Regiospecific preparation of 1,4,5-trisubstituted pyrazoles from 2-(1 H -1,2,3-benzotriazol-1-yl)-3-(4-aryl)-2-propenals

Treatment of α -benzotriazolyl- α , β -unsaturated aldehydes with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring and elimination of the benzotriazole group affords 1,4,5-trisubstituted pyrazoles in overall yields of 52–79%.

a For designation of Ar in 3 and 4, see Table 1.

Scheme 1 a
Reaction of 3a-f with aqueous HCl in THF at room temperature for 48 h provided α,βunsaturated aldehydes 4a-f in 85−99% yield (Table 1).For comparison, compounds 4a,e have been previously obtained in 43 and 63 % yields, 25 where our method allows the preparation of the intermediates 4a and 4e in 99 and 90% yields, respectively.
In conclusion we have used easily available α-benzotriazolyl-α,β-unsaturated aldehydes to prepare pyrazole derivatives regiospecifically.This method will be useful as a general route to either 1,5-di-or 1,4,5-trisubstituted pyrazoles, which are compounds of major synthetic, biological, and medicinal importance.

Experimental Section
General Procedures.Melting points were determined using a capillary melting point apparatus equipped with a digital thermometer and are uncorrected. 1H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were recorded in CDCl 3 (with tetramethylsilane as the internal standard), unless otherwise stated.Elemental analyses were performed on a Carlo Erba EA-1108 instrument.THF was distilled from sodium-benzophenone ketal prior to use.Column chromatography was performed on silica gel 200-425 mesh.

General procedure for preparation of 2a and 2a'
A mixture of benzotriazole (21.4 g, 0.18 mol), potassium bicarbonate (18.0 g, 0.18 mol) and 2chloroacetaldehyde dimethylacetal (20.5 mL, 0.18 mol) in 180 mL of DMF was refluxed for 18 h.The reaction mixture was cooled, diluted with 180 mL of water and extracted with ether.The combined organic layers were washed with water, brine and dried over MgSO 4 .After evaporation of the solvent under vacuum, the residue was purified by silica gel column chromatography (EtOAc/hexane, 1:4) to afford the pure 2a and 2a'.General Procedure for Preparation of 5 Hydrazine (3.1 mmol) was added to a stirred solution of 7 (3.1 mmol) in 15 mL of ethanol.The reaction mixture was heated under reflux for 4 h, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography eluted with EtOAc/hexane 1:9 to give pure 5.

General procedure for preparation of 6
To a stirred solution of 5 (1.7 mmol) in anhydrous THF (20 mL) at -78 o C, n-BuLi (1.1 mL of 1.6 M in hexane, 1.7 mmol) was added dropwise and stirring was continued for 0.5 h at -78 o C. A solution of methyl iodide (0.12 mL, 1.9 mmol) was then added.The reaction mixture was allowed to warm to room temperature while stirring for 2 h, quenched by the addition of saturated NH 4 Cl, and extracted with ether.The combined extracts were washed with brine, dried 5H); 4.35 (d, J = 14.0 Hz, 1H); 3.66 (d, J = 14. 1

General procedure for preparation of 7
A solution of 4 (1.0 mmol) and hydrazine (1.0 mmol) in 5 mL of ethanol was heated at 78 o C for 12 h.After cooling, sodium (0.05 g, 2.1 mmol) was added and the reaction mixture was heated under reflux again for additional 12 h.After evaporation of solvent, the residue was chromatographed on silica gel eluted with EtOAc/hexane 1:19 to give pyrazole 7. 1-Methyl-5-phenyl-1H-pyrazole (7a).Colorless oil (75%); bp 91-93 o C/1.5 mmHg (lit. 26bp 90-95 o C/1.5 mmHg); 1 H NMR δ 7.51 (d, J = 1.8 Hz, 1H), 7.47-7.37(m, 5H), 6.30 (d, J = 1.8 Hz, 1H), 3.89 (s, 3H); 13 C NMR δ 143. 5, 138.4,130.7, 128.7, 128.6, 128.3, 106.0, 37.4.General procedure for preparation of 8 from 5 A solution of 5a (1.1 mmol) in anhydrous THF (20 mL) was cooled to -78 o C and then treated dropwise with n-BuLi (0.75 mL of 1.6 M in hexane, 1.2 mmol) and stirred at this temperature for 0.5 h.A solution of methyl iodide (0.08 ml, 1.3 mmol) in 5 mL of THF was added slowly at -78 o C. The reaction mixture was allowed to warm to room temperature while stirring for 2 h, quenched by the addition of saturated NH 4 Cl, and extracted with ether.The organic extracts were washed with brine, dried over MgSO 4 and concentrated under vacuum.The residue was dissolved in MeOH (10 mL) and MeONa (0.21 g, 0.0038 mol) was added.The reaction mixture was heated under reflux for 12 h.The solvent was evaporated and the residue was dissolved in EtOAc (15 mL).The solution was washed with water, brine, dried over MgSO 4 and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography using EtOAc/hexane (1:9) to give pure 8a.1,4-Dimethyl-5-phenyl-1H-pyrazole (8a).Colorless oil (63%); (lit. 27 General procedure for preparation of 8 from 6 MeONa (0.06 g, 1.1 mmol) was added to a stirred solution of 6 (0.33 mmol) of methanol (10 mL).The reaction mixture was heated under reflux for 12 h.The solvent was evaporated and the residue was dissolved in EtOAc (15 mL).The solution was washed with water, brine, dried over MgSO 4 and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give pure 8b-h.