Intramolecular [3 + 2]-Cycloadditions of Azomethine Ylides Derived from Secondary Amines via Redox-Neutral C–H Functionalization

Abstract

Azomethine ylides are accessed under mild conditions via benzoic acid catalyzed condensations of 1,2,3,4-tetrahydroisoquinolines or tryptolines with aldehydes bearing a pendent dipolarophile. These intermediates undergo intramolecular [3 + 2]-cycloadditions in a highly diastereoselective fashion to form polycyclic amines with four new stereogenic centers. Challenging substrates such as piperidine, morpholine, and thiomorpholine undergo the corresponding reactions at elevated temperatures.

Redox‐Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine α‐ and β‐C−H Functionalization

“…[11e] Our group has reported ar elated intramolecular [3+ +2] cycloaddition, in which an azomethine ylide intermediate is formed upon benzoic-acid-catalyzed condensation of pyrrolidinew ith 23 to ultimately afford product 24. [13] The potentialo fp yrrolidine-derivatives to form enamines such as 7 was indicatedi nt he formation of 26,i nw hich 25 underwent a,b-difunctionalizationu pon reaction with para-chlorobenzaldehyde. [14][15][16] However,m ore direct evidence for enamines is lacking.…”

The Rügheimer–Burrows reaction revisited: facile preparation of 4-alkylisoquinolines and 3,5-dialkylpyridines from (partially) saturated amines

“…4 While this type of reactivity has historically been limited to relatively activated amines (e.g., α-amino esters or amines with benzylic α-C–H bonds), it has recently been expanded to less reactive substrates. 5 The pericyclic chemistry of azomethine ylides, generated via amine/aldehyde condensations or otherwise, has been well studied, in particular in regard to [3+2]-cycloadditions. 4 Our group has developed a range of transformations in which an initial condensation of a secondary amine with an aldehyde or a ketone, via the intermediacy of an azomethine ylide, ultimately leads to amine α-functionalization, 6 α,α-difunctionalization, 7 or α,β-difunctionalization.…”

Diastereoselective synthesis of fused oxazolidines and highly substituted 1H-pyrrolo [2,1-c][1,4] oxazines via C–H functionalization

“…In continuation of our interest in in-situ generated azomethine ylide followed by the intermolecular [3 + 2]-cycloaddition reaction 10 and synthesis of heterocyclic compounds 11 we explored a method to access intermolecular [3 + 2]-cycloadditions of azomethine ylides from simple THIQs and trypolines under mild conditions. To facilitate reaction development, we began our investigation with THIQ (1.0 equiv) and 2-bromoobenzaldehyde (2.0 equiv) under reflux for 18 h in toluene.…”

“…The mild acids like acetic acid and 2-ethyl hexanoic acid were quite less effective (Table 1, entries 17-18) and strong acids such as CF 3 COOH and p-toluene sulfonoic acid were ineffective. The solvents screened included CH 3 CN, THF, EtOAc, xylene, DMF and toluene among which CH 3 CN was found to be the prefered solvent (Table 1, entries [9][10][11][12][13]. A lower amount of the desired product was obtained Having identified a useful set of reaction conditions, remarkable tolerance toward electronic demands of substituent's in the aldehyde precursors was shown (Scheme 2).…”

“…Examples of azomethine ylide formation from simple, unfunctionalized cyclic amines like pyrrolidine remain rare as they require relatively high reaction temperatures . 10,12 The reaction up to difuctionalization and aromatization was reported under harsh and microwave condition (scheme. 1).…”