1、WuXi AppTecTraining CommitteeOxidation MethodsRui ZhangActivated DMSO: Swern, Pfitzner-MoffattMetal oxidants: MnO2, Corey, Jones, Ley (TPAP) Other oxidants: Dess-Martin (DMP) TEMPO, O3Books 2. When (COCl)2is used, the initial intermediate is unstable above -60 0C for benzyl or allylic alcohols, or a
2、bove -20 0C for other alcohols;3. Yield of Swern Oxidation is high. However, the condition can cause epimerization of alfa -chiral center and C=C migration and was not good in too small (mg) or too large scale (Kg).S OOClOClCl OClOOSOClOOSSCl+CO2+COClSClR1R2HOR1R2OSClHR1R2OSHNEt3R1R2OSR1R2OSHR1OR2+M
3、e2SR1R2OSR1R2OSByproductProductOOO OHOHOHOHOOO OHOHOHO1. DMSO, (COCl)2DCM, -60 0C, 45 min2. Et3N, 15 min81%J. Org. Chem. 1988, 41, 2972-297912Page 1WuXi AppTecTraining CommitteeOxidation MethodsRui ZhangAlfa-epimerization is a common problem for activated DMSO oxidation. Lower temperature and bulky
4、base can reduce epimerization.Cl substitution occured at higher reaction temperature for benzyl and allylic alcohols.Oxidation of Alcohols: Pfitzner-Moffatt OxidationOOOAcOHOOOAcO1. DMSO, (COCl)2,DCM-600C, 30 min2. Et3N, -300C-rt,1h(91%)J. Or g. Chem. 1985,50, 4673-468156OHClDMSO, (COCl)2,Et3N, DCM,
5、 -200CJ. Org. Chem. 1979,44, 4148-4150HO HHOHOH HClDMSO (moist), (COCl)2Et3N, DCM10 (40%)J. Am. Chem. Soc. 1986,108, 3513-35157 89NCNR3R3NC NR3R3NCNHR3R3HSOSOHNCNHR3R3SOR2R1HOHNCNR3R3SH3CH2COR2R1OHSCH3H2CR2R1OHNCHNR3R3OH- +SH3CCH2R2R1OHR2R1O+Me2SActivition of DMSOActivation of the alcoholFormation o
6、f the productOHOOHCO2EtOHOOHCO2Et1. DCC (10 eq.)TFA/PyridineDMSO (20 eq.)benzene, 5.5 h, rt; 57%2. NaBH4(4 eq.)THF, -60 to 0 0C, 2 h44%J. Chem. Soc., PerkinTrans. 11991, 1951-195811 12OHNHOCO2HBnOOHNOCO2HBnODMSO, SO3.PyEt3N, rt, 1hJ. Chem. Soc. PerkinTrans11985, 391-3984(48%,50%ee)3Mechanism of Pfit
7、zner-MoffattGeneral features of Pfitzner-Moffatt Oxidation1. Milder than Swern oxidation, but unprotected tertiary alcohols are often eliminated; 2. Water soluble activator EDC can be used instead of DCC, which is difficult to remove.Page 2WuXi AppTecTraining CommitteeOxidation MethodsRui ZhangOxida
8、tion of Alcohols: MnO2Oxidation of Alcohols: Corey Oxidation General features of Corey OxidationGeneral features of MnO2oxidationR2R1OHR1R2OPCC/PDC, CH2Cl2,Additives,rtR1=H,Alkyl,orArylNHCrO3Cl-PCCNHCr2O72-2PDCOHR1R1OHOPDC, DMFAdditives,rtOHPCC (1.5 eq.), CH2Cl2,NaOAc, rt. 2h, 84%OPCC (1.1 eq.), CH2
9、Cl2,NaOAc, rt. 2min, 100%J.Org.Chem.1979, 44,2809-2810OHO7 815 16PCC (1.5 eq.), CH2Cl2,NaOAc, rt. 2h,100%OHOPCC (2 eq.), CH2Cl2,NaOAc, rt. 2h, 88%J.Org.Chem.1977,42,682-6851718O O OPCC (1 eq.), sealed tubeCH2Cl2, 60-700C, 12h70%J. Org. Chem. 1984, 49,1647-164919201. Used in oxidizing benzyl or allyl
10、ic alcohols; 2. MnO2 can be re-activated at 110-130 0C for 3-4 h before used (Infra-red oven);3. The reaction was carried out at room temperature, excess (10 eq) MnO2needed to get to completion.1. Additives (NaOAc, silica gel, celites, MS) are necessary for PCC and PDC oxidation. 2. PDC is much weak
11、er than PCC, but not acidic. PDC in DMF was a useful way to oxidize alcohols to acids without alfa-epimerizationNNSOHHNNNSOHNWO2007/163921314MnO2(15 eq.), THFPage 3WuXi AppTecTraining CommitteeOxidation MethodsRui ZhangCleavage of active C=COxidizing of allylic C-HOxidizing of 1,2-diolOxidation of A
12、lcohols: Ley (TPAP) OxidationGeneral features of Ley OxidationOver-oxidation of primary alcohol caused by waterO OPCC (4 eq.), CeliteCH2Cl2,rt.2h21 2265%OOTetrahedron 1995, 51,10875-10882CO2EtOTBDMSPCC (20 eq.), PhH4AMS,reflux,24h65%Synth. Commun.1984, 14, 89-9423 24CO2EtTBDMSO OR1R2OHR1R2OTPAP (5%
13、mol)/NMO ( 1.5 eq.)Solvent/4A MS/rtR1-2= H, alkyl, aryl, alkenyl, alkynylSolvent: CH2Cl2, MeCNRu OOOOTPAPRu OHOOHONOONMO+NOH2O(i-Pr)4N(i-Pr)4NPhOMeHONHONHBocPhOMeHONHONHBocO1. TPAP (10 mol%)NMO (2 eq.)CH3CN, r.t., 1h2. TPAP (8 mol%)NMO (2 eq.)H2O(1eq.)18h, 87%J.Org.Chem.1999,64, 3000-30012728Ley Oxi
14、dationRecycle of Ru oxidant1. Catalytic amount of TPAP used, good ee retention of -chiral center;2. 1alcohols are oxidized to aldehydes in absence of water (when finely ground 4 MS added), to acids in presence of water;3. Adding TPAP in portions and keeping adequate cooling is necessary to avoid pot
15、ential explosion.OHOHOOPCC (20 eq.), CH2Cl24AMS,rt,2h79%Synth. Commun.1982, 12, 833-8382526Page 4WuXi AppTecTraining CommitteeOxidation MethodsRui ZhangCascade reactions used to prepare alkenes/alkynes 1, -Diols oxidized to lactones (resulting hemiacetal further oxidized)OBnOHOHOOOBnOOOOTPAP (1 mol%
16、)NMO (6 eq.)CH2Cl2, r.t., 8h51%J. Am. Chem. Soc.2000, 122, 3830-38383132HOOTBSOONOBnOTBSOONOBnBrBr1. TPAP, NMO2. CBr4, PPh3,NEt355%J. Org. Chem. 1996,61, 8366-836729 30IOOAcOOAcOAcDMPR1R2CHOH R1R2CODMPR1R2C=N-OH R1R2CODMPOxidation of Alcohols: Dess-MartinIOOAcOOAcOAcDMPIOOAcOOAcR2OHR1- AcOHR2OR1HOOI
17、OOOAc+AcO- AcOH-R2OR1iodinaneCarbonylcompoundPreparation of IBX and DMPGeneral features of Dess-Martin OxidationICOOH2-iodobenzoicacidIOOOOHKBrO3,H2SO4Oxone(1.3eq.)H2O, 700C, 3hJ. Or g. Chem. 1983,48, 4155-4156J. Or g. Chem. 1999, 64, 4537-4538Ac2O0.5% TsOH800C, 2 hJ. Chem. Soc., PerkinTrans. 2, 199
18、7, 589-591J.Org.Chem. 1993,58, 2899-2899IBXDMPOxone, 2 KHSO5-KHSO4-K2SO4, commercially availableOROOROArArCHONuOHOROArODMPTetrahedron Lett.2001, 42, 3939-3941Mechanism of Dess-Martin oxidation1. Mild reaction conditions (room temperature, neutral pH); selectively oxidizing alcohol.2. IBX can oxidizi
19、ng 1and 2alcohol to carboxyl product in DMSO under mild conditions.Page 5WuXi AppTecTraining CommitteeOxidation MethodsRui ZhangGood ee retention of near chiral centerConfiguration of conjugating C=C remainedDMP is especially good for Fluo-containing compoundsDMP used in the hydrazone protection rem
20、oval of C=OOxidation of Alcohols: TEMPO OxidationNO1/2 NaOClTEMPONONOORHHNOHRCHONaClO2RCOOHNaOClMechanism of TEMPO OxidationGeneral features of TEMPO OxidationOOH OOOO OODMP, CH2Cl2,25 0C, 1.5h95%Synlett. 2001, 1974-19763536PhHOFFOOEtPhOFFOOEtDMP, CH2Cl2, rt, 25min79%J. Org. Chem. 1989, 54, 661-6683
21、7 38NBuCOOHOOOOHNBuCOOHOOOOHOTEMPONaClO,NaClO2J. Org. Chem. 1999,64, 2564-2566MeCN/H2O2-4h85-100%3940R NOHR R1OR1DMP, CH2Cl2,rt,20min90%Synthesis 2000, 1469-14731. The oxidation is cheap, mild and can be carried out in small and large scales; 2. Selectively oxidizing primary alcohols;3. Alcohols can
22、 be conversed to aldehydes or acids at different conditions (pH, oxidants).HONHFmocOCH3HOHNHFmocOCH3O96% eeSwern: 81% eeTEMPO: 90% eeDess-Martin: 96% eeTetrahedron lett.2000, 41, 1359-136233 34Page 6WuXi AppTecTraining CommitteeOxidation MethodsRui ZhangOxidation of C=C: Criegee OzonolysisTypical pr
23、ocedure: ozone is bubbled through a solution of the alkene in dichloromethane at 78 0C until the solution takes on a characteristic blue color, which indicates consumption of the olefin.Oxidation of C=C: Wacker OxidationGeneral features of Wacker OxidationExpansion of Wacker OxidationRH R1R2O3CH2Cl2
24、OOORH R1R2ROHR1R2OH+NaBH4ROHR1R2O+H2O2OROHR1R2O+PPh3or Me2SORH HHRO HHPd(II)-complex (Cat.),H2O/organic solventCu(I)or Cu(II)salt (Cat.)O2atomosphereRH HHRNu HHPd(II)-complex (Cat.),NuH/organic solventCu(I)or Cu(II)salt (Cat.)O2atomosphereROROOPd(II)-complex (Cat.),H2O/organic solventCu(I)or Cu(II)s
25、alt (Cat.)O2atomosphereR1 R1RNa2PdCl4(Cat.),TBHP or H2O2H2O, AcOH/i-PrOH/NMPR1ORR1OOOOOOOOOOHOONa2PdCl4(40 mol%)TBHP (20 mol%)AcOH:H2O(1:1)800C, 50h; 69%Org. Lett. 2002, 4, 859-86243 44NHBocOHPhONHBocOHO3(stream)CH2Cl2/MeOH(5:1), -780C, 5minMe2S(5eq.)rt, overnightJ. Am. Chem. Soc. 2003, 125, 3442-34
26、434142 Terminal alkenes react much faster than internal or 1,1-disubstituted alkenes ,-unsaturated ketones and esters are oxidized regioselectively to the corresponding -keto compounds using catalytic amounts of Na2PdCl4and TBHP (t-BuOOH)or H2O2as co-oxidants;Page 7WuXi AppTecTraining CommitteeOxida
27、tion MethodsRui Zhang Swern Oxidation is a mild way to oxidizing alcohols to aldehydes or ketones in good yield at low temperature; PCC and PDC, which can give good yield with solid additives added, are reliable oxidants to converse alcohols to aldehydes, ketones or carboxylic acids. Dess-Martin Oxi
28、dation was mild and can give stericalretention products. Ley Oxidation (TPAP) tolerates most of sensitive functional groups and has a special application in floride and hydrazone. TEMPO Oxidation was a green reaction that can be used in small and large scales and can oxidizing primary alcohols to al
29、dehyde or acids. MnO2was widely used for oxidation of benzyl and allylic alcohol. Ozonolysis was used to cleave C=C and can give alcohols, aldehydes/ketones or acids, depending on the work up methods.Review Questions (Provide the most suitable conditions or major products for the below reactions)OO?
30、45 46?45 47OTBSTBSOHOOHOTBSTBSOOO?48 49NHOCbzRNHOCbzRO5051?HNHOBocOMOMPh2t-BuSiODMP, Py, CH2Cl2,rt,30min?52TPAP (5%), NMO (4 eq.)4AMS,CH2Cl2,rt,12h?OHOHOOOOOOOHOOOOHOHSummaryPage 8WuXi AppTecTraining CommitteeOxidation MethodsRui Zhang45 47OOOHOHOOOOHMnO2,CH2Cl2,rtAnswers of the review questionsOTBS
31、TBSOHOOHOTBSTBSOOO48 49TPAP (5%), NMO (4 eq.)4AMS,CH2Cl2,rtHNHOBocOMOMt-BuPh2SiODMP, Py, CH2Cl2, rt, 30min52TPAP (5%), NMO (4 eq.)4 A MS, CH2Cl2, rt, 12hNBocOMOMt-BuPh2SiO53NBocOMOMt-BuPh2SiO54ONHOCbzRNHOCbzRO50 51PDC, DMF, rtTPAP, NMO,H2O, CH3CN, rtH5IO6,CrO3(Cat.)Wet MeCN1. DMP/CH2Cl22. NaClO2,t-BuOHOOOHOOO4546DMSO, (COCl)2,CH2Cl2TEA, -600COOHPCC, NaOAc, CH2Cl2rtDMP, CH2Cl2,rtTPAP, NMO, 4A MSCH3CN, rtPage 9
