Next Article in Journal
A Study of Pigment, Adhesive, and Firing Temperature in Pottery Figurines Excavated from the Tomb of Qibi Ming, China
Next Article in Special Issue
A Natural Compound Containing a Disaccharide Structure of Glucose and Rhamnose Identified as Potential N-Glycanase 1 (NGLY1) Inhibitors
Previous Article in Journal
Cobalt Ferrite Synthesized Using a Biogenic Sol–Gel Method for Biomedical Applications
Previous Article in Special Issue
A Direct Method for Synthesis of Quinoxalines and Quinazolinones Using Epoxides as Alkyl Precursor
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 23
10.3390/molecules28237738
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

Transition-Metal-Free One-Pot Synthesis of Fused Benzofuranamines and Benzo[b]thiophenamines

by
Ran Liu
1,
Lili Lv
2,
Bingchuan Yang
1,3,4,5,*,
Ziyi Gu
1,
Chenglong Li
6,
Xueyan Lv
4,
Chengcheng Ding
4,
Xianqiang Huang
1 and
Dong Yuan
3,*
1
School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252000, China
2
China Petroleum Planning and Engineering Institute, Dongying 257237, China
3
College of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250013, China
4
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
5
The Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA
6
Shandong Weijiao Holding Group Co., Ltd., Weifang 262404, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(23), 7738; https://doi.org/10.3390/molecules28237738
Submission received: 17 October 2023 / Revised: 17 November 2023 / Accepted: 20 November 2023 / Published: 23 November 2023
(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Discovery, Evaluation and Applications)
Browse Figures
Versions Notes

Abstract

:
A series of benzofuran and benzo[b]thiophen derivatives was synthesized via a transition-metal-free one-pot process at room temperature. This one-pot protocol enables the synthesis of compounds with high reaction efficiency, mild conditions, simple methods, and a wide-ranging substrate scope. Regioselective five-membered heterocycles were constructed in good-to-excellent yields.

Graphical Abstract

1. Introduction

Benzofuran and benzo[b]thiophen derivatives have attracted considerable interest given their outstanding medicinal and biological properties [1,2]. Compounds with benzofuran functionalities have been widely employed to cure different kinds of diseases [3,4,5,6]. For example, Tasimelteon [7] is a small-molecule melatonin receptor agonist used to treat non-24-hour sleep disorders in patients with total blindness. Amiodarone hydrochloride [8,9] is a third class of antiarrhythmic drugs widely used for the treatment and prevention of arrhythmia and has a direct dilation effect on coronary arteries and peripheral vessels. Fruquintinib [10,11] can inhibit the formation of tumor neovascularization and eventually exert a tumor growth inhibition effect. It is a highly selective inhibitor of tumor angiogenesis. Khellin [12] is a micranochromone that has antiproliferative activity in vitro; meanwhile, it also has antispasmodic and coronary diastolic effects (Scheme 1). Fused benzofuran and benzothiophen also have antimicrobial, anti-inflammatory, antihypertensive, and analgesic activities [13].
As a result, all kinds of methods have been developed for the construction of benzofuran and benzothiophen derivatives [14]. Classical methods for the synthesis of these derivatives are described in the literature. Zhang’s group [15] developed a palladium-catalyzed aryldifluoroalkylation method that involves the reaction of 1,6-enynes with ethyl difluoroiodoacetate and arylboronic acids, thereby achieving the desired derivatives. Jiangs’ group [16] developed a palladium-catalyzed fluoroalkylative cyclization of olefins with the formation of Csp3–CF2 and C–O/N bonds in one step to obtain difluoroalkylated 2,3-dihydrobenzofuran and indolin derivatives. In the synthesis of 2,3-disubstituted benzofuran, the Sonogashira coupling reaction [17] can be completed with a one-step reaction. It is prepared by coupling–cyclizing o-iodophenol with a terminal alkyne in the presence of powder potassium-fluoride-doped alumina and a mixture of powder palladium, cuprous iodide, and tri-phenylphosphine. However, these methods still suffer from some drawbacks, such as vigorous reaction conditions and multiple steps (Scheme 2). In this context, the development of a novel synthetic method to fulfill the atom economy and achieve great efficiency is highly desired [18,19,20].
A one-step synthetic route would be a very useful improvement [21,22]. We focused on the development of the direct synthesis of heterocyclic systems using tandem reactions. Herein, we report an efficient and convergent one-pot synthetic strategy approach to benzofuran and benzothiophen derivatives under mild conditions. Benzofuran and benzothiophen scaffolds were obtained through the reaction of 2-fluorobenzonitriles and substituted alcohol at room temperature (Scheme 3).

2. Results

To obtain the optimized conditions, 2-fluorobenzonitrile, 1a, and 1-hydroxypropan-2-one, 2a, were chosen as models. As shown in Table 1, the reaction base, solvent, and time were investigated. The reaction proceeded with different bases in DMSO at room temperature, and Cs2CO3 provided the highest yields (Table 1, entry 5). In weak basic systems such as K2CO3 or K3PO4 at room temperature, no desired product, 3a, was obtained (Table 1, entries 1,3). When we used the organic base Et3N in the reaction, no desired compound, 3a, was detected either. In constructing 3a, Cs2CO3 performed much better than KOH and t-BuOK, with a yield of 76% (Table 1, entries 5–7). The investigation of the solvent proved that the yields of the product in DMSO were higher than in CH3CN, THF, and DMF with the same base system (Table 1, entries 5, 9, 10, 11). Finally, we chose Cs2CO3 in DMSO as the most efficient system to accomplish the synthesis of the benzofuran derivatives, 3 (Table 1, entry 5).
To explore the range of this methodology, various primary alcohols were studied (Table 2) under the selected reaction condition (Scheme 2). The structures of products 3a–3q are shown in Figure 1. As shown in Table 2, both ketone and ester led to the formation of bicyclic products with high yields. However, 2-fluorobenzonitrile with strong electron-withdrawing groups (Table 2, entry 6, 7, 16, 17) obtained better yields than the non-substituted derivatives, and 2,4-difluorobenzonitrile obtained the best reaction yield of all the halogen-substituted scaffolds (Table 2, entry 3–5).
Additionally, a steric hindrance affected the reaction very slightly. Ethyl 2-hydroxyacetate (Table 2, entry 11–17) also obtained a high yield of 3.
As shown in Table 3, a variety of substituted methanethiols, 4, were used to expand the applicability of this methodology. Substituted 2-fluorobenzonitrile bearing methoxyl obtained a low yield of 31% in the reaction (Table 3, entry 9), whereas 2-fluorobenzonitrile with electron-withdrawing groups obtained higher yields (Table 3, entries 6–8). The steric hindrance affected the reaction very slightly, and butyl 2-hydroxyacetate also provided a high yield of 5 (Table 3, entry 4).
Aromatic substituted methanethiol also obtained a high yield of 5 (Table 3, entry 5). The structures of products 5a–5i are shown in Figure 2.
Based on our previous work [23], a plausible reaction mechanism is presented in Scheme 4. Compounds 1a and 2a undergo nucleophilic aromatic substitution, providing compound 6. In the presence of Cs2CO3, the carbanion, 7, that forms attacks the nitrile group, leading to cyclization and imine anion formation. Then, proton addition and tautomerism lead to the corresponding product, 3a.
To demonstrate the structure of benzothiophene, the molecular configuration of product 5g was determined through X-ray crystallographic analysis (Figure 3).

3. Experimental Section

3.1. General

1H and 13C NMR spectra were recorded with a 300 spectrometer or a 400 spectrometer in CDCl3. HRMS spectra were determined with a Q-TOF spectrograph. Compounds 3a–3q and 5a–5i were prepared according to the literature. Other reagents (Adamas) were commercially available and were used without further purification. All reactions were monitored via thin-layer chromatography (TLC). For the NMR spectrum of compounds see the Supplementary Materials.

3.2. General Experimental Procedure for 1-(3-Aminobenzofuran-2-yl)ethan-1-one (3a)

To a solution of DMSO (15 mL), 2-fluorobenzonitrile, 1a (0.12 g, 1.0 mmol); propionic acid, 2a (0.037 g, 0.5 mmol); and Cs2CO3 (0.98 g, 3.0 mmol) were added and stirred for 1 h at room temperature; then, more propionic acid, 2a (0.037 g, 0.5 mmol), was added and stirred at r.t. over 4 h. Brine (40 mL) was poured into the solution, and the mixture was extracted with CH2Cl2 (3 × 40 mL). The organic layers were combined and dried by over-anhydrous Na2SO4. The product was purified via flash chromatography on silica gel (Hexane/EtOAc = 5:1). Compound 3a was obtained as a white solid (mp: 175–176 °C, 0.13 g, 76% yield). 1H NMR (CDCl3, 300 MHz): δ 7.59–7.56 (m, 1H), 7.52–7.46 (m, 1H), 7.42–7.40 (d, J = 8.1 Hz, 1H), 7.26–7.21 (m, 1H), 5.59 (s, 2H), 2.50 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.8, 154.0, 138.5, 135.4, 129.4, 122.2, 121.3, 120.3, 112.6, 25.9; FT-HRMS (ESI) calcd for C10H9NO2 [(M + H)+]: 176.0667; found, 176.0691.

3.3. General Experimental Procedure for 1-(3-Amino-7-fluorobenzo[b]thiophen-2-yl)ethan-1-one (5a)

This compound was prepared in the same way as described for 3a by using 2,3-difluorobenzonitrile (0.14 g, 1.0 mmol), 1,2-difluoro-4-nitrobenzene 4a (0.09 g, 1.0 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO (15 mL) at room temperature. The product was purified via flash chromatography on silica gel (hexane/EtOAc = 5:1) to obtain 5a (mp: 245–246 °C, 0.16 g, 78% yield) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.88 (s, 1H), 7.48 (t, J = 8.8 Hz, 2H), 5.88 (s, 2H), 3.89 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 165.6, 147.9, 141.3, 128.8 (JC,F = 267 Hz), 125.9, 122.4 (JC,F = 22 Hz), 51.4; FT-HRMS (ESI) calcd for C10H8FNOS [(M + H)+]: 210.0344; found, 210.0567.

3.4. X-ray Crystal Structure Analysis of Compound 5g [24,25]

Single crystals of 5g suitable for X-ray crystal analysis were obtained via recrystallization from a hexane/CH2Cl2 mixed solvent. Intensity data were collected at 293 K with an X-ray diffractometer with Mo Kα radiation (λ = 0.71073 Å) and a graphite monochrometer. A total of 1137 reflections were measured at a maximum 2θ angle of 50.0°, of which 1781 were independent reflections (Rint = 0.0406). The structure was determined with direct methods (SHELXS-97)22 and refined by using full-matrix least-squares on F2 (SHELEXL-97)22. The crystal data are as follows: C10H8FNO2S; FW = 225.03; crystal size, 0.12 × 0.10 × 0.10 mm3; monoclinic, P21/c, a = 13.7929(8) Å, b = 3.9422(3) Å; c = 22.5228(15) Å; V = 991.90(12) Å3; Z = 4. The refinement converged to R1 = 0.0637, wR2 = 0.1604 (I > 2σ(I)).

3.5. Characterization Data

  • 1-(3-Amino-7-fluorobenzofuran-2-yl)ethan-1-one (3b): 155 mg (80% yield), white solid, mp: 188–189 °C; 1H NMR (CDCl3, 300 MHz): δ 7.35 (dd, J = 1.5, 7.5 Hz, 1H), 7.25–7.14 (m, 2H), 5.31 (s, 1H), 2.53 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 190.0, 148.6 (JC,F = 249 Hz), 141.4 (JC,F = 13 Hz), 138.1, 136.1, 124.8, 122.8 (JC,F = 6 Hz), 115.7, 115.1 (JC,F = 16 Hz), 25.97; FT-HRMS (ESI) calcd for C10H8FNO2 [(M + H)+]: 194.0573; found, 194.0625.
  • 1-(3-Amino-6-fluorobenzofuran-2-yl)ethan-1-one (3c): 158 mg (82% yield), white solid, mp: 188–189 °C; 1H NMR (CDCl3, 400 MHz): δ 7.56 (t, J = 8.0 Hz, 1H), 6.79–6.71 (m, 2H), 4.70 (s, 2H), 3.83 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 163.1, 159.7 (JC,F = 257 Hz), 157.9 (JC,F = 11 Hz), 129.70, 109.3, 106.7, 98.5 (JC,F = 23 Hz), 89.6 (JC,F = 16 Hz), 26.0; FT-HRMS (ESI) calcd for C10H8FNO2 [(M + H)+]: 194.0573; found, 194.0653
  • 1-(3-Amino-6-chlorobenzofuran-2-yl)ethan-1-one (3d): 163 mg (78% yield), white solid, mp: 217–219 °C; 1H NMR (CDCl3, 400 MHz): δ 7.50 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.24 (dd, J = 1.6, 8.4 Hz, 1H), 5.58 (s, 2H), 2.50 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 189.7, 153.9, 137.8, 135.4, 123.3, 120.9, 120.0, 113.1, 110.0, 25.9; FT-HRMS (ESI) calcd for C10H8ClNO2 [(M + H)+]: 211.0214; found, 211.0265.
  • 1-(3-Amino-6-bromobenzofuran-2-yl)ethan-1-one (3e): 142 mg (56% yield), white solid, mp: 247–249 °C; 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 1.6, 8.4 Hz, 1H), 5.56 (s, 2H), 2.49 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 189.8, 154.0, 137.8, 135.6, 125.9, 123.1, 121.1, 120.3, 116.1, 26.0; FT-HRMS (ESI) calcd for C10H8BrNO2 [(M + H)+]: 254.9718; found, 254.9816.
  • 1-(3-Amino-6-(trifluoromethyl)benzofuran-2-yl)ethan-1-one (3f): 219 mg (90% yield), white solid, mp: 203–204 °C; 1H NMR (CDCl3, 400 MHz): δ 7.70 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 5.60 (s, 2H), 2.53 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 190.3, 152.8, 137.1, 136.6, 131.5 (JC,F = 32 Hz), 130.8 (JC,F = 33 Hz) 125.3, 124.1, 122.6, 119.0 (JC,F = 3 Hz), 110.3 (JC,F = 4 Hz), 26.1; FT-HRMS (ESI) calcd for C11H8F3NO2 [(M + H)+]: 244.0541; found, 244.0645.
  • 1-(3-Amino-6-nitrobenzofuran-2-yl)ethan-1-one (3g): 178 mg (81% yield), white solid, mp none; 1H NMR (CDCl3, 400 MHz): δ 8.35 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 2.0, 8.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 5.59 (s, 2H), 2.56 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 190.5, 152.3, 148.3, 138.2, 136.5, 126.4, 120.6, 117.5, 109.1, 26.2; FT-HRMS (ESI) calcd for C10H8N2O4 [(M + H)+]: 221.0518; found, 221.0589.
  • Methyl 3-amino-5-fluorobenzofuran-2-carboxylate (3h): 161 mg (77% yield), white solid, mp: 180–182 °C; 1H NMR (CDCl3, 400 MHz): δ 7.40–7.34 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.90–6.86 (m, 1H), 5.21 (s, 2H), 3.96 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 163.4, 161.5, 157.3 (JC,F = 250 Hz), 129.4 (JC,F = 9 Hz), 111.1 (JC,F = 18 Hz), 108.7 (JC,F = 5 Hz), 107.8 (JC,F = 18 Hz), 51.5; FT-HRMS (ESI) calcd for C10H8FNO3 [(M + H)+]: 210.0522; found, 210.0539.
  • Methyl 3-amino-6-chlorobenzofuran-2-carboxylate (3i): 173 mg (72% yield), white solid, mp: 210–211 °C; 1H NMR (CDCl3, 400 MHz): δ 7.49–7.45 (m, 2H), 7.24 (dd, J = 1.6, 8.4 Hz, 1H), 4.99 (s, 2H), 3.97 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.6, 153.9, 138.2, 134.9, 125.9, 123.3, 120.4, 120.2, 113.0, 110.0, 103.1, 51.6; FT-HRMS (ESI) calcd for C10H8ClNO3 [(M + H)+]: 227.0163; found, 227.0195.
  • Methyl 3-amino-7-fluorobenzofuran-2-carboxylate (3j): 164 mg (78% yield), white solid, mp: 180–182 °C; 1H NMR (CDCl3, 400 MHz): δ 7.35–7.32 (m, 1H), 7.22–7.17 (m, 2H), 5.02 (s, 2H), 3.97 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.7, 148.4 (JC,F = 250 Hz), 141.4 (JC,F = 13 Hz), 138.6, 126.2, 125.0 (JC,F = 3 Hz), 123.0 (JC,F = 6 Hz), 115.2 (JC,F = 4 Hz), 114.7 (JC,F = 16 Hz), 51.6; FT-HRMS (ESI) calcd for C10H8FNO3 [(M + H)+]: 210.0522; found, 210.0598.
  • Ethyl 3-aminobenzofuran-2-carboxylate (3k): 146 mg (71% yield), white solid, mp: 179–180 °C; 1H NMR (CDCl3, 300 MHz): δ 7.57–7.54 (m, 1H), 7.46–7.44 (m, 2H), 7.27–7.22 (m, 2H), 4.96 (s, 1H), 4.45 (q, J = 6.9 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 161.67, 154.02, 130.91, 128.85, 128.77, 125.56, 122.30, 121.67, 119.59, 112.66, 65.58, 60.46, 30.59, 29.71, 19.19, 14.66, 13.72; FT-HRMS (ESI) calcd for C11H11NO3 [(M + H)+]: 206.0772; found, 206.0785.
  • Ethyl 3-amino-4-fluorobenzofuran-2-carboxylate (3l): 162 mg (73% yield), white solid, mp: 192–193 °C; 1H NMR (CDCl3, 400 MHz): δ 7.39–7.34 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 8.0, 9.6 Hz, 1H), 5.19 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.4, 157.3 (JC,F = 250 Hz), 155.2, 129.3 (JC,F = 7 Hz), 111.1 (JC,F = 20 Hz), 108.8 (JC,F = 5 Hz), 107.7, (JC,F = 18 Hz), 60.5, 14.6; FT-HRMS (ESI) calcd for C11H10FNO3 [(M + H)+]: 224.0678; found, 224.0693.
  • Ethyl 3-amino-5-fluorobenzofuran-2-carboxylate (3m): 179 mg (80% yield), white solid, mp: 192–193 °C; 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J = 8.0 Hz, 1H), 7.37–7.32 (m, 1H), 6.94 (dd, J = 8.0, 9.6 Hz, 1H), 6.31 (s, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 165.2, 159.6 (JC,F = 250 Hz), 147.6, 142.1, 128.8 (JC,F = 9 Hz), 120.3 (JC,F = 14 Hz), 119.2 (JC,F = 4 Hz), 109.3 (JC,F = 20 Hz), 97.6, 60.4, 14.49; FT-HRMS (ESI) calcd for C11H10FNO3 [(M + H)+]: 224.0678; found, 224.0695.
  • Ethyl 3-amino-7-fluorobenzofuran-2-carboxylate (3n): 181 mg (81% yield), white solid, mp: 192–193 °C; 1H NMR (CDCl3, 400 MHz): δ 7.34–7.32 (m, 1H), 7.22–7.17 (m, 2H), 5.00 (s, 2H), 4.45 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.4, 148.4 (JC,F = 250 Hz), 141.4 (JC,F = 13 Hz), 138.4, 126.5, 125.1 (JC,F = 3 Hz), 122.8 (JC,F = 6 Hz), 115.1 (JC,F = 4 Hz), 114.5 (JC,F = 15 Hz), 60.6, 14.5; FT-HRMS (ESI) calcd for C11H10FNO3 [(M + H)+]: 224.0678; found, 224.0689.
  • Ethyl 3-amino-6-chlorobenzofuran-2-carboxylate (3o): 177 mg (74% yield), white solid, mp: 221–222 °C; 1H NMR (CDCl3, 400 MHz): δ 7.47 (d, J = 8.8 Hz, 2H), 7.24 (dd, J = 2.0, 8.4 Hz, 1H), 4.97 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.4, 153.9, 134.7, 123.3, 120.3, 113.0, 60.6, 14.6; FT-HRMS (ESI) calcd for C11H10ClNO3 [(M + H)+]: 241.0320; found.
  • Ethyl 3-amino-6-(trifluoromethyl)benzofuran-2-carboxylate (3p): 246 mg (90% yield), white solid, mp: 207–208 °C; 1H NMR (CDCl3, 400 MHz): δ 7.73 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 5.02 (s, 2H), 4.46 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.3, 152.8, 137.5, 131.1, 130.8, 130.3 (JC,F = 30 Hz), 128.0, 127.3, 125.3, 124.4, 122.6, 120.4, 119.1 (JC,F = 3 Hz), 110.2 (JC,F = 4 Hz), 60.8, 14.6; FT-HRMS (ESI) calcd for C12H10F3NO3 [(M + H)+]: 274.0646; found, 274.0686.
  • Ethyl 3-amino-6-nitrobenzofuran-2-carboxylate (3q): 218 mg (87% yield), white solid, mp none; 1H NMR (CDCl3, 400 MHz): δ 7.68 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 1.6, 8.4 Hz, 1H), 5.88 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 165.2, 162.6, 147.7, 140.9, 134.4, 129.8, 124.7, 122.9, 122.0, 99.8, 60.6, 14.5; FT-HRMS (ESI) calcd for C11H10N2O5 [(M + H)+]: 251.0623; found, 251.0635.
  • Methyl 3-aminobenzo[b]thiophene-2-carboxylate (5b): 157 mg (76% yield), pale yellow solid, mp: 224–225 °C; 1H NMR (CDCl3, 300 MHz): δ 7.73 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.49–7.44 (m, 1H), 7.39–7.34 (m, 1H), 5.80 (s, 2H), 3.89 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 165.9, 148.5, 140.0, 131.3, 128.2, 123.9, 123.4, 121.2, 99.0, 51.5; FT-HRMS (ESI) calcd for C10H9NO2S [(M + H)+]: 208.0388; found, 208.0398.
  • Ethyl 3-aminobenzo[b]thiophene-2-carboxylate (5c): 164 mg (74% yield), pale yellow solid, mp: 235–237 °C; 1H NMR (CDCl3, 300 MHz): δ 7.72 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.49–7.43 (m, 1H), 7.39–7.34 (m, 1H), 5.61 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 165.6, 148.3, 140.0, 131.5, 128.1, 123.8, 123.4, 121.2, 99.5, 60.4, 14.5; FT-HRMS (ESI) calcd for C11H11NO2S [(M + H)+]: 222.0544; found, 222.0609.
  • Butyl 3-aminobenzo[b]thiophene-2-carboxylate (5d): 192 mg (77% yield), pale yellow solid, mp: 258–259 °C; 1H NMR (CDCl3, 300 MHz): δ 7.73–7.66 (m, 2H), 7.48–7.42 (m, 1H), 7.38–7.33 (m, 1H), 5.26 (s, 2H), 4.30 (t, J = 6.6 Hz, 2H), 1.80–––1.69 (m, 2H), 1.54–1.41 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 165.6, 147.9, 140.0, 131.5, 128.2, 123.9, 123.4, 121.2, 100.0, 64.3, 30.9, 19.3, 13.8; FT-HRMS (ESI) calcd for C13H15NO2S [(M + H)+]: 250.0857; found, 250.0903.
  • 2-Phenylbenzo[b]thiophen-3-amine (5e): 191 mg (85% yield), pale yellow solid, mp: 253–255 °C; 1H NMR (CDCl3, 300 MHz): δ 7.78 (dd, J = 1.5, 6.9 Hz, 1H), 7.64–7.57 (m, 3H), 7.49–7.44 (m, 2H), 7.42–7.29 (m, 3H), 4.07 (s, 2H); 13C NMR (CDCl3, 75 MHz): δ 137.6, 134.5, 134.3, 133.6, 129.2, 128.4, 127.0, 124.8, 123.9, 122.7, 119.9, 115.6; FT-HRMS (ESI) calcd for C14H11NS [(M + H)+]: 226.0646; found, 226.0649.
  • Methyl 3-amino-5-fluorobenzo[b]thiophene-2-carboxylate (5f): 169 mg (75% yield), pale yellow solid, mp: 237–238 °C; 1H NMR (CDCl3, 400 MHz): δ 7.67 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (dd, J = 2.4, 8.8 Hz, 1H), 7.25–7.21 (m, 1H), 5.83 (s, 2H), 3.90 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 165.6, 160.4 (JC,F = 242 Hz), 147.8, 136.4, 135.2, 132.2 (JC,F = 8 Hz), 130.7, 124.8 (JC,F = 8 Hz), 117.2 (JC,F = 25 Hz), 109.9, 106.9 (JC,F = 23 Hz), 101.2, 51.7; FT-HRMS (ESI) calcd for C10H8FNO2S [(M + H)+]: 226.0293; found, 226.0356.
  • Methyl 3-amino-4-fluorobenzo[b]thiophene-2-carboxylate (5g): 171 mg (76% yield), pale yellow solid, mp: 237–238 °C; 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J = 8.0 Hz, 1H), 7.37–7.32 (m, 1H), 7.17 (t, J = 8.8 Hz, 1H), 5.92 (s, 2H), 3.90 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 165.6, 157.9 (JC,F = 246 Hz), 148.3, 134.5 (JC,F = 10 Hz), 127.1 (JC,F = 20 Hz), 125.4 (JC,F = 7 Hz), 117.1, 117.0, 113.2 (JC,F = 18 Hz), 99.9, 53.4, 51.7; FT-HRMS (ESI) calcd for C10H8FNO2S [(M + H)+]: 226.0293; found, 226.0348.
  • Ethyl 3-amino-5-fluorobenzo[b]thiophene-2-carboxylate (5h): 179 mg (75% yield), pale yellow solid, mp: 249–250 °C; 1H NMR (CDCl3, 400 MHz): δ 7.67 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (dd, J = 2.0, 8.8 Hz, 1H), 7.25–7.21 (m, 1H), 5.80 (s, 2H), 4.36 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 165.3, 160.4 (JC,F = 242 Hz), 147.6, 135.2, 132.3 (JC,F = 8 Hz), 124.8 (JC,F = 9 Hz), 117.1 (JC,F = 25 Hz), 106.9 (JC,F = 23 Hz), 60.6, 14.5; FT-HRMS (ESI) calcd for C11H10FNO2S [(M + H)+]: 240.0450; found, 240.0468.
  • Ethyl 3-amino-4-methoxybenzo[b]thiophene-2-carboxylate (5i): 78 mg (31% yield), pale yellow solid, mp: 282–283 °C; 1H NMR (CDCl3, 400 MHz): δ 7.37–7.28 (m, 1H), 7.24 (d, J = 4.0 Hz, 1H), 6.75 (s, 2H), 6.71–6.64 (m, 1H), 4.32 (q, J = 8.0 Hz, 2H), 2.62 (s, 3H), 1.37 (t, J = 8.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 165.5, 157.7, 148.8, 142.0, 129.0, 120.9, 115.8, 104.0, 60.0, 55.6, 14.5; FT-HRMS (ESI) calcd for C12H13NO3S [(M + H)+]: 252.0650; found, 252.0687.

4. Conclusions

In conclusion, a variety of benzofuran and benzo[b]thiophen derivatives was synthesized in good-to-excellent yields via Smiles rearrangement. At room temperature, an efficient and simple method was used to construct regioselective five-membered heterocycles. The outstanding features of this approach are mild conditions and transition-metal-free one-pot synthesis. This green and clean synthetic methodology has potential applications in the synthesis of biologically and medicinally relevant compounds. Our team is currently conducting more research to widen the applications of this technology.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28237738/s1, Table S1: Details of Crystal Structure Determination for 5g; Figure S1: X-ray structure of compound 5g; Figure S2: 1H NMR and 13C NMR spectra of compound 3a; Figure S3: 1H NMR and 13C NMR spectra of compound 3b; Figure S4: 1H NMR and 13C NMR spectra of compound 3c; Figure S5: 1H NMR and 13C NMR spectra of compound 3d; Figure S6: 1H NMR and 13C NMR spectra of compound 3e; Figure S7: 1H NMR and 13C NMR spectra of compound 3f; Figure S8: 1H NMR and 13C NMR spectra of compound 3g; Figure S9: 1H NMR and 13C NMR spectra of compound 3h; Figure S10: 1H NMR and 13C NMR spectra of compound 3i; Figure S11: 1H NMR and 13C NMR spectra of compound 3j; Figure S12: 1H NMR and 13C NMR spectra of compound 3k; Figure S13: 1H NMR and 13C NMR spectra of compound 3l; Figure S14: 1H NMR and 13C NMR spectra of compound 3m; Figure S15: 1H NMR and 13C NMR spectra of compound 3n; Figure S16: 1H NMR and 13C NMR spectra of compound 3o; Figure S17: 1H NMR and 13C NMR spectra of compound 3p; Figure S18: 1H NMR and 13C NMR spectra of compound 3q; Figure S19: 1H NMR and 13C NMR spectra of compound 5a; Figure S20: 1H NMR and 13C NMR spectra of compound 5b; Figure S21: 1H NMR and 13C NMR spectra of compound 5c; Figure S22: 1H NMR and 13C NMR spectra of compound 5d; Figure S23: 1H NMR and 13C NMR spectra of compound 5e; Figure S24: 1H NMR and 13C NMR spectra of compound 5f; Figure S25: 1H NMR and 13C NMR spectra of compound 5g; Figure S26: 1H NMR and 13C NMR spectra of compound 5h; Figure S27: 1H NMR and 13C NMR spectra of compound 5i.

Author Contributions

Investigation, C.D., L.L., D.Y. and Z.G.; methodology, B.Y. and X.H.; project administration, C.L.; supervision, X.L.; writing—original draft, R.L. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to the National Innovation and Entrepreneurship Training Program for College Students (CXCY2023105, S202210447044, 202210447015) for financial support of this research.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

Author Chenglong Li was employed by the Shandong Weijiao Holding Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Nevagi, R.J.; Dighe, S.N.; Dighe, S.N. Biological and medicinal significance of benzofuran. Eur. J. Med. Chem. 2015, 97, 561–581. [Google Scholar] [CrossRef]
  2. Keri, R.S.; Chand, K.; Budagumpi, S.; Somappa, S.B.; Patil, S.A.; Nagaraja, B.A. An overview of benzo [b] thiophene-based medicinal chemistry. Eur. J. Med. Chem. 2017, 138, 1002–1033. [Google Scholar] [CrossRef] [PubMed]
  3. Khanam, H.; Shamsuzzaman. Bioactive Benzofuran derivatives: A review. Eur. J. Med. Chem. 2015, 97, 483–504. [Google Scholar] [CrossRef] [PubMed]
  4. Miao, Y.; Hu, Y.; Yang, J.; Liu, T.; Sun, J.; Wang, X. Natural source, bioactivity and synthesis of benzofuran derivatives. RSC Adv. 2019, 9, 27510–27540. [Google Scholar] [CrossRef] [PubMed]
  5. de Brito, D.H.A.; Almeida-Neto, F.W.Q.; Ribeiro, L.R. Synthesis, structural and spectroscopic analysis, and antiproliferative activity of chalcone derivate (E)-1-(4-aminophenyl)-3-(benzo [b] thiophen-2-yl) prop-2-en-1-one in Trypanosoma cruzi. J. Mol. Struct. 2022, 1253, 132197. [Google Scholar] [CrossRef]
  6. Algso, M.A.S.; Kivrak, A. New strategy for the synthesis of 3-ethynyl-2-(thiophen-2-yl) benzo [b] thiophene derivatives. Chem. Pap. 2019, 73, 977–985. [Google Scholar] [CrossRef]
  7. Dhillon, S.; Clarke, M. Tasimelteon: First global approval. Drugs 2014, 74, 505–511. [Google Scholar] [CrossRef]
  8. Mhoumadi, A.; Elkhashab, M.; Prillieux, S.; Dumas, J.; Collas, F.; Louvain, N.; Fraisse, B.; Espeau, P. Characterization of the heat behavior of amiodarone hydrochloride. Thermochim. Acta 2022, 708, 179121. [Google Scholar] [CrossRef]
  9. McGovern, B.; Garan, H.; Kelly, E.; Ruskin, J.N. Adverse reactions during treatment with amiodarone hydrochloride. Br. Med. J. (Clin. Res. Ed.) 1983, 287, 175–180. [Google Scholar] [CrossRef]
  10. Shirley, M. Fruquintinib: First global approval. Drugs 2018, 78, 1757–1761. [Google Scholar] [CrossRef]
  11. Li, J.; Qin, S.; Xu, R.H. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: The FRESCO randomized clinical trial. JAMA 2018, 319, 2486–2496. [Google Scholar] [CrossRef]
  12. Valkova, S.; Trashlieva, M.; Christova, P. Treatment of vitiligo with local khellin and UVA: Comparison with systemic PUVA. Clin. Exp. Dermatol. 2004, 29, 180–184. [Google Scholar] [CrossRef] [PubMed]
  13. Berrade, L.; Aisa, B.; Ramirez, M.J.; Galiano, S.; Guccione, S.; Moltzau, L.R.; Levy, F.O.; Nicoletti, F.; Battaglia, G.; Molinaro, G.; et al. Novel Benzo[b]thiophene Derivatives as New Potential Antidepressants with Rapid Onset of Action. J. Med. Chem. 2011, 54, 3086–3090. [Google Scholar] [CrossRef] [PubMed]
  14. Liu, Z.; Xia, Y.; Zhou, S.; Wang, L.; Zhang, Y.; Wang, J. Pd-catalyzed cyclization and carbene migratory insertion: New approach to 3-vinylindoles and 3-vinylbenzofurans. Org. Lett. 2013, 15, 5032–5035. [Google Scholar] [CrossRef] [PubMed]
  15. Zhang, P.; Wang, C.; Cui, M.; Du, M.; Li, W.; Jia, Z.; Zhao, Q. Synthesis of difluoroalkylated benzofuran, benzothiophene, and indole derivatives via palladium-catalyzed cascade difluoroalkylation and arylation of 1, 6-enynes. Org. Lett. 2020, 22, 1149–1154. [Google Scholar] [CrossRef]
  16. Liao, J.; Fan, L.; Guo, W.; Zhang, Z.; Li, J.; Zhu, C.; Ren, Y.; Wu, W.; Jiang, H. Palladium-Catalyzed Fluoroalkylative Cyclization of Olefins. Org. Lett. 2017, 19, 1008–1011. [Google Scholar] [CrossRef] [PubMed]
  17. Kuram, M.R.; Bhanuchandra, M.; Sahoo, A.K. Direct access to benzo [b] furans through Palladium-catalyzed oxidative annulation of phenols and unactivated internal alkynes. Angew. Chem. Int. Ed. 2013, 52, 4607–4612. [Google Scholar] [CrossRef] [PubMed]
  18. Huang, X.; Rong, N.; Li, P.; Shen, G.; Li, Q.; Xin, N.; Cui, C.; Cui, J.; Yang, B.; Li, D.; et al. AIBN-promoted synthesis of bibenzo [b][1, 4] thiazines by the condensation of 2, 2′-dithiodianiline with methyl aryl ketones. Org. Lett. 2018, 20, 3332–3336. [Google Scholar] [CrossRef]
  19. Wang, D.; Lu, Q.; Li, Z.; Fang, C.; Liu, R.; Yang, B.; Shen, G. “One-Pot” CuCl2-Mediated Condensation/C–S Bond Coupling Reactions to Synthesize Dibenzothiazepines by Bi-Functional-Reagent N, N′-Dimethylethane-1, 2-Diamine. Molecules 2022, 27, 7392. [Google Scholar] [CrossRef]
  20. Liu, G.; Liu, S.; Li, Z.; Chen, C.; Li, J.; Zhang, Y.; Shen, G.; Yang, B.; Hu, X.; Huang, X. Metal-and oxidant-free electrochemically promoted oxidative coupling of amines. RSC Adv. 2022, 12, 118–122. [Google Scholar] [CrossRef]
  21. Khan, I.; Zaib, S.; Ibrar, A. New frontiers in the transition-metal-free synthesis of heterocycles from alkynoates: An overview and current status. Org. Chem. Front. 2020, 7, 3734–3791. [Google Scholar] [CrossRef]
  22. Suleymanov, A.A.; Scopelliti, R.; Fadaei Tirani, F.; Severin, K. One-Pot Synthesis of Trisubstituted Triazenes from Grignard Reagents and Organic Azides. Org. Lett. 2018, 20, 3323–3326. [Google Scholar] [CrossRef] [PubMed]
  23. Li, Y.; Zhan, C.; Yang, B.; Cao, X.; Ma, C. A one-pot transition-metal-free tandem process to 1, 4-benzodiazepine scaffolds. Synthesis 2013, 45, 111–117. [Google Scholar]
  24. Crystal Data for 5g: See the Supporting Information. CCDC 2285416 (5g) Contains the Supplementary Crystallographic Data for This Paper. These Data Can Be Obtained Free of Charge from The Cambridge Crysallographic Data Centre. Available online: www.ccdc.cam.ac.uk/data_request/cif (accessed on 31 July 2023).
  25. Sheldrick, G.M. SHELX-97. Program for the Refinement of Crystal Structure; University of Götingen: Götingen, Germany, 1997. [Google Scholar]
Molecules 28 07738 sch001
Scheme 1. Structures of some biologically important benzofurans.
Scheme 1. Structures of some biologically important benzofurans.
Molecules 28 07738 sch001
Molecules 28 07738 sch002
Scheme 2. Attempts to synthesize benzofuran and benzothiophen derivatives in previous work and this work.
Scheme 2. Attempts to synthesize benzofuran and benzothiophen derivatives in previous work and this work.
Molecules 28 07738 sch002
Molecules 28 07738 sch003
Scheme 3. Synthesis of benzofuran-3-amines and benzo[b]thiophen-3-amines.
Scheme 3. Synthesis of benzofuran-3-amines and benzo[b]thiophen-3-amines.
Molecules 28 07738 sch003
Molecules 28 07738 g001
Figure 1. Structures of the desired compounds, 3a–3q.
Figure 1. Structures of the desired compounds, 3a–3q.
Molecules 28 07738 g001
Molecules 28 07738 g002
Figure 2. Structures of the desired compounds, 5a–5i.
Figure 2. Structures of the desired compounds, 5a–5i.
Molecules 28 07738 g002
Molecules 28 07738 sch004
Scheme 4. Plausible mechanism of the formation of 3a.
Scheme 4. Plausible mechanism of the formation of 3a.
Molecules 28 07738 sch004
Molecules 28 07738 g003
Figure 3. X-ray structure of compound 5g.
Figure 3. X-ray structure of compound 5g.
Molecules 28 07738 g003
Table 1. Optimization of conditions a.
Table 1. Optimization of conditions a.
Molecules 28 07738 i001
EntryBaseSolventT (°C)Time (h)Yield (%) b
1K2CO3DMSOr.t.4n.d.
2K2CO3DMSO6066
3K3PO4DMSOr.t.4n.d.
4K3PO4DMSO60618
5Cs2CO3DMSOr.t.476
6KOHDMSOr.t.436
7t-BuOKDMSOr.t.156
8Et3NDMSOr.t.5n.d.
9Cs2CO3THFr.t.4n.d.
10Cs2CO3CH3CNr.t.4n.d.
11Cs2CO3DMFr.t.4n.d.
a Reaction conditions: 2-fluorobenzonitrile, 1a (1.0 equiv.); 1-hydroxypropan-2-one, 2a (1.0 equiv.); base (3.0 equiv.). b Isolated yields. n.d.: not detected.
Table 2. Synthesis of benzofuran-3-amines a.
Table 2. Synthesis of benzofuran-3-amines a.
Molecules 28 07738 i002
EntryR1R2Time (h)ProductYield (%) b
1H-COCH363a76
23-F-COCH363b80
34-F-COCH353c82
44-Cl-COCH363d78
54-Br-COCH363e56
64-CF3-COCH363f90
74-NO2-COCH363g81
85-F-COOCH363h77
94-Cl-COOCH363i72
103-F-COOCH363j78
11H-COOCH2CH363k71
126-F-COOCH2CH363l73
135-F-COOCH2CH363m80
143-F-COOCH2CH363n81
154-Cl-COOCH2CH363o74
164-CF3-COOCH2CH363p90
174-NO2-COOCH2CH363q87
a Reaction conditions: 2-fluorobenzonitrile, 1 (1.0 equiv.); primary alcohols, 2 (1.0 equiv.); Cs2CO3 (3.0 equiv.). b Isolated yields.
Table 3. Synthesis of benzo[b]thiophen-3-amines a.
Table 3. Synthesis of benzo[b]thiophen-3-amines a.
Molecules 28 07738 i003
EntryR1R3Time (h)ProductYield (%) b
13-F-COCH365a78
2H-COOCH365b76
3H-COOCH2CH355c74
4H-COOCH2CH2CH2CH365d77
5H-ph65e85
65-F-COCH365f75
73-F-COCH365g76
85-F-COOCH365h75
94-OMe-COOCH2CH365i31
a Reaction conditions: 2-fluorobenzonitrile, 1 (1.0 equiv.); α-substituted methanethiol, 4 (1.0 equiv.); Cs2CO3 (3.0 equiv.). b Isolated yields.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Liu, R.; Lv, L.; Yang, B.; Gu, Z.; Li, C.; Lv, X.; Ding, C.; Huang, X.; Yuan, D. Transition-Metal-Free One-Pot Synthesis of Fused Benzofuranamines and Benzo[b]thiophenamines. Molecules 2023, 28, 7738. https://doi.org/10.3390/molecules28237738

AMA Style

Liu R, Lv L, Yang B, Gu Z, Li C, Lv X, Ding C, Huang X, Yuan D. Transition-Metal-Free One-Pot Synthesis of Fused Benzofuranamines and Benzo[b]thiophenamines. Molecules. 2023; 28(23):7738. https://doi.org/10.3390/molecules28237738

Chicago/Turabian Style

Liu, Ran, Lili Lv, Bingchuan Yang, Ziyi Gu, Chenglong Li, Xueyan Lv, Chengcheng Ding, Xianqiang Huang, and Dong Yuan. 2023. "Transition-Metal-Free One-Pot Synthesis of Fused Benzofuranamines and Benzo[b]thiophenamines" Molecules 28, no. 23: 7738. https://doi.org/10.3390/molecules28237738

Article Metrics

Back to TopTop