3.1. Chemistry
All reagents and solvents were obtained from commercial suppliers and were used without any further purification. Melting points were determined in open capillary tubes on a Stuart Scientific melting point apparatus SMP3 and were uncorrected. To determine the purity of compounds elemental analyses were carried out on a C. Erba Model 1106 (Elemental Analyser for C, H, and N) instrument, and the obtained results were within ± 0.4% of the theoretical values. Merck silica gel 60 F254 plates were used for analytical TLC; flash column chromatography was performed on Merck silica gel (200–400 mesh).
1H and
13C and NMR spectra were recorded on a Varian 500 MHz spectrometer equipped with a ONE_NMR probe and operating at 499.74 and 125.73 MHz for
1H and
13C, respectively. We used the residual signal of the deuterated solvent as an internal standard. Splitting patterns are described as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quartet (q), multiplet (m), or broad singlet (bs).
1H and
13C NMR chemical shifts (δ) are expressed in ppm and coupling constants (
J) are given in Hz. All
1H- and
13C-NMR spectra are reported in the
Supporting Information (see Figures S1–S48).
Synthesis of P3-P2 synthons
Ethyl 2-(1H-indol-1-yl) acetate (14a)
In a double-neck round bottom flask containing NaH 57% dispersion in mineral oil (1.62 g, 0.038 mol), placed in an ice bath at 0 °C, 1H-indole 9 (3 g, 0.026 mol), previously solubilized in anhydrous DMF, was added dropwise, under nitrogen atmosphere. The reaction mixture was stirred for 1 h and then ethyl-2-bromoacetate 13a (4.26 mL, 0.038 mol) was added. The reaction mixture was stirred overnight at room temperature. After overnight stirring, the reaction mixture was quenched with a saturated NH4Cl solution at 0 °C; then, the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography using CHCl3/Acetone 95:5 to obtain the pure product 14a (1.74 g, 33%); consistency: light yellow oil; Rf = 0.43 (petroleum ether/EtOAc 9:1). 1H NMR (500 MHz, CDCl3) = δ:1.15 (t, J = 7.1 Hz, 3H), 4.10 (q, J = 7.1 Hz, 2H), 4.66 (s, 2H), 6.49 (d, J = 2.9 Hz, 1H), 6.96 (d, J = 2.9 Hz, 1H), 7.10–7.06 (m, 1H), 7.16 (d, J = 4.1 Hz, 2H), 7.59 (d, J = 7.9 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 13.89, 47.50, 61.34, 102.13, 108.77, 119.60, 120.86, 121.74, 128.35, 128.41, 136.28, 168.35. Elemental analysis: calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89; found: C 71.06, H 6.24, N 6.96.
Ethyl 2-(2-methyl-1H-indol-1-yl) acetate (15a)
To a 57% NaH suspension in anhydrous DMF (0.72 g, 0.017 mol), according to the same procedure described for 14a, 2-methyl-1H-indole 10 (1.5 g, 0.011 mol) and ethyl-2-bromoacetate 13a (1.9 mL, 0.017 mol) were added. The title compound 15a (836 mg, 35%) was obtained after purification by silica gel column chromatography using CHCl3/acetone 95:5 as eluent mixture; consistency: off-white oil; Rf = 0.61 (petroleum ether/EtOAc 9:1). 1H NMR (500 MHz, CDCl3) = δ: 1.26 (t, J = 7.1 Hz, 3H), 2.43 (s, 3H), 4.20 (q, J = 7.1 Hz, 2H), 4.64 (s, 2H), 6.31 (s, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 12.19, 13.79, 44.15, 61.05, 100.88, 108.12, 119.66, 119.70, 120.81, 128.02, 136.26, 136.90, 168.01. Elemental analysis: calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45; found: C 71.64, H 6.78, N 6.54.
Ethyl 2-(3-methyl-1H-indol-1-yl) acetate (16a)
To a 57% NaH suspension in anhydrous DMF (1.44 g, 0.034 mol), according to the same procedure described for 14a, 3-methyl-1H-indole 11 (3 g, 0.023 mol) and ethyl-2-bromoacetate 13a (4.26 mL, 0.034 mol) were added. The title compound 16a (1.15 g, 23%) was obtained after purification by silica gel column chromatography using petroleum ether/EtOAc 9:1 as eluent mixture; consistency: light yellow oil; Rf = 0.62 (petroleum ether/EtOAc 9:1). 1H NMR (500 MHz, CDCl3) = δ: 1.34 (t, J = 7.1 Hz, 3H), 2.44 (s, 3H), 4.27 (q, J = 7.1 Hz, 2H), 4.80 (s, 2H), 6.91 (s, 1H), 7.22–7.26 (m, 1H), 7.28–7.34 (m, 2H), 7.68–7.70 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 9.42, 13.96, 47.36, 61.32, 108.61, 111.30, 118.98, 121.75, 125.87, 128.83, 136.67, 137.01, 168.66. Elemental analysis: calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45; found: C 71.77, H 6.86, N 6.47.
Ethyl 2-(5-fluoro-1H-indol-1-yl) acetate (17a)
To a 57% NaH suspension in anhydrous DMF (0.701 g, 0.017 mol), according to the same procedure described for 14a, 5-fluoro-1H-indole 12 (1.5 g, 0.011 mol) and ethyl-2-bromoacetate 13a (1.85 mL, 0.017 mol) were added. The title compound 17a (0.565 g, 23%) was obtained after purification by silica gel column chromatography using petroleum ether/acetone/EtOAc 8:1.5:0.5 as eluent mixture; consistency: yellow oil; Rf = 0.63 (petroleum ether/acetone 8:2). 1H NMR (500 MHz, CDCl3) = δ: 1.28 (t, J = 7.1 Hz, 3H), 4.23 (q, J = 7.1 Hz, 2H), 4.76 (s, 2H), 6.55 (d, J = 3.2 Hz, 1H), 7.02 (t, J = 9.2 Hz, 1H), 7.12 (d, J = 3.2 Hz, 1H), 7.18 (dd, J = 8.9 and 4.2 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 13.88, 47.67, 61.46, 102.09 (d, J = 4.6 Hz), 105.62 (d, J = 23.4 Hz), 109.63 (d, J = 9.9 Hz), 110.02 (d, J = 26.4 Hz), 128.82, 130.22, 133.04, 157.91 (d, J = 234.0 Hz), 168.26. Elemental analysis: calcd for C12H12FNO2: C, 65.15; H, 5.47; N, 8.59; found: C 64.92, H 5.58, N 8.43.
Ethyl 3-(1H-indol-1-yl) propanoate (14b)
To a 57% NaH suspension in anhydrous DMF (1.05 g, 0.026 mol), according to the same procedure described for 14a, 1H-indole 9 and ethyl-3-bromopropionate 13b (3.27 mL, 0.026 mol) were added. The title compound 14b (1.22 g, 33%) was obtained after purification by silica gel column chromatography using petroleum ether/EtOAc/acetone 9:0.5:0.5 as eluent mixture; consistency: light yellow oil; Rf = 0.7 (petroleum ether/EtOAc 9:1). 1H NMR (500 MHz, CDCl3) = δ: 1.20 (t, J = 7.1 Hz, 3H), 2.82 (t, J = 6.9 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.46 (t, J = 6.9 Hz, 2H), 6.48 (s, 1H), 7.09–7.14 (m, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.9Hz, 1H); ppm; 13C NMR (125 MHz, CDCl3) = δ: 14.17, 25.95, 29.69, 41.82, 60.98, 101.55, 109.07, 119.46, 121.03, 121.59, 122.42, 127.89, 136.58, 170.66 ppm. Elemental analysis: calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45; found: C 71.78, H 6.86, N 6.54.
Ethyl 3-(2-methyl-1H-indol-1-yl) propanoate (15b)
To a 57% NaH suspension in anhydrous DMF (0.96 g, 0.023 mol), according to the same procedure described for 14a, 2-methyl-1H-indole 10 (2 g, 0.015 mol) and ethyl-3-bromopropionate 13b (2.93 mL, 0.023 mol) were added. The title compound 15b (971 mg, 28%) was obtained after purification by silica gel column chromatography using petroleum ether/EtOAc 65:35 as eluent mixture; consistency: yellow oil; Rf = 0.51 (petroleum ether/EtOAc 65:35). 1H NMR (500 MHz, CDCl3) = δ: 1.23 (t, J = 7.1 Hz, 3H), 2.38 (s, 3H), 2.68 (t, J = 7.3 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.36 (t, J = 7.5 Hz, 2H), 6.87 (s, 1H), 7.00 (t, J = 7.1 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 11.85, 14.09, 34.53, 38.46, 60.93, 109.06, 112.41, 119.05, 119.76, 119.83, 121.04, 125.30, 137.38, 170.88. Elemental analysis: calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06; found: C 72.69, H 7.36, N 5.89.
Ethyl 3-(3-methyl-1H-indol-1-yl) propanoate (16b)
To a 57% NaH suspension in anhydrous DMF (0.96 g, 0.023 mol), according to the same procedure described for 14a, 3-methyl-1H-indole 11 (2 g, 0.015 mol) and ethyl-3-bromopropionate 13b (2.93 mL, 0.023 mol) were added. The title compound 16b (1.25 g, 36%) was obtained after purification by silica gel column chromatography using petroleum ether/EtOAc 9:1 as eluent mixture; consistency: light yellow oil; Rf = 0.62 (petroleum ether/EtOAc 9:1). 1H NMR (500 MHz, CDCl3) = δ: 1.31 (t, J = 6.9 Hz, 3H), 2.44 (s, 3H), 2.85 (t, J = 6.9 Hz, 2H), 4.21 (q, J = 13 Hz, 2H), 4.45 (t, J = 6.9 Hz, 2H), 6.98 (s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) = δ: 9.65, 14.10, 35.03, 41.70, 60.97, 109.05, 110.64, 118.87, 119.18, 121.70, 125.60, 128.89, 136.23, 170.99. Elemental analysis: calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06; found: C 72.84, H 7.12, N 6.09.
Ethyl 3-(5-fluoro-1H-indol-1-yl) propanoate (17b)
To a 57% NaH suspension in anhydrous DMF (0.467 g, 0.011 mol), according to the same procedure described for 14a, 5-fluoro-1H-indole 12 (1 g, 0.007 mol) and ethyl-3-bromopropionate 13b (1.42 mL, 0.011 mol) were added. The title compound 17b (0.56 g, 32%) was obtained after purification by silica gel column chromatography using petroleum ether/acetone/EtOAc 9:0.5:0.5 as eluent mixture; consistency: pale yellow oil; Rf = 0.63 (petroleum ether/acetone 8:2). 1H NMR (500 MHz, CDCl3) = δ: 1.21 (t, J = 7.2 Hz, 3H), 2.80 (t, J = 6.8 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 4.43 (t, J = 6.8 Hz, 2H), 6.44 (d, J = 3.1 Hz, 1H), 6.97 (t, J = 6.7 Hz, 1H), 7.17 (d, J = 3.1 Hz, 1H), 7.24–7.28 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 14.06, 35.02, 42.05, 60.92, 101.53 (d, J = 4.7 Hz), 105.72 (d, J = 23.3 Hz), 109.69 (d, J = 9.8 Hz), 109.94, 128.88, 129.47, 132.32, 157.87 (d, J = 234.1 Hz), 171.08. Elemental analysis: calcd for C13H14FNO2: C, 66.37; H, 6.00; N, 5.95; found: C 66.58, H 6.12, N 5.91.
2-(1H-Indol-1-yl) acetic acid (18a)
To a solution of 14a (1.74 g, 0.0086 mol) in a mixture methanol/water/dioxane (1:1:1), placed in an ice bath at 0 °C, LiOH as powder (1.03 g, 0.043 mol) was added. The reaction mixture was allowed to stir overnight at room temperature. After overnight stirring, solvents were removed in vacuo and the residue was extracted in Et2O and water. The aqueous phase was brought to pH = 1–2 by addition of a 10% KHSO4 solution and extracted with EtOAc. The organic phase was then dried over Na2SO4, filtered and evaporated in vacuo to obtain the pure carboxylic acid 18a (827 mg, 55%); consistency: yellow powder. 1H NMR (500 MHz, DMSO) = δ: 5.01 (s, 2H), 6.44 (s, 1H), 7.03 (t, J = 7.0 Hz, 1H), 7.12 (t, J = 6.6 Hz, 1H), 7.32–7.34 (m, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 6.6 Hz, 1H) ppm. Elemental analysis: calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00; found: C 68.32, H 5.12, N 8.13.
2-(2-Methyl-1H-indol-1-yl) acetic acid (19a)
To a solution of 15a (238 mg, 1.1 mmol), according to the same procedure described for 18a, LiOH as powder (131.17 mg, 5.48 mmol) was added and the pure carboxylic acid 19a (195 mg, 94%) was obtained; consistency: burgundy powder. 1H NMR (500 MHz, CDCl3) = δ: 2.40 (s, 3H), 4.83 (s, 2H), 6.31 (s, 1H), 7.07–7.11 (m, 1H), 7.13–7.19 (m, 2H), 7.53 (d, J = 7.7 Hz, 1H) ppm. Elemental analysis: calcd for C11H11NO2: C, 68.83; H, 5.86; N, 7.40; found: C 68.66, H 5.93, N 7.46.
2-(3-Methyl-1H-indol-1-yl) acetic acid (20a)
To a solution of 16a (1.15 g, 0.005 mol), according to the same procedure described for 18a, LiOH as powder (634 mg, 0.026 mol) was added and the pure carboxylic acid 20a (195 mg, 94%) was obtained; consistency: yellow powder. 1H NMR (500 MHz, CDCl3) = δ: 2.32 (s, 3H), 4.83 (s, 2H), 6.84 (s, 1H), 7.12–7.15 (m, 1H), 7.18–7.24 (m, 2H), 7.57 (d, J = 7.7 Hz, 1H) ppm. Elemental analysis: calcd for C11H11NO2: C, 68.83; H, 5.86; N, 7.40; found: C 68.78, H 6.02, N 7.47.
2-(5-Fluoro-1H-indol-1-yl) acetic acid (21a)
To a solution of 17a (565 mg, 2.55 mmol), according to the same procedure described for 18a, LiOH as powder (305.83 mg, 12.79 mmol) was added and the pure carboxylic acid 21a (332 mg, 67%) was obtained; consistency: orange powder. 1H NMR (500 MHz, CDCl3) = δ: 4.86 (s, 2H), 6.53 (d, J = 3.2 Hz, 1H), 6.98 (t, J = 9.2 Hz, 1H), 7.09 (d, J = 3.2 Hz, 1H), 7.14 (dd, J = 8.9 and 4.2 Hz, 1H), 7.28 (dd, J = 9.2 and 2.3 Hz, 1H) ppm. Elemental analysis: calcd for C10H8FNO2: C, 62.18; H, 4.17; N, 9.83; found: C 61.99, H 4.23, N 9.86.
3-(1H-Indol-1-yl) propanoic acid (18b)
To a solution of 14b (538 mg, 2.48 mmol), according to the same procedure described for 18a, LiOH as powder (296.54 mg, 12.38 mmol) was added and the pure carboxylic acid 18b (205 mg, 44%) was obtained; consistency: orange powder. 1H NMR (500 MHz, CDCl3) = δ: 2.88 (t, J = 6.9 Hz, 2H), 4.45 (t, J = 6.9 Hz, 2H), 6.53 (s, 1H), 7.14–7.18 (m, 2H), 7.26 (t, J = 7.1 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H) ppm. Elemental analysis: calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40; found: C 69.78, H 6.00, N 7.42.
3-(2-Methyl-1H-indol-1-yl) propanoic acid (19b)
To a solution of 15b (121 mg, 0.52 mmol), according to the same procedure described for 18a, LiOH as powder (62.65 mg, 2.62 mmol) was added and the pure carboxylic acid 19b (105 mg, 97%) was obtained; consistency: orange powder. 1H NMR (500 MHz, CDCl3) = d: 2.33 (s, 3H), 2.68 (t, J = 7.4 Hz, 2H), 4.31 (t, J = 7.4 Hz, 2H), 6.84–6.87 (m, 1H), 6.99 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.1 Hz, 1H), 7.48 (d, J = 7.1 Hz, 1H) ppm. Elemental analysis: calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89; found: C 70.82, H 6.36, N 7.02.
3-(3-Methyl-1H-indol-1-yl) propanoic acid (20b)
To a solution of 16b (824 mg, 3.56 mmol), according to the same procedure described for 18a, LiOH as powder (426.62 mg, 17.81 mmol) was added and the pure carboxylic acid 20b (704 mg, 97%) was obtained; consistency: light yellow powder. 1H NMR (500 MHz, CDCl3) = d: 2.33 (s, 3H), 2.86 (t, J = 6.8 Hz, 2H), 4.40 (t, J = 6.9 Hz, 2H), 6.90 (s, 1H), 7.14 (t, J = 7.0 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H) ppm. Elemental analysis: calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89; found: C 70.99, H 6.56, N 7.00.
3-(5-Fluoro-1H-indol-1-yl) propanoic acid (21b)
To a solution of 17b (560 mg, 2.38 mmol), according to the same procedure described for 18a, LiOH as powder (285.08 mg, 11.9 mmol) was added and the pure carboxylic acid 21b (327 mg, 66%) was obtained; consistency: yellow powder. 1H NMR (500 MHz, CDCl3) = δ: 2.87 (t, J = 6.8 Hz, 2H), 4.43 (t, J = 6.8 Hz, 2H), 6.44 (d, J = 3.1 Hz, 1H), 6.96 (t, J = 6.7 Hz, 1H), 7.16 (d, J = 3.1 Hz, 1H), 7.23–7.28 (m, 2H) ppm. Elemental analysis: calcd for C11H10FNO2: C, 63.76; H, 4.86; N, 9.17; found: C 63.52, H 5.01, N 9.13.
N-((S)-1-Cyano-3-phenylpropyl)2-(1H-indol-1-yl)acetamide (1a)
To a solution of acid 2-(1H-indol-1-il)acetic 18a (32.8 mg, 0.19 mmol) in anhydrous DCM/DMF, placed in an ice bath at 0 °C, HOBt (31.62 mg, 0.23 mmol) and EDCI (44.87 mg, 0.23 mmol) were added. After 10 min, (S)-2-amino-4-phenylbutanitrile 22 (25 mg, 0.16 mmol) and DIPEA (33.28 µL, 0.19 mmol) were added and the reaction mixture was stirred overnight at room temperature. After overnight stirring, the solvents were evaporated in vacuo; then the residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using petroleum ether/EtOAc 7:3 to obtain the pure coupling product 1a (31 mg, 61%); consistency: yellow powder; M.p.: 120–121 °C, Rf = 0.52 (petroleum ether/EtOAc 7:3); 1H NMR (500 MHz, CDCl3) = δ: 1.84–1.91 (m, 1H), 1.91–1.99 (m, 1H), 2.49–2.60 (m, 2H), 4.73–4.79 (m, 1H), 4.82 (s, 2H), 5.50 (bs, 1H), 6.66 (s, 1H), 7.00 (d, J = 7.5 Hz, 2H), 7.02–7.05 (m, 1H), 7.18–7.24 (m, 4H), 7.28–7.32 (m, 2H), 7.69 (d, J = 7.5 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 31.36, 34.29, 39.95, 49.83, 104.25, 109.05, 117.72, 120.99, 121.70, 123.23, 126.84, 128.19, 128.35, 128.86, 128.99, 136.21, 138.82, 168.10. Elemental analysis: calcd for C20H19N3O: C, 75.59; H, 6.03; N, 13.24; found: C 75.42, H 6.12, N 13.42.
N-((S)-1-Cyano-3-phenylpropyl)-2-(2-methyl-1H-indol-1-yl)acetamide (2a)
According to the same procedure described for 1a, a solution of 2-(2-methyl-1H-indol-1-yl)acetic acid 19a (35.43 mg, 0.19 mmol) was reacted with (S)-2-amino-4-phenylbutanitrile 22 (25 mg, 0.16 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 8:2 to obtain the pure coupling product 2a (17 mg, 32%); consistency: yellow powder; M.p.: 131–133 °C, Rf = 0.37 (petroleum ether/EtOAc 8:2). 1H NMR (500 MHz, CDCl3) = δ: 1.82–1.90 (m, 1H), 1.90–1.98 (m, 1H), 2.39 (s, 3H), 2.48–2.59 (m, 2H), 4.72–4.78 (m, 3H), 5.46 (bs, 1H), 6.39 (s, 1H), 7.00 (d, J = 7.6 Hz, 2H), 7.13–7.18 (m, 2H), 7.18–7.22 (m, 2H), 7.24–7.27 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 12.69, 31.39, 34.46, 39.94, 46.77, 102.78, 108.61, 117.71, 120.61, 121.11, 122.29, 126.92, 128.38, 128.91, 136.11, 136.87, 138.77, 168.30. Elemental analysis: calcd for C21H21N3O: C, 76.11; H, 6.39; N, 12.68; found: C 76.03, H 6.19, N 12.87.
N-((S)-1-Cyano-3-phenylpropyl)-2-(3-methyl-1H-indol-1-yl)acetamide (3a)
According to the same procedure described for 1a, a solution of 2-(3-methyl-1H-indol-1-yl)acetic acid 20a (35.43 mg, 0.19 mmol) was reacted with (S)-2-amino-4-phenylbutanitrile 22 (25 mg, 0.16 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 8:2 to obtain the pure coupling product 3a (19 mg, 36%); consistency: pale yellow powder; M.p.: 114–115 °C, Rf = 0.35 (petroleum ether/EtOAc 8:2). 1H NMR (500 MHz, CDCl3) = δ: 1.84–1.91 (m, 1H), 1.92–1.99 (m, 1H), 2.35 (s, 3H), 2.51–2.59 (m, 2H), 4.74–4.79 (m, 3H), 5.55 (bs, 1H), 6.79 (s, 1H), 7.00 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.23–7.29 (m, 4H), 7.63 (d, J = 7.7 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 9.59, 31.28, 34.25, 39.80, 49.51, 108.79, 113.43, 117.65, 119.67, 120.22, 123.06, 125.50, 126.72, 128.24, 128.74, 129.34, 136.50, 138.75, 168.42. Elemental analysis: calcd for C21H21N3O: C, 76.11; H, 6.39; N, 12.68; found: C 76.24, H 6.42, N 12.85.
N-((S)-1-Cyano-3-phenylpropyl)-2-(5-fluoro-1H-indol-1-yl)acetamide (4a)
According to the same procedure described for 1a, a solution of 2-(5-fluoro-1H-indol-1-yl) acetic acid 21a (57.87 mg, 0.30 mmol) was reacted with (S)-2-amino-4-phenylbutanitrile 22 (40 mg, 0.25 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 7:3 to obtain the pure coupling product 4a (40.3 mg, 32%); consistency: white powder; M.p.: 150–152 °C, Rf = 0.42 (petroleum ether/EtOAc 7:3). 1H NMR (500 MHz, CDCl3) = δ: 1.85–1.93 (m, 1H), 1.93–2.00 (m, 1H), 2.57 (t, J = 7.6 Hz, 2H), 4.73–4.77 (m, 1H), 4.78 (s, 2H), 5.53 (bs, 1H), 6.60 (s, 1H), 7.02 (d, J = 7.4 Hz, 2H), 7.04–7.08 (m, 1H), 7.13–7.28 (m, 5H), 7.33 (d, J = 9.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 31.46, 34.38, 40.06, 50.13, 104.30 (d, J = 4.5 Hz), 106.74 (d, J = 23.6 Hz), 109.83 (d, J = 9.9 Hz), 111.77 (d, J = 26.6 Hz), 117.65, 126.97, 128.36, 128.97, 129.82, 131.03, 132.81, 138.76, 158.64 (d, J = 236.7 Hz), 167.74. Elemental analysis: calcd for C20H18FN3O: C, 71.63; H, 5.41; N, 12.53; found: C 71.42, H 5.26, N 12.63.
N-((S)-1-Cyano-3-phenylpropyl)-3-(1H-indol-1-yl)propanamide (1b)
According to the same procedure described for 1a, a solution of 3-(1H-indol-1-yl)propanoic acid 18b (42.51 mg, 0.22 mmol) was reacted with (S)-2-amino-4-phenylbutanitrile 22 (30 mg, 0.19 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 7:3 to obtain the pure coupling product 1b (26.4 mg, 21%); consistency: yellow powder; M.p.: 155–156 °C, Rf = 0.39 (petroleum ether/EtOAc 7:3). 1H NMR (500 MHz, CDCl3) = δ: 1.75–1.89 (m, 2H), 2.52–2.63 (m, 4H), 4.39–4.45 (m, 1H), 4.48–4.54 (m, 1H), 4.70 (dd, J = 14.9 Hz e 7.5 Hz, 1H), 5.35 (bs, 1H), 6.48 (d, J = 3.1 Hz, 1H), 7.04–7.07 (m, 3H), 7.11 (t, J = 7.0 Hz, 1H), 7.18–7.25 (m, 4H), 7.31 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 31.51, 34.04, 37.11, 40.27, 42.38, 102.10, 109.21, 119.89, 121.42, 121.98, 126.88, 128.13, 128.48, 128.93, 135.58, 139.14, 169.84. Elemental analysis: calcd for C21H21N3O: C, 76.11; H, 6.39; N, 12.68; found: C 76.13, H 6.29, N 12.86.
N-((S)-1-Cyano-3-phenylpropyl)-3-(2-methyl-1H-indol-1-yl)propanamide (2b)
According to the same procedure described for 1a, a solution of 3-(2-methyl-1H-indol-1-yl)propanoic acid 19b (53.28 mg, 0.26 mmol) was reacted with (S)-2-amino-4-phenylbutanitrile 22 (35 mg, 0.22 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 5:5 to obtain the pure coupling product 2b (32 mg, 42%); consistency: yellow powder; M.p.: 144–145 °C, Rf = 0.44 (petroleum ether/EtOAc 5:5). 1H NMR (500 MHz, CDCl3) = δ: 1.80–1.87 (m, 2H), 2.31 (s, 3H), 2.37–2.49 (m, 2H), 2.48–2.64 (m, 2H), 4.25–4.33 (m, 1H), 4.34–4.43 (m, 1H), 4.61 (dd, J = 15.2 Hz e 7.5 Hz, 1H), 5.86 (s, 1H), 6.86 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 7.04–7.11 (m, 3H), 7.17–7.23 (m, 3H), 7.45 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 11.93, 31.54, 33.81, 36.46, 39.05, 40.23, 109.38, 112.58, 118.26, 119.16, 120.12, 121.31, 125.41, 126.79, 128.52, 128.86, 135.70, 137.84, 139.35, 170.04. Elemental analysis: calcd for C22H23N3O: C, 76.49; H, 6.71; N, 12.16; found: C 76.26, H 6.84, N 12.22.
N-((S)-1-Cyano-3-phenylpropyl)-3-(3-methyl-1H-indol-1-yl)propanamide (3b)
According to the same procedure described for 1a, a solution of 3-(3-methyl-1H-indol-1-yl)propanoic acid 20b (53.28 mg, 0.26 mmol) was reacted with (S)-2-amino-4-phenylbutanitrile 22 (35 mg, 0.22 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 65:35 to obtain the pure coupling product 3b (28.8 mg, 38%); consistency: light yellow powder; M.p.: 130–132 °C, Rf = 0.48 (petroleum ether/EtOAc 65:35). 1H NMR (500 MHz, CDCl3) = δ: 1.75–1.86 (m, 2H), 2.26 (s, 3H), 2.49–2.55 (m, 2H), 2.55–2.61 (m, 2H), 4.31–4.38 (m, 1H), 4.39–4.47 (m, 1H), 4.68 (dd, J = 14.8 Hz and 7.6 Hz, 1H), 5.40 (bs, 1H), 6.83 (s, 1H), 7.05 (d, J = 7.4 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.2 Hz, 2H), 7.23–7.27 (m, 3H), 7.54 (d, J = 7.9 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 9.49, 31.34, 33.95, 37.02, 40.05, 42.01, 108.89, 111.09, 117.85, 119.01, 119.32, 121.75, 125.55, 126.70, 128.30, 128.75, 129.00, 135.72, 139.01, 169.91. Elemental analysis: calcd for C22H23N3O: C, 76.49; H, 6.71; N, 12.16; found: C 76.58, H 6.74, N 12.02.
N-((S)-1-Cyano-3-phenylpropyl)-3-(5-fluoro-1H-indol-1-yl)propanamide (4b)
According to the same procedure described for 1a, a solution of 3-(5-fluoro-1H-indol-1-yl) propanoic acid 21b (62.07 mg, 0.30 mmol) was reacted with (S)-2-amino-4-phenylbutanitrile 22 (40 mg, 0.25 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 6:4 to obtain the pure coupling product 4b (33 mg, 39%); consistency: pale yellow powder; M.p.: 142–143 °C, Rf = 0.46 (petroleum ether/EtOAc 6:4). 1H NMR (500 MHz, CDCl3) = δ: 1.78–1.85 (m, 1H), 1.85–1.92 (m, 1H), 2.52 (m, 2H), 2.61 (m, 2H), 4.34–4.41 (m, 1H), 4.43–4.50 (m, 1H), 4.68 (dd, J = 14.3 and 7.1 Hz, 1H), 5.66 (bs, 1H), 6.42 (s, 1H), 6.95 (t, J = 9.0 Hz, 1H), 7.05 (d, J = 7.3 Hz, 2H), 7.10 (s, 1H), 7.28–7.19 (m, 5H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 31.48, 34.05, 36.95, 40.25, 42.50, 101.97 (d, J = 4.8 Hz), 105.95, 106.13, 109.87 (d, J = 9.8 Hz), 110.29 (d, J = 26.3 Hz), 118.03, 126.88, 128.42, 128.93, 129.70, 132.26, 139.07, 158.01 (d, J = 234.5 Hz), 169.83. Elemental analysis: calcd for C21H20FN3O: C, 72.19; H, 5.77; N, 12.03; found: C 72.37, H 5.45, N 12.02.
N-(1-Cyanocyclopropyl)-2-(1H-indol-1-yl)acetamide (5a)
According to the same procedure described for 1a, a solution of 2-(1H-indol-1-yl)acetic acid 18a (25 mg, 0.14 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (20.3 mg, 0.17 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 5:5 to obtain the pure coupling product 5a (18 mg, 54%); consistency: light yellow powder; M.p.: 179–181 °C, Rf = 0.39 (petroleum ether/EtOAc 5:5). 1H NMR (500 MHz, CDCl3) = δ: 1.06 (t, J = 5.8 Hz, 2H), 1.48 (t, J = 5.8 Hz, 2H), 4.81 (s, 2H), 5.84 (bs, 1H), 6.63 (s, 1H), 7.03–7.06 (m, 1H), 7.18–7.23 (m, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 16.83, 20.23, 49.92, 104.13, 108.84, 119.23, 120.85, 121.55, 123.16, 128.86, 127.98, 136.00, 169.18. Elemental analysis: calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56; found: C 70.36, H 5.69, N 17.65.
N-(1-Cyanocyclopropyl)-2-(2-methyl-1H-indol-1-yl)acetamide (6a)
According to the same procedure described for 1a, a solution of 2-(2-methyl-1H-indol-1-yl)acetic acid 19a (40 mg, 0.21 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (30.08 mg, 0.25 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 5:5 to obtain the pure coupling product 6a (36 mg, 68%); consistency: light orange powder; M.p.: 178–180 °C, Rf = 0.45 (petroleum ether/EtOAc 5:5). 1H NMR (500 MHz, CDCl3) = δ: 1.16 (t, J = 6.0 Hz, 2H), 1.49 (t, J = 6.0 Hz, 2H), 2.56 (s, 3H), 4.76 (s, 2H), 6.22 (s, 1H), 6.98 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 12.46, 15.78, 19.92, 45.35, 100.04, 109.12, 119.28, 120.37, 120.74, 127.83, 137.32, 137.37, 169.37. Elemental analysis: calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59; found: C 70.99, H 5.98, N 16.88.
N-(1-Cyanocyclopropyl)-2-(3-methyl-1H-indol-1-yl)acetamide (7a)
According to the same procedure described for 1a, a solution of 2-(3-methyl-1H-indol-1-yl)acetic acid 20a (50 mg, 0.26 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (37.6 mg, 0.32 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 5:5 to obtain the pure coupling product 7a (23.7 mg, 36%); consistency: off-white powder; M.p.: 193–195 °C, Rf = 0.52 (EtOAc/petroleum ether 6:4). 1H NMR (500 MHz, CDCl3) = δ: 1.06 (t, J = 6.2 Hz, 2H), 1.47 (t, J = 6.2 Hz, 2H), 2.34 (s, 3H), 4.73 (s, 2H), 5.89 (bs, 1H), 6.80 (s, 1H), 7.14–7.21 (m, 2H), 7.25–7.29 (m, 1H), 7.61 (d, J = 7.9 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 9.63, 16.85, 20.24, 49.60, 108.54, 108.65, 113.45, 119.04, 119.31, 120.10, 122.81, 125.42, 129.31, 136.37, 169.45. Elemental analysis: calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59; found: C 70.98, H 5.97, N 16.54.
N-(1-cyanocyclopropyl)-2-(5-fluoro-1H-indol-1-yl)acetamide (8a)
According to the same procedure described for 1a, a solution of 2-(5-fluoro-1H-indol-1-yl) acetic acid 21a (50 mg, 0.26 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (36.83 mg, 0.31 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using EtOAc/petroleum ether 7:3 to obtain the pure coupling product 8a (28.4 mg, 42%); consistency: white powder; M.p.: 180–181 °C, Rf = 0.59 (EtOAc/petroleum ether 7:3). 1H NMR (500 MHz, CDCl3) = δ: 1.07 (t, J = 6.7 Hz, 2H), 1.49 (t, J = 6.7 Hz, 2H), 4.79 (s, 2H), 5.82 (bs, 1H), 6.59 (s, 1H), 7.02 (t, J = 8.9 Hz, 1H), 7.09 (s, 1H), 7.13 (dd, J = 8.9 and 3.9 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 16.93, 21.32, 49.94, 103.01 (d, J = 4.7 Hz), 106.34 (d, J = 23.7 Hz), 110.95 (d, J = 5.9 Hz), 111.06, 121.09, 130.68 (d, J = 10.2 Hz), 131.98, 134.75, 159.43 (d, J = 233.0 Hz), 171.81. Elemental analysis: calcd for C14H12FN3O: C, 65.36; H, 4.70; N, 16.33; found: C 65.22, H 4.55, N 16.51.
N-(1-Cyanocyclopropyl)-3-(1H-indol-1-yl)propanamide (5b)
According to the same procedure described for 1a, a solution of 3-(1H-indol-1-yl)propanoic acid 18b (50 mg, 0.26 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (37.6 mg, 0.32 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using petroleum ether/EtOAc 5:5 to obtain the pure coupling product 5b (29.9 mg, 45%); consistency: yellow oil; M.p.: 139–141 °C, Rf = 0.43 (EtOAc/petroleum ether 6:4). 1H NMR (500 MHz, CDCl3) = δ: 0.82 (t, J = 6.0 Hz, 2H), 1.32 (t, J = 6.0 Hz, 2H), 2.53 (t, J = 6.3 Hz, 2H), 4.42 (t, J = 6.3 Hz, 2H), 5.88 (bs, 1H), 6.46 (s, 1H), 7.05 (s, 1H), 7.10 (t, J = 7.9, Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 16.50, 20.18, 36.81, 42.14, 101.76, 109.17, 119.68, 119.74, 121.15, 121.79, 128.09, 128.64, 135.42, 171.28. Elemental analysis: calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59; found: C 71.23, H 5.77, N 16.68.
N-(1-Cyanocyclopropyl)-3-(2-methyl-1H-indol-1-yl)propanamide (6b)
According to the same procedure described for 1a, a solution of 3-(2-methyl-1H-indol-1-yl)propanoic acid 19b (50 mg, 0.25 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (35 mg, 0.30 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using EtOAc/petroleum ether 7:3 to obtain the pure coupling product 6b (26 mg, 39%); consistency: yellow powder; M.p.: 124–126 °C, Rf = 0.47 (EtOAc/petroleum ether 7:3). 1H NMR (500 MHz, CDCl3) = δ: 0.73 (t, J = 5.9 Hz, 2H), 1.35 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 2.43 (t, J = 5.4 Hz, 2H), 4.33 (t, J = 5.4 Hz, 2H), 5.22 (bs, 1H), 6.88 (s, 1H), 6.98 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 11.98, 16.41, 20.34, 38.88, 67.53, 109.51, 112.62, 119.20, 120.15, 121.39, 125.40, 128.94, 131.03, 135.72, 171.28. Elemental analysis: calcd for C16H17N3O: C, 71.89; H, 6.41; N, 15.72; found: C 71.99, H 6.62, N 15.64.
N-(1-Cyanocyclopropyl)-3-(3-methyl-1H-indole-1-yl)propanamide (7b)
According to the same procedure described for 1a, a solution of 3-(3-methyl-1H-indol-1-yl)propanoic acid 20b (50 mg, 0.25 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (35 mg, 0.30 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using EtOAc/petroleum ether 6:4 to obtain the pure coupling product 7b (34.7 mg, 52%); consistency: light orange powder; M.p.: 114–115 °C, Rf = 0.59 (EtOAc/petroleum ether 6:4). 1H NMR (500 MHz, CDCl3) = δ: 0.78 (t, J = 6.1 Hz, 2H), 1.34 (t, J = 6.1 Hz, 2H), 2.29 (s, 3H), 2.54 (t, J = 5.5 Hz, 2H), 4.40 (t, J = 5.5 Hz, 2H), 5.55 (bs, 1H), 6.84 (s, 1H), 7.11 (t, J = 6.9 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 9.48, 16.52, 20.18, 37.04, 42.02, 108.95, 111.00, 119.01, 119.24, 119.63, 121.77, 125.64, 128.91, 135.69, 171.26. Elemental analysis: calcd for C16H17N3O: C, 71.89; H, 6.41; N, 15.72; found: C 71.77, H 6.32, N 15.77.
N-(1-Cyanocyclopropyl)-3-(5-fluoro-1H-indol-1-yl)propanamide (8b)
According to the same procedure described for 1a, a solution of 3-(5-fluoro-1H-indol-1-yl) propanoic acid 21b (50 mg, 0.24 mmol) was reacted with 1-aminocyclopropanocarbonitrile 23 (34.33 mg, 0.29 mmol) and a crude residue was obtained. It was purified by silica gel column chromatography using EtOAc/petroleum ether 7:3 to obtain the pure coupling product 8b (22.5 mg, 28%); consistency: white powder; M.p.: 120–122 °C, Rf = 0.63 (EtOAc/petroleum ether 7:3). 1H NMR (500 MHz, CDCl3) = δ: 0.89 (t, J = 6.0 Hz, 2H), 1.38 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 6.2 Hz, 2H), 4.45 (t, J = 6.2 Hz, 2H), 5.79 (bs, 1H), 6.42 (s, 1H), 6.95 (t, J = 9.0 Hz, 1H), 7.11 (s, 1H), 7.20–7.26 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) = δ: 16.75, 20.45, 37.05, 42.56, 101.94 (d, J = 4.6 Hz), 105.94, 106.13, 109.88 (d, J = 9.9 Hz), 110.35 (d, J = 26.4 Hz), 119.69, 129.81, 132.19, 158.05 (d, J = 235.0 Hz), 171.10. Elemental analysis: calcd for C15H14FN3O: C, 66.41; H, 5.20; N, 15.49; found: C 66.32, H 5.36, N 15.66.