Nucleophiles, reaction with hydantoins

Classical reactions involving nucleophiles such as saponification ("OH as the nucleophile), aminolysis (with amines also ammonia in ammonolysis reactions), transesterification (alkoxides, "OR) and others (hydrazinolysis, hydroxamic acid synthesis, etc.) have been adapted to solid phane and used to obtain, for instance, carboxylic acids, amides and esters. Internal or intramolecular nucleophilic attack has been employed to obtain cyclic products such as lactones, lactams (including cyclic peptides) and a great variety of heterocycles (hydantoins, diketopiperazines, benzodiazepinones, etc.). 

Hydantoins can react with electrophiles at both nitrogen atoms and at C-5. The electrophilic carbonyl groups can be attacked by nucleophiles, leading to hydrolysis of the ring or to partial or total reduction of the carbonyl system. Other reactions are possible, including photochemical cleavage of the ring. 

A novel reaction of pyroglutamate (6) and an isocyanate promoted by NaH in THF leads to functionalized hydantoins (7) in good yields. The reaction involves the ring closure of intermediate (8) by a nucleophilic attack on the carbonyl of the ester function followed by expulsion of an alkoxide anion resulting in the formation of the bicyclic intermediate (9). The alkoxide anion in turn can open this bicyclic intermediate with formation of anions (10) and (11) leading to the final racemic hydantoins (7) (Scheme 3).8... 

The hydantoin is deprotonated with the non-nucleophilic base LiHMDS. Thus, the nucleophilicity of the nitrogen is increased. It attacks the iodomethane in an SN-type reaction to give 1 in 94 % yield. 

Condensation of urea with carbonyl compounds A rapid and efficient MW-assisted synthesis of hydantoins and thiohydantoins was described by Muccioli et al. [117]. The most straightforward conditions for synthesis of phenytoin are the base-catalyzed condensation using benzil and urea, known as the Biltz synthesis (Eq. 33). MW activation of the Biltz synthesis of phenytoin improved both yield and reaction time. The first step consists in MW activation of the reaction of benzil with (thio)urea the second includes the conversion of the resulting 2-(thio)hydantoin to hydantoin using hydrogen peroxide. When reactions were performed at the same temperature under both reaction conditions, yields were by far better under the action of MW and emphasized the evident specific MW effects. These are perfectly expected when one considers the polar TS involved in the first step (nucleophilic addition of neutral NH2 group on carbonyl moiety). 

For example, Yu et al. showed that polystyrene-bound peptides could be hydrolyzed in 7 min in a domestic MW oven, a process normally taking 24 h. Furthermore, traditional soHd-phase peptide couplings were achieved in 4 min in 99-100% conversion with no detected racemization. A broad range of solid-phase reactions was found to undergo substantial rate acceleration, including Claisen and Knoeve-nagel condensations, nucleophilic substitutions, sucdnimide and hydantoin formation, and Suzuki coupHngs. 

Reactions.— The nucleophilic reactivity of the thiocarbonyl sulphur atom in thioureas has been further exemplified in a series of papers reporting on S-alkylation reactions of open-chain " as well as cyclic thioureas using alkyl halides. Ried and his co-workers have reported that (4-quinazolyl)thioureas (315) react smoothly with methylene iodide in the presence of triethylamine to yield the 1,3-thiazetidines (316). The ready formation of (316) was attributed to the special effect of the intramolecular hydrogen bonding in (315), as common thioureas usually did not enter into this reaction in a well-defined and profitable way. 5,5-Diphenyl-2-thio-hydantoin reacted with symmetrical ao>-dibromo-alkanes to yield the cyclization products (317). The action of excess of methyl iodide on N -substituted N-(o-aminophenyl)thioureas afforded the benzimidazoles (318), alternatively obtainable by treatment of the same thioureas with mercuric chloride." " In a similar manner, l-amino-6,7-dimethoxy-3,4-di-hydroisoquinolines were formed by the action of mercuric chloride on the thioureas (319)" or their S-methyl derivatives (320). " A recent paper by Klayman and his co-workers deals with the reactivity of S-methiodide derivatives of thioureas that are activated by electron-withdrawing groups towards hydroxylic compounds. "... 

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