3,4-Pyridyne, formation

Low temperatures are necessary with orr/io-halolithiopyridines in order to prevent pyridyne formation, and an added complication with some bromopyridines is that rearrangement of the initial lithio derivative can occur via an intermolecular transmetalation process (Scheme 108)(79T1625 85T3433). This result has been used synthetically to give 2-bromo-3-substituted derivatives from 2,6-dibromopyridine [90JOM-... 

S235). Examples of halogen directed metallation include the lithiation of 5-bromopyrimidine (345) or chloropyrazine (346) by LDA. 3-Halopyridines are also lithiated regiospecifically at C-4, but pyridyne formation is then rapid. 

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. 

There is a complication if the nucleophile used in reactions with halopyridines is also a strong base for now the formation of a pyridyne is possible, and with sodamide in liquid ammonia (providing the NH2 ion , B), for example, both 3-aminopyridine and 4-aminopyridine are formed from 4-bromopyridine (Scheme 2.16). 

In 1972 Berry and co-worker detected 3,4-pyridyne (101) by MS. Trapping experiments also provided evidence for the existence of this intermediate, although the chemistry of 101 differs considerably from that of o-benzyne. Thus, neither anthracene nor dimethylfulvene form Diels-Alder adducts with 101. Nam and Leroi were able to generate 101 in nitrogen matrices at 13 K and characterized it by IR spectroscopy. Irradiation of 3,4-pyridinedicarboxylic anhydride (103) with 1 > 340 nm results in formation of 101, which upon short wavelength photolysis (k > 210 nm) fragments to buta-l,3-diyne (104) and HCN, and to acetylene (105) and cyanoacetylene (106, Scheme 16.24). The assignment of an intense... 

Fozard and Jones21 have reported the formation of 3-amino-1-hydroxyquinolizinium bromide (probable structure) by the treatment with ammonia of 2,2-dibromo-l,2,3,4-tetrahydro-l-oxo-quinolizinium bromide. A pyridyne-type intermediate is postulated to explain the formation of this compound. 

Similarly, 4-lithiated 3-bromo and 3-chloro pyridines generated from substrates 40, are stable between -60 and -40°C, and lithium halide elimination to 2-fluoro-3,4-pyridyne occurs only upon warming to room temperature, as evidenced by the formation of adduct 41 (Scheme 13) [72CR(C)(275)1439, 72CR(C)(275)1535]. 

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). 

Direct formation of aza-anthraquinones 181 has been achieved using in situ generated lithio cyanophthalide 177 (a 1,4-dipole equivalent) and 3,4-pyridyne 178 (Scheme 52) [88H(27)2643]. Thus, addition of 3-bromopyridine derivative to a solution of LDA and 177 at -40°C leads, when warmed to room temperature, to aza-anthraquinones 181 in good yields via intermediates 179 and 180. This type of reaction has also been applied to 4-bromoquinoline to give benzo[rf]-2-azaanthraquinone in 60% yield [88H(27)2643]. 

The scope of this methodology is restricted to the generation of 3,4-pyridyne. To date, analogous formation of 2,3-pyridyne from 2-halopyridines has not been reported. 

Pyridyne 1-oxide (893) is obtained by the action of potassium amide on 2-bromopyridine 1-oxide (892), as shown by the formation of a mixture of the 2- and 3-aminopyridine oxides. Reaction of 5-bromopyrimidine with sodium amide in liquid ammonia involves 4,5-pyrimidyne as an intermediate. 

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. 

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... 

Two of the reactions summarized in Tables VI and VII require some comment. The reaction of 3-hydroxypyridine with an excess of sodamide at 210° results in the elimination of the hydroxyl group and the formation of 2,6-diaminopyridine. Plazek288 attributed this to the reduction of the phenolic function by nascent hydrogen. More recently, however, this reaction has been interpreted as providing evidence for the intermediacy of a 2,3-pyridyne species in this reaction271 ... 

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... 

Recently H. L. Jones and D. L. Beveridge have presented molecular orbital calculations on the electronic structure of 2,3-pyridyne explaining the exclusive formation of 2-aminop3rridine from this intermediate [Tetrahedron Letters No. 24, 1677 (1964)]. 

Similarly, a novel one-pot microwave-assisted reaction has been described by Hulme and co-workers that enables the selective formation of 3-iminoaryl-imidazo[l,2-a]pyridines 19 and imidazo[l,2-a]pyridyn-3-ylamino-2-acetonitriles 20, in good yields. Reactions were performed in methanol by mixing a suitable a-aminopyridine, an aldehyde and trimethylsilylcyanide (TMSCN) with polymer-bound scandium triflate, to afford either product 19 or 20 (Scheme 16). Initially, the 3-iminoaryl-imidazo[l,2-a]pyridine 19, was observed as a minor side product (0-10%) during the pseudo-Ugi reaction affording the 3-aminoimidazo[l,2-a]pyridine 18. However, by increasing the aldehyde input to 2.2 equiv the reaction could be directed to the formation of 19 in moderate yields. Interestingly, low yields of... 

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