Organocopper Reagents for the Synthesis of Saturated, and -ethylenic Aldehydes and Ketones

Conjugate addition of organocopper reagents to ct,-ethylenic aldehydes is discussed. Use of cz,r3-ethylenic aminals is an— other approach to the same target, namely homologation of R-M to an aldehyde with three more carbon atoms. The c,-ethylenic aldehydes are easily prepared by carbocupration of c,13-acetylenic acetals. A new way to cz,t3-ethylenic ketones, mediated by organo copper reagents is disclosed. INTRODUCTION The conjugate addition of organo copper reagents to s,-unsaturated ketones and esters is used commonly in organic synthesis'. Several mechanisms have been put forward to rationalise the influence of the substrate (degree of substitution) and the influence of solvents or ligands. The most useful approach has been disclosed by House, who correlates the feasibility of such a reaction, with the ability of the substrate to accommodate a single electron in the antibonding Tsystem of the ethylenic substrate2 : the higher the reduction potential (always negative vs s.c.e.) the more stable the radical anion. An empirical rule, using increments, allows prediction for the reducti on potential of enones D 0 0 0 I e / R" C-R R" 0 R=H : -1.9 volts 1 volt 23.05 kcal/mole Alkyl groups (donors) are destabilizing by -0.1 V., alkoxy groups also, if located at R,R or R" (-0.3 V) whereas a phenyl group stabilizes the radical anion by + 0.4 V. when at R or R" or R" position. The real intermediacy of a radical anion has, however, been questioned and several elegant experiments have focussed on the related intermediacy of a copper III species, which could be,in turn, viewed in a more plausible way as a copper II reagent where two copper atoms of the cuprate dimer release one electron each4. The counter ion (lithium in most cases) is also considered as important since its coordination to the oxygen of the enone is a necessary first step The solvent also plays a role : addition of exces 12-crown-4-polyether inhibits the addition6, and good donor solvents (THF, DME, DMF) retard conjugate addition whereas best results are observed in Et20-Me2S or Et20-pentane mixtures7. The conjugate addition of cuprates to 8—unsaturated aldehydes, on the contrary, had not been systematically studied, since contradictory reports had shown that only 1-2 addition was operating89. Here too, in fact, the various parameters discussed above have to be considered : scattered examples of the conjugate addition were described10 when we undertook a systematic survey of this reaction1l. Lithium dimethyl cuprate adds to various enals, with erratic yields when the reaction is quenched by an acidic or an ammonium chloride solution, since aldolisation-crotonisation products are formed. On the contrary, trapping of the enolate species by trimethyl silyl 91 92 A. ALEXAKIS et al. chloride leads to reproducible yields (see table 1) 1/—CHO Bu OS i Me3 9 1 " 2/ Me3SiCl Bu2CuLi + ,,._OSiMe3 1 / N%7\ C HO , 75° B 2/ Me3SiCl Acroi n and cor 8-monosubsti tuted acrolei ns give practically only products originating from conjugate addition (see table 1); c,8or 8 ,8-disubstituted olefins give a small amount of 1-2 attack, which becomes more important with c,8,13-trisubstituted acroleins. In the latter case, an improvement has been disclosed by Clive et a112, by using the higher order cuprate Me5Cu3Li2 instead of Me2CuLi. Table 1 Addition of lithium dimethyl cuprate to various enal s, ratios of conjugate-versus carbonyl addition (Ether solvent)