both substrate : activated wastes derived from M and X one substrate : activated wastes derived from X

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1 October 20th, 2007 Lit. Seminar Transition Metal Catalyzed Intermolecular ormations of - Bond : post-cross Coupling i) Cross Coupling reaction -M + '- -' (M = Zn, Sn, B,,,) ii) Direct ylation - + '- -' iii) Oxidative coupling - + '- -' both substrate : activated wastes derived from M and one substrate : activated wastes derived from no preactivation oxidant : latent wastes (?) aerobic : favorable idetoshi oda (M2) Today's Topics 1. Direct ylation via C- activation -overview- 2. eteroarene Direct ylation 3. ene Direct ylation 4. Other Approaches 5. Catalytic Oxidative Coupling of - 1. Direct ylation via C- Activation -overview- oxidative addition Mtl or several proposed mechanism Mtl oxidative addition Mtl General Conditions # Metal : second-row transition metals in low oxidation states(h, u, Pd,,) # Ligand : depend on - and system for -I,Br : PhP 3 etc for -Br,Cl : electron rich and bulky trialkylphosphine, Buchwald's ligand, C etc ligand-free conditions is also reported # Base : most cases inorganic bases such as K 2 CO 3, Cs 2 CO 3, KOAc, tbuok, CsOPiv,,,, # Solvent : polar, aprotic solvents such as DM, DMA, C 3 C, MP, DMSO,,, # temp. : > 100 C # mechanism Although several mechanisms are proposed, exact ones depend on substrate, cat. system and so on. most suporrted few support limited case

2 2. eteroarene Direct ylation PG + Cl cat. Pd(PPh 3 ) 4 KOAc + DMA, reflux PG PG Ohta, A. et al. eterocycles 1985, 23, Chem. Pharm. Bull. 1989, 37, PG = : C2-selective Ts : C3-selective 2 eactivity order in S E is known to C5>C4>C2, but generally relatively less reactive toward electrophiles. Bull. Chem. Soc. Jpn. 1998, 71, 467. activated electrophile is needed (10 mol%) catalytic reaction involves an electrophilic attack of the arylhalopalladium(ii) species. (2 eq.) DM, 140 C, 24 h C5 selective role of base solubility of base : Cs 2 CO 3 >K 2 CO 3 >a 2 CO 3 solubility of salt : KI(1.55), KBr(0.065) CsBr(0.024), CsI(0.23) 2a = Ph-I 2a' = Ph-Br Indole produces C2-arylated product, which is "nonelectrophilic" regioselectivity. Org. Lett. 2004, 6, etc... # consideration of mechanism # support for S E mechanism J. Am. Chem. Soc. 2005, 127, EWG = cf) thermodynamically stable C-2 adduct?? Li Bs -100 to -20 C Bs Li J. Org. Chem. 1982, 47, 757. B(C 6 5 ) 3 B(C 6 5 ) kcal/mol stable (DT) Organometallics 2004, 23, 5135.

3 # chance to C-3 selective reaction (?) # realization 3 # strategy cf) other examples about regiocontroll J. Am. Chem. Soc. 2006, 128, Angew. Chem. Int. Ed. 2005, 44, ene Direct ylation arene : lower electron density than heteroarene (lower reactivity as to S E ) In order to overcome this problem, use of directing group is major strategy. (many reports) + I PdCl 2 (5 mol%) LiCl, K 2 CO 3 O (2 eq.) O Miura, M. et al. Chem. Lett. 1996, 823. other directing groups are amide, ketone, imine, pyridine, quinoline,,,, # ligand screening J. Am. Chem. Soc. 2006, 128, (3 mol%) (1.5 eq.) bulky and strongly pi-accepting ligand is effective

4 # nondirected direct arylation of simple arene nondirected 4 shows S E process (27 eq.) new mechanistic insights are appered from intramolecular rxn # substituent effects on regio (5 mol%) J. Am. Chem. Soc. 2006, 128, J. Am. Chem. Soc. 2007, 129, 6880.(full) Me 2 # base effect PPh 2 10a base has little role on selectivity. KIE 5.0 KIE 6.7 reaction proceeds at electron deficient ring vs 13.2 kcal/mol 43.3 vs 34.5 kcal/mol Pd Pd Br Br 3 P 3 P models for DT calculation (7f) Authors insisted "Assisted intermolecular pass" is suited. 3.0 kcal/mol = 40:1 at 135 C (25:1, experimental) 17.4 vs 14.4 kcal/mol J. Am. Chem. Soc. 2006, 128, broad substrate scope Even gives product in 8%. chance to cat. modification!? () : calculated eactivity parallels relative acidities. more electron deficient, higher reactivity

5 5 KIE = 3.0 slight modification I, Br, Cl, OTf Org. Lett. 2006, 8, DT cal. showed C2 is the lowest reaction barrier. There is no indication of catalyst-fluorine interactions. : nondirected OMe catalyst modification for neutral arenes PCy 2 OMe J. Am. Chem. Soc. 2006, 128, eq. with hydrodebromination and homocoupling too bulky nondirected 53 eq. 53 eq. 53 eq. 53 eq. reactivity compatible to proton-abstraction pathway A pivalate anion results in a decrease in transition state energy of 1.3 kcal/mol compared to a bicarbonate anion. (DT)

6 6 4. Other Approaches Chem. Commun. 2004, # radical pathway? = 4-2, 4-O 2, 4-C 3 : notm = Me, OMe, 1-apht yield : 20-70% reported ratio involved in Ph radical : 54/26/20 I without BT : 70% with BT : 10% CP*Ir(III) CP*Ir(II) aryl iodide radical aryl radical Angew. Chem. Int. Ed. 2007, 46, cf) effective catalyst for Suzuki-coupling of -Cl -ray (10 eq.) + -I 3 : [(P) 2 h][b{c 6 3 (C 3 ) 2 } 4 ] 70 C, 24 h 4 : [Et 4 ][h(cod)cl 2 ] TOs (yield) Angew. Chem. Int. Ed. 2002, 41, (78) (45) (31) (40) (32) # mechanism (13) bimetallic h : essential matched?? ρ = 1.33±0.02 typical value for radical reaction (?) reported ratio involved in Ph radical : 54/26/20 Authors insisted reaction proceeded via radical intermediates.

7 7 # concept cross-coupling Angew. Chem. Int. Ed. 2007, 46, # reaction of 1 + and 3 + resemblance if + is obtained directly from,,, # generation of 3 + strongly exothermic triplet cation can react selectively pi-component in polar solvent(some u) I, Br : homolytic (not applicable) - with EDG in polar solvent gives triplet cation under hv. polar solvent : stabilize ionic components Et 3 (0.05M) 20 eq. Et 3 : 2eq. to prevent de-si 5. Catalytic Oxidative Coupling of - Organometallics 2006, 25, conc. of TA is important for selectivity choice of aphthalene : more electron rich than benzene S E is occured to alpha-position (??) to prevent homocoupling : ratio higher about EWG-aromatic (entry9) lower about EDG-aromatic (entry8)

8 # KIE experiment # proposed reaction pathway 8 fast no KIE KIE choice of TA : Pd(OAc) 2 to more reactive Pd(TA) 2 (??) why conc. of TA is critical?? Org. Lett. 2007, 9, (3/2) 0.08M EDG seems to promote rxn rapidly (entry8), but things are not so simple... (1 atm) (1 atm) (3 atm) PMV = 4 PMo 11 VO 40 anisole benzene anisole itself involves in catalyst?? Science. 2007, 316, indole : -Me indole : dimerization ~30 eq. PivO 3-nitropyridien : stabilize Pd(0) CsOPiv : not clear

9 9 generally EDG promote and EWG retard, but entry 2 vs 5 dosen't follow this rule J. Am. Chem. Soc. 2007, 129, in situ metalation of indole to Cu(II) or Ag : denied conc. of Pd : high to C-3 selective (entry6~9) existance of OAc : C -2 selective (entry 4,5,10), but Cu(OAc) 2... Author's proposal Pd cluster Cu(OAc) 2 CsOAc or AgOAc Pd Pd Pd Pd (monomeric Pd) this type of approach? mixed Pd-Cu cluster EWG on indole : not big effect on yield (entry 3,6) Substituent on benzene : significant effect encounting cat. with arene- is rds?? (like organometallics 2006)

10 6. Trends and Perspectives # eteroarene of Direct ylation rxn of many types of heteroaromatic ring almost used up?? rxn under milder conditions ex) extremly mild condition 10 M. S. Sanford et al. J. Am. Chem. Soc. 2006, 128, realization of real alternative synthetic strategy to cross-coupling ex) Merck group Cl 3 C 3 C C + 90 C, 8 h Org. Proc. es. Dev. 2006, 10, 398. # ene of Direct ylation regioselectivity, reactivity problem for nondirected system 妄想 : use of pi-arene complex for arenen activation MLn OMe Pd + pka : low proton abstraction mechanism?? regio : m-selective?? cf) u-pi-arene complex in catalytic cycle for hydroamination 5 mol% u(cod)(methylallyl) 2 via 7 mol% DPPent / 10 mol% TfO + ' ' dioxane, 100 C, 24 h J.. artwig et al. J. Am. Chem. Soc. 2004, 126, J. Am. Chem. Soc. 2005, 127, removable directing group (but need environmentaly benign) ex) Benzoic acid as directing group CO 2 CO 2 + Pd(OAc) 2 cf) carboxylic acid as coupling partner J. Am. Chem. Soc. 2007, 129, o-coodinating group for Cu is needed Science 2006, 313, 662. CO 2 Pd[PtBu 3 ] 2 + Br Y Y heteroarene J. Am. Chem. Soc. 2006, 128, # Other Approaches regioselectivity problem, but maybe difficult to overcome in radicalic or cationic pathway reactivity problem # Oxidative Coupling obtain some information and understand mechanism etc... Keith agnou Current Position: Assistant Professor, Department of Chemistry, University of Ottawa Education: Ph.D. University of Toronto, 2002; M.Sc. University of Toronto, 2000, B.Ed. University of Saskatchewan, K. agnou' group :