Synthesis of pyridine ring

Heterocyclic azadienes like di- and triazines have been used in the synthesis of pyridine rings. In general terms the reaction involves a regiospecific inverse electron demand Diels-Alder cycloaddition between the heterocycle and the enamine 280 followed by elimination of HCN (diazines) or N2 (triazines) and an amine from the primary cycloadduct 281 or 283, respectively, to give pyridines 282 and 284 (equation 61). At least in one case the latter type of intermediate has been isolated and fully characterized148. 

Pyridine ring syntheses (48) can be classified into essentially two categories ring synthesis from nonheterocyclic compounds, and synthesis from other ring systems. The synthesis of pyridine derivatives by transformations on the pyridine ring atoms and side-chain atoms have been considered in the previous section. 

A few pyrolytic methods of synthesis are known, leading directly to the formation of pyridine rings by formation of the /3, y-bond. Alkylpyridines are obtained when unsaturated imines (116) or (117) are passed over heated zeolites (80IZV655) or alumina (72IZV2263). More dehydrogenation is achieved by the use of nickel or alumina, as in the synthesis of tetrahydroquinolines (118) or octahydrophenanthridine (119) (78IZV1446). 

An alternative synthesis of this ring system involves the conversion of the pyridine-3-sulfonic acid 229 into the pyridylsulfonylguanidine 230, then cyclization with K2CO3 in DMF (Scheme 35) <1993JME3211>. 

Pyridines and their benzo-derivatives have played an important role in the synthesis of biologically active synthetic and natural substances. As a result, the construction of this molecular architecture has attracted the attention of a diverse array of synthetic methodologies. Notably, transition metal catalysis, radical reactions and cycloaddition chemistry-based methods have been developed for the construction of this important ring system. Detailed herein is a summary of the methods developed for the synthesis of pyridines, quinolines, isoquinolines and piperidines that were disclosed in the literature in 2002. Rather than survey all existing methods for the construction of these compound classes, this review will serve as a supplement and update to the review published last year in this series. 

A convenient synthesis of unsaturated nitriles by a stereospecific alkylative cleavage of pyridine ring via borate process has been reported. Namely, the reaction of 2-bromo-6-lithiopyridine with trialkylboranes affords 5-alkyl-5-dialkylboryl-2-(25--4-(E)-pentadienenitriles (28), which are versatile intermediates for the preparation of 5-alkyl-2-(Z)-4-(E)-pentadienenitriles (29), 5,5-dialkyl-4-pentenenitriles (SO), and 5,5-dialkyl-2,4-pentadienenitriles (SJ), as depicted in Eq. 65 . 

The formation of bonds c and b can take a couple of forms, either a Darzens-type approach (i.e., addition of a nucleophile bearing a leaving group) or addition of a carbene. Both of these routes have been used in the synthesis of fused-ring aziridines as well as monocyclic aziridines. The addition of a carbene or nucleophile such as an ylide to an imine can provide a nice route to fused-ring aziridines. The necessary cyclic imines are sometimes more readily obtained and used than the acyclic imines. These methods have largely been used on pyridine and quinoline derivatives. 

A great variety of methods is available for the ring synthesis of pyridines the most obvious approach is to construct a 1,5-dicarbonyl compound, preferably also having further unsaturation, and allow it to react with ammonia, when loss of two mole equivalents of water produces the pyridine. 1,4-Dihydropyridines, which can easily be dehydrogenated to the fully aromatic system, result from the interaction of saturated... 

A most useful application of this process is the invention of a highly atom economic synthesis of pyridines, wherein the only stoichiometric by-product is water. Cycloisomerization of diyne 22 followed by reaction with hydroxylamine provides the tricyclic pyridine 23 with only water as the stoichiometric by-produd (Equation 1.26) [24]. The Ru-catalyzed cycloisomerization of propargyl alcohols can also generate six membered rings, which then form tetrahydroisoquinolines as shown in Equation 1.27. 

Zeolites are known to catalyze the formation of various nitrogen-containing aromatic ring systems. Examples include the synthesis of pyridines by dehydrogenation / condensation / cyclization of C -Cg precursors [1], the formation of methylpyridines by high-temperature isomerization of anilines [2], the amination of oxygen-containing heterocyclic compounds [3] and the Fischer indole synthesis [4,5]. The latter synthesis consists (see Scheme 1) of a condensation towards a phenylhydrazone followed by an acid-catalyzed cyclization with elimination of ammonia. The two reaction steps are usually combined in a one-pot procedure. 

The first step in the Katritzky pyridine synthesis is believed to be the Michael addition of a a-benzotriazolyl ketone 2 to the a,p-unsaturated carbonyl compound 1 to generate a 1,5-diketone derivative 4. The 1,5-diketone is not typically isolated although its formation has been confirmed via preparation under typical Michael reaction conditions in the absence of ammonium acetate. 1,5-Diketone derivatives are known intermediates in the synthesis of pyridines and undergo condensation with ammonia or its equivalent followed by cyclization to form dihydropyridine 5. Elimination of benzotriazole completes the aromatization process and generates the pyridine ring. 

C. Hollins, The Synthesis of Nitrogen Ring Compounds (New York, 1924) p 197 V. Migrdichian, The Chemistry of Organic Cyanogen Compounds (New York, 1947) p 322 H. S. Mosher, Heterocyclic Compounds 1, 466 (1950) R. W. Holder etal, J. Org. Chem. 47, 1445 (1982) D. J. Collins, A. M. James, Aust. J. Chem. 42,215 (1989). Cf Hantzsch (Dihvdro)Pvridine Synthesis KrOhnke Pyridine Synthesis. 

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