Carboxylic acids to ketones

Conversions of carboxylic acids to ketones are typically performed in stepwise fashion6 via intermediates such as acid chlorides,7 anhydrides,8 thioesters,9 or N-alkoxy amides,10 or by the direct reaction of carboxylic adds with lithium reagents.11 In this latter method trimethylsifyl chloride has been shown to be an effective reagent for trapping the tetrahedral alkoxide intermediates and for quenching excess organolithium reagent. 

Fries rearrangement—that is, the transformation of phenolic esters to isomeric hydroxyphenyl ketones—is related to Friedel-Crafts acylations.392,393 Olah et al.394 have found a convenient way to perform the Fries rearrangement of a variety of substituted phenolic esters in the presence of Nafion-H in nitrobenzene as solvent [Eq. (5.153)]. A catalytic amount of Nafion-H is satisfactory, and the catalyst can be recycled. In contrast, Nafion-silica nanocomposites, in general, exhibit low activities in the Fries rearrangement of phenyl acetate to yield isomeric hydroxyacetophe-nones.239,395 In a recent study, BF3-H20 was found to be highly efficient under mild conditions (80°C, 1 h) to transform phenolic esters of aliphatic and aromatic carboxylic acids to ketones (71-99% yields).396 In most cases the para-hydroxyphenyl isomers are formed with high (up to 94%) selectivity. 

Nicholson, J. W., Wilson, A. D. The conversion of carboxylic acids to ketones A repeated discovery. J. Chem. Educ. 2004, 81, 1362-1366. Bullerwell, R. A. F., Lawson, A., Morley, H. V. 2-Mercaptoglyoxalines. VIII. Preparation of 2-mercaptoglyoxalines from glutaric acid. J. Chem. Soc., Abstracts 1954, 3283-3287. 

The decarboxylation of carboxylic acid to ketone is known to be promoted by basic oxides such as CaO and 81203. The dimerization of HCHO to methyl formate by Tischenko reaction is known to be promoted by acid-base bifunctional action of catalyst. The decomposition of formic acid to CO2 is known to be promoted by basic sites. ... 

The chlorination of trimethylsilylmethyl sulfides with NCS and trifluoroacetic acid affords the product of chlorodesilation in high yield.3 The degradation of carboxylic acids to ketones can be achieved by a-sulfenation followed by reaction with NCS in the presence of NaHC03 (eq 6). The 5 -chlorosulfonium ion intermediate undergoes a decarboxylative Pummerer-like rearrangement to afford the ketone upon hydrolysis. a-Phenylthio esters... 

Organocuprates also react with acid chlorides to form a ketone. When 126 reacts with benzoyl chloride, for example, the product is 128. This reaction is a preferred method for the conversion of carboxylic acids to ketones. A reaction sequence that begins with 3-methylpentanoic acid first forms the acid chloride via reaction with thionyl chloride (Section 20.3.1), and subsequent reaction with lithium diethyl cuprate leads to the ketone 129. 

Aldehydes are easily oxidized to yield carboxylic acids, but ketones are generally inert toward oxidation. The difference is a consequence of structure aldehydes have a —CHO proton that can be abstracted during oxidation, but ketones do not. 

Further oxidation of the product to a carboxylic acid (Section 19.6) can be avoided by using a mild oxidizing agent. There is less risk of further oxidation for ketones than for aldehydes, because a C—C bond would have to be broken for a carboxylic acid to form. 

Ketones can also be obtained by treatment of the lithium salt of a carboxylic acid with an alkyllithium reagent (16-31). For an indirect way to convert carboxylic esters to ketones, see 16-33. 

Triple bonds can be monohydroborated to give vinylic boranes, which can be reduced with carboxylic acids to cis alkenes or oxidized and hydrolyzed to aldehydes or ketones. Terminal alkynes give aldehydes by this method, in contrast to the mercuric or acid-catalyzed addition of water discussed at 15-4. However, terminal alkynes give vinylic boranes (and hence aldehydes) only when treated with a hindered borane such as 47, 48, or catecholborane (p. 798)," or with BHBr2—SMe2. The reaction between terminal alkynes and BH3 produces 1,1-... 

Trimethylaluminum, which exhaustively methylates ketones (16-27), also exhaustively methylates carboxylic acids to give tert-butyl compounds (see also 10-99) ... 

Addition of carboxylic acids to alkynes Acylation of aldehydes or ketones Bisdecarboxylation of malonic acids Oxidation of arylmethanes with CrOs and AC2O... 

This is hardly stable and it was not until suitable conditions of dilution were found that it was possible to handle it in industry. Even at low temperatures it detonates easily, when it is in the solid or liquid state. Detonations occurred during attempts at liquefaction. Ite dilution in nitrogen at -181° stabilises it, but there was an accident under these conditions, which was due to the presence of carborundum that makes it sensitive to impact. In the gaseous state, it detonates at a pressure of 1.4 bar and above. It can only be kept under pressure when it is in a solution of acetone in which it is highly soluble. Alcohols to C4, ketones to C4, diols C3 and C4, and carboxylic acids to C4 all play the same stabilising role as acetone. 

Thus, the family of azolides represents a versatile system of reagents with graduated reactivity, as will be shown in the following section by a comparison of kinetic data. Subsequent chapters will then demonstrate that this reactivity gradation is found as well for alcoholysis to esters, aminolysis to amides and peptides, hydrazinolysis, and a great variety of other azolide reactions. The preparative value of azolides is not limited to these acyl-transfer reactions, however. For example, azolides offer new synthetic routes to aldehydes and ketones via carboxylic acid azolides. In all these reactions it is of special value that the transformation of carboxylic acids to their azolides is achieved very easily in most cases the azolides need not even be isolated (Chapter 2). 

Reductions. Silicon hydrides such as 1, which can achieve intramolecular pentacoordination, show enhanced reducing properties. Thus they can reduce aldehydes or ketones to alcohols,1 and reduce carboxylic acids to aldehydes via thermal decomposition of a silyl carboxylate (equation I).2 Reaction of acid chlo-... 

In the case of carboxylic acids [33], ketones [47] or sulfones [49], it was possible to prove a further prototropic rearrangement of allenes 19 with R2 = H yielding the alkynes 20. In other examples, the prototropic isomerization of the triple bond leads to conjugated dienes directly thus the allene of type 19 could only be postulated as an intermediate [50]. Braverman et al. showed that the allenes generated by prototropic isomerization of dipropargylic sulfones or sulfoxides, for example 24, are unstable. They are transferred rapidly via diradical intermediates to polycycles such as 27 [51-53],... 

Scheme 9.1 shows a generalized sequence of reactions for the oxidation of an alkane, via alcohol, ketone and carboxylic acid, to the completely oxidized products, water and carbon dioxide. The latter are often referred to as combustion products as they are the same as those formed by burning hydrocarbons. These are not normally desirable chemical products unless it is necessary to destroy a toxic, hazardous or otherwise unwanted waste material. Oxidation itself is not difficult to achieve, and is a highly exothermic or even explosive process. Selective oxidation, however, is a much greater challenge, as it is important to stop the sequence at the desired product without proceeding further down the oxidation pathway. 

In fluorosulfonic acid the anodic oxidation of cyclohexane in the presence of different acids (RCO2H) leads to a single product with a rearranged carbon skeleton, a 1-acyl-2-methyl-1-cyclopentene (1) in 50 to 60% yield (Eq. 2) [7, 8]. Also other alkanes have been converted at a smooth platinum anode into the corresponding a,-unsaturated ketones in 42 to 71% yield (Table 1) [8, 9]. Product formation is proposed to occur by oxidation of the hydrocarbon to a carbocation (Eq. 1 and Scheme 1) that rearranges and gets deprotonated to an alkene, which subsequently reacts with an acylium cation from the carboxylic acid to afford the a-unsaturated ketone (1) (Eq. 2) [8-10]. In the absence of acetic acid, for example, in fluorosulfonic acid/sodium... 

Scheme 25 Cathodic reduction of activated aliphatic carboxylic acids to aldehydes (R alkyl, yields 70-82%) and ketones (R benzyl, yields 66- 72%).

Carboxylic acid, aldehyde, ketone, ether, alcohol, ester, ester-R (the chain attached to the oxygen atom being a generic substituent), anhydride, acetal, amide, epoxide, acid halyde, primary amine, primary imine, cyano, secondary amine, secondary imine, tertiary amine, nitro derivative, metal-1, metal-2, carbene, halo derivative. 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

The strong oxidants Cr(VI) and Mn04 can also be used for oxidative cleavage of double bonds, provided there are no other sensitive groups in the molecule. The permanganate oxidation proceeds first to the diols and ketols, as described earlier (p. 757), and these are then oxidized to carboxylic acids or ketones. Good yields can be obtained provided care is taken to prevent subsequent oxidative degradation of the products. Entries 5 and 6 in Scheme 12.17 are illustrative. 

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