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By William Schulz Bechara Charette/Collins Literature Meeting April 8 th, 2014 14 MARCH 2014.

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Presentation on theme: "By William Schulz Bechara Charette/Collins Literature Meeting April 8 th, 2014 14 MARCH 2014."— Presentation transcript:

1 by William Schulz Bechara Charette/Collins Literature Meeting April 8 th, MARCH 2014

2 a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. Controlling Site Selectivity in C-H Functionalization Catalyst-based controlSubstrate-based control 1

3 a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. c) Colby, D. A.; Tsay, A.-S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. d) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, e) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, f) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, g) Shi Chem. Sci. 2013, 4, Directing Groups in Substrate-Based Control With Pd 2 MonodentateBidentateTridentate

4 Catalytic Manifolds in Pd-Catalyzed C-H Functionalization 3 Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.

5 Jin-Quan Yu 4  Education : East China Normal University - Shanghai, China : B.Sc. in Chemistry - Top 5% of national examination for admission to SIOC Shanghai Institute of Organic Chemistry (SIOC) - Shanghai, China : Coursework for M.Sc. degree Guangzhou Institute of Chemistry - Guangzhou, China : M.Sc. in Chemistry with S.D. Xiao University of Cambridge - Cambridge, UK : Ph.D. in Chemistry with Jonathan Spencer University of Cambridge - Cambridge, UK : Junior Research Fellow (JRF) of St. John's College Harvard University - Cambridge, MA, USA : Postdoctoral Fellow, supervisor: E.J. Corey  Academic Positions : University of Cambridge - Cambridge, UK Royal Society Research Fellow : Brandeis University - Waltham, MA, USA Assistant Professor of Chemistry : Scripps Research Institute - La Jolla, CA, USA Associate Professor of Chemistry : 2007 – 2010 Professor of Chemistry : 2010 – 2012 Frank and Bertha Hupp Professor of Chemistry : present 20 (or 16) years of academic studies!!

6 Pd(0)-Catalyzed Intermolecular Arylation of C(sp 3 )-H Bonds 5 Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886.

7 Pd(II)-Catalyzed Olefination of C(sp 3 )-H Bonds 6 Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680.

8 Key Features of the Weak Coordinating “N-Ar F ” DG Auxiliary 7 - Low pKa : Faster deprotonation. Lower pKa is instrumental for the presence of a larger population of the reactive deprotonated amide. - Weak coordination : EWG group coordinated to the N center pushes the hybridization toward a N(sp2) center and weakens the coordination to the Pd center (relative to other N(sp3)). - PES (potential energy surface/DFT studies) of the reaction is slightly flatter in presence of Ar F compared to fully H-substituted. Reductive elimination step is slightly more favorable. - Weak coordination has been successfully exploited to control the reactivity and selectivity of Pd-cat. C-H functionalization. Figg, T. M.; Wasa, M.; Yu, J.-Q.; Musaev, D. G. J. Am. Chem. Soc. 2013, 135,

9 8 Can one apply the Pd(II)-catalyzed C-H activation for the  -functionalization of Alanine based SM? Synthesis of Unnatural Chiral  -Amino Acids

10 a) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, b) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.- J.; Shi, B.-F. Angew. Chem. Int. Ed. 2013, 52, c) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed. 2012, 51, General Limitations - Long reaction time - Di-arylation - Low yields - Different N-Aux for mono- or di-arylation - Racemization - Limited to electron-rich Ar-X - No one-pot di-arylation with 2 different substituents

11 Pd-Catalyzed Arylation of Primary C(sp 3 )-H Bonds 10 a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, b) M. Wasa et al., J. Am. Chem. Soc. 2012, 134,  Substituted pyridine ligands can match the weak coordination of the amide auxiliary (CONHAr F )

12 Pd-Catalyzed Arylation of Primary C(sp 3 )-H Bonds 11 He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, *Gram-scale reaction.

13 Pd-Catalyzed Arylation of Primary C(sp 3 )-H Bonds 12 He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, *Gram-scale reaction.

14 Determination of Enantiomeric Purity 13 He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

15 Pd-Catalyzed Arylation of Secondary C(sp 3 )-H Bonds 14  Better yields using electron-donating 2-alkoxylpyridines.  The conformation of the lone pairs on the oxygen atom (in L10) is rigidified to favor  -conjugation with the pyridine ring. a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, b) M. Wasa et al., J. Am. Chem. Soc. 2012, 134,

16 15 Pd-Catalyzed Arylation of Secondary C(sp 3 )-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

17 16 Pd-Catalyzed Arylation of Secondary C(sp 3 )-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

18 17 Pd-Catalyzed Arylation of Secondary C(sp 3 )-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

19 Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot 18 He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

20 19 He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot

21 20 Ligand-Enabled C(sp3)–H Arylation With Heteroaryl Iodides He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

22 21 Synthesis of N-Fmoc-Protected Unnatural Amino Acid He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

23 22 C(sp3)–H Olefination of Alanine Derivatives (PdII/Pd0) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

24 23 Unnatural  –Amino Acid Elaboration He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

25 24 Crystallography of Primary C(sp3)–H Activation Intermediate He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

26 Crystallography of Secondary C(sp3)–H Activation Intermediate 25 He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

27 Catalytic Reactivity of Intermediates A and B 26 He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, TFA is required for this transformation, presumably to facilitate the dissociation of one of the pyridine ligands.

28 Intramolecular Kinetic Isotope Effect 27

29 Proposed Mechanism for Pd(II)/Pd(IV) Catalysis 28 CsF or AgCO 3 help scavenge the I from Pd by forming clusters* * M. Wasa et al., J. Am. Chem. Soc. 2012, 134,

30 - These rare and valuable C(sp3)–H insertion intermediates (A and B) provide a promising platform for further kinetic and computational study of elementary steps in a well-defined manner. Future Work 29

31 Thank You Questions?


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