Benzilic acid reaction conditions

Due to excellent yields, mild reaction conditions, and a fast reaction rate, the azolide method is well suited to the synthesis of isotopically labeled esters, even ones with very short half-lives, just as it is always useful for the esterification of sensitive carboxylic acids, alcohols, and phenols under mild conditions. An example is provided by the synthesis of [nC]-quinuclidinyl benzilate prepared from benzilic acid, CDI, and nC-labeled quinuclidinol.[147]... 

The well documented oxidation of 1,10-phenanthroline (4) to 2,2 -bipyridyl-3,3 -dicarboxylic acid (53) by alkaline permanganate has been repeated. It is now found that 4,5-diazafluoren-9-one (54) is consistently a coproduct of the reaction in 20% yield.253 This provides a convenient route to this hitherto difficultly accessible compound. The formation of 4,5-diazafluoren-9-one almost certainly occurs by way of the intermediate, but not isolated, l,10-phenanthroline-5,6-dione, which is known to undergo a benzilic acid type rearrangement in the presence of hydroxide ions to give the diazafluorenone. This rearrangement of l,10-phenanthroline-5,6-dione has recently been studied further.115 Under some conditions 5,6-dihydro-5,6-dihydroxy- 1,10-phenanthroline can be isolated with the diazafluorenone. 

Benzoins are useful intermediates for the synthesis of other compounds because they can be oxidized to 1,2-diones and reduced in stages to various products, depending upon the reaction conditions. The 1,2-diketone known as benzil, which is obtained by nitric acid oxidation of benzoin, undergoes a base-... 

Sterically demanding benzilic acid was used to optimize the reaction conditions in respect to reagent excess and reaction time. Complete conversion (98%) of benzilic acid to the corresponding methyl ester was obtained with two equivalents of the methyl triazene resin 10 after 6 h 96% conversion was obtained when using the n-butyl triazene resin 10. The reaction between p-nitrophenylacetic acid (1 equiv., 2 mg/ml) and the polymer-supported triazene (2 equiv.) in DCM was monitored by HPLC. A 53% conversion from the acid to the ester product was observed after 5 min data analysis indicated a second-order reaction as observed in homogeneous solution. 

Early workers [103] detected benzilic acid formed during the reduction of benzophenone in dimethylformamide in the presence of carbon dioxide. The carbon dioxide radical anion system is known to have E" = —2.2V (vs. SCE) [104] and will thus not be formed in preference to the ketone radical anion. Reaction occurs through trapping of aromatic carbonyl radical anions by carbon dioxide, and this has been developed into a convenient synthesis of aryllactic acids. The modern technological process uses constant current conditions. On a small scale, a divided cell with mercury cathode has been used to obtain benzilic acids from substituted benzophenones and carbon dioxide in 70-90% yields [105] and to convert 4-isopropylacetophenone to the corresponding phenyllactic acid in 85% yield [106]. On a technical scale, these reactions are best carried out in an undivided cell using a lead cathode and a sacrificial aluminum anode with dimethylformamide as solvent... 

Oxalyl chloride affords diketones (benzene gives benzil) but under the reaction conditions oxalyl chloride decomposes partly to phosgene, so that the acid chloride or monoketone may also be formed.606 The method thus has value also for preparation of carboxylic acids as examples, carboxylation of mesitylene in 65-70% yield by oxalyl chloride is recorded in Organic Syntheses,601 and l,l-di-(p-tolyl)ethylene gives 3,3-di-(/ -tolyl)acrylic acid in 80% yield.608... 

The remainder of this section will focus specifically upon several recent mechanistic studies that have identified acid catalysis in HTW and SCW. It should not be assumed that the increase in the value for water in HTW and SCW will result in an increase in the observed rate of acid catalysis. Many organic reactions can be both acid- and base-catalysed and, as the heterolytic fission of water produces equivalent amounts of H and OH, an observed increase in the rate of the reaction may arise from either the acid-or base-catalysed pathway or indeed both routes simultaneously. Furthermore, the dominant reaction pathway under ambient conditions can change in HTW and SCW. For example, Savage has shown that the rearrangement of benzil to benzilic acid, which is exclusively base catalysed under normal conditions, can also exhibit solvent and acid catalysis in HTW (Scheme 3.2). Thus, the... 

Polackova et alP studied the benzilic acid rearrangement of 4 under phase-transfer conditions with the effect of ultrasound. No rearrangement was observed when 50% KOH solution-toluene and benzyltriethylammo-nium chloride (TEBA) was used as phase transfer catalyst. The yields increased considerably to 60% when a powdered KOH was used instead of pellets. Ultrasonic reactor with the horn immersed into the reaction mixture proved to be much more effective, and 84% of the benzilic acid 5 was isolated after 15 min sonication even when KOH pellets were used. 

Although the major product is glyoxylic acid, the last two reaction steps are required to explain the observation that formic acid is produced in conditions of excess substrate. The oxidation of benzilic acid is similar but proceeds only to the ketone stage. 

The benzilic acid rearrangement can be catalyzed with cyanide, and the conditions do not require the addition of a strong base. Write a mechanism for this catalyzed reaction with the appropriate electron pushing. 

The reactions may proceed via a cationic intermediate (87). The reactions provide another source of cyclobutadienes. Heterogeneous Group VIII transition metals deformylate benzilic acid and its derivatives to the corresponding ketones. Solutions of Na2PtCl4 in acetic acid have similarly been shown to deformylate benzilic acid, possibly via a r-complex (88), to benzo-phenone. Benzhydrol does not deformylate under these conditions, but does undergo hydrogen-deuterium exchange. ... 

In 1910, Hinsberg described the reaction between benzil and diethylthiodiacetate, resulting in the preparation of the thiophene ring system. The reaction was run under Claisen condensation conditions, and after hydrolysis with aqueous acid at reflux, the free dicarboxylic acid 1 was produced. 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

In 2003, Balalaie and co-workers published a new paper in the area of imidazole synthesis39. In the above examples reported by Westman, ammonium acetate and primary amines act as the nitrogen source for the imidazole ring. In the Baladie novel one-pot three-component method, ammonium acetate was replaced by benzonitrile derivatives. Thus, benzil, primary amines and benzonitrile derivatives underwent a condensation reaction on acidic silica gel as the solid support, Scheme 5.23. The reaction mixtures were irradiated for 8 min in a domestic oven under solvent-free conditions to give the products in 58-92% yield. 

The reaction of benzil 135 with benzonitrile in the presence of the trifluoromethane-sulfonic acid leads to the bis-Af-benzoylimine 136. Under the same conditions benzoyla-cetone 137 reacts to give the bis-Af-benzoylimine 138s6 (equation 46). 

The reaction of amines with 1,2-diketo substrates led to a variety of substituted imidazole derivatives. Treatment of various substituted anilines 88 with glyoxals 89 gave the imine intermediate 90, which was then cyclized to the 1-arylimidazoles 91 with paraformaldehyde and ammonium chloride under acidic conditions <0382661>. A one-pot, three-component condensation of benzil 92, benzonitrile derivatives and primary amines on the surface of silica gel under solvent-free conditions and microwave irradiation provided tetrasubstituted imidazoles 93<03TL1709>. 

Diaminopyridine has been condensed with glyoxal, benzil, - diacetyl,and the pyridils 4. ° Ethyl oxalate yields the 2,3-dioxo compound. The conditions employed for these condensations can be critical. Thus glyoxal in neutral solution yields an unidentified, insoluble, infusible solid, whereas in the presence of acetic acid the reaction readily provides the parent heterocycle.The preferred method makes use of glyoxal sodium bisulfite. Many symmetrical dicarbonyl compounds have been condensed with a variety of 2,3-diaminopyridines substituted in the pyridine ring by bromo, ° chloro, methyl, " or combinations of these substituents. ... 

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