Hydantoin acetate

Starting materials Pyro catechol, Pyruvate, Ammonia Vanillin, hydantoin, acetic anhydride, hydrogen... 

Similarly, hydantoins can be arylated at N-3. For example, treatment of 5,5-diphenyIhydantoin (4), R = R = Cg (phenytoin), with -tolyUead triacetate in the presence of sodium hydride and a catalytic amount of copper(II) acetate (37) gives compound (7). 

Hydantoin itself can be detected ia small concentrations ia the presence of other NH-containing compounds by paper chromatography followed by detection with a mercury acetate—diphenylcarba2one spray reagent. A variety of analytical reactions has been developed for 5,5-disubstituted hydantoias, due to their medicinal iaterest. These reactions are best exemplified by reference to the assays used for 5,5-diphenylhydantoiQ (73—78), most of which are based on their cycHc ureide stmcture. Identity tests iaclude the foUowiag (/) the Zwikker reaction, consisting of the formation of a colored complex on treatment with cobalt(II) salts ia the presence of an amine (2) formation of colored copper complexes and (3) precipitation on addition of silver(I) species, due to formation of iasoluble salts at N. ... 

The addition proceeds most smoothly with highly functionalized (more polar) steroids as seen in examples by Bernstein and others. The polar reaction conditions pose solubility problems for lipophilic androstane, cholestane and pregnane derivatives. Improved yields can be obtained in some cases by using dimethyl sulfoxide or t-butanol " as solvents and by using sodium A-bromobenzenesulfonamide or l,3-dibromo-5,5-dimethyl hydantoin (available from Arapahoe Chemicals) as a source of positive bromine. The addition of bromo acetate and bromo formate to steroid olefins has been studied to a limited extent. ... 

In at least one case, the standard Bucherer-Bergs conditions gave rise to oxazole rather hydantoin. Specifically, when 5-benzyloxy-pyridine-2-carbaldehyde (11) was treated with potassium cyanide, ammonium chloride, and ammonium carbonate in boiling ethanol/water, 5-amino-oxazol-2-ol 12 was obtained. Subsequent heating of oxazole 12 with acetic acid at reflux overnight then produced the Bucherer-Bergs product, hydantoin 13. ... 

Hydantoin, the cyclic form of hydantoic acid, was detected in the Murchison meteorite and also as a product of polymerisation of HCN (Ferris et al 1974). The yields obtained (based on cyanoacetaldehyde) were 18% for cytosine-N -acetic acid, but only 1.8% for the corresponding uracil derivative (1 mM cyanoacetaldehyde and 2 M hydantoic acid were allowed to react at around 373 K). 

Hydantoin (5.2 g, 52 mmol) was added to piperidine (9.9 mL, 100 mmol) in a twonecked reaction flask equipped with a magnetic stirrer bar and heated to 130 °C under nitrogen flux. 4-Fluorobenzaldehyde (5 mL, 47 mmol) was added dropwise to the stirring mixture. The reaction was monitored by TLC (eluent ethyl acetate/cyclohex-ane, 1 4) and reached completion in 30 min. 

Mesoionic oxazolium-5-oxides 49 react with aminomalonic ester to give pyrrolidinones 50 as the major or exclusive products <99H(50)71> and the oxazolamine 51 is converted by sodium acetate in acetic acid into the hydantoin 52 <99JHC283>. The intramolecular Diels-Alder cycloaddition of the oxazole 53 and related compounds has been used as a route to substituted isoquinolines <99JOC3595>. ... 

The unstable thiazolinones are converted into stable hydantoines in order to facilitate their identification. Conversion and identification are carried out outside the instrument after extraction of the thiazolinones with butylchlor-ide. The conversion reaction as well as the problems associated with identification of the PTH-amino acids were studied in detail by Edman and described explicitly in Needleman s book on Protein Sequence Determination Conversion is generally carried out in 1 N HCl at 80 °C within 10 min. The PTH-derivatives are extracted from the aqueous phase with ethyl acetate with the exception of PTH-arginine, PTH-histidine and PTH-cysteine which remain in the aqueous phase. 

Tertiary amines were amongst the first initiators of NCA polymerisation which had been described in the literature and it seems that the polymerisation of all the known NCA s may be accomplished by their action. Wessely (77) reported in 1925 that glycine and phenyl alanine NCA s are readily polymerised in pyridine at ambient temperatures, and in the following paper (72) he reported a similar polymerisation of sarcosine NCA. The polypeptides produced by this initiator apparently formed cyclic polymers since no terminal end groups could be detected 41). It is significant that appreciable quantities (a few %) ot 3-acetic-hydantoin derivatives were found in the polymers formed from glycine and phenyl alanine NCA s but none was detected in the polymerised sarcosine NCA (72). This evidence suggests that the mechanisms of polymerisation initiated by aprotic bases may be different for the non-N-substituted NCA and the N-substituded anhydrides. 

The LiCl initiated polymerisation is also inhibited by acid, and hence the formation of hydantoin-3-acetic add leads to auto-inhibition. 

Hydantoin-3-acetic acid or its derivatives are frequent byproducts of these reactions. They were not found, however, amongst products of reaction initiated by sodium methoxide (Blout, private communication). 

It was found (43) that dilution of the polymerising solution increases the yield of the hydantoin-3-acetic acid and this result, predicted by Bamford s mechanism, provides additional evidence in its favour. 

The Ugi-4CR between cyclic ketones, primary amine hydrochlorides, potassium thiocyanate (or selenocyanate), and 2,2-diethoxyethyl isocyanide [91] afforded the spiro 2-thio-(or seleno)hydantoin-4-imines 166. On heating in acetic acid, compounds 166 underwent carbonyl deprotection and cyclization to spiro imidazo[l,5-ajimidazoles 167 (Scheme 2.60). 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

A condensation occurs between 5-hydroxymethylfurfural and malonic ester20 and in a similar way, two molecules of malonic ester react with furan 2,5-dialdehyde.88 A condensation product, XXXV, has also been obtained with hydantoin.89 5-Hydroxymethylfurfural and its acetyl derivative undergo the Perkin reaction with sodium acetate and acetic anhydride giving 5-acetoxymethylfuran 2-acrylic acid (XXXVI).70 Similar products of the same reaction are obtained from 5-methyl-furfural71 and 5,5 -diformyl-l,l -furylmethyl ether (XXVII).61,72... 

A variety of aldehydes—aliphatic, aromatic, and heterocyclic—have been condensed with hydantoin. Sodium acetate in a mixture of acetic acid and acetic anhydride as well as pyridine containing traces of piperidine serves as condensing agent. Reduction of the double bond is accomplished with phosphorus and hydriodic acid, ammonium sulfide, or stannous chloride, In a more recent modification, the hydantoins are synthesized from aldehyde or ketone cyanohydrins and ammonium... 

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

N -lsopropyl-Ureido] -Acetic Acid Azide (5-Iso-propyl-hydantoin acid azide). (CH3)2CH.NH.CO.NH.CH2.CO.N3 mw 185.22 N 37.82% OB to CO2 -133.89% mp ca 100° (deflagrates quickly when heated). Prepn is by reacting [N-isopropyl-ureido] -acetic acid-hydra-zide with Na nitrite dissolved in aq HCl Ref Beil 4, 1169 ... 

More direct evidence for mechanism (20a) may be adduced from the observation that hydantoin 3-acetic acid (XIV) can be isolated from the reaction between glycine NCA and lithium chloride in AT.AT-dimethyl-formamide solution (eqn. (22)) [37, 39]. 

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