Extending the Scope of the New Variant of the Castagnoli-Cushman Cyclocondensation onto o-Methyl Benzoic Acids Bearing Various Electron-Withdrawing Groups in the α-Position.

Based on the previously reported involvement of homophthalic acid monoesters in the Castagnoli-Cushman reaction-type cyclocondensation with imines, we tested a number of other o-methyl benzoic acids bearing various electron-withdrawing groups in the α-position. The majority of these substrates delivered the expected tetrahydroisoquinolone adducts on activation with CDI or acetic anhydride. Homophthalic acid mononitriles displayed the highest promise as substrates for the new reaction, both in terms of scope and product yields. Homophthalic acid monoamides either gave low yields or failed to react with imines. Sulfonyl-substituted substrates gave the desired (and hitherto unknown) type of tetrahydroisoquinolines. Despite the low yields, this approach to sulfonyl-substituted tetrahydroisoquinolines appears practical as alternative syntheses based on the traditional, carboxylic acid CCR adducts would presumably be cumbersome and multistep. The azido- and nitro-substituted o-methyl benzoic acids failed to react with imines.

Unexpected formal [4 + 2]-cycloaddition of chalcone imines and homophthalic anhydrides: preparation of dihydropyridin-2(1H)-ones.

A series of medicinally important dihydropyridin-2(1H)-ones have been prepared via a novel [4 + 2]-formal cycloaddition reaction of chalcone imines and homophthalic anhydrides, which is a rare example of lactam construction from an imine acting as a four-atom building block. In contrast to previous studies on the reactivity of homophthalic anhydrides towards similar substrates, N-tosyl chalcone imines, we found the possibility of switching chemoselectivity by changing substituents at the nitrogen atom, which leads to the formation of heterocycles instead of the expected carbocycles. This reaction is very similar in appearance to the classic 1,2-addition of cyclic anhydrides to imines, often referred to as the Castagnoli-Cushman reaction, but differs in mechanistic details (representing a 1,4-reaction of imine). The developed atom-economical, stereoselective and catalyst- and chromatography-free protocol provided facile access to 28 structurally diverse heterocyclic products (in up to 88% yield) including synthetically challenging annelated tricyclic and previously unreported pentaaryl-substituted dihydropyridin-2(1H)-ones.

Further Insight into the Castagnoli-Cushman-type Synthesis of 1,4,6-Trisubstituted 1,6-Dihydropyridin-2-(3H)-ones from 3-Arylglutaconic Acid Anhydrides.

The earlier reported three-component Castagnoli-Cushman-type synthesis of 1,4,6-trisubstituted 1,6-dihydropyridin-2-(3H)-ones from 3-arylglutaconic acids, primary amines, and aromatic aldehydes has been further investigated. It was shown to proceed via 3-arylglutaconic anhydrides, which, in turn, were found to give superior results in the two-component reactions with imines. The initial formation of the Castagnoli-Cushman carboxylic acids was shown to be the case, and their decarboxylation was found to follow a complex, "forked" pathway, which was confirmed by deuterium incorporation experiments.

Rh(II)-Catalyzed Spirocyclization of α-Diazo Homophthalimides with Cyclic Ethers.

Rh(II)-catalyzed decomposition of α-diazo homophthalimides in the presence of cyclic ethers gave spirocyclic products of Stevens-type [1,2]-alkyl shift within the postulated oxonium ylide intermediate. Such a reaction pathway is in line with thermodynamic predictions obtained from quantum chemical calculations performed at the B3LYP/6-31G* and B3LYP/6-311++G** levels of theory. These findings represent the first systematically investigated case of spirocyclization of cyclic α-diazocarbonyl compounds with cyclic ethers.

Concise approach toward tetrazolo[1,5-a][1,4]benzodiazepines via a novel multicomponent isocyanide-based condensation.

A novel and efficient method for the synthesis of heteroannulated [1,4]benzodiazepines via an isocyanide-based multicomponent reaction is reported. The tetrazolo[1,5-a][1,4]benzodiazepines were obtained by a facile azide Ugi five-center four-component reaction (U-5C-4CR) using ketones, sodium azide, ammonium chloride, and corresponding isocyanide. The aforementioned tetrazolodiazepines represent a notable class of compounds with proven platelet aggregation inhibitory and cholecystokinin agonist activities.