Piperidine formamidines alkylation

An a-substituted piperidine formamidine may be metalated at the a -position selectively, but the alkylation is not stereoselective, providing a 1 1 mixture of cis and trans stereoisomers, as illustrated in Scheme 10. ... 

Meyers and co-workers have continued their studies to exploit the synthetic potential of a-lithio-formamidines and have now described an efficient synthesis of 2-aryl- or 2-heteroaryl-pyrrolidines and -piperidines (266 ). " Alkylation of formamidines (264) gives intermediates (265) which cyclize in situ after cleavage of the amidine unit. The aza-Wittig reaction has been utilized in a general synthesis of heterocyclic vinylogous ure-thanes and amides (268). Staudinger reaction of azides (267)... 

Metalated piperidine amides and formamidines may be converted to a-alkylated piperidines, as illustrated in Scheme 9. Again, the two examples illustrate the superiority of the formamidine moiety in both yield and ease of removal. 

Proton removal adjacent to a heteroatom is further facilitated if the lithium can be internally coordinated to proximate electron donors, such as the carbonyl oxygen, permitting the formation of dipole-stabilized carbanions. Thus lithiations of various amides, thioamides, imides, esters, Boc derivatives of cyclic amines (pyrrolidines, piperidines, and hexahydroaze-pines), thioesters, )V,iV-dialkylthiocarbamates, and various formamidine derivatives are achieved conveniently using s-BuLi (eqs i3 i7) 32,43b.44.47a,48a Subsequent addition of electrophiles followed by hydrolytic removal of the activating carbonyl, carbamoyl, or formamidine moiety provides a valuable synthetic route to a variety of a-substituted amines, alcohols, and thiols. Successful alkylation of the dipole-stabilized car-banions may require the conversion of the initial lithio carban-ions into their organocuprate derivatives, e.g. by the addition of n-PrC=CCu. ... 

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