Denitrogenative Hydrotrifluoromethylation of Benzaldehyde Hydrazones: Synthesis of (2,2,2‐Trifluoroethyl)arenes

Abstract

Reacting hydrazones of arylaldehydes with To gni's CF 3 -benziodoxolone reagent, in the presenceo f potassium hydroxide and cesium fluoride, induces ad enitrogenative hydrotrifluoromethylation eventt op roduce (2,2,2-trifluoroethyl)arenes. This novel reactionw as tolerant to many electronically-diverse functionalg roups and substitution patterns, as well as naphthyl-and heteroarylderivedsubstrates. Advantages of this processi nclude the easy access to hydrazone precursors on al arge scale, speed and operational simplicity,a nd being transition metal-free.Organofluorine compounds play criticalr oles in many areas of modernr esearch,f rom medicinal chemistry to agrochemistry, and from materials science to medical imaging, [1] so the continued development of new fluorination methodologies is critical. Amongt he myriad important organofluorine motifs, (2,2,2-trifluoroethyl)arenes( 1)h ave received considerable attention from the synthetic community,d ue to their favorable biological properties including their increased metabolic stability over alkyl groups. [2] Efforts towards this motif are plentiful and span aw ide range of general synthetics trategies. They are prepared from aldehydes by am ulti-step sequence involving trifluoromethylation and deoxygenation (Scheme 1a,i ), [3,4] and also from b,b-difluorostyrenes by hydrofluorination( Scheme 1a, ii). [5] Nucleophilic displacementonavariety of activated benzylic compounds is achieved with in situ-generated "CuCF 3 " [6,7] (Scheme 1a,i ii). Metal-mediated cross-coupling strategies [8] between arenes or heteroarenes and (2,2,2-trifluoroethyl)-based reagents have been achieved with Cu-, [9] Ni-, [10] Co-, [11] Zn-, [12] Ir-, [13] and Pd-based [14,15] catalysts( Scheme 1a,i v) and arylboronic acids have also been effectively coupled with 2,2,2trifluorodiazoethane (Scheme 1a,v ). [16] Over the past few decades, the use of hypervalenti odine(III) (HVI) reagents in organic chemistry has undergone tremendous growth,d ue to the advantageso fm ild reactionc onditions and broad reactivity,a nd of recyclable,e nvironmentallybenignb y-products. [17] The synthesis of (2,2,2-trifluoroethyl)arenes has recently been accomplished with mesityl( 2,2,2-trifluoroethyl)-iodoniums alts, by electrophilicc oupling with arenes( Scheme 1b,i ). [18] Togni's CF 3 -containing HVI reagent (2) [19] has also been used in the synthesis of 1,throughthe radical trifluoromethylation of benzylic CÀHb onds (Scheme 1b, ii). [20] We were interested in exploitingt he electrophilic nature of 2 [21] to develop at ransitionmetal-free synthesis of 1,b ye xposingi tt oas uitable benzylic nucleophile such as ah ydrazone. [22] Arylaldehyde-derivedh ydrazones readily undergo trifluoromethylation at the azomethine carbon, [23] but to the best of our knowledge,t his reactivity has not been coupled with a denitrogenation event. Given our interest in HVI-mediated gem-difunctionalization reactions of diazo compounds and hydrazones, [24] we aimed to interrupt aW olff-Kishner reduction by having an anionic intermediat...

Deoxygenative Functionalizations of Aldehydes, Ketones and Carboxylic Acids

“…[79] Almost concurrently,M urphysg roup reported similar hydrotrifluoromethylation conditions for the denitrogenative hydrotrifluoromethylation of benzaldehyde hydrazones. [80]…”

Cu(I)-Catalyzed gem-Aminoalkynylation of Diazo Compounds: Synthesis of Fluorinated Propargylic Amines

“…In the past decade, they have been especially successful in multicomponent reactions involving ylide intermediates . They give access to fluorinated building blocks either by using fluorine-containing partners in the multicomponent reaction or starting from fluorinated diazo compounds . The latter approach has been exploited for the synthesis of nitrogen-containing compounds using nitriles, isocyanides, NFSI, and amines , as partners.…”

Visible-Light-Induced Regio- and Stereoselective C(sp2)–H Trifluoroethylation of Enamides with 2,2,2-Trifluoroethyl Iodide

“…Nonetheless, in contrast to the substantial advancements achieved in trifluoromethylation methodologies, the installment of trifluoroethyl entity into various molecules via homologous strategies still lagged behind. It was not until recently that several crucial breakthroughs on the C­(sp 2 )–CH 2 CF 3 , , C­(sp)–CH 2 CF 3 , and C­(sp 3 )–CH 2 CF 3 bond-forming reactions and trifluoroethylation on heteroatoms have been pioneeringly established by the groups of Carreira, , Hu, , Wang, , Ackermann, Zhang, ,,, and many others. Invoked by those achievements, the direct C–H trifluoroethylation reactions of alkenes have gained intensive research interest recently .…”