Oxygen-Substituted VCPs

Alkoxy-VCP 163 was found to be a very competent reagent in the intermolecular [5+2] cycloaddition (Tab. 13.12). With some minor optimization of the previous reaction conditions, namely the use of 1,2-dichloroethane (DCE) as solvent at a higher concentration (0.5 M) and reaction temperature (80 °C), the reaction was found to be complete in minutes in some cases with 0.5 mol% [RhCl(CO)2]2, while still providing good to excellent yields of cycloheptenone products. Significantly, reactive functionahty, including unprotected alcohols and carboxylic acids, is tolerated in the reaction. The reaction is also readily scaled, with comparable isolated yields over a 100-fold increase in scale. The formation of products in minutes is of consequence, as such reactions allow for the more time-efficient reahzation of synthetic goals. 

---

Scheme 13.15 Preparation of oxygen-substituted VCPs 142 (Eq. 1) and 163 (Eq. 2). Conditions (a) Na metal, TMSCI, Et20, A (b) MeOH, RT (c) vinylmagnesium bromide, EtjO, 0°C to RT (d) TBSOTf, 2,6-lutidine, CHjCb, RT (e) N-bromo-succinimide, 2-methoxyethanol, -78 °C to RT (f) KOH, RT to 90°C (g) 1.3 equiv. CH2I2, Zn metal, CuCI, AcCI, EtjO, A.

While the fadhty and effidency of the [5+2] cycloaddition of oxygen-substituted VCPs could be attributed solely to the electronic contribution of the heteroatom substituent, it could also be a consequence of its conformational influence. Substitution of a VCP, particularly at the 1-position, has been shown to reduce the difference in energy between the s-cis (local minimum) and s-trans (global minimum) conformations through steric effects [50]. Based on the proposed mechanisms for the [5+2] cycloaddition, only the s-cis conformations, 190 and 192, can lead to productive reaction, so biasing intermediates toward this conformation could therefore accelerate the reaction (Scheme 13.16). 

Wender s group has also developed rhodium-catalyzed intermolecular [5-1-2] cycloadditions. At first, they found the catalysis system of Rh(PPh3)3Cl for the intramolecular reactions was not effective at all for the intermolecular reactions. To effect the intermolecular [5-1-2] cycloadditions, [Rh(CO)2Cl]2 must be used and oxygen substitution of the cyclopropane was necessary (see (17)) [37-39]. Then they successfully expanded the substrate to unactivated vinylcyclopropanes by adjusting the substituents. For monosubstituted alkynes, the substitution on the olefin terminus directs the formation of single isomer that minimized steric hindrance (see (18)) [40]. The [5-1-2] cycloadditions can also be applied to VCPs with allenes (see (19)) [41]. It should be noted that the alkyne substituent did not interfere with the reaction, indicating that allenes as reaction partners were superior to alkyne in the [5-1-2] cycloadditions. Curiously, the authors didn t report the corresponding intermolecular [5-1-2] cycloadditions of VCPs with alkenes. 

---