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Dearomatization Reactions of Indoles to Access 3D Indoline Structures Hussein Abou-Hamdan, Cyrille Kouklovsky, Guillaume Vincent

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Dearomatization Reactions of Indoles to Access 3D Indoline Structures Hussein Abou-Hamdan, Cyrille Kouklovsky, Guillaume Vincent Dearomatization Reactions of Indoles to Access 3D Indoline Structures Hussein Abou-Hamdan, Cyrille Kouklovsky, Guillaume Vincent To cite this version: Hussein Abou-Hamdan, Cyrille Kouklovsky, Guillaume Vincent. Dearomatization Reactions of Indoles to Access 3D Indoline Structures. SYNLETT, Georg Thieme Verlag, 2020, 31 (18), pp.1775-1788. 10.1055/s-0040-1707152. hal-02960505 HAL Id: hal-02960505 https://hal.archives-ouvertes.fr/hal-02960505 Submitted on 12 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Synlett Account / Synpacts Dearomatization Reactions of Indoles to Access 3D Indoline Structures Hussein Abou-Hamdan a Cyrille Kouklovsky a Guillaume Vincent*a a Université Paris-Saclay, CNRS Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO) 91405, Orsay, France91405, Orsay France [email protected] Click here to insert a dedication. Received: procedure involved the oxidation of the phenol into a highly Accepted: Published online: electrophilic phenoxenium species which is immediately DOI: attacked by the nucleophilic indole. Unfortunately, all our Abstract This account summarizes our involvement in the development of attempts met with failures leading to mixtures of intractable dearomatization reactions of indoles that has for origin a total synthesis oxidized products. Yao was more persistent than us. Few years problematic. We present the effort from our group to obtain 3D-indolines after our attempts, his research group was able to achieve the scaffold from the umpolung of N-acyl indoles via activation with FeCl3, to the oxidative spirocyclizations of N-EWG indoles and via the use of oxidative cyclization of tryptophan-tyrosine diketopiperazine 3 electrochemistry. leading to over-oxidized benzofuroindoline 5 which was eventually converted into ent-azonazine (4).8 Key words Indole, dearomatization, indolines, FeCl3, radical chemistry, electrochemistry Introduction Indoline derivatives are three dimensional structures of interest in the context of drug discovery.1 In this context, the overall purpose of our research program is the development of new synthetic methods for the dearomatization of the indole nucleus to access such structures (Scheme 1).2 A dearomative process allows to transform a plain and achiral compound into a chiral scaffold.3 Scheme 1 Access to indolines of interest via the dearomatization of indoles. The starting point of our endeavors in this research field was our desire to perform the total synthesis of ent-azonazine (4),4 a benzofuroindoline-containing5 natural product which biosynthesis implies the oxidative coupling of the indole and phenol parts of diketopiperazine 3 (Scheme 2). Inspired by the impressive Harran’s total synthesis of diazonamide A (2) via benzofuroindoline 2 from tripeptide derivative 1,6 we planned to perform a bioinspired dearomative oxidative cyclization Scheme 2 Hypervalent-mediated oxidative coupling of indoles and phenols mediated by a hypervalent reagent such as PIFA or PIDA.7 This Template for SYNLETT © Thieme Stuttgart · New York 2020-11-12 page 1 of 13 Synlett Account / Synpacts towards the benzofuroindoline core of diazonamide A and azonazine. difficult task that we are currently investigating. In the meantime, we relied on the use of a N-acyl chiral auxiliary derived from The Harran’s oxidative coupling between indoles and phenols proline on 12 that delivered a modest diasteroselectivity. mediated by PIDA is unfortunately quite substrate dependent. Nevertheless, after separation, the major diastereoisomer 13a Not only the oxidative cyclization of diketopiperazine 3 toward could be converted into a benzofuroindoline 11a with a 94% ee. azonazine (4) is capricious, but an intermolecular version also invariably failed in our hands. While our incapacity to form the benzofuroindoline framework of azonazine was frustrating at that time, it was retrospectively an opportunity. It encouraged us to initiate a new research program which led us to investigate alternative dearomatization reactions of indoles. After having considered various tactics without success, we turned our attention towards the reversion of polarity of indoles (Scheme 3). Rather than using the innate C3-nucleophilicity of indoles, our dearomatization strategies mainly relies on an umpolung process leading to the generation of electrophilic indolenium derivatives which can be further functionalized.9 Scheme 3 Generation of electrophilic indoles. 1. Activation of N-acyl indoles with FeCl3 1.1 Hydroarylation of N-acyl indoles In our effort toward the synthesis of azonazine, we aimed to discover a general method to achieve a regioselective dearomative introduction of aryl groups at the C3-position of indoles1b and eventually to access benzofuroindolines. As we Scheme 4 Regioselective hydroarylation of N-acylindoles by phenols inspired already discussed it in a previous Synpact article,5a we were from Nakatsuka and co-workers. inspired by a report from Nakatsuka and co-workers, which described the regioselective C3-hydroarylation of N-Ac indoles 6 Since a limited number of substrates were investigated by into 3-arylindolines 8 mediated by a large excess of AlCl3 with the Nakatsuka and since we found that FeCl3 is a better promoter creation of one stereogenic center in a racemic form (Scheme than AlCl3, we decided to perform a thorough investigation of the 4).10 Very interestingly in this reaction, the C3-position of N-Ac hydroarylation of N-Ac indoles 6 (Scheme 5).12 Various electron- indole 6 could be formally considered as electrophilic.9 This work rich arenes 7 such as anisole, thioanisole, trimethoxybenene, was published in a journal10a which is not widely access by the toluene, xylenes or naphtalenes could be employed as the community of synthetic organic chemists and was unfortunately nucleophilic entity leading to 3-arylindolines 8. Very unnoticed despite its very high synthetic potential. Nevertheless, interestingly, we were also able to add some heterocyclic this method seemed well suited to access benzofuroindolines 11. aromatic nucleophiles including N-Ts indole, 3- Unfortunately, the reaction could not proceed with phenols 9 as methylbenzofuran and thiophene derivatives. Concerning the nucleophiles in presence of AlCl3 as the promotor. Investigation substitution of the indole moiety, both electron-donating groups, of various Lewis acids resulted in the discovery of FeCl3 as a very halogens and electron withdrawing groups on the benzene part potent mediator of the hydroarylation of N-Ac indoles 6 by are tolerated. It is noticeable that the reaction is faster with phenols 9.11 The 3-(2-hydroxyphenyl)-N-Ac-indolines 10 electron-donating groups: while the reaction is finished is less obtained were then converted into benzofuroindolines 11. Since than 1 hr with a methoxy group at the C5-position, 48 hrs are the direct oxidation of 10 did not lead to the corresponding N-Ac necessary for a nitro group at the same position. The C3-position benzofuroindolines, we removed the acetyl group in acidic tolerates phenyl, benzyl as well as alkyl substituents with conditions. Subsequently, oxidation of the indoline with TPAP functional groups such as ester or bromide. However, the and NMO or diisopropylazodicarboxylate (DIAD) led directly to presence of a nitrogen-containing group on the C3-alkyl chain the expected benzofuroindolines 11 in which indeed the fused completely inhibits the reaction. benzofurane and indoline parts are cis. The development of a catalytic enantioselective version of this hydroarylation reaction is highly desirable. However, it is a Template for SYNLETT © Thieme Stuttgart · New York 2020-11-12 page 2 of 13 Synlett Account / Synpacts indolines 19 were obtained (Scheme 7).15 Simultaneously to this work, Nishina reported the same transformation with boron trifluoride etherate in hexafluoro-iso-propanol (HFIP) but probably with a distinct mechanism since in the case of a 3- substituted indole, the 2-aryl-indoline is also obtained in a modest yield instead of the 3-arylindoline of type 8.16 We then gathered mechanistic insights of this general hydroarylation reaction which requires 2 equivalents of FeCl3.17 In situ IR analysis and the isolation of a FeCl3-(skatole N-Ac)2 complex suggests a pre-activation of the carbonyl of N-Ac skatole by FeCl3 such as in Ia via respective collaborations with Alejandro Perez-Luna from Pierre and Marie Curie University of Paris-6 and Nourredine Ghermani of the Faculty of pharmacy of Université Paris-Sud (Scheme 8). This activation would probably increase the delocalizing of the nitrogen lone pair into the carbonyl system. Thus the nitrogen lone-pair would be less delocalized into the enamide system and therefore the electron density at the C3 position would decrease. High resolution X-ray diffraction of the FeCl3-(skatole N-Ac)2 complex and of N-Ac skatole allowed us Scheme 5 General regioselective C3-hydroarylation of N-Ac indoles mediates by FeCl3. to experimentally observed that the coordination of FeCl3 to the acetyl group
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