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

Decarboxylative Coupling Decarboxylative Biaryl Coupling Decarboxylative Heck-Type Coupling

Biaryl Compounds Natural Products Pharmaceuticals Agrochemicals Liquid Crystals PAH Ligands

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.

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

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.

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.

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.

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

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

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.

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, 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.

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)

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.

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.

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.

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.

St-Onge Decarboxylative Coupling Reaction Starting Materials: Products:

Scope of the Aryl Bromide

Proposed Mechanism

Comparison of Regioselectivity with Direct Arylation

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.

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

Proposed Mechanism

Scope of Aryl Halide

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.

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

Examining the Decarboxylation

More General Catalytic Copper Conditions

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.

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

Application – Synthesis of Valsartan

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.

Scope of Aryl Carboxylate

Scope of Aryl Iodide

Decarboxylative Heck-Type Coupling

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.

Mechanism of the Heck Reaction of Aryl Halides

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, 11250.

Scope Scope of Aryl Carboxylic Acid: Scope Of Alkene:

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

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

Reaction of 2-Methyl-cyclopenten-1-one

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

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.

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.

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

X-Ray of Palladium Intermediate

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

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:

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

Other Interesting Transition-Metal Catalyzed Decarboxylative Couplings

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