Benzo-fused pyridines

We move from benzo-fused pyrroles to benzo-fused pyridines and meet quinoline and isoquinolinc. Isoquinolines will feature as benzyl isoquinoline alkaloids in Chapter 51 and their synthesis will mostly be discussed there. In this section we shall concentrate on the quinolines. 

Alkene RCM for the Synthesis of Benzene Rings in Indoles, Carbazoles, Benzo-Fused Pyridines and Pyridones, and Benzo-Fused Imidazoles... 

An example of the synthesis of a benzo-fused pyridine (i.e., a quinoline), containing an embedded ferrocene unit shown in structure 187, has been reported by Mamane and Fort [62], Commencing with the bisaldehyde 188 and subjecting it to a Wittig one-carbon homologation at each aldehyde group, it was converted into the bisvinyl complex 189, setting this up for an aUcene RCM reaction to... 

The benzo-fused dihydrotetrazolo[2,7]naphthyridine 308 is a minor end-product of a mixed Hantzsch pyridine synthesis involving 2-azido-3-nitrobenzaldehyde, /3-aminocrotononi trile, and methyl /3-aminocrotonate in ethanol (Scheme 76) <2001TL4507>. 

Oxidation of quinoline and isoquinoline under vigorous conditions with potassium permanganate results in oxidative degradation of the benzo-fused ring and formation of pyridine-2,3- and -3,4-dicarboxylic acid respectively. As expected, the presence of electron-donating substituents facilitates the reaction while electron-withdrawing substituents make oxidation much more difficult. Apart from A-oxide formation, little study has been devoted to the oxidation of other benzo-fused 7r-deficient systems. 

In general, 1,4-oxazepines and 1,4-thiazepine derivatives are stable compounds. Many of the (di)benzo derivatives are crystalline, while some of the more flexible monocyclic derivatives may be liquids. Conjugated (benzo)thiazepine derivatives can lose sulfur on heating, forming (fused) pyridines. This aspect of their reactivity is treated in Section 13.09.5. The completely or partially reduced derivatives of the title heterocycles and the benzo analogues may adapt different conformations, which has already been discussed in Section 13.09.2. The study of the tautomerism of lactams 9 has also been mentioned in Section 13.09.2. 

The comparative ionization potentials of various triazolopyridines and [l,2,3]-thiadiazolo-pyridines versus benzotriazole or benzothiadiazole were determined by electron-impact mass spectrometry (Table 2) <74CS222>. Since their ionization potentials are similar to the benzo-fused analogues, it infers that they have comparable aromaticity profiles. The same technique shows that the [l,2,3]oxadiazolopyridines (9a,b) occur exclusively as the ozy/zo-quinoid-like pyridodiazo-oxide tautomers (Equation (1)). 

The electron-withdrawing effect of the pyridine nucleus is very substantial, as evidenced by comparisons of the pK of the benzo-fused systems versus the pyridyl-fused systems. For example, the pK of benzotriazole (4) and triazolo[4,5-6]pyridine (5a) (in 80% aqueous 2-methoxyethanol) are 9.36 and 7.44, respectively <75HCA1521>. Similarly, the pKa for V-hydroxybenzotriazole (10), 3-hydroxytriazolo[4,5-Z ]pyridine (11), and l-hydroxytriazolo[4,5-Z ]pyridine (12) are 4.60, 3.28, and 3.02, respectively <76KGS1418>. 

An intramolecular reaction of an isocyanate on a benzo[l, 2-b 4,3-6 ]difuran constructed a fused pyridine ring, probably via a pericyclic reaction <86JHC1637>. Photolysis of the bisthiadiazoloquinone... 

A noticeable effect of Cu+ on the reaction of 3-pyridyl borates 84 with allylic halides can be found regioselective allylation at the 3-position of pyridines 85 results (85H117). This is a common feature with benzo-fused pyridyl borates (87JHC377) (Scheme 33). 

One of the more common ways to synthesize quinolines is through the Friedlander synthesis as a result, there have been a number of variations and improvements published for this reaction. Chelucci et al. presented a version of the Friedlander synthesis where the condensation and azaannulation reactions were carried out in a one-pot process. Additionally, they were able to synthesize quinoline analogs that were regiospecifically functionalized on both the pyridine and benzo-fused rings (Scheme 24) <05TL767, 05TL3493>. 

Similar discrepancies in determination of the tautomeric structures, as discussed above for acylmethyl-substituted pyridines, exist for their benzo-fused analogs. 

The detailed descriptions of the chemistry of the heterocyclic systems covered in this book are preceded at intervals, by six highly condensed and simplified discussions (Chapters 07, 10, 13, 15, 19 and 23) of the types of reaction, ease of such reactions and regiochemistry of such reactions for groups of related heterocycles. In this chapter the group comprises pyridine, as the prototype electron-poor six-membered heterocycle, and its benzo-fused analogues, quinoline and isoquinoline. As in each of these summary chapters, reactions are shown in brief and either as the simplest possible example, or in general terms. 

Bipyridine formation has been further explored in a series of reactions between stannylated pyridine and bromopyridines or benzo-fused homologs (Scheme 39), and has yielded a series of regioisomeric bipyridines (183). 3-Trimethylstannylquinoline reacts readily with 2-bromopyridine to furnish 184. 2,4-Distannylated pyridine can be coupled twice with 3-bromopyridine to form 185 (86S564). Coupling with 4-iodobenzoic acid ester proceeds equally well (186) (86TL4407). 

Values in parentheses are data which have subsequently been modified in the light of the discussion by Dewar and Trinajstie.12 0 For values of amino-substituted pyridines and phenyl-substituted benzo-fused heteroaromatic see Dewar el aZ. - ... 

Apy — Ax is the difference in resonance energy between the pyridine and pyridonoid structures, x referring to the exocyclic atom or group in the latter. Similar nomenclature follows for the benzo-fused series. 

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