Nickel promoted olefin dimerizations - Harvard...

M.C. White, Chem 253 Dimerization -241- Week of November 29, 2004

Nickel promoted olefin dimerizations

NiCl

ClNi

(i-Pr)2P(t-Bu) = PR3 NiIIR3P

Cl

EtAlCl2

NiIIR3P

EtCl2AlClδ+

NiIIR3P

EtCl2AlClδ+

NiIIR3P

EtCl2AlClδ+

δ-δ-

δ-

NiIIR3P

EtCl2AlClδ+δ-

H

NiIIR3P

EtCl2AlClδ+

H

δ-

NiIIR3P

EtCl2AlClδ+δ-

NiIIR3P

EtCl2AlClδ+δ- H

catalyst activationcatalytic cycle

Proposed mechanism:

Wilke ACIEE 1988 (27) 185.

NiCl

ClNi

cat.

EtAlCl2, chlorobenzene, -45oC

R3P+

(i-Pr)2P(t-Bu) P(Et)3

Product distribution of propylene dimersformed depends heavily on the phosphineligand. Diisopropyl-tert-butylphosphine givespredominantly 2,3-dimethyl-1-butene and alsoshowes the highest catalytic activity fordimerization. In the analogous process withethylene, the choice of bulky phosphine effects whether dimerization or polymerizationoccurs.

Ligand effects...

Very subtle...

NiCl

ClNi

cat.

EtAlCl2, chlorobenzene, -45oC

R3P+

(i-Pr)2P(t-Bu), dimer

n

(t-Bu)3P, polyethylene

trace

+

M.C. White, Q. Chen Chem 253 Dimerization -242- Week of November 29, 2004

ZrI V

Cl

Cl MAO ZrIV

ClAl(MAO)

Me

δ-

?

EtZrI V

ClAl(MAO)

Meδ-

Et

ZrI V

ClAl(MAO)δ-

Et

δ+ δ+

ZrI V

ClAl(MAO)

Hδ- Et

ZrIV

ClAl(MAO)

Hδ-

Et

δ+

ZrIV

ClAl(MAO)δ-δ+

Et

ZrIV

ClAl(MAO)δ-

Et

δ+

Et

ZrI V

ClAl(MAO)δ-δ+

EtEt

H

Et

Et

Bergman JACS 1996 (118) 4715.

Et

Et

Et

In zirconocene/MAO catalyzed polymerizations, a large excess of MAO is necessary toeffect an efficient process (Al/Zr ratios of 500:1 up to 10,000:1). The Cp2ZrCl2/MAO(Al/Zr ratio 1:1) system is very selective for the dimerization of terminal olefins overoligomerization and polymerization. One rationale for this is that an associated Cl promotes β-hydride elimination over insertion. The reason for this is unclear.

Cp2ZrCl2/MAO 0.5 mol %

(1:1 Zr:Al)

Cp2Zr(Cl)/MAO (Zr:Al, 1:1) leads to dimerization

M.C. White, Chem 253 Cyclodimerization -243- Week of November 29, 2004

Ni(0) catalyzed 1,3-diene cyclodimerization

Ni0R3P NiIIR3P

NiII

R3PNiII

R3P

NiII

PR3HNiII

PR3

NiII

H

PR3

PR3NiII

Ni0(COD)2PR3

2 COD

η1,η3-bis allyl

LnNi(0)

sterically unfavorable

favored when PR3 is bulky

Proposed mechanism:

Weimann ACIEE 1980 (19) 569, 570.Houk JACS 1994 (116) 330.

Once again, the dimerization product distribution is heavily dependent on the phosphine ligand used. Basic phosphinesare known to stabilize the 16e- η1,η3-bis-allyl intermediatewhich leads to the vinylcyclohexene product. Less basicphosphites are thought to stabilize the 18e- bis-η3-allylforms.

LnMn

oxidative coupling

reductive fragmentation (rare)LnMn+2

Note that thismechanism operatesfor metals in ligandenviroments that can increase theiroxidation state by 2units.

LnMn+2

concerted stepwise

LnMn LnMn+2

Oxidative coupling

Ni0(COD)2, PR3

basic phosphines(PPhEt2)

less basic phosphites

bulky e.g. P(OPh)3

non-bulky e.g. P(OMe)3

M.C. White, Chem 253 [4+4] -244- Week of November 29, 2004

Wender’s intramolecular cyclodimerization: [4+4]

EtO2C

EtO2C

Ni(COD)2 (11 mol%)

PPh3 (33 mol%), tol

60oC

H

H

EtO2C

EtO2C

H

H

EtO2C

EtO2C

H

H

70% (19:1)

+EtO2C

EtO2C

2.6% (if P(OTol)3 is used, the vinyl cyclohexene analog is the main product (37% yield)

3 carbon tether:

H

H

Ni0

PPh3NiII

PPh3

H

H

Ni

PPh3

H

H

NiIIPPh3

Ni0Ln

oxidative coupling

Ln(PPh3)Ni0

CO2Me

Ni(COD)2 (11 mol%)

PPh3 (33 mol%), tol

60oC

H

H

MeO2C

95:5 (trans:cis)99:1 (dr)

84%

H

H

Ni0

PPh3 H

H

NiIIPPh3

Ln(PPh3)Ni0

oxidative coupling

etc...

An analogous homoallylic substituted substratealso gave predominantly the trans fused productbut very poor dr (1:2.2). When the allylic ester is replaced with other bulky functionality, thediastereoselectivity remains high: CH2OAc (dr21:1) and CH3 (dr 20:1).

Wender JACS 1986 (108) 4678.Wender TL 1987 (28) 2451.

4 carbon tether:


Applications of [4+4] in TOS

Ni(COD)2 (11 mol%)

PPh3 (33 mol%), tol

60oC

O

O

H

67%H

O

O

H H

H

O

O

H HH

O

(+)-Asteriscanolide

First application of the [4+4] methodology in the total synthesis of (+)-Asteriscanolide. Wender JACS 1988 (110) 5904.

TBSO Ni(COD)2 (11 mol%)

PPh3 (33 mol%), tol

110oC

52%

TBSO

CO2CH3

Ni(COD)2 (11 mol%)

PPh3 (33 mol%), tol

110oCH

CO2CH3

92% yield97% de

AcO O

RO

OH OR

H

OH

O

OAc

Taxol

Model studies for the taxane skeleton. Wender TL 1987 (28) 2221.


Intramolecular dienyne cycloaddition: [4+2]

O

Ni(COD)2 (10 mol%)

P(O-o-biphenyl)3 (30 mol%), THF

rt

O

H

H H

rxn proceeds with complete stereocontrol in C-C bond formations: 99% yield, (trans: cis, >99:1)

H

O

Ni0

PR3

O

NiII

H

Me

H

R3P

ONiII

H

Me

H

R3P

Ln(PR3)Ni0Ln(PR3)Ni0

Proposed mechanism

Wender JACS 1989 (111) 6432.

Ni(COD)2 (10 mol%)

P(O-o-biphenyl)3 (30 mol%), THF

rtX

R'

R

R'X

HR

R'X

HR

R= CH2OTBS, R'= Me, X= CH2, >99%; (2:1), thermal 160oC

R= CH2OTBS, R'= TMS, X= CH2, 98% (1.2:1), thermal 140oC

R= CH2OAc, R'= Me, X = CH2CH2, 85% (1.8:1), thermal 200oC

The low reactivity of unactivated alkynesas dienophiles in thermal DA rxns requires extreme temperatures to effectcycloadditions. Elevated temperaturesoften lead to decomposition, particularlyfor substrates with remote functionality.Alternatively, the Ni(0) promotedcyclization proceeds at rt with outstandingyields.

3 and 4 carbon tethers used. 2 and 5 carbon tethers donot cyclize.

Unlike the Ni(0) catalyzed[4+4], PPh3 ligand results in slow reactions that areattended by substratedecomposition and productaromatization.


Intramolecular diene-allene cycloaddition: [4+2]

·

OTBS

RhIR3P

Cl

PR3

L

H

TBSO

RhICl

R3P

H

OTBS

RhI

R3P

R3PCl

RhIII

OTBS

R3P

Cl

HRhIII

OTBS

R3P

Cl

H

RhIII

OTBS

R3P

Cl

H

OTBS

HRhI

R3P

R3P Cl

OTBS

H

Proposed mechanism:

Wender JACS 1995 (117)1843.

Ni(COD)2 (10mol%)P(O-o-biphenyl)3 (30 mol%)

THF, rt97%

[Rh(COD)Cl]2 (5 mol%)

P(O-o-biphenyl)3 (48 mol%)

THF, 45oC

90%

OTBS

OTBS

H

OTBS

H

H

TBSO

RhICl

R3P

H

TBSO

H

Ni0R3P

Metal mediated reversal in chemoselectivity...

A complete reversal of chemoselectivityoccurs in the metal-mediated [4+2]diene-allene cycloaddition in switchingfrom a Ni(COD)2 catalyst to[Rh(COD)Cl]2. The known preference for Ni0 coordination to the less stericallyhindered π-bond of allenes is given as arationale for the observed difference inselectivities.

·


X

R

RhCl(PPh3)3 (0.1 mol% -0.5 mol%)

AgOTf (0.1 mol% - 0.5 mol%)

tol, 110oCX

R

Efficient route to 7 membered rings via 5+2 cycloadditions of vinylcyclopropanes and...

MeO2C

MeO2C

H

O

R

R'

MeO2C

MeO2C

Me

H

alkenes/alkynes

allenes

X

·

R

RhCl(PPh3)3 (1 mol%)

tol, 110oC

X

R

H

H

t-Bu

H

H

MeO2C

MeO2C

83% R = Me, 88% TMS, 83% CO2Me, 74%

92%

exclusive formation of the cis-fused product for the 5,7 ring system. Trans-fused product observed for the 6,7 ring system.

96%

XRhI PPh3

PPh3

oxidativecoupling

X RhIII

H

H

exclusive formation of the cis-fusedproduct is consistent with thepreferential formation of a cis-fused metallocyclopentane intermediate

PPh3

PPh3

ring-expansion X

H

Hvinylcyclopropanes are thought tohave diene-like properties becauseof significant p orbital character in the strained σ bond

RhIII

PPh3PPh3

reductiveelimination

X

H

H

-OTf -OTf -OTf

[LnRhI]+ (OTf-)

XRhIII

PPh3

PPh3 -OTf

or...

Wender JACS 1995 (117) 4720.Wender JACS 1998 (120) 1940.Wender JACS 1999 (121) 5348.for an intermolecular [5+2] w/ alkynes see: Wender JACS 1998 (120) 10976.

Proposed mechanism:

Wender’s [5+2] cycloadditions

M.C. White, Chem 253 [5+2]-249- Week of November 29, 2004

Applications of [5+2] in TOS Me

OHMe

CHO(+)-Allocyathin B2

·

OBn

[Rh(CO)2Cl]2

Toluene

100 oC

RhLn

OBnH

H

LnRh

OBn HOBn

Asymmetric total synthesis of (+)-Aphanamol I. Wender OL 2000 2:15 2323-2326.

93%

H

O

OBn

(+)-Aphanamol

Asymmetric synthesis of tricyclic core of (+)-Allocyathin B2. Wender OL 2001 3:13 2105-2108.

Me

HO

MeO O

OHMe

RhLn

Me

H

OOHMe Me

H

RhLn

Me

HO

O

Me

H

[Rh(CO)2Cl]2

DCE, 80 oC

5 mol%

90%

M.C. White, Chem 253 Cycloisomerization -250- Week of November 29, 2004

CO2CH3RTBDMSO

CO2CH3

RTBDMSO

CO2CH3RTBDMSO

Ru(II)Cp

Ru(IV)Cp

CO2CH3TBDMSOR

CO2CH3R

TBDMSO

Ru(IV)Cp

H

TBDMSOR

CO2CH3

Ru(IV)CpH

A

BC

TBDMSO R

CO2CH3

Ru(IV)Cp

TBDMSO R

H

R = CH3R = H

Cycle A Cycle B

CpRu(CH3CN)3PF6

10 mol%

acetone, rt

CpRu(CH3CN)3PF6

10 mol%

acetone, rt

R = H

R = Me

A1,3-type strain if R = Me

RuII

H3CNCCNCH3

CNCH3

(PF6-)

CO2CH3

R = H

R = Me

CO2CH3

CD3

RTBDMSOD

TBDMSO R

D

D

CO2CH3

The allylic C-H activation mechanism is supported by the following deuterium-labelling experiment

CpRu(CH3CN)3PF6

To rationalize the observed divergence in reaction course, the authors

suggest that when R = Me the oxidative coupling of A to form B is

disfavored due to steric congestion in the form of A1,3-type strain between

the quaternary center and the ester. Alternatively, allylic C-H activation

leads to the formation of intermediate C, which subsequently cyclizes to a

seven-membered ring

Trost JACS 1999 121 9728-9729.

Ru mediated cycloisomerization

M.C. White Chem 253 Cycloisomerization -251- Week of November 29, 2004

CO2CH3

N NPh Ph

CO2CH3

CO2CH3

PdII(OAc)2Ln

Nu

CO2CH3

PdII(OAc)Ln

Nu

H CO2CH3Nu PdIILn

AcO

HAcOH

CO2CH3Pd0Ln PdIILn

CO2CH3

H PdIILn

CO2CH3

H

Pd(OAc)2 (5 mol%)

6 mol% 83%

Trost JACS 1987 (109) 3484.

in situ generation of Pd(0) via Wacker type process:

+ Pd0Ln

Pd0Ln Pd0Ln

Pd mediated cycloisomerization

Pd2(dba)2 (2.5 mol%)

P(o-tol)3 (5 mol%)

AcOH (5 mol%)MeO2C

MeO2C

Cy

Cy

95%

MeO2C

MeO2C

Pd0Ln

AcOH

PdIILnAcO

H

MeO2C

MeO2C

CyPd OAc

H

MeO2C

MeO2C

CyPd OAc

Cy

MeO2C

MeO2CPd(OAc)Ln

H

When AcOD was used thedideuterated product is observed.The first deuterium isincorporated via exchange withacetylene H and the second via the proposed hydropalladation.

Cy

MeO2C

MeO2C

D

D

Trost JACS 1994 (116) 4268.

M.C. White, Q. Chen Chem 253 [2+2+2] -252- Week of November 29, 2004

[2+2+2] cycloaddition of diynes with isocyanates to give bicyclic pyridones

NPh

O

RuIICp*Cl

RuIVCp*Cl

PhNCORu

N

·O

Ph

NPh

RuCp*Cl

O

NPh

O

+

Cp*Ru(COD)Cl5 mol%

DCE, reflux, 2h

16e-

Cp*RuCl

Cp*Ru(COD)Cl

Cp*

Cl

· ON

Ph

Itoh. OL 2001 (3) 2117.


Ph Nt-Bu + CO

Ru3(CO)12 2 mol%

toluene, 180 oCNt-Bu

O

Ph

Although α,β-unsaturated imines react readily with early transition metals such as Ti and Zr to form the corresponding metallacyclopentenes, this is the first example of such a reaction with a latetransition metal complex.

(10 atm)

the authors propose that initialcoordination of a nitrogen to ruthenium facilitates the oxidative cyclization toyield the metallacycle intermediate

for the reaction of imines which contain a β-hydrogen, olefin isomerization occursto give the thermally more stableα,β-unsaturated γ-lactam

Ru0(CO)4

Ph Nt-Bu

Ru (CO)4

RuII (CO)4

Nt-Bu

Ru (CO)3

Nt-Bu

O

Nt-Bu

O

Ph

PhNt-Bu

O

Ph

oxidativecyclizationCO insertion

CO

Murai JACS 1999 (121) 1758.

Carbonylative [4+1]

M.C. White, M.W. Kanan Chem 253 Cycloisomerization -254- Week of November 29, 2004

TsN

H

H

CO2H

TsN

TsN NiLn

TsN

H

H

NiII

TsN

H

H

O

O

NiLn

TsN

H

H

O

OZnEt

LnNi

Et

TsN

H

H

O

OZnEt

NiLn

H

TsN

H

H

CO2ZnEt

Et2Zn

ZnEt2

TsN

H

H

CO2H

LnNi

Me

TsN

H

H

O

OZnMe

TsN

H

H

CO2ZnMe

NiII(acac)2

LnNi0

Mori JACS 2002 (124) 10008.

Ni(acac)2 5 mol%

PPh3, 10 mol%

CO2, 1 atm Me2Zn, 4.5 eq.

HF, 0°C

Ni(acac)2 5 mol%

PPh3, 10 mol%

CO2, 1 atm Et2Zn, 4.5 eq.

HF, 0°C

reductiveelimination

β-hydride elimination

reductive elimination

this intermediate has no β-hydrogens

·O

O

TsN

oxidativecoupling

insertion

transmetalation

Cycloisomerization/carboxylation of bis-1,3-dienes

M.C. White, Chem 253 Metal alkylidenes -255- Week of December 6, 2004

Metal Carbenes

singletcarbene

M CX

sp2

pz

R'

R

O C LnM=CR2

δ+δ-

Fischer Carbenes (formally derived from a singlet carbene)

(CO)5Cr0OMe

Ph OR

(CO)5CrII

PhOMe

OR

(CO)5CrII

Ph OMe

OR

COPh

OMeRO

Cr0(CO)6

Fischer Chem. Ber. 1972 (105) 3966.

· Low oxidation state, late metals· π-acceptor ligands on the metal· π-donar substituents on the carbene C

δ+δ-

+

· electrophilic carbenes· σ-donation is stronger than π-backbonding resulting in a partial positive charge on thecarbene carbon

note: that the formal charge for the carbene unit is zero, the #of electrons donated is 2.

π-donation from the carbene substituents competes w/π-donation from the metal

The presence of strongπ-acceptor ligands on themetal renders π-backbonding into the empty carbene porbital weak.

R'

X = heteroatoms

likened to a carbonyl:O

OMe

Me

δ+δ-

18 e-

triplet carbene

Schrock Carbenes (formally derived from a triplet carbene)

M CR

sp2

pz

R

· The metal-carbon bonds are morecovalent in nature and highly polarizedtowards C resulting in a partial negative charge on the carbene C.

alkyl (or H)

XR'

R'

LnM=CR2

δ-δ+

· High oxidation state, early metals· Non-π acceptor ligands on the metal (often π-donor ligands such as Cp or Cl)· alkyl (or H) substituents on the carbene.

· nucleophilic carbenes

The first characterized Schrock carbene:

TaV

t-Bu

t-Bu

t-Bu

t-Bu

δ-δ+

+

likened to a phosphorus ylide:Ph3P

t-Bu

δ-δ+

O

pentane/N2

O2 and moisture sensitive

-2 charge/4 electron donor

10 e-

(t-BuCH2)3TaV

t-Bu

O

(t-BuCH2)3TaV

O

t-Bu

highly oxophilic,early metal

(t-BuCH2)3TaV O

t-Bu

+

85%

Schrock JACS 1974 (96) 6796, 1976 (98) 5399.

M CR

sp2

pz

R

alkyl (or H)

XR'

R'

extreme π-backbonding: where the 2e- in theM(dπ) orbital aretransfered to the C(pz)orbital.


The first isolated and characterizedSchrock carbenes

The first isolated Schrock carbene:

TaV

Me

MeMe

18 e-

C(Ph)3 BF4

MeC(Ph)3

TaV

Me

CH2

16 e-

BF4H

base TaV

Me

CH2

18 e-

Schrock JACS 1975 (97) 6577, 6579.

2.026 Å

2.246Å

~ 10 % shorter Ta-C bondis suggestive of a significant amount of db character

The first characterized Schrock carbene:

(t-BuCH2)2(Cl)TaV t-BuCl

H

10 e- complex

α-agostic interactionprovides the metalw/extra electron density

2 eq t-BuCH2Li (t-BuCH2)2(Cl)TaV t-Bu

H

t-Bu

steric conjestion induces direct α-proton abstraction by one of the neopentane ligands resulting in the metal alkylidene.

(t-BuCH2)2TaV

t-Bu

ClCMe4

(t-BuCH2)3TaV

t-Bu

LiCl LiCl

Schrock JACS 1974 (96) 6796, Acc. Chem. Res. 1979 (12) 98.


Carbonyl methylenation: Tebbe’s reagent

TiIV

Cl

Cl

16 e-

+ 2 AlMe3

toluene

rt

TiIV

Cl

16 e-

AlMe2

CH4, AlMe2Cl

Tebbe's reagent: Tebbe JACS 1978 (100) 3611.

Tebbe's reagent 0.5M soln 100 mL/$363

(Aldrich 2001) TiIV

ClAlMe2 TiIV

O

TiIV

OR

R

CH2

16 e-

TiIV

ClAlMe2

stoichiometric

toluene, -15 oC

65%

Synthetic applications:

EtO2C

O

OTBS

OTBS

OBn

OBn

OTBS

OTBSCp2TiCH2ClAlMe2

tol-THF-Py,

-78oC to -15oC

82%

EtO2C

OTBS

OTBS

OBn

OBn

OTBS

OTBS

key intermediate in the total synthesisof Hikizimycin

Schreiber JACS 1990 (112) 9657.

OR

O

O

O Cp2TiCH2ClAlMe2

THF, rt, 1h85%

ORO

O

Nicolaou ACIEE 1994 (33), 2184, 2187, 2190

key intermediate in the total synthesisof Zaragozic acid

In situ prep: Grubbs JOC 1985 (50) 2386.


Tebbe’s reagent

TiIV

ClAlMe2 TiIV

16 e-

+

AlClMe2

TiIV

TiIV

Tebbe's reagent reacts with olefins to give metallocyclobutanes:

Titanium metallocyclobutane 1 reacts with acid chlorides to form Ti enolates.

1

Grubbs OM 1982 (1) 1658.

O

ClPh

tol, -20oC to 0oC

OTiClCp2

PhPhCHO

O

Ph

OH

Ph69%

TiIVTiIV O

ClPh

OCl

Ph

Grubbs JACS 1983 (105) 1665.


Olefin metathesis: Tebbe’s reagent

TiIV

ClAlMe2 TiIV

16 e-

+

t-Bu

AlClMe2

TiIV

t-Bu

Tebbe's reagent reacts with olefins to give titanacyclobutanes:

1

D

D D

t-Bu t-Bu

TiIV

t-Bu

D

t-Bu t-BuD

D

TiIV

D

D D

t-But-Bu

TiIV

D

DD

t-Bu

TiIV

t-Bu

D

DD

TiIV

t-Bu

DD

TiIV

t-Bu

DD

t-Bu

t-Bu

D

t-Bu

t-Bu

t-BuD

D

+1, cat

+

Titanacyclobutanes are effective catalysts for α-olefin metathesis .

Grubbs JACS 1982 (104) 7491.

O

t-BuO

O

t-BuO

TiCp2

O

t-BuO

TiCp2

t-BuO

HO OH

O

O

H H

H

Cp2TiCH2ClAlMe2

DMAP, benzene

25oC

90oC

p-TsOH

81% overallyield

Cp2Ti(O)

(±)-Capnellene

First application of olefin metathesis to synthesis:

Grubbs JACS 1986 (108) 855.


Carbonyl methylenation: Petasis reagent

OO

H

H3C

Me

O O

H3C O

OH3C OH3C

OTiCp2CD3

H3C CD3

H

H3C

Me

O

D3C

OH3C

H3C

OH3C

D

D

O

OCH3

O

OCH3

O

8 8 62 %

83 %

aldehydes ketones

esters chemoselectivity for ketones in the presence of esters

80 % 60 %

Cp2TiMe 2

3 eq.

toluene

60-65 oC

Cp2TiMe 2

3 eq.

toluene

60-65 oC

Cp2TiMe 2

3 eq.

toluene

60-65 oC

Cp2TiMe 2

1 eq.

toluene

60-65 oC

Based on deuterium labelling studies, Petasis originally proposed a mechanism involving initial carbonyl complexation to Cp2TiMe2 followed by methyl transfer and subsequent loss of methane and titanocene oxide.

Petasis JACS 1990 112 6392.

Difficulties with the Tebbe and Grubbs' Ti-mediated olefinations include the high cost of Ti reagent, long preparation times, short shelf life, and the need for specialtechniques due to sensitivity to air and water. Many of these difficulties are overcome with Petasis' procedure which uses dimethyltitanocene. Petasis JACS 1990 112 6392.

11

Cp2Ti(CD3)2

11 ?11

11

~50%

"significant amount of deuterium detected at C-3."

H313C O

OH3CO

TiCp2

H313C

EtO

H313C

OH3C

<1% incorporation of 13C

label into methylene position

Hughes finds that in the reaction with C-13 labelled ethyl acetate shown below, scrambling of the label only occurs if trifluoroacetic acid is present and proposes that this scrambling is due to an acid-catalyzed, degenerate [1,3]-hydrogen shift. He proposes that the scrambling observed by Petasis was likely due to adventitious acid present on all acid-washed glassware. To support this argument, Hughes repeated the deuterium labelling experiments reported by Petasis using glassware that was not acid washed and, contrary to Petasis, observed no scrambling of the label.

O Me

TiCp2

Me

O

Cp2Ti

CH2

H

CH3

CH2

O TiCp2

Petasis JACS 1990 112 6392.

Me

TiCp2

MeO

TiCp2

O

TiCp2

CH2

O TiCp2

Hughes uses these experiments in conjunction with detailed kinetic studies to provide strong support for a mechanism involving a titanium carbene.

Hughes OM 1996 15 663.

12

3

12

3


Olefin metathesisThe first reports of olefin cross metathesis (heterogeneous cat) by Banks:

2 Mo(CO)6 supported on Al

150oC, 30 atm.+

Banks Ind. and Eng. Chem. (Product Res. and Development) 1964 (3) 170.Haines Chem. Soc. Rev. 1975 (4) 155.

The first report of ROMP (ring opening metathesis polymerzation):

MXn + Al(Et)3

nMXn = TiCl4,ZrCl4, MoCl5, WCl6

Natta Makromol. Chem. 1963 (69) 163.Natta ACIEE 1964 (3) 723.

Well-defined WVI and MoVI olefin cross metathesis and ROMP catalysts:

WVI

N

t-BuO

O

F3C

H3C

F3C

F3CF3C

CH3

i-Pr i-Pr

MoVI

N

t-BuO

O

F3CH3C

F3C

F3CF3C

CH3

i-Pr i-Pr

· Wittig-type chemistry with aldehydes>ketones>> and esters(slow rates).

· Wittig-type chemistrywith aldehydes>>ketones (slow rates).

Schrock JACS 1986 (108) 2771.Schrock JACS 1990 (112) 3875, 8378;1991 (113) 6899.

Olefin cross metathesis:

Mn

t-Bu

12 e- 12 e-

Mn

t-Bu

Mn

Mn

Mn

Mn

ROMP (Ring opening metathesis polymerization)

Mn

R M

R

MnR

MnR

MnR

m

propagation

PhCHO

PhR

m

termination

+ Mn=O

initiation

Often called a "living polymerization" because termination only occurs uponaddition of a capping unit (oftenaldehyde).

Grubbs Science 1989 (243) 907.


Mo-mediated ring closing metathesis (RCM) of acyclic diene ethers

O PhO Ph

Me

benzene, rt15 min

92 % yield

O Ph

Me

O

Me

Ph

92 % yield

benzene, rt

15 min

O

O

Me

O

BnO OBn

Me

O

O

O

BnO

OBn

O

O

O

HO

OH

Me

O

Me

Ph

Me

O Ph

MeMebenzene, rt

3 h

93 % yieldMe

OPh

Et

Me

O Ph

benzene, rt4 h

75 % yield

1, 5 mol% 1, 5 mol%

1, 5 mol% 1, 5 mol%

MoV I

NO

O

i-Pr

i-Pr

MeMe

Ph

CF3F3C

Me

Me

F3C CF3

1

Grubbs JACS 1992 (114) 5426.

1, 12 mol%

85 % 95 %

Sophora compound IGrubbs JOC 1994 (59) 4029.

H2, Pd-C

Grubbs recognized the potential for applying olefin metathesis towards a productive synthetic pathway: RCM (Ring Closing Metathesis)

General mechanism:

X

LnMoVIR

LnMoVI

X

VIMoLn

X

RR

X

LnMoVI

X

LnMoVI

X

5-membered ring formation: dihydrofurans Tri-and tetrasubstituted olefins:

6-membered ring formation: dihydropyrans 7-membered heterocycles

R

Evaporative loss of the low molecularweight acyclic olefin generated and theentropic gain of generating 2 molecules from 1 are thought to be two factorsfavoring the RCM pathway.

An early synthetic application of RCM:


Mo-mediated RCM of acyclic diene amines and amides

N

Me

Bn

N

Me

Bn

N

O

R

N

Me

Bn

N

O

R Mo

N

Bn

Me

MoVI

NO

O

i-Pr

i-Pr

MeMe

Ph

CF3F3C

Me

Me

F3C CF3

N

O

R

N

OF3C

N

Bn

O

N

OF3C

N

Bn

O

benzene, rt3 h

93 % yield

86 % yield

benzene, rt

1 h

benzene, rt15 min

83 % yield

benzene, rt1.5 h

90 % yield

1, 4 mol% 1, 4 mol%

1, 4 mol% 1, 4 mol%1

Grubbs JACS 1992 114 5426.

Formation of 5- and 6-membered lactams via RCM of acyclic diene-amides is hindered by formation of stable chelate intermediates. This may be due to the Lewis acidic properties of the formally 12 e- Mo alkylidene.

1 N

O

R1

N

O

R

Mo

N

O

R

N

O

Bn

Me

N

O

Bn

Mo

Me

N

O

Bn

stablechelate

stablechelate

N

O

BnN

O

Bn

MoEt

N

O

Bn1, 10 mol%benzene

50 oC

1.5 h

74 % yieldEt 80 % yield

1, 10 mol%benzene

50 oC

1.5 h

This problem can be averted by directing the catalytic cycle with appropriate olefin substitution patterns. Because metathesis of monosubstituted olefins by 1 is faster thanthat of disubstituted olefins, the initial Mo alkylidene preferentially forms at the less substituted olefin where intramolecular chelate formation with the amide carbonyl is not favored.

Grubbs JACS 1992 (114) 7324, see also Schrock OM 1989 (8) 2260.

5-membered rings

6-membered rings 7-membered ring - lactam formation

12e-


Application of RCM-mediated macrolactam formation in TOS

MoVI

NO

O

i-Pr

i-Pr

MeMe

Ph

CF3F3C

Me

Me

F3C CF3

HN

Me

O

MeMe O

O

HO Me

OHH2N

Fluvirucin B1(Sch 38516)

HN

Me

OTBS

MeMe O

HN

OTBS

MeMe O

Me

25 mol %

THF (0.01M)

60 oC;

silica column

Hoveyda JACS 1995 117 2943-2944.

60 % yield>98% Z

N

O

Bn

CO2Me

H

N O

MoVI

NO

O

i-Pr

i-Pr

MeMe

Ph

CF3F3C

Me

Me

F3C CF3

5 mol %

benzene, 50 oC 4 h

63 % yield

N

O

Bn

CO2Me

H

NO

N

H

N

NNH

OH

Manzamine A

Martin TL 1994 35:5 691-694.

The high levels of stereoselectivity in these examples is an exception.Attaining reliable E/Z selectivity isstill an unsolved problem with thischemistry.


Synthesis of cycloalkenes via olefin metathesis/carbonyl olefination

OO Ph

3

MoVI

NO

O

i-Pr

i-Pr

MeMe

Ph

CF3F3C

Me

MeF3C CF3

O Ph

3

1 eq.

benzene, 20 oC

30 min[M]

OO Ph

3[M]

[M] OO Ph

3

[M] O

O Ph

3

[M] O

86 % yield

olefin metathesis carbonyl olefination

Effecting this process requires an alkylidene whichmetathesizes olefins more rapidly than it olefinatesketones. It had been demonstrated previously that thisMo-alkylidene efficiently metathesizes acyclic mono- and disubstituted alkenes at rt, but requires elevatedtemperatures to olefinate ketones.

six-membered rings seven-membered rings

O

O

Ph

MeO

Ph

Me

as above

84 % yield

O

OBn

OBn

86 % yield

as above

Grubbs JACS 1993 (115) 3800.

Schrock JACS 1990 (112) 3875.


Ru alkylidenesO OMe

OMe[RuII(H2O)6 ]2+(Tos)2

H2O

O OMe

OMeH2OnRuII RuIV

2+(Tos)2

R" "

proposed catalytically active species

O

m

MeO OMenote: RuCl3·H2O is also effective. Since identical olefin resonances are

observed by NMR during the reaction as those for RuII/olefin complex A (RuIII

does not form stable olefin complexes), Grubbs speculates that RuIII becomes

reduced in situ to RuII.

A

Grubbs JACS 1988 (110) 960, 7542.

RuII coordination complexes may form RuIV alkylidenes with strained cyclic olefins:

ClRuII

Cl PPh3

PPh3

PPh3

PPh3

+

Ph Ph

CH2Cl2/C6H6

53oC, 11h ClRuIV

Cl

PPh3

PPh3

Ph

Ph

·Stable to H2O (but insoluble pure H2O), alcohols, and acids·Unstable to O2

m

Grubbs JACS 1992 (114) 3974.

Efficient Ru catalyst for acyclic olefin metathesis.

Cl

RuIVCl

PCy3

PCy3

Ph

Ph

stronger σ-donor ligands

·Stable to O2

· High activity for low-strain cyclic olefins and for acyclic olefins.

ClRuIV

Cl

PCy3

PCy3

ClRuIV

Cl

PCy3

PCy3

propagating species: Ruethylidene and Ru propylidene observed by NMR

+

Grubbs JACS 1993 (115) 9858.

·No Wittig-like activity observed even with aldehydes· Poor activity for low-strain cyclic olefins and no activity for acyclic olefins.

Cl

RuIVCl

PCy3

PCy3

Ph

Generation 2 catalyst:

Cl

RuIICl PPh3

PPh3

PPh3

PPh3

1. N2CHR2. PCy3

Advantages of 2 vs. 1: More facile synthesis due to greater availability of diazoalkanes relative tocyclopropenes. Ru catalyst 2 is significantly morereactive than 1 because of more facile initiation.

1

2 Grubbs ACIEE 1995 (34) 2039.


Ru vs. Mo alkylidene catalysis of RCM

ClRuIV

Cl

PCy3

PCy3

Ph

Ph

1 (16e-, d4)

vs. MoVI

NO

O

i-Pr

i-Pr

MeMe

Ph

CF3F3C

Me

Me

F3C CF3

3 (12e-, d0)

Cl

RuIVCl

PCy3

PCy3

Ph

2 (16e-, d4)

Ru alkylidene complexes 1/2 are effective RCM catalyst in the presence of atmospheric O2, water and trace solvent impurities. Reagent grade solvents may be used directly for thereactions. Alternatively, Mo alkylidene complex 3 is highly sensitive to atmospheric O2,moisture and solvent impurities.

BocN

1 (2 mol%)solvent, air

BocN

88-93%

solvents: reagent-grade (undistilled): benzene, CH2Cl2, THF, t-BuOH

Ru alkylidenes 1/2 are highly functional group tolerant. Unlike Mo complex 3 which isknown to react with acids, alcohols, aldehydes (and ketones intramolecularly), complexes 1/2 are stable to these functionalities.

X

1 (2 mol%)C6H6, rt, 1h

XX = CO2H, 87% CH2OH, 88% CHO, 82%

RCM of acyclic diene-amides in 5- and 6-membered lactam formation is not complicated by the formation of stable chelated species as observed with 3. This may be due in part to theless oxophilic character of Ru vs. Mo. Moreover, the 16 e-, d4 Ru complex is lesselectrophilic than the 12e- d0 Mo complex.

N

O

Rn 1 (3 mol%)

C6H6, rt, 1hN

O

Rn

n= 0, 78% 1, 93%

Grubbs JACS 1993 (115) 9856.

Free amines are not tolerated by Ru catalysts and must be masked as the corresponding HCl salts:

NPh H

Cl 1. 1 (4 mol%)CH2Cl2, rt

36 h2. NaOH

NPh

(note: RCM of this amine with 3 took 40 min and proceeded in 89% yield; JACS 1992 (114) 5426)

79%

RCM of substituted olefins is problematic with 1 and 2. Dienesw/sterically demanding and/or electron withdrawing substituents can be cyclized more effectively w/ Mo catalyst 3.

RRO2C CO2R

R

RO2C CO2R

R= Et, 2 93%; 3 >99% t-Bu, 2 NR; 3 96% Ph, 2 25%, 3 97% CO2Me, 2 5%, 3 89%

RO2C CO2R RO2C CO2R

2 NR, 3 93%Grubbs JOC 1997 (62) 7310.


Grubbs’ third generation Ru alkylidene catalyst

Cl

RuIVCl

PCy3

PCy3

Ph

1 (16e-, d4)

Cl

RuIVCl

PCy3

Ph

NN MesMes

2 (16e-, d4)

MoV I

NO

O

i-Pr

i-Pr

MeMe

Ph

CF3F3C

Me

Me

F3C CF3

3 (12e-, d0)

t-BuRO2C CO2R

t-Bu

RO2C CO2R

RO2C CO2R

CO2R

CO2R

RO2C CO2R

RO2C CO2R

Improved E/Z ratios for macrocyclization

O

OO

O

LnRuIV

LnRuIV LnRuIV

Grubbs OL 2000 (2) 2145.

OHOH

Increased reactivity of 2 makes it comparable to 3 in many cases:

2 (5 mol%)

45oC, 60 min

recall: 1 gave NP

2 (5 mol%)

45oC, 90 min

>99%

90%

tetrasubstituted olefins

1 gave NP

not entirely general:

2 (5 mol%)

45oC, 24h

31%1 gave NP3 , 93%

Despite increased reactivity 2 has retained it's functional group tolerance (as well as air and H2O stability).

2 (5 mol%)

45oC, 10 min>99%

1, NP; 3, NP

Grubbs OL 1999 (1) 953.

Cross metathesis of terminal olefins with α-carbonyl functionalized olefins:

TBSO

7 CO2CH3

Cl

RuIVCl

PCy3

NN MesMes

4 (16e-, d4)

3 eq.slow addition

0.5 eq.

4 (5 mol%)

40oC, CH2Cl2

62%

TBSO

7

E/Z (>20:1)

CO2CH3

8 22 (1 mol%)

40oC, CH2Cl2, 40 min

>99%

1, E/Z (4.5:1)2, E/Z (11.5:1)

E/Z ratio increases over time with catalyst 2:Most likely due to a secondary "metathetical" isomerization via ring opening metathesis/ ring closing metathesis:

LnRuIV

CO2CH3

The ester-carbene complex isunstable and is not thought to be effective in olefin metathesis.

Grubbs JACS 2000 (122) 3783.


Asymmetric ring-closing metathesis with chiral molybdenum alkylidene complexes

R

MeMe

O

[Mo]

[Mo]

R

R

MoVI

N

OO

Me Me

Me

PhMe

R

R

O

Me

HMe

AcO

MoVI

NO

O

i-Pr

i-Pr

Me MePhCF3F3C

F3CCF3

O

O

AcO

O

AcO

O

benzene, 25 oC, 20 min

90 % conversion

+

Kinetic resolution in ring-closing metathesis

10 % recovered from reaction mix84% ee, krel = 2.02

k2(a)

k2(b)

k1

k-1

Grubbs and coworkers reasoned that the second (ring-closing) step would be suitable for asymmetric induction, because this step involves diastereomeric cyclic transition states which differ in energy. Diene substrates were chosen which contained a trisubstituted olefin to slow the cyclization step (and thus presumably increase the selectivity) and to control the site of the first metathesis.

Enantioselective synthesis of dihydrofurans by Mo-catalyzed desymmetrization.

Grubbs JACS 1996 (118) 2499.

Hoveyda/Schrock JACS 1999 (121) 8251.

5 mol %

benzene, rt, 6 h

86% yield, 93% ee

Mo*

toluene

-25 oC, 18h

Mo*

toluene

-25 oC, 18h

84% yield, 73% ee

91% yield, 82% ee

= Mo*

Enantioselective synthesis of quaternary carbon centers


Mechanism of Grubbs’ third generation Ru alkylidene catalyst

ClRuIV

Cl

PCy3

PCy3

Ph

1 (16e-, d4)

ClRuIV

Cl

PCy3

Ph

NN MesMes

2 (16e-, d4)

CNR

NR

stable diaminocarbene

Arduengo JACS 1995 (117) 11027.

M

Fisher-type carbene, strong σ-donor

Proposed mechanism:

ClRuIV

Cl

L

PCy3

Ph

L = PCy3

NN MesMes

or Phosphine dissociation

-PCy3

+PCy3 ClRuIV

Cl

LPhk1

k-1

14 e-

Cl

RuIVCl

L

Ph

R

R

k2k-2

R

ClRuIV

Cl

LPh

R

(or R after 1st cycle)

Cl

RuIVCl

LR

Ph

Ph

· The reaction is thought to proceed via adissociative mechanism to form the active 14e- catalytic species. Excess phosphineinhibits the rxn.

· Catalyst 2, whose propagation rates significantly exceed those of 1,exchanges phosphine 2 orders ofmagnitude slower than 1.

· The ratio of k-1/k2 determines if the 14e- intermediatebinds olefin to initiate metathesis or binds phosphine toreturn to its resting state. This ratio is 4 orders ofmagnitude greater for 1 than for 2 (1 = 15 300, 2 = 1.25).While 1 is faster to initiate by loosing phosphine, therebinding of phosphine is competitive with olefin binding. Alternatively, 2 dissociates phosphine more slowly butbinds the olefin with such high affinity that it may cyclethrough many times before binding phosphine andreturning to its resting state.

The strongly σ-donating N-heterocycliccarbene ligand of 2 is thought tosignificantly improve the bindingselectivity of 14 e- intermediate A forrelatively π-acidic olefins vs. σ-donating phosphines.

A

Grubbs JACS 2001 (123) 749.


OSiEt3

ClRuIV

Cl

PCy3

PCy3

Ph

PhOSiEt3

OSiEt3

OSiEt3

RuLn

OSiEt3

RuLn

OSiEt3

OSiEt3

RuLn

OSiEt3

RuLn

ClRuIV

Cl

PCy3

PCy3

ROSiEt3

OSiEt3

RuLn

LnRu

OSiEt3

RuLn

OSiEt3

RuLn

OSiEt3

OSiEt3

3 mol%+

1:1unsymmetrical dienyne

Cycle A Cycle B

OSiEt3

Et

RuLn

OSiEt3

EtLnRu

OSiEt3

OSiEt3

LnRu

Me

RuLn

OSiEt3

Me

OSiEt3

83%

Sterically differentiating the two olefins biases the intial site of metallocyclobutane formation and results in selectivity for one cycle vs. the other.

78%

Grubbs JACS 1994 (116) 10801.

Dienyne metathesis

M.C. White, M.S. Taylor Chem 253 Metal alkylidenes -272- Week of December 6, 2004

O O

Me

Me

H

H

Me OO

OH

(–) - Longithorone A

Me

MeO OTBS

TBSOH

OTBS

OTBS

TBSO OMe

Me

Me

Macrocyclization via ene-yne metathesis

Me

TBSO

OMe

Me OTBS

Ru

PCy3

PCy3Ph

HCl

Cl

OTBS

TBSO OMe

Me

Me

[Ru]

Me

OMe

Me

[Ru]

OTBS

TBSO

Ru

PCy3

PCy3Ph

HCl

Cl

OTBS

TBSO OMe

Me

Me

[Ru]

OTBS

TBSO OMe

Me

Me

(0.5 equiv.)

Ethylene (1 atm)CH2Cl2

>20:1 favoring atropisomer shown

Shair JACS 2002 (124) 773.

the protected benzylic hydroxyl was used to gear the atropisomerism of the aromatic rings during ene-yne metathesis

Me

TBSO

OMe

OTBS

TBSO

Ru

PCy3

PCy3Ph

HCl

Cl

Me

[Ru]

MeO OTBS

TBSOH

OTBS

Me

TBSO

OMe

OTBS[Ru]

TBSO

Me

[Ru]

MeO OTBS

TBSOH

OTBS

Me

MeO OTBS

TBSOH

OTBS

(0.5 equiv.)

Ethylene (1 atm)CH2Cl2

M.C. White, Chem 253 Metal alkylidynes -273- Week of December 6, 2004

Schrock Carbynes (formally derived from a triplet carbene)

M C R

M CR trianionic ligand (-3), 6 electron donor

Early example of catalytic alkyne metathesis by WVI-alkylidyne

Ph Et

WVI

ClCl Cl

OPEt3

Tol, rt

5 mol%

Ph Ph

+

Et Et

WLn

R

WLn

RPh

Et

WLn

RPh

Et

Ph Et Ph R

Schrock JACS 1981 (103) 3932.

Ring-closing diyne metathesis: Furstner ACIEE 1998 (37) 1734.

O

OO

O

WVI

(Me)3CO(Me)3CO

OC(Me)3

O

OO

O

4-6 mol%

C6H5Cl, Ar, 80oC73%

Functional group tolerance demonstrated for esters, amides, and sulfones.

note: catalyst isincompatible with terminal alkynes.

Lindlar hydrogenationstereoselectively generates Z-alkenes (still anunsolved problem forRCM of alkenes).

Novel Mo alkyne metathesis catalyst:

MoIV

Cl

N NN

N

O

O

O

O

O

OO

O

N

It is unclear how the halide Mo catalyts initiates the catalytic cycle. Thiscatalyst demonstrates increasedfunctional group tolerance (relative tothe W catalyst) for basic amines,thioethers, and ketones.

Furstner JACS 1999 (121) 9453.

Diyne metathesis

M.C. White/Q. Chen Chem 253 Metal alkylidynes -274- Week of December 6, 2004

OO

ROOR

O

OR

ORO

RO O

OR

CH3

CH3

O

H3C

OO

ROOR

O

OR

ORO

RO O

OR

CH3

O

N MoN

N

DDQ

R = PMB (note that this Mo-based catalystrequires protection of the hydroxyl groups.

Sophorolipid lactone

CH2Cl2/toluene, 80 °C

OO

ROOR

O

OR

ORO

RO O

OR

CH3

O

78% yield

H2 (1 atm)Lindlar catalyst

quinoline

CH2Cl2, rt

Corresponding RCM of a related substrate with terminal olefins gave 3:1 olefin ratio favoring the

undesired trans isomer.

OO

HOOH

O

OH

OHO

HO O

OH

CH3

OCH2Cl2/MeOH (18:1)

global deprotection

quantitative conversion

rt, 8 h

93 % yield

10 mol%

known to generate a mixture of LnMo-Cland LnMo CH , both known to initiate

diyne metathesis.

Ring-closing alkyne metathesis in TOS

Fürstner JOC 2000 (65) 8758.

A.G. Doyle/M.C. Whitw Chem 253 Metal alkylidynes -275- Week of December 6, 2004

Arylene Ethynlene Macrocycles Prepared by Precipitation-Driven Alkyne MetathesisMoore J. Am. Chem. Soc. 2004 (126) 12796.

R

R'R'

R

R R

R R

R

R'R'

EtC Mo[NAr(tBu)]3

p-nitrophenol

30 °C, 22h61-81%

Vacuum driven

RN

R'

RN

RN

NR

NR

R'EtC Mo[NAr(tBu)]3

p-nitrophenol

30 °C, 22hCCl4, 84%

R'R'

Precipitation driven

Shape Persistent Macrocycles have important applications in liquid crystal displays (the requirement is for a rigid core structure surrounded by aflexible periphery). Thus far synthesis has been able to supply macromolecules on hundred milligram scales.

Previous syntheses: Heck/Sonogashira couplings (see Moore et al. Langmuir 1999, 15, 6897 and references therein)

Alkyne metathesis: has been plagued with problems of low catalyst reactivity and stability (must be made in situ and in low yield), low substratetolerance, and difficulties overcoming equilibrium nature of the reaction.

N

ArMoN

tBu

ArN

tBu

Ar

tBuRCHCl2

THF, rt

N

ArMoN

tBu

ArN

tBu

Ar

tBuCl

N

ArMoN

tBu

ArN

tBu

Ar

tBuC

R

Mg

Reductive Recycle Approach to Mo(VI) alkylidyne complexes

Moore et al. JACS 2004, 126, 329-335. Furstner et al. JACS 1999, 121, 9453. Cummins JACS 1995, 117, 4999.

R'

R'

R

MM

R'

R'

R

M

R'

R'

R R

R'

R'

M

Alkylidyne Mechanism

R' R'

R R

M

R'R'

RR

R

R'

R

R'

R

R'

R

R' M

R

R' R'

R

R R'

R' R

M

M M

M

Metallacycle Mechanism

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