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Reports: DNI153951-DNI1: Facile Access to Vicinal Amino-Heteroatom Functionalities from N-X Bonds

Qiu Wang, PhD, Duke University

Scientific goals: The objective of this project is to develop novel amination strategies of nitrogen-halide bonds (N-X) to achieve a general and modular approach to access vicinal amino-heteroatom groups, such as 1,2-aminohalides, aminoalcohols, and diamines, all of which are important structural and functional motifs in catalyst ligands, chiral auxiliaries, as well as naturally occurring and biologically active molecules.

Progress: During the first year, we have focused on the development of a direct and modular approach to ortho-haloaminoarenes by aryne insertion reaction into nitrogen-halide bonds (Scheme 1). This transition-metal-free transformation displays a broad substrate scope of arynes, good compatibility with functional groups, and high regioselectivity. This method also overcomes limitations in previous methods for the synthesis of ortho-haloaminoarenes. With the importance of ortho-haloaminoarenes in pharmaceuticals, agrochemicals and catalysis, this general and efficient method, with its operational simplicity, presents great potential for its applications in organic synthesis, medicinal chemistry and drug discovery.

Scheme 1.

We established a one-pot protocol starting from amines for the synthesis of ortho-haloaminoarenes, which involved the formation of N-haloamine with N-halosuccinimide (NCS), followed by an insertion reaction with highly reactive benzyne intermediate generated in situ by CsF-mediated 1,2-elimination of 2-(trimethylsilyl)phenyl triflatetriflate (Scheme 2).

Scheme 2.

Furthermore, we found that the insertion reaction with more reactive N-chloro, N-bromo and N-iodoamines were more efficient under the TBAF-mediated aryne formation at room temperature, in comparison to the CsF-mediated conditions (Scheme 3).

Scheme 3.

In addition, both protocols were found effective on a broad range of aryne intermediates (Scheme 4). Arynes bearing multiple substitutions were well tolerated, giving a high level of regioselectivity. A significant pattern could be observed regarding substitution effects for these substrates, as the CsF-based protocol was found to be much more effective for electron-deficient arynes, whereas the TBAF-mediated protocol significantly favored more electron-rich arynes.

Scheme 4.

As aryl halides are one of the most frequently used synthetic handles in cross-coupling reactions to construct a variety of functionalized arenes, we also described representative transformations of the ortho-haloaminoarenes to highlight their utility for rapid access to diversely functionalized aminoarene derivatives (Scheme 5).

Scheme 5.

Impact: with the PRF funding in the past year, our progress on this project has several impacts: (1) it achieved a rapid and modular method to access ortho-haloaminoarenes; (2) it enabled us to build and test a set of hypotheses to significantly expand the scope of amination chemistries enabled by nitrogen-heteroatom bonds; and (3) it laid the foundation for future work on the synthesis and biological studies of biologically active ortho-functionalized aminoarenes.