development of transition metal-based catalytic system for c–f bond … · 2018. 3. 26. · the...

Development of Transition Metal-Based Catalytic System for C–F Bond Activation

via Fluorine Elimination

発表者　渡部陽太指導教員　市川淳士

フッ素脱離による炭素–フッ素結合活性化のための遷移金属触媒系の開発

Chapter 1 General Introduction

Chapter 2 Nickel-Catalyzed Defluorinative Couplings of 1,1-Difluoro-1-alkenes with Alkynes

　　　　　Chapter 3 Rhodium-Catalyzed [4 + 2] Cyclization of 　　　　　 1,1-Difluoro-1-alkenes with Biphenylenes

Chapter 4 Silver-Catalyzed Intramolecular Defluoroamination of　　　　　 β,β-Difluoro-o-sulfonamidostyrenes

Chapter 5 Nickel-Catalyzed Site-Selective Difluoroallylation of Indoles with 2-Trifluoromethyl-1-alkenes

Chapter 6 Conclusions

Table of Contents

Vinylic C–F Bond Activation

C–F Bond Activation

Allylic C–F Bond Activation

Pauling, L. The Nature of the Chemical Bond and the Structure of Molecules and Crystals: An Introduction to Modern Structural Chemistry, Cornell University Press, Ithaca, NY, 1939.

F

F cat. M

R

F cat. MFF F R

&

&

&

C Xcat. M

C R

X

HCNO

98.883.169.784.0

BDE/ kcal mol–1 X

FClBrI

105.478.565.954.4

BDE/ kcal mol–1

BDE : Bond dissociation energy (C–X).

M

C–F BondCleavage

(Oxidative Addition )

R

FF

M F BondFormation

M’R

F

F &

Vinylic C–F Bond Activation via Oxidative Addition

F

F

F F

Pd

F

cat. Pd2(dba)3

LiITHF, 40 °C, 2 h

Ogoshi, S. et al. J. Am. Chem. Soc. 2011, 133, 3256.Ogoshi, S. et al. Eur. J. Org. Chem. 2013, 443.(ArB); Organometallics 2014, 33, 3669.(ArSi)

FFZnPh

IF FF

F

F

F

Pd

cat. PdCl2dppp

THF, reflux, 48 h

Tamao, K. et al. Synlett 2005, 1771.cat = Ni, ArB: Cao, S. et al. Org. Biomol. Chem. 2015, 13, 7389.

ZnCl

F

BondFormation

BondFormation

F

Ar

C–F Bond Activation via Fluorine Elimination

M

C–F BondCleavage


R

FF

M F BondFormation

M’R

F

F &

◆ α-Fluorine Elimination

◆ β-Fluorine Elimination

◆ Oxidative Addition

M

FF

RC–F BondCleavage

(α-Fluorine Elimination )

MF

R

FR’

R’

M F

FR C–F BondCleavage

(β-Fluorine Elimination )

–

R

FMF

C–F Bond Activation via Fluorine Elimination

M

C–F BondCleavage


R

FF

M F BondFormation

M’R

F

F &

◆ Oxidative Addition

◆ α-Fluorine Elimination

◆ β-Fluorine Elimination

M

FF

RC–F BondCleavage

(α-Fluorine Elimination )

MF

R

FR’

R’

M F

FR C–F BondCleavage

(β-Fluorine Elimination )

–

R

FMF

F

F R’MR

BondFormation

MR

BondFormation

F

F

Insertion + Fluorine Elimination

Bond Formation + Fluorine Elimination

Ph+ Ph X

cat. Pd(OAc)2NEt3

X = Br or I

DMF, 115 °C β-FluorineEliminationInsertion

Heitz, W.; Knebelamp, A. Makromol. Chem., Rapid Commun. 1991, 12, 69.

F

F

Pd F

FPhPh Ph

Ph

F

Ln

CF2

Ph

NXcat. Pd(PPh3)4

PPh3

DMA, 110 °C

N

Pd

FF

Ph

N

Ph

F

β-FluorineElimination

Ichikawa, J. et al. Chem. Commun. 2005, 4684.

CF2

Ph

N

InsertionX

X = OCOC6F5

PdX

Ph

NXcat. Pd(PPh3)4

PPh3

DMA, 110 °C

N

PhN

Phβ-FluorineElimination

Ichikawa, J. et. al. Chem. Commun. 2006, 4425.

Ph

N

Insertion

X = OCOC6F5

PdX

F3C F3CPd

F3C F2C

X

Carbometalation + Fluorine Elimination

Bond Formation + Fluorine Elimination

Oxidative Cyclization + Fluorine Elimination


Carbo-metalation

CF2 CF2

Pd2+

Ichikawa, J. et al. Org. Lett. 2007, 9, 4639; Org. Lett. 2015, 17, 1126; J. Fluorine Chem. 2015, 179, 106.

Insertion


R

CF3

R'

R'

F

R

R'

R'

NiF2CR

R'

R'β-FluorineElimination R

CNiF

R'

R'F2

F

OxidativeCyclization

Ichikawa, J. et al. Angew. Chem., Int. Ed. 2014, 53, 7564; Dalton Trans. 2015, 44, 19460.See also: ACS Catal. 2015, 5, 5947.

cat. Ni+

FFF

Pd+

cat. Pd2+

Strategy: Bond Formation + Fluorine Elimination

M F M R

InertSpecies

C F C R

Bond FormationFluorine Elimination

M R

ActiveSpecies

Ni

R

R’

F F

β

α Ni

FF

R

R’R’

R

RhFF

X

N

FF

AgR

R’

β

β

Ar

R

F

F


Insertion

Amino-metalation


R’

R

R’

R

CF3 Ni

Metala-cyclopropanation

CF3R

β

α

β

β

ββ

Chapter 2

Chapter 3

Chapter 4

Chapter 5

NHR’

CF2

R

Regeneration of Catalytic Species by Fluoride Captor

Ni–X

Ni–FNi–ClNi–BrNi–I

440372360293

BDE/ kJ mol–1

BDE : Bond dissociation energy (C–X).

Si–FLi–FB–F

576577732

BDE/ kJ mol–1m F

H NiII F

m R

H NiII R

m F

HF

Ni0

HR

ActiveSpecies

InertSpecies

BDE: Bond dissociation energyLuo, Y. R. Comprehensive Handbook of Chemical Bond Energies, CRC Press, Boca Raton, FL, 2007.

Strategy: ① Bond Formation + Fluorine Elimination ② Fluoride Captor

M F M R

InertSpecies

C F C R

Bond FormationFluorine Elimination

M R

ActiveSpecies

m R’ m F

Ligand Exchange

①

②

Ni

R

R’

F F

β

α Ni

FF

R

R’R’

R

RhFF

X

N

FF

AgR

R’

β

β

Ar

R

F

F


Insertion

Amino-metalation


R’

R

R’

R

CF3 Ni


CF3R

β

α

β

β

ββ

Chapter 2

Chapter 3

Chapter 4

Chapter 5

NHR’

CF2

R







Table of Contents

Ikeda, S.; Saito, Y. et al. J. Am. Chem. Soc. 1999, 121, 2722.


Chem.—Eur. J. 2015, 21, 13225.

OO R

R

RR

R

R+

ONiIIcat. Ni

R

R

ONiII

R

R

RR


R

R

OxidativeCyclizationR'

R'

F

F

NiIIR'

R'

FF F

R’R’

R’ R’

cat. Ni NiIIF

F

R’

R’R’

R’

R'

R' αα

α-FluorineElimination

F

F+

Ph

Ph

F

Ph Ph

PhPh(0.50 mmol)(2.3 mmol)

Ni(cod)2 (5 mol%)PCy3 (5 mol%)

Toluene, 40 °C, 22 h

8%

Ni-Catalyzed [2 + 2 + 2] Cyclization

NiIIF

F

R

RR

RR

R R

R

HH

FNiII

FF

R R

RR

R R

R R

F

F

+cat. Ni0

H

H

HF

H NiII F


αα

F

F+

Ph

Ph

F

Ph Ph




8%

Ni-Catalyzed [2 + 2 + 2] Cyclization

NiIIF

F

R

RR

RR

R R

R

HH

FNiII

FF

R R

RR

R R

R R

F

F

+cat. Ni0

H

H


αα

HR

H NiII F

m R

H NiII R

m F

Screening of Fluoride Captor

BDE: Bond dissociation energyLuo, Y. R. Comprehensive Handbook of Chemical Bond Energies, CRC Press, Boca Raton, FL, 2007.

F

F+

Ph

Ph

F

Ph Ph



+

Toluene, 40 °C, 9–22 h

H NiII Fm R (1.0 equiv)

Ni–F : 440 kJ mol–1

HR m R

H NiII R

m F

Entry Yield / %

1

2

3

4a

HSi Et3

Li Oi-Pr

B Et3

B Et3 + Li Oi-Pr

20

37

44

84 (82)

m R

19F NMR yield (PhCF3). Isolated yield in parentheses. a Alkyne = 2.3 mmol.

BDE / kJ mol–1

Si–F 576

Li–F 577

B–F 732

(B–F 732)

Substrate ScopeNi(cod)2 (5 mol%)

PCy3 (5 mol%)

B Et3 (1.0 equiv)Li Oi-Pr (1.0 equiv)

Toluene, 40 °C

RR

R RF

F R

R+

F

(2.3 mmol)(2.3 mmol)

F

82% (12 h)

F

R1

R1R1

R1

F

R2 R2

R2R2

R1 = Me Bu OMe CF3

81% (12 h)79% (12 h)80% (12 h)76% (15 h)

R2 = Me Cl

72% (16 h)45% (12 h)

F

R3 R3

R3R3

R3 = Me CO2t-Bu CH2OBn CH2OTHP CH2OTMS

F

59% [84:16]a (18 h)a Regioisomer ratio (19F NMR).

60% [85:15]a (14 h)

79% (15 h)39% (16 h)58% (14 h)67% (14 h)68% (14 h)

F

MeO OMe

Application: Construction of Planar π-System

F F

FeCl3 (30 equiv)

DCE–MeNO2 (5:1)0 °C, 1 h

n-Bu

n-Bu n-Bu

n-Bu n-Bu

n-Bu n-Bu

n-Bu

74%

F

F R

RR = C6H4p-n-Bu

+

cat. Ni

(Δ[3]/Δt)t=0 ∝ [1]0, [2]0, [Ni]0

Mechanistic Study: Kinetics

y = 1.02x – 3.84 R2 = 0.99

y = 1.09x – 2.72 R2 = 0.99

y = 1.12x – 4.15 R2 > 0.99

Ni(cod)2, PCy3 (0.013–0.11 M)

(BEt3, i-PrOLi)Toluene, 40 °C, 5–15 min

PhPh

Ph PhF

F Ph

Ph+

F

2(0.20–0.90 M)

1(0.30–1.0 atm)

3

log

{(Δ[3

]/Δt) t

=0}

log

{(Δ[3

]/Δt) t

=0}

log

{(Δ[3

]/Δt) t

=0}

Mechanistic Study: Kinetics

(Δ[3]/Δt)t=0 ∝ [1]0, [2]0, [Ni]0

IIcat. Ni

3

Ni

Ph

PhII

FF

or

Ph

Ph

1

2


αα ββPh

Ph

2

F

F

NiPh

Ph

FF

F

Ph

PhPh

Ph

Confirmation of Regioselectivity


cat. Ni

F

F Ph

Ph+ NiIIPh

Ph

FF

NiIIPh

Ph

orF

Fα β


F

F

Ph

EtO2C

EtO2C Ni(cod)2 (100 mol%)PCy3 (100 mol%)


Ph

Ph

(1.0 equiv)

F

Ph Ph

Ph

60%

EtO2C

EtO2C

+

NiIIEtO2C

EtO2C

Ph

FF

NiII

PhPh

Ph

EtO2CEtO2C

F F

Ph Ph

PhEtO2C

EtO2C FNiII


Fαααα

Ph

Ph

Proposed Mechanism

H NiII HCH2=CH2

Ni0

H NiII F


β-HydrogenElimination

R

R

H NiII Et

ReductiveElimination

LigandExchange

NiII

Ni

R

R

R

RR

R

HH

FNi

R

RR

R

H H


+

i-PrO B Et3

i-PrO B Et2F

R

RInsertion

FF

RR

F

F

F

FF

R

R

IILi

Li


F

αα



R'

R'

F

F

NiIIR'

R'

R

FF Ar

ArF

R'R'

H

NiIIR'

R'

FF

R = H

R = Ar

F

R’R’

R’ R’

cat. Ni

cat. Ni


α NiIIF

F

R’

R’R’

R’

R'

R'

ArF

R'R'

NiIIF

B R’’

– BF

H HH

Montgomery, J. et al. J. Am. Chem. Soc. 1997, 119, 9065.


cat. Ni(cod)2

NiOPh

IIOxidativeCyclization

Ph

O Ph

Ph

HO Ph

PhZnMe2Ph

H

O

Ph

Ni

ZnMe

MeMe

60%

Ni-Catalyzed Hydroalkenylation of Alkynes

FR1

R3

R2

H

B Et3 (1.5 equiv)Li Oi-Pr (1.5 equiv)

Toluene, RT

F

FR1

R3

R2

(2.0 equiv)

Ni(cod)2 (10 mol%)PCy3 (10 mol%)ZrF4 (10 mol%)

F

Pr

H

Pr

RF

Pr

H

Pr

F

Pr

H

PrS

F

Me

H

i-Pr

Ph

F

Pr

H

PrO

F

Et

H

Et

PhF

Me

H

Ph

Ph

62% (40 °C, 12 h)

F

Pr

H

Pr

R = PhR = HR = i-Pr R = Cl

89% (24 h)77% (11 h)62% (18 h)84% (20 h)

86% (20 h)

85% (12 h)77% (10 h)

33%a (15 h)64%a (12 h)80% (17 h)

a: Single isomer.

Ph

(Δ[3]/Δt)t=0 ∝ [1]0, [2]0, [Ni]0

y = 1.08x – 3.53 R2 = 0.99

y = 0.910x – 3.09 R2 = 0.99

y = 1.01x – 3.64 R2 = 0.99

Determination of Reaction Order

Ni(cod)2, PCy3 (5.0–50 mM)

(ZrF4)BEt3, i-PrOLi

Toluene, RT, 10 min

F

FPr

Pr+

2(0.06–0.25 M)

1(0.12–0.30 M)

3

F

PrPr

H

log

{(Δ[3

]/Δt) t

=0}

log

{(Δ[3

]/Δt) t

=0}

log

{(Δ[3

]/Δt) t

=0}

Proposed Mechanism


FAr

R

NiII

R

H

i-PrOB Et3i-PrOB Et2FLi Li

+

FAr

R

H

R

BF Et3Li

O+ or

Ni0NiII

ArF F

R

R

FAr

R

NiII

R

F

R

R

F

FAr +

LigandExchange



Summary

Chem.—Eur. J. 2015, 21, 13225.

Synthesis 2017, 49, 3569.



R'

R'

F

F

NiIIR'

R'

R

FF Ar

ArF

R'R'

H

NiIIR'

R'

FF

R = H

R = Ar

F

R’R’

R’ R’

cat. Ni

cat. Ni


α NiIIF

F

R’

R’R’

R’

R'

R'

ArF

R'R'

NiIIF

B R’’

– BF

H HH







Table of Contents

Insertion + β-Fluorine Elimination

M = Ni: Eisch, J. J. et al. Organometallics 1985, 4, 224.M = Rh: Jones, W. D. et al. Organometallics 1997, 16, 2016.

(other M = Ir, Co, Pt, Fe, Pd)

Insertion

ββ-FluorineElimination

cat. M

F

F

R

R FM

RFF

R

MFF

MR R

M

RRR

R

MF

HR

F

δ–δ+

δ–δ+

&

Insertion

Rh-Catalyzed [4 + 2] Cyclization

Entry Yield /%

1

2

3

4

5

[RhCl(cod)]2[IrCl(cod)]2Ni(cod)2

Pd(PPh3)4

Pt(PPh3)4

80 (81)

N.D.

N.D.

N.D.

N.D.

Metal

19F NMR yield (PhCF3). Isolated yield in parentheses.

(x mol%)

(50)

(50)

(100)

(100)

(100)

F

FH

RR F

+

(1.0 equiv)

Metal

Toluene, reflux, 12 h

R = C6H4p-Ph


cat. RhI

F

F+

H

R

R FRh

RFF

R

Rh FFX

XIIIIII

Insertion

RRhH F

X

III


Entry Yield /%

1

2

[RhCl(cod)]2[RhCl(cod)]2

80 (81)

10 (9)

Metal


(x mol%)

(50)

(5)

F

FH

RR F

+

(1.0 equiv)

Metal


R = C6H4p-Ph


cat. RhI

F

F+

H

R

R FRh

RFF

R

Rh FFX

XIIIIII

Insertion

R

HF

RhH F

X

III


Entry Yield /%

1

2

[RhCl(cod)]2[RhCl(cod)]2

80 (81)

10 (9)

Metal


(x mol%)

(50)

(5)

F

FH

RR F

+

(1.0 equiv)

Metal


R = C6H4p-Ph


cat. RhI

F

F+

H

R

R FRh

RFF

R

Rh FFX

XIIIIII

Insertion

R

RhH F

X

III

HR m Rm F

RhH R

X

III

Screening of Additives[RhCl(cod)]2 (5 mol%)Additive (x equiv)F

R FR

H F+

R = C6H4(p-Ph)

Toluene, reflux

(1.1 equiv)

1

2

3

4

5

6

7

8

–

AgOTf (1.0)

CuOTf•C6H6 (1.0)

Cu(OTf)2 (1.0)

Me3SiOTf (1.0)

Cu(OTf)2 (0.05) + LiOTf (1.0)

Cu(OTf)2 (0.05)

LiOTf (1.0)

4

12

12

12

12

4

4

12


10

12

53

50

35

80

20

10

Yield / %Time / hAdditive (equiv)Entry

Substrate Scope

F

80%

Ph

F

57%a

H F

75%d

F

58%c

a: PhB(nep) (10 mol%) was added. b: 19F NMR yield. c: [RhCl(cod)]2 (50 mol%) was used without Cu(OTf)2 and LiOTf. d: Excess amount of 1,1-difluoroethylene was used.

F

54%a,b

i-Pr

Ph

F

FH

RR F

+

(1.1 equiv)

[Rh(cod)2]OTf (10 mol%)Cu(OTf)2 (5 mol%)LiOTf (1.0 equiv)


Elucidation of C–F Bond Activation Pathway

cat. Rh

F

+

R FH F

R

H FFR

– HF

Rh

RFF

XIII

β-FluorineElimination Rh

FH

R

FXIII

– HRhXF



[RhCl(cod)]2(50 mol%)

Toluenereflux, 12 h

F

+

(1.5 equiv)

H F

TsO F

TsO F

H

H FFTsO

Rh

OTsFF

XIII


FH

TsO

FXIII

– TsORhXF


– HF

[RhCl(cod)]2(50 mol%)

Toluenereflux, 12 h

F

+

(1.5 equiv)

H F

TsO

96%

F

TsO F

N.D.

H

N.D.

H FFTsO

Rh

OTsFF

XIII


FH

TsO

FXIII

– TsORhXF


– HF


Plausible Mechanism

RhH FXIII

Cu(OTf)2

FCuOTf

Li OTf

LiFOxidativeAddition

Insertion



H OTf


Insertion

Ligand Exchange

XRhI

F

F

R

R

Rh FF

Rh

δ–δ+

δ–δ+X

Rh

RF

FRhF

HR

F

R F

RhH OTfXIII

XIII

III

III

III







Table of Contents

◆ Aminometalation

Aminometalation + β-Fluorine Elimination

◆ Carbometalation

Ichikawa, J. et al. Org. Lett. 2007, 9, 4639.; Org. Lett. 2015, 17, 1126.; J. Fluorine Chem. 2015, 179, 106.

Carbo-metalation

CF2cat. Pd2+BF3•OEt2 CF2

Pd2+ F

(CF3)2CHOHRT–reflux (60 °C)

FFPd+


ββNHTs

CF2

n-Bu

NTs

F

n-Bu

NTs

CF2

n-Bucat. M+

M+

NTs

Mn-Bu

FF

Hβ-FluorineElimination

Amino-metalation

Ag-Catalyzed Defluoroamination

19F NMR yield (PhCF3).

Entry Yield (%)

1

2

3

4

5

6

7

8

9

–

Pd(OAc)2

Pt Cl2Au Cl

Cu(OTf)2

Ag OTf

Ag BF4

Ag SbF6

Ag F

Catalyst

N.D.

N.D.

N.D.

1

1

6

7

0

N.D.

<

1

NHTs

CF2

n-Bu

NTs

F

n-Bu

NTs

CF2

n-Bu M+

H

Catalyst (10 mol%)

(CF3)2CHOH, reflux, 5 h

Screening of Fluoride Captor

NHTs

CF2

n-Bu

NF

n-Bu

Ts

AgSbF6 (10 mol%)Additive (x equiv)

(CF3)2CHOH, reflux, 5 h

Entry Yield / %

1

2

3

N.D.

31

N.D.

Additive (x equiv)


NN Si Me3

Me3SiO

Si Me3

OSi Me3

NSiMe3

Me3SiHN

Si Me3

4

5

6

52

47

quant. (99)

(1.0)

(1.0)

(1.0)

(1.0)

(2.0)

(1.0) slow addition (2 h)(BSA)

Mechanistic Studies: Role of BSAAgSbF6 (10 mol%)BSA (1.0 equiv)

NHTs

CF2

n-Bu

(CF3)2CHOH, reflux, 3 h NTs

F

n-Bu

99%* Slow addition over 2 h

No Reaction

NHTs

n-Bu

AgF (1.0 equiv)

(CF3)2CHOHreflux, 1 h

No ReactionBSA (1.0 equiv)

(CF3)2CHOHreflux, 5 h

CF2

NTs

F

n-BuBSA (1.0 equiv)

reflux, 2 h

62%

OSi Me3

NSiMe3

BSA

Mechanistic Studies: Role of BSA

NHTs

CF2

BuAgSbF6 (100 mol%)


F

Bu

25%

AgSbF6 (10 mol%)BSA (1.0 equiv)

NHTs

CF2

n-Bu


F

n-Bu

99%* Slow addition over 2 h

CF2

n-Bu

NHTs

NTs

n-Bu

F(1.0 equiv)

AgF

OSiMe3

NSiMe3

(1.0 equiv)

(CF3)2CHOHreflux, 20 min

reflux, 30 minO

NSiMe3Ag+

+ Me3Si–F 92% 80%Detected by 19F NMR

–

OSi Me3

NSiMe3

BSA

Proposed Mechanism

O

NSiMe3Ag+–

Amino-metalation

NTs

AgF

NTs

F

n-Bu

FF

Agn-Bu

OSi Me3

NSiMe3

O

NSiMe3

F–Si Me3NH

n-Bu

O

NSiMe3–


Ts

CF2

NTs

CF2

n-Bu Ag+

H

H

LigandExchange

Substrate Scope

NHR3

CF2

R2

NF

R2

R1 R1

R3

AgSbF6 (10 mol%)BSA (1.0 equiv)*

(CF3)2CHOH, reflux

* Slow addition over 2 h

NTs

F

n-Bu

99% (3 h)

NTs

F

n-Bu

99% (4 h)

NTs

F

n-Bu

98% (6 h)

NTs

F

n-Bu

53% (6 h)

Me

Me

EtO2C

NTs

F

sec-Bu

88% (3 h)

NTs

F

Me3Si

82% (5 h)

NTs

F

Bn

52% (5 h)a

NMs

F

n-Bu

32% (6 h)

R1 R3

NTs

F

n-Bu

81% (4 h)a

NTs

F

n-Bu

85% (3 h)a

ClMeO

NNs

F

n-Bu

NS

F

n-Bu

65% (6 h)

98% (3 h)

R2

a:AgF (20 mol%) was used instead of AgSbF6.

O2Mes

Human 5-HT6 receptor modulator

Antibacterial agent

Summary

Schachtman, D. P.; Shin, R. Y. WO 2007127923, (A2) 2007.Albany Molecular Research Inc. WO Patent 2011/44134, (A1) 2011.

Firestone, G. L. et al. U.S. Patent 2005/58600, (A1) 2005.

Chem. Lett. 2016, 45, 964.

NH

F

CO2HNS F

O O

N

HN

HN NHF F

FF

F

F

FF

F

F

Plant growth hormoneRegulated transcription factor

NHR3

CF2

R2

NF

R2

R1 R1

R3

cat. Ag+BSA

Amino-metalation

β-FluorineEliminationN

R3

CF2

R2 Ag+

(CF3)2CHOHH

R1







Table of Contents

Bond dissociation energy (BDE)

Metalacyclopropanation + β-Fluorine Elimination

/ kcal mol–1

C FHH

HC FH

F

HC FF

F

H

110 120 128

< <

F F FNu

F F

OxidativeAddition

M

MF

F

F

M Fm

Nu

MFF

F

F

F

M

Nu


– m–F

– M BondFormation

MNu

F

F

m


Ni-Catalyzed Difluoroallylation of Indoles

Nu


F F

F cat. Ni

NH

F

F+ NB

R1

R2

R2

R1

m

F F FNu

F F

OxidativeAddition

M

MF

F

F

M Fm

Nu

MFF

F

F

F

M

Nu


– m–F

– M BondFormation

MNu

F

F

m


Screening of Additives

CF3

(1.0 equiv)

+

(1.0 equiv)

NiCl2(dppf) (10 mol%)Additive (x equiv)

CPME, Conditions

Ph

NH N

H

CF2

Ph

CPME = Cyclopentyl methyl ether

1

2

3

4

5

6

–

B Et3 (1.5)

B Et3 + Li Oi-Pr (2.0)

B Et3 + Na Oi-Pr (2.0)

B Et3 + K Oi-Pr (2.0)

B (Oi-Pr)3 + Li Oi-Pr (2.0)

60 °C, 6 h

60 °C, 6 h

RT, 10 h

RT, 12 h

RT, 12 h

RT, 12 h


0

0

97

6

16

6

Yield / %ConditionsAdditive (equiv)Entry

(96)

Substrate Scope

CF3

+

NiCl2(dppf) (10 mol%)Lii-PrOBEt3 (2.0 equiv)

CPME, RT, 12 hNH

NH

CF2

R1R1

(1.1 equiv) CPME = Cyclopentyl methyl ether

NH

CF2

NH

CF2

96%

SiMe3

NH

CF2

69%a

NH

CF2

63%a

NH

CF2

53%a

Ph

NH

CF2

39%a,c

RR = H

MeCNCF3PhClAc

96%86%98%89%a

45%a

33%a

57%a,b

NC

a: 19F NMR yield (PhCF3). b: Reaction was conducted at 0 °C. c: Excess amount of 1,1,1-trifluoropropene (1.0 atm) was used.

H

Substrate Scope

CF3

+

NiCl2(dppf) (10 mol%)Lii-PrOBEt3 (2.0 equiv)

CPME, RT, 12 hNH

NH

CF2Ph

Ph

(1.1 equiv) CPME = Cyclopentyl methyl ether

R2

R2

NH

CF2

Ph

NH

CF2

Ph

MeO

38%a

NH

CF2

Ph

NH

CF2

Ph

80%a

OMe

MeOOMe

53%a

a: 19F NMR yield (PhCF3).

42%a

Mechanistic Study: Reaction of Nickelacyclopropane

19F NMR (470 MHz, C6D6): δ 108.2 (d, JFP = 10 Hz, 3F).31P NMR (202 Hz, C6D6): δ 23.4 (d, JPP =19 Hz, 1P), 34.2 (dq, JPP = 19 Hz, JPF = 10 Hz, 1P).

CF3

Ni(cod)2 (1.0 equiv)dppf (1.0 equiv)

Toluene, RT, 2 h

Ar

Ar = p-Ac(C6H4)

Ni

PP CF3

Ar

98%

Detected by 19F NMR

CF2Ni F

Ar

PP

N.D.


19F NMR (470 MHz, C6D6): δ 108.2 (d, JFP = 10 Hz, 3F).31P NMR (202 Hz, C6D6): δ 23.4 (d, JPP =19 Hz, 1P), 34.2 (dq, JPP = 19 Hz, JPF = 10 Hz, 1P).

N

B X3Li

X = Et or Oi-Pr

Li i-PrOB Et3 (1.1 equiv)

Toluene, RT, 30 minNH

(1.2 equiv)

RT, 16 hNH

F

F

Ar

73%

CF3


Toluene, RT, 2 h

Ar

Ar = p-Ac(C6H4)

Ni

PP CF3

Ar

98%Detected by 19F NMR


N B

N

F

FF

F

Ni

R R

H

NH

F

F

R

N

FNi

FF


– B–F – Ni


N

B X3Li

X = Et or Oi-Pr

Li i-PrOB Et3 (1.1 equiv)

Toluene, RT, 30 minNH

(1.2 equiv)

RT, 16 hNH

F

F

Ar

73%

CF3


Toluene, RT, 2 h

Ar

Ar = p-Ac(C6H4)

Ni

PP CF3

Ar

98%Detected by 19F NMR

Summary


F F

F cat. Ni

NH

F

F+ NB

R1

R2

R2

R1

&

N B

N

F

FF

F

Ni

R R

H

NH

F

F

R

N

FNi

FF


– B–F – Ni








Table of Contents

Conclusion: ① Bond Formation + Fluorine Elimination ② Fluoride Captor

① ②

FR

Lii-PrOBEt3

Lii-PrOBEt3

Cu(OTf)2LiOTf

OSi Me3

NSi Me3

CF3 NiCF3

R

NB–

X3Li+

β-Fluorine EliminationMetalacyclopropanationNH

FF

R1

cat. Ni

cat. Ni

cat. Rh

cat. Ag

cat. Ni

β-Fluorine Elimination

Ni

R

R’

F F

Ni

FF

R

R’R’

R

RhF

FX

N

FF

AgR

Ts

Ar

R

R

R’ R’

R

FAr

R

H

R’

NF

R

Ts

F

F



α-Fluorine Elimination

Oxidative Cyclization

Insertion

Aminometalation

Oxidative Cyclization

R’

R

R’

R

F

development of transition metal-based catalytic system for c–f bond … · 2018. 3. 26. · the...

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