Synthetic organic chemistry is typically a wasteful process, reducing the number of steps taken allows for some alleviation of its ecological impact by consuming fewer resources and creating less waste. Multi-functionalized molecules allow for the modification of molecules with concurrent introduction of another functional group inherently increasing the efficiency of transformations. Ynamides, one such multi-functionalized moiety, are nitrogen atom substituted alkynes in which the nitrogen atom is neighboring an electron withdrawing group. Ynamides have been used in synthesis of biologically relevant molecules and have been shown to behave similarly to alkynes when used in transition metal catalyzed reactions, allowing for the efficient creation of complex ring systems. Although ynamides have been in the focus of the chemical community for almost 20 years, halogenated ynamides have never been used in synthesis and have rarely ever been made despite their potential utility in the production of natural products or pharmaceuticals. Thus far, halogenated ynamides have been made via a two-step process that starts with the introduction of the alkyne moiety followed by alkyne halogenation. In this project, the goal was to synthesize halogenated ynamides in a one-step haloalkynylation utilizing existing methodology that uses hypervalent iodonium salts such as ethynyl(phenyl)iodonium triflate but including a halide on the alkyne moiety. After initial reaction optimizations, our newly developed protocol has proven highly successful, yielding up to 70% product of aniline derived haloalkynes. Issues arose upon extending the scope to other starting materials such as benzylic and aliphatic amines, however. Based on preliminary data, our reaction seems to proceed well with benzylic sulfonamides but product recovery has so far been unsuccessful calling the inherent stability of benzylic haloynamides in question. In order to turn haloalkynylation into a generally applicable method, it is important to understand the structural requirements that contribute to the stability of halogenated ynamides as well as potential side reactions that might lead to product decomposition. To allow for a guided approach to the expansion of the scope of our newly developed reaction we are, in addition to our synthetic efforts, embarking on computational studies to further our understanding of the stability of haloynamides and how to harness their power.

One-step haloalkynylation of amines

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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