Carboxylic acid derivatives acyl chlorides, synthesis

As noted in the preceding section, one of the most general methods of synthesis of esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid derivative. Section 3.2.5 dealt with two other important methods, namely, reactions with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate esters. There is also the acid-catalyzed reaction of carboxylic acids with alcohols, which is called the Fischer esterification. 

The best yields are obtained when the ketene has an electronegative substituent, such as halogen. Simple ketenes are not very stable and must usually be generated in situ. The most common method for generating ketenes for synthesis is by dehydrohalo-genation of acyl chlorides. This is usually done with an amine such as triethylamine.167 Other activated carboxylic acid derivatives, such as acyloxypyridinium ions, have also been used as ketene precursors.168 Ketene itself and certain alkyl derivatives can be generated by pyrolysis of carboxylic anhydrides.169... 

The T2 linker has recently been shown to be a versatile backbone amide anchor. Immobilized disubstituted triazenes were acylated with carboxylic acid anhydrides or chlorides to give amide derivatives. These amides were cleaved under very mild conditions using trimethyl chlorosilane. This sequence thus employs the T2 system as backbone amine linker and was demonstrated in the automated library synthesis of substituted amide derivatives.54... 

At oxidation level 3, acid chlorides occupy a key position, since they may serve as a nearly universal substrate for an isohypsic transformation into any kind of carboxylic acid derivative. Acid halides are electrophiles that are synthetically equivalent to acyl cations (RCO ). In this capacity they are used for the synthesis of such important compounds as esters, amides (and hence, nitriles), thioesters, etc. (see Scheme 2.57), and for the formation of C-C bonds in the Friedel-Crafts reaction (see above). Acid chlorides may readily lose HCl upon treatment with triethylamine. This isohypsic conversion leads to ketenes, important reagents widely employed in [2 + 2] cycloadditions, as we will see later. 

In Chapter 9 you see the basic structure of each of the carboxylic acids and carboxylic acid derivatives. In this chapter we focus on the carboxylic acids and related compounds, such as esters, acyl chlorides, and acid anhydrides, and we also include some information on amides (see Chapter 13 for an additional examination of amides). Before you can get into synthesis and reactions, though, you need to understand the structure and nomenclature of these compounds. 

Activation of Carboxylic Acids Synthesis of Acyl Imidazoles. iV,AA-Carbonyldiimidazole (1) converts carboxylic acids into the corresponding acylimidazoles (2) (eq 1). The method can be applied to a wide range of aliphatic, aromatic, and heterocyclic carboxylic acids, including some examples (such as formic acid and vitamin A acid) where acid chloride formation is difficult. The reactivity of (2) is similar to that of acid chlorides, but the former have the advantage that they are generally crystalline and easily handled. Isolation of (2) is sirr5>le, but often unnecessary further reaction with nucleophiles is usually performed in the same reaction vessel. Conversion of (2) into acid chlorides (via reaction with HCl), hydrazides, hydroxamic acids, and peroxy esters have all been described. Preparation of the more irr5)ortant carboxylic acid derivatives is described below. 

Yet another piperidine-based antipsychotic agent replaces the butyrophenone or diarylpropyl function found in earlier compounds by a benzopyrimidine group. The synthesis starts by the conversion of the carboxylic acid in piperidine (22-1) to its acid chloride. Reaction with 1,3-difluorobenzene (22-2) in the presence of aluminum chloride affords the acylated product (22-3). Reaction with hydroxylamine leads to the corresponding oxime (22-4). Treatment of that derivative with a base... 

The most direct synthesis of 2-acylbenzo[6]thiophenes involves reaction of the readily available 2-lithio derivative with acylating agents, such as nitriles, acid anhydrides, etc. (equation 19). Benzo[f>]thiophene-2-carboxylic acids are available by a variety of cyclization reactions (Section 3.15.9.2.4) and the acid chlorides or esters can be used to synthesize 2-acyl derivatives by conventional means. 

Even the dilithium derivatives 86 of carboxylic acids 85 are acylated at carbon by acid chlorides.30 When the product 87 is worked up, it loses C02 in the usual way, making this a synthesis of ketones 88. Branched carboxylic acids work well in this sequence so it is the equivalent of the acylation of a secondary carbanion, i.e. the disconnection 88a is now acceptable. 

The second route to ipalbidine also provides the first synthesis of its /5-d-glucoside ipalbine.3 2-Methoxypyrroline (4) was condensed with methyl acetoacetate at 85 °C in the absence of solvent to give the keto-ester (5). Acylation of the sodium salt of (5) was achieved with p-methoxyphenylacetyl chloride, but the expected acyl derivative could not be isolated. However, after the addition of a further equivalent of sodium hydride and heating at 80 °C the cyclization product (6) was obtained in moderately good yield. Some of the corresponding carboxylic acid was also isolated. Demethylation and decarboxylation of (6) by means of 48 % hydrobromic acid then gave the tetrasubstituted pyridone (7), which was... 

---