A simple and expedient method for the preparation of N-chlorohydantoins

Abstract

A simple and efficient methodology for the preparation of N-chlorinated hydantoins is presented. These versatile chlorenium sources were isolated in high yield after a simple recrystallization. Among the ten examples are the first chiral N-chlorohydantoins.N-chlorinated hydantoins (e.g., 1) are important and versatile chlorinating agents that have found use in a range of synthetic operations. The prototypical example, 1,3-dichloro-5,5-dimethylhydantoin (DCDMH 3), has been employed as a chlorine source for the α-chlorination of acetophenones 1 and 1-aryl-2-pyrazolin-5-ones, 2 for the preparation of chlorohydrin derivatives of corticosteroids, 3 for the benzylic chlorination of 2-methylpyrazine, 4 and for the selective chlorination of a heavily functionalized quinolone derivative en route to the antibiotic In the latter case, DCDMH was found to be a milder, more selective reagent than sulfuryl chloride. Researchers at Schering Plough exploited the enhanced reactivity of DCDMH relative to NCS to improve upon the large-scale preparation of Davis' oxaziridine. 6,7 Moreover, DCDMH was employed to trap an enolate resulting from the attack of dimethylzinc onto an α,β-unsaturated ketone, thus generating an α-chloro-β-methyl ketone functionality en route to a building block of Amphotericin B. 8 DCDMH has been employed as an oxidant for a number of transformations including the halodeboronation of aryl boronic acids, 9 the oxidation of urazoles to provide triazolinediones, 10 the microwave-assisted cleavage of oximes, 11 the preparation of dialkyl chlorophosphates, 12 and as a terminal oxidant in the Sharpless asymmetric aminohydroxylation reaction. 13,14 The compound can also serve as a mild oxidant in the presence of wet silica gel in the sodium nitrite-mediated nitration of phenols 15 and in the preparation of N-nitrosoamines. 16 Furthermore, DCDMH has emerged as the reagent of choice for the activation, prior to loading, of silyl linkers for solid-phase organic synthesis. [17][18][19][20] Finally, DCDMH has been used as an oxidative activator of an iridium catalyst employed for the asymmetric hydrogenation of substituted quinolines. 21 Other uses of DCDMH include employment as redox titrants in nonaqueous media, 22 and as a cheap yet safe disinfectant and bactericide for municipal water sources. 23 N-chlorinated hydantoins have also received attention from the pharmacological community. The myriad of adverse side-effects associated with hydantoin-based drugs such as the anticonvulsant Dilantin and the aldose reductase inhibitor Sorbinil have been attributed to N-chloro metabolites generated in vivo via chlorination by myeloperoxidase and hydrogen peroxide. There are two classical methods for the preparation of N-chlorinated hydantoins. One approach involves passing chlorine gas through an aqueous alkaline solution of hydantoin. 27 The toxicity and reactivity of elemental chlorine make this approach somewhat undesirable. The second method involves treatment of the hydantoin with an aqueous sodium hypochlorite ...

An Organocatalytic Asymmetric Chlorolactonization

“…When the co-solvent and additive effects were combined, the desired lactone was produced in 89% ee (entry 11). This selectivity was maintained when the analogous DCDPH ( 4 )18 was applied as the terminal chlorine source (entry 12). We deferred to DCDPH, since it returned higher isolated yields during the course of scale-up experiments.…”

Acyclic and Cyclic Ureas (Update 2013)

“…[340] In addition, trichloroisocyanuric acid is a versatile chlorination agent for urea derivatives including hydantoins. [341,342] For example, treatment of various hydantoins with 2 equivalents of trichloroisocyanuric acid for 30 minutes at room temperature in acetonitrile affords the corresponding dichlorinated products 72 in yields of between 72 and 95% (Scheme 126). [342] The amount of trichloroisocyanuric acid can be reduced to as low as 0.7 equivalents without substantial reduction of yield.…”

“…[341,342] For example, treatment of various hydantoins with 2 equivalents of trichloroisocyanuric acid for 30 minutes at room temperature in acetonitrile affords the corresponding dichlorinated products 72 in yields of between 72 and 95% (Scheme 126). [342] The amount of trichloroisocyanuric acid can be reduced to as low as 0.7 equivalents without substantial reduction of yield. Chiral hydantoins can be chlorinated without loss of stereochemical integrity and hydantoins acetylated at one nitrogen atom furnish monochlorinated products under these conditions.…”

“…[343] Another application of trichloroisocyanuric acid is the chlorination of barbituric acid derivatives or glycolurils. [341] Scheme 126 Chlorination of Hydantoins with Trichloroisocyanuric Acid [342] N H It should be mentioned in this context that N-chlorinated urea derivatives such as chlorinated hydantoins [343] or 1,3-dichloro-1,3-bis(2,4,6-trichlorophenyl)urea [344] are themselves used as chlorinating agents in organic synthesis. In addition, N-chlorinated urea derivatives have been investigated with respect to their antimicrobial activity.…”

“…In addition, N-chlorinated urea derivatives have been investigated with respect to their antimicrobial activity. [340] 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (72,R 1 =R 2 =Me); Typical Procedure: [342] 5,5-Dimethylimidazolidine-2,4-dione (385 mg, 3 mmol) was suspended in MeCN (10 mL) in a 20-mL screw-top vial equipped with a magnetic stirrer bar. Trichloroisocyanuric acid (1.39 g, 6 mmol) was added in one portion and the resulting slurry was stirred for 30 min, during which time the mixture became clear.…”