Electrocatalysis in MIRC reaction strategy: facile stereoselective approach to medicinally relevant spirocyclopropylbarbiturates from barbituric acids and activated olefins

Abstract

The combined electrolysis of barbituric acids and benzylidenemalononitriles or benzylidenecyanoacetates in methanol in an undivided cell in the presence of sodium bromide results in efficient MIRC (Michael-initiated ring-closure) formation of the corresponding spirocyclopropylbarbiturates in 45-93% yield. The electrocatalytic reaction proceeds smoothly under neutral and mild conditions with benzylidenemalononitriles or benzylidenecyanoacetates bearing both electron-donating and electron-withdrawing groups. NMR and single X-ray diffraction studies indicate that the electrocatalytic MIRC transformation of barbituric acids and benzylidenecyanoacetates results in the stereoselective formation of spirocyclopropanes with an (E)-configuration of aryl and alkoxycarboxylate substituents. The implication of electrocatalysis in the MIRC reaction strategy allows the combination of the synthetic virtues of both methods and accounts for an efficient approach to medicinally relevant spirocyclopropylbarbiturates avoiding inconvenient direct use of molecular halogen or halogenated substrates in accordance with the concepts of modern green chemistry.

Bactericidal evaluation of N-halamine-functionalized silica nanoparticles based on barbituric acid

“…To improve the antibacterial activity, developing the N-halamine precursor with more imide groups in structure is axiomatic. Barbituric acid derivatives, well known as their pharmaceutical and biological effect, are promising heterocyclic compounds with two imide functional groups in the structure [20][21][22]. Prepared by halogenating imide group, barbituric acid derivative-based N-halamines can be the potential candidate with excellent antibacterial properties.…”

Facile and efficient approach for the synthesis of spirocyclopropylbarbiturates and 3-substituted-1,1,2,2-tetracyanocyclopropanes using N-halosulfonamides

“…Based on these results, a plausible reaction pathway for the cyclopropanation 2-arylidenemalononitriles 1 with barbituric acids 2 using N -halosulfonamides is shown in Scheme 3. First, deprotonation of barbituric acid 2 with the use of an acetate anion in aqueous ethanol gives the bar- of carbanion E to carbon atom containing bromine atom as an electrophile produces spirocyclopropylbarbiturates 3 [14,33].…”

“…Several methods have been developed for the synthesis of spirodicyanocyclopropyl barbiturates involving the reaction of electron-deficient alkenes with dibromomethylene compounds activated by cyano and ester groups in the presence of LiI or tetrabutylammonium bromide in DMF [12], the reaction of benzylidenemalononitriles with N, N -dialkylbarbituric acids in the presence of bromine and sodium ethoxide in ethanol [13], the combined electrolysis of benzylidenemalononitriles or benzylidenecyanoacetates and barbituric acids in methanol in the presence of sodium bromide [14], and the electrolysis of aldehydes, malononitrile, and barbituric acids in alcohol in the presence of sodium bromide [15].…”

Electrocatalytic and chemical methods in MHIRC reactions: the first example of the multicomponent assembly of medicinally relevant spirocyclopropylbarbiturates from three different molecules

“…The application of electrocatalysis in the MHIRC reaction strategy allowed the combination of the synthetic virtues of both methods and accounted for an efficient approach to medicinally relevant spirocyclopropylbarbiturates avoiding inconvenient direct use of molecular halogen or halogenated substrates in accordance with concepts of green chemistry. 23 Thus, on the next step of our research we used electrocatalytic methodology to realize multicomponent transformation of benzaldehydes 7, malononitrile and barbituric acids 2 into spirocyclopropylbarbiturates 3 (Scheme 5, Table 4). …”