On the Regioselectivity of the Gould–Jacobs Reaction: Gas‐Phase Versus Solution‐Phase Thermolysis

Abstract

A detailed investigation of the regioselectivity in the thermal cyclization of (pyridyl)aminomethylenemalonates both in the gas‐ and solution phase is presented. Flash vacuum pyrolysis (FVP) as a gas‐phase thermolysis technique is used to study the Gould–Jacobs reaction at temperatures between 450–650 °C, while different solution‐phase heating techniques (reflux, microwave, and continuous flow) were employed at 260–350 °C. Depending on the position of the substituent in the pyridine moiety and the applied thermolysis technique, the regioselectivity of the cyclization can be controlled either in favor of the kinetic (pyridopyrimidinone) or the thermodynamic (naphthyridinone) product. Under FVP conditions, 6‐substituted pyridopyrimidinones were obtained in high regioselectivity, which was not demonstrated before under standard Gould–Jacobs reaction conditions. DFT calculations have been additionally performed to provide further insights into the mechanistic pathways of this specific Gould–Jacobs reaction.

Regioselective Bond-Forming and Hydrolysis Reactions of Doubly Charged Vanadium Oxide Anions in the Gas Phase

“…The asymmetric structure of the H 2 NaV 3 O 10 2− reactant ion may reasonably explain the occurrence of the regioselective process, as the SO 2 molecule can approach the dianion from two chemically different extremities. Similar reactions have already been observed in the gas phase, where a plethora of different factors (e.g., thermodynamic, kinetic, electronic, steric, and orbital) can act by affecting the branching ratios of alternative reaction products [68][69][70]. As to the reactivity of the OH terminal of H 2 NaV 3 O 10 2− , it is worth recalling that hydroxylation of acidic sites of vanadium-oxide-based materials, due to the reaction of the ubiquitous water, is known to change the electronic properties and the structure of the catalytic active sites of such materials [71].…”

Recent Applications of Quinolinium Salts in the Synthesis of Annulated Heterocycles

“…22,23 Consequently, enormous efforts have been devoted to research on the construction of this type of heterocyclic scaffolds. Generally, quinoline skeletons are obtained via traditional strategies, such as, Skraup/Doebner-Miller, 24,25 Friedländer, 26 Pfitzinger, 27 Conrad-Limpach, 28 Gould-Jacobs, 29 and Povarov 30 methodologies. In addition, a number of novel strategies including transition-metal-catalyzed reactions have also been developed in recent years.…”

Acyl(imidoyl)ketenes: Reactive Bidentate Oxa/Aza-Dienes for Organic Synthesis

“…Thermolysis of diethyl 2-((pyridin-2-ylamino)methylene)malonates 4 leads to acyl (imidoyl)ketenes A5, which immediately undergoes intramolecular cyclization via acylation by ketene moiety of one of two reaction centers to afford 1,8-naphthyridines 10 (attack on the ortho-CH group) and/or 4H-pyrido[1,2-a]pyrimidines 11 (attack on the ortho-N atom) (Scheme 9) [42,43]. 4H-Pyrido[1,2-a]pyrimidines 11 are major products of this transformation under FVT (gas phase, contact times of 0.3 s, 450 • C) conditions and are kinetic products.…”

“…Another approach to acyl(imidoyl)ketenes A is based on the thermolysis of (quinoxalin-2-yl)furan-2,3-diones 3 (Scheme 2) [41]. Moreover, generation of acyl(imidoyl)ketenes A is possible in the course of Gould-Jacobs reaction via the thermolysis of 2-(aminomethylene)malonates 4 [42,43].…”