Pyridine nucleophilic aromatic substitution

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). 

The Ullman reaction has long been known as a method for the synthesis of aromatic ethers by the reaction of a phenol with an aromatic halide in the presence of a copper compound as a catalyst. It is a variation on the nucleophilic substitution reaction since a phenolic salt reacts with the halide. Nonactivated aromatic halides can be used in the synthesis of poly(arylene edier)s, dius providing a way of obtaining structures not available by the conventional nucleophilic route. The ease of halogen displacement was found to be the reverse of that observed for activated nucleophilic substitution reaction, that is, I > Br > Cl F. The polymerizations are conducted in benzophenone with a cuprous chloride-pyridine complex as a catalyst. Bromine compounds are the favored reactants.53,124 127 Poly(arylene ether)s have been prepared by Ullman coupling of bisphenols and... 

Since the nitrogen in pyridine is electron attracting it seemed reasonable to predict that the trihalopyridynes would also show the increased electrophilic character necessary to form adducts with aromatic hydrocarbons under similar conditions to those employed with the tetra-halogeno-benzynes. The availability of pentachloropyridine suggested to us and others that the reaction with w-butyl-lithium should lead to the formation of tetrachloro-4-pyridyl-lithium 82 84>. This has been achieved and adducts obtained, although this system is complicated by the ease with which pentachloropyridine undergoes nucleophilic substitution by tetrachloro-4-pyridyl lithium. Adducts of the type (45) have been isolated in modest yield both in the trichloro- and tribromo- 58) series. 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

Nucleophilic reagents attack pyridine at the a-position to form an adduct that rearomatizes by dissociation (Scheme 1). Only very strong nucleophiles, e.g. NH2-, RLi, LAH, Na-NH3, react, and for the second step to afford a substitution product (5), conditions that favour hydride loss are required. Adducts formed with hydride ions (from LAH) or carbanions (from lithium alkyls) are relatively more stable than the others at low temperature, and dihydropyridines (6) can be obtained by careful neutralization. Fusion of a benzene ring to pyridine increases reactivity towards nucleophiles, and attack is now found at both a- and y-positions in quinoline (7) and at C-l in isoquinoline (8). This may be attributed to a smaller loss of aromaticity in forming the initial adduct than in pyridine, and thus a correspondingly decreased tendency to rearomatize is also observed. Acridine reacts even more easily, but nucleophilic attack is now limited to the y -position (9), as attachment of nucleophiles at ring junctions is very rare. 

Nucleophilic aromatic substitutions Pyridine is more reactive than benzene towards nucleophilic aromatic substitutions because of the presence of electron-withdrawing nitrogen in the ring. Nucleophilic aromatic substitutions of pyridine occur at C-2 (or C-6) and C-4 positions. 

The nucleophilic properties of pyridine nitrogen have been assessed in studies on pyridine-catalyzed Schotten-Baumann reactions133 and aromatic sulfonyl chloride hydrolyses,134 from which highly accurate Bronsted and Hammett treatments arise. There is some doubt as to the mechanism of this reaction.45 Equations (13) and (14) accurately express the reactivity of 3- and 4-substituted pyridines toward ethyl iodide (using rate for equilibrium constants),133 while rates of N-methylation of 2-substituted pyridines have been used to estimate both steric and electronic effects.136... 

Reactions of 5f/-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-one 71, prepared by reaction of 1,2-diaminobenz-imidazole 72 with acetoacetic ester 73, with different reagents was described, in the search of new heterocycles with biological activity <2002CHE598>. When lactam 71 was treated with aromatic aldehydes in boiling 1-BuOH with addition of piperidine 74, 577-3-arylidene-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-ones 75a-c were obtained (Scheme 7). Coupling lactam 71 with phenyldiazonium chloride 76 in dioxane afforded the 3-phenylazo-substituted tricycle 77. When 71 was treated with phosphorus pentasulfide 78 in boiling dioxane or pyridine, its thio analog 79 was obtained. The reaction proceeded most efficiently when lactam 71 was refluxed with twofold excess of 78 in dry dioxane. These thiones 79 react with ammonia and amines by nucleophilic substitution. When 79 was refluxed with ammonia, benzylamine, piperidine, or morpholine, the 4-amino-substituted tricycles 80a-d were obtained. All the described compounds were identified by NMR, mass spectrometry, and IR spectroscopy. 

Heteroaromatic amines can oxidize to the corresponding N-oxide, which are typically stable enough to be isolated and detected as degradation products. The N-oxide functionality typically increases the reactivity of the aromatic ring. For example, the N-oxide functionality in pyridine N-oxide facilitates both electrophilic and nucleophilic substitution at the alpha and gamma positions (57). 

The effect of the heteroatom is to make the pyridine ring very unreactive to normal electrophilic aromatic substitution. Conversely, pyridines are susceptible to nucleophilic attack. These topics are discussed later. 

Since there are no extensive studies on the relative aromaticity of the heterocycles covered in this chapter, the relative order of aromaticity of these systems has been gleaned from disparate studies. A priori, the combined effects of the 7i-electron-deficient five-membered heterocycles annelated to a pyridine nucleus provides a series of bicyclic heterocycles with low reactivity towards electrophiles. In the presence of suitable leaving groups, they are prone to undergo nucleophilic substitution. Since these heterocycles are readily obtained from either appropriately substituted pyridines or five-membered heterocycles, methods for direct functionalization of the parent heterocycles are not frequently studied. Based on the diversity of reactions these heterocycles undergo, it can be inferred that the pyridofuroxans are the least aromatic. 

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