organic seminar prakash kumar shee - michigan state …€¦ · prakash kumar shee ......
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Prakash Kumar Shee Department of Chemistry Michigan State University
November 27, 2013
Organic Seminar
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OUTLINE
Introduction
Background
Recently Reported Approaches
Conclusion
Approach 1: Donor Atom Assistance
Approach 2: Using an End-on Template
Approach 3: Through Remote ortho-C-H activation
3
DRUG TARGETS THAT BENEFIT FROM META C-H ACTIVATION
Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518.
Friedel - Crafts Reaction:
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C-H ACTIVATION
Friedel, C.; Crafts, J. M. Competes Rendus 1877, 84, 1392.
ELECTROPHILIC AROMATIC SUBSTITUTION
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Difficulty:
Friedel, C.; Crafts, J. M. Competes Rendus 1877, 84, 1392.
Kitching, M. O.; Snieckus, V. Nature 2012, 486, 478.
TRANSITION METAL CATALYZED C-H BOND FUNCTIONALIZATION
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Directed C-H activation:
How to obtain meta functionalization selectively ?
Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518.
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OUTLINE
Introduction
Background
Recently Reported Approaches
Conclusion
Approach 1: Donor Atom Assistance
Approach 2: Using an End-on Template
Approach 3: Through Remote ortho-C-H activation
8
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.
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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.
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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.
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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
APPROACH 1: DONOR ATOM ASSISTANCE
Prof. Matthew J. Gaunt Department of Chemistry University of Cambridge Cambridge, UK
12 Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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
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APPROACH 2: USING AN END-ON TEMPLATE
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.
Remote ortho C-H activation leading to meta functionalization
Prof. Lutz Ackermann Dean of Research, Faculty of Chemistry, Georg-August-Universität Göttingen, Germany
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APPROACH 3: THROUGH REMOTE ORTHO C-H ACTIVATION
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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Approach 1 : Donor atom assistance
Approach 2: Using an end-on Template
Approach 3: Through Remote ortho C-H Activation
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OUTLINE
Introduction
Background
Recently Reported Approaches
Conclusion
Approach 1: Donor Atom Assistance
Approach 2: Using an End-on Template
Approach 3: Through Remote ortho-C-H activation
Only meta arylation No ortho / para product
APPROACH 1: DONOR ATOM ASSISTANCE
Reaction:
17 Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
Inspiration: Complementary Catalysis
Similarly,
18 Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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.
Inspiration: Complementary Catalysis
Similarly,
19 Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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.
REACTION OPTIMIZATION
entry R1 R2 Yield %
1 H Me 14
2 Me Me 43
3 Me OMe 45
4 Me NEt2 31
5 Me Ph 73
6 Me CMe3 79
Model System
Me3C-CO = Piv
20 Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
AMIDE GROUP IS NECESSARY
Decomposition No arylation product
21 Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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PROPOSED MECHANISM
Anti oxy-cupration
Reductive Elimination
Cu(I)/Cu(III) cycle
Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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SUBSTRATE SCOPE
diarylation
Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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SUBSTRATE SCOPE
Diarylation Stoichiometric control
Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
X Yield (%)
4-Me 82
4-CO2Et 82
4-NO2 60
4-I 49
3-CF3 70
3-Br 72
2-Me 44
SCOPE OF ARYL COUPLING PARTNER
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steric, electronic and functionally diverse
Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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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.
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ANTI-OXYCUPRATION IS EXTREMELY UNFAVORABLE
Amide is weak π electron donor
ortho-position is electron rich
Aromaticity broken without compensation
Typical C(sp3) – O bond 1.45 Å
Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668.
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OTHER CALCULATED REACTION PATHWAYS
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 Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668.
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EFFECT OF SUBSTITUENTS ON THE REACTION
entry R1 R2 1 2 TS1-b TS1-c
1 Me H 0.0 3.1 21.2 19.2
2 CMe3 H 0.0 0.2 18.0 16.1
3 CMe3 m-OMe 0.4 0.0 13.5 12.3
4 CMe3 P-F 0.0 0.4 19.9 17.8
Bigger CMe3
Electrophilic attack
Relative free energies in solvent (ΔGsol) in kcal/mol :
Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668.
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EFFECT OF SUBSTITUENTS ON THE REACTION
entry R1 R2 1 2 TS1-b TS1-c
2 CMe3 H 0.0 0.2 18.0 16.1
3 CMe3 m-OMe 0.4 0.0 13.5 12.3
Relative free energies in solvent (ΔGsol) in kcal/mol :
4.5 3.8 stabilization
Chen, B.; Hou, X. -L.; Li, Y. -X.; Wu, Y. -D. J. Am. Chem. Soc. 2011, 133, 7668.
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SEPARATE MODEL FOR m-METHOXY PIVANILIDE
ΔΔGsol (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.
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CLEAVAGE OF PIVALOYL
Phipps, R. J.; Gaunt, M. J. Science 2009, 329, 1593.
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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.
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AN APPROACH OVERCOMING THESE PROBLEMS
Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f.
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OUTLINE
Introduction
Background
Recently Reported Approaches
Conclusion
Approach 1: Donor Atom Assistance
Approach 2: Using an End-on Template
Approach 3: Through Remote ortho-C-H activation
39
APPROACH 2: USING AN END-ON TEMPLATE
σ – Chelation:
Cyclic pre transition state 6 or 7 membered ring
End-on Template:
Energetically disfavored
Distal C-H bond activation ( >10 bonds away)
Rigid cyclophane like pre transition state
Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518.
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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.
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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
Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f.
Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518.
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META SELECTIVE C-H ARYLATION USING A U-SHAPED TEMPLATE
Why This Motif?
Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f.
Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518.
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SUBSTRATE SCOPE
Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f.
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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.
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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.
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SCOPE OF ARYLBORONIC ACID ESTER
Ar Yield (%)
H 73
4-Me 72
4-OMe 70
4-F 83
3-CF3 75
4-CO2Me 85
EWG works better
Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. -Q. J. Am. Chem. Soc. 2013, ASAP, 10.1021/ja410760f.
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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.
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SUBSTRATE SCOPE FOR OLEFINATION USING A U-SHAPED TEMPLATE
Electronic bias overridden
Baclofen diversification
overcoming Steric hindrance
Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518.
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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.
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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.
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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.
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EASY REMOVAL OF TEMPLATE
Leow, D.; Li, G.; Mei, T. -S.; Yu, J. -Q. Nature 2012, 486, 518.
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META SELECTIVE C-H BOND ALKYLATION WITH 2o ALKYL HALIDES
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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OUTLINE
Introduction
Background
Recently Reported Approaches
Conclusion
Approach 1: Donor Atom Assistance
Approach 2: Using an End-on Template
Approach 3: Through Remote ortho-C-H activation
55
APPROACH 3: REMOTE ORTHO C-H ACTIVATION
Remote ortho C-H activation leading to meta functionalization
Ru-Caryl s bond directs SEAr
Frost:
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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.
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Reaction:
Other Directing Groups:
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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SUBSTRATE SCOPE
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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META SUBSTITUTED ARENES ARE LESS REACTIVE
Steric interaction: Reduced efficacy
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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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.
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INTERMOLECULAR COMPETITION EXPERIMENTS
18% conversion ratio = 2.6 :1.0
Electrophilic type activation
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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EVIDENCE OF CARBOXYLATE ASSISTANCE
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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EXPERIMENTS WITH DEUTERIUM LABELED SUBSTRATES
Cycloruthenation in the product
D5 Substrate:
Reversible ortho C-H metalation
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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D3 Substrate:
meta C-H cleavage is not kinetically relevant
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
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PROPOSED CATALYTIC CYCLE
Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
65
OUTLINE
Introduction
Background
Recently Reported Approaches
Conclusion
Approach 1: Donor Atom Assistance
Approach 2: Using an End-on Template
Approach 3: Through Remote ortho-C-H activation
66
SUMMARY
Approach 1
Operationally simple, mild and inexpensive
Electron deficient arenes give poor yield
Strongly electron donating group overrides meta-selectivity
67
SUMMARY
Approach 1
Approach 2
Operationally simple, mild and inexpensive
Electron deficient arenes give poor yield
Strongly electron donating group overrides meta-selectivity
Activates distal C-H bonds
Overrides intrinsic electronic and steric bias of molecules
Easily removable template
β-hydride elimination for 1o and 2o alkyls
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SUMMARY
Approach 1
Approach 2
Approach 3
Operationally simple, mild and inexpensive
Electron deficient arenes give poor yield
Strongly electron donating group overrides meta-selectivity
Activates distal C-H bonds
Overrides intrinsic electronic and steric bias of molecules
Easily removable template
β-hydride elimination for 1o and 2o alkyls
First meta selective metal- catalyzed alkylation with 2o alkyl halides
Works well with both EDG and EWG
Ru is more expensive than both Cu and Pd
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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