Saturated oxygen and nitrogen heterocycles via oxidative coupling of alkyltrifluoroborates with alkenols, alkenoic acids and protected alkenylamines.

Jonathan M. Shikora,Chanchamnan Um,Zainab M. Khoder,Sherry R. Chemler

doi:10.1039/c9sc02835h

Abstract

Saturated heterocycles are important components of many bioactive compounds. The method disclosed herein enables a general route to a range of 5-, 6- and 7-membered oxygen and nitrogen heterocycles by coupling potassium alkyltrifluoroborates with heteroatom-tethered alkenes, predominantly styrenes, under copper-catalyzed conditions, in the presence of MnO2. The method was applied to the synthesis of the core of the anti-depressant drug citalopram. The reaction scope and observed reactivity is consistent with a polar/radical mechanism involving intermolecular addition of the alkyl radical to the alkene followed by [Cu(iii)]-facilitated C-O (or C-N) bond forming reductive elimination.

Highlights

The exible, convergent synthesis of saturated oxygen and nitrogen heterocycles can be accomplished by the addition of a carbon radical to readily available alkenoic acids, alkenols and alkenyl amines under oxidative conditions (Scheme 1a).[1,2,3,4,5,6,7,8,9,10]
We recently reported on the synthesis of 2-arylpyrrolidines via copper-catalyzed oxidative coupling of styrenes with potassium N-carbamolyl-b-aminoethyl tri uoroborates (Scheme 1b).[13]
The copper-catalyzed addition of alkyltri uoroborates to heteroatom-tethered vinyl arenes under oxidative conditions has been demonstrated to be a general route to saturated oxygen and nitrogen heterocycles

Summary

Introduction

The exible, convergent synthesis of saturated oxygen and nitrogen heterocycles can be accomplished by the addition of a carbon radical to readily available alkenoic acids, alkenols and alkenyl amines under oxidative conditions (Scheme 1a).[1,2,3,4,5,6,7,8,9,10]The carbon radical source is an important variable in these alkene addition processes. The exible, convergent synthesis of saturated oxygen and nitrogen heterocycles can be accomplished by the addition of a carbon radical to readily available alkenoic acids, alkenols and alkenyl amines under oxidative conditions (Scheme 1a).[1,2,3,4,5,6,7,8,9,10] BnBF3K in the presence of 20 mol% Cu(OTf)[2, 25] mol% 1,10phenanthroline (3a) and MnO2 (2.6 equiv.) in 1,2-dichloroethane (DCE) at 105 C gave 78% of lactone 2a (Table 1, entries 1).

Results

Conclusion