A novel,simple,and facile synthesis of 3-(3-benzyl-2,3-dihydrobenzo[ d ]thiazol-2-yl)benzo[ d ]oxazole-2(3 H )-thione derivatives

Abstract

Novel 3-(3-benzyl-2,3-dihydrobenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione derivatives are efficiently synthesized in excellent yields by reactions of benzothiazoles, benzyl bromides, and 2-mercaptobenzoxazole in acetone under catalyst-free conditions in the presence of triethylamine. The structures of the products are confirmed by nuclear magnetic resonance spectroscopy, infrared spectroscopy, electron ionization mass spectrometry, and elemental analyses.

Keywords

2-mercaptibenzothiazole benzothiazoles benzyl bromides three-component reaction

Introduction

Multi-component reactions (MCRs) are economically and environmentally beneficial to industry and have attracted much attention. These reactions are perfectly applicable to organic synthesis and agrochemistry.^1,2 Benzoxazoles are an important class of heterocyclic compound consisting of a benzene-fused oxazole ring, and are known to exhibit remarkable biological activities.^3,4 Benzothiazole is a heterocyclic compound containing sulfur and nitrogen atoms and possesses high chemical and photophysical stability compared to other heteroaromatic molecules, and it is sometimes used as an electron acceptor due to its strong electron-withdrawing capability.⁵ Benzothiazoles and their analogues are important building blocks and synthetic intermediates in the synthesis of new drugs, pesticides, and dyes, and one utilized medicinal in chemistry.^6,7 Derivatives of benzothiazole have been reported to show a broad range of biological and agrochemical applications like antitubercular,⁷ antifolate,⁸ antihelmintic,⁹ anti-inflammatory,¹⁰ antioxidant,¹¹ and antileishmanial.¹² However, benzothiazoles are also widely used in a variety of consumer and industrial products such as in nonlinear optics (NLOs), organic light-emitting diodes (OLEDs), fluorescent probes, luminescence, chemosensors,^13–15 and liquid crystals.¹⁶ In this paper, the results of studies involving simple, novel, and catalyst-free reactions of benzothiazoles (1), benzyl bromides (2), and 2-mercaptobenzoxazole (3) for the synthesis of 3-(3-benzyl-2,3-dihydrobenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione derivatives 6a–g are reported (Scheme 1).

Scheme 1.

General procedure and the structures of compounds 6a–g containing benzothiazole and benzoxazole moieties.

Results and discussion

In continuation of our studies on the application of both benzothiazole and 2-mercaptobenzoxazole in MCRs,^17–19 a new, easy, and efficient route for the synthesis of 3-(3-benzyl-2,3-dihydrobenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione derivatives 6a–g in excellent yields is reported from benzothiazoles (1), benzyl bromides (2), and 2-mercaptobenzoxazole (3) in acetone under reflux conditions (Scheme 1). Although the mechanistic details of the reaction are not known, a plausible rationalization may be advanced to explain the product formation. Initially, salt 4 is obtained from the reaction of benzothiazoles (1) and benzyl bromides (2) for 1 h under reflux conditions. Next, 2-mercaptobenzoxazole (3) is added in the presence of Et₃N as a base, and the mixture was stirred for 2 h under same conditions to intermediate 5 that reacts with salt 4 to afford the products 6.

The ¹H and ¹³C nuclear magnetic resonance (NMR) spectra of the crude products clearly indicated the formation of compounds 6a–g. No products other than 6a–g could be detected by NMR spectroscopy. The structures of the newly synthesized compounds 6a–g were further confirmed from infrared (IR) spectroscopy, elemental analysis, and mass spectral data. For example, the ¹H NMR spectrum of 6a exhibited a singlet at 4.13 ppm (2H, CH₂) and the aromatic and NCHN protons occurred multiplets 6.69–7.86 ppm (13ArH and NCHN).^17–21 The ¹³C NMR spectrum of 6a showed 18 distinct resonances in agreement with the proposed structure. Product 6a displayed ¹³C NMR resonances at 51.4, 94.3, and 183.1 ppm, respectively, for the CH₂, the SCN, and C=S carbons.^17–26 The ¹H NMR and ¹³C NMR spectra of 6b–g were similar to those of 6a. The IR spectrum of compound 6a showed an absorption band due to the thiocarbonyl group at 1663 cm⁻¹. The mass spectrum of this compound displayed the molecular ion peak at m/z 376, which is in agreement with the proposed structure.

Conclusion

In this study, the target compounds containing both benzothiazole and benzoxazole moieties have been synthesized with excellent yields via a convenient and efficient method under catalyst-free conditions at reflux for 3 h. The method utilizes easily available starting materials in acetone as the solvent, and the work-up procedure is simple.

Experimental

Compounds 1, 2, and 3 were obtained from Merck (Germany) and Fluka (Buchs, Switzerland) and 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 benzothiazole (1) (1 mmol) and benzyl bromide (2) (1 mmol) was stirred in acetone (10 mL) under reflux for 1 h. Next, 2-mercaptobenzoxazole (3) (1 mmol) and Et₃N (1 equiv.) were added to the reaction mixture under the same conditions and stirring was continued 2 h. After 3 h, the reaction product was obtained as a brown 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 (3:1) to give 6a.

3-(3-Benzyl-2,3-dihydrobenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione (6a): Light brown powder, yield 92%, 0.35 g; m.p. 152–154 °C. IR (KBr): 1663 (C=S) cm⁻¹. MS (EI): m/z (%) = 376 (M⁺, 9), 299 (M-Ph, 75), 226 (M-C₇H₄NOS, 71), 150 (C₇H₄NOS, 59), 77 (Ph, 52). Anal. calcd for C₂₁H₁₆N₂OS₂ (376.36): C, 67.02; H, 4.29; N, 7.44; found: C, 66.98; H, 4.24; N, 7.33. ¹H NMR (250.1, CDCl₃); δ 4.13 (2H, s, CH₂), 6.69-7.86 (14H, m, 13ArH and SCHN), ¹³C NMR (62.9 MHz, CDCl₃); δ 51.4 (CH₂), 94.3 (SCN), 109.4, 110.9, 112.6, 114.2, 118.4, 121.7, 123.2, 125.1, 125.7, 126.2, 127.2, 131.6, 132.8, 145.7, 146.4 and 147.1, 183.1 (C=S).

3-(3-Benzyl-2,3-dihydro-2-methylbenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione (6b): Pale yellow powder, yield 90%, 0.35 g; m.p. 158–160 °C. IR (KBr): 1661 (C=S) cm⁻¹. MS (EI): m/z (%) = 390 (M⁺, 10), 375 (M-Me, 93), 313 (M-Ph, 73), 150 (C₇H₄NOS, 57), 77 (Ph, 55). Anal. calcd for C₂₂H₁₈N₂OS₂ (390.38): C, 67.69; H, 4.65; N, 7.17; found: C, 67.62; H, 4.71; N, 7.29. ¹H NMR (250.1 MHz, CDCl₃); δ 2.06 (3H, s, Me), 4.12 (2H, s, CH₂), 6.67-7.85 (13H, m, ArH). ¹³C NMR (62.9 MHz, CDCl₃); δ 21.4 (Me), 51.4 (CH₂), 96.2 (SCN), 109.8, 111.3, 112.7, 114.3, 118.6, 121.2, 122.9, 124.7, 125.1, 126.3, 127.5, 130.8, 132.3, 144.9, 146.7 and 147.5, 183.2 (C=S).

3-(3-Benzyl-2,3-dihydro-2,5-dimethylbenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione (6c): Golden yellow powder, yield 92%, 0.37 g; m.p. 155–157 °C. IR (KBr): 1662 (C=S) cm⁻¹. MS (EI): m/z (%) = 404 (M⁺, 8), 389 (M-Me, 92), 374 (M-2Me, 90), 254 (M-C₇H₄NOS, 75), 150 (C₇H₄NOS, 61), 77 (Ph, 48). Anal. calcd for C₂₃H₂₀N₂OS₂ (404.41): C, 68.31; H, 4.99; N, 6.92; found: C, 68.07; H, 5.06; N, 6.97. ¹H NMR (250.1 MHz, CDCl₃); δ 2.05 and 2.27 (6H, 2s, 2Me), 4.12 (2H, s, CH₂), 6.70-7.85 (12H, m, ArH). ¹³C NMR (62.9 MHz, CDCl₃); δ 21.9 and 24.2 (2Me), 51.3 (CH₂), 96.1 (SCN), 110.3, 111.6, 111.9, 113.1, 114.7, 116.8, 120.5, 123.3, 124.2, 125.2, 125.9, 130.7, 136.7, 145.7, 146.6 and 147.0, 182.9 (C=S).

3-(3-(4-Bromobenzyl)-2,3-dihydrobenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione (6d): Pale yellow powder, yield 91%, 0.41 g; m.p. 175–177 °C. IR (KBr): 1662 (C=S) cm⁻¹. MS (EI): m/z (%) = 455 (M⁺, 9), 305 (M-C₇H₄NOS, 79), 285 (M-C₇H₆Br, 61), 170 (C₇H₆Br, 51), 150 (C₇H₄NOS, 56). Anal. calcd for C₂₁H₁₅BrN₂OS₂ (455.35): C, 55.39; H, 3.32; N, 6.15; found: C, 55.28; H, 3.29; N, 6.23. ¹H NMR (250.1 MHz, CDCl₃); δ 4.13 (2H, s, CH₂), 6.72-7.86 (13H, m, 12ArH and SCHN). ¹³C NMR (62.9 MHz, CDCl₃); δ 51.5 (CH₂), 94.2 (SCN), 110.1, 111.2, 111.6, 112.8, 114.4, 117.2, 119.5, 121.8, 123.2, 124.4, 131.3, 133.9, 138.6, 145.3, 146.1 and 147.3, 183.2 (C=S).

3-(3-(4-Bromobenzyl)-2,3-dihydro-2-methylbenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione (6e): Pale yellow powder, yield 92%, 0.43 g; m.p. 171–173 °C. IR (KBr): 1660 (C=S) cm⁻¹. MS (EI): m/z (%) = 469 (M⁺, 10), 454 (M-Me, 94), 304 (M-C₇H₄NOS and Me, 75), 170 (C₇H₆Br, 47), 150 (C₇H₄NOS, 60). Anal. calcd for C₂₂H₁₇BrN₂OS₂ (469.37): C, 56.30; H, 3.65; N, 5.97; found: C, 56.22; H, 3.76; N, 5.94. ¹H NMR (250.1 MHz, CDCl₃); δ 2.05 (3H, s, Me), 4.11 (2H, s, CH₂), 6.74-7.87 (12H, m, ArH). ¹³C NMR (62.9 MHz, CDCl₃); δ 21.6 (Me), 51.4 (CH₂), 96.2 (SCN), 109.6, 110.7, 112.8, 113.8, 117.5, 119.4, 121.7, 122.9, 124.5, 126.7, 127.2, 129.8, 133.4, 141.7, 143.8 and 147.4, 182.8 (C=S).

3-(3-(4-Bromobenzyl)-2,3-dihydro-2,5-dimethylbenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione (6f): Pale brown powder, yield 91%, 0.44 g; m.p. 169–171 °C. IR (KBr): 1663 (C=S) cm⁻¹. MS (EI): m/z (%) = 483 (M⁺, 9), 468 (M-Me, 95), 453 (M-2Me, 87), 170 (C₇H₆Br, 50), 150 (C₇H₄NOS, 58). Anal. calcd for C₂₃H₁₉BrN₂OS₂ (483.4): C, 57.15; H, 3.96; N, 5.79; found: C, 57.30; H, 4.04; N, 5.91. ¹H NMR (250.1 MHz, CDCl₃); δ 2.03 and 2.29 (6H, 2s, 2Me), 4.11 (2H, s, CH₂), 6.72-7.85 (11H, m, ArH). ¹³C NMR (62.9 MHz, CDCl₃); δ 21.4 and 23.7 (2Me), 51.6 (CH₂), 96.3 (SCN), 111.3, 111.8, 112.6, 114.1, 116.8, 119.6, 122.2, 123.1, 124.6, 126.9, 127.3, 129.9, 133.2, 142.1, 145.8 and 146.9, 182.8 (C=S).

3-(3-(2-Methylbenzyl)-2,3-dihydrobenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione (6g): Yellow powder, yield 92%, 0.36 g; m.p. 153–155 °C. IR (KBr): 1664 (C=S) cm⁻¹. MS (EI): m/z (%) = 390 (M⁺, 10), 375 (M-Me, 96), 240 (M-C₇H₄NOS, 70), 225 (M-C₇H₄NOS and Me, 71), 150 (C₇H₄NOS, 52), 91 (C₇H₇, 55). Anal. calcd for C₂₂H₁₈N₂OS₂ (390.38): C, 67.69; H, 4.65; N, 7.17; found: C, 67.64; H, 4.67; N, 7.03. ¹H NMR (250.1 MHz, CDCl₃); δ 2.27 (3H, s, Me), 4.14 (2H, s, CH₂), 6.73-7.88 (13H, m, 12ArH and SCHN). ¹³C NMR (62.9 MHz, CDCl₃); δ 23.5 (Me), 51.4 (CH₂), 94.5 (SCN), 110.8, 111.9, 112.7, 113.3, 114.7, 115.8, 117.6, 119.5, 122.8, 124.6, 125.3, 127.4, 129.2, 133.6, 138.4, 142.5, 146.7 and 147.1, 183.1 (C=S).

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: I gratefully acknowledge the financial support received from the Research Council of Chabahar Maritime University.

ORCID iD

Mahmoud Nassiri

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