Diastereoselective Synthesis of Dispirobarbiturates through Et₃N-Catalyzed [3 + 2] Cycloaddition of Barbiturate-Based Olefins with 3-Isothiocyanato Oxindoles

Abstract

Under catalysis of 10 mol % of Et3N, the [3 + 2] cycloaddition of barbiturate-based olefins with 3-isothiocyanato oxindoles underwent smoothly and afforded the desired dispirobarbiturates in up to 99% yield with up to 99:1 dr. The relative configuration of the dispirobarbiturates was unambiguously determined by X-ray single-crystal structure analysis. The reaction mechanism was proposed to shed light on the diastereoselective formation of the dispirobarbiturates.

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents

“…Table S1). The majority of 5-substituted BAD and TBAD families described herein are known precursors of fused heterocycles reported in the literature [10,12,13,15,[17][18][19][20][21][22][23][24].…”

“…and C5, the latter being the most studied position. Within these structural modifications, various cyclization reactions at C5 and C6 of BA, thiobarbituric acid (TBA) and their derivatives (BADs and TBADs, respectively) [10][11][12][13][14][15][16][17][18][19] as well as at C5 with spiro formation [20][21][22][23][24] have been described. Interestingly, some of these transformations involve a multicomponent reaction (MCR) [11,14,16].…”

“…Interestingly, some of these transformations involve a multicomponent reaction (MCR) [11,14,16]. However, in most cases, the cyclization path is preceded by the formation of substituted methyl [10,18], arylidene [12,15,[19][20][21][22][23][24], or methylene [13,17,19] derivatives at C5 as key isolated or potential precursors of these modified pyrimidines.…”

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

“…This impels the quest to develop a series of synthons or new methodologies to construct the spirobarbiturates with diverse structures. In recent years, good progress has been achieved in the construction of racemates of spirobarbiturates and the enantioselective synthesis [24][25][26][27][28][29], but only limited progress has been made in the construction of bispirobarbiturates [30,31]. In 2019, for example, An and co-workers reported an asymmetric Michael/Mannich [3 + 2] cycloaddition reaction between N-(2,2,2-trifluoroethyl)isatin ketimines and barbiturate-based olefins (Scheme 1a) [32].…”

Enantioselective Catalytic Transformations of Barbituric Acid Derivatives

“…Reagents in (3+2) cycloaddition with alkylidene barbiturate.406For more than ten years, isothiocyanates have been engaged in catalytic reactions as 407 isothiocyanato amides, esters or phosphonates. In 2015, Liu's group published on a racemic (3+2) 408 cycloaddition between alkylidene barbiturates 8 and 3-isothiocyanato oxindoles 62 catalyzed by 409 triethylamine (Scheme 16)[38]. In 2016, the same authors reported on an enantioselective version 410 catalyzed by a Cinchona-based thiourea 64 leading to spirobarbiturates 63 in modest to excellent ees 411 and 20:1 dr in most cases (Scheme 16)[39].…”