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

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.

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 Due to its wide applications, it is meaningful to find some simple, e methods for the synthesis of dibenzothiazepines. In past studies, seve have been developed, including the reactions of 2-halobenz aminobenzenethiols or 2,2′-disulfanediyldianiline [10,11,12,13,14], cyclization reactions [9,15], the intramolecular rearrangement reactions methods (Scheme 1) [17]. The previous reports have mainly focused on reactions of 2-halogenated benzaldehyde with 2-aminobenze disulfanediyldianiline because it is direct and effective. However, catalyzed coupling reactions for the synthesis of dibenzothiazepine ar

Results
First, 2-iodobenzaldehyde (1a) and 2,2 -Disulfanediyldianiline (1b) were selected to optimize the reaction conditions ( Table 1). The reaction was conducted with CuCl 2 (15 mol%), 1a (0.3 mmol), 1b (0.15 mmol), Cs 2 CO 3 (0.6 mmol) and 4 Å molecular sieve (25 mg) in DMEDA (0.50 mL) at 110 • C under N 2 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 Cs 2 CO 3 ( Table 1, entry 4). When K 3 PO 4 (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 , CuSO 4 ·5H 2 O, 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][17][18][19][20][21][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 moderateto-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 ( 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 (                           (15 mol%  The scope of 2 -iodoacetophenones d and 2,2 -disulfanediyldianilines b/2aminobenzenethiol 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, CuCl 2 coordinates with DMEDA and is reduced to generate the Cu 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.  (15 mol%

Experimental Section
3.1. General 1 H NMR and 13 C NMR spectra were recorded 500 MHz (Bruker, Kanton Zug, Switzerland) instrument; CDCl 3 (δ H = 7.26 ppm, δ C = 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. . 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 Mg 2 SO 4 . 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. . 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 Mg 2 SO 4 . 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.

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