TEMPO-catalyzed oxidative homocoupling route to 3,2′-biindolin-2-ones via an indolin-3-one intermediate

Abstract

A combinative C2-selective arylation, and C3-selective carbonylation of free indole derivatives, by means of TEMPO catalysis and a silver oxidant under non-directing group conditions, was successful demonstrated. This new methodology is both atom and step efficient and is applicable to a broad scope of substrates, allowing the synthesis of a range of synthetically valuable 3,2′-biindolin-2-ones in moderate to excellent yields.

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Introduction

Biindole scaffolds are important motifs in an array of natural products with diverse biological activities,^1–3 exemplified by the TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) antagonist bisindigotin 1 (Fig. 1) from the Chinese medicinal herb Isatis indigotica.⁴ This herbal plant has long been used as a folk medicine in China for treatment of viral diseases and diseases with an inflammatory nature.⁴ In addition, indirubin, a bis-indole scaffold and its derivatives, are present in some traditional Chinese medicines and inhibit cyclin-dependent kinases (CDKs).⁵ These medicines have historically been used to treat chronic diseases including leukemia.⁶

Fig. 1 Representative natural products with a 2-substituent indolin-3-one structural unit.

Accordingly, synthesis and functionalization of biindolyls have attracted much attention over decades.^7–9 Recently, some progress on construction of the 2,3′-linked⁷ and 3,3′-linked⁸ biindolyl scaffolds was made, including the palladium- or copper-catalyzed intermolecular coupling reaction and iodine-induced dimerization of indoles. For example, Zhang and co-workers reported a mild and selective method for dimerization of indoles by palladium catalysis to give 2,3′-biindolyls in high yields at room temperature.^9b However, most of these procedures require expensive metal catalysts and high loading of metal oxidants. In addition, the regioselectivity control of C2 arylation can be quite challenging under non-directing group conditions. From the viewpoints of atom economy, cost efficiency and green chemistry, atmospheric oxygen is obviously superior to other reagents, and thus represents the quintessential oxidant.¹⁰ In the past decades, most efforts have been directed to the development of transition metal-based catalysts. In contrast, much less attention has been paid to the development of non-metallic oxidation systems, largely ignoring their inherent advantages.^10c The radical TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl radical) and its derivatives are well-established catalysts for oxidation processes, and now used extensively in organic synthesis and industrial applications as a mild, safe, and economical alternative to heavy metal reagents as highly selective oxidation catalysts for the production of pharmaceuticals, flavors, fragrances, agrochemicals, and a variety of other specialty chemicals.¹¹ As part of our ongoing investigations on environmentally benign, selective, and controllable C–H bond functionalization, we studied the TEMPO-catalyzed oxidative homocoupling of indoles in air.¹² Herein, we report the first successful example of TEMPO-catalyzed oxidative homocoupling of indoles affording substituted C2–C3′ bisindole-3-ones 9 (Scheme 1).

Scheme 1 Homocoupling of indole.

Results and discussion

Preliminary studies were carried out at 80 °C in an open tube, using commercially available unsubstituted indole (5a) in the presence of TEMPO and K₃PO₄. A variety of transition-metal catalysts, including FeCl₃·6H₂O, FeSO₄, ZrCl₄, ZnCl₂, CoCl₂, CuI, CuCl, and Ag₂CO₃, were screened. It was found that Ag₂CO₃ was the most efficient catalyst for this reaction, which gave the desired product 9a in 51% yield (Table 1, entry 8); while other transition-metal catalysts did not undergo the conversion under the reaction conditions. The structure of 9a was confirmed by X-ray crystallography (see ESI†). Among silver sources tested, including Ag₂CO₃, AgNO₃, AgOTf, and AgBF₄, were tested in DMF using TEMPO as the oxidant at 80 °C for 12 h, and Ag₂CO₃ was found to be the most effective catalyst (Table 1, entries 8–12). The amount of Ag₂CO₃ also has a large influence on the yield of 9a. In the absence of Ag₂CO₃ catalyst, the desired product was not obtained under these conditions, whereas, at 35 mol% of Ag₂CO₃, the desired product is obtained in 57% yield, and at lower or higher loading, the yield decreases (Table 1, entries 12–16). It was also found that the use of TEMPO as an oxidant is critical to the reaction. In the absence of TEMPO, the homocoupling reaction did not proceed. However, the slightly more loading amounts of TEMPO result in a dramatic influence on the yield (Table 1, entries 17–20). For example, 81% yield of 9a was obtained when using 0.15 mol% of TEMPO (Table 1, entry 19). Further assessment of the reaction solvents indicated that DMF was the optimal solvent, while other solvents gave lower yields or were ineffective (Table 1, entries 21–25).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol%)	TEMPO (mol%)	Solvent	Base (mol%)	Yield^b (%)
a Condition: 5a (0.3 mmol), solvent (1 mL), 80 °C, 12 h, under open air.b Isolated yields.
1	FeCl3·6H2O (15)	10	DMF	K3PO4 (10)	0
2	FeSO4 (15)	10	DMF	K3PO4 (10)	0
3	ZrCl4 (15)	10	DMF	K3PO4 (10)	0
4	ZnCl2 (15)	10	DMF	K3PO4 (10)	0
5	CoCl4 (15)	10	DMF	K3PO4 (10)	0
6	Cul (15)	10	DMF	K3PO4 (10)	Trace
7	CuCl2 (15)	10	DMF	K3PO4 (10)	Trace
8	Ag2CO3 (15)	10	DMF	K3PO4 (10)	51
9	AgNO3 (15)	10	DMF	K3PO4 (10)	24
10	AgOTf (15)	10	DMF	K3PO4 (10)	35
11	AgBF4 (15)	10	DMF	K3PO4 (10)	22
12	—	10	DMF	K3PO4 (10)	0
13	Ag2CO3 (5)	10	DMF	K3PO4 (10)	10
14	Ag2CO3 (25)	10	DMF	K3PO4 (10)	53
15	Ag2CO3 (35)	10	DMF	K3PO4 (10)	57
16	Ag2CO3 (45)	10	DMF	K3PO4 (10)	55
17	Ag2CO3 (35)	—	DMF	K3PO4 (10)	0
18	Ag2CO3 (35)	5	DMF	K3PO4 (10)	27
19	Ag2CO3 (35)	15	DMF	K3PO4 (10)	81
20	Ag2CO3 (35)	20	DMF	K3PO4 (10)	81
21	Ag2CO3 (35)	15	DMSO	K3PO4 (10)	67
22	Ag2CO3 (35)	15	Toluene	K3PO4 (10)	0
23	Ag2CO3 (35)	15	Pyridine	K3PO4 (10)	0
24	Ag2CO3 (35)	15	1,4-Dioxane	K3PO4 (10)	Trace
25	Ag2CO3 (35)	15	ClCH2CH2Cl	K3PO4 (10)	0
26	Ag2CO3 (35)	15	DMF	NaOAc (10)	87
27	Ag2CO3 (35)	15	DMF	LiOH (10)	0
28	Ag2CO3 (35)	15	DMF	NaHCO3 (10)	30
29	Ag2CO3 (35)	15	DMF	K2CO3 (10)	48

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Finally, we examined a series of bases (Table 1, entries 26–29). The observation revealed that NaOAc is slightly better than K₃PO₄ and other bases, such as LiOH, NaHCO₃, and K₂CO₃, are inferior to K₃PO₄. After a great deal of screening on different parameters we found that the combinative C2-selective arylation and C3-selective carbonylation of indole by using TEMPO (15 mol%) in air as catalyst, Ag₂CO₃ (35 mol%) as an oxidant, and NaOAc (10 mol%) as base in DMF at 80 °C led to the highest efficiency (87% yield, Table 1, entry 26).

With a set of optimized conditions in hand, we next examined the indole scope of this TEMPO-catalyzed oxidative homocoupling reaction. As shown in Table 2, the reaction can tolerate a variety of functional groups at the 4, 5, 6, and 7 positions of indoles, such as F, Cl, Br, CH₃, CH₃O, BnO, CO₂CH₃, and CN, and the corresponding reactions proceeded smoothly to afford the desired products in moderate to excellent yields with high regioselectivity. The substituent effect on the indole ring was then investigated. The results have shown that electronegativities of substituents played a major role in governing the reactivity of the substrates. Electron-donating substitutents showed better results than electron-withdrawing substitutents in this transformation. For example, 7-substituted indole derivatives with electron-donating substituents (CH₃, OCH₃, and OBn) afforded the desired 9l–n in yields ranging from 76% to 90%, while 7-substituted indole derivatives with electron-withdrawing substituents (Cl and Br) provided the desired products in 61 and 72% yields, respectively. It is worth noting that substrate with a strong electron-withdrawing substitutents at C4-position, such as CO₂CH₃ and CN, gave 9o and 9p in 63% and 38% yields, respectively. This is particularly important, since substrates with a strong electron-withdrawing group, such as a nitrile group, disfavored the homocoupling of indoles and there were few examples reported.^7,8

Table 2 Substrate scope^a

Entry	R	Product	Yield^b [%]
a Reaction conditions: indole (0.3 mmol), TEMPO (15 mol%), Ag2CO3 (35 mol%), NaOAc (10 mol%), DMF (1 mL), 80 °C.b Isolated yields.
1	H	9a	87
2	5-F	9b	66
3	5-Br	9c	75
4	5-CH3	9d	89
5	5-OCH3	9e	71
6	5-OBn	9f	78
7	6-F	9g	73
8	6-Cl	9h	64
9	6-CH3	9i	79
10	7-Cl	9j	61
11	7-Br	9k	72
12	7-CH3	9l	90
13	7-OCH3	9m	76
14	7-OBn	9n	82
15	4-CN	9o	38
16	4-CO2CH3	9p	63

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To gain some mechanistic insight into the process of this reaction, a series of control experiments were conducted (Scheme 2). Because the TEMPO-catalyzed oxidative homocoupling reaction was performed in air, the role of O₂ in this reaction was explored by conducting several control experiments. Under an O₂ atmosphere, the reaction yield was not increased, but a more rapid conversion of the starting material to the reaction product was observed by TLC detection compared to that performed under air conditions. However, only trace amount of the product was obtained under an argon atmosphere, even a long reaction time. These results indicated that O₂ is essential for the TEMPO-catalyzed transformation. In addition, in the control experiment of 5a with TEMPO but without Ag₂CO₃, compound 9a was obtained only in 12% yield. The result indicated that Ag₂CO₃ act as terminal oxidant. Under the optimized conditions, N–CH₃ indole was chosen as a substrate instead of indole. To our surprise, no conversion was observed, indicating that the substituents at the N1-position of the indole had a great influence on the reactivity.

Scheme 2 Mechanistic studies.

Although the detailed mechanism remained unclear at the current stage, a plausible reaction pathway based on the basis of the results described above and relevant literature¹³ is outlined in Scheme 3. First, indole was oxidized slowly in the presence of TEMPO, Ag₂CO₃ and O₂ into indenone 11 which should be unstable and was never isolated.^13a,d Then, a rapid nucleophilic addition of another indole molecule on the C=N bond of this intermediate gave the intermediate 12, which was oxidized rapidly to afford product 9a.

Scheme 3 Plausible reaction pathway.

To verify such a mechanistic scenario, we attempted to obtained the putative intermediate 12 or its derivatives. Fortunately, trace amounts of 13 can be determined in the reaction mixtures when 7-methyl-1H-indole was subjected to the standard reaction conditions, which showed us some clues on the reaction intermediate. In the next step, to obtain more information concerning the reaction pathway, we separated and collected the intermediate 13, and subjected it to react with TEMPO under standard reaction conditions, and this gave product 9l in 93% yield (Scheme 4). This result showed that 13 is the intermediate of the dimeric reaction.

Scheme 4 Investigation of the reaction mechanism.

Conclusions

In conclusion, we have developed a general and efficient method for the synthesis of 3,2′-biindolin-2-ones via a TEMPO-catalyzed oxidative homo dimerization in moderate to excellent yields with high regioselectivity. The advantages of this new method are broad substrate scope, operational simplicity, and high atom-economy. Moreover, the high halogen compatibility of the process can provide a facile access to halo-substituted 3,2′-biindolin-2-ones.

Acknowledgements

The authors are grateful to the NSF of China (No. 21462002), Natural Science Foundation of Jiangxi Province (No. 20161BAB203096) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental section and NMR data of the prepared compounds. CCDC 1453369. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra24834a

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