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Mechanism of Ni- Catalzyed C-C Bond Formation

Versatility of the Negishi Reaction. Mechanism of Ni- Catalzyed C-C Bond Formation. Paul White Stahl Group 03/25/10. Challenges of Carbon-Carbon Cross-Coupling. Strategy of Homocoupling vs Cross-Coupling. Obtain a mixture. Choice of X, M T , M.

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Mechanism of Ni- Catalzyed C-C Bond Formation

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  1. Versatility of theNegishi Reaction Mechanism of Ni-Catalzyed C-C Bond Formation Paul White Stahl Group 03/25/10

  2. Challenges of Carbon-Carbon Cross-Coupling Strategy of Homocouplingvs Cross-Coupling Obtain a mixture Choice of X, MT, M MT: Tunable Reactivity/Functional Group Tolerance MT = B (Suzuki-Miyaura), Sn (Stille), Zn (Negishi), Mg (Kumada-Tamao), Li X: Easy to activate R-X X = Halide or Pseudohalide (e.g. –OSO2CF3) M: Rapid reaction with R-X Focus: Group 10 M (Ni, Pd, Pt) Allred-Rochowelectronegativity scale Knochel, P. et. al. Angew. Chem. Int. Ed.2000, 39, 4414-4435 Pearson, R. G.; et. al. J. Am. Chem. Soc.1980, 102, 1541-1547.

  3. Typical Mechanism for Cross-Coupling 0/+2 or +2/+4 +1/+3 (Ni) -Characteristic Pd-catalysis -Commonly proposed for Ni -1,4 conjugate additions using MT -Some Ni-containing enzymes Why Nickel? Why Not Nickel? -More affordable than Pd -More reactive than Pd towards RX • Does not always do predictable • 2e- chemistry like Pd What set of oxidation states does Ni-catalyzed R-R formation operate under? Does mechanism differ between sp2-sp2 and sp3-sp3 couplings? By understanding the mechanism, is it possible to rationalize the chemistry?

  4. In the Beginning First nickel organic-halide coupling reaction: cod = 1,5 cyclooctadiene Immediate advantage over previous methods 1) Ullmann chemistry 2) Organo-lithium and -magnesium + M - limits range of functional groups Uses stoichiometricamount of Ni Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. J. Am. Chem. Soc.1971, 93, 5908-5910

  5. Milestone Study: Kochi’s Mechanistic Work Kochi recognized the need to evaluate the variety of mechanisms proposed to better understand the chemistry Step 1: Oxidative Addition Step 2: Three Proposed Mechanisms Disproportionation/Reductive Elimination Oxidative Addtion/Reductive Elimination Homolysis/Radical dimerization Approach of Study: Observe how ArNiIIXLn-2 reacts Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547-7560

  6. Disproportionation/Reductive Elimination Proposed Pathway: Experimental Evidence Against: *No disproportionation occurs under reaction conditions*

  7. Oxidative Addition/Reductive Elimination – NiII/NiIV Proposed Pathway: Experimental Evidence Against: Aryl scrambling Halide scrambling w/o aryl exchange *Due to NO aryl exchange, NiII/NiIV not operating*

  8. Presence of an Induction Period Additive Effects Reduce induction period: 0.2% PEt3 MeOTf -MeOTf: methylatesphosphine -NiBr2: acts as a phosphine sink NiBr2 None Increase induction period -0.2% PEt3: >> 0.2% = no reaction Induction period involves dissociation of a phospineligand

  9. Aryl Radical Addition/Reductive Elimination – NiI/NiIII Proposed Pathway: Evidence against: Trapping by 1,4 dihydrobenzene Experiment 1 TATM + DHB + (ArNiIIBr) Result: No change in rate of decomposition and trapping with or without ArNiIIBr Experiment 2 *Aryl radicals are NOT intermediates* 11% TATM + DHB + ArNiIIBr + PhI Result: No effect on rxn or induction period

  10. Inhibition by 1e- Acceptors Additive: O2 10 mol% Resume once consumed Strongly retards rate Complete inhibition *Suggests an odd-electron pathway (+1/+3)*

  11. Review of Experimental Results Previously proposed mechanisms: 1. Disproportionation/Reductive Elimination *Does not occur under reaction conditions* 2. Oxidative Addition/Reductive Elimination *NO aryl exchange observed* 3. Aryl Radicals *Aryl radicals not present in solution (trapping study)* None of the proposed mechanisms fit the data!

  12. A New Mechanism Proposed Knowns: 1) Clearly not 2e- chemistry (+0/+2, +2/+4) 2) Affected by 1e- acceptors (+1/+3) 3) Does not involve aryl radicals 4) Phosphine dependence in induction period Proposal: Test the viability of a NiIII radical species Oxidation of ArNiIIX Reduction of ArX Achieved chemically and electrochemically Reduction potential matches induction period ArI (2 min) < ArBr (60 min) < ArCl (80 min) Initiation Event:

  13. Proposed Mechanism – NiI/NiIII Must account for: NOTE! Not catalytic in Ni -forms NiX2 = unreactive ✓ - Halide scrambling ✓ - Aryl scrambling ✓ - No aryl exchange Radical Chain Propagation

  14. Move Towards Catalysis Problem associated with stoichiometric Ni reactions: • 1) [NiX] generated by initiation is very small • - poor electron donors/acceptors 2) NiX2 is an unreactive form of Ni Solution: Use reducing metals (Zn, Mg, Mn) to generate/regenerate NiI Role of Zn Pathway 1: Pathway 2: Kende, A. S.; et. al. Tet. Lett.1975, 39, 3375-3368, Kumada, M.; et. al. Tet. Lett.1977, 47, 4089-4092

  15. Negishi Reaction – Expanding Cross-Coupling Reactions Selective cross-coupling had been achieved with use of organometallics species - MT = Mg -> Kumada Reaction - MT = Li - Catalyst = Ni or Pd Negishi introduced the use of organozincs Ni works as efficiently as Pd Organozincs more functional group tolerant than RMgX or RLi Negishi, E-I.; King, A. O.; Okukado, N. J. Org. Chem.1977, 42, 1821-1823

  16. Summary of Mechanism and Methodology Highlights Ni-catalyzed aryl-aryl couplings Mechanism Stoichiometric reaction in Ni operates via +1/+3 pathway - different than Pd mechanisms (0/+2) Made catalytic in Ni by using reducing metal (Zn) - generates/regenerates NiI Methodology – Negishi reaction Ni performs as effectively as Pd Organozincs more tolerant of functionality than tradionalorganometallics - tolerant of C=O, CN and many more

  17. Challenges of Alkyl-Alkyl Cross-Coupling Problem 1: Slow reactivity towards R-X Solution 1: Choose conditions that provide rapid activation (X = I, M = Ni, MT = Zn) Problem 2: Rapid β-hydride elimination from M-R Solution 2a: Use chelating ligands Solution 2b: Use electron-deficient alkene additives Withdraws e- density from M - promotes reductive elimination Cardenas, D. J. Angew. Chem. Int. Ed. 2003, 42, 384-287; Rovis, T. Angew. Chem. Int. Ed. 2008, 47, 840-871

  18. Method Development By Knochel First selective Ni-catalyzed Csp3-Csp3 cross-coupling – requires alkene substrate NO cross-coupling Proposed mechanism based on work by Yamamoto and Sustmann Alkene Effect - withdraw e- density from Ni Knochel, P. et. al Angew. Chem. Int. Ed. 1995, 34, 2723-2725;

  19. Method Development *Requires various additives* *Primary electrophiles* Additive Effects: THF - 77% yield NMP co-solvent 2:1 THF:NMP - 90% yield - Increases yields p-CF3-styrene - Allows alkene-free substrates 70% Bu4NI - Allows use of RZnX instead of R2Zn 62% **Proved Ni is a potential catalyst for alkyl-alkyl couplings** Knochel, P.; et. al. Angew. Chem. Int. Ed. 1998, 37, 2387-2390; Knochel, P.; et. al. J. Org. Chem. 1999, 64, 3544-3553

  20. Alternative Method By Fu Recognized the need to use 2° alkyl electrophiles 68% 78% s-Bu-Pybox Typical phosphineligands and Pd didn’t work Does not need halide additive First 2°, unactived, β-hydride containing alkyl halide cross-coupling (Ni or Pd) 2° alkyl halide + chiralligand = asymmetric catalysis Zhou, J.; Fu, G. C. J. Am. Chem. Soc.2003, 125, 14726-14727

  21. Development of Asymmetric Catalysis 70%, 93% ee 78%, 95% ee 82%, 91% ee 69%, 94% ee Asymmetric catalysis is stereoconvergent Fu, G. C.; et. al. J. Am. Chem. Soc.2005, 127, 4594-4595; Fu, G. C.; et. al. J. Am. Chem. Soc.2005, 127, 10482-10483

  22. Csp3-Csp3Negishi Mechanism Around same time as Fu’s chemistry, Vicic observed reactivity of: Key Observation 1: No homocoupling quant. Key Observation 2: NiI shows same reactivity as a common Ni0 catalyst for Negishi reactions Key Observation 3 NiI/NiIII likely operative in sp3-sp3Negishi reaction Ni0/NiII NOT likely operative Vicic, D. A.; et. al. J. Am. Chem. Soc.2006, 128, 13175-13183

  23. Discussion of Mechanisms Proposed Radical Mechanism – ‘06 “Generally Accepted Mechanism for Alkanes” – ‘04 Ni0/NiII NiI/NiIII “Accepted” mechanism most likely proposed from analogous Pd chemistry Oxidation state when transmetalation occurs is different Anderson, T. J.; Vicic, D. A. Organometallics. 2004, 23, 623-625

  24. Computational Evaluation of Ni0/NiII Mechanism Computational Detail Method: B3LYP Basis set: C,H,N,O,Ni,Zn – 6-31+G* I – LANL2DZ + d (0.266) Ni0/NiII Transmet/red. elim. is thermoneutral Low-driving force for catalysis Lin, X.; Phillips, D. L. J. Org. Chem.2008, 73, 3680-3688

  25. Analysis of Alkyl Iodides in NiI/NiIII Cycle NiI/NiIII Strong driving force for reductive elimination Reduction elimination kinetically and thermodynamically favored

  26. Explanation for Fu’s High Enantioselectivity Stereoconvergent step

  27. Conclusions NiI/NiIIIsp3-sp3 Ni0/NiII pathway commonly propsed for Ni-catalyzed C-C bond formation Both Ni-catalyzed sp3-sp3Negishi reactions and aryl-aryl couplings undergo NiI/NiIII chemistry Odd-electron chemistry doesn’t necessarily mean uncontrolled reactions Nickel is an affordable and reactive catalyst for C-C bond formation

  28. Future Directions Activation of alkyl chloride bonds – traditionally most difficult 93%, 91% ee Reducing catalyst loading Fu, G. C.; et. al. J. Am. Chem. Soc.2008, 130, 2756-2757; Knochel, P. et. al. Tetrahedron. 2006, 62, 7521-7533

  29. Acknowledgements Shannon Stahl Practice Talk Attendees Teresa BearyBrad Ryland Jiao Jiao Rick McDonald NattawanDecharin Alison Suess Aaron McCoy Nicky Stephenson Adam Weinstein Jamie Chen James Gerken Matt Rigsby Jackie Brown Kelsey Mayer David Mannel Jessica Hoover Alison Campbell Stahl Group – Awesome people to be around!!

  30. A Sample of the Many Ni-Catalyzed Reactions Cyclooligomerization of Alkynes - Cyclotrimerizations 1,4 Conjugate Addition X = Br, I; R = sp3, sp2 Cyclozincation

  31. Random Junk Slide Palladium Nickel Electronic Structure: [Kr] 4d10 [Ar] 4s13d9 Common Oxidation States: 0,+2,(+4) 0, +1, +2, +3, (+4) EPR studies believe that the active site of nickel hydrogenase operates via a NiI/NiIII cycle Acetyl CoAsynthase: NiI/NiIII - Brunold

  32. Visualization of SOMO Spin-density plot of tpyNi-CH3 uB3LYP/m6-31+G*

  33. Further Reactivity of Alkyl Radicals fast (S)-sBu-Pybox Phapale, V. B.; Bunuel, E.; Garcia-Iglesias, M.; Cardenas, D. J. Angew. Chem. Int. Ed.2007, 46, 8790-8795

  34. Preparation of Organozinc Compounds Direct Insertion Aryls require more forcing conditions -OH, -NO2 and -N3 not tolerated When FG-RX is unactivated at α or β, and X = Br Works with many forms of Zn - dust, granules, powder, shot Reduces I2 which then converts the RBr into a more reactive RI

  35. Preparation of Organozinc Compounds Metal Exchange Boron Exchange Stereocenter set at first asymmetric hydroboration is retained

  36. Move Towards Catalysis Observations: 1) Rate dependent on [Zn] - e- transfer rate-limiting (NiII/NiI) 2) Activation parameters suggest associative mechanism -ΔH = 10 kcal/mol, ΔS = -36 eu 3) Excess halide promotes reaction 4) Bpy promotes reaction - forces aryls cisto each other

  37. Application to Total Synthesis Suh, Y-G.; et. al. Angew. Chem. Int. Ed.1999, 38, 3545-3547; Fu, G. C.; et. al. J. Am. Chem. Soc.2008, 130, 2756-2757

  38. Application to Total Synthesis Reported Preparation Asymmetric Negishi

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