Monosubstituted pyrrolizin-3-ones 1 with substituents at the 1-, 5-, 6-or 7-positions are prepared in excellent yield by flash vacuum pyrolysis (FVP) of appropriate Meldrum's acid derivatives 2. The mechanism involves formation of the pyrrol-2-ylmethylideneketene 29, which can also be generated thermally from 3-(pyrrol-2-yl)propenoate esters (e.g. 30). This alternative route has been used to make a range of 2-substituted pyrrolizin-3-ones, again in excellent yield. The 3-oxo-3H-pyrrolizine-2-carboxylic acid 42 could not be made in this way owing to facile decarboxylation to pyrrolizinone 1, and extension to the formation of the azaazulenone 48 was again unsuccessful.Some years ago we reported a simple and efficient synthesis of pyrrolizin-3-one 1 by flash vacuum pyrolysis (FVP) of the condensation product 2 of pyrrole-2-carbaldehyde and Meldrum's acid. 1 Later, we applied this methodology to the crystalline 6-bromo derivative 3, 2 and obtained the first X-ray crystallographic data for this ring system. 2 The Meldrum's acid route was also used to make certain azapyrrolizinone ring systems for the first time, 3 and their NMR spectra have been discussed in detail. 4 Since pyrrolizinones remain relatively unexplored in the literature, 5 we now report a more extensive study of the scope and mechanism of this synthetic route from which a complementary pyrolytic synthesis via pyrrolylpropenoic esters has evolved. 6 Our corresponding work on the azapyrrolizinones is discussed in the accompanying paper. 7Two routes to the key Meldrum's acid precursors were employed (Scheme 1). The classic Knoevenagel condensation N R 6 O O O O O N H 3 R 6 = Br 1 R 6 = H 2 Scheme 1 Reagents and conditions: i, piperidinium acetate, toluene, 20 ЊC; ii, acetonitrile, 20 ЊC O O O O N H R O O O O O O O O OMe N H R N H CHO ii i Route b Route a + + 4 Rusing piperidinium acetate catalyst 8 in toluene at room temperature (Scheme 1, route a) works well if the appropriate pyrrole-2-carbaldehyde is readily available. Thus, we have used the photochemical ring contraction of 4-substituted pyridine N-oxides 9-11 to prepare a range of 3-substituted pyrrole-2-carbaldehydes 5-7 containing electron donating and electron withdrawing groups, and we prepared ethyl 5-formylpyrrole-2-carboxylate 8 by Vilsmeier formylation of the ester using a literature method. 12 Yields for the Meldrum's acid condensation to give the derivatives 10-13 were in the range 62-98%. Condensation of Meldrum's acid with 2-acetylpyrrole 9 was achieved by the titanium tetrachloride method 13 though the yield of 18 obtained in this way was consistently lower than for the aldehyde reactions (57%). We have also reported a direct route to 2 by reaction of N H CHO R 3 N H CHO EtO 2 C N H Me O O O O O O O O O N H Me 9 8 5 R 3 = Me 6 R 3 = OMe 7 R 3 = CO 2 Me N R 4 R 3 R 5 H 18 10 R 3 = Me, R 4 = R 5 = H 11 R 3 = OMe, R 4 = R 5 = H 12 R 3 = CO 2 Me, R 4 = R 5 = H 13 R 3 = R 4 = H, R 5 = CO 2 Et 14 R 3 = R 4 = H, R 5 = Me 15 R 3 = R 4 = H, R 5 = Ph 16 R 3 = Ph, R 4 = R 5 = H 17 R 3 = R 5 = H, R 4...

Methoxymethylene Meldrum's acid 2 in acetonitrile solution acts as a useful C-electrophile for active substrates such as pyrrole, indole or tertiary enaminones to give substitution products (e.g. 5, 6 or 12, respectively). Primary enaminones react exclusively at the nitrogen atom under these conditions. The effect of ring substituents on the regiochemistry of electrophilic substitution of 3hydroxypyrroles and 3-methoxypyrroles was studied using methoxymethylene Meldrum's acid as the electrophile. Flash vacuum pyrolysis of the Meldrum's acid derivatives obtained in many of these reactions gave access to a range of heterocyclic systems, including the pyridone 48, quinolinedione 43, benzazepinedione 41 and fused pyrones 50,52 and 54.

Synthesis of Pyrrolizin-3-ones by Flash Vacuum Pyrolysis of Pyrrol-2-ylmethylidene Meldrum's Acid Derivatives and 3-(Pyrrol-2yl)propenoic Esters.-A more extensive study of the scope of the title reaction leading to heterocycles such as (II) and (IV) is presented. The synthesis of the starting material is described and mechanistical aspects are discussed in detail. -(CAMPBELL, S. E.; COMER, M. C.; DERBYSHIRE, P. A.; DESPINOY, X. L. M.; MCNAB, H.; MORRISON, R.; SOMMERVILLE, C. C.; THORNLEY, C.; J.

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