Oxalyl chloride reaction with carboxylic acids

Carboxylic acids react with thionyl chloride (SOQ2) to produce the corresponding add chlorides, as shown in the above reaction.Thionyl chloride is an attractive reagent due to its low cost, and the fact that both byproducts produced in the reaction are gases. Thus, the reaction is driven to completion by the evolution of HCl and SO2, and a nearly pure acid chloride is obtained. The major drawback to the reaction is that it produces a strong acid (HCl) and thus cannot be used with compounds that are acid sensitive. Oxalyl chloride is often used as an alternative reagent. 

The Vilsmeier-Haack type adduct, formed by the reaction of oxalyl chloride with DMF can be also be employed for the activation of carboxylic acids, as shown in Fig. 8 [200]. 

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. 

Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-f>]carbazole-5,ll-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with M-benzylindole-2,3-dicarboxylic anhydride (852) at —96°C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with f-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed... 

Even an oligopeptide has been attached to (Table 4.3, compound 130) [111]. This was achieved by a coupling reaction of the carboxylic group in the side chain of the cyclopropane ring as well. First, the tert-butylcarboxylate 129 was synthesized by the reaction of the corresponding diazomethylbenzoate with Cgg. After hydrolysis with trifluoromethanesulfonic acid, the acyl chloride was generated by treatment with oxalyl chloride. Finally, in a one-step procedure the fullerene peptide 130 was obtained by the reaction with the N-deprotected pentapeptide H-(L-Ala-Aib)2-L-Ala-OMe. 

Acid chlorides are prepared from the corresponding carboxylic acids, most commonly from the reaction with thionyl chloride or oxalyl chloride (see Section 5.5.5). 

Construction of the thiomorpholine moiety starts by protection of the carboxylic acid in penicillamine (102) by reaction with hexyl dimethylsUane (Dmhs). Condensation of 103 with 1,2-dichloroethane leads to formation of the heterocychc ring by sequential displacement of halogen by nitrogen and sulfur to yield 104. Reaction of intermediate 104 with the benzophe-none (101), leads to formation of the sulfonamide (105). Mild acid then serves to reveal the free carboxyhc acid (106). This function is then converted to the acid chloride with oxalyl chloride. Treatment of this reactive intermediate with hydroxylamine leads to acylation on nitrogen to afford the proteinase inhibitor 107. ... 

For the formation of carboxylic acid chlorides from carboxylic acids different procedures are known. Often thionyl chloride or oxalyl chloride, both with catalytic amounts of DMF, are used. The reaction with thionyl chloride requires elevated temperatures and often provides various byproducts. Oxalyl chloride is useable at room temperature or... 

Carboxylation. The reaction of mesitylene with oxalyl chloride catalyzed by aluminum chloride to produce mesitoic acid presumably involves monoacylation. 

Many methods have been developed for p-lactam synthesis, including cyclisation of the corresponding amino acids. The most widely used methods are two-component couplings, which occur via concerted cycloaddition or two-step mechanisms. Another simple route to 3-functionalised azetidinones is the reaction of aziridine-2-carboxylic acid sodium salt with oxalyl chloride or thionyl chloride. ... 

Oxalyl chloride (reaction c) is more reactive than phthaloyl chloride and its use enables the chlorides to be obtained from sensitive carboxylic acids1116 or their Na salts in benzene1117 at ambient temperature or below. Some of the nitro derivatives of benzoic acid afford only the mixed anhydrides when 2 moles of the acid are heated with 1 mole of oxalyl chloride.1118 To obtain the free acid chloride, and not its hydrochloride, from basic carboxylic acids an alkali salt of this acid may be treated with oxalyl chloride. 

Carboxylic acids can be converted to the corresponding acyl chlorides, which react with an amine containing chromophore. A few methods have been developed for conversion of acids to acyl chlorides. Hoffman and Liao [107] used a mixture of triphenylphosphine and carbon tetrachloride or polystyryldiphenylphosphine to prepare acyl chlorides of fatty acids. The reaction was carried out at 80 °C for 5 min. The intermediate acyl chlorides were then converted to amides with p-nitroaniline or p-melhoxyaniline. Thionyl chloride [108] and oxalyl chloride [109] were also applied to prepare acyl chloride. The conversion with oxalyl chloride was quantitative in 30 min at 70 °C. The commonly used amines were 1-naphthylamine [109] and p-chloroaniline [110]. The final derivatives were separated by RP-HPLC with either gradient [108] or isocratic elution [109,110]. 

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