Nucleophiles bidentate, enamine

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

Enamines such as 510 are bidentate nucleophiles, with both nitrogen and carbon functioning as nucleophiles.267 Alkylation at nitrogen is a problem with reactive halides such as methyl iodide or allyl bromide and when the groups on nitrogen are small. Nucleophilicity usually parallels that of the unsubstituted amine. 

Enaminones are compounds containing the system N—C=C—C=0. They are mono enamines of 1,3-diketones (vinylogous amides) or enamines of 3-keto esters (vinylogous urethanes). Their unique properties and the versatility of their applications in organic synthesis follow from the system Na Cb=Cc—Cd=Oe, which is tridentate (sites a, c, and e) toward electrophiles and bidentate (sites b and d) toward nucleophiles. This makes possible a wide variety of reactions, but with such a multiplicity of sites vulnerable to attack, reactions are sometimes unpredictable and can be unexpectedly complex. 

Mechanistically, the activation of the aldol donor substrates is achieved by stereospecific deprotonation along two different pathways (Fig. 2) [28] Class I aldolases bind their substrates covalently via imine/enamine formation to an active site lysine residue to initiate bond cleavage or formation (Fig. 2a) in contrast, class II aldolases utilize transition metal ions as a Lewis acid cofactor (usually Zn " ) which facilitates (Fig. 2b) deprotonation by a bidentate coordination of the donor to give the enediolate nucleophile [29]. Usually, the approach of the aldol acceptor to the enzyme-bound nucleophile occurs stereospecif-ically following an overall retention mechanism, while the facial differentiation of the aldehyde carbonyl is responsible for the relative stereoselectivity. In this manner, the stereochemistry of the C—C bond formation is completely controlled by the enzyme, in... 

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