Thionyl chloride, reaction with carboxylic

The equivalence of sulfur and oxygen in this ring system carries over to NSAIDs as well. Preparation of the sulfur analogue of isoxepac (6-4) starts with the alkylation of thiophenol (27-1) with benzyl chloride (26-1). Cyclization of the intermediate thioether (27-2) then affords the homothioxanthone (27-3). The carboxyl side chain is then extended by means of the Amdt-Eistert homologation reaction. The acid is thus hrst converted to its acid chloride by means of thionyl chloride. Reaction with excess diazomethane leads to the diazoketone (27-4). Treatment of that intermediate with silver benzoate and triethylamine leads the ketone to rearrange to an acetic acid. There is thus obtained tiopinac (27-5) [28]. 

Fig. Mechanism for the thionyl chloride reaction with a carboxylic acid to form an acid chloride.

Thionyl chloride reacts with carboxylic acids in the way as shown in the scheme below. In the first step the reaction yields HCl and the intermediate benzoyl chlorosulfonate ... 

Now let s draw the forward scheme. Acid catalyzed hydrolysis of the amide gives a carboxylic acid which is then converted to the acid chloride upon treatment with thionyl chloride. Reaction with a hthium friatkoxyaluminum hydride, followed by water, produces the aldehyde. Subsequent treatment of the aldehyde with methylamine under acid-catalyzed conditions (with removal of water) gives the desired imine. 

Carboxylic acids react with thionyl chloride to form acid chlorides. Reaction with alcohols gives esters, and with amines, amides are formed. 

Sulfonyl chloride 178 also has the common name oimesyl chloride. Another very common derivative is 4-methylbenzenesulfonyl chloride (179), also called />am-toluenesulfonyl chloride, which is also called tosyl chloride) (nomenclature for benzene-containing compounds is discussed in Chapter 21). This particular compound is introduced here because it so common and clearly fits into this section. Thionyl bromide (SOBrg) converts sulfonic acids to the corresponding sulfonyl bromide. This reaction is exactly analogous to the reactions with carboxylic acids. 

Carboxyl Activation Synthesis of Esters and Amides from Carboxylic Acids. 4-(Dimethylamino)pyridinium chlorosulfite chloride is more reactive than either thionyl chloride or thionyl chloride/pyridine for carboxyl activation. Aliphatic and aromatic, as well as amino acids (in racemic form), undergo activation (via the acyl halide) and subsequent esterification by reaction with an alcohol at — 20 °C (eq 1). The esterification step requires the addition of a second equivalent of DMAP and this method has been applied to a range of functionalized carboxylic acids. 

The formation of the 4,4-dichlorochromen compounds which have been mentioned several times in this review, is another example of reaction at the pyrone carbonyl group. Thionyl chloride reacts with the pyrone group of chromone-2-carboxylic esters to give 4,4-dichlorochromen-2-carboxylates (81) [162], a reaction which may be reversed by means of aqueous sodium bicarbonate at room temperature [168]. 

Due to the biological activity of bisphosphonic acids, a vast array of derivatives and precursors have been generated including bile salts (Scheme 4.166) [255]. The overall process started with protection of the alcohols on the parent bile salt through the addition of formic add. Once suitably protected, the addition of thionyl chloride converted the carboxylic acid into an add chloride. Since these conversions are typically carried out using an excess of the thionyl chloride, the ranoval of unreacted material can be particularly troublesome. In these reactions, the ranoval of the excess thionyl chloride was achieved through repeated trituration with benzene. The final steps in the synthesis entailed... 

Now let s draw the forward scheme. Hydrolysis of the nitrile to the carboxylic acid, followed by reaction with thionyl chloride, produces the acid chloride. Reaction with excess methyl magnesium bromide, followed by water work-up, results in the formation of a tertiary alcohol, with the incorporation of two new methyl groups. The tertiary alcohol can then serve as a nucleophile in an acetylation reaction (upon treatment with acetyl chloride) to give the desired ester. 

Oxidation of the primary alcohol gives the corresponding carboxylic acid (A). Reaction of A with thionyl chloride converts the carboxylic acid to the acid chloride (B). Reaction of B with excess ammonia produces the amide (C). Carboxylic acid (A) undergoes Fischer esterification upon reaction with ethanol and catalytic acid to produce the ethyl ester (D). Reaction of acid chloride B with a lithium trialkoxyalumimrm hydride produces aldehyde F, which can also be made from ester D by reaction with DIBAH (E). 

Acyl chlorides are readily available They are prepared from carboxylic acids by reaction with thionyl chloride... 

The 3-o-ch orophenvl-5-methvlisoxa2ole4-carboxylic acid, from which the acid chloride was prepared, was obtained by hydrolysis of the ester product of the reaction between o-chloro-benzohydroxamic chlorideand ethyl acetoacetate in methanolic sodium methoxide. Reaction with thionyl chloride gave the starting material. 

Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride (SOCl2), as we saw in the previous section. Similar reaction of a carboxylic acid with phosphorus tribromide (PB ) yields the acid bromide. 

Benzothiepins synthesized by a double Knoevenagel condensation (see Section 2.1.1.2.) contain free carboxylic acid groups if the reaction product is isolated under acidic conditions. Rcesterification can be performed by two methods via formation of the acid chloride and subsequent alcoholysis, or by reaction with diazomethane, e.g. the conversion of 3-benzo-thiepin-2,4-diearboxylic acid (5, R = C02H) with thionyl chloride and methanol gives the dimethyl ester 5 (R = C02Me) in 47% yield, while the diazomethane pathway provides 60% of the dimethyl ester.65 Use of excess diazomethane leads to cycloadducts (see Section 2.2.4.). 

Thionyl chloride is another activating agent employed for reactions between aromatic carboxylic acids and phenols in pyridine solution. The mechanism suggested does not involve the formation of an acid chloride but assumes the existence of an intermediary mixed sulfinic anhydride which undergoes reaction with phenolic endgroups (Scheme 2.32).311... 

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is by formation of the acyl chloride. Molecules devoid of acid-sensitive functional groups can be converted to acyl chlorides with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride provides the acyl chloride. When a salt is used, the reaction solution remains essentially neutral. 

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