The reaction of nitrones with organometallic compounds: Scope, limitations and synthetic applications

Synthetic organic chemists have widely exploited nitrones for the last 50 years as precious substrates for the assembly of complex nitrogen containing frameworks through inter and intramolecular 1,3-dipolar cycloadditions. In the last decade the interest for nitrones was further on increased by a second opportunity, offered by the nucleophilic addition of organometallic reagents to give N,N-disubstituted hydroxylamines. [GRAPHICS] Grignard, lithium reagents and allylic zinc derivatives react very efficiently with nitrones in a wide temperature range; both the reaction rate and the stereochemical outcome of the process can be significantly modified by the addition of nitrone-chelating Lewis acids. The allylation of nitrones is also carried out under Sakurai conditions in the presence of trimethylsilyltriflate, and different results are obtained using allylic silanes or stannanes. Homoallylic hydroxylamines, generated by the allylation of nitrones, are exploited in 5-exo-trig iodocyclizations to give 5-iodomethyl isoxazolidines, useful precursors of hydroxylated acyclic and cyclic amino compounds. Enolates and silyl enol ethers under Mukayama conditions are also investigated. In particular, 2-trimethylsilyloxyfuran reacts with nitrones, in the presence of nitrone activators, to give 3-substituted tetrahydrofuro[2,3-d]isoxazol-5(2H)-ones, easily transformed into a variety of polyhydroxylated piperidine and indolizidine azasugars. The most recent solutions to achieve the control of stereochemistry in nucleophilic additions to nitrones will be examined.