Pyridine electrophilic reactions

Heteroannulenes electrophilic reactions, 7, 726 tr-excessive synthesis, 7, 727 nucleophilic reactions, 7, 727 Hetero[l IJannulenes structure, 7, 715 Hetero[ 12]annulenes pyridine-like methano-bridged, 7, 715 Hetero[ 13]annulenes unrestricted structure, 7, 716... 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

Another feature that is clear from the resonance description of the pyri-dinium cation is that attack by nucleophiles is favoured at C-2(6) and C-4. This has importance in some reactions where at first sight it may appear that electrophilic reagents combine quite easily with pyridine. These reactions are more subtle in nature ... 

The preferred position for electrophilic substitution in the pyridine ring is the 3 position. Because of the sluggishness of the reactions of pyridine, these are often carried out at elevated temperatures, where a free radical mechanism may be operative. If these reactions are eliminated from consideration, substitution at the 3 position is found to be general for electrophilic reactions of coordinated pyridine, except for the nitration of pyridine-N-oxide (30, 51). The mercuration of pyridine with mercuric acetate proceeds via the coordination complex and gives the anticipated product with substitution in the 3 position (72). The bromina-tion of pyridine-N-oxide in fuming sulfuric acid goes via a complex with sulfur trioxide and gives 3-bromopyridine-N-oxide as the chief product (80). In this case the coordination presumably deactivates the pyridine nucleus in the 2 and... 

Only a few electrophilic reactions of selenolopyridines have been reported. In deuteriodeprotonation of selenolo[3,2-6]pyridine the 3-position is the preferred site of attack (78JCS(P2)86l>. In selenolo[3,2-6]pyridine and thieno[3,2-6]pyridine the C-2/C-3 reactivity ratio is ca. 10-3 whereas for furo[3,2-6]pyridine a value of ca. 10-5 has been determined. Logarithmic partial rate factors (Figure 13) show that seleno o[3,2-6 ]pyridine is the most reactive compound. As in the case of (9) and (261), the deuteriodeprotonation of (426) takes place on the protonated species. Both se enolo[2,3-6]- and [3,2-6]pyridine (423, 426) on treatment with potassium nitrate and concentrated sulfuric acid give yield the corresponding 3-nitro derivatives in 50% yield (10 °C, 3 h). 

In some electrophilic reactions of 1 the bicyclic ring system is preserved. It has been postulated that in the reaction of l,3-diiodobicyclo[l.l.l]pentane (15b) with sodium methox-ide, [1.1.1 [propellane generated in situ reacts with iodine in the presence of pyridine67 132 or with MeOI,66 an I+ source also generated in situ, to give the 3-iodobicyclo[l.l.l]pent-l-yl cation 6267 90. This cation is subsequently trapped with a nucleophile such as MeOH, N3, pyridine or triethylamine to give 63 (Table 15)66 67132. 

The unsubstituted nitrogen atom in 1,2,4-dithiazolidines is more prone to electrophilic reactions. Both the potassium salt 11 and the initial product 12 can participate in alkylation and acylation reactions. Alkylation of salt 11 with alkyl halides is carried out in DMF or MeCN and compound 12 can react with alkyl halides in MeCN in the presence of inorganic bases (NaH, Bu OK, AcONa, NaHCOj, CS2CO3) NaHCO( proved to be the base of choice. Yields of alkylation products 26 in some cases reach 85-90%. Compound 12 was acylated by benzoyl chloride in pyridine to form the iV-benzoyl derivative 25 (Scheme 15) <2000SL1622, 20030BC3015>. 

As with pyridine, not only does the electronegative nitrogen atom withdraw electron density from the ring, but under the acidic conditions of many electrophilic reactions the azole nitrogen is protonated. The azolium cation is relatively inert to further attack by a positively charged electrophile. 

Pyrazines are more resistant to electrophilic substitution reactions at the ring carbon atoms than the corresponding pyridines. Electrophilic attack normally takes place on the ring nitrogen atoms thus pyrazines form mono- and disalts with proton acids and mono- and... 

Quinoline forms part of quinine (structure at the head of this chapter) and isoquinoline forms the central skeleton of the isoquinoline alkaloids, which we will discuss at some length in Chapter 51. In this chapter we need not say much about quinoline because it behaves rather as you would expect—its chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution favours the benzene ring and nucleophilic substitution favours the pyridine ring. So nitration of quinoline gives two products—the 5-nitroquinolines and the 8-nitroquinolines—in about equal quantities (though you will realize that the reaction really occurs on protonated quinoline. 

The zwitterionic iodonium phenolate 253 is photochemically reactive and a variety of products can be obtained depending upon the substrate in which the reactions are carried out. The mechanism of formation of these products could be an electrophilic reaction of the iodonium species or could involve fission of the I—C bond to yield the phenolate zwitterion 254, which itself could undergo electrophilic reactions. Regardless of the route, addition of 254 to alkenes yields 255, to aUtynes gives 256 and to arenes produces the arylated products 257. Pyridine, thiourea, phenyliminobenzoxathiole and phenyl isocyanate also act as addends. ... 

The (benzo)pyridazines are inherently electron deficient ring systems, more so than pyridine, and while there are many examples of electrophilic reaction of (benzo)pyridazines on nitrogen, reactions such as protonation and A-oxidation occur less readily than with pyridine. 

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