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CAS No. :503-87-7 MDL No. :MFCD00005277
Formula : C3H4N2OS Boiling Point : -
Linear Structure Formula :- InChI Key :UGWULZWUXSCWPX-UHFFFAOYSA-N
M.W : 116.14 Pubchem ID :1274030
Synonyms :

Safety of [ 503-87-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P301+P312+P330 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 503-87-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 503-87-7 ]

[ 503-87-7 ] Synthesis Path-Downstream   1~84

  • 1
  • [ 503-87-7 ]
  • [ 487-89-8 ]
  • (5Z)-5-((1H-indol-3-yl)methylene)-2-thioxoimidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With sodium acetate; acetic acid for 2h; Heating;
87% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
82% With ethanolamine In ethanol at 60℃;
79% With ammonium acetate In toluene at 120℃; for 10h; 2.2 Synthesis of indole-hydantoin derivatives and prediction of 3D structures of IH-1 and IH-2 For synthesis of IH-1, the suspension of indole-3-carboxaldehyde (290mg, 2.00mmol), hydantoin (220mg, 2.20mmol), AcONH4 (658mg, 8.55mmol) in toluene (15mL) was refluxed for 24h. The yellow precipitate was collected by filtration, washed with water and methanol, successively, and dried over reduced pressure to give (Z)-5-(1H-Indole-3-ylmethlene) imidazolidine-2,4-dion (IH-1) (418mg, 92 %). For synthesis of IH-2, To a mixture of L-tryptophan methyl ester hydrochloride (230mg, 1.05mmol), CH2Cl2 (5mL), Et3N (1.40mL, 10.5mmol) was added trimethylsilyl isocyanate (1.21g, 10.5mmol) and stirred at room temperature for 17h. After the solvent was removed under reduced pressure, acetic acid (5.2mL) was added and whole mixture were reacted at 120°C for 22h, extracted with AcOEt, washed with brine and concentrated. The residue was treated with EtOH (10mL) and KOH (500mg, 9.36mmol) for 30min, and acidified with 1M HCl, and re-extracted with AcOEt twice, washed with brine and concentrated to give brown solid (202mg). Column chromatography (SiO2, n-Hexane:AcOEt=1:2 to 0:1) of the crude product gave 5-(1H-indole-3-ylmethyl)-imidazolidine-2,4-dione (IH-2) (124mg, 51%). For synthesis of IH-3, to the mixture of tert-Butyl 3-formyl-1H-indole-3-carboxaldehyde (106mg, 0.43mmol) and 3-phenyl hydantoin (93mg, 0.52mmol) in DMF was added t-BuOK (58mg, 0.52mmol) and stirred at room temperature for 40min. After the reaction was quenched with saturated NH4Cl aqueous solution, resultant non-colored precipitate was collected by filtration, washed with water and dried under vacuum. The crude product (117mg) was suspended in CH2Cl2 with excess trifluoroacetic acid (2mL) and stirred at room temperature for 7h. The non-colored precipitate was collected by filtration, washed with water and CH2Cl2 successively, and dried under vacuum to give (Z)-5-((1H-Indol-3-yl) methylene)-3-phenylimidazolidine-2,4-dione (IH-3) (58.1mg, 45 %). For synthesis of IH-4, to a suspension of indole-3-carboxaldehyde (58.0mg, 0.40mmol) and 2-thiohydantoin (70.0mg, 0.60mmol) in toluene (10mL) was added AcONH4 (160mg, 2.08mmol) and stirred at 120°C for 10h. The precipitate was collected by flirtation and washed with toluene and water, dried under vacuum to give (Z)-5-((1H-Indol-3-yl) methylene)-2-thioxoimidazolidin-4-one (IH-4) (76.8mg, 79 %). For synthesis of IH-5, the mixture of 1-Methyl-1H-indole-3-carboxyaldehyde (294mg, 1.85mmol), hydantoin (204mg, 2.04mmol) and AcONH4 (596mg, 7.40mmol) in toluene (8.0mL) was refluxed for 8h. The yellow precipitate was collected by flirtation and washed with toluene and methanol, dried under vacuum to give (Z)-5-((1-Methyl-1H-indol-3-yl) methylene) imidazolidine-2,4-dione (IH-5) (283mg, 64 %). For synthesis of IH-6, to a solution of 5-((1H-Indol-3-yl) methylene) imidazolidine-2,4-dione (2(Z), 90mg, 0.40mmol) in CH3CN (5mL)/DMSO (2mL) was added DMAP (24.4mg, 0.20mmol) and acetic anhydride (44.9mg, 0.44mmol), and stirred at room temperature for 12h. After the reaction mixture was quenched with water, resultant yellow precipitate was collected by flirtation and washed with water, dried under vacuum to give (Z)-5-((1-Acetyl-indol-3-yl) methylene)- imidazolidine-2,4-dione (88.7mg, 82 %) (Supplemental Fig. 1 ). Prediction of 3D structures of IH-1 and IH-2 calculated with DFT (ωB97X-D, 6-31G*) wereperformed by Spartan 18 (wavefunction, Inc).
In methanol for 2h; Heating;
With piperidine In ethanol at 20℃; for 12h;
With ethanolamine In ethanol for 1h; Reflux; General procedure for synthesis of 5a-e: General procedure: equimolar amounts of the appropriate indole aldehydes 1a-e and thiohydantoin 4 were dissolved inabs. EtOH and 1 mL of ETA was added. The mixture was heated at reflux for 1 h. After cooling the precipitate was filtered off and dried to yield compounds 5a-e, which were used without further purification.
With ethanolamine In ethanol for 1h; Reflux; General procedure for the synthesis of aplysinopsinanalogs 5a-e (GP2) General procedure: Equimolar amounts of the appropriate indole aldehydes 1a-e and thiohydantoin 4 were dissolved in abs. EtOH and 1 mL of ethanolamine was added. The mixture was heated at reflux for 1 h. After cooling the precipitate was filtered off and dried to yield compounds 5a-e, which were used without further purification.

  • 2
  • [ 503-87-7 ]
  • [ 100-52-7 ]
  • [ 583-46-0 ]
YieldReaction ConditionsOperation in experiment
97% Stage #1: 2-thiohydantoin; benzaldehyde With triethylamine In water Stage #2: With hydrogenchloride In water for 3h; 8 A flask equipped with a magnetic stirrer, nitrogen pressure, and reflux condenser was charged with thiohydantoin (24.9 g, 0.215 mol), benzaldehyde (22.8 g, 0.215 mol), triethylamine (43 g, 0.43 mol), and water (250 ml_). Slight warming and vigorous stirring brought everything into solution. The mixture was stirred overnight and then transferred to an Erlenmeyer flask equipped with a magnetic stirrer. The pH was brought to ca. 3 with 3 M hydrochloric acid, and the mixture was stirred for 3 hr. The resulting solid was collected and washed with water and 2 X 50 ml_ of diethyl ether. The product weighed 97.6 g (97%). No other components were found in an HPLC trace at 260 and 350 nm. NMR (de-DMSO) δ 7.2-7.8(m,5H), 6.4(s, 1 H), 3.5(bs,2H)
90% With sodium hydrogencarbonate at 140℃; for 0.166667h; Microwave irradiation;
With piperidine; pyridine
With sodium acetate; acetic acid
With sodium acetate; acetic acid
With sodium acetate In acetic acid Reflux;
With piperidine In water at 70℃;
With piperidine In ethanol at 80℃; Inert atmosphere;

  • 3
  • [ 503-87-7 ]
  • [ 123-11-5 ]
  • [ 95474-45-6 ]
YieldReaction ConditionsOperation in experiment
89% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
87% With sodium acetate; acetic acid at 140℃; for 0.333333h; Microwave irradiation; stereospecific reaction;
79% With sodium acetate; acetic acid for 2h; Inert atmosphere; Reflux;
79% With sodium acetate; acetic acid for 16h; Reflux; 4.6. General procedure E: Knoevenagel condensation of precursors General procedure: Knoevenagel condensation was undertaken according to the methodsdescribed by Vicini et al.35 A mixture the appropriate heterocycle (3.75mmol), 4-methoxybenzaldehyde (0.457 mL, 3.75 mmol) and sodiumacetate (1.23 g, 15.0 mmol) in acetic acid (8 mL) was set to heat underreflux overnight. After 16 h, the reaction was cooled to room temperatureand poured onto ice. The precipitate was collected via vacuumfiltration and washed with water to afford the desired compound.
67% With boric acid In neat (no solvent) at 160℃; for 0.666667h; Microwave irradiation; Sealed tube; Green chemistry; stereoselective reaction; 3.1. General Procedure for the Condensation Reaction General procedure: A mixture of substrate (1 mmol), aldehyde (1.2 mmol) and boric acid (0.2 mmol) was placed in a cylindrical quartz reactor ( θ = 4 cm). The reactor was introduced into an Explorer24 CEM apparatus. The stirred mixture was heated at 160 °C (P = 300 W) for 40 min, except for 3c (180 °C). After microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature and ethanol (10 mL) or mixture of H2O/EtOH (10 mL) was directly added in the cylindrical quartz reactor. The resulting precipitated product was filtered off and was purified by recrystallization from ethanol if necessary.
64% With sodium acetate In acetic acid for 4h; Inert atmosphere; Reflux;
60% With sodium acetate; acetic acid for 16h; Reflux; 47 Example 47- Synthesis of (Z)-5-(4-Methoxybenzyl idene)-2-thioxoi midazol idi n-4-one A mixture of thiohydantoin (0.500 g, 4.31 mmol), 4-methoxybenzaldehyde (0.524 mL, 4.31 mmol) and sodium acetate (1.41 g, 17.2 mmol) in acetic acid (8 mL) was set to heatunder reflux overnight. After 16 hours, the reaction was cooled to room temperature and poured onto ice. The precipitate was collected via vacuum filtration and washed with water to afford the desired compound (0.602 g, 60%). OH (400 MHz, DMSO) 12.30 (br 5, 1 H, NH), 12.07 (br 5, 1 H, NH), 7.74 (d, J8.0, 2H, ArH), 6.99 (d, J8.0, 2H, ArH), 6.47 (5, 1H, OH), 3.82 (5, 3H, OH3).
With sodium acetate; acetic acid
With sodium acetate In acetic acid for 2h; Heating;
Reflux;
With sodium acetate In acetic acid Reflux; 3.1.1. General Procedure to Obtain 5-Arylidenethiohydantoin (21, 23 and 24) General procedure: Thiohydantoin (2.90±5.80 g, 25±50 mmol), acetic acid (25±50 ml), sodium acetate (8.33±16.67 g,100-200 mmol) with appropriate arylidene aldehyde (25-50 mmol) in flat-bottom flask were heated in boiling point for 4±6 h and then mixed for 20 h. Reaction was controlled by TLC-chloroform/ethylacetate: 1/1. If necessary, purification was performed using crystallization from acetone or acetic acid. (Z)-5-(phenanthren-9-ylmethylene)-2-thioxoimidazolidin-4-one (21) Phenanthrene-9-carbaldehyde (30.5 mmol,6.29 g) and thiohydantoin (30.5 mmol, 3.54 g) were used. Yellow solid.

Reference: [1]Mendgen, Thomas; Steuer, Christian; Klein, Christian D. [Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 743 - 753]
[2]Tahtouh, Tania; Durieu, Emilie; Villiers, Benoît; Bruyère, Céline; Nguyen, Thu Lan; Fant, Xavier; Ahn, Kwang H.; Khurana, Leepakshi; Deau, Emmanuel; Lindberg, Mattias F.; Sévère, Elodie; Miege, Frédéric; Roche, Didier; Limanton, Emmanuelle; L’Helgoual’ch, Jean-Martial; Burgy, Guillaume; Guiheneuf, Solène; Herault, Yann; Kendall, Debra A.; Carreaux, François; Bazureau, Jean-Pierre; Meijer, Laurent [Journal of Medicinal Chemistry, 2022, vol. 65, # 2, p. 1396 - 1417]
[3]Location in patent: experimental part Gosling, Sandrine; Rollin, Patrick; Tatibouet, Arnaud [Synthesis, 2011, # 22, p. 3649 - 3660]
[4]Christoff, Rebecca M.; Soares da Costa, Tatiana P.; Bayat, Saadi; Holien, Jessica K.; Perugini, Matthew A.; Abbott, Belinda M. [Bioorganic and Medicinal Chemistry, 2021, vol. 52]
[5]Brun, Elodie; Safer, Abdelmounaim; Carreaux, Franois; Bourahla, Khadidja; L'Helgoua'ch, Jean-Martial; Bazureau, Jean-Pierre; Villalgordo, Jose Manuel [Molecules, 2015, vol. 20, # 6, p. 11617 - 11631]
[6]Kim, Hye Rim; Lee, Hye Jin; Choi, Yeon Ja; Park, Yun Jung; Woo, Youngwoo; Kim, Seong Jin; Park, Min Hi; Lee, Hee Won; Chun, Pusoon; Chung, Hae Young; Moon, Hyung Ryong [MedChemComm, 2014, vol. 5, # 9, p. 1410 - 1417]
[7]Current Patent Assignee: LA TROBE UNIVERSITY - WO2018/187845, 2018, A1 Location in patent: Paragraph 0203
[8]Johnson; Kohmann [Journal of the American Chemical Society, 1915, vol. 37, p. 1870,1880]
[9]Khodair; El-Subbagh; Al-Obaid [Phosphorus, Sulfur and Silicon and the Related Elements, 1998, vol. 140, p. 159 - 181]
[10]Kiec-Kononowicz, Katarzyna; Karolak-Wojciechowska, Janina; Michalak, Barbara; Pekala, Elzbieta; Schumacher, Britta; Mueller, Christa E. [European Journal of Medicinal Chemistry, 2004, vol. 39, # 3, p. 205 - 218]
[11]Rempel; Atzler; Behrenswerth; Karcz; Schoeder; Hinz; Kaleta; Thimm; Kiec-Kononowicz; Müller [MedChemComm, 2014, vol. 5, # 5, p. 632 - 649]
[12]Kaczor, Aneta; Witek, Karolina; Podlewska, Sabina; Czekajewska, Joanna; Lubelska, Annamaria; Zesławska, Ewa; Nitek, Wojciech; Latacz, Gniewomir; Alibert, Sandrine; Pagès, Jean-Marie; Karczewska, Elzbieta; Kieć-Kononowicz, Katarzyna; Handzlik, Jadwiga [Molecules, 2019, vol. 24, # 3]
  • 5
  • [ 503-87-7 ]
  • [ 52562-50-2 ]
  • 5-<3'-(5-methylindolal)>-2-thiohydantoin [ No CAS ]
  • 6
  • [ 503-87-7 ]
  • [ 1195-08-0 ]
  • [ 157365-66-7 ]
  • 7
  • [ 503-87-7 ]
  • [ 6625-96-3 ]
  • 5-<3'-(5-nitroindolal)>-2-thiohydantoin [ No CAS ]
  • 8
  • [ 503-87-7 ]
  • [ 1079-83-0 ]
  • [ 129502-13-2 ]
YieldReaction ConditionsOperation in experiment
72% With ammonium acetate; acetic acid In benzene Heating;
  • 9
  • [ 503-87-7 ]
  • [ 17380-18-6 ]
  • 5-<3'-(5-cyanoindolal)>-2-thiohydantoin [ No CAS ]
  • 10
  • [ 503-87-7 ]
  • [ 3414-19-5 ]
  • 5-<3'-(5-hydroxyindolal)>-2-thiohydantoin [ No CAS ]
  • 11
  • [ 503-87-7 ]
  • [ 123-08-0 ]
  • [ 6318-40-7 ]
YieldReaction ConditionsOperation in experiment
88% With sodium acetate In acetic acid for 2h; Heating;
85% With sodium acetate; acetic acid for 3h; Heating; (Z)-5-(4-Hydroxybenzylidene)-2-thiooxoimidazolin-4-one (I). 4-Hydroxybenzaldehyde (793 mg, 6.5 mmol),2-thiooxoimidazolin-4-one (580 mg, 5.0 mmol) andsodium acetate (1.76 g, 21.5 mmol) were dissolved in15 mL of glacial acetic acid, the resulting mixture wasboiled for 3 h and cooled to room temperature. Withvigorous stirring, 50 mL of water was added, the precipitateformed filtered out and washed with water(20 mL) and diethyl ether (10 mL), and then dried invacuum. Yellow powder (935 mg, 85%), mp 280°Cwith decomposition; 1H NMR: 6.43 (s, 1 H), 6.81 (d,J2 8.6, 2 H), 7.63 (d, J2 8.6, 2 H), 10.02 (broad s., 1 H),11.95 (broad s., 1 H), 12.22 (broad s., 1 H).
79% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
50% With ammonium acetate; acetic acid for 20h; Reflux; General procedure for the preparation of 5-benzylidene hydantoins 4a-4e and 5-benzylidene thiohydantoins 5a-5e. General procedure: To a stirred suspension of the corresponding benzaldehydes (3.33 mmol) and imidazolidine-2,4-dione (500 mg, 5 mmol) or 2-thioxoimidazolidin-4-one (580 mg, 5 mmol) in glacial acetic acid (5 mL) ammonium acetate (507 mg, 6.6 mmol) was added and the reaction mixture was heated under reflux for 20 h. The solution was cooled, and the precipitate was filtered off, washed with water and ethanol, and dried.
45% With sodium acetate; acetic acid for 4h; Reflux; 9-1 Synthesis of (Z)-5-(4-hydroxybenzylidene)-2-thioxoimidazolidin-4-one (Compound 98) [0252] Synthesis of Compounds 98 to 110, which are (Z)5-(substituted benzylidene)-2-thioxoimidazolidin-4-one analogs, was performed as follows. In detail, in an acetic acid (4 mE/sodium acetate 1 g) solvent, a mixture includingsubstitutedbenzaldhehyde (1.53 to 2.46 mmol), 2-thiohydan- tom (1.1 eq.), and sodium acetate (3 eq.) was refluxed for 424 hours. After cooling, water was added thereto, andproduced precipitate was filtered and in consideration of characteristics of the residual starting materials, the resultant precipitate was washed with water and ethyl acetate and/or methylene chloride to obtain solid Compounds 98 to 110 (yield:15.1 to 85.2%). [0253] Green solid; a reaction time of 4 hours; a yield of45.0%; a melting point of >300° C.; ‘H NMR (500 MHz,DMSO-d5) ö 12.23 (s, 1H), 11.96 (s, 1H), 10.02 (s, 1H), 7.61(d, 2H, J=8.0 Hz), 6.79 (d, 2H, J=8.5 Hz), 6.41 (s, 1H); ‘3CNMR (100 MHz, DMSO-d5) ö 178.9, 166.5, 159.7, 133.1,125.8, 124.0, 116.5, 113.5.
45% With sodium acetate In acetic acid for 4h; Inert atmosphere; Reflux;
45% With sodium acetate; acetic acid for 4h; Reflux; 9-1 Synthesis of (Z)-5-(4-hydroxybenzylidene)-2-thioxoimidazolidin-4-one General procedure: Synthesis of Compounds 98 to 110, which are (Z)-5-(substituted benzylidene)-2-thioxoimidazolidin-4-one analogs, was performed as follows. In detail, in an acetic acid (4 mL/sodium acetate 1 g) solvent, a mixture including a substituted benzaldhehyde (1.53 to 2.46 mmol), 2-thiohydantoin (1.1 eq.), and sodium acetate (3 eq.) was refluxed for 4 to 24 hours. After cooling, water was added thereto, and the produced precipitate was filtered and in consideration of characteristics of the residual starting materials, the resultant precipitate was washed with water and ethyl acetate and/or methylene chloride to obtain solid Compounds 98 to 110 (yield: 15.1 to 85.2%).
With sodium acetate In acetic acid for 2h; Heating;

  • 12
  • [ 98-03-3 ]
  • [ 503-87-7 ]
  • [ 280137-27-1 ]
YieldReaction ConditionsOperation in experiment
98% With sodium hydrogencarbonate at 140℃; for 1.5h; Microwave irradiation; Green chemistry;
89% With sodium acetate; acetic acid for 2h; Heating;
40% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
With sodium acetate In acetic acid for 2h; Heating;
With piperidine In ethanol at 20℃; for 12h;

  • 13
  • [ 503-87-7 ]
  • [ 123-11-5 ]
  • [ 7253-52-3 ]
YieldReaction ConditionsOperation in experiment
89% With ethanolamine In ethanol; water at 70 - 90℃; for 4h; 1.3 A solution of 2-thiohydantoin (1.16 g, 10 mmol) and p-methoxybenzaldehyde (1.36 g, 10 mmol) in 50 mL singleNeck flask, add 25ml of water, magnetic stirring, warmed to 70 ° C, ethanolamine (1.83g, 30mmol) was added and continued warming to 90 ° C, the reaction 4h, TLC followed until the conversion of the raw material. The mixture was cooled to 70 ° C, concentrated hydrochloric acid was added to adjust the pH to 4, and a solid precipitated. The residue was placed in an ice bath for 1 hour. The mixture was suction filtered, washed with water, dried and recrystallized from ethanol to give 2.08 g of a yellow solid with a yield of 89%
With sodium acetate; acetic acid
With piperidine In water at 70℃;
  • 16
  • [ 577-47-9 ]
  • [ 503-87-7 ]
  • [ 65-85-0 ]
YieldReaction ConditionsOperation in experiment
at 25.3℃; Hydrolysis;
  • 17
  • [ 577-47-9 ]
  • [ 503-87-7 ]
  • [ 65-85-0 ]
YieldReaction ConditionsOperation in experiment
at 20 - 41.5℃; Hydrolysis;
  • 18
  • [ 503-87-7 ]
  • [ 104-88-1 ]
  • [ 280137-25-9 ]
YieldReaction ConditionsOperation in experiment
With sodium acetate In acetic acid for 2h; Heating;
With sodium acetate; acetic acid
With sodium acetate; acetic acid Reflux;
Reflux;
With sodium acetate In acetic acid Reflux; 3.1.1. General Procedure to Obtain 5-Arylidenethiohydantoin (21, 23 and 24) General procedure: Thiohydantoin (2.90±5.80 g, 25±50 mmol), acetic acid (25±50 ml), sodium acetate (8.33±16.67 g,100-200 mmol) with appropriate arylidene aldehyde (25-50 mmol) in flat-bottom flask were heated in boiling point for 4±6 h and then mixed for 20 h. Reaction was controlled by TLC-chloroform/ethylacetate: 1/1. If necessary, purification was performed using crystallization from acetone or acetic acid. (Z)-5-(phenanthren-9-ylmethylene)-2-thioxoimidazolidin-4-one (21) Phenanthrene-9-carbaldehyde (30.5 mmol,6.29 g) and thiohydantoin (30.5 mmol, 3.54 g) were used. Yellow solid.
With sodium acetate In acetic acid at 140℃; for 0.333333h; Microwave irradiation;

  • 19
  • [ 503-87-7 ]
  • [ 100-52-7 ]
  • [ 95474-44-5 ]
YieldReaction ConditionsOperation in experiment
93% With sodium acetate; acetic acid at 140℃; Sealed tube; Microwave irradiation; Z In a 30 mL glass tube were placed successively commercial thiohydantoin (1 g, 8.61 mmol), 0.96 mL of benzaldehyde 12b (9.47 mmol, 1.1 equiv.), sodium acetate (777 mg, 9.47 mmol, 1.1 equiv.) and 4 mL of glacial acetic acid. The glass tube was sealed with a snap cap and placed in the Explorer 24 CEM microwave cavity (P = 300 W). The stirred mixture was irradiated at 140 °C for 20 min under vigorous stirring. After microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature after which 10 mL of deionized water were added in one portion. Then, the resulting mixture was triturated during 20 min. with slow stirring and yellow needles appeared in the suspension. The desired insoluble (5Z) 5-benzylidene-2-thioxo-imidazolidin-4-one 13b was collected by filtration then washed with deionized water (2 mL) and dried under high vacuum (10-2 Torr) at 25 °C for 1 h. The product 13b was obtained as yellow needles in 93% yield (1.63 g). Mp >250 °C. 1H NMR (300 MHz, DMSO-d6) δ = 6.48 (s, 1H, CH=), 7.51-7.30 (m, 3H, H-3, H-4, H-5), 7.73 (d, 2H, J = 4.1 Hz, H-2, H-6), 12.15 (br s, 1H, NH), 12.38 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6) δ = 111.50 (CH=), 127.68 (C-1), 128.74 (C-3, C-5), 129.19 (C-4), 130.13 (C-2, C-6), 132.27 (C-N), 165.74 (C=O), 179.18 (C=S). HRMS, m/z = 227.0251 found (calculated for C10H8N2OSNa, [M + Na]+ requires 227.0250).
72% With sodium acetate; acetic acid at 120℃; for 22h;
61% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
57% With ammonium acetate; acetic acid for 20h; Reflux; General procedure for the preparation of 5-benzylidene hydantoins 4a-4e and 5-benzylidene thiohydantoins 5a-5e. General procedure: To a stirred suspension of the corresponding benzaldehydes (3.33 mmol) and imidazolidine-2,4-dione (500 mg, 5 mmol) or 2-thioxoimidazolidin-4-one (580 mg, 5 mmol) in glacial acetic acid (5 mL) ammonium acetate (507 mg, 6.6 mmol) was added and the reaction mixture was heated under reflux for 20 h. The solution was cooled, and the precipitate was filtered off, washed with water and ethanol, and dried.
46% With sodium acetate; acetic acid at 140℃; for 0.333333h; Microwave irradiation; stereospecific reaction;
With sodium acetate In acetic acid for 2h; Heating;
Reflux;
96 %Spectr. With sodium hydrogencarbonate at 130℃; for 0.208333h; Microwave irradiation; Green chemistry;

Reference: [1]Burgy, Guillaume; Tahtouh, Tania; Durieu, Emilie; Foll-Josselin, Béatrice; Limanton, Emmanuelle; Meijer, Laurent; Carreaux, François; Bazureau, Jean-Pierre [European Journal of Medicinal Chemistry, 2013, vol. 62, p. 728 - 737]
[2]Arce, Elsa M.; Lamont, Scott G.; Davies, Paul W. [Advanced Synthesis and Catalysis, 2020, vol. 362, # 12, p. 2503 - 2509]
[3]Mendgen, Thomas; Steuer, Christian; Klein, Christian D. [Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 743 - 753]
[4]Arsovska, Emilija; Trontelj, Jurij; Zidar, Nace; Tomai, Tihomir; Mai, Lucija Peterlin; Kikelj, Danijel; Plavec, Janez; Zega, Anamarija [Acta Chimica Slovenica, 2014, vol. 61, # 3, p. 637 - 644]
[5]Tahtouh, Tania; Durieu, Emilie; Villiers, Benoît; Bruyère, Céline; Nguyen, Thu Lan; Fant, Xavier; Ahn, Kwang H.; Khurana, Leepakshi; Deau, Emmanuel; Lindberg, Mattias F.; Sévère, Elodie; Miege, Frédéric; Roche, Didier; Limanton, Emmanuelle; L’Helgoual’ch, Jean-Martial; Burgy, Guillaume; Guiheneuf, Solène; Herault, Yann; Kendall, Debra A.; Carreaux, François; Bazureau, Jean-Pierre; Meijer, Laurent [Journal of Medicinal Chemistry, 2022, vol. 65, # 2, p. 1396 - 1417]
[6]Khodair; El-Subbagh; Al-Obaid [Phosphorus, Sulfur and Silicon and the Related Elements, 1998, vol. 140, p. 159 - 181]
[7]Rempel; Atzler; Behrenswerth; Karcz; Schoeder; Hinz; Kaleta; Thimm; Kiec-Kononowicz; Müller [MedChemComm, 2014, vol. 5, # 5, p. 632 - 649]
[8]Alves Borges Leal, Antonio L.; Barreto, Humberto M.; Faillace, Martín S.; Muratori da Costa, Luciana; Peláez, Walter J.; Silva, Ana P. [ChemMedChem, 2020]
  • 20
  • [ 503-87-7 ]
  • [ 39515-51-0 ]
  • [ 373387-18-9 ]
YieldReaction ConditionsOperation in experiment
90%
Reflux;
With sodium acetate In acetic acid Reflux; 3.1.1. General Procedure to Obtain 5-Arylidenethiohydantoin (21, 23 and 24) General procedure: Thiohydantoin (2.90±5.80 g, 25±50 mmol), acetic acid (25±50 ml), sodium acetate (8.33±16.67 g,100-200 mmol) with appropriate arylidene aldehyde (25-50 mmol) in flat-bottom flask were heated in boiling point for 4±6 h and then mixed for 20 h. Reaction was controlled by TLC-chloroform/ethylacetate: 1/1. If necessary, purification was performed using crystallization from acetone or acetic acid. (Z)-5-(phenanthren-9-ylmethylene)-2-thioxoimidazolidin-4-one (21) Phenanthrene-9-carbaldehyde (30.5 mmol,6.29 g) and thiohydantoin (30.5 mmol, 3.54 g) were used. Yellow solid.
With sodium acetate; acetic acid Reflux;

  • 21
  • [ 503-87-7 ]
  • [ 66-77-3 ]
  • [ 256347-75-8 ]
YieldReaction ConditionsOperation in experiment
69% With sodium acetate; acetic acid for 0.25h; Heating;
With sodium acetate; acetic acid
With sodium acetate In acetic acid Reflux; 3.1.1. General Procedure to Obtain 5-Arylidenethiohydantoin (21, 23 and 24) General procedure: Thiohydantoin (2.90±5.80 g, 25±50 mmol), acetic acid (25±50 ml), sodium acetate (8.33±16.67 g,100-200 mmol) with appropriate arylidene aldehyde (25-50 mmol) in flat-bottom flask were heated in boiling point for 4±6 h and then mixed for 20 h. Reaction was controlled by TLC-chloroform/ethylacetate: 1/1. If necessary, purification was performed using crystallization from acetone or acetic acid. (Z)-5-(phenanthren-9-ylmethylene)-2-thioxoimidazolidin-4-one (21) Phenanthrene-9-carbaldehyde (30.5 mmol,6.29 g) and thiohydantoin (30.5 mmol, 3.54 g) were used. Yellow solid.
With sodium acetate; acetic acid at 20℃; Reflux;

  • 22
  • [ 503-87-7 ]
  • [ 66-99-9 ]
  • [ 152861-81-9 ]
YieldReaction ConditionsOperation in experiment
86% With sodium acetate; acetic acid for 1h; Heating;
83% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
With sodium acetate; acetic acid
With sodium acetate In acetic acid Reflux; 3.1.1. General Procedure to Obtain 5-Arylidenethiohydantoin (21, 23 and 24) General procedure: Thiohydantoin (2.90±5.80 g, 25±50 mmol), acetic acid (25±50 ml), sodium acetate (8.33±16.67 g,100-200 mmol) with appropriate arylidene aldehyde (25-50 mmol) in flat-bottom flask were heated in boiling point for 4±6 h and then mixed for 20 h. Reaction was controlled by TLC-chloroform/ethylacetate: 1/1. If necessary, purification was performed using crystallization from acetone or acetic acid. (Z)-5-(phenanthren-9-ylmethylene)-2-thioxoimidazolidin-4-one (21) Phenanthrene-9-carbaldehyde (30.5 mmol,6.29 g) and thiohydantoin (30.5 mmol, 3.54 g) were used. Yellow solid.
With sodium acetate; acetic acid at 20℃; Reflux;

  • 23
  • [ 503-87-7 ]
  • [ 120-57-0 ]
  • [ 110830-17-6 ]
YieldReaction ConditionsOperation in experiment
90% With piperidine; acetic acid at 140℃; for 0.5h; Autoclave; Microwave irradiation; 4.2 Standard procedures for the synthesis of conjugated derivatives from piperonal and various barbituric acids and 5-membered heterocycles General procedure: For compounds 20-22, piperonal (1.0g, 6.66mmol) and corresponding barbituric acid (13mmol) were loaded into an autoclave, and ethanol (16mL) was added. After heating to 120°C for 30min in a microwave reactor, the reaction mixture was cooled down. The product was collected by filtration and washed with water and used for the next step without any further purification (yield from 89% to 96%). For compounds, 24-27, Piperonal (1.0g, 6.66mmol), and corresponding 5-membered heterocycles (13mmol) were loaded into an autoclave, and acetic acid (16mL) was added. The reaction mixture was heated to 140°C for 30min in the presence of base piperidine for 24, 25, 27 (0.5mL, 5.06mmol), β-alanine for 26 (0.276g, 3.1mmol). The mixture was filtrated, washed with acetic acid, water and used for the next step without any further purification (yield from 87% to 94
90.13% With piperidine In toluene at 120℃; for 19h;
90% With piperidine In toluene at 120℃; for 19h; Inert atmosphere;
80% With sodium acetate; acetic acid for 0.5h; Heating;
75% With boric acid In neat (no solvent) at 160℃; for 0.666667h; Microwave irradiation; Sealed tube; Green chemistry; stereoselective reaction; 3.1. General Procedure for the Condensation Reaction General procedure: A mixture of substrate (1 mmol), aldehyde (1.2 mmol) and boric acid (0.2 mmol) was placed in a cylindrical quartz reactor ( θ = 4 cm). The reactor was introduced into an Explorer24 CEM apparatus. The stirred mixture was heated at 160 °C (P = 300 W) for 40 min, except for 3c (180 °C). After microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature and ethanol (10 mL) or mixture of H2O/EtOH (10 mL) was directly added in the cylindrical quartz reactor. The resulting precipitated product was filtered off and was purified by recrystallization from ethanol if necessary.
With sodium acetate; acetic acid at 140℃; for 0.333333h; Microwave irradiation;

  • 24
  • [ 503-87-7 ]
  • [ 1700-37-4 ]
  • (Z)-5-(3-(benzyloxy)benzylidene)-2-thioxoimidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With sodium acetate; acetic acid at 20℃; for 25.5h; Reflux;
74% With sodium acetate; acetic acid for 2h; Heating;
57.4% With sodium acetate; acetic acid for 4h; Reflux; 11.5; 11-16 Synthesis of (Z)-5-(3-(benzyloxy)benzylidene)-2- thioxoimidazolidin-4-one (Compound 138) General procedure: [0291] In an acetic acid (AcOH) (1.53 ml/10 eq. of sodium acetate) solvent, a solution including sodium acetate (3.0 to 10.0 eq.), 3-(benzyloxy)benzaldhehyde Compound 123a, 1.0 eq., used for the synthesis of 3-(benzyloxy)benzylidene analogue) or 4-(benzyloxy)benzaldhehyde (Compound 123b, 1.0 eq., used for the synthesis of 4-(benzyloxy)benzylidene analogue) and rhodanine (1.1 eq., used for the synthesis of Compounds 128 and 137), 2,4-thiazolidinedione (1.1 eq., used for the synthesis of Compounds 125 and 134), 2-thio- hydantoin(1.1 eq., used for the synthesis of Compounds 130 and 138), or pseudothiohydantoin (1.1 eq., used for the synthesis of Compounds 131 and 139) was refluxed. After cooling, water was added thereto. The produced precipitate was filtered and washed with water and a co-solvent of hexane and ethyl acetate (1:1) to obtain a solid target compound. [0308] A reaction time of 4 hours; a yield of 57.4%; ‘HNMR (500 MHz, DMSO-d5) ö 12.37 (s, 1H), 12.18 (s, 1H),7.46 (d, 2H, J=7.5 Hz), 7.39 (t, 2H, J=7.5 Hz), 7.35-7.3 1 (m,4H), 7.02 (brd, 1H, J=8.OHz), 6.44 (s, 1H), 5.16 (s, 2H); ‘3CNMR (100 MHz, DMSO-d5) ö 180.0, 166.5, 159.2, 137.6,134.3, 130.6,129.1, 128.6,128.5, 128.5,123.7, 116.7,116.6,112.2, 70.0;
57.4% With sodium acetate; acetic acid for 4h; Reflux; 11-16 Synthesis of (Z)-5-(3-(benzyloxy)benzylidene)-2-thioxoimidazolidin-4-one General procedure: In an acetic acid (AcOH) (1.53 mL/10 eq. of sodium acetate) solvent, a solution including sodium acetate (3.0 to 10.0 eq.), 3-(benzyloxy)benzaldhehyde Compound 123a, 1.0 eq., used for the synthesis of 3-(benzyloxy)benzylidene analogue) or 4-(benzyloxy)benzaldhehyde (Compound 123b, 1.0 eq., used for the synthesis of 4-(benzyloxy)benzylidene analogue) and rhodanine (1.1 eq., used for the synthesis of Compounds 128 and 137), 2,4-thiazolidinedione (1.1 eq., used for the synthesis of Compounds 125 and 134), 2-thiohydantoin (1.1 eq., used for the synthesis of Compounds 130 and 138), or pseudothiohydantoin (1.1 eq., used for the synthesis of Compounds 131 and 139) was refluxed. After cooling, water was added thereto. The produced precipitate was filtered and washed with water and a co-solvent of hexane and ethyl acetate (1:1) to obtain a solid target compound.
Reflux;

  • 25
  • [ 503-87-7 ]
  • [ 40359-32-8 ]
  • (Z)-5-[(3-allyloxy)benzylidene]-2-thiohydantoin [ No CAS ]
  • 26
  • [ 503-87-7 ]
  • [ 6745-75-1 ]
  • (Z)-5-(4-methoxy-2,5-dimethylbenzylidene)-2-thiohydantoin [ No CAS ]
  • 27
  • [ 503-87-7 ]
  • [ 3218-36-8 ]
  • (Z)-5-(4-phenylbenzylidene)-2-thioxoimidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
79%
70% With sodium acetate; acetic acid for 0.25h; Heating;
Reflux;
With sodium acetate In acetic acid Reflux; 3.1.1. General Procedure to Obtain 5-Arylidenethiohydantoin (21, 23 and 24) General procedure: Thiohydantoin (2.90±5.80 g, 25±50 mmol), acetic acid (25±50 ml), sodium acetate (8.33±16.67 g,100-200 mmol) with appropriate arylidene aldehyde (25-50 mmol) in flat-bottom flask were heated in boiling point for 4±6 h and then mixed for 20 h. Reaction was controlled by TLC-chloroform/ethylacetate: 1/1. If necessary, purification was performed using crystallization from acetone or acetic acid. (Z)-5-(phenanthren-9-ylmethylene)-2-thioxoimidazolidin-4-one (21) Phenanthrene-9-carbaldehyde (30.5 mmol,6.29 g) and thiohydantoin (30.5 mmol, 3.54 g) were used. Yellow solid.
With sodium acetate; acetic acid Reflux;

  • 28
  • [ 503-87-7 ]
  • [ 72908-87-3 ]
  • [ 649554-70-1 ]
  • 29
  • [ 503-87-7 ]
  • [ 4397-53-9 ]
  • (Z)-5-(4-(benzyloxy)benzylidene)-2-thioxoimidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
85.6% With sodium acetate; acetic acid for 9h; Reflux; 11.5; 11-8 Synthesis of (Z)-5-(4-(benzyloxy)benzylidene)-2- thioxoimidazolidin-4-one (Compound 130) General procedure: [0291] In an acetic acid (AcOH) (1.53 mE/i 0 eq. of sodium acetate) solvent, a solution including sodium acetate (3.0 to 10.0 eq.), 3-(benzyloxy)benzaldhehyde Compound 123a, 1.0 eq., used for the synthesis of 3-(benzyloxy)benzylidene analogue) or 4-(benzyloxy)benzaldhehyde (Compound 123b, 1.0 eq., used for the synthesis of 4-(benzyloxy)benzylidene analogue) and rhodanine (1.1 eq., used for the synthesis of Compounds 128 and 137), 2,4-thiazolidinedione (1.1 eq., used for the synthesis of Compounds 125 and 134), 2-thio- hydantoin(1.1 eq., used for the synthesis of Compounds 130 and 138), or pseudothiohydantoin (1.1 eq., used for the synthesis of Compounds 131 and 139) was refluxed. Afier cooling, water was added thereto. The produced precipitate was filtered and washed with water and a co-solvent of hexane and ethyl acetate (1:1) to obtain a solid target compound.[0300] A reaction time of 9 hours; a yield of 85.6%; ‘HNMR (500 MHz, DMSO-d5) ö 12.28 (s, 1H), 12.04 (s, 1H),7.72 (d, 2H, J=9.0 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.39 (t, 2H,J=7.5 Hz), 7.33 (t, 1H, J=7.0 Hz), 7.05 (d, 2H, J=8.5 Hz), 6.45(s, 1H), 5.17 (s, 2H); ‘3C NMR (100 MHz, DMSO-d5) ö179.3, 166.5, 160.0, 137.4, 132.8, 129.1, 128.6, 128.4, 126.6,125.7, 115.9, 112.7, 70.0.
85.6% With sodium acetate; acetic acid for 9h; Reflux; 11-8 Synthesis of (Z)-5-(4-(benzyloxy)benzylidene)-2-thioxoimidazolidin-4-one General procedure: In an acetic acid (AcOH) (1.53 mL/10 eq. of sodium acetate) solvent, a solution including sodium acetate (3.0 to 10.0 eq.), 3-(benzyloxy)benzaldhehyde Compound 123a, 1.0 eq., used for the synthesis of 3-(benzyloxy)benzylidene analogue) or 4-(benzyloxy)benzaldhehyde (Compound 123b, 1.0 eq., used for the synthesis of 4-(benzyloxy)benzylidene analogue) and rhodanine (1.1 eq., used for the synthesis of Compounds 128 and 137), 2,4-thiazolidinedione (1.1 eq., used for the synthesis of Compounds 125 and 134), 2-thiohydantoin (1.1 eq., used for the synthesis of Compounds 130 and 138), or pseudothiohydantoin (1.1 eq., used for the synthesis of Compounds 131 and 139) was refluxed. After cooling, water was added thereto. The produced precipitate was filtered and washed with water and a co-solvent of hexane and ethyl acetate (1:1) to obtain a solid target compound.
  • 30
  • [ 503-87-7 ]
  • [ 321726-55-0 ]
  • [ 708263-37-0 ]
YieldReaction ConditionsOperation in experiment
80% With sodium acetate; acetic acid for 2h; Heating;
  • 31
  • [ 503-87-7 ]
  • [ 2169-69-9 ]
  • [ 95474-44-5 ]
YieldReaction ConditionsOperation in experiment
72% With piperidine In ethanol at 80 - 90℃;
  • 32
  • [ 503-87-7 ]
  • [ 2017-87-0 ]
  • [ 95474-45-6 ]
YieldReaction ConditionsOperation in experiment
With piperidine In ethanol at 80 - 90℃;
  • 33
  • [ 584-26-9 ]
  • [ 503-87-7 ]
YieldReaction ConditionsOperation in experiment
98% With sodium methylate In methanol at 0 - 20℃; Inert atmosphere; Molecular sieve;
88.5% With hydrogenchloride In water for 1h; Reflux; 2 Preparation of thiohydantoin (5b) 5a (1 g, 6.3 mmol) was added to 20 mL of concentrated hydrochloric acid. It was stirred at reflux for 1h. It was concentrated and cooled to precipitate a solid. It was filtered, washed, and recrystallized with ethanol. It was dried to give a pale yellow solid 0.65 g, yield 88.5%.
74% With hydrogenchloride at 150℃; for 0.0833333h; microwave irradiation;
69% With hydrogenchloride In water at 100℃; for 1h; 1.2 synthesis of thiohydantoin 1-Acetyl-2-thiohydantoin (1.58 g, 10 mmol) was weighed into a 50 mL single-necked flask, and 16 mL of 10%(m / m) aqueous hydrochloric acid, magnetic stirring, heated to reflux, the reaction 1h. The reaction solution was treated with activated carbon and suction filtered. The filtrate was cooled to room temperature, sodium bicarbonate was added, the pH was adjusted to neutral, a solid precipitated, suction filtered, washed with water, dried, Recrystallized from ethanol to give a gray solid 800mg, 69% yield,
65% With hydrogenchloride; water for 1h; Reflux; 2- Thiohydantoin (12b) l -Acetyl-2-thiohydantoin (0.148 g, 0.94 mmol) was heated with hydrochloric acid (5 mL, 3 M) under reflux for 1 h. After allowing to cool, the resulting clear yellow solution was extracted with ethyl acetate (4 x 5 mL). The combined organic extracts were dried over MgS04 to give 2-thiohydantoin as pale orange microprisms (71 mg, 65%), m.p. 226 °C (decomp).
55% With hydrogenchloride at 110℃; for 1h; 2.2.3. General Procedure for Deacetylation. Synthesis of Thiohydantoins 1a-b General procedure: Corresponding acyl-thiohydantoin (1 mmol) was added at 10 mL of hydrochloric acid solution (5M) and was placed in a round bottomed flask and heated at 110C for 60 minutes under magnetic stirring. The mixture was allowed to cool down at room temperature and then, the resulting clear yellow solution was extracted with 3 x 10 mL of ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , concentrated, and dried under vacuum to afford the thiohydantoins of interesting.

  • 34
  • [ 577-47-9 ]
  • [ 503-87-7 ]
  • [ 65-85-0 ]
YieldReaction ConditionsOperation in experiment
at 25.3℃; Hydrolysis;
  • 35
  • [ 110-89-4 ]
  • [ 503-87-7 ]
  • [ 116313-85-0 ]
  • 4-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2-thioxoimidazolidin-5-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
5.0 g (71%) In acetic acid; EXAMPLE 1 4-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2 -thioxoimidazolidin-5-one A solution containing 2.9 g (0.025 mol) of 2-thiohydantoin, 4.6 g (0.025 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.25 ml of piperidine in 50 ml of acetic acid was heated for 7-8 h at 100 C. The crystalls were filtered and washed with 2-propanol. Yield 5.0 g (71%), mp>350 C. (decom.).
  • 36
  • [ 503-87-7 ]
  • [ 83393-46-8 ]
  • C12H10N4OS [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With boron trifluoride diethyl etherate; triethylamine; In tetrahydrofuran; at 20℃; for 120h; To a solution of 3-acetyl, 7-azaindole (320 mg, 2 mmol), thiohydantoin (465 mg, 3 mmol) and BF3.Et2O (1.52 mL, 12 mmol) in dry THF (14 mL), under argon, triethylamine (0.84 mL, 6 mmol) was added dropwise and the reaction mixture stirred for 5 days at RT. The mixture was poured in ice and pH made slightly basic by addition of sodium bicarbonate. The solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated to give an oil that crystallized from ethyl acetate (260 mg, 1 mmol, 50% yield).
  • 37
  • [ 503-87-7 ]
  • [ 937012-12-9 ]
  • [ 937012-13-0 ]
YieldReaction ConditionsOperation in experiment
80% With sodium acetate In acetic acid at 125℃; for 3h; 139 A mixture of N-(3-formyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetamide (0.2 g, 1 mmol), thiohydantoin (0.116 g, 1 mmol), sodium acetate (0.246 g, 3 mmol), glacial AcOH (5 mL) was warmed at 125° C. for 3 h. After cooling, water (5 mL) was added, the precipitate was filtered, washed with water and dried. The so obtained N-{3-[(5-oxo-2-thioxoimidazolidin-4-ylidene)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}acetamide(0.24 g, 0.79 mmol, 80% yield),
  • 38
  • [ 503-87-7 ]
  • [ 937012-15-2 ]
  • [ 937012-16-3 ]
YieldReaction ConditionsOperation in experiment
69% With sodium acetate; acetic acid at 120℃; for 3h;
69% With sodium acetate In acetic acid at 120℃; for 3h; 141 A mixture of 5-nitro-1H-pyrrolo[2,3-b]pyridine-3-arbaldehyde (0.57 g, 3 mmol), thiohydantoin (0.35 g, 3 mmol), sodium acetate (0.74 g, 9 mmol), glacial AcOH (15 mL) was warmed at 120° C. for 3 h. After cooling, water (20 mL) was added, the precipitate was filtered, washed with water and dried. 5-[(5-Nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one was obtained (0.6 g, 2.08 mmol, 69%).
  • 39
  • [ 503-87-7 ]
  • [ 757978-33-9 ]
  • (5Z)-5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With piperidine; In ethanol; for 2h;Reflux; a) (5Z)-5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one can be prepared as in Example 1 but from 655 mg of <strong>[757978-33-9]5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde</strong> in 6 cm3 of ethanol, 340 mg of 2-thioxoimidazolidin-4-one and 0.28 cm3 of piperidine. After refluxing for two hours, 700 mg of (5Z)-5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one is obtained in the form of orange powder with the following characteristics: 1H-NMR spectrum at 400 MHz: 6.82 (s, 1H); 8.37 (d, J=2.0 Hz, 1H); 8.57 (s, 1H); 8.64 (d, J=2.0 Hz, 1H); from 11.6 to 12.3 (m very broad, 2H); 12.6 (m spread out, 1H). Mass spectrum: HPLC-MS-DAD-ELSD: 323(+)=(M+H) (+); 321(-) (M-H)(-) (1 bromine atom Br present).
  • 40
  • [ 503-87-7 ]
  • [ 918515-16-9 ]
  • [ 1019436-06-6 ]
YieldReaction ConditionsOperation in experiment
60% With piperidine; In ethanol; for 2h;Reflux; a) (5Z)-5-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one can be prepared as in Example 1 but from 182 mg of <strong>[918515-16-9]4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde</strong> in 3 cm3 of ethanol, 117 mg of 2-thioxoimidazolidin-4-one and 0.1 cm3 of piperidine. After refluxing for two hours, 250 mg of a mixture containing 60% of (5Z)-5-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one is obtained in the form of orange powder. The characteristics of the isomer (5Z) are as follows: 1H-NMR spectrum at 400 MHz: 7.26 (s: 1H); 7.30 (m: 1H); 8.24 (d, J=5 Hz: 1H); 8.58 (s: 1H); from 11.5 to 13.0 (m very broad: 3H) Mass spectrum: LC-MS-DAD-ELSD: 243(-)=(M-H)(-); 245(+)=(M+H)(+)
  • 41
  • [ 503-87-7 ]
  • [ 858275-30-6 ]
  • [ 1019436-09-9 ]
YieldReaction ConditionsOperation in experiment
65% With piperidine; In ethanol; for 4.0h;Reflux; a) (5Z)-5-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one can be prepared as in Example 1 but from 400 mg of <strong>[858275-30-6]2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde</strong> in 15 cm3 of ethanol, 290 mg of 2-thioxoimidazolidin-4-one and 0.25 cm3 of piperidine. After four hours of reflux, 463 mg of a mixture containing 65% of (5Z)-5-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-thioxoimidazolidin-4-one is obtained in the form of orange powder which will be used as such for the next stage, and has the following characteristics: 1H-NMR spectrum at 400 MHz: 2.45 (s: 3H); 6.70 (s broad: 1H); 7.12 (dd, J=5 and 8 Hz: 1H); 7.88 (m: 1H); 8.20 (dd, J=1.5 and 5 Hz: 1H); 11.55 (s broad: 1H); from 12.0 to 12.2 (m spread out: 2H) Mass spectrum: LC-MS-DAD-ELSD: mixture containing the expected structure 259(+)=(M+H) (+)
  • 42
  • [ 503-87-7 ]
  • [ 1190321-17-5 ]
  • (5Z)-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylidene]-2-thioxoimidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With piperidine In ethanol for 4h; Reflux; Inert atmosphere; 17.a (5Z)-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylidene]-2-thioxoimidazolidin-4-one a) (5Z)-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylidene]-2-thioxoimidazolidin-4-one can be prepared as in Example 1 but from 500 mg of raw 5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde titrated at 65%, 362 mg of 2-thioxoimidazolidin-4-one and 106 mg of piperidine in 15 cm3 of ethanol. Heat the mixture under ethanol reflux for four hours under argon, then cool to 0° C. on an ice bath for ten minutes. Filter the suspension and concentrate the filtrate at reduced pressure to obtain 685 mg of (5Z)-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylidene]-2-thioxoimidazolidin-4-one in the form of a yellow powder with the following characteristics: LC-MS: retention time: 2.83 min, 259(+)=(M+H)(+). 1H-NMR spectrum at 400 Hz.: 2.42 (s: 3H); 6.73 (sb: 1H); 8.10 (d, J=2 Hz: 1H); 8.15 (d, J=2 Hz: 1H); 8.49 (s: 1H); 11.5-12.1 (massive: 2H); 12.26 (se, 1H).
  • 43
  • [ 503-87-7 ]
  • [ 1135283-53-2 ]
  • (5Z)-2-thioxo-5-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methylidene}imidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With piperidine In ethanol for 2.3h; Reflux; 18.a (5Z)-2-thioxo-5-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methylidene}imidazolidin-4-one a) (5Z)-2-thioxo-5-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methylidene}imidazolidin-4-one can be prepared as in Example 1, but from 174 mg of 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde in 6 cm3 of ethanol, 94 mg of 2-thioxoimidazolidin-4-one and 0.03 cm3 of piperidine. After refluxing for two hours and thirty minutes, 148 mg of a mixture containing 80% of (5Z)-2-thioxo-5-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methylidene}imidazolidin-4-one is obtained in the form of orange powder, for which the characteristics of the main compound are as follows: LC-MS: retention time 3.28 min; 313(+)=(M+H)(+). 1H-NMR spectrum at 400 MHz: 6.98 (s, 1H); 8.52 (d, J=2 Hz, 1H); 8.66 (d, J=2 Hz, 1H); 9.07 (s, 1H); 12.00 (s broad, 1H).
  • 44
  • [ 503-87-7 ]
  • [ 83393-46-8 ]
  • [ 937012-22-1 ]
  • 45
  • 4-(5-(3-formyl-1H-indol-1-yl)pentyloxy)benzonitrile [ No CAS ]
  • [ 503-87-7 ]
  • [ 1190367-69-1 ]
YieldReaction ConditionsOperation in experiment
82% With ethanolamine In ethanol at 60℃;
  • 46
  • [ 503-87-7 ]
  • [ 1190367-86-2 ]
  • [ 1190367-72-6 ]
YieldReaction ConditionsOperation in experiment
78% With ethanolamine In ethanol at 60℃;
  • 47
  • [ 503-87-7 ]
  • [ 1190367-90-8 ]
  • [ 1190367-83-9 ]
YieldReaction ConditionsOperation in experiment
79% With ethanolamine In ethanol at 60℃;
YieldReaction ConditionsOperation in experiment
With sodium acetate; acetic acid;Heating / reflux;Reactivity (does not react); EXAMPLE 4: The invention provides pharmaceutical compositions comprising dibromo- hymenialdesine (dBHD),1 and dBHD analogs, e.g., as described herein, and methods for making and using them. The invention also provides methods for making the compositions and pharmaceutical compositions of this invention, e.g., comprising protocols as illustrated inFigure 9, also illustrated as this scheme: <n="37"/>20002071040As shown in this scheme (above), after prep. HPLC purification, approximately 5 mg of 7 was obtained. Comparing condition 4 and ondition 5, we found condition 4 was better, i.e., gave a higher yield: 15 mg of compound 7 was the yield in total from the two reactions.The preparation following condition 6 and 7 was scaled up in parallel, and it was found that condition 6 was better; i.e., gave a higher yield: .8 g of 7 was obtained from the two batches. A second scaled up preparation of 7 gave a yield of 2.9 g, which was obtained from 5 g of 5.
  • 49
  • [ 503-87-7 ]
  • [ 72908-87-3 ]
  • C11H10N4O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With ammonium acetate; In N,N-dimethyl-formamide; at 70 - 130℃;Product distribution / selectivity; EXAMPLE 4: The invention provides pharmaceutical compositions comprising dibromo- hymenialdesine (dBHD),1 and dBHD analogs, e.g., as described herein, and methods for making and using them. The invention also provides methods for making the compositions and pharmaceutical compositions of this invention, e.g., comprising protocols as illustrated inFigure 9, also illustrated as this scheme: <n="37"/>20002071040As shown in this scheme (above), after prep. HPLC purification, approximately 5 mg of 7 was obtained. Comparing condition 4 and ondition 5, we found condition 4 was better, i.e., gave a higher yield: 15 mg of compound 7 was the yield in total from the two reactions.The preparation following condition 6 and 7 was scaled up in parallel, and it was found that condition 6 was better; i.e., gave a higher yield: .8 g of 7 was obtained from the two batches. A second scaled up preparation of 7 gave a yield of 2.9 g, which was obtained from 5 g of 5.
  • 50
  • [ 131543-46-9 ]
  • [ 17356-08-0 ]
  • [ 503-87-7 ]
YieldReaction ConditionsOperation in experiment
61% Stage #1: Glyoxal With phosphorus pentoxide; water at 20℃; for 0.0833333h; Stage #2: thiourea at 20℃; for 0.166667h; Synthesis of hydantoins and thiohydantoins using P4O10 general procedure General procedure: To a stirred solution of aldehyde (0.6 mmol) in H2O (10 mL), P4O10 (170 mg, 0.6 mmol) was added. After 5 min urea (or thiourea) (0.6 mmol) was added and the mixture was stirred at room temperature for 10 min. The solvent was partially removed by lyophilization ‘in vacuo’ and the product was isolated from the crude residue through several liquid/liquid extractions with ethyl acetate. After removal of the organic solvent, the product was purified by flash chromatography or by simple crystallization. The yields were in the range 60-70%.
  • 51
  • [ 503-87-7 ]
  • [ 1313397-92-0 ]
  • [ 1313397-07-7 ]
YieldReaction ConditionsOperation in experiment
78% With 3-amino propanoic acid In acetic acid for 15h; Reflux; 7 5-(l -Oxo-l,3- dihydroisobenzofuran-5-yl)thiophene-2-carbaldehyde (50 mg, 0.21 mmol), 2- thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound was isolated as a orange-brown solid after drying under vacuum (52 mg, 78%), mp (AcOH) >300°C. NMR [400 MHz, (CD3)2SO] δ 12.40 (br s, 1 H), 12.02 (br s, 1 H), 7.99 (br s, 1 H), 7.93 (dd, J = 8.1 , 1.4 Hz, 1 H), 7.83- 7.91 (m, 3 H), 6.65 (s, 1 H), 5.45 (s, 2 H). Anal. (Ci6H10N2O3S2) H, N. C; +0.5.
  • 52
  • [ 503-87-7 ]
  • [ 392704-83-5 ]
  • [ 697785-99-2 ]
YieldReaction ConditionsOperation in experiment
80% In ethanol at 20℃; for 72h; 4 5-(l-Oxo-l ,3- dihydroisobenzofuran-5-yl)furan-2-carbaldehyde (50 mg, 0.22 mmol) was suspended in EtOH (10 mL), to which was added 2-thiohydantoin (26 mg, 0.23 mmol) and piperidine (1 drop). This mixture was stined at RT for 72 h. The title compound was collected by filtration, directly from the reaction mixture, as a brown solid (57 mg, 80%), mp (EtOH) >300°C. NMR [400 MHz, (CD3)2SO] δ 12.20 (br s, 1 H), 12.02 (br s, 1 H), 8.18 (br s, 1 H), 8.15 (d, J = 8.2 Hz, 1 H), 7.92 (d, J= 8.1 Hz, 1 H), 7.44 (d, J = 3.8 Hz, 1 H), 7.38 (d, J = 3.8 Hz, 1 H), 6.44 (s, 1 H), 5.49 (s, 2 H). LRMS (APCI+) calcd for C16Hi ,N204S 327 (MH+), found 327. Anal. (C|6H,oN204S.0.75H20) C, H, N.
80% With piperidine In ethanol at 20℃; for 72h; 4.1.3. General procedure C: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)furan-2-yl)methylene)-2-thioxoimidazolidin-4-one (2) Compound 42 (50 mg, 0.22 mmol) was suspended in EtOH (10 mL), to which was added 2-thiohydantoin (26 mg, 0.23 mmol) and piperidine (1 drop). This mixture was stirred at rt for 72 h. The title compound 2 was collected by filtration, directly from the reaction mixture, as a brown solid (57 mg, 80%); mp (EtOH) >300 °C. 1H NMR [(CD3)2SO] δ 12.20 (br s, 1 H), 12.02 (br s, 1H), 8.18 (br s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 3.8 Hz, 1H), 7.38 (d, J = 3.8 Hz, 1H), 6.44 (s, 1H), 5.49 (s, 2H). LRMS (APCI+) calcd for C16H11N2O4S 327 (MH+), found 327. Anal. (C16H10N2O4S·0.75H2O) C, H, N.
  • 53
  • [ 503-87-7 ]
  • [ 5381-20-4 ]
  • [ 1312024-69-3 ]
  • 54
  • [ 503-87-7 ]
  • [ 4687-25-6 ]
  • [ 1312024-70-6 ]
  • 55
  • [ 503-87-7 ]
  • [ 24424-99-5 ]
  • [ 1253964-00-9 ]
YieldReaction ConditionsOperation in experiment
75% With dmap In acetonitrile at 20℃; for 48h; Inert atmosphere; 1 -tert-Butyloxycarbonyl-2-thiohvdantoin ( 12c) A mixture of 2-thiohydantoin (0.499 g, 4.30 mmol) di-/tvV-butyl dicarbonate ( 1.20 g, 5.48 mmol) and 4-dimethylamonopyridine (53 mg, 0.43 mmol) and acetonitrile (5 mL) was for was vigorously stirred at 20 °C under nitrogen for 48 h, then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml .) and water (100 mL), the organic layer dried over MgS04, filtered and the filtrate was evaporated under reduced pressure. The residue was dried under vacuum overnight to give 1 -i Y-butyloxycarbonyl- 2-thiohydantoin as a pink solid (0.70 g. 75%), m.p. 122 °C
3.53 g With dmap In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
  • 56
  • [ 503-87-7 ]
  • [ 67482-48-8 ]
  • (5Z)-5-((3-chlorothiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
  • 57
  • [ 503-87-7 ]
  • [ 555-16-8 ]
  • [ 37428-90-3 ]
YieldReaction ConditionsOperation in experiment
67% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
45% With ammonium acetate; acetic acid for 20h; Reflux; General procedure for the preparation of 5-benzylidene hydantoins 4a-4e and 5-benzylidene thiohydantoins 5a-5e. General procedure: To a stirred suspension of the corresponding benzaldehydes (3.33 mmol) and imidazolidine-2,4-dione (500 mg, 5 mmol) or 2-thioxoimidazolidin-4-one (580 mg, 5 mmol) in glacial acetic acid (5 mL) ammonium acetate (507 mg, 6.6 mmol) was added and the reaction mixture was heated under reflux for 20 h. The solution was cooled, and the precipitate was filtered off, washed with water and ethanol, and dried.
Reflux;
  • 58
  • [ 503-87-7 ]
  • [ 139-85-5 ]
  • [ 1112978-10-5 ]
YieldReaction ConditionsOperation in experiment
92% With ammonium acetate; acetic acid at 160℃; for 0.0833333h; Microwave irradiation;
76.6% With sodium acetate; acetic acid for 5h; Reflux; 9-2 Synthesis of (Z)-5-(3,4-dihydroxybenzylidene)-2- thioxoimidazolidin-4-one (Compound 99) [0252] Synthesis of Compounds 98 to 110, which are (Z)5-(substituted benzylidene)-2-thioxoimidazolidin-4-one analogs, was performed as follows. In detail, in an acetic acid (4 mE/sodium acetate 1 g) solvent, a mixture includingsubstitutedbenzaldhehyde (1.53 to 2.46 mmol), 2-thiohydan- tom (1.1 eq.), and sodium acetate (3 eq.) was refluxed for 424 hours. After cooling, water was added thereto, andproduced precipitate was filtered and in consideration of characteristics of the residual starting materials, the resultant precipitate was washed with water and ethyl acetate and/or methylene chloride to obtain solid Compounds 98 to 110 (yield:15.1 to 85.2%). [0254] Greenish yellow solid; a reaction time of 5 hours; ayield of 76.6%; a melting point of >300° C.; ‘H NMR (500MHz, DMSO-d5) ö 12.20 (s, 1H), 11.93 (s, 1H), 9.63 (s, 1H),9.04 (s, 1H), 7.09 (dd, 1H, J=2.0, 8.0 Hz), 7.07 (d, 1H, J=1.5Hz), 6.75 (d, 1H, J=8.0 Hz), 6.32 (s, 1H); ‘3C NMR (100MHz, DMSO-d5) ö 178.9, 166.5, 148.3, 146.1, 126.0, 124.4,123.6, 118.5, 116.5, 114.1.
76.6% With sodium acetate In acetic acid for 5h; Inert atmosphere; Reflux;
76.6% With sodium acetate; acetic acid for 5h; Reflux; 9-2 Synthesis of (Z)-5-(3,4-dihydroxybenzylidene)-2-thioxoimidazolidin-4-one General procedure: Synthesis of Compounds 98 to 110, which are (Z)-5-(substituted benzylidene)-2-thioxoimidazolidin-4-one analogs, was performed as follows. In detail, in an acetic acid (4 mL/sodium acetate 1 g) solvent, a mixture including a substituted benzaldhehyde (1.53 to 2.46 mmol), 2-thiohydantoin (1.1 eq.), and sodium acetate (3 eq.) was refluxed for 4 to 24 hours. After cooling, water was added thereto, and the produced precipitate was filtered and in consideration of characteristics of the residual starting materials, the resultant precipitate was washed with water and ethyl acetate and/or methylene chloride to obtain solid Compounds 98 to 110 (yield: 15.1 to 85.2%).

  • 59
  • [ 503-87-7 ]
  • [ 1359020-77-1 ]
  • [ 1359020-83-9 ]
YieldReaction ConditionsOperation in experiment
95% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 60
  • [ 503-87-7 ]
  • [ 1313397-96-4 ]
  • [ 1313397-11-3 ]
YieldReaction ConditionsOperation in experiment
89% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 61
  • [ 503-87-7 ]
  • [ 1313397-98-6 ]
  • [ 1313397-12-4 ]
YieldReaction ConditionsOperation in experiment
89% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 62
  • [ 503-87-7 ]
  • [ 1313398-69-4 ]
  • [ 1313397-62-4 ]
YieldReaction ConditionsOperation in experiment
88% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 63
  • [ 503-87-7 ]
  • [ 1313398-76-3 ]
  • [ 1313397-63-5 ]
YieldReaction ConditionsOperation in experiment
86% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 64
  • [ 503-87-7 ]
  • [ 1313398-86-5 ]
  • [ 1313397-64-6 ]
YieldReaction ConditionsOperation in experiment
86% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 65
  • [ 503-87-7 ]
  • [ 1313398-03-6 ]
  • [ 1313397-14-6 ]
YieldReaction ConditionsOperation in experiment
97% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 66
  • [ 503-87-7 ]
  • [ 1313399-55-1 ]
  • [ 1313397-84-0 ]
YieldReaction ConditionsOperation in experiment
90% With acetic acid; 3-amino propanoic acid for 15h; Reflux; 4.1.6. General procedure D: (E,Z)-5-((5-(1-oxo-1,3-dihydroisobenzofuran-5-yl)thiophen-2-yl)methylene)-2-thioxoimidazolidin-4-one (94) General procedure: Compound 43 (50 mg, 0.21 mmol), 2-thiohydantoin (26 mg, 0.23 mmol) and β-alanine (20 mg, 0.23 mmol) were suspended in AcOH (5 mL) and the mixture heated at reflux for 15 h. Upon cooling, a yellow-brown solid crystallized out of solution and was collected by filtration. This material did not require further purification. The title compound 94 was isolated as an orange-brown solid after drying under vacuum (52 mg, 78%).
  • 67
  • [ 503-87-7 ]
  • [ 17826-04-9 ]
  • [ 1393484-13-3 ]
YieldReaction ConditionsOperation in experiment
With ethanolamine; In ethanol; for 1h;Reflux; General procedure: equimolar amounts of the appropriate indole aldehydes 1a-e and thiohydantoin 4 were dissolved inabs. EtOH and 1 mL of ETA was added. The mixture was heated at reflux for 1 h. After cooling the precipitate was filtered off and dried to yield compounds 5a-e, which were used without further purification.
With ethanolamine; In ethanol; for 1h;Reflux; General procedure: Equimolar amounts of the appropriate indole aldehydes 1a-e and thiohydantoin 4 were dissolved in abs. EtOH and 1 mL of ethanolamine was added. The mixture was heated at reflux for 1 h. After cooling the precipitate was filtered off and dried to yield compounds 5a-e, which were used without further purification.
  • 68
  • [ 503-87-7 ]
  • [ 115666-21-2 ]
  • [ 1393484-14-4 ]
YieldReaction ConditionsOperation in experiment
With ethanolamine In ethanol for 1h; Reflux; General procedure for synthesis of 5a-e: General procedure: equimolar amounts of the appropriate indole aldehydes 1a-e and thiohydantoin 4 were dissolved inabs. EtOH and 1 mL of ETA was added. The mixture was heated at reflux for 1 h. After cooling the precipitate was filtered off and dried to yield compounds 5a-e, which were used without further purification.
With ethanolamine In ethanol for 1h; Reflux; General procedure for the synthesis of aplysinopsinanalogs 5a-e (GP2) General procedure: Equimolar amounts of the appropriate indole aldehydes 1a-e and thiohydantoin 4 were dissolved in abs. EtOH and 1 mL of ethanolamine was added. The mixture was heated at reflux for 1 h. After cooling the precipitate was filtered off and dried to yield compounds 5a-e, which were used without further purification.
  • 69
  • [ 503-87-7 ]
  • copper(l) chloride [ No CAS ]
  • [ 77309-56-9 ]
YieldReaction ConditionsOperation in experiment
57% Stage #1: copper(l) chloride In acetonitrile at 50℃; for 2h; Stage #2: 2-thiohydantoin at 50℃; for 0.5h; 1 2.3 General procedure for the synthesis of complexes 1-4 General procedure: A suspension of 0.5 mmol of copper(I) halide (49.5 mg for CuCl, 71.7 mg for CuBr) in 50 cm3 of dry acetonitrile was stirred for 2 h at 50 °C. The resulting clear solution was filtered of and then treated with a solution of the appropriate hydantoine (1 mmol) dissolved in a small amount (∼20 cm3) of ethanol or methanol and the new reaction mixture was stirred for additional 30 min at 50 °C. Slow evaporation of the clear solution at ambient afforded a microcrystalline solid, which was filtered off and dried in vacuo.
  • 70
  • [ 503-87-7 ]
  • [ 603-35-0 ]
  • copper(l) chloride [ No CAS ]
  • [ 1412895-90-9 ]
YieldReaction ConditionsOperation in experiment
61% In acetonitrile at 20℃; 1 2.4 General procedure for the synthesis of complexes 5-8 General procedure: A suspension of copper(I) halide (0.5 mmol) and triphenylphosphane (262 mg, 1 mmol) in 50 cm3 acetonitrile was stirred until a white precipitation was formed. A solution of the appropriate thiohydantoin (0.5 mmol) in methanol was then added and the mixture was stirred to clearness. The resulting solution was filtered of and kept at room temperature, whereupon crystals of the respective product were obtained after few days, which were filtered of and dried in vacuo.
  • 71
  • [ 503-87-7 ]
  • [ 7787-70-4 ]
  • [ 77309-57-0 ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: copper(I) bromide In acetonitrile at 50℃; for 2h; Stage #2: 2-thiohydantoin at 50℃; for 0.5h; 1 2.3 General procedure for the synthesis of complexes 1-4 General procedure: A suspension of 0.5 mmol of copper(I) halide (49.5 mg for CuCl, 71.7 mg for CuBr) in 50 cm3 of dry acetonitrile was stirred for 2 h at 50 °C. The resulting clear solution was filtered of and then treated with a solution of the appropriate hydantoine (1 mmol) dissolved in a small amount (∼20 cm3) of ethanol or methanol and the new reaction mixture was stirred for additional 30 min at 50 °C. Slow evaporation of the clear solution at ambient afforded a microcrystalline solid, which was filtered off and dried in vacuo.
  • 72
  • [ 503-87-7 ]
  • [ 603-35-0 ]
  • [ 7787-70-4 ]
  • [ 1412895-92-1 ]
YieldReaction ConditionsOperation in experiment
56% In acetonitrile at 20℃; 1 2.4 General procedure for the synthesis of complexes 5-8 General procedure: A suspension of copper(I) halide (0.5 mmol) and triphenylphosphane (262 mg, 1 mmol) in 50 cm3 acetonitrile was stirred until a white precipitation was formed. A solution of the appropriate thiohydantoin (0.5 mmol) in methanol was then added and the mixture was stirred to clearness. The resulting solution was filtered of and kept at room temperature, whereupon crystals of the respective product were obtained after few days, which were filtered of and dried in vacuo.
  • 73
  • [ 503-87-7 ]
  • [ 87-48-9 ]
  • [ 109-77-3 ]
  • C14H8BrN5O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With Co3O4 supported hyper cross linked copolymer prepared from N-methylenebisacrylamide and (1-(2-methacryloyloxy)ethyl)-3-vinylimidazolium bromide monomers In water for 0.166667h; Sonication; regioselective reaction; 2.5. General preparation of 3,3'-spirooxindoles General procedure: A mixture of isatin (1 mmol), activated methylene (1 mmol),4-hydroxy coumarin or hydantoin/2-thiohydantoin, and proposedcatalyst were sonicated in an ultrasonic bath for appropriate times.The reaction completion was checked by thin layer chromatographytechnique and then the heterogeneous catalyst wasmagnetically separated. As the last step of multicomponent reaction,the separated product was collected and washed with ethylacetate/ hexane mixture (3:7 ratio). All products were characterizedby melting point (m.p.), 1H NMR, 13C NMR, FTIR, andelemental analysis. The spectral data of all compounds areprovided in Supplementary Information.
60% Stage #1: 5-Bromo-1H-indole-2,3-dione; malononitrile With triethylamine In water at 20℃; for 0.166667h; Green chemistry; Stage #2: 2-thiohydantoin In water at 70℃; for 10h; Green chemistry; regioselective reaction;
  • 74
  • [ 503-87-7 ]
  • [ 39755-95-8 ]
  • [ 109-77-3 ]
  • C15H11N5O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With Co3O4 supported hyper cross linked copolymer prepared from N-methylenebisacrylamide and (1-(2-methacryloyloxy)ethyl)-3-vinylimidazolium bromide monomers In water for 0.2h; Sonication; regioselective reaction; 2.5. General preparation of 3,3'-spirooxindoles General procedure: A mixture of isatin (1 mmol), activated methylene (1 mmol),4-hydroxy coumarin or hydantoin/2-thiohydantoin, and proposedcatalyst were sonicated in an ultrasonic bath for appropriate times.The reaction completion was checked by thin layer chromatographytechnique and then the heterogeneous catalyst wasmagnetically separated. As the last step of multicomponent reaction,the separated product was collected and washed with ethylacetate/ hexane mixture (3:7 ratio). All products were characterizedby melting point (m.p.), 1H NMR, 13C NMR, FTIR, andelemental analysis. The spectral data of all compounds areprovided in Supplementary Information.
65% Stage #1: 5-methoxyisatine; malononitrile With triethylamine In water at 20℃; for 0.166667h; Green chemistry; Stage #2: 2-thiohydantoin In water at 70℃; for 9h; Green chemistry; regioselective reaction;
  • 75
  • [ 503-87-7 ]
  • [ 443-69-6 ]
  • [ 109-77-3 ]
  • C14H8FN5O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With Co3O4 supported hyper cross linked copolymer prepared from N-methylenebisacrylamide and (1-(2-methacryloyloxy)ethyl)-3-vinylimidazolium bromide monomers In water for 0.166667h; Sonication; regioselective reaction; 2.5. General preparation of 3,3'-spirooxindoles General procedure: A mixture of isatin (1 mmol), activated methylene (1 mmol),4-hydroxy coumarin or hydantoin/2-thiohydantoin, and proposedcatalyst were sonicated in an ultrasonic bath for appropriate times.The reaction completion was checked by thin layer chromatographytechnique and then the heterogeneous catalyst wasmagnetically separated. As the last step of multicomponent reaction,the separated product was collected and washed with ethylacetate/ hexane mixture (3:7 ratio). All products were characterizedby melting point (m.p.), 1H NMR, 13C NMR, FTIR, andelemental analysis. The spectral data of all compounds areprovided in Supplementary Information.
62% Stage #1: 5-fluoro-1H-indole-2,3-dione; malononitrile With triethylamine In water at 20℃; for 0.166667h; Green chemistry; Stage #2: 2-thiohydantoin In water at 70℃; for 10h; Green chemistry; regioselective reaction;
  • 76
  • [ 503-87-7 ]
  • [ 91-56-5 ]
  • [ 109-77-3 ]
  • C14H9N5O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With Co3O4 supported hyper cross linked copolymer prepared from N-methylenebisacrylamide and (1-(2-methacryloyloxy)ethyl)-3-vinylimidazolium bromide monomers In water for 0.15h; Sonication; regioselective reaction; 2.5. General preparation of 3,3'-spirooxindoles General procedure: A mixture of isatin (1 mmol), activated methylene (1 mmol),4-hydroxy coumarin or hydantoin/2-thiohydantoin, and proposedcatalyst were sonicated in an ultrasonic bath for appropriate times.The reaction completion was checked by thin layer chromatographytechnique and then the heterogeneous catalyst wasmagnetically separated. As the last step of multicomponent reaction,the separated product was collected and washed with ethylacetate/ hexane mixture (3:7 ratio). All products were characterizedby melting point (m.p.), 1H NMR, 13C NMR, FTIR, andelemental analysis. The spectral data of all compounds areprovided in Supplementary Information.
76% Stage #1: indole-2,3-dione; malononitrile With triethylamine In water at 20℃; for 0.166667h; Green chemistry; Stage #2: 2-thiohydantoin In water at 70℃; for 9h; Green chemistry; regioselective reaction;
  • 77
  • [ 98-01-1 ]
  • [ 503-87-7 ]
  • 5-(2-furylmethylidene)-2-thiohydantoin [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With sodium carbonate; rac-Ala-OH In water Reflux; 1.A Preparation example 1. Obtaining of 5-arylidene thiohydantoin. General procedure: In the first method of the preparation of 5-arylidene hydantoin (Method A), in a flat- bottomed flask were placed tiohydantoine (25-50 mmol), alanine (25-50 mmol), sodium carbonate 20 (12.5-25 mmol), distilled water (25-100 ml) and the appropriate aldehyde (25- 50 mmol). The mixture was stirred using a magnetic stirrer with thermoregulator at boiling temperature in a reflux cooler for 1-3 hours. The resulting mixture was poured into a beaker and acidified with 18% HCI, checking the pH with indicator paper, the precipitate was collected on a filter and rinsed with distilled water until a neutral reaction was achieved, and then dried. If necessary, it was purified by crystallization or by conversion into sodium salt in a solution of water and ethanol and precipitated with hydrochloric acid. 5-(2-furylmethylidene)-2-thiohydantoin The compound was obtained with method A. Reaction yield W: 88%, tt: 258-262 °C, Rf (I): 0.80. C8H6N202S , (M: 194.21) XH-NMR (DMSO-de) 0 [ppm]: 6.38 (s, 1H, CH=C), 6.65 (q, J=1.80 Hz, 1H, Fur-4-H), 7.12 (dd, Jl=3.59 Hz, J2=0.51 Hz, 1H, Fur-3-H), 7.83 (d, J=1.80 Hz, 1H, Fur-5-H), 11.79 (br.s, 1H, Nl-H), 12.32 (br.s, 1H, N3-H).
  • 78
  • [ 503-87-7 ]
  • [ 13750-81-7 ]
  • (4Z)-2-thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-allylimidazol-5(4H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With hydrogenchloride 1 Experimental 2.1 (4Z)-2-Thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-allyl-imidazol-5(4H)-one (3) 1-Methyl-2-imidazolecarbaldehyde (0.155 g, 1.4 mmol) was added to a solution of thiohydantoin 1 (0.22 g, 1.4 mmol) in 3 ml of 2% KOH solution in EtOH, and this mixture was stirred at room temperature for 3 h. The precipitate that formed was filtered off and then suspended in 5 ml of water. Concentrated HCl solution was added under stirring to bring the pH to 7. The yellow-orange precipitate was filtered off, washed with diethyl ether and dried in air to obtain compound 3 (0.358 g, 96%). M.p. 125-127 °C. 1H NMR (DMSO-d6), 3.82 (s, 3H, CH3), 4.41 (d, 2H, CH2, J = 5.09 Hz), 5.10 (d, 1H, CH2, J = 18 Hz), 5.16 (d, 1H, CH2, J = 10.5 Hz), 5.86 (ddd., 1H, =CH, J1 = 5.20 Hz, J2 = 10.5 Hz, J3 = 18 Hz), 6.71 (s, 1H, =CH), 7.29 (s, 1H, Im), 7.43 (s, 1H, =CH, Im). IR, ν/cm-1: 3239, 1741, 1720, 1650. UV-Vis, nm (ε, M-1 cm-1): 309 (2585), 389 (8250), 412 (9916). Anal. Calc. for С11Н12N4OS (3): С, 49.61; Н, 5.30; N, 21.04. Found: C, 49.47; Н, 4.62; N 21.06%.
  • 79
  • [ 503-87-7 ]
  • [ 13750-81-7 ]
  • (4Z)-2-thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-(n-propyl)imidazol-5(4H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With hydrogenchloride 2 (4Z)-2-Thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-allyl-imidazol-5(4H)-one (3) 2.2 (4Z)-2-Thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-(n-propyl)-imidazol-5(4H)-one (4) 1-Methyl-2-imidazolecarbaldehyde (0.25 g, 2.5 mmol) was added to a solution of thiohydantoin 2 (0.4 g, 2.5 mmol) in 5 ml of 2% KOH solution in EtOH, and this mixture was stirred at room temperature for 3 h. The precipitate that formed was filtered off and then suspended in 5 ml of water. Concentrated HCl solution was added under stirring to bring the pH to 7. The light-yellow precipitate was filtered off, washed with diethyl ether and dried in air to obtain compound 4 (0.61 g, 89%). M.p. 150-152 °C. 1H NMR (DMSO-d6), 0.86 (t, 3 H, CH3 J = 7.43 Hz); 1.63 (m, 2H, CH2), 3.73 (т, 2H, CH2, J = 7.04 Hz) 3.82 (s, 3H, CH3), 6.55 (s, 1H, =CH), 7.22 (s, 1H, Im), 7.36 (s, 1H, =CH, Im). IR, ν/cm-1: 2940, 1730, 1680. UV-Vis, nm (ε, M-1 cm-1): 311 (1700), 383 (5100), 410 (6200). Anal. Calc. for С11Н14N4OS (4): С, 52.78; Н, 5.64; N, 22.38. Found: C, 52.61; Н, 5.68; N 22.34%.
  • 82
  • [ 503-87-7 ]
  • [ 588715-60-0 ]
  • C17H12Cl2N2O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Reflux;
  • 83
  • [ 503-87-7 ]
  • [ 33696-06-9 ]
  • C17H12N2O3S [ No CAS ]
  • 84
  • [ 503-87-7 ]
  • [ 431998-21-9 ]
  • C17H11ClN2O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Reflux;
Same Skeleton Products
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