Of pyridynes

Quinolinic anhydride decomposes at a lower temperature than do the aromatic anhydrides (Fields and Meyerson, 1967e). For this reason, it was allowed to react with thiophene at 600° and 40 sec contact time. The products, quinoline, pyridothiophene, and pyridylthiophene, are those expected from the 1,4- and 1,2-additions and insertion of pyridyne with thiophene ... 

Whether the unusually high ratio of 1,4- to 1,2-addition product, 50 1, is due to a markedly different reactivity of pyridyne as compared with... 

Finally, an example of a 1,3-dipolar cycloaddition has appeared. Reaction of pyridynes and quinolynes with pyridazine-A-oxides 747 gave pyrido-oxepins 750 in 20-30% yields. The reaction is thought to involve cycloaddition to give 748 which, after a 1,3-shift of the oxygen from N to C and nitrogen loss, gives the product. The pyridynes were produced by lead tetraacetate oxidation of 1-aminotriazolopyridines. 

By the early 1960s there was strong evidence for the existence of pyridyne (2). This was based on the observation that both 3- and 4-halosubstituted pyridines (1) yielded the same ratio of the 3- and 4-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. 

The Boekelheide reaction has found utility in other synthetic methodology. An approach to 2,3-pyridynes made use of this chemistry in the preparation of the key intermediate 30. Treatment of 28 with acetic anhydride produced the desired pyridone 29. Lithiation was followed by trapping with trimethylsilyl chloride and exposure to triflic anhydride gave the pyridyne precursor 30. Fluoride initiated the cascade of reactions that resulted in the formation of 2,3-pyridyne 31 that could be trapped with appropriate dienes in Diels-Alder reactions. 

Whereas only one dehydrobenzene, benzyne, has been detected, two pyridynes are possible. Thus, the scheme we can write ab initio for the action of a nucleophile on the isomeric monosubstituted derivatives of pyridine involving 2,3- (26) and/or 3,4-pyridyne (31) is more complicated than that for the analogous reaction of the corresponding benzene derivative. The validity of this scheme can be checked using data available in the hterature on reactions of halogenopyridines with potassium amide and hthium piperidide involving pyridynes. 

The data described above give sound evidence for the existence of 3,4-pyridyne but do not indicate that 2,3-pyridyne occurs as an intermediate. The generation and reactivity of 3,4-pyridyne and some of its derivatives are discussed next. Section II, A, 3 deals with problems concerning 2,3-pyridyne. 

Those reactions of halogenopyridines with potassium amide and lithium piperidide which proceed via 3,4-pyridyne form the 3- and 4-substituted pyridine derivatives in ratios of 1 2 and 1 1, respectively (see Section II, A, 1). It appears that the ring nitrogen atom has an orienting effect on these additions, but the quantitative divergence of the addition of ammonia and piperidine is not understood at present. 

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. 

Pyridyne (26) has been shown to exist by trapping it with furan. It must be considered to be an intermediate in the reaction of 3-bromo-2-chloropyridine (49) with lithium amalgam because in the presence of furan a small amount (2%) of quinoline (50) is 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. 

In 57 a bromine migration possibly competes with the generation of 4-ethoxy-2,3-pyridyne (58), induced by the abstraction of a hydrogen ion from C-2 of 57 (cf. the isomerization of 1,2,4-tribromobenzene to... 

Quinolynes are generated and behave analogously to pyridynes. The reaction of 3-bromo-4-chloro- and 3-bromo-2-chloro-quinoline with lithium amalgam in the presence of furan gives phenanthridine (83, 9% yield) and acridine (85, 0.1% yield), respectively, via 3,4-... 

In an extensive investigation of the behavior of halogeno-pyridines and -quinolines towards potassium amide in liquid ammonia, tendencies to react according to the hetaryne type and other mechanisms were compared. The following results may be mentioned. 3-Fluoropyridine does not react via 3,4-pyridyne, but yields fluoro derivatives of 4,4 - and 2,4 -bipyridine. 3,6-Dibromopyridine is converted first into 6-bromo-3,4-pyridyne and not into 6-amino-3-bromopyridine. 2-Bromoquinoline yields 2-methylquinazoline together with 2-aminoquinohne. ... 

A new example of the reactivity of 3,4-pyridyne as a dienophile was reported (the conversion by cyclopentadiene ) and a remarkable orienting effect of the amino group on the addition of ammonia to the triple bond in amino derivatives of 3,4-pyridyne, e.g., the addition of the amide ion to C-4 in 5-amino-3,4-pyridyne. ... 

The scope of heteroaryne or elimination-addition type of substitution in aromatic azines seems likely to be limited by its requirement for a relatively unactivated leaving group, for an adjacent ionizable substituent or hydrogen atom, and for a very strong base. However, reaction via the heteroaryne mechanism may occur more frequently than is presently appreciated. For example, it has been recently shown that in the reaction of 4-chloropyridine with lithium piperidide, at least a small amount of aryne substitution accompanies direct displacement. The ratio of 4- to 3-substitution was 996 4 and, therefore, there was 0.8% or more pyridyne participation. Heteroarynes are undoubtedly subject to orientation and steric effects which frequently lead to the overwhelming predominance of... 

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. 

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