Organic Seminar. Prakash Kumar Shee Department of Chemistry Michigan State University November 27, 2013

Organic Seminar Prakash Kumar Shee Department of Chemistry Michigan State University November 27, 2013

OUTLINE Introduction Background Recently Reported Approaches Approach 1: Donor Atom Assistance Approach 2: Using an End-on Template Approach 3: Through Remote ortho-c-h activation Conclusion 2

DRUG TARGETS THAT BENEFIT FROM META C-H ACTIVATION Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. 3

C-H ACTIVATION Friedel - Crafts Reaction: Friedel, C.; Crafts, J. M. Competes Rendus 1877, 84, 1392. 4

ELECTROPHILIC AROMATIC SUBSTITUTION Difficulty: Friedel, C.; Crafts, J. M. Competes Rendus 1877, 84, 1392. Kitching, M. O.; Snieckus, V. Nature 2012, 486, 478. 5

TRANSITION METAL CATALYZED C-H BOND FUNCTIONALIZATION Directed C-H activation: How to obtain meta functionalization selectively? Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. 6

OUTLINE Introduction Background Recently Reported Approaches Approach 1: Donor Atom Assistance Approach 2: Using an End-on Template Approach 3: Through Remote ortho-c-h activation Conclusion 7

MALECZKA AND SMITH Previous Synthesis: Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III J. Am. Chem. Soc. 2003, 125, 7792. Hodgson, H. H.; Wignall, J. S. J. Chem. Soc. 1926, 129, 2077. 8

MALECZKA AND SMITH Mono substituted benzenes gives mixture of meta- and para-substituted product Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III Science 2002, 295, 305. 9

HARTWIG How to obtain meta-functionalized product exclusively starting from mono substituted benzene? Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434. 10

OUTLINE Introduction Background Recently Reported Approaches Approach 1: Donor Atom Assistance Approach 2: Using an End-on Template Approach 3: Through Remote ortho-c-h activation Conclusion 11

APPROACH 1: DONOR ATOM ASSISTANCE Prof. Matthew J. Gaunt Department of Chemistry University of Cambridge Cambridge, UK Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 12

APPROACH 2: USING AN END-ON TEMPLATE cyclophane like pre-transition state 12-membered ring Prof. Jin-Quan Yu Frank and Bertha Hupp Professor of Chemistry Scripps Research Institute La Jolla, CA, USA Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. Dai, H. -X.; Li, G.; Zhang, X. -G.; Stephan, A. F.; Yu, J. -Q. J. Am. Chem. Soc. 2013, 135, 7567. Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 13

APPROACH 3: THROUGH REMOTE ORTHO C-H ACTIVATION Remote ortho C-H activation leading to meta functionalization Prof. Lutz Ackermann Dean of Research, Faculty of Chemistry, Georg-August-Universität Göttingen, Germany Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 14

Approach 1 : Donor atom assistance Approach 2: Using an end-on Template Approach 3: Through Remote ortho C-H Activation 15

OUTLINE Introduction Background Recently Reported Approaches Approach 1: Donor Atom Assistance Approach 2: Using an End-on Template Approach 3: Through Remote ortho-c-h activation Conclusion 16

APPROACH 1: DONOR ATOM ASSISTANCE Reaction: Only meta arylation No ortho / para product Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 17

Inspiration: Complementary Catalysis Similarly, Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. Deprez, N. R.; Kalyani, D.; krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. Daugulis, O.; Zaitsev, V. G. Angew. Chem. Int. Ed. 2005, 44, 4046. Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 18

Inspiration: Complementary Catalysis Similarly, Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. Deprez, N. R.; Kalyani, D.; krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. Daugulis, O.; Zaitsev, V. G. Angew. Chem. Int. Ed. 2005, 44, 4046. Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 19

REACTION OPTIMIZATION entry R 1 R 2 Yield % 1 H Me 14 2 Me Me 43 3 Me OMe 45 4 Me NEt 2 31 5 Me Ph 73 6 Me CMe 3 79 Model System Me 3 C-CO = Piv Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 20

AMIDE GROUP IS NECESSARY Decomposition No arylation product Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 21

PROPOSED MECHANISM Reductive Elimination Cu(I)/Cu(III) cycle Anti oxy-cupration Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 22

SUBSTRATE SCOPE diarylation Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 23

SUBSTRATE SCOPE Diarylation Stoichiometric control Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 24

SCOPE OF ARYL COUPLING PARTNER steric, electronic and functionally diverse X Yield (%) 4-Me 82 4-CO 2 Et 82 4-NO 2 60 4-I 49 3-CF 3 70 3-Br 72 2-Me 44 Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 25

3- OXYGENATED PIVANILIDE meta to both -OTs and -NHPiv ortho to -NHPiv, para to -OMe Any other pathway involved? Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 26

ANTI-OXYCUPRATION IS EXTREMELY UNFAVORABLE Amide is weak π electron donor ortho-position is electron rich Aromaticity broken without compensation Typical C(sp 3 ) O bond 1.45 Å Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 27

OTHER CALCULATED REACTION PATHWAYS Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 28

Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 29

Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 30

Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 31

EFFECT OF SUBSTITUENTS ON THE REACTION Relative free energies in solvent (ΔG sol ) in kcal/mol : entry R 1 R 2 1 2 TS1-b TS1-c 1 Me H 0.0 3.1 21.2 19.2 2 CMe 3 H 0.0 0.2 18.0 16.1 3 CMe 3 m-ome 0.4 0.0 13.5 12.3 4 CMe 3 P-F 0.0 0.4 19.9 17.8 Bigger CMe 3 Electrophilic attack Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 32

EFFECT OF SUBSTITUENTS ON THE REACTION Relative free energies in solvent (ΔG sol ) in kcal/mol : entry R 1 R 2 1 2 TS1-b TS1-c 2 CMe 3 H 0.0 0.2 18.0 16.1 3 CMe 3 m-ome 0.4 0.0 13.5 12.3 stabilization 4.5 3.8 Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 33

SEPARATE MODEL FOR m-methoxy PIVANILIDE ΔΔG sol (TS1-b to TS1-c) = -0.9 kcal/mol Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668. 34

CLEAVAGE OF PIVALOYL Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. 35

LIMITATIONS Electron deficient arenes give poor yield Strong electron donating substituent changes the regioselectivity What besides aryl groups can be transferred? Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593. Maleczka, R. E., Jr. Science 2009, 323, 1572. 36

AN APPROACH OVERCOMING THESE PROBLEMS Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 37

OUTLINE Introduction Background Recently Reported Approaches Approach 1: Donor Atom Assistance Approach 2: Using an End-on Template Approach 3: Through Remote ortho-c-h activation Conclusion 38

APPROACH 2: USING AN END-ON TEMPLATE σ Chelation: Cyclic pre transition state 6 or 7 membered ring End-on Template: Distal C-H bond activation ( >10 bonds away) Rigid cyclophane like pre transition state Energetically disfavored Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. 39

Solution: Linear end-on binding Reversible weak coordination Cyclophane like pre transition state High strain for ortho-activation Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. 40

META SELECTIVE C-H ARYLATION USING A U-SHAPED TEMPLATE Distal meta C-H is 11 bonds away Readily cleavable amide linkage Nitrile is important Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 41

META SELECTIVE C-H ARYLATION USING A U-SHAPED TEMPLATE Why This Motif? Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 42

SUBSTRATE SCOPE Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 43

EFFECTIVE FOR OTHER MOTIFS ALSO Phenoxyl is strong EDG Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 44

Why These Motifs? Pharmacophores in the fibrate class of lipid lowering agents Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. Dai, H. -X.; Li, G.; Zhang, X. -G.; Stephan, A. F.; Yu, J. -Q. J. Am. Chem. Soc. 2013, 135, 7567. 45

SCOPE OF ARYLBORONIC ACID ESTER EWG works better Ar Yield (%) H 73 4-Me 72 4-OMe 70 4-F 83 3-CF 3 75 4-CO 2 Me 85 Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 46

EXPANDING THE FIELD: USE OF OTHER COUPLING PARTNER Olefination: Methylation: Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 47

SUBSTRATE SCOPE FOR OLEFINATION USING A U-SHAPED TEMPLATE overcoming Steric hindrance Electronic bias overridden Baclofen diversification Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. 48

OLEFINATION RECTION OF OTHER MOTIFS Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. Dai, H. -X.; Li, G.; Zhang, X. -G.; Stephan, A. F.; Yu, J. -Q. J. Am. Chem. Soc. 2013, 135, 7567. 49

PROPOSED CATALYTIC CYCLE FOR META C-H OLEFINATION Dai, H. -X.; Li, G.; Zhang, X. -G.; Stephan, A. F.; Yu, J. -Q. J. Am. Chem. Soc. 2013, 135, 7567. 50

META SELECTIVE C-H METHYLATION Alkylation in presence of b-hydrogen needs further investigation Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f. 51

EASY REMOVAL OF TEMPLATE Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518. 52

META SELECTIVE C-H BOND ALKYLATION WITH 2 o ALKYL HALIDES Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 53

OUTLINE Introduction Background Recently Reported Approaches Approach 1: Donor Atom Assistance Approach 2: Using an End-on Template Approach 3: Through Remote ortho-c-h activation Conclusion 54

APPROACH 3: REMOTE ORTHO C-H ACTIVATION Frost: Remote ortho C-H activation leading to meta functionalization Ru-C aryl s bond directs S E Ar Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.; Kociok-Kohn, G.; Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc. 2011, 133, 19298. Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 55

Reaction: Other Directing Groups: Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 56

SUBSTRATE SCOPE Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 57

META SUBSTITUTED ARENES ARE LESS REACTIVE Steric interaction: Reduced efficacy Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 58

INTRAMOLECULAR COMPETITION WITH ORTHO SUBSTITUTED ARENES More sterically congested arene is major product Preferred alkylation Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 59

INTERMOLECULAR COMPETITION EXPERIMENTS 18% conversion ratio = 2.6 :1.0 Electrophilic type activation Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 60

EVIDENCE OF CARBOXYLATE ASSISTANCE Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 61

EXPERIMENTS WITH DEUTERIUM LABELED SUBSTRATES D 5 Substrate: Reversible ortho C-H metalation Cycloruthenation in the product Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 62

D 3 Substrate: meta C-H cleavage is not kinetically relevant Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 63

PROPOSED CATALYTIC CYCLE Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877. 64

OUTLINE Introduction Background Recently Reported Approaches Approach 1: Donor Atom Assistance Approach 2: Using an End-on Template Approach 3: Through Remote ortho-c-h activation Conclusion 65

SUMMARY Approach 1 Operationally simple, mild and inexpensive Electron deficient arenes give poor yield Strongly electron donating group overrides meta-selectivity 66

SUMMARY Approach 1 Operationally simple, mild and inexpensive Electron deficient arenes give poor yield Strongly electron donating group overrides meta-selectivity Approach 2 Activates distal C-H bonds Overrides intrinsic electronic and steric bias of molecules Easily removable template β-hydride elimination for 1 o and 2 o alkyls 67

SUMMARY Approach 1 Operationally simple, mild and inexpensive Electron deficient arenes give poor yield Strongly electron donating group overrides meta-selectivity Approach 2 Activates distal C-H bonds Overrides intrinsic electronic and steric bias of molecules Easily removable template β-hydride elimination for 1 o and 2 o alkyls Approach 3 First meta selective metalcatalyzed alkylation with 2 o alkyl halides Works well with both EDG and EWG Ru is more expensive than both Cu and Pd 68

ACKNOWLEDGEMENTS Dr. Kevin D. Walker Chelsea Thornburg Dilini Ratnayake Ruth Muchiri Tyler Walter Dr. Buddhadeb Chattopadhyay Dr. Abhishek Dutta Chowdhury Dhritabrata Mandal Hadi Nayebi Tamal Kanti Ghosh and my friends and family 69