Pyridine 1-oxides electrophilic

When the donor atom is a part of the aromatic system, one would expect more obvious differences in reactivity. At present relatively little comparative information is available on such heterocyclic systems. Only on pyridine and its derivatives are there any reasonably extensive data. For pyridine a wide variety of coordination processes are available and pyridine-N-oxide as well as metallic complexes and complexes with nonmetallic Lewis acids must be considered. For comparative purposes the great reluctance with which pyridine undergoes electrophilic... 

In benzo- and phenyl-pyridines and in phenylpyridine 1-oxides, electrophilic substitution usually takes place in the benzene ring. In benzo-pyridones, -pyrones and -pyridine A-oxides, electrophilic substitution often occurs in either the benzene or the heterocyclic ring depending on the conditions sometimes mixtures are formed (see Section 3.2.3.2.1). 

Pyridine is frequently oxidized to pyridine oxide (equation 503) [729, 210, 263], Pyridine oxide is an oxidant capable of hydroxylating aromatic rings [994. But more important, the presence of oxygen on the nitrogen of the pyridine ring reverses the direction of electrophilic substitutions in the pyridine ring. Whereas electrophilic attacks on pyridine occur in P positions, attacks on pyridine oxide occur in a and -y positions. After the introduction of the electrophiles, the pyridine oxide is converted into pyridine by mild reductions, such as treatment with salts of iron or titanium. 

Reactions of pyridazine also show analogies to pyridine [136]. Electrophiles attack the ring N-atoms, for instance in protonation, alkylation or A -oxidation. S Ar reactions at the ring C-atoms are difficult to carry out, even in the presence of activating substituents due to the deactivation by the additional N-atom. However, iV-oxidation facilitates the substitution in some cases. 

Tetrafluoroethyl)pyridines can be prepared using an unusual reaction of the pyridine oxides with electrophilic fluoroolefins, such as hexafluoropropene (HFP). This reaction discovered by Mailey and Ocone, was further expanded by the Haszeldine group and recently was extensively studied by Makosza et al. The reaction between heterocyclic A-oxides and HFP rapidly proceeds in DMF at ambient temperature and atmospheric pressure, resulting in the formation of the corresponding 2-(l,l,l,2-tetrafluoroethyl)- heterocycles 86-88 (Fig. 7.30). ... 

Pyridine -oxides may be deprobmated to give ylides which react with electrophiles such as carbon dioxide and ketones. For example, 4-chloropyridine N-oidde reacts widi butyllithium at -65 C followed by quenching with carbon dioxide to give d hloropyridine A(-oxide 2 carboxylic acid in 49% yield, ( uinuclidine -oxide can be deprotonated with r-butyllitfaium to give the anicn which can be trapped with deuterium oxide or benzaldehyde. ... 

Peroxy acids react with pyridine to give pyridine-N-oxide (7) in an electrophilic oxygen transfer process (for reactions of pyridine-N-oxides, cf p. 360). Other functions transferred to pyridine as electrophiles are CN (from cyanogen bromide) or NH2 (from K-hydroxylamine-O-sulfonate/KI (- 8)). 

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. 

Electrophilic mercuration of isoxazoles parallels that of pyridine and other azole derivatives. The reaction of 3,5-disubstituted isoxazoles with raercury(II) acetate results in a very high yield of 4-acetoxymercury derivatives which can be converted into 4-broraoisoxazoles. Thus, the reaction of 5-phenylisoxazole (64) with mercury(II) acetate gave mercuriacetate (88) (in 90% yield), which after treatment with potassium bromide and bromine gave 4-bromo-5-phenylisoxazole (89) in 65% yield. The unsubstituted isoxazole, however, is oxidized under the same reaction conditions, giving mercury(I) salts. 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

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