Golden Face of Phosphine: Cascade Reaction to Bridgehead Methanophosphocines by Intramolecular Double Hydroarylation Rachida Babouri, †,‡ Lancine ́ Traore, †,§ Yves-Alain Bekro, § Victoria I. Matveeva, ∥ Yulia M. Sadykova, ∥ Julia K. Voronina, ∥ Alexander R. Burilov, ∥ Tahar Ayad, ⊥ Jean-Noë l Volle, † David Virieux,* ,† and Jean-Luc Pirat* ,† † ICGM, ENSCM, CNRS, Univ Montpellier, Montpellier, France ‡ Laboratoire d’Obtention de Substances Thé rapeutiques (LOST), Université Mentouri-Constantine, Dé partement de Chimie, Campus Chaabet Ersas, 25000 Constantine, Algeria § Laboratoire de Chimie Bio Organique et de Substances Naturelles, UFR-SFA, Université Nangui Abrogoua, 02 BP 801 Abidjan 02, Cô te d’Ivoire ∥ Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, Kazan 420088, Russian Federation ⊥ Institut de Recherche de Chimie Paris, PSL Research University, Chimie ParisTech − CNRS, 75005 Paris, France * S Supporting Information ABSTRACT: Reported herein is the first example of a gold-catalyzed cyclization of bis(arylmethyl)ethynylphosphine oxides. This represents an original approach to bridgehead methanophosphocines 1, eight- membered heterocycles. Gold catalyst in combination with triflic acid activates alkyne and induces a double hydroarylation. Mechanistic studies suggest that the reaction proceeds stepwise, forming first the 1H-isophosphinoline 2-oxide 5. Reduction and protection of the corresponding phosphine oxides 1 described herein also highlight the effectiveness of our approach to this new class of electron-rich ligands. I mportant toolboxes of organic transformations rely on the use of transition-metal catalysts. Among them, gold catalysis has emerged in the past recent years as an expanding field of research. 1 Compared to other common Lewis acids or transition metals, gold complexes show high preferences for unsaturated C−C bonds (e.g., alkenes, alkynes) because they are less oxophilic than other Lewis acids. 2 Therefore, gold predominantly activates C−C π-systems, making them prone to be attacked by nucleophiles including the weakest ones. 3 Established methodologies are using this unique catalytic activity of gold complexes to increase molecular complexity in mild reaction conditions. In this context, activation of alkynes by gold catalysts has emerged as a powerful method for the efficient synthesis of carbo- and heterocycles, including barely accessible ring systems. 4 As carbophilic Lewis acids, gold complexes may even activate electron-poor C−C π-bonds. 5 In a similar fashion, gold can also promote Friedel−Crafts-type additions formerly resulting on C−H hydroarylation of the alkynes. 6 Inspired by the work of François Mathey et al. on phosphanorbornadienes, we were interested in the formation of bridgehead phosphorus derivatives through an amenable approach. The synthesis of such phosphines is sparsely described. 7 Mathey et al. have probably developed to date one of the most straightforward syntheses of monodentate 1- phosphanorbornadienes from the formal [4 + 2]-cycloaddition of 1-arylphospholes and disubstituted alkynes at 160 °C (Figure 1). When unsymmetrical alkynes were used, the regioselective formation of a specific adduct was clearly affected by the nature of the alkyne, and both isomers were generally obtained, making this method not completely generalizable. We were interested in an approach to conformationally restrained bridgehead phosphine derivatives. The 1- phosphabicyclo[3,3,1]-nonane core 1 (methanophosphocine core) was originally described by Issleib in the late seventies through the radical cyclization of unsaturated and pyrophoric Received: October 31, 2018 Figure 1. Bridgehead phosphine synthesis. Letter pubs.acs.org/OrgLett Cite This: Org. Lett. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.8b03474 Org. Lett. XXXX, XXX, XXX−XXX Downloaded via UNIV OF SOUTH DAKOTA on December 18, 2018 at 17:32:45 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.