Hydrocyanation of unsaturated carbonyls

Hydrocyanation of unsaturated carbonyl compounds is a special case of the Michael reaction which can lead to β-cyanoketones, β-cyano-cyanohydrins, or vinyl cyanohydrins. Fine-tuning reaction conditions allows access to any of these products.

Hydrocyanation refers to the addition of the elements of hydrogen and cyanide across a multiple bond. When the multiple bond is polarized by an electron-withdrawing group, selective addition results. However, when the electron-withdrawing group is a carbonyl, the possibility of 1,2 (direct) addition to the carbonyl group exists. Methodological advances now permit access to both direct and conjugate addition products.

(1)

Diastereoselectivity can be achieved in prochiral, conformationally restricted substrates. Catalytic, enantioselective methods, however, are rare.

The distribution of products from conjugative hydrocyanation depends both on substrate structure and reaction conditions. Generally, however, acidic conditions favor 1,2-adducts, while basic conditions favor 1,4-adducts. As a result, under acidic conditions the cyanohydrins 2 and 4 are favored over the 1,4-adduct 3. Conditions of kinetic control also favor 1,2-adducts, while conditions of thermodynamic control favor the 1,4-adduct. Conducting the reaction at high temperatures under basic conditions thus facilitates formation of the conjugate addition product. Additions of alkali metal cyanides, for instance, lead exclusively to 1,4-addition.

(2)

When organoaluminum cyanides are used as the source of the nucleophile, two distinct mechanisms are possible, depending on the organoaluminum employed. When trialkylaluminums are combined with hydrogen cyanide prior to the introduction of the carbonyl compound, a cyanoaluminate anion forms and acts as the active cyanating agent (after activation of the carbonyl compound by a proton). Formation of the dicyano compound is rapid under these conditions, but conversion back to the keto form occurs under basic workup.

(3)

When neutral, pre-formed dialkylaluminum cyanides are used, both carbonyl activation and nucleophilic attack of cyanide are facilitated by the organoaluminum reagent. 1,2-Addition is rapid in this case but is also reversible, and slow but irreversible 1,4-addition eventually leads to the conjugate addition product.

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