Myers Oxidation Chem 115 General Introductory References Alkane R-CH3 March, J. In Advanced Organic Chemistry, John Wiley and Sons: New York, 1992, p. 1158! organoboranes RCH BR ' organometallics in general RCH M (M = Li, MgX, ZnX...) 1238. 2 2 2 Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry Part B, Plenum Press: New York, organosilanes RCH2SiR3' 1990, p. 615!664. Carruthers, W. In Some Modern Methods of Organic Synthesis 3rd Ed., Cambridge University Press: Cambridge, UK, 1987, p. 344!410. Alcohol R-CH2OH (R-CH2X ) Oxidation States of Organic Functional Groups alkyl halide X = halide alkane sulfonate X = OSO2R' alkyl azide X = N3 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 alkylamine X = NR'2 alkylthio ether X = SR' alkyl ether X = OR' 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: Aldehyde (Ketone) R-CHO (RCOR') OH O O NR'' OR'' or R''O OH N 2 N R R'(H) R R' R H hemiketal (hemiacetal) hydrazone oxime R R' R R' alcohol ketone aldehyde R R' R''O OR''' R''O NR2''' Dimethylsulfoxide-Mediated Oxidations Oppenauer Oxidation ketal (acetal) geminal dihalide RCX2R' aminal R R' R R' Dess-Martin Periodinane (DMP) Chromium (VI) Oxidants o-Iodoxybenzoic Acid (IBX) Sodium Hypochlorite R''O R'' N tetra-n-Propylammonium Perruthenate (TPAP) N-Bromosuccinimide (NBS) enol ether (enamine) dithiane S S imine R R' N-Oxoammonium-Mediated Oxidation Bromine R R' R R' Manganese Dioxide Cerium (IV) Oxidants Barium Manganate Carboxylic Acid R-CO H 2 O O O O O O O O R''' ester RCO2R' amide R N ketene R H R OH R H R OR' R R' R OR' O R'' R R' aldehyde acid aldehyde ester ketone ester thioester R SR' trihalomethyl RCX3 nitrile R C N O Sodium Chlorite Manganese Dioxide!NaCN!CH3OH Bayer-Villiger Oxidation O R' Silver Oxide Bromine hydroxamic acid orthoester (OBO ester shown) R N R O CH3 Potassium Permanganate OH O Pyridinium Dichromate (PDC) O O O OH O Carbonic Acid Ester ROH + CO2 (ROCO2H) R' R' R OH R OH R R HO O O O S OH carbamate R'' alkyl haloformate xanthate n n RO RO SR' alcohol acid ketone "-hydroxy diol lactone RO N X ketone R' O Ruthenium Tetroxide Form enolate; Davis Oxaziridine Fetizon's Reagent isocyanate R N C O carbodiimide R N C N R' urea R R' N N O2/Pt Form enolate; MoOPH O2/Pt Jones Oxidation Form silyl enol ether; mCPBA N-Oxoammonium- R'' R''' Mediated Oxidation Mark G. Charest, Jonathan William Medley 1 Myers Oxidation Chem 115 • Pummerer Rearrangement OH O O or HO CH3 OH HO CH3 OH R R'(H) R R' R H H3C H H3C H alcohol ketone aldehyde CF3CO2Ac, Ac2O B 2,6-lutidine H C O O H C O O H H Dimethylsulfoxide-Mediated Oxidations 3 H 3 H • Reviews S Ph –BH+ O + S Ph – Lee, T. V. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon O –RCO2 O Press: New York, 1991, Vol. 7, p. 291!303. R HO CH3 OH HO CH3 OH Tidwell, T. T. Synthesis 1990, 857!870. H3C H H3C H AcO– Tidwell, T. T. Organic Reactions 1990, 39, 297!557. O O H3C O OAc >60% H3C O General Mechanism H H S Ph S Ph • Dimethylsulfoxide (DMSO) can be activated by reaction with a variety of electrophilic reagents, + including oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide, acetic anhydride, and N- chlorosuccinimide. Schreiber, S. L.; Satake, K. J. Am. Chem. Soc. 1984, 106, 4186!4188. • The mechanism can be considered generally as shown, where the initial step involves Swern Procedure electrophilic (E+) attack on the sulfoxide oxygen atom. • Typically, 2 equivalents of DMSO are activated with oxalyl chloride in dichloromethane at or • Subsequent nucleophilic attack of an alcohol substrate on the activated sulfoxonium intermediate below –60 °C. leads to alkoxysulfonium salt formation. This intermediate breaks down under basic conditions to furnish the carbonyl compound and dimethyl sulfide. • 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. (CH3)2S O + E (CH3)2S X Huang, S. L.; Mancuso, A. J.; Swern, D. J. Org. Chem. 1978, 43, 2480!2482. + + –H H H CH3 – RCH2OH + (CH3)2S X S+ + X HO TBSO 1. TBSCl, Im, DMAP, CH2Cl2 R O CH3 HO TBSO 2. 10% Pd/C, AcOH, EtOAc – H CH H O O B H 2 3. (COCl)2, DMSO; Et3N S+ + (CH3)2S R O CH R O –78 " –50 °C 3 OBn O H alkoxysulfonium ylide 66% Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew. • Methylthiomethyl (MTM) ether formation can occur as a side reaction, by nucleophilic attack of Chem., Int. Ed. Engl. 1998, 37, 2354!2359. an alcohol on methyl(methylene)sulfonium cations generated from the dissociation of sulfonium CH CH ylide intermediates present in the reaction mixture. This type of transformation is related to the N 3 N 3 Pummerer Rearrangement. N N (COCl)2, DMSO; O Et N, –78 °C O CHO OH 3 + + RO S ROH H2C S CH3 CH + 3 O N Cl 99% O N Cl –H 100-g scale Fang, F. G.; Bankston, D. D.; Huie, E. M.; Johnson, M. R.; Kang, K.-C.; LeHoullier, C. S.; Lewis, G. Fenselau, A. H.; Moffatt, J. G. J. Am. Chem. Soc. 1966, 88, 1762!1765. C.; Lovelace, T. C.; Lowery, M. W.; McDougald, D. L.; Meetholz, C. A.; Partridge, J. J.; Sharp, M. J.; Xie, S. Tetrahedron 1997, 53, 10953!10970. Mark G. Charest, Jonathan William Medley 2 Myers Oxidation Chem 115 CH O CH CH3O CH3 3 3 OTBDPS OTBDPS DMSO, EDC O HO O O CH O HO CH3O O 3 OH O TFA, pyr OR1 OR1 CH BzO OCH BzO OCH CH3 3 3 3 (COCl)2, DMSO; O O N N FK506 94% CH CH3 Et N, –78 °C 3 H 3 H EDC = (CH3)2N (CH2)3 N C N CH2CH3 • HCl O 80% O OR O OR O H H OCH Hanessian, S.; Lavallee, P. Can. J. Chem. 1981, 59, 870!877. OCH3 R O 3 R1O 1 CH CH CH3 CH3 3 3 OR OR Parikh-Doering Procedure R = TIPS, R = TBS 1 • Sulfur trioxide-pyridine is used to activate DMSO. • Ease of workup and at-or-near ambient reaction temperatures make the method attractive for large- Jones, T. K.; Reamer, R. A.; Desmond, R.; Mills, S. G. J. Am. Chem. Soc. 1990, 112, 2998!3017. scale reactions. Pfitzner-Moffatt Procedure 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. Ph Ph SO3•pyr, Et3N, DMSO • Typically, oxidations are carried out with an excess of DCC at or near 23 °C. OH 8 " 23 °C O Bn2N Bn2N • Separation of the by-product dicyclohexylurea and MTM ether formation can limit usefulness. H 99.9% ee >95% 99.9% ee • Alternative carbodiimides that yield water-soluble by-products (e.g., 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC)) can simplify workup procedures. 190-kg scale Liu, C.; Ng, J. S.; Behling, J. R.; Yen, C. H.; Campbell, A. L.; Fuzail, K. S.; Yonan, E. E.; Mehrotra, D. Cl Ot-Bu DMSO, DCC Cl Ot-Bu V. Org. Process Res. Dev. 1997, 1, 45!54. OH TFA, pyr O H H SO3•pyr, Et3N, H H 87% O O H DMSO, CH2Cl2 H HO 0 23 °C Corey, E. J.; Kim, C. U.; Misco, P. F. Org. Synth. Coll. Vol. VI 1988, 220!222. O Br " OHC O Br H H H H 99% CH H H H 3 CHO CHO OH DMSO, DCC H H + O CO CH TFA, pyr CO CH CO CH 2 3 2 3 2 3 H O CH3 O CH3 O CH3 Et O Br S 9 : 1 #,$ : %,# S S H H Br H3C CH3 H3C CH3 H3C CH3 (–)-kumausallene Semmelhack, M. F.; Yamashita, A.; Tomesch, J. C.; Hirotsu, K. J. Am. Chem. Soc. 1978, 100, Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. Engl. 1999, 5565 5576. 38, 3175!3177. ! Mark G. Charest, Jonathan William Medley 3 Myers Oxidation Chem 115 Dess-Martin Periodinane (DMP) • Examples • DMP has found wide utility in the preparation of sensitive, highly functionalized molecules. H3C H3C H3C CH3 CH3 CH3 • DMP oxidations are characterized by short reaction times, use of a single equivalent of oxidant, H C 1. DIBAL H C H C 3 H H 3 H H 3 H H and can be moderated with regard to acidity by the incorporation of additives such as pyridine. H3C H3C H3C 2. DMP O TBSO O TBSO O HO AcO • DMP and its precurser o-iodoxybenzoic acid (IBX) are potentially heat and shock sensitive and should be handled with appropriate care. I 89% overall I (–)-7-deacetoxy- Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1983, 48, 4155!4156. PivO O H alcyonin acetate Boeckman, R. K.; Shao, P.; Mulins, J. J. Org. Synth. 1999, 77, 141!152.