Cs₂CO₃-promoted [3 + 2] cycloaddition providing an easy protocol toward imidazo[1,2-a]indole derivatives

Abstract

A base-promoted [3 + 2] cycloaddition for the construction of multi-functionalized imidazo[1,2-a]indole derivatives with good yields has been accomplished. This transformation provides an easy and facile protocol for the formation of diverse imidazo[1,2-a]indoles of chemical and biomedical importance using preformed 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles and readily available but-2-ynedioates under mild conditions.

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Introduction

The fused indole nucleus is one of the most important heterocyclic motifs found in natural products, pharmaceutically active compounds and agrochemicals.¹ Therefore, the search for an efficient construction of a fused indole skeleton of chemical and biomedical importance is an active but challenging subject in organic synthesis.² Structurally diverse imidazo[1,2-a]indole subunits commonly exist in nature and are represented by asperlicin,³ fumiquinazoline S,⁴ fiscalin A,⁵ and tryptoquivalins⁶ which exhibit a broad range of biological activities (Fig. 1). For example, asperlicins and its analogues have acted as cholecystokinin antagonist;³ fumiquinazolines have exhibited antifungal activity;⁴ fiscalins and its analogues were found to serve as the substance P antagonists;⁵ and tryptoquivalines have shown antibacterial and antibiofilm activity.⁶ Although these fused imidazo[1,2-a]indoles showed important biological activities, efficient and practical approaches to these molecules have been rarely documented. There are some limited methods for the assembly of imidazo[1,2-a]indoles, which suffer from the tedious steps,⁷ low efficiency,^7,8 and/or the narrow substrate scopes.⁹ Hence, the exploration of new, facile and versatile method for forming functionalized imidazo[1,2-a]indoles from readily available starting materials is still highly desired but full of challenge.

Fig. 1 Structurally related imidazo[1,2-a]indole alkaloids.

[3 + 2] cycloaddition reactions were one of the key tools that allow the one-step creation of several bonds in a single operation and offer remarkable advantages like convergence, high efficiency, and operational simplicity.¹⁰ In recent years, considerable efforts have been devoted to the development of various [3 + 2] cycloaddition reactions toward the formation of various five-membered heterocycles.¹¹ Recently, we reported the unprecedented synthesis of 3-sulfonyl-2-sulfonyldiazenyl-1H-indole derivatives through TBAI/TBHP-mediated oxidative reactions (Scheme 1).¹² Considering the nucleophilicity of free N–H of indole ring and the electrophilicity of azo unit, we reasoned that 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles can serve as 1,3-dipoles in the presence of base, allowing [3 + 2] cycloaddition reactions with electron-deficient alkynes for forming important multifunctional imidazo[1,2-a]indoles. Herein we report the successful realization of this concepts via a facile [3 + 2] cycloaddition using preformed 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles and readily available but-2-ynedioates under mild conditions, which providing densely functionalized imidazo[1,2-a]indole-2,3-dicarboxylates in a highly regioselective and functional-group-compatible manner (Scheme 2).

Scheme 1 Synthesis of 3-sulfonyl-2-sulfonyldiazenyl-1H-indole.

Scheme 2 Synthesis of imidazo[1,2-a]indoles.

Results and discussion

In our previous communication, to explore the potential applications of 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles, [3 + 2] cycloaddition reaction between 3-tosyl-2-(tosyldiazenyl)-1H-indole (1a) and diethyl acetylenedicarboxylate (2a) was carried out in the presence of Et₃N in EtOH at room temperature, affording one example of tricyclic pyridazino[3,4-b]indole-3,4-dicarboxylate 3a in 47% yield. After completion of this reaction, we believed that this reaction may be improved by screening appropriate reaction conditions. In order to obtain the optimal reaction conditions, the above model reaction was conducted to investigate the impact of various reaction conditions on the reaction outcome, including solvents, temperatures and bases. The results are listed in Table 1. The reaction using NaOH as a base promoter in EtOH gave a 57% yield of product 3a (entry 2). The use of Cs₂CO₃ delivered a higher yield (up to 62%, entry 3). The subsequent evaluation of base promoter was performed with EtOH as the reaction solvent. This evaluation showed that other bases including pyridine, K₂CO₃, and DBU all gave inferior results than that of Cs₂CO₃ (entries 4–6, respectively, vs. entry 2). Taking Cs₂CO₃ as the optimized base promoter, the effect of solvent were investigated. The solvent was switched to CH₂Cl₂, giving access to the expected product 3a in 73% yield (entry 7). Other aprotic solvents, such as acetone, ethyl acetate, acetonitrile, toluene, DMF, DMSO, and 1,4-dioxane, were inferior to CH₂Cl₂ in terms of reaction yields (entries 8–14). Lowering the amount of Cs₂CO₃ decreased the yield of product 3a (entry 15). Next, the reaction temperature was evaluated. Raising the temperature slightly to 40 °C proved less efficient, only providing 3a with a 52% yield (entry 16).

Table 1 Optimization of conditions for forming product 3a^a

Entry	Base (equiv.)	Solvent	t (°C)	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), base promoter (3.0 equiv.), solvent (2.0 ml), 20 hours.b Isolated yield based on 1.c Not detected (N.D).
1	Et3N (3.0)	EtOH	25	47
2	NaOH (3.0)	EtOH	25	57
3	Cs2CO3 (3.0)	EtOH	25	62
4	Pyridine (3.0)	EtOH	25	36
5	K2CO3 (3.0)	EtOH	25	N.D^c
6	DBU (3.0)	EtOH	25	37
7	Cs2CO3 (3.0)	CH2Cl2	25	73
8	Cs2CO3 (3.0)	Acetone	25	37
9	Cs2CO3 (3.0)	Ethyl acetate	25	46
10	Cs2CO3 (3.0)	CH3CN	25	66
11	Cs2CO3 (3.0)	Toluene	25	57
12	Cs2CO3 (3.0)	DMF	25	62
13	Cs2CO3 (3.0)	DMSO	25	N.D^c
14	Cs2CO3 (3.0)	1,4-Dioxane	25	56
15	Cs2CO3 (2.0)	CH2Cl2	25	70
16	Cs2CO3 (3.0)	CH2Cl2	40	52

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With the optimal conditions to access functional imidazo[1,2-a]indoles in hand, we then turned to evaluating the scope of the Cs₂CO₃-promoted [3 + 2] cycloaddition reaction for different substituted 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles and acetylenedicarboxylates (Scheme 3). Upon repeating the reaction with diethyl acetylenedicarboxylate 2a, we are pleased to find that a variety of functional groups of 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles including bearing electron-rich, electron-neutral, and electron-poor groups were well-tolerated under the above conditions to give corresponding adducts 3b–3g in good yields of 56–78%. Generally, substituents on the benzenesulfonyl nucleus bearing withdrawing groups showed the lower reactivity than their electron-donating counterparts. For instance, 1c with methoxy group was treated with diethyl but-2-ynedioate 2a, affording the corresponding product 3c in a 78% yield. In contrast, the presence of a bromo group of substrate 1g resulted in a 56% chemical yield. These observations indicated that electronic nature of substituents on the arylsulfonyl moiety had some effect on the reaction efficiency. Alternatively, dimethyl but-2-ynedioate 3b was successfully engaged in this [3 + 2] cycloaddition reaction, and the corresponding imidazo[1,2-a]indole products 3h–3l were obtained with 60–82% yields. In view of these results, we considered varying the substituents of the indole ring and select 5-methoxyl counterpart as a representative substrate to explore the feasibility of the reaction. As we had expected, 5-methoxylindoles bearing electron-donating, -neutral, or -withdrawing groups on the arylsulfonyl motif were reacted with acetylenedicarboxylates 2a and 2b, participating in the current Cs₂CO₃-promoted [3 + 2] cycloaddition successfully, and the desired imidazo[1,2-a]indole 3m–3q were formed with higher yields. Although imidazo[1,2-a]indoles 3 were characterized by their NMR spectroscopy and HRMS, their structures were determined by X-ray diffraction of compound 3a (Fig. 2) (see the ESI†).

Scheme 3 [3 + 2] cycloaddition reactions for forming products 3. Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cs₂CO₃ (3.0 equiv.) were stirred in CH₂Cl₂ (2.0 ml) at room temperature for 20 h.

Fig. 2 The ORTEP drawing of 3a.

To develop the efficiency of our method, a gram-scale reaction of easily prepared 1a with 2a was carried out under the standard conditions, providing in a 68% yield of 3a (Scheme 4), which offered the potential application in organic synthesis.

Scheme 4 Scale-up experiment.

On the basis of our experimental observations and literature precedents,¹¹ a plausible mechanistic pathway to products 3 is illustrated in Scheme 5. Initially, in the presence of base, indoles 1 undergoes deprotonation to indol-1-ide intermediate A, followed by [3 + 2] cycloaddition with acetylenedicarboxylates 2 to yield imidazo[1,2-a]indole intermediate B, which converts into the final products 3 via protonation.

Scheme 5 Plausible mechanism for forming products 3.

Conclusions

In conclusion, a reliable and mild base-promoted [3 + 2] cycloaddition reaction has been developed using readily preformed 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles and acetylenedicarboxylates, by which a wide set of imidazo[1,2-a]indole derivatives with a wide diversity in substituents are rapidly synthesized in a convergent fashion. This straightforward and operationally simple method allows installing two C–N bonds and imidazole skeleton. The flexibility of structural modification and mild reaction conditions make this strategy highly viable for future applications.

Experimental section

General

Example for the synthesis of 3a: diethyl 1-(4-methylphenylsulfonamido)-9-tosyl-1H-imidazo[1,2-a]indole-2,3-dicarboxylate. Typically, the substrate 4-methyl-N′-(3-tosyl-1H-indol-2-yl)benzenesulfonohydrazide (1a, 0.5 mmol, 0.228 g), diethyl but-2-ynedioate (2a, 1.0 mmol, 0.170 g), and CH₂Cl₂ (2.0 ml), were added to a 10 ml Schlenk tube, followed by addition of Cs₂CO₃ (3.0 equiv., 0.489 g). The mixture was stirred at 25 °C for 20 h. The solution was then extracted with CH₂Cl₂, the combined organic layers were dried over Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to afford the desired product 3a.

White solid, mp 185–186 °C; IR: 3134 (NH), 1727 (C=O), 1613 (C=O). ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 8.01–7.88 (m, 4H), 7.60 (d, J = 8.4 Hz, 2H), 7.40–7.37 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 7.27–7.23 (m, 1H), 4.45–4.39 (m, 2H), 3.89–3.68 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.6, 156.7, 143.2, 141.7, 140.4, 130.3, 129.9, 129.8, 128.3, 126.9, 125.6, 124.9, 121.5, 119.5, 114.2, 90.3, 63.4, 62.8, 21.5, 21.4, 14.1, 13.8. HRMS (ESI) m/z: calcd for C₃₀H₂₉N₃O₈S₂Na: 646.1288 [M + Na]⁺; found: 646.1299.

Diethyl 9-((4-t-butylphenyl)sulfonyl)-1-(4-(t-butyl)phenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3b). White solid, mp 201–202 °C; IR: 3115 (NH), 1715 (C=O), 1612 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.82–7.75 (m, 2H), 7.69–7.59 (m, 3H), 7.42–7.36 (m, 2H), 7.29 (s, 1H), 7.28–7.23 (m, 2H), 7.21–7.15 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 6.8 Hz, 3H), 1.45 (t, J = 6.8 Hz, 3H), 1.26 (s, 9H), 1.08 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 159.0, 158.7, 157.0, 156.3, 140.3, 138.0, 131.4, 129.5, 129.1, 128.7, 126.5, 125.9, 124.5, 121.5, 118.8, 116.2, 114.3, 88.9, 62.8, 35.1, 31.0, 30.6, 14.0, 14.0. HRMS (ESI, m/z): calculated for C₃₆H₄₀N₃O₈S₂ [M − H]⁻ 706.2251, found 706.2252.

Diethyl 9-((4-methoxyphenyl)sulfonyl)-1-(4-methoxyphenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3c). White solid, mp 204–205 °C; IR: 3135 (NH), 1719 (C=O), 1612 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.93 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.85–7.82 (m, 2H), 7.66–7.62 (m, 3H), 6.92–6.84 (m, 2H), 6.82–6.73 (m, 2H), 4.51 (q, J = 7.2 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 1.47–1.43 (m, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 163.8, 162.7, 158.7, 156.8, 140.2, 136.4, 130.6, 129.9, 129.1, 125.6, 124.8, 121.4, 119.4, 115.0, 114.5, 114.2, 90.6, 63.3, 62.8, 56.2, 56.0, 14.1, 13.8. HRMS (ESI, m/z): calculated for C₃₀H₂₈N₃O₁₀S₂ [M − H]⁻ 654.1215, found 654.1211.

Diethyl 1-(phenylsulfonamido)-9-(phenylsulfonyl)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3d). White solid, mp 226–227 °C; IR: 3177 (NH), 1724 (C=O), 1615 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.93 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.97–7.90 (m, 2H), 7.76–7.73 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.55–7.47 (m, 2H), 7.41–7.38 (m, 4H), 7.34–7.30 (m, 1H), 7.26–7.19 (m, 1H), 4.50 (q, J = 7.2 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.43 (q, J = 7.2 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 158.5, 156.9, 143.1, 138.5, 135.7, 134.6, 132.6, 129.4, 128.8(9), 128.8(5), 126.7, 126.3, 124.8, 121.7, 118.7, 116.2, 114.5, 62.9, 14.0, 14.0. HRMS (ESI, m/z): calculated for C₂₈H₂₄N₃O₈S₂ [M − H]⁻ 594.0999, found 594.1021.

Diethyl 9-((4-chlorophenyl)sulfonyl)-1-(4-chlorophenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3e). White solid, mp 209–211 °C; IR: 3223 (NH), 1731 (C=O), 1617 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.92–7.86 (m, 2H), 7.72 (m, 1H), 7.70–7.63 (m, 2H), 7.43–7.41 (m, 1H), 7.41–7.39 (m, 1H), 7.36–7.32 (m, 3H), 7.28–7.21 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.46–1.42 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 158.4, 156.8, 141.7, 139.1, 138.7, 134.2, 130.3, 129.8, 129.2, 129.1, 127.8, 126.7, 125.1, 122.1, 118.7, 116.5, 114.5, 88.4, 63.1, 63.0, 14.0, 14.0. HRMS (ESI, m/z): calculated for C₂₈H₂₂Cl₂N₃O₈S₂ [M − H]⁻ 662.0220, found 662.0225.

Diethyl 9-((4-bromophenyl)sulfonyl)-1-(4-bromophenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3f). White solid, mp 210–211 °C; IR: 3220 (NH), 1729 (C=O), 1617 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.69 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.82–7.80 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.63–7.54 (m, 4H), 7.56–7.47 (m, 2H), 7.37–7.35 (m, 1H), 7.28–7.24 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.45–1.42 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 158.4, 156.8, 142.2, 138.7, 134.8, 132.8, 132.2, 130.3, 129.3, 129.0, 127.7, 126.7, 125.1, 122.1, 118.8, 116.6, 114.5, 88.3, 63.1, 63.0, 14.0, 14.0. HRMS (ESI, m/z): calculated for C₂₈H₂₂Br₂N₃O₈S₂ [M − H]⁻ 751.9190, found 751.9193.

Diethyl 9-(naphthalen-2-ylsulfonyl)-1-(naphthalene-2-sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3g). White solid, mp 209–211 °C; IR: 3118 (NH), 1714 (C=O), 1611 (C=O). ¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 8.11–8.05 (m, 6H), 8.00–7.94 (m, 3H), 7.75–7.73 (m, 2H), 7.70–7.55 (m, 3H), 7.42–7.38 (m, 1H), 7.26–7.24 (m, 1H), 4.36–4.34 (m, 2H), 3.57 (s, 1H), 3.00 (s, 1H), 1.22 (t, J = 7.2 Hz, 3H), 0.65 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.6, 156.5, 141.3, 140.9, 135.1, 134.7, 132.1, 132.0, 130.0, 129.4, 129.0, 128.2, 127.7, 125.6, 125.1, 123.2, 122.6, 121.6, 119.6, 114.1, 90.0, 63.4, 62.5, 14.1, 13.1. HRMS (ESI, m/z): calculated for C₃₆H₂₈N₃O₈S₂ [M − H]⁻ 694.1312, found 684.1309.

Dimethyl 1-(4-methylphenylsulfonamido)-9-tosyl-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3h). White solid, mp 226–228 °C; IR: 3217 (NH), 1732 (C=O), 1616 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 8.21–8.18 (m, 1H), 7.82–7.80 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.61–7.57 (m, 2H), 7.33–7.30 (m, 1H), 7.26–7.18 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 4.04 (s, 3H), 3.90 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.0, 157.4, 146.2, 143.5, 140.3, 138.4, 132.1, 130.1(09), 130.1(07), 129.5, 129.4, 129.3, 128.9, 126.6, 126.3, 124.7, 121.7, 118.7, 116.0, 114.4, 89.1, 53.4, 53.3, 21.5. HRMS (ESI, m/z): calculated for C₂₈H₂₄N₃O₈S₂ [M − H]⁻ 594.0999, found 594.0999.

Dimethyl 9-((4-methoxyphenyl)sulfonyl)-1-(4-methoxyphenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3i). White solid, mp 206–207 °C; IR: 3112 (NH), 1731 (C=O), 1611 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.94 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.91–7.83 (m, 2H), 7.71–7.56 (m, 3H), 7.33–7.29 (m, 1H), 7.25–7.19 (m, 1H), 6.92–6.85 (m, 2H), 6.82–6.72 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.80 (s, 3H), 3.67 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.7, 162.9, 159.0, 157.5, 138.3, 134.9, 131.2, 129.4, 128.5, 126.6, 126.1, 124.7, 121.6, 118.6, 116.0, 114.8, 114.4, 114.1, 89.5, 55.7, 55.5, 53.4, 53.2. HRMS (ESI, m/z): calculated for C₂₈H₂₄N₃O₁₀S₂ [M − H]⁻ 626.0897, found 626.0897.

Dimethyl 9-((4-t-butylphenyl)sulfonyl)-1-(4-t-butylphenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3j). White solid, mp 195–197 °C; IR: 3221 (NH), 1729 (C=O), 1614 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.81–7.76 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.63–7.59 (m, 2H), 7.40–7.37 (m, 2H), 7.30 (s, 3H), 7.19–7.17 (m, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 1.26 (s, 9H), 1.09 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 159.0, 157.5, 156.4, 140.2, 137.9, 131.4, 130.9, 129.3, 129.1, 128.8, 128.7, 126.5, 126.0, 125.9, 124.6, 121.6, 118.8, 116.1, 114.3, 89.2, 53.4, 53.3, 35.1(2), 35.1(06), 31.0, 30.7. HRMS (ESI, m/z): calculated for C₃₄H₃₆N₃O₈S₂ [M − H]⁻ 678.1938, found 678.1947.

Dimethyl 9-((4-chlorophenyl)sulfonyl)-1-(4-chlorophenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3k). White solid, mp 223–224 °C; IR: 3217 (NH), 1736 (C=O), 1617 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.96–7.90 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.71–7.65 (m, 2H), 7.46–7.34 (m, 5H), 7.30–7.28 (m, 1H), 4.04 (s, 3H), 3.83 (s, 3H). HRMS (ESI, m/z): calculated for C₂₆H₁₈Cl₂N₃O₈S₂ [M − H]⁻ 633.9907, found 633.9885.

Dimethyl 9-((4-bromophenyl)sulfonyl)-1-(4-bromophenyl sulfonamido)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3l). White solid, mp 213–214 °C; IR: 3179 (NH), 1718 (C=O), 1615 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.95–7.87 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.71–7.62 (m, 2H), 7.48–7.33 (m, 5H), 4.04 (s, 3H), 3.83 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.2, 159.0, 145.9, 145.6, 141.2, 134.7, 131.9, 131.2, 130.8, 129.4, 129.3, 125.8, 125.5, 124.2, 123.5, 119.8, 119.1, 114.7, 110.6, 86.7, 53.1, 53.1. HRMS (ESI, m/z): calculated for C₂₆H₁₈Br₂N₃O₈S₂ [M − H]⁻ 721.8896, found 721.8891.

Diethyl 7-methoxy-1-(4-methylphenylsulfonamido)-9-tosyl-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3m). White solid, mp 183–185 °C; IR: 3177 (NH), 1722 (C=O), 1610 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.92 (s, 1H), 8.13 (m, 1H), 7.77–7.73 (m, 2H), 7.60–7.58 (m, 2H), 7.20–7.18 (m, 2H), 7.12–7.09 (m, 3H), 6.79–6.77 (m, 1H), 4.48 (q, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 1.43 (t, J = 7.2 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 158.6, 157.2, 157.0, 146.0, 143.4, 140.4, 138.4, 132.2, 129.5, 128.9, 126.1, 121.4, 116.0, 115.5, 110.8, 100.7, 88.6, 62.9, 62.7, 55.7, 21.6, 21.5, 14.0, 14.0. HRMS (ESI, m/z): calculated for C₃₁H₃₀N₃O₉S₂ [M − H]⁻ 652.1418, found 652.1438.

Diethyl 9-((4-chlorophenyl)sulfonyl)-1-(4-chlorophenyl sulfonamido)-7-methoxy-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3n). White solid, mp 235–236 °C; IR: 3172 (NH), 1714 (C=O), 1614 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 8.15–8.13 (m, 2H), 8.04–8.00 (m, 2H), 7.86–7.83 (m, 1H), 7.50–7.45 (m, 2H), 7.16–7.12 (m, 2H), 6.33–6.31 (m, 1H), 5.92–5.90 (m, 1H), 4.30 (q, J = 7.2, 2H), 3.96 (m, 1H), 3.70–3.59 (m, 1H), 3.37 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 158.9, 158.6, 156.7, 145.7, 145.4, 141.3, 136.4, 134.5, 134.1, 132.1, 129.2, 129.1, 129.0, 128.2, 120.7, 115.6, 110.6, 108.4, 86.7, 62.2, 61.9, 55.7, 14.3, 13.9. HRMS (ESI, m/z): calculated for C₂₉H₂₄Cl₂N₃O₉S₂ [M − H]⁻ 692.0325, found 692.0313.

Dimethyl 7-methoxy-1-(phenylsulfonamido)-9-(phenyl sulfonyl)-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3o). White solid, mp 215–216 °C; IR: 3236 (NH), 1724 (C=O), 1615 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 8.13–8.10 (m, 1H), 7.94–7.91 (m, 2H), 7.75–7.71 (m, 2H), 7.57–7.47 (m, 2H), 7.47–7.37 (m, 4H), 7.12–7.10 (m, 1H), 6.81–6.78 (m, 1H), 4.01 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H). HRMS (ESI, m/z): calculated for C₂₇H₂₂N₃O₉S₂ [M − H]⁻ 596.0792, found 596.0793.

Dimethyl 9-((4-chlorophenyl)sulfonyl)-1-(4-chlorophenyl sulfonamido)-7-methoxy-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3p). White solid, mp 233–234 °C; IR: 3201 (NH). 1727 (C=O), 1615 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 8.8 Hz, 2H), 8.03–8.01 (m, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.49–7.45 (m, 2H), 7.18–7.14 (m, 2H), 6.34–6.31 (m, 1H), 5.91 (d, J = 2.4 Hz, 1H), 3.42 (s, 3H), 3.35 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 159.3, 159.0, 156.7, 145.3, 141.2, 136.5, 132.0, 129.2, 129.1, 129.0, 128.2, 120.7, 115.5, 108.5, 101.8, 86.8, 55.7, 53.0, 53.0. HRMS (ESI, m/z): calculated for C₂₇H₂₀Cl₂N₃O₉S₂ [M − H]⁺ 664.0012, found 664.0059.

Dimethyl 1-((4-bromophenyl)sulfonamido)-9-((4-bromo phenyl)sulfonyl)-7-methoxy-1H-imidazo[1,2-a]indole-2,3-dicarboxylate (3q). White solid, mp 203–204.0 °C; IR: 3178 (NH), 1735 (C=O), 1616 (C=O). ¹H NMR (400 MHz, CDCl₃) δ 9.91 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.94–7.91 (m, 2H), 7.75–7.73 (m, 2H), 7.57–7.48 (m, 2H), 7.48–7.35–7.31 (m, 4H), 7.12–7.10 (m, 1H), 6.82–6.79 (m, 1H), 4.02 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 158.9, 157.4, 143.1, 138.5, 135.7, 134.6, 132.7, 130.7, 130.1, 129.4, 128.9, 128.6, 126.2, 121.3, 115.9, 115.5, 111.1, 100.9, 88.6, 55.6, 53.4, 53.2. HRMS (ESI, m/z): calculated for C₂₇H₂₀Br₂N₃O₉S₂ [M − H]⁻, 751.9008, found 751.9023.

Acknowledgements

We are grateful for financial support from the NSFC (No. 21232004, and 21472071), PAPD of Jiangsu Higher Education Institutions, the Qing Lan Project (12QLG006), and the Outstanding Youth Fund of Jiangsu Normal University (YQ2015003), and NSF of Jiangsu Normal University (14XLR005), the Open Foundation of Jiangsu Key Laboratory (K201505) and National Students' Innovative Training Program (grant number 201410320018).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1410586 (3a). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra13319j

‡ These authors have equal contribution to this work.

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