Nickel-Catalyzed Three-Component [3+2+2]Cocyclization of Ethyl Cyclopropylideneacetate

and Alkynes

Michel Grenon

April 1st, 2006

Selective Synthesis of Multisubstituted Cycloheptadienes

CO2Et R1

R2

Cat. Ni0R1

R2

CO2Et

Komagawa, S.; Saito, S. Angew. Chem., Int. Ed. Engl. 2006, 45, 2446

Michel Grenon @ Wipf Group 1 4/3/2006

Presentation Outline

Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091

Other Transition-Metal Catalyzed Cycloadditions for the Construction of Seven-Membered Rings

[6+1] Cycloaddition of arenes with !-diazo carbonyl compounds

[5+2] Cycloaddition of vinylcyclopropanes with alkynes

[4+3] Cycloaddition of dienes with TMM derivatives

Previous Examples of Transition-Metal Catalyzed(Mediated) [3+3+2] Cycloadditions for the Constructionof Seven-Membered Rings

Iridium-mediated allyl/alkyne [3+2+2] cycloaddition

Cobalt-mediated allyl/alkyne [3+2+2] cycloaddition

Nickel and Rhodium-catalyzed [3+2+2] cycloaddition of alkenyl Fischercarbene complexes and allenes

Nickel-Catalyzed Intermolecular [3+2+2] Cocyclization of Ethyl Cyclopropylideneacetate and Alkynes

Future Work

Michel Grenon @ Wipf Group 2 4/3/2006

Transition-Metal Catalyzed [6+1] Cycloaddition(Buchner Reaction)

Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091

Substituted arenes give mixtures of isomeric products

N2

OEt

O

, h!

CO2Et CO2Et

CO2Et

CO2Et

CO2Etvon E. Doering, W.; Laber, G.; Vonderwahl, R.; Chamberlain, N. F.; Williams, R. B.J. Am. Chem. Soc. 1956, 78, 5448

Anciaux, A. J.; Demonceau, A.; Noels, A. F.; Hubert, A. J.;Warin, R.; Teyssie, P. J. Org. Chem. 1981, 46, 873

(excess)

Rh(O2CCF3)2, rt

N2

OEt

O

CO2Et

100%

O

N2 O

ORh(OAc)2, rt

95%CH2Cl2

McKervey, M. A.; Tuladhar, S. M.; Twohig, M. F. J. Chem. Soc., Chem. Commun. 1984, 129

Michel Grenon @ Wipf Group 3 4/3/2006

Transition-Metal Catalyzed [5+2] Cycloaddition

Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49

Formation of a metallacycle, followed by a strain-driven cleavage of the cycloprane ring and areductive elimination to the cycloheptadiene

An increase in reaction rate is also observed when thereactions are performed in CF3CH2OH

Michel Grenon @ Wipf Group 4 4/3/2006

Transition-Metal Catalyzed [4+3] Cycloaddition

Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49

Freezing the diene in a cisoid conformation favors the formation of the seven-membered ring

MeO2CCO2Me

OAc

TMS

Pd(PPh3)4 (7 mol%)

dppe (1.5 mol%)

Dioxane, !, 8 hCO2Me

MeO2C

MeO2C CO2Me

98%3.8 1.0

Trost, B. M.; Nanninga, T. N.; Chan, D. M. T. Organometallics 1982, 1, 1543

Trost, B. M.; MacPherson, D. T. J. Am. Chem. Soc. 1987, 109, 3483

CO2CH2CH2Ph CO2CH2CH2Ph

OAc

TMS

Pd(OAc)2 (5 mol%)

P(OiPr)3 (35 mol%)

THF, !, 8 h

88%

Minor amounts of [3+2]cycloadduct observed

Michel Grenon @ Wipf Group 5 4/3/2006

Previous Examples of [3+2+2] Cycloadditions

Schwiebert, K. E.; Stryker, J. M. J. Am. Chem. Soc. 1995, 117, 8275

Stoichiometric reaction, and poor selectivities are obtained for unsymmetrical alkynes

Ir

*Cp

Me

Me

OTf

Ph Ph

CH2Cl2, 0 ˚C to rt, 24 h

Ph Ph

Me

Me

56%

Ir

*CpOTf

Ph Me

CH2Cl2, 0 ˚C to rt, 24 h

ca. 40% (3:1)Me Ph

Me

Me Ir

*CpOTf

Me Me

R'

R" Ir

*CpOTf

R', R" = Me, Ph

Similar results with phenylacetylene

Ir

TfO

*Cp Me Me

CH2Cl2, 0 ˚C to rt, 12 hMe

Me

78%

Ir

OTf

MeMe Cp*

Iridium-mediated allyl/alkyne [3+2+2] cycloaddition

Michel Grenon @ Wipf Group 6 4/3/2006

Previous Examples of [3+2+2] Cycloadditions

Etkin, N.; Dzwiniel, T. L.; Schweibert, K. E.; Stryker, J. M. J. Am. Chem. Soc. 1998, 120, 9702

Dramatic solvent effect (THF affords cyclopenta-dienyl complexes)

Conditions: CH2Cl2, excess alkyne (3 to 10 equiv.),−78 ˚C to rt, 12 h

Nucleophilic alkylation (Na-dimethylmalonate) of 3,followed by an oxidative decomplexation using[Cp2Fe]+−OTf affords substituted cycloheptadienes

Cobalt-mediated allyl/alkyne [3+2+2] cycloaddition

Michel Grenon @ Wipf Group 7 4/3/2006

Previous Examples of [3+2+2] Cycloadditions

Barluenga, J.; Vicente, R.; Barrio, P.; Lopez, L. A.; Tomas, M.; Borge, J. J. Am. Chem. Soc. 2004, 126, 14354

Reaction affords the [3+2] cycloadduct whenperformed in toluene

Done withNi(cod)2

Least substituted C=C bond of the alleneinserts (head-to-head allene−allene coupling)

Nickel and Rhodium-catalyzed [3+2+2] cycloaddition of alkenyl Fischercarbene complexes and allenes

Michel Grenon @ Wipf Group 8 4/3/2006

Previous Examples of [3+2+2] Cycloadditions

Barluenga, J.; Vicente, R.; Barrio, P.; Lopez, L. A.; Tomas, M.; Borge, J. J. Am. Chem. Soc. 2004, 126, 14354

Least substituted C=C bond of the alleneinserts (head-to-tail allene−allene coupling)

Done with[Rh(cod)Cl]2

Reversible metalla-[4+2] cycloaddition givesIV, which evolves to the more stable V

Nickel and Rhodium-catalyzed [3+2+2] cycloaddition of alkenyl Fischercarbene complexes and allenes

Michel Grenon @ Wipf Group 9 4/3/2006

Nickel-Catalyzed Intermolecular [3+2+2] Cocyclizationof Ethyl Cyclopropylideneacetate and Alkynes

Saito, S.; Masuda, M.; Komagawa, S. J. Am. Chem. Soc. 2004, 126, 10540

Other phosphines [P(Bu)3, P(Cy)3, P(t-Bu)3, dppe] were less effective

Other catalysts [RhCl(PPh3)3, CpCo(PPh3)2, CpCp(CO)2] were not effective

Good results obtained with sterically hindered terminal alkynes (entries 1−9)

Michel Grenon @ Wipf Group 10 4/3/2006

Nickel-Catalyzed Three-Component [3+2+2]Cocyclization of Ethyl Cyclopropylideneacetate

and Alkynes

Michel Grenon

April 1st, 2006

Selective Synthesis of Multisubstituted Cycloheptadienes

CO2Et R1

R2

Cat. Ni0R1

R2

CO2Et

Komagawa, S.; Saito, S. Angew. Chem., Int. Ed. Engl. 2006, 45, 2446

Michel Grenon @ Wipf Group 11 4/3/2006

Nickel-Catalyzed Intermolecular [3+2+2] Cocyclizationof Ethyl Cyclopropylideneacetate and Alkynes

Komagawa, S.; Saito, S. Angew. Chem., Int. Ed. Engl. 2006, 45, 2446

CO2EtTMS

R

(1 equiv.)

(4 equiv.)

Ni(cod)2 (10 mol%)PPh3 (20 mol%)

Toluene, rt, dropwiseaddition of reagents

TMS

CO2Et

R

Entry R Yield (%)

1 MeOCH2 69

2 TBDMSOCH2 67

3 PhCH2 66

4 n-C6H13 68

5 Ph 56

6 p-MeOC6H4 65

7 p-CF3C6H4 74

8 69HO(CH3)2C

Terminal alkyne doesn't need to be bulky in order to get good regioselectivities (see different R groups)

TBDMS

(4 equiv.)

BDMS

(4 equiv.)

t-Bu

(4 equiv.)

Pr

(4 equiv.)

Pr

Other alkynes;

DMF can also be used, but not THF, Et2O or CH2Cl2

Michel Grenon @ Wipf Group 12 4/3/2006

Nickel-Catalyzed Intermolecular [3+2+2] Cocyclizationof Ethyl Cyclopropylideneacetate and Alkynes

Komagawa, S.; Saito, S. Angew. Chem., Int. Ed. Engl. 2006, 45, 2446

TMS

R

Ni0Ni

R

TMS

Ni TMSR more sterically congested

Ni

R

TMS

EtO2C

path a

CO2Et

Ni

CO2Et

R

TMS

cyclopropylmethyl!butenylrearrangement

path b

Michel Grenon @ Wipf Group 13 4/3/2006

Future Work

Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091

Extend this reaction to other cyclopropylmethylene derivatives

Attempt to apply this methodology to the synthesis of complex natural products

O

R

O

OEt

R

EtO2C R

TMS

R'

?

O

OEt

Extend this reaction to cyclobutylmethylene derivatives

?(Feasible? Beilstein search resulted in no hits.)

Michel Grenon @ Wipf Group 14 4/3/2006