Synthetic routes to pyrrolizine-1,5-dione derivatives by flash vacuum pyrolysis of amidomethylene derivatives of Meldrum's acid

Abstract

Methoxymethylene Meldrum's acid 1 reacts with 5- and 6-membered lactams in refluxing acetonitrile to give the N-substituted products 9-15. If the reactions are continued for extended times, the Meldrum's acid derivatives decompose to provide enamidoesters e.g. 22-24. Flash vacuum pyrolysis of the 5-membered ring products 9-13 provides reasonable yields of the fused pyrrolones 31-35. The constitution of the products is supported by X-ray crystal structures of 10, 12, 19, 32 and 34.

Flash Flow Pyrolysis: Mimicking Flash Vacuum Pyrolysis in a High-Temperature/High-Pressure Liquid-Phase Microreactor Environment

“…Aminomethylene Meldrum’s acids of type 2 have been used as substrates for the preparation of 2-substituted-1,3-oxazin-6-ones 9 by either FVP at 500–550 °C or static thermolysis either in decaline solution or neat at 165–185 °C . The postulated mechanistic pathway for this transformation is shown in Scheme . , Pyrolysis of Meldrum’s acid 2 releases acetone and CO 2 with concomitant formation of a methyleneketene, which, upon H-transfer, leads to an N -acylimidoylketene of type 8 that subsequently undergoes electrocyclization to the 1,3-oxazin-6-one 9 in the final step …”

“…In general, the FVP of pyrroledione precursors (cheletropic extrusion of CO) requires significantly higher temperatures compared with the thermolysis of the corresponding Meldrum’s acid derivatives (concerted extrusion of CO 2 and acetone) to generate the corresponding imidoylketenes . For example, whereas the pyrolysis of pyrroledione 3 is carried out at 700 °C, Meldrum’s acid 2 only requires 500–550 °C to be fully thermolyzed in the gas phase . This difference is also reflected in the required solution phase , and neat thermolysis experiments, the latter revealing a CO extrusion at temperatures above 300 °C.…”

Cyclopropenones in the synthesis of indolizidine, pyrrolo[2,1-a]isoquinoline and indolizino[8,7-b]indole alkaloids

“…It is of interest that the biosynthesis of these bacterial natural products has recently attracted attention 19,20 and that it was established that the bridgehead-OH species (6, 9, 10, 12 and 13) are derived from a late stage biosynthetic oxidation of the corresponding naturally occurring bridgehead-H species, such as compounds 5, 14 and 15, the biosynthetic origins of which were also elucidated. Our own work, 21,22 and that of others [23][24][25][26] (as discussed later) suggests that an additional origin for the bridgehead-OH species is worthy of consideration whereby aerial oxidation might be responsible for the conversion of the bridgehead-H alkaloid into the bridgehead-OH alkaloid. In previous work, we have shown that a range of 5-and 6membered ring cyclic aldimines 16 (n = 1 or 2, Scheme 1) undergo reaction with cyclopropenones 17 to produce the fused bicyclic bridgehead-OH species 18 (with X-ray crystallographic confirmation) rather than the expected bridgehead-H species 19.…”

“…The exclusion of oxygen from our reaction media did not permit the isolation or observation of species 47, with reaction work-up always resulting in the isolation of the oxidised products 50. It has been noted by the research groups of Grošelj 23 and McNab [24][25][26] that the oxidation of 3-hydroxy pyrroles, or their tautomeric 1H-pyrrol-3(2H)-ones is a facile process. McNab obtained strong evidence 26 (ESR) that these oxidations do indeed proceed via a captodative radical such as that shown in Scheme 5.…”

“…5.1. Generation of (3aR,7S,7aR)-7-(benzyloxy)-2,2-dimethyl-3a,6,7,7a-tetrahydro- [1,3]dioxolo [4,5-c]pyridine (24) In an oven dried three neck RBF, the azido aldehyde 23 28 (140 mg, 0.459 mmol) was dissolved in dry THF (10 mL) under an atmosphere of nitrogen. Activated powdered 4 Å molecular sieves (100 mg) were added and the mixture was stirred at room temperature for 15 min.…”