Gold-catalyzed formation of indole derivatives from 2-alkynyl arylazides and oxygen-containing heterocycles

Abstract

A novel method for the formation of indole derivatives via gold-catalyzed tandem reactions of 2-alkynyl arylazides and oxygen-containing heterocycles has been developed. A variety of indole derivatives were prepared under mild reaction conditions.

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Indoles are very important core structures in organic chemistry, which can be found in many natural products and bioactive compounds.¹ They are also serve as versatile building blocks for functional materials.² For this reason, the development of a novel synthetic methodology to this class of N-containing heterocycles still remains highly active.^3,4 Recently, an increasing number of studies have demonstrated the use of 2-alkynyl arylazides as efficient substrates in gold-catalyzed indole formation strategies.⁵ In our continuing studies on gold-catalyzed tandem reactions,⁶ we recently reported an efficient and convenient synthetic method to 1H-indol-3-yl esters via gold-catalyzed tandem reactions of 2-alkynyl arylazides with carboxylic acids (Scheme 1a).⁷ Based on these earlier studies, we reasoned 1-azido-2-(phenylethynyl)benzene 1a might also undergo a similar intermolecular trapping of putative α-imino gold carbene species^5,8,9 generarated in situ by methanesulfonic acid. We anticipated the desired 2-phenyl-1H-indol-3-yl methanesulfonate 4a would be afforded under the similar gold-catalyzed reaction conditions, which could be a potential aryl mesylate cross-coupling reagent.¹⁰ In this reaction, 1,4-dioxane was used as solvent to dilute the methanesulfonic acid due to its highly activity. To our surprising, we did not detect the desired product 4a by analyzing the TLC and crud ¹H NMR spectrum. However, only the unexpected ring-opening product 2-(2-((2-phenyl-1H-indol-3-yl)oxy)ethoxy)ethyl methanesulfonate 3a was obtained in 95% yield (Scheme 1b).¹¹ Herein, we disclose the details of this efficient gold-catalyzed ring-opening reactions of 2-alkynyl arylazides with oxygen-containing heterocycles in the presence of methanesulfonic acid for the synthesis of novel indole derivatives.

Scheme 1 Our design for indole synthesis.

Initially, we chose to focus our attention on ring-opening reaction of 1-azido-2-(phenylethynyl)benzene 1a and 1,4-dioxane in the presence of 3 equivalents of methanesulfonic acid by a variety of gold catalysts to establish the reaction conditions (Table 1). This revealed treating a solution of reaction containing 1a (1 equiv.) and 2a (0.5 mL) with 2 mol% tBuXPhosAuNTf₂ in the presence of 3 equivalents of MsOH at 60 °C for 1 h gave the best result (entry 1). Under these conditions, 2-(2-((2-phenyl-1H-indol-3-yl)oxy)ethoxy)ethyl methanesulfonate 3a was obtained in 95% yield. On the other hand, a slightly lower product yields were observed when the gold catalyst was changed from tBuXPhosAuNTf₂ to PPh₃AuNTf₂, XPhosAuNTf₂ and IPrAuNTf₂ (entries 2–4). In contrast, the use of AuCl₃ as the catalyst led to a mixture of side products that could not be identified by ¹H NMR analysis (entry 5). Notably, only the starting material was recovered when JohnPhosAuCl or AgNTf₂ used as catalyst (entries 6–7). Similar result was obtained when this reaction was repeated in the absence of any gold catalyst (entry 8). The reaction temperature was also checked. High or low temperature led to a markedly lower yields of 59–71% (entries 9–10). Additional control experiment without MsOH led to a mixture of unknown products that could not be identified by TLC and ¹H NMR analysis (entry 11). In contrast, other acid additives were also examined. The corresponding product 2-(2-((2-phenyl-1H-indol-3-yl)oxy)ethoxy)ethyl 4-methylbenzenesulfonate 5 was obtained in 61% yield where the MsOH was replaced with p-TsOH·H₂O as the acid additive (entry 12). However, either no reaction or a mixture of unknown compounds were observed when TFA or TfOH was used as acid additive (entries 13–14).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	T (°C)	t (h)	Yield^b (%)
a Unless stated otherwise, all reactions were performed in 0.5 mL 1,4-dioxane with a catalyst/1a/MsOH ratio of 0.02 : 1 : 3. b Isolated yield. c Mixture of unknown side products afforded based on ^1H NMR analysis of the crude mixture. d No reaction was observed. Only starting material left. e Reaction conducted without catalyst. f Reaction conducted without MsOH. g p-TsOH·H2O used as acid additive. h TFA used as acid additive. i TfOH used as acid additive.
1	tBuXPhosAuNTf2	60	1	95
2	PPh3AuNTf2	60	1	92
3	XPhosAuNTf2	60	1	93
4	IPrAuNTf2	60	1	86
5	AuCl3	60	1	—^c
6	JohnPhosAuCl	60	1	n.r.^d
7	AgNTf2	60	1	n.r.^d
8	—^e	60	1	n.r.^d
9	PPh3AuNTf2	r.t.	24	59
10	PPh3AuNTf2	80	1	71
11	tBuXPhosAuNTf2	60	1	—^c^,^f
12	tBuXPhosAuNTf2	60	1	61^g
13	tBuXPhosAuNTf2	60	4	n.r.^d^,^h
14	tBuXPhosAuNTf2	60	1	—^c^,^i

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To define the scope of the present procedure, we next turned our attentions to the reactions of a variety of 2-alkynyl arylazides 1 with oxygen-containing heterocycles 2 (Table 2). These experiments showed that with tBuXPhosAuNTf₂, 2-alkynyl arylazides bearing para-substituted electron-donating or electron-withdrawing substituents on the phenyl ring or thienyl group 1b–f efficiently underwent the tandem ring-opening process and gave the corresponding products 3b–f in good to excellent yields. We also tested the effect of an aliphatic substituent on the alkyne carbon and found that, for substrates where R² = nC₅H₁₁ or nC₄H₉, lower yields 63% and 60% were obtained for 3g and 3i, respectively. Under the standard reaction conditions, the desired ring-opening indole 3 h was also provided with the sterically hindered substrate 1 h However, the substrate with cyclopropyl group 1j or terminal alkyne moiety 1k only gave a mixture of unknown side products that could not be identified by TLC and ¹H NMR analysis. Next, arylazides with Cl or Me group on the phenyl ring 3l–n also can provide the desired indole derivatives in moderate to excellent yields. Notably, the 5,7-dichloro-2-phenyl-1H-indol-3-yl methanesulfonate 4b was obtained in 29% yield as a side product when the substrate with disubstituted group on the aromatic ring was employed. Next, other oxygen-containing heterocycles were also examined under the optimal reaction conditions. When dioxane was changed to tetrahydro-2H-pyran, we found that the corresponding ring-opening indole product 3o was afforded in 73% yield. Very interesting, the reaction of 1a with oxetane 2c, tetrahydrofuran 2d, or 2-phenyloxirane 2e only gave a mixture of unknown side products that could not be identified by TLC and ¹H NMR analysis.

Table 2 Gold-catalyzed ring-opening reactions of 2-alkynyl arylazides 1 with 2^a,b

a Unless stated otherwise, all reactions were performed at 60 °C in 0.5 mL 1,4-dioxane with a catalyst/1/MsOH ratio of 0.02 : 1 : 3. b Values noted in parentheses denote isolated product yields and reaction times. c Unknown compounds based on ¹H NMR spectroscopic analysis of the crude mixture.

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We tentatively propose the present tBuXPhosAuNTf₂ catalyzed ring-opening indole-forming reaction to proceed by the mechanism outlined in Scheme 2, although it is highly speculative. This could involve activation of 1-azido-2-(phenylethynyl)benzene 1a through coordination of the gold catalyst with the alkyne, which would be attacked by the azide to deliver intermediate A. Subsequently, the α-imino gold carbene B was formed after the expulsion of N₂ with the assist of gold catalyst, which was further attacked by 1,4-dioxane to release the intermediate C. Ring opening of C with methanesulfonic acid would provide the complex D, which undergo a final protodemetalation step to deliver the 2-(2-((2-phenyl-1H-indol-3-yl)oxy)ethoxy)ethyl methanesulfonate 3a.

Scheme 2 Proposed mechanism for the formation of 3a.

In summary, an unexpected gold-catalyzed synthetic method to indole derivatives based on the ring-opening reaction of 2-alkynyl arylazides with oxygen-containing heterocycles in the presence of methanesulfonic acid has been reported. These results show that the reaction tolerates a structurally diverse set of 2-alkynyl arylazides substrates that can be prepared easily in two steps from commercially available materials. Moreover, the gold-catalyzed tandem reactions were also shown to be practical since inert and moisture-free conditions were not required. Further studies on the applications of this synthetic method are currently underway in our laboratory.

Acknowledgements

This project was supported by the National Natural Science Foundation of China Grant (21302096, 21502093), Natural Science Foundation of Jiangsu Province Grant (BK20130962, BK20150871) and the Project Fund from the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and analysis data for new compounds. See DOI: 10.1039/c6ra09761h

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