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. 2012 Aug 17;77(16):6689-702.
doi: 10.1021/jo300635m. Epub 2012 Jun 6.

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

Paul A Vadola  1 , Ignacio Carrera, Dalibor Sames
Affiliations

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

Paul A Vadola et al. J Org Chem. .

Abstract

We here report a study of the intramolecular amination of sp(3) C-H bonds via the hydride transfer cyclization of N-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to N-toluenesulfonamide in the presence of BF(3)·OEt(2) 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 N-tosylimine and the benzylic sp(3) 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 cis-2,5-disubstituted piperidines, while 3-substituted aldehydes afford trans-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.

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Figures

Figure 1
Figure 1
Examples of diverse structures prepared by HT-cyclization in our group. The bond formed during the process is highlighted in red. E = CO2Me, E′ = CO2Et, Ar = 4-MeO-C6H4.
Figure 2
Figure 2
Mechanistic Rationale for the Observed Diastereoselectivity. A/The experimental data supports the thermodynamic control of the stereoselectivity. The stereoisomer with the α-aryl group in the axial position is more stable due to the steric bulk of the N-tosyl group and its position on a partially sp2-hybridized nitrogen. ORTEP diagram from the X-ray analysis of the major isomer 11 is shown (right side). B/ The same ratinonale explains the formation of the cis-isomer of 2,5-disubstituted piperidine 19 as the major product. ORTEP diagram of 19 is shown (right side).
Scheme 1
Scheme 1
Two Complementary Approaches to α-Arylated Piperidines via C-H Bond Functionalizationa
Scheme 2
Scheme 2
Formation of Cyclic Amines via the HT-cyclization of Imines.
Scheme 3
Scheme 3
One-pot Condensation/HT-amination Protocol
Scheme 4
Scheme 4
HT-amination is Stereoselective
Scheme 5
Scheme 5
Deprotection of the N-tosyl Group
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