2,2,3-Tribromopropanal as a Versatile Reagent in the Skraup-Type Synthesis of 3-Bromoquinolin-6-ols

Abstract

2,2,3-Tribromopropanal, a reagent which almost became forgotten in the chemical literature after its first application in the 1950s, is used for the one-step transformation of diversely substituted 4-nitro- and 4-methoxyanilines into 3-bromo-6-nitroquinolines and 3-bromo-6-methoxyquinolines. These intermediates are then converted, in one further step, into 3-bromoquinolin-6-ols, which may carry additional substituents at positions 7 and 8.

Key words

anilines - quinolone - heterocycle - cyclization - Skraup reaction - kinase inhibitor - fungicide

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• 22 2,2,3-Tribromopropanal (2) Br₂ (103 mL, 319 g, 2.0 mol) was added dropwise over 2 h to a solution of acrolein (1) (131 mL, 112 g, 2.0 mol) in DCE (320 mL) at r.t. During the addition, the color changed from colorless to orange and the reaction temperature was kept in the range 20–40 °C. Following addition, the mixture was stirred for 2 h at r.t., then another equivalent of Br₂ (103 mL, 319 g, 2.0 mol) was added dropwise over 2 h. The red–brown mixture was stirred for 16 h at r.t., evaporated under reduced pressure, and the residue purified by Vigreux column distillation to deliver 2,2,3-tribromopropanal (2) (494 g, 1.68 mol, 84%) as a slightly yellowish liquid. Bp 80–85 °C (0.02 mbar); ¹H NMR (400 MHz, CDCl₃): δ = 4.23 (s, 2 H), 9.16 (s, 1 H).
• 23 3-Bromo-8-methylquinolin-6-ol (5); Typical Procedures
  Method A
  3-Bromo-8-methyl-6-nitroquinoline (3) 2,2,3-Tribromopropanal (2) (29.4 g, 0.1 mol) was added slowly to a suspension of 2-amino-5-nitrotoluene (15.2 g, 0.1 mol) in glacial AcOH (200 mL). The mixture was heated to 110 °C for 1 h, cooled to r.t. and filtered. The remaining solid was washed with Et₂O, then suspended in H₂O (150 mL) and treated with aq sat. NaHCO₃ solution until a pH of 9 was reached. The suspension was transferred to a separating funnel and extracted with EtOAc (2 × 200 mL). The organic phase was dried over MgSO₄ and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, using EtOAc and heptane as eluents to afford 3-bromo-8-methyl-6-nitroquinoline (3) (20.7 g, 77 mmol, 77%) as yellow crystals.¹H NMR (400 MHz, CDCl₃): δ = 2.86 (s, 3 H), 8.35 (d, J = 2.1 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.54 (d, J = 2.2 Hz, 1 H), 9.06 (d, J = 2.1 Hz, 1 H).3-Bromo-8-methylquinolin-6-ol (5) Reduced Fe powder (15 g, 0.27 mol) was added in portions to a suspension of 3-bromo-8-methyl-6-nitroquinoline (3) (20.6 g, 77 mmol) in a mixture of EtOH (400 mL) and 37% aq HCl (2 mL) at r.t. The mixture was heated at reflux temperature for 2 h, during which time the color of the suspension changed from grey–yellow to red–brown. The mixture was cooled to 40 °C, filtered through Celite, and the filtrate diluted with EtOH, treated with silica gel and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, using EtOAc and CH₂Cl₂ as eluents to deliver 6-amino-3-bromo-8-methylquinoline. This intermediate was suspended in a mixture of 85% aq phosphoric acid (125 mL) and H₂O (12 mL), and heated to 180 °C in a tantalum pressure vessel for 72 h. Subsequently, the mixture was cooled to r.t. and added to H₂O (250 mL). To this solution, 30% aq NaOH solution was added until a pH between 2–4 was reached. The resulting precipitate was filtered, washed with cold H₂O and dried to give 3-bromo-8-methylquinolin-6-ol (5) (12.3 g, 52 mmol, 67%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.64 (s, 3 H), 6.99 (d, J = 2.1 Hz, 1 H), 7.22 (d, J = 2.1 Hz, 1 H), 8.47 (d, J = 2.2 Hz, 1 H), 8.69 (d, J = 2.3 Hz, 1 H), 10.13 (s, 1 H). Method B 3-Bromo-6-methoxy-8-methylquinoline (4) 2,2,3-Tribromopropanal (2) (50.0 g, 0.18 mol) was added slowly to a suspension of 4-methoxy-2-methylaniline (25.0 g, 0.18 mol) in glacial AcOH (300 mL). The mixture was stirred for 6 h at r.t., then diluted with EtOAc (300 mL) and washed with H₂O (2 × 100 mL), brine (100 mL) and 2 M NaOH solution (100 mL). The organic layer was dried over MgSO₄ and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, using EtOAc and heptane as eluents to yield 3-bromo-6-methoxy-8-methylquinoline (4) (20.5 g, 81 mmol, 45%). ¹H NMR (400 MHz, CDCl₃): δ = 2.73 (s, 3 H), 3.90 (s, 3 H), 6.82 (d, J = 2.0 Hz, 1 H), 7.21 (d, J = 2.1 Hz, 1 H), 8.17 (d, J = 1.9 Hz, 1 H), 8.76 (d, J = 2.0 Hz, 1 H). 3-Bromo-8-methylquinolin-6-ol (5)A mixture of 3-bromo-6-methoxy-8-methylquinoline (4) (14.0 g, 55 mmol) in 48% HBr (250 mL) was slowly heated to 110 °C, and kept at this temperature for 20 h. Subsequently, the mixture was cooled and filtered. The residue was washed with H₂O, taken up in sat. aq NaHCO₃ solution and filtered again. The solid was washed with H₂O and dried under high vacuum to afford 3-bromo-8-methylquinolin-6-ol (5) (11.1 g, 47 mmol, 84%). The ¹H NMR spectroscopic data of the sample of compound 5 was identical to that obtained using method A.