(ph m.c. white, - harvard universitysites.fas.harvard.edu/~chem153/lectures/week4.pdf · nao t bu...

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


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


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


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


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


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


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


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


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


C-C coupling: α-arylation of ketones

PdII

Aryl

Br

P

PPd0

PhPh

PhPh

P

PPdII

ArylP

P

Aryl-Br

oxidative addition


(±)-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


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



C-O coupling: diaryl ether formation

LnPd

PdLX

MX base

X = Br, Cl, OTf

M = Na, K

oxidativeaddition

transmetalation


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.


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


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


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


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


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


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


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


R = n-Hex

Quan, L. G.; Cha, J.K. JACS 2002, ASAP.

(ph m.c. white, - harvard universitysites.fas.harvard.edu/~chem153/lectures/week4.pdf · nao t bu...

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