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Structure of 103-88-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
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| CAS No. : | 103-88-8 |
| Formula : | C8H8BrNO |
| M.W : | 214.06 |
| SMILES Code : | CC(NC1=CC=C(Br)C=C1)=O |
| English Name : | 4-Bromoacetanilide |
| MDL No. : | MFCD00000092 |
| InChI Key : | MSLICLMCQYQNPK-UHFFFAOYSA-N |
| Pubchem ID : | 7683 |
| GHS Pictogram: | |
| Signal Word: | |
| Hazard Statements: | |
| Precautionary Statements: | |
| Class: | |
| UN#: | |
| Packing Group: |
| Num. heavy atoms | 11 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.12 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 1.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 48.45 |
| TPSA ? Topological Polar Surface Area: Calculated from |
29.1 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.91 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.29 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.22 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.27 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.04 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.15 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.88 |
| Solubility | 0.281 mg/ml ; 0.00131 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.54 |
| Solubility | 0.619 mg/ml ; 0.00289 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.64 |
| Solubility | 0.0486 mg/ml ; 0.000227 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.98 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.12 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.


| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With Copper; potassium carbonate at 180℃; Erwaermen des Reaktionsprodukts mit wss. Natronlauge; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 65% | With acetyl hypofluorite In dichloromethane; Freon-11 at -75℃; | |
| 32.8% | With Selectfluor In acetonitrile at 70℃; for 48h; regioselective reaction; | 2.4.2.Conventional fluorinations in CH3CN General procedure: A 50-mL round-bottomed flask equipped with a stir bar was charged with 25 mL CH3CN and the appropriate mass of the N-phenylacetamide derivative for the desired concentration (0.020 M, 0.074 M or 0.185 M). To this solution was added the fluorinating agent (0.5, 1.0, 1.5, or 2.0 eqs Selectfluor; 1.0 eq NFSI or NFP-TFB) slowly over a 10 min period and the solution stirred until dissolution was complete. A reflux condenser was affixed and the temperature (22 C, 50 C or 70 C) maintained thermostatically for the duration of the reaction. The solvent was then evaporated in vacuo, the solid residue taken up in 20 mL Et2O, washed with 3 ×5 mL aliquots of distilled, deionized water, the organic layer dried over Na2SO4 and concentrated in vacuo. The crude fluorinated product mixture was purified by chromatography. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | With cetyltrimethylammonim bromide; trichlorophosphate In acetonitrile for 1.41667h; Heating; | |
| 85% | With trichlorophosphate at 0 - 90℃; | |
| 75% | With trichlorophosphate at 75℃; for 8h; | 4.2. General procedure for the synthesis of compounds 2a-2f General procedure: POCl3 (9.0 mL, 96 mmol) was added dropwise to DMF (2.8 mL,36 mmol) precooled at 0 C. Followed by adding acetanilide(10 mmol), the mixture was heated to 75 °C and stirred at thattemperature for 8 h. After been cooled to room temperature, themixture was poured to 100mL of ice-water. The precipitate wasobtained by suction filtration, washed with cold water and dried toafford the product.1H NMR and 13C NMR data of selected productsare shown as follows. |
| 74% | With trichlorophosphate at 80 - 90℃; for 12h; | General procedure for synthesis of 2-chloroquinoline-3-carbaldehydes 3 To stirred DMF (3.6 mL, 46 mmol), 12.5 mL POCl3 (134 mmol) were added dropwise at 0-5 °C. The mixture was allowed to stir for 30 min. Acetanilide 2 (18.5 mmol) was then added and the resulting solution heated for 12 h at 80-90 °C. The mixture was poured into ice-cold water and stirred for 10 min, which resulted in yellow precipitation of the desired 2-chloroquinoline-3-carbaldehydes 3. The precipitate was filtered and washed with water and then dried. The compounds were purified by recrystallization from ethyl acetate. |
| 68% | With trichlorophosphate In 1,2-dichloro-ethane at 40℃; for 1h; ultrasound irradiation; | |
| 60% | Stage #1: 4-bromoacetanilide; N,N-dimethyl-formamide With trichlorophosphate at 75℃; for 48h; Inert atmosphere; Stage #2: With water | |
| 45% | With trichlorophosphate at 85℃; for 24h; | |
| 35% | With trichlorophosphate at 80 - 90℃; for 16h; | |
| 35% | With trichlorophosphate at 0 - 80℃; for 16h; | |
| 28% | Stage #1: N,N-dimethyl-formamide With phosphorus pentachloride at 0℃; for 0.25h; Stage #2: 4-bromoacetanilide for 4h; Reflux; | Synthesis of 2-chloroquinoline-3-carbaldehydes 5a-i General procedure: Dimethylformamide (12 mmol, 3 equiv.) was cooled at 0°C in a round flask equipped with a drying tube and phosphorus pentachloride (18 mmol, 4.5 equiv.) was added slowly and the mixture was stirred for 15 minutes keeping the temperature below 0°C. To this solution was added in a portion the corresponding acetanilide (4 mmol, 1 equiv.) and the reaction mixture was heated under reflux and stirring for the appropiate time depending of the acetanilide. The resulted mixture was cooled to 0°C and the solution was poured slowly into ice-water and stirring for ten minutes, obtaining a yellow solid which was filtered, washed several time with cold water and dried under vacuum. The 2-chloroquinoline-3-carbaldehydes were recrystallized according to the literature. |
| 27% | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at -5℃; Inert atmosphere; Stage #2: 4-bromoacetanilide at 80℃; Inert atmosphere; | 5.2.1. 2-chloroquinoline-3-carbaldehyde (2a) General procedure: Phosphorus oxychloride (19 ml, 207.16 mmol) was added drop wise at -5°C to DMF (7 ml, 88 mmol) under N2, then the acetanilide 1a(4.000 g, 29.59 mmol) was added at room temperature. The mixture was stirred overnight at 80 °C, then slowly poured on ice, filtered and dried to obtain compound 2a as light yellow solid; yield (5.100 g, 90%)Rf (15% EtOAc/Hexane)- 0.56. |
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; Stage #2: 4-bromoacetanilide for 16h; Heating; | ||
| With trichlorophosphate at 75℃; for 48.5h; Inert atmosphere; Sealed tube; Cooling with ice; | II.1 Step 1; DMF (54 ml, 701 mmol, 2.5 eq.) was added dropwise (via a syringe pump) to phosphoryl trichloride (179 ml, 1962 mmol, 7.0 eq.) in a 350 mL sealed tube in an ice bath under nitrogen. After the addition, the water bath was removed and N-(4-bromophenyl) acetamide (60 g, 280 mmol) was added in one portion and the resulting mixture was stirred until a homogenous solution was observed (approx. 30 min.). The reaction vessel was sealed and heated at 75 °C for 48 h. The reaction was allowed to cool and slowly poured onto ice (final volume of 2 L) and stirred for 25 min. The solid was filtered and washed with water until the filtrate was no longer acidic (~3 L) and the product was dried in an oven vacuum overnight at 50 °C to afford a light tan/gold colored solid, 6-bromo-2- chloroquinoline-3 -carbaldehyde. | |
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate Cooling with ice; Sealed tube; Inert atmosphere; Stage #2: 4-bromoacetanilide at 75℃; for 48.5h; Stage #3: With water Cooling with ice; | 7.3 Step 3: MN-dimethylformamide (54 ml, 0.70 mol) was added dropwise (via a syringe pump) to phosphoryl trichloride (179 ml, 1.96 mol) in a 350 mL sealed tube in an ice bath under nitrogen. After the addition, the water bath was removed and N-(4- bromophenyl)acetamide (60 g, 0.28 mol) was added in one portion and stirred until a homogenous solution was observed (approx. 30 min.). The reaction vessel was sealed and heated at 75 °C for 48 h. The reaction was allowed to cool and slowly poured onto ice (final volume of 2 L) and stirred for 25 min. The solid was filtered and washed with water until the filtrate was no longer acidic (~3 L) and the product was dried in an oven vacuum overnight at 50 °C to afford 6-bromo-2-chloroquinoline-3-carbaldehyde as a light tan colored solid. | |
| With trichlorophosphate | ||
| With trichlorophosphate at 0℃; Reflux; | General procedure for the synthesis of 6-substituted-2-chloroquinoline-3-carbaldehydes 2a-d (Meth-Cohnet al., 1981) General procedure: Dimethylformamide 9.6 mL (0.125 mol)was cooled to 0 C, and phosphoryl chloride 32.2 mL(0.35 mol) was added drop-wise with stirring. To thissolution was added substituted acetanilide 1a-d (0.05 mol)and the reaction mixture was refluxed for 16-17 h. Reactioncompletion was monitored by TLC. The reactionmixture was poured into ice water (300 mL) and stirred for30 min at 0-10 °C. The resulting suspension was filteredand washed with water to give the intermediates 2a-d. | |
| With trichlorophosphate | ||
| With trichlorophosphate for 24h; Heating; | ||
| With trichlorophosphate at 70 - 80℃; for 16h; | Preparation of 2-chloroquinolin-3-carbaldehyde (6c-i) General procedure: Vilsmeir-Haack adduct was prepared by adding phosphorous oxychloride (0.35 mol) drop wise to the cold solution of DMF (0.125 mol) with constant stirring. To this adduct, substituted acetanilide (0.05 mol) was added slowly and stirred well for 15-20 min. The mixture was then refluxed for 16 h at 70-80°C. After completion of the reaction, the contents were poured into ice water and stirred for 30 min. The 2-chloroquinoline-3-carbaldehyde 6c-i precipitated out was filtered and washed well with water. Dried and recrystallized from ethyl acetate. | |
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.25h; Stage #2: 4-bromoacetanilide at 80℃; for 8h; | ||
| With trichlorophosphate for 6h; Reflux; | ||
| With trichlorophosphate at 80 - 90℃; | ||
| With trichlorophosphate at 80℃; | 3.2.1. Synthesis of 2-Chloroquinoline-3-carbaldehydes (6a-e) General procedure: These compounds were prepared by following the Meth-Cohn method [58]. DMF(11.6 mL, 150 mmol), in a round-bottom flask was cooled in an ice-water bath to0.0-2.5 C and phosphoryl chloride (32.2 mL, 350 mmol) was added dropwise with stirring.To this solution, the corresponding acetanilide (50 mmol) was added and the temperatureof the reaction mixture was raised to 80 C during 20 h. Finally, the mixture was pouredinto ice-water (300 mL) for 30 min. The precipitate formed was filtered off, washed withcold water and recrystallized from acetonitrile. | |
| 48 % | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at -5 - 0℃; Inert atmosphere; Schlenk technique; Stage #2: 4-bromoacetanilide at 20 - 90℃; Inert atmosphere; Schlenk technique; | |
| With trichlorophosphate at 0 - 90℃; | 4.2.2. General procedure for synthesis of compound 3 General procedure: DMF (42 mmol) was added dropwise to a solution of compound 2(16.7 mmol) in POCl3 (116.7 mmol) at 0 C, after completion, the icewaterbath was removed, the solution was heated to 90 C and stirredfor 6 h (monitored by TLC, VEA/VPE = 1/2). The solution was allowed tocool to room temperature, poured into ice water (200 mL) and theresulting mixture was stirred for 30 min. The precipitate was filtered andwashed with saturated sodium bicarbonate solution and afforded 3 as ayellow solid. Yield 40 % ~ 70 %. The crude 3 was used directly in thenext step without further purification. | |
| With trichlorophosphate at 0 - 90℃; | 4.2.2. General procedure for synthesis of compound 3 General procedure: DMF (42 mmol) was added dropwise to a solution of compound 2(16.7 mmol) in POCl3 (116.7 mmol) at 0 C, after completion, the icewaterbath was removed, the solution was heated to 90 C and stirredfor 6 h (monitored by TLC, VEA/VPE = 1/2). The solution was allowed tocool to room temperature, poured into ice water (200 mL) and theresulting mixture was stirred for 30 min. The precipitate was filtered andwashed with saturated sodium bicarbonate solution and afforded 3 as ayellow solid. Yield 40 % ~ 70 %. The crude 3 was used directly in thenext step without further purification. | |
| With trichlorophosphate at 0 - 90℃; | 2.2.1. General synthesis procedure of 2-Chloro-quinoline-3-carbaldehydederivatives 2a - 2b General procedure: To a solution of DMF (4.27 g, 58.39 mmol) was added POCl3 (32.23g, 210.22 mmol) dropwise at 0 C. Then acetanilide derivative 1a - 1b(23.36 mmol) was added and the reaction mixture was stirred andrefluxed at 90 C. After the reaction was completed through TLCdetection, the mixture was cooled to room temperature, poured into icewater(500 mL) and stirred for another 30 min. Then the solid wasfiltered, washed with water, and dried at room temperature to givecompounds 2a - 2b as brown solid with the yield of 31-55 %. | |
| With trichlorophosphate at 85℃; for 18h; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | Stage #1: 4-bromoacetanilide With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: iodomethane In N,N-dimethyl-formamide at 20℃; for 1h; | 7.ii (ii) N-(4-Bromophenyl)-N-methylacetamide Sodium hydride (101.5 mg, 2.33 mmol) (55% in paraffin liquid) was added to a solution of 249 mg (1.16 mmol) of the title compound produced in step (i) of Reference Example 7 in N,N-dimethylformamide (2.5 ml), and the mixture was stirred at room temperature for 30 min. Thereafter, methyl iodide was added, and the mixture was stirred at room temperature for 1 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 2 : 1) to give 239 mg (yield 90%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 1.88 (3H, s), 3.24 (3H, s), 7.08 (2H, d, J = 8.5 Hz), 7.54 (2H, d, J = 8.5 Hz). MS (FAB+) m/z: 227 (M+ + 1). |
| 84% | Stage #1: 4-bromoacetanilide With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran; mineral oil at 20℃; for 14h; Inert atmosphere; | |
| 82% | Stage #1: 4-bromoacetanilide With sodium hydride In tetrahydrofuran for 0.166667h; Sealed tube; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at 60℃; Inert atmosphere; Sealed tube; |
| 74% | Stage #1: 4-bromoacetanilide With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: iodomethane In N,N-dimethyl-formamide at 0 - 20℃; for 16h; | N-(4-Bromophenyl)-7V-methyl-acetamide (62) EPO 4-bromoacetanilide (1.0 g, 4.67 mmol) in DMF (5 mL) is added dropwise to a suspension of sodium hydride (224 mg, 5.61 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0°C. After stirring 1 h at 0°C, iodomethane (349 μl, 5.61 mmol) is added and the reaction mixture warmed to RT and stirred 16 h. The reaction is quenched with water (15 mL) and extracted into EtOAc (3 x 15 mL); the combined organic phases are then dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (40% EtOAc in heptane) gives the title compound. Yield: 780 mg (74%).LC/MS tr 1.17 min. MS(ES+) m/z 230, 228 (M+H |
| 74% | Stage #1: 4-bromoacetanilide With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: iodomethane In N,N-dimethyl-formamide at 0 - 20℃; for 16h; | Synthesis of Compound 318λf-(4-Bromophenyl)-λ''-methyl-acetamide (62)4-bromoacetanilide (1.0 g, 4.67 mmol) in DMF (5 mL) was added dropwise to a suspension of sodium hydride (224 mg, 5.61 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0°C. After stirring 1 h at 0°C, iodomethane (349 μl, 5.61 mmol) was added and the reaction mixture warmed to RT and stirred 16 h. The reaction was quenched with water (15 mL) and extracted into EtOAc (3 x 15 mL); the combined organic phases were then dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (40% EtOAc in heptane) gave the title compound.Yield: 780 mg (74%).LCZMS f1. 1.17 min.MS(ES+) m/z 230, 228 (M+H). |
| 74% | Stage #1: 4-bromoacetanilide With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: iodomethane In N,N-dimethyl-formamide at 20℃; for 16h; | JV-(4-Bromophenyl)-7V-methyl-acetamide (62); EPO 4-bromoacetanilide (1.0 g, 4.67 mmol) in DMF (5 mL) is added dropwise to a suspension of sodium hydride (224 mg, 5.61 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0°C. After stirring 1 h at 0°C, iodomethane (349 μl, 5.61 mmol) is added and the reaction mixture warmed to RT and stirred 16 h. The reaction is quenched with water (15 mL) and extracted into EtOAc (3 x 15 mL); the combined organic phases are then dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (40% EtOAc in heptane) gives the title compound. Yield: 780 mg (74%). LC/MS fr 1.17 min. MS(ES+) m/z 230, 228 (M+H). |
| 74% | Stage #1: 4-bromoacetanilide With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: iodomethane In N,N-dimethyl-formamide at 20℃; for 16h; | Synthesis of Compound 318; yV-(4-Bromophenyl)-7V-methyl-acetamide (62); 4-bromoacetanilide (1.0 g, 4.67 mmol) in DMF (5 mL) is added dropwise to a suspension of sodium hydride (224 mg, 5.61 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0°C. After stirring 1 h at 0°C, iodomethane (349 μl, 5.61 mmol) is added and the reaction mixture warmed to RT and stirred 16 h. The reaction is quenched with water (15 mL) and extracted into EtOAc (3 x 15 mL); the combined organic phases are then dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (40% EtOAc in heptane) gives the title compound. Yield: 780 mg (74%).LC/MS ;r 1.17 min. MS(ES+) m/z 230, 228 (M+H). |
| With sodium hydride In tetrahydrofuran at 20℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 73% | With pyridine; quinoline; nickel dichloride for 3h; Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate at 150℃; for 0.1h; Irradiation; microwave; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With caesium carbonate; XPhos In tetrahydrofuran; water at 80℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 46% | With caesium carbonate In water; toluene at 95℃; for 12h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: NaClO3, HCl / acetic acid / -0.1 °C 2: HCl 3: IBr, AcOH |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 182 mg (86%) | With potassium fluoride;palladium diacetate; In tetrahydrofuran; | EXAMPLE 38 Synthesis of N-acetyl-4-aminobiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol percent), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4'-bromoacetanilide (214 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 182 mg (86percent) of the title compound. |
| 182 mg (86%) | With potassium fluoride;palladium diacetate; In tetrahydrofuran; | Example 38 Synthesis of N-acetyl-4-aminobiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol percent), phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4'-bromoacetanilide (214 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 182 mg (86percent) of the title compound. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | With 2-acetonylpyridine; caesium carbonate; copper(I) bromide In dimethyl sulfoxide at 90℃; for 18h; Inert atmosphere; chemoselective reaction; | |
| 84% | With potassium phosphate; 2-di-tert-butylphosphino-2',4',6'-tricyclohexyl-3,6-dimethoxybiphenyl In 1,2-dimethoxyethane; toluene at 100℃; for 24h; Inert atmosphere; | |
| In dimethyl sulfoxide at 120℃; for 48h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94.7% | With thionyl chloride In methanol for 3h; Reflux; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 87% | With bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); caesium carbonate In water; toluene at 100℃; for 24h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 69% | With silver hexafluoroantimonate; [RhCl2(p-cymene)]2 In acetic acid at 130℃; for 24h; Inert atmosphere; Glovebox; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 71% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; triethylamine; In 1,4-dioxane; at 20 - 100℃;Inert atmosphere; | To a solution of compound 47 (250 mg, 1.45 mmol) in dioxane(6 mL) at room temperature was added bis(pinacolato)diboron(554 g, 2.18 mmol, 1.5 equiv.), and KOAc (427 mg, 4.35 mmol, 3equiv.). The reaction mixture was degassed under N2. Pd(dppf)Cl2(90 mg, 0.12 mmol, 0.1 equiv.) was added to the mixture anddegassed under N2. The reaction mixture was heated to 100 C andstirred overnight under nitrogen. The reaction mixture was monitoredusing TLC until completion, filtered through Celite andwashed with EA. The reaction solvent was evaporated underreduced pressure to give a residue, which was purified via silica gelcolumn chromatography (elution system - EA/Hexane 1: 1) togive compound 48 as a white solid (870 mg, 71%).Rf 0.43 (EA/Hexane 1: 1); 1H NMR (400 MHz, CDCl3) d 7.76(d, J 8.3 Hz, 2H), 7.51 (d, J 7.9 Hz, 2H), 7.19 (s, 1H), 2.18 (s, 3H),1.33 (s, 12H). |
| With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 2h;Reflux; Inert atmosphere; | General procedure: A mixture of substituted 3-(or 4-) bromobenzamides or 3-bromobenzoate or N-(3-(or 4-)bromophenyl)acetamide 3, (0.5 mmol), bis(pinacolato)diboron (0.14 g, 0.55 mmol), potassium acetate (0.15 g, 1.5 mmol), PdCl2(dppf) (0.03 g, 0.04 mmol) and 1,4-dioxane (10 mL) was refluxed for 2 h under nitrogen atmosphere. The solvent was evaporated under reduced pressure to afford a dark brown residue. To the residue was added intermediate 2 (0.4 mmol), sodium carbonate (0.16 g, 1.5 mmol), PdCl2(dppf) (0.03 g, 0.04 mmol), 1,2-dimethoxyethane (8 mL) and water (2 mL) and the mixture was refluxed for 2 h under nitrogen atmosphere. The mixture was evaporated under reduced pressure and purified by silica gel column chromatography using chloroform/methanol = 30: 1 as the eluent to afford the compounds T1-T6, T9-T10, T12 and T14-T21 as an off-white or a white solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 83% 2: 7% | With di-tert-butyl(methyl)phosphonium tetrafluoroborate salt; palladium diacetate; potassium carbonate In N,N-dimethyl acetamide at 110℃; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With potassium phosphate; copper(l) iodide; (2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide In dimethyl sulfoxide at 90℃; for 24h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 5 steps 1.1: aluminum (III) chloride / 6.5 h / 80 °C / Cooling with ice 2.1: hydrogenchloride / methanol; water / 6 h / Reflux 3.1: hydrogenchloride; sodium nitrite / water / 1 h / -5 - 0 °C 3.2: 2 h / 80 °C 4.1: N-Fluorobenzenesulfonimide; Lithium 1,1,1,3,3,3-hexamethyldisilazide / tetrahydrofuran; hexane / 1 h / -80 - -78 °C 5.1: aluminum (III) chloride / ethyl acetate / 5 h / 20 °C / Cooling with ice |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: trichlorophosphate / 8 h / 75 °C 2.1: hydroxylamine hydrochloride / water; tetrahydrofuran / 1 h / 20 °C 2.2: 1 h / Reflux |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With hydrogen fluoride In ethyl acetate for 8.5h; Cooling with ice; Industrial scale; | 1.4 Fourth step, preparation of 2-(4-ethoxybenzyl)-4-bromoacetanilide (IV) Take 152kg of 4-ethoxybenzyl alcohol, dissolve it in 300kg of ethyl acetate, add 212kg of 4-bromoacetanilide, add 40kg of HF in batches under ice bath, add in 60min, continue the reaction in ice bath for 30min, then heat the system. After refluxing for 7h, after the reaction is completed, it is cooled to room temperature, and the pH of the system is adjusted to 8-9 by 1mol/L sodium hydroxide solution. The organic layer is washed with saturated brine, washed with water until neutral, dried with anhydrous sodium sulfate, filtered, and the filtrate is reduced. The solvent was recovered by pressure, and 70% ethanol was crystallized to obtain 315 kg of yellow crystals, yield 91%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99% | In tetrahydrofuran at 20℃; for 1h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With tetraethylammonium chloride; trichloroacetonitrile In acetonitrile at 23℃; for 6h; Electrochemical reaction; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 56% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene Inert atmosphere; Reflux; Darkness; | 4.3.17. General procedure for biaryl ethyl Esters[19,20] General procedure: A solution of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4,Table 4) in toluene (10 mL) was transferred to a mixture of the arylbromide (Table 4), boronate ester 20 (Table 4) and K2CO3 (Table 4) in95% v/v aqueous ethanol (5 mL). The resulting mixture was stirred atreflux overnight, darkening over time. The following morning the reactionwas allowed to cool and quenched with water (10 mL). Theresulting mixture was filtered to remove Pd(0) and the volatile componentswere removed in vacuo. The product was extracted from theremaining solution with ethyl acetate (3 × 50 mL) and the combinedextracts were dried over anhydrous MgSO4. The solvent was removed invacuo giving the crude compound, which was purified by flashchromatography. 4.3.18. Ethyl 2-(2-pyridyl)benzoate[30] The general procedure for biaryl ethyl esters was applied to 2-bromopyridine,purifying by flash chromatography (19:1 DCM : Ether), to yieldthe ester (21) as a pale yellow solid (120 mg, 77%). MP: 67-69 C; IR(NaCl): 1721 (C- -O), 1286 (C-O); 1H NMR (δ, 400 MHz, CDCl3): 8.64(1H, d, J = 4.8 Hz H6′ ), 7.84 (1H, d, J = 7.6 Hz, H6), 7.74 (1H, td, J = 7.6Hz, 1.6 Hz, H4′ ), 7.53-7.57 (2H, m, H3, H4), 7.44-7.49 (2H, m, H3′ , H5),7.26 (1H, m, H5′ ), 4.14 (2H, q, J = 7.2 Hz, H1b), 1.05 (3H, t, J = 7.2 Hz,H1c); 13C NMR (δ, 100 MHz, CDCl3): 168.9 (C1a), 159.0 (C2′ ), 149.1 (C6′ ),141.1 (C2), 136.3 (C4′ ), 131.9 (C1), 131.2 (C4), 129.90 (C3), 129.89 (C6),128.4 (C5), 123.0 (C3′ ), 122.1 (C5′ ), 61.0 (C1b), 13.9 (C1c). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 43% | With potassium hexafluoridophosphate; nickel(II) chloride ethylene glycol dimethyl ether complex; [(2,6-bispyrazolylpyridine)MnCl2]; diphenyl(1-(2-isopropyl-quinazolin-4-yl)-2-naphthyl)phosphine In N,N-dimethyl-formamide at 20℃; Electrolysis; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 63% | With morpholine; (1,2-dimethoxyethane)dichloronickel(II); [Ir(dF(CF3)ppy)2(dtbbpy)]PF6; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl-formamide at 20℃; for 2h; Irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 50% | With morpholine; (1,2-dimethoxyethane)dichloronickel(II); [Ir(dF(CF3)ppy)2(dtbbpy)]PF6; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl-formamide at 20℃; for 2h; Irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With morpholine; (1,2-dimethoxyethane)dichloronickel(II); [Ir(dF(CF3)ppy)2(dtbbpy)]PF6; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl-formamide at 20℃; for 2h; Irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77% | With morpholine; (1,2-dimethoxyethane)dichloronickel(II); [Ir(dF(CF3)ppy)2(dtbbpy)]PF6; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl-formamide at 20℃; for 2h; Irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 96% | With morpholine; (1,2-dimethoxyethane)dichloronickel(II); [Ir(dF(CF3)ppy)2(dtbbpy)]PF6; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl-formamide at 20℃; for 2h; Irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 63 % | With [RuCl2(benzene)]2; silver(I) hexafluorophosphate In 1,2-dichloro-ethane at 60℃; Glovebox; Inert atmosphere; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 20 - 100℃; Inert atmosphere; | Buchwald-Hartwig Coupling; General Procedure A General procedure: An oven-dried 20-mL microwave vial equipped with a stir bar wascharged with aliphatic amine (1 equiv), BINAP (0.10 equiv), Pd(OAc)2(0.05 equiv), bromoarene (1.1 equiv) and Cs2CO3 (4 equiv). The vialwas sealed and flushed with N2 and 1,4-dioxane (0.2 M) was addedvia syringe. The reaction mixture was bubbled with N2 under vigorousstirring for ?15 min at rt, then placed in an oil bath at 100 °C andstirred overnight. The reaction mixture was cooled to rt, diluted withEtOAc and filtered through a short pad of silica gel. The combined organiclayers were concentrated under reduced pressure and the residuewas purified by column chromatography on silica gel (EtOAc incyclohexane from 0% to 100%) to afford the product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 64% | With bis(cyclopentadienyl)titanium dichloride; chloro-trimethyl-silane; NiBr2*diglyme; 4CzIPN; triethylamine; C48H74N4O2 In 1,4-dioxane at 20℃; for 24h; Irradiation; enantioselective reaction; |
Tags: 103-88-8 | 4-Bromoacetanilide | Aryls | Bromides | Amides | Amines | Benzene Compounds | Organic Building Blocks
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