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
a   Division of Fluoro and Agro Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
c   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
,
Gal Reddy Potuganti
a   Division of Fluoro and Agro Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
c   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
,
Jagadeesh Babu Nanubolu
b   Centre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
c   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
,
Manjula Alla∗
a   Division of Fluoro and Agro Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
c   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
› Author AffiliationsI.D.R. thanks DST and P.G.R. thanks Council of Scientific and Industrial Research, India (CSIR) for a fellowship.
› Further Information
   Permissions and Reprints All articles of this category


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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1500-6863.
  • Supporting Information


Publication History

Received: 03 March 2021

Accepted after revision: 05 May 2021

Accepted Manuscript online:
05 May 2021

Article published online:
28 May 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

  • 1 Peng H, Bryan J, Henson W, Zhdankin VV, Gandhi K, David S. J. Chem. Educ. 2019; 96: 2622
    CrossrefSearch in Google Scholar
  • 4 Koser GF. Aldrichimica Acta 2001; 34: 89
    CrossrefPubMedSearch in Google Scholar
  • 9 Roben C, Souto JA, Escudero-Ad EC, Muciz K. Org. Lett. 2013; 15: 1008
    CrossrefPubMedSearch in Google Scholar
  • 12 Kamal R, Kumar V, Kumar R. Asian J. Org. Chem. 2016; 11: 1988
    CrossrefPubMedSearch in Google Scholar
  • 13 Liu W, Chen C, Zhang Q, Zhu Z. Beilstein J. Org. Chem. 2011; 7: 1436
    CrossrefPubMedSearch in Google Scholar
  • 14 Yoshimura A, Zhdankin VV. Chem. Rev. 2016; 116: 3328
    CrossrefPubMedSearch in Google Scholar
  • 17 Li X, Du Y, Liang Z, Li X, Pan Y, Zhao K. Org. Lett. 2009; 11: 2643
    CrossrefPubMedSearch in Google Scholar
  • 18 Mukherjee P, Das AR. J. Org. Chem. 2016; 81: 5513
    CrossrefPubMedSearch in Google Scholar
  • 20 Bhattacharyya P, Pradhan k, Paul S, Das AR. Tetrahedron Lett. 2012; 53: 4687
    CrossrefSearch in Google Scholar
  • 21 Mukherjee P, Das AR. RSC Adv. 2016; 6: 132
    CrossrefSearch in Google Scholar
  • 22 Lin Z, Zhang X, You X, Gao Y. Tetrahedron 2012; 68: 6759
    CrossrefPubMedSearch in Google Scholar
  • 25 Bulumulla C, Gunawardhana R, Gamage PL, Miller JT, Kularatne RN, Biewer MC, Stefan MC. ACS Appl. Mater. Interfaces 2020; 12: 32209
    CrossrefPubMedSearch in Google Scholar
  • 26 Sharley DD. S, Williams JM. J. Chem. Commun. 2017; 53: 2020
    CrossrefPubMedSearch in Google Scholar
  • 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, 2θmax = 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