Pyridines carboxylic acid halides

Solid-liquid phase systems with no added solvent produce esters in high yield [e.g. 2, 3] and are particularly Useful when using less reactive alkyl halides [e.g. 15], for the preparation of sterically hindered esters [16], or where other basic sites within the molecule are susceptible to alkylation, e.g. anthranilic acid is converted into the esters with minimal A-alkylation and pyridine carboxylic acids do no undergo quat-emization [17]. Excellent yields of the esters in very short reaction times (2-7 minutes) are also obtained when the two-phase system is subjected to microwave irradiation [18]. Direct reaction of the carboxylic acids with 1,2-dichloroethane under reflux yields the chloroethyl ester [19], although generally higher yields of the esters are obtained under microwave conditions [20]. 

The formation of hydrated cobalt(n) complexes of pyridine carboxylic acids and the subsequent thermal decomposition to lower hydrates has been documented.82,83 Cobalt(n) halides react with 6-methylpicolinic acid (6-mpaH), picolinic acid (paH), nicotinic acid (naH), and pyridine-2,6-dicarboxylic acid (2,6-py) to form Co(6-mpa) (6-mpaH)X (X = Cl, Br, or NCS), Co(naH)nX2 (n = 2, X = Cl, Br n = 3, X = NCS), and Co(pa)(paH)X, EtOH (X = Cl, Br, or NCS) which are all probably octahedral.83 6-Methylpicolinic acid also formed Co(6-mpaH)4X2,2HX (X = Cl or Br) which were formulated [(6-mpaH)2H]2[CoX4], since the electronic spectra show absorptions characteristic of tetrahalogenocobaltate(n) ions.83... 

Pyridines from 2-acetylenealcohols and carboxylic acid halides... 

In the course of this study, the authors determined /Lvalues for dibenzyl, methyl phenyl, methyl p-nitrophenyl, di-p-tolyl, di-isopropyl and tetramethylene sulphoxides and for diethyl, dipropyl and dibutyl sulphites. The /Lscales are applied to the various reactions or the spectral measurements. The /Lscales have been divided into either family-dependent (FD) types, which means two or more compounds can share the same /Lscale, family-independent (FI) types. Consequently, a variety of /Lscales are now available for various families of the bases, including 29 aldehydes and ketones, 17 carboxylic amides and ureas, 14 carboxylic acids esters, 4 acyl halides, 5 nitriles, 10 ethers, 16 phosphine oxides, 12 sulphinyl compounds, 15 pyridines and pyrimidines, 16 sp3 hybridized amines and 10 alcohols. The enthalpies of formation of the hydrogen bond of 4-fluorophenol with both sulphoxides and phosphine oxides and related derivatives fit the empirical equation 18, where the standard deviation is y = 0.983. Several averaged scales are shown in Table 1588. 

Unsymmetrical as well as symmetrical anhydrides are often prepared by the treatment of an acyl halide with a carboxylic acid salt. The compound C0CI2 has been used as a catalyst. If a metallic salt is used, Na , K , or Ag are the most common cations, but more often pyridine or another tertiary amine is added to the free acid and the salt thus formed is treated with the acyl halide. Mixed formic anhydrides are prepared from sodium formate and an aryl halide, by use of a solid-phase copolymer of pyridine-l-oxide. Symmetrical anhydrides can be prepared by reaction of the acyl halide with aqueous NaOH or NaHCOa under phase-transfer conditions, or with sodium bicarbonate with ultrasound. 

Imides can be prepared by the attack of amides or their salts on acyl halides, anhydrides, and carboxylic acids or esters. The best synthetic method for the preparation of acyclic imides is the reaction between an amide and an anhydride at 100°C catalyzed by H2S04. When acyl chlorides are treated with amides in a2 l molar ratio at low temperatures in the presence of pyridine, the products are N,N-diacylamides, (RCO)3N. ... 

These reactions are most important for the preparation of acyl fluorides. " Acyl chlorides and anhydrides can be converted to acyl fluorides by treatment with polyhydrogen fluoride-pyridine solution" or with liquid HF at — 10°C. Formyl fluoride, which is a stable compound, was prepared by the latter procedure from the mixed anhydride of formic and acetic acids. Acyl fluorides can also be obtained by reaction of acyl chlorides with KF in acetic acid or with DAST. Carboxylic esters and anhydrides can be converted to acyl halides other than fluorides by the inorganic acid halides mentioned in 10-77, as well as with PhsPXa (X = Cl or but this is seldom done. Halide exchange can be carried out in a... 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

It is worth noting that the Ullmann-Goldberg condensation of aryl halides with phenols and anilines worked efficiently in the presence of copper in water.50 For example, the coupling of 2-chlorobenzoic acid with 4-chlorophenol (K2C03/pyridine/copper powder) gave 2-(4-chlorophenoxy)carboxylic acid (Eq. 6.23).51 The Cu(I)-catalyzed transformation of 2-bromobenzoic acid into salicylic acid has also been studied in aqueous media (Eq. 6.24).52... 

Ring contractions of pyran derivatives are occasionally valuable. The contraction of 3-halo-2-pyrones to 2-furoic acids under the influence of alkali has been studied and the conditions defined.58112113 The method is adaptable to the preparation of 3-furoic acid via furan-2,4-dicarboxylic acid58 and of 3,4,5-triphenylfuran-2-carboxylic acid.113 Another ring contraction involving halides is the conversion of 4-chloromethylpyrylium salts into furylmethyl ketones as indicated in Scheme 21.114 Pyridine oxides may be transformed with unexpected ease into furans through treatment with a thiol (Scheme 22).115... 

In a similar approach (Equation 53), the use of a resin-bound nitrile allowed access to the corresponding resin-bound amidoximes 274, which could be converted into 1,2,4-oxadiazoles 275 via acylation with either an appropriate acid halide/ anhydride in the presence of a base or a carboxylic acid in the presence of a coupling reagent followed by cyclization, where the latter step was performed by heating in pyridine or diglyme and could be accelerated by the use of a microwave oven. Cleavage from the resin was easily achieved by the use of TFA in dichloromethane <2000BML1431>. 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

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. 

Symmetrical (but not unsymmetrical) anhydrides are useful acylating reagents as milder alternatives to acyl halides. The most convenient procedure for their preparation involves the interaction in benzene solution of the acyl halide with the corresponding carboxylic acid in the presence of pyridine, which removes the hydrogen chloride liberated as the insoluble pyridinium chloride. 

The pyridinium salt formed from the acyl halide and pyridine in the absence of a carboxylic acid is able to diacylate water and hydrogen sulfide at -20° to give simple anhydrides and diacyl sulfides, respectively. ... 

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