Synthesis of spiro[benzo[4,5]imidazo[2,1- b ][1,3]thiazole-2,3-thiolane]s via sulfa-Michael/aldol cascade reactions

Abstract

The sulfa-Michael/aldol cascade reaction of (Z)-2-arylmethylidene-benzo[4,5]imidazo[2,1-b]thiazol-3(2H)-ones and 1,4-dithiane-2,5-diol afforded novel 2-aryl-4-hydroxy-spiro[benzo[4,5]imidazo[2,1-b][1,3]thiazole-2,3-thiolan]-3-ones in moderate yields. The structures of all the products were characterized thoroughly by nuclear magnetic resonance, infrared and high-resolution mass spectrometry together with X-ray crystallographic analysis.

Keywords

1,4-dithiane-2,5-diol sulfa-Michael/aldol reaction thiolane

Imidazo[2,1-b][1,3]thiazole derivatives, an important class of sulfur-containing heterocycles, have attract considerable interest of organist due to their biological and pharmaceutical activities such as antitumor,¹ antitubercular,² antidiabetic,³ antiinflammatory⁴ and antifungal activities.⁵

Thiolane (tetrahydrothiophene) is an important motif in many natural products and pharmaceutical active compounds. They display pronounced biological activities such as glucosidase inhibitors,⁶ antibacterial,⁷ anti-HIV,⁸ copper amine oxidase inhibitor⁹ and A3 adenosine receptors.¹⁰ The sulfa-michael/aldol cascade reactions of 1,4-dithiane-2,5-diol and electron-deficient alkenes are the general methods for the synthesis of tetrahydrothiophene derivatives.^11–16

In continuation of our work on the synthesis of heterocycle derivatives,^17–20 in this paper, we reported the synthesis of 2-aryl-4-hydroxyspiro(benzo[4,5]imidazo[2,1-b)[1,3]thiazole-2,3-thiolan]-3-ones derivatives by the sulfa-Michael/aldol cascade reaction of (Z)-2-arylmethylidene-benzo(4,5]imidazo[2,1-b)[1,3]thiazol-3(2H)-ones with 1,4-dithiane-2,5-diol in the presence of 1,8-diazabicyclo(5.4.0]undec-7-ene (DBU) (Scheme 1).

Scheme 1.

Synthesis of spiro[benzo[4,5]imidazo[2,1-b]thiazole-2,3′-thiolane]s.

Results and discussion

The structures of all compounds 3 were established by different spectroscopic techniques (nuclear magnetic resonance (NMR) and infrared (IR)) and high-resolution mass spectrometry (HRMS). The HRMS of 3f gave the molecular ion peak at m/z 401.0446. The IR spectrum of 3f displayed ν_C = _O at 1743.6 cm⁻¹. The ¹H NMR spectrum of 3f revealed a triplet at δ 2.92 ppm which assigned for H₂C-5′, a doubt of doublets at δ 3.39 ppm (J₁ = 10.5 Hz, J₂ = 7.5 Hz) assigned for H₂C-5′, a singlet at δ 5.41 for H-2′. The doublet of triplets signals at 5.05 ppm (J₁ = 16.0 Hz, J₂ = 7.0 Hz) are assigned for H₂C-4′.

The ¹³C NMR spectrum of the product 3f exhibited the presence of –SCH₃ carbon at δ 14.04, carbonyl carbons at δ 166.60 (C-3). The signal at δ 33.32, 51.36 and 79.30 are assignable to the carbons of H₂C-5′, H₂C-2′ and H₂C-4′, respectively (based on heteronuclear multiple-quantum correlation (HMQC)). The signals at δ 85.06 represent the spiro carbon of C-2. In the ¹H–¹³C heteronuclear multiple-bond correlation (HMBC) map of 3f (Figure 1), protons of H-5′, H-2′ and H-4′ correlate with a spiro carbon (C-2) (85.06 ppm), the carbonyl carbons at δ 166.60 (C-3) correlate with protons of H-2′ and H-4′. The carbons at δ 51.36 (C-2′) correlate with protons of H-5′ and H-4′. Furthermore, the structure of the product was confirmed by X-ray diffraction analysis of 3g (Figure 2).

Figure 1.

Partial HMBC correlation of 3f.

Figure 2.

ORTEP diagram of 3g with 50% probability.

Experimental analysis

Starting material 1 was synthesized as previously described.²¹ The analytical thin-layer chromatography (TLC) analyses were performed with silica gel 60 F254 plates. Column chromatography was carried out using silica gel 60 (200–300 mesh). All NMR spectra were recorded on a Bruker AV-II 500 MHz NMR spectrometer, operating at 500 MHz for ¹H and 125 MHz for ¹³C. Tetramethylsilane (TMS) was used as an internal reference for ¹H and ¹³C chemical shifts and dimethyl sulfoxide (DMSO-d₆) was used as solvent. Mass spectrometry (MS) was conducted with a Finnigan LCQ Advantage MAX mass spectrometer. IR spectra were recorded on a Perkin-Elmer spectrometer (Spectrum One). Melting points (m.p.s) were measured with a Yanaco MP500 m.p. apparatus and are uncorrected. Determination of the unit cell and data collection for 3g was performed on a Bruker Apex-II CCD diffractometer with monochromatic Mo Kα radiation (λ = 0.71073 Å) at 296(2) K. Crystal data for 3g: C₁₉H₁₆N₂O₂S₂, Mr = 368.46 g mol^‒1, triclinic space group P-1, a = 6.5959(2) Å, b = 8.6807(2) Å, c = 15.5822(4) Å, α = 92.823(2), β = 93.890(2), γ = 102.047(2), V = 868.69(4) Å³, T = 296(2) K, Z = 2, D_c = 1.409 g m⁻³, μ = 0.322 mm⁻¹, F(000) = 384, R_int = 0.0512, 2993 reflections, 1869 with I > 2σ(I) for 228 parameters, goodness of fit ref (GOF) = 1.036, R₁ = 0.0440, wR₂ = 0.0797 (I > 2σ(I)) and R₁ = 0.0904, wR₂ = 0.0959 (all data).

General procedure for the synthesis of (2RS,2′SR,4′SR)-2-aryl-4-hydroxyspiro[benzo[4,5]imidazo[2,1-b][1,3]thiazole-2,3-thiolan]-3-one

A mixture of (Z)-2-arylmethylidene-benzo[4,5]imidazo[2,1-b]thiazol-3(2H)-ones 1 (1 mmol), 1,4-dithiane-2,5-diol (1 mmol) and DBU (50 mol%) in tetrahydrofuran (THF) (5 mL) was stirred at room temperature for 2 h. The solvent was removed, and the product was purified by flash column using petroleum/ether–ethyl acetate mixture (3:1 v/v) as eluent to afford 3.

(2RS,2′SR,4′SR)-4′-hydroxy-2′-phenylspiro[benzo[4,5]imidazo[2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3a): White solid, yield 50%; m.p.: 230–233 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.92 (t, J = 10.0 Hz, 1H), 3.40 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 5.06 (dt, J₁ = 16.0 Hz, J₂ = 7.0 Hz, 1H), 5.45 (s, 1H), 6.57 (d, J = 6.0 Hz, 1H), 7.28–7.33 (m, 3H), 7.34–7.40 (m, 4H), 7.53 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.30, 51.83, 79.29, 85.01, 112.16, 118.82, 124.14, 126.19, 128.37, 128.73, 128.79, 129.17, 133.93, 148.47, 155.41, 166.63; IR (KBr) v: 1738.4 cm⁻¹; high-resolution electrospray ionization mass spectrometer (ESI-HRMS) calc. for [C₁₈H₁₅N₂O₂ S₂]⁺ (M + H): 355.0569; found: 355.0569.

(2RS,2′SR,4′SR)-2′-(4-fluorophenyl)-4′-hydroxyspiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3b): White solid, yield 58%; m.p.: 276–278 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.93 (t, J = 10.0 Hz, 1H), 3.41 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 5.05 (dt, J₁ = 14.0 Hz, J₂ = 7.0 Hz, 1H), 5.46 (s, 1H), 6.58 (d, J = 5.5 Hz, 1H), 7.14 (t, J = 8.5 Hz, 2H), 7.35 (dt, J₁ = 20.0 Hz, J₂ = 7.5 Hz, 2H), 7.43 (dd, J₁ = 8.5 Hz, J₂ = 5.5 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.44, 51.03, 79.20, 84.99, 112.18, 115.19, 115.37, 118.85, 124.16, 126.22, 129.19, 130.16, 130.18, 130.88, 130.95, 148.49, 155.27, 166.52; IR (KBr) v: 1736.4 cm⁻¹; ESI-HRMS calc. for [C₁₈H₁₄FN₂O₂ S₂]⁺ (M + H): 373.0475; found: 373.0476.

(2RS,2′SR,4′SR)-2′-(4-chlorophenyl)-4′-hydroxyspiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3c): White solid, yield 48%; m.p.: 284–287 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.94 (t, J = 10.0 Hz, 1H), 3.41 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 5.06 (dt, J₁ = 14.0 Hz, J₂ = 7.0 Hz, 1H), 5.47 (s, 1H), 6.60 (d, J = 6.0 Hz, 1H), 7.32–7.36 (m, 2H), 7.37–7.41 (m, 4H), 7.55 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.46, 51.05, 79.30, 84.80, 112.21, 118.86, 124.17, 126.23, 128.40, 129.21, 130.62, 133.14, 133.35, 148.50, 155.21, 166.47; IR (KBr) v: 1737.1 cm⁻¹; ESI-HRMS calc. for [C₁₈H₁₄ClN₂O₂ S₂]⁺ (M + H): 389.0180; found: 389.0184.

(2RS,2′SR,4′SR)-2′-(4-bromophenyl)-4′-hydroxyspiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3d): White solid, yield 53%; m.p.: 280–281 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.94 (t, J = 10.0 Hz, 1H), 3.41 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 5.05 (dd, J₁ = 16.0 Hz, J₂ = 7.0 Hz, 1H), 5.45 (s, 1H), 6.59 (d, J = 6.0 Hz, 1H), 7.32–7.39 (m, 4H), 7.50 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.46, 51.11, 79.33, 84.72, 112.21, 118.87, 121.98, 124.18, 126.24, 129.22, 130.91, 131.33, 133.59, 148.50, 155.20, 166.46; IR (KBr) v: 1736.7 cm⁻¹; ESI-HRMS calc. for [C₁₈H₁₄BrN₂O₂ S₂]⁺ (M + H): 432.9675; found: 432.9680.

(2RS,2′SR,4′SR)-4′-hydroxy-2′-(4-methoxyphenyl)spiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3e): White solid, yield 52%; m.p.: 254–256 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.90 (t, J = 10.0 Hz, 1H), 3.38 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 3.65 (s, 3H), 5.04 (dt, J₁ = 13.5 Hz, J₂ = 7.5 Hz, 1H), 5.38 (s, 1H), 6.54 (d, J = 6.0 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 7.30–7.32 (m, 2H), 7.33–7.38 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.30, 51.35, 54.97, 79.19, 85.32, 112.15, 113.68, 118.81, 124.12, 125.45, 126.19, 129.18, 130.05, 148.49, 159.37, 166.67; IR (KBr) v: 1736.4 cm⁻¹; ESI-HRMS calc. for [C₁₉H₁₇N₂O₃ S₂]⁺ (M + H): 385.0675; found: 385.0679.

(2RS,2′SR,4′SR)-4′-hydroxy-2′-(4-(methylthio)phenyl)spiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3f): White solid, yield 46%; m.p.: 248–250 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.38 (s, 3H), 2.92 (t, J = 10.0 Hz, 1H), 3.39 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 5.05 (dt, J₁ = 16.0 Hz, J₂ = 7.0 Hz, 1H), 5.41 (s, 1H), 6.57 (d, J = 6.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.29–7.33 (m, 2H), 7.34–7.39 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 14.04, 33.32, 51.36, 79.30, 85.06, 112.19, 118.85, 124.16, 125.23, 126.22, 129.20, 129.28, 130.13, 139.15, 148.49, 155.41, 166.60; IR (KBr) v: 1743.6 cm⁻¹; ESI-HRMS calc. for [C₁₉H₁₇N₂O₂ S₃]⁺ (M + H): 401.0447; found: 401.0446.

(2RS,2′SR,4′SR)-4′-hydroxy-2′-(p-tolyl)spiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3g): White solid, yield 61%; m.p.: 262–264 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.18 (s, 3H), 2.91 (t, J = 10.0 Hz, 1H), 3.39 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 5.05 (dt, J₁ = 13.5 Hz, J₂ = 7.5 Hz, 1H), 5.40 (s, 1H), 5.56 (d, J = 5.5 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 7.27–7.29 (m, 2H), 7.30–7.39 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 20.55, 33.26, 51.61, 79.31, 85.14, 112.15, 118.80, 124.12, 126.18, 128.62, 128.94, 129.19, 130.85, 138.20, 148.49, 155.51, 166.68; IR (KBr) v: 1736.1 cm⁻¹; ESI-HRMS calc. for [C₁₉H₁₇N₂O₂ S₂]⁺ (M + H): 369.0726; found: 369.0724.

(2RS,2′SR,4′SR)-4′-hydroxy-2′-(3-methoxyphenyl)spiro[benzo [4,5]imidazo[2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3h): White solid, yield 56%; m.p.: 196–198 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.92 (t, J = 10.0 Hz, 1H), 3.39 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 3.64 (s, 3H), 5.06 (dd, J₁ = 15.5 Hz, J₂ = 7.0 Hz, 1H), 5.43 (s, 1H), 6.57 (d, J = 6.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.90-6.95 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 7.35 (dt, J₁ = 19.5 Hz, J₂ = 7.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.28, 51.70, 54.95, 79.24, 84.90, 112.13, 113.89, 114.50, 118.83, 120.75, 124.16, 126.21, 129.20, 129.53, 135.55, 148.50, 155.49, 158.88, 166.71; IR (KBr) v: 1737.2 cm⁻¹; ESI-HRMS calc. for [C₁₉H₁₇N₂O₃ S₂]⁺ (M + H): 385.0675; found: 385.0678.

(2RS,2′SR,4′SR)-2′-(3,5-dimethoxyphenyl)-4′-hydroxyspiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3i): White solid, yield 57%; m.p.: 190–191 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.90 (t, J = 10.0 Hz, 1H), 3.38 (dd, J₁ = 9.5 Hz, J₂ = 8.5 Hz, 1H), 3.61 (s, 6H), 5.04 (dd, J₁ = 14.0 Hz, J₂ = 7.0 Hz, 1H), 5.37 (s, 1H), 6.38 (s, 1H), 6.48 (s, 2H), 6.56 (d, J = 5.5 Hz, 1H), 7.36 (dt, J₁ = 20.0 Hz, J₂ = 7.5 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.26, 51.80, 55.09, 79.14, 84.77, 99.96, 106.70, 112.08, 118.85, 124.19, 126.23, 129.22, 136.35, 148.52, 155.58, 160.12, 166.80; IR (KBr) v: 1745.9 cm⁻¹; ESI-HRMS calc. for [C₂₀H₁₉N₂O₄ S₂]⁺ (M + H): 415.0781; found: 415.0782.

(2RS,2′SR,4′SR)-4′-hydroxy-2′-(3,4,5-trimethoxyphenyl)spiro[benzo[4,5] imidazo[2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3j): White solid, yield 52%; m.p.: 211–213 °C; ¹H NMR (DMSO-d₆, 500 MHz): 2.91 (t, J = 10.0 Hz, 1H), 3.39 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 3.54 (s, 3H), 3.63 (s, 6H), 5.03 (dt, J₁ = 14.0 Hz, J₂ = 7.0 Hz, 1H), 5.38 (s, 1H), 6.56 (d, J = 6.0 Hz, 1H), 6.63 (s, 2H), 7.35 (dt, J₁ = 19.5 Hz, J₂ = 7.5 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 33.40, 52.24, 55.74, 59.91, 78.85, 85.02, 105.83, 112.00, 118.85, 124.17, 126.21, 129.23, 129.50, 137.48, 148.50, 152.38, 155.56, 166.82; IR (KBr) v: 1736.3 cm⁻¹; ESI-HRMS calc. for [C₂₁H₂₁N₂O₅ S₂]⁺ (M + H): 445.0886; found: 445.0888.

(2RS,2′SR,4′SR)-2′-(4-(tert-butyl)phenyl)-4′-hydroxyspiro[benzo[4,5]imidazo [2,1-b][1,3]thiazole-2,3-thiolan]-3-one (3k): White solid, yield 50%; m.p.: 225–227 °C; ¹H NMR (DMSO-d₆, 500 MHz): 1.16 (s, 9H), 2.93 (t, J = 10.0 Hz, 1H), 3.39 (dd, J₁ = 10.5 Hz, J₂ = 7.5 Hz, 1H), 5.05 (dd, J₁ = 16.0 Hz, J₂ = 7.5 Hz, 1H), 5.42 (s, 1H), 6.56 (d, J = 6.0 Hz, 1H), 7.31–7.33 (m, 4H), 7.34–7.37 (m, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): 30.86, 33.21, 34.22, 51.22, 79.65, 84.87, 112.21, 118.81, 124.11, 125.21, 126.15, 128.58, 129.24, 131.02, 148.47, 151.14, 155.54, 166.74; IR (KBr) v: 1740.6 cm⁻¹; ESI-HRMS calc. for [C₂₂H₂₃N₂O₂ S₂]⁺ (M + H): 411.1195; found: 411.1199.

Conclusion

We have developed a practical sulfa-Michael/aldol cascade reaction to synthesis spiro[benzo[4,5]imidazo[2,1-b][1,3]thiazole-2,3-thiolane]s derivatives with moderate yields. The stereochemistry configuration of the product was demonstrated by single crystal X-ray diffraction.

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 paper.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was supported by the National Natural Science Foundation of China (grant no.: 21671063).

Supplemental material

The Cambridge Crystallographic Data Center (CCDC), CCDC No. 1875724, contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the CCDC via .

References

Park

El-Gamal

Lee

et al . Eur J Med Chem 2011; 46: 5769.

Moraski

Markley

Chang

et al . Bioorg Med Chem 2012; 20: 2214.

Bemis

Disch

et al . J Med Chem 2009; 52: 1275.

Tozkoparan

Ertan

Kelicen

et al . Farmaco 1999; 54: 588.

Wan

Dai

Tang

et al . Eur J Med Chem 2018; 146: 471.

Yoshikawa

Morikawa

Matsuda

et al . Bioorg Med Chem 2002; 10: 1547.

Volkmann

Kelbaugh

Nason

et al . J Org Chem 1992; 57: 4352.

Haraguchi

Shimada

Tanaka

et al . J Med Chem 2005; 51: 1885.

Qiao

Ling

Shepard

et al . J Am Chem Soc 2006; 128: 6206.

10.

Jeong

Choe

Gunaga

et al . J Med Chem 2007; 50: 3159.

11.

Chauhan

Mahajan

Enders

. Chem Rev 2014; 114: 8807.

12.

Liu

Mei

Shen

et al . J Chem Res 2018; 42: 233.

13.

Kowalczyk

Wojciechowski

Albrecht

. Tetrahedron Lett 2016; 57: 2533.

14.

Kumara

CSP

Gowda

Kumar

KSV

et al . Tetrahedron Lett 2016; 57: 4302.

15.

Risi

Benetti

Fogagnolo

et al . Tetrahedron Lett 2013; 54: 283.

16.

Nagaraju

Sathish

Paplal

et al . Tetrahedron Lett 2017; 58: 2865.

17.

Ren

Huang

et al . J Chem Res 2018; 42: 374.

18.

Zeng

Ren

Huang

et al . J Chem Res 2018; 42: 371.

19.

Meng

et al . Chem Commun 2018; 54: 2510.

20.

Ren

Huang

et al . J Chem Res 2018; 42: 453.

21.

Feng

. Chin J Org Chem 2009; 29: 1129.