Pyridyne intermediates

Studies of the reaction of 3-deuteropyridine and 3-picoline with sodamide has shown that this type of amination does not proceed through a pyridyne intermediate as had been postulated recently. 

Two other important modes of substitution require mention here. They are the SNAr and elimination-addition reactions. Actually, it is sometimes difficult to distinguish between true aromatic nucleophilic substitutions and addition-elimination processes. The second group involves pyridyne intermediates (Scheme 53). Both of these reaction types are discussed fully under substituent reactions (Chapter 2.06). 

The base combination of sodium amide and sodium tert-butoxide in tetrahydrofuran (THF) containing a secondary amine converts halopyridines into aminopyridines via a pyridyne intermediate (Equation 82) <1997H(45)2113>. The regioselectivity varies depending upon the position and type of pyridine substituents. 

Despite the foregoing evidence already present in the literature, Jones and Beveridge292 have published molecular orbital calculations purporting to support the pyridyne intermediate mechanism, and have postulated lone-pair interaction, which can result in the formation of a 2,3- or of a 2,6-pyridyne interme diate and explain the absence of any 3-aminopyridines among the reaction products. It was stated that lone-pair interaction would make a 2,3-pyridyne intermediate more... 

Tschitschibabin reaction,290 thus counteracting the example based on 3-hydroxypyridine. The second reaction to be discussed is that of 2-picoline with sodamide at a relatively high temperature, when 3,6-diamino-2-picoline (126) is one of the products isolated.293 If this is so, this represents another example of the type of orientation recently observed in the phenylation of pyridine with phenylcalcium iodide which gave some 2,5-diphenylpyridine.264 Alternatively, a 3,4-pyridyne intermediate (125) might perhaps actually be involved here. The evolution of hydrogen is not mentioned in this case. The decarboxylation of pyridine carboxylic acids under strongly basic conditions is unexceptional. 

Phenacylpyridine and 4-aminopyridine are formed in the reaction of 3-bromopyridine with sodioacetophenone and sodamide in liquid ammonia.272 The 3,4-pyridyne intermediate (156) formed by elimination adds the nucleophiles present in solution. In view of the observations363-365 that when 3-halopyridines are treated with potassium... 

When 3-chloro- or 3-bromopyridine is heated with lithium piperidide and piperidine in boiling ether, 156 is formed, which reacts further with piperidine to give a mixture of 3- and 4-piperidinopyridine in the ratio of 48 52. No 2,3-pyridyne intermediate is apparently produced under these conditions.388 Such an intermediate is probably involved in the reaction of potassium amide in liquid ammonia with 3-bromo-4-ethoxypyridine, which gives 2-amino-4-ethoxypyridine (55-60%). The reaction is, however, complicated by the fact that 2-amino-5-bromo-4-ethoxypyridine (15-20%) and 4-ethoxypyridine (25%) are also obtained.387 The formation of these two by-products may proceed by the preliminary disproportionation of some 3-bromo-4-ethoxy-pyridine to 3,5-dibromo-4-ethoxypyridine and 4-ethoxypyridine.388 The remarkable observation that both 2-amino-6-ethoxypyridine (157) (85%) and 4-amino-2-ethoxypyridine (158) (15%) are formed during the amination of 2-bromo-6-ethoxypyridine367 still requires explanation. No such rearrangement is observed with lithium piperidide.3880... 

In contrast with the 3,4-didehydroquinoline intermediates, the 3,4-pyridyne intermediate obtained on pyrolysis of anhydride 734 cf 726) did not rearrange to a carbene or... 

Reaction of 2-chloro- or 2-iodo-pyridine with potassamide in liquid ammonia , or of 2-fluoropyridine with lithium piperidide in ether results in direct substitution without pyridyne intermediates. The reaction of 3-fluoropyridine with potassamide in liquid ammonia at —33° takes a surprising course . Evidently the base abstracts a proton from the 4-... 

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