Regioselective Trifluoromethylation Research Articles

Transition Metal and Base‐Free Electro‐Oxidative Regioselective Trifluoromethylation of Imidazo[1,2‐a]pyridines

AbstractA green electrochemical C(sp2)−H trifluoromethylation of imidazo[1,2‐a]pyridines by engaging Langlois’ reagent is reported. This oxidative regioselective CF3‐functionalization strategy operates under open atmosphere, in an undivided cell and at ambient temperature. Regioselective C−CF3 bond formation was achieved exclusively by applying this mild protocol exhibiting broad functional group compatibility affording the desired product up to 79% isolated yield. Mechanistic studies indicated a radical pathway for this electrochemical redox transformation.

Regioselective C-H Trifluoromethylation and Its Related Reactions of (Hetero)aromatic Compounds.

Fluorinated functional groups, including trifluoromethyl group, play important roles in the development of drugs, agrochemicals, and organic functional materials. Therefore, the development of highly effective and practical reactions to introduce fluorinated functional groups into (hetero)aromatic compounds is highly desirable. We have achieved several regioselective C-H trifluoromethylation and related reactions by electrophilic and nucleophilic activation of six-membered heteroaromatic compounds and steric protection of aromatic compounds. These reactions proceed in good to excellent yields, even on a gram scale, with high functional group tolerance, and are applicable to the regioselective trifluoromethylation of drug molecules. In this personal account, the background of the introduction reactions of fluorinated functional groups, our reaction designs to achieve regioselective C-H trifluoromethylation and the related reactions of (hetero)aromatic compounds are explained.

K2S2O8‐Glucose‐Mediated Metal‐Free Oxidative Trifluoromethylation of Indoles with Langlois’ Reagent on the C2 Position

AbstractAn efficient and regioselective trifluoromethylation method of indole at the C2 position with ecologically‐sound Langlois’ reagent (CF3SO2Na) under metal‐free conditions is described. K2S2O8 in presence of glucose at room temperature has been utilized for the generation of CF3 radicals from CF3SO2Na. The desired product can be obtained in good to excellent yields with a wide scope of substrate variability and gram scalability.

Radical Reactions of Vinyl Triflates and its Derivatives

Vinyl triflates are valuable precursors for vinyl cations, vinyl carbenes, and electrophiles for transition-metal-catalyzed cross-coupling reactions. However, in these reactions, the trifluoromethyl group is not installed in the final products. The radical reactions of vinyl triflates were limited until our beginning. We initially achieved the synthesis of α-trifluoromethylated ketones from vinyl triflates using triethyl borane as a radical initiator. Since the reaction proceeds chemoselectivity toward the conjugated vinyl triflates, we achieved the chemo- and regio-selective trifluoromethylation of 1,3-bis(vinyl triflates). We developed one-pot trifluoromethylation from aryl alkynes with perfluoroalkanesulfonic acids in the presence of AIBN as a radical initiator. In addition, a crossover experiment and DFT calculations support that the reaction proceeds through an intermolecular pathway. The radical reaction of vinyl triflates in the presence of alkenes afforded γ-trifluoromethylated ketones. We also developed a one-pot triflation-trifluoromethylation-triflation of imines leading trifluoromethyl-substituted vinyl trifluoromethanesulfonic amides.

Water-promoted regio-selective trifluoromethylation of vinyl conjugated diazoacetates

An efficient trifluoromethylation reaction of vinyldiazoacetates under mild reaction conditions was depicted.

Oxidative Copper‐Catalyzed Regioselective Trifluoromethylation of Fused Imidazo[1,5‐a]‐N‐heteroarenes using Langlois Reagent

AbstractA simple, mild, and efficient oxidative copper‐catalyzed regioselective trifluoromethylation of imidazo[1,5‐a]‐N‐heteroarenes have been developed using Langlois, (NaSO2CF3) reagent as CF3 source. This method gives biologically relevant trifluoromethylated fused imidazoles in moderate to good yields with good functional group tolerance. The key features of the reaction are mild conditions, short reaction time, and room temperature reaction.

The regioselective trifluoromethylation of 1,3-bis(vinyl triflates) in the absence of external trifluoromethyl sources

We report the regioselective trifluoromethylation of 1,3-bis(vinyl triflates) via an allyl radical intermediate. In this reaction, the trifluoromethyl radical exclusively attacks the 4-position of the 1,3-diketone derivatives. The observed regioselectivity can be rationalized on the basis of DFT calculations, which suggest that the attack at the 4-position is more favorable than that at the 2-position. We have also developed a one-pot procedure for the regioselective trifluoromethylation of 1,3-diketones.

Trifluoromethylation of Allenes: An Expedient Access to α-Trifluoromethylated Enones at Room Temperature.

A silver(I) catalyzed regioselective trifluoromethylation of allenes using Langlois's salt (NaOSOCF3 ) is demonstrated. This transformation enables direct expedient access to α-trifluoromethylated acroleins, which are valuable synthons for a number of pharmaceuticals and agrochemicals containing vinyl-CF3 moieties. Versatility of this trifluoromethylation method has been established with good yield and excellent regioselectivity. Preliminary experiments and computational studies were carried out to elucidate the mechanistic insight of this protocol.

ChemInform Abstract: Copper‐Catalyzed Synthesis of Trifluoromethyl(hetero)arenes from Di(hetero)aryl‐λ3‐iodanes.

AbstractA regioselective trifluoromethylation of diaryliodanes by (trifluoromethyl)trimethylsilane is presented.

Regioselective trifluoromethylation of N-heteroaromatic compounds using trifluoromethyldifluoroborane activator

Many important drugs, agrochemicals and their lead compounds contain trifluoromethyl group(s). Most processes currently used to access trifluoromethyl group-containing molecules are performed by substitution of the carboxy or trichloromethyl groups using hazardous fluorinating reagents under harsh reaction conditions. Cross-coupling reactions between organohalides or boronic acids/esters and trifluoromethylating reagents are also used. Direct C-H trifluoromethylation of organic molecules, however, is the ideal method of introducing trifluoromethyl group(s). Despite the recent advances in C-H trifluoromethylation of N-heteroaromatic compounds, regioselective C-H trifluoromethylation of six-membered heteroaromatic compounds has yet to be achieved. Herein we present a general and reliable method for the synthesis of trifluoromethyl group-containing N-heteroaromatics through highly regioselective addition of a trifluoromethyl nucleophile to pyridine, quinoline, isoquinoline and two or three heteroatom-containing N-heteroaromatic N-oxides activated by trifluoromethyldifluoroborane. The C-H trifluoromethylation proceeds under mild conditions in gram scale with high functional group tolerance. This method will be useful in both laboratory and industrial processes.

ChemInform Abstract: A New and Improved Synthesis of trans‐1,2‐Diiodoalkenes and Their Stereospecific and Highly Regioselective Trifluoromethylation.

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A New and Improved Synthesis of trans-1,2-Diiodoalkenes and Their Stereospecific and Highly Regioselective Trifluoromethylation

Reaction of terminal alkynes with iodine in the presence of CuI (5%) in acetonitrile under reflux for several hours gave the trans-1,2-diiodoalkenes in high yields. The trifluoromethylation of thes...