2-chloropyridines

Heteroaromatic esters such as 493 and amides are produced by the carbo-nylation of heterocyclic bromides[347,348]. Even dichloropyrazine (494) and chloropyridine are carbonylated under somewhat severe conditions (120 C, 40 atm)[349]. The carbonylation of trifluoroacetimidoyl iodide (495) proceeds under mild conditions, and can be used for the synthesis of the trifluoromethyl-glycine derivatives 496 and 497(350]. 

A new development features exchange fluorination of 2-chloropyridine with hydrogen fluoride—y-coUidine at 150—200°C to give 94% yield of product (381). 

Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

The N-oxides readily undergo nucleophilic addition followed by elimination, which forms the basis of several useful syntheses of 2-substituted pyridines. Chlorination of (13) with POCl to give 2-chloropyridine (17) is a good example (eq. 4) some chlorination may occur also at C-4 (11). 

The compounds 2- (16) and 4-pyridone (38) undergo chlorination with phosphoms oxychloride however, 3-pyridinol (39) is not chlotinated similarly. The product from (38) is 4-chloropyridine [626-61-9]. The 2- (16) and 4-oxo (38) isomers behave like the keto form of the keto—enol tautomers, whereas the 3-oxo (39) isomer is largely phenolic-like, and fails to be chlotinated (38). 

Chloropyridine N-oxide reacts with sodium hydrosulfide to give pyrithione [1121-31-9] (45), the zinc salt of which is used as an... 

Pyrroles may be ring-expanded to pyridines in reactions having a greater academic than practical interest. Treatment of pyrrole with chloroform and sodium ethoxide (in effect, with dichlorocarbene, CCl2) gives a low yield of 3-chloropyridine [626-60-8]. A much better yield (33%) is obtained if chloroform and pyrrole are heated together in the vapor phase at 550°C some 2-chloropyridine (17) is also formed (71). 

Most of them are generally classified as poisons. Exceptions to this rule are known. A notable one is 4-dimethyl aminopyridine (DMAP) (24), which is widely used in industry as a superior acylation catalyst (27). Quaternary salts of pyridines are usually toxic, and in particular paraquat (20) exposure can have fatal consequences. Some chloropyridines, especially polychlorinated ones, should be handled with extra care because of their potential mutagenic effects. Vinylpyridines are corrosive to the skin, and can act as a sensitizer for some susceptible individuals. Niacin (27), niacinamide (26), and some pyridinecarbaldehydes can cause skin flushing. 

Pyridine A Oxides. Analgesic and antiinflammatory dmgs niflumic acid [4394-00-7] (68) and pranoprofen [52549-17-4] (69) are manufactured from nicotinic acid N-oxide [2398-81 -4]. The antiulcer dmg omeprazole (66) is produced from 2,3,5-trimethylpyridine N-oxide [74409-42-0]. Zinc pyrithione, the zinc salt of pyrithione (45), is a fungicide derived from 2-chloropyridine N-oxide (45). 

Bayer introduced 2-sulfatoesters of A/-ethyl sulfonamide in 1958, 2,3-dichloroquinoxalines in 1961, and 2-methylsulfonyl-4-methyl-6-chloropyridine in 1966. 

An unusual final example of a synthesis from pyridines involves the 4-lithiotetra-chloropyridine (128), which with two moles of benzonitrile gave the trichlorodiphenyl-pyrido[3,4- f]pyrimidine (130) via the intermediate (129) (72JCS(P1)2190). The 2-lithio analogue gave the corresponding [3,2-c] derivative. 

Halides derived from certain heterocyclic aromatic compounds are often quite reactive toward nucleophiles. 2-Chloropyridine, for exfflnple, reacts with sodium methoxide some 230 million times faster than chlorobenzene at 50°C. 

Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism. Two examples are hexafluorobenzene and 2-chloropyridine. 

Nitrogen bears a portion of the negative charge in the anionic intermediate formed in the nucleophilic addition step in 4-chloropyridine, but not in 3-chloropyridine. 

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