Copper-Catalyzed Nitrene Transfer as a Tool for the Synthesis of N-Substituted 1,2-Dihydro- and 1,2,3,4-Tetrahydropyridines

Abstract

The sequential reaction of two different furans and PhI=NTs produces 1,2-dihydropyridines in a quantitative manner in the presence of Tp Br3 Cu(NCMe) (Tp Br3 = hydrotris(3,4,5-tribromopyrazolyl)borate) as the catalyst under very mild conditions. The use of a furan and ethyl vinyl ether with PhI=NTs has led to the corresponding 1,2,3,4-tetrahydropyridine. ■ INTRODUCTIONThe metal-mediated catalytic transfer of nitrene (NR) groups to saturated or unsaturated substrates constitutes a useful tool in organic synthesis, in both inter-and intramolecular fashions, the main transformations being the C−H amination or the C=C aziridination reactions (Scheme 1). 1 During the course of our investigations in this area, we found a novel reaction 2 in which alkyl-substituted furans could be selectively converted into 1,2-dihydropyridines, in a process involving two molecules of the heterocycle and one molecule of PhI=NTs (Ts = ptoluenesulfonyl) and with Tp x M complexes (Tp x = hydrotris(xsubstituted-pyrazolyl)borate ligand; M = Cu, Ag) as the catalyst. Mechanistic studies showed that this transformation takes place along four consecutive catalytic cycles, in which at least three of them were metal-mediated. The first step consisted of the aziridination of the furan (2-methylfuran in Scheme 2) and subsequent spontaneous opening of the aziridine AZ to give the aldehyde O1. This aldehyde was converted into the imine O2 throughout a transimination catalytic step (either metal-or water-induced). The third cycle involved in this transformation was a metal-induced aza-Diels− Alder reaction (ADAR) that afforded the bicyclic compound BC, which finally converted into the 1,2-dihydropyridine upon a metal-catalyzed H-elimination−migration process.Dihydropyridines (DHPs) are essential intermediates in the synthetic routes of organic compounds with important biological activity. 3 1,4-Dihydropyridines are starting materials for a variety of drugs such as Nifedipine 4 and AK-2-38 5 as Special Issue: Copper Organometallic Chemistry

Pyrrole Functionalization by Copper‐Catalyzed Nitrene Transfer Reactions

“…In a previous work from our laboratory we demonstrated that the copper catalyst Tp Br3 Cu(NCMe) induces the assembly of two molecules of furans and one NTs unit (from PhI=NTs) leading to the formation of 1,2‐dihydropyridines . We have now found the related transformation in which we employ one furan and one pyrrole along with PhI=NTs en route to the isolation of a 1,2‐dihydropyridine‐imine compound (Scheme ).…”

Development of Molecular Complexity through Nitrene-Transfer Reactions Catalyzed by Copper and Silver Scorpionate Complexes

“…The applicability of this method to the generation of multiple 1,2-dihydropyridines and 1,2,3,4-tetrahydropyridines was later emphasized, with studies that further evaluated the scope of this reaction. 13 In that work, a two-step synthesis was proposed. In a first step, several analogues of I2 were formed by a stoichiometric nitrene transfer to the corresponding furan by the complex Tp Br3 Cu(NCMe).…”

Silver(I) and Copper(I) Complexes of Semi‐Bulky Nitrogen‐Confused C‐Scorpionates

“…The CuTp R could also catalyze aziridination using chloramine‐T in CH 3 CN to give more environmentally benign NaCl (vs. PhI) as a co‐product . Tp Br3 Cu(CH 3 CN) was also found to catalyze nitrene transfer from PhI=NTs to furans in room temperature CH 2 Cl 2 to give dihydropyridines . AgTp* or Ag(Tp *,Br ) were found to be excellent catalysts for aziridination of styrenes, 2‐alkenes, and even E,E ‐hexadien‐1‐ol in room temperature CH 2 Cl 2 using PhI=NTs as a nitrene source .…”