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. 

Bis(thiosemicarbazones) [89-97] and AT-heterocyclic thiosemicarbazones comprise two interesting series of experimental chemotherapeutic agents. 2-formylpyridine thiosemicarbazone, the first of the latter series to be examined for biological activity, showed mild antileukemic activity against 1-1210 tumor in mice [98]. However, it was found to be toxic at the therapeutic dose levels which led to synthesis of other aromatic and heterocyclic thiosemicarbazones as potential agents [80, 99, 100]. However, the only active anticancer compounds besides glyoxal bis(thiosemicarbazones) were the iV-heterocyclic thiosemicarbazones [101], 2 formyl-3-hydroxypyridine thiosemicarbazone [102] and... 

With the synthesis of the hydroxypyridine 9 progressing in parallel, most of the effort was focused on the investigation of the far more challenging preparation of the chiral oc-arylpyrrolidine 12. At the outset of our studies, very few practical methods for enantioselective preparation of a-arylpyrrolidines were known [5], The four most attractive approaches are summarized in Scheme 8.4. 

A short and practical synthesis of glucokinase activator 1 was developed utilizing a convergent strategy involving an SNAr coupling of the activated aryl fluoride 11 with hydroxypyridine 9. 

A 1992 patent describes the carbonylation of EO to yield /3-propiolactone using a mixture of Co2(CO)8 and 3-hydroxypyridine.982 A recent re-investigation of this system has indicated that the major product is the alternating copolymer, a polyester, catalyzed by the [Co(CO)4] anion (Scheme 24).983 The synthesis of lactones via this methodology has successfully been achieved using Lewis acidic counter-cations (Scheme 25) 984,985 a similar strategy allows /3-lactams to be... 

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. 

Oxidation of N-acyl-2-aminoinethylflirans leads to an intermediate that can be converted by treatment with acid to a 3-hydroxypyridine [180, 181]. Such a transformation is used as one stage in a synthesis of pyridoxine [181,182]. 

Guitian et al. reported a total synthesis of ellipticine (228) using a modified Gribble methodology (722,723). This approach applied 2-chloro-3,4-pyridyne (1267) as a synthetic equivalent for 3,4-pyridyne and used the polar effect of the chlorine atom for improved yields and regiocontrol of the cycloaddition with the furoindole 544. Silylation of 2-chloro-3-hydroxypyridine (1263), followed by treatment of 1264 with LDA, afforded the 4-trimethylsilylpyridine 1265. This reaction probably involves... 

The synthesis of cis-1,4 polymers was also tried by e use of monomers with an s-cis conformation. The solid-state photopolymerization of pyridone derivatives, which is a six-membered cyclic diene amide and is a tautomer of 2-hydroxypyridine, was attempted [100]. Pyridones make hydrogen-bonded cocrystals with a carboxylic acid in the crystalline state. Because the cyclic structure fixes its s-cis conformation, if the polymerization proceeds, a cis-2,5 polymer would be obtained. Actually, however, the photopolymerization did not occur, contrary to our expectation, but [4-1-4] photodimerization proceeded when the carbon-to-carbon distance for the dimerization was small (less than 4 A) [101]. A closer stacking distance of the 2-pyridone moieties might be required for the topochemical polymerization of cychc diene monomers. 

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. 

The synthesis of the tetracyclic pyrido[3,2- >]furo [3,2-6Jbenzo[l,4j-diazepinone (47) starting with 2-cyano-3-hydroxypyridine (42) and 3-... 

When the blocking group is other than a halogen atom or a keto group, only tars are formed. 8-Hydroxy- 1,7-naphthyridine61 is obtained from 3-amino-2-hydroxypyridine, and 1,5-naphthyridine is obtained from the 2-halo-3-aminopyridines when they are subjected to the Skraup reaction. 3-Aminopyridine 1-oxide aifords the parent 1,5-naphthyridine,62 and both 3-amino-6-hydroxypyridine and 3-amino-6-chloropyridine give 2-hydroxy-l,5-naphthyridine.63 Hart64 has applied the Skraup synthesis to 3-amino-4-hydroxypyridine and has obtained the expected 4-hydroxy-l,5-naphthyridine. 

A new synthesis leading to a previously unknown 8-substituted indolizine involves initially the formation of the dihydropyridopyranyl ether (81) by reaction between a vinyl ether and a Mannich base obtained from 3-hydroxypyridine treatment with dilute hydrochloric acid... 

The 2- or 4-hydroxypyridines [(81) and (82)] are tautomeric and in solution exist preferentially in the corresponding pyridone forms. Their synthesis from the corresponding pyrones by a heteroatom exchange reaction is possible. 

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]. 

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