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...
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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
アリル位炭素−フッ素結合活性化: 戦略
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
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
NiIIF I
NiIII
Ar
F
RF
R
F F
R ArInsertionNi0
Ar
β-FluorineElimination
F
βα
INiIIAr I
NiIICl I
SiSi F ClReductant
アリル位炭素−フッ素結合活性化: 戦略
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
+
Ni(acac)2 (5 mol%)2,2'-bpy (5 mol%)Et3SiCl (1.1 equiv)
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
Mn (2.0 equiv)DMA, 40 ºC, 80 min
RRI
基質一般性: ジフルオロプロペン誘導体
R
F F+
Ni(acac)2 (5 mol%)2,2'-bpy (5 mol%)Et3SiCl (1.1 equiv)
R
F
Mn (2.0 equiv)DMA, 60 ºC, 80 min
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
Ni(acac)2 (5 mol%)2,2'-bpy (5 mol%)Et3SiCl (1.1 equiv)
Mn (2.0 equiv)DMA, 40 ºC, 80 min
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
β-FluorineElimination
F
βα
INiIIAr I
反応機構
NiIII
Ar
F
RF
R
F F
R ArInsertionNi0
Ar
β-FluorineElimination
F
βα
INiIIAr I
Ar
F+ Ph–I
Ni(acac)2 (5 mol%)2,2'-bpy (5 mol%)Et3SiCl (1.1 equiv)
Mn (2.0 equiv)DMA, 40 ºC, 80 min
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
Mn (2.0 equiv)DMA, 40 ºC, 80 min
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)
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)Et3SiCl (1.5 equiv)
Mn (2.0 equiv)Ar
F
Ar
F
H+
DMART to 80 ºC, 6 h
Me
(1.0 equiv) 8% 15%a a
a 19F NMR yield.
反応機構: アリールニッケル錯体を用いた検討
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+
DMART to 80 ºC, 6 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)
β-FluorineElimination
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)
β-FluorineElimination
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
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
Ph
FMe
HPh
FH
Me
JFH = 37.2 Hz JFH = 22.6 Hz
Shi, Y. et al. J. Org. Chem. 2009, 74, 8377.
構造決定 −モノフルオロアルケンの立体について−
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%+