Novel synthetic methods using photoexcited nitroarenes Raquel Sanchez 1 , Rory Mykura 2 , Esteban Matador 2 , Vincent Duong 1 , Baptiste Roure 1 , Lucrezia Angelini 1 , Rodrigo Carbajo 3 , Josep Llaveria 4 , Alessandro Ruffoni* 2, Daniele Leonori* 2 1 Department of Chemistry, University of Manchester, UK, 2 Institute of Organic Chemistry, RWTH Aachen University, Germany, 3 In Silico Discovery External Innovation, Janssen Research Development, Spain, 4 Global Discovery Chemistry, Janssen Research Development, Spain The synthesis of functionalized nitrogen heterocycles is integral to discover, manufacture and evolve high-value materials like drugs and agrochemicals. The availability of effective strategies for heterocycle synthesis often biases the frequency of specific ring systems over others in the core structures of bioactive leads. For example, while the six- and five-membered piperidine and pyrrolidine are widespread in medicinal chemistry libraries, the seven-membered azepane is essentially absent and this leaves open a significant area of three-dimensional chemical space .[1] Here we report a strategy that addresses this challenge and prepares complex azepanes from simple nitroarenes. This modular approach relies on a photochemical dearomative single-atom skeletal editing centred on the conversion of the nitro group into a singlet nitrene. This process is mediated by blue light, occurs at room temperature and transforms the six-membered benzenoid framework into a seven-membered ring system. A following hydrogenolysis provides the azepanes in just two steps. The retrosynthetic logic behind this approach allows direct translation of the nitroarene ortho, meta and para substitution pattern into the ones of the saturated azepane and thus streamlines access to poly-functionalised systems difficult to prepare by any other method. We have demonstrated the utility of the strategy with the synthesis of several azepane analogues of piperidine drugs available on the market and by comparing the binding poses of the drugs bound to their targets with those of the azepanes obtained via docking. Our group has also discovered that nitrobenzenes and amines can be directly converted into ortho- phenylenediamines without the need for ortho-halogenation and following stepwise synthetic manipulation. This strategy occurs under simple blue light irradiation and introduces an alternative retrosynthetic tactic whereby the amine coupling partner “seems” to displace the nitro group that shifts to its ortho position while being reduced and amidated in one-pot process. Mechanistically, this process capitalises on the conversion of nitrobenzenes into the corresponding single nitrenes, that undergo a series of N-insertion, electrocyclic ring expansion, amine addition and electrocyclic ring contraction en route to the ortho-phenylenediamines. [2]
References 1. Vitaku, E., Smith, D. T., Njardarson, J. T. J. Med. Chem. 2014 , 57 , 10257. Mykura, R. # , Sanchez, R. # , Matador, E. # , Duong, V., Varela, A., Ruffoni, A., Leonori, D. Nat.Chem accepted. 2. Sanchez, R., Roure, B., Ruffoni, A., Leonori, D. Chem accepted
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