Substituted hydantoin derivatives

H-nmr chemical shifts of N-1—H and N-3—H signals have been used as a criterion for distinguishing between N-l-substituted and N-3-substituted hydantoin derivatives (22). They can often be related to electronic properties, and thus good linear correlations have been found between the shifts of N—H and Hammett parameters of the substituents attached to the aryl group of 5-arylmethylenehydantoins (23). 

Substituted hydantoin derivatives have been used as precursors for d- and L-amino acids in chemical synthesis. However, they are hydrolyzed enantioselectively by the enzymes named hydantoinases some act specifically on D-5-substituted hydantoins, and others on the L-isomers. N-Carbamoyl amino acids formed are also hydrolyzed enantiospecifically by N-carbamoyl amino acid amidohydrolases to produce d- or l-amino acids (Fig. 17-15). Since the Kanegafuchi Chemical Industry, Japan, commercialized an enzymatic procedure for the production of D-p-hydroxyphenylglycine, which is a building block for the semisynthetic P-lactam antibiotic amoxycillin, various processes for amino acid production by means of hydantoinases have been developed 131 133. ... 

In a German patent issued in 1929, Bergs described a synthesis of some 5-substituted hydantoins by treatment of aldehydes or ketones (1) with potassium cyanide, ammonium carbonate, and carbon dioxide under several atmospheres of pressure at 80°C. In 1934, Bucherer et al. isolated a hydantoin derivative as a by-product in their preparation of cyanohydrin from cyclohexanone. They subsequently discovered that hydantoins could also be formed from the reaction of cyanohydrins (e.g. 3) and ammonium carbonate at room temperature or 60-70°C either in water or in benzene. The use of carbon dioxide under pressure was not necessary for the reaction to take place. Bucherer and Lieb later found that the reaction proceeded in 50% aqueous ethanol in excellent yields for ketones and good yields for aldehydes. ... 

Kim80 reported recently a convenient synthesis of hydantoin derivatives (41) by PTC-catalyzed nucleophilic substitution, followed by cyclization. 

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. 

Urea, methylurea, and dimethylureas react with glyoxylic acid and its methyl ester to give a-substituted hydantoic acid derivatives (16) and substituted allantoic acid derivatives (17), which can be cyclized to 5-substituted hydantoins (18). Although allantoin (18) formation from urea and... 

Hydantoins are weak acids which owe their acidic character to dissociation of the proton bonded to the 3-nitrogen atom since this allows for maximum delocalization of charge in anion 82.1 For unsaturated hydantoin derivatives, such as 5-arylidene- or 5-ethoxycarbonylmethylidenehydantoins, IR, UV, and NMR data show that the W-3-substituted derivatives lose the proton from the 1-nitrogen atom in alkaline solution, forming an anion which can delocalize through the 5-substituent.141,142... 

The other major class of cyclic amino acid derivative used in dynamic resolution reactions is the hydantoin group. Like oxazolinones, hydantoins readily undergo racemisation under mild conditions. Systems involving a two step procedure using D-hydantoinase and a carbamoylase were reported to provide a route to D-amino acids[S2, 53). Dynamic resolution of a p-hydroxyphenyl substituted hydantoin was reported in 1987[541. Using the intact cells of Pseudomonas sp. AJ-11220, the amino acid was prepared in over 90% yield, as shown in Fig. 9-24. This hydrolytic procedure leads directly to the amino acid, and the same enantiomer of product, the D-amino acid, was obtained independently of the stereochemistry of the substrate. 

Olefination reactions of the phosphonates (254) and (255) derived from hydantoin and 1-methylhydantoin, respectively, provide good yields of the expected C-5 unsaturated hydantoin derivatives (256), generally as mixtures of isomers. 52 Heterocyclic analogues, e.g. (257), of pulvinones and, e.g. (258), of permethylated pulvinic acids have been synthesized by Wadsworth-Emmons reactions of the phosphonates (259) and (260), themselves prepared directly from substituted maleic anhydrides. 55 The reaction of ylide (261) with aldehydes to give (262) has been used as a key... 

Beller s group described a pioneering palladium-catalyzed one-pot synthesis of 5-substituted hydantoins 27, 3,5-substi-tuted hydantoins 28, and 1,3,5-substituted hydantoins 30 based on the carbonylation of aldehydes in the presence of urea derivatives as an interesting alternative to Bucherer-Bergs reactions (Scheme 10.6) [29]. 

M. BeUer, M. Eckert, W. A. Moradi, H. Nemnaim, Angew. Chem. Int. Ed 1999, 38, 1454—1457. Palladium-catalyzed synthesis of substituted hydantoins—a new carbonylation reaction for the synthesis of amino acid derivatives. 

Moreover, in the past 10 years, a number of works involving a nucleophilic attack of a nitrogen nucleophile over an acylpalladium intermediate, generated in situ from simple and easily prepared starting compounds, has been reported to be dealing with the synthesis of heterocyclic compounds, that is, 2,3,4,5-tetrahydro-lH-2,4-benzodi-azepine-l,3-dione derivatives 30 [39], tetrahydro-P-carboline/tetrahydriisoquinoline fused 5-lactam derivatives 31 and 32, respectively [40], and substituted hydantoins 33 [41] (Scheme 13.14). 

The key structural feature of BIRT-377 (1) is the A-aryl-substituted-hydantoin bearing a quaternary stereogenic center. In our retrosynthetic analysis, the hydantoin ring can be synthesized by cyclization of the corresponding acyclic a-substituted amino acid amide (9), which could be derived from (Z>) or (L)-alanine. 

HF, they can be removed by hydrogenolysis. " A method for the masking of terminal amino-groups during peptide synthesis is to convert the C-terminally protected peptide [e.g. (202)] into the corresponding hydantoin derivative (203) using N,AT -carbonyldi-imidazole the reaction occurs without racemization. " A report has appeared on the use of various substituted phenylsulphenyl groups for N -protection of a-amino-acids. ... 

The imide proton N-3—H is more acidic than N-1—H and hence this position is more reactive toward electrophiles in a basic medium. Thus hydantoins can be selectively monoalkylated at N-3 by treatment with alkyl haUdes in the presence of alkoxides (2,4). The mono-A/-substituted derivatives (5) can be alkylated at N-1 under harsher conditions, involving the use of sodium hydride in dimethylform amide (35) to yield derivatives (6). Preparation of N-1 monoalkylated derivatives requires previous protection of the imide nitrogen as an aminomethyl derivative (36). Hydantoins with an increased acidity at N-1—H, such as 5-arylmethylene derivatives, can be easily monoalkylated at N-3, but dialkylation is also possible under mild conditions. 

The soluble polymer support was dissolved in dichloromethane and treated with 3 equivalents of chloroacetyl chloride for 10 min under microwave irradiation. The subsequent nucleophilic substitution utilizing 4 equivalents of various primary amines was carried out in N,N-dimethylformamide as solvent. The resulting PEG-bound amines were reacted with 3 equivalents of aryl or alkyl isothiocyanates in dichloromethane to furnish the polymer-bound urea derivatives after 5 min of micro-wave irradiation (Scheme 7.75). After each step, the intermediates were purified by simple precipitation with diethyl ether and filtration, so as to remove by-products and unreacted substrates. Finally, traceless release of the desired compounds by cyclative cleavage was achieved under mild basic conditions within 5 min of micro-wave irradiation. The 1,3-disubstituted hydantoins were obtained in varying yields but high purity. 

Condensation of formyl-pyrroles and -indoles with a wide range of other activated methylene compounds has been reported. These include, for example, hydantoin, which provides a useful synthetic route to tryptophane and j8- (pyrrolyl)alanines, thiohydantoin, rhodanine and AT-substituted barbituric acids (B-77MI30505, 79HC(25-3)357). Flash pyrolysis of the condensation product derived from 3-formyl-2,5-dimethylpyrrole with Meldrum s acid produces 6-hydroxy-2-methylindole, (440) — (441) (74AJC2605), whilst the analogous... 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

Reaction between diethyl piperidyl-1,2-carboxylate and hydrazine gives amino derivative 115 (71AP216), and the synthesis of other N-substituted derivatives with pesticidal properties is illustrated by the preparation of 118. The hydantoin (116) is treated with formaldehyde followed by hydrogen bromide to give 117, which reacts with 5-ammonium-0,0-dimethylphosphorothioate to give 118 (7IBRP1337269). 

A conceptual alternative way to the activation of the carboxylic acid function is the reaction of carboxylic acids with amino groups activated as isocyanates - and isothiocyanates (equation 16). Preparation of these derivatives is racemization free. The reaction proceeds via mixed acid anhydrides in aromatic hydrocarbon solvents at elevated temperatures, and decarboxylation leads to the V-substituted amide. Pyridine as solvent enhances the conversion rate but increases also the amount of the urea side product via disproportionation. Application to peptide chemistry is limited, because peptide ester fragments tend to form hydantoins. ... 

The ring contraction of barbiturates is observed in the course of hydrolytic degradation (Section III,D). N-Substituted barbiturates 151 (R1 = R2 = alkyl, R3 = H) yield the 5-substituted oxazolidine-2,4-dione 152, and N,N-unsymmetrically substituted barbiturates yield a mixture of both 152 and 153. 5-Bromobarbituric acid and its derivatives give a mixture of iminooxazolidin-4-one and hydantoin.409... 

---