Nickel-Catalyzed Reactions - Master Chimie

Rhodium-Catalyzed Carbon-Carbon
Bond Forming Reactions of
Organometallic Compounds
University of Marseille
November 2008
Mark Lautens
Mark Scott, Nai-Wen Tseng

Outline
• General introduction into transition-metal processes
• Stoichiometric reactions with Rh
� Organometallic reactions with Rh
� Structural properties of Rh complexes
� Other reactions with Rh(I) complexes
• Catalytic reactions with Rh
� 1,4-addition processes
� 1,2-addition processes
� Addition to unactivated alkenes and alkynes
2

Typical Transition
Metal-Mediated Processes
While Ni, Pd, Pt under transmetallation at one point in a catalytic cycle,
Rh(I) allows for two possible points of transmetallation in the cycle.
3

Stoichiometric Reactions with Rhodium:
Reaction with Organometallics
Similar transmetallation reactions are
possible for Rh(II) and Rh(III) species
Solvent used is important as well. Price found that competing transmetallation to solvent
can occur – likely via a C-H activation process:
Keim, W. J. Organomet. Chem. 1967, 8, P25. Darensbourg, D. J.; Grötsch, G.; Wiergreffe, P.; Rheingold, A. L. Inorg. Chem.
1987, 26, 3827. Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1674.
Price, R. T.; Andersen, R. A.; Muetterties, E. L. J. Organomet. Chem. 1989, 376, 407.
4

Structural Properties of
Aryl-Rhodium Complexes
Ortho substituents bearing lone pairs can
chelate to Rh, stabilizing the complex (X-ray proof):
Phenyl group exists orthogonal to the square plane to
minimize steric interactions. Ortho substituents
prevent coordination of vacant sites
→ can impact reaction progress
Dahlenburg, L.; Yardimciolu, A.; Hock, N. Inorg. Chim. Acta. 1984, 89, 213. Hay-Motherwell, R. S.; Koschmieder, S. U.;
Wilkinson, G.; Hussain-Bates, B.; Hursthouse, M. B. J. Chem. Soc., Dalton Trans. 1991, 2821. Boyd, S. E.; Field, L. D.;
Hambley, T. W.; Partidge, M. G. Organometallics 1993, 12, 1720. Yamamoto, M.; Onitsuka, K.; Takahashi, S.
Organometallics 2000, 19, 4669. Jones, R. A.; Wilkinson, G. J. Chem. Soc., Dalton Trans. 1979, 472.
5

Reactions of Rhodium-Aryl Complexes:
Protolytic Cleavage
In particular, aryl-Rh (and Ir) bonds are succeptable to protolytic cleavage.
Occurs via OA/RE sequence:
Observed spectroscopically!!
Protodemetallation can also occur via a similar pathway using H 2
Boyd, S. E.; Field, L. D.; Hambley, T. W.; Partidge, M. G. Organometallics 1993, 12, 1720.
Arpac, E.; Mirzael, F.; Yardimcioglu, A.; Dahlenburg, L. Z. Anorg. Allg. Chem. 1984, 519, 148.
Keim, W. J. Organomet. Chem. 1968, 14, 179.
6

Reactions of Rhodium-Aryl Complexes:
Migratory Insertion Reactions (1)
Keim reported the migratory insertion of CO:
CO 2 has also been used:
Keim, W. J. Organomet. Chem. 1969, 19, 161. Darensbourg, D. J.; Grötsch, G.; Wiergreffe, P.; Rheingold, A. L. Inorg. Chem. 1987, 26,
3827.
Kolomnikov, L. S.; Gusev, A. O.; Belopotapova, T. S.; Grigoryam, M. Kh.; Lysyak, T. V.; Struchkov, Yu. T.; Vol’pin, M. E. J. Organomet.
Chem. 1974, 69, C10.
7

Reactions of Rhodium-Aryl Complexes:
Migratory Insertion Reactions (2)
Insertion into other carbonyl containing compounds have been reported:
Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1674.
8

Reactions of Rhodium-Aryl Complexes:
C-C Formation via a Change in Oxidation State
Hegedus, L. S.; Lo, S. M.; Bloss, D. E. J. Am. Chem. Soc. 1973, 95, 3040.
Hegedus, L. S.; Kendall, P. M.; Lo, S. M.; Sheats, J. R. J. Am. Chem. Soc. 1975, 97, 5448.
Schwartz, J.; Hart, D. W.; Holden, J. L. J. Am. Chem. Soc. 1972, 94, 9269.
9

Catalytic 1,4-Addition to Activated Alkenes with
Organoboron Nucleophiles
Miyaura first reported:
Later, an asymmetric variant was disclosed by Hayashi:
Acrylates, α,β-unsaturated amides, alkenylphosphonates and nitroalkene
acceptors can also be used.
Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229. Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M. J. Am. Chem. Soc. 1998, 120,
5579. Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852. Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc.,
1999, 121, 11591. Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716.
10

Catalytic Cycle for Rhodium-Catalyzed
1,4-Addition
Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.
11

Rhodium-catalyzed 1,4-Addition:
Reaction to Heteroaromatic Alkenes
Role of ortho nitrogen atom:
Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358.
12

Rhodium-Catalyzed 1,4-Addition with
Organostannane and Organosilane Nucleophiles
Oi reported the use of organostannanes:
Mori reported the use of organosilanes:
Heck products could be obtained by tuning the reaction conditions.
Oi, S.; Moro, M.; Ono, S.; Inoue, Y. Chem. Lett 1998, 83. Oi, S.; Moro, M.; Ito, H.; Honma, Y.; Miyano, S.; Inoue, Y.
Tetrahedron 2002, 58, 91. Mori, A.; Danda, Y.; Fujii, T.; Hirabayashi, K.; Osakada, K. J. Am. Chem. Soc. 2001, 123, 10774.
Huang, T.-S.; Li, C.-J. Chem. Commun. 2001, 2348.
13

Rhodium-Catalyzed 1,4-Addition with
Organostannane and Organosilane Nucleophiles
Mori, A.; Danda, Y.; Fujii, T.; Hirabayashi, K.; Osakada, K. J. Am. Chem. Soc. 2001, 123, 10774.
Huang, T.-S.; Li, C.-J. Chem. Commun. 2001, 2348.
14

Rhodium-catalyzed 1,2-Addition
Reaction with Organoboron Nucleophiles
First report by Miyaura:
Recently, asymmetric variant by Feringa:
Reaction with imine substrate:
Sasai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 3279. Ueda, M.; Miyaura, N. J. Org. Chem. 2000,
65, 4450. Jagt, R. B. C.; Toullec, P. Y.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Org. Biomol. Chem. 2006, 4, 773. Ueda,
M.; Miyaura, N. J. Organomet. Chem. 2000, 595, 31. Ueda, M.; Miyaura, N. Synlett 2000, 1637.
15

Rhodium-Catalyzed 1,2-Addition:
Catalytic Cycle
Sasai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 3279. Ueda, M.; Miyaura, N. J. Org. Chem. 2000,
65, 4450. Jagt, R. B. C.; Toullec, P. Y.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Org. Biomol. Chem. 2006, 4, 773. Ueda,
M.; Miyaura, N. J. Organomet. Chem. 2000, 595, 31. Ueda, M.; Miyaura, N. Synlett 2000, 1637.
16

Rhodium-Catalyzed 1,2-Addition with
Organostannane nucleophiles
Asymmetric variant by Hayashi:
Oi, S.; Moro, A.; Inoue, Y. Chem. Commun. 1997, 1621. Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122, 976.
Hayashi, T.; Ishigedani, M. Tetrahedron 2001, 57, 2589.
17

Rhodium-catalyzed 1,2-Addition
with Organoboron Nucleophiles
How Rh-H re-enters the catalytic cycle remains unknown.
Oi, S.; Moro, A.; Inoue, Y. Chem. Commun. 1997, 1621. Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122, 976.
Hayashi, T.; Ishigedani, M. Tetrahedron 2001, 57, 2589.
18

Rhodium-Catalyzed 1,2-Addition
with Organosilane Nucleophiles
Role of added fluoride in the catalytic cycle:
Oi, S.; Moro, A.; Inoue, Y. Organometallics 2001, 20, 1036.
19

Reactions with Unactivated Alkenes
Non-styrenic alkenes were low yielding
due to competing olefin isomerization
Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358.
20

Reactions with Unactivated Alkenes:
Mechanism
Reaction is believed to occur via a Heck-type process:
Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358.
21

Reactions with Unactivated Alkenes (2)
Rh can also be used to add boronic acids to unactivated oxabicycles.
Murakami first reported:
Simultaneously, an asymmetric variant was disclosed:
Murakami, M.; Igawa, H. Chem. Commun. 2002, 390.
Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311.
22

Reactions with Unactivated Alkenes (2)
Murakami, M.; Igawa, H. Chem. Commun. 2002, 390.
Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311.
23

Reactions with Unactivated Alkynes
Hayashi reported an interesting mechanistic observation:
Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem. Soc. 2001, 123, 9918.
24

Reactions with Unactivated Alkynes:
Mechanism
Based on these observations:
Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem. Soc. 2001, 123, 9918.
25

Rhodium-Catalyzed Ullman-type Couplings
Larock reported the use organomercurials to prepare dienes and biaryls:
In the presence of CO:
Organobismuths have also been used by Uemura to prepare ketones
Larock, R. C.; Bernhardt, J. C. J. Org. Chem. 1977, 42, 1680. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5546. Larock, R. C.;
Hershberger, S. S. J. Org. Chem. 1980, 45, 3840. Uemura et al. Chem. Commun 1992, 453 and Bull. Chem. Soc. Jpn.
1995, 68, 950.
26

Rhodium-Catalyzed Ullman-type Couplings:
Mechanisms
Larock, R. C.; Bernhardt, J. C. J. Org. Chem. 1977, 42, 1680.
Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5546.
Larock, R. C.; Hershberger, S. S. J. Org. Chem. 1980, 45, 3840.
27

Rhodium-Catalyzed Ketone Formation
with Boronic Acids
Frost reported the formation of ketones with Ac 2 O:
Other boronic acid sources have also been used (e.g. Ph 4 BNa)
Frost, C. G.; Wadsworth, K. J. Chem. Commun. 2001, 2316.
Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Organomet. Chem. 2002, 648, 297.
28

Secondary Alkyl Halides in Transition Metal
Catalyzed Cross-Coupling Reactions
University of Marseille
November 2008
Mark Lautens, Alena Rudolph
University of Toronto
Angew. Chem. Mini-Review, 2008

The last three decades have seen huge advances in cross-coupling reactions of aryl and alkeny electrophiles with
organometallic reagents :
Suzuki:
Hiyama:
Stille:
Sonogashira:
Transition Metal Catalyzed Cross-Coupling
Reactions – An Introduction
Metal-Catalyzed Cross-Coupling Reactions (Eds: A. De Meijere, F. Diederich), 2 nd ed., WILEY-VCH, Weinheim, 2004.
2

Transition Metal Catalyzed Cross-Coupling
Reactions – An Introduction
For sp 2 -hybridized carbon electrophiles:
Reactions of C(sp 2 )-X electrophiles are well
developed:
• Ease of oxidative addition of the metal to the
C(sp 2 )-X bond.
• Reactions are selective due to the lack of βhydride
elimination pathways.
Metal-Catalyzed Cross-Coupling Reactions (Eds: A. De Meijere, F. Diederich), 2 nd ed., WILEY-VCH, Weinheim, 2004.
3

Transition Metal Catalyzed Cross-Coupling
Reactions of Alkyl Electrophiles
For sp 3 -hybridized carbon electrophiles:
Challenges associated with metal-catalyzed cross-coupling
reactions of β-hydrogen-containing alkyl halides:
• Slow oxidative addition (C(sp 3 )-X bond is more electron
rich).
• Rapid intramolecular β-hydride elimination and
hydrodehalogenation vs. intermolecular transmetallation.
• Many methods have now been developed with primary
alkyl halides.
• Secondary alkyl halides are more sterically encumbered.
• Methods for the coupling of secondary alkyl halides have dramatically increased over the last 5 years
• Nickel, iron, cobalt catalysis is common – radical mechanisms.
• Palladium is much more difficult – two-electron redox process.
For recent reviews see: A. C. Frisch, M. Beller, Angew. Chem. Int. Ed. 2005, 44, 674-688; M. R. Netherton, G. C. Fu in Topics in Organometallic
Chemistry: Palladium in Organic Synthesis (Ed.: J. Tsuji), Springer, New York, 2005, pp. 85-108.
4

Cross-Coupling Reactions of Primary Alkyl
Electrophiles – A Brief Overview
Most success is with palladium:
• Seminal report by Suzuki, 1992
• Further progress by Fu:
Suzuki coupling can also be
accomplished with boronic
acids: J. H. Kirchhoff, M. R.
Netherton, I. D. Hills, G. C.
Fu, J. Am. Chem. Soc.
2002, 124, 13662.
T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki, Chem. Lett. 1992, 691-694; M. R. Netherton, C. Dai, K. Neuschütz, G. C. Fu, J. Am. Chem. Soc.
2001, 123, 10099; J. H. Kirchhoff, C. Dai, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 1945; M. R. Netherton, G. C. Fu, Angew. Chem. Int. Ed.
2002, 41, 3910.
5

Cross-Coupling Reactions of Primary Alkyl
Electrophiles – A Brief Overview
• Use of bulky, electron-rich phosphine ligands, or NHC’s is important in most methodologies.
• Some other succuessful Pd-catalyzed coupling reactions of primary alkyl halides:
• Negishi, J. Am. Chem. Soc. 2003, 125, 12527.
• Coupling of organozirconium reagents, J. Am. Chem. Soc. 2004, 126, 82.
• Stille, J. Am. Chem. Soc. 2003, 125, 3718; Angew. Chem. Int. Ed. 2003, 42, 5079.
• Hiyama, J. Am. Chem. Soc. 2003, 125, 5616.
• Kumada, Angew. Chem. Int. Ed. 2002, 41, 4056.
• Sonogashira, J. Am. Chem. Soc. 2003, 125, 13642.
• For a complete overview, see: M. R. Netherton, G. C. Fu in Topics in Organometallic Chemistry: Palladium in Organic
Synthesis (Ed.: J. Tsuji), Springer, New York, 2005, pp. 85-108.
6

Advances with nickel:
Cross-Coupling Reactions of Primary Alkyl
Electrophiles – A Brief Overview
• Seminal report by Knochel in 1995:
• Double bond is important for cross-coupling:
• Ni(II)-olefin complex is more amenable to transmetallation-reductive elimination.
• π-acidity of olefin removes electron density from Ni, facilitates reductive elimination.
A. Devasagayaraj, T. Stüdemann, P. Knochel, Angew. Chem. Int. Ed. Engl. 1995, 34, 2723-2725; R. Giovannini, T. Stüdemann, A. Devasagayaraj, G.
Dussin, P. Knochel, J. Org. Chem. 1999, 64, 3544-3553; R. Giovannini, T. Stüdemann, G. Dussin, P. Knochel, Angew. Chem. Int. Ed. Engl. 1998, 37,
2387-2390; R. Giovannini, P. Knochel, J. Am. Chem. Soc. 1998, 120, 11186-11187.
7

Cross-Coupling Reactions of Primary Alkyl
Electrophiles – A Brief Overview
• Further studies lead to the development of methods that did not require a pendant olefin on the alkyl halide:
• For an overview, including Ni-catalyzed Suzuki, Hiyama and Kumada couplings of priamary alkyl halides, see: M. R.
Netherton, G. C. Fu, Adv. Synth. Catal. 2004, 346, 1525-1532.
A. Devasagayaraj, T. Stüdemann, P. Knochel, Angew. Chem. Int. Ed. Engl. 1995, 34, 2723-2725; R. Giovannini, T. Stüdemann, A. Devasagayaraj, G.
Dussin, P. Knochel, J. Org. Chem. 1999, 64, 3544-3553; R. Giovannini, T. Stüdemann, G. Dussin, P. Knochel, Angew. Chem. Int. Ed. Engl. 1998, 37,
2387-2390; R. Giovannini, P. Knochel, J. Am. Chem. Soc. 1998, 120, 11186-11187.
8

1) Negishi Coupling
2) Hiyama Coupling
Reactions of Secondary Alkyl Halides:
Nickel-Catalyzed Reactions
J. Zhou, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 14726-14727; N. A. Strotman, S. Sommer, G. C. Fu, Angew.Chem. Int. Ed. 2007, 46,
3556-3558.
9

3) Suzuki Coupling
Nickel-Catalyzed Reactions
F. González-Bobes, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 5360-5361.
10

4) Stille Coupling
Nickel-Catalyzed Reactions
• Reagent preparation is easy!
D. A. Powell, T. Maki, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 510-511.
11

5) Asymmetric Variants – reactions are stereoconvergent.
• Negishi:
Nickel-Catalyzed Reactions
• Ni(II) systems are insensitive to moisture and oxygen.
C. Fischer, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 4594-4595; F. O. Arp, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 10482-10483; S. Son, G. C.
Fu, J. Am. Chem. Soc. 2008, 130, 2756-2757.
12

Nickel-Catalyzed Reactions
• Asymmetric Negishi reaction #2:
F. O. Arp, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 10482-10483.
13

Nickel-Catalyzed Reactions
• Asymmetric Negishi reaction #3:
• Reactions of allylic chlorides occur preferentially at the least sterically hindered carbon and at the γ-position for
conjugated systems.
S. Son, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 2756-2757.
14

Nickel-Catalyzed Reactions
• Asymmetric Suzuki reaction:
• Asymmetric Suzuki coupling requires a homobenzylic bromide for good enantioselectivity.
B. Saito, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 6694-6695.
15

Nickel-Catalyzed Reactions
• Asymmetric Hiyama Coupling:
• Ligand, fluoride activator and organosilane all important for achieving high enantioselectivity.
• Reaction is sensitive to the steric bulk of the ester group and the alkyl group.
X. Dai, N. A. Strotman, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 3302-3303.
16

Nickel-Catalyzed Reactions
Nickel-catalyzed reaction of secondary alkyl halides are generally thought to proceed by radical mechanisms.
• Reaction of both exo- and endo-2-bromonorbornane give the exo-product as the major one, suggesting that both
substrates produce the same planar intermediate.
• Intramolecular cyclization occurs before cross-coupling. These reactions give the same cis/trans selectivity regardless of
coupling partner, or ligand used in the reaction. It is also the same cis/trans selectivity observed under known radical
conditions.
J. Zhou, G. C. Fu, J. Am. Chem. Soc. 2004, 126, 1340-1341; F. González-Bobes, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 5360-5361; D. A. Powell, G. C. Fu, J.
Am. Chem. Soc. 2004, 126, 7788-7789; D. A. Powell, T. Maki, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 510-511; G. Pandey, K. S. S. P. Rao, D. K. Palit, J. P.
Mittal, J. Org. Chem. 1998, 63, 3968-3978; V. B. Phapale, E. Buñuel, M. García-Iglesias, D. J. Cárdenas, Angew. Chem. Int. Ed. 2007, 46, 8790-8795.
17

Proposed catalytic cycle:
Nickel-Catalyzed Reactions
• Density functional theory calculations show that a traditional two-electron redox mechanism is energetically unfavourable.
Ni(II)-alkyl cation bound
to a reduced terpyridine
lignad, containing a
single unpaired electron.
The unpaired electron is
mostly ligand-bound.
Fast reductive
elimination of the alkyl
groups gives the coupled
product.
Reduction of the alkyl
halide via single electron
transfer from the ligand
to give an alkyl radical
Oxidative addition of the
alkyl radical occurs to
give a Ni(III) dialkyl
radical. If the ligand is
chiral, enantioselective
addition of the radical
may take place to afford
a chiral product.
G. D. Jones, J. L. Martin, C. McFarland, O. R. Allen, R. E. Hall, A. D. Haley, R. J. Brandon, T. Konovalova, P. J. Desrochers, P. Pulay, D. A. Vicic, J.
Am. Chem. Soc. 2006, 128, 13175-13183; X. Lin, D. L. Phillips, J. Org. Chem. 2008, 73, 3680-3688.
18

1) Kumada Coupling
With aryl Grignards:
With alkenyl Grignards:
Iron-Catalyzed Reactions
A variety of conditions have
been developed for the ironc
a t a l y z e d c o u p l i n g o f
secondary alkyl halides with
aryl Grignard reagents. A
summary can be found in
the following Mini-Review:
A. Rudolph, M. Lautens,
Angew. Chem. Int. Ed., DOI:
anie.200803611, in press.
The reaction did not affect
the Z/E ratio of the starting
alkenylmagnesium bromides,
as the same ratio was found
in the coupled products.
M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am. Chem. Soc. 2004, 126, 3686-3687; G. Cahiez, C. Duplais, A. Moyeux, Org. Lett. 2007, 9,
3253-3254.
19

Iron-Catalyzed Reactions
• Mechanism(s) of iron-catalyzed reacitons remain elusive.
• It has been postulated that highly-reduced iron-magnesium clusters [Fe(MgX) 2 ] n containing an Fe(-II) centre are the
catalytically active species.
• To test this hypothesis, Fürstner used a well-defined Fe(-II) complex to see if it would act as a catalyst in the Kumada
coupling of secondary alkyl halides.
• Fe(-II) is a highly active coupling catalyst.
• Cross-coupling out-competes nucleophilic attack of the Grignard reagent on functional groups such as ketones, esters,
chlorides and nitriles.
• All known oxidation states of iron were tested (+3, +2, +1, 0, -2). All are catalytically competent, but Fe(-II) is the most
active.
R. Martin, A. Fürstner, Angew.Chem. Int. Ed. 2004, 43, 3955-3957; A. Fürstner, R. Martin, H. Krause, G. Seidel, R. Goddard, C. W. Lehmann, J.
Am. Chem. Soc. 2008, 130, 8773-8787.
20

2) Negishi Coupling
Iron-Catalyzed Reactions
T h e p r e s e n c e o f a
magnesium salt from the
preparation of the diorganozinc
reagent is required for
conversion.
Mechanistic details:
• Proof for radical mechanisms:
• Reaction of chiral secondary alkyl halides lead to racemic coupled products.
• Reaction of exo- and endo-2-bromonorbornane lead to the exo-coupled product as the major one (see Ni-cat rxns).
• Reaction of substrates with a pendant olefin undergo intramolecular cyclization prior to coupling (see Ni-cat rxns).
• Reaction of (bromomethyl)cyclopropane leads to the ring-opened product:
M. Nakamura, S. Ito, K. Matsuo, E. Nakamura, Synlett 2005, 1794-1798; M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am. Chem. Soc.
2004, 126, 3686-3687; R. Martin, A. Fürstner, Angew.Chem. Int. Ed. 2004, 43, 3955-3957.
21

Iron-Catalyzed Reactions
• Further studies by Fürstner and co-workers show that carbon─carbon bond formation can occur by more than one
mechanism.
• Redox couples of the formal oxidation states Fe(I)/Fe(III), Fe(0)/Fe(II) and Fe(-II)/Fe(0) are all possible.
• All three manifolds are interconnected, making it difficult to determine the dominant redox cycle.
A. Fürstner, R. Martin, H. Krause, G. Seidel, R. Goddard, C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773-8787.
22

1) Kumada Coupling
With allyl Grignards:
With aryl Grignards:
Cobalt-Catalyzed Reactions
• The coupling of aryl Grignard reagents is more efficient with a diamine ligand (3) than a phosphine ligand (complete within
15 minutes).
• Some functional group compatibility such as an ester moiety in the alkyl halide, is observed.
T. Tsuji, H. Yorimitsu, K. Oshima, Angew.Chem. Int. Ed. 2002, 41, 4137-4139; H. Ohmiya, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2006,
128, 1886-1889.
23

Cobalt-Catalyzed Reactions
H. Ohmiya, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2006, 128, 1886-1889.
Substrates bearing a pendant olefin undergo
intramolecular cyclization prior to coupling (a
radical mechanism is operative).
Phenylation of some cyclic derivatives display
some enantioselectivity with a chiral ligand,
indicating that it might be possible to develop
asymmetric processes from racemic starting
materials.
Phenylations of Ueno-Stork acetals proceeds
with high diastereoselectivity. No evidence for
β-alkoxy elimination (radical mechanism is
operative).
24

2) Heck-Type Coupling
With styrene derivatives:
With terminal olefins,
Intramolecular:
Cobalt-Catalyzed Reactions
• The addition of Me 3 SiCH 2 MgBr is required for conversion, but it is not incorporated in the final product. Other trialkylsilylmethyl
Grignard reagents work, but alkyl or phenyl Grignard reagents do not.
• The Grignard reagent may coordinate to the catalyst, making it more electron rich.
• The reaction is tolerant of some functional groups due to the low reactivity of Me 3 SiCH 2 MgBr.
Y. Ikeda, T. Nakamura, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2002, 124, 6514-6515; T. Fujioka, T. Nakamura, H. Yorimitsu, K. Oshima,
Org. Lett. 2002, 4, 2257-2259.
25

Cobalt-Catalyzed Reactions
Four equiv of Grignard reagent (relative to
Co) are necessary to afford the catalytically
active species (and an equiv of biphenyl).
Complex A is a 17-electron
complex, active for a single
electron transfer to the substrate.
K. Wakabayashi, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2001, 123, 5374-5375; b) H. Ohmiya, K. Wakabayashi, H. Yorimitsu, K. Oshima,
Tetrahedron 2006, 62, 2207-2213; W. Affo, H. Ohmiya, T. Fujioka, Y. Ikeda, T. Nakamura, H. Yorimitsu, K. Oshima, Y. Imamura, T. Mizuta, K.
Miyoshi, J. Am. Chem. Soc. 2006, 128, 8068-8077.
26

Palladium-Catalyzed Reactions
• Fu has shown that the oxidative addition of Pd(P(t-Bu) 2 Me) 2 to primary alkyl electrophiles proceeds through a two-electron
redox process via an S N 2 mechanism.
• As such, the oxidative addition of Pd is sensitive to the steric bulk of the electrophile.
Entry R-Br k rel ΔG ǂ
1 1.0 19.5
2 0.19 20.3
3 0.054 21.0
4 24.0 [A]
[A] Extrapolated from a reaction run at 60 °C.
• The energy barrier to oxidative addition of Pd to a secondary alkyl halide is much higher than that of a primary alkyl
halide.
I. D. Hills, M. R. Netherton, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 5749-5752
27

1) Sonogashira Coupling
Palladium-Catalyzed Reactions
• The use of enantioenriched substrates leads to completely racemic product.
G. Altenhoff, S. Würtz, F. Glorius, Tetrahedron Lett. 2006, 47, 2925-2928.
28

2) Catellani Reaction
Palladium-Catalyzed Reactions
A. Rudolph, N. Rackelmann, M. Lautens, Angew. Chem. Int. Ed. 2007, 46, 1485-1488.
• The use of enantio-enriched
substrates gives the desired
products with inversion of
configuration at the stereocentre,
with minimal erosion of ee.
29

3) Suzuki Coupling
Palladium-Catalyzed Reactions
N. Rodríguez, C. Ramírez de Arellano, G. Asensio, M. Medio-Simón, Chem. Eur. J. 2007, 13, 4223-4229.
• The reaction proceeds
with inversion of
configuration at the
chiral centre.
• In a diastereomeric mixture of
bromo sulfoxides, on the cisisomer
undergoes Suzuki
coupling, while the trans-isomer
is unreactive.
• This result may pave the way
for the development of an
asymmetric process via the
resolution of racemic starting
materials.
30

Summary and Conclusions
• Nickel, iron, cobalt and more recently palladium show excellent activity towards secondary electrophiles.
• Reports on other transition metals such as zinc, copper, silver and zirconium are beginning to appear in
the literature.
• Asymmetric transformations on racemic starting materials have been demonstrated, as well as
stereospecific processes.
• Radical mechanisms are common, two-electron redox processes are more difficult.
• More active catalyst systems need to be developed.
• Need to expand on the range of nucleophilic coupling partners that may be used – increase functional
group compatibility.
• Increasing the repertoire of transformations available, particularly asymmetric ones, would be particularly
useful in the synthesis of complex molecules or natural products.
Reports on other transition metals - with Zn: a) C. Studte, B. Breit, Angew. Chem. Int. Ed. 2008, 47, 5531-5535; with Cu: b) M. Sai, H. Someya, H. Yorimitsu, K.
Oshima, Org. Lett. 2008, 10, 2545-2547; with Ag: c) H. Someya, H. Ohmiya, H. Yorimitsu, K. Oshima, Org. Lett. 2008, 10, 969-971; with Zr: d) J. Terao, S. A.
Begum, A. Oda, N. Kambe, Synlett 2005, 1783-1786.
31