MX2

Allyl Metals

X

MX

Virtually all transition metals can form η3-allyl complexes, but few are synthetically useful. Pd is most widely studied and has broad utility. Allyl complexes of Rh, Ir, Ru and Mo are becoming more important and display reactivity differences that are complimentary to Pd. These are usually quite stable (but still reactive), and their formation is typically preferred over other posibilities.

+ M(n)

n = 0, 1

oxidativeaddition M(n+2)X MgX + MX2

transmet.

η1-allyl

η3-allyl

H base

–X

R/H M +insertion

M

R/H

MXR/H/Nuc

M

Nuc

R/H M C+insertion

MX

R/H

M

R/H

Pd(0)L2

Allyl MetalsOnce formed the allyl palladium intermediate is available for a wide range of subsequent transformations.

LPd(0)

X

Pd(II) XL(SN2 or SN2')

Pd(II)X

L

Pd(II)L2NucNuc

"reductiveelimination"

+L–X–

Nuc

Pd(II)R

L

R M

R + Pd(0)L

transmetallation

oxidative addition

Pd(II)X

–L, +

insertionPd(II)X

H Pd X+

BHE

LPd(0)– HX

(inversion)

(retention)

(inversion)

(net inversion)

(net retention)

phosphine ligands are normally used

Pd Catalyzed Allylic AlkylationThe electrophileA wide range of leaving groups have been used all with varying rates of reaction and synthetic utility/ease of installation.

XRPd(0)

R

Pd+ X

X = Br, Cl, –OAc, –OCOR, –OP(OEt)2, –OSR, OPh, OH, R3N+, NO2, SO2Ph, CNO O O

OR

most commonly used

R

PdO

basic

R R

PdbasicO OR

O

RO

+ CO2

R R

Pdnot basic

OO

O

O

selective reactions possible: Cl > OCO2R > OAc >> OH

Pd Catalyzed Allylic AlkylationThe electrophile – regioselectivityBecause Pd proceeds through η3-allyl intermediate, it does not matter which isomer is used as the starting material. Other metals may behave differently.

R

X

XRPd(0)

R

PdX

Pd(0)

With Pd nucleophiles usually attack at less-substituted end. Can vary with ligands and other metals.

R

PdX

NucR

Nuc

NucR

minormajor

Stereoselectivity

With chiral substrates high levels of stereoselectivity are observed. Overall retention of configuration is the result of a "double inversion".

R1

X

R2 Pd(0)

(inversion)

R1

PdX

R2 Nuc R1

Nuc

R2 R2

Nuc

R1

or

(inversion)

Pd Catalyzed Allylic AlkylationThe nucleophileTypical carbon nucleophiles are relatively soft, stabilized carbanions. The anion can be pregenerated,or made in situ in the presence of an added base. Some of the leaving groups can serve as this base.

R

PdXR

Z YZ, Y = CO2R, COR, SO2Ph, CN, NO2

Z YY

Z

Intramolecular examples are kown and work well. Can be used to make rings from 3–11+ members.

Silyl enol ethers can also be used.

R

PdXR

OTMS

R2

O

R2

Pd Catalyzed Allylic Alkylation

OO

H

Me

PhO2C

cat. Pd(PPh3)4(–)CH(CO2Me)2

THF, 95% Me

CO2MeMeO2C

HCO2Ph

HO

OJ. Am. Chem. Soc. 1981, 103, 1864. complete chirality transfer

O

O

SO2Ph

PhO2S

OTBS

O

Pd(OAc)2P(Oi-Pr)3

O

O

OTBS

OHPhO2S SO2Ph

Tetrahedron Lett. 1986, 27, 5695.

26-membered ring

C5H11CHO

HCN

Ac2O C5H11 OAc

CN 5% Pd(PPh3)4THF, rt

COMeMeO2C C5H11 CN

COMeMeO2C

67%Tetrahedron Lett. 1981, 22, 2573. EWG controls regioselectivity

PdL*

Allylic Alkylation–StereoselectivityAcyclic allyl Pd intermediates are dynamic. This has important consequences with regard to regio- and stereoselectivity.

OAc

Pd(0)L* PdL*

(SN2)

Nuc

fast rxn(SN2)σ-allyl π-allyl

Nuc

PdL*PdL*σ-allyl π-allyl

PdL*

H

H

σ-allyl

H

H

PdL*

σ-allyl

Nucslow rxn

diastereomeric,different rxn ratesracemic

high ee

R1

OAc

R1 Pd(0)L*

racemic

R1R1

PdL*one isomer

(enantiotopic ends)

Nuc

high ee

R1

Nuc

R1

disubtituted acyclic – both enantiomers give same intermediate

π→σ→πisomerization

results in "enantioface exchange"

Allylic Alkylation–StereoselectivityThe π→σ→π isomerization pathway is not available to cyclic systems, but asymmetric induction has been acheived. Erosion of enantioenrichment is observed with chiral substrates and achiral catalysts at high metal loadings.

H

R

PdL*

H

R

PdL*

H

R

PdL*

LnPd

H

R

PdL*

"diastereoface exchange"Pd(II)L is leaving group for

Pd(0)L attack

Allylic Alkylation–StereoselectivityDesymmetrization of meso substrates is quite common. In these cases, the chiral catalyst can choose between the enantiotopic leaving groups.

OAcAcOPd(0)L*

Z Y(achiral)

Pd(0)L*

YZAcO

Z

Y(R) (S)OAc

Z

Y(R) (S)

The remaining allylic leaving group is available for a second reaction with an achiral catalyst.

AcOZ

Y

Pd(0)L

NucNuc

Z

Y

AcOZ

Y

Pd(0)L

Nuc

Z

Y

Nuc Nuc

Notice the tether altersthe regioselectivity

Enantioselective Allylic AlkylationSeveral different ligands have been used to impart asymmetry. The Trost ligands have demonstrated the widest utility.

Reviews: Chem. Rev. 1996, 96, 395. Acc. Chem. Res. 2006, 39, 747.

HNNHOO

PPh2 Ph2P

(S,S)-Trost Ligand

Enantioselective Allylic Alkylation

I

OH

OH

Me

OCO2MeCN

(±)

1% Pd2(dba)3, 2.7% (R,R)-Trost

CH2Cl2, rt, 97%, dr 92/8 I

OR

ORa. 10% PdCl2(CH3CN)2 HCO2H, PMP, DMF, 50 ºC

b. Ac2O, Et3N, DMAP, CH2Cl2 81% yield, 87% ee

MeCN

O

OAc

Me

MeCN

J. Am. Chem. Soc. 2002, 124, 11616.

OBz

BzOSO2PhO2N

(η3-allyl-PdCl)2(S,S)-Trost

NaHCO3, THF87%, >99% ee

NO

SO2Ph

O

J. Am. Chem. Soc. 1998, 120, 1732

Enantioselective Allylic Alkylation

NH

O

O

OOH

2.5% Pd2(dba)37.5% Trost

Cs2CO3, THF, rt87%, 82% ee

OHHONPhth

J. Am. Chem. Soc. 1996, 118, 6520.

Cl0.026% [(allyl)PdCl]2

0.054% Ligand

NaCH(CO2Me)2, THF93% yield, 95% ee

CO2Me

MeO2C1. NaOH, Δ2. KI, I2, NaHCO3 recrystallization

3. DBU, THF

O

O

HH

>99.9% eeAngew. Chem. Int. Ed. 2002, 41, 4054.

P N

O

t-Bu2-BiphPh

Mn(CO)3

ligand OMe

OMe

OCO2Me

OMe

OMe

NTs

Pd2(dba)3BINAPO

TsNHallylTHF, rt

80%, 86% ee

J. Org. Chem. 1997, 62, 3263.

Allylic Alkylation via TransmetallationUsed less frequently than other nucleophiles. Allylic acetates are not great substrates, but can work. Transmetallation is slowed due to tight coordination of acetate, and reductive elimination is slower with allyl groups than other alkyl/aryl groups.

Reactivity acheived with polar solvents (DMF), "ligandless" Pd [Pd2(dba)3, PdCl2(MeCN)2], and excess LiCl (facilitate transmetallation). Organostannanes work well (transmetallation facile relative to RB(OR)2). Reaction occurs on less substituted end, with net inversion of configuration (R.E. occurs with renention).

TESOTESO

Me

OTES

MeSnMe3

AcON

OMeOH

MeMe Me

O

+

TESOTESO

Me

OTES

Me Me

OH

MeN

OOMe

Me

Pd2(dba)3LiCl, DIEA

NMP, 40 ºC 86%

configurationmaintained

skipped dieneJ. Am. Chem. Soc. 2003, 125, 5393.

Allylic Alkylation via TransmetallationWorks better with allylic chlorides/carbonates and vinyl epoxides. Chlorides reactive enough that phosphines can be used.

MeO2C

MeO2C

SnBu3O

Me+

Pd cat 1

H2O, DMF, rt

Pd cat 2

H2O, DMF, rt(with Na salt of malonate)

MeO2C OH

MeO2C

Me

MeO2C SnBu3

MeO2C

MeOH

up to 93%

up to 92%

Pd cat 1: PdCl2(MeCN)2, Pd(cod)Cl2, Pd2(dba)3, Pd(bpy)Cl2

Pd cat 2: Pd(PPh3)4, Pd(dba)(dppf), Pd(dba)(PPh3)2, Pd(dba)(AsPh3)2

Tetrahedron Lett. 1996, 37, 6591.

N

S

OCO2CHPh2

Cl

NHO

Bn Pd2(dba)3, P(2-furyl)3

THF, 65 ºC

MeO SnBu3

N

S

OCO2CHPh2

NHO

BnOMe

Tetrahedron Lett. 1988, 29, 5739.

Reactions With Noncarbon NucleophilesThe nucleophile does not have to be carbon-based. Heteroatom nucleophiles also work.

Nitrogen nucleophiles: 1º, 2º amines (not NH3), amides, imides, sulfonamides, and azide (as TMSN3) all work. Stereo- and regioselectivity parallels malonates. Almost invariably ends up on less-substituted end.

O

OO

N

N NH

N

Cl

+Pd(PPh3)4

DMSO/THF53%

NHO

N

N

N

Cl

OMeOMe

OCO2Me

NHTs+

Pd2(dna)3(S)-binbpo

THF80% yield, 86% ee

OMeOMe

NTs

J. Org. Chem. 1997, 62, 3263.

J. Chem. Soc., Perkin Trans. 1 1998, 391

Reactions With Noncarbon NucleophilesIntramolecular aminations possible as well.

O

O Br

HN

OAc

Pd(PPh3)4TMG

MeCN, 45 ºC88%

O

O Br

N

Note: reaction in the prsence of aryl bromide

AcOO

NH2N

O

AcHN

O

NHN

O

AcHN

Pd(PPh3)4dppb

THF, 70 ºC89%

J. Am. Chem. Soc. 1999, 121, 10264.

J. Am. Chem. Soc. 1982, 104, 6881.

Reactions With Noncarbon NucleophilesNot as many examples with oxygen nucleophiles. Phenols work well. Glycosylations at the anomeric postions are known. Cyclizations with aliphatic alcohols work. Water and hydroxide are unknown, but Ph3SiOH can serve as an alternative.

O

O

OO

PhCO2

2% Pd2(dba)34% dppb, 8% PPh3

Ph3SiOH

THF, rt, 64%

O

O

O

PhCO2

OHPh3SiO

Tetrahedron Lett. 1993, 34, 1421.

Ph OTBDPS

OH

OBzO

H H

NaH, Me3SnCl20% Pd(OAc)2/PPh3

THF, 60 ºC, 77%OTBDPS

Ph

8:1 drNote: in this case the nucleophile attacks at more hindered position.

Org. Lett. 1999, 1, 1303.

Reactions With Noncarbon NucleophilesFormate salts: Reductions can be carried out by using ammonium formates or allyl formates. The hydride is delivered from same side as Pd (net inversion). Appears to prefer delivery of hydride to more substituted side.

Me OTBS

HCO2Me OTBS

Pd(acac)2, PBu3

THF, rt, 57%

H

Me OTBS

HCO2Me OTBS

Pd(acac)2, PBu3

THF, rt, 82%

HJ. Org. Chem. 1992, 57, 1326.

ArMeAcO

ArMe

H

Pd2(dba)3chiral lig.

Et3N, HCO2H

THF/dioxane86%, 90% ee

(±)Tetrahedron 2000, 56, 2247.

CO2EtOPMB

O

Me

CO2EtOPMB

Me

OH

OBn

OBn

Pd2(dba)3PBu3

HCO2H, Et3Ndioxane, rt

96%Tetrahedron Lett. 1996, 37, 6881.

Insertion Reactions with Allyl PdOnce formed, allylpalladium intermediates can also undergo insertion reactions with alkenes, alkynes and carbon monoxide much like we discussed in the previous section. Computational experiments have shown that the insertion occurs on the η3-allyl complex, but the η1-allyl complex coudl also be invoked.

Intramolecular reactions are quite common

AcO

Pd(0)

PdOAc

π → σ

PdOAc PdOAc

direct insertioncannot do

insertion onolefin

B.H.E.

alkene/alkyneinsertion transmetallation

CO

CO2MeCO2Me

10% Pd2(dba)3PPh3

CO (1 atm)

MeOH, 45 ºC81%

CO2MeCO2Me

Helv. Chim. Acta 1991, 74, 465.OAc

O

H

MeO

O

Insertion Reactions with Allyl Pd

SO2Ph

SO2Ph

ClAcO

+

SO2PhSO2Ph

AcO

5% Pd2(dba)320% PPh3

NaH, THF, 25 ºC68%

5% Pd2(dba)320% PPh3

AcOH, 80 ºC81%

SO2PhSO2Ph

Helv. Chim. Acta 1991, 74, 465.

CO2MeCO2Me

MeO2CMeO2C

AcOMe

H

H

HH CO2Me

CO2MeMeO2CMeO2C10% Pd2(dba)3

50% P(2-furyl)3

AcOH, 110 ºC

J. Org. Chem. 1991, 56, 6256.

OAc

NMe

PhO2S

N

MePhH

H

PhO2S

10% Pd(OAc)220% PPh3

NaBPh4anisole, 60 ºC

80%

Tetrahedron Lett. 1991, 32, 2545.

Decarboxylative AllylationA unique way to generate ketone enolates (and other anions) in a regiospecific manner and with no base.Chiral lignads allow enantioselective reactions to occur even with racemic starting materials.

O O

O

Allyl Enol Carbonates

OPd2(dba)3, PPh3

dioxane, rt

O O

OPd(PPh3)4

DMF, rt

O

67% yield

Allyl b-Ketoesters

Chem. Lett. 1983, 1325.

Silyl Enol Ethers

Pd2(dba)3•CHCl3dppe

diallyl carbonateTHF, ∆

O

O

Enol Acetates

OPd2(dba)3•CHCl3

dppe, MeOSnBu3dioxane, ∆

82% yield

O O

O

82% yield

OTMS O

H

76% yieldTetrahedron Lett. 1983, 24, 1793.

Tetrahedron Lett. 1983, 24, 4713.J. Am. Chem. Soc. 1980, 102, 6381.

Decarboxylative Allylation

Review: Chem. Rev.2011, 111, 1846.

The allylation occurs on the same side the enolate forms on. Scrambling of enolate position does not occur.

Tetrahedron Lett. 1983, 24, 1793.

O O

O

Pd2(dba)3, PPh3

dioxane, rt

O O O

O

O

only product only product

Pd2(dba)3, PPh3

dioxane, rt

O O

O

Pd(0)Ln

O

PdLn+ CO2

"tight ion pair"?reacts to quickly to

isomerize or protonate

O

Decarboxylative AllylationThis approach has also been extended to other substrates

I

N

Ph Ph

O

Oa. Pd(PPh3)4, Ag2SO4 DMF, 20 ºC, 5 min

b. Et3N, µw, 150 ºC

NPh

Ph

91% yield

NPh

Ph

IintermediateOrg. Lett. 2008, 10, 5131.

O2N CO2allylOBn

O2NOBnPd(PPh3)4

CH2Cl2, 23 ºC92%, dr 6.5:1

Org. Lett. 2010, 12, 740NO2 CO2Et

O

OMe

NO2 CO2Et

Me

Pd2(dba)3rac-BINAPtoluene, 110 ºC

J. Am. Chem. Soc. 2007, 129, 14860.

Ph

O

O

Ph

PhPhPd(PPh3)4

toluene, 75 ºC80%

J. Am. Chem. Soc. 2005, 127, 13510

Decarboxylative AllylationEnantioselective reactions with ketones.

O ORPd2(dba)3 (2.5 mol%)

(S)-t-BuPHOX (6.25 mol%)

THF, 25 °CPh2P N

O

(S)-t-BuPHOX

RO

O

Angew. Chem., Int. Ed. 2005, 44, 6924.

80-99% yield, 81-91% ee

O

O

O O

racemic

Pd2(dba)3 (2.5 mol%)ligand (5.5 mol%)

dioxane, 23 °C

93% yield, 99% eeHNNH

OO

PPh2 Ph2P

ligandJ. Am. Chem. Soc. 2005, 127, 2846–2847.

Allylations With Other MetalsPd is not the only metal to perform synthetically useful allyl complexes. Others include: Mo, Ir, Rh, Ru. While these have been investigated, their develpment is not nearly as extensive as Pd.

While the overall transformations and mechanisms are quite similar, these alternate metals often behave much differently with respect to regioselectivity and stereoselectivity.

Mo(0) – The regioselectivity of nucleophile attack is quite dependent on catalyst structure/ligands, but reaction at more-substituted end is common.

Rh(I), Ru(0 & II), Ir(I) – Alkylation of allylic acetates and carbonates occur at more-substituted position. Alkoxides and enolates can be used if Cu salt if formed.

Ph

O

OBn

+MeO2CO (S)(S)

Ph RhCl(PPh3)3, P(OMe)3

LiHMDS, CuI, 90%, dr 37:1

Ph

OBnPh

O

J. Am. Chem. Soc. 2004, 126, 8642.

MeO

OCO2t-BuOH 1. BuLi, CuI

2. [Ir(cod)Cl]2. L* 87%, >98% ee

MeO

O

Chem. Commun. 2006, 1968.

+

Allylations With Other MetalsWith some catalyst systems the nucelophile adds to the carbon bearing the leaving group, regardless of the substitution – "memory effect" likely due to an η1-allyl intermediate and not a η3-allyl intermediate.

Chem. Commun. 2007, 4283.

OAc

R

5% [RuCl2(p-cymene)]210% PPh3

CH2(CO2Me2), LHMDS

toluene

R

RuLn

η1-allyl?

R

MeO2C CO2Me

99:1

R

5% [RuCl2(p-cymene)]210% PPh3

CH2(CO2Me2), LHMDS

toluene RuLn

η1-allyl?CO2MeMeO2C

99:1

OAc

R R

R1

OCO2Me

R2

a R1 = Me, R2 = i-Prb R1 = i-Pr, R2 = Me

RhCl(PPh3)3P(OPh)3

NaCH(CO2Me)2 Me

OCO2Me

i-Pr i-Pr

OCO2Me

Me

from a: 97 : 3, 83% from b: 3 : 97, 87%

J. Am. Chem. Soc. 1998, 120, 5581.

Trimethylenemethane IntermediatesPd(0) complexes react with bifunctional allylic groups to form unstable (and uncharacterized) trimethylenemethane intermediates. Similar complexes have been formed and characterized with other metals, but they are too stable to be synthetically useful.

AcO TMSPd(0)Ln

LnPd

trimethylenemethane intermediate• zwitterionic• undergoes [3+2] reactions with electrophiles

nucleophilic

elecrophilicUnknown if cycloaddition is concerted. If stepwise, then ring closure is faster than bond rotation (stereochemistry in reaction partner conserved).

OO

MeO2C2% Pd(PPh3)PhMe, 80 ºC

78% yield, 3:1 dr

AcO TMS OO

CO2Me

H

H

OO

2% Pd(PPh3)PhMe, 80 ºC

69% yield, >50:1 dr

AcO TMS OO

CO2Me

H

HCO2Me

Tetrahedron Lett. 1986, 27, 4137.

trans product

cis product

Trimethylenemethane IntermediatesSubstituted precursors also react well and give highly regioselective reactions, regardless of the starting postion of the acetate and TMS groups.

AcO TMSPd(0)Ln

LnPdR

appears to react through this isomer irregardless of R group identity

LnPdR

R

J. Am. Chem. Soc. 1985, 107, 721.

Intramolecular reactions and enantioselective reactions possible

O

Me CO2Me

SO2Ph

TMSOAc

Pd(OAc)2P(O-i-Pr)3

Me3SnOAc

PhCH3, 110 ºC83% yield

O

MeH SO2Ph

CO2Me

HO

MeH SO2Ph

CO2Me

Me

2:1 dr

DBU

J. Am. Chem. Soc. 1996, 118, 10094.

Trimethylenemethane IntermediatesAldehydes and ketones also react. Unsymmetrical interedmaites can be poorly regioselective. Lewis acid additive can improve reactivity and regioselectivity.

AcO TMS

5% Pd(OAc)2-DIBALH40% P(2-MeOC6H4)3

10% In(acac)4PhCH3, 110 ºC

70% yield

OAcTMSO

Ph

O

Ph

sterically crowded,electron-rich catalyst

5% Pd(OAc)2-DIBALH40% PPh3

10% In(acac)4PhCH3, 110 ºC

81% yield

Ph

O

J. Am. Chem. Soc. 1992, 114, 7904.

AcO TMS

10% Pd(OAc)260% P(O-i-Pr)3

20% BuLiTHF, 65 ºC

J. Org. Chem. 2003, 68, 4286.

NTsR N

TsR

Raction with aziridines gives piperidines

44-82% yield

Trimethylenemethane IntermediatesTrimethylenemethane intermediates are also thought to be generated from methylenecyclopropanes and have similar reactivity.

R R

Intramolecular ractions also work well.

R

R

O

O

R

R

N

R R

R

R

NR

R

TMS

R

R R

R

TMS+ M(0)

O

MeO2C

C6H11

H

Pd2(dba)3P(Oi-Pr)3

PhMe, 110 ºC75% yield

O

MeO2C

H C6H11J. Am. Chem. Soc. 1996, 118, 9597.