Carboxylic acids and acid chlorides

Carboxylic acids and acid chlorides can be identified by adding the suffix -anoicacid and -anoyl chloride, respectively. Both these functional groups are always at the end of the main chain and need not be numbered ... 

Propose multistep syntheses using carboxylic acids and acid chlorides as starting materials and intermediates. 

The first application using MDS in molecular diversity analysis was introduced by a group at Chiron as a means of reducing the enormous dimensionality of binary chemical descriptors They found that 2048-bit Daylight fingerprints associated with 721 commercially available primary amines could be reduced to only five dimensions that reproduced all 260,000 original dissimilarities with a standard deviation of only 10%. Similarly, only seven dimensions were required to reduce the 642,000 pairwise similarities among a set of 1133 carboxylic acids and acid chlorides to the same standard deviation. 

A solid phase copolymer of 4-vinylpyridine is a highly effective catalyst for the synthesis of acid anhydrides from mixtures containing equimolar quantities of carboxylic acids and acid chlorides. The reaction can be simplified even more if a mixture of carboxylic acid and one-half equivalent of thionyl chloride in dichloromethane is treated with the solid state copolymer of 4-vinylpyridine. The conversion is accomplished equally well in batch or column mode. Some examples are given in Table 10. 

The most common O- and N-acylation procedures use acylating agents that are more reactive than caiboxylic acids or their esters. Carboxylic acid chlorides and anhydrides react rapidly with most unhindered hydroxy and amino groups to give esters and amides, respectively ... 

During electrochemical fluorination retention of important functional groups or atoms in molecules is essential. Acyl fluorides and chlorides, but not carboxylic acids and anhydrides (which decarboxylate), survive perfluorination to the perfluorinated acid fluorides, albeit with some cyclization in longer chain (>C4) species [73]. Electrochemical fluorination of acetyl fluoride produces perfluoro-acetyl fluoride in 36-45% yields [85]. Electrochemical fluorination of octanoyl chloride results in perfluorinated cyclic ethers as well as perfluorinated octanoyl fluonde. Cyclization decreases as initial substrate concentration increases and has been linked to hydrogen-bonded onium polycations [73]. Cyclization is a common phenomenon involving longer (>C4) and branched chains. a-Alkyl-substituted carboxylic acid chlorides, fluorides, and methyl esters produce both the perfluorinated cyclic five- and six-membered ring ethers as well as the perfluorinated acid... 

A. Reaction with Carboxylic Acid Chlorides, Anhydrides, and Ketenes 135... 

To a suspension of 12.0 grams of 3-methylflavone-8-carboxylic acid in 200 ml of anhydrous benzene Is added 10.0 grams of thionyl chloride. The mixture is refluxed for 2 hours during which the suspended solid goes into solution. The solvent is completely removed by distillation, the residue extracted with benzene and the extract evaporated to dryness. The product, 3-methylflavone-8-carboxylic acid chloride, is recrystallized from ligroin to give crystals melting at 155° to 156°C. 

To 11.0 grams of 3-methylf avone-8-carboxylic acid chloride dissolved in 150 ml of anhydrous benzene is added at room temperature 4,8 grams of piperidinoethanol and the mixture refluxed for 2 to 3 hours. The separated solid is filtered, washed with benzene and dried. The product, piperidinoethyl 3-methylflavone-8-carboxylate hydrochloride is obtained as a colorless crystalline solid, MP 232° to 234°C, (from U.S. Patent 2,921,070),... 

There is obtained from 4-[)3-[5-methyl-isoxazolyl-(3)-carboxamido]-ethyl]-benzene-sulfonamide (prepared from 5-methyl-isoxazole-(3)-carboxylic acid chloride and 4-()3-aminoethyl)-benzene-sulfonamide hydrochloride, MP 213° to 214°C in pyridine) and chloroformic acid methyl ester, in a yield of 69%, the compound N-[ [-4-[)3-[5-methyl-isoxazolyl-(3)-carbox-amido] -ethyl] ] -benzene-sulfonyl] ] -methyl-urethane in the form of colorless crystals of MP 173°C. 

B.5 parts of 1 -azaphenothiazine carboxylic acid chloride and 14 parts of piperidino-ethoxy-ethanol were introduced into 100 parts of chlorobenzene and the mixture boiled under reflux for 5 minutes. After cooling off the precipitated hydrochloride salt of piperidino-ethoxy-ethanol was filtered off on a suction filter. Water was added to the filtrate and the pH thereof adjusted to 5 to 6 with dilute HCI. The aqueous phase was then removed, a caustic soda solution added thereto and then extracted with ether. The ethyl extract waswashed with water, then dried with potash and the ether distilled off. 9.4 parts of the piperidino-ethoxy-ethyi ester of 1 -azaphenothiazine carboxylic acid were obtained. This product was dissolved in 20 parts of isopropanol and the solution neutralized with isopropanolic HCI. The monohydrochloride which precipitated out after recrystallization from isopropanol had a melting point of 160°Cto 161°C. 

Preparation of 2-Cyclopropylcarbony/amido-5-Chlorobenzophenone To 400.5 g (1.73 mols) of 2-amino-5-chlorobenzophenone dissolved in 220 g (2.18 mols) of triethylamine and 3.5 liters of tetrahydrofuran is added cautiously 181 g (1.73 mols) of cyclopropane-carboxylic acid chloride. The reaction is refluxed 2 /2 hours and allowed to cool to room temperature. The solvent is then removed under vacuum to obtain 2-cyclopropylcarbonyl-amido-5-chlorobenzophenone as a residue which is dissolved in 1 liter of methylene chloride, washed twice with 5% hydrochloric acid, and then twice with 10% potassium hydroxide. The methylene chloride solution is then dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. The residue is recrystallized from 1,500 ml of methanol, charcoal-treating the hot solution to give 356 g of 2-cyclopropylcarbonylamido-5-chlorobenzophenone, MP 105° to 105.5°C (69% yield). 

Alcohols react with carboxylic acids to give esters, a reaction that is common in both the laboratory and living organisms. In the laboratory, the reaction can be carried out in a single step if a strong acid is used as catalyst. More frequently, though, the reactivity of the carboxylic acid is enhanced by first converting it into a carboxylic acid chloride, which then reacts with the alcohol. We ll look in detail at the mechanisms of these reactions in Chapter 21. 

SECONDARY AND TERTIARY ALKYL KETONES FROM CARBOXYLIC ACID CHLORIDES AND LITHIUM PHENYLTHIO(ALKYL)CUPRATE REAGENTS tert-BUTYL PHENYL KETONE... 

The procedure described here illustrates the preparation of mixed lithium arylhetero(alkyl)cuprate reagents and their reactions with carboxylic acid chlorides,4 These mixed cuprate reagents also react with a,a -dibromoketones,12 primary alkyl halides,4 and a,/3-unsaturated ketones,4 with selective transfer of only the alkyl group. 

The reaction of tert-alkyl Grignard reagents with carboxylic acid chlorides in the presence of a copper catalyst provides ieri-alkyl ketones in substantially lower yields than those reported here.4,14 The simplicity and mildness of experimental conditions and isolation procedure, the diversity of substrate structural type, and the functional group selectivity of these mixed organocuprate reagents render them very useful for conversion of carboxylic acid chlorides to the corresponding secondary and tertiary alkyl ketones.15... 

For use of other organocopper reagents in converting carboxylic acid chlorides to ketones, see G. H. Posner and C. E. Whitten, Tetrahedron Lett., 1815 (1973) G. H. Posner, C. E. Whitten, and P. E. McFarland, J. Amer. Chem. Soc., 94, 5106 (1972). For a recent report on direct and convenient preparation of lithium phenylthio (alkyl)-cuprate reagents, see G H Posner, D J Brunelle, and L. Sinoway, Synthesis, 662 (1974). 

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. 

Biphilicylides 117 can enter in cyclocondensations with carboxylic acid chlorides, carbon disulfide, and acyl isothiocyanates [126]. Certain corresponding heterocychc products 118 obtained are described for the first time (Y =N(CO)Ph Y=S) and are precursors of the new l-(2-phenylthiazol-5-yl)-5-phenyltetrazole 119 (Scheme 33). 

The course of the reaction of phosphinous amides with carboxylic acid chlorides is dependent on the characteristics of the iV-residue. Thus with N-aryl compounds this reaction gives chlorophosphanes and carboxamides. With AT-alkyl analogs the primary reaction products have not been identified but they hydrolyzed to carboxaldehydes [120]. 

Amino acids activated at the amino group by a benzotriazolide moiety react with amino acids under elimination of benzotriazole and C02 to give peptides. Reaction is achieved by warming up equimolar amounts of the components in anhydrous acetonitrile or aqueous acetone.[45] The benzotriazolylcarbonylamino acids are prepared from benzo-triazolyl-1-carboxylic acid chloride and amino acids.[46]... 

The l-acyl-3-methylimidazole-2-thiones are easily obtained either from bis-l-methyl-2-imidazole disulfide, a carboxylic acid, and triphenylphosphine, or from 2-mercapto-l-methylimidazole and a carboxylic acid chloride in the presence of triethylamine.[32 ... 

Arndtsen and coworkers [154] described the first Pd-catalyzed synthesis of miinchnones 6/1-318 from an imine 6/1-316, a carboxylic acid chloride 6/1-317 and CO. The formed 1,3-dipol 6/1-318 can react with an alkyne 6/1-319 present in the reaction mixture to give pyrroles 6/1-321 via 6/1-320, in good yields. The best results in this four-component domino process were obtained with the preformed catalyst 6/1-322 (Scheme 6/1.83). 

The use of other simple carboxylic acid chlorides led to similar results the corresponding monoacyl- and diacyl-phospholes (23b,c and 26b,c) were formed. In these cases, the 2-acylphosphole (23b,c) was practically the only monoacylderiv-ative that was formed (Scheme 6) [27], The yields were all in the range of 21-50%. 

Monosubstituted and 4,5-disubstituted oxazoles were easily obtained from aryl-substituted tosylmethyl isocyanides and aldehydes . Tosyloxazoles 107, prepared from TosMIC 106 and carboxylic acid chlorides, led to 5-substituted derivatives 108 through ultrasound-promoted desulfonylation <00JCS(P1)527>. 

Figure 10.5. Drawing of the whole synthesis route. Hydroxylation followed by esterification on the left side and epoxidation followed by addition of a carboxylic acid chloride on the right side.

P.Y.108 is obtained under condensation from 1-aminoanthraquinone, 1,9-an-thrapyrimidine-2-carboxylic acid, and a chlorinating agent, or directly with 1,9-an-thrapyrimidine-2-carboxylic acid chloride in an organic solvent in the presence of an acid trap. 

Finer particle sizes are obtained if l,9-anthrapyrimidine-2-carboxylic acid chloride is condensed with 1-aminoanthraquinone in a dipolar aprotic solvent (such as N-methylpyrrolidone) at a temperature between 70 and 110°C. The reaction may be accelerated by using a proton acceptor such as triethylamine or tert-butanol,... 

---