Synthesis of Dihydropyrrole Derivatives by Oxidative Functionalization of 2-Amino-4H-Chromenes Using Hypervalent Iodine Reagents

Divakar Reddy Indukuri; Gal Reddy Potuganti; Jagadeesh Babu Nanubolu; Manjula Alla

doi:10.1055/a-1500-6863

Synlett, Inhaltsverzeichnis

Synlett 2021; 32(11): 1109-1116
DOI: 10.1055/a-1500-6863

letter

Synthesis of Dihydropyrrole Derivatives by Oxidative Functionalization of 2-Amino-4H-Chromenes Using Hypervalent Iodine Reagents

Divakar Reddy Indukuri

^aDivision of Fluoro and Agro Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India

^cAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

Gal Reddy Potuganti

^aDivision of Fluoro and Agro Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India

^cAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

Jagadeesh Babu Nanubolu

^bCentre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India

^cAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

Manjula Alla∗

^aDivision of Fluoro and Agro Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India

^cAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

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Abstract

Alle Artikel dieser Rubrik

Abstract

An efficient simple, metal-free, one-pot protocol for the synthesis of dihydropyrrole derivatives has been achieved via sequential addition of iodobenzenediacetate and secondary amine to 2-amino-4H- pyran derivatives. The one-pot protocol proceeds through tandem oxidative functionalization, rearrangement, and ring contraction to provide an entirely new strategy for the construction of the dihydropyrrole skeleton.

Key words

one pot - metal free - oxidative functionalization - rearrangement - ring contraction

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Referenzen

References and Notes
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27 General Procedure for the Preparation of Dihydropyrrole Derivatives A mixture of 2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (1 mmol, 1 equiv) and IBD (1.1 mmol, 1.1 equiv) in anhydrous DCM (3 mL) was stirred for 60 min, then secondary amine derivatives were added. Stirring was continued at room temperature until the starting material was completely consumed (TLC monitoring). After completion, the reaction mixture was extracted with DCM (20 mL) and washed with water (10 mL). The combined organic layers were dried (anhydrous Na₂SO₄) and evaporated under reduced pressure to dryness. The crude product thus obtained was purified by column chromatography (60–120 mesh, and EtOAc–hexane, 30:70) to afford the pure product.
28 Analytical Data
3-(4-Chlorophenyl)-4-oxo-2-(piperidine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5a) Yield: 134 mg (70%); white solid; mp156–158 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.35 (d, J = 8.4 Hz, 2 H), 7.25 (dd, J = 7.8, 5.4 Hz, 2 H), 5.53 (s, 1 H), 4.39 (s, 1 H), 3.58 (m, 4 H), 2.59 (q, J = 6.4 Hz, 2 H), 2.29–2.22 (m, 2 H), 2.11–2.03 (m, 2 H), 1.68–1.58 (m, 2 H), 1.30 (dt, J = 13.8, 7.0 Hz, 2 H), 0.88 (t, J = 7.1 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.38, 167.41, 163.51, 136.17, 134.48, 129.36, 115.88, 77.06, 67.33, 54.35, 47.59, 45.53, 36.44, 25.36, 25.13, 24.06, 23.70, 22.20. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₂₃O₂N₃Cl: 384.14869; found: 384.14733. 3-(4-Chlorophenyl)-2-[4-(4-fluorophenyl)piperazine-1-carbonyl]-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5b) Yield: 155 mg (65%); white solid; mp 212–214 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.39–7.36 (m, 2 H), 7.28–7.25 (m, 2 H), 7.02–6.97 (m, 2 H), 6.92–6.88 (m, 2 H), 5.47 (s, 1 H), 4.44 (s, 1 H), 4.07–3.62 (m, 4 H), 3.31–3.01 (m, 4 H), 2.61 (dd, J = 13.8, 6.7 Hz, 2 H), 2.29–2.24 (m, 2 H), 2.10–2.07 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.40, 167.21, 163.92, 159.26, 156.80, 147.11, 135.86, 134.68, 129.40, 119.02, 115.99, 115.77, 67.28, 54.55, 50.40, 49.76, 46.59, 44.22, 36.43, 23.70, 22.20. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₆H₂₅O₂N₄ClF: 479.16507; found: 479.16446. 3-(4-Chlorophenyl)-2-[4-(2-methoxyphenyl)piperazine-1-carbonyl]-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5c) Yield: 147 mg (60%); off-white solid; mp 204–206 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.32 (dd, J = 5.4, 3.5 Hz, 2 H), 7.29–7.27 (m, 1 H), 7.21 (dt, J = 6.8, 1.9 Hz, 1 H), 7.06 (m, 1 H), 6.95–6.89 (m, 3 H), 5.51 (s, 1 H), 4.44 (s, 1 H), 3.95 (s, 1 H), 3.90 (s, 3 H), 3.87–3.75 (m, 3 H), 3.22 (dd, J = 10.3, 5.9 Hz, 3 H), 3.07–2.99 (m, 1 H), 2.66–2.57 (m, 2 H), 2.31–2.26 (m, 2 H), 2.12–2.08 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.36, 167.51, 163.83, 152.30, 139.97, 139.42, 135.02, 130.44, 129.02, 128.12, 126.37, 124.04, 121.16, 118.72, 115.76, 115.55, 111.46, 67.26, 55.55, 54.73, 50.24, 49.80, 46.98, 44.54, 36.44, 23.71, 22.18. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₇H₂₈O₃N₄Cl: 491.18498; found: 491.18444. 3-(4-Chlorophenyl)-2-[4-(4-nitrophenyl)piperazine-1-carbonyl]-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5d) Yield: 189 mg (75%); yellow solid; mp 246–248 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.18–8.16 (m, 1 H), 7.35 (dd, J = 4.7, 1.9 Hz, 1 H), 7.31–7.28 (m, 1 H), 7.24–7.21 (m, 1 H), 6.91–6.87 (m, 2 H), 5.42 (s, 1 H), 4.42 (s, 1 H), 4.20–4.07 (m, 1 H), 3.93 (s, 1 H), 3.70 (dd, J = 68.9, 29.8 Hz, 4 H), 3.49–3.31 (m, 2 H), 2.70–2.57 (m, 2 H), 2.31–2.26 (m, 2 H), 2.14–2.07 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃ + DMSO): δ = 189.86, 167.29, 162.23, 153.13, 139.11, 137.40, 132.97, 129.03, 127.10, 126.91, 125.60, 124.51, 114.81, 112.00, 110.84, 66.83, 52.69, 44.93, 35.20, 22.22, 20.96. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₆H₂₅O₄N₅Cl: 506.16003; found: 506.15896 3-(4-Chlorophenyl)-4-oxo-2-[4-(pyridin-2-yl)piperazine-1-carbonyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5e) Yield: 168 mg (73%); white solid; mp 204–206 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.22 (ddd, J = 4.9, 1.9, 0.8 Hz, 1 H), 7.57–7.50 (m, 1 H), 7.42–7.33 (m, 1 H), 7.29–7.24 (m, 2 H), 6.75–6.66 (m, 2 H), 5.52 (s, 1 H), 4.44 (s, 1 H), 4.01–3.41 (m, 8 H), 2.60 (m, 2 H), 2.30–2.24 (m, 2 H), 2.12–2.06 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.36, 167.27, 164.09, 158.70, 148.09, 137.89, 135.88, 134.66, 129.43, 115.84, 115.62, 114.57, 107.45, 77.06, 67.38, 54.51, 46.22, 44.95, 44.49, 43.98, 36.42, 23.69, 22.20. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₅H₂₅O₂N₅Cl: 462.17025; found: 462.16913. 3-(4-Chlorophenyl)-2-(2,6-dimethylmorpholine-4-carbonyl)-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5f) Yield: 116 mg (56%); off-white solid; mp 200–202 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.27 (m, 2 H), 7.18 (dd, J = 36.9, 6.9 Hz, 2 H), 5.74 (s, 1 H), 4.34 (dd, J = 23.1, 13.8 Hz, 2 H), 3.81 (d, J = 12.8 Hz, 1 H), 3.67 (s, 2 H), 3.09–2.82 (m, 1 H), 2.59 (d, J = 27.8 Hz, 3 H), 2.26 (d, J = 6.3 Hz, 2 H), 2.13–2.01 (m, 2 H), 1.33–1.13 (m, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.33, 167.63, 163.92, 139.24, 134.97, 130.41, 129.07, 128.14, 126.26, 115.93, 115.21, 71.76, 71.12, 70.57, 67.35, 55.68, 53.83, 52.14, 51.79, 49.39, 48.95, 36.39, 23.65, 22.16, 18.65, 18.45. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₅O₃N₃Cl: 414.15821; found: 414.15790. 3-(4-Chlorophenyl)-4-oxo-2-(thiomorpholine-4-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5g) Yield: 118 mg (59%); white solid; mp 214–216 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.32 (td, J = 4.6, 3.0 Hz, 2 H), 7.28–7.25 (m, 1 H), 7.21–7.17 (m, 1 H), 5.42 (s, 1 H), 4.35 (s, 1 H), 4.31 (d, J = 11.7 Hz, 1 H), 4.02 (d, J = 10.2 Hz, 1 H), 3.80–3.71 (m, 1 H), 3.64–3.53 (m, 1 H), 2.96–2.85 (m, 1 H), 2.80–2.71 (m, 1 H), 2.61 (m, 4 H), 2.28 (dd, J = 9.5, 4.0 Hz, 2 H), 2.12–2.05 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.37, 167.46, 164.06, 139.27, 135.07, 130.49, 129.12, 128.06, 126.27, 115.71, 67.36, 54.60, 48.96, 47.03, 36.40, 27.22, 26.65, 23.69, 22.17. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₂₁O₂N₃ClS: 402.10532; found: 402.10509. tert-Butyl 4-[3-(4-Chlorophenyl)-2-cyano-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonyl]piperazine-1-carboxylate (5h) Yield: 134 mg (55%); white solid; mp 118–120 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.37 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2 H), 5.45 (s, 1 H), 4.38 (s, 1 H), 3.96–3.25 (m, 8 H), 2.65–2.56 (m, 2 H), 2.29–2.24 (m, 2 H), 2.11–2.04 (m, 2 H), 1.48 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.40, 167.21, 164.17, 154.36, 135.76, 134.70, 129.50, 115.84, 115.65, 80.92, 77.06, 67.29, 54.48, 46.36, 44.13, 36.41, 28.37, 23.68, 22.18. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₅H₃₀O₄N₄Cl: 485.19561; found: 485.19501. 3-(4-Chlorophenyl)-4-oxo-2-(pyrrolidine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5i) Yield: 98 mg (53%); off-white solid; mp 258–260 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (d, J = 8.4 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H), 5.47 (s, 1 H), 4.47 (s, 1 H), 3.75–3.40 (m, 4 H), 2.60 (t, J = 5.6 Hz, 2 H), 2.37–2.21 (m, 2 H), 2.12–2.02 (m, 4 H), 1.96 (dd, J = 13.1, 5.7 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.58, 167.69, 162.77, 136.22, 134.39, 129.30, 115.41, 77.06, 67.97, 53.43, 48.51, 47.56, 36.43, 26.70, 23.65, 23.34, 22.22. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₂₁O₂N₃Cl: 370.13359; found: 370.13302. 3-(4-Fluorophenyl)-4-oxo-2-(piperidine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5j) Yield: 98 mg (73%); white solid; mp 210–212 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.12 (m, 2 H), 7.14–6.90 (m, 2 H), 5.44 (s, 1 H), 4.40 (s, 1 H), 3.84–3.36 (m, 4 H), 2.67–2.46 (m, 2 H), 2.34–2.17 (m, 2 H), 2.09 (dd, J = 12.3, 6.1 Hz, 2 H), 1.86–1.58 (m, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.36, 167.35, 163.89, 163.58, 161.43, 133.46, 129.65, 116.18, 115.96, 115.76, 67.51, 54.19, 47.56, 45.47, 36.43, 25.34, 25.11, 24.04, 23.66, 22.19. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₂₁O₂N₃Cl: 354.17359; found: 354.17302 2-(2,6-Dimethylmorpholine-4-carbonyl)-3-(4-fluorophenyl)-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5k) Yield: 119 mg (60%); off-white solid; mp 150–152 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.26 (t, J = 10.3 Hz, 2 H), 7.08 (t, J = 8.4 Hz, 2 H), 5.49 (s, 1 H), 4.47–4.24 (m, 2 H), 4.06 (dd, J = 83.5, 21.9 Hz, 1 H), 3.82 (d, J = 12.4 Hz, 1 H), 3.64 (d, J = 31.2 Hz, 2 H), 2.58 (tt, J = 23.9, 11.8 Hz, 3 H), 2.29 (t, J = 19.2 Hz, 2 H), 2.15–2.00 (m, 2 H), 1.21 (dd, J = 47.3, 12.0 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.47, 167.16, 164.01, 163.66, 133.14, 129.71, 116.34, 116.12, 71.81, 71.09, 70.64, 67.43, 55.45, 53.72, 52.16, 49.43, 36.45, 23.71, 22.21, 18.67. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₅O₃N₃F: 398.18865; found: 398.18845. 3-(4-Fluorophenyl)-4-oxo-2-(4-phenylpiperazine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5l) Yield: 153 mg (69%); white solid; mp 232–234 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.27 (m, 1 H), 7.12–7.07 (m, 1 H), 6.95 (dd, J = 7.7, 3.6 Hz, 1 H), 5.49 (s, 1 H), 4.47 (s, 1 H), 4.06–3.58 (m, 4 H), 3.48–2.89 (m, 4 H), 2.70–2.49 (m, 2 H), 2.42–2.19 (m, 2 H), 2.09 (t, J = 6.3 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.42, 167.18, 164.01, 161.54, 150.48, 133.24, 129.74, 129.37, 121.23, 117.05, 116.36, 116.14, 115.94, 67.49, 54.43, 49.41, 48.82, 46.54, 44.19, 36.45, 23.69, 22.21. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₆H₂₆O₂N₄F: 445.20385; found: 445.20343. 3-(4-Fluorophenyl)-2-[4-(4-fluorophenyl)piperazine-1-carbonyl]-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5m) Yield: 173 mg (75%); white solid; mp 230–232 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.34–7.27 (m, 2 H), 7.12–7.05 (m, 2 H), 7.03–6.96 (m, 2 H), 6.93–6.84 (m, 2 H), 5.46 (s, 1 H), 4.46 (s, 1 H), 4.03 (d, J = 12.5 Hz, 1 H), 3.90–3.57 (m, 3 H), 3.35–2.99 (m, 4 H), 2.60 (m, 2 H), 2.31–2.24 (m, 2 H), 2.09 (t, J = 6.2 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.45, 167.07, 164.03, 161.57, 159.22, 156.82, 147.11, 133.20, 129.81, 129.72, 119.04, 116.39, 116.18, 116.00, 115.78, 67.45, 54.47, 50.42, 49.79, 46.60, 44.22, 36.47, 23.73, 22.23. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₆H₂₅O₂N₄F₂: 463.19430; found: 463.19401. 2-[4-(3-Chlorophenyl)piperazine-1-carbonyl]-3-(4-fluorophenyl)-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5n) Yield: 134 mg (64%); white solid; mp 248–250 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.28 (m, 2 H), 7.22–7.18 (m, 1 H), 7.12–7.07 (m, 2 H), 6.92–6.89 (m, 2 H), 6.82–6.78 (m, 1 H), 5.44 (s, 1 H), 4.45 (s, 1 H), 4.13–3.57 (m, 4 H), 3.24 (dd, J = 71.6, 62.7 Hz, 4 H), 2.65–2.57 (m, 2 H), 2.28 (m, 2 H), 2.12–2.07 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.44, 167.13, 164.05, 161.56, 151.51, 135.17, 133.15, 130.30, 129.80, 129.72, 120.90, 116.89, 116.40, 116.18, 115.90, 115.84, 114.80, 77.06, 67.47, 54.42, 48.88, 48.30, 46.31, 43.99, 36.44, 23.70, 22.21. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₆H₂₅O₂N₄ClF: 479.16507; found: 479.16446. 3-(4-Fluorophenyl)-2-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5o) Yield: 166 mg (70%); off-white solid; mp 158–160 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.28 (m, 2 H), 7.11–7.06 (m, 2 H), 6.94–6.89 (m, 2 H), 6.87–6.83 (m, 2 H), 5.47 (s, 1 H), 4.46 (s, 1 H), 4.00 (d, J = 11.1 Hz, 1 H), 3.83 (s, 1 H), 3.78 (s, 3 H), 3.76–3.64 (m, 2 H), 3.27–2.97 (m, 4 H), 2.61 (q, J = 6.5 Hz, 2 H), 2.27 (dd, J = 11.3, 6.2 Hz, 2 H), 2.09 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.45, 167.20, 163.97, 161.53, 154.85, 144.66, 133.23, 129.73, 119.34, 116.35, 116.01, 114.62, 77.07, 67.47, 55.58, 54.43, 50.87, 50.22, 46.72, 44.32, 36.45, 23.70, 22.21. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₇H₂₈O₃N₄F: 475.21482; found: 475.21400. 3-(4-Fluorophenyl)-2-[4-(4-nitrophenyl)piperazine-1-carbonyl]-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5p) Yield: 176 mg (72%); yellow solid; mp 242–244 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.23–8.11 (m, 2 H), 7.33–7.28 (m, 2 H), 7.16–7.06 (m, 2 H), 6.93–6.83 (m, 2 H), 5.42 (s, 1 H), 4.45 (s, 1 H), 4.14 (d, J = 10.5 Hz, 1 H), 3.92 (s, 1 H), 3.70 (d, J = 44.9 Hz, 4 H), 3.49–3.31 (m, 2 H), 2.66–2.57 (m, 2 H), 2.32–2.24 (m, 2 H), 2.09 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 189.94, 167.29, 162.04, 159.41, 152.98, 136.82, 132.53, 128.71, 124.29, 114.62, 114.19, 113.98, 111.69, 110.54, 66.89, 52.00, 44.51, 43.83, 41.95, 34.84, 21.86, 20.67. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₆H₂₅O₄N₅F: 490.18927; found: 490.18851 3-(4-Fluorophenyl)-4-oxo-2-[4-(pyridin-2-yl)piperazine-1-carbonyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5q) Yield: 162 mg (73%); off-white solid; mp 178–180 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.23–8.19 (m, 1 H), 7.57–7.50 (m, 1 H), 7.33–7.28 (m, 2 H), 7.09 (t, J = 8.5 Hz, 2 H), 6.75–6.65 (m, 2 H), 5.69 (s, 1 H), 4.47 (s, 1 H), 4.12–3.39 (m, 8 H), 2.83–2.47 (m, 2 H), 2.37–2.18 (m, 2 H), 2.08 (dd, J = 12.4, 6.2 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.44, 167.13, 164.05, 151.51, 135.17, 133.12, 130.30, 129.80, 120.90, 116.89, 116.40, 115.84, 114.80, 67.47, 54.42, 48.88, 48.30, 46.31, 43.99, 36.44, 23.70, 22.21. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₅H₂₅O₂N₅F: 446.21482; found: 446.21400 2-(4-Ethylpiperazine-1-carbonyl)-3-(4-fluorophenyl)-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5r) Yield: 129 mg (65%); white solid; mp 142–144 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.29–7.25 (m, 1 H), 7.10–7.05 (m, 1 H), 5.54 (d, J = 3.8 Hz, 1 H), 4.42 (s, 1 H), 3.87 (d, J = 38.8 Hz, 1 H), 3.74–3.52 (m, 3 H), 2.69–2.55 (m, 4 H), 2.53–2.40 (m, 4 H), 2.29–2.24 (m, 2 H), 2.11–2.05 (m, 2 H), 1.11 (t, J = 7.2 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.42, 167.21, 163.76, 161.50, 133.28, 129.79, 116.29, 116.07, 115.90, 67.42, 54.36, 52.09, 51.51, 46.63, 44.21, 36.45, 23.69, 22.20, 11.93. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₅N₄O₂F: 397.203979; found: 397.20519 3-(4-Methoxyphenyl)-4-oxo-2-(piperidine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5s) Yield: 117 mg (62%); white solid; mp 132–134 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.24–7.19 (m, 2 H), 6.93–6.87 (m, 2 H), 5.47 (s, 1 H), 4.38 (s, 1 H). 3.79 (s, 3 H), 3.78–3.71 (m, 1 H), 3.63 (d, J = 14.8 Hz, 1 H), 3.58–3.44 (m, 2 H), 2.59 (t, J = 8.0 Hz, 2 H), 2.28–2.23 (m, 2 H), 2.07 (dt, J = 11.9, 5.9 Hz, 2 H), 1.73 (s, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 192.51, 167.05, 163.88, 159.63, 129.60, 129.10, 116.15, 114.47, 77.06, 67.76, 55.23, 54.39, 47.61, 45.44, 36.51, 25.38, 25.14, 24.11, 23.73, 22.25. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₆N₃O₃: 380.19720; found: 380.19687. 4-Oxo-2-(piperidine-1-carbonyl)-3-(3,4,5-trimethoxyphenyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5t) Yield: 128 mg (58%); white solid; mp 198–200 °C. ¹H NMR (400 MHz, CDCl₃): δ = 6.53 (s, 2 H), 5.49 (s, 1 H), 4.34 (s, 1 H), 3.85 (d, J = 6.1 Hz, 9 H), 3.71–3.52 (m, 4 H), 2.66–2.54 (m, 2 H), 2.33–2.17 (m, 2 H), 2.12–2.06 (m, 2 H), 1.82–1.61 (m, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.47, 167.11, 163.82, 153.53, 138.34, 133.09, 115.96, 105.39, 67.63, 60.86, 56.27, 55.40, 47.59, 45.42, 36.54, 25.35, 24.09, 23.76, 22.30. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₆N₃O₃: 440.218000; found: 440.21798. 4-Oxo-3-phenyl-2-(piperidine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5u) Yield: 115 mg (66%); white solid; mp 204–206 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.38 (ddd, J = 7.5, 4.4, 1.3 Hz, 2 H), 7.34–7.29 (m, 3 H), 5.44 (s, 1 H), 4.41 (s, 1 H), 3.80–3.71 (m, 1 H), 3.67–3.44 (m, 3 H), 2.60 (dd, J = 11.5, 5.7 Hz, 2 H), 2.29–2.23 (m, 2 H), 2.12–2.05 (m, 2 H), 1.62 (dt, J = 16.2, 7.7 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.40, 167.30, 163.77, 137.55, 129.07, 128.63, 127.94, 116.01, 77.06, 67.61, 54.93, 47.59, 45.45, 36.47, 25.36, 25.11, 24.07, 23.69, 22.21. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₂₄N₃O₂: 350.18630; found: 350.18632. 4-Oxo-2-(piperidine-1-carbonyl)-3-(o-tolyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5v) Yield: 116 mg (64%); white solid; mp 162–164 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.43 (d, J = 7.5 Hz, 1 H), 7.24–7.14 (m, 3 H), 5.48 (s, 1 H), 4.67 (s, 1 H), 3.98 (s, 1 H), 3.44 (dd, J = 105.7, 41.0 Hz, 3 H), 2.58 (s, 3 H), 2.57–2.53 (m, 2 H), 2.21 (dt, J = 8.2, 4.6 Hz, 2 H), 2.03 (dd, J = 11.4, 5.2 Hz, 2 H), 1.68 (d, J = 21.4 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.31, 166.43, 164.05, 136.46, 135.59, 130.62, 128.19, 127.93, 126.78, 118.52, 116.44, 67.69, 50.22, 47.54, 45.61, 36.48, 25.31, 24.12, 23.74, 22.05, 19.72. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₂H₂₆N₃O₂: 364.20351; found: 364.20195. 3-(4-Nitrophenyl)-4-oxo-2-(piperidine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5w) Yield: 106 mg (54%); white solid; mp 170–172 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.29–8.22 (m, 2 H), 7.52–7.47 (m, 2 H), 5.57 (s, 1 H), 4.51 (s, 1 H), 3.82 (d, J = 13.0 Hz, 1 H), 3.51 (dt, J = 18.0, 12.1 Hz, 3 H), 2.63 (dd, J = 10.2, 5.5 Hz, 2 H), 2.27 (dd, J = 14.7, 6.9 Hz, 2 H), 2.10 (dd, J = 12.3, 6.1 Hz, 2 H), 1.62 (s, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 192.32, 167.84, 163.03, 147.97, 144.88, 129.16, 124.42, 115.61, 115.53, 66.87, 54.45, 47.63, 45.67, 36.34, 25.35, 25.15, 24.02, 23.73, 22.17. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₁H₂₂N₄O₄: 394.16420; found: 394.16340. 3-(4-Fluorophenyl)-6,6-dimethyl-4-oxo-2-(piperidine-1-carbonyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5x) Yield: 142mg (72%); white solid; mp 160–162 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.29 (ddd, J = 7.0, 4.5, 2.0 Hz, 2 H), 7.10–7.05 (m, 2 H), 5.35 (s, 1 H). 4.40 (s, 1 H), 3.79 (d, J = 13.2 Hz, 1 H), 3.61 (d, J = 13.4 Hz, 1 H), 3.47 (dd, J = 23.6, 14.8 Hz, 2 H), 2.44 (d, J = 5.8 Hz, 2 H), 2.14 (dd, J = 40.0, 16.4 Hz, 2 H), 1.73 (d, J = 4.7 Hz, 6 H), 1.10 (d, J = 2.3 Hz, 6 H).¹³C NMR (101 MHz, CDCl₃): δ = 191.83, 166.33, 163.92, 163.61, 161.46, 133.53, 129.64, 116.26, 116.05, 115.95, 114.47, 67.67, 54.11, 50.57, 47.60, 45.51, 37.42, 34.65, 29.07, 28.28, 25.37, 25.10, 24.06. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₃H₂₇O₂N₃F: 396.20818; found: 396.20904. 3-(4-Fluorophenyl)-6,6-dimethyl-4-oxo-2-[4-(pyridin-2-yl)piperazine-1-carbonyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5y) Yield: 172 mg (73%); white solid; mp 164–166 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.23–8.19 (m, 1 H), 7.53 (ddd, J = 8.9, 7.2, 2.0 Hz, 1 H), 7.34–7.29 (m, 2 H), 7.13–7.07 (m, 2 H), 6.74–6.70 (m, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 5.41 (s, 1 H), 4.45 (s, 1 H), 3.98 (d, J = 12.9 Hz, 1 H), 3.84 (t, J = 9.0 Hz, 3 H), 3.75–3.55 (m, 3 H), 3.50–3.40 (m, 1 H), 2.46 (s, 2 H), 2.18–2.09 (m, 2 H), 1.11 (d, J = 4.3 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 191.79, 165.99, 164.21, 158.72, 148.08, 137.91, 133.24, 129.79, 116.42, 116.21, 115.92, 114.57, 107.46, 67.68, 54.35, 50.62, 46.23, 44.98, 44.50, 43.99, 37.46, 34.70, 28.97, 28.38. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₇H₂₉O₂N₅F: 474.23108; found: 474.22998. 3-(4-Fluorophenyl)-4-oxo-6-phenyl-2-[4-(pyridin-2-yl)piperazine-1-carbonyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carbonitrile (5z) Yield: 164 mg (63%); white solid; mp 210–212 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.29–8.13 (m, 1 H), 7.60–7.48 (m, 1 H), 7.39–7.31 (m, 2 H), 7.25 (m, 5 H), 7.10 (m, 2 H), 6.72 (dd, J = 7.1, 4.9 Hz, 1 H), 6.69 (d, J = 8.5 Hz, 1 H), 5.58 (d, J = 15.4 Hz, 1 H), 4.50 (d, J = 7.9 Hz, 1 H), 3.98 (d, J = 12.5 Hz, 1 H), 3.80 (t, J = 18.3 Hz, 3 H), 3.76–3.56 (m, 3 H), 3.53–3.40 (m, 2 H), 2.90–2.79 (m, 2 H), 2.57–2.54 (m, 2 H).¹³C NMR (101 MHz, CDCl₃): δ = 191.03, 164.08, 158.68, 148.03, 142.26, 137.85, 129.84, 128.81, 127.18, 126.83, 126.72, 116.29, 116.08, 115.76, 114.52, 107.44, 77.06, 67.66, 54.36, 46.20, 44.94, 44.47, 43.93, 43.51, 41.07, 40.22, 31.28, 30.89. HRMS-ESI: m/z [M + H]⁺ calcd for C₃₁H₂₉O₂N₅F: 522.23097; found: 522.22998. 3-(4-Chlorophenyl)-2-cyano-N,N-diethyl-4-oxo-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxamide (5a′) Yield: 190 mg (52%); colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.30 (m, 2 H), 7.27 (d, J = 2.6 Hz, 1 H), 7.23–7.19 (m, 1 H), 5.69 (s, 1 H), 4.38–4.35 (m, 1 H), 3.54 (dt, J = 13.5, 6.8 Hz, 1 H), 3.50–3.37 (m, 3 H), 2.59 (dd, J = 12.4, 6.2 Hz, 2 H), 2.28 (dd, J = 6.9, 4.7 Hz, 2 H), 2.08 (dt, J = 12.6, 6.2 Hz, 2 H), 1.33 (t, J = 6.9 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 192.33, 167.80, 164.26, 139.64, 134.89, 130.33, 128.91, 128.06, 126.25, 115.81, 115.20, 67.54, 54.56, 42.27, 41.64, 36.41, 23.65, 22.17, 12.82, 12.40. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₀H₂₃N₃O₂Cl: 372.14882; found: 372.14956. 1-[4-(4-Fluorophenyl)piperazin-1-yl]ethan-1-one (7) ¹H NMR (400 MHz, CDCl₃): δ = 7.02–6.94 (m, 2 H), 6.92–6.83 (m, 2 H), 3.81–3.73 (m, 2 H), 3.67–3.57 (m, 2 H), 3.13–2.97 (m, 4 H), 2.14 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.05, 158.73, 156.35, 147.52, 118.59, 115.85, 115.53, 50.68, 50.32, 46.22, 41.35, 29.64, 21.30. HRMS-ESI: m/z [M + H]⁺ calcd for C₁₂H₁₆ON₂F: 223.12412; found: 223.12470. Crystal Data for 5a C₂₄H₂₂N₃O₂Cl₁, M = 401.88, monoclinic, space group P2₁ /n (No.14), a =14.005(12)Å, b = 14.440(12)Å, c = 10.998(9)Å, α = 90°, β = 112.583(18)°, γ = 90°, V = 2054(3)Å³, Z = 4, D _c = 1.300 g/cm³, F ₀₀₀ = 848, Bruker D8 QUEST PHOTON-100, Mo Kα radiation, λ = 0.71073 Å, T = 293(2) K, 2θ_max = 50°, μ = 0.212 mm^–1, 13591 reflections collected, 3595 unique (R _int = 0.0667), 265 parameters, R1 = 0.0618, wR2 = 0.1542, R indices based on 2598 reflections with I > 2σ(I) (refinement on F ²), final GooF = 1.025, largest difference hole and peak = –0.390 and 0.570 e Å^–3 (Figure 1). CCDC 2065225 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

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