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6-Oxidation.Pdf

Myers Oxidation Chem 115 General Introductory References 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 3rd Ed., Cambridge University Press: Cambridge, UK, 1987, p. 344!410. R-CH2OH (R-CH2X ) Oxidation States of Organic Functional Groups halide X = halide alkane sulfonate X = OSO2R' alkyl azide X = N3 The notion of is useful in categorizing many organic transformations. This is illustrated by the progression of a to a carboxylic in a series of 2-electron alkylamine X = NR'2 alkylthio X = SR' alkyl ether X = OR' oxidations, as shown at right. Included are several equivalents considered to be at the same oxidation state.

Summary of Reagents for Oxidative Functional Group Interconversions: () R-CHO (RCOR') OH O O NR'' OR'' or R''O OH N 2 N R R'(H) R R' R H hemiketal () R R' R R' alcohol ketone aldehyde R R'

R''O OR''' R''O NR2''' Dimethylsulfoxide-Mediated Oxidations ketal () geminal dihalide RCX2R' aminal R R' R R' Dess-Martin Periodinane (DMP) (VI) Oxidants o-Iodoxybenzoic Acid (IBX) Hypochlorite R''O R'' N tetra-n-Propylammonium Perruthenate (TPAP) N-Bromosuccinimide (NBS) ether (enamine) dithiane S S R R' N-Oxoammonium-Mediated Oxidation Bromine R R' R R' Dioxide (IV) Oxidants R-CO H 2 O O O O O O O O R''' RCO2R' R N R H R OH R H R OR' R R' R OR' O R'' R R'

aldehyde acid aldehyde ester ketone ester R SR' trihalomethyl RCX3 R C N O Sodium !NaCN!CH3OH Bayer-Villiger Oxidation O R' Bromine hydroxamic acid (OBO ester shown) R N R O CH3 OH O Pyridinium Dichromate (PDC) O O O OH O Ester ROH + CO2 (ROCO2H) R' R' R OH R OH R R HO O O O S OH R'' alkyl haloformate xanthate n n RO RO SR' alcohol acid ketone "-hydroxy RO N X ketone R' O Tetroxide Form enolate; Davis Fetizon's Reagent R N C O R N C N R' R R' N N O2/Pt Form enolate; MoOPH O2/Pt Form ; 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, trioxide, , 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 atom. • Typically, 2 equivalents of DMSO are activated with oxalyl chloride in at or • Subsequent nucleophilic attack of an alcohol substrate on the activated sulfoxonium intermediate below –60 °C. to alkoxysulfonium formation. This intermediate breaks down under basic conditions to furnish the carbonyl compound and dimethyl sulfide. • Subsequent addition of the alcohol substrate and leads to carbonyl formation. • The mild reaction conditions have been exploited to prepare many sensitive . + – + + 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()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 • - 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 that yield -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 . 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 Boeckman, R. K.; Shao, P.; Mulins, J. J. Org. Synth. 1999, 77, 141!152. Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683!2686.

Plumb, J. B.; Harper, D. J. Chem. Eng. News 1990, July 16, 3. HO O DMP Se Se OH I O ~100% 2.0 M H2SO4 + KBrO3 II + Ac2O + AcOH 65 °C, 2.5 h Polson, G.; Dittmer, D. C. J. Org. Chem. 1988, 53, 791!794. CO2H O • For the synthesis of sensitive $-amino aldehydes from the corresponding , the use of O IBX DMP suppresses epimerization. Ac OAc DMP Ph 85 °C O Ph II O then 23 °C, ~24 h OAc OH wet CH Cl FmocHN O FmocHN 2 2 23 °C H 74% overall O DMP 99% ee >95% 99% ee Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Tetrahedron • Addition of one equivalent of water has been found to accelerate the reaction Lett. 2000, 41, 1359!1362. with DMP, 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: • Use of other oxidants in the following example led to conjugation of the ",#-unsaturated ketone, which did not occur when DMP was used. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549!7552. CH3

R1 R2 H H C O Ac O H OAc 3 O R R CHOH O DEIPSO H O OTES 1 2 slow O 1. DDQ, CH2Cl2, H2O DMP II II + R1R2C=O + AcOH H CH CH 3 –AcOH CH3 H CH3 3 2. DMP, CH Cl , pyr OAc O H 2 2 O O TBSO TESO O Si(t-Bu) 93% overall I O OPMB O 2 OCH3 O CH R R CHOH CH O 3 CH 1 2 TESO 3 OTES 3 –AcOH H H C O R1 R2 3 O DEIPSO H OTES O O Ac O H OCHR1R2 H CH O CH CH 3 fast CH3 H H 3 3 II II + R1R2C=O + AcOH OCHR R (–)-cytovaricin TBSO O O 1 2 O TESO O Si(t-Bu)2 O OCH II O O O 3 CH O CH3 TESO 3 OTES Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277!7287. 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, Jonathan William Medley

4 Myers Oxidation Chem 115 • DMP oxidation in the presence of phosphorous ylides allows for the trapping of sensitive • IBX is used as a mild reagent for the oxidation of 1,2- without C-C bond cleavage. aldehydes. O O H3C H3C HO H3C IBX, DMSO H3C OH DMP, CH Cl , DMSO CH3O2C + 2 2 PhCO2H CO2CH3 AcO 85% AcO HO HO Ph3P=CHCO2CH3 OH O 94% (2.2 : 1 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. • are not oxidized at a rate competitive with the oxidation of a .

O NHFmoc NHFmoc CHO HO DMP H OH IBX, DMSO N N 99% SCH3 >90% SCH3

Myers, A. G.; Zhong, B.; Kung, D. W.; Movassaghi, M.; Lanman, B. A.; Kwon, S. Org. Lett. 2000, 2, Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019!8022. 3337!3340. • IBX has been shown to form ",#-unsaturated carbonyl compounds from the corresponding • DMP has been used to oxidize secondary acyclic and macrocyclic to the corresponding saturated alcohol or carbonyl compound. in moist DMSO/fluorobenzene at elevated temperature. • The reproducibility of the results of this and related IBX-mediated oxidations has been found to often depend on the presence of water in the IBX employed (for a discussion, see: http://blog- O 6.0 equiv DMP O O syn.blogspot.com/2013/03/blog-syn-003a-secret-ingredient.html) H H N OtBu wet DMSO, PhF N OtBu Me N Me N H 85 °C, 3.5 h H O O 4.0 equiv IBX 86% OH O N toluene, DMSO N Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005, 44, 5992!5997. H 84% o-Iodoxybenzoic Acid (IBX) O H O H 2.0 equiv IBX • The DMP precursor IBX is gaining use as a mild reagent for the oxidation of alcohols. TIPS TIPS toluene, DMSO • A simpler preparation of IBX has been reported. H H

OH 87% I O OH O oxone, H2O II 70 °C 6.0 equiv IBX CO2H O toluene, DMSO 79-81% O IBX OH O 52% Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537!4538.

Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596!7597. Mark G. Charest, Jonathan William Medley

5 Myers Oxidation Chem 115 + – tetra-n-Propylammonium Perruthenate (TPAP): Pr4N RuO4 CH3 CH3 • Reviews H C CH H C CH Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639!666. 3 O 3 TPAP, NMO 3 O 3 HO OR' O OR' Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13!19. O O CH2Cl2, 23 °C H3C CH3 H3C CH3 • (RuO , Ru(VIII)) and, to a lesser extent, the perruthenate (RuO –, OR OR 4 4 59% Ru(VII)) are powerful and rather nonselective oxidants. O O H3C CH3 H3C CH3 27-g scale • However, perruthenate salts with large organic counterions prove to be mild and selective O O oxidants in a variety of organic . R = cladinose, R' = 3-N'-demethyl-3'-N-phenylsulfonyl desosamine • In conjunction with a stoichiometric oxidant such as N-methylmorpholine-N-oxide (NMO), TPAP Jones, A. B. J. Org. Chem. 1992, 57, 4361!4367. oxidations are catalytic in ruthenium, and operate at room temperature. The reagents are CH CH relatively non-toxic and non-hazardous. H3C 3 H3C 3 CH O H CH3O CH O H CH3O 3 OTBS 3 OTBS • To achieve high catalytic turnovers, the addition of powdered molecular sieves (to remove both CH O TPAP, NMO, CH2Cl2 CH O 3 H H 3 H H

the water present in crystalline NMO and the water formed during the reaction) is essential. O O 4Å MS, 23 °C O O • The following oxidation state changes have been proposed to occur during the reaction: O 78% O OH O H Ru(VII) + 2e– " Ru(V) TBSO O TBSO O 2Ru(V) " Ru(VI) + Ru(IV) Julia-Lythgoe Ru(VI) + 2e– " Ru(IV) Olefination

Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, H3C CH3 H3C CH3 CH O H CH3O CH O H CH3O 1625!1627. 3 OTBS 3 OTBS CH3O CH3O • Examples H H H H O O O O

OH O O TPAP, NMO, CH2Cl2 O O O O OH 4 Å MS, 23 °C TPAP, CH Cl Bu N+F–, THF OCH3H OTBSO OCH3H OTBSO 2 2 4 CH O CH O N 3 O 3 O N N CH3 CH3 23 °C 0 °C CH 87% CH H 3 3 CH TEOC H TEOC H O CH3 OH O 3 TESO O TESO 84% 29% CH3 CH3

O OH H3C H3C H3C CH3 CH3 CH3 H3C CH3 (±)-indolizomycin H HO OAc CH O C 3 2 H H Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30!39. O O

O HO CH TPAP, NMO, CH2Cl2 O CH 3 3 OH H OH 4 Å MS, 23 °C CH3 O O H CH3 OH 70% O Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; CH3 Nishiyama, S.; Yamamura, S. Angew. Chem., Int. Ed. n-Pr O Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992, 48, 1145!1174. O Engl. 2000, 39, 2290!2294. bryostatin 3 Mark G. Charest, Jonathan William Medley

6 Myers Oxidation Chem 115

N-Oxoammonium-Mediated Oxidation • Examples • Reviews TEMPO, NaOCl OBn OBn de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153!1174. NaBr, NaHCO3 BocHN OH BocHN O Bobbitt, J. M.; Flores, C. L. Heterocycles 1988, 24, 509!533. EtOAc : toluene : H2O Rozantsev, E. G.; Sholle, V. D. Synthesis 1971, 401!414. C H (6 : 6 : 1) H 6 11 C6H11 • N-Oxoammonium salts are mild and selective oxidants for the conversion of primary and 77% >95% de 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. Leanna, R. M.; Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992, 33, 5029!5032. See also: Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gryza, H.; Prokopoxicz, P. Tetrahedron 1998, 54,

R + R H OH –HX O R R 6051!6064. 1 N 1 X– N + + O R2 R3 R2 R3 OH OH O

N-oxoammonium salt OTBDPS TEMPO, BAIB, CH2Cl2 H OTBDPS • Three possible transition states have been proposed: 23 °C H C CH H C CH R R 3 3 3 3 1 98% R + R1 R + R1 N N N O O O HO O – B O R H H 2 R R R 1 R H 2 OH 1 2 R O O 1 O H Ganem, B. J. Org. Chem. 1975, 40, 1998!2000. CHO Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A. Tetrahedron Lett. 1986, 27, 1119!1122. Jauch, J. Angew. Chem., Int. Ed. Engl. 2000, 39, 2764!2765. Bobbitt, J. M.; Ma, Z. J. Org. Chem. 1991, 56, 6110!6114. H H3C CH3 • N-Oxoammonium salts may be formed in situ by the acid-promoted of kuehneromycin A radicals. Alternatively, oxidation of a nitroxyl radical or hydroxyl can generate the corresponding N-oxoammonium salt. • Selective oxidation of allylic alcohols in the presence of sulfur and has been disproportionation demonstrated. R R1 + R R N +H 1 R R1 2 N + N O + PhS –H OH O TEMPO, BAIB, CH2Cl2

nitroxyl radical CH2OH 23 °C CHO

Golubev, V. A.; Sen', V. D.; Kulyk, I. V.; Aleksandrov, A. L. Bull. Acad. Sci. USSR, Div. Chem. 70% Sci. 1975, 2119!2126.

• 2,2,6,6-Tetramethyl-1-piperidinyloxyl (TEMPO) catalyzes the oxidation of alcohols to aldehydes H3C CH2OH TEMPO, BAIB, CH2Cl2 H3C CHO and in the presence of a variety of stoichiometric oxidants, including m- 23 °C chloroperoxybenzoic acid (m-CPBA), (NaOCl), [bis(acetoxy)-iodo] SePh SePh (BAIB), sodium bromite (NaBrO ), and Oxone (2KHSO •KHSO •K SO ). 2 5 4 2 4 55%

H3C CH3 TEMPO De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974! N H3C CH3 6977. O Mark G. Charest, Jonathan William Medley

7 Myers Oxidation Chem 115

Manganese Dioxide: MnO TBSO TBSO 2 H H H H SAr SAr • Reviews MnO2, Cahiez, G.; Alami, M. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing OAc OAc Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. 231! H H 76% H 236. HO HO O HO O HO

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. H CH3 CH3 CH3 The structure and reactivity of active manganese dioxide depends on the method of preparation. H3C CH3 MnO2 • OH acetone • Active manganese are nonstoichiometric materials (in general MnOx, 1.93 < x < 2) CH3 CH3 consisting of Mn (II) and Mn (III) oxides and , as well as hydrated MnO . 75% 2 HO CH3 OH • -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 CH3 CH3 CH3 MnO2 surface. H H3C CH3 • Examples O CH3 CH3 CH H3C CH3 CH3 H3C CH3 CH3 HO 3 MnO2 OH OH O paracentrone

CH3 >95% CH3 1-kg scale Haugan, J. A. Tetrahedron Lett. 1996, 37, 3887!3890.

Salman, M.; Babu, S. J.; Kaul, V. K.; Ray, P. C.; Kumar, N. Org. Process Res. Dev. 2005, 9, • Vinyl stannanes are tolerated. 302!305.

CH3 CH MnO2 3 CH OEt CH OEt H3C CH3 3 H3C CH3 3 Bu3Sn Bu3Sn MnO2 CH2OH CH2Cl2 CHO OEt OEt CH2Cl2, 0 °C 89% CH3 CH3 OH 76% O Alvarez, R.; Iglesias, B.; Lopez, S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659!5662. van Amsterdam, L. J. P.; Lugtenburg, J. J. Chem. Soc., Chem. Commun. 1982, 946!947. • Syn or anti vicinal diols are cleaved by MnO2.

EtO C CO Et OHC CHO 2 2 HO CH3 O O OH MnO 1. DIBAL, C H 2 6 6 H C CH CH 3 3 2. MnO , CH Cl 3 2 2 2 CH3 CH3 100% H C CH H C CH 3 3 74% 3 3 Ohloff, G.; Giersch, W. Angew. Chem., Int. Ed. Engl. 1973, 12, 401!402. Cresp, T. M.; Sondheimer, F. J. Am. Chem. Soc. 1975, 97, 4412 4413. ! Mark G. Charest, Jonathan William Medley

8 Myers Oxidation Chem 115

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 are deep green salts that can be used without • A classic oxidation method achieved by heating the alcohol to be oxidized with a metal in prior activation for the oxidation of primary and secondary allylic and benzylic alcohols. the presence of a carbonyl compound as a hydride acceptor.

• Examples • Effectively the reverse of the Meerwein!Pondorff!Verley Reduction. • The reaction is an equilibrium process and is believed to proceed through a cyclic transition state. H The use of easily reduced carbonyl compounds, such as quinone, helps drive the reaction in the Ph Ph desired direction. OH BaMnO , CH Cl O 4 2 2 R1 L S S R OH 23 °C O 3 M R2 O L Ph Ph H H O 85% R4 Proposed Transition State Firouzabadi, H.; Mostafavipoor, Z. Bull. Chem. Soc. Jpn. 1983, 56, 914!917. Djerassi, C. Org. React. 1951, 6, 207.

Oppenauer, R. V. Rec. Trav. Chim. Pays-Bas 1937, 56, 137!144.

OH O • Examples H3C H3C OH CH OH CHO OH BaMnO4 2 pivaldehyde, toluene

H3C CH3 2 mol % H3C CH3 92% F F H C 5 5 H C 3 B 3 Howell, S. C.; Ley, S. V.; Mahon, M. J. Chem. Soc., Chem. Commun. 1981, 507!508. (S)-perillyl alcohol OH 99%

Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 5664!5665. CH3 CH3 BaMnO , CH Cl H C CH OH 4 2 2 H C CHO • Highly reactive alkoxide catalysts undergo rapid exchange and can be used in 3 O 2 3 O H H H H substoichiometric quantities. SEMO 98% SEMO CH3 CH3

cat. Zr(O-t-Bu)4, Cl3CHO, CH2Cl2 Burke, S. D.; Piscopio, A. D.; Kort, M. E.; Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; OH 3 Å MS O Shankaran, K. J. Org. Chem. 1994, 59, 332!347. H3C CH3 86% H3C CH3 menthol

Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A. K.; Hayakawa, M. Synthesis 1996, 1341! 1344. Mark G. Charest, Jonathan William Medley

9 Myers Oxidation Chem 115

Chromium (VI) Oxidants Collins Reagent: CrO3•pyr2

• Reviews • CrO3•pyr2 is a hygroscopic red solid which is easily hydrolyzed to the yellow dipyridinium dichromate ([Cr O ]–2(pyrH+) ). Ley, S. V.; Madin, A. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., 2 7 2 Pergamon Press: New York, 1991, Vol. 7, p. 251 289. ! • Typically, 6 equiv of oxidant in a chlorinated leads to rapid and clean oxidation of alcohols. Luzzio, F. A. Organic Reactions 1998, 53, 1!122. Caution: Collins reagent should be prepared by the portionwise addition of solid CrO to • The mechanism of -mediated oxidation has been extensively studied and is • 3 pyridine. Addition of pyridine to solid CrO can to a violent reaction. commonly used as a model for other chromium-mediated oxidations. 3 Collins, J. C.; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 30, 3363!3366. – + R2CHOH + HCrO4 + H R2CHOCrO3H + H2O Collins, J. C.; Hess, W. W.; Org. Synth. 1972, 52, 5!9.

– + R2C O CrO3H R2C O + HCrO3 + BH • In situ preparation of the reagent circumvents the difficulty and danger of preparing the pure complex. H OH O B H3C H3C CrO3, pyr, CH2Cl2 Holloway, F.; Cohen, M.; Westheimer, F. H. J. Am. Chem. Soc. 1951, 73, 65!68. H H • A competing pathway involving free-radical intermediates has been identified. H3C CH3 95% H3C CH3

+ Ratcliffe, R.; Rodehorst, R. J. Org. Chem. 1970, 35, 4000!4003. R2CHOH + Cr(IV) R2COH + Cr(III) + H + + • Examples R2COH + Cr(VI) R2C=O + Cr(V) H + + + CH NHBoc CH NHBoc R2CHOH + Cr(V) R2C=O Cr(III) 2H 3 CrO3, pyr, CH2Cl2 3 OH O H C H C 3 !10 °C 3 Wiberg, K. B.; Mukherjee, S. K. J. Am. Chem. Soc. 1973, 96, 1884!1888. H >99.5% ee 67% >99.5% ee Wiberg, K. B.; Szeimies, G. J. Am. Chem. Soc. 1973, 96, 1889!1892. 50-g scale • Fragmentation has been observed with substrates that can form stabilized radicals. Rittle, K. E.; Homnick, C. F.; Ponticello, G. S.; Evans, B. E. J. Org. Chem. 1982, 47, 3016!3018.

OTBS + – O H O 1. n-Bu4N F , THF O • Ph C O Cr(IV) PhCHO + (CH3)3C 2. Collins Reagent –Cr(III) (CH3)3C O O CH3 CH2Cl2 CH3

CH3 CH Doyle, M.; Swedo, R. J.; Rocek, J. J. Am. Chem. Soc. 1973, 95, 8352!8357. 81% overall 3 (±)-periplanone B

• Tertiary allylic alcohols are known to undergo oxidative transposition. Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493!2495.

OH OCrO H O OCH OCH O 3 3 1. H2, 10% Pd-C 3 Cr O CH3O2C 2. Collins Reagent CH3O2C CHO O H O CH3 CH3 CH2Cl2 CH3 CH3 83% 90% overall

(+)-monensin Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682!685. Collum, D. B.; McDonald, J. H.; Still, W. C. J. Am. Chem. Soc. 1980, 102, 2117!2120. Mark G. Charest, Jonathan William Medley

10 Myers Oxidation Chem 115

Pyridinium Chlorochromate (PCC, Corey's Reagent) Sodium Hypochlorite: NaOCl • Sodium hypochlorite in solution selectively oxidizes secondary alcohols to ketones in – the presence of primary alcohols. ClCrO3 + N • A modified procedure employs hypochlorite, a stable and easily handled solid H hypochlorite oxidant. PCC • Examples: • 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 OH OH N,N- (DMF) or a suspension in chlorinated solvents. CH3 CH3 NaOCl, AcOH • The slightly acidic character of the reagent can be moderated by buffering the reaction mixture with powdered . 91% Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 26, 2647!2650. H3C OH H3C O

• Addition of molecular sieves can accelerate the rate of reaction. Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.; Albizati, K. F. Tetrahedron Lett. 1982, Antonakis, K.; Egron, M. J.; Herscovici, J. J. Chem. Soc., Perkin Trans. I 1982, 1967!1973. 23, 4647!4650.

• Examples Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982, 23, 35!38. HO CH3 O CH3

O PCC, 25 °C O OH O 1. NaOCl, AcOH H OTIPS H OTIPS H C OMOM Cl 4Å MS Cl H3C OH 3 O O 2. MOMCl, DIEA NC NC H 100% H 93%

Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871 8872. ! Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431!7432.

CH3 CH3 N N CH3 CH3 PCC, CH2Cl2 OH O NaOAc NaOCl, AcOH S S O OH 71% H H OH 86% OH H3C H3C Browne, E. J. Aust. J. Chem. 1985, 38, 756!776.

• Treatment of tertiary allylic alcohols with PCC affords enone products via oxidative transposition. Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777!12782.

H3C CH3 H3C CH3 H3C CH3 H3C CH3 n-C9H19 CH2OH n-C9H19 CH2OH

PCC, CH2Cl2 OH NaOCl, AcOH O 23 °C CH CH O CH O CH OH 3 O O 3 3 3 CH3 71% CH3 94% Cr CrO3 O2

Winter, E.; Hoppe, D. Tetrahedron 1998, 54, 10329!10338. Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682!685. Mark G. Charest, Jonathan William Medley

11 Myers Oxidation Chem 115 Selective Oxidations Using N-Bromosuccinimide (NBS) or Bromine Selective Oxidations using Other Methods • NBS in aqueous dimethoxyethane selectively oxidizes secondary alcohols in the presence of • Cerium (IV) complexes catalyze the selective oxidation of secondary alcohols in the presence of primary alcohols. primary alcohols and a stoichiometric oxidant such as sodium (NaBrO3). • Examples: Tomioka, H.; Oshima, K.; Noxaki, H. Tetrahedron Lett. 1982, 23, 539!542. • In the following example, catalytic tetrahydrogen cerium (IV) tetrakissulfate and stoichiometric CH3 CH3 HO OH HO O potassium bromate in aqueous was found to selectively oxidize the secondary NBS, DME, H2O alcohol in the substrate whereas NaOCl with acetic acid and NBS failed to give the desired . CH3 CH3 >98% O O O O O O H3C H3C CH CH 3 3 Ce(SO4)2•2H2SO4, KBrO3 NPh NPh O OH 7 : 3 CH3CN, H2O, 80 °C O O CH OH CH2OH CH Corey, E. J.; Ishiguro, M. Tetrahedron Lett. 1979, 20, 2745!2748. 2 48% 3 (±)-palasonin • Bromine has been employed for the selective oxidation of activated alcohols. In the following Rydberg, D. B.; Meinwald, J. Tetrahedron Lett. 1996, 37, 1129!1132. example, a lactol is oxidized selectively in the presence of two secondary alcohols. • 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) O as a stoichiometric oxidant and tetrabutylammonium chloride (Bu N+Cl–). O HO H 4 HO H O HO H O O O O O OH TEMPO, NCS, OH O H Br2, AcOH H t-Bu t-Bu + – O O Bu4N Cl + H3C NaOAc H3C OH H HO H CH2Cl2, H2O, OH HO O O CHO O >51% O pH 8.6 (±)-ginkgolide B 77% 0.50% Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem. 1996, 61, 7452!7454. Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-Meade, A. S.; Thomas, J. B.; Watterson, S. • catalysts and H2O2 have been used to oxidize secondary alcohols in the presence H.; Wagman, A. S. J. Am. Chem. Soc. 2000, 122, 8453!8463. of primary alcohols: (NH4)6Mo7O24•4H2O H O ,nBu NCl • Stannylene are oxidized in preference to alcohols in the presence of bromine: 2 2 4 O OH THF, 23 °C OH OH 88%

CH3 OH CH3 CH3 OH CH3 Trost, B. M.; Masuyama, Y. Tetrahedron Lett. 1984, 25, 173!176. N N N N H OH Cbz Cbz Cbz Cbz H H • Schreiner's has been shown to catalyze the selective oxidation of secondary alcohols by N O O CH3 NBS: H3C OH Br2 OH H2 H3C O H3C O O O Bu3SnOCH3 O O Pd/C HO O CF3 CF3 H HO HO O N O CH3 CH3 O OH H C H S NBS, CH Cl O 70% O 90% 3 2 2 Sn OH OH (+)-spectinomycin !30 °C Bu F3C N N CF3 Bu H H (0.1 equiv) 80%

Hanessian, S.; Roy, R. J. Am. Chem. Soc. 1979, 101, 5839!5841. Tripathi, C. B.; Mukherjee, S. J. Org. Chem. 2012, 77, 1592!1598. Mark G. Charest, Jonathan William Medley

12 Myers Oxidation Chem 115

O O 1. (CF3CO2)2IPh, Cl Cl CH3CN, H2O, 0 °C R H R OH OH OH 2. NaClO2, NaH2PO4 Aldehyde Acid 2-methyl-2-,

Sodium Chlorite: NaClO2 OTBDPS t-BuOH, H2O CO H OTBDPS S S 2 • Sodium chlorite is a mild, inexpensive, and selective reagent for the oxidation of aldehydes to the corresponding carboxylic under ambient reaction conditions. 82% • 2-methyl-2-butene is often incorporated as an additive and has been proposed to function as a scavenger of any electrophilic species generated in the reaction.

Lindgren, B. O.; Nilsson, T. Acta. Chem. Scand. 1973, 27, 888!890. Br Cl Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825!4830. H3C O • Examples (+)-obtusenyne H NaClO , NaH PO , H H C O 2 2 4 H C O 3 3 Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A. J. Org. Chem. 2-methyl-2-butene 1999, 64, 2616!2617. CHO t-BuOH, H2O CO2H • The two-step oxidation of an alcohol to the corresponding carboxylic acid is most common. TBSO CH3 TBSO CH3 80% n-Bu Sn O CH3 n-Bu Sn O CH3 Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825-4830. 3 1. TPAP, NMO, CH2Cl2 3

O O 2. NaClO2, NaH2PO4 O O H3C H3C CF OCO 1. NaClO2, NaH2PO4, 2-methyl-2-butene, 3 O 2-methyl-2-butene O THF, t-BuOH, H2O t-BuOH, H O OH OH TBSO 2 TBSO H3C >52% H3C 2. CF CH OH, CO2CH3 CHO CO2CH3 3 2 O 2,6-lutidine Nicolaou, K. C.; Ohshima, T.; Murphy, F.; Barluenga, S.; Xu, J.; Winssinger, N. J. Chem. Soc., Chem. Commun. 1999, 809!810. >95% OH OMOM 1. DMP, CH2Cl2, pyr O H C H3C 3 H3C CH3 HO CH3O 2. NaClO2, NaH2PO4 Corey, E. J.; Myers, A. G. J. Am. Chem. Soc. 1985, 107, 5574! H3C CO H 2-methyl-2-butene, 2 HO O O O O O OSEM 5576. O H H H H OCH H3C H 3 t-BuOH, H O CH3 CH3 2 (±)-antheridic acid H3C 3. CH2N2 OCH OCH 3 NaClO , NaH PO , 3 98% OTf 2 2 4 OTf 2-methyl-2-butene OMOM H OH H C H3C acetone, H2O 3 H3C CH3 CH3O O O (+)-monensin A CH3O2C OMOM 90% OMOM O O O O O OSEM H H C H H H H OCH3 CH CH 3 3 3 H3C Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004-1015. Ireland, R. E.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7166!7172. Mark G. Charest

13 Myers Oxidation Chem 115

Potassium Permanganate: KMnO4 • In the following example, a number of other oxidants (including Jones reagent, NaOCl, and RuO2) Review: failed: Fatiadi, A. J. Synthesis 1987, 85!127. 1. KMnO4, NaH2PO4, • is a mild reagent for the oxidation of aldehydes to the corresponding t-BuOH, H O, 0 °C carboxylic acids over a relatively large pH range. Alcohols, , and other functional groups N TsN 2 N TsN are also oxidized by potassium permanganate. Ts H 2. (CH3)3SiCHN2 Ts H H CH3O • Oxidation occurs through a coordinated permanganate intermediate by hydrogen atom- H H abstraction or hydride transfer. O 80% O

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 N to effectively oxidize the aldehyde in the following polyoxygenated substrate to the corresponding N H H H carboxylic acid whereas Jones reagent, RuCl3(H2O)n-NaIO4, and failed. H OTBS OCH (–)-yohimbane BnO 3 OTBS KMnO4, NaH2PO4 Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237!3243. O O O O O t-BuOH, H O CHO 2 H C CH H C CH Silver Oxide: Ag2O 3 3 3 3 85% • A classic method used to oxidize aldehydes to carboxylic acids. OTBS OTBS OCH3 • Cis/trans isomerization can be a problem with unsaturated systems under the strongly basic BnO OTBS reaction conditions employed.

O O O O O • Examples: CO2H H3C CH3 H3C CH3 CHO CO2H OTBS 1. Ag2O, NaOH Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S. Tetrahedron Lett. 1986, 27, 4537!4540. HO 2. HCl HO OCH3 OCH3 • Examples: 90-97% vanillic acid O CN O CN KMnO4, NaH2PO4 Pearl, I. A. Org. Synth. IV 1963, 972!978. t-BuOH, H O, 5 °C N CHO 2 N CO2H Boc 93.5% Boc CHO COOH

CHO Ag2O, NaOH CHO H3C H3C O HO O 23 °C HO O O O NH HO HO N H H N (CH ) N H CH3 (±)-K-76 (±)-K-76 monocarboxylic acid 3 2 O H3C (–)-nummularine F Corey, E. J.; Das, J. J. Am. Chem. Soc. 1982, 104, 5551!5553. Heffner, R. J.; Jiang, J.; Joullié, M. M. J. Am. Chem. Soc. 1992, 114, 10181!10189. Mark G. Charest, Jonathan William Medley

14 Myers Oxidation Chem 115 • In the following example, all chromium-based oxidants failed to give the desired acid. • Additional Examples OH O O O H C O CO2H H3C 3 S OCH3 S PDC H C H H C H CHO 1. Ag2O, NaOH CO2H 3 3 97% OMEM 2. HCl OMEM O H H O H H 50-g scale O O O 81% O N N Wuts, P. G. M.; Ritter, A. R. J. Org. Chem. 1989, 54, 5180!5182.

Ovaska, T. V.; Voynov, G. H.; McNeil, N.; Hokkanen, J. A. Chem. Lett. 1997, 15!16. • PDC can oxidize aldehydes to the corresponding methyl in the presence of . It appears that in certain cases, the oxidation of methanol by PDC is slow in comparison to the oxidation of the methyl hemiacetal. + Pyridinium Dichromate: (pyrH )2Cr2O7 • Attempts to form the ethyl and isopropyl esters were less successful. • Review • Note that in the following example sulfide oxidation did not occur. 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 O H CH3O O PDC, DMF O • PDC is a stable, bright orange solid prepared by dissolving CrO3 in a minimun volume of water, BnO SEt BnO SEt adding pyridine and collecting the precipitated product. BnO 6 equiv CH3OH BnO BnO BnO Non-conjugated aldehydes are readily oxidized to the corresponding carboxylic acids in good • >71% 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. TBSO CH TBSO CH H H 3 H H 3 OH PDC, DMF H3C CH3 H3C CH3 H3C H3C CO2H O O O O NH NH 1. PDC, DMF O O CHO CO CH 91% AcO AcO 2 3 2. CH2N2 BnO CH BnO CH 3CH3 CH3 3CH3 CH3 Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetrahedron 1988, 44, 2149!2165. 78%

other • However, a suspension of PDC in dichloromethane oxidizes alcohols to the corresponding H3C CH3 H3C CH3 aldehyde. oxidants O O O O Ph Ph [O] CH S S AcO OH 3 PDC, CH2Cl2 AcO O O BnO CH3CH3 CH3 BnO CH3CH O 3 CH2OH CHO S S 68%

Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem. 1985, 50, 2095!2105. Terpstra, J. W.; van Leusen, A. M. J. Org. Chem. 1986, 51, 230!238.

Mark G. Charest, Jonathan William Medley

15 Myers Oxidation Chem 115

O O Bromine

R H R OR' • Review Aldehyde Ester Palou, J. Chem. Soc. Rev. 1994, 357!361.

Manganese Dioxide!NaCN!CH3OH • Bromine in alcoholic solvents is a convenient and inexpensive method for the direct conversion • A convenient method to convert unsaturated aldehydes directly to the corresponding methyl of aldehydes into ester derivatives. esters. • Under the reaction conditions employed, secondary alcohols are not oxidized to the • Cis/trans isomerization, a problem when other reagents such as basic silver oxide are corresponding ketones. employed, is avoided. • Oxidation of a hemiacetal intermediate is proposed. • The aldehyde substrate is initially transformed into a cyanohydrin intermediate. Subsequent oxidation of the cyanohydrin furnishes an acyl which is then trapped with methanol to • Olefins, benzylidine acetals and thioketals are incompatiable with the reaction conditions. give the desired methyl ester. • A variety of esters can be prepared. • Conjugate addition of cyanide ion can be problematic. • Examples • Examples H OH H OH OH OH O H3C O Br2, H2O, alcohol H3C CHO CO R O O NaHCO 2 CH3 CH3 H C O 3 H C O O MnO2, NaCN 3 O 3 O CH O CH H H O 3 AcOH, CH OH O 3 R = Me, 94% 3 O O CHO NOBn O NOBn R = Et, 91% R = i-Pr, 80% 81% OCH3 Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W. Tetrahedron Lett. 1988, 29, OH 5087!5090. OH Lichtenthaler, F. W.; Jargils, P.; Lorenz, K. Synthesis 1988, 790!792.

O OH H TBSO TBSO O O O NH Br2, H2O, CH3OH O N H NaHCO3 N OCH3 CO CH CO CH (–)-lycoricidine 2 3 2 3 78%

Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176!5190. Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenländer, F. Tetrahedron 1996, 52, 6409!6420.

• A variation of this reaction using NBS as oxidant has been employed in tandem with the catalytic • In the following example, stepwise addition of reagents proved to be essential to achieve high enantioselective Michael addition of nitromethane to an enal: yields.

CHO COOMe H C CH3 H C CH3 PhCO2H (0.2 equiv) 3 CH3 1. NaCN, AcOH, 3 CH3 F C Ph CH3NO2, CH3OH; F C NO CH3OH, 1 h 3 Ph 3 2 O O N NBS CHO 2. MnO2, CH3OH CO2CH3 H OTMS HO CH3 HO CH3 (0.1 equiv) 69%, 93% ee 97% (2Z, 4E)-xanthoxin Jensen, K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jørgensen, K. A. Org. Lett. 2012, Yamamoto, H.; Oritani, T. Tetrahedron Lett. 1995, 36, 5797!5800. 14, 1516!1519. Mark G. Charest, Jonathan William Medley

16 Myers Oxidation Chem 115

O O • Examples

R R' R OR' HO H CH O CH3O Ketone Ester 3 CO H m-CPBA, NaHCO3 2 O CH3 Bayer-Villiger Oxidation CH2Cl2 O H • Reviews O HO HO H 95% (±)-PGF2! Krow, G. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 7, p. 671-688. Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675-5677.

Krow, G. R. In Organic Reactions, Paquette, L. A., Ed., John Wiley and Sons: New York, 1993, Ph Vol. 43, p. 251-296. Ph OCH3 A classic method for the oxidative conversion of ketones into the corresponding esters or OCH3 m-CPBA, Li CO n-C16H33 • n-C H N O 2 3 N O by oxygen insertion into an acyl C-C bond. 16 33 CH2Cl2 O O The migratory preference of alkyl groups has been suggested to reflect their electron-releasing O • O ability and steric bulk. 99% O

• Typically, the order of migratory preference is tertiary > secondary > allyl > primary > methyl. Miller, M.; Hegedus, L. S. J. Org. Chem. 1993, 58, 6779-6785.

• The reactivity order of Bayer-Villiger oxidants parallels the acidity of the corresponding • Selective Bayer-Villiger oxidation in the presence of unsaturated ketones and isolated olefins has carboxylic acid (or alcohol): CF3CO3H > p-nitroperbenzoic acid > m-CPBA = HCO3H > CH CO H > HOOH > t-BuOOH. been achieved. 3 3 COR' O CH3 CH3 O O H2O2 (anhydrous), O R'CO3H –R'CO2H BOMO BOMO R Ti(Oi-C3H7)4, ether O H O H R R RL RLO R L O DIEA, –30 °C H3C H3C O H H O H R = Large Group L >55% • Primary and secondary stereoelectronic effects in the Bayer-Villiger reaction have been O demonstrated. COR primary effect O CH3 O AcO H O O • Primary effect: antiperiplanar alignment of RL and "O-O Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am. RL R H3C O OH • Secondary effect: antiperiplanar alignment of O and "# Chem. Soc. 1983, 105, 625-627. H lp C-RL secondary O OH effect O Proposed TS eucannabinolide • have been prepared in some cases. Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. Engl. 2000, 39, 2852-2855.

• The Bayer-Villiger reaction occurs with retention of stereochemistry at the migrating center. CH3 CH3 N O O O N H D H O D H O D m-CPBA, CH OH CF3CO3H + O 3 O D T Na HPO D T D T N 2 4 N O CH3 70% CH3

Azizian, J.; Mehrdad, M.; Jadid, K.; Sarrafi, Y. Tetrahedron Lett. 2000, 41, 5265-5268. 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. Mark G. Charest

17 Myers Oxidation Chem 115

O OMOM OMOM AcHN RuO (H O) , NaIO AcHN R OH R OH 2 2 2 4 OH CH CN, CCl , H O OH Alcohol Acid N 3 4 2 N Boc Boc O Ruthenium Tetroxide: RuO4 98%

• RuO4 is used to oxidize alcohols to the corresponding carboxylic acid. It is a powerful oxidant that also attacks aromatic rings, olefins, diols, , and many other functional groups. Clinch, K.; Vasella, A.; Schauer, R. Tetrahedron Lett. 1987, 28, 6425!6428.

• Catalytic procedures employ 1-5% of ruthenium metal and a stoichiometric oxidant, such as • In the following example, sodium cleaves the 1,2-diol to an aldehyde, which (NaIO4). is further oxidized to the corresponding carboxylic acid by RuO4. The amine is protonated and thereby protected from oxidation. • Sharpless has introduced the use of acetonitrile as solvent to improve catalyst turnover. It is proposed to avoid the formation of insoluble Ru- complexes and return the metal to the catalytic cycle. HO 1. RuCl -NaIO , H 3 4 O OH OCH3 Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838!3840. CH N CH3CN, CCl4, H2O CH3N 3 OBz OBz 2. (CH ) SiCHN Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936!3938. •HF 3 3 2 • Examples (S)-(+)-cocaine 78% overall CO2H RuCl3, NaOCl Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773!4775. CCl4, H2O CO2H Molecular Oxygen 70% • Molecular oxygen in the presence of a catalyst is a classic method for the oxidation of Sptzer, U. A.; Lee, D. G. J. Org. Chem. 1974, 39, 2468!2469. primary alcohols to the corresponding carboxylic acids.

• Examples

RuO2, NaIO4 O Bn O2/Pt Bn CCl4, H2O HO2C CO2H OH OH O NH NH Boc Boc 68% 65%

Smith, A. B., III; Scarborough, R. M., Jr. Synth. Commun. 1980, 10, 205!211. Mehmandoust, M.; Petit, Y.; Larcheveque, M. Tetrahedron Lett. 1992, 33, 4313!4316.

CH CH 3 3 • Primary alcohols are oxidized selectively in the presence of secondary alcohols. O O R H RuCl -NaIO R H 3 4 OH O O OH O O CH CN, CCl , H O R 3 4 2 R HO 1. O2/Pt CH3O OCH OCH 3 2. CH I 3 H H O NHPf 3 O O NHPf OBz 60% OBz HO HO O CH3 CH3 CH3 85% CH3 R = CH3 (±)-scopadulcic acid B Pf = 9-phenylfluorenyl

Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1997, 119, 12031!12040. Park, K. H.; Rapoport, H. J. Org. Chem. 1994, 59, 394!399.

Mark G. Charest

18 Myers Oxidation Chem 115 Jones Oxidation N-Oxoammonium-Mediated Oxidation of Alcohols to Carboxylic Acids • Jones reagent is a standard solution of chromic acid in aqueous . • A general method for the preparation of nucleoside 5'-: • Acetone is often benefical as a solvent and may function by reacting with any excess oxidant. B B O HO C O • Isolated olefins usually do not react, but some olefin isomerization may occur with 2 HO TEMPO, PhI(OAc)2 unsaturated carbonyl compounds. CH3CN, H2O • 1,2-diols and "-hydroxy ketones are susceptible to cleavage under the reaction conditions. O O O O

H3C CH3 B = A (90%) H3C CH3 • Examples: O O B = U (76%) CH3 CH3 CH3 CH3 B = C (72%, NaHCO added) Jones reagent 3 B = G (75%, Na salt, NaHCO added) 0 °C 3

CH3 CH3 85% Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293!295. CO2H OH • A brief follow-up treatment with sodium chlorite was necessary to obtain complete oxidation to Corey, E. J.; Trybulski, E. J.; Melvin, L. S.; Nicolaou, K. C.; Secrist, J. A.; Lett, R.; Sheldrake, P. the bis-carboxylic acid in the following example. W.; Flack, J. R.; Brunelle, D. J.; Haslanger, M. F.; Kim, S.; Yoo, S. J. Am. Chem. Soc. 1978, 100, 4618!4620. OBn

• Silyl ethers can be cleaved under the acidic conditions of the Jones oxidation. 1. H2, 20% Pd(OH)2-C, O OBn CF3CONH O EtOAc, EtOH OTBS OPiv BnO Jones reagent BnO CO2H PivO O 2. PhI(OAc)2, TEMPO O O –10 # 23 °C CO CH H O CH CN, NaHCO , H O CO2CH3 2 3 Ph N NH 3 3 2 N O 3. NaClO2, t-BuOH, H2O 88-97% O O N NaH2PO4, isopentene Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew. Chem., Int. Ed. Engl. 1999, CH2OBn 38, 3175!3177. O 49% overall HO OH O Jones reagent HO2C HO2C –5 °C O O NCBz NCBz H2N O CF3CONH O CO2H OH CO2H OPiv >86%, 78-g scale HO O PivO O NH3, CH3OH O H O H2N NH 55 °C Ph N NH Thottahil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M. K. Y.; Kissick, T. P. J. Org. Chem. 1986, N O N O 51, 3140!3143. O O O NH 65% NH • concerns inherent to chromium(VI) species can be minimized by employing CrO as a 3 O O catalyst in the presence of periodic acid as stoichiometric oxidant.

4-desamino-4-oxo-ezomycin A2 O CrO (1.1 mol %) Ph 3 Ph OH OH H5IO6 90% Knapp, S. K.; Gore, V. K. Org. Lett. 2000, 2, 1391 1393. Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. ! Tetrahedron Lett. 1998, 39, 5323!5326. Mark G. Charest, Jonathan William Medley

19 Myers Oxidation Chem 115

O O • A related diastereoselective conjugate addition/"-oxidation protocol has been employed on R' R' industrial scale for the synthesis of an HCV protease inhibitor. R R OH H3C CH3 Ketone "-Hydroxy Ketone CH3 CH3 CH3 Davis Oxaziridine Ph NBn O S N O Ph NBn OLi Ph NBn O • Reviews Li O O Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919!934. n-Bu Ot-Bu n-Bu Ot-Bu n-Bu Ot-Bu OH Jones, A. B. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon 81% (single isomer isolated) Press:• New York, 1991, Vol. 7, p. 151!191. 27-kg scale N-Sulfonyloxaziridines are prepared by the biphasic oxidation of the corresponding sulfonimine Traverse, J.; Leong, W. W.; Miller, S. P.; Albaneze-Walker, J.; Hunter, T. J.; Wang, L.; Liao, H.; with m-CPBA or Oxone. Arasappan, A.; Trzaska, S. T.; Smith, R. M.; Lekhal, A.; Bogen, S. L.; Kong, J.; Bennett, F.; Njoroge, O F. G.; Poirier, M.; Kuo, S.-C.; Chen, Y.; Matthews, K. S.; Demonchaux, P.; Ferreira, A. Patent: WO m-CPBA or Oxone R' RSO2N=CHR' N 2011014494. RSO2 O O 1. KHMDS, HMPA, O O Davis oxaziridine: R = R' = Ph OH THF, –10 °C H O H O • Nucleophilic attack by enolates on the electrophilic oxaziridine oxygen furnishes "-hydroxy CH3 2. –78 °C CH3 O O ketones. TBDPSO OTBS TBDPSO OTBS H H3C CH3 H S S • Potassium enolates are generally the most successful.

• Examples O S N O O OH OH O CH3 KHMDS, Davis CH3 OH O O 73% H O oxaziridine, THF CH3 taxol O (±)-breynolide HO OH CH –78 # –20 °C CH H HO 3 HO 3 S CO2Et CO2Et 97% at Smith, A. B., III; Empfield, J. R.; Rivero, R. A.; Vaccaro, H. A.; Duan, J. J.-W.; Sulikowski, M. M. J. 57% conversion Am. Chem. Soc. 1992, 114, 9419!9434. O O Wender, P. A.; et al. J. Am. Chem. Soc. 1997, 119, 2757!2758. OH OCH3 1. NaHMDS OCH3 2. H C CH • Enantioselective hydroxylation of prochiral ketones has been demonstrated. 3 3 CH3O O OCH3 Cl CH3O O OCH3

O O Cl 1. NaHMDS O S N CH3 CH3 O O Ph 2. H3C CH3 Ph OCH3 CH3O Cl OH 50% (94% ee) Cl O S N H O O 61% (95% ee) OH CH3O O Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919!934. Davis, F. A.; Chen, B. J. Org. Chem. 1993, 58, 1751!1753. (+)-O-trimethylbrazilin Mark G. Charest, Jonathan William Medley

20 Myers Oxidation Chem 115

Molybdenum peroxy compounds: MoO5•pyr•HMPA Rubottom Oxidation O O • Epoxidation of a silyl enol ether and subsequent silyl migration furnishes "-hydroxylated ketones. O Mo O O • Silyl migration via an oxocarbenium ion has been postulated. ((CH3)2N)3P O N

SiR SiR3 SiR3 O 3 O O O O – + OSiR3 • Oxodiperoxymolybdenum(pyridine) (MoOPH) is commonly used to O R R R1 R1 1 oxidize enolates to the corresponding hydroxylated compound. 1 R2 R2 R2 R2 • It is proposed that nucleophilic attack of the enolate occurs at a peroxyl oxygen atom, leading to O-O bond cleavage. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 4319-4322. • !-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.

CHO O OHC OHO H3C H3C CH CH O 1. LDA, THF, –78 °C O TBDPSO O 3 TBDPSO O 3 2. MoOPH CH3 CH3 O O H3C CH3 91% H3C CH3 m-CPBA, NaHCO3 Et3SiO O + H H H3O EtOAc CH3 HO CH3

H C 70% H C OHC OH 3 3 H C 3 CHO

Clive, D. L. J.; Zhang, C. J. Org. Chem. 1995, 60, 1413-1427. H3C CH3 (±)-warburganal

OTBS O Jansen, B. J. M.; Sengers, H.; Bos, H.; de Goot, A. J. Org. Chem. 1988, 53, 855-859. PMBO PMBO OTBS dimethyldioxirane camphorsulfonic acid BOMO OTBS BOMO OTBS OTBS OTBS H3C R H3C O CH3 O 1 CH3 79% R2 H3C H3C H 1. LDA, THF, –78 °C H O CH 2. MoOPH, –40 °C dimethyldioxirane = 3 O CH3 CH3 CH3 CH3 CH3 O S R1 = H, R2 = OH 45% O S

R1 = OH, R2 = H 25% CH3S CH3S Reddy, K. K.; Saady, M.; Falck, J. R. J. Org. Chem. 1995, 60, 3385-3390.

Kato, N.; Okamoto, H.; Arita, H.; Imaoka, T.; Miyagawa, H.; Takeshita, H. Synlett. 1994, 337-339. Mark G. Charest

21 Myers Oxidation Chem 115 OH O • Lactols are oxidized selectively.

HO O HO OH HO O n n O O diol lactone O O Ag2CO3 on H C O H C O • Review 3 H Celite, toluene 3 H H3C CH3 H3C CH3 Procter, G. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon 75-85 °C Press: New York, 1991, Vol. 7, p. 312!318. H C H C Fetizon's Reagent 3 77% 3 (+)-mevinolin • Silver absorbed on Celite has been found to selectively oxidize primary diols to lactones. Clive, D. L. J.; et al. J. Am. Chem. Soc. 1990, 112, 3018!3028.

Fetizon, M.; Golfier, M.; Louis, J.-M. J. Chem. Soc., Chem. Commun. 1969, 1102!1118. Other Methods

Fetizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 13, 4445!4448. • Platinum and oxygen have been used for the selective oxidation of primary alcohols to lactones.

Kakis, F. J.; Fetizon, M.; Douchkine, N.; Golfier, M.; Mourgues, P.; Prange, T. J. Org. Chem. H3C H3C CH3 1974, 39, 523!533. H OH Pt/O2 acetone, water O Ag2CO3 on HO H3C OH HO H3C O H3C OH HO O O 96% O O Celite, C6H6 CH3 CH3 O O N reflux N damsin Kretchmer, R. A.; Thompson, W. J. J. Am. Chem. Soc. 1976, 98, 3379!3380. >74% (±)-bukittinggine • TEMPO has been employed as a catalyst for the preparation of lactones. Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem. 1992, 57, 2575!2585. OH OH

H3C CH3 H3C CH3 OH CH O MOMO OBn Ag2CO3 on CH O MOMO OBn TEMPO, (AcO) IPh 3 3 Boc 2 Boc Celite, C H N N 6 6 H3C H C OH OH H C O O 3 CH Cl , 23 °C 3 80 °C 2 2 CH3 OH CH3 CH3 CH3 O H CH3 CH3 CH3 H3C O CH3 H3C O CH3 O 95% 75%

Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron O Lett., 2003, 44, 57!59. O CH O • Ru complexes have also been employed. 3 N H O O CH3 RuH2(PPh3)4, H C OCH O H C 3 3 H3C 3 OH PhCH=CHCOCH3 O H C O NH2 3 CH3O OH toluene H3C CH CH 3 3 CH3 100% (±)-macbecin I Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S. J. Org. Chem. 1986, 51, 2034!2039. Coutts, S. J.; Kallmerten, J. Tetrahedron Lett. 1990, 31, 4305!4308. Mark G. Charest, Jonathan William Medley

22 Oxidative Cleavage of Diols TBS TBS TBS PhS PhS PhS O O O O O O Sodium periodate (NaIO4) HO O Pb(OAc) O O 4 • Reviews: O OH O O toluene, 0 °C O HO HO 20–45 min Wee, A. G.; Slobodian, J. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing H Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. 420–423. 90% (CH2)6OBn (CH2)6OBn (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 O OH PMBO H PMBO • !-Hydroxyketones can be cleaved as well: O O NaIO4, NaOH, EtOH O O C H C8H15 0 " 25 °C, 2 h H C 8 15 H3C 3 O CH3 H O O OCH3 O H C H3C OH H3C >95% 3 O H3C O Pb(OAc)4 H3C Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.; Jung, J.; Choi, H.-S.; Yoon, W. H. J. Am. Chem. Soc. O CH3 CH3 2002, 124, 2202–2211. CH3OH–PhH (1:2) H3C 0 °C, 30 min CH3 H C CH3 3 CO2CH3 CO CH 82% 2 3

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, • Oxidative cyclizations sometimes occur. This process likely proceeds by a free-radical p. 190–195. 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. OAc OAc Rubottom, G. M. In Oxidation in Organic Chemistry, Trahanovsky, W. S., Ed.; Organic Chemistry, H3C H3C A Series of Monographs, Vol 5, 1982, Part D, p. 1–145. H Pb(OAc)4 H H3C • A common reagent for the cleavage of diols. However, Pb(OAc)4 is a strong oxidant and can PhH, 80 °C, 18 h react with a variety of functional groups. H O H AcO 68% AcO • Examples: H CH H HO 3 CH3

O HO 1. Pb(OAc) , PhH OTBDPS 4 HO OH Bowers, A.; Denot, E.; Ibáñez, L. C.; Cabezas, M. A.; Ringold, H. J. J. Org. Chem. 1962, 27, O 1862–1867. 2. NaBH , CH OH HO CH3 4 3 OTBDPS H3C Mihailovic, M. L.; Cekovic, Z. Synthesis 1970, 5, 209–224. 84% (two steps)

• In addition, Pb(OAc)4 can oxygenate alkenes, oxidize allylic or benzylic C–H bonds, and has been used to introduce an acetate group ! to a ketone. Takao, K.; Watanabe, G.; Yasui, H.; Tadano, K. Org. Lett. 2002, 4, 2941–2943.

Landy Blasdel

23 • Examples Oxidative Cleavage of Alkenes CH 3 O CH3 OH OH 1. O , CH Cl –CH OH H C OBn 3 2 2 3 3 (15:1), –78 °C H3C OBn • Reviews: H H H H Berglund, R. A. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing O 2. thiourea, –78 °C O Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, H3C H C 65% 3 p. 270–275. OTMS OTMS OTBS OTBS Ph O 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. 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 with sterically hindered olefins is difficult, and can be formed instead: Murray, R. W. Acc. Chem. Res. 1968, 1, 313–320. CH3 CH3 • Ozone is the most common reagent for the oxidative cleavage of olefins. 1. O3, (ClH2C)2, 0 °C H3C H3C 2. Zn, HOAc, 75 °C • The reaction is carried out in two steps: H C H3C O 3 CH3 H3C CH3 H C 71% 3 (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. Hochstetler, A. R. J. Org. Chem. 1975, 40, 1536–1541. (2) reductive or oxidative work-up. • Alkenes are ozonized more readily than : • Mechanism: R R O R4 1 3 O O O H3CO H H3CO H R3 1. O , CH Cl , CH OH O + + 3 2 2 3 O O R1 R3 R R O O 2. S(CH ) O R2 R4 R R 1 2 3 2 2 4 O N Ph N OH molozonide 3. NaBH4 R 3 R4 92% O O reductant OTBS OTBS + O O • When a TMS-protected was used in the example above, the authors observed R1 R2 R3 R4 R O 1 products arising from of the alkyne as well. R2 ozonide Banfi, L.; Guanti, G. Tetrahedron Lett. 2000, 41, 6523–6526.

• Considered to be a concerted 3 + 2 of O3 onto the . • Ozonolysis of silyl enol ethers can afford carboxylic acids as products: • Because are known to be , they are rarely isolated and typically are transformed directly to the desired carbonyl compounds. OTMS 1. O , CH OH–CH Cl • Dimethyl is the most commonly used reducing agent. Others include I , , 3 3 2 2 2 (3:1), –78 °C thiourea, catalytic , tetracyanoethylene, Zn–HOAc, LiAlH4, and NaBH4. The latter O CH3 OCH3 two reductants afford alcohols as products. 2. S(CH ) , O 3 2 HO H3C OCH3 –78 °C ! 23 °C • Oxidative workup provides either ketone or carboxylic acid products. The most common oxidants H are H2O2, AgO2, CrO3, KMnO4, or O2. 92%

• Alkenes with electron-donating are cleaved more readily than those with electron- Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan, S. M. J. Org. Chem. 1997, 62, 78–87. withdrawing substituents, see: Pryor, W. A.; Giamalva, D.; Church, D. F. J. Am. Chem. Soc. 1985, 107, 2793–2797. Landy Blasdel

24 Oxidative Cleavage of Alkenes

OCH3 OCH3

OsO4, NaIO4 OCH3 OCH3 1 or 2 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, NTs NTs O 1999, p. 423–426. H3CO H3CO OBn OBn H Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 7, p.564.

VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973. OsO4 (cat.), NaIO4, THF–H2O (3:1)...... 77%

1. OsO4 (cat.), NMO, acetone–H2O–t-BuOH (4:2:1); 2. 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.

• This procedure offers an alternative to ozonolysis, where it can be difficult to achieve • Frequently the two-step protocol is found to be superior to the one-pot procedure. In the example selectivity for one olefin over another due to difficulties in adding precise quantities of ozone. shown, over-oxidation of the aldehyde was observed in the one-pot reaction.

• Sharpless dihydroxylation conditions (AD-Mix !/") can lead to enhanced selectivities. Bianchi, D. A.; Kaufman, T. S. Can. J. Chem. 2000, 78, 1165–1169.

OPMB PMBO OH PMBO O cat. OsO , NMO NaIO H C 4 H C OH 4 H C 3 3 3 H THF, acetone, THF, H2O • An improved one-pot procedure uses 2,6-lutidine as a buffering agent: CH3 CH3 CH3 CH3 CH3 CH3 H2O, 23 °C 23 °C 93% (two steps)

Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.; Sheidt, K. A. J. Org. Chem. CH3 OPMB OsO4, NaIO4, CH3 OPMB CH3 OPMB 2002, 67, 4275–4283. 2,6-lutidine H + CH CH HO CH 3 dioxane–H O (3:1) 3 3 OTBS 2 O OTBS O OTBS • The procedure is most often performed in two steps, but the transformation is sometimes accomplished in one: 90% 6%

H CO H3CO H3CO 3 • Ozonolysis of this substrate resulted in PMB removal. O OsO4, NaIO4 O CH3MgI O • The authors found that without , the !-hydroxyketone was formed in ~30% yield. N N N Using pyridine as base, epimerization of the aldehyde product was observed. H THF, H2O, 23 °C H THF H H CO H3CO H3CO 3 62% conversion 47% (two steps) H 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

25 Oxidative Cleavage of Alkenes Ketone !,"-Unsaturated Ketone

RuO4 See also: o-Iodobenzoic Acid • References: (IBX) earlier in handout General Reference: 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: Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., New York, 1999, p. 346–353. Pergamon Press: New York, 1991, Vol. 7, p. 119–149.

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. Saegusa Oxidation Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013. Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838–3840. • 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. • The reaction can be performed with stoichiometric Pd(II), or can be rendered catalytic if a • RuO4 has been used to cleave alkenes where other oxidation methods (e.g., O3, OsO4/NaIO4) terminal oxidant, such as O2 or p-benzoquinone, is used. have failed. • 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. O OTMS Pd(OAc) PdII OTMS • Solvent mixtures of CCl4, H2O and CH3CN have been determined to be optimal. CH3CN is TMS-Cl 2 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.

TMS-OAc • 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). O II It will also remove aryl and alkyne groups, leaving carboxylic acids. O "-elim Pd PdII O

Pd(0) CH3 CH3 H

CH3 RuO2, NaIO4 CH3 Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013. H C H H 3 CCl –CH CN–H O O Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem. Int. Ed. 1999, 38, CH3 4 3 2 CH3 (1:1:1.5), 23 °C, 1 h 2015–2016 CH3 CH3 68% H3C LiTMP, TMS-Cl O H H Myers, A. G.; Condroski, K. R. J. Am. Chem. Soc. 1995, 117, 3057–3083. O OTIPS THF, –78 °C TMSO OTIPS PMBO PMBO

Pd(dba) •CHCl (5 mol%), O 2 3 H H diallyl carbonate, CH3CN H3C H O OTIPS RuO2, NaIO4 CH3 90% (two steps) CH3 PMBO CCl4–CH3CN–H2O CH3 H CH H 3 82% O CH3 • In this case, diallyl carbonate is used as a terminal oxidant.

Mehta, G.; Krishnamurthy, N. J. Chem. Soc., Chem. Commun. 1986, 1319–1321. Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546–14547.

Landy Blasdel

26 Ketone !,"-Unsaturated Ketone • Examples:

1. LDA, THF Selenation/Oxidation/Elimination O O O –78 °C H2O2, pyridine SePh Ph 2. PhSeBr Ph CH2Cl2–H2O, Ph Buckle, D. R.; Pinto, I. L. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., 25 °C, 30 min Pergamon Press: New York, 1991, Vol. 7, p. 128–135. 66%

Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 14, 1979–1982. • Generating the enolate under kinetic conditions can allow for formation of the less-substituted double bond. Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem. Soc. 1973, 95, 6137–6139.

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.

Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 5434–5447. O O 1. LDA; PhSeCl • PhSeBr and PhSeCl can be used to selenate enolates of ketones, esters, lactones and . H3C 2. H O H3C CH3 2 2 CH3 • PhSeSePh can be used as well, but ketone enolates are unreactive H3C H3C

• Aldehydes can be selenated via: 64%

– 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 H O O – one-step procedure with PhSeSePh, SeO , and a catalytic amount of H SO : Miyoshi, N.; 2 2 4 O O Yamamoto, T.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett. 1982, 23, 4813–4816. 1. LDA, THF, 1. LDA, THF, HMPA, –78 °C HMPA, –78 °C 2. PhSeSePh H H 2. PhSeSePh • Mechanism: CH3 CH3 88% cis-fused trans-fused 85% O O base PhSeBr O H H O O SePh O O

H SePh H SePh [O] CH3 CH3

H2O2, THF, H2O, H2O2, THF, H2O, O AcOH, 0 °C AcOH, 0 °C O Se + H Ph OH ~ 100% 96% Se Ph O H H H O O O O + O O • Common oxidants include H2O2, O3, and NaIO4. H H CH3 • Elimination is syn-specific, see: Jones, D. N.; Mundy, D.; Whitehouse, R. D. J. Chem. Soc., 10 : 90 Chem. Commun. 1970, 86–87. • The example above illustrates how the stereospecificity (syn) of the elimination can be used to • Electron withdrawing groups on the phenyl ring facilitate the elimination step, which can be achieve selectivity in olefin formation. difficult with primary or "- or #-branched selenoxides: Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947–948. Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120–122. Landy Blasdel

27 Alkene Allylic alcohol • Examples:

CH3 CH3 OH SeO2 O CH O CH • References 3 SeO2, t-BuOOH 3 O OH O OH Bulman Page, P. C.; McCarthy, T. J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., CH O dioxane, 23 °C CH O Eds.; Pergamon Press: New York, 1991, Vol. 7, p. 84–91, 108–110. 3 O 3 O H C H C 3 CH 95% 3 CH Rabjohn, N. In Organic Reactions, 1976,Vol 24, p. 261–415. 3 3

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.

• Although the reaction can be performed with stoichiometric SeO2, catalytic methods employing a stoichiometric oxidant (e.g., t-BuOOH) are more frequently used. H3C H3C H C H C • Mechanism: 3 SeO2, t-BuOOH 3

O OH H3C H3C OH Se CH2Cl2 0 °C CH O Se O H H H H H C 3 H C 99% 3 3 TBSO TBSO CH3 ene reaction CH3

[2,3]-sigmatropic rearrangement Yu, W.; Jin, Z. J. Am. Chem. Soc. 2001, 123, 3369–3370.

Se OH HO O Br O H3C H3C CH3 CH3 H

H Singleton, D. A.; Hang, C. J. Org. Chem. 2000, 65, 7554–7560. CbzN CH3

SeO2, t-BuOOH CH2Cl2, 0 °C " 23 °C Selectivity:

(a) oxidation typically occurs at the more highly substituted terminus of the alkene O Br Br Br (b) the order of reactivity of C–H bonds is CH2 > CH3 > CH O O H O [rule (a) takes precedence over rule (b)] + + HO O (c) when the double bond is within a ring, oxidation occurs within the ring H H H

(4) gem-dimethyl trisubstituted alkenes form (E)-!-hydroxy alkenes stereoselectively H H H CbzN CH3 CbzN CH3 CbzN CH3

14% 77% trace 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. Muratake, H.; Natsume, M. Angew. Chem. Int. Ed., Eng. 2004, 43, 4646–4649. Landy Blasdel

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