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Department of Chemistry, Imperial College London 03-Feb-2010

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1 Department of Chemistry, Imperial College London 03-Feb-2010
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)
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. 3

4 N-Heterocyclic Carbene Ligands
4

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

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

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

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. 8

9 CATALYSTS PREPARATION
9

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

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

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

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, 13

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

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

16 Catalytic Studies HYDROSILYLATION REACTIONS
16

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

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. 18

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

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

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. Organometallics 2006, 25, 2355–2358. [(IPr)CuCl]: Kaur et al. Organometallics 2004, 23, 1157–1160. 21

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

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% 0.5 h, 99% 1.5 h, 50% 1.5 h, 97% 0.25 h, 99% 0.6 h, 96% [(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. 23

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

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

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

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. 27

28 Hydrosilylation Reactions: The Director’s 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 %), 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. 28

29 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. Formation of [(IPr)2Cu]X (~ 10 %) [(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. 29

30 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. ~ 70% [(SIMes)2Cu]X [(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. 30

31 Hydrosilylation Reactions: The Director’s Cut
Initial Screening: Azolium Salts Sluggish formation of the complex [(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. 31

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. 32

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

34 Assembly processes inspired by Nature
Click Chemistry 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 [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. Huisgen, R. Pure Appl. Chem. 1989, 61, 613–628. 34

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

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

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. 37

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. 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. 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.. 38

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

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

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. 41

42 Díez-González et al. Chem.–Eur. J. 2006, 12, 7558–7564.
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. 42

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 43

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

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

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

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 47

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 48

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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