Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes by Rh(III)-Catalyzed C–H Activation

Abstract

α,β-Unsaturated oxime pivalates are proposed to undergo reversible C(sp2)-H insertion with cationic Rh(III) complexes to furnish five-membered metallacycles. In the presence of 1,1-disubstituted olefins, these species participate in irreversible migratory insertion to give, after reductive elimination, 2,3-dihydropyridine products in good yields. Catalytic hydrogenation was then used to convert these molecules into piperidines, which are important structural components of numerous pharmaceuticals.

Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C–H Activation Reactions: An Experimental and Computational Study

“…Steric and electronic manipulation of the Cp ligand, sometimes quite subtle, leads to significant changes in reactivity as well as regio-, diastereo-, and chemoselectivity: The use of electron-deficient Cp ligands such as Cp* CF3 9 and Cp E 10 in place of Cp*Rh(III) complexes increases reactivity for the synthesis of dihydropyridines 11 and indoles (eqs. 1 and 2).…”

Theoretical prediction on the synthesis of 2,3‐dihydropyridines through Co(III)‐catalysed reaction of unsaturated oximes with alkenes

“…Assuming that the singlet and triplet species can easily interconvert via minimum‐energy crossing points (MECPs), the likely optimum reaction path is 1‐CF 3 T → 1‐CF 3 T2 → 2T (→ 2S → 3S ) → 3T → 4T → 5dT → 5dS → 6dS → 6dT → 8dT‐2 → 8dT → 8dS → 9dS → 10dS → 10dT → 11cT + 12dS → 1‐CF 3 T + 12dS + t , and the calculated apparent activation energy for the overall reaction is 43.3 kcal/mol. When 1‐CF 3 is replaced with the analogous Rh(III) catalyst, the apparent activation energy is lower (32.7 kcal/mol, ignoring hydrogen bond effects) and the reaction was found experimentally to require a temperature of 50–60°C . Therefore, it can be inferred that the title reaction catalysed by 1‐CF 3 could proceed at higher temperatures.…”

“…The solvent effects were included using the PCM solvation model . 2‐Propanol instead of hexafluoroisopropanol (HFIP, which is used experimentally for the Cp*Rh(III) complex‐catalysed reaction) was considered for solvation because there are no physical parameters for HFIP in the G09 program. For the basis set (BS), the Co atoms are described by the LANL2DZ basis sets with ECP, which were modified by Couty and Hall .…”

“…However they are regarded as versatile intermediates in biosynthetic methodology, and can be reduced to piperidines which are important building blocks for numerous pharmaceuticals . Recently, Rovis and coworkers reported the synthesis of 2,3‐dihydropyridines through Cp*Rh(III) complex‐catalysed reaction of unsaturated oximes with alkenes, featuring a broad range of substrates and high diastereoselectivity . The actual active species for this reaction is the cationic [Cp*RhOAc] + .…”

“…[117][118][119][120] Recently, Rovis and coworkers reported the synthesis of 2,3-dihydropyridines through Cp*Rh(III) complexcatalysed reaction of unsaturated oximes with alkenes, featuring a broad range of substrates and high diastereoselectivity. [121] The actual active species for this reaction is the cationic [Cp*RhOAc] 1 . [122] The reaction has been confirmed to include steps such as concerted metalation-deprotonation (CMD), migration insertion of alkenes into the RhAC bond, and reductive elimination/NAO bond cleavage.…”