[d002] Selenium catalyzed oxidation of alkynes in aqueous media Claudio Santi*, Benedetta Battistelli, Blerina Gjoka, Stefano Santoro, Chun-wing Steven Si, Lorenzo Testaferri, Marcello Tiecco. employed on the synthesis of the imidazole core 4 present in a Abstract series of well known drugs such as: hystidine, etomidate, 3 equivalents of ammonium persulfate in a 3:1 mixture of MeCN and water cimetidine, omeprazole, ketoconazole and flumazenil. slowly convert alkynes into the corresponding 1,2-dicarbonyl compounds. Several methods are reported in literature for the preparation The oxidation rate is enhanced by the presence of diphenyl diselenide that of these products starting from different compounds. form in situ the electrophilic PhSeOSO 3 H able to promote a “one pot” Particular attention has been devoted to the oxidation of hydroxyselenenyilation-deselenenylation reaction. alkynes that, in most cases, are complicated by the Introducrtion overoxidation that afford the corresponding carboxylic acids. 5 The development of improved and eco-friendly oxidation reactions is an area of great current interest in both academic Results and Discussion and industrial laboratories. Recently we reported the use of Here we report that ammonium persulfate in aqueous diphenyl diselenide as a pre-catalyst in the ammonium conditions can effect this oxidation and that the diphenyl persulfate as well as in the hydrogen peroxide mediated diselenide can catalyze the process leading directly to the dihydroxylation of olefins. 1 formation of unprotected 1,2-dicarbonyl derivatives. In the first case 1a the reactions were performed in a mixture of acetonitrile and water at 70° C proceeding through an (PhSe) 2 cat O hydroxyselenenylation followed by an oxidation of the Oxidant Ph corresponding selenide and a subsequent substitution by a Ph Me Me H 2 O/CH 3 CN molecule of water. This method resulted to be effective for O 1:3 1a 2a the conversion of cyclic alkenes in 1,2-diols but it failed when applied to acyclic olefins. Using hydrogen peroxide as Scheme 1. Oxidation of 1-phenyl-1-propyne oxidant 1b the method is of more general application and the mechanism has been demonstrated to involve an epoxidation by the “in situ” formed peracid, followed by the attack of a Preliminary experiments were carried out on 1-phenyl-1- molecule of water that occurs as a S N 2 ring-opening reaction propyne 1a using as oxidant ammonium persulfate and or through the formation of a carbocationic intermediate. hydrogen peroxide in the presence of a different As an extension of our investigation concerning the use of concentration of catalyst (PhSe) 2 and different temperature organoselenium compounds as catalysts for greener synthetic (Scheme 1). procedures we take in consideration the oxidation of carbon The results summarized on table 1 clearly demonstrated that carbon triple bond. the H 2 O 2 is not a suitable oxidant for this reaction. On the Tiecco et al . 2 previously demonstrated that diphenyl contrary ammonium persulfate at 60°C slowly converts 1a diselenide, in refluxing methanol in the presence of an excess into the corresponding diketone 2a and the reaction can be of ammonium persulfate converts alkynes into the strongly accelerated by the presence of diphenyl diselenide. α -dicarbonylic corresponding di- or monoprotected compounds reporting also one example in which a Table 1. Preliminary investigation on reaction conditions. stoichiometric amount of diphenyl diselenide produce the Oxidant % (PhSe) 2 Yield % a unprotected derivatives when the solvent is an MeCN/H 2 O mixture. (NH 4 ) 2 S 2 O 8 10 75 1,2-Dicarbonyl derivatives are known to be useful and (NH 4 ) 2 S 2 O 8 100 80 versatile synthones. 3 Recently they were successfully (NH 4 ) 2 S 2 O 8 0 27 H 2 O 2 10 -- [ ∗ ] Prof. Claudio Santi Dipartimento di Chimica e Tecnologia del Farmaco H 2 O 2 100 -- Università degli Studi di Perugia H 2 O 2 0 -- Via del Liceo 1, 06134 Perugia-Italy Fax: (+) 39 075 5855116 [a] all the reactions were carried out at 60°C for 24h E-mail: santi@unipg.it Homepage http://www.metodifisici.net 1
Non appreciable differences have been observed between chromatography the pre-catalyst (PhSe) 2 can be completely the reactions carried out with catalytic or stoichiometric recovered and then reused . amounts of diselenide. The role of the (PhSe) 2 is depicted in Starting from a terminal alkyne 1g , in contrast with a previously reported result, 2 the α -ketoaldehyde 2g cannot be the mechanism proposed in scheme 2. The actual catalyst is the strong electophilic PhSe-sulfate produced by the reaction isolated and its formation has been observed only from the of diphenyl diselenide with ammonium persulfate. 1 H-NMR of the crude in which it is in equilibrium with the Resonably the electrophile, in the presence of water, promote hydrated form 7g . an hydroxyselenenylation on the triple bond leading to the enol 3 that exists in a tautomeric equilibrium with the ketone 4 . The excess of ammonium persulfate activate the phenyl Table 2. Scope of the reaction selenium moiety to the nuclephilic substitution by a molecule of water as we reported for the dihydroxylation of olefins. O (PhSe) 2 cat The formation of the α -hydroxyketone 6 is demonstrated by (NH 4 ) 2 S 2 O 8 R 1 R 1 R the presence of a GC-MS peak [M+ m/z = 150] in the R H 2 O/CH 3 CN analysis effected during the ongoing reaction. In the used O 1:3 1a-g 2a-g experimental conditions it is resonable to suppose a quick 60 °C, 24h oxidation of 6 to afford the corresponding 1,2-dicarbonyl 2 . Noteworthy these experimental evidences suggest that the reaction mechanism, in the presence of water, is different Entry Substrate Product Yield % from those observed in 1991 by Tiecco et al 2 for similar reactions effected in methanol. O Ph Ph Me Me 1 75 1a O R OH 2a O R' H 2 O PhSe 3 C 3 H 7 C 3 H 7 C 3 H 7 C 3 H 7 R R' 2 20 = S 2 O 8 1b O 1 47 a 2b R O O PhSe R' Ph 4 O R' Ph (PhSe) 2 3 20 + PhSeOSO 3 H O 1c R SePh (NH 4 ) 2 S 2 O 8 OSO 3 - 2c 5 O H 2 O Ph C 3 H 7 Ph 4 30 1d O 2d O R' O R' S 2 O 8= O R O R OH Ph 2 6 5 Ph Ph Ph 5 1e 85 b O Scheme 2. Proposed mechanism 2e O With the optimized conditions in hand we investigated the C 8 H 17 C 8 H 17 Me 30 scope of this methodology starting from a series of Me 6 substituted alkynes 1a-g . 1f O 57 a The results are collected in table 2. All the reaction were 2f stopped after 24 hours and the corresponding 1,2-dicarbonyl OH derivatives 2a-g were purified by flash chromatography and Ph fully characterized on the basis of GC-MS analysis, 1 H and Ph H OMe 7 65 c 13 C-NMR spectral data. The yields, referred to the amount of 1g O isolated compounds, are from moderate to good. Starting 8g from the alkynes 1b (entry 2), 1e (entry 5) and 1f (entry 6), we demonstrated that longer reaction time produce a positive [a] reaction time 48h [b] reaction time 200h [c] after chromatography effect on the yields even if for reaction time longer than 200 SiO 2 -eluant CH 2 Cl 2 /MeOH hours in some substrates the overoxidation seems to be the main process. The alkynes 1a , 1d , 1e , and 1g were quantitatively converted into benzoic acid in one week. In all After silica gel chromatography, using a the cases after purification on silica gel column dichloromethane/methanol (99:1) mixture as eluant the methoxy hemiacetal 8g is recovered in 65% of yield. 2
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