Substituted acetic acids pyridines

Vinamidinium salts are important intermediates in the synthesis of heterocycles. The 2-chloro-l,3-bis(dimethylamino)trimethinium hexafluorophosphate salt has been used in the preparation of the highly selective Cox-2 inhibitor etoricoxib (Scheme 1). This method describes a straight-forward preparation of the hexafluorophosphate salt which is a crystalline, thermally and shock-stable, non-hygroscopic solid. The submitters have extensively studied the preparation of vinamidinium salts and demonstrated that the method is applicable to substituted acetic acids that contain an electron-withdrawing group (Table 1)." The annulation reaction is also general and useful for the preparation of pyridines, pyridones and pyridine N-oxides. ... 

IR K for H bond formation, ion pair formation between pyridine and halogen substituted acetic acids in GCli, CHCls. 

The Gif system, which consists of triplet oxygen, acetic acid, pyridine, zinc and an iron catalyst, oxidizes saturated hydrocarbons mainly to ketones and gives minor amounts of aldehydes. Tertiary hydrogen is only substituted in exceptional cases. With the Gif-Orsay II system in which zinc is replaced by the cathode [divided cell, cpe at — 0.6 to —0.7 V vs see, trifluoroacetic acid, pyridine, Fe30(0Ac)6Pyr3.5], adamantane is converted in 3.8% coulombic yield the ratio of attack at a secondary tertiary CH bond (C /C ratio) is 15.0. Comparable conversions were carried out with cyclododecane to afford 21% oxidation with a ratio of alcohol ketone = 1 14. TranS decalin yielded 22% product, consisting of 0.6% 9-ol, 0.9% l-ol, 9.0% 1-on 0.65% 2-ol and 11% 2-one. A radical mechanism for this conversion can be excluded since for the cobalt-catalyzed radical oxidation of trans-decalin the C /C ratio is 0.13, which is far removed from 36 found with the Gif system. 

Various otiier qtproaches have been applied in changing flie Grubbs catalysts, such as the introduction of election-withdrawing phosphines, " bidentate Schiff bases, piridinyl-alcoholate ligands, pyridines (with formation of bis(py-ridine) complex 3), pyridinecarboxylate," different halides," " alkoxides,"" phenoxides," " and substituted acetic acid groiqis." IndenyUdene has been successfully introduced as a substitute for benzylidene. Furthermore, the benzylidene has been successfully altered by Piers et al. through introduction of a phosphonium salt which created a highly active and stable 14-electron initiator. " ... 

Oxidative Decarboxylation. Certain substituted acetic acids and their anhydrides undergo oxidative decarboxylation to aldehydes and ketones on treatment with pyridine N-oxide in toluene or xylene at reflux (eqs 1—3). Acids require an equivalent of Acetic Anhydride to dehydrate them to the anhydride. ... 

A technique for the hydrolysis of hindered esters using acetic acid or a substituted acetic acid in refluxing quinoline, pyridine, collidine, or DMF. Yields range from 74 to 100%. Seven examples cited. 

The electrophilic substitution of thiophene is much easier than that of benzene thus, thiophene is protonated in aqueous sulphuric acid about 10 times more rapidly than benzene, and it is brominated by molecular bromine in acetic acid about 10 times more rapidly than benzene. Benzene in turn is between 10 and lo times more reactive than an uncharged pyridine ring to electrophilic substitution. 

The positions of substitution, orientation, and configuration of the stable form are determined by a balance between opposing steric and dipole ef-fects. There is less agreement regarding the factors influencing kinetically controlled reaction (see below). Essentially neutral conditions, such as provided by an acetate or pyridine buffer, are required to avoid isomerization. Frequently, however, bromination will not proceed under these conditions, and a compromise has been used in which a small amount of acid is added to start and maintain reaction, while the accumulation of hydrogen bromide is prevented by adding exactly one equivalent of acetate... 

Isopropylidene and benzylidene hydrazones of the selenazoles w hich are unsubstituted in the 5-position react with p-nitrosodiethyl-and p-nitrosodimethyl-aniline in organic solvents on heating and the addition of acetic acid or pyridine. - Thus result crystalline, deeply colored, 2-hydrazono-5-(p-dialkylaminophenylimino)selenazoles (correspondingly substituted in the 4-position), details are given in Table VII. The presence of an aromatic residue in the 4-position of the selenazole ring appears to be needed to obtain crystalline compounds. 

Azcpincs under acid conditions reportedly117-225 yield aniline derivatives although ring contraction to pyridines is more usual. Thus, highly substituted 3//-azepines, e.g. 28, with a vacant 7-position, formed by cycloaddition of 2//-azirines with cyclopentadienones, on heating in acetic acid isomerize rapidly to the correspondingly substituted anilines 29.117... 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

Substitution as a preceding reaction. In addition to the well known determination of primary and secondary alcohols via esterification with acetic anhydride in pyridine at about 98° C, esterification is possible at room temperature in ethyl acetate with perchloric acid117 or 2,4-dinitrobenzenesulphonic acid118 as a catalyst. However, as tertiary alcohols preferably split off their hydroxy group, they can be adequately determined by OH-substitution with HBr in glacial acetic acid according to... 

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

In the presence of bis(acetylacetonato)nickel, a-dicarbonyl compounds readily add at the nitrile group of 4-R-substituted l,2,5-oxadiazole-3-carbonitriles 219 to form enaminofurazans 220. The adducts obtained from 4-amino-3-cyanofurazan underwent intramolecular cyclization upon heating with acetic acid in ethanol to give furazano[3,4- ]pyridine 221 derivatives in high yields (Scheme 51) <2001RCB1280>. 

The synthesis of the furan-imidazole derivatives, shown in Scheme 2, were also described by Wang et al. [34]. Reaction of 4-(dimethylamino)benzalde-hyde (20) with trimethylsilylcyanide (TMS)-CN in the presence of Znl2 produced the TMS cyanohydrin 21. Compound 21 was treated with LDA followed by the addition of 3,4,5-trimethoxybenzaldehyde to give the benzoin intermediate 22. Oxidation with CUSO4 in aqueous pyridine, followed by reaction with 3-furaldehyde in acetic acid, produced the substituted imidazole 23. 

Spickett and Wright investigated the reactions of 4-substituted 3-amino-1,2,4-triazoles and EMME in acetic acid for 24-48 hr [67JCS(C)503]. Generally, they obtained [l,2,4]triazolo[l,5-a]pyrimidine-7-ones (1124) in 38-56% yields. In the case of the benzyl derivative (R = CH2Ph), the isomeric triazolo[l, 5-a]pyrimidin-5-one (1125) was also isolated from the mother liquor, in 5% yield. From the 4-ethyl and 4-phenethyl derivatives (R = Et, CH2CH2Ph), l-(l,2,4-triazol-3-yl)pyridin-2-ones (1126) were also obtained in 1-2% yields. 

O-linked polymer-bound Af-substituted hydroxylamines are prepared by reduction of resin-bound oximes with borane-pyridine complex in the presence of dichloroacetic acid (Scheme 94). Other reducing systems commonly used for imine or oxime reduction are ineffective, including borane-pyridine in the presence of acetic acid. Subsequently, the A-substituted products are acylated and cleaved from the resin to afford Af-substituted hydroxamic acids 220. ... 

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