Carboxylic esters, acylation alkylation

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

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. 

As in Section 5.06.9.1, the assignments are sometimes arbitrary. Important routes to oxadiazoles, aminooxadiazoles, oxadiazolinones, and oxadiazolinethiones involving the reaction of hydrazides RCONHNH2 with carboxylic acids, acyl chlorides, alkyl esters, or trialkyl orthoesters are described in Section 5.06.9.2.1, reactions with carbon disulfide... 

This has been applied to the cyclization of dihalides [45, 46], nonconjugated, unsaturated ketones [47] and esters [48], oxoalkylpyridinium salts [49], aldehydes and unsaturated nitriles [50], halides, and unsaturated esters [51], The umpoled acceptors, mostly radical anions or carban-ions (see Scheme 1), can also be used in intermolecular reactions such as acylation, alkylation, or carboxylation (Eq. 5). 

Hydroxylamines and hydrazines can be acylated on insoluble supports using the same type of acylating agent as is used for the acylation of amines [146-149]. Because of their higher nucleophilicity, hydroxylamines or hydrazines can be acylated more readily than amines, and unreactive acylating agents such as carboxylic esters can sometimes be successfully employed (Table 13.10). Polystyrene-bound O-alkyl hydroxamic acids can be N-alkylated by treatment with reactive alkyl halides and bases such as DBU (Entry 5, Table 13.10). 

Carboxylic esters. The molecular ion of the ester 1R-C022R is usually observed in those cases where the alkyl group, 2R, is smaller than C4. The characteristic ions in the spectrum arise from McLafferty rearrangements, which can occur with either the acyl- or alkoxy-alkyl group, providing they are at least three or two carbon atoms long respectively. 

If the alcoholate or the alkylating reagent contains a carboxylic acid ester, acylation of the alcoholate can compete with alkylation. This potential side reaction does not cause trouble in the examples sketched in Scheme 6.14 (first and third reactions), because these esters are sterically hindered and devoid of a hydrogen (no ketene formation can occur) but, as illustrated in Scheme 6.15, less hindered esters can readily undergo transesterification with alcoholates. 

N-Trifluoroacetyl derivatives were applied in the GC analysis of amino acids in combination with different alkyl esters. TFA anhydride serves as a strong acylating agent, which is very efficient in the derivatization of all protonic groups except carboxyl. An acylation medium, usually a mixture of TFA anhydride and methylene chloride, may be injected into the GC column without any preliminary evaporation. This is a very important fact as TFA derivatives are very sensitive towards moisture and mere evaporation can lead to decomposition, particularly of acylated hydroxy and thiol groups. Possible losses of more volatile derivatives are also eliminated. 

Other acyl alkyl esters have been utilized only sporadically. Makita et al. [241] analysed N-isobutyloxycarbonyl methyl esters of protein amino acids. During the first step of the preparation, the amino group reacts with isobutyl chloroformate according to Scheme 5.21. The reaction is accomplished in 10 min in an aqueous medium in the presence of sodium carbonate at room temperature. Excess of the reagent is extracted with diethyl ether and the reaction mixture is saturated with NaCl, acidified with ortho-phosphoric acid to pH 1—2 and extracted with diethyl ether. Methanol is added to the ethereal extract and the carboxyl group is esterified with diazomethane at room temperature for 5 min, The solvent is removed under a stream of nitrogen at 50°C and the residue is dissolved in ethyl acetate. Arg does not provide a volatile derivative when sub-... 

The most important method for the preparation of aryl ketones is known as Friedel-Crafts acylation. The reaction is of wide scope. Reagents other than acyl halides can be used," including carboxylic acids," anhydrides, and ketenes. Oxalyl chloride has been used to give diaryl 1,2-diketones." Carboxylic esters usually give alkylation as the predominant product (see 11-11)." A-Carbamoyl p-lactams reacted with naphthalene in the presence of trifluoromethanesulfonic acid to give the keto-amide." ... 

We have previously seen (10-70) that dianions of carboxylic acids can be alkylated in the a position. These ions can also be acylated on treatment with a carboxylic ester ° to give salts of p-keto acids. As in 10-70, the carboxylic acid can be of the form RCH2COOH or RR CHCOOH. Since p-keto acids are so easily converted to ketones (12-40), this is also a method for the preparation of ketones R C0CH2R and R COCHRR, where R can be primary, secondary, or tertiary alkyl, or aryl. If the ester is ethyl formate, an a-formyl carboxylate salt (R = H) is formed, which on acidification spontaneously decarboxylates into an alde-hyde. ° This method accomplishes the conversion RCH2COOH RCH2CHO, and is an alternative to the reduction methods discussed in 19-39. When the carboxylic acid is of the form RR"CHCOOH, better yields are obtained by acylating with acyl halides rather than esters. 

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