Exploration of Forbidden Povarov Processes as a Source of Unexpected Reactivity: A Multicomponent Mannich–Ritter Transformation

Abstract

When a door closes, a window opens! The use of geometrically or electronically restricted imines for Povarov-type processes does not afford the anti-Bredt tetrahydroquinolines, but leads instead to highly functionalized structures through novel reaction pathways (see picture; LA=Lewis acid). The exploration of "forbidden" routes constitutes a valuable approach in the search for new multicomponent reactions.

Evolution of a Multicomponent System: Computational and Mechanistic Studies on the Chemo‐ and Stereoselectivity of a Divergent Process

“…Since the DA reaction is not feasible for dihydropyran, the pseudo‐axial intermediate evolves to the pseudo‐equatorial form, which has now the opposite stereochemistry compared to the corresponding intermediate formed from the endo ‐ 5 attack. Finally, as noted in previous studies,9, 18 the attack of acetonitrile syn to the indolyl group is the preferred route, as expected from the greater stability of the chair‐like TS compared to the boat‐like TS formed by anti addition. It is worth noting that the intermediate formed from the syn addition has the suitable orientation for cyclization with the indole nitrogen atom, leading to the formation of 4 a .…”

“…Reactivity and mechanistic studies : Following the Povarov‐type MCR involving cyclic imines, nucleophilic alkenes and nitriles to yield cyclic amidines,9 cyclohexadiene ( 2 b ) affords the MRA adduct as the minor component ( 4 b , 7 %),10, 11 the main product being the imino‐DA cycloadduct ( 5 , 68 %; Scheme ). Interestingly, 5 did not evolve to 4 b under reaction conditions nor with BF 3 ⋅ Et 2 O treatment 12.…”

“…We have recently reported a Povarov‐type MCR involving cyclic imines ( 1 ), nucleophilic alkenes ( 2 a ), and nitriles ( 3 ) in a Mannich–Ritter‐amidine (MRA) cascade process yielding cyclic amidines (Scheme ) 9. It was found that the nature of the olefin plays a major role in determining the outcome of this MCR.…”

Organocatalytic Synthesis of gem‐Difluorinated C2‐Spiro Indolines and Pyrimido[1,2‐a]benzimidazoles from 2‐Alkynyl‐3,3‐Difluoro‐3H‐Indoles

“…Lavilla et al. realized an Sc(OTf) 3 catalyzed three‐component cascade Mannich‐Ritter sequence of 2‐phenyl‐3,3‐difluoro‐3 H ‐indole, 2 H ‐dihydropyran and acetonitrile to construct complex polycyclic difluorinated indoline scaffold (Scheme , eq3) . Despite these elegant achievements in the synthesis of polycyclic fused gem ‐difluorinated indolines, the synthesis of difluorinated C2‐spiro indolines from readily accessible materials remains unexplored.…”

Highly Diastereo‐ and Enantioselective Silver‐Catalyzed Double [3+2] Cyclization of α‐Imino Esters with Isocyanoacetate

“…The cyclic α‐imino ester 6 a (for structure see Table 1) was chosen as the model substrate because of its unique α‐imino aryl ester structure, as well as its easy synthesis 12. The proposed double cyclization with both imine and aryl ester moieties with isocyanoacetate will also be entirely atom economical as the product incorporates all portions of the starting materials.…”