Wittig Reaction - Phosphorous Ylides O + Ph3P CHCH3 R H H3C R ylide •Stereoselectivity increases as the size of R increases •cis-olefin is derived from non-stabilized ylides Mechanism: Irreversible [2+2] cycloaddition O PPh P Ph3 Ph P O 3 H 3 + Ph PO + O 3 H H H3C R R R H H3C H H C H H3C R !" ! 3 R group of aldehyde 2!a + 2!s cycloaddition far away from ylide CH3 NaHMDS PPh3 OMe O O O Chem Ber. 1976, 1694. H OMe E-selective Wittig Reactions O R H O PPh PhLi O PPh 2 3 LiO PPh3 1 eq. HCl 3 Ph3P CHR1 ylide R1 R2 R1 R2 R2 R1 "Schlosser" Wittig equilibrates to the more stable oxaphosphetane ACIEE, 1966, 126 R1 R2 E:Z R2 CH3 C5H11 99:1 C5H11 CH3 96:4 R1 CH3 Ph 99:1 Stabilized Ylides are much less reactive than alkyl ylides; the react with aldehydes, but only slowly with ketones O O PPh3 O Na2CO3 Ph P Br Ph3P 3 OR OR OR A slow O PPh3 O PPh3 + Stabilize ylides thus form A + R1CHO E alkenes as major products R reversible 1 CO2R R1 CO2R minor kinetic major kinetic fast slow CO2R thermodynamic product: R CO2R R 1 1 major minor Horner-Wadsworth-Emmons Wittig: E-selective Phosphonate esters are easily deprotonated and are more basic/nucleophilic than stabilized ylides; they react with both ketones and aldehydes Synthesis: Claisen Condensation: O O O 1. LDA O O POEt)3 O Br EtO P EtO P CH EtO P OR 3 O R' OR 2. Arbuzov EtO EtO EtO H3C reaction R' OEt TL, 1976, 2829 Mechanism of Olefin Formation: RDS O O NaO P(OEt) O O Reversible 2 NaO P(OEt)2 O O NaH + EtO P EtO P OEt OEt R CO Et EtO R CHO 1 2 R1 CO Et EtO 1 2 JOC, 1961, 1733 O- O- O O P(OEt) O P(OEt) + 2 2 HO P(OEt)2 Good for: water soluble R CO Et R CO Et O phosphate can be 1 2 1 2 W= CN, CO2R, EtO P W COR, CHO removed in aqueous workup SO Ph, Ph fast slow EtO 2 CO2R thermodynamic product: R CO2R R 1 1 major minor Modifications to the Horner-Emmons Wittig Masamune and Roush: for Base-sensitive substrates, use LiCl/tertuary amine (Et3N, DBU, iPr2NEt) O O BzCHN O EtO P BzCHN O EtO H TL, 1984, 2183 LiCl, iPr2NEt JOC, 1989, 896 CH3 CH3 CH3CN, 23°C metal ion coordination lowers pKa further: M O O EtO P EtO H H NR3 Both hindered phosphonates and hindered aldehydes increase E-selectivity: CH3 CH3 BnO H BnO CO2R O + PPh3=CHCO2Et 7 :1 E:Z (iPrO)2POCH2CO2Et/KOtBu 95:5 E:Z (MeO)2POCH2CO2Me/KOtBu 1:3 E:Z TL, 1981, 3873. Modifications to the Horner Emmons Wittig, continued Z-selective olefin synthesis: Still modified phosphonate: TL, 1983, 4407 O O O R + KHMDS, F3CH2CO P R' R H OCH3 1 18-crown-6 F3CH2CO R CO2Me Z:E >10:1 O O F3CH2CO P OCH O 3 F3CH2CO H KHMDS, 18-c-6 CO2Me O O CO Me F3CH2CO P 2 CO Me CH EtO P 2 F CH CO 3 3 2 EtO CH3 CH CO2Me 3 H BnO NaH, THF BnO CO2Me BnO KH, THF O 83%, 12:1 E:Z 84%, 11:1 Z:E Tetrahedron, 1987, 2369 Trisubstituted Olefins: O O R1O P O OR2 R O CH3 1 CH CO2R2 Ph Ph 3 Ph H + CH3 CO2R2 tBuOK, THF CH CH3 CH3 3 R1 R2 E:Z CH3 CH3 5:95 CH3 Et 10:90 Et Et 40:60 iPr Et 90:10 iPr iPr 95:5 O O O KHMDS, CH3 + F3CH2CO P R1 R H OCH3 1 18-crown-6 F3CH2CO CO2Me CH3 Z:E >10:1 R1 Z:E >50:1 >50:1 TL, 1983, 4403 >50:1 Peterson Olefination: An alternative to the Wittig Reaction 2-step procedure: Addition to aldehyde (non-stereoselective) and silanol elimination (stereospecific) JOC, 1968, 781 Me3Si M=Li, Mg M Isolate and separate silanol diastereomers irreversible R2CHO Me Si OH Me Si OH Li 3 3 Me3Si + R non- R1 R2 R1 R2 1 diastereoselective Elimination Step is Stereospecific: anti elimination R1 OH2 H R1 R2 + H H3O cis Me3Si R2 Me3Si OH control geometry of olefin with conditions for elimination! R1 R2 R2 NaH Me3Si ONa Me3Si O (base) R R1 1 R1 R2 R2 syn elimination trans Stereoselective Additions in the Peterson Olefination: threo product favored by small SiR3 (Me3Si) erythro product favored by large SiR3 (t-BuPh2Si) large SiR3 small SiR3 Ph R3Si H H - R Si O- Ph R3Si O R3Si 3 H Ph H Ph H R O O H H H R R R threo erythro maintain an anti relationship between aldehyde R and largest substitutent on the silicon reagent Elimination Step is Stereospecific: anti elimination tBuPh Si 2 OH 3.0 KH R Z:E Me 92:8 Ph 85:15 vinyl 95:5 Ph R Ph R tBuPh2Si OH Bu BF3•OEt2 Ph Bu Ph E:Z = 99:1 Synthesis, 2000, 1223 Julia Olefination: E-selective synthesis mixture of diastereomers: major SO R SO2R O Non stereoselective 2 R1 R2 Ac2O Na/Hg + R1 R1 R1 H R2 R2 SO2R R2 OH OAc reductive fragmentation TL 1973, 4833. H R1 R2 OAc radical intermediate prefers R1 and R2 trans OMe OMe OMe O O O BuLi 1. MsCl, Et3N OH 76% TBSO C H CHO TBSO 2. Na/Hg TBSO 5 11 C5H11 C5H11 PhO S PhO2S 2 OH R2 R2 TL, 1990, 7105 BuLi SmI R R1 2 1 see also: THF O2S N JOC, 1995, 3194 O2S N Org. Lett. 2005, 2373. R1CHO R N 2 N Tebbe Reagent: Cp2Ti AlMe2 Cl Reacts with aldehydes, ketones, esteres, lactones, amides to give methylene compounds: Tebbe O CH2 JACS, 1978, 3611 X X O CH2 Tebbe Tebbe O CH2 Ph Ph OEt OEt O CH2 Tebbe Ph Ph N N O Tebbe CH2 O O see also: Petasis reagent: Cp2TiMe2 JACS, 1990, 6392. Corey-Winter Reaction: Vicinal Diol Elimination Carbene: S S -CO2 O P(OEt)3 HO OH O O O Cl Cl H H H H H H R' heat R R' R R R' syn R' R elimination + (EtO)3PS JACS, 1963, 2677 JACS,1965, 934 Shapiro Reaction: N Ts N N Ts O TsNHNH2 2 MeLi N N N H H H H O+ TL, 1975, 1811. H 3 vinyl anion R-I R Shapiro Reaction: BuBr 2 BuLi TsNHNH2 + H3O O NNHTs Li H Acc. Chem. Res. 1983, 55. Dehydration of alcohols to form alkenes O O O for 2° and 3° alcohols only Burgess Reagent: S O N JACS, 1970, 5224 NEt3 JOC, 1973, 26 O O O O S S Burgess N R' OH O NEt3 H R' H R Exothermic R cis elimination R H R' OH Burgess Ph Ph Ph H D Ph D OH Ph Burgess Ph Ph Ph D H H Burgess JACS, 1990, 8433 CH3 CH3 HO Martin Sulfurane: Ph OC(CF3)2Ph for 2° and 3° alcohols only JACS, 1971, 4327 S JOC, 1973, 26 Ph OC(CF3)2Ph Ph OR Ph Martin Sulfurane S S R' OH O Ph O Ph R' R' R' R R R R H H OR Eliminations for 1° alcohols: Grieco method NO2 SeCN NO2 OH Se MsCl OMs NaBH4 Et3N H O JOC, 1975, 1450. 2 2 Other selenide eliminations: see JACS, 1973, 5813 - JOC, 1975, 542. retro-hetero-ene H O reaction NO2 Se.