Pyridines with halogens

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

A very large number of complexes of pyridines and quinolines with all the halogens and interhalogen compounds are known, and as they have been enumerated elsewhere (74HQ14-S2)407,77HC(32-1)319) just a few examples are illustrated (Scheme 14). Treatment of pyridine with chlorine or bromine in the presence of aluminum chloride yields 4-pyridylpyridinium salts (equation 29), but rather curiously the action of iodine chloride on pyridinium hydrochloride at 250 °C produces the 2-isomer (51 equation 30). 

Thieno[2,3-. ]pyridines, 115, form via a condensation reaction with halogenated carbonyl compounds, as shown in Scheme 35. Depending on the base strength of the reagent and reaction conditions, intermediate 114 may be isolated <2005CCA63>. 

At room temperature pyridines react reversibly with halogens and interhalogens, e.g. IC1, to give unstable adducts, which behave as mild halogenating agents. X-Ray diffraction studies of the pyridine-iodine complex have given its structure (73). 

Styrene oxides are preferentially attacked by halides at the benzylic position, especially so under acidic reaction conditions. It has been claimed, however, that in water in the presence of cyclodextrins, styrene oxides react with halides to yield exclusively benzylic alcohols [382], Benzylic alcohols can also be obtained from styrene oxides by treatment with halogens in the presence of pyridines [383],... 

It is possible to halogenate selectively at the methyl position of alkylpyridines to give halogenoalkylpyridines. Low to moderate yields of fluoromethylpyridines are obtained on fluorination of 2- and 4-methyl pyridines with (V-fluoro-bis[(trifluoromethyl)sulfonyl]imide 52 in the presence of sodium carbonate in dichloromethane <1996T15>. 2-Methylpyridine is fluorinated in 20% yield and 4-methylpyridine in 72% yield under these conditions. Reagent 52 also effects the selective fluorination of 2,4,6-collidine to give the 2-fluoromethylated product in moderate yield (Equation 35). 

In some ylides photolytic conditions were necessary for their transylidation [30]. The conversion of iodonium ylides into a-halogeno derivatives of the parent carbonyl compound (or other precursor) with hydrogen halides is normally effected directly, without isolation of their iodonium salts. A similar reaction with halogens leads to the formation of a,a-bis halogenated products [31]. The reaction of pyridines with the non-isolable PhI=C(CN)2 is of interest, since it permits the ready transfer of the C(CN)2 functionality to the nitrogen of pyridine, quinoline, etc. the yields here were generally moderate but in some cases the products could not be obtained using other dicyanocarbene precursors [32],... 

Treatment of 6-chloro-4-methylpyrrolo[2,3-6]pyridine with methoxide ion resulted in only 39% yield of the product from chloride displacement, even under very harsh conditions (300 °C). Ethynyl-ation of the halogenated pyrrolopyridines was also carried out. The reaction was successful using compound (73), after protection of the pyrrole nitrogen, and trimethylsilylethyne. However, with unsubstituted ethyne only the iodo derivative was reactive. In this case a disubstituted ethyne derivative (74) was obtained (Scheme 22) <68RCR55i>. 

On the other hand if a pyridine structure which is amenable to halogenation is required, then the pyridine is halogenated and connected ready made with the rest of the molecular structure no special cyclisation being required. 

As a first approximation, the reactions of pyridines with electrophiles can be compared with those of trimethylamine and benzene. Thus, pyridine reacts easily at the nitrogen atom with reagents such as proton acids, Lewis acids, metal ions, and reactive halides to form salts, coordination compounds, complexes, and quaternary salts, respectively. Under much more vigorous conditions it reacts at ring carbons to form C-substitution products in nitration, sulfonation, and halogenation reactions. 

Of the substituted pyridines, the halogenated derivatives have been the most intensively studied.144,145 Treatment of 3,5-dichloropyridine A-oxide at 74° with 0.1 A NaOD led to exchange in three positions of the molecule, whereas with 3-chloropyridine iV-oxide relative rates of exchange were position 2>6>4>5. In l-methyl-4-pyridone, 1,3,5-trimethyl-4-pyridone, and 3,5-dibromo-l-methyl-4-pyridone, deuteration in basic D20 at 100° gives 2- and 6-substitution.146 With the poly-azaindenes (45) -(47) already discussed in the acid exchange section,141 base-catalyzed deuteration occurs in the positions indicated 45 3 and 5 46 2, 3, 5, and 6 and 47 2, 5, 6, and 7. In other isolated heterocycles some selectivity is observed in base-catalyzed exchange, e.g., certain imidazoles,147 thiazole,148 isothiazole,148 benzothiazole,149 and benzoxazole.149... 

Not only gem-difluorides arc obtained from diazo compounds the reaction of pyridinium poly(hydrogen fluoride) [(HF) /pyridine] with diazo compounds gives the corresponding monofluoro derivatives. In the presence of a halogen source (IV-halosuccinimide), gem-fluorohalides are obtained as reaction products (see Table 9 and also Vol. ElOa, p732). ... 

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