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Article

Base-Catalyzed Nucleophilic Addition Reaction of Indoles with Vinylene Carbonate: An Approach to Synthesize 4-Indolyl-1,3-dioxolanones

by
Xia Chen
1,2,
Xiao-Yu Zhou
1,* and
Ming Bao
2,*
1
School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui 553004, China
2
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(21), 7450; https://doi.org/10.3390/molecules28217450
Submission received: 20 October 2023 / Revised: 30 October 2023 / Accepted: 4 November 2023 / Published: 6 November 2023
(This article belongs to the Special Issue The Design and Synthesis of Indole Derivatives and Their Metal Complexes)
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Abstract

:
The N-functionalized indole is a privileged structural framework in a wide range of bioactive molecules. The nucleophilic addition between indoles with vinylene carbonate proceeded smoothly in the presence of K2CO3 as the catalyst to produce novel indolyl-containing skeletons and 4-indolyl-1,3-dioxolanones in satisfactory to excellent yields (up to >97% yield). Various synthetically useful functional groups, such as halogen atoms, cyano, nitro, and methoxycarbonyl groups, remained intact during the regioselective N-H addition reactions. The developed catalytic system also could accommodate 2-naphthalenol to achieve the target O-H additive product in good yield.

1. Introduction

The indole moiety is a ubiquitous structural framework in natural products and widely recognized as privileged components in biologically, physiologically, and pharmacologically relevant compounds [1,2,3,4,5,6,7,8]. Therefore, an impressive number of practical techniques as well as methods have been developed for the synthesis of indole-containing compounds and related functionalization. Among them, N-functionalization of indoles is of particular importance for the synthesis of N-substituted indoles with bioactivity. The indoles normally serve as nucleophilic coupling partners to react with diverse electrophiles, such as activated olefins, ketones, imines, and alkynes [9,10,11,12,13]. Olefins, as a stable and atom-economic synthon, are one of the fundamental synthetic materials in organic chemistry and provide a desired alternative for alkylating agents. As a result, extensive efforts have been devoted to realizing the Friedel–Crafts reaction of indoles with electron-deficient olefins for the preparation of C3-alkylated indoles [14,15,16,17,18]; in contrast, N-alkylation of indoles with olefins is much more challenging, due to the higher nucleophilicity toward the C3 position of indoles compared to the N1 site (Scheme 1, Equation (1)). Typically, three main approaches have been developed to enhance the reactivity of the N1 position of indoles (Scheme 1, Equation (2)). One approach involves the installation of a substituent at the C3 position to absolutely overcome the competitive transformations and thus create more opportunities for the N-functionalization [19,20]. Another approach involving the introduction of an electron-withdrawing group at the C2 position can increase the acidity of the N-H bond to dramatically avoid the competitive transformations from the nucleophilicity of the C3 position [21,22,23,24,25]. On the other hand, the N1-H bond possessing weak acidity [26] enables the generation of nitrogen anions in the presence of a base, thus enhancing the nucleophilicity of N1. Indeed, such an elegant strategy is the most straightforward, economical, and convenient method to realize the N-functionalization of N-H indoles without complex transition-metal catalysts and organocatalysts.
Vinylene carbonate has been regarded as a valuable and versatile C2 surrogate in organic synthesis [27,28,29,30,31]. In particular, vinylene carbonate has been extensively employed in the transition-metal-catalyzed C−H bond activation and annulation, resulting in the construction of value-added N-heterocyclic frameworks [32,33,34,35,36]. Vinylene carbonate is an inexpensive electron-deficient olefin; nevertheless, the nucleophilic additions between indoles with vinylene carbonate for the preparation of indolyl-containing ethylene carbonates have not been reported. Furthermore, indolyl-containing ethylene carbonates can undergo further transformation so as to obtain structurally diverse indolyl-containing skeletons [37,38,39,40,41].
In the course of our continuous research on the development of novel methods to achieve indole functionalization [42,43,44,45,46,47,48,49,50,51], we achieved the efficient synthesis of 4-indolyl-1,3-dioxolanones through the base-catalyzed nucleophilic addition reaction of N-H indoles with vinylene carbonate. The results are described in this paper.

2. Results

Initially, the nucleophilic addition reaction of indole (1a) with vinylene carbonate (2, 4 equiv.) was performed as a model to optimize the reaction parameters. The results are summarized in Table 1. The base catalyst was firstly screened using acetonitrile (CH3CN) as the solvent at 70 °C. Among the examined bases [triethylamine (NEt3), sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3), sodium acetate (NaOAc), potassium carbonate (K2CO3), sodium formate (HCOONa∙2H2O), DABCO (1,4-diaza[2.2.2]bicyclooctane), and DBU (1,8-diazabicyclo[5,4,0]-7-undecene)], K2CO3 proved to be the best base, providing the product, 4-(1H-indol-1-yl)-1,3-dioxolan-2-one (3a), with 71% yield (entries 1–8). The structure of product 3a was confirmed through X-ray crystallographic analysis (Figure 1, CCDC 2299714). A relatively high yield was observed when the loading of catalyst K2CO3 was increased to 30 mol% and 40 mol%, respectively (entries 9 and 10 vs. entry 5). However, the yield was found to be decreased when the base loading was further increased (entry 11 vs. entries 9 and 10). The reaction temperature was subsequently screened using 40 mol% of K2CO3 as the catalyst. The results obtained indicated that 60 °C was the best reaction temperature (entry 10 vs. entries 12–14). Then, the solvent was investigated under 60 °C conditions. Non-polar solvents [benzene and toluene] and polar solvents [CH3CN, tert-butyl methyl ether (MTBE), 1,2-ethanediol dimethyl ether (DME), tetrahydrofuran (THF), and 1,4-dioxane] were examined, respectively (entry 13, 15–20). Except for CH3CN, the use of other solvents showed almost no reaction, and most of the starting materials were recovered. This reaction had a strong dependence on solvent, whereas the exact factors involved remain unclear. Relatively low yields were obtained when either decreasing or increasing the amounts of vinylene carbonate (entry 13 vs. entries 21 and 22). Therefore, the subsequent nucleophilic addition reaction of various N-H indoles with vinylene carbonate (4.0 equiv.) was performed in the presence of K2CO3 (40 mol%) in CH3CN (3 mL) at 60 °C.
Given the optimized reaction conditions, the scope and limitation of this reaction were explored, and the results are summarized in Scheme 2. The electron-donating group, such as methyl (Me) and phenyl (Ph) linked on the pyrrole ring in substrate 1, would severely hamper the reaction, and no target products were detected. Nevertheless, the electron-withdrawing group, such as methoxycarbonyl (COOMe) linked on the pyrrole ring, was tolerated well, and the corresponding addition product 3e was obtained with 66% yield. The results suggested that the electron-donating group linked on the pyrrole ring could greatly weaken the acidity of the N–H bond, which was consistent with the formation of the indole nitrogen anion. In contrast, reactions of indole substrates 1 bearing the Me group linked on different positions of benzene ring proceeded smoothly under standard conditions; the corresponding 4-indolyl-1,3-dioxolanone products 3f, 3n, and 3w were obtained in moderate yields. Other electron-donating groups, such as methoxyl (OMe) and benzyloxyl (OBn), were also tolerated well in this nucleophilic addition reaction, providing the desired products 3g–3h, 3o–3p, and 3x–3y in 28–76% yields, respectively. Reactions of N-H indole substrates 1 bearing the electron-withdrawing group, such as COOMe, nitro (NO2), and cyano (CN), linked on different positions of the benzene ring were subsequently investigated under the optimized reaction conditions. The 4-indolyl-1,3-dioxolanone products 3k–3m, 3t–3v, and 3z were obtained in good to excellent yields (82–97%). These results mentioned above indicated that the electron properties (electron donating or electron withdrawing) of substituents linked on either pyrrole or benzene ring significantly affect the reactivity of 1. The reason for these results may be that the electron-withdrawing group, compared to electron-donating group, is more conducive to the formation and stabilization of indole nitrogen anion. The suitability of indole substrates 1i–1j, 1q–1s, and 1aa having halogen atoms (Cl, Br, and I) in the current nucleophilic addition reaction was investigated. The desired products 3i–3j, 3q–3s, and 3aa were also obtained in good to excellent yields (80–92%). The survival of synthetically useful functional groups, such as halogen atoms (Cl, Br, and I), CN, and CO2Me, under the reaction conditions will further increase structural diversification. In general, this nucleophilic addition exhibits broad scope and proceeds efficiently with electron-poor and -rich indoles, especially electron-poor indoles. However, the presence of groups at the C2-position of indole, with significant steric hindrance, would severely hamper the reaction.
Continued substrate extension studies showed that the 2-naphthalenol (4) was also applicable to this transformation and provided the desired addition product, 4-(naphthalen-2-yloxy)-1,3-dioxolan-2-one (5), in 87% yield (Scheme 3, Equation (1)). Subsequently, instead of the benzene ring in substrate 1 studies addressed a pyridine ring and found that the reactions of 1H-pyrrolo[3,2-b]pyridine (6) and 1H-pyrrolo[2,3-b]pyridine (8) also proceeded smoothly to furnish the addition products 7 and 9 in 81% and 88% yields, respectively (Scheme 3, Equations (2) and (3)).
Based on the experimental results and previous reports [48,49,52], a plausible reaction mechanism for the synthesis of N-functionalized indoles is depicted in Scheme 4. Initially, indole nitrogen anion 10 was generated in situ through the deprotonation of indole in the presence of the base K2CO3. The indole nitrogen anion 10 then underwent nucleophilic addition to vinylene carbonate. Meanwhile, KHCO3 provided a proton to yield the addition product 3 and the regenerated base K2CO3.

3. Materials and Methods

3.1. General Information

Unless otherwise noted, all reactions were carried out in oven-dried 25-mL Schlenk tubes under a nitrogen atmosphere. An IKA plate was used as the heat source. All reagents and solvents were of pure analytical grade. Thin layer chromatography (TLC) was performed on HSGF254 silica gel, pre-coated on glass-backed plates coated with 0.2 mm silica and was revealed with either a UV lamp (λmax = 254 nm). The products were purified by using flash column chromatography on silica gel 200–300 mesh. 1H and 13C NMR spectra were recorded on a 400 MHz spectrometer (1H 400 MHz, 13C 101 MHz) using d6-DMSO or CDCl3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. The chemical shifts are reported in ppm downfield (δ) from TMS, and the coupling constants J are given in Hz. The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. The NMR spectra of all compounds are demonstrated in Supplementary Materials. High-resolution mass spectra were recorded on either Q-TOF mass spectrometry or LTQ Orbitrap XL mass spectrometry. X-ray crystallography analysis was performed on a Bruker D8 Quest X-ray diffractionmeter.

3.2. Synthetic Procedures

3.2.1. The Typical Procedure for the Synthesis of 4-Indolyl-1,3-dioxolanones 3

A mixture of indoles 1 (0.50 mmol), vinylene carbonate (172 mg, 2.0 mmol, 4.0 equiv), and K2CO3 (27.6 mg, 0.20 mmol, 40 mol%) in CH3CN (3 mL) was added into a Schlenk flask (25 mL) and stirred at 60 °C. After the reaction was finished, the solvent was evaporated under reduced pressure and the residue was purified by using column chromatography (petroleum ether/ethyl acetate 5:1 to 1:1) to provide the product 3.
  • 4-(1H-indol-1-yl)-1,3-dioxolan-2-one (3a): Yield: 80%, 80.9 mg, white solid, mp 132–134 °C, Rf = 0.41 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.71 (d, J = 3.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 6.3 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.69 (d, J = 3.3 Hz, 1H), 5.04 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 154.1, 136.0, 129.5, 126.2, 123.2, 121.6, 121.6, 110.4, 105.6, 82.3, 68.4. [M + H]+ calculated for C11H10NO3, 204.0661; found 204.0657.
  • methyl 1-(2-oxo-1,3-dioxolan-4-yl)-1H-indole-3-carboxylate (3e): Yield: 66%, 86.6 mg, white solid, mp 206–208 °C, Rf = 0.32 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 8.53 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.42–7.33 (m, 2H), 7.28–7.21 (m, 1H), 5.17–4.99 (m, 2H), 3.86 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 164.5, 153.8, 136.0, 133.5, 126.9, 124.4, 123.5, 121.7, 111.2, 109.5, 82.4, 68.3, 51.6. HRMS (ESI) m/z: [M + H]+ calculated for C13H12NO5, 262.0715; found 262.0714.
  • 4-(4-methyl-1H-indol-1-yl)-1,3-dioxolan-2-one (3f): Yield: 53%, 57.7 mg, white solid, mp 118–120 °C, Rf = 0.36 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.68 (d, J = 3.4 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.23–7.14 (m, 2H), 6.98 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 3.3 Hz, 1H), 5.03 (d, J = 6.4 Hz, 2H), 2.49 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 154.1, 135.7, 130.6, 129.4, 125.6, 123.3, 121.7, 107.9, 104.1, 82.5, 68.4, 18.7. HRMS (ESI) m/z: [M + H]+ calculated for C12H12NO3, 218.0817; found 218.0815.
  • 4-(4-methoxy-1H-indol-1-yl)-1,3-dioxolan-2-one (3g): Yield: 74%, 86.0 mg, white solid, mp 172–174 °C, Rf = 0.33 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.59 (d, J = 3.4 Hz, 1H), 7.23–7.15 (m, 3H), 6.69 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 5.01 (d, J = 6.4 Hz, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 154.0, 153.4, 137.3, 124.7, 124.4, 119.7, 103.5, 102.6, 101.9, 82.5, 68.4, 55.6. HRMS (ESI) m/z: [M + H]+ calculated for C12H12NO4, 234.0766; found 234.0765.
  • 4-(4-(benzyloxy)-1H-indol-1-yl)-1,3-dioxolan-2-one (3h): Yield: 65%, 100.3 mg, white solid, mp 146–148 °C, Rf = 0.32 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.61 (d, J = 3.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.1 Hz, 1H), 7.21–7.14 (m, 3H), 6.78 (d, J = 6.5 Hz, 1H), 6.71 (d, J = 3.3 Hz, 1H), 5.26 (s, 2H), 5.02 (d, J = 6.4 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 154.0, 152.4, 137.8, 137.4, 128.9, 128.2, 127.9, 124.9, 124.3, 120.1, 103.7, 103.4, 102.6, 82.5, 69.6, 68.4. HRMS (ESI) m/z: [M + H]+ calculated for C18H16NO4, 310.1079; found 310.1075.
  • 4-(4-chloro-1H-indol-1-yl)-1,3-dioxolan-2-one (3i): Yield: 84%, 100.0 mg, white solid, mp 130–132 °C, Rf = 0.48 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.86 (d, J = 3.5 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.33–7.22 (m, 3H), 6.73 (d, J = 3.3 Hz, 1H), 5.05 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.9, 136.8, 127.8, 127.5, 125.5, 124.2, 121.2, 109.7, 103.4, 82.3, 68.5. HRMS (ESI) m/z: [M + H]+ calculated for C11H9ClNO3, 238.0271; found 238.0266.
  • 4-(4-bromo-1H-indol-1-yl)-1,3-dioxolan-2-one (3j): Yield: 87%, 123.0 mg, white solid, mp 154–156 °C, Rf = 0.36 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.87 (d, J = 3.4 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.3 Hz, 2H), 6.65 (d, J = 3.4 Hz, 1H), 5.05 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.9, 136.4, 133.2, 129.7, 127.5, 124.5, 124.3, 114.5, 110.2, 105.1, 82.3, 68.5. HRMS (ESI) m/z: [M + H]+ calculated for C11H9BrNO3, 281.9766; found 281.9758.
  • methyl 1-(2-oxo-1,3-dioxolan-4-yl)-1H-indole-4-carboxylate (3k): Yield: 91%, 119.0 mg, white solid, mp 146–148 °C, Rf = 0.39 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.92 (d, J = 7.5 Hz, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 6.2 Hz, 1H), 7.19 (d, J = 3.3 Hz, 1H), 5.07 (dd, J = 8.6, 3.5 Hz, 2H), 3.92 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 167.1, 153.9, 136.9, 128.8, 128.3, 124.5, 122.7, 121.8, 115.6, 106.2, 82.0, 68.5, 52.4. HRMS (ESI) m/z: [M + H]+ calculated for C13H12NO5, 262.0715; found 262.0708.
  • 4-(4-nitro-1H-indol-1-yl)-1,3-dioxolan-2-one (3l): Yield: 90%, 111.7 mg, light yellow solid, mp 188–190 °C, Rf = 0.30 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 8.20 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 8.1 Hz, 1H), 7.36 (t, J = 6.2 Hz, 1H), 7.26 (d, J = 3.3 Hz, 1H), 5.13–5.04 (m, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.8, 140.2, 138.2, 131.0, 123.1, 122.8, 119.0, 118.1, 104.8, 81.9, 68.67. HRMS (ESI) m/z: [M + H]+ calculated for C11H9N2O5, 249.0511; found 249.0510.
  • 1-(2-oxo-1,3-dioxolan-4-yl)-1H-indole-4-carbonitrile (3m): Yield: 91%, 112.2 mg, white solid, mp 166–168 °C, Rf = 0.35 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 8.05 (d, J = 3.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 6.3 Hz, 1H), 6.85 (d, J = 3.3 Hz, 1H), 5.06 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.8, 135.9, 130.4, 129.6, 126.9, 123.4, 118.4, 116.0, 103.5, 102.8, 82.0, 68.6. HRMS (ESI) m/z: [M + H]+ calculated for C12H9N2O3, 229.0613; found 229.0612.
  • 4-(5-methyl-1H-indol-1-yl)-1,3-dioxolan-2-one (3n): Yield: 51%, 55.6 mg, light yellow solid, mp 112–114 °C, Rf = 0.36 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.64 (d, J = 3.4 Hz, 1H), 7.47–7.40 (m, 2H), 7.18 (t, J = 6.3 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 3.3 Hz, 1H), 5.02 (d, J = 6.3 Hz, 2H), 2.39 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 154.1, 134.3, 133.2, 130.3, 129.9, 126.3, 124.6, 121.2, 110.1, 105.1, 82.5, 68.3, 21.4. HRMS (ESI) m/z: [M + H]+ calculated for C12H12NO3, 218.0817; found 218.0810.
  • 4-(5-methoxy-1H-indol-1-yl)-1,3-dioxolan-2-one (3o): Yield: 28%, 33.0 mg, white solid, mp 141–143 °C, Rf = 0.32 (H/E = 2:1). 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 3.4 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.00 (dd, J = 8.9, 2.0 Hz, 1H), 6.73 (dd, J = 7.2, 5.1 Hz, 1H), 6.64 (d, J = 3.3 Hz, 1H), 4.98-4.85 (m, 2H), 3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.5, 153.3, 130.5, 130.2, 124.9, 113.4, 110.1, 106.2, 103.7, 82.2, 67.9, 55.8. HRMS (ESI) m/z: [M + H]+ calculated for C12H12NO4, 234.0766; found 234.0758.
  • 4-(5-(benzyloxy)-1H-indol-1-yl)-1,3-dioxolan-2-one (3p): Yield: 41%, 63.3 mg, white solid, mp 146–148 °C, Rf = 0.32 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.66 (d, J = 3.2 Hz, 1H), 7.47 (d, J = 8.1 Hz, 3H), 7.40 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 6.9 Hz, 1H), 7.23 (s, 1H), 7.16 (t, J = 6.2 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 5.13 (s, 2H), 5.01 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 154.10, 154.08, 137.9, 131.0, 130.2, 128.9, 128.2, 128.1, 126.9, 113.5, 111.1, 105.4, 105.0, 82.6, 70.1, 68.3. HRMS (ESI) m/z: [M + H]+ calculated for C18H16NO4, 310.1079; found 310.1078.
  • 4-(5-chloro-1H-indol-1-yl)-1,3-dioxolan-2-one (3q): Yield: 85%, 100.4 mg, white solid, mp 127–129 °C, Rf = 0.37 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.81–7.79 (m, 1H), 7.70 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.22 (t, J = 6.3 Hz, 1H), 6.68 (d, J = 3.4 Hz, 1H), 5.04 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 154.0, 134.6, 130.7, 127.8, 126.1, 123.1, 120.8, 112.0, 105.2, 82.2, 68.5. HRMS (ESI) m/z: [M + H]+ calculated for C11H9ClNO3, 238.0271; found 238.0265.
  • 4-(5-bromo-1H-indol-1-yl)-1,3-dioxolan-2-one (3r): Yield: 80%, 112.5 mg, white solid, mp 108–110 °C, Rf = 0.37 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.85 (s, 1H), 7.79 (d, J = 3.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.22 (t, J = 6.3 Hz, 1H), 6.68 (d, J = 3.2 Hz, 1H), 5.03 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.9, 134.9, 131.4, 127.7, 125.7, 123.8, 114.1, 112.5, 105.1, 82.2, 68.4. HRMS (ESI) m/z: [M + H]+ calculated for C11H9BrNO3, 281.9766; found 281.9757.
  • 4-(5-iodo-1H-indol-1-yl)-1,3-dioxolan-2-one (3s): Yield: 86%, 141.6 mg, white solid, mp 134–136 °C, Rf = 0.36 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 8.02 (s, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.20 (t, J = 6.3 Hz, 1H), 6.65 (d, J = 3.2 Hz, 1H), 5.02 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.9, 135.3, 132.1, 131.1, 130.0, 127.2, 112.9, 104.8, 85.6, 82.1, 68.4. HRMS (ESI) m/z: [M + H]+ calculated for C11H9INO3, 329.9627; found 329.9619.
  • methyl 1-(2-oxo-1,3-dioxolan-4-yl)-1H-indole-5-carboxylate (3t): Yield: 82%, 107.2 mg, white solid, mp 164–166 °C, Rf = 0.34 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 8.33 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 3.3 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.28 (t, J = 6.3 Hz, 1H), 6.85 (d, J = 3.3 Hz, 1H), 5.05 (d, J = 6.2 Hz, 2H), 3.87 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 167.2, 153.9, 138.7, 129.2, 127.7, 124.0, 123.8, 123.1, 110.6, 106.7, 82.1, 68.6, 52.4. HRMS (ESI) m/z: [M + H]+ calculated for C13H12NO5, 262.0715; found 262.0708.
  • 4-(5-nitro-1H-indol-1-yl)-1,3-dioxolan-2-one (3u): Yield: 91%, 112.5 mg, light yellow solid, mp 188–190 °C, Rf = 0.40 (H/E = 1:1). 1H NMR (400 MHz, d6-DMSO) δ 8.64 (s, 1H), 8.18 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 3.4 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.32 (t, J = 6.3 Hz, 1H), 6.97 (d, J = 3.4 Hz, 1H), 5.12–4.99 (m, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.8, 142.6, 139.2, 129.5, 128.9, 118.4, 118.3, 111.2, 107.6, 81.9, 68.7. HRMS (ESI) m/z: [M + H]+ calculated for C11H9N2O5, 249.0511; found 249.0503.
  • 1-(2-oxo-1,3-dioxolan-4-yl)-1H-indole-5-carbonitrile (3v): Yield: 97%, 111.0 mg, white solid, mp 186–188 °C, Rf = 0.40 (H/E = 1:1). 1H NMR (400 MHz, d6-DMSO) δ 8.19 (s, 1H), 7.95 (d, J = 3.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.30 (t, J = 6.2 Hz, 1H), 6.83 (d, J = 3.3 Hz, 1H), 5.05 (d, J = 5.8 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.8, 137.9, 129.3, 128.6, 127.0, 126.1, 120.5, 111.9, 106.2, 103.9, 81.9, 68.6. HRMS (ESI) m/z: [M + H]+ calculated for C12H9N2O3, 229.0613; found 229.0607.
  • 4-(6-methyl-1H-indol-1-yl)-1,3-dioxolan-2-one (3w): Yield: 47%, 51.2 mg, white solid, mp 130–132 °C, Rf = 0.36 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.61 (d, J = 3.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.18 (t, J = 6.3 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 3.2 Hz, 1H), 5.02 (d, J = 6.3 Hz, 2H), 2.44 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 154.1, 133.2, 132.5, 127.3, 125.4, 123.2, 121.2, 110.3, 105.5, 82.3, 68.3, 22.0. [M + H]+ calcd for C12H12NO3, 218.0817; found 218.0810.
  • 4-(6-methoxy-1H-indol-1-yl)-1,3-dioxolan-2-one (3x): Yield: 55%, 63.9 mg, white solid, mp 152–154 °C, Rf = 0.34 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.54 (d, J = 3.5 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.23 (t, J = 6.3 Hz, 1H), 7.19 (s, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 3.3 Hz, 1H), 5.02 (d, J = 6.3 Hz, 2H), 3.81 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 157.0, 154.1, 137.2, 124.4, 123.2, 122.0, 111.2, 105.7, 94.4, 82.1, 68.4, 55.9. HRMS (ESI) m/z: [M + H]+ calculated for C12H12NO4, 234.0766; found 234.0765.
  • 4-(6-(benzyloxy)-1H-indol-1-yl)-1,3-dioxolan-2-one (3y): Yield: 55%, 85.0 mg, white solid, mp 139–141 °C, Rf = 0.36 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.55 (d, J = 3.4 Hz, 1H), 7.52–7.48 (m, 3H), 7.41 (t, J = 7.4 Hz, 2H), 7.37–7.31 (m, 2H), 7.21 (t, J = 6.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 3.3 Hz, 1H), 5.19-5.12 (m, 2H), 5.02 (d, J = 6.3 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 156.0, 154.1, 137.6, 137.2, 133.2, 128.9, 128.3, 128.2, 124.6, 123.5, 122.1, 111.7, 105.7, 95.8, 82.1, 70.2, 68.3. HRMS (ESI) m/z: [M + H]+ calculated for C18H16NO4, 310.1079; found 310.1071.
  • methyl 1-(2-oxo-1,3-dioxolan-4-yl)-1H-indole-6-carboxylate (3z): Yield: 90%, 116.9 mg, white solid, mp 140–142 °C, Rf = 0.37 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 8.28 (s, 1H), 7.98 (d, J = 3.3 Hz, 1H), 7.80-7.73 (m, 2H), 7.38 (t, J = 6.3 Hz, 1H), 6.80 (d, J = 3.3 Hz, 1H), 5.16–4.92 (m, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, d6-DMSO) δ 167.3, 153.9, 135.6, 133.2, 129.7, 124.3, 122.2, 121.5, 112.2, 105.87, 82.0, 68.5, 52.5. HRMS (ESI) m/z: [M + H]+ calculated for C13H12NO5, 262.0715; found 262.0712.
  • 4-(6-chloro-1H-indol-1-yl)-1,3-dioxolan-2-one (3aa): Yield: 92%, 109.0 mg, white solid, mp 152–154 °C, Rf = 0.38 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.76 (s, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.30–7.17 (m, 2H), 6.72 (d, J = 3.3 Hz, 1H), 5.03 (d, J = 6.0 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.9, 136.7, 133.2, 128.1, 128.0, 126.9, 122.9, 121.9, 110.6, 105.9, 82.0, 68.5. HRMS (ESI) m/z: [M + H]+ calculated for C11H9ClNO3, 238.0271; found 238.0264.

3.2.2. The Typical Procedure for the Synthesis of 5

To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar was added 2-naphthol substrate 4 (0.50 mmol, 1.0 equiv.), vinylene carbonate (172 mg, 2.0 mmol, 4.0 equiv.), K2CO3 (27.6 mg, 0.20 mmol, 40 mol%), and CH3CN (3 mL) under an air atmosphere. The reaction mixture was stirred at 60 °C for 24 h and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by using silica gel column chromatography to afford the desired products 5 as a white solid (100.0 mg, yield: 87%).
  • 4-(naphthalen-2-yloxy)-1,3-dioxolan-2-one (5): Yield: 87%, 100.0 mg, white solid, mp 106–108 °C, Rf = 0.45 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 7.96 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.59 (s, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.32 (dd, J = 8.9, 2.3 Hz, 1H), 6.71 (d, J = 3.9 Hz, 1H), 4.88 (dd, J = 9.9, 5.5 Hz, 1H), 4.66 (d, J = 10.0 Hz, 1H). 13C NMR (101 MHz, d6-DMSO) δ 154.1, 153.3, 134.1, 130.5, 130.2, 128.1, 127.7, 127.3, 125.4, 118.9, 111.3, 98.1, 70.9. HRMS (ESI) m/z: [M + H]+ calculated for C13H11O4, 231.0657; found 231.0654.

3.2.3. The Typical Procedure for the Synthesis of 7 and 9

To an oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar was added pyrrolo-pyridine substrate 6 or 8 (0.50 mmol, 1.0 equiv.), vinylene carbonate (172 mg, 2.0 mmol, 4.0 equiv.), K2CO3 (27.6 mg, 0.20 mmol, 40 mol%), and CH3CN (3 mL) under an air atmosphere. The reaction mixture was stirred at 60 °C for 24 h, and then cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by using silica gel column chromatography to afford the desired products 7 or 9.
  • 4-(1H-pyrrolo [3,2-b]pyridin-1-yl)-1,3-dioxolan-2-one (7): Yield: 81%, 82.2 mg, white solid, mp 176–178 °C, Rf = 0.31 (EtOAc). 1H NMR (400 MHz, d6-DMSO) δ 8.47 (d, J = 4.7 Hz, 1H), 8.05 (d, J = 3.5 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 8.3, 4.6 Hz, 1H), 7.23 (t, J = 6.3 Hz, 1H), 6.81 (d, J = 3.4 Hz, 1H), 5.05 (d, J = 6.2 Hz, 2H). 13C NMR (101 MHz, d6-DMSO) δ 153.9, 147.6, 144.8, 129.8, 128.9, 118.0, 117.9, 106.1, 82.3, 68.4. HRMS (ESI) m/z: [M + H]+ calculated for C10H9N2O3, 205.0613; found 205.0613.
  • 4-(1H-pyrrolo [2,3-b]pyridin-1-yl)-1,3-dioxolan-2-one (9): Yield: 88%, 89.3 mg, white solid, mp 169-171 °C, Rf = 0.37 (H/E = 2:1). 1H NMR (400 MHz, d6-DMSO) δ 8.33 (d, J = 4.7 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 3.7 Hz, 1H), 7.28-7.12 (m, 2H), 6.66 (d, J = 3.7 Hz, 1H), 5.08-4.98 (m, 2H). 13C NMR (101 MHz, d6-DMSO) δ 154.3, 147.5, 143.8, 130.0, 128.0, 121.9, 118.0, 102.9, 81.6, 68.4. HRMS (ESI) m/z: [M + H]+ calculated for C10H9N2O3, 205.0613; found 205.0608.

3.3. X-ray Crystallographic Analysis

The structure of 3a was determined based on single-crystal X-ray analysis. The detailed procedure was as follows: The 3a solid was dissolved in AcOEt (1 mL). Then, the solvent was placed in the inner tube, and n-hexane (5 mL) was placed in the outer container. The crystals of 3a were grown from solution, which is suitable for X-ray diffraction analysis.
CCDC No. 2299714 (3a) contains the supplementary crystallographic data for this paper. The crystal data can be obtained free of charge from the Cambridge Crystallographic Data Centre through www.ccdc.cam.ac.uk/datarequest/cif (accessed on 7 October 2023).

4. Conclusions

In summary, employing a base-catalyzed transition-metal-free strategy, we have successfully developed a convenient and alternative method to achieve N-functionalization of indoles with high regioselectivity. The nucleophilic addition reaction of various N-H indoles with vinylene carbonate proceeded smoothly to produce 4-indolyl-1,3-dioxolanones in satisfactory to excellent yields (up to >97% yield). These 4-Indolyl-1,3-dioxolanones, as novel indolyl-containing skeletons, are a type of indolyl-containing ethylene carbonate which could undergo further transformation to obtain structurally diverse bioactive molecules containing indole moiety. The readily available starting materials, the mild reaction conditions, and the experimental simplicity make the present methodology highly useful in the synthesis of 4-indolyl-1,3-dioxolanones. Based on the universality and significance of indole moiety in drugs, functional materials, and bioactive molecules, we believe that both this methodology and the synthesized indolyl-containing skeletons could be of interest to organic chemists and provide many medicinally active scaffolds.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28217450/s1: Crystallographic data and copies of NMR spectra.

Author Contributions

Conceptualization, X.-Y.Z.; methodology, X.C.; investigation, X.C., X.-Y.Z. and M.B.; writing—original draft preparation, X.C.; writing—review and editing, X.-Y.Z. and M.B.; supervision, X.-Y.Z. and M.B.; project administration, X.-Y.Z. and M.B.; funding acquisition, X.-Y.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (Nos. 22062012, 22262019 and 22172014), and the Natural Science Foundation of Guizhou Province (No. qiankehejichu-ZK [2023]zhongdian048) is also thanked for its financial support. This work was also supported by the Foundation of Guizhou Educational Committee (No. qianjiaoji [2023]088) and Scientific Research Projects of Liupanshui Normal University (LPSSYZDZK202201).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data obtained in this project are contained within this article and are available upon request from the authors.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 07450 sch001
Scheme 1. The addition reaction between indole with activated olefins toward the formation of alkylated indoles and three main approaches to enhance the reactivity of N1 position of indole.
Scheme 1. The addition reaction between indole with activated olefins toward the formation of alkylated indoles and three main approaches to enhance the reactivity of N1 position of indole.
Molecules 28 07450 sch001
Molecules 28 07450 g001
Figure 1. The crystal structure of 3a.
Figure 1. The crystal structure of 3a.
Molecules 28 07450 g001
Molecules 28 07450 sch002
Scheme 2. Substrate scope. Reaction conditions: 1 (0.50 mmol), 2 (172 mg, 2.0 mmol, 2.0 equiv.), and K2CO3 (27.6 mg, 0.20 mmol, 40 mol%) in CH3CN (3 mL) at 60 °C under an air atmosphere for 24 h; isolated yield.
Scheme 2. Substrate scope. Reaction conditions: 1 (0.50 mmol), 2 (172 mg, 2.0 mmol, 2.0 equiv.), and K2CO3 (27.6 mg, 0.20 mmol, 40 mol%) in CH3CN (3 mL) at 60 °C under an air atmosphere for 24 h; isolated yield.
Molecules 28 07450 sch002
Molecules 28 07450 sch003
Scheme 3. Substrate extension studies.
Scheme 3. Substrate extension studies.
Molecules 28 07450 sch003
Molecules 28 07450 sch004
Scheme 4. The plausible reaction mechanism.
Scheme 4. The plausible reaction mechanism.
Molecules 28 07450 sch004
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 28 07450 i001
EntryCat. (x mol)Solvent Temp. (°C)Yield (%) b
1NEt3 (20)CH3CN 7047
2KHCO3 (20)CH3CN 7029
3Na2CO3 (20)CH3CN 70trace
4NaOAc (20)CH3CN 70trace
5K2CO3 (20)CH3CN 7071
6HCO2Na∙2H2O (20)CH3CN 70n.d. c
7DABCO (20)CH3CN 70n.d. c
8DBU (20)CH3CN 70n.d. c
9K2CO3 (30)CH3CN 7074
10K2CO3 (40)CH3CN 7079
11K2CO3 (50)CH3CN 7068
12K2CO3 (40)CH3CN 8050
13K2CO3 (40)CH3CN 6080
14K2CO3 (40)CH3CN 5056
15K2CO3 (40)benzene 60n.d. c
16K2CO3 (40)toluene 60n.d. c
17K2CO3 (40)MTBE 60n.d. c
18K2CO3 (40)DME 60n.d. c
19K2CO3 (40)THF 60n.d. c
20K2CO3 (40)1,4-dioxane 60n.d. c
21 dK2CO3 (40)CH3CN 6051
22 eK2CO3 (40)CH3CN 6074
a Reaction conditions: 1a (59 mg, 0.50 mmol), 2 (172 mg, 2.0 mmol, 4.0 equiv.), catalyst (20–60 mol%), solvent (3.0 mL) under heating for 24 h. b Isolated yield. c The desired product was not detected; the starting material 1a was recovered. d 3.0 equivalents of 2 (129 mg, 1.5 mmol) was added. e 5.0 equivalents of 2 (215 mg, 2.5 mmol) was added.
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Chen, X.; Zhou, X.-Y.; Bao, M. Base-Catalyzed Nucleophilic Addition Reaction of Indoles with Vinylene Carbonate: An Approach to Synthesize 4-Indolyl-1,3-dioxolanones. Molecules 2023, 28, 7450. https://doi.org/10.3390/molecules28217450

AMA Style

Chen X, Zhou X-Y, Bao M. Base-Catalyzed Nucleophilic Addition Reaction of Indoles with Vinylene Carbonate: An Approach to Synthesize 4-Indolyl-1,3-dioxolanones. Molecules. 2023; 28(21):7450. https://doi.org/10.3390/molecules28217450

Chicago/Turabian Style

Chen, Xia, Xiao-Yu Zhou, and Ming Bao. 2023. "Base-Catalyzed Nucleophilic Addition Reaction of Indoles with Vinylene Carbonate: An Approach to Synthesize 4-Indolyl-1,3-dioxolanones" Molecules 28, no. 21: 7450. https://doi.org/10.3390/molecules28217450

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