In the literature one can find many 1,3-dipolar cycloaddition reactions proceeding by an intermolecular process where 1,3-dipole generated by different methods is taking part in a reaction with a dipolarophile under formation of five-membered ring.¹ Only some of them are microwave initiated.² Reactions of the intramolecular type are in the literature even less frequent and represent a source for synthesis of fused heterocyclic systems. Microwaves on azomethine ylides were used only ones.³ Besides reactions with azomethine ylides we tried also to generate in situ nitrones for the subsequent intramolecular reaction. In our work we concentrated on preparation of fused hexahydrochromeno[4,3-b]pyroles 3 (Scheme 1).

Scheme 1.

Such a structural motive was found in several naturally occurring alkaloides^4-6 and even hexahydrochromeno[4,3-b]pyroles show interesting biological properties.⁷ The reaction was carried out as "one pot" process under solvent free conditions when the 1,3-dipole was generated in situ by the reaction of o-allyloxybenzaldehyde 1 (sometimes w-substituted with substituents R², R³) with a secondary amine 2 containing electron-withdrawing group. Influence of the substitution at the side chain double bond as well as the substitution R¹ at the nitrogen atom and the electron-withdrawing groups (EWG) upon the yield and stereochemistry of products were searched.⁸ The reaction was attempted also with o-propargyloxybenzaldehyde but there we have not any success. Reactions ended with formation of tar products. Always the reactions were compared with the same reactions under classical heating. It has been proved rather high sensitivity of the chemical reaction on the bulkiness of substituents bound at nitrogen atom of amine. The reactions with unsubstituted allyloxy group proceed with excellent stereoselectivity when only one stereoisomer is formed. The same stereoselectivity was observed when dipolarophiles in cis-configuration at double bond bound in side chain of aromatic ring playing dipolarophile role were used (only one steroisomer was formed). When the configuration on double bond was trans two stereoisomers were isolated in different ratio depending on the substitution R², R³. Nevertheless, the generated ylide always in the reaction possessed anti conformation. We suppose the transition state and its sterical demands influence the stereochemistry of the product formed. The developed method on systems without side chain enabled application for preparation of substituted imidazolidin-4-ones⁹ - versatile synthon for syntheses of a-amino acids and di- or tripeptides. Finally lot of effort was devoted to the application already developed method for in situ nitrone generation and its intramolecular cyclization to fused isoxazoles. Nevertheless the best achieved yield when the conditions of the reaction were many times varied was about 16% only.

References:

1) Padwa A.: 1,3-Dipolar Cycloaddition Chemistry, Wiley, New York, 1984, Vol.1 and Vol.2. 2) Loupy A., Hamelin J., Petit A., Texier-Bullet F., Jacquault P., Mathe D.: Synthesis 1998,1213. 3.Cheng Q., Zhang W., Tagami Y., Oritani T.: J. Chem. Soc., Perkin Trans. 1, 2001, 452. 4) P. N. Confalone, E. M. Huie, J. Am. Chem. Soc. 1984, 106, 7178. 5) C.J. Lovely a H. Mahmud: Tetrahedron Lett. 1999, 40, 2079. 6) H. Mahmud, C.J. Lovely, H.V. Rasika Dias: Tetrahedron 2001, 57, 4095. 7) M. Rosini, R. Budresi, M.G. Bixel, M.L. Bolognesi, A. Chiarini, F. Hucho, P. Krogsgaard-Larsen, I.R. Povl, A. Minardi, V. Tumiatti, P.N.R. Usherwood, C. Melichiorre: J. Med. Chem. 1999, 42, 5212. 8) J. Pospisil, M. Potacek: European Journal of Organic Chemistry, 2004, 3, 710.. 9) J. Pospisil, M. Potacek: Heterocycles, 2004, 63, 5, 1165.

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