C–H Bond Functionalization
via Hydride Transfer:
Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines
via Stereoselective Intramolecular Amination of Benzylic C–H
Bonds
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Abstract
We here report a study of the intramolecular amination
of sp<sup>3</sup> C–H bonds via the hydride transfer cyclization
of <i>N</i>-tosylimines (HT-amination). In this transformation,
5-aryl
aldehydes are subjected to <i>N</i>-toluenesulfonamide in
the presence of BF<sub>3</sub>·OEt<sub>2</sub> to effect imine
formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines
in a one-pot procedure. We examined the reactivity of a range of aldehyde
substrates as a function of their conformational flexibility. Substrates
of higher conformational rigidity were more reactive, giving higher
yields of the desired products. However, a single substituent on the
alkyl chain linking the <i>N</i>-tosylimine and the benzylic
sp<sup>3</sup> C–H bonds was sufficient for HT-cyclization
to occur. In addition, an examination of various arenes revealed that
the electronic character of the hydridic C–H bonds dramatically
affects the efficiency of the reaction. We also found that this transformation
is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity
is a consequence of thermodynamic control. The pseudoallylic strain
between the arene and tosyl group on the piperidine ring is proposed
to rationalize the greater stability of the isomer with the aryl ring
in the axial position. This preferential placement of the arene is
proposed to affect the observed stereoselectivity