Benzo-fused nitroheterocycles via benzannulation with nitro-1,3-butadienes: synthesis and application.
Creators: name: PAGANO, ANGELA
Publisher: name: Universit� degli studi di Genova
Year: 2020

description: Nitroindoles, despite their scanty occurrence in nature, are attractive reactive intermediates in organic synthesis thanks to the coupling of the properties of the nitro group and of the indole moiety.[1] While nitration of the pyrrole nucleus can be easily achieved, nitration on the benzene ring represents a more challenging target. Ex-novo construction of the pyrrole onto a functionalized benzene derivative is, by far, the synthetic strategy most frequently exploited to access indole nitrated on the benzene ring. Herein, we expand the synthetic access to such nitroindoles reporting an original protocol based on the ex-novo construction of the benzene ring onto pyrrole employing mono- or dinitro-1,3-butadienes as powerful C4 benzannulating agents. This appealing, metal-free process characterized by high atom economy and mild reaction conditions allows to synthesize nitroindoles characterized by patterns of substitution not easy to be obtained otherwise.[2] Such unusual substitution patterns have demonstrated to be promising for further elaborations, i.e. the application of the classic Cadogan reaction conditions in order to access pyrrolocarbazoles with a rarely reported ring fusion.[3] 
A very interesting side project regarded the synthesis of a series of atropisomeric naphthyl nitroindoles with two stereogenic axes originated from steric hindrances forcing the naphthyl groups out of the indole plane; the asymmetry of the indole ?spacer? makes both the syn and anti diastereoisomers entail an atropisomeric pair. A stereodynamic analysis of such new atropisomeric nitroindoles has been done resolving atropisomers by chiral HPLC and determining their absolute configuration and the rotational barriers of the indole?naphthyl axes.[4]
This work, within an Erasmus+ project, demonstrates also the photochemical activity of electron donor-acceptor (EDA) complexes providing a way to generate radicals under mild conditions. This strategy has recently found application in chemical synthesis. Reported methods classically relied on the formation of intermolecular EDA complexes. Herein, we further expand the synthetic utility of this strategy demonstrating that indole-tethered ynones form an intramolecular electron donor-acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols.[5] This initiates a novel radical chain sequence, based on dearomatizing spirocyclization with concomitant C?S bond formation. Sulfur-containing spirocycles are formed in high yields using this simple and mild synthetic protocol, in which neither transition metal catalysts nor photocatalysts are required. The proposed mechanism is supported by various mechanistic studies, and the unusual radical initiation mode represents only the second report of the use of an intramolecular electron donor-acceptor complex in synthesis.

[1] G. W. Gribble, in Prog. Heterocycl. Chem., Vol. 31, Elsevier, 2020, pp. 83-117.
[2] A. Pagano, M. Mancinelli, L. Bianchi, G. Giorgi, M. Maccagno, G. Petrillo, C. Tavani, Tetrahedron 2019, 75, 4506-4515.
[3] A. Benzi, L. Bianchi, M. Maccagno, A. Pagano, G. Petrillo, C. Tavani, Molecules 2019, 24, 3802.
[4] A. Pagano, E. Marotta, A. Mazzanti, G. Petrillo, C. Tavani, M. Mancinelli, Synlett 2018, 29, 2161-2166.
[5] H. E. Ho, A. Pagano, J. A. Rossi-Ashton, J. R. Donald, R. G. Epton, M. J. James, P. O'Brien, R. J. K. Taylor, W. P. Unsworth., Chem. Sci. 2020, DOI: 10.1039/c9sc05311e.