Hydroxylation of heterocycles

Free-radical hydroxylation of heterocyclic compounds has almost always been studied in the context of the relation of chemical hy-... 

The mechanism of hydroxylation of heterocyclic compound has not been studied, but the mechanistic aspects of hydroxylation of homocyclic compounds may again serve as a basis for discussion. 

The products obtained in the hydroxylation of heterocyclic compounds are set out in Table XI. 

Little is known about the hydroxylation of heterocyclic substrates, and more experimental work is needed in this area. Achromobacter xylosoxydans (DSM 2783) and Pseudomonas putida (NCIB 8176 or 10521) are particularly effective in the hydroxylation of nicotinic acid (107) to 6-hydroxynicotinic acid (108 equation 39), and commercial processes capable of giving up to 97% yield have been developed. It is interesting to note that in this case the product is precipitated as it forms by formation of its magnesium or barium salt, and this could serve to protect the product from further degradation as well as facilitating its recovery. 

FIGURE 17.6 A reaction mechanism for the aldehyde oxidase group of molybdenum hydroxylases. As with hydroxylation of heterocycles, the conversion of aldehydes to the corresponding carboxylic acids has been proposed to proceed via bases-assisted nucleophilic attack of the Mo—OH on the substrate carbonyl, with concomitant hydride transfer to the Mo=S. (From Hille, 2005. Copyright 2005 with permission from Elsevier.)... 

Free-radical substitutions of heterocyclic compounds have been carried out with alkyl, aryl, and hydroxyl radicals in solution and with halogen atoms in the gas phase. Of these, arylations have been the most extensively investigated. 

As for the aerobic degradation of pyridines, hydroxylation of the heterocyclic ring is a key reaction in the anaerobic degradation of azaarenes by Clostridia. Whereas in Clostridium barkeri, the end products are carboxylic acids, CO2, and ammonium, the anaerobic sulfate-reducing Desulfococcus niacinii degraded nicotinate completely to CO2 (Imhoff-Stuckle and Pfennig 1983), although the details of the pathway remain incompletely resolved. 

The selective monohydroxylation of heterocyclic compounds such as piperidine derivatives1741 and the 7-lactam (19)[751 have been studied. It is also been shown that hydroxylation of phenylcyclohexane can be effected using cytochrome P450 and the regioselectivity of hydroxylation can be altered by site-directed mutagenesis of the enzyme1761. 

Another series of heterocyclic bioisosters of DA and w-tyramine were evaluated for their affinity and agonist activity at Dl and D2 receptors [46]. Compound (47), in which the m-hydroxyl in DPDA has been replaced with a thiazol-2-one ring system, has a higher D2 receptor affinity and a more... 

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

Electron density calculations suggest that electrophilic attack in pyridine (42) is favored at C-3, whereas nucleophilic attack occurs preferentially at C-2 and to a lesser extent at C-4. Cytochrome P-450 mediated ring hydroxylation of pyridine would, therefore, be expected to occur predominantly at C-3, the most electron-rich carbon atom. Although 3-hydroxypyridine is an in vivo metabolite in several species, the major C-oxidation product detected in the urine of most species examined was 4-pyridone (82MI10903). The enzyme system catalyzing the formation of this latter metabolite may involve the molybdenum hydroxylases and not cytochrome P-450 (see next paragraph). In the related heterocycle quinoline (43), positions of high electron density are at C-3, C-6 and C-8, while in isoquinoline (44) they are at C-5, C-7 and C-8. Nucleophilic substitution predictably occurs... 

Tertiary amines catalyze the homopolymerization of epoxy resins in the presence of hydroxyl groups, a condition which generally exists since most commercial resins contain varying amounts of hydroxyl functionality (B-68MI11501). The efficiency of the catalyst depends on its basicity and steric requirements (B-67MI11501) in the way already discussed for amine-catalyzed isocyanate reactions. A number of heterocyclic amines have been used as catalytic curatives pyridine, pyrazine, iV,A-dimethylpiperazine, (V-methylmorpholine and DABCO. Mild heat is usually required to achieve optimum performance which, however, is limited due to the low molecular weight polymers obtained by this type of cure. 

The ability to oxidize to a corresponding hydroxyl-containing heterocycle is typical for dihydro derivatives of pyrazolo[l,5-a]pyrimidines 331 and pyri-mido[l,2- ]benzimidazoles 333. Simply dissolving these compounds in CHC13, DMF and alcohols at ambient conditions produces compounds 334 and 336 as major products together with heterocycles 340 and 342 (in some cases the latter products were not observed) [168, 293]. It is interesting to note that compounds 334-336 have a very high resistance to the action of... 

Both malonyl-CoA and methylmalonyl-CoA are then utilized as extender units. The heterocyclic rings are easily accounted for the spiro system is merely a ketal, though the tetrahydrofu-ran ring requires further hydroxylations of the basic skeleton for its construction. Avermectins are usually isolated as a mixture in which the main a component has a 2-methylpropyl group... 

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