Efficient, Iron-Catalyzed Synthesis of 2-Mercaptobenzothiazole Through S

Synthetic Communications An International Journal for Rapid Communication of Synthetic Organic Chemistry

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Efficient, Iron-Catalyzed Synthesis of 2- Mercaptobenzothiazole Through S-Arylation/ Heterocyclization of 2-Haloaniline with Potassium Xanthate

Min Gao, Chunqing Lou, Ning Zhu, Weijing Qin, Quanling Suo, Limin Han & Hailong Hong

To cite this article: Min Gao, Chunqing Lou, Ning Zhu, Weijing Qin, Quanling Suo, Limin Han & Hailong Hong (2015) Efficient, Iron-Catalyzed Synthesis of 2-Mercaptobenzothiazole Through S-Arylation/Heterocyclization of 2-Haloaniline with Potassium Xanthate, Synthetic Communications, 45:20, 2378-2385, DOI: 10.1080/00397911.2015.1085573

To link to this article: http://dx.doi.org/10.1080/00397911.2015.1085573

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Accepted online: 26 Aug 2015.

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Download by: [Inner Mongolia University of Technology] Date: 30 September 2015, At: 01:34 Synthetic Communications1, 45: 2378–2385, 2015 Copyright © Taylor & Francis Group, LLC ISSN: 0039-7911 print/1532-2432 online DOI: 10.1080/00397911.2015.1085573

EFFICIENT, IRON-CATALYZED SYNTHESIS OF 2-MERCAPTOBENZOTHIAZOLE THROUGH S-ARYLATION/HETEROCYCLIZATION OF 2- HALOANILINE WITH POTASSIUM XANTHATE

Min Gao, Chunqing Lou, Ning Zhu, Weijing Qin, Quanling Suo, Limin Han, and Hailong Hong Chemical Engineering College, Inner Mongolia University of Technology, Hohhot, China GRAPHICAL ABSTRACT

Abstract A mild and practical method for the synthesis of 2-mercaptobenzothiazole has been developed by using iron as an efficient catalyst. The present tandem reaction process allows access to a wide range of 2-mercaptobenzothiazoles in good to excellent yields by the reaction of 2-haloaniline with potassium O-ethyl dithiocarbonate in the 0 0 presence of FeF3 as a catalyst and 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl as a ligand under an atmosphere of argon.

Keywords 2-Haloaniline; iron-catalyzed synthesis; 2-mercaptobenzothiazole; tandem reaction

INTRODUCTION

Benzothiazole-containing compounds are common synthetic targets because of their interesting pharmaceutical and industrial applications. 2-Mercaptobenzothia- zoles (or 1,3-benzothiazole-2(3H)-thiones)[1,2] and 2-thio-substituted benzothiazoles, categorized as a derivative of benzothiazole, have been used as bioactive agents[3–6] Downloaded by [Inner Mongolia University of Technology] at 01:34 30 September 2015 and potential luminophores[7,8] (Fig. 1). For example, 6-methyl-2-mercaptobenzothiazole 1 has been used as radioprotector to protect normal tissues adjacent to the tumor treated by radiotherapy,[3] and 2 might have the potential to be employed

Received April 25, 2015. Address correspondence to Ning Zhu, Chemical Engineering College, Inner Mongolia University of Technology, Hohhot 010051, P. R. China. E-mail: [email protected] Color versions of one or more of the figures in the article can be found online at www.tandfonline. com/lsyc.

2378 SYNTHESIS OF 2-MERCAPTOBENZOTHIAZOLE 2379

Figure 1. Examples of 2-mercaptobenzothiazoles.

as a new herbicide for weed control of wheat fields.[5] 2-Mercaptobenzothiazole derivatives 3 and 4 were evaluated for their potent antibacterial activity.[4] In addition, 2-mercaptobenzothiazole 5 can act not only as an accelerator of rubber vulcanization[2] but also as a significant ligand to form metallic complexes, which have promising luminescent properties.[7,8] Because of the importance of 2-mercaptobenzothiazole derivatives, an efficient synthesis of 2-mercaptobenzothiazole under very mild reaction conditions has attracted much attention.[1,2,9–11] Conventionally, 2-mercaptobenzothiazole was prepared by the reaction of aniline with carbon disulfide under high pressure, which was used in the industrial production[12,13] (Scheme 1, route a). Though the starting material aniline was readily commercial available, the reaction was carried out under high pressure, and the harsh reaction conditions posed a serious threat to the manipulators. Furthermore, o-aminothiophenol reacted with carbon disulfide[14–18] or potassium=sodium O-ethyl dithiocarbonate[19] are usually used to produce 2-mercaptobenzothiazole (Scheme 1, route b). However, the starting material 2-aminobenzenethiols, especially those bearing additional substituents, were readily oxidized to stable disulfides and are not always easily available. Therefore, the disulfide, 2,20-disulfanediyldianiline, was used as starting material reacted with carbon disulfide in the presence of 1,8-diazabicyclo [5.4.0]undec-7-ene/ethanethiol (DBU/EtSH) to produce 2-mercaptobenzothiazole by our research group[9] (Scheme 1, route c). The odorous EtSH was used in this new Downloaded by [Inner Mongolia University of Technology] at 01:34 30 September 2015

Scheme 1. Strategies for the synthesis of 2-mercaptobenzothiazoles. 2380 M. GAO ET AL.

synthetic method. An alternative approach to prepare 2-mercaptobenzothiazole used the DBU-promoted tandem reaction of 2-haloanilides with carbon disulfide[1,10] or nucleophilic aromatic substitution (SNAr) reaction of a potassium=sodium O-ethyl dithiocarbonate with 2-fluoroaniline, 2-chloroaniline, or 2-bromoaniline followed by a subsequent intramolacular cyclization[6,11,20–23] (Scheme 1, route d). However, the reaction of 2-iodoaniline with potassium=sodium O-ethyl dithiocarbonate could not afford the 2-mercaptobenzothiazole effectively in the present reaction conditions. Because of the cheap, efficient, nontoxic, and environmentally benign iron catalyst, the iron-catalyzed carbon-sulfur bond formation reactions have received [24] [25–29] [30] [31] [32,33] much attention. Recently, FeCl3, FeCl3 ·6H2O, FeCl2, FeF3, [34] [35] [36] Fe3O4, Fe(BF4)2, and Fe complexes had been used to catalyze cross-coupling and thia-Michael addition reactions for the formation of carbon–sulfur bonds. However, different reaction models needed different iron salts and ligands to make the reaction occur efficiently. Moreover, to the best of our knowledge, no report about the iron-catalyzed cross-coupling reaction of 2-haloaniline with potassium xanthate was found in the references. Herein we report a new facile and efficient FeF3-catalyzed tandem protocol for the synthesis of 2-mercaptobenzothiazole involving an S-arylation=intramolacular cyclization process.

RESULTS AND DISCUSSION

We began our study by examining the reaction of 2-iodoaniline (1a) with potassium O-ethyl dithiocarbonate (2) in dimethylformamide (DMF) by using different iron catalysts and ligands under various reaction conditions. Under the protection of an inert atmosphere, when 2-iodoaniline reacted with 3 equiv of potassium O-ethyl dithiocarbonate in the absence of any catalysts and ligands at 90 °C, only 15% yields of desired products were obtained as determined by mass spectrometry (MS) and NMR methods (Table 1, entry 1). Then various iron catalysts (10 mol%) were inves- tigated for this reaction under similar conditions. The use of anhydrous FeCl3, FeCl3 · 6H2O, and FeF3 all gave the desired product in moderate yield, and the results indicated that iron can play a catalytic role in this reaction (entries 2–4). Encouraged by these results, various nitrogen and phosphine ligands[26,28] (20 mol%) were subsequently evaluated under the catalysis of FeCl3 ·6H2O (entries 5–10). Among the various ligands examined, 2,20-bis(diphenylphosphino)-1,10-binaphthyl (L1) was the most effective ligand. However, the individual L1 ligand was ineffective in this reaction system (entry 11), which showed that L1 ligand and FeCl3 ·6H2O cocatalyzed the reaction of 1a and 2 to form 2-mercaptobenzothiazoles 3a in 73% yield. Furthermore, when FeF3 was used as the cocatalyst, the yield of 3a was increased to 83% (entry 12).

Downloaded by [Inner Mongolia University of Technology] at 01:34 30 September 2015 When the reaction temperature was improved to 110 °C, the yield of corresponding product increased to 91% (entry 13), which indicated that the reaction temperature was another important factor for the yield of the product. After optimization of the ratio of the catalyst to ligand and other reaction conditions, it turned out that 5 mol% L1 ligand combined with 10 mol% FeF3 under 110 °C could provide the best results (entries 14–16). Bolm and Buchwald reported that trace amounts of copper impurities in iron catalyst could efficiently catalyze heteroatom to form C-S, C-O, and C-N in organic synthesis.[37] To verify that iron could catalyze the reaction of 2-iodoaniline with SYNTHESIS OF 2-MERCAPTOBENZOTHIAZOLE 2381

Table 1. Optimization of the reaction conditionsa

Entry Catalyst Ligand Temp. (°C) Yieldb (%)

1 ——90 15

2 FeCl3 ·6H2O — 90 35 3 FeCl3 — 90 22 4 FeF3 — 90 41 5 FeCl3 ·6H2O L-Proline 90 41 0 6 FeCl3 ·6H2O 2,2 -Bipyridine 90 43 7 FeCl3 ·6H2O Dppe 90 31 8 FeCl3 ·6H2O Dppp 90 23 9 FeCl3 ·6H2OL2 90 19 10 FeCl3 ·6H2OL1 90 73 11 — L1 90 16

12 FeF3 L1 90 83 13 FeF3 L1 110 91 14 FeF3 L1 (10 mol%) 110 90 15 FeF3 L1 (5 mol%) 110 97 16 FeF3 L1 (1 mol%) 110 32

aConditions: 1a (0.6 mmol), 2 (1.8 mmol), catalyst (10 mol %), ligand (20 mol %), 4 mL DMF, 6 h, under an atmosphere of argon. bIsolated yield based on 1a.

potassium O-ethyl dithiocarbonate in our reaction system, the high-purity FeCl3 (>99.99%) was used as catalyst under the optimized reaction conditions. The experimental result showed that the aim product was obtained in 80% yield, which indicated that the iron was a true catalyst in this coupling reaction system. Having optimized the reaction conditions through the use of FeF3 as catalyst and L1 as ligand, we explored the scope and limitations of this tandem reaction Downloaded by [Inner Mongolia University of Technology] at 01:34 30 September 2015 system, and the results are summarized in Table 2. When a variety of 2-haloaniline reactions with potassium O-ethyl dithiocarbonate were examined, the results demon- strated that 2-I, 2-Br, or 2-Cl substituted aniline could produce the product 3a in excellent yield (Table 2, entries 1–3). Furthermore, 4-fluoro, 4-chloro, 4-bromo, and 3-chloro substituted 2-iodoaniline also gave corresponding product 3 in good yields and the halo substituted functional groups were well tolerated under the optimized reaction conditions (entries 4–7). Electron-withdrawing group (F-, CF3-, CN-) substituted 2-iodoaniline reacted with potassium O-ethyl dithiocarbonate to easily 2382 M. GAO ET AL.

Table 2. Reaction of 2-haloanilines with potassium O-ethyl dithiocarbonate (2)a

Entry 1 Time (h) Product Yieldb (%)

1 6 3a 97

2 5 3a 98

3 12 3a 91

4 3 3b 99

5 18 3c 77

6 18 3d 72

7 12 3e 79

8 12 3f 85

9 10 3g 98 Downloaded by [Inner Mongolia University of Technology] at 01:34 30 September 2015

10 10 3h 83

11 8 3i 73

(Continued) SYNTHESIS OF 2-MERCAPTOBENZOTHIAZOLE 2383

Table 2. Continued

Entry 1 Time (h) Product Yieldb (%)

12 21 3j 61

a Conditions: 1 (0.6 mmol), 2 (1.8 mmol), FeF3 (10 mol %), L1 (5 mol %), 4 mL DMF, under an atmosphere of argon. bIsolated yield based on 1.

Scheme 2. Formation process of 2-mercaptobenzothiazole.

afford the target product 3 in good yields (entries 4, 8, and 9). Electron-donating group (4-methyl, 5-methyl) substituted 2-iodoaniline also produced the product 3 in good yields (entries 10 and 11). However, electron-withdrawing group (CF3-) substituted 2-bromoaniline gave the product 3j in a relative poor yield. Table 2 showed that electron-donating and electron-withdrawing group substituted 2-haloanilines all served as suitable partners for coupling with potassium O-ethyl dithiocarbonate to prepare 2-mercaptobenzothiazole in good to excellent yields. In general, according to the literature,[11] intermediate A is formed by coupling reaction of 2-iodoaniline 1a with potassium O-ethyl dithiocarbonate 2 in the presence of FeF3 catalyst (Scheme 2). Subsequently, the amine group of A attacks the C=S group intramolecularly to provide the expected product B, which yields 2-mercaptobenzothiazole 3a upon elimination of an alcohol EtOH.

CONCLUSIONS

In summary, we have developed an iron-catalyzed coupling of 2-haloaniline Downloaded by [Inner Mongolia University of Technology] at 01:34 30 September 2015 with potassium O-ethyl dithiocarbonate to synthesize 2-mercaptobenzothiazole in good yields. This new coupling reaction underlines the potential of using FeF3 as an environmental friendly, mild, and efficient catalyst for the coupling of C-S.

EXPERIMENTAL

A 25-mL reaction tube was charged with 2-haloaniline 1 (0.6 mmol), potassium 0 O-ethyl dithiocarbonate 2 (1.8 mmol), FeF3(0.06 mmol), 2,2 -bis 2384 M. GAO ET AL.

(diphenylphosphino)-1,10-binaphthyl (0.03 mmol), and DMF (4 mL). The reaction vessel was flushed with argon three times and sealed. Then the mixture was stirred electromagnetically in an oil bath at 110 °C for 3–21 h. The reaction process was monitored by thin-layer chromatography (TLC) on silica gel. After the reaction was completed, the reaction mixture was cooled to room temperature, and then 4 mL HCl (3 mol=L) was added and stirred for another 30 min. Then the reaction mixture solution was extracted by ethyl acetate (3 × 20 mL). Subsequently, the combined organic solution was dried by anhydrous sodium sulfate and the target product was purified by silica-gel column chromatography (eluent: petroleum ether=ethyl acetate) to give the corresponding pure products 3a–3h.

FUNDING

This work was supported by the National Natural Science Foundation of China (21362019) and the Inner Mongolia Natural Science Foundation of China (2012MS0204).

SUPPLEMENTAL MATERIAL

Experimental procedures, characterization data, and NMR spectra of all compounds for this article can be accessed on the publisher’s website.

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