Carboxylic esters typical procedures

Methylation of Heteroatoms. The most widely used feature of the chemistry of diazomethane is the methylation of carboxylic acids. Carboxylic acids are good substrates for reaction with diazomethane because the acid is capable of protonating the dia-zomethane on carbon to form a diazonium carboxylate. The car-boxylate can then attack the diazonium salt in what is most likely an Sn2 reaction to provide the ester. Species which are not acidic enough to protonate diazomethane, such as alcohols, require an additional catalyst, such as Boron Trifluoride Etherate, to increase their acidity and facilitate the reaction. The methylation reaction proceeds under mild conditions and is highly reliable and very selective for carboxylic acids. A typical procedure is to add a yellow solution of diazomethane to the carhoxylic acid in portions. When the yellow color persists and no more gas is evolved, the reaction is deemed complete. Excess reagent can be destroyed by the addition of a few drops of acetic acid and the entire solution concentrated to provide the methyl ester. 

A convenient method for the synthesis and derivatization of enantiopure a-iso-cyanato carboxylic acid esters starting from a-amino acid esters has been devised [314], The isocyanates are obtained in enantiomerically pure form (> 99% ee) by a DMAP-catalyzed isocyanation with B0C2O, which proceeds in 10 min at room temperature (for typical procedures employing B0C2O, see the B0C2O Section of the present chapter). In situ derivatization of the isocyanates by reaction with amines and alcohols affords the corresponding enantiopure ureas and carbamates. Methyl esters of various amino acids 472 have been carbonylated by B0C2O at ambient temperature [314]. 

Typical procedure. 4-Bromo-3-[2-isocyano-2-(methoxycarbonyl)ethyl]ir dole-l-carboxylic acid tert-butyl ester 1559 [1187] The N-formyl-N -Boc-4 -bromo-tryptophan methyl ester 1558 (0.05 g, 0.14 mmol) was suspended in dry dichloromethane (3 mL) under argon and the solution was cooled to below 0 °C using an ice/salt bath. Tri-ethylamine (0.09 g, 0.86 mmol) was added through a septum, and then a solution of triphosgene (0.014 g, 0.05 mmol) in dichloromethane (1 mL) was added dropwise. The solution was allowed to warm to room temperature and stirred for a further... 

A common example for auxiliary-contfolled anti-aldol reactions is the Masamnne-Abiko process since the procedure covers the synthesis of both enantiomers depending on the nature of the auxiliary, which is readily available in both enantiomeric forms [15]. This anti-selective aldol reaction has been performed by using enantiomerically pure carboxylic esters derived from (-)- or (-i-)-norephedrine. The method is applicable to a wide range of aldehydes with high selectivity (both antilsyn and diastereoselectivity of anti-isomer) [16]. A typical example of this aldol approach is depicted in Scheme 2.113. It is proposed that the reaction proceeds via a six-membered Zimmerman-Traxler transition state. 

C, which decomposes when heated above the melting point. Its solubility at 25°C in g/100 g solvent is water. 111 methanol, 5 ethanol, 1.4 acetone, 0.04 and carbon tetrachloride, 0.004. Because its carbon—fluorine bond is unreactive under most conditions, this salt can be converted by standard procedures to typical carboxylic acid derivatives such as fluoroacetyl esters (11,12), fluoroacetyl chloride [359-06-8] (13), fluoroacetamide (14), or fluoroacetonitrile [503-20-8] (14). 

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 carboxylic acid coupling partner is initially deprotonated by triethylamine typically, forming the carboxylate ion which then reacts with the acid chloride to give a mixed anhydride. This forms the first part of the two-step procedure. The acylating agent dimethyiaminopyridine (DMAP) is then added, which reacts with the mixed anhydride to form an acyl pyridinium salt with the elimination of an aromatic carboxylate anion. The second coupling partner, the alcohol, then reacts with the acyl pyridinium salt to give the desired ester. 

There are very few exceptions. The most important are the methylation of alcoholic and carboxylic OH groups with diazomethane. This reaction is used for cases where high yields and mild conditions are required, e. g., for expensive hydroxy compounds like certain natural products. The methyl ester formation as well as the methylation of phenols does not need an acid catalyst as these substrates catalyze themselves the dediazoniation. For ether formation an acid catalyst, e. g., HBF4, is added (except from phenols). Typical is the methylation of 3)ff-hydroxycholestane, which proceeds in dichloromethane in 95 0 yield, as shown in the Organic Syntheses method of Neeman and Johnson (1973). Analogously, ethers can be transferred in dialkylmethyloxonium salts, as described in another Organic Syntheses procedure (Helmkamp and Pettitt, 1973) for the formation of a trimethyloxonium salt obtained... 

Esterification of thermally unstable carboxylic adds. Bicyclic jS-keto acids can be converted into ethyl esters by diethyl sulfate at 20° or lower with DBN as base. Methyl esters are obtained in the same way. Typical esters and the yields obtained by this procedure are given. ... 

Sn 1-active alkyl halides require longer reaction times (typically 3-6 h), and the yields are lower. f-Butyl chloride and adamantyl bromide have been used successfully, but the generality of the procedure needs to be demonstrated (eq 4). In contrast, acylation reactions using a wide variety of carboxylic acid chlorides have been carried out (eq 5). The initial products are protected forms of Q ,/3-diketo esters which can be isolated in yields of 72-93%. Deprotection is accomplished using MeOH/HCl. The products are vicinal tricarbonyl compounds having the usual characteristic chemical properties such as rapid formation of hydrated derivatives. The protected forms can be used directly in the synthesis of heterocycles. ... 

This synthetic procedure describes a typical method for preparing alkyl esters and for the preparation of alkoxy biphenyl-carboxylic acids. As with many liquid crystals, purification is important, and in this case chromatography can be used to produce products with better than 99.5% purity, which makes the materials eminently suitable for physical studies. 

Carboxyl groups, which are present when carboxylated supports, such as succinylated LCAA-CPG, are used, are usually blocked as amides. This blocking is typically a two-step procedure (Fig. 3) in which an activated p-nitrophenyl or pentachlorophenyl ester is first prepared. This ester is then treated with piperidine to create a more stable secondary amide. All of these capping reactions are quite simple to perform and very efficient. 

Typical experimental procedure for (S)-3-(l,3-dioxo-l,3-dihy-dro-isoindol-2-yl)-3-fluoro-2-oxo-piperidin-l-carboxylic acid tert-butyl ester (precursor of 3S-fluorothalidomide) using the dihydroquinine/NFSI combination with TMEDA Lithium bis (trimethylsilyl)amide solution l.OM in THF (0.087mL, 0.087 mmol) was added to the solution of 3-(l,3-dioxo-l,3-dihydro-iso-indol-2-yl)-2-oxo-piperidin-l-carboxylic acid tert-hutyl ester (20 mg, 0.058 mmol) and tetramethylethylenediamine (0.013 mL, 0.087 mmol) in THF (l.OmL) at -80°C under Ar. After being stirred for 0.5 hours, the suspension of the dihydroquinine/NFSI combination [the solution of dihydroquinine (28.4 mg, 0.087 mmol) and N-fluorobenzenesulfonimide (27.4 mg, 0.087 mmol) in THF (2.0 mL) was stirred for 1 hour at room temperature under Ar] was dropwise and then stirred for overnight at -80 °C. The reaction was quenched with IN hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica-... 

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