ニッケル触媒によるアリル位炭素ーフッ素結合活性化を利用 …...炭素−フッ素結合活性化 Bond Dissociation Energies (CH3–X)/ kJ mol–1 F H CH3

ニッケル触媒による

アリル位炭素ーフッ素結合活性化を利用した

還元的カップリング法

　　　　　　　　　　　　　　　氏　　　名　小林優太郎指導教員　市川　淳士

炭素−フッ素結合活性化

Bond Dissociation Energies (CH3–X)

/ kJ mol–1

F

H

CH3

~ 452

~ 434

~ 368

NH2 ~ 333

X / kJ mol–1

OH

Cl

~ 383

~ 345

Br

I

~ 291

~ 233

X

遷移金属触媒による炭素−フッ素結合活性化

F

sp2 C–F Bond Activation

+ PhMgBr

OH PPh2(1 mol%)

NiCl2(dppe) (1 mol%)

Et2O, RT, 1 hPh

Nakamura, E. et al. J. Am. Chem. Soc. 2005, 127 , 17978.See also: Chatani, N. et al. J. Am. Chem. Soc. 2011, 133 , 19505.

Love, J. A. et al. Org. Lett. 2007, 9, 5629.

sp3 C–F Bond Activation

(10 mol%)CuCl (3 mol%)

THF, RT, 6 h

Kambe, N. et al. J. Am. Chem. Soc. 2003, 125 , 5646.

n-HexF

n-Hexn-Prn-PrMgBr+

(1.3 equiv)

アリル位炭素−フッ素結合活性化：求核剤との反応

CF3

TsN

KH (1.5 equiv)

DMF, 120 ºC, 2 hN

F2C

Ts

F

TsN

CF2

78%Ichikawa, J. et al. Chem. Lett. 2005, 34, 778.

FF F

NO

CH3CN, 70 °C, 22 h

[Pd(dppf)Cl2]·CH2Cl2(5 mol%)

OHN (2.5 equiv)

Paquin, J.-F. et al. Angew. Chem., Int. Ed. 2010, 49, 1123.72%

FPdIIF

F

OAc

[Pd(η3-C3H5)Cl2] (2.5 mol%)dppf (5 mol%)

NaCH(CO2Me)2 (3.0 equiv)15-crown-5 (3.0 equiv)

CH2Cl2, RT, 8 h

CH(CO2Me)2

OAc

53%Gouverneur, V.; Brown, J. M. et al. Angew. Chem., Int. Ed. 2009, 48, 1296.

OAc

PdIIF

H

アリル位炭素−フッ素結合活性化：求電子剤との反応

R

F

OSm

OEt

PhNHBoc

F F

PhNHBoc

F

82%

THF, 0 ºC, 1 hO

OEt OEt

O

SmI2 (3.0 equiv)

MeMe

O+

MeOH

Me

(3 equiv)

MeMe

O

SmI2

– F

Fujii, N. et al. J. Org. Chem. 2004, 69, 1634.

N

O

BnF F

Me3CuLi2·LiI·3LiBr(2.0 equiv)

+ Me–ITHF, –78 ºC to 0 ºC

2.5 hN

O

BnF

Me

Fujii, N. et al. J. Org. Chem. 2006, 71, 4118.

(8 equiv)

60%(cis/trans = 50:50)

N

OM

BnF

M = Cu or Li

I+ C8H17I

(5 mol%)NiI2·xH2O (11 mol%)

o-(Ph2P)2C6H4 (5 mol%)

Pyridine (10 mol%)Mn (2.0 equiv)

DMPU, 80 ºC, 24 h

N N

t-Bu t-Bu

C8H17

77%

Weix, D. J. et al. J. Am. Chem. Soc. 2010, 132 , 920.

" "

+

4%

アリル位炭素−フッ素結合活性化：還元的カップリング

R

F F+

cat. Ni

R

F

ArAr I

""

Reductant+ Ar Ar

RR

RR

F M

RR

RR

M

F

βα

β-Fluorine Elimination

アリル位炭素−フッ素結合活性化：戦略

R

F F+

cat. Ni

R

F

ArAr I

""

Reductant

Ichikawa, J. et al. Angew. Chem., Int. Ed. 2014, 53, 7564.See also: Ichikawa, J. et al. ACS Catal. 2015, 5, 5974.

Ichikawa, J. et al. Dalton Trans. 2015, 44, 19460.

Ar

C+

Pr

Pr

Ni(cod)2 (1.0 equiv)PCy3 (1.0 equiv)

RT, 3 h1,4-Dioxane

NiII Pr

PrAr = C6H4(p-Ac)

F2C

Ar

FF Pr

PrAr

73%

α

βF FF


NiIII

Ar

F

RF

R

F F

R ArInsertionNi0

Ar

β-FluorineElimination

F

βα

I

Reductant

NiIIAr I

NiIIF I

R

F F+

cat. Ni

R

F

ArAr I

""

Reductant


R

F F+

cat. Ni

R

F

ArAr I

""

Reductant

NiIIF I

NiIII

Ar

F

RF

R

F F

R ArInsertionNi0

Ar


F

βα

INiIIAr I

NiIICl I

SiSi F ClReductant


NH

O

NH

O≈ C

H

F

MeO2S

ClN O

N

NH3+

TFA–

N

O

MeO2S

ClN O

N

NH3+

TFA–

C

F

IC50 0.017 µM (血糖値抑制効果) IC50 0.0075 µM

モノフルオロアルケン: アミド結合の生物学的等価体

R

F F+

cat. Ni

R

F

ArAr I

""

Reductant

配位子の検討

Ph IAr

F F+

Ni(acac)2 (5 mol%)Ligand (5 mol%)

Et3SiCl (1.1 equiv)

Ar

F

PhMn (2.0 equiv)THF, 40 ºC, 80 min

(1.5 equiv)Ar =

Entry Ligand Yield (%)

a) 19F NMR yield based on PhCF3. b) Ligand (10 mol%) was used.

1

2

3

4

5

N.D.

7

4

80

83

PPh3

dppe

pyridine

1,10-phen

2,2'-bpyN N

2,2'-bpy

N N

1,10-phen

Ph2PPPh2b

b

dppe

a

溶媒の検討

Entry Solvent Yield (%)

a) 19F NMR yield based on PhCF3. b) 45 min.

1

2

3

4

5

83

N.D.

6

75

88

THF

Toluene

EtOH

DMF

DMA

DMA

N

O

b

a

Ph IAr

F F+

Ni(acac)2 (5 mol%)2,2'-bpy (5 mol%)Et3SiCl (1.1 equiv)

Ar

F

PhMn (2.0 equiv)Solvent, 40 ºC, 80 min

(1.5 equiv)Ar =

基質一般性：ヨードアレーン

F F

+


F

Mn (2.0 equiv)DMA, 40 ºC, 80 min

RRI

a) 2,2'-bpy (10 mol%). b) 19F NMR yield based on PhCF3.

F

R

H Me OMen-BuNHTs

85%70%77%71%68%

FClAcCO2EtCF3

77%75%50%40%11%

R = R =

a

FMe

F Me

65% 23%b b

基質一般性：ヨードアレーン

a) 2,2'-bpy (10 mol%). b) 19F NMR yield based on PhCF3.

F

R

H Me OMen-BuNHTs

85%70%77%71%68%

FClAcCO2EtCF3

77%75%50%40%11%

R = R =

a

FMe

F Me

65% 23%b b

64%28%

F F

+

Ni(acac)2 (5 mol%)2,2'-bpy (5 mol%)

Me3SiCl (1.5 equiv)

F


RRI

基質一般性：ジフルオロプロペン誘導体

R

F F+


R

F


I

a) 40 ºC, 80 min. b) 19F NMR yield based on PhCF3 . c) DMF was used instead of DMA.

F

60%(E /Z = 12:88)

R

F

PhMet-BuAc

85%76%74%13%

R' =

OMe

Ph

b

b

F

63% c

a

Ar

F F+ Ph–I



Ar

F

Ph Ar

F

H+

(1.5 equiv) 88% 9%Ar =

反応機構

NiIII

Ar

F

RF

R

F F

R ArInsertionNi0

Ar


F

βα

INiIIAr I

反応機構

NiIII

Ar

F

RF

R

F F

R ArInsertionNi0

Ar


F

βα

INiIIAr I

Ar

F+ Ph–I



Ar

F

Ph Ar

F

H+

(1.5 equiv) 88% 9%Ar =

Ar

F NiF

H+Ni

"

F

反応機構：酸化的付加の速度

Ni(acac)2 (1.0 equiv)2,2'-bpy (1.0 equiv)Et3SiCl (1.1 equiv)

Mn (2.0 equiv)DMA, 40 ºC, 80 min quant.

(1H NMR yield)

I

1/2

1/2Disproportionation

NiIIPh I

NiIII I

NiIIPh Ph

Ar

F F


Ar

F

H

9%

Ni(acac)2 (1.0 equiv)2,2'-bpy (1.0 equiv)Et3SiCl (1.1 equiv)

+

40%a a

a 19F NMR yield.

Ar =

Ar

F F

反応機構：アリールニッケル錯体を用いた検討

(1.0 equiv)

THF, 0 ºC, 30 min

32%

MeMgCl

NiCl2·6H2O(0.45 equiv) EtOH

70 ºC, 30 minCl

NiIICl

PhCy2P

PCy2Ph

63%

Jamison, T. F. et al. J. Am. Chem. Soc. 2013, 135 , 1585.

PhCy2P Ni PCy2Ph

Me

ClPCy2Ph(1.0 equiv)

PhCy2P NiII PCy2Ph

Me

Cl

Ar =

Ar

F F+

2,2'-bpy (1.0 equiv)Ar

F

Ar

F

H+

DMART to 80 ºC, 7 h

Me

N.D. N.D.(1.0 equiv)


(1.0 equiv)

THF, 0 ºC, 30 min

32%

MeMgCl

NiCl2·6H2O(0.45 equiv) EtOH

70 ºC, 30 minCl

NiIICl

PhCy2P

PCy2Ph

63%

Jamison, T. F. et al. J. Am. Chem. Soc. 2013, 135 , 1585.

PhCy2P Ni PCy2Ph

Me

ClPCy2Ph(1.0 equiv)

PhCy2P NiII PCy2Ph

Me

Cl

Ar =

Ar

F F+

2,2'-bpy (1.0 equiv)Et3SiCl (1.5 equiv)

Mn (2.0 equiv)Ar

F

Ar

F

H+


Me

(1.0 equiv) 8% 15%a a

a 19F NMR yield.


PhCy2P NiII PCy2Ph

Me

Cl

Ar =

Ar

F F+

(1.0 equiv)

2,2'-bpy (1.0 equiv)Et3SiCl (1.1 equiv)

Mn (2.0 equiv)Ar

F

Ar

F

H+


Me

8% 15%a a

a 19F NMR yield.

F

NiIII

Path (a)

Mn0

MnII

R

F F

R

FF

NiI

OxidativeAddition

ReductiveElimination

R

F

Ar

Ar

InsertionPath (b)


Ni0

Ar

NiIAr

R

F F

I

R

F

ArNiIIAr I

まとめ

R

F F+

cat. NiMn

Et3SiCl

R

F

ArAr I

"

"

まとめ

R

F F+

cat. NiMn

Et3SiCl

R

F

ArAr I

"

"

NH

O

NH

O≈ C

H

F

モノフルオロアルケン: アミド結合の生物学的等価体

F3C

OHN

CH3

· HCl

塩酸フルオキセチン（抗うつ剤）

N

OCO2HF

NHN

シプロフロキサシン（合成抗菌剤）

N

O CF3

CH3

SO

N

NH

ランソプラゾール（抗潰瘍作用）

含フッ素有機化合物

F1）全元素中最大の電気陰性度（耐酸化性の向上）

2）水素に次いで2番目に小さい（ミミック効果）

3）強力な炭素–フッ素結合（ブロック効果）

Entry Yield (%) S.M. (%)

1

2

3

4

5

55

55

23

58

70 (64)

35

0

24

35

0

a) 19F NMR yield based on PhCF3 as internal standard.

Isolated yield is shown in parentheses. S.M. = Starting Material

a a

40 ºC, 80 min

40 ºC, 80 min

40 ºC, 80 min

40 ºC, 80 min

40 ºC, 70 min

Conditions

Et3SiCl (1.1)

Me2SiCl2 (1.1)

PhMe2SiCl (1.1)

Me3SiCl (1.1)

Me3SiCl (1.5)

Si (eq)

Ar

F F+

Ni(acac)2 (5 mol%)2,2'-bpy (5 mol%)Si (x equiv)

Mn (2.0 equiv)DMA, Conditions

Ar

F

(1.5 eq)

CO2Et

Ar = biphenyl-4-yl

I

CO2Et

反応条件の検討 (電子求引基を有するヨードアレーン)

電子求引基を有するヨードアレーン

F

NiIII

Path (a)

Mn0

MnII

R

F F

R

FF

NiI

OxidativeAddition

ReductiveElimination

R

F

Ar

Ar

InsertionPath (b)


Ni0

Ar

NiIAr

R

F F

I

R

F

ArNiIIAr I

ArAr

Si X

+NiIII I1/2 Ni01/2

CH

F

NH

O

F F OOH

F F O≈

≈

≈NH

O

生物学的等価体としての含フッ素有機化合物

·加水分解に対する耐性→化合物の安定性向上·脂溶性の増加·配座の固定化

モノフルオロアルケンの立体選択性

F NiIIIF

Ph

HF

F

HNiIIIF

NiIII

F

Z体（主生成物）

E体

含フッ素有機化合物の合成法

安全性コストの面で難あり

HF

Bu4N+F– (TBAF)

CsF

AgF

��

F2

��

N ClN

F 2BF4

Selectfluor®ArIF2

F F

C–F Bond Formation

F

F

or

:Nu+

E+

F Nu

F E

or

C–F Bond ActivationF F F F

F F

F F F F

R F

構造決定 −モノフルオロアルケンの立体について−

Ar

F

PhH

Ar

FH

Ph

or

JFH = 36.3 Hz


Ar

F

PhH

Ar

FH

Ph

or

JFH = 36.3 Hz

Ph

FMe

HPh

FH

Me

JFH = 37.2 Hz JFH = 22.6 Hz

Shi, Y. et al. J. Org. Chem. 2009, 74, 8377.


JFH = 36.3 Hz

Ar

F

PhH

Ar

FH

Ph

or

Ph

FMe

HPh

FH

Me

JFH = 37.2 Hz JFH = 22.6 Hz

Shi, Y. et al. J. Org. Chem. 2009, 74, 8377.

炭素–フッ素結合活性化

F

(1 mol%)NiCl2(dppe) (1 mol%)

+ PhMgBrEt2O, RT, 1 h

Ph

94%

PPh2OH

Nakamura, E. et al. J. Am. Chem. Soc. 2005, 127 , 17978.

F

F F

F

cat. Pd2(dba)3cat. PPh3

LiI (2.4 equiv)THF/THF-d8, 40 ºC, 2–75 h

+ ZnAr2

(3.5 atm) (1.0 equiv)Ar

F F

F10–71%

Ogoshi, S. et al. J. Am. Chem. Soc. 2011, 133 , 3256.

n-Hex F

(10 mol%)CuCl (3 mol%)

n-PrMgBr (1.3 equiv)

THF, RT, 6 hn-Hex C3H7

94%Kambe, N. J. Am. Chem. Soc. 2003, 125 , 5646.

反応機構研究: アリールニッケル

NiI I

R

F NiII

Et3Si–F

R

F F

R

F

Ph

Ni0Oxidativeaddition

Reductiveelimination

1/2 Mn0

1/2 MnIII2

R

F NiI

R

F NiIII

Ph

I

Et3Si–Cl 1/2 Mn0

1/2 MnIICl2

Oxidativeaddition

Ph I

F

R

F NiIICl

Ar

F FNi(acac)2 (1.0 eq)2,2'-bpy (1.0 eq)

Mn (2.0 eq)DMA, 40 ºC, 80 min

Ar

F NiII

Ar

F

H3%Ar = 4-biphenyl

F 6 M HCl

recovery: 94%+

Documents

ニッケル触媒による アリル位炭素ーフッ素結合活性化を利用 …...炭素−フッ素結合活性化 Bond Dissociation Energies (CH3–X)/ kJ mol–1 F H CH3

ニッケル触媒によるアリル位炭素ーフッ素結合活性化を利用 …...炭素−フッ素結合活性化 Bond Dissociation Energies (CH3–X)/ kJ mol–1 F H CH3