2-CHLOROQUINOLINE-3-CARBALDEHYDE

Yellow to yellow-brown crystalline powder

This example provides a process for the synthesis of 2-chloro-3-formylquinoline with the following main steps: under ice-salt bath, 2.73 g (20.22 mmol) acetanilide, 8.19 g (27.58 mmol) of BTC and 10 mL of trichloromethane 4.2 mL (54.66mmol) DMF was added dropwise over 30 min after the temperature was maintained below -5 °C. The rate of the bubble overflow was controlled by the tail gas uptake rate. After the addition of the DMF, the mixture was stirred continuously for 10 min. For water bath, plus Heat to 40 °C, reaction 4 hours, steaming part of the solvent, adding ice water, 10percent NaOH to adjust the pH to 8 ~ 9, pumping, ethyl acetate recrystallization. The yield was 91.62percent.Dry DMF (3mmol) was cooled to 0°C in a flask equipped with a drying tube and then POClTo stirred DMF (3.6 mL, 46 mmol), 12.5 mL POClAt 0 C to a stirred solution of POCl3 (39.6 g, 259 mmol) and anhydrous DMF (8 g, 111 mmol) was added acetanilide (5 g, 37 mmol). The mixture was then heated to 65 C, and the progress of the reaction was monitored by thin-layer chromatography (TLC) analysis. After 8 h the reaction mixture was cooled to room temperature and added cautiously into ice-cold water. The precipitated solid was collected by filtration to isolate compound 1a as yellow solid. Yield 6.2 g (87 percent), yellow solid.General procedure: At 0 °C to a stirred solution of POCl3 (39.6 g, 259 mmol) and anhydrous DMF (8 g, 111mmol) was added acetanilide (5 g, 37 mmol). The mixture was then heated to 65 °C and the progress of the reaction was monitored by TLC analysis. After 8 h the reaction mixturewas then cooled to room temperature and added cautiously into ice-cold water. The solid precipitated was collected by filtration to isolate the compound 1a as yellow solid.Synthesis of 2-chloroquinoline-3-carbaldehyde (4a) [44–55] To a s o l u t i o n o f a c e t a n i l i d e(N-phenylacetamide) (5 mmoles) in dry DMF (15mmoles) at 0-5oC POCl3 (60 mmoles) was addeddropwise with stirring and the mixture was thenstirred at 80 – 100oC for time ranging between 4-16hr. The mixture was poured on to crush ice, stirredfor 5 minutes and the resulting solid fltered, washedwell with water and dried. The compounds wererecrystallized from ethyl acetate. Phosphoryl chloride(commonly called phosphorus oxychloride) is acolorless liquid with the formula POCl3. It hydrolysesin moist air to phosphoric acid to release choking fumes of hydrogen chloride. It is manufacturedindustrially on a large scale from phosphorustrichloride and oxygen or phosphorus pentoxide. Itis mainly used to make phospha (Table 1).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. 2-Chloroquinoline-3-carbaldehyde (5a): Recristalization eluent: Ethyl acetate; Yield 552 mg (72percent); yellow pale solid, mp 145-146 C. IR (KBr): 3043 (st. C-H), 2872 (st. C-H), 1688 (st.C=O), 1615-1553 (st. C=C) cm-1. 1H-NMR (270 MHz, J Hz, CDCl3) δ: 10, 55 (s, 1H); 8, 76 (s, 1H); 8, 07 (d, J=8, 6; 1H); 7, 98 (d, J=7, 9; 1H); 7, 89 (dd, J1=8, 3; J2=7, 7; 1H); 7, 64 (dd, J1=8, 3;J2= 7, 9; 1H). 13C-NMR (100 MHz, CDCl3) δ: 189, 4 (d); 150, 3 (s); 140, 5 (d); 133, 7 (d); 130, 6(s); 129, 6 (s); 129, 1 (d); 127, 7(d); 126, 6 (d); 121, 2. Anal. Calcd for C10H6ClNO: C, 62, 48; H, 3, 11; N, 7, 23 percent. Found: C, 62, 68; H, 3, 16; N, 7, 31 percent.General procedure: [00119] Acetanilide (2a)/substituted acetanilides (2b - 2h) (0.05 mol) were dissolved in 9.6 ml of dimethyl formamide (0.125 mol) and to this solution, 32 ml of phosphorus oxychloride (0.35 mol) was added gradually at 0 °C. The reaction mixture was taken in a round bottom flask (RBF) equipped with a reflux condenser fitted with a drying tube and was heated for 4-16 hours on oil bath at 75-80 °C. The solution was then cooled to room temperature and subsequently poured onto 100 ml of ice water. The precipitate formed was collected by filtration and recrystallized from ethyl acetate.Example 35; Synthesis of (3, 5-bis-trifluoromethyl-benzyl)- [2-(cyclopentylmethyl-ethyl-amino)- quinolin-3-ylmethyl]-carbamic acid methyl ester; Step (i): Synthesis of 2-chloroquinoline-3-carbaldehyde:; Dimethylformamide (9.13 grams, 0.125 mol) was cooled to 0 2-Chloroquinoline-3-carbaldehyde was synthesized from acetanilide via Vilsmeier–Haack reaction (Srivatava and Singh, 2005). To a solution of acetanilide (0.005 mol; 0.67 g) in dry dimethylformamide (0.015 mol; 1.09 ml) at 0–5 °C with stirring, phosphorous oxychloride (0.06 mol; 5.59 ml) was added drop wise and the mixture stirred at 80–90 °C for 12 h. The mixture was poured into crushed ice and stirred for 5 min, and the resulting solid filtered was washed well with water and dried. The compound was purified by recrystallization from ethyl acetate. It was obtained as yellow solid, yield 65 percent; m.p. 146–148 °C; IR(KBr) vmax 2871, 1687, 749 cmAcetanilide (15.6 mmol, 1.0 eq) (14) was treated with POCl3(156.0 mmol, 10.0 eq.) and DMF (51.48 mmol, 3.3 eq.) at 80 °C for 8 h.The reaction mixture was cooled to room temperature (40 °C) andpoured into crushed ice under stirring. Pale yellow precipitates wereformed, which were washed with cold water several times and dried togive 2-chloro-quinoline-3-carbaldehyde (15). 2-Chloro-quinoline-3-carbaldehyde (15): yellow solid, yield 65percent, m.p. 150–151 °C; IR (KBr): max cm−1 3043, 2872, 1722, 1684, 1567, 1489, 760, 748; 1H NMR (CDCl3, 400 MHz): δ 10.55 (s, 1H), 8.74 (s, 1H), 8.06 (d, 1H, J=8.5 Hz), 7.98 (d, 1H, J=8.2 Hz), 7.88 (ddd, 1H, J=1.4, 7.0 and 8.4 Hz), 7.65 (td, 1H, J=1.0 and 7.6 Hz); 13C NMR(CDCl3, 100 MHz): δ 189.1, 150.1, 149.6, 140.3, 133.6, 129.7, 128.6, 128.1, 126.5, 126.4; ESI-MS found m/z 191.96 [M+H]+ and 193.98[M+H+2]+.Dimethyl formamide (9.6 mL, 0.125 mol) was cooled to 0 C in aflask equipped with a drying tube, and phosphoryl chloride(32.2 mL, 0.35 mol) was added dropwise with stirring. To this solution, acetanilide (0.05 mol) was added, and, after 5 min, the solutionwas heated under reflux at 75 C for 16.5 h in a temperaturecontrolledoil bath. After completion of the reaction, as indicated by TLC, the solution was cooled to room temperature and pouredinto 100 mL of ice water. The precipitate was collected by filtrationand recrystallized from ethyl acetate to yield 2-chloroquinoline-3-carbaldehyde as pale yellow crystals. 64percent yield.General procedure: N, N-Dimethylformamide (0.025 mol) was cooled in an ice-salt bath and treated with phosphorylchloride (0.070 mol) for 20 min. The resulting mixture was added dropwise to a cooled solution ofthe appropriate acetylated aniline (8–10) (0.010 mol) in N, N-dimethylformamide (10 mL) with stirring.The mixture was stirred at 90 C for 12 h. A small amount of crushed ice was added and the mixturewas basified to pH 14 with 5 M NaOH. After stirring at ambient temperature for 1 h, the precipitatewas filtered, washed with water, and dried to give the title compound. 2-Chloroquinoline-3-carbaldehyde (5) [76]. Yellow solid, yield: 60percent; m.p. 150–152 C (lit. [76] m.p.146–149 C); 1H-NMR (CDCl3): 10.59 (1H, s, CHO), 8.79 (1H, s, H4), 8.11–7.65 (4H, m, H5, H6, H7, H8).POCI3 (1.29 mL, 14.1 mmol, 9.5 eq) was added to DMF (0.379 mL, 4.89 mmol, 3.3 eq) at 0°C. The mixture was stirred for an additional 5 minutes at 0°C before the addition of N-phenylethanamide (200 mg, 1 .48 mmol). The mixture was then heated to 75°C and stirred for 12 hours. Upon completion, the reaction was quenched very carefully with cold water and extracted 3 times with Et20. The combined organic layers were dried (MgSO4), concentrated, and the crude material was purified by combiflash 0->30percent EtOAc in hexanes to provide 2-chloroquinoline-3-carbaldehyde (139 mg, 49percent yield).EXAMPLE 7 EXAMPLE 7 EXAMPLE 8 EXAMPLE 8 General procedure: To the prepared TCTA–DMFreagent, 9.8 mmol of the Acetanilide was added and stirred under refluxconditions. Progress of the reaction was checked by TLC till the completion ofthe reaction. Analytical TLC was carried out using Merck aluminum-backed0.2 mm silica gel 60 F-254 plates. Column chromatography was conductedusing Merck silica gel 60 (230–400 mesh). After completion of the reaction, water was added to the reaction mixture and stirred for a few more minutes toextract inorganic components into water. The organic layer was separated andthe crude product thus obtained was further purified with columnchromatography (silica gel, ethyl acetate/n-hexane)

Molecular Weight:191.61
XLogP3:2.6
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:191.0137915
Monoisotopic Mass:191.0137915
Topological Polar Surface Area:30
Heavy Atom Count:13
Complexity:197
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes