Recent Advances in Palladium-Catalyzed C─H Activation/C─C

Cross Coupling

Dung Tien Do March 31, 2011

Outline

I.  Introduction II.  Pd-Catalyzed Olefination III.  Pd-Catalyzed Arylation IV.  Pd-Catalyzed Alkylation & Enantioselective C─H Activation V.  Conclusion

Introduction

Tradditional Pd-Catalyzed C─C Cross Coupling

Pd-Catalyzed C─H Activation/C─C Cross Coupling

C-H Activation through Cyclopalladation or The Complex-Induced Proximity Effect

Yu, J. Q. et al. Angew. Chem. Int. Ed. 2009,48, 5094-5115 Engle, K. M.; Wang, D. H.; Yu, J. Q. JACS, 2010, 132, 14137-14151

Snieckus, V.; Beak, P. et al. Angew. Chem. Int. Ed. 2004,43, 2206-2225

Machanistic Manifolds

Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147-1169

Pd-Catalyzed Olefination

Olefination of C(sp2)─H Bonds: PdII/Pd0 Catalysis

Amide-Directed ortho-Selective Olefination of Arenes

Regioselective Olefination of Pyrroles

Beck, E. M.; Grimster, N. P.; Haltley, R.; Gaunt, M. J. JACS, 2006, 128, 2528

Olefination of C(sp2)─H Bonds: PdII/Pd0 Catalysis

Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. JACS. 2002, 124, 1586

meta-Olefination of Electron-Deficient Arenes

Zhang, Y. H.; Shi, B. F.; Yu, J. Q. JACS, 2009, 131, 5027

• The use of a rationally designed mutually repulsive ligand was crucial for C-H activation of electron-deficient arenes

• 1 atm O2 can be used as the sole oxidant • A combination of C-H acidity and steric hindrance seem to govern the reactivity of the

different sites, suggesting a concerted mechanism.

Carboxylic Acids as The Directing Group

Yu, J. Q. et al. Angew. Chem. Int. Ed. 2009,48, 5094-5115

• Pd(II) is forced to coordinate with the unhindered lone pair of electrons on the oxygen atom B triggering C-H insertion

A working model for cationic counter ions promoted Pd(II)-insertion

• Counter cations coordinate with the carboxylate group in a ҡ2 fashion A

Coordination modes of palladium(II) with carboxylic acids

Olefination of Phenylacetic Acid Substrates

Wang, D. H.; Engle, K. M,; Shi, B. F.; Yu, J. Q. Science, 2010, 327, 315-319

Proposed Catalytic Cycle

Engle, K. M.; Wang, D. H.; Yu, J. Q. JACS, 2010, 132, 14137-14151

Pd(II)-Catalyzed Hydroxyl-Directed C-H Olefination

Lu. Y.; Wang D. H.; Engle, K. M.; Yu, J. Q. JACS, 2010, 132, 5916-5921

Amide-Directed Olefination of sp3 C-H Bonds

• LiCl addition increase the yield. Solvent choice was critical: polar, strong coordinate amide solvent giving best reactivity

• Order of selectivity: Cyclopropanyl > Methyl > Secondary • More electron-withdrawing CONHAr group improved yield: More electron deficient aryl

gave better yield Wasa, M.; Engle, K. M.; Yu, J. Q. JACS, 2010, 132, 3680-3681

Pd-Catalyzed Arylation

Pd-Catalyzed C―H Bonds: Arylation

C-H Arylation with Prefunctionalized Arylating Reagents (PdII/PdIV)

Sanford’s approach for directed C-H activation/arylation

Kalyani, D.; Deprez, N. R,; Desai, L. V.; Sanford, M. S. JACS, 2005, 127, 7330

Proposed Mechanism for C-H Arylation of 3-Methyl-2-phenylpyridine (PdII/PdIV)

Deprez, N. R,; Sanford, M. S. JACS, 2009, 127, 11234-11241

Arylation of C-H Bonds Using ArI

Daugulis, O.; Zaitsev, V. G. Angew. Chem. 2005, 117, 4114 Daugulis, O.; Shabashov, D. J. Org. Chem. 2007, 72, 7720

Daugulis, O.; Shabashov, D.; Do, H.Q. Acc. Chem. Res. 2009, 42, 1074-1086

Daugulis. O.; Zaitsev, V. G.; Shabashov, D. JACS. 2005, 127, 13154

Pyridine-Directed Arylation of sp3 C―H bonds

• Palladation forming a five-membered ring is prefered. • When the directing group is Pyridyl, primary C―H

bonds react faster than the secondary C―H bonds, allowing for the selective monoarylation of methyl groups.

Intramolecular Alkane Arylation

• Selective at primary position • Concerted inner-sphere palladation-deprotonation pathway involed a three-center agostic interaction:

Lafrance, M.; Gorelsky, S. I.; Fagnou, K. JACS, 2007, 129, 1470-1471

Shi’s Amide-Directed Arylation Using Organometallic Reagents

Early study by de Vries and coworkers suggested that reactions of these anilides with Pd(OAc)2 proceed by electrophilic palladation.

These highly reactive anilide substrates can also be ortho coupled with arylboronic acids

Yang, S.; Li, B.; Wan, S.; Shi, Z. JACS , 2007, 129, 6066-6067

Shi, Z. et al. Angew. Chem, 2007, 119, 5650

Arylation Using Carboxylic Acids as The Directing Group

Wang, D. H.; Mei, T. S.; Yu, J. Q. JACS. 2008, 130, 17676

• Air or Oxygen can be used as oxidants • Wide range of functional groups were tolerated

Substrate Scope: Phenyl Acetic Acids

Wang, D. H.; Mei, T. S.; Yu, J. Q. JACS 2008, 130, 17676

Cross Coupling of Unactivated Arenes

Stuart, D. R.; Fagnou, K. Science, 2007, 136, 1172-1175

Fagnou’s Cross-Coupling of Unactivated Arenes

Stuart, D. R.; Fagnou, K. Science, 2007, 136, 1172-1175

• Microwave heating reduced reaction time to 5 h (typically 48 h) with a slight drop in A:B • A:B can be improved by decreasing catalyst loading • Completely selective for arene cross-coupling, no homo-coupling observed.

Sanford’s Benzoquinoline/Arene Cross-Coupling

Hull, K. L.; Sanford, M. S. JACS. 2007, 129, 11904-11905

Chemoselectivity for Cross-Couping

Benzoquinoline/Arene Cross-Coupling

Scope of Benzoquinoline/Arene Cross-Coupling

Hull, K. L.; Sanford, M. S. JACS. 2007, 129, 11904-11905

• Coupling at p- and m- positions was significantly favored over the o-position • Increased methylation of the BQ led to a dramatic decrease in coupling at the o-position

Preliminary Proposed Mechanism

Hull, K. L.; Sanford, M. S. JACS. 2007, 129, 11904-11905

Buchwald’s Examples of Using O2 as Sole Oxidant for Cross-Coupling

Brasche, G.; Garcia-Fortanet, J.; Buchwald, S. Org. Lett. 2008, 10, 2207-2010

• Using fewer equiv of arenes • Oxygen (1 atm) is the only oxidant • Regioselectivity is governed by steric factors

Pd-Catalyzed Alkylation & Enantioselective C─H Activation

• K2CO3 is critical • The use of bulky solvent was believed to prevent homocoupling and β-hydride

elimination • Oxygen can be used as sole oxidant

Yu, J. Q. et al. JACS, 2008, 130, 7190-7191

Alkylation Using Boronic Acids

Pd-Catalyzed Enantioselective C-H Activation

Using Pyridine as Directing Group

Shi, B. F.; Maugel, N.; Zhang, Y. H.; Yu, J. Q. Angew. Chem. Int. Ed. 2008,47,4882-4886

Pd(II)- Catalyzed Enantioselective C-H Olefination of Diphenylacetic Acids

Shi, B. F.; Zhang, Y. H.; Lam, J. K.; Wang. D. H.; Yu, J. Q. JACS, 2010, 132, 460-461

• Acrylates were found to be efficient coupling partners affording 99% ee

Pd(II)- Catalyzed Enantioselective C-H Olefination of Diphenylacetic Acids

Shi, B. F.; Zhang, Y. H.; Lam, J. K.; Wang. D. H.; Yu, J. Q. JACS, 2010, 132, 460-461

Conclusion

• However, development in this field is still at an early stage compared to the state of the art of traditional cross-coupling reactions. Major challenges must still be overcome before having broad applicability:

-Air as the oxidant -Reduced catalyst loading -Directing group issues -Regioselectivity -Enantioselectivity

• Various catalytic cycles have been developed to accomplish the olefination, arylation, and alkylation of unactivated C-H bonds. Significant advances in developing novel reactions and mechanistic understanding have broadened applicability of this catalyst.

Acknowledgements

Advisor: Prof. Jeff Johnson Jeff Johnson Group

Greg Boyce Dan Schmitt Mike Slade Austin Smith Kimberly Steward

Justin Malinowski

Michael Corbett Ryan Carris Scott Krabbe Ericka Malow Rani Ulrich

Examples of Arylation of C(sp3)-H

Yu, J. Q. et al. JACS, 2007, 129, 3510-3511

• First examples of carboxyl-directed Pd-insertion into sp3 β-C-H bond

• PdII/PdIV pathway is likely

Carboxyl-Directed Arylation

Arylation of C(sp3)-H Using Air as Sole Oxidant

• The presence of K2CO3 is critical. • PdII/Pd0 pathway is likely

Yu, J. Q. et al. JACS, 2008, 130, 7190-7191

Ligand-Accelerated C-H Activation Reaction

Accelerated Pd(II)-catalyzed C-H Olefination of Phenylacetic Acid Substrates

The Pretransition State Coordination Structures prior to Pd(II)-Mediated C-H Cleavage

Wang, D. H.; Engle, K. M,; Shi, B. F.; Yu, J. Q. Science, 2010, 327, 315-319

• Only BQ gave low conversion after 2 hours (<20%) • Ac-Ile-OH led to higher conversion (>99% in most cases) • Amino acid ligands also enable selectivity for unsymmetric aryl substrates

Engle, K. M.; Wang, D. H.; Yu, J. Q. JACS, 2010, 132, 14137-14151

Pd-Catalyzed Alkynylation

Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250

Amide-directed alkynylation

Pd-Catalyzed Carboxylation

Amide-directed ortho-carboxylation

Carboxylic acid-directed ortho-carboxylation

Giri, R.; Yu, J. Q. JACS, 2008, 130, 14082-14083 Giri, R.; Lam, J. K.; Yu, J. Q. JACS, 2010, 132, 686-693

Hydroxyl-Directed C-H Carbonylation

Lu, Y.; Leow, D.; Wang, X.; Engle, K. M.; Yu, J. Q. Chem. Science, 2011, 1-6