Thionyl chloride, reaction with carboxylic acid derivs

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. 

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... 

Any carboxylic acid derivative can be converted to any other using one or more of the reactions discussed in the previous sections. If the conversion requires going from a less reactive derivative to a more reactive one, then an indirect route may be necessary. Remember that any derivative can be hydrolyzed to a carboxylic acid using water and acid or base. Also remember that the carboxylic acid can be converted to the acyl chloride with thionyl chloride, providing access to the other derivatives. 

Due to the attractivity of this method several groups have developed onium salt supported versions of classical reactions. For example, starting from hydroxyl derived imidazolium salts, formation of supported acrylates with acryloyl chloride followed by reaction with diene in refluxing toluene afforded Diels Alder adduct in good yields (>65%). After saponification, products are isolated without further purification [127], Alternatively, starting from carboxylic acid derived imidazolium salts, acyl chloride formation with thionyl chloride in acetonitrile, followed by reaction with 4-aminophenol led to supported N-arylamide. Williamson alkylation using NaOH as a base and subsequent cleavage from the onium salt support under acidic condition (HCI/I I2()/ AcOH) allowed for isolation of various alkoxy substituted anilines with >98% purity... 

Acyl halides are among the most reactive of carboxylic acid derivatives. Acyl chlorides are more common and less expensive than bromides or iodides. They can be prepared from acids by reaction with thionyl chloride. 

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

The carboxylic functionalities inserted onto the tubes can be used as platforms to obtain further transformations (Fig. 3.5). A commonly utilized route is the reaction of carboxylic groups with thionyl chloride or oxalyl chloride to prepare the corresponding acyl chlorides, which are useful intermediates for amidation or esterification reactions. Amides can also be prepared directly from the acids by means of standard solution chemistry conditions, using carbodiimide derivatives in the presence of the selected amine. 

The synthesis of the heteroarylcarboxylic acid chlorides is fraught with difficulties. When isolated, the acid chlorides are generally unstable and readily produce bisheteroaryl ketones (see Section 3.05.1.2.9). Using standard preparative procedures the increase in the acidity of the reaction medium can cause polymerization, whilst the addition of a base can result in the formation of compounds of the type (403) and (404). Attempts to prepare indole-2 -carboxylic acid chloride using thionyl chloride result in the isolation of sulfur-containing derivatives, which arise from electrophilic attack at the 3-position (64JOC178). 

A concerted elimination-cyclization mechansim, involving a sulfenyl halide in a 1,3-butadiene-1-thio system, is the most probable mechanism for the formation of benzo[6 Jthiophenes from cinnamic acids or 4-aryl-2-butanones by treatment with thionyl chloride. The reactions shown in Scheme 5 have been carefully worked out, and the intermediates isolated (75JOC3037). The unique aspect of this synthesis is the reduction of the sulfinyl chloride (a) by thionyl chloride to form the sulfenyl chloride (b). The intermediate (b) was isolated and converted in pyridine to the 3-chlorobenzo[6]thiophene-2-carbonyl chloride in 36% yield (73TL125). The reaction is probably initiated by a sulfenyl ion attack on the aromatic ring, since it is promoted by electron-releasing groups para to the site of ring closure. For example, when X in (36) was N02, a 23% yield of (37), a mixture of 5-and 7-nitro derivatives, was obtained, but when X in (36) was OMe, a 54% yield of (37) was obtained, contaminated with some 3,4-dichloro-5-methoxybenzo[6]thiophene-2-carboxylic acid. 

The derivatization of DCCH to a carboxylic acid required conversion of the acid to acid chloride using thionyl chloride before reaction with the carbohydrazide group. To evaluate the chemiluminescent characteristics of this coumarin compound, the amide derivative of DCCH was isolated by preparative TLC. Although CL was observed from this product, detection limits were not determined because of the difficulty in quantitative transfer from TLC plates. 

In the event, iodolactonization of the carboxylate salt derived from the ester 458 afforded 459, and subsequent warming of the iodo lactone 459 with aqueous alkali generated an intermediate epoxy acid salt, which suffered sequential nucleophilic opening of the epoxide moiety followed by relactonization on treatment with methanol and boron trifluoride to deliver the methoxy lactone 460. Saponification of the lactone function in 460 followed by esterification of the resulting carboxylate salt with p-bromophenacylbromide in DMF and subsequent mesylation with methanesulfonyl chloride in pyridine provided 461. The diazoketone 462 was prepared from 461 by careful saponification of the ester moiety using powdered potassium hydroxide in THF followed by reaction with thionyl chloride and then excess diazomethane. Completion of the D ring by cyclization of 462 to the keto lactam 463 occurred spontaneously on treatment of 462 with dry hydrogen chloride. 

An example of the separation of the anilides of the eight lowest straight-chain carboxylic acids on sodium dodecylbenzene sulphonate is shown in Fig. 5.14. The problem of the procedure described above consists in that formanilide cannot be prepared as CO, SO2 and HC1 are produced by the action of thionyl chloride on formic acid. Formanilide must, therefore, be prepared in an aqueous medium, the other acids must be extracted into a non-aqueous medium. The yield of the extraction varies considerably depending on the type of the acid, and the presence of water in the reaction medium may affect the reaction yield significantly, which makes quantitative analysis difficult. Condensates with toluidine, which were used for the determination of formic acid by GC, are prepared by an analogous procedure. As other toluidine isomers may serve as the reagents, formyl derivatives have been suggested for the separation of these substances [181]. 

Enantiomers of carboxylic acids may sometimes be separated by GC as methyl esters, but special derivatives are mostly prepared for this purpose. Ackman et al. [188] resolved enantiomers of isoprenoid fatty acids after their conversion into L-menthyl esters. The acids under analysis were chlorinated by refluxing with distilled freshly prepared thionyl chloride and the chlorides produced were treated with L-menthol in the presence of pyridine under strictly anhydrous conditions. GC separation was carried out in a capillary column coated with butanediol succinate polyester. Annett and Stumpf [189] made use of L-menthyloxycarbonyl derivatives for the separation of enantiomers of methyl esters of hydroxy acids. The derivatization reagent, L-menthyl chloroformate, was prepared by the reaction of L-menthol with phosgene, with cooling with ice. Diastereoisomers of different hydroxy acids were thus separated on 1.5% OV-210. 

An acyl chloride is an acyl group bonded to a chlorine atom. Acyl chlorides are made by reaction of the corresponding carboxylic acids with thionyl chloride. Therefore, acyl chlorides are also called acid chlorides. We consider acyl chlorides in more detail when we study acid derivatives in Chapter 21. 

Methylisoxazole-5-carboxylic acid was converted into the corresponding 5-carboxamides and 5-(l/7-pyrazol-l-ylcarbonyl) derivatives in satisfactory yields by treatment with thionyl chloride and amines or pyrazoles <2002SC425>. A three-component assembly of isoxazole-5-carboxylic acid chloride, 1,1-dimethylallene, and bis-pinacolatodiboron, catalyzed by a phosphine-free palladium complex, gave 2-acylallylboronate derivatives regiose-lectively (Equation 47) <2003JA12576>. On the other hand, a mild procedure allowed the preparation of /3,7-unsaturated ketones by simple reaction of 3-aryl-5-methylisoxazole-4-carboxylic acid chlorides with allyl bromide and indium in DMF (Equation 48) <1997TL8745>. 

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