Phản ứng oxidation

MoOPH RO N O R R R N C O RCO2R R SR O R N O OH R R R RO R R RO OH R R RO OR RO X O R N C N R N NR2 R R O R O CH3 R N O R R RCX2R S S R R RCX 3 N N O R R R R RO SR S R R N OR R R N R R C N R R RO NR2 O R R Myers Oxidation States of Organic Functional Groups Alcohol General Introductory References March, J. In Advanced Organic Chemistry, John Wiley and Sons: New York, 1 992, p. 1 1 581 238. Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry Part B, Plenum Press: New York, 1 990, p. 61 5664. Carruthers, W. In Some Modern Methods ofOrganic Synthesis 3rd Ed., Cambridge University Press: Cambridge, UK, 1 987, p. 34441 0. Mark G. Charest Oxidation Chem 215 The notion of oxidation state is useful in categorizing many organic transformations. This is illustrated by the progression of a methyl group to a carboxylic acid in a series of 2 electron oxidations, as shown at right. Included are several functional group equivalents considered to be at the same oxidation state. Alkane RCH3 Alcohol RCH2OH (RCH2X ) Aldehyde (Ketone) RCHO (RCOR) Carboxylic Acid RCO2H Carbonic Acid Ester ROH + CO2 (ROCO2H) organometallics in general RCH2M (M = Li, MgX, ZnX...) alkyl halide X = halide alkylamine X = NR2 alkylthio ether X = SR alkyl ether X = OR alkane sulfonate X = OSO2R alkyl azide X = N3 hemiketal (hemiacetal) ketal (acetal) dithiane hydrazone oxime geminal dihalide enol ether (enamine) ester orthoester nitrile ketene trihalomethyl hydroxamic acid carbamate alkyl haloformate xanthate isocyanate carbodiimide aminal thioester amide urea Summary of Reagents for Oxidative Functional Group Interconversions: Fetizons Reagent DimethylsulfoxideMediated Oxidations DessMartin Periodinane (DMP) oIodoxybenzoic Acid (IBX) tetranPropylammonium Perruthenate (TPAP) NOxoammoniumMediated Oxidation Manganese Dioxide Barium Manganate Oppenauer Oxidation Chromium (VI) Oxidants Sodium Hypochlorite NBromosuccinimide (NBS) Bromine Cerium (IV) Oxidants imine organoboranes RCH2BR2 organosilanes RCH2SiR3 Aldehyde Sodium Chlorite Potassium Permanganate Aldehyde Ketone BaeyerVilliger Oxidation Alcohol Ruthenium Tetroxide Ketone Davis Oxaziridine Diol O 2Pt NOxoammoniumMediated Oxidation O 2Pt Jones Oxidation Silver Oxide Pyridinium Dichromate (PDC) Lactone αHydroxy Ketone Acid Ester Ester Acid Aldehyde or Ketone CoreyGilmanGanem Oxidation Rubottom Oxidation Bromine (OBO ester shown) RCH 2OH (CH3)2S O H R OS CH 2 CH 3 H (CH3)2SX E –H+ R O H (CH3)2SX HH R OS CH 3 CH 3 X– OO H HOCH 3 H 3C OH H 3C S Ph O H OO H HOCH 3 H 3C OH H 3C S Ph OAc H O OBn HO HO (CH3)2S ROHH2C S CH3 –H+ RO S CH 3 HO OCH 3 OTBS –BH+ –RCO2 – O OCH 3 OTBS H O TBSO TBSO OH OO H HOCH 3 H 3C OH H 3C S Ph H OO H HOCH 3 H 3C OH H 3C S Ph O H H H O R AcO B Alcohol Aldehyde or Ketone DimethylsulfoxideMediated Oxidations General Mechanism Methylthiomethyl (MTM) ether formation can occur as a side reaction, by nucleophilic attack of an alcohol on methyl(methylene)sulfonium cations generated from the dissociation of sulfonium ylide intermediates present in the reaction mixture. This type of transformation is related to the Pummerer Rearrangement. + Dimethylsulfoxide (DMSO) can be activated by reaction with a variety of electrophilic reagents, including oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide, acetic anhydride, and Nchlorosuccinimide. The mechanism can be considered generally as shown, where the initial step involves electrophilic (E+ ) attack on the sulfoxide oxygen atom. Subsequent nucleophilic attack of an alcohol substrate on the activated sulfoxonium intermediate leads to alkoxysulfonium salt formation. This intermediate breaks down under basic conditions to furnish the carbonyl compound and dimethyl sulfide. Fenselau, A. H.; Moffatt, J. G. J. Am. Chem. Soc.1966,88, 17621765. Lee, T. V. InComprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York,1991,Vol. 7, p. 291303. Tidwell, T. T.Synthesis1990, 857870. Tidwell, T. T.Organic Reactions1990,39, 297557. Mark G. Charest • Reviews • Pummerer Rearrangement (CF3CO)2O, Ac2O 2,6lutidine >60% Schreiber, S. L.; Satake, K. J. Am. Chem. Soc.1984,106, 41864188. Swern Procedure Typically, 2 equivalents of DMSO are activated with oxalyl chloride in dichloromethane at or below –60 °C. Subsequent addition of the alcohol substrate and triethylamine leads to carbonyl formation. The mild reaction conditions have been exploited to prepare many sensitive aldehydes. Careful optimization of the reaction temperature is often necessary. Huang, S. L.; Mancuso, A. J.; Swern, D.J. Org. Chem.1978,43, 24802482. 66% Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M.Angew. Chem., Int. Ed. Engl.1998,37, 23542359. 1. TBSCl, Im, DMAP, CH2Cl2 2. 10% PdC, AcOH, EtOAc 3. (COCl)2, DMSO; Et3N –78→ –50 °C 90% (COCl)2, DMSO; Et 3N, –78 °C Smith, A. B., III; Wan, Z.J. Org. Chem.2000,65, 37383753. • + – + + + alkoxysulfonium ylide + ++ + + + – • + + + – • OH O OO N CH3 CH 3 OCH 3 OR H CH3O CH 3O CH 3 R 1O CH3 OR CH 3 OR 1 HO H O O OO N CH 3 CH3 OCH 3 OR H CH 3O CH3O CH3 R 1O CH3 OR CH3 OR O 1 H CH3 OH H 3C N O O Bn O BzO OCH3 HO OTBDPS (CH3)2N(CH2)3N C N CH2CH3 Cl OtBu OH Cl OtBu O OCH3 CO 2CH 3 OH H S H 3C CH 3 OCH3 CO 2CH 3 CHO H S H 3C CH 3 OCH3 CO 2CH 3 H CHO CH 3 S H 3C CH 3 O H O HBr H H H HO O BzO OCH3 O OTBDPS • HCl O H O HBr H H Et H Br O H O HBr H H OHC H CH3 O H 3C N O O Bn FK506 PfitznerMoffatt Procedure The first reported DMSObased oxidation procedure. Dicyclohexylcarbodiimide (DCC) functions as the electrophilic activating agent in conjunction with a Brønsted acid promoter. Typically, oxidations are carried out with an excess of DCC at or near 23 °C. Separation of the byproduct dicyclohexylurea and MTM ether formation can limit usefulness. Alternative carbodiimides that yield watersoluble byproducts (e.g., 1(3dimethylaminopropyl)3 ethylcarbodiimide hydrochloride (EDC)) can simplify workup procedures. DMSO, DCC TFA, pyr 87% Corey, E. J.; Kim, C. U.; Misco, P. F.Org. Synth. Coll. Vol. VI1988, 220222. ParikhDoering Procedure Sulfur trioxidepyridine is used to activate DMSO. Ease of workup and atornear ambient reaction temperatures make the method attractive for largescale reactions. SO3•pyr, DIEA, DMSO CH2Cl2, –15 °C Evans, D. A.; Ripin, D. H.; Halstead, D. P.; Campos, K. R.J. Am. Chem. Soc.1999,121, 68166826. Parihk, J. R.; Doering, W. von E.J. Am. Chem. Soc.1967,89, 55055507. 95% Mark G. Charest DMSO, EDC TFA, pyr 94% Hanessian, S.; Lavallee, P.Can. J. Chem.1981,59, 870877. 80% (COCl)2, DMSO; Et 3N, –78 °C Jones, T. K.; Reamer, R. A.; Desmond, R.; Mills, S. G.J. Am. Chem. Soc.1990,112, 29983017. R = TIPS, R1 = TBS Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L.Angew. Chem., Int. Ed. Engl. 1999,38, 31753177. SO 3•pyr, Et3N, DMSO, CH2Cl 2 0→ 23°C 99% (–)kumausallene • Examples DMSO, DCC TFA, pyr 9 : 1β,γ : α,β + Semmelhack, M. F.; Yamashita, A.; Tomesch, J. C.; Hirotsu, K.J. Am. Chem. Soc.1978,100, 55655576. EDC • • = I CO2H + KBrO 3 I R 1R 2CHOH –AcOH DMP II Ac I O O O O OAc H R 1R 2 Ac I O O O O OCHR 1R 2 H R 1R 2 R 1R 2CHOH –AcOH Ac I O O OAc O OAc I O O OH O DMP I O O OAc I O O OCHR1R 2 IBX Ac2O AcOH O H 3C H 3C CH 3 I PivO HH H 3C TBSO OPMB O O H 3C DEIPSO HCH 3 O CH 3 H H HO OTES CH 3 O CH 3 TESO CH 3 O OCH 3 OTES OCH 3 O TESO Si(tBu)2 TBSO CH 3H O CH3O OH O Se HO DMP DMP O H 3C H 3C CH 3 I O HH H 3C TBSO H Se O O CH 3O CHO O O O O H 3C DEIPSO HCH 3 O CH 3 H H HO OTES CH 3 O CH 3 TESO CH O 3 OCH 3 OTES OCH 3 O TESO Si(tBu)2 TBSO CH 3H O H 3C H 3C CH 3 H H 3C HOAcO H Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J.J. Am. Chem. Soc.1990,112, 70017031. Polson, G.; Dittmer, D. C. J. Org. Chem.1988,53, 791794. Danishefsky, S. J.; Mantlo, N. B.; Yamashita, D. S.; Schulte, G. K.J. Am. Chem. Soc.1988,110, 68906891. DessMartin Periodinane (DMP)• Examples DMP has found wide utility in the preparation of sensitive, highly functionalized molecules. DMP oxidations are characterized by short reaction times, use of a single equivalent of oxidant, and can be moderated with regard to acidity by the incorporation of additives such as pyridine. DMP and its precurseroiodoxybenzoic acid (IBX) are potentially heat and shock sensitive and should be handled with appropriate care. 2.0 M H 2SO 4 65 °C, 2.5 h + + 85 °C then 23 °C, ~24 h Dess, D. B.; Martin, J. C.J. Am. Chem. Soc.1983,48, 41554156. Boeckman, R. K.; Shao, P.; Mulins, J. J. Org. Synth.1999,77, 141152. Plumb, J. B.; Harper, D. J.Chem. Eng. News1990, July 16, 3. 1. DIBAL 2. DMP 89% overall Overman, L. E.; Pennington, L. D.Org. Lett.2000,2, 26832686. ~100% 70% 74% overall Mark G. Charest – + + R 1R 2C=O + AcOH Addition of one equivalent of water has been found to accelerate the reaction, perhaps due to the formation of an intermediate analogous to II. It is proposed that the decomposition ofII is more rapid than the initially formed intermediateI. slow fast + R 1R 2C=O + AcOH Meyer, S. D.; Schreiber, S. L.J. Org. Chem.1994,59, 75497552. (–)7deacetoxyalcyonin acetate 1. DDQ, CH2Cl2, H2O 2. DMP, CH2Cl2, pyr 93% overall (–)cytovaricin Use of other oxidants in the following example led to conjugation of the β,γunsaturated ketone, which did not occur when DMP was used. • • Dess, D. B.; Martin, J. C.J. Am. Chem. Soc.1991,113, 72777287. HO OH H 3C H 3C AcO HO OH O I CO 2H HONHFmoc SCH 3 DMP Ph 3P=CHCO2CH 3 SCH3 H O NHFmoc I O O OH O H 3C H 3C AcO HO O O CH 3O 2C CO 2CH 3 IBX N OH OH H TIPS O N OH OH OH O N O H O O H TIPS O N CHO Mark G. Charest – + DMP oxidation in the presence of phosphorous ylides allows for the trapping of sensitive aldehydes. DMP, CH2Cl2, DMSO PhCO2H 94% (2.2 : 1E,E:E,Z) Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M.J. Org. Chem.1997,62, 93769378. • IBX is used as a mild reagent for the oxidation of 1,2diols without CC bond cleavage. IBX, DMSO 85% • Pyridines are not oxidized at a rate competitive with the oxidation of a primary alcohol. IBX, DMSO 99% Frigerio, M.; Santagostino, M.Tetrahedron Lett.1994,35, 80198022. oxone, H2O 70 °C 7981% Frigerio, M.; Santagostino, M.; Sputore, S.J. Org. Chem.1999,64, 45374538. • oIodoxybenzoic Acid (IBX) • The DMP precursor IBX is gaining use as a mild reagent for the oxidation of alcohols. • A simpler preparation of IBX has recently been reported. IBX has been shown to formα,βunsaturated carbonyl compounds from the corresponding saturated alcohol or carbonyl compound. • 2.3 equiv IBX toluene, DMSO 88% 4.0 equiv IBX toluene, DMSO 84% 2.0 equiv IBX toluene, DMSO 87% Frigerio, M.; Santagostino, M.Tetrahedron Lett.1994,35, 80198022.Nicolaou, K. C.; Zhong, Y.L.; Baran, P. S.J. Am. Chem. Soc.2000,122, 75967597. >90% Myers, A. G.; Zhong, B.; Kung, D. W.; Movassaghi, M.; Lanman, B. A.; Kwon, S.Org. Lett., in press. 6.0 equiv IBX toluene, DMSO 52% + N TEOC O OH H H 3C CH 3 HO CH 3 N TEOC O H H 3C CH 3 O OCH 3 H N O OH H H 3C CH 3 O O H HO H 3CCH 3 OAc H H O O OH H CH 3 CH3 OH O O CH 3O2C O CH 3 OH nPr O O O HCH 3O H 3CCH 3 OTBS CH 3O CH 3O H OH H O TBSOO O O HCH 3O H 3C CH 3 OTBS CH 3O CH 3O H H O O OCH 3H CH 3 CH 3 TESO OTBSO O CH 3 CH 3 CH 3 O O N H 3C F OH N H 3C F CHO O O HCH 3O H 3CCH 3 OTBS CH 3O CH 3O H H H O TBSOO O O O HCH 3O H 3C CH 3 OTBS CH 3O CH 3O H H O O OH OCH 3H CH 3 CH 3 TESOOH OTBSO O CH 3 CH 3 CH 3 Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun.1987, 16251627. tetranPropylammonium Perruthenate (TPAP): Pr4N+ RuO 4 – Ruthenium tetroxide (RuO4, Ru(VIII)) and, to a lesser extent, the perruthenate ion (RuO4 – , Ru(VII)) are powerful and rather nonselective oxidants. However, perruthenate salts with large organic counterions prove to be mild and selective oxidants in a variety of organic solvents. In conjunction with a stoichiometric oxidant such asNmethylmorpholineNoxide (NMO), TPAP oxidations are catalytic in ruthenium, and operate at room temperature. The reagents are relatively nontoxic and nonhazardous. To achieve high catalytic turnovers, the addition of powdered molecular sieves (to remove both the water of crystallization of NMO and the water formed during the reaction) is essential. The following oxidation state changes have been proposed to occur during the reaction: Ru(VII) + 2e– → Ru(V) 2Ru(V)→ Ru(VI) + Ru(IV) Ru(VI) + 2e– → Ru(IV) TPAP, CH2Cl2 23 °C 84% Bu4N+ F– , THF 0 °C 29% (±)indolizomycin Kim, G.; ChuMoyer, M. Y.; Danishefsky, S. J.; Schulte, G. K.J. Am. Chem. Soc.1993,115, 3039. TPAP, NMO, CH2Cl 2 4 Å MS, 23 °C 78% Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S.Angew. Chem., Int. Ed. Engl.2000,39, 22902294. bryostatin 3 TPAP, NMO, CH2Cl 2 4 Å MS, 23 °C 87% TPAP, NMO, CH2Cl 2 4 Å MS, 23 °C 79% Robol, J. A.; Duncan, L. A.; Pluscec, J.; Karanewsky, D. S.; Gordon, E. M.; Ciosek, C. P.; Rich, L. C.; Dehmel, V. C.; Slusarchyk, D. A.; Harrity, T. W.; Obrien, K. A.J. Med. Chem.1991,34, 28042815. TPAP, NMO, CH2Cl 2 4 Å MS, 23 °C 70% Ley, S. V.; Smith, S. C.; Woodward, P. R.Tetrahedron1992,48, 11451174. Mark G. Charest • Reviews Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.Synthesis1994, 639666. Griffith, W. P.; Ley, S. V.Aldrichimica Acta1990,23, 1319. • Examples • • JuliaLythgoe Olefination OH N O CH 3 H 3C Boc disproportionation +H+ –H+ N R O R 1 N R R 1 OR 2R 3 OH R 2R 3 O R NR1 O O H R 2 R 1 N R R 1 HO O R 1 H R 2 B R NR 1 O HR 2 R 1 O OH OTBDPS H3C CH3 PhS CH 2OH –HX R NR 1 OH R NR 1 OH N RR 1 O X– SePh CH H 3C 2OH O CHO H 3C CH 3 O H OOH H PhS CHO SePh HCHO 3C H O N O CH3 H 3C Boc H O OTBDPS H 3C CH 3 NOxoammoniumMediated Oxidation Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gryza, H.; Prokopoxicz, P.Tetrahedron1998,54, 60516064. NOxoammonium salts are mild and selective oxidants for the conversion of primary and secondary alcohols to the corresponding carbonyl compounds. These oxidants are unstable and are invariably generated in situ in a catalytic cycle using a stable, stoichiometric oxidant. 2 ++ de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H.Synthesis1996, 11531174. Bobbitt, J. M.; Flores, C. L.Heterocycles1988,24, 509533. Rozantsev, E. G.; Sholle, V. D.Synthesis1971, 401414. • Three possible transition states have been proposed: TEMPO, NaOCl, NaBr EtOAc : toluene : H2O (1 : 1 : 0.15) 90% TEMPO, BAIB, CH2Cl 2 23 °C 98% Jauch, J.Angew. Chem., Int. Ed. Engl.2000,39, 27642765. kuehneromycin A Mark G. Charest • Reviews• Examples TEMPO, BAIB, CH2Cl2 23 °C 70% De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G.J. Org. Chem.1997,62, 69746977. + 2,2,6,6Tetramethyl1piperidinyloxyl (TEMPO) catalyzes the oxidation of alcohols to aldehydes and ketones in the presence of a variety of stoichiometric oxidants, including mchloroperoxybenzoic acid (mCPBA), sodium hypochlorite (NaOCl), bis(acetoxy)iodobenzene (BAIB), sodium bromite (NaBrO2), and Oxone (2KHSO5•KHSO4•K2SO4). Noxoammonium salt NOxoammonium salts may be formed in situ by the acidpromoted disproportionation of nitroxyl radicals. Alternatively, oxidation of a nitroxyl radical or hydroxyl amine can generate the correspondingNoxoammonium salt. nitroxyl radical Golubev, V. A.; Sen, V. D.; Kulyk, I. V.; Aleksandrov, A. L.Bull. Acad. Sci. USSR, Div. Chem. Sci. 1975, 21192126. Ganem, B.J. Org. Chem.1975,40, 19982000. Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A.Tetrahedron Lett.1986,27, 11191122. Bobbitt, J. M.; Ma, Z.J. Org. Chem.1991,56, 61106114. • TEMPO, BAIB, CH2Cl 2 23 °C 55% Selective oxidation of allylic alcohols in the presence of sulfur and selenium has been demonstrated. • N O H 3C CH 3 H 3C CH 3 TEMPO + + + – H H 3C CH 3 EtO2CCO2Et OH CH3 H3C CH3CH3CH3 CH 2OH MnO 2 pet. ether MnO 2 CHO H 3C CH 3 OHCCHO O CH3 H3C CH3CH3CH3H HO O OAc SAr HO TBSO H H Bu 3Sn CH 2OH CH 3 CH3 OH CH 3 CH HO 3 CH 3 H 3C HOCH3 CH3 OH CH 3 CH 3CH 3 OH CH H3 MnO 2 MnO2 CH 2Cl 2 CH3 H 3C CH HO3 CH3 OH CH3 CH3CH3 O HCH3 Bu 3Sn CHO CH 3 H 3C CH 3 O O CH3 MnO 2 acetone HO HO OAc SAr O TBSO H H A heterogenous suspension of active manganese dioxide in a neutral medium can selectively oxidize allylic, benzylic and other activated alcohols to the corresponding aldehyde or ketone. The structure and reactivity of active manganese dioxide depends on the method of preparation. Active manganese oxides are nonstoichiometric materials (in general MnOx, 1.93 < x < 2) consisting of Mn (II) and Mn (III) oxides and hydroxides, as well as hydrated MnO2. Hydrogenbond donor solvents and, to a lesser extent, polar solvents have been shown to exhibit a strong deactivating effect, perhaps due to competition with the substrate for the active MnO2 surface. Examples Manganese Dioxide: MnO2 Crombie, L.; Crossley, J.J. Chem. Soc.1963, 49834984. 61% Trost, B. M.; Caldwell, C. G.; Murayama, E.; Heissler, D.J. Org. Chem.1983,48, 32523265. • Syn or anti vicinal diols are cleaved by MnO2. 100% Cahiez, G.; Alami, M. InHandbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York,1999, p. 231236. Fatiadi, A. J.Synthesis1976, 65104. Fatiadi, A. J.Synthesis1976, 133167. Mark G. Charest • Reviews Ohloff, G.; Giersch, W.Angew. Chem., Int. Ed. Engl.1973,12, 401402. 89% Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A. R.Tetrahedron Lett.1998,39, 56595662. • Vinyl stannanes are tolerated. 75% Haugan, J. A.Tetrahedron Lett.1996, 37, 38873890. paracentrone • 80% Ball, S.; Goodwin, T. W.; Morton, R. A.Biochem. J.1948,42, 516523. 1. DIBAL, C6H 6 2. MnO2, CH2Cl2 74% Cresp, T. M.; Sondheimer, F.J. Am. Chem. Soc.1975, 97, 44124413. MnO2, acetone 76% R = CH 3 R CH 2OH CH 2OH H 3C CH 3 H 3C OH OH H 3C CH 3 H 3C O OH R CHO CHO H 3C CH 3 CH3 OH H3C CH2OH F 5 B OH F 5 BaMnO 4 H O M O L L R 3 R1 R 2 R 4 H 3C CHO H 3C CH 3 CH3 O Oppenauer Oxidation Review A classic oxidation method achieved by heating the alcohol to be oxidized with a metal alkoxide in the presence of a carbonyl compound as a hydride acceptor. Effectively the reverse of the MeerweinPondorffVerley Reduction. The reaction is an equilibrium process and is believed to proceed through a cyclic transition state. The use of easily reduced carbonyl compounds, such as quinone, helps drive the reaction in the desired direction. Barium Manganate: BaMnO4 Review Barium manganate and potassium manganate are deep green salts that can be used without prior activation for the oxidation of primary and secondary allylic and benzylic alcohols. Examples BaMnO4, CH2Cl2 40 °C Gilchrist, T. L.; Tuddenham, D.J. Chem. Soc., Chem. Commun.1981, 657658. 66% 92% Howell, S. C.; Ley, S. V.; Mahon, M.J. Chem. Soc., Chem. Commun.1981, 507508. Proposed Transition State Djerassi, C.Org. React.1951,6, 207. Oppenauer, R. V.Rec. Trav. Chim. PaysBas1937,56, 137144. menthol cat. Zr(OtBu)4, Cl3CHO, CH2Cl2 3 Å MS Highly reactive zirconium alkoxide catalysts undergo rapid ligand exchange and can be used in substoichiometric quantities. Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A. K.; Hayakawa, M.Synthesis1996, 13411344. pivaldehyde, toluene 99% 86% (S)perillyl alcohol Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem.1997,62, 56645665. Mark G. Charest • • Examples • • • • O CH 2OH H CH 3 H SEMO H 3C O CHO H CH 3 H SEMO H 3C Burke, S. D.; Piscopio, A. D.; Kort, M. E.; Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; Shankaran, K.J. Org. Chem.1994,59, 332347. BaMnO 4, CH2Cl 2 98% • 2 mol % Fatiadi, A. J.Synthesis1987, 85127.de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J.Synthesis1994, 10071017. R 2CHOH R2COH R 2CHOH B R 2C O H CrO 3H C O Cr(IV) (CH3)3C H Ph Cr(IV) Cr(VI) Cr(V) –Cr(III) R 2CO R 2COH R2C=O R 2C=O PhCHO Cr(III) Cr(V) Cr(III) H 3C OH CH3 H 3C H OTBS O O CH3 CH 3 O HO H H H 3C O O O Cr O O OHOCrO 3H H O CH3O2C O CH3CH3 OCH 3 O O H H H 3C O H O 3C O CH3 H 3C H O O O CH3 CH3 CH 3O 2C CHO CH3CH3 OCH 3 Chromium (VI) Oxidants The mechanism of chromic acidmediated oxidation has been extensively studied and is commonly used as a model for other chromiummediated oxidations. 83% Ley, S. V.; Madin, A. InComprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York,1991,Vol. 7, p. 251289. Luzzio, F. A. Organic Reactions1998,53, 1122. • Tertiary allylic alcohols are known to undergo oxidative transposition. Mark G. Charest R 2CHOH + HCrO4– + H+ R 2CHOCrO 3H + H 2O + HCrO 3– + BH+ • A competing pathway involving freeradical intermediates has been identified. H+ H+ 2H+ • Fragmentation has been observed with substrates that can form stabilized radicals. • Reviews Doyle, M.; Swedo, R. J.; Rocek, J.J. Am. Chem. Soc.1973,95, 83528357. Holloway, F.; Cohen, M.; Westheimer, F. H.J. Am. Chem. Soc.1951,73, 6568. Wiberg, K. B.; Mukherjee, S. K.J. Am. Chem. Soc.1973,96, 18841888. Wiberg, K. B.; Szeimies, G.J. Am. Chem. Soc.1973,96, 18891892. CrO 3, pyr, CH2Cl2 Ratcliffe, R.; Rodehorst, R. J. Org. Chem.1970,35, 40004003. 95% CrO 3, pyr 89% • Examples Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H.J. Am. Chem. Soc.1953,75, 422428. • + + + +(CH3)3C• Collins Reagent: CrO3•pyr2 CrO 3•pyr2 is a hygroscopic red solid which is easily hydrolyzed to the yellow dipyridinium dichromate (Cr2O7–2 (pyrH+ )2). Typically, 6 equiv of oxidant in a chlorinated solvent leads to rapid and clean oxidation of alcohols. Caution: Collins reagent should be prepared by the portionwise addition of solid CrO3 to pyridine. Addition of pyridine to solid CrO3 can lead to a violent reaction. • Collins, J. C.; Hess, W. W.; Frank, F. J.Tetrahedron Lett.1968,30, 33633366. Collins, J. C.; Hess, W. W.;Org. Synth.1972,52, 59. In situ preparation of the reagent circumvents the difficulty and danger of preparing the pure complex. • 1.nBu 4N+ F– , THF 2. Collins Reagent CH 2Cl 2 81% overall Still, W. C. J. Am. Chem. Soc.1979,101, 24932495. (±)periplanone B 1. H 2, 10% PdC 2. Collins Reagent CH 2Cl 2 90% overall Collum, D. B.; McDonald, J. H.; Still, W. C. J. Am. Chem. Soc.1980,102, 21172120. (+)monensin S N OH CH3 O HO OTIPS NC Cl O H CH3 H N H PCC ClCrO3– N NNOH CH 2Ph PhCH2 O O O OTIPS NC Cl O H CH 3 H N O CH3 S N NNO CH 2Ph PhCH2 OH Pyridinium Chlorochromate (PCC, Coreys Reagent) PCC is an airstable yellow solid which is not very hygroscopic. Typically, alcohols are oxidized rapidly and cleanly by 1.5 equivalents of PCC as a solution in N,Ndimethylformamide (DMF) or a suspension in chlorinated solvents. The slightly acidic character of the reagent can be moderated by buffering the reaction mixture with powdered sodium acetate. Addition of molecular sieves can accelerate the rate of reaction. Examples PCC, 25 °C 4ÅMS 100% Corey, E. J.; Wu, Y.J. J. Am. Chem. Soc.1993,115, 88718872. Mark G. Charest + PCC, CH2Cl2 NaOAc 71% Browne, E. J.Aust. J. Chem.1985,38, 756776. • PCC, 25 °C 4ÅMS 100% Knapp, S.; Hale, J. J.; Bastos, M.; Gibson, F. S.Tetrahedron Lett.1990,31, 21092112. Corey, E. J.; Suggs, J. W.Tetrahedron Lett.1975,26, 26472650. Antonakis, K.; Egron, M. J.; Herscovici, J. J. Chem. Soc., Perkin Trans. I1982, 19671973. H 3C OH OH H 3COH CH3 OH CH 3 OH nC9H 19CH2OH CH3 OH OH H3C H H 3CO CH3 OH CH O 3 nC9H 19CH 2OH H CH3 O OH H 3C H 3C OMOM O Sodium Hypochlorite: NaOCl • Sodium hypochlorite in acetic acid solution selectively oxidizes secondary alcohols to ketones in the presence of primary alcohols. A modified procedure employs calcium hypochlorite, a stable and easily handled solid hypochlorite oxidant. Examples • NaOCl, AcOH 91% Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.; Albizati, K. F. Tetrahedron Lett.1982, 23, 46474650. Nwaukwa, S. O.; Keehn, P. M.Tetrahedron Lett.1982,23, 3538. • NaOCl, AcOH 86% Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc.1998,120, 1277712782. NaOCl, AcOH 71% Winter, E.; Hoppe, D.Tetrahedron1998,54, 1032910338. 1. NaOCl, AcOH 2. MOMCl, DIEA 93% Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc.1999,121, 74317432. OH CH3 H 3C CH3 CH 3 HO O CH3 H 3C CH3 CH 3 HO O NPh O OH CH2OH O H 3CO OH O N OH N OH Cbz CH 3 Cbz CH 3 O O H 3C O O O O N OH N OH Cbz CH 3 Cbz CH 3 Sn BuBu Br 2 Bu 3SnOCH 3 OO O H OtBu H O O HOH O HO H 3C O O O OH H NCH3 HO NH HO H H H 3C H 3C HO OO H OtBu H O O HOH O HO H 3C O HOH OH OH OH OH CHO OH OH CHO O NPh O CH 2OH OH O O OH O O O O CH3 (+)spectinomycin Hanessian, S.; Roy, R.J. Am. Chem. Soc.1979,101, 58395841. Mark G. Charest Selective Oxidations UsingNBromosuccinimide (NBS) or Bromine • NBS in aqueous dimethoxyethane selectively oxidizes secondary alcohols in the presence of primary alcohols. • Examples NBS, DME, H2O >98% Corey, E. J.; Ishiguro, M.Tetrahedron Lett.1979,20, 27452748. Bromine has been employed for the selective oxidation of activated alcohols. In the following example, a lactol is oxidized selectively in the presence of two secondary alcohols. Br 2, AcOH NaOAc >51% Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; KimMeade, A. S.; Thomas, J. B.; Watterson, S. H.; Wagman, A. S.J. Am. Chem. Soc.2000,122, 84538463. Stannylene acetals are oxidized in preference to alcohols in the presence of bromine. • (±)ginkgolide B H 2 PdC 70% 90% Selective Oxidations using Other Methods Cerium (IV) complexes catalyze the selective oxidation of secondary alcohols in the presence of primary alcohols and a stoichiometric oxidant such as sodium bromate (NaBrO3). Tomioka, H.; Oshima, K.; Noxaki, H.Tetrahedron Lett.1982,23, 539542. • In the following example, catalytic tetrahydrogen cerium (IV) tetrakissulfate and stoichiometric potassium bromate in aqueous acetonitrile was found to selectively oxidize the secondary alcohol in the substrate whereas NaOCl with acetic acid and NBS failed to give the desired imide. • Ce(SO4)2•2H 2SO 4, KBrO3 7 : 3 CH3CN, H2O, 80 °C Rydberg, D. B.; Meinwald, J.Tetrahedron Lett.1996,37, 11291132. (±)palasonin TEMPO catalyzes the selective oxidation of primary alcohols to aldehydes in a biphasic mixture of dichloromethane and aqueous buffer (pH = 8.6) in the presence ofNchlorosuccinimide (NCS) as a stoichiometric oxidant and tetrabutylammonium chloride (Bu4N+ Cl– ). TEMPO, NCS, Bu4N+ Cl– CH 2Cl 2, H2O, pH 8.6 77% 0.50% + • Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.L.J. Org. Chem.1996,61, 74527454. 8 88 + TEMPO, NCS, Bu 4N+ Cl– CH2Cl2, H2O, pH 8.6 82% 52% 1. DMP, CH2Cl2, pyr 2. NaClO 2, NaH2PO 4 2methyl2butene, tBuOH, H2O 3. CH2N2 98% (+)monensin A Ireland, R. E.; Meissner, R. S.; Rizzacasa, M. A.J. Am. Chem. Soc.1993,115, 71667172. • 1. NaClO 2, NaH2PO 4, 2methyl2butene tBuOH, H2O 2. CF 3CH 2OH, 2,6lutidine >95% Corey, E. J.; Myers, A. G.J. Am. Chem. Soc.1985,107, 55745576. (±)antheridic acid • Lindgren, B. O.; Nilsson, T.Acta. Chem. Scand.1973,27, 888890. Kraus, G. A.; Roth, B.J. Org. Chem.1980,45, 48254830. N Ts TsN H O H H O OCH 3 OO OTBS OO OTBS OTBS CHO H 3CCH 3H 3CCH 3 BnO O OCH3 OO OTBS OO OTBS OTBS CO 2H H 3CCH 3H 3CCH 3 BnO N O CHO Boc CN NH N H O CH 3 O H 3C N O (CH3)2N O N O CO2H Boc CN OCH 3 CHO HO H 3C CHO CH 3 CH 3 H 3C CO2H CH 3 CH 3 OCH 3 CO 2H HO N Ts TsN CH 3O O H H N H N H H H Potassium Permanganate: KMnO4 Potassium permanganate is a mild reagent for the oxidation of aldehydes to the corresponding carboxylic acids over a relatively large pH range. Alcohols, alkenes, and other functional groups are also oxidized by potassium permanganate. Oxidation occurs through a coordinated permanganate intermediate by hydrogen atomabstraction or hydride transfer. Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S.Tetrahedron Lett.1986, 27, 45374540. KMnO 4, NaH2PO 4 tBuOH, H2O 85% • Examples 1. KMnO4, NaH2PO4, tBuOH, H2O, 0 °C 2. (CH3)3SiCHN 2 80% In the following example, a number of other oxidants (including Jones reagent, NaOCl, and RuO2) failed. Bergmeier, S. C.; Seth, P. P.J. Org. Chem.1999,64, 32373243. (–)yohimbane Mark G. Charest Potassium permanganate in the presence oftertbutyl alcohol and aqueous NaH2PO4 was shown to effectively oxidize the aldehyde in the following polyoxygenated substrate to the corresponding carboxylic acid whereas Jones reagent, RuCl3(H2O)nNaIO 4, and silver oxide failed. Silver Oxide: Ag2O A classic method used to oxidize aldehydes to carboxylic acids. Cistrans isomerization can be a problem with unsaturated systems under the strongly basic reaction conditions employed. Examples Freeman, F.; Lin, D. K.; Moore, G. R.J. Org. Chem.1982,47, 5659. Rankin, K. N.; Liu, Q.; Henrdy, J.; Yee, H.; Noureldin, N. A.; Lee, D. G.Tetrahedron Lett.1998,39, 10951098. Heffner, R. J.; Jiang, J.; Joullié, M. M.J. Am. Chem. Soc. 1992,114,1018110189. KMnO 4, NaH2PO 4 tBuOH, H2O, 5 °C 93.5% (–)nummularine F • Review Fatiadi, A. J.Synthesis1987,85127. Sonawane, H. R.; Sudrik, S. G.; Jakkam, M. M.; Ramani, A.; Chanda, B.Synlett.1996,175176. 1. Ag2O, NaOH 2. HCl 9097% vanillic acid Pearl, I. A.Org. Synth. IV1963,972978. Ag2O, CH3OH 0°C 72% • • O CHO S OCH 3 O OMEM NO CO2H SCO 2H OMEM N CH 3O O H O OTBDPS O SEt BnO H O BnO BnO AcO CHO OO H 3C CH 3 CH BnOCH 3 3CH 3 O AcO CO2CH3 OO H 3C CH 3 CH BnOCH 3 3CH 3 AcO OO H 3C CH 3 BnOCH3CH3CH3 OHAcOCH 3 OO H 3C CH3 BnOCH3CH3O NH O H 3C H OH CH 3 H TBSO SCH 2OH S Ph O NH O H 3C CO 2H TBSO HHCH3 SCHO S Ph O O SEt BnO CH3O O BnO BnO CH 3OOH O OTBDPS O Pyridinium Dichromate: (pyrH+ )2Cr2O7 PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume of water, adding pyridine and collecting the precipitated product. Nonconjugated aldehydes are readily oxidized to the corresponding carboxylic acids in good yields in DMF as solvent. Primary alcohols are oxidized to the corresponding carboxylic acids in good yields. Corey, E. J.; Schmidt, G.Tetrahedron Lett.1979,20, 399402. Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U.J. Org. Chem.1985,50, 20952105. 1. PDC, DMF 2. CH 2N 2 78% In the following example, PDC was found to be effective while many other reagents led to oxidative CC bond cleavage. other oxidants PDC can oxidize aldehydes to the corresponding methyl esters in the presence of methanol. It appears that in certain cases, the oxidation of methanol by PDC is slow in comparison to the oxidation of the methyl hemiacetal. Attempts to form the ethyl and isopropyl esters were less successful. Note that in the following example sulfide oxidation did not occur. PDC, DMF 6 equiv CH3OH >71% OConnor, B.; Just, G.Tetrahedron Lett.1987,28, 32353236. Garegg, P. J.; Olsson, L.; Oscarson, S.J. Org. Chem.1995,60, 22002204. Ley, S. V.; Madin, A. InComprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York,1991,Vol. 7, p. 251289. Mark G. Charest • Review • In the following example, all chromiumbased oxidants failed to give the desired acid. 1. Ag2O, NaOH 2. HCl 81% Ovaska, T. V.; Voynov, G. H.; McNeil, N.; Hokkanen, J. A.Chem. Lett.1997,1516. • • PDC, DMF 91% Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.Tetrahedron1988,44, 21492165. However, a suspension of PDC in dichloromethane oxidizes alcohols to the corresponding aldehyde. PDC, CH2Cl 2 68% Terpstra, J. W.; van Leusen, A. M.J. Org. Chem.1986,51, 230238. • PDC has also been used to oxidize alcohols to the corresponding carboxylic acids. • • Additional Examples PDC, DMF 100% Mazur, P.; Nakanishi, K.J. Org. Chem.1992,57, 10471051. CH3 CHO CH HO 3 H 3CCH 3 O O CHO NOBn OH O CH 3 CH3 CH3 CO 2CH 3 CH HO 3 H 3CCH 3 O O NOBn OH O CH3 CH 3 OCH 3 O O OH OH OH NH O N CO 2CH 3 TBSO H O O OO H OH CHO H 3C H 3C O O CHO CH 3 H 3C O Ph O H O O OH CO 2R H 3C H3C O O CO2CH3 CH 3 H 3C O Ph N CO2CH3 TBSO OCH 3 O Aldehyde Ester CoreyGilmanGanem Oxidation A convenient method to convert unsaturated aldehydes directly to the corresponding methyl esters. Cistrans isomerization, a problem when other reagents such as basic silver oxide are employed, is avoided. The aldehyde substrate is initially transformed into a cyanohydrin intermediate. Subsequent oxidation of the cyanohydrin furnishes an acyl cyanide which is then trapped with methanol to give the desired methyl ester. Conjugate addition of cyanide ion can be problematic. Examples MnO 2, CH3CN AcOH, CH3OH 81% Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D.J. Am. Chem. Soc. 1999,121,51765190. Bromine Bromine in alcoholic solvents is a convenient and inexpensive method for the direct conversion of aldehydes into ester derivatives. Under the reaction conditions employed, secondary alcohols are not oxidized to the corresponding ketones. Oxidation of a hemiacetal intermediate is proposed. Olefins, benzylidine acetals and thioketals are incompatiable with the reaction conditions. A variety of esters can be prepared. Examples Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W.Tetrahedron Lett.1988,29, 50875090. Lichtenthaler, F. W.; Jargils, P.; Lorenz, K.Synthesis1988,790792. Mark G. Charest R = Me, 94% R = Et, 91% R =iPr, 80% (2Z, 4E)xanthoxin In the following example, stepwise addition of reagents proved to be essential to achieve high yields. 1. CH 3CN, AcOH, CH3OH, 1 h 2. MnO 2 Yamamoto, H.; Oritani, T.Tetrahedron Lett.1995,36,57975800. 97% (–)lycoricidine • Br 2, H2O, alcohol NaHCO 3 • • • • • • Review Palou, J.Chem. Soc. Rev.1994,357361. • 78% Br 2, H2O, CH3OH NaHCO 3 Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenländer, F.Tetrahedron1996, 52,64096420. Br 2, H2O, CH3OH NaHCO 3 89% • R LR ORCO 3H R L O O R O COR H –RCO 2H R LO R O CH 3O O N O O O OCH3 Ph nC 16H 33 H 3C CH 3 BOMO O O H H O CH3O O O D T H D CF3CO3H Na 2HPO 4 O O DT H OD DT HD O O RR L O H O COR N O CH3 N CH 3 H 3C CH3 BOMO O O O N O O Ph O O OCH 3 nC 16H 33 N O N CH3 CH 3 O H 3C CH 3 O O O OH OH AcO H CO2H H HO HOHOH CH3 Ketone Ester Selective BayerVilliger oxidation in the presence of unsaturated ketones and isolated olefins has been achieved. BayerVilliger Oxidation • Reviews • The BayerVilliger reaction occurs with retention of stereochemistry at the migrating center. A classic method for the oxidative conversion of ketones into the corresponding esters or lactones by oxygen insertion into an acyl CC bond. The migratory preference of alkyl groups has been suggested to reflect their electronreleasing ability and steric bulk. Typically, the order of migratory preference is tertiary > secondary > allyl > primary > methyl. The reactivity order of BayerVilliger oxidants parallels the acidity of the corresponding carboxylic acid (or alcohol): CF3CO 3H > pnitroperbenzoic acid >mCPBA = HCO 3H > CH 3CO 3H > HOOH >tBuOOH. + Turner, R. B.J. Am. Chem. Soc.1950,72, 878882. Gallagher, T. F.; Kritchevsky, T. H.J. Am. Chem. Soc.1950,72, 882885. mCPBA, NaHCO3 CH 2Cl 2 95% Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.J. Am. Chem. Soc.1969,91, 56755677. (±)PGF2α H 2O2 (anhydrous), Ti(OiC3H 7)4, ether DIEA, –30 °C Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K.J. Am. Chem. Soc.1983,105, 625627. >55% eucannabinolide Krow, G. R. InComprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York,1991,Vol. 7, p. 671688. Krow, G. R. InOrganic Reactions, Paquette, L. A., Ed., John Wiley and Sons: New York,1993, Vol. 43, p. 251296. Criegee Intermediate primary effect secondary effect Primary and secondary stereoelectronic effects in the BayerVilliger reaction have been demonstrated. • Primary effect: antiperiplanar alignment of RL andσOO • Secondary effect: antiperiplanar alignment of Olp andσ∗ CRL Crudden, C. M.; Chen, A. C.; Calhoun, L. A.Angew. Chem., Int. Ed. Engl.2000,39, 28522855. • Proposed TS • Examples • Carbamates have been prepared in some cases. mCPBA, CH3OH 70% Azizian, J.; Mehrdad, M.; Jadid, K.; Sarrafi, Y.Tetrahedron Lett.2000,41, 52655268. mCPBA, Li2CO 3 CH2Cl2 99% Miller, M.; Hegedus, L. S.J. Org. Chem.1993,58, 67796785. • RL = Large Group H H O NOH OMOM AcHN Boc •HF R OBz H O H CH3 R HO R = CH 3 CH 3N OBz OH HO H CO 2H CO2H OHO2CCO2H HO OCH 3 OH NHPf OO O CH 3 CH 3 Bn OH NH Boc RuCl3NaIO4 CH3CN, CCl4, H2OR OBz H O H CH 3 R HO Bn OH NH Boc O CH3O OCH3 OH NHPf OO O CH3 CH3 O N OMOM AcHN Boc OH O CH 3N OBz OCH 3 O AlcoholAcid Clinch, K.; Vasella, A.; Schauer, R.Tetrahedron Lett.1987,28, 64256428. Ruthenium Tetroxide: RuO4 1. RuCl3NaIO4, CH3CN, CCl4, H2O 2. (CH3)3SiCHN2 78% overall(S)(+)cocaine Lee, J. C.; Lee, K.; Cha, J. K.J. Org. Chem.2000,65, 47734775. 60% Overman, L. E.; Ricca, D. J.; Tran, V. D.J. Am. Chem. Soc.1997,119, 1203112040. (±)scopadulcic acid B Molecular Oxygen Molecular oxygen in the presence of a platinum catalyst is a classic method for the oxidation of primary alcohols to the corresponding carboxylic acids. Examples O 2Pt 65% Mehmandoust, M.; Petit, Y.; Larcheveque, M.Tetrahedron Lett.1992,33, 43134316. Pf = 9phenylfluorenyl 1. O 2Pt 2. CH 3I 85% • Primary alcohols are oxidized selectively in the presence of secondary alcohols. Park, K. H.; Rapoport, H.J. Org. Chem.1994,59, 394399. RuO 4 is used to oxidize alcohols to the corresponding carboxylic acid. It is a powerful oxidant that also attacks aromatic rings, olefins, diols, ethers, and many other functional groups. Catalytic procedures employ 15% of ruthenium metal and a stoichiometric oxidant, such as sodium periodate (NaIO4). Sharpless has introduced the use of acetonitrile as solvent to improve catalyst turnover. It is proposed to avoid the formation of insoluble Rucarboxylate complexes and return the metal to the catalytic cycle. RuO 2(H2O)2, NaIO4 CH3CN, CCl4, H2O • 98% • In the following example, sodium periodate cleaves the 1,2diol to an aldehyde, which is further oxidized to the corresponding carboxylic acid by RuO4. The amine is protonated and thereby protected from oxidation. RuCl 3, NaOCl CCl 4, H2O 70% Sptzer, U. A.; Lee, D. G.J. Org. Chem.1974,39, 24682469. RuO 2, NaIO4 CCl4, H2O 68% Smith, A. B., III; Scarborough, R. M., Jr.Synth. Commun.1980,10, 205211. Djerassi, C.; Engle, R. R.J. Am. Chem. Soc.1953,75, 38383840. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.J. Org. Chem.1981,46, 39363938. • Examples • O OO CH3 O O O H CH 3 OH H CO O 2tBu H CO2CH3 BnO OTBS O O CH CH 33 CH 3 OH O CH CH 33 CH 3 CO2H BnO CO 2H O CO 2CH 3 OO CH3 O O O H CH 3 O H CO O 2H H O OO HO B H 3C CH 3 O PivO CF3CONH O OPiv O O NHO N N O CH2OBn H N Ph OO OBn OBn O NH O H 2N O HO HO 2C H 2N O O CO2H NHO OH N O O OO HO2C B H 3C CH 3 O PivO HO 2C CF3CONH O O CO2H NHO OPiv N NH O O H N Ph OO NOxoammoniumMediated Oxidation of Alcohols to Carboxylic Acids Epp, J. B.; Widlanski, T. S.J. Org. Chem.1999,64, 293295. Jones Oxidation Mark G. Charest Jones reagent is a standard solution of chromic acid in aqueous sulfuric acid. Acetone is often benefical as a solvent and may function by reacting with any excess oxidant. Isolated olefins usually do not react, but some olefin isomerization may occur with unsaturated carbonyl compounds. 1,2diols andαhydroxy ketones are susceptible to cleavage under the reaction conditions. Examples • A general method for the preparation of nucleoside 5carboxylates: TEMPO, PhI(OAc)2 CH 3CN, H2O B = A (90%) B = U (76%) B = C (72%, NaHCO3 added) B = G (75%, Na salt, NaHCO3 added) • Silyl ethers can be cleaved under the acidic conditions of the Jones oxidation. Jones reagent –10→23 °C 8897% Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L.Angew. Chem., Int. Ed. Engl.1999, 38, 31753177. Jones reagent 0 °C 85% Corey, E. J.; Trybulski, E. J.; Melvin, L. S.; Nicolaou, K. C.; Secrist, J. A.; Lett, R.; Sheldrake, P. W.; Flack, J. R.; Brunelle, D. J.; Haslanger, M. F.; Kim, S.; Yoo, S.J. Am. Chem. Soc.1978,100, 46184620. • (–)CP263,114 1. Jones reagent 2. HCO2H 96% overall • Ketones have been prepared efficiently by oxidation of the corresponding secondary alcohol. NH 3, CH3OH 55 °C 65% Knapp, S. K.; Gore, V. K. Org. Lett.2000,2, 13911393. 4desamino4oxoezomycin A2 Waizumi, N.; Itoh, T.; Fukuyama, T.J. Am. Chem. Soc.2000,122, 78257826. • 1. H 2, 20% Pd(OH)2C, EtOAc, EtOH 2. PhI(OAc)2, TEMPO CH 3CN, NaHCO3, H2O 3. NaClO2,tBuOH, H2O NaH 2PO 4, isopentene A brief followup treatment with sodium chlorite was necessary to obtain complete oxidation to the biscarboxylic acid in the following example. 49% overall • 3 3 RSO2N=CHR CO 2Et CH3 O CH3 HO H 3COTBS O OTMS O O H H 3COTBS O OTMS H HO CO 2Et CH3 O CH3 HO OH N O R RSO2 Davis oxaziridine: R = R = Ph S O O O H TBDPSO H O CH 3O OCH 3 OCH 3 Ph CH3 O O CH 3 OTBS CH H 3C 3 N S O O O H 3CCH3 N S O O O Cl Cl CH H 3C 3 N S O O O Cl Cl Ph CH3 O OH S O O O H TBDPSO H OH S O O OH H HO H OH O CH 3O OCH 3 OCH 3 OH CHO 3O OH OCH3 CH3O O CH3 OH O CH3 OTBS KetoneαHydroxy Ketone Wender, P. A.; et al.J. Am. Chem. Soc.1997,119, 27572758. Davis Oxaziridine Mark G. Charest Nucleophilic attack by enolates on the electrophilic oxaziridine oxygen furnishesαhydroxy ketones. Potassium enolates are generally the most successful. Examples KHMDS, Davis oxaziridine, THF –78→ –20 °C 97% at 57% conversion KHMDS, Davis oxaziridine, THF –78→ –20 °C 68% 1. KHMDS, HMPA, THF, –10 °C 2. –78 °C (±)breynolide Smith, A. B., III; Empfield, J. R.; Rivero, R. A.; Vaccaro, H. A.; Duan, J. J.W.; Sulikowski, M. M.J. Am. Chem. Soc.1992, 114 , 94199434. • Enantioselective hydroxylation of prochiral ketones has been demonstrated. 1. NaHMDS 2. 61% (95% ee) Davis, F. A.; Chen, B.Chem. Rev.1992,92,919934. NSulfonyloxaziridines are prepared by the biphasic oxidation of the corresponding sulfonimine withmCPBA or Oxone. mCPBA or Oxone Grandi, M. J. D.; Coburn, C. A.; Isaacs, R. C. A.; Danishefsky, S. J.J. Org. Chem.1993,58 77287731. • taxol taxol 1. NaHMDS 2. 50% (94% ee) Davis, F. A.; Chen, B.J. Org. Chem.1993,58,17511753.(+)Otrimethylbrazilin •Reviews Davis, F. A.; Chen, B.Chem. Rev.1992,92, 919934. Jones, A. B. InComprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York,1991,Vol. 7, p. 151191. 73% H H3C H 3C CH 3 O CHOO H 3C CH3 H 3C CH3 S CH 3S O CH 3 O H MoO O O O O O N ((CH3)2N)3P H3O+ H3C H 3C CH 3 OHC OH CHO H 3C CH3 H 3C CH3 CH3 O H S CH 3S O R 1 R2 H 3C H 3C CH 3 O OHC OHO R 1 R 2 O SiR 3 OTBS BOMO OTBS OTBS PMBO Et 3SiO CH3 H H 3C O OCH 3 CH 3 TBDPSO R 1 R 2 O SiR 3 O R 1 R 2 O SiR 3 O O CH 3 CH3 O CH 3 H H 3C O OCH3 CH 3 TBDPSO HO OTBS O BOMO OTBS PMBOOTBS R 1 R 2 O OSiR 3 Jansen, B. J. M.; Sengers, H.; Bos, H.; de Goot, A.J. Org. Chem.1988,53, 855859. Molybdenum peroxy compounds: MoO5•pyr•HMPA Mark G. Charest + – Oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) is commonly used to oxidize enolates to the corresponding hydroxylated compound. It is proposed that nucleophilic attack of the enolate occurs at a peroxyl oxygen atom, leading to OO bond cleavage. βDicarbonyl compounds are not hydroxylated. Examples (±)warburganal Rubottom Oxidation • Epoxidation of a silyl enol ether and subsequent silyl migration furnishesαhydroxylated ketones. • Silyl migration via an oxacarbenium ion has been postulated. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R.Tetrahedron Lett.1974, 43194322. Brook, A. G.; Macrae, D. M.J. Organomet. Chem.1974,77, C19C21. Hassner, A.; Reuss, R. H.; Pinnick, H. W.J. Org. Chem.1975,40, 34273429. 1. LDA, THF, –78 °C 2. MoOPH 91% R1 = H, R2 = OH 45% R1 = OH, R2 = H 25% 1. LDA, THF, –78 °C 2. MoOPH, –40 °C Kato, N.; Okamoto, H.; Arita, H.; Imaoka, T.; Miyagawa, H.; Takeshita, H.Synlett.1994, 337339.Reddy, K. K.; Saady, M.; Falck, J. R.J. Org. Chem.1995,60, 33853390. • dimethyldioxirane camphorsulfonic acid 79% dimethyldioxirane = mCPBA, NaHCO3 EtOAc 70% Clive, D. L. J.; Zhang, C.J. Org. Chem.1995,60, 14131427. OHCH3 OHOBn CH3 CH 3O MOMO CH3CH3 N OH OH CH 3 N O CH3 O N H O O CH3 O NH 2 CH 3 O O H3C CH3O CH 3 OCH 3 CH 3O H 3C CH3O HCH3 MOMO CH3CH3 OBn O O H 3C HOH3C H 3C HO OH O CH 3 H HO OH O H3C H 3C O H 3C HO OH OH OH H 3C H3C N H 3C H 3CCH 3 CH3 OBz O H HO3C H 3C O O O O O O H 3C CH 3 O CH 3 H HO O O H3C H 3C O H 3C OH 3C CH3 O O O H Diol Lactone Procter, G. InComprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York,1991,Vol. 7, p. 312318. Fetizon, M.; Golfier, M.; Louis, J.M. J. Chem. Soc., Chem. Commun.1969, 11021118. Fetizon, M.; Golfier, M.; Mourgues, P.Tetrahedron Lett.1972, 13, 44454448. Kakis, F. J.; Fetizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T.J. Org. Chem. 1974,39, 523533. Silver carbonate absorbed on Celite has been found to selectively oxidize primary diols to lactones. Fetizons Reagent (±)bukittinggine Ag2CO 3 on Celite, C6H 6 reflux Heathcock, C. H.; Stafford, J. A.; Clark, D. L.J. Org. Chem.1992,57, 25752585. >74% (±)macbecin I • Lactols are oxidized selectively. Ag2CO3 on Celite, toluene 7585 °C 77% (+)mevinolin Clive, D. L. J.; et al.J. Am. Chem. Soc.1990,112, 30183028. • Platinum and oxygen have been used for the selective oxidation of primary alcohols to lactones. PtO 2 acetone, water damsin Kretchmer, R. A.; Thompson, W. J.J. Am. Chem. Soc.1976,98, 33793380. 96% • Epimerizable lactones have been prepared. Ag2CO3 on Celite, C6H6 80 °C 75% Coutts, S. J.; Kallmerten, J.Tetrahedron Lett.1990, 31, 43054308. Other Methods • TEMPO derivatives have been employed in the preparation of lactones. NaBrO 2, CH2Cl 2 NaHCO3 (aq) 94% Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S.J. Org. Chem.1990,55, 462466. • Ru complexes have also been employed. RuH2(PPh3)4, PhCH=CHCOCH 3 toluene 100% Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S.J. Org. Chem.1986,51, 20342039. • •Review Landy Blasdel • Reviews: Mihailovic, M. L.; Cekovic, Z. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 1 90–1 95. Butler, R. N. In Synthetic Reagents, Pizey, J. S., Ed., 1 977, Vol 3, p. 277–41 9. Rubottom, G. M. In Oxidation in Organic Chemistry, Trahanovsky, W. S., Ed.; Organic Chemistry, A Series of Monographs, Vol 5, 1 982, Part D, p. 1 –1 45. • A common reagent for the cleavage of diols. However, Pb(OAc)4 is a strong oxidant and can react with a variety of functional groups. • Examples: HO HO O CH3 OTBDPS 1 . Pb(OAc)4, PhH 2. NaBH4, CH3OH 84% (two steps) O H 3C OTBDPS HO OH Takao, K.; Watanabe, G.; Yasui, H.; Tadano, K. Org. Lett. 2002, 4, 2941 –2943. O HO OH O O O (CH2)6OBn PhS TBS O O O O O (CH2)6OBn PhS TBS H O O O (CH2)6OBn PhS TBS HO O toluene, 0 °C 20–45 min 90% Tan, Q.; Danishefsky, S. J. Angew. Chem. Int. Ed., Eng. 2000, 39, 4509–451 1 . • αHydroxyketones can be cleaved as well: O H 3C CH3 OH OH3 C CH3 CO2CH3 CH3 H 3C CH3 CO2CH3 O CH3 H 3C H 3C H O O OCH3 Corey, E. J.; Hong, B. J. Am. Chem. Soc. 1 994, 116, 31 49–31 50. Pb(OAc)4 CH3OH–PhH (1 :2) 0 °C, 30 min 82% H 3C H 3C OAc AcO H HO CH3 H Lead Tetraacetate (Pb(OAc)4) H Pb(OAc)4 PhH, 80 °C, 1 8 h 68% H 3C OAc AcO H OC H 3 H H • Oxidative cyclizations sometimes occur. This process likely proceeds by a freeradical mechanism involving homolytic cleavage of an RO–Pb bond. Bowers, A.; Denot, E.; Ibáñez, L. C.; Cabezas, M. A.; Ringold, H. J. J. Org. Chem. 1 962, 27, 1 862–1 867. Mihailovic, M. L.; Cekovic, Z. Synthesis 1 970, 5, 209–224. • In addition, Pb(OAc)4 can oxygenate alkenes, oxidize allylic or benzylic C–H bonds, and has been used to introduce an acetate group α to a ketone. O O O H 3C H 3C PMBO HO OH C8H1 5 NaIO4, NaOH, EtOH 0 → 25 °C, 2 h >95% O O O H 3C H 3C PMBO O H C8H1 5 Nicolaou, K. C.; Zhong, Y.L.; Baran, P. S.; Jung, J.; Choi, H.S.; Yoon, W. H. J. Am. Chem. Soc. 2002, 124, 2202–221 1 . Sodium periodate (NaIO4) • Reviews: Wee, A. G.; Slobodian, J. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 420–423. • One of the most common reagents for cleaving 1 ,2diols. HO Pb(OAc)4 Oxidative Cleavage of Diols Ozone • Ozone is the most common reagent for the oxidative cleavage of olefins. • The reaction is carried out in two steps: (1 ) a stream of O3 in air or O2 is passed through the reaction solution at low temperature (0 °C to –78 °C) until excess O3 in solution is evident from its blue color. (2) reductive or oxidative workup. • Mechanism: O O O R 2 R 1 R3 R 4 O O O R 1 R 2 R4 R 3 + molozonide O R 1 R2 O R 4 R 3 O O O O R 1 R 2 R 3 R 4 ozonide O R R1 2 O R R3 4 + + reductant • Considered to be a concerted 3 + 2 cycloaddition of O3 onto the alkene. • Because ozonides are known to be explosive, they are rarely isolated and typically are transformed directly to the desired carbonyl compounds. • Dimethyl sulfide is the most commonly used reducing agent. Others include I2, phosphine, thiourea, catalytic hydrogenation, tetracyanoethylene, Zn–HOAc, LiAlH4, and NaBH4. The latter two reductants afford alcohols as products. • Oxidative workup provides either ketone or carboxylic acid products. The most common oxidants are H2O2, AgO2, CrO3, KMnO4, or O2. • Alkenes with electrondonating substituents are cleaved more readily than those with electronwithdrawing substituents, see: Pryor, W. A.; Giamalva, D.; Church, D. F. J. Am. Chem. Soc. 1 985, 107, 2793–2797. • Ozonolysis of silyl enol ethers can afford carboxylic acids as products: OTMS H 3C OCH3 HO O H O CH3 OCH3 1 . O3, CH3OH–CH2Cl2 (3:1 ), –78 °C 2. S(CH3)2, –78 °C → 23 °C 92% H 3C OH CH3 OTMS Ph OTBS O OBn H 3C H H 1 . O3, CH2Cl2–CH3OH (1 5:1 ), –78 °C 2. thiourea, –78 °C 65% H 3C OH O CH3 OTMS O OTBS O OBn H 3C H H Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1 997, 119, 1 2976–1 2977. N H 3CO H Ph OTBS O 1 . O3, CH2Cl2, CH3OH 2. S(CH3)2 3. NaBH4 N H 3CO H OH OTBS O 92% • When a TMSprotected alkyne was used in the example above, the authors observed products arising from ozonolysis of the alkyne as well. Banfi, L.; Guanti, G. Tetrahedron Lett. 2000, 41, 6523–6526. • Forming the primary ozonide with sterically hindered olefins is difficult, and epoxides can be formed instead: H 3C H 3C H 3C CH3 CH3 H 3C H 3C CH3 CH3 OH3 C 1 . O3, (ClH2C)2, 0 °C 2. Zn, HOAc, 75 °C 71 % Hochstetler, A. R. J. Org. Chem. 1 975, 40, 1 536–1 541 . Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan, S. M. J. Org. Chem. 1 997, 62, 78–87. Landy Blasdel • Reviews: Berglund, R. A. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 270–275. Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1 991 , Vol 7, p. 543–558, 574–578. Murray, R. W. In Techniques and Methods ofOrganic and Organometallic Chemistry , Denny, D. B., Ed., Marcel Dekker: New York, 1 969, Vol 1 , p. 1 –32. Murray, R. W. Acc. Chem. Res. 1 968, 1, 31 3–320. • Examples Oxidative Cleavage of Alkenes • Alkenes are ozonized more readily than alkynes: Landy Blasdel OsO4, NaIO4 • A twostep procedure involving initial dihydroxylation with OsO4 to form 1 ,2diols, followed by cleavage with periodate. • This procedure offers an alternative to ozonolysis, where it can be difficult to achieve selectivity for one olefin over another due to difficulties in adding precise quantities of ozone. • Sharpless dihydroxylation conditions (ADMix αβ) can lead to enhanced selectivities. H 3C CH3 OPMB CH3 cat. OsO4, NMO H 3C CH3 PMBO CH3 Wee, A. G.; Liu, B. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 423–426. Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1 991 , Vol. 7, p.564. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1 976, 1 973. OH OH THF, acetone, H 2O, 23 °C H 3C CH3 PMBO CH3 H O NaIO4 THF, H2O 23 °C 93% (two steps) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.; Sheidt, K. A. J. Org. Chem. 2002, 67, 4275–4283. • The procedure is most often performed in two steps, but the transformation is sometimes accomplished in one: N H 3CO O H 3CO H OsO4, NaIO4 THF, H2O, 23 °C 62% conversion N H 3CO O O H 3CO H H CH3MgI N H 3CO OH O H 3CO H H 3C THF 47% (two steps) Maurer, P. J.; Rapoport, H. J. Med. Chem. 1 987, 30, 201 6–2026. • An improved onepot procedure uses 2,6lutidine as a buffering agent: CH3 OTBS CH3 OPMB OsO4, NaIO4, 2,6lutidine dioxane–H2O (3:1 ) O CH3 OTBS CH3 OPMB • Ozonolysis of this substrate resulted in PMB removal. • The authors found that without base, the αhydroxyketone was formed in ~30% yield. Using pyridine as base, epimerization of the aldehyde product was observed. H O CH3 OTBS CH3 OPMB HO 90% 6% + Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 321 7–321 9. • Notice that in the example above, the lesshindered olefin was cleaved selectively. NTs H 3CO OBn OCH3 OCH3 NTs H 3CO OBn OCH3 OCH3 O H 1 or 2 steps OsO4 (cat.), NaIO4, THF–H2O (3:1 )...................................77% 1 . OsO4 (cat.), NMO, acetone–H2O–tBuOH (4:2:1 ); 2. NaIO4, THF–H2O (3:1 )...................................................89% Bianchi, D. A.; Kaufman, T. S. Can. J. Chem. 2000, 78, 1 1 65–1 1 69. • Frequently the twostep protocol is found to be superior to the onepot procedure. In the example shown, overoxidation of the aldehyde was observed in the onepot reaction. Oxidative Cleavage of Alkenes Landy Blasdel Ketone α, βUnsaturated Ketone Saegusa Oxidation OP MBO OTIPS H TMSO PMBO OTIPS H OP MBO OTIPS H LiTMP, TMSCl THF, –78 °C Pd(dba)2•CHCl3 (5 mol%), diallyl carbonate, CH3CN 90% (two steps) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 1 4546–1 4547. • A twostep procedure involving silyl enol ether formation, followed by treatment with Pd(II). • The reaction can be performed with stoichiometric Pd(II), or can be rendered catalytic if a terminal oxidant, such as O2 or pbenzoquinone, is used. • Mechanism: O TMSCl OTMS PdII OTMS PdII O Pd(OAc)2 O PdII H O βelim Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1 978, 43, 1 01 1 –1 01 3. Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem. Int. Ed. 1 999, 38, 201 5–201 6 TMSOAc Pd(0) • In this case, diallyl carbonate is used as a terminal oxidant. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1 978, 43, 1 01 1 –1 01 3. General Reference: Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1 991 , Vol. 7, p. 1 1 9–1 49. • References: Martín, V. S.; Palazón, J. M.; Rodríguez, C. M. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 346–353. Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1 991 , Vol 7, p.564–571 , 587. Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1 953, 75, 3838–3840. • RuO4 is a powerful oxidant that is nevertheless useful in many synthetic transformations. • RuO4 has been used to cleave alkenes where other oxidation methods (e.g., O3, OsO4NaIO4) have failed. • Reaction conditions are relatively mild and usual involving generation of RuO4 in situ from RuO2•2H2O or RuCl3•H2O and an oxidant, such as NaIO4. • Solvent mixtures of CCl4, H2O and CH3CN have been determined to be optimal. CH3CN is a good ligand for low valent Ru, and it prevents formation of stable Ru(IIIII)–carboxylate complexes which remove Ru from the catalytic cycle. See: Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1 981 , 46, 3936–3938. • RuO4 will also oxidize alcohols (to ketones), ethers (to lactones or to two carboxylic acids), diols (to two carboxylic acids), alkynes (to 1 ,2diketones), and aryl rings (to carboxylic acid products). It will also remove aryl and alkyne groups, leaving carboxylic acids. RuO4 O H 3C O CH3 CH3 H CH3 CH3 CH3 CH3 H CH3 CH3 H 3C RuO2, NaIO4 CCl4–CH3CN–H2O (1 :1 :1 .5), 23 °C, 1 h 68% Myers, A. G.; Condroski, K. R. J. Am. Chem. Soc. 1 995, 117, 3057–3083. H 3C CH3 H CH3 H O O H CH3 CH3 CH3 RuO2, NaIO4 CCl4–CH3CN–H2O 82% Mehta, G.; Krishnamurthy, N. J. Chem. Soc., Chem. Commun. 1 986, 1 31 9–1 321 . Oxidative Cleavage of Alkenes See also: oIodobenzoic Acid (IBX) earlier in handout Landy Blasdel Ketone α, βUnsaturated Ketone SelenationOxidationElimination Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1 991 , Vol. 7, p. 1 28–1 35. Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1 973, 14, 1 979–1 982. Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem. Soc. 1 973, 95, 61 37–61 39. Reich, H. J.; Reich, I. L.; Renga, J. M. J. Am. Chem. Soc. 1 973, 95, 581 3–581 5. Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1 975, 97, 5434–5447. • PhSeBr and PhSeCl can be used to selenate enolates of ketones, esters, lactones and lactams. • PhSeSePh can be used as well, but ketone enolates are unreactive • Aldehydes can be selenated via: – enol ethers: Nicolaou, K. C.; Magolda, R. L.; Sipio, W. J. Synthesis 1 979, 982–984. – enamines: Williams, D. R.; Nishitani, K. Tetrahedron Lett. 1 980, 21, 441 7–4420. – onestep procedure with PhSeSePh, SeO2, and a catalytic amount of H2SO4: Miyoshi, N.; Yamamoto, T.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett. 1 982, 23, 481 3–481 6. • Mechanism: O base O PhSeBr O SePh O O Se Ph O H O + Ph Se OH • Common oxidants include H2O2, O3, and NaIO4. • Elimination is synspecific, see: Jones, D. N.; Mundy, D.; Whitehouse, R. D. J. Chem. Soc., Chem. Commun. 1 970, 86–87. • Electron withdrawing groups on the phenyl ring facilitate the elimination step, which can be difficult with primary or β or γbranched selenoxides: Sharpless, K. B.; Young, M. W. J. Org. Chem. 1 975, 40, 947–948. • Examples: O H3C CH3 H 3C 1 . LDA; PhSeCl O H3C CH3 H 3C 2. H 2O2 • Generating the enolate under kinetic conditions can allow for formation of the lesssubstituted double bond. Annis, G. D.; Paquette, L. A. J. Am. Chem. Soc. 1 982, 104, 4504–4506. Ph O 1 . LDA, THF –78 °C 2. PhSeBr Ph O SePh Ph O H 2O2, pyridine CH2Cl2–H2O, 25 °C, 30 min Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1 975, 97, 5434–5447. • The example above illustrates how the stereospecificity (syn) of the elimination can be used to achieve selectivity in olefin formation. O O H CH3 O O H CH3 O O H CH3 SePh O O H CH3 SePh 1 . LDA, THF, HMPA, –78 °C 2. PhSeSePh O O H O O H O O H CH3 H 2O2, THF, H2O, AcOH, 0 °C ~ 1 00% H 2O2, THF, H2O, AcOH, 0 °C 96% 88% cisfused transfused 1 . LDA, THF, HMPA, –78 °C 2. PhSeSePh 85% 1 0 : 90 + Grieco, P. A.; Miyashita, M. J. Org. Chem. 1 974, 39, 1 20–1 22. 64% 66% Alkene Allylic alcohol SeO2 • References Bulman Page, P. C.; McCarthy, T. J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: New York, 1 991 , Vol. 7, p. 84–91 , 1 08–1 1 0. Rabjohn, N. In Organic Reactions, 1 976,Vol 24, p. 261 –41 5. CH3 H 3C CH3 O Se O CH3 H 3C Se O OH ene reaction 2,3sigmatropic rearrangement CH3 H 3C O Se HO CH3 H 3C OH Singleton, D. A.; Hang, C. J. Org. Chem. 2000, 65, 7554–7560. Selectivity: (a) oxidation typically occurs at the more highly substituted terminus of the alkene (b) the order of reactivity of C–H bonds is CH2 > CH3 > CH rule (a) takes precedence over rule (b) (c) when the double bond is within a ring, oxidation occurs within the ring (4) gemdimethyl trisubstituted alkenes form (E) αhydroxy alkenes stereoselectively Hoekstra, W. J. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 358–359. Bhalerao, U. T.; Rapoport, H. J. Am. Chem. Soc. 1 971 , 93, 4835–4840. • General method for oxidizing alkenes to allylic alcohols. • Although the reaction can be performed with stoichiometric SeO2, catalytic methods employing a stoichiometric oxidant (e.g., tBuOOH) are more frequently used. • Mechanism: • Examples: O O O O OH H 3C CH3 CH3 CH3 CH3 O O O O OH H 3C CH3 CH3 CH3 CH3 OH SeO2, tBuOOH dioxane, 23 °C 95% Xia, W. J.; Li, D. R.; Shi, L.; Tu, Y. Q. Tetrahedron Lett. 2002, 43, 627–630. TBSO H 3C H H 3C H 3C OH H TBSO H 3C H H 3C H 3C H SeO2, tBuOOH CH2Cl2 0 °C 99% Yu, W.; Jin, Z. J. Am. Chem. Soc. 2001 , 123, 3369–3370. CbzN H CH3 H O Br CbzN H CH3 H O Br HO CbzN H CH3 H O Br O SeO2, tBuOOH CH2Cl2, 0 °C → 23 °C 1 4% CbzN H CH3 H O Br H O 77% trace Landy Blasdel Muratake, H.; Natsume, M. Angew. Chem. Int. Ed., Eng. 2004, 43, 4646–4649. + +

Myers General Introductory References Alkane R-CH3 March, J In Advanced Organic Chemistry, John Wiley and Sons: New York, 1992, p 1158-1238 Carey, F A.; Sundberg, R J In Advanced Organic Chemistry Part B, Plenum Press: New York, 1990, p 615-664 Carruthers, W In Some Modern Methods of Organic Synthesis 3rd Ed., Cambridge University Press: Cambridge, UK, 1987, p 344-410 Oxidation States of Organic Functional Groups The notion of oxidation state is useful in categorizing many organic transformations This is illustrated by the progression of a methyl group to a carboxylic acid in a series of 2electron oxidations, as shown at right Included are several functional group equivalents considered to be at the same oxidation state Summary of Reagents for Oxidative Functional Group Interconversions: Alcohol RCH2SiR3' Alcohol R-CH2OH (R-CH2X ) alkyl halide X = halide alkane sulfonate X = OSO2R' alkyl azide X = N3 alkylamine X = NR'2 alkylthio ether X = SR' alkyl ether X = OR' Aldehyde (Ketone) R-CHO (RCOR') hemiketal (hemiacetal) Oppenauer Oxidation Chromium (VI) Oxidants Sodium Hypochlorite N-Bromosuccinimide (NBS) Bromine Cerium (IV) Oxidants R Pyridinium Dichromate (PDC) R' R RCX2R' geminal dihalide dithiane R S S R R' R' Carboxylic Acid R-CO2H ester Bromine Ester R' R''O NR2''' aminal R R' N imine R R'' R' O O RCO2R' amide R N R'' thioester R SR' trihalomethyl R R' N OH orthoester ketene R RCX3 O hydroxamic acid R''' nitrile R' R C N O R O O CH3 (OBO ester shown) Acid O2/Pt Jones Oxidation Carbonic Acid Ester ROH + CO2 (ROCO2H) MoOPH Rubottom Oxidation Lactone isocyanate O2/Pt O O α-Hydroxy Ketone Davis Oxaziridine Fetizon's Reagent oxime R OR'' N R''O carbamate Diol R' enol ether (enamine) Ester Ruthenium Tetroxide Ketone R' R''O OR''' ketal (acetal) Baeyer-Villiger Oxidation Alcohol R N NR''2 hydrazone O Corey-Gilman-Ganem Oxidation Ketone organosilanes organometallics in general RCH2M (M = Li, MgX, ZnX ) Acid Sodium Chlorite Silver Oxide Potassium Permanganate Aldehyde organoboranes RCH2BR2' R''O OH Aldehyde or Ketone Dimethylsulfoxide-Mediated Oxidations Dess-Martin Periodinane (DMP) o-Iodoxybenzoic Acid (IBX) tetra-n-Propylammonium Perruthenate (TPAP) N-Oxoammonium-Mediated Oxidation Manganese Dioxide Barium Manganate Aldehyde Chem 215 Oxidation N-Oxoammonium-Mediated Oxidation RO N R' R'' R N C O alkyl haloformate RO S X xanthate RO SR' O carbodiimide R N C N R' urea R N R'' R' N R''' Mark G Charest Alcohol • Pummerer Rearrangement Aldehyde or Ketone HO CH3 OH H3C H Dimethylsulfoxide-Mediated Oxidations H3C (CF3CO)2O, Ac2O 2,6-lutidine O O H • Reviews Tidwell, T T Organic Reactions 1990, 39, 297-557 • Dimethylsulfoxide (DMSO) can be activated by reaction with a variety of electrophilic reagents, including oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide, acetic anhydride, and N-chlorosuccinimide • The mechanism can be considered generally as shown, where the initial step involves + electrophilic (E ) attack on the sulfoxide oxygen atom • Subsequent nucleophilic attack of an alcohol substrate on the activated sulfoxonium intermediate leads to alkoxysulfonium salt formation This intermediate breaks down under basic conditions to furnish the carbonyl compound and dimethyl sulfide + – Ph O HO CH3 OH H 3C H O O OAc H >60% O O H3C – AcO H S Ph S Ph + Schreiber, S L.; Satake, K J Am Chem Soc 1984, 106, 4186-4188 Swern Procedure • Typically, equivalents of DMSO are activated with oxalyl chloride in dichloromethane at or below –60 °C • Subsequent addition of the alcohol substrate and triethylamine leads to carbonyl formation • The mild reaction conditions have been exploited to prepare many sensitive aldehydes Careful optimization of the reaction temperature is often necessary + + + +S O R H3C General Mechanism H H H –BH+ – –RCO2 O HO CH3 OH H3C H Tidwell, T T Synthesis 1990, 857-870 B O O H3C S Ph Lee, T V In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 291-303 (CH3)2S O HO CH3 OH H 3C H E (CH3)2S X X H H CH3 + + S CH3 R O Huang, S L.; Mancuso, A J.; Swern, D J Org Chem 1978, 43, 2480-2482 RCH2OH + + (CH3)2S X– HO – H R + (CH3)2S TBSO 10% Pd/C, AcOH, EtOAc O O (COCl)2, DMSO; Et3N O –78 → –50 °C OBn alkoxysulfonium ylide TBSO TBSCl, Im, DMAP, CH2Cl2 HO CH2 + S CH3 O H H R –H+ O H 66% • Methylthiomethyl (MTM) ether formation can occur as a side reaction, by nucleophilic attack of an alcohol on methyl(methylene)sulfonium cations generated from the dissociation of sulfonium ylide intermediates present in the reaction mixture This type of transformation is related to the Pummerer Rearrangement Evans, D A.; Carter, P H.; Carreira, E M.; Prunet, J A.; Charette, A B.; Lautens, M Angew Chem., Int Ed Engl 1998, 37, 2354-2359 OTBS OTBS (COCl)2, DMSO; + ROH + H2C S CH3 RO –H+ S CH3 HO OCH3 Et3N, –78 °C 90% Fenselau, A H.; Moffatt, J G J Am Chem Soc 1966, 88, 1762-1765 O OCH3 H Smith, A B., III; Wan, Z J Org Chem 2000, 65, 3738-3753 Mark G Charest CH3O CH3O CH3 HO OR1 CH3O CH3 CH3O OH O (COCl)2, DMSO; N CH3 H R1 O CH3 OCH3 CH3 OR R = TIPS, R1 = TBS Hanessian, S.; Lavallee, P Can J Chem 1981, 59, 870-877 Parikh-Doering Procedure • Sulfur trioxide-pyridine is used to activate DMSO Jones, T K.; Reamer, R A.; Desmond, R.; Mills, S G J Am Chem Soc 1990, 112, 2998-3017 Pfitzner-Moffatt Procedure • Ease of workup and at-or-near ambient reaction temperatures make the method attractive for large-scale reactions Parihk, J R.; Doering, W von E J Am Chem Soc 1967, 89, 5505-5507 • The first reported DMSO-based oxidation procedure • Examples • Dicyclohexylcarbodiimide (DCC) functions as the electrophilic activating agent in conjunction with a Brønsted acid promoter H3 C • Typically, oxidations are carried out with an excess of DCC at or near 23 °C OH DMSO, DCC Cl O 87% H O CH3 : β,γ : α,β S H3 C CH3 H CHO CO2CH3 O CH CH3 O O O SO3•pyr, Et3N, H O H Br H DMSO, CH2Cl2 O H → 23 °C OHC H O Br H 99% + CO2CH3 O CH H S CH3 H CHO S H3 C CH3 N 95% H HO H DMSO, DCC OH CO2CH3 TFA, pyr Bn CH2Cl2, –15 °C O H Corey, E J.; Kim, C U.; Misco, P F Org Synth Coll Vol VI 1988, 220-222 H O Evans, D A.; Ripin, D H.; Halstead, D P.; Campos, K R J Am Chem Soc 1999, 121, 6816-6826 Ot-Bu O TFA, pyr SO3•pyr, DIEA, DMSO CH3 N • Alternative carbodiimides that yield water-soluble by-products (e.g., 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDC)) can simplify workup procedures Ot-Bu H 3C OH Bn • Separation of the by-product dicyclohexylurea and MTM ether formation can limit usefulness Cl OCH3 EDC = (CH3)2N (CH 2)3 N C N CH2CH3 • HCl H CH3 BzO 94% O O R1O OR OCH3 FK506 H OR O TFA, pyr N CH3 OCH3 HO O DMSO, EDC O BzO O 80% O O CH3 CH3 OTBDPS OTBDPS O O OR1 Et3N, –78 °C H OR CH3 H3 C CH3 Semmelhack, M F.; Yamashita, A.; Tomesch, J C.; Hirotsu, K J Am Chem Soc 1978, 100, 5565-5576 Evans, P A.; Murthy, V S.; Roseman, J D.; Rheingold, A L Angew Chem., Int Ed Engl 1999, 38, 3175-3177 O H H Et Br H O Br H (–)-kumausallene Mark G Charest Dess-Martin Periodinane (DMP) • Examples • DMP has found wide utility in the preparation of sensitive, highly functionalized molecules • DMP oxidations are characterized by short reaction times, use of a single equivalent of oxidant, and can be moderated with regard to acidity by the incorporation of additives such as pyridine • DMP and its precurser o-iodoxybenzoic acid (IBX) are potentially heat and shock sensitive and should be handled with appropriate care Dess, D B.; Martin, J C J Am Chem Soc 1983, 48, 4155-4156 H3C H3C H H3 C TBSO H DIBAL DMP O I CH3 CH3 H3C H H3C TBSO H3C H H3C HO AcOO H O H I 89% overall PivO Boeckman, R K.; Shao, P.; Mulins, J J Org Synth 1999, 77, 141-152 H3C H3C CH3 O (–)-7-deacetoxyalcyonin acetate H Overman, L E.; Pennington, L D Org Lett 2000, 2, 2683-2686 Plumb, J B.; Harper, D J Chem Eng News 1990, July 16, HO – I + O OH + I 2.0 M H2SO4 KBrO3 65 °C, 2.5 h CO2 H ~100% IBX Polson, G.; Dittmer, D C J Org Chem 1988, 53, 791-794 O 74% overall O CH3O DMP OH • Addition of one equivalent of water has been found to accelerate the reaction, perhaps due to the formation of an intermediate analogous to II It is proposed that the decomposition of II is more rapid than the initially formed intermediate I DMP R1R2CHOH –AcOH O I OAc I + R1R2C=O + AcOH slow O O O R1R2CHOH –AcOH R1 R2 Ac O O I O II O H OCHR1R2 I + R1R2C=O + AcOH fast OCHR1R O O Dess, D B.; Martin, J C J Am Chem Soc 1991, 113, 7277-7287 CHO • Use of other oxidants in the following example led to conjugation of the β,γ-unsaturated ketone, which did not occur when DMP was used H OAc 70% O CH3O CH3 R1 R2 H DMP Danishefsky, S J.; Mantlo, N B.; Yamashita, D S.; Schulte, G K J Am Chem Soc 1988, 110, 6890-6891 Meyer, S D.; Schreiber, S L J Org Chem 1994, 59, 7549-7552 Ac O O I O O Ac OAc O I OAc O 85 °C Se Se + Ac2O + AcOH O O then 23 °C, ~24 h O DMP H3C DEIPSO O O OTES O O DDQ, CH2Cl2, H2O H CH3 CH3 CH3 CH3 H DMP, CH2Cl2, pyr H O TBSO TESO 93% overall O Si(t-Bu)2 OPMB OCH3 O CH3 O CH3 CH3 OTES TESO H O H3C O OTES H DEIPSO O O H CH CH3 CH3 CH3 H H (–)-cytovaricin O TBSO TESO O Si(t-Bu)2 O OCH3 O CH3 O CH3 OTES TESO H Evans, D A.; Kaldor, S W.; Jones, T K.; Clardy, J.; Stout, T J J Am Chem Soc 1990, 112, 7001-7031 Mark G Charest • DMP oxidation in the presence of phosphorous ylides allows for the trapping of sensitive aldehydes • Pyridines are not oxidized at a rate competitive with the oxidation of a primary alcohol HO OH OH DMP, CH2Cl2, DMSO + CH 3O2C N PhCO2H CHO IBX, DMSO N 99% CO2CH Ph3P=CHCO2CH3 94% (2.2 : E,E : E,Z) Frigerio, M.; Santagostino, M Tetrahedron Lett 1994, 35, 8019-8022 Barrett, A G M.; Hamprecht, D.; Ohkubo, M J Org Chem 1997, 62, 9376-9378 • IBX has been shown to form α,β-unsaturated carbonyl compounds from the corresponding saturated alcohol or carbonyl compound O NHFmoc HO DMP NHFmoc H O OH >90% SCH3 2.3 equiv IBX SCH3 toluene, DMSO Myers, A G.; Zhong, B.; Kung, D W.; Movassaghi, M.; Lanman, B A.; Kwon, S Org Lett., in press 88% o-Iodoxybenzoic Acid (IBX) 4.0 equiv IBX • The DMP precursor IBX is gaining use as a mild reagent for the oxidation of alcohols OH N • A simpler preparation of IBX has recently been reported H O OH + I oxone, H2O CO2H O N 84% – I toluene, DMSO 70 °C O O 79-81% O O H IBX TIPS Frigerio, M.; Santagostino, M.; Sputore, S J Org Chem 1999, 64, 4537-4538 H 2.0 equiv IBX TIPS toluene, DMSO H H 87% • IBX is used as a mild reagent for the oxidation of 1,2-diols without C-C bond cleavage H3 C H3 C AcO HO O H3 C 85% 6.0 equiv IBX H3 C IBX, DMSO AcO OH Frigerio, M.; Santagostino, M Tetrahedron Lett 1994, 35, 8019-8022 toluene, DMSO OH HO O OH O O 52% O Nicolaou, K C.; Zhong, Y.-L.; Baran, P S J Am Chem Soc 2000, 122, 7596-7597 Mark G Charest tetra-n-Propylammonium Perruthenate (TPAP): Pr4N+RuO4 – F • Reviews F OH Ley, S V.; Norman, J.; Griffith, W P.; Marsden, S P Synthesis 1994, 639-666 Griffith, W P.; Ley, S V Aldrichimica Acta 1990, 23, 13-19 TPAP, NMO, CH2Cl2 N H3C CHO H 3C Å MS, 23 °C – • Ruthenium tetroxide (RuO4, Ru(VIII)) and, to a lesser extent, the perruthenate ion (RuO4 , Ru(VII)) are powerful and rather nonselective oxidants N 79% • However, perruthenate salts with large organic counterions prove to be mild and selective oxidants in a variety of organic solvents Robol, J A.; Duncan, L A.; Pluscec, J.; Karanewsky, D S.; Gordon, E M.; Ciosek, C P.; Rich, L C.; Dehmel, V C.; Slusarchyk, D A.; Harrity, T W.; Obrien, K A J Med Chem 1991, 34, 2804-2815 • In conjunction with a stoichiometric oxidant such as N-methylmorpholine-N-oxide (NMO), TPAP oxidations are catalytic in ruthenium, and operate at room temperature The reagents are relatively non-toxic and non-hazardous • To achieve high catalytic turnovers, the addition of powdered molecular sieves (to remove both the water of crystallization of NMO and the water formed during the reaction) is essential H3C CH3 HCH3O CH3O OTBS TPAP, NMO, CH Cl 2 CH3O H H O O Å MS, 23 °C CH 3O CH3O The following oxidation state changes have been proposed to occur during the reaction: O • OH – Ru(VII) + 2e → Ru(V) TBSO 78% H3C CH3 HCH3O OTBS H H O O O O H O TBSO 2Ru(V) → Ru(VI) + Ru(IV) Julia-Lythgoe Olefination Ru(VI) + 2e– → Ru(IV) Griffith, W P.; Ley, S V.; Whitcombe, G P.; White, A D J Chem Soc., Chem Commun 1987, 1625-1627 • Examples O OH O O O N TEOC 23 °C H N TEOC °C H OCH3 H OTBS O O O CH3 N CH3 TESO H O CH O TPAP, NMO, CH2 Cl2 Å MS, 23 °C CH3 CH3 O H3C CH3 87% CH3 TESO O OCH3 H OTBS O O O OH O CH3 CH3 CH3 OH H 3C H 3C CH3 H3C CH3 HCH3O OTBS H H O O CH3 O CH3O O OH 29% 84% H3C CH3 HCH3O OTBS H H O O CH3O CH3O Bu4N+F–, THF TPAP, CH2Cl2 O CH3 CH3 (±)-indolizomycin CH3O2C Kim, G.; Chu-Moyer, M Y.; Danishefsky, S J.; Schulte, G K J Am Chem Soc 1993, 115, 30-39 H3 C CH H HO OAc H H O O O HO CH3 TPAP, NMO, CH2 Cl2 Å MS, 23 °C CH3 O OH H OH O CH3 H CH3 70% Ley, S V.; Smith, S C.; Woodward, P R Tetrahedron 1992, 48, 1145-1174 O CH3 n-Pr O bryostatin O Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S Angew Chem., Int Ed Engl 2000, 39, 2290-2294 OH O Mark G Charest N-Oxoammonium-Mediated Oxidation • Reviews • Examples de Nooy, A E J.; Besemer, A C.; van Bekkum, H Synthesis 1996, 1153-1174 H3 C Bobbitt, J M.; Flores, C L Heterocycles 1988, 24, 509-533 O Rozantsev, E G.; Sholle, V D Synthesis 1971, 401-414 CH3 N Boc OH TEMPO, NaOCl, NaBr EtOAc : toluene : H2O CH3 H3 C O N H (1 : : 0.15) • N-Oxoammonium salts are mild and selective oxidants for the conversion of primary and secondary alcohols to the corresponding carbonyl compounds These oxidants are unstable and are invariably generated in situ in a catalytic cycle using a stable, stoichiometric oxidant Boc O 90% Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gryza, H.; Prokopoxicz, P Tetrahedron 1998, 54, 6051-6064 X– R + N O R1 H OH + R2 O –HX R + R2 R3 R3 R1 N OH OH N-oxoammonium salt O OTBDPS • Three possible transition states have been proposed: R + N –O R R1 O H + N HO R2 R1 R N OTBDPS H3C CH3 R1 H3C CH3 98% O O B H R2 R1 H 23 °C R1 O TEMPO, BAIB, CH2Cl2 H R2 R1 O O Ganem, B J Org Chem 1975, 40, 1998-2000 O OH H CHO Jauch, J Angew Chem., Int Ed Engl 2000, 39, 2764-2765 Semmelhack, M F.; Schmid, C R.; Cortés, D A Tetrahedron Lett 1986, 27, 1119-1122 H H3C CH3 Bobbitt, J M.; Ma, Z J Org Chem 1991, 56, 6110-6114 kuehneromycin A • N-Oxoammonium salts may be formed in situ by the acid-promoted disproportionation of nitroxyl radicals Alternatively, oxidation of a nitroxyl radical or hydroxyl amine can generate the corresponding N-oxoammonium salt • Selective oxidation of allylic alcohols in the presence of sulfur and selenium has been demonstrated disproportionation R N O +H+ R1 –H R + R N OH R + N O R1 PhS TEMPO, BAIB, CH2Cl2 CH2OH PhS 23 °C CHO nitroxyl radical 70% Golubev, V A.; Sen', V D.; Kulyk, I V.; Aleksandrov, A L Bull Acad Sci USSR, Div Chem Sci 1975, 2119-2126 • 2,2,6,6-Tetramethyl-1-piperidinyloxyl (TEMPO) catalyzes the oxidation of alcohols to aldehydes and ketones in the presence of a variety of stoichiometric oxidants, including m-chloroperoxybenzoic acid (m-CPBA), sodium hypochlorite (NaOCl), [bis(acetoxy)-iodo]benzene (BAIB), sodium bromite (NaBrO2 ), and Oxone (2KHSO5•KHSO4•K2SO4 ) H3 C H3 C CH3 N O CH3 TEMPO H3 C CH2 OH SePh TEMPO, BAIB, CH2Cl2 23 °C H 3C CHO SePh 55% De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G J Org Chem 1997, 62, 6974-6977 Mark G Charest Manganese Dioxide: MnO2 TBSO H TBSO H SAr • Reviews Cahiez, G.; Alami, M In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S D.; Danheiser, R L., Eds., John Wiley and Sons: New York, 1999, p 231-236 HO HO H O H H OAc H SAr MnO2, acetone 76% HO O HO OAc H Fatiadi, A J Synthesis 1976, 65-104 Trost, B M.; Caldwell, C G.; Murayama, E.; Heissler, D J Org Chem 1983, 48, 3252-3265 Fatiadi, A J Synthesis 1976, 133-167 • A heterogenous suspension of active manganese dioxide in a neutral medium can selectively oxidize allylic, benzylic and other activated alcohols to the corresponding aldehyde or ketone • The structure and reactivity of active manganese dioxide depends on the method of preparation • Active manganese oxides are nonstoichiometric materials (in general MnOx, 1.93 < x < 2) consisting of Mn (II) and Mn (III) oxides and hydroxides, as well as hydrated MnO2 • Hydrogen-bond donor solvents and, to a lesser extent, polar solvents have been shown to exhibit a strong deactivating effect, perhaps due to competition with the substrate for the active MnO2 surface H3C CH3 CH3 H CH CH3 CH3 HO MnO2 OH acetone CH3 75% CH3 OH H CH CH3 CH3 H3C CH3 O • Examples CH3 H 3C CH3 CH3 CH3 H 3C CH3 OH CH3 CH3 H MnO2 CH3 OH O pet ether CH3 HO CH3 • Vinyl stannanes are tolerated Ball, S.; Goodwin, T W.; Morton, R A Biochem J 1948, 42, 516-523 CH3 CH2OH Bu3Sn CHO CH 2OH 61% CO2Et OHC CHO 74% CHO • Syn or anti vicinal diols are cleaved by MnO2 HO MnO2, CH2Cl2 CH3 CH2 Cl2 CH3 Bu3Sn Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A R Tetrahedron Lett 1998, 39, 5659-5662 DIBAL, C6H6 H3 C MnO2 89% Crombie, L.; Crossley, J J Chem Soc 1963, 4983-4984 EtO2C paracentrone Haugan, J A Tetrahedron Lett 1996, 37, 3887-3890 80% MnO2 CH3 CH3 OH O H3 C CH H3 C Cresp, T M.; Sondheimer, F J Am Chem Soc 1975, 97, 4412-4413 CH3 CH3 O MnO2 100% CH3 CH Ohloff, G.; Giersch, W Angew Chem., Int Ed Engl 1973, 12, 401-402 Mark G Charest Barium Manganate: BaMnO4 Oppenauer Oxidation • Review • Review Fatiadi, A J Synthesis 1987, 85-127 de Graauw, C F.; Peters, J A.; van Bekkum, H.; Huskens, J Synthesis 1994, 1007-1017 • Barium manganate and potassium manganate are deep green salts that can be used without prior activation for the oxidation of primary and secondary allylic and benzylic alcohols • A classic oxidation method achieved by heating the alcohol to be oxidized with a metal alkoxide in the presence of a carbonyl compound as a hydride acceptor • Effectively the reverse of the Meerwein-Pondorff-Verley Reduction • Examples R • The reaction is an equilibrium process and is believed to proceed through a cyclic transition state The use of easily reduced carbonyl compounds, such as quinone, helps drive the reaction in the desired direction R CH2 OH BaMnO4, CH2Cl2 R1 L R3 M R2 O L H O R4 CHO 40 °C CH 2OH CHO 66% R = CH3 Proposed Transition State Gilchrist, T L.; Tuddenham, D J Chem Soc., Chem Commun 1981, 657-658 Djerassi, C Org React 1951, 6, 207 Oppenauer, R V Rec Trav Chim Pays-Bas 1937, 56, 137-144 OH O H 3C H3 C OH • Examples OH BaMnO4 CH2OH CHO pivaldehyde, toluene 92% H3C CH3 H3 C CH3 mol % F5 H3 C Howell, S C.; Ley, S V.; Mahon, M J Chem Soc., Chem Commun 1981, 507-508 (S)-perillyl alcohol F5 B OH H3 C 99% CH3 H3 C H SEMO O CH2OH CH BaMnO4, CH2Cl2 H3 C H H 98% O CHO H Ishihara, K.; Kurihara, H.; Yamamoto, H J Org Chem 1997, 62, 5664-5665 • Highly reactive zirconium alkoxide catalysts undergo rapid ligand exchange and can be used in substoichiometric quantities SEMO CH3 CH3 cat Zr(O-t-Bu)4 , Cl3CHO, CH2Cl2 OH Burke, S D.; Piscopio, A D.; Kort, M E.; Matulenko, M A.; Parker, M H.; Armistead, D M.; Shankaran, K J Org Chem 1994, 59, 332-347 H3 C CH3 Å MS 86% O H3 C CH3 menthol Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A K.; Hayakawa, M Synthesis 1996, 1341-1344 Mark G Charest Chromium (VI) Oxidants Collins Reagent: CrO3 •pyr2 • Reviews Ley, S V.; Madin, A In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 251-289 Luzzio, F A Organic Reactions 1998, 53, 1-122 • The mechanism of chromic acid-mediated oxidation has been extensively studied and is commonly used as a model for other chromium-mediated oxidations • CrO3 •pyr2 is a hygroscopic red solid which is easily hydrolyzed to the yellow dipyridinium dichromate ([Cr2O7]–2 (pyrH+)2) • Typically, equiv of oxidant in a chlorinated solvent leads to rapid and clean oxidation of alcohols • Caution: Collins reagent should be prepared by the portionwise addition of solid CrO3 to pyridine Addition of pyridine to solid CrO3 can lead to a violent reaction Collins, J C.; Hess, W W.; Frank, F J Tetrahedron Lett 1968, 30, 3363-3366 R 2CHOH + HCrO4– R2 C O CrO3H H + H + R2CHOCrO3H + H2O R2C O Collins, J C.; Hess, W W.; Org Synth 1972, 52, 5-9 + HCrO3– + BH+ • In situ preparation of the reagent circumvents the difficulty and danger of preparing the pure complex OH O H3 C H3 C B CrO3, pyr, CH2Cl2 Holloway, F.; Cohen, M.; Westheimer, F H J Am Chem Soc 1951, 73, 65-68 H H3 C • A competing pathway involving free-radical intermediates has been identified 95% CH3 R2CHOH + Cr(IV) R2COH + Cr(III) + H+ Ratcliffe, R.; Rodehorst, R J Org Chem 1970, 35, 4000-4003 R2COH + Cr(VI) R2C=O + Cr(V) + H+ • Examples R2CHOH + Cr(V) R2C=O + Cr(III) + 2H + HO H3 C O Wiberg, K B.; Mukherjee, S K J Am Chem Soc 1973, 96, 1884-1888 • Fragmentation has been observed with substrates that can form stabilized radicals + OTBS OH Cr O O OCrO3H n-Bu4 N+F–, THF CH3 CH3 O O CH 2Cl2 81% overall O CH3 CH3 (±)-periplanone B Still, W C J Am Chem Soc 1979, 101, 2493-2495 O H2, 10% Pd-C OCH3 H Collins Reagent CH3O2C O CH3 CH3 83% O H Collins Reagent O Doyle, M.; Swedo, R J.; Rocek, J J Am Chem Soc 1973, 95, 8352-8357 O H O (CH3)3C• –Cr(III) • Tertiary allylic alcohols are known to undergo oxidative transposition CH Poos, G I.; Arth, G E.; Beyler, R E.; Sarett, L H J Am Chem Soc 1953, 75, 422-428 O PhCHO O 89% O Wiberg, K B.; Szeimies, G J Am Chem Soc 1973, 96, 1889-1892 H Ph C O Cr(IV) (CH 3)3C O H O H3 C CrO3, pyr H H H3 C CH2Cl2 CH3O2C OCH3 CHO CH3 CH3 90% overall (+)-monensin Collum, D B.; McDonald, J H.; Still, W C J Am Chem Soc 1980, 102, 2117-2120 Mark G Charest Potassium Permanganate: KMnO4 • In the following example, a number of other oxidants (including Jones reagent, NaOCl, and RuO2) failed • Review Fatiadi, A J Synthesis 1987, 85-127 KMnO4, NaH2PO4, • Potassium permanganate is a mild reagent for the oxidation of aldehydes to the corresponding carboxylic acids over a relatively large pH range Alcohols, alkenes, and other functional groups are also oxidized by potassium permanganate • Oxidation occurs through a coordinated permanganate intermediate by hydrogen atom-abstraction or hydride transfer t-BuOH, H2 O, °C TsN N Ts H H O H TsN N Ts CH3O (CH3)3SiCHN H O 80% H Freeman, F.; Lin, D K.; Moore, G R J Org Chem 1982, 47, 56-59 Rankin, K N.; Liu, Q.; Henrdy, J.; Yee, H.; Noureldin, N A.; Lee, D G Tetrahedron Lett 1998, 39, 1095-1098 • Potassium permanganate in the presence of tert-butyl alcohol and aqueous NaH2PO4 was shown to effectively oxidize the aldehyde in the following polyoxygenated substrate to the corresponding carboxylic acid whereas Jones reagent, RuCl3 (H2O)n-NaIO4, and silver oxide failed OCH3 BnO H3C O CH3 O H3C H H OTBS O N N HH Bergmeier, S C.; Seth, P P J Org Chem 1999, 64, 3237-3243 O O OTBS (–)-yohimbane KMnO4, NaH2PO4 Silver Oxide: Ag2O t-BuOH, H2O CHO CH3 • A classic method used to oxidize aldehydes to carboxylic acids 85% • Cis/trans isomerization can be a problem with unsaturated systems under the strongly basic reaction conditions employed OTBS OTBS OCH3 BnO OTBS • Examples CHO Abiko, A.; Roberts, J C.; Takemasa, T.; Masamune, S Tetrahedron Lett 1986, 27, 4537-4540 O H3C O CH3 O H3 C O O CO2 H CH3 CO2H Ag2O, NaOH HO HCl HO OCH3 OTBS OCH3 90-97% vanillic acid • Examples O CN CN O Pearl, I A Org Synth IV 1963, 972-978 KMnO4, NaH2 PO4 CHO N Boc t-BuOH, H2O, °C 93.5% H3C CO2H N Boc H3 C CH3 CH3 CHO O O NH N O °C CH3 CH3 CO2H 72% O Heffner, R J.; Jiang, J.; Joullié, M M J Am Chem Soc 1992, 114, 10181-10189 (CH3)2N Ag2O, CH3OH N H H3C (–)-nummularine F Sonawane, H R.; Sudrik, S G.; Jakkam, M M.; Ramani, A.; Chanda, B Synlett 1996, 175-176 CH3 Mark G Charest • Additional Examples • In the following example, all chromium-based oxidants failed to give the desired acid O S O S OCH3 CHO O OTBDPS H CH3O CO2H Ag2O, NaOH HCl OMEM O OTBDPS PDC, DMF OH CH3O O 100% OMEM Mazur, P.; Nakanishi, K J Org Chem 1992, 57, 1047-1051 81% O CO2H O N N • PDC can oxidize aldehydes to the corresponding methyl esters in the presence of methanol It appears that in certain cases, the oxidation of methanol by PDC is slow in comparison to the oxidation of the methyl hemiacetal Ovaska, T V.; Voynov, G H.; McNeil, N.; Hokkanen, J A Chem Lett 1997, 15-16 • Attempts to form the ethyl and isopropyl esters were less successful Pyridinium Dichromate: (pyrH+)2Cr2O7 • Note that in the following example sulfide oxidation did not occur • Review O Ley, S V.; Madin, A In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 251-289 O H O BnO BnO • PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume of water, adding pyridine and collecting the precipitated product SEt BnO CH3O BnO BnO PDC, DMF equiv CH 3OH O SEt BnO >71% • Non-conjugated aldehydes are readily oxidized to the corresponding carboxylic acids in good yields in DMF as solvent • Primary alcohols are oxidized to the corresponding carboxylic acids in good yields O'Connor, B.; Just, G Tetrahedron Lett 1987, 28, 3235-3236 Garegg, P J.; Olsson, L.; Oscarson, S J Org Chem 1995, 60, 2200-2204 Corey, E J.; Schmidt, G Tetrahedron Lett 1979, 20, 399-402 • PDC has also been used to oxidize alcohols to the corresponding carboxylic acids • In the following example, PDC was found to be effective while many other reagents led to oxidative C-C bond cleavage O O O PDC, DMF CHO AcO BnO CH3 CH3 CH3 H H CH3 H3 C H3C CH3 H3C CH3 TBSO TBSO OH H H PDC, DMF H3 C CO2H NH O O CH3 NH 91% O CO2CH AcO BnO CH3 CH3 CH3 CH 2N2 Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S Tetrahedron 1988, 44, 2149-2165 78% • However, a suspension of PDC in dichloromethane oxidizes alcohols to the corresponding other oxidants H3C CH3 O O AcO OH BnO CH3 CH3 CH3 aldehyde H3C CH3 [O] O Ph S O O AcO BnO CH3 CH3 O CH3 Heathcock, C H.; Young, S D.; Hagen, J P.; Pilli, R.; Badertscher, U J Org Chem 1985, 50, 2095-2105 S Ph S O PDC, CH2Cl2 CH2OH 68% S CHO Terpstra, J W.; van Leusen, A M J Org Chem 1986, 51, 230-238 Mark G Charest Aldehyde Ester Bromine • Review Corey-Gilman-Ganem Oxidation Palou, J Chem Soc Rev 1994, 357-361 • A convenient method to convert unsaturated aldehydes directly to the corresponding methyl esters • Bromine in alcoholic solvents is a convenient and inexpensive method for the direct conversion of aldehydes into ester derivatives • Cis/trans isomerization, a problem when other reagents such as basic silver oxide are employed, is avoided • Under the reaction conditions employed, secondary alcohols are not oxidized to the corresponding ketones • The aldehyde substrate is initially transformed into a cyanohydrin intermediate Subsequent oxidation of the cyanohydrin furnishes an acyl cyanide which is then trapped with methanol to give the desired methyl ester • Oxidation of a hemiacetal intermediate is proposed • Conjugate addition of cyanide ion can be problematic • A variety of esters can be prepared • Examples OH O O O • Examples OH O CH3 CH3 O MnO2, CH3CN O AcOH, CH3OH O O O CHO NOBn 81% • Olefins, benzylidine acetals and thioketals are incompatiable with the reaction conditions CH3 CH3 H OH H3C CHO H3C NOBn H OH O O O H Br2, H2O, alcohol H3C O NaHCO3 H3C O CO2R H R = Me, 94% R = Et, 91% R = i-Pr, 80% OCH3 O OH OH O Keck, G E.; Wager, T T.; Rodriquez, J F D J Am Chem Soc 1999, 121, 5176-5190 O OH NH O O H3C O Ph O Br2, H2O, CH3 OH CHO O NaHCO3 O CH3 H3C 89% Ph CO2CH3 O CH3 (–)-lycoricidine • In the following example, stepwise addition of reagents proved to be essential to achieve high yields H3C HO CH3 O CH3 CH3 CH 3CN, AcOH, H3C MnO2 Lichtenthaler, F W.; Jargils, P.; Lorenz, K Synthesis 1988, 790-792 CH3 TBSO CH3 OH, h CHO CH3 Williams, D R.; Klingler, F D.; Allen, E E.; Lichtenthaler, F W Tetrahedron Lett 1988, 29, 5087-5090 HO 97% Yamamoto, H.; Oritani, T Tetrahedron Lett 1995, 36, 5797-5800 O CH3 CO2CH3 (2Z, 4E)-xanthoxin TBSO O N CO2CH3 Br2 , H2O, CH3OH H NaHCO3 O N CO2CH3 OCH3 78% Herdeis, C.; Held, W A.; Kirfel, A.; Schwabenländer, F Tetrahedron 1996, 52, 6409-6420 Mark G Charest Ketone Ester • Examples Bayer-Villiger Oxidation Krow, G R In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 671-688 HO CH3 O CH3O • Reviews H CO2H CH3 m-CPBA, NaHCO3 O CH2Cl2 O O H HO HO H (±)-PGF2α 95% Krow, G R In Organic Reactions, Paquette, L A., Ed., John Wiley and Sons: New York, 1993, Vol 43, p 251-296 Corey, E J.; Weinshenker, N M.; Schaaf, T K.; Huber, W J Am Chem Soc 1969, 91, 5675-5677 • A classic method for the oxidative conversion of ketones into the corresponding esters or lactones by oxygen insertion into an acyl C-C bond • The migratory preference of alkyl groups has been suggested to reflect their electron-releasing ability and steric bulk n-C16 H33 • Typically, the order of migratory preference is tertiary > secondary > allyl > primary > methyl • The reactivity order of Bayer-Villiger oxidants parallels the acidity of the corresponding carboxylic acid (or alcohol): CF3CO3 H > p-nitroperbenzoic acid > m-CPBA = HCO3H > CH3 CO3H > HOOH > t-BuOOH COR' O O O R'CO3H O –R'CO2H R RL R RL O RL R O H RL = Large Group Criegee Intermediate effect OCH3 N O n-C16H33 m-CPBA, Li2CO3 CH2Cl2 O 99% O O O O O Miller, M.; Hegedus, L S J Org Chem 1993, 58, 6779-6785 • Selective Bayer-Villiger oxidation in the presence of unsaturated ketones and isolated olefins has been achieved CH3 H2O2 (anhydrous), BOMO O H3 C • Primary and secondary stereoelectronic effects in the Bayer-Villiger reaction have been demonstrated COR primary O effect O H O • Primary effect: antiperiplanar alignment of RL and σO-O RL R secondary • Secondary effect: antiperiplanar alignment of Olp and σ∗C-RL Ph OCH3 N Ph Ti(Oi-C3H7)4 , ether H DIEA, –30 °C H CH3 BOMO O H3 C O H H O >55% O CH3 AcO Still, W C.; Murata, S.; Revial, G.; Yoshihara, K J Am Chem Soc 1983, 105, 625-627 Proposed TS H3 C O H O O OH OH O eucannabinolide Crudden, C M.; Chen, A C.; Calhoun, L A Angew Chem., Int Ed Engl 2000, 39, 2852-2855 • Carbamates have been prepared in some cases • The Bayer-Villiger reaction occurs with retention of stereochemistry at the migrating center D O O O H D T CF3CO3 H Na2HPO4 H D O D T + H D Turner, R B J Am Chem Soc 1950, 72, 878-882 Gallagher, T F.; Kritchevsky, T H J Am Chem Soc 1950, 72, 882-885 O CH3 CH3 D N T N O N CH3 m-CPBA, CH3OH O 70% N O CH3 Azizian, J.; Mehrdad, M.; Jadid, K.; Sarrafi, Y Tetrahedron Lett 2000, 41, 5265-5268 Alcohol Acid OMOM OMOM AcHN RuO2 (H2O)2, NaIO4 Ruthenium Tetroxide: RuO4 • RuO4 is used to oxidize alcohols to the corresponding carboxylic acid It is a powerful oxidant that also attacks aromatic rings, olefins, diols, ethers, and many other functional groups • Catalytic procedures employ 1-5% of ruthenium metal and a stoichiometric oxidant, such as sodium periodate (NaIO4 ) • Sharpless has introduced the use of acetonitrile as solvent to improve catalyst turnover It is proposed to avoid the formation of insoluble Ru-carboxylate complexes and return the metal to the catalytic cycle OH N Boc CH3CN, CCl4, H2O 98% OH • In the following example, sodium periodate cleaves the 1,2-diol to an aldehyde, which is further oxidized to the corresponding carboxylic acid by RuO4 The amine is protonated and thereby protected from oxidation HO H Carlsen, P H J.; Katsuki, T.; Martin, V S.; Sharpless, K B J Org Chem 1981, 46, 3936-3938 RuCl3 -NaIO4, OH CH3N •HF • Examples O CH3 CN, CCl4 , H2O OBz OCH3 CH3N OBz (CH3)3SiCHN2 CO 2H CCl4, H2O N Boc O Clinch, K.; Vasella, A.; Schauer, R Tetrahedron Lett 1987, 28, 6425-6428 Djerassi, C.; Engle, R R J Am Chem Soc 1953, 75, 3838-3840 RuCl3 , NaOCl AcHN (S)-(+)-cocaine 78% overall Lee, J C.; Lee, K.; Cha, J K J Org Chem 2000, 65, 4773-4775 CO 2H 70% Molecular Oxygen • Molecular oxygen in the presence of a platinum catalyst is a classic method for the oxidation of primary alcohols to the corresponding carboxylic acids Sptzer, U A.; Lee, D G J Org Chem 1974, 39, 2468-2469 • Examples O RuO2 , NaIO4 CCl4, H2O O HO2C Bn CO2H Boc 68% Smith, A B., III; Scarborough, R M., Jr Synth Commun 1980, 10, 205-211 O O H R OBz R = CH3 60% HO NH OH Boc 65% NH • Primary alcohols are oxidized selectively in the presence of secondary alcohols H R CH3 CN, CCl4 , H2 O H HO R RuCl3-NaIO4 Bn Mehmandoust, M.; Petit, Y.; Larcheveque, M Tetrahedron Lett 1992, 33, 4313-4316 CH3 CH3 R OH O2/Pt OH O H OBz O (±)-scopadulcic acid B OH O O HO OCH3 O NHPf CH3 CH3 O2/Pt CH3I 85% Pf = 9-phenylfluorenyl Overman, L E.; Ricca, D J.; Tran, V D J Am Chem Soc 1997, 119, 12031-12040 O CH3O Park, K H.; Rapoport, H J Org Chem 1994, 59, 394-399 OCH3 O O NHPf CH3 CH3 Jones Oxidation N-Oxoammonium-Mediated Oxidation of Alcohols to Carboxylic Acids • A general method for the preparation of nucleoside 5'-carboxylates: • Jones reagent is a standard solution of chromic acid in aqueous sulfuric acid • Acetone is often benefical as a solvent and may function by reacting with any excess oxidant O HO • Isolated olefins usually not react, but some olefin isomerization may occur with unsaturated carbonyl compounds B • 1,2-diols and α-hydroxy ketones are susceptible to cleavage under the reaction conditions CH3CN, H2O O O H3C CH3 O O H3C B = A (90%) • Examples B O HO2C TEMPO, PhI(OAc)2 CH3 B = U (76%) O O CH3 CH3 Jones reagent B = C (72%, NaHCO3 added) CH3 CH3 B = G (75%, Na salt, NaHCO3 added) °C CH3 Epp, J B.; Widlanski, T S J Org Chem 1999, 64, 293-295 CH3 85% CO2H • A brief follow-up treatment with sodium chlorite was necessary to obtain complete oxidation to the bis-carboxylic acid in the following example OH Corey, E J.; Trybulski, E J.; Melvin, L S.; Nicolaou, K C.; Secrist, J A.; Lett, R.; Sheldrake, P W.; Flack, J R.; Brunelle, D J.; Haslanger, M F.; Kim, S.; Yoo, S J Am Chem Soc 1978, 100, 4618-4620 • Silyl ethers can be cleaved under the acidic conditions of the Jones oxidation OBn O CF3CONH O PivO OTBS BnO O CO2CH3 CO2H BnO Jones reagent O –10 → 23 °C O H N Ph H2, 20% Pd(OH)2-C, OBn NH O PhI(OAc)2, TEMPO CH3CN, NaHCO3, H2O O N CO2CH3 EtOAc, EtOH OPiv O O N 88-97% NaClO2, t-BuOH, H2O CH2OBn NaH2PO4, isopentene O 49% overall Evans, P A.; Murthy, V S.; Roseman, J D.; Rheingold, A L Angew Chem., Int Ed Engl 1999, 38, 3175-3177 HO2C • Ketones have been prepared efficiently by oxidation of the corresponding secondary alcohol OH O O H O O O O CH3 O Jones reagent H CH3 HCO2H O O O CO2t-Bu CH3 O H2N NH H PivO NH3, CH3OH O N O NH CH3 CO2H O CF3CONH OH O 96% overall HO2C O CO H O H H O O HO O H H2N 55 °C O CO H O H N Ph O NH OPiv O N NH 65% O O O O 4-desamino-4-oxo-ezomycin A2 (–)-CP-263,114 Waizumi, N.; Itoh, T.; Fukuyama, T J Am Chem Soc 2000, 122, 7825-7826 Knapp, S K.; Gore, V K Org Lett 2000, 2, 1391-1393 Mark G Charest α-Hydroxy Ketone Ketone • Enantioselective hydroxylation of prochiral ketones has been demonstrated O Davis Oxaziridine Ph • Reviews O NaHMDS CH3 H3C Davis, F A.; Chen, B Chem Rev 1992, 92, 919-934 OH Cl N O S OO Jones, A B In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 151-191 CH3 Ph CH3 Cl 61% (95% ee) • N-Sulfonyloxaziridines are prepared by the biphasic oxidation of the corresponding sulfonimine with m-CPBA or Oxone m-CPBA or Oxone RSO2N=CHR' RSO2 O N Davis, F A.; Chen, B Chem Rev 1992, 92, 919-934 R' O O THF, –10 °C O H Davis oxaziridine: R = R' = Ph O TBDPSO S H O KHMDS, HMPA, CH3 OTBS • Nucleophilic attack by enolates on the electrophilic oxaziridine oxygen furnishes α-hydroxy ketones –78 °C CH3 H3C • Examples O HO CH3 CO2 Et CH3 OH KHMDS, Davis O oxaziridine, THF taxol –78 → –20 °C HO 97% at O H O O HO H S O OCH3 NaHMDS CH3O O OCH3 H3C CH3 Cl CH3 OH (±)-breynolide O 57% conversion CH3 OTBS OH OH O Smith, A B., III; Empfield, J R.; Rivero, R A.; Vaccaro, H A.; Duan, J J.-W.; Sulikowski, M M J Am Chem Soc 1992, 114, 9419-9434 CH3 CO2Et H S 73% CH3 O H TBDPSO O S N OO • Potassium enolates are generally the most successful OH O CH3O OH OCH3 O OCH3 Wender, P A.; et al J Am Chem Soc 1997, 119, 2757-2758 H3C OTBS KHMDS, Davis oxaziridine, THF O H O –78 → –20 °C OTMS HO H3C Cl O S N OO OTBS OCH3 CH3O 50% (94% ee) taxol O H O H OTMS OH 68% CH3 O Grandi, M J D.; Coburn, C A.; Isaacs, R C A.; Danishefsky, S J J Org Chem 1993, 58 7728-7731 Davis, F A.; Chen, B J Org Chem 1993, 58, 1751-1753 O (+)-O-trimethylbrazilin Mark G Charest Rubottom Oxidation Molybdenum peroxy compounds: MoO5•pyr•HMPA O O O Mo • Epoxidation of a silyl enol ether and subsequent silyl migration furnishes α-hydroxylated ketones O O • Silyl migration via an oxacarbenium ion has been postulated ((CH3)2N)3P O N O • Oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) is commonly used to oxidize enolates to the corresponding hydroxylated compound SiR3 O SiR3 O R1 R1 SiR3 + O O – R2 OSiR3 R1 R1 R2 • It is proposed that nucleophilic attack of the enolate occurs at a peroxyl oxygen atom, leading to O-O bond cleavage O R2 R2 Rubottom, G M.; Vazquez, M A.; Pelegrina, D R Tetrahedron Lett 1974, 4319-4322 • β-Dicarbonyl compounds are not hydroxylated Brook, A G.; Macrae, D M J Organomet Chem 1974, 77, C19-C21 • Examples Hassner, A.; Reuss, R H.; Pinnick, H W J Org Chem 1975, 40, 3427-3429 H3C OHC OH O H3C CHO O LDA, THF, –78 °C O O TBDPSO O CH3 MoOPH O H3C CH3 91% H3C CH3 Et3SiO H3 O+ OHC OH H3 C O m-CPBA, NaHCO3 H CH3 O EtOAc HO 70% H 3C CH3 O TBDPSO CH3 H CH3 CH3 H3C CHO Jansen, B J M.; Sengers, H.; Bos, H.; de Goot, A J Org Chem 1988, 53, 855-859 Clive, D L J.; Zhang, C J Org Chem 1995, 60, 1413-1427 H3 C CH3 (±)-warburganal O OTBS O H3C H3C H CH3 LDA, THF, –78 °C H3C H H C O R1 R2 PMBO BOMO MoOPH, –40 °C CH3 O CH3S S CH3 CH3 R1 = H, R2 = OH 45% R1 = OH, R2 = H 25% O S dimethyldioxirane CH3 OTBS OTBS camphorsulfonic acid PMBO OTBS BOMO OTBS OTBS 79% CH3 dimethyldioxirane = CH3S Kato, N.; Okamoto, H.; Arita, H.; Imaoka, T.; Miyagawa, H.; Takeshita, H Synlett 1994, 337-339 O O CH3 CH3 Reddy, K K.; Saady, M.; Falck, J R J Org Chem 1995, 60, 3385-3390 Mark G Charest Diol Lactone • Lactols are oxidized selectively HO OH HO O • Review H3 C O H3C Fetizon's Reagent • Silver carbonate absorbed on Celite has been found to selectively oxidize primary diols to lactones H CH3 75-85 °C reflux • Platinum and oxygen have been used for the selective oxidation of primary alcohols to lactones H3C CH3 H Pt/O2 O acetone, water O CH3 HO H3C HO N HO H3C OH 96% O H3C O O >74% (±)-bukittinggine damsin O NaBrO2, CH2Cl2 HO MOMO OBn Ag2CO3 on Celite, C6 H6 CH3 OH CH3 CH3 CH3 O • TEMPO derivatives have been employed in the preparation of lactones • Epimerizable lactones have been prepared CH3 O O O Kretchmer, R A.; Thompson, W J J Am Chem Soc 1976, 98, 3379-3380 Heathcock, C H.; Stafford, J A.; Clark, D L J Org Chem 1992, 57, 2575-2585 OH CH3 H 3C 77% H3C Celite, C6H6 H Other Methods OH N O H 3C (+)-mevinolin Kakis, F J.; Fetizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T J Org Chem 1974, 39, 523-533 Ag2CO3 on H3C Celite, toluene Clive, D L J.; et al J Am Chem Soc 1990, 112, 3018-3028 Fetizon, M.; Golfier, M.; Mourgues, P Tetrahedron Lett 1972, 13, 4445-4448 OH O O Ag2CO3 on H3C Fetizon, M.; Golfier, M.; Louis, J.-M J Chem Soc., Chem Commun 1969, 1102-1118 CH3 O O Procter, G In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 312-318 CH3O MOMO OH OBn O NaHCO3 (aq) OBz H3C 80 °C O H3C O H CH3 CH3 CH3 H3 C 75% N O CH3 CH3 94% Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S J Org Chem 1990, 55, 462-466 O CH3O Coutts, S J.; Kallmerten, J Tetrahedron Lett 1990, 31, 4305-4308 O H 3C CH3O O • Ru complexes have also been employed N H CH3 OCH3 H C H3C O O CH3 CH3 (±)-macbecin I H3 C NH2 O RuH2(PPh3)4, OH OH PhCH=CHCOCH3 toluene 100% O H3C CH3 Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S J Org Chem 1986, 51, 2034-2039 Oxidative Cleavage of Diols TBS O Sodium periodate (NaIO4) TBS PhS O O HO O O • Reviews: Wee, A G.; Slobodian, J In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S D.; Danheiser, R L., Eds., John Wiley and Sons: New York, 1999, p 420–423 TBS PhS O HO (CH2)6OBn toluene, °C 20–45 O O H 90% (CH2)6OBn O O Pb(OAc)4 O OH HO PhS O O (CH2)6OBn • One of the most common reagents for cleaving 1,2-diols Tan, Q.; Danishefsky, S J Angew Chem Int Ed., Eng 2000, 39, 4509–4511 HO PMBO O OH NaIO4, NaOH, EtOH O H3C C8H15 O H3C PMBO H O → 25 °C, h >95% O • α-Hydroxyketones can be cleaved as well: O H3C C8H15 H3C CH3 OH O H3C Nicolaou, K C.; Zhong, Y.-L.; Baran, P S.; Jung, J.; Choi, H.-S.; Yoon, W H J Am Chem Soc 2002, 124, 2202–2211 H O Pb(OAc)4 O CH3 H3C CH3 CO2CH3 O O OCH3 H3C H3C O CH3OH–PhH (1:2) °C, 30 H3C CH CH3 CO2CH3 82% Lead Tetraacetate (Pb(OAc)4) Corey, E J.; Hong, B J Am Chem Soc 1994, 116, 3149–3150 • Reviews: Mihailovic, M L.; Cekovic, Z In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S D.; Danheiser, R L., Eds., John Wiley and Sons: New York, 1999, p 190–195 • Oxidative cyclizations sometimes occur This process likely proceeds by a free-radical mechanism involving homolytic cleavage of an RO–Pb bond Butler, R N In Synthetic Reagents, Pizey, J S., Ed., 1977, Vol 3, p 277–419 H3C OAc Rubottom, G M In Oxidation in Organic Chemistry, Trahanovsky, W S., Ed.; Organic Chemistry, A Series of Monographs, Vol 5, 1982, Part D, p 1–145 H3C • A common reagent for the cleavage of diols However, Pb(OAc)4 is a strong oxidant and can react with a variety of functional groups HO O HO OTBDPS CH3 Pb(OAc)4, PhH NaBH4, CH3OH H H Pb(OAc)4 H AcO • Examples: H H3C OAc HO CH3 PhH, 80 °C, 18 h 68% O AcO H H CH3 O HO H3C 84% (two steps) OH OTBDPS Bowers, A.; Denot, E.; Ibáñez, L C.; Cabezas, M A.; Ringold, H J J Org Chem 1962, 27, 1862–1867 Mihailovic, M L.; Cekovic, Z Synthesis 1970, 5, 209–224 • In addition, Pb(OAc)4 can oxygenate alkenes, oxidize allylic or benzylic C–H bonds, and has been used to introduce an acetate group α to a ketone Takao, K.; Watanabe, G.; Yasui, H.; Tadano, K Org Lett 2002, 4, 2941–2943 Landy Blasdel • Examples Oxidative Cleavage of Alkenes CH3 O CH3 OH Ozone H3C H • Reviews: Berglund, R A In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S D.; Danheiser, R L., Eds., John Wiley and Sons: New York, 1999, p 270–275 H3C OBn H O thiourea, –78 °C OTMS 65% Ph Lee, D G.; Chen, T In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 543–558, 574–578 OTBS OH O3, CH2Cl2–CH3OH (15:1), –78 °C H3C H OBn H O H3C O OTMS OTBS Wender, P A.; Jesudason, C D.; Nakahira, H.; Tamura, N.; Tebbe, A L.; Ueno, Y J Am Chem Soc 1997, 119, 12976–12977 Murray, R W In Techniques and Methods of Organic and Organometallic Chemistry , Denny, D B., Ed., Marcel Dekker: New York, 1969, Vol 1, p 1–32 • Forming the primary ozonide with sterically hindered olefins is difficult, and epoxides can be formed instead: Murray, R W Acc Chem Res 1968, 1, 313–320 CH3 CH3 O3, (ClH2C)2, °C • Ozone is the most common reagent for the oxidative cleavage of olefins H3C H3C • The reaction is carried out in two steps: (1) a stream of O3 in air or O2 is passed through the reaction solution at low temperature (0 °C to –78 °C) until excess O3 in solution is evident from its blue color Zn, HOAc, 75 °C H3C CH3 H3C H3C 71% O CH3 H3C Hochstetler, A R J Org Chem 1975, 40, 1536–1541 (2) reductive or oxidative work-up • Alkenes are ozonized more readily than alkynes: • Mechanism: R1 O O R3 O + O R2 R1 R4 R2 O R4 O O + R3 R4 R1 R2 R3 H3CO O O O H O3, CH2Cl2, CH3OH S(CH3)2 N R3 R4 O + R1 R2 R3 R4 H N OH NaBH4 reductant O O Ph molozonide O H3CO R1 O O R2 ozonide 92% OTBS OTBS • When a TMS-protected alkyne was used in the example above, the authors observed products arising from ozonolysis of the alkyne as well Banfi, L.; Guanti, G Tetrahedron Lett 2000, 41, 6523–6526 • Considered to be a concerted + cycloaddition of O3 onto the alkene • Because ozonides are known to be explosive, they are rarely isolated and typically are transformed directly to the desired carbonyl compounds • Ozonolysis of silyl enol ethers can afford carboxylic acids as products: OTMS • Dimethyl sulfide is the most commonly used reducing agent Others include I2, phosphine, thiourea, catalytic hydrogenation, tetracyanoethylene, Zn–HOAc, LiAlH4, and NaBH4 The latter two reductants afford alcohols as products • Oxidative workup provides either ketone or carboxylic acid products The most common oxidants are H2O2, AgO2, CrO3, KMnO4, or O2 • Alkenes with electron-donating substituents are cleaved more readily than those with electronwithdrawing substituents, see: Pryor, W A.; Giamalva, D.; Church, D F J Am Chem Soc 1985, 107, 2793–2797 H3C O3, CH3OH–CH2Cl2 (3:1), –78 °C OCH3 S(CH3)2, –78 °C → 23 °C 92% O CH3 OCH3 O HO H Padwa, A.; Brodney, M A.; Marino, J P., Jr.; Sheehan, S M J Org Chem 1997, 62, 78–87 Landy Blasdel Oxidative Cleavage of Alkenes OCH3 OCH3 OsO4, NaIO4 OCH3 OCH3 or steps Wee, A G.; Liu, B In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S D.; Danheiser, R L., Eds., John Wiley and Sons: New York, 1999, p 423–426 OsO4 (cat.), NMO, acetone–H2O–t-BuOH (4:2:1); NaIO4, THF–H2O (3:1) 89% • A two-step procedure involving initial dihydroxylation with OsO4 to form 1,2-diols, followed by cleavage with periodate • Frequently the two-step protocol is found to be superior to the one-pot procedure In the example shown, over-oxidation of the aldehyde was observed in the one-pot reaction • This procedure offers an alternative to ozonolysis, where it can be difficult to achieve selectivity for one olefin over another due to difficulties in adding precise quantities of ozone • Sharpless dihydroxylation conditions (AD-Mix α/β) can lead to enhanced selectivities cat OsO4, NMO THF, acetone, H2O, 23 °C CH3 CH3 PMBO H3C OH OH Bianchi, D A.; Kaufman, T S Can J Chem 2000, 78, 1165–1169 PMBO H3C NaIO4 THF, H2O 23 °C CH3 CH3 H OBn OsO4 (cat.), NaIO4, THF–H2O (3:1) 77% VanRheenen, V.; Kelly, R C.; Cha, D Y Tetrahedron Lett 1976, 1973 OPMB O NTs H3CO OBn Lee, D G.; Chen, T In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p.564 H3C NTs H3CO O H CH3 CH3 • An improved one-pot procedure uses 2,6-lutidine as a buffering agent: 93% (two steps) Roush, W R.; Bannister, T D.; Wendt, M D.; Jablonowski, J A.; Sheidt, K A J Org Chem 2002, 67, 4275–4283 CH3 OPMB CH3 OTBS • The procedure is most often performed in two steps, but the transformation is sometimes accomplished in one: dioxane–H2O (3:1) CH3 OPMB H O CH3 OTBS CH3 OPMB + HO O 90% CH3 OTBS 6% H3CO H3CO H3CO OsO4, NaIO4, 2,6-lutidine • Ozonolysis of this substrate resulted in PMB removal OsO4, NaIO4 O H H3CO N THF, H2O, 23 °C 62% conversion H H3CO N H THF 47% (two steps) H O CH3MgI O N • The authors found that without base, the α-hydroxyketone was formed in ~30% yield Using pyridine as base, epimerization of the aldehyde product was observed H3CO O H3C OH Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z Org Lett 2004, 6, 3217–3219 • Notice that in the example above, the less-hindered olefin was cleaved selectively Maurer, P J.; Rapoport, H J Med Chem 1987, 30, 2016–2026 Landy Blasdel Oxidative Cleavage of Alkenes Ketone α,β-Unsaturated Ketone RuO4 See also: o-Iodobenzoic Acid (IBX) earlier in handout • References: Martín, V S.; Palazón, J M.; Rodríguez, C M In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S D.; Danheiser, R L., Eds., John Wiley and Sons: New York, 1999, p 346–353 Lee, D G.; Chen, T In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p.564–571, 587 Ito, Y.; Hirao, T.; Saegusa, T J Org Chem 1978, 43, 1011–1013 • A two-step procedure involving silyl enol ether formation, followed by treatment with Pd(II) • RuO4 is a powerful oxidant that is nevertheless useful in many synthetic transformations • RuO4 has been used to cleave alkenes where other oxidation methods (e.g., O3, OsO4/NaIO4) have failed • Solvent mixtures of CCl4, H2O and CH3CN have been determined to be optimal CH3CN is a good ligand for low valent Ru, and it prevents formation of stable Ru(II/III)–carboxylate complexes which remove Ru from the catalytic cycle See: Carlsen, P H J.; Katsuki, T.; Martin, V S.; Sharpless, K B J Org Chem 1981, 46, 3936–3938 • RuO4 will also oxidize alcohols (to ketones), ethers (to lactones or to two carboxylic acids), diols (to two carboxylic acids), alkynes (to 1,2-diketones), and aryl rings (to carboxylic acid products) It will also remove aryl and alkyne groups, leaving carboxylic acids CH3 O CH3 CH3 CH3 RuO2, NaIO4 CCl4–CH3CN–H2O (1:1:1.5), 23 °C, h 68% CH3 CH3 O β-elim O H Porth, S.; Bats, J W.; Trauner, D.; Giester, G.; Mulzer, J Angew Chem Int Ed 1999, 38, 2015–2016 O PMBO OTIPS THF, –78 °C O CCl4–CH3CN–H2O CH3 O CH Mehta, G.; Krishnamurthy, N J Chem Soc., Chem Commun 1986, 1319–1321 H TMSO PMBO O PMBO OTIPS Pd(dba)2•CHCl3 (5 mol%), diallyl carbonate, CH3CN H CH3 H LiTMP, TMS-Cl H RuO2, NaIO4 82% PdII Ito, Y.; Hirao, T.; Saegusa, T J Org Chem 1978, 43, 1011–1013 O H CH3 O PdII CH3 H3C Myers, A G.; Condroski, K R J Am Chem Soc 1995, 117, 3057–3083 H3C PdII OTMS Pd(OAc)2 TMS-OAc Pd(0) H O OTMS TMS-Cl CH3 H H CH3 • The reaction can be performed with stoichiometric Pd(II), or can be rendered catalytic if a terminal oxidant, such as O2 or p-benzoquinone, is used • Mechanism: • Reaction conditions are relatively mild and usual involving generation of RuO4 in situ from RuO2•2H2O or RuCl3•H2O and an oxidant, such as NaIO4 H Buckle, D R.; Pinto, I L In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 119–149 Saegusa Oxidation Djerassi, C.; Engle, R R J Am Chem Soc 1953, 75, 3838–3840 H3C General Reference: OTIPS 90% (two steps) • In this case, diallyl carbonate is used as a terminal oxidant Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M J Am Chem Soc 2002, 124, 14546–14547 Landy Blasdel Ketone α,β-Unsaturated Ketone • Examples: LDA, THF –78 °C O Selenation/Oxidation/Elimination Buckle, D R.; Pinto, I L In Comprehensive Organic Synthesis, Trost, B M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol 7, p 128–135 Sharpless, K B.; Young, M W.; Lauer, R F Tetrahedron Lett 1973, 14, 1979–1982 Sharpless, K B.; Lauer, R F.; Teranishi, A Y J Am Chem Soc 1973, 95, 6137–6139 Ph O SePh Ph PhSeBr O H2O2, pyridine Ph CH2Cl2–H2O, 25 °C, 30 66% • Generating the enolate under kinetic conditions can allow for formation of the less-substituted double bond Reich, H J.; Renga, J M.; Reich, I L J Am Chem Soc 1975, 97, 5434–5447 Reich, H J.; Reich, I L.; Renga, J M J Am Chem Soc 1973, 95, 5813–5815 Reich, H J.; Renga, J M.; Reich, I L J Am Chem Soc 1975, 97, 5434–5447 O O LDA; PhSeCl • PhSeBr and PhSeCl can be used to selenate enolates of ketones, esters, lactones and lactams H3C H3C • PhSeSePh can be used as well, but ketone enolates are unreactive H3C H3C H2O2 CH3 CH3 64% • Aldehydes can be selenated via: – enol ethers: Nicolaou, K C.; Magolda, R L.; Sipio, W J Synthesis 1979, 982–984 Annis, G D.; Paquette, L A J Am Chem Soc 1982, 104, 4504–4506 – enamines: Williams, D R.; Nishitani, K Tetrahedron Lett 1980, 21, 4417–4420 H – one-step procedure with PhSeSePh, SeO2, and a catalytic amount of H2SO4: Miyoshi, N.; Yamamoto, T.; Kambe, N.; Murai, S.; Sonoda, N Tetrahedron Lett 1982, 23, 4813–4816 • Mechanism: base O PhSeBr H CH cis-fused H H O OH + LDA, THF, HMPA, –78 °C PhSeSePh H CH trans-fused 85% O Ph O H • Elimination is syn-specific, see: Jones, D N.; Mundy, D.; Whitehouse, R D J Chem Soc., Chem Commun 1970, 86–87 ~ 100% 96% • Electron withdrawing groups on the phenyl ring facilitate the elimination step, which can be difficult with primary or β- or γ-branched selenoxides: Sharpless, K B.; Young, M W J Org Chem 1975, 40, 947–948 + : SePh CH3 H2O2, THF, H2O, AcOH, °C H O O H 10 H H2O2, THF, H2O, AcOH, °C H O O • Common oxidants include H2O2, O3, and NaIO4 O O SePh CH3 H Se H O O [O] Se O O SePh Ph O O LDA, THF, HMPA, –78 °C PhSeSePh 88% O H O 90 CH3 O O H • The example above illustrates how the stereospecificity (syn) of the elimination can be used to achieve selectivity in olefin formation Grieco, P A.; Miyashita, M J Org Chem 1974, 39, 120–122 Landy Blasdel Alkene Allylic alcohol • Examples: CH3 CH3 OH SeO2 O • References CH3 O Bulman Page, P C.; McCarthy, T J In Comprehensive Organic Synthesis; Trost, B M.; Fleming, I., Eds.; Pergamon Press: New York, 1991, Vol 7, p 84–91, 108–110 OH CH3 O H3C Rabjohn, N In Organic Reactions, 1976,Vol 24, p 261–415 • Although the reaction can be performed with stoichiometric SeO2, catalytic methods employing a stoichiometric oxidant (e.g., t-BuOOH) are more frequently used O CH3 O Se O OH Se OH CH3 O H3C O CH3 H3C H OH H 99% TBSO CH3 HO H3C H3C SeO2, t-BuOOH CH2Cl2 °C H [2,3]-sigmatropic rearrangement H3C 95% H3C H3C ene reaction OH CH3 O dioxane, 23 °C O CH3 H3C H3C • Mechanism: CH3 SeO2, t-BuOOH Xia, W J.; Li, D R.; Shi, L.; Tu, Y Q Tetrahedron Lett 2002, 43, 627–630 • General method for oxidizing alkenes to allylic alcohols H3C O H TBSO Yu, W.; Jin, Z J Am Chem Soc 2001, 123, 3369–3370 Se O CH3 Br O H3C CH3 H CbzN Singleton, D A.; Hang, C J Org Chem 2000, 65, 7554–7560 H CH3 SeO2, t-BuOOH CH2Cl2, °C → 23 °C Selectivity: (a) oxidation typically occurs at the more highly substituted terminus of the alkene (b) the order of reactivity of C–H bonds is CH2 > CH3 > CH [rule (a) takes precedence over rule (b)] (c) when the double bond is within a ring, oxidation occurs within the ring (4) gem-dimethyl trisubstituted alkenes form (E)-α-hydroxy alkenes stereoselectively Hoekstra, W J In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S D.; Danheiser, R L., Eds., John Wiley and Sons: New York, 1999, p 358–359 Bhalerao, U T.; Rapoport, H J Am Chem Soc 1971, 93, 4835–4840 Br O HO O + H CbzN H 14% CH3 O O Br Br O H + H CbzN H H 77% CH3 CbzN H CH3 trace Muratake, H.; Natsume, M Angew Chem Int Ed., Eng 2004, 43, 4646–4649 Landy Blasdel