DOI: 10.1002/ejoc.201800682 Full Paper Continuous-Flow Chemistry Continuous-Flow retro-Diels–Alder Reaction: A Process Window for Designing Heterocyclic Scaffolds Imane Nekkaa, [a] Márta Palkó, [a] István M. Mándity, [a,b,c] Ferenc Miklós, [a] and Ferenc Fülöp* [a,d] Abstract: 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 Introduction Heterocyclic skeletal transformations are some of the most powerful synthetic methods for the construction of complex molecular frameworks from simple feedstocks. [1] In this context, Diels–Alder (DA) and retro-Diels–Alder (rDA) reactions are the prevailing approaches, since they lead to valuable N-hetero- cycles with high biological activities, such as isoindoloquinaz- olinones, pyrroloquinazolinones, and 2-spiroquinazolinones. The reactivity and skeletal transformations of these compounds under mild conditions have been widely examined and dis- cussed by our group. [2] The DA/rDA approach makes use of the rigidity and chirality of the DA adducts that are formed by reactions between cyclic dienes and cyclic dienophiles. [3,4] The rDA enantiomers are obtained when enantiomerically pure DA products are modified diastereoselectively and then undergo thermal [4+2] cycloreversion through distillation under reduced pressure [5] or boiling in a solvent, [6] or through the use of micro- wave (MW) irradiation [7] or flash vacuum pyrolysis. [8] We recently revealed the potential of the use of continuous- flow (CF) technology for the synthesis of various functionalized pyrimidinone systems through rDA reactions. [9] Our interest in [a] Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary E-mail: fulop@pharm.u-szeged.hu http://www2.pharm.u-szeged.hu/gyki/index.php/en/ [b] Institute of Organic Chemistry, Semmelweis University, Hogyes Endre u. 7, 1092 Budapest, Hungary [c] MTA TTK Lendület Artificial Transporter Research Group, Institute of Materials and Environmental Chemistry, Research Center for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary [d] MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eötvös u. 6, 6720 Szeged, Hungary Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under https://doi.org/10.1002/ejoc.201800682. Eur. J. Org. Chem. 2018, 4456–4464 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4456 processes. These results were achieved through careful optimi- zation of the reaction parameters. We also developed an alter- native time-efficient route for the synthesis of intermediate quinazolinones 2–16 involving a three-step domino ring-clo- sure reaction followed by spirocyclization under continuous- flow conditions, starting from -aminonorbornene carbox- amides 1a–1d and γ-keto acids or cycloalkanones. CF processes can be explained, at least in part, by the number of potential advantages that CF processes have over traditional batch chemistry. These include the ease of scale-up, high repro- ducibility, excellent heat transfer and mixing, as well as the in- herently greater safety resulting from the small reactor vol- umes. [10–19] Moreover, the accurate tuning of residence times can further broaden the versatility of CF processes. [20] Thus, flow chemistry has for a long time been chosen as an efficient method for the synthesis of more complex chemical structures that are otherwise inaccessible. Focussing on the biological potential of fused pyrimidinones, and continuing our work on the synthesis of new N-hetero- cycles, we intended to further capitalize on the CF rDA protocol by synthesizing more complex pyrimidinone-fused moieties in both racemic and enantiopure forms. Pyrrolopyrimidines have a wide range of applications in medicinal chemistry; they show antimicrobial, [21] antitumor, [22] antiasthmatic, [23] antihyperten- sive, [24] and anti-inflammatory [25] activities. Pyrimidoisoindoles show high vasorelaxtant, [26a] antiplasmodial, [26b] and antifun- gal [27] actions. The spiroquinazolinone, spiropiperidine, and spiroadamantane skeletons, in turn, are known to have a wide range of pharmacological properties, including antimalarial [28] and anti-influenza activities. [29] Moreover, they also function as inhibitors of several key enzymes, such as nitric oxide syn- thase [30] and nosine-5′-monophosphate dehydrogenase. [31] In addition, they are present in several natural frameworks, e.g., prostanoids, alkaloids, and nucleosides. In this paper, we describe an extension of our previously reported CF rDA process for the synthesis of racemic and enantiopure tricyclic and tetracyclic pyrrolopyrimidinones, pyr- imidoisoindoles, and spiropyrimidinone derivatives. We have also developed an alternative preparation for quinazolinone in- termediates by: (i) a three-step domino ring-closure reaction, and (ii) spirocyclization under CF conditions with diexo- and diendo--aminonorbornene carboxamides and γ-keto acids or