Carboxylic esters, acylation reduction

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

Anhydrides are reduced with relative ease. McAlees and McCrindle 20) established the following increasing order of difficulty for various carbonyls acid chlorides > aldehydes, ketones > anhydrides > esters > carboxylic acids > amides. Reduction may proceed by 1,2-addilion of hydrogen or by cleavage of an oxygen-carbonyl bond. If 1,2-addition to the carbonyl occurs, as in the presence of strong protic acids over palladium, 1,1-diesters are formed by acylation 26). 

Aldehydes and ketones can be converted to ethers by treatment with an alcohol and triethylsilane in the presence of a strong acid or by hydrogenation in alcoholic acid in the presence of platinum oxide. The process can formally be regarded as addition of ROH to give a hemiacetal RR C(OH)OR", followed by reduction of the OH. In this respect, it is similar to 16-14. In a similar reaction, ketones can be converted to carboxylic esters (reductive acylation of ketones) by treatment with an acyl chloride and triphenyltin hydride. " ... 

Modifications at the carboxyl group include reduction (with dibor-ane260 or borohydride, after activation with soluble carbodiimide261,262), esterification (with diazomethane,101,223,283,264 or acyl or aryl chlorides224,264), and formation of amide esters.263,265... 

Reduction of carboxylic acids 9-42 Reduction of carboxylic esters 9-43 Reduction of carboxylic esters with titanocene dichloride 9-44 Reduction of anhydrides 9-45 Reduction of acyl halides 9-53 Reduction of nitriles 9-57 Reduction of hydroperoxides 9-60 Reduction of peroxides 9-69 Reaction between aldehydes and base (Cannizzaro)... 

Figure 26.2. Synthesis of an Ether Phospholipid. Steps in the synthesis include (1) acylation of dihydroxyacetone phosphate by acyl CoA, (2) exchange of an alcohol for the carboxylic acid, (3) reduction by NADPH, (4) acylation by a second acyl CoA, (5) hydrolysis of the phosphate ester, and (6) transfer of a phosphocholine moiety.

We have previously seen (10-70) that dianions of carboxylic acids can be alkylated in the a position. These ions can also be acylated on treatment with a carboxylic ester ° to give salts of p-keto acids. As in 10-70, the carboxylic acid can be of the form RCH2COOH or RR CHCOOH. Since p-keto acids are so easily converted to ketones (12-40), this is also a method for the preparation of ketones R C0CH2R and R COCHRR, where R can be primary, secondary, or tertiary alkyl, or aryl. If the ester is ethyl formate, an a-formyl carboxylate salt (R = H) is formed, which on acidification spontaneously decarboxylates into an alde-hyde. ° This method accomplishes the conversion RCH2COOH RCH2CHO, and is an alternative to the reduction methods discussed in 19-39. When the carboxylic acid is of the form RR"CHCOOH, better yields are obtained by acylating with acyl halides rather than esters. 

Alternative methodologies for the indirect reduction of carboxylic derivatives employ as intermediates 2-substituted 1,3-benzoxathiolium tetrafluoborates (prepared from carboxylic acids, acyl chlorides, anhydrides, or esters) and dihydro-1,3-... 

A variety of terminal functional groups and their chemical transformations on SAMs have been examined for example, (i) olefins—oxidation [23,24,131,132], hydroboration, and halogenation [23,24] (ii) amines—silyla-tion [145,146], coupling with carboxylic acids [22,146], and condensation with aldehydes [22,147] (iii) hydroxyl groups—reactions with anhydrides [148,149], isocyanates [150], epichlorohydrin [151], and chlorosilanes [152] (iv) carboxylic acids—formation of acyl chlorides [153], mixed anhydrides [154], and activated esters [148,155] (v) carboxylic esters—reduction and hydrolysis [156] (vi) thiols and sulfides—oxidation to generate disulfides [157-159] and sulfoxides [160] and (vii) aldehydes—condensation with active amines [161], Nucleophilic... 

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