Reports: ND153767-ND1: Insertion Reactions of Diarylcarbenes for the Assembly of Complex Organic Molecules

Jared T. Shaw, University of California, Davis

During the third and final year of funding from no-cost extension, we hit several milestones. First, we published a full account of our work in the synthesis of benzodihydrofurans, following up on our initial communication in this area. Second, we have completed most of the experiments for the next three publications. The first one to be submitted will be a communication on the synthesis of indolines, indanes, and benzodihydrothiophenes, which will be submitted later this year. The next will be a follow up to our initial paper on ester formation in which we described broader results with one particular reagent that we think serves as a safer alternative to diazomethane for routine esterifications. Finally, we have completed most of the necessary work on a tandem dipolarcycloaddition/rearrangement sequence and anticipate publishing this work early in 2018. All told, work conducted during the funding period will have supported, in whole or in part, experiments leading to six publications. Finally, the results gained during years one and two of the funding period were used as the basis for the submission of a grant (R01) for the 10/5/16 deadline for NIH/NIGMS. This application was well-received, got a score that was favorable (yet not fundable), and was recently (7/5/17) re-submitted.

While the intramolecular C-H insertion reactions to form 5-membered rings are well-developed for benzodihydrofurans, we made significant advances in three other substrates. At the time of the last report, we had made some advances with indanes, and have now extended that success to indolines and benzodihydrothiophenes. These substrates are significant because they are almost absent from the literature for acceptor-substituted carbenes due to the Lewis basicity and metallo-philicity, respectively, of basic nitrogen and thioethers. We have also documented a high level of chemoselectivity with a substrate that has a benzylic alcohol that neither interferes with insertion nor undergoes oxidation in the presence of manganese dioxide.

We recently expanded the insertion reactions to form 6 membered rings, which are significantly more challenging and less-represented in the literature. That said, each of these ring systems appears broadly in both natural products and drug-like molecules. The additional carbon unit places a heteroatom (oxygen or nitrogen) four bonds away from the carbene center, opening up the possibility of direct nucleophilic attack and ylide formation. Due to the reduced electrophilicity of the donor-donor metallo-carbene, we see insertion occur faster than direct attack, and have successfully synthesized chromans by this route. The analogous tetrahydroisoquinolines are in progress.

We have also pursued two reactions that do not involve metal carbenes. First, we have nearly completed a substrate table for the addition of the diazo intermediates to alkynes, which form pyrazoles that undergo an interesting ring-contracting rearrangement. We have also collaborated with the Tantillo group (UC Davis) on computational work to support this project. The student working on this area recently took a break to get the benzodihydrothiophenes done for the impending paper, after which she will finish this off. Second, we expanded our work with the formation of diazo compounds in situ and their use for esterification. During the course of the studies for our first paper, we noted that the hydrazone of 2,4,6-trimethylbenzaldehyde can be formed in high yield without competing azine formation, undergoes rapid oxidation, and converts a wide variety of carboxylic acids to esters. As such, we see this reagent as a replacement for diazomethane, which was once common in organic chemistry labs and is now avoided due to safety concerns. This work was advanced over the summer in conjunction with a visiting undergraduate that was part of the UC-HBCU partnership for which I serve as PI and director. The final substrates are being examined now, and the paper will go out later this year.

In summary, the two and a half years of funding from the ACS-PRF has fulfilled the mission of catalyzing new research directions in my research group. I anticipate that the impact will be felt for years to come as more funding is acquired and the project expands.