Pyridine ring annellation

The applied Gould-Jacobs reaction is very often used to prepare angularly annelated pyridine-ring-substituted imidazoquinolines in inert media under conditions of thermal cyclocondensation, for example at temperatures above 250°C. 

X-Ray crystal structures of aryl derivatives of pyrrolo[2,3- ]pyridines, 29, confirm that steric interactions between the annelated ring and the electron-withdrawing substituent on the 4-position of the pyridine ring cause the pyridine ring to twist out of coplanarity <2006JOC3494>. 

In the annelation of pyrazole-3 (or 5)-acetonitriles or -acetic acids, a cyano or carboxamido substituent in the 4-position is necessary to supply the nitrogen atom of the pyridine ring. The majority of reports concern the formation of 2-substituted products. Thus cyclization of the nitriles 142a... 

The o values of rings annelated to pyridine in systems such as quinoline, isoquinoline, benzoquinolines, acridine, and phenanthridine and determined by the basicity of the ring nitrogen atom are predicted186 and found to be small.33,34 This is an important point stressed and elucidated previously,181 and demonstrating the validity of the basic assumptions of the Hammett equation. 

A useful expansion of the pyrrole-ring annelation methodology was found when 3-alkynyl-6,8-dimethylpyrimido[4,5-< ]pyridazine-5,7(6//,8//)-dione reacts with an amine and silver permanganate pyridine complex. It was postulated that first amination at the C4-position takes place, followed by an intramolecular cyclization into the pyrrolopyridazinopyrimidine derivative (Scheme 35). A similar reaction was reported with 6-alkynyl-l,3-dimethylpyrimido[4,5-Z]pyrazinedione (03MI3). 

The annellation of a benzene ring to the 5 and 6 positions of the benzopyran moiety in CH2, instead of the pyridine ring in CHI, does not essentially affect the structure of the naphthopyran fragment. The pyran rings in CHI and CH2 are nonplanar with folding along O- -C(2) and O- -0(3) in a similar manner as in SPs and SOs. The Cspiro-0 bond in CHI and CH2 is elongated, and the 0-CPh bond is shortened (Table 5). 

Quinoline formation by annelation of a benzene ring onto a pyridine ring is a less commonly adopted approach but this possibility has been realised by a reaction sequence starting from 2-bromomethyl-3-phenylsulphonylmethylpyridine (77) (Scheme 18). 97... 

Hi) Annelation with the formation of the middle pyridine ring... 

Bis-annelatiom. Danishefsky et al have shown that this reagent can be used (o effect bis-annelation. The product of addition of (1) to an enamine of a ketone, for example cyclohexanone, gives, after ketalization, the product (2). riie key step involves Birch reduction of the pyridine ring to a dihydro product... 

Ch. 1 Synthetic and Natural Sources of the Pyridine Ring Ch. 2 Carbocyclic Annelated Pyridines Ch. 3 Macrocyclic Pyridines... 

Quinoline and isoquinoline, the two possible structures in which a benzene ring is annelated to a pyridine ring, represent an opportunity to examine the effect of fusing one aromatic ring to another. Clearly, both the effect the benzene ring has on the reactivity of the pyridine ring, and vice versa, and comparisons with the chemistry of naphthalene must be made. Thus the regiose-lectivity of electrophilic substitution, which in naphthalene is faster at an a-position, is mirrored in quinoline/isoquinoline chemistry by substitution at 5-... 

N-Condensed imidazole ring annelation with zl -PV-l,4,2-oxazaphospholines l,8a-Dihydroimidazo[l,5-a]pyridines... 

As a rule, cyclizations of 1-substituted 8-fluoroquinolones have an advantage in comparison with annelation of the pyridine ring to a benzazine moiety, thus allowing one to vary annelated fragments to a greater extent. However, the synthesis of levofloxacin is an exception, since the scheme suggesting to obtain first the optically active benzoxazine, as the key intermediate, followed by annelation of the pyridone fragment proved to be a more successful one. 

Four additional isomeric isothiazolo-pyridine ring-systems have been synthesized by annelating the isothiazole ring to the pre-formed pyridine ring. 

These results show that inverse Diels-Alder reactions of pyrimidines open an easy access to a number of differently substituted pyridines and especially to compounds, in which the carbocyclic ring and the heterocyclic rings are annelated on the b position of pyridine. An interesting illustrating example... 

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