Glyoxal rearrangement

It is evident that some leeway is available in the substituents tolerable in the m-position. The bronchodilator sulfonterol (28) is descended from this observation. Chloromethylanisole (29) is reacted with methylmereaptan to give 30, and the newly introduced group is oxidized to the methyl-sulfonyl moiety of 31 with hydrogen peroxide. Ether cleavage, acetylation and Fries rearrangement of the phenolic acetate produces 32, which is next brominated with pyrrolidinone hydrobromide tribromide and then oxidized to the glyoxal (33) with dimethyl sulfoxide. 

Several mechanisms34 have been proposed for this reaction. That of Weygand,36 in which an Amadori rearrangement is proposed, has considerable merit.37 Illustrations of unusual osazone formation are described by Bonner and Drisko.38 When phenyl /S-D-xylopyranosyl sulfone (XXII) or /J-D-glucopyranosyl sulfone (XXIV) is oxidized by periodic acid, a dialdehyde oxidation product (XXIII or XXV), which is susceptible toward further oxidation, is obtained. The reaction of XXIII or XXV with phenylhydrazine yields glyoxal phenylosazone and benzenesulfinic acid. Surprisingly, both XXII and XXIII react with phenylhydrazine to form D-xylosazone and D-glucosazone, respectively. 

Investigation of the mechanism of these reactions has suggested ways in which the yields can be improved. Acidic conditions (pH 2) will prevent Cannizzaro rearrangement of any glyoxal-type species and also serve to hydrolyse any Schiff bases which result from side reactions of aldehyde and amine. Conditions should be adjusted so that the rate of hydrolysis of linear products is equal to the rate of cyclocondensation, allowing accumulation of the imidazole products. From glyoxal, formaldehyde and ammonium chloride the yield of imidazole can be inereased to 85% by careful control of the conditions. With an appropriate alkylammonium chloride, 1-substituted imidazoles are also accessible (e.g. 1-methyl (56%), 1-isopropyl (46%), 1-cyclohexyl (49%), 1-n-butyl (55%), 1-t-butyl (25%)). The process may have some applications, but yields drop off with branched alkyl compounds [22 j. Imidazolium salts are also available under similar conditions when two molar equivalents of a primary alkylamine are used [23]. 

The a-substituted carbonyl compounds, glyoxal, methyl glyoxal, and chloral hydrate, react with the titanous-peroxide system to give rearranged radicals whose formation is accounted for in the same way as that of 01120110 from glycol (above) (Dixon et al., 1964 Buley et al., 1966) ... 

O Meara, D., Richards, G. N. Mechanism of saccharinic acid formation. IV. Influence of cations in the benzilic acid rearrangement of glyoxal. J. Chem. Soc. 1960, 1944-1945. 

Novelli, A., Barrio, J. R. Carbon-14 tracer studies in the benzilic acid type rearrangement of 1-phenyl-and 1-(4-methoxyphenyl)-2-(3-pyridyl) glyoxal. Tetrahedron Lett. 1969, 3671-3672. 

The prototype reaction is the conversion of glyoxal into glycolic acid (equation 2), and here the benzilic acid rearrangement mechanism coincides with that for an intramolecular Cannizzaro reaction. The reaction is observed with other purely aliphatic a-diketones such as f-butyl 2,3-dioxobutyrate and cyclohexane-1,2-dione (equations 3 and 4), but the scope is limited in the aliphatic series by competing (c.g. aldol) reactions. Suitably constructed heterocyclic systems also rearrange, and the conversion of alloxan (3) into alloxanic acid (4) was among the first of the benzilic acid rearrangements to be discovered (equation 5). ... 

In basic solution there is convincing evidence, at least for one reaction, that an intramolecular hydride ion shift occurs. When phenylglyoxal is treated with barium deuteroxide, mandelic acid is formed which contains no deuterium attached to a carbon atom.24 Furthermore, the reaction is first order in hydroxide ion and the glyoxal,25 and there is no rearrangement in the carbon skeleton during the transformation.24 26 This can mean only that the transfer of the hydrogen atom with its pair of electrons to the carbonyl group must take place by an intramolecular path. 

The Benzilic Acid Rearrangement When benzil is treated with sodium hydroxide, benzilic acid is fornied and the reaction appears to proceed by the intramolecular addition of a group with an electron pair to the carbonyl carbon atom. A mechanism which seems quite plausible for the reaction is the following.50 It is identical mechanistically with the glyoxal-glyoolic acid rearrangement (p. 107). 

The released end-group forms an a-dicarbonyl structure which rearranges by an intramolecular, Cannizzaro type of reaction to yield saccharinates. Intramolecular reactions of the Cannizzaro type can occur not only with dialdehydes but also with a-ketoaldehydes and a-diketones ( benzilic acid rearrangement ) they can be exemplified by the base-catalyzed rearrangement of phenylglyoxal (VIII) [or of (2,4,6-trimethylphenyl)-glyoxal ] to the salt of mandelic acid (IX) (or of 2,4,6-trimethylmandelic acid). 

As expected, pentoses react similarly to hexoses in the Maillard reaction, with the formation of 1- and 3-deoxyosones. However, the initial two-carbon fragment formed from the reaction of xylose with alanine is not the glycolal-dehyde expected from retro-aldolisation of the Amadori rearrangement product, but glyoxal, for reasons which are not clear. ... 

The landem aza-Cope/Mannich cyclization reaction has also been used in the synthesis of enantiomerically pure tx-amino acid derivatives, e.g., proline derivative 741l49. Thus, the rearrangement of intermediate 70, derived from 69 and glyoxal by acid treatment, produces a 1 1 mixture of 72 and the head-to-tail self-condensation product 73, which can be transformed to 72 by subsequent acid treatment. 

The reaction of amino alcohol 1 with glyoxal leads to the aza-Cope precursor 2, which upon rearrangement and hydrolysis yields 4 in 54% yield1149. 

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