Acid-catalyzed acylation

Scheme 25). The introduction of greater diversity at C-2 and C-4 can be achieved by intercepting the tetrahydropyridinone intermediate in a multi-step sequence involving C-2 ammonolysis, microwave-assisted N-acylation, acid-catalyzed cyclization (to introduce diversity at C-2), treatment with POCI3, and either microwave-assisted nucleophiUc substitution or Suzuki couphng (to introduce diversity at C-4) [89]. 

The most apparent chemical property of carboxylic acids their acidity has already been examined m earlier sections of this chapter Three reactions of carboxylic acids—con version to acyl chlorides reduction and esterification—have been encountered m pre vious chapters and are reviewed m Table 19 5 Acid catalyzed esterification of carboxylic acids IS one of the fundamental reactions of organic chemistry and this portion of the chapter begins with an examination of the mechanism by which it occurs Later m Sec tions 19 16 and 19 17 two new reactions of carboxylic acids that are of synthetic value will be described... 

The mechanism of acid catalyzed ester hydrolysis is presented m Figure 20 4 It IS precisely the reverse of the mechanism given for acid catalyzed ester formation m Section 19 14 Like other nucleophilic acyl substitutions it proceeds m two stages A... 

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

The acid-catalyzed rearrangements of substituted pyrroles and thiophenes consequent on ipso protonation have been referred to previously (Section 3.02.2.4.2). There is some evidence that these rearrangements are intramolecular in nature since in the case of acid-induced rearrangement of 2-acylpyrroles to 3-acylpyrroles no intermolecular acylation of suitable substrates could be demonstrated (Scheme 10) (8UOC839). 

Acid-catalyzed hydrogen exchange Halogenation Acylation and alkylation Mercuration Diazo coupling Nitrosation... 

A number of examples of acid catalyzed ring expansion of acyl and thioacyl azetidines to sbc-membered rings have been reported (B-73MI50903). This type of rearrangement (Scheme 2) is similar to the more general vinylaziridine to pyrroline ring expansion. 

Although the previous two sections of this chapter emphasized hydrolytic processes, two mechanisms that led to O- or N-acylation were considered. In the discussion of acid-catalyzed ester hydrolysis, it was pointed out that this reaction is reversible (p. 475). Thus, it is possible to acylate alcohols by reaction with a carboxyhc acid. To drive the reaction forward, the alcohol is usually used in large excess, and it may also be necessary to remove water as it is formed. This can be done by azeotropic distillation in some cases. 

The acid catalyzed elimination of acylated amines has recently been described and is said to resemble the acid dehydration of alcohols in character ... 

Acetic anhydride has also been used as the acylating agent. The formation of thiiranes from thiocyanatohydrins having a tertiary hydroxy group is best achieved by p-toluenesulfonic acid-catalyzed acetylation.The analogous thiocyanatohydrins with a secondary hydroxyl and a tertiary thiocyanate function give a predominance of epoxide from thiocyanatohydrin acetates since the hydrolysis rate of the secondary acetate grouping becomes competitive with that of the tertiary thiocyanate. 

A very interesting steric effect is shown by the data in Table 7-12 on the rate of acid-catalyzed esterification of aliphatic carboxylic acids. The dissociation constants of these acids are all of the order 1(T, the small variations presumably being caused by minor differences in polar effects. The variations in esterification rates for these acids are quite large, however, so that polar effects are not responsible. Steric effects are, therefore, implicated indeed, this argument and these data were used to obtain the Es steric constants. Newman has drawn attention to the conformational role of the acyl group in limiting access to the carboxyl carbon. He represents maximum steric hindrance to attack as arising from a coiled conformation, shown for M-butyric acid in 5. 

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need to use an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. 

Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid. 

Fischer esterification reaction (Section 21.3) The acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol to yield an ester. 

Acyl-l-aryl-3-methyltriazenes are potential prodrugs of the methylating agents l-aryl-3-methyl-triazenes. The groups of Iley and Rosa (Iley et al., 1989 Carvalho et al., 1993) studied therefore the base- and acid-catalyzed hydrolysis of such acylated triazenes. 

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