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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
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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 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.
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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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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
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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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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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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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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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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
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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