7r-deficient heterocycles

Simple considerations such as these account adequately for many of the familiar reactions of substituted 7r-deficient heterocycles, such as nucleophilic displacement, tautomerism in hydroxy, mercapto and amino heterocycles, facile deprotonation of alkyl substituents, decarboxylation of carboxymethyl groups and electrophilic substitution of benzo-fused and aryl-substituted heterocycles. These individual effects are discussed separately in the following subsections. 

The chemistry of the aryl and heteroaryl substituents is very largely predictable and unremarkable it is governed by the number and nature of other substituent groups in the ring, including the electron-withdrawing 7r-deficient heterocyclic system. 

Apart from nucleophilic substitution reactions, the chemistry of the halo derivatives of the 7r-deficient heterocycles is fairly similar to that of aromatic halides. Thus, heterobiaryls can be prepared by the Ullman reaction, and Grignard reagents and organolithium compounds can be prepared, although in many instances, and especially with Grignard reagents,... 

The chemistry of aryl groups attached to the 7r-deficient heterocycles is unexceptional and much as might be expected. Thus, electrophilic substitution of phenylpyridines occurs exclusively in the phenyl ring. 4-Phenylpyridine gives mononitration products in the ratio o m p, 20 33 47 (68JCS(B)862, 71JCS(B)712). The oxidation of phenylpyridines can lead to either a pyridinecarboxylic acid or benzoic acid. 

Oxidation of the pyridoins, e.g. with iodine, gives the corresponding a-diketones. The significant electron withdrawal exerted by the 7r-deficient heterocyclic system on carbonyl groups at the a- and y-positions can be demonstrated in the behaviour of the diketones under benzilic acid rearrangement conditions. Whereas 3,3 -pyridil (73) gives a normal... 

Ketones of the 7r-deficient heterocycles form the usual derivatives, phenylhydrazones, semicarbazones, etc. The oximes undergo the Beckmann rearrangement (70JCS(B)1687). 

The chemistry of the IV-linked substituents of the 7r-deficient heterocycles principally concerns the reactivity of amino and nitro functions. The many other nitrogen functions are usually derived from either or both the amino or nitro parents and so are discussed within the two main Sections (2.06.4.1 and 2.06.4.2) below, as appropriate. 

This route to the a-nitroso derivatives of the 7r-deficient heterocycles has permitted an exploration of their chemistry. They are extremely reactive and condense readily with 1,3-dienes to give 3,6-dihydro-l,2-oxazines (e.g. 99), and with aromatic amines in the presence of acid to give azo compounds (Scheme 86). This latter reaction is particularly useful in view of the instability of the corresponding 2-pyridinediazonium salts referred to above, which limits conventional access. The a-nitroso heterocycles are oxidized by ozone or sodium hypochlorite to the a-nitro compounds (Scheme 86) (82JOC553). 

In common with 7r-deficient heterocycles, e.g. 2-methylpyridine, it is found that the 2-methyl protons in 3//-azepines, e.g. (176), exchange rapidly (20 min at 80 °C) in D20. 7-Methyl protons also exchange but at a much slower rate (24 h at 80 °C) (74JOC3076). The acidity of 2-methyl protons is also demonstrated by the ease with which they undergo base-catalyzed condensation with benzaldehyde to give the benzylidene derivative. 

Further applications of nitrene cyclizations have also been reported in which the intermediate nitrene inserts into a 7r-deficient heterocycle or a nitrene on a -deficient nucleus inserts into a proximal carbon-hydrogen bond. In general, the preferred source of the nitrene is the photolysis or thermolysis of an azide. The versatility of this approach is shown in two syntheses of pyrrolo[3,2-J]thiazoles (selenazoles) (177), (178), (180) (Equations (52) and (53)). Thermolysis of the / -thiazolyl (selenazolyl)-a-azido-esters (176) or the / -(4-azido-5-thiazolyl)-x,/J-enones (179) affords these bicyclic heterocycles in excellent yields (79JHC1563, 92JCS(Pi)973>. The same strategy has also been... 

The AMI SCF-MO method was applied to calculate properties of all possible diazinodiazines and their monocations in order to get information about the site of protonation in these 7r-deficient heterocycles. Since some of these polyazanaphthalenes, like pteridine, are masked by the covalent hydration phenomenon the pA) values belong in fact to their hydrates, solvates, and mixtures of the adducts with the unmodified forms. Pteridine was found to be the strongest base in this series due to the high proton affinity at N-l <88JOC3900>. 

In a typical reaction (Scheme 69), 2- or 3-bromo-6-methoxypyridine is lithiated in THF with rerf-butyllithium in THF at - 78°C. Low temperature and a bulky lithiating reagent are used to limit (or avoid) the tendency for adduct formation between the 7r-deficient heterocycles and the reagent. The lithiated species is reacted in the cold with zinc chloride to form the zincated derivative (299). 3-Bromo-2,6-dimethylpyridine, a benzenoid bromide, is zincated by heating in THF with magnesium, and the metal-metal exchange is effected by zinc chloride (300). The pyridylzinc chlorides can be coupled with 3-bromo- or iodo-2-quinolines using Pd-... 

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