| 87% |
With bromine; iron In acetic acid at 20℃; for 72h; |
|
| 87.9% |
With bromine; acetic acid at 20℃; for 39.1h; Large scale; |
1.1 Preparation of 6-Bromobenzo 1 ,3]dioxole-5-carbaldehyde
A solution of bromine (33.0 kg, 206.49 mol) in acetic acid (27.5 L) was added slowly to a solution of piperonal (1a) (29.9 kg, 199.16 mol) in acetic acid (105 L) at room temperature over a period of 50 min and the reaction mixture was stirred at room temperature for 14.2 h. Additional solution of bromine (33 kg, 206.49 mol) in acetic acid (27.5 L) was added slowly to the reaction mixture over a period of 2 h and the reaction mixture was stirred for 22 h. The reaction mixture was quenched by addition of ice water (500 L) with stirring over a period of 6 h and continued stirring for additional 1.25 h. The mixture was allowed to settle and most of the supernatant liquid was decanted to a waste container using nitrogen pressure. Water (600 L) was added to the solid, stirred, mixture was allowed to settle and then most of the supernatant liquid was decanted to a waste container using nitrogen pressure. Water (100 L) was added to the decanted mixture, stirred for 15 min and the solid obtained was collected by filtration using a centrifuge. The solid was washed with water (2 x 100 L) and air-dried in a tray drier for 3.75 h to afford the crude product 1 b (52 kg). The crude product (51.2 kg) was stirred in n-hexane (178 L) for 3 h, collected by filtration, washed with n-hexane (25 L) and dried to afford 6-bromobenzo[1 ,3]dioxole-5-carbaldehyde (1b) (40.1 1 kg, 87.9%) as a light brown solid. MP: 109-112°C. 1H NMR (300 MHz, CDCI3) δ 10.21 (s, 1 H), 7.37 (s, 1 H), 7.07 (s, 1 H), 6.10 (s, 2H); HNMR (DMSO-cf6): δ 10.06 (s, 1 H), 7.42 (s, 1 H), 7.29 (s, 1 H), 6.20 (d, J =12.3 Hz, 2H) |
| 87.9% |
With bromine In acetic acid at 20℃; for 39.03h; Large scale; |
1.1 Step-1 : Preparation of 6-Bromobenzo[l,3]dioxole-5-carbaldehyde (lb):
A solution of bromine (33.0 kg, 206.49 mol) in acetic acid (27.5 L) was added slowly to a solution of piperonal (la) (29.9 kg, 199.16 mol) in acetic acid (105 L) at room temperature over a period of 50 min and the reaction mixture was stirred at room temperature for 14.2 h. Additional solution of bromine (33 kg, 206.49 mol) in acetic acid (27.5 L) was added slowly to the reaction mixture over a period of 2 h and the reaction mixture was stirred for 22 h. The reaction mixture was quenched by addition of ice water (500 L) with stirring over a period of 6 h and continued stirring for additional 1.25 h. The mixture was allowed to settle and most of the supernatant liquid was decanted to a waste container using nitrogen pressure. Water (600 L) was added to the solid, stirred, mixture was allowed to settle and then most of the supernatant liquid was decanted to a waste container using nitrogen pressure. Water (100 L) was added to the decanted mixture, stirred for 15 min and the solid obtained was collected by filtration using a centrifuge. The solid was washed with water (2 χ 100 L) and air-dried in a tray drier for 3.75 h to afford the crude product lb (52 kg). The crude product (51.2 kg) was stirred in -hexane (178 L) for 3 h, collected by filtration, washed with -hexane (25 L) and dried to afford 6-Bromobenzo[l,3]dioxole-5-carbaldehyde (lb) (40.1 1 kg, 87.9%) as a light brown solid. MP: 109-1 12°C. NMR (300 MHz, CDCh) δ 10.21 (s, 1H), 7.37 (s, 1H), 7.07 (s, 1H), 6.10 (s, 2H); NMR (OMSO-de): δ 10.06 (s, 1H), 7.42 (s, 1H), 7.29 (s, 1H), 6.20 (d, J =12.3 Hz, 2H). |
| 85% |
With bromine; acetic acid at 20 - 50℃; for 26h; |
|
| 85% |
With iodine pentoxide; potassium bromide In water at 20℃; for 23h; regioselective reaction; |
Typical Procedure for the Bromination of Aromatic CompoundsUsing I2O5-KBr in Water
General procedure: A mixture of arene (0.5 mmol), I2O5 (334 mg, 1.0 mmol), and KBr (148 mg, 1.25 mmol) was dissolved in 2mL of H2O. The reaction was complete after stirring for the indicated time at room temperature. The mixture was extracted by ethyl acetate and concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel) to afford the desired product. |
| 84% |
With bromine; iron In acetic acid |
|
| 84% |
With bromine; iron(III) chloride; acetic acid |
|
| 82% |
With bromine In acetic acid |
|
| 82% |
With bromine In acetic acid for 20h; Ambient temperature; |
|
| 79% |
With bromine In acetic acid at 20℃; for 24h; |
|
| 77% |
With bromine; iodine; acetic acid In carbon disulfide at 20℃; for 48h; |
|
| 76% |
With bromine; iron; acetic acid at 20℃; for 72h; |
|
| 70% |
With bromine; iodine In carbon disulfide; acetic acid |
|
| 70% |
With bromine; iodine; acetic acid In carbon disulfide at 20℃; |
|
| 70% |
With bromine; iodine; acetic acid In carbon disulfide at 20℃; for 48h; |
|
| 70% |
With bromine; acetic acid In methanol at 20℃; |
|
| 70% |
With bromine; acetic acid at 20℃; for 3.5h; |
Synthesis of 23: 6-bromobenzo[d] [l,3]dioxole-5-carbaldehyde (0256) Three necked RBF (500 mF) equipped with dropping funnel, magnetic stirrer, and stopper was charged with benzo[d][l ,3]dioxole-5-carbaldehyde (22, 17 g, 0.12 mol) and acetic acid (130 mF). To this solution was added bromine (12.3 mF) in acetic acid (60 mF) dropwise with constant stirring over half an hour and stirring was further continued for 3 hours at room temperature. During this time all the starting materials was consumed as confirmed by TFC (3:7, EtOAc: Hexane). Water (250 mF) was added to the reaction mixture and cooled to 0 °C. The precipitated solid was filtered off, washed with cold water and dried under vacuum to get a white solid 6-bromobenzo[d][l,3]dioxole-5-carbaldehyde (23). (0257) Pure compound = 18 gm. % Yield = 70 %. |
| 68% |
With bromine; iron; acetic acid at 0 - 20℃; |
|
| 67.3% |
With bromine In acetic acid Inert atmosphere; |
1.1.4 Synthesis of 2-bromo-4,5-methylenedioxybenzaldehyde (3d)
Prepared essentially according to the literature [4], starting with piperonal (45.04 g, 0.3 mol) and bromine (18.5 mL, 0.36 mol) in glacial acetic acid (250 mL). Workup was performed using column chromatography (Silica gel, n-hexane/THF 8/1), yielding 3d as colourless needles (46.2 g, 67.3%), mp 129-130°C (EtOH). Chemical formula: C8H5BrO3. Molecular weight: 229.03. Elemental analysis: Calculated: C, 41.95; H, 2.20; found: C, 41.73; H, 2.14. 1H-NMR (400 MHz; CDCl3): 6.08 (s, 2H, OCH2O), 7.05 (s, 1H, C3-H), 7.35 (s, 1H, C6-H), 10.17 (s, 1H, CHO). 13C-{1H}-NMR (100 MHz; CDCl3): 102.7, 108.1, 113.3, 121.6, 128.0, 148.1, 153.3, 190.4. |
| 65% |
With bromine; acetic acid at 20℃; for 72h; |
|
| 63% |
With bromine; iodine In acetic acid for 72h; Ambient temperature; |
|
| 63% |
With bromine; acetic acid for 18h; |
|
| 60% |
With bromine In acetic acid for 48h; Ambient temperature; |
|
| 59% |
With bromine In acetic acid Ambient temperature; |
|
| 56% |
With bromine; acetic acid at 18℃; for 16h; |
|
| 54% |
With bromine; acetic acid |
|
| 54% |
With bromine In acetic acid for 18h; |
|
| 50% |
With bromine In water; acetic acid |
1.A Part A.
Part A. 2-Bromo-4,5-methylenedioxybenzaldehyde Piperonal (30 g, 0.2 mol) was dissolved in glacial acetic acid and treated with a solution of bromine (80 g, 0.5 mol) in glacial acetic acid (100 mL). The resulting brown solution was stirred 16 hours at room temperature and then water (300 mL) was added. The solid precipitate was collected by filtration under reduced pressure, washed with water and recrystallized from 10% aqueous methanol (450 mL) to give the product (23 g, 50%) as white needles, mp 123-125° C. 1 H NMR (200 MHz, CDCl3) δ 10.18 (1H, s), 7.38 (1H, s), 7.08 (1H, s), 6.10 (2H, s). |
| 48% |
With bromine; acetic acid at 20℃; for 24.5h; |
1.1 Preparation of 6-bromobenzofdl[1,3ldioxole-5-carbaldehvde (1b)
To a mixture of piperonal (1a) (498 g, 3.32 mol) in glacial acetic acid (1000 mL) was added a solution of bromine (200 mL, 3.89 mol) in glacial acetic acid (500 mL) over a period of 30 min and stirred at room temperature for 24h. The reaction mixture was poured into water (2000 mL) and the solid that separated was collected by filtration. The solid was dissolved in boiling ethanol (4000 mL) and cooled to room temperature. The solid obtained on cooling was collected by filtration to furnish 6-bromobenzo[d][1 ,3]dioxole-5-carbaldehyde (lb) (365 g, 48 %) as a white solid, MP 126 °C; HNMR (300 MHz, DMSO-d6): δ 10.06 (s, 1 H), 7.42 (s,1 H), 7.29 (s, 1 H), 6.20 (d, J=12.3, 2H); IR (KBr) 3434, 2866, 1673,1489, 1413, 259, 1112, 1031 , 925 cm"1; Analysis calculated for CeH5BrO3.O 25H C, 41.15; H, 2.37; Found: C, 41.07; H, 2.11. |
|
With carbon disulfide; bromine; iodine |
|
|
With bromine; acetic acid |
|
|
With bromine In acetic acid for 2h; Ambient temperature; |
|
|
With bromine; sodium acetate; acetic acid |
|
| 36 %Chromat. |
With nitric acid; potassium bromide In acetic anhydride at 20℃; |
|
|
With bromine In acetic acid at 20℃; Inert atmosphere; |
|
|
With bromine; acetic acid In acetic acid |
6-bromo-l,3-benzodioxole-5-carbaldehyde
To a solution of Intermediate 30 (2170 mg, 14.5 mmol) in acetic acid (10 mL) was added bromine (2.4 g, 15.0 mmol). The solution was stirred for 5 hours before bromine (2.4 g) was added. The solution was stirred for a further 18 hours. The solvent was removed, and the oil was pre-absorbed onto silica. Purification by flash column chromatography eluting with a gradient of 0 to 20% of EtOAc in heptane afforded the title compound as a pale-yellow solid (1.1 g, 33% yield) as well as a 2:1 mixture of intermediates 31 & 30 (2.67 g). LCMS [M+H]+ 228/230, RT 1.81 minutes (Method 4). |
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