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CAS No. : | 73568-25-9 | MDL No. : | MFCD00130079 |
Formula : | C10H6ClNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SDKQWXCBSNMYBN-UHFFFAOYSA-N |
M.W : | 191.61 | Pubchem ID : | 690958 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 52.14 |
TPSA : | 29.96 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.62 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | 2.61 |
Log Po/w (WLOGP) : | 2.7 |
Log Po/w (MLOGP) : | 1.7 |
Log Po/w (SILICOS-IT) : | 3.22 |
Consensus Log Po/w : | 2.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.18 |
Solubility : | 0.128 mg/ml ; 0.000668 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.89 |
Solubility : | 0.248 mg/ml ; 0.00129 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.27 |
Solubility : | 0.0103 mg/ml ; 0.000054 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.38 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
84% | With hydrogen; sodium acetate; palladium dichloride In methanol at 35℃; for 3 h; | Typical procedures: 6-bromonicotinaldehyde (930 mg, 5.0 mmol), NaOAc (820 mg, 10.0 mmol), MeOH (30 mL), and PdCl2 (45 mg) were mixed in a glass bottle capped with a balloon filled with hydrogen. After stirred at 35 °C for 4 h, the mixture was filtered and washed with MeOH. The solvent was removed and the residue was dissolved in water, neutralized with solid NaHCO3, and extracted with ethyl acetate. The organic phase was dried over anhyd Na2SO4, and then filtered. The solvent was removed and the residue was subjected to chromatography to yield pyridin-3-ylmethanol (428 mg, 78percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ammonium hydroxide; ammonium cerium (IV) nitrate; hydroxylamine hydrochloride In water at 0℃; | A suspension of 2-chloroquinoline-3-carbaldehyde (0.01 mol) in30percent aqueous ammonia (30 mL) was stirred for 5 min at room temperature,resulting in formation of a turbid solution. To this, cericammonium nitrate (0.01 mol) was added with constant stirring at0 C. After completion of the reaction (monitored by TLC, 10–15 min), the mixture was extracted with chloroform–ethyl acetate(5:3), dried with anhydrous sodium sulfate, and concentrated underreduced pressure to give a crude product, which was crystalized inethanol to give pure 2-chloroquinoline-3-carbonitrile as pale yellowcrystals. Yield: 82percent. |
58% | With pyridine; ammonium peroxydisulfate; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy In acetonitrile at 0.5℃; for 24 h; Molecular sieve; Sealed tube; Irradiation | General procedure: To an oven-dried 2 ml reaction vial equipped with a stir bar wasadded the aldehyde 3a (0.136 g, 1 mmol, 1 equiv) and pyridine(0.474 g, 6.0 mmol, 6 equiv), followed by acetonitrile (2 ml, 0.5M in 3a). The vial was then charged with Ru(bpy)3(PF6)2 (0.017g, 0.02 mmol, 0.02 equiv), 2 (0.043 g, 0.20 mmol, 0.20 equiv),(NH4)2S2O8(0.501 g, 2.2 mmol, 2.2 equiv), and activated 3 Åmolecular sieves (ca. 0.2 g), sealed with a cap, and irradiated inblue LED reactor for 24 h. In the absence of fan cooling, the temperatureof the reaction mixture plateaued at approximately 50°C . After the irradiation was complete, the reaction mixturewas quenched with EtOAc and transferred to a separatoryfunnel. Further EtOAc (30 ml) was added, followed by 0.5 MHCl(aq) (30 ml). The layers were separated, and the aqueous layerwas extracted with EtOAc (3 × 20 ml). The organic layers werethen combined and washed with 0.5 M 0.5 M HCl(aq) (2 × 20 ml),saturated aqueous sodium bicarbonate (2 × 20 ml), and finallybrine (20 ml). The organic layer was then dried over sodiumsulfate and the solvent removed in vacuo to afford the crudeproduct. The resulting crude mixture was adhered to silica gelusing 1.5 weight equivalents of SiO2(relative to the theoreticalyield). The dry-packed material was gently added on top of asilica gel plug. The plug was washed with an excess of hexanes(ca. 5 column volumes). The desired product was eluted off theplug via a 90:10 by volume mixture of hexanes/EtOAc (3–4column volumes). The solvent was removed in vacuo by rotaryevaporation affording the pure nitrile 3c (0.066 g, 50percent) as awhite solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tert.-butylhydroperoxide In 1,2-dichloro-ethane at 80℃; for 7 h; | General procedure: A Solution of 2-(phenylethynyl)quinoline-3-carbaldehyde 1 (0.5 mmol), TBHP (4.0 equiv.) and DCE (2.0 mL) was heated at 80 °C for 6 to 8h in aerobic atmosphere. After completion of the reaction, solvent was evaporated under reduced pressure. Water was added to the reaction mixture and extracted with EtOAc. Organic phase was washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and obtained residue was purified by column chromatography (hexane: ethyl acetate = 15:5) to afford 2. |
84% | With potassium permanganate; sodium hydroxide In water; <i>tert</i>-butyl alcohol at 70 - 80℃; for 4 h; | To a solution of aldehyde 1[46] (3.8 g, 20 mmol) in a mixture of H2O/t-butanol (1 : 1, 30 mL) was added a solution of KMnO4 (4.0 g, 25 mmol) in H2O (30 mL) at 70–80 °C over 30 min. Then, a solution of NaOH (10percent, 30 mL) was added with stirring until the solution turned alkaline. The reaction mixture was stirred at the same temperature for 4 h. The reaction mixture was filtered and the resulting clear filtrate was acidified with HCl solution (40 mL, 30percent). The resulting acid was purified by dissolving in NaHCO3 solution (50 mL, 10percent) and the whole solution was filtered on hot and then neutralized with dilute HCl. The resulting precipitate was filtered, washed with water, and dried to give (3.6 g, 88percent) of crude acid. Crystallization from methanol gave 3.4 g (84percent) of pure 2-chloroquinoline-3-carboxylic acid (2) as white crystals, mp 178–180 °C (lit. 181–182 °C[47]). νmax (KBr)/cm-1 3090, 2980, 2950, 1720, 1605, 1585, 1460, 1435, 1395, 1225, 745. δH (90 MHz, CDCl3) 6.8–8.0 (m, 5H, Ar–H), 10.5 (s, 1H, COOH). δC (100 MHz, CDCl3) 126.6 (1C,Ar, C-4a), 127.1 (1C, Ar, C-6), 127.2 (1C, Ar, C-5), 128.0 (1C, Ar, C-8), 128.8 (1C, Ar, C-3), 129.0 (1C, Ar, C-7), 129.6 (1C, Ar, C-4), 149.4 (1C, Ar, C-8a), 151.0 (1C, Ar, C-2), 165.5 (1C, COOH). m/z (EI, 70 eV) (percent) 209 (M++2, 18), 207 (45), 190 (100), 172 (30), 162 (64), 127 (32), 104 (16), 91 (50), 76 (18). Anal. Calc. for C10H6ClNO2 (207.5): C 57.83, H 2.89, N 6.74, Cl, 17.10. Found: C 57.73, H 2.91, N 6.80 Cl, 17.28percent. |
67% | Stage #1: With sodium hydroxide; silver nitrate In ethanol; water at 20℃; for 4.25 h; Stage #2: With hydrogenchloride In water |
A suspension of silver nitrate (6.8 g, 40 mmol) in ethanol (100 mL) was added to a solution of 2- chloro-quinoline-3-carbaldehyde (4.8 g, 25 mmol) in ethanol (200 mL). A solution of sodium hydroxide (5 g, 125 mmol) in 80percent ethanol (100 mL) was added over 15 minutes. The resulting black suspension was stirred at ambient temperature for 4 hours. The mixture was filtered through a pad of celite, and the pad was washed generously with ethanol. The combined ethanolic solutions were concentrated in vacuo and diluted with water. The aqueous solution was neutralized with concentrated hydrochloric acid, and the product precipitated. The product was collected by filtration and washed with water. The solid was triturated in hot ethanol, cooled and collected by filtration to give a colorless solid, 3.5 g (67percent). MS: m/z 208 (MH+). 1H NMR (DMSO-D6) : δ 7. 74 (d of d, 1 H), 7.94 (d of d, 1 H), 8.01 (d, 1 H), 8.18 (d, 1 H), 8.95 (s, 1 H) and 13.81 (s, 1 H). |
60.5% | With sodium chlorite; sodium dihydrogenphosphate dihydrate In acetonitrile at 20℃; | 2-chloro-3-quinolinecarboxaldehyde (23.48 mmol, 4.5g) was suspended in MeCN (100 ml) and a solution of sodium dihydrogen phosphate dihydrate (1 17 mmol, 94 ml) was added followed by sodium chlorite (70.5 mmol, 6.37 g). The reaction was stirred at rt overnight and then quenched by the addition of sodium sulfite (96 mmol, 96 ml) followed by stirring for 1 h. The aqueous layer was acidified with 2M HCI to pH -3 and extracted with EtOAc (2 x 200ml). The organic layers were combined, dried over Na2S04 and concentrated in vacuo to afford 2-chloroquinoline-3-carboxylic acid as a pale yellow solid (60.5 percent, 2.95 g, 14.21 mmol), M.S. (ESI) (m/z): 208[M+H]+. |
26% | With sodium acetate In acetonitrile at 80℃; Sonication | General procedure: Compounds 17a, 15a and 18e were subjected to the above reaction conditions but using 3-butyl-4-methylthiazolium chloride instead of the imidazolium salt. After solvent was removed under reduced pressure, the resulting solid was dissolved in H2O and neutralized with 20percent HCl. The precipitate formed was filtered and washed with water to afford compounds 23a and 24a,e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.62% | With bis(trichloromethyl) carbonate In chloroform at -5 - 40℃; for 4.66667 h; Green chemistry | 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. |
90% | at 0℃; Heating | Dry DMF (3mmol) was cooled to 0°C in a flask equipped with a drying tube and then POCl3 (12mmol) was added drop-wise with stirring. To this solution, acetanilide (1mmol) was added in small portions and after 25–30min the reaction mixture was heated for 24h on a boiling water bath. The reaction mixture was poured into ice water and stirred for 30min. The work-up was performed with aqueous NaOH to form a precipitate, to hydrolyse the imine salt and remove any acid formed. The solid was filtered, dried and purified from ethyl acetate to give 2-chloro-3-formyl quinoline in high yield (90percent). |
89% | at 80 - 90℃; for 12 h; | 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. |
87% | at 0 - 65℃; for 8 h; Inert atmosphere | At 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. |
87% | at 0 - 65℃; for 8 h; | 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. |
82% | at 85 - 90℃; Reflux | Synthesis of 2-chloroquinoline-3-carbaldehyde (4a) [44–55] To a stirred solution of N-phenylacetamide(3a) (5 mmoles) in dry DMF (15 mmoles), POCl3 (60 mmoles) was added drop-wise. The mixture was refluxed for overnight on water bath at 85-90 °C. The reaction mixture was quenched with crushed ice present in a 500 mL beaker and stirred well for some time. The precipitate obtained was filtered, dried and purified by recrystallization processby using ethyl acetate to afford pure compound 4a in 82percent yield. Similarly, the other aldehydes 4b-c were prepared by using the procedures reported earlier. |
79% | at 80 - 100℃; | 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). |
72% | Stage #1: at 0℃; for 0.25 h; Stage #2: for 4 h; Reflux |
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. |
72% | at 0 - 80℃; | 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. |
68% | at 65℃; for 16 h; | 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 0C in a flask equipped with a drying tube, and phosphorous oxychloride (53.7 grams, 0.35 mol) was added drop-wise with stirring. To this solution was added acetanilide (6,55 grams, 0.05 mol) and the mixture was heated under reflux for 16 hours at 65 0C. Excess phosphorous oxychloride was distilled off, water was added, and the solution was extracted with ethyl acetate. The solvent was evaporated and the crude purified over silica gel (100-200 mesh) using 2percent ethyl acetate/petroleum ether. Yield: 68percent, mp: 145 0C;1H NMR (CDCl3, 400 MHz): d 10.5 (s, IH); 8.78 (s, IH), 8.12-7.90 (m, 3H); 7.70 (t, J =7.3 Hz, IH);Mass m/z (EI-MS): 192 (M+l, 100percent). |
65% | at 0 - 90℃; for 12 h; | 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 cm-1; 1H NMR (DMSO,300 MHz): δ = 10.25 (s, 1H, CHO), 7.70 (t, 1H, J = 6.2,H-7), 7.25 (d, 1H, J = 6.5 Hz, H-6), 6.89 (d, 1H,J = 6.3 Hz, H-8), 6.78 (t, 1H, J = 7.1 Hz, H-5); 13C NMR(DMSO, 75 MHz): δ = 190 (CH, –CHO), 153 (C, C-2),145.4 (CH, C-4), 134 (CH, C-8), 129.8 (C, C-3), 129.3(CH, C-6), 128.5 (C, C-5), 128 (CH, C-9), 127.2 (CH, C-5); EIMS m/z: 191.01 (M+); Anal. Calcd. for C10H6ClNO: C,62.68; H, 3.16; N, 7.31. Found: C, 62.71; H, 3.18; N, 7.33. |
65% | at 80℃; for 8 h; | Acetanilide (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]+. |
64% | at 0 - 75℃; for 16.5 h; | 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. |
60% | Stage #1: for 0.333333 h; Cooling Stage #2: at 90℃; for 12 h; |
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). |
49% | Stage #1: at 0℃; for 0.0833333 h; Stage #2: at 75℃; for 12 h; |
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With n-butyllithium; diisopropylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; acetic acid | EXAMPLE 7 2-Chloro-3-quinolinecarboxaldehyde To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THF at 0° C. was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 min the solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0 mmol) was added neat. The mixture was stirred at -78° C. for 30 min, then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and the reaction mixture was stirred an additional 30 min at this temperature. After quenching at -78° C. with glacial acetic acid (1 mL), the mixture was warmed to room temperature and diluted with ether (30 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), and was dried over MgSO4. Concentration afforded 2-chloro-3-quinolinecarboxaldehyde (530 mg, 92percent) as a light yellow solid (mp 145°-149 ° C.), which was used directly in the next step without further purification. Recrystallization from ethyl acetate afforded the pure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C. reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520.). 1 H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.77 (s, 1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9 Hz), 7.67 (t, 1H, J=9 Hz); IR (nujol) 1685, 1575, 1045, 760, 745 cm-1. |
92% | With n-butyllithium; diisopropylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; acetic acid | EXAMPLE 7 2-Chloro-3-quinolinecarboxaldehyde To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THF at 0° C. Was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 min the solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0 mmol) was added neat. The mixture was stirred at -78° C. for 30 min, then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and the reaction mixture was stirred an additional 30 min at this temperature. After quenching at -78° C. with glacial acetic acid (1 mL), the mixture was warmed to room temperature and diluted with ether (30 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), and was dried over MgSO4. Concentration afforded 2-chloro-3-quinolinecarboxaldehyde (530 mg, 92percent) as a light yellow solid (mp 145°-149 ° C.), which was used directly in the next step without further purification. Recrystallization from ethyl acetate afforded the pure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C. reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520.). 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.77 (s, 1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9 Hz), 7.67 (t, 1H, J=9 Hz); IR (nujol) 1685, 1575, 1045, 760, 745 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With trichlorophosphate In <i>N</i>-methyl-acetamide; ice-water | EXAMPLE 8 Preparation of 2-Chloro-3-quinolinecarboxaldehyde from acetanilide Following a literature procedure (see Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520), a phosphorus oxychloride (24.0 mL, 260 mmol) was added dropwise to an ice-cold solution of dimethylformamide (7.20 mL, 93.0 mmol) and the deep-red solution was stirred at 0° C. for 30 min. Acetanilide (5.0 g, 37.0 mmol) was added neat and the mixture was stirred at 0° C. for 30 min., then heated at 75° C. for 16 h. The cooled mixture was poured into 250 mL of ice-water and stirred at 0°-5° C. for 30 min. The product was filtered, washed with water, and recrystallized from ethyl acetate to give 5.2 g (74percent) of 2-chloro-3-quinoline-carboxaldehyde as a light yellow solid: mp 147°-149° C. |
74% | With trichlorophosphate In <i>N</i>-methyl-acetamide; ice-water | EXAMPLE 8 Preparation of 2-Chloro-3-quinoline-carboxaldehyde from acetanilide Following a literature procedure (see Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520), phosphorus oxychloride (24.0 mL, 260 mmol) was added dropwise to an ice-cold solution of dimethylformamide (7.20 mL, 93.0 mmol) and the deep-red solution was stirred at 0° C. for 30 min. Acetanilide (5.0 g, 37.0 mmol) was added neat and the mixture was stirred at 0° C. for 30 min, then heated at 75° C. for 16 h. The cooled mixture was poured into 250 mL of ice-water and stirred at 0°-5° C. for 30 min. The product was filtered, washed with water, and recrystallized from ethyl acetate to give 5.2 g (74percent) of 2-Chloro-3-quinoline-carboxaldehyde as a light yellow solid: mp 147°-149° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | for 11 h; Reflux | 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) |
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