Bucherer synthesis

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Fig. 7.12. Mechanism for the formation of hydantoin from 3-(methylthio)propional-dehyde, ammonium hydrogen carbonate and sodium cyanide, the initial reaction of the Strecker/Bucherer synthesis of methionine according to Figure 7.11.

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... 

Synthesis from Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoias ia a oae-pot procedure (Bucherer-Bergs reactioa) that proceeds through a complex mechanism (69). Some derivatives, like oximes, semicarbazones, thiosemicarbazones, and others, are also suitable startiag materials. The Bucherer-Bergs and Read hydantoia syntheses give epimeric products when appHed to cycloalkanones, which is of importance ia the stereoselective syathesis of amino acids (69,70). 

Synthesis from Thiohydantoins. A modification (71) of the Bucherer-Bergs reaction consisting of treatment of an aldehyde or ketone with carbon disulfide, ammonium chloride, and sodium cyanide affords 2,4-dithiohydantoias (19). 4-Thiohydantoias (20) are available from reaction of amino nitriles with carbon disulfide (72). Compounds (19) and (20) can be transformed iato hydantoias. 

BUCHERER LE PETIT Naphthol (Naphihylamine) Synthesis Synthesis of naphihylamines tram naphthols and naphihols from naphthylamines... 

The Bucherer carbazole synthesis " involves the treatment of a naphthyl alcohol (1 or 4) or a naphthyl amine (2 or 5) with a phenylhydrazine 3 in the presence of aqueous sodium bisulfite to afford, after acidic work-up, either a benzo[a]carbazole 4 or benzo[c]carbazole 6. 

The Bucherer carbazole synthesis was first demonstrated when 7 was heated in the presence of phenylhydrazines 8, sodium hydroxide and sodium bisulfite after acidic work-up, the benzocarbazole product 9 was isolated (-70% yield). When 2-naphthol was used the reaction was significantly slower with the yield of benzocarbazole being only 46% after several days at 130 °C Bucherer and co-workers investigated this reaction extensively concluding, incorrectly, that intermediate products were probably carbazole-Al-sulfonic acids due to the ease with which they lost the sulfonic acid residues to yield benzocarbazoles. 

Whereas the similarity between the Bucherer carbazole synthesis and the Fischer indolisation was noted by Bucherer and Seyde in their pioneering work, it was only later... 

When naphthyl amines e.g. 23) are used in the Bucherer carbazole synthesis, they are converted by the catalytic action of aqueous bisulfite into tetralonesulfonic acid derivative 13 by the Bucherer reaction. Addition of NaHSOs gives an enamine, which tautomerises to the imine 24 24 is hydrolysed to keto form 13 and subsequent Bucherer carbazole synthesis follows to afford the benzocarbazole product 20. ... 

The Bucherer carbazole synthesis is, to a certain extent, limited by the availabilty of the starting naphthol and naphthylamine reagents. However, a variety of substituents have been used and these are illustrated for the conversion of 25 to 27. The use of 2-aminoanthracene in the Bucherer carbazole synthesis has also been demonstrated."... 

The Bucherer carbazole synthesis was pivotal in the preparation of the first hexahelicene 37a. Reaction of 2,7-dihydroxynaphthalene 35 with phenylhydrazine and sodium bisulfite afforded helicene 37a although in low yield. More recently, the synthesis was extended to the preparation of 37b using 2,5-dimethylphenylhydrazine 36b. ... 

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. 

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 ... 

A particularly useful application of MW-assisted synthesis at elevated pressure has been in the preparation of radiopharmaceuticals containing isotopes with short half-lives, such as C-ll (half-life 20 min) and F-18 (half-life 110 min) [25-27]. Clearly, these compounds have to be synthesized very rapidly in order to give products with high radiochemical yield. For example, [1-11C] tyrosine 12 was synthesized using the two step Bucher-Strecker method by the reaction of p-hydroxyphenylacetaldehyde bisulfite adduct 11 with K11CN and (NH4)2C03 followed by hydrolysis with aqueous NaOH (Scheme 4.7)... 

The technical preparation of crystal violet and of its methyl-free parent substance, parafuchsine, almost the oldest of the triphenylmethane dyes, is not so easily explained. As is well known, in this process aniline and p-toluidine are united by oxidation in an acid melt. (In the preparation of fuchsine itself, which contains a methyl group attached to one of the benzene rings, o-toluidine is an additional ingredient.) Although all the phases of this important synthesis have not yet been experimentally established, we may nevertheless explain it on the basis of a dehydrogenation similar to that involved in the formation of malachite green. Moreover, the union of several molecules of base proceeds exactly according to the principle on which indamines are formed (p. 321) (Bucherer). 

Analysis of the details of the pathway was helped by the discovery by Nancy Bucher (1953) that cholesterol synthesis took place in cell-free post-mitochondrial supernatants. ATP, Mg2+ and NAD+ were required. Tchen and Bloch extended these findings to show that squalene could be formed anaerobically but the conversion of squalene to cholesterol was oxygen dependent, the oxygen of the intermediate lanosterol being derived from 8C>2 not H2180. It therefore became possible to focus either on the conversion of acetate to squalene or on the latter s cyclization to the sterol. 

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