Bucherer-Bergs hydantoin synthesis

The Bucherer-Bergs hydantoin synthesis has been employed to build spiro compounds 221 as 5-HTlA modulators [81]. The compounds were prepared from... 

Other references related to the Bucherer-Bergs hydantoin synthesis are cited in the literature. ... 

An interesting and useful example of synthesis of a-amino acids has been recently reported by Wuts and coworkers, describing a scalable process to prepare the INOS inhibitor PHA-399733 42 using the Bucherer-Bergs hydantoin synthesis as key step to introduce the amino acid function present in the final skeleton (Scheme 10.11) [41]. The methodology was applicable to the isolation of 39.9 kg (75% yield) of the racemic hydantoin 41, and the desired enantiomer was then opened in basic conditions giving the corresponding amino acid moiety. 

SCHEME 10.11 Synthesis of PHA-399733E 42 through Bucherer-Bergs hydantoin. 

SCHEME 10.12 First-generation synthesis of LY2140023 46 through Bucherer-Bergs hydantoin. 

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. 

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. 

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 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 ... 

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. 

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. 

Several hydrolytic enzymes other than esterases have been applied for synthetic purposes. One important subject is the chemoenzymatic preparation of amino acids. An industrial method for the synthesis of unnatural d- or L-amino acids employs the enzymatic hydrolysis of hydantoins, prepared by Bucherer-Bergs condensation using either D- or L-hydantoinase (cf Section 3.2.1.4) [33]. Another efficient method of preparing natural and unnatural amino acids is the two-step synthesis which features a Pd-catalyzed amidocarbonylation (eq. (2) cf Section 2.1.2.4) to afford racemic A-acyl amino acids followed by enantioselective hydrolysis using various acylases [34]. 

The Bucherer-Bergs synthesis is of general application to carbonyl compounds, employing potassium cyanide and ammonium carbonate.1,4 Carbonyl derivatives such as semicarbazones, thiosemicarbazones, oximes, azines, phenylhydrazones, imidazolidines, and azomethines also are readily converted directly to the corresponding hydantoins 44 The extent to which the reaction occurs appears unrelated to the hydrolytic stability of the starting material. The proposed mechanism is given in Scheme 1. 

Since the discovery of hydantoin in 1861, when Baeyer isolated it in his uric acid studies, that system has been an important precursor of a-amino acids owing to its lability toward alkali, especially for those acids that are difficult to prepare by other methods.300 Furthermore, the stereochemical courses of the Bucherer-Bergs and Read methods of synthesis for hydantoins (Section II,E), permit the preparation of epimeric amino acids.301-305 Some of these amino acids have been tested as possible tumor growth inhibitors,306,307 as metabolism-resistant amino acid analogues for transport system studies,72,308... 

As many of the classical multicomponent reactions, the Strecker synthesis also takes advantage of the versatile chemistry of the initially formed imine. The formation of the amino nitrile, however, is reversible under the reaction conditions which usually results in lower yields. This problem was elegantly solved in the Bucherer-Bergs variation,3 4-376 where the initially formed aminonitrile is irreversibly trapped by formation of a hydantoin as depicted in Scheme 1.8 (entry b). 

Although the Bucherer-Bergs reaction is mainly employed for the synthesis of a-amino acids, the synthesis of interesting hydantoins can be also addressed (Fig. 10.1) [17]. Curiously, hydantoins were initially observed as undesired by-products in the synthesis of peptides [18]. However, nowadays, this motif displays many important biological and pharmacological properties and is commonly used in drug discovery research lines [4a,b, 19]. These features have... 

Interestingly, Thomas and coworkers have recently developed a series of l,3,4,4a,10,10a-hexahydropyrano[4,3-( ] chromene analogues using for their synthesis a Bucherer-Bergs strategy, which allows the obtainment of the hydantoin cycle intermediate 18 necessary for the preparation of the final products 19 (Scheme 10.4) [27], Compounds 19 were analyzed as BACEl inhibitors for Alzheimer s disease with the aim of obtaining efficient inhibitors able to cross the... 

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]. 

More recently, based on a Bucherer-Bergs protocol, Conway and coworkers have developed a one-pot gallium(III) triflate-catalyzed synthesis of 5-substituted and 5,5-disub-stituted hydantoins 31 from the corresponding aldehydes and ketones in CH Clj (Scheme 10.7) [30], This one-pot synthesis of hydantoins avoids the difficulty associated with the isolation and purification of the a-aminonitrile intermediate in these processes. 

For the preparation of the dy-linker 55, a slight variation in the synthesis was required since the di-oriented bis-hydantoins cannot be obtained via Bucherer-Bergs reaction for this structure. 

C. Montagne, M. Shipman, Synlett 2006, 2203-2206. Modified Bucherer-Bergs reaction for the one-pot synthesis of 5,5 -disubstituted hydantoins from nitriles and organometallic reagents. 

Synthesis.—Optimum conditions have been systematically worked out for the preparation of the spiro-4-thiohydantoin (217) from cyclohexanone hydrolysis of (217) leads to the corresponding a-amino-acid. " This overall Bucherer-Bergs reaction is a useful alternative to the classical Strecker synthesis and hopefully the optimum conditions found will be applicable to other ketones. Hydrolysis of 5-substituted hydantoins can be effected enzymatically, giving optically active a-amino-acids of varying purity. ... 

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. ... 

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