yamashita m thesis pp - 筑波大学 · nu metal metal nu nu h nu h metal x metal hx h. 1....

含フッ素ヘテロ環構築を指向した遷移金属触媒

によるジフルオロアルケンの求電子的活性化法

氏　名　　山下茂之

指導教員　市川淳士�

1. Electrophilic Activation of Alkenes

orEE

E

Nu

E

Nu Nu

MetalNuMetal

Nu

Nu

H

NuH Metal

X Metal

HX H

1. Electrophilic Activation of Alkenes

orEE

E

Nu

E

Nu Nu

MetalNuMetal

Nu

Nu

H

NuH Metal

X Metal

HX H

Reversal of Reactivities

2. Application of Electrophilic Activation

NHBoc

OH

OBnMOMO OBn

cat. PdCl2(CH3CN)2

THF NBoc

OBnMOMO OBn

Miyazawa, M. et al. Org. Lett. 2000, 2, 16.

OMe

OMe

OMe

OMe

OMe

OMe

Au

cat. AuCl3

toluene

95%

Mamane, V. et al. J. Org. Chem. 2002, 67, 6264.

86%

NHBoc

OH

OBnMOMO OBn

Pd

n-PentNHTs

・

n-PentNHTs

n-PentBr

NHTs

TsN

Br

n-PentPd+

Pd・

72% (Z/E) = 93:7

cat. Pd(OAc)2

LiBrCu(OAc)2

K2CO3

MeCN

Jonasson, C. et al. J. Am. Chem. Soc. 2000, 122, 9600.

Br－

3. Electrophilic Activation of Difluoroalkenes

CF2CO2Me

CO2Me

SnCl4 (1.8 eq)

CH2Cl2 MeO2C CO2Me

F

88%

SnCl4Et3N

Taguchi, T. et al. J. Fluorine Chem. 2003, 123, 75.

Cl3SnF

FSO3H･SbF5(2 eq)

(CF3)2CHOH

H2O

82% Synthesis 2005, 39.

HCF2 CF2

H

FF

O

CF2CO2Me

CO2Me

F

FR

RElectron Poor Alkene

3. Electrophilic Activation of Difluoroalkenes

CF2CO2Me

CO2Me

SnCl4 (1.8 eq)

CH2Cl2 MeO2C CO2Me

F

88%

SnCl4Et3N

Taguchi, T. et al. J. Fluorine Chem. 2003, 123, 75.

Cl3SnF

FSO3H･SbF5(2 eq)

(CF3)2CHOH

H2O

82% Synthesis 2005, 39.

HCF2 CF2

H

FF

O

CF2CO2Me

CO2Me

F

FR

RElectron Poor Alkene

Metal

Difficult to Activate

4. Catalytic Electrophilic Activation of Difluoroalkenes

F

F R

R cat. MLn F

F R

RMLn

NuH

R

MLn-1R

F

NuF

－ MLn-1

－ SiF

F

Nu R

R

SiXH

SiX

(TfOH)TsHN

n-Bu

CF2 PdCl2 (10 mol%)Me3SiOTf (2.0 eq)

(CF3)2CHOHreflux, 24 h

HNO

n-Bu

86%

Chem. Lett. 2010, 39, 248.

－ HX

+

L

TsHN

n-BuPd

CF2

5. Fluoride Ion Scavenger

TsHN

n-Bu

CF2PdCl2 (10 mol%)

TsNF

n-BuBSA (1.0 eq)

(CF3)2CHOH

OSiMe3

NSiMe3(BSA)

F－

－Me3SiF

OSiMe3

NH

H+

5. Fluoride Ion Scavenger

TsHN

n-Bu

CF2PdCl2 (10 mol%)

TsNF

n-BuBSA (1.0 eq)

(CF3)2CHOH

OSiMe3

NSiMe3(BSA)

F－

－Me3SiF

OSiMe3

NH

H+

6. Remote Activation of Difluoroalkenes

R

F Fcat. MLn

SiX R

F F

MLn

NuH

－MLn-1－SiF－HX

R

CF F

R

F

MLn-1

Nu+

6. Remote Activation of Difluoroalkenes

n-Bu

Cr(CO)6 (1.0 eq)

Bu2O－THF, reflux, 36 h

CF2TsHN

R

F Fcat. MLn

SiX R

F F

MLn

NuH

－MLn-1－SiF－HX

R

CF F

R

F

MLn-1

Nu

n-Bu

CF2TsHN

Cr(CO)3

TsNF

n-Bu

1%

+

7. Late Transition-Metal Arene Complexes

Copper(I)－Arene η2- Complex Gold(I)－Arene η2- Complex

+

PF6－

+

Cl－

Tipton, A. A. et al. Inorg. Chem. 1999, 38, 2833. Zhang, Z,-Z. Inorg. Chem. 2006, 45, 1888.

Cu

N

S

S

AuNPPh2

N

8. Effect of Transition-Metal Catalysts

―1

2

3

4

PdCl2

NiCl2

PtCl2

AuCl

―

―

1

a) 19F NMR yield (PhCF3 as standard).

TsHN

n-Bu

CF2MXn (10 mol%)

TsNF

n-Bu

Entry MXn Yield (%) a

BSA (1.0 eq)

(CF3)2CHOHreflux, 5 h

7

8

6

5

AgOTf

AgBF4

AgSbF6

CuCl

47

71

79

22

Entry MXn Yield (%) a

8. Effect of Transition-Metal Catalysts

―1

2

3

4

PdCl2

NiCl2

PtCl2

AuCl

―

―

1

a) 19F NMR yield (PhCF3 as standard).

TsHN

n-Bu

CF2MXn (10 mol%)

TsNF

n-Bu

Entry MXn Yield (%) a

BSA (1.0 eq)

(CF3)2CHOHreflux, 5 h

7

8

6

5

AgOTf

AgBF4

AgSbF6

CuCl

47

71

79

22

Entry MXn Yield (%) a

8. Effect of Transition-Metal Catalysts

―1

2

3

4

PdCl2

NiCl2

PtCl2

AuCl

―

―

1

a) 19F NMR yield (PhCF3 as standard).

TsHN

n-Bu

CF2MXn (10 mol%)

TsNF

n-Bu

Entry MXn Yield (%) a

BSA (1.0 eq)

(CF3)2CHOHreflux, 5 h

7

8

6

5

AgOTf

AgBF4

AgSbF6

CuCl

47

71

79

22

Entry MXn Yield (%) a

9. Effect of Fluoride Ion Scavengers

TsHN

n-Bu

CF2AgSbF6 (10 mol%)

TsNF

n-Bu

Entry

3

4

5

6

1

2

Additive (X eq) Yield (%)a

a) 19F NMR yield (PhCF3 as standard).

OSiMe3

NSiMe3

(0)

(0.5)

(1.0)

(2.0)

―(1.0)

(1.0)

9b

37

73

68

29

b) 5 h.

Me3SiN N

Me3SiOSiMe3

Additive (X eq)

(CF3)2CHOHreflux, 2 h

9. Effect of Fluoride Ion Scavengers

TsHN

n-Bu

CF2AgSbF6 (10 mol%)

TsNF

n-Bu

Entry

3

4

5

6

1

2

Additive (X eq) Yield (%)a

a) 19F NMR yield (PhCF3 as standard).

OSiMe3

NSiMe3

(0)

(0.5)

(1.0)

(2.0)

―(1.0)

(1.0)

9b

37

73

68

29

b) 5 h.

Me3SiN N

Me3SiOSiMe3

Additive (X eq)

(CF3)2CHOH

reflux, 2 h

10. Reaction Scope

TsHN

R1

CF2AgSbF6 (10 mol%)

TsNF

R1

TsNF

n-BuTsN

F

H

TsNF

n-BuTsN

F

n-Bu

MeMe

45%84%

trace70%

(CF3)2CHOH

reflux, 4-24 h

BSA (1.0 eq)

TsNF

s-Bu

78%

TsNF

n-Bu

Cl16%

TsNF

n-Bu

OMe13%

TsNF

Et

30%

R2R2

11. Discussion 1

TsNF

EtTsN

F

H

trace30%

TsNF

s-Bu

78%

TsHN

R1

CF2

R2

11. Discussion 1

TsNF

EtTsN

F

H

trace30%

TsNF

s-Bu

78%

銀触媒はアレーン部を活性化

TsHN

R1

CF2

R2

12. Discussion 2

TsNF

n-BuTsN

F

n-Bu

MeMe

45%84%

TsNF

n-Bu

Cl

16%

TsNF

n-Bu

OMe

13%

High yield Low yield

TsHN

R1

CF2

R2

12. Discussion 2

TsNF

n-BuTsN

F

n-Bu

MeMe

45%84%

TsNF

n-Bu

Cl

16%

TsNF

n-Bu

OMe

13%

High yield Low yield

TsHN

R1

CF2

トシルアミド基のパラ位の周辺で銀に配位

R2

13. Plausible Reaction Mechanism TsHN

n-Bu

CF2

NSiMe3

OSiMe3

TsNF

n-Bu

NH

OSiMe3

+

+

Me3SiF

Ag+

TsHN

n-Bu

CF2

Ag+

TsHN

Nn-Bu

FTs

FSiMe3N

H

OSiMe

A

CAg

Cationic Intermediate

n-Bu

CF2

B

Ag

+

13. Plausible Reaction Mechanism TsHN

n-Bu

CF2

NSiMe3

OSiMe3

TsNF

n-Bu

NH

OSiMe3

+

+

Me3SiF

Ag+

TsHN

n-Bu

CF2

Ag+

TsHN

Nn-Bu

FTs

FSiMe3N

H

OSiMe

A

CAg

Cationic Intermediate

n-Bu

CF2

B

Ag

+

BSA

14. Summary

R1

CF2

cat. AgSbF6

TsHNTsN

F

R1NSiMe3

OSiMe3

R2R2

・Electrophilic Activation of Difluoroalkenes・Development of new synthetic method of 2-Fluoroindoles

12. Discussion 2

TsHN

R1

CF2

TsHN

R1

CF2TsHN

R1

CF2

R2R2 Ag+Ag

TsHN

R1

CF2

Ag+

High yield Low yield

パラ位に置換基がある場合、銀触媒へのアレーンの配位が妨げられるために収率が低下する

R2+

TsHN CF2

n-Bu

Electrostatic Charge

－0.186

－0.163

－0.069

－0.282

0.340

0.654

TsHN CF2

n-Bu

TsHN CF2

n-Bu3 kcal / mol

AgAg

++

C F

α-Cation stabilizing effect

+

RHN

n-Bu

CF2 AgSbF6 (10 mol%)BSA (1.0 eq)

(CH3)2CHOHreflux, Time

RNF

n-Bu

Entry

1

2

3

4

Yield (%) a

a) 19F NMR yield (PhCF3 as standard).

quant

78

22

50

Time (h)

Ts 5

Ms 24

Ns 24

MesSO2 2

R

Effect of the Substituents on Nitrogen Atom

TsHN

n-Bu

CF2 AgSbF6 (10 mol%)

Solvent, Condition

TsNF

n-Bu

Entry

1

2

3

4

5

Solvent Yield (%) a

a) 19F NMR yield (PhCF3 as standard).

―

78

―

―

―

Condition

(CH3)2CHOH reflux 5 h

DMF reflux 24 h

Toluene reflux 24 h

CH2Cl2 reflux 24 h

Et2O reflux 24 h

BSA (1.0 eq)

Effect of Solvents

Synthesis of 2-Fluoroindole

NTs

F

61%

NTs

SnMe3 FOSO2Cs

Widdowson, D. A. et al. Tetrahedoron 1994, 50, 1899.

Cr(CO)3 Cr(CO)3 Cr(CO)3

C(CH3)2CN

THF, －78 ℃ to rt

NC(H3C)2CNC(H3C)2C

H

34%Keller, L. et al. J. Am. Chem. Soc. 1980, 102, 6584.

Ag(I)-Arene Complexes

+ AgX

Ag

Ag

X－

X－

+

+ η2-Type

η1-TypeH

5 kcal / mol

2-Fluoroindole

NH

F

HN

NH

FO

O

5-Fluorouracil (5-Fu)

N N

OCOOHF

HN

Enoxacin

Fluorine-Containing Compounds

Indomethacin

NH

NH2S

MeHNOO

Sumatriptan

N

CO2HMeO

O

Cl

Me

NH

HN

SO O

N

O

N

N

HN

Delavirdine mesylate

N

HN

O

O

MeO

NHS

OO O

Zafirlukast

Major Indole Derivatives for Medicines

CF3CH2OTs

1) n-BuLi (2.1 eq)THF,－78 ℃, 30 min

2) BR3 (1.1 eq)－78 ℃, 1 h then rt, 3 h

F2CBR2

R

TsHNI

R'

(0.9 eq)

Pd2(dba)3・CHCl3 (5 mol%)

CuI (1.0 eq)

THF－HMPA (4:1), rt

TsHN CF2

R

R'

PPh3 (20 mol%)

CF3CH2OTs

1) n-BuLi (2.1 eq)THF, －78 ℃, 30 min

2) B(n-Bu)3 (1.1 eq)－78 ℃, 1 h to rt, 3 h

F2CB(n-Bu)2

n-Bu

NH・MgII (0.9 eq)

CuI (1.0 eq)

THF－HMPA (4:1), rt

NH2 CF2

n-Bu

Pd2(dba)3・CHCl3 (5 mol%)PPh3 (20 mol%)PPh3 (20 mol%)

F2C CH2

s-BuLi (1.0 eq)TMEDA (1.3 eq)

THF－Et2O (4:1)-100 ℃, 20 min

ZnCl2 (1.0 eq)

-100 ℃

F

F ZnCl・TMEDA

H

Pd(PPh3)4 (1.5 mol%)

reflux, 1 h

H2NI (0.8 eq)

CF2H2N CF2TsHNTsCl (1.5 eq)

Pyridine, rt, 1.5 h

1g

92% (2 steps)