From Alkylarenes to Anilines via Site-Directed Carbon-Carbon Amination

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Our paper “From Alkylarenes to Anilines via Site-Directed Carbon-Carbon Amination” published in Nature Chemistry can be found here:

The development of new nitrogenation transformations to construct N-containing compounds from simple industrial chemicals is our major goal in Jiao’s group at Peking University. The focus of this research is, especially, on the functionalization of unstrained carbon-carbon bonds.

As anilines play an important role in the academic and chemical industrial fields, recently, C-H primary amination of electron-rich arenes to produce anilines has made a breakthrough. However, there are limitations to this strategy; the amination of electron-deficient arenes remains a challenging task and the amination of electron-rich arenes has limited control of regioselectivity, with the formation of meta-aminated products being particularly difficult.

Inspired by the classical Hock process, we thus further envisaged whether the substituted anilines could be synthesized via site-directed de-alkylating C-C amination of alkylarenes such as cumene (Scheme 1), then it may address the above problems in the C-H primary amination of arenes. To the best of our knowledge, it is highly attractive but still unknown.

Scheme 1

Alkylarenes is a group of chemicals readily available  from coal and crude oil. The study on the C-H functionalization of  alkylarenes has been well developed in forming carbon-carbon and carbon-heteroatom bonds. However, further research on the thermodynamic data indicates that the site-directed de-alkylating C-C activation of alkylarenes remains previously elusive owing to the higher BDEs (Scheme 2). Additionally, the Csp2-Csp3 bonds are surrounded and hindered by more C-H and C-C bonds. Therefore, such C-C σ-bonds are thermodynamically stable and kinetically inert which in turn has led to direct C-C bond functionalization being underdeveloped.

Scheme 2

At the beginning of this project, we explored and synthesized many active nitrogenation reagents for this transformation. However, the desired C-C amination product could not be detected. Inspired by our previous mechanistic study of our nitrogenation strategy, we recognized that a selected acid additive might proton the azido intermediates and enable their rearrangement. Interestingly, the target product was detected with the addition of TFA in the reaction system in the presence of DDQ oxidant. Excitingly, the simple secondary alcohols could also be efficiently transformed into the anilines in n-hexane with acid as an additive instead of solvent (Scheme 3). It also demonstrates the potential application in the depolymerization of lignin. This chemistry provides an opportunity for the late-stage transformation of alkyl group to amino group at the aryl rings. Moreover, after the persistent investigation of related literature, we found some more preferable synthetic application with regard to the regioselectivity and compatibility of the Friedel-Crafts alkylation of arenes followed by de-alkylation pathway when compared with traditional nitration/reduction process.

Scheme 3

Overall, a variety of readily available alkylarenes and secondary alcohols could be efficiently transformed into the corresponding anilines via this site-directed C-C amination process. It provides an alternative advance in the development of amination chemistry and demonstrates great potential in academic and industrial preparation of substituted anilines. Many new transformations based on this process are under investigation in our laboratories.

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