Synthesis of Furo[3,4-d]pyrimidine Derivatives Using Ethyl 4-Bromoacetoacetate

Abstract

A b s t r a c t -Reaction of ethyl 4-bromoacetoacetate (1)' with benzaldehyde (a) and urea in the presence of hydrochloric acid gave 6-bromomethyl-5-ethoxycarbonyl-4-phenyl-3,4-dihydro- 2(1H)-pyrimidinoneSimilarly, reaction of 1 and urea with p-anisaldehyde ( G ) , p-hydroxybenzaldehyde (g) , and furfural (=) afforded the corresponding 6-hromomethyl-3,4-dihydro-Z(1H)-pyrimldinones *As.Thermolysis of compounds &-g gave rise to the corresponding 4,7-dihydrofuro[3,4-d]pyrimidine-2,5(1H,3H)-diories 3-9.The ~eist-B6naryl reaction of ethyl 4-bromoacetoacetate (1) with chloroacetaldehyde was reported to give 2-bromomethylfuran derivative.'On the other hand, we have reported the reaction of 1 with diketene to give ethyl u-bromoorsellinate. 3In these reactions, the ketocarbonyl and active methylene groups of 1 take part in the ring formation.Since there are few references concerning such a ring formation using 1 , we have investigated the ~i ~i n e l l i ~ reaction of 1 in a Continuation of our study on the synthesis of heterocyclic compounds using haloacetoacetic acid derivative^.^-^When a solution of ethyl 4-bromoacetoacetate ( L ) , benzaldehyde (a), and urea in ethanol in the presence of hydrochloric acid was warmed at 40°C for 24 h, 6-bromomethyl-5-ethoxycarbonyl-4-phenyl-3,4-dihydro-2(lH)-pyrimidinone (&la was obtained in 62% yield.The structure assignment was established by spectroscopic data.Infrared (ir) spectrum of & indicated the presence of a,@-unsaturated ester carbonyl and ureido carbonyl absorption at 1690 and 1640 cm-l, respectively.Nuclear magnetic resonance (nmr) spectrum of g showed the signals due to methylene protons, the C -methine Proton, and two ureido protons.4 Similarly, the Biginelli reaction using 1 and aromatic aldehydes such as panisaldehyde (s), p-hydroxybenzaldehyde ( & ) , and furfural (a) under the same condition afforded the corresponding 6-bromomethyl-3,4-dihydro-Z(1H)-pyrimi- dinones z-g in 43-57% yields.0 0 H Cl BrdO~t + RCHO + NHzCONH2 Chart 1 Heatlng of compound at 210-23O0C gave 4-phenyl-4,7-dihydrofuro[3,4-d]pyrlmi- dine-2,5(1H,3H)-dione in 76% yield.Similarly, thermolysis of =-a gave rise to the corresponding 4,7-dihydrofuro-i3,4-dlpyrirnidine-2,5(lH,3H)-diones +-g in 51-80% yields.These results are also consistent with the indicated structure of %-a.The melting points and ir spectra for g -3 and g-F are listed in Table I.HETEROCYCLES, Vol 22, No 3,