偶联反应小结
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偶联反应 Cross-Coupling Reaction
经典反应式
R'-X Substrate
+ R-MX'
Catalyst (Ni or Pd
R--R'
+ MXX'
Coupling Partner ......?) Coupling Product Metal Halide
(Organic (Organometallic Electrophile) Nucleophile)
CH2CH2CH3 Ni - Ph L2
PhCH2CH2CH3
[ Ni-P* ]
H
H2C CHCH 2CH 2Br + PhMgBr
H2C C
H C* Me Ph
(3) 反应中涉及的双键的立体化学
Ph
Br +
NiCl2L2 MeMgBr
Ph
CH 3
Ph
来自百度文库
+
NiCl2L2 MeMgBr
Ph
Br
CH 3
PR2
R = Me dmpf R = Ph dppf
H10B10
Ph Ph
Ph Ph
dppc
格氏试剂上烷基部分的异构化
Cl
Mg Cl
L2Ni
+
Ph H3C CH 3
H3C CH 3
Ni L2 Ph
CH2 = CHCH3
H - Ni - Ph L2
Ph H3C CH 3
CH2 = CHCH3 +
PhH
2. Buchwald-Hartwig coupling (C-N, C-O, C-S Formation: C-X + Nu (N, O, S)-H)
3. a-Arylation of Ketone (C-C Formation: C-X + C-H)
4. Heck, Sonogashira coupling (Alkene and alkyne Formation: C-X + C-H)
Sp3 C-X substrate?
MgXX'
RMgX
2 RMgX
L2NiX2
5
L2NiR2
6
2 MgX2
R'X'
R-R
R' L2 Ni X'
7
R - R'
3
R'
L2 Ni R
2
R'X'
R'X'
R' L2 Ni R
配体的影响
PhCl + BuMgBr
NiCl2L2 ( 1 % )
Et2O, reflux 20h
Dynamic kinetic Resolution
R1 R2 C R4 R3
R4 X' [ ML*]
PhBu
dppp > dmpf > dppe > dmpe > dppc > cis - dpen Ph2P(CH2)nPPh2 Me2P(CH2)2PMe2 cis-Ph2PCH=CHPPh2 n = 2 dppe dmpe cis-dpen n = 3 dppp n = 4 dppb
PR2 Fe
4
RMgX + R'X' NiX2L2
R - R' + MgXX'
催化剂: 溶剂: 反应条件:
R’X’:
NiX2L2 ( L2 = 双 膦 )
Et2O or THF 0 oC ~ R.T., reflux, 1 ~ 20 h,
[Ni] / R’X’ = 10 -2 ~ 10 sp2 碳 的 卤 化 物
(R)-(S)-PPFA
63% ee (S)
(S)-(R)-PPFA
59% ee (R)
PPh2 NMe2 H Me
(S) - (R) - PPFA
H RC Me2N
CH2 PPh2
(S)-Valphos (R = i-Pr) 81% ee (S) (R)-t-Leuphos (R = t-Bu) 94% ee (R)
X Cl, Br, I, OTs Br, I Cl, Br, I, OTs
Cl, Br, I, OTs
Cl, Br, I, OTs Br, I, OTs
1. Kumada, Suzuki, Stille, Negishi, Hiyama coupling (C-C Formation：C-X + C-M)
General Mechanism
Kumada, Kumada-Corriu Coupling
1960年Chatt和Shaw:
X L2Ni
X
R
L2Ni + X
1
R'MgX
1970年Uchino等:
R L2Ni +
R' 2
MgX2
(bipy)Ni R R
3
+ R'-X
(bipy)Ni R' + R-R X
R = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl R' = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl, acyl X = I, Br, Cl, OTf, OTs M = Mg, Zn, Cu, Sn, Si, B,...... Cat. = Pd, Ni, others Cu Fe......
Negishi (1977) Stille (1978) Suzuki (1979)
Ni or Pd Zn Aryl, allyl, benzyl, propargyl
Pd
Sn Aryl, vinyl,benzyl,
alkynyl
Pd
B Aryl, alkyl
Hiyama (1988)
Ni or Pd Si Aryl
Ph
MgBr + ArX NiCl2 ( dmpe )
Ph
Ar
Ph
+
Ar
(4) 碳－碳键的不对称形成 (Asymmetric formation of carbon-carbon single bonds)
PhMeCHMgCl +
[ Ni * ]
*
Br
PhMeCHCH = CH2
PPFA Y: 83 ~ 99% ee: 52 ~ 63%
R'
Aryl, alkyl, vinyl
Aryl, alkyl, vinyl
Aryl, alkyl, vinyl, alkynyl, benzyl, allyl Aryl, alkyl, vinyl, benzyl, allyl, acyl Aryl, alkyl, alkynyl
Aryl, alkyl, vinyl
R'-X + R-MX'
Catalyst R-R' + MXX'
Cross-Coupling Catalyst M
R
Reactions
Kumada-Corriu (1972)
Ni or Pd Mg Aryl, alkyl, vinyl
Sonogashira (1975) Pd/CuI Cu Aryl, alkyl
经典反应式
R'-X Substrate
+ R-MX'
Catalyst (Ni or Pd
R--R'
+ MXX'
Coupling Partner ......?) Coupling Product Metal Halide
(Organic (Organometallic Electrophile) Nucleophile)
CH2CH2CH3 Ni - Ph L2
PhCH2CH2CH3
[ Ni-P* ]
H
H2C CHCH 2CH 2Br + PhMgBr
H2C C
H C* Me Ph
(3) 反应中涉及的双键的立体化学
Ph
Br +
NiCl2L2 MeMgBr
Ph
CH 3
Ph
来自百度文库
+
NiCl2L2 MeMgBr
Ph
Br
CH 3
PR2
R = Me dmpf R = Ph dppf
H10B10
Ph Ph
Ph Ph
dppc
格氏试剂上烷基部分的异构化
Cl
Mg Cl
L2Ni
+
Ph H3C CH 3
H3C CH 3
Ni L2 Ph
CH2 = CHCH3
H - Ni - Ph L2
Ph H3C CH 3
CH2 = CHCH3 +
PhH
2. Buchwald-Hartwig coupling (C-N, C-O, C-S Formation: C-X + Nu (N, O, S)-H)
3. a-Arylation of Ketone (C-C Formation: C-X + C-H)
4. Heck, Sonogashira coupling (Alkene and alkyne Formation: C-X + C-H)
Sp3 C-X substrate?
MgXX'
RMgX
2 RMgX
L2NiX2
5
L2NiR2
6
2 MgX2
R'X'
R-R
R' L2 Ni X'
7
R - R'
3
R'
L2 Ni R
2
R'X'
R'X'
R' L2 Ni R
配体的影响
PhCl + BuMgBr
NiCl2L2 ( 1 % )
Et2O, reflux 20h
Dynamic kinetic Resolution
R1 R2 C R4 R3
R4 X' [ ML*]
PhBu
dppp > dmpf > dppe > dmpe > dppc > cis - dpen Ph2P(CH2)nPPh2 Me2P(CH2)2PMe2 cis-Ph2PCH=CHPPh2 n = 2 dppe dmpe cis-dpen n = 3 dppp n = 4 dppb
PR2 Fe
4
RMgX + R'X' NiX2L2
R - R' + MgXX'
催化剂: 溶剂: 反应条件:
R’X’:
NiX2L2 ( L2 = 双 膦 )
Et2O or THF 0 oC ~ R.T., reflux, 1 ~ 20 h,
[Ni] / R’X’ = 10 -2 ~ 10 sp2 碳 的 卤 化 物
(R)-(S)-PPFA
63% ee (S)
(S)-(R)-PPFA
59% ee (R)
PPh2 NMe2 H Me
(S) - (R) - PPFA
H RC Me2N
CH2 PPh2
(S)-Valphos (R = i-Pr) 81% ee (S) (R)-t-Leuphos (R = t-Bu) 94% ee (R)
X Cl, Br, I, OTs Br, I Cl, Br, I, OTs
Cl, Br, I, OTs
Cl, Br, I, OTs Br, I, OTs
1. Kumada, Suzuki, Stille, Negishi, Hiyama coupling (C-C Formation：C-X + C-M)
General Mechanism
Kumada, Kumada-Corriu Coupling
1960年Chatt和Shaw:
X L2Ni
X
R
L2Ni + X
1
R'MgX
1970年Uchino等:
R L2Ni +
R' 2
MgX2
(bipy)Ni R R
3
+ R'-X
(bipy)Ni R' + R-R X
R = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl R' = Alkyl, aryl, vinyl, allyl, alkynyl, benzyl, acyl X = I, Br, Cl, OTf, OTs M = Mg, Zn, Cu, Sn, Si, B,...... Cat. = Pd, Ni, others Cu Fe......
Negishi (1977) Stille (1978) Suzuki (1979)
Ni or Pd Zn Aryl, allyl, benzyl, propargyl
Pd
Sn Aryl, vinyl,benzyl,
alkynyl
Pd
B Aryl, alkyl
Hiyama (1988)
Ni or Pd Si Aryl
Ph
MgBr + ArX NiCl2 ( dmpe )
Ph
Ar
Ph
+
Ar
(4) 碳－碳键的不对称形成 (Asymmetric formation of carbon-carbon single bonds)
PhMeCHMgCl +
[ Ni * ]
*
Br
PhMeCHCH = CH2
PPFA Y: 83 ~ 99% ee: 52 ~ 63%
R'
Aryl, alkyl, vinyl
Aryl, alkyl, vinyl
Aryl, alkyl, vinyl, alkynyl, benzyl, allyl Aryl, alkyl, vinyl, benzyl, allyl, acyl Aryl, alkyl, alkynyl
Aryl, alkyl, vinyl
R'-X + R-MX'
Catalyst R-R' + MXX'
Cross-Coupling Catalyst M
R
Reactions
Kumada-Corriu (1972)
Ni or Pd Mg Aryl, alkyl, vinyl
Sonogashira (1975) Pd/CuI Cu Aryl, alkyl