One-pot organocatalyzed synthesis of tricyclic indolizines

• Published in: Organic & biomolecular chemistry Vol. 21; no. 17; pp. 3567 - 3581
• Main Authors: Zeoly, Lucas A, Acconcia, Lais V, Rodrigues, Manoel T, Santos, Hugo, Cormanich, Rodrigo A, Paniagua, Juan C, Moyano, Albert, Coelho, Fernando
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 03.05.2023; Royal Society of Chemistry
• Subjects: Adducts; Atom economy; Bioactive compounds; Biological activity; Chemical synthesis; Chemistry; Chemistry, Organic; Dehydration; Imidazole; Physical Sciences; Science & Technology; ROUTE; ANTIMYCOBACTERIAL; DESIGN; FACILE SYNTHESIS; HYDRAZIDES; NITROGEN-HETEROCYCLES; BIOLOGICAL-ACTIVITY; BAYLIS-HILLMAN REACTION; DERIVATIVES; CYCLIZATION
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d3ob00346a

Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends. Tricyclic indolizines can be obtained in water in one step by a Morita-Baylis-Hillman/aza-Michael cyclization/dehydration cascade.