Pyridine 1-oxide formation

Closure of the triazole ring can be achieved either by oxidative formation of the N-N bond, or condensation of an fV-aminopyridone. The latter was formed by iV-amination of pyridines with mesitylhydroxylamine (MSH), or by forming the pyridine ring, starting from cyanoacetic hydrazide with malononitrile or 2-cyanoacrylates. 

Natural sesquiterpene pyridine alkaloid formation needs two precursors, one for the pyridinium moiety and another for the sesquiterpene moiety. The a for formation of the pyridinium moiety is nicotinic acid, which reacts with isoleucine and, by oxidative reaction, produces evoninic acid, wilfordic acid or edulinic acids, a for the sesquiterpene moiety is still open to question, but E, E-famesyl cation has been suggested as one possibility and hedycarylol as a second. This moiety is dihydroagarofuran. Therefore, a for the sesquiterpene pyridine alkaloids is nicotinic acid and E, E-famesyl cation and, controversially, hedycaryol. The /3 is amacrocycling ring formation substance (two moieties), from which the alkaloid forms (Figure 62). 

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. 

The 5,ll-dihydro-[l]benzothiepino[4,3- ]pyridine derivatives 74 and 76 were oxidized to the corresponding sulfones 75 and 77, respectively, with MCPBA in a CH2CI2 solution containing 3-5equiv of methanesulfonic acid, which prevented pyridine Ar-oxide formation (Scheme 9) <1998BML2521>. 

Depending on the method of preparation (cf. Section 4.33.4.2.1), 1,3,2-dioxathioIane 2-oxide (16) or its derivatives are obtained at first in the form of low molecular weight polymers which at elevated temperatures depolymerize to the corresponding monomers (57USP2798877, 61ZOB1332). The polymerization of such cyclic sulfites is catalyzed by bases (e.g. dialkylanilines or pyridines). The formation of polymers on thermolysis of 1,3,2-dioxathiolan-4-one 2-oxides has been described in Section 4.33.3.1.2. 

The [l,2,4]triazolo[l,5- ]pyridine system is usually constructed by the closure of the triazole ring either by oxidative formation of the NN bond or by condensation of the N-aminopyridine derivatives . Various compounds 78 were obtained by the oxidation of the amidine 77 with Mn02 (Scheme 47) <2003IJB2901, 2005ARK(xiii)21>. A dehydrative cyclization by treatment of formamidoximes 79 with trifluoroacetic anhydride (TFAA) has been used in the synthesis of 80 (Scheme 48), which are key building blocks in the preparation of DPP (IV) inhibitors <2005EJ03761, 2006JME3614>. 

Sainsbury and co-workers (121) have synthesized several ellipticine dimers tethered through the C-5 methyl group (333) (Scheme 53) or the C-9 position (334). The 9-methoxy derivative of 333 was also prepared. The nitrile 329 was available from the Sainsbury ellipticine synthesis (122) and was transformed into the alkaloid 17-oxoellipticine (148). A clever maneuver was to add nitric acid to protonate the pyridine nitrogen of 330. This precluded A-oxide formation during dithiane hydrolysis. Reductive amination in two steps afforded the amine 332. Coupling with adipic acid gave the target bisellipticine 333. 

Both reactions (10.11) and (10.12) can be promoted, and the yields improved, by using a stoicheiometric quantity of a base, such as a tertiary amine [1358]. The reactions can also be catalysed for example, pyridine, 4-nltropyridine and pyridine -oxide have been used to catalyse the formation of bis(2,2,2-trinltroethyl)carbonate [870a]. 

Pyridine, benzazines, diazines and their benzo derivatives are basic and can be attacked by electrophiles at the N-atoms in alkylation, acylation and V-oxide formation. 

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