Radical-Mediated Dearomatization of Indoles with Sulfinate

Letter pubs.acs.org/OrgLett

Radical-Mediated Dearomatization of Indoles with Sulfinate Reagents for the Synthesis of Fluorinated Spirocyclic Indolines Dmytro Ryzhakov, Maxime Jarret, Régis Guillot, Cyrille Kouklovsky, and Guillaume Vincent* Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Equipe Méthodologie, Synthèse et Molécules Thérapeutiques, Univ. Paris Sud, CNRS, Université Paris-Saclay, 15, rue Georges Clemenceau, 91405 Orsay, Cedex, France S Supporting Information *

ABSTRACT: The dearomative introduction of trifluoromethyl and 1,1-difluoroethyl radicals, generated from their corresponding sulfinate salts, into the C2 position of indole derivatives allows the diastereoselective synthesis of threedimensional 3,3-spirocyclic indolines over C−H functionalized indoles.

T

Scheme 1. Radical-Mediated C−H Functionalization versus Dearomatization of Indoles

he indole nucleus is the major constituent of a large number of molecules with significant biological activity, including approved drugs or compounds in clinical trials. Therefore, the indole scaffold is an important structural unit for the discovery of new drug candidates.1 On the other hand, fluorine atoms and, in particular the trifluoromethyl unit (CF3) offer unique biological properties and are encountered in a high number of commercial medicines.2 The 1,1-difluoroethyl group is considered to be a metabolically stable bioisoster of the methoxy group in drug discovery.3 Finally, the pharmaceutical industry is in need of scaffolds containing saturations (sp3 carbons); three-dimensional drug candidates are more likely to succeed than flat ones.4 For instance, the spiroindoline scaffold is encountered in several medicinally relevant molecules.5 Dearomatization reactions are perfectly suited to achieve this goal, since they could transform rapidly achiral starting materials into chiral compounds with an important increase of complexity.6 Most of the time, dearomatization reactions rely on the innate nucleophilic character of indoles which react with electrophiles.5,7 We have recently described that the dearomatization of indoles could be possible via the generation of electrophilic indole intermediates.8 We now wish to study a radical-mediated approach.9 Over the years, several functionalization reactions of heteroarenes, including indoles, were reported which involve the addition of free radicals into a heteroaromatic substrate 1 which delivers a dearomatized intermediate I with a radical on the carbon adjacent to the newly formed bond (Scheme 1).10−12 Usually, this radical is then oxidized by single electron transfer (SET) into a carbocation II which is followed by a very fast aromatization event via elimination of a proton to yield functionalized heteroarene 2. In contrast, the challenge is to intercept carbocation II by a nucleophile before the aromatization step to obtain 2,3-difunctionalized indoline 3. Few reports,13,14 including our work,14a described the addition of radicals, generated from aziridines,13a oxaziridines,13b azides,13c or phenols,14 at C2 of indoles followed by trapping of the C3 resulting carbocations before the aromatization. In order to introduce fluorine-containing carbon-centered radicals © 2017 American Chemical Society

on the indole nucleus, we selected sodium trifluoromethyl sulfinate,15 since sulfinates are known to easily generate radicals in mild oxidative conditions via homolytic cleavage of the relatively weak C−S bond and elimination of SO2 and are therefore versatile reagents to perform C−H functionalization of arenes.12 This strategy would allow us to have general access to original fluorine-containing spiroindolines.16 We selected 3-(3-hydroxypropyl)-NCO2Et-indole 1a as a model substrate to evaluate our approach (Table 1). In that case, carbocation II would be intramolecularly intercepted by an alcohol to yield spirofuranoindoline 3a. Different oxidative systems to generate the trifluoromethylene radical from sodium triflyl sulfinate were investigated. With tert-butyl hydroperoxide, only few amounts of 3a were detected, along with remaining indole 1a and unidentified products (Table 1, entries 1 and 2). Only traces of the desired 3a were obtained with hypervalent iodine reagent PIFA (Table 1, entry 3). A catalytic amount of silver nitrate and a sup-stoichiometric amount of potassium persulfate at 80 °C delivered 3a in 30% yield (Table 1, entry 4). Manganese(III) acetate at 80 °C in acetonitrile afforded 3a in a gratifyingly 61% yield (Table 1, entry 5). Ceric ammonium Received: October 10, 2017 Published: November 14, 2017 6336

DOI: 10.1021/acs.orglett.7b03155 Org. Lett. 2017, 19, 6336−6339

Letter

Organic Letters Table 1. Optimization of the 3-Oxy-2-trifluoromethylation of Indole 1a with Sodium Trifluoromethyl Sulfinate

entry 1

t-BuOOH (5)

2 3 4

t-BuOOH (5) PIFAa (3) AgNO3 (0.1), K2S2O8 (2) Mn(OAc)3 (3) CANb (3) CANb (3) CANb (3)

5 6 7 8 a

oxidant (equiv)

solvent CH3CN/H2O (2:1) CH3CN CH3CN CH3CN/H2O (1:1) CH3CN CH3CN CH3CN CH3CN

temp (°C)

3a isolated yield (%)

rt

10%

rt rt 80

traces traces 30

80 rt −10 −30

61 51 69 slow conversion

Scheme 2. Synthesis of Fluorinated Spirocyclic Indolines from Sulfinate Reagents

PhI(OCOCF3)2. b(NH4)2Ce(NO3)6.

nitrate (CAN) in acetonitrile at room temperature delivered 3a in 51% yield and also CF3-containing indole 2a and undetermined compounds (Table 1, entry 6). Performing the reaction at −10 °C allows the intramolecular trapping by the alcohol of carbocation II to be favored over its aromatization, and 3a was isolated in 69% yield (Table 1, entry 7). The reaction proved to be too slow at −30 °C (Table 1, entry 8). Remarkably, indoline 3a was obtained as a unique diasteroisomer with the CF3 group at C2 and the oxygen at C3 in a trans relationship as demonstrated by X-ray analysis of crystals of 3a.17,18 Having found suitable conditions to perform our desired dearomative 3-oxy-2-trifluoromethylation of indoles, we evaluated the scope of this reaction (Scheme 2).18 The influence of the substitution of the nitrogen of the indole nucleus was first studied. The Boc and acetyl groups were as well permitted as the CO2Et since 3b17 and 3c were obtained in 74% and 78% yield, while a lower yield was obtained with a tosyl group (3d, 43%). Different functional groups on the benzene ring of the indole nucleus were then scrutinized. Electron-donating groups, such as methoxy at the C5-position (3e, 55%), methyl at the C5 (3f, 78%) and C7 (3g, 69%) positions, or halogens such as fluorine (3h, 60%), chlorine (3i, 71%), and bromine (3j, 61%) at C5, were well tolerated. The reaction also operates with an electron-withdrawing group at C5, such as a cyano group (3k, 57%). Next, the nature of the nucleophile was investigated. A tertiary alcohol was as efficient as a primary one since indoline 3l was obtained in 70% yield. The carboxylic acid was also a very good oxygenated nucleophile since 3m was isolated in 87% yield. Trifluoromethylated-lactones containing a 5-methoxy (3n, 72%), 7-methyl (3o, 80%), and 6-chlorine (3p, 35%)19 group on the benzene part of the indole ring were also obtained. To solubilize the starting carboxylic acids, the reaction leading to 3o and 3p were performed in acetone at a higher dilution. Nitrogenated nucleophiles were also competent to deliver spiropyrrolidinoindolines. The cyclization of indoles displaying a N-tosyl amine on the C3-side chain gave 3q in 66% yield and

a

0.022 M in acetone. b2.5 equiv of MeCF2SO2Na and 4 equiv of CAN.

indolines containing, respectively, a methyl (3r, 70%),17 a methoxy (3s, 53%), and a fluorine (3t, 61%) at the C5-position. Finally, it was possible to introduce a 1,1-difluoroethyl group in lieu of the trifluoromethyl by using the corresponding sodium sulfinate.12e Gratifyingly, we obtained moderate yields of spirofuranoindoline 3u (28%) and spiropyrrolidinoindoline 3v (27%).20 To further demonstrate the synthetic potential of this dearomative method, a gram-scale experiment allowed 3f to be obtained in 73% yield. 6337


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A mechanism involving free-radical intermediates is indeed suggested by the incorporation of the trifluomethyl group into compounds 3 via desulfonation from the sulfinate reagent.21 In order to gain additional mechanistic insights, we submitted indole 1b to the oxidative reaction conditions with CAN without the presence of the trifluoromethylative reagent, and in that case, the starting indole was rapidly consumed into several oxidation products, among which hydroxyl indoline 4 and dimer 5 were isolated and their structures tentatively assigned (Scheme 3). A radical cation such as III could be postulated to

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Guillaume Vincent: 0000-0003-3162-1320 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS D.R. and M.J. thank respectively the MENESR and the ANR for PhD fellowships. We also gratefully acknowledge the Université Paris Sud and the CNRS for financial support.

Scheme 3. Control Experiment

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REFERENCES

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explain the formation of such compounds. If both the indole 1 and the sulfinate reagent could be oxidized by CAN,22 it is presumed that the sulfinate reagent should be oxidized faster than indoles 123,24 and it supports the mechanism depicted in Scheme 1. However, we cannot exclude an alternative mechanism which involves the oxidation of 125 and the sulfinate reagent into, respectively, the radical cation III and the trifluoromethyl radical, followed by a radical recombination event into carbocation II.26 In conclusion, we developed a diastereoselective dearomative 3,3-spirocyclization of indoles via the addition of fluorinatedcarbon radicals, generated from sulfinate reagents, at the C2position of indoles, in the presence of ceric ammonium nitrate as the oxidant. The prominent feature of this strategy is the interception of the transient carbocation at the C3-position before aromatization into a C2-functionalized indole through elimination of a proton. This protocol has a broad substrate scope and tolerates various nucleophiles. We believe that this method is potentially of high interest in the discovery of biologically active compounds.

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Letter

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03155. Experimental procedures, characterizations, and NMR spectra of all new compounds (PDF) Accession Codes

CCDC 1575354−1575356 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 6338


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Galstyan, A.; Strassert, C. A.; Studer, A. Chem. Commun. 2016, 52, 5997. (17) CCDC 1575354−1575356 (3a, 3b, 3r) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (18) Only one diastereoisomer was detected by 1H NMR of the crude mixture after aqueous workup for all compounds. The trans stereochemistry may be controlled by electronic factors during the attack of the nucleophile on the carbocation at C3. (19) The low yield could be attributed to the low solubility of both the starting indole 1p and the spiroindoline product 3p. (20) Dimers such as 5 (Scheme 3) were obtained as the main byproducts and resulted from the oxidation of indoles 1 with CAN. This result can be explained by the low solubility of the sodium 1,1difluoroethyl sulfinate. (21) Moreover, upon addition of TEMPO as a radical scavenger to the reaction, no spiroindoline 3b was observed. Instead 59% of 1b was recovered along with an undefined dimer of 1b. (22) The redox potential of CAN is 1.61 V vs NHE; for a review on CAN as a single-electron oxidant: Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862. (23) The oxidation potential of CF3SO2K is 1.05 V vs SCE; see: Tommasino, J.-B.; Brondex, A.; Médebielle, M.; Thomalla, M.; Langlois, B. R.; Billard, T. Synlett 2002, 1697. (24) The oxidation potential of 3-methyl-N-acetylindole has been determined to be 1.10 V vs Ag/AgCl; see ref 14b. (25) The redox potentials of the sulfinate reagent and indoles substituted by electron-withdrawing groups at the nitrogen are close. Moreover, the presence of electron-donating groups on the indole nucleus may lower the oxidation potential of the indole since 3methyl-5-methoxyl-N-acetylindole has an oxidation potential of 0.98 vs Ag/AgCl; see ref 14b. (26) Radical cations generated from indoles substituted at the nitrogen by electron-withdrawing groups could be persistent and lead to selective coupling reaction with a transient radical; see ref 14b for a discussion.

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Radical-Mediated Dearomatization of Indoles with Sulfinate

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