Trifluoromethylation Copper-Catalyzed Trifluoromethylation of Hydrazones Leading to the Formation of Quaternary a-Trifluoromethyl Diazenes

International audienceThe copper-catalyzed azomethine trifluorome-thylation of ketone-derived hydrazones with To gni'sh y-pervalent iodine(III)-CF 3 reagent is described. The reaction gives rise to quaternary a-trifluoromethyl diazenes under mild conditions andi sp roposed to proceed via ar adical process. The trifluoromethyl (CF 3)g roup has gained extreme importance in the pharmaceutical and agrochemical industries owing to its unique ability to modulate physicochemical and biological properties of lead compounds in drug discovery. [1] For these reasons, intensiveresearchefforts have been recently devotedt ot he development of practical methods for direct and selectivei ncorporation of aC F 3 moiety into organic molecules. [2] In this area, creationo fC F 3-containing quaternary ste-reocenters remains ah ighly desirable yet challenging task due to the steric congestion encountered duringt he CÀCF 3 bond formation. [3] While nucleophilic 1,2-additions of aC F 3 group across unsaturated moieties, including C=Oa nd C=Nb onds, have been widely exploited toward this goal, [4] quaternary ster-eogenicity arising from electrophilic and radical processes remains relativelyu nexplored. To date, achievements in this area have essentially concerned the synthesis of all-carbon quater-nary a-CF 3 ketones and carboxylic esters through metal-cata-lyzed a-trifluoromethylation of carbonyl compounds, [5] or via their enol ether surrogates. [6, 7] Diazenesa re important organic reagents commonly involved in aw idev ariety of reactions including cycloadditions [8] and radicalp rocesses. [9] Mainly used as dyes andp igmentsi nm any industry sectors, [10] they have also found application as azo prodrugs for bioactive amine delivery. [11] However,w hile synthetic methods for preparing azobenzenes (Ar-N=N-Ar) are now well-established, [12] the development of efficient processes targetinga liphatic diazenes remains challenging, partly due to their inherentt hermal and photoinstability.A saconsequence, very limited synthetic methodsa re availablef or preparing dia-zenes with an adjacent quaternary carbon stereocenter. These essentially rely on the diazenylation of carbonyl compounds, [13] silyl enol ethers, [14] and non-activated olefins [15] with arene di-azonium salts (or aromatic triazenes)t oa fford the corresponding aryl(alkyl)diazenes(Ar-N=N-Alkyl). Currently,t here is no convenient methoda vailable to access a-trifluoromethyl diazenes.T his situation promptedu st od e-velop as ynthetic procedure to preparet hesep otentially useful compounds directly from readily available hydrazone derivatives [16] and an electrophilics ource of CF 3 .I ndeed, we recently developed av ery mild procedure for CÀHt rifluoromethylation of N,N-disubstituted aldehyde-derived hydrazones by using To gni reagent 1 under copper catalysis (Scheme 1a). The radi-cal/single electron transfer (SET)-initiated reactionw as proposed to follow an addition-elimination pathway involving the intermediate cationic species I that restored the hydrazone moiety upon protona bstraction. [17] We therefore anticipated that application of this strategyt oN-monosubstituted ketone-derived hydrazones would eventuallyl ead to the formation of quaternary a-CF 3 diazene derivativesv ia alternative protona b-straction from cationic species II (Scheme 1b). We report herein the successful execution of this strategy. For preliminary experiments ethyl pyruvate N-methylhydra-zone (2a)w as chosen as am odel substrate (Table 1). Initial tri-fluoromethylation with reagent 1 under our previously established reaction conditions (CuCl (20 mol %), CHCl 3 ,2 5 8C) led only to am oderate yield of the expected diazene 3a.S everal other solvents and copper sourcesw ere then screened, which Scheme1.Cu-catalyzed trifluoromethylation of hydrazones with Togni re-agent 1

Copper-catalyzed trifluoromethylationof N,N-dialkylhydrazones

International audienceMild and practical: Trifluoromethylation of (hetero)aromatic aldehyde N,N-dialkylhydrazones was achieved at room temperature by using Togni's trifluoromethylation reagent under CuCl catalysis (see scheme). This simple reaction is believed to occur by a CF3-radical-transfer mechanism and yields useful trifluoromethylated building blocks