Heterocycle transformation, pyridine synthesis

Knoevenagel reactions are used in the synthesis of a wide variety of O- and N-heterocycles. In the typical Knorr pyrrole synthesis, a 1,3-dicarbonyl compound is condensed with an oximino- or azimino-1,3-dicarbonyl compound followed by reductive cyclization. Thus, catalytic hydrogenation of benzyl acetoacetate (243) and diethyl oximinoacetonedicarboxylate (242) affords pyrrole (244), which is transformed to (245) by another Knoevenagel reaction (Scheme 49). A rational synthesis of all four uropor-phyrines has been achieved by cyclization of appropriate pyrroles such as (245). ° Another typical preparation of a heterocycle that involves a Knoevenagel condensation is the Hantzsch 1,4-dihydro-pyridine synthesis. Here, an aldehyde and two molecules of a 1,3-dicarl30nyl compound react in the... 

Treatment of 6-ethoxy-2-phenyl-3-carboxy-5,6-dihydro-4/7-pyran with hydroxylamine transforms the heterocycle to 2-phenylnicotinate <97JHC93>. However, an isoxazole is obtained if the pyran is substituted with an acyl group rather than the ester functionality. Nitriles continue to be key components in pyridine synthesis. The bicyclic ketal 8 is converted cleanly to the pyridine 9 in the presence of an alkyl nitrile using 5 equiv of TMSOMs and 1 equiv of BFrEt20. This combination, generating the active ingredient boron difluoromethanesulfonate, avoids the byproduct cyclohexanones <97JHC325>. 

In the first chapter, N. M. Ahmad and J. J. Li (Pfizer, Ann Arbor, USA) discuss the use of palladium in quinoline synthesis, thus filling an important gap in a recent monograph on the uses of palladium catalysis in heterocyclic synthesis authored by the same group. This is followed by an account of pyrimidine-pyridine interconversions by H. C. van der Plas (Wageningen University, The Netherlands) the immense variety of heterocyclic chemistry is illustrated by the large number of diverse strategies for such transformations. 

Methods for the construction of the thieno[2,3-c]pyridine skeleton based on the formally simultaneous formation of both the pyridine and thiophene rings were documented. Under the Pummerer rearrangement conditions, ( -s ul liny lain idc 222 underwent a cascade transformation into 223, which was oxidized to fused lactam 224 in low yield (1999JOC2038). Data on the use of cascade transformations, including the Pummerer rearrangement - cycloaddition sequence, in the synthesis of complex heterocyclic systems were summarized in a review (1997S1353). 

As a result of interaction of 843 and pyridine, the adduct 845 is formed [53], The structures of coordination compounds 844 and 845 were proved by x-ray diffraction. As shown above (Sec. 3.4.3.2), the direct ammonia synthesis [55,56] with participation of various ligands (especially aliphatic, aromatic, and heterocyclic amines, aminoalcohols), elemental metals (or their oxides), and NH4SCN in mostly non-aqueous media, opens definite possibilities for obtaining thiocyanate complexes. In this respect, transformation (4.9) should be mentioned [57] ... 

Synthesis of heterocycles. The 1,5-diketone (1) on reaction with trityl perchlorate undergoes dehydrogenative cyclization to the pyrylium salt (2), which is transformed by reaction with ammonium acetate into the pyridine derivative (3). ... 

The susceptibility of pyrylium salts to attack at C-2 by nucleophiles and the subsequent ring opening and ring closure is of value in the synthesis of a range of heterocyclic compounds. During the course of the transformation of the primary amino group into another functionality, pyrylium salts are converted into pyridinium salts and thence into pyridine derivatives (A.R. Katritzky, Tetrahedron, 1980, 36, 679). 

The chemistry of furfural is mainly determined by the aldehyde function and the heteroaromatic furan ring. Many chemical transformations are therefore similar to those of aromatic aldehydes. However, the aromatic character of the heterocycle is low when compared to isocyclic compounds such as benzene derivatives or other related heterocycles such as pyrroles and pyridines. Therefore, the furan ring also resembles to a diene which significantly enriches the chemistry of furfural [112]. Many applications of furfural to organic synthesis are reported in the literature... 

Among the methods for synthesis of six-membered heteroarenes, cyclocondensations are applied in a nearly universal scope, less frequently used are cycloaddition (e.g. for pyridines) and ring transformation reactions (e.g. for quinolines and isoquinolines). For partially unsaturated and saturated heterocycles special methods (e.g. SnI processes for piperidines, 1,4-dioxanes or morpholines) are available. 

A similar approach was used in case of aromatic fluorinated heterocycles. Ring-fluorinated pyridines containing one, two, and three fluorine substituents are reviewed in Chapter 6, whUe Chapter 7 focuses on the synthesis and typical chemical transformations of aromatic heterocycles containing perfluoroalkyl groups. 

Imidazopyridines (IPs) may be synthesized from pyridine or imidazole derivatives by building up the second ring, and also by ring transformations from the other heterocyclic compounds. However, these methods are not of equal efficiency, and the most important preparative procedures utilize amino derivatives of pyridine as initial compounds for IP s synthesis. The main IP s precursors are o-diaminopyridines (o-DAP). 

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