Hydrocyanation of unsaturated carbonyls 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[1].
Introduction edit
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.
Diastereoselectivity can be achieved in prochiral, conformationally restricted substrates. Catalytic, enantioselective methods, however, are rare[2].
Mechanism and Stereochemistry edit
Prevailing Mechanism edit
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 3 are favored over the 1,4-adduct. Conditions of kinetic control also favor 1,2-adducts, while thermodynamic conditions 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[3].
When organoaluminum cyanides are used as the source of 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 proton). Formation of the dicyano compound is rapid under these conditions, but conversion back to the keto form occurs under basic workup[4].
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[5].
Control of 1,2- versus 1,4-Addition edit
Direct versus conjugate addition depends on a number of factors. The structure of the carbonyl compound is important, as β-substitution and nearby angular substituents sterically disfavor 1,4-addition. The nature of the cyanating reagent also plays a role—when dialkylaluminum cyanides are used, the development of a six-membered transition state with s-cis enones may favor 1,4-addition. "Bare" cyanating reagents such as alkali metal cyanides and cyanoaluminates tend to add in a 1,4 fashion, while Lewis acid cyanides, such as TMSCN, favor 1,2-addition.
Scope and Limitations edit
Hydrogen cyanide is not reactive enough on its own to add to carbonyl groups; as a result, base catalysis is necessary. Conjugative hydrocyanation is limited by some side reactions and the strongly basic conditions typically employed. Product hydrolysis should be expected in reactions of alkali metal cyanides. Epimerization at the α-position of carbonyls, double bond isomerization, and α-aetoxy rearrangements have all been observed as side reactions under basic conditions. Nucleophilic solvents may add competitively to the carbonyl substrate. Michael addition of cyanated products to the unsaturated carbonyl starting material is also an important side reaction.
Beyond a requirement for base-stable functionality, a wide variety of carbonyl substrates undergo conjugative hydrocyanation. Acetylenic substrates undergo the reaction, as do a variety of carbonyl derivatives: imines[6], esters[7], nitriles[8], and others.
When alkali metal cyanides are used, at least partial neutralization of the reaction medium is usually necessary to provide desired products. This can be accomplished through an acidic group on the substate itself (internal neutralization)[9] or through the addition of an external acid (external neutralization)[10].
Synthetic Applications edit
Conjugative hydrocyanation has been heavily used for steroid synthesis. Originally, it was used to prepare the steroidal D ring, but other approaches have also been employed[11]. Diastereoselectivity is generally high in these addition reactions, and the resulting β-cyano carbonyl compounds can be converted to a number of steroidal products.
Comparison with Other Methods edit
Conjugate hydrocyanation is most comparable to the conjugate addition of alkyl groups mediated by organocopper species. While copper conjugate addition is best suited for the introduction of alkyl groups at the β-position, hydrocyanation works well for the introduction of functional groups that may undergo further chemistry. Cyanating reagents are much less sensitive to the steric environment of the β-position than organocopper reagents[12], and organoaluminum cyanating reagents are not sensitive to halogens while organocopper reagents are.
Experimental Conditions and Procedure edit
Typical Conditions edit
Cyanation reagents are highly toxic and should be handled with care. Most cyanating agents are commercially available, but a number of procedures also exist for their simple preparation from alkali metal cyanides. Concentration, solvent, temperature, and time should all be optimized to minimize by-products. For alkali metal cyanide methods and methods employing acetone cyanohydrin, alcoholic solvents are commonly used. Special workup procedures are needed for reactions of imines, acid chlorides, and acid cyanides. Generally however, methods employing organoaluminums should involve a very careful basic workup (to avoid hydrolysis or epimerization of products). Chromatography should be carried out under acidic conditions to avoid nitrile hydrolysis (10% acetic acid is sometimes added).
Example Procedure[13] edit
Ethyl diphenylmethylenecyanoacetate (118.5 g, 0.428 mol) was dissolved in 180 ml of warm ethanol and treated with a solution of 58.5 g (0.9 mol) of potassium cyanide in 180 ml of water. The resulting clear yellow solution was refluxed for 15 minutes, cooled, and acidified with excess concentrated hydrochloric acid. The product separated, nearly quantitatively, as a viscous oil which solidified on cooling overnight. Recrystallization from aqueous ethanol gave 116.5 g (90%) of cyano product as white crystals, mp 89–91°.
References edit
- ^ Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255.
- ^ Sammis, G.M.; Danjo, H.; Jacobsen, E.N. J. Am. Chem. Soc. 2004, 126, 9928-9929.
- ^ D. T. Mowry, Chem. Rev., 42, 189–244 (1948).
- ^ E. Bonitz, Chem. Ber., 88, 742 (1955).
- ^ W. Nagata, Proc. R. A. Welch Foundation on Chem. Res., XVII, 185 (1973).
- ^ W. Nagata, M. Yoshioka, T. Okumura, and M. Murakami, J. Chem. Soc., C, 1970, 2355.
- ^ C. F. H. Allen and H. B. Johnson, Org. Synth., Coll. Vol. IV, 804 (1963).
- ^ P. Kurtz, Ann. Chem., 572, 23 (1951).
- ^ P. Crabbé, M. Pérez, and G. Vera, Can. J. Chem., 41, 156 (1963).
- ^ A. Lapworth and E. Wechsler, J. Chem. Soc., 97, 38 (1910).
- ^ W. Nagata, T. Terasawa, S. Hirai, and K. Takeda, Tetrahedron Lett., 1960, No. 17, 27.
- ^ G. H. Posner, Org. React., 19, 1 (1972).
- ^ J. A. McRae and R. A. B. Bannard, Org. Synth., Coll. Vol. IV, 393 (1963).