Pyridine derivatives aromaticity

There is another important factor in the low reactivity of pyridine derivatives toward electrophilic substitution. The —N=CH— unit is basic because the electron pair on nitrogen is not part of the aromatic n system. The nitrogen is protonated or complexed with a Lewis acid under many of the conditions typical of electrophilic substitution reactions. The formal positive charge present at nitrogen in such species further reduces the reactivity toward electrophiles. 

Reduction of aromatic rings with lithium or calcium " in amines (instead of ammonia—called Benkeser reduction) proceeds further and cyclohexenes are obtained. It is thus possible to reduce a benzene ring, by proper choice of reagent, so that one, two, or all three double bonds are reduced. Lithium triethylborohy-dride (LiBEtsH) has also been used, to reduce pyridine derivatives to piperidine derivatives." ... 

Fuchita, Y, leda, H. and Yasutake, M. (2000) First intramolecular aromatic substitution by gold(III) of a ligand other than pyridine derivatives. 

The above-mentioned results indicate the additive effect of protons. Actually, a catalytic process is formed by protonation of the metal-oxygen bond instead of silylation. 2,6-Lutidine hydrochloride or 2,4,6-collidine hydrochloride serves as a proton source in the Cp2TiCl2-catalyzed pinacol coupling of aromatic aldehydes in the presence of Mn as the stoichiometric reduc-tant [30]. Considering the pKa values, pyridinium hydrochlorides are likely to be an appropriate proton source. Protonation of the titanium-bound oxygen atom permits regeneration of the active catalyst. High diastereoselectivity is attained by this fast protonation. Furthermore, pyridine derivatives can be recovered simply by acid-base extraction or distillation. 

Transition metal complexes have been used in a number of reactions leading to the direct synthesis of pyridine derivatives from acyclic compounds and from other heterocycles. It is pertinent also to describe two methods that have been employed to prepare difficultly accessible 3-alkyl-, 3-formyl-, and 3-acylpyridines. By elaborating on reported194,195 procedures used in aromatic reactions, it is possible to convert 3-bromopyridines to products containing a 3-oxoalkyl function196 (Scheme 129). A minor problem in this simple catalytic process is caused by the formation in some cases of 2-substituted pyridines but this is minimized by using dimethyl-formamide as the solvent.196... 

A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP only procedures involving solvent-free conditions under the action of irradiation led to the aromatized pyridine derivatives. 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

Nitrogen. Pyridine is one of the most important heterocycles. The aromaticity of pyridine was intensively connected to structural considerations and chemical behavior. The relative difference between the aromaticity of benzene and pyridine is controversial generally calculations give similar orders of magnitude and differences depend on the criterion of aromaticity considered and the mode of calculation used. A comprehensive review on the theoretical aspects in connection with the aromaticity of pyridine was published.191 Pyridine is about as aromatic as benzene according to theoretical calculations and to experimental data, while quinoline is about as aromatic as naphthalene and more aromatic than isoquinoline.192193 The degrees of aromaticity of pyridine derivatives strongly depend on their substituents. 

Effectively, this is another example of the addition of a functional aromatic compound to an alkene, as the Murai reaction, but the mechanism is different. Alkyl substituted pyridine derivatives are interesting molecules for pharmaceutical applications. The a-bond metathesis reaction is typical of early transition metal complexes as we have learnt in Chapter 2. 

The commercial availability of basic pyridine derivatives has encouraged a tremendous amount of research into pharmaceutically active compounds. Two reviews in particular list a large number of medicinal compounds (B-80MI20900,77CZ389) based on the pyridine ring. Likewise, the occurrence of benzopyridine natural products with chemotherapeutic activity has stimulated the production of synthetic materials from aromatic amine precursors. Some important examples are presented below. 

We also discovered the ability of 2-azadienes of this sort to cycloadd to unactivated carbon—carbon double and triple bonds in an intramolecular fashion (89CC267) (Scheme 50) such a process appears to be one of the first examples of intramolecular [4 + 2] cycloadditions of simple 2-azadienes. Azadiene 216 was made from O-allyl salicylaldehyde 215 (R = allyl) and heated at 120°C in toluene to furnish the trans-fused tricyclic adduct 217 in excellent yield further dehydrogenation of 217 with DDQ afforded 5H-[ 1 ]-benzopyran[4,3-6]pyridine 218. On the other hand, when 0-(2-butynyl) salicylaldehyde 215 (R = 2-butynyl) was transformed into azadiene 219 and subjected to heating in a sealed tube at 150°C, pyridine 222 was isolated in very high yield. Its formation can be rationalized to occur via the expected Diels-Alder intermediate 220 thus, [1,5]-H shift in 220 would give rise to tautomer 221, which would suffer electro-cyclic ring-opening and aromatization to pyridine derivative 222. 

Triazines react also with electron-rich dienophiles such as ethyl vinyl ether (401 R = Et) or vinyl acetate (401 R = Ac) in boiling dioxane to yield the pyridine derivatives (376). After the usual [4 + 2] cycloaddition and nitrogen elimination from the bicyclic compound (402), the dihydropyridines (403) eliminate ethanol or acetic acid to give the aromatic pyridines (376). The dienophiles (401) can therefore be used as alkyne equivalents (69TL5171). 

The basicity of the aromatic amine iV-oxide can be substantially varied by the introduction of substituents on the aromatic ring. IR spectra of free N-oxides display a prominent band between 1200 and 1300 cm-1, attributable to the nitrogen-oxygen stretching frequency v(NO). The more activating the substituent, the lower the energy of the absorption. Upon coordination, v(NO) is decreased by up to 60 cm-1. IR data for pyrazole and pyridine derivatives are given in Table 42.281-286... 

A peculiar dehydrofluorination occurs when dihydro(trifluoromelhyl)pyridine derivatives such as 21 are treated with organic bases. A double-bond shift and a hydrogen migration convert one trifluoromethyl group into a difluoromethyl group and aromatize the ring to give, for example, compound 22.148... 

The 13C-NMR spectra of l-arylbenzo[c]pyrylium salts have been investigated in comparison with those of 1-arylnaphthalenes, N-methyliso-quinolinium, and 1-arylisoquinoline derivatives 75ZN(B)943]. The correlation obtained is analogous to relationships found for a series of pyrylium and pyridinium salts, and pyridine derivatives [82AHC(Suppl)]. The, 3C shifts of 1 -aryl-benzo[c]pyrylium salts are also a valuable source of information for ptfa values, aromatic character, and conjugative effects of these compounds (760MR324). 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

Thus, the hydrodesulfurization process is a very complex sequence of reactions due, no doubt, to the complexity of the feedstock. Furthermore, the fact that feedstocks usually contain nitrogen and oxygen compounds (in addition to metal compounds) increases the complexity of the reactions that occur as part of the hydrodesulfurization process. The nitrogen compounds that may be present are typified by pyridine derivatives, quinoline derivatives, carbazole derivatives, indole derivatives, and pyrrole derivatives. Oxygen may be present as phenols (Ar-OH, where Ar is an aromatic moiety) and carboxylic acids (-C02H). The most common metals to occur in petroleum are nickel (Ni) and vanadium (V) (Reynolds, 1997). 

Tetrahydroquinolones can be transformed also by (diacetoxyiodo)benzene 3 to the aromatic arylquinolines, a structure found in various alkaloids [101]. Depending on the reagent, it is possible to oxidize flavanones 50 either into flavones 51 or into rearranged isoflavones 52 [102, 103]. (Diacetoxyiodo)-benzene 3 or the polymer-supported reagent 18 were also efficient reagents for the oxidation of 1,4-dihydropyridines 53 to the corresponding pyridine derivatives 54, Scheme 23 [104]. 

Polytrimethylsilylated piperidines have been obtained through the reductive silylation of quinoline (Section III.B.2.d). Among these compounds are SMA derivatives that are readily oxidized in the presence of air and hydrolyzed into pyridine derivatives. Trimethylsilyl groups on the non-aromatic ring were found to be in an all-fraws relationship.179... 

A further hydrogen-bonding example which has also been demonstrated with pyridine derivatives is the aromatic C-H- -N interaction <2001T5791, 2002AXCo697>. These interactions are exemplified by the solid state of pyridine dicarboxylate esters, with the interactions supplemented by C-H- -0=C contacts <2001CE0170>, and pyridiny-lisoxazoles <2000TL5827>. 

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