Arylhydrazononitriles as precursors to 2-substituted 1,2,3-triazoles and 4-amino-5-cyano-pyrazole derivatives utilizing microwave and ultrasound irradiation

Abstract

Cyanoacetamides 3a–d were prepared by reacting ethyl cyanoacetate with primary aliphatic amines 2a–d. The formed cyanoacetamides 3a–d were coupled with aromatic diazonium salts to give the corresponding arylhydrazones 4a–i which were used as precursors to title triazoles and pyrazoles by reacting with hydroxylamine and chloroacetonitrile. Yields of products formed by conventional heating are compared with those of microwave and ultrasound irradiation

Keywords:

• green synthetic approaches
• 2-arylhydrazononitriles
• X-ray crystal structure determination
• 4-amino-5-cyano-pyrazoles
• 1,2,3-triazoles

Introduction

Recently, many papers have been published dealing with 2-arylhydrazononitriles as precursors to heteroaromatics 1–6. Elnagdi et al. 7–10 have reported efficient synthetic approaches to functionally substituted pyrazoles and 1,2,3-triazoles utilizing arylhydrazononitrile precursors. In the light of our recent interest in adopting green synthetic methodologies for the synthesis of functionally substituted heteroaromatics utilizing microwave (Mw) heating and ultrasound (Us) irradiation 11–25, we aim in this work to report on the synthesis and utility of arylhydrazononitrile as precursors to 1,2,3-traizoles 7, 10, and pyrazole derivatives 13.

Results and discussion

Ethyl cyanoacetate 1 was reacted with a variety of aliphatic amines 2a–d under Mw heating or Us activation to yield cyanoacetamides 3a–d (Scheme 1).

Scheme 1.  Synthesis of cyanoacetamides

Compounds 3a–d were coupled readily with aromatic diazonium salts to yield the corresponding arylhydrazononitriles 4a–i, in 67–95% yields (Scheme 2). The structures of compounds 4a–i were established on the basis of their elemental analyses and spectral data. ¹H NMR spectra of compounds 4a–i showed a singlet signal in region 11.10–14.97 ppm corresponding to the hydrazone (NH) proton. The structure assigned to compounds 4a–i could be unequivocally established by single crystal X-ray diffraction of compound 4c 26, as shown in Figure 1.

Figure 1.  X-ray crystal structure of 4c.

Scheme 2.  Synthesis of 2-arylhydrazononitrile derivatives.

Parallel to the recent literature data 7 8 27–29, compounds 4a–i reacted with hydroxylamine hydrochloride in the presence of sodium acetate to yield the amidoximes 5a–h. It has been found that the reaction completion time was 1 h in refluxing ethanol and 2–5 min under Mw heating. The structures of the new amidoximes 5a–h have been elucidated by elemental analyses and spectroscopic measurements. For example, the ¹H NMR spectra of compound 5a revealed the presence of (NH₂) protons at Δ6.52 ppm and a broad singlet signal at Δ14.21 ppm corresponding to (OH) proton. The IR spectra of compound 5a showed absorption bands at ν = 3587, 3456, and 3420 cm⁻¹ due to OH and NH₂ groups, respectively.

Upon heating 5 in dimethylformamide (DMF) at reflux temperature for 1 h or under Mw irradiation for 2–5 min or by utilizing Us irradiation for 1 h at 40°C, this compound gave solid products whose structures were assumed to be 6, 7, or 8 (Scheme 3 ).

Scheme 3.  Synthesis of 5-amino-1,2,3-triazole and 1,2,3-triazolo[4,5-d]pyrimidin-7-one derivatives

The structure of isoxazoles 6 was readily ruled out for the reaction products on the basis of spectral data. Thus, the presence of an amide carbonyl absorption in region ν = 1642–1658 cm⁻¹ in the IR spectra of the reaction products allowed us to discard the possible structure 6. Moreover, ¹³C NMR spectra of the reaction products confirmed the presence of a CO carbon at Δ≈164 ppm. If the reaction product was the isomer 6, it would be difficult to assign this signal. Elemental analysis and spectral data could not unequivocally differentiate the two isomers 7 and 8. Therefore, the 1,2,3-triazolo[4,5-d]pyrimidines 10 was prepared to chemically verify the structure of 7. Reaction of aminotriazoles 7 with dimethylformamide dimethylacetal (DMF DMA), under different reaction conditions, gave the ring-closed 1,2,3-triazolo[4,5-d]pyrimidines 10, via the intermediate 9 (Scheme 3). It is difficult to obtain these reaction products 10 with the isomer 8.

Recently, Elnagdi et al. 2 7 30 have reported that refluxing 2-arylhydrazononitriles with functionally substituted alkyl halides afforded 4-aminopyrazole derivatives. Now, compound 4 was next reacted with chloroacetonitrile, under conventional heating, Mw irradiation, and sonication, to afford the 4-aminopyrazoles 13, via the acyclic non-isolable intermediate 12 (Scheme 4 ). The identity of compounds 13 was supported by correct elemental analyses and mass spectra as well as the IR and NMR spectra which were compatible with assigned structures (see Section “Experimental”). The reaction times and yields of the products formed via traditional methods were compared with those of Mw and Us irradiation (see Table 1).

Scheme 4.  Synthesis of pyrazole derivatives.

Table 1. Yield as well as reaction times by the three methodologies are compared.

No.	Time			Yield%
	Δ	Mw	Us	Δ	Mw	Us
3a	3 h	4 min	7 min	67	89	74
3b	4 h	3 min	10 min	90	91	88
3c	2 h	2 min	5 min	83	90	80
3d	1 h	1 min	2 min	89	93	90
5a	1 h	2 min	30 min	40	80	72
5b	1 h	5 min	30 min	37	74	70
5c	1 h	4 min	30 min	48	80	76
5d	1 h	3 min	30 min	35	35	66
5e	1 h	2 min	30 min	40	75	78
5f	1 h	3 min	30 min	44	89	81
5g	1 h	5 min	30 min	48	80	77
5h	1 h	3 min	30 min	39	79	78
7a	1 h	2 min	1 h	40	60	58
7b	1 h	2 min	1 h	44	73	70
7c	1 h	3 min	1 h	45	77	68
7d	1 h	2 min	1 h	43	79	71
7e	1 h	4 min	1 h	40	66	56
10a	7 h	2 min	–	47	90	–
10b	7 h	2 min	–	46	88	–
13a	1 h	2 min	1 h	60	77	73
13b	1 h	2 min	1 h	55	84	78
13c	1 h	2 min	1 h	59	79	70
13d	1 h	2 min	1 h	58	89	84
13e	1 h	2 min	1 h	54	80	78

In conclusion, we have shown that the synthesis of 2-aryl-1,2,3-triazoles and 4-aminopyrazoles from arylhydrazononitriles is better conducted by green methodologies through the avoidance of heating and excessive use of solvents. On the other hand, it should be noted that reactions occur at different temperatures with these techniques and therefore strict comparisons will require a balance between effectiveness and energy costs.

Experimental

General

All melting points were measured on a Gallenkamp electrothermal melting point apparatus and are uncorrected. The IR absorption spectra were measured on a Nicolet Magna 520FT IR spectrophotometer. ¹H and ¹³C NMR spectra were recorded in deuterated dimethylsulfoxide (DMSO) or deuterated chloroform (CDCl₃) at Bruker DPX 400 MHz spectrometer using tetramethylsilane (TMS) as an internal reference. Mass spectra were performed on a Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 eV. Mw irradiation was carried out using the commercial Mw oven (SGO 1000 W). A thermocouple used to monitor the temperature inside the Mw vessel during the reactions found that the temperature was approximately 105–110°C. Us irradiation was carried out with a microprocessor controlled-2004, high intensity ultrasonic processor with temperature controller (750 W). The ultrasonic frequency of the cleaning bath used was equal to 25 KHz. The reaction temperature was stabilized at 35–40°C even after more than 1 h by addition or removal of water in ultrasonic bath to keep the required temperature. Elemental analyses were measured by means of Perkin Elmer 2400 CHN elemental analyzer flowchart. X-ray crystallography was carried out on a Kappa CCD Enraf Nonius FR 590 diffractometer, at National Research Center, Dokki, Cairo, Egypt.

General procedure for the preparation of N-substituted-2-cyano-acetamide 3a–d

Method I (Δ)

Equimolar amounts (0.1 mol) of both ethyl cyanoacetate and the aliphatic amines 2a–d were stirred at room temperature for 1–4 h and the resulting solid product was re-crystallized from ethanol.

Method II (µω)

A mixture of ethyl cyanoacetate (0.1 mol) and the appropriate amount of aliphatic amines 2a–d (0.1 mol) was placed in the Mw oven and irradiated at 460 W for 1–4 min. Then, the reaction mixture was left to cool to room temperature. The solid product so-formed was filtered and re-crystallized from ethanol.

Method III (Us)

Equimolar amounts (0.1 mol) of both ethyl cyanoacetate and the aliphatic amines 2a–d were mixed and heated under Us irradiation at 40°C for 2–10 min, and then left to cool to room temperature. The solid product so-formed was filtered and re-crystallized from ethanol.

N-Butyl-2-cyanoacetamide (3a)

Orange crystals from ethanol; mp 72°C; IR ν_max cm⁻¹: 3299 (NH), 2954 (CH aliphatic), 2258 (CN), and 1653 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.85 (t, 3H, CH₃, J=7 Hz), 1.27 (m, 2H, CH₂, J=7 Hz), 1.38 (m, 2H, CH₂, J=7 Hz), 3.06 (q, 2H, CH₂ , J=7 Hz), 3.56 (s, 2H, CH₂CN), and 8.18 (br s, 1H, NH) ppm; ¹³C NMR; (DMSO-d ₆); Δ = 14.02, 20.00, 25.76, 31.40 (butyl carbons), 39.27 (CH₂CN), 116.71 (CN), and 162.39 (C = O) ppm; MS: 141 [M⁺+1]. Analysis calculated for C₇H₁₂N₂O (140.19): C, 59.98; H, 8.63; and N, 19.98. found: C, 59.90; H, 8.70; and N, 19.92.

2-Cyano-N-hexyl-acetamide (3b)

Yellow crystals from ethanol; mp 67°C; IR ν_max cm⁻¹: 3299 (NH), 2932 (CH aliphatic), 2260 (CN), and 1645 (C = O); ¹H NMR; (CDCl₃); Δ = 0.81 (t, 3H, CH₃, J=6 Hz), 1.24 (m, 6H, 3CH₂), 1.45 (m, 2H, CH₂, J=7 Hz), 3.17 (q, 2H, CH₂, J=7 Hz), 3.42 (s, 2H, CH₂CN), and 7.17 (s, 1H, NH) ppm; ¹³C NMR; (CDCl₃); Δ = 13.99, 22.54, 26.04, 26.55, 29.11, 31.43 (hexyl carbons), 40.45 (CH₂CN), 115.22 (CN), and 162.03 (C = O) ppm; MS: 169 [M⁺+1]. Analysis calculated for C₉H₁₆N₂O (168.24): C, 64.25; H, 9.59; and N,16.65. Found: C, 64.20; H, 9.61; and N, 16.69.

2-Cyano-N-cyclohexyl-acetamide (3c)

Colorless crystals from ethanol; mp 136°C; IR ν_max cm⁻¹: 3272 (NH), 2933 (CH aliphatic), 2261 (CN), and 1628 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 1.12 − 1.68 (m, 6H, 3CH₂), 1.70–2.03 (m, 4H, 2CH₂), 3.46–3.54 (m, 1H, CH), 3.22 (s, 2H, CH₂CN), and 8.14 (d, 1H, NH, J=7 Hz) ppm; ¹³C NMR; (DMSO-d ₆); Δ = 24.35, 24.87, 25.62, 25.84, 30.91, 32.60 (cyclohexyl carbons), 48.73 (CH₂CN), 116.73 (CN), and 161.51 (C = O) ppm; MS: 166 [M⁺]. Analysis calculated for C₉H₁₄N₂O (166.22): C, 65.05; H, 8.49; and N, 16.85. Found: C, 65.10; H, 8.36; and N, 16.89.

N-Benzyl-2-cyano-acetamide (3d)

Brown crystals from ethanol; mp 124°C; IR ν_max cm⁻¹: 3295 (NH), 3091 (CH aromatic), 2923 (CH aliphatic), 2220 (CN), and 1640 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 3.71 (s, 2H, CH₂CN), 4.30 (d, 2H, PhCH₂, J=5 Hz), 7.29–7.34 (m, 5H, ph–H), and 8.74 (t, 1H, NH, J=7 Hz) ppm; MS: 174 [M⁺]. Analysis calculated for C₁₀H₁₀N₂O (174.20): C, 68.95; H, 5.79; and N, 16.08. Found: C, 68.90; H, 5.67; and N, 16.20.

Preparation of arylhydrazone derivatives 4a–i

A cold solution of aryldiazonium salt (10 mmol) was prepared by adding a solution of sodium nitrite (1g into 10 mL H₂O) to a cold solution of arylamine hydrochloride or arylamine nitrate (10 mmol) with stirring. The resulting solution of the aryldiazonium was then added to a cold solution of N-substituted-2-cyanoacetamides 3a–d (0.1mol) in ethanol (50 mL) containing sodium acetate (1 g into 10 mL H₂O). The mixture was stirred at room temperature for 1 h and the solid product so-formed was collected by filtration and re-crystallized from ethanol.

2-[N′-(Butylcarbamoyl-cyano-methylene)-hydrazino]-benzoic acid methyl ester (4a)

Yellow crystals from ethanol; yield 70%, mp 166°C; IR ν_max cm⁻¹: 3388 (NH), 3026 (CH aromatic), 2953 (CH aliphatic), 2214 (CN), 1696 (C = O ester), and 1668 (C = O amide); 1H NMR; (DMSO-d ₆); Δ = 0.89 (t, 3H, CH₃, J=7 Hz), 1.31 (m, 2H, CH₂, J=7 Hz), 1.49 (m, 2H, CH₂, J=7 Hz), 3.23 (q, 2H, CH₂, J=7 Hz), 3.91 (s, 3H, ester CH₃), 7.20 (t, 1H, Ar H, J=7 Hz), 7.69 (t, 1H, Ar H, J=7 Hz), 7.98 (d, 1H, Ar H, J=8 Hz), 8.16 (d, 1H, Ar H, J=8 Hz), 8.58 (t, 1H, NH, J=5 Hz), and 12.28 (s, 1H, NH) ppm; 13C NMR; (DMSO-d ₆); Δ = 14.26, 20.15, 31.92 (butyl carbons), 53.33 (ester CH₃), 111.18, 112.99, 113.53, 123.60, 131.23, 135.51 (C6H₄COOCH₃-o), 116.54 (CN), 143.67 (C = N–NH), and 159.97, 168.15 (2C = O) ppm; MS: 301 [M + –1]. Analysis calculated for C15H18N4O3 (302.34): C, 59.59; H, 6.00; and N, 18.53. Found: C, 59.68; H, 6.35; and N, 18.43.

2-[N′-(Cyano-hexylcarbamoyl-methylene)-hydrazino]-benzoic acid methyl ester (4b)

Yellow crystals from ethanol; yield 67%, mp 140°C; IR ν_max cm⁻¹: 3391 (NH), 3023 (CH aromatic), 2951 (CH aliphatic), 2215 (CN), 1697 (C = O ester), and 1670 (C = O amide); ¹H NMR; (DMSO-d ₆); Δ = 0.83 (t, 3H, CH₃CH₂, J=6 Hz), 1.24 (m, 6H, 3CH₂), 1.48 (m, 2H, CH₂, J=7 Hz), 3.17 (q, 2H, CH₂, J=7 Hz), 3.88 (s, 3H, ester CH₃), 7.16 (t, 1H, Ar H, J=7 Hz), 7.63 (t, 1H, Ar H, J=7 Hz), 7.95 (d, 1H, Ar H, J=8 Hz), 8.12 (d, 1H, Ar H, J=8 Hz), 8.50 (t, 1H, NH, J=5 Hz), and 14.97 (s, 1H, NH) ppm; MS: 330 [M⁺]. Analysis calculated for C₁₇H₂₂N₄O₃ (330.39): C, 61.80; H, 6.71; and N, 16.96. Found: C, 61.74; H, 6.98; and N, 16.79.

2-[N′-(Cyano-cyclohexylcarbamoyl-methylene)-hydrazino]-benzoic acid methyl ester (4c)

Orange crystals from ethanol; yield 77%, mp 166°C; IR ν_max cm⁻¹: 3290 (NH), 3032 (CH aromatic), 2935 (CH aliphatic), 2210 (CN), 1720 (C = O ester), and 1689 (C = O amide); ¹H NMR; (DMSO-d ₆); Δ = 1.09–1.62 (m, 6H, 3CH₂), 1.78–2.11 (m, 4H, 2CH₂), 3.62–3.88 (m, 1H, cyclohexyl CH), 3.91 (s, 3H, COOCH₃), 7.01 (d, 1H, NH, J=7 Hz), 7.20 (t, 1H, Ar H, J=7 Hz), 7.70 (t, 1H, Ar H, J=7 Hz), 7.79 (d, 1H, Ar H, J= 8 Hz), 8.13 (d, 1H, Ar H, J=8 Hz), and 12.28 (s, 1H, NH) ppm; ¹³C NMR; (DMSO-d ₆); Δ = 25.58, 25.73, 32.76, 49.01 (cyclohexyl carbons), 53.33 (ester CH₃), 111.24, 113.23, 113.54, 123.61, 131.22, 135.48 (C₆H₄COOCH₃-o), 116.66 (CN), 143.62 (C = N–NH), and 159.17, 168.15 (2C = O) ppm; MS: 327[M⁺–1]. Analysis calculated for C₁₇H₂₀N₄O₃ (328.37): C, 62.18; H, 6.14; and N, 17.06. Found: C, 62.26; H, 6.32; and N, 17.00.

N′-Butyl-2-[(4-chlorophenyl)-hydrazono]-2-cyano-acetamide (4d)

Brown crystals from ethanol; yield 90%, mp 185°C; IR ν_max cm⁻¹: 3380 (2NH), 3086 (CH aromatic), 2927 (CH aliphatic), 2211 (CN), and 1646 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.86 (t, 3H, CH₃, J=7 Hz), 1.28 (m, 2H, CH₂, J=7 Hz), 1.45 (m, 2H, CH₂ , J=7 Hz), 3.19 (q, 2H, CH₂, J=7 Hz), 7.35 (d, 2H, Ar H, J=8 Hz), 7.63 (d, 2H, Ar H, J=8 Hz), 8.26 (t, 1H, NH, J=5 Hz), and 13.90 (s, 1H, NH) ppm; MS: 277[M⁺–1]. Analysis calculated for C₁₃H₁₅ClN₄O (278.74): C, 56.02; H, 5.42; and N, 20.10. Found: C, 56.15; H, 5.58; and N, 20.22.

2-[(4-Chlorophenyl)-hydrazono]-2-cyano-N-hexyl-acetamide (4e)

Orange crystals from ethanol; yield 85%, mp 176°C; IR ν_max cm⁻¹: 3391 (NH), 3089 (CH aromatic), 2939 (CH aliphatic), 2212 (CN), and 1654 (C = O); ¹H NMR; (CDCl₃); Δ = 0.60 (t, 3H, CH₃, J=6 Hz), 1.30 (m, 6H, 3CH₂), 2.29 (m, 2H, CH₂, J=7 Hz), 3.05 (q, 2H, CH₂, J=7 Hz), 6.90 (t, 1H, NH, J=5 Hz), 6.98 (dd, 2H, Ar H, J=8 Hz), 7.18 (d, 2H, Ar H, J=8 Hz), and 11.10 (s, 1H, NH) ppm; ¹³C NMR; (CDCl₃); Δ = 13.93, 22.36, 26.42, 29.53, 31.30 (hexyl carbons), 108.74, 128.83, 129.02, 140.75 (C₆H₄–Cl-p), 117.06 (CN), 157.30 (C = N–NH), and 160.56 (C = O) ppm; MS: 306 [M⁺]. Analysis calculated for C₁₅H₁₉ClN₄O (306.80): C, 58.73; H, 6.24; and N, 18.26. Found: C, 58.51; H, 6.15; and N, 18.40.

N′-Benzyl-2-[(4-chlorophenyl)-hydrazono]-2-cyano-acetamide (4f)

Yellow crystals from ethanol; yield 85%, mp 129°C; IR ν_max cm⁻¹: 3336 (NH), 3032 (CH aromatic), 2928 (CH aliphatic), 2218 (CN), and 1643 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 4.29 (d, 2H, CH₂ph, J=5 Hz), 7.23–7.36 (m, 5H, Ph–H), 7.41 (d, 2H, Ar–H, J=8 Hz), 7.70 (d, 2H, Ar–H, J=8 Hz), 9.12 (t, 1H, NH, J=5 Hz), and 13.83 (s, 1H, NH) ppm;¹³C NMR; (DMSO-d ₆); Δ = 43.02 (CH₂ph), 107.22, 108.91, 111.87, 127.58 (C₆H₄Cl-p), 116.75 (CN), 127.95, 128.82, 128.91, 139.10 (phenyl carbons), 141.72 (C = N–NH), and 162.73 (C = O) ppm; MS: 311 [M⁺–1]. Analysis calculated for C₁₆H₁₃ClN₄O (312.76): C, 61.45; H, 4.19; and N, 17.91. Found: C, 61.65; H, 4.29; and N, 17.85.

N′-Butyl-2-cyano-2-[(4-nitrophenyl)-hydrazono]-acetamide (4g)

Orange crystals from ethanol; yield 89%, mp 144°C; IR ν_max cm⁻¹: 3242 (NH), 3072 (CH aromatic), 2957 (CH aliphatic), 2220 (CN), and 1660 (C = O); ¹H NMR; (CDCl₃); Δ = 0.77 (t, 3H, CH₃, J=7 Hz), 1.22 (m, 2H, CH₂, J=7 Hz), 1.41 (m, 2H, CH₂, J=7 Hz), 3.22 (q, 2H, CH₂, J=7 Hz), 7.06 (t, 1H, NH, J=5 Hz), 7.44 (d, 2H, Ar H, J=8 Hz), 8.03 (d, 2H, Ar H, J=8 Hz), and 11.60 (s, 1H, NH) ppm;¹³C NMR; (CDCl₃); Δ = 13.78, 20.04, 31.11, 31.68 (butyl carbons), 110.57, 112.10, 123.37, 125.32, 134.72, 143.27 (C₆H₄–NO₂-p), 115.58 (CN), 147.42 (C = N–NH), and 160.04 (C = O) ppm; MS: 288 [M⁺–1]. Analysis calculated for C₁₃H₁₅N₅O₃ (289.30): C, 53.97; H, 5.23; and N, 24.21. Found: C, 53.83; H, 5.42; and N, 24.22.

2-Cyano-N-hexyl-2-[(4-nitrophenyl)-hydrazono]-acetamide (4h)

Brown crystals from ethanol; yield 92%, mp 186°C; IR ν_max cm⁻¹: 3369 (NH), 3091 (CH aromatic), 2929 (CH aliphatic), 2218 (CN), and 1656 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.84 (t, 3H, CH₃, J=6 Hz), 1.26 (m, 6H, 3CH₂), 1.49 (m, 2H, CH₂, J=7 Hz), 3.21 (q, 2H, CH₂, J=7 Hz), 7.80 (d, 2H, Ar H, J=8 Hz), 8.19 (d, 2H, Ar H, J=8 Hz), 8.50 (t, 1H, NH, J=5 Hz), and 13.88 (s, 1H, NH) ppm; ¹³C NMR; (DMSO-d ₆); Δ = 14.44, 22.59, 26.65, 29.74, 31.59 (hexyl carbons), 111.33, 112.51, 125.74, 143.13 (C₆H₄–NO₂-p), 116.32 (CN), 148.32 (C = N–NH), and 160.26 (C = O) ppm; MS: 316 [M⁺–1]. Analysis calculated for C₁₅H₁₉N₅O₃ (317.35): C, 56.77; H, 6.03; and N, 22.07. Found: C, 56.69; H, 6.15; and N, 22.31.

2-Cyano-N-cyclohexyl-2-[(4-nitrophenyl)-hydrazono]-acetamide (4i)

Brown crystals from ethanol; yield 88%, mp 212°C; IR ν_max cm⁻¹: 3313 (NH), 3020 (CH aromatic), 2931 (CH aliphatic), 2214 (CN), and 1651 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 1.09–410 (m, 11H, cyclohexyl H), 7.58 (d, 2H, Ar H, J=8 Hz), 8.07 (d, 2H, Ar H, J=8 Hz), 8.24 (d, 1H, NH, J=7 Hz), and 13.71 (s, 1H, NH) ppm; MS: 314 [M⁺–1]. Analysis calculated for C₁₅H₁₇N₅O₃ (315.33): C, 57.14; H, 5.43; and N, 22.21. Found: C, 57.26; H, 5.18; and N, 22.11.

Preparation of 5a–h

Method I (Δ)

To a solution of hydroxylamine hydrochloride (0.1 mol) and hydrazono-2-cyanoacetamide derivatives 4a–i (0.1 mol) in ethanol (50 mL), anhydrous sodium acetate (0.1 mol) was added and the reaction mixture was refluxed for 1 h. After concentration and cooling to room temperature, the solid product so-formed was filtered and re-crystallized from ethanol.

Method II (µω)

A mixture of hydroxylamine hydrochloride (0.1 mol), hydrazono-2-cyanoacetamide derivatives 4a–i (0.1 mol), anhydrous sodium acetate, and drops of ethanol was irradiated under Mw irradiation at 460 W for 1–5 min, until no starting materials were present (monitored by TLC) in 1-min intervals. The reaction mixture was left to cool to room temperature. The solid product so-formed was filtered and re-crystallized from ethanol.

Method III (Us)

To a solution of hydroxylamine hydrochloride (0.1 mol) and hydrazono-2-cyanoacetamide derivatives 4a–i (0.1 mol) in ethanol (50 mL), anhydrous sodium acetate (0.1 mol) was added and the reaction mixture was irradiated under Us irradiation at 40°C for 30 min, until no starting materials were present (monitored by TLC). The solid product so-formed was filtered and re-crystallized from ethanol.

2-{N-[Hexylcarbamoyl-(N-hydroxycarbamimidoyl)-methylene]-hydrazino}-benzoic acid methyl ester (5a)

Yellow crystals from ethanol; mp 130°C; IR ν_max cm⁻¹: 3587 (br OH), 3456, 3420 (NH₂), 3379 (br 2NH), 3097 (CH aromatic), 2955 (CH aliphatic), 1701 (C = O ester), and 1651 (C = O amide); ¹H NMR; (CDCl₃); Δ = 0.87 (t, 3H, CH₃, J=6 Hz), 1.35 (m, 6H, 3CH₂), 1.59 (m, 2H, CH₂, J=7 Hz), 3.34 (q, 2H, CH₂, J=7 Hz), 3.87 (s, 3H, ester CH₃), 6.52 (s, 2H, NH₂), 6.98 (t, 1H, NH, J=5 Hz), 7.16 (t, 1H, Ar H, J=7 Hz), 7.50 (t, 1H, Ar H, J=7 Hz), 7.70 (d, 1H, Ar H, J=8 Hz), 7.96 (d, 1H, Ar H, J=8 Hz), 13.88 (s, 1H, NH), and 14.21 (s, 1H, OH) ppm; ¹³C NMR; (CDCl₃); Δ = 14.10, 22.68, 26.76, 29.68, 31.56, 39.48 (hexyl carbons), 52.33 (ester CH₃), 113.98, 114.65, 121.31, 122.23, 131.34, 134.29 (C₆H₄COOCH₃-o), 145.30 (C = N–NH), 151.35 (C = N–OH), 165.70 (HN–C = O), and 167.29 (COOCH₃) ppm; MS: 363 [M⁺]. Analysis calculated for C₁₇H₂₅N₅O₄ (363.42): C, 56.19; H, 6.93; and N, 19.27. Found: C, 56.31; H, 6.45; and N, 19.55.

2-{N-[Cyclohexylcarbamoyl-(N-hydroxycarbamimidoyl)-methylene]-hydrazino}-benzoic acid methyl ester (5b)

Brown crystals from ethanol; mp 134°C; IR ν_max cm⁻¹: 3520 (br OH), 3423, 3401 (NH₂), 3279 (NH), 3088 (CH aromatic), 2933 (CH aliphatic), and 1650 (2C = O); MS: 361 [M⁺]. Analysis calculated for C₁₇H₂₃N₅O₄ (361.40): C, 56.50; H, 6.41; and N, 19.38. Found: C, 56.36; H, 6.70; and N, 19.25.

N-Butyl-2-[(4-chlorophenyl)-hydrazono]-2-(N-hydroxycarbamimidoyl)-acetamide (5c)

Orange crystals from ethanol; mp 86°C; IR ν_max cm⁻¹: 3568 (OH), 3498, 3471 (NH₂), 3379, 3356 (NH), 3047 (CH aromatic), 2958 (CH aliphatic), and 1643 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.89 (t, 3H, CH₃, J=7 Hz), 1.30 (m, 2H, CH₂, J=7 Hz), 1.46 (m, 2H, CH₂, J=7 Hz), 3.21 (q, 2H, CH₂, J=7 Hz), 6.72 (s, 2H, NH₂), 7.29 (d, 2H, Ar H, J=8 Hz), 7.44 (d, 2H, Ar H, J=8 Hz), 8.32 (t, 1H, NH, J=5 Hz), 10.11 (s, 1H, NH), and 13.48 (s, 1H, OH) ppm; ¹³C NMR; (DMSO-d ₆); Δ = 14.20, 19.10, 20.24, 20.29 (butyl carbons), 116.21, 122.76, 126.39, 129.73 (C₆H₄–Cl-p), 142.50 (C = N–NH), 151.05 (C = N–OH), and 163.85 (C = O) ppm; MS: 310 [M⁺–1]. Analysis calculated for C₁₃H₁₈ ClN₅O₂ (311.77): C, 50.08; H, 5.82; and N, 22.46. Found: C, 50.45; H, 5.75; and N, 22.36.

2-[(4-Chlorophenyl)-hydrazono]-N-hexyl-2-(N-hydroxycarbamimidoyl)-acetamide (5d)

Colorless crystals from ethanol; mp 82°C; IR ν_max cm⁻¹: 3585 (br OH), 3470, 3434 (NH₂), 3392 (NH), 3085 (CH aromatic), 2918 (CH aliphatic), and 1636 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.84 (t, 3H, CH₃, J=6 Hz), 1.05 (m, 6H, 3CH₂), 1.43 (quintet, 2H, CH₂, J=7 Hz), 3.17 (t, 2H, CH₂, J=7 Hz), 6.66 (s, 2H, NH₂), 7.26 (d, 2H, Ar H, J=8 Hz), 7.39 (d, 2H, Ar H, J=8 Hz), 8.22 (t, 1H, NH, J=5 Hz), 13.36 (s, 1H, NH), and 13.52 (s, 1H, OH) ppm; MS: 338 [M⁺–1]. Analysis calculated for C₁₅H₂₂N₅O₂Cl (339.83): C, 53.02; H, 6.53; and N, 20.61. Found: C, 53.31; H, 6.45; and N, 20.55.

N-Benzyl-2-[(4-chlorophenyl)-hydrazono]-2-(N-hydroxycarbamimidoyl)-acetamide (5e)

Yellow crystals from ethanol; mp 135°C; IR ν_max cm⁻¹: 3580 (OH), 3483, 3432 (NH₂), 3390 (NH), 3091 (CH aromatic), 2923 (CH aliphatic), and 1640 (C = O); ¹H NMR; (CDCl₃); Δ = 4.51 (d, 2H, CH₂ph, J=5 Hz), 6.65 (s, 2H, NH₂), 7.31–7.80 (m, 9H, Ar–H), 9.62 (t, 1H, NH, J=5 Hz), 13.10 (s, 1H, NH), and 13.98 (s, 1H, OH) ppm; MS: 344 [M⁺–1]. Analysis calculated for C₁₆H₁₆N₅O₂Cl (345.79): C, 55.58; H, 4.66; and N, 20.25. Found: C, 55.70; H, 4.52; and N, 20.16.

N-Butyl-2-(N-hydroxycarbamimidoyl)-2-[(4-nitrophenyl)-hydrazono]-acetamide (5f)

Brown crystals from ethanol; mp185°C; IR ν_max cm⁻¹: 3535 (OH), 3471, 3451 (NH₂), 3391 (NH), 3052 (CH aromatic), 2918 (CH aliphatic), and 1643 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.87 (t, 3H, CH₃, J=7 Hz), 1.32 (m, 2H, CH₂, J=7 Hz), 1.45 (m, 2H, CH₂, J=7 Hz), 3.20 (q, 2H, CH₂, J=7 Hz), 6.62 (s, 2H, NH₂), 7.57 (d, 2H, Ar H, J=8 Hz), 8.16 (d, 2H, Ar H, J=8 Hz), 9.41 (t, 1H, NH, J=5 Hz), 13.10 (s, 1H, NH), and 13.65 (s, 1H, OH) ppm; MS: 322 [M⁺]. Analysis calculated for C₁₃H₁₈N₆O₄ (322.33): C, 48.44; H, 5.63; and N, 26.07. Found: C, 48.22; H, 5.75; and N, 26.15.

N-Hexyl-2-(N-hydroxycarbamimidoyl)-2-[(4-nitrophenyl)-hydrazono]-acetamide (5g)

Brown crystals from ethanol; mp 195°C; IR ν_max cm⁻¹: 3548 (OH), 3491, 3442 (NH₂), 3385 (NH), 3049 (CH aromatic), 2922 (CH aliphatic), and 1653 (C = O); MS: 350 [M⁺]. Analysis calculated for C₁₅H₂₂N₆O₄ (350.38): C, 51.42; H, 6.33; N, 23.99. Found: C, 51.56; H, 6.29; and N, 23.81.

N-Cyclohexyl-2-(N-hydroxycarbamimidoyl)-2-[(4-nitrophenyl)-hydrazono]-acetamide (5h)

Brown crystals from ethanol; mp 282°C; IR ν_max cm⁻¹: 3501 (br OH), 3454, 3398 (NH₂), 3242 (NH), 3103 (CH aromatic), 2925 (CH aliphatic), and 1644 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 1.11–1.65 (m, 6H, 3CH₂), 1.78–2.12 (m, 4H, 2CH₂), 3.61–3.89 (m, 1H, cyclohexyl CH), 6.62 (s, 2H, NH₂), 7.59 (d, 2H, Ar H, J=8 Hz), 8.05 (d, 2H, Ar H, J=8 Hz), 9.52 (d, 1H, NH, J=7 Hz), 13.23 (s, 1H, NH), and 13.56 (s, 1H, OH) ppm; MS: 348 [M⁺]. Analysis calculated for C₁₅H₂₀N₆O₄ (348.36): C, 51.72; H, 5.79; and N, 24.12. Found: C, 51.61; H, 5.50; and N, 24.38.

Preparation of triazole compounds 7a–e

Method I (Δ)

To a solution of compounds 5c and 5e–h (0.1 mol) in DMF (10 mL), triethylamine (0.1 mol) was added. The reaction mixture was heated under reflux for 1 h. Then, it was left to cool to room temperature. The solid product so-formed was filtered and re-crystallized from ethanol.

Method II (µω)

A mixture of compounds 5c and 5e–h (0.1 mol) and triethylamine (0.1 mol) was placed in a tightly closed tube and subjected to a Mw irradiation for 1–5 min until completion of the reaction (monitored by TLC). The reaction mixture was left to cool to room temperature. The solid product so-formed was filtered and re-crystallized from ethanol.

Method III (Us)

Triethylamine (0.1 mol) was added to a solution of compounds 5c and 5e–h (0.1 mol) in DMF (10 mL). The reaction mixture was irradiated under Us irradiation at 40°C for 1 h. Then, it was left to cool to room temperature. The solid product so-formed was filtered and re-crystallized from ethanol.

5-Amino-2-(4-chlorophenyl)-2H-[1,2,3]triazole-4-carboxylic acid butyl amide (7a)

Yellow crystals from ethanol; mp120°C; IR ν_max cm⁻¹: 3474, 3431 (NH₂), 3335 (NH), 3080 (CH aromatic), 2930 (CH aliphatic), and 1648 (C = O); ¹H NMR; (CDCl₃); Δ = 0.93 (t, 3H, CH₃, J=7 Hz), 1.39 (m, 2H, CH₂, J=7 Hz), 1.57 (m, 2H, CH₂, J=7 Hz), 3.34 (q, 2H, CH₂, J= 7 Hz), 6.69 (s, 2H, NH₂), 7.08 (d, 2H, Ar H, J=8 Hz), 7.26 (d, 2H, Ar H, J=8 Hz), and 9.28 (t, 1H, NH, J=5 Hz) ppm; ¹³C NMR; (CDCl₃); Δ = 13.87, 20.26, 31.34, 38.81 (butyl carbons), 115.44, 119.34, 128.06, 129.48 (C₆H₄–Cl-p), 141.46, 153.50 (triazole carbons), and 165.67 (C = O) ppm; MS: 293 [M⁺]. Analysis calculated for C₁₃H₁₆ClN₅O (293.76): C, 53.15; H, 5.49; N, 23.84. Found: C, 53.26; H, 5.35; and N, 23.80.

5-Amino-2-(4-chlorophenyl)-2H-[1,2,3]triazole-4-carboxylic acid benzyl amide (7b)

Brown crystals from ethanol; mp 137°C; IR ν_max cm⁻¹: 3461, 3430 (NH₂), 3221 (NH), 3021 (CH aromatic), 2920 (CH aliphatic), and 1642 (C = O); ¹H NMR; (CDCl₃); Δ = 5.21 (d, 2H, CH₂ph, J=5 Hz), 6.67 (s, 2H, NH₂), 7.31–7.83 (m, 9H, Ar–H), and 7.97 (t, 1H, NH, J=5 Hz) ppm; MS: 327 [M⁺]. Analysis calculated for C₁₆H₁₄ClN₅O (327.78): C, 58.63; H, 4.31; and N, 21.37. Found: C, 58.60; H, 4.47; and N, 21.41.

5-Amino-2-(4-nitrophenyl)-2H-[1,2,3]triazole-4-carboxylic acid butyl amide (7c)

Brown crystals from ethanol; mp103°C; IR ν_max cm⁻¹: 3484, 3452 (NH₂), 3325 (NH), 3099 (CH aromatic), 2990 (CH aliphatic), and 1658 (C = O); ¹H NMR; (DMSO-d ₆); Δ= 0.93 (t, 3H, CH₃, J=7 Hz), 1.35 (m, 2H, CH₂, J=7 Hz), 1.56 (m, 2H, CH₂, J=7 Hz), 3.41 (q, 2H, CH₂, J=7 Hz), 6.68 (s, 2H, NH₂), 7.19 (d, 2H, Ar H, J=8 Hz), 7.51 (d, 2H, Ar H, J=8 Hz), and 9.31 (t, 1H, NH, J=5 Hz) ppm; MS: 304 [M⁺]. Analysis calculated for C₁₃H₁₆N₆O₃ (304.31): C, 51.31; H, 5.30; and N, 27.62. Found: C, 51.24; H, 5.42; and N, 27.51.

5-Amino-2-(4-nitrophenyl)-2H-[1,2,3]triazole-4-carboxylic acid hexyl amide (7d)

Brown crystals from ethanol; mp 176°C; IR ν_max cm⁻¹: 3492, 3386 (NH₂), 3344 (NH), 3053 (CH aromatic), 2920 (CH aliphatic), and 1653 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.84 (t, 3H, CH₃, J=6 Hz), 1.27 (m, 6H, 3CH₂), 1.48 (m, 2H, CH₂, J=7 Hz), 3.19 (t, 2H, CH₂, J=7 Hz), 6.18 (s, 2H, NH₂), 7.58 (d, 2H, Ar H, J =8 Hz), 8.12 (d, 2H, Ar H, J=8 Hz), and 9.40 (t, 1H, NH, J=5 Hz) ppm; MS: 332 [M⁺]. Analysis calculated for C₁₅H₂₀N₆O₃ (332.37): C, 54.21; H, 6.07; and N, 25.29. Found: C, 54.29; H, 6.16; and N, 25.32.

5-Amino-2-(4-nitrophenyl)-2H-[1,2,3]triazole-4-carboxylic acid cyclohexyl amide (7e)

Brown crystals from ethanol; mp167°C; IR ν_max cm⁻¹: 3479, 3448 (NH₂), 3367 (NH), 3078 (CH aromatic), 2924 (CH aliphatic), and 1651 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 1.07–1.67 (m, 6H, 3CH₂), 1.71–2.86 (m, 4H, 2CH₂), 2.93–3.80 (m, 1H, cyclohexyl CH), 7.20–8.28 (m, 4H, Ar–H), 6.70 (s, 2H, NH₂), and 9.32 (d, 1H, NH, J=7 Hz) ppm; ¹³C NMR; (DMSO-d ₆); Δ = 24.59, 25.62, 29.75, 32.48 (cyclohexyl carbons), 113.56, 125.01, 125.33, 125.96 (C₆H₄–NO₂-p), 142.38, 147.92 (triazole carbons), and 162.33 (C = O) ppm; MS: 330 [M⁺]. Analysis calculated for C₁₅H₁₈N₆O₃ (330.35): C, 54.54; H, 5.49; and N, 25.44. Found: C, 54.39; H, 5.35; and N, 25.20.

General method to reaction of triazole compounds 7a–e with dimethylformamide dimethylacetal (DMF DMA)

Method I (Δ)

To a solution of compounds 7a–e (0.1 mol) in dry xylene (20 mL), DMF DMA (0.1 mol) was added. The reaction mixture was refluxed for 30 min. Then it was left to cool to room temperature, and poured into ice-cold water. The solid product so-formed was filtered and re-crystallized from ethanol.

Method II (µω)

A mixture of compounds 7a–e (0.1 mol) and of DMF DMA (0.1 mol) was placed in a tightly closed tube, and subjected to a Mw irradiation for 2–5 min until completion of the reaction (monitored by TLC). The reaction mixture was left to cool to room temperature, and then poured into ice-cold water. The solid product so-formed was filtered and re-crystallized from ethanol.

2-(4-Chlorophenyl)-6-hexyl-2,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one (10a)

Yellow crystals from ethanol; mp 78°C; IR ν_max cm⁻¹: 3089 (CH aromatic), 2925 (CH aliphatic), and 1645 (C = O); ¹H NMR; (CDCl₃); Δ = 0.91 (t, 3H, CH₃, J=6 Hz), 1.29 (m, 6H, 3CH₂), 1.47 (m, 2H, CH₂, J=7 Hz), 3.29 (t, 2H, CH₂, J=7 Hz), 7.05 (s, 1H, pyrimidine CH), 7.32 (d, 2H, Ar, H, J=8 Hz), and 7.61 (d, 2H, Ar, H, J=8 Hz) ppm; MS: 331 [M⁺]. Analysis calculated for C₁₆H₁₈ClN₅O (331.81): C, 57.92; H, 5.47; and N, 21.11. Found: C, 57.75; H, 5.25; and N, 21.47.

6-Butyl-2-(4-nitrophenyl)-2,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one (10b)

Brown crystals from ethanol; mp 190°C; IR ν_max cm⁻¹: 3092 (CH aromatic), 2939 (CH aliphatic), and 1670 (C = O); ¹H NMR; (CDCl₃); Δ = 0.89 (t, 3H, CH₃, J=6 Hz), 1.40 (m, 2H, CH₂, J=7 Hz), 1.66 (m, 2H, CH₂, J=7 Hz), 3.49 (q, 2H, CH₂, J=7 Hz), 7.15 (s, 1H, pyrimidine CH), 7.31 (d, 2H, Ar, H, J=8 Hz), and 7.65 (d, 2H, Ar, H, J=8 Hz) ppm; MS: 314 [M⁺]. Analysis calculated for C₁₄H₁₄N₆O₃ (314.31): C, 53.50; H, 4.49; and N, 26.74. Found: C, 53.72; H, 4.64; and N, 26.59.

Preparation of pyrazole compounds 13a–e

Method I (Δ)

To a solution of compounds 4a–i (0.1 mol) in triethylamine (20 mL) and chloroacetonitrile (0.1 mol) were refluxed for 30 min. The reaction mixture was left to cool to room temperature, and then poured into ice-cold water. The solid product so-formed was filtered and re-crystallized from ethanol.

Method II (µω)

To a mixture of compounds 4a–i (0.1 mol) and chloroacetonitrile (0.1 mol), a few drops from triethylamine were added, then the mixture was placed in a tightly closed tube and subjected to a Mw irradiation for 2 min until completion of the reaction (monitored by TLC). The reaction mixture was left to cool to room temperature, and then poured into ice-cold water. The solid product so-formed was filtered and re-crystallized from ethanol.

Method III (Us)

Chloroacetonitrile (0.1 mol) was added to a solution of compounds 4a–i (0.1 mol) in triethyl amine (20 mL), under Us irradiation at 40°C for 30 min. The reaction mixture was left to cool to room temperature, and then poured into ice-cold water. The solid product so-formed was filtered and re-crystallized from ethanol.

2-(4-Amino-5-cyano-3-cyclohexylcarbamoyl-pyrazol-1-yl)-benzoic acid methyl ester (13a)

Brown crystals from ethanol; mp >300°C; IR ν_max cm⁻¹: 3438, 3395, 3277 (NH, NH₂), 3088 (CH aromatic), 2933 (CH aliphatic), 2261 (CN), and 1648 (C = O); ¹H NMR; (CDCl₃); Δ = 1.18–3.77 (m, 11H, cyclohexyl H), 3.93 (s, 3H, ester CH₃), 6.67 (s, 2H, NH₂), 7.20 (t, 1H, Ar H, J=7 Hz), 7.44 (t, 1H, Ar H, J=7 Hz), 7.63 (d, 1H, Ar H, J=8 Hz), 7.94 (d, 1H, Ar H, J=8 Hz), and 9.75 (t, 1H, NH, J=7 Hz) ppm; MS: 367 [M⁺]. Analysis calculated for C₁₉H₂₁N₅O₃ (367.41): C, 62.11; H, 5.76; and N, 19.06. Found: C, 62.26; H, 5.80; and N, 19.17

4-Amino-1-(4-chlorophenyl)-5-cyano-1H-pyrazole-3-cyclohexylic acid butyl amide (13b)

Brown crystals from ethanol; mp 117°C; IR ν_max cm⁻¹: 3472, 3378, 3329 (NH, NH₂), 3020 (CH aromatic), 2957 (CH aliphatic), 2212 (CN), and 1644 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.91 (t, 3H, CH₃, J=7 Hz), 1.37 (m, 2H, CH₂, J=7 Hz), 1.54 (m, 2H, CH₂, J=7 Hz), 3.38 (q, 2H, CH₂, J=7 Hz), 6.71 (s, 2H, NH₂), 7.43 (d, 2H, Ar H, J=8 Hz), 7.59 (d, 2H, Ar H, J=8 Hz), and 9.34 (t, 1H, NH, J=5 Hz) ppm; ¹³C NMR; (DMSO-d ₆); Δ = 13.78, 20.14, 31.80, 38.71 (butyl carbons), 116.93 (CN), 110.93, 123.07, 129.66, 132.87 (C₆H₄–Cl-p), 134.48, 137.01, 143.09 (pyrazole carbons), and 162.25 (C = O) ppm; MS: 317 [M⁺]. Analysis calculated for C₁₅H₁₆ClN₅O (317.78): C, 56.70; H, 5.08; and N, 22.04. Found: C, 56.62; H, 5.20; and N, 22.29.

4-Amino-1-(4-chlorophenyl)-5-cyano-1H-pyrazole-3-cyclohexylic acid hexyl amide (13c)

Brown crystals from ethanol; mp 125°C; IR ν_max cm⁻¹: 3450, 3428, 3388 (NH, NH₂), 3109 (CH aromatic), 2926 (CH aliphatic), 2210 (CN), and 1645 (C = O); ¹H NMR; (DMSO-d ₆); Δ = 0.88 (t, 3H, CH₃, J=6 Hz), 1.30 (m, 6H, 3CH₂), 1.57 (m, 2H, CH₂, J=7 Hz), 3.38 (t, 2H, CH₂, J=7 Hz), 6.49 (s, 2H, NH₂), 7.15 (d, 2H, Ar H, J= 8 Hz), 7.36 (d, 2H, Ar H, J=8 Hz), and 8.96 (t, 1H, NH, J=5 Hz) ppm; MS: 345 [M⁺]. Analysis calculated for C₁₇H₂₀ClN₅O (345.83): C, 59.04; H, 5.83; and N, 20.25. Found: C, 59.17; H, 5.42; and N, 20.54.

4-Amino-1-(4-chlorophenyl)-5-cyano-1H-pyrazole-3-cyclohexylic acid benzyl amide (13d)

Brown crystals from ethanol; mp 130°C; IR ν_max cm⁻¹: 3371, 3326, 3299 (NH, NH₂), 3064 (CH aromatic), 2923 (CH aliphatic), 2225 (CN), and 1644 (C = O) cm⁻¹; ¹H NMR; (DMSO-d ₆ ); Δ = 4.28 (d, 2H, phCH₂, J=5 Hz), 6.21 (s, 2H, NH₂), 7.25–8.10 (m, 9H, Ar–H), and 8.89 (t, 1H, NH, J=5 Hz) ppm; MS: 351 [M⁺]. Analysis calculated for C₁₈H₁₄ClN₅O (351.80): C, 61.46; H, 4.01; and N, 19.91. Found: C, 61.54; H, 4.20; and N, 19.83.

4-Amino-5-cyano-1-(4-nitrophenyl)-1H-pyrazole-3-cyclohexylic acid hexyl amide (13e)

Brown crystals from ethanol; mp 153°C; IR ν_max cm⁻¹: 3401, 3358, 3226 (NH, NH₂), 3090 (CH aromatic), 2927 (CH aliphatic), 2218 (CN), and 1660 (C = O); ¹H NMR; (CDCl₃); Δ = 0.88 (t, 3H, CH₃, J=6 Hz), 1.32 (m, 6H, 3CH₂), 1.58 (m, 2H, CH₂, J=7 Hz), 3.40 (t, 2H, CH₂, J=7 Hz), 6.59 (s, 2H, NH₂), 7.40 (d, 2H, Ar H, J=8 Hz), 7.95 (d, 2H, Ar H, J=8 Hz), and 9.62 (t, 1H, NH, J=5 Hz) ppm; MS: 356 [M⁺]. Analysis calculated for C₁₇H₂₀N₆O₃ (356.39): C, 57.29; H, 5.66; and N, 23.58. Found: C, 57.20; H, 5.72; and N, 23.68.

X-ray crystallography

A single crystal of compound 4c was obtained by slow evaporation from a mixture of ethanol:DMF (2:1). The crystal structure was solved and refined using maxus (nonius, Deflt and MacScience, Japan) 21 Mo–Kα radiation (λ = 0.71073 Å) and a graphite monochromator were used for data collection. The chemical formula and ring labeling system is shown in Figure 1. Crystallographic data (Table 2, excluding structure factors) for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 686225. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union, Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [email protected]].

Table 2. Crystal data of compound 4c.

Chemical formula	C17H20N4O3
M	328.372
System	Monoclinic
Space group	P21/c
a	9.9877 (6) Å
b	18.0058 (8) Å
c	9.8843 (4) Å
α	90.00°
β	96.078 (2)°
V	1767.6 (2) Å^3
Z	4
Dc	1.234 mg m^−3
κ	2.910–24.713°
µ(Mo–Kα)	0.09 mm^−1
T	298 K
Measured reflections	4990
Independent reflections	3497
Observed reflections	1335
R int	0.031
R(all)	0.140
WR(ref)	0.184
WR(all)	0.238
S(ref)	1.429
S(all)	1.364
D/smax	0.027
Drmax	0.38e Å^3
Drmin	−0.41e Å^3