Divergent Construction of Pyrazoles via Michael Addition of N-Aryl Hydrazones to 1,2-Diaza-1,3-dienes

Transcription

1 Divergent Construction of Pyrazoles via Michael Addition of N-Aryl Hydrazones to 1,2-Diaza-1,3-dienes Serena Mantenuto, Fabio Mantellini, Gianfranco Favi,* and Orazio A. Attanasi Department of Biomolecular Sciences, Section of Organic Chemistry and Organic Natural Compounds, University of Urbino Carlo Bo, Via I Maggetti 24, Urbino (PU), Italy gianfranco.favi@uniurb.it SUPPORTING INFORMATION Table of Contents 1. General remarks S2 2. Experimental procedures and spectral data S2 S11 Synthesis of β-azohydrazones 3a k Synthesis of pyrazoles 4a j Synthesis of pyrazoles 5a h S2 S6 S H and 13 C NMR spectra of all products S12 S36 4. References and notes S37 1

2 Experimental Section 1. General Remarks. All the commercially available reagents and solvents were used without further purification. N-Aryl hydrazones 1a g were prepared from corresponding hydrazines and aldehydes in EtOH. 1 1,2- Diaza-1,3-dienes 2a e were synthesized as a mixture of E/Z isomers as previously reported. 2,3 Chromatographic purification of compounds was carried out on silica gel ( μm). TLC analysis was performed on pre-loaded (0.25 mm) glass supported silica gel plates (Kieselgel 60); compounds were visualized by exposure to UV light and by dipping the plates in 1% Ce(SO4) 4H2O, % (NH4)6Mo7O24 4H2O in 10% sulphuric acid followed by heating on a hot plate. All 1 H NMR and 13 C NMR spectra were recorded at 400 and 106 MHz, respectively. Proton and carbon spectra were referenced internally to solvent signals, using values of δ = 2.49 ppm for proton (middle peak) and δ = 30 ppm for carbon (middle peak) in DMSO-d6 and δ = 7.26 ppm for proton and δ = 70 ppm for carbon (middle peak) in CDCl3. The following abbreviations are used to describe peak patterns where appropriate: s = singlet, d = doublet, t = triplet q = quartet, m = multiplet and br = broad signal. All coupling constants (J) are given in Hz. FT-IR spectra were obtained as Nujol mulls. Mass spectra were recorded in the EI mode (70eV). Melting points were determined in open capillary tubes and are uncorrected. 2. Experimental procedures and spectral data. General procedure for the NaH-Catalyzed Conjugated Addition of N-Aryl hydrazones 1a g with Diaza-1,3-dienes 2a e; Synthesis of β-azohydrazone Adducts 3a k. N-Aryl hydrazones 1a g (0.8 mmol) in CH3CN (3 ml) was added dropwise to a stirred solution of 1,2-diaza-1,3-dienes 2a e (1.2 mmol) in the presence of a catalytic amount of NaH (10 mol %) in CH3CN (3 ml). Upon completion (10 min h, monitored by TLC), the reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel to afford the products 3a k. Important: changing the addition order of the reagents, by adding NaH to the solution of AHs 1 and DDs 2 the reactions gave lower yield. During the course of the reactions, the following work-up, and the long standing, compounds 3a k give a partial isomerization and/or degradation reaction. 2

3 tert-butyl methoxy-4-oxobut-2-en-2-yl}hydrazinecarboxylate (3a ): N-Michael adduct (hydrazino form) 3a was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) (entries 2 9, Table 1); White solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1 (s, 9H), 1.80 (s, 3H), 8 (s, 3H), 6.45 (br, 1H), (m, 1H), (m, 6H), 7.46 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), (s, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 13.2 (q), 28.2 (q), 5 (q), 82.2 (s), (d), (d), (d), (d), (d), (s), 13 (s), (s), (s), (s), (s), (s); IR (nujol): max = 3194, 1690, 1660 cm -1 ; MS m/z (%): 459 (M + ) (3), 111 (100); anal. calcd. for C23H27ClN4O4 (458.94): C 60.19, H 5.93, N 12.21; found: C 60.30, H 5.80, N tert-butyl 2-{3-[2-(4-chlorobenzylidene)-1-phenylhydrazinyl]-4-2-[4-(4-chlorophenyl)-3-(methoxycarbonyl)-4- (phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3a): β- Azohydrazone (C-Michael adduct) 3a was isolated by column chromatography (ethyl acetate/cyclohexane 80:20) in 83% yield (304.7 mg) ( h; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 55:45, *denotes minor diastereoisomer signals): δ = 1.38 (s, 9H), 1.41* (s, 9H), 1.72 (s, 3H), 1.81* (s, 3H), 3.46* (s, 3H), 6 (s, 3H), 4.38 (d, J = 11.2 Hz, 1H), 4.47* (d, J = 10.8 Hz, 1H), 5.36* (d, J = 10.8 Hz, 1H), 5.70 (d, J = 11.2 Hz, 1H), (m, 9H), 1 (s, 1H), 9* (s, 1H). MeO 2 C Me HN CO 2t-Bu N N O N Ph OMe solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 53:47, *denotes minor diastereoisomer signals): δ = 1.38 (s, 9H), 1.40* (s, 9H), 1.72 (s, 3H), 1.83* (s, 3H), 3.45* (s, 3H), 7 (s, 3H), 3.81 (s, 3H), 3.83* (s, 3H), 4.41 (d, J = 10.8 Hz, 1H), 1* (d, J = 10.8 Hz, 1H), 5.43* (d, J = 10.8 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), (m, 5H), 7.66* (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.95* (d, J = 8.4 Hz, 2H), 9.48 (s, 1H), 9.60* (s, 1H). tert-butyl tert-butyl 2-[4-(4-methoxycarbonylphenyl)-3-(methoxycarbonyl)-4- (phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3b): β- Azohydrazone 3b was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 90% yield (347.4 mg) ( h; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow 2-[4-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-4- (phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3c): β- Azohydrazone 3c was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 90% yield (355.3 mg) (10 min.; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 54:46, *denotes minor diastereoisomer signals): δ = 3

4 1.38 (s, 9H), 1.39* (s, 9H), 1.72 (s, 3H), 1.87* (s, 3H), 3.49* (s, 3H), 3.62 (s, 3H), 4.47 (d, J = 10.8 Hz, 1H), 5* (d, J = 10.4 Hz, 1H), 5.91 * (d, J = 10.4 Hz, 1H), 6.10 (d, J = 10.8 Hz, 1H), (m, 8H), 9.48 (s, 1H), 9.61* (s, 1H). Ethyl 2-[4-(4-bromophenyl)-3-(ethoxycarbonyl)-4- (phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3d): β- Azohydrazone 3d was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 87% yield (305.4 mg) (10 min.; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 70:30, *denotes minor diastereoisomer signals): δ = 0.94* (t, J = 7.2 Hz, 3H), 4 (t, J = 7.2 Hz, 3H), (m, 3H), 1.75 (s, 3H), 1.84* (s, 3H), (m, 4H), 4.37 (d, J = 11.2 Hz, 1H), 4.43* (d, J = 10.8 Hz, 1H), 5.34* (d, J = 10.8 Hz, 1H), 5.67 (d, J = 11.2 Hz, 1H), (m, 9H), 9.81 (s, 1H), 9.85* (s, 1H). tert-butyl 2-[4-(3-bromophenyl)-3-(methoxycarbonyl)-4-((E)- phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3e): β- Azohydrazone 3e was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 87% yield (350.4 mg) (10 min.; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 54:46, *denotes minor diastereoisomer signals): δ = 1.38 (s, 9H), 1.42* (s, 9H), 1.74 (s, 3H), 1.82* (s, 3H), 3.47* (s, 3H), 6 (s, 3H), 4.40 (d, J = 11.2 Hz, 1H), 0* (d, J = 10.8 Hz, 1H), 5.35* (d, J = 11.2 Hz, 1H), 5.69 (d, J = 10.8 Hz, 1H), 7.28 (t, J = Hz, 1H), 7.34* (t, J = Hz, 1H), (m, 8H), 4 (s, 1H), 9* (s, 1H). tert-butyl 2-[4-(4-cyanophenyl)-3-(methoxycarbonyl)-4- (phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3f): β- Azohydrazone 3f was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 99% yield (35 mg) ( h; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 51:49, *denotes minor diastereoisomer signals): δ = 1.38 (s, 9H), 1.42* (s, 9H), 1.73 (s, 3H), 1.83* (s, 3H), 3.46* (s, 3H), 8 (s, 3H), 4.44 (d, J = 11.2 Hz, 1H), 0* (d, J = 10.4 Hz, 1H), 5.45* (d, J = 10.4 Hz, 1H), 5.79 (d, J = 11.2 Hz, 1H), (m, 5H), 7.63 (d, J = 8.4 Hz, 2H), 7.72* (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.84* (d, J = 8.4 Hz, 2H), 6 (s, 1H), 9.61* (s, 1H). 4

5 Cl Me HN CO 2t-Bu N tert-butyl 2-[4-(4-chlorophenyl)-3-(ethoxycarbonyl)-4- (phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3g): β- N O N Ph OEt 3g Azohydrazone 3g was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 100% yield (378.3 mg) (10 min.; TLC check) as a single isomer. Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C): δ = 5 (t, J = 7.2 Hz, 1H), 1.41 (s, 9H), 1 (q, J = 7.2 Hz, 2H), 4.35 (d, J = 11.2 Hz, 1H), 5.68 (d, J = 11.2 Hz, 1H), (m, 9H), 9.49 (s, 1H). Methyl (phenyldiazenyl)pentan-3-ylidene]hydrazinecarboxylate (3h): β- Azohydrazone 3h was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 49% yield (168.9 mg) (10 min.; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 62:38, *denotes minor diastereoisomer signals): δ = 0.66 (t, J = 7.6 Hz, 3H), 0.90* (t, J = 7.6 Hz, 3H), (m, 2H), 3.45* (s, 3H), 6 (s, 3H), 9* (s, 3H), 3.65 (s, 3H), 4.39 (d, J = 10.8 Hz, 1H), 7* (d, J = 10.8 Hz, 1H), 2* (d, J = 10.8 Hz, 1H), 5.75 (d, J = 10.8 Hz, 1H), (m, 9H), 11 (s, 1H). tert-butyl phenylbutan-2-ylidene}hydrazinecarboxylate (3i): β-azohydrazone 3i was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 45% yield (165.2 mg) (20 min.; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 55:45, *denotes minor diastereoisomer signals): δ = 1.34 (s, 9H), 1.40* (s, 9H), 1.71 (s, 3H), 1.80* (s, 3H), 3.43* (s, 3H), 5 (s, 3H), 4.39 (d, J = 11.2 Hz, 1H), 4.48* (d, J = 10.8 Hz, 1H), 5.34* (d, J = 10.8 Hz, 1H), 5.67 (d, J = 11.2 Hz, 1H), (m, 9H), 1 (s, 1H), 9* (s, 1H). tert-butyl 3-[5-(4-chlorophenyl)-4-(methoxycarbonyl)-5-2-{4-[(4-chlorophenyl)diazenyl]-3-(methoxycarbonyl)-4-2-[4-(4-chlorophenyl)-3-(benzyloxycarbonyl)-4- (phenyldiazenyl)butan-2-ylidene]hydrazinecarboxylate (3j): β- Azohydrazone 3j was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 90% yield (385.2 mg) (10 min.; TLC check) as a mixture of inseparable isomers (determined by 1 H NMR). Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C) (dr: 63:37, *denotes minor diastereoisomer signals): δ = 1.35 (s, 9H), 1.38* (s, 9H), 1.72 (s, 3H), 1.82* (s, 3H), 4.46 (d, J = 11.2 Hz, 1H), 2* (d, J = 10.8 Hz, 1H), 4.93* (d, J = 12.8 Hz, 1H), 0* (d, J = 12.8 Hz, 1H), 4 (d, J = 12.8 Hz, 1H), 5.10 (d, J = 12.8 Hz, 1H), 5.38* (d, J = 10.8 Hz, 1H), 5.74 (d, J = 11.2 Hz, 1H), (m, 14H), 4 (s, 1H), 9.62* (s, 1H). 5

6 General procedure for the Amberlyst 15(H)-Mediated Cyclization of β-azohydrazone Adducts 3a k to Pyrazoles 4a j. To a magnetically stirred solution of β-azohydrazone adducts 3 ( mmol) in CH2Cl2 (3 ml) was added Amberlyst 15(H) (0.25 g) and the reaction was allowed to stand at room temperature until the complete disappearance of 3a k (2 36 h, monitored by TLC). The solution was filtered, concentrated under reduced pressure and then products 4a j were isolated by chromatography on silica gel column. tert-butyl 3-[5-(4-chlorophenyl)-4-(methoxycarbonyl)-5- (phenyldiazenyl)pentan-3-ylidene]hydrazinecarboxylate (3k): β- Azohydrazone 3k was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 100% yield (378.3 mg) (10 min.; TLC check) as a single isomer. Yellow solid; 1 H NMR (400 MHz, DMSO-d6, 25 C): δ = 0.66 (t, J = 7.6 Hz, 3H), 1.45 (s, 9H), (m, 2H), 5 (q, J = 7.2 Hz, 2H), 4.37 (d, J = 10.8 Hz, 1H), 5.74 (d, J = 11.2 Hz, 1H), (m, 9H), 9.67 (s, 1H). Methyl 3-(4-chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (4a): Pyrazole 4a was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 93% (from 3a) or 65% (from 3l) yield (151.9 mg) (2 h; TLC check). White solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 7 (s, 3H), 3.78 (s, 3H), 7.35 (d, J = 8.4 Hz, 2H), 7.42 (m, 5H), (d, J = 8.4 Hz, 2H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.8 (q), 51.1 (q), (s), (d), (d), (d), (d), (d), 13 (s), (s), (s), (s), 15 (s), (s); IR (nujol): max = 1716 cm -1 ; MS m/z (%): 326 (M + ) (100), 311 (7), 295 (89); anal. calcd. for C18H15ClN2O2 (326.78): C 66.16, H 4.63, N 7; found: C 63, H 4, N Methyl 3-[4-(methoxycarbonyl)phenyl]-5-methyl-1-phenyl-1H-pyrazole-4- carboxylate (4b): Pyrazole 4b was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 95% yield (166.4 mg) (12 h; TLC check). Pale yellow solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 9 (s, 3H), 3.76 (s, 3H), 3.93 (s, 3H), 7.45 (m, 5H), (d, J = 8.4 Hz, 2H), (d, J = 8.4 Hz, 2H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.7 (q), 51.1 (q), 52.1 (q), 11 (s), (d), (d), 12 (d), (d), (d), (s), (s), (s), (s), 15 (s), (s), 16 (s); IR (nujol): max = 1715 cm -1 ; MS m/z (%): 350 (M + ) (100), 335 (7), 319 (70); anal. calcd. for C20H18N2O4 (350.37): C 66, H 5.18, N 0; found: C 68.45, H 5.26, N

7 Methyl 3-(2,4-dichlorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (4c): Pyrazole 4c was isolated by column chromatography (ethyl acetate/cyclohexane 15:85) in 74% yield (133.6 mg) (5 h; TLC check). Yellow oil; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 2.62 (s, 3H), 3.70 (s, 3H), 7.27 (m, 8H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.4 (q), 51.1 (q), (s), (d), (d), (d), 12 (d), (d), (s), (d), (s), (s), (s), (s), (s), 16 (s); IR (nujol): max = 1715 cm -1 ; MS m/z (%): 360 (M + ) (2), 327 (36), 325 (100); anal. calcd. for C18H14Cl2N2O2 (361.22): C 59.85, H 3.91, N 7.76; found: C 59.99, H 3.85, N Ethyl 3-(4-bromophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (4d): Pyrazole 4d was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 74% yield (14 mg) (12 h; TLC check). White solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.25 (t, J = 7.2 Hz, 3H), 7 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 7.44 (m, 9H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.7 (q), 14.1 (q), 60.1 (t), (s), 12 (s), (d), (d), (d), (d), (d), 13 (s), (s), 14 (s), (s), (s); IR (nujol): max = 1710 cm -1 ; MS m/z (%): 386 (M + +2) (199), 384 (M + ) (100), 341 (50), 339 (55); anal. calcd. for C19H17BrN2O2 (385.25): C 59.23, H 4.45, N 7.27; found: C 59.14, H 4.33, N The spectroscopic data of compound 4d are in good agreement with those reported in the literature 4 Methyl 3-(3-bromophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (4e): Pyrazole 4e was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 76% yield (141.1 mg) (12 h; TLC check). Yellow oil; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 8 (s, 3H), 3.78 (s, 3H), (m, 1H), 7.44 (m, 7H), 7.84 (m, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.7 (q), 51.1 (q), (s), (s), (d), (d), (d), (d), (d), (d), (d), (s), (s), (s), 15 (s), (s); IR (nujol): max = 1716 cm -1 ; MS m/z (%): 372 (M + +2) (58), 370 (M + ) (66), 341 (42), 339 (48), 111 (100); anal. calcd. for C18H15BrN2O2 (371.23): C 58.24, H 7, N 5; found: C 58.38, H 3.96, N Methyl 3-(4-cyanophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (4f): Pyrazole 4f was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 81% yield (12 mg) (12 h; TLC check). Yellow solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 8 (s, 3H), 3.79 (s, 3H), 7.44 (m, 5H), 7.69 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H); 13 C NMR (100 MHz, 7

8 CDCl3, 25 C): δ = 12.8 (q), 51.3 (q), (s), 11 (s), (d), (d), (d), (d), 13 (d), (s), (s), (s), (s), (s); IR (nujol): max = 1718 cm -1 ; MS m/z (%): 317 (M + ) (94), 286 (100); anal. calcd. for C19H15N3O2 (317.34): C 71.91, H 4.76, N 13.24; found: C 76, H 4.86, N Cl N N Ph O Me 4g OEt Ethyl 3-(4-chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (4g): Pyrazole 4g was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 95% yield (161.9 mg) (3 h; TLC check). White solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.24 (t, J = 7.2 Hz, 3H), 8 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.43 (m, 5H), 7.62 (d, J = 8.8 Hz, 2H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.8 (q), 14.1 (q), 60.1 (t), 11 (s), (d), (d), (d), (d), (d), (s), (s), (s), 14 (s), (s), 16 (s); IR (nujol): max = 1714 cm -1 ; MS m/z (%): 340 (M + ) (100), 295 (81); anal. calcd. for C19H17ClN2O2 (340.80): C 66.96, H 3, N 8.22; found: C 66.82, H 5.14, N Methyl 3-(4-chlorophenyl)-5-ethyl-1-phenyl-1H-pyrazole-4-carboxylate (4h): Pyrazole 4h was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 100% (from 3h) (170.4 mg) (12 h; TLC check) or 54% yield (from 3k) (9 mg) (2 h; TLC check). Colorless oil; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.21 (t, J = 7.2 Hz, 3H), 2.94 (q, J = 7.2 Hz, 3H), 3.77 (s, 3H), 7.35 (m, 9H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 13.8 (q), 19.3 (t), 51.1 (q), (s), (d), (d), (d), (d), (d), (s), (s), (s), 15 (s), (s), (s); IR (nujol): max = 1715 cm -1 ; MS m/z (%): 340 (M + ) (100), 309 (65); anal. calcd. for C19H17ClN2O2 (340.80): C 66.96, H 3, N 8.22; found: C 67.13, H 5.14, N 9. Methyl 1-(4-chlorophenyl)-5-methyl-3-phenyl-1H-pyrazole-4-carboxylate (4i): Pyrazole 4i was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 77% yield (125.8 mg) (5 h; TLC check). White solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 8 (s, 3H), 3.76 (s, 3H), 7.35 (m, 9H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.8 (q), 51.2 (q), (s), 12 (d), (d), (d), (d), (d), (s), (s), (s), (s), (s), (s); IR (nujol): max = 1714 cm -1 ; MS m/z (%): 326 (M + ) (83), 295 (100); anal. calcd. for C18H15ClN2O2 (326.78): C 66.16, H 4.63, N 7; found: C 61, H 4.74, N Benzyl 3-(4-chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (4j): Pyrazole 4j was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 91% yield (183.4 mg) (5 h; TLC check). Colorless oil; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 8 (s, 3H), 5.24 (s, 2H), 7.20 (m, 14H); 13 C NMR 8

9 (100 MHz, CDCl3, 25 C): δ = 12.8 (q), 65.9 (t), (s), (d), (d), (d), (d), (d), (d), (d), (d), 13 (s), (s), (s), 13 (s), (s), (s), (s); IR (nujol): max = 1696 cm -1 ; MS m/z (%): 402 (M + ) (63), 295 (100); anal. calcd. for C24H19ClN2O2 (402.87): C 75, H 4.75, N 6.95; found: C 71.71, H 4.69, N General procedure for the NaH-Mediated Cyclization of β-azohydrazone Adducts 3a k to Pyrazoles 5a h. To a magnetically stirred solution of β-azohydrazone adducts 3a k ( mmol) in CH3CN (3 ml) was added NaH (60% w/w in mineral oil, mmol) and the reaction was allowed to stand at room temperature until the complete disappearance of 3a k (3 36 h, monitored by TLC). The solution was concentrated under reduced pressure and then products 5a h were isolated by chromatography on silica gel column. tert-butyl 2-{1-[3-(4-chlorophenyl)-5-hydroxy-1-phenyl-1H-pyrazol-4- yl]ethylidene}hydrazinecarboxylate (5a): Pyrazole 5a was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 46% (from 3a) (98.2 mg) (18 h; TLC check) or 33% (from 3g) (70.4 mg) (12 h; TLC check) or 65% (from 3j) yield (138.7 mg) (3 h; TLC check). Pale yellow solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.46 (s, 9H), 1.97 (s, 3H), (s, 1H), 7.18 (t, J = 7.6 Hz, 2H), 7.27 (m, 5H), 7.99 (d, J = Hz, 2H), (br, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 15.1 (q), 2 (q), 82.9 (s), 9 (s), (d), 12 (d), (d), (d), (d), (s), (s), (s), (s), (s), (s), 16 (s); IR (nujol): max = 3145, 1736 cm -1 ; MS m/z (%): 370 (7), 326 (58), 311 (16), 295 (63), 281 (59), 111 (100); anal. calcd. for C22H23ClN4O3 (426.90): C 61.90, H 5.43, N 13.12; found: C 61.76, H 6, N 14. tert-butyl 2-(1-{5-hydroxy-3-[4-(methoxycarbonyl)phenyl]-1-phenyl- 1H-pyrazol-4-yl}ethylidene)hydrazinecarboxylate (5b): Pyrazole 5b was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 75% yield (168.9 mg) (5 h; TLC check). Pale yellow solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.45 (s, 9H), 1.96 (s, 3H), 3.94 (s, 3H), 7.16 (m, 3H), 7.39 (t, J = 7.6 Hz, 1H), (d, J = Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 8.10 (d, J = Hz, 2H), (br, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 15.2 (q), 2 (q), 52.3 (q), 82.9 (s), 9 (s), (d), (s), (d), (d), (d), 13 (d), (s), (s), (s), (s), (s), (s), (s); IR (nujol): max = 3322, 1726 cm -1 ; MS m/z (%): 393 (2), 348 (10), 111 (100); anal. calcd. for C24H26N4O5 (450.49): C 63.99, H 5.82, N 12.44; found: C 63.90, H 5.69, N

10 tert-butyl 2-{1-[3-(2,4-dichlorophenyl)-5-hydroxy-1-phenyl-1Hpyrazol-4-yl]ethylidene}hydrazinecarboxylate (5c): Pyrazole 5c was isolated by column chromatography (ethyl acetate/cyclohexane 10:90)in 69% yield (149.9 mg) (12 h; TLC check). White solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.46 (s, 9H), 1.92 (s, 3H), 5 (s, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.33 (m, 4H), (d, J = Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H), (br, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 13.6 (q), 2 (q), 8 (s), 9 (s), (d), (d), (d), (d), 12 (d), (s), (d), (s), (s), (s), 14 (s), (s), (s), (s); IR (nujol): max = 3315, 1735 cm -1 ; MS m/z (%): 461 (M + ) (7), 404 (42), 369 (50), 360 (31), 345 (40), 325 (100), 310 (82); anal. calcd. for C22H22Cl2N4O3 (461.34): C 57.28, H 4.81, N 12.14; found: C 57.14, H 4.68, N Ethyl 2-{1-[3-(4-bromophenyl)-5-hydroxy-1-phenyl-1H-pyrazol-4- yl]ethylidene}hydrazinecarboxylate (5d): Pyrazole 5d was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 52% yield (115.3 mg) (24 h; TLC check). Brown solid; mp: C; 1 H NMR (400 MHz, DMSO-d6, 25 C): δ = 1.21 (t, J = 7.2 Hz, 3H), 1.97 (s, 3H), 2.11 (s, 3H), 4.12 (q, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H); 13 C NMR (100 MHz, DMSO-d6, 25 C): δ = 14.4 (q), 15.3 (q), 61.6 (t), 9 (s), 11 (d), (d), 12 (s), (d), (d), (d), (s), (s), 14 (s), 15 (s), (s), 16 (s); IR (nujol): max = 3378, 1736 cm -1 ; MS m/z (%): 443 (M + ) (13), 341 (12), 306 (9), 207 (42), 111 (100); anal. calcd. for C20H19BrN4O3 (443.29): C 54.19, H 4.32, N 12.64; found: C 55, H 4.20, N 15. tert-butyl 2-{1-[3-(3-bromophenyl)-5-hydroxy-1-phenyl-1H-pyrazol- 4-yl]ethylidene}hydrazinecarboxylate (5e): Pyrazole 5e was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 51% yield (120.2 mg) (36 h; TLC check). White solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.45 (s, 9H), 1.96 (s, 3H), 7.15 (m, 5H), 6 (d, J = Hz, 1H), 7.66 (s, 1H), 7.99 (d, J = Hz, 2H), (br, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 15.2 (q), 2 (q), 82.8 (s), 98.8 (s), (d), 12 (s), (d), 12 (d), (d), (d), 13 (d), (d), 13 (s), 13 (s), (s), (s), 16 (s), (s); IR (nujol): max = 3148, 1744 cm -1 ; MS m/z (%): 413 (33), 149 (83), 109 (100); anal. calcd. for C22H23BrN4O3 (471.35): C 56, H 4.92, N 11.89; found: C 56.15, H 1, N

11 NC N N Ph Me OH N H N CO t-bu (135.7 mg) (4 h; TLC check). Pale yellow solid; mp: C; 1 H NMR 5f (400 MHz, CDCl3, 25 C): δ = 1.47 (s, 9H), 0 (s, 3H), 7 (s, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.40 (t, J = Hz, 2H), 7.62 (d, J = Hz, 2H), 7.72 (d, J = Hz, 2H), 7.98 (d, J = Hz, 2H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 15.4 (q), 28.1 (q), 83.1 (s), 98.8 (s), (s), (s), (d), (d), (d), 13 (d), (d), (s), (s), (s), (s), (s), (s); IR (nujol): max = 3196, 1741 cm -1 ; MS m/z (%): 317 (100), 286 (114.6 mg) (24 h; TLC check). Pale yellow solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 0.97 (t, J = 7.6 Hz, 2H), 1.47 (s, 9H), 2.34 (q, J = 7.6 Hz, 2H), 6.81 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.35 (m, 6H), 0 (d, J = Hz, 2H), (br, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 12.3 (q), 20.8 (q), 2 (q), 83.1 (s), 98.4 (s), (d), 12 (d), (s), (d), (d), 13 (s), (s), (s), 14 (s), 15 (s), (s), (s); IR (nujol): max = 3149, 1745 cm -1 ; MS m/z (%): 340 (10), 311 (5), 149 (66), 111 (100); anal. calcd. for C23H25ClN4O3 (440.92): C 62.65, H 5.71, N 12.71; found: C 69, H 5.83, N tert-butyl 2-{1-[3-(4-cyanophenyl)-5-hydroxy-1-phenyl-1H-pyrazol-4- yl]ethylidene}hydrazinecarboxylate (5f): Pyrazole 5f was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 65% yield (83), 272 (19), 149 (55), 111 (74); anal. calcd. for C23H23N5O3 (417.46): C 66.17, H 5, N 16.78; found: C 66.31, H 5.47, N tert-butyl 2-{1-[3-(4-chlorophenyl)-5-hydroxy-1-phenyl-1H-pyrazol-4- yl]propylidene}hydrazinecarboxylate (5g): Pyrazole 5g was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 52% yield tert-butyl 2-{1-[1-(4-chlorophenyl)-5-hydroxy-3-phenyl-1H-pyrazol-4- yl]ethylidene}hydrazinecarboxylate (5h): Pyrazole 5h was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 76% yield (162.2 mg) (5 h; TLC check). Pale yellow solid; mp: C; 1 H NMR (400 MHz, CDCl3, 25 C): δ = 1.41 (s, 9H), 1.87 (s, 3H), 7.21 (d, J = 8.8 Hz, 2H), 7.30 (m, 5H), (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), (br, 1H); 13 C NMR (100 MHz, CDCl3, 25 C): δ = 16.2 (q), 28.1 (q), 84.9 (s), 97.8 (s), 12 (s), (d), (d), (d), (d), (d), (s), (s), (s), (s), 15 (s), 16 (s); IR (nujol): max = 3166, 1748 cm -1 ; MS m/z (%): 326 (52), 311 (71), 297 (22), 295 (46), 281 (42), 149 (57), 129 (80), 127 (89), 111 (100); anal. calcd. for C22H23ClN4O3 (426.90): C 61.90, H 5.43, N 13.12; found: C 63, H 5.34, N

12 3. 1 H and 13 C NMR spectra of products

13 N N Ph N Me HN CO 2 Bu O OMe MeO 2 C 3b

14

15

16 t- 3g

17

18

19

20

21

22

23

24

25 g

26

27

28

29 a N N Ph OH N H N CO2 t-bu Me Cl

30

31

32

33

34 N N Ph OH N H N CO2 t-bu Me NC

35

36

37 4. References. (1) Deng, X.; Mani, N. S. J. Org. Chem. 2008, (2) Sommer, S. Tetrahedron Lett. 1977, 18, 117. (3) (a) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984, 671. (b) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis 1984, 873. (c) Preti, L.; Attanasi, O. A.; Caselli, E.; Favi, G.; Ori, C.; Davoli, P.; Felluga, F.; Prati, F. Eur. J. Org. Chem. 2010, (4) (a) Safaei, S.; Mohammadpoor-Baltork, I.; Khosropour, A. R.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. Synlett. 2011, (b) Shen, L.; Cao, S.; Liu, N.; Wu, J.; Zhu, L.; Qian, X. Synlett. 2008,