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Selective Syntheses of Difluoromethylene Compounds via Difluorocarbene Catalyses
ジフルオロカルベンを用いた触媒反応による ジフルオロメチレン化合物の選択的合成
発表者 指導教員
青野竜也 市川淳士
Bioactive Difluoromethylene Compounds
Takahashi, S. et al.! WO2014142221, 2014.
Diederich, F. et al.!Org. Biomol. Chem. 2009, 7, 3947.
Jones, R. M. et al. !Br. J. Anaesth. 1990, 64, 11.
Danishefsky, S. J. et al.! J. Am. Chem. Soc. 2004, 126, 7881.
Desflurane (麻酔薬)
OCHF2F3C
F
(抗がん作用)
OHCl
HO
O O
O
HFF
(抗マラリア作用)
N
O
n-C5H11
FF
O
(呼吸器疾患治療効果)
O
FF
NNMe
F
F
SO
NH
ON
NN
N
NH2
O
O FF
OHHO
Hetal, L. W. et al.!Cancer. Res. 1990, 50, 4417.
Gemcitabine (抗がん剤)
(除草剤)Selby, T. P. et al. !
US005389600A, 1995.
N OCHF2
H3C
F3C
Synthesis of Difluoromethylene Compounds
Introduction of Two Fluorine Substituents
Diederich, F. et al. Org. Biomol. Chem. 2009, 7, 3947.
Dmowski, W. et al. J. Fluorine Chem. 1983, 23, 207.
O H
O KF (1.3 eq)
neat, 150 °C, 90 h O H
F F
35%
+
(1.8 eq)
S FF
FF
Stavber, S. et al. Synthesis 2005, 18, 3947.
OOAc
R(2.2 eq)
CH2Cl2, reflux, 18 hF
OAc
R67%
FS FF
FN+
89%(2.0 eq)
1. CH3CN, reflux, 4–12 h+
N
NN
Cl2HC
F
2 BF4
O
FF
n-Bu
2. aq. HCl, RT, 20 min
Synthesis of Difluoromethylene Compounds
OTBS
R1FF
OTBS
R1
LnM CF2R2R3 R2
R3
OTBS
R1
R2R3
FF
CF
F
MF
F
Introduction of Difluoromethylene Group
R1NH
R2
ON R2
OCHF2: CF2
R1
Table of Contents
Chapter 1. General Introduction Chapter 2. O-Selective Difluoromethylation of Amides Chapter 2. with Free Difluorocarbene Chapter 3. Regioselective Syntheses of Chapter 3. gem-Difluorocyclopentanone Derivatives with Chapter 3. Transition Metal Difluorocarbene Complexes Chapter 4. Conclusion
1. Strong Base
2. High Temperature
Schlosser, M. et al.!Tetrahedron 1990, 46, 5213.
Miller, T. G. et al. !J. Org. Chem. 1960, 25, 2009.
3. Toxic Reagent
Seyferth, D. et al.!J. Am. Chem. Soc. 1969, 91, 6536.
Generation of Free Difluorocarbene (: CF2)
On-BuH3C H3C On-Bu
F F
Triglyme, 165 °C, 30 min
ClCF2CO2Na (4.0 eq)
42%
Benzene, reflux, 19 h
PhHgCF3 (1.0 eq)NaI (2.3 eq) F
F
83%
OH HCF2Cl (excess)NaOH (5 eq)
Dioxane, 70 °C, 70 min
OCHF2
65%
Difluoromethylation of Amides
Nawrot, E. et al. J. Fluorine Chem. 2006, 127, 943.
HCF2Cl (1.0 eq) NaOH (3.0 eq)
cat. BnEt3NClBenzene, 20 oC, 3 h
N Ph
OPh
PhNH
Ph
O
19%
PhN Ph
O
+CHF2
26%
HO
amidate ion
N Ph
OCHF2
Ph
Dolbier, W. R., Jr. et al. Org. Lett. 2000, 2, 563.!Dolbier, W. R., Jr. et al. J. Fluorine Chem. 2004, 125, 459.
FS
O O
F F
O
O
TFDA
:CF2SiMe3
cat. NaF
Toluene, reflux
F
(Weak Base)
Difluoromethylation of Amides
HCF2Cl (1.0 eq) NaOH (3.0 eq)
cat. BnEt3NClBenzene, 20 oC, 3 h
N Ph
OPh
PhNH
Ph
O
19%
PhN Ph
O
+CHF2
26%
HO
amidate ion
N Ph
OCHF2
Ph
Nawrot, E. et al. J. Fluorine Chem. 2006, 127, 943.
0%
PhNH
Ph
O
Toluene, reflux, 30 min
PhN Ph
O+
N Ph
OCHF2
CHF2
0%
(TFDA, 2.0 eq)
NaF (5 mol%)
(Weak Base)Ph
FS
O O
F F
O
OSiMe3
NHC for TFDA Activator
Ichikawa, J. et al. Chem. Lett. 2011, 40, 1189.
2 : CF2F
F F
F
NMesMesN NMesMesN NPhN
PhN
Ph
Nucleophilicity Large Small
O Na2CO3 (20 mol%)
(2 mol%)OCHF2
74%Toluene, 80 oC, 30 min
N N
FSO2CF2CO2SiMe3 (2.0 eq)
(Neutral Conditon)
O-Selective Difluoromethylation
PhNH
Ph
OPh
N Ph
O
+
21
N Ph
OCHF2
CHF2Ph
Cat. 1 / %
56
53
80
MesN NMes Cl
ClMesN NMes
BrN
PhN NPh
SMe
Mes = 2,4,6-trimethylphenyl. 19F NMR yield on (CF3)2C(C6H4CH3)2.
TFDA / %
2
2
3
Entry
1
2
3
2 / %
–
–
–
Mayr's N Value
23
22
14
Cat. (5 mol%)FSO2CF2CO2SiMe3 (2.0 eq)
Toluene, 80 oC, 15−30 minNa2CO3 (20 mol%)
NMesMesN NMesMesN NPhN
PhN
Ph
Nucleophilicity Large Small
Plausible Reaction Mechanisms
◆ Generation of Free Difluorocarbene
◆ Difluoromethylation of Amides
RNH
R
O :CF2
RNH
R
OCF2N R
OCHF2
R
RNH
R
O
FS
O O
F F
O
O
TFDA
:CF2
CO2, SO2
NR
RN
NHC
SiMe3
NR
RN
Me3Si+ + +F
– FSiMe3
Synthesis of Difluoromethyl Imidates
Product Yield / %
77
62
62
67
72
BrN
PhN NPh
SMe
Entry
1
2
3
4
5
R1
NH
R2
O
N R2
OCHF2
(5 mol%)
N CH3
OCHF2 R = H
R = Me
R = OMe
R = F
R = Cl
N R
OCHF2 84
81
80
6
7
8
R = i-Pr
R = Cy
R = Ph
R1
R
FSO2CF2CO2SiMe3 (2.0 eq)
Toluene, 80 oC, 15−30 minNa2CO3 (20 mol%)
(除草剤) Primisulfuron-methyl (除草剤)
Bollag, J.-M. et al. J. Agric. !Food Chem. 2000, 48, 2565.
Selby, T. P. et al. !US005389600A, 1995.
N OCHF2
H3C
F3C
N
N
OCHF2
OCHF2
HN
HN
OS
O OMeO2C
HN O
DDQ (1.0 eq)
100 °C50 min 92%
as above N OCHF2 N OCHF2
Na2CO3 (20 mol%)Toluene, 80 oC, 20 min 60% (19F NMR)
HN O N OCHF2
BrN
PhN NPh
SMe
(5 mol%)
FSO2CF2CO2SiMe3 (2.0 eq)
Synthesis of Difluoromethoxypyridines
Synthesis of Difluoromethylene Compounds
OTBS
R1FF
OTBS
R1
LnM CF2R2R3 R2
R3
OTBS
R1
R2R3
FF
CF
F
MF
F
Chapter 2. Free Difluorocarbene
Chapter 3. Metal Difluorocarbene
R1NH
R2
ON R2
OCHF2: CF2
R1
Application of Carbene Complexes
Doyle, M. P. et al. Synthesis 1981, 787.
Shmidt, B. et al. J. Org. Chem. 2003, 68, 799.
Moody, C. J.; Padwa, A. et al. Tetrahedron 1996, 52, 2489.!
OMe
PhN2
O
OEt
cat. Rh2(OAc)4
Et2O, 25 °COMePh
CO2Et
94%
[Rh]O
OEt
NO
CN
98%
N O
[Rh]
CH2Cl2, RTMeMe
cat. Rh2(NHCOC3F7)4
N O
N2
Me
CN CNH
OPh
HOPh
RuPh
PCy3
PCy3
ClCl OPh
HOPh
90%
cat.
CH2Cl2, RT
O
[Ru]
Ph
HOPh
Application of Metal Difluorocarbene Catalyst
Takahira, Y. et al. J. Am. Chem. Soc. 2015, 137, 7031.!
MF
F
Difluorocarbenecomplex Olefin Metathesis
C–H InsertionR1 CHF2
F F
R2R1
R4R3
Difluorocyclopropanation
n-C12H25O
64%
n-C12H25O F
F
cat. LnRu=CHR
Preparation of Metal Difluorocarbenes
Roper, W. R. et al. J. Chem. Soc., Chem. Commun. 1983, 719.
Grubbs, R. H. et al. Angew. Chem., Int. Ed. 2001, 40, 3441.
Grushin, V. V. et al. J. Am. Chem. Soc. 2009, 131, 4236.!
Ru
Ph3P
Ph3P
PPh3OCOC Ru
Ph3P
Ph3P
OCOC
CF2CdCF3
Ru
Ph3P
Ph3P
CF2OCOC
Cd(CF3)2•diglyme
– FCdCF3
F
Rh F
Ph3P
Ph3P
Ph3P
Me3SiCF3Rh CF2
Ph3P
Ph3P
Ph3PRh
Ph3P
Ph3P
CF2F
F
RuCl
Cl
PCy3
NMesMesNPhH
CH2 CF2Ru
Cl
Cl
PCy3
NMesMesN
CF2– Stylene
Strategy for Generation of M=CF2
Grushin, V. V. et al. J. Am. Chem. Soc. 2009, 131, 4236.!
– CO2
M1 CF2
– M2Y – X–M1YM2OCOCF2X
M1 CF2
X
C CF2
XOOM1
A B
C
or
M1 CF2X
Rh FMe3SiCF3
Rh CF2 Rh CF2
F F
– Me3SiF
1. Generation of M‒CF2X intermediates via metal carboxylate
2. Use of a good leaving group in place of F ‒
Optimization of Cyclopropanation
Ph
OTBS
PhOTBS
FF
NNN N
N
H3C CH3
NiBr
BrRhCl(PPh3)3
Ni(PPh3)4
Catalyst 1 / %a
3072
57
a: 19F NMR yield based on (CF3)2C(C6H4CH3)2. b: Inamoto, K. et al. Organometallics 2006, 25, 3095.IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
Toluene, 100 oC, 1 h
TBS = SiMe2(t-Bu) 1
Entry
6b3
Catalyst (5 mol%)Me3SiOCOCF2SO2F (TFDA, 2.0 eq)
Catalyst 1 / %a
12
40
Entry
5
7 IPrCuCl
Pt(PPh3)4
2
01 Rh2(OAc)4
594 Pd(PPh3)4
[M=CF2]
Optimization of Cyclopropanation
Ph
OTBS
PhOTBS
FF
NNN N
N
H3C CH3
NiBr
BrRhCl(PPh3)3
Ni(PPh3)4
Catalyst 1 / %a
3072
57
a: 19F NMR yield based on (CF3)2C(C6H4CH3)2. b: Inamoto, K. et al. Organometallics 2006, 25, 3095.IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
Toluene, 100 oC, 1 h
TBS = SiMe2(t-Bu) 1
Entry
6b3
Catalyst (5 mol%)Me3SiOCOCF2SO2F (TFDA, 2.0 eq)
Catalyst 1 / %a
12
40
Entry
5
7 IPrCuCl
Pt(PPh3)4
2
01 Rh2(OAc)4
594 Pd(PPh3)4
[M=CF2]
Fe CF2
COCp
COBF4 Fe CF2
PPh3Cp
COBF4
Decomposed above –78 °C Isolated at RT
Shriver, D. F. et al. Organometallics 1984, 3, 314.!Shriver, D. F. et al. Organometallics 1985, 4, 1830.!
Scope of Difluorocyclopropanation
R3OR
R1
R2
F F
R3OR
R2
R1
F F
PhOTBS
F F
PhOTBS
OTBSFF
73% 63% 78%
F F
On-C12H25
40%
(5 mol%)
Me3SiOCOCF2SO2F (TFDA, 2.0 eq)Toluene, 100 °C, 1 h
TBS = Si(t-Bu)Me2. a: Ratio of starting material: E /Z = 4:96.
F F
PhOTBS
68% (d.r. = 89:11)a
NNN N
N
H3C CH3
NiBr
Br
Proposed Mechanism
N Ni
NMeN
N NMe
CF2
SO2
N Ni
NMeN
N NMe
Br
X
R1
OTBS
R1
OTBSFF
N NiNMeN
N NMe
A
X
F–
Me3SiBr
2+
DifluorocarbeneComplex C
R2R3
R2
R3
O CO
2 X–
(X = Br or F)
LnNiF F
R1OTBS
R2R3
2+
2 X–
D
CO2
N NiNMeN
N NMe
B
X
CF2
CF2
SO2F
Me3SiOCOCF2SO2F
SO2F
Proposed Mechanism
N Ni
NMeN
N NMe
CF2
SO2
N Ni
NMeN
N NMe
Br
X
R1
OTBS
R1
OTBSFF
N NiNMeN
N NMe
A
X
F–
Me3SiBr
2+
DifluorocarbeneComplex C
R2R3
R2
R3
O CO
2 X–
(X = Br or F)
LnNiF F
R1OTBS
R2R3
2+
2 X–
D
CO2
N NiNMeN
N NMe
B
X
CF2
CF2
SO2F
Me3SiOCOCF2SO2F
SO2F
Barefield, E. K. et al. Organometallics 1985, 4, 2278.
(2.0 eq)
[(PPh3)(SMe2)CpNi=CH2]PF6
CH3CN, reflux, 17 h
49%
H H
Trapping of Ni(II) Difluorocarbene Complexes
Roper, W. R. et al. J. Chem. Soc., Chem. Commun. 1983, 719.
Ru CF2
PPh3
PPh3
OCOC MeNH2
– HFRu l•
PPh3
PPh3
OCOC NMe
δ+δ–
– HFRu
PPh3
PPh3
OCOC
F
NHMe
Toluene, RT, 2 h
TFDA (1.5 eq)
Ni CF2
NMesN
N
N NMes
Ni l•
NMesN
N
N NMes
NAr
Ar = 2,6-dimethylphenyl
Ni Cl
NMesN
N
N NMes
BF4
ArNH2 (10 eq)
2+ 2+
(C38H38N6Ni)
Trapping of Ni(II) Difluorocarbene Complexes
Toluene, RT, 2 h
TFDA (1.5 eq)
Ni CF2
NMesN
N
N NMes
Ni l•
NMesN
N
N NMes
NAr
Ar = 2,6-dimethylphenyl
Ni Cl
NMesN
N
N NMes
BF4
ArNH2 (10 eq)
2+ 2+
(C38H38N6Ni)
Observed(ESI+):[M]2+ Simulated:[C38H38N6Ni]2+
Inte
nsity
m/z m/z
Inte
nsity
318.1253 318.1256
Synthetic Strategy of α,α-Difluorocyclopentanone
FF
OSiR3
FF
OSiR3
N
O
n-C5H11
FF
Oα
FF
OSiR3
a cleavage a
FF
OSiR3VinylcyclopropaneRearrangementLnM CF2
OSiR3
Diederich, F. et al.!Org. Biomol. Chem. !2009, 7, 3947.
(抗マラリア作用)
CO2MeOAc
OF
HO
α
Yamada, Y. et al.!Chem. Pharm. Bull. 1989, 37, 1173
(抗白血病作用)
Dolbier, W. R., Jr. et al. J. Org. Chem. 1982, 47, 1.!See also: Percy, J. M. et al. Chem. Eur. J. 2014, 20, 14305.
FF
FF
+
96%(cleavage a)
4%(cleavage b)
a
bFF
a > b224 °C
VinylcyclopropaneRearrangement
Dolbier, W. R., Jr. et al. Chem. Rev. 2003, 103, 1071.
H H
60.0°
1.515 Å
114.5° F F
63.3°1.477 Å
109.8°
Ring Strain Energy 26.5–28.7 kcal / mol 35.7–42.4 kcal / mol
1.550 Å
Synthetic Strategy of α,α-Difluorocyclopentanone
Optimization of Reaction Conditions
a: 19F NMR yield based on (CF3)2C(C6H4p-CH3)2. b: 1H NMR yield based on 19F NMR yield of 1 or 2.
Entry 1 / %a 2 / %aTemp. / °C Time / min
1 80 60 22 31
2 100 60 – 74
OTBS (5 mol%)O
+
2 3
Ph Ph
NNN N
N BrNiBr
FSO2CF2CO2SiMe3 (TFDA, 2.0 eq)
1
3 / %b
34
21
OTBSFF
FF
OTBS
PhPh
3 130 30 – 72
4 140 30 – 82
15
9
5 160 10 – 84 9
Solvent
Toluene
Toluene
p-Xylene
p-Xylene
Mesitylene
H3C CH3
Synthesis of 5,5-Difluorocyclopent-1-en-1-yl Silyl Ethers
FF
OTBS
R1FF
OTBS
Ph
R2
FF
OTBS
FF
OTBS
PhR3
a: 19F NMR yield based on (CF3)2C(C6H4p-CH3)2. b: Reaction was conducted with NaH (200 mol%) at 100 °C.c: single diastereomer.
R2OTBS
p-Xylene, 140 °C, 30 min
R3
R1
NNN N
N BrNiBr
(5 mol%)
FF
OTBS
R1
R2
R3
83%
79%
80%
R1 = Ph
R1 = p-MeC6H4
R1 = p-ClC6H4
R1 = n-Pr 71%
73%
74%
74%
R2 = Me
R2 = Ph
R2 = Br
54%a,cR3 = Me 60%b
TFDA (2.0 eq)
CH3H3C
Synthesis of Cyclopentanone (I)
FF
OTBS
Ph
FF
O
Ph
Fluorinated silyl enol ether
80% (19F NMR)
(n-Bu)4NF (2.0 eq)THF–HCO2H–H2O (6:3:1)
55 °C, 1.5 d
N
O
Br
O
(NBS, 1.0 eq)
CH2Cl2 (0.007 M), RT, 4 dFF
O
Ph86%
OH3C
OO
O OH
H
H
HHH
N
O
n-C5H11
FF
Oα
Diederich, F. et al.!Org. Biomol. Chem. !2009, 7, 3947.
(抗マラリア作用)(+)-macquarimicin!
(血管新生阻害物質)
McAlpine, J. B. et al.!J. Antibiot. 1995, 48, 462.
Synthesis of Cyclopentanone (II)
FF
O
Ph
FF
OH
Phquant (d.r. = 67:33)
FF
N
Phquant
OH
FF
N
Ph74%
NHTs
NaBH4 (2.0 eq)MeOH, reflux, 2 h
NH2OH·HCl (1.5 eq)MeOH, 50 °C, 12 h
NH2NHTs (1.5 eq)MeOH, reflux, 9 h
Synthesis of Cyclotene
Kawai, M. et al. !Agric. Biol. Chem. 1974, 38, 2273.
FF
OTBS
Ph
O
OOH
(mCPBA 3.0 eq)
CH2Cl2, –20 °C to RT, 17 h FFTBSO
Ph
O
KHF2 (1.0 eq)
85% (d.r. = 78:22)
OH
Ph
F O
54%
THF–H2O (1:1), RT, 22 h FF
OH
Ph
OHaq. NaHCO3
Cl
OHOH3C
OHOH3C
CH3
OHOH3C
H3CCH3
Cyclotene!(香料成分)
Strategy for Regioselective Synthesis
FF
FF Ring Expansion
FF
FF MLn
OSiR'3
OSiR'3Ring Closure
OSiR'3
OSiR'3
OSiR'3
R
R
R
R
R
LnM CF2
Difluoro-cyclopropanation
Electrophilic Addition
(A)
(B)
Synthetic Strategy of β,β-Difluorocyclopentanone
Fu, G. C. et al. J. Am. Chem. Soc. 2007, 129, 1046.!
RO
R'
Cu
O
R
R`AcOCOCu
OAcOCO R
R'
AcOCO
FCu
CF2
Cu
F2C
OSiR3OSiR3
FF
FOSiR3
Ni=CF2
OSiR3
Strategy for Generation of Cu=CF2
Liu, L. et al. Angew. Chem., Int. Ed. 2009, 48, 9350.
Cu CF2
A B
C
– CO2
NaOCOCF2Br
– Br–CF2COO
Cu CuX
BrCF2CuBr
Cu CF2
orBr
CuI (10 mol%)PhI (1.0 eq)
Diglyme, 130 °C
99%
COO
Cu
F
F F
F
F
KOCO
F
F F
F
F
Ph
F
F F
F
F
Optimization of Catalyst
OTBS
Ph
OTBS
Ph
FFNaOCOCF2Br (1.1 eq)
Metal
MeCN, 50 oC, 12–15 h
Entry 2 / %aMetal (mol%)
a: 19F NMR yield based on (CF3)2C(C6H4p-CH3)2. b: 1H NMR yield based on (CF3)2C(C6H4CH3)2.SIMes = 1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene.
4 9
2 19
1 / %a
65
10
1 400
N
NCu Br
PPh3
1 2
OTBS
FF Ph
3 1037Ph Cu
SIMesCuCl (100)
(100)R
R5 772
R = H (5)
R = Me (2)
NCuI
NMe
Me
(100)
H
H
Synthesis of 4,4-Difluorocyclopent-1-en-1-yl Silyl Ethers
(5 mol%)
NaOCOCF2Br (1.1 eq)MeCN, 50 oC, 12 h
OTBS
FF R1
R2OTBS
R2
R1
N
NCu Br
PPh3
Me
Me
OTBS
R1
OTBS
Ph
Me
OTBS
71%
70%
62%
R1 = Ph
R1 = p-MeOC6H4
R1 = p-MeC6H4
R1 = p-BrC6H4 59%
69%
63%FF
59%R1 = 2-naphthyl
R1 = n-Pr 57%a
a: Reaction time was 36 h.
FF
FF
Proposed Mechanism
OTBS
NaOCOCF2Br
OTBS
FF
CuN
NCF2
CuN
NCF2
OCu
CuN
N
N
N
CF2CuN
N
NaBr
CO2Br
Br
Br
OTBS
CuN
N CF2
BrOTBS
A
BC
D
CO
CF2
Br
Br
N
N
N
N
Me
Me
Proposed Mechanism
OTBS
NaOCOCF2Br
OTBS
FF
CuN
NCF2
CuN
NCF2
OCu
CuN
N
N
N
CF2CuN
N
NaBr
CO2Br
Br
Br
OTBS
CuN
N CF2
BrOTBS
A
BC
D
CO
CF2
Br
Br
N
N
N
N
Me
Me
Trapping of Cu(I) Difluorocarbene Complexes
Observed(ESI+):[M]+ Simulated:[C19H21CuN3]+
Inte
nsity
m/z
Inte
nsity
m/z
354.1031354.1028
CH3CN, RT, 21 h
BrCF2CO2Na (5.5 eq)n-BuNH2 (10 eq)
Cu CF2N
NCu
N
N
PPh3
BrCu l•
N
NNn-Bu
(C19H21CuN3)
Me
Me
Me
Me
Me
Me
Trapping of Cu(I) Difluorocarbene Complexes
N
NCu
Ar
ArP
t-Bu
t-Bu
SiMe3
SiMe3
Peters, J. C. et al. !Chem. Commun. 2008, 1061.!
Hofmann, P. et al. !Inorg. Chem. 2008, 47, 11755.!
PCu
PPh2B
Ph
Pht-Bu t-Bu
t-Bu t-Bu
CH3CN, RT, 21 h
BrCF2CO2Na (5.5 eq)n-BuNH2 (10 eq)
Cu CF2N
NCu
N
N
PPh3
BrCu l•
N
NNn-Bu
(C19H21CuN3)
Me
Me
Me
Me
Me
Me
Trapping of Cu(I) Difluorocarbene Complexes
(5 mol%)
BrCF2CO2Na (1.1 eq)MeCN, 50 oC, 12 h
N
NCu Br
PPh3
Me
MeOTBS
Ph
OTBS
FF Ph
32%0.2 eqPPh3
72%0 eqPPh3
CH3CN, RT, 21 h
BrCF2CO2Na (5.5 eq)n-BuNH2 (10 eq)
Cu CF2N
NCu
N
N
PPh3
BrCu l•
N
NNn-Bu
(C19H21CuN3)
Me
Me
Me
Me
Me
Me
Synthesis of Cyclopentanone
O
PhF
HO
(抗真菌効果)
Clark, D. S.; Tius, M. A. et al. !J. Comb. Chem. 2001, 3, 346.!
O
FF
NNMe
F
F
SO
NH
ON
N
（呼吸器疾患治療効果）
Takahashi, S. et al.! WO2014142221, 2014.
(n-Bu)4NF (2.0 eq)
THF–HCO2H (5:1)0 °C to RT 10 h
– HF
70%
OTBS
PhFF
O
PhFF
O
PhF
Conclusion
FF
FF
OSiR'3
OSiR'3
R
R
LnNi CF2
LnCu CF2
MF
F
NPhN NPh
SMe
N R2
OCHF2
R1
CF
F
F F
R3OSiR3
R2
R1
イミド酸エステルの双極子モーメント
N
O
Me
Me
Me
N
O
Me
Me
Me
Z-isomerE-isomer
1.14 D 2.40 D
Walter, W. et al. J. Am. Chem. Soc. 1974, 96, 2259.
アミドのアルキル化
Ototake, N. et al. Chem. Eur. J. 2009, 15, 5090.
Ar NH
MeI (1.5 eq) NaH (1.5 eq)
DMF, RT, 2 h+
43% 55%
EtO
Ar N EtO
N EtOMe
Ar N EtO
Ar = 2,4,6-(t-Bu)3C6H4
Na
MeAr
Ph NH
MeI (13 eq) Ag2O (2.0 eq)
neat, reflux, 5 h
72%
i-PrO
N i-PrOMe
Ph NH
i-PrOMe
I
Ph
Wenkert, E. et al. J. Am. Chem. Soc. 1956, 78, 797.
ジフルオロカルベン錯体の合成例
Vogel, P. et al. Org. Lett. 2004, 6, 95.
Roddick, D. M. et al. Organometallics 1991, 10, 591.
Davidson, E. R.; Caulton, K. G. et al. J. Am. Chem. Soc. 2000, 122, 8916.
Roper, W. R. et al. Aus J. Chem. 1986, 39, 1315.
Davidson, E. R.; Caulton, K. G. et al. J. Am. Chem. Soc. 2000, 122, 8916.
Hughes, R. P.; Rucker, A. N. et al. J. Am. Chem. Soc. 2005, 127, 15020.
Roper, W. R. et al. J. Organomet. Chem. 1990, 394, 615.
Baker, R. T. et al. J. Am. Chem. Soc. 2013, 135, 18296.
Mo CF2
CO
Cp*
OC
OCOTf Ru
P(i-Pr)3
OC
H
P(i-Pr)3
F CF2 Os
P(i-Pr)3
OC
H
P(i-Pr)3
F CF2
Os CF2
PPh3
PPh3
ON
ClCo CF2
Ph3P
Cp Co CF2Ph3P
Cp
Pt CF2
CF3F3C
S N NBu4Ir CF2
PPh3
PPh3
OC
F3C
Baker, R. T. et al. Organometallics 2015, 34, 5683.
NiCF2
P
P
Ph2
Ph2
P(OMe)3
ハロゲン化スルホニルの酸化的付加反応
– SO2ArS
O
Cl
O
ArS
O
[Pd]
OCl Cl
[Pd]Ar
Ar'B(OH)2 (2 eq)Pd(PPh3)4 (8 mol%)
K2CO3 (3 eq)THF, reflux, 15–35h
Ar Ar'30–78%
Ar'B(OH)2
Vogel, P. et al. Org. Lett. 2004, 6, 95.
ニッケルカルベン錯体の合成例
PNi(cod)
(t-Bu)2P
THF PNi
(t-Bu)2P
NN
PhPh
95%
Sm(OTf)3 (7 mol%)
benzene, 75 oC PNi
(t-Bu)2P Ph
Ph
70%
N2CPh2
(t-Bu)2 (t-Bu)2 (t-Bu)2
Mindiola, D. L. et al. J. Am. Chem. Soc. 2002, 124, 9976.
Ni NPhPPPh2
PPh2
2 HBF4
THF, RT, 3 h NiPhPPPh2
PPh2
NH
H
2+
[BF4-]2
85%
Hou, H. et al. Organometallics 2003, 22, 2817.
Ni＝CF2 v.s. : CF2
Ph
OTBS
Toluene, 100 oC, 1 hTBS = SiMe2(t-Bu)
Ni=CF2 72%: CF2 45%
PhPhFF
FF
PhOTBS
Ph Ph
Ni=CF2 72%: CF2 42%
Toluene, 100 oC, 1 h
FSO2CF2CO2SiMe3 (TFDA, 2.0 eq)
FSO2CF2CO2SiMe3 (TFDA, 2.0 eq)
(5 mol%)
NNN N
N BrNiBrH3C CH3
Ni=CF2
(5 mol%)
NNN N
N2Br
H3C CH3
Na2CO3(20 mol%)
: CF2
Niカルベン錯体によるシクロプロパン化
Otsuka, S.; Ibers, J. A. et al. J. Am. Chem. Soc. 1977, 99, 2108.
Hillhouse, G. L. et al. J. Am. Chem. Soc. 2003, 125, 13350.
NiP
P
t-But-Bu
t-Bu t-Bu
Ph
Ph Toluene, 110 °C, 5 d
H2C CH2 Ph Ph
85%
(1 atm)
CH2N2 (1.25 eq)
CO2CH3Ni(PPh3)4 (10 mol%)
Et2O, –78 °C to RT, 1.5 hCH2LnNi
CO2CH3
72%
H H
(2.0 eq)
NiCp(PPh3)[CH2S(CH3)2]PF6
CH3CN, reflux, 17 h
49%
H H
Barefield, E. K. et al. Organometallics 1985, 4, 1178.
Niカルベン錯体によるシクロプロパン化
Kanai, H. et al. Bull. Chem. Soc. Jpn. 1983, 56, 1592.
MeO2C MeO2C CO2Me
Ni catalyst (1.0 eq)NaI (1.0 eq)Zn (3.0 eq)
CH2Br2 (1.0 eq)
CH3CN, RT, 40 hcis 0%
+MeO2C CO2Me
trans 59%
CO2Me
(E)-isomer
MeO2C CO2Me MeO2C CO2Me
Ni catalyst (1.0 eq)NaI (1.0 eq)Zn (3.0 eq)
CH2Br2 (1.0 eq)
CH3CN, RT, 24 hcis 71%
+MeO2C CO2Me
trans 7%(Z)-isomer
Ni CH3CN
CO2MeMeO2C
MeO2CMeO2C
Ni catalyst
NHC錯体の検討
Toluene, 100 °C, 1 h
Metal complex (5 mol%)TFDA (2.0 eq)
Entry Metal complex Product / %a
3
4
5
6
6462
62
68
a: 19F NMR yield based on (CF3)2C(C6H4CH3)2. b: 1H NMR yield based on 19F NMR yield of 2. Mesityl = 2,4,6-trimethylphenyl.
Me
n-Bu
Mesityl
Mesityl
N NiNRN
N NRCF2Ni
N
X
NN N
NX'
R R
R =
R =
R =
R =
N PdNRN
N NRCF2Pd
N
X
NN N
NX'
R R
N PtNRN
N NRCF2Pt
N
X
NN N
NX'
R R
1
2
72
37
Me
Mesityl
R =
R =
Ph
OTBS
PhOTBS
FF
OTBS
Ph
FF
1,5-H shift
OTBS
Ph
FF
H
27%H
FF
OTBS
PhH3C
OTBSH3C
PhE /Z = 33:67
Toluene, 100 °C, 1 h(TFDA, 2.0 eq)
NNN N
N Br
H3C CH3
NiBr
(5 mol%)
54%
ビニルシクロプロパン転位
ビニルシクロプロパンの1,5-Hシフト
Dolbier, W. R., Jr. et al. J. Org. Chem. 1982, 47, 1.
FF
FFΔ(200 °C)
34%
FF
+
66%
銅錯体の脱炭酸
Ardizzoia, G. A. et al. J. Organomet. Chem. 1988, 348, 279.
