Cross-Coupling Reactions of Organoboranes: p g g An Easy Way for - PowerPoint PPT Presentation

N-1 Nobel Lecture, December 8, 2010 Cross-Coupling Reactions of Organoboranes: p g g An Easy Way for Carbon-Carbon Bonding y y g Akira Suzuki S

N-2 Conjugated Alkadienes R' R' R' R R R R R' R R trans trans trans-trans trans cis trans-cis cis trans cis-trans cis-cis cis cis M R X R + MY R' R' R' R' M X + MY MY R R M : transition metal catalyst

N-3 Syntheses of (E)- and (Z)-1-Alkenylboranes Syntheses of (E)- and (Z)-1-Alkenylboranes R R H H HBY 2 RC CH + H BY 2 trans > 99 % O (Siamyl) 2 , = Y 2 O O HBY 2 t -BuLi R X R BY 2 RC CX H H BY 2 BY 2 H H H H cis > 98 % X = I or Br X = I or Br Y = Siamyl Cyclohexyl Y = Siamyl, Cyclohexyl

N-4 X X H H R H H R' H (trans trans) (trans, trans) H R H Pd X R' H R' base H BY 2 R R H H 2 H H (trans, cis) R' H H H H H H R' H R' X X H H R R (cis, trans) H R BY 2 Pd H H H H H H H H H H base X R' R (cis, cis) R' H H H H

N-5 Common Catalytic Cycle Involving Sequential Oxidative Addition (a), Transmetalation (b), and Reductive Elimination (c) ( ), ( ), ( ) Atomic charge in 0.01 e.u. M R-R R R' R-X (Gropen & Haaland, 1973) + 12 (c) (c) ( ) (a) CH 3 B CH 3 - 4 CH 3 R M R' R' R-M-X R M X - 12 (b) CH 3 CH CH 3 B CH 3 B CH R CH 3 R B OR' - 22 R R'-M' (R 3 B) R -M (R 3 B)

N-6 Bu Bu Bu Bu Br Br + + BX 2 Ph Ph 3 2 1 Catalyst b) Base React. Yield (%) 1 a) Solvent (equiv / 2) time (h) of 3 (mol %) PdL 4 (3) PdL (3) 1b 1b N None 6 6 0 0 THF THF PdL 4 (3) 1b None Benzene 6 0 PdL 4 (3) 1a 2M NaOEt (2)-EtOH 2 73 THF PdL 4 (3) PdL 4 (3) 1b 1b 2M NaOEt (2)-EtOH 2M NaOEt (2)-EtOH 4 4 78 78 THF THF PdL 4 (1) 1b 2M NaOEt (2)-EtOH Benzene 2 86 O b) L = PPh 3 a) 1a, X 2 = (Sia) 2 1b, X 2 = O O

N-7 Yield (%) 1-Alkenylborane 1 Alkenylborane 1-Alkenyl Bromide 1-Alkenyl Bromide Product Product [Purity (%)] Ph Br Ph Bu b) 86 [98] B B Bu Bu Bu Bu B Br a) 49 [99] Ph Ph Ph Ph Bu Bu B Br Ph a) 42 [89] Ph Ph Hex Br Hex Bu b) 88 [99] B Bu Bu Bu Br Hex B a) 49 [98] Hex Ph Ph b) 89 [98] B Br Ph Ph Reaction conditions: 1-3 mol % of Pd(PPh 3 ) 4 / NaOEt / Benzene / Reflux 2h a) Disiamyl b) 1,3,2-Benzodioxaboryl

N-8 Pd(PPh 3 ) 4 Bu R Bu BY 2 + RX RX NaOEt / benzene reflux, 2 h Purity (%) P it (%) BY 2 BY Product Yield (%) (%) RX B(Sia) 2 49 >98 Bu Br Hex B(OPr i ) 2 Hex 87 >99 >94 >94 B(Si ) B(Sia) 2 58 8 Bu Ph B( ) 2 49 PhI >83 B(OPr i ) 2 >97 98 B(Sia) 2 Bu 54 >92 I B(OPr i ) 2 87 87 >99 >99 B(OPr ) 2

N-9 OH O O H 2 N H N O O OH HO OH HO OH OH O HO OH Me HO OH HO HO OH OH OH OH OH O HO HO OH OH OH OH O O O O M Me OH OH MeHO M HO OH OH HO N N O H H OH OH OH HO HO Me O O Me OH O OH HO O Me OH Me OH Me O OH O OH HO OH OH HO OH OH "P l t "Palytoxin" C 129 H 223 N 3 O 54 (MW. 2678.6) i " C H N O (MW 2678 6) Synthesis: Kishi et al., J. Am. Chem. Soc , 1989, 111 , 7525, 7530

N-10 Reaction Mechanism: PdL PdL 4 Me M Br + Bu Bu Ph B(Sia) 2 Ph 9 % Cl Cl Cl Cl Cl Cl PdL 4 NaOMe Cl Cl PdOMe·L 2 PdOMe L 2 Cl Cl PdCl·L 2 PdCl L Cl Cl Cl Cl Fitton (1968) Otsuka (1976) without base without base Hex Hex O O Cl Cl no reaction B r.t./17 h + O Cl PdCl·L 2 Cl Cl NaOMe N OM r.t./2 h Cl 89 % Hex Hex Hex O O Cl Cl without base B 66 % + r.t./15 min O Cl PdOMe·L 2 without base 97 % r.t./1 h

N-11 Catalytic Formulation of the Vinyl-Vinyl Cross-Coupling R Pd(0) R R" R X F. Maseras et al., JACS , 2005, 127 , 9298 R Pd R R" B R" PdX R'ONa R" B OR' R R" R B OR OR' PdOR' A. Monteiro et al., J. Braz. Chem. Soc. 2007, 18 NaX

N-12 Reaction of B Alkylboranes Reaction of B-Alkylboranes R 1 R 3 R 1 R 3 Pd(0) R 4 X R 4 X + + Base R 2 R 2 R 4 B R 4 : 1-Alkenyl R : 1 Alkenyl Aryl 1-Alkynyl Allyl Allyl Benzyl R 4 X R 4 + R B R R : Alkyl

N-13 PdCl 2 (dppf) (3 mol%) PdCl 2 (dppf) (3 mol%) + B C 8 H 17 C 8 H 17 I NaOMe / THF, reflux 98 % PdCl 2 (dppf) (3 mol%) B Br + NaOMe / THF, reflux 88 % 88 % B (CH 2 ) 3 OMe Br ( (CH 2 ) 3 2 ) 3 OMe + OMe OMe 87 % 87 % PdCl 2 (dppf) (3 mol%) B C 8 H 17 + C 8 H 17 Br NaOMe / THF, reflux NaOMe / THF, reflux 94 %

N-14 Alkyl-Vinyl Coupling: Total Synthesis of Polycyclic Ether Natural Product M. Sasaki, Bull. Chem. Soc. Jpn. 2007, 80 , 856 TfO O OR 2 O H O O O 9-BBN 9-BBN R 1 O R 1 O Pd(0) OP OP aq. base H H H O O O O O O O O 1. hydroboration 1 hydroboration OR 2 OR 2 R 1 O R 1 O 2. oxidation OP O OP H H acetal O O formation R 1 O OR 2 O H OH

N-15 Polycyclic Ether Marine Natural Products: HO Me Me Me Me H H H H O O H H O HO H H O O O O H H H H H H H H H M H Me O Me H OH Gambierol Me HO OH H H O H H H H H O O H Me H H H H H OHC O O O O O H H H H H H H O O M Me H H O O H O O O OH H H H H Me H H O Gymnocin-A y Me

N-16 Aromatic-Aromatic Cross-Coupling Reactions Z Z + Br B(OH) 2 Z Z Pd(PPh ) Pd(PPh 3 ) 4 aq Na 2 CO 3 benzene, reflux

N-17 Suzuki Coupling: X B(OH) 2 + R R Pd(0), base R R X B(OH) 2 + R' R R R Pd(0) b Pd(0), base R' R' R R Ullmann Reaction: R R X X + R R R' R Cu high temp Cu, high temp. R' R' R R R' R'

N-18 Valsartan (Novartis): Antihypertensive V l t (N ti ) A tih t i CH 3 CH 3 O CH 3 CH N COOH N N HN N Suzuki Coupling 3.5 million users in Japan 22 million users in the whole world

N-19 Angiotensin II R Receptor Antagonist t A t i t (Losartan) Cl HO Cl HO N N CPh 3 CPh 3 CPh 3 N C 4 H 9 N N N N N N N N N N N N N N 4 9 N C 4 H 9 N N N N N 1. BuLi Br B(OH) 2 2 B(OPr i ) 3 2. B(OPr ) 3 Pd(OAc) 2 / 3 PPh 3 Pd(OAc) / 3 PPh aq. K 2 CO 3 3. IPA-NH 4 Cl THF / DME -H 2 O 90% reflux reflux 93% 93% Losartan (Antihypertensive) (Antihypertensive) Merck , J. Org. Chem . 59 , 6391 (1994)

N-20 Suzuki coupling is a shortcut to biaryls (BASF's Boscalid Process) (BASF s Boscalid Process) O OCH 3 PRE-SUZUKI ROUTE PRE-SUZUKI ROUTE N COOH Cl H N 5 Synthetic steps Cl Boscalid Multi-purpase Fungicide for Specialty Crops CN 1 Step SUZUKI ROUTE C t l Catalyst t Base CN + (HO) 2 B Cl

N-21 Boscalid; Agrochemicals (BASF Germany) Boscalid; Agrochemicals (BASF, Germany) N Cl O H N Cl B Boscalid lid

N-22 Liquid crystal: q y Chisso (Japan) ( p ) F LC Glass substrate + C 5 H 11 B(OH) 2 ( ) 2 I F 5 11 F F Pd catalyst / base Pd catalyst / base C 5 H 11 F F Merck (Germany) F F F C 3 H 7 OCF 3 R OCF 3 F

N-23 EL Polymer materials (HO) 2 B B(OH) 2 Br Br Br Br Pd(PPh ) Pd(PPh 3 ) 4 C 8 H 17 C 8 H 17 Na 2 CO 3 (solid) C 8 H 17 C 8 H 17 n DMAc, 120 °C

N-24 Pd cat X + (1979) B base Pd cat X + (1980) B base Pd cat X B + (1981) base Pd cat X + (1985) B base Pd cat X + (1992) B base Fu 2001-2002 F 2001 2002 Pd cat X B + Soderquist and (base) Fürstner 1995 Fürstner 1995

N-25 Advantages of the Cross-Coupling Reaction between Ad t f th C C li R ti b t Organoboron Compounds and Organic Electrophiles: 1. Ready availability of reagents: hydroboration and transmetalation 2. Mild reaction conditions: base problem 3. Water stability 3 Water stability 4. Easy use of the reaction both in aqueous and heterogeneous conditions 5. Toleration of a broad range of functional groups 6. High regio- and stereoselectivity of the reaction 7 7. Insignificant effect of the steric hindrance I i ifi t ff t f th t i hi d 8. Use of a small amount of catalysts 9. Application in one pot synthesis 9. Application in one-pot synthesis 10. Nontoxic reaction 11. Easy separation of inorganic boron compounds