Pyridinols, substituted

Irradiation of the unsymmetrically substituted 2,3,4,6-tetraphenylpyridine 1-oxide (5) under these conditions gives 2,4,6,7-tetraphenyl-l, 3-oxazepine (7) in 30 % yield, together with 2,4,5,6-tetraphenylpyridin-3-ol (10) in 37% yield and 2,3,4,6-tetraphenylpyridine (30%).11 It has been suggested that the reaction proceeds by way of the oxaziridines 6 (which yields 7) and 8 (which yields the isomeric oxazepine 9) the latter rearranges to the pyridinol 10. 

Experimental assessments of the concentration of the minor hydroxy tautomer of 2-pyridone and substituted derivatives in cyclohexane and acetonitrile solution may be carried out by the use of fluorescence spectroscopy (85JCS(P2)1423). For the parent compound, the pyridinol component in cyclohexane is estimated to be 4% and in acetonitrile 1.2% this preference for the hydroxy form in the former over the latter solvent is maintained over a fair range of variously substituted pyridones. Ab initio calculations (85JA7569) on 4-hydroxypyridine, the minor tautomer in aqueous solution, include 92 water molecules in the estimations, and thus give a very detailed picture of the solvated molecule, while the experimental technique of microwave spectroscopy not only gives an accurate estimation of the 2-hydroxypyridine / 2-pyridone ratio of 3 1 in the gas phase but also reveals that the former isomer is predominantly in the (Z)-form (80) and that both isomers are planar (93JPC46). 

Preparation of 7-arylmethyl-17/-pyrrolo[3,4-r-]pyridine-l,3-(27/)-diones 128 from 5-bromonicotinamide, arylaceto-nitriles, and lithium diisopropylamide (LDA) occurs via a pyridyne mechanism (Scheme 21). Under similar conditions, 5-chloro-3-pyridinol and arylacetonitriles afford the C-5 substitution products (Equation 49) <1998T3391>. 

Herbicides that act as inhibitory uncouplers are dinitro-phenols, N-phenylcarbamates, acylanilides, halogenated benzoni-triles, substituted imidazoles, substituted benzimidazoles, bromofenoxim, substituted 2,6-dinitroanilines, pyridinols, and substituted 1,2,4-thiadiazoles (2). 

Similar methods lead to ring closure on a variety of other ring systems. The substituted pyrimidinethione 260 with polypho-sphoric acid formed the thiazolo [5,4-<7 pyrimidine 261 (Scheme 146) <1965JOG1916>. The cyclization of jV-acylated amino-pyridinols such as 262 affords oxazolopyridines 263 (Scheme 147) <2005TL9001, CHEC-III(4.04.9.3)524>. 

A regioselective halogenation of pyridinols to provide bromo- and iodohydroxypyridines in excellent yields has been developed. These heterocycles are useful intermediates to other substituted pyridines <03SL1678>. 

A synthesis of 4-alkyl-3-pyridinols (55) from 3-benzyloxypyridine (52) utilizes a copper-catalyzed Grignard reaction. The dihydropyridine intermediates 53 are aromatized to 4-alkyl-3-benzyloxypyridines (54), which on hydrogenolysis provide the pyridinols 55 (85JHC1419). Substitution at the 4-position of 3-pyridinecarboxaldehydes can be achieved via 1-acylpyri-dinium salt 56. The intermediate acetal 57 is hydrolyzed to give pyridine-carboxaldehyde 58 (84H339). 

The condensation of ethyl 5-ethoxyoxazole-4-acetate (189) with a variety of dienophiles has permitted the syntheses of several 4,5-di-substituted 2-ethoxycarbonylmethyl-3-pyridinols.348 347 Very often the... 

The electrophilic aromatic substitution of the pyridine ring continues to be explored as a way to prepare substituted pyridines. Bw-( 5y w-collidine)-iodine(I) and bromine (I) are effective iodinating or brominating agents, respectively, of pyridinols, although the di- or tri-halogenated products are obtained <97TL2467>. lodination of 3-pyridinol produces 5-hydroxy-... 

Furan derivatives are prepared by reaction of o-iodophenols. 2-Phenylbenzo-[ >]furan was prepared by the reaction of o-iodophenol (64) with 1-alkyne in one step [40]. It should be noted that similar 2-arylbenzo[i>]furan formation occurred by the use of Pd-free, copper-phosphine complex [41]. Similarly 2-substituted furo[3.2-i ]pyridine 66 was prepared from 2-iodo-3-pyridinol (65) in a one-pot reaction [42]. Naturally occurring ailanthoidol was synthesized by the reaction of 67 and 68 to give the cyclized product 69 [43]. 

A large variety of ring closure reactions have been applied to the direct formation of pyridinols and pyridones. Judicious choices of open-chain intermediates often can provide excellent routes to a variety of substituted pyridines and fused ring systems. 

Acylfurans, convenient intermediates for the synthesis of 2-substituted-3-hydroxypyridines, are s)mthesized by acylation of furans or by acylation of aromatic substrates with 2-furoyl halides. 3-Pyridinols (XII-272), pyrrolyl ketones, and pyrroyl ketimines are formed on treatment with ammonia. ... 

A variety of 2-substituted-3-pyridinols can be prepared by well-known methods. For example, diarylmethyl 2-lliryl ketones are prepared in good yield from ethyl fliroate and diarylmethanes using KNH2 or NaNHj in liquid ammonia and are conveniently converted to XII-279. p-Chlorobenzyl 2-furyl ketones, which can be converted to XU-280, can be prepared from p-chlorophenylacetonitrile and ethyl furoate by condensation in the presence of alkoxide followed by hydrolysis and decarboxylation. 2-Pyrryl ketones are also formed in the last step. Several 2-furyl ketones are cleaved under these reaction conditions and do not give 3-pyridinols. ... 

The activating influence of the ring nitrogen provides an important versatility for the synthesis of pyridones, pyridinols, and pyridine ethers, by nucleophilic substitution at the 2- and 4- and even the 3-position. Further, the potential of accomplishing these substitutions via pyridine W-oxides contributes to the scope of this method. 

A nitro group in the 2- or 4-position of the pyridine ring is susceptible to nucleophilic substitution under relatively mild conditions, and in these reactions it competes with a 3- or 5-halogen. 3-Halo-4-nitropyridines (halo = Cl, Br, I) react with aqueous barium or potassium hydroxide to form 3-halo-4-pyridones and with alkoxides to form 4-alkoxy-3-halopyridines. However, 3-fluoro-4-nitropyridine is converted to 4-nitro-3-pyridinol or 3-alkoxy-4-nitropyri-dines. The corresponding iV-oxides react similarly. (See Section 1.6.A., p. 688). 

Tautomeric equilibrium constants Kf = [pyridone]/[pyridinol] have been measured for a number of 2-pyridones (Table XII-8). The constant Kf has been estimated by a Hiickel approximation for 2- and 4-pyridone. The Kf values obtained from ultraviolet spectra and those obtained from acidity constants are in poor agreement for 6-chloro-4-substituted-2-pyridones (XII477 R = CH3, CeHs) and 6-chloro-3,4-polymethylene-2-pyridones (XII-478 n = 3,4) in water. For example, in XII477 where R = CH3, values of 6% and 44%respec-tively of pyridinol tautomer (XII477b) are obtained from ultraviolet data and from acidity constants. However, values obtained from ultraviolet studies appear to be more reliable. ... 

The course of alkylation of 2- and 6-substituted-3-pyridinols is subject 10 a steric effect. Sodium salts of 3-pyridinol in ethanol are N-alkylated by methyl bromo- or iodoacetate. However, 2-bromo-3-pyridinol is N-alkylated by methyl and ethyl iodide in dimethylformamide but is 0-alkylated by haloacetates to XII-563 (Rj = Br, R = H). 2-Bromo-6-methyl-3-pyridinol (XH-562, Rj = Br, R = CH3) is A-alkylated by methyl and ethyl iodide and 6>-alkylated by diazomethane, but reacts with bromoacetic acid in chlorobenzene to give 3-hydroxy-6-methyl-2-pyridone (XII-565), possibly via 2-(a-bromoacetoxy)-6-methyl-3-pyridinol (XII-S64). With 6-methyl-2-methylthio-3-pyridinol (XII-562 Rj = CH3S, R = CH3), A-alkylation should be favored electronically, particularly by electron release by the 2-methylthio group. However, quaternization is difficult even with the simple alkyl halides and only 0-alkylation is observed when methyl iodoacetate is used. ... 

The alkaloid Syphilobin F,a2-substituted-3-pyridinol(see Section VI., p. 861), is 0-methylated by diazomethane in diethyl ether-benzene in 43% yield. Anhydro-3-hydroxy-N-roethylpyridiniumhydroxide (XII-S67) can be formed by the reaction between 3-pyridinol and diazomethane, by the reaction of Mmethyl-3-hydroxypyridinium chloride with anhydrous sodium carbonate and by thermal decomposition of 3-methoxypyridine iodomethylate. However, its preparation from the dimer complex of Mmethyl-3-hydroxypyridinium iodide (XII-S68) by treatment with silver oxide was the most convenient method. It has also been prepared from the quaternary iodide. ... 

Methyl-3-pyridinol is brominated in pyridine to give 2-bromo- and then 2,4-dibromo-6-methyl-3-pyridinol. lodination with sodium iododichloride gives 2-iodo-6-methyl-3-pyridinol. lodination of 2-(/7-substituted phenyl)-3-pyri-dinols (Xn-665 R = H, CHj, C Hs, CH(CH3)2. C(CH3)3, Q, OCHj) gives 2-aiyl-6-iodo-3-pyridinols. This should be contrasted with nitration of these pyridinols, which occurs first on the phenyl group " (Section II1.2.D.,... 

Since 2-pyridones are nitrated mainly as their free bases and are probably in the pyridone form, °° it is not likely that a transition state involving hydrogen-bond participation by OH as has been suggested for ortho-nitration of phenol and for nitration of 2-substituted-3-pyridinols at the 4-position (this section, p. 809) is responsible for the formation of 3-nitro-2-pyridone, the major product. ... 

Aminomethylation of 2- p-anisyl)-3-pyridinol gives 6-mono- and 4,6-bis(di-methylaminomethyl)-2-(p-anisyl)-3-pyridinol. Aminomethylation at the anisyl group is not observed. Aminomethylation of 2-(p-hydroxyphenyl)-3-pyridinol occurs at both the 3- and 5-position of the p-hydroxyphenyl group, followed by aminomethylation at the 6- and then the 4-position of the pyridinol ring. Proton chemical shifts and LCAO calculated charge distributions have been correlated with reactivity and substitution sequences in the Mannich reactions of 3-pyridinols. ... 

The rate of substitution of bromide in (Pt(dien)Br] by a series of pyridine derivatives including 2-pyridone and 3-pyridinol has been considered to be governed by steric properties of the entering group rather than by its basicity. ... 

Alkyl and Aryl Alkyloxy, Aryloxy, and Hydroxy Amino, Substituted Amino, and Imino Carboxylic Acids, Aldehydes, Amides and Esters Nitriles Halo Nitro and Nitroso and Sulfur Containing Pyridinols and Pyridones. 

A further extension of this concept is shown in the 6-substituted 3-pyridinol synthesis described in eq 7. Treatment of condensation product (19) with 1 M HCl initiates Stabase deprotection that is followed by acid-catalyzed rearrangement of the resulting amino alcohol to pyridine (20). ... 

The diazotization of aminopyridines has been used extensively as a source of pyridinols Table 5,2S). The precise mechanism of the substitution is unknown. Since loss of nitrogen from the protonated pyridine diazonium ion would produce a doubly charged carbonium ion, the carbonium ion mechanism i2 seems unlikely in this series, and 5n2 substitution may be... 

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