* 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.
With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); water; 3-cyano-1-methylquinolinium cation In acetonitrile at 20℃; for 5 h; Inert atmosphere; Irradiation; Green chemistry
1-methyl-3-cyanoquinoline salt as a photosensitizer, cobalt oxime complex 2 as a cobalt catalyst, 5mL of acetonitrile was added2.69 mg (1 × 10 -2 mmol) of photosensitizer and 2.80 mg (6 × 10 -3 mmol) of cobalt catalyst were charged, the atmosphere was replaced with Ar atmosphere, and then0.2 mmol of 3'-chloroacetophenone (R1 is COCH3, R3 is Cl, R2, R4 are independently H) and 2 mmol of H2O are added. Room temperature, high pressureMercury lamp irradiation 5h. After the reaction was completed, the H2 production was detected by GC (TCD) and the conversion of benzene by GC (FID), Then over the column points. Nuclear magnetic resonance spectroscopy and mass spectrometry identification of broad-based as 3 '- chloro -2_ hydroxyacetophenone, 3' - chloro -4_ light base acetophenone and 3 '- chloro-6_Hydroxyacetophenone.The conversion of 3'-chloroacetophenone was 43percent. The conversion of 3'-chloro-2-hydroxyacetophenone, 3'-chloro-4-hydroxyacetophenone and 3'-chloro-6-hydroxyacetophenone The yields were 6percent, 2percent and 34percent respectively, and the H2 yield was 42percent.
Reference：
[1] Patent: CN107324975, 2017, A, . Location in patent: Paragraph 0126-0127
2
[ 118-93-4 ]
[ 1450-74-4 ]
[ 3321-92-4 ]
[ 3226-34-4 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 2, p. 809 - 813
3
[ 4525-75-1 ]
[ 3226-34-4 ]
[ 2892-29-7 ]
Yield
Reaction Conditions
Operation in experiment
31%
With aluminum (III) chloride In 1,2-dichloro-benzene at 20 - 100℃; for 5 h;
At room temperature, 6 (152.5 g, 893.7 mmol) was added dropwise to a solution of aluminium chloride (119.0 g, 893.7 mmol) in dichlorobenzene (120 mL). The reaction mixture was stirred at 100 °C for 5 h. After cooling to room temperature, dichloromethane was added and the resulting mixture was poured into H2SO4 2 N at 0 °C. Precipitated 3-chloro-4-hydroxyacetophenone was removed by filtering the mixture. The aqueous layer was separated and extracted with dichloromethane. The organic phases were combined, rinsed with water, dried and concentrated. The residue was crystallized from cyclohexane, yielding additional undesired 3-chloro-4-hydroxyacetophenone (23.6 g) as a yellowish solid and, by concentration of the crystallization mother liquor, 47.3 g (31.0percent) of the desired product 7 as a yellow oil: 1H NMR (CDCl3) δ 12.84 (br s, 1H, exchangeable with D2O), 7.67 (dd, 1H), 7.57 (dd, 1H), 6.87 (dd, 1H), 2.66 (s, 3H). 3-Chloro-4-hydroxyacetophenone: m.p. 109 °C; 1H NMR (CDCl3) δ 7.98 (d, 1H), 7.81 (m, 1H), 7.08 (m, 1H), 6.30 (br s, 1H, exchangeable with D2O), 2.56 (s, 3H).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 184 - 191
[2] Journal of the Indian Chemical Society, 1959, vol. 36, p. 784
[3] Journal of the Indian Chemical Society, 1959, vol. 36, p. 784
[4] Journal of Chemical Research, Miniprint, 1989, # 11, p. 2713 - 2739
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 1, p. 132 - 140
4
[ 99-02-5 ]
[ 1450-74-4 ]
[ 3226-34-4 ]
Yield
Reaction Conditions
Operation in experiment
6%
With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); water; 3-cyano-1-methylquinolinium cation In acetonitrile at 20℃; for 5 h; Inert atmosphere; Irradiation; Green chemistry
1-methyl-3-cyanoquinoline salt as a photosensitizer, cobalt oxime complex 2 as a cobalt catalyst, 5mL of acetonitrile was added2.69 mg (1 × 10 -2 mmol) of photosensitizer and 2.80 mg (6 × 10 -3 mmol) of cobalt catalyst were charged, the atmosphere was replaced with Ar atmosphere, and then0.2 mmol of 3'-chloroacetophenone (R1 is COCH3, R3 is Cl, R2, R4 are independently H) and 2 mmol of H2O are added. Room temperature, high pressureMercury lamp irradiation 5h. After the reaction was completed, the H2 production was detected by GC (TCD) and the conversion of benzene by GC (FID), Then over the column points. Nuclear magnetic resonance spectroscopy and mass spectrometry identification of broad-based as 3 '- chloro -2_ hydroxyacetophenone, 3' - chloro -4_ light base acetophenone and 3 '- chloro-6_Hydroxyacetophenone.The conversion of 3'-chloroacetophenone was 43percent. The conversion of 3'-chloro-2-hydroxyacetophenone, 3'-chloro-4-hydroxyacetophenone and 3'-chloro-6-hydroxyacetophenone The yields were 6percent, 2percent and 34percent respectively, and the H2 yield was 42percent.
Reference：
[1] Patent: CN107324975, 2017, A, . Location in patent: Paragraph 0126-0127
5
[ 87428-45-3 ]
[ 99-02-5 ]
[ 3226-34-4 ]
Reference：
[1] Patent: US4489074, 1984, A,
[2] Patent: US4495185, 1985, A,
6
[ 42524-22-1 ]
[ 3226-34-4 ]
Reference：
[1] Synthetic Communications, 2000, vol. 30, # 8, p. 1521 - 1527
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2002, vol. 41, # 6, p. 1302 - 1304
7
[ 99585-09-8 ]
[ 3226-34-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 619 - 622
8
[ 118-93-4 ]
[ 1450-74-4 ]
[ 3321-92-4 ]
[ 3226-34-4 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 2, p. 809 - 813
9
[ 4525-75-1 ]
[ 3226-34-4 ]
Reference：
[1] Journal of Natural Products, 2018, vol. 81, # 8, p. 1803 - 1809
10
[ 95-57-8 ]
[ 3226-34-4 ]
[ 2892-29-7 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 184 - 191
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 1, p. 132 - 140
11
[ 95-57-8 ]
[ 75-36-5 ]
[ 3226-34-4 ]
Reference：
[1] Journal of the Indian Chemical Society, 1949, vol. 26, p. 366,367
[2] Monatshefte fuer Chemie, 1965, vol. 96, p. 1214 - 1223
12
[ 3226-34-4 ]
[ 3260-93-3 ]
Reference：
[1] Journal of the Indian Chemical Society, 1959, vol. 36, p. 784
13
[ 3226-34-4 ]
[ 74-88-4 ]
[ 99585-09-8 ]
Reference：
[1] Journal of Natural Products, 2018, vol. 81, # 8, p. 1803 - 1809
14
[ 3226-34-4 ]
[ 77-78-1 ]
[ 99585-09-8 ]
Reference：
[1] Journal of the Indian Chemical Society, 1959, vol. 36, p. 784
With aluminum (III) chloride; In 1,2-dichloro-benzene; at 20 - 100℃; for 5h;
At room temperature, 6 (152.5 g, 893.7 mmol) was added dropwise to a solution of aluminium chloride (119.0 g, 893.7 mmol) in dichlorobenzene (120 mL). The reaction mixture was stirred at 100 C for 5 h. After cooling to room temperature, dichloromethane was added and the resulting mixture was poured into H2SO4 2 N at 0 C. Precipitated 3-chloro-4-hydroxyacetophenone was removed by filtering the mixture. The aqueous layer was separated and extracted with dichloromethane. The organic phases were combined, rinsed with water, dried and concentrated. The residue was crystallized from cyclohexane, yielding additional undesired 3-chloro-4-hydroxyacetophenone (23.6 g) as a yellowish solid and, by concentration of the crystallization mother liquor, 47.3 g (31.0%) of the desired product 7 as a yellow oil: 1H NMR (CDCl3) delta 12.84 (br s, 1H, exchangeable with D2O), 7.67 (dd, 1H), 7.57 (dd, 1H), 6.87 (dd, 1H), 2.66 (s, 3H). 3-Chloro-4-hydroxyacetophenone: m.p. 109 C; 1H NMR (CDCl3) delta 7.98 (d, 1H), 7.81 (m, 1H), 7.08 (m, 1H), 6.30 (br s, 1H, exchangeable with D2O), 2.56 (s, 3H).
With aluminum (III) chloride; at 100℃; for 20h;
General procedure: To a solution of aluminum chloride (2.08 g, 15.57 mmol) in dichlorobenzene was added a solution of 12 (1.2 g, 7.79 mmol) in dichlorobenzene at room temperature. The reaction was warmed to 100 C and further stirred for 20 h. After the reaction mixture was allowed to cool to room temperature, added with dichloromethane, and poured into 10% HCl cooled at 0 C. The aqueous layer was separated and extracted with CH2Cl2. The combined organic phases were washed with water, dried over Na2SO4. The filtrate was evaporated under vacuum, and the residue was purified by column chromatography (EtOAc/hexane, 1:4, v/v) to give a white solid (0.75 g, 62.5%).
With potassium hydroxide; iodobenzene diacetic acid; In methanol; diethyl ether; ethanol; water;
The 2-hydroxy-m-chloroacetophenone ethoxycarbonylhydrazone used as starting material was obtained as follows: Iodobenzene diacetate (32.2 g.) was added during 15 minutes to a stirred solution of m-chloroacetophenone (15.4 g.) and potassium hydroxide (28.0 g.) in methanol (300 ml.) which was kept at 0 C., and the mixture was allowed to warm up to laboratory temperature, stirred at that temperature for 2 hours and then evaporated to dryness under reduced pressure. The residue was shaken with water (200 ml.) and diethyl ether (200 ml.) and the ethereal solution was separated, dried over magnesium sulphate and evaporated to dryness. A mixture of the residue, ethanol (35 ml.) and aqueous 2N-hydrochloric acid (35 ml.) was stirred at 25 C. for 20 hours and then filtered, and the solid product was crystallized from methanol. There was thus obtained 2-hydroxy-m-chloroacetophenone, m.p. 103-105 C. A mixture of the above compound (5.5 g.), ethyl carbazate (3.3 g.) and ethanol (150 ml.) was stirred at 25 C. for 60 hours and then concentrated to small volume by evaporation. The residue was heated until a clear solution was obtained, and was then cooled and filtered. There was thus obtained as solid residue 2-hydroxy-m-chloroacetophenone ethoxycarbonylhydrazone, m.p. 109-110 C. The process described above was repeated except that the appropriate acetophenone was used as initial starting material. There were thus obtained the compounds described in the following table:
With potassium hydroxide; iodobenzene diacetic acid; In methanol; diethyl ether; ethanol; water;
The 2-hydroxy-m-chloroacetophenone ethoxycarbonylhydrazone used as starting material was obtained as follows: Iodobenzene diacetate (32.2 g.) was added during 15 minutes to a stirred solution of m-chloroacetophenone (15.4 g.) and potassium hydroxide (28.0 g.) in methanol (300 ml.) which was kept at 0 C., and the mixture was allowed to warm up to laboratory temperature, stirred at that temperature for 2 hours and then evaporated to dryness under reduced pressure. The residue was shaken with water (200 ml.) and diethyl ether (200 ml.) and the ethereal solution was separated, dried over magnesium sulphate and evaporated to dryness. A mixture of the residue, ethanol (35 ml.) and aqueous 2N-hydrochloric acid (35 ml.) was stirred at 25 C. for 20 hours and then filtered, and the solid product was crystallized from methanol. There was thus obtained 2-hydroxy-m-chloroacetophenone, m.p. 103-105 C. A mixture of the above compound (5.5 g.), ethyl carbazate (3.3 g.) and ethanol (150 ml.) was stirred at 25 C. for 60 hours and then concentrated to small volume by evaporation. The residue was heated until a clear solution was obtained, and was then cooled and filtered. There was thus obtained as solid residue 2-hydroxy-m-chloroacetophenone ethoxycarbonylhydrazone, m.p. 109-110 C. The process described above was repeated except that the appropriate acetophenone was used as initial starting material. There were thus obtained the compounds described in the following table:
General procedure: 4.1.1. General procedure for the synthesis of 4-oxo-3,4-dihydrospiro[chromene-2,4'-piperidines] 5a-f. A solution of appropriate 2'-hydroxyacetophone derivative 3 (100 mmol), N-tert-butoxycarbonyl-4-piperidone 4 (19.92 g, 100 mmol) and pyrrolidine (8.21 mL, 100 mmol) in methanol (150 mL) was stirred at room temperature for 18-24h. Upon completion of the reaction (monitored by TLC), the mixture was concentrated under vacuum and the brown residue thus obtained was partitioned between EtOAc (500 mL) and 1N hydrochloric acid (500 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic extracts were successively washed with water (2×250 mL), saturated NaHCO3 solution (250 mL) and brine (200 mL). The residue obtained after evaporation of the solvent was purified by flash silica gel column chromatography using 20-30% EtOAc in petroleum ether (PE) as eluent.
With pyrrolidine; In xylene; at 100℃; for 20h;
A mixture of l-(3-chloro-2-hydroxyphenyl)ethanone (500 mg, 2.93 mmol), l-boc-4- piperidone (584 mg, 2.93 mmol) and pyrrolidine (61 muL, 0.738 mmol) in Xylene (4 mL) was heated to 100 0C for 20 h. The reaction mixture was purified by column chromatography on SiO2 (40 g, gradient from 0 to 40% EtOAc/hexanes) to afford the title compound as a white solid. LC- MS: m/z = 376.1, 374.1 (M+Na).
With pyrrolidine; In methanol; at 22 - 26℃; for 24.3333h;
To a stirred solution of <strong>[3226-34-4]3-chloro-2-hydroxyacetophenone</strong> (26 g, 152.439 mmol) and pyrrolidine (12.66 mL, 152.439 mmol) in methanol (260 mL) was added N- /er/-butoxycarbonyl-4-piperidone (30.37 g, 152.439 mmol) at room temperature over 20 min. The reaction mixture was stirred at the same temperature for 24 h. The reaction mixture was concentrated and partitioned between ethyl acetate (500 mL) and 2N hydrochloric acid (250 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 25 % ethyl acetate in petroleum ether to afford 42.18 g of the product as a pale yellow solid; 1H NMR (300 MHz, OMSO-d6) delta 1.40 (s, 9H), 1.64-1.68 (m, 2H), 1.88-1.99 (m, 2H), 2.92 (s, 2H), 3.06 (br s, 2H), 3.79-3.83 (m, 2H), 6.07 (t, J = 7.8 Hz, IH), 7.70 (d, J = 7.8 Hz, IH), 7.76 (d, J = 7.5 Hz, IH); APCI-MS (m/z) 252.17 (M-IOO)+.
3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-ones; All starting spirochromene-4-ones required for the synthesis of 3,4-dihydrospirochromen-4-amine were prepared by the reaction of commercially available 2-hydroxy acetophenones (1 equivalent) and cycloalkanones (1 equivalent) in presence of excess triethylamine (2-3 equivalents) in refluxing methanol.
With tetrabutylammomium bromide; sodium hydroxide; In water; at 20℃; for 5h;
Tetrabutylammonium bromide (8.94 g, 27.7 mmol) and 10% aqueous NaOH (222 mL) were added to a solution of 7 (47.3 g, 277.3 mmol) in dichloromethane (500 mL). Benzyl bromide (36.5 mL, 305.1 mmol) was added dropwise to the mixture while vigorously stirring. After 5 h at room temperature, the organic phase was separated, treated with 10% HCl (450 mL), separated again, washed with water, dried and concentrated. Column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 95:5) of the resulting residue allowed 48.5 g (67.1%) of 8 to be isolated as a yellow oil: 1H NMR (CDCl3) delta 7.56 (dd, 1H), 7.48 (m, 3H), 7.38 (m, 3H), 7.15 (t, 1H), 5.02 (s, 2H), 2.55 (s, 3H).
(4S)-8-chloro-1'-[4-(trifluoromethoxy)phenyl]carbamoyl}-3,4-dihydrospiro[chromene-2,4'-piperidine]-4-yl N-[(benzyloxy)carbonyl]-L-tryptophanate[ No CAS ]
(4R)-8-chloro-1'-[4-(trifluoromethoxy)phenyl]carbamoyl}-3,4-dihydrospiro[chromene-2,4'-piperidine]-4-yl N-[(benzyloxy)carbonyl]-L-tryptophanate[ No CAS ]
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