3137-63-1|4-Chloro-2-(trichloromethyl)quinazoline| Ambeed

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1
[ 1769-24-0 ]
[ 3137-63-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With phosphorus pentachloride; trichlorophosphate for 0.333333h; Microwave irradiation;
82%	With phosphorus pentachloride; trichlorophosphate for 0.333333h; Microwave irradiation;
76%	With phosphorus pentachloride; trichlorophosphate for 24h; Heating;

75%	With phosphorus pentachloride; trichlorophosphate for 15h; microwave irradiation;
75%	With phosphorus pentachloride; trichlorophosphate for 0.25h; Microwave irradiation;
75%	With phosphorus pentachloride; trichlorophosphate for 0.25h; Microwave irradiation;	4.1.2. Preparation of 4-chloro-2-trichloromethylquinazoline 1 Compound 1 was prepared as described previously refPreviewPlaceHolder[12] and was obtained after purification by silica gel column chromatography, eluting with dichloromethane/petroleum ether (1:1), as a white solid in 75% yield; mp 127 °C 1H NMR (200 MHz, CDCl3) δ: 7.82-7.90 (m, 1H), 8.03-8.12 (m, 1H), 8.20-8.24 (m, 1H), 8.33-8.38 (m, 1H). 13C NMR (50 MHz, CDCl3) δ: 95.9 (C), 122.9 (C), 126.0 (CH), 129.7 (CH), 130.6 (CH), 135.9 (CH), 150.2 (C), 159.9 (C), 164.0 (C). Anal. Calcd for C9H4Cl4N2: C, 38.34; H, 1.43; N, 9.94. Found: C, 38.25; H, 1.14; N, 9.60.
72%	With phosphorus pentachloride; trichlorophosphate at 0 - 100℃; for 24h;	4-Chloro-2-trichloromethylquinazoline (6) PCl5 (3.90 g, 18.7 mmol) and POCl3 (9.4 mL, 37 mmol) were added to 2-methylquinazolin-4-one (0.50 g, 3.1 mmol) at 0 °C.The mixture was then heated to reflux and stirred for 24 hours. After cooling, the solution was diluted with CHCl3 (30 mL) and ultra-sound was used to completely dissolve the reaction product. The solution was then added to a beaker of ice and alkalinized with dry NaHCO3 (180 g) while stirring. Alkalinity of the water layer was confirmed with a universal pH indicator. The solution was filtered to remove the salt and the solution was extracted with CHCl3 (50 mL). The brown organic layer was dried over anhydrous MgSO4, which was removed by filtration and the filtrate concentrated under vacuum. Purification of the brown solid was performed by flash chromatography with CH2Cl2-petroleum ether (1:1) as eluent to give the product as white powder (0.63 g, 72 % yield).
	With phosphorus pentachloride; phosphorus trichloride at 170℃; im Rohr;

Reference： [1]Gellis, Armand; Kieffer, Charline; Primas, Nicolas; Lanzada, Gilles; Giorgi, Michel; Verhaeghe, Pierre; Vanelle, Patrice [Tetrahedron, 2014, vol. 70, # 44, p. 8257 - 8266]
[2]Gellis, Armand; Primas, Nicolas; Hutter, Sébastien; Lanzada, Gilles; Remusat, Vincent; Verhaeghe, Pierre; Vanelle, Patrice; Azas, Nadine [European Journal of Medicinal Chemistry, 2016, vol. 119, p. 34 - 44]
[3]Verhaeghe, Pierre; Rathelot, Pascal; Gellis, Armand; Rault, Sylvain; Vanelle, Patrice [Tetrahedron, 2006, vol. 62, # 34, p. 8173 - 8176]
[4]Verhaeghe, Pierre; Azas, Nadine; Gasquet, Monique; Hutter, Sebastien; Ducros, Christophe; Laget, Michele; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 396 - 401]
[5]Location in patent: scheme or table Maillard-Boyer, Martine; Castera-Ducros, Caroline; Verhaeghe, Pierre; Sifredi, France; Rathelot, Pascal; Vanelle, Patrice [Molecules, 2010, vol. 15, # 4, p. 2719 - 2729]
[6]Location in patent: experimental part Castera-Ducros, Caroline; Azas, Nadine; Verhaeghe, Pierre; Hutter, Sebastien; Garrigue, Philippe; Dumtre, Aurelien; Mbatchi, Litaty; Laget, Michle; Remusat, Vincent; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4184 - 4191]
[7]Hamann, Anton R.; De Kock, Carmen; Smith, Peter J.; Van Otterlo, Willem A.L.; Blackie, Margaret A.L. [South African Journal of Chemistry, 2013, vol. 66, p. 231 - 236]
[8]Dehoff [Journal fur praktische Chemie (Leipzig 1954), 1890, vol. <2> 42, p. 352] Bogert; May [Journal of the American Chemical Society, 1909, vol. 31, p. 512]

2
[ 3137-63-1 ]
[ 162607-20-7 ]
[ 1008132-74-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 396 - 401

3
[ 15862-94-9 ]
[ 3137-63-1 ]
[ 1314885-43-2 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 3810 - 3813

4
[ 6320-03-2 ]
[ 3137-63-1 ]
[ 1336933-33-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 2-chlorothiphenol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;	General procedure for the preparation of compounds 2-18: 1 equiv ofthe appropriate thiophenol was dissolved in DMSO, then added onto 2 equiv ofNaH 95%, and stirred under N2 for 20 min. 1 equiv of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, then added to themixture, and stirred at room temperature for 1 h. The reaction medium wasthen extracted three times by dichloromethane. The organic layer was washedwith water five times, dried over anhydrous Na2SO4 and concentrated in vacuo.The crude product was purified by column chromatography on silica gel withappropriate solvent to afford the corresponding nucleophilic aromaticsubstitution product.

Reference： [1]Location in patent: experimental part Verhaeghe, Pierre; Dumtre, Aurélien; Castera-Ducros, Caroline; Hutter, Sébastien; Laget, Michle; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 6003 - 6006]

5
[ 937-00-8 ]
[ 3137-63-1 ]
[ 1336930-62-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: 3-trifluoromethyl-thiophenol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;	General procedure for the preparation of compounds 2-18: 1 equiv ofthe appropriate thiophenol was dissolved in DMSO, then added onto 2 equiv ofNaH 95%, and stirred under N2 for 20 min. 1 equiv of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, then added to themixture, and stirred at room temperature for 1 h. The reaction medium wasthen extracted three times by dichloromethane. The organic layer was washedwith water five times, dried over anhydrous Na2SO4 and concentrated in vacuo.The crude product was purified by column chromatography on silica gel withappropriate solvent to afford the corresponding nucleophilic aromaticsubstitution product.

Reference： [1]Location in patent: experimental part Verhaeghe, Pierre; Dumtre, Aurélien; Castera-Ducros, Caroline; Hutter, Sébastien; Laget, Michle; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 6003 - 6006]

6
[ 3137-63-1 ]
[ 2557-77-9 ]
[ 1336930-57-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 3-fluorothiophenol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;	General procedure for the preparation of compounds 2-18: 1 equiv ofthe appropriate thiophenol was dissolved in DMSO, then added onto 2 equiv ofNaH 95%, and stirred under N2 for 20 min. 1 equiv of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, then added to themixture, and stirred at room temperature for 1 h. The reaction medium wasthen extracted three times by dichloromethane. The organic layer was washedwith water five times, dried over anhydrous Na2SO4 and concentrated in vacuo.The crude product was purified by column chromatography on silica gel withappropriate solvent to afford the corresponding nucleophilic aromaticsubstitution product.

Reference： [1]Location in patent: experimental part Verhaeghe, Pierre; Dumtre, Aurélien; Castera-Ducros, Caroline; Hutter, Sébastien; Laget, Michle; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 6003 - 6006]

7
[ 3137-63-1 ]
[ 2557-78-0 ]
[ 1336930-56-3 ]

Yield	Reaction Conditions	Operation in experiment
48%	Stage #1: 2-fluorothiophenol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;	General procedure for the preparation of compounds 2-18: 1 equiv ofthe appropriate thiophenol was dissolved in DMSO, then added onto 2 equiv ofNaH 95%, and stirred under N2 for 20 min. 1 equiv of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, then added to themixture, and stirred at room temperature for 1 h. The reaction medium wasthen extracted three times by dichloromethane. The organic layer was washedwith water five times, dried over anhydrous Na2SO4 and concentrated in vacuo.The crude product was purified by column chromatography on silica gel withappropriate solvent to afford the corresponding nucleophilic aromaticsubstitution product.

Reference： [1]Location in patent: experimental part Verhaeghe, Pierre; Dumtre, Aurélien; Castera-Ducros, Caroline; Hutter, Sébastien; Laget, Michle; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 6003 - 6006]

8
[ 3137-63-1 ]
[ 1122-41-4 ]
[ 1336930-75-6 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 2,4-dichlorobenzenethiol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;	General procedure for the preparation of compounds 2-18: 1 equiv ofthe appropriate thiophenol was dissolved in DMSO, then added onto 2 equiv ofNaH 95%, and stirred under N2 for 20 min. 1 equiv of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, then added to themixture, and stirred at room temperature for 1 h. The reaction medium wasthen extracted three times by dichloromethane. The organic layer was washedwith water five times, dried over anhydrous Na2SO4 and concentrated in vacuo.The crude product was purified by column chromatography on silica gel withappropriate solvent to afford the corresponding nucleophilic aromaticsubstitution product.

Reference： [1]Location in patent: experimental part Verhaeghe, Pierre; Dumtre, Aurélien; Castera-Ducros, Caroline; Hutter, Sébastien; Laget, Michle; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 6003 - 6006]

9
[ 3137-63-1 ]
[ 825-83-2 ]
[ 1336930-63-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 4-trifluoromethylbenzenethiol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;	General procedure for the preparation of compounds 2-18: 1 equiv ofthe appropriate thiophenol was dissolved in DMSO, then added onto 2 equiv ofNaH 95%, and stirred under N2 for 20 min. 1 equiv of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, then added to themixture, and stirred at room temperature for 1 h. The reaction medium wasthen extracted three times by dichloromethane. The organic layer was washedwith water five times, dried over anhydrous Na2SO4 and concentrated in vacuo.The crude product was purified by column chromatography on silica gel withappropriate solvent to afford the corresponding nucleophilic aromaticsubstitution product.

Reference： [1]Location in patent: experimental part Verhaeghe, Pierre; Dumtre, Aurélien; Castera-Ducros, Caroline; Hutter, Sébastien; Laget, Michle; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 6003 - 6006]

10
[ 3137-63-1 ]
[ 13333-97-6 ]
[ 1336930-60-9 ]

Yield	Reaction Conditions	Operation in experiment
31%	Stage #1: o-trifluoromethylbenzenethiol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide; mineral oil at 20℃; for 1h; Inert atmosphere;	General procedure for the preparation of compounds 2-18: 1 equiv ofthe appropriate thiophenol was dissolved in DMSO, then added onto 2 equiv ofNaH 95%, and stirred under N2 for 20 min. 1 equiv of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, then added to themixture, and stirred at room temperature for 1 h. The reaction medium wasthen extracted three times by dichloromethane. The organic layer was washedwith water five times, dried over anhydrous Na2SO4 and concentrated in vacuo.The crude product was purified by column chromatography on silica gel withappropriate solvent to afford the corresponding nucleophilic aromaticsubstitution product.

Reference： [1]Location in patent: experimental part Verhaeghe, Pierre; Dumtre, Aurélien; Castera-Ducros, Caroline; Hutter, Sébastien; Laget, Michle; Fersing, Cyril; Prieri, Marion; Yzombard, Julien; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice; Azas, Nadine [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 6003 - 6006]

11
[ 150-19-6 ]
[ 3137-63-1 ]
[ 1334477-50-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dmap In toluene at 130℃; for 1h; Microwave irradiation; Sealed tube;	29 4.1.3. General procedure for the preparation of compounds 2 to 34 General procedure: A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5mL). The reaction mixture was irradiated in a monomode microwave oven, for 1 h at 130°C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent. 4.1.29 4-(3-Methoxyphenoxy)-2-trichloromethylquinazoline (27) Yield 98%. White powder. Mp 101 °C (Lit. 101 °C [19] ), (isopropanol). 1H NMR (200 MHz, CDCl3) δ = 8.39-8.43 (m, 1H), 8.13-8.17 (m, 1H), 7.95-8.03 (m, 1H), 7.72-7.80 (m, 1H), 7.32-7.40 (m, 1H), 6.96-7.05 (m, 2H), 6.83-6.89 (m, 1H), 3.83 (s, 3H). 13C NMR (50 MHz, CDCl3) δ = 167.4, 160.4, 160.1, 153.1, 151.0, 134.8, 129.7, 129.1, 128.9, 123.7, 115.4, 113.5, 112.0, 107.2, 96.8, 55.5 LC-MS (ESI+) tR 5.10 min, m/z [M + H]+ 369.01/371.15/373.09. MW: 369.63 g/mol. Anal. Calcd for C16H11Cl3N2O2: C, 51.99; H, 3.00; N, 7.58. Found: C, 52.16; H, 3.07; N, 7.67.
25%	Stage #1: O-methylresorcine With sodium hydride In dimethyl sulfoxide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-chloro-2-(trichloromethyl)quinazoline In dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere;	4.1.4. General procedure for the preparation of compounds 3-24 General procedure: 1 equivalent of the appropriate aryl alcohol was dissolved in dimethylsulfoxyde (DMSO), then added onto 2 eq. of NaH 95%, and stirred under N2 for 20 min. 1 eq. of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, added to the mixture and stirred at RT for 24 h under nitrogen atmosphere. The reaction was stopped by addition of water and the reaction mixture was then extracted three times with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with an appropriate solvent to afford the corresponding nucleophilic aromatic substitution product.

Reference： [1]Gellis, Armand; Primas, Nicolas; Hutter, Sébastien; Lanzada, Gilles; Remusat, Vincent; Verhaeghe, Pierre; Vanelle, Patrice; Azas, Nadine [European Journal of Medicinal Chemistry, 2016, vol. 119, p. 34 - 44]
[2]Location in patent: experimental part Castera-Ducros, Caroline; Azas, Nadine; Verhaeghe, Pierre; Hutter, Sebastien; Garrigue, Philippe; Dumtre, Aurelien; Mbatchi, Litaty; Laget, Michle; Remusat, Vincent; Sifredi, France; Rault, Sylvain; Rathelot, Pascal; Vanelle, Patrice [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4184 - 4191]

12
[ 444-30-4 ]
[ 3137-63-1 ]
[ 1334477-35-8 ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: 1 equivalent of the appropriate aryl alcohol was dissolved in dimethylsulfoxyde (DMSO), then added onto 2 eq. of NaH 95%, and stirred under N2 for 20 min. 1 eq. of 4-chloro-2-trichloromethylquinazoline was dissolved in DMSO, added to the mixture and stirred at RT for 24 h under nitrogen atmosphere. The reaction was stopped by addition of water and the reaction mixture was then extracted three times with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with an appropriate solvent to afford the corresponding nucleophilic aromatic substitution product.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 4184 - 4191

13
[ 29927-08-0 ]
[ 3137-63-1 ]
5,6-dimethyl-N-[2-(trichloromethyl)quinazolin-4-yl]benzo[d]thiazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; In toluene; at 139℃; for 2h;Microwave irradiation; Sealed tube;Catalytic behavior;	General procedure: 4.4. General procedure for the preparation of compounds 4-25. A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate heteroarylamine (1.41 mmol, 2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5 mL). The reaction mixture was irradiated in a monomode microwave oven, for 2 h at 130 C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent.

Reference： [1]Tetrahedron,2014,vol. 70,p. 8257 - 8266

14
[ 61-80-3 ]
[ 3137-63-1 ]
5-chloro-N-[2-(trichloromethyl)quinazolin-4-yl]benzo[d]oxazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; In toluene; at 130℃; for 2h;Microwave irradiation; Sealed tube;Catalytic behavior;	General procedure: 4.4. General procedure for the preparation of compounds 4-25. A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate heteroarylamine (1.41 mmol, 2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5 mL). The reaction mixture was irradiated in a monomode microwave oven, for 2 h at 130 C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent.

Reference： [1]Tetrahedron,2014,vol. 70,p. 8257 - 8266

15
[ 3137-63-1 ]
[ 1622-57-7 ]
N-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-(trichloromethyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap In toluene at 130℃; for 2h; Micellar solution; Sealed tube;	10 4.4.10. N-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-(trichloromethyl)quinazolin-4-amine (13) General procedure: 4.4. General procedure for the preparation of compounds 4-25. A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate heteroarylamine (1.41 mmol, 2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5 mL). The reaction mixture was irradiated in a monomode microwave oven, for 2 h at 130 °C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent.

Reference： [1]Gellis, Armand; Kieffer, Charline; Primas, Nicolas; Lanzada, Gilles; Giorgi, Michel; Verhaeghe, Pierre; Vanelle, Patrice [Tetrahedron, 2014, vol. 70, # 44, p. 8257 - 8266]

16
[ 580-22-3 ]
[ 3137-63-1 ]
N-(quinolin-2-yl)-2-(trichloromethyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With dmap; In toluene; at 130℃; for 2h;Microwave irradiation; Sealed tube;Catalytic behavior;	General procedure: 4.4. General procedure for the preparation of compounds 4-25. A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate heteroarylamine (1.41 mmol, 2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5 mL). The reaction mixture was irradiated in a monomode microwave oven, for 2 h at 130 C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent.

Reference： [1]Tetrahedron,2014,vol. 70,p. 8257 - 8266

17
[ 619-73-8 ]
[ 3137-63-1 ]
4-(4-nitrobenzyloxy)-2-(trichloromethyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap In toluene at 130℃; for 1h; Microwave irradiation; Sealed tube;	8 4.1.3. General procedure for the preparation of compounds 2 to 34 General procedure: A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5mL). The reaction mixture was irradiated in a monomode microwave oven, for 1 h at 130°C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent. 4.1.8 4-(4-Nitrobenzyloxy)-2-(trichloromethyl)quinazoline (6) Yield 96%. Yellow powder. Mp 199 °C, (isopropanol). 1H NMR (200 MHz, CDCl3) δ = 8.34-8.30 (m, 3H), 8.18-8.15 (m, 1H), 8.04-7.98 (m, 1H), 7.85-7.74 (m, 3H), 5.88 (s, 2H). 13C NMR (50 MHz, CDCl3) δ = 167.1, 159.8, 150.5, 147.9, 142.8, 134.8, 129.3, 129.1, 129.0, 123.9, 123.4, 115.3, 97.0, 68.0. LC-MS (ESI+) tR 5.06 min, m/z [M + H]+ 397.93/399.91/402.06. MW: 398.63 g/mol. Anal. Calcd for C16H10Cl3N3O3: C, 48.21; H, 2.53; N, 10.54. Found: C, 48.33; H, 2.55; N, 10.41.

Reference： [1]Gellis, Armand; Primas, Nicolas; Hutter, Sébastien; Lanzada, Gilles; Remusat, Vincent; Verhaeghe, Pierre; Vanelle, Patrice; Azas, Nadine [European Journal of Medicinal Chemistry, 2016, vol. 119, p. 34 - 44]

18
[ 3137-63-1 ]
[ 536-60-7 ]
4-(4-isopropylbenzyloxy)-2-(trichloromethyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap In toluene at 130℃; for 1h; Microwave irradiation; Sealed tube;	12 4.1.3. General procedure for the preparation of compounds 2 to 34 General procedure: A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5mL). The reaction mixture was irradiated in a monomode microwave oven, for 1 h at 130°C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent. 4.1.12 4-(4-Isopropylbenzyloxy)-2-(trichloromethyl)quinazoline (10) Yield 81%. Pale beige powder. Mp 121 °C, (isopropanol). 1H NMR (200 MHz, CDCl3) δ = 8.23 (d, J = 8 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 7.93-7.85 (m, 1H), 7.67-7.53 (m, 3H), 7.28 (d, J = 8 Hz, 2H), 5.72 (s, 2H), 2.94 (sept, J = 7 Hz, 1H), 1.27 (d, J = 7 Hz, 6H). 13C NMR (50 MHz, CDCl3) δ = 167.6, 160.2, 150.4, 149.5, 134.4, 133.0, 129.3, 128.7, 128.6, 126.7, 123.8, 115.6, 97.3, 68.5, 34.0, 24.0. LC-MS (ESI+) tR 5.73 min, m/z [M + H]+ 395.10/396.96/399.02. MW: 395.71 g/mol. Anal. Calcd for C19H17Cl3N2O: C, 57.67; H, 4.33; N, 7.08. Found: C, 57.76; H, 4.35; N, 7.21.

Reference： [1]Gellis, Armand; Primas, Nicolas; Hutter, Sébastien; Lanzada, Gilles; Remusat, Vincent; Verhaeghe, Pierre; Vanelle, Patrice; Azas, Nadine [European Journal of Medicinal Chemistry, 2016, vol. 119, p. 34 - 44]

19
[ 3137-63-1 ]
[ 93-03-8 ]
4-(3,4-dimethoxybenzyloxy)-2-(trichloromethyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dmap In toluene at 130℃; for 1h; Microwave irradiation; Sealed tube;	13 4.1.3. General procedure for the preparation of compounds 2 to 34 General procedure: A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5mL). The reaction mixture was irradiated in a monomode microwave oven, for 1 h at 130°C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent. 4.1.13 4-(3,4-Dimethoxybenzyloxy)-2-(trichloromethyl)quinazoline (11) Yield 64%. Beige powder. Mp 127 °C, (isopropanol). 1H NMR (200 MHz, CDCl3) δ = 8.22 (d, J = 8 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.90 (t, J = 8 Hz, 1H), 7.63 (t, J = 8 Hz, 1H), 7.20-7.16 (m, 2H), 6.89 (d, J = 8 Hz, 1H), 5.68 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H) . 13C NMR (50 MHz, CDCl3) δ = 167.6, 160.1, 150.4, 149.4, 149.0, 134.4, 129.0, 128.7, 128.6, 128.1, 126.8, 123.7, 122.2, 115.6, 112.6, 111.0, 97.3, 69.7, 56.0, 55.9. LC-MS (ESI+) tR 4.95 min, m/z [M + H]+ 413.00/414.75/416.93. MW: 413.68 g/mol. Anal. Calcd for C18H15Cl3N2O3: C, 52.26; H, 3.65; N, 6.77. Found: C, 52.09; H, 3.64; N, 6.72.

Reference： [1]Gellis, Armand; Primas, Nicolas; Hutter, Sébastien; Lanzada, Gilles; Remusat, Vincent; Verhaeghe, Pierre; Vanelle, Patrice; Azas, Nadine [European Journal of Medicinal Chemistry, 2016, vol. 119, p. 34 - 44]

20
[ 3137-63-1 ]
[ 1475-13-4 ]
4-(1-(2,4-dichlorophenyl)ethoxy)-2-(trichloromethyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap; In toluene; at 130℃; for 1h;Microwave irradiation; Sealed tube;	General procedure: A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5mL). The reaction mixture was irradiated in a monomode microwave oven, for 1 h at 130C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent. 4.1.16 4-(1-(2,4-Dichlorophenyl)ethoxy)-2-(trichloromethyl)quinazoline (14) Yield 69%. Brown powder. Mp 123 C, (isopropanol). 1H NMR (200 MHz, CDCl3) delta = 8.31 (d, J = 8 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 7.96-7.87 (m, 1H), 7.69 (t, J = 7 Hz, 1H), 7.49-7.39 (m, 2H), 7.20 (dd, J = 2 Hz; 8 Hz, 1H), 6.78 (q, J = 7 Hz, 1H), 1.81 (d, J = 7 Hz, 3H) . 13C NMR (50 MHz, CDCl3) delta = 165.3, 159.2, 150.8, 135.3, 131.6, 130.8 129.4, 129.3, 129.0, 128.6, 123.4, 115.4, 96.9, 72.7, 21.0. LC-MS (ESI+) tR 6.02 min, m/z [M + H]+ 434.74/436.86/438.81. MW: 436.55 g/mol. Anal. Calcd for C17H11Cl5N2O: C, 46.77; H, 2.54; N, 6.42. Found: C, 46.41; H, 2.52; N, 6.51.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 119,p. 34 - 44

21
[ 3137-63-1 ]
[ 1700-30-7 ]
4-(3-(benzyloxy)benzyloxy)-2-(trichloromethyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap In toluene at 130℃; for 1h; Microwave irradiation; Sealed tube;	21 4.1.3. General procedure for the preparation of compounds 2 to 34 General procedure: A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5mL). The reaction mixture was irradiated in a monomode microwave oven, for 1 h at 130°C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent. 4.1.21 4-(3-(Benzyloxy)benzyloxy)-2-(trichloromethyl)quinazoline (19) Yield 68%. Yellow powder. Mp 96 °C, (isopropanol). 1H NMR (200 MHz, CDCl3) δ = 8.23 (dd, J = 1 Hz; 8 Hz, 1H), 8.10 (d, J = 8 Hz, 1H), 7.91 (td, J = 1 Hz; 8 Hz, 1H), 7.69-7.61 (m, 1H), 7.47-7.18 (m, 8H), 5.72 (s, 1H), 5.72 (s, 2H), 5.10 (s, 2H). 13C NMR (50 MHz, CDCl3) δ = 167.6, 160.1, 159.0, 150.4, 137.2, 136.9, 134.5, 130.0, 129.7, 128.9, 128.8, 128.6, 128.0, 127.5, 123.7, 121.4, 115.5, 115.3, 115.0, 97.2, 70.1, 69.3. LC-MS (ESI+) tR 5.87 min, m/z [M + H]+ 458.74/460.72/462.84. MW: 459.75 g/mol. Anal. Calcd for C23H17Cl3N2O2: C, 60.09; H, 3.73; N, 6.09. Found: C, 59.87; H, 3.70; N, 5.98.

Reference： [1]Gellis, Armand; Primas, Nicolas; Hutter, Sébastien; Lanzada, Gilles; Remusat, Vincent; Verhaeghe, Pierre; Vanelle, Patrice; Azas, Nadine [European Journal of Medicinal Chemistry, 2016, vol. 119, p. 34 - 44]

22
[ 521-74-4 ]
[ 3137-63-1 ]
4-(5,7-dibromoquinolin-8-yloxy)-2-(trichloromethyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With dmap; In toluene; at 130℃; for 1h;Microwave irradiation; Sealed tube;	General procedure: A mixture of 4-chloro-2-trichloromethylquinazoline 1 (0.2 g, 0.71 mmol), DMAP (26 mg, 0.21 mmol, 0.3 equiv) and adequate alcohol derivative (0.85 mmol, 1.2 equiv) in toluene (3 mL) was introduced in miniaturized sealed reactor (5mL). The reaction mixture was irradiated in a monomode microwave oven, for 1 h at 130C. After removal of the toluene under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from appropriate solvent. 4.1.36 4-(5,7-Dibromoquinolin-8-yloxy)-2-(trichloromethyl)quinazoline (34) Yield 98%. Brown powder. Mp 186 C, (isopropanol). 1H NMR (200 MHz, CDCl3) delta = 8.77-8.55 (m, 3H), 8.21-8.12 (m, 2H), 8.04 (t, J = 8 Hz, 1H), 7.83 (t, J = 6 Hz, 1H), 7.56-7.53 (m, 1H). 13C NMR (50 MHz, CDCl3) delta = 167.13, 159.6, 151.4, 151.3, 146.5, 142.2, 136.2, 135.1, 133.3, 129.3, 128.9, 127.8, 124.1, 122.8, 119.5, 116.9, 114.8, 96.4. LC-MS (ESI+) tR 5.37 min, m/z [M + H]+ 546.08/547.52/549.54. MW: 548.44 g/mol. Anal. Calcd for C18H8Br2N3O: C, 39.42; H, 1.47; N, 7.66. Found: C, 39.49; H, 1.50; N, 7.51.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 119,p. 34 - 44

23
[ 3137-63-1 ]
[ 38762-41-3 ]
N-(4-bromo-2-chlorophenyl)-2-trichloromethylquinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	In isopropyl alcohol; for 48h;Reflux;	General procedure: A 100mL round-bottomed single-neck flask equipped with a condenser and a magnetic stir bar was charged with 4-chloro-2-trichloromethylquinazoline E [24] (500mg, 1.77mmol), 2 equiv. of the appropriated dihalogeno-aniline (3.54mmol) and 30mL of isopropanol. The mixture was refluxed for 48h. After cooling, water was added (50mL), and the resulting solution was extracted three times with CH2Cl2. Then, the combined organic layers were washed with water and dried (Na2SO4). Finally, the solvent was evaporated under reduced pressure. The residue was purified by trituration with CH2Cl2 and filtration yielding the N-(2,4-dihalogenophenyl)-2-trichloromethylquinazolin-4-amines (10-13).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 68 - 86

24
[ 3137-63-1 ]
[ 619-56-7 ]
4-chloro-N-(2-trichloromethylquinazolin-4-yl)benzamide [ No CAS ]