Continuous‐Flow retro‐Diels–Alder Reaction: A Process Window for Designing Heterocyclic Scaffolds

• Published in: European journal of organic chemistry Vol. 2018; no. 32; pp. 4456 - 4464
• Main Authors: Nekkaa, Imane, Palkó, Márta, Mándity, István M., Miklós, Ferenc, Fülöp, Ferenc
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 31-08-2018
• Subjects: Chemical synthesis; Cycloaddition; Diels-Alder reactions; Flow chemistry; Microreactors; Nitrogen heterocycles; Organic chemistry; Quinazolinones; Spiro compounds; Synthetic methods
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201800682

The synthesis of racemic and enantiopure tricyclic and tetracyclic pyrrolopyrimidinones, pyrimidoisoindoles, and spiropyrimidinones, as valuable new chemical entities (NCE), based on a highly controlled continuous‐flow (CF) retro‐Diels–Alder protocol is presented. This approach ensures enhanced safety, and gave the target pyrimidinone derivatives 17–25 in yields higher than those obtained in batch and microwave processes. These results were achieved through careful optimization of the reaction parameters. We also developed an alternative time‐efficient route for the synthesis of intermediate quinazolinones 2–16 involving a three‐step domino ring‐closure reaction followed by spirocyclization under continuous‐flow conditions, starting from β‐aminonorbornene carboxamides 1a–1d and γ‐keto acids or cycloalkanones.
An approach based on a highly controlled continuous‐flow (CF) retro‐Diels–Alder reaction was developed for the synthesis of new compounds. Using this approach, we were able to rapidly screen reaction conditions to obtain the desired pyrimidinone moieties in short reaction times and high yields. We also present an alternative route for the synthesis of intermediates by CF cyclization.