Synthesis of 1,2,3-triazole-substituted 6,7-dihydroindolizin-8(5 H )-one derivatives mediated by Selectfluor

Abstract

The 1,2,3-triazole and 1H-1,2,3-benzotriazole-substituted 6,7-dihydroindolizin-8(5H)-one derivatives were synthesized by the reaction of (E)-7-(arylmethylidene)-6,7-dihydroindolizin-8(5H)-ones with 1,2,3-triazole and 1H-1,2,3-benzotriazole in the presence of Selectfluor in moderate yield. 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.

Introduction

The indolizine core is a prevalent heterocyclic structure in a wide range of biological activities alkaloids, such as the kinganone, ¹ (+)-monomorine, ² polygonatines, ³ and indolizidine 209D. ⁴ It is also widely screened for anti-HIV, ⁵ glycogen synthase kinase-3β inhibitors, ⁶ hypoglycemic, ⁷ antimicrobial, ⁸ and antitumor activities. ⁹

1,2,3-triazoles, a versatile nitrogen-based heterocycle, has been widely used in organic chemistry, ¹⁰ material chemistry, ¹¹ and medicinal chemistry. ¹² It also features promising and broad biological applications such as agonistic antigen, ¹³ metallo-lactamase inhibitors, ¹⁴ and RNA-binding agents. ¹⁵

Selectfluor has risen to prominence in recent years as a versatile commercially available reagent which is widely used in the synthesis of nitrogen-containing heterocycle.^16–20

In continuation of our work^21–24 on the synthesis of indolizin-8(5H)-one derivatives, in this paper, we reported the synthesis of 1,2,3-triazole and 1H-1,2,3-benzotriazole (BHT)-substituted 6,7-dihydroindolizin-8(5H)-one derivatives by the reaction of (E)-7-(arylmethylidene)-6,7-dihydroindolizin-8(5H)-ones with 1,2,3-triazole and BHT in the presence of Selectfluor (Scheme 1).

Scheme 1.

Synthesis of 1,2,3-triazole-substituted 6,7-dihydroindolizin-8(5H)-one derivatives.

Results and discussion

The structures of all compounds 2a–f and 3a–f were established by different spectroscopic techniques (nuclear magnetic resonance (NMR), infrared (IR)) and high-resolution mass spectrometry (HRMS). The high-resolution mass spectrum of 3c gave the molecular ion peak at m/z = 419.0507. The IR spectrum of 3c displayed ν_C=O at 1665 cm⁻¹. The ¹H NMR spectrum of 3c revealed a singlet at δ 7.84 ppm (1-NH), a doublet at δ 8.16 (d, J = 8.5 Hz, 1H) ppm (2-NH), two triplets at δ 3.24 (t, J = 5.5, 2H) ppm (5-CH₂), and δ 4.11 (t, J = 6.0, 2H) ppm (6-CH₂), and a doublet at δ 6.59 (d, J = 4.0 Hz, 1H) ppm (H-7).

The ¹³C NMR spectrum of the product 3c exhibited the presence of signals at δ 26.80 and δ 41.86. The signals at δ 26.80 and δ 41.86 are assignable to the carbon of −C5 and −C6, respectively. The signals at δ 107.07, δ 120.44, and δ 145.4 are assignable to the carbon of −C7, −C2, and −C1, respectively, and the presence of −C=O carbon was at δ 177.76. The assignment of all ¹H and ¹³C NMR signals of 3c was based on two-dimensional (2D) NMR (heteronuclear single-quantum correlation spectroscopy (HSQC), heteronuclear multiple-bond correlation spectroscopy (HMBC), and correlation spectroscopy (COSY)). Some important HMBC correlations of 3c are shown in Figure 1. Furthermore, the structures of the products were confirmed by X-ray diffraction analysis of 2a (Figure 2).

Figure 1.

HMBC correlations of 3c.

Figure 2.

ORTEP diagram of 2a with 50% probability.

The possible reaction pathway is shown in Figure 3. 1,2,3-triazole/BHT radicals were generated from 1,2,3-triazole/BHT with Selectfluor through a single electron transfer. The nucleophilic addition of the 1,2,3-triazole/BHT radical to 1 gave the radical 2(3)′. 2(3)′ got oxidized by Selectfluor to give the cation 2(3)″, which underwent a deprotonation process to generate the product 2(3).

Figure 3.

Possible reaction pathway.

Experimental

Starting material 1 was synthesized as described previously. ²¹ All of the reagents from commercial suppliers were used without further purification. The analytical thin-layer chromatographies (TLCs) 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. 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.) were measured with a Yanaco MP500 melting point apparatus and are uncorrected. Determination of the unit cell and data collection for 2a were performed on a Bruker Apex-II CCD diffractometer with monochromatic Mo Kα radiation (λ = 0.71073 Å) at 296(2) K. Crystal data for 2a are as follows: C₁₇H₁₄N₄O, Mr = 290.32 g mol^–1, orthorhombic space group -P 2ac 2ab, a = 11.71(2) Å, b = 8.549(16) Å, c = 28.67(6) Å, α = 90°, β = 90°, γ = 90°, V = 2870(10) ų, T = 296(2) K, Z = 8, D_c = 1.344 g m⁻³, μ = 0.088 mm⁻¹, F(000) = 1216, Rint = 0.0989, 2489 reflections, 1424 with I > 2σ(I) for 199 parameters, goodness of fit ref (GOF) = 1.035, R₁ = 0.0493, wR₂ = 0.1042 (I > 2σ(I)) and R₁ = 0.1034, wR₂ = 0.1343 (all data). CCDC 1868964 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

General procedure for the synthesis of 1,2,3-triazole-substituted 6,7-dihydroindolizin-8(5H)-one derivatives

To a solution of CH₃CN (4 mL) was added 1,2,3-triazole (52 mg, 0.75 mmol) or BHT (89 mg, 0.75 mmol), Selectfluor (230 mg, 0.65 mmol), and (E)-7-(arylmethylidene)-6,7-dihydroindolizin-8(5H)-ones 1 (0.5 mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in 10 mL of CH₂Cl₂, filtered through a celite pad, and then washed with 20–30 mL of CH₂Cl₂. The combined filtrates were concentrated and purified via column chromatography on silica gel using petroleum ether/ethyl acetate (4:1) as an eluent to afford the desired products 2/3.

(E)-7-benzylidene-3-(1H-1,2,3-triazol-1-yl)-6,7-dihydroindolizin-8(5H)-one (2a): White solid; yield 57%; m.p.: 221–222 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.27 (t, J = 5.5 Hz, 2H), 4.13 (t, J = 6.0 Hz, 2H), 6.43 (d, J = 4.5 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.35–7.44 (m, 5H), 7.86 (s, 1H), 7.89–7.91 (s, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.74, 42.17, 106.27, 114.29, 125.88, 128.19, 128.66, 129.02, 129.79, 130.61, 131.22, 133.77, 135.14, 137.64, 178.10; IR (KBr) v: 1638 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₁₇H₁₅N₄O]⁺ (M + H⁺): 291.1240; found: 291.1245.

(E)-7-(4-chlorobenzylidene)-3-(1H-1,2,3-triazol-1-yl)-6,7-dihydroindolizin-8(5H)-one (2b): White solid; yield 55%; m.p.: 194–195 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.23 (t, J = 5.5 Hz, 2H), 4.07 (t, J = 6.0 Hz, 2H), 6.68 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 4.0 Hz, 1H), 7.52–7.58 (m, 4H), 7.70 (s, 1H), 8.04 (s, 1H), 8.66 (s, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.61, 41.94, 107.31, 114.08, 127.93, 128.96, 129.15, 130.16, 132.15, 133.10, 134.04, 134.14, 134.26, 134.93, 177.50; IR (KBr) v: 1649 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₁₇H₁₄ClN₄O]⁺ (M + H⁺): 325.0851; found: 325.0850.

(E)-7-(4-bromobenzylidene)-3-(1H-1,2,3-triazol-1-yl)-6,7-dihydroindolizin-8(5H)-one (2c): White solid; yield 60%; m.p.: 191–192 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.23 (t, J = 5.5 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 6.44 (d, J = 4.5 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 7.27–7.28 (m, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.81 (s, 1H), 7.87 (s, 1H), 7.89 (s, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.74, 42.09, 106.29, 114.53, 123.29, 125.80, 128.33, 130.52, 131.25, 131.79, 131.92, 133.81, 134.01, 136.30, 177.75; IR (KBr) v: 1664 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₁₇H₁₄BrN₄O]⁺ (M + H⁺): 369.0346; found: 369.0343.

(E)-7-(4-methylbenzylidene)-3-(1H-1,2,3-triazol-1-yl)-6,7-dihydroindolizin-8(5H)-one (2d): White solid; yield 57%; m.p.: 170–172 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 2.39 (s, 3H), 3.28 (t, J = 5.5 Hz, 2H), 4.14 (t, J = 6.0 Hz, 2H), 6.43 (d, J = 4.5 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 7.23–7.25 (m, 2H), 7.31–7.33 (m, 2H), 7.87 (d, J = 9.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 21.43, 26.81, 42.14, 106.19, 114.18, 125.85, 128.08, 129.40, 129.91, 130.39, 130.71, 132.31, 133.78, 137.85, 139.40, 178.22; IR (KBr) v: 1646 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₁₈H₁₇N₄O]⁺ (M + H⁺): 305.1397; found: 305.1392.

(E)-7-(4-fluorobenzylidene)-3-(1H-1,2,3-triazol-1-yl)-6,7-dihydroindolizin-8(5H)-one (2e): White solid; yield 60%; m.p.: 199–200 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.25 (t, J = 6.0 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 6.43 (d, J = 4.5 Hz, 1H), 7.12 (t, J = 8.5 Hz, 2H), 7.18 (d, J = 4.0 Hz, 1H), 7.39–7.41 (m, 2H), 7.85 (d, J = 7.5 Hz, 2H), 7.91 (s, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.67, 42.08, 106.26, 114.36, 115.74, 115.91, 125.84, 128.25, 130.54, 131.02, 131.23, 131.26, 131.70, 131.77, 133.77, 136.46, 177.88; IR (KBr) v: 1648 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₁₇H₁₄FN₄O]⁺ (M + H⁺): 309.1146; found: 309.1151.

(E)-4-{(8-oxo-3-(1H-1,2,3-triazol-1-yl)-5,6-dihydroindolizin-7(8H)-ylidene)methyl}benzonitrile (2f): White solid; yield 50%; m.p.: 232–234 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.24 (t, J = 5.5 Hz, 2H), 4.20 (t, J = 6.0 Hz, 2H), 6.46 (d, J = 4.5 Hz, 1H), 7.23 (d, J = 4.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.86–7.90 (m, 3H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.77, 42.12, 106.38, 112.34, 114.97, 118.39, 125.73, 128.64, 130.12, 130.36, 132.39, 133.83, 133.86, 135.13, 139.77, 177.23; IR (KBr) v: 1664 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₁₈H₁₄N₅O]⁺ (M + H⁺): 316.1193; found: 316.1196.

(E)-3-(1H-1,2,3-benzotriazol-1-yl)-7-benzylidene-6,7-dihydroindolizin-8(5H)-one (3a): White solid; yield 61%; m.p.: 158–160 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.29 (t, J = 6.0 Hz, 2H), 4.09 (t, J = 6.0 Hz, 2H), 6.58 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.36–7.38 (m, 1H), 7.40–7.43 (m, 4H), 7.49 (t, J = 7.5 Hz, 1H), 7.57–7.63 (m, 2H), 7.94 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.82, 41.98, 107.04, 110.01, 114.54, 120.43, 124.98, 127.05, 128.65, 128.97, 129.16, 129.78, 130.72, 131.37, 134.06, 135.23, 137.67, 145.43, 178.14; IR (KBr) v: 1656 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₂₁H₁₇N₄O]⁺ (M + H⁺): 341.1397; found: 341.1400.

(E)-3-(1H-1,2,3-benzotriazol-1-yl)-7-(4-chlorobenzylidene)-6,7-dihydroindolizin-8(5H)-one (3b): White solid; yield 65%; m.p.: 221–222 °C; 1H NMR (500 MHz, CDCl₃, 298 K) δ: 3.25 (t, J = 6.0 Hz, 2H), 4.11 (t, J = 6.0 Hz, 2H), 6.59 (d, J = 4.5 Hz, 1H), 7.31 (d, J = 4.5 Hz, 1H), 7.32–7.35 (m, 2H), 7.38–7.40 (m, 2H), 7.49 (t, J = 7.0 Hz, 1H), 7.57–7.63 (m, 2H), 7.87 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.79, 41.87, 107.06, 109.99, 114.74, 120.44, 125.02, 127.22, 128.94, 129.20, 130.59, 131.02, 131.87, 133.63, 134.00, 134.97, 136.25, 145.42, 177.78; IR (KBr) v: 1662 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₂₁H₁₆ClN₄O]⁺ (M + H⁺): 375.1007; found: 375.1008.

(E)-3-(1H-1,2,3-benzotriazol-1-yl)-7-(4-bromobenzylidene)-6,7-dihydroindolizin-8(5H)-one (3c): White solid; yield 63%; m.p.: 226–227 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.24 (t, J = 5.5 Hz, 2H), 4.11 (t, J = 6.0 Hz, 2H), 6.59 (d, J = 4.0 Hz, 1H), 7.28–7.30 (m, 2H), 7.32 (d, J = 4.5 Hz, 1H), 7.49 (t, J = 7.0 Hz, 1H), 7.54–7.62 (m, 4H), 7.84 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.80, 41.86, 107.07, 109.99, 114.76, 120.44, 123.24, 125.02, 127.23, 129.20, 130.58, 131.23, 131.90, 131.96, 134.00, 134.08, 136.28, 145.42, 177.76; IR (KBr) v: 1665 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₂₁H₁₆BrN₄O]⁺ (M + H⁺): 419.0502; found: 419.0507.

(E)-3-(1H-1,2,3-benzotriazol-1-yl)-7-(4-methylbenzylidene)-6,7-dihydroindolizin-8(5H)-one (3d): White solid; yield 74%; m.p.: 177–179 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 2.38 (s, 3H), 3.28 (t, J = 6.0 Hz, 2H), 4.08 (t, J = 6.0 Hz, 2H), 6.57 (d, J = 4.0 Hz, 1H), 7.22–7.24 (m, 2H), 7.30 (d, J = 4.5 Hz, 1H), 7.31–7.33 (m, 2H), 7.48 (t, J = 7.0 Hz, 1H), 7.52–7.62 (m, 2H), 7.91 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 21.43, 26.87, 29.71, 41.91, 107.00, 110.03, 114.39, 120.40, 124.97, 126.93, 129.14, 129.39, 129.91, 130.55, 130.77, 132.36, 134.07, 137.80, 139.33, 145.42, 178.22; IR (KBr) v: 1658 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₂₂H₁₉N₄O]⁺ (M + H⁺): 355.1553; found: 355.1553.

(E)-3-(1H-1,2,3-benzotriazol-1-yl)-7-(4-fluorobenzylidene)-6,7-dihydroindolizin-8(5H)-one (3e): White solid; yield 70%; m.p.: 193–194 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.26 (t, J = 6.0 Hz, 2H), 4.11 (t, J = 6.0 Hz, 2H), 6.59 (s, 1H), 7.11 (t, J = 8.0 Hz, 2H), 7.29–7.31 (m, 1H), 7.38–7.40 (m, 2H), 7.49 (t, J = 7.0 Hz, 1H), 7.60–7.62 (m, 2H), 7.88 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.74, 41.87, 107.03, 110.01, 114.62, 115.72, 115.90, 120.40, 125.01, 127.13, 129.19, 130.61, 131.18, 131.29, 131.32, 131.69, 131.76, 134.01, 136.46, 145.40, 161.84, 163.83, 177.90; IR (KBr) v: 1662 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₂₁H₁₆FN₄O]⁺ (M + H⁺): 359.1303; found: 359.1300.

(E)-4-{(3-(1H-1,2,3-benzotriazol-1-yl)-8-oxo-5,6-dihydroindolizin-7(8H)-ylidene)methyl}benzonitrile (3f): White solid; yield 64%; m.p.: 276–277 °C; ¹H NMR (500 MHz, CDCl₃, 298 K) δ: 3.25 (t, J = 6.0 Hz, 2H), 4.15 (t, J = 6.0 Hz, 2H), 6.61 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 4.0 Hz, 1H), 7.49–7.51 (m, 3H), 7.58–7.63 (m, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃, 298 K) δ: 26.81, 41.87, 107.14, 109.97, 112.27, 115.17, 118.41, 120.47, 125.10, 127.58, 129.28, 130.13, 130.38, 132.38, 133.91, 134.01, 135.08, 139.83, 145.43, 177.23; IR (KBr) v: 1664 cm⁻¹ (−C=O); ESI-HRMS calcd for [C₂₂H₁₆N₅O]⁺ (M + H⁺): 366.1349; found: 366.1346.

Conclusion

In summary, we have successfully developed a method for the synthesis of 1,2,3-triazole/1H-1,2,3-benzotriazole-indolizin-8(5H)-one derivatives by nucleophilic functionalization of indolizin-8(5H)-one with 1,2,3-triazole/BHT in CH₃CN under very mild reaction conditions.