Sterically Controlled C-H Olefination of Heteroarenes

Abstract

The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein we report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is shown to be useful in the context of late-stage functionalization.

Keywords: C−H activation; Fujiwara-Moritani reaction; heteroarenes; olefination; palladium.

Scheme 1

Overview of the regioselective olefination of 3‐substituted heteroarenes.

Figure 1

Steric control in dual ligand‐enabled nondirected C−H activation with palladium catalysts.

Scheme 2

Scope of donor‐substituted thiophenes. The structures of the respective starting materials are shown for simplicity. All reactions were conducted on a 0.2 mmol scale. Yields given in parentheses were obtained on a 2 mmol scale under otherwise identical conditions. Ethyl acrylate was used as the olefin reaction partner to evaluate the thiophene scope. 3‐Phenylthiophene (1 d) was used as substrate to evaluate the scope of the olefin reaction partners. HFIP=1,1,1,3,3,3‐hexafluoroisopropanol.

Scheme 3

Scope of acceptor‐substituted thiophenes (A) and furans (B). The structures of the respective starting materials are shown for simplicity. All reactions were conducted on a 0.2 mmol scale. Yields given in parentheses were obtained on a 2 mmol scale under otherwise identical conditions. Ethyl acrylate was used as the olefin reaction partner to evaluate the heteroarene scope. 3‐(1,3,5‐(i‐Pr)₃C₆H₂)Furan (1 r) was used as the substrate to evaluate the scope of the olefin reaction partners at 70 °C. [a] The reaction was conducted at 70 °C. [b] The olefination (21 %) and allylation (30 %) products were isolated separately.

Scheme 4

Scope of pyrroles. The structures of the respective starting materials are shown for simplicity. All reactions were conducted on a 0.2 mmol. Yields given in parentheses were obtained on a 2 mmol scale under otherwise identical conditions. Ethyl acrylate was used as the olefin reaction partner to evaluate the heteroarene scope. 3‐mesityl‐N‐methyl‐pyrrole (1 y) was used as the substrate to evaluate the scope of the olefin reaction partners with 1.15 equivalents of the olefin reaction partner. [a] 1.15 equivalents of olefin were used. [b] The product was obtained as a mixture of allylation, E‐olefination, and Z‐olefination products (88:11:1). [c] The allylation (29 %) and olefination (8 %) products were isolated separately.