Pyridynes amination

Amines or ammonia replace activated halogens on the ting, but competing pyridyne [7129-66-0] (46) formation is observed for attack at 3- and 4-halo substituents, eg, in 3-bromopyridine [626-55-1] (39). The most acidic hydrogen in 3-halopyridines (except 3-fluoropyridine) has been shown to be the one in the 4-position. Hence, the 3,4-pyridyne is usually postulated to be an intermediate instead of a 2,3-pyridyne. Product distribution (40% (33) and 20% (34)) tends to support the 3,4-pyridyne also. 

Ethoxy derivatives of 3,4-pyridyne were found to play a role in the amination of bromoethoxypyridines with potassium amide in liquid... 

Ethoxy-3,4-pyridyne (46) is involved in the amination of 3- and 4-bromo-2-ethoxypyridine, and mixtures of aminoethoxypyridines of the same composition are formed in both reactions. Thus, from 4-bromo-2-ethoxypyridine only the 3-hydrogen atom, situated between the bromine and ethoxyl groups (and not the 5-hydrogen atom) is abstracted. Pyridyne 47 is an intermediate in the amination of 4- and 5-bromo-3-ethoxypyridine. In the last-mentioned substance, just as in 5- (or 3-)bromopyridine, only the 4-hydrogen atom, and not the 2-hydrogen atom, is abstracted. The amination of 3-bromo-6-ethoxypyridine proceeds via 6-ethoxy-3,4-pyridyne (48). again the 2,3-pyridyne derivative is not formed. 

While awaiting the results of tracer experiments, the present authors prefer to desist from assuming that the route from 24 to 25 via the addition product shown is the only pathway followed in the amination of 2-halogenopyridines. This is the more so since it seems probable that in the experiments described below derivatives of 2,3-pyridyne occur as intermediates. 

The amination of 2-chloropyridine-A-oxide (53) with potassium amide in liquid ammonia yielded a mixture of 2-(55) and 3-amino-pyridine-A-oxide (56) in 5-10% total yield.This rearrangement might be explained by an aryne mechanism involving 2,3-pyridyne-A-oxide (54). Since the structure of 56, with its quaternary nitrogen atom, is more analogous to that of 3-methoxybenzyne (39) than to that of 2,3-pyridyne (26), an orientation effect directing the amide ion to C-3 can be expected here. 

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. 

Amination of 2-chloro-, 2-bromo-, and 2-iodopyridine with potassium amide in liquid ammonia gave exclusively 2-aminopyridine. In this case an Addition-Mimination mechanism (Sn(AE) mechanism) has been proposed. The intermediacy of 2,3-pyridyne was considered to be highly unlikely (65AHC121). 

On the other hand, LDA metalation of 3-bromopyridine (42) at -70°C yields, after hydrolysis, a mixture of 3- and 4-substituted products (43 and 44) in addition to starting material 42 (Scheme 14) (82T3035). A potential explanation for these results involves the formation of 3,4-pyridyne, which undergoes nonregioselective attack by amine or lithio amide to give 43 and 44. An alternative rationalization is the isomerization of 42 into the 4-isomer 45 under the metalation conditions (see Section II,B,4), followed by the conversion of either isomer into the radical anions 46 which, via the caged radical pairs 47, is converted into 43 and 44 (Radical Anion-Radical Pair = RARP pathway). 

The mechanism of the Chichibabin amination of pyridine has been discussed in terms of an addition-elimination mechanism via a covalent a-adduct.38 39 The possible formation of 2,3-didehydropyridine (2,3-pyridyne) as intermediate in the Chichibabin amination has been advocated, but this is now definitely rejected.38 39 In this section we discuss the Chichibabin amination of the parent naphthyridines and their derivatives and the products that are obtained in these aminations. The formation of their precursors (the covalent n-adducts) has already been discussed in Section II,A and II,B. 

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. 

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... 

Intermolecular aminations of pyridine 1-oxides with amide ions have not been as well investigated as those of the neutral molecules. Most of the examples studied involve halo JV-oxides, where a competition between Type B behaviour and pyridyne reaction compete (Scheme 91) (67RTC655). 

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