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M.C. White, Chem 153 Cross-Coupling -120- Week of October 8, 2002
Sonogashira: in situ, metal assisted deprotonation
Cl
PdIIPh3P Cl
PPh3
Ph H
Br
+(5 mol%)
CuI (10 mol%), Et2NH solventrt, 3h
The first report:
Ph
90% yield100% stereospecificitySonogashira TL 1975 (50) 4467.
pKa = 23
Cl
PdIIPh3P Cl
PPh3
catalytic cycle:
RICu
CuXRH
R3NH+ X-
PdIIPPh3
PPh3
R
R
transmetalation
(PPh3)2Pd0
note: can also start with a Pd(0) source (e.g. Pd(Ph3P)4).
R'
PdIIPh3P X
PPh3
RR
R' XR' = aryl, alkenylX = I, Br, OTf, Cl
RICuCuX
RH R3NH+ X-
(Ph3P)nPdII
R'
R
transmetalation
oxidativeaddition
reductiveelimination
R R'
Ph H Et3NH+
pKa = 10.75
Compare pKa's:
The acidity of the acetylene hydrogen is enhanced via π-complexation :
HR
CuI
Order of reactivity of Csp2-X component:
I, Br
>
I
>Cl
>>
Br
Mild aryl bromide Sonogashira couplings with P(t-Bu)3
Br
R
R= COMe, H, MeOMe, NMe2
R'
R' = Ph, hexyl,C(OH)(CH3)2
R'
R
CuI (3%)NEt3 (1.2 eq)
dioxane, rt
Pd(CH3CN)2Cl2 (3%)P(t-Bu)3 (6%)
70-90%
P(t-Bu)3 is uniquely effective under these conditions. All other phosphines screened (PPh3, P(o-tol)3, dppf, PCy3) gave less than 2% yield.
Buchwald & Fu OL 2000 (2) 1729.
Sonogashira JOMC 2002 (653) 46.
M.C. White, Chem 153 Cross-coupling -121- Week of October 8, 2002
O
Me
Me
Me
OMe O
O
O
O
MeO NH
NO
O
O
O
Me
Me
Me
OMe O
OH
O
O
HO
MeO NH
NO
O
O
+
Leucascandrolide A
Sonogashira: Csp-Csp2 coupling method of choice
Panek JOC 2002 67 6812-6815
ON
OTfTBDPSO N
HOMe
O
H
NH
OMe
O
ICu
Pd(PPh3)4
ON
PdTBDPSO
PPh3
Ph3P
ON
PdTBDPSO
PPh3
Ph3P HN
OMe
O
ON
TBDPSO
NH
OMeO
+
Pd(PPh3)4 (10 mo%)CuI (5 mol%)
2,6-lutidinedioxane, rt
84%CuI, 2,6-lutidinesoft deprotonation
oxidative addition
transmetalation
reductive elimination
TfO-
+
M.C White/Q. Chen Chem 153 Cross-Coupling-122- Week of October 8, 2002
Sonogashira: FG Tolerance
PMBO OH H
O
N
CO2Me
MeO
I
ON
MeO2C
MeO
PdI
L LPMBO OH CuIL
PdL
PMBO OH
O
N
CO2Me
MeO
PMBO OH
O
N
CO2Me
MeO
+
Pd(CH3CN)2Cl2 (4 mol%), CuI (14%), Et3N (5 eq)
CH3CN, -20 °C to rt 87%
L = CH3CN
in situ deprotonation oxidative addition
transmetalation
reductiveelimination
O
NOMe
O
O
N OMe
OO
O
Disorazole C1
Functional groups well tolerated: ester, free hydroxyl, allylic ether, and benzylic ethers, etc.
Hillier, M.C.; Meyers, A.I. JOC 2001, 66, 6037-6045.
M.C White, Chem 153 Cross-Coupling-123- Week of October 8, 2002
Sonogashira/Suzuki 3-Component Coupling
BrB(OiPr)2
NH2
Cl
Cl
BrCO2Me
OMe
H2N
Cl
Cl
PdBr
Ph3P
Ph3P
B(OiPr)2
CuIEt3N
H2N
Cl
Cl
ICu PdPh3P
Ph3P
B(OiPr)2
ClCl
NH2
NH2
Cl
Cl
CO2Me
OMe
BrCO2Me
OMe
PdBr
L
L
CO2MeMeO
NH2
Cl Cl
(PriO)2B
CuI (5 mol%), Pd(PPh3)2Cl2 (2.5 mol%)Et3N (2 eq.)THF, rt;
CsF (3 eq.)
Pd2dba3 (1 mol%)
H2O, acetone 50 oC 59% Yield
Pd2dba3
NH2
Cl
Cl
Pd
OMeMeO2C
L
oxidative addition 1
transmetalation 1
reductiveelimination 1
in situ deprotonation
transmetalation 2
oxidative addition 2
reductiveelimination 2
CsF-
B OiPrPriO
F_
Yu TL 1998 (39) 9347
M.C. White, Chem 153 Cross Coupling -124- Week of October 8, 2002
Migita's original report:
Br + (Bu)3Sn N
(o-tol)3P
Pd(II)Cl P(o-tol)3
Cl
10 mol%
toluene, 100oC, 3h
87%
N + n-Bu3SnBr
Migita Chem Lett 1983, 927.
reactions limited to electron neutral aryl bromides
Stille: C-N bond formation
Hartwig JACS 1994 (116) 5969.
Pd(II)
(o-tol)3PPd(II)Aryl
Br
(o-tol)3PPd(II)Aryl
NEt2
Aryl NEt2
Cl
P(o-tol)3
P(o-tol)3Pd(0)Aryl-Br
oxidative addition
transmetalation
reductiveelimination
Elegant mechanistic studies:
(o-tol)3P
ClPd(II)
Cl
Cl
(o-tol)3P
(Et)2HN
12
2 was isolated /characterized by x-raycrystallography and shown to be aviable catalyst for the aryl amination(yields identical to those obtained for 1).
Bu3SnNEt2
Pd(0)
3
(o-tol)3P P(o-tol)3
3 was independently synthesized toconfirm that the reaction procedes viaPd(0) intermediates. Reaction with 3was faster than those with 2, making it kinetically competent as anintermediate in the reaction. Thereaction was retarded by excessphosphine, indicating phosphinedissociation occurs before oxidativeaddition.
P(o-tol)3
Pd(II)Cl
Cl
Aryl
(o-tol)3P
4
Pd(II)P(o-tol)3
Aryl
4 was isolated/characterized by x-raycrystallography and shown to react withBu3SnNEt2 to give the arylamine product in 90% yield. The inability of 4 to undergoexchange with other aryl bromides (i.e.p-BuAr-Br) indicates that it is a legitimateintermediate in the catalytic cycle.
Et2N-SnBu3BrSnBu3
M.C. White, Chem 153 Cross Coupling -125- Week of October 8, 2002
Stille: C-N bond formationMigita's original report:
Br + (Bu)3Sn N
(o-tol)3P
Pd(II)Cl P(o-tol)3
Cl
10 mol%
toluene, 100oC, 3h
87%
N + n-Bu3SnBr
Migita Chem Lett 1983, 927.
reactions limited to electron neutral aryl bromides
Demonstration of Synthetic Utility:
(Bu)3Sn N + HNRR'
80oCAr purge
HNEt2
(Bu)3Sn N
RR' Br
R'
Buchwald hypothesizes that the lack of generality of Migata's system is due to the high reactivity/instability of aminostannes which hinders their isolation and further
use. To address this problem he develops a one-pot procedure that involves in situ generation of the aminostannes coupled with Migata's Pd catalyzed aryl amination.
The substrate scope is significantly expanded to include a wide variety of 2o aryl /alkyl amines (only example of a 1o amine is aniline) and aryl bromides substituted with
both electron withdrawing and electron donating groups.
transaminationthe more volatileamine is removed via the Ar purge
(o-tol)3P
Pd(II)Cl P(o-tol)3
Cl1-2.5 mol%
toluene, 105oC
55-88%
N
RR'
R'
Representative examples:
EtO2C N
Ph
88%
Me2N N
Ph
81%
N
(CH2)17CH3
79%
N
66%
Buchwald JACS 1994 (116) 7901.
one-pot
M.C. White, Chem 153 Cross Coupling -126- Week of October 8, 2002
Sn Free C-N bond formation: Pd-mediated soft deprotonation
Making use of a bidentate ligand may be a way to inhibit pathways that errode productformation (i.e. β-hydride elimination, bis(amine) aryl halide and bridging amido
complex formation). However, kinetic studies by Hartwig showing that both oxidativeaddition and reductive elimination go through 3 coordinate intermediates indicated thatbidentate ligands may shut the reaction down.
(o-tol)3PPd(II)Aryl
Br(o-tol)3PPd(II)
Aryl
N(CH2R1)R2
Aryl NR1R2 P(o-tol)3Pd(0)Aryl-Br
oxidative addition
reductiveelimination
P(o-tol)3
Pd(II)HN(CH2R1)R2
Br
Aryl
(o-tol)3P
HN(CH2R1)R2
+ NaBr
(o-tol)3PPd(II)Aryl
H
ββββ-hydrideelimination
reductive elimination
Ar-H
P(o-tol)3Pd(0)
Reduced side-product is observed in large
quantities when using 1o aliphatic aminessoft
deprotonation
N
R1H
R2
HN(CH2R1)R2
Pd(II)HN(CH2R1)R2
Br
Aryl
R2(R1H2C)NH
catalytically inactivebis(amine) aryl halidecomplexes
HOt-Bu
NaOt-Bu
Pd(II)
R1R2
N
NR1R2
Aryl
(o-tol)3PPd(II)
P(o-tol)3
Aryl
bridging amido complex resists reductive elimination
Buchwald OM 1996 (15) 2745 and 2755.Buchwald OM 1996 (15) 3534.
BrMe2N HN(Ph)Me NMe2N
Ph
Me
N
Ph
O n-hexyl
H
BrMeO HN NMeO NBu
n-Bu
H
Initial results limited to coupling of 2o amines and 1o amines with electron-deficient aryl bromides
Buchwald ACIEE 1995 (34) 1348.
+
[Pd(dba)2]/2 P(o-tol)3, 2 mol%or PdCl2(P(o-Tol)3)2
NaOtBu (1.4 eq)
65-100oC, toluene89% 72%
1o amine: only w/ para electron
withdrawing groups: Why?
Hartwig TL 1995 (36) 3609.
PdCl2(P(o-Tol)3)2 , 5 mol%
LiN(TMS)2 (1.2 eq)
100oC, toluene
+
94% <2% (1:50; amine:arene)
1o amine
M.C. White, Chem 153 Cross-Coupling -127- Week of October 8, 2002
C-N coupling: bidentate ligands extend substrate scopeBuchwald JACS 1996 (118) 7215: BINAP. 1o amines coupled with electron rich and deficient aryl bromides.
Br H2N(n-hexyl) N N
n-hexyl
H
n-hexyl
HNC
Among bidentate ligands, BINAP works uniquely well...
Ligand % Conversion
BINAP
P(o-tol)3
dppe
dppp
dppb
dppf
100 %
88 %
7%
>2%
18%
100%
ratio of 1 toaryl-H
40/1
1.5/1
1.5/4
---
1/1.6
13.2/1
ratio of 1 to doublyarylated amine
39/1
7.6/1
---
---
---
2.2/1
isolatedyield of 1
88%
35%
---
---
---
54%
PdII
Aryl
Br
Aryl N(CH2R1)R2
HOt-Bu
NaOt-Bu
P
PPd0
PhPh
PhPh
P
P
PdII
Aryl
Br
P
P
N(CH2R1)R2H
PdII
Aryl
N(CH2R1)R2
P
P
Aryl-Br
oxidative addition
reductiveelimination
HN(CH2R1)R2+ NaBr
softdeprotonation
(±)-BINAP
+
[Pd2(dba)3] BINAP 0.5 mol%
NaOtBu (1.4 eq)
80oC, toluene
88%98%1
N
H
t-Bu
79%
BINAP is thought to:· effectively prevents β-hydride elimination pathway by blocking cis coordination sites. · inhibit formation of catalytically inactive bis(amine)aryl halide complexes· inhibit formation of bridging amido complexes that resisist reductive elimination.
Buchwald OM 1996 (15) 3534. Reviews: Hartwig ACIEE 1998 (37) 2046; Buchwald Acc. Chem. Res. 1998 (31) 805.
Hartwig JACS 1996 (118) 7217: dppf. 1o amines coupled with electron deficient aryl bromides. Dialkyl amines led to formation of aryl-H products. Aryl iodides effectively
coupled with 1o aniline derivatives. In general, Buchwald BINAP system is more general and higher yielding.
Br H2N(n-hexyl) N
n-hexyl
HPh
O
Ph
O
N
HPh
O
+(dppf )PdCl2 5.0 mol%
NaOtBu (1.4 eq)
100oC, THF (sealed tube)
96%84%
Buchwald has developed aprocedure for aryl chlorides using:
P(t-Bu)2
Buchwald JOC 2000 (65) 1144.
Nolan and Hartwig have developed procedures for aryl chlorides using in situ generated N-heterocyclic carbenes
N NBF4
-
+R R
Nolan OL 1999 (1) 1307: Hartwig OL 2000 (2) 1423
M.C. White/Q. Chen Chem 153 Cross-Coupling -128- Week of October 8, 2002
N
N
F
Cl
NH
NH2
2HCl
N
N
F
N NH2
N
N
F
NH
NH
+ .
1
2
norastemizole
K2CO3/glycol
140 oC
thermal amination
Pd2dba3, BINAP,
NaOtBu, 85 oC
Pd-catalyzed amination
(selectivity 1:2 = 6:1)
(selectivity 2:1 > 35:1)
PPh2
PPh2
PdL L
NHN
N
F
NH
L L=
proposed intermediate in Pd-catalyzed amination
The thermal reaction showed selectivity for the more nucleophilic secondary amine to produce 1.
In contrast, Pd-catalyzed amination showed selectivity for amination with the primary amine to produce 2.
Senanayake TL 1998, 39, 3121-2124.
Selective C-N bond formation
M.C. White, Chem 153 Cross-Coupling -129- Week of October 8, 2002
C-C coupling: α-arylation of ketones
PdII
Aryl
Br
P
PPd0
PhPh
PhPh
P
PPdII
ArylP
P
Aryl-Br
oxidative addition
reductiveelimination
(±)-BINAP
R
ONa
NaBr
RO
O
R
Ar
Br
O
O
OPd2(dba)3, 1.5 mol%Tol-BINAP, 3.6 mol%
NaOt-Bu, THF, 70oC
O
O
O
76%
Buchwald JACS 1997 (119) 11108
OBr
Asymmetric generation of all carbon quaternary centers
Pd2(dba)3, 10-20 mol%(-)-BINAP, 12-24 mol%
NaOt-Bu, tol, 100oC
66%, 73% ee
O
Ph
Bidentate ligands are required to prevent β-hydride elimination when unhinderedaliphatic ketones are substrates. Moreover, the steric bulk of BINAP is thought toaccount for the high levels of steric selectivity for ketones with 2 enolizable positions.
Proposed mechanism
Buchwald JACS 1998 (120) 1918.
Soft deprotonation when a weak base is used:Milder base extends substrate scope:
PdII
Aryl
Br
P
P
O R
HB:
O
PPh2 PPh2 (t-Bu)2P
Xantphos Buchwald 1
Br
CO2Me
O
K3PO4, THF, 80oC
OCO2Me
Pd2(dba)3, 1.5 mol%Xantphos, 3.6 mol%
74%base sensitive functionality
pKa = 16.7
note: pKa of K2HPO4 ~ 12deprotonation must be assisted byketone binding to electrophilic metal
Br
CO2Me
O OK3PO4, dioxane, 100oC
Pd(OAc)2, 1.0 mol%1, 2 mol%
96%
O O
CO2Me
Buchwald JACS 2000 (122) 1360.
M.C. White, Chem 153 Cross Coupling -130- Week of October 8, 2002
C-O coupling: diaryl ether formation
LnPd
PdLX
MX base
X = Br, Cl, OTf
M = Na, K
oxidativeaddition
transmetalation
reductiveelimination
Electron-rich, bulky phosphine ligands for diaryl ether formation
NMe2P(t-Bu)2 P(t-Bu)2
P(1-Adamantyl)2
adamantane =
Buchwald JACS 1999 (121) 4369.Hartwig JACS 1999 (121) 3224.
P(t-Bu)2
Fe P(t-Bu)3
General conditions:2-5 mol% Pd(dba)22-5 mol% Phosphinepre-formed Na phenolate
General conditions:2 mol% Pd(OAc)23 mol% PhosphineNaH or K2PO4
Cl NaO
MeO
5 mol% Pd(dba)2
5 mol% P(t-Bu)3
toluene, 110oC, 24hOMe
BrMeO2C HO2 mol% Pd(OAc)2, 3 mol% 2
K2PO4, toluene 100oC
1 2 3
81%89%
X
R
R
in situ formation of K phenolate:
Dimeric species are not thought to be intermediates in thecatalytic cycle. Preformed dimeric species undergo reductive elimination to form aryl ethers in poor yields: 22%.Moreover, higher yields for the catalytic reaction areobserved at lower concentrations (e.g. 82% at 0.2M arylhalide vs. 23% at 1M aryl halide).
FcP(t-Bu)2
OH
R'
OM
R'
PdLO
R
R'
O
O
R' R
O
MeO2C
Pd(II)X
X
Aryl
Fc(t-Bu)2PPd(II)
P(t-Bu)2Fc
Aryl
ONa
Pd(II) O
O
Aryl
Fc(t-Bu)2PPd(II)
P(t-Bu)2Fc
Aryl
Ph
Ph
Hartwig JACS 1999 (121) 3224.
M.C. White, Chem 153 Cross-Coupling -131- Week of October 8, 2002
In situ reduction of Pd(II) to Pd(0)
Reduction via transmetalation:
LnPdIIX
XBrMg R 2 eq. LnPdII
R
R
transmetalation reductiveelimination
LnPd0
MgBrX
Reduction by tertiary aliphatic amines:
LnPdIIX
X
coordination
R2N(CH2)R
X-
PdIIL
R2N
X
R
H
β-hydride elimination
R2NRX- +
LnPdIIX
H
reductiveelimination
LnPd0
HX
Reduction by electron rich phosphines and base
LnPdIIX
X
coordination
PR3
X-
PdIIL PR3
XLnPd0
L
+
:Nu
+ NuPR3+ X-
phosphonium intermediategets converted to phosphine oxide in the presence ofatmospheric O2.
Beletskaya Chem. Rev. 2000 (100) 3009. Review of the Heck reaction.
M.C. White, Chem 153 Cross-Coupling -132- Week of October 8 , 2002
Heck ReactionThe Heck Reaction:
H
R
+ R'XL2PdIIX2 cat.
Base
R'
R
R' = aryl, heterocyclic, vinyl, benzylX = Br, I, OTf, ClBase:
2o or 3o amine, NaOAc,
K2CO3, KHCO3, KOAc
+ Base H+ X-
The base may serve a dualpurpose: reducing the Pd(II)precatalyst to Pd(0) and promoting reductive elimination of thePdH(X) intermediate by shiftingthe equilibrium towards Pd(0).
Catalyst:Pd(II) sources often used: Pd(OAc)2 , PdCl2PR3, PdCl2(CH3CN)Pd (0) sources: Pd(PPh3)4, Pd(dba)2+ PR3
Increasing the db substitution dramatically decreases therate of intermolecular Heck reactions:
> >
Olefin:
Heck is stereoselective for E olefin formation
Heck Org. React. 1982 (27) 345.
L2PdIIX2
NEt3
Et2N+
L2Pd0
PdIIR'
LX
R
cis migratoryinsertion
oxidativeaddition
PdII
XL
R
H
R'
LPd(II)H
X
PdII
R'
L
L
X
R'X
ββββ-hydrideelimination (cis)
X- +HNEt3
reductiveelimination
PdII
LX
Neutral mechanism: coordination of olefin viadissociation of a neutral ligand. Thought to operatewhen X = strong σ-donor (i.e.Cl, Br or I). When arylor vinyl halides are used, bidentate ligands can result in a partial or complete suppression of the reaction.
L
R'
R
HH
H
internalrotation
PdIIH
XL
R
R'
R
R
The reaction is stereoselective for the Eolefin because the corresponding TSleading to the cis olefin involvesenergetically unfavorable R'/R eclipsing interactions.
PdII
XL
H
H
H
reversible β-hydride elimination can lead to olefin isomerizationwhen R= alkyl
R'
R
also known as: olefin insertion, carbopalladation
M.C. White, Chem 153 Cross-Coupling -133- Week of October 8, 2002
L2PdII(X)2
NEt3
Et2N+
L2Pd0
PdIIR'
LL
R
cis migratoryinsertion
oxidativeaddition
PdII
LL
R
H
R'
LPd(II)H
PdIIR'
L
L
Br
R'Br
ββββ-hydrideelimination (cis)
HNO3
PdII
LL
Cationic mechanism: coordination of olefin via dissociation of a weakly associated anionic ligand. Thought to operate when X = OTf, OAc or when Ag or Tl salts (AgY or TlY; Y= CO3, OTf, OAc) are used that are capable of halide abstraction (metathesis- see Structure & Bonding -12-)
R'
R
HH
H
internalrotation
PdIIH
LL
R
R'
R
R
+
NO3-+
NO3-
+
NO3-
+
NO3-
PdII
XL
H
H
H
R'
R
Faster dissociation of the olefin leads to less β-hydride elimination.
AgNO3
AgBr
Heck Reaction
N
PhO
I
Halide abstraction additives minimize db isomerization
N
O
Ph N
O
PhN
O
PhPd(OAc)2 (10 mol%)
PPh3 (20 mol%)
CH3CN, 80oC
none TlOAc (1.2 eq)AgOAc (1.2 eq)
1: 2: 51: 0: 01: 0: 0
1st product formed Pd-H insertion product I Pd-H insertion product II
First example:Overman JOC 1987 (52) 4133.Grigg TL 1991 (32) 687.
Cabri Acc. Chem. Res. 1995 (28) 2.Beletskaya Chem. Rev. 2000 (100) 3009
M.C. White, Chem 153 Cross-Coupling -134- Week of October 8, 2002
Heck: Regioselectivity of migratory insertionwith neutral Pd complexes
Heck Org. React. 1982 (27) 345.Heck JACS 1974 (96) 1133.Hallberg Tetrahedron 1994 (50) 285.
H
R
Br (I)
CO2Me CN Ph C4H9
R
CO2Me Ph N
O
OCH3
+
PdII(OAc)2 1 mol%
PPh3 2 mol%
NEt3 or
For intermolecular Heck reactions with neutral Pd complexes and unactivated or electron-poor alkenes, the regioselectivity for R' insertion is under steric control, resulting in substitution at the less sterically hindered position. In contrast, with neutral Pd complexes and electron-rich alkenes (e.g. heteroatomsubstituted olefins), the regioselectivity of R' insertion is under electronic control, resulting in substitution α to the electron-donating group.
TMED (tetramethylethylene diamine)ββββ
100% 100% 100% 100%99%
1%
80%
20%
60% 40%
αααα
100%
or
R
M.C. White, Chem 153 Cross-Coupling -135- Week October 8, 2002
Heck: Regioselectivity of migratory insertionwith cationic Pd complexes
Cabri Acc. Chem. Res. 1995 28, 2-7.Cabri JOC 1992, 57, 1481-1486.Cabri Tet. Lett. 1991 32:14, 1753-1756.
H
R
OTf
CO2Me CN Ph C4H9 N
O
OH
R
OAc
R'
O-n-Bu
+
PdII(OAc)2
P(dppp)
For intermolecular Heck reactions with cationic Pd complexes, the regioselectivity for R' insertion is predominantly under electronic control for all substrate classes. Coordination of the olefinπ-system to a cationic Pd complex results in an increase in polarization of the C=C bond, and selectivemigration of the aryl moiety onto the carbon with lower charge density is observed.
ββββ
100% 100% 60% 20%
80%
100%
αααα
40% 100% 95% 100%5%
or Ar-X + TlOAc
NEt3 or iPr2NEt
R'
R
R'or
M.C. White, Chem 153 Cross-Coupling -136- Week of October 8, 2002
PdL X
Pd(L)n(X)
exo-trig
PdL X
endo-trig
Pd(L)n(X)
For the formation of small rings (5,6, or 7 membered rings) conformational effects dominate and the exo-trig mode ofcyclization is generally preferred.
In contrast, for the formation of macrocyclic structures(>9-membered rings), steric effects dominate and the endo-trig mode of cyclization is generally preferred.
NO
I
O
O
N
O
O
O
Pd(OAc)2 N
OO
O
N
O
O
O
n
nTri-o-tolphosphine
Et3N, CH3N
n=3, 29%n=5, 24%n=7, 38%
Stocks Tet. Lett. 1995 36:36 6555-6558.
I
CO2CH3Pd(OAc)2
Ph3P, Et3N
CO2CH3
H86%
H
N
I
CO2CH3Pd(OAc)2
Ph3P, Et3N
H
NCO2CH3
H
74%
Overman JOC 1987 52 4130-4133.
Intramolecular Heck: “exo-trig” vs “endo-trig” cyclization
M.C. White/ M.W. KananChem 153 Cross-Coupling -137- Week of October 8, 2002
Tandem Heck: construction of adjacent quaternary C centers
N
O O
N
OO
Bn BnI I
BnN
O
NBn
O
OO
Pd(PPh3)2Cl2 (10 mol%)
Et3N, DMA, 100°C
90%
BnN
O
OO
N
IBn
O
PdI
PPh3
BnN
O
OO
PdIL O
N
BnI
H
BnN
O
OO
N
I
O
Bn
BnN
O
NBnO
OOPdLI
BnN
O
NBnO
OO
Pd
I
L
The stereochemistry of the acetonide controls the Heck cyclizations such that only a singlestereoisomer is observed. Despite the stericcongestion of the olefins in the twocylcizations (tetra- and tri-substituted), theoverall transformation proceeds efficiently.
Pd(PPh3)2
oxidative addition
olefin insertion
β-hydrideelimination
oxidativeaddition
olefin insertion
β-hydrideelimination
Overman JACS 1999 (121) 7702.
M.C. White/M.W. Kanan Chem 153 Cross-Coupling -138- Week of October 8, 2002
Pd0P
P
TfO OMOM
HO
OH
OBOM
Pd OMOM
HO
OH
OBOMP
P
OMOMOBOM
OH
HO
PdPP
OMOM
OBOM
OH
HO
PdP
P
TfO-
Et3N
PdP
P
Et3N
OMOM
OBOM
OH
HO
OMOM
OBOM
OH
HO
Et2N
PdP
P
H
PdP
P
H
OMOM
OBOM
OH
HO
OMOM
OBOM
OH
HO
Pd2(dba)3 (15 mol%)
dppb (40 mol%)Et3N, DMAc, 120°C
+
+
++
+
oxidative addition
olefin insertion
b-hydride elimination
reductive elimination
In the initial insertion intermediate, there is no β-hydrogen to enable elimination of
PdII and regeneration of olefin. Et3N serves as a hydride donor, generating an
alkyl-hydrido species that reductively eliminates to release the desired product.
Hirama Org. Lett. 2002 (4) 1627.
84%
Et2N+
Intramolecular Mizoroki-Heck to construct a quaternary carbon center
M.C. White/Q.Chen Chem 153 Cross-Coupling -139- Week of October 8, 2002
Tandem Heck-Hiyama Coupling
O
O
OEt
I
SiR
iPriPr
OSi
OH
iPr iPr
O
EtO
R
O
O
OEt
SiR
iPriPr
(dppp)PdI
O
OSi
R
iPr iPr
Pd(dppp)
OEt
IOH
O
OSi
R
iPr iPr
Pd(dppp)
OEt
IOH
O
OSi
I
iPr iPr
Pd(dppp)
OEt
OHR
10% Pd(OAc)2, 20% dpppIsoprostanes &Neuroprostanes
73%Pd(dppp)
Pd(dppp), I
Following olefin insertion, there is no syn hydrogen available for β-hydride elimination. Instead, this intermediate is proposed toundergo a hydroxide-promoted, intramolecular Hiyama-typetransmetalation followed by reductive elimination to yield thedesired product.
Et3N (5 eq), H2O (2 eq), DMF, 80 °C
oxidative addition
olefininsertion
intramoleculartransmetalation
reductiveelimination
R = n-Hex
Quan, L. G.; Cha, J.K. JACS 2002, ASAP.