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 Pharmaceuticals Agrochemicals
Liquid Crystals
PAH
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 Drawbacks: - stoichiometric amount of copper
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. Synlett 1991, 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. Science 2007, 316, 1172.
Stuart, D. S.; Villemure, E.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129,
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,

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
- 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,

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. Science 2006, 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: excellent yield
Aryl-Aryl Coupling - Catalytic Cu: excellent yield
Protodecarboxylation - Catalytic Cu: excellent yield
Aryl-Aryl Coupling - Stoichiometric Cu: modest yield
Aryl-Aryl Coupling - Catalytic Cu: no reaction
Protodecarboxylation - Catalytic Cu: modest 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
Optimized Conditions:
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,

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,

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:

51. Competition Experiments
Conclusions: These differences are due to the electron-deficient nature of the Pd(II) species

52. Other Interesting Transition-Metal Catalyzed Decarboxylative Couplings

53. The End I Love CO2! Albert Arnold (Al) Gore Jr.
Nobel Peace Prize 2007 and future CO2 lover