Parallel screening of suitable reaction conditions for Cu(I)-catalyzed [3+2] cycloadditions of (1Z,4R*,5R*)-4-benzoylamino-1-benzylidene-5-phenyl-3-oxopyrazolidin-1-ium-2-ide (1a) to methyl propiolate (2) has established that this reaction proceeds smoothly at room temperature in acetonitrile in the presence of CuI and Hünig's base. The optimized reaction conditions were then applied in regio-and stereo-selective 1,3-dipolar cycloadditions of racemic azomethine imines 1a-e to tert-butyl (S)-(3-oxopent-4-yn-2-yl)carbamate (6) leading to mixtures of diastereomeric non-racemic chromatographically separable cycloadducts 7a-d, 7 a-d, 8e, and 8 e. The structures of the products were confirmed by NMR spectroscopy.
Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ-hexahydropyrazolo[1,5-a]pyridin-8-ium-1-ide, were prepared in seven steps from the respective commercially available δ-keto acids. The addition of Grignard reagents followed by N-alkylation at position 1 afforded the 1,7,7-trisubstituted hexahydropyrazolo[1,5-a]pyridin-2(1H)-ones, whereas 1,3-dipolar cycloadditions of these dipoles to typical acetylenic and olefinic dipolarophiles gave 4a-substituted 2a,2a-diazacyclopenta[cd]indene derivatives as the first representatives of a novel heterocyclic system. Regio- and stereoselectivity as well as the mechanism of these [3 + 2]-cycloadditions were evaluated using computational and experimental methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism via the energetically favorable syn/endo-transition states.
A novel simple five-step synthesis of 1,6-disubstituted tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones has been developed. The synthetic protocol starts with 'ring switching' transformation of commercially available 5,6-dihydro-2H-pyran-2-one into the 5-(2-hydroxyethyl)pyrazolidin-3-one, followed by addition of the latter to isocyanates, Appel bromination, cyclization, and N(1)-alkylation with alkyl halides to give the title compounds. In comparison to a 12-step synthesis reported recently, the present method is clearly superior with respect to the number of synthetic steps and versatility of substituents at position 6.
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