Photoredox-Catalyzed Trifluoromethylative Intramolecular Cyclization

Letter Cite This: Org. Lett. 2018, 20, 1698−1702

pubs.acs.org/OrgLett

Photoredox-Catalyzed Trifluoromethylative Intramolecular Cyclization: Synthesis of CF3‑Containing Heterocyclic Compounds Hong Sik Han,†,‡ Eun Hye Oh,‡,§ Young-Sik Jung,†,‡ and Soo Bong Han*,†,‡ †

Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217 Gajeongro, Yuseong, Daejeon 34113, Republic of Korea ‡ Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea § Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea S Supporting Information *

ABSTRACT: A general photoredox-catalyzed intramolecular cyclization was developed for the synthesis of trifluoromethylated heterocyclic compounds. The reaction proceeded smoothly under mild photocatalytic conditions with high functional group tolerance, allowing the preparation of oxygen-, sulfur-, or nitrogen-containing heterocycles of different sizes. The broad substrate scope demonstrated the complexity-building potential of the strategy.

T

rifluoromethylated heterocyclic compounds1 have attracted considerable interest in various fields of chemistry, owing to both the importance of fluorine2 and the applications of heterocycles in the pharmaceutical, agrochemical, and material industries.3 In particular, trifluoromethylated nonaromatic heterocyclic compounds have been widely used in medicinal chemistry due to the spatial advantage of their architecture.4 For example, a novel human CCR2 antagonist containing a CF3-substituted tetrahydropyran ring with excellent potency in both binding and chemotaxis assays has been reported (Figure 1).5 In addition, CF3-substituted

genation7 and addition reactions,8 to form various saturated ring systems. For instance, a C−H trifluoromethylation of glycals (Scheme 1, a)9 and a photoredox-catalyzed tandem cyclization (Scheme 1, b)10 for the formation of CF3-containing chromones have been reported by Ye and by Yang and Chen, respectively. Moreover, Ding and Hou reported a domino trifluoromethylative cyclization of homopropargylamines to form 5-endodihydropyrrolium ions (Scheme 1, c).11 In addition, a method to generate CF3-containing isochromenes via alkynol cyclization and subsequent trapping by a CF3 radical has been described (Scheme 1, d).12 Although these protocols are efficient and versatile, a mild and general method for the synthesis of heteroatom (O, N, and S)-containing rings of various sizes is still highly desirable. As part of our efforts to construct complex molecules containing a CF3 group by multicomponent coupling reactions,13 we designed a photoredox-catalyzed trifluoromethylative intramolecular cyclization to form CF3-bearing heterocyclic rings of different sizes (Scheme 2).14 In the proposed mechanism, an excited photoredox catalyst is generated (from Mn to *Mn), which reduces the CF3 source.15 The resulting CF3 radical can be trapped by an alkyne16 to form a vinyl radical intermediate stabilized by resonance with the adjacent aromatic ring.17 The vinyl radical can be oxidized by

Figure 1. CF3-containing nonaromatic heterocycles.

piperidine derivatives exhibit high biological activity against inflammation and Janus kinase.6 Despite the versatility of trifluoromethylated compounds, only a few methods have been reported for the preparation of CF3-substituted ring systems. Among them, the construction of CF3-vinyl heterocycles is particularly attractive because the olefin functionality provides a handle for further chemical modifications, such as hydro© 2018 American Chemical Society

Received: February 22, 2018 Published: March 23, 2018 1698

DOI: 10.1021/acs.orglett.8b00648 Org. Lett. 2018, 20, 1698−1702

Letter

Organic Letters Scheme 1. Synthesis of CF3-Substituted Vinyl Heterocycles

Table 1. Optimization of Trifluoromethylative Intramolecular Cyclizationa

Scheme 2. Proposed Pathway for Trifluoromethylative Intramolecular Cyclization

a Reactions were carried out with 1a (0.10 mmol), CF3 source (0.20 mmol), catalyst (2.0 mol %), base (0.20 mmol), and solvent (2.0 mL) at 25 °C under N2 atmosphere for 12 h. bYields were determined by 1 H NMR using 1,1,2,2-tetrachloroethane as an internal standard. cIn the dark. dWithout catalyst.

solvents were screened, and acetonitrile proved to be optimal. Notably, whereas other solvents were ineffective (entries 9 and 10), acetone afforded 3a in 60% yield along with α-CF3substituted ketone as the major byproduct (entry 8), which was presumably formed by attack of residual H2O instead of the pendant alcohol. Moreover, no product was formed without visible light (entry 11). Interestingly, the reactivity dramatically decreased in the absence of a catalyst (entry 12), supporting the involvement of a photoredox process.21 With the optimized reaction conditions in hand, the substrate scope was examined with alkynols 1a−i (Table 2) bearing different substituents on the aromatic ring. The reactions of alkynes containing acetyl (1a)-, p-tosyl (1b)-, and Bocprotected (1c) amine-substituted aryl groups proceeded smoothly (76%, 64%, and 78% yields, respectively). Unsubstituted (1d) and tert-butyl-substituted alkynols (1e) produced the corresponding products in moderate (53%) and high (74%) yields, respectively. Moreover, substrate 1f bearing an ether substituent efficiently afforded product 3f in 78% yield. Halogen substituents were also well tolerated to give 3g and 3h in 66% and 60% yields, respectively. Notably, a methyl group substituent on the tethered chain was not detrimental to the reaction, and the desired product was obtained in good yield (73%, 3i).22 Encouraged by the successful synthesis of vinyl ether derivatives, the protocol was extended to the preparation of cyclic enamines (Table 3). First, various N-protecting groups, including tosyl (4a), mesyl (4b), Boc (4c), and Cbz (4d), were examined; pleasingly, all reactions proceeded smoothly to the corresponding products 5a−d (80%, 60%, 54%, and 57% yields, respectively). These results demonstrate the strong diversity of N-nucleophiles with different protecting groups, which can be applied for the synthesis of complex molecules. Next, our protocol was tested using alkynamines with various substituents

Mn+1 to give a vinyl cation, which can be attacked intramolecularly by the tethered heteroatom nucleophile (XH) to give the desired CF3-containing heterocycle. It should be noted that the catalyst, Mn, is regenerated in the oxidation step, thus closing the catalytic cycle.18 On the basis of this design, we set out to explore the trifluoromethylative intramolecular cyclization of alkynol 1a using Umemoto reagent 2a and various photoredox catalysts under visible light irradiation to form six-membered trifluoromethylated cyclic enol ether 3a (Table 1, entries 1−4). Gratifyingly, using fac-Ir(ppy)3 as the catalyst, the desired product was obtained in high yield (79%, entry 4), presumably owing to the high reducing power of fac-Ir(ppy)3 compared to that of other catalysts.19 For further optimization, other CF3 sources, namely, Togni I and II reagents, were examined, but were less effective (40% and 47% yields, respectively; entries 5 and 6).20 Moreover, in the absence of base, a mixture of unidentified byproducts was obtained (entry 7). Next, various 1699

DOI: 10.1021/acs.orglett.8b00648 Org. Lett. 2018, 20, 1698−1702

Letter

Organic Letters Table 2. Synthesis of CF3-Bearing Cyclic Enol Ethers from Alkynolsa

Table 3. Synthesis of CF3-Bearing Cyclic Enamines from Alkynaminesa

a

a

Reactions were carried out with alkynamine (0.20 mmol), Umemoto reagent 2a (2.0 equiv), Ir(ppy)3 (2.0 mol %), and Li2CO3 (2.0 equiv) in MeCN (4.0 mL) for 12 h. bIsolated yields are shown in parentheses. c X-ray crystal structure was obtained (see the Supporting Information).

on the aromatic ring and tosyl-protected amine as the nucleophile. Aromatic alkynamines bearing an acetyl (4e), ptosyl amine (4f), or Boc-protected amine (4g) substituent at the para position were efficiently transformed into the corresponding products 5e−g in moderate to high yields (45−73%). Moreover, unsubstituted (4h) and halogensubstituted aromatic rings (4i and 4j) showed moderate reactivity (50%, 42%, and 41% yields, respectively). Most

interestingly, N-Boc-protected aniline could be used as a nucleophile to give bicyclic ring 5k (53%), demonstrating the utility of this strategy for the construction of complex ring systems. To further highlight the versatility of this transformation, we attempted to synthesize heterocycles of different sizes. As shown in Scheme 3, six-, seven-, and eight-membered rings containing heteroatoms (namely, O, N, or S) were successfully prepared. In particular, trifluoromethylated seven- and eightmembered rings containing an oxygen atom were smoothly obtained in 71% (6a) and 47% (6b) yields, respectively. Our protocol could also be applied to the synthesis of the sevenmembered nitrogen heterocycle 6c (50%), as well as the CF3-

Reactions were carried out with alkynol (0.20 mmol), Umemoto reagent 2a (2.0 equiv), Ir(ppy)3 (2.0 mol %), and Li2CO3 (2.0 equiv) in MeCN (4.0 mL) for 12 h. bIsolated yields are shown in parentheses. c X-ray crystal structure was obtained (see the Supporting Information).

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DOI: 10.1021/acs.orglett.8b00648 Org. Lett. 2018, 20, 1698−1702

Organic Letters

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Scheme 3. Trifluoromethylated Six-, Seven-, and EightMembered Rings Containing N, O, or Sa−c

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Young-Sik Jung: 0000-0001-9492-6848 Soo Bong Han: 0000-0002-7831-1832 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Korea Research Institute of Chemical Technology (Grant Nos. KK1803-C00 and KK1706G08).

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a

Reactions were carried out with alkyne (0.20 mmol), Umemoto reagent 2a (2.0 equiv), Ir(ppy)3 (2.0 mol %), and Li2CO3 (2.0 equiv) in MeCN (4.0 mL) for 12 h. bIsolated yields are shown in parentheses. c X-ray crystal structure was obtained (see the Supporting Information).

substituted sulfur heterocycle 6d (60%). These examples clearly show the potential applicability of the proposed approach to the construction of complex heterocyclic systems. In summary, we have developed a photoredox-catalyzed trifluoromethylative intramolecular cyclization to form sixmembered cyclic enol ethers or cyclic enamines from the corresponding alkynes. The protocol employs easy-to-handle, solid Umemoto reagent and a photocatalyst under visible light irradiation, allowing the facile construction of nonaromatic heterocycles containing a vinyl CF3 group. CF3-bearing, different-sized heterocycles containing different heteroatoms (O, N, or S) could also be prepared, providing evidence for the applicability of the method to the construction of more complex molecules.

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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.8b00648. Experimental procedures and characterization for new compounds and crystallographic data for 3b, 5i, and 6c (PDF) Accession Codes

CCDC 1825229−1825231 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. 1701

DOI: 10.1021/acs.orglett.8b00648 Org. Lett. 2018, 20, 1698−1702

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DOI: 10.1021/acs.orglett.8b00648 Org. Lett. 2018, 20, 1698−1702