Arylboration of Enecarbamates for the Synthesis of Borylated Saturated N-Heterocycles

Abstract

Two catalytic systems have been developed for the arylboration of endocyclic enecarbamates to deliver synthetically versatile borylated saturated N-heterocycles in good regio- and diastereoselectivities. A Cu/Pd dual catalytic reaction enables the synthesis of borylated, α-arylated azetidines, while a Ni-catalysed arylboration reaction efficiently functionalizes 5-, 6-, and 7-membered enecarbamates. In the case of the Cu/Pd-system, a remarkable additive effect was identified that allowed for broader scope. The products are synthetically useful, as demonstrated by manipulations of the boronic ester to access biologically active compounds.

Keywords: Alkene; Arylation; Boron; Cross Coupling; Heterocycles.

Scheme 1

Occurrence and synthesis of saturated N‐heterocycles.

Scheme 2

Cu/Pd‐catalysed synthesis of azetidines. a,c,e) Crude yields & dr's determined by ¹H NMR relative to mesitylene. e.) Yields are reported as the average of two isolated experiments and products were isolated in >20 : 1 dr & rr. Crude yields, dr's, and rr's are reported as the average of two experiments in parentheses and were determined through ¹H NMR analysis of the crude reaction mixture relative to an internal standard. Yields for reactions with N−Me‐morpholine are in purple. ^a Isolated as the alcohol after Bpin oxidation. ^b Absolute configuration has not been determined, but is predicted based on the model provided in f.

Scheme 3

Ni‐catalysed arylboration of enecarbamates. a,b) Yields are reported as the average of two isolated experiments, and products were isolated as single diastereomers. Crude yields, dr's, and rr's are reported as the average of two experiments in parentheses and were determined through ¹H NMR analysis of the crude reaction mixture relative to an internal standard. All products formed in >20 : 1 crude dr. Note: where rr could not be accurately determined due to rotamers, but a major regioisomer was clearly formed, the rr was assigned as >10 : 1 rr. ^a Run at 30 °C. ^b Run under standard Ni‐catalysed arylboration conditions, but with 1 : 1 THF/DMA, 3 equiv PhBr, and at 30 °C.

Scheme 4

Large scale arylborations, further functionalizations and applications in synthesis.