Formation of isomeric pyrrolones by flash vacuum pyrolysis of bisaminomethylene derivatives of Meldrum’s Acid

The bisaminomethylene derivatives, 7a–7c, of Meldrum’s acid were made by reaction of appropriate N-methylaniline derivatives with the chloro-compound 15. Under flash vacuum pyrolysis (FVP) conditions (600 °C, 0.005 Torr), 7a–7c were transformed into mixtures of the pyrrolones 10a–10c and 12a–12c. The ratio of 10:12 is essentially independent of the nature of a para -substituent on the aryl ring; the implications of this result on the mechanism of the process are discussed


Introduction
Flash vacuum pyrolysis (FVP) of readily available N,N-disubstituted aminomethylene Meldrum's acid derivatives 1 provides a simple and direct synthetic route to 1-substituted 3hydroxypyrroles and their tautomers, 1H-pyrrol-3-(2H)-ones 5 (Scheme 1). 1,2The general method can also be applied to the synthesis of the corresponding thiophenones (Scheme 1, S replacing NR 1 ). 2 The early stages of the pyrolytic mechanisms of many Meldrum's acid derivatives have been thoroughly investigated by Brown and Eastwood 3 and more recently by Wentrup et al., 4 and the involvement of methyleneketenes and related intermediates has been rigorously established.Indeed, a detailed study by matrix isolation of the course of such reactions of 1 has shown that an intermediate anhydride 2 is formed as the precursor of the methyleneketene, 3. 5 A particularly stable methyleneketene, 6, whose spectra in solution persist even up to room temperature, has been isolated from such precursors. 5However, the later stages of the formation of 1H-pyrrol-3(2H)-ones 5 (and the corresponding thiophenones) from the methyleneketenes 3 are less well defined (Scheme 1) because no further intermediates have been detected by matrix isolation. 6ore information on these stages has been inferred by chemical methods.Thus the 1,4hydrogen transfer from a site adjacent to the nitrogen atom (e.g., 3 → 4) has been confirmed by deuterium labelling. 7The measured value for the deuterium isotope effect (k H /k D = 1.9) is typical of FVP processes. 7The hydrogen transfer (e.g., 3 → 4) and the new C-C bond formation (e.g., 4 → 5) could be either stepwise or concerted processes.Initial assumptions that a diradical intermediate might be involved in the transfer 8 were discounted on the grounds of substituent effects; for example, hydrogen transfer from a primary site is favored over that from a tertiary site by a factor of ca.2:1 (after statistical correction). 9In addition, a concerted hydrogentransfer-cyclisation process from the methyleneketene 3 can be excluded because the configuration of an asymmetric center at the site of hydrogen transfer (e.g., Scheme 1, R 1 = Pr i , R 2 = Me, R 3 = Ph) is partially lost in the final pyrrolone. 10It has been proposed that it is the 1,5dipolar species 4 which undergoes the final electrocyclic ring closure to give the products 5 in both the nitrogen and the sulfur series, [9][10][11] but why are such intermediates not observable spectroscopically?

60-80%
In this paper we report the results of a series of Hammett-type experiments designed to shed further light on these questions.Thus, the substrates 7 were designed so that they can react via the methyleneketene 8 by two different hydrogen-transfer modes, either from the N-aryl-Nmethyl group (route 1) or from the N,N-dimethyl group (route 2), leading to the pyrrolones 10 and 12, respectively (Scheme 2).Applying the mechanism of Scheme 1, route 1 provides a potential resonance-stabilized dipolar intermediate 9, whereas route 2 provides the alternative structure 11.Variation of substituents in the Ar group might then be expected to influence the stability of these intermediates in different ways and hence affect the ratio of the two pyrrolone products.

Results and Discussion
The precursors 7a-7c were made in two steps from Meldrum's acid 13 (Scheme 3).Treatment with phosgeniminium chloride (Viehe's reagent, 14) under neutral conditions in chloroform gives the chlorodimethylaminomethylene derivative 15 (60%). 12This procedure is occasionally temperamental, but works best when fresh reagent and dry solvent are used and the product is purified as described in the Experimental Section.The product 15 is very reactive towards nucleophiles and has proved invaluable in the preparation of a wide variety of dimethylaminomethylene Meldrum's acid derivatives. 13Treatment of 15 with appropriate Nmethylanilines in the presence of triethylamine in acetonitrile solution at room temperature for 1-5 days gave the pyrolysis precursors 7a-7c in 65-81% yield; in contrast, reaction of 15 with N-methyl-4-nitroaniline was unsuccessful, owing to the low nucleophilicity of the amine.The substituents were chosen to give a range of Hammett σ-values (see

Scheme 3
The products 7a-7c all gave molecular ions in their electron-impact mass spectra and showed typical breakdown patterns of Meldrum's acid derivatives [e.g., (M-C 3 H 6 O-CO 2 ) peak generally present].However, the major initial breakdown peak observed in all cases (base peak for 7a and 7c) is formed by loss of fragment(s) totaling 76 Da from the molecular ions.This may be owing to cleavage of C 3 H 6 O and H 2 O (as we have previously confirmed in the special case of N-amino groups with saturated cyclic substituents) 9 but the nature of the species formed requires further investigation.The NMR spectra of 7a-7c are in accord with the proposed structures.The appearance of the C-methyl groups of the Meldrum's acid ring as two singlets (particularly in the 13 C-NMR spectra) indicates that the methylene double bond is substantially twisted, as recently reported by Wentrup and co-workers for some related Meldrum's acid derivatives. 14It is also noteworthy that the quaternary signals for C(5) of the Meldrum's acid ring resonate at very low frequency in the 13 C NMR spectrum (δC ca.76) in accord with the electron-rich nature of this site (cf.ref. 14).
Flash vacuum pyrolysis (FVP) reactions of the Meldrum's acid derivatives 7a-7c were carried out under our standard conditions for such substrates (600 °C and 0.001-0.005Torr).In each case two pyrrolone products were obtained, as shown by the two signals at δH ca.4.8 owing to the proton at the 4-position of the heterocycle (Scheme 4).Assignment of the two products as 10a-c and 12a-c was readily established by the ratios of the aliphatic protons (6:2 in the cases of the dimethylamino compounds 10 and 3:3:1 in the case of the anilino-compounds 12) (see Experimental Section).The ratios of the two pyrrolones 10 and 12 in each pyrolysis were therefore easily obtained by comparison of the integral values.The results are shown in the Table 1.In the first place, these results show that hydrogen transfer from the dimethylamino groups is consistently favored over that from the N-methylarylamino groups (statistical ratio 67:33).This may be owing to the relative electron donating abilities of a methyl group vis-à-vis an aryl group (e.g., Me, σ m -0.07; Ph, σ m +0.06) stabilizing 11 more effectively than 9. Secondly, it is clear that the two pyrrolones 12a-c and 10a-c were obtained in ca.17:83 ratio (within ± 5% experimental error), independent of the nature of the aryl substituent.In other words, the Hammett ρ parameter for the reaction is 0.0.What are the implications of these results for the mechanism of the cyclization, given that both concerted and stepwise radical processes have already been ruled out?It is possible that the reaction has a very early transition state with little charge build-up on the nitrogen atom(s) prior to the actual cyclization event.This may explain why no late intermediates could be detected by matrix isolation and also why only partial racemization of an asymmetric center takes place during the cyclization process.A theoretical study of the reaction profile would now be of great interest.

Experimental Section
General Procedures. 1 H-and 13 C-NMR spectra were recorded at 80 (or 200) and 20 MHz respectively for solutions in [ 2 H]-chloroform. 13C-NMR signals are for one CH resonance unless otherwise stated; assignments were generally confirmed by DEPT experiments.Mass spectra were obtained under electron impact (EI) ionization conditions unless otherwise stated.
In the reactions of the above compound with nitrogen nucleophiles, it should be noted that the success depended largely on the quality of the starting material.Often with poor quality starting material the yields decreased dramatically from the norm and work-up became increasingly difficult.

ISSN 1424-6376
Page 131 © ARKAT USA, Inc some cases a gum was obtained, but trituration with a mixture of cyclohexane and ethanol always gave the required solid in good yield.
Table) for the final analysis.

Table 1 .
Relative yields of 10 and 12 in FVP reactions of 7 a Estimated error from integral values, ±5%.