Ester carboxylic

Carboxylic acids may be converted to esters directly by using a primary or secondary alcohol and a small amount of strong acid catalyst. This is a reversible equilibrium, where ester formation is favored by using excess of the alcohol or by removing the water produced. Azeotropic distillation of the water or consumption of the water by concurrent hydrolysis of an acetal is usually effective. 

The highly reactive acid chlorides and anhydrides give esters irreversibly. Acetate esters of complex alcohols are routinely prepared by treating with acetic anhydride and pyridine. 

Several methods are available that do not begin with alcohols. The sodium or potassium salts of carboxylic acids are sufficiently nucleophilic to displace primary iodides (Eq. 6.7) [12]. 

Under neutral conditions, a carboxylic acid will react with diazomethane in ether to give nitrogen gas plus the methyl ester in high yield and purity (Eq. 6.8) [13]. This reaction is ordinarily performed on a small scale because diazomethane is volatile, toxic, and explosive. 

Ketones may be oxidized to esters by peracids or hydrogen peroxide, a process known as the Baeyer-Villiger oxidation. Unsymmetric ketones are oxidized selectively at the more substituted a carbon and that carbon migrates to oxygen with retention of configuration. Trifluoroperacetic acid generated in situ gave the double example in Equation 6.9 [14]. Cyclic ketones afford lactones (Eq. 6.10) [15]. 

The reaction of carboxylic acid esters with a mixture of chlorosulfonic acid and phthaloyl chloride affords a useful one-step procedure for the conversion of esters directly into the acyl chlorides. For instance, heating an equimolar mixture of chlorofluoroacetate 99, phthaloyl chloride 100 and chlorosulfonic acid afforded chlorofluoroacetyl chloride 101 (88% yield) (Equation 41).  

A detailed study on the conventional benzoylation and pivaloylation of d-fructose has been undertaken following consideration of factors such as equilibration rates and the distribution of tautomeric forms at given temperatures, practical procedures for the selective preparation of either pyranose, furanose, or acyclic peresters have been worked out. The selectivities in electrochemically induced esterifications of D-glycals have been investigated and compared with selectivities in chemically induced ester formations.  

6-Tetra-0-ben2yl-l-0-trimethylsilyl-a-D-mannopyranose reacted with a series of carboxylic acids in the presence of Bp3.0Et2 to give a-esters 1 in good 

Alkyl a- and p-hexopyranosides with protected primary hydroxyl groups were, as a rule, selectively acetylated at 0-2 and 0-3, respectively, by vinyl acetate and Pseudomonas cepacia lipase the effects of variations in the size and hydrophobi-city of the anomeric and primary substituents on the regioselectivity of these reactions have been discussed in terms of enzyme-substrate binding. Methyl P-D-ribopyranoside, methyl P-D-arabinopyranoside, methyl P-D-xylopyranoside, and methyl-a-L-rhamnopyranoside were all acetylated at 0-4 by lipases from 

Sucrose 1 -methacrylate, a highly desirable starting material for making new polymers, has been obtained by treatment of sucrose with vinyl methacrylate in the presence of subtilisin. A theoretical study of the subtilisin-promoted esterification of sucrose with vinyl esters in organic solvents showed that with increasing hydrophobicity of the solvent and chain-length of the acyl group the preference for reaction at the 1 -position decreased in favour of reaction at 0-6.  

A single acyl group has been introduced into P-cyclodextrin, either at a 2- or a 3-position, by exposure to benzoyl- or a- or P-naphthoyl chloride in alkaline aqueous acetonitrile. A Lipid A disaccharide esterified with (5)-3-hydroxytetra-decanoic acid and a Lipid A monosaccharide carrying a fluorinated JV-acyl group are referred to in Chapters 3 and 9, respectively. 

The most difficult step in the catalytic cycle is the first an oxidative insertion of the palladium catalyst a into the C—O bond of the carboxylic ester 3c, leading to the acyl complex b. This was unprecedented even for activated esters, and is increasingly endothermic with increasing basicity of the alkoxide leaving group. In analogy to the de Vries process, an 

The reaction was successfully applied to both electron-rich and electron-poor 4-nitrophenyl carboxylates among them, the conversion of the electron-deficient esters was found to be faster and more efficient. Many functional groups are tolerated on both the side of the carboxylic ester (halo, keto, formyl, ester, cyano, nitro and protected amino groups, heterocyclic and a,-unsaturated carboxylic esters) and of the alkene (electron-rich alkyl-substituted alkenes, electron-poor acrylate derivatives, trimethylvinylsilane as an ethylene surrogate). The cinnamate derivatives could become particularly useful substrates, since the availability of the synthetically equivalent vinyl halides is rather limited. In analogy to conventional Mizoroki-Heck chemistry, linear (Zi)-substituted alkenes are predominantly but not exclusively obtained. Selected examples are shown in Table 4.1. 

Beside 4-nitrophenyl esters, other activated esters and amides (e.g. of pentafluorophenol, imidazole and meanwhile even 3-chlorophenol) have been shown to be viable substrates. However, substantial additional progress in catalyst development is required to extend the scope of the reaction further to carboxylic acid alkyl esters, which can be regenerated by in situ esterification. This is strictly required, as a two-step process is not likely to be able to compete with the standard Mizoroki-Heck reaction from a purely economical standpoint. 

Ar = substituted aryl, heteroaryl vinyl R = CO2R, Ph, CN, alkyl 

The substrate scope was found to be very similar to that described above for the 4-nitrophenyl esters, although the selectivity for the hnear alkene products in the Mizoroki-Heck reaction was somewhat lower. The reaction tolerates many functionalities, including esters, ethers, nitro, keto, trifluoromethyl and even formyl groups (Table 4.1). 

1 Synthesis - A short review (5 refs.) on the recently introduced 2-(chloro-acetoxymethyl) benzoyl- (CAMB) and 2-(2-chloroacetoxyethyl)benzoyl- (CAEB) protecting groups has been published.  

The stereochemistry of the C-methylation of l,2 5,6-di-0-isopropylidene-a-D-gulofuranose 3-esters (1 - 2) using various lithium-containing bases has been examined. Results were inconsistent with the Li-chelate formation proposed by 

Mohr (Vol. 22, Chapter 7, Ref. 1) but indicative of a Li-bridged post-enolization complex as proposed by Seebach (Helv. Chim. Acta, 1985,68,1373).  

Whereas acetolysis (H2SO4, AC2O) of peracetylated D-galactose diethyl dithioa-cetal 3 furnishes product 4, as expected, the unprotected diethyl dithioacetal 5 gave penta-O-acetyl-D-galactofuranose 6 under these conditions.  

Carbohydrate Chemistry, Volume 30 The Royal Society of Chemistry, 1998 

---

Lensink, M., Mavri, J., Berendsen, H.J.C. Simulation of a slow reaction with quantum character Neutral hydrolysis of a carboxylic ester. Submitted (1998). 

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

Indanedioiie (III) may also be prepared by condensation of diethyl phthalate (V) with ethyl acetate in the presence of sodium ethoxide the resulting sodium 1 3-indanedione-2-carboxylic ester (VI) upon warming with sulphuric acid yields (HI). 

Perhaps the most extensively studied catalytic reaction in acpreous solutions is the metal-ion catalysed hydrolysis of carboxylate esters, phosphate esters , phosphate diesters, amides and nittiles". Inspired by hydrolytic metalloenzymes, a multitude of different metal-ion complexes have been prepared and analysed with respect to their hydrolytic activity. Unfortunately, the exact mechanism by which these complexes operate is not completely clarified. The most important role of the catalyst is coordination of a hydroxide ion that is acting as a nucleophile. The extent of activation of tire substrate througji coordination to the Lewis-acidic metal centre is still unclear and probably varies from one substrate to another. For monodentate substrates this interaction is not very efficient. Only a few quantitative studies have been published. Chan et al. reported an equilibrium constant for coordination of the amide carbonyl group of... 

Methylsulfinyl enolates are more recently developed d -reagents. They are readily prepared from carboxylic esters and dimsyl anion. Methanesulfenic acid can be eliminated thermally after the condensation has taken place. An example is found in Bartlett s Brefeldin synthesis (P.A. Bartlett. 1978). 

The reductive coupling of aldehydes or ketones with 01, -unsaturated carboxylic esters by > 2 mol samarium(II) iodide (J.A. Soderquist, 1991) provides a convenient route to y-lactones (K. Otsubo, 1986). Intramolecular coupling of this type may produce trans-2-hy-droxycycloalkaneacetic esters with high stereoselectivity, if the educt is an ( )-isomer (E.J. Enholm, 1989 A, B). 

Asymmetric hydrogenation has been achieved with dissolved Wilkinson type catalysts (A. J. Birch, 1976 D. Valentine, Jr., 1978 H.B. Kagan, 1978). The (R)- and (S)-[l,l -binaph-thalene]-2,2 -diylblsCdiphenylphosphine] (= binap ) complexes of ruthenium (A. Miyashita, 1980) and rhodium (A. Miyashita, 1984 R. Noyori, 1987) have been prepared as pure atrop-isomers and used for the stereoselective Noyori hydrogenation of a-(acylamino) acrylic acids and, more significantly, -keto carboxylic esters. In the latter reaction enantiomeric excesses of more than 99% are often achieved (see also M. Nakatsuka, 1990, p. 5586). 

The conversion of primary alcohols and aldehydes into carboxylic acids is generally possible with all strong oxidants. Silver(II) oxide in THF/water is particularly useful as a neutral oxidant (E.J. Corey, 1968 A). The direct conversion of primary alcohols into carboxylic esters is achieved with MnOj in the presence of hydrogen cyanide and alcohols (E.J. Corey, 1968 A,D). The remarkably smooth oxidation of ethers to esters by ruthenium tetroxide has been employed quite often (D.G. Lee, 1973). Dibutyl ether affords butyl butanoate, and tetra-hydrofuran yields butyrolactone almost quantitatively. More complex educts also give acceptable yields (M.E. Wolff, 1963). 

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

COi is another molecule which reacts with conjugated dienes[10,95,96], COt undergoes cyclization with butadiene to give the five- and six-membered lactones 101. 102. and 103, accompanied by the carboxylic esters 104 and 105[97.98], Alkylphosphines such as tricyclohcxyl- and triisopropylphosphine are recommended as ligands. MeCN is a good solvent[99],... 

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 main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Preparation of indole-2-carboxylate esters by the Hemetsberger method... 

The Japp-Klingeraann coupling of aryidiazonium ions with enolates and other nucleophilic alkenes provides an alternative route to arylhydrazones. The reaction has most frequently been applied to P-ketoesters, in which deacylation follow S coupling and the indolization affords an indole-2-carboxylate ester. 

N-Substituted arylhydroxylamities add to methyl propyiioate and rearrangement occurs to give indolc-3-carboxylate esters[3]. With unsubstituted... 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

The reaction of alcohols with acyl chlorides is analogous to their reaction with p toluenesulfonyl chloride described earlier (Section 8 14 and Table 15 2) In those reactions a p toluene sulfonate ester was formed by displacement of chloride from the sulfonyl group by the oxygen of the alcohol Carboxylic esters arise by displacement of chlonde from a carbonyl group by the alcohol oxygen... 

Other Methods. Newer methods for forming pyrrole and related heterocyctic rings iaclude the formatioa of substituted pyrrole 2-carboxylate esters by coadeasatioa of P-dicarboayl compouads with glyciaate esters (25). 

An intramolecular Diels-Alder cyclization produces excellent yields of 2-aminoquinoline-3-carboxylate esters (57). Equally fine yields of the requited carbodiimides have been reported, making this an attractive route to an unusual substitution type. 

Nontoxic ahphatic compounds containing carboxyl, ester, or hydroxyl groups are readily biodegradable. Those with dicarboxyhc groups require longer acclimation times than those with a single carboxyl group. 

---