Traceless Solid-Phase Synthesis of Bicyclic Dihydropyrimidones Using Multidirectional Cyclization Cleavage

Abstract

Solid-phase and solution-phase protocols for the synthesis of furo[3,4-d]pyrimidines, pyrrolo[3,4-d]pyrimidines, and pyrimido[4,5-d]pyridazines are reported. The multistep solid-phase sequence involves the initial high-speed, microwave-promoted acetoacetylation of hydroxymethylpolystyrene resin with methyl 4-chloroacetoacetate. The immobilized 4-chloroacetoacetate precursor was subsequently subjected to three-component Biginelli-type condensations employing urea and a variety of aromatic aldehydes. The resulting 6-chloromethyl-functionalized resin-bound dihydropyrimidones served as common chemical platforms for the generation of the desired heterobicyclic scaffolds using three different traceless cyclative cleavage strategies. The corresponding furo[3,4-d]pyrimidines were obtained by microwave flash heating in a rapid, thermally triggered, cyclative release. Treatment of the chloromethyl dihydropyrimidone intermediates with a variety of primary amines followed by high-temperature microwave heating furnished the anticipated pyrrolo[3,4-d]pyrimidine scaffolds via nucleophilic cyclative cleavage. In a similar way, reaction with monosubstituted hydrazines resulted in the formation of pyrimido[4,5-d]pyridazines. All compounds were obtained in moderate to good overall yields and purities.

Controlled Microwave Heating in Modern Organic Synthesis

“…[221] This approach required the synthesis of the 4-chloroacetoacetate resin as the key starting material, which was prepared by microwave-assisted acetoacetylation of hydroxymethyl polystyrene resin. In analogy to earlier work, [222] this transesterification was best carried out under open-vessel conditions in 1,2-dichlorobenzene (170 8C) to allow the formed methanol to be removed from the equilibrium (see also Scheme 20).…”

Dielectric heating effects on the activity and SO2 resistance of La0.8Ce0.2MnO3 perovskite for methane oxidation

“…As dielectric heating is a bulk technique, it is faster than heating based on conduction. Moreover, yet unexplained and surprisingly high catalytic reaction rates have been reported [10][11][12][13][14][15][16]. The present objective is to assess the feasibility of using a microwave sensitive catalytic material as a soot filter coating.…”

An efficient synthesis of 2,3,6,7-tetrasubstituted 4,6-dihydro-4-oxo-3H-pyrrolo[3,4-d]pyrimidin-7-carbonitrile derivatives

“…[4][5][6] There are many methods for the synthesis of fused pyrrolo [3,4-d]pyrimidine derivatives. One of the generally used approach is elaboration of a pyrrolo ring onto the prefabricated pyrimidine ring which bearing reactive functionalities at C-4 and C-5, [7][8][9] another popularly used method involved the formation of a pyrimidine ring onto the 3-aminopyrrole intermediate. [10][11][12][13][14][15] Although some pyrrolo [3,4-d]pyrimidine derivatives have been constructed, but the synthesis of 2,3,6,7-tetrasubstituted 4,6-dihydro-4-oxo-3H-pyrrolo [3,4-d]pyrimidin-7-carbonitrile derivatives is rarely described.…”