Grignard reagents hydride transfer

The heterocyclic derivative successfully protects the acid from attack by Grignard or hydride-transfer reagents. The carboxylic acid group can be regenerated by acidic hydrolysis or converted to an ester by acid-catalyzed reaction with the appropriate alcohol. 

Reactions of highly electron-rich organometalate salts (organocuprates, orga-noborates, Grignard reagents, etc.) and metal hydrides (trialkyltin hydride, triethylsilane, borohydrides, etc.) with cyano-substituted olefins, enones, ketones, carbocations, pyridinium cations, etc. are conventionally formulated as nucleophilic addition reactions. We illustrate the utility of donor/acceptor association and electron-transfer below. 

If the Grignard reagent has a hydrogen in the (3-position, reduction of the carbonyl group by hydride transfer may compete with the addition reaction (Table 7.3). 

On the basis of these observations the draft mechanism shown in Scheme 3.160 has been proposed for the catalytic reaction, by analogy with the previous reaction. The reaction of CoCl2(dpph) with M( jSiCH2MgOl gives complex 168, which is electron-rich, because of coordination of the Grignard reagent. Complex 168 effects single-electron transfer to an alkyl halide to yield an anion radical of the halide and cobalt complex 169. Immediate loss of halide from the anion radical affords an alkyl radical intermediate, which adds to styrene to yield a benzyl radical. Cobalt species 169 would then recombine with the carbon-centered radical to form cobalt species 170. Finally, /i-hydride elimination provides... 

Hydride-transfer reactions suffer from the several shortcomings. First, a conventional optical resolution must usually be performed to obtain an optically active carbinol, which is then converted to the halide when the Grignard method is to be used. The actual reduction is generally not the only reaction pathway hence carbinol by-product is produced. More undesirable, however, is the fact that the asymmetric center of the organometallic reagent is sacrificed when the new chiral center is created. Unless the reaction is stereospecific, which is rarely the case, a net overall decrease in chirality results. 

Note that the approach outlined in Scheme 5.10 uses piperonal as the aldehyde component and requires funetionali/alion at die h -posiiion of 14-16 after the key addition step and auxiliary removal. Kelly Rein tried a more direct approach initially, as shown in. Scheme 5.11. but reduction of the aldehyde was the major pathway 68. No addition product was found, hut the isoquinolylox-a/oline could he recovered in MY/i yield. Grignard reagents may reduce carbonyls by cither fi-hydride elimination or electron transfer. Since there are no / -hydrogens in this Grignard. SET is the only possible alternative lor die production of the observed lactone. 

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