Carboxylic methyl esters, hindered

The methyl ester (100, R = CH3), derived from this A-nor acid by treatment with diazomethane, is different from the ester (102) obtained either by Favorskii rearrangement of 2a-bromo-5a-cholestan-3-one (101) or by the action of cyanogen azide on 3-methoxy-5a-cholest-2-ene (103) followed by hydrolysis on alumina. The ketene intermediate involved in photolysis of (99) is expected to be hydrated from the less hindered a-side of the molecule to give the 2j -carboxylic acid. The reactions which afford (102) would be expected to afford the 2a-epimer. These configurational assignments are confirmed by deuteriochloroform-benzene solvent shifts in the NMR spectra of esters (100) and (102). ... 

The O-methylated extract was derivatized with 99 percent C-enriched methyl iodide. The NMR spectrum of the extract showed a strong absorption at 56 ppm (relative to TMS), which can be attributed to unhindered aryl methyl ethers (67%), a smaller absorption at 60 ppm, attributable to hindered aryl methyl ethers (23%), and a resonance at 51 ppm, assignable to methyl esters derived from carboxylic acids (10%).(16) TTiese results are consistant with those of Liotta l al, who studied the alkylation of whole Illinois No. 6 coal.(12)... 

Typical synthetic procedures include the reaction of alkyl halides with the silver salts of carboxylic acids, the reaction of carboxylate anions in alkali with an excess of a dialkyl sulphate, (especially dimethyl sulphate), and heating tertiary184 or quaternary ammonium salts of carboxylic acids. These routes are particularly valuable for the preparation of esters of seriously sterically hindered acids. For example, Fuson et al.iK made the methyl ester of 2,4,6-triethylbenzoic acid by heating the tetramethyl ammonium salt to 200-250°C, viz. 

The wide range of standard procedures that are available for the formation of carboxylic esters of primary and secondary alcohols in the presence of suitable acid catalysts is discussed in detail in Section 5.12.3, p. 695. Also included is the mild method for methyl ester formation from the carboxylic acid and diazomethane, and a method appropriate for sterically hindered esters involving the acid, a secondary or tertiary alkyl halide, and the non-nucleophilic base DBU (Expt 5.151). An example of the formation of a t-butyl ester is noted in Expt 6.165. 

Esterification. Dimethyl sulfate has been used widely for O-racthylation of phenols and alcohols, but has been used only a few times for esterification of carboxylic acids the method has not attracted much attention. Actually dimethyl sulfate is a useful reagent for this purpose, especially for esterification of hindered acids such as (1). This acid has been converted into the methyl ester in over 95% yield by either of two methods. Concentrated aqueous NaOH (I. I moles) is added at room temperature to a well-stirred mixture of (I, I mole) and dimethyl sulfate in dioxane followed by a... 

Carboxylic acids are converted into their methyl esters in high yield by this combination of reagents in refluxing acetone. The method is useful for esto ification of hindered acids. Tropolone is converted into 2-methoxylropone in 96% yield under the same conditions. ... 

Titanium alkoxide is quite effective, presumably as an acid/base catalyst, at facilitating transesterification between esters and alcohols [511-513]. The reaction conditions are mild and relatively hindered alcohols can be used. Methyl phenylacetate has been transformed to other esters of relatively hindered alcohols under the influence of Ti(OEt)4 (Eq. 216) [514]. Ethyl (or methyl) esters of a variety of functionalized carboxylic acids could be converted into menthyl esters in good yields under titanium catalysis (Eq. 217) [514]. 

Trimethyl phosphate has been suggested as a convenient reagent for esterify-ing hindered carboxylic acids and was used in this manner to convert 1,1 -binaphthyl-8-carboxylic acid into its methyl ester. Trialkyl phosphates have also been investigated as reagents for alkylating heterocyclic nitrogen bases. ... 

The direct coupling of t-butyl thiazole-4-carboxylate at C-2 is successful with a wide range of (hetero) aryl halides, the hindered ester (rather than the methyl ester), together with the use of tri-o-tolylphosphine as ligand, giving optimum selectivity for C-2 vs. C-5 for iodoarenes and heteroarenes. Changing the ligand to JohnPhos allows extension to chloro- and bromo-heterocycles. ... 

Zeolites have been employed to shift the equilibrium in transesterifica-tions by absorbing smaller molecules [57]. For example, the methyl ester of benzoic acid can be converted into the tertiary-butyl ester by refluxing in tertiary-butanol in the presence of zeolite 5A. Selective esterification of sterically hindered carboxylic acids with alkyl chloroformates over silica bound hexaalkylguanidinium chloride achieves high yields [58]. For example, benzyl 2,4,6-trimethylbenzoate was synthesised from the carboxylic acid and benzyl chloroformate in 96% yield at 120°C. 

An improved reagent for the G-alkyl cleavage of methyl esters by nucleophilic displacement has been found by a Stanford group lithium n-propyl mercaptide (from n-butyl-lithium and n-propyl mercaptan) in hexa-methylphosphoramide smoothly and selectively cleaves methyl esters to the corresponding carboxylic acid salts. The use of boron trichloride in dichloro-methane is recommended for the cleavage of sterically hindered methyl esters methyl ethers are unaffected. 

Figure 7.44 Top demonstration of how steric crowding increases in the tetrahedral intermediate formed during ester hydrolysis. Bottom the ultra-short-acting anesthetic remifentanil is a good example of using structure to design drugs with certain properties. Here an unhindered methyl ester undergoes rapid hydrolysis by esterase to form an inactive carboxylic acid giving the drug a very short half-life. Note that neither the hindered ester nor the amide are metabolized as rapidly.

This procedure provides a convenient method for the esterification ol a wide variety of carboxylic acids. The reaction proceeds smoothly with sterically hindered acids6 and with acids which contain various functional groups. Esters are obtained in high purity using Kugelrohr distillation as the sole purification technique. In cases where traces of dichloromethane present no problems, the crude product is usually pure enough to be used directly in subsequent reactions. Methyl and ethyl ethers of phenols may also be prepared by this procedure (see Note 8). 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

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