Rhodium(III)‐Catalyzed Regioselective Direct C‐2 Alkenylation of Indoles Assisted by the Removable N‐(2‐Pyrimidyl) Group

Abstract

The C‐2‐alkenylindole unit is a key component of numerous natural products and pharmacophores. However, the intermolecular direct construction of the core structural motif remains challenging in organic synthesis. Here we report a new, efficient, and versatile methodology for the synthesis of C‐2‐alkenylindoles through rhodium(III)‐catalyzed direct CH functionalization of indoles with acrylates under air by employing a metal‐directing group strategy. This strategy gives a rare selectivity for the alkenylation N‐(2‐pyrimidyl)indoles at the C‐2 position and provides the functionalized C‐2‐ alkenylindoles under mild conditions with broad substrate tolerance. An expansion of the methodology has also been demonstrated to, for example, the direct alkenylation of pyrrole and facile deprotection of the pyrimidyl group. All the results suggest that this methodology could be served as a highly attractive alternative for the direct construction of biologically important C‐2‐alkenylindoles.magnified image

Computational Investigation of the Role Played by Rhodium(V) in the Rhodium(III)‐Catalyzed ortho‐Bromination of Arenes

“…In our theoretical calculations, N , N ‐diisopropylbenzamide was selected as the model reaction to study the mechanism of bromination. Cleavage of the C−H bond is generally considered to be the rate‐determining step in the majority of Rh‐catalyzed C−H bond functionalization reactions reported to date ,,–. With this in mind, we considered that this step would occur after the oxidative addition of NBS and initially calculated the free energy profiles for pathway A.…”

Regioselective Direct C‐Alkenylation of Indoles

“…The utilization of the N‐ (2‐pyrimidyl) group for the selective C‐2 alkenylation of indoles is effective using Rh III complexes coupled with Cu(OAc) 2 , or molecular oxygen as terminal oxidants (Scheme ) . The yields of the prepared adducts are comparable with those previously obtained using the same metal and the N , N ‐dimethylcarbamoyl directing group.…”

“…Ac atalytic system composed by [Cp*RhCl 2 ] 2 and AgSbF 6 leads to at andem alkenylation-deprotection of the corresponding indole, although the alkenylated products are obtained with lower chemical yields compared to the twosteps method (46-85 %). [48] The utilization of the N-(2-pyrimidyl) group for the selective C-2 alkenylation of indoles is effective using Rh III complexes coupled with Cu(OAc) 2 , [49] or molecular oxygen as terminal oxidants (Scheme 14). [50] The yields of the prepared adducts are comparable with those previouslyo btained using the same metal andt he N,N-dimethylcarbamoyl directing group.…”

Rhodium(III)‐Catalyzed Selective Direct Olefination of Imidazoles

“…In these reports, Cp*(pentamethylcyclopentadienyl) ligated rhodium complexes proved to be effective catalysts for this kind of transformation, and a variety of directing groups containing oxygen, nitrogen and sulfur atoms have exhibited their remarkable ability to promote the reactivity and selectivity. In particular, the 2‐pyrimidyl and 2‐pyridyl groups performed well as readily installable and removable directing groups in direct olefination of N‐heterocycles such as indoles,,,,, pyrroles,,, and indolines. Inspired by these elegant studies, we envisioned that the installation of a pyrimidyl or pyridyl directing groups on the N atom of the imidazole ring may facilitate direct C−H olefination of imidazoles in the presence of a Rh(III) catalyst.…”