Émilie Morin Literature Meeting January 18th 2017

John F. Hartwig Academic Background AB Princeton University 1986 PhD (R. G. Bergman + R. A. Anderson) U.C. Berkeley 1990 PDF (S. J. Lippard) MIT 1990-1992 Career Professor (assistant, associate, full) Yale University 1992-2004 Irénée P. Dupont Professor Yale University 2004-2006 Kenneth L. Rinehart Jr. Professor University of Illinois 2006-2011 Henry Rapoport Professor U. C. Berkeley 2011-now Research Interests Organometallic Chemistry Catalysis with transition metal complexes Mechanistic Studies Cross-Coupling Chemistry

John F. Hartwig Famous Reactions Buchwald-Hartwig Reaction C-H Borylation (40 papers) Publications: Since 2014, published 53 papers (363 in total) 2 Nature 1 Science 26 JACS 14 ACIE C-H borylation of alkanes first Ishiyama, T.; Takagi, J.; Hartwig, J. F.;Miyaura, N.  Angew. Chem. Int. Ed. 2002, 41, 3056. Hartwig, J.F. Acc. Chem. Res. 2012, 45, 864.

Pinjing Zhao Academic Background BS Beijing University 1997 PhD (D.B. Collum) Cornell University 2004 PDF (J. F. Hartwig) Yale University 2004-2006 PDF (J. F. Hartwig) University of Illinois 2006-2007 Career Associate Professor North Dakota State University 2008 - present Research Interests Organometallic Chemistry Homogeneous Catalysis (Rh, Ru, Ni) Publications: Since 2009, published 13 papers 1 Nat. Chem. 1 Nat. Comm. 3 Angew. Chem. Int. Ed. + 1 Angew. Chem. 3 J. Am. Chem. Soc. 1 Chem. Eur. J. C-H activation, Decarboxylation (but oxydative coupling on the COOH position), alkynes/alkenes, hydroamination, NHC + 11 abstracts of papers of the ACS

Hydroarylation of Alkynes Definition: Addition of an aryl group and a hydrogen across an alkyne to form a conjugated aromatic alkene. Advantages of C-H Functionalization Atom-economical Less waste Fewer reaction steps Two Mechanistic Pathways Alkyne Activation Arene Activation Kitamura, T. Eur. J. Org. Chem. 2009, 1111.

Alkyne Activation Friedel-Crafts Alkenylation Mechanism: SEAr Disadvantages Scope limited to electron-rich arenes No regioselectivity on the arene Ionic liquid = stabilize the unstable vinyl cationic intermediate in highly polar ionic liquid Faster, better yields, electron-deficient alkynes, Nevado, C.; Echavarren, A . M. Synthesis, 2005, 167. ; Li, R.; Wang, S. R.; Lu, W. Org. Lett., 2007, 9, 2219. Song, C. E.; Jung, D.; Choung, S. Y.; Roh, E. J.; Lee, S. Angew. Chem. Int. Ed. 2004, 43, 6183.

Arene Activation Directed ortho-Metalation Accelerates the C-H activation Controls the regiochemistry First Example: Lewis and Smith First Catalytic Example: Murai Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108, 2728. Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S. Chem Lett. 1995, 681-682.

Arene Activation C-H Functionalization Directing Group Strategies Non-Removable DG Scope limited Removable DG Requires an additional step to remove or modify the DG Traceless DG One-pot functionalization and removal of DG Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906.

Arene Activation Aliphatic alkynes not tolerated Active AgSbF6 induces isomerization into the thermodinamically more stable Z-isomer. Aliphatic alkynes not tolerated Min, M.; Kim D.; Hong, S. Chem. Commun. 2014, 50, 8028.

Protodecarboxylation Ecological Advantages Carboxylic acids are easily available (often from renewable sources) Decarboxylation only produces CO2 as by-product Protodecarboxylation Slow reaction Requires high temperatures Ortho substituents are often needed Stoichiometric amounts of a Cu or Ag salt are used Gooßen Methodology with catalytic amount of Cu Rodríguez, N.; Gooßen, L. J. Chem. Soc. Rev. 2001, 40, 5030. Gooßen, L. J.; Thiel, W. R.; Rodríguez, N.; Linder, C.; Melzer, B. Adv. Synth. Catal. 2007, 349, 2241.

Tandem sequences Tandem Arylation/Protodecarboxylation Requires ortho-substituents (EWG or EDG) Produces a meta-selective C-H arylation Tandem Alkoxylation/Protodecarboxylation Alkoxylation catalyzed by Cu Protodecarboxylation catalyzed by Ag Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem. Int. Ed. 2011, 50, 9429. Bhadra, S.; Dzik, W. I.; Gooßen, L. J. Angew. Chem. Int. Ed. 2013, 52, 2959.

Tandem sequences Aliphatic alkynes not tolerated Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362.

This Paper Remaining Challenges One-pot removal of directing group Access to meta- and para-substituted alkenylarenes Great regio- and stereoselectivities Aliphatic alkynes tolerance Chemoselective reaction Mild conditions (temperature, stoechiometric Cu and Ag salts) Strategy: Use of carboxylic acids as directing group for hydroarylation and use of the alkene just formed as an activating unit for the decarboxylation. Mild and redox-neutral conditions to achieve a large substrate scope Zhang, J. Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

Ruthenium (II) Catalyst Hydroarylation Decarboxylation Also works with arenes that do not bear an ortho substituant, but the yields are lower. Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.; Miura, M. Org. Lett. 2012, 14, 2058. Shi, X.-Y.; Dong, X.-F.; Fan, J.; Liu, K.-Y.; Wei, J.-F.; Li, C.-J. Sci. China. Chem., 2015, 58, 1286.

Optimization Precatalyst (mol%) T° Ligand Additive Solvent 3a 4a 5a 6a [Ru(p-cymene)Cl2]2 (5) 100 - NaOAc PhMe 55 4 2 3 PCy3 18 5 < 2 [Ru(p-cymene)(OAc)2]2 (5) 16 [Ru(p-cymene)(OAc)2]2 (10) 66 80 25 mesitylene 27 1,4-dioxane 15 heptane 17 mixed 65

Mechanism Zhang, J. Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

Mechanism : By-Products Formation Isocoumarin Control Experiments 50 mol% PivOH favored desired product over by-products Confirm protonation steps in Path A Synthesis of a Ru(0) complex with naphtalene ligand that does not promote the reaction Path C leads to catalyst deactivation Naphtalene Zhang, J. Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

Scope: para-Benzoic acids Naphtalene 6 is the major by-product Deactivation of catalyst when forming this by-product explains the low yields Zhang, J. Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

Scope: Benzoic acids Ortho Substituents Meta Substituents (48 h) No ortho-products detected No ipso-selective decarboxylation Confirm that decarboxylation is not facilitated by steric effects Coordination on alkene is necessary for decarboxylation Zhang, J. Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

Scope: Alkynes Symmetrical alkynes Unsymmetrical alkynes Ortho-substituent gives higher yield by preventing formation of naphtalene by-product Unsymmetrical alkynes Terminal alkynes not tolerated (unproductive Ru(II) complexe) Simple alkyl chains (Me, Et, n-Bu) are less reactive 20 mol% Cu(OAc)2 is added to regenerate the catalyst Ru(0) into Ru(II) 2-(MeO)Ph : higher yields pcq steric effects prevent the formation of by-product 6 Zhang, J. Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

Conclusion Selling Points Weaknesses Traceless directing group removed in a one-pot sequence Broad scope (mild conditions, no ortho-substituent needed) High stereoselective syn hydroarylation Controlled chemo- and regioselectivity Commercially available benzoic acids and less expensive than aryl halides Weaknesses Uncompatible with terminal alkynes More difficult with alkyls and electron-deficient substrates Glovebox chemistry Zhang, J. Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

While this paper was submitted… Hydroarylation with CO2H as DG One-pot Hydroarylation/Decarboxylation Alkyl-substituted alkynes do not allow high-yielding coupling Those conditions do not promote only decarboxylation on alkenyl-arenes Huang, L.; Biafora, A.; Zhang, G.; Bragoni, V.; Gooßen, L. J. Angew. Chem. Int. Ed. 2016, 55, 6933.

Thank you!