c-sp 3 coupling using alkyl halides as electrophiles: work by gregory fu

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

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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


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


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

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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)

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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


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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

13

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 %

+


THF, reflux

87%

MgBrEtI

+


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

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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


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


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 +


(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


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 +


(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


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


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


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


Cl4

NC


Ph

Me

Me

OBn


39


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


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


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


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



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



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

c-sp 3 coupling using alkyl halides as electrophiles: work by gregory fu

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