One-Pot Synthesis of Polynuclear Indole Derivatives by Friedel–Crafts Alkylation of γ-Hydroxybutyrolactams

Abstract

The Friedel–Crafts reaction of novel 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones was used for low cost, one-pot preparation of polycyclic indole derivatives structurally similar to Ergot alkaloids.

A New, Convenient Way to Fully Substituted α,β-Unsaturated γ-Hydroxy Butyrolactams

“…of MeONa in methanol—is superior both in terms of yields and experiment duration to the other studied systems (entries 5–12) utilizing different bases or/and solvents. This result is in agreement with our previous finding [ 16 ] where the herein-discussed synthetic methodology towards highly functionalized γ-hydroxy lactams were used to construct the LSD-like polycyclic indoles ( Scheme 2 ).…”

“…of MeONa in methanol-is superior both in terms of yields and experiment duration to the other studied systems (entries 5-12) utilizing different bases or/and solvents. This result is in agreement with our previous finding [16] where the herein-discussed synthetic methodology towards highly functionalized γ-hydroxy lactams were used to construct the LSD-like polycyclic indoles (Scheme 2). Thus, with the optimized reaction conditions in hand, we synthesized a focused, 30-substance-strong collection of novel 3,5-diaryl/heteroaryl-4-benzyl substituted 5-hydroxy 3-pyrrolin-2-ones 4 (Table 2 and Scheme 3).…”

“…By the time we embarked on this project, well-functioning reaction conditions (KOH/ DMSO/H 2 O, rt, 1 h) for the ring closure of β-ketonitriles 2 to 3,5 disubstituted γ-hydroxy lactams 1 had been established [1]. Additionally, the feasibility of preparation of 3,4,5trisubstituted lactams 4 (Scheme 1b) was demonstrated earlier [16] with indole-4-carbaldehyde as a non-enolizable carbonyl component 3 (Scheme 2). Still, the scope and limitations of the proposed method as well as optimized conditions for the expected cascade transformation-aldol condensation, double bond isomerization and successive cyclization-were yet to be found.…”

“…It should be noticed that while numerous synthetic approaches to 5-hydroxy-3-pyrrolin-2-one derivatives have been reported [ 7 , 8 , 9 , 10 , 11 , 12 ], to our best knowledge, to date, there are just a few methods leading to 3,5-diaryl substituted γ-hydroxy butyrolactams 1 [ 1 , 13 , 14 ], and none that would afford the herein-described 3,5-di-aryl/heteroaryl-4-benzyl pattern. Thus, the developed procedures greatly expand the chemical space [ 15 ] of available 5-hydroxy 3-pyrrolin-2-ones which, in turn, could be used among other things for a convenient access to other heterocyclic systems [ 16 ].…”

γ-Hydroxy-γ-butyrolactams as 1,2-bis-electrophiles in a Brønsted/Lewis acid-free synthesis of condensed nitrogen heterocycles

“…These compounds are relatively stable reagents that, upon exposure to acidic or thermal conditions, can undergo dehydration to generate highly reactive N-acyliminium ions (Scheme 2a) 18,19 able to catch a wide range of both carbon 20 and heteroatom 21 nucleophiles and therefore provide a versatile and controllable method of carbon-carbon and carbon-heteroatom bond formation (Scheme 2b and c). [22][23][24][25][26] While the literature thoroughly describes hemiaminal fragment transformations, only a single instance of subsequent Michael addition at the acrylamide double bond has been reported (Scheme 2d). 27 Herein, we want to present the synthetic utility of unsaturated g-hydroxybutyrolactams as hidden analogs of 1,2-dicarbonyl compounds in catalyst-free reactions with N,N-bis-nucleophiles to access annulated nitrogen heterocycles.…”