Synthesis of Acids and Esters

Carbonylation of RX into acids or esters is one of the best known and most utilized reactions. Its scope is unusually large since it has been applied to vinylic, aromatic, heterocyclic, benzylic, aliphatic and allylic halides or pseudohalides (Table III). 

Iodides are always more reactive than bromides chlorides are, as usual, less reactive, especially in the aromatic series, where high temperatures (hence high pressures) are necessary. 

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The selectivity and mildness of the Pd(0)-catalyzed deprotection of allyl (All) esters and the allyloxycarbonyl (Aloe) urethanes117 181 reaction also allowed for the successful and efficient application of this blocking group technology in the synthesis of acid- and base-labile lipidated pepti-... 

The adducts (94) of triphenylphosphine and alkylphenyl-AT-p-tosylsulphilimines also act as dehydrating agents, and have been employed in the synthesis of acid anhydrides, esters, and amides.90-91... 

The above reagents serve as condensing reagents and have different reactivities for peptides 279, p-lactams 281, esters, thioesters, and mixed phosphates, as well as for the direct preparation of 3-acyl-2(3F/)-oxazolones. The bis(2-oxo-3-oxazohnyl)phosphinate 282 is useful for Zr(IV)-catalyzed phosphorylation of alcohols, leading to the general synthesis of acid- and base-labile mixed phosphate esters 284 (Fig. 5.67). ... 

Ribonucleic acids (RNAs) were employed as catalysts in the synthesis of amides and esters, peptide bond formation and Diels-Alder reactions. The approach suffers from the fact that it requires the reactants to be either RNA itself or a compound covalently tethered to RNA. Indeed, there is one prominent example where RNA acts as a true catalyst in a bimolecular Diels-Alder cycloaddition without tethering the substrates [11. ... 

Preparation.—Synthesis of acid-labile esters can be achieved by treatment of the corresponding lithium alkoxide, from the alcohol and n-butyl-lithium, with an acid chloride t-butyl pivalate can be obtained in 64% yield by this procedure. Hindered acids are esterified by triethyloxonium fluoroborate in the presence of ethyl di-isopropylamine. The use of boron trifluoride etherate-alcohol is recommended as a mild, efficient esterification method, as is the employment of alkyl t-butyl ethers, which react with carboxylic acids under acid catalysis to give the alkyl ester, isobutene, and water, no free alcohol being ever present. 

Currently, Candida rugosa and Pseudomonas cepacia lipases, thermolysin, subtilisin, and penicillin acylase are commercially available from Altus Biologies Inc. and have proved to be very effective catalysts for the synthesis of peptides and esters, and the resolution of acids, alcohols, amines, and amino acids in a variety of media [370-372,374-377,379-381]. In addition, proteinase K, lactate dehydrogenase, horse liver alcohol dehydrogenase, and rabbit muscle aldolase have also been crossUnked and shown to operate efficiently in synthetic reactions [305,374,378,382,383]. The unique features, and the advantages and drawbacks of using CLECs, are outlined in Table 9. 

The monosubstituted malonic ester still possesses an activated hydrogen atom in its CH group it can be converted into a sodio derivative (the anion is likewise mesomeric) and this caused to react with an alkyl halide to give a C-disubstituted malonic ester. The procedure may accordingly be employed for the synthesis of dialkyImalonic and dialkylacetic acids ... 

Ethylene Cyanohydrin Process. This process, the fkst for the manufacture of acryhc acid and esters, has been replaced by more economical ones. During World War I, the need for ethylene as an important raw material for the synthesis of ahphatic chemicals led to development of this process (16) in both Germany, in 1927, and the United States, in 1931. 

Formic acid is used as an intermediate in the production of a number of dmgs, dyes, flavors, and perfume components. It is used, for example, in the synthesis of aspartame and in the manufacture of formate esters for flavor and fragrance appHcations. 

Garboxylation Reaction. The carboxylation reaction represents the conversion of acetylene and olefins into carboxyHc acids (qv) or their derivatives. The industrially important Reppe process is used in the synthesis of P-unsaturated esters from acetylene. Nickel carbonyl is the catalyst of choice (134). 

The chemical inertness of the three-membered ring permitted many conversions of functional groups in diazirines. Esterifications, cleavage of esters and acetals, synthesis of acid chlorides, oxidation of hydroxy groups to carboxyl groups as well as Hofmann alkenation all left the three-membered ring intact (79AHC(24)63). 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

The main use of acrolein is to produce acrylic acid and its esters. Acrolein is also an intermediate in the synthesis of pharmaceuticals and herhicides. It may also he used to produce glycerol hy reaction with isopropanol (discussed later in this chapter). 2-Hexanedial, which could he a precursor for adipic acid and hexamethylene-diamine, may he prepared from acrolein Tail to tail dimenization of acrolein using ruthenium catalyst produces trans-2-hexanedial. The trimer, trans-6-hydroxy-5-formyl-2,7-octadienal is coproduced. Acrolein, may also he a precursor for 1,3-propanediol. Hydrolysis of acrolein produces 3-hydroxypropionalde-hyde which could he hydrogenated to 1,3-propanediol. ... 

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

Photosensitive functions are in many cases also heat sensitive, so the preparation of photosensitive polyimides needs smooth conditions for the condensations and imidization reactions. Some chemical reactants, which can be used for polyamide preparation, have been patented for the synthesis of polyimides and polyimide precursors. For example, chemical imidization takes place at room temperature by using phosphonic derivative of a thiabenzothiazoline.102 A mixture of N -hydroxybenzotriazole and dicyclohexylcarbodiimide allows the room temperature condensation of diacid di(photosensitive) ester with a diamine.103 Dimethyl-2-chloro-imidazolinium chloride (Fig. 5.25) has been patented for the cyclization of a maleamic acid in toluene at 90°C.104 The chemistry of imidazolide has been recently investigated for the synthesis of polyimide precursor.105 As shown in Fig. 5.26, a secondary amine reacts with a dianhydride giving meta- and para-diamide diacid. The carbonyldiimidazole... 

Figure 29 (a) Synthesis route of the molecule (b) (i) S8, NaOH, tetraethyleneglycol dimethyl ether, heat, (28%). (b) Adamantane upper rim derivative based on the thiacalix[4]arene platform. (c,d) The carboxylic acid and ester derivative of adamantane can also be used as substituents. Taken from Ref. [109] with permission. 

The preparation of phosphate esters has been reviewed and full details have appeared of the use of 2-chloromethyl-4-nitrophenyl esters (reported last year) in the synthesis of monoesters and mixed dialkyl esters of phosphoric acid. 

By the enzymatic esterification of diglycerol with lauric acid, the corresponding monolaurate ester is obtained [84]. This is an important industrial reaction for the cosmetic, pharmaceutical and feed industries, since this ester is used as biodegradable non-ionic surfactant. In recent years, the synthesis of this and other polyglycerols with fatty acids has attracted growing interest in industry, leading also to a demand for enantiomerically and isomerically pure products. 

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