Pyridines 2-hydroxypyridines synthesis

The Guareschi-Thorpe pyridine synthesis is closely related to the Hantzsch protocol. The primary point of difference lies in the use of cyanoacetic esters. This modification assembles pyridine 23 by the condensation of acetoacetic esters 21 with cyanoacetic esters 22 in the presence of ammonia. A second variation of this method involves reaction of cyanoacetic ester 22 with P-diketone 24 in the presence of ammonia to generate the 2-hydroxypyridine 25. 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

In conclusion, structures containing polyiodide anions, with cationic aromatic ligands as counter parts of formulae [(L)(HL+)] (I ) are known to be synthesized by the treatment of the appropriate amide with HI [26-28], In contrast, the complexes with PYOH, in the present case, were formed by the direct reaction of 2-hydroxypyridine with di-iodine in a molar ratio of 2 1 and 1 2. This is a redox reaction, where 2-hydroxy-pyridine firstly is oxidized to pyridinone-2 radical cation. In the case of 2-hydroxy-pyridine however, peroxide structures are not formed like disulphides in the case of PYSH. Polyiodide anions are simultaneously produced in this case This should be a consequence of redox differences between -SH and OH groups and may be proven a useful pathway for the synthesis of polyiodide materials. 

Chloro-3-hydroxypyridine is a readily available starting point for the synthesis of furo[2,3- ]pyridines via iodina-tion followed by a palladium cross-coupling reaction with alkynes to afford alkynylpyridines, 107. Cyclization of compound 107 leads to furo[2,3- ]pyridine products <1998JME1357, 1998JOC7851 Similarly, reaction of 5-bromo-... 

The powerful 7V,7V-diethylcarbamate DMG serves admirably for the synthesis of substituted oxygenated pyridines. Thus, metalation of all isomeric pyridyl O-carbamates 317 with sec-BuLi/TMEDA followed by quench with numerous electrophiles affords diversely substituted products 318 in good to excellent yields (Scheme 96) (85JOC5436). Base-induced hydrolysis provides access to pyridones and hydroxypyridines. 

The construction of the furan ring in a Feist-Benary type reaction starting from 4-hydroxy-6-methylpyran-2-one (66) has also proved to be useful for the synthesis of furo[3,2-c]pyridines (Scheme 14) (75JHC461, cf. 71BSF4041). Quite recently the synthesis of the hitherto unknown furo[3,2-c]pyridin-3-ols has been described (79LA371). 4-Hydroxypyridine-3-carboxylates (e.g. 69), which are available from diketene and /3-aminocrotonic esters, react with a-halogenoketones in the presence of potassium carbonate to give compounds of type 70. 

Alkynyliodonium tosylates have been similarly employed with the potassium salts of 3- and 4-hydroxypyridines for the synthesis of furopyridines (Scheme 58) [160]. As expected, the 3-hydroxypyridines afford mixtures of regioisomer-ic furopyridines, corresponding to carbenic insertions into the non-equivalent ortho-CH bonds of the pyridine ring. 

Among the other possible Gif products shown in Scheme 1, the oxidative transformation of pyridine to bipyridines and hydroxypyridines is of rather limited use, because of the formation of isomers that are not amenable to facile separation. Nevertheless, the reaction has precedence in the historic synthesis [35] of bipyridines via radical pyridine coupling mediated by FeCl3 in the presence of Zn, but has been superseded by more selective coupling reactions that enable synthesis of unsymmetrically substituted bipyridines [36]. 

Cycloaddition of nitriles with dipropargyl ethers. A new synthesis of pyridoxine (4, vitamin BJ is based on the (2 + 2 + 2 cyclo.iddition of acetonitrile with dipropargyl ethers catalyzed by Cp,Co or Cp(CO),Co to torn the pyridine derivative I. Subsequent steps involve rearrangement of the N-oxide of 1 to the 3-hydroxypyridine 2 with acetic anhydride. The final step involves the known cleavage of the dihydrofuranc ring. 

Electrochemical synthesis of pyridines 84AHC(37)167. )8-Hydroxypyridines 82KFZ(4)28. 

Bifunctional catalysis. Some time ago Swain and Brown1 observed that 2-hydroxypyridine catalyzed the mutarotation of tetramethylglucose by a concerted base-acid catalysis and that it is more effective than pyridine plus phenol. A few years later Beyerman and van den Brink2 showed that 2-hydroxypyridine and other bifunctional compounds catalyze the reaction of amines with cyano-methyl esters (reactive esters) as well as low-energy esters in peptide synthesis. Pyrazole and 1,2,4-triazole (1,1188), were equally effective. 

More recently Openshaw and Whittaker3 in a synthesis of emetine alkaloids needed to effect condensation of an amine with a low-energy ester and in the particular case studied found that use of hydroxy pyridine raised the yield from 2% to 87%. Twelve other mono- or polyhydroxylated heterocyclics were examined, but 2-hydroxypyridine was clearly superior. 

Ab initio calculations on hydroxypyridine-pyridone gas-phase equilibria have been carried out the split-valence basis that was used, together with full optimization of geometry, is said to give considerably greater accuracy than previously achievedAn improved synthesis of 2-amino-3-alkoxy-pyridines by phase-transfer-catalysed alkylation of 2-amino-3-hydroxy-pyridines has been reported Irradiation of 4-methyl-2(l// )-pyridone (28) gives the bicyclic lactam (29), which has been transformed into an isomeric mixture of jS-lactams (30) (Scheme 17). ... 

Nitriles. A convenient synthesis of nitriles is based on the Grignard reaction with 2-PyOCN. The latter compound is available from the reaction of 2-hydroxypyridine with cyanogen bromide (with pyridine as a base). 

Fuss, A. Koch, V. Chemistry of 3-hydroxypyridine. Part 4. Synthesis of 2- and 2,3-sub-stituted 5[fluoro(chloro)alkoxy]p3Tidines via 5-hydroxy-2-(4-nitrophenylazo)pyridines. Synthesis 1990, 8, 681-685. 

When using cyanoacetic esters instead of aldehydes, the Guareschi-Thorpe pyridine synthesis assembles pyridines 155 by the condensation of acetoacetic esters 153 with cyanoacetic esters 154 in the presence of ammonia. A variation of this method involves the reaction of cyanoacetic ester 156 with 3-diketone 157 in the presence of ammonia to generate 2-hydroxypyridine 158." The mechanism of this reaction has been studied, and it was initiated by an ester/amide exchange on cyanoacetic ester 156 with... 

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