Efficient Synthesis and Reactions of New Piperidinyl Tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolines and Related Heterocycles

Acetylation of 1-amino-5-(piperidin-1-yl)-N-phenyl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxamide (3) with acetic anhydride afforded unexpected [1,3]oxazinothienoisoquinolinone derivative in an excellent yield instead of the expected N-phenylpyrimidothienoisoquinolinone. Diazotization of 3 using sodium nitrite in acetic acid and sulfuric acid yielded the corresponding triazinothienoisoquinoline, while the reaction with triethyl orthoformate in acetic acid produced N-phenylpyrimidine derivative 7. Chloroacetylation of compound 3 with chloroacetyl chloride in dioxane at 60–70°C yielded chloroacetamido compound 8, which underwent ring closure upon reflux in acetic anhydride to produce the chloromethyl oxazinone derivative 9. Oxazinone derivatives 5 and 9 underwent nucleophilic substitution upon treatment with ammonium acetate/acetic acid mixture and hydrazine hydrate to afford pyrimidinone analogues 11–13. Methylpyrimidinone 11 was converted into chloropyrimidine derivative 14 by the action of phosphoryl chloride under reflux. Compound 14 underwent SNAr reaction with sodium azide and hydrazine hydrate to afford new heterocyclic systems, 5-methyl-11-(piperidin-1-yl)-7,8,9,10-tetrahydrotetrazolo[1″,5″:1′,6′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquino­line 15 and 8-hydrazinyl-10-methyl-5-(piperidin-1-yl)-1,2,3,4-tetrahydropyrimido[4′,5′:4,5]thieno[2,3-c]iso­quinoline 16, respectively. Hydrazinopyrimidine derivative 16 was used as a versatile key intermediate for the synthesis of other heterocycles with a pyrimidothienoisoquinoline moiety through reactions with various reagents. The structures of the new heterocyclic compounds were elucidated based on elemental analysis and spectral techniques.