1. 1 C-sp 3 Coupling Using Alkyl Halides as Electrophiles: Work by Gregory Fu Presented by Pascal Cérat Litterature meeting March 31 th 2009

2. 2 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

3. 3 Outlines 1)Introduction on cross-coupling methodologies a) Kumada-Corriu b) Negishi c) Stille d) Hiyama e) Suzuki 2) Difficulties with sp 3 -alkyl halides possessing  -H 3) First advancements on sp 2 -sp 3 and sp 3 -sp 3 cross-coupling - Corey first sp 3 -sp 3 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

4. 4 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. 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. Proposed catalytic cycle: Disadvantage: Grignards are not compatible with a lot of functional groups

5. 5 Negishi Coupling Reaction with Organozinc Reagents 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. Simplified catalytic cycle: 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 ZnX 2 along with the usual Pd or Ni catalyst. Advantage : RZnCl are more easily fonctionnalized

6. 6 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. 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. Proposed mechanism for Palladium cycle:

7. 7 Stille Coupling Reaction with Tetraorganotin Reagents S E 2(open): Case of an open associative transmetallation - Use of polar and coordinating solvents - Absence of bridging abitlity in the complex. 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. Transmetallation process S E 2(cyclic): Case of an cyclic associative transmetallation - Non-coordinating solvents - The presence of a bridging ligand. Retention of configuration Inversion of configuration

8. 8 Hiyama Coupling Reaction with Organosilicon Compounds 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. Proposed mechanism of palladium-catalyzed fluorosilane cross-coupling:

9. 9 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. 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. Catalytic cycles for trialkylboranes derivatives by Soderquist: All the cross-coupling reactions been shown so far are involving the creation of an sp 2 -sp 2 bound!

10. 10 Problematic of Alkyl Halides as Electrophiles Alkyl halides are said to react slowly with Pd 0 and Ni 0 in the oxidative addition step, because of the more electron-rich C(sp 3 )-X bond compare to an C(sp 2 )-X Two main possibilities are found for the oxidative addition of alkyl halide to a metal: 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. Oxidative addition Usual cis-complexes are obtained during the oxidative addition with C(sp 2 )-X electrophiles: - By a free radical pathway - By an associative bimolecular S N 2 pattern (mainly for low valent metals)

11. 11 Problematic of Alkyl Halides as Electrophiles 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.  -Elimination In the case of alkyl metal species the lack of  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  -hydrogen make possible a decomposition of the alkyl-Pd(II) complex by a fast elimination of the hydrogen.

12. 12 Problematic of Alkyl Halides as Electrophiles 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.  -Elimination  -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(PPh 3 ) 4 and PdCl 2 (dppf) 2 ) can favor reductive elimination over  -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.

13. 13 First Examples of Alkyl Halides Coupling Corey, E.J.; Semmelhack, M.F. J. Am. Chem. Soc. 1967, 89, 2755. 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  - and epi-  -santalene:

14. 14 Controversy with Castle and Widdowson Methodology 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. 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  -elimination in the final intermediate and that this reaction could lead to sp 3 -sp 3 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)PdCl 2.

15. 15 Controversy with Castle and Widdowson Methodology 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. Reduction of alkyl halides with (dppf)PdCl 2 : Later, in 1991, Yuan and Scott reported a system using Ni(dppf)Cl 2 as the catalyst for a Kumada-Corriu coupling unactivated neopentyl idodes with grignard reagents.

16. 16 Boro-Alkyl Suzuki-Miyaura Cross Coupling Reaction Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691. 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

17. 17 Cross-Coupling of Iodocyclopropanes Charette, A.B.; Giroux, A. J. Org. Chem. 1996, 61, 8718. Cyclopropyl halides are interesting electrophiles for cross-coupling as the  -hydride elimination is not favoured because of the strain that is generated in the cyclopropene.

18. 18 Cross-Coupling of Iodocyclopropanes Charette, A.B.; Freitas-Gil, R.P. Tet. Lett. 1997, 38, 2809. Martin, S.F.; Dwyer, M.P. Tet. Lett. 1998, 39, 1521. Synthesis of polycyclopropanes by Suzuki-type cross-coupling: Tri-substituted cyclopropanes by Martin:

19. 19 Knochel’s Work on Nickel-Catalysed Cross-Coupling 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. Preliminary work with organozincs: The need of the double bond restraint the scope of the reaction.

20. 20 Knochel’s Work on Nickel-Catalysed Cross-Coupling 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. 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 [PdCl 2 (CH 3 CN) 2 ] leads only to the bromine-zinc exchange product.

21. 21 Knochel’s Work on Nickel-Catalysed Cross-Coupling 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. In 1998 to 1999, Knochel reported the used of a promotor (co-catalyst) with the nickel complex: Diorganozinc reagent can also be coupled:

22. 22 Knochel’s Work on Nickel-Catalysed Cross-Coupling 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. Some primary alkyl bromides were also used using the same system. Other cocatalysts tried during these studies:

23. 23 Kambe’s Following on the Use of 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. 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.

24. 24 Kambe’s Following on the Use of Co-catalyst 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. 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.

25. 25 Gregory C. Fu 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. 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 post- doctoral 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. The man behind the study His research

26. 26 P(t-Bu) 3 and PCy 3 as Ligands in Coupling Reactions with Aryl Electrophiles 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. Suzuki reactions: For aryl triflates, no reaction is obtained with P(t-Bu) 3 and PCy 3 must be used:

27. 27 P(t-Bu) 3 and PCy 3 as Ligands in Coupling Reactions with Aryl Electrophiles 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. Stille reactions: Negishi reactions:

28. 28 What’s the Difference Between PCy 3 and P(t-Bu) 3 ? In the course of their study on the Heck acylation, Prof. Gregory Fu has found that PCy 3 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. Hills, I.D.; Fu, G.C. J. Am. Chem. Soc. 2004, 126, 13178. angle P-Pd-P : 180 o angle P-Pd-P : 161 o The steric effect that is brought in the case of the P(t-Bu) 3 ligand seem to favorise the reductive elimination.

29. 29 Introduction of the Ligand P(t-Bu) 2 Me 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. Early methodology for Suzuki reactions on primary alkyl halides: In 2002, Prof. Fu tried to expand the reaction to OTs, but the used of PCy 3 and P(t-Bu) 3 as the ligand seemed too sterically demanding. A less bulky ligand P(t-Bu) 2 Me was then used with success.

30. 30 Introduction of the Ligand P(t-Bu) 2 Me Investigations on the stereochemistry of the oxidative addition of an alkyl tosylate to Pd/P(t-Bu) 2 Me: Netherton, M.R.; Fu, G.C. Angew. Chem. Int. Ed. 2002, 41, 3910. Oxidative addition: inversion of configuration Reductive elimination: retention of configuration

31. 31 Utility of P(t-Bu) 2 Me for Primary Alkyl Halides Suzuki cross-coupling: Kirchhoff, J.H.; Netherton, M.R.; Hills, I.D.; Fu, G.C. J. Am. Chem. Soc. 2002, 124, 13662. The corresponding phosphonium salt of the ligand which is air- and moisture stable can also be used.

32. 32 Utility of P(t-Bu) 2 Me for Primary Alkyl Halides Stille 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. Hiyama cross-coupling:

33. 33 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. 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. Negishi cross-coupling:

34. 34 Nickel in Cross-Couplings for Secondary Alkyl Halides 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. Suzuki cross-coupling sp 2 -sp 3 :

35. 35 Nickel in Cross-Couplings for Secondary Alkyl Halides 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. Hiyama cross-coupling sp 2 -sp 3 :

36. 36 Nickel in Cross-Couplings for Secondary Alkyl Halides 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. Stille cross-coupling sp 2 -sp 3 with trichlorostannates (less toxic and easier for purification):

37. 37 Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides Fischer, C.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 4594. Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2. Negishi coupling of secondary  -bromo amides:

38. 38 Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides Arp, F.O.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 10482. Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2. Negishi coupling of secondary benzylic bromides:

39. 39 Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides Son, S.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 2756. Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2. Negishi coupling of secondary allylic chlorides:

40. 40 Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides 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. Hiyama coupling of secondary  -bromo esters:

41. 41 Asymmetric Cross-Couplings of Racemic Secondary Alkyl Halides Saito, B.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 6694. Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2. Enantioselective alkyl-alkyl Suzuki cross-coupling of secondary homobenzylic bromides:

42. 42 Mechanistic Studies of Nickel Cross-Coupling 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. Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2. 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 (CH 3 ZnI) followed by the reductive elimination shown above is greatly disfavored.  G = 21.1 kcal/mol

43. 43 Mechanistic Studies of Nickel Cross-Coupling 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. Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2. 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  G = -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.

44. 44 Mechanistic Studies of Nickel Cross-Coupling 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. Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2. 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.

45. 45 Conclusion In conclusion, we have seen different methodologies to do cross-coupling for unactived alkyl chlorides using P(t-Bu) 3 and PCy 3. Gregory Fu has been able to successfully coupled primary alkyl halides using Suzuki, Negishi and Stille reactions with the Pd/P(t-Bu) 2 Me 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. There is still work to be done to expand the scope of functionality that can be tolerated. fluvirucinine A