Esters, carboxylic acid hydrogenolysis

The blocking and deblocking of carboxyl groups occurs by reactions similar to those described for hydroxyl and amino groups. The most important protected derivatives are /-butyl, benzyl, and methyl esters. These may be cleaved in this order by trifluoroacetic acid, hydrogenolysis, and strong acid or base (J.F.W. McOmie, 1973). 2,2,2-Trihaloethyl esters are cleaved electro-lytically (M.F. Semmelhack, 1972) or by zinc in acetic acid like the Tbeoc- and Tceoc-protected hydroxyl and amino groups. 

The dibenzosuberyl ester is prepared from dibenzosubeiyl chloride (which is also used to protect —OH, —NH, and —SH groups) and a carboxylic acid (Et N, reflux, 4 h, 45% yield). It can be cleaved by hydrogenolysis and, like t-butyl esters, by acidic hydrolysis (aq. HCl/THF, 20°, 30 min, 98% yield). ... 

Ester enolates which contain the chiral information in the acid moiety have been widely used in alkylations (see Section D.1.1.1,3.) as well as in additions to carbon-nitrogen double bonds (sec Section D.1.4.2.). Below are examples of the reaction of this type of enolate with aldehydes720. The (Z)-enolate generated from benzyl cinnamate (benzyl 3-phenylpropcnoate) and lithium (dimethylphenylsilyl)cuprate affords the /h/-carboxylic acid on addition to acetaldehyde and subsequent hydrogenolysis, The diastereoselectivity is 90 10. 

On the other hand, syn-carboxylic acids are obtained from a deprotonation of the /5-silyl ester, giving the (E)-enolate, followed by reaction with different aldehydes and subsequent hydrogenolysis. No diastereomers of the aldol product are detected720. 

Hydrogenolyses of carboxylic acids and esters to the corresponding aldehydes seems very attractive due to their simplicity. Copper chromites are the most widely used catalysts.15 Raney copper and zinc oxide-chromium oxide have also been used for this process.16-18 The hydrogenolysis of methyl benzoate to benzaldehyde was studied on various metal oxides at 300-350°C. ZnO, Zr02 and Ce02 presented high activities and selectivities (Scheme 4.8). 

Benzyl esters of carboxylic acids are frequently used in organic synthesis for the protection of carboxyl groups. The C-O bond in benzyl esters can be cleaved more easily than the corresponding benzyl ether bond. The hydrogenolysis of an ester leads to carboxylic acid and toluene. Examples of debenzylation of benzyl esters of carboxylic acids on Pd/C catalysts are summarized in Table 4.4. 

Thiol esters undergo smooth reduction to give aldehydes by the Fukuyama hydrosilylation procedure, which is an alternative way to transform carboxylic acids to aldehydes. Upon treatment with Et3SiH and 10% Pd/C, a thioester underwent smooth reduction to give an aldehyde.409,410 For example, to a stirred mixture of thioester and Pd/C in acetone may be added Et3SiH at room temperature under an Ar atmosphere. Stirring is continued until the hydrogenolysis is complete (0.5-1 h) (Scheme 4.117). 

The hydrogenolysis of the thiol esters of carboxylic acids offers a delicate method for reducing an acid to the corresponding aldehyde or alcohol application of this method to the sugar series has been made by Wolfrom and Karabinos who reduced D-ribonyl chloride tetraacetate (LXXV) to aldehydo-D-ribose tetraacetate (LXXVII) in 22% yield via ethyl thiol-D-ribonate tetraacetate (LXXVI). The desulfurization of the thiol ester (LXXVI) was carried out with a somewhat aged sample of Raney nickel" which doubtless had less activity than the... 

Carbenicillin Carbenicillin, [25 -(2a,5a,6j3)]-3,3-dimethyl-7-oxo-6-(2-carboxy-2-phenylacetamido)-4-thia-l-azabicyclo[3.2.0]-heptan-2-carboxylic acid (32.1.1.32), is synthesized by direct acylation of 6-APA in the presence of sodium bicarbonate by phenylmalonic acid monobenzyl ester chloride, which forms the benzyl ester of carbenicillin (32.1.1.31), the hydrogenolysis of which using palladium on carbon or calcium carbonate as catalyst gives the desired product (32.1.1.32) [51-58]. 

The amino ester 16 was then hydrolyzed to the carboxylic acid and isolated in 90% yield (Scheme 5.6). Subsequently, the amino acid was coupled with triazole 3 using EDC activation to afford the amide 17 in 90% assay yield. Removal of the chiral auxiliary was achieved via hydrogenolysis using Pd/C or Pd(OH)2 as catalyst to obtain sitagliptin in 83% assay yield. 

Benzyl alcohol linkers, such as those described in Section 3.1.1.1, can also be cleaved by palladium-catalyzed hydrogenolysis. Carboxylic acids have, for example, been obtained by hydrogenolysis of insoluble benzyl esters with Pd(OAc)2/DMF/H2 [89,161]. Resin-bound benzylic carbamates [162,163] and amides [164] can also be released by treatment with Pd(OAc)2 in DMF in the presence of a hydrogen source, such as 1,4-cyclohexadiene or ammonium formate. These reactions are quite surprising, because they require the formation of metallic palladium within the gelated beads. 

Diphenylmethyl (benzhydryl) esters.3 These esters can be cleaved either by acid hydrolysis or hydrogenolysis. They have been prepared by reaction of carboxylic acids with diphenyldiazomethane, generated in situ by oxidation of ben-... 

Conversion of the methyl ester of 1-adamantane carboxylic acid to 1-ada-mantyl dimethylcarbinol (66) by reaction with CH3Mgl followed by dehydration and subsequent hydrogenation provides a convenient route to 1-iso-propyladamantane (66a) 164> 20°). Simmons-Smith cyclopropanation of 1-isopropenyladamantane (67) followed by hydrogenolysis of the cyclopropane ring gives 1-r-butyladamantane (68) 204>. An alternative synthesis... 

Fig. 13.40. Alkylation of an ester enolate for the preparation of an a-hydroxycarboxylic acid (for the preparation of enantiomerically pure a-hydroxy carboxylic acid through alkylation of an enantiomerically pure ester enolate cf. Figure 13.41). The initially formed benzyl ester B contains two benzylic C—0 bonds, which can be cleaved by means of hydrogenolysis.

Other esters are sometimes used to protect carboxylic acids, especially when there is a desire to deprotect the acid by using different conditions from those available for methyl esters. Benzyl esters are prepared in the usual manner but can be cleaved by reaction with hydrogen and a catalyst. Again it is the benzylic carbon-oxygen bond that is broken in the hydrogenolysis reaction ... 

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