Next Article in Journal
Photocatalytic Aerobic Oxidation of Biomass-Derived 5-HMF to DFF over MIL-53(Fe)/g-C3N4 Composite
Previous Article in Journal
Continuous-Flow Chemistry and Photochemistry for Manufacturing of Active Pharmaceutical Ingredients
Previous Article in Special Issue
Lewis Acid-Catalyzed 2,3-Dihydrofuran Acetal Ring-Opening Benzannulations toward Functionalized 1-Hydroxycarbazoles
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 23
10.3390/molecules27238538
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Huaxin Lin
1,2,
Senling Tang
1,2,
Yang Pan
1,2,
Peng Liang
1,2,
Xiaofeng Ma
1,
Wei Jiao
1,* and
Huawu Shao
1,*
1
Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
2
University of Chinese Academy of Sciences, Beijing 100049, China
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(23), 8538; https://doi.org/10.3390/molecules27238538
Submission received: 20 October 2022 / Revised: 28 November 2022 / Accepted: 2 December 2022 / Published: 4 December 2022
(This article belongs to the Special Issue Benzannulations in Organic Synthesis)
Browse Figures
Versions Notes

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.

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).
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).
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.
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.
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.
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%.
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).

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.

Funding

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).

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.

References

  1. Simonetti, S.O.; Larghi, E.L.; Bracca, A.B.J.; Kaufman, T.S. Angular Tricyclic Benzofurans and Related Natural Products of Fungal Origin. Isolation, Biological Activity and Synthesis. Nat. Prod. Rep. 2013, 30, 941–969. [Google Scholar] [CrossRef] [PubMed]
  2. Radadiya, A.; Shah, A. Bioactive Benzofuran Derivatives: An Insight on Lead Developments, Radioligands and Advances of the Last Decade. Eur. J. Med. Chem. 2015, 97, 356–376. [Google Scholar] [CrossRef] [PubMed]
  3. Okamoto, Y.; Ojika, M.; Suzuki, S.; Murakami, M.; Sakagami, Y. Iantherans A and B, Unique Dimeric Polybrominated Benzofurans as Na, K-ATPase Inhibitors from a Marine Sponge, Ianthella sp. Bioorg. Med. Chem. 2001, 9, 179–183. [Google Scholar] [CrossRef] [PubMed]
  4. Srivastava, V.; Negi, A.S.; Kumar, J.K.; Faridi, U.; Sisodia, B.S.; Darokar, M.P.; Luqman, S.; Khanuja, S.P.S. Synthesis of 1-(3′,4′,5′-Trimethoxy) Phenyl Naphtho[2,1b]Furan as a Novel Anticancer Agent. Bioorg. Med. Chem. Lett. 2006, 16, 911–914. [Google Scholar] [CrossRef]
  5. Hiremathad, A.; Patil, M.R.; Chethana, K.R.; Chand, K.; Santos, M.A.; Keri, R.S. Benzofuran: An Emerging Scaffold for Antimicrobial Agents. RSC Adv. 2015, 5, 96809–96828. [Google Scholar] [CrossRef]
  6. Ryu, C.-K.; Kim, Y.H.; Im, H.A.; Kim, J.Y.; Yoon, J.H.; Kim, A. Synthesis and antifungal activity of 6,7-bis(arylthio)-quinazoline-5,8-diones and furo[2,3-f]quinazolin-5-ols. Bioorg. Med. Chem. Lett. 2012, 22, 500–503. [Google Scholar] [CrossRef]
  7. Chen, C.Y.; Lin, C.M.; Lin, H.C.; Huang, C.F.; Lee, C.Y.; Si Tou, T.C.; Hung, C.C.; Chang, C.S. Structure-activity relationship study of novel 2-aminobenzofuran derivatives as P-glycoprotein inhibitors. Eur. J. Med. Chem. 2017, 125, 1023–1035. [Google Scholar] [CrossRef]
  8. Eldehna, W.M.; Nocentini, A.; Elsayed, Z.M.; Al-Warhi, T.; Aljaeed, N.; Alotaibi, O.J.; Al-Sanea, M.M.; Abdel-Aziz, H.A.; Supuran, C.T. Benzofuran-based carboxylic acids as carbonic anhydrase inhibitors and antiproliferative agents against breast cancer. ACS Med. Chem. Lett. 2020, 11, 1022–1027. [Google Scholar] [CrossRef]
  9. Oliva, P.; Romagnoli, R.; Manfredini, S.; Brancale, A.; Ferla, S.; Hamel, E.; Ronca, R.; Maccarinelli, F.; Giacomini, A.; Rruga, F.; et al. Design, synthesis, in vitro and in vivo biological evaluation of 2-amino-3-aroylbenzo[b]furan derivatives as highly potent tubulin polymerization inhibitors. Eur. J. Med. Chem. 2020, 200, 112448. [Google Scholar] [CrossRef]
  10. Ishikawa, T.; Miyahara, T.; Asakura, M.; Higuchi, S.; Miyauchi, Y.; Saito, S. One-Pot Multistep Synthesis of 4-Acetoxy-2-Amino-3-Arylbenzofurans from 1-Aryl-2-Nitroethylenes and Cyclohexane-1,3-Diones. Org. Lett. 2005, 7, 1211–1214. [Google Scholar] [CrossRef]
  11. Murai, M.; Miki, K.; Ohe, K. A New Route to 3-Acyl-2-Aminobenzofurans: Palladium-Catalysed Cycloisomerisation of 2-(Cyanomethyl)Phenyl Esters. Chem. Commun. 2009, 23, 3466–3468. [Google Scholar] [CrossRef] [PubMed]
  12. Borra, S.; Chandrasekhar, D.; Khound, S.; Maurya, R.A. Access to 1a, 6b-Dihydro-1H-Benzofuro[2, 3-b]Azirines and Benzofuran-2-Amines via Visible Light Triggered Decomposition of α-Azidochalcones. Org. Lett. 2017, 19, 5364–5367. [Google Scholar] [CrossRef] [PubMed]
  13. Kong, Y.; Jiang, K.; Cao, J.; Fu, L.; Yu, L.; Lai, G.; Cui, Y.; Hu, Z.; Wang, G. Synthesis of 3-Alkyl-or 3-Allenyl-2-Amidobenzofurans via Electrophilic Cyclization of o-Anisole-Substituted Ynamides with Carbocations. Org. Lett. 2013, 15, 422–425. [Google Scholar] [CrossRef] [PubMed]
  14. Rathore, V.; Sattar, M.; Kumar, R.; Kumar, S. Synthesis of Unsymmetrical Diaryl Acetamides, Benzofurans, Benzophenones, and Xanthenes by Transition-Metal-Free Oxidative Cross-Coupling of sp3 and sp2 C-H Bonds. J. Org. Chem. 2016, 81, 9206–9218. [Google Scholar] [CrossRef]
  15. Luan, Y.; Schaus, S.E. Enantioselective Addition of Boronates to o-Quinone Methides Catalyzed by Chiral Biphenols. J. Am. Chem. Soc. 2012, 134, 19965–19968. [Google Scholar] [CrossRef] [Green Version]
  16. Saha, S.; Alamsetti, S.K.; Schneider, C. Chiral Brønsted Acid-Catalyzed Friedel–Crafts Alkylation of Electron-Rich Arenes with in situ-Generated ortho-Quinone Methides: Highly Enantioselective Synthesis of Diarylindolylmethanes and Triarylmethanes. Chem. Commun. 2015, 51, 1461–1464. [Google Scholar] [CrossRef] [Green Version]
  17. Wu, B.; Gao, X.; Yan, Z.; Chen, M.W.; Zhou, Y.G. C-H Oxidation/Michael Addition/Cyclization Cascade for Enantioselective Synthesis of Functionalized 2-Amino-4H-Chromenes. Org. Lett. 2015, 17, 6134–6137. [Google Scholar] [CrossRef]
  18. Jeong, H.J.; Kim, D.Y. Enantioselective Decarboxylative Alkylation of β-Keto Acids to ortho-Quinone Methides as Reactive Intermediates: Asymmetric Synthesis of 2,4-Diaryl-1-Benzopyrans. Org. Lett. 2018, 20, 2944–2947. [Google Scholar] [CrossRef]
  19. Bai, W.J.; David, J.G.; Feng, Z.G.; Weaver, M.G.; Wu, K.L.; Pettus, T.R.R. The Domestication of ortho-Quinone Methides. Acc. Chem. Res. 2014, 47, 3655–3664. [Google Scholar] [CrossRef] [Green Version]
  20. Huang, H.M.; Wu, X.Y.; Leng, B.R.; Zhu, Y.L.; Meng, X.C.; Hong, Y.; Jiang, B.; Wang, D.C. Cu(ii)-Catalyzed formal [4 + 2] cycloaddition between quinone methides (QMs) and electron-poor 3-vinylindoles. Org. Chem. Front. 2020, 7, 414–419. [Google Scholar] [CrossRef]
  21. Jaworski, A.A.; Scheidt, K.A. Emerging Roles of in situ Generated Quinone Methides in Metal-Free Catalysis. J. Org. Chem. 2016, 81, 10145–10153. [Google Scholar] [CrossRef] [PubMed]
  22. Yang, B.; Gao, S. Recent Advances in the Application of Diels–Alder Reactions Involving o-Quinodimethanes, aza-o-Quinone Methides and o-Quinone Methides in Natural Product Total Synthesis. Chem. Soc. Rev. 2018, 47, 7926–7953. [Google Scholar] [CrossRef] [PubMed]
  23. Alden-Danforth, E.; Scerba, M.T.; Lectka, T. Asymmetric Cycloadditions of o-Quinone Methides Employing Chiral Ammonium Fluoride Precatalysts. Org. Lett. 2008, 10, 4951–4953. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Hsiao, C.C.; Liao, H.H.; Rueping, M. Enantio- and Diastereoselective Access to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho-Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalysis. Angew. Chem. Int. Ed. 2014, 53, 13258–13263. [Google Scholar] [CrossRef]
  25. Lee, A.; Scheidt, K.A. N-Heterocyclic Carbene-Catalyzed Enantioselective Annulations: A Dual Activation Strategy for a Formal [4+2] Addition for Dihydrocoumarins. Chem. Commun. 2015, 51, 3407–3410. [Google Scholar] [CrossRef] [Green Version]
  26. Alamsetti, S.K.; Spanka, M.; Schneider, C. Synergistic Rhodium/Phosphoric Acid Catalysis for the Enantioselective Addition of Oxonium Ylides to ortho-Quinone Methides. Angew. Chemie Int. Ed. 2016, 55, 2392–2396. [Google Scholar] [CrossRef]
  27. Lv, H.; Jia, W.Q.; Sun, L.H.; Ye, S. N-Heterocyclic Carbene Catalyzed [4+3] Annulation of Enals and o-Quinone Methides: Highly Enantioselective Synthesis of Benzo-ε-Lactones. Angew. Chemie Int. Ed. 2013, 52, 8607–8610. [Google Scholar] [CrossRef]
  28. Chen, M.W.; Cao, L.L.; Ye, Z.S.; Zhou, Y.G.; Jiang, G.F. A Mild Method for Generation of o-Quinone Methides under Basic Conditions. The Facile Synthesis of Trans-2,3-Dihydrobenzofurans. Chem. Commun. 2013, 49, 1660–1662. [Google Scholar] [CrossRef] [Green Version]
  29. Wu, B.; Chen, M.W.; Ye, Z.S.; Yu, C.B.; Zhou, Y.G. A Streamlined Synthesis of 2,3-Dihydrobenzofurans via the ortho-Quinone Methides Generated from 2-Alkyl-Substituted Phenols. Adv. Synth. Catal. 2014, 356, 383–387. [Google Scholar] [CrossRef]
  30. Meisinger, N.; Roiser, L.; Monkowius, U.; Himmelsbach, M.; Robiette, R.; Waser, M. Asymmetric Synthesis of 2,3-Dihydrobenzofurans by a [4 + 1] Annulation Between Ammonium Ylides and In Situ Generated o-Quinone Methides. Chem. Eur. J. 2017, 23, 5137–5142. [Google Scholar] [CrossRef]
  31. Rodriguez, K.X.; Vail, J.D.; Ashfeld, B.L. Phosphorus(III)-Mediated Stereoconvergent Formal [4 + 1]-Cycloannulation of 1,2-Dicarbonyls and o-Quinone Methides: A Multicomponent Assembly of 2,3-Dihydrobenzofurans. Org. Lett. 2016, 18, 4514–4517. [Google Scholar] [CrossRef] [PubMed]
  32. Osyanin, V.A.; Osipov, D.V.; Klimochkin, Y.N. Reactions of o-Quinone Methides with Pyridinium Methylides: A Diastereoselective Synthesis of 1,2-Dihydronaphtho[2,1-b]Furans and 2,3-Dihydrobenzofurans. J. Org. Chem. 2013, 78, 5505–5520. [Google Scholar] [CrossRef] [PubMed]
  33. Cheng, Y.Y.; Fang, Z.Q.; Li, W.J.; Li, P.F. Phosphine-mediated enantioselective [4 + 1] annulations between ortho-quinone methides and Morita–Baylis–Hillman carbonates. Org. Chem. Front. 2018, 5, 2728–2733. [Google Scholar] [CrossRef]
  34. Jiang, X.L.; Liu, S.J.; Gu, Y.Q.; Mei, G.J.; Shi, F. Catalytic Asymmetric [4 + 1] Cyclization of ortho-Quinone Methides with 3-Chlorooxindoles. Adv. Synth. Catal. 2017, 359, 3341–3346. [Google Scholar] [CrossRef]
  35. Liang, P.; Pan, Y.; Ma, X.; Jiao, W.; Shao, H. A Facile Method for the Synthesis of Fused Perhydropyrano[2,3-b]Pyrans Promoted by Yb(OTf)3. Chem. Commun. 2018, 54, 3763–3766. [Google Scholar] [CrossRef]
  36. Zhang, X.; Pan, Y.; Liang, P.; Pang, L.; Ma, X.; Jiao, W.; Shao, H. Oxadiazepine Synthesis by Formal [4+3] Cycloaddition of o-Chloromethyl Arylsulfonamides with Nitrones Promoted by NaHCO3. Adv. Synth. Catal. 2018, 360, 3015–3019. [Google Scholar] [CrossRef]
  37. Ma, X.; Tang, Q.; Ke, J.; Zhang, J.; Wang, C.; Wang, H.; Li, Y.; Shao, H. Straightforward and Highly Diastereoselective Synthesis of 2,2-Di-Substituted Perhydrofuro[2,3-b]Pyran (and Furan) Derivatives Promoted by BiCl3. Chem. Commun. 2013, 49, 7085–7087. [Google Scholar] [CrossRef] [Green Version]
  38. Ma, X.; Tang, Q.; Ke, J.; Yang, X.; Zhang, J.; Shao, H. InCl3 Catalyzed Highly Diastereoselective [3+2] Cycloaddition of 1,2-Cyclopropanated Sugars with Aldehydes: A Straightforward Synthesis of Persubstituted Bis -Tetrahydrofurans and Perhydrofuro[2,3-b]Pyrans. Org. Lett. 2013, 15, 5170–5173. [Google Scholar] [CrossRef]
  39. Ma, X.; Zhang, J.; Tang, Q.; Ke, J.; Zou, W.; Shao, H. Stereospecific [3+2] Cycloaddition of 1,2-Cyclopropanated Sugars and Ketones Catalyzed by SnCl4: An Efficient Synthesis of Multi-Substituted Perhydrofuro[2,3-b]Furans and Perhydrofuro[2,3-b]Pyrans. Chem. Commun. 2014, 50, 3505–3508. [Google Scholar] [CrossRef]
  40. Zhang, X.; Pan, Y.; Liang, P.; Ma, X.; Jiao, W.; Shao, H. An Effective Method for the Synthesis of 1,3-Dihydro-2H-Indazoles via N-N Bond Formation. Adv. Synth. Catal. 2019, 361, 5552–5557. [Google Scholar] [CrossRef]
  41. Winkler, J.D.; Asselin, S.M. Synthesis of Novel Heterocyclic Structures via Reaction of Isocyanides with S-trans-Enones. Org. Lett. 2006, 8, 3975–3977. [Google Scholar] [CrossRef] [PubMed]
  42. Masdeu, C.; Gómez, E.; Williams, N.A.O.; Lavilla, R. Double Insertion of Isocyanides into Dihydropyridines: Direct Access to Substituted Benzimidazolium Salts. Angew. Chem. Int. Ed. 2007, 46, 3043–3046. [Google Scholar] [CrossRef] [PubMed]
  43. Gao, Q.; Zhou, P.; Liu, F.; Hao, W.J.; Yao, C.; Jiang, B.; Tu, S.J. Cobalt(II)/Silver Relay Catalytic Isocyanide Insertion/Cycloaddition Cascades: A New Access to Pyrrolo[2,3-b]Indoles. Chem. Commun. 2015, 51, 9519–9522. [Google Scholar] [CrossRef]
  44. Pan, Y.Y.; Wu, Y.N.; Chen, Z.Z.; Hao, W.J.; Li, G.; Tu, S.J.; Jiang, B. Synthesis of 3-Iminoindol-2-Amines and Cyclic Enaminones via Palladium-Catalyzed Isocyanide Insertion-Cyclization. J. Org. Chem. 2015, 80, 5764–5770. [Google Scholar] [CrossRef]
  45. Prasad, B.; Nallapati, S.B.; Kolli, S.K.; Sharma, A.K.; Yellanki, S.; Medisetti, R.; Kulkarni, P.; Sripelly, S.; Mukkanti, K.; Pal, M. Pd-Catalyzed Isocyanide Insertion/Nucleophilic Attack by Indole C-3/Desulfonylation in the Same Pot: A Direct Access to Indoloquinolines of Pharmacological Interest. RSC Adv. 2015, 5, 62966–62970. [Google Scholar] [CrossRef]
  46. Senadi, G.C.; Hu, W.P.; Boominathan, S.S.K.; Wang, J.J. Palladium(0)-Catalyzed Single and Double Isonitrile Insertion: A Facile Synthesis of Benzofurans, Indoles, and Isatins. Chem. Eur. J. 2015, 21, 998–1003. [Google Scholar] [CrossRef] [PubMed]
  47. ITO, Y.; Kobayashi, K.; Maeno, M.; Saegusa, T. A New Synthetic Method for Preparation of 1,3,4,5-Tetrahydro-2H-1-Benzazepin-2-One Derivatives. Chem. Lett. 1980, 9, 487–490. [Google Scholar] [CrossRef]
  48. Liang, M.; Zhang, S.; Jia, J.; Tung, C.H.; Wang, J.; Xu, Z. Synthesis of Spiroketals by Synergistic Gold and Scandium Catalysis. Org. Lett. 2017, 19, 2526–2529. [Google Scholar] [CrossRef]
  49. Liu, S.; Chen, K.; Lan, X.C.; Hao, W.J.; Li, G.; Tu, S.J.; Jiang, B. Synergistic Silver/Scandium Catalysis for Divergent Synthesis of Skeletally Diverse Chromene Derivatives. Chem. Commun. 2017, 53, 10692–10695. [Google Scholar] [CrossRef]
  50. Thirupathi, N.; Tung, C.H.; Xu, Z. Scandium (III)-Catalyzed Cycloaddition of in Situ Generated ortho-Quinone Methides with Vinyl Azides: An Efficient Access to Substituted 4H-Chromenes. Adv. Synth. Catal. 2018, 360, 3585–3589. [Google Scholar] [CrossRef]
  51. Wang, L.; Ferguson, J.; Zeng, F. Palladium-Catalyzed Direct Coupling of 2-Vinylanilines and Isocyanides: An Efficient Synthesis of 2-Aminoquinolines. Org. Biomol. Chem. 2015, 13, 11486–11491. [Google Scholar] [CrossRef] [PubMed]
  52. Daina, A.; Michielin, O.; Zoete, V. SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug- Likeness and Medicinal Chemistry Friendliness of Small Molecules. Sci. Rep. 2017, 7, 42717. [Google Scholar] [CrossRef] [Green Version]
  53. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv. Drug Deliv. Rev. 2001, 46, 3–26. [Google Scholar] [CrossRef] [PubMed]
  54. Veber, D.F.; Johnson, S.R.; Cheng, H.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 2002, 45, 2615–2623. [Google Scholar] [CrossRef] [PubMed]
  55. Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. AdmetSAR: A Comprehensive Source and Free Tool for Assessment of Chemical ADMET Properties. J. Chem. Inf. Model. 2012, 52, 3099–3105. [Google Scholar] [CrossRef] [PubMed]
  56. Guan, L.; Yang, H. ADMET-Score—A Comprehensive Scoring Function for Evaluation of Chemical Drug-Likeness. Med. Chem. Commun. 2019, 10, 148–157. [Google Scholar] [CrossRef]
  57. Wang, H.; Tang, S.; Zhang, G.; Pan, Y.; Jiao, W.; Shao, H. Synthesis of N-Substituted Iminosugar C-Glycosides and Evaluation as Promising a-Glucosidase Inhibitors. Molecules 2022, 27, 5517. [Google Scholar] [CrossRef]
  58. Gfeller, D.; Michielin, O.; Zoete, V. Shaping the Interaction Landscape of Bioactive Molecules. Bioinformatics 2013, 29, 3073–3079. [Google Scholar] [CrossRef] [Green Version]
  59. Antoine, D.; Michielin, O.; Zoete, V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucl. Acids Res. 2019, 47, 357–364. [Google Scholar] [CrossRef] [Green Version]
  60. Fan, J.; Wang, Z. Facile Construction of Functionalized 4H-Chromene via Tandem Benzylation and Cyclization. Chem. Commun. 2008, 42, 5381–5383. [Google Scholar] [CrossRef]
Molecules 27 08538 sch001 550
Scheme 1. Strategies for the diversified synthesis of 2-aminobenzofurans.
Scheme 1. Strategies for the diversified synthesis of 2-aminobenzofurans.
Molecules 27 08538 sch001
Molecules 27 08538 sch002 550
Scheme 2. 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.
Scheme 2. 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.
Molecules 27 08538 sch002
Molecules 27 08538 sch003 550
Scheme 3. 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.
Scheme 3. 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.
Molecules 27 08538 sch003
Molecules 27 08538 sch004 550
Scheme 4. Plausible reaction mechanism.
Scheme 4. Plausible reaction mechanism.
Molecules 27 08538 sch004
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 27 08538 i001
EntryPromoterSolventYield b (%)
1TsOHCH2Cl218
2TfOHCH2Cl215
3benzoic acidCH2Cl2trace
4BF3·Et2OCH2Cl240
5InCl3CH2Cl223
6Sc(OTf)3CH2Cl253
7Sc(OTf)3THF29
8Sc(OTf)3MeCN37
9Sc(OTf)3DCE50
10Sc(OTf)3toluene60
11 cSc(OTf)3toluene75
12 dSc(OTf)3toluene71
13 c,eSc(OTf)3toluene81
14 c,fSc(OTf)3toluene69
15 c,e,gSc(OTf)3toluene87
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.
Table
Table 2. Physiochemical properties of the compounds predicted using SwissADME.
Table 2. Physiochemical properties of the compounds predicted using SwissADME.
Compound NameMWnHetero AtomsRotatable
Bonds		H-Bond AcceptorH-Bond DonorTPSA (Å sqr)MlogP
3aa330.34543170.994.03
3ba344.37543170.993.44
3ca344.37543170.993.44
3da344.37543170.993.44
3ea386.45553170.994.90 *
3fa360.37654180.223.71
3ga348.33644170.993.60
3ha364.79643170.993.71
3ia409.24643170.993.82
3ja344.37543170.993.44
3ka344.37543170.993.44
3la358.40543170.993.66
3ma372.42553170.994.69 *
3na360.37654180.223.71
3oa360.37654180.223.71
3pa380.40543170.994.73 *
3qa348.33644170.993.60
3ra364.79643170.993.71
3sa398.34856170.994.04
4ab319.79331125.174.79 *
4ac364.24331125.174.90 *
4ad319.79331125.174.79 *
4ae299.37231125.174.52 *
4af335.31231125.174.99 *
4ag295.34463151.472.80
4ah265.36231125.173.79
(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
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.
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 NameHuman
Intestinal Absorption		Blood Brain BarrierCaco-2
Permeability		Ames
Mutagenesis		CarcinogenicityAcute Oral ToxicityAverage Score
3ba0.98680.75000.71840.74000.50000.51180.7012
3fa0.98480.75000.78690.74000.60200.56360.7379
3ga0.98740.75000.75670.68000.53810.47060.6971
3ha0.98600.75000.64510.76000.58810.53960.7115
3ia0.98350.75000.58900.70000.53710.53250.6820
3ka0.98680.75000.83200.79000.50000.51180.7284
3na0.98480.75000.73560.77000.60200.56360.7343
3qa0.98740.75000.77160.76000.53810.47060.7130
3ra0.98600.75000.56740.81000.58810.53960.7069
4ab0.99390.90000.68130.55000.54190.54390.7018
4ac0.99250.90000.65290.63000.59290.52200.7151
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lin, H.; Tang, S.; Pan, Y.; Liang, P.; Ma, X.; Jiao, W.; Shao, H. A Novel Method to Construct 2-Aminobenzofurans via [4 + 1] Cycloaddition Reaction of In Situ Generated Ortho-Quinone Methides with Isocyanides. Molecules 2022, 27, 8538. https://doi.org/10.3390/molecules27238538

AMA Style

Lin H, Tang S, Pan Y, Liang P, Ma X, Jiao W, Shao H. A Novel Method to Construct 2-Aminobenzofurans via [4 + 1] Cycloaddition Reaction of In Situ Generated Ortho-Quinone Methides with Isocyanides. Molecules. 2022; 27(23):8538. https://doi.org/10.3390/molecules27238538

Chicago/Turabian Style

Lin, Huaxin, Senling Tang, Yang Pan, Peng Liang, Xiaofeng Ma, Wei Jiao, and Huawu Shao. 2022. "A Novel Method to Construct 2-Aminobenzofurans via [4 + 1] Cycloaddition Reaction of In Situ Generated Ortho-Quinone Methides with Isocyanides" Molecules 27, no. 23: 8538. https://doi.org/10.3390/molecules27238538

APA Style

Lin, H., Tang, S., Pan, Y., Liang, P., Ma, X., Jiao, W., & Shao, H. (2022). A Novel Method to Construct 2-Aminobenzofurans via [4 + 1] Cycloaddition Reaction of In Situ Generated Ortho-Quinone Methides with Isocyanides. Molecules, 27(23), 8538. https://doi.org/10.3390/molecules27238538

Article Metrics

Back to TopTop