Construction of benzo[a]carbazole derivatives via Diels–Alder reaction of arynes with vinylindoles

Abstract

A new protocol for a highly efficienct and versatile Diels–Alder reaction of vinylindoles with arynes (generated form 2-(trimethylsilyl)aryl triflate) has been developed. Various functionalized benzo[a]carbazoles were afforded in good to perfect yields via [4 + 2] cycloaddition/aromatization.

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Carbazoles are an important class of heterocycles and have gained extensive interest of scientists not only because of the observably biological activity¹ but also due to their unique optical properties.² Benzo[a]carbazoles, as a subunit of carbazoles, have also received much attention, as they exhibit a broad range of pharmacological activities,^3–6 such as antitumor,³ antiinflammatory⁴ and antiestrogenic properties,⁵ or kinase inhibitory activities.⁶ Therefore, great efforts have been directed toward the development of efficient synthetic methods for the preparation of this advantageous framework with various substitution patterns in the past decades.^7–10 Most of the representative approaches have focused on: (a) the Fischer–Borsche reaction of various substituted quinolyhydrazones or iso-quinolyhydrazones,⁷ (b) transition-metal-catalyzed cyclization reactions of indole derivatives,⁸ (c) cascade cyclization of diynes,⁹ and (d) intramolecular photoinduced cyclization of indole derivatives.¹⁰ Although these procedures are useful and general, there are still some restrictions such as the preparation of raw materials, poor atom economy and the cost of the catalytic system. Thus, it is highly desirable to provide efficient and facile strategies for the preparation of benzo[a]carbazole derivatives.

In the last century, Pindur and co-workers reported a new route to synthesise benzo[a]carbazoles via the Diels–Alder reaction of arynes (generated form o-benzenediazonium carboxylate) with 3-vinyl-indoles,¹¹ but the reaction was limited due to the harsh conditions, with low yields. In recent years, 2-(trimethylsilyl)aryl triflates, as aryne precursors, have been broadly used for the preparation of cyclic compounds via addition under mild reaction conditions.¹² As part of our ongoing studies on the development of aryne chemistry,¹³ we continued to explore the feasibility of synthesizing useful and biologically important compounds by Diels–Alder reactions of dienes with 2-(trimethylsilyl)aryl triflates.¹⁴ After a series of trials, we have successfully developed an efficient and mild reaction of vinylindoles with 2-(trimethylsilyl)aryl triflates by the Diels–Alder reaction, leading to the synthesis of benzo[a]carbazole derivatives in good to perfect yields (Scheme 1). Herein, we detail our results.

Scheme 1 Reaction of vinylindoles and arynes.

Initially, the reaction of 1-methyl-3-(2-nitrovinyl)-1H-indole (1a) with 2-(trimethylsilyl)aryl triflate (2a) was chosen as a model reaction to screen the optimal reaction conditions, and the results are summarized in Table 1. To our delight, the treatment of 1a with 2a using 3.0 equiv. of CsF in 2 mL CH₃CN at 80 °C under an open air atmosphere afforded the corresponding benzo[a]carbazole (3a) in a 83% yield (entry 1). Encouraged by this result, a series of other solvents, including THF, toluene and dioxane were tested, and the results showed that they are unfavourable to the cycloaddition reaction (entries 2–4). Then, KF and TBAF were investigated as fluoride sources, and it was found that they were both less effective than CsF (entries 5–6). The product yield of 3a was increased to 91% when the reaction was carried out under an O₂ atmosphere (entry 7). However, the replacement of O₂ with N₂ led to a low yield (entry 8). Obviously, these experiments revealed that oxidants are necessary for the oxidative aromatization of the cycloaddition product. Therefore, different oxidants such as TBHP, DDQ, PhI(OAc)₂ and m-CPBA were examined (entries 9–12), and the results indicated that the oxidant O₂ is the best choice for this transformation. Further examination of the reaction temperature showed that 3a could be obtained in 95% isolated yield at 60 °C (entries 13 and 14). Thus, the optimized reaction conditions were as follows: 1a (0.3 mmol), 2a (0.45 mmol), CsF (0.9 mmol), in CH₃CN (2 mL) at 60 °C under an O₂ atmosphere.

Table 1 Optimization of reaction conditions^a

Entry	Solvent	F^− source	Oxidant	Yield^b (%)
a Unless otherwise noted, the reactions were carried out on a 0.3 mmol scale of 1a with 1.5 equiv. of 2a, F^− source (3.0 equiv.), and the oxidant (1.0 equiv.) in solvent (2.0 mL) at 80 °C under an air atmosphere, 6 h.b Isolated yields; nr: no reaction.c Under O2.d Under N2.e At 60 °C.f At 50 °C.
1	CH3CN	CsF		83
2	THF	CsF		Trace
3	Toluene	CsF		nr
4	Dioxane	CsF		nr
5	CH3CN	KF		56
6	CH3CN	TBAF		Trace
7^c	CH3CN	CsF		91
8^d	CH3CN	CsF		21
9	CH3CN	CsF	TBHP	52
10	CH3CN	CsF	DDQ	Trace
11	CH3CN	CsF	PhI(OA)2	46
12	CH3CN	CsF	m-CPBA	45
13^c^,^e	CH3CN	CsF		95
14^c^,^f	CH3CN	CsF		88

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With the optimized conditions in hand, the scope of this cycloaddition reaction of various substituted vinylindoles 1a with 2-(trimethysilyl)phenyl triflate 2a was investigated, and the results are summarized in Table 2. Initially, 3-(2-nitrovinyl)indoles were screened with a different substituents on the nitrogen atom. The results demonstrate that various N-substituted vinylindoles could be smoothly transformed into the desired products (3b–3f). For example, N-cyclopropylmethyl and N-benzyl substituted 3-vinylindoles, were well tolerated in the cycloaddition reaction providing 3b and 3c in 87% and 85% yield respectively, and the structure of 3c was unambiguously confirmed by single crystal X-ray analysis (Fig. 1). Importantly, the substrates 1d and 1e, bearing N-allyl or N-propyl groups respectively, were translated into the expected products, 3d and 3e, in good yields. We next also evaluated the R² group (R² = EWG), such as COPh, COMe, COOMe and CN, and the results indicated that the corresponding desired products (3g–3j) were obtained in 94–99% yield under the optimized reaction conditions. Unfortunately, when the R² group was methyl or phenyl, the desired products could not be isolated. These results indicated that the Diels–Alder reaction with an inverse-electron-demand is dominated by the interaction of the HOMO of the electron-rich aryne and the LUMO of the electron-deficient vinylindole.¹⁵ The indoles bearing electron-donating groups such as Me and OMe or electron-withdrawing groups such as F, Cl and Br were reacted smoothly and provided corresponding cycloaddition products (3k–3p) in perfect yields (96–99%). These results indicated that the electronic or steric effect on the benzene ring did not play a significant role in regulating the reaction. Finally, tri-substituted vinyl indoles were investigated. When the R⁴ group was methyl or phenyl, the corresponding products, 3q and 3r, were obtained in good yields.

Table 2 Cycloaddition reaction of vinylindoles (1) with an aryne precursor (2a)^a,b

a Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), and CsF (0.9 mmol), in CH₃CN (2 mL) at 60 °C under an O₂ atmosphere, 6 h.b Isolated yields.

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Fig. 1 ORTEP structure of 3c.

To expand the scope of this [4 + 2] cycloaddition methodology, various substituted aryne precursors (2b–2e) were examined (Table 3). Under the optimized reaction conditions, the o-silyl aryltriflates bearing methyl, F, or Cl groups on the aryl moiety, could effectively react with 1g, and afforded the target products in perfect yields. These results show that the reactivity was not affected by the electronic effect of the arynes. However, these unsymmetrical arynes generated from substrates 2c and 2e, provided two regioisomers, respectively, in a 1.1 : 1 ratio and a 1 : 1 ratio. The lack of regioselectivity of the reaction was consistent with the intermediate of arynes, and clearly supported that the reaction takes place through a [4 + 2] cycloaddition.

Table 3 Cycloadditon reaction of vinylindole (1g) with aryne precursors (2)^a,b

Entry	Substrate 2	Product 3^b (%)
a Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), and CsF (0.9 mmol), in CH3CN (2 mL) at 60 °C under an O2 atmosphere, 6 h.b Isolated yields.
1
2
3
4

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On the basis of our research and the previously reported mechanism,^12–14 a reasonable mechanism is illustrated in Scheme 2. Firstly, aryne could be generated in situ form 2-(trimethysilyl)phenyl triflate 2 by the fluoride-induced 1,2-elimination. Subsequently, the 3-vinyl-indole 1, as a diene, reacts with aryne, and affords the intermediate 4 via a [4 + 2] cycloaddition reaction. Finally, intermediate 4 undergoes aromatization to gain the desired benzo[a]carbazoles 3 under an O₂ atmosphere.

Scheme 2 Possible mechanism.

In conclusion, we have developed a new protocol for a highly efficient and mild Diels–Alder reaction of 3-vinyl-indoles with arynes. The reaction allows the synthesis of various benzo[a]carbazole derivatives with excellent yields, which are significant structural units in a number of biologically active compounds. In addition, the cycloaddition reaction could be performed under transition-metal-free conditions and therefore represents an efficient and environmentally benign protocol for the synthesis of benzo[a]carbazoles.

Acknowledgements

This work was supported by the Natural Science Foundation of China (21072054, 21202206), the Ministry of Education of China (213027A), the Hunan Provincial Natural Science Foundation (12JJ2009), the Scientific Research Fund of Hunan Provincial Education Department (15A109) and the Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1059087. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra11025d

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