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