Transition-Metal-Catalyzed Decarboxylative Coupling November 13, 2007 Dino Alberico

1. Transition-Metal-Catalyzed Decarboxylative Coupling November 13, 2007 Dino Alberico

2. Decarboxylative Coupling Decarboxylative Biaryl Coupling Decarboxylative Heck-Type Coupling

3. Biaryl Compounds Natural Products Agrochemicals Pharmaceuticals PAH Liquid Crystals Ligands

4. Biaryl Formation Using Transition Metals Transition Metal (either stoichiometric or catalytic): Cu, Ni, Pd, Pt, Ru, Rh, Ir X, Y: I, Br, Cl, OTf, ONs, B, Sn, Si, Zn, Mg, H Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev.2002, 102, 1359.

5. Ullmann Coupling Ullmann, F.; Bielecki, J. Chem. Ber.1901, 34, 2174. Example: Kelly, T. R.; Xie, R. L. J. Org. Chem.1998, 63, 8045. Drawbacks: - stoichiometric amount of copper - high reaction temperatures - limited to symmetrical biaryls - unsymmetrical biaryl can be formed by using aryl halides of different reactivity but require a large excess of the activated aryl halide

6. Transition-Metal-Catalyzed Cross-Coupling Suzuki Coupling Lin, S.; Danishefsky, S. J. Org. Lett.2000, 2, 2575. Stille Coupling Sauer, J.; Heldmann, D. K.; Pabst, R. Eur. J. Org. Chem.1999, 1, 313.

7. Transition-Metal-Catalyzed Cross-Coupling Hiyama Coupling Hatanaka, Y.; Hiyama, T. Synlett1991, 845. Negishi Coupling Bumagin, N. A.; Sokolova, A. F.; Beletskaya, I. P. Russ. Chem. Bull.1993, 42, 1926. Kumada Coupling Amatore, C.; Jutand, A.; Negri, S.; Fauvarque, J.-F. J. Organomet. Chem.1990, 390, 389.

8. Direct Arylation Cross-Coupling Direct Arylation Challenge: - how to arylate a typically unreactive aryl C-H bond - how to selectively arylate an aryl C-H bond 1. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.2007, 107, 174. (Shameless Promotion) 2. Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev.2007, 36, 1173.

9. Direct Arylation Intramolecular Direct Arylation Examples: Bringmann, G.; Ochse, M.; Götz, R. J. Org. Chem.2000, 65, 2069. Julie Côté, Shawn K. Collins

10. Direct Arylation Intermolecular Direct Arylation – Using a Directing Group Examples: Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113. Alexandre Larivée, James Mousseau, André Charette

11. Direct Arylation Intermolecular Direct Arylation – Electronic Bias of Heterocycles Examples: Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles, 1990, 31, 1951.

12. Cross-Coupling of Aromatic C-H Substrates Li, X.; Hewgley, B.; Mulrooney, C.A.; Yang, J.; Kozlowski, M.C. J. Org. Chem.2003, 68, 5500. Stuart, D. S.; Fagnou, K. Science2007, 316, 1172. Stuart, D. S.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc.2007, 129, 12072. Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett.2007, 9, 3137. Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.2007, 129, 11904.

13. Limitations to Aforementioned Transition-Metal Catalyzed Methods • preparation of organometallic partner can require several synthetic steps • more solvents, more purifications, more time, higher costs, more harmful to the enviroment • a stoichiometric amount of undesired, and sometimes toxic, organometallic by-product is produced • - challenging to control regioselectivity • for intermolecular direct arylation reactions of arenes, a directing group is needed; • which may take several steps to introduce and then remove if not desired in the final product - challenging to control regioselectivity - large excess of one arene is needed - an excess of oxidant is needed (sometimes an organometallic reagent is used)

14. Aryl-Aryl Bond Formation via Decarboxylative Coupling Advantages (for best case scenario): - aryl carboxylic acids are ubiquitous in nature - many are commercially available and inexpensive - easier to control regioselectivity - no extra steps are needed to introduce the acid moiety - fewer purifications - use of less solvent - less time - less energy wasted www.carbonfootprint.com - lower costs - more environmentally friendly - more environmentally friendly CO2 by-product (compared to toxic organometallic reagents) Disadvantages: CO2 Sucks! Albert Arnold (Al) Gore Jr. Nobel Peace Prize 2007 Academy Award Winner 2007 Baudoin, O. Angew. Chem. Int. Ed.2007, 46, 1373.

15. It’s Done in Nature Enzymatic decarboxylation of orotidine monophosphate (OMP), followed by protonation of the carbanion Begley, T. P.; Ealick, S. E. Curr. Opin. Chem. Biol.2004, 8, 508.

16. Earlier Work – Stoichiometric Transition Metal Nilsson, M. Acta Chem. Scand. 1966, 20, 423. Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J. 2000, 6, 1147.

17. Catalytic Decarboxylative Coupling of Heteroaryl Carboxylates Effect of the Additive: Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc.2006, 128, 11350.

18. St-Onge Decarboxylative Coupling Reaction Starting Materials: Products:

19. Scope of the Aryl Bromide

20. Proposed Mechanism

21. Comparison of Regioselectivity with Direct Arylation

22. Decarboxylative Coupling of Aromatic Carboxylates • These substrates were selected for optimization for two reasons: • 1. Reactants, products, and by-products can be detected by GC • 2. The product is a precursor to Boscalid (BASF) Goossen, L. J.; Deng, G.; Levy, L. M. Science2006, 13, 662. Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc.2007, 129, 4824.

23. Optimization Other Notable Reagents: Pd Source: PdCl2 Ligands: BINAP, P(Cy)3 Additives: KBr, NaF Base: Ag2CO3 Solvents: DMSO, DMPU, diglyme

24. Proposed Mechanism

25. Scope of Aryl Halide

26. Scope of Aryl Carboxylate Stoichiometric Cu Conditions: Works well for a wide range of aryl carboxylic acids. Catalytic Cu Conditions: Only works with 2-nitro substituted aryl carboxylic acid.

27. Examining the Decarboxylation In order to design an effective catalyst for a range of carboxylic acids, they examined the relative reactivity toward decarboxylation compared to 2-nitrobenzoic acid. Discrepancies: Aryl-Aryl Coupling - Stoichiometric Cu: modest yield Aryl-Aryl Coupling - Catalytic Cu: no reaction Protodecarboxylation - Catalytic Cu: modest yield Aryl-Aryl Coupling - Stoichiometric Cu: excellent yield Aryl-Aryl Coupling - Catalytic Cu: excellent yield Protodecarboxylation - Catalytic Cu: excellent yield

28. Examining the Decarboxylation

29. More General Catalytic Copper Conditions

30. Application – Synthesis of Valsartan Buhlmayer, P.; Furet, P.; Criscione, L.; de Gasparo, M.; Whitebread, S.; Schmidlin, T.; Lattmann, R.; Wood, J. Bioorg. Med. Chem. Lett.1994, 4, 29.

31. Application – Synthesis of Valsartan Goossen, L. J.; Melzer, B. J. Org. Chem.2007, 72, 7473.

32. Application – Synthesis of Valsartan

33. Decarboxylative Coupling of Electron-Rich Aryl Carboxylates Optimization: Other Reagents Examined: Catalyst Source: PdCl2(MeCN)2, Pd(O2CCF3)2, Pd(CN)2, Pd(OAc)2, Pd(dppf)2Cl2(CH2Cl2)2, Pd(PPh3)4, Pd2(dba)3, NiCl2(PPh3)2, Ni(acac)2 Ligands: BINAP, P(Cy)3, DavePhos, xanthphos Additives: LiBH4, LiCl, MgCl, CaCl2, CsCl, BiCl3, CuI Base: Li2CO3, Na2CO3, K2CO3, Cs2CO3, AgOAc, TMSOK Solvents: DMA, DMF, DMSO/DMF mixtures, sulfolane Becht, J.-M.; Catala, C.; Le Drain, C.; Wagner, A. Org. Lett.2007, 9, 1781.

34. Scope of Aryl Carboxylate

35. Scope of Aryl Iodide

36. Decarboxylative Heck-Type Coupling

37. Heck-Mizoroki Reaction Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn.1971, 44, 581. Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem.1972, 37, 2320. Review: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.2000, 100, 3009. Example: Larson, R. D. et. al.J. Org. Chem.1996, 61, 3398.

38. Mechanism of the Heck Reaction of Aryl Halides

39. Decarboxylative Heck-Type Coupling OptimizedConditions: Notes: - 5:95 DMSO/DMF is important - DMF alone or DMSO alone gave lower yields - at least one ortho substitutent is needed Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.2002, 124, 11250.

40. Scope Scope of Aryl Carboxylic Acid: Scope Of Alkene:

41. Side Reactions Importance of ortho substituent Importance of 5% DMSO-DMF These side reactions probably occur by a C-H insertion or ortho-palladation reaction

42. Arylation of 2-Cycloalken-1-ones Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.

43. Reaction of 2-Methyl-cyclopenten-1-one

44. Heck Reactions of Aryl Carboxylates vs Aryl Halides ineffective in decarboxylative Heck-type coupling

45. Mechanistic Studies – Insight into the Decarboxylation Step Heck Reaction with Aryl Halides – Oxidative Addition Occurs Heck Reaction with Aryl Carboxylic Acids – What Happens? Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc.2005, 127, 10323.

46. Mechanistic Studies – Insight into the Decarboxylation Step 1H NMR Studies At 80 oC, A and B start disappearing and C forms. After 15 min at 80 oC, only C is observed.

47. Mechanistic Studies – Insight into the Decarboxylation Step 13C NMR Studies After 8 min at 60 oC, C and 13CO2 observed

48. X-Ray of Palladium Intermediate

49. Proposed Mechanism for the Decarboxylation Step • Importance of DMSO: • rate of decarboxylation is dependent on the solvent • 19:1 DMF-d7 : DMSO-d6 was 2-fold greater than DMSO-d6 alone • this is consistent with the dissociation of DMSO occurring prior to or during the rate-determining step • Trifluoroacetate Plays a Key Role in the Decarboxylative Palladation • - an excess of NaO2CCF3 only slightly slowed the rate of decarboxylative palladation • addition of 1.1 equiv of LiBr or nBu4NBr results in no decarboxylative palladation • Pd(OAc)2, PdCl2, PdO2, Pd(OTf)2 were ineffective • electron-donating phosphine or trialkyl amine ligands inhibit the reaction • Conclusion: electron-deficient Pd center is needed for decarboxylative palladation

50. Final Steps: Alkene Insertion and β-Hydride Elimination NMR, X-ray, and deuterium experiments indicate the final steps are alkene insertion and β-hydride elimination (similar to Heck reactions involving aryl halide) However, NMR studies indicate a reactivity pattern opposite to that of Heck reactions of aryl halides, that is: