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. 2022 Dec 4;27(23):8538. doi: 10.3390/molecules27238538

A Novel Method to Construct 2-Aminobenzofurans via [4 + 1] Cycloaddition Reaction of In Situ Generated Ortho-Quinone Methides with Isocyanides

Huaxin Lin 1,2, Senling Tang 1,2, Yang Pan 1,2, Peng Liang 1,2, Xiaofeng Ma 1, Wei Jiao 1,*, Huawu Shao 1,*
Editor: Antonio Palumbo Piccionello
PMCID: PMC9737762  PMID: 36500630

Abstract

A new approach for the synthesis of 2-aminobenzofurans has been described via Sc(OTf)3 mediated formal cycloaddition of isocyanides with the in situ generated ortho-quinone methides (o-QMs) from o-hydroxybenzhydryl alcohol. Notably, as a class of readily available and highly active intermediates, o-QMs were first used in the construction of benzofurans. This [4 + 1] cycloaddition reaction provides a straightforward and efficient methodology for the construction of 2-aminobenzofurans scaffold in good yield (up to 93% yield) under mild conditions.

Keywords: 2-aminobenzofurans, isocyanides, ortho-quinone methides, [4 + 1] cycloaddition

1. Introduction

Benzofuran core, an important class of structural fragments, is widely distributed in natural products and biologically active compounds [1,2,3,4]. The benzofuran subunit is also present in a host of medicines, such as amiodarone, methoxypsoralen, dronedarone, etc [5]. Therefore, various methods for the preparation of benzofurans have been developed. As a special kind of functionalized benzofurans, 2-aminobenzofurans are of considerable interest and feature profound bioactivities, such as antifungal, P-glycoprotein inhibitors, anticancer activities, and tubulin polymerization inhibitors [6,7,8,9].

Although such structures are important, only limited methods have been reported for accessing 2-aminobenzofurans and the structural diversity of the products is insufficient. For example, in 2005, Ishikawa’s group reported the synthesis of 2-aminobenzofurans from 1-aryl-2-nitroethylenes and cyclohexane-1,3-diones via a one-pot multistep strategy, but only moderate yield can be obtained. Moreover, unsymmetrical cyclohexane-1,3-diones have poor regiochemistry (Scheme 1a, Equation (1)) [10]. Soon after, Ohe and co-workers provided a new method to obtain 2-aminobenzofurans through palladium-catalyzed intramolecular cycloisomerization of 2-(cyanomethyl) phenyl ester; however, the substrate range is relatively limited (Scheme 1a, Equation (2)) [11]. In addition, Maurya’s group also demonstrated the synthesis of very similar products (3-acyl-2-aminobenzofurans) via visible light-triggered intramolecular cyclization of α-azidochalcones (Scheme 1a, Equation (3)) [12]. In 2013, Cao’s group developed a method for the synthesis of 3-alkyl- or 3-allenyl-2-amidobenzofurans by carbocation-induced electrophilic cyclization of o-anisole-substituted ynamides (Scheme 1a, Equation (4)) [13]. In this method, the substituent on the benzene ring is fixed at the 5 position, and at least one electron withdrawing substituent is required on nitrogen. Finally, Kumar et al. reported strong base (tBuOK) mediated synthesis of 3-phenylbenzofuran-2-amines (one example) (Scheme 1a, Equation (5)) [14]. While those methods allow 2-aminobenzofurans to be obtained in an efficient way, new methods that can access a variety of structural skeletons under mild reaction conditions and from simple starting materials are still highly desired (Scheme 1b).

Scheme 1.

Scheme 1

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Strategies for the diversified synthesis of 2-aminobenzofurans.

In recent years, ortho-quinone methides (o-QMs) [15,16,17,18,19,20,21,22], a versatile class of building blocks, have been widely used in organic synthesis. o-QMs could be generated from o-hydroxybenzhydryl alcohol derivatives and directly participate in various [4 + n] (n = 2, 3) cycloadditions [23,24,25,26,27]. The [4 + 1] cycloadditions involved in o-QMs, however, are only developed for the construction of 2,3-dihydrobenzofuran skeletons and have never been used to synthesize benzofurans [28,29,30,31,32,33,34], let alone 2-aminobenzofurans.

2. Results

Our continuous interest in cycloaddition [35,36,37,38,39,40] led us to envision that the reaction of o-QMs with isocyanides [41,42,43,44,45,46] would achieve the benzofuran motifs via an intermolecular formal [4 + 1] cycloaddition. To test the feasibility of our hypothesis, we chose o-hydroxybenzhydryl alcohol 1a and p-nitrophenyl isocyanide 2a as the model substrates to optimize the reaction conditions (Table 1).

Table 1.

Optimization of reaction conditions a.

graphic file with name molecules-27-08538-i001.jpg
Entry Promoter Solvent Yield b (%)
1 TsOH CH2Cl2 18
2 TfOH CH2Cl2 15
3 benzoic acid CH2Cl2 trace
4 BF3·Et2O CH2Cl2 40
5 InCl3 CH2Cl2 23
6 Sc(OTf)3 CH2Cl2 53
7 Sc(OTf)3 THF 29
8 Sc(OTf)3 MeCN 37
9 Sc(OTf)3 DCE 50
10 Sc(OTf)3 toluene 60
11 c Sc(OTf)3 toluene 75
12 d Sc(OTf)3 toluene 71
13 c,e Sc(OTf)3 toluene 81
14 c,f Sc(OTf)3 toluene 69
15 c,e,g Sc(OTf)3 toluene 87
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a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), promoter (0.05 mmol), dry solvent (1 mL), at room temperature under N2, for 30 min. b Isolated yield. c Sc(OTf)3 (0.1 mmol). d Sc(OTf)3 (0.12 mmol). e The reaction was performed at 0 °C. f The reaction was performed at −10 °C. g 4 Å MS (50 mg) was employed.

The initial experiment was conducted in CH2Cl2 in the presence of various Brønsted acids, such as benzoic acid, TsOH and TfOH, at room temperature. It was observed that, except for benzoic acid, which only offered a trace amount of the desired product, both TsOH and TfOH provided the cycloaddition product 3a in roughly the same yield, even though the yield was relatively low (entries 1–3). Considering that isocyanide could be hydrolyzed under fairly strong acidic conditions [47], we replaced Brønsted acids with Lewis acids to further optimize reaction conditions. A range of Lewis acids, such as BF3·Et2O, InCl3, and Sc(OTf)3, were then screened (entries 4–6). Among them, the desired cycloaddition product 3a could be obtained with 53% isolated yield when 0.5 equiv. of Sc(OTf)3 was employed. To further improve the yield, different solvents, including THF, MeCN, and toluene, were also examined (entries 7−10). Toluene proved to be the best solvent for this transformation.

Encouraged by these results, we investigated the effect of the loading of Sc(OTf)3. It was found that, when we increased the loading of Sc(OTf)3 from 0.5 equiv. to 1.0 equiv., the yield of 3a was improved to 75% (entry 11). However, when 1.2 equiv. of Sc(OTf)3 was used, the yield was reduced slightly (entry 12). It is noteworthy that the cycloaddition product 3a could be improved to 81% yield (entry 13) when the reaction was performed at 0 °C, but further cooling the temperature to −10 °C led to the yield’s reduction to 69% (entry 14). Lastly, the addition a small number of 4 Å MS could increase the yield of 3a to 87% (entry 15).

With the optimized conditions in hand, a number of 2-aminobenzofurans were successfully obtained in moderate to excellent yields within 30 min through the formal [4 + 1] cycloaddition of o-hydroxybenzhydryl alcohol (1a–1s) and p-nitrophenyl isocyanide 2a (Scheme 2). As shown in Scheme 2, both electron-donating substituents (3ba–3fa) and electron-deficient substituents (3ga–3ia) on the phenol were well tolerated in this formal [4 + 1] cycloaddition reaction and afforded the desired products in 70% to 84% yields. Obviously, the position of the substituents on phenol moiety had little influence on the reaction (3ba and 3ca). The structure of products was unambiguously confirmed by single-crystal X-ray analysis of 3ia (please see Supplementary Materials). Next, different substitutions on the benzyl phenol moiety were examined. We found that methyl substitution at the ortho-, meta- and para- of benzyl alcohol moiety can afford the corresponding products (3ja, 3ka, and 3la) good to excellent yields. Strong electron-donating substituent (methoxy) in a different position was also converted smoothly into the desired 2-aminobenzofurans (3na and 3oa). Notably, the benzyl alcohol with high steric hindrance substitutions at ortho-position also efficiently underwent the formal [4 + 1] addition to provide corresponding products (3ma and 3pa) in 73% and 58% yields, respectively. Electron-withdrawing substituents, including F, Cl, and CF3, were also suitable for this transformation, providing the 2-aminobenzofurans with good results (3qa–3sa). From the above results, it can be concluded that both strong electron-donating substituents and electron-withdrawing substituents at the benzyl alcohol slightly reduce the yield; the yield of the product decreases slightly when high steric hindrance substitutions at ortho-position of the benzyl alcohol take place.

Scheme 2.

Scheme 2

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Scope of o-hydroxybenzhydryl alcohols. Standard reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), Sc(OTf)3 (0.1 mmol), 4 Å MS (50 mg), dry toluene (1 mL), at 0 °C, 30 min. b 20 min.

We further evaluated the substrate scope of isocyanides (Scheme 3). A series of phenylisocyanides, with electron-withdrawing substituents at para- and meta-positions of the benzene ring, were smoothly converted to the corresponding products (4ab–4ad). However, for methyl substituted phenyl isocyanides, the yield decreased (4ae). Therefore, it can be inferred that electron-withdrawing substituents on phenyl isocyanides are beneficial to the formation of the product. β-Naphthyl isocyanide were employed in the transformation, offering the corresponding 2-aminobenzofurans in 83% yield (4af). Notably, alkyl isocyanides, including ethyl isocyanoacetate and tert-butyl isocyanide, could also smoothly transform to the desired cycloaddition products in 46% and 85% yields, respectively (4ag and 4ah), which enriched the diversity of structural skeletons.

Scheme 3.

Scheme 3

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Scope of isocyanides. Standard reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), Sc(OTf)3 (0.1 mmol), 4 Å MS (50 mg), dry toluene (1 mL), at 0 °C, 20 min. b Reaction time is 3 min. c Reaction time is 10 min.

According to previous reports on Sc(OTf)3-triggered transformation of o-hydroxybenzhydryl alcohol [48,49,50,51], a plausible mechanism for the [4 + 1] cycloaddition was proposed (Scheme 4), the nucleophilic addition of the isocyanides to o-QMs (Ⅰ) generated in situ from o-hydroxybenzyl alcohol 1a, which formed intermediate Ⅱ. Subsequently, Ⅱ undergoes intramolecular cyclization producing the intermediate Ⅲ, which isomerised to the desired 2-aminobenzofurans 3.

Scheme 4.

Scheme 4

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Plausible reaction mechanism.

Given that 2-aminobenzofurans have been proven to have a variety of biological activities, we decide to conduct in silico researches of the synthesized 2-aminobenzofurans to evaluate their drug-likeness, which were carried out using the SwissADME platform [52]. Satisfyingly, except for compounds 3ea, 3ma, 3pa, and 4ab–4af, other compounds were found to have good obedience (100%) with two drug-likeness filters (Lipinski [53] and Veber [54]) (Table 2). In addition, some substituted (Cl, F, Br, CH3, OCH3) 2-aminobenzofurans’ pharmacokinetic properties were predicted through admetSAR [55], and it was found that these products showed a great range of average ADMET score [56,57] (0.68–0.74) with regard to human intestinal absorption, blood–brain barrier penetration, Caco-2 permeability, Ames mutagenicity, carcinogenicity, and acute oral toxicity class (Table 3). Finally, taking 4ae as an example, we predicted its possible molecular targets using SwissTargetPrediction [58,59]. The results show that it can act on multiple targets, such as nuclear receptor, family A-G protein-coupled receptor, etc., and the probability of prediction is around 10%.

Table 2.

Physiochemical properties of the compounds predicted using SwissADME.

Compound Name MW nHetero Atoms Rotatable
Bonds		 H-Bond Acceptor H-Bond Donor TPSA (Å sqr) MlogP
3aa 330.34 5 4 3 1 70.99 4.03
3ba 344.37 5 4 3 1 70.99 3.44
3ca 344.37 5 4 3 1 70.99 3.44
3da 344.37 5 4 3 1 70.99 3.44
3ea 386.45 5 5 3 1 70.99 4.90 *
3fa 360.37 6 5 4 1 80.22 3.71
3ga 348.33 6 4 4 1 70.99 3.60
3ha 364.79 6 4 3 1 70.99 3.71
3ia 409.24 6 4 3 1 70.99 3.82
3ja 344.37 5 4 3 1 70.99 3.44
3ka 344.37 5 4 3 1 70.99 3.44
3la 358.40 5 4 3 1 70.99 3.66
3ma 372.42 5 5 3 1 70.99 4.69 *
3na 360.37 6 5 4 1 80.22 3.71
3oa 360.37 6 5 4 1 80.22 3.71
3pa 380.40 5 4 3 1 70.99 4.73 *
3qa 348.33 6 4 4 1 70.99 3.60
3ra 364.79 6 4 3 1 70.99 3.71
3sa 398.34 8 5 6 1 70.99 4.04
4ab 319.79 3 3 1 1 25.17 4.79 *
4ac 364.24 3 3 1 1 25.17 4.90 *
4ad 319.79 3 3 1 1 25.17 4.79 *
4ae 299.37 2 3 1 1 25.17 4.52 *
4af 335.31 2 3 1 1 25.17 4.99 *
4ag 295.34 4 6 3 1 51.47 2.80
4ah 265.36 2 3 1 1 25.17 3.79
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(Lipinski: MW ≤ 500, MlogP ≤ 4.15, N or O ≤ 10, NH or OH ≤ 5; Veber: Rotatable bonds ≤ 10, TPSA ≤ 140). * The asterisk indicates that it is outside the standard range.

Table 3.

ADMET score for human intestinal absorption, Caco-2 permeability, blood–brain barrier, carcinogenicity, Ames mutagenesis and acute oral toxicity, as predicted using admetSAR.

Compound Name Human
Intestinal Absorption		 Blood Brain Barrier Caco-2
Permeability		 Ames
Mutagenesis		 Carcinogenicity Acute Oral Toxicity Average Score
3ba 0.9868 0.7500 0.7184 0.7400 0.5000 0.5118 0.7012
3fa 0.9848 0.7500 0.7869 0.7400 0.6020 0.5636 0.7379
3ga 0.9874 0.7500 0.7567 0.6800 0.5381 0.4706 0.6971
3ha 0.9860 0.7500 0.6451 0.7600 0.5881 0.5396 0.7115
3ia 0.9835 0.7500 0.5890 0.7000 0.5371 0.5325 0.6820
3ka 0.9868 0.7500 0.8320 0.7900 0.5000 0.5118 0.7284
3na 0.9848 0.7500 0.7356 0.7700 0.6020 0.5636 0.7343
3qa 0.9874 0.7500 0.7716 0.7600 0.5381 0.4706 0.7130
3ra 0.9860 0.7500 0.5674 0.8100 0.5881 0.5396 0.7069
4ab 0.9939 0.9000 0.6813 0.5500 0.5419 0.5439 0.7018
4ac 0.9925 0.9000 0.6529 0.6300 0.5929 0.5220 0.7151
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In summary, we have developed a novel and efficient method for the acquisition of 2-aminobenzofuran derivatives via Sc(OTf)3-promoted [4 + 1] cycloaddition reaction of isocyanides with the in situ generated ortho-quinone methides (o-QMs) under mild conditions. In addition, o-QMs were first successfully used in this transformation and its advantage of this transformation is the simplicity of the reaction and the increased variety of 2-aminobenzofurans. Further exploration of the construction of other heterocyclics from o-QMs and applications of this product is in progress.

3. Experimental

3.1. General Procedures

Unless otherwise noted, reagents were commercially available and were used without further purification. A 4 Å molecular sieve was pre-dried in an oven at 200 °C for 3 h Thin-layer chromatography (TLC) was performed using silica gel GF254 precoated plates (0.20 mm thickness). Visualization on TLC was achieved by UV light (254 nm). Column chromatography was performed on silica gel 90, 200–300 mesh. 1H NMR and 13C NMR spectra were recorded at 25 °C on a Bruker Avance 400 spectrometer (1H: 400 MHz and 13C: 101 MHz). 1H NMR chemical shifts are reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3, δ 7.26 ppm; DMSO-d6, δ 2.5 ppm). 13C NMR chemical shifts were determined relative to the signal of the solvent: CDCl3 at δ 77.00 ppm, DMSO-d6 at δ 39.5 ppm. Data for 1H and 13C NMR were recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets), coupling constants (Hz), and integration. ESI-HRMS spectra were recorded on a BioTOF Q instrument. Infrared (IR) spectra are obtained by the use of Spectrum One and expressed in wave number (cm−1). o-hydroxybenzhydryl alcohols 1a–1s [60] and isocyanides 2a–2f [51] were synthesized according to the previously reported.

3.2. Typical Procedure for Synthesis of 3aa

To a solution of p-nitrophenyl isocyanide 2a (0.2 mmol, 30 mg) in toluene (0.5 mL), we immediately added the o-hydroxybenzhydryl alcohols 1a (0.1 mmol, 20 mg), Sc(OTf)3 (0.1 mmol, 49 mg) in toluene (0.5 mL) under N2 in a Schlenck tube. The reaction mixture was stirred at 0 °C for 30 min. Upon completion, the reaction mixture was quenched with water, and then extracted with EtOAc and washed with brine. The combined organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated under vacuum. The crude product was purified using flash chromatography column eluting with (petroleum ether:ethyl acetate = 15:1) to obtain the product 3aa.

Detailed physicochemical properties of novel 2-aminobenzofuran derivatives:

  • N-(4-Nitrophenyl)-3-phenylbenzofuran-2-amine (3aa): Petroleum ether: ethyl acetate = 10:1, Rf = 0.5, yield: 87%, red solid, mp 123 °C.IR: 3309, 1639, 1589, 1494, 1393, 1311, 1242, 1190, 1114. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 7.3 Hz, 2H), 7.50 (q, J = 7.4 Hz, 3H), 7.37 (dt, J = 13.6, 6.9 Hz, 3H), 7.02 (d, J = 8.8 Hz, 2H), 6.66 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 151.2, 148.3, 145.3, 141.0, 131.2, 129.6, 128.2, 128.1, 127.6, 126.0, 124.3, 123.6, 119.5, 114.6, 111.1, 108.1. ESI-HRMS: m/z calcd for C20H15N2O3 [M + H]+: 331.1077, found: 331.1075.

  • 5-Methyl-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3ba): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 84%, red solid, mp 108 °C. IR: 3368, 2922, 1586, 1492, 1323, 1239, 1192, 1110. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.1 Hz, 2H), 7.58–7.51 (m, 2H), 7.51–7.42 (m, 3H), 7.41–7.33 (m, 2H), 7.18–7.12 (dd, J = 8.4 Hz, 0.8Hz, 1H), 7.03–6.95 (m, 2H), 6.54 (s, 1H), 2.47 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.6, 148.3, 145.3, 141.1, 133.1, 131.4, 129.2, 128.2, 128.0, 127.6, 126.0, 125.4, 119.4, 114.5, 110.6, 108.0, 21.5. ESI-HRMS: m/z calcd for C21H17N2O3 [M + H]+: 345.1234, found: 345.1239.

  • 6-Methyl-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3ca): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 86%, red solid, mp 109 °C. IR: 3360, 2920, 1596, 1496, 1322, 1304, 1248, 1188, 1109. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.1 Hz, 2H), 7.56 (dd, J = 11.8, 7.7 Hz, 3H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.31 (s, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.99–6.91 (m, 2H), 6.53 (s, 1H), 2.51 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 151.7, 148.7, 144.4, 141.0, 134.8, 131.4, 129.2, 128.1, 127.6, 126.0, 125.3, 124.8, 119.2, 114.4, 111.4, 109.0, 21.7. ESI-HRMS: m/z calcd for C21H17N2O3 [M + H]+: 345.1234, found: 345.1234.

  • 7-Methyl-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3da): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 79%, red solid, mp 141 °C. IR: 3364, 2923, 1591, 1501, 1385, 1325, 1248, 1183, 1110. 1H NMR (400 MHz, CDCl3) δ 8.19–8.11 (m, 2H), 7.59–7.51 (m, 3H), 7.47 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.03–6.96 (m, 2H), 6.60 (s, 1H), 2.56 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.2, 148.4, 144.9, 141.0, 131.4, 129.2, 128.2, 127.6, 127.5, 126.0, 125.4, 123.6, 121.4, 117.1, 114.5, 108.6, 15.0. ESI-HRMS: m/z calcd for C21H17N2O3 [M + H]+: 345.1234, found: 345.1255.

  • 5-(tert-butyl)-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3ea): Petroleum ether: ethyl acetate = 15:1, Rf = 0.7, yield: 80%, red solid, mp 97 °C. IR: 3356, 2960, 1591, 1503, 1340, 1285, 1186, 1111. 1H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 9.0 Hz, 2H), 7.68 (s, 1H), 7.56 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.43 (s, 2H), 7.38 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.62 (s, 1H), 1.41 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 149.5, 148.5, 146.8, 145.3, 141.0, 131.4, 129.3, 128.3, 127.6, 126.0, 122.2, 115.7, 114.5, 110.5, 108.7, 34.9, 31.9. ESI-HRMS: m/z calcd for C24H23N2O3 [M + H]+: 387.1703, found: 387.1704.

  • 5-Methoxy-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3fa): Petroleum ether: ethyl acetate = 10:1, Rf = 0.4, yield: 75%, red solid, mp 165 °C. IR: 3371, 2931, 1586, 1479, 1322, 1296, 1225, 1191, 1152, 1110. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.1 Hz, 2H), 7.56–7.51 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.42–7.34 (m, 2H), 7.12 (d, J = 2.5 Hz, 1H), 7.05–6.97 (m, 2H), 6.92 (dd, J = 8.9, 2.6 Hz, 1H), 6.62 (s, 1H), 3.85 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.6, 148.1, 146.0, 146.0, 141.1, 131.3, 129.3, 128.7, 128.2, 127.6, 126.0, 114.6, 112.3, 111.6, 107.9, 102.5, 56.0. ESI-HRMS: m/z calcd for C21H17N2O4 [M + H]+: 361.1183, found: 361.1187.

  • 5-Fluoro-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3ga): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 70%, red solid, mp 141 °C. IR: 3343, 1586, 1502, 1476, 1325, 1311, 1242, 1195, 1140, 1110. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.10 (d, J = 9.0 Hz, 2H), 7.62 (dd, J = 10.3, 5.9 Hz, 3H), 7.53–7.41 (m, 3H), 7.36 (t, J = 7.3 Hz, 1H), 7.17 (td, J = 9.2, 2.3 Hz, 1H), 7.04 (d, J = 9.1 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ159.6 (d, J = 232.3 Hz), 150.0, 148.1, 147.3, 140.1, 131.0, 129.5, 129.3, 128.4, 127.9, 126.2, 115.1, 112.7, 118.0 (d, J = 20.2 Hz), 108.3, 105.6, 105.3. 19F NMR (376 MHz, DMSO-d6) δ −119.35. ESI-HRMS: m/z calcd for C20H14FN2O3 [M + H]+: 349.0983, found: 349.0992.

  • 5-Chloro-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3ha): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 74%, red solid, mp 198 °C. IR: 3366, 1588, 1500, 1384, 1325, 1234, 1109. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.10 (d, J = 9.1 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.37 (td, J = 6.3, 5.5, 2.7 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 149.9, 149.6, 147.9, 140.1, 130.8, 129.9, 129.6, 128.5, 128.5, 128.0, 126.2, 124.4, 118.9, 115.1, 113.2, 107.6. ESI-HRMS: m/z calcd for C20H14ClN2O3 [M + H]+: 365.0687, found: 365.0678.

  • 5-Bromo-N-(4-nitrophenyl)-3-phenylbenzofuran-2-amine (3ia): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 80%, red solid, mp 210 °C. IR: 3367, 1585, 1504, 1468, 1324, 1232, 1109. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.09 (d, J = 9.1 Hz, 2H), 7.88 (d, J =1.2 Hz, 1H), 7.59 (d, J = 7.3 Hz, 3H), 7.54–7.44 (m, 3H), 7.36 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 9.1 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 149.9, 149.9, 147.7, 140.1, 130.8, 130.5, 129.6, 128.5, 128.0, 127.1, 126.2, 121.8, 116.4, 115.1, 113.6, 107.4. ESI-HRMS: m/z calcd for C20H13BrN2NaO3 [M + Na]+: 431.0002, found: 430.9998.

  • N-(4-Nitrophenyl)-3-(o-tolyl)benzofuran-2-amine (3ja): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 93%, red solid, mp 145 °C. IR: 3347, 2925, 1593, 1503, 1327, 1248, 1169, 1112. 1H NMR (400 MHz, CDCl3) δ 8.17–8.11 (m, 2H), 7.54–7.49 (m, 1H), 7.37–7.27 (m, 7H), 7.08–7.02 (m, 2H), 6.44 (s, 1H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 151.0, 147.6, 145.8, 141.1, 137.6, 130.9, 130.5, 129.8, 129.1, 128.4, 126.4, 125.9, 123.8, 123.4, 119.6, 114.7, 110.9, 106.2, 20.2. ESI-HRMS: m/z calcd for C21H17N2O3 [M + H]+: 345.1234, found: 345.1234.

  • N-(4-Nitrophenyl)-3-(p-tolyl)benzofuran-2-amine (3ka): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 91%, red solid, mp 138 °C. IR: 3359, 2920, 1591, 1524, 1384, 1248, 1175, 1109. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.1 Hz, 2H), 7.72–7.64 (m, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.37–7.30 (m, 2H), 7.28 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 9.1 Hz, 2H), 6.58 (s, 1H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 151.2, 148.4, 145.0, 141.0, 137.5, 130.0, 128.1, 128.1, 128.1, 126.0, 124.2, 123.5, 119.6, 114.5, 111.1, 108.3, 21.3. ESI-HRMS: m/z calcd for C21H16N2NaO3 [M + Na]+: 367.1053, found: 367.1054.

  • 3-(3,5-Dimethylphenyl)-N-(4-nitrophenyl)benzofuran-2-amine (3la): Petroleum ether: ethyl acetate = 12:1, Rf = 0.6, yield: 89%, red solid, mp 92 °C. IR: 3342, 2922, 1592, 1502, 1384, 1326, 1182, 1111. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.1 Hz, 2H), 7.67 (dd, J = 6.0, 2.7 Hz, 1H), 7.49 (dd, J = 6.5, 2.2 Hz, 1H), 7.33 (dt, J = 6.6, 4.7 Hz, 2H), 7.16 (s, 2H), 7.03 (d, J = 9.2 Hz, 3H), 6.64 (s, 1H), 2.37 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 151.1, 148.2, 145.3, 141.0, 138.9, 131.0, 129.4, 128.2, 126.0, 124.0, 123.5, 119.6, 114.7, 111.0, 107.7, 21.5. ESI-HRMS: m/z calcd for C22H18N2NaO3 [M + Na]+: 381.1210, found: 381.1206.

  • 3-(2-Isopropylphenyl)-N-(4-nitrophenyl)benzofuran-2-amine (3ma): Petroleum ether: ethyl acetate = 12:1, Rf = 0.6, yield: 73%, red solid, mp 170 °C. IR: 3319, 2961, 1642, 1592, 1499, 1384, 1323, 1306, 1237, 1186, 1112. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.50–7.40 (m, 2H), 7.32–7.28 (m, 5H), 7.05 (d, J = 9.0 Hz, 2H), 6.49 (s, 1H), 3.02 (hept, J = 6.6 Hz, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.9, 148.9, 147.9, 146.0, 141.1, 130.9, 129.8, 129.0, 128.3, 126.3, 126.3, 125.9, 123.8, 123.5, 119.3, 114.6, 110.9, 106.3, 30.1, 24.5, 24.1. ESI-HRMS: m/z calcd for C23H21N2O3 [M + H]+: 373.1547, found: 373.1547.

  • 3-(4-Methoxyphenyl)-N-(4-nitrophenyl)benzofuran-2-amine (3na): Petroleum ether: ethyl acetate = 10:1, Rf = 0.4, yield: 74%, red solid, mp 177 °C. IR: 3358, 2950, 1594, 1502, 1307, 1231, 1152, 1114. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.0 Hz, 2H), 7.70–7.63 (m, 1H), 7.48 (t, J = 7.1 Hz, 3H), 7.37–7.28 (m, 2H), 6.99 (dd, J = 11.2, 8.9 Hz, 4H), 6.50 (s, 1H), 3.85 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.1, 151.2, 148.5, 144.7, 141.0, 129.4, 128.2, 126.0, 124.3, 123.4, 123.3, 119.6, 114.7, 114.4, 111.1, 108.4, 55.4. ESI-HRMS: m/z calcd for C21H17N2O4 [M + H]+: 361.1183, found: 361.1183.

  • 3-(3-Methoxyphenyl)-N-(4-nitrophenyl)benzofuran-2-amine (3oa): Petroleum ether: ethyl acetate = 10:1, Rf = 0.4, yield: 77%, red solid, mp 107 °C. IR: 3315, 2920, 1591, 1501, 1325, 1309, 1239, 1183, 1110. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.1 Hz, 2H), 7.69 (dd, J = 6.5, 2.2 Hz, 1H), 7.50 (dd, J = 6.9, 1.9 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.36–7.28 (m, 2H), 7.13 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 2.0 Hz, 1H), 7.03 (d, J = 9.1 Hz, 2H), 6.91 (dd, J = 8.2, 2.3 Hz, 1H), 6.63 (s, 1H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.2, 151.1, 148.1, 145.4, 141.1, 132.5, 130.4, 128.0, 126.0, 124.2, 123.6, 120.5, 119.5, 114.7, 114.0, 112.8, 111.1, 107.5, 55.3. ESI-HRMS: m/z calcd for C21H16N2NaO4 [M + Na]+: 383.1002, found: 383.1004.

  • 3-(Naphthalen-1-yl)-N-(4-nitrophenyl)benzofuran-2-amine (3pa): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 58%, red solid, mp 194 °C. IR: 3309, 2920, 1637, 1587, 1498, 1322, 1305, 1242, 1183, 1110. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 9.1 Hz, 2H), 7.99–7.91 (m, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.51–7.61 (m, 4H), 7.44 (t, J = 7.5 Hz, 1H), 7.36–7.31 (m, 1H), 7.29 (d, J = 6.7 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.06 (d, J = 9.1 Hz, 2H), 6.46 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 151.0, 147.4, 146.8, 141.1, 134.1, 131.7, 129.6, 128.8, 128.8, 128.2, 128.1, 126.7, 126.4, 125.8, 125.8, 125.4, 123.7, 123.6, 119.7, 114.9, 110.9, 104.1. ESI-HRMS: m/z calcd for C24H17N2O3 [M + H]+: 381.1234, found: 381.1225.

  • 3-(4-Fluorophenyl)-N-(4-nitrophenyl)benzofuran-2-amine (3qa): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 81%, red solid, mp 126 °C. IR: 3332, 2920, 1587, 1500, 1472, 1325, 1108. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.10 (d, J = 9.2 Hz, 2H), 7.72–7.58 (m, 4H), 7.40–7.28 (m, 4H), 7.00 (d, J = 9.2 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.7 (d, J = 252.5 Hz), 151.2, 150.5, 146.3, 139.9, 130.5, 130.4, 128.0, 127.8, 126.3, 124.8, 124.0, 119.7, 116.4 (d, J = 20.2 Hz), 114.8, 111.6, 108.0. 19F NMR (376 MHz, DMSO-d6) δ -114.37. ESI-HRMS: m/z calcd for C20H14FN2O3 [M + H]+: 349.0983, found: 349.0977.

  • 3-(4-Chlorophenyl)-N-(4-nitrophenyl)benzofuran-2-amine (3ra): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 70%, red solid, mp 177 °C. IR: 3312, 2920, 1638, 1588, 1491, 1390, 1308, 1241, 1114. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 7.1 Hz, 1H), 7.53–7.47 (m, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7.39–7.29 (m, 2H), 7.00 (d, J = 9.0 Hz, 2H), 6.54 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 151.2, 148.0, 145.3, 141.3, 133.5, 129.7, 129.5, 129.5, 127.7, 126.0, 124.5, 123.7, 119.3, 114.6, 111.2, 107.3. ESI-HRMS: m/z calcd for C20H14ClN2O3 [M + H]+: 365.0687, found: 365.0687.

  • N-(4-Nitrophenyl)-3-(4-(trifluoromethyl)phenyl)benzofuran-2-amine (3sa): Petroleum ether: ethyl acetate = 10:1, Rf = 0.6, yield: 74%, red solid, mp 226 °C. IR: 3311, 2967, 1590, 1311, 1307, 1272, 1239, 1112, 1066. 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.13 (d, J = 9.2 Hz, 2H), 7.85 (s, 4H), 7.75 (dd, J = 6.6, 2.2 Hz, 1H), 7.63 (dd, J = 6.9, 1.8 Hz, 1H), 7.43–7.32 (m, 2H), 7.08 (d, J = 9.2 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 151.1, 149.9, 147.5, 140.1, 136.0, 129.1, 128.0, 127.7, 127.6, 126.4, 126.3, 126.3, 126.1, 124.8, 124.2, 123.4, 119.5, 115.2, 111.7, 106.5. 19F NMR (376 MHz, DMSO-d6) δ −60.99. ESI-HRMS: m/z calcd for C21H13F3N2NaO3 [M + Na]+: 421.0770, found: 421.0766.

  • N-(4-Chlorophenyl)-3-phenylbenzofuran-2-amine (4ab): Petroleum ether: ethyl acetate = 15:1, Rf = 0.6, yield: 83%, white solid, mp 102 °C. IR: 3371, 1636, 1594, 1479, 1384, 1238, 1183. 1H NMR (400 MHz, CDCl3) δ 7.62–7.67 (m, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.51–7.44 (m, 3H), 7.35 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 3.6 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1H), 7.25–7.20 (m, 2H), 7.00–6.93 (m, 2H), 6.13 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 150.9, 147.9, 140.8, 132.0, 129.3, 129.2, 128.6, 128.1, 127.1, 126.1, 123.3, 123.2, 118.8, 117.3, 110.8, 104.5. ESI-HRMS: m/z calcd for C20H15ClNO [M + H]+: 320.0837, found: 320.0822.

  • N-(4-Bromophenyl)-3-phenylbenzofuran-2-amine (4ac): Petroleum ether: ethyl acetate = 15:1, Rf = 0.6, yield: 74%, white solid, mp 137 °C. IR: 3360, 1636, 1590, 1489, 1379, 1241, 1174. 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 5.4, 3.3 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.51–7.43 (m, 3H), 7.40–7.32 (m, 3H), 7.30–7.26 (m, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.12 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 150.9, 147.7, 141.3, 132.2, 132.0, 129.12, 128.5, 128.1, 127.1, 123.3, 123.2, 118.8, 117.7, 113.3, 110.8, 104.7. ESI-HRMS: m/z calcd for C20H15BrNO [M + H]+: 364.0332, found: 364.0323.

  • N-(3-Chlorophenyl)-3-phenylbenzofuran-2-amine (4ad): Petroleum ether: ethyl acetate = 15:1, Rf = 0.6, yield: 81%, white solid, mp 134 °C. IR: 3359, 1637, 1593, 1492, 1378, 1242, 1173. 1H NMR (400 MHz, Chloroform-d) δ 7.68 (dd, J = 6.1, 2.9 Hz, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.48–7.52 (m, 3H), 7.37 (t, J = 7.4 Hz, 1H), 7.32–7.29 (m, 2H), 7.20 (t, J = 8.1 Hz, 1H), 7.05 (t, J = 1.9 Hz, 1H), 6.99–6.86 (m, 2H), 6.15 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 151.0, 147.3, 143.6, 135.1, 131.9, 130.4, 129.2, 128.4, 128.2, 127.2, 123.4, 123.3, 121.1, 119.0, 115.9, 114.1, 110.9, 105.5. ESI-HRMS: m/z calcd for C20H13ClNO [M − H]−: 318.0680, found: 318.0685.

  • 3-Phenyl-N-(p-tolyl)benzofuran-2-amine (4ae): Petroleum ether: ethyl acetate = 15:1, Rf = 0.6, yield: 56%, white solid, mp 92 °C. IR: 3380, 2925, 1608, 1517, 1384, 1196, 1071. 1H NMR (400 MHz, Chloroform-d) δ 7.69–7.56 (m, 3H), 7.52–7.42 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 7.29–7.22 (m, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.8, 149.2, 139.5, 132.5, 129.9, 129.2, 128.9, 128.1, 126.8, 123.1, 122.6, 118.4, 116.7, 110.7, 102.6, 20.7. ESI-HRMS: m/z calcd for C21H18NO [M + H]+: 300.1383, found: 300.1380.

  • N-(Naphthalen-2-yl)-3-phenylbenzofuran-2-amine (4af): Petroleum ether: ethyl acetate = 15:1, Rf = 0.6, yield: 73%, White solid, mp 124 °C. IR: 3377, 1629, 1600, 1454, 1381, 1220, 1184. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.77 (d, J = 6.2 Hz, 1H), 7.75 (d, J = 5.3 Hz, 1H), 7.72–7.69 (m, 1H), 7.68–7.65 (m, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.56–7.60 (m, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.39–7.34 (m, 1H), 7.33–7.27 (m, 3H), 7.27–7.24 (m, 1H), 7.22–7.25 (m, 1H), 7.19 (d, J = 2.0 Hz, 1H). ESI-HRMS: m/z calcd for C24H16NO [M − H]−: 334.1226, found: 334.1239.

  • Ethyl-(3-phenylbenzofuran-2-yl) glycinate (4ag): Petroleum ether: ethyl acetate = 6:1, Rf = 0.5, yield: 46%, White solid, mp 96 °C. IR: 3349, 2927, 1734, 1612, 1463, 1393, 1206, 1122. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.2 Hz, 2H), 7.45–7.55 (m, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.12–7.06 (m, 1H), 5.05 (t, J = 5.6 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.18 (d, J = 5.9 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.7, 153.7, 150.0, 133.2, 130.2, 129.2, 127.6, 126.0, 123.1, 120.6, 117.1, 109.9, 93.9, 61.6, 45.4, 14.2. ESI-HRMS: m/z calcd for C18H18NO3 [M + H]+: 296.1281, found: 296.1281.

  • N-(tert-butyl)-3-phenylbenzofuran-2-amine (4ah): Petroleum ether: ethyl acetate = 20:1, Rf = 0.6, yield: 85%, White solid, mp 108 °C. IR: 3367, 2967, 1606, 1458, 1379, 1210, 1015. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.0 Hz, 2H), 7.51 –7.45 (m, 3H), 7.37 (d, J = 7.9 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.10 (t, J =7.2 Hz, 1H), 4.39 (s, 1H), 1.43 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 155.2, 150.4, 133.7, 129.6, 129.2, 127.8, 125.9, 122.8, 120.6, 117.0, 110.0 97.0, 53.5, 30.6. ESI-HRMS: m/z calcd for C18H20NO [M + H]+: 266.1539, found: 266.1537.

3.3. X-ray Crystallographic Data of 3ia

The crystal of 3ia for XRD analysis was prepared by recrystallization from the DMSO (see the supporting information for details). CCDC 1914402 containing the supplementary crystallographic data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif (accessed on 5 July 2019). (remarks: The unit cell contains several 3ia and DMSO, which are weakly clustered together, but this does not affect the structural characterization of compound 3ia.)

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238538/s1, Figure S1: X-ray molecular structure of 3ia; Table S1: Crystal data and structure refinement for 3ia; Figures S2–S56: NMR spectra of the products (3aa–3sa, 4ab–4ah).

Click here for additional data file. (5MB, zip)

Author Contributions

Conceptualization, H.L., W.J. and H.S.; data curation, S.T.; investigation, H.L. and X.M.; methodology, H.L. and Y.P.; visualization, P.L.; validation, H.L., W.J. and H.S.; writing—original draft preparation, H.L.; writing—review and editing, S.T. and W.J.; funding acquisition, project administration and supervision, W.J. and H.S. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The details of the data supporting the report results in this research were included in the paper and Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This work was funded by the Key Research and Development Program of Sichuan Province (No. 2022YFS0001) and the National Natural Science Foundation of China (No. 21672205 and No. 21772192).

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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