Recent advances in the use ofphosphoranyl radical
2021/10/28
M1 Tomoyuki Fukuta

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Today’s Contents

1.Introduction: What is phosphoranyl radical?
2.Application
ー O-radical trap (C1 synthon)ー unique C-O bond activation
ー catalytic α-scission pathway(hydroamination with sulfonamides)

3. Summary2What is phosphoranyl radical?

✓ One of the P-centered radicals✓ First detection by ESR in 1960.
✓ Mediator to generate valuable radicals✓ Advancing field acerated by photocatalyst
3Taylor, R. J. K. et al. ACS Catal. 2020, 10, 7250−7261.

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Overview of phosphoranyl Radical Reactivity

Taylor, R. J. K. et al. ACS Catal. 2020, 10, 7250−7261.

4Overview of phosphoranyl Radical Reactivity

Taylor, R. J. K. et al. ACS Catal. 2020, 10, 7250−7261.

5Formation of phosphoranyl radical
 Radical addition✓ Mainly determined by stability of radical
Selective reaction (P-O bond formation)
Taylor, R. J. K. et al. ACS Catal. 2020, 10, 7250−7261.

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Overview of phosphoranyl Radical Reactivity✓ Scission occurs in the weakest bond in phosphoranyl radical.
✓ Strong P=O bond formation can be a driving force for β-scission.

Taylor, R. J. K. et al. ACS Catal. 2020, 10, 7250−7261.

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Today’s Contents

1.Introduction: What is phosphoranyl radical?
2.Application
ー O-radical trap (C1 synthon)ー unique C-O bond activation
ー catalytic α-scission pathway(hydroamination with sulfonamides)

3. Summary8

C1 synthon

 Conventional approaches for hydromethylation

Leonori, D. et al. Chem. Sci.,2021, 12, 10448.

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Application to C1 synton

high reactivity
to O-centeredradicalLeonori, D. et al. Chem. Sci.,2021, 12, 10448. 10

Halogen-Atom Transfer using aminoalkyl radical Previous report✓ XAT under mild conditions
with high chemoselectivity✓ Aminoalkyl radicals
from simple amines.

Leonori, D. et al Science 2020, 367, 1021–1026.

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Optimization

4CzIPN*Ered=-1.04 V vs SC

Leonori, D. et al. Chem. Sci.,2021, 12, 10448.
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Trapping transient O-radical

Lakhdar, S. et al. Org. Lett. 2020, 22, 4404−4407.

✓ Trapping is diffusion-controlled rate
✓ O-selective trap (Addition of C-radical is reversible. )13

Substrate scope

14

Leonori, D. et al. Chem. Sci.,2021, 12, 10448.

Proposed mechanism~109 M-1 s-1

Leonori, D. et al. Chem. Sci.,2021, 12, 10448. 15

XAT by phosphoranyl radical

 Supporting evidence of XAT by phosphoranyl radical

Leonori, D. et al. Chem. Sci.,2021, 12, 10448.

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SET by phosphoranyl radical
Proposed Mechanism

Katritzky‘s pyridinium salt

✓ Application to other alkyl radical precursors✓ Sustain a chain propagation by phosphoranyl radical
Leonori, D. et al. Chem. Sci.,2021, 12, 10448. 17

Short summary✓ New approach for C1 synthon (hydromethylation)✓ Overcome the unfavored addition by trapping O radical with PPh3

✓ New reactivity of phosphoranyl radical ; XAT, SET

Leonori, D. et al. Chem. Sci.,2021, 12, 10448. 18

Today’s Contents

1.Introduction: What is phosphoranyl radical?
2.Application
ー O-radical trap (C1 synthon)ー unique C-O bond activation
ー catalytic α-scission pathway(hydroamination with sulfonamides)

3. Summary19

Deoxygenation by Photocatalyst

× Activation methods depend on the substrate

× Multistep conversion to activate C-O bonds
× Substrate limitation
Single strategy applicable to various substrate is required.
Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 20Deoxygenation via phosphoranyl radical✓ Unique C-O bond activation using phosphine & Photoredox cat.

✓ Single strategy to activate various alcohols and carboxylic acids

Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 21

Deoxygenation via phosphoranyl radical
Ered=0.97 vs SCE
cf. PPh3
E1/2=0.98 V vs SCE

Proposed mechanism

Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 22

Substrate scope ①

Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 23

Deoxygenation of aliphatic carboxylic acid

Z 3P

EOX vs Ag/Ag+PPh3

1.19

PPh2(OMe)

1.21

PPh(OMe)2

1.49P(OMe)3

1.87✓ Tune Ph2PX to avoid over-oxidation✓ Dilute conditions help β-scission bfr oxi.

J. Phys. Org. Chem. 2013, 26, 1090–1097

Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 24

Substrate scope ②✓ intramolecular cyclization (Aromatic & Aliphatic)
Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 25

Short summary✓ Unique C-O bond activation approach✓ Access the corresponding radical from alcohol and carboxylic acid(Aromatic & Aliphatic)✓ Tunable mediator ( PPh3 → PPh2OEt)
Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 26

Today’s Contents

1.Introduction: What is phosphoranyl radical?
2.Application
ー O-radical trap (C1 synthon)ー unique C-O bond activation
ー catalytic α-scission pathway(hydroamination with sulfonamides)

3. Summary27

Anti-Markovnikov Hydroamination of Olefin
 JACS ASAP paper✓ New synthetic approach using α-scission✓ Dual catalytic system; phosphine & photoredox cat.

Doyle, A. G. et al J. Am. Chem. Soc. 2021, ASAP.

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Optimization

2.0 equiv of olefin (entry 12)

Doyle, A. G. et al. J. Am. Chem. Soc. 2021, ASAP.

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Optimization

Doyle, A. G. et al. J. Am. Chem. Soc. 2021, ASAP.

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Substrate scope✓ Medicinally relevant motifs
Doyle, A. G. et al J. Am. Chem. Soc. 2021, ASAP.

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Mechanistic study①
 Alternative mechanism; PCET pathway✓ PCET pathway is not operative.
Doyle, A. G. et al J. Am. Chem. Soc. 2021, ASAP.

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Mechanistic study②
 Alternative mechanism; reductive elimination

Not detected

Doyle, A. G. et al J. Am. Chem. Soc. 2021, ASAP.

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Mechanistic study③
 Catalytic performance of by-products

Doyle, A. G. et al J. Am. Chem. Soc. 2021, ASAP.

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Summary✓ Tunable mediator to generate valuable radicals✓ Quickly advancing area in synthetic chemistry✓ Open up a new innovative radical reactivity!

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36

Appendix

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History of phosphorayl radical
Early reaction via Phosphoranyl Radical (1950s)✓ Proposed as an intermediate of desulfurization rxn.
✓ Later, P-centered radical was detected by ESR.
Hoffmann, F. W. et al. J. Am. Chem. Soc. 1956, 78, 6414−6414.
Walling, C. et al. J. Am. Chem. Soc. 1957, 79, 5326−5326.

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Brief history of phosphoranyl radcial
 Before the development of photoredox catalyst
× Hard to generate radicals in mild conditions

× Further oxidation under stoichiometric conditions

 Photoredox catalyst mediated reaction (2000s~)

Doyle, A. G. et al J. Am. Chem. Soc. 2021, ASAP.

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Structure of phosphoranyl radicalJ. Phys. Chem. A 2005, 109, 10013-10021.

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Radical stability explains the reactivity… irreversible… reversible… no addition

J. Am. Chem. Soc. 1997, 119, 1388-1399.

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Today’s Contents

1.Introduction: What is phosphoranyl radical?
2.Application
ー O-radical trap (C1 synthon)ー unique C-O bond activation
ー catalytic α-scission pathway(hydroamination with sulfonamides)

3. Summary

42

Halogen-Atom Transfer using aminoalkyl radical
 Previous report
4CzIPN

Leonori, D. et al Science 2020, 367, 1021–1026.

43

Halogen-Atom Transfer using aminoalkyl radical
 Previous report
4CzIPN

Leonori, D. et al Science 2020, 367, 1021–1026.

44

Application to C1-synton

 Addition to formaldehyde is reversible and endothermic.

Chem. Sci.,2021, 12, 10448.
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Trapping reagent Phos. vs Borane

P{BSmall, R. D. et al. J. Am. Chem. Soc. 1979, 101, 14, 3780–3785.

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Today’s Contents

1.Introduction: What is phosphoranyl radical?
2.Application
ー O-radical trap (C1 synthon)ー unique C-O bond activation
ー catalytic α-scission pathway(hydroamination with sulfonamides)

3. Summary47

Direct reduction of carboxylic acid to aldehyde

Non-substrate-specific strategy is required.

Chem. Commun., 2017, 53, 10228 48

Deoxgenation reaction

C-O bond activation via phosphoranyl radical

ACS Catal. 2018, 8, 11134−11139.

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Proposed mechanism in the presence of ArSSAr

Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 50

Proposed mechanism

Doyle, A. G. et al. ACS Catal. 2018, 8, 11134−11139. 51

Today’s Contents

1.Introduction: What is phosphoranyl radical?
2.Application
ー O-radical trap (C1 synthon)ー unique C-O bond activation
ー catalytic α-scission pathway(hydroamination with sulfonamides)

3. Summary52

Memory effectAcc. Chem. Res. 1982, 15, 117-125. 53

Phosphine screening

Doyle, A. G. et al. J. Am. Chem. Soc. 2021, ASAP.

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