Ketones, preparation from carboxylic acid

Ketones, preparation from carboxylic acid, 66, 119 8-Lactams, 65, 140... 

Electrochemical reduction of oxazolinium salts 36 gives the anions 37, which add efficiently to alkyl halides or, in the presence of McsSiCl, to methyl acrylate, methyl vinyl ketone, and acrylonitrile. Simple acid hydrolysis then gives the ketone products 38 and 39, and this method is quite general since the starting salts are readily prepared from carboxylic acids, R C02H (87TL4411). 

Methyl ketones are often directly prepared from carboxylic acids by reaction with methyllithium. Other simple alkyl ketones may also be prepared in the same fashion, making this a method that should be considered whenever these substrates are required. An important demonstration of this protocol was reported by Masamune and coworkers in their synthesis of chiral propionate surrogates (Scheme 13). The ethyl and cyclopropyl ketones are important starting materials for macrolide total synthesis and have been prepared on a large scale. The overall yield for the ethyl ketone is 65% using 3.5 equiv. of ethyllithium without protection of the hydroxy group. 

Other acylating agents are similarly effective in the formation of ketones by reaction with homocuprates. Kim has demonstrated that activated esters such as the 2-pyridyl carboxylates are satisfactory cuprate traps.These esters can be prepared from carboxylic acids and 2-pyridyl chloroformate, provided a catalytic amount of DMAP is utilized (Scheme 35). 

The reaction of trivalent carbocations with carbon monoxide giving acyl cations is the key step in the well-known and industrially used Koch-Haaf reaction of preparing branched carboxylic acids from al-kenes or alcohols. For example, in this way, isobutylene or tert-hutyi alcohol is converted into pivalic acid. In contrast, based on the superacidic activation of electrophiles leading the superelectrophiles (see Chapter 12), we found it possible to formylate isoalkanes to aldehydes, which subsequently rearrange to their corresponding branched ketones. 

The haloform reaction is sometimes used for the preparation of carboxylic acids from methyl ketones... 

Grignard reagents can be successfully prepared from 4-iodoisoxazoles and these react with CO2 and ketones to give carboxylic acids and methanols, respectively. 3-Bromo- or... 

Differences in solubility of the reactants may for example be utilized as follows. Sodium iodide is much more soluble in acetone than are sodium chloride or sodium bromide. Upon treatment of an alkyl chloride or bromide with sodium iodide in acetone, the newly formed sodium chloride or bromide precipitates from the solution and is thus removed from equilibrium. Alkyl iodides can be conveniently prepared in good yields by this route. Alkyl bromides are more reactive as the corresponding chlorides. Of high reactivity are a-halogen ketones, a-halogen carboxylic acids and their derivatives, as well as allyl and benzyl halides. 

Iodine in functionalization of C 19 meth> 1 group of 3d acetoxy 20/3 hydroxy 5 pregnene 46, 58 Iron powder in preparation of ketones from carboxylic acids, 47, 75 Isobutene, 45, 49... 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Ketones can also be prepared directly from carboxylic acids by activation as mixed anhydrides by dimethyl dicarbonate.236 These conditions were used successfully with alkanoic and alkanedioic acids, was well as aromatic acids. 

Because of the toxicity of cadmium compounds two alternative methods for the preparation of ketones from carboxylic acid derivatives are worthy of attention. The first involves the reaction of organocopper reagents [formed from copper(i) iodide and an alkyllithium] with a carboxylic acid chloride.12 7a,b... 

In the organic field the experiments using the rotating cryostat have been aimed at the preparation of the radical anions of some aliphatic compounds which had not been prepared previously namely, the radical anions from carboxylic acids and ketones. 

The reaction depicted was run in THF at 0 C, other solvents having been found to be inferior. The S-(2-pyridyl) thioates may be prepared through reaction of the corresponding acid chloride and 2-pyridine-thiol in the presence of a tertiary amine. They are also available directly from carboxylic acids by reaction with 2,2 -dipyridyl disulfide (Aldrithiol-2) and triphenylphosphine. In the case illustrated above, protection of the ketone would seem unnecessary if Grignard addition was selective for the thiol ester however, the starting material, 5-(2-pyridyl) y-oxopentanethioate, is not stable to the lactonization shown in equation (18). 

Conductivity measurements have revealed that DMF and carboxylic acid chlorides form salt-like adducts (22) in an equilibrium reaction (equation 12). Such adducts can be prepared either from DMF and acid halides (chlorides and bromides) or from chloromethyleneiminium salts and salts of carboxylic acids. Acyloxyiminium salts (23) can be prepared in the pure state by reacting acid amides with carboxylic acid chlorides in the presence of silver trifluoromethanesulfonate (equation 13). Salts of type (24 equation 14) are regarded as being intermediates in the synthesis of ketones from carboxylic acids and Grignard reagents in the presence of a-chloroenamines as well as in the preparation of acyl halides (F, Cl, Br, I) by action of a-haloenamines on carboxylic acids. ... 

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