M.C. White, Chem 153 Nu attack on olefins -327 Week of November 25, 2002 Olefin functionalization via metal promoted nu attack Recall that the balance of electron flow in olefin-metal bonding can be shifted predominantly in one direction pending on the electronic properties of the metal he metal is electron withdrawing. M-L o-bonding predominates and withdraws electron density from the bond of the olefin(see Structure and Bonding, pg 39). This results in the induction of a 8+ charge on the olefin that activates it towards nucleophilic attack. Duncanson model C-H o-donation to the electrophilic metal activates the metal alkyl towards lefin o-donation to the electrophilic metal activates it towards Nu attack B-hydride elimination ecall that the equilibrium for late T-backbonding etals lies towards the olefin form which is stabilized via T-backbonding Catalyst regeneration O,/2 HX Pd 2Cux 2 CuX Pall
M.C. White, Chem 153 Nu attack on Olefins -327- Week of November 25, 2002 Olefin functionalization via metal promoted Nu attack C C M Dewar-ChattDuncanson Model Recall that the balance of electron flow in olefin-metal bonding can be shifted predominantly in one direction depending on the electronic properties of the metal. If the metal is electron withdrawing, M-L σ-bonding predominates and withdraws electron density from the π-bond of the olefin (see Structure and Bonding, pg. 39). This results in the induction of a δ+ charge on the olefin that activates it towards nucleophilic attack. L PdII X X R Nu σ donation>> π-backbonding Nu L R PdII X X δ+ olefin σ-donation to the electrophilic metal activates it towards Nu attack C-H σ-donation to the electrophilic metal activates the metal alkyl towards β-hydride elimination. Nu L H PdII X R Nu R L PdII X H recall that the equilibrium for late metals lies towards the olefin form which is stabilized via π-backbonding. L PdII L H X L Pd0 L RE HX O2/ 2 HX 2 CuII X2 O O 2 HX stoichiometric oxidants L PdII L O O L PdII L O O H H H2O2 L PdII L X X O O Pd0 Ln O OH PdIILn O OH PdII Ln 2 CuI X Catalyst regeneration H+ H+ HO OH
M.C. White, Chem 153 Nu attack on olefins -328 Week of November 25, 2002 Wacker oxidation CuCh(cat) 2 mechanistic possibilities for hydroxypalladation HO. HCI The Wacker oxidation is used H,O nOH习y industrially to produce -4 million tons of acetaldehyde/year CI H0 1n2 O 2 CuCI H,0 2 CuCh Deuterium labeling study indicates that hydroxypalladation proceeds Ln Pd(o) via palladium-nucleophile anti-addition HCl H,0 H LmPd OH H,O 阝 hydride elimination HO merical production of hyde OH Binding specificity: terminal olefins Regioselectivity: 2 carbon Remote functionality tolerated Stille JOMC 1979(169)239
M.C. White, Chem 153 Nu attack on Olefins -328- Week of November 25, 2002 2 mechanistic possibilities for hydroxypalladation: Cl Pd H2O II OH R syn hydroxypalladation Cl PdII H2O OH R Cl Pd H2O Cl II R anti hydroxypalladation OH2 Cl Pd H2O II Cl OH R Deuterium labeling study indicates that hydroxypalladation proceeds via palladium-nucleophile anti-addition. LnPdII H D D H D H LnPdII OH H D OH2 H+ CO HD D H OH O PdII Ln O H D DH O Pd0 Ln Stille JOMC 1979 (169) 239. Wacker Oxidation H2O HCl 2 CuCl H2O 2 Cl Pd H2O II Cl OH2 Cl Pd H2O Cl II R Cl Pd H2O Cl II OH2 + R Cl Pd H2O II OH R H Cl Pd H2O H II OH R H2O Pd H2O II Cl H R R HO O R R O R HCl Commericial production of acetaldehyde β-hydride elimination LnPd(0) 2 CuCl 1/2 O2 + 2 HCl · Binding specificity: terminal olefins · Regioselectivity: 2o carbon · Remote functionality tolerated PdCl2 (cat) CuCl2 (cat) O2, H2O, HCl The Wacker oxidation is used industrially to produce ~ 4 million tons of acetaldehyde/year. hydroxypalladation
M.C. White, Chem 153 Nu attack on olefins -329- Week of November 25, 2002 Oxidation of terminal olefins Standard Wacker conditions Selective oxidation of terminal olefins PdCh(cat) CuCh(cat. yo DMF/HO Chadha Chem Soc. perkin /1979 2346 Cuprous chloride(Cucyozas the oxidant system leads to faster reactions with no chlorinated biproducts H H PdCl(30 mol%) PC2(20mo%) CuCI(1.6 CuCI(10 mol%)O, DMF/H2O(10: 1.2) DMF/H0(9: 1) H OTHI 77 H OTHP OTBS 91% Ikegami Tetrahedron 1981(37)4411 Cu(oAc)O, oxidant system Benzoquinone can be used as a stoichiometric oxidant. H Pd(oAch(10 mol%) PdCh(10 mol%) HCIO4(0.3M), CH3CN ao cose 20 mayo H H Smith JACS1999(121)10468 Santelli tl1994(35)6481
M.C. White, Chem 153 Nu attack on Olefins -329- Week of November 25, 2002 Oxidation of terminal olefins Selective oxidation of terminal olefins O PdCl2 (cat.) CuCl2 (cat.)/O2 DMF/H2O O O 70% Chadha J. Chem. Soc. Perkin I 1979 2346. Cuprous chloride (CuCl)/O2 as the oxidant system leads to faster reactions with no chlorinated biproducts. H H OTHP O H H OTHP O O PdCl2 (30 mol%) CuCl (1.6 eq)/O2 DMF/H2O (10:1.2) 77% Ikegami Tetrahedron 1981 (37) 4411. H PdCl2 (20 mol%) CuCl (10 mol%)/O2 DMF/H2O (9:1) 91% OTBS O O H OTBS O O O Money Tetrahedron 1996 (52) 6307. Benzoquinone can be used as a stoichiometric oxidant: H H H O O H Pd(OAc)2 (10 mol%) HClO4 (0.3M), CH3CN O O 85% H H H O O H O Santelli TL 1994 (35) 6481. Cu(OAc)2/O2 oxidant system: O O PdCl2 (10 mol%) Cu(OAc)2 (20 mol%)/O2 DMF: H2O (7:1) O O O Smith JACS 1999 (121) 10468. Standard Wacker conditions:
M.C. White, M.s. Taylor Chem 153 Olefin Nu attack -330 Week of November 25, 2002 Palladium(1-mediated 3, 3/-sigmatropic rearrangements OAc PdCl(MeCN) (10mo%) Bno BnO OB THF.23° OAc 82% BnOH2( BnOc (10mol%) Clpd ChPd THF.23°C Chpd- CH3 Saito tl1988(29)1157 The vinyl ether I is unreactive to Pd(ii) catalysis. However, the similar substrate 2 shows good reactivity PdCl(Mech PdCl(MeCN)h (10mol%) Recovered starting THF23°C kelhaupt1986(27)6267 The authors speculate that when reacting with 1, Pd(n) binds preferentially to the electron-rich vinyl ether olefin over the terminal olefin. Such binding does not lead to a productive reaction. When the steric bulk of the vinyl ether is increased, as in 2, binding to the vinyl ether is less favourable Pd(in)coordination to the terminal allylic olefin occurs resulting in catalysis of the Claisen rearrrangement. Note that these structural requirements limit the scope of this reaction
M.C. White,M.S. Taylor Chem 153 Olefin Nu attack -330- Week of November 25, 2002 Cl2Pd O O CH3 R BnOH2C BnO OBn OAc OAc Cl2Pd O O R BnOH2C CH3 BnO OBn OAc OAc Cl2Pd O O CH3 R BnOH2C PdCl2(MeCN)2 (10 mol%) THF, 23°C 82% BnO OBn OAc OAc PdCl2(MeCN)2 (10 mol%) THF, 23°C Palladium (II)-mediated [3,3]-sigmatropic rearrangements Saito TL 1988 (29) 1157. Et O Et O Me Et O Me The vinyl ether 1 is unreactive to Pd(II) catalysis. However, the similar substrate 2 shows good reactivity: PdCl2(MeCN)2 (10 mol%) THF, 23°C Recovered starting material 1 PdCl2(MeCN)2 (10 mol%) THF, 23°C 71% The authors speculate that when reacting with 1, Pd(II) binds preferentially to the electron-rich vinyl ether olefin over the terminal olefin. Such binding does not lead to a productive reaction. When the steric bulk of the vinyl ether is increased, as in 2, binding to the vinyl ether is less favourable. Pd(II) coordination to the terminal allylic olefin occurs resulting in catalysis of the Claisen rearrrangement. Note that these structural requirements limit the scope of this reaction. 2 Bickelhaupt TL 1986 (27) 6267
M.C. White, Chem 153 Nu attack on olefins -331 Week of novem ber 25. 2002 Cyclic ether formation Pd(oAch(20 mol%) Cu(OAch(50 mol%)o Meoh/ho Pd(oac)2 Pd(oac)z 2Cu(OA)、/12O2 OAc Cycle A Cvcle B +2 HOAc <甲 2 Cu(oAch H20 HOAc H10::1mm!m195(48)153. Asymmetric version 5 membered ring formation Pd(ococF3h2(10 (S, S-boxax(10 D mol%) Meoh OH 0 5-exo-trig 6 membered ring formation Pd(ococF3)2 (10 mol%) (S, S)boxx(10 mol%) oOCOCF3 OCOCF3 6-exo-trig 61% yield Hayashi JACS 1997(119)506 97%ee
M.C. White, Chem 153 Nu attack on Olefins -331- Week of November 25, 2002 N O R O N R PdII OCOCF3 OCOCF3 Asymmetric version: OH Pd(OCOCF3)2 (10 mol%) (S,S)-boxax (10 mol%) MeOH O O (4 eq) O OH Pd(OCOCF3)2 (10 mol%) (S,S)-boxax (10 mol%) MeOH O O (4 eq) 5 membered ring formation 6 membered ring formation O * 71 % yield 93 % ee 61 % yield Hayashi 97 % ee JACS 1997 (119) 5063. OH Pd(OAc)2 (20 mol%) Cu(OAc)2 (50 mol%)/O2 MeOH/H2O O 54% OH PdII O OAc O O PdII H O O HOAc LnPdII H OAc Pd(OAc)2 LnPd0 Pd(OAc)2 HOAc 2 Cu(OAc)2 2 Cu(OAc) 1/2 O2 + 2 HOAc H2O Cycle A Cycle B Hosokawa Bull. Chem. Soc. Jpn. 1975 (48) 1533. Cyclic ether formation 5-exo-trig 5-exo-trig 6-exo-trig
M.C. White, M.S. Taylor Chem 15 Nu attack on olefins -332 Week of november 25, 2002 Application of an intramolecular Wacker oxidation in the synthesis of garsubellin A Napdcly(40 mol%) t-BuOoH ACOH/H20 ACOH/H2O -HcI reductive Garsubellin a elimination HCIPdll t-BuOOH Pd"CI 阝- hydride Pdc CP心 d la Shibasaki OL 2002(4)859
M.C. White, M.S. Taylor Chem 15 Nu attack on Olefins -332- Week of November 25, 2002 Application of an intramolecular Wacker oxidation in the synthesis of Garsubellin A O O O O HO Garsubellin A Shibasaki OL 2002 (4) 859. O O O O O Na2PdCl4 (40 mol%) t-BuOOH O O O OH HO O O O OH HO Cl2PdII O O O O HO PdIICl2 t-BuOOH PdIICl2 O O O O HO O O O O HO PdIICl AcOH / H2O 69% AcOH / H2O Pd0 – HCl – HCl O O O O HO HClPdII H HCl β-hydride elimination reductive elimination of HCl
M.C. White, Chem 153 Nu attack on olefins -333 Week of November 25. 2002 Tandem oxopalladation/Heck-type cyclization F3COCo OCOCF3 20 mol% OBz 0(4 eq)CH,Ch,0C Sasai JACS 2001(123)2907 27%60%ee +"ocoCF3 HO→ OBz 6-endo-tr OCF3 OCOCF3 2HOCOCF3+ OCOCE HOCOCF3
M.C. White, Chem 153 Nu attack on Olefins -333- Week of November 25, 2002 HO OBz PdII OCOCF3 N N OCOCF3 O OBz PdII N N H OCOCF3 O OBz PdII N N HOCOCF3 H O OBz PdII N N H OCOCF3 O OBz PdII N N HOCOCF3 O OBz PdII N N H O OBz OCOCF3 PdII N N H OCOCF3 O H OBz Pd N N H OCOCF3 O H OBz Pd0 N N O O OH OH PdII N N OCOCF3 OCOCF3 * 6-endo-trig 2 HOCOCF3 + Proposed mechanism: Tandem oxopalladation/Heck-type cyclization Sasai JACS 2001 (123) 2907. HO OBz O N N O H H i-Pr i-Pr i-Pr i-Pr PdII F3COCO OCOCF3 O O CH2Cl2, 0oC O H OBz O OBz O OBz 20 mol% (4 eq) 68%, 95% ee (single diastereomer) + 5%, 45% ee 27%, 60% ee
M.C. White. Chem 153 Nu attack on olefins-334- Week of november 25. 2002 Tandem sequences Oxo-palladation/intermolecular Heck CO,Me CO,Me Pd(OAch(10 mol%) d CuCl(1 eq)o, DMF (or Ph) B-hydride elimination is not option for this intermediate Pd(C)2(10mo9%) CuCh(3 eq), Meoh 30% of the IOMe furan product te: O, is not necessary to re-oxidize pd if supra-stoichiometric amounts of Cu(ln) salts Semmelhack JACS 1984(106)1496 are used OMe o OMe OMe m Pd(ci)(10 mol%) CuCl2 (3 eq), MeOH CO CO,Me COMe 70%(mans:cs,3:1) Semmelhack JACS 1982(104)5850
M.C. White, Chem 153 Nu attack on Olefins -334- Week of November 25, 2002 OH Pd(OAc)2 (10 mol%) CuCl (1 eq)/O2, DMF CO2Me O PdII AcO CO2Me (or Ph) O CO2Me 89% Semmelhack TL 1993 (34) 7205. β-hydride elimination is not an option for this intermediate Oxo-palladation/intermolecular Heck R OH Pd(Cl)2 (10 mol%) CuCl2 (3 eq), MeOH CO R O PdII CO L Cl R O O Pd(Cl)Ln HOMe R O O OMe note: O2 is not necessary to re-oxidize Pd if supra-stoichiometric amounts of Cu(II) salts are used 70% + 30% of the furan product Semmelhack JACS 1984 (106) 1496. Oxo-palladation/carbonylation OMe O O Pr OH CO OMe O O O Pr PdII L Cl CO OMe O O O Pr CO2Me Pd(Cl)2 (10 mol%) CuCl2 (3 eq), MeOH OH O O O Pr CO2Me 70% (trans:cis ,3:1) Semmelhack JACS 1982 (104) 5850. Tandem sequences
M.C. White, Chem 153 Nu attack on olefins -335- Week of November 25. 2002 Nitrogen nucleophiles Comversion of o-allylanilines to indoles: PdcI2(CHy CNh(10 me The excess quinone and the Cl are thought to alter the regioselectivity R (1 eq) Both benzoquinone and cu() salts R=Me.89% are effective stoichiometric oxidants for Pd(o)in the presence of readily PdCl2(CH3) Hydrogenation of" trapped"Pd-alkyl intermediate leads to formal hydroamination product standard conditions LiCI(10 eq) 0 PdCh(CH:CN( eg) Pdcl no reaction occurs in the absence of nety NHz mproduct 79% Hegedus JACS 1978( 100)5800 5 mol% pre-cat*/AgOCOCF3 CH2 Cl2: MeNo(I: D -0C0F3 rt(10-20h) X=O,96%(91%e) ee Ts Pd CH2,95%909%e) HOCOCF3 OCOR JACS2001(124)12
M.C. White, Chem 153 Nu attack on Olefins -335- Week of November 25, 2002 Nitrogen nucleophiles N H PdCl2(CH3CN)2 (10 mol%) THF O O (1 eq) N R N R Both benzoquinone and Cu(II) salts are effective stoichiometric oxidants for Pd(0) in the presence of readily oxidized o-allylanilines and indoles. Conversion of o-allylanilines to indoles: R R= H, 86% R = Me, 89% R= C(O)CH3, 71% NH2 O O N H N The excess quinone and the Cl are thought to alter the regioselectivity of aminopalladation by coordinating to the Pd. Disubstituted olefins PdCl2(CH3CN)2 (10 mol%) LiCl (10 eq) (2 eq) standard cat. conditions mj. product 79% Hegedus JACS 1978 (100) 5800. NH2 PdCl2(CH3CN) (1 eq) NEt3, THF no reaction occurs in the absence of NEt3 N H PdClLn H2 NH Hydrogenation of "trapped" Pd-alkyl intermediate leads to formal hydroamination product + NH2 O NHTs X OAc 5 mol% pre-cat*/AgOCOCF3 CH2Cl2:MeNO2 (1:1) rt (10-20 h) X NTs O H X = O, 96% (91% ee) NH, 96% (90% ee) CH2, 95% (90% ee) Asymmetric synthesis of 5-membered nitrogen heterocycles pre-catalyst: Fe SiMe3 N O t-Bu PdII I Proposed mechanism: X O NH Ts O O R PdII C N OCOCF3 X OCOR PdII O N Ts N C or Ts N X O O O R Pd N C * Ts N X O * PdII C N O O Overman JACS 2001 (124) 12. HOCOCF3
M.C. White. Chem 153 Nu attack on olefins -336 Week of november 25. 2002 Nitrogen nucleophiles/o2 as a stoichiometric oxidant Pd(oAch(10 mol%) pyridine(10 mol%) y O2, toluene,80°C Proposed mechanism 2 ACOH OAc NHR AcOH sterically prefered AcOH site of elimination+ NTS Stahl ACIEE 2002(41)164 Stahl JACS 2001(129)7188
M.C. White, Chem 153 Nu attack on Olefins -336- Week of November 25, 2002 Nitrogen nucleophiles/O 2 as a stoichiometric oxidant NHR Pd(OAc)2 (10 mol%) pyridine (10 mol%) O2, toluene, 80o C Ts N R = Ts, 87% Ns, 87% Cbz, 76% Ts N 60% Ts N 91% N PdII N OAc OAc NHR N PdII N OAc NHR OAc N PdII N OAc NTs N PdII N NTs H statistically and sterically prefered site of elimination OAc N PdII N OAc H N Pd0 N N PdII N O O AcOH Ts N AcOH O2 2 AcOH H2O2 Proposed mechanism: Stahl ACIEE 2002 (41) 164. Stahl JACS 2001 (129) 7188. N N Ph Ph PdII O O
