1- Bromopyridine

three-neck flask is equipped with a stirrer, a dropping funnel, and a wide-bore distillation head with attached air condenser and distillation receiver. Bromine (800 g., 5.0 moles) is added to 1155 g. (10.0 moles) of pyridine hydrochloride in the flask over a period of 5 minutes with stirring. (Hood.) The flask is heated to 160-170° for 1 hour and then to 195-200° for another hour as evolution of hydrogen chloride ceases. The system is evacuated with a water pump, and a manometer is connected to the flask in place of the dropping funnel. The distillation receiver is cooled with running water. 3,5-Dibromopyridine distils over, followed by 3-bromopyridine hydrobromide as the bath temperature is raised to 220° and the pressure drops to about 25 mm. The combined solid distillate is treated with a solution of 200 g. of sodium hydroxide in 1 1. of water, the mixture is extracted with benzene, and the benzene solution is distilled. There is obtained 300 g. (37%) of 3-bromopyridine boiling at 61-63°/15 mm. The residue from the above operation is distilled with steam to give in the distillate 144 g. (26%) of 3,5-dibromopyridine, m.p. 110-111°. 

Submittf rl by C. F. H. Allen and John R. Thirtle. Checked by Clcee S. Hamilton and Carol K. Ikeda. 

In a 5-1, 3-necked flask fitted with a mechanical stirrer (Note 1), a dropping funnel, and a thermometer for reading low temperatures is placed 790 ml. (7 moles) of 48% h drobromic acid. The fl.ask and contents are cooled to 10-20 in an ice-salt bath, and 150 g, (1.59 moles) of 2-aminopyridine (Note 2) is added over a period of about 10 minutes. While the temperature is kept at 0° or lower, 240 ml. (4.7 moles) of bromine is added dropwise (Note 3). A solution of 275 g. (4 moles) of sodium nitrite in 400 ml. of water is added dropwise over a period of 2 hours, the temperature being carefully maintained at 0° or lower (Note 4). After an additional 30 minutes of stirring, a solution of 600 g. (15 moles) of sodium hydroxide in 600 ml. of water is added at such a rate that the temperature does not rise above 20-25° (Note 5). The nearly colorless reaction mixture is extracted with 

A stirrer which gives efficient stirring near the walls of the flask is advisable. The fittings should not be gas tight since oxides of nitrogen and bromine are evolved during the reaction. It is advisable to work in a hood or out-of-doors. 

The checkers used Eastman Kodak Company s Practical grade of 2-aminopyridme. 

The reaction mixture thickens, owing to formation of a yellow-orange perbromide during the addition of about one-half of the bromine the first half of the bromine is added over a period of 30 minutes the second half, over a period of 15 minutes. 

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Bromopyridine has been made by direct bromination of pyridine - from N-methyl-2-pyridone with phosphorus penta-bromide and phosphorus oxybromide from 2-aminopyridine by diazotization with amyl nitrite in 20% hydrobromic acid from sodium 2-pyridinediazotate by solution in concentrated hydrobromic acid and from 2-aminopyridinc by diazotization in the presence of bromine and concentrated hydrobromic acidd The method described here is essentially that of Craig. 

In a variation of this method, 2-bromopyridine A-oxide (60) has been converted by sodium sulfide to the thiohydroxamic acid (61). 

Amination of derivatives of 2-bromopyridine gave, just as did the same reaction of 2-bromopyridine itself, no decisive answer concerning the mechanism of these processes, except that 2-bromo-3-ethoxy-... 

Attempts to get more information on this interesting meta-rearrangement by choosing derivatives of 2-bromopyridine containing various substituents in the 6-position for the starting material led to a remarkable result. Whereas 2-bromo-6-picoline gave a mixture of 2-and 4-amino-6-picoline (in a ratio of 60 1) in 25% total yield together with a resinous mass, 2,6-dibromopyridine (79) was converted into a pyrimidine, i.e. 4-amino-2-methylpyrimidine (80), in 20% yield. The same pyrimidine was obtained from 2,6-dichloropyridine and, in small amount, also from 2,4-dibromopyridine (81). The course of the... 

The effect of a carboxy group is illustrated by the reactivity of 2-bromopyridine-3- and 6-carboxylic acids (resonance and inductive activation, respectively) (cf. 166) to aqueous acid under conditions which do not give hydroxy-debromination of 2-bromopyridine and also by the hydroxy-dechlorination of 3-chloropyridine-4-car-boxylic acid. The intervention of intermolecular bifunctional autocatalysis by the carboxy group (cf. 237) is quite possible. In the amino-dechlorination (80°, 4 hr, petroleum ether) of 5-carbethoxy-4-chloropyrimidine there is opportunity for built-in solvation (167) in addition to electronic activation. This effect of the carboxylate ion, ester, and acid and its variation with charge on the nucleophile are discussed in Sections I,D,2,a, I,D,2,b, and II,B, 1. A 5-amidino group activates 2-methylsulfonylpyridine toward methanolic am-... 

Intramolecular nucleophilic displacement of the bromo group by an azine-nitrogen occurs in the cyclization of A-2-quinaldyl-2-bromo-pyridinium bromide (248) to give the naphthoimidazopyridinium ring system. The reaction of 2-bromopyridine and pyridine 1-oxide yields l-(2-pyridoxy)pyridinium bromide (249) which readily undergoes an intramolecular nucleophilic substitution in which departure of hydrogen as a proton presumably facilitates the formation of 250 by loss of the JV-oxypyridyl moiety. 

Amino group of 7-aminomethyl-2-substituted perhydropyrido[l,2-u]pyr-azines were reacted with 2-bromopyridine and 2-chloropyrimidines to give 7-(hetarylamino)methyl derivatives in the presence of Na2C03 in DMF at 100-120°C for 18h in 13-51% yields (00MIP15). An aminomethyl group of... 

Cyclization of the side chain onto the nitrogen atom leads to compounds with sedative and tranquilizing activity. The lack of structural specificity, that is, the fact that both positional isomers (41,43) show the same activity, is notable. Thus, condensation of the Grignard reagent from 2-bromopyridine with ben-zophenone affords the tertiary carbinol, 40. Catalytic reduction... 

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). ... 

To a solution of 35.3 parts of phenylacetonitrile and 47.6 parts of 2-bromopyridine in 175 parts of dry toluene is added 53.4 parts of sodamide slowly with stirring over a period of 45 minutes. The resultant mixture is stirred at 100 C for 2 hours before it is cooled and the excess sodamide is decomposed by the addition of water. The toluene layer is separated and washed with water to remove excess alkali. The toluene solution is extracted with 6N hydrochloric acid and the acid extract is made alkaline and then extracted with toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. Recrystal-lization of the residue from alcohol-hexane gives a-phenvl-2-pyridineacetonitrile melting at about 87°-88°C. 

Bromopyridine (193 g, 1.22 mols) is then added dropwise over 20 minutes, the temperature of the reaction mixture being maintained at -50 2°C. The mixture is stirred for 10 minutes at -50°C and p-methyl-cj-pyrrolidinopropiophenone (112.5 g, 0.5 mol) in dry benzene is then added dropwise over ca 30 minutes, at a temperature of -50 2°C. The mixture is stirred for a further 2 hours, the temperature being allowed to rise to -30°C but no higher. 

Although iodides are more reactive than bromides, 2-(trifluoro-methyl)pyridine was obtained in 95% yield from 2-bromopyridine and CF3Br using an undivided electrochemical cell, DMF, and a sacrificial copper anode. CF3Cu was the reactive intermediate (92CC53). Photochem-... 

Alkylzinc halides have also been prepared under microwave irradiation. The Reformatsky reagents (2-t-butoxy-2-oxoethyl)zinc bromide and [(2-dibenzylamino)-2-oxoethyl]zinc bromide were synthesized from the corresponding bromides via reaction with zinc in THF (Scheme 5) [24], The oxidative addition was executed at 100 °C in 5 min. The obtained reagents were subsequently used in Negishi reactions on 2-bromopyridine, 3-bromopyridine, 2-bromo-5-nitropyridine, and 2-bromo-5-trifluoromethyl-pyridine using Pd(PPh3)4 as a catalyst (Scheme 5). 

Remarkably, one year later Leadbeater described that biaryls can be synthesized via a Suzuki-type coupling under transition-metal free conditions [51, 52]. The reaction conditions were almost identical to those reported for the ligand-free process, with the difference being that a larger amoimt of Na2C03 and arylboronic acid were used. Only one successful example of a heteroaryl haUde substrate is shown namely, the coupling of 2-bromopyridine with phenylboronic acid (Scheme 32). 3-Bromothiophene did not couple under the same reaction conditions. Unfortimately, attempts to use heteroarylboronic acids such as 3-pyridinylboronic acid, 3-thienylboronic acid, and lH-indol-5-ylboronic acid on 4-bromoacetophenone completely failed. 

Homolytic aromatic substitution often requires high temperatures, high concentrations of initiator, long reaction times and typically occurs in moderate yields.Such reactions are often conducted under reducing conditions with (TMSlsSiH, even though the reactions are not reductions and often finish with oxidative rearomatization. Reaction (68) shows an example where a solution containing silane (2 equiv) and AIBN (2 equiv) is slowly added (8h) in heated pyridine containing 2-bromopyridine (1 equiv) The synthesis of 2,3 -bipyridine 75 presumably occurs via the formation of cyclohexadienyl radicals 74 and its rearomatization by disproportionation with the alkyl radical from AIBN. ... 

Aminopyridine (I) is converted by diazotisation in the presence of bromine and concentrated hydrobromic acid Into 2-bromopyridine (II) the latter upon treatment with copper powder in the presence of p-cymene yields 2 2 -dipyridyl (III). 

A disubstituted butyramide, disopyramide, distantly related to some acyclic narcotics interestingly shows good antiarrhythmic activity. Alkylation of the anion from phenylacetonitrile with 2-bromopyridine yields 99. Alkylation of the anion from the latter with N,N-diisopropyl-2-chloroethyl-amine leads to the amine 100. Hydration of the... 

Preparation of a rather more complex imidazoline drug starts with the alkylation of the carbanion from p-chlorophenylacetonitrile (128) with 2-bromopyridine. Reaction of the product (129) with ethylenediamine serves to form the imidazoline ring (130). Air oxidation then affords the tertiary carbinol by attack at the highly activated, multiply benzylic carbon. There is thus obtained the antidepressant dazadrol (131).31... 

In the same report, the Strauss group furthermore presented the effective use of palladium on porous glass to achieve quantitative conversions in couplings of phe-nylacetylene with iodobenzene and 4-bromobenzaldehyde. Additionally, satisfactory results were obtained for couplings of phenylacetylene with 4-bromoacetophenone and 2-bromopyridine [146]. 

Upon microwave ( rw) irradiation, benzotriazole and its derivatives react readily with 2-chloropyridine to afford products 113-115 in 87%, 72%, and 70% yield, respectively (Scheme 9). 2-Chloroquinoline reacts similarly. 2-Bromopyridine and 2-bromoquinoline give generally lower yields in these reactions <20060L415>. 

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