2-Methylnicotinic acid, reaction with

In 1958, Ikekawa10 synthesized 2,7-naphthyridine and various substituted derivatives. His approach involved the reaction of 4-methylnicotinic acid with formaldehyde to afford the lactone 99 (R = H). The reaction of 99 with ammonia in methanol yields the amide (100) which, on oxidation with chromium trioxide, afforded 2,7-naphthyridin-l-one (101). This substance was converted into 2,7-naphthyridine (102, R = H) by consecutive treatment with phosphorus oxychloride, hydrazine, and copper sulfate. The 3-methyl derivative was similarly prepared starting with acetaldehyde. 

Two year later, Pinel group used (S) proline and (S) pyroglutamic esters as chiral auxiliaries for the diastereoselective hydrogenation of 2 methylnicotinic acid with up to 35% de [50]. They tried to improve diastereoselectivity of these reactions, but no better result was obtained (Scheme 10.37). 

An interesting transformation of various 4-methylnicotinic acids, in which the activated 4-methyl group enters into the reaction of the carboxyl group with thionyl chloride, leads to a l,3-dioxo-l,3-dihydrothienol 3,4-clpyridine74 [Eq. (22)1. 

Nicotine.—Nicotine (33) is assembled in Nicotiana species from nicotinic acid (31) and N-methyl-A -pyrroline (32). Administration to Nicotiana plants of 5-fluoronicotinic acid and derivatives of (32) methylated at C-2 and C-3 has resulted in the formation in vivo of unnatural nicotine analogues.In contrast, 4-methylnicotinic acid has been found not to be transformed in vivo into 4-methylnicotine, presumably because this particular methyl group interferes sterically with the appropriate enzyme reactions involved in nicotine biosynthesis. ... 

The use of cupric nitrate as a catalyst in these systems has also been described. The reaction usually proceeds to isocinchomeronic acid (X-5S, R = CO2 H), which is decarboxylated to nicotinic acid (X-S6) either in situ or in a subsequent operation. Under specific conditions of temperature and pressure, the reaction can be stopped at the 6-methylnicotinic acid (X-55, R = CHj) stage. It thus seems clear that under those conditions the 5-alkyl group is more prone to oxidative attack. The same nitric acid reaction system, with or without... 

---