N-1

Nobel Lecture, December 8, 2010

Cross-Coupling Reactions of Organoboranes:p g g

An Easy Way for Carbon-Carbon Bondingy y g

Akira SuzukiS

Conjugated AlkadienesN-2

RR'

R'

R'RR' R

RR

R

trans trans trans cis cis trans cis cistrans-trans trans-cis cis-trans cis-cis

+RMY X R

R' R'M

+MY

XR' R'M

RMY

R

M : transition metal catalyst

N-3

Syntheses of (E)- and (Z)-1-Alkenylboranes

R H

Syntheses of (E)- and (Z)-1-Alkenylboranes

R

H

H

BY2

+ HBY2RC CH

O

O

trans > 99 %

(Siamyl)2,=Y2O

R

H

X

BY2

R

H

BY2

H

t-BuLiHBY2RC CX

H BY2 H H

X = I or Br Y = Siamyl Cyclohexyl

cis > 98 %

X = I or Br Y = Siamyl, Cyclohexyl

N-4

HX

H

HX

R' HRH (trans trans)

H

HR

BY2

Pd R'XH

H R'HRbase

(trans, trans)

2 H H

H

HR

H

R'

H

(trans, cis)

H H

X

R'H

H RR'H

BY2R

X H

Pd HH H

R

HH

HH

(cis, trans)

H H X R'

H

R

H

base HH

R' (cis, cis)H H

N-5Common Catalytic Cycle Involving Sequential Oxidative Addition (a), Transmetalation (b), and Reductive Elimination (c)

R R' Atomic charge in 0.01 e.u.

( ), ( ), ( )

MR-X R-R

( ) (c)

(Gropen & Haaland, 1973)

+ 12

CH3 BCH3

(a) (c)

CH3 - 4

MR

R'R M X

BCH3

CHCH

(b)- 12R'R-M-X

B OR'R

RR

B CH3CH3CH3

R'-M' (R3B) - 22R -M (R3B)

N-6

Bu Br Bu+BuBX2

BrPh

BuPh+

31 2

THF

Catalystb)

(mol %)1a) Base

(equiv / 2)

1b PdL (3) N

Solvent React.time (h)

Yield (%)of 3

6 0THF1b PdL4 (3) None

1b PdL4 (3) None Benzene

6

6

0

0

THF

THF

1a PdL4 (3)

1b PdL4 (3)

2M NaOEt (2)-EtOH

2M NaOEt (2)-EtOH

2

4

73

78THF1b PdL4 (3)

1b PdL4 (1)

2M NaOEt (2)-EtOH

2M NaOEt (2)-EtOH Benzene

4

2

78

86

O

O

a) 1a, X2 = (Sia)2 1b, X2 = b) L = PPh3

O

N-7

1-Alkenyl Bromide Product Yield (%)1-Alkenylborane

BuB

Br PhBu

Ph

1-Alkenyl Bromide Product [Purity (%)]

b) 86 [98]

1 Alkenylborane

B

Bu B BrPh

Bu

BuPha) 49 [99]

Bu B Br Ph

Ph Ph

BuPh

a) 42 [89]

Br Hex

Ph

BuHex

b) 88 [99]BuB

Br Hex BuHex

a) 49 [98]Bu B

PhB Br Ph Ph

Phb) 89 [98]

Reaction conditions: 1-3 mol % of Pd(PPh3)4 / NaOEt / Benzene / Reflux 2h a) Disiamyl b) 1,3,2-Benzodioxaboryl

N-8Bu BY2 RX

Pd(PPh3)4 Bu R+ RX

BY

NaOEt / benzenereflux, 2 h

(%) P it (%)

Bu

BY2 RX Product Yield (%) Purity (%)

B(Sia)2 49 >98Br Hex HexB(OPri)2 87 >99

B(Si ) 8 >94

Bu PhPhI

B(Sia)2

B( )2

58 >94

49 >83

B(OPri)2 98 >97

IBu

B(OPri)2

B(Sia)2 54 >92

87 >99B(OPr )2 87 >99

N-9

H N

OHO

OH

OH

HOHO OH

OHO

H2N OO

O

HOHO

OH

OHMe

OH

HO

HO OH

O

OHOH

OHOH

HOM HOOHMOO OH OHOH

HOHO

O

HOMeHO

OHNH

OHMe

OH

O

NH

O

HO

OH

OH

OHMe O

O OH

OHO

Me

MeOH

OHMe

O

O OH MeHO

O

HOHOOH

OHOH OHOH

"P l t i " C H N O (MW 2678 6)"Palytoxin" C129H223N3O54 (MW. 2678.6)Synthesis: Kishi et al., J. Am. Chem. Soc, 1989, 111, 7525, 7530

N-10

M PdL

Reaction Mechanism:

BuB(Sia)2

Me BrPh Bu

Ph+ PdL4

9 %

Cl

ClCl

Cl

Cl

PdCl LCl

Cl NaOMe Cl

PdOMe·L2Cl

ClPdL4

Cl Cl

Hex O

PdCl·L2Cl PdOMe L2ClFitton (1968) Otsuka (1976)

without baseCl

PdCl·L2Cl

Cl HexBO

O

N OMCl Cl

+ r.t./17 hwithout base no reaction

Hex O

NaOMeCl

Hex89 %r.t./2 h

Cl

PdOMe·L2Cl

Cl HexBO

O+ r.t./15 min 66 %

without base

r.t./1 h97 %

without base

N-11Catalytic Formulation of the Vinyl-Vinyl Cross-Coupling

RR

R"Pd(0)

XR

RF. Maseras et al., JACS,2005, 127, 9298

R

PdX

Pd

R"R"

B

R'ONa

RR" OR'

R"B

OR'

PdOR'R

BOR

NaXA. Monteiro et al., J. Braz.Chem. Soc. 2007, 18

N-12

Reaction of B-Alkylboranes

R4XPd(0)

Reaction of B Alkylboranes

+R1 R3 R1 R3

R4XBase

R4 : 1-Alkenyl

+R2 B R2 R4

R : 1 Alkenyl Aryl 1-Alkynyl

AllylAllyl Benzyl

R B R4X R R4+

R : Alkyl

N-13

PdCl2(dppf) (3 mol%)I B C8H17 C8H17+

PdCl2(dppf) (3 mol%)NaOMe / THF, reflux

98 %

BrB

+PdCl2(dppf) (3 mol%)

88 %

NaOMe / THF, reflux

Br OMe

88 %

+ (CH2)3 (CH2)3 OMeB

OMe

87 %

( 2)3

OMe

Br B C8H17 C8H17

87 %

+PdCl2(dppf) (3 mol%)

NaOMe / THF, refluxNaOMe / THF, reflux94 %

N-14

Alkyl-Vinyl Coupling:Total Synthesis of Polycyclic Ether Natural Product

M. Sasaki, Bull. Chem. Soc. Jpn. 2007, 80, 856

O

OTfOOR2

O HO

OP

9-BBNR1O

Pd(0)aq. base

O

OPR1O

9-BBN

O OH1 hydroboration O OH H

O

OPR1O

OOR2

1. hydroboration

2. oxidation

O

OPR1O

OOR2

O

O OH H

R1O OR2

acetalformation

OH OH

N-15Polycyclic Ether Marine Natural Products:

HOMe Me H H

O

O

O

O

OO

OH H H H H M

HO

Me Me H HH

HH H

OH H H H H Me

MeH OH

MeGambierol

OHH H

HHO OH

OO O

O

OO O O

OH H H HH

HH

H

HHHHHMeH

HHM

OHC

OO O O

O

O

HH

H H H H Me HH

OH

HMe

Gymnocin-AMe

y

N-16

Aromatic-Aromatic Cross-Coupling Reactions

ZB(OH)2 Br+

Z

Pd(PPh ) ZPd(PPh3)4

aq Na2CO3benzene, reflux

Z

N-17Suzuki Coupling:

B(OH)2 + XR Pd(0), baseR R R

B(OH)2 + XR Pd(0) bR' R R'R Pd(0), baseR R R'

Ullmann Reaction:R R

X + XR Cu high tempR' R R'R Cu, high temp.R R R'

R' R'

N-18

V l t (N ti ) A tih t iValsartan (Novartis): Antihypertensive

CH3 CH3O

CHN COOH

CH3

NNN

HN

Suzuki Coupling

3.5 million users in Japan22 million users in the whole world

N-19Angiotensin II R t A t i t Receptor Antagonist (Losartan)

ClHO

NNCPh3

NNCPh3

NNCPh3

NN

ClHO

NN

C4H9N

NNN N

NNN

B(OH)2

NNN

NN

C4H9

4 9

1. BuLi

2 B(OPri)3

Br

Pd(OAc) / 3 PPh2. B(OPr )3

3. IPA-NH4Cl -H2O 90%

Pd(OAc)2 / 3 PPh3aq. K2CO3THF / DMEreflux 93%

Losartan(Antihypertensive)

reflux 93%

(Antihypertensive)Merck , J. Org. Chem. 59, 6391 (1994)

N-20Suzuki coupling is a shortcut to biaryls (BASF's Boscalid Process)

OCH3PRE-SUZUKI ROUTE

O

(BASF s Boscalid Process)

COOHPRE-SUZUKI ROUTE

N

N

ClH

5 Synthetic steps ClBoscalid

CNMulti-purpase Fungicidefor Specialty Crops

1 Step

C t l tSUZUKI ROUTE

CatalystBase

CN

Cl (HO)2B+

N-21

Boscalid; Agrochemicals (BASF Germany)Boscalid; Agrochemicals (BASF, Germany)

N

O

Cl

HN

ClB lidBoscalid

N-22

Liquid crystal:q y

Chisso (Japan)

C5H11 B(OH)2 I F

F

+

( p )

LC

Glass substrate5 11 ( )2

FF

Pd catalyst / baseC5H11 F

F

Pd catalyst / base

FFF

Merck (Germany)

C3H7 OCF3

F

R OCF3

N-23

EL Polymer materials

Br Br Pd(PPh )

(HO)2B B(OH)2

Br Br

C8H17 C8H17C8H17 C8H17 n

Pd(PPh3)4Na2CO3 (solid)DMAc, 120 °C

N-24

BX

+Pd cat

base (1979)

B X (1980)+ Pd cat

base

XB + (1981)Pd catbase

BX+ (1985)

Pd catbase

BX+ (1992)

Pd catbase

F 2001 2002

B X+ Soderquist andFürstner 1995

Pd cat(base)

Fu 2001-2002

Fürstner 1995

N-25

Ad t f th C C li R ti b t Advantages of the Cross-Coupling Reaction between Organoboron Compounds and Organic Electrophiles:

1. Ready availability of reagents: hydroboration and transmetalation 2. Mild reaction conditions: base problem3 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 I i ifi t ff t f th t i hi d 7. Insignificant effect of the steric hindrance 8. Use of a small amount of catalysts9. Application in one-pot synthesis 9. Application in one pot synthesis

10. Nontoxic reaction11. Easy separation of inorganic boron compounds