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Spiro-connected hexahydropyrimidine-2,4,6-trione heterocyclic rings have received increasing attention from the viewpoint of biological activity and synthetic methods due to the importance of the rigid heterocyclic system and unique orientation of the functional substituents. Since 1900, numerous studies have exploited the synthesis of various spirobarbiturate-fused carbo- and heterocycles by applying different strategies. Due to the importance of barbiturate-based olefins as activated alkenes, these substrates have been utilized in many reactions. In addition, the nucleophilic addition of 1,3-disubstituted barbituric acid to different electrophiles has been applied to prepare highly functionalized spirobarbiturate scaffolds. This short review highlights various strategies for synthesizing spirobarbiturate-fused 3- to 7-membered carbo- and heterocyclic rings and some catalytic diastereoselective and enantioselective chemical reactions to access chiral compounds. The sections are divided by the incorporation of 3- to 7-membered heterocyclic or carbocyclic rings into a spirobarbiturate scaffold, and are presented in different subsections depending on the mechanistic details.

A piperidine-catalyzed reaction between 3-formylchromone, 1,3-dimethyl barbituric acid, and ylidenemalononitriles is developed that offers chromonyl diene products in good yields. This cascade reaction proceeds

A novel iodine-mediated rearrangement of heterocyclic [3.3.3]propellanes under green conditions is described. This metal-free transformation for the straightforward synthesis of substituted 2-azaanthraquinones proceeds via ring opening/dissociation of C–O and C–N bonds/intramolecular C(sp3)–C(sp3) bond formation/ring expansion/aza-ring closure/1,3-N to N alkyl migration. High atom-efficiency, synthetically useful yields, easily accessible starting materials, and mild reaction conditions are advantages of this process.

A regioselective [3+2] cycloaddition (32CA) reaction to synthesize unsymmetric spiro-barbituric pyrazolines containing a chromone or phenolic pyrazole moiety was achieved, providing good to excellent yields. These rigid spiro-barbiturates exhibited good functional group tolerance, and they remained stable in the presence of an excessive amount of hydrazine. Spectral data and DFT calculations demonstrated the predominance of restricted rotation about a single C–C bond over annular tautomerism. The proposed one-pot sequential synthetic strategy allows for the efficient regio- and chemoselective preparation of new spiro-barbiturate scaffolds containing a locked phenolic pyrazole moiety, offering a much broader scope for obtaining stable drug functionalities under green conditions.

A piperidine-catalyzed reaction between 3- formylchromone, 1, 3-dimethyl barbituric acid, and ylidenemalononitriles is developed that offers chromonyl diene products in good yields. This cascade reaction proceeds via the insertion of ylidenemalononitriles between the Knoevenagel adduct obtained from 3-formylchromone and 1, 3- dimethylbarbituric acid, where the pyrimidine- based enaminone is integrated with the chromone through the central diene linker. Similarly, introducing pyrimidine-based enaminone into the terminal part of the chromonyl diene scaffold gave an equilibrium mixture of rotational isomers in DMSO, which could be separated and isolated by crystallization. The computational analysis confirmed the role of barbiturate in directing the type of final chromonyl diene via kinetic or thermodynamic control. Moreover, computations revealed that one of these species, observed in the NMR spectra, is produced by the bond cleavage in the spirocyclic intermediate.

An efficient one-pot synthesis of 2-[3-(2-amino-4-oxo-4Hchromen-3-yl)-1-arylallylidene]malononitriles as intermediates and 2-aryl-5H-chromeno[2,3-b]pyridin-5-ones as final products comprises Et3N-catalyzed condensation of alkylidenemalononitriles, 3-formylchromones and hydroxylamine hydrochloride. The transformation involves stages of 1,4-nucleophilic addition, phenolate–nitrile coupling and Mannich-type heterocyclization reactions.

An efficient, eco-friendly protocol has been described for the chemoselective synthesis of tetracyclic pyrido-fused dibenzodiazepines derivatives via catalyst-free, three-component reaction of dimedone, 1,2-diamines, 3-formylchromones, and malononitrile. The significant advantages of this cascade approach are to create two new rings and four new σ bonds containing three C–N and one C–C bond, as well as the breakdown of a C–O bond.

A highly regio- and chemo-selective heteroannulation protocol for the synthesis of unreported polysubstituted thiaazatricyclododecanes has been developed by a sequential four-component reaction of isoquinoline, 2-bromoacetophenones, aryl isothiocyanates, and methyl 4-chloro-3-oxobutanoate under mild conditions in CH 3 CN. To the best of our knowledge there are no previous reports for the synthesis of these classes of thiaazatricyclododecanes. The method features formation of various C N, C S, and C C bonds, low-cost and readily available substrates, as well as simple one-pot operation, which makes this process highly profitable. This synthesis serves as a nice addition to chemistry in which purification via chromatography and recrystallization can be avoided, and the pure products were obtained simply by washing the crude products with hexane–ethyl acetate (10:1).

A new protocol has been developed for the diastereoselective synthesis of 1,3-cyclohexadienes using vinyl malononitriles, dibenzalacetones and NaH as reagents in THF. This transformation is comprised of interesting steps like Michael addition, cyclization and ring-opening reactions.

A convenient approach for the synthesis of thiazolo[3,4-a]-benzimidazole derivatives has been developed. Three-component reaction of readily available o-phenylenediamines, aryl isothiocyanate, and 4-chloro-3-oxobutanoate in toluene–dichloromethane without any catalyst proceeds under reflux to afford the title compounds in high yields. The structure of the target molecule was confirmed by X-ray diffraction.

A convenient approach for the synthesis of thiazolo[3,4-a]-benzimidazole derivatives has been developed. Three-component reaction of readily available o-phenylenediamines, aryl isothiocyanate, and 4-chloro-3-oxobutanoate in toluene–dichloromethane without any catalyst proceeds under reflux to afford the title compounds in high yields. The structure of the target molecule was confirmed by X-ray diffraction.