Synthesis of Spiro-β-lactam-pyrroloquinolines as Fused Heterocyclic Scaffolds through Post-transformation Reactions

Abstract

A sequential post-transformation of Ugi four-component reaction/ nucleophilic substitution was developed for the synthesis of spiro-β-lactampyrroloquinolines. This method involves the Ugi-4CR of 2-chloro-3-formyl quinolines 1a−h, amines 2a−d, 2-chloroacetic acid 3, and isocyanides 4a, 4b for the synthesis of versatile precursors 5a−v. The Ugi adducts were intramolecularly cyclized under basic conditions through the sequential nucleophilic aromatic substitution (S N Ar)/second-order nucleophilic substitution (S N 2) reaction to give spiro-β-lactam-pyrroloquinoline scaffolds 6a−t. This approach is an efficient method for the synthesis of fused bioactive heterocyclic backbones containing quinoline, pyrrolidone, and β-lactam with high bond-forming efficiency.

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…Al‐Harrasi, Balalaie and co‐workers described the synthesis of a library of spiropyrroloquinoline β‐lactams 141 using four‐component Ugi‐adducts 140 as precursors (Scheme 42). [58] These spirocyclic bis‐β,γ‐lactams were obtained as racemic mixtures in moderate to high yields (54–88%). The Ugi‐adducts 140 were synthesized through a four‐component reaction of 2‐chloro‐3‐formyl quinolines 136 , 2‐chloroacetic acid ( 137 ), amines 138 , and isocyanides 139 .…”

Six‐Component Reactions and Beyond: The Nuts and Bolts

“…[34,35] Recent developments exemplify the versatility of the Ugi-adduct, describing the preparation high utility scaffolds via metal-mediated or metalfree post-Ugi transformations. [36][37][38][39][40][41][42][43] In addition to the Ugi reaction, a battery of MCRs are available in the tool box of the modern day chemist namely Petasis, Povarov and Groebke-Blackburn-Bienaymé reactions to name but a few. [44][45][46] Indeed, it must be noted that the discovery of each new MCR often spawns efforts from prominent chemists drawn on these named reactions to shorten and create a novel synthetic routes.…”

“…Moreover, the Ugi‐4CR has influenced a growing body of research in material sciences and chemical biology [34,35] . Recent developments exemplify the versatility of the Ugi‐adduct, describing the preparation high utility scaffolds via metal‐mediated or metal‐free post‐Ugi transformations [36–43] . In addition to the Ugi reaction, a battery of MCRs are available in the tool box of the modern day chemist namely Petasis, Povarov and Groebke‐Blackburn‐Bienaymé reactions to name but a few [44–46] .…”

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

“…disclosed a two‐step Ugi‐4CR/S N Ar/SN 2 reaction sequence to furnish highly decorated spiro‐β‐lactam‐pyrroloquinolines 65 in 54–88% yields (Scheme 22). [55] Plausible reaction mechanism involved nucleophilic aromatic substitution owing to high electrophilicity at C2‐position of quinoline, followed by intramolecular nucleophilic substitution via peptidyl anion trapping. The abstraction of acidic amide proton by t BuOK led to intermediate 64‐A , which on subsequent nucleophilic aromatic substitution afforded intermediate 64‐B .…”

“…In another recent report, Balalaie et al disclosed a two-step Ugi-4CR/S N Ar/SN 2 reaction sequence to furnish highly decorated spiro-β-lactam-pyrroloquinolines 65 in 54-88% yields (Scheme 22). [55] Plausible reaction mechanism involved nucleo- 64-C, which upon intramolecular nucleophilic substitution furnished spiro-β-lactam-pyrroloquinoline 65.…”