Synthesis of Dibenzothiophenes and Related Classes of Heterocycles by Using Functionalized Dithiocarbamates (2010)

A round trip: Readily available dithiocarbamates can undergo ring closure to give functionalized sulfur heterocycles (see scheme). These heteroaromatic compounds can be further functionalized by directed alumination and subsequently trapped with various electrophiles. Dibenzothiophenes, benzo[b]thiophenes, and benzo[c]thiophenes have found numerous applications as dyes, pharmaceuticals, agrochemicals, or as building blocks for the synthesis of conducting polymers.1, 2 Several straightforward strategies for the synthesis of such S heterocycles have been reported.3 Palladium-catalyzed ring closures leading to S heterocycles are especially difficult, but were realized recently, despite the deactivating effect of sulfur on transition-metal catalysts.4, 5 To avoid this poisoning of the transition-metal catalysts by thiols and thiolates, we have envisioned a ring-closure procedure involving main-group benzothiolates such as 1 as precursors, which will provide an intermediate such as 2 by an addition/elimination reaction.6 The elimination of Met-X should result in various dibenzothiophenes of type 3 (Scheme 1). Preparation of S heterocycles by an addition/elimination reaction. FG=functional group, Met=K, X=Br, Cl. Herein we report the successful synthesis of various classes of S heterocycles of types 3 and 47 as well as [1]benzothieno[3,2-b][1]benzothiophene 58 and the previously unknown [1]benzothieno[2,3-b][1]benzofuran 6 (Scheme 1), starting from readily available biaryls of type 7. A Br/Mg or I/Mg exchange on the aryl bromides or iodides 8 was first carried out with iPrMgCl⋅LiCl9 (−20 °C, 0.5–2 h) and then transmetalated with ZnCl2. A subsequent Negishi cross-coupling reaction10–12 ([Pd(dba)2] (2 mol %; dba=trans,trans-dibenzylideneacetone), tri-2-furylphosphine (tfp; 4 mol %, 50 °C, 1.5 h)) with functionalized 1-chloro-2-iodobenzene derivatives 9 then afforded the polysubstituted biphenyls 10 in 75–92 % yield. Br/Li exchange proved to be superior (nBuLi (1.1 equiv), −95 °C, 30 min) as these biphenyls did not undergo complete Br/Mg exchange because of steric hindrance. After transmetalation with the THF-soluble magnesium complex MgCl2⋅LiCl,13, 14 the resulting aryl magnesium species were treated with tetramethylthiuram disulfide (Me2NC(S)S)2 (0.9 equiv, 0 °C to 25 °C, 1 h)15 to provide the biphenyl dithiocarbamates 7 a–f in yields of 80–94 % (Scheme 2). Preparation of the starting dithiocarbamates 7. This synthesis was also extended to the preparation of benzothiophenes 11 a–d and benzofurans 12 a/b. Thus, 3-bromobenzothiophene (13 a) was magnesiated with iPrMgCl⋅LiCl9 (1.1 equiv, −15 °C, 24 h) to the corresponding magnesium derivative. Subsequent transmetalation with ZnCl2 and a Negishi cross-coupling reaction10–12 with 1-bromo-2-iodobenzene derivatives 14 ([Pd(dba)2] (2 mol %), tfp (4 mol %), 50 °C, 1.5 h) then resulted in the formation of the 3-arylated benzothiophenes 15 a–d (63–75 % yield; Scheme 3). The magnesiation of compounds 15 with TMPMgCl⋅LiCl16 (1.1 equiv, 0 °C, 2 h) followed by a trapping reaction with (Me2NC(S)S)2 (0.9 equiv, 0 °C to 25 °C, 12 h) afforded the desired benzothienyl dithiocarbamates 11 a–d in 80–90 % yield. Similarly, 3-bromobenzofuran (13 b) was converted using the same two-step sequence into the benzofuryl dithiocarbamate (12 a/b; 81–87 %) via the intermediates 16 a/b (76–80 %; Scheme 3). Preparation of starting dithiocarbamates 11 and 12. TMP=2,2,6,6-tetramethylpiperidyl. The chloro-substituted dithiocarbamates 7 were converted by treatment with tBuOK (3.0 equiv, THF, 50 °C) into the corresponding potassium thiolates, which undergo an addition/elimination ring closure to provide the desired functionalized dibenzothiophenes 3 a–f in 71–96 % yield within 0.75–24 h (Table 1, entries 1–6). The rate of the cyclization depends on the substitution pattern of both aromatic rings. In general, electron-withdrawing substituents on the ring bearing the leaving group (chloride) enhance the reaction rates (entries 4 and 5). Microwave irradiation dramatically accelerates the cyclization of 7 c and 7 f. These substrates do not undergo ring closure under thermal conditions, but the reaction is complete after 45 minutes of microwave irradiation (90 °C). Bromo-substituted precursors such as 11 a–d and 12 a/b can also be used in such a ring-closure reaction. Treatment with nBuLi (1.05 equiv, THF, −20 °C) leads to a complete cyclization within 30 minutes at −20 °C and furnishes the tetracyclic heterocyclic products 4 a–d in 78–90 % yield (entries 7–10) and 6 a/b in 72 and 76 % yield, respectively (entries 11 and 12). A possible mechanism may involve a Br/Li exchange,17 followed by a substitution reaction of the intermediate aryl lithium compound on the dithiocarbamate group to give the desired products as well as dimethylthiocarbamoyllithium (LiC(S)NMe2),18 which may decompose under these conditions. An alternative radical mechanism cannot be excluded.19 Entry Substrate T [°C][a] Product[b] Entry Substrate T [°C][a] Product[b] 1 7 a 50 (12)[c] 3 a: 94 %[b] 7 11 a −20 (0.5)[e] 4 a: 80 %[b] 2 7 b 50 (18)[c] 3 b: 81 %[b] 8 11 b −20 (0.5)[e] 4 b: 90 %[b] 3 7 c 90 (0.75)[d] 3 c: 78 %[b] 9 11 c −20 (0.5)[e] 4 c: 83 %[b] 4 7 d 50 (4)[c] 3 d: 96 %[b] 10 11 d −20 (0.5)[e] 4 d: 78 %[b] 5 7 e 50 (4)[c] 3 e: 81 %[b] 11 12 a −20 (0.5)[e] 6 a: 72 %[b] 6 7 f 90 (0.75)d 3 f: 71 %[b] 12 12 b −20 (0.5)[e] 6 b: 76 %[b] An isomeric structure of heterocycles of type 4, namely the substituted [1]benzothieno[3,2-b][1]benzothiophene 5, could be prepared by a slight modification of the procedure shown in Scheme 1. Thus, a selective I/Mg exchange on 3-bromo-2-iodo-benzothiophene (17; iPrMgCl⋅LiCl (1.1 equiv), −40 °C, 1 h) followed by a transmetalation with ZnCl2 and Negishi cross-coupling with 2,4-dichloroiodobenzene (9 a) provides the 2-arylated benzothiophene 18 in 82 % yield. A Br/Mg exchange of 18 with iPrMgCl⋅LiCl (1.1 equiv, −5 °C, 18 h) and subsequent quenching with (Me2NC(S)S)2 furnishes 19 in 76 % yield. This dithiocarbamate undergoes a smooth ring closure in the presence of tBuOK (3.0 equiv, THF, 50 °C, 18 h) to give the tetracyclic heterocycle 5 in 73 % yield (Scheme 4). Preparation of the S-heterocycle 5. The S heterocycles prepared can be further functionalized by a regioselective alumination by using the hindered aluminum amide 20.20, 21 Thus, treatment of the O,S-tetracyclic compound 6 a with 20 (1.0 equiv, THF, −20 °C, 2 h) led to a regiospecific alumination at the α position to the furan unit (left arrow in Scheme 5). This result arises from a preferential complexation of the hindered aluminum base to the oxygen atom. The resulting aluminum organometallic compound 21 was acylated (1: ZnCl2 (1.1 equiv); 2: CuCN⋅2 LiCl (1.1 equiv); 3: PhCOCl (1.1 equiv, −20 °C→25 °C, 4 h)) to provide the ketone 22 a in 71 % yield. Furthermore, Negishi cross-coupling of 21 (1: ZnCl2 (1.1 equiv); 2: [Pd(dba)2] (5 mol %), tfp (10 mol %), ethyl 4-iodobenzoate (1.1 equiv, 50 °C, 8 h)) led to the arylated product 22 b in 73 % yield. It was possible to regiospecifically metalate the heterocycles 4 b and 5 by using the same base. The substituents present in those substrates (for example, a chloride or a methoxy group) fully direct the alumination. Trapping either with iodine (1: 20 (1.0 equiv, 0 °C, 4 h) 2: ZnCl2 (1.1 equiv); 3: I2 (1.5 equiv , −20 °C→25 °C, 0.5 h)) or acylation (1: 20 (1.0 equiv, −40 °C, 2 h) 2: ZnCl2 (1.1 equiv); 3: CuCN⋅2 LiCl (1.1 equiv); 4: PhCOCl (1.1 equiv, −20 °C→25 °C, 4 h)) afforded the substituted heterocycles 23 and 24 in yields of 71 and 82 %, respectively (Scheme 5). Alumination and subsequent acylation, iodolysis, or Negishi cross-coupling reaction to give the substituted heterocyles 22 a/b, 23, and 24. In summary, we have developed a cyclization reaction that leads to various condensed S heterocycles. The precursors for the ring-closing reaction are readily prepared by a palladium-catalyzed cross-coupling method. We have also shown that the newly formed S heterocycles can be regioselectively functionalized using the hindered aluminum base 20. Further extensions of this method for preparing material-relevant compounds are currently underway. Synthesis of 3 a (Table 1, entry 1): A dry and argon-flushed 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with a solution of 7 a (342 mg, 1.0 mmol) and KOtBu (337 mg, 3.0 mmol) in dry THF (10 mL). This solution was then heated at 50 °C for 12 h. After standard work up, the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (pentane/diethyl ether; 9:1) to give 3 a (206 mg, 94 %) as a colorless solid. Synthesis of 4 a (Table 1, entry 7): A dry and argon-flushed 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with a solution of 11 a (408 mg, 1.0 mmol) in dry THF (10 mL) and cooled to −20 °C. nBuLi (0.49 mL, 2.14 M in hexane, 1.05 mmol) was then added dropwise and the mixture stirred for 0.5 h. The reaction was stopped by the addition of MeOH (5 drops) and the solvents were evaporated in vacuo. The crude product was purified by flash chromatography (pentane) to give 4 a (201 mg, 84 %) as a colorless solid. 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