Reactant-induced photoactivation of in situ generated organogold intermediates leading to alkynylated indoles via Csp2-Csp cross-coupling

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Gold(I) complexes can hardly perform oxidative additions with organic halides in cross-coupling reactions due to a high Au(I)/Au(III) redox potential.1 To address this issue, some strategies have been considered, including the use of an external strong oxidant,2 photoredox catalysis3a-c or a set of bidentate hemilabile ligands.4 However, this issue remains challenging nowadays and, in this context, the photoactivation of a metallic center represents an attractive solution.5 In 2019, our team developed a gold-catalyzed alkylynative cyclization of o-ethynyl-phenols to form 2,3-substituted benzofurans6 through the photo-triggered oxidative addition of an alkyne iodine to a vinylgold(I)intermediate. This approach was recently extended to the behaviour of o-ethynyl-tosylanilines under similar conditions.7 Surprisingly, we observed that for this class of substrates cross-couplings occur without exogenous photocatalyst, while the corresponding phenols provided poor yields. The scope of this transformation has been explored with Fen Zhao, one of the associate authors, with the support of Dr. Wided Hagui and Maria Ballarin-Marion, 1st year PhD student. The process tolerates a large variety of electron withdrawing and donating functional groups leading to a wide range of 2,3-disubstituted indoles. Our methodology notably enables the cross-couplings of unusual electrophilic partners such as 2-iodoynamides, opening new perspectives for the synthesis of various building blocks including benzo[a]carbazole or oxazolone backbones after post-functionalization of the indole products.  

Figure 1. Gold(I) photocatalyzed alkynylative cyclization of ortho-alkynyl tosyl-anilines

Besides the high synthetic potential of this process, the difference in reactivity between the phenol- and the aniline-based substrates appeared very puzzling. To rationalize it, I focused on elucidating the mechanism with the crucial and challenging issue to address: which substance, in the case of indoles can act as a photosensitizer while neither the substrates nor the vinylgold(I) intermediate absorb the blue LED light? I have always been fascinated by puzzles and enigma and then I considered this study as a challenging task where merging photochemistry and physical chemistry to organic synthesis was mandatory to find the solution.  After considering the substrates, we examined the reactant formed by the action of the base on the NHTs group and, as simply as dissolving the related salt in the MeCN, we observed a strong luminescence (See Figure 2.) that provided us the first warning hint about the photocatalyst identity.

Figure 2. Optical properties of the aggregate 

Discussions with Dr. Vincent Corcé and absorption experiments led us to consider this photoactive substance formed presumably by deprotonation not as a lonely molecule but as a supramolecular assembly that will be at the basis of the photoexcitation. This behaviour of supramolecular aggregate was confirmed by DOSY NMR experiments performed by Pr. Stéphanie Delbaere and Dr. Jérôme Berthet and supported by X-Ray diffraction analysis of the aggregate.  To confirm this hypothesis and after discussions with Pr. Ludovic Jullien, Dr. Agathe Espagne and Dr. Thomas Le Saux, luminescence decay and Stern-Volmer experiments were performed and fitted with the hypothesis of an energy transfer.
The next step was to determine how this energy transfer occurs. To do so, Stern-Volmer experiments were performed at different temperatures in order to modulate the solvent viscosity. We notably observed that a lower temperature have a beneficial effect on the quench efficiency, which is in line with a static quenching process, where the photosensitizer and the substrate form an association complex prior to light absorption to provide the key excited vinylgold(I) complex able to achieve the oxidative addition.

Another interesting point was the effect of the halogen bond with the iodoalkyne partner8 on the optical properties of the aggregate. We assumed that this interaction was a driving force gathering the excited metallic center to the key Csp-I bond to be cleaved but further experiments revealed that the energy transfer was fourfold more efficient due to this interaction!

For me, the most remarkable aspect of this reaction is the strong synergy that exists between each part of the catalytic system, the aggregate being the main actor endowing the roles of ligand, dye, and substrate!

1 Hopkinson, M., N., Tlahuext-Aca, A. & Glorius, F., Acc. Chem. Res. 2016, 49, 2261-2272.
2 Hopkinson, M., N., Gee, A., D. & Gouverneur, V.,  Chem. Eur. J. 2011, 17, 8248-8262.
3  a: Xia, Z., Khaled, O., Mouriès-Mansuy, V., Ollivier, C. & Fensterbank, L., J. Org. Chem.  2016, 81, 16, 7182–7190.; b : Sahoo, B., Hopkinson, M., N. & Glorius, F.,  J. Am. Chem. Soc. 2013, 135, 55055508.; c : Shu, X.-Z.; Zhang, M., He, Y., Frei, H. & Toste, F. D., J. Am. Chem. Soc. 2014, 136, 16, 5844–5847.
4  Rigoulet, M., Thillaye du Boullay, O., Amgoune, A. & Bourissou, D., Angew. Chem. Int. Ed., 2020, 59, 16625–16630.
5   Sadek, O., Abdellaoui, M., Millanvois, A., Ollivier, C. & Fensterbank, L., Photochem. Photobiol. Sci. 2022, https://doi.org/10.1007/s43630-022-00181-8
6   Xia, Z., Corcé, V., Zhao, F., Przybylski, C., Espagne, A., Jullien, L., Saux, T. L., Gimbert, Y., Dossmann, H., Mouriès-Mansuy, V., Ollivier, C. & Fensterbank, L., Nat. Chem. 2019, 11 ,797–805.
7  Zhao, F., Abdellaoui, M., Berthet, J., Corcé, V., Delbaere, S., Espagne, A., Forté, J., Jullien, L., Le Saux, T.,
Mouriès-Mansuy, V., Ollivier, C. & Fensterbank, L., Nat. Commun. 2022, 13, 2295.
8    Dumele, O., Wu, D., Trapp, N., Goroff, N.   &   Diederich, F.,   Org. Lett.    2014,  16,   4722–4725.

Mehdi Abdellaoui

PhD student, Sorbonne Université