Insertion Reactions

The Pd(II) species formed via oxidative addition can be engaged into other reactions not involving transmetallation. Migratory insertion reactions are very common. These can involve olefins, alkynes, and CO. Cascade reactions in which multiple insertion reactions take place are also possible. Depending on how the sequence is devised, the reaction can be terminated by either reductive elimination or β-hydride elimination.

R1 Pd X

Pd XCO

CO

R1

L

L

R1 X L

L

L Pd LO.A.

RR R1 Pd

R R

L

XL

ROH or

NHR2

ORCO

R1 NR2CO

R1

other insertions,transmetallation,carbonaylation

R1

R RB.H.E.

Carbonylation Reactions Of Carbon ElectrophilesIn contrast to acylrhodium intermediates, acylpalladium (and nickel) intermediates are reasonably stable at low pressures of CO (1 atm). They can also be formed directly from acid chlorides.

R1 X

R = alkene, arene, allylX = Br, I, OTf, etc.

PdLnR1 Pd Ln

CO

X

ROH orNHR2

– Pd(0)R1 Pd

O

Ln

XR1 OR

O

Final trapping can also be intramolecular

X

OH

+ HX

R1 NR2

O

OO

PdLn

Base

Acyl metal intermediate can undergo insertions by alkenes/alkynes

X

PdLn

BaseMeOH O O

OMe

By running the carbonylation in the prsence of an alcohol or amine, esters or amides can be formed.

Alkenyl triflates are some of the more common substrates as they can be easily made from ketones.

Review: Organometallics 2008, 27, 5402.

Carbonylation Reactions

Me

H

OMe

MeO

MeTMSO

1. MeLi, THF then PhN(SO2CF3)2 94%

2. 5% Pd(OAc)2, 6% dppf Bu3N, CO (1 atm) DMF, MeOH, 90ºC 99%

from Robinson annulationand Li/NH3 reduction

Me

H

OMe

MeO

MeMeO2C

J. Org. Chem. 1994, 59, 406.

OH

OMeMeO

I

2% PdCl2(PPh3)2K2CO3, CO (4 atm)

DMF, 50 ºC78%

OMeMeO

O

O

J. Am. Chem. Soc. 1980, 102, 4193.

OH1.6% PdCl2(PPh3)2K2CO3, CO (1 atm)

THF, 25 ºC71%

BrO

O

Carbonylation Reactions

J. Org. Chem. 1987, 52, 2469.

J. Am. Chem. Soc. 1986, 108, 452.

NH

NBr

NHR

O

N

N NHR

OO1.2% PdCl2(PPh3)23.2% PPh3, Bu3N

CO (200 psi)

10:1 DMF/H2O, 100 ºC70–75% after recryst.

136 g

Performing the carbonylation at higher pressures (3+ atm) in the presence of Bu3SnH or slow addition of the tin hydride will form the aldehyde.

MeOTf Pd(PPh3)4

CO, Bu3SnH

THF

MeCHO

53% (89% GC)

I Pd(PPh3)4CO, Bu3SnH

THF

CHO

70%Br Br

Pd(PPh3)4CO, Bu3SnH

toluene55%

I

OH

CHO

OH

Heck Reactions

In general terms, the Heck (or Mizoroki-Heck) reaction involves an oxidative addition followed by insertion into an alkene. The reaction is terminated by a β-hydride elimination to "regenerate" the olefin.

R1 XR1 = alkene, arene, allylX = Br, I, OTf, etc.

In principle any halide or pseudohalide electrophile can be used, except those with β-hydrides.

Z+PdLn

base ZR1

Bull. Chem. Soc. Jpn 1971, 44, 581.; J. Org. Chem. 1972, 37, 2320.

Phosphines required with aryl bromides, but hinder reactions with iodides. Typically amines bases are used. Originally, high reaction temps were required. The insertion step is thought to be the difficult step.

So-called "Jeffery condtions" have become quite popular as they allow lower reaction temperatures to be used. These conditions involve ligandless Pd(OAc)2 with polar solvents (e.g., DMF, NMP) and tetraalkylammonium salts (usually Bu4NCl or Bu4NBr), often with carbonate bases. There is evidence that Pd nanoparticles are formed and are stabilized by the anions (Angew. Chem. Int. Ed. 2000, 39, 165.). Chloride anions also help promote oxidative addition processes (J. Am. Chem. Soc. 1991, 113, 8375.).

Jeffery conditions: Chem. Commun. 1984, 1287.; Tetrahedron Lett. 1985, 26, 2667.; Tetrahedron Lett. 1988, 29, 905.; Synthesis 1987, 70.; Tetrahedron 1996, 52, 10113.

Wide range of olefins can be employed: cyclic and acyclic, electron-deficent (esters, amides, ketones, nitriles, aldehydes), unactivated, electron-rich (enol ethers).

The insertion proceeds with syn-addition of R group and metal. BHE is a cis process as well.

usually selective for E olefin

Heck ReactionsElectron-poor and unactivated are sterically controlled and place R-group on less-substituted position.

CO2MeMeO2C

Br

MeO

+

Pd(OAc)2Me(Cy)2N

Et4NCl

DMA, 95 ºC72% MeO

CO2Me

CO2MeE:Z = 11:1Chem. Eur. J. 1999, 5, 3107.

OO

I

OMeCO2Me+

Pd(OAc)2, K2CO3Bu4NBr, rt

86%(solvent)

OO OMe

CO2Me

E:Z = 9:1J. Am. Chem. Soc. 1998, 120, 7133.

OMe

MeO OTf

O

O Me

5

OMe

MeO

O

O Me

5

CH2=CH2 (40 bar)5% PdCl2(PPh3)2

LiCl, Et3N

DMF, 90 ºC92%

J. Org. Chem. 2000, 65, 7990.

Heck ReactionsRegioselectivity of electron-rich olefins is more complex. With cyclic systems, α-arylation is observed. Mixtures with acyclic enol ethers. Bidentate phosphines and electron-rich halides favor α-arylation. Electron-poor halides favor β-arylation. (J. Org. Chem. 1987, 52, 3529.)

O

α β

Ar PdLnX O

Ar

RO Ar PdLnX RO

Ar

RO

Ar

or

Ar w/ EWG

α β

I

OMe

O

OEt

OTIPSO10% Pd(OAc)2Bu3N, NaOAc

DMF, rt85%

OMe

O

OEtO

OMOMO

MOMO

Organometallics 1990, 9, 3151.

OPhOPh

OMePd2(dba)3•CHCl3

NaOAc,

CH3CN, 20 ºC80%

OMe

N2

BF4 32% w/ PhI @ 80 ºCChem. Commun. 2003, 1656.

Heck ReactionsUse of allylic alcohols gives aldehyde or ketone via β-hydride elimination toward alcohol.

O

O

OH

Br

Pd2(dba)3, dppb

Ag2PO4, CaCO3DMA, 79% O

O

CHO

Angew. Chem. Int. Ed. 1999, 38, 3662.

Ph

OHCO2Me Ph Br

Pd(OAc)2Bu4NBr, NaHCO3

THF, reflux, 81%Ph

OCO2Me

PhTetrahedron 1998, 54, 4943.

O

OEt

TBSOPd(OAc)2, PPh3Et3N, Bu4NHSO4

MeCN, H2O, 67%

β-alkoxide (or hydroxide) eliminations can occur if BHE cannot.

J. Org. Chem. 1997, 62, 1341.

OBr

O

TBSO

O

Heck ReactionsIntramolecular Heck reactions work especially well and many examples exist. Regioselectivity is usually high, but mode of addition (exo vs endo) is less predictable. In general, 5-exo and 6-eso are favored.

N

NO

BrMe

N

NO

Me

H

H

5% Pd(OAc)220% PPh3

proton spongeK2CO3, PhMe110 ºC, 82%

J. Org. Chem. 1998, 63, 9146.

N

Br

Br Boc

O

BocNO

Pd2(dba)3, Et3N

THF-NMP, rt86% N

Br

O

Boc

N

O

Boc

Org. Lett. 2001, 3, 2863.

5 vs. 6

OO

I

OO

Pd(OAc)2, PPh3

MeCN, Et3N, 58%

J. Chem. Soc., Perkin Trans. 1 1992, 539.

anti-elimination?

Asymmetric Heck ReactionsMany olefins are prochiral. By including chiral ligands, Heck reactions can, in principle, be usde to generate to stereocenters. In order for this to occur, the β-hydride elimination must occur away from the newly formed stereocenter. This restricts substrates to cyclic olefins or the formation of quaternary stereocenters.

HBHA Ar Pd X

HD

HC

HD

HC

Ar PdHBHA

X

syn-palladation

antisyn

can't rotate to makeHA and Pd syn

ArHA

HB

HD

new stereocentercyclic substrates

acyclic substrates – mixtures likely

R

HBHA Ar Pd X

HD

HC RHD

HC

Ar PdHBHA

X

syn-palladation R

ArHA

HB

HD

new stereocenter

R R R

ArHD

HC

HA PdHBRX

RAr

HB

R

R

Asymmetric Heck Reactions

MeO

NMe

O

Me

OTIPSI1. 10% Pd2(dba)3 23% (S)-BINAP PMP, DMAC, 100 ºC

2. 3N HCl

MeO

NMe

O

MeCHO

84% yield, 95% ee

J. Org. Chem. 1993, 58, 6949.

NOTf CO2Me

BocNH

10% Pd(OAc)2, t-BuPHOXPMP, toluene, 170 ºC, µw

75-87% yield, 99% ee NCO2Me

BocNH

J. Am. Chem. Soc. 2008, 130, 5368.

O

O

TfO+

3% Pd2(dba)36% t-BuPHOX

DIPEA, THF70 ºC

O

O70% yield, 92% ee

Angew. Chem. Int. Ed. Engl. 1996, 35, 200.

"Aromatic" Heck Reactions"Insertions" can also occur with electron-rich (or neutral) aromatic groups. Two mechanisms are possible, likely due to electronics of aromatic partner. Calculations have supported both.

I Pd(OAc)2, PCy3•HBF4

K2CO3, AgCO381%

J. Am. Chem. Soc. 2006, 128, 581.

"metathesis" mechanism – neutral aromatics

O

O

MeO

Me

O

OTf

Me

O

OMe

Pd(PPh3)4

DMA, DIPEA70%

Angew. Chem. Int. Ed. 2002, 41, 1569.

electrophilic addition – electron-rich aromatics

Reductive Heck ReactionsIf the insertion is set up such that β-hydride elimination is not possible, the σ-alkyl palladium intermediate can be intercepted by other processes. If carried out in the presence of formic acid or ammonium formate, a "reductive Heck" reaction will take place. This is most common with bicyclic olefins.

I

Br

+

(excess)

1 mol% PdCl2(PPh3)2Et3N, HCO2H, DMF, 50 ºC

91% (5.5 g)

H

Br

J. Am. Chem. Soc. 2005, 127, 52.

O

OTBS

Me

I

PhTMSO

O

OTBS

PhTMSO

Me

HPd(OAc)2, KO2CH

Bu4NBr

DMF, rt79%

J. Am. Chem. Soc. 2001, 123, 5590.

Cascade ReactionsCascade reactions are alo possible. In these cases, several alkene/alkyne insertions take place with a polyunsaturated substrate. Excellent strategy for constructing polycyclic products. Incorporating CO is also possible, but high pressures required to supress β-hydride elimination.

MeO

MeO

OTf

OO

MePd2(dba)3, (S)-BINAP

toluene, base, 110 ºC82% yield, 68% ee

O

MeO

MeO O

Me

J. Am. Chem. Soc. 1996, 118, 10766.

Pd(0)

[Pd]

OO

Me

O

Me[Pd]

O O

O

Me[Pd]

BHE

Cascade Reactions

J. Am. Chem. Soc. 1990, 112, 8590.

I

Me

PdCl2(PPh3)2, CO (40 atm)

MeOH, Et3N, MeCN, PhH70% yield Me

HO

O

O

OMe

Angew. Chem. Int. Ed. 1996, 35, 2125.

Me

EtO2CCO2Et

Me

EtO2CCO2Et

I

Pd(PPh3)4, Et3N

MeCN, 76%

4 rings, 4 C–C bonds1 new stereocenter

O

O

TBSOPd(OAc)2, PPh3Et3N, Bu4NBr

MeCN, 75%

Tetrahedron Lett. 1996, 37, 59.

OBr

OTBSO

O O