Pyridine formation

Organocobalt complexes catalyze the cyelocotrimerization of acetylenes and nitriles, which affords pyridine and benzene derivatives (100). (Cyclo-pentadienyl)cobalt complexes such as CoCp(COD) favor pyridine formation (100), and modification of the Cp ligand has considerable influence on the activity of the catalyst and the chemo- and regioselectivity of the catalytic process (101). 

Workers at Merck recently reported three variants for pyridine formation in conjunction with the synthesis of COX-2-Specific inhibitor 8 (Scheme 1). Acid catalyzed annulation (path a) was achieved in 72% with 2 equivalents of methanesulfonic acid and four equivalents of 2-chloro-3-aminoacrolein. Base-promoted annulation between 7 and 2,3-dichloroacrolein provided 8 in 58% yield. Finally, base-promoted annulation with 2-chloro-iV,jV-dimethyl-armnotrimethinium hexafluorophosphate afforded 8 in 97% yield . Other alkylation-based strategies for pyridine formation include the work of Manna <00BMC1883> and Parra <00S273>. 

When 2,3,4,5-tetraphenylzirconacyclopentadiene was treated with NiCl2(dppe) under reflux, the 2,3,4,5-tetraphenylnickelacyclopentadiene-dppe complex 36 was obtained as a red solid in 78% isolated yield, along with Cp2ZrCl2 (98% yield by NMR) (Eq. 2.27) [8a]. This complex was the same as that prepared from NiCl2(dppe) and l,4-dilithio-l,2,3,4-tetraphe-nyl-1,3-diene [30], In the case of NiCl2(PPh3)2, a similar transmetalation can proceed. Using this method, benzene and pyridine formation and CO insertion have been developed [8a,8b,46],... 

Pyridine formation, by the reaction of a metallacyclopentadiene with a nitrile, has been extensively investigated in the case of cobalt [If]. When pyridine derivatives are prepared from two different alkynes and a nitrile, specific substituents are needed for the selective coupling reactions. In most cases, a mixture of two isomers (91 and 92) is obtained, the formation of which can be rationalized as shown in Eq. 2.61 [If,27a,44]. 

It is clear from a study of thermal and radical-induced decompositions of N-alkoxycarbonyldihydropyridines that radical processes are of minor importance, and that pyridine formation is probably a consequence of 1,2-elimination of formate (Scheme 6). It has also been concluded that the rate of 1,4-elimination of formate from iV-alkoxycarbonyl-l,4-dihydropyridines at higher temperatures is too rapid to be explained by a homolytic process. 

We (79TH1 81GEP3117363 84USP4588815) and others (87MI1) have studied acetylacetonato and rj -cp-rhodium complexes as catalysts in the pyridine formation [Eq.(l)]. Resin-attached cp-rhodium complexes are also active in the cocyclization of alkynes and nitriles, and the activity is... 

Comparison of the different types of cobalt catalysts shows that the in situ system [Eq.(2)] is most accessible while the Rep-, R(ind)-, and bori-ninato ligands having electron-withdrawing substitutents are the most active. The difference between the 14e" and the 12e core complexes makes itself apparent in the chemoselectivity of the reaction. Catalysts containing a 14-electron core favor pyridine formation, whereas those containing a 12-electron core (i.e., the rj -allylcobalt systems) favor the formation of benzene derivatives by cyclotrimerization of the alkynes. For example, in the reaction of propyne and propionitrile at 140°C in the presence of a 12-electron system (5), a 2 1 ratio of benzene to pyridine product is formed, whereas a catalyst containing the cpCo moiety (a 14-electron system) leads (under identical conditions) to the predominant formation of pyridine derivatives (84HCA1616). 

As can be deduced from Eq.(2), the liberation of the catalytically active [YCo] species is of prime importance, the neutral ligand L merely stabilizing the catalyst as the isolable complexes YCoL. The influence of the neutral ligand at cobalt on the temperature at which initial pyridine formation occurred was investigated using the test reaction [Eq.(42)]. 

These results can be summarized as follows (1) the cobalt-mediated pyridine formation and alkyne cyclotrimerization depend on the square of the alkyne concentration and are independent of the nitrile concentration (2) a common cobaltacydopentadiene intermediate is responsible for both the pyridine and the benzene formation and may be regarded as a key intermediate for both hetero- and carbocyclic pathways. 

An alternate approach to the formation of pyridylboronic acids is the cross-coupling of a halopyridine with a diboronate ester (usually bis(pinacolato)diboron, 7.7.)9 The analogous reaction of 2-chloropyridine led to pyridine formation through protodeboronation. The product of the reaction, either after hydrolysis to the boronic acid or in the ester form, can be further reacted with another aryl halide to give a biaryl. In certain cases the reaction might also be carried out in a one-pot manner.10... 

This reaction appears to be similar to the imidazo-pyridine formation mentioned above, most likely via a [5+1] insertion reaction of the isocyanide into the corresponding hydrazone. This reaction mechanism seems likely since only electron-rich aromatic hydrazines yielded cinnolines. The Ugi 4-CR reaction with phe-nylhydrazine is known and has been reported to give the expected Ugi-type 4-CR product. 

The application of Diels-Alder methodology to pyridine formation can take different approaches. The heteroatom can be sourced from the diene or the dienophile and by varying its position in the starting materials can lead to strategies for different substitution patterns in the pyridine product. While such approaches are well documented, recent reports have both extended the range of derivatives available and incorporated new technology to assist in the optimization of reactions. 

In a recently reported synthesis of pyridines, lithiated methoxyallenes react with nitriles in the presence of trifluoroacetic acid (Scheme 107) <2004CEJ4283>. The mechanism is postulated to proceed via initial protonation followed by nucleophilic addition of the trifluoroacetate ion with subsequent intramolecular acyl transfer and aldol condensation to give the pyridine. An additional pyridine formation starting from azaenyne allenes forms a-5-didehydro-3-picoline diradicals, which can be trapped by 1,4-cyclohexadiene, chloroform, and methanol to produce various pyridines <20040L2059>. 

Direct photolysis of 2-halopyridines in methanol, ethanol or acetonitrile (with 1% water) affords pyridine, together with alkoxy-, or hydroxypyridines376. The formation of the substitution products will be discussed in Section IV.C. The reductive dehalogenation is considered to proceed via homolysis of the carbon-halogen bond. The efficiency of pyridine formation decreases in the order Br > Cl > I. The 3- and 4-halopyridines produce pyridine exclusively. 

Frandsen H, Alexander J (2000) N-Acetyltransferase-dependant activation of 2-hydroxyamino-l-methyl-6-phenylimidazo[4,5-b]pyridine formation of 2-amino-l-methyl-6-(5-hydroxy)phenylimidazo[4,5-b]pyridine, a possible biomarker for the reactive dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Carcinogenesis 21 1197-1203... 

It is clear that (3-picoline formation is a higher order reaction than pyridine formation, since the reactions involve 5 and 4 molecules respectively. Since a lower order reaction is favored in a more shape-selective environment, pyridine production is highest on ZSM-5 zeolites. Alternatively, one might try to maximize the fraction of (3-isomers in the picoline products. With a H-Beta zeolite, more than 98% of the picolines consist of (3-picoline, which highly simplifies the product purification (12) ... 

Like the 5-amino aldopentoses, the 5-amino aldohexoses have a pronounced tendency to form the pyranose ring in alkaline solution. In acid solution, three molecules of water are eliminated per molecule, to give the corresponding derivative of 3-pyridinol. 5-Amino-5-deoxyaldohexopyranoses are, however, distinctly more stable, as the Amadori rearrangement and pyridine formation occur at pH 5.7—6.2. With the pentose analogs, these reactions begin at pH 7—8. Because of the reactive a-amino alcohol arrangement at C-1, the 5-amino-5-... 

The transition metal-mediated [2 -i- 2 -i- 2] cyclocotrimerization of two alkynes and a nitrile is a powerful and straightforward route to substituted pyridines [9]. In particular, catalytic cyclocotrimerization is undoubtedly desirable as a metal-atom economically and environmentally benign process. Effective catalysis, however, has been confined to cobalt [40], although a variety of transition metals (Ti [41], Zr/Ni [42], Ta [43], Co [44], and Rh [45]) have been found to mediate the stoichiometric cyclocotrimerization. With respect to ruthenium, pyridine formation from acetoni-... 

Applying the versatility of the cobalt-catalyzed pyridine formation (eq. (2)), Vollhardt [45] has varied the basic reaction extensively. Using rather sophisticated alkyne and nitrile precursors with 77 -Cp-cobalt dicarbonyl as the catalyst, the preparation of a number of polyheterocyclic systems having physiological interest was brought about. Using eq. (14) a synthetic route to the isoquino[2,l-(7] [2,6]naphthyridine nucleus (eq. (16)) was developed [46]. 

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