Introduction

Disulfides are a class of valuable chemicals which can be used as antiviral agents in the treatment of AIDS [1], somatostatin agonists [2, 3], oxytocin analogs [4, 5], anti-tumor agents [6], and so on [7, 8]. Furthermore, disulfides are used as common organic reagents to construct new C–S bonds [9, 10].

Traditionally, disulfides are synthesized mainly through oxidation of thiols [11–13], reductive coupling of sulfonyl chlorides [14, 15] or sulfur chloride [16, 17], disulfides exchange [18, 19], or others [7, 20, 21]. Unsymmetrical disulfides are mainly synthesized via rhodium-catalyzed disulfide exchange. Efficient and green methodologies for the synthesis of unsymmetrical disulfides, especially with heterocyclic structures, are still strongly sought after [7].

As part of our ongoing research on reactions of tert-butanesulfinamide [22–25], the reaction of 2-mercaptobenzothiazole and tert-butanesulfinamide to yield N-(tert-butylsulfinyl)-2-aminobenzothiazole or 2-(tert-butylsulfinyl)thiobenzothiazole was explored. Nevertheless, the product was unexpectedly determined to be a 2-(tert-butyldisulfanyl)benzothiazole, based on 1H, 13C NMR, and mass spectra data.

The formation of 2-(tert-butyldisulfanyl)heterocycles was indeed verified via single crystal X-ray diffraction; the product 3a was identified as 2-(tert-butyldisulfanyl)heterocycles, featuring an S–S single bond (Fig. 1).

Fig. 1
figure 1

Single crystal diagram of compound 3a

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In essence, an efficient method to synthesize unsymmetrical disulfides from commercially available thio-heterocycles and tert-butanesulfinamide under mild conditions was revealed. To the best of our knowledge, tert-butanesulfinamide is firstly reported to act as oxidant and sulfur source rather than as nucleophiles and electrophiles in the reactions (Scheme 1) [26, 27].

scheme 1

Results and discussion

Typical Ullman conditions with K2CO3 as base and DMF as solvent were initially applied, obtaining a product with extremely low yield (Table 1, entry 1). Subsequently, a weak base (sodium acetate) was applied as additive, and 2-(tert-butyldisulfanyl)benzothiazole was obtained in much higher yield (entry 2). Solvents including DMA, DMSO, toluene, and 1,4-dioxane were also screened, but no better yield was obtained (entries 3–6 vs. 2). Changes of the copper source to CuBr, CuCl, Cu, and Cu(OAc)2 were accompanied by poorer yields (entries 7–10 vs. 2). However, the use of Na2SO4 as an additive was observed to give an obvious increase of yield (entry 11). Surprisingly, magnesium sulfate dramatically increased the yield of 2-(tert-butyldisulfanyl)benzothiazole up to 96 % (entry 12). To increase temperature and to prolong reaction time are prove to be unnecessary (entries 13, 14 vs. 12). No addition of copper(I) iodide resulted in no product (entries 13 vs. 15).

Table 1 Optimization of reaction conditions of 2-mercaptobenzothiazole and tert-butanesulfinamide
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The reaction of 2-mercapto sulfur-containing heterocycles and tert-butanesulfinamide were then examined under the optimized conditions (Table 2). One equivalent of tert-butanesulfinamide was enough, and excess substrate was not necessary (entries 2 vs. 1). However, benzo[d]oxazole-2-thiol afforded a lower yield of 51 % (entry 3), perhaps benzoxazole cycle has higher aromaticity. For 2-mercapto-1,3,4-thiadiazole, good yield was obtained (entry 4). It can be assumed that an electron-donating methyl on 2-mercapto-1,3,4-thiadiazole benefits this reaction (entry 5). Interestingly, both the two mercapto groups in 1,3,4-thiadiazole-2,5-dithiol reacted with tert-butanesulfinamide (entry 6). In addition, 2-mercaptoazoles, thiophene-2-thiol reacted with tert-butanesulfinamide to produce 2-(tert-butyldisulfanyl)thiophene in 89 % yield as well (entry 7).

Table 2 Reactions of 2-mercaptoheterocycles and tert-butanesulfinamide
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A plausible mechanism for condensation of 2-mercaptobenzothiazole and tert-butanesulfinamide to synthesize 2-(tert-butyldisulfanyl)heterocycles (Scheme 2) is, therefore, proposed. Under the reaction conditions, interaction of CuI and 2-mercaptobenzothioazole produces a cuprous salt of 2-mercaptobenzothioazole (4) and releases hydrogen iodide. The cuprous salt and tert-butanesulfinamide perform coordination transfer and nucleophilic attack (5). And then a complex 6 is formed. The complex 6 is not stable, and reductive elimination of complex 6 affords the final product 3a, and releases hydroxylamine and CuI [28, 29].

scheme 2

In conclusion, a novel synthetic method of 2-(tert-butyldisulfanyl)heterocycles has been developed. CuI-catalyzed condensation of 2-mercapto sulfur-containing heterocycles and tert-butanesulfinamide afforded 2-(tert-butyldisulfanyl)heterocycles. This protocol is simple, cost-efficient, and practical.

Experimental

The chemicals were purchased from Aldrich, Adamas, Aladdin, Alfa Aesar, and Kelong Chemical Companies, and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) using commercial silica gel plates (GF254). Purification of the synthesized compounds was carried out by flash column chromatography with silica gel (300–400 mesh). Melting points were determined on an X-4 melting-point apparatus with microscope. 1H and 13C NMR spectra were recorded on a Bruker Avance-300 or -400 spectrometer (300 or 400 MHz for 1H NMR, and 75 or 101 MHz for 13C NMR, respectively). Chemical shifts (δ) were reported in ppm referenced to an internal tetramethylsilane standard or the deuterated solvent DMSO-d 6 or CDCl3. Coupling constants J were reported in Hertz (Hz). High-resolution mass spectra (HR-MS) were obtained with micrOTOF-Q II (Bruker Daltonics). All IR spectra were taken on a Bruker Tensor-27 infrared spectrometer with an OPUS workstation.

Typical procedure for CuI-catalyzed amination of 2-mercaptothiazole analogs 3a–3f

2-Mercaptobenzothiazole (167 mg, 1.0 mmol, 1.0 equiv.) and 121 mg tert-butanesulfinamide (1.0 mmol, 1.0 equiv.) were added into a clean oven-dried test tube equipped with a stirring bar, then 10 mg CuI (0.05 mmol, 5 mol %) and 2.0 equiv. of anhydrous MgSO4 were added to the mixture, seal the tube, and then 4 cm3 of DMF was injected in the tube by syringe. The mixture stirred in an oil bath heated at 100 °C for 24 h. After cooled to room temperature, 4 cm3 water was injected into the mixture and extracted the mixture with ethyl acetate (15 cm3 × 3); the organic layer was washed with brine, and then dried over anhydrous Na2SO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography to give product 3a.

2-(tert-Butyldisulfanyl)benzothiazole (3a)

Yield 96 %; light yellow solid; m.p.: 78–80 °C (Ref. [30] 82 °C).

2-(2-tert-Butyldisulfanyl)benzo[d]oxazole (3b, C11H13NOS2)

Yield 51 %; yellow oil; 1H NMR (300 MHz, CDCl3): δ = 7.68–7.62 (m, 1H), 7.51-7.43 (m, 1H), 7.29 (dd, J = 6.7, 4.5 Hz, 2H), 1.65 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ = 163.80, 151.21, 141.93, 124.56 (J = 8.25 Hz), 124.20 (J = 6.75 Hz), 119.18 (J = 24.0 Hz), 110.04 (J = 22.5 Hz), 49.65, 30.91 ppm; IR (KBr): \(\bar v \) = 3416, 3236, 2926, 2032, 1620, 1385, 1099, 991, 869, 621, 480 cm−1; HRMS: m/z calcd for C11H14NOS2 ([M + H]+) 240.0511, found 240.0481.

5-(tert-Butyldisulfanyl)-1,3,4-thiadiazole (3c, C6H10N2S3)

Yield 78 %; yellow solid; m.p.: 66–67 °C; 1H NMR (300 MHz, CDCl3): δ = 9.01 (s, 1H), 1.36 (s, 9H) ppm; 13C NMR (151 MHz, CDCl3): δ = 174.87, 152.64, 50.74, 29.74 ppm; IR (KBr): \(\bar v \) = 3929, 3415, 3236, 2378, 2029, 1618, 1385, 1089, 990, 847, 704, 621, 480 cm−1; HRMS: m/z calcd for C6H11N2S3 ([M + H]+) 207.0079, found 207.0058.

2-(tert-Butyldisulfanyl)-5-methyl-1,3,4-thiadiazole (3d)

Yield 91 %; yellow solid; m.p.: 70–72 °C (Ref. [31]: 55 °C).

2,5-Bis(2-tert-butyldisulfanyl)-1,3,4-thiadiazole (3e)

Yield 92 %; yellow solid; m.p.: 69–71 °C (Ref. [31]: 63 °C).

2-(tert-Butyldisulfanyl)thiophene (3f, C8H12S3)

Yield 89 %; pale yellow oil; 1H NMR (300 MHz, CDCl3): δ = 7.33 (dd, J = 5.3, 1.1 Hz, 1H), 7.21 (dd, J = 3.5, 1.1 Hz, 1H), 6.93 (dd, J = 5.2, 3.6 Hz, 1H), 1.37 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ = 136.89, 132.51, 129.42, 127.38 (J = 12 Hz), 48.98, 30.52 ppm; IR (KBr): \(\bar v\) = 3927, 3415, 3236, 2960, 2894, 2858, 2033, 1620, 1454, 1401, 1363, 1216, 1162, 1086, 988, 871, 846, 702, 621, 482 cm−1; HRMS: m/z calcd for C8H13S3 ([M + H]+) 205.0174, found 205.0187.