Pyridine derivatives nucleophilic aromatic substitution

A wide variety of other heterocyclic ring systems can conceivably serve as the conjugated backbone in nonlinear organic molecules. We will give examples from preliminary work on two of these, the thiazole and pyrimidine heterocycle derivatives 65-72 in Table VIII. These two heterocycles were chosen because the appropriate haloderivatives are commercially available as starting materials for nucleophilic aromatic substitution. The pyrimidine derivatives are of particular interest since their absorption edges ( 400 nm) are shifted hypsochromically an additional 30 nm relative even to the pyridines. 

Recently37, the importance of CT complexes in the chemistry of heteroaromatic N-oxides has been investigated in nucleophilic aromatic substitutions. Electron acceptors (tetracyanoethylene and p-benzoquinones) enhance the electrophilic ability of pyridine-N-oxide (and of quinoline-N-oxide) derivatives by forming donor-acceptor complexes which facilitate the reactions of nucleophiles on heteroaromatic substrates. 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

A transition metal-free direct amination of halo(pyridine or pyrimidine) has been developed in good yields under the action of computer-controlled microwave irradiation [202]. This solvent-free reaction is useful for coupling of halo(pyridine and pyrimidine) with pyrrolidine and piperidine derivatives by nucleophilic aromatic substitution (S Ar). 

Reaction of 164 with K2CO3 induces nucleophilic aromatic substitution to yield, mainly, the pyridine 165 as well as the benzo-l-oxa-2,4-diazine 166 ( 15% yield) (Equation 28) <2000JHC297>. Hydrolysis of the carboxy ester in 166 followed by exposure to various amines produces the C-8 amino derivatives, the syntheses of which are considered in Section 9.05.7.2. 

Nitrogen can be incorporated in the macroring by inclusion of a small-ring nitrogen heterocycle such as pyridine or pyrimidine. Three approaches should be noted. If the pyridyl unit is incorporated as a 2,6-bis(methyleneoxy)pyridine derived from lutidine, the precursor will normally be a lutidine dihalide or diol. In the case of sulfur, the diol would be a dithiol. If the pyridyl unit is to be attached by 2,6-aminomethyl groups, amide formation followed by reduction is a possibility. In the event that the heterocycle will be attached directly to a macroring heteroatom, nucleophilic aromatic substitution may be useful. 

Other reactive bases can be used in this reaction. Pyridine reacts with phenyllithium at 100°C, for example, to give 2-phenylpyridine. This reaction is limited in scope because powerful nucleophiles are required and the reaction conditions can be harsh. Nonetheless, several interesting transformations are observed. Five-membered ring heterocycles are less prone to nucleophilic aromatic substitution, in part because the reparation of the requisite halogen-substituted derivatives can be difficult. 

Oxazolines (4) are easily prepared from benzoic acids and behave as activating groups in nucleophilic aromatic substitution. Thus, o-methoxy- or o-fluoro-substituents are replaced by the alkyl group of RLi. " The same oxazoline group in the 4-position of pyridine promotes 3-lithiation, whereas in the 3-position it induces nucleophilic alkylation to give 1,4-dihydropyridine derivatives. Benzyl alcohol is lithiated in the 2-position of the benzene nucleus. Solvent effects are suggested to be responsible for the quantitative syn selectivity in the alkylation of lithiated ketimines (5). ... 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

An aryne multicomponent reaction involving isoquinoline and 5-bromo-1-methylisatin resulted in spirooxazino isoquinolines (Scheme 66).The reaction occurs with a number of iV-substituted isatins. Quinoline can replace the isoquinoline as well. Carbonyls other than the isatins can trap the anion as well. A variety of aromatic, aliphatic, and heteroaromatic aldehydes can function as the electrophile. When pyridine replaces isoquinoUne as the nucleophilic trap, the reaction forms an oxindole but not an oxazino pyridine derivative (14SL608). 

The reactivity of pyridine derives from its dual nature as both an aromatic molecule and a cyclic imine. Both electrophilic and nucleophilic substitution processes may occur, leading to a variety of substituted derivatives. 

Sulfoxides are oxidized to sulfoximides by HN3 in the presence of H2SO4 [1, 19]. The nucleophilic substitution of chloride by azide is accelerated, when the solution of HN3 and alkyl halide is allowed to react in a column filled with acidic AI2O3 [20]. The exchange of halide substituents of arenes by azide requires activating groups in other positions of the aromatic system. Pyridine derivatives frequently yield tetrazoles [8]. Aromatic C-nitroso compounds and twice the molar quantity of HN3 form the aromatic azide, N2, and H2O... 

Compound 40 has not yet been synthesized. However, there is a large body of synthetic data for nucleophilic substitution reactions with derivatives of 41 [synthesized from aliphatic and aromatic aldehydes, pyridine, and trimethylsilyl triflate (92S577)]. All of these experimental results reveal that the exclusive preference of pathway b is the most important feature of 41 (and also presumably of 40). 

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