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Well-Defined Copper(I) Complexes: Useful Tools in Organic Synthesis Dr. Silvia D íez-González

Well-Defined Copper(I) Complexes: Useful Tools in Organic Synthesis Dr. Silvia D íez-González. Department of Chemistry, Imperial College London 03-Feb-2010. Overview: NHC–Metal Complexes. N-Heterocyclic Carbene Ligands (NHC). saturated/unsaturated substituted/unsubstituted tunable at will.

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Well-Defined Copper(I) Complexes: Useful Tools in Organic Synthesis Dr. Silvia D íez-González

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  1. Well-Defined Copper(I) Complexes:Useful Tools in Organic SynthesisDr. Silvia Díez-González Department of Chemistry, Imperial College London 03-Feb-2010

  2. Overview: NHC–Metal Complexes

  3. N-Heterocyclic Carbene Ligands (NHC) saturated/unsaturated substituted/unsubstituted tunable at will tunable appending groups -donor and -acceptor (stabilization of the carbene) stabilized and localized lone pair excellent -donor ligand Strong NHC-metal bond, low degradation, low toxicity Reviews: (a) Special Issue Chem. Rev. 2009, 109, 3209–3884. (b) Angew. Chem., Int. Ed.2008, 47, 3122–3172.

  4. N-Heterocyclic Carbene Ligands

  5. Synthesis of NHCs: IPr as a Showcase Flexible and scalable synthesis

  6. Large Scale Synthesis: 3 Kg of IPr•HCl

  7. Large Scale Synthesis: 3 Kg of IPr•HCl IPrHCl DAB-Pr

  8. [(NHC)Cu] Complexes in Catalysis • Allylic Alkylation • N-Arylation ATRC • Aziridination • Diboration • Conjugate Addition • Hydroamination • Hydroalkoxylation Reviews: (a) Díez-González, S.; Nolan, S. P. Aldrichimica Acta2008, 41, 43–51. (b) Díez-González, S.; Nolan, S. P. Synlett 2007, 2158–2167.

  9. CATALYSTS PREPARATION

  10. Synthesis of [(NHC)CuX] Complexes X= Cl, Br or I 19 Highly Stable Complexes

  11. [(NHC)CuX]: Crystal Structures [(IPr)CuCl] [(ICy)CuCl] Cu–C1 = 1.956 Å C1–Cu–Cl = 180.0° Cu–C1 = 1.925 Å C1–Cu–Cl = 171.6°

  12. [(NHC)CuX]: Crystal Structures (II) [(IAd)CuI] [(ICy)CuI] Cu–C =1.927/1.973Å Cu(1)–Cu(2) = 2.453 Å Cu(1)–C(1) = 1.946 Å C(1)–Cu(1)–I(1) = 137.9°

  13. Undesired Reaction: New Family of Complexes First [(NHC)Cu] known in the literature: Arduengo, A. J., III; Rasika Dias, H. V.; Calabrese, J. C.; Davidson, F. Organometallics1993, 12, 3405-3409.

  14. Synthesis of [(NHC)2Cu]X Complexes X= PF6 or BF4 14 Highly Stable Complexes

  15. [(NHC)2Cu]X: Crystal Structures [(IAd)2Cu]PF6 [(IPr)2Cu]BF4 Cu–C(1) = 1.938 Å N1–C1–Cu–C1’–N1’ = 49.9° Cu–C1 = 1.933 Å N1–C1–Cu–C1’–N1’ = 86.8°

  16. Catalytic StudiesHYDROSILYLATION REACTIONS

  17. Previous work with [(NHC)CuX] Complexes ,-Unsaturated Ketones and Esters Jurkauskas, V.; Sadighi, J.; Buchwald, S. L. Org. Lett.2003, 5, 2417-2420. Simple Ketones Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P. Organometallics2004, 23, 1157-1160.

  18. Hydrosilylation of Challenging Substrates Hindered Ketones Functionalized Ketones Díez-González, S.; Kaur, H. Zinn, F. K.; Stevens, E. D.; Nolan, S. P. J. Org. Chem.2005, 70, 4784–4796.

  19. Hydrosilylation of Challenging Substrates (II) Heteroaromatic Ketones Díez-González et al. J. Org. Chem.2005, 70, 4784–4796.

  20. Proposed Mechanism Díez-González et al. J. Org. Chem.2005, 70, 4784–4796.

  21. [(NHC)2Cu]X: Hydrosilylation of Simple Ketones [(IPr)2Cu]BF4 vs [(IPr)CuCl] 0.5 h, 98% 1 h, 96% 0.33 h, 99% 4 h, 94% 0.33 h, 98% 2 h, 93% 4 h, 88% 5 h, 86% 3 h, 93% 1 h, 97% [(IPr)CuCl] (3 mol%), NaOt-Bu (12 mol%), Et3SiH (3 equiv), toluene, RT Díez-González, S.; Scott, N. M.; Nolan, S. P. Organometallics2006, 25, 2355–2358. [(IPr)CuCl]: Kaur et al.Organometallics2004, 23, 1157–1160.

  22. [(NHC)2Cu]X: Hydrosilylation of Aldehydes Also an ester: Díez-González et al. Organometallics2006, 25, 2355–2358.

  23. [(NHC)2Cu]X: Hydrosilylation of Hindered Ketones [(ICy)2Cu]BF4 vs [(ICy)CuCl] 1.5 h, 98% 5 h, 96% 0.5 h, 95% 2.5 h, 94% 1.5 h, 50% 0.5 h, 99% 0.25 h, 99% 0.6 h, 96% 1.5 h, 97% [(ICy)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et3SiH (3 equiv), toluene, 80°C [(ICy)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et3SiH (2 equiv), toluene, 55ºC Díez-González et al.Chem.–Eur. J.2008, 14, 158–168. [(ICy)CuCl]: Díez-González et al. J. Org. Chem.2005, 70, 4784–4796.

  24. Mechanistic Studies: Decomposition and Exchange Rates Díez-González, et al.Chem.–Eur. J.2008, 14, 158–168.

  25. Mechanistic Studies: Active Species Mono-NHC species as “true” catalyst Díez-González et al.Organometallics2006, 25, 2355–2358.

  26. Mechanistic Studies: Role of the Base Base as a pre-catalyst activator Díez-González et al.Organometallics2006, 25, 2355–2358.

  27. Postulated Mechanism Díez-González, et al.Chem.–Eur. J.2008, 14, 158–168. Díez-González, et al.J. Org. Chem.2005, 70, 4784–4796.

  28. Hydrosilylation Reactions: The Director’s Cut Initial Screening: Azolium Salts [(NHC)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et3SiH (3 equiv), toluene, RT Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P. Organometallics2004, 23, 1157–1160. Díez-González, S.; Escudero-Adán, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted.

  29. Hydrosilylation Reactions: The Director’s Cut Formation of [(IPr)2Cu]X (~ 10 %) [(NHC)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et3SiH (3 equiv), toluene, RT [(NHC)2Cu]X (3 mol %), NaOt-Bu (12 mol %), Et3SiH (2 equiv), THF, RT Díez-González, et al.Chem.–Eur. J.2008, 14, 158–168. Díez-González, S.; Escudero-Adán, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted. Initial Screening: Azolium Salts

  30. Hydrosilylation Reactions: The Director’s Cut ~ 70% [(SIMes)2Cu]X [(NHC)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et3SiH (3 equiv), toluene, RT [(NHC)2Cu]X (3 mol %), NaOt-Bu (12 mol %), Et3SiH (2 equiv), THF, RT Díez-González, et al.Chem.–Eur. J.2008, 14, 158–168. Díez-González, S.; Escudero-Adán, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted. Hydrosilylation Reactions: The Director’s Cut Initial Screening: Azolium Salts

  31. Hydrosilylation Reactions: The Director’s Cut Sluggish formation of the complex Hydrosilylation Reactions: The Director’s Cut Initial Screening: Azolium Salts [(NHC)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et3SiH (3 equiv), toluene, RT Díez-González, S.; Escudero-Adán, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted.

  32. Hydrosilylation Reactions: [(SIMes)CuCl] Excellent activity under smoother conditions Compared to [(IPr)CuCl] Compared to [(ICy)CuCl], reactions at 80ºC Díez-González, S.; Escudero-Adán, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted.

  33. Catalytic Studies[3+2] CYCLOADDITION REACTIONSCLICK CHEMISTRY

  34. Click Chemistry [Cu]: (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064. (b) Rostovtev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599. Assembly processes inspired by Nature - Modular reactions under simple reaction conditions - Straightforward isolation (no chromatography!) for very high yields Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.2001, 40, 2004–2021. Huisgen [3+2] Cycloaddition Huisgen, R. Pure Appl. Chem. 1989, 61, 613–628.

  35. [(NHC)CuX] Screening Díez-González, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem.–Eur. J.2006, 12, 7558–7564.

  36. Scope of the Reaction Díez-González et al. Chem.–Eur. J.2006, 12, 7558–7564.

  37. [(SIMes)CuBr] vs [(IAd)CuI] for Click Chemistry Díez-González, S.; Escudero-Adán, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted.

  38. Further Applications of [(NHC)CuX] as Click Catalysts Porphyrine Functionalisation: Séverac, M.; Le Pleux, L.; Scarpaci, A.; Blart, E.; Odobel, F.Tetrahedron Lett.2007, 48, 6518–6522. Carbanucleosides as anti-pox agents (a) Broggi, J.; Díez-González, S.; Petersen, J. L.; Berteina-Raboin, S.; Nolan, S. P.; Agrofoglio, L. A. Synthesis2008, 141–148. (b) Broggi, J.; Joubert, N.; Díez-González, S.; Berteina-Raboin, S.; Zevaco, T.; Nolan, S. P.; Agrofoglio. L. A. Tetrahedron2009, 65, 1162–1170. Chelators for anti-cancer drugs Maisonial, A.; Serafin, P.; Traïkia, M.; Debiton, E.; Théry, V.; Aitken, D. J.; Lemoine, P.; Viossat, B.; Gautier, A.Eur. J. Inorg. Chem.2008, 298–305..

  39. Latent Click Catalyst Díez-González, S.; Stevens, E. D.; Nolan, S. P. Chem. Commun. 2008, 4747–4749.

  40. In Situ Generated Azides Previously reported conditions: Water/t-BuOH, 75 - 125°C MW 10 – 15 min Appukkuttan et al.Org. Lett. 2004, 6, 4223–4225 Díez-González et al. Chem.–Eur. J.2006, 12, 7558–7564.

  41. Accepted Reaction Mechanism Internal alkynes would not react under these conditions… Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc.2004, 127, 210–216.

  42. Internal Alkynes Copper AND Ligand Effect: Mechanistic implications… Díez-González et al. Chem.–Eur. J.2006, 12, 7558–7564. For another example, see: Candelon, N.; Lastécouères, D.; Diallo, A. K.; Ruiz Aranzaes, J.; Astruc, D.; Vincent, J.-M. Chem. Commun. 2008, 741–743.

  43. DFT Calculations: Novel Activation of Alkynes The NHC facilitates the  -Cu-alkyne binding and permits the cycloaddition Díez-González et al. Chem.–Eur. J.2006, 12, 7558–7564. Activation towards cycloaddition via-binding unfavoured Himo et al.J. Am. Chem. Soc.2004, 127, 210–216.

  44. Distinct Mechanisms Depending on the Alkyne Nature Díez-González et al. Chem.–Eur. J.2006, 12, 7558–7564.

  45. [(NHC)2Cu]X as Click Catalysts: Very Low [Cu] Loadings TONs up to 20 250; TOFs up to 5000 h-1 Díez-González, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2008, 47, 8881–8884.

  46. Proposed Mechanism for [(NHC)2Cu]X Catalysts Díez-González, S. et al.Angew. Chem., Int. Ed. 2008, 47, 8881–8884.

  47. [(NHC)CuI] Complexes: CONCLUSIONS [(NHC)CuX] & [(NHC)2Cu]X • Practical preparation, high stability • Excellent catalysts for hydrosilylation and [3+2] cycloaddition reactions [(NHC)CuX] [(NHC)2Cu]X • Catalysts of choice for very challenging ketones • Low catalyst loading (< 1 mol %) • Use of internal alkynes • Latent catalyst • Active under smoother conditions • Enhanced catalytic activity • Active at ppm levels • KEY ROLE OF THE SECOND NHC

  48. [(NHC)CuI] Complexes: CONCLUSIONS Preparation of a library of well-defined complexes • Organometallic interest: - Synthetic procedures - Coordination chemistry • Better chances of finding the optimal catalysts • Improved control of the species present in the reaction media - Catalytic performance - Mechanistic implications

  49. ACKNOWLEDGEMENTS • Crystallography: Prof. Edwin D. Stevens & Dr. Natalie M. Scott (UNO) Prof. Jeffrey Petersen (West Virginia) Eduardo Escudero, Dr. Jordi Benet (ICIQ) Prof. Alex M. Z. Slawin (St. Andrews) • DFT Calculations: Dr. Andrea Correa & Prof. Luigi Cavallo (Salerno) • Hosting: Prof. Deryn Fogg (Ottawa) • Collaborators: Prof. Hélène Lebel (Montreal) Prof. Arnaud Gautier (Blaise-Pascal – Clermont) Prof. Olivier Riant (Louvain)

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