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            Funding from the ACS-PRF has allowed us to develop a research program in catalytic C–C s-bond activation and functionalization.  This chemistry is rare, with most examples prior to our work using strained C–C s-bonds.  Our initial proposal was to develop activation of C–C bonds adjacent to ketones to explore non-traditional reactivity from this standard functional group.  Our initially proposed research was aimed at activating simple ketones by using the principles of organocatalysis to form the corresponding ketimine and performing organometallic catalysis to functionalized the C–C bond via chelation-assisted bond activation (Scheme 1, left).  Our initial work in this area proved somewhat difficult.  After identifying that the initial ketimine formation step was a problem step, we made the early tactical decision to move examine feasibility of the organometallic catalysis portion.  In this mode, the activation and functionalization takes place when a chelating heteroatom is embedded in the ketone substrate (7 to 8, via 9, Scheme 1, right).  We have termed this net addition of a carbon and acyl substituent across an alkene "carboacylation."

Scheme 1: Our initially proposed reaction, and our first successful C–C activation chemistry.

            We have explored this carboacylation reaction of alkenes in inter- and intramolecular contexts.  This work has been published and the publications added to the ACS-PRF web reporting system.  The work was summarized in our prior progress report, and I will not discuss it further here.

            Just before the last reporting period, an undergraduate student, Michael Capp, garnered some important preliminary data on intramolecular carboacylation of alkynes via C–C bond activation.  We were initially concerned that salicylaldehyde-derived 8-acyl quinolines containing propargylic phenolic ethers would be prone more prone to the rhodium-mediated ether cleavage (to 26, Scheme 2) that was occasionally observed in alkene carboacylation.  After examining several reaction conditions, Michael Cap was able to identify a product resulting from alkyne carboacylation.  Although we were initially challenged by competitive ether cleavage, Michael Wentzel and Ashley Dreis followed up on these results, showing this bi-product could be avoided in most cases by judicious choice of Rh catalyst and solvent.  Also, they showed that a wide variety of functional groups are tolerated in the reaction, and that the propargyl either cleavage problem was more pronounced when the phenolic component was substituted with electron-withdrawing groups. (Scheme 2)  The substrate scope and substituent effect study is complete, and we expect to submit a manuscript on this work in the next few weeks.

Scheme 2: Alkyne carboacylation

            Also at the end of the previous reporting period, graduate student T. Giang Hoang had initially started to probe the potential for carboacylation of ketones via C–C activation.  The outlined experiments were along the lines alkene carboacylation, but using the directing group to one ketone for activation and addition across the other.  Giang typically saw low conversion in this attempted experiments, so he attempted a reaction with a stoiciometric amount of Wilkinson's catalyst.  Surprisingly, we isolated a stable rhodium-phosphine complex, and tentatively assigned the structure as 32 based on spectroscopy.  Even more surprisingly, the complex forms in 82% yield (by ¹HNMR) at temperatures as low as –20 °C! Giang's results lead us to question whether the final proposed C–O reductive elimination was actually feasible in this system.  Phrased another way, we wondered if catalytic quinoline-directed C–O activation of esters would be a possible (such as 33 to 32), and if so, would it allow an entry into "oxy-acylation" of alkenes.  Giang undertook a study into this reaction manifold and has recently garnered some promising catalytic results, showing TON up to 8 for intramolecular oxyacylation.  Giang has explored the substrate scope of this reaction and his results have been submitted for publication.  We will report via the ACS-PRF's web reporting system once the work is published.

Scheme 3: Attempted Ketone Carboacylation and C–O Activation allows "Oxy-Acylation" of Alkenes

            At the end of my previous report, I stated that we would return to the initially proposed 2-amino pyridine system, now armed with the knowledge of what C–C activation can accomplish with 8-acyl quinolines.  A study of our initial failed attempts at carboacylation of alkenes using these organic co-catalysts revealed that imine formation was particularly slow (as determined by in-situ NMR).  Thinking to make the 2-amino-picoline a more potent nucleophile, graduate student Evgeny (Eugene) Beletski and post-doc Sudheer Chava examined a series of 2-aminopyridines substituted with additional electron donor groups.  Among those examined, the structures containing a 5-amino group were most effective at promoting imine formation. 

Scheme 4: New 2-aminopyridines for C–C and C–H Bond Activation Reactions

            Armed with this knowledge, we examined the reaction of acetone (as proposed in our initial application) with various alkenes under the action of rhodium catalysts and our more reactive 2-aminopicoline 25 (Scheme 4).  Unfortunately, only alpha olefins have thus far been induced to react in this system.  We can convert acetone into higher ketones.  This reaction only works with our more electron rich aminopicoline additives.  We are currently working to expand the system into more complex alkenes and ketones, and will re-examine intramolecular alkene carboacylation as we find more reactive catalyst mixtures.

            Concurrently, we became interested in 2-amino-picoline/Rh catalyzed hydroacylation (Scheme 4, bottom).  Using some of the more active picoline derivatives, we have been able to achieve the intramolecular hydroacylation reaction to form cycloheptanones (28 ˆ 29), a class of molecules that are traditionally quite challenging to access via hydroacylation.  Taking another cue from our original proposal, we examined chiral non-racemic 2-aminopyridine derivatives for asymmetric induction in these hydroacylation reaction.  Although not yet synthetically useful, our preliminary results with the 2-aminopicoline derivative 30 are highly encouraging.

            Funding from the ACS-PRF in the Type G award has been instrumental in garnering the initial results that my career will no doubt be exploring for some time.  Please accept my sincere thanks for that support over the last two years.

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