Convenient synthesis of 1,2,3,4‐tetrahydro‐pyrimidin‐5‐ylbenzoxazoles

Abstract

2‐Pyrimidin‐5‐ylbenzoxazoles 7 have been synthesized by condensation of 5‐pyrimidinecarboxaldehyde 4 with substituted aminophenols 5 followed by oxidative cyclization of the resulting Schiff's bases 6 with iodobenzene diacetate. Subsequent formation of methylpyrimidinium salts 8 and reduction thereafter afforded tetrahydropyrimidinylbenzoxazoles 10. This method has been utilized in the synthesis of M1 muscarinic agonist candidates.

Synthesis and Muscarinic Activity of 1,2,3,4-Tetrahydropyrimidine Derivatives

“…Although several products were expected in the hydride reduction of 5-substituted pyrimidines, NaBH 4 reduction of 3a-3g in MeOH yielded the 1,2,3,4-tetrahydropyrimidine derivatives as the sole products, after purification by column chromatography. The structure of reductive compounds, 1,2,3,4-tetrahydropyrimidine derivatives, can be deduced from X-ray crystallography [10] . They are structural congeners of milameline, and were further converted into the oxalate salts 4a-4g to improve the stability and purity of the compounds ( 1 H NMR data and 13 C NMR data are summarized in Table 1).…”

“…The E-isomers were separated by column chromatography, then reacted with alkyl halides. Subsequent quarternization to 8a-8g and reduction under similar conditions for the aldimines afforded the only isolable products, 1,2,3,4-tetrahydropyrimidine derivatives [10] , which were treated with oxalic acid to give the final oxalate salts 9a-9g ( Table 2). As can be seen in the Experimental Section, the methyl protons of ketoximes are observed in the range of 1.85-1.90 ppm in DMSO-d 6 .…”

Synthesis of 1,2,5,6‐/1,2,3,6‐tetrahydropyridinyl‐tetrahydro‐cyclopentaisoxazole derivatives

“…Chemically, they possess a 1,2,5,6-tetrahydropyridine ring while the unstable ester moiety of arecoline has been replaced with its bioisosteres alkoxythiadiazole and alkoxyimino groups, respectively. The structure of xanomeline (II) shows a resemblance to that of tetrahydropyridinylbenzoxazoles (IV) [6] and tetrahydropyrimidinylbenzoxazoles (V) [7] previously prepared in our laboratory (Figure 2). Compounds IV and V, which possess a benzoxazole ring, exhibited interesting biological activity as potential agrochemicals as well as clinical drugs.…”