Nitrile, unsaturated, conjugate addition

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

The Michael-type conjugate addition of an alkoxide such as methoxide to an a,p-unsaturated nitrile or aldehyde proceeds in solution quite readily, being complete in 5—10 minutes. In the gas phase however, it was found that reaction (6a) does not occur there is no evidence of the addition product even at the longest trapping times, nor in the unquenched mode. Rather, the sole product observed is due to proton loss from the nitrile, to form a nominal vinyl anion, reaction (6b). 

Experimental evidence indicates that cuprates in solution exist largely as dimer (RiCuLi) (25), which is found as the reactive species in conjugate addition. The kinetic results were consistent with the participation of the dimer (R2CuLi)2/enone complex 26 (Figure 24) in the C—C bond-forming process of the conjugate addition. Relatively unreactive a, -unsaturated ketones, esters and nitriles were also found to form complexes represented by 26 in Figure 24. 

Tetraalkylammonium bromide was found to be a good catalyst for the conjugate addition of thiols to a,p-unsaturated nitriles, carboxylic esters, ketones, aldehydes, and nitro alkenes. The reactions proceeded rapidly and gave high yields of products (typically, 90%) (160). 

See page 1809, Section 6 for analogous conjugate additions to a,/ -unsaturated, esters and nitriles. 

CONJUGATE ADDITION TO a, -UNSATURATED NITRILES, CARBOXYLIC ACIDS AND DERIVATIVES... 

Reformatsky first introduced electron-withdrawing substituents on the a-carbon of an organozinc halide, leading to the more reactive and thermally stable a-(alkoxycarbonyl)alkylzinc halides (123).107 Typically these reagents react with aldehydes or ketones to afford 3-hydroxy esters while nitriles afford 3-keto esters (Blaise reaction),l07b>c but 1,4-conjugate additions to select a,3 unsaturated ketones are precedented (Section 1.2.2.2.2). 

Stereoselective intramolecular conjugate addition reactions (Scheme 4) of dithiane anions tethered to an a,/ -unsaturated nitrile have been developed to advantage for the synthesis of axially substituted indolizidines and quinolizidines.81 The control of axial nitrile orientation by a peg-in-a-pocket template effect has been discussed. 

Dithiane anions undergo intramolecular conjugate addition to die a,/ -unsaturated nitrile moiety in (150) to produce indolizidine and quinolizidine (151), in which the nitrile group exhibits a strong, thermodynamic preference for die axial orientation.108... 

RCu-BF3 (8,334-335 9,333). Yamamoto etal.,15 have reviewed and extended their research on the RCu-BF3 system. This system is superior to R2CuLi for conjugate addition to sterically hindered a,/(-unsaturated ketones and esters, but is less useful in reactions with a,/3-unsaturated acids and is unsatisfactory for additions to a,/l-unsaturated nitriles. A typical example is formulated in equation (I). 

Unsaturated nitro compound and nitriles do not usually suffer nucleophilic attack by enols or enolates and both are good at conjugate addition. The addition of the morpholine enamine 57 of cyclohexanone to 58 demonstrates that the nitro group is more effective than the ester at promoting conjugate addition.7... 

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