Electrophilic trifluoromethylation of carbonyl compounds and their nitrogen derivatives under copper catalysis

Recent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on copper-catalysed (or mediated) C–CF3 bond forming reactions. Ketones and aldehydes (notably via their enol ether and enamine derivatives) enable electrophilic trifluoromethylation at the α-carbon of the carbonyl compounds, whereas aldehyde N,N-disubstituted hydrazones undergo electrophilic attack of the cationic or radical CF3 species at the azomethine carbon, thus providing an umpolung alternative to nucleophilic trifluoromethylation of carbonyl compounds. A reversal in reactivity is also observed for conjugated systems. While α,β-unsaturated ketones regioselectively incorporate the CF3 moiety at the α-position of the enones, trifluoromethylation occurs preferentially at the olefinic β-carbon of the corresponding hydrazones

Palladium et synthèse organique

Le prix Nobel de chimie 2010 a été décerné à l’Américain Richard F. Heck (Delaware University, Newark, Delaware, États-Unis) et aux Japonais Eiichi Negishi (Purdue University, West Lafayette, Indiana, États-Unis) et Akira Suzuki (Hokkaido University, Sapporo, Japon) pour le développement de nouvelles méthodes de formation de liaisons carbone-carbone catalysées par le palladium. Des molécules organiques complexes ont alors pu être rapidement atteintes permettant, entre autres, la production de nouveaux médicaments et molécules bioactives, de produits phytosanitaires, d’arômes et parfums et de composés utilisés dans l’industrie électronique

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 Double C−H Alkylation of Aldehyde-Derived N,N-Dialkylhydrazones with Polyhalomethanes: Flexible Access to 4-Functionalized Pyrazoles

International audienceHere, 4-functionalized pyrazoles have been made accessible in a single step from readily available aldehyde-derived N,N-dialkyl hydrazones and functionalized polyhalomethane derivatives. The process is believed to follow copper-catalyzed cascade C(sp 2)−H haloalkylation/C(sp 3)−H cyclization/aromatization reaction sequences

Amines as key building blocks in Pd-assisted multicomponent processes

In the last few years, palladium-mediated three-component synthesis has emerged as an important synthetic methodology to gain access to nitrogen-containing structures. The latest developments in this area are discussed in this review

Ruthenium-Catalyzed Tandem C–H Fluoromethylation/Cyclization of N -Alkylhydrazones with CBr 3 F: Access to 4-Fluoropyrazoles

International audienc

Electrophilic trifluoromethylation of carbonyl compounds and their nitrogen derivatives under copper catalysis

International audienceRecent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on copper-catalysed (or mediated) C–CF3 bond forming reactions. Ketones and aldehydes (notably via their enol ether and enamine derivatives) enable electrophilic trifluoromethylation at the α-carbon of the carbonyl compounds, whereas aldehyde N,N-disubstituted hydrazones undergo electrophilic attack of the cationic or radical CF3 species at the azomethine carbon, thus providing an umpolung alternative to nucleophilic trifluoromethylation of carbonyl compounds. A reversal in reactivity is also observed for conjugated systems. While α,β-unsaturated ketones regioselectively incorporate the CF3 moiety at the α-position of the enones, trifluoromethylation occurs preferentially at the olefinic β-carbon of the corresponding hydrazones

C−H Difluoroalkylation of Aldehyde Hydrazones with Functionalized Difluoromethyl Bromides under Copper Catalysis

International audienceThe Cu-catalyzed direct difluoroalkylation of aldehyde hydrazones with functionalized difluoromethyl bromides is described. The reaction yields stereodefined α,α−difluoro-β-keto hydrazones under mild conditions and can be carried out at a scale that opens up the possibility of practical applications

Palladium-catalyzed C(sp2)-H alkylation of aldehyde-derived hydrazones with functionalized difluoromethyl bromides

International audienceA palladium-catalyzed C(sp2)−H difluoromethylation of aldehyde-derived hydrazones using bromodifluoromethylated compounds to afford the corresponding functionalized difluoromethylketone hydrazones has been established. It is proposed that a radical/SET mechanism proceeding via a difluoroalkyl radical may be involved in the catalytic cycle. Applications of the methodology to the synthesis of α,α-difluoro-β-ketoesters and α,α-difluoroketones (RCOCF2H) have been illustrated

Palladium-Catalyzed C(sp 2 )−H Alkylation of Aldehyde-Derived Hydrazones with Functionalized Difluoromethyl Bromides

International audienceA palladium-catalyzed C(sp 2) À Hd ifluoromethylation of aldehyde-derived hydrazones using bromodifluorome-thylated compounds to affordt he corresponding functional-ized difluoromethylketone hydrazones has been established. It is proposed that ar adical/SET mechanism proceeding via ad ifluoroalkylr adical mayb ei nvolved in the catalytic cycle. Applications of the methodology to the synthesis of a,a-difluoro-b-ketoesters and a,a-difluoroketones (RCOCF 2 H) have been illustrated