A Metal-Free Route to Heterocyclic Trifluoromethyl- and

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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A Metal-Free Route to Heterocyclic Trifluoromethyl- and Fluoroalkylselenolated Molecules Quentin Glenadel, Ermal Ismalaj, and Thierry Billard* Institute of Chemistry and Biochemistry (ICBMS UMR CNRS 5246), Univ Lyon, Université Lyon 1, CNRS, 43 Bd du 11 novembre 1918, 69622 Villeurbanne, France S Supporting Information *

ABSTRACT: A metal-free methodology to easily synthesize various CF3Se-containing heterocyclic compounds has been developed through intramolecular ring closures of alkynes promoted with CF3SeCl. Moreover, this strategy has also been extended to other fluoroalkylselenyl groups. hese last decades, fluorinated compounds have received growing interest in various applications.1 Better resistance to metabolism, increased lipophilicity, enhanced activity, and modifications of physicochemical properties can partly explain the positive effect of the fluorine atom in the life sciences.2 Variability of fluorinated substituents offers modulation of properties depending on the targeted application. Hence, in recent years combination of fluoroalkyl groups (in particular CF3) with heteroatoms has been used to deliver specific physicochemical properties to molecules. Thus, trifluoromethoxy (CF3O) and trifluoromethylsulfanyl (CF3S) moieties have been largely studied, especially because of their high lipophilicity.3 In contrast, the trifluoromethylselanyl group (CF3Se) has experienced scarce interest to date. Nevertheless, selenylated molecules have already found applications in the life sciences4 and drug design.5 Furthermore, the CF3Se moiety possesses interesting electronic (Hammett constants σp = 0.45, σm = 0.44; Swain−Lupton constants F = 0.43, R = 0.02)6 and lipophilicity (Hansch−Leo parameter πR = 1.29) properties.7 Consequently, this group is a valuable substituent for the development of new molecules. Heterocyclic molecules play an important role in the life sciences and drug design.8 Indeed, numerous natural products and bioactive molecules present at least one heterocyclic core. Therefore, the design of trifluoromethylselenolated heterocycles could be of interest in the development of new bioactive molecules. However, despite such an interest in these compounds, synthetic strategies to achieve such molecules are still underdeveloped and mainly restricted to a few heteroaromatic scaffolds.9,10 Indeed, in the literature trifluoromethylselenolations of heterocyclic molecules onto the heterocyclic part are

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© XXXX American Chemical Society

mainly restricted to some simple and unsubstituted compounds. Furthermore, these examples are essentially aromatic compounds, and very few trifluoromethylselenolations of nonaromatic elaborated heterocycles have been described. Finally, most of these reactions generally require the use of a metal.9,10 This relative underdevelopment of strategies to synthesize trifluoromethylselenolated heterocycles, aromatic or nonaromatic, under metal-free conditions, is partly due to the lack of efficient reagents to perform trifluoromethylselenolation reactions.9 Ring closure of alkynes is a well-established method to obtain heterocyclic structures.11 This strategy generally requires the use of a Lewis acid or transition metal to favor the cyclization. For instance, this has been recently described to obtain trifluoromethylthiolated heterocyclic compounds in the presence of an electrophilic trifluoromethylthiolating reagent and a Lewis acid.12 Our group recently described an efficient method to generate in situ the volatile CF3SeCl reagent to perform electrophilic trifluoromethylselenolations.10g In particular, electrophilic additions onto alkenes have been described. Because of the high electrophilicity of this reagent, the use of a Lewis acid has not been required.13 On the basis of these previous results, we postulated that ortho-heteroatom-substituted alkynylaryl compounds 1 could undergo electrophile-promoted nucleophilic cyclizations with CF3SeCl under metal-free conditions. We were delighted to observe the formation of the corresponding trifluoromethylselenolated benzofuran 2a in Received: October 27, 2017

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DOI: 10.1021/acs.orglett.7b03338 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

disfavors the 5-endo-dig cyclization relative to the chloride anion opening facilitated by the more nucleophilic “benzylic” position (Scheme 2). It is noteworthy that only one isomer of 3b was obtained, which is in accordance with the transient formation of the episelenonium species. The exact configuration was not unambiguously determined, but we can reasonably suppose that the E isomer was formed. Encouraged by this outcome, we investigated the formation of six-membered-ring heterocycles (Scheme 3). Generally,

good yield simply by adding CF3SeCl to 1-methoxy-2-(2phenylethynyl)benzene (1a) (Scheme 1). Benzothiophenes 2c Scheme 1. Syntheses of Fluoroalkylselenolated Benzofurans and Benzothiophenesa

Scheme 3. Syntheses of Fluoroalkylselenolated SixMembered-Ring Heterocyclesa

a

Yields shown are those of isolated products; yields determined by 19F NMR spectroscopy with PhOCF3 as an internal standard are shown in parentheses. bNot isolated; identified by 19F NMR spectroscopy and GC−MS.

and 2d were also obtained following the same strategy. Interestingly, this strategy was efficiently extended to other fluoroalkylselenyl moieties (2e, 2f) that were not synthesizable by previous methods described in the literature. Whereas both benzothiophenes were obtained in good yields starting from phenyl- or hexyl-substituted alkynes (1c, 1d), only benzofuran 2a was obtained in good yield. In the case of hexyl-substituted alkyne 1b, only traces of the desired benzofuran 2b were formed, with the major product being the adduct 3b (Scheme 2). Such a surprising result could be potentially rationalized by a kinetic competition. After reaction with CF 3 SeCl, an episelenonium species is formed. From this intermediate, the shorter C−O bond (compared with the C−S bond) kinetically

a

Yields shown are those of isolated products; yields determined by 19F NMR spectroscopy with PhOCF3 as an internal standard are shown in parentheses. bWith 2 equiv of CF3SeCl.

satisfactory to excellent yields were obtained. Starting from the corresponding methyl esters, various isocoumarins were easily obtained (5a−f). This family of compounds presents interesting pharmacological activities.14 Thus, trifluoromethylselenolated derivatives were obtained (5a−c), but other fluoroalkylselenyl moieties were also introduced (5d−f), in particular the HCF2Se group, which can form hydrogen bonds,15 and two moieties bearing a functional group (SeCF2CO2Me and SeCF2SO2Ph), which can undergo further post-transformations.10g,16 The 6-endo-dig cyclization was confirmed by the single-crystal X-ray diffraction analysis of 5d (Figure 1). A trifluoromethylselenolated isoquinoline (5g) was also obtained in satisfactory yield using tert-butylimine as

Scheme 2. Reaction of CF3SeCl with 1ba

a

Yields shown are those of isolated products; yields determined by 19F NMR spectroscopy with PhOCF3 as an internal standard are shown in parentheses

Figure 1. Single-crystal X-ray structure of 5d. B

DOI: 10.1021/acs.orglett.7b03338 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

starting material. In this case, 2 equiv of CF3SeCl was required in order to obtain a satisfactory yield. Unfortunately, the attempt to form isoquinolinone 7a from the corresponding methyl amide afforded a complex mixture of products. Nevertheless, such a structure is of interest since it is found in IPI-549,17 an innovative selective phosphoinositide-3kinase (PI3K)-γ inhibitor18 in Phase 1 clinical evaluation in subjects with advanced solid tumors.19 Consequently, the synthesis of trifluoromethylselenolated isoquinolinones was investigated through a multistep pathway (Scheme 4).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Quentin Glenadel: 0000-0002-0687-0854 Ermal Ismalaj: 0000-0003-2015-2303 Thierry Billard: 0000-0002-2937-9523

Scheme 4. Synthesis of the Isoquinolinone Core

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the Centre National de la Recherche Scientifique (CNRS), France, and the French Ministry of Research for financial support. The French Fluorine Network (GIS Fluor) is also acknowledged for its support. We thank Dr. Erwann Jeanneau (Centre de Diffractométrie Henri Longchambon) for collecting the crystallographic data and solving the structure of 5d.

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Compound 5a, previously obtained from ester 4a, underwent aminolysis by reaction with aniline and AlMe3 to furnish amide 6a in good yield. This amide was then recyclized under acidic conditions to afford the desired trifluoromethylselenolated isoquinolinone 7a. This final product was obtained in three steps from methyl ester 4a in a good overall yield of 48%. Consequently, although isoquinolinones could not be achieved by direct cyclization, this multistep pathway constitutes a valuable alternative to quickly obtain this important family of compounds. To conclude, we have described an easy and rapid access to various trifluoromethylselenolated heterocyclic compounds. The cyclization reaction readily occurs with in situ preformed CF3SeCl to afford various five- and six-membered-ring heterocycles under mild conditions. The strategy can also be extrapolated to other fluoroalkylselanyl moieties containing functional groups such as ester or sulfone. The rapid posttransformation sequence of newly formed isocoumarins gives easy access to the isoquinolinone core. We believe that this work represents an easy and straightforward way to access various new fluorinated heterocyclic molecules for further applications, in particular in medicinal chemistry.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03338. Experimental procedures and compound characterization data (PDF) Accession Codes

CCDC 1548879 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge C

DOI: 10.1021/acs.orglett.7b03338 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.7b03338 Org. Lett. XXXX, XXX, XXX−XXX