c-sp 3 coupling using alkyl halides as electrophiles: work by gregory fu
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C-sp 3 Coupling Using Alkyl Halides as Electrophiles: Work by Gregory Fu. Presented by Pascal Cérat Litterature meeting March 31 th 2009. Cross-Coupling in Chemistry. - PowerPoint PPT PresentationTRANSCRIPT
1
C-spC-sp33 Coupling Using Alkyl Coupling Using Alkyl Halides as Electrophiles: Halides as Electrophiles:
Work by Gregory FuWork by Gregory Fu
Presented by Pascal Cérat
Litterature meetingMarch 31th 2009
2
Cross-Coupling in ChemistryCross-Coupling in Chemistry
Cross-coupling offers a direct and easy way for the creation of a C-C bounds from an electrophile (C-X) with an organometallic nucleophile (C-M).
Metals use to catalyze these reactions: Pd, Ni, Cu, Fe, Co and Mn.
Also, a lot of different organometallic compounds can be used as nucleophiles such as grignard reagents, organozinc, tin, boron, and even silicon derivatives.
Cross-coupling reactions allow the presence of functional groups as the reaction is particularly selective.
There are a lot of examples of cross-coupling in synthesis of natural compounds and pharmaceutical chemistry:
OBnB O
O
OMeO
NHCbz +
NH
O
NBoc
O
I
PdCl2(dppf)2, CH2Cl2
K2CO3, DME, 80oC,2h, 75% MeO
OMe
O
NHCbz
O
NBoc
steps
HO
NH
O
HONH
O
HN O
NH
O
NH2O
NH
O
OTMC-95A
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374. Masse, J.P.; Corriu, J.P. J. Chem. Soc., Chem. Comm. 1972, 144.Milstein, D.; Stille, J.K. J. Am. Chem. Soc. 1979, 101, 4992.Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340.Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.Lin, S.; Danishefsky, S.J. Angew. Chem. Int. Ed. Engl. 2002, 41, 512
3
OutlinesOutlines
1) Introduction on cross-coupling methodologiesa) Kumada-Corriub) Negishic) Stilled) Hiyamae) Suzuki
2) Difficulties with sp3-alkyl halides possessing -H
3) First advancements on sp2-sp3 and sp3-sp3 cross-coupling- Corey first sp3-sp3 example- Caslte and Widdowson controversy- Suzuki’s work- Knochel’s development with a cocatalyst- Kambe’s work using 1,3-butadienes
4) Gregory Fu’s cross-coupling methodologies- Unactivated aryl chloride system- Primary alkyl halides (Cl, Br, I and OTs)- Secondary alkyl halides (Br, I)- Assymetric cross-coupling with Ni-complex- Mechanistic studies
4
Kumada-Corriu Discovery of Coupling with GrignardsKumada-Corriu Discovery of Coupling with Grignards
In 1972, Kumada and Corriu reported a cross-coupling reaction with grignard reagents using a nickel complex as the catalyst.
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374.Masse, J.P.; Corriu, J.P. J. Chem. Soc., Chem. Comm. 1972, 144.Kumada, M. Pure Appl. Chem. 1980, 52, 669.
BrPh + ArMgBr
Ni(acac)2 (0.5 mol%)
RPh
Yield: 40 - 75 %
Et2O, r.t.
Corriu (1972):Kumada (1972):
Cl + R'MgBrNi(dipy)2 (0.7 mol%)
R'Et2O, 0oC to reflux R = aryl, alkenyl
R' = alkyl, aryl R = aryl, alkenyl
Yield: 80 - 98 %
R R
Proposed catalytic cycle:
Disadvantage: Grignards are not compatible with a lot of functional groups
L2NiX2
2 RMgX
2 MgX2
L2NiR2
R'-X'
R-R
L2NiR'X'
RMgX
MgXX'
L2NiR'R
R'-X'
L2NiR'R
R'X'
R-R'
Transmetallation
Reductiveelimination
Transmetallation
CoordinationOxidativeaddition
L = bidentate phosphine (dppp, dmpf, dppe) or monodentate phosphine (Ph3P)
X = Cl, Br
Oxidativeaddition
5
Negishi Coupling Reaction with Organozinc ReagentsNegishi Coupling Reaction with Organozinc Reagents
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Negishi, E.-I.; King, A.O.; Okukado, N. J. Org. Chem. 1977, 42, 1921.Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340.
Simplified catalytic cycle:
MLn
R1-X
R1-MLn-XR2
2Zn
R1-MLn-R2
R1-R2
M = Ni, Pd
Negishi reported in 1976 the cross-coupling with Ni- and Pd-complex using organoaluminums.
Between 1976 to 1978, his group explored different aspects of the reaction such as:
- Using different organometals containing Al, B, Zn and Zr.
- Demonstration of Pd- or Ni-catalysed hydrometallation-cross-coupling and carbometallation in a domino process.
- Demonstration of double metal catalysis by the addition of ZnX2 along with the usual Pd or Ni catalyst.
Negishi (1977):
Ar1ZnCl +
Cl2Pd(PPh3)2 (cat.),
THF, r.t.
Yield : 70 - 95 %or
Ni(PPh3)4
(i-Bu)2AlH
Ar2-X Ar1-Ar2 + ZnXCl
Advantage : RZnCl are more easily fonctionnalized
6
Stille Coupling Reaction with Tetraorganotin ReagentsStille Coupling Reaction with Tetraorganotin Reagents
In 1979, Stille then developed a new cross-coupling reaction with Pd as the catalyst where the nucleophile can be more functionalized than Grignard.
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Milstein, D.; Stille, J.K. J. Am. Chem. Soc. 1979, 101, 4992.
Stille (1979):
Br + R4SnPhCH2Pd(PPh3)Cl
HMPA
R + R3SnBr
R = Me, n-Bu, Ph or vinylYield : 62 - 100 %
+ R4SnPhCH2Pd(PPh3)Cl
HMPA+ R3SnBr
R = Me or PhYield : 78 - 95 %
Ar-Br Ar-R
Proposed mechanism for Palladium cycle: L2Pd(II)X2
[PdL2]
PdL
RX
L
PdL
RL
R'
PdL
RR'
L
R-X
R'SnR''3XSnR''3
R-R'
Oxidative addition (syn)
Transmetallation
Isomerization
Reductiveelimination
Highly Toxic!
PdL
RL
X
Isomerization
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Stille Coupling Reaction with Tetraorganotin ReagentsStille Coupling Reaction with Tetraorganotin Reagents
SE2(open): Case of an open associative transmetallation
- Use of polar and coordinating solvents
- Absence of bridging abitlity in the complex.
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Stille, J.K.; Lau, K.S.Y. Acc. Chem. Res. 1977, 10, 434.
Transmetallation processSE2(cyclic): Case of an cyclic associative transmetallation
- Non-coordinating solvents
- The presence of a bridging ligand.
Retention of configuration Inversion of configuration
L2Pd(II)X2
[PdL2]
PdL
RX
L
PdL
R
R'
X
PdL
RR'
R-X
R'SnR''3
R-R'
Oxidative addition (syn)
Transmetallation
Isomerization
Reductiveelimination
PdL
RL
X
L
Sn
SnX
L
RPd LLX
R' Sn
+ S- S
RPd LLS
+
X-PdRL
L X
SnR''3
S = L or solvent
PdL
RL
R'
8
Hiyama Coupling Reaction with Organosilicon CompoundsHiyama Coupling Reaction with Organosilicon Compounds
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918.Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
Proposed mechanism of palladium-catalyzed fluorosilane cross-coupling:
Ar-XSiMe3 +[( -allyl)PdCl]2 (2.5 mol%)
TSAF, HMPA, 50oCAr + SiMe3X
Yield : 84 - 98 %
Hiyama (1988):
R-SiMe3 + R'-XP(OEt)3 (1.5 mol%)TSAF, THF, 50oC
[( -allyl)PdCl]2 (2.5 mol%)R-R' + SiMe3X
R, R' = alkenylYield : 32 - 100 %
RSiMe2FF-
Activation[RSiMe2F2]-
X-Pd-ArF2Me2Si
XPd-Ar
R
TransmetallationF2Me2Si
XPd-Ar
RR-Pd-Ar
R-Ar
9
Miyaura-Suzuki Coupling Reaction with Organoboron ReagentsMiyaura-Suzuki Coupling Reaction with Organoboron ReagentsOrganoboron has a lot of advantages as they are generally thermally stable and are inert to water and oxygen which make them a great choice as reagent for coupling process.
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866.Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.Matos, K.; Soderquist, J.A. J. Org. Chem. 1998, 63, 461.
Catalytic cycles for trialkylboranes derivatives by Soderquist:
Suzuki-Miyaura (1979):
R-BY2 + Ar-XPd(PPh3)4 (0.1 eq.)
R-Ar + XBY2EtOH, NaOEt
R = alkenylY2 = Bis(1,2-dimethoxypropyl) or
O
O
Yield : 41 - 100%
PdL2 [R1PdXL2]R1-X
BR2
OH
R1L2Pd
BR2
HO
X-
OH-
BR2
HO
ate-complex
[R1R2PdL2]
R1-R2
All the cross-coupling reactions been shown so far are involving the creation of an sp2-sp2 bound!
10
Problematic of Alkyl Halides as ElectrophilesProblematic of Alkyl Halides as Electrophiles
Alkyl halides are said to react slowly with Pd0 and Ni0 in the oxidative addition step, because of the more electron-rich C(sp3)-X bond compare to an C(sp2)-X
Two main possibilities are found for the oxidative addition of alkyl halide to a metal:
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Stille, J.K.; Lau, K.S.Y. Acc. Chem. Res. 1977, 10, 434.Cárdenas, D.J. Angew. Chem. Int. Ed. 1999, 38, 3018.Luh, T.-Y.; Leung, M.; Wong, K.T. 2000, 100, 3187.Rudolph, A.; Lautens, M.; Angew. Chem. Int. 2009, 48, 2.
Oxidative additionUsual cis-complexes are obtained during the oxidative addition with C(sp2)-X electrophiles:
PdL
L+
RX
PdL
L
R
XPd
L R
XL
NiL
LL
R + CR'
RH
X NiL
LL
RX
+H
CR
R'
Racemization
PdL2+CR'
RH
X PdR'
HR
L
L
X
PdR'
HR
PPh3
PPh3
X
SN2
Inversionof configuration
- By a free radical pathway
- By an associative bimolecular SN2 pattern (mainly for low valent metals)
11
Problematic of Alkyl Halides as ElectrophilesProblematic of Alkyl Halides as Electrophiles
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Cárdenas, D.J. Angew. Chem. Int. Ed. 1999, 38, 3018.Luh, T.-Y.; Leung, M.; Wong, K.T. 2000, 100, 3187.Rudolph, A.; Lautens, M.; Angew. Chem. Int. 2009, 48, 2.
-Elimination
In the case of alkyl metal species the lack of electrons available to interact with the empty d-orbitals of the metal center are less stable than an aryl or alkenyl species.
The presence of -hydrogen make possible a decomposition of the alkyl-Pd(II) complex by a fast elimination of the hydrogen.
MmLnR1
X
Oxidativeaddition (slow)
R1M(m+2)
H H -Hydrideelimination
R1 + HXM(m+2)Ln
Decomposition process
X
R1M(m+2)
H H R2
R2M'YmXM'Ym
Transmetallation
R1R2
Reductiveelimination
12
Problematic of Alkyl Halides as ElectrophilesProblematic of Alkyl Halides as Electrophiles
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Cárdenas, D.J. Angew. Chem. Int. Ed. 1999, 38, 3018.Luh, T.-Y.; Leung, M.; Wong, K.T. 2000, 100, 3187.Rudolph, A.; Lautens, M.; Angew. Chem. Int. 2009, 48, 2.
-Elimination-elimination requires several conditions such as the existence of a vacant coordination site and the possibility to arrange the M-C-C-H atoms in the same plane.
Large bulky and electron rich ligands (like: Pd(PPh3)4 and PdCl2(dppf)2) can favor reductive elimination over -hydride elimination.
- Phosphines with small bite angle:
- Larger bite angle:
Also, the use of coordinating cocatalyst may prevent the formation of vacant coordination sites or simply accelerate the reductive elimination step.
PdP
PR' R''
Reductive elimination
PdP
P R''R'
HH
-Hydride eliminationPdP
PR'
R''H
PdR' R''
Reductive elimination
H
-Hydride eliminationR''P
P
Pd R''HP
P R'PdR'
HP
P
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First Examples of Alkyl Halides CouplingFirst Examples of Alkyl Halides Coupling
Corey, E.J.; Semmelhack, M.F. J. Am. Chem. Soc. 1967, 89, 2755.
The first example reported of the use of an alkyl halide during a cross-coupling procedure was done by E.J. Corey using the complex of metallylnickel(I) bromide.
This methodology was then used for the synthesis of - and epi--santalene:
I
+ NiBr
2
DMF
-santalene88 % yield
I
+ NiBr
2
DMF
epi--santalene90 % yield
Corey (1967):
R X + NiBrBr
NiDMF
R
(0.6 eq.) R = methyl (90 %) = cyclohexyl (91 %) = 4-hydroxycyclohexyl (88 %) = t-butyl (25 %)
14
Controversy with Castle and Widdowson MethodologyControversy with Castle and Widdowson Methodology
Castle, P.L.; Widdowson, D.A. Tet. Lett. 1986, 27, 6013.Yuan, K.; Scott, W.J. Tet. Lett. 1989, 30, 4779.Yuan, K.; Scott, W.J. J. Org. Chem. 1990, 55, 6188.Yuan, K.; Scott, W.J. Tet. Lett. 1991, 32, 189.
In 1986 a methodology using a palladium complex, done by Castle and Widdowson, could catalyzed a Kumada-Corriu reaction with alkyl halides.
The group of Widdowson claimed that using dppf ligand suppresses -elimination in the final intermediate and that this reaction could lead to sp3-sp3 coupling reaction.
In 1989, Yuan and Scott failed to reproduced the work of Castle and Widdowson. Only the corresponding alkanes from the reduction of the alkyl halides could be isolated using (dppf)Pd(0) or (dppf)PdCl2.
+
Pd(dppf)Cl2 (5 mol%),DIBAL (0,1 eq.)
THF, reflux100 %
MgBrn-C6H13I n-C6H14 + n-C6H13
0 %
+
Pd(dppf)Cl2 (5 mol%),DIBAL (0,1 eq.)
THF, reflux
87%
MgBrEtI
+
Pd(dppf)Cl2 (5 mol%),DIBAL (0,1 eq.)
THF, refluxMgBrn-C6H13I
Et
n-C6H13
63 %
15
Controversy with Castle and Widdowson MethodologyControversy with Castle and Widdowson Methodology
Yuan, K.; Scott, W.J. Tet. Lett. 1989, 30, 4779.Yuan, K.; Scott, W.J. J. Org. Chem. 1990, 55, 6188.Yuan, K.; Scott, W.J. Tet. Lett. 1991, 32, 189.
R X(dppf)PdCl2 (2.2 mol%)
EtMgBr (3.5 eq.),THF, reflux
R-H
HX = Br (76 %)
Ph HX = I (76 %) = Br (91 %) = Cl (76 %)
Ph H
X = I (80 %) HX = I (57 %)
Reduction of alkyl halides with (dppf)PdCl2:
Later, in 1991, Yuan and Scott reported a system using Ni(dppf)Cl2 as the catalyst for a Kumada-Corriu coupling unactivated neopentyl idodes with grignard reagents.
RI
(dppf)NiCl2 (10 mol%)
Aryl-MgBr (4 eq.),Et2O, reflux, 12 h.
RAryl
71 %
CH3
71 %OMe
94 %
S
59 %
OMe
80 %
Yuan and Scott (1991):
16
Boro-Alkyl Suzuki-Miyaura Cross Coupling ReactionBoro-Alkyl Suzuki-Miyaura Cross Coupling Reaction
Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691.
In 1992, Suzuki and Miyaura developed a coupling reaction between a boronate (9-BBN) group and an alkyl halide.
R9-BBN-H
HydroborationB
R
No bromide or chloride were used
OMe
O
45 %
OCH2Ph
58 %
NC
61 %
MeO
OOO
57 % 64 %
Restricted scope to mainly long alkyl chains without FG, except: ester, cyano, alkene and ether groups
R I + R' BPd(PPh3)4 (3 mol %)
K2CO3 (3.0 eq.),dioxane, 60 oC
R R'
R, R' = alkyl
Miyaura and Suzuki (1992):
71 - 45% yield1.0 eq,
17
Cross-Coupling of IodocyclopropanesCross-Coupling of Iodocyclopropanes
Charette, A.B.; Giroux, A. J. Org. Chem. 1996, 61, 8718.
Cyclopropyl halides are interesting electrophiles for cross-coupling as the -hydride elimination is not favoured because of the strain that is generated in the cyclopropene.
PdI
R R
cyclopropene
+ HPdI-H elimination
OR4Ph
R4 = Bn (84 %) = H (81 %)
Ph
OBn82 %
OBnBnO
64 %
OBn
86 %
Vinyl boronate esters:
Arylboronic acids:
Ph OBn
80 %
Ph
78 %OBn MeO
OBn
85 %
OBn
Me
80 %*
OBn
70 %*
S
* Done with CsF (4.5 eq.) in DMF
IR + R2-B(OR3)2 R2 R
Pd(OAc)2 (10 mol%)PPh3 (0.5 eq.)
1.5 eq. K2CO3 (3 eq.), Bu4NCl (2 eq.),DMF/H2O (4:1), 90oC, 4-20 h.
Charette (1996):
86 - 35% yield
18
Cross-Coupling of IodocyclopropanesCross-Coupling of Iodocyclopropanes
Charette, A.B.; Freitas-Gil, R.P. Tet. Lett. 1997, 38, 2809.Martin, S.F.; Dwyer, M.P. Tet. Lett. 1998, 39, 1521.
Synthesis of polycyclopropanes by Suzuki-type cross-coupling:
BR2O
O+I OR
Pd(OAc)2 (10 mol%),PPh3 (0.5 eq.)
ORR2
Charette (1997):
(1.1 eq.)
t-BuOK (2 eq.),DME, 80oC
Bu OH
64 %
OBn
60 %
Ph OBn
71 %
BnO
Tri-substituted cyclopropanes by Martin:
O
H
H
I Ht-BuLi, THF, -78oC;
ZnCl2, -40oC;then Ar-I, Pd(Ph3)4
60 - 72 %O
H
H
Ar H
Ar = Ph, 4-MeO-Ph
PhB(OH)2, Pd(OAc)2,PPh3, K2CO3, Bu4NCl,
DMF/H2O, 90oC
88 %O
H
H
Ph H
19
Knochel’s Work on Nickel-Catalysed Cross-CouplingKnochel’s Work on Nickel-Catalysed Cross-Coupling
Devasagayaraj, A.; Stüdemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1995, 34, 2723.Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am. Chem. Soc. 1971, 93, 3350.Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
Preliminary work with organozincs:
The need of the double bond restraint the scope of the reaction.
R
Pent
R = Ph (80%) = Bu (72%)
84 %
CO2EtEt
CO2EtOPiv
R
R = Ph (90%) = Bu (70%)
OPiv
79 %
CO2Et
78 %
OAc
OTMS
Zn2
OCO2Et
65 %
I(FG-R)2Zn +Ni(acac)2 (7 mol %)
THF : NMP (2:1)-35 oC, 0.5-18 h.
R2n
n = 3,4R2 = H, CO2R
FG-R R2n
Knochel (1995):
84 - 65% yield
20
Knochel’s Work on Nickel-Catalysed Cross-CouplingKnochel’s Work on Nickel-Catalysed Cross-Coupling
Devasagayaraj, A.; Stüdemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1995, 34, 2723.Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am. Chem. Soc. 1971, 93, 3350.Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
The coordination of the Nickel to the double bond has been found to remove electron density from the metal and favors the reductive elimination to obtain the desired cross-coupling product.
Proposed mechanism:
Ni XL
L
R1R1
X
The double-bond stabilizethe nickel-complex
[NiL2]
[Ni(acac)2]
R22Zn
Ni R2L
L
R1
Defavorable interaction
Reductiveelimination
Ni R2L
L
R1 R22Zn
Transmetallation ZnX
R1
R2
R1
Favored by low temperature
High temperature promotes the dissociation of the alkene to the complex which then undergo transmetallation followed by an halogen-zinc exchange.
Replacement of the [Ni(acac)2] by [PdCl2(CH3CN)2] leads only to the bromine-zinc exchange product.
21
Knochel’s Work on Nickel-Catalysed Cross-CouplingKnochel’s Work on Nickel-Catalysed Cross-Coupling
Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186.Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 2387.Piber, M.; Jensen, A.E.; Rottländer, M.; Knochel, P. Org. Lett. 1999, 1, 1323.Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
In 1998 to 1999, Knochel reported the used of a promotor (co-catalyst) with the nickel complex:
FG1RCH2I + (FG2RCH2)2Zn
[Ni(acac)2] (10 mol%)THF/NMP, -35oC
F3C
(0.2 - 1.0 eq.)
FG1RCH2CH2RFG2
Knochel (1998):
81 - 59% yield
FG1RCH2I +
[Ni(acac)2] (10 mol%)THF/NMP, -35oC
(1.0 eq.)
FG1RCH2Ar
Knochel (1998):
ArZnBr
F3C
ArSS
Ar = Ph (75 %) = p-MeO-Ph- (77 %) = p-CN-Ph- (80 %) = m-EtO2C-Ph- (72 %)
Ar OEt
O
Ar = p-Cl-Ph (71 %) = p-MeO-Ph- (78 %) = p-CN-Ph- (75 %)
OMeO
72 %
S
75 %
Ar N
O
Ar = p-CN-Ph (71 %) = o-EtO2C-Ph- (72 %)
O
EtO2C71 %*
* 3 eq. of Bu4NI was added as additive
CO2Et
1.05 eq. 81 - 63 % yield
Diorganozinc reagent can also be coupled:
22
Knochel’s Work on Nickel-Catalysed Cross-CouplingKnochel’s Work on Nickel-Catalysed Cross-Coupling
Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186.Giovannini, R.; Stüdemann, T.; Dussin, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 2387.Giovannini, R.; Stüdemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.Jensen, A.E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
Some primary alkyl bromides were also used using the same system.
Other cocatalysts tried during these studies:
CH3
O
F3C
CH3
OF3C
CF3
CF3
CF3
O O
F5 F5
CF3 CF3
F3C CF3
NO2
NO2
F3C CF3
CF3
FG1RCH2Br +
[Ni(acac)2] (10 mol%)THF/NMP, -35oC
(1.0 eq.)
FG1RCH2-R2
Knochel (2002):
R2ZnBr
F
55 - 73% yield
23
Kambe’s Following on the Use of Co-catalystKambe’s Following on the Use of Co-catalyst
Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222.Terao, J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Lett. 2003, 32, 890.Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646.
In 2002, Kambe introduced his work on the cross-coupling reactions of grignard reagents on alkyl halides and tosylates with 1,3-butadienes as co-catalyst.
R X + R' MgX'
R = alkylX = Cl, Br, OTs
R' = alkyl, aryl
NiCl2 (1 - 3 mol%)
butadiene (0.1 - 1 eq.),THF, 0 oC to r.t.
R R'
Kambe (2003):
Br
n-Bu(X = Br) 100 %
Et(X = OTs) 87 %
Et
(X = OTs) 56 %
n-Oct
(X = Br) 99 %
n-Oct
(X =Cl) 96 %(X = Br) 87 %
Suggest that radical intermediatesare not possible
100 - 56% yield
R X + R' MgX'
R = alkylX = Cl, Br, OTs
R' = alkyl, aryl
Pd(acac)2 (1 - 3 mol%)
butadiene (0.1 - 1 eq.),THF, 0 oC to r.t.
R R'
Kambe (2003):
n-Oct
(X = Br) 86 %
Br
n-Bu(X = OTs) 71 %
Cl
n-Hep
(X = OTs) 96 %
n-Bu(X = Br) 77 %
ClEt
(X = OTs) 86 %
BrPh
(X = OTs) 69 %* 8% reacted on the bromide
Better chemoselectivity for the OTs with Pd(acac)2 than with NiCl2
100 - 69% yield
24
Kambe’s Following on the Use of Co-catalystKambe’s Following on the Use of Co-catalyst
De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004.Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222.
Kambe then proposed a mechanism in which the nickel-complex is stabilized by the donation of electronic density from allyl species.
These kind of complexes seem possible witch nickel, but for palladium to pass through a Pd(IV) complex is less possible.
Ni
Ni(0)
R'-MgX
NiR'
MgX
R-X
MgX2
NiR'R
R'-R(II)
(II)
(IV)
Dimerization
25
Gregory C. FuGregory C. Fu
Professor’s Fu research first started on the development of a planar-chiral heterocycles for enantioselective nucleophilic catalysts. He has been able to created chiral derivatives of the well known DMAP for catalysis in nucleophilic reactions.
More recently, he has also focused his work on the chemistry of boron heterocycles, palladium and nickel- catalyzed coupling processes. Improvement have been seen for the coupling of chloro-aryl compounds as well as primary and secondary alkyl halides.
Gregory C. Fu received a degree from MIT in 1985, where he worked in the laboratory of Prof. Barry Sharpless. After earning a Ph. D. from Havard under the guidance of Prof. David Evans, he spent 2 years as a post-doctoral fellow with Prof. Robert Grubbs at Caltech.
In 1993, he returned to MIT where he is currently working as the Firmenich Professor of Chemistry. During all his years of research, Prof. Fu gained multiple awards. The most recent one is the Catalysis Science Award obtained in 2007.
The man behind the study
His research
Ralkyl-X + R-M Ralkyl-R
cat. Pd or Ni, PR3
X = Cl, Br, OTs
Fe
PhPh Ph
PhPh
N
N
Used for kinetic resolutionof secondary alcools
26
P(t-Bu)P(t-Bu)33 and PCy and PCy33 as Ligands in Coupling Reactions with Aryl Electrophiles as Ligands in Coupling Reactions with Aryl Electrophiles
Littke, A.F.; Fu, G.C. Angew. Chem. Int. Ed. 1998, 37, 3387.Littke, A.F.; Dai, C.; Fu, G.C. J. Am. Chem. Soc. 2000, 122, 4020.Fu, G.C. Acc. Chem. Res. 2008, 41, 1555.
Suzuki reactions:
For aryl triflates, no reaction is obtained with P(t-Bu)3 and PCy3 must be used:
Ar X + (HO)2B Ar1 Ar Ar1
Pd2(dba)3 (0.5 - 1.5 mol %),P(t-Bu)3 (1.0 - 4.5 mol %)
KF (3.3 eq.),THF or dioxane,
r.t. to 90 oCX = Cl, Br, I
Ar-X
MeO Cl
(OH)2B-Ar1 yield (%)
NCl
Cl
Me
(HO)2B
Me
(HO)2B
Me
Ar-X (OH)2B-Ar1 yield (%)
(HO)2B
Me
H2N BrS
(HO)2B
(HO)2B
Me
I (HO)2B
Me
Me
Br
Me
Me
OMe
88
97
93
99
97
94
99 - 88% yield1.1 eq.
Ar OTf + (HO)2B Ar1 Ar Ar1
Pd(OAc)2 (1 mol %),PCy3 (1.2 mol %)
KF (3.3 eq.),THF, r.t. 82 - 98 % yield1.1 eq.
27
P(t-Bu)P(t-Bu)33 and PCy and PCy33 as Ligands in Coupling Reactions with Aryl Electrophiles as Ligands in Coupling Reactions with Aryl Electrophiles
Littke, A.F.; Fu, G.C. Angew. Chem. Int. Ed. 1999, 38, 2411.Littke, A.F.; Dai, C.; Fu, G.C. J. Am. Chem. Soc. 2000, 122, 4020.Littke, A.F.; Schwarz, L.; Fu, G.C. J. Am. Chem. Soc. 2002, 124, 6343.Fu, G.C. Acc. Chem. Res. 2008, 41, 1555.
Stille reactions:Ar X + Bu3Sn R Ar R
Pd2(dba)3 (0.5 - 3 mol %),P(t-Bu)3 (1.1 - 6 mol %)
CsF (2.2 eq.),THF, r.t. to 100 oCX = Cl, Br
1.1 eq. 98 - 76% yield
Ar-X
MeO Cl
yield (%)
MeO Cl
Cl
Bu3Sn
Bu3Sn
Me
OEtBu3Sn
Ar-X yield (%)
Bu3Sn Br
Me
Bu3Sn
94
89
98
87
82
94
Me
Me
Me
Me
MeO Cl
MeO ClBu3Sn
SnBu3-R SnBu3-R Ar-X yield (%)SnBu3-R
Ar X + ClZn R Ar RPd[P(t-Bu)3]2 (2 mol %),
THF/NMP,100 oCX = Cl
1.5 eq. 94 - 76% yield
Negishi reactions:
Ar-X
MeO Cl
yield (%)
Cl
ClZn
ClZn
Ar-X yield (%)
Cl
94
76
82
85
Cl
BO
O
Me
CN
MeO OMe
ClZn
Me
ZnCl-R ZnCl-R
ClZnMe
28
What’s the Difference Between PCyWhat’s the Difference Between PCy33 and P( and P(tt-Bu)-Bu)33??
In the course of their study on the Heck acylation, Prof. Gregory Fu has found that PCy3 couldn’t react where P(t-Bu)3 could. This observation allowed them to explore the chemistry of palladium hydrides.
During the process, they found some important information on the structure of such palladium complexes.
Hills, I.D.; Fu, G.C. J. Am. Chem. Soc. 2004, 126, 13178.
angle P-Pd-P : 180o angle P-Pd-P : 161o
Pd LLH
Cl+ Cy2NMe Pd LL + [Cy2NHMe]Cl
Dioxane, 20 oC
L
P(t-Bu)3
PCy3
L2PdHCl : PdL2
<2 : >98>98 : <2
The steric effect that is brought in the case of the P(t-Bu)3 ligand seem to favorise the reductive elimination.
29
Introduction of the Ligand P(t-Bu)Introduction of the Ligand P(t-Bu)22MeMe
Netherton, M.R.; Dai, C.; Neuschütz, K.; Fu, G.C. J. Am. Chem. Soc. 2001, 123, 10099.Kirchhoff, J.H.; Dai, C.; Fu, G.C. Angew. Chem Int. Ed. 2002, 41, 1945.
Early methodology for Suzuki reactions on primary alkyl halides:
R1 Br + R2 9-BBN R1 R2
Pd(OAc)2 (4 mol %),PCy3 (8 mol %)
K3PO4 . H2O (1.2 eq.),THF, r.t.
R1, R2 = alkyl93 - 58% yield1.2 eq.
R1 Cl + R2 9-BBN R1 R2
[Pd2(dba)3] (5 mol %),PCy3 (20 mol %)
CsOH . H2O (1.1 eq.),THF, r.t.R1, R2 = alkyl
83 - 65% yield1.2 eq.
In 2002, Prof. Fu tried to expand the reaction to OTs, but the used of PCy3 and P(t-Bu)3 as the ligand seemed too sterically demanding. A less bulky ligand P(t-Bu)2Me was then used with success.
R1 OTs + R2 9-BBN R1 R2
Pd(OAc)2 (4 mol %),P(t-Bu)2Me (16 mol %)
NaOH (1.2 eq.),dioxane, 50 oCR1, R2 = alkyl
1.2 eq. 80 - 55% yield
R1-OTs yield (%)
67
60
R2-(9-BBN)
TESO (9-BBN)
MeOOTs
R1-OTs yield (%)
7655
R2-(9-BBN)
O
OTsMe
OO
6 11
BnO (9-BBN)
5
n-Oct (9-BBN)
ON
OTs
15
O
9
MeOTs
O
6TESO (9-BBN)
11
R1-OTs yield (%)R2-(9-BBN)
64OTsNC6
9BBN
PCy2R
P(t-Bu)2R
R =iPrCy Et Me
4% Pd(OAc)2,16% phosphine ligand
NaOH (1.2 eq.),dioxane, 50 oC
TsO n-Dodec n-Oct (9-BBN)+ n-Oct n-Dodec 46%
---
44%
<2% <2%
70% 48%
78%
30
Introduction of the Ligand P(t-Bu)Introduction of the Ligand P(t-Bu)22MeMeInvestigations on the stereochemistry of the oxidative addition of an alkyl tosylate to Pd/P(t-Bu)2Me:
t-BuOTs
DH
D H
Enantiopure
t-BuPdLn
HD
D H
Pd/P(t-Bu)2Me
dioxane, 70 oC
t-BuPdLn
DH
D H
D
t-Bu H
D
H
t-Bu D
H
D
t-Bu D
H
H
t-Bu H
D
Inversion ofconfiguration
Retention ofconfiguration
inversionretention
= 10
-H elimination
-D elimination
-H elimination
-D elimination
kH
kD= 3
Favored
t-BuOTs
DH
D H
Enantiopure
t-BuPh
HD
D H
Pd/P(t-Bu)2Me
NaOH (1.2 eq.)dioxane, 70 oC
t-BuPh
DH
D H
Overall inversion
Overallretention
inversionretention
= 6
Favored
+ 9-BBN-Ph
Netherton, M.R.; Fu, G.C. Angew. Chem. Int. Ed. 2002, 41, 3910.
Oxidative addition: inversion of configuration
Reductive elimination: retention of configuration
31
Utility of P(t-Bu)Utility of P(t-Bu)22Me for Primary Alkyl HalidesMe for Primary Alkyl Halides
Suzuki cross-coupling:
Kirchhoff, J.H.; Netherton, M.R.; Hills, I.D.; Fu, G.C. J. Am. Chem. Soc. 2002, 124, 13662.
The corresponding phosphonium salt of the ligand which is air- and moisture stable can also be used.
Br R1alkyl R2 B(OH)2 R1 R2
Pd(OAc)2 (5 mol %),P(t-Bu)2Me (10 mol %)
KOt-Bu (3 eq.),t-amyl alcool, r.t.
R1-Br yield (%)
87
68
97
R2-B(OH)2
n-Oct Br PhBr
10
R1-Br yield (%)
89
85
R2-B(OH)2
CyBr
R2 = aryl, alkyl, vinyl
+1.5 eq.
O Br 4-(MeS)C6H44
t-Bu
O
4-(CF3)C6H4BrTBSO4
ON
BrO
5o-tolyl
63
71
O
O1-naphtyl
mesityl
BrNC4
97 - 63 % yield
Br R1alkyl R2 B(OH)2 R1 R2
Pd(OAc)2 (5 mol %) ,[HP(t-Bu)2Me]BF4 (10 mol %)
KOt-Bu (3 eq.),t-amyl alcool, r.t.
R2 = aryl, alkyl, vinyl
+1.5 eq. 93 - 62% yield
32
Utility of P(t-Bu)Utility of P(t-Bu)22Me for Primary Alkyl HalidesMe for Primary Alkyl Halides
Stille cross-coupling:
Menzel, K.; Fu, G.C. J. Am. Chem. Soc. 2003, 125, 3718.Lee, J.-Y.; Fu, G.C. J. Am. Chem. Soc. 2003, 125, 5616.
Hiyama cross-coupling:
Br R1alkyl R2 SnBu3 R1 R2
[(-allyl)PdCl]2 (2.5 mol %),P(t-Bu)2Me (15 mol %) or
([HP(t-Bu)2Me]BF4 (15 mol %))
Me4NF (1.9 eq.),3A molec. sieves,
THF, r.t.R2 = vinyl
+
1.1 eq.96 - 55% yield
(92 - 53% yield)
X R1alkyl Ar Si(OMe)3 R1 Ar
PdBr2 (4 mol %),P(t-Bu)2Me (10 mol %) or
([HP(t-Bu)2Me]BF4 (10 mol %))
Me4NF (2.4 eq.),THF, r.t.
+
1.2 eq.84 - 36% yield
(88 - 42% yield)X = Br, I
33
Nickel in Cross-Couplings for Secondary Alkyl HalidesNickel in Cross-Couplings for Secondary Alkyl HalidesThe attractiveness of all these coupling process stay in the achievement of coupling more hindered electrophiles as reaction partners, like secondary halides.
Secondary alkyls are more interesting than primary species as they allow the reaction to create a new chiral center.
Zhou, J.; Fu, G.C. J. Am. Chem. Soc. 2003, 125, 14726.Netherton, M.R.; Fu, G.C. Adv. Synth. Catal. 2004, 346, 1525.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Negishi cross-coupling:
X R1alkyl YZn R2
alkyl+
Ni(cod)2 (4 mol %),s-Bu-Pybox (8 mol %)
DMA, r.t.R1 R2
R1 = primary or secondaryX = Br, I
NO
N N
O
s-Bu s-Bus-Bu-Pybox
62 - 88% yield1.6 eq.
R1-X yield (%)
66
62
78
R2-ZnY R1-X yield (%)
65
R2-ZnY
TsN BrIZn Me
Me
Br BrZn OPh
Et
EtI BrZn OEt
O
3
62
IBrZn NEt2
O
4
N
O
O
Br
4BrZn Ph
PhI
O
BrZn O
O
MeI
Me MeBrZn Ph
74
73
Primaryalkyls
34
Nickel in Cross-Couplings for Secondary Alkyl HalidesNickel in Cross-Couplings for Secondary Alkyl Halides
Zhou, J.; Fu, G.C. J. Am. Chem. Soc. 2003, 126, 1340.Gonzáles-Bobes, F.; Fu, G.C. J. Am. Chem. Soc. 2006, 128, 5360.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Suzuki cross-coupling sp2-sp3:
NH2
OHtrans-2-aminocyclohexanol
HN
OH
prolinol
X (HO)2B R
Ni(cod)2 (4 mol %),bathophenanthroline (8 mol %)
KOt-Bu, s-butanol,60 oC, 5 h.
R
X = Br, I 44 - 91% yield
R1
R2N N
Ph Ph
bathophenanthroline
+R1
R2
R = aryl or vinyl
1.2 eq.
R-X yield (%)
91
67
63*
68
R-B(OH)2 R-X yield (%)
62
65
R-B(OH)2
BrMe
MeBr
I
MeI
BrNMe
(HO)2B
Br
OTBS
CF3(HO)2B
(HO)2B OMe(HO)2B
(HO)2B
O
O
Me
(HO)2BPh
* The trans product is formed
X (HO)2B Ar
NiI2 (6 mol %)trans-2-aminocyclohexanol (6 mol %)
NaHMDS (2.0 eq.)i-PrOH, 60oC
Ar
X = Br, I 66 - 92% yield
R1
R2+
R1
R21.2 eq.
Cl (HO)2B Ar
NiCl2.glyme (6 mol %), prolinol (12 mol %)
KHMDS (2.0 eq.)i-PrOH, 60oC
Ar
Yield: 46 - 80%
R1
R2+
R1
R21.5 eq.
35
Nickel in Cross-Couplings for Secondary Alkyl HalidesNickel in Cross-Couplings for Secondary Alkyl Halides
Powell, D.A.; Fu, G.C. J. Am. Chem. Soc. 2004, 126, 7788.Strotman, N.A.; Sommer, S.; Fu, G.C. Angew. Chem. Int. Ed. 2007, 46, 3556.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Hiyama cross-coupling sp2-sp3:
HO NH2
Ph Menorephedrine
R-X yield (%)
82
82
86
Ar-SiF3
CbzN Br F3Si
F3Sii-Pr
Ot-Bu
O
Br
F3SiMe
N
O
Cl O
X F3Si Ar
Ni(cod)2 (6.5 mol %),bathophenanthroline (7.5 mol %)
CsF (3.8 eq.),DMSO, 60 oC
Ar
X = Br, I 82 - 60% yield
R1
R2N N
Ph Ph
bathophenanthroline
+R1
R21.5 eq.
R-X yield (%)
80
82
60
Ar-SiF3 R-X yield (%)
72
60
Ar-SiF3
Br
Br
Br
F3Si
OMeF3Si
Cl F3Si
O
Me
Cl
Br
Me
F3Si
OO
IH
H
F3Si
X F3Si Ar
NiCl2.glyme (6 mol %),norephedrine (12 mol %)
LiHMDS (12 mol%),H2O (8 mol%),
DMA, 60oC
Ar
94 - 59% yield
R1
R2+
R1
R21.5 eq.
X = Cl, Br
36
Nickel in Cross-Couplings for Secondary Alkyl HalidesNickel in Cross-Couplings for Secondary Alkyl Halides
Powell, D.A.; Maki, T.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 510.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Stille cross-coupling sp2-sp3 with trichlorostannates (less toxic and easier for purification):
R-X yield (%)
74
47
68
55
Ar-SnCl3 R-X yield (%)
62
Ar-SnCl3
Br
Cl3Sn
Cl3SnOMeCl3Sn
Cl3Sn
Br
Me
8
OMe Cl3Sn
Br
Me
Mei-Bu Me
H
H Me
HI
N I
4
SnBu3
Cl
Commerciallyavailable
1.2 eq.
SnCl4 (1.2 eq.)
r.t.
Br
NiCl2 (15 mol %)2,2'-bipyridine (10 mol %) Cl
66%
X Cl3Sn Ar
NiCl2 (10 mol %),2-2'-bipyridine (15 mol %)
KOt-Bu (7.0 eq.),t-BuOH/i-BuOH,
60 oC, 12 h.
Ar
X = Br, I 82 - 60% yield
R1
R2N N
2,2'-bipyridine
+R1
R21.2 eq.
37
Asymmetric Cross-Couplings of Racemic Secondary Alkyl HalidesAsymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Fischer, C.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 4594.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Negishi coupling of secondary -bromo amides:
XZn R1
NiCl2.glyme (10 mol %)(R)-(i-Pr)-Pybox (15 mol %)
DMI/THF, 0 oC
Yield: 51 - 90%87 - 98% ee
+1.2 eq.
NN
OO
N
i-Pri-Pr(DMI = 1,3-dimethyl-2-imidazolidinone)(R)-(i-Pr)-Pybox
NR
Br
OBn
PhN
R
R1
OBn
Ph
NR
n-Hex
OBn
Ph
R = Et, 90% yield 96% eeR = n-Bu, 85% yield 96% ee
NR
Me
OBn
Ph
R = Et, 90% yield 91% eeR = i-Bu, 78% yield 87% ee
NEt
OBn
Ph
77% yield96% ee
OBn4
NMe
OBn
Ph
77% yield96% ee
2O O
NEt
OBn
Ph
51% yield96% ee
NPht3
NEt
OBn
Ph
70% yield93% ee
CN4
38
Asymmetric Cross-Couplings of Racemic Secondary Alkyl HalidesAsymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Arp, F.O.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 10482.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Negishi coupling of secondary benzylic bromides:
XZn R1
NiBr2.glyme (10 mol %)
(S)-(i-Pr)-Pybox (15 mol %)
DMA/THF, 0 oC
Yield: 39 - 89%75 - 99% ee
+1.6 eq.
NN
OO
N
i-Pri-Pr(DMA = N,N-dimethylacetamide)(S)-(i-Pr)-Pybox
X
X = Br, Cl
R1
R R
n-Hex
X = Br89% yield96% ee
X = Br89% yield, 96% ee
X = Cl56% yield, 91% ee
CNMe
X = Br69% yield94% ee
Cl4
NC
X = Br76% yield98% ee
Ph
Me
Me
OBn
X = Br63% yield75% ee
39
Asymmetric Cross-Couplings of Racemic Secondary Alkyl HalidesAsymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Son, S.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 2756.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Negishi coupling of secondary allylic chlorides:
XZn R
NiCl2.glyme (5 mol %)(S)-BnCH2-Pybox (5.5 mol %)
NaCl (4.0 eq.)DMA/DMF (1:1), -10 oC
Yield: 54 - 97%79 - 98% ee
+1.2 eq.
NN
OO
N
(DMA = N,N-dimethylacetamide)(S)-BnCH2-Pybox
93% yield90% ee
R1 R3
Cl
R2R1 R3
R
R2
Bn Bn
Me Me
OO
57% yield69% ee
iPr iPr
OTBS
54% yield98% ee
Me MeMe
OMe
85% yield81% ee
tBu Me
CO2Me
86% yield96% ee
EtO2C Me
Me
Me
91% yield93% ee
Me
CO2Me
O
NMe
OMe
40
Asymmetric Cross-Couplings of Racemic Secondary Alkyl HalidesAsymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Dai, X.; Strotman, N.A.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 3302.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Hiyama coupling of secondary -bromo esters:
(MeO)3Si R
NiCl2.glyme (10 mol %)(S,S)-1 (12 mol %)
TBAT (2.0 eq.),dioxane, r.t.
Yield: 64 - 84%75 - 99% ee
1.3 eq.
80% yield99% ee
R1OR2
O
Br
R = aryl, alkenyl
R1OR2
O
R+
MeHN NHMe
Ph Ph
(S,S)-1
BHTO
O
Me
80% yield92% ee
BHTO
O
OMe
O
BHTO
OBr
70% yield86% ee
80% yield99% ee
BHTO
O
Me
78% yield80% ee
BHTO
O
OMe
72% yield75% ee
BHTO
O
Me
Me
72% yield94% ee
BHTO
O
Me
Cl 72% yield92% ee
BHTO
O
Me
Ph
41
Asymmetric Cross-Couplings of Racemic Secondary Alkyl HalidesAsymmetric Cross-Couplings of Racemic Secondary Alkyl Halides
Saito, B.; Fu, G.C. J. Am. Chem. Soc. 2008, 130, 6694.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Enantioselective alkyl-alkyl Suzuki cross-coupling of secondary homobenzylic bromides:
R (9-BBN)
Ni(cod)2 (10 mol %)(S,S)-1 (12 mol %)
KOt-Bu (1.2 eq.),i-BuOH,
i-Pr2O, 5 oC or r.t. Yield: 62 - 86%40 - 94% ee
1.5 eq.Ar R1
Br
R = alkyl
+
MeHN NHMe(R,R)-1
F3C CF3Ar R1
R
Me
Me
Ph74% yield88% ee
Me
Ph84% yield90% ee
MeO
Me
Ph82% yield70% ee
F3C
Me
Ph86% yield86% ee
Me
Me
OTBS68% yield78% ee
Me
74% yield85% ee
OMe
OMe
O
O
Me
OTBS62% yield66% ee
O
42
Mechanistic Studies of Nickel Cross-CouplingMechanistic Studies of Nickel Cross-Coupling
Lin, X.; Phillips, D.L. J. Org. Chem. 2008, 73, 3680.Jones, G.D.; Martin, J.L.; McFarland, C.; Allen, O.R.; Hall, R.E.; Haley, A.D.; Brandon, R.J.; Konovalova, T.; Desrochers, P.J.; Pulay, P.; Vivic, D.A. J. Am. Chem. Soc. 2006, 128, 13175.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
Postulated reaction mechanisms for alkyl-alkyl cross-coupling:
MmLnR1
X
Oxidativeaddition
R1M(m+2)
H H X
R1M(m+2)
H H R2
R2M'YmXM'Ym
Transmetallation
R1R2
Reductiveelimination
MX H
R1
R1
MX H
MmLn
-Hydrideelimination
B
BH+X-
NN
NNiR
Ni(tpy)-CH3(tpy = 2,2'6',2''-terpyridine)
Calculations where done to etablish if such process is possible with the use of a methylterpyridyl-Ni(I) catalyzing a Negishi reaction.
In this case, the oxidative product of Ni(II) reacting with the transmetalating reagent (CH3ZnI) followed by the reductive elimination shown above is greatly disfavored.
G = 21.1 kcal/mol
43
Mechanistic Studies of Nickel Cross-CouplingMechanistic Studies of Nickel Cross-Coupling
Lin, X.; Phillips, D.L. J. Org. Chem. 2008, 73, 3680.Jones, G.D.; Martin, J.L.; McFarland, C.; Allen, O.R.; Hall, R.E.; Haley, A.D.; Brandon, R.J.; Konovalova, T.; Desrochers, P.J.; Pulay, P.; Vivic, D.A. J. Am. Chem. Soc. 2006, 128, 13175.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
The Ni(I)-methyl complex seem to undergo a charge-transfert state in which we then obtained a Ni(II)-alkyl cation by contribution of the metal d-orbital in the SOMO of the ligands (by DFT calculation).
Updated possible mechanism for the nick-catalyzed alkyl-alkyl Negishi using a radical process Ni(I)-Ni(III):
NN
NNiCH3
NN
NNiR
+
I
NN
NNiR
+
I
NN
NNi
R
I
NN
NNiI
+
R
Alkyl halide reduction by the ligand
Oxidative radical addition
Fast radicalelimination
Ni(III)-dialkyl specie
R-ZnBrTransmetallation
Overall G = -27.8 kcal/mol
Alkyl radical is postulated to stay in close proximity of the metal center. At this point, if the ligand is chiral, enantioselective addition of the radical may take places like in Fu’s case.
44
Mechanistic Studies of Nickel Cross-CouplingMechanistic Studies of Nickel Cross-Coupling
Lin, X.; Phillips, D.L. J. Org. Chem. 2008, 73, 3680.Jones, G.D.; Martin, J.L.; McFarland, C.; Allen, O.R.; Hall, R.E.; Haley, A.D.; Brandon, R.J.; Konovalova, T.; Desrochers, P.J.; Pulay, P.; Vivic, D.A. J. Am. Chem. Soc. 2006, 128, 13175.Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 2.
By calculation, the catalytic process can be summarized on the energetic matter by:
-The oxidative addition is slightly endothermic
-The reduction elimination is largely exothermic
-The transmetallation is mildly endothermic
The limiting step in this process is the halogen atom transfert step and the solvation effect increases the rate of this step.
Also, the rate of Ni(III) species decomposition is larger than that of its reductive elimination and this may lead to lower uield of the cross-coupled product in some cases.
45
ConclusionConclusion
In conclusion, we have seen different methodologies to do cross-coupling for unactived alkyl chlorides using P(t-Bu)3 and PCy3.
Gregory Fu has been able to successfully coupled primary alkyl halides using Suzuki, Negishi and Stille reactions with the Pd/P(t-Bu)2Me catalyst system.
Secondary alkyl halides which are more hindered and so more difficult to cross-coupling (slow oxidative addition) can be readily coupled with organozinc, organotin and organoboron reagents by different nickel complex.
The development of assymetric cross-coupling of secondary alkyl halides is of an important impact as it can be readily use for the synthesis of natural products.
There is still work to be done to expand the scope of functionality that can be tolerated.
NH
Me
Et Me
OH
O
NH2
Me
Et
O
H
Suh Me
Cl
EtO2C
+
Et
Cl
EtO2C
+
BrZn
O
O
fluvirucinine A