Hydrogenation of Arenes
for Organic Synthesis
Literature Seminar #3
2020/10/23
M2 Yuki Hirao

Catalytic Hydrogenation

2

Hydrogenation of Arenes
Aromatic Stabilization Energy (ASE) contributes to the greater
resistance by hydrogenation.

Coord. Chem. Rev. 2016, 314, 134.

3

Application
Industrial Application

Material Science

Natural Product

Medicinal Chemistry

Angew. Chem. Int. Ed. 2019, 58, 10460.

4

Challenges
Reactivity
The hydrogenation ofarenes is hindered by theadded kinetic barrier
resulting from thearomatic stabilizationenergy.

Stereoselectivity

Chemoselectivity

The hydrogenation ofmultisubstituted arenes
may form several
diastereomers.
Substituted saturated
carbo- & heterocycles areoften chiral.

Elaborate substrates often
exhibit competingside reactions.
ex.) more reductively labileunits, such as carbonyls,hydrodefunctionalizations

Angew. Chem. Int. Ed. 2019, 58, 10460.

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Contents
1. Introduction

2. Stereoselectivity
・diastereoselectivity
・enantioselectivity

3. Chemoselectivity

・FG tolerance
・mechanistic investigation

4. Summary6

cis-Selectivity
cis isomer vs trans isomer

kinetically thermodynamically
The formation of the trans isomer requires a π-facialexchange (catalyst dissociation-reassociation process).
✓Hydrogenation of dearomatized intermediates should be faster than thatof stabilized aromatic substrate.
✓The catalyst would have to bind to the sterically more hindered π-face.

Arene hydrogenation generally proceeds with highcis selectivity.

RSC Adv. 2016, 6, 18419.

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Enantioselectivity

Chem. Rev. 2012, 112, 2557.

8

Chiral Auxiliary

Angew. Chem. Int. Ed. 2004, 43, 2850.

9

Chiral BrØnsted Acid Catalyst

Angew. Chem. Int. Ed. 2006, 45, 3683.

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Chiral Ligand

Angew. Chem. Int. Ed. 2019, 58, 10460.

11

Application in Total Synthesis

B. M. Stoltz et al. Science 2019, 363, 270.

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Retrosynthesis of (-)-Jorumycin

B. M. Stoltz et al. Science 2019, 363, 270.

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Enantio- & Diastereoselective Hydrogenation

B. M. Stoltz et al. Science 2019, 363, 270.

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Catalyst Screening

B. M. Stoltz et al. Science 2019, 363, 270.

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Short Summary

Angew. Chem. Int. Ed. 2019, 58, 10460.

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Contents
1. Introduction

2. Stereoselectivity
・diastereoselectivity
・enantioselectivity

3. Chemoselectivity

・FG tolerance
・mechanistic investigation

4. Summary17

Chemoselectivity | FG tolerance
Challenges
1. Other reducible sites
2. Hydrodefunctionalization
3. Sterically hinderance
4. Negative influence in electronical properties

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Phenol Hydrogenation to Cyclohexanone

T. Jiang, B. Han et al. Science 2009, 326, 1250.

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Aromatic Carbonyl Compounds

X. Zeng et al. J. Am. Chem. Soc. 2015, 137, 9250.

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Substrate Scope

X. Zeng et al. J. Am. Chem. Soc. 2015, 137, 9250.

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Hydrogenation of Fluoroarenes

F. Glorius et al. Science 2017, 357, 908.

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Reaction Optimization

F. Glorius et al. Science 2017, 357, 908.

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Substrate Scope

F. Glorius et al. Science 2017, 357, 908.

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Mechanistic Experiments

F. Glorius et al. Science 2017, 357, 908.

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Deuterium-Labeling Experiments

X. Zeng et al. Angew. Chem. Int. Ed 2019, 58, 16785.

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Fluoropyridines

F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Dearomatization Strategy

T. Ohmura, M. Suginome et al. J. Am. Chem. Soc. 2012, 134, 3699.
F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Substrate Scope

F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Application

F. Glorius et al. Nat. Chem. 2019, 11, 264.

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Contents
1. Introduction

2. Stereoselectivity
・diastereoselectivity・enantioselectivity

3. Chemoselectivity

・FG tolerance
・mechanistic investigation

4. Summary31

Sillica gel improves the reactivity

F. Glorius et al. Angew. Chem. Int. Ed 2018, 57, 8297.

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Catalyst Poisoning Study

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Catalyst Filtlation & Rycycling

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Kinetic Study

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Observation of Ligand

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Comparing the Performance

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Summary

Silica gel-supported Rh(0) NPs as active catalytic species

CAAC-derived pyrrolidium and pyrrolidine act as modifiers that are key incontrolling the chemoselectivity.

F. Glorius et al. ACS Catal. 2020, 10, 6309.

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Summary

Functionalization of arene is more facile than that of thesaturated products.
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