Enantiospecific Synthesis of ortho-Substituted Benzylic Boronic Esters by a 1,2-Metalate Rearrangement/1,3-Borotropic Shift Sequence.

Stefan Aichhorn,Varinder K Aggarwal,Raphael Bigler,Eddie L Myers

doi:10.1021/jacs.7b05880

Stefan Aichhorn, Varinder K Aggarwal + Show 2 more

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https://doi.org/10.1021/jacs.7b05880

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Abstract

Coupling reactions between benzylamines and boronic esters have been investigated. ortho-Lithiated benzylamines react with boronic esters and a N-activator to afford ortho-substituted benzylic boronic esters with formal 1,1′-benzylidene insertion into the C–B bond. The reaction occurs by a SN2′ elimination and 1,2-metalate rearrangement of the N-activated boronate complex to afford a dearomatized intermediate, which undergoes a Lewis-acid catalyzed 1,3-borotropic shift to afford the boronic ester products in high yield and with excellent enantiospecificity. The use of enantioenriched α-substituted benzylamines gave the corresponding secondary boronic esters with high ee.

Highlights

We recently reported an alternative transition metal-free and stereospecific sp2−sp[3] coupling of chiral secondary and tertiary boronic esters with electron-rich aryl lithium reagents that showed considerable scope (Scheme 1a).[4]
Inspired by the coupling reactions with pyridines, we considered a related transformation with ortho-lithiated benzylamines (Scheme 1c).[8]
We considered that N-activation of the corresponding boronate complex would trigger the 1,2migration/anti-SN2′ elimination of the carbamate to give a dearomatized intermediate, which should undergo a suprafacial 1,3-borotropic shift.[9]

Summary

Introduction

Inspired by the coupling reactions with pyridines, we considered a related transformation with ortho-lithiated benzylamines (Scheme 1c).[8] We considered that N-activation of the corresponding boronate complex would trigger the 1,2migration/anti-SN2′ elimination of the carbamate to give a dearomatized intermediate, which should undergo a suprafacial 1,3-borotropic shift.[9] This would lead to the desired aromatic product in which the boron moiety is retained. We describe the realization of this transformation to give a variety of ortho-substituted benzylic boronic esters in high yield and with excellent enantiospecificity.

Results

Conclusion