1C-H activation using
Metal-Organic Cooperative Catalysis

2016/2/27 B4 Hirano Ryo

Contents
1. Introduction
C-H activation using intramolecular Directing-Group(DG)

2. Metal-Organic Cooperative Catalysis (MOCC)
ExamplesKetone-α-H activation by MOCC
Mechanism

3. Summary

2

Contents34

1. Introduction

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C-H activation
Very strong synthetic method

・Short-step・Atom economical

But・Difficult to proceed・Difficult to distinguish C-H bonds
Directing group is effective.

Chem. Rev., 2015, 115 , 3468–3517

First synthetically useful C-H activation

6

Murai et. al. Nature 1993, 366, 529-531.

C-H activation –mechanism

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Oxidative addition

Olefin insertion

Reductive elimination

Morokuma et. al. J. Am. Chem. Soc. 1998, 120, 12692-12693.

C-H activation –Ex

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2. Metal-Organic Cooperative Catalysis (MOCC)

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Outer directing group (1)β-HPossible!

α-H

Possible?

aldehyde-H
Possible?

Outer directing group (2)11α-HPossible!

Sahoo et al. Org. Lett., 2014, 16 , 5258–5261.

Concept of MOCC
C-H activation using catalytic outer DG
α-H

12MOCC ex1

13

DG is catalytic.
Work-up is not needed.

Bedford et al. Angew. Chem. Int. Ed. 2003, 42, 112-114.

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MOCC ex2

stereoselective.
DG is catalytic.
Preparation/work-up is not needed.

Jin. Q. Yu et al. Science 2016, 351, 252-256.

MOCC -today’s topic
α-H (main topic)

aldehyde-H

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MOCC aldehyde-H ex1

DG is not catalytic.
Imine formation is needed in advance.
Yield is bad.

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Suggs et al. J. Am. Chem. Soc. 1979, 101, 489.

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MOCC aldehyde-H ex2

Stoichiometric amount of amine is needed.
Jun et al. Angew. Chem. Int. Ed. 2000, 39, 3070-3072.

MOCC aldehyde-H ex3

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DG is catalytic.
Preparation/work-up is not needed.
Jun et al. Eur. J. Org. Chem. 2006, 2504–2507.

MOCC ketone α-H ex1

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Substrate is limited.
Stoichiometric amount of amine is needed.
Dong et al. J. Am. Chem. Soc. 2012, 134, 13954-13957.

MOCC ketone α-H ex2(main topic)

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Regioselective.
DG is catalytic.
Preparation/work-up is not needed.

Dong et al. Science 2014, 68-72.

Usefulness of MOCC –vs. aldol-21α-H MOCC -Ketone substrate22α-H MOCC -Olefin

23α-H MOCC –Direction group24α-H MOCC -Ligand

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α-H MOCC -Mechanistic insight

Oxidative addition occurs.

Olefin insertion occurs as expected.

α-H MOCC -Mechanism

How does reaction proceeds?
Wang et al. J. Am. Chem. Soc. 2015, 137, 6279-6291.
Reaction mechanism was investigated by DFT computations.

27α-H MOCC –Mechanism : SM of catalytic cycle28α-H MOCC –Mechanism : oxidative addition

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α-H MOCC –Mechanism : oxidative addition : trans-effect30

α-H MOCC –Mechanism : insertion of olefin

31α-H MOCC –Mechanism : reductive elimination32

α-H MOCC –Mechanism : total steps

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α-H MOCC –Mechanism : energy profiles (1)34α-H MOCC –Mechanism : energy profiles (2)Reductive elimination is most difficult step.

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α-H MOCC -reactivity

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α-H MOCC –reactivity : regioselectivity

Regioselective!

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α-H MOCC –reactivity : regioselectivity

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α-H MOCC –reactivity : structure of DG

Difficulty ofenamine formation
andreductive elimination
changes due tothe structure of DG

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α-H MOCC –reactivity : structure of DG

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α-H MOCC –reactivity : structure of DG

40.5

α-H MOCC –reactivity : metal ligand41

α-H MOCC –reactivity : metal ligand

energy profiles42α-H MOCC –reactivity : metal ligand43α-H MOCC summary

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Summary
・DG is useful to achieve
regioselective, high-yield C-H activation.
・Outer DG enables chelation-assisted C-H activation
to substrate that doesn’t contain DG.
・Concept of MOCC is helpful
for greener, shorter-step C-H activation.
・But, to achieve MOCC, one have to take account of
the combination of substrate and DG,
in addition to reactant, metal, and ligand.

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C-H activation

Appendix -Outer DG Mechanism

Appendix-MOCC ex1 Mechanism

Appendix -MOCC ex2 Mechanism

C-H activation –deuterium labeling experiment

・H/D scrambling occurred among two ortho and three olefinic position.
Oxidative addition and Olefin insertion occurs.
・Not among meta and para position.
Directing is necessary for C-H bond cleavage.
・Product wasn’t gained.
Reductive elimination doesn’t occur.

C-H activation –detailed mechanism (2)C-H activation -13C kinetic effect(1)Murai et. al. Chem. Lett. 1996, 109-110

C-H activation -calculation
Reductive elimination is difficult.

Matsubara et al. Organomatallics 2000, 19, 2318-2329