不对称交叉偶联反应

不对称交叉偶联反应

陶忠林2012/06/16

• 1.介绍• 2. sp2-sp2的不对称交叉偶联• 3. 含 sp3碳的不对称交叉偶联反应• 4.总结

1.主要内容R1 M R2 X

CatR1 R2

Pd(0) R2 X

PdR2 X

R1 MPdR2 R1

R1 R2

不包括 Heck反应以及烯丙基话反应

2. sp2-sp2的不对称交叉偶联

手性联萘骨架在不对称合成中具有重要作用。

O

OP

O

OH

Ar

Ar

OH

OH

NH

COOH

ONMe3

Ar

O

O

P

PCy2

NMe2

MgBr

RBr

5 mol% NiBr/L

ether/toluene ( l / l ), -15oC, 92 h

R

up to 95% ee

RFe

PPh2

OMe

Me

L

Hayashi, T. J. Am. Chem. Soc. 1988, 110, 8153-8156

TfO OTf R OTf

5 mol% Cat1 eq LiBr

ether/toluene-30oC, 48h

PPd

N Cl

Cl

Me Me

Ph Ph

Bn

Catup to 93%ee

RMgBr2.1 eq


TfO OTfRMgBr/LiBr

R OTf5 mol% Cat

ether/toluene(1:1)-20oC, 48h

PPd

N Cl

Cl

Me Me

Ph Ph

Me

Catup to 95%ee

Hayashi, T. Tetrahedron 1999, 55, 3455-3466

Hayashi, T. Tetrahedron Lett. 1996 , 37, 3161-3164

OTf

9-BBN

THF

OTf

9-BBN

9-BBN

10 mol% Pd2(dba)3 5 mol% L, 5 eq K2CO3,40oCTHF

2). 3N NaOH, H2O2

OH

2up to 28%ee

Fe

PPh2

OCOCH3

Me

LPPh2

Shibasaki, M. Tetrahedron: Asymmetry 1998, 9, 3751–3754

Br

P(O)(OR1)2

B(OH)2

P(O)(OR1)2

R1=Et

NMe2

PCy2

1.5 equiv

1 mol% Pd2(dba)32.4 mol% L

2 equiv K3PO4

teluene, 70oC

R

R2

L

(S)

P(O)(OMe)2

99% ee

PhMgBr,DME

45oC, 24 h 89%

P(O)Ph2

99% ee

PMHS,Ti(O-i-Pr)4

THF, 70oC24 h, 86%

PPh2

99% ee

Buchwald, S.L J. Am. Chem. Soc. 2000, 122, 12051-12052

X

R1

B(OR2)2

Me

DME, CsF, reflux

R1

Me

X=Br, I

Fe

PPh2

NMe2

Me3 mol% PdCl26 mol% L

L

up to 85% ee50% yield

Cammidge, A. N. Chem. Commun., 2000, 1723–1724

Buchwald, S.L J. Am. Chem. Soc. 2010, 132, 11278-11287

S

1. 3 mol% Ni(cod)2/LRMgX,THF

2. H+, H2O

R

SH PPh2 N

O

L


Hayashi, T. J. Org. Chem. 2004, 69, 3811-3823

Br B(OH)265% yield,54% ee

K3PO4, 8 eq H2O60-75 oC, toluene

2 mol% [Pd(NCMe)4](BF4)25 mol% L

Fe

PCy2

1-Naphthyl

L1.5 eq

Johannsen, M. Org. Lett. 2003 , 5, 3025-3028

Baudoin, O. J. Org. Chem. 2003, 68, 4897-4905

NH2

B(pin) I

OMOM

H2N

OMOM

OO

HN

Ba(OH)2 8H2O (2.0 equiv), 100oC, 1 h

2.5 mol%Pd2dba3 CHCl36 mol% L

NMe2

PCy2

L

40% ee, 92% ee after crystal

Br

RB(OH)2

3 mol% Pd2+ cat3 mol% L

Ba(OH)2(2 eq), DME80oC

R

up to 84% ee Pd2+ cat

PR2

R2PPd2+

2(SbF6)-

Mikami, K. Chem. Commun. 2004 , 2082–2083

I

R1

B(OR2)2

Me

DME, CsF, reflux, 6 days

R1

Me Fe

PPh2

NMe2

Me3 mol% PdCl26 mol% L

L

up to 85% ee60% yield

PPh2

Cammidge, A.N. Tetrahedron 2004, 60, 4377–4386

Br

RB(OH)2

R'

up to 90% ee

R'

R

DME, CsF(3 eq), reflux

3 mol% [Pd(NCMe)4](BF4)212 mol% L

Fe

PPh2

NMe2

Me

L

Espinet, P. Chem. Eur. J. 2006, 12, 9346–9352

Br

R1

B(OH)2

R1

up to 70% ee

R2

R2

5 mol% Pd2dba3(Pd(OAc)2)20 mol% L, MW

100oC,DME(THF),45-60 min

Br

R1Zn

R2

Fe

PPh2

NMe2

Me

L

2

R1

up to 48% ee

R2

5 mol% Pd2dba3(Pd(OAc)2)20 mol% L, MW

100oC,DME(THF),45-60 min

Espinet, P. Tetrahedron: Asymmetry 2007, 18, 625–627

Br

R1

B(OH)2R2 5mol% cat

toluene, Cs2CO3, 20oC

R1

R2N

PdN

Cl Cl

N N

Ph

Ph

Ph

PhCat

Fernández, R. J. Am. Chem. Soc. 2008, 130, 15798–15799

Br

OB(OH)2

(S)-BINAP Pd NPs

R.T, DME/H2O(9/1)

O

96% yield, 69% ee

Fujihara, H. Angew. Chem. Int. Ed. 2008, 47, 6917–6919

X

RB(OH)2

nBu4NF,H2O,80oC,24 h

R

96% yield, 94 % eeX=Cl,Br,I

R'

10 mol% Pd(OAc)2

PS-PEG-L*(Pd/P=1:1)R'

O O HN

O

(CH2)3 NN

O

PCy2

H

PS

n

PS-PEG-L*

Uozumi, Y. Angew. Chem. Int. Ed. 2009, 48, 2708–2710

X

P(O)(OR)2 K3PO4,THF/H2O(10:1),40oC,48 h

Ar

X=Cl,Br; R=Me, Et

1 mol%{ [PdCl( allyl)]2}

(P)-(R)-L(P/Pd = 2:1)P(O)(OR)2ArB(OH)2

N

N

O

O

~950 N

N

R2P

~50

up to 93%, 94% ee

Suginome, M. Angew. Chem. Int. Ed. 2011, 50, 8844 –8847

X

R1

B(OH)2

R1

1.5 equiv

5 mol% PdCl2L15 mol% L

2.5 equiv Cs2CO3

teluene, 25oC

R2 R2

Ar

ArPdCl Cl

PdCl2L, Ar= 3,5-(Me)2-C6H3up to 90% ee

Lin, G.Q. Org. Lett. 2010, 12, 5546-5549

Br

P(O)(OR1)2 B(OH)2

Ar

P(O)(OR1)2

R1=Et2.0 equiv

2 mol% Pd2(dba)34.8 mol% L

3 equiv K3PO4

teluene, 40oC

Ar

O

O

O

PAr1

L, Ar1=3,5-t-Bu2C6H3up to 98% yield97 % ee

Qiu, L.Q. Org. Lett. 2012, 14, 1966–1969

I

I

33

R3

3

R

R

10 mol% PdCl2(CH3CN)2/L

10 mol% CuI, Cs2CO3(4 eq)THF, r.t.

PPh2

NMe2

Fe PPh2

Lup to 79% ee

Shibata, T. Chem. Commun. 2009, 1870–1872

Kumada, M. J. Am. Chem. Soc. 1976, 98, 3718-3719Kumada, M. J. Am. Chem. Soc. 1982. 104, 180-186

BrMgCl

0.5 mol% NiCl2

-20-0oC, Et2O

1.0 mol% L

99% yield63% ee

Fe

PPh2

NMe2

Me

L(2-4 eq)

Ph2P

Me2N

MgCl

Ni Br

H PhMe

Fe

Nagel, U. Chem. Ber./Recueil 1997, 130, 535-542

ClMgCl

N Bz

Ph2P

1 mol% NiCl2

-78oC, Et2O

1.1 mol L

Lup to 88% ee

3 . 含 sp3碳的不对称交叉偶联反应

Ph

Br

MgCl

2 eq

2.5 mol% Pd2(dba)3 CHCl35 mol% L

CF3-C6H5, 0oC

Ph

Ph(E/Z=6:1)

NN

PPh2

Lup to 80% ee

Aoyama, T. Tetrahedron 2004, 60, 10701–10709

O

NBn

Ph Br

RR1 ZnX

!0 mol% NiCl2 glyme13 mol% L

DMI/THF, 0oC

O

NBn

Ph R1

RNO

N N

O

i-Pr i-PrL

Fu, G.C. J. Am. Chem. Soc. 2005, 127, 4594-4595

1).体系具有较好的选择性，能够兼容非活泼一级或者二级溴代物 ;

2).当加入 0.8 eq 锌试剂时，未反应的溴代物的 ee值为 0，反应不存在拆分。

X

X=Br or Cl

R R1 ZnX

10 mol% NiCl2 diglyme13 mol% L

DMA, 0oC

R1

R

1.6 equiv

NO

N N

O

i-Pr i-PrLup to 89% yield99% ee

Fu, G.C. J. Am. Chem. Soc. 2005, 127, 10482-10483

Fu, G.C. J. Am. Chem. Soc. 2008, 130, 2756-2757

反应对水和氧并不十分敏感

反应条件下，苯环上的 Cl不参与反应。

不存在拆分现象

R1

R2R3

Cl

R-ZnBr

5 mol% NiCl2 glyme5.5 mol% L

4 equiv NaClDMA/DMF, -10oC1.2 equiv

R1

R2R3

R NO

N N

O

LBn Bnup to 98% ee

R1 和 R3相同时，不存在区域选择性问题；R1 和 R3为不同烷基时，区域选择性较差；R1为吸电子基团， R3为烷基时，选择性较好。

O

R1OR2

Br

R3 Si(OMe)3

10 mol% NiCl2 glyme12 mol% L

2.0 equiv TBATdioxane, r.t.1.3 equiv

O

R1OR2

R3

Ph Ph

MeHN NHMeL

Fu, G.C. J. Am. Chem. Soc. 2008, 130, 3302-3303

Ar

Br

alkylAlkyl19-BBN

10 mol% Ni(cod)212 mol% L

1.5 equiv1.2 KOt-Bu2.0 i-BuOHi-Pr2O, 5oC

Ar

Alkyl1

alkyl

LNHMeMeHN

F3C CF3

Fu, G.C. J. Am. Chem. Soc. 2008, 130, 6694–6695

BrBr

5%ee 14%ee

alkyl

Br

TMSAr-ZnEt

2.0 equiv


glyme, -20oC alkyl

Ar

TMS NO

N N

O

L

H

H

H

H

Fu, G.C. J. Am. Chem. Soc. 2008, 130, 12645–12647

O

ArR1

Br

Ar1 ZnI


glyme/THF, -30oC1.3 equiv

O

ArR1

Ar1

NO

N N

OPh Ph

MeO OMeL

Fu, G.C. Angew. Chem. Int. Ed. 2009, 48, 154 –156

O

R1

Br

R2 R3 MgBr

7 mol% NiCl2 glyme9 mol% L

DME, -40 or -60oC

O

R1

R3

R2

O

N N

O

Ph Ph

O

N N

O

Ph Ph

Fu, G.C. J. Am. Chem. Soc. 2010, 132, 1264–1266

O

R1

Br

R2 Cp2ClZrR3


DME/THF, 10oC

O

R1 R2

R3

O

N N

O

Ph Ph

PhPh

L

Fu, G.C. J. Am. Chem. Soc. 2010, 132, 5010–5011

Fu, G.C. J. Am. Chem. Soc. 2010, 132, 11027–11029

N

O

R

Cl

Ar (9-BBN)

1.5 eq

8 mol% NiBr2 diglyme10 mol% L

1.3 eq KOt-Bu1.5 eq i-BuOHtoluene, -5oC

N

O

R

Ar

LNHMeMeHN

F3C CF3

PGO

R

X

PG =NBnPh

O

R19-BBN

2.0 equiv


1.4 KOt-Bu1.8 p-hexanoli-Pr2O, r.t

PGO

R

R1

Ph Ph

MeHN NHMeL

Fu, G.C. J. Am. Chem. Soc. 2010, 132, 11908–11909

NAr

R

R1

ClR2 (9-BBN)


1.2 KOt-Bu2.0 n-hexanoli-Pr2O, r.t

Ar' Ar'

MeHN NHMe

L Ar/= 1-naphthyl

NAr

R

R1

R2

1.8 eq

Fu, G.C. J. Am. Chem. Soc. 2011, 133, 8154–8157

R2 (9-BBN)

2.0 eq


1.4 eq KOt-Bu1.8 eq n-hexanolEt2O/hexanes(1:1), r.tX

R1

Y

O Ph Ph

MeHN NHMeLR2

R1

Y

O

up to 91% ee

Fu, G.C. J. Am. Chem. Soc. 2011, 133, 15362–15364

DGR1

ClR2 (9-BBN)


1.4 KOt-Bu1.8 n-hexanoli-Pr2O, r.t

Ar' Ar'

MeHN NHMe

L Ar= ph or 3-(CF3)-C6H4

NAr

R

R1

R2

2.0 eqDG=carbamate sulfonamide sulfone

Fu, G.C. J. Am. Chem. Soc. 2012, 134, 5794−5797

R1NC

Br

R2 ZnR2

10 mol% NiBr2 glyme13 mol% L

20 mol% TMEDA-60 oC or -78 oC, THF

1.2 eq

R1NC

R2 N N

O O

i-Pr i-PrL

Fu, G.C. J. Am. Chem. Soc. 2012, 134, 9102−9105

alkyl

OCO2Ar1R

Ar-ZnI

1.5 equiv

10 mol% NiCl2(PCy3)213 mol% L

DME/THF(1:1),10oC

alkyl

Ar

R NO

N N

O

L

H

H

H

H

Fu, G.C. J. Am. Chem.Soc. 2012, 134, 2966−2969

LnNi X M-Nu

LnNi Nu

R-X

oxidativeaddition step 1

oxidativeaddition step 2

NuLnNi

XR

NuLnNi

XR

Nu-R

非活泼卤代物的机理

4.总结

1.Sp2 与 Sp2或者 Sp的偶联研究的比较多，得到的联萘骨架的产物在不对称合成中具有较多运用。

2. 含 sp3碳的不对称偶联反应主要是 Fu 的 Ni体系，研究的相对较少。新的体系有待发展。

不对称交叉偶联反应

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