N-1

Cross-Coupling Reactions of Organoboranes:

An Easy Way for Carbon-Carbon Bonding

Akira Suzuki

N-2

Conjugated Alkadienes

R'R'

R

R

R'

trans-trans

MY

MYR

R

trans-cis

+ X R'

R'

+ X

R'R R

cis-trans cis-cis

MR

R'

R'M

R

M : transition metal catalyst

N-3

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

R HRC CH + HBY 2

O

Y2 = (Siamyl)2 ,O

HBY2 R X

RC CXH BY2

H BY2

trans > 99 %

t-BuLi R BY2

H H

cis > 98 %

X = I or Br Y=Siamyl, Cyclohexyl

N-4

X H

R H

H BY 2

R BY

H H

Pd

base

Pd

base 2

H R'

X R'

H H

H R'

X H

H H

X R'

R HH

HH R'

R HR'

HH H

H R'R

HH H

H HR

R'H H

(trans, trans)

(trans, cis)

(cis, trans)

(cis, cis)

N-5Common Catalytic Cycle Involving Sequential Oxidative

Addition (a), Transmetalation (b), and Reductive Elimination (c)

MR-X

(a)

R-R

(c)

Atomic charge in 0.01 e.u.

(Gropen & Haaland, 1973)

+ 12

CH3 CH3 B

R-M-X

(b)

R'-M' (R3B)

R M R'

R R B OR'

R

CH3 -4

- 12

CH3

CH3 B CH3

CH3

- 22

N-6

Bu

1

BX2+ Br Ph

2

Bu Ph3

1a)Catalystb)

(mol %)Base(equiv / 2)

Yield (%)Solvent React.time (h) of 3

1b PdL4 (3) None THF 6 0

1b PdL4 (3) None Benzene 6 0

1a PdL4 (3)2M NaOEt (2)-EtOH THF 2 73

1b PdL4 (3)2M NaOEt (2)-EtOH THF 4 78

1b PdL4 (1)2M NaOEt (2)-EtOH Benzene 2 86

Oa)1a, X2 = (Sia)2 1b, X2 = b) L = PPh 3

O

N-7

1-Alkenylborane 1-Alkenyl Bromide Product Yield (%)[Purity (%)]

BuB

Bu B

Bu B

BuB

Bu B

Ph

b)

a)

a)

b)

a)

b)

PhBr PhBu

BuBrPh Ph

Br Ph BuPh

HexBr HexBu

Br Hex BuHe

x

Ph

86 [98]

49 [99]

42 [89]

88 [99]

49 [98]

89 [98]B Br Ph Ph

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

N-8

Bu BY2P

d(PPh3)4+ RXNaOEt / benzene

reflux, 2 h

Bu R

BY2 RX Product Yield (%) Purity (%)

B(Sia)2

B(OPri)2 Br

BuHex Hex

49 >98

87 >99

B(Sia)2

B( ) 2 PhI

B(OPri)2

58 >94

Bu Ph 49 >83

98 >97

B(Sia)2 Bu 54 >92I

B(OPri)2 87 >99

N-9OH

H2N

O

HO N NH H

O

O Me

OHMe

Me

OO OH

OHO

HOHO

OHHO

OH MeHO

OOH

O HO

O Me

HOHO

OHM

eOH

OH

OH

OH

OHOHOH

OHOH

HO

OHOH

OH

O OHOH

HOO

HOHO

Me OH

HOHO

"Palytoxin" C129H223N3O54 (MW. 2678.6)

O

OHOHOHOH

OH

Synthesis: Kishi et al., J. Am. Chem. Soc, 1989, 111, 7525, 7530

Reaction Mechanism:

Me

N-10

PdL4Bu +

BrB(Sia)2

BuPh Ph9 %

Cl Cl

Cl Cl

Cl Cl

PdL4

Fitton (1968)

H

ex

+

Cl Cl

Cl PdCl·L2

O

BO

NaOMe

Otsuka (1976)

without baser.t./17 h

Cl Cl

Cl PdOMe·L2

no reaction

Cl PdCl·L2

Cl Cl+

Cl PdOMe·L 2

Hex O B O

NaOMe

r.t./2 h

without base

r.t./15 min

without base

r.t./1 h

Cl Cl

Cl89 % Hex

66 %

97 %

Catalytic Formulation of the Vinyl-Vinyl Cross-Coupling

R

R Pd(0)

X

F. Maseras et al., JACS,2005, 127, 9298 R

R Pd

N-11

R"

R"B

R'ONa

R" OR'B

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

PdX

R

NaX

R"

R" OR'PdOR‘ B

N-12

Reaction of B-Alkylboranes

R1 R3

+ R4X

R2 B

R4 : 1-AlkenylAryl1-AlkynylAllyl

Benzyl

R B + R4X

R : Alkyl

Pd(0)

Base

R1 R3

R2 R4

R R4

N-13

PdCl2(dppf) (3 mol%)I

Br

Br

Br

+

+

+

+

B C8H17NaOMe / THF, reflux

B PdCl2(dppf) (3 mol%)

NaOMe / THF, reflux

B (CH2)3 OMe

OMe

PdCl2(dppf) (3 mol%)B C8H17NaOMe / THF, reflux

C8H17

98 %

88 %

(CH2)3 OMe

OMe

87 %

C8H17

94 %

N-14

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

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

TfO O

O 9-BBNR1O OP

H

OH9-BBN

R1OOP

OR2

Pd(0)aq. base

H HO O

R1O OR 2

OP

acetal

1. hydroboration

2. oxidation

OR1O

O

P

H H

OOR2

O

formationR1O

O O OR2

OH OH

N-15

Polycyclic Ether Marine Natural Products:

HO

HO

O

Me Me H HO O

O

HO H

HO HH H H H H

Gambierol

HO

MeMe O

H

O

OHMe

OHC

Me

H

H HH

OO O O

H H H H

OHH

O HMe

O

H OH

H H H H HO O HO H

O O OH H H H Me

Gymnocin-AH

HO

OH

Me

N-16

Aromatic-Aromatic Cross-Coupling Reactions

ZB(OH)2 + Br

Pd(PPh3)4Z

aq Na2CO3

benzene, reflux

Suzuki Coupling:

B(OH)2

+ XR

B(OH)2

+ XR

Ullmann Reaction:

X

+

XR

R Pd(0), base

R' Pd(0), base

R' Cu, high temp

N-17

R R

R R'

R R

R R'

R' R'

N-18

Valsartan (Novartis): Antihypertensive

CH3

CH3 CH3

O

N COOHN N

HN N

Suzuki Coupling

3.5 million users in Japan

22 million users in the whole world

N-19

Angiotensin II Receptor Antagonist (Losartan)

CPh3

N N NN N N

HO

CPh3

N N

Cl

N

NC4H9 N

N

HO Cl

CPh3 NN N N C 4H91. BuLi

2. B(OPri)3

3. IPA-NH4Cl-H 2 O

B(OH)2

90%

Br

Pd(OAc)2 / 3 PPh3

aq. K2CO3

THF / DMEreflux 93%

Losartan(Antihypertensive)

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

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

OCH3PRE-SUZUKI ROUTE

COOHN

5 Synthetic steps

N-20

O

N

HCl

ClBoscalid

Multi-purpase Fungicide

CN

1 Step

CatalystBase

for Specialty Crops

SUZUKI ROUTE

CN

Cl + (HO)2B

N-21

Boscalid; Agrochemicals (BASF, Germany)

N Cl

O

H N

Cl

Boscalid

N-22

Liquid crystal:

Chisso (Japan)

C5H11 B(OH)2

Pd catalyst / base

Merck (Germany)

F F

R OCF3

F

+ I F

F

C5H11

C3H7

LC

Glass substrate

F

F

F

F

OC

F3

F

N-23

EL Polymer materials

Br Br

C8H17 C8H17

(HO)2B B(OH)2

Pd(PPh3)4Na2CO3 (solid)DMAc, 120 °C

C8H17 C8H17n

N-24

B

B

B

B

B

B

XPd cat+ base

Pd cat+ X

base

Pd cat+ X

base

XPd cat+ base

XPd cat+ base

XPd cat+ (base)

(1979)

(1980)

(1981)

(1985)

(1992)

Fu 2001-2002

Soderquist andFürstner 1995

N-25

Advantages of the Cross-Coupling Reaction betweenOrganoboron Compounds and Organic Electrophiles:

1. Ready availability of reagents: hydroboration and transmetalation2. Mild reaction conditions: base problem

3. Water stability4. Easy use of the reaction both in aqueous and heterogeneous

conditions5. Toleration of a broad range of functional groups6. High regio- and stereoselectivity of the reaction

7. Insignificant effect of the steric hindrance8. Use of a small amount of catalysts9. Application in one-pot synthesis

10. Nontoxic reaction11. Easy separation of inorganic boron compounds

ReferencesScientific articles

1) Heck, R. F. and Nolley, J. P. J. Org. Chem. 1972 , 37, p. 2320.2) Negishi, E.-I., King, A. O. and Okukado, N. J. Org. Chem. 1977, 42, p. 18213) Miyaura, N. and Suzuki, A. J. Chem. Soc. Chem. Commun., 1979, p 866.

Review articles

1) Negishi, E. A profile of Professor Richard F. Heck Discovery of the Heck reaction. Journal of Organometallic Chemistry , 1999, 576, p. XV-XVI.2) Rouhi, M. Chem. & Eng. News, 2004, 82 (36), Sept. 6, p. 49–58. [Article about Suzuki.]3) de Meijere, A. and Diederich, F. (Eds.), Metal-Catalyzed Cross-Coupling Reactions, 2004,vol. 1 and 2,Wiley-VCH, Weinheim. pp. 916.4) Buchwald, S. L. (Ed.) Accounts of Chemical Research, 2008 Vol. 41, Nov. 11, p. 1439–1564. [Special issue on Cross Coupling.]

Online Resources

1)Royal Swedish Academy of Sciences, http://kva.se, and at http://nobelprize.org.2)Prezi.com3)www.openaccesschemistry.com

Acknowledgement

Nobelprize.org

Principal, Jawaharlal nehru Technological University Hyderabad

Dr. Pramod Kumar Dubey

My Research Friends