Pyridine 1-oxide, nucleophile

Nucleophilic Trapping of Radical Cations. To investigate some of the properties of Mh radical cations these intermediates have been generated in two one-electron oxidant systems. The first contains iodine as oxidant and pyridine as nucleophile and solvent (8-10), while the second contains Mn(0Ac) in acetic acid (10,11). Studies with a number of PAH indicate that the formation of pyridinium-PAH or acetoxy-PAH by one-electron oxidation with Mn(0Ac)3 or iodine, respectively, is related to the ionization potential (IP) of the PAH. For PAH with relatively high IP, such as phenanthrene, chrysene, 5-methyl chrysene and dibenz[a,h]anthracene, no reaction occurs with these two oxidant systems. Another important factor influencing the specific reactivity of PAH radical cations with nucleophiles is localization of the positive charge at one or a few carbon atoms in the radical cation. 

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]. 

Pyridine could function as a nucleophile in ozonization. It is soluble in hydrocarbons and is rather stable towards ozone (8, 11). Pyridine does have a dramatic effect on the course of ozonization. Slomp and Johnson (13) in their work on the ozonolysis of 4,22-stigmastadien-3-one propose that two moles of aldehyde are formed for each mole of double bond oxidized and that pyridine is oxidized to pyridine oxide. They also propose that pyridine oxide oxidizes aldehyde to acid with regeneration of pyridine. 

Ample opportunities are opened with synthesis of trifluoromethylated azines via oxidative nucleophilic substitution of hydrogen by trifluoromethyl carbanions [175], This pathway to the synthesis of trifluoromethylazines includes reaction of quatemization of azines 283 by p-methoxybenzylbromide (PMB) (284) to obtain salts 285. Further KF is added to reaction mixture of salt 285 and CF3Si(CH3)3 to generate anion 286. Regioselective trifluoromethylation results in formation of 1,2-dihydropyridines 287 which then have been oxidized by action CAN to get appropriate trifluoromethylazines 288 (Table 4) [ 175] (Scheme 85). Regioselectivity of the reactions is determined by the nature of substituent at pyridine s cycle. So in case of an ether of nicotinic acid and 3-benzoylpyridine the mixture of 2-and 6-trifluoromelhylpyridines are formed (Table 5). 

As expected, 4-aryloxy groups in pyridine oxides can be replaced by amines . 4-Alkoxy709 and 4-aryloxy-groups706 in quaternary pyridinium salts are readily replaced. In contrast to 4-phenoxypyridine, 4-phenoxy-pyridine hydrochloride does not react with arylamine hydrochlorides, presumably because of the lowering of the nucleophilic power of the amine... 

A number of nucleophilic substitutions starting from pyridine oxides may be in a sense cine-substitutions the oxide group being modified to a quaternary form and then expelled nucleophilically as an anion ... 

Unsymmetric anhydrides that react selectively on one side are useful. Although formic anhydride is unstable above 10°C, acetic formic anhydride can be prepared by stirring sodium formate with acetyl chloride in ether (64% yield, bp 27-28°C) [22]. It is useful for the formylation of alcohols and amines. A stable solid formylating agent is the mixed anhydride prepared in 89% yield from p-methoxybenzoyl chloride and sodium formate catalyzed by a polymeric pyridine oxide [23]. Ethyl chlorofor-mate gives mixed anhydrides with various carboxylic acids which are then susceptible to nucleophilic substitution at the carboxylic carbonyl carbon. 

Nucleophilic Attack at Carbon or Hydrogen. Only the strongest of nucleophiles (eg, —NH2) can replace a hydrogen in pyridine. However, N-oxides and quaternary salts rapidly undergo addition, followed by subsequent transformations (12). 

The N-oxides readily undergo nucleophilic addition followed by elimination, which forms the basis of several useful syntheses of 2-substituted pyridines. Chlorination of (13) with POCl to give 2-chloropyridine (17) is a good example (eq. 4) some chlorination may occur also at C-4 (11). 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

Pyrazine and quinoxaline fV-oxides generally undergo similar reactions to their monoazine counterparts. In the case of pyridine fV-oxide the ring is activated both towards electrophilic and nucleophilic substitution reactions however, pyrazine fV-oxides are generally less susceptible to electrophilic attack and little work has been reported in this area. Nucleophilic activation generally appears to be more useful and a variety of nucleophilic substitution reactions have been exploited in the pyrazine, quinoxaline and phenazine series. 

In addition to their reactions with amines, Zincke salts also combine with other nitrogen nucleophiles, providing various A -substituted pyridine derivatives. Pyridine A -oxides result from the reaction with hydroxylamine, as exemplified for the conversion of Zincke salt 38 to the A -oxide 39 Reactions of Zincke salts with hydrazine, meanwhile, lead... 

Chapman and co-workers have investigated the nucleophilic displacement of chlorine in various chloronitropyridines by three pyridines. In each of these series of three compounds, an excellent correlation is observed, but, again, longer series would be extremely desirable. Similarly, the nucleophilic attack of a series of four pyridines on propylene oxide follows the Hammett equation with high pre-... 

Acylation with acetyl chloride (giving 94) or protonation permits rapid displacement of the nitro group from 4-nitropyridine A-oxide by the weakly nucleophilic chloride Pyridine A-oxide... 

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. 

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