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文档下载 免费文档下载 http://doc.xuehai.net/ 中国科学技术大学有机合成讲义-2 本文档下载自文档下载网,内容可能不完整,您可以复制以下网址继续阅读或下载: http://doc.xuehai.net/bc956988fd90b0ed78020c467.html Oxidation 1. Oxidation of Alcohols 1.1. Metal Based Reagents Chromium Reagents - Cr(VI) based, exact structure depends on solvent, concentration and pH. - The mechanism of chromic acid-mediated oxidation has been extensively studied and is commonly used as a model for other chromium-mediated oxidations. H CrOR2C=OR2CHOH R2 H2Cr(III)H2CrO3 文档下载 免费文档下载 http://doc.xuehai.net/ Holloway, F.; Cohen, M.; Westheimer, F. H. J. Am. Chem. Soc. 1951, 73, 65. Collins Reagent: CrO3?2Py - CrO3?2Py is a hygroscopic red solid, useful for the oxidation of acid-sensitive compounds. Typically, 6 eq. 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. In situ preparation of the cirhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlcumvents and danger of preparing the pure complex. OH(70-84%)CH2Cl2 Collins, J. C. et al. Org. Synth. 1972, 52, 5. Jones Oxidation reagent the difficulty 文档下载 免费文档下载 http://doc.xuehai.net/ - Jones reagent is a standard solution of chromic acid in aqueous sulfuric acid, which generates a mixture of H2Cr2O7 and H2CrO4. Acetone is often beneficial as a solvent and serves to protect substrate from over oxidation. Isolated olefins usually do not react, but some olefin isomerization may occur with unsaturated carbonyl compounds. 1,2-diols and α-hydroxy ketones are susceptible to cleavage under the reaction conditions. It is not a good method for acid-sensitive groups and compounds. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422. OH Me3Si JACS 1982, 104, 5558 1) Jonesreagento2) CH2N2, ether, 0 C Me3Si 75% (two steps)://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlar OCH3 2Me Jones reagent o2Me 文档下载 免费文档下载 http://doc.xuehai.net/ Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. 1999,38, 3175. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825. Pyridinium Chlorochromate (PCC) Preparation: CrO3 (1 eq.) 6 M HCl (1 eq.) pyridine (1 eq.) ClCrO3 Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 26, 2647. - PCC is an air-stable yellow solid which is not very hygroscopic. Typically, alcohols are oxidized rapidly and cleanly by 1.5 equivalents of PCC as a solution in 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 (Antonakis, K.; Egron, M. J.; Herscovici, J. J.http://doc.xuehai.net/bc956988fd90b0ed78020c467.html Chem. Soc., Perkin Trans. I 1982, 1967). 文档下载 免费文档下载 http://doc.xuehai.net/ Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871. SPh OH Me3Si Me3Si JACS 1982, 104, 5558 - The slight acidity of PCC may cause side reactions, but can also be taken advantage of in PCC oxidation reactions. Corey, E. J. Tetrahedron Lett. 1978, 2461. - In the oxidation of 3°, allylic alcohols, [3,3]-sigmatropic rearrangement may occur. OH Srikrishna, A.; Gharpure, S. J.; Kumar, P. P. Tetrahedron Lett. 2000, 41, 3177. Pyridinium Dichromate (PDC) ClCrO3 文档下载 免费文档下载 http://doc.xuehai.net/ PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume of water, adding pyridine and collecting the precipitatedproduct (Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20 , 399). - PDC is not as acidic as PCC, can selectively alcohohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlls to oxidize aldehyde 1° or carboxylic acid depending on the solvent Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetrahedron 1988, 44, 2149. CH2OH S CHO CrO3-H5IO6 - It is catalytic in CrO3 (1-2%, industrial scale chromium-based oxidations), can oxidize 1° alcohols to carboxylic acids with no racemization, and oxidize 2° 文档下载 免费文档下载 http://doc.xuehai.net/ alcohols to ketones. Terpstra, J. W.; van Leusen, A. M. J. Org. Chem. 1986, 51, 230. Zhao, Reider Tetrahedron Lett. 1998, 39, 5323. Manganese Reagents Manganese Dioxide (MnO2 ) - 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. mahttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlnganese nonstoichiometric materials (in general MnOx, 1.93 MnO, CHCl62% J. Chem. Soc. 1953, 2189; JACS 1955, 77, 4145. Bu3 oxides Active are 文档下载 免费文档下载 http://doc.xuehai.net/ Ruthenium Reagents Ruthenium Tetroxide: RuO4 - RuO4 is used to oxidize alcohols to the corresponding carboxylic acids. It is a powerful oxidant that also attacks aromatic rings, olefins, diols, ethers, and many other functional groups. Catalytic Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659. procedures employ 1-5% of ruthenium metal and a stoichiometric oxidant, such as sodium periodate (NaIO4) (Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838). 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 (Carlsen, http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlP. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936). RuO2(H2O)2, NaIO4 BocClinch, K.; Vasella, A.; Schauer, R. TetrahedronLett.1987,28,6425. RuO4, NaIO4CCl , HO, MeCN, rt 文档下载 免费文档下载 http://doc.xuehai.net/ 75% 96% ee RuO4, NaIO4 CCl , HO, MeCN, rt 92% 94% ee Carlsen, P. H. J.; Katsuki, T.; Martin,V.S.;Sharpless,K.B.J.Org.Chem. 1981, 46, 3936. Tetra-n-propylammonium Perruthenate (TPAP, n-Pr4N RuO4-) - Review: Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639-666. - 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 http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmloxidant 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. 文档下载 免费文档下载 http://doc.xuehai.net/ TPAP, NMO, CHCl22o Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290. Silver Reagent Fétizon's Reagent - Silver carbonate absorbed on Celite has been found to selectively oxidize primary diols to lactones [a) Fétizon, M.; Golfier, M.; Louis, J.-M. J. Chem. Soc., Chem. Commun. 1969, 1102. b) Fétizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 13, 4445. c) Kakis, F. J.; Fétizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T. Jhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html. Org. Chem. 1974, 39, 523.] Lange, G. L.; Lee, M. J. Org. Chem. 1987, 52 , 325. Ag2CO3 on Celite, o 文档下载 免费文档下载 http://doc.xuehai.net/ Coutts, S. J.; Kallmerten, J. Tetrahedron Lett. 1990, 31, 4305. Ag2CO3 on Celite, tolueneo Clive, D. L. J.; et al. J. Am. Chem. Soc. 1990, 112, 3018. O2/Pt - Molecular oxygen in the presence of a platinum catalyst is a classic method for the oxidation of primary alcohols to the corresponding carboxylic acids. Mehmandoust, M.; Petit, Y.; Larcheveque, M. Tetrahedron Lett. 1992, 33, 4313. 1. O2/Pt Pf = 9-phenylfluorenyl Park, K. H.; Rapoport, H. J. Org. Chem. 1994, 59, 394. Pt/O2 文档下载 免费文档下载 http://doc.xuehai.net/ Kretchmer, R. A.; Thompson, W. J. J. Am. Chem. Soc. 1976, 98, 3379. Oppenauer Oxidation - Review: de Graauw, C. F.; Peters, J. A.; van Bekkum, H.;http://doc.xuehai.net/bc956988fd90b0ed78020c467.html Huskens, J. Synthesis 1994, 1007-1017. - 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 (the reverse of the Meerwein-Pondorff-Verley 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. 6F5 (2 mol%) 99% Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62 , 5664. Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A. K.; Hayakawa, M. 文档下载 免费文档下载 http://doc.xuehai.net/ Synthesis 1996, 1341. 1.2. Non-Metal Based Reagents Dimethylsulfoxide-Mediated Oxidations - Review: Tidwell, T. T. Organic Reactions 1990, 39, 297-557. - Dimethylsulfoxide (DMSO) can be activated http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlby reaction with a variety of electrophilic reagents, including oxalyl chloride, dicyclohexylcarbodiimide, sulfur trioxide, acetic anhydride, and N-chlorosuccinimide. O NuE-O E =(CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F3CSO2H,PO5, H3PO4, Br2 Nu =R-OH, Ph-OH, R-NH2, RC=NOH, enols Swern Oxidation - 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 文档下载 免费文档下载 http://doc.xuehai.net/ aldehydes. Careful optimization of the reaction temperature is often necessary (Huang, S. L.; Mancuso, A. J.; Swern, D. J. Org. Chem. 1978, 43, 2480). SMe2 B: CO2 1. TBSCl, Im, DMAP, CH2Cl2 23-78 to -50 oC;http://doc.xuehai.net/bc956988fd90b0ed78020c467.html 66% Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew.Chem., Int. Ed . 1998, 37, 2354. (COCl)2, DMSO,o Smith, A. B., III; Wan, Z. J. Org. Chem.2000,65,3738. Moffatt Oxidation - The first reported DMSO-based oxidation procedure (Pfitzner, K. E.; Moffatt, J. 文档下载 免费文档下载 http://doc.xuehai.net/ G. J. Am. Chem. Soc. 1965, 87, 5661). Dicyclohexylcarbodiimide (DCC) functions as the electrophilic activating agent in conjunction with a Br?nsted acid promoter. Typically, oxidations are carried out with an excess of DCC at or near 23 °C. Separation of the by-product dicyclohexylurea and MTM ether formation can limit usefulness. Alternative carbodiimides that yield water-soluble by-products (e.g., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)) can simplify workup procedures. O- RR' Cl OH OBu-t DMSOhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html, DCCCl O OBu-t Corey, E. J.; Kim, C. U.; Misco, P. F. Org. Synth. Coll. Vol. VI 1988, 220. HO 文档下载 免费文档下载 http://doc.xuehai.net/ OBzOMe OBzOMe DMSO, EDC,Hanessian, S.; Lavallee, P. Can. J. Chem. 1981, 59, 870. Parikh-Doering Oxidation - Sulfur trioxide-pyridine is used to activate DMSO. Ease of work-up 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). 3 JOC, 1998, 63, 6597. Dess-Martin Periodinane (DMP) - 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) arehttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html potentially heat and shock sensitive and should be handled with appropriate care. See: a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1983, 48, 4155. b) Boeckman, R. K.; Shao, P.; Mulins, J. J. Org. Synth. 1999, 77, 141. IBX DMP 文档下载 免费文档下载 http://doc.xuehai.net/ Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. Danishefsky, S. J.; Mantlo, N. B.; Yamashita, D. S.; Schulte, G. K. J. Am. Chem. Soc. 1988,110, 6890. DMP, PhCO2H, Ph3P=CHCO2Me, MeO2C CO2Me Barrett, A. G. M.; Hamprecht, D.; Ohkubo,M.J.Org.Chem.1997,62,9376. o-Iodoxybenzoic Acid (IBX) - A simpler preparation of IBX has recently been reported. IBX Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537. 文档下载 免费文档下载 http://doc.xuehai.net/ H IBX (2.0 eq.)H OTIPS Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, http://doc.xuehai.net/bc956988fd90b0ed78020c467.html7596. N-Oxoammonium-Mediated Oxidation - Review: de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153-1174. - 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. XRR'RR'N-oxoammonium salt - 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 (Golubev, V. A.; Sen', V. D.; Kulyk, I. V.; 文档下载 免费文档下载 http://doc.xuehai.net/ Aleksandrov, A. L. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1975, 2119). nitroxyl radical . . TEMPO OH 2,2,6,6-Tetramhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlethyl-1-piperi dinyloxyl (TEMPO) catalyzes the oxidation of alcohols to aldehydes and ketones in the presence of a m-chloroperoxy-benzoic variety acid [bis(acetoxy)iodo]benzene of stoichiometric (m-CPBA), (BAIB), sodium sodium bromite oxidants, including hypochlorite (NaOCl), (NaBrO2), and Oxone (2KHSO5?KHSO4?K2SO4). TEMPO, NaOCl, NaBr EtOAc:toluene:HO (1:1:0.15) BocCHO Jurczak, J.; Gryko, D.; Kobrzycka, E.;Gryza,H.;Prokopoxicz,P.Tetrahedron 1998, 54 , 6051. 文档下载 免费文档下载 http://doc.xuehai.net/ TEMPO, BAIB,CH2Cl2,De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974. - 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 of N-chlorosuccinimide (NCS) as a stoichiometric oxidant and tetrabutylammonium chloride (Bu4N Cl–). TEMPO, NCS, Bu4N Cl-8 http://doc.xuehai.net/bc956988fd90b0ed78020c467.html. 882% 8 OH Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem. 1996, 61, 7452. HO OH TEMPO, NaBrO2, Inokuchi, Nishiyama,T.;Torii,S.J.Org.Chem.1990,55,462. Sodium Hypochlorite: NaOCl T.; Matsumoto, S.; 文档下载 免费文档下载 http://doc.xuehai.net/ - 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. 1. NaOCl,AcOHKende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431.n-C9 Winter, E.; Hoppe, D. Tetrahedron 1998, 54, 10329. N-Bromosuccinimide (NBS) or Bromine - NBS in aqueous dimethoxyethane selectively oxidizes secondary alcohols in the presence of primary alcohols. Corey, E. J.; Ishiguro, M. Tetrahedrohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlnLett.1979,20,2745 . 2. Oxidation of Aldehydes Sodium Chlorite: NaClO2 - Sodium chlorite is a mild, inexpensive, and selective reagent for the oxidation of aldehydes to the corresponding carboxylic acids under ambient reaction conditions. 文档下载 免费文档下载 http://doc.xuehai.net/ 2-methyl-2-butene is often incorporated as an additive and has been proposed to function as a scavenger of any electrophilic chlorine species generated in the reaction. O CHO TBSO NaClO2, NaH2PO4,2TBSO O COOH Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A. J. Org. Chem. 1999, 64, 2616. 1. TPAP, NMO, CH2Cl2n-Bu3n-Bu32. NaClO2, NaH2PO4 2-methyl-2-butene, Nicolaou, K. C.; Ohshima, T.; Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. J. Chem. Soc.,Chem. Commun. 1999, 809. 文档下载 免费文档下载 http://doc.xuehai.net/ Potassihttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlum Permanganate: KMnO4 - Review: Fatiadi, A. J. Synthesis 1987, 85-127. - 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. Potassium permanganate in the presence of t-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. KMnO4 , NaH2PO4 t-BuOH, HO; 85% Abiko, A.; Roberts, J. C.; Takemasa,T.;Masamune,S.TetrahedronLett.1986, 27, 4537. 1. KMnO4, NaH2PO4,t-BuOH, H2O, 0 oC A number of ohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlther oxidants (including Jones reagent, NaOCl, and RuO2) failed. 文档下载 免费文档下载 http://doc.xuehai.net/ Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237. Silver Oxide: Ag2O - A classic method used to oxidize aldehydes to carboxylic acids. Cis/trans isomerization can be a problem with unsaturated systems under the strongly basic reaction conditions employed. CHO HO Pearl, I. A. Org. Synth. Coll. IV 1963, 972. o Sonawane, H. R.; Sudrik, S. G.; Jakkam, M. M.; Ramani, A.; Chanda, B. Synlett. 1996 , 175. Pyridinium Dichromate - Non-conjugated aldehydes are readily oxidized to the corresponding carboxylic acids in good yields in DMF as solvent. 1. PDC, DMF 2Me 文档下载 免费文档下载 http://doc.xuehai.net/ Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem. 1985,50, 2095. MeO OTBDPS CHO OTBDPS COOH://doc.xuehai.net/bc956988fd90b0ed78020c467.html Mazur, P.; Nakanishi, K. J. Org. Chem. 1992, 57, 1047. Corey-Gilman-Ganem Oxidation - A convenient method to convert unsaturated aldehydes directly to the corresponding methyl esters. Cis/trans 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. MnO2, NaCN 文档下载 免费文档下载 http://doc.xuehai.net/ Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121 , 5176. - In the following example, stepwise addition of reagents proved to be essential to achieve high yields. 1. NaCN, AcOH, 2 2Me 97% (2Z, 4E)-xanthoxin Yamamotohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html, H.; Oritani, T. Tetrahedron Lett. 1995, 36, 5797. Bromine - Review: Palou, J. Chem. Soc. Rev. 1994, 357-361. - 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. 文档下载 免费文档下载 http://doc.xuehai.net/ Br2, H2O, MeOH2Me Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W. Tetrahedron Lett. 1988, 29, 5087.2Br2, H2 O, MeOH2 Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenl?nder, F. Tetrahedron 1996, 52, 6409. 3. Oxidations of Ketones Bayer-Villiger Oxidation - Reviews: Krow, G. R.http://doc.xuehai.net/bc956988fd90b0ed78020c467.html In Organic Reactions, Paquette, L. A., Ed., John Wiley and Sons: New York, 1993, Vol. 43, p. 251-296. - 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. 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): CF3CO3H > p-nitroperbenzoic acid > 文档下载 免费文档下载 http://doc.xuehai.net/ m-CPBA = HCO3H > CH3CO3H > HOOH > t-BuOOH. OR R' R"COH ROOR' Primary and secondary stereoelectroniceffectsintheBayer-Villiger reactionhave been demonstrated. effect secondary effect -Primary effecthttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html: antiperiplanar alignment of RL and σO-O -Secondary effect: antiperiplanar alignment of Olp and σ?C-RL 文档下载 免费文档下载 http://doc.xuehai.net/ Proposed TS Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. 2000, 39, 2852. - The Bayer-Villiger reaction occurs with retention of stereochemistry at the migrating center. m-CPBA, NaHCO3MeOMeOCorey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675. n-C16HMiller, M.; Hegedus, L. S. J. Org. Chem. 1993, 58, 6779. m-CPBA, Li2CO3n-C16H Meinwald J. Am. Chem. Soc. 1960, 82, 5235. exo face. Sauers J. Am. Chem. Soc.1961, 83, 2759. 4. Oxidative Cleavage of Carbon-Carbon Multiple Bonds Potassium Permanganate RRR R'R' 文档下载 免费文档下载 http://doc.xuehai.net/ R' 2H Midland, M. M.; Lee, P. E. J. Org. Chem. 1981, 46, 3933. ://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlrRuthenium Reagents 2Bn .Bn 42HOOC 2BnBnTakano, S.; Kamikubo, T.; Moriya, M.;Ogasawara,K.Synthesis1994,601. Ozonolysis - Ozone is best viewed as a resonance species with four contributors. Mechanism, Review: Criegee Angew. Chem., Int. Ed. 1975 , 14, 745. 文档下载 免费文档下载 http://doc.xuehai.net/ 1,3-dipolar1,3-dipolar carbonyl oxide (Criegee zwitterion) ozonide in situ Note: Ozonide explosive when isolated or concentrated. - Ozone (O3) exhibits very light blue color, and ozonolysis completes when color persists. The reaction rate for this electrophilic reagent is: electron-rich > neutral > electron-deficient olefin. 1) O3Smith, III, A. B.; Wan, Z. J. Org. Chem. 2000, 65, 3738. 5. Epoxidation of Olefins - The value of epoxides in synthesis is due largely to their opening by nucleophilic reagents, which alhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlmost always takes place with high stereoselectivity, and often with high regioselectivity. The range of effective nucleophiles is wide, and it is rare for epoxide opening to be complicated by elimination. Peroxide Induced Epoxidations - Peroxides used for epoxidation: hydrogen peroxide (H2O2), alkyl hydroperoxide and 文档下载 免费文档下载 http://doc.xuehai.net/ peroxyacids. - The oxidizing power of the epoxide is inversely related to the pKa of the conjugate acid generated by loss of the leaving group (ROH): ROOH ROH 5.1. Peracid Epoxidation -Antiperiplanar arrangement of O-O bond and reacting alkene, n-π* stabilization by reacting lone pair in plane. The synchronicity of epoxide C-O bond formation and an overall transitionstate structure postulated using ab initio calculations and experimental kinetic isotope effects(Singleton, Houk J. Am. Chem. Soc. 1997, 119, 3385). R://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlpar Reaction rates are governed by olefinnucleophilicity.Theratesofepoxidation of the indicatedolefin relative to cyclohexene are provided below: OHOAcOH 文档下载 免费文档下载 http://doc.xuehai.net/ krel 1.000.550.0460.42 The isolated double bond is more reactive toward electrophiles than the double bond having ahydroxy group at the allylic carbon because the interaction between the π-orbital of the doublebond and the σ*-orbital of the C-O bond lowers the level of HOMO of the allylic alcohol. White, J. D.; Somers, T. C. J. Am. Chem. Soc. 1994, 116, 9912. R =HR =Me 99% 1?% Less hindered face of olefin is epoxidized. Brown J. Am. Chem. Soc. 1970, 92, 6914. - Review: Hoveyda, Evans, Fu Chem. Rev. 1993, 93, 1307 Ganem TL 1985, 26, 4895 文档下载 免费文档下载 http://doc.xuehai.net/ Transition State Hydrogen Bonding HR ethersOK 7http://doc.xuehai.net/bc956988fd90b0ed78020c467.html5% ds 95:5 JOC 1987, 52, 5127. 5.2. Alkyl hydroperoxide - Reviews: Org. React. 1996, 48, 1-299. - Catalysts: VO(acac)2, Mo(CO)6, Ti(OiPr)4; Oxidants: t-BuOOH, PhC(CH3)2OOH; Regioselective epoxidation of allylic and homo-allylic alcohols; Will not epoxidize isolated double bonds; Epoxidation occurs stereoselectively with respect to the alcohol. Bu 文档下载 免费文档下载 http://doc.xuehai.net/ Relative Rates and DiastereoselectivitiesfortheEpoxidationofCyclohexene Derivatives SubstratemCPBAMo(CO)6VO(acac)21.00 1.00 1.00 The relative rate data OH apply only to a given 0.55 (92:8) 4.5 (98:2)>200 (98:2) column. Values in parenthesis OAc refer to the ratio of 0.046 (37:63) 0.07 (40:60)-- syn:anti epoxide.JACS 1973, 95, 6136 OH 文档下载 免费文档下载 http://doc.xuehai.net/ 0.42 (60:40) 11.0 (98:2)10.0 (98:2) ://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlar JACS 1973, 95, 6136 threo erythro Reagentthreo:erythro MCPBA 95:5TBHP/VO(acac)271:29 X TBHP/Mo(CO)684:16 YHMeHH HX =H, V, Mo ...HY =RCO, tBu HMe 文档下载 免费文档下载 http://doc.xuehai.net/ XMajor TS MinorTS RCO3H Transition States and BiteAngles 1,3-allylic strain! o Major TS H Minor TS ~120V Transition States and Bite Angleso Major TS threo erythro 文档下载 免费文档下载 http://doc.xuehai.net/ ReagentmCPBATBHP/VO(acac)2TBHP/Mo(CO)6TBHP/Al(OtBu)3threo:erythro95:5 86:14 95:5 100:0 threo erythro ReagentmCPBATBHP/VO(acac)2TBHP/Mo(CO)6TBHP/Al(OtBu)3threo:erythro 64:36 29:71 62:38 64:36 TL 1980, 21, 1657, 4843; TL 1979, 20,4733 http://doc.xuehai.net/bc956988fd90b0ed78020c467.html 文档下载 免费文档下载 http://doc.xuehai.net/ 1978, 19, 2869. Homoallylic Alcohols (Mihelich, JACS 1981,103,7690) n-C5HTBHP n-C 5H n-C5H 104:1 dr OHMe n-C5H11 Me TBHP n-C5H11 OHMe Me n-C5H1:70 dr 文档下载 免费文档下载 http://doc.xuehai.net/ Bishomoallylic Alcohols (JACS, 1978,100,2933.) 1) VO(acac)22) HOAc 5.3 Sharpless Asymmetric Epoxidation (AE) - K. Barry Sharpless received the 2001 Nobel Prize in chemistry for his contribution to catalytic asymmetric epoxidation and dihydroxylation of olefins. - Reviews: a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158. b) Katsuki, T. Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. II, chap. 18, p 621-648. D-(-) dialkyl tartrate[Ohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html] RO22RR =Me, D-(-)-dimethyl tartrate (DMT)R =Et, D-(-)-diethyl tartrate (DET) R =iPr, D-(-)-diisopropyltartrate(DIPT) RO2C CO2RR =Me, L-( )-DMTR =Et, L-( )-DETR=iPr,L-( )-DIPT 文档下载 免费文档下载 http://doc.xuehai.net/ - Typical "catalytic conditions" use 5-10 mol% of chiral tartrate and Ti(OiPr)4 (ratio 1.1:1 to 1.2:1). The addition of molecular sieves is to "soak" up any water. The sense of enantioface selection is determined by the chirality of the dialkyl tartrate used. High enantioselectivity has been obtained for a wide substrate scope. The empirical model provided by Sharpless enables one to predict the stereochemical outcome of the epoxide formed in the reaction. R1R2R3 Me CH2OBn CH2CH=CHC5H11HHHHMeMeHnBuHHBnHHHMe Tartrate( )-DIPT(-)-DET( )-DMT( )-DIPT( )-DET( )-DIPT( )-DET(-)-DET( )-DET(-)-DE T( )-DET( )-DET(-)-DIPT( )-DIPT(-)-DET( )-DET( )-DET( )-DIPT ://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlaree?92949294>91959595>958994909 4>95>959394 HHHHHHHMe iPrH CH=CH2H 文档下载 免费文档下载 http://doc.xuehai.net/ (CH2)3CH=CH2H CH2CH2OTBSH CH2CH=CHMe2H HMe HMe MeMe CH2OBnMe PhMe HCH2OBn cyclohexylH R1, R2 =(CH2)2R1, R2 =(CH2)10 Complied from a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158. b) Katsuki, T. Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. II, chap. 18, p 621-648. 文档下载 免费文档下载 http://doc.xuehai.net/ -Sharpless AE is sensitive to the geometry of olefins and the position of substituents. t 75%, 25% eet52%, 95% ee 42%, 85% ee t - Proposed transition state of Sharpless AE Burns, C. J.; Martin, C. A.; Sharpless, K. B. J. 54,http://doc.xuehai.net/bc956988fd90b0ed78020c467.html 2826. - Reagent control overrides substrate control: TBHP, Ti(Oi Pr), (single isomer) BnO Org. Chem. 1989, 文档下载 免费文档下载 http://doc.xuehai.net/ OH 222CH2ClBnO OH(single isomer) TL, 1995, 36, 8247 (-)-DET; 91% 2CH2Cl - Alkenyldimethylsilanols, which are structurally similar to allylic alcohols, are amenable to epoxidation. n-C8H90% eeChan, T. H., Chen, L. M., Wang, D., Li,L.H.Can.J.Chem.1993,60,60. - The reactivity of the substrate bearing an electronwithdrawing group is low and the epoxidation of this class of substrates requires a long reaction time or an elevated reaction temperature. 91% ee TL,1991,32,2045. 文档下载 免费文档下载 http://doc.xuehai.net/ - Nucleophilic functional groups such as hydroxy, carbonyl, and carbamate groups often react in situ with the produced epoxides intramolecularly to products.://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlar , 49 , 2582.TBHP, Ti(OiPr)4, Me OHO PMBO2TL, 1987, 28, 3605. JOC, 1982, 47, 5384. PMBO2TBHP, Ti(OiPr)4, - Derivatize or open the epoxy alcohol in situ water soluble TBHP, Ti(OiPr)(-)-DIPT OH 4, give the cyclized 文档下载 免费文档下载 http://doc.xuehai.net/ 88-92% ee m-NO 2C6H4SO2Cl JOC, 1986, 51, 3710; JOC, 1986, 51, 5413 Kinetic Resolution of Racemic Allylic Alcohols - Sharpless AE of an allylic alcohol which carry a substituent at C-1 is also a most useful procedure. The above Sharpless empirical model for the predication of stereochemical outcome can also be applied. (-)-tartrate R2R 1 RRR3 OHRR( )-tartrate 文档下载 免费文档下载 http://doc.xuehai.net/ (-)-tartrate ( )-tartrate RRRR - The enantiomeric excess of both product epoxide and unreacted allylic alcohol will dehttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlpend on the relative rate of epoxidation and on the extent of reaction, which will depend on the structure of the substrate. krel =104 krel =700T, 1988, 44, 4073 krel =20 JACS, 1981, 103, 6237 JACS, 1988, 110,2978 , 52, 2187 文档下载 免费文档下载 http://doc.xuehai.net/ OH The enantiomeric excess of the major anti-epoxy alcohol was observed to increase (84, 93, >97% ee) as the reaction time was extended (3, 24, 140 h) (Schreiber, JACS, 1987, 109, 1525). -Nucleophilic opening of terminalepoxidesisoftenhighlyregioselective. LiAlH4 (CH 3)2CuLi Behrens, C. H.; Sharpless, K. B.;AldrichimicaActa,1983,16,67. MeS I-, BuLi, THF, -10~25 oC99% BnOBnO OH Crimmins, M. JACS, 2004, 126, 10264. 文档下载 免费文档下载 http://doc.xuehai.net/ Ti(OPr-i)4 can catalyze the additionofnucleophilestoC-3of2,3-epoxyalcohols: ://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlparO OH C-3 C-2 NuEt2NHEt2NHi-PrOHi-PrOH(allyl)2NHallyl alcoholNH4OBzNH4OAcKCN Ti(OiPr)4 (eq.) 01.501.51.51.51.51.51.7 C-3:C-23.7 : 120 : 1--100 : 1100 : 1100 : 1100 : 165 : 12.4 : 1 yield (%)4900889690747376 RiPr)3 Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557. - The heat stability, reactivity, and easy preparation of dimethylsulfoxonium methylide allows convenient access to 2,3-disubstituted THF rings in a highly diastereoselective and 文档下载 免费文档下载 http://doc.xuehai.net/ enantioselective fashion. The stereochemistry that is set by the asymmetric epoxidation is translated fully to the final product. O HO 97% eeOBn MeS OI-, NaH, DMSO, 85 oC 78% 97% ee - Catalytic and regio- and stereoselective rearrangement of epoxides to aldehydes via alkyl migration can http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlusing be realized a high-valent metalloporphyrin complex, Cr(TPP)OTf (chromium(III) tetraphenylporphyrin triflate), in low catalyst loading (1-20 mol %). The yield and regio- and stereoselectivity of the catalytic process are generally good to high. Cr(TPP)OTf: 文档下载 免费文档下载 http://doc.xuehai.net/ chromium(III) tetraphenylporphyrin triflate 99%, 96% ee Suda, K. JACS, 2004, 126, 9554. - Internal nucleophiles may be used to open 2,3-epoxy alcohols. 1) PhNCO, TEA511Corey, E. J.; Hopkins, P. B.; Munroe, J. E.; Marfat, A.; Hashimoto, S.-I. J. Am. Chem. Soc.1980, 102, 7986. (HCHO)n, Cs2CO3o Ph OH McCombie, S. W.; Metz, W. A. TetrahedronLett.1987,28,383. - In the sharpless AE, the substrate must possess a group capable of coordinating to the catalyst, almost always a hydroxyl group, and without such a group asymmetric epoxidation does not take http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlHowever, place. highly enantioselctive asymmetric epoxidation of “isolated” alkenes lacking this type of coordination site can be realized by other catalytic systems, the most useful of which are the Jacobsen asymmetric epoxidation and the Shi asymmetric epoxidation. In 文档下载 免费文档下载 http://doc.xuehai.net/ addition, the catalysts for both Jacobsen AE and Shi AE are also readily available. (S,S)-1 (4 mol %)CH2Cl2, 4 C t R77%, 92% ee 2Et Ph 2Et15%, 78% ee (S,S)- 1 52%, 97% ee t-Bu Bu-t 96%, 97% ee63%, 94% ee79%, 84% eett(R,R)-1 Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063. -Selectivity is determined through nonbonded interactions. 文档下载 免费文档下载 http://doc.xuehai.net/ -In general, R is aryl, alkenyl or alkynyl and R' is a bulky group. -cis-Disubstituted conjugated olefins are epoxidizedwith high levels of enantioselectivityhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html. -trans-Disubstituted olefins react more slowly and with diminished selectivity. -Terminal olefins are poor substrates. -Addition of substoichiometric amounts of 4-phenylpyridine N-oxide improves both catalyst selectivity and turnover numbers. Related: Jacobsen Catalytic Asymmetric Epoxide-Opening Reactions Hydrolytic Kinetic Resolution (HKR): (S,S)-1 RMe CH2Cl(CH2)3MePhCH=CH2 krel>400502902030 Bu-t 文档下载 免费文档下载 http://doc.xuehai.net/ tM =Co(OAc)(OH2) (S,S)-1 t-BuMBu-t R H2O (0.50-0.70 eq.) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936-938. Kinetic Resolution of Terminal EpoxideswithTrimethylsilylAzide: (R,R)-1R CH2ClCH2CNCH(OEt)2CH2Ph 3 t-Bu Bu-t R 文档下载 免费文档下载 http://doc.xuehai.net/ TMSN3(0.50 eq.) krelhttp://doc.xuehai.net/bc956988fd90b0ed78020c467.html100454471 O3tt(R,R)-1 Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420. 5.5. Shi Asymmetric Epoxidation - Review: "Organocatalytic Asymmetric Epoxidation of Olefins by Chiral Ketones", Shi, Y.Acc. Chem. Res. 2004, 37, 488-496. R 1 R2R3 ketone 1, oxone, 23R2 - Ketone 1 can be readily prepared from D-fructose by ketalization (acetone, HClO4, 0 °C, 53%) and oxidation (PCC, 23 °C, 93%). L-Fructose can be prepared in 3 steps from readily available L-sorbose. Ketone 1 can be used catalytically (20–30 mol %). Oxone (a commercial mixture of 2:1:1 KHSO5:KHSO4:K2SO4) is used as the stoichiometric 文档下载 免费文档下载 http://doc.xuehai.net/ oxidant but H2O2/CH3CN can also be used (peroxyimidic acid is the proposed oxidant). Generally, the optimum pH for dioxirane epoxidation is 7–8. At higher pH, Oxone tends to decompose. However, at pH 7–8 the Shi http://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlcatalyst decomposes due to the competing Baeyer-Villiger reaction. By increasing the pH to 10.5 (by addition of K2CO3), the amount of ketone used can be reduced to a catalytic amount (30 mol %) and the amount of Oxone can be reduced to a stoichiometric amount (1.5 equiv), suggesting that at this pH the ketone is sufficiently reactive to compete with Oxone decomposition. Dimethoxymethane (DMM) and CH3CN (2:1 v/v) solvent mixtures generally provide higher ee's. Reaction temperatures range from –10 to 20 °C. Catalytic Cycle: 2 R R2 R1 SO4 2- 文档下载 免费文档下载 http://doc.xuehai.net/ Competing spiro and planar transition states for the epoxidation with ketone 1 23 spiroplanar It is proposed that the Shi epoxidation proceeds through a dioxirane intermediate and a spirotransition state and that a so-called planar transition state is a main comphttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmleting pathway. The spiro transition state is believed to be electronically favored as a result of a stabilizing interaction between an oxygen lone pair of the dioxirane with the π* orbital of the olefin. Epoxidation Examples of Trans andTrisubstitutedOlefinswithKetone1 95% ee 94% ee 98% ee 6H13-n 94% ee95% ee 文档下载 免费文档下载 http://doc.xuehai.net/ 93% 92% ee 92% ee 94% ee94% ee n98% ee97% ee91% ee 94% ee 94% ee Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.Warren, J.D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099. Epoxidation Examples of ConjugatedDienesandEnyneswithKetone1 96% ee 89% ee 95% ee 93% ee 文档下载 免费文档下载 http://doc.xuehai.net/ Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948.Wang,http://doc.xuehai.net/bc956988fd90b0ed78020c467.html Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646. Epoxidation of α,β-Unsaturated EsterswithKetone2 The original Shi catalyst decomposes (via the Baeyer-Villiger pathway)faster than it reacts with electron-deficient α,β-unsaturated esters. A second-generation catalyst, incorporating electronwithdrawing acetate groups, Baeyer-Villiger decomposition. 2EtCO2Et Ph CO2 Et 96% ee96% ee93% ee 94% ee 82% ee Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792. Epoxidation of Cis and Terminal OlefinswithKetone3 slows the 文档下载 免费文档下载 http://doc.xuehai.net/ 91% ee 97% ee 85% ee Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551.Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929. Tian, H.; She, X.; Yu, H.; Shu, L.; Shi,Y.J.Org.Chem.2002,67,2435. http://doc.xuehai.net/bc956988fd90b0ed78020c467.html2O, Morimoto, Y.; Nishikawa, Y.; Takaishi, M. J. Am. Chem. Soc. 2005, 127, 5806. 6. Dihydroxylation of Olefins 6.1 Dihydroxylation with Osmium Tetroxide - Criegee found that osmium tetroxide (OsO4) is reduced by alkenes to give the cis-diol (Justus Liebigs Ann. Chem. 1936, 522, 75). O OOs (VIII) 文档下载 免费文档下载 http://doc.xuehai.net/ - Osmium Tetroxide is an electrophilic reagent, and it behaves as a large reagent. Ligands such as pyridine accelerate the osmylation of olefins (Criegee, R.; Marchand, B.; Wannowius, H. Liebigs Ann. Chem. 1942, 550, 99). Strained, unhindered olefins react faster than unstrained, sterically hindered olefins. Electron-rich olefins react faster than electron-deficient olefins. The dihydroxylation with osmium tetroxide is diastereospecific, with attack on the C=C from the least hindered face. But OsO4 is expensive, volatile, and toxic. Various improvements include: 1) only catalythttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlic amount of OsO4 used; 2) use of an equivalent osmium salt [K2OsO2(OH)4]. Turnover is achieved by re-oxidation with stoichiometric oxidants: N-methylmorpholine N-oxide (NMO) O VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973.K3Fe(CN)6Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766. 6.2 Sharpless Asymmetric Dihydroxylation (AD) - Review: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547. Os (VI) - In the original Sharpless procedure, using NMO as the cooxidant, reoxidation was believed to compete with hydrolysis, leading to a competing 2nd-cycle oxidation that was less 文档下载 免费文档下载 http://doc.xuehai.net/ enantioselective (Ogino, Y.; Chen, H.; Kwong, H.-L.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 3965). Using the potassium ferricyanide cooxidant system, the non-enantioselective secondary cycle appears to suppressed,http://doc.xuehai.net/bc956988fd90b0ed78020c467.html higher enantiomeric excesses are obtained. Catalytic Cycle of the AD ReactionUsingNMOastheCooxidant low ee R OH Catalytic Cycle of the AD ReactionUsingK3Fe(CN)6astheCooxidant 2OH- 2Fe(CN)63-2H2O 2Fe(CN)64- C2-symmetric, pseudo-enantiomeric ligands: (DHQ)2AQN(DHQ)2PYR AD-mix reagents are commercially available: have been consequently 文档下载 免费文档下载 http://doc.xuehai.net/ 1) 1.4 g AD-mix-α will oxidize 1 mmol olefin, contains: 0.98 g K3Fe(CN)6 (3 mmol), 0.41 g K2CO3 (3 mmol), 0.0078 g (DHQ)2PHAL (0.01 mmol), 0.00074 g K2OsO2(OH)4 (0.002 mmol) 2) AD-mix-β contains (DHQD)2PHAL as the ligand. Conditions: t-BuOH, H2O (1:1), 0 °C, 6-24 h. For non-terminal olefins, the addition of CH3SO2NH2 leads to faster reaction (Sharpless, K. B., et al. J. Org. Chem. 1992, 57, 2768). Mnemonic Device of Sharpless ADReaction DHQD-R://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlr Sharpless Asymmetric Dihydroxylation Reaction (Sharpless, K. B., et al. J. Org. Chem. 1992, 57, 2768.) ligandee(%)configurationolefin n-BuPhn-C5H11 Phn-Bu Bu-nPhCO2EtCO2Et (DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2 文档下载 免费文档下载 http://doc.xuehai.net/ PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(DHQ)2PHAL(DHQD)2PHAL(D HQ)2PHAL 9793>99>99999697959895999797978480 R,RS,SR,RS,S2S,3R2R,3S2S,3R2R,3SRSR,RS,SRSRS PhPhn-C8H17 (DHQD)2PHAL ClBnO Ph 44% ee63% ee77% ee, (DHQD)2AQN90% ee88% ee78% ee (DHQD)2AQN is often a superior ligand. Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 448. Asymmetric Dihydroxylation of Dienes - The asymmetric dihydroxylation of dienes tends to be highly regio- and chemoselective. Indeed, in most cases and withohttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmlut special control of the 文档下载 免费文档下载 http://doc.xuehai.net/ reaction conditions, selective monohydroxylation of the diene takes place, affording enediols which are useful precursors to a range of optically active intermediates. It appears that the presence of the diol moiety significantly lowers the reactivity of the remaining olefin towards further dihydroxylation. Moreover, we have already seen earlier that the addition of the diol unit typically occurs on the most electron-rich alkene. Furthermore, it was also shown that unsubstituted olefins reacted more sluggishly than disubstituted or conjugated olefins. Regioselectivity of AD with Diene Substrates(Using(DHQD)2PHALasthe Ligand) olefin product78 73 70 Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570. On the Origin of the Enantioselectivity in the AD Process - The explanation of the high enantioselectivity ihttp://doc.xuehai.net/bc956988fd90b0ed78020c467.htmln the AD reaction has been divided into two proposals, one by Sharpless and one by Corey. The Sharpless Model - The key point of the Sharpless model is the two-step mechanism for the addition 文档下载 免费文档下载 http://doc.xuehai.net/ of osmium tetroxide to an alkene. 9898 Et 93 95 78 9293 yield (%) ee (%) Schematic representation of the concerted (3 2) and the stepwise (2 2) addition of osmium tetroxide to an alkene. Balance of evidence appears to favor 3 (vs. 2 2 Mechanism 2 pathway). See: Corey, E.J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1996, 37, 4899. DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. 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