2-Amino-6-bromopyridine, reaction with

The presence of unsaturation in the side chain is also compatible with antihistaminic activity. Mannich condensation of p-chloroacetophenone with formaldehyde and pyrollidine affords the amino ketone, 109. Reaction with an organometallic reagent from 2-bromopyridine gives 110. Dehydration leads to triproli-dine (111). ... 

Chlorination of the derivatives (500) with phosphorus oxychloride followed by reaction with ammonia, gives the 2-amino-3-bromopyridines (501). Cyclization of (501 R = 4-pyridyl) was accomplished by heating with ethyl potassium xanthate in l-methyl-2-pyrrolidinone at 160-165 °C to give the thiazolo[4,5-6]pyridine (502 R = 4-pyridyl) in near quantitative yield (Scheme 61) (94JMC248). 

Azine approach. Cyclocondensation between 3-amino-4-hydroxypyridines and carboxylic acids leads to oxazole fusion as in (233) (77CR(C)(284)73>. The 2-phenyl derivative (235) has been obtained via a pyridyne-type reaction 3-benzamido-5-bromopyridine reacts with lithium piperidide via an intermediate which can be visualized as the pyridyne enolate (234) (73CB220). 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

Cyclocondensation of 2-amino-6-bromopyridine and 4-chloroacetoace-tate in PPA at 100 °C for 4h afforded a mixture of 2-chloromethyl-, 2-bromomethyl-6-bromo-, and 2-chloromethyl-, 2-bromomethyl-6-chloro-4//-pyrido[l,2-n]pyrimidin-4-ones in 84% yield (99JHC1065). The pyrido-[l, 2-a]pyrimidin-4-ones were separated by preparative reversed phase HPFC. The pure 2-bromomethyl-6-bromo-4//-pyrido[l,2-n]pyrimi-din-4-one was prepared from 2-amino-6-bromopyridine with ethyl 4-bromoacetoacetate in 63% yield. Reaction of 2-aminomethylpyridines and ethyl 4-chloroacetoacetate in PPA at 110°C gave 2-chloromethyl-4//-pyrido[l,2-n]pyrimidin-4-ones (95FFS69, 01H(55)535). 

For Negishi reactions in which the pyridines are nucleophiles, the pyridylzinc reagents are usually prepared from the corresponding halopyridines [6, 20, 21]. An excess of 2-chlorozincpyridine /V-oxide (26), arising from 2-bromopyridine N-oxide hydrochloride (25), was coupled with vinyl triflate 27 in the presence of Pd(Ph3p)4 to furnish adduct 28 [20]. Recently, an efficient Pd-catalyzed cyanation of 2-amino-5-bromo-6-methylpyridine (29) using zinc cyanide has been reported to afford pyridyl nitrile 30 [22]. 

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... 

The reaction of A-methyl-A-acetyl-2-chloro-3-amino tion in THF-hexane (-78 °C) gave azaindole in 83% yield used to prepare the key intermediate for the synthesis of Eupolauramine339. Thus, o-metallation of 3-bromopyridine and treatment with MeNCO gave the anion 319, which reacts with PhCOCH2Br forming the product 320 (equation 191). 

The stabilities of pyridine-2- and -4-diazonium ions resemble those of aliphatic rather than benzenoid diazonium cations. Benzenediazonium ions are stabilized by mesomerism which involves electron donation from the ring, but such electron donation is unfavorable in 2- and 4-substituted pyridines. On formation, pyridine diazonium cations normally immediately react with the aqueous solvent to form pyridones. However, by carrying out the diazotization in concentrated HC1 or HBr, useful yields of chloro- and bromopyridines 752 can be obtained. Iodinated pyridines can be obtained in good yield using the Sandmeyer reaction. Aminopyridazines and -pyrazines, 2- and 4-aminopyrimidines, and amino-1,2,4-triazines behave similarly. Nucleophilic fluorination via the BalzSchiemann reaction of diazonium fluoroborates yields fluoropyridines, including 2-fluoropyridines. Fluoroborates can also be converted into fluoro compounds by ultraviolet irradiation. 

Substituted 4- or 5-halopyrimidines with sodium amide in liquid ammonia give 4-methyl-1,3,5-triazines (Scheme 317) the reaction is general and yields are good cf., the related conversion of 6-substituted 2-bromopyridines into pyrimidines (Section 4.3.3.3.4). 4-Amino-5-nitrosopyrimidines are converted into 1,3,5-triazines by acetic anhydride or phosphorus oxychloride (Scheme 318). 1,3,5-Triazines can be obtained from 1,3,5-oxadiazinium cations (Section 3.2.1.6.1.3). 

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