Decarboxylation acetone

Hamilton marked the carbonyl group of acetoacetic acid with ieO, and then carried out the enzymic decarboxylation (Hamilton and Westheimer, 1959). The product of the decarboxylation, acetone, contained none of the label. This result is demanded by the ketimine mechanism, whereas the mechanism of uncatalyzed decarboxylation would have required that the label appear intact in the product. Of course, in order to make these statements we had to carry out an elaborate set of control experiments, since 180 is washed out of both acetone and acetoacetic acid by buffers and even more... 

Regioselectivity of C—C double bond formation can also be achieved in the reductiv or oxidative elimination of two functional groups from adjacent carbon atoms. Well estab llshed methods in synthesis include the reductive cleavage of cyclic thionocarbonates derivec from glycols (E.J. Corey, 1968 C W. Hartmann, 1972), the reduction of epoxides with Zn/Nal or of dihalides with metals, organometallic compounds, or Nal/acetone (seep.lS6f), and the oxidative decarboxylation of 1,2-dicarboxylic acids (C.A. Grob, 1958 S. Masamune, 1966 R.A. Sheldon, 1972) or their r-butyl peresters (E.N. Cain, 1969). 

Trichloroacetic acid K = 0.2159) is as strong an acid as hydrochloric acid. Esters and amides are readily formed. Trichloroacetic acid undergoes decarboxylation when heated with caustic or amines to yield chloroform. The decomposition of trichloroacetic acid in acetone with a variety of aUphatic and aromatic amines has been studied (37). As with dichloroacetic acid, trichloroacetic acid can be converted to chloroacetic acid by the action of hydrogen and palladium on carbon (17). 

Amino-2-hydroxybenZOiC acid. This derivative (18) more commonly known as 4-aminosa1icy1ic acid, forms white crystals from ethanol, melts with effervescence and darkens on exposure to light and air. A reddish-brown crystalline powder is obtained on recrystallization from ethanol —diethyl ether. The compound is soluble ia dilute solutioas of nitric acid and sodium hydroxide, ethanol, and acetone slightly soluble in water and diethyl ether and virtually insoluble in benzene, chloroform or carbon tetrachloride. It is unstable in aqueous solution and decarboxylates to form 3-amiaophenol. Because of the instabihty of the free acid, it is usually prepared as the hydrochloride salt, mp 224 °C (dec), dissociation constant p 3.25. 

A better yield was obtained when, in place of acetone, calcium acetonedicarboxylate was used, the initial product in this case being calcium tropinonedicarboxylate, from which the free dibasic acid is readily isolated and can be decarboxylated by heating in acid solution, yielding tropinone. This idea was taken up in Germany, and a number of processes for the production of tropinone derivatives have been described, mostly in patent literature. According to Willstatter and Pfannenstiel, a yield of... 

Ethyl acetoacetate reacts with ehaleone in the presence of boron fluoride etherate affording 3-carbethoxy-2-methyl-4,6-diphenylpyryl-ium this can be hydrolyzed and decarboxylated to 2-methyl-4,6-diphenylpyrylium which should theoretically result from acetone and ehaleone. 

Related and equally important reactions are the acetoacetic ester synthesis and the eyanoaeetie ester synthesis Here too the initial substituted product can be hydrolyzed and decarboxylated, to yield a ketone 11 (i.e. a substituted acetone) from acetoacetic ester 10, and a substituted acetonitrile 14 from eyanoaeetie ester 13 respectively. Furthermore a substituted acetoacetic ester can be cleaved into a substituted acetic ester 12 and acetate by treatment with strong alkali ... 

Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and d(—)-3-liydroxyl)utyrate (P-hydroxybutyrate). Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three substances are collectively known as the ketone bodies (also called acetone bodies or [incorrectly ] ketones ) (Figure 22-5). Acetoacetate and 3-hydroxybu-... 

Co-adsorption experiments show a complex role of the nature and concentration of chemisorbed ammonia species. Ammonia is not only one of the reactants for the synthesis of acrylonitrile, but also reaction with Br()>nsted sites inhibits their reactivity. In particular, IR experiments show that two pathways of reaction are possible from chemisorbed propylene (i) to acetone via isopropoxylate intermediate or (ii) to acrolein via allyl alcoholate intermediate. The first reaction occurs preferentially at lower temperatures and in the presence of hydroxyl groups. When their reactivity is blocked by the faster reaction with ammonia, the second pathway of reaction becomes preferential. The first pathway of reaction is responsible for a degradative pathway, because acetone further transform to an acetate species with carbon chain breakage. Ammonia as NH4 reacts faster with acrylate species (formed by transformation of the acrolein intermediate) to give an acrylamide intermediate. At higher temperatures the amide may be transformed to acrylonitrile, but when Brreform ammonia and free, weakly bonded, acrylic acid. The latter easily decarboxylate forming carbon oxides. 

It is also possible to use the dilithium derivative of acetoacetic acid as the synthetic equivalent of acetone enolate.49 In this case, the hydrolysis step is unnecessary and decarboxylation can be done directly on the alkylation product. 

The other ketone bodies are derived from acetoacetate P-hydroxybutyrate, by reduction with the involvement of NAD-dependent hydroxybutyrate dehydrogenase, and acetone, by decarboxylation of acetoacetate with the participation of aceto-acetate decarboxylase ... 

Further studies by Spenser demonstrated that l,2-13C-labeled acetate (13) was incorporated into lycopodine but gave a distribution of the labels that did not account for the pelletierine-route that was hypothesized (Scheme 6.2) [11]. An intact 3-carbon unit was desired for testing, but labeled acetoacetate (l,2,3,4-13C-acetoacetate (14), which could undergo decarboxylation to provide an intact 3-carbon unit) was found to give the same incorporation pattern as acetate (and therefore must have been cleaved to acetate prior to uptake). In addition, feeding studies using deuterated, 13C-labeled acetate provided a loss or washout of deuterium at the C16 methyl group. This could only occur if an intermediate had formed that would provide for facile enolization. Both the equal distribution of the 13C labels and loss of the deuteriums led the researchers to propose that the intermediate was symmetric, such as acetone dicarboxylic acid (15). 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

A mixture of 9.5 g pyrrolyl-2-aldehyde, 29.2 g dimethyl-succinate and NaH (9.6 g of 50% suspension in oil) in 100 ml benzene is stirred at room temperature 6 hours, cooled and carefully acidified with glacial acetic acid. Add water and ether and dry, evaporate in vacuum or work up (JACS 72,501 (1950), JCS 1025(1959)) to get ca. 17 g (80%) 3-methoxycarbonyl-4-(2 -pyrrolyl)-3-butenoic acid (I) (recrystallize-acetone-benzene). A mixture of 12 g (I), 7 g sodium acetate and 70 ml acetic anhydride is left overnight at room temperature with occasional shaking. Then gradually raise the temperature to 70-75° over 2 hours, maintain for 4 hours and work up (see JCS 1714(1955), 986( 1958)) to get ca. 8 g (60%) methyl-4-acetoxy-indole-6-carboxylate (II) (recrystallize-petroleum ether). If desired, this can be converted to 4-OH-indole-6-COOH and 4-methoxyindole-COOH as described in the ref. or decarboxylated as described elsewhere here. If the 1-methyl cpd. is used, 1-Me-indole results. 

Griesbeck et al. successfully transformed w-phthalimidoalkanoates via PET with concomitant decarboxylation and C,C combination leading to medium- and large-ring compounds with yields in the range 60-80%. Thereby, the solvent system acetone/water and K2CO3 employed for the deprotonation of the carboxylic acids were crucial (Scheme 45) [66]. 

Acetone cyanohydrin nitrate, a reagent prepared from the nitration of acetone cyanohydrin with acetic anhydride-nitric acid, has been used for the alkaline nitration of alkyl-substituted malonate esters. In these reactions sodium hydride is used to form the carbanions of the malonate esters, which on reaction with acetone cyanohydrin nitrate form the corresponding nitromalonates. The use of a 100 % excess of sodium hydride in these reactions causes the nitromalonates to decompose by decarboxylation to the corresponding a-nitroesters. Alkyl-substituted acetoacetic acid esters behave in a similar way and have been used to synthesize a-nitroesters. Yields of a-nitroesters from both methods average 50-55 %. 

At high concentrations of acetyl-CoA in the liver mitochondria, two molecules condense to form acetoacetyl CoA [1]. The transfer of another acetyl group [2] gives rise to 3-hydroxy-3-methylglutaryl-CoA (HMC CoA), which after release of acetyl CoA [3] yields free acetoacetate (Lynen cycle). Acetoacetate can be converted to 3-hydroxybutyrate by reduction [4], or can pass into acetone by nonenzymatic decarboxylation [5]. These three compounds are together referred to as "ketone bodies," although in fact 3-hydroxy-butyrate is not actually a ketone. As reaction [3] releases an ion, metabolic acidosis can occur as a result of increased ketone body synthesis (see p. 288). 

This enzyme [EC 4.1.1.4] catalyzes the decarboxylation of acetoacetate to form acetone and carbon dioxide. 

Some CO2 is also formed via a decarboxylation of AC2O to acetone (Me2CO) (Eq. (7)). 

While some phenol is produced by the nucleophilic substitution of chlorine in chlorobenzene by the hydroxyl group (structure 17.17), most is produced by the acidic decomposition of cumene hydroperoxide (structure 17.18) that also gives acetone along with the phenol. Some of the new processes for synthesizing phenol are the dehydrogenation of cyclohexanol, the decarboxylation of benzoic acid, and the hydrogen peroxide hydroxylation of benzene. 

Examples of this approach to the synthesis of ketones and carboxylic acids are presented in Scheme 1.6. In these procedures, an ester group is removed by hydrolysis and decarboxylation after the alkylation step. The malonate and acetoacetate carbanions are the synthetic equivalents of the simpler carbanions lacking the ester substituents. In the preparation of 2-heptanone (entries 1, Schemes 1.5 and 1.6), for example, ethyl acetoacetate functions as the synthetic equivalent of acetone. It is also possible to use the dilithium derivative of acetoacetic acid as the synthetic equivalent of acetone enolate.29 In this case, the hydrolysis step is unnecessary, and decarboxylation can be done directly on the alkylation product. 

The method described is that of Hampton, Harris, and Hauser6 and is an improvement over the benzyne method, which gives poor yields.6,7 This /J-diketone has been prepared by Claisen condensation of ethyl phenylacetate with acetone,8 but the yield is poorer and the product has been shown by gas chromatography to be impure.6 The j8-diketone has also been prepared by the hydrolysis of 4-methoxy-5-phenyl-3-penten-2-one and by hydrolysis and decarboxylation of ethyl a-acetyl-/3-oxo-y-phenylbutyrate10 but these compounds are more difficult to obtain than the starting materials used in the present synthesis. 

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