Uses
2-Bromo-6-nitroaniline, is an intermediate used for the synthesis of metabolite of Brimonidine (B677520), which is an α2 receptor agonist. It is a drug used to treat glaucoma.
Synthesis
N-bromosuccinimide (44.5 g, 0.25 mol) was added to a solution of 2-nitroaniline (34.5 g, 0.25 mol) in acetic acid (400 mL) in batches over a period of 30 minutes over a temperature range of 308-318 K. The reaction mixture was stirred continuously for 3 hours. The reaction mixture was stirred continuously at 318 K for 3 hours, followed by warming to 363 K and continued stirring for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and poured into vigorously stirred cold water (4 L). After standing for 10 min, the orange precipitate was collected by filtration and washed with cold water (2 x 200 mL). The crude product was recrystallized by 80% ethanol and dried under vacuum to give pure 4-bromo-2-nitroaniline (39.9 g, 74% yield) as an orange crystalline solid. A second crystalline product (6.81 g) was isolated from the mother liquor and analyzed as a mixture of 4-bromo-2-nitroaniline and 2-bromo-6-nitroaniline (ratio 1:0.3). The nuclear magnetic resonance hydrogen spectroscopy (1H NMR) data were in agreement with those reported in the literature (Manley et al., 2003; Lemaire et al., 1989).The 1H NMR (300 MHz, CDCl3) data for 4-bromo-2-nitroaniline: δ 8.26 (dd, J = 2.3, 0.4 Hz, 1H), 7.42 (dd, J = 8.9 , 2.3 Hz, 1H), 6.73 (dd, J = 8.9, 0.4 Hz, 1H), 6.10 (s, 2H).1H NMR (400 MHz, CDCl3) data for 2-bromo-6-nitroaniline: δ 8.14 (dd, J = 8.7, 1.5 Hz, 1H), 7.70 (dd, J = 7.7, 1.5 Hz, 1H), 6.63 (s, 2H). 6.63 (s, 2H), 6.62 (dd, J = 8.7, 7.7 Hz, 1H). Single crystals of 4-bromo-2-nitroaniline and 2-bromo-6-nitroaniline were obtained by sublimation of the second crystallization product (from chloroform) and slow evaporation under reduced pressure conditions (323 K, 10 mbar; 1 bar = 105 Pa), respectively.
References
[1] Polyhedron, 2013, vol. 52, p. 246 - 254
[2] Synthetic Communications, 2000, vol. 30, # 20, p. 3669 - 3675
[3] Acta Crystallographica Section C: Structural Chemistry, 2018,
[4] Synthetic Communications, 2004, vol. 34, # 12, p. 2143 - 2152
[5] Tetrahedron Letters, 2012, vol. 53, # 2, p. 127 - 131
