Applications of Non-Commercially Available Metathesis...

Ru

Cl

Cl

NN MesMes

PCy3

Ph

Ru

Cl

Cl

NN

O

MeMe

38% 87%

MacMillan Group MeetingJanuary 16, 2008

BzO

Me

AcO

OAc+ 3 mol% catalyst

PhH, reflux, 6h BzO

MeOAc

Applications of Non-CommerciallyAvailable Metathesis Catalysts

or

A Simple Guide to Optimizing Metathesis Reactions

OMeOHO

Cl

NHBocO

HN

NH

TBSO

MeO2C

O

OMeBr

Pd2(dba)3, (o-tolyl)3P

PhMe/MeOH/1N Na2CO3

OMeOHO

Cl

NHBocO

HN

NH

TBSO

MeO2C

O

OMeMeO

OMe

NHCbzMEMO

88%

Boger, D. L. et al. J. Am. Chem. Soc. 1999, 121, 3226.

An Alternate Reality

Consider a situation wherein only four phosphine ligands are commercially available

PPh3, P(tBu)3, dppf and BINAP would accomplish many, if not most, coupling reactions

Certain total syntheses would be conspicuously absent

•

•

•

An Alternate Reality

NN

OO

MeOMs

AcO

Me

O

BocI

OBnOMe

Me

NN

OO

MeOMs

AcOO

Boc

MeOMe

BnO

Pd2(dba)3, (o-tolyl)3PTEA, MeCN, reflux

83%

Fukuyama, T. et al. J. Am. Chem. Soc. 2002, 124, 6552.

NH

NMe

HN

MeN

I

INH

NMe

HN

MeN

NBn

NMeTsO

OTf

NMeTs

BnN

O

OTf NH

NMe

HN

MeN

BnN

NBn

O

ONMeTs

NMeTs

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

CuI, NMP, rt

Pd(OAc)2, (R)-Tol-BINAP

PMP, MeCN, 80 °C

71% 62%, 90% ee

Overman, L. E. et al. J. Am. Chem. Soc. 2002, 124, 9008.

Phosphine vs. Catalyst Choice

• Clearly, the commercial availability of a variety of phosphines is key

• Few research groups use 'homemade' phosphine ligands

• Are we justified in also using only commercially available metathesis catalysts?

PHOSPHINE LIGANDS METATHESIS CATALYSTS

Widely commercially available Few commercially available

Difficult to synthesize Often simple to synthesize

Few guiding mechanistic principles Based strongly on mechanism

Phosphine vs. Catalyst Choice

• Clearly, the commercial availability of a variety of phosphines is key

• Few research groups use 'homemade' phosphine ligands

• Are we justified in also using only commercially available metathesis catalysts?

PHOSPHINE LIGANDS METATHESIS CATALYSTS

Widely commercially available Few commercially available

Difficult to synthesize Often simple to synthesize

Few guiding mechanistic principles Based strongly on mechanism

The key to time and fiscal efficiency is selection of the proper catalyst

RuLX PR3

X

R1

– PR3

+ PR3

k1

k–1

RuLX

X

R1

+ olefin– olefin

k2

k–2

RuLX

X

R1 R1

k3 k–3

RuLX

XR1

R1k3

k–3RuLX

X

R1 R1

k2 k–2

Selection of a Metathesis Catalyst• First, one should ensure that the substrate has been optimized for commercially available catalysts

• After optimization, a catalyst to be synthesized should be rationally determined

• Both processes require an intimate working knowledge of the mechanism of olefin metathesis

Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543.


RuLX PR3

X

R1

– PR3

+ PR3

k1

k–1

RuLX

X

R1

+ olefin– olefin

k2

k–2

RuLX

X

R1 R1

k3 k–3

RuLX

XR1

R1k3

k–3RuLX

X

R1 R1

k2 k–2

Observations on Phosphine Dissociation• Surprisingly, 2nd generation catalyst (L = H2IMES) phosphine dissocation is 100 times less favored

• Methylidine species (R1 = H) for either generation catalyst decompose competitively

• For all systems investigated, initiation in dichloromethane is 30% faster than in toluene


RuLX PR3

X

R1

– PR3

+ PR3

k1

k–1

RuLX

X

R1

+ olefin– olefin

k2

k–2

RuLX

X

R1 R1

k3 k–3

RuLX

XR1

R1k3

k–3RuLX

X

R1 R1

k2 k–2

Observations on Olefin Binding• 2nd generation catalyst (L = H2IMES) k–1/k2 is 10000 times lower (in favor of olefin binding)

• Somewhat surprisingly, is fairly independent of phosphine nature (PCy3 vs. PPh3 = factor of 2)

• For comparison, relative rates of phosphine dissociation for PPh3/PCy3 differ by 70-fold

RuLX PR3

X

R1

– PR3

+ PR3

k1

k–1

RuLX

X

R1

+ olefin– olefin

k2

k–2

RuLX

X

R1 R1

k3 k–3

RuLX

XR1

R1k3

k–3RuLX

X

R1 R1

k2 k–2

van der Eide, E. F.; Romero, P. E.; Piers, W. E. J. Am. Chem. Soc. submitted

van Rensburg, W. J. et al. J. Am. Chem. Soc. 2004, 126, 14332.

Observations on Ruthenacyclobutane• Use of Piers' catalysts at low (–60 or –78 °C) temperature allow observation of ruthenacyclobutane

• When ethylene is not removed from solution, unsubstituted cyclobutane is dominant Ru species

• Unsubstituted metallacyclobutane is known to decompose to hydride containing species

van der Eide, E. F.; Romero, P. E.; Piers, W. E. J. Am. Chem. Soc. submitted

van Rensburg, W. J. et al. J. Am. Chem. Soc. 2004, 126, 14332.

Observations on Ruthenacyclobutane• Use of Piers' catalysts at low (–60 or –78 °C) temperature allow observation of ruthenacyclobutane

• When ethylene is not removed from solution, unsubstituted cyclobutane is dominant Ru species

• Unsubstituted metallacyclobutane is known to decompose to hydride containing species

N N

Ru

Mes Mes

PR3

ClB(C6F5)3

Cl

ClMeO2C CO2Me

CD2Cl2, –60 °C

N N

Ru

Mes Mes

ClCl

MAJOR

MINOR

β-hydride elim.N N

Ru

Mes Mes

ClCl

H

MeO2C CO2MeN N

Ru

Mes Mes

ClCl

CO2Me

CO2Me

Stage 1: Optimization of Reaction Conditions

• Combination of two terminal olefins and phosphine bearing catalyst may be problematic

• If both terminal olefins cannot be avoided due to substrate synthesis, choose Hovyeda-Grubbs

RuXX

Ph

N

NMes

MesRuX

XN

NMes

Mes

– styrene

– RuXX

CH2

N

NMes

Mes+ PR3 RuX

X

CH2

N

NMes

Mes PR3

SLOW reentry intocatalytic cycle

RuXX

Ph

N

NMes

MesRuX

XN

NMes

Mes

– styrene

– RuXXN

NMes

MesRuX

XN

NMes

MesMeMe

Me

+ PR3

– PR3

PR3

Me

RAPID reentry intocatalytic cycle


• Substrate templating may offer a solution for cyclization of heteroatom rich macrocycles

OO

OO

Grubbs' Gen. 1 (5 mol%)CH2Cl2/THF 0.02M39%, 6:4 trans:cis

with LiClO4: >95%, 100% cisO

OO

O

OO

OO

m

LiClO4, CH2Cl2/THF0.02M, >95%

CH2Cl21.2M, >95%

Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem. Int. Ed. 1997, 36, 1101.

• Cyclodepoymerization is an especially important observation in these systems


• Oligomers have been detailed as common intermediates in RCM

• Most efficient macrocyclization strategy may involve polymerization at high concentrationfollowed by dilution and macrocycle formation

Conrad, J. C. et al. J. Am. Chem. Soc. 2007, 129, 1024.

O

O

84

O

O

Grubbs' Gen. 2 (5 mol%)Method A or B

Method A: 0.005M, 9h, 99% conv.Method B: 0.1M, then dilute to 0.005M, 1h total, 99% conv.

O

O

8

4

n

Stage 2: Selection of a Catalyst

• Even perfect substrate/reaction condition optimization may not solve every metathesis problem

• A number of easily synthesized catalysts have been recently reported, based on one of

• One must identify which of these factors will yield the greatest influence on reaction outcome

three improvements: rapid initiation, lessened steric demand or improved catalyst lifetime.

RuLX PR3

X

R1

– PR3

+ PR3

k1

k–1

RuLX

X

R1

+ olefin– olefin

k2

k–2

RuLX

X

R1 R1

k3 k–3

RuLX

XR1

R1k3

k–3RuLX

X

R1 R1

k2 k–2


Catalysts Based on Rapid Initiation

Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 4035.

Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem. Int. Ed. 2002, 41, 4038.Wakamatsu, H.; Blechert, S. Angew. Chem. Int. Ed. 2002, 41, 2403.

Romero, P. E.; Piers, W. E.; McDonald, R. Angew. Chem. Int. Ed. 2004, 43, 6161.

RuLX PR3

X

R1

– PR3

+ PR3

k1

k–1

RuLX

X

R1

+ olefin– olefin

k2

k–2

RuLX

X

R1 R1

k3 k–3

RuLX

XR1

R1k3

k–3RuLX

X

R1 R1

k2 k–2

• Better intitation results in a higher effective concentration of catalyst in solution

• The groups of Grubbs, Piers, Grela and Blechert have introduced rapidly initiating catalysts

Grubbs' Third Generation

Replacement of phosphine with two 3-bromopyridine ligands yields new precatalyst

Ru

Cl

Cl

NPh

NN MesMes

N

Br

Br

excess3-BrC5H4NRu

Cl

Cl

PCy3Ph

NN MesMes

• Ease of synthesis = Exceptional

Ru

Cl

Cl

NPh

NN MesMes

N

Br

BrLove, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 4035.

Ru

Cl

Cl

NPh

NN MesMes

N

Br

Br

excess3-BrC5H4NRu

Cl

Cl

PCy3Ph

NN MesMes

• Ease of synthesis = Exceptional

Grubbs' Third Generation

Replacement of phosphine with two 3-bromopyridine ligands yields new precatalyst

Ru

Cl

Cl

NPh

NN MesMes

N

Br

Br

Ru

Cl

Cl

NPh

NN MesMes

N

Br

Br

N

Br

N

Br

+

–Ru

Cl

Cl

NPh

NN MesMes

Br

N

Br

N

Br

+

–

Ru

Cl

Cl

Ph

NN MesMes

• While the precatalyst is coordinatively saturated, dissociation is rapid

Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 4035.

RuCl

Cl

NN MesMes

O NO2

Ru

Cl

Cl

PCy3Ph

NN MesMes

O

NO2

2 steps - 49%

O OH

NO2

• Ease of synthesis = Very Good– styrene

RuCl

Cl

NN MesMes

O NO2

Grela's Nitro-Aryl Catalyst

Electronic deactivation of isopropoxy-donor is key design feature

Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem. Int. Ed. 2002, 41, 4038.

RuCl

Cl

NN MesMes

O NO2

Ru

Cl

Cl

PCy3Ph

NN MesMes

O

NO2

2 steps - 49%

O OH

NO2

• Ease of synthesis = Very Good– styrene

RuCl

Cl

NN MesMes

O NO2

• Nitro group renders the isopropoxy donor less Lewis basic, thus more labile

RuCl

Cl

NN MesMes

O NO2

RuCl

Cl

NN MesMes

O

O2N

initial metathesis event

RuCl

Cl

R

NN MesMes

Grela's Nitro-Aryl Catalyst

Electronic deactivation of isopropoxy-donor is key design feature

Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem. Int. Ed. 2002, 41, 4038.

• Ease of synthesis = Very Good

RuCl

Cl

NN MesMes

O

Ru

Cl

Cl

PCy3Ph

NN MesMes

O(i–Pr)3 steps - 51%OH

– styrene

Blechert's Biphenyl Catalyst

Steric interation between ortho substituents disfavors chelation

RuCl

Cl

NN MesMes

O

PhWakamatsu, H.; Blechert, S. Angew. Chem. Int. Ed. 2002, 41, 2403.

• Ease of synthesis = Very Good

RuCl

Cl

NN MesMes

O

Ru

Cl

Cl

PCy3Ph

NN MesMes

O(i–Pr)3 steps - 51%OH

– styrene

Blechert's Biphenyl Catalyst

Steric interation between ortho substituents disfavors chelation

RuCl

Cl

NN MesMes

O

Ph

RuCl

Cl

NN MesMes

O RuCl

Cl

NN MesMes

Oinitial metathesis event

RuCl

Cl

R

NN MesMes

• Steric interaction in planar chelate disfavors coordination

Wakamatsu, H.; Blechert, S. Angew. Chem. Int. Ed. 2002, 41, 2403.

Piers' Phosphonium Catalyst

Phosphine donor is removed as vinylphosphonium species

RuCl

Cl

PCy3

NN MesMes

OTf

RuCl

Cl

PCy3

NN MesMes

OTf

Ru

Cl

Cl

PCy3Ph

NN MesMes

CO2MeMeO2C

3 steps - 25%

O O

Me

Me

EtO2C

– methyl fumarateRu

Cl

Cl

PCy3

NN MesMes

HOTf

• Ease of synthesis = Good




RuCl

Cl

PCy3

NN MesMes

OTf

RuCl

Cl

PCy3

NN MesMes

OTf

Ru

Cl

Cl

PCy3Ph

NN MesMes

CO2MeMeO2C

3 steps - 25%

O O

Me

Me

EtO2C

– methyl fumarateRu

Cl

Cl

PCy3

NN MesMes

HOTf

• Ease of synthesis = Good

RuCl

Cl

PCy3

NN MesMes

OTf

initial metathesis eventRu

Cl

Cl

R

NN MesMes

• No preequilibrium event before metathesis can begin• Re-metathesis of vinylphosphonium salt essentially not possible




RuCl

Cl

PCy3

NN MesMes

OTfRomero, P. E.; Piers, W. E.; McDonald, R. Angew. Chem. Int. Ed. 2004, 43, 6161.

Ru

Cl

Cl

NPh

NN MesMes

N

Br

Br

NMo

(F3C)2H3CCO(F3C)2H3CCO

Ph

MeMe

RuCl

Cl

PCy3

NN MesMes

OTf



RuCl

Cl

PCy3

NN MesMes

OTfRomero, P. E.; Piers, W. E.; McDonald, R. Angew. Chem. Int. Ed. 2004, 43, 6161.

Substrate Product R Catalyst Loading time (min) Conversion (%)

R

CO2EtEtO2C EtO2C CO2Et

R

H

H

Me

1.0 mol%

0.1 mol%

1.0 mol%

<2

30

<10

100

100

100

CO2EtEtO2C

RR

EtO2C CO2Et

H

Me

1.0 mol%

1.0 mol%

<10

60

100

98

CO2EtEtO2C EtO2C CO2Et

– 5.0 mol% <10 85

Catalysts Based on Improved Olefin Binding

• Replacement of PR3 by a carbene donor markedly improved selectivity for olefin binding

• Could further alteration of the NHC donor provide further improvement?

RuLX PR3

X

R1

– PR3

+ PR3

k1

k–1

RuLX

X

R1

+ olefin– olefin

k2

k–2

RuLX

X

R1 R1

k3 k–3

RuLX

XR1

R1k3

k–3RuLX

X

R1 R1

k2 k–2

Grubbs' Serendipitous Observations

• While attempting to develop an asymmetric catalyst, production of highly substitutedolefins is observed

Berlin, J. M. et al. Org. Lett. 2007, 9, 1339.

Me Me

OSi

Me Me

catalyst (5 mol%) SiO

Me

Me MeMe

Me Me

OSi

Me Me

Ru

Cl

Cl

NN MesMes

O> 95% trisubstituted olefin Ru

Cl

Cl

Ph

NN

PCy3

Ph Ph

i–Pr

i–Pr

70% trisubstituted olefin30% tetrasubstituted olefin


Ru

Cl

Cl

Ph

NN

PCy3

t–But–Bu

t–Bu t–Bu

Ru

Cl

Cl

Ph

NN

PCy3

11

12

NHC-Ligand Optimization

Me Me

EtO2C CO2EtEtO2C CO2Et

Me Me

catalyst (5 mol%)

CH2Cl2, 30 °C

• Applying the Blechert modification produces a highly active catalyst for theformation of tetrasubstituted olefins


Ru

Cl

Cl

Ph

NN

PCy3

t–But–Bu

t–Bu t–Bu

12

Ru

Cl

Cl

NN

O

t–But–Bu

t–Bu t–Bu

22



• Most recently reported modification involves the tolyl-substitued NHC ligand

Ru

Cl

Cl

NN

O

MeMe

X

Me Me

5 mol% catalyst0.1M, C6D6, 60 °C

X

Me Me

Substrate Product Yield

Me Me

E E

Me

E EMe

E EMeMe

Me Me

E E

E E

MeMe

E E

Me

Me

>95%

>95%

87%


TsN

Me Me

>95%

>95%

88%

MeTsN

Me

MeO

Me

MeO Me

O

Me Me

O

MeMe

E = CO2Et

Stewart, I. C. et. al J. Am. Chem. Soc. 2007, 9, 1589.

Hindered Cross-Metathesis Reactions

• Further ligand optimization has allowed for difficult cross-metathesis reactionsto be successfully performed

BzO

Me

AcO


PhH, reflux, 6h BzO

MeOAc

Ru

Cl

Cl

NN MesMes

O

Ru

Cl

Cl

NN MesMes

PCy3

Ph

Ru

Cl

Cl

NN

O

MeMe

38% 59% 87%

Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. ASAP.


• Further ligand optimization has allowed for difficult cross-metathesis reactionsto be successfully performed

BzO

Me

AcO


PhH, reflux, 6h BzO

MeOAc

Ru

Cl

Cl

NN MesMes

O

Ru

Cl

Cl

NN MesMes

PCy3

Ph

Ru

Cl

Cl

NN

O

MeMe

38% 59% 87%


OAc+ 5 mol% catalystCH2Cl2, reflux, 24h

OAcLESS efficient with dimethyl catalyst

• Why does the less bulky catalyst show lower reactivity when forming a trisubstituted olefin


• The less sterically demanding catalyst may be performing rapid, but non-productivemetathesis reactions


• Could increasing the steric demand of the NHC ligand force desired olefin termini into contact?


• The less sterically demanding catalyst may be performing rapid, but non-productivemetathesis reactions


N N

RuCl

Me Me

R1

R3R2

N N

RuCl

Me Me

R1R2

R3

N N

RuCl

R1

R3R2

i–Pr

i–Pr

i–Pr

i–Pr

N N

RuCl

R1

i–Pr

i–Pr

i–Pr

i–Pr

R2R3

Steric interaction between substituted carbon atoms dominates Steric interaction with ortho ligand substituents dominates

• The application of a carbene ligand with bulky groups in the ortho aryl positions resultsin efficient formation of trisubstituted olefins, but with some limitations.


Ru

Cl

Cl

NN

O

i–Pri–Pr

R

ROAc+ 5 mol% catalyst

CH2Cl2, reflux, 24h R

R OAc i–Pr i–Pr


OAc

BzO

BzO

BzO

BzO

OAc

PhOAc

Ph

98%

96%

7%


General NHC Synthetic Scheme

• Three step synthesis transforms aniline into corresponding NHC

• Silver is typically used as a carbene transfer agent

NH2R

HN

RO

NH

OR H

NR

NH

R N N

H

R R

Cl

(COCl)2 BH3 HClHC(OEt)3

Ritter, T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 11768.

N N

H

R R

Cl

1. AgO, CH2Cl22. Grubbs' Gen. I Ru

Cl

Cl

PCy3Ph

NNR R

• An increase in catalyst lifetime will positively influence any metathesis reaction

• Fogg group observes formation of triply chloride-bridges ruthenium species as adeactivation pathway

Other Catalyst Decomposition Pathways

Rupy

IMes OC6F5OC6F5

Ph

Rupy

IMes OC6Cl5Cl

Ph

Rupy

IMes OC6Br5Br

Ph

RuClClCl

RuPh3PPh3P

PPh3

ClPPh3

RuCl

Ph3P ClPPh3

• Substitution with pseudo-halide ligands yields efficient catalysts

• Currently, however, the syntheses of these catalysts is prohibitive

Amoroso, D.; Yap, G. A. P.; Fogg, D. E. Organometallics, 2002, 21, 3335.Conrad, J. C.; Fogg, D. E. Curr. Org. Chem. 2006, 10, 185.

Real World Examples (A Positive Sense)

Stewart, I. C. et. al J. Am. Chem. Soc. 2007, 9, 1589.

Wood, J. L. et al. J. Am. Chem. Soc. 2004, 126, 16300.

O

Me

Me

MeO

O

O

Me

Me

MeO

OOPMB

OH

Me

Me

Me

H

O

O

OH

Me

Me

Me

H

O

O

OPMB

80 mol% catalyst43% yield

25 mol% catalyst76% yield

MesMes

Ru

Cl

Cl

NN

O

Ru

Cl

ClCy3P

PCy3Ph

EtO2C CO2EtMeMe

EtO2C CO2Et

Me

Me

5 mol% catalyst0.1M, C6D6, 60 °C

Ru

Cl

Cl

NN

O

MeMe

Sealed tube: 62%Open vessel (remove C2H4): 87%

O

PMBOMe

OH

O

PMBOMe

OH

10 mol% Grubbs Gen. 20.001M, 35% yield

• What three modifications would you make to this procedure as an attempt to improve yield?

Trost, B. M.; Guangbin, G.; Vance, J. A. J. Am. Chem. Soc. 2007, 129, 4540.

An Example with Room for Improvement

O

PMBOMe

OH

O

PMBOMe

OH





• First, run the reaction briefly at high concentration, followed by dilution to 0.001M

O

PMBOMe

OH

O

PMBOMe

OH





• Next, try a phosphine-free commercial catalyst (i.e., Hoyveda-Grubbs) at these conditions


O

PMBOMe

OH

O

PMBOMe

OH





• Finally, if the reaction only slowly yields product, look to a more active catalyst (Blechert, Piers)

• Next, try a phosphine-free commercial catalyst (i.e., Hoyveda-Grubbs) at these conditions


Applications in the MacMillan Laboratory

• Formation of tetrasubstituted olefins is a significant extension for natural product synthesis

• Cross metathesis to form trisubstituted unsaturated aldehydes for Hanztch reduction maybenefit from use of diisopropyl substituted catalyst

Ru

Cl

Cl

NN

O

i–Pri–Pr

R

R O+

5 mol% catalystCH2Cl2, reflux, 24h R

R i–Pr i–Pr

H

O

H

• Formation of complicated disubstituted unsaturated aldehydes may also benefitfrom the use of an altered NHC catalyst

Ru

Cl

Cl

NN

O

MeMe

O+

5 mol% catalystCH2Cl2, reflux, 24hH

O

HR1

R2

R1

R2

• Use of highly active catalysts may allow for significant reduction in catalyst loadings,potentially important for early-stage metathesis in total synthesis

• Slight changes to substrate structure and reaction conditions may yield significant gains

• Many recently reported catalysts are easily synthesized

• Careful consideration of each specific metathesis challenge can guide investigations

Metathesize Smarter, not Harder

Ru

Cl

Cl

NPh

NN MesMes

N

Br

Br

RuCl

Cl

PCy3

NN MesMes

OTf

Ru

Cl

Cl

NN

O

MeMe

Ru

Cl

Cl

NN

O

i–Pri–Pr

i–Pr i–Pr

Don't be afraid to use cutting edge metathesis technology

Applications of Non-Commercially Available Metathesis...

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