scheme 3). The structure of 9 was confirmed by analytical and
spectroscopic data. The IR spectrum of 9c showed absorption bands at 3,183 (NH),
1
2,108 (C:N), and 1,641 (C=O). Its H NMR spectrum in DMSO-d6 revealed the
presence of singlet signals at d 2.45, 2.55, and 3.85 ppm, characteristic for three
methyl groups. The two doublet signals at d 6.90 and 7.40 ppm were attributed to
aromatic protons. Two singlet signals at d 8.20 and 11.35 ppm were assigned to
N=CH and NH protons, respectively. Also, the structure 9c is supported by its mass
spectrum which showed a molecular ion peak at m/z = 322 (52.4 %) corresponding
to the formula (C14H15N3O2S2)?1.
Polarized a-cyanoketene dithioacetals are versatile starting materials for the
synthesis of a wide variety of heterocycles. Thus, heating of ketene dithioacetals 9
Scheme 3 Synthetic route to 3-amino-N0-arylidene-5-methylthio-1H-pyrazole-4-carbohydrazides 10a–
c and 11a–c
123

Efficient synthesis of some new functionalized pyrazole derivatives
with hydrazine hydrate afforded the corresponding 3-Aminopyrazole derivatives 10.
The chemical structure of compounds 10 was secured by their correct spectral data
1
(IR, H NMR, and MS) and elemental analyses.
Cyclocondensation of compound 9 with benzenesulfonyl hydrazide in refluxing
DMF containing potassium carbonate furnished the novel aminopyrazole derivative
11. The formation of 11 is assumed to proceed through Michael0s addition of the
amino group to the ethylenic bond in 9 with elimination of methanethiol followed
by intramolecular cyclization at the cyano group to form 11. The chemical structure
of product 11 was established by analytical and spectral data. The infrared spectrum
of compound 11b was characterized by the appearance of absorption bands at 3,367,
3,275, 3,182 cm-1 corresponding to NH2 and NH functions, in addition to the
1
carbonyl absorption at 1,650 cm-1. Also, the H NMR spectrum displayed two
singlet signals at d 2.40 and 2.55 ppm for two methyl groups, a multiplet signal in
the range d 7.20–7.80 ppm for aromatic protons, a singlet signal at 8.30 ppm due to
the CH=N proton and two singlet signals at d 9.20 and 12.05 ppm due to NH2 and
NH protons, respectively.
Our investigation was extended to examine the base-promoted nucleophilic
addition of compound 7 into phenyl isothiocyanate in DMF containing potassium
hydroxide. Subsequent treatment of the non-isolable sulfide salt 12 with an
equimolar amount of methyl iodide afforded the corresponding ketene-N,S-acetal
13. The aminopyrazole derivatives of the type 14 were synthesized in high yields by
refluxing a mixture of ketene-N,S-acetal 13 with hydrazine hydrate in ethanol for
Scheme 4 Synthetic route to 3-amino-N0-arylidene-5-phenylamino-1H-pyrazole-4-carbohydrazides 14a–c
123

E. Abdel-Latif, A.-G. M. Khalil
4 h as shown in Scheme 4. The structure of the obtained products was confirmed
from their agreeable elemental and spectral data. Bands at 3,358, 3,272, 3,194 cm-1
(NH2 and NH), and 1,654 cm-1 (C=O) in the IR spectrum and molecular ion peak
m/z at 335 (100 %) in the mass spectrum confirmed the structure of compound 14b.
The 1H NMR spectrum of compound 14b showed a singlet signal at d 2.48 ppm due
to methyl protons, a multiplet signal in the range d 6.90–7.70 ppm for the aromatic
protons, a singlet signal at d 8.25 ppm for CH=N proton, and a singlet signal at d
8.85 ppm assignable to NH2 protons, in addition to three singlet signals at d 9.75,
10.75, and 12.60 for three NH groups.
Conclusion
In summary, 15 different functionalized 3-amino- and 5-aminopyrazole derivatives
were efficiently synthesized under mild reaction conditions. 5-Amino-1-substituted-
4-pyrazolin-3-one derivatives 3 and 6 were obtained by coupling of N0-substituted-
2-cyanoacetohydrazide with different aryl diazonium chlorides, while 3-amino-5-
1H-pyrazole-4-carbohydrazide derivatives 10, 11, and 14 were obtained by
cyclocondensation of ketene dithioacetal 9 and ketene-N,S-acetal 13 with hydrazine
and/or benzenesulfonyl hydrazide. The synthesized aminopyrazole derivatives were
characterized by IR, NMR, mass spectroscopy, and elemental analyses.
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