Regioselective and diastereoselective addition of organometallic reagents to (S )-N-[(2-pyridyl)methylene]-O-(trimethylsilyl)valinol. Synthesis of (S )-1-(2-pyridyl)alkylamines

Abstract

The imine prepared by condensation of pyridine-2-carbaldehyde and (S )-valinol, followed by protection of the hydroxy group as its trimethylsilyl ether, undergoes addition of organometallic reagents at either the carbon and/or nitrogen atom of the C[double bond, length half m-dash]N double bond. Primary alkylmagnesium halides (R = Et, Bu, cyclohexylmethyl) add preferentially at nitrogen to give tertiary amines. By using hex-5-enylmagnesium bromide as a probe for the single-electron-transfer mechanism, only the N-(hex-5-enyl) adduct is obtained. Other Grignard reagents RMgX (R = Me, Prⁱ, Bn, allyl, vinyl, Ph) and organolithium and zincate reagents add at the carbon atom to give the secondary amines as the main or exclusive regioisomers. Ketimines are the main by-products in the reactions of methyl-, isopropyl- and vinyl-magnesium halides, (isopropyl)dimethylzincate and tert-butylmetal reagents. With the latter reagents, other by-products are also observed, presumably coming from C,N-dialkylation of the C[double bond, length half m-dash]N double bond and attack on the pyridine ring. The C-alkylation products are formed with excellent or perfect diastereoselectivity (si face attack), apart from the tert-butyl and benzyl reagents; then, after acidic work-up, the (S,S )-amino alcohols are converted to (S )-1-(2-pyridyl)alkylamines by oxidative cleavage of the auxiliary. The superior asymmetric induction provided by O-(trimethylsilyl)valinol as auxiliary, with respect to valine esters, is rationalized on the basis of the lower basicity of the oxygen atom. Polar and radical mechanisms, explaining the formation of regioisomeric products and by-products, are discussed.

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