Persistent/Stable sulfur-based radical
cations in organic chemistry2022. 9. 29
M2 Yuri Katayama
1

Contents

1. Introduction of persistent radicals
2. Site-selective C-H functionalization by thianthrenation
I. Ritter’s first work
II. Mechanistic insight into site-selectivity
3. PTH catalyzed C(sp3)-O formation
4. Summary & Perspective2

What is a “persistent radical” ?

“Persistent” radical : lifetime is significantly longer than ･CH3
↔ “transient” < 10-3 s

Kinetic stability“Stabilized” radical : BDE (R-H) < BDE of C-H alkanes↔ “destabilized” > 104.9 kcal/mol (BDE for H3C-H)

Thermodynamic
stability

Defined by Griller and Ingold
Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 9, 13.
Leifert, D.; Studer, A. Angew. Chem. Int. Ed. 2020, 59, 74.
3Persistent Radical Effect (PRE)One example of PRE-mediated cross-coupling reactions
1963 Perkins

Stephenson, C. R. J. et al., Chem. Soc. Rev. 2018, 47, 7851. 4
Leifert, D.; Studer, A. Angew. Chem. Int. Ed. 2020, 59, 74.

Contents

1. Introduction of persistent radicals
2. Site-selective C-H functionalization by thianthrenation
I. Ritter’s first work
II. Mechanistic insight into site-selectivity
3. PTH catalyzed C(sp3)-O formation
4. Summary & Perspective

5

Ritter’s workü High para-selective C-H functionalization
ü No need for directing groups
ü Arylthianthrenium salts as syntheticallyversatile linchpins
Ritter, T. et al., Nature. 2019, 567, 223.

6

BackgroundSite-selective aromatic C-H functionalization
2012. Yu
2017. Chattopadhyay

J.-Q., Yu. et al., Nature 2012, 486, 518.
Chattopadhyay, B. et al., J. Am. Chem. Soc.
2017, 139, 7745.
J.-Q., Yu. et al., J. Am. Chem. Soc. 2020, 142,10571.

Chelation-assisted site-selectivity requires particular directing group orsubstitution patterns.
No report can introduce synthetically useful linchpins.

7

BackgroundSite-selective aromatic C-H functionalization
MeMe MeO

MeO

H

Br

B

R

R
Brominationelectronic control

R
Borylation
steric control

R = Etp:o = 6:1
(NBS, HFIP, rt)

p:m = 2:1
(Ir cat., B2pin2,hexane, 85 ℃)

Site-selective bromination and borylation of undirected arenes ischallenging.
Ritter, T. et al., Nature. 2019, 567, 223.
Itami, K. et al., J. Am. Chem. Soc. 2015, 137, 5193.
8

BackgroundPara-selective TEDArylation by Ritter

ClNClHFN

BF4Ru(bpy)3PF6Pd(II) complex

N

BF4

MeCN

F
Selectfluor

N

BF4
BF4F
p : o > 99 : 1ClNN• TEDA dication with high electron affinity• Arene-to-radical charge transfer inradical aromatic substitution

TEDA2+･

Highly site-selective but not synthetically useful
Ritter, T. et al., Nat. Chem. 2016, 8, 810.
9

Background
Pyridinium radical cation
NOTf
NRarene
1.0 equiv.

EtEt

1. Ru(bpy)3PF6 cat.
MeCN, visible lightNH2

2. aminolysis

OTfR

1.5 equiv.
NviaREt

electron-rich R = OAc o:m:p = 24 : 21 : 30
electron-poor R = NO2 o:m:p = 23 : 49 : 19

Highly exergonic radical addition with an early TS→ Small electronic bias leads to low site-selectivity.
Ritter, T. et al., Angew. Chem. Int. Ed. 2019, 58, 532.

10Hypothesis• High endergonic radical addition with a late transition state• Larger electronic difference leads to higher selectivity

Electrophilic persistent sulfur-based radicals
ü No deleterious side reactions
ü An endergonic radical addition with a late TSSSThianthrene radical cation
Studied from 1970s by Shine et al• Persistent radical• Sulfonium salts as versatile intermediates
Ritter, T. et al., Nature. 2019, 567, 223.
11

Previous study about thianthrene radical cations
Para-selective thianthrenation
SSSS

R
ClO4

R = OMe, MeS
H

MeCN or MeNO2or neat, rtS
R
1:1
Almost quant. (R = OMe)

Electrophilic addition of thianthrene radical cation or dication
Shine, H. J. et al., J. Org. Chem. 1971, 36, 2923.

×Limited to electron-rich arenes
×Low functional group tolerance
×No synthetic utility
×No detailed investigation towards the selectivity
12

Reaction design
FH

R

TFT (1-3 mol%)
TFTSO (1.0 equiv.)
TFAA (3.0 equiv.)
HBF4OEt2 (1.1- 4.5 equiv.)
MeCN, 0-25 ℃
1-24 h

F

S
S

F
F

F

S

F

F

O
S

F

S

F

F

S

TFT

TFTSO

bench-stable
Rp:o>500:1, p:m > 200:1

13F
F

Reaction design

ü A large substrate scope (electron-rich ~ electron-deficient arenes)ü High site-selectivity (R = Et, p:o>500:1, p:m > 200:1)
ü Monofunctionalization due to an electron-deficient sulfonium groupü Not sensitive to O2 and traces of H2O
ü Stable thianthrenium salts

14Application -1- cross-coupling
Previous cross-coupling :Arylalkyl sulfonium salts were not tolerant of nucleophiles.
R SnnBu3

Aryl/Heteroaryl
Alkenyl
BenzylSPd cat.

R B(OH)2R

Aryl/Heteroaryl
Alkenyl
BenzylNi cat.

RZn

Liebeskind, L. S. et al., J. Am. Chem. Soc. 1997, 119, 12376.
SMeR
Ar

B2pin2

OTfBpinPd cat.
ArYorimitsu, H. et al., ACS Catal. 2018, 8, 579.

This work : Pd-catalyzed cross-coupling
FFF

SFS

FS

FS
Pd0Ln

R

LnPdII
Foxidativeaaddition

ü More stable structureü More resistant to nucleophiles
ü Faster oxidative addition
reactivity than ArBr and ArOTf→ Chemoselectivity

F15R

Application -1- cross-coupling
Carbonylation

Suzuki coupling

Sonogashira coupling

OMeOOEt

Pd-catalyzed
cross-coupling

N

91 %

90 %

95 %

Negishi coupling

Heck reaction

Sulfonylation

MePh

TFTO

nC H
4 9

BF4O

pyriproxyfen
59 %

78 %

O OSPh86 %78 %Chemoselectivity
OTf

OTfMeO

B(OH)2

iPrOH/dioxane

BF4TFT

Pd(dppf)Cl2
K3PO4
MeO

50 ℃

92 %
MeO

O
TFT

Br
BF4B(OH)2

Pd(dppf)Cl2
K3PO4O
MeO

Br

iPrOH/dioxane

50 ℃

96 %

16

Application -2- photoredox catalysis
Borylation
MeO

MePhotoredox
catalysis

N

O

TFT

O

BF4O

Chemoselectivity

Ru(bpy)3(PF6)2
450 nm

NEt2
I
O

O
I

B

Phosphorylation

MeMeO

O
P

Me

69 %

Pseudohalogenation

Chlorination

Iodination

SCF3

ClI

53 %

53 %

66 %

NEt21) Thianthrenation
2) Cu(MeCN)4BF4, LiCl,
CF3CO2H,Ru(bpy)3(PF6)2 (cat.)
450 nm, MeCN

IO

O
I
BuClAmiodarone

O
50 % (2 steps)

I

TFT

OPh58 %O

BF4NOPh76 %Bu
H

Cynation

CuCN
NBu4CNRu(bpy)3(PF6)2 (cat.)
MeCN/zDMSO
450 nm

I

NC

83 %

ü Transformations withvarious nucleophiles
ü Tolerant of arylhalides
17

Reaction mechanism
O
F

F

S

F

S

F

F

S

F

O

TFAA
O
S

CF3CO2

Radical cation
CF3F
F

F

H

F

S

F

F

S

S

Uncertain step

R

F

S

F

F
F
TFT

F

S

F

F

S

H

F-H
Irreversible
deprotonation R

R
Dication adduct• Radical cations : supported by EPR• Electrochemical oxidation gave the similar result.
• The Hammet analysis supports a cationic intermediate and ρ = -11indicates a late TS.
• The step of dication adduct formation is uncertain.

18

Application – various functionalization
C-N couplingThiolation

CNSCF3

69 %

53 %

NN

MeCyanation

NPC

NOO

TT/TFT
O

59 %

CF3OH

F

40 %

49 %

52 %

BF4

MeDeuteration Tritiation
OPd cat.

NO

2H

3H

TT/TFT
98 %OFluorination

Trifluoromethylation Hydroxylation

26.6 Ci mmol-1

Alkylation
SiMe390 %

O
72 %

BF4

Ritter et al., Nature. 2019, 567, 223.
Nature 2021, 600, 444.
J. Am. Chem. Soc. 2021, 143, 7909.
Synlett. 2022, 33, 339.
19

Contents

1. Introduction of persistent radicals
2. Site-selective C-H functionalization by thianthrenation
I. Ritter’s first work
II. Mechanistic insight into site-selectivity
3. PTH catalyzed C(sp3)-O formation
4. Summary & Perspective

20

Wang’s report
Wang’s para-selective C-H functionalization using phenoxathiine or thianthrene
just several months after Ritter’s.
XHBpinSulfoxide (TTSO or POSO)Tf2O(Bpin)2, DMAP
4CzIPN (5 mol%)

SOTf

DCM, - 40 ℃ to rt
R

MeCN, rtBlue LED

RROOSSSOTTSO (X = S)POSO (X = O)

R = Me
X = S, 97 %, p : o = 95.3 : 1.0
X = O, 98 %, p : o = 76.8 : 1.0

ü High para-selective borylation by a transient mediator approachü One-pot synthesis
× Electron-deficient arenes (X = Cl, Br, CO2Me, COMe, CF3)
Wang, P. et al., Sci. China Chem. 2020, 63, 336.

21

Wang’s mechanistic study

What determines high site-selectivity ?
• Sulfoxide screening→ Steric effect (partially)• EPR experiment→ Radical cation intermediates
However,
low concentration didn’t afford TM.
Heterolysis What is a real reactive species ?

DFT calculations→ A larger free energy difference
between ortho and para intermediates
was detected in case of dications.

Wang, P. et al., Sci. China Chem. 2020, 63, 336.

22

Wang’s mechanistic study

Mechanism
1. Heterolysis of sulfide ditriflate
2. Highly electrophilic dication reacts with toluene
3. Deprotonation
Para-selectivity• High electrophilicity of the sulfide dications• The favorable para-intermediate minimizes the electrostatic
repulsions.
23

Ritter’s mechanistic study
2021 Ritter unraveled the origin of the site-selectivity.

4 : toluene

Reactive species …TT+-TFA or TT2+
Ritter, T. et al., J. Am. Chem. Soc. 2021, 143, 16041.

24

Different thianthrenation protocols

Different conditions gave the similar selectivity.
→ The selectivity is determined at the step after formation of
a common Wheland intermediate.

25

Source of p/m & p/o selectivity

The p/m selectivity is determined by the electronic effectand predicted by the Hammet value ρ,
but the p/o selectivity is not in the case.

26

Source of p/m & p/o selectivity
Different p/o selectivity between bromination and thianthrenation→ The size of a substituent…steric effectIntermolecular competition experiment
Selectivity of toluene over mesitylene+ KIE>1→ Deprotonation is slower at themesitylene-based Whelandintermediate.

27

Computational study• The TSs of deprotonation are early TS, which are more SM-like.
• The high energy differences rationalize the exquisite para-selectivity.
• The reversible interconversion enables all o, m-I to generate p-I.
28

Comparison of other sulfoxides• The reversible homolysis can be explained by the stability of thepersistent thianthrene radical cation.
• TFT, TT, and PXT shows reversible 1e- oxidation, which means
persistent radical formation and a primary KIE, which means
reversible Wheland int. formation.
29

Guideline 1
The energy of Wheland intermediates

Energy of Wheland intermediates
Halogenation : electronic control
Borylation : steric control
Thianthrenation : electronic & steric control→ High para-selectivity30

Guideline 2
TS resembles Wheland int. in the sds: Late TS for electrophilic addition or early TS for deprotonation• Thianthrenation : The early TS in the selectivity-determining step
resembles Wheland intermediates.
→ The energy difference in Wheland int. contributes to selectivity.

31

Guideline 3
Reversible electrophilic additionp/m = 54 : 1
p/o = 162 : 1③②①
persistent radical

32

Contents

1. Introduction of persistent radicals
2. Site-selective C-H functionalization by thianthrenation
I. Ritter’s first work
II. Mechanistic insight into site-selectivity
3. PTH catalyzed C(sp3)-O formation
4. Summary & Perspective

33

Photoredox-catalyzed C(sp3)-O formation
OR1OH

R2R3NOOO

Photoredox catalyst
R4Blue LED

R1
R2R4O
R3R6R5R6 R5Ph
N
Photoredox catalyst =S
Phenothiazine structure

Ohmiya, H. et al., J. Am. Chem. Soc. 2020, 142, 1211.

34

BackgroundC(sp3)-X-C(sp3) formation
Conventional methods : Alkylheteroatom nucleophile & alkyl electrophile• Nucleophilic substitution
× Functional group tolerance (SN2, SN1)
× Not tolerant of sterically demanding substrates (SN2)• Transition-metal catalysis
× Slow oxidative addition
× β-hydride elimination instead of reductive elimination

This work• Radical-polar crossover (RPC) reaction
R-e-R35

RPC reaction
1993 Murphy

RPC catalysis−N2tetrathiafulvalene
Ovia

J. Chem. Soc., Chem. Commun. 1993, 295.

• TTF as an RPC catalyst• Radical to cation by trapping TTF･+• Persistent radical effectTowards C(sp3)-O-C(sp3) formation,
× Low reducing ability of TTF: Eox = −0.2 V vs SCE in MeCN
→ Strong redox property of organosulfide RPC catalyst
by visible light excitation

36

Hypothesis
ArN
S
N-Ar-phenothiazine(PTH)• Excitation in the UV-vis area (λmax = 320 nm)• High reduction potential (Ar = Ph, E1/2*= − 2.1 V vs SCE)
• Persistent radical cation

Alkylsulfonium salt is formed
from alkyl radical and PTH
radical cation.

37

Optimization• The extension of π-conjugation or the introduction of anelectron-deficient group→ PTH1 is the best photocatalyst.
• Ir or Ru photocatalyst gave lower yield.
38

Substrate scopeü Access to sterically hindered ether compounds
ü Tertiary benzyl groups afforded high yield due to the stabilizationof benzyl carbocations.
39

Substrate scopeü An alkyl halide and olefin were compatible.
ü Acetonide- and Boc- protecting group were not removed.
ü Chemoselectivity of the primary alcoholü Water, amines, and thiol were also used as nucleophiles.

40Mechanistic Study
1,2-Hydride shift

The intermediate

1,2-Carbocation rearrangement• The intermediacy of alkylsulfonium or free carbocation
Radica-radical coupling or single electron oxidation• Lower yield when PC without S was used
• PTH･+ derivatives E1/2 =0.42-1.02 V vs SCE> tBu E1/2ox =0.09 V vs SCE• PRE for oxidation of transient alkyl radical
More plausible ?

41

Contents

1. Introduction of persistent radicals
2. Site-selective C-H functionalization by thianthrenation
I. Ritter’s first work
II. Mechanistic insight into site-selectivity
3. PTH catalyzed C(sp3)-O formation
4. Summary

42

SummarySX

X = S, O, N

• Ritter’s work : High site-selective C-H functionalization
ü Stability of the persistent radical enables the reversible interconversion.

• Ohmiya’s work : Photoredox-catalyzed C(sp3)-O formation
ü The persistent radical selectively oxidizes a transient alkyl radical.
ü Extended π-conjugation renders PTH a photoredox catalyst.
OR1OHNR2 R3OOPhO

Photoredox catalyst
R4R6 R5Blue LED

R1R2R4O
R3R

R56N
Photoredox catalyst =S
Phenothiazine structure43PerspectiveIn order to make C-H thianthrenation more convenient,
it is important to realize the reactions. with thianthrene catalysts­2e-SSFG

STT

SH

R

TT to TT•+ = 1.21 V vs SCETT•+ to TT++ = 1.74 V vs SCE
Ritter, T. et al., Angew. Chem. Int. Ed.
2020, 59, 5626.

RRStrategy• 2e- oxidation of thianthrene by external strong oxidants• Thianthrene derivative itself as PC
towards my next research seminar

44