Construction of the Pyridine Ring

Extension of this work by studying the reaction of 3-methyl-5-nitro-pyrimidin-4(3//)-one with -X-arylketones in the presence of ammonium acetate surprisingly revealed the formation of a mixture of 4-arylpyrimidines and 6-arylpyridin-2(l//)-ones (00JCS(P1)27). The ratio between pyridine and pyrimidine formation is dependent on the substituent X. With electron-donating substituents the formation of the pyridin-2(l//)-ones is favored, with electron-attracting substituents the formation of the pyrimidine derivatives (Scheme 21) In the formation of the 6-arylpyridin-2(l//)-ones the C-4- C-5-C-6 part of the pyrimidone-4 is the building block in the construction of the pyridine ring. Therefore, the pyrimidone can be considered as an activated o -nitroformylacetic acid (Scheme 21). 

An ingenious method for the construction of the pyridine ring based on the tert-amino effect was used (1990RTC481) in the synthesis of a series of [3,2-Z>]-annu-lated thienoazines. Prolonged refluxing of diene aminodinitriles 166 in butanol affords thieno[3,2-Z>]indolizines and thieno[2,3-e]quinolizines of general formula 167. 

Utilization of the 3-carbon side chain of the phenylalanine-cinnamic acid intermediates for the construction of the pyridine ring in the A4 alkaloid, as indicated in Schemes 45 and 46, is easily ascertained in principle by an... 

This ring system can be constructed by building one of the two heterocyclic rings on the other preformed ring the construction of the thiazeto ring on a quinoline moiety or generating a pyridine ring on a... 

A general method for the construction of a pyridine ring is the Hantzsch synthesis. A condensation reaction of two equivalents of a /3-ketoester 1 with an aldehyde 2 and ammonia leads to a 1,4-dihydropyridine 3, which can be oxidized to the corresponding pyridine 4—for example by nitric acid ... 

A large diversity of microorganisms has been shown to degrade pyridine. Numerous studies have been performed and a large number of metabolites have been detected. The proposed hypothetical pathway was constructed to fit all the results. Certain set of intermediates were identified for specific microorganisms and some enzymes were also identified or detected (e.g., aliphatic intermediates). However, the mechanism(s) of cleavage of the pyridine ring remain(s) unknown. 

The only report concerning the construction of the heterocyclic ring of diazafluorenes was described in CHEC-11(1996) <1996CHEC-II(7)921> using a variant of the Hantzsch pyridine synthesis. Somewhat surprisingly, no further reports using this method have been found. 

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. 

Most of the known methods for the synthesis of these compounds are based on the use of readily accessible 3-aminothiophenes or their /V-derivatives. The following main ways of the pyridine ring construction (J-N) are possible ... 

The majority of methods for the synthesis of thieno[2,3-c]pyridines and related fused structures can be tentatively divided into two groups based on the construction of the pyridine or thiophene rings, respectively. 

Synthetic approaches to thienopyridines are conveniently considered under two headings, according to which heterocyclic ring is constructed. Generally syntheses involving formation of the pyridine ring have been adaptations of classical quinoline and isoquinoline syntheses. 

It is also interesting to note that Van Bergen and Kellogg have used the Hantzsch condensation to construct the pyridine ring in situ <76CC964>. Construction of the pyridine unit from the / -keto ester places the pyridine nitrogen exocyclic (12), unlike (9)-(ll) in which the pyridine N is endocyclic. 

Maryanoff et al. carried out a comprehensive study of Co-catalyzed hetero-[2 - - 2 - - 2] cycloaddition of two alkynes and a nitrile for construction of a pyridine ring. They submitted diynes having a relatively long tether to the reaction and realized the first synthesis of pyridinophanes by [2- -2-1-2] cycloaddition (Scheme 8.7) [7a]. The ratio of meta and para cycloadducts was affected by the length of the tether. They improved the yield from 61% to 87% (meta/para 1 7) under more diluted conditions (0.005 M) in refluxed 1,4-dioxane [7b]. 

---