Organoselenium-catalyzed synthesis of indoles through intramolecular C–H amination

Abstract

A new and efficient route for organoselenium-catalyzed synthesis of indoles via intramolecular C–H amination has been developed. The reaction conditions were mild and the desired products were formed in up to 99% yield. When the method was applied in the reaction of a trisubstituted alkene, the corresponding indole was obtained in 99% yield via 1,2-phenyl migration.

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Indoles are important and valuable heterocycles because their structural units are frequently found in pharmaceuticals and bioactive natural products.¹ In the past few decades, many efforts have been devoted to their synthesis. Currently, a large number of protocols are available to prepare indoles via different pathways.² One strategy is to use 2-alkenylanilines as the starting materials to give indoles via C–N bond coupling by only losing two hydrogen atoms.^3,4 This kind of C–H amination is atom-economical and straightforward compared to other known methods. Based on the advantages of C–H amination, transition metals as catalysts are successfully applied in indole synthesis with 2-alkenylanilines.³ In contrast to metal catalysis, metal-free indole synthesis is greener, less toxic, and cheaper. Developing a metal-free C–H amination to prepare indoles is an attractive goal.

Recently, Muñiz reported a sulfonic acid-catalyzed synthesis of indoles with iodosobenzene and 2-vinylanilines as the substrates.^4a In this particular transformation, only 2,3-nonsubstituted indoles could be achieved. Later on, Youn demonstrated an efficient metal-free C–H amination of 2-alkenylanilines using DDQ as an oxidant to afford various 2-aryl indoles.^4b When they used an α-aryl-β-alkylalkene as the substrate, dihydroquinoline was generated in modest yield instead of the corresponding indole. Deng has described a NIS-mediated synthesis of indoles with 2-alkenylanilines under mild conditions.^4c However, this method falls short of efficiency in the production of 2-long-chain alkyl indoles. Overall, for the above transformations with 2-alkenylanilines, the reaction efficiency was low to synthesize 2-long-chain alkyl indoles or 2,3-disubstituted indoles via functional group migration. Very recently, Breder reported a diselenide-catalyzed synthesis of 2-long-chain alkyl indoles.⁵ But the synthesis of 2,3-disubstituted indoles via functional group migration was not covered in their work. Thus, a general approach to synthesize various indoles via direct C–H amination is desirable.

Organoselenium compounds are low-cost in contrast to common metal complexes and belong to the non-metal category.⁶ They could mediate organic reactions through selenation–deselenation assisted by an oxidant.⁷ Thirty-five years ago, Sharpless first reported a diselenide-catalyzed chlorination of alkenes with NCS.⁸ After that, Tiecco and several other groups worked on this area and made important contributions.⁹ In the past decade, diselenide catalysis has been paid more and more attention.¹⁰ Different oxidants such as PhI(OOCF₃)₂, H₂O₂, and other peroxides were utilized. Although some progress has been made in this field, the study of diselenide catalysis is still in the infant stage and efficient reaction systems as well as new reactions need to be further developed. Our group is interested in organoselenium catalysis. We have demonstrated an efficient diselenide-catalyzed, hydroxy-controlled regio- and stereoselective amination of terminal alkenes with N-fluorobenzenesulfonimide (NFSI) as a nitrogen source.¹¹ In order to diversify the nitrogen source, other amines were employed for this intermolecular C–H amination, but no desired aminated products were observed. We conceived that intramolecular transformations are easier than the intermolecular ones. Therefore, when 2-alkenylanilines were used as the starting materials, the desired indoles could be generated by diselenide-catalyzed intramolecular C–N coupling. The route might provide a broad substrate scope, overcoming the existing drawbacks in the known metal-free synthesis. Herein, we report our achievements in indole synthesis by diselenide-catalyzed intramolecular C–N amination.

In the known metal-free processes with 2-alkenylanilines,⁴ the formation of 2-long-chain alkyl indoles is challenging. We initiated our investigation with N-Ts-2-(1-butenyl)aniline (1a) as the model substrate. Excitingly, when the reaction was carried out in acetonitrile at 30 °C for 18 h using NFSI as an oxidant, the desired product N-Ts-2-ethylindole (2a) was produced in 32% NMR yield (Table 1, entry 1). No (PhSO₂)₂N-functionalized alkene was observed by the direct reaction of 1a with NFSI.¹² Different solvents were screened. Polar solvents, i.e. DMF and MeOH, were not effective resulting in almost no reaction (Table 1, entries 5 and 6). When THF was used as the solvent, product 2a was formed in 70% yield. The highest yield (79% isolated yield) was obtained when dioxane was replaced with THF as the solvent (Table 1, entry 10). When the reaction time was reduced from 18 h to 6 h, the transformation was not completed giving the product in 66% yield (Table 1, entry 11). The reaction temperature affected the reaction heavily. Only a trace amount of product was generated when the reaction was run at 0 °C (Table 1, entry 12). An increase in temperature did not result in higher yield (Table 1, entry 13). In order to increase the nucleophilicity of nitrogen, a base such as pyridine and NaHCO₃ was added to the reaction which did not promote the reaction, and 2a was formed in lower yield (Table 1, entries 14 and 15). Other oxidants, e.g. Selectfluor and PhI(OOCCF₃)₂, were utilized for this transformation. To guarantee the efficiency of the oxidants, the reactions were conducted in suitable solvents. No better conversion was obtained (Table 1, entries 16 and 17). When 2-alkenylaniline was protected by other protecting groups, i.e., Cbz, Ac, and Boc, instead of the tosyl group, the corresponding indoles could not be produced. Probably, the nitrogen on the substrate was not nucleophilic enough to attack the intermediate seleniranium ion.¹³ However, when an electron-withdrawing sulfonyl protecting group such as 4-nitrobenzenesulfonyl (Ns) or ethylsulfonyl (Es) was immobilized on the nitrogen, the corresponding products (Ns-protected indole 2b and Es-protected indole 2c) were formed in acceptable yields.

Table 1 Condition optimization^a

Entry	R	Oxidant^b	Additive	Solvent	Temp. (°C)	Yield^c (%)
a Reaction conditions: alkenes 1, 1.05 equiv.; oxidant, 0.1 mmol; PhSeSePh, 10 mol%; solvent, 1 mL; additive, 0.2 equiv.; 18 h. b NFSI: N-fluorobenzenesulfonimide. c Refers to ^1H NMR yield using benzyl benzoate as the internal standard; isolated yield is in the parenthesis. d Reaction time: 6 h instead of 18 h.
1	Ts	NFSI	—	CH3CN	30	32
2	Ts	NFSI	—	DCM	30	32
3	Ts	NFSI	—	DCE	30	38
4	Ts	NFSI	—	PhMe	30	38
5	Ts	NFSI	—	DMF	30	Trace
6	Ts	NFSI	—	MeOH	30	0
7	Ts	NFSI	—	AcOEt	30	65
8	Ts	NFSI	—	Et2O	30	30
9	Ts	NFSI	—	THF	30	70
10	Ts	NFSI	—	Dioxane	30	79(79)
11^d	Ts	NFSI	—	Dioxane	30	66
12	Ts	NFSI	—	Dioxane	0	Trace
13	Ts	NFSI	—	Dioxane	50	77
14	Ts	NFSI	Pyridine	Dioxane	30	34
15	Ts	NFSI	NaHCO3	Dioxane	30	69
16	Ts	Selectfluor	—	CH3CN	30	70
17	Ts	PhI(OOCCF3)2	—	DCM	30	10
18	Cbz	NFSI	—	Dioxane	30	0
19	Ac	NFSI	—	Dioxane	30	0
20	Boc	NFSI	—	Dioxane	30	0
21	Ns	NFSI	—	Dioxane	30	59(61)
22	Es	NFSI	—	Dioxane	30	56(54)

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Next, we explored the substrate scope under the optimal conditions (Table 2). N-Ts-2-vinylaniline gave a trace amount of product 2d. The 2,3-group-free indole could be accessed in good yield by Muñiz's method.^4a When our method was applied in the synthesis of 2-long-chain alkyl indoles, the desired products were obtained in good yield (2e–i, 60–84%). The ester group could be tolerated in the reaction. However, nitrile-containing aniline only gave the product 2j in 31% yield. It is likely that the nitrile group participated in the transformation to slow down the formation of the desired product 2j. This method is quite efficient for the transformation of 2-arylindoles as well. The corresponding products were achieved in excellent yields (2k–p, 89–99%).

Table 2 Synthesis of N-Ts-2-substituted indoles^a

a Reaction conditions: alkenes 1, 1.05 equiv.; NFSI, 0.1 mmol; PhSeSePh, 10 mol%; dioxane, 1 mL; 30 °C, 18 h. b The products contain ca. 10% inseparable N-Ts-3-(4-methoxyphenyl)indole.

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When different substituents were put on the aromatic ring of substrates to vary the nitrogen nucleophilicity, the C–H amination was slightly affected. All the desired products were generated in high yields (Table 3). For example, substrates with electron-neutral Me– and electron-deficient CF₃– at the same position underwent C–N coupling to give the corresponding products in similar yields (2q, 91%; 2u, 93%).

Table 3 Effect of different substituents on the aromatic ring of substrates^a

a Reaction conditions: alkenes 1, 1.05 equiv.; NFSI, 0.1 mmol; PhSeSePh, 10 mol%; dioxane, 1 mL; 30 °C, 18 h.

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To further extend the generality of our method, trisubstituted alkene 3 was employed as the substrate. Surprisingly, only 2-methyl-3-phenyl indole 4 was formed in excellent yield of 99% via 1,2-phenyl migration (Scheme 1). No methyl migration product was observed. In the literature, there has been no report on the efficient preparation of the same product via phenyl migration.^3e,4b,c For the formation of 4, the possible mechanism might involve the generation of intermediate 5. The PhSe group was removed by the oxidation of NFSI or other active species to form 6. Then phenyl group migrates from the 2-position to give intermediate 7. By proton elimination, the indole 4 is produced.

Scheme 1 Formation of 4via 1,2-phenyl migration.

In summary, we have demonstrated an efficient approach for the synthesis of indoles via intramolecular C–H amination. The particular reactions were accomplished by organoselenium catalysis and the reaction conditions were mild. When the method was applied in the reaction of a trisubstituted alkene, the corresponding indole was obtained in 99% yield via 1,2-phenyl migration. In the field of diselenide catalysis, our discovery provides a possibility to develop more new organoselenium-catalyzed reactions. The mechanistic study is ongoing in our laboratory.

Acknowledgements

We thank Sun Yat-Sen University, the “One Thousand Youth Talents” Program of China and the Natural Science Foundation of Guangdong Province (Grant No. 2014A030312018) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00179j

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