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45092-GB1
Synthesis and Transition Metal-Catalyzed [3+2] Cycloadditions of Methyleneaziridines

Christopher J. T. Hyland, California State University (Fullerton)

The main focus of the initially proposed work was the synthesis and reactivity of methyleneaziridines. However, as part of our broader interest in the synthetic potential of small highly-strained ring systems we also began investigating the reactivity of cyclopropenes.¹ During this work we have uncovered a novel 3,3-sigmatropic rearrangement of the cyclopropenyl acetates 5 (Scheme 1). These cyclopropenes undergo Lewis-acid mediated rearrangement to methylenecyclopropane 2. This transformation represents a new synthesis of methylenecyclopropanes, which have proven to be important and versatile synthetic intermediates.[1] It should be noted that methylenecyclopropanes 6 would be difficult to prepare via other methods.

Divergent reactivity of cyclopropenes 5 has been uncovered upon treatment with the more powerfully Lewis-acidic TiCl₄. When 5 is treated with TiCl₄ at low temperatures chlorodienes 7 are obtained. We propose that this transformation proceeds via loss of the acetate group, ring-opening results to an allenyl-cation and finally interception of this cation by chloride from the Lewis-acid. The reaction appears to be selective for the Z-isomer and the stereochemistry of diene 7 was unequivocally shown by X-ray crystallography.

A range of cyclopropenes with a pendant acetate group have been prepared using a modification of Baird's method followed by acetylation (Scheme 2).[2] This method is ideal as it can be carried out in one-pot and R, R¹ and R² are easily varied. Yields steps 1 and 2 varied from 40-85% while the acetylation typically gave yields from 80-90%. The 1,1,2-trihalogenocyclopropanes required for this sequence were easily prepared under bi-phasic reaction conditions from commercially available bromo-alkenes 4.

The resulting substrates have been used to test the generality of the 3,3-sigmatropic rearrangement and the chloro-diene formation. Interestingly, the stereoselectivity of the 3,3-sigmatropic rearrangement was found to be dependent upon Lewis-acid loading and reaction time. Short reaction times and a full equivalent of BF₃.OEt₂ resulted in selective formation of the E-methylenecyclopropane. In contrast sub-stoichiometric amounts of the Lewis-acid and longer reaction times led to an equilibrium mixture of E/Z-methylenecyclopropanes. We believe these observations are a result of the reversibility of the rearrangement, however, further studies are necessary to fully elucidate the mechanism. The TiCl₄-mediated rearrangement has proved general for a number of substrates (figure 2) and we are continuing to optimize the yields.

In summary, we have uncovered two Lewis-acid mediated rearrangements of cyclopropenyl acetates. These transformations contribute fundamentally to the understanding of how cyclopropenyl acetates behave with different Lewis acids. In addition, the rearrangements allow preparation of synthetically important heteroatom-substituted methylenecyclopropanes and chloro-dienes.  While making a significant impact on the area of cyclopropene chemistry, the two rearrangements leave a number of questions unanswered and have opened up a number of avenues for further investigation. In future studies we will investigate the exact nature of the Lewis-acid interaction to see if it is activating the oxygen of the acetate or the p-bond of the cyclopropene. We also plan to develop extend the 3,3-sigmatropic rearrangement to cyclopropenyl trichloroacetimidates to allow preparation of aminated methylenecyclopropenes. We believe the TiCl₄-mediated rearrangement is potentially powerful method for preparation of highly substituted dienes, so future studies here will focus on introducing nucleophiles besides chloride.

The research described in this report has had a significant impact on my career by allowing me to obtain significant initial results, while opening up two new avenues of investigation. In addition, the results obtained under the auspices of this grant have already enabled me to make both oral and poster presentations at the National ACS meeting in Philadelphia and the Organic Reactions and Processes Gordon Conference in Rhode Island. Following optimization of the yields for some of the reactions shown above I plan to submit peer-reviewed publication in the very near future, thus firmly establishing me in the synthetic community as an independent researcher.

Three undergraduate students have been directly involved with this research project through paid summer research, with one student being a PRF SUMR scholar. This focused research experience allowed the students to get a taste of what real research is like and as a result the PRF SUMR scholar is now planning to pursue a Ph.D. in chemistry. Another two undergraduate students have worked on the project during the semester and were so excited by the chance to carry out organic research that they successfully applied for the NSF REU and NIH MARC (Minority Access to Research Careers) programs respectively. One of these students is preparing his applications for Ph.D. programs in organic chemistry and the other will be doing the same in two years.  Their decisions to enter graduate school in chemistry were directly influenced by their involvement with this project.

[1] For a review on the transition-metal catalyzed reactions of these systems, see: Rubin, M.; Rubina, M.; Gervorgyan, V. Chem. Rev. 2007, 107, 3117.

[2] Baird, M. S.; Hussain, H. H. Tetrahedron, 1987, 43, 215.

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