Mild and Regioselective Synthesis of 3‐CF₃‐Pyrazoles by the AgOTf‐Catalysed Reaction of CF₃‐Ynones with Hydrazines

Abstract

Gold‐ and silver‐catalysed reactions of trifluoromethylated ynones with aryl (alkyl) hydrazines were investigated. The use of (THD‐Dipp)AuOTf and AgOTf resulted in quick heterocyclization reactions to selectively give 3‐CF3‐pyrazoles. AgOTf was found to be the catalyst of choice, and various 3‐CF3‐pyrazoles were formed in up to 99 % isolated yield with high regioselectivity. The reaction has a broad scope: 3‐CF3‐pyrazoles with alkyl and aryl substituents as well as different functional groups can be prepared by this approach. The known pyrazole drugs Celebrex® and SC‐560 were efficiently prepared to demonstrate the utility of the method. Mechanistic investigations revealed that the reaction involves the formation of a hemiaminal as a key intermediate.

Synthesis of trifluoromethyl or trifluoroacetyl substituted heterocyclic compounds from trifluoromethyl‐α,β‐ynones

“…From 2015 to 2019, the regioselectivity of the cyclocondensation of trifluoromethyl‐α,β‐ynones 3 or 3a ‐ c with hydrazines 19 or hydrazine hydrochlorides 22 , hydroxylamine, or 3,5‐dimethyl‐4‐nitropyrazole 30 being readily tuned to afford trifluoromethyl‐pyrazoles 20 , 21 , 24 , 28, or 29 , trifluoromethyl‐isoxazole 26, and trifluoromethyl‐pyrazolo[1,5‐ a ]pyridine 31 was developed by the groups of Hsieh, Nenajdenko, Grygorenko, and Suresh (Scheme 8). [ 13,45–50 ] The reactions between ynones 3 and hydrazines 19 in DMSO at 110°C, [ 45 ] in CH 2 Cl 2 catalyzed by Cu(OAc) 2 , [ 45 ] in hexafluoroisopropanol (HFIP) at 7°C to room temperature, [ 46 ] or in CHCl 3 catalyzed by AgOTf, [ 47 ] delivered the target products 20 and 21 in good to excellent yields (Hsieh's group: 82–95% yields of 20 , 78–95% yields of 21 ; Nenajdenko's group: 73–99% yields of 20 and 21 mixture, 87–99% yields of 21 ). Hydrazine hydrochlorides 22 reacted with ynones 3 in DMSO at room temperature or in EtOH at 60–65°C accompanied by dehydration to form hydrazones 23 , which can further afford 66–99% yields of 3‐CF 3 ‐pyrazoles 21 or 87–100% yields of 4‐iodo‐3‐CF 3 ‐pyrazoles 24 in the presence of NaOH, t ‐BuOK, or DBU as base, or I 2 and NaHCO 3 in CH 3 CN at room temperature for 24 hr.…”

Solvent- and Metal-Controlled Regiodivergent Synthesis of Tri­fluoromethylated Pyrazol-3-yl- and Pyrazol-5-ylphosphonates

“…21 As a rule, use of a highly polar aprotic solvent facilitates the formation of pyrazoline 4 via 1,4-addition. 21a 22 As reported previously, in the case of CF 3 -ynones, 21b the first stage of the process of formation of pyrazoles 3 is reversible, and in the reaction of hydrazines bearing electron-withdrawing groups with 1 , the cyclization process that leads to the formation of 3 can be slowed down, affording the synthesis of the regioisomers of 3 , in other words, compounds 5 . These considerations would explain our results with respect to the formation of pyrazoles 3 from hydrazines comprising electron-withdrawing groups via reactions whereby the use AgOTf or PPh 3 PAuCl/AgOTf as catalysts was necessary.…”

Synthesis of 1‐Trifluoromethylated Propargyl Alcohols by Two Successive Reactions of Cyclopentylmagnesium Bromide in a One‐Pot Manner

“…1,5-Diphenyl-3-(trifluoromethyl)-1H-pyrazole (18 a). [28] Yield 10%; R f 0.21 (hexane/dichloromethane = 4/1); m.p. = 90.9 °C; IR (KBr) 1597 (N=C) cm À 1 ; 1 H NMR (CDCl 3 ) δ 7.37-7.30 (m, 8H, aryl H), 7.24-7.21 (m, 2H, aryl H), 6.76 (s, 1H, aryl H); 19 F NMR (CDCl 3 ) δ À 62.1 (s, 3F); 13 C NMR (CDCl 3 ) δ 144.8, 143.3 (q, J = 38.5 Hz), 139.4, 129.34, 129.25, 129.1, 128.9, 128.8, 128.6, 125.6, 121.4 (q, J = 268.7 Hz), 105.7.…”