Simple,novel,and efficient synthesis of ethyl 2-(2-(1 H -indol-3-yl)benzo[ d ]thiazol-3(2 H )-yl)-2-cyanoacetate or acetate via a three-component reaction

Abstract

Ethyl 2-(2-(1H-indol-3-yl)benzo[d]thiazol-3(2H)-yl)-2-cyanoacetate or acetate 6a–f as a series of novel compounds were synthesized from the reactions of benzothiazole, 2-methylbenzothiazole, or 2,5-dimethylbenzothiazole and ethyl bromocyanoacetate with indole derivatives. The reactions proceeded in acetone as a solvent under reflux for 5 h in good yields. The structures of new compounds were confirmed by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, infrared, elemental analyses, and mass spectroscopy.

Keywords

benzothiazole ethyl bromocyanoacetate indole novel three-component reaction

Introduction

Multi-component reactions (MCRs) are economically and environmentally beneficial to the industry and have attracted much attention during the two recent decades. These reactions are perfectly applicable to organic synthesis and agrochemical chemistry.^1,2 Due to their interest as natural and unnatural compounds, nitrogen heterocycles are of special interest in organic synthetic chemistry.³ The sulfur- and nitrogen-containing aromatic heterocyclic compounds known as benzothiazoles and analogs play a crucial role in the synthesis of new drugs.⁴ These compounds have different pharmacological and biological effects, and have different applications in the production of carbonic anhydrase enzyme inhibitory,^5,6 anti-inflammatory,⁷ anticancer,⁷ antimicrobial,⁸ antitumor,⁸ Alzheimer,⁹ antibacterial,¹⁰ antiallergic,¹¹ and antioxidant¹² drugs. Benzothiazoles are also widely used in a variety of consumer and industrial products such as nonlinear optics (NLOs), textiles, α-glucosidase inhibitors, organic light-emitting diodes (OLEDs), fluorescent probes, and chemosensors.^13–15 The indole moiety occurs in a number of natural products and alkaloids, and its derivatives are widely used in various medicine formulations. It has been reported that they exhibit numerous biological activities, including antirheumatoidal,¹⁶ antioxidant,¹⁶ antibacterial,¹⁷ antiviral,¹⁷ antiallergic,¹⁸ and antileukemic¹⁹ activities. In this article, we report the results of our studies involving the simple, novel, and catalyst-free reactions of benzothiazole, 2-methylbenzothiazole, or 2,5-dimethylbenzothiazole 1 and ethyl bromocyanoacetate 2 with indole derivatives 4 which provide a synthesis of ethyl 2-(2-(1H-indol-3-yl)benzo[d]thiazol-3(2H)-yl)-2-cyanoacetate or acetate 6a–f (see Scheme 1 and Table 1).

Scheme 1.

A plausible mechanism for the formation of compounds 6.

Table 1.

Benzothiazole, indole, and ethyl bromocyanoacetate.

Results and discussion

The reactions of benzothiazole, 2-methylbenzothiazole, or 2,5-dimethylbenzothiazole 1 and ethyl bromocyanoacetate 2 with indole or 2-methylindole 4 were conducted under reflux conditions in acetone and were complete within 5 h. The different stages of the reactions included mixing the benzothiazole with ethyl bromocyanoacetate for 2 h, followed by the addition of the indole and heating under reflux for 3 h. The 1H and 13C nuclear magnetic resonance (NMR) spectra of the crude products clearly indicated the formation of compounds 6a–f. No product other than 6a–f could be detected by NMR spectroscopy. The structures of newly synthesized compounds 6a–f were deduced from their 1H NMR, 13C NMR, infrared (IR), elemental analysis, and mass spectral data. For example, the 1H NMR spectrum of 6a exhibited four signals as follows: δ = 1.12 ppm, t, 3H, 3J_HH = 7.30 Hz, CO₂CH₂CH₃, 4.10 ppm, q, 2H, 3J_HH = 7.30 Hz, CO₂CH₂CH₃, 7.46 ppm, s, 1H, HN-CH=C and 8.86 ppm, s, 1Hbr, HN-CH=C. Aromatic protons with multiplets as follows were also present: δ = 6.70–8.30 ppm, m, 8ArH, 1 from S-CH and NC-CH. ^1,2,20–24 The C NMR spectrum of 6a showed 20 distinct resonances in agreement with the proposed structure. In addition, product 6a displayed 13C NMR resonances at δ = 14.5, 59.5, 69.7, 92.3, and 117.6 ppm, respectively, for the CO₂CH₂CH₃, CO₂CH₂CH₃, HC-CN, S-C-N, and CN carbons.^{1,2,22,25–30} The 1H NMR and 13C NMR spectra of 6b–f are similar to those of 6a. Although the mechanistic details of the reactions are not known, a plausible rationalization may be advanced to explain the product formation (see Scheme 1 and Table1). Presumably, the salt intermediate 3 formed from benzothiazole 1 and ethyl bromocyanoacetate 2 is attacked by indole 4 to produce 5. At the end, this compound 5 is converted into product 6 by a formal [1,3] hydrogen shift.^{23,24,28–30}

Conclusion

A new method to access a novel class of heterocyclic derivatives has been described. The new compounds 6a–f were synthesized from the reactions of benzothiazoles with ethyl bromocyanoacetate in the presence of indole or 2-methylindole without using any catalyst in good yield; the reactants can be mixed without any prior activation or modification. This procedure will be very useful for the functionalization of benzothiazole in a one-pot operation.

Experimental

Compounds 1, 2, and 4 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 obtained from a BRUKER DRX-250 AVANCE instrument with CDCl₃ as solvent and tetramethylsilane (TMS) as the internal standard at 250.1 and 62.9 MHz, respectively.

General Procedure (preparation of compound 6a)

A mixture of benzothiazole 1 (1 mmol) and ethyl bromocyanoacetate 2 (1 mmol) was refluxed in acetone (10 mL) as a solvent for 2 h. Then, indole 4 was added to the reaction mixture under the same conditions and heated for 3h. The solvent was then removed, and the product, a pale yellow solid, was washed with cold n-hexane (3 × 3 mL). The residue was recrystallized from 4:1 n-hexane/EtOAc to give 6a.

Ethyl 2-(2-(1H-indol-3-yl)benzo[d]thiazol-3(2H)-yl)-2-cyanoacetate (6a)

Pale yellow powder, yield 92%, 0.33 g; m.p. 116–118 °C, IR (KBr) (v_max/cm⁻¹): 1730. MS, m/z (%) = 318 (M-OEt, 87), 290 (M-CO₂Et, 80), 251 (M-C₅H₆NO₂, 79), 202 (M-C₈H₆N and OEt, 47), 116 (C₈H₆N, 74), 112 (C₅H₆NO₂, 62), 73 (CO₂Et, 56), 45 (OEt, 34). Anal. calcd for C₂₀H₁₇N₃O₂S (363.35): C, 66.11; H, 4.71; N, 11.56%, Found: C, 66.22; H, 4.79; N, 11.51%. 1H NMR (250.1, CDCl₃), δ: 1.12 (3H, t, 3J_HH = 7.3 Hz, CO₂CH₂CH₃), 4.10 (2H, q, 3J_HH = 7.3 Hz, CO₂CH₂CH₃), 6.70–8.30 (11H, m, 9 ArH, 1 from S-CH and NC-CH), 8.86 (1Hbr, s, HN). 13C NMR (62.9 MHz, CDCl₃), δ: 14.5 (CO₂CH₂CH₃), 59.5 (CO₂CH₂CH₃), 69.7 (NC-CH), 92.3, (S-CH), 103.3, 106.1, 108.7, and 109.8 (4 aromatic carbons), 117.6 (CN), 118.6, 120.5, 121.7, 122.1, 124.3, 124.9, 127.2, 132.7, 146.5, and 147.6 (10 aromatic carbons), 169.2 (C=O).

Ethyl 2-cyano-2-(2-(2-methyl-1H-indol-3-yl)benzo[d]thiazol-3(2H)-yl)acetate (6b)

Pale yellow powder, yield 92%, 0.35 g; m.p. 109–111 °C, IR (KBr) (v_max/cm⁻¹): 1728. MS, m/z (%) = 333 (M-Et and Me, 88), 332 (M-OEt, 83), 362 (M-Me, 92), 304 (M-CO₂Et, 76), 247 (M-C₉H₈N, 58), 130 (C₉H₈N, 69). Anal. calcd for C₂₁H₁₉N₃O₂S (377.38): C, 66.84; H, 5.07; N, 11.13%, Found: C, 66.92; H, 5.12; N, 11.19%. 1H NMR (250.1 MHz, CDCl₃), δ: 1.15 (3H, t, 3J_HH = 7.2 Hz, CO₂CH₂CH₃), 2.46 (3H, s, Me), 4.11 (2H, q, 3J_HH = 7.2 Hz, CO₂CH₂CH₃), 6.67–8.32 (10H, m, 8 ArH, 1 from S-CH and NC-CH), 8.83 (1Hbr, s, HN).13C NMR (62.9 MHz, CDCl₃), δ: 13.75 (Me), 14.3 (CO₂CH₂CH₃), 61.2 (CO₂CH₂CH₃), 71.1 (NC-CH), 93.8, (S-CH), 104.3, 105.2, 107.8, and 109.4 (4 aromatic carbons), 116.5 (CN), 117.9, 120.2, 120.8, 121.3, 122.3, 123.1, 126.2, 136.4, 147.1, and 148.4 (10 aromatic carbons), 169.8 (C=O).

Ethyl 2-(2-(1H-indol-3-yl)-2-methylbenzo[d]thiazol-3(2H)-yl)-2-cyanoacetate (6c)

Yellow powder, yield 90%, 0.34 g; m.p. 126–128 °C, IR (KBr) (v_max/cm⁻¹): 1731. MS, m/z (%) = 362 (M-Me, 93), 347 (M-2Me, 91), 317 (M-OEt and Me, 85), 304 (M-CO₂Et, 68), 261 (M-C₈H₆N, 59), 116 (C₈H₆N, 73). Anal. calcd for C₂₁H₁₉N₃O₂S (377.38): C, 66.84; H, 5.07; N, 11.13%, Found: C, 66.78; H, 5.01; N, 11.17%. 1H NMR (250.1 MHz, CDCl₃), δ: 1.10 (3H, t, 3J_HH = 7.3 Hz, CO₂CH₂CH₃), 2.11 (3H, s, Me), 4.13 (2H, q, 3J_HH = 7.3 Hz, CO₂CH₂CH₃), 6.65–8.30 (10H, m, 9 ArH, 1 from NC-CH), 8.79 (1Hbr, s, HN).13C NMR (62.9 MHz, CDCl₃), δ: 13.9 (CO₂CH₂CH₃), 29.7 (Me), 61.6 (CO₂CH₂CH₃), 70.8 (NC-CH), 97.4, (S-CMe), 106.3, 108.9, 110.5, and 112.4 (4 aromatic carbons), 118.2 (CN), 119.7, 120.4, 121.2, 122.7, 123.1, 123.9, 135.1, 136.5, 147.3, and 149.0 (10 aromatic carbons), 168.4 (C=O).

Ethyl 2-cyano-2-(2-methyl-2-(2-methyl-1H-indol-3-yl)benzo[d]thiazol-3(2H)-yl)acetate (6d)

Pale brown powder, yield 89%, 0.35 g; m.p. 119–121 °C, IR (KBr) (v_max/cm⁻¹): 1730. MS, m/z (%) = 376 (M-Me, 92), 361 (M-2Me, 87), 346 (M-OEt, 70), 318 (M-CO₂Et, 66), 261 (M-C₉H₈N, 76), 130 (C₉H₈N, 69). Anal. calcd for C₂₂H₂₁N₃O₂S (391.4): C, 67.51; H, 5.41; N, 10.73%, Found: C, 67.60; H, 5.30; N, 10.79%. 1H NMR (250.1 MHz, CDCl₃), δ: 1.17 (3H, t, 3J_HH = 7.4 Hz, CO₂CH₂CH₃), 2.16 and 2.50 (6H, 2s, 2Me), 4.09 (2H, q, 3J_HH = 7.4 Hz, CO₂CH₂CH₃), 6.58–8.28 (9H, m, 8 ArH, 1 from NC-CH), 8.76 (1Hbr, s, HN). 13C NMR (62.9 MHz, CDCl₃), δ: 13.9 (CO₂CH₂CH₃), 14.4 (Me), 29.5 (Me), 62.2 (CO₂CH₂CH₃), 68.8 (NC-CH), 98.6, (S-CMe), 105.6, 109.1, 110.4, and 111.8 (4 aromatic carbons), 117.3 (CN), 120.3, 120.9, 122.2, 122.6, 123.0, 124.1, 134.7, 136.9, 148.2, and 148.8 (10 aromatic carbons), 168.9 (C=O).

Ethyl 2-(2-(1H-indol-3-yl)-2,5-dimethylbenzo[d]thiazol-3(2H)-yl)-2-cyanoacetate (6e)

Brown powder, yield 90%, 0.35 g; m.p. 129–131 °C, IR (KBr) (v_max/cm⁻¹): 1733. MS, m/z (%) = 376 (M-Me, 81), 361 (M-2Me, 77), 346 (M-OEt, 66), 318 (M-CO₂Et, 57), 275 (M-C₈H₆N, 62), 116 (C₈H₆N, 51). Anal. calcd for C₂₂H₂₁N₃O₂S (391.4): C, 67.51; H, 5.41; N, 10.73%, Found: C, 67.64; H, 5.50; N, 10.70%. 1H NMR (250.1 MHz, CDCl₃), δ: 1.21 (3H, t, 3J_HH = 7.5 Hz, CO₂CH₂CH₃), 1.80 and 2.30 (6H, 2s, 2Me), 4.20 (2H, q, 3J_HH = 7.5 Hz, CO₂CH₂CH₃), 6.64–8.20 (9H, m, 8 ArH and 1 from NC-CH), 8.73 (1Hbr, s, HN).13C NMR (62.9 MHz, CDCl₃), δ: 13.7 (Me), 14.1 (CO₂CH₂CH₃), 14.6 (Me), 60.7 (CO₂CH₂CH₃), 67.5 (NC-CH), 97.2, (S-CMe), 103.7, 107.4, 109.9, and 112.3 (4 aromatic carbons), 117.7 (CN), 119.4, 120.8, 121.6, 122.7, 123.0, 125.2, 133.6, 138.3, 147.2, and 149.1 (10 aromatic carbons), 171.2 (C=O).

Ethyl 2-cyano-2-(2, 5-dimethyl-2-(2-methyl-1H-indol-3-yl)benzo[d]thiazol-3(2H)-yl)acetate (6f)

Brown powder, yield 88%, 0.36 g; m.p. 135–137 °C, IR (KBr) (v_max/cm⁻¹): 1732. MS, m/z (%) = 390 (M-Me, 93), 375 (M-2Me, 85), 360 (M-OEt, 61), 345 (M-OEt and Me, 51), 332 (M-CO₂Et, 53), 275 (M-C₉H₈N, 59). Anal. calcd for C₂₃H₂₃N₃O₂S (405.43): C, 68.14; H, 5.72; N, 10.36%, Found: C, 68.02; H, 5.80; N, 10.29%. 1H NMR (250.1 MHz, CDCl₃), δ: 1.27 (3H, t, 3J_HH = 7.1 Hz, CO₂CH₂CH₃), 1.85, 2.27 and 2.50 (9H, 3s, 3Me), 4.23 (2H, q, 3J_HH = 7.1 Hz, CO₂CH₂CH₃), 6.54–8.25 (8H, m, 7 ArH and 1 from NC-CH), 8.77 (1Hbr, s, HN).13C NMR (62.9 MHz, CDCl₃), δ: 13.7 (Me), 14.4 (CO₂CH₂CH₃), 21.6 and 27.8 (2Me), 61.3 (CO₂CH₂CH₃), 68.6 (NC-CH), 99.1, (S-CMe), 103.3, 106.9, 108.7, and 113.2 (4 aromatic carbons), 118.1 (CN), 118.9, 120.7, 122.3, 123.2, 123.8, 126.1, 133.5, 137.4, 148.3, and 149.4 (10 aromatic carbons), 170.5 (C=O).

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: The study received financial support from the Research Council of Chabahar Maritime University.

ORCID iD

Mahmoud Nassiri

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