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Relevant academic research and scientific papers

One-Pot Successive Turbo Grignard Reactions for the Facile Synthesis of α-Aryl-α-Trifluoromethyl Alcohols

A novel straightforward one-pot methodology for two successive turbo Grignard reagent (iPrMgCl·LiCl) reactions, was developed for a facile synthesis of α-aryl-α-trifluoromethyl alcohols, motifs of value in pharmaceutical chemistry. The method displayed broad functional group tolerance, including reducible groups. Dual roles of iPrMgCl·LiCl were exploited in the tandem reaction with commercially available iodoarenes or iodoheteroarenes and 2,2,2-trifluoroethyl trifluoroacetate. The process encompasses three successive reactions in a one-pot process: the iPrMgCl·LiCl-mediated iodine/magnesium-exchange reaction of iodoarenes or iodoheteroarenes; nucleophilic addition of various generated aryl or heteroarylmagnesium reagents to 2,2,2-trifluoroethyl trifluoroacetate; and the reduction of in-situ generated aryl trifluoromethyl ketones with iPrMgCl·LiCl, to produce the corresponding α-aryl or α-heteroaryl-α-trifluoromethyl alcohols bearing various substituents, including reducible functional groups in good to excellent yields.

The reduction of aryl trifluoromethyl ketones by N-carbamoylmethyl-1,4-dihydronicotinamide

The reaction of 15 aryl trifluoromethyl ketones with N-carbamoylmethyl-1,4-dihydronicotinamide has been studied in aqueous sulfolane buffer.The unsubstituted ketone and those containing electron-withdrawing groups in the ring have the following reaction characteristics: (a) a high yield of alcohol is obtained, (b) the observed reaction rate is independent of ring substituent; however, when corrections are made for degree of hydration of the ketones the rate is correlated with Hammett ? values with a rho of 1.98, (c) a secondary isotope effect of approximately 1.08 and primary isotope effects of 1.45-1.62 are observed at 43.4 deg C for the reaction of the dihydronicotinamide containing one or two atoms of deuterium at C-4, (d) ΔH = 15.2 kcal mol-1, and ΔS = -27.0 cal deg-1 mol-1 for the unsubstituted compound, uncorrected for ketone hydration; ΔS for reaction of the unhydrated ketone and dihydronicotinamide is estimated to be -45 to -50 cal deg-1 mol-1.The mechanism for the reduction is consistent with hydride transfer from reductant to oxidant, very possibly accompanied by blind-alley formation of an adduct between ketone hydrate and dihydronicotinamide.Ketones containing electron-donating groups in the ring react with the dihydronicotinamide in some undetermined way, giving little or no alcohol as product.

The reduction of aryl trifluoromethyl ketones by sodium borohydride. The hydride transfer process

The rates of reduction of 17 aryl trifluoromethyl ketones by sodium borohydride in 2-propanol have been measured.The rho (ρ) value is 3.12, excluding the 4-amino and 4-dimethylamino groups, which both lower the rate to a greater extent than their ? values predict.The close correspondence between substituent effects for hydride addition in the methyl and trifluoromethyl series (excluding the amino groups) suggests that normal substituent effects are to be expected for oxidation processes involving hydride removal in trifluoromethyl compounds.The present results are consistent with the oxidation of aryl trifluoromethyl carbi ols by permanganate taking place by hydrogen atom abstraction.The effect of substituents on the rate of reduction of the trifluoromethyl ketones is almost identical to that on the equilibrium constant for formation of the ketone hydrates.The application of the reactivity-selectivity principle to the reduction reaction is also considered.Reduction of the 4-ethyl compound has ΔH = 2.7 kcal mol-1 and ΔS = -38 cal deg-1 mol-1.