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HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 10531-41-6 * 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.
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 5, p. 703 - 706
2
[ 88-15-3 ]
[ 10531-41-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With bromine In dichloromethane at 25℃; for 1 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Example 1.12: 2-Bromo-1 -(thiophene-2-yl)ethan-1-one.A solution of bromine (2.53 g, 0.82 mL, 0.0158 mol) in dichloromethane (8 mL) is drop wise added to a solution of 2- acethylthiophene (2.0 g, 1.71 ml_, 0.0158 mol) in same solvent (10 ml_). The reaction mixture is stirred at 25°C per 1 hour and then neutralized with sodium hydrogen carbonate saturated aqueous solution. The organic layer is washed with water and dried. After solvent removal the solid residue is purified by column chromatography (silica gel, ethyl acetate: n-hexane 5:95 as eluent) to give 2-bromo-1-(thiophen-2- yl)ethan-1-one as an oil (2.60 g, 80percent). [Alternative preparation of 1- (thiophen-2-yl)ethan-1-one has been reported recently: Ostrowski, T.; Golankiewicz, B.; De Clercq, E.; Andrei, G.; Snoeck, R. Synthesis and anti-VZV activity of 6-heteroaryl derivatives of tricyclic acyclovir and 9- [cis-1 \\2'-bis(hydroxymethyl)cycloprop-1 '-yl]methyl}guanine analogues. Eur. J. Med. Chem. 2009, 44, 3313-3317].
78%
With bromine In benzene
1. 2-Bromo-1-(2-thienyl)ethan-1-one To a stirred solution of 2-acetylthiophene (5.38 mL, 50 mmol) in benzene (100 mL) is added dropwise bromine (2.55 mL, 50 mmol). The reaction is stirred under nitrogen at room temperature overnight. The reaction mixture is washed three times with 2 M Na2CO3, dried over MgSO4, and concentrated to give a brown oil (8.0 g, 78percent yield). MS-APCI: M+1=206.0.
70%
With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 85℃; for 4 h;
General procedure: A mixture of substituted arylethanones 14a-i (10 mmol), N-bromosuccinimide (1.4 g, 12 mmol) and p-toluenesulphonic acid (2.8 g, 15 mmol) in acetonitrile (50 mL) was stirred at 85 °C for 4 h. After completion of reaction (indicated by TLC), the reaction mass was allowed to reach ambient temperature and evaporated excess of acetonitrile under reduced pressure. The residue so obtained was mixed in water, extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuuo. The crude product obtained was recrystallized from n-hexane to afford pure 1-aryl-2-bromoethanones 15a-i in 75-85percent yields.
57%
at 20℃;
To a solution of 2-acetylthiophene (0.310 g, 2.46 mmol) in 33percent of HBr in acetic acid (5.0 mL) was added phenyltrimethylammonium tribromide (0.970 g, 2.58 mmol) at room temperature. After the solution was stirred for overnight, it was poured into ice water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-40percent CH2Cl2 in n-hexane) to give 2-bromo-1-(2-thiophenyl)ethanone (0.287 g, 57percent) as a brown oil. 1H NMR (CDCl3, 400 MHz) δ 7.81 (d, 1H), 7.72 (d, 1H), 7.17 (dd, 1H), 4.36 (s, 2H).
37%
With CH3COOH; hydrogen bromide; bromine In chloroform
a) Synthesis of 2-bromo-1-(2-thienyl)ethan-1-one: To a solution of 500 mg (3.96 mmol) of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved in 20 mL of CHCl3, was added 1 drop of 30percent HBr/CH3COOH (Aldrich Chemical Co.) followed by 3.96 mmol (633 mg; 204 μL) of bromine (Aldrich Chemical Co.) added dropwise over 30 min. The reaction was allowed to stir for 1 h. The solution was concentrated to an oil and dried in vacuo. The crude product was purified on 1 mm silica prep plates eluding with neat CH2Cl2 to obtain 300 mg (37percent yield) of 2-bromo-1-(2-thienyl)ethan-1-one. 1H-NMR (CDCl3; 300 MHz) δ7.8 (m, 2 H), 7.18 (m, 1 H), 4.37 (s, 2 H).
37%
With CH3COOH; hydrogen bromide; bromine In chloroform
a) 2-Bromo-1-(2-thienyl)ethan-1-one
To a solution of 500 mg (3.96 mmol) of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved in 20 mL of CHCl3, was added 1 drop of 30percent HBr/CH3COOH (Aldrich Chemical Co.) followed by 3.96 mmol (633 mg; 204 μL) of bromine (Aldrich Chemical Co.) added dropwise over 30 min. The reaction was allowed to stir for 1 h. The solution was concentrated to an oil and dried in vacuo. The crude product was purified on 1 mm silica prep plates eluding with neat CH2Cl2 to obtain 300 mg (37percent yield) of 2-bromo-1-(2-thienyl)ethan-1-one. 1H-NMR (CDCl3; 300 MHz) δ 7.80 (m, 2H), 7.18 (m, 1H), 4.37 (s, 2H).
14 g
With bromine In methanol at 0 - 20℃; for 2.5 h;
Step 1 : Synthesis of 2-bromo- 1 -(thiophen-2-yl)ethan- 1 -one: [0257] To the stirred solution of l-(thiophen-2-yl)ethan-l-one (10 g, 68.9 mmol) in 110 ml of MeOH at 0°C was added Bromine (2.8 ml, 17.7 mmol) (dropwise addition), stirred for about 30 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The obtained solid was filtered and washed with n-hexane then dried and proceeded for next step (wt: 14. Og).
Reference：
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[2] Synthetic Communications, 1996, vol. 26, # 6, p. 1083 - 1096
[3] Russian Journal of Organic Chemistry, 2001, vol. 37, # 9, p. 1210 - 1219
[4] ChemMedChem, 2018, vol. 13, # 11, p. 1102 - 1114
[5] Phosphorus, Sulfur and Silicon and the Related Elements, 2013, vol. 188, # 12, p. 1835 - 1844
[6] Chemistry Letters, 2006, vol. 35, # 3, p. 270 - 271
[7] Tetrahedron Letters, 2004, vol. 45, # 1, p. 191 - 193
[8] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 3, p. 1159 - 1160
[9] Patent: WO2011/121629, 2011, A1, . Location in patent: Page/Page column 21-22
[10] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8394 - 8406
[11] RSC Advances, 2014, vol. 4, # 107, p. 62308 - 62320
[12] Patent: US2004/44057, 2004, A1,
[13] MedChemComm, 2017, vol. 8, # 12, p. 2258 - 2262
[14] Synthetic Communications, 2002, vol. 32, # 10, p. 1523 - 1528
[15] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 7, p. 1145 - 1150
[16] European Journal of Medicinal Chemistry, 2009, vol. 44, # 8, p. 3313 - 3317
[17] RSC Advances, 2014, vol. 4, # 99, p. 56489 - 56501
[18] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 4, p. 979 - 988
[19] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 6, p. 1379 - 1384
[20] Patent: US2017/56377, 2017, A1, . Location in patent: Paragraph 0419; 0420; 0421
[21] Organic and Biomolecular Chemistry, 2016, vol. 14, # 30, p. 7268 - 7274
[22] Patent: US2002/37915, 2002, A1,
[23] Patent: US6291514, 2001, B1,
[24] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6267 - 6272
[25] Journal of the American Chemical Society, 1949, vol. 71, p. 10
[26] Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 441,458
[27] Journal of Medicinal Chemistry, 1987, vol. 30, # 8, p. 1497 - 1502
[28] Journal of Pharmaceutical Sciences, 1988, vol. 77, # 12, p. 1050 - 1054
[29] Synthesis, 1996, # 6, p. 702 - 706
[30] Russian Chemical Bulletin, 1998, vol. 47, # 1, p. 127 - 133
[31] Journal of the Chinese Chemical Society, 2002, vol. 49, # 2, p. 207 - 212
[32] Journal of the Indian Chemical Society, 2004, vol. 81, # 4, p. 344 - 345
[33] Pharmacy and Pharmacology Communications, 2000, vol. 6, # 8, p. 351 - 354
[34] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4374 - 4377
[35] Journal of Organometallic Chemistry, 2010, vol. 695, # 23, p. 2532 - 2539
[36] Tetrahedron Letters, 2009, vol. 50, # 33, p. 4714 - 4719
[37] ACS Combinatorial Science, 2011, vol. 13, # 1, p. 72 - 78
[38] Russian Journal of Applied Chemistry, 2010, vol. 83, # 6, p. 1027 - 1031
[39] Synlett, 2012, vol. 23, # 12, p. 1797 - 1800
[40] Heterocycles, 2012, vol. 85, # 8, p. 1941 - 1948
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[42] Tetrahedron, 2013, vol. 69, # 31, p. 6392 - 6398
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[48] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 14 - 35
[49] European Journal of Medicinal Chemistry, 2015, vol. 104, p. 1 - 10
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[51] Organic and Biomolecular Chemistry, 2016, vol. 14, # 10, p. 2819 - 2823
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[54] Organic and Biomolecular Chemistry, 2016, vol. 14, # 34, p. 8026 - 8029
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[64] Chemical Communications (Cambridge, United Kingdom), 2018, vol. 54, # 86, p. 12182 - 12185
3
[ 88-15-3 ]
[ 7789-45-9 ]
[ 10531-41-6 ]
Reference：
[1] Patent: US6121300, 2000, A,
[2] Patent: US4908357, 1990, A,
[3] Patent: US4024156, 1977, A,
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 25, p. 5140 - 5142
8
[ 88-15-3 ]
[ 506-68-3 ]
[ 10531-41-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1923, vol. 430, p. 104
[2] Justus Liebigs Annalen der Chemie, 1923, vol. 430, p. 104
9
[ 88-15-3 ]
[ 75-15-0 ]
[ 7726-95-6 ]
[ 10531-41-6 ]
Reference：
[1] Chemische Berichte, 1886, vol. 19, p. 2893
10
[ 10531-41-6 ]
[ 13669-05-1 ]
Yield
Reaction Conditions
Operation in experiment
51%
With titanium(IV) isopropylate; ethylmagnesium bromide In tetrahydrofuran; diethyl ether; water at 23℃; for 18 h; Inert atmosphere
General procedure: Ti(OiPr)4 (0.18 mL, 0.602 mmol) was added to a solution of 2-bromoacetophenone (4, 100. mg, 0.502 mmol) in THF (5 mL) atroom temperature. EtMgBr (0.47 mL, 1.41 mmol, 3 M in Et2O)was then added dropwise over 20 min during which the reactionmixture turned from clear to yellow to black. After 18 h,water (5 mL) was added, and the mixture was extracted EtOAc(3 × 5 mL). The combined organic layers were washed withbrine (1 × 10 mL), dried with MgSO4, and concentrated in vacuo.Purification by column chromatography (15percent EtOAc/hexanes)afforded 1,4-diketone 8 as a white powder (47 mg, 79percent).
With copper (II) bromide In ethyl acetate at 85℃; for 24h;
96%
With bromine In diethyl ether for 0.25h;
96%
With copper (II) bromide In chloroform; ethyl acetate for 4h; Heating;
95%
With N,N'-diacetylpiperazine hydrogen tribromide In methanol at 40℃;
92%
With bromine; glacial acetic acid at 20℃; for 8h;
88.21%
With bromine; glacial acetic acid at 20℃; for 3h; Heating;
83%
With tetra-N-butylammonium tribromide In methanol; dichloromethane at 20℃;
83%
Stage #1: 2-Acetylthiophene With [Hydroxy(tosyloxy)iodo]benzene for 0.025h; microwave irradiation;
Stage #2: With magnesium(II) bromide for 0.0333333h; microwave irradiation; Further stages.;
80%
With tetra-N-butylammonium tribromide In methanol; dichloromethane for 2h; Ambient temperature;
80%
Stage #1: 2-Acetylthiophene With bromine In dichloromethane at 25℃; for 1h;
Stage #2: With Sodium hydrogenocarbonate In dichloromethane; water monomer
1.12
Example 1.12: 2-Bromo-1 -(thiophene-2-yl)ethan-1-one.A solution of bromine (2.53 g, 0.82 mL, 0.0158 mol) in dichloromethane (8 mL) is drop wise added to a solution of 2- acethylthiophene (2.0 g, 1.71 ml_, 0.0158 mol) in same solvent (10 ml_). The reaction mixture is stirred at 25°C per 1 hour and then neutralized with sodium hydrogen carbonate saturated aqueous solution. The organic layer is washed with water and dried. After solvent removal the solid residue is purified by column chromatography (silica gel, ethyl acetate: n-hexane 5:95 as eluent) to give 2-bromo-1-(thiophen-2- yl)ethan-1-one as an oil (2.60 g, 80%). [Alternative preparation of 1- (thiophen-2-yl)ethan-1-one has been reported recently: Ostrowski, T.; Golankiewicz, B.; De Clercq, E.; Andrei, G.; Snoeck, R. Synthesis and anti-VZV activity of 6-heteroaryl derivatives of tricyclic acyclovir and 9- [cis-1 2'-bis(hydroxymethyl)cycloprop-1 '-yl]methyl}guanine analogues. Eur. J. Med. Chem. 2009, 44, 3313-3317].
80%
With bromine In dichloromethane at 25℃; for 1h;
80%
With copper (II) bromide In chloroform; ethyl acetate for 12.5h; Reflux;
78%
With bromine In benzene
61.1 1.
1. 2-Bromo-1-(2-thienyl)ethan-1-one To a stirred solution of 2-acetylthiophene (5.38 mL, 50 mmol) in benzene (100 mL) is added dropwise bromine (2.55 mL, 50 mmol). The reaction is stirred under nitrogen at room temperature overnight. The reaction mixture is washed three times with 2 M Na2CO3, dried over MgSO4, and concentrated to give a brown oil (8.0 g, 78% yield). MS-APCI: M+1=206.0.
77%
With NBS; toluene-4-sulfonic acid In water monomer; acetonitrile at 60℃; for 4h;
76%
With copper (II) bromide In ethyl acetate for 2h; Heating;
76%
With copper (II) bromide In ethyl acetate Heating;
73%
With Aluminum Chloride; bromine In tetrahydrofuran at 0℃;
73.6%
With bromine In dichloromethane at 25℃; for 2h; Inert atmosphere;
72%
With bromine In diethyl ether at 0℃; for 1.5h;
70%
With NBS; toluene-4-sulfonic acid In acetonitrile at 85℃; for 4h;
5.1-Aryl-2-bromoethanones (15a-i)
General procedure: A mixture of substituted arylethanones 14a-i (10 mmol), N-bromosuccinimide (1.4 g, 12 mmol) and p-toluenesulphonic acid (2.8 g, 15 mmol) in acetonitrile (50 mL) was stirred at 85 °C for 4 h. After completion of reaction (indicated by TLC), the reaction mass was allowed to reach ambient temperature and evaporated excess of acetonitrile under reduced pressure. The residue so obtained was mixed in water, extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuuo. The crude product obtained was recrystallized from n-hexane to afford pure 1-aryl-2-bromoethanones 15a-i in 75-85% yields.
57%
With hydrogen bromide; trimethylphenylammonium perbromide; glacial acetic acid at 20℃;
64.1 2-Bromo-1-(2-thiophenyl)ethanone
To a solution of 2-acetylthiophene (0.310 g, 2.46 mmol) in 33% of HBr in acetic acid (5.0 mL) was added phenyltrimethylammonium tribromide (0.970 g, 2.58 mmol) at room temperature. After the solution was stirred for overnight, it was poured into ice water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-40% CH2Cl2 in n-hexane) to give 2-bromo-1-(2-thiophenyl)ethanone (0.287 g, 57%) as a brown oil. 1H NMR (CDCl3, 400 MHz) δ 7.81 (d, 1H), 7.72 (d, 1H), 7.17 (dd, 1H), 4.36 (s, 2H).
53%
With hydrogen bromide; bromine In dichloromethane at 0 - 25℃; for 3h;
37%
With CH3COOH; hydrogen bromide; bromine In chloroform
15.a Synthesis of 5-methylthio-4(4(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidine acetate
a) Synthesis of 2-bromo-1-(2-thienyl)ethan-1-one: To a solution of 500 mg (3.96 mmol) of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved in 20 mL of CHCl3, was added 1 drop of 30% HBr/CH3COOH (Aldrich Chemical Co.) followed by 3.96 mmol (633 mg; 204 μL) of bromine (Aldrich Chemical Co.) added dropwise over 30 min. The reaction was allowed to stir for 1 h. The solution was concentrated to an oil and dried in vacuo. The crude product was purified on 1 mm silica prep plates eluding with neat CH2Cl2 to obtain 300 mg (37% yield) of 2-bromo-1-(2-thienyl)ethan-1-one. 1H-NMR (CDCl3; 300 MHz) δ7.8 (m, 2 H), 7.18 (m, 1 H), 4.37 (s, 2 H).
37%
With CH3COOH; hydrogen bromide; bromine In chloroform
15.a 5-Methylthio-4-(4-(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidine acetate
a) 2-Bromo-1-(2-thienyl)ethan-1-one To a solution of 500 mg (3.96 mmol) of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved in 20 mL of CHCl3, was added 1 drop of 30% HBr/CH3COOH (Aldrich Chemical Co.) followed by 3.96 mmol (633 mg; 204 μL) of bromine (Aldrich Chemical Co.) added dropwise over 30 min. The reaction was allowed to stir for 1 h. The solution was concentrated to an oil and dried in vacuo. The crude product was purified on 1 mm silica prep plates eluding with neat CH2Cl2 to obtain 300 mg (37% yield) of 2-bromo-1-(2-thienyl)ethan-1-one. 1H-NMR (CDCl3; 300 MHz) δ 7.80 (m, 2H), 7.18 (m, 1H), 4.37 (s, 2H).
35%
With bromine In diethyl ether at 0℃;
With Carbon tetrachloride; bromine; iron(0)
With diethyl ether; bromine
With bromine In chloroform for 0.25h; Ambient temperature;
With bromine In diethyl ether for 1.5h;
With bromine; iron(0) In Carbon tetrachloride at 60℃; for 3h;
With bromine In methanol at 20 - 25℃;
With bromine In glacial acetic acid for 3h;
With bromine In Carbon tetrachloride at 0 - 20℃;
With bromine
With bromine at 0 - 20℃;
With bromine In glacial acetic acid Inert atmosphere;
With hydrogen bromide; bromine In 1,4-dioxane; diethyl ether at 0℃;
With bromine In 1,4-dioxane; diethyl ether
With copper (II) bromide In chloroform; ethyl acetate
With Aluminum Chloride; bromine In diethyl ether at 0 - 20℃;
With copper(II) bromide In ethyl acetate Reflux;
With copper (II) bromide In ethanol; chloroform Inert atmosphere; Reflux;
With NBS; toluene-4-sulfonic acid In acetonitrile for 1h; Reflux;
2.5 Synthesis of starting material 4 (4a as an example):
General procedure: N-Bromobutanimide (NBS, 356 mg, 2.0 mmol) and 4-Methylbenzenesulfonic acid (PTSA, 344 mg, 2.0 mmol) were added to a well-stirred solution of aryl methyl ketone 8a (240 mg, 2.0 mmol) in anhydrous MeCN (15 mL). The mixture was stirred at room temperature for 1 h, and then refluxed for another 1-2.5 h. After disappearance of aryl methyl ketone 8a (monitored by TLC), the solvent was removed under reduced pressure, then added 50mL water to the mixture, extracted with EtOAc 3 times (3 × 50 mL). The extract was washed with 10% NaCl solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was puried by column chromatography on silica gel to yield the desired product 4a as a white solid in 90% yield.
With bromine In ethyl acetate at 20℃; Inert atmosphere;
With bromine In diethyl ether Inert atmosphere;
With copper (II) bromide In chloroform; ethyl acetate for 8h; Reflux;
14 g
With bromine In methanol at 0 - 20℃; for 2.5h;
38.1 Step 1 : Synthesis of 2-bromo- 1 -(thiophen-2-yl)ethan- 1 -one:
Step 1 : Synthesis of 2-bromo- 1 -(thiophen-2-yl)ethan- 1 -one: [0257] To the stirred solution of l-(thiophen-2-yl)ethan-l-one (10 g, 68.9 mmol) in 110 ml of MeOH at 0°C was added Bromine (2.8 ml, 17.7 mmol) (dropwise addition), stirred for about 30 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The obtained solid was filtered and washed with n-hexane then dried and proceeded for next step (wt: 14. Og).
With copper (II) bromide In ethyl acetate at 60℃;
12 4.1.4. General procedure B: preparation of ketones brominated using copper (II) bromide
General procedure: The ketones were brominated by adding CuBr2 (1.2 eq) in ethylacetate (EtOAc) (1 ml) at T = 60 °C to a 1 eq of the appropriate ketone monitoring the reaction with HPLC-MS. At the end of the reaction the mixture were washed with water (3 x 2 ml), dried over Na2SO4 and the organic phase was concentrated under vacuum. The dry organic phases were controlled by HPLC and ESI-MS in order to verify the presence of expected products. These bromoketones intermediates were obtained in 80-90% overall yield, with purities generally >90% as determined by HPLC-MS.
With copper (II) bromide In chloroform; ethyl acetate Reflux;
Substituted 2-bromo-1-arylethanone 7a-o
General procedure: Substituted 2-bromo-1-arylethanone 7a-o A solution of the appropriate ketone 3a-o (25 mmol) in hot chloroform (25 mL) was added to a preheated, stirred suspension of copper (II) bromide (50 mmol) in ethyl acetate (25 mL). The resulting reaction mixture was refluxed with vigorous stirring till completion of the reaction which detected by TLC monitoring. The reaction mixture was filtered while hot to remove copper (I) bromide then concentrated under reduced pressure. After cooling, the separated solid was filtered, washed with petroleum ether and dried to give compounds 7a-o [49] .
With copper (II) bromide In chloroform; ethyl acetate
Synthesis of Hydrazones 23a-g
General procedure: To a stirred solutionof the appropriate 2-oxo-N-(4-substitutedphenyl)-propanehydrazonoyl chloride 16a-e, i, j (5 mmol) in THF(20 mL), thiophene-2-carbohydrazide 12 (5 mmol) was added.The reaction mixture was heated under reflux for 10 h. Thesolid product obtained upon cooling was filtered off and recrystallizedfrom dioxan to afford the corresponding hydrazones23a-g with 65-80% yield. (1Z,2E)-N-Phenyl-2-(2-(thiophene-2-carbonyl)hydrazono)propanehydrazonoyl Chloride (23a) Yellow powder(yield 75%), mp 220°C; IR (KBr, ν cm-1): 3414, 3325 (2NH),1636 (C=O) and 1598 (C=N); 1H-NMR (DMSO-d6) δ ppm:2.38 (s, 3H, CH3), 6.93-7.95 (m, 8H, ArH), 10.18 (s, D2O exch.,1H, =NNH-), 11.00 (s, D2O exch., 1H, -CONH-); 13C-NMR(DSMO-d6) δ ppm: 13.95, 114.31 (2C), 121.65, 123.81, 127.63,129.62, 134.56 (2C), 135.32, 143.96, 152.00; MS m/z [%]: 322[(M+2)+, 3.7], 320 [M+, 9.5], 284 [100].
With copper (II) bromide In chloroform; ethyl acetate for 6h;
With bromine In diethyl ether
With copper (II) bromide In chloroform; ethyl acetate for 2h; Reflux;
With copper (II) bromide In chloroform; ethyl acetate at 90℃; for 3h;
A 100mL single-mouth flask, equipped with a reflux condenser, was added cupric bromide (8.934g, 40mmol), 2-acetylthiophene (2.523g, 20mmol).Add chloroform 10mL, ethyl acetate 10mL. Move to an oil bath at 90 deg.C and react for 3H; cooled to room temperature, the solid was filtered to give a liquid after spin dry column to give α-bromo-2-acetylthiophene.
With copper (II) bromide In ethyl acetate at 100℃; for 1h; Reflux;
With bromine In chloroform at 0 - 25℃; for 6h; Inert atmosphere;
With copper (II) bromide In ethanol at 60℃;
With bromine In dichloromethane at 20℃;
With NBS In water monomer at 80℃; for 0.5h; Green chemistry;
A. General Procedure for the Synthesis of imidazo[1,2-a]pyridine/imidazo[1,2-a]pyrimidine/imidazo[2,1-b]thiazole (3)
General procedure: To a round bottom flask containing 1,3-diketones/β-keto esters/aryl ketones (1.05 mmol) and water (5 mL) was added NBS (1.2 mmol) and mixture was allowed to stir at 80 °C for 30 min. Subsequently, 2-aminopyridine/2-aminopyrimidine/2-aminothiazole (1.0 mmol) was added and reaction mixture was further heated to 80 °C for 30 min. After completion of reaction (checked by TLC), it was allowed to cool to room temperature and then the mixture was poured into 10 mL of sodium carbonate solution. The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with water, saturated brine solution, dried over anhydrous Na2SO4 and concentrated in vaccuo. The resulting crude product was purified by silica gel column chromatography with petroleum ether-ethyl acetate to give corresponding imidazo[1,2-a]pyridine/imidazo[1,2-a]pyrimidine/imidazo[2,1-b]thiazole.
With NBS; citric acid In ethanol; water monomer for 0.666667h; Reflux;
With copper (II) bromide In ethyl acetate for 12h; Reflux;
General procedure: In the synthesis process, different 1-(aryl/heteroaryl)ethanone(50 mmol) derivatives were brominated in the presence of copper(II) bromide (100 mmol) followed by a reaction with equimolarpyrimidine-2-carbothioamide (50 mmol). In the course of the reaction,the components were mixed in ethanol acetate for approximately1 h in room temperature and then refluxed at 77-78 Cfor 15-20 min. After cooling, the precipitate was filtered, neutralizedwith sodium acetate, and recovered from the HBr salt. Allthe synthesized compounds were purified twice by crystallizationfrom ethanol. Pyrimidine-2-carbonitrile and phosphorus pentasulfidewere mixed in dioxane for 48 h to obtain pyrimidine-2-carbothioamideas the starting material. This is the first time in theliterature that synthesis of pyrimidine thioamides has been undertakenwith this method
With tetra-N-butylammonium tribromide In tert-Amyl alcohol at 20℃;
With bromine In diethyl ether at 0 - 20℃;
With bromine In chloroform at 20℃; for 1h; Cooling with ice;
19.1 (1) Synthesis of 2-bromo-1-(thiophen-2-yl)ethan-1-one
2-acetylthiophene(1.26 g, 10 mmol) dissolved in 100 ml of chloroform,Br2 (1.91 g, 12 mmol) was slowly added dropwise under ice bath, and the mixture was stirred at room temperature for 1 h.After the reaction, the reaction was quenched with saturated sodium sulfite and the organic layer was washed with saturated sodium hydrogen sulfate and brine.After dried over anhydrous sodium sulfate, the solvent was removed in vacuo to give a crude product 2.05g.
With hydrogen bromide; dimethyl sulfoxide In ethyl acetate at 60℃; for 6h;
Experimental Section for Products 3
General procedure: General procedure for products 3: ketone 1 (0.3 mmol), HBr (0.36 mmol), DMSO (0.36 mmol) and EtOAc (1.5 mL) were added to a 25 mL tube with magnetic stirrer bar. The reaction mixture was stirred at 60°C (oil bath temperature) for 6 h, then added sodium sulfinates (0.6 mmol) and (HOCH2)2 (1.0 mL) to continue the reaction at 80 oC for 17 h. After the reaction was finished (monitored by TLC), the mixture was cooled to room temperature, quenched with solution of NaHCO3 (10 mL) and extracted with EtOAc (3 10 mL). The combined organic layers were dried over anhydrous MgSO4 and the solvent was removed under vacuum. The crude product was purified by column chromatography (EtOAc/hexanes) on silica gel.
With bromine In diethyl ether at 20℃; for 12h;
1.1. General procedure for the synthesis of 1a
General procedure: Bromine (20.0 mmol, 1.0 eq) was added dropwise to a solution of ketone (20.0 mmol, 1.0 equiv.) in Et2O (30 mL). The reaction mixture was stirred at room temperature for 12 h. A saturated sodium thiosulfate solution (70 mL) was added and stirred for 30 min. The organic layer was washed by saturated NaHCO3 solution (30 mL × 3) and dried over with anhydrous Na2SO4. After evaporation, the resulting residue was subjected to column chromatography (hexane:EtOAc = 15:1) to get the substituted methyl bromide.1 A mixture of 1H-pyrrole-2-carboxaldehyde (5.0 mmol, 1.0 equiv.), substituted methyl bromide (5.5 mmol, 1.1 equiv.) and K2CO3 (6.0 mmol, 1.2 equiv.) was stirred in CH3CN (40 mL) at room temperature. After being stirred for 12 h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc (30 mL), and washed with H2O (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL) one more time. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane:EtOAc = 10:1) to afford 1a as white solid.2
With copper (II) bromide In chloroform; ethyl acetate for 2h; Reflux;
With NBS; toluene-4-sulfonic acid In methanol Reflux;
With copper (II) bromide In ethyl acetate Reflux;
With NBS; toluene-4-sulfonic acid In acetonitrile at 60℃; for 4h;
With copper (II) bromide In chloroform; ethyl acetate Reflux;
With tetrabutylammonium bromide; bromine In ethyl acetate at 37 - 43℃; for 1h;
Synthesis of Compound 13
10.0 g of 2-acetylthiophene was dissolved in 71 g of ethyl acetate, 5.0 g of tetrabutylammonium bromide was added thereto, and the solution was heated until the internal temperature reached 37° C. to 43° C. After the internal temperature was maintained at 37° C. to 43° C. and 15 g of bromine was added dropwise to the reaction system, the solution was stirred at the same temperature for 1 hour. Next, 6 g of thiourea and 60 g of water were added thereto. After the resulting solution was stirred at an internal temperature of 37° C. to 43° C. for 1 hour, the solution was air-cooled and stirred until the internal temperature reached 30° C. or lower. After the solid in the reaction solution was collected by filtration, the obtained solid was washed with ethyl acetate and dried, thereby obtaining 16.2 g of a compound F as a brown solid.
With NBS; toluene-4-sulfonic acid In acetonitrile at 90℃;
With NBS; toluene-4-sulfonic acid In acetonitrile at 50℃; for 24h; Inert atmosphere;
With bromine In dichloromethane at 0 - 20℃; for 2h;
Stage #1: 2-Acetylthiophene With copper(II) bromide In ethyl acetate Inert atmosphere;
Stage #2:
With copper (II) bromide In ethyl acetate for 5h; Schlenk technique; Inert atmosphere; Reflux;
Stage #1: 2-Acetylthiophene With toluene-4-sulfonic acid In ethyl acetate for 0.166667h; Inert atmosphere;
Stage #2: With NBS In ethyl acetate at 25℃; for 24h; Inert atmosphere;
With copper (II) bromide In ethyl acetate at 20℃;
With bromine In diethyl ether at 20℃; Inert atmosphere;
With copper (II) bromide at 60℃; for 24h;
With NBS; toluene-4-sulfonic acid In dichloromethane for 12h; Reflux;
17 Example 17 Synthesis of 4-((3,5-Dimethylisoxazol-4-yl)methoxy)-N-(4-(thiophen-2-yl)-1H-imidazol-2-yl)benzamide
2-Acetylthiophene and TsOH (0.1 eq) were dissolved in dichloromethane, stirred at room temperature, NBS (1.0 eq) was added in portions,Heating to reflux, after 12h, TLC detected that the reaction was complete,The reaction solution changed from pale yellow to reddish brown.After cooling to room temperature, add an appropriate amount of saturated brine to wash,Extracted with dichloromethane, dried over anhydrous sodium sulfate,The solvent was evaporated under reduced pressure, and the residue was separated by column chromatography to give 2 as a brown-red oil.Dissolve oil 2 in DMF,3a (1-acetylguanidine, 3.0 eq) was added to the stirred solution, and the temperature was raised to 60°C and stirred.After 12h, the TLC detection reaction was complete,The reaction solution turned from pale yellow to reddish brown.After cooling, the DMF was washed with a large amount of saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The residue was separated by column chromatography to give a pale yellow solid.The isolated pale yellow solid was dissolved in methanol,To the stirred mixture was added 8M HCl and heated to reflux.After 4h, TLC detected that the reaction was complete, cooled to room temperature,6M NaOH adjusts the pH value of the solution to 10, extracts with ethyl acetate,Dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure,The residue was separated by column chromatography to obtain pale yellow solid 4'a in a yield of 37%.
With copper (II) bromide In ethyl acetate at 100℃; for 1h;
Reflux;
In ethanol for 2h; Reflux;
With triethylamine In ethanol at 20℃; for 3h; Reflux;
General procedure of synthesis of 2-aminothiazolederivatives 3-6
General procedure: The mixture of phenacyl bromide derivatives 1 (0.1 mol) and thiourea 2 (0.11 mol) in anhydrous ethanol (100 ml) was heated at reflux for 3 h in presence of drops of trimethylamine (TEA). After that, the solvent was removed and a saturated aqueous NaHCO3 was added to adjust the pH to about 8-9. Then, the mixture was filtered to afford 3-6 as a white solids.
With triethylamine In ethanol at 20℃; for 3h; Reflux;
General procedure of synthesis of 2-aminothiazolederivatives 3-6
General procedure: The mixture of phenacyl bromide derivatives 1 (0.1 mol) and thiourea 2 (0.11 mol) in anhydrous ethanol (100 ml) was heated at reflux for 3 h in presence of drops of trimethylamine (TEA). After that, the solvent was removed and a saturated aqueous NaHCO3 was added to adjust the pH to about 8-9. Then, the mixture was filtered to afford 3-6 as a white solids.
With lithium hydroxide monohydrate; triphenylantimony at 120℃; for 0.166667h; Microwave irradiation;
69%
With diethyl ether In lithium hydroxide monohydrate at 20℃; for 17h; Schlenk technique; Irradiation;
3. General procedure for the reaction of reductive dehalogenation
General procedure: To a 10 mL schlenk tube, 1 (0.2 mmol), H2O (1.6 mmol) and Et2O (4 mL) were added in sequence. The reaction mixture was stirred and irradiated by 40 W Kessil purple LED (390 nm) at room temperature . After the reaction was completed, the reaction mixture was purified by flash column chromatography using PE/EtOAc as the eluent to give the desired product.
Multi-step reaction with 2 steps
1: 75 percent / ethanol / 1 h / Heating
2: 8 percent / diethyl ether; tetrahydrofuran / 6 h / Irradiation
Multi-step reaction with 2 steps
1: N,N,N-tributyl-1-butanaminium iodide; potassium carbonate / dichloromethane; lithium hydroxide monohydrate / 20 °C
2: bis[(2,2,2-trifluoroacetyl)oxy]palladium; 5,5'-bis[di(3,5-di-t-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole; hydrogen / propan-2-one / 24 h / 20 °C / 22502.3 Torr / Glovebox; Autoclave
With potassium carbonate In acetone at 20℃; for 1.5h; Heating / reflux;
41.A Example 41 (General procedure (A)); (E/Z)- [4- [3- (5-BROMOBENZO [b] FURAN-2-YL)-3- (THIOPHEN-2-YL) ALLYLSULFANYL]-2-METHYLPHENOXY]- acetic acid
Potassium carbonate (12.0 g, 0.087 mol) and subsequently 2-BROMO-1- (THIOPHEN-2- YL) ethanone (7.0 g, 0.034 mol ; prepared as described in J. Med. Chem. 30, 1497 (1987) ) were added to a stirred solution of 5-BROMOSALICYLALDEHYDE (6.9 G, 0. 034 mol) in acetone (150 mL). The mixture was stirred at ambient temperature for 30 min at first and then refluxed for 1 h. Solid mass was filtered off, washed with hot acetone (2X50 mL) and the filtrate was evapo- rated in vacuo. The residue (11.3 G) was crystallized from ethanol (15 mL) giving (5-bromo- benzo [b] FURAN-2-YL)- (THIOPHEN-2-YL) methanone. Yield : 8.0 G (77%). M. p. 84-86 °C. RF (SI02, hexane/ethyl acetate 3: 1) 0.70.
77%
With potassium carbonate In acetone at 20℃; for 1.5h; Heating / reflux;
41
Potassium carbonate (12.0 g, 0.087 mol) and subsequently 2-bromo-1-(thiophen-2-yl)ethanone (7.0 g, 0.034 mol; prepared as described in J.Med.Chem. 30, 1497 (1987)) were added to a stirred solution of 5-bromosalicylaldehyde (6.9 g, 0.034 mol) in acetone (150 mL). The mixture was stirred at ambient temperature for 30 min at first and then refluxed for 1 h. Solid mass was filtered off, washed with hot acetone (2×50 mL) and the filtrate was evaporated in vacuo. The residue (11.3 g) was crystallized from ethanol (15 mL) giving (5-bromo-benzo[b]furan-2-yl)-(thiophen-2-yl)methanone. Yield: 8.0 g (77%). M.p. 84-86° C. RF (SiO2, hexane/ethyl acetate 3:1) 0.70
77%
With potassium carbonate In acetone at 20℃; for 1.5h; Heating / reflux;
4.A Example 4; General Procedure (A); (E/Z)-[2-Methyl-4-[3-[5-(5-methylthiophen-2-yl)benzo[b]furan-2-yl]-3-(thiophen-2-yl)allylsulfanyl]phenoxy]acetic Acid
Potassium carbonate (12.0 g, 0.087 mol) and subsequently 2-bromo-1-(thiophen-2-yl)ethanone (7.0 g, 0.034 mol; prepared as described in J.Med.Chem. 30, 1497 (1987)) were added to a stirred solution of 5-bromosalicylaldehyde (6.9 g, 0.034 mol) in acetone (150 mL). The mixture was stirred at ambient temperature for 30 min at first and then refluxed for 1 h. Solid mass was filtered off, washed with hot acetone (2×50 mL) and the filtrate was evaporated in vacuo. The residue (11.3 g) was crystallized from ethanol (15 mL) giving (5-bromobenzo[b]furan-2-yl)-(thiophen-2-yl)methanone. Yield: 8.0 g (77%). M.p. 84-86° C. RF (SiO2, hexane/ethyl acetate 3:1) 0.70.
77%
With potassium carbonate In acetone at 20℃; for 1.5h; Heating / reflux;
4.A Example 4; (General procedure (A)); (E/Z)- [2-METHYL-4- [3- [5- (5-METHYLTHIOPHEN-2-YL) benzo [b] furan-2-yl]-3- (thiophen-2-yl) ally- ISULFANYL] phenoxy] acetic acid
Potassium carbonate (12.0 g, 0.087 mol) and subsequently 2-BROMO-1- (THIOPHEN-2- YL) ethanone (7.0 g, 0.034 mol ; prepared as described in J. Med. Chem. 30,1497 (1987) ) were added to a stirred solution of 5-bromosalicylaldehyde (6.9 g, 0.034 mol) in acetone (150 mL). The mixture was stirred at ambient temperature for 30 min at first and then refluxed for 1 h. Solid mass was filtered off, washed with hot acetone (2X50 mL) and the filtrate was evapo- rated in vacuo. The residue (11.3 g) was crystallized from ethanol (15 mL) giving (5- bromobenzo [b] FURAN-2-YL)- (THIOPHEN-2-YL) methanone. Yield : 8.0 g (77%). M. p. 84-86 °C. RF (SI02, HEXANE/ETHYL acetate 3: 1) 0.70.
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a stirred suspension of (4-chlorophenyl) (4-piperidyl) methanone hydrochloride [(100MG,] 0.41mmol) in DCM [(5ML)] was added triethylamine (104mg, 1. [03MMOL)] and 2- [BROMO-L- (2-THIENYL)-L-ETHANONE] (76mg, 0. [37MMOL).] The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was transferred to a separating funnel and washed with 2M hydrochloric acid. The organic layer was separated and washed with water then evaporated to yield an impure solid. This material was partitioned between DCM and saturated sodium hydrogencarbonate solution. The organic layer was separated and washed with brine then dried [(MGS04),] filtered and evaporated to give a solid. This solid was dissolved in ether and treated with hydrochloric acid in ether. The resulting solid was filtered off to yield the product as a solid (24mg, 17%). NMR (DMSO-d6): 2.00 [(M,] 4H), 3.20 [(M,] 2H), 3.50 [(M,] 1H), 3.60 [(M,] 2H), 5.00 (s, 2H), 7.35 (s, 1H), 7.60 (d, 2H), 8.05 (d, 2H), 8.10 (s, 1H), 8.20 (d, [1H),] 10.20 (br s, 1H) ; m/z: 348.
1.A Method A
Method A A mixture of 5-chloropyrimidin-2-one hydrochloride (0.668 g) and 2-bromoacetylthiophene (0.820 g) in ethanol (25 ml) was treated at room temperature with triethylamine (1.3 ml). After stirring at room temperature for 6 days the reaction mixture was cooled in an ice-bath and the precipitate was collected, washed with cold ethanol and dried to give an off white crystalline solid (0.536 g). The solid was crystallized once from acetone and then once from ethanol to give colourless needles of the title pyrimidinone (0.207 g). m.p. 209°-211° C. (Kofler), λmax (EtOH) 226 nm (ε 9,530), 260 nm (ε 8,430), 288 nm (ε 6,830).
EXAMPLE 6 5-Fluoro-1-(2-thenoylmethyl)pyrimidin-2-one A mixture of <strong>[2022-78-8]5-fluoropyrimidin-2-one</strong> (456 mg) and 2-bromoacetylthiophene (820 mg) in triethylamine (1.33 ml) and ethanol (25 ml) was stirred at room temperature. After 2.5 h. the reaction mixture was concentrated to ca. 5 ml, diluted with ethyl acetate (300 ml) washed with water (3*50 ml), dried (MgSO4) and evaporated to a foam. This was crystallized from acetone to give the title pyrimidinone (225 mg), m.p. 183-190 C. (dec) lambdamax (EtOH) 260 nm (epsilon10,308), 285.5 nm (epsilon 8,430).
Intermediate 17: (+/-V1-r3-Methyl-6-(2-thienvnimidazor2.1-biϖ .3lthiazol-2-yllethanolA solution of 2-bromo-1-(2-thienyl)ethanone (commercially available from Acros Organics) (0.820 g, 4 mmol) in ethanol (12 ml) was added to 1-(2-amino-4-methyl- 1 ,3-thiazol-5-yl)ethanone (commercially available from Aldrich) (0.625 g, 4.00 mmol). The reaction mixture was heated at reflux over night. 1-Butanol (5 ml) was added and the reaction mixture was stirred at reflux for 2 days. The mixture was evaporated under vacuum. Ethanol (25ml) followed by NaBH4 (197 mg, 5.20 mmol) were added and the reaction mixture was stirred at room temperature over night. Water (2ml) was added and the solvent removed under vacuum to obtain a solid which was dissolved <n="41"/>in 50% MeOH/DCM. The MeOH/DCM solution was loaded onto a SCX-2 cartridge. The cartridge was washed with MeOH (40ml) then eluted with a solution of NI-13/MeOH (0.5M) (60ml). The eluant was evaporated to dryness and the residue was purified by MDAP to give the title compound (1 1 mg); MS: ES+ m/z: 265 [MH+] at RT 2.6 min. Ci2H12N2OS2 requires 264 (analysed by LCMS A).
With toluene-4-sulfonic acid; In toluene; at 130℃;Product distribution / selectivity;
Example 23; Synthesis of (4S)-trans-,cis-2-(4-chlorophenyl)-2-bromomethyl-4-chloromethyl-1,3-dioxolane suppressing halogen exchange between substrates A mixture of 2-bromo-4'-chloroacetophenone (4.94 g, 2-chloro-4'-chloroacetophenone content=0.09%), p-toluenesulfonic acid monohydrate (0.20 g, 0.05 equivalent) and toluene (100 mL) was refluxed at 130C using an azeotropic distillation device with a Dean-Stark tube, and (S)-monochlorohydrin (2.59 g, 1.1 equivalents, >99%ee) was added dropwise under reflux such that the amount of the (S)-monochlorohydrin present in the reaction solution would be not more than 0.1 equivalent (not more than 2.1 mmol) relative to the amount of 2-bromo-4'-chloroacetophenone to be used (21.2 mmol), while analyzing the progress of the reaction by GC. After confirmation of the completion of the azeotropic distillation, the reaction mixture was cooled and washed with 10% aqueous sodium hydrogen carbonate solution and 10% brine. The solvent was evaporated under reduced pressure to give (4S)-trans-,cis-2-(4-chlorophenyl)-2-bromomethyl-4-chloromethyl-1,3-dioxolane (6.56 g, >99%ee). Here, the content percentage of (4S)-trans-,cis-2-(4-chlorophenyl)-2-chloromethyl-4-chloromethyl-1,3-dioxolane halogen-exchanged with a chlorine atom was 0.09%. Examples 30 to 41 Synthesis of (4S)-trans-cis-2-aryl-2-bromomethyl-4-chloromethyl-1,3-dioxolane suppressing halogen exchange In Examples 30 to 41, reactions were performed according to Example 23 and using aryl(bromomethyl)ketones (halogen-exchanged compound content<0.1%) shown in Table 7 and Table 8. The results are shown in Table 9 and Table 10 together with Example 23.
Stage #1: 2-Bromoacetylthiophene; aniline at 25℃; for 3h;
Stage #2: at 25 - 100℃; for 0.0333333h; Microwave irradiation;
1.13
Example 1.13: 2-(Thiophen-2-yl)-1H-indole.A mixture of 2-bromo-1-(thiophen-2-yl)ethan-1-one (0.5 g, 0.0024 mol) and aniline (0.4 g, 0.4 ml_, 0.0041 mol) is maintained at 25°C under occasional stirring for 3 hours. After the addition of a catalytic amount of DMF, the reaction mixture is microwave irradiated at 150 W (closed vessel mode, Pmax = 250 PSI). The temperature is increased from 25°C to 100°C under stirring in 1 min, then the temperature is maintained for one further minute. After cooling the mixture is diluted with 1 N HCI and extracted with ethyl acetate. The organic layer is washed with water and dried. After solvent removal the solid residue is purified by column chromatography (silica gel, ethyl acetate: n-hexane 3:7 as eluent) to give 2-(thiophen-2-yl)-1H-indole (0.19 g, 40%), melting point 175-180°C (after cyclohexane crystallization). [2-(Thiophen-2-yl)- 1 /-/-indole is prepared according to a different procedure according to: Hudkins, R. L; Diebold, J. L; Marsh, F. D. Synthesis of 2-aryl- and 2- vinyl-1 /-/-indoles via palladium-catalyzed cross-coupling of aryl and vinyl halides with 1-carboxy-2-(tributylstannyl)indole. J. Org. Chem. 1995, 60, 6218-6220, melting point 167-168°C (da hexane)].
40%
In N,N-dimethyl-formamide at 25 - 100℃; for 3h; Microwave irradiation;
3-(2-oxo-2-(thiophen-2-yl)ethyl)-6-propylthieno[2,3-d]pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With triethylamine In acetone at 0 - 20℃; for 4h;
Stage #1: 6-(n-propyl)thieno[2,3-d]pyrimidin-4(3H)-one With potassium carbonate at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: 2-Bromoacetylthiophene at 20℃; for 12h; Inert atmosphere;
With caesium carbonate In acetonitrile at 20℃; for 4h; Inert atmosphere;
General Procedure for S-Alkylation
General procedure: To a 1 dram vial was added 8 (1.0 eq.), CH3CN (0.2 M), alkyl halide (1.3 eq.), and Cs2CO3 (1.5 eq.), andfollowing brief sonication to homogenize the slurry, the reaction was stirred at rt for 4 h. To the slurrywas added cold water, and in the event of product precipitation, the precipitate was collected by filtrationand washed with ice water and cold CH3CN. In the absence of precipitation, the mixture was added tosaturated NH4Cl and extracted 3 x with CH2Cl2. The combined organic layers were dried with MgSO4,filtered, and concentrated. Products were recrystallized from CH3CN.
N-(2,6-dimethylphenyl)-4-(thiophen-2-yl)-1,3-thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In ethanol; at 70℃; for 2h;
General procedure: Compounds 17-29and 43-61 were prepared following this general protocol unless otherwise noted. To substituted2-bromoethanone in ethanol was added substituted thiourea (1.02 eq). The mixture wasstirred at 70C. The reaction was monitored via LC/MS. After 2 h, the reaction mixture wascooled to room temperature and precipitate was formed. The precipitate was collected by vacuumfiltration and washed with acetone. The solid was dissolved in 2 MNaOH (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 andconcentrated in vacuo desired product.
4,6-dimethyl-2-[2-oxo-2-(thiophen-2-yl)ethyl]sulfanyl}pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium hydroxide In water; N,N-dimethyl-formamide for 4h;
Alkylation of compound 4
General procedure: To a mixture of 1.64 g (10 mmol) of compound 4 and 15 mL of DMF we added under stirring in succession 5.6 mL (10 mmol) of 10% aqueous KOH and 10 mmol of alkylating agent 5a-5n or 7. The mixture was stirred for 4 h and diluted with an equal volume of water, and the precipitate of 6a-6n or 8 was filtered off, and washed with water, ethanol, and hexane.
2-(2-oxo-2-(thiophen-2-yl)ethyl)-9H-pyrido[3,4-b]indol-2-ium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In ethanol at 80℃; Microwave irradiation;
6. β-Carbolinium bromides (16a-t)
General procedure: β-Carboline 12 or 13 (0.1 g, 0.6 mmol), 1-aryl-2-bromoethanone 15 (0.72 mmol) and ethanol (3 mL) were taken in 10 mL microwave (MW) vial. The resulting mixture was irradiated in focused MW oven for 20 min at 80 °C. Upon completion of reaction as indicated by TLC, ethanol was evaporated in vaccuo and the residue so obtained was precipitated with ethyl acetate. The obtained solid was filtered and washed with ethyl acetate (2 x 10 mL) to afford 16a-t in 75-92% yields.
2-((4-methylpyrimidin-2-yl)thio)-1-(thiophen-2-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: Sodium carbonate (0.108 g, 1.02 mmol) was added to a solution of 2-mercaptopyridine (0.078 g, 0.680 mmol) in a mixture of ethanol (11 mL) and water (11 mL). The reaction mixture was stirred at room temperature for 30 minutes then bromoacetyl furazan (0.150 g, 0.680 mmol) was added and the reaction stirred at room temperature for 1.5-2 hours. 1M Hydrochloric acid (23 mL) was added and the reaction extracted with ethyl acetate (3 x 20 mL). The organic layer was dried with magnesium sulfate and concentrated via rotary evaporation. The crude product was purified by column chromatography (silica; 5:95 ethyl acetate/hexanes elution increasing to 50:50) to yield compound 3
4-(thiophen-2-yl)-2-(pyrimidine-2-yl)thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In ethanol at 20 - 78℃;
17 General procedure for the synthesis of 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole (1-21)
General procedure: In the synthesis process, different 1-(aryl/heteroaryl)ethanone(50 mmol) derivatives were brominated in the presence of copper(II) bromide (100 mmol) followed by a reaction with equimolarpyrimidine-2-carbothioamide (50 mmol). In the course of the reaction,the components were mixed in ethanol acetate for approximately1 h in room temperature and then refluxed at 77-78 Cfor 15-20 min. After cooling, the precipitate was filtered, neutralizedwith sodium acetate, and recovered from the HBr salt. Allthe synthesized compounds were purified twice by crystallizationfrom ethanol. Pyrimidine-2-carbonitrile and phosphorus pentasulfidewere mixed in dioxane for 48 h to obtain pyrimidine-2-carbothioamideas the starting material. This is the first time in theliterature that synthesis of pyrimidine thioamides has been undertakenwith this method.
With titanium(IV) isopropylate; ethylmagnesium bromide; In tetrahydrofuran; diethyl ether; water; at 23℃; for 18h;Inert atmosphere;
General procedure: Ti(OiPr)4 (0.18 mL, 0.602 mmol) was added to a solution of 2-bromoacetophenone (4, 100. mg, 0.502 mmol) in THF (5 mL) atroom temperature. EtMgBr (0.47 mL, 1.41 mmol, 3 M in Et2O)was then added dropwise over 20 min during which the reactionmixture turned from clear to yellow to black. After 18 h,water (5 mL) was added, and the mixture was extracted EtOAc(3 × 5 mL). The combined organic layers were washed withbrine (1 × 10 mL), dried with MgSO4, and concentrated in vacuo.Purification by column chromatography (15% EtOAc/hexanes)afforded 1,4-diketone 8 as a white powder (47 mg, 79%).
2-oxo-2-(2-thienyl)ethyl (S)-2-(benzyloxycarbonylamino)-3-cyclohexylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
General procedure: (S)-2-(Benzyloxycarbonylamino)-3-cyclohexylpropanoic acid (1; 3.05g, 10 mmol) or (R)-2-(benzyloxycarbonylamino)-3-cyclohexylpropanoicacid (2; 3.05 g, 10 mmol) was dissolved in anhydrous DMF (25mL) and K2CO3 (1.66 g, 12 mmol) was added. After 10 min of stirringat room temperature, the respective alkylating agent was added (11mmol) and the reaction mixture was stirred at room temperature fora further 4 h. The mixture was then diluted with H2O (60 mL) and extractedwith EtOAc (120 mL). The organic layer was dried usingNa2SO4, filtered, and evaporated to dryness. The residue was purifiedby column chromatography on silica gel.
2-[5-chloro-2-(methylaminosulfonyl)phenyl]sulfanyl}-1-(thiophen-2-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
Stage #1: 4-chloro-N-methylbenzenesulfonamide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.666667h;
Stage #2: 2-Bromoacetylthiophene With sulfur In tetrahydrofuran; hexane at 0℃; for 0.166667h;
Typical Procedure for the Preparation of o-[(Aroylmethyl)sulfanyl]benzenesulfonamides (2) and Related Compounds (4)
General procedure: 2-[2-(Methylaminosulfonyl)phenyl]sulfanyl}-1-phenylethanone (2a). To a stirred solution of 1a (0.34 g, 2.0 mmol) in THF (7 mL) at 0 °C was added n-BuLi (1.6 M in hexane; 4.0 mmol) dropwise. After 40 min, a solution of sulfur (S8) (64 mg, 0.25 mmol) in THF (10 mmol) and PhCOCH2Br (0.40 g, 2.0 mmol) were successively added, and stirring was continued for 10 min. Saturated aqueous NH4Cl (30 mL) was added and the mixture was extracted with AcOEt (3 × 15 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on SiO2 (Et2O/hexane 3:1) to afford 2a (0.36 g, 56%)
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