Benzoylacetic acids

Schopf and Lehmann found that lobelanine could be synthesised by keeping at 25° a mixture of glutardialdehyde, methylamine hydrochloride and benzoylacetic acid in a buffered solution. The best yield was obtained at pH 4-5, and appeared to be complete in forty hours. At pH 7 or 9, 11 or 13, the yield was very small. This synthesis under physiological conditions is represented as occurring in accordance with the following scheme —... 

MI37-5 Benzoylacetic Acid, MjlO Buffer Exp. I (40 hours)... 

The alkaloid sedamine has been prepared under physiological conditions too (318). Aldolization of the immonium salt 200, obtained by mercuric acetate dehydrogenation of (2S,8R)-(—)-sedamine (199), with benzoylacetic acid produces (2S,6R,8S)-(—)-8,10-diphenyllobelinol (i.e., (—)-lobeline) (201). This determines its absolute configuration (319, 320). 

The carboxylation of ketones is carried out essentially as in the preceding experiment, but at slightly higher temperatures (requiring an oil bath or mantle). Thus, acetophenone (6 g, 0.05 mole) in 100 ml of approx. 2 M MMC is stirred and heated at 110-120° for 1 hour. After cooling, hydrolysis in the acid-ice mixture, and isolation from ether, benzoylacetic acid, mp 99-100°, is obtained in 68% yield. Similarly, 1-indanone gives l-indanone-2-carboxylic acid, mp 100-101°, in 91 % yield. 

Although the reaction of certain acetylenes such as phenylacetylene and ethyl phenylpropiolate with cold concentrated sulfuric acid to give acetophenone (15) and benzoylacetic acid (16) has been known since the 1880 s, it was only in the 1960 s that this reaction was studied mechanistically. 

The benzoic acid, the acid moiety found in cocaine (98), is also derived from phenylalanine (141). Feeding of [4-3H]phenylalanine to E. coca led to the benzoyl moiety, where 96% of the 3H was located at the para position (138). The intermediacy of cinnamic, 3-hydroxy-3-phenylpropionic, and benzoylacetic acid in the formation of benzoic acid has been suggested (138). 

Maximal Rate Constants and Dissociation Constants of Cycloheptaamylose-Benzoylacetic Acid Complexes at 50.3°°... 

Recently, an example of cycloamylose-induced catalysis has been presented which may be attributed, in part, to a favorable conformational effect. The rates of decarboxylation of several unionized /3-keto acids are accelerated approximately six-fold by cycloheptaamylose (Table XV) (Straub and Bender, 1972). Unlike anionic decarboxylations, the rates of acidic decarboxylations are not highly solvent dependent. Relative to water, for example, the rate of decarboxylation of benzoylacetic acid is accelerated by a maximum of 2.5-fold in mixed 2-propanol-water solutions.6 Thus, if it is assumed that 2-propanol-water solutions accurately simulate the properties of the cycloamylose cavity, the observed rate accelerations cannot be attributed solely to a microsolvent effect. Since decarboxylations of unionized /3-keto acids proceed through a cyclic transition state (Scheme X), Straub and Bender suggested that an additional rate acceleration may be derived from preferential inclusion of the cyclic ground state conformer. This process effectively freezes the substrate in a reactive conformation and, in this case, complements the microsolvent effect. 

The rate of decarboxylation of benzoylacetic acid is also accelerated in mixed dioxane-water (Hay and Tate, 1970) and acetonitrile-water (Straub and Bender, 1972) solutions. In no case, however, has an acceleration greater than 2.5 been observed. In aprotic solvents, such as benzene, decarboxylation rates are depressed (Swain et al., 1961). 

J>-Benzoqumone, 35, 26 Benzoylacetanilide, 37, 2 Benzoylacetic acid, ethyl ester, 37, 3 Benzoylacetic acid, ethyl ester, 37, 32 Benzoylation, of o-hydroxyacetophenone, 32, 72... 

The reaction of 2-anilino-l,4-naphthoquinone 374 with benzoylacetic acid hydrazide gives 3-hydrazino-pyrazolyl derivative 375, that is acetylated to produce 5-[[l,4-dihydro-l,4-dioxo-3-(phenylamino)-2-naphthalenyl]sulfonyl]-3-methyl-6-phenyl-5/7-pyrazolo[5,l-c][l,2,4]triazole 51. This latter derivative is also obtained in 51% yield from reaction of 374 with benzoylacetic acid hydrazide in the presence of a mixture of acetic acid-sodium acetate <2004PS(179)1907> (Scheme 39). 

Condensation reactions of aniline and of other bases with aromatic aldehydes to give Schiff s bases are accelerated by ultraviolet light in buffered media. For example, o-phenylenediamine reacts with formic acid to yield benzimidazole and acetylacetone reacts with guanidine to form 2-amino-4,6-dimethylpyrimidine.162 Similarly, lobelanine is formed by the photocondensation of glutaraldehyde, benzoylacetic acid, and methylamine hydrochloride.163... 

SAMPLE SOLUTION (a) By analogy to the thermal decarboxylation of malonic acid, we represent the corresponding reaction of benzoylacetic acid as... 

It is difficult to hydrogenate benzoylacetic acid derivatives with a high optical yield. Recently, an (R)-SEGPHOS/Ru complex-catalyzed hydrogenation of the ethyl ester with an S/C of 10,000 under 30 atm of H2 afforded the S alcohol in 97.6% ee (Table of Scheme 20) [36]. MeO-BIPHEP and Tol-P-Phos also performed with a high level of enantioselection [49, 60], Hydrogenation of N-methylbenzoylacetamide with the (R)-BINAP/Ru catalyst gave the S alcohol in >99.9% ee and 50% yield [61]. 

In comparison, the l,3-dialkylimidazolium-2-carboxylate isolated by Tommasi et al. [27, 40] was revealed to be a more versatile catalyst that allowed the synthesis of benzoylacetic acid from benzophenone and C02 in good yield and under mild conditions (isolated yield 81%). The presence of tetrafluoroborate- or tetraphenyl-borate sodium salts in the reaction was essential, as this allowed the formation of the related 1,3-dialkylimidazolium tetrafluoroborate or tetraphenylborate and the concomitant quantitative trans-carboxylation to sodium benzoylacetate. Likewise, compounds such as acetone, cyclohexanone, and phenylacetonitrile could also be converted with this system to afford the corresponding carboxylate salts (methyl a-cyanophenylacetate) (Scheme 5.8). Following the same general procedure, acetone was carboxylated, being simultaneously the cosolvent and reagent. 

Keto acids form pyranones in the presence of acid, decarboxylation sometimes accompanying the cyclization, as in the case of benzoylacetic acid (25CB2318). 

The oxidation of ethyl p-xylyl ketone (2,5-dimethylpropiophenone) with cold dilute aqueous potassium permanganate furnishes 2,5-dimethyl-benzoylacetic acid (a p-keto acid) in an unstated yield [599]. 

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