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Product Details of [ 459-57-4 ]

CAS No. :459-57-4 MDL No. :MFCD00003378
Formula : C7H5FO Boiling Point : -
Linear Structure Formula :- InChI Key :UOQXIWFBQSVDPP-UHFFFAOYSA-N
M.W : 124.11 Pubchem ID :68023
Synonyms :

Calculated chemistry of [ 459-57-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 31.79
TPSA : 17.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.44
Log Po/w (XLOGP3) : 1.54
Log Po/w (WLOGP) : 2.06
Log Po/w (MLOGP) : 1.88
Log Po/w (SILICOS-IT) : 2.42
Consensus Log Po/w : 1.87

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.01
Solubility : 1.22 mg/ml ; 0.00984 mol/l
Class : Soluble
Log S (Ali) : -1.51
Solubility : 3.86 mg/ml ; 0.0311 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.58
Solubility : 0.326 mg/ml ; 0.00262 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 459-57-4 ]

Signal Word:Danger Class:3
Precautionary Statements:P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235 UN#:1989
Hazard Statements:H225-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 459-57-4 ]

* 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.

  • Upstream synthesis route of [ 459-57-4 ]
  • Downstream synthetic route of [ 459-57-4 ]

[ 459-57-4 ] Synthesis Path-Upstream   1~110

  • 1
  • [ 110-91-8 ]
  • [ 459-57-4 ]
  • [ 1204-86-0 ]
YieldReaction ConditionsOperation in experiment
89% With Aliquat (at)366; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a–g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia–g. 4-Morpholinobenzaldehyde Id
Yield 89percent as yellow crystals, mp 69 °C, (as reported) [49,50].
85% With potassium carbonate In N,N-dimethyl-formamide for 24 h; Reflux General procedure: 4-Fluoro benzaldehyde (2.036mL, 0.019mol), pyrrolidine or morpholine (0.019mol), and potassium carbonate (K2CO3) (2.622g, 0.019mol) were refluxed in DMF (20mL) for 24h. After completion of the reaction, the mixture was poured into ice-water (50mL), precipitated product was filtered, washed with deionised water, dried, and recrystallized from EtOH. For compound 1a; yield: 85percent, measured M.P.=59.8°C, reported M.P.=62–63°C [46]. For compound 1b; yield: 82percent, measured M.P.=75.3°C, reported M.P.=78–79°C [47].
60% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h; p-Fluorobenzaldehyde (1.07 mL, 10 mmol) was dissolved in dimethylformamide (30 mL) where potassium carbonate (2.52 g, 20 mol) and morpholine (814 mL, 10 mmol) were added, and this was stirred at room temperature for 14 hours.
The reaction mixture solution was filtered through filter paper, the solvent was distilled off.
Purification was carried out by silica gel column chromatography (elude: hexane: ethyl acetate =1:1) which resulted in a pale yellow solid (1.15 g, 60percent yield).
1H NMR (300 MHz, CDCl3) δ: 9.81 (1H, s), 7.76-7.93 (2H, m), 6.91-6.94 (2H, m), 3.85-3.88 (2H, m), 3.34-3.37 (2H, m).
55% With sodium carbonate In water at 100℃; for 18 h; 4-Fluorobenzaldehyde 15 (1.8 mL,17.24 mmol), 1-acetylpiperazine (1 mL, 11.49 mmol) and Na2CO3 (1.83 g, 17.24 mmol) weredissolved in H2O (40 mL) and the stirred at 100°C overnight. After extraction with DCM, thecombined organic layers were concentrated under reduced pressure and silica gel columnchromatography (20percent EtOAc/PE) yielded 17b (2.36 g, 55percent). 1H NMR (400 MHz, DMSO-d6)δ 9.97 (s, 1H), 9.73 (s, 1H), 8.11-7.89 (m, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.43 (q, J = 8.4 Hz, 2H),7.03 (d, J = 8.9 Hz, 2H), 3.72 (m, 4H), 3.32 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 191.0,154.9, 131.7, 126.7, 118.3, 65.8, 46.6; HRMS (ESI-MS): Calculated for C11H14NO2 [M+H]+:192.10191; found: 192.10186.

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  • 2
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  • [ 348-37-8 ]
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  • 3
  • [ 288-32-4 ]
  • [ 459-57-4 ]
  • [ 10040-98-9 ]
YieldReaction ConditionsOperation in experiment
92% With Aliquat (at)366; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a–g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia–g. 4-(1H-imidazol-1-yl) benzaldehyde Ia
Yield 92percent as yellow crystals, mp 152 °C, (as reported) [34,44].
76% With potassium carbonate In N,N-dimethyl-formamide at 110℃; General procedure: A mixture of 4-fluoro acetophenone/4-fluorobenzaldehyde (10 mmol) and imidazole/triazole (10 mmol) were dissolved in dry DMF (20 mL). K2CO3 (12 mmol) was added in small portion within a period of 15 min to the above stirred solution. Mixture was stirred for 10-12 h at 110 °C. Heating discontinued, K2CO3 was filtered off, filtrate extracted with ethyl acetate (3 .x. 15 mL). Organic layer was washed with water (3 .x. 15 mL), dried over anhydrous sodium sulphate and concentrated to given an oil which was purified on silica gel column (60-120 mesh) taking methanol: chloroform (1:99) as an eluent.
1 g With potassium carbonate In N,N-dimethyl-formamide for 6 h; Reflux Intermediate 1 Ethyl 5-(4-(lH-imidazol- l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate Step- 1 : Preparation of 4-(lH-imidazol-l-yl)benzaldehyde To a solution of 4-fluorobenzaldehyde (1.0 g, 8.06 mmol) in DMF (3 mL) were added 1H- imidazole (2.1 g, 32.2 mmol) and K2C03 (2.2 g, 16.12 mmol). The reaction mass was heated at reflux for 6 h before it was diluted with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.03 (s, 1H), 8.47 (s, 1H), 8.07-8.04 (d, = 8.4 Hz, 2H), 7.95-7.93 (m, 3H), 7.17 (s, 1H); MS (m/z): 173 (M+H)+.
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[2] New Journal of Chemistry, 2007, vol. 31, # 6, p. 906 - 910
[3] Bioorganic Chemistry, 2014, vol. 57, p. 65 - 82
[4] Journal of Molecular Structure, 2007, vol. 829, # 1-3, p. 202 - 207
[5] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
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[7] European Journal of Medicinal Chemistry, 2009, vol. 44, # 11, p. 4654 - 4660
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[9] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4302 - 4310
[10] Tetrahedron, 2001, vol. 57, # 22, p. 4781 - 4785
[11] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[12] Tetrahedron, 2008, vol. 64, # 8, p. 1823 - 1828
[13] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[14] Chemical Communications, 2018, vol. 54, # 69, p. 9603 - 9606
[15] Journal of Medicinal Chemistry, 1987, vol. 30, # 6, p. 1023 - 1029
[16] RSC Advances, 2015, vol. 5, # 92, p. 75425 - 75433
[17] Patent: US7138432, 2006, B1, . Location in patent: Page/Page column 46
[18] Tetrahedron Letters, 2009, vol. 50, # 12, p. 1286 - 1289
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[20] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1756 - 1761
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[23] Patent: WO2016/128905, 2016, A1, . Location in patent: Page/Page column 47
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  • 4
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  • [ 109-89-7 ]
  • [ 120-21-8 ]
YieldReaction ConditionsOperation in experiment
92% With Aliquat 336; potassium carbonate In dimethyl sulfoxide at 95℃; for 72 h; 4-fluorobenzaldehyde (2.5 g, 0.02 mol), diethyl amine(5.12 g, 0.07 mol), K2CO3 (4.15 g), DMSO (25.0 mL) and Aliquat-336 (0.05 mL) were added into a one-necked flask (100 mL) fitted with a stirrer and a condenser. The mixture was stirred for 72 h at 95C, and then cooled to room temperature. The yellow precipitation was obtained after ice water wasintroduced into the flask. The crude product was washed with cool water for 2-3 times, and thenrecrystallized from ethanol. Yellow solid (4-diethylaminobenzaldehyde) was obtained. Yield: 92percent.Anal. Calcd. for C11H15NO: C, 74.54; H, 8.53; N, 7.90; Found: C, 74.67; H, 8.58; N, 7.85; 1H NMR(500 MHz, CDCl3, ppm) δ 9.71(s, 1H), 7.72(q, 2H), 6.69 (d, J = 8.8 Hz, 2H), 1.24 (t, 6H), 3.46 (q,4H). The second step: The potassium (0.78 g, 0.02 mol) was introduced into tert-butanol (11.3 mL,0.12 mol) in a 50 mL one-necked flask fitted with a condenser. After fully reaction, 4-picoline (0.975mL, 10 mmol) and 4-diethylaminobenzaldehyde (1.77 g, 10 mmol) were added. The mixture washeated for 2 hours at 80°C under stirring; tert-butanol was evaporated, then added to 200 mLdichloromethane and washed once with 200 mL ice water, stirred. The water phase was extracted withdichloromethane for 3 times. The organic phase was dried on sodium sulfate, solvent was evaporated,and the crude solid was recrystallized in toluene. Yield: 86percent. 1H NMR (500 MHz, DMSO, ppm) δ8.43 (d, J = 5.2 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H), 7.23 (d, J = 5.4 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H),6.27-6.66 (m, 2H), 3.39 (m, 4H), 1.13 (t, 6H). 13C NMR (500 MHz, CDCl3, ppm) δ 148.56-146.96 (m,py), 134.57 (s, py), 128.86 (s, benzene) 120.51-119.95 (d, benzene), 111.56 (s, CH=CH), 44.47 (s,CH2), 12.62 (s, CH3). Anal. Calcd. for C17H20N2 (EI-MS: 253.3): C, 80.91; H, 7.99; N, 11.10. Found: C,80.76; H, 7.91; N, 11.01. IR data (KBr, cm−1): 3026 w, 2974 m, 1581 s, 1520 vs, 1408 m, 1355 m,1329 w, 1272 m, 1185 m, 1158 m, 1074 w, 972 w, 818 m, 795 m, 518 w. m.p. 258 °C.
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YieldReaction ConditionsOperation in experiment
72% With potassium carbonate In N,N-dimethyl-formamide at 110℃; General procedure: A mixture of 4-fluoro acetophenone/4-fluorobenzaldehyde (10 mmol) and imidazole/triazole (10 mmol) were dissolved in dry DMF (20 mL). K2CO3 (12 mmol) was added in small portion within a period of 15 min to the above stirred solution. Mixture was stirred for 10-12 h at 110 °C. Heating discontinued, K2CO3 was filtered off, filtrate extracted with ethyl acetate (3 .x. 15 mL). Organic layer was washed with water (3 .x. 15 mL), dried over anhydrous sodium sulphate and concentrated to given an oil which was purified on silica gel column (60-120 mesh) taking methanol: chloroform (1:99) as an eluent.
65% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h; Example 91Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5); To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3.x.100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65% With potassium carbonate In N,N-dimethyl-formamide Example 91
Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5)
To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h.
After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3*100 mL).
The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h; Example 91: Preparation of 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4- triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 °C for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H20 and extracted with EtOAc (3 xlOO mL). The combined EtOAc layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149 °C: ]H NMR (400 MHz, CDC13) δ 10.08 (s, IH), 8.70 (s, IH), 8.16 (s, IH), 8.06 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h; To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h; To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h.
After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3*100 mL).
The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h; Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).

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  • [ 27469-60-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2018,
  • 10
  • [ 459-57-4 ]
  • [ 67-68-5 ]
  • [ 3446-89-7 ]
YieldReaction ConditionsOperation in experiment
60% With N-ethyl-N,N-diisopropylamine In water at 189℃; for 48 h; General procedure: To a round bottomed flask equipped with magnetic stir bar and reflux condenser were added: the aryl halide (2.0 mmol), dimethylsulfoxide (10 mL), N,N-diisopropylethylamine (0.35 mL, 2.0 mmol), and water (approximately 0.04 mL, 2.0 mmol). The reaction was heated to reflux temperature (189 °C) in a sand bath and stirred for the specified time. Reaction progress was monitored by TLC and/or 1H NMR analysis. When complete consumption of the starting material was evident, the reaction was cooled to room temperature extracted with ethyl acetate (x3) and the combined organic extracts were washed with 2 M HCl, brine, and dried over MgSO4.The solvent was removed en vacuo and the crude product was purified by column chromatography on silica gel (Hexanes/EtOAc, gradient elution).
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 38, p. 5323 - 5326
  • 11
  • [ 459-57-4 ]
  • [ 459-46-1 ]
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 27, p. 5161 - 5164
[2] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1428,1430[3] Chem.Abstr., 1960, p. 5518
[4] Journal of Steroid Biochemistry and Molecular Biology, 2013, vol. 137, p. 332 - 344
[5] Chemical Communications, 2014, vol. 50, # 28, p. 3692 - 3694
[6] Organic Letters, 2014, vol. 16, # 2, p. 484 - 487
[7] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 561 - 569
[8] Chemical Biology and Drug Design, 2016, p. 97 - 109
[9] Acta Pharmacologica Sinica, 2016, vol. 37, # 11, p. 1516 - 1524
[10] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114
[11] Chem, 2018, vol. 4, # 1, p. 124 - 137
[12] Chinese Chemical Letters, 2016, vol. 27, # 2, p. 295 - 301
  • 12
  • [ 459-57-4 ]
  • [ 15017-52-4 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 16, p. 3131 - 3138
[2] Heterocycles, 1999, vol. 51, # 9, p. 2041 - 2063
[3] Tetrahedron Letters, 1996, vol. 37, # 17, p. 3023 - 3026
[4] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5535 - 5542
[5] European Journal of Organic Chemistry, 2011, # 17, p. 3165 - 3170
  • 13
  • [ 459-57-4 ]
  • [ 67-63-0 ]
  • [ 18962-05-5 ]
Reference: [1] Synthetic Communications, 2010, vol. 40, # 14, p. 2122 - 2129
  • 14
  • [ 71-23-8 ]
  • [ 459-57-4 ]
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Reference: [1] Synthetic Communications, 2010, vol. 40, # 14, p. 2122 - 2129
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2547 - 2550
  • 15
  • [ 78-83-1 ]
  • [ 459-57-4 ]
  • [ 18962-07-7 ]
YieldReaction ConditionsOperation in experiment
0.6 g With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In water; toluene at 50 - 52℃; Example 2g: Alternatively 4-zso-butyloxybenzylamine (SM2) and 4-iso- but loxybenzylamine acetate (SM2b) are prepared according to following scheme. [0214] KOH (1.36g, 24.2 mmol, 3 eq) was dissolved in water (1.4 ml) and added to the solution of 4-fluorobenzaldehyde (1.0 g, 8.1 mmol, 1 eq). Isobutanol (0.66 g, 8.9 mmol, 1.1 eq) and tetrabutyl ammonium hydrogensulfate (TBAH, 0.27 g) in toluene (7 ml). The reaction mixture was vigorously stirred at 50-52 °C overnight and thereafter diluted with water (5 ml), dried and concentrated in vacuo to give 0.877 g of crude product. The crude product was purified by column chromatography using ethyl acetate : heptane to give 0.6 g of 4-isobutoxy benzaldehyde. 4-Isobutoxy benzaldehyde can thereafter be converted to SM2 and SM2b respectively using the procedure outline in example 2b.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2547 - 2550
[2] Patent: WO2017/15272, 2017, A1, . Location in patent: Paragraph 0214
  • 16
  • [ 459-57-4 ]
  • [ 4278-08-4 ]
Reference: [1] Patent: WO2014/138279, 2014, A1,
[2] Journal of the American Chemical Society, 2016, vol. 138, # 25, p. 7820 - 7823
[3] Patent: WO2011/109059, 2011, A1,
  • 17
  • [ 288-36-8 ]
  • [ 459-57-4 ]
  • [ 41498-10-6 ]
  • [ 179056-04-3 ]
YieldReaction ConditionsOperation in experiment
29% With potassium carbonate In N,N-dimethyl-formamide at 20 - 100℃; for 5 h; Inert atmosphere [000338] Synthesis of 4-(2H-1, 2, 3-triazol-2-yl) benzaldehyde & 4-(1H-1, 2, 3-triazol-1-yl) benzaldehyde (418 & 419): To a stirred solution of 4-fluorobenzaldehyde 417 (2 g, 16 mmol) in DMF (50 mL) under argon atmosphere were added 1H-1, 2, 3-triazole 417 (1.32 g, 19.2 mmol), potassium carbonate (3.3 g, 24 mmol) at RT; heated to 100 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (35 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20percent EtOAc/ hexanes to afford compound 418 (800 mg, 29percent) and using 40percent EtOAc/ hexanes to afford compound 419 (1 g, 36percent) as yellow solids.
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[2] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000338
  • 18
  • [ 459-57-4 ]
  • [ 25569-77-1 ]
Reference: [1] RSC Advances, 2018, vol. 8, # 43, p. 24203 - 24208
[2] Tetrahedron Letters, 2017, vol. 58, # 26, p. 2533 - 2536
  • 19
  • [ 5724-03-8 ]
  • [ 459-57-4 ]
  • [ 456-03-1 ]
Reference: [1] Advanced Synthesis and Catalysis, 2009, vol. 351, # 16, p. 2657 - 2666
  • 20
  • [ 459-57-4 ]
  • [ 456-03-1 ]
Reference: [1] Organic Letters, 2016, vol. 18, # 8, p. 1916 - 1919
  • 21
  • [ 110-89-4 ]
  • [ 459-57-4 ]
  • [ 10338-57-5 ]
YieldReaction ConditionsOperation in experiment
98% With Aliquat (at)366; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a–g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia–g. 4-(Piperidin-1-yl) benzaldehyde Ic
Yield 98percent as yellow crystals, mp 64 °C, (as reported) [47,48].
90%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.5 h;
Stage #2: at 80℃; for 6 h;
In 4.0ml of DMF of piperidine (0.0gm, 0.001mol) was dissolved. To this solution K2CO3 (0.27gm, 0.002mol) was added and heated at 80 °C with stirring. After 30 min 4-fluorobenzaldehyde 0.175 gm, 0.001mol) was added and heating was continued for six hours. On completion of reaction, the reaction mixture was cooled and added drop wise to ice water. The separated product was filtered and dried. The product obtained was pure and used further without any purification. (M.P.-289°C)
Reference: [1] Bioorganic Chemistry, 2014, vol. 57, p. 65 - 82
[2] Russian Journal of General Chemistry, 2013, vol. 83, # 10, p. 1864 - 1868[3] Zh. Obshch. Khim., 2013, vol. 83, # 10, p. 1654 - 1659,6
[4] Oriental Journal of Chemistry, 2013, vol. 29, # 4, p. 1531 - 1534
[5] European Journal of Organic Chemistry, 2017, vol. 2017, # 35, p. 5219 - 5224
[6] Tetrahedron, 2001, vol. 57, # 22, p. 4781 - 4785
[7] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 44 - 60
[9] Tetrahedron Letters, 1998, vol. 39, # 17, p. 2471 - 2474
[10] Journal of Materials Chemistry, 1999, vol. 9, # 9, p. 2251 - 2258
[11] Monatshefte fur Chemie, 2009, vol. 140, # 4, p. 431 - 437
[12] Phosphorus, Sulfur and Silicon and the Related Elements, 2011, vol. 186, # 1, p. 149 - 158
[13] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3741 - 3749
[14] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1365 - 1369
[15] Tetrahedron, 2013, vol. 69, # 26, p. 5355 - 5366
[16] Medicinal Chemistry Research, 2013, vol. 22, # 10, p. 4610 - 4614
[17] Journal of Chemical Research, 2014, vol. 38, # 8, p. 498 - 501
[18] Russian Journal of General Chemistry, 2014, vol. 84, # 10, p. 2058 - 2059[19] Zh. Obshch. Khim., 2014, vol. 84, # 10, p. 1757 - 1758,2
[20] Journal of the Brazilian Chemical Society, 2015, vol. 26, # 6, p. 1086 - 1097
[21] Biochemical and Biophysical Research Communications, 2017, vol. 482, # 4, p. 615 - 624
[22] Biological and Pharmaceutical Bulletin, 2017, vol. 40, # 11, p. 1883 - 1893
[23] Molecules, 2018, vol. 23, # 1,
[24] Tetrahedron, 2018, vol. 74, # 6, p. 652 - 660
[25] Research on Chemical Intermediates, 2018, vol. 44, # 4, p. 2779 - 2805
[26] Molecules, 2018, vol. 23, # 4,
[27] Molecules, 2018, vol. 23, # 5,
  • 22
  • [ 459-57-4 ]
  • [ 1075-11-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 4, p. 715 - 734
  • 23
  • [ 459-57-4 ]
  • [ 1481-32-9 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1973, p. 3092 - 3095
  • 24
  • [ 59-48-3 ]
  • [ 459-57-4 ]
  • [ 3476-86-6 ]
YieldReaction ConditionsOperation in experiment
85% With piperidine In ethanol at 90℃; Inert atmosphere General procedure: The appropriate aldehyde (1 equiv) was added to EtOH (3 mL/0.2 mmol) and the mixture was stirred until complete solution. Theoxindole (1 equiv) and piperidine (0.1 equiv) were added, and themixture was heated to 90°C for 3-7 h, and cooled. The resultingprecipitatewas filtered, washed with cold ethanol and dried to givethe pure compound. If necessary, additional recrystallization inethanol was applied to obtain the pure product.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 286 - 307
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 5, p. 2077 - 2090
[3] Journal of Chemical Research, 2018, vol. 42, # 5, p. 244 - 246
  • 25
  • [ 59-48-3 ]
  • [ 459-57-4 ]
  • [ 3476-86-6 ]
  • [ 90828-17-4 ]
YieldReaction ConditionsOperation in experiment
25% With piperidine In ethanol for 3 h; Reflux General procedure: The preparation of compounds 3-25 was carried out by refluxing oxindole with different aromatic aldehydes in ethanol in the presence of a catalytic amount of piperidine were refluxed for 3 h. After cooling reaction mixture was concentrated at reduced pressure to obtain solid of 3-oxindole derivatives, then washed with 1:1 mixture of hexane-ethyl acetate (25 mL) and dried to afford titles compoundsin good yields (Table 1). Only in two cases (10 and21), both E and Z isomers were obtained, these isomers wereseparated by column chromatography using 1:9 ethyl acetate: hexane as eluent. The structures of synthetic compounds 3-25 were elucidated by 1H NMR and EI MS. Elemental analysis results were also found to be satisfactory.
Reference: [1] Medicinal Chemistry, 2013, vol. 9, # 5, p. 681 - 688
  • 26
  • [ 104-87-0 ]
  • [ 459-57-4 ]
  • [ 3476-86-6 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 4, p. 615 - 620
  • 27
  • [ 109-97-7 ]
  • [ 459-57-4 ]
  • [ 23351-05-5 ]
Reference: [1] Tetrahedron, 2001, vol. 57, # 22, p. 4781 - 4785
  • 28
  • [ 459-57-4 ]
  • [ 37656-48-7 ]
Reference: [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 11, p. 1998 - 2008
  • 29
  • [ 459-57-4 ]
  • [ 52031-15-9 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1973, p. 3092 - 3095
  • 30
  • [ 459-57-4 ]
  • [ 2923-96-8 ]
Reference: [1] Chinese Chemical Letters, 2014, vol. 25, # 1, p. 87 - 89
  • 31
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  • [ 459-31-4 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1973, p. 3092 - 3095
[2] Patent: WO2005/48932, 2005, A2,
  • 32
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  • [ 21567-18-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1801 - 1804
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 16, p. 2795 - 2798
[3] Synthesis, 1991, # 1, p. 63 - 68
  • 33
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  • [ 703-67-3 ]
Reference: [1] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
  • 34
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  • [ 456-06-4 ]
Reference: [1] New Journal of Chemistry, 2016, vol. 40, # 10, p. 8846 - 8854
  • 35
  • [ 59382-59-1 ]
  • [ 459-57-4 ]
  • [ 917614-64-3 ]
  • [ 1975-50-4 ]
Reference: [1] Tetrahedron, 2006, vol. 62, # 49, p. 11381 - 11390
  • 36
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  • [ 345-90-4 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1977, p. 1051 - 1057
[2] Organic Letters, 2011, vol. 13, # 1, p. 98 - 101
  • 37
  • [ 13138-21-1 ]
  • [ 459-57-4 ]
  • [ 4640-67-9 ]
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 29, p. 6380 - 6384
  • 38
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  • [ 41201-58-5 ]
Reference: [1] Patent: US2016/168113, 2016, A1,
[2] Patent: US2016/168108, 2016, A1,
[3] Patent: WO2017/106520, 2017, A1,
  • 39
  • [ 459-57-4 ]
  • [ 453-71-4 ]
Reference: [1] Archiv der Pharmazie, 1963, vol. 296, p. 324 - 336
  • 40
  • [ 623-73-4 ]
  • [ 459-57-4 ]
  • [ 1999-00-4 ]
Reference: [1] Tetrahedron, 2005, vol. 61, # 4, p. 875 - 878
  • 41
  • [ 459-57-4 ]
  • [ 1999-00-4 ]
Reference: [1] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2073 - 2079
[2] RSC Advances, 2013, vol. 3, # 31, p. 12616 - 12620
  • 42
  • [ 459-57-4 ]
  • [ 56096-89-0 ]
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 40, p. 5445 - 5447
  • 43
  • [ 459-57-4 ]
  • [ 460-00-4 ]
  • [ 365-24-2 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With magnesium In diethyl ether
Stage #2: at -18℃;
Synthesis begins with the preparation of Grignard reagent 2 from aromatic bromide 1 with magnesium in ether. Fluorobenzaldehyde 3 is added at -18° C. to Grignard solution 2 to give fluorobenzhydrol 4. It should be noted that instead of using fluorobenzaldehyde 3, it is possible to use ethyl formate to condense 2 units of Grignard 2. This option is economically advantageous as fluorobenzaldehyde 3 is relatively expensive.
94%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.35 h;
Stage #2: at -78℃; for 1.25 h;
Stage #3: With acetic acid In tetrahydrofuran; hexanes
I. Bis(4-fluorophenyl)methanol; [00290] To a solution of 1 -bromo-4-fluorobenzene (1.00 g, 5.71 mmol) in anhydrous mol) dropwise , 5.71 mmol) in y ( ) y g -780C for 75 minutes, quenched with glacial acetic acid (1 mL) and then allowed to warm to room temperature. The reaction mixture was poured into H2O, and the product was extracted into diethyl ether. The organic layer was washed with saturated NaCl, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel eluting with 1 :9 EtOAc/hexanes (1.19 g, 94percent).
Reference: [1] Patent: US2013/295196, 2013, A1, . Location in patent: Paragraph 0114
[2] Patent: WO2008/79371, 2008, A1, . Location in patent: Page/Page column 99
[3] Organic Letters, 2011, vol. 13, # 1, p. 98 - 101
[4] Organic Letters, 2012, vol. 14, # 18, p. 4850 - 4853,4
  • 44
  • [ 459-57-4 ]
  • [ 352-13-6 ]
  • [ 365-24-2 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1977, p. 1051 - 1057
[2] Organic Letters, 2015, vol. 17, # 4, p. 1034 - 1037
[3] Organic and Biomolecular Chemistry, 2017, vol. 15, # 23, p. 4984 - 4991
[4] Bioorganic and Medicinal Chemistry, 2018,
  • 45
  • [ 459-57-4 ]
  • [ 365-24-2 ]
Reference: [1] Patent: EP1757605, 2007, A1, . Location in patent: Page/Page column 19-20
  • 46
  • [ 459-57-4 ]
  • [ 1132-68-9 ]
  • [ 18125-46-7 ]
Reference: [1] RSC Advances, 2017, vol. 7, # 7, p. 4203 - 4208
  • 47
  • [ 459-57-4 ]
  • [ 1132-68-9 ]
Reference: [1] Tetrahedron, 2016, vol. 72, # 46, p. 7256 - 7262
  • 48
  • [ 459-57-4 ]
  • [ 1132-68-9 ]
  • [ 459-32-5 ]
  • [ 151911-23-8 ]
Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
  • 49
  • [ 2031-62-1 ]
  • [ 459-57-4 ]
  • [ 405-70-9 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With dicarbonyl(pentamethylcyclopentadienyl)(4-methoxyphenyl)iron In dichloromethane for 4 h; Inert atmosphere; Irradiation; Schlenk technique
Stage #2: With sodium hydroxide In methanol; waterSchlenk technique; Inert atmosphere
General procedure: In a Schlenk tube under 1 atm of argon, a solution of the substrate (2 mmol, 1 equiv), the precatalyst (0.04 mmol, 0.02 equiv), and the silane (3 mmol, 1.5 equiv) in methylene chloride (15 mL) was irradiated for 4h. After removal of the solvent, methanol (5 mL) and aqueous NaOH solution (2.5 M, 5 mL) were added and the resulting suspension was stirred overnight. Neutralization with aqueous HCl solution (2 M, 30 mL) and brine (20 mL) followed by standard workup gave the desired products as pure yellow oils.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 37, p. 5015 - 5018
  • 50
  • [ 20035-08-9 ]
  • [ 459-57-4 ]
  • [ 50899-03-1 ]
YieldReaction ConditionsOperation in experiment
80% at 125℃; for 20 h; [00151] To a solution of 4-fluorobenzaldehyde (24.6 g, 198 mmol) in dimethylsulf oxide (60 mL) was added sodium ethanesulfinate (46 g, 396 mmol). The resulting mixture was stirred at 125 °C for 20 h. After cooling to rt, the reaction mixture was triturated with 350 mL of H20. The product was filtered, washed with two 10-mL portions of EtOH and dried under vacuum to afford 4-(ethylsulfonyl)benzaldehyde as a light yellow solid (31.2 g, 80percent yield). LC-MS tR = 1.19 min in 2 min chromatography, MS (ESI) m/z 199.1 [M+H]+. 1H NMR (CDCI3) δ 10.14 (s, 1H), 8.09 (s, 4H), 3.16 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).
80% at 125℃; for 20 h; To a solution of 4-fluorobenzaldehyde (24.6 g, 198 mmol) in dimethylsulfoxide (60 mE) was added sodium ethanesulfinate (46 g, 396 mmol). The resulting mixture was stirred at 125° C. for 20 h. After cooling to rt, the reaction mixture was triturated with 350 mE of H20. The product was filtered, washed with two 10-mE portions of EtOH and dried undervacuum to afford 4-(ethylsulfonyl)benzaldehyde as a light yellow solid (31.2 g, 80percent yield). EC-MS tR=i.19 mm inmm chromatography, MS (ESI) m/z 199.1 [M+H]. ‘H NMR (CDC13) ö 10.14 (s, 1H), 8.09 (s, 4H), 3.16 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).
80% at 125℃; for 20 h; To a solution of 4-fluorobenzaldehyde (24.6 g, 198 mmol) in dimethylsulfoxide (60 mL) was added sodium ethanesulfinate (46 g, 396 mmol). The resulting mixture was stirred at 125 °C for 20 h. After cooling to rt, the reaction mixture was triturated with 350 mL of H20. The product was filtered, washed with two 10-mL portions of EtOH and dried under vacuum to afford 4-(ethylsulfonyl)benzaldehyde as a light yellow solid (31.2 g, 80percent yield). LC-MS tR = 1.19 mm in 2 mm chromatography, MS (ESI) m/z 199.1 [M+H]. 1H NMR (CDC13) 5 10.14 (s, 1H), 8.09(s, 4H), 3.16 (q,J= 7.2 Hz, 2H), 1.30 (t,J= 7.2Hz, 3H).
80% at 125℃; for 20 h; [00213] Step 1 : 4-(ethylsulfonyl)benzaldehyde [1004] [00214] To a solution of 4-fluorobenzaldehyde (24.6 g, 198 mmol) in dimethylsulfoxide (60 mL) was added sodium ethanesulfinate (46 g, 396 mmol). The resulting mixture was stirred at 125 °C for 20 h. After cooling to rt, the reaction mixture was triturated with 350 mL of H20. The product was filtered, washed with two 10-mL portions of EtOH and dried under vacuum to afford 4-(ethylsulfonyl)benzaldehyde as a light yellow solid (31.2 g, 80percent yield). LC-MS tR = 1.19 min in 2 min chromatography, MS (ESI) m/z 199.1 [M+H]+. 1H NMR (CDC13) S 10.14 (s, 1H), 8.09 (s, 4H), 3.16 (q, 7 = 7.2 Hz, 2H), 1.30 (t, 7 = 7.2 Hz, 3H)
1 g at 125℃; for 20 h; To a solution of 4-fluorobenzaldehyde (1.3 g, 10.47 mmol) in DMSO (10 mL) was added sodium ethanesulfinate (2.43 g, 20.94 mmol) and the resulting mixture was stirred at 125 °C for 20 h. The mixture was cooled to RT and partitioned between ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane and the solid was collected through filtration to yield 1.0 g of the titled product. 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, = 7.2 Hz, 3H), 3.38 (q, = 7.2 Hz, 2H), 8.10 (d, = 8.1 Hz, 2H), 8.16 (d, = 8.1 Hz, 2H), 10.14 (s, 1H).

Reference: [1] Patent: WO2016/61160, 2016, A1, . Location in patent: Paragraph 00151
[2] Patent: US9481674, 2016, B1, . Location in patent: Page/Page column 49; 50
[3] Patent: WO2017/87608, 2017, A1, . Location in patent: Paragraph 00133; 00134
[4] Patent: WO2017/132432, 2017, A1, . Location in patent: Paragraph 1003-1004
[5] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 582 - 586
[6] Patent: WO2018/42342, 2018, A1, . Location in patent: Page/Page column 54
  • 51
  • [ 459-57-4 ]
  • [ 50899-03-1 ]
Reference: [1] Patent: US2010/305120, 2010, A1,
  • 52
  • [ 459-57-4 ]
  • [ 7116-38-3 ]
Reference: [1] European Journal of Organic Chemistry, 2006, # 20, p. 4573 - 4577
[2] European Journal of Medicinal Chemistry, 1988, vol. 23, # 1, p. 53 - 62
[3] Patent: WO2005/48932, 2005, A2,
  • 53
  • [ 141-82-2 ]
  • [ 459-57-4 ]
  • [ 459-32-5 ]
YieldReaction ConditionsOperation in experiment
94% With lithium perchlorate In pyridine for 5 h; Reflux General procedure: To a stirred solution of benzaldehyde (1a, 1.7 ml, 16.04mmol, 1 equiv) and malonic acid (2, 2 g, 24.06 mmol, 1.5equiv) in pyridine (5 mL) was added LiClO4 (0.34 g, 3.2mmol, 0.2 equiv) and refluxed for 5 hrs. The progress ofreaction was monitored by TLC using eluent EtOAc: nhexane(4:6). After completion of reaction, the solution wasacidified with concentrated HCl to afford a white precipitate.The precipitate was filtered and washed with water (10 ml)twice, further dried to afford 2.2 g (93percent) of 3a as the finalproduct. All synthesized compounds were characterized byIR, NMR and mass with satisfactory spectral data.
88% Reflux General procedure: A solution of suitably substituted carbaldehyde (200mmol), propenedioic acid (20.8g, 200mmol) in pyridine (10mL, 120mmol) and piperidine (1mL) was warmed at reflux for 2h. The resultant solution was poured into 2M HCl aq. and cooled to room temperature. The solid was filtered, washed with water and recrystallized in ethanol/water
Reference: [1] Archiv der Pharmazie, 2018, vol. 351, # 2,
[2] Letters in Organic Chemistry, 2018, vol. 15, # 8, p. 688 - 692
[3] Journal of Chemical Research, 2005, # 6, p. 364 - 365
[4] Arkivoc, 2016, vol. 2016, p. 284 - 296
[5] Arkivoc, 2016, vol. 2016, # 6, p. 284 - 296
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 20, p. 5479 - 5493
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[14] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 16, p. 4730 - 4738
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[16] Chinese Journal of Chemistry, 2011, vol. 29, # 11, p. 2394 - 2400
[17] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 2, p. 535 - 540
[18] Chemical Biology and Drug Design, 2013, vol. 81, # 2, p. 275 - 283
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[21] European Journal of Medicinal Chemistry, 2015, vol. 97, p. 32 - 41
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[23] Chemistry - A European Journal, 2015, vol. 21, # 30, p. 10654 - 10658
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[26] Asian Journal of Chemistry, 2016, vol. 28, # 9, p. 1895 - 1898
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[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 11, p. 1998 - 2008
[3] Tetrahedron Asymmetry, 2005, vol. 16, # 14, p. 2475 - 2485
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[4] Tetrahedron: Asymmetry, 2012, vol. 23, # 15-16, p. 1206 - 1212,7
[5] Tetrahedron Asymmetry, 2012, vol. 23, # 15-16, p. 1206 - 1212
[6] Chinese Chemical Letters, 2013, vol. 24, # 7, p. 553 - 558
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[2] Heterocycles, 1999, vol. 51, # 9, p. 2041 - 2063
[3] Tetrahedron Letters, 1996, vol. 37, # 17, p. 3023 - 3026
[4] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5535 - 5542
[5] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 3, p. 720 - 726
[6] Bioscience, Biotechnology and Biochemistry, 2015, vol. 79, # 5, p. 707 - 709
  • 63
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  • [ 75-04-7 ]
  • [ 79865-89-7 ]
YieldReaction ConditionsOperation in experiment
30% With sodium carbonate In water at 130℃; for 15 h; Autoclave A mixture of an 4-fluorobenzaldehyde (12.4 g, 0.1 mol), 60percent aqueous ethylamine solution (50 mL, 0.67 mol), and a stirring bar was sealed in a 100 mL autoclave and stirred electromagnetically in an oil bath at 130 °C for 15 h [23,24]. The mixture was extracted with ethyl acetate for 3 times (50 mL × 3), combined organic extracts and washed by 10percent hydrochloric acid twice (50 mL × 2). The pH of the aqueous phase was adjusted to 9 by 10percent sodium carbonate solutions. The aqueous phase was extracted with ethyl acetate for 3 times (30 mL × 3), combined organic extracts and dried with NaSO4. Then the solvent was evaporated on a rotary evaporator until dry. The solid was purified on silica gel chromatography (200–300 mesh) eluted with dichloromethane. The target product was obtained as light yellow solid (4 g, yield: 30percent). HR-MS (EI) C9H11NO calcd. 149.0841, found [M + H]+ 149.0840.
25% With tetrabutylammomium bromide; potassium carbonate In dimethyl sulfoxide at 95℃; for 72 h; General procedure: To a solution of p-fluoro benzaldehyde (1 equiv.), tetrabutylammonium bromide (0.3 equiv.) and the appropriate amine (1.5 equiv.) in DMSO, K2CO3 (1 equiv.) was added and the mixture was stirred at 95 for 3d. The reaction was quenched by the addition of water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product which was purified by silica gel column chromatography with EtOAC/ petroleum ether as eluent.
Reference: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 35, p. 5219 - 5224
[2] Dyes and Pigments, 2013, vol. 96, # 2, p. 383 - 390
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7683 - 7687
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8483 - 8492,10
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8483 - 8492
  • 64
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YieldReaction ConditionsOperation in experiment
72% With ammonium acetate In butan-1-olReflux General procedure: A mixture of appropriate aldehyde 2.40 g (1-15), 2.44 g ofmalonic acid and 3.54 g of ammonium acetate (1:1.1:2.3), in 200mLof the 1-butanol was refluxed for 1.5-2 h until the evolution of CO2ceased. The precipitate formed was filtered and washed withboiling 1-butanol (2 x 50 mL), boiling ethanol (2 x 50 mL) and100mL of water. Precipitates were dried at 80-100 °C for 8-10 h.Purity of product was checked by TLC, and yield obtained about65-80percent in each reaction.
62.8% With ammonium acetate In ethanol at 75 - 80℃; for 8 h; To 150 mL of ethanol were added 30.5 g (0.25 mol) of 4-fluorobenzaldehyde, 25.6 g (0.25 mol) of malonic acid and 28.4 g (0.37 mol) of ammonium acetate, and the mixture was reacted while stirring under reflux (75 to 80°C) for 8 hours. After completion of the reaction, the obtained reaction mixture was stirred at room temperature for 1 hour, filtered and dried under reduced pressure at 45°C to give 28.3 g of 3-amino-3-(4-fluorophenyl)propionic acid (racemic mixtures) (isolation yield based on 4-fluorobenzaldehyde: 62.8percent) as white powder. Incidentally, physical properties of the 3-amino-3-(4-fluorophenyl)propionic acid (racemic mixtures) were as follows. 1H-NMR (δ (ppm), D2O): 2.49 (dd, 1H, J=17.1, 6.8Hz), 2.62 (dd, 1H, J=17.1, 7.8Hz), 4.20 (dd, 1H, J=7.8, 6.8Hz), 6.58-6.62 (m, 2H), 6.88-6.91 (s, 1H) 13C-NMR (δ (ppm), D2O): 37.1, 50.5.1, 115.5, 115.8, 128.9, 130.4, 172.6 MS (EI) m/z: 183 (M+) MS (CI, i-C4H10) m/z: 184 (MH+)
Reference: [1] Chemical Communications, 2011, vol. 47, # 20, p. 5894 - 5896
[2] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 260 - 264
[3] Journal of Medicinal Chemistry, 2001, vol. 44, # 12, p. 1938 - 1950
[4] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 252 - 268
[5] European Journal of Medicinal Chemistry, 1992, vol. 27, # 9, p. 961 - 965
[6] Patent: EP1621529, 2006, A1, . Location in patent: Page/Page column 35
[7] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 395 - 406
[8] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
[9] Preparative Biochemistry and Biotechnology, 2013, vol. 43, # 2, p. 207 - 216
[10] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 1290,1293; engl. Ausg. S. 1376, 1378
[11] Yaoxue Xuebao, 1959, vol. 7, p. 237,240[12] Chem.Abstr., 1960, p. 12096
[13] Bulletin de la Societe Chimique de France, 1987, # 6, p. 1079 - 1083
[14] Synthesis, 2002, # 14, p. 2023 - 2036
[15] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 16, p. 3685 - 3690
[16] European Journal of Organic Chemistry, 2013, # 3, p. 557 - 565
[17] Patent: WO2017/46737, 2017, A1, . Location in patent: Page/Page column 121
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Reference: [1] Patent: US6306909, 2001, B1,
[2] Patent: US5135947, 1992, A,
[3] Patent: EP288188, 1991, B1,
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[2] Russian Journal of General Chemistry, 2005, vol. 75, # 7, p. 1113 - 1124
  • 67
  • [ 459-57-4 ]
  • [ 42564-51-2 ]
YieldReaction ConditionsOperation in experiment
98% at -5 - 20℃; for 1 h; 4-Fluorobenzaldehyde (11, 4.94 mL, 46.13 mmol) was slowly added dropwise to a solution of H2SO4 (24 mL) and HNO3 (3 mL) at −5 °C. The temperature was kept under 5 °C. Then the solution was warmed to room temperature over 1 h. After pouring into ice, the aqueous phase was extracted by CH2Cl2 (50 mL × 2),and then the combined organic layer was washed successively with saturated NaHCO3 and brine, and dried over anhydrous MgSO4.The solvent was removed in vacuo and the residue was purified by flash column chromatography on a silica gel (hexane−EtOAc, 96:4) to afford 12 (7.61 g, 98percent) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.56 (dd, J = 7.2, 2.2 Hz, 1H), 8.18 (ddd, J = 8.5,4.2, 2.2 Hz, 1H), 7.48 (dd, J = 10.0, 8.5 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ188.58, 159.84, 157.13, 136.01, 132.85, 127.43, 119.70.
79% at 0 - 20℃; for 0.5 h; Inert atmosphere General procedure: 10 mmol of the desired p-substituted benzaldehyde was dissolved in 5 mL of conc. sulfuric acid, and cooled to 0 °C, and then 1.2 equiv. of nitric acid was dissolved in 1 mL of conc. sulfuric acid, and then slowly added to the reaction mixture. The reaction was allowed to warmgradually to room temperature and stirred for 30 min at room temperature. It was then poured into 50 mL of ice-cold water. The produced precipitate was filtered and washed with cold water. The product was purified on reverse phase column chromatography with gradient increase of methanol in water containing 0.1percent of formic acid as eluent.
77% at 0 - 20℃; for 1.33333 h; Intermediate Example 4.4-Fluoro-3 -nitrobenzaldehydeNitration mixture (sulfuric acid 40 ml + nitric acid 5.5 ml) was added dropwise to 4-fluorobenzaldehyde (10 g, 80.57 mmol) at 0 °C and the mixture was stirred at 5 °C for 20 min and at RT for 1 h. The mixture was quenched by the addition of crushed ice. The precipitate formed was filtered and was washed repeatedly with water to give white solid. The solid was dried under vacuum to give the product in 77 percent yield (10.5 g). 1H NMR (300 MHz, CDC13): δ 10.04 (s, 1H), 8.58 (dd, 1H), 8.22-8.18 (m, 1H), 7.5 (t, 1H).
77% at 0 - 20℃; for 1.33333 h; Nitration mixture (sulfuric acid 40 ml+nitric acid 5.5 ml) was added dropwise to 4-fluorobenzaldehyde (10 g, 80.57 mmol) at 0° C. and the mixture was stirred at 5° C. for 20 min and at RT for 1 h.
The mixture was quenched by the addition of crushed ice.
The precipitate formed was filtered and was washed repeatedly with water to give white solid.
The solid was dried under vacuum to give the product in 77percent yield (10.5 g).
1H NMR (300 MHz, CDCl3): δ 10.04 (s, 1H), 8.58 (dd, 1H), 8.22-8.18 (m, 1H), 7.5 (t, 1H).
63% at 0 - 40℃; for 1 h; General procedure: The nitration of aldehydes was carried out in a three-neckedflask of 50 ml with magnetic stirrer. H2SO4 25 ml (0.47 M)were cooled to 0 °C, 3.1 ml (0.070 M) of HNO3 were added,and then the aldehyde (0.06 M) was slowly added. Thereaction was carried out at a temperature of 0–5 °C. Then,the mixture was heated at 40 °C for 1 h. The reaction waspoured into ice water and filtered under a vacuum; thenitrobenzaldehydes were purified by recrystallization. Thescheme of reaction is showed in Fig. 1 (Furniss et al. 1989).The spectrums of 1H NMR of nitrobenzaldehydes wereobtained in CDCl3 and TMS as reference.
53% With sulfuric acid; nitric acid In water at 0℃; for 2.58333 h; A 50 mL flask was charged with 4-fluorobenzaldehyde (2.20 mL, 20.5 mmol) andconcentrated sulfuric acid (10 mL). The solution was cooled to 0°C and fuming nitric acid (1.10 mL, 90percent w/w in water, 23.3 mmol) was added dropwise over 5 mm by pipet. The reaction was stirred for 2.5 hours and allowed to warm as the ice-bath melted. The reaction was poured into rapidly stirred ice-water (150 mL), and was stirred for an additional 15 mm. The resultingprecipitate was collected by vacuum filtration, and the collected solid was washed with water(2x10 mL). Air-drying provided 1.84 g (53percent) of the title compound as a white solid: ‘H NIVIR(400 IVIHz, DMSO-d6) 0 10.07 (s, 1H), 8.68 (dd, J 7.5, 2.1 Hz, 1H), 8.33 (ddd, J=8.6, 4.3, 2.2Hz, 1H), 7.82 (dd, J=11.0, 8.6 Hz, 1H); ‘9F NMR (376 MHz, DMSO-d6) 0-109.6 (s, iF); LCMS (ESI+) m/z: [M+H] Calcd for C7H5FNO3 170.0; Found 170.1.

Reference: [1] Journal of the Chemical Society - Series Chemical Communications, 1994, # 4, p. 439 - 440
[2] Organic letters, 2001, vol. 3, # 25, p. 4079 - 4082
[3] Tetrahedron Letters, 2014, vol. 55, # 47, p. 6500 - 6503
[4] Heterocycles, 1999, vol. 51, # 9, p. 2041 - 2063
[5] European Journal of Organic Chemistry, 2011, # 17, p. 3165 - 3170
[6] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 3, p. 720 - 726
[7] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 361 - 377
[8] Patent: WO2013/53983, 2013, A1, . Location in patent: Page/Page column 30
[9] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0133
[10] Bioscience, Biotechnology and Biochemistry, 2015, vol. 79, # 5, p. 707 - 709
[11] Medicinal Chemistry Research, 2018, vol. 27, # 7, p. 1782 - 1791
[12] European Journal of Organic Chemistry, 2003, # 16, p. 3131 - 3138
[13] Patent: WO2018/35346, 2018, A1, . Location in patent: Paragraph 00171
[14] Chemische Berichte, 1957, vol. 90, p. 1586,1588
[15] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5535 - 5542
[16] Tetrahedron Letters, 1996, vol. 37, # 17, p. 3023 - 3026
[17] Patent: US2012/108583, 2012, A1, . Location in patent: Page/Page column 36
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Reference: [1] Patent: CN108129414, 2018, A,
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[2] Patent: CN108341788, 2018, A,
[3] Patent: CN108341788, 2018, A,
[4] Patent: CN108341788, 2018, A,
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[2] Patent: US2008/306116, 2008, A1, . Location in patent: Page/Page column 23
[3] Chemistry - A European Journal, 2014, vol. 20, # 24, p. 7241 - 7244
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7586 - 7589
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YieldReaction ConditionsOperation in experiment
61% With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 37 h; Inert atmosphere 4-Hydroxypiperidine (6.24 g, 0.06 mol),4-Fluorobenzaldehyde (5 g, 0.04 mol)And K2CO3 (8.44 g, 0.06 mol)Was dissolved in dimethylformamide (150 mL)And stirred at 70 & lt; 0 & gt; C for 37 hours under a nitrogen atmosphere,K2CO3 was removed by suction filtration and the dimethylformamide was vaporized.Then, it was dried in a vacuum oven at 80 for 12 hours and then purified by a chromatographic method to obtain 4- (4-hydroxypiperidin-1-yl) benzaldehyde. [Yield = 61percent.
52% With sodium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 8 h; Dimethylformamide (15 mL) was added to 4-fluorobenzaldehyde (1.5 g, 0.012 mol) and sodium carbonate (2.5 g, 0.018 mol). Piperidin-4-ol (1.47 g, 0.015 mol) was slowly added dropwise thereto, followed by stirring for 8 hours at 70 to 80°C. Dichloromethane was added to the reaction solution, and the mixture was washed with an aqueous solution of saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting residue was crystallized with n-hexane to obtain the title compound (1 .5 g, yield: 52percent). 'H-NMR(300 MHZ, DMSO-d6) δ 1 .40 (m, 2H), 1.79 (m, 2H), 3.10 (m, 2H), 3.75 (m, 3H), 4.77 (d, 1H), 7.02 (d, 2H), 7.68 (d, 2H), 9.67 (s, 1 H)
Reference: [1] Synthesis, 1981, # 8, p. 606 - 608
[2] CrystEngComm, 2016, vol. 18, # 31, p. 5832 - 5841
[3] Patent: KR101797358, 2017, B1, . Location in patent: Paragraph 0086; 0087
[4] Patent: WO2013/100631, 2013, A1, . Location in patent: Page/Page column 18
[5] Journal of the American Chemical Society, 1994, vol. 116, # 23, p. 10498 - 10506
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  • 76
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  • [ 99662-34-7 ]
YieldReaction ConditionsOperation in experiment
29% With potassium carbonate In N,N-dimethyl-formamide at 100℃; To a solution of Compound 1 (10 g, 80.6 mmol) in dry DMF (100 mL) were added pyrazole (5.5 g, 80.6 mmol) and K2C03 (12.2 g, 88.7 mmol). The resulting solution was stirred at 100 °C for overnight. After cooling to RT, the residue was treated with water and extracted with EA. The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give a crude oil. The crude product was purified by recrystallization to afford Compound 2 (4 g, 29 percent).1HNMR (CDC13, 300 MHz) ö: 6.5-6.6 (s, 1 H), 7.7-7.8 (s, 1 H), 7.9-8.0 (d, 2 H), 8.0-8.1 (d, 2 H), 8.1-8.2 (s, 1 H), 10.0-10.1 (s, 1 H).
Reference: [1] New Journal of Chemistry, 2018, vol. 42, # 17, p. 14630 - 14641
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[3] ChemMedChem, 2013, vol. 8, # 6, p. 967 - 975
[4] Journal of Medicinal Chemistry, 2013, vol. 56, # 12, p. 5213 - 5217
[5] Patent: WO2016/77232, 2016, A2, . Location in patent: Page/Page column 42; 43
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[7] Patent: CN106966981, 2017, A, . Location in patent: Paragraph 0055-0057
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  • [ 27913-99-1 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.5 h;
Stage #2: at 80℃; for 6 h;
In 4.0 ml of DMF, 1-methylpiperazine (0.1 gm. 0.001mol) was dissolved. To this solution K2CO3 (0.20gm, 0.00015 mol) was added and heated at 80 °C with stirring. After 30 min 4-flurobenzaldehyde (0.124 gm, 0.001mol) was added and heating was continued for 6 hours. On completion of reaction, the reaction mixture was cooled and added drop wise to ice-water. The separated product was filtered and dried. The product obtained was pure and used further without any purification.(M.P. 60-62°C)
92% With sodium carbonate In water for 21 h; Heating / reflux A mixture of 4-fluorobenzaldehyde (49.6 gm, 0.40 moles) and N- methylpiperazine (69.5 gm, 0.695 moles) in water (400 mL) containing sodium carbonate (63.0 gm, 0.60 moles) was stirred at reflux for 21 hours. After cooling, the mixture was poured into a separatory funnel containing water (1000 mL) and the oily product was extracted into methylene chloride (3 X 200 mL). The combined extracts were washed with water and the solvent was then stripped under vacuum to give the aldehyde as an oil which solidified upon cooling. The solid was triturated in hexane and was then isolated by filtration. After drying there was obtained 75 gm (92percent) of N- methyl-N'-(4-formyl)phenyl-piperazine as a tan solid.
87% With Aliquat (at)366; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a–g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia–g. 4-(4-Methylpiperazin-1-yl) benzaldehyde Ie
Yield 87percent as yellow crystals, mp 64 °C, (as reported) [45,51].
65% With potassium carbonate In N,N-dimethyl-formamide for 12 h; Inert atmosphere 4-Fluorobenzaldehyde (400 mg, 3.22 mmol), N-methyl piperazine(322 mg, 3.22 mmol) and K2CO3 (469 mg, 3.40 mmol) were stirred in dry DMF at 130 °C under nitrogen atmosphere. After 12 h,the reaction was quenched by addition of water. The resulting mixture was extracted with EtOAc (3 50 mL), washed with brine,and dried over anhydrous Na2SO4. The resulting residue waspurified by flash chromatography (PE/EtOAc 1:4). Yield 65percent, white solid. 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.76 (d, J 8.8 Hz,2H), 6.92 (d, J 8.8 Hz, 2H), 3.46-3.37 (m, 4H), 2.59-2.54 (m, 4H),2.36 (s, 3H). LC-MS: (positive mode,m/z) calculated 205.1431, found205.1321 for [MH]
40% With sodium carbonate In water at 0℃; for 12 h; Water (30 mL) was added to 4-fluorobenzaldehyde (3.0 g, 0.024 mol) and sodium carbonate (3.83 g, 0.036 mol). 1-methylpiperazin (4.1 1 g, 0.041 mol) was slowly added dropwise thereto, followed by stirring for 12 hours at 0°C. Dichloromethane was added to the reaction solution, and washed with an aqueous solution of saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure, and the resulting residue was crystallized with n-hexane to obtain the title compound (2.9 g, yield:40percent). 'H-NMR(300 MHZ, DMSO-d6) δ 2.21 (s, 3H), 2.42 (m, 4H), 3.35 (m, 4H), 7.02 (d, 2H), 7.69 (d, 2H), 9.71 (s, 1H)

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  • [ 459-57-4 ]
  • [ 77771-02-9 ]
YieldReaction ConditionsOperation in experiment
97% at 30 - 40℃; for 5.91667 h; Inert atmosphere Into a 500 mL four necked flask fitted with an overhead stirrer, a condenser and a thermometer pocket, 65percent Oleum 204g (7.5 times w.r.t. 4- Fluorobenzaldehyde ) was added to the flask slowly followed by iodine 0.27g (1 wtpercent w.r.t 4-Fluorobenzaldehyde) addition. The mixture was stirred under N2 atm. for 5 min. Then zinc bromide 0.68g (2.5wtpercent w.r.t 4- Fluorobenzaldehyde) was added to the reaction mass and the stirring was continued for another 5.0min. Then 4-Fluorobenzaldehyde (27.2g, 0.219mole) was added dropwise over a period of 1.0 h at temperature below 300C. The resulting mixture was stirred for 15 min and then bromine (6.8mL, 0.13 lmol) was added drop wise over a period of 3h at a temperature below 300C. Then the reaction mass was heated to 400C and maintained at same temperature for 90 min. and the reaction was monitored by G.C every 30 min. G.C areapercent showed 98percent product formation. The reaction mass was cooled to 10 0C and was quenched in ice (128.Og) over a period of 2h at a temperature below 25 0C. The organic portion was extracted with 2x 100 mL of toluene followed by washing with 3xl00mL water. The organic layer was treated with thiosulfate to remove unreacted bromine present in the crude. The final mass was washed with water and then the organic layer was separated and dried over Na2SO4 and the liquid was evaporated to give crude pale yellow product 43.19 gm ( 97percent yield). GC purity was 96percent.
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  • [ 93939-74-3 ]
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  • [ 133721-87-6 ]
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  • [ 19883-57-9 ]
  • [ 93939-74-3 ]
Reference: [1] Tetrahedron Asymmetry, 2004, vol. 15, # 18, p. 2793 - 2796
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  • [ 157662-77-6 ]
Reference: [1] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5535 - 5542
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
  • 84
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  • [ 551-93-9 ]
  • [ 155370-03-9 ]
YieldReaction ConditionsOperation in experiment
94% With C22H48N4O12S4(4+)*4HO4S(1-) In ethanol; water at 20℃; for 1.6 h; Irradiation; Reflux 1 mmol of p-fluorobenzaldehyde, 1 mmol of o-aminoacetophenone and 0.09 mmol of high acidity ionic liquid were separately added to a 50 ml one-necked flask with a condenser tube containing 8 ml of 95percent aqueous ethanol and stirred at room temperature. Heating and refluxing, ultrasonic irradiation under the reaction for 1.6h, TLC (thin plate chromatography) detection, the disappearance of raw materials, the end of the reaction cooled to room temperature to precipitate a large number of solid, put it into the ice bath to continue cooling the solid, the amount of solid is no longer increased The precipitated solid was allowed to stand, suction, and the residue was washed with absolute ethanol (3 ml x 3) and dried in vacuo at 75 ° C to give2- (4-fluoro) -phenyl-2,3-dihydro-4 (1H) -quinolinone,The purity was 99.0percent and the yield was 94percent by high performance liquid chromatography. The filtrate is directly added to the fluorobenzaldehyde, o-amino acetophenone after repeated use.
85% With silver trifluoromethanesulfonate In methanol for 18 h; Reflux; Inert atmosphere General procedure: AgOTf (26 mg, 10 molpercent) was added to a solution of an o-aminoacetophenone (1.0 mmol) and an aryl aldehyde (1.2 mmol) in MeOH (5mL) at r.t. The reaction mixture was stirred under reflux for 12–24 h. After the reaction was complete, as indicated by TLC, the excess solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexanes–EtOAc, 20:1) to yield the desired product.
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[3] Tetrahedron Letters, 2007, vol. 48, # 28, p. 4935 - 4937
[4] Tetrahedron Letters, 2016, vol. 57, # 49, p. 5442 - 5445
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[2] Turkish Journal of Chemistry, 2015, vol. 39, # 4, p. 850 - 866
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Reference: [1] Patent: WO2013/173218, 2013, A1,
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  • [ 459-57-4 ]
  • [ 57260-71-6 ]
  • [ 197638-83-8 ]
YieldReaction ConditionsOperation in experiment
72% With potassium carbonate In 1-methyl-pyrrolidin-2-one at 135℃; Step 1: To a solution containing compound 1 (3.9 g, 31 mmol) and Boc-piperazine (6.3 g, 34 mmol) in N-methyl-2-pyrrolidone (NMP) (30 ml) was added K2C03 (8.5 g, 62 mmol). The mixture was stirred overnight at 135 C. After completion of the reaction, the mixture was poured into ice water, and the precipitate was collected to afford the desired product as a yellow solid (6.4 g, 72percent).
39% With potassium carbonate In N,N-dimethyl-formamide at 20℃; Synthesis of 4-(4-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1). A mixture of 4-(tert-butyl-l -piperazinecarboxylate (556 mg, 3.0 mmol), 4- fluoro-benzaldehyde (315 μl, 3.0 mmol) and K2CO3 (514 mg, 3.7 mmol) in DMF (5 ml) was stirred at ambient temperature overnight. Reaction was diluted with water (30 ml) and extracted with EtOAc (50 ml x 2). Organic layer was washed with water (20 ml), 1 M aq. HCl (20 ml), water (20 ml x 2) and brine (20 ml) and dried over MgSO4 (anh.). Solvent was evaporated in vacuum. Residue was triturated with hexane. Formed precipitate was filtrated and dried in vacuum overnight to provide target compound (1) (342 mg, 39percent) as off-white solid. LC-MS [M+H] 291.2 (C16H22N2O3+H, requires 291.38).
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[2] Patent: WO2013/11518, 2013, A1,
[3] Patent: WO2013/11518, 2013, A1,
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Reference: [1] Patent: US5384330, 1995, A,
  • 91
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  • [ 459-57-4 ]
  • [ 90035-20-4 ]
YieldReaction ConditionsOperation in experiment
73% With caesium carbonate In N,N-dimethyl-formamide at 20 - 85℃; Intermediate 52: 4-[4-(Trifluoromethyl)phenyl]oxy}benzaldehyde; To a solution of the commercially available of 4-(trifluoromethyl)phenol (9.1 g, 56 mmol, 1.2 equiv.) in DMF (100 mL) was added successively cesium carbonate (22.8 g, 70 mmol, 1.5 equiv.) and 4-fluorobenzaldehyde (5 mL, 46.6 mmol) at room temperature. The reaction mixture was then stirred at 85°C for 16h before being cooled and filtered. The resulting filtrate was concentrated to dryness and the crude oil was purified by flash chromatography (SiO2, cyclohexane/ethyl acetate 70/30) to give the title compound (9.0 g, 73percent yield) as a colorless oil. 1H NMR (CDCI3) δ 9.97 (s, 1 H), 7.91 (m, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.20-7.11 (m, 4H). LCMS: (M+H)+ = 267, Rt= 3.53 min.
70% With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 4 h; Inert atmosphere To a homogeneous mixture of 4-(trifluoromethyl)phenol (1.2 g, 7.5 mmol) and 4-fluorobenzaldehyde (0.8 mL, 7.5 mmol) in anhydrous DMF (15 mL), under an argon atmosphere, was added potassium carbonate (1.04 g, 7.5 mmol). The mixture was heated at 150 °C for 4 h before being poured over ice. The resultant precipitate was isolated by vacuum filtration, washed thoroughly with water, dried under vacuum to afford the desired compound (1.4 g, 70percent) as a cream colored solid, which was used without further purification. MS (ESI): 267.1 (M + H)+.
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[3] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 1, p. 15 - 30
[4] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1801 - 1804
[5] Journal of Medicinal Chemistry, 2015, vol. 58, # 7, p. 3036 - 3059
[6] Patent: US9266841, 2016, B2, . Location in patent: Page/Page column 18
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