Cyanohydrins unsaturated anions

Addition of the a,3-unsaturated anion (21) to the Michael acceptor (22), in which either alkylation or 1,4-addition is possible, affords only the Michael product. Internal alkylation of the interme ate ester enolates leads to cyclopropyl derivatives (equation 7). Terpenoid polyenes are prepared through conjugate addition of the lithiat protected cyanohydrins (23) to dienyl sulfoxide (24 equation 8). ... 

Anions of protected cyanohydrins of aliphatic, aromatic or a,3-unsaturated aldehydes undergo 1,4-addition to cyclic and acyclic enones. The synthetic utility of protected cyanohydrins in 1,4-addition depends on regioselectivity, since a competing reaction is 1,2-addition to Ae carbonyl group. The regioselectivity of these reactions (1,4- versus 1,2-addition) is dependent on the structure of the protected cyanohydrin, the enone and the reaction solvent. Some general principles which influence die regioselectivity can be defined. 

Conjugate additions predominate with bulky anions or with an enone containing a hindered carbonyl function. Anions deriv from protected cyanohydrins of a,3-unsaturated aldehydes favor 1,4-additions. Anions derived from aryl aldehydes, especially if substituted with electron-withdrawing substituents, give predominantly conjugate addition. Increas bulk at the 3-position of the enone, such as in 3,3-di-substituted enones, leads to increased amounts of 1,2-addition. ... 

The anions of protected cyanohydrins derived from saturated aliphatic aldehydes undergo competitive 1,2- and 1,4-addition to unsaturated carbonyl electrophiles. The pnqmrtion of the adducts >pears to vary as a function of both structure and solvent Steric interactions that favor dissociation of the reversibly formed 1,2-addition product increase the proportion of the 1,4-addition product For example, increasing the size of the substituent R in a protect cyanohydrin (29) from methyl to n-pentyl increases the ratio of 1,4-addition product (30) to 1,2-addition inoduct (31) from 1.5 1 to 2.7 1 (equation 14). ... 

Trimethylsiloxy cyanohydrins (9) derived from an a,3-unsaturated aldehyde form ambident anions (9a) on deprotonation. The latter can react with electrophiles at the a-position as an acyl anion equivalent (at -78 C) or at the y-position as a homoenolate equivalent (at 0 C). The lithium salt of (9) reacts exclusively at the a-position with aldehydes and ketones. The initial kinetic product (10) formed at -78 °C undergoes an intramolecular 1,4-silyl rearrangement at higher temperature to give (11). Thus the initial kinetic product is trapped and only products resulting from a-attack are observed (see Scheme 11). The a-hydroxyenones (12), y-lactones 3) and a-trimethylsiloxyenones (11) formed are useful precursors to cyclopentenones and the overall reaction sequence constitutes a three-carbon annelation procedure. 

Takahashi and coworkers have employed intramolecular reactions of anions of unsaturated protected cyanohydrins to produce unsaturated carbocyclic systems containing 10-, 14- and 16-membered rings which are convertible into natural products. These reactions occur regiospecifically at the a-position and usually do not involve ( ) — ( isomerization of P,7-double bonds. The preparation of 2-cyclopen-tadecenone (155), which is convertible into the macrocyclic perfumes muscone and exaltone, is illustrative of this methodology (Scheme 76). 

Metallation of a-substituted a,P-unsaturated nitriles followed by introduction of dry oxygen gas results in the regioselective trapping of the delocalized anion at the a carbon to produce the hydroperoxide. Reduction with aqueous NujSO, and exposure of the cyanohydrin to NaOH affords the p.y-unsaturated ketones in good yields (Scheme 6.57).- 5 ... 

Heteroatom-stabilized Carbanions. Heteroatom-stabilized and allylic carbanions serve as homoenolate anions and acyl anion equivalents, e.g. a-anions of protected cyanohydrins of aldehydes and Q ,/3-unsaturated aldehydes are intermediates in general syntheses of ketones and Q ,/3-unsaturated ketones (eq 36). Allylic anions of cyanohydrin ethers may be a-alkylated (eq 37) or, if warmed to —25°C, may undergo 1,3-silyl migration to cyanoenolates which may be trapped with TMSCl. Metalated Q -aminonitriles of aldehydes are used for the synthesis of ketones and enamines (eq 38). Similarly, allylic anions from 2-morpholino-3-alkenenitriles undergo predominantly a-C-alkyl-ation to give, after hydrolysis, a,/3-unsaturated ketones (eq 39). ... 

Another modification of the cyanohydrin approach involves the use of anions derived from arylacetonitriles after alkylation the substituted nitriles can be oxidized to the cyanohydrin derivatives, which can be deprotected to give ketones. An example of the application of this approach for nucleophilic Michael-type acylation of a/3-unsaturated esters is shown in Scheme 3. ... 

Terminally silylated a-lithio formamidine anions react with ketones to give nitriles and the effect of additives on cuprate 1,4-additions with Mc3SiCN examined, while azomethine ylide results from N-trimethylsilylphthalimide . The influence of various catalysts on the conversion of aldehydes to cyanohydrins using Me3SiCN have been studied, and the factors involved in the addition of aldehydes and ketones to a,P-unsaturated alddehydes and ketones using... 

One of the many useful applications of anions of vinyl cyanohydrins, derived from a.jS-unsaturated aldehydes, is in the spiro-lactonization of cyclic ketones for example, cyclohexanone can be converted into (71) in 60% isolated yield. The a-aminonitrile analogues of the cyanohydrins can be used in much the same way. The same spiro-lactonization of ketones can also be carried out using trimethylsilylallylzinc chloride followed by Sharpless epoxidation, hydrolysis, and oxidation, or by using dianions derived from phosphorodiamidates. ... 

Protected cyanohydrin anions also behave as acyl carbanion equivalents, and this method can be extended to aj3-unsaturated derivatives (5). The reaction of yet another type of acyl carbanion equivalent (6) with esters gives products of type (7), which are useful for the synthesis of novel heterocyclic compounds. Species of type (8 Y = 0,S), are further modified acyl carbanion equivalents, and behave towards carbonyl compounds as synthetic equivalents of the Wittig reagents PhaP = C(YR)CHO. Compounds (9) are j8-acylvinyl anion equivalents. ... 

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