a73 Introduction & Overview of E2 Process a73 Dehydration: Burgess Reagent & Martin Sulfurane a73 Selenoxide Elimination & Applications a73 Ramberg-Backland & Related Cheletropic Rxns a73 Vicinal Debromination and Related Rxns a73 The Takai Reaction a73 The McMurry Reaction a73 The Julia Reaction Chemistry 206 Advanced Organic Chemistry Handout 27A Vicinal Elimination Reactions: An Overview Matthew D. Shair Wednesday, November, 20, 2002 Chem 115 D. A. Evans Elimination & Fragmentation Reactions in C=C Bond Constructions a73 Dehydrohalogenation: base a73 Selenoxide Elimination: Anti Stereochemistry Syn Stereochemistry ? –HOSeAr –HX –HONR 2 ? Syn Stereochemistry a73 Cope Elimination: + – – + Anti Stereochemistry a73 Hoffmann Elimination: + – base –HNR 3 Vicinal Elimination reactions: One Heteroatom – + –HOSAr ? Syn Stereochemistry a73 Sulfoxide Elimination: ? –HOXCR Syn Stereochemistry a73 Acetate/Xanthate Pyrolysis: X(–) H(+) The following discussion is intended to provide a general overview of useful elimination reactions of value in the construction of olefins ? ? ? Review: Lowry & Richardson, Mechanism & Theory in Org. Chem. , 3rd Ed, p 588-620 X = O, S a73 Elimination Reactions: The limiting cases + X – +B – E1 family E1cb family –X – (E1 conjugate base) : – +B – –BH –BH rds rds rds –BH E2 family +B – +B – δ – δ – ? δ – δ – E1-like TS E2 δ – δ – δ – δ – E1cb-like TS a73 The E2 process encompasses a range of synchronous geometries a73 Why is the anti elimination geometry preferred? For π Bonds: Better than σ C–H HOMO X σ * C–X LUMO σ * C–X LUMO σ C–HY HOMO X H H Better than Anti Geometry Syn Geometry Trost, Ed., Comprehensive Organic Synthesis 1992 , Vol 6, Chapter 5.1 Comprehensive Organic Synthesis , 6 , Ch 5.1, p 949 Comprehensive Organic Synthesis , 6 , Ch 5.1, p 949 Comprehensive Organic Synthesis , 6 , Ch 5.3, p 1011 Comprehensive Organic Synthesis , 6 , Ch 5.3, p 1011 Comprehensive Organic Synthesis , 6 , Ch 5.3, p 1011 Comprehensive Organic Synthesis , 6 , Ch 5.3, p 1011 ? C H C R 2 X C C C C H CC CC C H CX C H C C CX X CX C H B H B C X CC H CX B H B CX R 2 R 1 R 2 H Se R 1 R 1 R 2 O Ar N R O H X R 1 R 2 R 2 R 1 R 1 H R 2 R NR R 2 R 2 R 1 R 1 H R R S Ar O R 2 R 1 R 1 H R 2 H R R 2 R 1 R 1 X O R 2 R 1 R 2 R 1 X H C AB AB CC CC 27A-01-Elimination Rxns 12/7/93 12:00 PM 25 → 75 °C exothermic Chem 115 D. A. Evans Elimination Reactions: The E2 Process a73 Syn E2 elimination can be promoted by steric or torsional factors 98 : 2 Brown JACS 1970 , 92 , 200 RONa + + anti syn base base % syn R 1 R 2 base Ph Me 2 CH HO – 6925 HO – Me PhPh D E tO – <5 Saunders JACS 1983 , 105 , 3183 a73 Direction of E2 elimination can be controlled by leaving group MeO – 81:19 X = I X Ratio X =Br 72:2867:33 X =ClX =F 30:6005:95 X =NMe 3 + + + HO – HO – Nonbonding interactions disfavor internal elimination (Hoffmann) Some of the Practical Dehydrating Agents a73 The Burgess Reagent: Burgess: JACS , 1970 , 92 , 5224-5226. Burgess: JOC , 1973 , 38 , 26-31. Burgess: Org. Synth. Coll. Vol. VI. 788-791 (preparation of the reagent). - + 1 a73 The Basic Process: 1 - + HNEt 3 a73 Dehydration usually proceeds via a cis -elimination: - 11 - Burgess: JACS , 1970 , 92 , 5224-5226. a73 Dehydration of 2° and 3° alcohols: Crabbé, JOC , 1970 , 35 , 2594-2596. 1 , PhH, 25 °C 75% 1 , MeCN 66% Duncan, JACS , 1990 , 112 , 8433-8442 Ph Ph H H OH H O S O O Ph Ph N CO 2 Me Ph D Ph R R H OH H O S O O R R MeO N S NEt 3 O O O H Ph Ph D OH D O S O O Ph Ph N CO 2 Me Ph H Ph H DH DH D H OTs H D H H CC H NMe 3 D H R 1 R 2 C R 1 R 2 C H D NMe 3 H C H R 2 C D R 1 C R 2 C D R 1 H X Me Me Me Me Me C H H 9 C 4 C H Me N H Me Me CC H NMe 3 C 4 H 9 H H H Me Me Me Me Me MeH HO N CO 2 Me RH R H Me MeH OO OH Me Me 27A-02-E2 elimination 12/6/93 10:26 AM 70 °C, 2 h P. Wipf ring closure occurs with inversion a73 Cyclodehydrations to form oxazolines: Westellamide JACS , 1992 , 114 , 10975-10978 JOC , 1993 , 58 , 1575-1578 Tet. Let , 1992 , 33 , 907 a73 Dehydration of primary amides to form nitriles: Other uses of the Burgess Reagent: - + 1 3 equiv 1 82% no dehydration of 2° alcohols observedClaremon, TL , 1988 , 29 , 2155-2158. This allylic rearrangement has not been exploited McCague, JCS PT1 , 1987 , 1011-1015 2.8 : 1 1 or a73 Cationic behavior noted in some instances Burgess: JOC , 1973 , 38 , 26-31. 1) 1 , THF then 2) NaH, RT 94% 1 , triglyme, 75 °C 73% a73 Allylic alcohols can undergo a [3,3] sigmatropic rearrangement: Burgess: Org. Synth. Coll. Vol. VI. 788-791. 1 , 95° 80% a73 Primary alcohols are displaced to form the urethane: Chem 115 D. A. Evans & D. Barnes Elimination Reactions: The Burgess Reagent Me OH Me NH OMe O Me Me OH Me Me Me Ph Me NHCO 2 Me Ph H HO Et OMe Ph Ph OH H Et MeO Ph Ph OMe Et Ph Et OMe Ph Me O Me S N MeO OO O M Me O Me H OH CONH 2 HO Me Me O Me O Me H OH CN HO Me Me O MeO N S NEt 3 O O O R HN OMe O O Me HO O N R O OMe Me ON O NH Me Me N O HN Me Me N O NH O Me Me Me Me Me O 27A-03-Burgess reagent-2 12/6/93 10:33 AM 25°C 98% 1 a73 Rxns with amides result in transesterification: Martin, JACS , 1974 , 97 , 6137 Elimination Reactions: The Martin Sulfurane 1 a73 Rxns with diols generate cyclic ethers: Martin, JACS , 1974 , 96 , 4604-4611 1 Evans, JACS , 1978 , 100 , 1548-1557 1 (±)-Cherylline a73 Applications: 1 Martin Sulfurane: Only product (92%)Burgess Reagent: 1 : 4 Snieckus, TL , 1982 , 23 , 1343-1346 – OC(CF 3 ) 2 Ph + + HOC(CF 3 ) 2 Ph a73 Mechanism: Reagent provides both good leavilng group and moderate base 82% 0 °C 45 min Martin, JACS , 1971 , 93 , 4327-4329 JACS , 1972 , 94 , 5003-5010 However, 1° alcohols react to give the ether: 1 1 a73 Dehydrations to form alkenes: Martin: Org. Synth. Coll. Vol. VI. 163-166. a73 Preparation of the Martin Sulfurane: D. A. Evans, D. M. Barnes Chem 115 1 MsCl, SOCl 2 , p -chlorobenzoyl chloride, CSA, Burgess Reagent, TFAA / base, Tf 2 O / pyridine all ineffective in the dehydration. Evans, Black, JACS , 1993 , 115 , 4497 fast 100% 1 25 °C seconds 90:10 R R S OC(CF 3 ) 2 Ph OH OC(CF 3 ) 2 Ph PhPh R R Me OH Me Me Me Me OH CH 2 Me OH R R S Ph Ph OC(CF 3 ) 2 Ph OC(CF 3 ) 2 Ph R R O S Ph OR S Ph H Ph O Ph R R R R HOMe Me Me Me CONMe 2 Me Me Me Me CONMe 2 Me CONMe 2 Me Me NMe OH OMe MeO O MeO BnO OH NMe OMe MeO O MeO BnO NMe MeO HO Ph NH Me O O O Ph CF 3 CF 3 Ph Me Me HO Cl R OH MeO Cl Me Me OH O Et HO H OH H H OTBS OTIPS Me O OH H H O Et O OH H H OTBS OTIPS Me O H H Me Me OC F 3 CF 3 Ph 27A-04-MartinSulfurane 12/6/93 10:20 AM Tomoda, Chem. Commun 1982 , 871; Tet. Lett 1982 , 23 , 1361 PhSeCN ? [Ox] a73 Functionalization of Olefins: Sharpless, J. Org. Chem. 1974 , 39 , 429. 3 <1 2 49 97999851 OAcOHOMeCl Chapter 5, Selenium Reagents and Intermediates in Organic Synthesis , C. Paulmier,1986 Pergamon Press. Chapter 4, Organoselenium Chemistry , D. Liotta, 1987 Wiley-Interscience. RSeCN or RSeSeR and NaBH 4 , RSe - M + , RSeH (with Lewis Acid) Chapter 1, Organoselenium Chemistry , D. Liotta, 1987 Wiley-Interscience. RSeCl, RSeBr, RSe(O)Cl, RSeSeR, alkyl selenium succinimide, RSeSO 2 Ar, ... H 2 O 2 , MCPBA, RCOOOH, NaIO 4, , O 3 , ( t -BuO) 2 , Th III Nitrate, NCS or NBS/H 2 O a73 Some useful oxidizing agents: a73 Electrophilic Selenium Reagents: a73 Nucleophilic Selenium Reagents: The selenoxide elimination is usually two steps: A. Selinide formationB. Oxidation & elimination. Selenium in Natural Products Synthesis , K. C. Nicolaou, N. A. Petasis Organoselenium Chemistry , D. Liotta, 1987 Wiley-Interscience. Selenium Reagents and Intermediates in Organic Synthesis , C. Paulmier, ? 1986 Pergamon Press. General Selenium References: -20?C → 40?C Elimination Reactions of Selenoxides D. H. Ripin & D. A. Evans Chem 115 + The Selenoxide Elimination Reaction + ? By comparison: ? + + 80 ?C → 130?C -PhSeOH-PhSOH 20?C The first example: Jones, Chem. Commun 1970 , 86. O 3 + PhSe– X [Ox] ? X Ratio X = OAc, OH, CN, Cl, Br, +X – a73 Epoxide Ring Opening-Refunctionalization: PhSe– SePh NaBH 4 [Ox] Both of the above reactions have been heavily exploited in synthesis SePhCN Me Se H H Se Me Se–Ph MeH Ph–Se H R R H H O– R HH R XX Ph H H Ph O - X SePh O SePhOH OH Se O H H R R H Ph S Ph H O RR H H R H HR Ph–S O– H H R R H CN 27A-05-Selenoxide elim-1 12/6/93 11:00 AM free radical addn Rollin Synthesis 1984 , 134. ? NaIO 4 NaHCO 3 83% 85% BF 3 OEt 2 55% [Ox] Raucher Tet. Lett. 1979 , 3057. H + steps 25 °C DBU, xylene, ↑↓ Holmes J. Am. Chem. Soc. 1993 , 115 , 10400. NaIO 4 NaHCO 3 73% (+)-Laurencin Metz, Tet. Lett 1982 , 23 , 4067 [Ox] ? CH 2 =CHOEt PhSeBr h ν PhSe-SO 2 Ph ? [Ox] Kice, Tet. Lett 1980 , 21 , 4155 Raucher, Tet. Lett 1977 , 3909 [Ox] ? PhSeBr MeCN This is kinetic product at lower temperatures Beau, JACS , 1983 , 105 , 621 pyr H 2 O 2 Cl – 0 °C PhSeCl a73 Functionalization of Olefins: + Synthetic Applications Chem 115 D. H. Ripin & D. A. Evans Elimination Reactions of Selenoxides These rxns are quite valuable in setting up Claisen rearrangements OO OTBDPS SePh O OTBDPS O H OAc O Et Br H OTBDPS OO OH Me CO 2 Me Me PhSe C(OMe) 3 SePh Me Me Me OTBS OTBS Me CO 2 Me OOAc AcO AcO Ph Se OH AcO AcO OO SePh O O AcO AcO AcO AcO O Me SePh Cl SePh Me OTBS Me Me OTBS Me Br Cl SePh C 6 H 13 C 6 H 13 C 6 H 13 SePh Br SO 2 Ph Ph Ph Ph SO 2 Ph OH H MeOCH 2 Br OEt PhSe MeOCH 2 HO OEt SePh EtO 2 C CHO H MeOCH 2 27A-06-Selenoxide elim-2 12/7/93 12:02 PM Clive JOC 1982 , 47 , 1632. Kowakski JACS 1980 , 102 , 7950. Note the different mechanism for eliminationin this case MsCl/Et 3 N ZnCl 2 b) H 2 O 2 , THF, 0?C o -O 2 NC 6 H 4 SeCN NaBH 4 , 20?C 59% Grieco J. Org. Chem. 1975 , 40 , 1450. H 2 O 2 3 : 1 Sharpless, Tet. Lett. 1973 , 1979. H 2 O 2 69% H 2 O 2 4 : 1 Reich J. Am. Chem. Soc. 1973 , 95 , 5813. 9 : 1 Grieco J. Org. Chem. 1975 , 40 , 542. Elimination Reactions of Selenoxides D. H. Ripin & D. A. Evans Chem 115 a73 Epoxide Cleavage/Refunctionalization: Ph 2 Se 2 NaBH 4 H 2 O 2 63% steps lycoricidine Ohta, Tet. Lett 1975 , 2279 NaBH 4 Ph 2 Se 2 NaIO 4 70% Ac 2 O MCPBA Ph 2 Se 2 NaBH 4 NaIO 4 steps lycorine Tsuda, Chem. Commun 1975 , 933 NH OO O THPO THPO OH SePh O O NH NH OO OH THPO OH O O Me O Me SePh Me O Me NH OH OO OH O O N H H H HN Me O O Me SePh HH O O H OO HH O Me Me PhSe H Me Ph Me H Ph MePh Me Me OMe MeOOC MsO MeOOC OMe OTMS Me SePh O H O OO O HO SePh H HO O O O N H H HN OO O AcO O OH H AcO O O O N H N OO HO OH Me SePh OH Me O 27A-07-Selenoxide elim-3 12/6/93 1:10 PM Effects the transformation of alkenes to 1,3-dienes. ( E ):( Z ) = 94:6 tBuOK tBuOH, ? 1,3-diene alkene ( E ):( Z ) = 17:83 tBuOH, ? tBuOK DBU CH 2 Cl 2 , h ν BrCH 2 SO 2 Br ( E ):( Z ) = 10:1 a73 Vinylogous Ramberg-Backlünd Reaction a73 Reviews Modified procedure allows one-pot conversion of sulfone to olefin.Reaction of resulting olefin with dichlorocarbene generated in stronglybasic chlorinating medium can sometimes complicate reaction: tBuOH, ? KOH, CCl 4 Chem 115 D. A. Evans Cheletropic Elimination Reactions Block, JACS 1983 , 105 , 6164, 6165. a73 Acyclic Olefin Synthesis t-BuOK DMSO ( E ):( Z ) > 97:3 ( E ):( Z ) = 21:79 aq NaOH ? ? Olefin geometry dependent upon reaction conditions. The Ramburg-Backlünd Reaction Base a73 General Reaction Protocol NaH NCS orC 2 Cl 6 NaOMe MeOH, ? Meyers' Modification: X = halogen, tosylate, triflate Paquette, Organic Reactions 1977 , 25 , 1. Magnus, Tetrahedron 1977 , 33 , 2019. Vedejs, Tetrahedron 1982 , 38 , 2857. Trost, Ed., Comprehensive Organic Synthesis 1992 , Vol 3, Ch 3.8. Meyers, JACS 1969 , 91 , 7510 KOH, CCl 4 tBuOH, ? + 35% 65% 97% 66% Scholz, Liebigs Ann. Chem. 1984 , 264. ? Strong base (tBuOK) equilibrates episulfone intermediate to thermodynamically favored trans configuration giving ( E )-olefins. (Z)-vinylogous sulfones yield opposite olefin geometry ( trans ): 59% 61% base X Ph S R O O O S O O O R Ph Cl Ph O R 1 SR 2 R OO Ph Ph S P h O O Ph nC 5 H 11 nC 4 H 9 SB r O O Br S R 1 R 2 O O R 1 R 2 Cl HO 2 CS E t O O Et S O O Br HO 2 C HO 2 C Et nC 4 H 9 nC 4 H 9 nC 4 H 9 SB r O O nC 4 H 9 S O O Cl Cl S O O R 2 R 1 R 1 R 2 27A-08-Ramberg-Backlund Rxn 12/6/93 1:11 PM A wide variety of annulation procedures for direct 9-member ring formationwere unsuccessful. Boeckman, JACS 1991 , 113 , 9682. 85% 82% Eremantholide A a73 Eremantholide A 9-15% Wender, Tet. Lett. 1988 , 29 , 909. Cheletropic elimination occurs with σ rather than π -bond formation. PhH/CH 3 CN Ph 2 CO, h ν a73 Neocarzinostatin Chromophore: A Related Reaction Nicolaou, JACS 1992 , 114 , 7360. 32-52% Neidlein, Leibigs Ann. Chim. 1980 ,1540. If cheletropic elimination is sufficiently slow, dehydrohalogenation can compete. Base Paquette, JACS 1974 , 96 , 5801. 81% a73 Deuterated Olefins 18% Gassman, JACS 1983 , 105 , 667. 35-49% Intraannular Ramberg-Backlünd reactions succeed where many annulation procedures fail in producing highly strained ring systems. Chem 115 D. A. Evans, S. Nelson Cheletropic Elimination Reactions Becker, Helv. Chim. Acta 1983 , 66 , 1090. a73 Enediyne Synthesis: Calicheamicin/Esperamicin Models Applications to Synthesis a73 Strained Ring Systems tBuOK, THF -75 °C to rt NaOD D 2 O ? tBuOK, THF Acidity of α -methylene groups provides ready access to deuterated olefins via the Ramberg-Backlünd reaction. Na 2 S 1) NCS, CCl 4 2) mCPBA tBuOK Et 2 O, 0 °C n tBuOK THF, -78 °C n n = 3-8 Et 3 COK HMPA, DME ? H 3 O + SO O Br SO 2 O 2 S (CH 2 ) Cl Cl (CH 2 ) O O O O 2 S MeH O Me Me O Me Cl O Me Me O H Me D D Cl SO 2 D DD H H S OTs TsO H H H H O 2 S Cl HH O Me O O O O MeO MeH O Me Me O OH SO 2 SO 2 HH Cl HO SO 2 Me HO Me 27A-09-Ramberg Applications 12/7/93 12:04 PM Gaoni, Tet. Let 1977 , 947 (the LAH cleavage procedure) LiAlH 4 /Et 2 O Chou, JOC 1987 , 52 , 5082. 74% LHMDS 97% + El(+) Retro [4+2] preceeds cheletropic elimination of SO 2 . a73 1,3-Diene Synthesis Related Cheletropic Eliminations a73 Dihydrothiepin-1,1-dioxide: 1, 3, 5-Trienyl Anion Equivalent Cheletropic Elimination Reactions D. A. Evans Chem 115 LHMDSacetone ? X = H, Me, Ph 100% E 53-95% Yamada, JCS Chem Comm 1987 , 332. 1) Base, R 1 X 2) Base, R 2 X 76-93% ? >91% stereoselectivity for ( E, E )-diene Bloch, Tet. Lett. 1983 , 24 , 1247. a73 α -Sinensal LHMDS + ? α -Sinensal 60% Desai, Syn. Comm. 1990 , 24 , 523. 56-83% 1) nBuLi 2) RX or RCHO 175 °C68-77% a73 The Reactions: Rigby, Synlett 1993 , 829. (-) + El(+) -SO 2 (-) equivalency Equivalent Synthons 1)TBHP, SeO 2 2) PDC S X O O S O O X Me Me OH Me Me OH X S O O S O O SO 2 SO 2 R R S O O S O O S O O ElEl R 1 R 2 H R 1 R 2 Me S O O Me Me Me Br Me Me Me SO 2 Me Me SO 2 Me CHO Me Me CHO Me Me S SO 2 O O Me Me Me Me Me Br Br Me Me Me Me S O O 27A-10-Related Eliminations 12/6/93 1:35 PM NaI NBS, HCl X(+) Y(–) –HOSiR 3 Syn Stereochemistry base a73 X = HO; Y = SiR 3 : acid –HOSiR 3 Anti Stereochemistry base Syn Stereochemistry –HOPR 3 + –HOPR 2 Anti Stereochemistry PCl 3 Lawrence, Chem. Commun. 1993 , 1187 Krief, Tet. Lett. 1976 , 3743 PCl 3 Anti Stereochemistry –HOSePh (Peterson elimination) a73 X = HO; Y = PR 3 : (Wittig Reaction) a73 X = HO; Y = PR 2 : a73 X = HO; Y = SePh : a73 X = HO; Y = SPh : –HOSPh Anti Stereochemistry Pl 3 Krief, Tet. Lett. 1979 , 4111 D. A. Evans Chem 115 Vicinal Elimination reactions: Two Heteroatoms Y(–) X(–) + 2e - Reductive Fragmentation Reactions a73 Representative Substrates: Comprehensive Organic Synthesis , 6 , Ch 5.1, p 949 a73 Vicinal Dihalides: These reactions are nearly stereospecific Sonnett, Tet 1980 , 36 , 577 Sonnett, JOC 1980 , 41 , 3284 93% (Z), 95% overall yield 85 °C -78 °C NaI, DMF a73 Vicinal Dihalides: Inversion of olefin geometry is possible Fe/Gr Savoia, JOC 1982 , 47 , 376 Fe/Gr 96.4% (Z) is also an effective reducing agent: Engmann, Tet. Let. 1982 , 23 , 3601 X Y R 2 R 1 R 2 R 1 R 2 R 1 R 2 R 1 HO PR 3 R 1 R 2 R 2 R 1 PR 2 HO R 1 R 2 R 2 R 1 HO SePh R 1 R 2 R 2 R 1 SPh HO R 1 R 2 R 2 R 1 SiR 3 HO R 1 R 2 HO OH R 1 R 2 Br Br(OR) R 1 R 2 R 2 R 1 SO 2 R AcO Ph Ph Br Br C 4 H 9 Ph Ph Br Br C 4 H 9 C 4 H 9 R 2 R 1 R 2 R 1 Y X C 4 H 9 S TeNa Me OAc I Cl Me RR Me Cl Br OAc Me 27A-11-HO-X eliminations 12/7/93 12:06 PM 2 CrCl 2 mechanism ? CCl 4 Bu 3 P D. A. Evans Chem 115 Vicinal Elimination reactions: Two Heteroatoms a73 halohydrins: These substrates behave much like vicinal dihalides NBS NaBH 4 Zn/i-PrOH 75% Sinay, JACS 1983 , 105 , 621 CHI 3 , CrCl 2 Li/NH 3 Ireland, JACS 1983 , 105 , 1988 a73 Takai Reaction: These rxns are not stereospecific: Takai, JACS 1986 , 108 , 7408 (E) selectivity 80:20 CrCl 2 Hodgson, Tet Let 1992 , 33 , 5603 ( E ):( Z ) Yield Time Solvent 8h 22:1 40% 4d 4:1 73% 4h 13:1 69% 6:1 Dioxane:THF Dioxane THF CHI 3 CrCl 2 Reaction stereoselectivity can be influenced by solvent (JACS 1993 , 115, 4497 ) 71% diastereoselection 10:1 ( E ):( Z ) = 9:1 80% CHI 3 , CrCl 2 , dioxane/THF 25 °C Me 2 AlCl, CH 2 Cl 2 , 0 °C 2 CrCl 2 Bolandi, SynLett 1993 , 837 (E) selective [H] Zn, CrCl 3 See lecture 13 (Fragment Coupling) for related uses of Cr(II) RCHO RCHO 2 CrCl 2 Mechanistic options O O O TBS OMe Me O Ph Ph O O Br Me OMeOTBS O HO Ph O O TBS OMe Me O O Ph O Me HOTBS O ( β) Npˇ OHC Me OTBS O O ( β) Npˇ Me OTBS O I HC II I C Cr(III) I Ph H O TBSO Ph O Ph O O Me OHOTBS I TBSO I H HC I Cr(III) Cr(III) O H R R O OTIPS OTES O Me Et O O O RO Me OH Me Me Me Me Cl Me RO O O O O HO I Me RO Me H O O O Me Et R OM OAc Et Et OAc Br OCr(III) R I RH O HC BrBr SnBu 3 SnBu 3 R OX P OTBS I H O OTES OTIPS O O Me Et OTBS H H H H H X P Cr(III) I R OCr(III) R I 27A-12-HO-X eliminations-2 12/7/93 12:08 PM See this paper for the optimized procedure: McMurry, JOC 1989 , 54 , 3748 a73 Recent Review: J. McMurry, Chem. Rev . 1989 , 89 , 1513 Vicinal Elimination reactions: The McMurry Reaction Chem 115 D. A. Evans + "low-valent Ti" This rxn accomplishes the reverse of olefin ozonolysis Mechanism: + TiCl 3 Zn-Cu a73 Pinacol Step: Ti(0) surface + Ti(0) surface + ? ? Ti(0) surface Ti(0) surface Ti(0) surface ? Ti(0) surface a73 Elimination Step: Ti(0)Ti(0) ratio: 91 : 9ratio: 60 : 40 a73 The elimination step is not stereospecific: McMurry, JOC 1978 , 43 , 3255 Zn-Cu TiCl 3 94% yield a73 Hindered double bonds may be readily prepared: McMurry, JOC 1989 , 54 , 3748 a73 Extended conjugation can be tolerated: McMurry, JACS 1974 , 96 , 4708 a73 Intramolecular Rxns are possible: TiCl 3 Zn-Cu retinal β -Carotene 94% yield TiCl 3 Zn-Cu 75% yield Burnell, Tet. Let 1988 , 29 , 4369 Zn-Cu TiCl 3 McMurry, Tet. Let 1982 , 23 , 1777 78% yield (E):(Z) = 2 : 1 For a general review of vicinal deoxygenation see: Kocienski in Comprehensive Organic Synthesis , 6 , Ch 5.2, p 949 Me Me Me Me Me Me Me Me Me O MeMe O R RR O O R R R RR O R R O R R RR R R OTi TiO RR R R O R R RR O O R R RR O O O R R R R O R RR R O O O R R R R RR R R O O Bu Bu OH OHOH Bu Bu Bu OH Bu Bu Bu Me Me MeMe Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me O H OO Me O Me Me O Me Me Me Me Me MeMe Me Me Me Me OHC O 27A-13-McMurry Rxn 12/7/93 1:27 PM D. A. Evans, P. Carter Chem 206 Sulfur-Based Functional Groups-5: Julia Olefin Synthesis Problem: Work out the mechanism of reduction step. Good sulfone review: Trost, Bull Chem. Soc. Japan, 1988 , 61 , 107-124. Elimination is stepwise; therefore, not stereospecific Ac 2 O major MeOH Na(Hg) BuLi R'CHO Julia Trans Olefin Synthesis: SO 2 Ph R SO 2 Ph R R' OH R' R OAc R' R SO 2 Ph R' R Julia Olefination - Ionomycin 1. add RCHO, -78 o C; add Ac 2 O, -78 o C to R.T. 2. Na/Hg, EtOAc/MeOH, -30 o C 70% yield 86:14 olefin mixture Evans, et al. JACS 1990 , 112 , 5290. PhO 2 SL i OTBDPS Me Me Me Me O O Me Me HM e H M e OTBS Me O O OTBDPS Me Me Me Me O O Me Me CHO HM e H M e OTBS Me O O Review: Kocienski etal. Phosphorus & Sulfur 1985 , 24 , 97-127 Kochenski, J. Chem. Soc Perkin Trans I, 1978 , 834 Na(Hg) ? or – ? + + e- ? + e- The reduction step is not stereosecific R 2 R 1 SO 2 R X X R 2 R 1 R 2 R 1 R 1 R 2 SO 2 Ar OAc OAc SO 2 Ar OAc Cytovaricin Synthesis: JACS 1990 , 112 , 7001 Free acid must be used to prevent loss of C 4 OH in 2nd step C 21 OH deprotection 21 C=C construction Reactions accomplished: overall yield, 66% Ac 2 O, pyr 6% Na(Hg) -40 °C 2 LiNEt 2 , THF 21 3 1 + TESO Me SiO O OTES H O Me OTES H MeO H H O t-Bu t-Bu Me PhSO 2 Me TESO O H Me OCH 2 OCH 2 CCl 3 O H MeH O H H DEIPSO Me CHO Me TBSO OPMB HO OPMB OTES H H H O OTES Me MeO O HO H Me DEIPSO H O O H Me H H OHMe H TBSO Me H O OTES Me O O Me TESO Si t-Bu Me t-Bu 27A-14 Julia-1 11/13/01 12:27 PM D. A. Evans, P. Carter Chem 206 Sulfur-Based Functional Groups-5: Julia Olefin Synthesis-2 Me Br MeO O H H O O N O Me H H H HO H CH 2 Me O MeO OH H N O H H O O H H Me HO 46 38 33 19 1 4 9 13 C 39 –C 46 Synthon Phorboxazole B Synthesis Br OMe NaHMDS THF, -78?C - rt CH 3 I CH 3 I 75% O H E/Z = >95:5 Br OMe S S N O O Evans, Smith, Fitch, Cee JACS 2000 , 122 , 10033-10046. disconnection Br OMe CH 3 I Julia Construction Br OMe CH 3 I O–Na S O O S N NaHMDS RCHO Br OMe CH 3 I S N NaO Mechanism?? The Mechanism: CH 3 I O–Na S O O S N R CH 3 I O S O O S N R SO 2 CH 3 I O S O O S N R R CH 3 I SO 2 S N NaO Olefin stereochemistry could be established in the formation of A . A Recent Modifications of the Julia Process: Kocienski, SynLett 2000 , 3 , 365-366. N O 2 S C 4 H 9 N N NN Ph C 9 H 19 OHC KHMDS –60 °C → rt C 4 H 9 E/Z: 99:1 (75%) N O 2 S Ph N N NN R OHC KHMDS –60 °C → rt C 9 H 19 Ph R = Ph : E/Z: 29:71 (70%) R = tBu : E/Z: <1:99 (95%) N O 2 S N N NN Ph R KHMDS –60 °C → rt H R' O Me RO R' Me RO R E/Z: >10:1 (64%) Metternich, JOC 1999 , 54 , 9632 27A-15 Julia-2 11/13/01 5:31 PM