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.
AБайду номын сангаасkyl 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
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
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
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.
General Mechanism
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
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......
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.
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
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
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
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
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)
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)
*
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)
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
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
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.
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 -
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