# Simple Thalidomide Analogs in Melanoma: Synthesis and Biological Activity
## Materials and Methods
### Chemistry
Yield: 55%: mp 201-202 \({}^{\circ}\)C (CHCl\({}_{3}\)/hexane); GC/MS (70 eV) _m/z_ (%): 329 (M\({}^{+}\), 100); \({}^{1}\)H NMR (300 MHz, CDCl\({}_{3}\)): 8 2.15-2.36 (m, 3H, CH\({}_{3}\)), 6.97 (d, \(J\) = 8.2 Hz, 2H, Ar), 7.11 (d, \(J\) = 21.7 Hz, 2H, Ar), 7.16 (d, \(J\) = 8.2 Hz, 2H, Ar), 7.34 (d, \(J\) = 8.8 Hz, 2H, Ar), 7.76-7.79 (m, 2H, Ar), 7.92-7.95 (m, 2H, Ar); \({}^{13}\)C NMR (125 MHz, CDCl\({}_{3}\)): \(\delta\) 20.7 (1C), 118.3 (2C), 119.7 (2C), 123.7 (2C), 125.9 (1C), 128.0 (2C), 130.4 (2C), 131.8 (2C), 133.6 (1C), 134.4 (2C), 154.0 (1C), 157.8 (1C), 167.4 (2C). Anal C\({}_{21}\)H\({}_{15}\)NO\({}_{3}\) (329.11): calcd %: C 76.58; H 4.59; N 4.25. Found %: C 76.43; H 4.53; N 4.35. _Synthesis of 2-(4-phenoxyphenyl)-1H-isointol-1,3(2H)-dione_**(2d)**. Prepared as described for 2a starting from 4-phenoxyavailine. Grey solid. Yield: 65%: mp 161-162 \({}^{\circ}\)C (CHCl\({}_{3}\)/hexane); GC/MS (70 eV) _m/z_ (%): 315 (M\({}^{+}\), 100); \({}^{1}\)H NMR (500 MHz, CDCl\({}_{3}\)): \(\delta\) 7.06-7.15 (m, 5H, Ar), 7.35-7.38 (m, 4H, Ar), 7.78-7.79 (m, 2H, Ar), 7.94-7.95 (m, 2H, Ar); \({}^{13}\)C NMR (125 MHz, CDCl\({}_{3}\)): \(\delta\) 117.7 (d, 129.9 (2C), 134.4 (2C), 156.5 (1C), 157.2 (1C), 167.4 (2C). Anal C\({}_{20}\)H\({}_{13}\)NO\({}_{3}\)-0.20 H\({}_{2}\)O (318.69): calcd %: C 75.32; H 4.23; N 4.39. Found %: C 75.60; H 4.08; N 4.48. _Synthesis of 2-(4-chloro-2-fluorophenyl)-1H-isointol-1,3(2H)-dione_**(2e)**. Prepared as described for 2a starting from 4-chloro-2-fluorosaniline. White solid. Yield: 35%: mp 145-146 \({}^{\circ}\)C; GC/MS (70 eV) _m/z_ (%): 275 (M\({}^{+}\), 100); \({}^{1}\)H NMR (500 MHz, CDCl\({}_{3}\)): \(\delta\) 7.25-7.32 (m, 3H, Ar), 7.78-7.82 (m, 2H, Ar), 7.90-7.98 (m, 2H, Ar); \({}^{13}\)C NMR (125 MHz, CDCl\({}_{3}\)): \(\delta\) 117.7 (d, \(J_{\rm CF}\) = 22.9 Hz, 1C), 118.2 (d, \(J_{\rm CF}\) = 96.4 Hz, 1C), 124.0 (2C), 125.1 (d, \(J_{\rm CF}\) = 3.8 Hz, 1C), 130.5 (1C), 131.8 (2C), 134.6 (2C), 135.8 (d, \(J_{\rm CF}\) = 9.6 Hz, 1C), 157.7 (d, \(J_{\rm CF}\) = 256.5 Hz, 1C), 166.2 (2C). Anal C\({}_{14}\)H\({}_{2}\)CIFNO\({}_{2}\)-0.25 H\({}_{2}\)O (279.51): calcd %: C 60.02; H 2.70; N 5.00. Found %: C 60.42; H 2.50; N 5.07. _Synthesis of 2-(2-bromo-4-chlorophenylonyl)-1H-isointol-1,3(CDC\({}_{3}\)): $ 7.24-7.30 (m, 1H, Ar), 7.45 (d, \(l\) = 8.8 Hz, 1H, Ar), 7.75 (s, 1H, Ar), 7.79-7.86 (m, 2H, Ar), 7.94-8.01 (m, 2H, Ar); 1\({}^{3}\)C NMR (125 MHz, CDCl\({}_{3}\)): $ 123.9 (c), 124.0 (1C), 128.8 (2C), 130.1 (1C), 131.5 (1C), 131.8 (2C), 133.4 (1C), 134.6 (2C), 136.3 (1C), 166.3 (2C). Anal. C\({}_{14}\)H\({}_{2}\)BrCINO\({}_{2}\) (344.93): calcd %: C 49.96; H 2.10; N 4.16. Found %: C 49.96; H 2.05; N 4.15. _Synthesis of 2-(2-cloro-4-fluorophenyl)-1H-isionid-1,3(2H)-dione_ (**2g**). Prepared as described for **2a** starting from 2-cloro-4-fluororaniline. White solid. Yield: 68%: mp 188-189 \({}^{\circ}\)C (CHCl\({}_{3}\)/hexane); GC/MS (70 eV) _m/z_ (%): 275 (M\({}^{+}\), 7), 240 (100); \({}^{1}\)H NMR (500 MHz, CDCl\({}_{3}\)): $ 7.13 (t, \(l\) = 8.0 Hz, 1H, Ar), 7.32-7.35 (m, 2H, Ar), 7.80-7.84 (m, 2H, Ar), 7.94-8.00 (m, 2H, Ar); \({}^{13}\)C NMR (125 MHz, CDCl\({}_{3}\)): $ 115.1 (d, \(J_{\rm CF}\) = 22.9 Hz, 1C), 117.9 (d, \(J_{\rm CF}\) = 25.8 Hz, 1C), 124.0 (2C), 125.8 (d, \(J_{\rm CF}\) = 3.9 Hz, 1C), 131.8 (d, \(J_{\rm CF}\) = 8.7 Hz, 1C + s, 2C), 134.4 (d, \(J_{\rm CF}\) = 11.4 Hz, 1C), 134.6 (2C), 162.7 (d, \(J_{\rm CF}\) = 252.8 Hz, 1C), 166.6 (2C). Anal. C\({}_{14}\)H\({}_{2}\)ClFINO\({}_{2}\) (275.01): calcd %: C 61.00; H 2.56; N 5.08. Found %: C 60.71; H 2.49; N 5.06. _Synthesis of 2-(3,4-difluororphenyl)-1H-isionid-1,3(2H)-dione_ (**2h**). Prepared as described for **2a** starting from 3,4-difluororaniline. White solid.