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

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.


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 palladiumcatalyzed 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 C sp3 -CF 2 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 Molecules 2023, 28, 7738 2 of 12 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].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].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).
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).

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).

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 Cs 2 CO 3 provided the highest yields (Table 1, entry 5).In weak basic systems such as K 2 CO 3 or K 3 PO 4 at room temperature, no desired product, 3a, was obtained (Table 1, entries 1,3).When we used the organic base Et 3 N in the reaction, no desired compound, 3a, was detected either.In constructing 3a, Cs 2 CO 3 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 CH 3 CN, THF, and DMF with the same base system (Table 1, entries 5, 9, 10, 11).Finally, we chose Cs 2 CO 3 in DMSO as the most efficient system to accomplish the synthesis of the benzofuran derivatives, 3 (Table 1, entry 5).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).

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).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).Additionally, a steric hindrance affected the reaction very slightly.Ethyl 2-hydroxyacetate (Table 2, entry 11-17) also obtained a high yield of 3.
b Isolated yields.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. 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. 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 Cs 2 CO 3 , 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.
Molecules 2023, 28, x FOR PEER REVIEW 7 of 12 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).To demonstrate the structure of benzothiophene, the molecular configuration of product 5g was determined through X-ray crystallographic analysis (Figure 3).To demonstrate the structure of benzothiophene, the molecular configuration of product 5g was determined through X-ray crystallographic analysis (Figure 3).

General
1 H and 13 C 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.

General
1 H and 13 C NMR spectra were recorded with a 300 spectrometer or a 400 spectrometer in CDCl 3 .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.

Scheme 2 .
Scheme 2. Attempts to synthesize benzofuran and benzothiophen derivatives in previous work and this work.

Scheme 4 .
Scheme 4. Plausible mechanism of the formation of 3a.

Scheme 4 .
Scheme 4. Plausible mechanism of the formation of 3a.

Scheme 4 .
Scheme 4. Plausible mechanism of the formation of 3a.

Table 1 .
Optimization of conditions a .

Table 1 .
Optimization of conditions a .

Table 1 .
Optimization of conditions a .