One-pot organocatalyzed synthesis of tricyclic indolizines

Author(s)

Zeoly, Lucas A. ; Acconcia, Lais V. ; Rodrigues Jr, Manoel T. ; Santos, Hugo ; Cormanich, Rodrigo A. ; Paniagua, Juan C. ; Moyano, Albert ; Coelho, Fernando

• Document type: Journal article
• Source: ORGANIC & BIOMOLECULAR CHEMISTRY; v. 21, n. 17, p. 15-pg., 2023-04-14.

Abstract

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 degrees 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. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/26027-5 - Bi-functional catalyst for the Morita-Baylis-Hillman: new applications
• Grantee: Laís Vaz Acconcia
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• FAPESP's process: 13/24386-5 - Syntheis and evaluation of the pharmacological potential of Pyrazolones and Pyrazolidinones, from Morita-Baylis-Hillman adducts
• Grantee: Laís Vaz Acconcia
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 18/02611-0 - Post-Functionalization of Small Ply-functionalized Molecules: A Robust Approach to the Synthesis of New Structural Patterns with POtential Biological Activity
• Grantee: Fernando Antonio Santos Coelho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/00975-7 - Synthesis of bioactive compounds and studies of relative stereochemistry by hydrogen nuclear magnetic resonance (1H NMR)
• Grantee: Rodrigo Antonio Cormanich
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/09205-0 - New frontiers of the Morita-Baylis-Hillman reaction: 1) New applications of a bifunctional catalyst derived from imidazole. 2) Studies on the asymmetric synthesis of a natural high-potency sweetener
• Grantee: Hugo dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)