Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

Abstract

A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1H-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower temperature and microwave power, although requiring much longer time. A possible mechanism for the cyclization is presented, and further functionalization of the newly created pyrrole ring in the dihydropyrrolizine core is described.

Total synthesis of lamellarin G trimethyl ether through enaminone cyclocondensation

“…With the required isoquinolinium bromide 3 and acylating agents 6–9 in hand, the exploration of the key pyrrole ring formation was undertaken. It was envisioned that N -alkylated 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolinium salt 3 will be deprotonated to the enamine which should in turn react with acylating reagents 40–42 to form intermediate 12 , which should directly undergo intramolecular condensation via elimination of water 14,43 to give pyrrolo[2,1- a ]isoquinolines 13 . The results of optimization of the reaction conditions for pyrrole ring formation are summarized in Table 1.…”

Coupling of acceptor-substituted diazo compounds and tertiary thioamides: synthesis of enamino carbonyl compounds and their pharmacological evaluation

“…Such groups are also tolerated in the reaction, and we obtained 5e–5g in good yields. 3,38,39 Thioformamides are rarely reported in the metal-catalyzed coupling of thioamides and diazo compounds. 24,25 However, they gave good yields of coupled products ( 5h and 5i ).…”

“…1 Enamino carbonyl compounds are essential synthetic intermediates. 2–4 They possess multiple nucleophilic and electrophilic sites that are manipulable to make diverse substrates. Due to their importance in synthesis, several methods exist for preparing enamino carbonyl compounds.…”

“…Due to their importance in synthesis, several methods exist for preparing enamino carbonyl compounds. 2,3,5,6 However, only a few of these methods make enamino carbonyl compounds with an exocyclic double bond (Fig. 1).…”

“…2,7,10 Traditionally exocyclic enamino carbonyl synthesis is achieved by the imino ester approach or the Eschenmoser coupling reaction. 2,3,11,12 New strategies, such as involving rhodium azavinylcarbenes and isatins, have been reported that complement the imino ester approach and the Eschenmoser coupling reaction. 13 However, they all have limitations.…”