Oxidative (3 + 2) Cycloaddition Reactions of Diaza-Oxyallyl Cationic Intermediates and Indoles for the Synthesis of Imidazoloindolines Devendar Anumandla, Arjun Acharya, and Christopher S. Jeffrey* Department of Chemistry, University of Nevada, Reno, Nevada 89557-0216, United States * S Supporting Information ABSTRACT: An oxidative diaza-(3 + 2) cycloaddition reaction of simple urea derivatives with substituted indoles has been developed. This transformation provides rapid access to highly functionalized imidazoloindolines that are repre- sented in bioactive compounds. The reported method is compatible with a wide variety of functional groups and directly provides unique heterocyclic scaffolds from indoles and a simple urea derivative. T he indole core is broadly represented in numerous biologically active natural products such as alkaloids and pharmaceuticals. 1-6 2,3-Diamino indole analogues have dem- onstrated promising biological activity, bringing significant motivation to develop methods to construct this heterocyclic motif. Imidazo[4,5-b]indole derivatives exhibit significant anti- inflammatory, antibacterial, and antifungal activities (Figure 1). 7-9 6H-Indolo[2,3-b]quinoxaline analogues comprise an important class of DNA intercalating agents 10-12 and possess a broad spectrum of pharmacological activities that includes antiviral, anticancer, antimutagenic, and antiarthritic activities. There are only a few reported methods to construct the diamino indoles, and these approaches often involve multistep processes using organoazide derivatives. 13-17 Despite the pharmacological importance of 2,3-diamino indole derivatives, a straightforward synthesis of 2,3-diamino indoles has yet to be realized. Dearomative (3 + 2) cycloaddition reactions provide direct means to 2,3-difunctionalize indole nuclei. 18, 19, 25 Recently, Wu and co-workers reported dearomative (3 + 2)- cycloaddition reactions of substituted indoles and oxyallylic cations to provide [2,3-b]-cyclopentanone fused indoline scaffolds. 19 Our group has reported a series of papers that describe the generation and the aza-(4 + 3) cycloaddition reaction of a putative aza-oxyallylic cation to provided highly functionalized caprolactam intermediates. 20-22 Later we found that diaza-oxyallylic cations could be generated by either dehydrodehalogenation of N-chlorourea derivatives or later by the direct oxidation of N,N′-dibenzyloxy urea and that these intermediates efficiently reacted with aromatic and nonaromatic cyclic dienes and, in the latter case, acyclic 1,3-dienes. 23,24 Recently, our group along with Wu and co-workers found that aza-oxyallyl cationic intermediates underwent a dearomative (3 + 2) annulation reaction with 1,3-disubstituted indoles 5. 25 This discovery led us to consider the development of a dearomative (3 + 2)-heteroannulation reaction of a diaza- oxyallylic cation and substituted indoles 5 (Scheme 1). Building on our group’s previous development of an oxidative 1,4- diamination of 1,3-dienes, we envisioned that dearomative cycloaddition of the indole 5 with oxidatively generated diaza- oxyallyl cation 3 would be a concise approach to access the 2,3- diaminoindoles 9. Our previous investigations identified that the desired diaza- oxyallyl cationic intermediate 3 could be oxidatively generated from urea 1 by using (diacetoxyiodo)benzene in the presence of a base and the diene reactant. Likewise, oxidative (3 + 2) reactions of 1,3-dimethylindole 10 with N,N-dibenzyloxy urea 1 and PhI(OAc)2 (BAIB) in 2,2,3,3-tetrafluoropropanol (TFP) furnished the desired cycloadduct in 21% yield. Further optimization of this reaction revealed that the addition of the oxidant (BAIB) in CH 3 CN improved the yield to 58%, likely due to competitive oxidation of the indole by BAIB. 26 Upon extensive screening of reaction conditions, the slow addition of BAIB (1.5 equiv) in CH 3 CN to the mixture of base (TFP-Na, 1.2 equiv), indole (1.0 equiv), and urea (2.0 equiv) in TFP over 3 h at 0 °C was found to be the optimal reaction conditions, Received: December 12, 2015 Figure 1. Examples of biologically active [2,3-b]- and [4,5-b]-indole compounds and natural products. Letter pubs.acs.org/OrgLett © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.5b03527 Org. Lett. XXXX, XXX, XXX-XXX