Followed by a Michael Addition Reaction

Bunce and coworkers explored the tandem SN2/Michael addition cascade of 6- and 7-halo-2-alkenoate esters using both primary amines and thiourea to form 

More recently, Bunce and coworkers examined the stereoselectivity of the substi-tution/Michael addition sequence for the formation of bicyclic systems. For example, the d.s-disubstitutcd cyclohexane derivative 381 underwent reaction with BnNH2 and Et3N when heated in EtOH to produce a mixture of 382 and 383 in 80 and 5%, respectively (02JHC1049). The traw-derivative 384, when subjected to the same conditions, was less selective and provided 385 and 386 in 70 and 12% yields, respectively. 

Alkynes can also undergo this double addition cascade as shown by the reaction of 411 with cyclohexanedione that also gave 408 in 71-92% yield. The reaction of alkyne 411 with 412 provided 413 in 81-93% yield. 

Another double Michael addition sequence was reported by Carreno, and in this work catalytic amounts of TiCl2(0/-Pr)2 were used as the Lewis acid. Thus, treatment of / -quinamine 435 with cyclopentenone in the presence of TiCl2(0/-Pr)2 gave 436 in 60% yield (equation (9)) (02AG2753). Cyclohexenone and ethyl vinyl ketone also reacted with 435 under similar conditions to give compounds related to 436 in 60 and 51% yield, respectively. The stereoselectivity of the reaction is quite remarkable and is thought to arise form a tightly coordinated titanium complex. 

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