Transcript Synthesis of Enantiopure Allenes from Activated Cyclopropanes

C-sp3 Coupling Using Alkyl
Halides as Electrophiles:
Work by Gregory Fu
Presented by Pascal Cérat
Litterature meeting
March 31th 2009
1
Cross-Coupling in Chemistry
Cross-coupling offers a direct and easy way for the creation of a C-C bounds from an electrophile (C-X)
with an organometallic nucleophile (C-M).
Metals use to catalyze these reactions: Pd, Ni, Cu, Fe, Co and Mn.
Also, a lot of different organometallic compounds can be used as nucleophiles such as grignard
reagents, organozinc, tin, boron, and even silicon derivatives.
Cross-coupling reactions allow the presence of functional groups as the reaction is particularly selective.
There are a lot of examples of cross-coupling in synthesis of natural compounds and pharmaceutical
chemistry:
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374. Masse, J.P.; Corriu, J.P. J. Chem. Soc., Chem. Comm. 1972, 144.
Milstein, D.; Stille, J.K. J. Am. Chem. Soc. 1979, 101, 4992.
Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340.
Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
Lin, S.; Danishefsky, S.J. Angew. Chem. Int. Ed. Engl. 2002, 41, 512
2
Outlines
1)
Introduction on cross-coupling methodologies
a) Kumada-Corriu
b) Negishi
c) Stille
d) Hiyama
e) Suzuki
2) Difficulties with sp3-alkyl halides possessing b-H
3) First advancements on sp2-sp3 and sp3-sp3 cross-coupling
- Corey first sp3-sp3 example
- Caslte and Widdowson controversy
- Suzuki’s work
- Knochel’s development with a cocatalyst
- Kambe’s work using 1,3-butadienes
4) Gregory Fu’s cross-coupling methodologies
- Unactivated aryl chloride system
- Primary alkyl halides (Cl, Br, I and OTs)
- Secondary alkyl halides (Br, I)
- Assymetric cross-coupling with Ni-complex
- Mechanistic studies
3
Kumada-Corriu Discovery of Coupling with Grignards
In 1972, Kumada and Corriu reported a cross-coupling reaction with grignard reagents using a nickel
complex as the catalyst.
Proposed catalytic cycle:
Disadvantage: Grignards are not compatible with a lot of functional groups
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374.
Masse, J.P.; Corriu, J.P. J. Chem. Soc., Chem. Comm. 1972, 144.
Kumada, M. Pure Appl. Chem. 1980, 52, 669.
4
Negishi Coupling Reaction with Organozinc Reagents
Negishi reported in 1976 the cross-coupling with Ni- and Pd-complex using organoaluminums.
Between 1976 to 1978, his group explored different aspects of the reaction such as:
- Using different organometals containing Al, B, Zn and Zr.
- Demonstration of Pd- or Ni-catalysed hydrometallation-cross-coupling and carbometallation in a domino
process.
- Demonstration of double metal catalysis by the addition of ZnX2 along with the usual Pd or Ni catalyst.
Simplified catalytic cycle:
Advantage : RZnCl are more easily fonctionnalized
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Negishi, E.-I.; King, A.O.; Okukado, N. J. Org. Chem. 1977, 42, 1921.
Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340.
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Stille Coupling Reaction with Tetraorganotin Reagents
In 1979, Stille then developed a new cross-coupling reaction with Pd as the catalyst where the
nucleophile can be more functionalized than Grignard.
Proposed mechanism for Palladium cycle:
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Milstein, D.; Stille, J.K. J. Am. Chem. Soc. 1979, 101, 4992.
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Stille Coupling Reaction with Tetraorganotin Reagents
Transmetallation process
SE2(cyclic): Case of an cyclic associative
transmetallation
SE2(open): Case of an open associative
transmetallation
- Non-coordinating solvents
- Use of polar and coordinating solvents
- The presence of a bridging ligand.
- Absence of bridging abitlity in the complex.
Retention of configuration
Inversion of configuration
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Stille, J.K.; Lau, K.S.Y. Acc. Chem. Res. 1977, 10, 434.
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Hiyama Coupling Reaction with Organosilicon Compounds
Proposed mechanism of palladium-catalyzed fluorosilane cross-coupling:
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918.
Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
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Miyaura-Suzuki Coupling Reaction with Organoboron Reagents
Organoboron has a lot of advantages as they are generally thermally stable and are inert to water and
oxygen which make them a great choice as reagent for coupling process.
Catalytic cycles for trialkylboranes derivatives by Soderquist:
All the cross-coupling reactions been shown so far are involving the creation of an sp2-sp2 bound!
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866.
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
Matos, K.; Soderquist, J.A. J. Org. Chem. 1998, 63, 461.
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Problematic of Alkyl Halides as Electrophiles
Oxidative addition
Usual cis-complexes are obtained during the oxidative addition with C(sp2)-X electrophiles:
Alkyl halides are said to react slowly with Pd0 and Ni0 in the oxidative addition step, because of
the more electron-rich C(sp3)-X bond compare to an C(sp2)-X
Two main possibilities are found for the oxidative addition of alkyl halide to a metal:
- By an associative bimolecular SN2 pattern (mainly for low valent metals)
- By a free radical pathway
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Stille, J.K.; Lau, K.S.Y. Acc. Chem. Res. 1977, 10, 434.
Cárdenas, D.J. Angew. Chem. Int. Ed. 1999, 38, 3018.
Luh, T.-Y.; Leung, M.; Wong, K.T. 2000, 100, 3187.
Rudolph, A.; Lautens, M.; Angew. Chem. Int. 2009, 48, 2.
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Problematic of Alkyl Halides as Electrophiles
b-Elimination
In the case of alkyl metal species the lack of p electrons available to interact with the empty d-orbitals of
the metal center are less stable than an aryl or alkenyl species.
The presence of b-hydrogen make possible a decomposition of the alkyl-Pd(II) complex by a fast
elimination of the hydrogen.
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Cárdenas, D.J. Angew. Chem. Int. Ed. 1999, 38, 3018.
Luh, T.-Y.; Leung, M.; Wong, K.T. 2000, 100, 3187.
Rudolph, A.; Lautens, M.; Angew. Chem. Int. 2009, 48, 2.
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Problematic of Alkyl Halides as Electrophiles
b-Elimination
b-elimination requires several conditions such as the existence of a vacant coordination site and the
possibility to arrange the M-C-C-H atoms in the same plane.
Large bulky and electron rich ligands (like: Pd(PPh3)4 and PdCl2(dppf)2) can favor reductive elimination
over b-hydride elimination.
- Phosphines with small bite angle:
- Larger bite angle:
Also, the use of coordinating cocatalyst may prevent the formation of vacant coordination sites or simply
accelerate the reductive elimination step.
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Cárdenas, D.J. Angew. Chem. Int. Ed. 1999, 38, 3018.
Luh, T.-Y.; Leung, M.; Wong, K.T. 2000, 100, 3187.
Rudolph, A.; Lautens, M.; Angew. Chem. Int. 2009, 48, 2.
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First Examples of Alkyl Halides Coupling
The first example reported of the use of an alkyl halide during a cross-coupling procedure was done by
E.J. Corey using the complex of metallylnickel(I) bromide.
This methodology was then used for the synthesis of a- and epi-b-santalene:
Corey, E.J.; Semmelhack, M.F. J. Am. Chem. Soc. 1967, 89, 2755.
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Controversy with Castle and Widdowson Methodology
In 1986 a methodology using a palladium complex, done by Castle and Widdowson, could catalyzed a
Kumada-Corriu reaction with alkyl halides.
The group of Widdowson claimed that using dppf ligand suppresses b-elimination in the final intermediate
and that this reaction could lead to sp3-sp3 coupling reaction.
In 1989, Yuan and Scott failed to reproduced the work of Castle and Widdowson. Only the corresponding
alkanes from the reduction of the alkyl halides could be isolated using (dppf)Pd(0) or (dppf)PdCl2.
Castle, P.L.; Widdowson, D.A. Tet. Lett. 1986, 27, 6013.
Yuan, K.; Scott, W.J. Tet. Lett. 1989, 30, 4779.
Yuan, K.; Scott, W.J. J. Org. Chem. 1990, 55, 6188.
Yuan, K.; Scott, W.J. Tet. Lett. 1991, 32, 189.
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Controversy with Castle and Widdowson Methodology
Reduction of alkyl halides with (dppf)PdCl2:
Later, in 1991, Yuan and Scott reported a system using Ni(dppf)Cl2 as the catalyst for a Kumada-Corriu
coupling unactivated neopentyl idodes with grignard reagents.
Yuan, K.; Scott, W.J. Tet. Lett. 1989, 30, 4779.
Yuan, K.; Scott, W.J. J. Org. Chem. 1990, 55, 6188.
Yuan, K.; Scott, W.J. Tet. Lett. 1991, 32, 189.
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Boro-Alkyl Suzuki-Miyaura Cross Coupling Reaction
In 1992, Suzuki and Miyaura developed a coupling reaction between a boronate (9-BBN) group and an
alkyl halide.
No bromide or
chloride were used
Restricted scope to mainly long alkyl chains without FG, except: ester, cyano, alkene and ether groups
Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691.
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Cross-Coupling of Iodocyclopropanes
Cyclopropyl halides are interesting electrophiles for cross-coupling as the b-hydride elimination is not
favoured because of the strain that is generated in the cyclopropene.
Charette, A.B.; Giroux, A. J. Org. Chem. 1996, 61, 8718.
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Cross-Coupling of Iodocyclopropanes
Synthesis of polycyclopropanes by Suzuki-type cross-coupling:
Tri-substituted cyclopropanes by Martin:
Charette, A.B.; Freitas-Gil, R.P. Tet. Lett. 1997, 38, 2809.
Martin, S.F.; Dwyer, M.P. Tet. Lett. 1998, 39, 1521.
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Knochel’s Work on Nickel-Catalysed Cross-Coupling
Preliminary work with organozincs:
The need of the double bond restraint the scope of the reaction.
Devasagayaraj, A.; Stüdemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1995, 34, 2723.
Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am. Chem. Soc. 1971, 93, 3350.
Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
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Knochel’s Work on Nickel-Catalysed Cross-Coupling
The coordination of the Nickel to the double bond has been found to remove electron density from the
metal and favors the reductive elimination to obtain the desired cross-coupling product.
Proposed mechanism:
High temperature promotes the dissociation of the alkene to the complex which then undergo
transmetallation followed by an halogen-zinc exchange.
Replacement of the [Ni(acac)2] by [PdCl2(CH3CN)2] leads only to the bromine-zinc exchange product.
Devasagayaraj, A.; Stüdemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1995, 34, 2723.
Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am. Chem. Soc. 1971, 93, 3350.
Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
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Knochel’s Work on Nickel-Catalysed Cross-Coupling
In 1998 to 1999, Knochel reported the used of a promotor (co-catalyst) with the nickel complex:
Diorganozinc reagent can also be coupled:
Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186.
Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 2387.
Piber, M.; Jensen, A.E.; Rottländer, M.; Knochel, P. Org. Lett. 1999, 1, 1323.
Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
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Knochel’s Work on Nickel-Catalysed Cross-Coupling
Some primary alkyl bromides were also used using the same system.
Other cocatalysts tried during these studies:
Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186.
Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 2387.
Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
Jensen, A.E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
22
Kambe’s Following on the Use of Co-catalyst
In 2002, Kambe introduced his work on the cross-coupling reactions of grignard reagents on alkyl halides
and tosylates with 1,3-butadienes as co-catalyst.
Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222.
Terao, J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Lett. 2003, 32, 890.
Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646.
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Kambe’s Following on the Use of Co-catalyst
Kambe then proposed a mechanism in which the nickel-complex is stabilized by the donation of
electronic density from allyl species.
These kind of complexes seem possible witch nickel, but for palladium to pass through a Pd(IV) complex
is less possible.
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.
Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222.
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Gregory C. Fu
The man behind the study
Gregory C. Fu received a degree from MIT in 1985, where he worked in the
laboratory of Prof. Barry Sharpless. After earning a Ph. D. from Havard
under the guidance of Prof. David Evans, he spent 2 years as a postdoctoral fellow with Prof. Robert Grubbs at Caltech.
In 1993, he returned to MIT where he is currently working as the Firmenich
Professor of Chemistry. During all his years of research, Prof. Fu gained
multiple awards. The most recent one is the Catalysis Science Award
obtained in 2007.
His research
Professor’s Fu research first started on the development of a planar-chiral heterocycles for
enantioselective nucleophilic catalysts. He has been able to created chiral derivatives of the well known
DMAP for catalysis in nucleophilic reactions.
More recently, he has also focused his work on the chemistry of boron heterocycles, palladium and
nickel- catalyzed coupling processes. Improvement have been seen for the coupling of chloro-aryl
compounds as well as primary and secondary alkyl halides.
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P(t-Bu)3 and PCy3 as Ligands in Coupling Reactions with Aryl Electrophiles
Suzuki reactions:
For aryl triflates, no reaction is obtained with P(t-Bu)3 and PCy3 must be used:
Littke, A.F.; Fu, G.C. Angew. Chem. Int. Ed. 1998, 37, 3387.
Littke, A.F.; Dai, C.; Fu, G.C. J. Am. Chem. Soc. 2000, 122, 4020.
Fu, G.C. Acc. Chem. Res. 2008, 41, 1555.
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P(t-Bu)3 and PCy3 as Ligands in Coupling Reactions with Aryl Electrophiles
Stille reactions:
Negishi reactions:
Littke, A.F.; Fu, G.C. Angew. Chem. Int. Ed. 1999, 38, 2411.
Littke, A.F.; Dai, C.; Fu, G.C. J. Am. Chem. Soc. 2000, 122, 4020.
Littke, A.F.; Schwarz, L.; Fu, G.C. J. Am. Chem. Soc. 2002, 124, 6343.
Fu, G.C. Acc. Chem. Res. 2008, 41, 1555.
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What’s the Difference Between PCy3 and P(t-Bu)3?
In the course of their study on the Heck acylation, Prof. Gregory Fu has found that PCy3 couldn’t react
where P(t-Bu)3 could. This observation allowed them to explore the chemistry of palladium hydrides.
During the process, they found some important information on the structure of such palladium complexes.
The steric effect that is brought in the case of the
P(t-Bu)3 ligand seem to favorise the reductive
elimination.
angle P-Pd-P : 180o
Hills, I.D.; Fu, G.C. J. Am. Chem. Soc. 2004, 126, 13178.
angle P-Pd-P : 161o
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Introduction of the Ligand P(t-Bu)2Me
Early methodology for Suzuki reactions on primary alkyl halides:
In 2002, Prof. Fu tried to expand the reaction to OTs, but the used of PCy3 and P(t-Bu)3 as the ligand
seemed too sterically demanding. A less bulky ligand P(t-Bu)2Me was then used with success.
Netherton, M.R.; Dai, C.; Neuschütz, K.; Fu, G.C. J. Am. Chem. Soc. 2001, 123, 10099.
Kirchhoff, J.H.; Dai, C.; Fu, G.C. Angew. Chem Int. Ed. 2002, 41, 1945.
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Introduction of the Ligand P(t-Bu)2Me
Investigations on the stereochemistry of the oxidative addition of an alkyl tosylate to Pd/P(t-Bu)2Me:
Oxidative addition: inversion of configuration
Reductive elimination: retention of configuration
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Netherton, M.R.; Fu, G.C. Angew. Chem. Int. Ed. 2002, 41, 3910.
Utility of P(t-Bu)2Me for Primary Alkyl Halides
Suzuki cross-coupling:
The corresponding phosphonium salt of the ligand which is air- and moisture stable can also be used.
Kirchhoff, J.H.; Netherton, M.R.; Hills, I.D.; Fu, G.C. J. Am. Chem. Soc. 2002, 124, 13662.
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Utility of P(t-Bu)2Me for Primary Alkyl Halides
Stille cross-coupling:
Hiyama cross-coupling:
Menzel, K.; Fu, G.C. J. Am. Chem. Soc. 2003, 125, 3718.
Lee, J.-Y.; Fu, G.C. J. Am. Chem. Soc. 2003, 125, 5616.
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Nickel in Cross-Couplings for Secondary Alkyl Halides
The attractiveness of all these coupling process stay in the achievement of coupling more hindered
electrophiles as reaction partners, like secondary halides.
Secondary alkyls are more interesting than primary species as they allow the reaction to create a new
chiral center.
Negishi cross-coupling:
Zhou, J.; Fu, G.C. J. Am. Chem. Soc. 2003, 125, 14726.
Netherton, M.R.; Fu, G.C. Adv. Synth. Catal. 2004, 346, 1525.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Nickel in Cross-Couplings for Secondary Alkyl Halides
Suzuki cross-coupling sp2-sp3:
Zhou, J.; Fu, G.C. J. Am. Chem. Soc. 2003, 126, 1340.
Gonzáles-Bobes, F.; Fu, G.C. J. Am. Chem. Soc. 2006, 128, 5360.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Nickel in Cross-Couplings for Secondary Alkyl Halides
Hiyama cross-coupling sp2-sp3:
Powell, D.A.; Fu, G.C. J. Am. Chem. Soc. 2004, 126, 7788.
Strotman, N.A.; Sommer, S.; Fu, G.C. Angew. Chem. Int. Ed. 2007, 46, 3556.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Nickel in Cross-Couplings for Secondary Alkyl Halides
Stille cross-coupling sp2-sp3 with trichlorostannates (less toxic and easier for purification):
Powell, D.A.; Maki, T.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 510.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Negishi coupling of secondary a-bromo amides:
Fischer, C.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 4594.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Negishi coupling of secondary benzylic bromides:
Arp, F.O.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 10482.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Negishi coupling of secondary allylic chlorides:
Son, S.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 2756.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Hiyama coupling of secondary a-bromo esters:
Dai, X.; Strotman, N.A.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 3302.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Enantioselective alkyl-alkyl Suzuki cross-coupling of secondary homobenzylic bromides:
Saito, B.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 6694.
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
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Mechanistic Studies of Nickel Cross-Coupling
Postulated reaction mechanisms for alkyl-alkyl cross-coupling:
Calculations where done to etablish if such process is possible with the use of a methylterpyridyl-Ni(I)
catalyzing a Negishi reaction.
In this case, the oxidative product of Ni(II) reacting with the
transmetalating reagent (CH3ZnI) followed by the reductive
elimination shown above is greatly disfavored.
DG = 21.1 kcal/mol
Lin, X.; Phillips, D.L. J. Org. Chem. 2008, 73, 3680.
Jones, G.D.; Martin, J.L.; McFarland, C.; Allen, O.R.; Hall, R.E.; Haley, A.D.; Brandon, R.J.; Konovalova, T.; Desrochers, P.J.; Pulay, P.; Vivic, D.A. J.
Am. Chem. Soc. 2006, 128, 13175.
42
Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Mechanistic Studies of Nickel Cross-Coupling
The Ni(I)-methyl complex seem to undergo a charge-transfert state in which we then obtained a Ni(II)alkyl cation by contribution of the metal d-orbital in the SOMO of the ligands (by DFT calculation).
Updated possible mechanism for the nick-catalyzed alkyl-alkyl Negishi using a radical process Ni(I)Ni(III):
Overall DG = -27.8 kcal/mol
Alkyl radical is postulated to stay in close proximity of the metal center. At this point, if the ligand is chiral,
enantioselective addition of the radical may take places like in Fu’s case.
Lin, X.; Phillips, D.L. J. Org. Chem. 2008, 73, 3680.
Jones, G.D.; Martin, J.L.; McFarland, C.; Allen, O.R.; Hall, R.E.; Haley, A.D.; Brandon, R.J.; Konovalova, T.; Desrochers, P.J.; Pulay, P.; Vivic, D.A. J.
Am. Chem. Soc. 2006, 128, 13175.
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Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Mechanistic Studies of Nickel Cross-Coupling
By calculation, the catalytic process can be summarized on the energetic matter by:
-The oxidative addition is slightly endothermic
-The reduction elimination is largely exothermic
-The transmetallation is mildly endothermic
The limiting step in this process is the halogen atom transfert step and the solvation effect increases the
rate of this step.
Also, the rate of Ni(III) species decomposition is larger than that of its reductive elimination and this may
lead to lower uield of the cross-coupled product in some cases.
Lin, X.; Phillips, D.L. J. Org. Chem. 2008, 73, 3680.
Jones, G.D.; Martin, J.L.; McFarland, C.; Allen, O.R.; Hall, R.E.; Haley, A.D.; Brandon, R.J.; Konovalova, T.; Desrochers, P.J.; Pulay, P.; Vivic, D.A. J.
Am. Chem. Soc. 2006, 128, 13175.
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Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Conclusion
In conclusion, we have seen different methodologies to do cross-coupling for unactived alkyl chlorides
using P(t-Bu)3 and PCy3.
Gregory Fu has been able to successfully coupled primary alkyl halides using Suzuki, Negishi and Stille
reactions with the Pd/P(t-Bu)2Me catalyst system.
Secondary alkyl halides which are more hindered and so more difficult to cross-coupling (slow oxidative
addition) can be readily coupled with organozinc, organotin and organoboron reagents by different nickel
complex.
The development of assymetric cross-coupling of secondary alkyl halides is of an important impact as it
can be readily use for the synthesis of natural products.
fluvirucinine A
There is still work to be done to expand the scope of functionality that can be tolerated.
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