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Structure of 51012-65-8 * Storage: {[proInfo.prStorage]}
* 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 hydrogen bromide In hexane; water; ethyl acetate; acetonitrile
Example 6 Preparation of 2-bromo-1-o-tolylethanone (I15) To a solution of 2-methylbenzoyl chloride (169 μl, 1.29 mmol) in dry acetonitrile (5 ml) and cooled at 0° C., under nitrogen atmosphere, was added (diazomethyl)-trimethylsilane (1.94 ml, 3.88 mmol, 2M in hexane). The reaction was stirred at room temperature for 15 hours, then it was cooled at 0° C. and 48percent HBr (512 μl, 4.53 mmol) was slowly added. The reaction was stirred at room temperature for 3 hours. EtOAc and water were added, the organic layer was separated and the aqueous phase was neutralized with 1M NaOH and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to obtain 2-bromo-1-o-tolylethanone (250 mg, 91percent yield). This intermediate was used in the next step without any further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.91 (m, 1H), 7.45-7.52 (m, 1H), 7.25-7.40 (m, 2H), 4.86 (s, 2H), 2.41 (s, 3H).
91%
Stage #1: at 0 - 20℃; for 15 h; Inert atmosphere Stage #2: With hydrogen bromide In hexane; water; acetonitrile at 0 - 20℃; for 3 h;
To a solution of 2-methylbenzoyl chloride (169 μ, 1.29 mmol) in dry acetonitrile (5 ml) and cooled at 0°C, under nitrogen atmosphere, (diazomethyl)trimethylsilane (1.94 ml, 3.88 mmol, 2M in hexane) was added. The reaction was stirred at room temperature for 15h, then it was cooled at 0°C and 48percent HBr (512 μ, 4.53 mmol) was slowly added. The reaction was stirred at room temperature for 3h. EtOAc and water were added, the organic layer was separated and the aqueous phase was neutralized with 1M NaOH and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to obtain 2-bromo-l-o- tolylethanone (250 mg, 91percent yield). This intermediate was used in the next step without any further purification.1H NMR (300 MHz, DMSO- 6) δ ppm 7.82 - 7.91 (m, 1 H), 7.45 - 7.52 (m, 1 H), 7.25 - 7.40 (m, 2 H), 4.86 (s, 2 H), 2.41 (s, 3 H).
With N-Bromosuccinimide; silica gel In methanol for 0.283333 h; Reflux
General procedure: The α-bromination reaction was carried out using acetophenone (1200 mg, 10 mmol), N-bromosuccinimide (2136 mg, 12 mmol), 10percent (w/w) silica gel (120mg) in 10 mL of methanol at reflux conditions until the disappearance of the substrate. (Note: 2136mg of N-bromosuccinimide was added portion wise i.e. 356 mg for each time in six portions). The progress of the reaction was monitored by TLC. The reaction mass was filtered after the completion of the reaction as per TLC and the catalyst was collected for reuse. The filtrate was concentrated under vacuum. Double distilled water was added to the reaction mixture and quenched with aqueous sodium thiosulfate and the product extracted with dichloromethane (Caution: Severe burning sensation of eyes was observed during the work-up process). The layers were separated and the organic layer was collected and washed thrice with distilled water (3×50mL). The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude product was purified by column chromatography over silica gel (60–120 mesh) using n-hexane–EtOAc (99:1 ratio). With the aim of studying the recycling of the catalyst, the isolated catalyst was washed with ethyl acetate (5mL) after its filtration from the reaction medium, collected and dried in vacuum at 70°C to a constant weight. Subsequently it was reused for the α-bromination of acetophenone and achieved 95percent, 86percent and 83percent yields of product (2a) for first, second and third reuse of catalyst respectively. All products gave spectroscopic data in agreement with the literature [15,21,27–30]. The method is also very practical for scale up in process development. We attempted large scale (100 gram scale) synthesis of 2-bromo-1-phenylethanone 2a and obtained fruitful results with isolated yields ranging from 93percent to 96percent.
47%
With trimethylsilyl bromide; potassium nitrate In dichloromethane at 20℃; for 16 h;
General procedure: In a Nalgene.(R). bottle, to acetophenone (2 mmol) in dichloromethane (10 mL), potassium nitrate (4 mmol) and chloro/bromotrimethylsilane (8 mmol) were added. The heterogeneous mixture was stirred vigorously at 60 °C (for chlorination) or room temperature (for bromination) until the reaction went to completion (monitored by 1H NMR spectroscopy). The reaction mixture was then filtered and solvent removed under reduced pressure. The chlorinated/brominated acetophenone derivatives were obtained upon purification by flash chromatography (silica gel) with hexane as eluent. The products were characterized by comparing their spectroscopic data with those of the authentic samples.
Reference：
[1] Chinese Chemical Letters, 2014, vol. 25, # 1, p. 179 - 182
[2] Tetrahedron Letters, 2011, vol. 52, # 11, p. 1217 - 1221
4
[ 577-16-2 ]
[ 51012-65-8 ]
Yield
Reaction Conditions
Operation in experiment
92%
With Oxone; ammonium bromide In methanol at 20℃; for 26 h;
General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
52.5%
With pyridinium hydrobromide perbromide; hydrogen bromide; acetic acid In water at 0 - 20℃; for 3 h;
Intermediate 9: 2-Bromo-1-(2-methylphenyl) ethanoneTo a 250 mL RB flask fitted with magnetic stirrer was charged 60 mL of Acetic acid. To the stirred solvent was added 1-o-tolyl-ethanone (3.0 g, 22.35 mmol) RM cooled to 0 was added 47percent hydrobromic acid (9.7 mL, 178.63 mmol), pyridinium hydro bromide per bromide (8.6 g, 26.89 mmol) slowly. The resulting mixture was stirred at RT for 3 h. The RM was then quenched with 10percent sodium bicarbonate solution in water (150 mL) at 0 and extracted with ethyl acetate (75 mL X 2). The organic layer was washed with saturated brine solution (50 mL) and dried over anhydrous Na2S04 and evaporated to dryness. The crude compound thus obtained was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate (ratio) as eluent to give the product (2.50 g, yield: 52.5percent)
96%
With hydrogenchloride; bromine In diethyl ether; acetic acid
a. 2'-Methylacetophenone (25.0 g, 186 mMole) was dissolved in glacial acetic acid (250 ml) and concentrated HCl (250 uL) was added followed by a dropwise addition of bromine (9.6 ml, 186 mmole) over 15 minutes. The mixture was stirred 3 hours and then concentrated under reduced pressure. The residue was taken up in ethyl ether and washed with saturated NaHCO3 solution. The ether layer was dried over Na2SO4, filtered, and concentrated to yield 38.0 g, (96percent) of crude 2-bromo-2'-methylacetophenone which was used without further purification.
167 g
With pyridinium hydrobromide perbromide In ethyl acetate for 1 h;
2'-methylacetophenone (100 g), stirred mixture of ethyl acetate (800 mL)While, was added Pyridinium bromide perbromide(252g). The reaction solution After stirring for 1 hour.The addition of water (500 mL), to remove the separated water layer. The obtained organic layer, 1 N hydrochloric acid (500 mL), then washed with saturated color fountain (500 mL), washed with 5percent aqueous sodium thiosulfate solution (500 mL). The resulting organic layer was dried over sodium sulfate, and concentrated to give, to give the intermediate 301F (167g).
Reference：
[1] Tetrahedron Letters, 2012, vol. 53, # 2, p. 191 - 195
[2] Synthetic Communications, 2013, vol. 43, # 19, p. 2603 - 2614
[3] Archiv der Pharmazie, 1993, vol. 326, # 5, p. 253 - 258
[4] Organic Letters, 2016, vol. 18, # 4, p. 852 - 855
[5] Patent: WO2012/11125, 2012, A1, . Location in patent: Page/Page column 67-68
[6] Journal of the Chemical Society, 1938, p. 445,447
[7] Journal of the Chemical Society, 1935, p. 997,999
[8] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 3, p. 601 - 621
[9] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1291 - 1295
[10] Patent: US2002/13319, 2002, A1,
[11] Patent: US6020342, 2000, A,
[12] Patent: US4626543, 1986, A,
[13] Patent: EP1803709, 2007, A1,
[14] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 107-108; 284
[15] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 138-139; 287
[16] Patent: US2011/306769, 2011, A1, . Location in patent: Page/Page column 27
[17] Patent: WO2012/27965, 2012, A1, . Location in patent: Page/Page column 17
[18] Journal of Medicinal Chemistry, 2013, vol. 56, # 1, p. 84 - 96
[19] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7175 - 7179
[20] Chemistry - A European Journal, 2014, vol. 20, # 20, p. 5983 - 5993
[21] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7707 - 7715
[22] MedChemComm, 2015, vol. 6, # 6, p. 1036 - 1042
[23] Chemical Biology and Drug Design, 2015, vol. 86, # 4, p. 849 - 856
[24] Patent: EP2336107, 2015, B1, . Location in patent: Paragraph 0197
[25] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 8, p. 1166 - 1173
[26] Patent: JP5827901, 2015, B2, . Location in patent: Paragraph 0214; 0215
[27] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3298 - 3314
[28] Organic Letters, 2017, vol. 19, # 11, p. 2877 - 2880
[29] Organic and Biomolecular Chemistry, 2017, vol. 15, # 38, p. 8134 - 8139
[30] Patent: US2018/44284, 2018, A1, . Location in patent: Paragraph 0172; 0173
[31] Advanced Synthesis and Catalysis, 2018, vol. 360, # 8, p. 1628 - 1633
[32] Tetrahedron Letters, 2018, vol. 59, # 33, p. 3214 - 3219
5
[ 577-16-2 ]
[ 51012-65-8 ]
Reference：
[1] Patent: US5859035, 1999, A,
6
[ 611-15-4 ]
[ 51012-65-8 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 48, p. 11389 - 11395
[2] Synlett, 2010, # 15, p. 2335 - 2339
7
[ 577-16-2 ]
[ 51012-65-8 ]
Reference：
[1] Patent: EP885869, 1998, A1,
8
[ 933-88-0 ]
[ 51012-65-8 ]
Reference：
[1] Journal of the Chemical Society, 1935, p. 997,999
[2] Journal of the Chemical Society, 1938, p. 445,447
9
[ 75-15-0 ]
[ 7446-70-0 ]
[ 106-38-7 ]
[ 75-36-5 ]
[ 51012-65-8 ]
Reference：
[1] Chemische Berichte, 1922, vol. 55, p. 2056
[2] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
10
[ 75-15-0 ]
[ 7446-70-0 ]
[ 95-46-5 ]
[ 75-36-5 ]
[ 51012-65-8 ]
Reference：
[1] Chemische Berichte, 1922, vol. 55, p. 2056
[2] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine[ No CAS ]
[ 1643-19-2 ]
[ 51012-65-8 ]
[ 209222-51-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydroxide In toluene
112.2 Preparation of 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine
Step 2 Preparation of 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine 2-Oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.54 g) was suspended in toluene (22 ml), 2-bromo-2'-methylacetophenone (1.05 g), 1N aqueous sodium hydroxide (11 ml) and tetra n-butylammonium bromide (25 mg) were added, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 2.26 g of the titled compound (Yield: 100%). 1H-NMR(CDCl3) δ: 1.40(9H, s), 1.68(3H, s), 2.13(3H, s), 2.36(3H, s), 2.49(3H, s), 3.86(1H, dd), 4.39(1H, t), 4.56-4.63(1H, m), 4.94(1H, d), 5.17(1H, d), 5.28(1H, brs), 5.50(1H, d), 7.01-7.04(3H, m), 7.26-7.31(2H, m), 7.42(1H, t), 7.72(1H, d)
117.2 Preparation of 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine
Step 2 Preparation of 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine 2-Bromo-2'-methylacetophenone (0.51 g), 1N aqueous sodium hydroxide (20 ml), toluene (20 ml) and tetra n-butylammonium bromide (20 mg) were added to 2-Oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.80 g), the mixture was stirred at room temperature for 4 hours. The reaction mixture was separated into organic layer and aqueous layer, the aqueous layer was extracted with ethyl acetate, the extract was combined with the former organic layer. The combined extract was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.02 g of the title compound as colorless amorphous (Yield: 96%). 1H-NMR(CDCl3) δ: 1.42(9H, s), 2.39(3H, s), 2.52(3H, s), 4.07-4.16(1H, m), 4.41-4.50(1H, m), 4.63-4.74(2H, m), 5.44(1H, d), 5.72(1H, brd), 6.82-7.77(10H, m)
Stage #1: 5-bromo-2-methyl-4-nitro-1H-imidazole With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: 2-bromo-1-o-tolylethanone In N,N-dimethyl-formamide at 20℃; for 48h;
2
In 500 ml round-bottomed flask equipped with a tube containing anhydrous calcium chloride placed 30 ml of DMF and 2 g MgSO4 was added as a water-binding agent. Next, 2.32g of 5(4)- bromo-2-methyl-4(5)-nitro-lH-imidazole and 0.95g sodium bicarbonate were added.The reaction mixture was stirred at room temperature for 15 minutes until CO2 ceased to be emitted. Next, 2.4g α-bromo-2-methylacetylphenone were added. The mixture was stirred at room temperature for 48 hours. Next, the flask contents were poured into 150 ml distilled water and left at 50C for 3h. The precipitate formed was filtered out and dried. This produced a mixture o f 4-bromo-2-methyl-l-(2-methylphenacyl)-5-nitroimidazole and 5-bromo-2-methyl-l-(2- methylphenacyl)-4-nitroimidazole. The isomer mixture was separated on a chromatography column with a silica gel with EtOAc as the mobile phase. This resulted in 5-bromo-2-methyl-l-(2-methylphenacyl)-4-nitroimidazole at a 50% efficiency, t.t=203-205°C;1H NMR δ[ppm]; 8.15-7.39 (4H, m, Ph); 5.89 (2H, s, CH2); 2.45 (3H, s, PhCH3); 2.42 (3H, s,CHs-imi).13C NMR δ[ppm]: 194.09 (C=O); 146.48 (C2-imi); 143.22 (C4-imi); 138.75 (Ph); 133.60 (Ph);133.03 (Ph); 132.14 (Ph); 129.67 (Ph); 126.20 (Ph); 107.63 (C5-imi); (CH2) 53.91. 21.03(PhCH3); 13.50 (CH3-imi). as well as 4-bromo-2-methyl-l-(2-methylphenacyl)-5-nitroimidazole at an efficiency of 6%, t.t=161-162°C;1H NMR δ[ppm]: 8.05-7.40 (4H, m, Ph); 5.77 (2H, s, CH2); 2.45 (3H, s, PhCH3), 2.39 (3H, s,CH3 -imi). 13C NMR δ[ppm]: 194.53 (C=O); 150.69 (C2-imi); 143.28 (C5-imi); 138.63 (Ph); 133.89 (Ph);132.77 (Ph); 132.09 (Ph); 129.37 (Ph); 126.16 (Ph); 1 19.69 (C4-imi); 55.06 (CH2); 20.83(PhCH3); 13.52 (CH3-imi).
Step 1: Preparation of 5-(2-oxo-2-(o-tolyl)ethyl)-<strong>[885-70-1]5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one</strong> <strong>[885-70-1]5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one</strong> (1.0 g, 1 eq.) was suspended in dimethylacetamide (DMA) (30 mL). The reaction was cooled to 0 C. and sodium hydride (60% in mineral oil) (380 mg, 2.0 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0 C. and 2-bromo-1-(o-tolyl)ethanone (1.2 g, 1.2 eq.) was added. The reaction was stirred at 50 C. overnight. The reaction was poured onto 80 mL water and extracted with dichloromethane (2*100 mL). The organic extracts were combined, washed with water (2*100 mL), brine (2*100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product, 5-(2-oxo-2-(o-tolyl)ethyl)-<strong>[885-70-1]5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one</strong> (0.65 g) was used without purification. LCMS: 344 [M+H].
2-(2,3-dimethoxyphenyl)-5-(2-methylphenyl)oxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With iodine; potassium carbonate; In N,N-dimethyl-formamide; for 18h;Heating;
General procedure: Iodine (4.87g, 19mmol) was added to a stirred solution of 2-bromo-2′-methoxyacetophenone (10a) (2.00g, 8.7mmol), 2,3-dimethoxybenzylamine (11a) (1.6mL, 11mmol) and K2CO3 (4.83g, 35mmol) in DMF (87mL). The mixture was stirred at 80C for 18h. After cooling to room temperature, the reaction was quenched with 10% aqueous Na2S2O3 (30mL), and the resulting mixture was extracted with Et2O (3×60mL). The combined extracts were washed with brine (2×60mL), then dried with Na2SO4. The mixture was concentrated in vacuo, and the residue was purified by recrystallization (hexane/ CHCl3 3:1) to give 12 (1.65g, 60%) as off-white powders.
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