Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles

Abstract

A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl-substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.

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.…”

HFO‐1234yf as a CF3‐Building Block: Synthesis and Chemistry of CF3‐Ynones

“…This offers selective access to the opposite isomer from that recently reported by Grygorenko from CF 3 ‐ynones with the structure CF 3 COC≡CR. [21a] Pyrazole 11a [21b] and isoxazole 11b [21c] have been synthesised previously, the latter requiring copper catalyst and two equivalents of zinc bromide in contrast to our transition metal free approach. Together with previously unknown compounds 11c – f , these systems provide useful scaffolds for the construction of more complex compounds in, for example, pharmaceutical discovery programmes.…”

“…178–179 °C from toluene). [21b] δ H (400 MHz; CDCl 3 ) 1.69 (br s, N‐H), 7.56 (2H, m, ArH), 7.66 (1H, d, 4 J CF 1.1, C(2)H), 7.90 (3H, m, ArH), 8.03 (1H, m, ArH), 8.09 (1H, m, ArH). δ F (376 MHz; CDCl 3 ) –74.16 (d, 4 J CF 1.1).…”

The Wonderful World of β‐Enamino Diketones Chemistry

“…Given that regioselective approaches for obtaining trifluoromethyl‐containing pyrazoles are continuously being sought for biological/pharmacological purposes, [ 46–51 ] synthetic methods associated with these structures have been, and still remain, of great interest. [ 52–55 ] Using a similar approach, trifluoromethyl β‐enamino diketones 9 were used in a regio‐ and chemoselective cyclocondensation reaction with phenylhydrazine (Scheme 12). [ 34 ] The corresponding pyrazoles 29 were obtained in refluxing MeCN for 7 h (with addition of BF 3 (OEt) 2 ), at moderate to good yields (60–84 %).…”