Hydantoins reactions

A traceless perfluoroalkylsulfonyl linker for the deoxygenation of phenols has been reported by Holmes. A more lightly fluorous variant has also been presented by Zhang, where microwave heating was applied to increase the speed of the reaction. The traceless tag was exemplified in syntheses of triaryl-substituted pyrimidines and hydantoins (Reaction Scheme 10). 

Y.-D. Gong, S. Nadji, M. M. Olmstead, M. J. Kurth, Solid-phase synthesis Intramolecular azomethine ylide cycloaddition ( proline) and carbanilide cyclization (—> hydantoin) reactions. J. Org. Chem. 1998, 63, 3081-3086. 

The above reaction is an example of Bucherer s hydantoin synthesis. The following mecJiavism has been proposed ... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

Uses, cx-Aminonitriles may be hydrolyzed to aminoacids, such as is done in producing ethylenediaminetetracetate (EDTA) or nittilotriacetate (NTA). In these cases, formaldehyde is utilized in place of a ketone in the synthesis. The principal use of the ketone-based aminonitriles described above is in the production of azobisnittile radical initiators (see below). AN-64 is also used as an intermediate in the synthesis of the herbicide Bladex. Aminonitriles are also excellent intermediates for the synthesis of substituted hydantoins by reaction with carbon dioxide however, this is not currently commercially practiced. 

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. 

Reactions at G-5. The C-5 atom of hydantoins can be considered as an active methylene group, and therefore is a suitable position for base-cataly2ed condensation reactions with aldehydes (44). 2-Thiohydantoins give the reaction more readily than their oxygen counterparts ... 

Miscellaneous Reactions. Some hydantoin derivatives can serve as precursors of carbonium—immonium electrophiles (57). 5-Alkoxyhydantoins are useful precursors of dienophiles (17), which undergo Diels-Alder cycloadditions under thermal conditions or in the presence of acid catalysis (58). The pyridine ring of Streptonigrine has been constmcted on the basis of this reaction (59). 

Synthesis from OC-Amino Acids and Related Compounds. Addition of cyanates, isocyanates, and uiea derivatives to a-amino acids yields hydantoin piecuisois. This method is called the Read synthesis (2), and can be considered as the reverse of hydantoin hydrolysis. Thus the reaction of a-amino acids with alkaline cyanates affords hydantoic acids, which cyclize to hydantoins in an acidic medium. 

In a modification of the original method. Read (60) replaced a-amino acids with a-amino nitriles. This reaction is sometimes known as Strecker hydantoin synthesis, the term referring to the reaction employed for the synthesis of the a-amino nitrile from an aldehyde or ketone. The cycli2ation intermediate (18) has been isolated in some cases (61), and is involved in a pH-controUed equiUbrium with the corresponding ureide. 

A related reaction sequence, which proceeds through a Curtius rearrangement, allows the transformation of a-cyano acids into hydantoins (66) ... 

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. ... 

Products that are allowed to remain on the skin are differentiated from those that are meant to be rinsed off. Components of products left on the skin can be expected to penetrate the viable epidermis and to be systematically absorbed. Products that are rinsed off shordy after skin contact, such as shampoos, can, if propedy labeled, contain preservatives that might eUcit adverse reactions if left on the skin. Typical examples of such preservatives are formaldehyde, formaldehyde releasers such as Quatemium 15 or MDM hydantoin, and the blend of methylchloroisothia2olinone and methylisothia olinone. 

In a somewhat related reaction the fused lactone (142) furnishes the decahydropyrido[3,4- f]pyrimidine (143) during the reaction of a-(hydantoin-5-ylidene)-7-butyrolactone with ammonia in ethylene glycol at 200 °C (71KGS1280). 

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 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. ... 

The first improvement of the Bucherer-Bergs reaction was the Bucherer-Lieb variation using the diluted alcoholic solution as described at the end of section 7.2.2. The Bucherer-Lieb variation is possibly the most popular process for synthesizing hydantoins. Another notable variation is the Henze modification using fusing acetamide as the solvent in place of water, benzene or 50% alcohol. Recently, ultrasound-promoted hydantoin synthesis has been reported to accelerate the reaction. 

The other most important synthetic utility of the Bucherer-Bergs reaction is the preparation of amino acids from the hydrolysis of hydantoins. When carbonyl 1 was symmetrical, the Henze modification gave hydantoin 2, which was then hydrolyzed to the... 

In most cases, however, many substrates give a mixture of stereoisomers with a certain degree of stereoselectivity. When ketone 39 was treated with potassium cyanide and ammonium carbonate in ethanol/water, a mixture of epimeric hydantoins 40 and 41 were isolated.Similarly, the Bucherer-Bergs reaction of ketone 42 gave rise to a... 

In summary, the Bucherer-Bergs reaction converts aldehydes or ketones to the corresponding hydantoins. It is often carried out by treating the carbonyl compounds with potassium cyanide and ammonium carbonate in 50% aqueous ethanol. The resulting hydantoins, often of pharmacological importance, may also serve as the intermediates for amino acid synthesis. 

Using the standard Bucherer-Lieb variation, a mixture of 9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-pyrido[2,l-fl]isoquinolin-2-one (14, 3 g, 12 mmol), potassium cyanide (1.17 g, 18 mmol) and ammonium carbonate (6.9 g) was dissolved in a 2 1 water-ethanol solution (45 mL). The reaction flask was sealed and heated for 48 h in an oven at 60°C. The cooled reaction mixture left a precipitate, which was filtered to yield 3.7 g (97%) of crude hydantoin 15. Further analysis revealed that it was consisted of 83% of ( )-25,1 lb5 isomer 15a and 9% of ( )-2/ ,llb5 isomer 15b. 

Condensation of o-phenylenediamine or xV-methyl-o-phenylcne-diamine with alloxan (8) in neutral solution gives the ureides (9) and (10), respectively However, reaction of o-phenylenediamine with 1,3-dimethylalloxan (13) yields quinoxalin-3-one-2-carboxymethyl-amide (14), rather than the dimethyl ureide. Methylation of (9) in acetone in the presence of potassium carbonate gives the spiro-hydantoin (11). 

A variant of the Strecker synthesis is the Bucherer-Bergs reaction it gives better yields, and proceeds via formation of an intermediate hydantoin 5 ... 

The reaction mixture is removed and about half of the liquid evaporated, an oil separating during the process. The mixture is acidified with concentrated hydrochloric acid and extracted with two 100 cc portions of ether. The extracts, which contain the 5-phenyl-5-(2-thienyOhydantoin, are combined and the combined ether extracts are shaken with two 25 cc portions of 5% potassium hydroxide solution. The alkaline solution, which dissolves the 5-phenvl-5-(2-thienvl)hydantoin to form the potassium salt thereof, is acidifed with hydrochloric acid and heated to expel ether. 

Chemically synthesised D,L-hydantoins prepared from the corresponding aldehydes via die Bucherer Berg reaction are converted by the bacterial cells (Bacillus brevis), containing a D-spedfic hydantoinase, to a mixture of D-N-carbamoyl amino acid and L-hydantoin. The latter compound undergoes rapid and spontaneous racemisation under the conditions of the reaction, therefore, in principle 100% of the hydantoin is converted into the D-N-carbamoyl compound. The D-amino add is obtained after treatment of the D-N-carbamoyl compound with nitrous add. This process is operated on an industrial scale by the Japanese firm Kanegafuchi. 

Q Impaired Oral M u cous Membranes related to adverse drug reactions (hydantoins)... 

A. 5-(p-Hydroxybenzal)hydantoin. An intimate mixture of 6.11 g. (0.050 mole) of />-hydroxybenzaldehyde (Note 1) and 5.5 g. (0.055 mole) of hydantoin (Note 2) is placed in a 250-ml. round-bottomed flask. Dry piperidine (10 ml.) is added, a reflux condenser protected by a calcium chloride tube is fitted to the flask, and the flask is immersed in an oil bath so that the level of the reaction mixture is the same as the oil level of the bath. The oil bath is heated slowly to 130° and is held at this temperature for 30 minutes foaming and gentle boiling occur. The reaction mixture is cooled, and 200 ml. of water at about 60° is added. The contents of the flask are stirred by means of a glass rod until a clear red solution is obtained (Note 3). Any traces of tarry material are removed by filtration. The solution is cooled to room temperature, transferred to an Erlenmeyer flask, and acidified by dropwise addition of 20 ml. of 12N hydrochloric acid. The mixture stands at room temperature a few hours, and then the yellow... 

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