46778-G1
N-Allyl- and N-Alkynylhydrazones: Ideal Compounds for Efficient Organic Transformations
In the past year since the award of the PRF Type G grant, my research group at Northwestern University has initiated a study into the reactivity of N-allyl and N-propargylhydrazones, with a view to discovering new and efficient chemical reactions. At the core of the submitted proposal was the notion that condensation of an allylhydrazine with a petrochemical feedstock-derived aldehyde or ketone is a thermodynamically favored process driven by loss of water. Our long-term goal was to then convert the derived hydrazone intermediates into useful and diverse substrates through a sigmatropic rearrangement. There was little precedent for such a reaction, since the thermal variant has proven to be low yielding and not very general. Our plan was to use modern concepts of catalysis to overcome these problems. Discovery of a New Transformation: The first goal upon beginning our program on hydrazone-based chemistry was to determine the best set of conditions to prepare a variety of N-allylhydrazones. We chose to use the method developed by Jamart-Grégoire and coworkers,1 which allows access to both linear and branched hydrazine derivatives. Condensation of these Boc-hydrazines with a number of aldehydes afforded the desired hydrazones in excellent yields. By using 4 equivalents of CuCl2¬ and 1 equivalent of diisopropylethylamine in acetonitrile at reflux, we were able to affect complete consumption of the starting material within 20 min and obtain a number of benzylic chlorides in good yield.2 In this previously unknown transformation, both a new carbon-carbon bond and a new carbon-chlorine bond are formed in a single process. The reaction sequence proved to be quite general for a variety of aryl aldehydes (13 examples), and importantly, other allyl fragments may be used to generate either additional sp3 stereocenters or stereodefined olefins. These last substrates are especially important in light of the proposed research. We have conducted preliminary mechanistic studies to gain insight into this transformation. Deuterium incorporation alpha to the hydrazine nitrogen led to complete incorporation into the terminal olefin position, providing strong evidence for intramolecular carbon–carbon bond formation. We suspected that CuCl¬2 might be acting as an oxidant, and thus facilitating rearrangement by way of a radical–cation species. To test this notion we treated a hydrazone with one equivalent of (4 BrPh)3N•SbCl6, a stable aminium salt known to promote radical–cation mediated reactions,3 and observed the formation of the desired chlorinated product. This work was published and the ACS PRF award acknowledged in The Journal of the American Chemical Society. Already, this work has stimulated interest in the field of chemistry, with Prof. Tantillo's group at UC Davis publishing a manuscript dedicated to DFT-calculations of our reaction.4 Since this time we have further developed this halogenation chemistry to allow for a one-pot synthesis of dienes and trienes from N-allylhydrazones. These useful products will be critical in our exploration of cascade processes, whereby simple petrochemical feedstock aldehydes will be converted into complex polycyclic molecules related to bioactive natural products. These highly conjugated products may also find use as precursors to dendralenes and other polyconjugated organic molecules of potential interest for their electron-transfer properties. A manuscript detailing this new diene/triene synthesis has been prepared and will be submitted shortly. Our on going research will focus on developing effective catalysis of these hydrazone rearrangements. (1) Brosse, N.; Pinto, M. F.; Jamart-Gregoire, B. Eur. J. Org. Chem. 2003, 4757-4764. (2) Mundal, D. A.; Lee, J. J.; Thomson, R. J. J. Am. Chem. Soc. 2008, 130, 1148-1149. (3) Bauld, N. L.; Bellville, D. J.; Harirchian, B.; Lorenz, K. T.; Pabon, R. A.; Reynolds, D. W.; Wirth, D. D.; Chiou, H. S.; Marsh, B. K. Acc. Chem. Res. 1987, 20, 371-378. (4) Siebert, M. R.; Tantillo, D. J. Org. Lett. 2008, 10, 3219-3222.
