Pyridines highly substituted

A synthetically powerful method, an approach based on cycloaddition chemistry, allows one to assemble the pyridine ring in one step. Not only is this method efficient, atom economy, but also its convergency allows for the preparation for highly substituted systems in which one can, in principle, control all five positions on the pyridine ring. A versatile example of this methodology is the Boger reaction. It has been applied to the synthesis of a very diverse set of targets. 

Azcpincs under acid conditions reportedly117-225 yield aniline derivatives although ring contraction to pyridines is more usual. Thus, highly substituted 3//-azepines, e.g. 28, with a vacant 7-position, formed by cycloaddition of 2//-azirines with cyclopentadienones, on heating in acetic acid isomerize rapidly to the correspondingly substituted anilines 29.117... 

Trifluoroacetohydroximoyl bromide etherate is a synthon for thiadiazo-lines and oxadiazolines (87JHC1391). A fused isoxazolopyridine was obtained with excess malononitrile but, unexpectedly, dimeric malononitrile gave a highly substituted 2-(CF3)-pyridine, albeit in 9% yield (87BCJ4480). 

More recently, this chemistry has been extended to the synthesis of isoquinolines by employing the i-butylimines of o-halobenzaldehydes (Scheme 4).5 By employing vinylic halides, one obtains highly substituted pyridines. 

Formation of the central six-membered ring is the key to the synthesis of the highly substituted irnidazo[4,5-r]-[2,7]naphthyridines, 67 and 68 (Equations 15 and 16) the bicyclic precursors 65 and 66 are themselves the products of Hantzsch pyridine syntheses <1999PHA814>. 

Substitution of one ligand by another can generate, or alter, spin crossover characteristics. The systems studied early provide the classic illustration of this effect. Thus [Fe(py)4(NCS)2] is high spin at room temperature and does not undergo a thermal spin transition. Substitution of two of the pyridine molecules by a phenanthroline molecule gives [Fe (phen)(py)2 (NCS)2] which does undergo a thermal transition [99, 141], as does the species in which the remaining two pyridines are substituted [Fe(phen)2 (NCS)2]. As would be expected, T1/2 for the former complex (106 K) is lower... 

The acyclic version of Larock s heteroannulation was successfully applied to the synthesis of highly substituted pyridines [166]. The annulation of rert-butylimine 210 with phenyl propargyl alcohol produced pyridine 211 regioselectively in excellent yield. The regiochemistry obtained was governed by steric effects. Furthermore, the choice of imines was crucial to the success of the heteroannulations. terr-Butylimine was the substrate of choice, since all other imines including methyl, isopropyl, allyl and benzyl imines failed completely to produce the desired heterocyclic products. 

A novel solid-phase synthesis of pyrrolo[3,4- ]pyridines using a sequence of Knoevenagel and Hantzsch condensation reactions has been reported <199981951 >. The reactions lead to a variety of highly substituted pyrrolo[3,4- ]pyridines, 70. 

Thiophenes can be synthesized from a sequence involving the reaction of activated methylene compounds with carbon disulfide in base. The resulting disulfide salts, without isolation, are reacted with phenacyl bromide to afford highly substituted thiophenes, 78. Compound 78 reacts with ethyl cyanoacetate, malononitrile, or acrylonitrile to afford thieno[3,2-/ ]pyridine derivatives <1995CCC1578>. 

H-Azepines are more rare than 1H- or 3H-azepines and only a few synthetic approaches have been developed. Of these the two main methods involve the ring expansion of six-membered heterocycles. Early studies revealed that highly substituted 4f/-azepines (269) result from the base-catalyzed ring expansion of 4-(chloromethyl)-l,4-dihydro-pyridines (267 Scheme 37). The reaction was found to be temperature and solvent sensitive, and azepines (268)-(270) have been isolated and characterized. However, later studies (68JCS(C)1675) on cyano derivatives (267 E = CN) show the reaction to be even more... 

The highly substituted 3,4-diazabicyclo[4.2.0]octatrienes (177) have been obtained by cyclization of cis- 3,4-dibenzoylcyclobutenes with hydrazine (69CB1928). The triene (R = H) undergoes thermal ring opening to give a vinylpyridazine, but with bridgehead substituents (e.g. R = Me) conversion to the substituted benzene (181) occurs in pyridine at 70-80 °C... 

The fluorination of heterocyclic compounds with xenon difluoride has received much less attention. Pyridine reacts readily with xenon difluoridc in dichloromethane without a catalyst to form 2-fluoropyridine (35 %), 3-fluoropyridine (20 %) and 2,6-difluoropyridine (11 %).80 8-Hydroxyquinoline treated with xenon difluoride forms 5-fluoro-8-hydroxyquinoline at room temperature in 35% yield.80 Uracil reacts with xenon difluoride to give 5-fluorouracil in 10% yield.81 Only one example exists of a highly substituted pyrrole fluorinated with xenon difluoride in acetonitrile in 35% yield.82... 

Highly substituted pyridinium salts of type 1 are easily accessible by Hantzsch-type synthesis. They are valuable products in that they can often be transformed easily into otherwise difficultly accessible, highly substituted benzenes or pyridines by base-catalysed rearrangement. For example, treatment of the salt 2 with ethanolic sodium hydroxide at room temperature for one hour gives 2,4-diacetyl-lV,5-dimethylaniline 3 in 85% yield, while 3-acetyl-5-cyano-6-methyl-2-methylamino-4-phenylpyridine 5 is obtained in 88% yield from the salt 4 under the same conditions. 

Obvious" and "Non-Obvious" Pathways to a Highly Substituted Pyridine and Aniline... 

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