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

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Presentation on theme: "Well-Defined Copper(I) Complexes: Useful Tools in Organic Synthesis Dr. Silvia Díez-González Department of Chemistry, Imperial College London 03-Feb-2010."— Presentation transcript:

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

2 Overview: NHC–Metal Complexes

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

4 N-Heterocyclic Carbene Ligands

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

6 Large Scale Synthesis: 3 Kg of IPrHCl

7 DAB-Pr IPr HCl

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 Acta 2008, 41, 43–51. (b) Díez-González, S.; Nolan, S. P. Synlett 2007, 2158–2167.

9 CATALYSTS PREPARATION

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

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

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

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. Organometallics 1993, 12, 3405-3409.

14 Synthesis of [(NHC) 2 Cu]X Complexes 14 Highly Stable Complexes X= PF 6 or BF 4

15 [(NHC) 2 Cu]X: Crystal Structures [(IPr) 2 Cu]BF 4 [(IAd) 2 Cu]PF 6 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 Studies HYDROSILYLATION REACTIONS

17 Previous work with [(NHC)CuX] Complexes, -Unsaturated Ketones and Esters Simple Ketones Jurkauskas, V.; Sadighi, J.; Buchwald, S. L. Org. Lett. 2003, 5, 2417-2420. Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P. Organometallics 2004, 23, 1157-1160.

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

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

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

21 [(NHC) 2 Cu]X: Hydrosilylation of Simple Ketones [(IPr) 2 Cu]BF 4 vs [(IPr)CuCl] Díez-González, S.; Scott, N. M.; Nolan, S. P. Organometallics 2006, 25, 2355–2358. [(IPr)CuCl]: Kaur et al. Organometallics 2004, 23, 1157–1160. [(IPr)CuCl] (3 mol%), NaOt-Bu (12 mol%), Et 3 SiH (3 equiv), toluene, RT 3 h, 93%2 h, 93%4 h, 88%5 h, 86%1 h, 97% 0.5 h, 98%1 h, 96%0.33 h, 99%4 h, 94%0.33 h, 98%

22 [(NHC) 2 Cu]X: Hydrosilylation of Aldehydes Díez-González et al. Organometallics 2006, 25, 2355–2358. Also an ester:

23 [(NHC) 2 Cu]X: Hydrosilylation of Hindered Ketones [(ICy) 2 Cu]BF 4 vs [(ICy)CuCl ] Díez-González et al. Chem.–Eur. J. 2008, 14, 158–168. [(ICy)CuCl]: Díez-González et al. J. Org. Chem. 2005, 70, 4784–4796. [(ICy)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et 3 SiH (3 equiv), toluene, 80°C 0.5 h, 99% 1.5 h, 97% 0.25 h, 99%0.6 h, 96% [(ICy)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et 3 SiH (2 equiv), toluene, 55ºC 1.5 h, 50% 1.5 h, 98% 5 h, 96%0.5 h, 95%2.5 h, 94%

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

25 Mechanistic Studies: Active Species Díez-González et al. Organometallics 2006, 25, 2355–2358. Mono-NHC species as true catalyst

26 Mechanistic Studies: Role of the Base Díez-González et al. Organometallics 2006, 25, 2355–2358. Base as a pre-catalyst activator

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 Directors Cut Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P. Organometallics 2004, 23, 1157–1160. Initial Screening: Azolium Salts [(NHC)CuCl] (3 mol %), NaOt-Bu (12 mol %), Et 3 SiH (3 equiv), toluene, RT Díez-González, S.; Escudero-Ad á n, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted.

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

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

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

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

33 Catalytic Studies [3+2] CYCLOADDITION REACTIONS CLICK CHEMISTRY

34 Click Chemistry Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021. Assembly processes inspired by Nature - Modular reactions under simple reaction conditions - Straightforward isolation (no chromatography!) for very high yields Huisgen [3+2] Cycloaddition Huisgen, R. Pure Appl. Chem. 1989, 61, 613–628. [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.

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

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-Ad á n, E.; Benet-Buchholz, J.; Stevens, E. D.; Slawin, A. M. Z.; Nolan, S.P., submitted.

38 Further Applications of [(NHC)CuX] as Click Catalysts (a) Broggi, J.; Díez-González, S.; Petersen, J. L.; Berteina-Raboin, S.; Nolan, S. P.; Agrofoglio, L. A. Synthesis 2008, 141–148. (b) Broggi, J.; Joubert, N.; Díez-González, S.; Berteina-Raboin, S.; Zevaco, T.; Nolan, S. P.; Agrofoglio. L. A. Tetrahedron 2009, 65, 1162–1170. Carbanucleosides as anti-pox agents Porphyrine Functionalisation: S é verac, M.; Le Pleux, L.; Scarpaci, A.; Blart, E.; Odobel, F. Tetrahedron Lett. 2007, 48, 6518–6522. Chelators for anti-cancer drugs Maisonial, A.; Serafin, P.; Tra ï kia, M.; Debiton, E.; Th é ry, 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 Díez-González et al. Chem.–Eur. J. 2006, 12, 7558–7564. Water/t-BuOH, 75 - 125°C MW 10 – 15 min Appukkuttan et al. Org. Lett. 2004, 6, 4223–4225 Previously reported conditions:

41 Accepted Reaction Mechanism 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. Internal alkynes would not react under these conditions…

42 Internal Alkynes 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. Copper AND Ligand Effect: Mechanistic implications…

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

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

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

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

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

48 [(NHC)Cu I ] 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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