3.2. Synthesis
3.2.1. General Procedure for the Synthesis of Thioureas (1) and Thiohydantoins (2)
Amine (1 equiv) was added to a solution of ethyl isothiocyanatoacetate (1 equiv) in ether. The resulting mixture was stirred for 1 hour at room temperature. After the reaction was completed (TLC control), the solvent was evaporated in vacuo and the formed precipitate was filtered off, washed with cold diethyl ether and dried in air.
Ethyl 2-(3-benzylthioureido)acetate (1a)
From 0.54 g (5.0 mmol) of benzylamine and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1a (1.0 g, 83%) was obtained as a white solid.1H-NMR (400 MHz, CDCl3) δ: 8.25 (bs, 1H, NH), 7.40 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 6.70 (bs, 1H, NH), 4.42 (s, 2H), 4.22 (q, J = 9.2 Hz, 2H), 1.29 (t, J = 9.2 Hz, 3H). HRMS (ESI+) m/z calcd. for (C12H16N2O2S, M + H): 253.1005, found: (M + H): 253.1015.
Ethyl 2-(3-allylthioureido)acetate (1b)
From 0.29 g (5.0 mmol) of allylamine and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1b (0.93 g, 98%) was obtained as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 6.82 (bs, 1H, NH), 6.74 (s, 1H, NH), 5.85 (m, 1H), 5.28 (d, J = 17.1 Hz, 1H), 5.20 (d, J = 10.2 Hz, 1H), 4.38 (d, J = 4.9 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.05 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H). HRMS (ESI+) m/z calcd. for (C8H15N2O2S, M + H): 203.0849, found: (M + H): 203.0857.
Ethyl 2-(3-(4-methoxyphenyl)thioureido)acetate (1c)
From 0.62 g (5.0 mmol) of 4-methoxyaniline and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1c (0.77 g, 61%) was obtained as a light yellow solid. M.p. 94–96 °C. 1H-NMR (400 MHz, CDCl3) δ: 8.12 (bs, 1H, NH), 7.23 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.60 (bs, 1H, NH), 4.41 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). HRMS (ESI+) m/z calcd. for (C12H16N2O3S, M + H): 269.0954, found: (M + H): 269.0958.
Ethyl 2-(3-(4-ethoxyphenyl)thioureido)acetate (1d)
From 0.69 g (5.0 mmol) of 4-ethoxyaniline and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1d (1.30 g, 97%) was obtained as a purple solid. M.p. 124–126 °C. 1H-NMR (400 MHz, CDCl3) δ: 7.90 (bs, 1H, NH), 7.19 (d, J = 9.1 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.44 (bs, 1H, NH), 4.41 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 4.04 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). HRMS (ESI+) m/z calcd. for (C13H18N2O3S, M + H): 283.1111, found: (M + H): 283.1106.
Ethyl 2-(3-(p-tolyl)thioureido)acetate (1e)
From 0.54 g (5.0 mmol) of 4-methylaniline and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1e (0.89 g, 75%) was obtained as a plum solid. M.p. 132–134 °C. 1H-NMR (400 MHz, CDCl3) δ: 7.91 (bs, 1H, NH), 7.21 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.45 (bs, 1H, NH), 4.41 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).
Ethyl 2-(3-(4-chlorophenyl)thioureido)acetate (1f)
From 0.64 g (5.0 mmol) of 4-chloroaniline and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1f (1.16 g, 90%) was obtained as a white solid. M.p. 154–156 °C. 1H-NMR (400 MHz, CDCl3) δ: 8.25 (bs, 1H, NH), 7.40 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 6.70 (bs, 1H, NH), 4.42 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). HRMS (ESI+) m/z calcd. for (C11H13ClN2O2S, M + H): 273.0459, found: (M + H): 273.0468.
Ethyl 2-(3-(4-fluorophenyl)thioureido)acetate (1g)
From 0.56 g (5.0 mmol) of 4-fluoroaniline and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1g (0.97 g, 76%) was obtained as a white solid. M.p. 119–120 °C. 1H-NMR (400 MHz, CDCl3) δ: 8.15 (bs, 1H, NH), 7.33–7.25 (m, 2H), 7.14 (t, J = 8.5 Hz, 2H), 6.56 (bs, 1H, NH), 4.42 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). HRMS (ESI+) m/z calcd. for (C11H13FN2O2S, M + H): 257.0755, found: (M + H): 257.0766.
Ethyl 2-(3-(3-chlorobenzyl)thioureido)acetate (1h)
From 0.74 g (5.0 mmol) of e-chlorobenzylamine and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate. compound 1h (1.12 g, 84%) was obtained as a white solid. M.p. 122–123 °C. 1H-NMR(400 MHz, CDCl3) δ: 7.39–7.19 (m, 5H), 4.67 (bs, 2H), 4.38 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). HRMS (ESI+) m/z calcd. for (C12H15ClN2O2S, M + H): 287.0616, found: (M + H): 287.0628.
Ethyl 2-(3-(3-chloro-4-fluorophenyl)thioureido)acetate (1i)
From 0.73 g (5.0 mmol) of 4-fluoro,3-chloroaniline and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1i (1.08 g, 74%) was obtained as a white solid. M.p. 111–112 °C. 1H-NMR (400 MHz, CDCl3) δ: 8.26 (bs, 1H, NH), 7.42 (dd, J1 = 2.4 Hz, J2 = 6.4 Hz, 1H), 7.26–7.17 (m, 2H), 6.71 (bs, 1H, NH), 4.42 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). HRMS (ESI+) m/z calcd. for (C11H12ClFN2O2S, M + H): 291.0365, found: (M + H): 291.0377.
Ethyl 2-(3-cyclopropylthioureido)acetate (1j)
From 0.29 g (5.0 mmol) of cyclopropylamine and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1j (0.8 g, 87%) was obtained as a white solid. M.p. 129–130 °C. 1H-NMR (400 MHz, CDCl3) δ: 6.86 (bs, 1H, NH), 6.56 (bs, 1H, NH), 4.45 (d, J = 4.5 Hz, 2H), 4.27 (q, J = 7.0 Hz, 2H), 2.54 (bs, 1H), 1.32 (t, J = 7.2 Hz, 1H), 0.92–0.85 (m, 2H), 0.76–0.69 (m, 2H).
3-(3-Morpholinopropyl)-2-thioxoimidazolidin-4-one (2b)
From 0.72 g (5.0 mmol) of 3-(N-morpholino)propylamine and 0.73 g (5.0 mmol) of ethyl isothiocyanatoacetate, compound 1k (0.82 g, 68%) was obtained as a pink solid. M.p. 149–151 °C. 1H-NMR (400 MHz, CDCl3) δ: 8.33 (bs, 1H, NH), 4.08 (s, 2H), 3.89 (t, J = 6.9 Hz, 2H), 3.82–3.74 (m, 4H), 2.72–2.55 (m, 6H), 2.04–1.93 (m, 2H).
3.2.2. General Procedure for the Synthesis of 5-Substituted-2-thiohydantoins 3a–x
Thioureidoacetate 1 or 2-thioxoimidazolidine 2 (1 equiv) was dissolved in 2% KOH/EtOH; then isatin or 5-chloroisatin (1 equiv) was added. The resulting mixture was stirred for 30 min. After the reaction was completed (TLC control), the mixture was poured into water and neutralized with HCl. The formed precipitate was filtered off, washed with cold water, then washed with cold diethyl ether and dried in air.
(Z)-3-(1-Benzyl-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3a)
From 1a (0.36 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3a (0.48 g, 94%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.56 (s, 1H, NH), 11.10 (s, 1H, NH)8.53 (d, J = 7.8 Hz, 1H), 7.43–7.26 (m, 6H), 7.03 (td, J1 = 1.0 Hz, J2 = 7.7 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 5.06 (s, 2H). HRMS (ESI+) m/z calcd. for (C18H13N3O2S, M + H): 336.0801, found: (M + H): 336.0797.
(Z)-3-(1-Benzyl-5-oxo-2-thioxoimidazolidin-4-ylidene)-5-chloroindolin-2-one (3b)
From 1a (0.36 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3b (0.51 g, 92%) was obtained as a dark red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.63 (s, 1H, NH), 11.18 (s, 1H, NH),8.55 (m, 1H), 7.43–7.25 (m, 6H), 6.92 (d, J = 8.3 Hz, 1H), 5.05 (s, 2H). HRMS (ESI+) m/z calcd. for (C18H12ClN3O2S, M + H): 370.0411, found: (M + H): 370.0411.
(Z)-3-(1-Allyl-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3c)
From 1b (0.28 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol,) compound 3c (0.36 g, 83%) was obtained as a red solid. M.p. 257–259 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.50 (bs, 1H, NH), 11.07 (s, 1H, NH),8.52 (d, J = 7.8 Hz, 1H), 7.32 (td, J1 = 1.0 Hz, J2 = 7.7 Hz, 1H), 7.04 (td, J1 = 0.7 Hz, J2 = 7.7 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 5.86 (m, 1H), 5.20 (dd, J1 = 1.0 Hz, J2 = 9.7 Hz, 1H), 5.17 (m, 1H), 4.45 (d, J = 5.0 Hz, 2H). HRMS (ESI+) m/z calcd. for (C14H11N3O2S, M + H): 286.0644, found: (M + H): 286.0643.
(Z)-3-(1-Allyl-5-oxo-2-thioxoimidazolidin-4-ylidene)-5-chloroindolin-2-one (3d)
From 1b (0.28 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3d (0.40 g, 83%) was obtained as a dark red solid. M.p. 258–260 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.56 (bs, 1H, NH), 11.19 (s, 1H, NH),8.55 (d, J = 2.0 Hz, 1H), 7.36 (dd, J1 = 2.2 Hz, J2 = 8.3 Hz, 1H), 6.93 (d, J = 8.31 Hz, 1H), 5.86 (m, 1H), 5.25–5.16 (m, 2H), 4.45 (d, J = 5.1 Hz, 2H). HRMS (ESI+) m/z calcd. for (C14H10ClN3O2S, M + H): 320.0255, found: (M + H): 320.0252.
(Z)-3-(1-(4-Methoxyphenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3e)
From 1c (0.38 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3e (0.49 g, 93%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.60 (bs, 1H, NH), 10.95 (bs, 1H, NH), 8.56 (d, J = 7.70 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.29–7.22 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H),6.90 (d, J = 7.8 Hz, 1H), 2.38 (s, 3H). HRMS (ESI+) m/z calcd. for (C18H13N3O3S, M + H): 352.0750, found: (M + H): 352.0771.
(Z)-5-Chloro-3-(1-(4-methoxyphenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3f)
From 1c (0.38 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3f (0.54 g, 94%) was obtained as a dark red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.69 (bs, 1H, NH), 11.24 (bs, 1H, NH), 8.54 (d, J = 2.2 Hz, 1H), 7.36–7.29 (m, 5H), 6.96 (dd, J1 = 2.2 Hz, J2 = 8.3 Hz, 1H), 2.39 (s, 3H). HRMS (ESI+) m/z calcd. for (C18H12ClN3O3S, M + H): 386.0360, found: (M + H): 386.0387.
(Z)-3-(1-(4-Ethoxyphenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3g)
From 1d (0.40 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3g (0.49 g, 89%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.62 (bs, 1H, NH), 11.14 (s, 1H, NH), 8.50 (d, J = 7.6 Hz, 1H), 7.37–7.29 (m, 3H), 7.06 (d, J = 8.9 Hz, 2H), 7.02 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 1.36 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calcd. for (C19H15N3O3S, M + H): 366.0906, found: (M + H): 366.0895.
(Z)-5-Chloro-3-(1-(4-ethoxyphenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3h)
From 1d (0.40 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3h (0.52 g, 88%) was obtained as a dark red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.66 (bs, 1H, NH), 11.23 (s, 1H, NH),8.55 (s, 1H), 7.37 (dd, J1 = 2.2 Hz, J2 = 8.4 Hz, 1H), 7.33 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.3 Hz, 1H), 4.09 (q, J = 6.8 Hz, 2H), 1.36 (t, J = 6.8 Hz, 3H). HRMS (ESI+) m/z calcd. for (C19H15ClN3O3S, M + H): 400.0517, found: (M + H): 400.0496.
(Z)-3-(5-oxo-2-thioxo-1-(p-tolyl)imidazolidin-4-ylidene)indolin-2-one (3i)
From 1e (0.36 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3i (0.48 g, 95%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.62 (s, 1H, NH), 11.14 (s, 1H, NH), 8.50 (d, J = 7.8 Hz, 1H), 7.38–7.30 (m, 3H), 7.09 (d, J = 8.8 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 3.83 (s, 3H). HRMS (ESI+) m/z calcd. for (C18H13N3O2S, M + H): 336.0801, found: (M + H): 336.0796.
(Z)-5-Chloro-3-(5-oxo-2-thioxo-1-(p-tolyl)imidazolidin-4-ylidene)indolin-2-one (3j)
From 1e (0.36 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3j (0.51 g, 92%) was obtained as a dark red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.67 (bs, 1H, NH), 11.25 (s, 1H, NH),8.55 (d, J = 1.4 Hz, 1H), 7.40–7.32 (m, 3H), 7.09 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H). HRMS (ESI+) m/z calcd. for (C18H12ClN3O2S, M + H): 370.0411, found: (M + H): 370.0414.
(Z)-3-(1-(4-Chlorophenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3k)
From 1f (0.39 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3k (0.45 g, 84%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.69 (bs, 1H, NH), 11.14 (bs, 1H, NH),8.48 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H). HRMS (ESI+) m/z calcd. for (C17H10ClN3O2S, M + H): 356.0255, found: (M + H): 356.0257.
(Z)-5-Chloro-3-(1-(4-chlorophenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3l)
From 1f (0.39 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3l (0.51 g, 86%) was obtained as a dark red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.76 (bs, 1H, NH), 11.24 (s, 1H, NH), 8.53 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.38 (dd, J1 = 2.1 Hz, J2 = 8.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H). HRMS (ESI+) m/z calcd. for (C17H9Cl2N3O2S, M + H): 389.9865, found: (M + H): 389.9846.
(Z)-3-(1-(4-Fluorophenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3m)
From 1g (0.38 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3m (0.45 g, 89%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.68 (s, 1H, NH), 11.13 (s, 1H, NH), 8.50 (d, J = 7.0 Hz, 1H), 7.58–7.46 (m, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.33 (t, 7.5 Hz, 1H), 7.03 (t, J = 7.0 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H). HRMS (ESI-) m/z calcd. for (C17H10FN3O2S, M-H): 338.0394, found: (M-H): 338.0405.
(Z)-5-Chloro-3-(1-(4-fluorophenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3n)
From 1g (0.38 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3n (0.51 g, 91%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.75 (s, 1H, NH), 11.24 (s, 1H, NH), 8.56–8.52 (m, 1H), 7.55–7.48 (m, 2H), 7.46–7.35 (m, 3H), 6.96 (dd, J1 = 3.6 Hz, J2 = 8.3 Hz, 1H). HRMS (ESI-) m/z calcd. for (C17H9ClFN3O2S, M-H): 372.0004, found: (M-H): 372.0017.
(Z)-3-(1-(3-Chlorobenzyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3o)
From 1h (0.43 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3o (0.48 g, 87%) was obtained as a red solid. M.p. 296–298 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.59 (bs, 1H, NH), 11.09 (s, 1H, NH), 8.52 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.40–7.29 (m, 4H), 7.03 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 5.05 (s, 2H). HRMS (ESI-) m/z calcd. for (C18H12ClN3O2S, M-H): 368.0266, found: (M-H): 368.0255.
(Z)-5-Chloro-3-(1-(3-chlorobenzyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3p)
From 1h (0.43 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3p (0.53 g, 87%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.66 (bs, 1H, NH), 11.18 (s, 1H, NH), 8.56 (d, J = 1.7 Hz, 1H), 7.46 (s, 1H), 7.41–7.32 (m, 4H), 6.94 (d, J = 8.3 Hz, 1H), 5.05 (s, 2H). HRMS (ESI-) m/z calcd. for (C18H11Cl2N3O2S, M-H): 401.9865, found: (M-H): 401.9879.
(Z)-3-(1-(3-Chloro-4-fluorophenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3q)
From 1i (0.44 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3q (0.47 g, 84%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.75 (bs, 1H, NH), 10.92 (s, 1H, NH), 8.56 (d, J = 7.8 Hz, 1H), 7.73 (dd, J1 = 1.88 Hz, J = 6.5 Hz, 1H), 7.61 (t, J = 9.0 Hz, 1H), 7.48 (m, 1H), 7.27 (t, J = 7.3 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H). HRMS (ESI-) m/z calcd. for (C17H9ClFN3O2S, M-H): 372.0004, found: (M-H): 372.0017.
(Z)-5-Chloro-3-(1-(3-chloro-4-fluorophenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3r)
From 1i (0.44 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3r (0.53 g, 86%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.81 (bs, 1H, NH), 11.24 (s, 1H, NH), 8.51 (d, J = 1.8 Hz, 1H), 7.77 (dd, J1 = 2.3 Hz, J2 = 6.7 Hz, 1H), 7.65 (t, J = 8.99 Hz, 1H), 7.52 (m, 1H), 7.37 (dd, J1 = 2.02 Hz, J2 = 8.38 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H). HRMS (ESI-) m/z calcd. for (C17H8Cl2FN3O2S, M-H): 405.9615, found: (M-H): 405.9628.
(Z)-3-(1-Cyclopropyl-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3s)
From 1j (0.30 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3s (0.26 g, 92%) was obtained as a red solid. M.p. 277–279 °C (decomp.). 1H-NMR (400 MHz, DMSO-d6) δ: 11.35 (bs, 1H, NH), 11.08 (s, 1H, NH), 8.52 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 2.80 (m, 1H), 1.04–0.98 (m, 4H). HRMS (ESI-) m/z calcd. for (C14H11N3O2S, M-H): 284.0488, found: (M-H): 284.0499.
(Z)-5-Chloro-3-(1-cyclopropyl-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3t)
From 1j (0.30 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3t (0.29 g, 92%) was obtained as a red solid. M.p. 286–288 °C (decomp.). 1H-NMR (400 MHz, DMSO-d6) δ: 11.40 (s, 1H, NH), 11.19 (s, 1H, NH), 8.56 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H), 6.94 (dd, J1 = 2.1 Hz, J = 8.3 Hz, 1H), 2.80 (m, 1H), 1.04–0.99 (m, 4H). HRMS (ESI-) m/z calcd. for (C14H10ClN3O2S, M-H): 318.0099, found: (M-H): 318.0112.
(Z)-3-(1-(3-Morpholinopropyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one hydrochloride (3u)
From 2a (0.37 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3u (0.57 g, 93%) was obtained as a red solid. M.p. 270–272 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.54 (s, 1H), 11.18 (s, 1H), 11.07 (bs, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 3.96–3.88 (m, 4H), 3.78 (t, J = 11.8 Hz, 2H), 3.36 (d, J = 11.8 Hz, 2H), 3.22–3.13 (m, 2H), 3.07–2.95 (m, 2H), 2.19–2.09 (m, 2H). HRMS (ESI+) m/z calcd. for (C18H20N4O3S, M + H): 373.1328, found: (M + H): 373.1322.
(Z)-5-Chloro -3-(1-(3-morpholinopropyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one hydrochloride (3v)
From 2a (0.37 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound 3v (0.63 g, 95%) was obtained as a dark red solid. M.p. 249–251 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.61 (s, 1H), 11.31 (s, 1H), 11.09 (bs, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.37 (dd, J1 = 2.2 Hz, J2 = 8.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.96–3.88 (m, 4H), 3.85–3.75 (m, 4H), 3.35 (d, J = 11.6 Hz, 2H), 3.22–3.13 (m, 2H), 3.07–2.95 (m, 2H), 2.20–2.10 (m, 2H). HRMS (ESI+) m/z calcd. for (C18H19Cl1N4O3S, M + H): 407.0939, found: (M + H): 407.0917.
(Z)-3-(5-Oxo-1-phenyl-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3w)
From 2b (0.29 g, 1.5 mmol) and isatin (0.22 g, 1.5 mmol), compound 3w (0.45 g, 93%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.57 (s, 1H, NH), 10.87 (s, 1H, NH), 8.46 (d, J = 7.8 Hz, 1H), 7.52–7.41 (m, 3H), 7.37–7.33 (m, 2H), 7.21 (td, J1 = 1.1 Hz, J2 = 7.7 Hz, 1H), 6.91 (td, J1 = 1.0 Hz, J2 = 7.7 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H). HRMS (ESI-) m/z calcd. for (C17H11N3O2S, M-H): 320.0488, found: (M-H): 320.0506.
(Z)-5-Chloro-3-(5-oxo-1-phenyl-2-thioxoimidazolidin-4-ylidene)indolin-2-one (3x)
From 2b (0.29 g, 1.5 mmol) and 5-chloroisatin (0.27 g, 1.5 mmol), compound three times (0.50 g, 94%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.74 (bs, 1H, NH), 11.25 (s, 1H, NH), 8.55 (m, 1H), 7.59–7.49 (m, 3H), 7.47–7.42 (m, 2H), 7.37 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H). HRMS (ESI-) m/z calcd. for (C17H10ClN3O2S, M-H): 354.0099, found: (M-H): 354.0113.
3.2.3. General Procedure for the Synthesis of Dispiroindolinones 4a–x
Corresponding 5-indolidene-2-thioxoimidazolidin 3 (1equiv) and sarcosine (4 equiv) were dissolved in toluene and the mixture heated to a boiling point. After that, paraformaldehyde (4 equiv) was added. The resulting mixture was refluxed for 5–8 hours (TLC control). After the reaction was completed, the solvent was evaporated in vacuo. The product was then purified using column chromatography (silica gel 60, 0.04–0.063 mm/230–400 mesh, CHCl3:MeOH/50:1) to afford products as a yellow or pink solid. This solid was washed with acetone to yield corresponding dispirooxindole as white crystalline solid.
1′-Methyl-1-benzyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4a)
From 3a (0.22 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4a (0.21 g, 82%) was obtained as a white solid. M.p. 189–190 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.42 (bs, 1H, NH), 7.26 (t, J = 7.6 Hz, 1H), 7.23–7.10 (m, 4H), 7.08 (d, J = 7.7 Hz, 1H), 6.86–6.74 (m, 3H), 4.74 (d, J = 15.3 Hz, 1H), 4.66 (d, J = 15.3 Hz, 1H), 4.38 (d, J = 12.6 Hz, 1H), 4.23 (d, J = 12.6 Hz, 1H), 3.40–3.30 (m, 3H), 3.25 (dd, J1 = 6.7 Hz, J2 = 9.4 Hz, 2H), 3.06 (d, J = 9.9 Hz, 1H), 2.44 (s, 3H), 2.17 (s, 6H). HRMS (ESI+) m/z calcd. for (C21H20N4O2S, M + H): 393.1379, found: (M + H): 393.1364.
5″-Chloro-1′-methyl-1-benzyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4b)
From 3b (0.24 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde, (0.08 g, 2.6 mmol) compound 4b (0.21 g, 76%) was obtained as a white solid. M.p. 152–153 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.54 (bs, 1H, NH), 7.34 (dd, J1 = 2.0 Hz, J2 = 8.3 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.20–7.12 (m, 4H), 7.09 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 6.5 Hz, 2H), 4.74 (d, J = 15.5 Hz, 1H), 4.67 (d, J = 15.5 Hz, 1H), 4.37 (d, J = 12.7 Hz, 1H), 4.20 (d, J = 12.7 Hz, 1H), 3.40–3.30 (m, 3H), 3.19 (t, J = 10.8 Hz, 2H), 3.07 (d, J = 9.7 Hz, 1H), 2.43 (s, 3H), 2.12 (s, 6H). HRMS (ESI+) m/z calcd. for (C21H19ClN4O2S, M + H): 427.0990, found: (M + H): 427.0976.
1′-Methyl-1-allyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4c)
From 3c (0.19 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4c (0.15 g, 67%) was obtained as a white solid. M.p. 281–283 °C(decomp.). 1H-NMR (400 MHz, DMSO-d6) δ: 10.57 (s, 1H, NH), 10.44 (s, 1H, NH), 7.19 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 5.47 (m, 1H), 4.89 (d, J = 10.4 Hz, 1H), 4.59 (d, J = 17.4 Hz, 1H), 4.18–4.03 (m, 2H), 3.40 (d, J = 9.8 Hz, 1H), 3.32 (d, J = 9.8 Hz, 1H), 3.16 (d, J = 9.9 Hz, 1H), 3.05 (d, J = 10.0 Hz, 1H), 2.45 (c, 3H). HRMS (ESI+) m/z calcd. for (C17H18N4O2S, M + H): 343.1223, found: (M + H): 343.1207.
5″-Chloro-1′-methyl-1-allyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4d)
From 3d (0.21 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4d (0.09 g, 38%) was obtained as a white solid. M.p. 141–142 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.49 (bs, 1H, NH), 7.33 (dd, J1 = 1.9 Hz, J2 = 8.4 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 5.47 (m, 1H), 4.88 (d, J = 10.2 Hz, 1H), 4.55 (d, J = 17.2 Hz, 1H), 4.38 (d, J = 12.6 Hz, 1H), 4.22 (d, J = 12.6 Hz, 1H), 4.20–4.02 (m, 2H), 3.30–3.21 (m, 3H), 3.04 (d, J = 10.0 Hz, 1H), 2.44 (s, 3H), 2.19 (s, 6H). HRMS (ESI+) m/z calcd. for (C17H17ClN4O2S, M + H): 377.0833, found: (M + H): 377.0822.
1′-Methyl-1-(4-methoxyphenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4e)
From 3e (0.23 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4e (0.08 g, 28%) was obtained as a white solid. M.p. 155–156 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.67–10.57 (m, 2H, NH), 7.26 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.5 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 8.1 Hz, 2H), 3.49 (d, J = 9.9 Hz, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 3.07 (d, J = 10.2 Hz, 1H), 2.47 (s, 3H), 2.31 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H20N4O3S, M + H): 409.1328, found: (M + H): 409.1323.
5″-Cchloro-1′-methyl-1-(4-methoxyphenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4f)
From 3f (0.25 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4f (0.14 g, 49%) was obtained as a white solid. M.p. 289–290 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.79 (s, 1H, NH), 10.74 (s, 1H, NH), 7.34 (dd, J1 = 2.0 Hz, J2 = 8.3 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 2H), 3.45–3.30 (m, 3H), 3.09 (d, J = 10.2 Hz, 1H), 2.47 (s, 3H), 2.32 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H19ClN4O3S, M + H): 443.0939, found: (M + H): 443.0940.
1′-Methyl-1-(4-ethoxyphenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4g)
From 3g (0.24 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4g (0.10 g, 35%) was obtained as a white solid. M.p. 240–241 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.63 (s, 1H, NH), 10.60 (s, 1H, NH), 7.26 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.98–6.89 (m, 3H), 6.68 (d, J = 7.7 Hz, 1H),6.73 (d, J = 8.6 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.49 (d, J = 10.0 Hz, 1H), 3.40–3.28 (m, 2H),3.07 (d, J = 10.0 Hz, 1H), 2.47 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). HRMS (ESI+) m/z calcd. for (C22H22N4O3S, M + H): 423.1485, found: (M + H): 423.1480.
5″-Chloro-1′-methyl-1-(4-ethoxyphenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4h)
From 3h (0.26 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4h (0.08 g, 27%) was obtained as a white solid. M.p. 268–271 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.80–10.61 (bs, 2H, NH), 7.33 (dd, J1 = 1.6 Hz, J2 = 8.2 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H),6.87 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 4.04 (q, J = 7.0 Hz, 2H), 3.45–3.34 (m, 3H),3.40–3.28 (m, 2H), 3.09 (d, J = 10.3 Hz, 1H), 2.47 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). HRMS (ESI+) m/z calcd. for (C22H21ClN4O3S, M + H): 457.1095, found: (M + H): 457.1090.
1′-Methyl-1-(p-tolyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4i)
From 3i (0.22 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4i (0.10 g, 39%) was obtained as a white solid. M.p. 155–157 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.61 (bs, 1H, NH), 10.57 (bs, 1H, NH), 7.26 (dd, J1 = 1.0 Hz, J2 = 7.7 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.97–6.91 (m, 3H), 6.86 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 8.8 Hz, 2H), 3.76 (s, 3H), 3.49 (d, J = 10.1 Hz, 1H), 3.37 (d, J = 10.1 Hz, 1H), 3.32 (m, 1H), 3.07 (d, J = 10.1 Hz, 1H), 2.47 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H20N4O2S, M + H): 393.1379, found: (M + H): 393.1384.
5″-Chloro-1′-methyl-1-(p-tolyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4j)
From 3j (0.24 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4j (0.14 g, 50%) was obtained as a white solid. M.p. 159–160 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.76 (s, 1H, NH), 10.69 (bs, 1H, NH), 7.33 (dd, J1 = 2.2 Hz, J2 = 8.3 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.99–6.94 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.80–6.75 (m, 2H), 3.78 (s, 3H), 3.44–3.32 (m, 3H), 3.09 (d, J = 10.2 Hz, 1H), 2.47 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H19ClN4O2S, M + H): 427.0990, found: (M + H): 427.0987.
5″-Chloro-1′-methyl-1-(4-chlorophenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4k)
From 3k (0.23 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4k (0.13 g, 48%) was obtained as a white solid. M.p. 163–164 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.72 (bs, 1H, NH), 10.62 (s, 1H, NH), 7.53–7.48 (m, 2H), 7.26 (td, J1 = 1.2 Hz, J2 = 7.7 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.93 (td, J1 = 0.9 Hz, J2 = 7.7 Hz, 1H), 6.91–6.87 (m, 2H), 6.86 (d, J = 7.9 Hz, 1H), 3.49 (d, J = 10.1 Hz, 1H), 3.39–3.33 (m, 2H), 3.08 (d, J = 10.0 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H17ClN4O2S, M + H): 413.0833, found: (M + H): 413.0829.
5″-Chloro-1′-methyl-1-(4-chlorophenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4l)
From 3l (0.25 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4l (0.03 g, 10%) was obtained as a white solid. M.p. 239–240 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.84 (bs, 1H, NH), 10.77 (s, 1H, NH), 7.55–7.50 (m, 2H), 7.26 (dd, J1 = 2.2 Hz, J2 = 8.3 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.94–6.89 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 3.49 (d, J = 10.1 Hz, 1H), 3.44–3.38 (m, 2H), 3.33 (m, 1H), 3.10 (d, J = 10.4 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H16Cl2N4O2S, M + H): 447.0443, found: (M + H): 447.0433.
1′-Methyl-1-(4-fluorophenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4m)
From 3m (0.22 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4m (0.06 g, 24%) was obtained as a white solid. M.p. 273–274 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.91 (bs, 1H, NH), 10.79 (s, 1H, NH), 7.55 (t, J = 9.0 Hz, 1H), 7.43 (dd, J1 = 2.1 Hz, J2 = 8.3 Hz, 1H), 7.13–7.07 (m, 2H), 6.94 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 3.45–3.37 (m, 2H), 3.32 (d, J = 10.2 Hz, 1H), 3.10 (d, J = 10.2 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H17FN4O2S, M + H): 397.1129, found: (M + H): 397.1115
5″-Chloro-1′-methyl-1-(4-fluorophenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4n)
From 3n (0.24 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4n (0.10 g, 35%) was obtained as a white solid. M.p. 273–274 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.82 (bs, 1H, NH), 10.78 (bs, 1H, NH), 7.37–7.26 (m, 3H), 7.12 (s, 1H), 6.97–6.85 (m, 3H), 3.43–3.38 (m, 2H), 3.32 (d, J = 10.2 Hz, 1H), 3.10 (d, J = 10.2 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H16FClN4O2S, M + H): 431.0739, found: (M + H): 431.0760.
1′-Methyl-1-(3-chlorobenzyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4o)
From 3o (0.24 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4o (0.24 g, 87%) was obtained as a white solid. M.p. 273–274 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.59 (bs, 1H, NH), 10.57 (bs, 1H, NH), 7.28 (d, J = 7.6 Hz, 1H), 7.23–7.11 (m, 2H), 7.05 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 4.76 (d, J = 15.5 Hz, 1H), 4.66 (d, J = 15.5 Hz, 1H), 3.39 (d, J = 10.1 Hz, 1H), 3.20 (d, J = 10.0 Hz, 1H), 3.05 (d, J = 10.0 Hz, 1H), 2.44 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H19ClN4O2S, M + H): 427.0995, found: (M + H): 427.0981.
5″-Chloro-1′-methyl-1-(3-chlorobenzyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4p)
From 3p (0.26 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4p (0.18 g, 61%) was obtained as a white solid. M.p. 261–262 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.71 (s, 1H, NH), 10.68 (bs, 1H, NH), 7.29–7.20 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 7.3 Hz, 1H), 4.77 (d, J = 15.7 Hz, 1H), 4.68 (d, J = 15.7 Hz, 1H), 3.30 (d, J = 11.0 Hz, 1H), 3.24 (d, J = 8.8 Hz, 2H), 3.07 (d, J = 9.9 Hz, 1H), 2.44 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H18Cl2N4O2S, M + H): 461.0600, found: (M + H): 461.0610.
1′-Methyl-1-(3-chloro-4-fluorophenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione(4q)
From 3q (0.24 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4q (0.21 g, 75%) was obtained as a white solid. M.p. 252–254 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H, NH), 10.64 (s, 1H, NH), 7.51 (t, J = 8.9 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.3 Hz, 2H), 6.93 (t, J = 7.5 Hz, 1H), 6.89–6.81 (m, 3H), 3.47 (d, J = 10.2 Hz, 1H), 3.37 (d, J = 10.8 Hz, 2H), 3.08 (d, J = 10.2 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H16ClFN4O2S, M + H): 431.0739, found: (M + H): 431.0721.
5″-Chloro-1′-methyl-1-(3-chloro-4-fluorophenyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4r)
From 3r (0.27 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4r (0.10 g, 33%) was obtained as a white solid. M.p. 177–180 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.91 (bs, 1H, NH), 10.79 (s, 1H, NH), 7.55 (t, J = 9.0 Hz, 1H), 7.34 (dd, J1 = 2.1 Hz, J2 = 8.3 Hz, 1H), 7.13–7.07 (m, 2H), 6.94 (m, 1H), 6.89 (d, J = 8.3 Hz,1H), 3.45–3.37 (m, 2H), 3.32 (d, J = 10.2 Hz, 1H), 3.10 (d, J = 10.2 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H15Cl2FN4O2S, M + H): 465.0350, found: (M + H): 465.0341.
1′-Methyl-1-cyclopropyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4s)
From 3s (0.19 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4s (0.12 g, 54%) was obtained as a white solid. M.p. 272–273 °C (decomp.). 1H-NMR (400 MHz, DMSO-d6) δ: 10.50 (s, 1H, NH), 10.28 (s, 1H, NH), 7.19 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 3.30 (d, J = 10.0 Hz, 1H), 3.25 (d, J = 10.0 Hz, 1H), 3.14 (d, J = 10.0 Hz, 1H), 3.01 (d, J = 10.0 Hz, 1H), 2.45 (m, 1H), 2.43 (s, 3H), 0.82–0.70 (m, 2H), 0.62 (m, 1H), 0.11 (m, 1H). HRMS (ESI+) m/z calcd. for (C17H18N4O2S, M + H): 343.1223, found: (M + H): 343.1241.
5″-Chloro-1′-methyl-1-cyclopropyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4t)
From 3t (0.21 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4t (0.06 g, 25%) was obtained as a white solid. M.p. 275–276 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.65 (s, 1H, NH), 10.41 (s, 1H, NH), 7.26 (m, 1H), 7.10 (m, 1H), 6.79 (dd, J1 = 2.1 Hz, J2 = 8.3 Hz, 1H), 3.26–3.16 (m, 3H), 3.02 (d, J = 10.0 Hz, 1H), 2.43 (s, 3H), 0.89–0.74 (m, 2H), 0.59 (m, 1H), 0.11 (m, 1H). HRMS (ESI+) m/z calcd. for (C17H17ClN4O2S, M + H): 377.0834, found: (M + H): 377.0851.
1′-Methyl-1-(3-morpholinopropyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4u)
From 3u (0.24 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4u (0.08 g, 25%) was obtained as a white solid. M.p. 216–217 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.55 (s, 1H, NH), 10.39 (s, 1H, NH), 7.22–7.14 (m, 2H), 6.88 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 3.61–3.43 (m, 6H), 3.38 (d, J = 7.1 Hz, 1H), 3.31 (d, J = 10.6 Hz, 1H), 3.15 (d, J = 10.0 Hz, 1H), 3.04 (d, J = 10.0 Hz, 1H), 2.44 (s, 3H), 2.28–2.18 (m, 4H), 2.05 (t, J = 6.7 Hz, 2H), 1.42–1.33 (m, 2H). HRMS (ESI+) m/z calcd. for (C21H27N5O3S, M + H): 430.1907, found: (M + H): 430.1904.
5″-Chloro-1′-methyl-1-(3-morpholinopropyl)-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4v)
From 3v (0.26 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4v (0.05 g, 15%) was obtained as a white solid. M.p. 224–225 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.69 (s, 1H, NH), 10.49 (s, 1H, NH), 7.25 (dd, J1 = 1.8 Hz, J2 = 8.5 Hz, 1H), 7.19 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 3.64–3.46 (m, 6H), 3.30–3.18 (m, 3H), 3.06 (d, J = 9.9 Hz, 1H), 2.43 (s, 3H), 2.28–2.19 (m, 4H), 2.10–2.03 (m, 2H), 1.44–1.28 (m, 2H). HRMS (ESI+) m/z calcd. for (C21H26ClN5O3S, M + H): 464.1517, found: (M + H): 464.1519.
1′-Methyl-1-phenyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4w)
From 3w (0.21 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 4w (0.07 g, 27%) was obtained as a white solid. M.p. 273–274 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.65 (bs, 1H, NH), 10.63 (s, 1H, NH), 7.45–7.36 (m, 3H), 7.27 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.89–6.82 (m, 3H), 3.51 (d, J = 10.0 Hz, 1H), 3.37 (d, J = 10.0 Hz, 2H), 3.08 (d, J = 10.2 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H18N4O2S, M + H): 379.1223, found: (M + H): 379.1236.
5″-Chloro-1′-methyl-1-phenyl-2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (4x)
From three times (0.23 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound four times (0.14 g, 49%) was obtained as a white solid. M.p. 268–269 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.79 (bs, 1H, NH), 10.78 (bs, 1H, NH), 7.47–7.39 (m, 3H), 7.34 (dd, J1 = 1.6 Hz, J2 = 8.3 Hz, 1H), 7.14 (s, 1H), 6.91–6.85 (m, 3H), 3.43 (d, J = 10.2 Hz, 1H), 3.39 (d, J = 10.2 Hz, 1H), 3.34 (d, J = 10.2 Hz, 1H), 3.10 (d, J = 10.2 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H17ClN4O2S, M + H): 413.0834, found: (M + H): 413.0850.
3.2.4. General Procedure for the Synthesis of Dispiroindolinones 6
Corresponding 5-indolidene-2-selenoxoimidazolidin 5 (1 equiv) and sarcosine (4 equiv) were dissolved in toluene and the mixture heated to a boiling point. After that paraformaldehyde (4 equiv) was added. The resulting mixture was refluxed for 5–8 hours (TLC control). After the reaction was completed, the solvent was evaporated in vacuo. The product was then purified using column chromatography (silica gel 60, 0.04–0.063 mm/230–400 mesh, CHCl3:MeOH/50:1) to afford products as a white solid. This solid was washed with cold methanol to yield corresponding dispirooxindole as light brown crystalline solid.
5″-Chloro-1-(3-chloro-4-fluorophenyl)-1′-methyl-2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (6r)
From 5r (0.30 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 6r (0.19 g, 57%) was obtained as light brown solid. M.p. 193–194 °C (decomp.). 1H-NMR (400 MHz, DMSO-d6) δ: 11.62 (s, 1H, NH), 10.81 (s, 1H, NH), 7.57 (t, J = 9.0 Hz, 1H), 7.36 (dd, J1 = 1.8 Hz, J2 = 8.3 Hz, 1H), 7.12 (m, 1H), 7.10 (m, 1H), 6.96 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.43 (s, 2H), 3.32 (m, 1H), 3.12 (d, J = 10.2 Hz, 1H), 2.49 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H17ClN4O2S, M + H): 512.9800, found: (M + H): 513.0050.
5″-Chloro-1-(4-methoxyphenyl)-1′-methyl-2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-dione (6f)
From 5f (0.28 g, 0.65 mmol), sarcosine (0.23 g, 2.6 mmol) and paraformaldehyde (0.08 g, 2.6 mmol), compound 6f (0.19 g, 71%) was obtained as a white solid. M.p. 284–285 °C (decomp.).1H-NMR (400 MHz, DMSO-d6) δ: 11.41 (bs, 1H, NH), 10.79 (s, 1H, NH), 7.33 (dd, J1 = 1.9 Hz, J2 = 8.3 Hz, 1H), 7.13 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.6 Hz, 2H), 3.77 (s, 3H), 3.45–3.37 (m, 2H), 3.31 (m, 1H), 3.10 (d, J = 10.2 Hz, 1H), 2.48 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H20ClN4O3Se, M + H): 491.0384, found: (M + H): 491.0385.
3.2.5. General Procedure for the Synthesis of 5-Substituted Hydantoins 8
Corresponding 5-substituted-2-thiohydantoin 4 (1 equiv) was added to solution of the potassium hydroxide (1.05 equiv) in EtOH at room temperature (~4 mL EtOH for 100 mg of 3). After that, MeI (1.5 eq) was added and the reaction mixture was stirred at room temperature overnight. Then EtOH:HCl conc.(1:1) was added to the reaction (~4 mL EtOH for 100 mg of 3) and refluxed for 2 hours. Further, the reaction cooled to room temperature and formed precipitate was filtered off, washed with ethanol and dried in air. All compounds were obtained as red crystalline powders.
(Z)-5-Chloro-3-(1-(4-methoxyphenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (8f)
From 3f (0.116 g, 0.30 mmol), KOH (0.018 g, 0.32 mmol) and MeI (0.064 g, 0.45 mmol), compound 8f (0.089 g, 80%) was obtained as a red solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.08 (s, 1H, NH), 11.06 (s, 1H, NH), 8.59 (d, J = 2.0 Hz, 1H), 7.95 (s, 1H, Ar), 7.39 (d, J = 8.8 Hz, 2H), 7.33 (dd, J1= 2.2 Hz, J2 = 8.4 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H). HRMS (ESI+) m/z calcd. for (C18H12ClN3O4 M + H): 370.0595, found: (M + H): 370.0588.
(Z)-5-Chloro-3-(1-(4-ethoxyphenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (8h)
From 3h (0.120 g, 0.30 mmol), KOH (0.018 g, 0.32 mmol) and MeI (0.064 g, 0.45 mmol), compound 8h (0.097 g, 84%) was obtained as a white solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.66 (s, 1H, NH), 11.24 (s, 1H, NH), 8.54 (m, 1H), 7.39–7.70 (m, 3H), 7.09–7.04 (m, 2H), 6.94 (m, 1H) 4.08 (q, J = 6.9 Hz, 2H), 1.36 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calcd. for (C19H14ClN3O4, M + H): 084.0751, found: (M + H): 413.0781.
(Z)-5-Chloro-3-(1-(3-chloro-4-fluorophenyl)-5-oxo-2-thioxoimidazolidin-4-ylidene)indolin-2-one (8r)
From 3r (0.122 g, 0.30 mmol), KOH (0.018 g, 0.32 mmol) and MeI (0.064 g, 0.45 mmol), compound 8r (0.093 g, 79%) was obtained as a white solid. M.p. > 300 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 11.22 (s, 1H, NH), 11.10 (s, 1H, NH), 8.54 (m, 1H), 7.77 (dd, J1 = 2.2 Hz, J2 = 6.7 Hz, 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.36 (m, 1H), 6.95 (t, J = 9.0 Hz, 1H). HRMS (ESI+) m/z calcd. for (C17H9Cl2FN3O3, M + H): 392.0005, found: (M + H): 491.0998.
3.2.6. General Procedure for the Synthesis of Dispiroindolinones 9
Corresponding imidazolidin 8 (1 equiv) and sarcosine (4 equiv) were dissolved in toluene and the mixture heated to a boiling point. After that, paraformaldehyde (4 equiv) was added. The resulting mixture was refluxed for 5–8 hours (TLC control). After the reaction was completed, the solvent was evaporated in vacuo. The product was then purified using column chromatography (silica gel 60, 0.04–0.063 mm/230–400 mesh, CHCl3:MeOH/50:1) to afford products as a white solid. This solid was washed with acetone to yield corresponding dispirooxindole as a white crystalline solid.
5″-Chloro-1-(4-methoxyphenyl)-1′-methyldispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2,2″,5-trione (9f)
From 8f (0.074 g, 0.20 mmol), sarcosine (0.071 g, 0.80 mmol) and paraformaldehyde (0.026 g, 0.80 mmol), compound 9f (0.061 g, 72%) was obtained as a white solid. M.p. 295–296 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.74 (s, 1H NH), 8.80 (s, 1H, NH), 7.33 (dd, J1 = 2.2 Hz, J2 = 8.3 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 6.87 (m, 1H), 3.44–3.36 (m, 2H), 3.31 (d, J = 10.2 Hz, 1H), 3.08 (d, J = 10.3 Hz, 1H), 2.47 (s, 3H). HRMS (ESI+) m/z calcd. for (C21H19ClN4O4, M + H): 427.1173, found: (M + H): 427.1177.
5″-Chloro-1-(4-ethoxyphenyl)-1′-methyldispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2,2″,5-trione (9f)
From 8h (0.076 g, 0.20 mmol), sarcosine (0.071 g, 0.80 mmol) and paraformaldehyde (0.026 g, 0.80 mmol), compound 9h (0.055 g, 72%) was obtained as a white solid. M.p. 273–274 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.74 (s, 1H, NH), 8.80 (s, 1H, NH), 7.32 (m, 1H), 7.17 (s, 1H), 7.00–6.92 (m, 2H), 6.92–6.82 (m, 3H), 4.08–3.98 (m, 2H), 3.45–3.36 (m, 2H), 3.29 (m, 1H), 3.07 (m, 1H), 2.46 (s, 3H), 1.37–1.27 (m, 3H). HRMS (ESI+) m/z calcd. for (C22H21ClN4O4 M + H): 441.1330, found: (M + H): 441.1295.
5″-Chloro-1-(3-chloro-4-fluorophenyl)-1′-methyldispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2,2″,5-trione (9r)
From 8r (0.078 g, 0.20 mmol), sarcosine (0.071 g, 0.80 mmol) and paraformaldehyde (0.026 g, 0.80 mmol), compound 9r (0.067 g, 75%) was obtained as a white solid. M.p. 197–198 °C. 1H-NMR (400 MHz, DMSO-d6) δ: 10.75 (s, 1H, NH), 8.99 (s, 1H, NH), 7.55 (t, J = 9.0 Hz, 1H), 7.33 (dd, J1 = 2.2 Hz, J2 = 8.3 Hz, 1H), 7.24 (dd, J1 = 2.5 Hz, J2 = 6.7 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.06 (m, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.41–3.34 (m, 3H), 3.08 (d, J = 10.2 Hz, 1H), 2.46 (s, 3H). HRMS (ESI+) m/z calcd. for (C20H16Cl2FN4O3, M + H): 449.0578, found: (M + H): 449.0589.