Organic Seminar Prakash Kumar Shee - Michigan State …€¦ · Prakash Kumar Shee ... ELECTROPHILIC AROMATIC SUBSTITUTION 5 Difficulty: ... Background Recently Reported Approaches

Prakash Kumar Shee Department of Chemistry Michigan State University

November 27, 2013

Organic Seminar

2

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

5

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 ?


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OUTLINE

Introduction

Background


Conclusion




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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





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


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


Conclusion




Only meta arylation No ortho / para product

APPROACH 1: DONOR ATOM ASSISTANCE

Reaction:


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.

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.

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


AMIDE GROUP IS NECESSARY

Decomposition No arylation product


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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


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SUBSTRATE SCOPE

Diarylation Stoichiometric control


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


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3- OXYGENATED PIVANILIDE

meta to both -OTs and -NHPiv ortho to -NHPiv, para to -OMe

Any other pathway involved ?


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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


29 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 :


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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


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SEPARATE MODEL FOR m-METHOXY PIVANILIDE

ΔΔGsol (TS1-b to TS1-c) = -0.9 kcal/mol


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CLEAVAGE OF PIVALOYL


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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?


Maleczka, R. E., Jr. Science 2009, 323, 1572.

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AN APPROACH OVERCOMING THESE PROBLEMS


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OUTLINE

Introduction

Background


Conclusion




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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


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Solution:

Linear end-on binding

Reversible weak coordination

Cyclophane like pre transition state

High strain for ortho-activation


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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



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META SELECTIVE C-H ARYLATION USING A U-SHAPED TEMPLATE

Why This Motif?



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SUBSTRATE SCOPE


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EFFECTIVE FOR OTHER MOTIFS ALSO

Phenoxyl is strong EDG


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Why These Motifs?

Pharmacophores in the fibrate class of lipid lowering agents



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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


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EXPANDING THE FIELD: USE OF OTHER COUPLING PARTNER

Olefination:

Methylation:



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SUBSTRATE SCOPE FOR OLEFINATION USING A U-SHAPED TEMPLATE

Electronic bias overridden

Baclofen diversification

overcoming Steric hindrance


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OLEFINATION RECTION OF OTHER MOTIFS



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PROPOSED CATALYTIC CYCLE FOR META C-H OLEFINATION


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META SELECTIVE C-H METHYLATION

Alkylation in presence of b-hydrogen needs further investigation


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EASY REMOVAL OF TEMPLATE


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META SELECTIVE C-H BOND ALKYLATION WITH 2o ALKYL HALIDES


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OUTLINE

Introduction

Background


Conclusion




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APPROACH 3: REMOTE ORTHO C-H ACTIVATION

Remote ortho C-H activation leading to meta functionalization

Ru-Caryl s bond directs SEAr

Frost:


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:


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SUBSTRATE SCOPE


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META SUBSTITUTED ARENES ARE LESS REACTIVE

Steric interaction: Reduced efficacy


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INTRAMOLECULAR COMPETITION WITH ORTHO SUBSTITUTED ARENES

More sterically congested arene is major product

Preferred alkylation


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INTERMOLECULAR COMPETITION EXPERIMENTS

18% conversion ratio = 2.6 :1.0

Electrophilic type activation


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EVIDENCE OF CARBOXYLATE ASSISTANCE


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EXPERIMENTS WITH DEUTERIUM LABELED SUBSTRATES

Cycloruthenation in the product

D5 Substrate:

Reversible ortho C-H metalation


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D3 Substrate:

meta C-H cleavage is not kinetically relevant


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PROPOSED CATALYTIC CYCLE


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OUTLINE

Introduction

Background


Conclusion




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SUMMARY

Approach 1

Operationally simple, mild and inexpensive


Strongly electron donating group overrides meta-selectivity

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SUMMARY

Approach 1

Approach 2




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




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

Organic Seminar Prakash Kumar Shee - Michigan State …€¦ · Prakash Kumar Shee ... ELECTROPHILIC AROMATIC SUBSTITUTION 5 Difficulty: ... Background Recently Reported Approaches

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