1. Émilie Morin Literature Meeting January 18th 2017

2. 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
Career
Professor (assistant, associate, full) Yale University
Irénée P. Dupont Professor Yale University
Kenneth L. Rinehart Jr. Professor University of Illinois
Henry Rapoport Professor U. C. Berkeley now
Research Interests
Organometallic Chemistry
Catalysis with transition metal complexes
Mechanistic Studies
Cross-Coupling Chemistry

3. 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.

4. Pinjing Zhao Academic Background BS Beijing University 1997
PhD (D.B. Collum) Cornell University 2004
PDF (J. F. Hartwig) Yale University
PDF (J. F. Hartwig) University of Illinois
Career
Associate Professor North Dakota State University 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

5. 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.

6. 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,

7. 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,

8. 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.

9. 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.

10. 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,

11. 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.

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

13. 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.

14. 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.

15. 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

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

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. Thank you!