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Reports: ND152040-ND1: The Generation of Acylnitrenes Via Oxidation of Nitriles

Liming Zhang, University of California (Santa Barbara)

Due to difficulty encountered in the original proposed project, with the permission from the PRF manager, we changed the research topic to “the generation of acylnitrenes via oxidation of nitriles”. As shown in Scheme 1, C-H insertion by nitrene is a highly versatile, efficient and straightforward approach for the construction of C-N bonds, which is ubiquitous but often difficult to construct. However, the state of the art with this approach is the elegant chemistry developed by Du Bois, where a carbamate or a sulfamate is used to access a reactive Rh nitrene intermediate under oxidative conditions. However, it does not work with acylnitrenes due to the competing and often dominating Wolff-type rearrangement (see the bottom half of the scheme). We propose a novel approach via a metal-catalyzed oxidation of a nitrile (see the top half of the scheme), where the Wolff-rearrangement could be avoided due to the lack of appropriate orbital alignment. This approach would substantially expand the utility of the nitrene C-H insertion chemistry in organic synthesis and offer an expedient approach to the construction of nitrogen-containing natural products and bioactive compounds.

For nearly a year Dr. Guojun Pan was supported by this grant and focused on exploiting this design. This ambitious and rarely precedent strategy was highly challenging and proven to be difficult to implement. For example, we tried intramolecular strategies (Scheme 2) to facilitate the oxidation by tethering an oxidant to the cyano group. Unfortunately, no desired product was detected. Other strategies to force the requisite h2-coordination of metal to cyano group were also examined albeit without success. Partly due to the lack of progress Dr. Pan left in March 2014 for an industry job in China. Other graduate students were later supported by this grant and further worked on the project. At this stage little progress could be made. It is our intention to find additional support to try other strategy to implement this important transformation.

At the meanwhile, consistent with the idea of new direction, this grant partially funded a new project, which concerned oxidation of alkynes into ketenes via Ru catalysis and was hence different from our continuing homogeneous gold catalysis. As shown in Scheme 3, oxidation of Ru vinylidenes, in situ-generated from terminal alkynes and a Ru catalyst, into ketenes is realized using tethered mild sulfoxides. The net result is a Ru-catalyzed oxidative transformation of terminal alkynes into highly valuable ketenes. Moreover, the ketenes generated in this paper are demonstrated to undergo the characteristic ketene [2+2] cycloaddition reactions with tether alkenes and external imines, yielding synthetically versatile bicyclic cyclobutanones and β-lactams, respectively. Although Ru vinylidene has been extensively studied, this novel oxidation opens a new approach to further exploring its synthetic utility.

In conclusion, although we have not been able to generate metal acylnitrene intermediates and study their synthetic utility, this ND grant provides me valuable opportunities to explore new research topics and my graduate students and postdoctoral associates needed financial support to gain research experience with a variety of metal catalysis.