# Mild Copper-Catalyzed, l-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate

Vilija Kederienė, Indrė Jaglinskaitė, Paulina Voznikaitė, Jolanta Rousseau, Patrick Rollin, Algirdas Šačkus, Arnaud Tatibouët

<figure><img src="image_1.png" /></figure>

To cite this version:

Vilija Kederienė, Indrė Jaglinskaitė, Paulina Voznikaitė, Jolanta Rousseau, Patrick Rollin, et al. "Mild Copper-Catalyzed, l-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate." Molecules, 2021, Molecules, 26 (22), pp.6822. 10.3390/molecules26226822. hal-04136103

HAL Id: hal-04136103

https://hal.univ-lille.fr/hal-04136103

Submitted on 21 Jun 2023

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Article

# Mild Copper-Catalyzed, L-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate

Vilija Kederienė<fnref n="1" />,*, Indrė Jaglinskaitė<fnref n="1" />, Paulina Voznikaitė<fnref n="1" />, Jolanta Rousseau<fnref n="2" />, Patrick Rollin<fnref n="3" />, Algirdas Šačkus<fnref n="1" /> and Arnaud Tatibouët<fnref n="3" />,*

<figure><img src="image_3.png" /></figure>

check for
updates

**Citation:** Kederienė, V.; Jaglinskaitė, I.; Voznikaitė, P.; Rousseau, J.; Rollin, P.; Šačkus, A.; Tatibouët, A. Mild Copper-Catalyzed, L-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate. *Molecules* **2021**, *26*, 6822. https://doi.org/10.3390/molecules26226822

Academic Editors:
Dzmitry Kananovich, Zhuofeng Ke
and Xinfang Xu

Received: 30 September 2021
Accepted: 8 November 2021
Published: 11 November 2021

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

<figure><img src="image_4.png" /></figure>

**Copyright:** © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

**Abstract:** Cu-catalyzed *N*-arylation is a useful tool for the chemical modification of aromatic heterocycles. Herein, an efficient carbon–nitrogen cross-coupling of methyl 3-amino-1-benzothiophene-2-carboxylate with a range of (hetero)aryl iodides using CuI, *L*-proline and *Cs*₂*CO*₃ in dioxane at moderate temperature is described. The procedure is an extremely general, relatively cheap, and experimentally simple way to afford the *N*-substituted products in moderate to high yields. The structures of the new heterocyclic compounds were confirmed by NMR spectroscopy and HRMS investigation.

**Keywords:** benzo[b]thiophene; copper catalysis; *L*-proline; *N*-arylation; aryl iodides

## 1. Introduction

Compounds containing the benzothiophene frame are important building blocks in organic synthesis and are used in a broad range of applications [1]. The benzothiophene skeleton is present in many organic materials, such as solar cells, light-emitting diodes (OLEDs), and field-effect transistors [2–4]. In the medical field, synthetic benzothiophene-based derivatives show various biological activities [5]. Recently, they were evaluated as inhibitors of tubulin polymerization [6] and as candidates for the treatment of human cancer [6]; furthermore, they can be used for anti-HCV (hepatitis C virus) applications [7] as anti-inflammatory agents [8]. Moreover, a number of aminobenzothiophene derivatives are recognized as antioxidant I [9,10], photochemotherapeutic II [11], antimitotic III [12], antimicrobial IV [13], antiproliferative V [14], and anti-inflammatory VI agents [9,15] (Figure 1).

The importance of the aforementioned class of compounds supported our interest in the synthesis of the anthranilic acid analogues in which the thiophene moiety is present as a benzene ring bioisostere [16]. Moreover, *N*-substituted anthranilic acids are broadly used in the treatment of various diseases, such as arthritis, atypical dermatitis, and bronchial asthma, and they are also described as anti-allergic, analgesic, and anticancer agents [17–21].

Many methods have been developed for the synthesis of anthranilic acids. Copper-catalyzed arylation is one of the most powerful tools for the synthesis of *N*-arylanthranilic acids, which are important precursors for the synthesis of substituted acridines and acridones [22–27].

<footnote n="1">¹ Department of Organic Chemistry, Kaunas University of Technology, Radvilėny pl. 19, LT-50254 Kaunas, Lithuania; indrejag@gmail.com (I.J.); paulina.voznikaite@ktu.lt (P.V.); algirdas.sackus@ktu.lt (A.Š.)</footnote>

<footnote n="2">² Univ. Artois, CNRS, Centrale Lille, Univ. Lille, UMR 8181—UCCS—Unité de Catalyse et Chimie du Solide, F-62300 Lens, France; jolanta.rousseau@univ-artois.fr</footnote>

<footnote n="3">³ Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans et CNRS, UMR 7311, BP 6759, F-45067 Orléans, France; patrickrollin@univ-orleans.fr</footnote>

<footnote>* Correspondence: vilija.kederiene@ktu.lt (V.K.); arnaud.tatibouet@univ-orleans.fr (A.T.)</footnote>
<figure><img src="image_5.png" /><figcaption>**Figure 1.** Biologically active building blocks I–VI with an aminobenzothiophene frame in drug discovery.</figcaption></figure>

The traditional Ullmann-type reaction requires specific reaction conditions, such as strong base and high temperature, and offers a limited substrate scope [28]. Following important earlier breakthroughs, a major improvement came in 2001 with the discovery of new versatile and efficient copper/ligand systems. For example, Buchwald and co-workers reported that diamine ligands enable the formation of the C–N bond under much milder Cu-catalyzed conditions [29–31]. The same year, Venkataraman and co-workers discovered that the coupling of aryl halides with various nucleophiles could be successfully performed with 1,10-phenanthroline as ligand [32]. Ma and co-workers described that, by using L-proline as an additive, the copper-catalyzed cross-coupling reactions under mild conditions gave N-arylazoles in excellent yields [33,34]. This discovery was followed by several studies to improve C–N coupling conditions with the effect of L-proline as a ligand [35–37]. In view of these research studies, copper-catalyzed N-arylation of amines has become one of the most attractive and highly efficient methods to synthesize these compounds due to excellent catalytic selectivity and high functional group compatibility, as well as low toxicity and economic attractiveness [36].

To date, N-substituted benzo[b]thiophene derivatives have been synthesized using palladium-ligand complexes by the C–N coupling method of 3-halobenzo[b]thiophenes with anilines and aminopyridines [38–42] and the substitution of aminobenzo[b]thiophenes with bromobenzenes and bromopyridines [43,44]. Coupling reactions were successful; however, this synthetic pathway requires relatively expensive, air-sensitive, and highly toxic Pd catalysts systems [45]. Moreover, there exist difficulties with removing palladium traces during the purification stage, which is usually time-demanding and expensive; for this reason, this poses a serious practical problem in the pharmaceutical industry [46,47].

For the above reasons, we wish to report mild copper-catalyzed cross-coupling of aminobenzo[b]thiophene derivatives with (hetero)aryl iodides bearing various functional groups. The application of an Ullmann-type methodology to heteroaromatic systems is still relatively rare.

## 2. Results and Discussion

Here, we report an efficient catalytic system, which makes the methodology environmentally benign and economical, using commercially available copper(I) iodide and natural amino acid. Many copper complexes are effective catalyst precursors for N-arylation reactions. However, copper(I) salts give superior results, compared to copper(II), as they are a more active species [48]. We chose to focus on the use of CuI owing to its stability in air and lower strictness of the reaction conditions.
The precursor methyl 3-amino-1-benzothiophene-2-carboxylate **1** was synthesized under modified conditions by treatment of 2-fluorobenzonitrile with methyl thioglycolate in DMF [49,50].

The coupling reaction between methyl 3-amino-1-benzothiophene-2-carboxylate **1** and 4-iodoanisole was chosen as a model to optimize the reaction conditions with regard to bases, solvents, and ligands (Scheme 1, Table 1). Several details are worth commenting on. Firstly, a strongly electron-donating agent, N,N'-dimethylethylenediamine (DMEDA), was initially investigated as an additive for the present reaction because of its known and excellent activity in CuI-catalyzed cross-coupling [51]. Since a sensitive carboxylate group is present in substrate **1** [49], we used milder standard bases (K₃PO₄, Cs₂CO₃, and K₂CO₃), which are often used for catalytic arylation. The coupling reaction proceed well in the presence of Cs₂CO₃ as a base in dioxane at a reflux temperature for 24 h; the expected N-arylated coupling product **3a** was obtained in 31% yield. Other bases commonly employed for these couplings, such as K₂CO₃ and K₃PO₄, were inferior to Cs₂CO₃, affording **3a** in 5 and 15% yield, respectively (Table 1, entries 1–3). Therefore, Cs₂CO₃ was selected as the base of choice for further screening reactions.

<figure><img src="image_6.png" /><figcaption>**Scheme 1.** Reagents and conditions: (1) 6 M aq. HCl, 65 °C, 20 min; then, keeping at −18 °C, 1 h; (2) NaNO₂ (1.1 equiv), −10 °C, 30 min; (3) KI (1.5 equiv), from 0 to 70 °C, 30 min.</figcaption></figure>

<table><caption>**Table 1.** CuI-catalyzed N-arylation of 3-aminobenzothiophene derivative **1**—optimization of the catalysis conditions.</caption><thead><tr><th>Entry</th><th>Base (B)</th><th>Solvent (S)</th><th>Ligand (L)</th><th>3a, Yield (%) <sup>[a]</sup></th></tr></thead><tbody><tr><td>1</td><td>K<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>DMEDA</td><td>5 <sup>[b]</sup></td></tr><tr><td>2</td><td>K<sub>3</sub>PO<sub>4</sub></td><td>Dioxane</td><td>DMEDA</td><td>15 <sup>[b]</sup></td></tr><tr><td>3</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>DMEDA</td><td>31 <sup>[b]</sup></td></tr><tr><td>4</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMSO</td><td>DMEDA</td><td>traces <sup>[b]</sup></td></tr><tr><td>5</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>DMEDA</td><td>traces <sup>[b]</sup></td></tr><tr><td>6</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Toluene</td><td>DMEDA</td><td>20 <sup>[c]</sup></td></tr><tr><td>7</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>1,10-phenanthroline</td><td>9 <sup>[b]</sup></td></tr><tr><td>8</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>L-proline</td><td>58 <sup>[b]</sup></td></tr><tr><td>9</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>L-proline</td><td>12 <sup>[d]</sup></td></tr><tr><td>10</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>L-proline</td><td>38 <sup>[e]</sup></td></tr></tbody></table>
<table><caption>**Table 1.** *Cont.*</caption><thead><tr><th>Entry</th><th>Base (B)</th><th>Solvent (S)</th><th>Ligand (L)</th><th>3a, Yield (%) <sup>[a]</sup></th></tr></thead><tbody><tr><td>11</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>L-proline</td><td>28 <sup>[f]</sup></td></tr><tr><td>12</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Dioxane</td><td>L-proline</td><td>61 <sup>[g]</sup></td></tr></tbody></table>

[a] After purification by column chromatography. [b] Reactions were carried out using methyl 3-amino-1-benzothiophene-2-carboxylate **1** (1.0 equiv), 4-iodoanisole (1.5 equiv), base (2.0 equiv), CuI (0.2 equiv) and ligand (0.6 equiv) at 100 °C for 24 h, unless stated otherwise. [c] At 110 °C. [d] Using methyl 3-iodo-1-benzothiophene-2-carboxylate **2** (1.0 equiv) as starting compound and *p*-anisidine (1.5 equiv) as coupling partner. [e] Using 4-bromoanisole (1.5 equiv) as coupling partner. [f] For 6 h. [g] For 48 h.

In the assessment of the effect of the solvent, the coupling results showed that dioxane was the most effective solvent, while DMSO and DMF gave only traces of the desired coupling product (Table 1, compare entries 3–6). On the other hand, dioxane is easily removable from reaction mixtures. Several bidentate N,N-ligands (DMEDA [51] and 10-phenanthroline [52]), which are commonly used as standard ligands in Cu-catalyzed cross-coupling reactions, were examined and significant differences in yield were observed (Table 1, entries 3 and 7). Conversely, amino acids can also act as effective bidentate N,O-chelators in the C–N coupling [53]; therefore, we focused our attention on employing L-proline as the additive. As expected, when N,O-donor L-proline was used, the reaction provided the coupling product in a much higher yield, 58% (Table 1, entry 8). L-proline capability for promoting Cu-catalyzed C–N coupling reactions might be dependent on its reactivity as the coupling agent and coordination ability as a bidentate additive [53]. In the literature has been reported an accelerating effect induced by the structure of amino acids and possible catalytic mechanisms for Cu-catalyzed amino acids promoted coupling reactions [33,34,53].

To compare the reactivity, we also studied the copper-catalyzed amination using methyl 3-iodo-1-benzothiophene-2-carboxylate **2** and 4-anisidine as coupling reagent (Table 1, entry 9). The precursor **2** was already known [54] and was synthesized, here, in a higher yield, 73%, via a diazotization–iodination reaction of compound **1** (Scheme 1). However, to our surprise, cross-coupling was not successful, as compound **2** afforded only 12% of product **3a**, which, we suppose, was possibly because of a radical reaction mechanism [55]. The literature has described several speculative mechanisms for Ullmann-type coupling reactions for the aryl halide activation step and one of them is a possible radical pathway-atom transfer mechanism involving aryl radical, which causes the transfer of the halide atom from the aryl halide [56]. Methyl 3-iodo-1-benzothiophene-2-carboxylate **2** may form an inactive radical, which leads to the formation of **3a** in a very low yield.

The coupling reaction of methyl 3-amino-1-benzothiophene-2-carboxylate (1) with 4-bromoanisole was also tested. Under these conditions, 4-bromoanisole was less reactive, affording coupled product **3a** in a 38% yield (Table 1, entry 10), while 4-iodoanisole exhibited greater reactivity. These results established the reactivity order of the aryl halides: iodides > bromides > chlorides [57].

It also seems that the reaction time played an important role. After 6 h of heating using 4-iodoanisole, the yield of the coupled product **3a** was only 28%, while, upon allowing the reaction to continue for 24 h, the yield was increased to 58% (Table 1, entries 8, 11–12). A longer reaction time (48 h) did not improve the efficiency of the coupling transformation.

For a copper-catalyzed N-arylation, the choice of a suitable stoichiometric quantity of copper catalyst and ligand is very important. For further optimization of the reaction conditions, the increase in the yields of the coupling products was observed by changing the molar ratio of CuI:L-proline (Scheme 2). As summarized in Table 2, it was found that the ratio of 1:1 for CuI and L-proline was necessary to ensure a satisfactory result. It was noticed that, when different ratios of reagents were used, lower yields of reaction products were obtained (Table 2, compare entries 2–5). Moreover, the ratio of Cu(I) to L-proline used in this study was only equal to 1:1, whereas the ratio generally used in most of the other copper-catalyzed cross-coupling reactions using amino acids as ligands is 1:2 [53]. When
20 mol% of CuI and L-proline each was used, the reaction was complete in 24 h and gave methyl 3-[(4-methoxyphenyl)amino]-1-benzothiophene-2-carboxylate **3a** in excellent yield (Table 2, entry 2). Reducing the amounts of copper catalyst and L-proline as a promoter to 10 mol% gave a similar yield (Table 2, entry 6), while 5 mol% afforded slightly worse results (Table 2, entry 7). Thus, the appropriate ratio of CuI:L-proline is essential for the optimal reaction outcome. More importantly, we were pleased to observe that the control experiment with methyl 3-amino-1-benzothiophene-2-carboxylate **1** without ligand was also successful (Table 2, entry 1).

<figure><img src="image_7.png" /><figcaption>**Scheme 2.** Synthesis of compound **3a**.</figcaption></figure>

<table><caption>**Table 2.** Comparative studies utilizing various ratios of catalyst and ligand.</caption><thead><tr><th>Entry</th><th>CuI:Ligand (Ratio)</th><th>CuI</th><th>L-Proline</th><th>3a, Yield (%) <sup>[a], [b]</sup></th></tr></thead><tbody><tr><td>1</td><td>1:0</td><td>0.2</td><td>-</td><td>54</td></tr><tr><td>2</td><td>1:1</td><td>0.2</td><td>0.2</td><td>87</td></tr><tr><td>3</td><td>1:2</td><td>0.2</td><td>0.4</td><td>65</td></tr><tr><td>4</td><td>1:3</td><td>0.2</td><td>0.6</td><td>58</td></tr><tr><td>5</td><td>1:4</td><td>0.2</td><td>0.8</td><td>60</td></tr><tr><td>6</td><td>1:1</td><td>0.1</td><td>0.1</td><td>86</td></tr><tr><td>7</td><td>1:1</td><td>0.05</td><td>0.05</td><td>61</td></tr></tbody></table>

[a] Reagents and conditions: methyl 3-amino-1-benzothiophene-2-carboxylate 1 (1.0 equiv); 4-iodoanisole (1.5 equiv); Cs₂CO₃ (2.0 equiv); CuI; L-proline; dioxane; Δ; 24 h. [b] After purification by column chromatography.

To improve the reaction yield, as well as to shorten the reaction time, an attempt was made to use microwave (MW) irradiation heating (Scheme 3, Table 3). Our previous results showed that dioxane and acetonitrile were the more suitable solvents, while THF, toluene, or DMF gave poor yields of coupling products under MW heating. According to the literature, dioxane is microwave-transparent, and the reaction in this solvent can be thermally activated only if other components in the reaction mixture respond to microwave energy, i.e., if the reaction mixture contains either polar reactants or ions [58]. However, in our case, despite the presence of polar amine and Cs₂CO₃ in the reaction mixture, MW activation was not very effective. MW heating using acetonitrile did not increase the yields of the coupling products either, contrary to using conventional heating (Table 3). For this reason, further experiments were carried out using conventional heating in dioxane for 24 h.

<figure><img src="image_8.png" /><figcaption>**Scheme 3.** Synthesis of compound **3a-s**.</figcaption></figure>
<table><caption>**Table 3.** Comparative studies utilizing MW and conventional heating [a].</caption><thead><tr><th>Entry</th><th>Substituent (Ar)</th><th>Product</th><th>Yield (%) [b]</th><th>Yield (%) [c]</th><th>Yield (%) [d]</th><th>Yield (%) [e]</th></tr></thead><tbody><tr><td>1</td><td>4-OCH<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3a</b></td><td>86</td><td>10</td><td>35</td><td>61</td></tr><tr><td>2</td><td>2-OCH<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3b</b></td><td>72</td><td>10</td><td>32</td><td>52</td></tr><tr><td>3</td><td>4-FC<sub>6</sub>H<sub>5</sub></td><td><b>3c</b></td><td>94</td><td>53</td><td>75</td><td>29</td></tr><tr><td>4</td><td>2-FC<sub>6</sub>H<sub>5</sub></td><td><b>3d</b></td><td>79</td><td>20</td><td>26</td><td>50</td></tr><tr><td>5</td><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3e</b></td><td>97</td><td>75</td><td>23</td><td>51</td></tr><tr><td>6</td><td>4-CF<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3f</b></td><td>73</td><td>18</td><td>45</td><td>30</td></tr></tbody></table>

[a] After purification by column chromatography. Reagents and conditions: methyl 3-amino-1-benzothiophene-2-carboxylate 1 (1.0 equiv); aryl iodide (1.5 equiv); $Cs_2CO_3$ (2.0 equiv); $CuI$ (0.1 equiv); L-proline (0.1 equiv).

[b] Dioxane; Δ; 24 h. [c] Dioxane; MW; 1 h. [d] Acetonitrile; MW; 1 h. [e] Acetonitrile; Δ; 24 h.

Thus, the optimized reaction conditions utilized 10 mol% of $Cu(I)$, 10 mol% of L-proline, and $Cs_2CO_3$ (2 equiv) in dioxane at reflux under argon. These reaction conditions were applied to the coupling of methyl 3-amino-1-benzothiophene-2-carboxylate 1 with various functionalized aryl iodides to synthesized coupling compound **3a-s** (Figure 2, Tables 3 and 4). To study the steric and electronic effects on the product selectivity, reactions with aryl iodides having electron-donating and electron-withdrawing groups such as $NO_2$, $OCH_3$, $CF_3$, F, OH, and $NH_2$ were further examined. Tables 3 and 4 show that all *para-*, *meta-*, and *ortho*-substitutions on the aryl halide were tolerated under these reaction conditions. For example, the palladium-catalyzed C-N coupling of *ortho*-substituted aryl halides is difficult and is the major drawback of this method [59]. We showed that N-substituted methyl 3-amino-1-benzothiophene-2-carboxylates **3a-o** can be obtained in moderate to high yields using activated aryl iodides as starting reagents.

<figure><img src="image_9.png" /><figcaption>**Figure 2.** Synthesized compounds **3a-o**.</figcaption></figure>
<table><caption>**Table 4.** Cu(I)-catalyzed cross-coupling of methyl 3-amino-1-benzothiophene-2-carboxylate **1** with aryl iodides. [a].</caption><thead><tr><th>Entry</th><th>Substituent (Ar)</th><th>Product</th><th>Yield (%) <sup>[b]</sup></th></tr></thead><tbody><tr><td>1</td><td>2-CF<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3g</b></td><td>72</td></tr><tr><td>2</td><td>3-OCH<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3h</b></td><td>76</td></tr><tr><td>3</td><td>4-NO<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3i</b></td><td>60</td></tr><tr><td>4</td><td>3-NO<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3j</b></td><td>79</td></tr><tr><td>5</td><td>2-NO<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3k</b></td><td>75</td></tr><tr><td>6</td><td>C<sub>6</sub>H<sub>5</sub></td><td><b>3l</b></td><td>55</td></tr><tr><td>7</td><td>4-OHC<sub>6</sub>H<sub>5</sub></td><td><b>3m</b></td><td>25</td></tr><tr><td>8</td><td>4-OCOCH<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3m</b></td><td>50</td></tr><tr><td>9</td><td>4-NH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3n</b></td><td>15</td></tr><tr><td>10</td><td>4-NHCOCH<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3o</b></td><td>55</td></tr><tr><td>11</td><td>2-OHC<sub>6</sub>H<sub>5</sub></td><td><b>3p</b></td><td>trace</td></tr><tr><td>12</td><td>2-NH<sub>2</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3r</b></td><td>trace</td></tr><tr><td>13</td><td>2-NHCOCH<sub>3</sub>C<sub>6</sub>H<sub>5</sub></td><td><b>3s</b></td><td>trace</td></tr></tbody></table>

[a] Reagents and conditions: methyl 3-amino-1-benzothiophene-2-carboxylate **1** (1.0 equiv); aryl iodide (1.5 equiv); $Cs_2CO_3$ (2.0 equiv); Cul (0.1 equiv); and L-proline (0.1 equiv) in dioxane at reflux for 24 h. [b] After purification by column chromatography.

The steric hindrance did not seem to influence cross-coupling, as the reaction of aminobenzothiophene **1** with *ortho-, meta-, or para*-substituted iodides gave products in similar yields. It is noteworthy that activated iodides bearing electron-withdrawing groups such as iodoanisoles gave good yields (Table 3, entries 1–4, and Table 4, entry 1). The coupling of non-substituted phenyl iodide with compound **1** gave a lower yield of the desired product **3l** (Table 4, entry 6).

A variety of functional groups can be present on aryl halides; nonetheless, for electron-rich aryl iodides bearing free hydroxy and amino functional groups, low conversion was observed under the above-described standard reaction conditions (Table 4, entries 7 and 9). After some experimentation, we found out that this problem could be easily solved by the protection of those functional groups (Table 4, entries 8 and 10). For that purpose, N-(4-iodophenyl)acetamide and 4-iodophenyl acetate were prepared from 4-iodophenol and 4-iodoaniline, respectively, following known procedures [60]. Acylation of the –OH and –NH<sub>2</sub> groups proved to be crucial and resulted in the formation of the products **3m** and **3o** in higher yield (Table 4, entries 8, 10). The cross-coupling approach of compound **1** with 4-iodophenyl acetate formed the same final product **3m** as coupling with 2-iodophenol (Table 4, entries 7–8). Coupling reactions of methyl 3-amino-1-benzothiophene-2-carboxylate **1** with 2-iodoaniline, N-(2-iodophenyl)acetamide and 2-iodophenol were unsuccessful and gave traces of the products (Table 4, entries 11–13).

However, the Ullmann-type reaction between 2-iodoaniline and compound **1** after additional heating for 72 h gave an interesting tetracyclic derivative **4** in a 41% yield (Scheme 4). This new diazepinone **4** was the result of a C–N coupling, followed by spontaneous intramolecular condensation in one step, with loss of methanol. Careful NMR analysis permitted the elucidation of structure **4**. The combined application of HSQC, HMBC, and COSY experiments finally enabled the unambiguous assignment of 5a,7-dihydro-6H-benzothieno[3,2-b][1,5]benzodiazepin-6-one **4**.

The study of the literature revealed only a few recently described examples via the C–N cross-coupling of diazepinone compounds. For example, recently reported synthetic pathways to dibenzodiazepine analogues required catalytic quantities of palladium [61]. Typically, several steps are required to prepare dibenzodiazepinones, beginning with the copper-catalyzed coupling reactions of anthranilic acids or substituted benzoates [62]. On
the other hand, double amination of *ortho*-substituted aryl bromides has been reported, which revealed a strong *ortho*-substituent effect caused by *N*-aryl aminocarbonyl groups during copper-catalyzed aryl amination [63]. To our knowledge, only one example of a tricyclic benzothieno[3,2-*b*]diazepinone derivative has been described and was studied as an antiherpetic agent [64]. For this reason, we are currently working on the improved synthesis of benzothieno[3,2-*b*][1,5]benzodiazepinones via copper-catalyzed cross-coupling, whose results will be reported in due course.

<figure><img src="image_10.png" /><figcaption>**Scheme 4.** Ullmann-type reaction between 2-iodoaniline and compound 1.</figcaption></figure>

The reaction of methyl 3-amino-1-benzothiophene-2-carboxylate **1** with 2-iodobenzoic acid using the above conditions failed to give any conversion to the desired product. The possible explanation could be that coordination of the resulting aryl carboxylate to copper resulted in the inactivation of the catalytic species and that the aryl carboxylate might have limited solubility in dioxane [51].

The optimized Cu-catalyzed reaction conditions also were applied to the coupling of methyl 3-amino-1-benzothiophene-2-carboxylate **1** with hetero iodide **2** to synthesized coupling compound **5** (Scheme 5).

<figure><img src="image_11.png" /><figcaption>**Scheme 5.** Synthesis of compound 5.</figcaption></figure>

The result indicated that methyl 3-amino-1-benzothiophene-2-carboxylates **1** must play an important role in accelerating the Cu(I)-catalyzed cross-coupling reactions. This effect might be influenced by a possible chelating effect of the aminobenzo[b]thiophene N atom, the Cu complex, and the oxygen atom of the 2-carbonyl unit. For example, Liebeskind and co-workers reported Ullmann-type cross-coupling reactions of substituted aryl, heteroaryl, and alkenyl halides using copper(I)-thiophene-2-carboxylate (CuTC) as a promoter [65]. According to the literature, Liebeskind's catalyst CuTC is superior to other catalysts in various cross-couplings [66].

### 3. Materials and Methods

#### 3.1. *General Information*

Reactions in anhydrous conditions were performed under argon atmosphere in pre-dried flasks, using anhydrous solvents (distilled when necessary according to D. D. Perrin, W. L. F. Armarego and D. R. Perrin in *Purification of Laboratory Chemicals*, Pergamon, Oxford, 1986). All reagents and solvents were purchased from commercial chemical suppliers and used without further purification. The course of the reactions was monitored by initial TLC analysis on aluminum foil-backed plates (Merck Kieselgel 60 F₂₅₄, Darmstadt, Germany), which were developed using standard visualization techniques or agents: UV fluorescence (254 nm) and by staining with a 1% aq KMnO₄ solution. Flash column chromatography was performed with Silica Gel 60 Å (230–400 µm, Merck KGaA, Darmstadt, Germany).
Melting points [°C] were measured with a Thermo Scientific 9200 capillary apparatus, Büchi Melting Point M-560 (Büchi Labortechnik AG, Flawil, Switzerland) (for compounds 3c, 3e, 3f), and are uncorrected. NMR spectra were recorded on a 400 MHz Bruker Avance 2 400 and Bruker Avance III 400 (for compounds 3c, 3e, 3f) spectrometers (Bruker BioSpin AG, Fallanden, Switzerland) (400 MHz (¹H), 100 MHz (¹³C), 376 MHz (¹⁹F)). Chemical shifts are expressed in parts per million (ppm) downfield from TMS internal standard. Coupling patterns for ¹H-NMR are designated as s = singlet, d = doublet, t = triplet, m = multiplet, (some ¹³C-NMR are designated as d = doublet, q = quartet), and coupling constants are given in Hz. NMR peak assignments were elucidated via DEPT, COSY, and HSQC techniques when necessary. IR spectra from samples in neat form were measured with a Thermo Scientific Nicolet iS10 FT-IR spectrophotometer (Thermo Fisher Scientific Inc., Waltham, MA, USA) and Bruker Tensor 27 (Bruker Optic GmbH, Ettlingen, Germany) (KBr pellets, for compounds 3c, 3e, 3f). IR absorption frequencies are given in cm⁻¹. Low-resolution mass spectra were recorded with Perkin-Elmer Sciex API 300 spectrometer (PerkinElmer Inc., Waltham, MA, USA) and Shimadzu LCMS-2020 (Shimadzu Corporation, Kyoto, Japan) (for compounds 3c, 3e, 3f). High-resolution mass spectra (HRMS) were recorded with a Bruker MaXis spectrometer (Bruker Daltonik GmbH, Bremen, Germany) in the electrospray ionization (ESI) mode. ¹H-, ¹³C-, ¹⁹F-, DEPT, and some COSY, HSQC NMR spectra, and HRMS data of all new compounds are provided in Supplementary Materials as Figures S1–S61.

### 3.2. Synthesis of Methyl 3-Amino-1-benzothiophene-2-carboxylate (1)

To a solution of 2-fluorobenzonitrile (0.45 mL, 4.15 mmol) in dry DMF (2 mL) at room temperature methyl thioglycolate (0.41 mL, 4.58 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 10 min, and K₂CO₃ (680 mg, 4.92 mmol) was added. After stirring at 105 °C for 2 h, the reaction mixture was poured into crushed ice-water (50 mL). The resulting precipitate was collected by filtration, rinsed with cold water, and air dried to give compound **1** as a pale beige solid; yield: 840 mg, 98%; m.p. 107–108 °C (lit. [67] m.p. 110–111 °C). MS (ESI): *m/z* = 208 [M + H]⁺.

### 3.3. Synthesis of Methyl 3-Iodo-1-benzothiophene-2-carboxylate (2)

Methyl 3-amino-1-benzothiophene-2-carboxylate (601 mg, 2.90 mmol) was gradually added to a vigorously stirred 6 M hydrochloric acid solution (2 mL). The reaction mixture was stirred for 20 min at 60 °C. Then mixture was cooled below 0 °C (ice and NaCl bath), and slowly diazotized with sodium nitrite (219 mg, 3.186 mmol). The resulting diazonium salt was stirred for 1 h at this temperature and was poured at once into a well stirred solution of potassium iodide (721 mg, 4.343 mmol) in water (2 mL). The reaction mixture was heated at 60 °C and once evolution of nitrogen had finished, resulting reaction mixture was cooled. Then, mixture extracted with chloroform (3 × 30 mL) and washed with water (50 mL), brine, and finally dried over MgSO₄. After filtration, the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography, *Rf* = 0.24 (PE/EtOAc 97:3). Yield: 700 mg, 73%; pale yellow solid; m.p. 92–93 °C (lit. [54] m.p. 92–93.5 °C). ¹H-NMR (400 MHz, CDCl₃): *δ* = 3.98 (s, 3H, OCH₃), 7.47–7.54 (m, 2H, 5-H, 6-H), 7.80–7.83 (m, 1H, 7-H), 7.96–7.98 (m, 1H, 4-H) ppm. ¹³C-NMR (100 MHz, CDCl₃): *δ* = 52.8 (OCH₃), 88.4 (Cq), 122.8 (C-4), 126.1 (C-6), 128.3 (C-5, C-7), 130.2 (Cq), 140.4 (Cq), 142.0 (Cq), 162.2 (C=O) ppm. IR (neat): *νmax* = 1713 (C=O), 1497, 1218 (C-O), 1082, 1052 (C=C) cm⁻¹. MS (ESI): *m/z* = 319 [M + H]⁺. HRMS (ESI): *m/z* [M + H]⁺ calcd. for C₁₀H₈IO₂S 318.92842, found 318.92847. HRMS (ESI): *m/z* [M + Na]⁺ calcd. for C₁₀H₇INaO₂S 340.91036, found 340.91040. Compound **2** was previously prepared using a different synthetic pathway. The ¹H- and ¹³C-NMR spectra are in good agreement with the literature data [54].

### 3.4. Synthesis Procedure for the Preparation of Compounds 3a–o

Under argon atmosphere, a mixture of methyl 3-amino-1-benzothiophene-2-carboxylate (1 equiv), aryl iodide (1.5 equiv), Cs₂CO₃ (2 equiv), CuI (0.1 equiv), and L-proline (0.1 equiv)
in dry dioxane (2 mL) was stirred under reflux for 24 h. After the mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography using PE/EtOAc as eluent to afford the corresponding compounds. The data for selected compounds is described below.

### 3.4.1. Methyl 3-[(4-Methoxyphenyl)amino]-1-benzothiophene-2-carboxylate (3a)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3a** (260 mg, 86%); $R_f = 0.30$ (PE/EtOAc 97:3); yellow solid, m.p. 103–104 °C. ¹H-NMR (400 MHz, CDCl₃): $\delta = 3.83$ (s, 3H, OCH₃), 3.91 (s, 3H, COOCH₃), 6.86 (d, J = 8.9 Hz, 2H, 2-HPh, 6-HPh), 7.06–7.10 (m, 3H, 3-HPh, 5-HPh, 6-H), 7.20 (d, J = 8.2 Hz, 1H, 7-H), 7.35–7.39 (m, 1H, 5-H), 7.72 (d, J = 8.2 Hz, 1H, 4-H), 8.79 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): $\delta = 51.9$ (COOCH₃), 55.7 (OCH₃), 103.5 (Cq), 114.5 (CPh-3, CPh-5), 123.4 (C-4, C-7), 125.2 (CPh-2, CPh-6), 125.8 (C-6), 127.7 (C-5), 131.7 (Cq), 135.1 (Cq), 140.5 (Cq), 148.0 (Cq), 157.0 (Cq), 166.2 (C=O) ppm. IR (neat): $v_{max} = 3297$ (N-H), 1666 (C=O), 1577, 1508, 1440, 1397, 1230 (C–O), 1146, 1031 (C=C, C–N) cm⁻¹. MS (IS): *m/z* = 282 [M–OCH₃]⁺, 314 [M + H]⁺, 336 [M + Na]⁺. HRMS (ESI): *m/z* [M + H]⁺ calcd. for C₁₇H₁₆NO₃S 314.08454, found 314.08440. HRMS (ESI): *m/z* [M + Na]⁺ calcd. for C₁₇H₁₅NNaO₃S 336.06649, found 336.06626. H⁻, 95%). HRMS (ESI⁺) for C₂₁H₂₉N₃NaO₅ ([M + Na]⁺) calcd 426.1999, found 426.2001.

### 3.4.2. Methyl 3-[(2-Methoxyphenyl)amino]-1-benzothiophene-2-carboxylate (3b)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3b** (218 mg, 72%); $R_f = 0.22$ (PE/EtOAc 98:2); yellow solid; m.p. 123–124 °C. ¹H-NMR (400 MHz, CDCl₃): $\delta = 3.89$ (s, 3H, COOCH₃), 3.91 (s, 3H, OCH₃), 6.76–6.80 (m, 1H, HPh), 6.88 (dd, J = 0.9 Hz, J = 7.8 Hz, 1H, 6-HPh), 6.93 (dd, J = 1.1 Hz, J = 8.0 Hz, 1H, 3-HPh), 6.97–7.02 (m, 1H, HPh), 7.14–7.18 (m, 1H, 6-H), 7.40 (td, J = 0.95 Hz, J = 8.1 Hz, 1H, 5-H), 7.52 (d, J = 8.3 Hz, 1H, 7-H), 7.74 (d, J = 8.1 Hz, 1H, 4-H), 8.56 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): $\delta = 52.1$ (COOCH₃), 55.9 (OCH₃), 108.0 (Cq), 111.0 (CPh-3), 119.7 (CPh-6), 120.5 (CPh), 123.0 (C-4), 123.4 (CPh), 123.6 (C-6), 125.9 (C-7), 127.8 (C-5), 131.8 (Cq), 132.6 (Cq), 140.1 (Cq), 145.6 (Cq), 150.7 (Cq), 165.6 (C=O) ppm. IR (neat): $v_{max} = 3378$ (N–H), 1684 (C=O), 1563, 1530, 1502, 1437, 1274, 1239 (C–O), 1218, 1109, 1025 (C=C, C–N) cm⁻¹. MS (ESI): *m/z* = 282 [M–OCH₃]⁺, 314 [M + H]⁺, 336 [M + Na]⁺, 352 [M + K]⁺. HRMS (ESI): *m/z* [M + H]⁺ calcd. for C₁₇H₁₆NO₃S 314.08454, found 314.08405.

### 3.4.3. Methyl 3-[(4-Fluorophenyl)amino]-1-benzothiophene-2-carboxylate (3c)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3c** (273 mg, 94%); $R_f = 0.22$ (PE/EtOAc 98:2); yellowish crystals; m.p. 92–93 °C. ¹H-NMR (400 MHz, CDCl₃): $\delta = 3.95$ (s, 3H, OCH₃), 6.99–7.05 (m, 2H, HAr), 7.06–7.11 (m, 2H, HAr), 7.14–7.18 (m, 1H, HBT), 7.26–7.32 (m, 1H, HBT), 7.43–7.49 (m, 1H, HBT), 7.77 (d, J = 8.2 Hz, 1H, 4-HBT), 8.75 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): $\delta = 52.0$ (OCH₃), 105.9 (Cq), 115.9 (d, $^2J_{C,F}$ = 23.0 Hz, 2xCH), 123.5 (d, $^3J_{C,F}$ = 14.0 Hz, CH), 124.1 (d, $^3J_{C,F}$ = 8.0 Hz, CH), 125.6 (CH), 127.8 (CH), 131.7 (Cq), 138.4 (d, $^3J_{C,F}$ = 2.0 Hz, Cq), 140.3 (Cq), 146.8 (Cq), 159.7 (d, $^1J_{C,F}$ = 242.0 Hz, Cq), 166.1 (C=O) ppm. ¹⁹F-NMR (376 MHz, CDCl₃): $\delta = -119.03$ (s, 1F) ppm. IR (KBr): $v_{max} = 3313$ (N–H), 1674 (C=O), 1674, 1433, 1278, 1253, 1242, 1147, (C–O, C–F, C=C, C–N) cm⁻¹. MS (ESI): *m/z* = 302 [M + H]⁺.

### 3.4.4. Methyl 3-[(2-Fluorophenyl)amino]-1-benzothiophene-2-carboxylate (3d)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3d** (230 mg, 79%); $R_f = 0.45$ (PE/EtOAc 98:2); yellowish crystals; m.p. 126–127 °C. ¹H-NMR (400 MHz, CDCl₃): $\delta = 3.93$ (s, 3H, OCH₃), 6.96–7.06 (m, 3H, 4-HPh, 5-HPh, 6-HPh), 7.12–7.21 (m, 2H, 3-HPh, 6-H), 7.41–7.45 (m, 2H, 5-H, 7-H), 7.78 (d, J = 8.3 Hz, 1H, 4-H), 8.53 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): $\delta = 52.1$ (OCH₃), 108.4 (Cq),
116.0 (d, $^2J_{C,F}$ = 19.1 Hz, C<sub>Ph</sub>-3), 122.2 (d, $^4J_{C,F}$ = 1.4 Hz, C<sub>Ph</sub>-5), 123.4 (C-4), 123.8 (C-6), 123.8 (d, $^3J_{C,F}$ = 7.2 Hz, C<sub>Ph</sub>-4), 124.1 (d, $^3J_{C,F}$ = 3.8 Hz, C<sub>Ph</sub>-6), 125.2 (C-7), 127.8 (C-5), 130.6 (d, $^2J_{C,F}$ = 11.3 Hz, C<sub>Ph</sub>-1), 132.2 (C<sub>q</sub>), 140.0 (C<sub>q</sub>), 145.0 (C<sub>q</sub>), 155.0 (d, $^1J_{C,F}$ = 245.5 Hz, C<sub>Ph</sub>-2), 165.6 (C=O) ppm. <sup>19</sup>F-NMR (376 MHz, CDCl<sub>3</sub>): $\delta$ = -127.42 (s, 1F) ppm. IR (neat): $v_{max}$ = 3324 (N-H), 1675 (C=O), 1433, 1277, 1243 (C-O), 1190 (C-F, C=C, C-N) cm<sup>-1</sup>. MS (ESI): *m/z* = 270 [M-OCH<sub>3</sub>]<sup>+</sup>, 302 [M + H]<sup>+</sup>, 324 [M + Na]<sup>+</sup>, 340 [M + K]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C<sub>16</sub>H<sub>13</sub>FNO<sub>2</sub>S 302.06455, found 302.06373.

### 3.4.5. Methyl 3-{[4-(Trifluoromethyl)phenyl]amino}-1-benzothiophene-2-carboxylate (3e)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3e** (297 mg, 97%); $R_f$ = 0.43 (PE/EtOAc 98:2); yellowish crystals; m.p. 125–126 °C. <sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>): $\delta$ = 3.96 (s, 3H, OCH<sub>3</sub>), 7.08 (d, *J* = 8.4 Hz, 2H, 2xH<sub>Ar</sub>), 7.28–7.31 (m, 1H, H<sub>Ar</sub>), 7.48–7.54 (m, 4H, H<sub>Ar</sub>, H<sub>BT</sub>), 7.82–7.85 (m, 1H, H<sub>BT</sub>), 8.68 (s, 1H, NH) ppm. <sup>13</sup>C-NMR (100 MHz, CDCl<sub>3</sub>): $\delta$ = 52.3 (OCH<sub>3</sub>), 110.7 (C<sub>q</sub>), 119.3 (2 × CH), 123.5 (CH), 124.0 (CH), 124.3 (q, $^2J_{C,F}$ = 33.0 Hz, C<sub>q</sub>), 125.4 (CH), 126.5 (q, $^3J_{C,F}$ = 4.0 Hz, 2 × CH), 128.0 (CH), 132.2 (C<sub>q</sub>), 140.0 (C<sub>q</sub>), 143.9 (C<sub>q</sub>), 145.8 (C<sub>q</sub>), 165.5 (C=O) ppm. <sup>19</sup>F-NMR (376 MHz, CDCl<sub>3</sub>): $\delta$ = -61.71 (s, 3F) ppm. IR (KBr): $v_{max}$ = 3317 (N-H), 1668 (C=O), 1328, 1280, 1260, 1244, 1117, 1110 (C-F, C-O-C, C=C, C-N) cm<sup>-1</sup>. MS (ESI): *m/z* = 352 [M + H]<sup>+</sup>.

### 3.4.6. Methyl 3-{[3-(Trifluoromethyl)phenyl]amino}-1-benzothiophene-2-carboxylate (3f)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3f** (248 mg, 73%); $R_f$ = 0.45 (PE/EtOAc 98:2); yellowish crystals; m.p. 133–134 °C. <sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>): $\delta$ = 3.93 (s, 3H, OCH<sub>3</sub>), 7.16–7.23 (m, 2H, H<sub>Ar</sub>), 7.28–7.31 (m, 2H, H<sub>Ar</sub>), 7.37 (dd, *J* = 8.0 Hz, *J* = 11.5 Hz, 2H<sub>BT</sub>), 7.43–7.49 (m, 1H, H<sub>BT</sub>), 7.80 (d, *J* = 8.1 Hz, 1H<sub>BT</sub>), 8.72 (s, 1H, NH) ppm. <sup>13</sup>C-NMR (100 MHz, CDCl<sub>3</sub>): $\delta$ = 52.3 (OCH<sub>3</sub>), 109.4 (C<sub>q</sub>), 117.2 (q, $^3J_{C-F}$ = 4.0 Hz, CH), 119.4 (q, $^3J_{C-F}$ = 4.0 Hz, CH), 123.5 (CH), 123.6 (CH), 123.9 (CH), 124.0 (q, $^1J_{C-F}$ = 272.0 Hz, C<sub>q</sub>), 125.3 (CH), 128.0 (CH), 129.7 (CH), 131.7 (q, $^2J_{C-F}$ = 32.0 Hz, C<sub>q</sub>), 131.9 (C<sub>q</sub>), 140.1 (C<sub>q</sub>), 143.2 (C<sub>q</sub>), 144.6 (C<sub>q</sub>), 165.7 (C=O) ppm. <sup>19</sup>F-NMR (376 MHz, CDCl<sub>3</sub>): $\delta$ = -62.86 (s, 3F) ppm. IR (KBr): $v_{max}$ = 3312 (N-H), 1680 (C=O), 1337, 1275, 1165, 1143, 1120 (C-F, C-O-C, C=C, C-N) cm<sup>-1</sup>. MS (ESI): *m/z* = 352 [M + H]<sup>+</sup>.

### 3.4.7. Methyl 3-{[2-(Trifluoromethyl)phenyl]amino}-1-benzothiophene-2-carboxylate (3g)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3g** (224 mg, 72%); $R_f$ = 0.45 (PE/EtOAc 98:2); pale pink needles; m.p. 152–153 °C. <sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>): $\delta$ = 3.92 (s, 3H, OCH<sub>3</sub>), 6.94 (d, *J* = 8.1 Hz, 1H, 6-H<sub>Ph</sub>), 7.11 (t, *J* = 7.6 Hz, 1H, 4-H<sub>Ph</sub>), 7.14–7.18 (m, 1H, 5-H<sub>Ph</sub>), 7.27–7.33 (m, 2H, 6-H, 7-H), 7.41 (td, *J* = 1.1 Hz, *J* = 8.2 Hz, 1H, 5-H), 7.67 (d, *J* = 7.8 Hz, 1H, 3-H<sub>Ph</sub>), 7.77 (d, *J* = 8.2 Hz, 1H, 4-H), 8.82 (s, 1H, NH) ppm. <sup>13</sup>C-NMR (100 MHz, CDCl<sub>3</sub>): $\delta$ = 52.4 (OCH<sub>3</sub>), 110.4 (C<sub>q</sub>), 121.3 (q, $^2J_{C,F}$ = 29.8 Hz, C<sub>Ph</sub>-2), 122.3 (C<sub>Ph</sub>-6), 122.7 (C<sub>Ph</sub>-4), 123.6 (C-4), 124.0 (C<sub>Ph</sub>-5), 124.5 (q, $^1J_{C,F}$ = 272.8 Hz, CF<sub>3</sub>), 125.4 (C-7), 126.9 (q, $^3J_{C,F}$ = 5.3 Hz, C<sub>Ph</sub>-3), 127.9 (C-5), 132.1 (C<sub>q</sub>), 132.5 (C-6), 140.1 (C<sub>q</sub>), 141.0 (C<sub>q</sub>), 144.2 (C<sub>q</sub>), 165.6 (C=O) ppm. <sup>19</sup>F-NMR (376 MHz, CDCl<sub>3</sub>): $\delta$ = -62.01 (s, 3F) ppm. IR (neat): $v_{max}$ = 3316 (N-H), 1678 (C=O), 1588, 1463, 1321, 1293, 1274, 1251 (C-O), 1115 (C-F), 1102, 1033 (C=C, C-N) cm<sup>-1</sup>. MS (ESI): *m/z* = 320 [M-OCH<sub>3</sub>]<sup>+</sup>, 352 [M + H]<sup>+</sup>, 374 [M + Na]<sup>+</sup>, 390 [M + K]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C<sub>17</sub>H<sub>13</sub>F<sub>3</sub>NO<sub>2</sub>S 352.06136, found 352.06111. HRMS (ESI): *m/z* [M + Na]<sup>+</sup> calcd. for C<sub>17</sub>H<sub>12</sub>F<sub>3</sub>NNaO<sub>2</sub>S 374.04331, found 374.04331. HRMS (ESI): *m/z* [M + K]<sup>+</sup> calcd. for C<sub>17</sub>H<sub>12</sub>F<sub>3</sub>KNO<sub>2</sub>S 390.01724, found 390.01729.

### 3.4.8. Methyl 3-{[3-Methoxyphenyl]amino}-1-benzothiophene-2-carboxylate (3h)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3h** (230 mg, 76%); $R_f$ = 0.25 (PE/EtOAc 98:2); pale beige solid; m.p. 89–90 °C. <sup>1</sup>H-NMR (400 MHz, CDCl<sub>3</sub>): $\delta$ = 3.74 (s, 3H, OCH<sub>3</sub>), 3.92 (s, 3H, COOCH<sub>3</sub>), 6.62–6.66 (m, 3H, H<sub>Ph</sub>), 7.15–7.20 (m, 2H, H<sub>Ph</sub>, 6-H), 7.39–7.43 (m, 1H, 5-H), 7.47 (d, *J* =
8.3 Hz, 1H, 7-H), 7.75 (d, *J* = 8.2 Hz, 1H, 4-H), 8.71 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): *δ* = 52.0 (COOCH₃), 55.4 (OCH₃), 107.1 (Cq), 107.2 (CPh), 109.3 (CPh), 114.1 (CPh), 123.3 (CPh), 123.6 (C-4), 125.9 (C-7), 127.8 (C-5), 129.9 (C-6), 132.2 (Cq), 140.1 (Cq), 143.7 (Cq), 146.1 (Cq), 160.5 (Cq), 165.9 (C=O) ppm. IR (neat): *ν*<sub>max</sub> = 3310 (N-H), 1669 (C=O), 1574, 1536, 1435, 1391, 1274, 1238 (C–O), 1196, 1036 (C=C, C–N) cm<sup>-1</sup>. MS (ESI): *m/z* = 282 [M–OCH₃]<sup>+</sup>, 314 [M + H]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C₁₇H₁₆NO₃S 314.08454, found 314.08484. HRMS (ESI): *m/z* [M + Na]<sup>+</sup> calcd. for C₁₇H₁₅NNaO₃S 336.06649, found 336.06691.

### 3.4.9. Methyl 3-[(4-Nitrophenyl)amino]-1-benzothiophene-2-carboxylate (3i)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3i** (190 mg, 60%); $R_f = 0.20$ (PE/EtOAc 9:1); yellow solid; m.p. 139–140 °C (lit. [43] 133–135 °C). ¹H-NMR (400 MHz, CDCl₃): *δ* = 3.94 (s, 3H, OCH₃), 6.98 (d, *J* = 8.9 Hz, 2H, 2-H<sub>Ph</sub>, 6-H<sub>Ph</sub>), 7.31 (t, *J* = 7.6 Hz, 1H, 6-H), 7.49–7.52 (m, 2H, 5-H, 7-H), 7.84 (d, *J* = 8.3 Hz, 1H, 4-H), 8.14 (d, *J* = 8.9 Hz, 2H, 3-H<sub>Ph</sub>, 5-H<sub>Ph</sub>), 8.65 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): *δ* = 52.5 (OCH₃), 113.6 (Cq), 117.7 (C<sub>Ph</sub>-2, C<sub>Ph</sub>-6), 123.7 (C-4), 124.5 (C-6), 125.1 (C-5), 125.7 (C<sub>Ph</sub>-3, C<sub>Ph</sub>-5), 128.2 (C-7), 132.3 (Cq), 139.8 (Cq), 141.9 (Cq), 142.0 (Cq), 148.9 (Cq), 165.1 (C=O) ppm. IR (neat): *ν*<sub>max</sub> = 3340 (N-H), 1686 (C=O), 1589 (N–O), 1507, 1318 (N–O), 1238 (C–O), 1111 (C=C, C–N) cm<sup>-1</sup>. MS (ESI): *m/z* = 329 [M + H]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C₁₆H₁₃N₂O₄S 329.05905, found 329.05911. HRMS (ESI): *m/z* [M + Na]<sup>+</sup> calcd. for C₁₆H₁₂N₂NaO₄S 351.04100, found 351.04112. ¹H- and ¹³C-NMR spectra are in good agreement with the literature data [43].

### 3.4.10. Methyl 3-[(3-Nitrophenyl)amino]-1-benzothiophene-2-carboxylate (3j)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3j** (241 mg, 79%); $R_f = 0.33$ (PE/EtOAc 9:1); yellow solid; m.p. 141–142 °C. ¹H-NMR (400 MHz, CDCl₃): *δ* = 3.94 (s, 3H, OCH₃), 7.23 (dd, *J* = 1.0 Hz, *J* = 8.2 Hz, 1H, 6-H<sub>Ph</sub>), 7.29 (dd, *J* = 1.4 Hz, *J* = 8.1 Hz, 1H, 4-H<sub>Ph</sub>), 7.39–7.43 (m, 2H, 5-H, H<sub>Ph</sub>), 7.47 (td, *J* = 1.0 Hz, *J* = 8.1 Hz, 1H, 6-H), 7.81–7.83 (m, 2H, 7-H, H<sub>Ph</sub>), 7.87 (dd, *J* = 1.0 Hz, *J* = 8.1 Hz, 1H, 4-H), 8.70 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): *δ* = 52.3 (OCH₃), 111.0 (Cq), 114.4 (C-7), 117.2 (C-4), 123.7 (C<sub>Ph</sub>), 124.2 (C<sub>Ph</sub>-6), 125.0 (C<sub>Ph</sub>), 125.5 (C<sub>Ph</sub>-4), 128.1 (C-6), 129.9 (C-5), 131.9 (Cq), 140.0 (Cq), 143.6 (Cq), 144.1 (Cq), 149.1 (Cq), 165.5 (C=O) ppm. IR (neat): *ν*<sub>max</sub> = 3321 (N-H), 1680 (C=O), 1573 (N–O), 1465, 1343 (N–O), 1281, 1240 (C–O) 1064 (C=C, C–N) cm<sup>-1</sup>. MS (ESI): *m/z* = 297 [M–OCH₃]<sup>+</sup>, 329 [M + H]<sup>+</sup>, 351 [M + Na]<sup>+</sup>, 367 [M + K]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C₁₆H₁₃N₂O₄S 329.05905, found 329.05903. HRMS (ESI): *m/z* [M + Na]<sup>+</sup> calcd. for C₁₆H₁₂N₂NaO₄S 351.04100, found 351.04092.

### 3.4.11. Methyl 3-[(2-Nitrophenyl)amino]-1-benzothiophene-2-carboxylate (3k)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3k** (238 mg, 75%); $R_f = 0.41$ (PE/EtOAc 9:1); orange needles; m.p. 209–210 °C (lit. [43] 207–209 °C). ¹H-NMR (400 MHz, CDCl₃): *δ* = 3.92 (s, 3H, OCH₃), 6.84 (d, *J* = 8.5 Hz, 1H, H<sub>Ph</sub>), 6.91 (td, *J* = 1.0 Hz, *J* = 8.3 Hz, 1H, 6-H), 7.27–7.33 (m, 2H, H<sub>Ph</sub>), 7.46–7.49 (m, 2H, 5-H, H<sub>Ph</sub>), 7.83 (d, *J* = 8.3 Hz, 1H, 4-H), 8.21 (dd, *J* = 1.3 Hz, *J* = 8.5 Hz, 1H, 7-H), 10.29 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): *δ* = 52.7 (OCH₃), 118.6 (Cq), 118.9 (C<sub>Ph</sub>), 119.7 (C-6), 123.7 (C-4), 124.7 (C<sub>Ph</sub>), 124.8 (C-5), 126.6 (C-7), 128.0 (C<sub>Ph</sub>), 133.5 (C), 135.0 (C<sub>Ph</sub>), 135.9 (Cq), 139.1 (Cq), 139.7 (Cq), 140.5 (Cq), 163.8 (C=O) ppm. IR (neat): *ν*<sub>max</sub> = 3319 (N–H), 1678 (C=O), 1575 (N–O), 1490, 1435, 1339 (N–O), 1269, 1233 (C–O), 1150 (C=C, C–N) cm<sup>-1</sup>. MS (ESI): *m/z* = 329 [M + H]<sup>+</sup>, 351 [M + Na]<sup>+</sup>, 367 [M + K]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C₁₆H₁₃N₂O₄S 329.05905, found 329.05894. HRMS (ESI): *m/z* [M + Na]<sup>+</sup> calcd. for C₁₆H₁₂N₂NaO₄S 351.04100, found 351.04099. HRMS (ESI): *m/z* [M + K]<sup>+</sup> calcd for C₁₆H₁₂KN₂O₄S 367.01494, found 367.01501. ¹H- and ¹³C-NMR spectra are in good agreement with the literature data [43].
### 3.4.12. Methyl 3-(Phenylamino)-1-benzothiophene-2-carboxylate (3l)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3l** (145 mg, 55%); $R_f = 0.45$ (PE/EtOAc 98:2); pale beige solid; m.p. 116–117 °C. ¹H-NMR (400 MHz, CDCl₃): $\delta = 3.91$ (s, 3H, CH₃), 7.06–7.15 (m, 4H, HPh, 6-H), 7.25–7.30 (m, 2H, HPh), 7.37 (d, $J = 7.9$ Hz, 1H, 7-H), 7.41 (d, $J = 8.1$ Hz, 1H, 5-H), 7.75 (d, $J = 8.1$ Hz, 1H, 4-H), 8.74 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): $\delta = 52.0$ (OCH₃), 106.7 (Cq), 121.8 (2 × CPh), 123.4 (CPh), 123.5 (C-6), 123.6 (C-4), 125.8 (C-7), 127.8 (C-5), 129.2 (2 × CPh), 132.1 (Cq), 140.2 (Cq), 142.4 (Cq), 146.3 (Cq), 165.9 (C=O) ppm. IR (neat): $v_{max} = 3320$ (N–H), 1666 (C=O), 1567, 1532, 1235 (C–O), 1061 (C=C, C–N) cm⁻¹. MS (ESI): *m/z* = 252 [M–OCH₃]⁺, 284 [M + H]⁺, 306 [M + Na]⁺, 322 [M + K]⁺. HRMS (ESI): *m/z* [M + H]⁺ calcd. for C₁₆H₁₄NO₂S 284.07398, found 284.07412.

### 3.4.13. Methyl 3-[(4-Hydroxyphenyl)amino]-1-benzothiophene-2-carboxylate (3m)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3m** (73 mg, 25%) using 4-iodophenol as coupling reagent; to yield **3m** (145 mg, 50%) using 4-iodophenyl acetate as coupling reagent; $R_f = 0.29$ (PE/EtOAc 8:2); yellow solid; m.p. 166–167 °C. ¹H-NMR (400 MHz, CDCl₃): $\delta = 3.92$ (s, 3H, OCH₃), 4.97 (s, 1H, OH), 6.79 (d, $J = 8.7$ Hz, 2H, 2-HPh, 6-HPh), 7.01–7.04 (m, 2H, 3-HPh, 5-HPh), 7.06–7.10 (m, 1H, H-6), 7.21 (d, $J = 8.3$ Hz, 1H, 7-H), 7.37 (td, $J = 1.0$ Hz, $J = 8.1$ Hz, 1H, 5-H), 7.72 (d, $J = 8.1$ Hz, 1H, 4-H), 8.75 (s, 1H, NH). ¹³C-NMR (100 MHz, CDCl₃): $\delta = 51.9$ (OCH₃), 103.5 (Cq), 116.0 (CPh-2, CPh-6), 123.4 (C-6), 123.4 (C-4), 125.4 (CPh-3, CPh-5), 125.8 (C-7), 127.8 (C-5), 131.7 (Cq), 135.2 (Cq), 140.5 (Cq), 148.0 (Cq), 153.0 (Cq), 166.3 (C=O). IR (neat): $v_{max} = 3453$ (O–H), 3307 (N–H), 1650 (C=O), 1512, 1441, 1280, 1240, 1191, 1068 (C–O, C=C, C–N, C–O–H) cm⁻¹. MS (ESI): *m/z* = 268 [M–OCH₃]⁺, 300 [M + H]⁺, 322 [M + Na]⁺, 338 [M + K]⁺. HRMS (ESI): *m/z* [M + H]⁺ calcd. for C₁₆H₁₄NO₃S 300.06889, found 300.06887. HRMS (ESI): *m/z* [M + Na]⁺ calcd. for C₁₆H₁₃NNaO₃S 322.05084, found 322.05069.

### 3.4.14. Methyl 3-[(4-Aminophenyl)amino]-1-benzothiophene-2-carboxylate (3n)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3n** (43 mg, 15%); $R_f = 0.17$ (PE/EtOAc 8:2); brown solid; m.p. 169–172 °C. ¹H-NMR (400 MHz, CDCl₃): $\delta = 3.66$ (br s, 2H, NH₂), 3.91 (s, 3H, OCH₃), 6.66 (d, $J = 8.5$ Hz, 2H, 2-HPh, 6-HPh), 6.99 (d, $J = 8.5$ Hz, 2H, 3-HPh, 5-HPh), 7.03–7.07 (m, 1H, 6-H), 7.21 (d, $J = 8.3$ Hz, 1H, 7-H), 7.35 (td, $J = 1.0$ Hz, $J = 8.1$ Hz, 1H, 5-H), 7.70 (d, $J = 8.1$ Hz, 1H, 4-H), 8.79 (br s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): $\delta = 51.8$ (OCH₃), 102.1 (Cq), 115.8 (CPh-2, CPh-6), 123.3 (C-4, C-6), 126.0 (CPh-3, CPh-5), 126.0 (C-7), 127.7 (C-5), 131.7 (Cq), 133.1 (Cq), 140.6 (Cq), 144.0 (Cq), 148.6 (Cq), 166.3 (C=O) ppm. IR (neat): $v_{max} = 3472$ (N–H), 3375 and 3312 (NH₂), 1630 (C=O), 1572, 1514, 1439, 1390, 1237 (C–O), 1064 (C=C, C–N) cm⁻¹. MS (ESI): *m/z* = 267 [M–OCH₃]⁺, 299 [M + H]⁺. HRMS (ESI): *m/z* [M + H]⁺ calcd. for C₁₆H₁₅N₂O₂S 299.08487, found 299.08533.

### 3.4.15. Methyl 3-[(4-(Acetylamino)phenyl)amino]-1-benzothiophene-2-carboxylate (3o)

The representative experimental procedure was applied to compound **1** (200 mg, 0.965 mmol) to yield **3o** (180 mg, 55%); $R_f = 0.18$ (PE/EtOAc 7:3); yellow solid; m.p. 240–241 °C. ¹H-NMR (400 MHz, DMSO-d₆): $\delta = 2.03$ (s, 3H, COCH₃), 3.82 (s, 3H, COOCH₃), 7.00 (d, $J = 8.7$ Hz, 2H, 2-HPh, 6-HPh), 7.22–7.28 (m, 2H, 6-H, 7-H), 7.46–7.51 (m, 3H, 3-HPh, 5-HPh, 5-H), 7.95 (d, $J = 8.2$ Hz, 1H, 4-H), 8.72 (s, 1H, NH), 9.90 (s, 1H, NHCOCH₃) ppm. ¹³C-NMR (100 MHz, DMSO-d₆): $\delta = 23.9$ (COCH₃), 51.9 (COOCH₃), 106.1 (Cq), 119.7 (CPh-3, CPh-5), 121.5 (CPh-2, CPh-6), 123.6 (C-4), 123.9 (C-6), 124.8 (C-7), 128.0 (C-5), 132.0 (Cq), 135.0 (Cq), 137.4 (Cq), 139.1 (Cq), 145.1 (Cq), 164.3 (C=O), 168.0 (HN-C=O) ppm. IR (neat): $v_{max} = 3279$ (N–H), 3275 (N–H), 1670 (C=O), 1538, 1241 (C–O, C=C, C–N) cm⁻¹. MS (ESI): *m/z* = 309 [M–OCH₃]⁺, 341 [M + H]⁺, 363 [M + Na]⁺. HRMS (ESI): *m/z* [M + H]⁺ calcd. for C₁₈H₁₇N₂O₃S 341.09544, found 341.09575. HRMS (ESI): *m/z* [M + Na]⁺ calcd. for C₁₈H₁₆N₂NaO₃S 363.07738, found 363.07767.
### 3.5. Synthesis of 5a,7-Dihidro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-6-one (4)

Compound **1** (100 mg, 0.482 mmol) was dissolved in dry dioxane (2 mL) and treated with 2-iodoaniline (160 mg, 0.724 mmol), Cs₂CO₃ (315 mg, 0.965 mmol), CuI (10 mg, 0.050 mmol), and L-proline (6 mg, 0.048 mmol) under argon atmosphere. Reaction mixture was stirred under reflux for 72 h. After the mixture was cooled to room temperature and diluted with water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (SiO₂, eluent: petroleum ether/ethyl acetate, 7:3, R_f = 0.17) to provide compound **4** as white solid. Yield 53 mg (41%), m.p. 214–215 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ = 6.72 (d, *J* = 7.7 Hz, 1H, H<sub>BT</sub>), 6.95–6.99 (m, 1H, H<sub>BT</sub>), 7.06 (d, *J* = 7.7 Hz, 1H, H<sub>BT</sub>), 7.09–7.13 (m, 1H, H<sub>BT</sub>), 7.38–7.49 (m, 3H, H<sub>Ar</sub>), 8.08 (s, 1H, CH), 8.11 (d, *J* = 8.0 Hz, 1H, H<sub>Ar</sub>), 11.23 (br s, 1H, NH) ppm. ¹³C-NMR (100 MHz, DMSO-d₆): δ = 108.3 (C<sub>BT</sub>), 109.2 (C<sub>BT</sub>), 121.0 (C<sub>BT</sub>), 121.6 (C<sub>Ar</sub>), 121.8 (C<sub>BT</sub>), 123.5 (C<sub>Ar</sub>), 124.6 (C<sub>Ar</sub>), 125.1 (C<sub>Ar</sub>), 125.3 (C<sub>Ar</sub>), 126.6 (C<sub>q</sub>), 128.6 (C<sub>q</sub>), 130.8 (C<sub>q</sub>), 134.5 (C<sub>q</sub>), 138.1 (C<sub>q</sub>), 153.3 (C=O) ppm. IR (neat): ν<sub>max</sub> = 3126 (N-H), 3072, 1686 (C=O), 1480, 1389, 1289, 752 (C=C, C-N, C=N) cm<sup>-1</sup>. MS (ESI): *m/z* = 267 [M + H]<sup>+</sup>, 389 [M + Na]<sup>+</sup>, 305 [M + K]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C<sub>15</sub>H<sub>11</sub>N<sub>2</sub>OS 267.05866, found 267.05844. HRMS (ESI): *m/z* [M + Na]<sup>+</sup> calcd. for C<sub>15</sub>H<sub>10</sub>N<sub>2</sub>NaOS 289.04060, found 289.04039. HRMS (ESI): *m/z* [M + K]<sup>+</sup> calcd. for C<sub>15</sub>H<sub>10</sub>KN<sub>2</sub>OS 305.01454, found 305.01432.

### 3.6. Synthesis of Dimethyl 3,3'-Iminobis(benzo[b]thiophene-2-carboxylate) (5)

Compound **1** (100 mg, 0.482 mmol) was dissolved in dry dioxane (2 mL) and treated with compound **2** (230 mg, 0.724 mmol), Cs₂CO₃ (315 mg, 0.965 mmol), CuI (10 mg, 0.050 mmol), and L-proline (6 mg, 0.048 mmol) under argon atmosphere. Reaction mixture was stirred under reflux for 24 h. After the mixture was cooled to room temperature, it was diluted with water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (SiO₂, eluent: petroleum ether/ethyl acetate, 95:5, R_f = 0.26) to provide compound **5** as yellow solid. Yield 32 mg (25%), m.p. 236–237 °C. ¹H-NMR (400 MHz, CDCl₃): δ = 3.90 (s, 6H, 2 × OCH₃), 7.00–7.04 (m, 2H, 2 × 6-H), 7.16 (d, *J* = 8.3 Hz, 2H, 2 × 7-H), 7.34–7.38 (m, 2H, 2 × 5-H), 7.77 (d, *J* = 8.2 Hz, 2H, 2 × 4-H), 9.84 (s, 1H, NH) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ = 52.3 (2 × OCH₃), 110.6 (2 × C<sub>q</sub>), 123.3 (2 × C-4), 124.2 (2 × C-6), 125.0 (2 × C-7), 127.8 (2 × C-5), 133.5 (2 × C<sub>q</sub>), 139.5 (2 × C<sub>q</sub>), 142.5 (2 × C<sub>q</sub>), 164.7 (2 × C=O) ppm. IR (neat): ν<sub>max</sub> = 3323 (N-H), 1677 (C=O), 1574, 1438, 1277, 1228 (C-O), 1166, 1065 (C=C, C-N) cm<sup>-1</sup>. MS (ESI): *m/z* = 398 [M + H]<sup>+</sup>, 420 [M + Na]<sup>+</sup>. HRMS (ESI): *m/z* [M + H]<sup>+</sup> calcd. for C<sub>20</sub>H<sub>16</sub>NO₄S₂ 398.05153, found 398.05196.

## 4. Conclusions

In summary, we demonstrated that the methyl 3-amino-1-benzothiophene-2-carboxylate **1** is a suitable precursor for modern Ullmann-type cross-coupling reactions. We successfully developed an efficient and mild CuI-catalyzed N-arylation reaction of functionalized aminobenzo[b]thiophene with a broad selection of aromatic iodides using L-proline as N,O-donor ligand, providing the coupling products **3a-o** in moderate to good yields. A tetracyclic diazepinone **4** was obtained from the coupling of methyl 3-amino-1-benzothiophene-2-carboxylate **1** with 2-iodoaniline in a one-pot via C-N coupling followed by immediate intramolecular cyclization. The structures of all synthesized compounds were confirmed by detailed NMR spectroscopy and HRMS investigations.

It is noteworthy that L-proline is significantly inexpensive and readily available as a promoter, and it can be easily removed from the crude reaction mixtures by simply washing them with water.
**Supplementary Materials:** The following are available online. Figure S1: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 2, Figure S2: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 2, Figure S3: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3a, Figure S4: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3a, Figure S5: HRMS (ESI) of compound 3a, Figure S6: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3b, Figure S7: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3b, Figure S8: HRMS (ESI) of compound 3b, Figure S9: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3c, Figure S10: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3c, Figure S11: ¹⁹F-NMR (100 MHz, CDCl₃) spectrum of compound 3c, Figure S12: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3d, Figure S13: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3d, Figure S14: ¹⁹F-NMR (100 MHz, CDCl₃) spectrum of compound 3d, Figure S15: HRMS (ESI) of compound 3d, Figure S16: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3e, Figure S17: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3e, Figure S18: ¹⁹F-NMR (100 MHz, CDCl₃) spectrum of compound 3e, Figure S19: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3f, Figure S20: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3f, Figure S21: ¹⁹F-NMR (100 MHz, CDCl₃) spectrum of compound 3f, Figure S22: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3g, Figure S23: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3g, Figure S24: ¹⁹F-NMR (100 MHz, CDCl₃) spectrum of compound 3g, Figure S25: HRMS (ESI) of compound 3g, Figure S26: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3h, Figure S27: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3h, Figure S28: DEPT135 (100 MHz, CDCl₃) spectrum of compound 3h, Figure S29: HRMS (ESI) of compound 3h, Figure S30: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3i, Figure S31: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3i, Figure S32: HRMS (ESI) of compound 3i, Figure S33: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3j, Figure S34: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3j, Figure S35: HRMS (ESI) of compound 3j, Figure S36: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3k, Figure S37: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3k, Figure S38: HRMS (ESI) of compound 3k, Figure S39: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3l, Figure S40: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3l, Figure S41: HRMS (ESI) of compound 3l, Figure S42: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3m, Figure S43: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3m, Figure S44: HRMS (ESI) of compound 3m, Figure S45: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 3n, Figure S46: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 3n, Figure S47: DEPT135 (100 MHz, CDCl₃) spectrum of compound 3n, Figure S48: HRMS (ESI) of compound 3n, Figure S49: ¹H-NMR (400 MHz, DMSO-d₆) spectrum of compound 3o, Figure S50: ¹³C-NMR (100 MHz, DMSO-d₆) spectrum of compound 3o, Figure S51: HRMS (ESI) of compound 3o, Figure S52: ¹H-NMR (400 MHz, DMSO-d₆) spectrum of compound 4, Figure S53: ¹³C-NMR (100 MHz, DMSO-d₆) spectrum of compound 4, Figure S54: DEPT135 (100 MHz, CDCl₃) spectrum of compound 4, Figure S55: COSY spectrum of compound 4, Figure S56: HSQC spectrum of compound 4, Figure S57: HRMS (ESI) of compound 4, Figure S58: ¹H-NMR (400 MHz, CDCl₃) spectrum of compound 5, Figure S59: ¹³C-NMR (100 MHz, CDCl₃) spectrum of compound 5, Figure S60: DEPT135 (100 MHz, CDCl₃) spectrum of compound 5, Figure S61: HRMS (ESI) of compound 5.

**Author Contributions:** Conceptualization, A.T. and A.Š.; Methodology, J.R.; Validation, V.K., I.J. and P.V.; Formal analysis, V.K. and I.J.; Investigation, V.K., I.J. and P.V.; Data curation, J.R.; Writing—original draft preparation, V.K., A.Š., P.R. and P.V.; Writing—review and editing, J.R., P.R. and A.T.; Visualization V.K. and I.J.; Resources, A.T. and A.Š., Supervision, A.T. and A.Š. All authors have read and agreed to the published version of the manuscript.

**Funding:** This project has received funding from the Research Council of Lithuania (LMTLT), agreement No [SDS-2010-022].

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding authors.

**Acknowledgments:** The authors express deep gratitude to Aneta Juknaitė for her valuable contribution.

**Conflicts of Interest:** The authors declare no conflict of interest.

**Sample Availability:** Samples of the compounds are not available from the authors.
References

1. Duc, D.X. Recent Progress in the Synthesis of Benzo[b]Thiophene. *Curr. Org. Chem.* **2020**, *24*, 2256-2271. [CrossRef]

2. Hu, L.; Liu, S.; Xie, G.; Yang, W.; Zhang, B. Bis(benzothiophene-S,S-dioxide) fused small molecules realize solution-processible, high-performance and non-doped blue organic light-emitting diodes. *J. Mater. Chem. C* **2020**, *8*, 1002–1009. [CrossRef]

3. Cho, W.; Kim, H.; Gal, Y.S.; Jin, S.H. Highly reliable benzothiophene-phenylquinoline based heteroleptic Ir(III) complexes; The solution process NIR phosphorescence organic light-emitting diodes. *Mol. Cryst. Liq. Cryst.* **2017**, *654*, 62–72. [CrossRef]

4. Seo, C.; Choi, J.M.; Hong, S.S.; Lee, J.Y.; Seo, S.Y. Synthesis of novel benzothiophene derivative as a host material for blue phosphorescent organic light-emitting diodes. *Dyes Pigm.* **2017**, *136*, 145–149. [CrossRef]

5. Keri, R.S.; Chand, K.; Budagumpi, S.; Somappa, S.B.; Patil, S.A.; Nagaraja, B.M. An Overview of Benzo[b]Thiophene-Based Medicinal Chemistry. *Eur. J. Med. Chem.* **2017**, *138*, 1002–1033. [CrossRef] [PubMed]

6. Romagnoli, R.; Baraldi, P.G.; Salvador, M.K.; Preti, D.; Tabrizi, M.A.; Bassetto, M.; Brancale, A.; Hamel, E.; Castagliuolo, I.; Bortolozzi, R.; et al. Synthesis and Biological Evaluation of 2-(Alkoxycarbonyl)-3-anilinobenzo[b]thiophenes and Thieno[2,3-b]pyridines as New Potent Anticancer Agents. *J. Med. Chem.* **2013**, *56*, 2606–2618. [CrossRef] [PubMed]

7. Ai, T.; Xu, Y.; Qiu, L.; Geraghty, R.J.; Chen, L. Hydroxamic Acids Block Replication of Hepatitis C Virus. *J. Med. Chem.* **2015**, *58*, 785–800. [CrossRef] [PubMed]

8. Fakhri, I.M.I.; Radwan, M.A.A.; El-Batran, S.; El-Salam, O.A.M.E.; El-Shenawy, S.M. Synthesis and pharmacological evaluation of 2-substituted benzo[b]thiophenes as anti-inflammatory and analgesic agents. *Eur. J. Med. Chem.* **2009**, *44*, 1718–1725. [CrossRef]

9. Metwally, M.A.; Khalifa, M.E.; El-Hiti, G.A. Recent trends in the chemistry of aminobenzo[b]thiophenes. *J. Sulfur Chem.* **2010**, *31*, 205–229. [CrossRef]

10. Gouda, M.A.; Eldien, H.F.; Girges, M.M.; Berghot, M.A. Synthesis and Antioxidant Activity of Novel Series of Naphthoquinone Derivatives Attached to Benzothiophene Moiety. *Med. Chem.* **2013**, *3*, 2228–2232. [CrossRef]

11. Fossa, P.; Mosti, L.; Menozzi, G.; Marzano, C.; Baccichetti, F.; Bordin, F. Novel angular furo and thieno-quinolinones: Synthesis and preliminary photobiological studies. *Bioorg. Med. Chem.* **2002**, *10*, 743–751. [CrossRef]

12. Romagnoli, R.; Baraldi, P.G.; Lopez-Cara, C.; Preti, D.; Tabrizi, M.A.; Balzarini, J.; Bassetto, M.; Brancale, A.; Fu, X.H.; Gao, Y.; et al. Concise Synthesis and Biological Evaluation of 2-Aroyl-5-Amino Benzo[b]Thiophene Derivatives As a Novel Class of Potent Antimitotic Agents. *J. Med. Chem.* **2013**, *56*, 9296–9309. [CrossRef]

13. Ferreira, I.C.F.R.; Calhelha, R.C.; Estevinho, L.M.; Queiroz, M.J.R.P. Screening of antimicrobial activity of diarylamines in the 2,3,5-trimethylbenzo[b]thiophene series: A structure-activity evaluation study. *Bioorg. Med. Chem. Lett.* **2004**, *14*, 5831–5833. [CrossRef] [PubMed]

14. Romagnoli, R.; Baraldi, P.G.; Cara, C.L.; Hamel, E.; Basso, G.; Bortolozzi, R.; Viola, G. Synthesis and biological evaluation of 2-(3',4',5'-trimethoxybenzoyl)-3-aryl/arylaminobenzo[b]thiophene derivatives as a novel class of antiproliferative agents. *Eur. J. Med. Chem.* **2010**, *45*, 5781–5791. [CrossRef] [PubMed]

15. Radwan, M.A.A.; Shehab, M.A.; El-Shenawy, S.M. Synthesis and biological evaluation of 5-substituted benzo[b]thiophene derivatives as anti-inflammatory agents. *Monatsh. Chem.* **2009**, *140*, 445–450. [CrossRef]

16. Moreira-Lima, L.; Barreiro, E.J. Bioisosterism: A useful strategy for molecular modification and drug design. *Curr. Med. Chem.* **2005**, *12*, 23–49. [CrossRef]

17. Cimolai, N. The potential and promise of mefenamic acid. *Expert Rev. Clin. Pharmacol.* **2013**, *6*, 289–305. [CrossRef]

18. Osman, S.; Raza, A.; Al-Zaidan, L.; Inchakalody, V.P.; Merhi, M.; Prabhu, K.S.; Abdelaziz, N.; Hydrose, S.; Uddin, S.; Dermime, S. Anti-cancer effects of Tranilast: An update. *Biomed. Pharmacother.* **2021**, *141*, 111844. [CrossRef]

19. Prasher, P.; Sharma, M. Medicinal chemistry of anthranilic acid derivatives: A mini review. *Drug Dev. Res.* **2021**, *1–14*. [CrossRef]

20. Inglis, J.J.; Criado, G.; Andrews, M.; Feldmann, M.; Williams, R.O.; Selley, M.L. The anti-allergic drug, N-(3',4'-dimethoxycinnamoyl) anthranilic acid, exhibits potent anti-inflammatory and analgesic properties in arthritis. *Rheumatology* **2007**, *46*, 1428–1432. [CrossRef]

21. Congiu, C.; Cocco, M.T.; Lilliu, V.; Onnis, V. New Potential Anticancer Agents Based on the Anthranilic Acid Scaffold. Synthesis and Evaluation of Biological Activity. *J. Med. Chem.* **2005**, *48*, 8245–8252. [CrossRef] [PubMed]

22. Hikawa, H.; Mori, Y.; Kikkawa, S.; Azumaya, I. A Radical Pathway for Direct Substitution of Benzyl Alcohols with Water-Soluble Copper Catalyst in Water. *Adv. Synth. Catal.* **2016**, *358*, 765–773. [CrossRef]

23. Bueno, M.A.; Silva, L.R.S.P.; Corrêa, A.G. Microwave-Promoted Synthesis of Novel N-Aryl Anthranilic Acids. *J. Braz. Chem. Soc.* **2008**, *19*, 1264–1269. [CrossRef]

24. Mei, X.; August, A.T.; Wolf, C. Regioselective Copper-Catalyzed Amination of Chlorobenzoic Acids: Synthesis and Solid-State Structures of N-Aryl Anthranilic Acid Derivatives. *J. Org. Chem.* **2006**, *71*, 142–149. [CrossRef] [PubMed]

25. Singh, P.; Kumar, A.; Sharma, A.; Kaur, G. Identification of amino acid appended acridines as potential leads to anti-cancer drugs. *Bioorg. Med. Chem. Lett.* **2015**, *25*, 3854–3858. [CrossRef] [PubMed]

26. Kaur, M.; Singh, P. Targeting Tyrosine kinase: Development of acridone-pyrrole-oxindole hybrids against human breast cancer. *Bioorg. Med. Chem. Lett.* **2019**, *29*, 32–35. [CrossRef]

27. Velingkar, V.S.; Dandekar, V.D. Microwave-Assisted Synthesis and Evaluation of Substituted Aryl Propyl Acridone-4-Carboxamides as Potential Chemosensitizing Agents for Cancer. *Lett. Drug Des. Discov.* **2011**, *8*, 268–275. [CrossRef]

28. Sambiagio, C.; Marsden, S.P.; Blacker, A.J.; McGowan, P.C. Copper catalysed Ullmann type chemistry: From mechanistic aspects to modern development. *Chem. Soc. Rev.* **2014**, *43*, 3525–3550. [CrossRef]
29. Kiyomori, A.; Marcoux, J.F.; Buchwald, S.L. An efficient copper-catalyzed coupling of aryl halides with imidazoles. *Tetrahedron Lett.* **1999**, *40*, 2657–2660. [CrossRef]

30. Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S.L. A General and Efficient Copper Catalyst for the Amidation of Aryl Halides and the N-Arylation of Nitrogen Heterocycles. *J. Am. Chem. Soc.* **2001**, *123*, 7727–7729. [CrossRef]

31. Wolter, M.; Klapars, A.; Buchwald, S.L. Synthesis of N-Aryl Hydrazides by Copper-Catalyzed Coupling of Hydrazides with Aryl Iodides. *Org. Lett.* **2001**, *3*, 3803–3805. [CrossRef]

32. Gujadhur, R.K.; Bates, C.G.; Venkataraman, D. Formation of Aryl-Nitrogen, Aryl-Oxygen, and Aryl-Carbon Bonds Using Well-Defined Copper(I)-Based Catalysts. *Org. Lett.* **2001**, *3*, 4315–4317. [CrossRef]

33. Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. Accelerating Effect Induced by the Structure of α-Amino Acid in the Copper-Catalyzed Coupling Reaction of Aryl Halides with α-Amino Acids. Synthesis of Benzolactam-V8. *J. Am. Chem. Soc.* **1998**, *120*, 12459–12467. [CrossRef]

34. Ma, D.; Xia, C. CuI-Catalyzed Coupling Reaction of β-Amino Acids or Esters with Aryl Halides at Temperature Lower than That Employed in the Normal Ullmann Reaction. Facile Synthesis of SB-214857. *Org. Lett.* **2001**, *3*, 2583–2586. [CrossRef]

35. Yoo, J.M.; Dao, P.D.Q.; Cho, C.S. Copper-Catalyzed C-N Coupling and Cyclization of 2-(2-Bromophenyl)-1H-Indoles with Primary Amides Leading to Indolo[1,2-c]Quinazolines. *Bull. Korean Chem. Soc.* **2018**, *39*, 1105–1108. [CrossRef]

36. Ding, Z.; Nie, N.; Chen, T.; Meng, L.; Wang, G.; Chen, Z.; Hu, J. L-Proline N-oxide dihydrazides as an efficient ligand for cross-coupling reactions of aryl iodides and bromides with amines and phenols. *Tetrahedron* **2021**, *79*, 131826. [CrossRef]

37. Xu, L.; Peng, Y.; Pan, Q.; Jiang, Y.; Ma, D. Assembly of Substituted 3-Aminoindazoles from 2-Bromobenzonitrile via a CuBr-Catalyzed Coupling/Condensation Cascade Process. *J. Org. Chem.* **2013**, *78*, 3400–3404. [CrossRef]

38. Gaber, H.M.; Bagley, M.C. Regioselective synthesis and biological evaluation of some novel thiophene-containing heterocyclic scaffolds as potential chemotherapeutic agents. *Eur. J. Chem.* **2011**, *2*, 214–222. [CrossRef]

39. Queiroz, M.J.R.P.; Begouin, A.; Ferreira, I.C.F.R.; Kirsch, G.; Calhelha, R.C.; Barbosa, S.; Estevinho, L.M. Palladium-Catalysed Amination of Electron-Deficient or Relatively Electron-Rich Benzo[b]Thienyl Bromides—Preliminary Studies of Antimicrobial Activity and SARs. *Eur. J. Org. Chem.* **2004**, *17*, 3679–3685. [CrossRef]

40. Lamanna, G.; Menichetti, S. 2,3-Disubstituted Benzo[b] thiophenes from Diarylalkynes via Electrophilic Addition-Cyclization and Palladium-Catalyzed Cross-Coupling. *Adv. Synth. Catal.* **2007**, *349*, 2188–2194. [CrossRef]

41. Ferreira, I.C.F.R.; Queiroz, M.J.R.P.; Kirsch, G. Palladium-catalyzed amination and cyclization to heteroannellated indoles and carbazoles. *Tetrahedron* **2003**, *59*, 3737–3743. [CrossRef]

42. Salman, G.A.; Hussain, M.; Iaroshenko, V.; Villinger, A.; Langer, P. Thienopyrroles and Benzothienoquinolines via Palladium-Catalyzed Domino Reactions. *Synfacts* **2011**, *5*, 0475. [CrossRef]

43. Queiroz, M.J.R.P.; Calhelha, R.C.; Kirsch, G. Reactivity of several deactivated 3-aminobenzo[b]thiophenes in the Buchwald-Hartwig C-N coupling. Scope and limitations. *Tetrahedron* **2007**, *63*, 13000–13005. [CrossRef]

44. Calhelha, R.C.; Queiroz, M.J.R.P. Synthesis of new thieno[3,2-b]pyridine derivatives by palladium-catalyzed couplings and intramolecular cyclizations. *Tetrahedron Lett.* **2010**, *51*, 281–283. [CrossRef]

45. Egorova, K.S.; Ananikov, V.P. Toxicity of Metal Compounds: Knowledge and Myths. *Organometallics* **2017**, *36*, 4071–4090. [CrossRef]

46. Chen, Y.J.; Chen, H.H. 1,1,1-Tris(Hydroxymethyl)Ethane as a New, Efficient, and Versatile Tripod Ligand for Copper-Catalyzed Cross-Coupling Reactions of Aryl Iodides with Amides, Thiols, and Phenols. *Org. Lett.* **2006**, *8*, 5609–5612. [CrossRef]

47. Senra, J.D.; Aguiar, L.C.S.; Simas, A.B.C. Recent Progress in Transition-Metal-Catalyzed C-N Cross-Couplings: Emerging Approaches towards Sustainability. *Curr. Org. Synth.* **2011**, *8*, 53–78. [CrossRef]

48. Jiao, J.; Zhang, X.R.; Chang, N.H.; Wang, J.; Wei, J.F.; Shi, X.Y.; Chen, Z.G. A Facile and Practical Copper Powder-Catalyzed, Organic Solvent-and Ligand-Free Ullmann Amination of Aryl Halides. *J. Org. Chem.* **2011**, *76*, 1180–1183. [CrossRef]

49. Kriščiūnienė, V.; Matulevičiūtė, G.; Paliulis, O.; Rollin, P. Šačkus, A. Conversion of 2-Thioxo-2,3-Dihydroquinazolin-4(1H)-Ones to N(3)-Unsubstituted 2-(Het)Arylquinazolin-4(3H)-Ones by Copper-Mediated Pd-Catalysed Cross-Coupling Reactions. *Heterocycles* **2016**, *93*, 150–163. [CrossRef]

50. Sun, J.; Yoo, S.E.; Yi, K.Y.; Kim, N.; Kim, E.; Jung, E.; Lee, Y.S.; Suh-Kim, H. Benzofuran and Benzothiophene Derivatives Substituted with Amide Process for the Preparation Thereof, and Pharmaceutical Compositions Containing the Same. WO Patent WO2009/048274A2, 16 April 2009.

51. Liu, Y.; Bai, Y.; Zhang, J.; Li, Y.; Jiao, J.; Qi, X. Optimization of the Conditions for Copper-Mediated N-Arylation of Heteroarylamines. *Eur. J. Org. Chem.* **2007**, *36*, 6084–6088. [CrossRef]

52. Liu, Z.; Chen, Y. Efficient synthesis of 2,3-dihydro-1,4-benzoxazines via intramolecular copper-catalyzed O-arylation. *Tetrahedron Lett.* **2009**, *50*, 3790–3793. [CrossRef]

53. Zhang, H.; Cai, Q.; Ma, D. Amino Acid Promoted CuI-Catalyzed C-N Bond Formation between Aryl Halides and Amines or N-Containing Heterocycles. *J. Org. Chem.* **2005**, *70*, 5164–5173. [CrossRef]

54. Rejňák, M.; Klíma, J.; Svoboda, J.; Ludvík, J. Synthesis and Electrochemical Reduction of Methyl 3-Halo-1-Benzothiophene-2-Carboxylates. *Collect. Czech. Chem. Commun.* **2004**, *69*, 242–260. [CrossRef]

55. Lindley, J. Tetrahedron report number 163: Copper assisted nucleophilic substitution of aryl halogen. *Tetrahedron* **1984**, *40*, 1433–1456. [CrossRef]
56. Jones, G.O.; Liu, P.; Houk, K.N.; Buchwald, S.L. Computational Explorations of Mechanisms and Ligand-Directed Selectivities of Copper-Catalyzed Ullmann-Type Reactions. *J. Am. Chem. Soc.* **2010**, *132*, 6205–6213. [CrossRef]

57. Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. A Versatile and Efficient Ligand for Copper-Catalyzed Formation of C-N, C-O, and P-C Bonds: Pyrrolidine-2-Phosphonic Acid Phenyl Monoester. *Chem. Eur. J.* **2006**, *12*, 3636–3646. [CrossRef]

58. Kappe, C.O. Controlled Microwave Heating in Modern Organic Synthesis. *Angew. Chem. Int. Ed.* **2004**, *43*, 6250–6284. [CrossRef]

59. Hu, Y.L.; Wanga, P.C.; Chen, T.; Lu, M. Facile and Efficient Amination of Organic Halides Catalyzed by Copper Sulfate in PEG1000-DIL/Methylcyclohexane Temperature-Dependent Biphasic System. *J. Chin. Chem. Soc.* **2010**, *57*, 604–611. [CrossRef]

60. Hoshino, J.; Park, E.J.; Kondratyuk, T.P.; Marler, L.; Pezzuto, J.M.; Van Breemen, R.B.; Mo, S.; Li, Y.; Cushman, M. Selective Synthesis and Biological Evaluation of Sulfate-Conjugated Resveratrol Metabolites. *J. Med. Chem.* **2010**, *53*, 5033–5043. [CrossRef]

61. Tsvelikhovsky, D.; Buchwald, S.L. Concise Palladium-Catalyzed Synthesis of Dibenzodiazepines and Structural Analogues. *J. Am. Chem. Soc.* **2011**, *133*, 14228–14231. [CrossRef]

62. Al-Tel, T.H.; Al-Qawasmeh, R.A.; Schmidt, M.F.; Al-Aboudi, A.; Rao, S.N.; Sabri, S.S.; Voelter, W. Rational Design and Synthesis of Potent Dibenzazepine Motifs as β-Secretase Inhibitors. *J. Med. Chem.* **2009**, *52*, 6484–6488. [CrossRef] [PubMed]

63. Diao, X.; Xu, L.; Zhu, W.; Jiang, Y.; Wang, H.; Guo, Y.; Ma, D. The N-Aryl Aminocarbonyl Ortho-Substituent Effect in Cu-Catalyzed Aryl Amination and Its Application in the Synthesis of 5-Substituted 11-Oxo-Dibenzodiazepines. *J. Am. Chem. Soc.* **2011**, *13*, 6422–6425. [CrossRef]

64. Hamilton, H.W.; Nishiguchi, G.; Hagen, S.E.; Domagala, J.D.; Weber, P.C.; Gracheck, S.; Boulware, S.L.; Nordby, E.C.; Cho, H.; Nakamura, T.; et al. Novel benzthiodiazepinones as antiherpetic agents: SAR improvement of therapeutic index by alterations of the seven-membered ring. *Bioorg. Med. Chem. Lett.* **2002**, *12*, 2981–2983. [CrossRef]

65. Zhang, S.; Zhang, D.; Liebeskind, L.S. Ambient Temperature, Ullmann-like Reductive Coupling of Aryl, Heteroaryl, and Alkenyl Halides. *J. Org. Chem.* **1997**, *62*, 2312–2313. [CrossRef]

66. Wang, M.; Lin, Z. Stille Cross-Coupling Reactions of Alkenylstannanes with Alkenyl Iodides Mediated by Copper(I) Thiophene-2-Carboxylate: A Density Functional Study. *Organometallics* **2010**, *29*, 3077–3084. [CrossRef]

67. Beck, J.R. A Direct Synthesis of Benzo[b]Thiophene-2-Carboxylate Esters Involving Nitro Displacement. *J. Org. Chem.* **1972**, *37*, 3224–3226. [CrossRef]