Switchable Copper-Catalyzed Approach to Benzodithiole, Benzothiaselenole, and Dibenzodithiocine Skeletons

A copper-catalyzed reaction between 2-bromo-benzothioamides and S8 or Se involving sulfur rearrangement is reported, enabling access to benzodithioles 2 and benzothiaselenoles 6 in the presence of Cs2CO3. In the absence of S8 or Se, the reaction affords dibenzodithiocines 7 via two consecutive C(sp2)–S Ullmann couplings.

O rganosulfur compounds display prominent potential for diverse functionalization and exhibit attractive pharmacological properties. 1 In this regard, copper-catalyzed crosscoupling reactions between aryl halides and carbon-or heteroatom-based nucleophiles represent an established synthetic strategy for forging carbon−carbon and carbon− heteroatom bonds. 2 In recent years, elemental sulfur (S 8 ) has been demonstrated to be an effective sulfur source for C(sp 2 )− S bond formation under copper-catalyzed conditions. For example, Liu and coworkers disclosed a copper-catalyzed three-component reaction involving o-iodobenzamides, S 8 , and CH 2 Cl 2 to afford 2,3-dihydrobenzothiazinones in good yields ( Figure 1). 3 Similarly, the Shi group reported a coppermediated C−S bond-forming protocol to access benzoisothiazolones from benzamides via C−H activation. 4 Recently, a solvent-free method for the synthesis of 2-acylthieno [2,3b]quinolines was described through dual copper/nitroxyl radical catalysis. 5 In this regard, benzodithiols (BDTs) and derivatives thereof, which contain a fused bicyclic molecule bearing a benzene ring connected to a five-membered 1,2-or 1,3-dithiol-containing ring, have been reported to possess promising bioactivity including anti-HBV, 6 antitumor, 7 antimicrobial, 8 anti-Mycobacterium avium, 9 and antibovine viral diarrhea virus activities. 10 Therefore, numerous methods have been explored for accessing more potent and structurally diverse BDTs. 11 −15 Here 3H-benzo [c][1,2]dithiol-3-ones is an important member of 1,2-BDTs and has, for example, been utilized in the preparation of fluorescent probes. 16 In our recent study, 2-bromo-N-phenylbenzothioamide (1a) was subjected to a terminal alkyne in the presence of a copper catalyst to afford the corresponding 4H-thiochromen-4imine. 17 We reasoned that replacing the alkyne with S 8 as a sulfur source would furnish benzo[d]isothiazole-3(2H)-thione through C aryl −Br thiolation. However, the reaction underwent an unexpected sulfur rearrangement, leading to 3H-benzo[c]-[1,2]dithiol-3-imine. As a continuation of our studies on construction of heterocycles catalyzed by copper(I) or silver(I), 18 herein we disclose an efficient and modular copper-catalyzed protocol for synthesis of benzodithiole derivatives 2 through the reaction of 2-bromo-benzothioamides 1 with S 8 under alkaline conditions. Furthermore, this copper-mediated reaction provided benzothiaselenole derivatives 6 when S 8 was replaced with Se powder.
As shown in Table 1, the model reaction of 2-bromo-Nphenylbenzothioamide (1a) and S 8 was performed in refluxing pyridine using 10 mol % CuI as a catalyst, affording 2a in 46% yield (Table 1, entry 1). To improve the yield, several reaction parameters were varied, including the copper source, base, ligand, and solvent. Using alternative copper precursors, such as CuBr, CuCl, and CuOAc, demonstrated that CuI was superior (cf. Table 1, entry 1 and entries 2−4). Furthermore, the use of copper(II) precursors, such as CuBr 2 and Cu(OAc) 2 , led to no desired product formation (Table 1, entries 5 and 6). The addition of frequently used ligands, such as Ph 3 P, o-phen, and L-proline, revealed that a substantial increase in yield was possible when using o-phen, providing 2a in 68% yield (Table 1, entry 9). A survey of inorganic bases showed that Cs 2 CO 3 furnished product 2a in 76% yield (Table  1, entry 10). Other carbonate bases, such as K 2 CO 3 , Na 2 CO 3 , and NaHCO 3 , also promoted the reaction (Table 1, entries 11−13) but provided lower yields of 2a compared with Cs 2 CO 3 . Finally, the reaction also proceeded in common organic solvents, such as DMF, dioxane, DMSO, DMA, and toluene (Table 1, entries 14−20). Here DMF was found to be the best solvent for this reaction, leading to 2a in 85% yield (Table 1, entry 14). 19−21 With the optimized reaction conditions in hand, we examined the generality of the protocol (Scheme 1). Initially, substrates with various substituents on the imine nitrogen atom were investigated.
In addition to aliphatic groups, the reaction tolerated various aromatic substituents bearing either electron-donating (methyl, methoxy, iso-propyl) or electron-withdrawing substituents, such as nitro and chloro, as well as heteroaryl motifs. All of these substrates underwent the cascade coupling/cyclization smoothly to afford products 2a−q in good to excellent yields (62−90%, Scheme 1). The structure of product 2 was supported through single-crystal X-ray diffraction analysis of 2l, as shown in Scheme 1.
With respect to the substituents on the benzene ring, we were delighted to find that various groups, such as methyl, methoxy, chloro, and fluoro, at either the fiveor sevenposition could be employed, furnishing the corresponding benzodithiole products 2r−ad in 75−91% yields (Scheme 1). Additionally, a pyridine derivative was also an effective coupling/cyclization partner, affording product 2ae in 91% yield.
To evaluate possible further applications of the developed protocol, several benzodithioles were transformed into their corresponding BDT derivatives (3a−e) in high yields via acidic hydrolysis (Scheme 1). The developed protocol undoubtedly provides an efficient and practical method for the preparation of these valuable and medicinally relevant compounds. Furthermore, the synthetic conversion of 3a into the important compounds 4 22 (Beaucage's reagent) and 5 23 was attained in good yield by reacting with m-CPBA and hydrogen peroxide, respectively.
A proposed mechanism for the synthesis of 2 and 6 is detailed in Scheme 3. According to the structure of the products 2 and 6, benzothietane-2-imine B is envisioned as a key intermediate. Initially, benzothioamide 1 is believed to be converted to anion A in the presence of a base. Then, benzothietane-2-imine B is produced via an intramolecular copper-catalyzed Ullmann coupling reaction to form thietane adduct B. 24 Subsequent cleavage of the C−S bond occurs to give the ring-opened thiophenolate D. In the following step, intermediate D reacts with S 8 or Se to form an S−S or S−Se bond, which is similar to reacting Na 2 S with S 8 to form Na 2 S 2 . Finally, intermediate E undergoes an addition/elimination process to give the target structure 2 or 6. An alternative mechanism involves the initial formation of a copper thiolate adduct (G), which undergoes oxidative addition into the C−Br bond to form the five-membered cupracycle H. The subsequent migration and insertion of sulfur or selenium  Finally, conducting the reaction under standard conditions but in the absence of S 8 or Se provided a new product, dibenzodithiocine 7a, derived from two consecutive C(sp 2 )−S coupling reactions (Scheme 4). The initial yield (42%) for this copper-catalyzed coupling product could be improved to 79% upon changing the ligand and base to PPh 3 and K 2 CO 3 , respectively. A total of 20 dibenzodithiocines (7a−o) were obtained in 72−85% yield, and the structure of 7n was supported by X-ray diffraction analysis (Scheme 4).
In conclusion, an efficient and switchable copper-catalyzed method for the synthesis of benzodithioles and benzothiaselenoles using S 8 or Se as the chalcogen source is disclosed. Conducting the reaction in the absence of S 8 or Se affords eight-membered dibenzodithiocine annulation products via two consecutive C(sp 2 )−S coupling reactions. Considering the importance of sulfur and selenium compounds, this protocol may be of great value for synthetic chemists and pharmacologists in the future.