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
(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.
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
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
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)
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
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
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
Scale: 20t/y Solvent: From Ether to THF, with Toluene as co-solvent.
22
Suzuki Coupling
R - X + R'-B
[ Pd ] R - R'
4
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
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
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
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
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
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
4
General Mechanism
5
Kumada, Kumada-Corriu Coupling
1960年Chatt和Shaw:
X L2Ni
X
Rபைடு நூலகம்
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
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.
63% ee (S)
(S)-(R)-PPFA
59% ee (R)
PPh2 NMe2 H Me
(S) - (R) - PPFA