Effect of microwave irradiation on reaction of furo[3,2-b ]pyrrole and furo[2,3-b ]pyrrole-2-carbaldehydes with some active methylene compounds

The synthesis of methyl 4-(methoxymethyl)furo[3,2-b ]pyrrole-5-carboxylate (1d) and methyl 2- formyl-4-(methoxymethyl)furo[3,2-b ]pyrrole-5-carboxylate (2d) is described. The effect of microwave irradiation on the condensation reactions of methyl 2-formylfuro[3,2-b ]pyrrole-5-carboxylates 2a-2d and methyl 2-formylfuro[2,3-b ]pyrrole-5-carboxylates 3a-3d with active methylene compounds as are: 2-thioxothiazolidine-4-one (rhodanine), 2-thioxoimidazolidine-4-one (thiohydantoine), and 3-amino-2-thioxothiazolidine-4-one (3-aminorhodanine) was studied and compared with "classical" conditions. The results show that microwave irradiation shortens the reaction time while maintaining comparable yields.


Introduction
Investigations of indole (furopyrroles, thienopyrroles) isosters, in which the benzene ring is replaced by furan or thiophene ring, have resulted in the discovery of many biologically active compounds. 1Therefore, efficient synthetic routes to these types of heterocycle are of great interest. 13][4][5][6][7][8] In our previous studies, 6 comparing the course of Diels-Alder reactions of furo [3,2-b]pyrroles with their [2,3-b] isomers, we concluded that the [2,3-b]  system is the more reactive diene than its [3,2-b] isomer.This observation is supported by the high-level ab initio calculations. 8We have also reported 7 the results of the use of substituted furo [3,2-b]pyrrole and furo [2,3-b]pyrrole-type aldehydes in the synthesis. 7A formyl substituent at C2 results in the reactivity of both systems being comparable.
The aim of this study was to synthesise some new condensation products of furo [3,2b]pyrrole (2) and furo [2,3-b]pyrrole-type aldehydes (3) by reaction with active methylene compounds (Schemes 2 and 3) and to compare the "classical" method with the effect of microwave irradiation and to find conditions in to increase the yield of the condensations.As it was shown before, 9 microwave irradiation can shorten the duration of condensation reactions.For example condensations of thiohydantoin with aromatic aldehydes without solvents 10 and substituted 3-formylchromones in acetic anhydride 11 under microwave irradiation have been described.

Results and Discussion
In our previous paper 2 , we described the preparation of 1b and 1c from methyl 4H-furo[3,2b]pyrrole-5-carboxylate (1a) under phase transfer catalysis conditions and the formylation of these compounds under conditions of the Vilsmeier reaction.This paper presents a synthesis of methyl 6-(methoxymethyl)furo[3,2-b]pyrrole-5-carboxylate (1d), which was obtained more effectively by direct substitution of in situ prepared sodium salt of 1a in DMF, and its formylation under the condition used in ref. 2 In this reaction, 2-formylated product 2d was obtained (Scheme 1).

Scheme 2
Analogously 3a-3d gave 8a-8d (Scheme 3).2a and 2c were used for the preparation of 4a and 4d using microwave irradiation.Although the yields by both methods were almost the same, the reactions in a microwave oven were considerably faster.
All synthesised compounds are stable solids, which are rather sparingly soluble in common solvents, and with high melting points.The structures of the studied compounds have been confirmed by 1  In conclusion, we can state, on the basis of the present studies and our previous reaction studies of both fused ring systems, that the 1,4-system is more stable than its 1,6 positional isomer.In the described experiments we ascertained that if the formyl group occupies the C2 position, the reactivity as well as stability of both systems is comparable.We noticed a remarkable difference in solubility of the two types of aldehyde.Compounds 3a-3d are less soluble than 2a-2d.This observation can be explained by the 1,4-system having a significantly larger calculated dipole moment, 5 which may result in the greater solubility.Although the yields by both "classical" and microwave oven procedures were almost the same, the reactions in a microwave oven were faster.

Experimental Section
General Procedures.Melting points were determined on a Kofler hot plate apparatus and are uncorrected.Samples for analysis were dried over P 4 O 10 at 60 o C and 30 Pa for 8-10 h. 1 H NMR (80 MHz) spectra were recorded on a Tesla BS 587 spectrometer and on a 300 MHz spectrometer VARIAN GEMINI 200.TMS was used as an internal standard; chemical shifts are given in ppm (d-scale), coupling constants (J) in Hz.The reaction progress and purity of all prepared compounds was followed by TLC (SILUFOL UV 254 , Kavalier, Votice, Czech Republic) in the system chloroform-methanol 9:1 visualising spots with UV lamp or iodine vapour.Solvents were purified by published methods.All microwave assisted reactions were carried out in a Lavis -1000 multi Quant microwave oven.The apparatus was adapted for laboratory applications with magnetic stirring and an external reflux condenser.
The following compounds were prepared by this procedure: H NMR spectra, which display signals of furo[3,2-b]pyrrole and furo[2,3b]pyrrole protons, respectively and the double bond H-7 signals.