Flow trifluoromethylation of carbonyl compounds by Ruppert–Prakash reagent and its application for pharmaceuticals, efavirenz and HSD-016

Abstract

Flow trifluoromethylation of carbonyl compounds using the Ruppert–Prakash reagent, Me3SiCF3 is disclosed including enantioselective trifluoromethylation. Synthesis of pharmaceuticals, efavirenz and HSD-016 were achieved by this flow method.

Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate–Carbanion Dichotomy by Stopped-Flow NMR/IR

“… 14 Mechanism II has been extensively adopted in the design and interpretation of asymmetric trifluoromethylation. 16 , 29 , 31 …”

Real-Time Spectroscopic Analysis Enabling Quantitative and Safe Consumption of Fluoroform during Nucleophilic Trifluoromethylation in Flow

“…The presence of HMDS could then cause the decomplexation of the polymeric THF-solvate. The real-time 19 F NMR monitoring provided important information concerning the reaction progress under the conditions described in Table 1 - Table 1, entry 5). Also the hypothesis of a progressive cleavage of the trimethylsilyl group from 4a was taken into account, whereby the fluoride anion, derived hypothetically from the decomposition of the trifluoromethanide anion, would be responsible.…”

“…67,68 The reaction conditions were accurately investigated, taking advantage of the real-time monitoring of the reaction mixture. It was found that a lower temperature (-40 °C) and longer residence time (57 minutes The reaction was continuously monitored by FT-IR (Figure 5c) and by 19 F NMR (Figure 5d), discovering that an excess of chlorotriethylsilane (Et 3 SiCl, 2M), used as electrophile, was crucial to suppress the formation of triethylsilyl fluoride (Et 3 SiF; signal at -151.02 ppm in the 19 F NMR spectrum) as by-product. Under these reaction conditions, full consumption of CF 3 H was observed (Figure 5c, blue line, trend of the peak at 1132 cm -1 ; Figure 5d, disappearance of the doublet at -79.49 ppm) and clean formation of compound 8 was detected (Figure 5d, green line, trend of the peak at 1251 cm -1 ; Figure 5d, appearance of the singlet at -61.44 ppm).…”

“…[13][14][15] In particular, significant advances have been achieved during the last decade in the development of new reagents and general approaches for trifluoromethylation, including electrophilic, radical and nucleophilic reactions. [16][17][18][19][20][21][22][23][24] Among these methods, the use of CF 3 H for installing directly the trifluoromethyl moiety into an organic compound remains an appealing approach, in terms of raw material availability and atom-economy. Nevertheless, as a greenhouse gas, CF 3 H must not be dispersed into the atmosphere.…”

Solvent‐Promoted Catalyst‐Free Nucleophilic Fluoroalkylation of Aldehydes

“…upon treatment of activators. Bases such as the fluoride ion, metal alkoxides, hydroxides, acetates, carbonates, phosphates, amines, amine oxides, phosphines, or N ‐heterocyclic carbenes can activate Me 3 Si‐CF 3 and nucleophilic trifluoromethylation proceeds very smoothly under mild conditions . Acids, which activate carbonyl compounds, are also effective for nucleophilic trifluoromethylation ,.…”