* 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.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 1, p. 350 - 364
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2115 - 2137
2
[ 551-93-9 ]
[ 40621-84-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 1, p. 350 - 364
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2115 - 2137
3
[ 551-93-9 ]
[ 122-51-0 ]
[ 700-46-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1253 - 1259
4
[ 551-93-9 ]
[ 77287-34-4 ]
[ 700-46-9 ]
Reference：
[1] Molecules, 2005, vol. 10, # 9, p. 1190 - 1196
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, # 1-12, p. 396 - 397
5
[ 5257-06-7 ]
[ 700-46-9 ]
[ 551-93-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1986, p. 2295 - 2304
6
[ 551-93-9 ]
[ 700-46-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 37, p. 6246 - 6249
7
[ 551-93-9 ]
[ 318276-72-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
8
[ 551-93-9 ]
[ 15873-56-0 ]
[ 6220-93-5 ]
Reference：
[1] Monatshefte fuer Chemie, 1949, vol. 80, p. 607,615
9
[ 551-93-9 ]
[ 18514-84-6 ]
Yield
Reaction Conditions
Operation in experiment
23%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 20℃;
Intermediate 1 : Preparation of 1.4-Dihvdro-4-cinnolinone: <n="30"/>A solution of sodium nitrite (4.0 g, 59 mmol) in water (10 ml) was added over 20 minutes to a stirred mixture of 2 -aminoacetophenone (5.0 g, 37.03 mmol) and concentrated hydrochloric acid (31 ml) cooled in an ice bath. The resulting mixture was stirred at the same temperature for 2h and then at room temperature overnight. The mixture was concentrated under reduced pressure. Work-up (AcOEt/brine) after neutralization of the residue with aqueous sodium acetate gave the title compound (1.25 g, 23percent). 1H-NMR (δ ppm, OMSO-d6, 300 MHz): 13.48 (br. s, IH); 8.01 (d, J = 8.1, IH); 7.82-7.73 (m, 2H); 7.57 (d, J = 8.1, IH); 7.41 (t, J = 7.8, IH).
Reference：
[1] Heterocycles, 2008, vol. 75, # 1, p. 77 - 86
[2] Australian Journal of Chemistry, 1981, vol. 34, # 12, p. 2619 - 2627
[3] Patent: WO2009/53799, 2009, A1, . Location in patent: Page/Page column 28-29
[4] Journal of the Chemical Society, 1947, p. 917,920
To a solution of l-(2-aminophenyl)ethanone (1.50 g, 11.1 mmol) in THF (11 mL, cooled at 0 °C and under a small flow of Ar was added slowly methylmagnesium bromide (1.0 mol/L in THF, 28 mL, 27.7 mmol). The reaction mixture was warmed to room temperature. The reaction mixture was quenched carefully with sat. ammonium chloride aqueous solution and and the reaction mixture was extracted with ethyl acetate (3*20 mL), dried and concentrated. The crude brown oil was purified by flash chromatography to give 2- (2-aminophenyl)propan-2-ol as a pale oil (1.20 g, 72percent). LCMS: 0.24 min; ES+ 134 ( M-OH-); XH NMR (CHLOROFORM-d, 400MHz): δ (ppm) 7.15 (d, IH), 7.06 (t, IH), 6.72 (t, IH), 6.65 (d, IH), 3.65 (br s, IH), 1.67 (s, 6H).
Reference：
[1] Patent: WO2018/17490, 2018, A1, . Location in patent: Paragraph 0163; 0164
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 189 - 192
[3] Organic and Biomolecular Chemistry, 2015, vol. 13, # 47, p. 11486 - 11491
22
[ 551-93-9 ]
[ 15833-00-8 ]
Reference：
[1] Patent: US5665719, 1997, A,
23
[ 917-64-6 ]
[ 551-93-9 ]
[ 15833-00-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 15, p. 4669 - 4678
[2] Patent: US2005/227975, 2005, A1, . Location in patent: Page/Page column 10-11
24
[ 551-93-9 ]
[ 34801-09-7 ]
Yield
Reaction Conditions
Operation in experiment
60%
With hydroxylamine hydrochloride In acetonitrileReflux
General procedure: Ketones (1 mmol) and hydroxylamine hydrochloride (0.0694g,1 mmol) were dissolved in CH3CN (10 mL) and stirred for 10 - 15 min. The complex (CS-SalBr-Zn-L) (10 molpercent) were added tothe reaction flask. The reaction mixture was heated under reflux for specific time (3e7 h). After completion, the reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was treated with ethyl acetate (3 10 mL).The combined organic layers were treated with saturated brine solution and dried over anhydrous sodium sulphate. The removal of solvent yields crude product, which after purification by column chromatography over Silica gel (100e200 mesh), afforded the desired products.
Reference：
[1] Synthetic Communications, 2003, vol. 33, # 17, p. 2971 - 2978
[2] Journal of Molecular Structure, 2017, vol. 1130, p. 368 - 373
[3] Annali di Chimica (Rome, Italy), 1958, vol. 48, p. 1329,1332, 1333
25
[ 352353-17-4 ]
[ 575-90-6 ]
[ 551-93-9 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 5, p. 357 - 360
26
[ 77152-08-0 ]
[ 551-93-9 ]
[ 17408-14-9 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 71, p. 10237 - 10240
27
[ 551-93-9 ]
[ 2142-70-3 ]
Reference：
[1] Organic Letters, 2015, vol. 17, # 21, p. 5448 - 5451
[2] Organic Letters, 2015, vol. 17, # 24, p. 6006 - 6009
[3] Synthesis, 2007, # 1, p. 81 - 84
[4] Synthesis, 2009, # 6, p. 941 - 944
[5] Russian Journal of Organic Chemistry, 2008, vol. 44, # 8, p. 1243 - 1244
[6] Advanced Synthesis and Catalysis, 2014, vol. 356, # 1, p. 153 - 159
[7] Chemische Berichte, 1925, vol. 58, p. 48
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 16, p. 5863 - 5870
30
[ 551-93-9 ]
[ 74-88-4 ]
[ 1859-75-2 ]
Yield
Reaction Conditions
Operation in experiment
53%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25 h; Inert atmosphere Stage #2: at 20℃; for 72 h; Inert atmosphere
To an oven-dried round-bottomed flask containing K2CO3 (3.46 g, 25 mmol, 1 equiv) suspended in anhydrous DMF (15 mL), was added 1-(2-aminophenyl)ethan-1-one (3.04 mL, 25 mmol) under argon atmosphere and reaction mixture was stirred at RT for 15 min. A solution of MeI (1.56 mL, 25 mmol, 1 equiv) in anhydrous DMF was added dropwise to the reaction mixture. The reaction mixture was stirred at RT for 3 days. The reaction mixture was diluted with H2O (60 mL) and extracted with ethyl acetate (340 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. The filtered olution was concentrated in vacuo and purified by column chromatography (3percent-5percent ethyl acetate in petroleum ether) to yield 1-(2-(methylamino)phenyl)ethan-1-one (1.98 g, 53percent) as yellow crystals. To an oven-dried high-pressure sealed tube was added 1-(bromomethyl)-2-iodobenzene (1.48 g, 5 mmol), 1-(2-(methylamino)phenyl)ethan-1-one (895 mg, 6 mmol, 1.1 equiv), K2CO3 (1.38 g,10 mmol, 2 equiv) and acetonitrile (5 mL). The reaction mixture was stirred at 85° C for 4 days. The reaction mixture was cooled to RT, diluted with H2O (20 mL) and extracted with dichloromethane (315 mL). The combined organic phases were washed with brine (40 mL) and dried over anhydrous sodium sulfate. The filtered solution was concentrated in vacuo and purified by column chromatography (5percent ethyl acetate in petroleum ether) to yield 1-(2-((2-iodobenzyl) (methyl)amino)phenyl)ethan-1-one 44 (1.45 g, 79percent) as orange crystals;
Reference：
[1] Liebigs Annalen der Chemie, 1990, # 8, p. 795 - 805
[2] Tetrahedron, 2016, vol. 72, # 48, p. 7875 - 7887
[3] Journal of Organic Chemistry, 2011, vol. 76, # 8, p. 2635 - 2647
[4] RSC Advances, 2016, vol. 6, # 70, p. 65988 - 65994
[5] Advanced Synthesis and Catalysis, 2014, vol. 356, # 2-3, p. 353 - 358
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 16, p. 5722 - 5736
[7] Organic Letters, 2008, vol. 10, # 5, p. 1021 - 1023
[8] Journal of Organic Chemistry, 2003, vol. 68, # 9, p. 3706 - 3709
[9] Angewandte Chemie - International Edition, 2018, vol. 57, # 4, p. 929 - 932[10] Angew. Chem., 2018, vol. 130, p. 941 - 944,4
31
[ 551-93-9 ]
[ 77-78-1 ]
[ 1859-75-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1996, # 2, p. 269 - 274
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.
Reference：
[1] Patent: CN107162970, 2017, A, . Location in patent: Paragraph 0050; 0051; 0052
[2] Synthesis (Germany), 2015, vol. 47, # 24, p. 3881 - 3890
[3] Tetrahedron Letters, 2007, vol. 48, # 28, p. 4935 - 4937
[4] Tetrahedron Letters, 2016, vol. 57, # 49, p. 5442 - 5445
34
[ 551-93-9 ]
[ 155370-03-9 ]
Reference：
[1] South African Journal of Chemistry, 1994, vol. 47, # 1, p. 21 - 25
[2] Journal of Chemical Research, Miniprint, 1994, # 2, p. 367 - 382
[3] Archiv der Pharmazie, 2013, vol. 346, # 1, p. 7 - 16
[4] Letters in Drug Design and Discovery, 2013, vol. 10, # 4, p. 327 - 334
[5] Turkish Journal of Chemistry, 2015, vol. 39, # 4, p. 850 - 866
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; N,N-dimethyl-formamide; at 90℃;
General procedure: T3P catalyzed synthesis of quinolines under conventional heating: To a mixture of 2-aminoaryl ketone/aldehyde (1, 0.01 mol) and ketone (2, 0.01 mol) in DMF (10 mL) was added T3P (20 mol percent, 50percent soln in EtOAc). The resulting reaction mixture was stirred at 90 °C for 4-6 h under conventional heating. When the reaction was completed (monitored by TLC), the solvent was removed under vacuum and the residue was diluted with water (20 mL). The solid product which separated out was filtered, washed with water, and dried to afford the desired quinolines in good purity. The oily quinolines were extracted with ethyl acetate (2 .x. 15 mL) and the combined organic phase was washed with saturated NaHCO3 solution (1 .x. 10 mL) and brine. The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was passed through a small plug of silica to afford the quinolines in good purity and yield.
Intermediate 1 : Preparation of 1.4-Dihvdro-4-cinnolinone: <n="30"/>A solution of sodium nitrite (4.0 g, 59 mmol) in water (10 ml) was added over 20 minutes to a stirred mixture of 2 -aminoacetophenone (5.0 g, 37.03 mmol) and concentrated hydrochloric acid (31 ml) cooled in an ice bath. The resulting mixture was stirred at the same temperature for 2h and then at room temperature overnight. The mixture was concentrated under reduced pressure. Work-up (AcOEt/brine) after neutralization of the residue with aqueous sodium acetate gave the title compound (1.25 g, 23%). 1H-NMR (delta ppm, OMSO-d6, 300 MHz): 13.48 (br. s, IH); 8.01 (d, J = 8.1, IH); 7.82-7.73 (m, 2H); 7.57 (d, J = 8.1, IH); 7.41 (t, J = 7.8, IH).
With hydroxylamine hydrochloride; In acetonitrile;Reflux;
General procedure: Ketones (1 mmol) and hydroxylamine hydrochloride (0.0694g,1 mmol) were dissolved in CH3CN (10 mL) and stirred for 10 - 15 min. The complex (CS-SalBr-Zn-L) (10 mol%) were added tothe reaction flask. The reaction mixture was heated under reflux for specific time (3e7 h). After completion, the reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was treated with ethyl acetate (3 10 mL).The combined organic layers were treated with saturated brine solution and dried over anhydrous sodium sulphate. The removal of solvent yields crude product, which after purification by column chromatography over Silica gel (100e200 mesh), afforded the desired products.
A formylation mixture was prepared from 41.2 mL (444.4 mmol, 6.00 mol eq) of POCl3 that was added dropwise to 90.0 mL of DMF (abs) at 0 C. Resulted solution was stirred for 15 min under Ar at rt. Then 9.0 mL (74.0 mmol,1.00 mol eq) of 1-(2-aminophenyl)ethanone was added dropwise to the stirred formylation mixture within 30 min and the mixture heated to 60 C for 16 h (instead of 4 h, described previously in the literature) (Seixas et al. 2011). Then, the mixture was cooled to rt by adding 400 g of crashed ice in 200 mL H2O and the reaction neutralized to pH 7 by solid NaHCO3. Precipitated yellow product was filtered off, dissolved in CHCl3, extracted with water. A separated organic layer was dried over Na2SO4, filtered, concentrated by RVO and HV. Crystallization from EA with charcoal bleaching provided 8.50 g (44.4 mmol, 60%) of 4-chloroquinoline-3-carbaldehyde in form of a white solid material. A suspension of the crude 4-chloroquinoline-3-carbaldehyde in 80 mL of HCOOH (54%aqueous) was hydrolyzed at 50 C within 2 h. The mixture was cooled down and left in refrigerator overnight. The formed solid product was filtered off, washed with H2O, Et2O and dried under HV. The 1,4-dihydro-4-oxoquinoline-3-carbaldehyde (1a) was obtained as a white solid 7.15 g (41.23 mmol, 93 or 56%overallyield) and used for further synthetic step (Scheme 1).
50%
General procedure: POCl3 (16.1 g, 0.105 mol) was added dropwise to DMF (10 mL) at 0 C, and the resulting mixture was stirred for 15 min under N2 at r.t. A solution of the appropriate 1-(2-aminophenyl)ethanone 1 (15.0mmol) in DMF (10 mL) was added dropwise from a syringe, and the mixture was heated at 90 C for 12 h. After it had been cooled to r.t., the mixture was distilled to remove excess POCl3. The viscous oily residue was slowly added to crushed ice, and the mixture was neutralized with sat. aq NaHCO3. The product was extracted with CHCl3 (2 × 50 mL) and the combined organic phases were washed with water, dried (MgSO4), filtered, and concentrated. The residue was driedin vacuo to give a crude product that was purified by column chromatography(silica gel).
43%
With trichlorophosphate; at 0 - 90℃; for 4h;
To a 00C solution of l-(2-aminophenyl)ethan-l-one (2.0 g, 14.8 mmol) in anhydrous DMF (10 mL) was added dropwise phosphorus oxychloride (5.5 mL, 59.2 mmol). The reaction mixture was stirred at room temperature for 1 hour and at 900C for 3 hours. After cooling to room temperature, the mixture was poured in a mixture of ice/water/NH4OAc to neutralize. The mixture was stirred at room temperature overnight. The product was recovered by filtration and washed with water (2 x 20 mL). The solid material was dissolved in ethyl acetate (100 mL). The solution was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 4- chloroquinoline-3-carbaldehyde (1.2 g, 43% yield). The product was used without further purification.
General procedure: (E)-3-styrylquinolin-4(1H)-ones 1a-1k and 1t were prepared according to theliterature procedure (Scheme 1).1, 2 POCl3 (123.4 mmol) was added dropwise to 25mL dry N,N-dimethylformamide (DMF) at 0 C under argon, and the mixture wasstirred for 15 min at room temperature. Then a solution of 3 1-(2-aminophenyl)ethanones (20.6 mmol) in dry DMF (3 mL) was added dropwise. The reactionsolution was heated to 60 C and stirred for 4 h. The reaction was stopped by pouredinto 100 g ice and 100 mL water, and neutralized with NaHCO3. The formed solid wasfiltered off, dissolved into 200 mL CH2Cl2 and washed with 3 × 200 mL water. Theorganic layer was dried over Na2SO4 and concentrated under reduced pressure. Theresulting solid was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 20:1-10:1) to afford 4-chloroquinoline-3-carbaldehydes 4.
With trichlorophosphate; at 0 - 60℃; for 4h;
To an anh. DMF (20 ml_), POCI3 (8.27 ml_, 88.8 mmol, 6 eq) was added dropwise at 0C. Then 1-(2-aminophenyl)ethan-1-one (2.00 g, 14.8 mmol, 1 eq) in anh. DMF (5 ml.) was added drop- wise, and the reaction was heated for 4 h at 60C. Afterwards, the reactions was cooled down to 0C, quenched with water. Then solution was neutralized with saturated NaHCC>3 aqueous solution, diluted in water and extracted with DCM. The layers were separated. Organic layer was dried over MgS04, filtered off and concentrated in vacuo to afford the title compound (1.43 g, 7.49 mmol, yield 51 %) as an orange solid that was taken to the next step without additional purification. ESI-MS: 192 [M+H]+
2-aminoacetophenone (81 g) was added to 600 ml of hydrochloric acid (37%), and the aqueous solution of NaNO2 (80 g of sodium nitrite was added to 400 ml of water) was added dropwise at 0 to 10 C for 1 hour, and SnCl2 H2O hydrochloric acid solution (200 g dissolved in 300 ml hydrochloric acid (37%)) was stirred overnight. The reaction solution into the ice water filtration, the filtrate adjusted PH = 8,A large amount of solid precipitated and filtered to give 71 g of an off-white solid in 90% yield.
90%
The above 2'-aminoacetophenone 81g was added to 600 ml of hydrochloric acid (mass to volume ratio 37%) and a NaNO2 aqueous solution (80 g of sodium nitrite was added to 400 ml of water) was added dropwise at a temperature of 0 to 10 C., keeping the temperature at 0-10 C. and stirring for 1 hour.At this temperature, a SnCl2 ·H2O hydrochloric acid solution (200 g of SnCl2 ·H2O dissolved in 300 ml of a 37% by mass mass ratio of hydrochloric acid) was slowly added dropwise, and the mixture was stirred overnight at the temperature of 0 to 10C, and the reaction solution was poured into ice water. Filtration, the filtrate was adjusted to slightly alkaline pH = 8, a large number of solids precipitated, filtered and dried to give an off-white solid 71g, yield 90%, purity 99.8%,
To a solution of l-(2-aminophenyl)ethanone (1.50 g, 11.1 mmol) in THF (11 mL, cooled at 0 C and under a small flow of Ar was added slowly methylmagnesium bromide (1.0 mol/L in THF, 28 mL, 27.7 mmol). The reaction mixture was warmed to room temperature. The reaction mixture was quenched carefully with sat. ammonium chloride aqueous solution and and the reaction mixture was extracted with ethyl acetate (3*20 mL), dried and concentrated. The crude brown oil was purified by flash chromatography to give 2- (2-aminophenyl)propan-2-ol as a pale oil (1.20 g, 72%). LCMS: 0.24 min; ES+ 134 ( M-OH-); XH NMR (CHLOROFORM-d, 400MHz): delta (ppm) 7.15 (d, IH), 7.06 (t, IH), 6.72 (t, IH), 6.65 (d, IH), 3.65 (br s, IH), 1.67 (s, 6H).
With C22H48N4O12S4(4+)*4HO4S(1-); In ethanol; water; at 20℃; for 1.6h;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 95% 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 99.0% and the yield was 94% 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 18.0h;Reflux; Inert atmosphere;
General procedure: AgOTf (26 mg, 10 mol%) 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.
EXAMPLE 4; 1-{3-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-3-methyl-butyl}-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; a) 4,4-dimethyl-1,4-dihydro-benzo[1,3]oxazin-2-one; 112 g (1.13 mol) phosgene are piped into 500 mL THF. Then a solution of 52 g (0.34 mol) 2-(2-amino-phenyl)-propan-2-ol, prepared from 2-aminoacetophenone and methylmagnesium iodide, in 300 mL THF is added. The reaction mixture is left to stand overnight, evaporated down and combined with 500 ml pyridine. After the pyridine has been distilled off water is added and the mixture is extracted with diethyl ether. The organic phases are washed successively with 2 N hydrochloric acid, sodium hydroxide solution and water, dried with sodium sulphate and evaporated down. The residue remaining (46 g) is further reacted directly without any more purification.
In tetrahydrofuran; at -40 - 20℃; for 12h;
2.1 Preparation of 2-(2-aminophenyl)propan-2-ol 5.0 g of o-aminoacetophenone was added into 150 ml of anhydrous tetrahydrofuran and 2 equivalents of methyl magnesium iodide in tetrahydrofuran solution were added dropwise at -40 degrees Celsius. The reaction was slowly warmed to room temperature and stirred for 12 hours. The reaction was quenched by adding the saturated aqueous ammonium chloride and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate. The organic phase was concentrated to give 4.2 g of a yellow crude product, without further purification and the yield was 75%.
1-(1-(2,4-dimethoxybenzoyl)piperidin-4-yl)-4,4-dimethyl-1,2-dihydro-4(H)-3,1-benzoxazin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With methylmagnesium bromide; In tetrahydrofuran; toluene;
EXAMPLE 61 1-(1-(2,4-dimethoxybenzoyl)piperidin-4-yl)-4,4-dimethyl-1,2-dihydro-4(H)-3,1-benzoxazin-2-one STR81 Step 1: To a 0 C. solution of methylmagnesium bromide (45 mL of a 1.4M solution in toluene, 63 mmol) under nitrogen atmosphere was added a solution of ortho-aminoacetophenone (2.9 g, 21.5 mmol) in THF (20 mL). The mixture was warmed to ambient temperature for 45 min, cooled to 0 C., and poured into ice-water. The mixture was acidified with 6N HCl, adjusted to ca. pH 6 with saturated sodium bicarbonate solution, and then extracted with ether (2*100 mL). The combined ether fractions were dried (MgSO4), filtered and the solvent was removed under reduced pressure to give the oily product, 2-aminophenyldimethyl carbinol.
1-(2-methylcarbonylphenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
EXAMPLE I Preparation of: 1-(2-methylcarbonylphenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To a stirred solution of 0.01 mole of chlorosulfonyl isocyanate in methylene chloride maintained at 0°-5° C. via an ice bath was added 1.4 grams (0.01 mole) of <strong>[1668-54-8]2-amino-4-methyl-6-methoxy-1,3,5-triazine</strong>. After two hours reaction time, a methylene chloride solution containing 1.35 grams (0.01 mole) of o-amino acetophenone and 1.0 gram (0.01 mole) of triethylamine is added dropwise. The reaction mixture was stirred rapidly while in the ice bath and was then removed and allowed to warm to room temperature. After standing overnight, the reaction mixture was poured into aqueous sodium carbonate. The aqueous layer was washed once with chloroform and filtered. Acidification with dilute aqueous hydrochloric acid resulted in a white precipitate which after suction filtration and vacuum drying afforded 2.4 grams of material confirmed by NMR analysis as the desired product.
With triethylamine; In dichloromethane;
Example I Preparation of: 1-(2-methylcarbonylphenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To a stirred solution of 0.01 mole of chlorosulfonyl isocyanate in methylene chloride maintained at 0-5°C. via an ice bath was added 1.4 grams (0.01 mole) of <strong>[1668-54-8]2-amino-4-methyl-6-methoxy-1,3,5-triazine</strong>. After two hours reaction time, a methylene chloride solution containing 1.35 grams (0.01 mole) of o -amino acetophenone and 1.0 gram (0.01 mole) of triethylamine is added dropwise. The reaction mixture was stirred rapidly while in the ice bath and was then removed and allowed to warm to room temperature. After standing overnight, the reaction mixture was poured into aqueous sodium carbonate. The aqueous layer was washed once with chloroform and filtered. Acidification with dilute aqueous hydrochloric acid resulted in a white precipitate which after suction filtration and vacuum drying afforded 2.4 grams of material confirmed by NMR analysis as the desired product.
Example 54; 1-(2-(5-tert-butyl-1H-indol-2-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea; 54a. 2-(5-tert-butyl-1H-indol-2-yl)aniline; 2-aminoacetophenone (1 g, 7.4 mmol), 4-tertbutylphenylhydrazine hydrochloride (1.48g, 7.4 mmol) and acetic acid (0.5 mL) were added to EtOH (25 mL) and refluxed for 30 min. The mixture was evaporated in vacuo. Methanesulfonic acid (17 mL) and phosphorus pentoxide (2.2 g, 15.5 mmol) were added and the mixture was heated at 80° C. for 2 h. The reaction mixture was poured over crushed ice and basified using sodium hydroxide pellets. The solid formed was isolated by filtration, washed with water and air dried to yield the desired material (4.45 g, directly used in the next step without further purification).
In toluene; for 18h;Heating / reflux; Dean-Stark condenser;
A mixture of 2-aminoacetophenone (2 g, 14.8 mmol) and ethyl (2-methyl- benzoyl)acetate (3.66 g, 17.8 mmol) in toluene (70 mL) was heated at reflux for 18 h using a Dean-Stark condenser. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by column chromatography (SiO2, 0-50% EtOAc in heptane) to give a yellow oil (407 mg). To a solution of this oil (350 mg, 1.15 mmol) in TetaF (15 mL) under N2 cooled to 00C was added dropwise a l.OM solution of lithium aluminium hydride in TetaF (2.3 mL, 2.30 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 90 minutes. The mixture was re-cooled to 00C and quenched with water (0.2 mL), 15% NaOH solution (0.2 mL) and water (0.6 mL), allowed to warm to r.t. and stirred for 30 minutes. The mixture was filtered through MgSO4 and washed with TetaF (20 mL). The filtrate was concentrated in vacuo to give a yellow oil (250 mg). This was dissolved in DCM (10 mL) and to the solution was added phosphorus tribromide (0.11 mL, 1.2 mmol). The mixture was stirred at r.t. for 90 minutes and then poured into cold 10% K2CO3 solution (20 mL) and extracted with DCM (2 x 50 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 0-50% EtOAc in heptane) gave a clear colourless oil. This was dissolved in DMF (3 mL) and to this solution was added 6- mercaptopurine (14 mg, 0.08 mmol) and K2CO3 (11 mg, 0.08 mmol). The mixture was stirred at r.t. for 72 h. The mixture was diluted with EtOAc (100 mL) and washed with water (5 x 30 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-10% MeOH in DCM) gave the title compound (14 mg, 0.3%) as a white solid. deltaeta (CDCl3) 12.11 (br s, IH), 8.64 (s, IH), 8.22 (d, J 10 Hz, IH), 8.10 (d, J 10 Hz, IH), 7.86 (s, IH), 7.75 (t, J 8 Hz, IH), 7.62 (t, J 8 Hz, IH), 7.35 (d, J 10 Hz, IH), 7.30-7.10 (m, 9H), 4.92 (d, J 12.5Hz, IH), 4.57 (d, J 12.5 Hz, IH), 2.91 (s, 3H), 2.12 (s, 3H). LCMS (ES+) 398.2 (M+H)+, RT 2.32 minutes {Method 1)
With C22H48N4O12S4(4+)*4HO4S(1-); In ethanol; water; at 20℃; for 2.1h;Irradiation; Reflux;
1 mmol of benzaldehyde,1 mmol of o-aminoacetophenone and 0.10 mmol of high acidity ionic liquid were separately added to a 50 ml single-necked flask with a condenser tube containing 8 ml of a 94% aqueous ethanol solution and stirred at room temperature.Heating and refluxing, ultrasonic irradiation under the reaction 2.1h, TLC (thin plate chromatography) detection, the raw material disappeared, the end of the reaction to room temperature precipitation of a large number of solid, Into the ice water bath to continue to cool out the solid, the amount of solid is no longer increased when the crushing of the solid, standing, suction, Washed with ethanol (3 ml x 3) and dried in vacuo at 75 C to give 2-phenyl-2,3-dihydro-4 (1H) -quinolinone, The purity was 99.1% and the yield was 92%. The filtrate is directly added with benzaldehyde and o-aminoacetophenone reuse.
88%
With silver trifluoromethanesulfonate; In methanol; for 12h;Reflux; Inert atmosphere;
General procedure: AgOTf (26 mg, 10 mol%) 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.
With L-proline; In methanol; for 48h;
General procedure: To a solution of L-Proline (0.44 mmol) in methanol (5 mL) was added 2-aminoacetophenone (1.4 mmol) and aldehyde (1.4 mmol) and the mixture was stirred for 48 h. The mixture was treated with 5 mL of saturated ammonium chloride solution and extracted with dichloromethane (3 x 10 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by column chromatography.
Solutions of an arylhydrazine, or its hydrochloride, and the ketone (1 - 3 mmol each) in either ethanol or methanol (15 - 25 ml) were refluxed for 1 h, rotary evaporated and the residue recrystallised from ethanol, methanol or acetone.
1-(2-aminophenyl)-3-hydroxy-3-phenylpropan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%; 13%
With silver trifluoromethanesulfonate; In methanol; for 3h;Reflux; Inert atmosphere;
AgOTf (26 mg, 10 molpercent) was added to a solution of o-aminoacetophenone(1a; 135 mg, 1.0 mmol) and benzaldehyde (2a; 127 mg, 1.2 mmol) in MeOH (5 mL) at r.t. The reaction mixture was stirred under reflux for 3 h only. The excess solvent was removed under reduced pressure and the residue was purified by silica gel gradient column chromatography (hexanes?EtOAc, 20:1?5:1) to yield 1a (104 mg, 77percent, recovered), 3a (17 mg, 8percent), and 4a (31 mg, 13percent).
(E)-1-(2-aminophenyl)-3-(benzo[b]thiophen-3-yl)-prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In ethanol; at 20℃;
General procedure: To a stirred solution of benzo[b]thiophene-3-carbaldehyde1 (1.62 g, 10 mmol) in ethanol (5 mL), 2-ethanonederivatives (2a, 2b) (10 mmol) dissolved in ethanol(2-3 mL) was added portion wise (Scheme 1). The reactionmixture was stirred at room temperature for 20 min,during which it turned to a homogeneous solution. ThenKOH solution (40 %, 2 mL) was added drop wise and theresultant mixture was stirred at room temperature for3-4 h. The precipitated product of chalcone was thencollected by filtration. The crude product was purified byrecrystallization from chloroform-methanol (1:1 v/v,10 mL) to afford (80-85 % yield) the product as yellow tolight brown needles (3a, 3b). Single crystals suitable forX-ray diffraction of both of the chalcones were obtained byrecrystallization from a saturated solution in DMSO.
With tri-tert-butyl phosphine; potassium acetate; potassium carbonate; In toluene; for 24h;Reflux;
The reaction flask to <strong>[62162-97-4]2-bromo-phenanthrene</strong> 30.0g (116.7mmol), compound [219-1] 18.9g (140.0 mmol), palladium (II) acetate, 524mg (2.33 mmol), potassium carbonate and 24.2g (175.1 mmol), toluene 500mL, was added to tert-butylphosphine tree 2.2mL (4.66 mmol) was stirred under reflux for 24 hours. After completion of the reaction was poured into a saturated ammonium aqueous solution to the reaction solution and extracted with ethyl acetate. After separation the organic layer was filtered then dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and, after purification by column chromatography to prepare an intermediate compound of a yellow solid [219-2] 28.2g (78wtpercent).
7-methyl-6-phenyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 60℃; for 24h;Inert atmosphere;
General procedure: To a mixture of 2-aminobenzophenone (1.1mmol, 0.22g) and 2-phenyl-2,3-dihydroquinolin-4-one (1.1mmol, 0.25g) was added T3P® (2.2mmol, 0.70g) and the reaction mixture stirred at 60°C for 24h. Water (100mL) was added to dissolve T3P® and the mixture extracted with dichloromethane (3×60mL). The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was recrystallized from methanol to give product 6a as yellow needles (57percent).
6-(4-fluorophenyl)-7-methyl-5,6-dihydrodibenzo[b,h][1,6]naphthyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 60℃; for 24.0h;Inert atmosphere;
General procedure: To a mixture of 2-aminobenzophenone (1.1mmol, 0.22g) and 2-phenyl-2,3-dihydroquinolin-4-one (1.1mmol, 0.25g) was added T3P (2.2mmol, 0.70g) and the reaction mixture stirred at 60C for 24h. Water (100mL) was added to dissolve T3P and the mixture extracted with dichloromethane (3×60mL). The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was recrystallized from methanol to give product 6a as yellow needles (57%).
(4-methylquinolin-3-yl)(4-(trifluoromethyl)phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With [2,2]bipyridinyl; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper diacetate; In toluene; at 120℃; for 36h;Inert atmosphere; Sealed tube;
To a 15 mL reaction tube was added 1 c (0.5 mmol, 60.6 muL), toluene (3 mL), Cu (OAc) 2 (0.05 mmol,9.1 mg),2,2'-bipyridine (0.25 mmol, 39.0 mg), TEMPO (1 mmol, 156.2 mg) and 2c (0.6 mmol,121.2 mg). After the vacuum was purged with nitrogen, the reaction tube was sealed and placed in an oil bath at 120 ° C for 36 h. The reaction was stopped, 15 mL of dichloromethane was added, followed by washing with water and saturated NaCl solution successively, and the organic phase was dried over anhydrous MgSO4. Filtration, spin drying, silica gel column separation (petroleum ether / ethyl acetate = 10/1)The target product 3i (77.2 mg, 49percent) was obtained.
With oxygen; triethylamine; copper(l) chloride; In tetrahydrofuran; for 12h;Reflux;
In 150 mL of tetrahydrofuran, 6.05 g (45 mmol) of o-aminoacetophenone and 4.68 g (50 mmol) of 2-chloroacetamide were added, and 0.45 g (4.5 mmol) of catalyst cuprous chloride and 9.11 g (90 mmol) of triethylamine were present. Next, pass in oxygen and stir under reflux for 12 hours.The progress of the reaction was monitored by TLC. After the reaction was completed, the solvent was removed under reduced pressure. After column chromatography, 7.61 g (39.5 mmol) of the compound 2-chloromethyl-4-methylquinazoline was obtained with a yield of 88%.
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