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.
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