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Synthesis 2020; 52(20): 3058-3064
DOI: 10.1055/s-0040-1707204
paper
© Georg Thieme Verlag Stuttgart · New York

Iodine- and TBHP-Promoted Acylation of Benzothiazoles under Metal-Free Conditions

Bin Wang
,
Qianwei Zhang
,
Zhongqi Guo
,
Keyume Ablajan  ∗
College of Chemistry, Xinjiang University, Urumqi 830046, P. R. of China   Email: ablajan209@xju.edu.cn   Email: ablajan209@hotmail.com
› Author Affiliations

This work was supported by the National Science Foundation of China (Grant Nos. 21961038 and 21462041).
Further Information

Publication History

Received: 14 June 2020

Accepted after revision: 16 June 2020

Publication Date:
23 July 2020 (online)

 
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Abstract

A simple protocol for the synthesis of 2-acylbenzothiazoles using aryl ketones and benzothiazoles in the presence of I2 and TBHP is described. Acylation of the benzothiazoles is achieved through a sequence involving oxidation of the aryl ketone to an aryl glyoxal, ring-opening of the benzothiazole followed by condensation of the amino group with the aryl glyoxal, cyclization and oxidation. The method avoids the use of metals and toxic solvents. In addition, this protocol has the advantage of broad scope and provides good to excellent product yields.


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Key words

benzothiazoles - 2-acylbenzothiazoles - acylation - metal-free - 2-aminothiophenols
Zoom Image
Scheme 1 Previous routes and our strategy for the synthesis of 2-acylbenzothiazoles

The benzothiazole moiety is an important heterocyclic core belonging to five-membered heterocycles. It is often found in diverse natural products[1] and is a common structural unit in synthetic drugs. Numerous research has indicated that compounds containing a thiazole ring exhibit effective pharmacological properties, with examples including ampicillin, amoxicillin, and piperacillin. Studies on benzothiazoles have also shown that they have a wide range of therapeutic activities. Some benzothiazoles can be used as labeling reagents to aid in the diagnosis of Alzheimer’s disease (AD) at an early-to-moderate stage and to monitor the efficiency of treatment.[2] In addition, other studies have revealed that several benzothiazoles can serve as promising scaffolds for potent CaMKII[3] and 17β-HSD1 inhibitors­.[4] Benzothiazoles also serve as important intermediates for the preparation of antiviral agents,[5] fatty acid amide hydrolase inhibitors[6] and anticancer agents.[7]

Table 1 Optimization of the Reaction Conditionsa

Entry

Oxidant (equiv)

Time (h)

Temp (°C)

Solvent

Yield (%)b

1

TBHP (2)

5

80

EtOH

nd

2

TBHP (2)

5

80

DMF

nd

3

TBHP (2)

5

80

MeCN

nd

4

TBHP (2)

5

80

CH2Cl2

nd

5

TBHP (2)

5

80

EtOAc

nd

6

TBHP (2)

5

80

DMSO

60

7

DTBP (2)

5

80

DMSO

trace

8

aq H2O2 (31%) (2)

5

80

DMSO

trace

9

TBHP (3)

5

80

DMSO

77

10

TBHP (4)

5

80

DMSO

74

11c

TBHP (3)

5

80

DMSO

60

12d

TBHP (3)

5

80

DMSO

78

13

TBHP (3)

5

90

DMSO

81

14

TBHP (3)

5

70

DMSO

86

15

TBHP (3)

5

60

DMSO

84

16

TBHP (3)

5

50

DMSO

80

17

TBHP (3)

6

60

DMSO

81

18

TBHP (3)

3

60

DMSO

85

19

TBHP (3)

2

60

DMSO

78

a Reaction conditions: 1a (0.4 mmol, 0.0541 g), 2a (0.4 mmol, 0.0481 g), I2 (1 equiv), solvent (3 mL).

b Yield of isolated product; nd = not detected.

c I2 (0.5 equiv).

d I2 (2.0 equiv).

Because of the wide application and pharmacological importance of 2-acylbenzothiazoles, a number of different methods for their synthesis have been reported previously (Scheme [1]). These methods include the condensation of acetophenones with anilines in the presence of NaHS·nH2O (eq. a),[8] an in situ cross-trapping strategy for the acylation of benzothiazoles with aryl ketones (eq. b),[9] methods catalyzed by copper[10] or by Fe3+ (eq. c),[11] reactions of 2-aminothiophenols with phenylacetylenes (eq. d)[12] or α-hydroxyacetophenones (eq. e),[13] and decarboxylative acylation of heteroarenes via sp2 C–H functionalization (eq. f).[14] It is noted that several different strategies have been developed to assemble benzothiazoles.[15] However, these previous methods usually require high temperatures, a strong base, long reaction times, metal catalysis or toxic solvents. Therefore, in order to overcome these disadvantages, the development of novel routes for the synthesis of 2-acylbenzothiazoles is necessary. Thus, in continuation of our efforts on the synthesis of potentially bioactive key intermediates, we have designed an economic and straightforward strategy for the synthesis of 2-acylbenzothiazoles via the reaction of benzothiazoles with aryl ketones (eq. g).

To determine the optimum conditions, the reaction of benzothiazole (1a) with acetophenone (2a) was chosen as a model reaction in the presence of I2 and TBHP using different solvents (Table [1], entries 1–6). The results showed that the reaction only occurred in the presence of DMSO, giving the desired product in 60% yield at 80 °C (entry 6). Next, we tested the effect of different oxidants on the reaction and found that low yields of compound 3a were produced when the oxidant was hydrogen peroxide (H2O2) or di-tert-butyl peroxide (DTBP) (entries 7 and 8). To our delight, using 3 equivalents of tert-butyl hydroperoxide (TBHP, 70% in water) as the oxidant gave compound 3a in 77% yield (entry 9). However, when the loading of TBHP was more than 3 equivalents the yield did not increase (entries 10). Therefore, TBHP was chosen as the most appropriate oxidant for the reaction. Next, the effect of the loading of I2 on the reaction yield was explored (entries 11 and 12). Decreased yields were observed when the I2 loading was reduced to 0.5 equivalents (entry 11) or was increased to 2 equivalents (entry 12).

Furthermore, the effect of the temperature and reaction time on the yield of 3a was examined (Table [1], entries, 13–19). It turned out that the conversion resulted in an 85% yield when the reaction was run at 60 °C for 3 h (entry 18). However, extending or shortening the reaction time did not improve the yield of 3a (entries 17 and 19). Thus, equimolar quantities of reactants 1a and 2a in DMSO in the presence of 1 equivalent of I2 and 3 equivalents of TBHP as the oxidant were the optimum conditions for the synthesis of 3a (entry 18).

Next, with optimized conditions in hand, the substrate scope of this transformation was investigated (Scheme [2]). Aromatic ketones bearing electron-donating or electron-withdrawing groups were well tolerated. This showed that the position of the substituent on the phenyl ring of the aromatic ketone had no obvious effect on the reaction yield. Additionally, the scope of the benzothiazoles was also investigated. Both electron-withdrawing and electron-donating groups on the phenyl ring of the benzothiazole were compatible in reactions with different aryl ketones. In all cases, the corresponding products were obtained in good to excellent yields of 78–94% .

Zoom Image
Scheme 2 Scope of the benzothiazoles and aromatic ketones. Reagents and conditions: 1 (0.4 mmol), 2 (0.4 mmol), I2 (0.1015 g, 0.4 mmol, 1 equiv), TBHP (0.1545 g, 70% in water, 3 equiv), DMSO (3 mL), 60 °C, 3 h.

To gain insight into the mechanism of this acylation, we carried out several control experiments in DMSO at 60 °C for 3 hours (Scheme [3]). At first, acetophenone was replaced with benzaldehyde (eq. 1), however, none of the target compound 3a was obtained. This proved that the reaction was not a cross-dehydrogenative coupling reaction between the aldehyde and benzoxazole. Next, we explored the mechanism behind the ring-opening of the benzothiazole (1a). The benzothiazole ring remained intact when 1a was heated in DMSO in presence of 3 equivalents of TBHP (70% in water) without using I2 (eq. 2). With the addition of 3 equivalents of I2, benzothiazole (1a) was transformed into 2-aminothiophenol (1b) (eq. 3). Interestingly, when 4 equivalents of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) were added to the reaction system, 2-aminothiophenol (1b) was not observed (eq. 4). As expected, when benzothiazole was replaced with 2-aminothiophenol and reacted in the presence of I2, compound 3a was obtained in a yield of 80% (eq. 5). However, only a trace amount of 2-acylbenzothiazole 3a was obtained when 4 equivalents of TEMPO were added to the template reaction (eq. 6).

Zoom Image
Scheme 3 Control experiments; nd = not detected

Based on the results from the control reactions described above and previous reports,[16] a proposed mechanism for the formation of 2-acylbenzothiazoles is depicted in Scheme [4]. At first, acetophenone can be sequentially converted into phenylglyoxal A in the presence of I2 in DMSO based on a Kornblum oxidation.[15a] [17] In the process, the byproduct HI can be oxidized by DMSO or TBHP to regenerate I2.[18] As 2-aminothiophenol (1b) (see Scheme [3], eq. 3) was only detected in the presence of benzothiazole 1a with TBHP and I2, we can speculate that the presence of I2, TBHP and water causes ring opening of the thiazole moiety. Condensation between intermediates 1b and A forms imine intermediate B. Next, intermediate C is generated by an intramolecular addition reaction. A subsequent substitution reaction between C and I2 generates intermediate D, which finally produces the desired product 3a through elimination of HI.

In summary, we have developed a cheap and efficient method for the metal-free acylation between benzothiazoles and aryl ketones. The products were obtained in high yields using I2 and TBHP as ring-opening reagents. Compared with previous reports, this method has the advantages of a reduced reaction time and lower temperature, and avoids the use of metals, ligands and toxic solvents.

All reagents and solvents were obtained from commercial sources and were used without further purification. Reactions were routinely carried out under an airtight atmosphere with magnetic stirring. A IKA Plate (RCT digital) heating mantle was used to provide a stable heat source. TLC was conducted with Rushan Taiyang precoated glass-backed plates (silica gel 60 GF254) and visualized by exposure to UV light (254 nm). Flash column chromatography was performed on silica gel (300–400 mesh). Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400 MHz and 100 MHz, respectively. Chemical shifts are reported in ppm relative to the solvent signal, coupling constants (J) are given in hertz (Hz). Multiplicities are defined by standard abbreviations. High-resolution mass spectra (HRMS) were obtained using ESI ionization (positive) mode.

Zoom Image
Scheme 4 Proposed mechanism

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Benzo[d]thiazol-2-arylmethanones 3; General Procedure

A mixture of benzothiazole 1 (0.4 mmol), aryl ketone 2 (0.4 mmol), I2 (0.4 mmol) and TBHP (70%, 1.2 mmol) was heated at 60 °C in DMSO for 3 h. After completion of the reaction, EtOAc and saturated aqueous Na2S2O3 solution were added. The organic layer was separated, dried (MgSO4), filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (silica gel, petroleum ether/ethyl acetate, 25:1 to 8:1) to give product 3a–t.


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Benzo[d]thiazol-2-yl(phenyl)methanone (3a)[9]

Yellow solid; yield: 81 mg, 0.34 mmol (85%); mp 97–99 °C.

1H NMR (400 MHz, CDCl3): δ = 8.61–8.51 (m, 2 H), 8.25–8.18 (m, 1 H), 7.98 (dd, J = 8.2, 1.3 Hz, 1 H), 7.68–7.61 (m, 1 H), 7.58–7.49 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 185.30, 167.09, 153.85, 136.98, 133.91, 131.28, 128.50, 127.62, 126.92, 125.72, 122.16.

HRMS (ESI): m/z [M + H]+ calcd for C14H10NOS: 240.0477; found: 240.0472.


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Benzo[d]thiazol-2-yl(naphthalen-2-yl)methanone (3b)[9]

Yellow solid; yield: 106 mg, 0.368 mmol (92%); mp 166–168 °C.

1H NMR (400 MHz, CDCl3): δ = 9.33 (s, 1 H), 8.42 (dd, J = 8.7, 1.7 Hz, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 8.09–7.99 (m, 2 H), 7.96 (d, J = 8.7 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.66–7.50 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 185.04, 167.37, 153.91, 137.00, 135.94, 134.36, 132.43, 132.19, 130.22, 129.01, 128.32, 127.76, 127.58, 126.91, 126.72, 125.79, 125.74, 122.16.

HRMS (ESI): m/z [M + H]+ calcd for C18H12NOS: 290.0634; found: 290.0630.


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Benzo[d]thiazol-2-yl(4-ethoxyphenyl)methanone (3c)[8]

Yellow solid; yield: 107 mg, 0.376 mmol (94%); mp 112.5–115.3 °C.

1H NMR (400 MHz, CDCl3): δ = 8.66–8.58 (m, 2 H), 8.24–8.18 (m, 1 H), 8.02–7.93 (m, 1 H), 7.59–7.45 (m, 2 H), 7.02–6.98 (m, 2 H), 4.13 (q, J = 7.0 Hz, 2 H), 1.45 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.25, 167.94, 163.82, 153.86, 136.83, 133.83, 127.50, 127.31, 126.74, 125.48, 122.07, 114.28, 63.84, 14.65.

HRMS (ESI): m/z [M + H]+ calcd for C16H14NO2S: 284.0740; found: 284.0735.


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Benzo[d]thiazol-2-yl(o-tolyl)methanone (3d)[11]

Yellow solid; yield: 89 mg, 0.352 mmol (88%); mp 111–113 °C.

1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 9.2 Hz, 1 H), 8.03–7.97 (m, 2 H), 7.58–7.51 (m, 2 H), 7.47 (t, J = 6.9 Hz, 1 H), 7.34 (t, J = 7.3 Hz, 2 H), 2.52 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 189.17, 167.56, 153.79, 139.08, 137.25, 135.15, 132.02, 131.56, 131.38, 127.67, 126.93, 125.81, 125.33, 122.24, 20.70.

HRMS (ESI): m/z [M + H]+ calcd for C15H12NOS: 254.0634; found: 254.0628.


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Benzo[d]thiazol-2-yl(m-tolyl)methanone (3e)[11]

White solid; yield: 92 mg, 0.364 mmol (91%); mp 73–74 °C.

1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 8.3 Hz, 2 H), 8.22 (d, J = 7.9 Hz, 1 H), 7.99 (d, J = 8.6 Hz, 1 H), 7.60–7.49 (m, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 2.45 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.87, 167.43, 153.86, 144.98, 136.94, 134.72, 132.38, 131.39, 129.24, 128.37, 127.46, 126.81, 125.64, 122.11, 21.84.

HRMS (ESI): m/z [M + H]+ calcd for C15H12NOS: 254.0634; found: 254.0628.


#

Benzo[d]thiazol-2-yl(p-tolyl)methanone (3f)[9]

Yellow solid; yield: 86 mg, 0.34 mmol (85%); mp 95–97 °C.

1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 8.3 Hz, 2 H), 8.24 (dd, J = 7.4, 1.4 Hz, 1 H), 8.01 (dd, J = 7.6, 1.8 Hz, 1 H), 7.63–7.51 (m, 2 H), 7.39–7.33 (m, 2 H), 2.47 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.87, 167.42, 153.85, 144.99, 136.93, 132.36, 131.39, 129.24, 127.47, 126.82, 125.64, 122.12, 21.85.

HRMS (ESI): m/z [M + H]+ calcd for C15H12NOS: 254.0634; found: 254.0628.


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Benzo[d]thiazol-2-yl(4-bromophenyl)methanone (3g)[9]

Yellow solid; yield: 104 mg, 0.328 mmol (82%); mp 121–123 °C.

1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 8.7 Hz, 2 H), 8.19 (d, J = 8.7 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 1.9 Hz, 2 H), 7.57–7.47 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 183.94, 166.72, 153.75, 137.00, 133.57, 132.73, 131.77, 129.46, 127.75, 126.99, 125.72, 122.14.

HRMS (ESI): m/z [M + H]+ calcd for C14H9BrNOS: 317.9583; found: 317.9577.


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Benzo[d]thiazol-2-yl(3-bromophenyl)methanone (3h)

Yellow solid; yield: 102 mg, 0.32 mmol (80%); mp 98–100 °C.

1H NMR (400 MHz, CDCl3): δ = 8.70 (t, J = 1.8 Hz, 1 H), 8.54 (dt, J = 7.8, 1.3 Hz, 1 H), 8.30–8.24 (m, 1 H), 8.05–8.00 (m, 1 H), 7.82–7.77 (m, 1 H), 7.64–7.54 (m, 2 H), 7.45 (t, J = 7.9 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 183.87, 166.35, 153.77, 137.04, 136.65, 136.62, 133.97, 130.01, 129.87, 127.86, 127.06, 125.86, 122.62, 122.17.

HRMS (ESI): m/z [M + H]+ calcd for C14H9BrNOS: 317.9583; found: 317.9577.


#

Benzo[d]thiazol-2-yl(3-chlorophenyl)methanone (3i)[11]

Yellow solid; yield: 85 mg, 0.312 mmol (78%); mp 98–100 °C.

1H NMR (400 MHz, CDCl3): δ = 8.56 (t, J = 2.1 Hz, 1 H), 8.50–8.46 (m, 1 H), 8.29–8.24 (m, 1 H), 8.05–8.01 (m, 1 H), 7.67–7.62 (m, 1 H), 7.62–7.54 (m, 2 H), 7.52 (t, J = 8.1 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 184.00, 166.40, 153.78, 137.04, 136.41, 134.66, 133.76, 131.12, 129.78, 129.40, 127.86, 127.06, 125.85, 122.17.

HRMS (ESI): m/z [M + H]+ calcd for C14H9ClNOS: 274.0088; found: 274.0083.


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(3-Bromophenyl)(5-chlorobenzo[d]thiazol-2-yl)methanone (3j)

Yellow solid; yield: 114 mg, 0.324 mmol (81%); mp 107–108 °C.

1H NMR (400 MHz, CDCl3): δ = 8.68 (t, J = 1.7 Hz, 1 H), 8.51 (d, J = 7.9 Hz, 1 H), 8.25 (d, J = 2.0 Hz, 1 H), 7.93 (d, J = 8.6 Hz, 1 H), 7.79 (dd, J = 8.0, 2.0 Hz, 1 H), 7.52 (dd, J = 8.6, 2.0 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 183.46, 168.14, 154.49, 136.87, 136.29, 135.23, 134.00, 133.19, 130.06, 129.86, 128.48, 125.35, 122.94, 122.68.

HRMS (ESI): m/z [M + H]+ calcd for C14H8BrClNOS: 351.9193; found: 351.9189.


#

(5-Chlorobenzo[d]thiazol-2-yl)(m-tolyl)methanone (3k)

Yellow solid; yield: 100 mg, 0.348 mmol (87%); mp 114–116 °C.

1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 7.5 Hz, 1 H), 8.26 (s, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 7.91 (d, J = 8.6 Hz, 1 H), 7.52–7.45 (m, 2 H), 7.43 (t, J = 7.5 Hz, 1 H), 2.46 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 185.10, 169.01, 154.55, 138.36, 135.17, 134.95, 134.62, 132.93, 131.46, 128.64, 128.41, 128.12, 125.20, 122.91, 21.44.

HRMS (ESI): m/z [M + H]+ calcd for C15H11ClNOS: 288.0244; found: 288.0240.


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(5-Chlorobenzo[d]thiazol-2-yl)(phenyl)methanone (3l)

White solid; yield: 93 mg, 0.34 mmol (85%); mp 134–136 °C.

1H NMR (400 MHz, CDCl3): δ = 8.55 (dt, J = 8.1, 1.8 Hz, 2 H), 8.24 (d, J = 2.0 Hz, 1 H), 7.94 (d, J = 8.6 Hz, 1 H), 7.69 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.7 Hz, 2 H), 7.53 (dd, J = 8.6, 2.4 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 184.89, 168.89, 154.57, 135.18, 134.61, 134.11, 132.98, 131.27, 128.54, 128.20, 125.21, 122.93.

HRMS (ESI): m/z [M + H]+ calcd for C14H9ClNOS: 274.0088; found: 274.0083.


#

(5-Chlorobenzo[d]thiazol-2-yl)(p-tolyl)methanone (3m)

White solid; yield: 102 mg, 0.356 mmol (89%); mp 115–117 °C.

1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 8.3 Hz, 2 H), 8.24 (d, J = 2.5 Hz, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.52 (dd, J = 8.6, 2.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 2 H), 2.48 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.36, 169.25, 154.57, 145.27, 135.14, 132.88, 132.05, 131.40, 129.29, 128.04, 125.14, 122.89, 21.86.

HRMS (ESI): m/z [M + H]+ calcd for C15H11ClNOS: 288.0244; found: 288.0240.


#

(4-Bromophenyl)(5-chlorobenzo[d]thiazol-2-yl)methanone (3n)[15a]

Yellow solid; yield: 113 mg, 0.32 mmol (80%); mp 184–186 °C.

1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 8.6 Hz, 2 H), 8.21 (s, 1 H), 7.92 (d, J = 8.6 Hz, 1 H), 7.69 (d, J = 8.6 Hz, 2 H), 7.51 (dd, J = 8.6, 2.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 183.75, 168.52, 154.50, 135.21, 133.31, 133.13, 132.73, 131.89, 129.77, 128.38, 125.23, 122.95.

HRMS (ESI): m/z [M + H]+ calcd for C14H8BrClNOS: 351.9193; found: 351.9189.


#

(5-Methoxybenzo[d]thiazol-2-yl)(naphthalen-2-yl)methanone (3o)[9]

Yellow solid; yield: 119 mg, 0.372 mmol (93%); mp 179–182 °C.

1H NMR (400 MHz, CDCl3): δ = 9.30 (s, 1 H), 8.41 (d, J = 10.3 Hz, 1 H), 8.14 (d, J = 9.1 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.66–7.59 (m, 1 H), 7.59–7.53 (m, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.19 (d, J = 11.6 Hz, 1 H), 3.92 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.85, 164.87, 159.73, 148.56, 139.08, 135.84, 134.04, 132.45, 132.39, 130.16, 128.85, 128.22, 127.73, 126.64, 126.46, 125.84, 117.59, 103.38, 55.84.

HRMS (ESI): m/z [M + H]+ calcd for C19H14NO2S: 329.0740; found: 329.0735.


#

(5-Methoxybenzo[d]thiazol-2-yl)(4-methoxyphenyl)methanone (3p)

Yellow solid; yield: 109 mg, 0.364 mmol (91%); mp 147–149 °C.

1H NMR (400 MHz, CDCl3): δ = 8.61 (d, J = 9.0 Hz, 2 H), 8.06 (d, J = 9.1 Hz, 1 H), 7.37 (s, 1 H), 7.14 (d, J = 11.6 Hz, 1 H), 7.00 (d, J = 9.0 Hz, 2 H), 3.88 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 183.13, 165.35, 164.17, 159.52, 148.48, 138.86, 133.66, 127.89, 126.20, 117.37, 113.77, 103.36, 55.79, 55.50.

HRMS (ESI): m/z [M + H]+ calcd for C16H14NO3S: 300.0689; found: 300.0685.


#

(4-Ethoxyphenyl)(5-methoxybenzo[d]thiazol-2-yl)methanone (3q)

Yellow solid; yield: 115 mg, 0.368 mmol (92%); mp 158–160 °C.

1H NMR (400 MHz, CDCl3): δ = 8.69–8.53 (m, 2 H), 8.14–8.05 (m, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.18 (dd, J = 9.1, 2.5 Hz, 1 H), 7.05–6.98 (m, 2 H), 4.16 (q, J = 6.9 Hz, 2 H), 3.93 (s, 3 H), 1.47 (q, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.11, 165.35, 163.54, 159.41, 148.40, 138.77, 127.60, 126.12, 117.28, 114.12, 103.26, 63.71, 55.72, 14.56.

HRMS (ESI): m/z [M + H]+ calcd for C17H16NO3S: 314.0845; found: 314.0840.


#

(4-Bromophenyl)(5-methoxybenzo[d]thiazol-2-yl)methanone (3r)

Yellow solid; yield: 123 mg, 0.352 mmol (88%); mp 192–193 °C.

1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 8.6 Hz, 2 H), 8.07 (d, J = 9.1 Hz, 1 H), 7.67 (d, J = 8.6 Hz, 2 H), 7.38 (d, J = 2.5 Hz, 1 H), 7.17 (dd, J = 9.1, 2.5 Hz, 1 H), 3.91 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.96, 164.18, 159.88, 148.43, 139.16, 133.85, 132.63, 131.74, 129.16, 126.47, 117.77, 103.34, 55.84.

HRMS (ESI): m/z [M + H]+ calcd for C15H11BrNO2S: 347.9688; found: 347.9682.


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(5-Methoxybenzo[d]thiazol-2-yl)(p-tolyl)methanone (3s)

Yellow solid; yield: 93 mg, 0.328 mmol (82%); mp 153–154 °C.

1H NMR (400 MHz, CDCl3): δ = 8.46 (d, J = 8.2 Hz, 2 H), 8.09 (d, J = 9.1 Hz, 1 H), 7.40 (d, J = 2.5 Hz, 1 H), 7.35 (dd, J = 7.8, 0.8 Hz, 2 H), 7.17 (ddd, J = 9.0, 2.5, 0.7 Hz, 1 H), 3.92 (s, 3 H), 2.46 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.57, 164.83, 159.52, 148.39, 144.58, 138.88, 132.45, 131.16, 129.07, 126.25, 117.38, 103.25, 55.71, 21.71.

HRMS (ESI): m/z [M + H]+ calcd for C16H14NO2S: 284.0740; found: 284.0738.


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(3-Bromophenyl)(5-methoxybenzo[d]thiazol-2-yl)methanone (3t)

Yellow solid; yield: 114 mg, 0.328 mmol (82%); mp 160–161 °C.

1H NMR (400 MHz, CDCl3): δ = 8.66 (t, J = 1.8 Hz, 1 H), 8.49 (d, J = 7.9 Hz, 1 H), 8.10 (d, J = 9.1 Hz, 1 H), 7.79–7.72 (m, 1 H), 7.42 (d, J = 7.9 Hz, 1 H), 7.39 (d, J = 2.7 Hz, 1 H), 7.18 (dd, J = 9.1, 2.5 Hz, 1 H), 3.91 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.60, 163.82, 159.94, 148.43, 139.20, 136.85, 136.39, 133.86, 129.94, 129.75, 126.59, 122.55, 117.82, 103.31, 55.85.

HRMS (ESI): m/z [M + H]+ calcd for C15H11BrNO2S: 347.9688; found: 347.9685.


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2-Aminobenzenethiol (1b)

Yellow solid; yield: 49 mg (98%); mp 70–72 °C.

1H NMR (400 MHz, CDCl3): δ = 7.18 (dd, J = 7.7, 0.9 Hz, 2 H), 6.71 (d, J = 7.6 Hz, 1 H), 6.63–6.59 (m, 1 H), 4.33 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 148.68, 136.84, 131.67, 118.69, 118.24, 115.31.

HRMS (ESI): m/z [M + H]+ calcd for C6H8NS: 126.0372; found: 126.0368.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707204.
  • Supporting Information

Primary Data

    for this article are available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-000040-1707204 and can be cited using the following DOI: 10.4125/pd0120th.
  • Primary Data


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Scheme 1 Previous routes and our strategy for the synthesis of 2-acylbenzothiazoles
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Scheme 2 Scope of the benzothiazoles and aromatic ketones. Reagents and conditions: 1 (0.4 mmol), 2 (0.4 mmol), I2 (0.1015 g, 0.4 mmol, 1 equiv), TBHP (0.1545 g, 70% in water, 3 equiv), DMSO (3 mL), 60 °C, 3 h.
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Scheme 3 Control experiments; nd = not detected
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Scheme 4 Proposed mechanism