Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 1
Organo-transition Metal Chemistry
1. Some Basics
Chemistry involves intermediates containing transition-metal carbon bonds
M CL2
L4L5
L1
LnM C
LnM C
LnM C
LnM
sp3
sp2
sp LnM
LnM C
LnM CH
ligand sphere
Coordination
LnM H
Metal-ca
L3 LnM C
rbon sigma bond
LnM
LnMC O
Electron Counting:
• Formal neutral ligand (L): PR3, NR3, CO, alkyne, Alkene • Formal anionic ligand (X): R, Ar, H, X, CN, RCO
PdPPh3
PPh3Ph3P
Ph3P
PdPh3P
Ph3P
Ar I
PdI
ArPh3P
Ph3P
ML4 Pd(0) d10 = 10 ePPh3 2 e X 4 = 8 e
18 e
ML2 Pd(0) d10 = 10 ePPh3 2 e X 2 = 4 e
14 e
ML2X2 Pd(II) d8 = 8 eAr, I 2 e, 2 e = 4 ePPh3 2 e X 2 = 4 e
16 e
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 2
Ligand Exchange: Ligand Association and Ligand Dissociation
LnM L' + :L'
L-dissociation L-dissociation
PdPPh3
Ph3P
Ph3P
PPh3Pd
PPh3Ph3P
PPh3
MLn
PdPPh3
PPh3
- PPh3
Ligand association
Ligand dissociation
- PPh3
Vacant site
Oxidative Addition/Reductive Elimination
M(n)Ln
I
X
X
+
Oxidative Addition.
Y
IPdPh3P
PPh3Pd0PPh3
PPh3
Pd2
IPPh3
PPh3
M(n+2)LnY
Pd2PPh3
PPh3
R
Pd(PPh3)2
R
usually polar bond
Oxidative Addition.
Reductive Elimination
Reductive Elimination
M(nM(n
I
Y
IPdPdPh3PPh3P
PPh3PPh3Pd0Pd0PPh3PPh3
PPh3PPh3
Pd2Pd2
IPPh3PPh3
PPh3PPh3
M(n+2)LnM(n+2)LnY
Pd2Pd2PPh3PPh3
PPh3PPh3
R
Pd(PPh3)2Pd(PPh3)2
R
usually polar bondusually polar bond
Oxidative Addition.Oxidative Addition.
Reductive EliminationReductive Elimination
Reductive EliminationReductive Elimination
)Ln)Ln X
X
+
Oxidative Addition.Oxidative Addition.
Ligand effect: Electron donating ligands facilitate oxidative addition (e.g. PR3, R, H); electron withdrawing ligands facilitate reductive elimination (e.g., CO, CN, olefins).
Migratory Insertion/De-insertion: Migration of one ligand to a neighboring unsaturated ligand (CO, RNC, alkyne, alkene), generating a vacant site. Usually reversible. Vacant site is cis to the newly formed ligand.
LnM LnMR
O
LnM L MC
CH
R2H
R
n
R
R2
R
Insertion
De-insertion
C O
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 3
Carbometallation/β-elimination
LnMLn
vacant site
Carbometallation
β-elimination
M R
R PdH
R
RRR
Φ = 0 O
LnPdH
H Pd Ln
Rβ-Hydride EliminationRRH R
LnPd
H
R
R
R
H R
R
Dehydropalladation
LnPdLnPdH
H PdPd LnLn
Rβ-Hydride Eliminationβ-Hydride EliminationRRH R
LnPdLnPd
H
R
R
R
H R
R
DehydropalladationDehydropalladation
• Carbometallation: Insertion into alkene/alkyne group • Migrating aptitude of β-Eliminaton : H >> Alkyl, Ar > RCO> OR • β-Hydride Elimination : Very common pathway for the decomposition of alkylmetal
complexes
2. Heck Reaction
ICO2Me
CO2Me
10 mol %Pd(OAc)2
PPh3, K2CO3CH3CN100 oC, 90 %
R1 X R2 R2R1 +
cat. PdX
Base, PR3
• R1: Aryl, Vinyl, Benzylic, Allylic, Acyl • X: N2+ > I > Br~OSO2CF3 >> Cl (relative rate of oxidative addition) • PdX: Pd(0) or Pd(II). Active Pd(0) species can be instantaneously made from Pd(II) in
reaction media
• Base : Scavenger of HX • PR3: Prevents Pd(0) from precipitation to make palladium mirror • Solvent: Often coordinating solvents such as NMP, DMA, DMF, acetonitrile but
sometimes toluene can be used • Temperature: room temp. to 140 oC
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 4
Catalytic cycle:
Pd(PPh3)4
- HXR 1 X
R 1R 1
R 1R 1
R 1
Ph3)2X R 1
Pd(0 )(PPh 3)2
Pd (II)(PPh3)2XH Pd(II)(PPh3)2X
R 2R 2
H Pd (II)(PPh3)2X Pd (II)(PPh3)2X
R 2R 2
R 2
H Pd(P
H R 2
Pd(PPh3)2X
- 2 PPh3
BaseO xidative A ddition
Syn- Carbopalldation
internal ro ta tion
Syn-β -H-E lim ina tion
R eductiveE lim ination
H H
H H
Intramolecular Heck Cascade
SiMe3
I
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
Pd(0)
Carbopalladati
Oxidative addition ligand association Carbopalladation
DehydropalladationBeta-H-elimination
ligand association
PdLn
PdLn' I
H PdLn
PdLn
H PdLn
PdLn
on
β-H-elimination
Tandem Heck Reaction
• Intermolecular Heck reaction followed by intramolecular one • Syn-Carbopalladation leads to only one geometric isomer
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 5
Stable Organo-Pd intermediate
without syn β-H
Syn-carbopalladation
I
Me MeLnPd MeLnPd
CO2Me
Me
MeO2C
3 mol %Pd(PPh3)4
2.5 eq. Et3N100 oC, 12 h
80 %
Sequential Tandem Heck Reaction
H
OtBu
HMeO
OtBu
Br HPd
POAc
R
OtBu
HMeO
H
H
HMeO
OtBu
H
H
LnPdLnPd Ha
HMeO
OtBu
H
120 oC
(R: o-t10 %Pd(OAc)2,22 % PPh3,
60 oC, 60 h.CH3CN, DMFnBu4N(OAc)
2.0 eq
63 %
Syn- Elimination
LnPd
R
BrBr
HeHa He
ol)
MoreReactive
Syn-carbopalladation
H
OtBuOtBu
HMeOMeO
OtBuOtBu
BrBr HPdPd
POAcOAc
R
OtBuOtBu
HMeOMeO
H
H
HMeOMeO
OtBuOtBu
H
H
LnPdLnPdLnPdLnPd HaHa
HMeOMeO
OtBuOtBu
H
120 oC120 oC
(R: o-t(R: o-t10 %Pd(OAc)2,22 % PPh3,
60 oC, 60 h.CH3CN, DMFnBu4N(OAc)
10 %Pd(OAc)2,22 % PPh3,
60 oC, 60 h.CH3CN, DMFnBu4N(OAc)
2.0 eq2.0 eq
63 %63 %
Syn- EliminationSyn- Elimination
LnPdLnPd
R
BrBrBrBr
HeHeHaHa HeHe
ol)ol)
MoreReactiveMoreReactive
Syn-carbopalladation
Syn-carbopalladation
Stable Organo-Pd Intermediates
• Intermediate organo-palladium species are thermally stable due to the absence of hydrogen β-syn to palladium
R
R
R
R
R1 PdLn
R1 PdLn
R1PdLn
RR
RPdLn
R1
R
R X
R1 PdLn
PdLn
R
R1PdLn
Pd+L2
- X
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 6
3. Stille Coupling Reaction
Br
H3C H3C3C
Bu3Sn
10 mol %Pd(PPh3)4
PhCH100 o
R1
• R1, R2 : sp2-hybridized carbon
X R2 SnBu3 R1 R2 X SnBu3+ +cat. Pd
• X: I > OSO2CF3 > Br >> Cl • Ability for transmetalation: alkynyl> alkenyl> benzyl, allyl> alkyl • Exceptional functional group tolerance • High cost and toxicity of organotin reagent
4. Suzuki Coupling Reaction
Br
OHC OHC (HO)2B
10 mol %Pd(OAc)2
PPh3, Na2CO3iPrOH, H2O,reflux. 86 %
B
CNCN
3 mol %PdCl2(dppf)2.0 eq. K2CO3DMF, THF, 50 oC81 %
O
Br
O
• Less expensive, less toxic alternative to Stille coupling • Sp3 carbon can be involved in coupling partner • Relative rates of reductive elimination: aryl-aryl > alkyl -aryl> alkyl-alkyl • Somewhat basic conditions needed
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 7
Catalytic Cycle of Stille/Suzuki Coupling
R1R1
R1
X
Pd(II)Ln
X M
R2
Pd(II)Ln
Pd(0)LnOxidative Addition
Transmetallation
Reductive Elimination
X
R2 M
R2
Pd(II)LnX
R2M
R1
R1
• Transmetallation step is supposed to be the slowest in the Stille coupling • Depending on the leaving group, oxidative addition can be a rate determining step in
Suzuki coupling
Termination with Carbonylation
R Pd(II)LnCO
R Pd(II)Ln
stable organo-Pd species
Heck Nu
Suzuki Stille
R
O
R'
R R2
O
R R3
O
R Nu
O
NuR2NHROHArOH
CO
R Pd(II)Ln
O
• Higher affinity and fast insertion of CO ligand to Pd • Relative migratory insertion rate: alkyne > carbon monoxide (ca. 1 atm) > alkene
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 8
OtBu
OTIPS
Me3Sn
Ph I
R1 SnBu3
MeN
N
NMe
I
O
R2 X
Ph SnBu3
CO
(PPh3)2PdCl2
R1 R2
O
Ph
O
Ph
OTIPS
OtBu
ON
MeN
MeN
O
X SnBu3+
R2 = Aryl-, Alkyl-, Allylhalogenide und -triflate
+Pd catalyst
+
+11 bar CO
70%
J. K. Stille J. Am. Chem. Soc. 1984, 106, 6417
2.5 mol % Pd2(dba)3+
L. E. Overman J. Am. Chem. Soc. 1993 , 115 , 3966
22% Ph3AsCO (12 bar)LiCl , NMP
70o C80%
OtBuOtBu
OTIPSOTIPS
Me3SnMe3Sn
PhPh I
R1R1 SnBu3SnBu3
MeNMeN
N
NMeNMe
I
O
R2R2 X
PhPh SnBu3SnBu3
COCO
(PPh3)2PdCl2(PPh3)2PdCl2
R1R1 R2R2
O
PhPh
O
PhPh
OTIPSOTIPS
OtBuOtBu
ON
MeNMeN
MeNMeN
O
X SnBu3SnBu3+
R2 = Aryl-, Alkyl-, Allylhalogenide und -triflateR2 = Aryl-, Alkyl-, Allylhalogenide und -triflate
+Pd catalystPd catalyst
+
+11 bar CO11 bar CO
70%70%
J. K. Stille J. Am. Chem. Soc. 1984, 106, 6417J. K. Stille J. Am. Chem. Soc. 1984, 106, 6417
2.5 mol % Pd2(dba)32.5 mol % Pd2(dba)3+
L. E. Overman J. Am. Chem. Soc. 1993 , 115 , 3966L. E. Overman J. Am. Chem. Soc. 1993 , 115 , 3966
22% Ph3AsCO (12 bar)LiCl , NMP
70o C80%
22% Ph3AsCO (12 bar)LiCl , NMP
70o C80%
Examples of the Stille reaction:
ON
MeO
O
O
OMeMe
OH
OMe
O
Me
Me
OMe O
MeOMe
OH
HOMeO
Me
N
O
O
O
OMeMe
OH
OMe
O
Me
MeI
OMe
O
MeOMe
OH
HOMeBu3Sn SnBu3
20 mol% Pd(MeCN)2Cl2i-Pr2NEt
25 °CDMF/THF48 hours
I
ON
MeMeO
O
O
OMeMeMeMe
OHOH
OMeOMe
O
MeMe
MeMe
OMeOMe O
MeMeOMeOMe
OHOH
HOHOMeMeO
MeMeO
NO
O
OMeMeMeMe
OHOH
OMeOMe
O
MeMe
MeMeI
OMeOMeHOHOMeMe
SnBu3SnBu3Bu3SnBu3Sn
OOMeOMe
MeMe OHOH
20 mol% Pd(MeCN)2Cl220 mol% Pd(MeCN)2Cl2i-Pr2NEt
25 °CDMF/THF48 hours
i-Pr2NEt25 °C
DMF/THF48 hours
I
K. C. Nicolaou, Chem. Eur. J. 1995, 1, 318.
R1 SnBu3 R2 Cl
O
R2 R1O
Cl SnBu3Pd catalyst
R1 = Alkyl, Alkenyl, Aryl, Alkynyl, H
R2 = Alkyl, Alkenyl, Aryl, Alkynyl
++R1R1 SnBu3SnBu3 R2R2 ClCl
O
R2R2 R1R1O
ClCl SnBu3SnBu3Pd catalystPd catalyst
R1 = Alkyl, Alkenyl, Aryl, Alkynyl, HR1 = Alkyl, Alkenyl, Aryl, Alkynyl, H
R2 = Alkyl, Alkenyl, Aryl, AlkynylR2 = Alkyl, Alkenyl, Aryl, Alkynyl
++
The coupling of acid chlorides proceeds without Pd catalyst in many cases.
O
O
O
NHBoc
SnMe3HN O
O
O
NHBoc
HN R2
OK2CO3
i-Pr2NEt
R2COCl
Pd2dba3•CHCl3O
O
O
NHBocNHBoc
SnMe3SnMe3HNHN O
O
O
NHBocNHBoc
HNHN R2R2
OK2CO3K2CO3
i-Pr2NEti-Pr2NEt
R2COClR2COCl
Pd2dba3•CHCl3Pd2dba3•CHCl3
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 9
Stille reactions with triflates
OMe
R1 R2O
OTfMe
Me3Sn SiMe3
R1 R2OTf
THF, ΔLiCl
Pd(PPh3)4 Me
SiMe3
1. LiNi-Pr2
2. Tf2O
Tf = CF3SO2
W. D. Wulff Tetrahedron Lett. 1988, 29, 4795.
1. LiNi-Pr2(< 1 equivalent)
2. Tf2O
OMeMe
R1R1 R2R2O
OTfOTfMeMe
Me3SnMe3Sn SiMe3SiMe3
R1R1 R2R2OTfOTf
THF, ΔTHF, ΔLiClLiCl
Pd(PPh3)4Pd(PPh3)4 MeMe
SiMe3SiMe3
1. LiNi-Pr21. LiNi-Pr2
2. Tf2O2. Tf2O
Tf = CF3SO2Tf = CF3SO2
W. D. Wulff Tetrahedron Lett. 1988, 29, 4795.W. D. Wulff Tetrahedron Lett. 1988, 29, 4795.
1. LiNi-Pr21. LiNi-Pr2(< 1 equivalent)(< 1 equivalent)
2. Tf2O2. Tf2O
Preparation of stannanes from triflates:
OTfMe Me3Sn SnMe3
SnMe3Me
Pd(PPh3)4
W. D. Wulff J. Org. Chem. 1986, 51, 277.
LiCl, Li2CO3
oder(Me3Sn)2Cu(CN)Li2
OTfOTfMeMe Me3SnMe3Sn SnMe3SnMe3
SnMe3SnMe3MeMe
Pd(PPh3)4Pd(PPh3)4
W. D. Wulff J. Org. Chem. 1986, 51, 277.W. D. Wulff J. Org. Chem. 1986, 51, 277.
LiCl, Li2CO3LiCl, Li2CO3
oder(Me3Sn)2Cu(CN)Li2
oder(Me3Sn)2Cu(CN)Li2
Heterocycles:
N
N
N
N
N
Br
Br N
OO
Bu3Sn
Pd(PPh3)4
N
N
NBr
N
O
O
+
T. R. Kelly J. Org. Chem. 1997, 62, 2774.
37%
N
N
N
N
N
BrBr
BrBr N
OO
Bu3SnBu3Sn
Pd(PPh3)4Pd(PPh3)4
N
N
NBrBr
N
O
O
+
T. R. Kelly J. Org. Chem. 1997, 62, 2774.T. R. Kelly J. Org. Chem. 1997, 62, 2774.
37%37%
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 10
Palladium on charcoal can be used as a source of the catalyst:
H3CO
I
I
OMe
SnBu3
SnBu3
MeO
H3CO
10 mol % CuI20 mol % AsPh312 hrs.
(82 %)
+0.5 mol % Pd (10 mol % Pd/C)
(88%)
0.5 mol % Pd (10 mol % Pd/C)
+
10 mol % CuI20 mol % AsPh316 hrs.95 % trans
100 % trans
Liebeskind , L. ,Tetrahedron Letters , 1995 , 36 , 2191.
H3COH3CO
I
I
OMeOMe
SnBu3SnBu3
SnBu3SnBu3
MeOMeO
H3COH3CO
10 mol % CuI20 mol % AsPh312 hrs.
10 mol % CuI20 mol % AsPh312 hrs.
(82 %)(82 %)
+0.5 mol % Pd (10 mol % Pd/C)0.5 mol % Pd (10 mol % Pd/C)
(88%)(88%)
0.5 mol % Pd (10 mol % Pd/C)0.5 mol % Pd (10 mol % Pd/C)
+
10 mol % CuI20 mol % AsPh316 hrs.
10 mol % CuI20 mol % AsPh316 hrs.95 % trans95 % trans
100 % trans100 % trans
Liebeskind , L. ,Tetrahedron Letters , 1995 , 36 , 2191.Liebeskind , L. ,Tetrahedron Letters , 1995 , 36 , 2191.
Examples of the Suzuki reaction:
OR BrR1
B(OH)2
R1B(OH)2
SR BrOR
OR
R1
R1
+Pd(OAc)2 (2 mol%)
5°C, 2h
45-76%
+Pd(OAc)2 (2 mol%)
5°C, 2h
50-82%
R = H, CHO
NBu4Br
NBu4Br
K2CO3, H2O, 2
K2CO3, H2O, 2
R = H, CHO
The addition of tetrabutylammonium bromide facilitates the reaction.
Bu BX2I
B MeMe
Me
BX2
B(c-C6H11)2
B(Oi-Pr)2
Bu+
3 mol% Pd(PPh3)4
2 M NaOEt in EtOHC6H6, Δ
E:Z
2
58 94 : 6
49 83 : 17
98 >97 : 3
Yield
BuBu BX2BX2I
B MeMeMeMe
MeMe
BX2BX2
B(c-C6H11)2B(c-C6H11)2
B(Oi-Pr)2B(Oi-Pr)2
BuBu+
3 mol% Pd(PPh3)43 mol% Pd(PPh3)4
2 M NaOEt in EtOH2 M NaOEt in EtOHC6H6, ΔC6H6, Δ
E:ZE:Z
2
5858 94 : 694 : 6
4949 83 : 1783 : 17
9898 >97 : 3>97 : 3
Yield
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 11
Yields with alkyl boron compounds are often low because of protodeboronation. Boronates are better reagents. Rate of protodeboronation: 9-BBN > B(c-C6H11)2 > B(OR)2
Coupling of primary alkylboron compounds:
OI
TBSO
BCO2Me
Ph3AsCs2CO3
O
TBSO
CO2Me+PdCl2(dppf)
70-80%
DMF/THF/H2O25 °C
Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014.
OI
TBSOTBSO
BCO2MeCO2Me
Ph3AsPh3AsCs2CO3Cs2CO3
O
TBSOTBSO
CO2MeCO2Me+PdCl2(dppf)PdCl2(dppf)
70-80%70-80%
DMF/THF/H2ODMF/THF/H2O25 °C25 °C
Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014..
Diazonium salts can be coupled in Suzuki reactions:
N2
MeO
(HO)2B Pd(OAc)2 Ph
MeO
J.-P. Genêt Bull. Soc. Chim. Fr. 1996, 133, 1095.
1,4-dioxane22 °C79%
+N2N2
MeOMeO
(HO)2B(HO)2B Pd(OAc)2Pd(OAc)2 PhPh
MeOMeO
J.-P. Genêt Bull. Soc. Chim. Fr. 1996, 133, 1095.J.-P. Genêt Bull. Soc. Chim. Fr. 1996, 133, 1095.
1,4-dioxane1,4-dioxane22 °C79%22 °C79%
+
Although not very reactive, chloroarenes can be used in the Suzuki reaction:
Cl
Me O
Ph
Me O
(HO)2B
W. Shen Tetrahedron Lett. 1997, 38, 5575.
+5 mol% PdCl2(PCy3)2
CsF, NMP100 °C
98%
ClCl
MeMe O
PhPh
MeMe O
(HO)2B(HO)2B
W. Shen Tetrahedron Lett. 1997, 38, 5575.W. Shen Tetrahedron Lett. 1997, 38, 5575.
+5 mol% PdCl2(PCy3)25 mol% PdCl2(PCy3)2
CsF, NMP100 °C
98%
CsF, NMP100 °C
98%
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 12
5. Pd-catalyzed allylic alkylation (Tsuji–Trost reaction)
CO2Et
CO2Et
10 mol %Pd(PPh3)4, PPh3
NaCH(CO2Et)2THF, reflux
AcO
• General reactivty of substrates: Halide, Carbonate > Acetate > epoxide (?)
• Nucleophile: C-nucleophile- malonate, active methylene nucleophile; heteroatom (N, O, S, P, Si)-based nucleophile; hydride (B-H, Sn-H, Al-H and formates); organo-metallics (Zn-R, Zr-R, Sn-R etc.).
Catalytic cycle:
Pd+
NuNu
Nu Pd(0)
R
RLnPd
PdL X
- XL L
LnPd
Ligand association
Oxidative AdditionSN2'-like (invesrion)
Nu-attackSecond invesrion
Ligand dissociation
X
X
RR
R
R
Pd+Pd+
Pd(0)Pd(0)
R
RLnPdLnPd
PdPdL X
- X- XL L
LnPdLnPd
Ligand associationLigand association
Oxidative AdditionSN2'-like (invesrion)Oxidative AdditionSN2'-like (invesrion)
Nu-attackSecond invesrionNu-attackSecond invesrion
Ligand dissociationLigand dissociation
X
X
RR
R
R
NuNuNuNu
NuNu
Active cationic form of η3- allyl Pd complex intermediate is favoured by the bidentate phosphine ligand. Stereoselectivity: Retention of the carbon atom configuration by double inversion.
RX
H
PdLn
R
PdLn
H
NuNu
RH
PdLn
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 13
Allylic alkylation with ketone enolates
Enolates can be used as the nucleophile in allylic alkylations, which broadens the scope of the reaction even further. In the example on the left, the enantioselectivity of the reaction (the direction of attack of the nucleophile to the prochiral allyl cation) is controlled by the chiral C2 symmetric ligand (R)-BINAP. The example on the right uses the same chemistry, but a different C2 symmetric chiral ligand to control the enantioselectivity of the reaction. Literatur: Angew. Chem. Int. Ed. 2006, 45, 6952.
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 14
6. Palladium-catalyzed Amination
Cl
R1HN
R2
Pd(OAc)2 (1-2 mol%)
R
P(tBu)2
Ligand (2-4 mol%)
Toluol, Raumtemp
Ligand =
NPhMeMe
Me N O MeO N O
RNR1
R1
NHBn
OMe
+NaOtBu (1.4 equiv)
14-20 h
98% 94% 90% 99%
Nucleophilic aromatic substitution. Pd-catalysis allows reaction of non-activated arenes.
Catalytic cycle:
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 15
Examples:
Nickel-catalyzed aromatic amination
Copper-catalyzed aromatic amination
Diarylethers are accessible by a similar reaction using phenols as nucleophile.
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 16
A variation is the coupling of aryl boronic acids with amines or phenols. The reaction is called the Chan-Lam coupling.
Mechanism:
7. Palladium-catalyzed Alkyne coupling reactions
R1 Cu I R2 R2
R1
A. Castro-Stevens Kupplung
+R1R1 CuCu I R2R2 R2R2
R1R1
A. Castro-Stevens KupplungA. Castro-Stevens Kupplung
+
R1 H X R2 R2
R1
B. The Sonogashira-Hagihara Kupplung
NH
X = I, Br, Cl
PdCl2(PPh3)2 (2 mol%)CuI oder CuOAc(1 mol%)
25 °CAmin = Et2NH, Et3N oder
+R1R1 H X R2R2 R2R2
R1R1
B. The Sonogashira-Hagihara KupplungB. The Sonogashira-Hagihara Kupplung
NHNH
X = I, Br, ClX = I, Br, Cl
PdCl2(PPh3)2 (2 mol%)PdCl2(PPh3)2 (2 mol%)CuI oder CuOAc(1 mol%)CuI oder CuOAc(1 mol%)
25 °C25 °CAmin = Et2NH, Et3N oderAmin = Et2NH, Et3N oder
+
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 17
The amine is necessary to deprotonate the alkyne. Best coupling results are obtained in THF.
The mechanism is similar to the Suzuki or Stille coupling, but an organocopper species is transmetallated.
R1 H R1 CuCuI + R1R1 H R1R1 CuCuCuICuI ++
The halide, substituents in both coupling components, the catalyst and the amine influence the rate of the reaction. THF or amines are usually used as solvents.
I
Br
Br
Pd(PPh3)2Cl2 (cat)R2
Cl
R1 R1R2
= > ArI > > ArBr
Et3N, THF
CuI (cat)
I
BrBr
BrBr
Pd(PPh3)2Cl2 (cat)Pd(PPh3)2Cl2 (cat)R2R2
ClCl
R1R1 R1R1R2R2
= > ArI >> ArI > > ArBr> ArBr
Et3N, THFEt3N, THF
CuI (cat)CuI (cat)
4-CHO4-COMe2-CO2Me3-CO2Me4-CO2Me4-COMe4-COMe4-CHO
Me3SiMe3SiMe3SiMe3SiMe3Sin-BuPhPh
R1 R2 [%]
25°C / 1h25°C / 1h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h
9992888788918782
Reaction conditions Yield
4-CHO4-COMe2-CO2Me3-CO2Me4-CO2Me4-COMe4-COMe4-CHO
4-CHO4-COMe2-CO2Me3-CO2Me4-CO2Me4-COMe4-COMe4-CHO
Me3SiMe3SiMe3SiMe3SiMe3Sin-BuPhPh
Me3SiMe3SiMe3SiMe3SiMe3Sin-BuPhPh
R1 R2 [%]
25°C / 1h25°C / 1h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h25°C / 16h
9992888788918782
Reaction conditions Yield
ClC5H11
C5H11C5H11
C5H11
[Pd] (5%), CuI (10%), Amin, RTClClC5H11C5H11
C5H11C5H11C5H11C5H11
C5H11C5H11
[Pd] (5%), CuI (10%), Amin, RT[Pd] (5%), CuI (10%), Amin, RT
PdCl2(PhCN)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
[Pd] [h] [%]
piperidine
piperidine
piperidine
n-PrNH2
0.5
20
16
60
93
93
11
62
amine time yield
PdCl2(PhCN)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PhCN)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
[Pd] [h] [%]
piperidine
piperidine
piperidine
n-PrNH2
piperidine
piperidine
piperidine
n-PrNH2
0.5
20
16
60
0.5
20
16
60
93
93
11
62
93
93
11
62
amine time yield
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 18
Mechanisms: Palladium-copper co-catalysis (left); copper-free (right)
Examples:
Br Br
SiMe3Me3Si
SiiPr3
HH
SiiPr3Pr3iSi
+1) Pd(0) / Cu(I)
2) K2CO3, MeOH
F. Diederich, Angew. Chem. 1993, 105, 437-40
BrBr BrBr
SiMe3SiMe3Me3SiMe3Si
SiiPr3SiiPr3
HH
SiiPr3SiiPr3Pr3iSiPr3iSi
+1) Pd(0) / Cu(I)1) Pd(0) / Cu(I)
2) K2CO3, MeOH2) K2CO3, MeOH
F. Diederich, Angew. Chem. 1993, 105, 437-40F. Diederich, Angew. Chem. 1993, 105, 437-40
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 19
BrBr
BrBr
Br
BrSiMe3
H
H
H
H
H
H
+1) Pd(0) / Cu(I)
2) KOH, MeOH
28%
K.P.C. Vollhart, Angew. Chem. 1986, 25, 268-9.
BrBrBrBr
BrBrBrBr
BrBr
BrBrSiMe3SiMe3
H
H
H
H
H
H
+1) Pd(0) / Cu(I)1) Pd(0) / Cu(I)
2) KOH, MeOH2) KOH, MeOH
28%28%
K.P.C. Vollhart, Angew. Chem. 1986, 25, 268-9K.P.C. Vollhart, Angew. Chem. 1986, 25, 268-9..
Indole synthesis:
Ligand (10 mol%)
All in one: Tandem Heck-Stille-Sonogashira Reaction
BrPdLn
SnBu3R'
Br
transmetallation
BrBnO
Br
BnO
OTBS
OTBSBu3Sn
OH
Br
BnOBu3SnBr
BnO
OTBS
OH
Br
BnO
PdLn
TBSO
3 mol %Pd(PPh3)4
2.5 eq. NEt3100 oC, 12 h80 %
Red.Elim.
Pd(PPh3)4, CuI
BrBrPdLnPdLn
SnBu3SnBu3R'R'
BrBr
transmetallationtransmetallation
BrBrBnOBnO
BrBr
BnOBnO
OTBSOTBS
OTBSOTBSBu3SnBu3Sn
OHOH
BrBr
BnOBnOBu3SnBrBu3SnBr
BnOBnO
OTBSOTBS
OHOH
BrBr
BnOBnO
PdLnPdLn
TBSOTBSO
3 mol %Pd(PPh3)4
2.5 eq. NEt3100 oC, 12 h80 %
3 mol %Pd(PPh3)4
2.5 eq. NEt3100 oC, 12 h80 %
Red.Elim.Red.Elim.
Pd(PPh3)4, CuIPd(PPh3)4, CuI
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 20
8. Palladium-N-heterocyclic carbene (NHC) ligands for cross coupling reactions
Synthetically useful NHC ligands derived from imidazolium (I) and 4,5 dihydroimidazolium (SI) salts. Aldrichimica Acta, 2006, 39, 97.
General description of NHC generation from various precursors and their complexation with palladium
NHC•HCl Precursors typically used in in situ cross-coupling protocols
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 21
Active Pd-precatalysts with NHC ligands
Use of NHC ligands in the Suzuki cross coupling reaction
Ligand 13
Use of NHC ligands in N-aryl coupling reactions
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 22
9. Olefin Metathesis
Olefin Metathesis: metal-catalyzed exchange of olefins
R1
R1R1
R1
R2
R2+
M
R2
+
R2
Catalysts: Metal-carbene Complex
LnMR
RLnM
R
XR
Nucleophilic Electrophilic
Schrock-carbene(metal-alkylidene)
Fishcer-carbene(Hetero-atom stabilized)
d0
Pre-catalysts with a defined structure have been developed
N NMes Mes
Ru
PCy3
RCl
ClPCy3
Ru
PCy3
RCl
ClO
OMo
N
Ph
i-Pr i-Pr
F3C CF3
F3C
F3C
WO
Cl O
O Cl
Br
Br
BrBr
Aldehydes
Ketones
Olefins
Olefins
Olefins
Esters, amides
Aldehydes
Ketones
Esters, amides
Aldehydes
Ketones
Esters, amides
Oxophilicreactive
RuPh
PCy3
PCy3
Cl
Cl
PCy3Cl2Ru
PCy3Ph
Cl2Ru
PCy3
N NN N
Mes Mes
Ph Cl2RuPCy3
PhDistorted Square planar
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 23
Overview: Modern olefin metathesis catalysts
Reaction mechanism: Sequence of reversible formal [2+2] cycloaddition/ cycloreversion processes.
R1
R2
R1
R2R2
R2
CR2
R1
R1
LnM
R1 R1
R2
LnM
R1
R2
R1
R2
MLn
R1
LnM
R1 R2
R2
pre-catalyst
RR
R
start
MLn
LnM
R R1
R2
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 24
Direction of metathesis reactions:
• RCM (Ring-closing metathesis)A B C
• ROM (Ring-opening metathesis) C B A
• CM (Cross metathesis)A B D
• ROMP (Ring-opening metathesis polymerization)
C B E
M
n nn
n n
n a
n
R
A B C
D
E
n( a times)
R
Ways to push the process in one direction:
M
n nn
polymer
• Ethylene gas generally decreases RCM rate • Lower concentration can prevent polymerization and cross metathesis • Higher temperature usually promotes RCM process ( ΔS gain)
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 25
Factors influencing the ring closing metathesis:
PCy3Cl2Ru
PCy3Ph
R
Cl2RuPCy
R
31 eq. R'
R1 R1
R1
R1
PhR'
PCy3
3
R1
R1 Ph
N.R.100 8 3k rel
Substrate specific reactivity of catalysts – still difficult to predict!
X
X
X
OH
N NMes Mes
Cl2RuPCy3
Ph
PCy3Cl2Ru
PCy3R
RORO
MoN
Ph
Ar'
1 A 1 B 2A
X
X
X
OH
O O
O
O
O O
O
O
1 A
1 B
2A
> 99 %
> 99 %
> 31 %
> 99 %
> 99 %
20 %
0 %
0 %
> 99 %
> 99 %
93 %
0 %
X = CH(CO2Et)2
35 %
E/Z2:1
39 %
E/Z1.6: 1
15 %
E/Z1.6: 1
Examples of RCM in synthesis:
N
NH
OH
CHOH
HNO
Me
OEM Sugar
OHMeIrcinal A
Dactylol
Fluvirucin
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 26
O
O
N
S
O
R2O
O OR1
Yield (E/Z)
86 % (1: 2)65 % (1: 2)
R2
TBSH
epothilone A
R1
TBSHO
O
N
S
O
R2OR2O
O OR1OR1
Yield (E/Z)
86 % (1: 2)65 % (1: 2)
R2
TBSH
epothilone Aepothilone A
R1
TBSH
Fluvirucin B synthesis
Cyclophane synthesis
Large scale pharmaceutical synthesis
Note: Many functional groups are tolerated.
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 27
Double RCM reactions:
O
OO
HH
OPMB
PCy3Cl2Ru
PCy3Ph
O
OO
HH
OPMB
PCy3Cl2Ru
PCy3Ph
O
OO
HH
OPMB
O
O
HH
OPMBO
CH2Cl245 oC
25 mol %
88 %
CH2Cl2 45 oC
20 mol %
77 %
Synthesis of macrocycles:
10- 12
OO
R
OO
R
0 %
R: H 52 % -R: CH3 10 % 72 %
Yield of RCM product using
PCy3Cl2Ru
PCy3Ph
O
O
Presence of functional groupthat serves to assemble the reacting sites (not too basic)
Appropriate distance from functional group to olefin (not too close)
Low steric congestion near the olefin
Ring opening and cross metatheses reaction in synthesis:
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 28
Examples of cross metathesis reactions:
RCHO
R =AcOCH2(CH2)2
BzO
R
R =AcOCH2(CH2)2
RSi(OEt)3
R =AcOCH2(CH2)2
BzOR
R CHO
R Si(OEt)3
2.0 eq.
2.0 eq.
2.0 eq.
92 % (E/Z >20:1)
81 % (E/Z >4:1)
81 % (E/Z >11:1)
cat. A
cat. A
cat. B
N NMes Mes
Cl2RuPCy3
Ph
N NMes Mes
Cl2RuPCy3
CH3
CH3
cat. A cat. B
Diyne Metathesis
Catalyst (Schrock alkylidyne complex)
(t-BuO)3WMe
MeMe
R2
R1 R3
R4
R1 R3
R4R2
LnM R'
Mechanism:
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 29
Examples
R1 = H; 70 %
Alkyne RCM in combination with Lindlar partial hydrogenation is a selective way to generate macrocyclic (Z)-olefins.
LnM R'
R1 R2 R2R1
H2
Lindlar cat.n
n > 4n n
Z
Prof. Dr. Burkhard König, Institut für Organische Chemie, Universität Regensburg 30
Alkane metathesis