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Download Author Version (PDF) Organic & Biomolecular Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/obc Page 1 of 10Organic & BiomolecularOrganic & Biomolecular Chemistry Dynamic Article Links ► Chemistry Cite this: DOI: 10.1039/c0xx00000x Full Paper www.rsc.org/xxxxxx Insights into the Mechanistic and Synthetic Aspects of the Mo/P- Catalyzed Oxidation of N-Heterocycles Oleg V. Larionov,* David Stephens, Adelphe M. Mfuh, Hadi D. Arman, Anastasia S. Naumova, Gabriel Chavez, and Behije Skenderi Manuscript 5 Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A Mo/P catalytic system for an efficient gram-scale oxidation of a variety of nitrogen heterocycles to N- oxides with hydrogen peroxide as terminal oxidant has been investigated. Combined spectroscopic and crystallographic studies point to the tetranuclear Mo4P peroxo complex as one of the active catalytic 10 species present in the solution. Based on this finding an optimized catalytic system has been developed. The utility and chemoselectivity of the catalytic system has been demonstrated by the synthesis of over 20 Accepted heterocyclic N-oxides. Catalytic oxidation reactions with hydrogen peroxide as a Introduction terminal oxidant have recently gained significant attention due to 45 their low environmental impact, as well as low cost (<0.7 Heterocyclic N-oxides have significant synthetic value as USD/kg) and high atom efficiency (47%) of hydrogen peroxide.13 15 intermediates en route to diversely functionalized N- In addition, such oxidations are generally carried out under mild heterocycles.1 In particular, recent examples of regioselective C– 2 3 4 conditions, and require less intensive purification, as the only by- H-arylation, as well syntheses of 2-halo 2-amino, and 2-cyano product that stems from the oxidant is water. Most of the azines5 constitute an important domain of modern heterocyclic 50 produced H2O2 (3.8 million metric tons/year) is currently used for synthesis (Figure 1). In addition, N-oxides have been employed 14 bleaching and detoxification, but the number of industrial Chemistry 20 as ligands and catalysts, as synthetic intermediates in the synthetic processes utilizing this environmentally benign oxidant industrial syntheses of pharmaceuticals (e.g. pranoprofen and has been growing at a fast pace, e.g. hydrogen peroxide is omeprazole), as well as new pharmacophores in drug discovery. currently used as an oxidant in the multi-ton scale propylene In the course of studies aimed at development of new reactions of 3 15 6 55 oxidation and caprolactam production. Although redox heterocyclic N-oxides we had to prepare multigram quantities of 0 potential of H2O2 is relatively high (E = 1.76V for the half- 25 various compounds of this class. A survey of the literature + – 5 reaction H2O2 + 2H + 2e → 2H2O), most oxidations of typical showed that current approaches to heterocyclic N-oxides are organic substrates (alcohols, aldehydes, alkenes, sulfides, largely limited to stoichiometric oxidations by peroxyacids, either phenols, etc) by H2O2 are slow and require some activation of the generated in situ from large excess of hydrogen peroxide in acetic 13a 7 60 O–O-bond. The O–O-activation can be effected by Brønsted or trifluoroacetic acids at elevated temperatures, 16 or as a acids via protonation or formation of peracids, as well as 30 commercially available reagent (e.g. meta-chloroperbenzoic 17 8 transition metal catalysts (e.g. Fe, Mn, V, Ti, Mo, Re, W) via acid). Both methods have significant drawbacks. The in situ formation of highly active oxo and peroxymetal species. While method furnishes impure products that have been reported to 9 significant progress has been achieved in the catalytic hydrogen detonate shortly after isolation. On the other hand, stable 18 19 65 peroxide-mediated oxidations of alkenes, sulfides and Biomolecular peroxyacids are more expensive and produce significant amounts 20 21 alcohols, including asymmetric modifications, other less 35 of waste. Other less common methods include oxidation with 22 10 11 readily oxidizable substrates, such as N-heterocycles, have & dimethyldioxirane (DMDO) and HOF·MeCN. There is, generally been prepared using stronger oxidants, in part due to therefore, an unmet need for inexpensive and environmentally 0 substantially higher oxidation potentials (e.g. E = 1.41V for benign methods of azine and azole N-oxide synthesis based on 23 12 70 pyridine N-oxide/pyridine, versus 0.16V for (CH3)2SO/ readily available catalysts. Herein, we report a combined 24 (CH3)2S ). Examples of catalytic H2O2-based methods include 40 mechanistic and synthetic study of the oxidation of a variety of methyltrioxorhenium (MTO)-catalyzed oxidation of azines azines and azoles catalyzed by molybdenum-phosphate catalysts developed by Sharpless,25 and Mn(TCDPP)Cl26-catalyzed with hydrogen peroxide as a terminal oxidant. 27 reaction reported by Mansuy. However, methyltrioxorhenium is 75 expensive and undergoes Re–C bond cleavage that leads to a Organic This journal is © The Royal Society of Chemistry 2014 Organic & Biomolecular Chemistry, 2014, [vol], 00–00 | 1 Organic & Biomolecular Chemistry Page 2 of 10 decrease in the catalytic activity and prevents catalyst recycling. In asymmetric catalysis OH On the other hand, Mn(TCDPP)Cl is not commercially available OH and can only be prepared in low yields.28 Hence, more recent 29 approaches have focused on polyoxometallates as catalysts for N+ + + Ph N 5 the oxidation of pyridines by H2O2. Some of the catalysts studied - N O + include Na [(WZn (H O) ][(ZnW O ) ],30 various mixed -O O- N 12 3 2 2 9 34 2 -O 31 W/V/Mo-based heteropolyacids, M8[BW11O39H] (M = K or Ph 32 33 34 R4N), -Na8HPW9O34, [(C18H37)2(CH3)2N]7[PW11O39], and As synthetic intermediates 35 K6[PW9V3O40]. Notwithstanding this progress, significant CO2H CO2H 10 problems remain unaddressed. Thus, the synthetic utility and the scope of these catalytic systems have not been assessed, and N+ N O Pranoprofen practical procedures amenable to multi-gram preparation of O- (NSAID) heterocyclic N-oxides have not been described. These H Manuscript deficiencies may have contributed to the persistence of the less N O 15 efficient and less environmentally benign N-oxidation methods. S N Furthermore, while oxidations of pyridines have been studied to N+ O N Omeprazole - some extent, applicability of polyoxometallate catalysis to the O (Proton-pump inhibitor) synthesis of N-oxides of five-membered N-heterocycles (azoles) O In pharmaceuticals has not been investigated. Although, N-methylimidazole is O 20 known to undergo uncatalyzed oxidation by H2O2, other less N CO2CH3 electron-rich imidazoles and thiazoles require use of such harsh H and non-chemoselective reagents as HOF·MeCN36 and O N peroxyacids at high temperatures.37 In addition, most of the N Br Accepted catalytic systems are based on tungsten that has recently been 38 25 implicated as carcinogen. On the other hand, more NH N environmentally benign molybdenum catalysis of N-oxidation NH2 and the mechanistic aspects thereof remain poorly studied. Early O pioneering studies by Griffith, Galindo and Longo indicate that Otamixaban Ancriviroc N+ N+ H2O2-mediated N-oxidation of pyridine can be catalyzed by (CCR5 Inhibitor) (Direct factor Xa 39 -O O- inhibitor) 30 molybdate either in stoichiometric or in catalytic fashion, but little is known about the scope and applicability of this catalytic Fig. 1. Examples of applications of heterocyclic N-oxides in organic 60 chemistry and drug discovery. system. Table 1. Catalytic N-Oxidation of Quinoline.a Results and Discussion Chemistry Initial comparison of catalyst performance in acetonitrile at 50 C 35 with quinoline as a test substrate has revealed that molybdenum- based catalysts have consistently outperformed other catalytic systems. Thus, neither triflic nor trifluoroacetic acids were Entry Catalyst Solvent Yield, % catalytically active (Table 1). Interestingly, Sc(OTf)3 mediated (x mol%) (Temperature, C) the oxidation, however the conversion was low. Fe(III), Cu(II), 1 – CH3CN (50) 0 40 [Ru(p-cumene)Cl]2 and Na2WO4 were also catalytically inactive. 2 – C2H5OH (50) 0 On the other hand, Mimoun’s catalyst, 3 CF3SO3H (10) CH3CN (50) 0 oxodiperoxymolybdenum(VI) HMPA complex,40 provided an 4 CF3CO2H (10) CH3CN (50) 0 5 Sc(O3SCF3)3 (10) CH3CN (50) 13 encouraging result with 22% yield of quinoline N-oxide 2. 6 FeCl3 (10) CH3CN (50) 0 Subsequent investigation of catalytic activities of other 7 CuCl2 (10) CH3CN (50) 0 45 molybdenum compounds has shown that sodium molybdate, 8 [Ru(p-cumene)Cl]2 (10) CH3CN (50) 0 9 Na2WO4 (10) CH3CN (50) 0 molybdenum(VI) oxide, or several other molybdenum Biomolecular 10 Mo(O2)2O·HMPA (10) CH3CN (50) 22 compounds did not offer substantial improvements in catalytic 11 MoO3 (10) CH3CN (50) 19 efficiency. Phosphomolybdic acid, on the contrary, has lead to 12 Na2MoO4 (10) CH3CN (50) 33 & clean conversion of 1 to quinoline N-oxide. 13 MoO2Cl2 (10) CH3CN (50) 13 14 Mo(CO)6 (10) CH3CN (50) 14 50 Encouragingly, the amount of the phosphomolybdic acid can be 15 (NH4)2Mo7O24 (10) CH3CN (50) 16 reduced to 0.5 mol% without jeopardizing the yield.
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