One-pot,simple,and facile synthesis of 4-(3-benzylbenzo[ d ]thiazol-2(3 H )-ylidene)-cyclohexa-2,5-dien-1-one derivatives via a novel three-component reaction

Abstract

In this study, a series of 4-(3-benzylbenzo[d]thiazol-2(3H)-ylidene)-cyclohexa-2,5-dien-1-one derivatives are efficiently synthesized in excellent yields by reactions of 2-chlorobenzothiazole, benzyl bromides, and phenols in acetonitrile under reflux and catalyst-free conditions in the presence of triethylamine for 2 h. The structures of the products are characterized by NMR, IR, EI-MS, and elemental analyses.

Introduction

Multicomponent reactions (MCRs) are a type of organic reaction that consists of two or more synthetic steps that are carried out without isolation of any intermediate; therefore, they help to save time, money, energy, and raw materials.^1,2 These reactions are economically and environmentally beneficial to industry and have attracted much attention. On the other hand, they are perfectly applicable to organic synthesis and agrochemistry.^3,4 Benzothiazole is a bicyclic heterocyclic compound in which benzene is fused with the thiazole ring at the 4, 5-positions, containing both sulfur and nitrogen electron-rich heteroatoms in its ring.^5,6 Benzothiazoles and their analogues are important building blocks and synthetic intermediates in the synthesis of new drugs, pesticides, and dyes, and are utilized in medicinal chemistry.^7,8 Derivatives of benzothiazole have been reported to show a wide spectrum of pharmacological activities and agrochemical applications like anti-convulsant, ⁹ antiallergy, ¹⁰ antifungal, ¹⁰ anti-microbial, ¹¹ anti-oxidant, ¹² anti-inflammatory, ¹² anti-diabetic, ¹³ neuroprotective, and many others ¹⁴ (Figure 1). On the other hand, benzothiazoles are also widely used in a variety of consumer and industrial products such as nonlinear optics (NLOs), organic light-emitting diodes (OLEDs), fluorescent probes, luminescence, chemosensors,^15–17 and liquid crystals. ¹⁸ In this paper, the results of studies involving new, easy, and catalyst-free multicomponent reactions of 2-chlorobenzothiazole (1), benzyl bromides (2), and phenols (3) for the preparation of 4-(3-benzylbenzo[d]thiazol-2(3H)-ylidene)-cyclohexa-2,5-dien-1-one derivatives 4a–i are reported (Scheme 1 and Scheme 2).

Figure 1.

Chemical structures of some drugs containing benzothiazole nuclei.

Scheme 1.

Proposed mechanism for the preparation of compounds 4.

Scheme 2.

Chemical structures of compounds 4a–i containing benzothiazole and phenol moieties.

Results and discussion

In continuation of our studies on the application of both benzothiazole and phenol in multicomponent reactions,^19–22 a new, simple, and efficient method for the synthesis of 4-(3-benzylbenzo[d]thiazol-2(3H)-ylidene)-cyclohexa-2,5-dien-1-one derivatives 4a–i in excellent yields is reported from 2-chlorobenzothiazole (1), benzyl bromides (2), and 2,6-dimethylphenol or 2,6-di-tert-butylphenol (3) in acetonitrile under reflux and catalyst-free conditions in the presence of triethylamine as a base for 2 h (Scheme 1 and Scheme 2). Although the mechanistic details of the reaction are not known, a plausible rationalization may be advanced to explain the product formation. At first, salt 5 is obtained from the reaction of 2-chlorobenzothiazole (1) and benzyl bromides (2) for 1 h under reflux conditions. Next, phenols (3) are added in the presence of Et₃N as a base, and the mixture is stirred for 1 h under the same conditions in order to produce 6. At the end, this compound 6 is converted into product 4. The ¹H and ¹³C NMR spectra of the crude products clearly indicated the formation of compounds 4a–i. No products other than 4a–i could be detected by NMR spectroscopy. The structures of the newly synthesized compounds 4a–i were further confirmed from their IR, elemental analysis, and mass spectral data. For example, the ¹H NMR spectrum of 4a exhibited three singlets at 1.92 and 1.94 ppm (6H, 2Me) and 4.17 ppm (2H, CH₂). In addition, signals due to the two olefinic protons were observed as two singlets 6.42 and 6.43 (2H, 2CH=CMe). The aromatic protons gave multiplets at 6.62–7.46 ppm (9ArH) for the benzothiazole and benzyl moieties.^19–24 The ¹³C NMR spectrum of 4a showed 22 distinct resonances in agreement with the proposed structure. In addition, product 4a displayed ¹³C NMR resonances at δ 15.20, 15.21, 51.6, 105.6, 132.6, 143.7, 149.3, and 185.4 ppm, respectively, for the 2Me, CH₂, S-C=C, C=CMe, S-C=C, and C=C-C=O carbons.^19–27 The ¹H NMR and ¹³C NMR spectra of 4b–i are similar to those of 4a. The IR spectrum of compound 4a showed an absorption band due to the carbonyl group at 1748 cm^‒1. The mass spectrum of this compound displayed the molecular ion peak at m/z 345, which is in agreement with the proposed structure.

Conclusion

In this study, the target compounds containing both benzothiazole and phenol moieties have been synthesized with excellent yields via a convenient and efficient method, under catalyst-free conditions at reflux for 2 h. On the other hand, simple work-up, short reaction time, and easily available starting materials are the other advantages of this procedure with acetonitrile as the solvent.

Experimental

All the chemicals used in this work were purchased from Merck (Germany) and Fluka (Buchs, Switzerland) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus. The mass spectra were recorded on a GCMS-QP5050A mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. The ¹H and ¹³C NMR spectra were recorded using a BRUKER DRX-250 AVANCE instrument with CDCl₃ as the solvent and TMS as the internal standard at 250.1 and 62.9 MHz, respectively.

Preparation of compound 6a; typical procedure

A mixture of 2-chlorobenzothiazole (1) (1 mmol) and benzyl bromide (2) (1 mmol) was stirred in acetonitrile (10 mL) under reflux for 1 h. Next, phenol (3) (1 mmol) and Et₃N (1 equiv.) were added to the reaction mixture under the same conditions, and stirring was continued for 1 h. After 1 h, the reaction product was obtained as a yellow solid. The solvent was then removed, and the product was washed with cold diethyl ether (3 × 3 mL). The residue was recrystallized from n-hexane/EtOAc 4:2 to give 4a.

4-(3-Benzylbenzo[d]thiazol-2(3H)-ylidene)-2,6-dimethylcyclohexa-2,5-dien-1-one (4a)

Yellow powder, yield 91%, 0.31 g; m.p. 142–144 °C. IR (KBr): 1748 (C=O) cm^‒1. MS (EI): m/z (%) = 345 (M⁺, 6), 330 (M-Me, 91), 315 (M-2Me, 84), 268 (M-Ph, 59), 254 (M-C₇H₇, 63), 91 (C₇H₇, 46). Anal. calcd for C₂₂H₁₉NOS (345.39): C, 76.50; H, 5.54; N, 4.05; found: C, 76.52; H, 5.59; N, 3.94. ¹H NMR (250.1, CDCl₃): δ 1.92 and 1.94 (6H, 2s, 2Me), 4.17 (2H, s, CH₂), 6.42 (1H, s, CH=CMe), 6.43 (1H, s, CH=CMe), 6.62–7.46 (9H, m, 9ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 15.20 and 15.21 (2Me), 51.6 (CH₂), 105.6 (S-C=C), 113.7, 114.2, 116.3, 118.8, 125.2, 127.4, 128.5, 129.6, 132.6 (CH=CMe), 132.8 (CH=CMe), 143.7 (CH=CMe), 143.9 (CH=CMe), 144.1, 145.2 and 149.3 (S-C=C), 185.4 (C=O).

2,6-Dimethyl-4-(3-(2-methylbenzyl)benzo[d]thiazol-2(3H)-ylidene)cyclohexa-2,5-dien-1-one (4b)

Yellow powder, yield 91%, 0.33 g; m.p. 135–137 °C. IR (KBr): 1749 (C=O) cm^‒1. MS (EI): m/z (%) = 359 (M⁺, 7), 344 (M-Me, 94), 329 (M-2Me, 86), 268 (M-C₇H₇, 70), 254 (M-C₈H₉, 62), 253 (M-C₇H₇ and Me, 59), 105 (C₈H₉, 47). Anal. calcd for C₂₃H₂₁NOS (359.41): C, 76.86; H, 5.89; N, 3.90; found: C, 76.93; H, 5.92; N, 3.80. ¹H NMR (250.1, CDCl₃): δ 1.93, 1.94 and 2.12 (9H, 3s, 3Me), 4.16 (2H, s, CH₂), 6.41 (1H, s, CH=CMe), 6.43 (1H, s, CH=CMe), 6.61–7.44 (8H, m, 8ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 15.19 and 15.20 (2Me), 23.4 (Me), 51.6 (CH₂), 105.8 (S-C=C), 113.8, 114.4, 117.2, 119.8, 121.4, 125.2, 126.3, 127.6, 128.4, 128.6, 132.7 (CH=CMe), 132.8 (CH=CMe), 143.8 (CH=CMe), 143.9 (CH=CMe), 144.7, 145.6 and 149.4 (S-C=C), 185.4 (C=O).

2,6-Dimethyl-4-(3-(2-nitrobenzyl)benzo[d]thiazol-2(3H)-ylidene)cyclohexa-2,5-dien-1-one (4c)

Pale yellow powder, yield 90%, 0.35 g; m.p. 152–154 °C. IR (KBr): 1749 (C=O) cm^‒1. MS (EI): m/z (%) = 390 (M⁺, 6), 375 (M-Me, 93), 268 (M-C₆H₄NO₂, 72), 254 (M-C₇H₆NO₂, 51), 253 (M-C₆H₄NO₂ and Me, 59), 136 (C₇H₆NO₂, 54). Anal. calcd for C₂₂H₁₈N₂O₃S (390.38): C, 67.69; H, 4.65; N, 7.17; found: C, 67.72; H, 4.59; N, 7.10. ¹H NMR (250.1, CDCl₃): δ 1.93 and 1.95 (6H, 2s, 2Me), 4.20 (2H, s, CH₂), 6.43 (1H, s, CH=CMe), 6.44 (1H, s, CH=CMe), 6.60–7.46 (8H, m, 8ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 15.18 and 15.21 (2Me), 52.0 (CH₂), 105.7 (S-C=C), 114.7, 115.6, 117.9, 119.8, 123.6, 125.7, 127.4, 129.1, 130.3, 132.9 (CH=CMe), 133.0 (CH=CMe), 140.1, 144.0 (CH=CMe), 144.1 (CH=CMe), 146.8, 147.7 and 149.4 (S-C=C), 185.5 (C=O).

4-(3-Benzylbenzo[d]thiazol-2(3H)-ylidene)-2,6-dimethoxycyclohexa-2,5-dien-1-one(4d)

Yellow powder, yield 92%, 0.35 g; m.p. 146–148 °C. IR (KBr): 1750 (C=O) cm^‒1. MS (EI): m/z (%) = 377 (M⁺, 8), 362 (M-Me, 95), 347 (M-2Me, 89), 346 (M-OMe, 68), 300 (M-Ph, 70), 269 (M-Ph and OMe, 49), 91 (C₇H₇, 57). Anal. calcd for C₂₂H₁₉NO₃S (377.39): C, 70.02; H, 5.07; N, 3.71; found: C, 70.05; H, 5.05; N, 3.80. ¹H NMR (250.1, CDCl₃): δ 3.42 and 3.43 (6H, 2s, 2OMe), 4.22 (2H, s, CH₂), 6.37 (1H, s, CH=COMe), 6.39 (1H, s, CH=COMe), 6.58–7.37 (9H, m, 9ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 49.1 and 49.2 (2OMe), 51.8 (CH₂), 106.4 (S-C=C), 113.9, 116.3, 117.4, 121.8, 126.2, 129.3, 130.7, 133.8 (CH=COMe), 134.1 (CH=COMe), 136.8, 143.2, 145.7, 148.6 (S-C=C), 156.4 (CH=COMe), 156.5 (CH=COMe), 186.7 (C=O).

2,6-Dimethoxy-4-(3-(2-methylbenzyl)benzo[d]thiazol-2(3H)-ylidene)cyclohexa-2,5-dien-1-one (4e)

Golden yellow powder, yield 91%, 0.36 g; m.p. 140–142 °C. IR (KBr): 1749 (C=O) cm^‒1. MS (EI): m/z (%) = 391 (M⁺, 9), 376 (M-Me, 94), 361 (M-2Me, 76), 360 (M-OMe, 82), 345 (M-OMe and Me, 69), 286 (M-C₈H₉, 60), 271 (M-C₈H₉ and Me, 55). Anal. calcd for C₂₃H₂₁NO₃S (391.41): C, 70.58; H, 5.41; N, 3.58; found: C, 70.54; H, 5.47; N, 3.49. ¹H NMR (250.1, CDCl₃): δ 2.09 (3H, s, Me), 3.42 and 3.44 (6H, 2s, 2OMe), 4.21 (2H, s, CH₂), 6.38 (1H, s, CH=COMe), 6.39 (1H, s, CH=COMe), 6.59–7.38 (8H, m, 8ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 23.7 (Me), 49.1 and 49.3 (2OMe), 52.0 (CH₂), 106.4 (S-C=C), 114.7, 116.8, 117.7, 121.5, 123.4, 126.5, 128.3, 129.8, 132.1, 133.9 (CH=COMe), 134.1 (CH=COMe), 136.5, 143.3, 145.9, 148.8 (S-C=C), 156.5 (CH=COMe), 156.7 (CH=COMe), 186.7 (C=O).

2,6-Dimethoxy-4-(3-(2-nitrobenzyl)benzo[d]thiazol-2(3H)-ylidene)cyclohexa-2,5-dien-1-one (4f)

Pale yellow powder, yield 91%, 0.38 g; m.p. 157–159 °C. IR (KBr): 1750 (C=O) cm^‒1. MS (EI): m/z (%) = 422 (M⁺, 6), 407 (M-Me, 93), 376 (M-OMe and Me, 70), 360 (M-2OMe, 54), 300 (M-C₆H₄NO₂, 58), 224 (M-C₇H₆NO₂ and 2OMe, 28), 136 (C₇H₆NO₂, 47). Anal. calcd for C₂₂H₁₈N₂O₅S (422.38): C, 62.56; H, 4.29; N, 6.63; found: C, 62.61; H, 4.33; N, 6.51. ¹H NMR (250.1, CDCl₃): δ 3.44 and 3.46 (6H, 2s, 2OMe), 4.25 (2H, s, CH₂), 6.36 (1H, s, CH=COMe), 6.38 (1H, s, CH=COMe), 6.62–7.40 (8H, m, 8ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 48.9 and 49,1 (2OMe), 52.3 (CH₂), 106.6 (S-C=C), 115.1, 116.6, 118.3, 121.7, 122.4, 126.5, 128.2, 130.0, 132.3, 134.2 (CH=COMe), 134.3 (CH=COMe), 136.8, 143.5, 146.1 and 148.9 (S-C=C), 156.8 (CH=COMe), 157.1 (CH=COMe), 186.9 (C=O).

4-(3-Benzylbenzo[d]thiazol-2(3H)-ylidene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (4g)

Yellow powder, yield 91%, 0.39 g; m.p. 138–140 °C. IR (KBr): 1751 (C=O) cm^‒1. MS (EI): m/z (%) = 429 (M⁺, 7), 414 (M-Me, 92), 372 (M-CMe₃, 85), 352 (M-Ph, 77), 323 (M-C₇H₇ and Me, 53), 295 (M-Ph and CMe₃, 50), 91 (C₇H₇, 37), 57 (CMe₃, 48). Anal. calcd for C₂₈H₃₁NOS (429.55): C, 78.29; H, 7.27; N, 3.26; found: C, 78.27; H, 7.24; N, 3.18. ¹H NMR (250.1, CDCl₃): δ 1.14 and 1.16 (18H, 2s, 2CMe₃), 4.21 (2H, s, CH₂), 6.35 (1H, s, CH=CCMe₃), 6.37 (1H, s, CH=CCMe₃), 6.59–7.37 (9H, m, 8ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 27.4 and 27,5 (2CMe₃), 31.7 and 31.8 (2CMe₃), 51.7 (CH₂), 107.3 (S-C=C), 114.4, 115.9, 117.8, 122.7, 127.1, 128.5, 132.8, 135.1 (CH=CCMe₃), 135.3 (CH=CCMe₃), 138.2, 141.4, 142.1, 144.3 (CH=CCMe₃), 144.4 (CH=CCMe₃), 148.2 (S-C=C), 185.7 (C=O).

2,6-Di-tert-butyl-4-(3-(2-methylbenzyl)benzo[d]thiazol-2(3H)-ylidene)cyclohexa-2,5-dien-1-one (4h)

Yellow powder, yield 92%, 0.41 g; m.p. 147–149 °C. IR (KBr): 1748 (C=O) cm^‒1. MS (EI): m/z (%) = 443 (M⁺, 8), 428 (M-Me, 90), 413 (M-2Me, 82), 386 (M-CMe₃, 79), 371 (M-CMe₃ and Me, 56), 338 (M-C₈H₉, 42), 105 (C₈H₉, 48), 57 (CMe₃, 50). Anal. calcd for C₂₉H₃₃NOS (443.58): C, 78.52; H, 7.50; N, 3.16; found: C, 78.59; H, 7.45; N, 3.25. ¹H NMR (250.1, CDCl₃): δ 1.15 and 1.16 (18H, 2s, 2CMe₃), 2.14 (3H, s, Me), 4.20 (2H, s, CH₂), 6.33 (1H, s, CH=CCMe₃), 6.34 (1H, s, CH=CCMe₃), 6.60–7.39 (8H, m, 8ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 23.6 (Me), 27.3 and 27,5 (2CMe₃), 31.7 and 31.9 (2CMe₃), 51.8 (CH₂), 107.2 (S-C=C), 113.8, 115.6, 118.7, 123.8, 125.4, 127.1, 129.2, 132.8, 134.2, 135.0 (CH=CCMe₃), 135.2 (CH=CCMe₃), 138.4, 141.3, 142.0, 144.4 (CH=CCMe₃), 144.6 (CH=CCMe₃), 148.1 (S-C=C), 185.6 (C=O).

2,6-Di-tert-butyl-4-(3-(2-nitrobenzyl)benzo[d]thiazol-2(3H)-ylidene)cyclohexa-2,5-dien-1-one (4i)

Pale yellow powder, yield 90%, 0.43 g; m.p. 159–161 °C. IR (KBr): 1750 (C=O) cm^‒1. MS (EI): m/z (%) = 474 (M⁺, 7), 459 (M-Me, 87), 417 (M-CMe₃, 66), 360 (M-2CMe₃, 40), 352 (M-C₆H₄NO₂, 62), 337 (M-C₆H₄NO₂ and Me, 46), 136 (C₇H₆NO₂, 53), 57 (CMe₃, 47). Anal. calcd for C₂₈H₃₀N₂O₃S (474.54): C, 70.87; H, 6.37; N, 5.90; found: C, 70.81; H, 6.41; N, 5.79. ¹H NMR (250.1, CDCl₃): δ 1.16 and 1.18 (18H, 2s, 2CMe₃), 4.27 (2H, s, CH₂), 6.35 (1H, s, CH=CCMe₃), 6.37 (1H, s, CH=CCMe₃), 6.58–7.40 (8H, m, 8ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ 27.7 and 27,9 (2CMe₃), 31.8 and 31.9 (2CMe₃), 52.4 (CH₂), 107.4 (S-C=C), 115.5, 116.7, 119.6, 124.7, 126.2, 128.1, 132.8, 134.2, 135.3 (CH=CCMe₃), 135.5 (CH=CCMe₃), 137.3, 138.2, 141.4, 142.0, 144.2 (CH=CCMe₃), 144.3 (CH=CCMe₃), 148.4 (S-C=C), 185.9 (C=O).