3- Phenylpyridine, Chichibabin amination

The results of some of the many aminations of pyridine and its derivatives that have been carried out appear in Table 14. Yields are quoted where possible but these should not be used for quantitative comparisons as reaction and work up conditions vary widely. 2-Alkylpyridines aminate at the vacant a-position, except when the substituent is very large. 2-f-Butylpyridine does not undergo the Chichibabin reaction, probably because the bulky 2-f-butyl group prevents adsorption on to the sodamide surface. In contrast, 2-phenylpyridine undergoes amination in very good yield. Aminations of 2- and 4-methyl-pyridines do not involve attack on the anhydrobases in aprotic solvents, but some ionization does take place in liquid ammonia. 4-Benzylpyridine forms a carbanion (148) which is only aminated with difficulty by a second mole of sodamide (equation 103). 

Amination of 3-substituted pyridines occurs preferentially at the a-position, i.e., 2(6) position. One example is the amination of 3-phenylpyridine (9) which gives the 2-amino isomer 10 in a 52% yield under the classical Chichibabin amination conditions. ... 

The fused bicycle phenylimidazo[4,5-6]pyridine and its different isomers, such as 2-amino-l-methyl-6-phenylimidazo[4,5-6]pyridine (1-Me-6-PhIP) and l-Me-5-PhIP (55), are suspected procarcinogens. Chichibabin amination is used in the synthesis of these PhIP isomers.Synthesis of 1-Me-5-PhIP is affected by the amination of 5-phenylpyridine (51) using NaNH2 in DMA at 170 C. This gives the 2-aminopyridine adduct 52 in an 81% yield. The 2-amino adduct is then protected and followed by various transformations to give 55. l-Me-6-PhIP isomer is also formed under the aforementioned conditions from 2-amino-5-phenylpyridine 10 vide supra). 

In the laboratory of J.S. Felton, the synthesis of 2-amino-1-methyl-6-phenyl-1/-/-imidazo[4,5- i]pyridine (PHIP), a mutagenic compound isolated from cooked beef, and its 3-methyl isomer have been accomplished. The synthesis of PHIP began with the commercially available 3-phenylpyridine, which was aminated at the 6-position with sodium amide in toluene by the Chichibabin reaction in 58% yield. 

---