偶联反应小结
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O OMe X n-HexMgBr O O Fe(acac)3 (5 mol%) OMe + OMe THF-NMP Hex 0oC to rt, 5 min a, coupling product b, reduction product
Entry
X a
Yield (GC, %) b 46 50 -
Sn
Cl, Br, I, OTs
Suzuki (1979) Hiyama (1988)
Pd Ni or Pd
B Si
Cl, Br, I, OTs Br, I, OTs
1. Kumada, Suzuki, Stille, Negishi, Hiyama coupling (C-C Formation：C-X + C-M)
MgBr A + Br B Fe(acac)3 (5 mol%) Solvent, 20 oC, 30 min (CH2)5Ph + C (Desired product) + E F D +
Entry
Solvent C
Product Yield (%) D 25 27 19 18 E 24 20 12 9 F* 26 25 12 9
RMg X + R'X'
NiX2L2
R - R' +
MgXX '
催化剂: NiX2L2 ( L2 = 双 膦 ) 溶剂: Et2O or THF 反应条件: 0 oC ~ R.T., reflux, 1 ~ 20 h, [Ni] / R’X’ = 10 -2 ~ 10 2 R’X’: sp 碳 的 卤 化 物
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
Ph PR2 Fe PR2 R = Me dmpf R = Ph dppf H10B10 Ph Ph Ph dppc
[ Ni * ] PhMeCHMgCl + Br
* P hMeCH CH = CH 2
PPFA Y: 83 ~ 99% (R)-(S)-PPFA (S)-(R)-PPFA
ee: 52 ~ 63% 63% ee (S) 59% ee (R)
PPh2 NMe2 H Me (S) - (R) - PPFA
General MechanΒιβλιοθήκη Baidusm
Kumada, Kumada-Corriu Coupling
1960年Chatt和Shaw:
X L2Ni X 1 L2Ni X R + R'MgX L2Ni 2 R' R + MgX2
1970年Uchino等:
(bipy)Ni 3 R R + R'-X (bipy)Ni 4 R' X + R-R
*
H H2C C
H C* Me Ph
(3) 反应中涉及的双键的立体化学
Ph Br MeMgBr NiCl2L2 Ph CH3
+
Ph + Br MeMgBr
NiCl2L2
Ph CH3
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)
Alkyl Derivatives as Substrate
TMEDA plays a crucial role to reduce β-hydride elimination
Br Ph + Ph-Ph E F Me2N NMe2 TMEDA + PhMgBr FeCl3 Cat. + + THF, Additive B C D -78 oC to 0 oC (Desired 30 min product)
5 3 8 20 15
6 (1.2 equiv), TMEDA(1.2 equiv), 71 min. additive 30
19
3
Trace
10
Nakamura, E. et. al. J. Am. Chem. Soc. 2004, 126, 3686.
Synthesis of R-(+)-Muscopyridine and immuno suppressive agent FTY720
1 2 3 4 5
I Br Cl OTf OTs
27 38 >95 >95 >95
Fürstner, A. et. al. Angew. Chem. Int. Ed. Engl. 2002, 41, 609.
Alkyl Derivatives as Substrate
β-Hydride elimination and homocoupling are the major setback with the cross-coupling of 1o and 2o alkyl substrates with aryl Grignard reagents
o o
O O OH Fe-catalyzed cross-coupling
O RN O (85%) S
HN
S O Latrunculin B
Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 5358.
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)
格氏试剂上烷基部分的异构化
Cl L2Ni Ph + H3C CH3 MgCl
H3C Ni L2
CH3 Ph
CH2 = CHCH3 H - Ni - P h L2
CH2CH2CH3 Ni - P h L2
Ph H3C CH3
CH2 = CHCH3 + P hH
P hCH2CH2CH3
[ Ni-P ] H2C CHCH CH2Br + PhMgBr 2
1 2 3 4
THF/NMP THF Et2O Et2O (reflux)
25 27 60 69
*Amount after 0.05 mmol (equivalent to catalyst) subtracted.
Hayashi, T. et. al. Org. Lett. 2004, 6, 1297.
R'-X
Cross-Coupling Reactions Kumada-Corriu (1972) Sonogashira (1975)
+ R-MX'
M Mg Cu
Catalyst
R-R'
R' Aryl, alkyl, vinyl Aryl, alkyl, vinyl
+
MXX'
X Cl, Br, I, OTs Br, I
Catalyst Ni or Pd Pd/CuI
R Aryl, alkyl, vinyl Aryl, alkyl
Negishi (1977)
Ni or Pd
Zn
Aryl, allyl, benzyl, propargyl
Aryl, vinyl,benzyl, alkynyl Aryl, alkyl Aryl
H R Me2N C CH2 PPh2 (S)-Valphos (R = i-Pr) 81% ee (S)
(R)-t-Leuphos (R = t-Bu) 94% ee (R)
Dynamic kinetic Resolution R1 C R R3
2 4
R
R4 X' [ ML*]
R1 R2 C R
+ PhMgX (1 equiv) + PhMgX (1 equiv)
THF, 25 oC
Ph
H
H Ph (32%) DME, -20 oC to rt Ph H H Ph
O O-
(1 equiv)
(90%)
Ph dbm Ph
Reaction condition: Fe(dbm)3 cat., 1-2 h
A
Entrya
Additive C
Product Yield (GC, %) D 79 78 72 2 3 E 0 0 0 0 Trace A 4 11 4 75 79 F 6 5 5 3 4
1 2 3 4 5
aPhMgBr
None Et3N N-Methyl morpholine DABCO NMP
Aryl, alkyl, vinyl, alkynyl, benzyl, allyl
Aryl, alkyl, vinyl, benzyl, allyl, acyl Aryl, alkyl, alkynyl Aryl, alkyl, vinyl
Cl, Br, I, OTs
Stille (1978)
Pd
偶联反应 Cross-Coupling Reaction
经典反应式
R'-X Substrate (Organic Electrophile) + Catalyst + R-MX' R--R' MXX' (Ni or Pd Coupling Partner ......?) Coupling Product Metal Halide (Organometallic Nucleophile) 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......
Synthesis of Latrunculin B
MgBr TfO O OR Fe(acac)3 (10 mol%) THF, -30 oC Fe-catalyzed cross-coupling O OR (97%) O O RN O S Cl MeMgBr Fe(acac)3 (1.5 mol%) THF, -78 C to 0 C
3
R1 MgX XMg C R2 R3
R4 X' [ ML*] R4 C
R1 R2 R3
New development of the catalyst
Fe-catalyst Low initial temperature (-20 °C) is beneficial
Ph
H
H Br (3 equiv) Ph H H Br
Sp3 C-X substrate?
MgXX'
RMgX L2 Ni 2 RMgX L2NiX2
5
R' R R'X'
R'X' L2NiR2
6
2
L2 Ni
7
R' X'
R'X'
2 MgX2
R-R R - R'
3
L2 Ni
R' R
配体的影响
NiCl2L2 ( 1 % ) PhCl + BuMgBr Et2O, reflux 20h PhBu
Molander, G. A. et. al. Tetrahedron Lett. 1983, 24, 5449.
Aryl chlorides, triflates and tosylates are better substrates than aryl bromides and iodides
1. Fe-catalyzed cross-coupling
H
MgBr N
Cl
N
OTf
Fe(salen)Cl 1 (5 mol%) THF-NMP 0 oC 2. MgBr
1. RCM 2. H2/cat.
N
N O
N Fe O Cl
H
(60%)
(R)-(+)-Muscopyridine
Fe(salen)Cl 1
Fe-catalyzed cross-coupling O O OTf OctMgBr Fe(acac)3 cat. THF-NMP, rt, 2 h O O (84%) OH H2N OH Immunosuppressive agent FTY720
Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 308. Fürstner, A. et. al. J. Org.Chem. 2004, 69, 3950.
Entry
X a
Yield (GC, %) b 46 50 -
Sn
Cl, Br, I, OTs
Suzuki (1979) Hiyama (1988)
Pd Ni or Pd
B Si
Cl, Br, I, OTs Br, I, OTs
1. Kumada, Suzuki, Stille, Negishi, Hiyama coupling (C-C Formation：C-X + C-M)
MgBr A + Br B Fe(acac)3 (5 mol%) Solvent, 20 oC, 30 min (CH2)5Ph + C (Desired product) + E F D +
Entry
Solvent C
Product Yield (%) D 25 27 19 18 E 24 20 12 9 F* 26 25 12 9
RMg X + R'X'
NiX2L2
R - R' +
MgXX '
催化剂: NiX2L2 ( L2 = 双 膦 ) 溶剂: Et2O or THF 反应条件: 0 oC ~ R.T., reflux, 1 ~ 20 h, [Ni] / R’X’ = 10 -2 ~ 10 2 R’X’: sp 碳 的 卤 化 物
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
Ph PR2 Fe PR2 R = Me dmpf R = Ph dppf H10B10 Ph Ph Ph dppc
[ Ni * ] PhMeCHMgCl + Br
* P hMeCH CH = CH 2
PPFA Y: 83 ~ 99% (R)-(S)-PPFA (S)-(R)-PPFA
ee: 52 ~ 63% 63% ee (S) 59% ee (R)
PPh2 NMe2 H Me (S) - (R) - PPFA
General MechanΒιβλιοθήκη Baidusm
Kumada, Kumada-Corriu Coupling
1960年Chatt和Shaw:
X L2Ni X 1 L2Ni X R + R'MgX L2Ni 2 R' R + MgX2
1970年Uchino等:
(bipy)Ni 3 R R + R'-X (bipy)Ni 4 R' X + R-R
*
H H2C C
H C* Me Ph
(3) 反应中涉及的双键的立体化学
Ph Br MeMgBr NiCl2L2 Ph CH3
+
Ph + Br MeMgBr
NiCl2L2
Ph CH3
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)
Alkyl Derivatives as Substrate
TMEDA plays a crucial role to reduce β-hydride elimination
Br Ph + Ph-Ph E F Me2N NMe2 TMEDA + PhMgBr FeCl3 Cat. + + THF, Additive B C D -78 oC to 0 oC (Desired 30 min product)
5 3 8 20 15
6 (1.2 equiv), TMEDA(1.2 equiv), 71 min. additive 30
19
3
Trace
10
Nakamura, E. et. al. J. Am. Chem. Soc. 2004, 126, 3686.
Synthesis of R-(+)-Muscopyridine and immuno suppressive agent FTY720
1 2 3 4 5
I Br Cl OTf OTs
27 38 >95 >95 >95
Fürstner, A. et. al. Angew. Chem. Int. Ed. Engl. 2002, 41, 609.
Alkyl Derivatives as Substrate
β-Hydride elimination and homocoupling are the major setback with the cross-coupling of 1o and 2o alkyl substrates with aryl Grignard reagents
o o
O O OH Fe-catalyzed cross-coupling
O RN O (85%) S
HN
S O Latrunculin B
Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 5358.
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)
格氏试剂上烷基部分的异构化
Cl L2Ni Ph + H3C CH3 MgCl
H3C Ni L2
CH3 Ph
CH2 = CHCH3 H - Ni - P h L2
CH2CH2CH3 Ni - P h L2
Ph H3C CH3
CH2 = CHCH3 + P hH
P hCH2CH2CH3
[ Ni-P ] H2C CHCH CH2Br + PhMgBr 2
1 2 3 4
THF/NMP THF Et2O Et2O (reflux)
25 27 60 69
*Amount after 0.05 mmol (equivalent to catalyst) subtracted.
Hayashi, T. et. al. Org. Lett. 2004, 6, 1297.
R'-X
Cross-Coupling Reactions Kumada-Corriu (1972) Sonogashira (1975)
+ R-MX'
M Mg Cu
Catalyst
R-R'
R' Aryl, alkyl, vinyl Aryl, alkyl, vinyl
+
MXX'
X Cl, Br, I, OTs Br, I
Catalyst Ni or Pd Pd/CuI
R Aryl, alkyl, vinyl Aryl, alkyl
Negishi (1977)
Ni or Pd
Zn
Aryl, allyl, benzyl, propargyl
Aryl, vinyl,benzyl, alkynyl Aryl, alkyl Aryl
H R Me2N C CH2 PPh2 (S)-Valphos (R = i-Pr) 81% ee (S)
(R)-t-Leuphos (R = t-Bu) 94% ee (R)
Dynamic kinetic Resolution R1 C R R3
2 4
R
R4 X' [ ML*]
R1 R2 C R
+ PhMgX (1 equiv) + PhMgX (1 equiv)
THF, 25 oC
Ph
H
H Ph (32%) DME, -20 oC to rt Ph H H Ph
O O-
(1 equiv)
(90%)
Ph dbm Ph
Reaction condition: Fe(dbm)3 cat., 1-2 h
A
Entrya
Additive C
Product Yield (GC, %) D 79 78 72 2 3 E 0 0 0 0 Trace A 4 11 4 75 79 F 6 5 5 3 4
1 2 3 4 5
aPhMgBr
None Et3N N-Methyl morpholine DABCO NMP
Aryl, alkyl, vinyl, alkynyl, benzyl, allyl
Aryl, alkyl, vinyl, benzyl, allyl, acyl Aryl, alkyl, alkynyl Aryl, alkyl, vinyl
Cl, Br, I, OTs
Stille (1978)
Pd
偶联反应 Cross-Coupling Reaction
经典反应式
R'-X Substrate (Organic Electrophile) + Catalyst + R-MX' R--R' MXX' (Ni or Pd Coupling Partner ......?) Coupling Product Metal Halide (Organometallic Nucleophile) 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......
Synthesis of Latrunculin B
MgBr TfO O OR Fe(acac)3 (10 mol%) THF, -30 oC Fe-catalyzed cross-coupling O OR (97%) O O RN O S Cl MeMgBr Fe(acac)3 (1.5 mol%) THF, -78 C to 0 C
3
R1 MgX XMg C R2 R3
R4 X' [ ML*] R4 C
R1 R2 R3
New development of the catalyst
Fe-catalyst Low initial temperature (-20 °C) is beneficial
Ph
H
H Br (3 equiv) Ph H H Br
Sp3 C-X substrate?
MgXX'
RMgX L2 Ni 2 RMgX L2NiX2
5
R' R R'X'
R'X' L2NiR2
6
2
L2 Ni
7
R' X'
R'X'
2 MgX2
R-R R - R'
3
L2 Ni
R' R
配体的影响
NiCl2L2 ( 1 % ) PhCl + BuMgBr Et2O, reflux 20h PhBu
Molander, G. A. et. al. Tetrahedron Lett. 1983, 24, 5449.
Aryl chlorides, triflates and tosylates are better substrates than aryl bromides and iodides
1. Fe-catalyzed cross-coupling
H
MgBr N
Cl
N
OTf
Fe(salen)Cl 1 (5 mol%) THF-NMP 0 oC 2. MgBr
1. RCM 2. H2/cat.
N
N O
N Fe O Cl
H
(60%)
(R)-(+)-Muscopyridine
Fe(salen)Cl 1
Fe-catalyzed cross-coupling O O OTf OctMgBr Fe(acac)3 cat. THF-NMP, rt, 2 h O O (84%) OH H2N OH Immunosuppressive agent FTY720
Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 308. Fürstner, A. et. al. J. Org.Chem. 2004, 69, 3950.