For general experimental details see chapter 6.1.
Memorandum
Parts of the results presented in this section were subject of a thesis of the bachelor's degree program Life Science at the University of Konstanz. The thesis was successfully completed by B. Sc. Annika Hantusch.
7.2) Synthesis of precursor aldehydes and acetophenon SM59‐84
3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59
A solution of 4‐methylbenzenethiol SM86 (1 g, 5.4 mmol) and 4‐chloro‐3‐nitrobenzaldehyde (0.58 g, 5.4 mmol), NaHCO3 (0.45 g, 5.4 mmol), 3.33 ml water and 6.66 mL ethanol was heated at reflux for 2 h. After being allowed to cool to room temperature, the precipitate was filtered out, washed with H2O and dried under vacuum. The crude product was re‐crystallized from AcOH to yield yellow crystalline SM59 in 92% (1.29 g (4.7 mmol).
M.p. 142°C. Rf 0.4 (PE–EtOAc, 5:1 ). 1H NMR (400 MHz, DMSO‐d6) δ 9.95 (s, 1H), 8.67 (d, J 1.8, 1H), 7.77 (dd, J 8.5, 1.8, 1H), 7.47‐ 7.43 (m, 2H), 7.31 (d, J 7.9, 2H), 6.98 (d, J 8.5, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 189.26, 148.20, 144.87, 141.52, 136.07, 133.21, 131.90, 131.51, 128.93, 128.04, 126.26, 21.66. CHN analysis: calcd: C 61.52, H 4.06, N 5.12;
found: C 61.47, H 4.09, N 5.24.
General procedure for the synthesis of precursor SM60‐75
To a stirred solution of the corresponding thiophenol (1 eq) in anhydrous DMF (~3 mL per 1 mmol thiol) K2CO3 (2 eq) was added, followed by the corresponding para‐haloginated‐
benzaldehyde or acetophenone (1 eq.). The reaction mixture was then heated to 80°C until
the reaction was completed. The reaction mixture was allowed to cool to room temperature and partitioned between 20 mL ether and 10 mL H2O. The phases were separated and the aqueous layer was washed with ether (3×25 mL). The combined organic layers were washed with 10 mL of H2O and 10 mL brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography using n‐hexane/EtOAc mixtures or by recrystallization from isopropyl alcohol to yield the pure product.
3‐Nitro‐4‐(o‐tolylthio)benzaldehyde SM60
Reaction batch: 2‐Methylbenzenethiol SM87 (1.0 g, 8.1 mmol), 4‐chloro‐3‐
nitrobenzaldehyde (1.49 g, 8.1 mmol). Golden solid in 79% (1.74 g, 6.4 mmol) yield.
M.p. 91°C. Rf = 0.51 (PE–EtOAc, 4:1). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.73 (d, J 1.7 Hz, 1H), 7.79 (dd, J 8.5, 1.8 Hz, 1H), 7.59 (d, J 7.6 Hz, 1H), 7.48 (td, J 7.5, 1.0 Hz, 1H), 7.43 (d, J 7.0 Hz, 1H), 7.34 (td, J 7.5, 0.9 Hz, 1H), 6.84 (d, J 8.5 Hz, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 189.17, 146.81, 144.95, 143.47, 137.23, 133.15, 132.09, 131.83, 131.53, 128.76, 128.22, 128.13, 128.10, 20.63. CHN analysis: calcd: C 61.52, H 4.06, N 5.12; found: C 61.47, H 4.01, N 5.28.
3‐Nitro‐4‐(m‐tolylthio)benzaldehyde SM61
Reaction batch: 3‐Methylbenzenethiol SM88 (373 mg, 3.0 mmol), 4‐chloro‐3‐
nitrobenzaldehyde (557 mg, 3.0 mmol). Yellow solid in 85% (693 mg, 2.5 mmol). M.p. 97°C.
Rf = 0.48 (PE–EtOAc, 4:1). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.70 (d, J 1.7 Hz, 1H), 7.80
(dd, J 8.5, 1.8 Hz, 1H), 7.46 – 7.38 (m, 3H), 7.38 – 7.34 (m, 1H), 7.01 (d, J 8.5 Hz, 1H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 188.89, 147.53, 144.48, 140.45, 136.17, 132.83, 132.72, 131.57, 131.41, 130.13, 129.13, 128.68, 127.65, 21.14. CHN analysis: calcd: C 61.52, H 4.06, N 5.12; found: C 61.58, H 4.02, N 5.15.
1‐(3‐Nitro‐4‐(p‐tolylthio)phenyl)ethanone SM62
Reaction batch: 4‐Methylbenzenethiol SM86 (372 mg, 3.0 mmol), 1‐(4‐chloro‐3‐nitrophenyl) ethanone (598 mg, 3.0 mmol). Yellow solid in 70% (598 mg, 2.1 mmol). M.p. 106°C. Rf 0.44 (PE–EtOAc, 2:1). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J 1.9 Hz, 1H), 7.87 (dd, J 8.6, 2.0 Hz, 1H), 7.49 – 7.44 (m, 2H), 7.32 (d, J 7.9 Hz, 2H), 6.93 (d, J 8.6 Hz, 1H), 2.60 (s, 3H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 195.25, 146.43, 144.45, 141.26, 136.03, 133.75, 131.95, 131.35, 128.43, 126.41, 126.06, 26.60, 21.58. CHN analysis: calcd: C 62.70, H 4.56, N 4.87; found: C 62.62, H 4.70, N 5.25.
3‐Fluoro‐4‐(p‐tolylthio)benzaldehyde SM63
Reaction batch: 4‐Methylbenzenethiol SM86 (497 mg, 4.0 mmol), 3,4‐difluorobenzaldehyde (568 mg, 4.0 mmol). Light yellow solid in 78% (768 mg, 3.1 mmol) yield. M.p. 52°C. Rf 0.64 (PE–EtOAc, 6:1). 1H NMR (400 MHz, CDCl3) δ 9.87 (d, J 1.8 Hz, 1H), 7.52 (dd, J 9.6, 1.5 Hz, 1H), 7.46 – 7.42 (m, 3H), 7.27 (d, J 6.6 Hz, 2H), 6.90 (t, J 7.6 Hz, 1H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.22 (d, J 2.0 Hz), 158.86 (d, J 247.5 Hz) 140.26, 136.03 (d, J 17.1 Hz), 135.28, 135.21, 130.97, 128.31 (d, J 2.4 Hz), 126.34 (d, J 3.0 Hz), 125.66 (d, J 1.6 Hz), 114.90 (d, J 21.9 Hz), 21.47. 19F NMR (376 MHz, CDCl3) δ ‐111.07. CHN analysis: calcd: C 68.27, H 4.50; found: C 68.33, H 4.68.
5‐Formyl‐2‐(p‐tolylthio)benzonitrile SM64
Reaction batch: 4‐Methylbenzenethiol SM86 (497 mg, 4.0 mmol), 2‐fluoro‐5‐
formylbenzonitrile (597 mg, 3.0 mmol). Light yellow solid in 75% (748 mg, 3.0 mmol) yield.
M.p. 131°C. Rf 0.53 (PE–EtOAc, 4:1). 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.06 (d, J 1.7 Hz, 1H), 7.77 (dd, J 8.4, 1.8 Hz, 1H), 7.48 – 7.45 (m, 2H), 7.31 (d, J 8.0 Hz, 2H), 6.94 (d, J 8.4 Hz, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 189.22, 153.08, 141.25, 135.66, 134.96, 133.28, 132.61, 131.33, 126.87, 124.80, 115.83, 110.42, 21.54. CHN analysis: calcd: C 71.12, H 4.38, N 5.53; found: C 71.08, H 4.59, N 5.58.
4‐((3‐Fluoro‐4‐methylphenyl)thio)‐3‐nitrobenzaldehyde SM65
Reaction batch: 3‐Fluoro‐4‐methylbenzenethiol SM89 (250 mg, 1.76 mmol), 4‐chloro‐3‐nitro‐
benzaldehyde (326 mg, 1.76 mmol). Yellow solid in 83% (424 mg, 1.5 mmol) yield.
M.p. 167°C. Rf 0.64 (PE–EtOAc, 3:1). 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.70 (d, J 1.7 Hz, 1H), 7.82 (dd, J 8.5, 1.8 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.42 – 7.38 (m, 1H), 7.17 (t, J 8.8 Hz, 1H), 6.99 (d, J 8.5 Hz, 1H), 2.34 (d, J 1.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 189.15, 163.03 (d, J 251.3 Hz), 147.65, 144.77, 139.33 (d, J 6.0 Hz), 135.50 (d, J 8.7 Hz), 133.27, 132.02, 128.74, 128.03 (d, J 18.3 Hz), 127.97, 124.53 (d, J 3.7 Hz), 117.51 (d, J 23.2 Hz), 14.73 (d, J 3.4 Hz). 19F NMR (376 MHz, CDCl3) δ ‐112.72. CHN analysis: calcd: C 57.72, H 3.46, N 4.81; found:
C 57.57, H 3.48, N 4.94.
3‐Bromo‐4‐((3‐fluoro‐4‐methylphenyl)thio)benzaldehyde SM66
Reaction batch: 3‐Fluoro‐4‐methylbenzenethiol SM89 (250 mg, 1.76 mmol), 3‐bromo‐4‐
fluorobenzaldehyde (357 mg, 1.76 mmol). White solid in 65% (369 mg, 1.1 mmol) yield.
M.p. 77°C. Rf 0.46 (PE–EtOAc, 10:1). 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 8.00 (d, J 1.6 Hz, 1H), 7.57 (dd, J 8.2, 1.7 Hz, 1H), 7.43 (dd, J 7.1, 1.6 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.13 (t, J 8.8 Hz, 1H), 6.73 (d, J 8.2 Hz, 1H), 2.32 (d, J 1.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 189.82,
162.56 (d, J 250.4 Hz), 149.31, 139.03 (d, J 5.9 Hz), 135.15 (d, J 8.6 Hz), 134.32, 133.62, 128.39, 127.50 (d, J 18.1 Hz), 126.51, 124.66 (d, J 3.9 Hz), 120.30, 117.07 (d, J 23.1 Hz), 14.55 (d, J 3.5 Hz). 19F NMR (376 MHz, CDCl3) δ ‐113.83. CHN analysis: calcd: C 51.71, H 3.10;
found: C 51.50, H 3.25.
3‐Nitro‐4‐((2,3,5,6‐tetrafluoro‐4‐(trifluoromethyl)phenyl)thio)benzaldehyde SM67
Reaction batch: 2,3,5,6‐Tetrafluoro‐4‐(trifluoromethyl)benzenethiol SM90 (750 mg, 3.0 mmol), 4‐chloro‐3‐nitro‐benzaldehyde (557 mg, 3.0 mmol). Yellow solid in 85% (1.01 g, 2.5 mmol) yield. M.p. 136°C. Rf 0.58 (PE–EtOAc, 4:1). 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.80 (d, J 1.7 Hz, 1H), 8.00 (dd, J 8.4, 1.8 Hz, 1H), 7.04 (d, J 8.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 188.64, 149.14 – 146.36 (m), 146.22 – 143.28 (m), 145.84, 140.05, 134.83, 133.21, 128.16, 128.04, 121.96 – 121.79 (m), 119.20 – 119.03 (m), 115.63 – 114.98 (m). 19F NMR (376 MHz, CDCl3) δ ‐56.44 (t, J 22.0 Hz, 3F), ‐127.96 – ‐128.17 (m, 2F), ‐136.59 – ‐136.97 (m, 2F). CHN analysis: calcd: C 42.12, H 1.01, N 3.51; found: C 42.00, H 1.48, N 3.75.
3‐Bromo‐4‐(p‐tolylthio)benzaldehyde SM68
O S
Br
Reaction batch: 4‐Methylbenzenethiol SM86 (500 mg, 4.0 mmol); 3‐bromo‐4‐
fluorobenzaldehyde (818 mg, 4.0 mmol). Light yellow crystals in 83% (1.03 g, 3.3 mmol) yield. M.p. 92°C. Rf 0.70 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.99 (d, J 1.6 Hz, 1H), 7.54 (dd, J 8.3, 1.6 Hz, 1H), 7.49 – 7.44 (m, 2H), 7.30 (d, J 7.9 Hz, 2H), 6.74 (d, J 8.3 Hz, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.02, 149.90, 140.76, 135.87, 134.33, 133.74, 131.19, 128.44, 126.69, 126.48, 120.43, 21.55. CHN analysis: calcd: C 54.74, H 3.61;
found: C 54.72, H. 3.74
4‐(p‐Tolylthio)benzaldehyde SM69
Reaction batch: 4‐Methylbenzenethiol SM86 (500 mg, 4.0 mmol); 4‐fluorobenzaldehyde (496 mg, 4.0 mmol). Light yellow crystals in 89% (814 mg, 3.6 mmol) yield. M.p. 73°C. Rf 0.93 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.73 – 7.68 (m, 2H), 7.46 – 7.42 (m, 2H), 7.28 – 7.23 (m, 2H), 7.22 – 7.18 (m, 2H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 191.33, 148.32, 139.86, 134.99, 133.63, 130.80, 130.23, 127.42, 126.74, 21.46. CHN analysis:
calcd: C 73.65, H 5.30; found: C 73.61, H 5.35.
3‐Chloro‐4‐(p‐tolylthio)benzaldehyde SM70
Reaction batch: 4‐Methylbenzenethiol SM86 (509 mg, 4.1 mmol); 3‐chloro‐4‐
fluorobenzaldehyde (648 mg, 4.1 mmol). White solid in 61% (651 mg, 2.5 mmol) yield.
M.p. 72°C. Rf 0.57 (PE–EtOAc, 5:1). 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 7.82 (d, J 1.7 Hz, 1H), 7.49 (dd, J 8.3, 1.7 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.32 – 7.28 (m, 2H), 6.77 (d, J 8.2 Hz, 1H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.13, 147.91, 140.70, 135.87, 134.21, 131.15, 131.03, 130.20, 127.97, 126.69, 125.93, 21.52. CHN analysis: calcd: C 64.00, H 4.22;
found: C 63.57, H 4.17.
4‐(p‐Tolylthio)‐3‐(trifluoromethyl)benzaldehyde SM71
Reaction batch: 4‐Methylbenzenethiol SM86 (503 mg, 4.0 mmol); 4‐fluoro‐3‐
(trifluoromethyl) benzaldehyde (776 mg, 4.0 mmol). Yellowish solid in 59% (701 mg, 2.4 mmol) yield. M.p. 58°C. Rf 0.47 (PE–EtOAc, 5:1). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.11 (d, J 1.5 Hz, 1H), 7.72 (dd, J 8.3, 1.5 Hz, 1H), 7.49 – 7.42 (m, 2H), 7.29 (d, J 7.9 Hz, 2H),
7.01 (d, J 8.3 Hz, 1H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.11, 148.15, 140.78, 135.82, 132.91, 131.94, 131.18, 128.72, 128.30 (q, J 5.6 Hz), 127.43 (q, J 32.0 Hz), 126.23 (q, J 1.7 Hz), 126.11 (q, J 274.1 Hz), 21.51. 19F NMR (376 MHz, CDCl3) δ ‐62.15. CHN analysis:
calcd: C 60.80, H 3.74; found: C 60.86, H 3.90.
3‐Fluoro‐4‐(o‐tolylthio)benzaldehyde SM77
Reaction batch: 2‐Methylbenzenethiol SM87 (87 mg, 0.7 mmol); 3,4‐difluorobenzaldehyde (99 mg, 0.7 mmol). Colorless oil in 86% (151 mg, 0.6 mmol) yield. Rf 0.56 (PE–EtOAc, 6:1). 1H NMR (400 MHz, CDCl3) δ 9.87 (d, J 1.9 Hz, 1H), 7.55 – 7.54 (m, 1H), 7.54 – 7.51 (m, 1H), 7.43 (dd, J 8.1, 1.6 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.30 – 7.24 (m, 1H), 6.76 – 6.69 (m, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.16 (d, J 2.1 Hz), 159.01 (d, J 247.5 Hz), 142.95, 136.59, 135.15 (d, J 5.8 Hz), 134.92 (d, J 17.3 Hz), 131.45, 130.49, 128.16 (d, J 1.4 Hz), 127.67 (d, J 2.5 Hz), 127.59, 126.47 (d, J 3.0 Hz), 114.88 (d, J 21.7 Hz), 20.69. 19F NMR (376 MHz, CDCl3) δ ‐ 111.10. CHN analysis: calcd: C 68.27, H 4.50; found: C 68.63, H 4.53.
4‐(o‐Tolylthio)‐3‐(trifluoromethyl)benzaldehyde SM73
Reaction batch: 2‐Methylbenzenethiol SM87 (62 mg, 0.5 mmol); 4‐fluoro‐3‐(trifluoromethyl) benzaldehyde (96 mg, 0.5 mmol). Colorless oil in 80% (124 mg, 0.4 mmol) yield. Rf 0.51 (PE–EtOAc, 6:1). 1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 8.02 (d, J 1.6 Hz, 1H), 7.61 (dd, J 8.3, 1.4 Hz, 1H), 7.48 (dd, J 7.6, 1.1 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.31 – 7.27 (m, 1H), 7.24 – 7.17 (m, 1H), 6.76 (d, J 8.3 Hz, 1H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.05, 147.03, 143.21, 137.19, 132.92, 132.09, 131.69, 130.96, 128.75 (q, J 1.6 Hz), 128.35 (q, J 5.6 Hz), 127.99, 127.74, 127.54 (q, J 31.9 Hz), 123.53 (q, J 274.3 Hz), 20.66. 19F NMR (376 MHz, CDCl3) δ ‐62.43. CHN analysis: calcd: C 60.80, H 3.74; found: C 60.95, H 4.07.
2,4‐Bis(p‐tolylthio)benzaldehyde SM74
Reaction batch: 4‐Methylbenzenethiol SM86 (2eq, 1.03 g, 8.3 mmol); 2,4‐
difluorobenzaldehyde (1eq, 595 mg, 4.1 mmol); K2CO3 (4eq, 2.29 g, 16.6 mmol). Yellow solid in 78% (1.12 g, 3.2 mmol) yield. M.p. 74°C. Rf 0.45 (PE–EtOAc, 10:1). 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.64 (d, J 8.2 Hz, 1H), 7.28 – 7.23 (m, 4H), 7.14 – 7.09 (m, 4H), 6.93 (dd, J 8.1, 1.8 Hz, 1H), 6.58 (d, J 1.8 Hz, 1H), 2.39 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.40, 148.19, 144.17, 139.65, 139.18, 135.04, 134.58, 132.75, 130.58, 130.57, 129.87, 127.92, 126.64, 125.24, 122.88, 21.51, 21.49. CHN analysis: calcd: C 71.96, H 5.18;
found: C 72.01, H 5.16.
4‐Bromo‐5‐(p‐tolylthio)thiophene‐2‐carbaldehyde SM75
Reaction batch: 4‐Methylbenzenethiol SM86 (186 mg, 1.5 mmol); 4,5‐dibromothiophene‐2‐
carbaldehyde (405 mg, 1.5 mmol). White solid in 87% (407 mg, 1.3 mmol) yield. M.p. 106°C.
Rf 0.33 (PE–EtOAc, 8:1). 1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 7.60 (s, 1H), 7.50 – 7.45 (m,
2H), 7.28 – 7.24 (m, 2H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 180.75, 149.60, 141.41, 140.69, 139.03, 133.94, 131.02, 127.89, 110.67, 21.47. CHN analysis: calcd: C 46.01, H 2.90;
found: C 46.02, H 3.01.
General procedure for the synthesis of precursor SM76‐83
A mixture of the corresponding thiol (1 eq), KOH (1 eq) and methanol (~3 mL per 1 mmol thiol) was stirred at room temperature until the KOH was dissolved. After evaporation of the
solvent under reduced pressure, the thiolate was dissolved in anhydrous DMF (~3 mL per 1 mmol thiol). The corresponding para‐haloginated‐benzaldehyde (1eq) was added to the stirred mixture in small portions at 0°C. The reaction mixture was allowed to warm to room temperature and was stirred till TLC indicated completion. The reaction mixture was partitioned between ether 20 mL and 10 mL H2O. The aqueous layer was washed with ether (3×25 mL) and the combined organic layers were washed with 10 mL of H2O and 10 mL brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography using n‐hexane/EtOAc mixtures or by recrystallization from isopropyl alcohol to give the pure product.
4‐(Cyclohexylthio)‐3‐nitrobenzaldehyde SM76
Reaction batch: Cyclohexanethiol SM91 (630 mg, 5.4 mmol); 4‐chlor‐3‐nitrobenzaldehyde (1.0 g, 5.4 mmol). Orange solid in 35% (504 mg, 1.9 mmol) yield. M.p. 94°C. Rf 0.67 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.62 (d, J 1.8 Hz, 1H), 8.01 (dd, J 8.4, 1.8 Hz, 1H), 7.60 (d, J 8.5 Hz, 1H), 3.53 – 3.26 (m, 1H), 2.16 – 2.07 (m, 2H), 1.90 – 1.84 (m, 2H), 1.77 – 1.66 (m, 1H), 1.63 – 1.22 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 189.26, 146.31, 145.33, 132.48, 131.75, 128.39, 127.69, 44.30, 32.44, 26.05, 25.65. CHN analysis:
calcd: C 58.85, H 5.70, N 5.28; found: C 58.99, H 5.62, N 5.40.
4‐(Naphthalene‐2‐ylthio)‐3‐nitrobenzaldehyde SM77
Reaction batch: Naphthalene‐2‐thiol SM92 (481 mg, 3.0 mmol), 4‐chlor‐3‐nitrobenzaldehyde (557 mg, 3.0 mmol). Yellow solid in 33% (296 mg, 1.0 mmol) yield. M.p. 124°C. Rf 0.70 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.72 (d, J 1.8 Hz, 1H), 8.20 (s, 1H), 7.98 (d, J 8.5 Hz, 1H), 7.96 – 7.87 (m, 2H), 7.76 (dd, J 8.5, 1.8 Hz, 1H), 7.62 (pd, J 7.0, 1.5 Hz, 2H), 7.53 (dd, J 8.5, 1.8 Hz, 1H), 7.03 (d, J 8.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 189.17,
147.46, 136.52, 134.16, 133.97, 133.30, 131.99, 131.37, 130.57, 129.19, 128.29, 128.22, 128.14, 127.93, 127.45, 126.92. CHN analysis: calcd: C 66.01, H 3.58, N 4.53; found: C 65.85, H 3.74, N 4.73.
4‐(3,5‐Dimethylphenylthio)‐3‐nitrobenzaldehyde SM78
Reaction batch: 3,5‐Dimethylbenzenethiol SM93 (300 mg, 2.2 mmol), 4‐chlor‐3‐
nitrobenzaldehyde (403 mg, 2.2 mmol). Golden yellow needles in 49% (308 mg, 1.1 mmol) yield. M.p. 112°C. Rf 0.69 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.69 (d, J 1.8 Hz, 1H), 7.81 (dd, J 8.5, 1.8 Hz, 1H), 7.21 (s, 2H), 7.17 (s, 1H), 7.03 (d, J 8.5 Hz, 1H), 2.37 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 189.13, 140.39, 133.38, 132.96, 132.55, 131.70, 129.04, 129.00, 128.97, 127.87, 125.20, 21.22. CHN analysis: calcd: C 62.70, H 4.56, N 4.87; found: C 62.69, H 4.70, N 5.15.
4‐(4‐Ethylphenylthio)‐3‐nitrobenzaldehyde SM79
Reaction batch: 4‐Ethylbenzenethiol SM94 (300 mg, 2.2 mmol), 4‐chlor‐3‐nitrobenzaldehyde (403 mg, 2.2 mmol). Orange crystals in 73% (457 mg, 1.6 mmol) yield. M.p. 93°C. Rf 0.80 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.70 (d, J 1.7 Hz, 1H), 7.80 (dd, J 8.5, 1.8 Hz, 1H), 7.52 – 7.48 (m, 2H), 7.38 – 7.34 (m, 2H), 7.01 (d, J 8.5 Hz, 1H), 2.75 (q, J 7.6 Hz, 2H), 1.31 (t, J 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 189.22, 148.18, 147.62, 136.08, 135.39, 133.11, 131.85, 130.25, 128.89, 128.02, 126.34, 28.89, 15.37. CHN analysis: calcd: C 62.70, H 4.56, N 4.87; found: C 62.74, H 4.77, N 4.91.
3‐Nitro‐4‐(4‐(trifluoromethyl)phenylthio)benzaldehyde SM80
Reaction batch: 4‐(Trifluoromethyl)benzenethiol SM95 (600 mg, 3.4 mmol), 4‐chlor‐3‐
nitrobenzaldehyde (631 mg, 3.4 mmol). Yellow solid in 62% (687 mg, 2.1 mmol) yield.
M.p. 114°C. Rf 0.74 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.72 (d, J 1.7 Hz, 1H), 7.86 (dd, J 8.5, 1.8 Hz, 1H), 7.79 (d, J 8.4 Hz, 2H), 7.74 (d, J 8.4 Hz, 2H), 7.00 (d, J 8.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 188.97, 145.53, 145.28, 136.18, 134.85, 133.76, 133.02, 132.69, 132.35, 129.02, 127.83, 127.44 (q, J 3.6 Hz), 125.04. 19F‐NMR (376 MHz, CDCl3) δ ‐ 62.97. CHN analysis: calcd: C 51.38, H 2.46, N 4.28; found: C 51.08, H 2.69, N 4.53.
4‐(Cyclopentylthio)‐3‐nitrobenzaldehyde SM81
Reaction batch: Cyclopentanethiol SM96 (300 mg, 2.9 mmol), 4‐chlor‐3‐nitrobenzaldehyde (546 mg, 2.9 mmol). Orange crystals in 47% (349 mg, 1.4 mmol) yield. M.p. 76°C. Rf 0.79 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.65 (d, J 1.8 Hz, 1H), 8.01 (dd, J 8.4, 1.8 Hz, 1H), 7.65 (d, J 8.5 Hz, 1H), 3.83 – 3.66 (m, 1H), 2.36 – 2.15 (m, 2H), 1.89 – 1.78 (m, 2H), 1.79 – 1.65 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 189.27, 147.26, 145.77, 132.41, 131.85, 128.25, 128.10, 44.03, 33.28, 25.41. CHN analysis: calcd: C 57.35, H 5.21, N 5.57;
found: C 57.18, H 5.23, N 5.74.
3‐Nitro‐4‐((4‐(trifluoromethoxy)phenyl)thio)benzaldehyde SM82
Reaction batch: 4‐(Trifluoromethoxy)benzenethiol SM97 (311 mg, 1.6 mmol), 4‐chlor‐3‐
nitrobenzaldehyde (297 mg, 1.6 mmol). Yellow solid in 77% (430 mg, 1.3 mmol) yield.
M.p. 96°C. Rf 0.56 (PE–EtOAc, 5:1). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.71 (d, J 1.7 Hz, 1H), 7.85 (dd, J 8.5, 1.7 Hz, 1H), 7.71 – 7.59 (m, 2H), 7.38 (d, J 8.5 Hz, 2H), 6.99 (d, J 8.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 189.04, 151.21, 151.20, 146.50, 144.98, 137.81, 133.53, 132.27, 128.74, 128.29, 127.88, 122.70, 120.47 (q, J 259.0 Hz). 19F‐NMR (376 MHz, CDCl3) δ ‐ 57.69. CHN analysis: calcd: C 48.98, H 2.35, N 4.08; found: C 48.56, H 2.72, N 4.18.
4‐(o‐Tolylthio)benzaldehyde SM83
S
O
Reaction batch: 2‐Methylbenzenethiol SM87 (1.61g, 13.0 mmol), 4‐fluorobenzaldehyde (1.61 g, 13.0 mmol). White solid in 97% (2.91 g, 12.6 mmol) yield. M.p. 44°C. Rf 0.70 (PE–EtOAc, 4:1). 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.62 – 7.57 (m, 2H), 7.44 (d, J 7.5 Hz, 1H), 7.32 – 7.23 (m, 2H), 7.20 – 7.13 (m, 1H), 7.04 – 6.99 (m, 2H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 191.30, 147.34, 142.66, 136.42, 133.59, 131.35, 130.32, 130.20, 129.89, 127.42, 126.43, 20.84. CHN analysis: calcd: C 73.65, H 5.30; found: C 73.64, H 5.29.
Synthesis of 3‐nitro‐4‐tosylbenzaldehyde SM84
NaBH4 (416 mg, 11.0 mmol) was added portion wise to a suspension of 33 (3.0 g, 11.0 mmol)
in methanol (25 mL). The reaction mixture was stirred at room temperature for 1 h. H2O (30 mL) was added, and the reaction mixture was extracted with EtOAc (4×30 mL). The organic layers were combined, washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure to give the (3‐nitro‐4‐(p‐tolylthio)phenyl)methanol intermediate as a yellow solid in 98% (2.94 g, 10.8 mmol) yield. M.p. 96°C. Rf 0.42 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J 1.4 Hz, 1H), 7.47 – 7.43 (m, 2H), 7.33 (dd, J 8.4, 1.7 Hz, 1H), 7.28 (d, J 8.0 Hz, 2H), 6.85 (d, J 8.4 Hz, 1H), 4.70 (s, 2H), 2.43 (s, 3H).
Refluxing of (3‐nitro‐4‐(p‐tolylthio)phenyl)methanol (1.5 g, 5.5 mmol) in 20 mL AcOH containing 2.73 mL H2O2 (30%) furnished the (3‐nitro‐4‐tosylphenyl)methanol intermediate
SM85. The solvent was removed in vacuo and the residue was recrystallized from AcOH to yield the light yellowish product SM85 in 61% (1.02 g, 3.3 mmol) yield. M.p. 131°C. Rf 0.21 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 8.31 – 8.27 (m, 1H), 7.88 – 7.81 (m, 2H), 7.75 – 7.69 (m, 2H), 7.34 (d, J 8.1 Hz, 2H), 4.84 (s, 2H), 2.43 (s, 3H).
To a solution of SM85 (1.0 g, 3.3 mmol) in CH2Cl2 (40 mL), DMP (5.29 g, 12.4 mmol) was added portion wise and the mixture was stirred at room temperature over night. After completion of the reaction, the mixture was quenched with 100 mL of a 1.3 M NaOH solution. The organic layer was separated and the aqueous layer was extracted with ether (3×20 mL). The combined organic layers were dried over MgSO4, concentrated and purified by silica gel column chromatography (n‐hexane/EtOAc mixtures) to give the white crystals of SM84 in 53% (0.63 g, 1.7 mmol) yield. M.p. 150°C. Rf 0.50 (PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.51 (d, J 8.0 Hz, 1H), 8.22 (dd, J 8.1, 1.5 Hz, 1H), 8.16 (d, J 1.5 Hz, 1H), 7.94 – 7.82 (m, 2H), 7.38 (d, J 8.1 Hz, 2H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 188.41, 149.10, 145.92, 140.21, 139.46, 136.58, 132.75, 132.67, 130.13, 128.84, 124.85, 21.89. CHN analysis: calcd: C 55.08, H 3.63, N 4.59; found: C 54.68, H 3.91, N 4.83.
7.3) Synthesis of small‐molecules SM1, 4, 10, 12, 16, 17, 21, 23, 27‐58
MemorandumSmall‐molecules SM1, 4, 10, 16, 17, 21, 23, 27, 28 were synthetisized during my privious diploma thesis76 and are listed herin for completeness.
General procedure for the synthesis of small‐molecule SM1, 4, 10, 12, 16, 17, 21, 23, 27‐32, 35‐58
The condensation products SM1, 4, 10, 12, 16, 17, 21, 23, 27‐32, 35‐58 were synthesized in a millimol range as described in literature. This was performed by refluxing 1 eq of the corresponding aldehyde, 1 eq rhodanine (or rather N‐allyl rhodanine, thioazolidine‐2,4‐
dione, thiohydantoine, rhodanine‐3‐acetic acid, 3‐phenyl‐2‐thioxothiazolidin‐4‐one, pseudothiohydantoin) together with (12 mL per 1 mmol aldehyde) an anhydrous NaOAc solution (2.5 M in AcOH) over night (thermodynamic reaction control). Afterwards the mixture was allowed to cool to room temperature and the products were isolated by
filtration. The yellowish products were washed thoroughly with toluene, H2O, ethanol and ether and purified via recrystallization or column chromatography.
(Z)‐5‐(3‐Nitro‐4‐(p‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM1
Reaction Batch: 3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59 (0.273 g, 1 mmol); rhodanine (0.133 g, 1 mmol). Yellow solid 96% (0.374 g, 0.96 mmol) yield. M.p. 264°C. Rf 0.33 (PE–EtOAc, 3:2). 1H NMR (400 MHz, DMSO‐d6) δ 13.83 (bs, 1H), 8.39 (d, J 2.0 Hz, 1H), 7.61 (dd, J 8.7, 2.1 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J 8.1 Hz, 2H), 7.31 (d, J 7.9 Hz, 2H), 6.83 (d, J 8.6 Hz, 1H), 2.30 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 182.99, 144.56, 140.82, 140.77, 135.62, 134.24, 134.24, 131.25, 130.41, 130.41, 128.63, 128.36, 127.60, 125.72, 20.91. ESI‐MS: m/z [M‐H]‐ calcd for C17H12N2O3S3: 387.0; found: 387.0. HRMS: m/z [M‐H]‐ calcd for C17H12N2O3S3: 386.9937; found: 386.9922.76
(Z)‐5‐(4‐Chloro‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM4
Reaction Batch: 4‐Chloro‐3‐nitrobenzaldehyde (0.186 g, 1 mmol); rhodanine (0.133 g, 1 mmol). Orange solid in 96% (0.374 g, 0.96 mmol) yield. M.p. 255°C. Rf 0.42 (PE–EtOAc, 1:1).
1H NMR (400 MHz, DMSO‐d6) δ 14.00 (bs, 1H), 8.31 (d, J 2.1 Hz, 1H), 7.91 (d, J 8.5 Hz, 1H), 7.83 (dd, J 8.5, 2.1 Hz, 1H), 7.69 (s, 1H). 13C NMR (101 MHz, DMSO‐d6) δ 195.05, 169.27, 147.94, 134.12, 133.46, 132.68, 129.17, 127.67, 127.13, 126.39. ESI‐MS: m/z [M‐H]‐ calcd for C10H5ClN2O3S2: 298.9; found: 298.9. HRMS: m/z [M‐H]‐ calcd for C10H5ClN2O3S2: 298.9357;
found: 298.9350.76
(Z)‐5‐(3‐Nitro‐4‐(5‐(trifluoromethyl)pyridin‐2‐ylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM10
Reaction Batch: 3‐Nitro‐4‐((5‐(trifluoromethyl)pyridin‐2‐yl)thio)benzaldehyde (0.456 g, 1.39 mmol); rhodanine (0.185 g, 1.39 mmol). Yellow solid in 62% (0.381 g, 0.86 mmol) yield.
M.p. 255°C. Rf 0.42 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 14.00 (bs, 1H), 8.90 (s, 1H), 8.43 (s, 1H), 8.23 (d, J 6.2 Hz, 1H), 7.77 (m, 4H), 7.74 (s, 1H). 13C NMR (101 MHz, DMSO‐
d6) δ 195.00, 169.30, 160.41, 149.41, 147.05, 135.38, 135.30, 135.07, 135.02, 133.85, 133.72,
129.83, 128.93, 128.06, 127.04, 125.38. 19F NMR (376 MHz, DMSO‐d6): δ ‐60.87. ESI‐MS: m/z [M‐H]‐ calcd for C16H8F3N3O3S3: 442.0; found: 441.9. HRMS: m/z [M‐H]‐ calcd for C16H8F3N3O3S3: 441.9607; found: 441.9597.76
(Z)‐5‐(4‐(Cyclohexylthio)‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM12
Reaction batch: 4‐(Cyclohexylthio)‐3‐nitrobenzaldehyde SM91 (200 mg, 0.75 mmol), rhodanine (100 mg, 0.75 mmol). Orange solid in 45% (128 mg, 0.34 mmol) yield. M.p. 237°C.
Rf 0.49 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.95 (bs, 1H), 8.37 (d, J 1.5 Hz, 1H),
7.87 – 7.83 (m, 2H), 7.70 (s, 1H), 3.65 – 3.58 (m, 1H), 2.06 – 1.99 (m, 2H), 1.79 – 1.58 (m, 2H), 1.51 – 1.17 (m, 6H). 13C NMR (101 MHz, DMSO‐d6) δ 146.45, 137.59, 133.94, 129.98, 128.95, 127.44, 43.08, 31.97, 25.30, 25.10. ESI‐MS: m/z [M‐H]‐ calcd for C16H16N2O3S3: 379.0; found:
379.0. HRMS: m/z [M‐H]‐ calcd for C16H16N2O3S3: 379.0239; found: 379.0229.
(Z)‐5‐(3‐Bromo‐4‐(4‐fluorobenzyloxy)benzylidene)‐2‐thioxothiazolidin‐4‐one SM16
Reaction Batch: 3‐Bromo‐4‐((4‐fluorobenzyl)oxy)benzaldehyde (0.309 g, 1 mmol); rhodanine (0.133 g, 1 mmol). Yellow solid 90% (0.381 g, 0.90 mmol) yield. M.p. 206°C. Rf 0.26 (PE–EtOAc, 5:2). 1H NMR (400 MHz, DMSO‐d6) δ 13.83 (bs, 1H), 7.89 (d, J 2.2 Hz, 1H), 7.60 (s, 1H), 7.59‐7.51 (m, 3H), 7.37 (d, J 8.8 Hz, 1H), 7.29‐7.22 (m, 2H), 5.29 (s, 2H). 13C NMR (400 MHz, DMSO‐d6) δ 195.27, 156.06, 135.43, 132.25, 131.01, 130.12, 129.82, 129.73, 127.27, 124.16, 115.51, 115.29, 114.62, 112.08, 69.71. 19F NMR (376 MHz, DMSO‐d6) δ ‐114.00. ESI‐
MS: m/z [M‐H]‐ calcd for C17H11BrFNO2S2: 421.9 (79Br), 423.9 (81Br); found: 421.9 (79Br), 423.9 (81Br). HRMS: m/z [M‐H]‐ calcd for C17H11BrFNO2S2: 421.9326 (79Br), 423.9305 (81Br); found:
421.9316 (79Br), 423.9294 (81Br).76
(Z)‐5‐(4‐(4‐Fluorobenzyloxy)‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM17
Reaction Batch: 4‐((4‐Fluorobenzyl)oxy)‐3‐nitrobenzaldehyde (0.275 g, 1 mmol); rhodanine (0.133 g, 1 mmol). Yellow solid in 89%: (0.347 g, 0.89 mmol) yield. M.p. 228°C. Rf 0.23 (PE–EtOAc, 2:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.90 (bs, 1H), 8.18 (d, J 2.2 Hz, 1H), 7.85 (dd, J 8.9, 2.3 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J 9.0 Hz, 1H), 7.55‐7.49 (m, 2H), 7.30‐7.22 (m, 2H), 5.38 (s, 2H). 13C NMR (101 MHz, DMSO‐d6) δ 195.17, 169.30, 163.20, 160.77, 152.03, 139.84, 135.52, 131.75, 131.72, 129.93, 129.84, 129.19, 127.17, 125.78, 125.70, 116.49, 115.57, 115.36, 70.25. 19F NMR (376 MHz, DMSO‐d6) δ ‐113.72. ESI‐MS: m/z [M‐H]‐ calcd for C17H11FN2O4S2: 389.0; found: 389.0. HRMS: m/z [M‐H]‐ calcd for C17H11FN2O4S2: 389.0071;
found: 389.0063.76
(Z)‐4‐((4‐Oxo‐2‐thioxothiazolidin‐5‐ylidene)methyl)phenyl‐2‐chlorobenzoat SM21
Reaction Batch: 4‐Formylphenyl 2‐chlorobenzoate (0.261 g, 1 mmol); rhodanine (0.133 g, 1 mmol). Yellow solid in 84% (0.315 g, 0.84 mmol) yield. M.p. 246°C. Rf 0.26(PE–EtOAc, 5:2).
1H NMR (400 MHz, DMSO‐d6) δ 13.89 (bs, 1H), 8.41‐7.97 (m, 1H), 7.73 (d, J 8.7 Hz, 2H), 7.69 (s, 1H), 7.70‐7.66 (m, 2H), 7.61‐7.53 (m, 1H), 7.51 (d, J 8.7 Hz, 2H). 13C NMR (101 MHz, DMSO‐d6) δ 195.76, 169.69, 163.12, 151.66, 134.23, 132.70, 131.99, 131.96, 131.15, 130.48, 128.47, 127.61, 126.00, 123.01. ESI‐MS: m/z [M‐H]‐ calcd for C17H10ClNO3S2: 374.0; found:
374.0. HRMS: m/z [M‐H]‐ calcd for C17H10ClNO3S2: 373.9718; found: 373.9702.76
(Z)‐5‐(3‐Nitro‐4‐(p‐tolyloxy)benzylidene)‐2‐thioxothiazolidin‐4‐one SM23
Reaction Batch: 3‐Nitro‐4‐(p‐tolyloxy)benzaldehyde (0.257 g, 1 mmol); rhodanine (0.133 g, 1 mmol). Orange crystals in 60% (0.225 g, 0.60 mmol) yield. M.p. 246°C. Rf 0.21 (PE–EtOAc, 5:2). 1H NMR (400 MHz, DMSO‐d6) δ 13.92 (bs, 1H), 8.33 (d, J 2.3 Hz, 1H), 7.80 (dd, J 8.9, 2.3 Hz, 1H), 7.69 (s, 1H), 7.29 (d, J 8.2 Hz, 3H), 7.15‐7.05 (m, 3H), 2.33 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.26, 169.39, 152.11, 151.44, 140.55, 135.46, 134.92, 130.92, 128.75, 127.98, 127.94, 126.84, 119.92, 119.76, 20.37. ESI‐MS: m/z [M‐H]‐ calcd for C17H12N2O4S2: 371.0;
found: 371.0. HRMS: m/z [M‐H]‐ calcd for C17H12N2O4S2: 371.0166; found: 371.0148.76
(Z)‐3‐Allyl‐5‐(3‐nitro‐4‐(p‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM27
Reaction Batch: 3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59 (0.119 g, 0.5 mmol); N‐allyl rhodanine (0.087 g, 0.5 mmol). Yellow solid in 63% (0.103 g, 0.96 mmol) yield. M.p. 243°C.
Rf 0.65 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 8.58 (d, J 2.0 Hz, 1H), 7.90 (s, 1H),
7.77 (dd, J 8.7, 2.1 Hz, 1H), 7.58‐7.53 (m, 2H), 7.42 (m, 2H), 6.96 (d, J 8.6 Hz, 1H), 5.89‐5.78 (m, 1H), 5.21‐5.10 (m, 2H), 4.66‐4.62 (m, 2H), 2.41 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 192.54, 166.51, 144.58, 141.30, 140.87, 135.71, 134.31, 131.32, 130.18, 130.13, 128.72, 128.10, 125.67, 124.16, 120.81, 117.90, 46.18, 20.96. CHN analysis: calcd: C 56.05, H 3.76, N 6.54; found: C 56.25, H 3.87, N 6.57.76
(Z)‐5‐(3‐Nitro‐4‐(p‐tolylthio)benzylidene)‐3‐phenyl‐2‐thioxothiazolidin‐4‐one SM28
Reaction batch: 3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59 (273 mg, 1.0 mmol), 3‐phenyl‐2‐
thioxothiazolidin‐4‐one (209 mg, 1.0 mmol). Yellow solid in 56% (262 mg, 0.6 mmol).
M.p. 251°C. Rf 0.30 (PE–EtOAc, 5:1). 1H NMR (400 MHz, DMSO‐d6) δ 8.60 (d, J 2.0 Hz, 1H), 7.90 (s, 1H), 7.82 (dd, J 8.7, 2.0 Hz, 1H), 7.61 – 7.51 (m, 5H), 7.46 – 7.39 (m, 4H), 6.99 (d, J 8.6 Hz, 1H), 2.42 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 193.32, 166.80, 144.57, 141.18, 140.87, 135.73, 135.64, 135.09, 134.26, 131.35, 131.31, 130.39, 129.55, 129.36, 128.72, 127.97, 125.63, 125.12, 20.95. No response in ESI and HRMS. CHN analysis: calcd: C 59.46, H 3.47, N 6.03; found: C 59.41, H 3.58, N 6.20.76
(Z)‐5‐(3‐Nitro‐4‐(p‐tolylthio)benzylidene)thiazolidine‐2,4‐dione SM29
Reaction batch: 3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59 (273 mg, 1.0 mmol), thioazolidine‐2,4‐dione (117 mg, 1.0 mmol). Orange solid in 51% (189 mg, 0.5 mmol) yield.
M.p. 291°C (decomposition). Rf 0.24 (PE–EtOAc, 1:2). 1H NMR (400 MHz, DMSO‐d6) δ 8.42 (d, J 1.6 Hz, 1H), 7.70 (dd, J 8.6, 1.7 Hz, 1H), 7.55 – 7.51 (m, 2H), 7.54 (s, 1H), 7.52 (d, J 8.8 Hz, 2H), 7.39 (d, J 8.1 Hz, 2H), 6.89 (d, J 8.6 Hz, 1H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 209.67, 174.69, 170.87, 144.58, 140.62, 138.82, 135.62, 134.16, 132.15, 131.21, 128.36, 126.09, 126.03, 123.94, 20.95. ESI‐MS: m/z [M‐H]‐ calcd for C17H12N2O4S2: 371.0; found:
370.8. HRMS: m/z [M‐H]‐ calcd for C17H12N2O4S2: 371.0155; found: 371.0149.
(Z)‐2‐(5‐(3‐Nitro‐4‐(p‐tolylthio)benzylidene)‐4‐oxo‐2‐thioxothiazolidin‐3‐yl)acetic acid SM30
Reaction batch: 3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59 (273 mg, 1.0 mmol), rhodanine‐3‐
acetic acid (191 mg, 1.0 mmol). Yellow solid in 83% (371 mg, 0.8 mmol) yield. M.p. 284°C.
Rf 0.45 (CH2Cl2–MeOH, 1:0.1). 1H NMR (400 MHz, DMSO‐d6) δ 13.46 (bs, 1H), 8.59 (d, J 1.9
Hz, 1H), 7.95 (s, 1H), 7.78 (dd, J 8.7, 1.9 Hz, 1H), 7.55 (d, J 8.0 Hz, 2H), 7.42 (d, J 8.0 Hz, 2H), 6.97 (d, J 8.6 Hz, 1H), 4.74 (s, 2H), 2.41 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 192.60, 167.23, 166.22, 144.53, 141.56, 140.87, 135.70, 134.26, 131.30, 131.02, 130.10, 128.69, 128.33, 125.62, 123.51, 45.08, 20.95. ESI‐MS: m/z [M+Na]+ calcd for C19H14N2O5S3: 469.0;
found: 469.4. HRMS: m/z [M‐H]‐ calcd for C19H14N2O5S3: 444.9981; found: 444.9982.
(Z)‐5‐(3‐Nitro‐4‐(p‐tolylthio)benzylidene)‐2‐thioxoimidazolidin‐4‐one SM31
Reaction batch: 3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59 (273 mg, 1.0 mmol), thiohydantoine (116 mg, 1.0 mmol). Orange solid in 20% (65 mg, 0.2 mmol) yield.
M.p. 253°C. Rf 0.64 (PE–EtOAc, 2:3). 1H NMR (400 MHz, DMSO‐d6) δ 12.45 (bs, 1H), 12.24 (bs, 1H), 8.46 (d, J 1.8 Hz, 1H), 7.81 (dd, J 8.6, 1.9 Hz, 1H), 7.59 – 7.47 (m, 2H), 7.39 (d, J 8.0 Hz, 2H), 6.77 (d, J 8.6 Hz, 1H), 6.50 (s, 1H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 179.53, 165.46, 144.96, 140.57, 138.16, 135.56, 134.64, 131.12, 130.14, 129.32, 127.90, 126.45, 126.16, 108.05, 20.88. ESI‐MS: m/z [M‐H]‐ calcd for C17H13N3O3S2: 370.0; found:
369.8. HRMS: m/z [M‐H]‐ calcd for C17H13N3O3S2: 370.0315; found: 370.0322.
(Z)‐2‐Imino‐5‐(3‐nitro‐4‐(p‐tolylthio)benzylidene)thiazolidin‐4‐one SM32
Reaction batch: 3‐Nitro‐4‐(p‐tolylthio)benzaldehyde SM59 (273 mg, 1.0 mmol), pseudothiohydantoin (116 mg, 1.0 mmol). Yellow solid in 89% (331 mg, 0.9 mmol).
M.p. 296°C. Rf 0.33 (PE–EtOAc, 1:2). 1H NMR (400 MHz, DMSO‐d6) δ 9.55 (bs, 1H), 9.27 (bs, 1H), 8.41 (d, J 2.0 Hz, 1H), 7.74 (dd, J 8.7, 2.0 Hz, 1H), 7.59 (s, 1H), 7.56 – 7.50 (m, 2H), 7.40 (d, J 7.9 Hz, 2H), 6.91 (d, J 8.6 Hz, 1H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 180.04, 175.06, 144.60, 140.70, 139.49, 135.61, 134.76, 131.69, 131.40, 131.25, 128.50, 126.04, 126.02, 125.42, 20.95. ESI‐MS: m/z [M‐H]‐ calcd for C17H13N3O3S2: 370.0; found: 370.1.
HRMS: m/z [M‐H]‐ calcd for C17H13N3O3S2: 370.0315; found: 370.0323.
(Z)‐5‐(3‐Nitro‐4‐tosylbenzylidene)‐2‐thioxothiazolidin‐4‐one SM35
Reaction batch: 3‐Nitro‐4‐tosylbenzaldehyde SM84 (305 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Yellow solid in 69% (290 mg, 0.7 mmol) yield. M.p. 270°C. Rf= 0.30 (PE–EtOAc, 1:6). 1H NMR (400 MHz, DMSO‐d6) δ 13.89 (bs, 1H), 8.43 (d, J 8.3 Hz, 1H), 8.24 (d, J 1.7 Hz, 1H), 8.01 (dd, J 8.5, 1.7 Hz, 1H), 7.89 – 7.83 (m, 2H), 7.68 (s, 1H), 7.50 (d, J 8.0 Hz, 2H), 2.41 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.11, 169.43, 148.00, 145.52, 139.98, 136.66, 132.87, 132.66, 132.30, 132.04, 130.21, 127.98, 126.49, 126.28, 21.17. ESI‐MS: m/z [M+Na]+ calcd for C17H12N2O5S3: 443.0; found: 442.5. HRMS: m/z [M‐H]‐ calcd for C17H12N2O5S3: 418.9825;
found: 418.9815.
(Z)‐5‐Benzylidene‐2‐thioxothiazolidin‐4‐on SM36
Reaction batch: Benzaldehyde (101 μL, 1 mmol), rhodanine (133 mg, 1 mmol). Orange solid in 73% (161 mg, 0.73 mmol) yield. M.p. 203°C. Rf 0.64 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.84 (bs, 1H), 7.65 (s, 1H), 7.63 – 7.48 (m, 5H). 13C NMR (101 MHz, DMSO‐d6) δ 195.76, 169.45, 132.97, 131.58, 131.25, 130.72, 130.45, 129.44, 128.21, 125.58. No response in ESI‐MS. HRMS: m/z [M‐H]‐ calcd for C18H14N2O3S3: 219.9885; found: 219.9895.
(Z)‐2‐Thioxo‐5‐(4‐(p‐tolylthio)benzylidene)thiazolidin‐4‐one SM37
S S NH
O
S
Reaction batch: 4‐(p‐Tolylthio)benzaldehyde SM69 (300 mg, 1.3 mmol), rhodanine (175 mg, 1.3 mmol). Yellow solid 66% (295 mg, 0.9 mmol) yield. M.p. 197°C. Rf 0.90 (PE–EtOAc, 1:1).
1H NMR (400 MHz, DMSO‐d6) δ 13.83 (bs, 1H), 7.55 (s, 1H), 7.52 – 7.48 (m, 2H), 7.44 – 7.40
(m, 2H), 7.32 – 7.29 (m, 2H), 7.24 – 7.19 (m, 2H), 2.35 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.79, 170.15, 141.65, 139.16, 134.02, 131.24, 130.75, 130.57, 130.45, 127.60, 127.42, 125.30, 20.81. ESI‐MS: m/z [M‐H]‐ calcd for C17H13NOS3: 342.0; found: 342.0. HRMS: m/z [M‐
H]‐ calcd for C17H13NOS3: 342.0076; found: 342.0070.
(Z)‐5‐(3‐Fluoro‐4‐(p‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM38
Reaction batch: 3‐Fluoro‐4‐(p‐tolylthio)benzaldehyde SM63 (246 mg, 1.0 mmol); rhodanine (133 mg, 1.0 mmol). Yellow solid in 77% (280 mg; 0.8 mmol) yield. M.p. 182°C. Rf 0.31 (PE–
EtOAc, 3:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.86 (bs, 1H), 7.58 (s, 1H), 7.53 (dd, J 11.0, 1.5 Hz, 1H), 7.44 – 7.40 (m, 2H), 7.34 – 7.29 (m, 3H), 7.03 (t, J 8.1 Hz, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.37, 169.54, 158.50 (d, J 244.1 Hz), 139.28, 133.70, 132.90 (d, J 7.9 Hz), 130.80, 129.96 (d, J 2.2 Hz), 129.46, 128.00 (d, J 17.4 Hz), 126.74, 126.50 (d, J 2.9 Hz), 125.99 (d, J 1.1 Hz), 117.34 (d, J 22.8 Hz), 20.75. 19F NMR (376 MHz, DMSO‐d6) δ ‐110.97.
ESI‐MS: m/z [M‐H]‐ calcd for C17H12FNOS3: 360.0; found: 359.9. HRMS: m/z [M‐H]‐ calcd for C17H12FNOS3: 359.9981; found: 360.0021.
(Z)‐5‐(3‐Chloro‐4‐(p‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM39
Reaction batch: 3‐Chloro‐4‐(p‐tolylthio)benzaldehyde SM70 (262 mg, 1.0 mmol); rhodanine (133 mg, 1.0 mmol). Yellow solid in 81% (311 mg, 0.8 mmol) yield. M.p. 197°C. Rf 0.37 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.86 (bs, 1H), 7.77 – 7.75 (m, 1H), 7.57 (s, 1H), 7.51 – 7.47 (m, 2H), 7.42 – 7.35 (m, 3H), 6.80 (d, J 8.4 Hz, 1H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.24, 169.36, 141.00, 140.12, 135.07, 131.49, 131.08, 130.17, 129.46,
128.62, 127.45, 126.20, 126.15, 125.38, 20.84. ESI‐MS: m/z [M‐H]‐ calcd for C17H12ClNOS3: 376.0; found: 375.8. HRMS: m/z [M‐H]‐ calcd for C17H12ClNOS3: 375.9686; found: 375.9688.
(Z)‐5‐(3‐Bromo‐4‐(p‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM40
Reaction batch: 3‐Bromo‐4‐(p‐tolylthio)benzaldehyde SM68 (305 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Yellow solid in 71% (295 mg, 0.7 mmol) yield. Visual nature. M.p. 213°C.
Rf 0.88 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.86 (bs, 1H), 7.88 (d, J 1.8 Hz, 1H),
7.53 (s, 1H), 7.50 – 7.46 (m, 2H), 7.40 (dd, J 8.6, 1.9 Hz, 1H), 7.37 (d, J 8.0 Hz, 2H), 6.72 (d, J 8.4 Hz, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.59, 170.05, 143.00, 140.21, 135.17, 134.72, 134.71, 131.68, 131.14, 129.07, 127.22, 126.54, 125.91, 120.15, 20.90. ESI‐
MS: m/z [M‐H]‐ calcd for C17H12BrNOS3: 419.9 (79Br), 421.9 (81Br); found: 419.9 (79Br), 421.9 (81Br). HRMS: m/z [M‐H]‐ calcd for C17H12BrNOS3: 419.9181 (79Br), 421.9160 (81Br); found:
419.9171 (79Br), 421.9153 (81Br).
(Z)‐2‐Thioxo‐5‐(4‐(p‐tolylthio)‐3‐(trifluoromethyl)benzylidene)thiazolidin‐4‐one SM41
Reaction batch: 4‐(p‐Tolylthio)‐3‐(trifluoromethyl)benzaldehyde SM71 (297 mg, 1.0 mmol);
rhodanine (133 mg, 1.0 mmol). Yellow solid in 61% (253 mg, 0.6 mmol) yield. M.p. 235°C.
Rf 0.29 (PE–EtOAc, 3:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.86 (bs, 1H), 8.02 (d, J 1.6 Hz, 1H),
7.68 (s, 1H), 7.65 (dd, J 8.5, 1.5 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.37 – 7.33 (m, 2H), 7.08 (d, J 8.5 Hz, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.14, 169.32, 140.63, 140.11, 134.90, 133.09, 131.12, 131.04, 130.59, 129.84, 129.44, 129.36, 126.75, 126.53, 126.22, 125.92, 124.79, 122.06, 20.85. 19F NMR (376 MHz, DMSO‐d6) δ ‐60.58. ESI‐MS: m/z [M‐H]‐ calcd for
C18H12F3NOS3: 410.0; found: 409.8. HRMS: m/z [M‐H]‐ calcd for C18H12F3NOS3: 409.9949;
found: 409.9982.
(Z)‐5‐((4‐Oxo‐2‐thioxothiazolidin‐5‐ylidene)methyl)‐2‐(p‐tolylthio)benzonitrile SM42
Reaction batch: 5‐Formyl‐2‐(p‐tolylthio)benzonitrile SM64 (253 mg, 1.0 mmol); rhodanine (133 mg, 1.0 mmol). Yellow solid in 83% (322 mg, 0.8 mmol) yield. M.p. 247°C. Rf 0.24 (PE–EtOAc, 3:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.88 (bs, 1H), 8.11 (d, J 2.0 Hz, 1H), 7.68 (dd, J 8.8, 2.1 Hz, 1H), 7.58 (s, 1H), 7.53 – 7.47 (m, 2H), 7.40 – 7.38 (m, 2H), 7.03 (d, J 8.6 Hz, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.27, 169.54, 145.20, 140.26, 136.15, 134.64, 134.43, 133.74, 131.10, 131.02, 128.42, 128.05, 125.07, 115.97, 110.39, 20.82. ESI‐
MS: m/z [M‐H]‐ calcd for C18H12N2OS3: 367.0; found: 366.9. HRMS: m/z [M‐H]‐ calcd for C18H12N2OS3: 367.0028; found: 367.0027.
(Z)‐5‐(4‐((4‐Ethylphenyl)thio)‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM43
Reaction batch: 4‐((4‐Ethylphenyl)thio)‐3‐nitrobenzaldehyde SM79 (287 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Yellow solid in 80% (322 mg, 0.8 mmol) yield. M.p. 254°C.
Rf 0.83 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.90 (bs, 1H), 8.48 (s, 1H), 7.76 –
7.69 (m, 1H), 7.68 (s, 1H), 7.56 (d, J 7.9 Hz, 2H), 7.44 (d, J 8.0 Hz, 2H), 6.95 (dd, J 8.6, 0.9 Hz, 1H), 2.71 (q, J 7.6 Hz, 2H), 1.24 (t, J 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.10, 169.41, 146.83, 144.54, 140.88, 135.71, 134.28, 130.38, 130.09, 128.64, 128.51, 127.71, 127.43, 125.97, 27.96, 15.20. ESI‐MS: m/z [M‐H]‐ calcd for C18H14N2O3S3: 401.0; found: 401.0.
HRMS: m/z [M‐H]‐ calcd for C18H14N2O3S3: 401.0083; found: 401.0071.
(Z)‐5‐(3‐Nitro‐4‐((4‐(trifluoromethyl)phenyl)thio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM44
Reaction batch: 3‐Nitro‐4‐((4‐(trifluoromethyl)phenyl)thio)benzaldehyde SM80 (300 mg, 0.9 mmol), rhodanine (122 mg, 0.9 mmol). Yellow solid in 80% (339 mg, 0.7 mmol) yield.
M.p. 268°C. Rf 0.73 (PE–EtOAc, 1:1): 1H NMR (400 MHz, DMSO‐d6) δ 13.93 (bs, 1H), 8.46 (d, J 1.8 Hz, 1H), 7.91 (d, J 8.4 Hz, 2H), 7.86 (d, J 8.3 Hz, 2H), 7.73 (dd, J 8.6, 2.0 Hz, 1H), 7.56 (s, 1H), 7.08 (d, J 8.6 Hz, 1H). 13C NMR (101 MHz, DMSO‐d6) δ 196.88, 145.60, 137.18, 135.76, 135.57, 134.39, 132.00, 130.91 – 130.57 (m), 130.41, 130.09, 129.83, 127.23, 127.13 (q), 126.48 – 125.77 (m), 125.25, 122.55. 19F NMR (376 MHz, DMSO‐d6) δ ‐61.36. ESI‐MS: m/z [M‐H]‐ calcd for C17H9F3N2O3S3: 441.0; found: 441.0. HRMS: m/z [M‐H]‐ calcd for C17H9F3N2O3S3: 440.9644; found: 440.9669.
(Z)‐5‐(3‐Nitro‐4‐((4‐(trifluoromethoxy)phenyl)thio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM45
Reaction batch: 3‐Nitro‐4‐((4‐(trifluoromethoxy)phenyl)thio)benzaldehyde SM82 (275 mg, 0.8 mmol), rhodanine (107 mg, 0.8 mmol). Yellow solid in 65% (236 mg, 0.5 mmol) yield.
M.p. 281°C. Rf 0.32 (PE–EtOAc, 1:4). 1H NMR (400 MHz, DMSO‐d6) δ 13.91 (bs, 1H), 8.49 (d, J 1.9 Hz, 1H), 7.84 – 7.78 (m, 2H), 7.73 (dd, J 8.6, 1.9 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J 8.1 Hz, 2H), 7.00 (d, J 8.6 Hz, 1H). 13C NMR (101 MHz, DMSO‐d6) δ 195.28, 169.93, 149.82, 144.86, 139.23, 137.67, 134.35, 130.90, 129.01, 128.80, 128.12, 127.94, 127.58, 122.70, 121.22, 121.49 – 118.27 (m). 19F NMR (376 MHz, DMSO) δ ‐56.67. ESI‐MS: m/z [M‐H]‐ calcd for C17H9F3N2O4S3: 357.0; found: 356.8. HRMS: m/z [M‐H]‐ calcd for C17H9F3N2O4S3: 456.9593;
found: 456.9619.
(Z)‐5‐(4‐((3‐Fluoro‐4‐methylphenyl)thio)‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM46
Reaction batch: 4‐((3‐Fluoro‐4‐methylphenyl)thio)‐3‐nitrobenzaldehyde SM65 (291 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Yellow solid in 77% (312 mg, 0.8 mmol) yield.
M.p. 262°C. Rf 0.61 (PE–EtOAc, 1:4). 1H NMR (400 MHz, DMSO‐d6) δ 13.92 (bs, 1H), 8.50 (d, J 1.9 Hz, 1H), 7.73 (dd, J 8.7, 2.0 Hz, 1H), 7.70 (s, 1H), 7.64 (dd, J 7.3, 1.8 Hz, 1H), 7.54 (ddd, J 7.4, 4.9, 2.3 Hz, 1H), 7.42 – 7.34 (m, 1H), 6.98 (d, J 8.6 Hz, 1H), 2.29 (d, J 0.8 Hz, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.15, 169.62, 162.11 (d, J 248.3 Hz), 144.44, 140.49, 139.09 (d, J 5.9 Hz), 135.53 (d, J 8.8 Hz), 134.30, 130.49, 128.72, 128.25, 127.62, 127.16 (d, J 18.2 Hz), 124.48 (d, J 3.3 Hz), 117.27 (d, J 23.1 Hz), 14.03 (d, J 3.1 Hz). 19F NMR (376 MHz, DMSO‐d6) δ
‐114.06. ESI‐MS: m/z [M‐H]‐ calcd for C17H11FN2O3S3: 405.0; found: 404.8. HRMS: m/z [M‐H]‐
calcd for C17H11FN2O3S3: 404.9832; found: 404.9853.
(Z)‐5‐(3‐Nitro‐4‐((2,3,5,6‐tetrafluoro‐4‐(trifluoromethyl)phenyl)thio) benzylidene)‐2‐thioxo‐
thiazolidin‐4‐one SM47
Reaction batch: 3‐Nitro‐4‐((2,3,5,6‐tetrafluoro‐4‐(trifluoromethyl)phenyl)thio)benzaldehyde SM67 (399 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Yellow solid in 80% (401 mg, 0.8 mmol) yield. M.p. 296°C (decomposition). Rf 0.29 (PE–EtOAc, 1:4). 1H NMR (400 MHz, DMSO‐
d6) δ 13.99 (bs, 1H), 8.58 (d, J 1.9 Hz, 1H), 7.79 (s, 1H), 7.76 (dd, J 8.6, 2.0 Hz, 1H), 7.42 (d, J 8.5 Hz, 1H). 13C NMR (101 MHz, DMSO‐d6) δ 194.81, 169.26, 149.04 – 145.91 (m), 145.85 – 145.56 (m),145.05, 135.24, 133.98, 132.20, 129.07, 128.38, 128.12, 127.77, 122.40 – 121.23 (m), 119.34 – 119.19 (m), 114.93 (t, J 21.2 Hz). 19F NMR (376 MHz, DMSO‐d6) δ ‐55.78 (t, J 21.5 Hz, 3F), ‐129.95 – ‐130.48 (m, 2F), ‐139.46 – ‐139.89 (m, 2F). ESI‐MS: m/z [M‐H]‐ calcd
for C17H5F7N2O3S3: 512.9; found: 512.7. HRMS: m/z [M‐H]‐ calcd for C17H5F7N2O3S3: 512.9267;
found: 512.9271.
(Z)‐5‐(3‐Nitro‐4‐(m‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM48
Reaction batch: 3‐Nitro‐4‐(m‐tolylthio)benzaldehyde SM61 (273 mg, 1.0 mmol); rhodanine (133 mg, 1.0 mmol). Yellow solid in 81% (301 mg, 0.8 mmol) yield. M.p. 247°C. Rf 0.30 (PE–EtOAc, 3:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.89 (bs, 1H), 8.48 (s, 1H), 7.75 – 7.69 (m, 1H), 7.67 (s, 1H), 7.53 – 7.40 (m, 4H), 6.98 (d, J 8.5 Hz, 1H), 2.37 (s, 3H).13C NMR (101 MHz, DMSO‐d6) 195.02, 169.30, 144.58, 140.56, 140.28, 135.93, 134.28, 132.65, 131.45, 130.43, 129.01, 128.81, 128.52, 127.67, 127.37, 20.80. ESI‐MS: m/z [M‐H]‐ calcd for C17H12N2O3S3: 387.0; found: 386.8. HRMS: m/z [M‐H]‐ calcd for C17H12N2O3S3: 386.9926; found: 386.9926.
(Z)‐5‐(3‐Nitro‐4‐(o‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM49
Reaction batch: 3‐Nitro‐4‐(o‐tolylthio)benzaldehyde SM60 (273 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Golden solid in 73% (284 mg, 0.7 mmol) yield. M.p. 245°C. Rf 0.30 (PE–EtOAc, 1:4). 1H NMR (400 MHz, DMSO‐d6) δ 13.90 (bs, 1H), 8.53 – 8.59 (m, 1H), 7.74 – 7.69 (m, 1H), 7.68 (s, 1H), 7.63 (d, J 7.5 Hz, 1H), 7.58 – 7.50 (m, 2H), 7.40 (td, J 7.4, 2.1 Hz, 1H), 6.79 (d, J 8.5 Hz, 1H), 2.30 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 194.97, 169.25, 144.70, 142.74, 139.53, 136.79, 134.42, 131.62, 131.34, 130.36, 128.50, 128.26, 128.02, 127.93, 127.89, 127.33, 20.00. ESI‐MS: m/z [M‐H]‐ calcd for C17H12N2O3S3: 387.0; found:
386.8. HRMS: m/z [M‐H]‐ calcd for C17H12N2O3S3: 386.9926; found: 386.9929.
(Z)‐5‐(4‐((3,5‐Dimethylphenyl)thio)‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM50
Reaction batch: 4‐((3,5‐Dimethylphenyl)thio)‐3‐nitrobenzaldehyde SM78 (300 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Yellow solid in 55% (230 mg, 0.6 mmol) yield.
M.p. 266°C. Rf 0.39 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.94 (bs, 1H), 8.49 (d, J 2.0 Hz, 1H), 7.72 (dd, J 8.7, 2.0 Hz, 1H), 7.68 (s, 1H), 7.29 (s, 2H), 7.25 (s, 1H), 7.00 (d, J 8.6 Hz, 1H), 2.34 (s, 6H). 13C NMR (101 MHz, DMSO‐d6) δ 195.15, 169.50, 144.60, 140.63, 140.03, 134.28, 133.01, 132.26, 130.42, 128.88, 128.72, 128.46, 127.65, 127.49, 20.70. ESI‐MS: m/z [M‐H]‐ calcd for C18H14N2O3S3: 401.0; found: 401.0. HRMS: m/z [M‐H]‐ calcd for C18H14N2O3S3: 401.0083; found: 401.0111.
(Z)‐5‐(4‐(Naphthalen‐2‐ylthio)‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM51
Reaction batch: 4‐(Naphthalen‐2‐ylthio)‐3‐nitrobenzaldehyde SM77 (240 mg, 0.8 mmol), rhodanine (103 mg, 0.8 mmol). Yellow solid in 74% (245 mg, 0.6 mmol) yield. M.p. 251°C.
Rf 0.70 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.88 (bs, 1H), 8.46 (d, J 1.9 Hz, 1H),
8.37 (d, J 1.4 Hz, 1H), 8.10 (d, J 8.6 Hz, 1H), 8.07 – 8.01 (m, 2H), 7.72 – 7.58 (m, 4H), 7.50 (s, 1H), 7.00 (d, J 8.6 Hz, 1H). 13C NMR (101 MHz, DMSO‐d6) δ 199.21, 174.16, 144.92, 135.62, 134.30, 133.59, 133.23, 131.12, 130.22, 129.17, 128.07, 127.89, 127.84, 127.16, 127.00, 126.94. ESI‐MS: m/z [M‐H]‐ calcd for C20H12N2O3S3: 423.0; found: 423.0. HRMS: m/z [M‐H]‐ calcd for C20H12N2O3S3: 422.9926; found: 422.9919.
(Z)‐5‐(4‐(Cyclopentylthio)‐3‐nitrobenzylidene)‐2‐thioxothiazolidin‐4‐one SM52
Reaction batch: 4‐(Cyclopentylthio)‐3‐nitrobenzaldehyde SM81 (200 mg, 0.8 mmol), rhodanine (106 mg, 0.8 mmol). Yellow solid in 74% (216 mg, 0.6 mmol) yield. M.p. 257°C.
Rf 0.65 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.93 (bs, 1H), 8.40 (s, 1H), 7.83 (s,
2H), 7.72 (s, 1H), 4.06 – 3.70 (m, 1H), 2.38 – 2.13 (m, 2H), 1.79 – 1.34 (m, 6H). 13C NMR (101 MHz, DMSO‐d6) δ 194.91, 169.29, 145.52, 140.18, 134.10, 129.53, 128.97, 128.78, 127.47, 126.95, 43.04, 32.64, 24.79. ESI‐MS: m/z [M‐H]‐ calcd for C15H14N2O3S3: 365.0; found: 365.0.
HRMS: m/z [M‐H]‐ calcd for C15H14N2O3S3: 365.0083; found: 365.0115.
(Z)‐5‐(3‐Bromo‐4‐((3‐fluoro‐4‐methylphenyl)thio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM53
Reaction batch: 3‐Bromo‐4‐((3‐fluoro‐4‐methylphenyl)thio)benzaldehyde SM66 (241 mg, 0.7 mmol); rhodanine (98 mg, 0.7 mmol). Yellow solid in 98% (334 mg, 0.7 mmol) yield.
M.p. 257°C. Rf 0.37 (PE–EtOAc, 3:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.85 (bs, 1H), 7.90 (d, J 1.9 Hz, 1H), 7.58 (dd, J 7.5, 2.0 Hz, 1H), 7.56 (s, 1H), 7.47 (ddd, J 7.6, 4.9, 2.4 Hz, 1H), 7.43 (dd, J 8.6, 1.9 Hz, 1H), 7.38 – 7.30 (m, 1H), 6.77 (d, J 8.4 Hz, 1H), 2.28 (d, J 1.5 Hz, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.15, 169.26, 161.85 (d, J 247.7 Hz), 142.89, 138.65 (d, J 5.9 Hz), 135.05 (d, J 8.7 Hz), 134.78, 131.59, 129.44, 129.13, 127.25, 127.05 (d, J 18.1 Hz), 125.99, 124.55 (d, J 3.6 Hz), 120.04, 117.16 (d, J 23.0 Hz), 14.06 (d, J 3.1 Hz). 19F NMR (376 MHz, DMSO‐d6) δ ‐114.73. ESI‐MS: m/z [M‐H]‐ calcd for C17H11BrFNOS3: 437.9 (79Br), 439.9 (81Br);
found: 437.7 (79Br), 439.7 (81Br). HRMS: m/z [M‐H]‐ calcd for C17H11BrFNOS3: 437.9086 (79Br), 439.9066 (81Br); found: 437.9081 (79Br), 439.9065 (81Br).
(Z)‐2‐Thioxo‐5‐(4‐(o‐tolylthio)benzylidene)thiazolidin‐4‐one SM54
Reaction batch: 4‐(o‐Tolylthio)benzaldehyde SM83 (228 mg, 1.0 mmol), rhodanine (133 mg, 1.0 mmol). Yellow solid in 90% (309 mg, 0.9 mmol) yield. M.p. 178°C. Rf 0.51 (PE–EtOAc, 4:1).
1H NMR (400 MHz, DMSO‐d6) δ 13.82 (bs, 1H), 7.57 (s, 1H), 7.54 – 7.46 (m, 3H), 7.45 – 7.39
(m, 2H), 7.34 – 7.27 (m, 1H), 7.18 – 7.13 (m, 2H), 2.31 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 195.47, 169.48, 141.29, 140.84, 135.22, 131.37, 131.24, 130.96, 130.30, 129.92, 129.88, 127.53, 127.37, 124.80, 20.22. ESI‐MS: m/z [M‐H]‐ calcd for C17H13NOS3: 342.0; found: 342.0.
HRMS: m/z [M‐H]‐ calcd for C17H13NOS3: 342.0076; found: 342.0103.
(Z)‐5‐(3‐Fluoro‐4‐(o‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM55
Reaction batch: 3‐fluoro‐4‐(o‐tolylthio)benzaldehyde SM72 (150 mg, 0.6 mmol); rhodanine (79.1 mg, 0.6 mmol). Yellow solid in 88% (192 mg; 0.53 mmol) yield. M.p. 161°C. Rf 0.63 (PE–
EtOAc, 2:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.80 (bs, 1H), 7.51 (dd, J 11.1, 1.6 Hz, 1H), 7.46 (s, 1H), 7.45 – 7.36 (m, 3H), 7.33 – 7.26 (m, 2H), 6.91 (t, J 8.1 Hz, 1H), 2.33 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 197.06, 158.90 (d, J 244.1 Hz), 140.73, 134.25, 133.72 (d, J 7.6 Hz), 131.18, 129.92, 129.86 (d, J 2.0 Hz), 129.63, 129.37 (d, J 2.9 Hz), 128.99, 128.68 (d, J 4.9 Hz), 127.55, 127.38 (d, J 5.5 Hz), 126.47 (d, J 2.7 Hz), 117.11 (d, J 22.7 Hz), 20.02. 19F NMR (376 MHz, DMSO‐d6) δ ‐110.93. ESI‐MS: m/z [M‐H]‐ calcd for C17H12FNOS3: 360.0; found: 359.7.
HRMS: m/z [M‐H]‐ calcd for C17H12FNOS3: 359.9981; found: 359.9990.
(Z)‐2‐Thioxo‐5‐(4‐(o‐tolylthio)‐3‐(trifluoromethyl)benzylidene)thiazolidin‐4‐one 56
Reaction batch: 4‐(o‐Tolylthio)‐3‐(trifluoromethyl)benzaldehyde SM73 (107 mg, 0.4 mmol);
rhodanine (48 mg, 0.4 mmol). Yellow solid in 91% (131 mg; 0.3 mmol) yield. M.p. 217°C. Rf 0.60 (PE–EtOAc, 2:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.89 (bs, 1H), 8.02 (d, J 1.2 Hz, 1H), 7.63 (s, 1H), 7.66 – 7.59 (m, 1H), 7.54 (d, J 7.5 Hz, 1H), 7.49 – 7.44 (m, 2H), 7.40 – 7.31 (m, 1H), 6.90 (d, J 8.5 Hz, 1H), 2.29 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 196.18, 142.32, 139.76, 136.61, 133.64, 132.03, 131.28, 131.14, 130.03 – 129.64 (m), 129.59, 129.22 – 128.94 (m), 128.28, 128.21 – 128.09 (m), 127.08, 126.78, 125.32, 122.59, 20.52. 19F NMR (376 MHz, DMSO‐d6) δ ‐60.89. ESI‐MS: m/z [M‐H]‐ calcd for C18H12F3NOS3: 410.0; found:
409.7. HRMS: m/z [M‐H]‐ calcd for C18H12F3NOS3: 409.9949; found: 409.9956.
(Z)‐5‐(2,4‐Bis(p‐tolylthio)benzylidene)‐2‐thioxothiazolidin‐4‐one SM57
Reaction batch: 2,4‐Bis(p‐tolylthio)benzaldehyde SM74 (355 mg, 1.0 mmol); rhodanine (133 mg, 1.0 mmol). Yellow solid in 45% (210 mg, 0.5 mmol) yield. M.p. 209°C. Rf 0.51 (PE–EtOAc, 3:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.84 (bs, 1H), 7.80 (s, 1H), 7.37 (d, J 8.3 Hz, 1H), 7.30 – 7.25 (m, 2H), 7.22 – 7.11 (m, 7H), 6.62 (d, J 2.0 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H).
13C NMR (101 MHz, DMSO‐d6) δ 195.38, 169.10, 142.80, 140.76, 139.29, 138.65, 134.18,
132.97, 130.59, 130.51, 128.87, 128.50, 127.65, 127.06, 126.66, 126.58, 126.06, 124.96, 20.82, 20.75. No response in ESI and HRMS. CHN analysis: calcd: C 61.90, H 4.11, N 3.01;
found: C 61.66, H 4.11, N 3.17.
(Z)‐5‐((4‐Bromo‐5‐(p‐tolylthio)thiophen‐2‐yl)methylene)‐2‐thioxothiazolidin‐4‐one SM58
Reaction batch: 4‐bromo‐5‐(p‐tolylthio)thiophene‐2‐carbaldehyde SM75 (150 mg, 0.48 mmol); rhodanine (64 mg, 0.48 mmol). Yellow solid 83% (171 mg; 0.4 mmol) yield.
M.p. 209°C. Rf 0.57 (PE–EtOAc, 2:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.86 (bs, 1H), 7.76 (s, 1H), 7.76 (s, 1H), 7.37 – 7.32 (m, 2H), 7.26 (d, J 8.1 Hz, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 193.95, 168.98, 139.33, 138.92, 138.73, 136.99, 130.84, 130.61, 129.37, 125.23, 122.37, 116.88, 20.69. ESI‐MS: m/z [M‐H]‐ calcd for C15H10BrNOS4: 425.9 (79Br), 427.9 (81Br);
found: 425.6 (79Br), 427.6 (81Br). HRMS: m/z [M‐H]‐ calcd for C17H11BrFNOS3: 425.8745 (79Br), 427.8724 (81Br); found: 425.8752 (79Br), 427.8727 (81Br).
Synthesis of (Z)‐5‐(1‐(3‐Nitro‐4‐(p‐tolylthio)phenyl)ethylidene)‐2‐thioxothiazolidin‐4‐one SM33
A mixture of 1‐(3‐nitro‐4‐(p‐tolylthio)phenyl)ethanone SM62 (191 mg, 0.67 mmol), rhodanine (144 mg, 1.08 mmol and NH4OAc (81 mg, 1.03 mmol) in toluene (5 mL) was stirred at reflux until the reaction was completed. The reaction mixture was cooled to room temperature and H2O (6 mL) was added. The precipitate was washed thoroughly with toluene, H2O, ethanol and ether to get the pure ocher SM33 in 78% (210 mg, 0.52 mmol) yield. M.p. 228°C. Rf= 0.70 (PE–EtOAc, 1:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.42 (bs, 1H), 8.34 (d, J 1.9 Hz, 1H), 7.59 (dd, J 8.5, 2.0 Hz, 1H), 7.56 – 7.52 (m, 2H), 7.40 (d, J 7.9 Hz, 2H), 6.76 (d, J 8.5 Hz, 1H), 2.40 (s, 3H), 2.21 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 194.37, 165.77, 143.77, 143.31, 140.60, 138.57, 135.79, 135.70, 133.89, 131.17, 126.99, 126.04, 125.61, 99.51, 26.77, 20.89. ESI‐MS: m/z [M‐H]‐ calcd for C18H14N2O3S3: 401.0; found: 400.8.
HRMS: m/z [M‐H]‐ calcd for C H N O S : 401.0083; found: 401.0077.
Synthesis of 5‐(3‐Nitro‐4‐(p‐tolylthio)benzyl)‐2‐thioxothiazolidin‐4‐one SM34
A stirred suspension of SM1 (0.504 g, 1.30 mmol) in toluene (50 mL) was treated with diethyl 2,6‐dimethyl‐1,4‐dihydro‐3,5‐pyridinedicarboxylate (0.427 g, 1.69 mmol) and silica gel 60 (1.3 g, 1 g mmol‐1), previously activated by heating at 120°C for 5 h. The mixture was heated to 100°C for 24 h under N2 atmosphere and the exclusion of light. The reaction mixture was cooled and filtered. The filter cake was rinsed with EtOAc. The filtrates were combined, rinsed and concentrated in vacuo. The residue was dissolved in EtOAc (30 mL) and washed with aq HCl (1 M, 3×30 mL) and brine (30 mL). The organic phase was dried over MgSO4, concentrated in vacuo and the crude product was purified by silica gel column chromatography using n‐hexane/EtOAc mixtures to give compound SM34 as a yellow solid in 82% (0.413 g, 1.06 mmol) yield. M.p. 80°C. Rf= 0.30 (PE–EtOAc, 3:1). 1H NMR (400 MHz, DMSO‐d6) δ 13.18 (bs, 1H), 8.15 (d, J 1.8 Hz, 1H), 7.52 – 7.48 (m, 2H), 7.45 (dd, J 8.4, 1.9 Hz, 1H), 7.37 (d, J 7.9 Hz, 2H), 6.77 (d, J 8.4 Hz, 1H), 5.03 (dd, J 8.2, 5.4 Hz, 1H), 3.41 (dd, J 14.2, 5.4 Hz, 1H), 3.28 (dd, J 14.2, 5.4 Hz, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO‐d6) δ 203.15, 177.82, 144.28, 140.33, 136.81, 135.48, 135.37, 134.93, 131.07, 127.99, 126.43, 126.25, 54.81, 35.14, 20.87. ESI‐MS: m/z [M‐H]‐ calcd for C17H14N2O3S3: 389.0; found: 388.8.
HRMS: m/z [M‐H]‐ calcd for C17H14N2O3S3: 389.0083; found: 389.0090.