偶联反应小结

O
n-HexMgBr
O
O
OMe
Fe(acac)3 (5 mol%) THF-NMP
OMe +
OMe
X
0oC to rt, 5 min
Hex a, coupling product b, reduction product
Entry
X
1
I
Yield (GC, %)
a
b
27
46
2
Br
38
50
3
Cl
>95
60
19
12
12
4
Et2O (reflux)
69
18
9
9
*Amount after 0.05 mmol (equivalent to catalyst) subtracted.
18 Hayashi, T. et. al. Org. Lett. 2004, 6, 1297.
Alkyl Derivatives as Substrate
2
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
NMe2
TMEDA
Entrya
Additive
Product Yield (GC, %)
C
D
E
A
F
1
None
5
79
0
4
6
2
Et3N
3
78
0
11
5
3
N-Methyl
8
72
0
4
5
morpholine
4
DABCO
20
2
0
75
3
5
NMP
15
3
Trace
79
4
6
TMEDA
71
19
aPhMgBr (1.2 equiv), additive (1.2 equiv), 30 min.
PhCH2CH2CH3
11
[ Ni-P* ]
H
H2C CHCH 2CH 2Br + PhMgBr
H2C C
H C* Me Ph
12
(3) 反应中涉及的双键的立体化学
Ph
Br +
NiCl2L2 MeMgBr
Ph
CH 3
Ph
+
NiCl2L2 MeMgBr
Ph
Br
CH 3
Ph
MgBr + ArX NiCl2 ( dmpe )
63% ee (S)
(S)-(R)-PPFA
59% ee (R)
PPh2 NMe2 H Me
(S) - (R) - PPFA
14
H RC Me2N
CH2 PPh2
(S)-Valphos (R = i-Pr) 81% ee (S) (R)-t-Leuphos (R = t-Bu) 94% ee (R)
Ph Ph
Fe
R = Ph dppf
H10B10
dppc
Ph
PR2
Ph
9
10
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
CH2CH2CH3 Ni - Ph L2
20
Synthesis of Latrunculin B
MgBr
TfO O OR
Fe(acac)3 (10 mol%) THF, -30 oC
O OR
(97%)
O Cl
RN S
O
MeMgBr Fe(acac)3 (1.5 mol%)
THF, -78 oC to 0 oC
O
RN S
O (85%)
Fe-catalyzed cross-coupling
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
R = Me dmpf
X Cl, Br, I, OTs Br, I Cl, Br, I, OTs
Cl, Br, I, OTs
Cl, Br, I, OTs Br, I, OTs
3
1. Kumada, Suzuki, Stille, Negishi, Hiyama coupling (C-C Formation：C-X + C-M)
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
Cl N OTf
THF-NMP 0 oC
2.
MgBr
Fe-catalyzed cross-coupling
N
1. RCM
N
2. H2/cat.
(60%)
(R)-(+)-Muscopyridine
H
H
NN
Fe
O ClO
Fe(salen)Cl 1
O
OTf OctMgBr
Fe(acac)3 cat.
O
O
THF-NMP, rt, 2 h
4
General Mechanism
5
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
Scale: 20t/y Solvent: From Ether to THF, with Toluene as co-solvent.
22
Suzuki Coupling
R - X + R'-B
[ Pd ] R - R'
Ph
Ar
Ph
+
Ar
13
(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)-(S)-PPFA
Dynamic kinetic Resolution
R1 R2 C R4 R3
R4 X' [ ML*]
R1 R2 C R3
MgX
XMg
R1 C R2
R3
R4 X' [ ML*]
R1 R4 C R2
R3
15
New development of the catalyst
Fe-catalyst Low initial temperature (-20 °C) is beneficial
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)
Ph H H Br
(3 equiv)
+ PhMgX (1 equiv)
THF, 25 oC
Ph H
H Ph (32%)
Ph H + PhMgX DME, -20 oC to rt H Br
Ph H H Ph
(1 equiv) (1 equiv)
(90%)
Reaction condition: Fe(dbm)3 cat., 1-2 h
O O-
Ph
Ph
dbm
Molander, G. A. et. al. Tetrahedron Lett. 1983,1264, 5449.
➢ Aryl chlorides, triflates and tosylates are better substrates than aryl bromides and iodides
TMEDA plays a crucial role to reduce β-hydride elimination
Br
Ph
+ PhMgBr FeCl3 Cat. THF, Additive
+
+
+ Ph-Ph
A
B -78 oC to 0 oC C
D
E
F
30 min
(Desired product)
Me2N
4ຫໍສະໝຸດ Baidu
6
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 = 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......
-
4
OTf
>95
-
5
OTs
>95
-
Fürstner, A. et. al. Angew. Chem. Int. Ed. Engl. 20021,741, 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
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
O
O
O
OH
HN
Fe-catalyzed
S O
cross-coupling
Latrunculin B
Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003,2412, 5358.
Industrial examples
Hokko Chemical Industry, Japan
Sp3 C-X substrate?
7
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
8
配体的影响
PhCl + BuMgBr
NiCl2L2 ( 1 % )
Et2O, reflux 20h
3
Trace
10
19 Nakamura, E. et. al. J. Am. Chem. Soc. 2004, 126, 3686.
Synthesis of R-(+)-Muscopyridine and immuno suppressive agent FTY720
1.
MgBr
Fe(salen)Cl 1 (5 mol%)
MgBr
(CH2)5Ph +
A
Fe(acac)3 (5 mol%)
C
+
Solvent, 20 oC, 30 min (Desired product)
Br
+
B
E
+ D
F
Entry
Solvent
Product Yield (%)
C
D
E
F*
1
THF/NMP
25
25
24
26
2
THF
27
27
20
25
3
Et2O
偶联反应 Cross-Coupling Reaction
1
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)
O
(84%)
Fe-catalyzed cross-coupling
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.