有機合成方法

1、有機合成方法有機合成方法蔡春教授,博士生導師南京理工大學化工學院課堂教學內(nèi)容課堂教學內(nèi)容1.有機合成的基本概念和實驗方法2.官能團的轉(zhuǎn)化3.有機分子設(shè)計4.保護基團技術(shù)5.現(xiàn)代有機合成化學熱點1.有機合成的基本概念和實驗方法有機合成的基本概念和實驗方法n基本的有機合成反應(yīng):游離基反應(yīng);取代反應(yīng);加成反應(yīng);氧化和還原;重排等n有機合成實驗的基本規(guī)則:實驗方案的設(shè)計;反應(yīng)過程的判斷和跟蹤;產(chǎn)物的定性和定量等n有機合成的主要文獻基本的有機合成反應(yīng)基本的有機合成反應(yīng)游離基反應(yīng):鹵化反應(yīng)(烷烴,芳環(huán)側(cè)鏈等) 分子氧進行的氧化反應(yīng) (醇,醛,酮)聚合反應(yīng)(自由基聚合)游離基的產(chǎn)生游離基的產(chǎn)生CH3CCH3

2、O紫外光CH3COCH32CH3CO60(CH3)4Pb600PbCH3C6H5CO)2O(C6H5COOC6H5CO2H+eHCH3CCH3OHCH3CH3COH飽和碳上的親核取代反應(yīng)飽和碳上的親核取代反應(yīng)SN1, SN2機理，碳正離子中間體X-CRRRYCXYRRRCXRRR由醇制備鹵代烷、鹵代烷的水解 形成形成C=C重鍵的消除反應(yīng)重鍵的消除反應(yīng)鹵代烷中脫鹵化氫：E1，E2，E1cb機理季銨堿中消除三烷基胺（Hoffmann降解），該類反應(yīng)要求有-HRCH2NCH2CH2OHCH3CH3RCH2NCH3CH3CH2CH2向活化和非活化向活化和非活化C-C重鍵的加成反應(yīng)重鍵的加成反應(yīng)烯烴和炔

3、烴的親電加成：鹵素、鹵化氫、次鹵酸、硫酸等RCHCH2H2SO4RCHCH3OSO3H親核加成反應(yīng) 多見于活化雙鍵，如Michael加成 HCCHRONaROHCH2CHORCH2CHCOORROHROCH2CH2COORROCH2CHCOHOR芳香族化合物的親電和親核取代反應(yīng)芳香族化合物的親電和親核取代反應(yīng)親電取代反應(yīng)：硝化、亞硝化反應(yīng)磺化反應(yīng)鹵化反應(yīng)（金屬或路易斯酸催化）F-C烷基化反應(yīng)由羰基化合物進行的親電取代： Vilsmeier甲?；磻?yīng) ArHNCHOC6H5CH3POCl3ArCHOHNC6H5CH3親核取代親核取代ClNO2OH-OHNO2NRLiNR氧化和脫氫氧化和脫氫 甲基

4、、次甲基的氧化伯醇、仲醇、醛、酮的氧化C-C鍵的氧化裂解常用的氧化劑常用的氧化劑 應(yīng)用過氧化物的氧化過氧化氫或過氧化有機酸 RCHCH2CH3CO3HRCHCH2O單過硫酸（Caro酸）：常用于環(huán)酮合成內(nèi)酯 CCOH2SO5COCO含氧的高價無機化合物 HOOHCrO3CH2Cl2OO二氧化硒是一種具有特殊性的氧化劑，它比較專一地氧化羰基的-甲基或亞甲基及C=C雙鍵旁的-亞甲基：CH3CCH3OSeO2CH3CCHOO脫氫脫氫 是加氫反應(yīng)的逆反應(yīng)，原則上加氫催化劑亦可用作脫氫催化劑，常用的脫氫催化劑是一些金屬的氧化物，如Cr2O3, ZnO, Fe2O3等 CH2CH3CHCH2Fe2O3-K

5、2CO3-Cr2O3540還原和加氫還原和加氫 不飽和鍵的加氫硝基的還原常用的還原劑：催化氫化：催化劑的選擇性可以通過配體來調(diào)節(jié) OH2, C6H6(Ph3P)3RhClO化學還原法化學還原法有兩種主要形式:其一是電子，對不飽和化合物進行加成，繼而質(zhì)子轉(zhuǎn)移，該方法中金屬作為電子的來源，水、醇、酸作為質(zhì)子的供給體 CH3CCH3ONa/NH3C2H5OHCH3CHCH3OH其二是氫負離子加成，接著以獨立的一步發(fā)生質(zhì)子化，應(yīng)用最廣的氫負離子轉(zhuǎn)移試劑是氫化鋁鋰和硼氫化鈉 CH2CHCHCHCHOLiAlH4CH2CHCHCHCH2OH羰基化合物的反應(yīng)羰基化合物的反應(yīng)羰基化合物與堿的反應(yīng)：醛、酮與氨基

6、化合物的反應(yīng)RCCH2RORNH2RCOHNHRCH2RRCCH2RNR醛、酮與水、醇的反應(yīng) RCCH2ROROHH+RCOHORCH2RROHH+RCORORCH2R羰基化合物與C-H酸性化合物的反應(yīng)HCN對醛、酮的加成RCROHCNRCROHCN羰基化合物的乙炔化RCRORCROHCCHHCCH醇醛縮合反應(yīng)醇醛縮合反應(yīng)酸、堿均可以催化該反應(yīng)RCOCH2RRCOHCH2RCHRCRO羰基化合物與隱堿的反應(yīng)格氏(Grignard)反應(yīng) 有機鋰試劑與羰基化合物的加成RMgXCOR1R2CR1R2ROMgXH2OH+CRR1R2OHLiCH2COOLICORR1CRR1CH2OHCOHO重排反應(yīng)重

7、排反應(yīng)碳正離子引起的重排 CRROHCRROHH2OH+CRRCRROHCRRRCRO卡賓引起的重排如以重氮甲烷和酰氯生成的重氮酮的重排 RCClOCH2N2RCCHN2ORCCHN2ON2RCCHORCHCOH2OROHNH3RCH2COOHRCH2COORRCH2CONH2氮賓引起的重排（Hofmann降解） RCNH2OBr2NaOHRCNOHBrHBrRCNORNCOH2ORNHCOOHCO2RNH2芳香族化合物的重排反應(yīng)Fries重排聯(lián)苯胺重排NRNOHXNHRNONHRNONHNHH2NNH2環(huán)化反應(yīng)環(huán)化反應(yīng)電環(huán)反應(yīng)多烯烴化合物的體系的末端可以閉合成環(huán)狀化合物 heatlight環(huán)

8、加成反應(yīng)Diels-Alder反應(yīng)CHCOOC2H5CHCOOC2H5COOC2H5COOC2H5卡賓及氮賓對不飽和鍵的加成反應(yīng)CCCCCCNCCCCN有機合成實驗的基本規(guī)則反應(yīng)的后處理: 揮發(fā)性,極性,穩(wěn)定性反應(yīng)產(chǎn)物的分離和純化: 蒸餾,升華,重結(jié)晶,水蒸氣蒸餾,層析純度的標準和純度的檢驗: 熔點,沸點,旋光度(已知化合物) GC,TLC,HPLC(未知化合物)有機合成的主要數(shù)據(jù)庫常用數(shù)據(jù)庫:nSDOSnACS publicationnSpringernWiley intersciencenTaylor & FrancisnRSC有機合成的重要文獻1.Tetrahedron Lett

9、ers2.Journal of Organic Chemistry3.Chemical Communication4.Chemical Reviews5.Accounts of Chemical Research6.Chemistry Letters7.Journal of American Chemical Society8.Organic Letters9.Synthetic Communication10.Organic Process Research & Development2.官能團的轉(zhuǎn)化烯烴CCCCHOHH2O+CCHOCCH3OheatCCOOCS(RO)3PCCHX

10、X=hal, OSO2RbaseCC(CH3)3SiHICCPd/C/H2: ZLi/NH3: ECOCPPh3乙烯基硅烷氫交換 OAcOAcHSiEt3Et3SiOAcOAcHIOAcOAc三乙基硅烷與炔烴發(fā)生選擇性加成，經(jīng)氫交換后可得順式加成產(chǎn)物-二醇消除羥基 OHOHOOCSCSCl2(RO)3P反應(yīng)過程利用生成環(huán)狀中間體而保持構(gòu)型，繼而進行順式消除，立體定向地生成順（或反）異構(gòu)烯烴 炔烴RCCCCHRhalbaseRCCHHhalhalbaseRCCHHhalhalbaseCCNaRhalRCCNNNH2H2NRCONNHTos氧化二酮的雙腙制備炔烴 OONH2NH2NNH2NNH2O

11、2CuCl氯化亞銅/吡啶/氧的配合物使二腙進行氧化裂解，失去氮氣生成炔烴 ,環(huán)氧酮的對甲苯磺酰腙的裂解反應(yīng) OOTosNHNH2NNHTosOheatO氧化異佛爾酮鹵代烴CCOSO2RX-CCXCCOHHXPX3, SOCl2CX4/PPh3親核取代親核取代CCHX(含HF)鹵代烴COCXCOCHOOOOBrBr親電取代(CH3)3SiOCCX2(CH3)3SiOCCXXCCCXCCCXNOOX親電取代X=Cl, Br, I醇CCOHCCONaBH4, LiAlH4CCOROLiAlH4CCONa, NH3LiAlH4CCBH3, H2O2,NaOH(反馬規(guī)則)Hg(OAc)2, NaBH4(

12、馬氏規(guī)則)CCOH OHOsO4(cis diol)N2O, H+(trans diol)H3COHOOKBH4H3COONaOHH2OH3COHOHO酮酸中羥基的選擇性還原，產(chǎn)物以內(nèi)酯形式生成 烯烴的硼氫化反應(yīng) CH2OHBH3, THFNaOH, H2O2蒎烯 （）-（）-順式桃金娘烷醇醚和環(huán)氧化合物COCO-CXX-COHCCRROCCRRRCO3HCCRRH2O2OH-COH2CSRR醚用作保護基團CHOOCH3OHPhCH2ClCHOOCH3OCH2PhCH2COOHCOOHOCH3OCH2PhCHCHCOOHH2Pd/COCH3OHCH2CH2COOH二氫阿魏酸锍葉立徳與羰基化合物

13、環(huán)氧化 SH3CCH3CH3IH2CSCH3CH2PhPhOPhPhOHH含硫化合物R1S-XRR1SRNa2S2XRNaXRSRRSROOR1XSRRR1X三烷基锍鹽（锍葉立 ）ORSROO砜R1XSRRR1OX氧化锍葉立RSO2ClRSO2H (亞磺酸)H一定條件下產(chǎn)生的硫自由基，可以和鹵代烷進行反應(yīng)生成硫醚，產(chǎn)物的收率較高 BrR78.CBuLiSSRRCH2BrSRR98%Tetrahedron Lett., 2002,43:2145胺(伯胺)RNO2HRNH2RCXOX=NH2 Hofmann重排X=N3 Curtius 重排X=OH NH3 Schmidt 重排X=NHOH Los

14、sen 重排RCNHNH3RXCCRRRRNCCH3Hg2+(H. C. Brown酰胺汞化反應(yīng))Delepine反應(yīng)合成伯胺 NNNNNNNNCH2PhClCH2PhClSO2PhCH2NHCH2OSO2H亞磺酸芐氨基甲酯HClKOHPhCH2NH2胺(仲胺)RNH212HC(OR)3H2O, H+RNHRRNH2CR1R2ORNH2RXRNH2CN胺(叔胺和季銨鹽)RNH2(CH3)2SO4RNRRRNH2HCHOHCO2H(RNHCH2OH, RN=CH2, RNHCH3)R1XNRRRR1X醛RCHORCH2OHCr2O72-/H2SO4PCC, PDC, MnO2RCClOLiHAl

15、(OtBu)3RCN氫化二異丁基鋁（DIBAH）RCH2XX=hal, OTosDMSOLiHAl(OEt)3RCN(CH3)2ORXX=hal1 Mg2 HCO2MgX(Vilsmeier合成芳醛)酮RCR1OCRR1OHHCr2O72-/H2SO4ArHR1CClOlewis acidRCClOR1MgXR1CdR1MgXRCNNO(Meyers醛合成法，N季銨化、水解得醛)氯鉻酸吡啶鎓鹽 (PCC)OHNa2Cr2O7H2SO4HO85%PCC: NHClCrO3NHClCrO3重鉻酸吡啶鎓鹽 (PDC)CrO3C6H5NH2O(C6H5NH)2Cr2O72PDCOHPCC/Al2O3O

16、薄荷酮OHPDCCH2Cl2HO香茅醛Kornblum氧化反應(yīng) 氧化對甲苯磺酸酯合成醛（DMSO，Kornblum氧化反應(yīng)） OHH3CSO2ClNaOHOSO2PhCH3HODMSONCH3CH3OLiHAl(OtBu)3HOLiAlH4NCH3CH3CNDIBAH酸性水解堿性水解HOCHNHDIBAH: (CH3)2CHCH22AlH, 二異丁基氫化鋁醛(酮的衍生物)CHCOCCNXX=R, OH, NHRH2NXCHCORORH(COR)3ROHCCORCCH2Zn/Hg, HClH2NNH2, OH-HNR2CCNR2R2HNR2CCNR2HS(CH2)nSHCCSS(CH2)nHO(

17、CH2)nOHCCOO(CH2)nn=2,3n=2,3烯胺烷基化反應(yīng) OCH3ONCH3ONCH3ICH3OCH3NIH2O, H+CH3OCH3O選擇性差羧酸RCO2HRCHOCrO3KMnO4RCH2OHCrO3KMnO4Nickel peroxideArCCH3OTl(NO3)2嗎啉RCCH3OKClOKMnO4(only for cyclic ketones)RCH3(R=phenyl)KMnO4Cl2, hr/NaOH/HClH2SO4RCNRM (M=Li, MgBr)CO2硝酸鉈（III）使芳酮起氧化重排反應(yīng) CCH3OCCH2OHOCCH2BrOTl(NO3)3/K10CH2C

18、OHOCCH2CH3OCHCH3COHOCCH2CH2CH3OCHCOHOC2H5對其它芳基酮的氧化主要產(chǎn)物是2-取代苯乙酸 次氯酸鹽氧化甲基酮 CH3CH3CCHCCH3OKClOCH3CH3CCHCOHO(千里光酸)次氯酸鹽氧化甲基酮，生成少一個碳原子的羧酸 羧酸衍生物RCOHOSOCl2PCl5RCClORCOCROOROHH+RCOROROHbaseHNR2, H2ORCNRROHNR2baseHNR2i5-7-gfedcbaedcbaihgfedcbahgfedcbahgfedcba6-4-3-1-2-ihgfedcbaC=C-C(O)-CH3CH-CHCH-CXF Fu un nc

19、 ct ti io on na al l G Gr ro ou up p I In nt te er rc co on nv ve er rs si io on nC=CC CC=CC CRCH2-SO2PhRC CHC CC-NH2; C-NO2C-OHC(OR)2; C(SR)2C=C-OR; C=C-SRC CC NC=N-OH, C=N-HC=SC=OC=OC-C(O)ZC=CC=OC-OHC-XC-NC-HC-NC=OC-OHC-OC(O)RC-XC-OCH2ORC-NH2C-ORC-HC-OHC=CC-HC(O)ORC-(OR)2C-OHC-ORC-CHOC-CO2HC-CNC=C

20、C=OC-SC-XC-OHC-HC=CjC(O)XhC NjkC-HC-Br8-C-XiC-OHC-OHC(O)ZdcbaedcbafC-NH2C-HjCX-CYCCXC=OhgfiC CHRCH(CO2H)-CH3-C(O)-CH3OOOXCRR=CHXjC OC-NH2C-CN9-C-CH3C-XaeC=O1-adry pyridine: from CaH2 and distilled(an ester)triflatemesylatetosylateSOOORCH2CF3SOOORCH2CH3thiocarbonatedry PyCH3CH3CH3OH(2). for 3 alcohol

21、:LiAlH4(1). for 1, 2 alcohol: C-HC-OH1-ihgfedcbaC-CHOC-CO2HC-CNC=CC=OC-SC-NH2C-XC-OHC-HO CSO PhSnBu3CH3CH3CH3Hn-Bu3SnHCSOPhClO CSO PhRCH2-HCH3SOOORCH2CH3SOOClRCH2OHsteric OKpurification textbook $ 30 / Kgtoluenesulfonyl chloride (s)methanesulfonyy chloride (l) $ 30 / KgjC(O)XPh2SiHCl / InCl3PhPhHPhO

22、HPhJOC, 2001, 66, 7741.ii. Ph2SiHCl / InCl3i. p-TsCl / LiAlH4i. ClC(S)OPh / n-Bu3SnHPhPhOCl2InCl SiPh2Hvia:via:a unique Lewis acid catalyst, acceleratedeoxgyenationInCl3indium trichlorideii. Et3SiH / Lewis acid J. Org. Chem. 2000, 65, 6179JOC, 2000, 65, 6179.CHCl2rt, 3 hr1-bBu3SnH: (l), easy to remo

23、vePh3SnH: (s), hard to removeMe3SnH: too volatile, toxic(AIBN)NNCNCN- N2CNazobisisobutyronitrilen-BuSnHn-BuSnBrRn-BuSnBrRHRunstable in acid, form H2 gas; stable in weak baseNaBH3CN: stable at pH 5-6hygroscopic, dried self, suggest: buy small amount each time(Grignard reagent)H2OMg / Et2OJOC, 1969, 3

24、4, 3923.HBrNa / NH3; Li / NH3; Na / EtOHZn; Fe; Sn; Mg(3). metal reduction(2). hydride reduction(1). free radical reduction JACS, 1972, 94, 8905.C-HC-XAIBNn-Bu3SnHHBrradical initiatorNaBH4 / InCl3 / CH3CNradical reagentn-Bu3SnH / AlBNJACS, 2002, 124, 906.iiii NaBH3CNi LiAlH4iiiii NaBH4iiTHL, 1969, 3

25、095.JOC, 1976, 41, 3064.iv LiBHEt3 (super hydride)n-BuSnHn-BuSnmechanism uncertain, probably radicalburn filter paper if dryRaney Nickel: Ni - Al alloy, suspensiontosylimidetosylamideJCS Perkin Trans I, 1973, 654.(3). LiAlH4 / CuCl2NaBH4 / NiCl2NaBHEt3 / FeCl2 (or CoCl2, VCl3)(2). Li / NH3(1). Raney

26、 NiNSO2ArSO2ArRCH2RCH2NSO2Ar- BuHRCH2NHSO2ArBuLiLiAlH4RCH2-HCH3SOOClRCH2NH2BuLi1-d1-cC-HC-SLiAlH4C-HC-NH2RCH2-HRCH2NH2Hinsbergs testradical mechanismweaker C-N bondChemistry:R-SHR-S-RR2SOR2SO2R-SS-Rremove: Hg+; Ni(1).(2).Ar-HNaNO2HClH3PO2Ar-NH2RCH2NH2RCH2NMe3R=CH2R-CH3(4).X-RCH2NMe3OH-Ag2OJOC, 1985,

27、 50, 427.p-TsClNaHNaHp-TsClNH2Clvia:NNH2SO2ArArNaHNNHArNNArAr-H- ArSO2H(3).Ar-NH2Ar-Hp-TsClJOC, 2001, 66, 8293.ArSO2ClRaney NiNHNSMeO2CCH2PhEtO2CONHNHMeO2CCH2PhEtO2Cfor acyclic, may C=C side productbasicneutralacidicHHH-N N TsCH2Cl2C=OC-H1-e(1). Clemmensen reduction: Zn-Hg / HCl(2). thioketal: (3).

28、Wolff-Kishner reduction:(5). Tosylhydrazone reduction (Shapiro reaction): (modified Wolff-Kishner reduction):)(6). enol derivatives: SHSH/ BF3, CH2Cl2 / RaNiN2H4, OH-, heatTsNHNH2 / REDlimit: for -H compd.HHRa(Ni)BF3,SSHHSSHHOthioketal: inert to LAH; react with RaNi; smell terrible and stay long; di

29、scard shosesthioketalmajor side-product: drawback of the reactionNN- N2OH-HNNHN NHOH-NNH2N2H4OHHNCHCOCF3SOOOSOCF3OCCOTfH2PtO2CCHHHTf2O / N/ H2 / PtO2LAH, NaBH4: 2 group compete at Stanford U.B2H6: very flamable, fire if shoot out from syringeOOB Hbest suitable for aryl ketone (ArCOR); not good for c

30、onjugate ketone preparation: HgCl2 into ZnRED choice: MeLi; NaBH3CN (good)PtO2 + H2 = PtOHOC6H13similar: Sn / HCl(4). Pd-C / HCO2NH4: mild, efficientPhPhOPhPhSynthesis, 2001, 16, 2370.HCO2NH4Pd-C(7). Et3SiH / CF3COOHPhONO2PhNO2JOC, 1973, 38, 2675.CF3COOHEt3SiHHOOHHHPtO2H2HOOH$ 50 / 25 gJOC, 1993, 58

31、, 4979.syn-additionprepare isotopeCH3CO2DHDC=CC-C-H1-f(1). H2 / cat(2). HN=NH (diimide)(3). B2H6 / RCO2H, heatWilkinsons catalyst: regioselective, prefer isolated double bondsoluble in org solvent, 9 Ph groupstereoselcetive: same side as OH (due to H bond)catalyst: Pd-CPtO2Rh-C; Rh-Al2O3; RhCl(PPh3)

32、3NiOORhCl(PPh3)3N2H2: unstable; generated in situ from DEAD (diethyl azodicarboxylate) or from: N2H4 + H2O2; N2H4 + Cu(II) + O2; NH2OH + NH2OSO3via: HB RRNNCO2EtEtO2CNNCO2HHO2COH- 2 CO2NNOOHOOHNNHH- N2CCRRRRCCRRRRHHJCS, PT1, 1986, 546.OOCO2MeOOCO2MeRhCl(PPh3)312 hrJACS, 1979, 101, 7020.NRNRH2 , PtO2

33、TFA , 60 R = NHAc , NH2JOC, 2002, 67, 7890.in acetic conditionbenzene(4). n-Bu2SnI / MgBr2-Et2O / H3O+OEtOH3O+OEtOMgBr2-Et2On-Bu2SnIJOC, 2001, 66, 8690.OSnHOEtIRROOEtSnIRHRvia:not radical mech.pyridinium betainesolventNPhPhPhRRHNPhPhPhRRCO2- CO2b.p. 230 Chighly toxic, cancer suspected agent?= HMPT:

34、hexamethylphosphoric triamide (Me2N)3P=Otoxic?characteristcs: IR, CMRwhich is + ?CCRNnot quite same: not for H-e-CO2HCO2H(3). organic electrochemistry-CO2(1). particular structure: C-H1-g(1). K / Al2O3 K / HMPA(2). Na / NH31-h(2). normal structure: SOCl2 / PhSeH / n-Bu3SnHC CNJOC, 1980, 45, 3227CN:

35、X (pseudo halogen), form KCN, NaCN with IA elementsHMPA: hexamethylphosphoramide (Me2N)3P=Oyes for white mouse, uncertain for humanmodified to: NNOC CO2HC-HCOSePhRCH2RCH2HCOOHRCH2COClRCH2PhSeHn-Bu3SnHSOCl2(radical mechanism?)other Cl sources: PCl5; (COCl)2oxalyl chlorideorganoselenium chemistryOHORO

36、1-iCHOC-H(1). RhCl(PPh3)3 (Wilkinsons cat)(2). Rh(DPPD)2+ Cl-oxidative additionrearrangementreductive eliminationRhPPh3PPh3CClO+RHRhPPh3PPh3CROClHRhPPh3PPh3ClHRCORCOHRhPPh3PPh3Cl- PPh3ClRhPPh3PPh3PPh3DPPD = Ph2P-CH2CH2-PPh21-jC(O)X-CH3RClORCH3HSiEt3 / B(C6F5)3JOC, 2001, 66, 1672.OOOOHAlCl3LiAlH4acti

37、vator / hydride sourceHOCH3HClOCH3OCH3OCH3RCH2 OROORRORORRCH2 OCH2CH2OH(3). AlCl3 / LiAlH4(2). HCl / NaBH3(CN)(1). h / HSiCl3RC-(OR)2RC-OR2-bSiPhPhClSiCH3CH3ClCH3SiCH3CH3ClNNH/ TBDMS-ClTBDPS-ClEt3N / TMS-Clacid: H2SO4H3PO4BF3-Et2ORC-OCH2CH=CH2RC-OCPh3 = RC-OTrRC-OtBuRC-OCH3RC-OSiR3RC-OCH2Ph = RC-OBZ

38、l = RC-OBni. Willianson synthesis OK: Si - Cl bond longii. stability of silyl in acid/base: RC-O-TBDPS RC-O-TBDMS RC-O-TBSiii. abbrev.: TBDMS = tert-butyl-dimethylsilyl = TBS = Silyl group:(RO-Tr)Trityl group: (tirphenylmethyl)i. SN1 reactionii. abbreviation: triphenylmethyl = trityl = -CPh3 = -Trii

39、i. advantage: high MW, easy to handle (small amount become large amount)baseBrWillianson synthesis (base, SN2) not work: elimination side-product with baset-Butyl group:i. abbreviation: benzyl = PhCH2 = Bzl = Bnii. deprotecting: H2 / Pd-CPhCH2-ClPhCH2-Br: reactivity goodPhCH2-I: reactivity better th

40、an PhCH2Br, generated in situ, PhCH2Br + NaIPhCH2-X: Benzyl- group:i. Williamson ether synthesis, SN2 typeii. not a good protecting group, too stable to convert back to alcoholMe group:CH3-X: CH3I; CH3OSO2R; (CH3)3O+ BF4-, (CH3)2SO4base: NaH, n-BuLi, Ag2O(4). t-Bu: acid cat / (3). allyl: base / Br(6

41、). silyl: Et3N / R3SiCl(5). trityl: py / Ph3C-Br(2). PhCH2-: base / PhCH2-Xapplication: for protecting groupedcba2-RC=CRC-HRC(O)ORRC-(OR)2RC-OHRC-ORRC-OHRC-OR(1). Me: base / CH3-X2-a(7). acetal / ketal: (see 3e)fRC-CNgenerate H2, or butane gasJOC, 1988, 53, 2985.trimethyloxonium tetrafluoroborateJCS

42、, 1930, 2166.(8). ArF / CsFROHFNO2RONO2aromatic substitution reactionusually contain NO2, F as leaving groupCsFsee mech-13hvI2 / Pb(OAc)4 OOHOIHOHOIlimit: for 56 ring neighboring OH group(1). I2 / Pb(OAc)4 / hvradical mechanism: SiCl3t-BuORaNi with C=SJOC, 1983, 48, 1127.JOC, 1974, 39, 2470.RaNiLawe

43、sson reagentSOOOO P4S10tBu-OO-tBuHClOOOR COOR2-cRC-OR2-dRC-ORRC-H(1). hv / HSiCl3(2). HCl / tBu-OO-tBu(3). Lawesson reagent / RaNi(4). BF3 / NaBH4PSPSSSOCH3CH3OOOOOArArOOArArBF3NaBH4Lawesson reagent(2). Organoelectro Chemistry: e- / Pt, R4NOTsNOHPhNOPhe/ PtR4NOTs(79 %)NOHPhRRMgBrAngew Chem Int Eng.,

44、 1964, 8, 525.limit for: lactoneHNNHNH2OHHHNNHNH2OOCH3 NCS(3). NCS / MeOHMeOHJOC, 2002, 67, 4498.limit: for allylic alcoholC-C-OR2-eC CCCONaBH4OEtCO2EtOHCO2EtHHOHHOHOOi. Hg(OCOCF3)2, ROH / NaBH4i. peracidii. via halohydrin: HOBr, H2O / K2CO3iii. Sharpless asymmetric epoxidation: t-BuOOH, Ti(OiPr)4 /

45、 (+)-diethyl tartrateHg(O COCF3)2OOmCPBAH2OHOBrBrBrOHtrans-diaxial attack!Olimit for allyl alcohol, high e.e.Sharplessstereoselectiveracemic productsHg O+COCF3racemic productsHOBr generation: NBS + H2O + DMSOOOconversion: HOAcOHOAcOSO2MeOAcEtOHC=C-ORC=C-ORC-C-ORC CC CC CCCO2-e.12-e.22-e.3ii. HCHOPri

46、ns RxnOSO2MeOHOOOHOHOHHCHO (aq)OOvia:H2OHCHOSynthesis, 1980, 871.CO3HCO3HClCF3CO3HCO3HCO2Hgood resultperoxybenzoic acidMCPBA(m-chloroperoxybenzoic acid)stable solid, 85 % (contain MCBA) for safetyperacid:iv. t-BuOOH, Mo(CO)6v. KHSO5vi. H2O2, t-BuOH, MnSO4 / NaHCO3, pH 8JACS, 2001, 123, 2933.HO2CHO2C

47、Onew, cheap, simple, green chemistrypotassium hydrogen preoxideconvenient, inexpensive, powerful.JOC, 1980, 45, 4758.JOC, 1982, 47, 2670.OOHOOBr2via:Br2 / ROHOOBrHHeterocyclic Chem, 1990, 27, 583.C-C-OR2-fC NCROH / HClEtCNEtCOEtOEtOEtEtOHHClJACS, 1942, 64, 1825.(+)-diethyl tartratechiral sourceJOC,

48、2001, 66, 521.C-OHC-HC-ORC-NH2C-X3-abcd3-aC-OHC-HOH(1). PhI(OAc)-O2-Mn(TPP)(2). organic electrochemistryPhI(OAc)-O2-Mn(TPP)JACS, 1983, 105, 3515.JACS, 1983, 105, 2920.NO2NH2OHe-H2O(3). X2 / hv / OH-indirectHOHOHOOHHOH3-a.13-a.23-a.3HROSeOROHSeHOORSeOHROHSe(OH)2H2ORHROHSeO2JACS, 1972, 94, 7154.SeO2fo

49、r allyl H:(1) Me3SiCl / MPCBA/H3O+(2). O2, LDA, (EtO)3PROCO2RROCO2ROHOOROROOPOEtOEtvia:JACS, 1975, 97, 6909.PhOPhOSiMe3OPhOSiMe3PhOSiMe3OHOHPhOOH1. Me3SiClMCPBAJOC, 1975, 40, 3427.H3OO2, LDA,(EtO)3PPhOPhOOH2. MCPBAMe3SiClihgfeC=OC-OHC-OC(O)RC-OCH2ORC=CjC O(1). Me: application: deprotecting(2). PhCH2

50、- (5). trityl: (6). silyl: (3). allyl: (4). t-Bu: RC-OCH2Ph = RC-OBZl = RC-OBnRC-OSiR3RC-OCH3RC-OtBuRC-OCPh3 = RC-OTrRC-OCH2CH=CH2C-OHC-ORNi. TMSIii. BF3-Et2O / R-SH (or HS-CH2CH2-SH)iii. BBr3 / CH2Cl2, 0-10 C/ LiI, heatvi. RCH2-OHRCH2-O-SiMe3Me3Si-IRCH2OCH3SiMe3- CH3IRCH2-O-CH3I- I-RCH2-O-CH3RCH2OC

51、H3BF3BF3- RSCH3RSHRCH2-OHOCH3OH+heat- CH3Cli. H2 / Pd-Cii. CNCNClClOO, OH-OOH- tolueneOH-OHO COCH3OO CH2OCH3H2 / Pd-CO CH2RhCl(PPh3)3, H3O+- EtCHO- Ph3COHHOAcHOHHO CPh3- Me3CCF3CO2HOHOH3O+RhCl(PPh3)3HOHHOHOi. TFA (CF3CO2H)ii. HBr / HOAciii. TMS-Ii. HOAc: weak acid: good leaving groupii. H2 / Pd-C: r

52、eserve, too strong, might affect other groupneed stronger acidi. F- : HF, Py-H+ F-; n-Bu4N+ F-ii. mild base: not for TBDPSiii. mild acid: only for TMS, not for TBDMS, TBDPS-SiMe3-SiBuMe2-SiBuPh2Si - F: 140 Kcal/molif HOBr: OK for TMDMS JOC, 1987, 52, 4973.OCOCF3+JOC, 1973, 38, 3224.iv. AlCl3 / RSHTH

53、L, 2001, 42, 9207.MeOCO2MeHOCO2MeCH3(CH2)11SHodorlessAlCl3v. / heatCl-NH3-b NHCl-triphenylmethylorganic base: TMGORCH3CNNHNNOHR = TBDMS, TBDPS, AcTMG1h1,1,3,3-TetramethylguanidineTMG:Organic Letters, 2003, 5, 209.3-c(1). HNO2 / H3O+C-OHC-X(1). OH-(2). KO2 / DMSO3-dC-OHC-NH2not practically useful: R-

54、OH cheaper than R-XJOC, 1975, 40, 1678.(2). Na2Fe(CN)5(NO) / K2CO3 / H2ONO+H3O+OHN2+X-NH23-eR-OHR-OC(O)R(1). Symmetry:ketal: use H3O+acetal: use H3O+(2). unsymetry: RO-MOMRO-MEMRO-MTMRO-THPMeOH+H3O+OHHOMeOMe+OHHOH3O+OOOi. H3O+; ii. HCl / MeOH; iii. BBrMe2p-TsOH / MeOH i. H3O+; ii. ZnBr2 / CH2Cl2; ii

55、i. BBrMe2HgCl2 / CH3CN (aq.)actually, acetal exchange rather than hydrolysisH3O+RO-HRO-HRO-HRO-HRO-CH2SCH3RO-CH2OCH3R OOSO3HOCH3OCH2ClCH3OCH2CH2OCH2ClCH3SCH2Clp-TSOHOp-TSOHCSA (camphorsulfonic acid)(p-toluenesulfonic acid)SO3HCH3or CSARO-MOM highly toxic, world top 10 killer, discardnot toxicnot dan

56、gerousTHP: tetrahydropyranRO-CH2OCH2CH2OCH3JOC, 1984, 49, 3912.(3). Ag2O / H2OH3O+H3O+H3O+THL, 1975, 3183.JOC, 1986, 51, 3913.RO2C(CH2)3CHRNH2RO2C(CH2)3CHROHNa2Fe(CN)5(NO)K2CO3 / H2O3-f(1). base: KHCO3 (or K2CO3, NH3) / MeOH; NaOH (1 %, or 0.5 N)(3). RED: (2). acid: H3O+PPh3 / DEAD / RCO2H / OH-3-gR

57、 C O ROR OHC OHCOHMitsunobu inversion Synthesis, 1981, 1.JOC, 1987, 52, mon esters: formate = HCO2R - KHCO3 (or K2CO3, or NH3) / MeOHtrifluoroacetate = CF3CO2R - KHCO3 (or K2CO3, or NH3) / MeOHacetate = CH3CO2R = ROAc - KHCO3 (or K2CO3, or NH3) / MeOHbenzoate = PhCO2R = ROBz - NaOH (1 %) / MeOHpival

58、ate = tBu-CO2R = ROPv - NaOH (0.5 N) / EtOH(or K2CO3 / MeOH)MeOHMeOHP-TsOHLAHHClOOOHOOHOHOOHOOOOselectivity:PPh3 / DEADR-O-H*PhCO2HN NHCO2EtEtO2CPPhORPhPhOH-PhCOROHOPhCO2H*HOPPh3N NHCO2EtEtO2CPPh3ROHEtO2CNNCO2Eti LiAlH4ii. NaAlH2(OCH2CH2OCH3)CH3O2CCO2CH3HOOHNaAlH2(OCH2CH2OCH3)2C6H6, r.t.hydride:elec

59、tron:Na / NH3 AGIEE, 2002, 41, 3028.regioselectivity determined by reactivity. reactivity: ald ketone estergenerate acetoneopposite to Oppenauer oxidationJCS, 1969, 1653.JCS, 1970, 785.JACS, 1972, 94, 7159.OIrCl4Al(OiPr)3O+AlOiPrOiPrOHLAHOOOOHHHO Al(OiPr)2IrCl3OHHOHHOHLAH - almost all: ald, ketone,

60、acie, ester, acyl X, anhydrideNaBH4 - not for acid, ester (but LiBH4 work for ester)B2H6 - not for ester, acyl X, anhydride; from top: LiAlH4; NaBH4; Na / NH3Al (OiPr)3 / iPrOH - Meerwein-Pondorf-Verley rxnIrCl4 / iPrOH / P(OMe)3 - Henbest rxnLiBH(secBu)3 - H. C. Brownfrom bottom:COHC O(2). stereoselective: