Hydantoins aldehydes

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 ... 

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. 

Amino acid synthesis from aldehydes and hydantoin (Bergmann), synthesis of serine derivatives (Erlenmeyer) or of y-hydroxyaminoacids (Plochl)... 

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. ... 

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. 

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. 

Tryptophane (10, 100) By condensation of indole-3-aldehyde with hydantoin in the presence of piperidine, followed by treatment of the product with ammonium sulfide and ammonium hydroxide at ioo° for 500 hours, Boyd and Robson, Biochem. J. ag, 2256 (1935). 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

The hydantoin route for synthesis of the 2-oxoacid° has been performed with a variety of starting aldehydes and appears to work more reliably than the method described earlier. In spite of the restricted solubility of the intermediate oxoacid substrate for the biocatalytic step, the reaction proceeds to a good final overall yield with more substrate dissolving to replace that consumed in the reaction. The combined procedure appears to be quite versatile. 

The scope of the reaction depends on the availability of the starting aldehyde (or ketone). A drawback is the toxicity of the hydrogen cyanide used as reactant. 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 Hydantoin Process. Hydantoins are produced by reacting aldehydes with sodium cyanide and ammonium carbonate, Upon hydrolysis, or-amino acids will be yielded... 

Synthesis From Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoins in a one-pot procedure (Bucherer-Bergs reaction) that proceeds through a complex mechanism. Some derivatives, like oximes, semicarbazones. Iliiosetricarbazones. and others, are also suitable starting materials. 

An efficient solid-phase protocol for the synthesis of substituted (5-biphenyltetrazolyl)-hydantoins and -thiohydantoins has been developed. Suzuki cross-coupling between resin-bound 2-(tetrazol-5-yl)-phenylborinane 333 and 4-bromobenzaldehyde gave the corresponding tetrazolylbiphenyl aldehyde 334 (Equation 59) <2004BML317>. 

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. 

Reaction of phenylhydrazine with the /J-keto ester (64) gives the pyrazolone (65).55 The hydantoin (66) has been obtained by the action of potassium cyanide and ammonium carbonate on ferrocenecarbox-aldehyde.67-69 The potentiometric titration64 of hydantoin (67) has been reported. 

Since an important feature of Biicherer-Bergs hydantoin formation is that the process can only work for a-aminonitriles without substituent on the amino group, it follows that one compound of the equilibrium mixture formed from an aldehyde, ammonia, and cyanide is selectively reacted through an irreversible process leaving N-alkylated aminonitriles or imino-dinitriles unreacted. However, the difficulty with this process is that CAAs and hydantoins are poorly reactive towards hydrolysis and need long periods of time to be converted into free AAs. But, CAAs may also have per se a prebi-otic importance in activation pathways towards polypeptides (see Sect. 3.3.7). CAAs can also be synthesized by reaction of free amino acids with cyanic acid/cyanate (a likely prebiotic compound [50]). In the presence of a steady-state concentration of either cyanate or urea in aqueous medium, CAAs are at equilibrium with A A [51]. 

Resin-bouda-amino esters, besides being traditionally used for making peptides, have served as key intermediates for the construction of various heterocyclic scaffolds. Thus, they react smoothly with isocyanates to form ureas, which upon heating under acidic conditions cyclize to form hydantoins 53 [27]. A one-pot, three-component condensation of resin-bound a-amino esters with aldehydes and a-mercapto acids affords 4-thiazolidi-... 

Monosubshtuted hydantoins are a-amino acids cyclically protected at both the carboxyl- and the a-amino group. They can be easily prepared from an aldehyde and isocyanate or by the Bucherer-Bergs synthesis and similar methods. Indeed, the hydantoin synthesis is also a prachcal method for the preparahon of the racemic amino acid. Enzymes belonging to the dihydro-pyrimidinase family hydrolyze hydantoins to the carbamoyl amino acid. The latter can be hydrolyzed in turn to the amino acid by a second enzyme, a carbamoylase. Both enzymes can discriminate between enantiomers and, if their action is cooperative, either the L- or the D-amino acid can be obtained (Scheme 13.10) [36]. What makes the system of special interest is that the proton in the 5-position of the hydantoin ring (it will become the a-hydrogen in the a-amino acid) is considerably more acidic than conventional protons in amino acid esters or amides and much more acidic than the amino acid itself. Thus, the hydantoin can be often racemized in situ at slightly basic pH where the enzymes are stiU stable and active. If these condihons are met. 

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... 

Figure 2 The detailed mechanisms for irreversible transformations of a-aminonitriles 5. (a) Aldehyde-catalyzed pathway of hydration predominant in neutral and alkaline aqueous solutions, (b) Bucherer-Bergs conversion of a-aminonitriles into hydantoins.

Dihydiopyiiinidinase- (hydantoinase-) based processes have been successfully employed for the production of D-amino adds, particularly D-p-hydroxyphenylglydne (7,25,77,78). D,L-hydantoins are chemically synthesized from the corresponding aldehydes using the Bucherer-Berg... 

Bucherer, H. T., Libe, V. A. Syntheses of hydantoins. II. Formation of substituted hydantoins from aldehydes and ketones. J. Prakt. Chem. 

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