3-Cyanopyridines synthesis

Vinylpyridine (23) came into prominence around 1950 as a component of latex. Butadiene and styrene monomers were used with (23) to make a terpolymer that bonded fabric cords to the mbber matrix of automobile tires (25). More recendy, the abiUty of (23) to act as a Michael acceptor has been exploited in a synthesis of 4-dimethylaminopyridine (DMAP) (24) (26). The sequence consists of a Michael addition of (23) to 4-cyanopyridine (15), replacement of the 4-cyano substituent by dimethylamine (taking advantage of the activation of the cyano group by quatemization of the pyridine ring), and base-cataly2ed dequatemization (retro Michael addition). 4-r)imethyl aminopyri dine is one of the most effective acylation catalysts known (27). 

The pyridine-N-oxide 245 was converted into the cyanopyridine 246 and its isomer (Scheme 80). Grignard reaction, Fischer s indole synthesis, and N-protection gave a pyridinyl indole 247. Selenium dioxide selectively oxidized the methyl group to give the isonicotinic acid. The synthesis of Flavocarpine (244) was finally accomplished by a set of standard reactions as outlined in Scheme 80 (87TL5259). 

A process research investigation on p38 MAP kinase inhibitors examined the synthesis (on 7 mol scale) of a group of closely related pyrimidinones such as 37, by condensation of a number of arylacetic esters with 4-cyanopyridine and methyl isothiocyanate. Other nitriles were also examined but were much less successful than 4-cyanopyridine 3-cyanopyridine gave a much lower yield and both benzonitrile and 2-cyanopyridine failed completely <06T11714>. 

Nitrilase-mediated conversion of 3-cyanopyridine into nicotinic acid is an attractive alternative to chemical methods of nicotinic acid synthesis.It has been synthesized using whole cells (containing nitrilase) of some microorganisms and involves the following reaction ... 

The cobalt-catalyzed synthesis enables 2,2 -dipyridyl to be prepared directly from 2-cyanopyridine and acetylene in a 72% yield with a cyanopy-ridine conversion of 21%. The pyridine benzene ratio in the product is 2.7 1 [Eq.(18)]. 

The reaction proceeds via ANRORC-recyclization induced by alkoxide ion, and subsequent oxidative aromatization. Authors believe that aroma-tization occurs at the expense of disproportionation of the intermediate dihydropyridine because yields never exceed 50%. These results were reproduced and expanded (00PHA269), and used in a synthesis of 4,6-diaryl-2-methoxy-3-cyanopyridines and annulated methoxypyridines (88TL2703) (with low yields). 

A number of routes are available for the synthesis of 2,2 -bipyridines where one of the pyridine rings is built up from simpler entities. For example, condensation of 2-(aminomethyl)pyridine (31) with acetaldehyde or acetylene over a silicon-alumina catalyst at 450°C gives 2,2 -bipyridine, ° whereas 2-cyanopyridine reacts with acetylene at 120°C in the presence of a cobalt catalyst to afford 2,2 -bipyridine in 95% yield.2-Acetylpyridine with acrolein and ammonia gives 2,2 -bipyridine in the presence of dehydrating and dehydrogenating catalysts, and related condensations afford substituted 2,2 -bipyridines. ° In a similar vein, condensation of benzaldehyde with 2 mol of 2-acetylpyridine in the presence of ammonia at 250°C affords 2,6-di(2-pyridyl)-4-phenylpyridine, ° and related syntheses of substituted 2,2 6, 2"-terpyridines have been described. Likewise, formaldehyde with two moles of ethyl picolinoylacetate and ammonia, followed by oxidation of the product and hydrolysis and decarboxylation, affords a good... 

The acid-catalyzed cyclization of salts (188 Scheme 101) prepared from 2-cyanopyridine by quaternization with a benzyl halide provides the only method yet developed for the synthesis of 11-aminoacridzinium salts (189). The prototype quaternary salt (188 R = H) was cyclized in sulfuric acid in an overall yield of 25% (73JOC4167). A better yield (59%) was obtained when the point of electrophilic attack was activated by a para methoxy group. 

Pyridylzinc bromide, a commercially available reagent, was used in the synthesis of a series of bipyridyl derivatives (7.20.). Activated coupling partners, such as 2-chloro-4-cyanopyridine, reacted readily at room temperature in the presence of a palladium based catalyst, while less electron deficient halopyridines were coupled at elevated temperatures.27 The same approach was also extended to the preparation of other heterobiaryls.28... 

Aromatization of a tetrahydroquinolizone (5) by means of acetic anhydride and sulfuric acid or acetic anhydride alone leads to the formation of a variety of mono- or di-substituted quinolizinium compounds. Glover and Jones 8 achieved the synthesis of a number of these derivatives starting from 2-cyanopyridine and condensing it with appropriate Grignard reagents followed by cyclization and aromatization as outlined in Eq. (2). An identical method was simultaneously worked out by Nesmeyanov and Rybinskaya9 for the specific synthesis of 2-substituted quinolizinium compounds. This... 

It is known that 3-aminobenzo[6]furan can be prepared from o-cyanophenols and a-halogenocarbonyl compounds with subsequent Thorpe cyclization (73JPR779). The extension of this synthesis to heteroatom substituted benzo[6]furans is straightforward (76JPR313). The reaction of potassium salts of 3-cyano-2-pyridones (e.g. 27) with a-halogenocarbonyl compounds (esters, ketones) yields 2-alkoxy-3-cyanopyridines which can be cyclized in the presence of sodium ethoxide to give 3-aminofuro[2,3-6]pyridines (Scheme 6). 

A further example of the preparation of amides by the ammonolysis of esters (cf. succinamide, Expt 5.155) is provided by the preparation of nicotinamide described in Expt 6.169 as a stage in the synthesis of 3-cyanopyridine. 

Examples of the synthesis of thieno[2,3-Z>]pyridines according to method C are scarce. In this case, the synthesis of the starting 3-cyanopyridine-2(l //)-thione, its -alkylation, and cyclization of an intermediate occur as a multicomponent one-pot process. For example, the reaction of thioamides 28 with l-(4-morpho-lino)cyclohexene (29) in anhydrous ethanol followed by treatment with a twofold excess of KOH and then with a-bromo ketones produced thienoquinolines 30 (1997KGS1384). 

---