Reports: B4

48578-B4 Fundamental Studies on the Nature of Diradical Intermediates in [1,3] Carbon Migrations of Bicyclic and Tricyclic Vinylcyclobutanes

Phyllis A. Leber, Franklin and Marshall College

A recent reappraisal1 of thermal [1,3] sigmatropic rearrangements of vinylcyclopropanes and vinylcyclobutanes has rejected a concerted mechanism under orbital symmetry control2 in favor of a stepwise mechanism involving diradical intermediates that are not statistically equilibrated.  An obvious empirical test of this mechanistic analysis would be to utilize the cyclopropylcarbinyl (CPC) rearrangement previously previously applied to indirect detection of free radicals3 as an experimental probe for an incipient diradical intermediate. The two systems that we have designed as potential CPC precursors are 8-exo-cyclopropylbicyclo-[4.2.0]oct-2-ene (1) and spiro[bicyclo[4.2.0]oct-2-ene-7,1¢-cyclopropane] (2).

The preparation of 8-endo-cyclopropylbicyclo[4.2.0]oct-2-en-7-one was accomplished via ketene cycloaddition of 1,3-cyclohexadiene and cyclopropylketene, which was generated in situ by treatment of cyclopropylacetyl chloride with triethylamine.  A two-step low-temperature Wolff-Kishner cyclobutanone reduction4 was employed to convert the ketone to the corresponding hydrocarbon 1 with associated base-catalyzed epimerization of the endo epimer of the ketone to the exo epimer of compound 1.  The endo epimer of the [1,3] sigmatropic rearrangement product afforded by compound 1, 5-endo-cyclopropylbicyclo-[2.2.2]oct-2-ene, was prepared from bicyclo[2.2.2]oct-5-en-2-carbaldehyde5 (96% endo) by a two-step sequence of Wittig methylenation followed by selective Simmons-Smith cyclopropanation of the exocyclic olefin.  We intend to report more details about this novel selective cyclopropanation that was performed at -10 ¼C using diethylzinc in hexane and diiodomethane.

We have recently completed a thorough gas-phase kinetic analysis of compound 1 at 275 ¼C. The si/sr ratio is 1.8, a value that is quite similar to the 2.4 reported for 8-exo-methylbicyclo[4.2.0]oct-2-ene.5  This result suggests that conformationally flexible bicyclic vinylcyclobutanes experience little, if any, orbital symmetry control of the [1,3] shift. The dominant thermal pathway however is epimerization of the exo epimer to the less thermodynamically stable endo epimer, and the phenomenon of one-centered stereomutation or epimerization offers compelling albeit indirect experimental evidence for a diradical intermediate.  The observation of a greater contribution of total isomerization, both epimerization and [1,3] migration, for compound 1 compared to its 8-exo-methyl analog can be rationalized by an enhanced endo trajectory, using Houk terminology,6 for the migrating carbon C-8 due to greater steric repulsion between the cyclopropyl substituent at C-8 and the bridgehead hydrogen at C-6 in the cyclobutane conformer where the cyclopropyl group adopts a pseudo-axial position and that is transformed to the exo trajectory upon bond excitation and cleavage.

There is some indirect evidence for a CPC rearrangement in the thermal profile of compound 1.  A minor exit channel constituting only 2% of the product mixture affords an isomer whose mass spectrum is consistent with a putative CPC product that has been tentatively identified as 5-(1-pent-2-enyl)-1,3-cyclohexadiene deduced from the base peak at m/z 79 corresponding to a cyclohexadienyl cation and a strong peak at m/z 68 due to an allylic pentenyl radical cation.  This minor product, which has not yet been fully characterized, is thermally stable at 275 ¼C because it continues to increase in concentration as compound 1 undergoes thermal rearrangement.

Considerable progress has been achieved in the synthesis of compound 2.  We have already prepared the immediate precursor 7-methylenebicyclo[4.2.0]oct-2-ene via Wittig methylenation of bicyclo[4.2.0]oct-2-en-7-one,7 and we anticipate that this system will be amenable to the selective cyclopropanation methodology recently developed. The [1,3] product will be similarly prepared by Wittig methylenation of bicyclo[2.2.2]oct-5-en-2-one7 followed by selective cyclopropanation.  Given the absence of a stereocenter on the migrating carbon in compound 2, only a single [1,3] thermal product is expected; thus, compound 2 will not provide any stereochemical information about the [1,3] carbon shift. Due to the potential for compound 2 to produce a cyclic allylic primary alkyl diradical, which is inherently less stable than the corresponding diradical afforded by compound 1, and the added strain in a spiro linkage, we expect compound 2 however to exhibit a greater tendency to undergo a CPC rearrangement. Compound 2 therefore appears to offer a better probe of a potential CPC rearrangement than does compound 1.

Impact of Research

The present study represents an extension of our research on [1,3] sigmatropic rearrangements by designing substrates that has the potential to undergo CPC rearrangement, an experimental probe of free radicals.  We are also continuing our productive collaboration with Professor John E. Baldwin of Syracuse University.  Although the administrative burdens associated with my service as departmental chair has impeded our research progress, our work has proceeded albeit at a slower pace.  I am currently writing the first manuscript on the thermal behavior of 8-exo-cyclopropylbicyclo[4.2.0]oct-2-ene (1).

To date three undergraduate students have received summer research stipends through PRF Grant #48578-B4.  Anthony Nocket '09, who is currently a first-year graduate student in chemistry at Penn State University, will be the only student coauthor on the study of compound 1.  Ryan Bell '11 and Andrew Bensinger '11 are both F&M chemisty majors.  Andrew has initiated the synthesis of compound 2; Ryan Bell, its bicyclo[3.2.0] analog.

References

  1. Baldwin, J. E.; Leber, P. A.  Molecular rearrangements through thermal [1,3] carbon shifts.  Org. Biomol. Chem. 2008, 6, 36-47.

  2. Woodward, R. B.; Hoffmann, R.  The Conservation of Orbital Symmetry; Academic Press: New York, 1970.

  3. Griller, D.; Ingold, K. U.  Free-Radical Clocks.  Acc. Chem. Res. 1980, 13, 317-323.

  4. Burkey, J. D.; Leber, P. A.; Silverman, L. S.  Preparation of 7-Methyl-7-vinylbicyclo[3.2.0]hept-2-ene via Cyclobutanone Reduction.  Synth. Commun. 1986, 16, 1363-1370.

  5. Bogle, X. S.; Leber, P. A.; McCullough, L. A.; Powers, D. C. J. Org. Chem. 2005, 70, 8913-8918.

  6. Northrop, B. H.; Houk, K. N.  Vinylcyclobutane-Cyclobutane Rearrangement: Theoretical Exploration of Mechanism and Relationship to the Diels-Alder Potential Surface. J. Org. Chem. 2006, 71, 3-13.

  7. Powers, D. C.; Leber, P. A.; Gallagher, S. S.; Higgs, A. T.; McCullough, L. A.; Baldwin, J. E.  Thermal Chemistry of Bicyclo[4.2.0]oct-2-enes. J. Org. Chem. 2007, 72, 187-194.