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Article

“One-Pot” CuCl2-Mediated Condensation/C–S Bond Coupling Reactions to Synthesize Dibenzothiazepines by Bi-Functional-Reagent N, N′-Dimethylethane-1,2-Diamine

by
Dehe Wang
1,†,
Qichao Lu
1,†,
Zhanjun Li
1,
Chen Fang
2,
Ran Liu
1,
Bingchuan Yang
1,3,4,* and
Guodong Shen
1,5,*
1
School of Chemistry and Chemical Engineering, Liaocheng University, 1 Hunan Avenue, Liaocheng 252000, China
2
Zhejiang Heze Pharmaceutical Technology, 1 Street, Qiantang New District, Hangzhou 310018, China
3
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
4
The Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA
5
School of Chemistry and Chemical Engineering, Jinan University, 106 Jiwei Road, Jinan 250022, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2022, 27(21), 7392; https://doi.org/10.3390/molecules27217392
Submission received: 19 September 2022 / Revised: 13 October 2022 / Accepted: 17 October 2022 / Published: 31 October 2022
(This article belongs to the Special Issue Green Approaches in Organic Chemistry)
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Abstract

:
The efficient “One-pot” CuCl2-catalyzed C–S bond coupling reactions were developed for the synthesis of dibenzo[b,f][1,4]thiazepines and 11-methy-ldibenzo[b,f][1,4]thiazepines via 2-iodobenzaldehydes/2-iodoacetophenones with 2-aminobenzenethiols/2,2′-disulfanediyldianilines by using bifunctional-reagent N, N′-dimethylethane-1,2-diamine (DMEDA), which worked as ligand and reductant. The reactions were compatible with a range of substrates to give the corresponding products in moderate to excellent yields.

1. Introduction

Dibenzothiazepine derivatives are a class of molecules with important biological and pharmaceutical activities [1,2,3,4]. For example, Clotiapine (A) has good anti-hallucination, the delusion and the anti-excited restlessness function [5]. Quetiapine fumarate (B) is effective for both positive symptoms and negative symptoms of schizophrenia, it can also reduce the emotional symptoms associated with schizophrenia, such as depression, anxiety and cognitive deficits [6,7,8]. The 6-Sulfamoyl-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxylic acid (C) is a structural analogue of nitroxazepine with high activity, indicating its potential medicinal value (Figure 1) [9].
Due to its wide applications, it is meaningful to find some simple, efficient and practical methods for the synthesis of dibenzothiazepines. In past studies, several typical methods have been developed, including the reactions of 2-halobenzaldehyde and 2-aminobenzenethiols or 2,2′-disulfanediyldianiline [10,11,12,13,14], the intramolecular cyclization reactions [9,15], the intramolecular rearrangement reactions [16], and some other methods (Scheme 1) [17]. The previous reports have mainly focused on the classic coupling reactions of 2-halogenated benzaldehyde with 2-aminobenzenethiols or 2,2′-disulfanediyldianiline because it is direct and effective. However, the classic copper-catalyzed coupling reactions for the synthesis of dibenzothiazepine are complicated, often required the copper salt, ligand, base and solvent and the substrate application scopes were limited [18]. For example, in 2009, Reiko Yanada et al. employed a Pd(OAc)2-catalyzed one-pot reaction to synthesize dibenzo[b,f][1,4]thiazepines by microwave-accelerated tandem process of 2-brmobenzaldehyde and 2-aminobenzenethiols [19]. In 2015, Yie-jia Cherng et al. also reported the microwave-assisted strategy to assemble dibenzo[b,f][1,4]thiazepines [10]. In the same year, Anuj Sharma et al. utilized a standard base-catalyzed condensation of amines with aldehydes to afford dibenzo[b,f][1,4] thiazepines [11]. Recently, Yun Luo and Jiaxi Xu et al. synthesized these heterocyclic molecules using K2CO3 and ethane-1,2-diol. [20] Copper-catalyzed coupling reactions is a powerful tool for the construction of C–X (X = S, N, O, etc.) bonds and can be applied in the efficient synthesis of heterocyclic compounds in organic synthesis [21,22,23,24,25,26,27]. Simplifying the copper-catalyzed reaction conditions is also an irreplaceable advantage for the application of the reaction. Our group has been working on the copper-catalyzed coupling reactions to synthesize heterocyclic compounds, in continuation of our works to modify the copper-catalyzed cross-coupling reactions [28,29]. Here, we reported an “One-pot” CuCl2-catalyzed C–S bond coupling reactions for the synthesis of dibenzo[b,f][1,4]thiazepines and 11-methyldibenzo[b,f][1,4]thiazepines via 2-iodobenzaldehydes/2-iodoacetophenones with 2-aminobenzenethiols/2,2′-disulfanediyldianilines by using bi-functional-reagent DMEDA. Compared to the previous reports of synthesizing dibenzothiazepines in entry 1, our research used DMEDA in small quantities as a bifunctional reagent, which worked as ligand and reductant; the substrate scope is wide (the reaction substrates 2-iodobenzaldehydes/2-iodoacetophenones and 2-aminobenzenethiols/2,2′-disulfanediyldianilines could cross-react with each other) and the reaction conditions were simplified, making the reaction conditions more suitable for large-scale production.

2. Results

First, 2-iodobenzaldehyde (1a) and 2,2′-Disulfanediyldianiline (1b) were selected to optimize the reaction conditions (Table 1). The reaction was conducted with CuCl2 (15 mol%), 1a (0.3 mmol), 1b (0.15 mmol), Cs2CO3 (0.6 mmol) and 4 Å molecular sieve (25 mg) in DMEDA (0.50 mL) at 110 °C under N2 atmosphere for 24 h, the product 1c was produced in 73% (Table 1, entry 1). When we decreased the amount of DMEDA, 0.25 mL showed the best results (Table 1, entries 1–3). There was a significant decrease without inorganic base Cs2CO3 (Table 1, entry 4). When K3PO4 (0.6 mmol) was used for the reaction, 1c was improved in 82% yield (Table 1, entries 5–6). Then, the reaction temperature was screened, it was found that higher reaction temperature did not change the reaction yield; 110 °C was the best choice (Table 1, entries 7–8). Finally, other copper salts, such as Cu(OAc)2, CuSO4·5H2O, CuI, were surveyed under the conditions, the yields of 1c were not increased (Table 1, entries 9–11). Without the 4 Å molecular sieves, the reaction yield was also reduced (Table 1, entry 12). A gram-scale reaction was also conducted, the yield of 1c was the same as entry 5 (Table 1, entry 13). From the above results we could conclude that the bi-functional reagent DMEDA was necessary for the reaction.
With the optimized reaction conditions in hand, the reaction scope was investigated (Table 2). Our initial studies were focused on the reaction of 2-iodobenzaldehydes a, with 2,2′-disulfanediyldianilines b, and the products c could be isolated in moderate-to-good yields. The 2-Bromobenzaldehyde and 2-chlorobenzaldehyde were used to react with 1b, and the yields decreased. When 2,2′-disulfanediyldianilines bearing electron-donating and electron-withdrawing groups were used to react with 1a, the products were obtained in good yields (Table 2, entries 2–4). Substituted 2-iodobenzaldehydes were also used to react with 1b, and the reactions yields were basically kept in good yields (Table 2, entries 5–9). Some cross-reactions were tested, and moderate-to-excellent yields were obtained. (Table 2, entries 10–12). The above results indicated that the reaction yields of 2-iodobenzaldehydes a with 2,2′-disulfanediyldianilines b were not influenced significantly by the electronic effect and steric effect. Subsequently, we examined the reaction of 2-iodobenzaldehydes a with 2-aminobenzenethiols b′; the reactions proceeded smoothly, and the reaction yields were obtained in moderate-to-good yields (Table 2, entries 16–22).
The scope of 2′-iodoacetophenones d and 2,2′-disulfanediyldianilines b/2-aminobenzenethiol 1b′ was also investigated (Table 3). The 2′-Iodoacetophenone 1d and 2,2′-disulfanediyldianiline 1b were used under the optimal conditions, and 75% yield of 1e was isolated (Table 3, entry 1). We used 2′-iodoacetophenones 1d and substituted 2,2′-disulfanediyldianilines 2b–5b to do the reaction, and the products e were isolated in moderate-to-good yields (Table 3, entries 2–5). Then, 2,2′-disulfanediyldianiline 1b was replaced by 2-aminobenzenethiols 1b′ and reacted with 2′-iodoacetophenone 1d to obtain the desired product in 95% yield (Table 3, entry 6). Finally, (2-iodophenyl)(phenyl)methanone 3d was used, and it could not react with 1b to generate the product 6e (Table 3, entry 7).
Finally, a possible mechanism was proposed for the reaction based on the experimental results (Scheme 2). Firstly, CuCl2 coordinates with DMEDA and is reduced to generate the Cu(I) complex (A). At the same time, the starting material 1a could react with 1b to form the intermediate (B) through the intermolecular condensation. The intermediate (C) could be generated via the oxidative addition of (A) and (B). Then, (C) was converted to the intermediate (D), and DMEDA might act as the reductant. For the substrate 1a and 1b′, the intermediate (D) is also generated during the reaction process. After the transmetallation/reductive elimination reaction, the product 1c could be formed. From the possible mechanism, we found that the bifunctional reagent DMEDA worked as ligand and reductant.

3. Experimental Section

3.1. General

1H NMR and 13C NMR spectra were recorded 500 MHz (Bruker, Kanton Zug, Switzerland) instrument; CDCl3 (δH = 7.26 ppm, δC = 77.16 ppm) was used as the internal standard. Chemical shifts were reported in ppm. Multiplicity was recorded: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), m (multiplet). The direct used reagents and solvents were pure analytical grade and purchased from commercial sources, if not stated otherwise. The starting substrates were synthesized according to the known literature. Column chromatography was hand packed with silica gel (200–300 mesh). The melting points were uncorrected. High-resolution mass spectra (HRMS) were recorded on a Q-TOF Premier (ESI, Waters, Milford, CT, USA). The silica gel plates (GF254, 0.2 mm thick) were used for TLC testing.

3.2. General Procedure for the Synthesis of Dibenzo[b,f][1,4]thiazepines (1c–12c) Catalyzed by CuCl2 in DMEDA

An oven-dried 25 mL flask equipped with a rubber stopper was charged with a magnetic stir bar, CuCl2 (15 mol%, 0.045 mmol), 2-iodobenzaldehyde a (0.3 mmol), 2,2′-disulfanediyldianilines b (0.15 mmol)/ 2-aminobenzenethiols b′ (0.3 mmol), K3PO4 (0.6 mmol), 4 Å molecular sieve (25 mg) and DMEDA (0.5 mL). The reaction mixture was stirred at 110 °C for 24 h. The reaction was monitored by TLC. When benzaldehydes a was consumed, the reaction was stopped and cooled to room temperature, the crude reaction mixture was diluted with 20 mL water, extracted with ethyl acetate (20 mL × 3), combined with organic phase, then washed organic phase with brine (20 mL), dried organic phase with anhydrous Mg2SO4. The organic phase was concentrated and the residue was purified directly by column chromatography on silica gel using petrol/EtOAc as eluent to give the pure products c.

3.3. General Procedure for the Synthesis of 11-Methyldibenzo[b,f][1,4]thiazepines (1e–5e) Catalyzed by CuCl2 in DMEDA

An oven-dried 25 mL flask equipped with a rubber stopper was charged with a magnetic stir bar, CuCl2 (15 mol%, 0.045 mmol), 1-(2-iodophenyl)ethan-1-ones d (0.3 mmol), 2,2′-disulfanediyldianilines b (0.15 mmol)/2-aminobenzenethiols b′ (0.3 mmol), K3PO4 (0.6 mmol), 4 Å molecular sieve (25 mg) and DMEDA (0.5 mL). The reaction mixture was stirred at 110 °C for 24 h. The reaction was monitored by TLC. When benzaldehydes d was consumed, the reaction was stopped and cooled to room temperature, the crude reaction mixture was diluted with 20 mL water, extracted with ethyl acetate (20 mL × 3), combined with organic phase, then washed organic phase with brine (20 mL), dried organic phase with anhydrous Mg2SO4. The organic phase was concentrated and the residue was purified directly by column chromatography on silica gel using petrol/EtOAc as eluent to give the pure products e. For the NMR spectrum of compounds see the Supplementary Materials.

3.4. Characterization Data

The dibenzo[b,f][1,4]thiazepine 1c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp: 126–128 °C (Lit: m.p. 124 °C) [30]; 52.0 mg; 82% yield (1a and 1b were used); 51.3 mg; 81% yield (1a and 1b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.90 (s, 1H), 7.44–7.30 (m, 7H), 7.19–7.15 (m, 1H). 13C NMR (125 MHz, CDCl3/TMS): δ 162.4, 148.7, 139.5, 137.4, 132.9, 131.8, 131.6, 129.5, 129.4, 129.0, 128.4, 127.3, 127.1.
The 7-methyldibenzo[b,f][1,4]thiazepine 2c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp: 115–117 °C; 54.0 mg; 80% yield (1a and 2b were used); 54.0 mg; 80% yield (1a and 2b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.85 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.39–7.33 (m, 3H), 7.24–7.20 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 161.8, 146.3, 139.3, 137.6, 137.5, 133.2, 131.7, 131.5, 130.2, 129.5, 128.5, 128.3, 127.0, 20.7.
The 7-methoxydibenzo[b,f][1,4]thiazepine 3c (Flash column chromatography on silica gel using petrol/EtOAc (5:1, v:v) as eluent). Yellow solid; mp: 101–102 °C; 62.2 mg; 86% yield (1a and 3b were used); 62.2 mg; 86% yield (1a and 3b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.80 (s, 1H), 7.43–7.34 (m, 4H), 7.24 (s 1H), 6.95 (d, J = 3.0 Hz, 1H), 6.88 (dd, J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 160.8, 159.1, 142.4, 138.6, 137.5, 131.7, 131.5, 129.6, 129.4, 128.5, 128.4, 117.0, 115.6, 55.7. HRMS (ESI): m/z calcd for C14H12NOS [M + H]+: 242.0634, found: 242.0641.
The 7-chlorodibenzo[b,f][1,4]thiazepine 4c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp: 75–76 °C; 65.6 mg; 89% yield (1a and 4b were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.87 (s, 1H), 7.44–7.36 (m, 5H), 7.28 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3/TMS): δ 162.7, 147.2, 138.6, 137.2, 132.8, 132.3, 131.90, 131.88, 130.3, 129.6, 129.5, 128.7, 128.0.
The 3-methyldibenzo[b,f][1,4]thiazepine 5c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent) Yellow solid; mp: 93–94 °C; 56.7 mg; 84% yield (2a and 1b were used); 52.8 mg; 78% yield (2a and 1b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.86 (s, 1H), 7.42–7.40 (m, 1H), 7.33–7.28 (m, 3H), 7.20–7.14 (m, 3H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 162.5, 148.7, 138.5, 137.2, 136.2, 132.8, 132.4, 131.6, 130.1, 129.29, 129.28, 127.2, 127.0, 21.1.
The 2-methyldibenzo[b,f][1,4]thiazepine 6c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp: 92–94 °C; 49.3 mg; 73% yield (3a and 1b were used); 56.1 mg; 83% yield (3a and 1b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.86 (s, 1H), 7.42–7.40 (m, 1H), 7.33–7.28 (m, 3H), 7.20–7.14 (m, 3H), 2.34 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 162.5, 148.8, 138.5, 137.2, 136.3, 132.8, 132.4, 131.6, 130.1, 129.33, 129.28, 127.2, 127.1, 21.1.
The 3-chlorodibenzo[b,f][1,4]thiazepine 7c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). White solid; mp: 107–109 °C; 63.3 mg; 86% yield (4a and 1b were used); 64.7 mg; 88% yield (4a and 1b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.84 (s, 1H), 7.45 (d, J = 1.0 Hz 1H), 7.41 (dd, J1 = 7.5 Hz, J2 = 1.0 Hz, 1H), 7.37–7.29 (m, 4H), 7.19 (td, J1 = 7.0 Hz, J2 = 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3/TMS): δ 161.2, 148.6, 141.1, 137.8, 135.7, 133.0, 131.6, 130.5, 129.7, 128.6, 128.2, 127.6, 127.2.
The 3-fluorodibenzo[b,f][1,4]thiazepine 8c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp: 54–56 °C; 53.5 mg; 78% yield (5a and 1b were used); 61.1 mg; 89% yield (5a and 1b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.84 (s, 1H), 7.42–7.30 (m, 4H), 7.22–7.15 (m, 2H), 7.05 (td, J1 = 8.5 Hz, J2 = 3.0 Hz, 1H). 13C NMR (125 MHz, CDCl3/TMS): δ 164.4 (d, J = 253.6 Hz), 161.2, 148.6, 141.8 (d, J = 8.3 Hz), 133.7 (d, J = 3.4 Hz), 133.0, 131.4 (d, J = 9.3 Hz), 129.7, 128.2, 127.5, 127.1, 118.8 (d, J = 22.3 Hz), 115.6 (d, J = 21.8 Hz).
The 2-chlorodibenzo[b,f][1,4]thiazepine 9c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp: 111–112 °C; 61.2 mg; 83% yield (6a and 1b were used); 58.9 mg; 80% yield (6a and 1b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.82 (s, 1H), 7.41 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 7.37–7.29 (m, 5H), 7.18 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3/TMS): δ 160.7, 148.5, 138.5, 138.0, 134.7, 133.0, 132.9, 131.5, 129.7, 129.3, 128.5, 127.6, 127.1.
The 7-methoxy-3-methyldibenzo[b,f][1,4]thiazepine 10c (Flash column chromatography on silica gel using petrol/EtOAc (5:1, v:v) as eluent). Yellow solid; mp: 128–129 °C; 56.8 mg; 74% yield (2a and 3b were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.76 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 7.0 Hz, 2H), 6.94 (d, J = 3.0 Hz, 1H), 6.87 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 3.78 (s, 3H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 160.9, 159.0, 142.5, 138.6, 137.3, 135.2, 132.3, 131.6, 130.1, 129.7, 128.4, 116.9, 115.5, 55.7, 21.1. HRMS (ESI): m/z calcd for C15H14NOS [M + H]+: 256.0791, found: 256.0794.
The 2-chlorodibenzo[b,f][1,4]thiazepine 11c (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Gray solid; mp: 110–111 °C; 65.4 mg; 84% yield (6a and 2b were used); 60.8 mg; 78% yield (6a and 2b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.77 (s, 1H), 7.36–7.32 (m, 3H), 7.24–7.19 (m, 2H), 7.16–7.13 (m, 1H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 160.1, 146.1, 138.5, 137.9, 137.8, 134.6, 133.2, 132.9, 131.4, 130.5, 129.3, 128.0, 127.1, 20.7. HRMS (ESI): m/z calcd for C14H11ClNS [M + H]+: 260.0295, found: 260.0284.
The 2-chloro-7-methoxydibenzo[b,f][1,4]thiazepine 12c (Flash column chromatography on silica gel using petrol/EtOAc (5:1, v:v) as eluent). Yellow solid; mp: 111–112 °C; 62.0 mg; 75% yield (6a and 3b were used); 66.1 mg; 80% yield (6a and 3b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 8.71 (s, 1H), 7.34 (s, 3H), 7.25 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.90 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 159.3, 159.0, 142.2, 138.6, 137.0, 134.8, 133.0, 131.4, 129.3, 128.9, 128.6, 117.1, 115.8, 55.8. HRMS (ESI): m/z calcd for C14H11ClNOS [M + H]+: 276.0244, found: 276.0235.
The 11-methyldibenzo[b,f][1,4]thiazepine 1e (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp:75–76 °C (Lit: m.p. 76 °C) [31]; 50.0 mg; 75% yield (1d and 1b were used); 64.2 mg; 95% yield (1d and 1b′ were used); 1H NMR (500 MHz, CDCl3/TMS): δ 7.46–7.45 (m, 1H), 7.42–7.40 (m, 2H), 7.34–7.30 (m, 2H), 7.28–7.24 (m, 1H), 7.18 (dd, J1 = 1.3 Hz, J2 = 8.0 Hz, 1H), 7.05 (td, J1 = 1.3 Hz, J2 = 7.5 Hz, 1H), 2.66 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 169.9, 148.8, 140.0, 139.5, 132.5, 132.0, 130.8, 129.2, 128.9, 128.5, 128.0, 125.6, 125.4, 29.6.
The 7,11-dimethyldibenzo[b,f][1,4]thiazepine 2e (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent) Yellow solid; mp: 115–117 °C; 53.1 mg; 74% yield (1d and 2b were used); 1H NMR (500 MHz, CDCl3/TMS): δ 7.46–7.43 (m, 1H), 7.42–7.38 (m, 1H), 7.33–7.29 (m, 2H), 7.23 (s, 1H), 7.09–7.05 (m, 2H), 2.65 (s, 3H), 2.27 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 169.3, 146.4, 139.9, 139.5, 135.6, 132.8, 131.9, 130.7, 130.1, 128.40, 128.39, 128.0, 125.3, 29.6, 20.7.
The 7-methoxy-11-methyldibenzo[b,f][1,4]thiazepine 3e (Flash column chromatography on silica gel using petrol/EtOAc (5:1, v:v) as eluent). Yellow solid; mp: 130–132 °C; 52.9 mg; 69% yield (1d and 3b were used); 1H NMR (500 MHz, CDCl3/TMS): δ 7.46–7.43 (m, 1H), 7.42–7.39 (m, 1H), 7.34–7.30 (m, 2H), 7.12 (d, J = 8.9Hz, 1H), 6.96 (d, J = 2.9 Hz, 1H), 6.83 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H), 3.76 (s, 3H), 2.64 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 168.5, 157.6, 142.5, 139.6, 139.4, 132.0, 130.7, 129.2, 128.5, 128.0, 126.6, 116.6, 115.7, 55.7, 29.5. HRMS (ESI): m/z calcd for C15H14NOS [M + H]+: 256.0791, found: 256.0794.
The 7-chloro-11-methyldibenzo[b,f][1,4]thiazepine 4e (Flash column chromatography on silica gel using petrol/EtOAc (6:1, v:v) as eluent). Yellow solid; mp: 115–117 °C; 47.5 mg; 61% yield (1d and 4b were used); 1H NMR (500 MHz, CDCl3/TMS): δ 7.47–7.44 (m, 1H), 7.43–7.39 (m, 2H), 7.36–7.33 (m, 2H), 7.21 (dd, J1 = 2.3 Hz, J2 = 8.6 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 2.65 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 170.4, 147.4, 139.3, 139.2, 132.2, 131.9, 131.0, 130.8, 130.1, 129.3, 128.8, 128.0, 126.4, 29.6. HRMS (ESI): m/z calcd for C14H11ClNS [M + H]+: 260.0295, found: 260.0275.
The 2,3,9-trimethoxy-11-methyldibenzo[b,f][1,4]thiazepine 5e (Flash column chromatography on silica gel using petrol/EtOAc (3:1, v:v) as eluent). Yellow solid; mp: 52–54 °C; 72.9 mg; 77% yield (2d and 5b were used); 1H NMR (500 MHz, CDCl3/TMS): δ 7.10 (d, J = 8.8 Hz, 1H), 6.95–6.90 (m, 2H), 6.86 (s, 1H), 6.83 (dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H), 3.87 (d, J = 10.5 Hz, 6H), 3.76 (s, 3H), 2.62 (s, 3H). 13C NMR (125 MHz, CDCl3/TMS): δ 167.9, 157.5, 150.9, 149.3, 142.5, 132.0, 130.9, 129.7, 126.5, 116.4, 115.6, 114.3, 110.7, 56.3, 56.2, 55.7, 29.3. HRMS (ESI): m/z calcd for C17H18NO3S [M + H]+: 316.1002, found: 316.1012.

4. Conclusions

In summary, this paper reported a ‘one-pot’ CuCl2 catalyzed synthesis of dibenzo[b,f][1,4]thiazepines and 11-methyldibenzo[b,f][1,4]thiazepines via the condensation/C–S bond coupling reactions of 2-iodobenzaldehydes/2-iodoacetophenones with 2-aminobenzenethiols/2,2′-disulfanediyldianilines in moderate-to-good yields. The reaction is easy to operate, uses readily available and bi-functional-reagent DMEDA working as ligand and reductant, and exhibits functional group tolerance.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27217392/s1, Figure S1: 1H NMR (CDCl3) spectrum of Compound (1c); Figure S2: 13C NMR (CDCl3) spectrum of Compound (1c); Figure S3: 1H NMR (CDCl3) spectrum of Compound (2c); Figure S4: 13C NMR (CDCl3) spectrum of Compound (2c); Figure S5: 1H NMR (CDCl3) spectrum of Compound (3c); Figure S6: 13C NMR (CDCl3) spectrum of Compound (3c); Figure S7: 1H NMR (CDCl3) spectrum of Compound (4c); Figure S8: 13C NMR (CDCl3) spectrum of Compound (4c); Figure S9: 1H NMR (CDCl3) spectrum of Compound (5c); Figure S10: 13C NMR (CDCl3) spectrum of Compound (5c); Figure S11: 1H NMR (CDCl3) spectrum of Compound (6c); Figure S12: 13C NMR (CDCl3) spectrum of Compound (6c); Figure S13: 1H NMR (CDCl3) spectrum of Compound (7c); Figure S14: 13C NMR (CDCl3) spectrum of Compound (7c); Figure S15: 1H NMR (CDCl3) spectrum of Compound (8c); Figure S16: 13C NMR (CDCl3) spectrum of Compound (8c); Figure S17: 1H NMR (CDCl3) spectrum of Compound (9c); Figure S18: 13C NMR (CDCl3) spectrum of Compound (9c); Figure S19: 1H NMR (CDCl3) spectrum of Compound (10c); Figure S20: 13C NMR (CDCl3) spectrum of Compound (10c); Figure S21: 1H NMR (CDCl3) spectrum of Compound (11c); Figure S22: 13C NMR (CDCl3) spectrum of Compound (11c); Figure S23: 1H NMR (CDCl3) spectrum of Compound (12c); Figure S24: 13C NMR (CDCl3) spectrum of Compound (12c); Figure S25: 1H NMR (CDCl3) spectrum of Compound (1e); Figure S26: 13C NMR (CDCl3) spectrum of Compound (1e); Figure S27: 1H NMR (CDCl3) spectrum of Compound (2e); Figure S28: 13C NMR (CDCl3) spectrum of Compound (2e); Figure S29: 1H NMR (CDCl3) spectrum of Compound (3e); Figure S30: 13C NMR (CDCl3) spectrum of Compound (3e); Figure S31: 1H NMR (CDCl3) spectrum of Compound (4e); Figure S32: 13C NMR (CDCl3) spectrum of Compound (4e); Figure S33: 1H NMR (CDCl3) spectrum of Compound (5e); Figure S34: 13C NMR (CDCl3) spectrum of Compound (5e).

Author Contributions

Synthesis and investigation, D.W., Q.L., Z.L., C.F. and R.L.; writing—original draft, G.S.; conceptualization and writing, G.S.; Project administration, B.Y. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to by the Shandong Provincial Natural Science Foundation (ZR2019QB022) and Liaocheng University fund (318051403) 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

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Molecules 27 07392 g001 550
Figure 1. Some biological and pharmaceutical active dibenzothiazepines.
Figure 1. Some biological and pharmaceutical active dibenzothiazepines.
Molecules 27 07392 g001
Molecules 27 07392 sch001 550
Scheme 1. Previous work and this work to synthesize dibenzothiazepine derivatives.
Scheme 1. Previous work and this work to synthesize dibenzothiazepine derivatives.
Molecules 27 07392 sch001
Molecules 27 07392 sch002 550
Scheme 2. Possible mechanism.
Scheme 2. Possible mechanism.
Molecules 27 07392 sch002
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 27 07392 i001
EntryCatalystDMEDA (mL)BaseYield (%) b
1CuCl20.50Cs2CO373
2CuCl20.25Cs2CO373
3CuCl20.15Cs2CO346
4CuCl20.25/22
5CuCl20.25K3PO482
6CuCl20.25K2CO362
7CuCl20.25K3PO482 c
8CuCl20.25K3PO473 d
9Cu(OAc)20.25K3PO466
10CuSO4·5H2O0.25K3PO469
11CuI0.25K3PO472
12CuCl20.25K3PO469 e
13CuCl21.25K3PO482 f
a Reaction conditions: copper catalyst (15 mol%), 2-iodobenzaldehyde 1a (0.3 mmol), 2,2′-disulfanediyldianiline 1b (0.15 mmol), base (0.6 mmol), 4 Å molecular sieve (25 mg) in DMEDA reacted at 110 °C under N2 atmosphere for 24 h. b The yields were determined by 1H NMR analysis using 1,3,5-Trimethoxybenzene as the internal standard. c The reaction temperature is 120 °C. d The reaction temperature is 100 °C. e No 4 Å molecular sieve was used. f Gram-scale (5 mmol scale) reaction.
Table
Table 2. Scope of the CuCl2-catalyzed condensation/C–S bond coupling reaction of 2-iodobenzaldehydes and 2,2′-disulfanediyldianilines/2-aminobenzenethiols in DMEDA a.
Table 2. Scope of the CuCl2-catalyzed condensation/C–S bond coupling reaction of 2-iodobenzaldehydes and 2,2′-disulfanediyldianilines/2-aminobenzenethiols in DMEDA a.
Molecules 27 07392 i002
Entryab/b′ProductYield (%) b
1Molecules 27 07392 i0031aMolecules 27 07392 i0041bMolecules 27 07392 i0051c82 (53 c, 35 d)
21aMolecules 27 07392 i0062bMolecules 27 07392 i0072c80
31aMolecules 27 07392 i0083bMolecules 27 07392 i0093c86
41aMolecules 27 07392 i0104bMolecules 27 07392 i0114c89
5Molecules 27 07392 i0122a1bMolecules 27 07392 i0135c84
6Molecules 27 07392 i0143a1bMolecules 27 07392 i0156c73
7Molecules 27 07392 i0164a1bMolecules 27 07392 i0177c86
8Molecules 27 07392 i0185a1bMolecules 27 07392 i0198c78
9Molecules 27 07392 i0206a1bMolecules 27 07392 i0219c83
102a3bMolecules 27 07392 i02210c74
116a2bMolecules 27 07392 i02311c84
126a3bMolecules 27 07392 i02412c75
131aMolecules 27 07392 i0251b′1c81
141aMolecules 27 07392 i0262b′2c80
151aMolecules 27 07392 i0273b′3c86
162a1b′5c78
173a1b′6c83
184a1b′7c88
195a1b′8c89
206a1b′9c80
216a2b′11c78
226a3b′12c80
a Reaction conditions: CuCl2 (15 mol%), 2-iodobenzaldehydes a (0.3 mmol), 2,2′-disulfanediyldianilines b (0.15 mmol)/2-aminobenzenethiols b′ (0.3 mmol), K3PO4 (0.6 mmol), 4 Å molecular sieve in DMEDA (0.25 mL) reacted at 110 °C under N2 atmosphere for 24 h. b Isolated yield after flash chromatography based on a; c 2-Bromobenzaldehyde was used; d 2-Chlorobenzaldehyde was used.
Table
Table 3. Scope of the CuCl2-catalyzed condensation/C–S bond coupling reaction of 2′-iodoacetophenones and 2,2′-disulfanediyldianilines/2-aminobenzenethiol in DMEDA a,b.
Table 3. Scope of the CuCl2-catalyzed condensation/C–S bond coupling reaction of 2′-iodoacetophenones and 2,2′-disulfanediyldianilines/2-aminobenzenethiol in DMEDA a,b.
Molecules 27 07392 i028
Entrydb/b′ProductYield (%) b
1Molecules 27 07392 i0291d1bMolecules 27 07392 i0301e75
21d2bMolecules 27 07392 i0312e74
31d3bMolecules 27 07392 i0323e69
41dMolecules 27 07392 i0334bMolecules 27 07392 i0344e61
5Molecules 27 07392 i0352dMolecules 27 07392 i0365bMolecules 27 07392 i0375e77
61d1b′1e95
7Molecules 27 07392 i0383d1bMolecules 27 07392 i0396e
a Reaction conditions: CuCl2 (15 mol%), 2′-iodoacetophenones d (0.3 mmol), 2,2′-disulfanediyldianilines b (0.15 mmol)/2-aminobenzenethiols 1b′ (0.3 mmol) in DMEDA reacted at 110 °C for 24 h. b Isolated yield after flash chromatography based on d.
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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. https://doi.org/10.3390/molecules27217392

AMA Style

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(21):7392. https://doi.org/10.3390/molecules27217392

Chicago/Turabian Style

Wang, Dehe, Qichao Lu, Zhanjun Li, Chen Fang, Ran Liu, Bingchuan Yang, and Guodong Shen. 2022. "“One-Pot” CuCl2-Mediated Condensation/C–S Bond Coupling Reactions to Synthesize Dibenzothiazepines by Bi-Functional-Reagent N, N′-Dimethylethane-1,2-Diamine" Molecules 27, no. 21: 7392. https://doi.org/10.3390/molecules27217392

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