Acid chlorides, reaction with ester enolates

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

Silyl alkyl ketene acetals, as ester enolate equivalents, are capable of regioselective acylation by acid chlorides. Rathke and Sullivan showed that a variety of acid chlorides reacted with the acetal (3) to give protected -keto esters (Scheme 11). Acid hydrolysis of the silylated products gave the free -keto ester. The reaction was successful with a variety of acyl chlorides, including acetic, butanoic, (2 )-buten-... 

An alternative reagent, trimethylsilyldiazomethane in hexane, is commercially available and appears useful for preparation of bile acid methyl esters [62], Like carboxylic acid groups, hydroxyl groups also require protection prior to GC-MS analysis. A common and mild method to prepare trimethylsilyl (TMS) ethers is to react the sample with a mixture of dry pyridine, hexamethyldisilazane (HMDS), and trimethylchlorosilane (TMCS), 3 2 1 or 9 3 1 (by volume) with, or without heating [32], However, if 0X0 groups are present in the bile acid, this reaction can yield enol-TMS ethers and multiple products. This artifact can be avoided by converting the 0X0 group into an oxime, usually a methyloxime (MO). To do this, the sample is dissolved in 50 pL pyridine with 5 mg methoxyammonium chloride and heated for 30 min at 60°C [32]. 

The acylation of enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

Constitution of the Esters of the (3-Ketocarboxylic Acids and of the P-Diketones.—Ethyl acetoacetate is taken as example. It reacts like a ketone with phenylhydrazine, bisulphite, and other ketone reagents on the other hand it shows an acid reaction, it dissolves in alkalis, and gives the colour reaction with ferric chloride characteristic of ends and also of phenols. From this double behaviour it was formerly concluded that it was either purely ketonic or purely enolic and that the reactions in the other form were to be attributed to a rearrangement caused by the reagents used. The true state of affairs was first disclosed by... 

Acylation of ester enolates can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must be done in inert solvents to avoid solvolysis of the acylating agent. The preparation of diethyl benzoylmalonate (entry 1 in Scheme 2.14) is an example employing an acid anhydride. Entries 2-5 illustrate the use of acyl chlorides. Acylations with these more reactive compounds can be complicated by competing O-acylation. /V-Mcthoxy-iV-methylamidcs are also useful for acylation of ester enolates. 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

The third procedure illustrated by this preparation involves the reaction of ketones with trifluoromethanesulfonic anhydride in a solvent such as pentane, methylene chloride, or carbon tetrachloride and in the presence of a base such as pyridine, lutidine, or anhydrous sodium carbonate.7-11,15 This procedure, which presumably involves either acid-catalyzed or base-catalyzed enolization of the ketone followed by acylation of the enol with the acid anhydride, has also been used to prepare other vinyl sulfonate esters such as tosylates12 or methanesulfonates.13... 

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