Paladium Catalysed Transformations in Organic Synthesis Paul Docherty, 2005 Palladium-Catalyzed Cross-Coupling Reactions in Total Synthesis K. C. Nicolaou,

Paladium Catalysed Transformations in Organic Synthesis

Paul Docherty, 2005

Palladium-Catalyzed Cross-Coupling Reactions in Total SynthesisK. C. Nicolaou, Paul G. Bulger, David SarlahAngewandte Chemie International EditionVolume 44, Issue 29, 2005. Pages 4442-4489

Introduction• Since Mizoroki[1] developed the first palladium catalysed reaction, research in this

area has developed exponentially, with each new issue of Angewandte Chemie or JACS highlighting the latest techniques and processes.

• These reactions show a breadth of applications, not just in the type of transformation, but in the target structure and scale of the process. Indeed, it is common to see the retrosynthesis of industrial targets hinge upon a crucial palladium-mediated reaction.

1. T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 1971, 44, 581

(There is still some debate as to which coupling was developed first; many claim that the Kumada coupling of sp2 grignard reagents with aryl, vinyl or alkyl halides was the first. However, the intrinsic reactivity of grignard reagents with other common functionalities mean that this coupling is seldom used.)

Pd

Why Palladium?• Why is palladium such an adept catalyst centre? Why not sodium?• The reason seems to be based around its electronegativity, which leads to relatively

strong Pd-H and Pd-C bonds, and also develops a polarised Pd-X bond.• It allows easy access to the Pd (II) and Pd (0) oxidation states, essential for processes

such as oxidative addition, transmetalation and reductive elimination,• Pd (I), Pd (III) and Pd (IV)[2] complexes are also known, though less thoroughly, with

Pd (IV) species essential in C-H activation mechanisms.

2. Pd (VI) complexes has also been proposed (W. Chen, S. Shimada, M. Tanaka, Science, 2002, 295, 308), but theoretical articles counter-argue this (E. C. Sherer, C. R. Kinsinger, B. L. Kormos, J.D. Thompson, C. J. Cramer Angew. Chem., Int. Ed. 2002, 41, 1953). The debate is ongoing.

The Heck Reaction• Broadly defined as the palladium-catalyzed coupling of

alkenyl or aryl (sp2) halides or triflates with alkenes to yield products which formally result from the substitution of a hydrogen atom in the alkene coupling partner.

• First discovered by Mizoroki, though developed and applied more thoroughly by Richard F. Heck in the early 1970s.[3]

• Generally thought of as the original palladium catalysed cross-coupling, and probably the best evolved, including a multitude of asymmetric varients.[4]

3. R. F. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37, 2320

4. Review on asymmetric Heck reactions: A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 – 2963

H

R1

R2

R3

R4 X R4

R1

R2

R3

cat. [Pd0Ln]

base

R4 = aryl, benzyl, vinylX = Cl, Br, I, OTf

Mechanism of the Heck Reactionneutral

PPh3

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

PPh3

- PPh3

- PPh3

Pd0

Pd0

Pd0

BrPd

Ph3P

Br PPh3

PdI I

O

O

PdPh3P

Br PPh3

OO

PdI I -Complex

PdPh3P

Br

O O

H H

PdI I -Intermediate

PdPh3P H

Br PPh3

OO

PdI I -Complex

PdPh3P H

Br PPh3

B

HBr / B

PdI IO

O

OxidativeAddition

-hydrideElimination

ReductiveElimination

Mechanism of the Heck Reactioncationic

PPh3

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

PPh3

- PPh3

- PPh3

Pd0

Pd0

Pd0

BrPd

Ph3P

Br PPh3

PdI I

O

OPd

Ph3P

PPh3

OO

PdI I -Complex

PdPh3P

O O

H H

PdI I -Intermediate

PdPh3P H

PPh3

OO

PdI I -Complex

PdPh3P H

PPh3

B

PdI IO

O

OxidativeAddition

-hydrideElimination

ReductiveElimination

BrAg

HB

Ag

Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135.

Regioselectivity in the Heck Reaction

a) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.

b) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 1481–1486.

Ph

Y N

CH3 OH

O

OH

100 90 100

10

100 60 80

40 20

Y = CO2R CN CONH2

Ph

Y N

CH3 OH

O

OH

60 5

95

100 10

100 90

Y = CO2R CN CONH2

40 100

Neutral Catalytic Cycle Cationic Catalytic Cycle

• The type of mechanism in action is incredibly important, as it can manifest itself in a variety of ways, especially the regioselectivity.

• In the neutral catalytic cycle, the regioselectivity is governed by steric factors – generally addition occurs to the terminal end of the alkene.

• However, in the cationic cycle, regiochemistry is affected by electronics. The cationic Pd complex increases the polarization of the alkene favouring transfer of the vinyl or aryl group to the site of least electron density.

• The type of mechanism in effect is generally controlled by choice of halide/pseudohalide acting as a leaving group in the cationic cycle; triflate promotes, whereas bromide detracts.

The Heck Reaction: Dehydrotubifoline

a) V. H. Rawal, C. Michoud, R. F. Monestel, J. Am. Chem. Soc. 1993, 115, 3030 – 3031

b) V. H. Rawal, C. Michoud, J. Org. Chem. 1993, 58, 5583 – 5584.

N

RH

N I

Me

H

N

N

Me

HH

N

N

Me

H PdIILnOMeO

H

N

N

H

H

MeO2C

PdIILn

MeH

N

N

H

H

MeO2C

PdIILn

second 1,2-insertion

-hydrideelimination

bond rotation,rearrangement

Pd(OAc)2, K2CO3nBu4NCl, DMF, 60 °C

N

N

Me

HH

MeO2C

Heck Cyclisation3: (±)-dehydrotubifoline

dehydrotubifoline

1: R=H2: R=CO2Me

4

5 6

7

The Heck Reaction: Capnellene

a) K. Kagechika, M. Shibasaki, J. Org. Chem. 1991, 56, 4093 –4094

b) K. Kagechika, T. Ohshima, M. Shibasaki, Tetrahedron, 1993, 49, 1773 – 1782.

TfO

Me

Me

PdP

P*

Me

PdP

P*

Pd(OAc)2 (1.7 mol%)(S)-binap (2.1 mol%)

nBu4NOAcDMSO, 20 °C

major minor

OTf OTf

14

15 18

catalysicasymmetricHeck Cyclisation

P

P

*

H MePd

AcO

OAc

(89% yield,80% ee)

anioncapture

16

H

Me

OAc

17

MeHO

MeH

OH

H

HOMe

MeHO

HOH

H

HOMe

HO

capnellene

9(12)-capnellene-3,8,10-triol

9(12)-capnellene-3,8,10,14-tetraol

H

Me

OAc

19

PPh2

PPh2

P

P* =

(S)-binap

The Heck Reaction: Taxol

a) S. J. Danishefsky, J. J. Masters, W. B. Young, J. T. Link, L. B. Snyder, T. V. Magee, D. K. Jung, R. C. A. Isaacs, W. G. Bornmann, C. A. Alaimo, C. A. Coburn, M. J. Di Grandi, J. Am. Chem. Soc. 1996, 118, 2843 – 2859

b) J. J. Masters, J. T. Link, L. B. Snyder, W. B. Young, S. J. Danishefsky, Angew. Chem. Int. Ed. Engl. 1995, 34, 1723 – 1726.

OO

O

OTf

Me

HBnO

O

OTBSMe

OO

O

Me

HBnO

O

OTBSMe

HOBzO

Me

HAcO

O

OHMe

AcO

O

O

BzHN

OH

Ph

O

taxol

[Pd(PPh3)4] (110 mol%)M. S. (4 A)

K2CO3, MeCN, 90 °C

(49%)

IntramolecularHeck Reaction

22

23

24: taxol

The Heck Reaction: Estrone

L. F. Tietze, T. NVbel, M. Spescha, J. Am. Chem. Soc. 1998, 120, 8971 – 8977.

MeO

BrBr

Me OtBu

Pd(OAc)2, PPh3nBu4NOAc

DMF/MeCN/H2O70 °C

IntermolecularHeck Reaction

MeO

BrPdLn

Br

MeOtBu

H

5

4

MeO

Br H

Me OtBu

H

MeO

H

Me OtBu

HH

HO

H

Me O

HHA

D

29, nBu4NOAcDMF/MeCN/H2O

115 °C(99%)

(50%)

IntramolecularHeck Reaction

25

26

27

26

28

3030: estrone

estronePPd

o-Tol o-TolO

O PPd

o-Tolo-TolO

O

Me

Me

Domino Heck Reactions

Y. Zhang, G.Wu, G. Angel, E. Negishi, J. Am. Chem. Soc. 1990, 112, 8590 – 8592.

Me

EtO2CEtO2C

I

Me

EtO2CEtO2C

I

Me

EtO2CEtO2C

[Pd(PPh3)4] (3 mol%)Et3N (2 eq.)MeCN, 85 °C

(76%)

IntramolecularDomino HeckCyclisation32 33

Domino Heck Reactions

a) L. E. Overman, D. J. Ricca, V. D. Tran, J. Am. Chem. Soc. 1993, 115, 2042 – 2044

b) D. J. Kucera, S. J. OIConnor, L. E. Overman, J. Org. Chem. 1993, 58, 5304 – 5306.

O

O

I

TBSO

Me

H

Pd(OAc)2 (10 mol%)PPh3 (20 mol%)

Ag2CO3THF, 70 °C

OxidativeAddition

PdLn

TBSO

Me

H

I

1,2-insertion

OO

TBSO

Me

HPdLnI

1,2-insertion

TBSO

Me LnPd

H

OO

I

TBSO

Me LnPd

H

OO

I

OBz

Me

H

-HydrideElimination

scopadulic acid

O

HO2C

Me

H

HO

42: Scopadulic Acid B

4140

393837

(82% overall)

OO

Intramolecular Heck Cascade

The Stille Coupling

5. Original Report; a) M. Kosugi, K. Sasazawa, Y. Shimizu, T. Migita, Chem. Lett. 1977, 301 – 302; b) M. Kosugi, K. Sasazawa, T. Migita, Chem. Lett. 1977, 1423 – 1424.

6. a) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636 – 3638; b) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4992 – 4998; c) For a review of Stille Reactions, see; V. Farina, V. Krishnamurthy,W. J. Scott, Org. React. 1997, 50, 1 – 652

7. T. Hiyama, Y. Hatanaka, Pure Appl. Chem. 1994, 66, 1471

8. T. R. Kelly, Tetrahedron Lett. 1990, 31, 161

• Originally discovered by Kosugi et al[5] in the late 1970s, the Stille Coupling was later developed as a tool for organic transformations by the late Professor J. K. Stille.[6]

• Milder than the older Heck reaction, and more functional-group tolerant, the Stille coupling remains popular in organic synthesis.

• A close relative of the Stille coupling is the Hiyama; this involves the palladium catalysed reaction of a organosilicon with organic halides/triflates et c., but requires activation with fluoride (TBAF) or hydroxide.[7]

• It is possible to couple bis-aryl halides using R3Sn-SnR3, in a varient known as a Stille-Kelly reaction, but the toxicity of these species is a somewhat limiting factor.[8]

R1 R2 Xcat. [Pd0Ln]

base

R1 = alkyl, alkynyl, aryl, vinylR2 = acyl, alkynyl, allyl, aryl, benzyl, vinylX = Br, Cl, I, OAc, OP(=O)(OR)2, OTf

SnR3 R1 R3

Mechanism of the Stille Coupling

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

Ph3P

- PPh3

- PPh3

Pd0

Pd0

Pd0

Br

PdPh3P

Br PPh3

PdI I

PdPh3P

PPh3

PdPh3P

Ph3P

BrSnBu3

SnBu3R2

R1

R3

R2 R3

R1

R2

R1

PdI I

PdI I

R1

R1R2

R1

The Stille Coupling: Rapamycin

a) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato, J. Am. Chem. Soc. 1993, 115, 4419 – 4420; K. C. Nicolaou, A. D. Piscopio, P. Bertinato, T. K. Chakraborty, , N. Minowa, K. Koide, Chem. Eur. J. 1995, 1, 318 –333.

b) A. B. Smith III, S. M. Condon, J. A. McCauley, J. L. Leazer, Jr.,J. W. Leahy, R. E. Maleczka, Jr., J. Am. Chem. Soc. 1995, 117, 5407 – 5408.

OO

NO

I

Me

I

O

Me

O

OO

H

OH

H

Me

Me

OH

MeOMe

Me

H OH

Me

OMe

OMe

Bu3Snn

SnnBu3

[PdCl2(MeCN)2](20 mol%)

iPr2NEt, DMF,THF, 25°C

IntermolecularStille Coupling

OO

NO

I

Me

O

Me

O

OO

H

OH

H

Me

Me

OH

MeOMe

Me

H OH

Me

OMe

OMe

SnnBu3

IntramolecularStille Coupling

OO

NOMe

O

Me

O

OO

H

OH

H

Me

Me

OH

MeOMe

Me

H OH

Me

OMe

OMe

OO

NOMe

O

Me

O

OO

H

OTIPS

H

Me

Me

OTBS

MeOMe

Me

H TESO

Me

OMe

OMeSnnBu3

I

1. [PdCl2(MeCN)2] (20 mol%)iPr2NEt, DMF, THF, 25°C (74%)

IntramolecularStille Coupling

2. Deprotection (61%)

27%Overall

rapamycin

76: Rapamycin75

7472

"Stitching Cyclisation"

The Stille Coupling: Dynamycin

a) M. D. Shair, T.-Y. Yoon, K. K. Mosny, T. C. Chou, S. J. Danishefsky, J. Am. Chem. Soc. 1996, 118, 9509 – 9525;

b) M. D. Shair, T.-Y. Yoon, S. J. Danishefsky, Angew. Chem. 1995, 107, 1883 – 1885; Angew. Chem. Int. Ed. Engl. 1995, 34, 1721 – 1723;

c) M. D. Shair, T. Yoon, S. J. Danishefsky, J. Org. Chem. 1994, 59, 3755 – 3757.

TeocNO

OH

OH

H

Me

II

OTBS

Me3Sn SnMe3

[Pd(PPh3)4] (5 mol%)DMF, 75 °C

81%

TandemIntermolecularStille Coupling

TeocNO

OH

OH

H

Me

OTBS

HNO

CO2H

OMe

H

Me

OH

O

O

OH

OH

79

dynemicin

81: (±) Dynamycin77

Teoc = 2-(trimethylsilyl)ethoxycarbonyl

The Stille Coupling: Sanglifehrin

a) K. C. Nicolaou, J. Xu, F. Murphy, S. Barluenga, O. Baudoin, H.-X.Wei, D. L. F. Gray, T. Ohshima, Angew. Chem. Int. Ed. 1999, 38, 2447 – 2451;

b) K. C. Nicolaou, F. Murphy, S. Barluenga, T. Ohshima, H. Wei, J. Xu, D. L. F. Gray, O. Baudoin, J. Am. Chem. Soc. 2000, 122, 3830 – 3838.

N

NH

OO

O

NH

O

OH

HNO

MeMe

OMe

O Me

SnnBu3

Me

I

I

[Pd2(dba)3]•CHCl3AsPh3,

iPr2NEtDMF, 25 °C, 62%

ChemoselectiveIntramolecular

Stille macrocyclisation

N

NH

OO

O

NH

O

OH

HNO

MeMe

OMe

O MeMe

I

1. [Pd2(dba)3]•CHCl3AsPh3,

iPr2NEtDMF, 40°C, 45%

2. aq. H2SO4

THF/H2O(33%)

IntermolecularStille Coupling

N

NH

OO

O

NH

O

OH

HNO

MeMe

OMe

O MeMeMe

NH

O

O

Me

OH

Me

Me

Me

Me

Me

NH

O

O

Me

OH

Me

Me

Me

Me 88

86 87

87: sanglifehrin A

sanglifehrin

SnnBu3

23

22

The Stille Coupling: Manzamine A

a) S. F. Martin, J. M. Humphrey, A. Ali, M. C. Hillier, J. Am. Chem. Soc. 1999, 121, 866 – 867;

b) J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y.-L. Wong, H.-J. Chen, A. K. Courtney, S. F. Martin, J. Am. Chem. Soc. 2002, 124, 8584 – 8592.

NBoc

OTBDPS

ON

TBDPSO

BrCO2Me

SnnBu3

[Pd(PPh3)4)] (4 mol%)toluene, 120 °C

IntermolecularStille Coupling

109

NBoc

OTBDPS

ON

TBDPSO

CO2Me

N

O

TBDPSO

N

OTBDPS

HBoc E

110

N

O

OTBDPS

CO2Me

NBoc

OTBDPS

H

H

111

endo-intramolecularDiels-Alder Reaction

(68% Overall)

N NH

N

NH

H

OH

H

A B

C

D

112: Manzamine A

manzamine

The Carbonylative Stille Coupling: Jatrophone

A. C. Gyorkos, J. K. Stille, L. S. Hegedus, J. Am. Chem. Soc. 1990, 112, 8465 – 8472.

O

O Me

Me O

Me

Me

Me

O

O Me

Me

Me

Me

Me O

O Me

Me

Me

Me

Me

[PdCl2(MeCN)2]LiCl, CO (50 psi)

DMF, 25 °C

IntermolecularCarbonylativeStille CouplingSnnBu3

OTfSnnBu3

PdLnCl

O

O Me

Me

Me

Me

Me

SnnBu3

53% Overall

8382

8485: (±)-2-epi-jatrophone

jatrophone

PdLn

O

Cl

CarbonylInsertion

The Suzuki Coupling

9. Original Report; a) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437 – 3440; b) N. Miyaura, A. Suzuki, J. Chem. Soc. Chem. Commun. 1979, 866 – 867

10. a) R. F. Heck in Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research XVII. Organic-Inorganic Reagents in Synthetic Chemistry (Ed.W. O. Milligan), 1974, p. 53–98; b) H. A. Dieck, R. F. Heck, J. Org. Chem. 1975, 40, 1083 – 1090.

11. E. Negishi in Aspects of Mechanism and Organometallic Chemistry (Ed.: J. H. Brewster), Plenum, New York, 1978, p. 285.

12. a) T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki, Chem. Lett. 1992, 691 – 694. b) J. Zhou, G.C. Fu, J. Am. Chem. Soc. 2004, 126, 1340 – 1341, and references therein. c) A. C. Frisch, M. Beller, Angew. Chem. Int. Ed. 2005, 44, 674 – 688. d) For a relatively recent review, see N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.

• The Suzuki reaction was formally developed by Suzuki Group in 1979[9], although the inspiration for this work can be traced back to publications by Heck[10] and Negishi,[11] and their earlier presentation of these papers at conferences.

• The popularity of this reaction can be partially attributed to the ease of preparation of the organoboron reagents required, their general stability, and the lack of toxic by-products.

• Progress in the last quarter-century has shown that the Suzuki reaction is incredibly powerful, with examples of C(sp2)–C(sp3) and even C(sp3)–C(sp3) now well documented.[12]

R1 R2 Xcat. [Pd0Ln]

base

R1 = alkyl, alkynyl, aryl, vinylR2 = alkyl, alkynyl, aryl, benzyl, vinylX = Br, Cl, I, OAc, OP(=O)(OR)2, OTf

BY2 R1 R2

Mechanism of the Suzuki Coupling

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

PPh3

- PPh3

- PPh3

Pd0

Pd0

Pd0

IPd

Ph3P

IPh3P

PdI I

PdPh3P PPh3

PdI I -Complex

NaOEtNaI

PdPh3P

OEtPh3P

PdI I

R1

R2

BF3

R3

K

BF3OEt

PdPh3P

Ph3P

PdI I

R3 R2

R1

R3

R2 R1

R3

R2

R1

The Suzuki Coupling: Palytoxin

O

O

OTBS

NHTeoc

O Me

Me

O

TBSO OTBSOTBS

B

OTBS

TBSO

TBSO

OTBS

TBSO OTBS

HO

OH

O

IOAc

OTBSOTBSTBSO

OTBS

OTBSO

CO2Me

TBSO

TBSO

H

OTBS

OTBS

[Pd(PPh3)4] (40 mol%)TlOH, THF/H2O, 25 °C

(70%)

IntermolecularSuzuki Coupling

OO

OTBSTeocHN

O

Me

Me

OTBSO

OTBSTBSO OTBS

TBSO

TBSO OTBS

OTBS

OTBS

O

OAc

OTBS

OTBS

OTBSOTBS

TBSO

OMeO2C

OTBS OTBS

HTBSOOTBS

a) R.W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli, W. J. McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M. Yonaga, J. Am. Chem. Soc. 1989, 111, 7525 – 7530;

b) R.W. Armstrong, J.-M. Beau, S. H.Cheon,W. J. Christ, H. Fujioka,W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,W. J. McWhorter, Jr.,M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M.Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 – 7533;

c) E. M. Suh, Y. Kishi, J. Am. Chem. Soc. 1994, 116, 11205 – 11206.

The Suzuki Coupling: Palytoxin

a) R.W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli, W. J. McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M. Yonaga, J. Am. Chem. Soc. 1989, 111, 7525 – 7530;

b) R.W. Armstrong, J.-M. Beau, S. H.Cheon,W. J. Christ, H. Fujioka,W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,W. J. McWhorter, Jr.,M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M.Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 – 7533; c) E. M. Suh, Y. Kishi, J. Am. Chem. Soc. 1994, 116, 11205 – 11206.

O

O

OH

NH2

O Me

Me

O

HO OHOH

OH

HO

OH

OH

OH OH

O

OH

O

OH

OH

OH

HO

O

OH

OH

HHO

OH

OH

O

OHHO

OH

OHHO

OO

Me OH

OH

OHHO

OHO

HO OH

OH

HHN

OHMeOHMe

OH

O

HN O

OH

palytoxin

a) D. A. Evans, J. T. Starr, J. Am. Chem. Soc. 2003, 125, 13531 –13540

b) D. A. Evans, J. T. Starr, Angew. Chem. 2002, 114, 1865 – 1868; Angew. Chem. Int. Ed. 2002, 41, 1787 – 1790.

The Suzuki Coupling: FR182887MeO

Me

O

Br

BrMeMe

OTBSTBDPSO

B

OTBS

OTBS

Me

HO

OH

[Pd(PPh3)4)] (5 mol%)Tl2CO3, THF/H2O, 23 °C

(84%)

IntermolecularSuzuki Coupling

TBDPSO

OTBS

OTBS

Me

MeO

Me

O

BrMeMe

OTBS

O

HO

OH

H Me

Br

H H

HCO2Et

H

HOMe

Me

H

B

OB

O

BO Me

Me

Me

[PdCl2(dppf))] (10 mol%)Cs2CO3, DMF/H2O, 100 °C

(71%)

O

HO

OH

H Me

Me

H H

HCO2Et

H

HOMe

Me

H O

HO

OH

H Me

Me

H H

H

H

OMe

Me

H

O

fr182887

132: FR182887131

130 129128

127126

IntermolecularSuzuki Coupling

a) N. K. Garg, D. D. Capsi, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 9552 – 9553.

b) For a failed alternative route without Pd Catalysis: N. K. Garg, R. Sarpong, B. M. Stoltz, J. Am. Chem. Soc. 2002, 124, 13179 – 13184.

The Suzuki Coupling: DragmacidinMe

TBSO

HOO N

SEM

Br

[Pd(PPh3)4] (10 mol%)toluene/MeOH/H2O, 23 °C

IntermolecularHeck Reaction

Me

TBSO

HOO N

SEM

PdOAc

TBSO

HOO

NSEM

H

(74%)

TBSO

MeO

O NSEM

HB O

O

[Pd(PPh3)4] (10 mol%)161, toluene/MeOH/H2O

NaCO3, 50 °C, 77%

IntermolecularSuzuki Reaction

TBSO

MeO

O NSEM

H

NTs

BrN

N

OMe

167

165166

162 164

HO

O NH

H

MeNH

BrNH

N

O

N

N

H2N

dragmacidin

168: dragmacidin

TsN

B

Br

OH

HO N

N I

Br OMe

[Pd(PPh3)4] (10 mol%)toluene/MeOH/H2O, 23 °C(71%)

IntermolecularSuzuki

Coupling

NTs

BrN

N

Br OMe

161

160159

13) a) N. Miyaura, T. Ishiyama, M. Ishikawa, A. Suzuki, Tetrahedron Lett. 1986, 27, 6369 – 6372; b) not to be confused with the Miyaura boration, in which an aryl halide is converted to an aryl boronate via palladium catalysis and a diboron reagent. However, this is a useful preparation of the organoboron reagents required for the Suzuki reaction. See: T. Ishiyama, M. Murata, N. Miyuara. J. Org. Chem. 1995, 60, 7508.

14) Review of the development, mechanistic background, and applications of the B-alkyl Suzuki-Miyaura cross-coupling reaction, see S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4544 – 4568.

15) Q. Tan, S. J. Danishefsky, Angew. Chem. Int. Ed. 2000, 39, 4509 – 4511.

The Suzuki-Miyaura B-Alkyl Coupling: CP-236,114

O

ITBSO

TBSO

H

OTBS

O

HOTBS

OTBS

OTBS

HOTBS

I

OTBS

OTBS

HOTBS

OBn6

OO

O

O O

O

CO2H

HMe

O

H

Me

[Pd(OAc)2(PPh3)2]Et3N, THF, 65 °C

(92%)

IntermolecularHeck Reaction

B{(CH2)6OBn}3[PdCl2(dppf)]

CsCO3, AsPh3, H2O, 25 °C(70%)

Suzuki-MiyauraB-Alkyl Reaction

174: CP-263,114

169 170

171173

CP-263,114

• An important trend in Suzuki chemistry is the development of a C(sp3)–C(sp2) methodology, which has become known as the Suzuki-Miyaura B-Alkyl varient.[13-15]

• Often used as an alternative to RCM, leaving a single isolated double bond, rather than the conjugated systems produced by a regular Suzuki coupling.

a) P. J. Mohr, R. L. Halcomb, J. Am. Chem. Soc. 2003, 125, 1712 – 1713

b) N. C. Callan, R. L. Halcomb, Org. Lett. 2000, 2, 2687 – 2690.

The Suzuki Coupling: Phomactin A

O

O

HMe

MeOTMS

OTES

Me

I

9-BBNTHF, 40 °C

O

O

HMe

Me OTMSOTES

Me

I

B

O

O

HMe

OTMSOTES

Me

Me

Me

O

O

HMe

OHOH

Me

Me

Me

TBAF(78%)

Suzuki-MiyauraB-Alkyl

Macrocyclisation

[PdCl2(dppf)] (100 mol%)AsPh3(200 mol%), Tl2CO3

THF/DMF/H2O, 25 °C(37%)

200: phomactin A

phomactin

M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles, 2000, 53, 553 – 556

The Suzuki Coupling: Yuehhukene

N

O ODirected

o-Metallation

tBuLi, THF, then BEt3

NBoc

BEt3

Li

Me

TfOMe Me

[PdCl2(PPh3)2CO (10 atm)THF, 60 °C

75%

CarbonylativeSuzuki Coupling

NBoc O

Me

Me Me

HN

Me

H

H

MeMe

NH

yuehchukene

205: yuehhukene

204

202

201

203

The Sonogashira Coupling

16. L. Cassar, J. Organomet. Chem. 1975, 93, 253 – 259.

17. H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93, 259 – 263.

18. K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467 – 4470.

19. For a brief historical overview of the development of the Sonogashira reaction, see: K. Sonogashira, J. Organomet. Chem. 2002, 653, 46 – 49.

20. R. D. Stephens, C. E. Castro, J. Org. Chem. 1963, 28, 3313 – 3315.

21. a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34, 6403 – 6406; b) J.-P. Genet, E. Blart, M. Savignac, Synlett 1992, 715 – 717; c) C. Xu, E. Negishi, Tetrahedron Lett. 1999, 40, 431 – 434;

• The coupling of terminal alkynes with vinyl or aryl halides via palladium catalysis was first reported independently and simultaneously by the groups of Cassar[16] and Heck[17] in 1975.

• A few months later, Sonogashira and co-workers demonstrated that, in many cases, this cross-coupling reaction could be accelerated by the addition of cocatalytic CuI salts to the reaction mixture.[18,19]

• This protocol, which has become known as the Sonogashira reaction, can be viewed as both an alkyne version of the Heck reaction and an application of palladium catalysis to the venerable Stephens–Castro reaction (the coupling of vinyl or aryl halides with stoichiometric amounts of copper(I) acetylides).[20]

• Interestingly, the utility of the “copperfree” Sonogashira protocol (i.e. the original Cassar–Heck version of this reaction) has subsequently been “rediscovered” independently by a number of other researchers in recent years.[21]

R2 Xcat. [Pd0Ln]

base

R1 = alkyl, aryl, vinylR2 = alkyl, benzyl, vinylX = Br, Cl, I, OTf

R2R1 H R2

Mechanism of the Sonogashira Coupling

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

Ph3P

- PPh3

- PPh3

Pd0

Pd0

Pd0

Br

PdPh3P

Br PPh3

PdI I

PdPh3P

PPh3

R1

R1

Cu

CuBr

H

R1

NEt3

PdPh3P

Ph3P

R1

R1

R1

NEt3H

PdI I

PdI I

K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106, 5734 – 5736

The Sonogashira Coupling: Eicosanoid 212

MeBr

OTBS

TMS

SonogashiraCoupling

[Pd(PPh3)4] (4 mol%)CuI (16 mol%)

nPrNH2, C6H6, 25 °CR

Me

OTBS

AgNO3,KCN

208: R = TMS

209: R = H

210, [Pd(PPh3)4] (4 mol%)CuI (16 mol%)

nPrNH2, C6H6, 25 °C76% Overall from 208

BrCO2Me

OTBS

Me

OTBS

CO2MeOTBS

Me

OH

CO2HOH

SonogashiraCoupling

206

207

210

211212

P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346 –15347.

The Sonogashira Coupling: Disorazole C1

Me

PMBO

Me

OH

MeMe

PMBO

Me

OH

Me

MeO O

N

CO2Me

SonogashiraCoupling

218[Pd(PPh3)2Cl2] (4 mol%)

CuI (30 mol%), Et3NMeCN, -20 °C, 94%

220, DCC, DMAP80%

Me

PMBO

Me

O

Me

MeO O

N

CO2Me

O

N

O

I

OMe

218[Pd(PPh3)2Cl2] (5 mol%)

CuI (20 mol%), Et3NMeCN, -20 °C, 94%

SonogashiraCoupling

Me

PMBO

Me

O

Me

MeO O

N

CO2Me

O

N

O OMe

OH

Me Me

OPMB

Me

Me

OH

Me

O

Me

MeO O

N

O

N

O OMe

O

Me Me

OH

Me

O

disorazole

N

O

RO

O

I

OMe

218: R = Me220: R = H

217 219

221

222223: Disorazole C1

The Sonogashira Coupling: Dynemicin

MeO2CN

OMe

Me

O

O

Br

MeO2CN

OMe

Me

O

OIntramolecularSonogashira

Coupling

[Pd(PPh3)4] (2 mol%)CuI (20 mol%)toluene, 25 °C

243 244

MeO2CN

OMe

Me

O

O

244

HH

H

H

MeO2CN

OMe

Me

OH

246

[Pd(PPh3)4] (2 mol %)CuI (20 mol %)toluene, 25 °C

BrCO2Me

1)

2) LiOH, THF/H2O65% overall

SonogashiraCoupling

MeO2CN

OMe

Me

OH

CO2H

Diels-Alder

2,4,6-Cl3C2H2COClDMAP, toluene, 25 °C

50%

248

247

YamaguchiMacrolactonisation/

Diels-Alder

HN

OMe

Me

H

OO

O

OMe

OMe

OMe

CO2Me

dynemicin

249: tri-O- methyl dynemicin Amethyl ester

a) J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 10 378 – 10379

b) J. L. Wood, J. A. Porco, Jr., J. Taunton, A. Y. Lee, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc.

1992, 114, 5898 – 5900

c) H. Chikashita, J. A. Porco, Jr., T. J. Stout, J. Clardy, S. L. Schreiber, J. Org. Chem. 1991, 56, 1692 – 1694

d) J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 7410 – 7411.

The Tsuji-Trost Reaction

22. For early reviews of the Tsuji-Trost reaction, see a) B. M. Trost, Acc. Chem. Res. 1980, 13, 385 – 393; b) J. Tsuji, Tetrahedron 1986, 42, 4361 – 4401.

23. J. Tsuji, H. Takahashi, Tetrahedron Lett. 1965, 6, 4387 – 4388.

24. For recent reviews of the palladium-catalyzed asymmetric alkylation reaction, see: a) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921 – 2943; b) B. M. Trost, J. Org. Chem. 2004, 69, 5813 – 5837.

• The palladium catalysed nucleophilic substitution of allylic compounds was discovered independently by Trost and Tsuji, and represents the first example of a metalated species acting as an electrophile.[22]

• Originally developed as a stoichiometric process, Trost succeeded in transforming the allylation of enolates with p-allyl–palladium complexes into the catalytic process of renown.[23,24]

• A wide range of allylic substrates undergo this reaction with a correspondingly wide range of carbanions, making this a versatile and important process for the formation of carbon–carbon bonds.

• Whilst the most commonly employed substrates for palladium-catalyzed allylic alkylation are allylic acetates, a variety of leaving groups also function effectively—these include halides, sulfonates, carbonates, carbamates, epoxides, and phosphates. cat. [Pd0Ln]

base

X = Br, Cl, OCOR, OCO2R, CO2R, P(=O)(OR)2NuH = -dicarbonyls, -ketosulfones, enamines, enolates

X NuH Nu

Mechanism of the Tsuji-Trost Reaction

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

PPh3

- PPh3

- PPh3

PdPPh3Ph3P

R1 OAc

R2

R1 OAc

R2

PdPPh3Ph3P

R1 R2

PdPPh3Ph3P

R1

R2

PdPPh3Ph3P

R1 R2

PdPPh3Ph3P

R1 R2

Nu

Nu

Nu

*

*

R1 R2

Nu*

R1 R2

Nu*

or

or

The Tsuji-Trost Reaction: Strychnine

a) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293 – 9294

b) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1995, 117, 5776 – 5788.

PdLnOAcO OMe

O

OtBuO CO2Et

[Pd2(dba)3] (1 mol%)PPh3 (15 mol%)NaH, THF, 23 °C

[-CO2, -MeO ]

Tsuji-TrostReaction

AcO

OtBuO CO2Et

AcOOtBu

O

CO2Et

H91%

Me3Sn

TIPSO

OtBu

[Pd2(dba)3] (3 mol%)AsPh3 (22 mol%), CO (50 psi)

LiCl, NMP, 70 °C

80%

CarbonylativeStille Coupling

TIPSO

OtBu

O

N

MeN

MeN

O

N

OO

H

H

H

H

strychnine

250

251252

253

MeN

N

NMe

O

I

254256: Strychnine 255

OTBS

MeO2C

PhO2S

O[Pd2(dba)3] (1 mol%)

PPh3 (15 mol%)NaH, THF, 23 °C

Tsuji-TrostMacrocyclisation

TBSO

MeO2C

PhO2S

OLnPd

TBSO

MeO2C

PhO2S

OHLnPd

O OO

PhO2S PhO2SHOMeO2C

OTBS

-[Pd0Ln]85%

BnNH2[Pd(PPh3)4] (15 %)THF, 35 °C, 70%

Tsuji-TrostReactionO

PhO2SNBn

HO

N

O

NHCl

MeO

MeMe

Roseophilin

263 264 265

266267268

269: Roseophilin

The Tsuji-Trost Reaction: Roseophilin

a) A. Fürstner, H. Weintritt, J. Am. Chem. Soc. 1998, 120, 2817 – 2825;

b) A. Fürstner, T. Gastner, H. Weintritt, J. Org. Chem. 1999, 64, 2361 – 2366.

The Tsuji-Trost Reaction: Hamigeran B

B. M. Trost, C. Pissot-Soldermann, I. Chen, G.M. Schroeder, J. Am. Chem. Soc. 2004, 126, 4480 – 4481.

Pd

Me

O

OtBu

OAc

[{3-C3H5PdCl}2] (1 mol%)ligand 285 (2 mol%)LDA, tBuOH, Me3SnCl

DME, 25 °C

AsymmetricAllylic Alkylation

Me

O

tBuO

P P

Pd

PP

a

b

*

*

O

OtBu

Me

77%, 93% ee

OOMe

Me OTf

MeMe

Me

Pd(OAc) (10 mol%)dppb (20 mol%)

K2CO3toluene, 110 °C, 58%

IntramolecularHeck Reaction

OOMe

MeH

Me

Me

Me

OOMe

MeH

Me

Me

Me

NHO

PPh

Ph

HNO

PPh

Ph

hamigeran B

285

284

286

287288

289290: hamigeran

The Tsuji-Trost Reaction: (+)--lycorane

H. Yoshizaki, H. Satoh, Y. Sato, S. Nukui, M. Shibasaki, M. Mori, J. Org. Chem. 1995, 60, 2016 – 2021.

OBz

OBzBzO

O

O Br

NHMeO2C

O

[Pd2(OAc)3] (5 mol%)293 (10 mol%)

LDA THF/MeCN, 0 °C

AsymmetricAllylic Alkylation

O

O

Br

NH

MeO2C

OPd

PP* 66%, 54% ee

O

O

Br

NH

MeO2C

OOBz

Pd(OAc) (5 mol%)dppb (20 mol%)

NaHDMF, 50 °C

IntramolecularAllylic Alkylation/

Heck ReactionCascade

O

O

Br

N

MeO2C

O PdLn

O O

BrN

MeO2C

O

H

H

iPr2NEt, 100 °C

O O

N

CO2Me

O H

HH

O

O

N

H HH

lycorane

299: (+)--lycorane

298

297 296

295294292

291

O

O

PPh2

PPh2

293

The Negishi Coupling

25. a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821 – 1823; for a discussion, see: b) E. Negishi, Acc. Chem. Res. 1982, 15, 340 – 348.

26. a) E. Erdik, Tetrahedron 1992, 48, 9577 – 9648; b) E. Negishi, T. Takahashi, S. Babu,D. E. Van Horn, N. Okukado, J. Am. Chem. Soc. 1987, 109, 2393 – 2401.

• The use of organozinc reagents as the nucleophilic component in palladium-catalyzed cross-coupling reactions, known as the Negishi coupling, actually predates both the Stille and Suzuki processes, with the first examples published in the 1970s.[25]

• However, the stunning progress in the latter procedures left the Negishi process behind, underappreciated and underutilised.

• Organozinc reagents exhibit a very high intrinsic reactivity in palladium-catalyzed cross-coupling reactions, which combined with the availability of a number of procedures for their preparation and their relatively low toxicity, makes the Negishi coupling an exceedingly useful alternative to other cross-coupling procedures, as well as constituting an important method for carbon–carbon bond formation in its own right.[26]

R1 R3 Xcat. [Pd0Ln]

R1 = alkyl, alkynyl, aryl, vinylR3 = acyl, aryl, benzyl, vinylX = Br, I, OTf, OTs

ZnR2 R1 R3

Mechanism of the Negishi Coupling

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

PPh3

- PPh3

- PPh3

Pd0

Pd0

Pd0

IPd

Ph3P

PPh3I

PdI I

PdPh3P PPh3

PdI I -Complex

R1

R2

ZnBr

R3

PdPh3P

Ph3P

PdI I

R3 R2

R1

R3

R2 R1

R3

R2

R1

Zn (dust) 1.5 eqI2 (5 mol %)DMA, 80 °C

ZnBrI

R1

R2

Br

R3

PdPh3P

PPh3

R3R2

R1

PdI I

The Negishi Coupling: Discodermolide

a) A. B. Smith III, T. J. Beauchamp, M. J. LaMarche, M. D. Kaufman, Y. Qiu, H. Arimoto, D. R. Jones, K. Kobayashi, J. Am. Chem. Soc. 2000, 122, 8654 – 8664;

b) A. B. Smith III, M. D. Kaufman, T. J. Beauchamp,M. J. LaMarche, H. Arimoto, Org. Lett. 1999, 1, 1823 – 1826.

c) For a review of the chemistry and biology of discodermolide, see: M. Kalesse, ChemBioChem 2000, 1, 171 – 175

d) For examples of other approaches to discodermolide, see: I. Paterson, G. J. Florence, Eur. J. Org. Chem. 2003, 2193 – 2208.

e) In the synthesis of discodermolide by the Marshall group, a B-alkyl Suzuki–Miyarua fragment-coupling strategy was employed to form the C14C15 bond, in which 2.2 equivalents of an alkyl iodide structurally related to 309 was required: J. A. Marshall, B. A. Johns, J. Org. Chem. 1998, 63, 7885 – 7892.

I

Me Me

TBSO O O

PMP

Me

tBuLi, ZnCl2Et2O

-78 °C Zn

Me Me

TBSO O O

PMP

Me[Pd(PPh3)4] (5 mol%)

311Et2O, 25 °C, 66%

Negishi Coupling

Me Me

OTBS O O

PMP

Me

Me

PMBO

Me

OTBS

Me

IPMBO

Me

OTBS

Me

Me= 311

Me Me

OH O

Me

MeMeOH

Me

NH2

OO

O

HO

HO

Me

HO

discodermolide

313: discodermolide

312310309

151515

14

14

15

14

The Negishi Coupling: Amphidinolide T1

a) C. Aïssa, R. Riveiros, J. Ragot, A. Fürstner, J. Am. Chem. Soc. 2003, 125, 15 512 – 15520.

OMe

R

OMOM

TBDPSO Me

314: R = ZnI(315: R = I)(316: R = H)

[Pd2(dba)3] (3 mol%)285

P(2-furyl)3 (6 mol %)toluene/DMA, 25 °C, 50%

Negishi Coupling

O

O

MeMe

Cl O

OMe

OMOM

TBDPSO Me

O

O

MeMe

O

OMe

OMOM

TBDPSO Me

O

O

MeMe

O

317

318

319: Amphidinolide T1

amphidinolide

The Fukuyama Coupling

27) H. Tokuyama, S. Yokoshima, T. Yamashita, S.-C. Lin, L. Li, T. Fukuyama, J. Braz. Chem. Soc., 1998, 9, 381-387.

• The Fukuyama Coupling is a modification of the Negishi Coupling, in which the electrophilic component is a thioester.

• The product of the coupling with a Negishi-type organozinc reagent is carbonyl compound, thus negating the need for a carbon monoxide atmosphere.

R1 R3 cat. [Pd0Ln]

R1 = alkyl, alkynyl, aryl, vinylR3 = acyl, aryl, benzyl, vinylR4 = Me, Et, et c.

ZnR2 R1 R3

O

SR4

O

MeO

SEt

O ZnI [PdCl2(PPh3)2] (10 mol%)toluene, 25 °C, 5 min, 87%

Fukuyama Coupling MeO

O

Palladium Catalysis: Outlook And Summary

28) For an example of palladium-mimicking rhodium catalysis, see: M. Lautens and J. Mancuso, Org. Lett. 2002, 4, 2105

29) For a recent review of "atom ecconomic" ruthenium catalysis, see: B. M. Trost, M. U. Frederiksen, M. T. Rudd, Angew. Chem. Int. Ed., 2005, 41, 6630 – 6666.

30) For the complementary review on Metathesis Reactions in Total Synthesis, see: K. C. Nicolaou, P. G. Bulger, D. Sarlah , Angew. Chem. Int. Ed., 2005, 41, 4490-4527.

31) A. Fürstner, R. Martin, Chem. Lett. 2005, 34, 624-629.

• This review has highlighted only a small number of applications of palladium catalysis in organic synthesis, but new examples are published every month.

• Each example pushes the field forwards, towards universal conditions, where application of them results in a useful yield without prior optimisation.

• However, palladium is only one metal; the breadth of catalysis available from rhodium,[28] ruthenium[29] and platinum based systems extend far further, and into the realms of metathesis.[30] Fürstner has shown analogous procedures using Iron catalysts,[31] with obvious economic and toxicity benefits.