Hydantoins alkylation

Gas chromatography has been applied to the determination of a wide range of organic compounds in trade effluents including the following types of compounds which are reviewed in Table 15.15 aromatic hydrocarbons, carboxylic acids aldehydes, non ionic surfactants (alkyl ethoxylated type) phenols monosaccharides chlorinated aliphatics and haloforms polychlorobiphenyls chlorlignosulphonates aliphatic and aromatic amines benzidine chloroanilines chloronitroanilines nitrocompounds nitrosamines dimethylformamide diethanolamine nitriloacetic acid pyridine pyridazinones substituted pyrrolidones alkyl hydantoins alkyl sulphides dialkyl suphides dithiocaibamate insecticides triazine herbicides and miscellaneous organic compounds. 

Mass spectral fragmentation patterns of alkyl and phenyl hydantoins have been investigated by means of labeling techniques (28—30), and similar studies have also been carried out for thiohydantoins (31,32). In all cases, breakdown of the hydantoin ring occurs by a-ftssion at C-4 with concomitant loss of carbon monoxide and an isocyanate molecule. In the case of aryl derivatives, the ease of formation of Ar—NCO is related to the electronic properties of the aryl ring substituents (33). Mass spectrometry has been used for identification of the phenylthiohydantoin derivatives formed from amino acids during peptide sequence determination by the Edman method (34). 

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. 

Similar alkylations may be effected on oxygen. l-(2-Chloroethyl)imidazolidin-2-one (312) when treated with potassium hydroxide or sodium hydride underwent ring closure to the tetrahydroimidazo[2,l-6]oxazole (313) (57JA5276). This approach can be used for the preparation of bicyclic hydantoins and the corresponding dihydro derivatives of (313) using the mesylate of (312) and NaH (77JHC5U, 79JMC1030). 

The study of the iV-alkyl derivatives of allantoxaidine was taken up by Biltz who proceeded from its formerly accepted hydantoin structure and obtained its monomethyB and dimethyB derivatives. 

One of the earliest preparations of this ring system starts with displacement of the hydroxyl of benzaldehyde cyanohydrin (125) by urea. Treatment of the product (126) with hydrochloric acid leads to addition of the remaining urea nitrogen to the nitrile. There is thus obtained, after hydrolysis of the imine (127), the hydantoin (128). Alkylation by means of ethyl iodide affords ethotoin (129)... 

Hydantoin 9 has also been used as a heterocyclic starting material for glyphosate via interme ate 10 (14). Similarly, the phosphonomethylation of 3-V-alkyl hydantoins produced the corresponding unsymmetrically substituted cyclic analogs (14). 

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

A series of 29 3-alkyl 5-arylimidazolidinones, or hydantoins, active at the CBi receptor has been published by Kanyonyo et al. [344] with a subsequent publication describing the relationship between the experimentally derived lipophilicity and proposed modes of binding for non-polar and polar hydantoins derivatives [345] (Table 6.49). 

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. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

Alkylation of the hydantoin (89-2) from benzaldehyde with ethyl iodide takes place at the imide nitrogen to afford ethitoin (89-3) [93]. In much the same vein, treatment of the hydantoin (89-5) from propiophenone with methyl iodide (89-5) in the presence of a base affords mephenytoin (89-6) [94]. Replacement of the quite acidic imide proton by an aUcyl group is not required for activity the well-known anticonvulsant phenytoin (89-8) consists of simply the hydantoin obtained from benzophenone (89-7) [95] this is often formulated as its sodium salt. 

Phenytoin is a diphenyl-substituted hydantoin with the structure shown. It has much lower sedative properties than compounds with alkyl substituents at the 5 position. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use this phosphate ester compound is rapidly converted to phenytoin in the plasma. 

A further method for preparing hydantoins is the N-alkylation of other hydantoins with reactive alkyl halides in the presence of strong bases [154]. Hydantoinimines have been synthesized from polystyrene-bound isonitriles by an Ugi-type multicomponent condensation (Entry 15, Table 15.13). 

The oxidation of phenylhydrazine and 1,2-disubstituted hydrazines to hydrazones and diazenes by CI2C proceeds via formation of unstable azomethine imines.95 The conversion of alcohols into alkyl halides is achieved by reaction with CCI4 (or CBr4) in DMF under electrochemical reduction.96 The reaction of dihalocarbene X2C with DMF to form a Vilsmaier reagent (93) is proposed as the key process. The reaction of simple isocyanates (RNCO) with dimethoxycarbene normally gives hydantoin-type products. In the reaction with vinyhsocyanates such as (94), however, hydroindoles (95) are formed in good yields.97... 

To increase the number of diversities, the hydantoin (or thiohydantoin) formation reaction was performed starting from N-alkylated dipeptides (Fig. 3). In the last synthesis step, the hydantoin (or thiohydantoin) ring was alkylated followed by the cleavage from the resin. Using 54 different amino acids for the first position of diversity (R1), 60 different amino acids for the second position of diversity (R2), and four different alkylating... 

Topaquinone (TPQ), the oxidized form of 2,4,5-trihydroxyphenylalanine (TOPA), is the cofactor of copper-containing amine oxidases. The following model compounds have been prepared in order to understand the catalytic function of TPQ the jV-pivaloyl derivative of 6-hydroxydopamine in aqueous acetonitrile [38] topaquinone hydantoin and a series of 2-hydroxy-5-alkyl-l,4-benzoquinones in anhydrous acetonitrile (o- as well as />-quinones) [39] 2-hydroxy-5-methy 1-1,4-benzoquinone in aqueous system [40] and 2,5-dihydroxy-1,4-benzoquinone [41]. Reaction of model compounds with 3-pyrrolines revealed why copper-quinopro-tein amine oxidases cannot oxidize a secondary N [42], The studies clearly showed that certain model compounds do not require the presence of Cu for benzylamine oxidation whereas TPQ does [38,40] the aminotransferase mechanism proceeds via the -quinone form [39] the 470 nm band can be ascribed to a 71-71 transition of TPQ in />-quinonic form with the C-4 hydroxyl ionized but hydrogen bonded to some residue [40] hydrazines attack at the C-5 carbonyl, forming an adduct in the azo form [41], Electrochemical characterization has been carried out for free TPQ [43],... 

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