Photoredox-catalyzed bisarylation of bromonitroalkanes enabled by the dual role of nitro functionality: synthesis of bis(indolyl)methanes as promising α-glucosidase inhibitors

Abstract

Disclosed herein is an interesting photoredox catalysis for the direct bisarylation of bromonitroalkanes with 2-arylindoles to provide a simplified synthetic route to 3,3′-diindolylmethane (DIM) derivatives, where the nitro functionality plays a dual role as an activating and leaving group. The bromonitroalkanes can be used in situ in a one-pot, two-step reaction to generate bis(indolyl)methanes in high yields. A wide range of 2-arylindoles is also successfully employed to create the corresponding bis(indolyl)methanes. A preliminary in vitro biological evaluation study demonstrates that these compounds possess promising α-glucosidase inhibitors (IC₅₀ = 5.45 ± 0.64–28.06 ± 0.40 μM).

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Introduction

Functionalization of C–H bonds is a topic of interest in synthetic chemistry. N-heteroarenes are ubiquitous in pharmaceuticals and natural products.¹ The late-stage functionalization (LSF) of complex scaffolds containing N-heteroarenes is crucial in drug design and discovery.^2,3 The Minisci reaction provides a method for synthesizing alkyl-substituted N-heteroarenes via a radical pathway. Photocatalysis offers a new path for realizing the C–H bond functionalization of N-heteroarenes under mild conditions and provides an abundant radical precursor to pave the way toward complementary and previously unattainable regio- and chemoselectivities.^4,5 The photoredox catalysis expands the range of possible radical precursors and unconventional pathways for generating carbon (or heteroatom-based) radicals.⁶ Nitro compounds such as nitroalkanes, nitroolefins, and nitroarenes are available synthetic intermediates. The strong electron-withdrawing ability and cleavability properties of the nitro group enable the versatile reactivity of nitro compounds. Strikingly, the nitro group can activate the scaffold framework through inductive and resonance effects, making it easy to react with nucleophilic reagents or undergo single-electron reduction.⁷ The existence of a keto–enol type equilibrium involves the nitroalkane and its nitronic acid tautomer (aci/nitro equilibrium).⁸ Furthermore, nitroalkanes can be used as substrates for cross-coupling, in which the nitro group is substituted with various nucleophiles.⁹ In recent years, the work on photocatalysis showed the direct cleavage of the C–NO₂ bond through a radical pathway (Scheme 1). Most of the reported visible light-mediated reactions of nitroalkanes are limited to the substitution reactions of β-nitrostyrenes.^10–13 But some pioneering work has also been reported, e.g., Hyster reported a highly chemoselective and enantioselective Csp³–Csp³ cross-electrophile coupling (XEC) between alkyl halides and nitroalkanes catalyzed by flavin-dependent ‘ene’-reductases (EREDs),¹⁴ in which the nitro group was contextually eliminated as a nitrite anion. The photocatalytic reactions of other nitroalkanes involve only nitro group transitions, such as nitroalkanes to alkylnitrones,¹⁵ nitroalkanes to the corresponding nitriles¹⁶ and formylation of terminal alkynes using nitromethane as a formyl anion.¹⁷

Scheme 1 Previous protocol and this work for cleavage of the C(sp³)–NO₂ bond.

With the increasing incidence of diabetes worldwide, there is a constant need for novel antidiabetic agents. Natural products have been extensively used for treating diabetes with fewer side effects and improved symptoms of diabetic complications.¹⁸ Indole alkaloids are essential in natural products due to their diverse structures and adaptable biological activities, which show potential for discovering new antidiabetic drugs.¹⁹ Therefore, synthesizing indole derivatives, which possess properties similar to natural indole alkaloids, is a long-term pursuit of synthetic chemists.²⁰ For example, 3,3′-diindolylmethane (DIM) is a significant phytochemical originally extracted from cruciferous vegetables.²¹ They have various biological and pharmacological activities, including antimicrobial,²² anticancer,²³ and antiglycation.²⁴ DIMs are traditionally constructed via the reaction of indoles with diverse aromatic or aliphatic aldehydes in the presence of Lewis acids or Brønsted acids.²⁵ Methylene sources such as DMF,²⁶ DMSO,²⁷ methanol,²⁸ C₁/C₂ alcohols,²⁹ and dichloromethane³⁰ can also be used to construct DIMs. Moreover, using amines and amides as carbon sources via C–N bond cleavage has emerged as a viable method for DIM synthesis.³¹ We previously reported the visible light-catalyzed oxidation of tertiary amines as methylene sources for synthesizing 3-arylmethylindole derivatives.³²

Bromonitromethanes are ubiquitous reagents widely used in synthesizing α-functionalized terminal nitroalkanes,³³ nitrocyclopropanes,³⁴ nitroheterocycles,³⁵ and 1,3-dipolar cycloadditions.³⁶ Replacing a nitro group with other atoms or groups has considerable value.³⁷ In particular, in choreographed one-pot multi-step transformations, bromonitromethanes can react with various carbon-based nucleophiles. These advantages of bromonitromethanes as synthons led us to wonder if they could also be used as a novel methylene source to access 3,3′-diindolylmethanes (DIMs). On the other hand, photocatalysis has been widely used due to its unique advantage in forming different radicals in a mild and selective manner. Photocatalytic dissociation of the C–X bond can generate alkyl radicals when using alkyl halides as radical precursors.³⁸ Visible light-promoted reactions of electron-rich heteroaromates with malonates have been reported. The addition of classical protocols of haloalkane-derived carbon radicals to an indole ring by photocatalysis may be considered an inverse-electron demand Minisci reaction,^39–42 which usually requires an electron-donating sacrificial agent namely diisopropylethylamine (DIPEA), triphenylamine, or N,N,N′,N′-tetramethylethane-1,2-diamine (TMEDA). Therefore, we envision employing α-halonitromethanes to generate a highly active open-shell intermediate via SET homolytic cleavage of the carbon–halogen bond and nitromethane radicals. Subsequently, the nitromethane radicals will undergo subsequent denitrification reactions to form methylene intermediates. Herein, we report a novel photocatalytic strategy using bromonitromethane (BrCH₂NO₂) as a methylene source to successfully achieve the efficient synthesis of 3,3′-diindolylmethanes without an electron-donating sacrificial agent under mild reaction conditions, which can serve as promising α-glucosidase inhibitors.

Results and discussion

In our initial investigation, 2-phenylindole (1a) and bromonitromethane (2a) were the standard substrates. In the presence of 2 mol% of Ru(bpy)₃Cl₂·6H₂O, a solution of 1a (0.5 mmol) and 2a (0.6 mmol) in methanol (1.0 mL) was irradiated with a 10 W blue light-emitting diode (LED) at ambient temperature for 24 h. We were delighted to find that the desired product 3a was obtained with a yield of 28% (ESI,†Table 1, entry 2). A series of photocatalysts were screened to explore a better reaction efficiency, but no better results were obtained than those using Ru(bpy)₃Cl₂·6H₂O as the photocatalyst (ESI,†Table 1, entry 1). Subsequently, the effects of photocatalyst loading, molar ratio, solvent volume, and reaction time were separately analyzed (ESI, Tables S2–S6†). Finally, 3a acquired an 87% yield under the following optimal conditions (ESI, Table S6,† entry 5): substrates: 1a (0.6 mmol) and 2a (0.2 mmol), photocatalyst: Ru(bpy)₃Cl₂·6H₂O (2 mol%), solvent: 1,2-dichloroethane, reaction time: 30 h, and room temperature. Control experiments indicated that visible light and Ru(bpy)₃Cl₂·6H₂O are indispensable for the reaction (Table 1, entries 2 and 3). When the reaction was carried out under a N₂ atmosphere, the yield of 3a was similar to that obtained under air conditions (Table 1, entry 5), thus confirming that oxygen is not involved in the reaction.

Table 1 Control experiments^a

Entry	Variations from standard conditions	Yield^b (%)
a Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), and Ru(bpy)3Cl2·6H2O (2 mol%) in DCE (1 mL) at 30 °C for 30 h. b Yield of the isolated product after silica gel chromatography.
1	None	87
2	Performed in the dark	NR
3	Without Ru(bpy)3Cl2·6H2O	NR
4	Without BrCH2NO2	NR
5	Under N2	86
6	TEMPO	Trace

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With the optimized conditions in hand, a broad range of 2-substituted indoles were studied to reveal the substrate scope of the reaction (Table 2). 2-Phenylindoles containing different substituents at various positions on the 2-phenyl group were initially examined. The position and electronic properties of the substituents on indoles affected the experimental results. In general, 2-phenylindoles with a substituent on the para-position (Table 2, entries 2–7) of the 2-phenyl group gave higher yields than those with a substituent on the meta-position (Table 2, entries 8–12), possibly due to steric hindrance. The 2-phenylindoles with an electron-donating group namely –Me or –OMe on the para-position of the 2-phenyl group gave a higher yield than those containing an electron-withdrawing group (Table 2, entries 1–7). Similarly, the substituents on the indole skeleton with an electron-withdrawing group gave lower yields than those with an electron-donating group (Table 2, entries 13–18). 2-Thienylindole was also suitable for this reaction, which reacted with bromonitromethane 2a to give 3s in a good yield (Table 2, entry 19). However, no obvious product was detected when the N1-position of the indole was substituted. Fifteen new bis(indolyl)methane derivatives were obtained, and their structures were confirmed by HRMS, ¹H NMR, and ¹³C NMR (please see the ESI†).

Table 2 Substrate scope^a

Entry	R^1	R^2	Product	Yield^b (%)
a Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), and Ru(bpy)3Cl2·6H2O (2 mol%) in DCE (1 mL) at 30 °C for 30 h. b Yield of the isolated product after silica gel chromatography.
1	H	H	3a	87
2	4-CF3	H	3b	54
3	4-F	H	3c	76
4	4-Cl	H	3d	58
5	4-Br	H	3e	56
6	4-Me	H	3f	76
7	4-MeO	H	3g	67
8	3-F	H	3h	55
9	3-Cl	H	3i	54
10	3-Br	H	3j	62
11	3-Me	H	3k	51
12	3-MeO	H	3l	46
13	H	5-F	3m	41
14	H	5-Cl	3n	39
15	H	5-Br	3o	28
16	H	5-Me	3p	83
17	H	6-F	3q	48
18	H	6-Me	3r	84
19			3s	58

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Several control experiments were carried out to probe the mechanism of this reaction. Firstly, to verify whether a radical pathway was involved in this reaction, the reaction of 2-phenylindole (1a) and bromonitromethane (2a) was conducted in the presence of a free radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), which only gave product 3a in a trace amount (Table 1, entry 6). UPLC-QTOF-MS/MS detected the radical intermediate (˙CH₂NO₂) captured by TEMPO (Scheme 2). This result indicated that the reaction might occur through a radical pathway. We hypothesized that bromonitromethane could be used as a methylene source because nitromethane generates the corresponding ketones or aldehydes by the classical Nef reaction.^43,44 2-Phenyl-1H-indole-3-carbaldehyde was allowed to react with 2-phenylindole under the standard reaction conditions. The desired product 3a was not detected in the reaction, indicating that 2-phenyl-1H-indole-3-carbaldehyde is not an intermediate for this reaction.

Scheme 2 Radical trapping experiments.

For further exploration of the free radical species involved in the photocatalytic cycle, Stern–Volmer quenching experiments of Ru(II)* were performed, and the results revealed that both 2-phenylindole and bromonitromethane could quench the fluorescence of the excited states of Ru(II)* (Fig. 1). These results are consistent with literature reports that the electron transfer quenching of excited tris(2,2′-bipyridyl)ruthenium(II) can be completed by bromonitromethane,⁴⁵ and 2-phenylindole (1a) can be oxidized by the excited states of Ru(II)*.^46,47 Subsequently, the cyclic voltammetry (CV) measurement of 1b was performed (ESI, Fig. S6†). The results showed that the onset potential for the reduction of 1b was around −0.625 V (vs. SCE in MeCN). The data indicated that 1b could be reduced by the excited Ru(II)* (vs. SCE in MeCN).⁴⁸ Furthermore, the oxidation potential of 1a (E_ox = +0.08 V vs. SCE in MeCN) was determined in our previous work,⁴⁶ which can be oxidized by Ru(III) (E^II/III_1/2 = +1.29 V vs. SCE).⁴⁸ Therefore, based on these experimental results, we speculate that the process may involve an oxidative quenching cycle in the reaction.

Fig. 1 Stern–Volmer quenching profile of 0.05 mM Ru(bpy)₃Cl₂·6H₂O by using various concentrations of 1a (2-phenylindole) and 2a (bromonitromethane).

Based on our experimental data, prior work, and the literature,^12,49,50 the following mechanism was proposed for the photocatalytic Minisci type reaction (Scheme 3). Firstly, upon visible light irradiation, the photosensitizer Ru(II) reaches its excited state (Ru[II])*, which reduces bromonitromethane (BrCH₂NO₂) delivering simultaneously carbon-centered radical (˙CH₂NO₂) I and Ru(III). Then, coupling this electron-deficient radical at C3 of the electron-rich arene affords a stabilized radical intermediate II. Single-electron oxidation of intermediate II by Ru(III) generates radical cation intermediate III and regenerates the Ru(II) photosensitizer. The intramolecular proton transfer of III-A forms intermediate III-B, which can obtain intermediate IV. Subsequently, intermediate IV undergoes an elimination reaction of NO₂˙ and generates azafulvalene intermediate V.^10,26 Finally, the nucleophilic attack of 1a on intermediate V gives 3a. At the same time, we detected the presence of intermediates III-B and V in the reaction by using UPLC-TOF-MS/MS (please see the ESI†).

Scheme 3 Possible mechanism.

All 19 diindolylmethane derivatives (3a–3s) were examined for their activity towards α-glucosidase enzyme inhibition (Fig. 2). A limited structure–activity relationship (SAR) suggested that the position and nature of different substituted groups on the indole moiety have different influences on the α-glucosidase inhibition. Among the series of experiments, all derivatives showed a variable degree of α-glucosidase inhibition with IC₅₀ values ranging from 5.45 ± 0.64 to 28.06 ± 0.40 μM. The SAR was mainly based on different substituents on the phenyl part in the indole C-2 position and the indole ring. In particular, compound 3e was the most potent compound with an IC₅₀ value of about 5.45 ± 0.64 μM.

Fig. 2 IC₅₀ values of 3a–3s with α-glucosidase inhibition.

Conclusions

In conclusion, we have developed a new photoredox method for the direct bisarylation of bromonitromethanes with 2-arylindoles under considerably mild conditions without requiring additional additives. This method has transformed a wide range of 2-arylindoles into functionalized bis(indolyl)methanes with high yields. In this study, a series of new bis(indolyl)methanes were synthesized through one step, and the in vitro inhibition activity of α-glucosidase aided in developing new potential α-glucosidase inhibitors. These molecules demonstrated superior efficacy against the studied α-glucosidase. Furthermore, investigation is currently ongoing in our laboratory to broaden the applicability of potential α-glucosidase inhibitors.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (No. 22201307), Yunnan Fundamental Research Projects (202201AT070286), the Yunnan Science and Technology Talents and Platform Program (No. 202105AG070011), the Science and Technology Project of Yunnan Province (No. 202102AA100020), and the Fundamental Research Funds for the Central Universities (3332022049).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01208a

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