Cycloaddition Reagents

Aldrich ChemFiles 2006, 6.2, 8.

Aldrich ChemFiles 2006, 6.2, 8.

1-(2-Methoxyethoxy)-1-vinycyclopropane

Vinylcyclopropanes (VCPs) are excellent scaffolds for construction of seven-membered and bicyclic ring systems. Paul Wender, of Stanford University, has developed a simple but versatile VCP reagent (1-(2-methoxyethoxy)-1-vinycyclopropane, Figure 3) capable of participating in a variety of rhodiumcatalyzed cycloaddition reactions.

Figure 3


Exposure of the VCP reagent to alkynes in the presence of catalytic [Rh(CO)2Cl]2 results in the expeditious formation of substituted cycloheptenones via [5+2] cycloaddition (Scheme 24, Table 3).1 The reaction is tolerant to a variety of functional groups (OH, NHTs, CO2H), as well as both mono- and disubstituted acetylenes. The combination of rapid reaction times, low catalyst loadings, and the ability to perform the reaction on a significant scale (100 mmol), make this method of cycloheptenone formation extraordinarily cost-effective.

Scheme 24


Using similar conditions, Wender expanded the scope of this methodology to perform three-component [5+2+1] cycloadditions by performing the reaction under mild CO pressure.2 With the presence of CO, an intermediate cyclooctadienone is formed by CO insertion. This species rapidly undergoes transannular closure. Subsequent hydrolysis of the enol ether furnishes the observed bicyclo[3.3.0]octenone (Scheme 25). This general method was used to prepare an array of bicyclooctenes in good to excellent yield (Table 4). Notably, the cycloaddition occurs with complete regioselectivity and with tolerance of heteroatom-containing functional groups.

Scheme 25


Table 4


A final elaboration of this methodology was achieved by use of phenylacetylenes in a non-polar solvent system to give hydroxyindanones (Scheme 26).3 With this relatively simple change, a two-fold CO insertion occurs, resulting in a net four-component [5+1+2+1] cycloaddition!

Scheme 26


Lastly, the scope of this general class of reactions was broadened to include other π-systems. Specifically, allenes participate in intermolecular [5+2] cycloadditions with the VCP reagent to give cycloheptanone derivatives (Scheme 27).4

Scheme 27


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Materials

     

References

  1. (a) Wender, P. A. et al. Org. Lett. 2000, 2, 1609; (b) Wender, P. A. et al. J. Am. Chem. Soc. 2004, 126, 9154.
  2. Wender, P. A. et al. J. Am. Chem. Soc. 2002, 124, 2876.
  3. Wender, P. A. et al. J. Am. Chem. Soc. 2005, 127, 2836.
  4. Wender, P. A. et al. J. Am. Chem. Soc. 2005, 127, 6530.

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