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