Phosphorus pentachloride with carboxylic acids

Several papers have been devoted to the subject of reactions of phosphoranes with carboxylic acids and their derivatives. Thus triphenylphosphine dibromide (111) in acetonitrile cleaves lactones,93 while the corresponding dichloride (112) converts esters into acid chlorides.94 The reactions of esters with phosphorus pentachloride (101) have been studied further,95 and the influence of structural changes on the yields of products (113) and (114) has resulted in minor modifications to the mechanism previously96 outlined. 

For example, treatment of imino chloride 144 derived from 7p-(2-phenyl-2-bromo) acetamido-3-methyl 3-cephem benzhydryl ester (143) and phosphorus pentachloride, with an excess of methanolic lithium methoxide in THF at -78°C for 20 min, followed by quenching with acetic acid, afforded 7 -phenylketenimino-7a-methoxy- -lactam (146) in 60% yield. This material was reasonably stable to silica gel chromatography and, when treated with trifluoroacetic acid followed by aqueous quenching, quantitatively afforded 7p-phenylacetamido-7a-methoxy-3-methyl-3-cephem-4-carboxylic acid. Similar treatment of imino chlorides (144) or ketenimines (146) with lithium methoxide at -20 C provided iminoethers (147) in good yield. In the case of the imino chloride formed from 7p-dichloroacetamido-7-deacetoxycephalosporanic acid methyl ester, the corresponding iminoether (147) was obtained in 80% yield with lithium methoxide, even at — 78°C. The same imino chloride reacted... 

Treatment of phthalocyaninesulfonic or -carboxylic acids with chlorinating agents such as phosphorus pentachloride or thionyl chloride leads to the corresponding acid chlorides, e.g. 7. 

The stereochemistry of the addition of phosphorus pentachloride to isolated acetylenes in non-polar solvents has been shown by n.m.r. to be CIS, as illustrated for the adduct (46) from propyne. This observation has been explained in terms of a four-centre process. Contrary to a previous report, the reaction of triphenylphosphine hydrobromide with phenyl-acetylene carboxylic acid (47) yields both the trans- and the known c/5-adducts. 

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. 

The )V-(2,2-diethoxycarbonyl)vinyl derivative of cephalosporin C (34) was reacted with thiols in water at pH 6.5 at 60°C for 5-6 hr, or in boiling methylene chloride for 50 min, or in the absence of a solvent at 140°C for 15 min to give the mercapto derivatives (1584) (82EUP45717). When the mercapto derivatives (1584) first were reacted with dimethylaniline and dichlorodimethylsilane at 30°C for 10 min, the mixtures were then cooled to -10°C, and phosphorus pentachloride was added, followed by stirring at -5°C for 40 min, the 7-aminoceph-3-ene-4-carboxylic acid derivatives (1585) were obtained after work-up. 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides for example, 5-hydroxy-2-pyrazinecarboxylic acid, rather than 5(477)-pyrazinone-2-carboxylic acid, is chlorinated with phosphorus pentachloride/phosphoryl chloride to afford a 63% yield of 5-chloro-2-pyrazinecarbonyl chloride <1994SL814>. Sato and Narita provided an improved synthesis of various halogenopyrazines in which 2(l//)-pyrazinones were activated with chlorotrimethylsilane to give silyl ethers (Section 8.03.7.3). This procedure is most effective for synthesis of bromopyrazines whose overall yields are 62-81% <1999JHC783>. Bromopyrazine is directly prepared by treatment of 2-(l//)-pyrazinone with phosphoryl... 

All attempts to isolate 2-halogeno-l,3-dioxolanes or -1,3-dioxanes were unsuccessful. For instance, 2-chloro-l,3-dioxolane was detected only by photochlorination of 1,3-dioxolane (Ref. 118) at low temperature and 2-chloro-2-methyl-l,3-dioxolane was prepared by treatment of 2-methyl-l,3-dioxolane-2-carboxylic acid with phosphorus pentachloride at —60°, and shown119 to rearrange to 2-chloroethyl acetate on warming to 0°. For other examples of such problems, see especially, references 120 and 121. 

Xanthone is unreactive towards hydrazine and phenylhydrazine. The oxime is obtained by reaction of xanthione (xanthene-9-thione) with hydroxylamine, or from xanthone and hydroxylamine in pyridine. When the oxime is heated in water with phenylhydrazine, the phenylhydrazone is formed. In acid solution, xanthone reacts normally with 2,4-dinitro-phenylhydrazine but xanthone-1 -carboxylic acid (435) gives the pyridazinone (436), possibly via the hydrazone (57JCS1922). When the oxime is heated with phosphorus pentachloride it undergoes a Beckmann rearrangement to give the amide (437) (70MI22300). 

Carboxylic acids react with phosphorus trichloride, phosphorus pentachloride, or thionyl chloride with replacement of OH by Cl to form acyl chlorides, RCOC1 ... 

In neutral medium the deuterium solvent isotope effect, (A h2o/ D2o) in the hydrolysis of diaryldiacyloxyspirosulphuranes483, 404-407 has been found to be 1.66. In acidic medium the ratio of catalytic rate constants has been found to be 0.56. Heterocondensed imidazoles 408, are produced in the reaction of N-benzylamides, 409, of nitrogen heterocyclic carboxylic acids with phosphorus pentachloride. Deuterium labelling experiments have been carried out to understand the mechanism of this reaction involving a nitrile ylide species484. 

Formation of the carboxylic acid chloride, e.g. with thionyl chloride or with phosphorus. pentachloride. 

General methods for the preparation of acid halides from aliphatic carboxylic acids are described in Section 5.12.1, p. 692. Phosphorus pentachloride is the preferred chlorinating agent for aromatic acids which contain electron-withdrawing substituents, and which do not react readily with thionyl chloride. The preparation of both p-nitrobenzoyl chloride and 3,5-dinitrobenzoyl chloride is described in Expt 6.161. These particular acid chlorides are valuable reagents for the characterisation of aliphatic alcohols and simple phenols, with which they form crystalline esters (see Section 9.6.4, p. 1241 and Section 9.6.6, p. 1248). 

The treatment of 4-oxo-4Z/-pyrido[ 1,2-a]pyrimidine-3-carboxylic acid 429 with phosphorus pentachloride in dichloromethane at 0°C gave acid chloride 430, which reacted with amine 431 in tetrahydrofuran in the presence of /V-methyl-TV-trimethylsilyl trifluoroacetamide at room temperature overnight to give /-substituted 3-carboxamide 432 (88USP4777252). After catalytic debenzylation, the 3-substituent of 4//-pyrido[l, 2-a]py-rimidin-4-one 433 was involved in different reactions to give antibacterial derivative 434 (see Scheme 25). 

One of the earliest attempts to prepare analogues of FA as potential inhibitors involved the synthesis of 2-amino-4,7-dihydroxypteridine-6-carboxylyl-p-ami-nobenzoic acid (612) (in which the change from the structure of FA itself is exchange of the methylene bridge for a carbonyl group, and oxidation of position 7 to a lactam). This compound, which was a surprisingly effective inhibitor, was prepared from isoxanthopterin carboxylic acid (611) by in situ conversion to its acid chloride with a mixture of phosphorus oxychloride and phosphorus pentachloride, followed by addition of p-aminobenzoylglutamic acid (Scheme 3.132) [115]. 

The 8-oxo-7-phenylacetylamino-5-thia-l-aza-bicyclo[4.2.0]oct-l-ene-2-carboxylic acid benzhydryl ester is reacted with phosphorus pentachloride/pyridine reagent in methylene dichloride, and the reaction mixture is thereafter cooled to -35°C and treated with methanol to produce hydrochloride of 7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester. This hydrochloride is reacted with 4-(3-aminothiophen-2-yl)-5-oxohex-3-enoic acid 3-methylbut-2-enyl ester. Then 7-[2-(2-benzoylamino-thiazol-5-yl)(3-tert-butyl-4,4-dimethylpent-2-enoxycarbonyl)-pent-2-enoylamino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid synthesized is reacted with aluminum chloride in anisole and diluted hydrochloric acid and then with dimethylmalonate to give 5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-2-(2-amino-4-thiazolyl)-4-carboxy-l-oxo-2-butenyl)amino)-8-oxo-, (6R,7R)- (Ceftibuten). 

Thieno[2,3-c]isothiazole-3-carboxylic acid was the compound obtained by the reaction of ethyl 3-cyano-5,5-diethoxy-2-oxopentanoate with phosphorus pentachloride in refluxing toluene, previously assumed (55JA4069) to yield thieno[3,4-c ]isothiazole-4-carboxylic acid. The proposed mechanism involves the cyclization of the intermediate 3-cyano-2,5-dithioxopentanoate as shown in Scheme 20. The parent heterocycle, which is a weak base and fails to give quaternary salts with alkyl halides, was obtained by decarboxylation of the acid and also by independent synthesis (82AJC385). 

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