* 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] Synthetic Communications, 1984, vol. 14, # 1, p. 1 - 10
[2] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
[3] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
[4] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
2
[ 88-13-1 ]
[ 1641-09-4 ]
Reference：
[1] Patent: CN104557357, 2018, B,
3
[ 17249-80-8 ]
[ 201230-82-2 ]
[ 22913-26-4 ]
[ 88-13-1 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
4
[ 872-31-1 ]
[ 201230-82-2 ]
[ 22913-26-4 ]
[ 88-13-1 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
5
[ 67-56-1 ]
[ 88-13-1 ]
[ 22913-26-4 ]
Yield
Reaction Conditions
Operation in experiment
81%
for 24 h; Heating / reflux
To a solution of 3-thiophene carboxylic acid (2.Og, 15.60mmol) in methanol (30ml) was added a catalytic amount of sulphuric acid (0.5ml) and the reaction mixture was heated to reflux for 2 hr. The solvent was removed under reduced pressure and the residue was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, concentrated and dried to give 3-thiophene carboxylic acid methyl ester (1.8g, 81percent).
Reference：
[1] Patent: WO2006/123145, 2006, A1, . Location in patent: Page/Page column 44
[2] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 643,648[3] Recueil des Travaux Chimiques des Pays-Bas, 1936, vol. 55, p. 991
[4] Patent: WO2016/115013, 2016, A1, . Location in patent: Page/Page column 70
[5] Patent: WO2006/108701, 2006, A1, . Location in patent: Page/Page column 61
6
[ 186581-53-3 ]
[ 88-13-1 ]
[ 22913-26-4 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6931 - 6937
[2] Bioscience, Biotechnology, and Biochemistry, 1994, vol. 58, # 7, p. 1336 - 1337
[3] Journal of Molecular Structure, 2012, vol. 1010, p. 158 - 168
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 23, p. 5033 - 5040
7
[ 872-31-1 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 22913-26-4 ]
[ 88-13-1 ]
Reference：
[1] Synthetic Communications, 1993, vol. 23, # 10, p. 1361 - 1370
[2] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
8
[ 88-13-1 ]
[ 4525-33-1 ]
[ 22913-26-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2003, vol. 345, # 8, p. 943 - 947
9
[ 17249-80-8 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 22913-26-4 ]
[ 88-13-1 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
10
[ 88-13-1 ]
[ 7664-93-9 ]
[ 22913-26-4 ]
Reference：
[1] Patent: US6150413, 2000, A,
11
[ 88-13-1 ]
[ 18107-18-1 ]
[ 22913-26-4 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 28, p. 9467 - 9470
12
[ 88-13-1 ]
[ 22913-26-4 ]
Reference：
[1] Archiv der Pharmazie, 1998, vol. 331, # 12, p. 405 - 411
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran for 1 h; Stage #2: for 1 h;
Compound 9 was synthesized as reported previously [24]. To a solution of diisopropylamine (233g, 2.30mol) in THF (2.3L), a solution of n-BuLi (1.6M in n-hexane, 1.50L, 2.40mol) was added dropwise at 0°C. After stirring at the same temperature for 40min, the reaction mixture was cooled to−60°C, compound 8 (223g, 1.74mol) in THF (500mL) added dropwise, and stirred at the same temperature for 1h. After the addition of MeI (254g, 1.79mol), the reaction mixture was allowed to warm to room temperature and stirred for 1h. Next, the mixture was concentrated under reduced pressure, acidified with 6N aqueous HCl (to pH 1), and extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure and the residue was crystallized with H2O/AcOH to give 209g (85percent) of 9 as a pale-yellow solid: 1H NMR (400MHz, CDCl3) δ 7.45 (d, J=5.4Hz, 1H), 7.01 (d, J=5.4Hz, 1H), 2.78 (s, 3H); MS (ESI) m/z: 143 (M+H)+, 141 (M−H)−.
82.1%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 20℃; for 2 h;
1 (15.00 g, 0.12 mol) was dissolved in THF (50ml). Under argon protection, n-butyl lithium (2.0 M THF solution, 120 ml) wasadded dropwise at -78 °C. The reaction mixture was stirred for 1 h at -78 °C.To this mixture was added CH3I (8.7 ml, 0.14 mol), then the reactionmixture was allowed to warm to room temperature and stirred for 2 hours. Slowlyquenched the reaction with hydrogen chloride (2.0 M ethyl acetate solution), thenstirred the mixture at room temperature for 30 min before concentrating in vacuo. The residue was diluted with H2O(100 ml) and extracted with ethyl acetate (200 ml). The combined organic layerswere washed with H2O (50 ml ×2) and brine (50 ml ×2), dried overanhydrous Na2SO4, and filtrated, then the solvent wasevaporated under reduced pressure to give a yellow crude solid, which waspurified by recrystallization from acetic acid/H2O to afford 2 (14.00 g, 82.1percent ) as a white solid:mp 108-110 °C. 1H NMR (400 MHz, CDCl3)δ 7.45 (d, J = 5.5 Hz, 1H), 7.01 (d, J = 5.5, 1H), 2.73 (s, 3H). MS (EI) m/z: 142 (M+).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5417 - 5422
[2] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 269 - 294
[3] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 471 - 476
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, p. 791 - 794
[5] Patent: US6340759, 2002, B1, . Location in patent: Example 290
[6] Patent: US2012/101137, 2012, A1, . Location in patent: Page/Page column 14
13 ml (200 mmol) of thionyl chloride are added dropwise, at 0oC, to a solution of 9 g (70 mmol) of 3-thiophenecarboxylic acid and 86 mg (0.7 mmol) of 4-dimethylaminopyridine in 100 ml of ethanol. The reaction medium is stirred from 0oC to room temperature over 48 hours and then evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 1/1 heptane/dichloro- methane mixture. 10 g (91percent) of ethyl thiophene-3- carboxylate are obtained.
Reference：
[1] Patent: WO2004/113331, 2004, A1, . Location in patent: Page 38-39
[2] Organic Process Research and Development, 2017, vol. 21, # 7, p. 947 - 955
[3] Organic Letters, 2008, vol. 10, # 9, p. 1851 - 1854
[4] Angewandte Chemie - International Edition, 2017, vol. 56, # 33, p. 9924 - 9929[5] Angew. Chem., 2017, vol. 129, p. 10056 - 10061,6
[6] Patent: WO2018/170851, 2018, A1, . Location in patent: Page/Page column 17; 18
19
[ 88-13-1 ]
[ 6964-21-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
20
[ 88-13-1 ]
[ 189329-94-0 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
[2] ACS Chemical Neuroscience, 2017, vol. 8, # 1, p. 115 - 127
21
[ 88-13-1 ]
[ 100523-84-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
With bromine In acetic acid
(d) 5-bromo-3-thiophenecarboxylic acid A solution containing 16 g of Br2 (0.1 mol) in glacial acetic acid (200 ml) is added slowly to a solution of 3-thiophenecarboxylic acid (12.8 g; 0.1 mol) in 100 ml of glacial acetic acid. The mixture is stirred for 20' and then poured into water and ice. The white precipitate is filtered, washed and crystallized from water. Yield, 70percent.
50%
With bromine In acetic acid at 20℃; for 0.25 h;
A. To a stirred solution of 3-thiophenecarboxylic acid (1.00 g, 7.80 mmol) in glacial acetic acid (9 mL) at ambient temperature under nitrogen atmosphere was slowly added bromine (0.39 mL, 7.53 mmol) in glacial acetic acid (6 mL). The reaction mixture was stirred for 15 minutes, then quenched with cold water (50 mL). The precipitate was filtered, washed with water and dried in vacuum oven at 50° C. to afford 5-bromo-3-thiophenecarboxylic acid as a colorless solid (0.78 g, 50percent): mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.5 Hi, 1H), 7.51 (d, J=1.5 Hz, 1H).
46%
With bromine In acetic acid at 0 - 20℃;
A solution of bromine (2 mL, 39.06 mmol) in glacial acetic acid (64 mL) was added slowly to a stirred solution of Int-1 (5 g, 39.06 mmol) in glacial acetic acid (37 mL) at 0° C. and stirred at room temperature for 20 minutes. The reaction mixture was then poured into ice water while stirring vigorously. The white precipitated solid was filtered, washed with water and recrystallised from hot water to afford pure Int-2 as white solid (3.68 g, 46percent). 1H NMR (200 MHz, dmso-d6): δ 7.55 (s, 1H), 8.17 (s, 1H). To a stirred solution of Int-2 (3.4 g, 16.42 mmol) in methanol (40 mL) was added H2SO4 (321 mg, 3.28 mmol) and stirred under reflux for 12 hours. Volatiles from the reaction mixture were distilled off under reduced pressure and the resulting residue was extracted with DCM (75 mL). The organic extract was washed with water (40 mL), saturated aqueous NaHCO3 solution (40 mL), brine (40 mL) and dried over Na2SO4, filtered and concentrated under vacuum to afford pure Int-3 as colorless viscous oil (3.3 g, 91percent). 1H NMR (200 MHz, dmso-d6): δ 7.98 (s, 1H), 7.44 (s, 1H), 3.87 (s, 3H). To a stirred solution of Int-3 (0.5 g, 2.26 mmol) in dioxane (25 mL) was added Int-4 (0.51 g, 2.26 mmol) followed by Pd (OAc) 2 (105 mg, 0.45 mmol), xanthpos (265 mg, 0.497 mmol) and CS2CO3 (1.18 g, 3.62 mmol). The reaction mixture was degassed under vacuum, bubbled with N2 for 10 minutes and stirred under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure and was purified by column chromatography to isolate product and a very close spot together eluting with EtOAc. This mixture (140 mg) was further purified with preparative HPLC to obtain pure Int-5 as a yellow solid (80 mg, 10percent). Mass (m/z): 366.0 [M++1]. 1H NMR (200 MHz, dmso-d6): 9.50 (d, J=7 Hz, 1H), 8.51 (d, J=7 Hz, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.74 (brs, 1H), 7.66 (d, J=11.8 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=5.6 Hz, 1H), 6.87 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.73 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.91 mmol) in THF: MeOH: H2O (2:1:2) (50 ml) was added LiOH (0.24 g, 5.74 mmol) at room temperature and stirred while heating at 50° C. for 16 hours. Volatiles from the reaction mixture were distilled off under reduced pressure, the reaction mixture was acidified to about pH 5-6 with 2N HCl. The precipitated solid was filtered and dried under vacuum to afford pure Int-6 (0.51 g, 76percent). Mass (m/z): 352.0 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 12.45 (brs, 1H), 10.87 (s, 1H), 9.70 ((brs, 1H), 8.60 (d, J=4.68 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (t, J=8.4 Hz, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.04 (s, 2H), 2.65 (s, 3H).
26%
With bromine In acetic acid for 0.5 h;
To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0 mmol) in acetic acid(140 mL), was added dropwise, a solution of bromine (6.60 g, 40.0 mmol) in acetic acid (40 mL). The reaction mixture was stirred for 30 minutes and then poured into water. The resultant solid was collected by filtration to afford the title compound as a grey solid (2.07g, 26percent). LCMS (Method B): RT = 2.9 min, M+H+ = 208.
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 11, p. 1460 - 1462
[2] Patent: US4767758, 1988, A,
[3] Journal of Materials Chemistry C, 2018, vol. 6, # 14, p. 3731 - 3742
[4] Chemistry of Materials, 2010, vol. 22, # 19, p. 5617 - 5624
[5] Angewandte Chemie - International Edition, 2018, vol. 57, # 26, p. 7714 - 7718[6] Angew. Chem., 2018, vol. 130, # 26, p. 7840 - 7844,5
[7] Patent: US2009/156615, 2009, A1, . Location in patent: Page/Page column 18
[8] Journal of Materials Chemistry, 1999, vol. 9, # 9, p. 2155 - 2163
[9] Monatshefte fuer Chemie, 1989, vol. 120, p. 53 - 63
[10] Patent: US2010/29638, 2010, A1, . Location in patent: Page/Page column 110
[11] RSC Advances, 2016, vol. 6, # 20, p. 16437 - 16447
[12] Organic Letters, 2011, vol. 13, # 4, p. 672 - 675
[13] Patent: WO2009/151598, 2009, A1, . Location in patent: Page/Page column 129
[14] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
[15] Patent: EP186252, 1992, B1,
[16] Patent: WO2005/105808, 2005, A1, . Location in patent: Page/Page column 26
[17] Patent: US5498630, 1996, A,
[18] Patent: US5840917, 1998, A,
[19] Patent: US2009/275585, 2009, A1, . Location in patent: Page/Page column 12; 16
[20] Patent: WO2005/9941, 2005, A1, . Location in patent: Page 43
[21] Patent: WO2011/33255, 2011, A1, . Location in patent: Page/Page column 71-72
[22] ACS Chemical Neuroscience, 2017, vol. 8, # 1, p. 115 - 127
[23] Patent: US2003/8867, 2003, A1,
[24] Patent: US2005/227959, 2005, A1, . Location in patent: Page/Page column 53
[25] Patent: EP2241569, 2010, A1, . Location in patent: Page/Page column 25
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6931 - 6937
24
[ 88-13-1 ]
[ 24287-95-4 ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: With bromine In tetrahydrofuran; hexane at -78 - 20℃;
An oven-dried 100 mL round bottom flask was charged with compound 1 (2.00 g, 15.6 mmol) and tetrahydrofuran (THF; 30 mL). The solution was cooled to -78.0 °C and 2.50 M n-butyllithium in hexane (12.6 mL, 31.5 mmol) was slowly added dropwise. The reaction mixture was stirred for 30 min at -78.0 °C and bromine (0.86 mL, 16.4 mmol) was added dropwise. Stirring was continued for 1 h at -78.0 °C and the mixture was heated to room temperature. After stirring the mixture overnight, a small amount of dilute 1M HCl (50.0 mL) was added to quench the reaction and the solution was then concentrated. After extracting the resultant mixture using ether and water, the organic layer was dried with Na2SO4. The compound was recrystallized twice using a H2O/ether mixture to furnish the compound as faint yellow needles (2.13 g, yield 66.0percent; 1H NMR (500 MHz, DMSO‑d6, d (ppm)): 7.63-7.62 (d,J 5.8 Hz, 1H), 7.32-7.31 (d, J 5.8 Hz, 1H)).
50%
With carbon tetrabromide; lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h;
The reaction temperature was -78 , the reaction time was 2h, the yield was about 50percent. In a 1 L two-necked flask, 24.5 g of 3-methylthiophene (98 g mol-1,24.5 g, 250 mmol) was added and 400 mL of chloroform / glacial acetic acid (V: V = 1: / L,Favoring the inhibition of the bis-brominated product), 44.5 g of NBS (178 g mol-1, 44.5 g, 250 mmol) were added in portions in an ice-water bath.After the addition of NBS to continue stirring for 2-3 hours, TLC monitoring. After treatment: deionized water to quench the reaction, liquid separation, the organic phase was NaOH solution, washed with water, dried, concentrated vacuum pump with fractional distillation.
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6931 - 6937
[2] Polymer, 2018, vol. 146, p. 142 - 150
[3] Patent: CN106588868, 2017, A, . Location in patent: Paragraph 0025-0029; 0043; 0053-0055
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
[2] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
27
[ 88-13-1 ]
[ 7311-70-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 50℃; for 18 h; Darkness
3-Thenoic acid (1.49 g, 11.7 mmol) and N-bromosuccinimide (NBS) (4.60 g, 25.8 mmol) were added to degassed DMF (24 mL). The flask was then wrapped with aluminum foil to shield the reaction mixture from light. The mixture was then stirred at 50 °C for 28 h. The mixture was allowed to cool to room temperature, after which it was poured into water (300 mL). The resulting precipitate was collected by filtration and washed with saturated NaCl aq., dried over anhydrous MgSO4, and then filtrated to afford 2,5-dibromo-3-thenoic acid as a white dasolid in 88percent yield.
80.7%
at 60℃; for 24 h;
Compound 1 (2.00 g, 15.6 mmol) was dissolved in glacial acetic acid (25.0 mL) and Br2 (12.4 g, 78.0 mmol) was added to the above solution dropwise at room temperature. The mixture was heated and stirred at 60 °C for 24 h. After the reaction was completed, the mixture was poured into 200 mL of deionized water to quench the reaction. The precipitate was filtered and dissolved in ethyl acetate(EA). The solution in EA was dried with Na2SO4. After evaporation of the solvent, the crude product was purified by recrystallization from EtOH-H2O to give the product as a white powder (3.60 g, yield 80.7percent; 1H NMR (500 MHz, CDCl3; d (ppm)): 13.29 (s, 1H), 7.44(s, 1H)).
31%
at 50℃; for 24 h;
To a solution of 3-thiophenecarboxylic acid (25.3 g) in acetic acid (200 mL) was added dropwise bromine (21.3 mL), and the mixture was stirred at 50°C for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (17.3 g, 31percent) as a white solid. 1H NMR(300MHz, CDCl3) δ ppm 7.40(m,1H)
Reference：
[1] Journal of Materials Chemistry A, 2017, vol. 5, # 26, p. 13757 - 13762
[2] Chemistry Letters, 2015, vol. 44, # 7, p. 1013 - 1015
[3] Journal of Organic Chemistry, 2008, vol. 73, # 17, p. 6831 - 6834
[4] New Journal of Chemistry, 2010, vol. 34, # 7, p. 1417 - 1423
[5] Polymer, 2018, vol. 146, p. 142 - 150
[6] Macromolecules, 2004, vol. 37, # 7, p. 2353 - 2362
[7] Patent: EP2210876, 2010, A1, . Location in patent: Page/Page column 90
[8] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
[9] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 16, p. 3604 - 3614
[10] Revue Roumaine de Chimie, 2013, vol. 58, # 2-3, p. 153 - 160
[11] RSC Advances, 2014, vol. 4, # 99, p. 56385 - 56405
[12] European Journal of Medicinal Chemistry, 2014, vol. 83, p. 317 - 337
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5417 - 5422
[2] Patent: US2012/101137, 2012, A1,
[3] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 471 - 476
[4] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 269 - 294
31
[ 88-13-1 ]
[ 109-89-7 ]
[ 73540-75-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 2 h; Inert atmosphere Stage #2: at 0 - 20℃; for 16 h; Inert atmosphere
A 250 mL round bottom flask charged with 3-thiophenecarboxylic acid (10.0 g, 78 mmol) was evacuated andrefilled with N2 gas for three times followed by the addition of150 mL anhydrous CH2Cl2. To this solution, anhydrous dimethylformamide(15 drops) was added and the reaction temperaturewas cooled down to 0 C. Oxalyl chloride (11.1 g, 87 mmol) wasadded to the reaction mixture and the mixturewas stirred for 2 h at0 C. The solvent was removed under reduced pressure and thereaction mixture was re-dissolved in CH2Cl2 (150 mL). To the abovesolution, diethylamine (11.4 g, 156 mmol) was added at 0 C andstirred for 16 h at room temperature. The reaction mixture waspoured into 1M aqueous HCl (200 mL) and extracted with CH2Cl2(200 mL). The organic extract was washed with saturated aqueouspotassium chloride (1 20 mL) and brine (1 20 mL) and driedover anhydrous Na2SO4. The solvent was removed under reducedpressure and crude product obtained was purified on silica gelcolumn chromatography (50percent ethyl acetate and hexane eluent) toobtain the title compound as a pale yellow oil (yield 90percent).1H NMR (500 MHz, CDCl3, d ppm): 1.20 (t, J 8.5 Hz, 6H), 3.45(bs, 4H), 7.19 (dd, J1 2.0 Hz and J2 4.5 Hz, 1H), 7.31e7.33 (m, 1H),7.46e7.48 (m, 1H).
Reference：
[1] Organic Electronics: physics, materials, applications, 2016, vol. 37, p. 312 - 325
[2] Dyes and Pigments, 2014, vol. 109, p. 81 - 89
[3] Patent: US9127020, 2015, B2, . Location in patent: Page/Page column 48
[4] Physical Chemistry Chemical Physics, 2017, vol. 19, # 31, p. 20513 - 20522
32
[ 88-13-1 ]
[ 73540-75-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 11, p. 1585 - 1599
[2] Doklady Chemistry, 2011, vol. 440, # 1, p. 257 - 262
[3] Macromolecules, 2014, vol. 47, # 3, p. 1008 - 1020
[4] Advanced Synthesis and Catalysis, 2014, vol. 356, # 7, p. 1527 - 1532
[5] New Journal of Chemistry, 2015, vol. 39, # 3, p. 2248 - 2255
[6] Journal of the American Chemical Society, 2015, vol. 137, # 4, p. 1448 - 1451
[7] Chemistry - A European Journal, 2015, vol. 21, # 45, p. 16252 - 16265
[8] Tetrahedron, 2016, vol. 72, # 17, p. 2219 - 2225
[9] Patent: KR101495152, 2015, B1,
[10] Patent: CN105968124, 2016, A,
33
[ 109-02-4 ]
[ 88-13-1 ]
[ 3282-30-2 ]
[ 109-89-7 ]
[ 73540-75-7 ]
Reference：
[1] Patent: EP354303, 1990, A1,
34
[ 88-13-1 ]
[ 75-65-0 ]
[ 19228-91-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: for 3.5 h; Heating / reflux Stage #2: at 0℃;
Preparation Example U-1. Thiophen-3-yl-carbamic acid tert-butyl ester Thiophene-3-carboxylic acid (2.50g, 19.5mmol), diphenylphosphoryl azide (4.62mL, 21.5mmol), triethylamine (3.26mL,23.4mmol) were dissolved in tert-butanol (50mL), and the solution was stirred for 3.5 hours under reflux. Water was added to the reaction solution at 0°C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the title compound (3.33g, 16.7mmol,86percent) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) δ (ppm):1.46 (9H, s), 6.97 (1H, d, J=5.2Hz), 7.16 (1H, s), 7.38 (1 H, m), 9.61 (1H, s).
86%
for 3.5 h; Heating / reflux
Thiophene-3-carboxylic acid (2.50g, 19.5mmol), diphenylphosphoryl azide (4.62mL, 21.5mmol), triethylamine (3.26mL, 23.4mmol) were dissolved in tert-butanol (50mL), and the solution was stirred for 3.5 hours under reflux. Water was added to the reaction solution at 0°C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and the title compound (3.33g, 16.7mmol,86percent) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) δ(ppm) :1.46 (9H, s), 6.97 (1H, d, J=5.2Hz), 7.16 (1H, s), 7.38 (1 H, m), 9.61 (1 H, s).
69%
for 22 h; Heating / reflux
3-Thiophenecarboxylic acid (31 g, 0.24 mol), Diphenylphosphoryl azide (57 mL, 0.26 mol) and triethylamine (36 mL, 0.26 mol) were combined in dry tert-butanol (450 mL) and the resulting solution was heated to reflux. After 22 h the cooled solution was concentrated in vacuo to remove solvent. The residue was taken up in diethyl ether (1.5 L) and washed with 5percent aqueous citric acid, water and brine (1.5 L each), dried (Na2SO4), and concentrated in vacuo to give the crude product as a tacky tan solid (51 g). Recrystallization from hot ethyl acetate-hexane gave the title compound (33 g, 69percent, m.p. 139-41° C.) as shiny off-white needles. 1H NMR δ 1.45 (s, 9 H, (CH3)3), 6.97 (m, 1 H, ArH), 7.16 (broad s, 1 H, ArH), 7.37 (m, 1 H, ArH), 9.60 (broad s, 1 H, NH). MS (ESI) m/z 198 [M-H]- Analysis calc. for C18H13FO3S: C, 54.25; H, 6.58; N, 7.03 Found: C, 54.26; H, 6.48; N, 6.99
With lithium hydroxide monohydrate; chromium(VI) oxide In diethyl ether
80%
With chromic acid In diethyl ether at 0℃; for 3h;
2.3 3, The preparation of 3-thiophene carboxylic acid
The reaction temperature was zero, the reaction time was 3h, the yield was about 80%. In a 1 L two-necked flask, 24.5 g of 3-methylthiophene (98 g mol-1,24.5 g, 250 mmol) was added and 400 mL of chloroform / glacial acetic acid (V: V = 1: / L,Favoring the inhibition of the bis-brominated product), 44.5 g of NBS (178 g mol-1, 44.5 g, 250 mmol) were added in portions in an ice-water bath.After the addition of NBS to continue stirring for 2-3 hours, TLC monitoring. After treatment: deionized water to quench the reaction, liquid separation, the organic phase was NaOH solution, washed with water, dried, concentrated vacuum pump with fractional distillation.
76%
With lithium hydroxide monohydrate; triethylamine for 2.5h; Reflux;
With sodium hydroxide; silver(I) oxide
With sodium hydroxide; potassium permanganate at 50℃;
With potassium permanganate In lithium hydroxide monohydrate; acetonitrile
26 mg
With oxygen In 1,4-dioxane at 80℃; for 24h; Green chemistry;
2 g
With lithium hydroxide monohydrate; silver(I) nitrate at 70℃; for 1h; Alkaline conditions;
With NHPI; oxygen In lithium hydroxide monohydrate; acetonitrile at 100℃; for 0.2h;
To a solution of 3-thiophene carboxylic acid (2.Og, 15.60mmol) in methanol (30ml) was added a catalytic amount of sulphuric acid (0.5ml) and the reaction mixture was heated to reflux for 2 hr. The solvent was removed under reduced pressure and the residue was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, concentrated and dried to give 3-thiophene carboxylic acid methyl ester (1.8g, 81%).
With sulfuric acid; In 1,2-dichloro-ethane; at 90℃;
Step 1 : Synthesis of methyl thiophene-3-carboxylate Into a 500-mL round-bottom flask, was placed thiophene-3-carboxylic acid (20 g, 156.07 mmol, 1 .00 equiv), DCE (150 mL, 30.00 equiv), methanol (7.5 g, 234.08 mmol, 1 .50 equiv) and sulfuric acid (23 g, 234.50 mmol, 1 .50 equiv). The resulting solution was stirred overnight at 90C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with DCM (500 mL). The resulting mixture was washed with 0.5mol/L sodium hydroxide (aq.) (3x250 mL). The resulting mixture was washed with brine(3x250 mL). The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum, to yield methyl thiophene-3-carboxylate as a brown liquid.LC-MS (ES, m/z): 143 [M+H]+
sulfuric acid; for 3.5h;Heating / reflux;
Preparation 88: methyl 3-thiophenecarboxylate; 3-thiophenecarboxylic acid (2.0 g) was dissolved in MeOH (27 ml_) and concentrated sulphuric acid (1.5 mL) was added. The reaction mixture was refluxed for 3 hours and 30 min., then concentrated under reduced pressure. A saturated NaHCO3 solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated in vacuo to give 1.98 g of the title compound as a colourless liquid which was used without further purification.NMR (1H1 CDCI3): delta 8.12 (m, 1 H), 7.55 (m, 1 H), 7.33 (m, 1 H), 3.88 (s, 3H).
With oxalyl dichloride In dichloromethane for 1.91667h; Inert atmosphere; Reflux;
91%
With oxalyl dichloride In dichloromethane at 0 - 20℃;
78%
With oxalyl dichloride In dichloromethane at 0℃; for 12h;
7 Preparation of Thiophene-3-carbonyl chloride (compound g-1)
250mL thiophene-3-carboxylic Acid into a tea (5g) in a round flask, 100mL of methylene chloride is injected. After slowly inject (9mL) oxalyl chloride at 0 °C, it stirred for 12 hours. After 12 hours, removing the organic solvent, it is possible to obtain a yellow liquid (thiophene-3-carbonyl chloride (compound g-1)). (Yield: 78%)
75%
With dichlorosulfoxide In N,N-dimethyl-formamide at 20℃; for 12h;
1 Preparation of thiophene-3-carbonyl chloride
In a 500 mL three-necked flask, thiophene-3-carboxylic acid (12.8 g, 0.1 mol) was dissolved in N,N-dimethylformamide, and 20 ml of thionyl chloride was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 12 hours. After that, the reaction was stopped, the reaction was quenched with water, extracted with methylene chloride and dried over anhydrous magnesium sulfate, and then concentrated to give a pale yellow solid, purified by silica gel column chromatography, petroleum ether / dichloromethane /1, v/v) was the eluent to give a white solid, yield 75%. The results of 1H NMR, 13C NMR, MS and elemental analysis indicated that the obtained compound was the target product, and the chemical reaction equation of the preparation process was as follows:
53%
With dichlorosulfoxide In benzene for 2h; Reflux;
With dichlorosulfoxide
With dichlorosulfoxide for 1h; Heating;
With dichlorosulfoxide In dichloromethane
With dichlorosulfoxide for 2h; Heating;
With dichlorosulfoxide for 18h; Ambient temperature;
With dichlorosulfoxide In chloroform for 3h; Heating;
With dichlorosulfoxide for 0.25h; Heating;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
With dichlorosulfoxide at 50℃; for 0.75h;
With dichlorosulfoxide In N,N-dimethyl-formamide; toluene for 1h; Heating;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
With dichlorosulfoxide for 2h; Heating;
With dichlorosulfoxide In toluene at 115℃; for 3h;
With dichlorosulfoxide
With dichlorosulfoxide In chloroform for 2h; Heating / reflux;
26
Thiophene-3-carboxylate (10 g, 78 mmol) was dissolved in chloroform (500 ml), treated with thionyl chloride (6.83 ml, 93.6 mmol) and heated to reflux for 2 hours. This solution was then added by cannulation to a solution of Weinreb Amine (11.4 g, 117 mmol) and triethylamine (30 ml, 210.6 mmol) in chloroform (100 ml). The reaction was then stirred at room temperature overnight. The solvent was reduced in vacuo to 100 ml, washed with water (150 ml), dried (Na2SO4) and concentrated. The resulting orange oil was purified by vacuum distillation (150 ° C. at 5 mbar) to give the title compound as a pale yellow oil (8.50 g, 64%). MS (ES+) 172. δH (d6 DMSO): 3.25 (3H, s), 3.64 (3H, s), 7.43 (1H, d), 7.56 (1H, d), 8.25 (1H, s).
With dichlorosulfoxide
14 2,2'-Benzo[1,2-b:4,5-b']dithiophen-4,8-diyldioxy)bis-N,N-diethyl ethylamine, dihydrochloride
A 100 g. portion of thionyl chloride is added to 34.8 g. of 3-thiophene carboxylic acid. This mixture is stirred and warmed on a steam bath for 15 minutes, then heated at reflux for 45 minutes. The excess thionyl chloride is distilled off and the remaining reaction mixture is fractionated at 32-36 mm. pressure, giving 34.0 g. of 3-thiophene carbonyl chloride.
With dichlorosulfoxide
19.a (a)
(a) 3-Thiophenecarboxylic acid chloride 5.12 g (44 mmol) of 3-thiophenecarboxylic acid are added to 50 ml of thionyl chloride, the mixture is heated to boiling for 2 h and then evaporated, the residue is taken up with toluene and the latter is evaporated off. 5 g of residue are obtained, this being used without further treatment in the following stage.
With dichlorosulfoxide
6 EXAMPLE 6
EXAMPLE 6 Thiophene-3-carboxylic acid is converted to the acid chloride by reaction with thionyl chloride. Thiophene-3-carbonyl chloride is isolated by distillation at 80°-85° C./0.25 mm.
With dichlorosulfoxide at 20℃; for 12h;
With dichlorosulfoxide In toluene Reflux;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;
55
Oxalyl chloride (2 mmol) and DMF (2 drops) were added sequentially to a stirred solution of the corresponding acid (1.5 mmol) in CH2C12 at room temperature, then further stirred for 2 h under argon atmosphere. The solvent was removed under vacuum at room temperature to yield corresponding acid chloride. A solution of 1- benzyl-2-oxo-4-piperazin-1-yl-1, 2-DIHYDRO- [1, 8]-NAPHTHYRIDINE-3-CARBOXYLIC acid ethyl ester (5) (392 mg, 1 mmol) in dry pyridine (5 mL) was added to the residue under argon atmosphere and briefly sonicated. The solution was stirred overnight at room temperature under argon atmosphere. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and purified by flash chromatography eluting with 0-2 % MEOH in a CH2C12 gradient. ; Synthesis of 1-Benzyl-2-oxo-4-[4-(thiophene-3-carbonyl)-piperazin-1-yl]-1,2- DIHYDRO- [1, 8]-NAPHTHYRIDINE-3-CARBOXYLIC acid ethyl ester (55) [0334] The compound was prepared according to general method D. White solid, yield 68 %, mp 115 °C. 1H-NMR (DMSO-D6) : d 1.29 (t, J= 7.2 Hz, 3H), 3.14 (b, 4H), 3.75 (b, 4H), 4.30 (q, J= 7.2 Hz, 2H), 5.56 (s, 2H), 7.25 (m, 6H), 7. 37 (m, 1H), 7.65 (m, 1H), 7. 85 (dd, J= 1.2, 2.8 Hz, 1H), 8.34 (dd, J= 2.0, 8. 0 Hz, 1H), 8.67 (dd, J= 2.0, 4.8 Hz, 1H) ; EIMS m/z 503 (M+1).
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
With dichlorosulfoxide at 20℃; for 16h;
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran for 1h; Inert atmosphere;
With dichlorosulfoxide In benzene
With dichlorosulfoxide; N,N-dimethyl-formamide In toluene for 16h;
5.2.1. General procedure for the synthesis of acid chlorides (2a-f, 5a-c)
General procedure: Heterocyclic carbolic acids refPreviewPlaceHolder[23], refPreviewPlaceHolder[24] and refPreviewPlaceHolder[25] (1 equiv) were suspended in dry toluene (150 mL) at room temperature. Thionyl chloride (5 equiv) was added dropwise. The reaction mixtures were stirred for 5 min at room temperature and then DMF (3-5 drops) was added. The mixtures were stirred for 16 h and then evaporated to dryness. The residues were used directly in the next step.
With dichlorosulfoxide at 85℃; for 2h;
With dichlorosulfoxide Heating;
With oxalyl dichloride In dichloromethane
With dichlorosulfoxide for 1h; Reflux;
With oxalyl dichloride In dichloromethane
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Inert atmosphere;
With dichlorosulfoxide In dichloromethane at 0 - 50℃; for 3h;
11.A Step A: N-methoxy-N-methylthiophene-3-carboxamide
To a stirred solution of thiophene-3-carboxylic acid (20 g, 1.0 eq) in CH2C12 at 0 °C was added SOCl2 (59 mL, 5.2 eq). After gas evolution became less vigorous, the reaction mixture was refluxed for 3 h at 50 °C. The mixture was then concentrated and the residue was used directly in the next step without further purification. N, O-dimethylhydroxylamine hydrochloride (16.8 g, 1.1 eq) was added to a solution of the above residue in CH2C12 at 0 °C, then to the resulting solution was added dropwise Et3N (44 mL, 2.0 eq). The mixture was stirred at rt for 3 h, washed with water, and extracted by CH2C12. The extract was dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc = 5: 1 to give the desired product as a yellow solid (17.2 g, 64% yield). :H NMR (400 MHz, CDC13) δ 8.07 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H), 3.36 (s, 3H).
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
General Procedure for amide formation from carboxylic acids
General procedure: Oxalyl dichloride (21 mmol, 1.05 equiv) was added to asuspension of the carboxylic acid (20 mmol, 1 equiv) in CH2Cl2(50 mL) at room temperature. A drop of DMF was added and the reaction stirredat room temperature for 1 h (bubbling ceased and the reaction becomes homogeneousduring this period). The volatiles were removed under vacuum, then the oilyresidue was dissolved in CH2Cl2 (50 mL) and cooled in anice-bath. The amine (20 mmol, 1 equiv) and triethylamine (22 mmol, 1.1 equiv)were added in CH2Cl2 (10 mL), and the reaction wasstirred for 30 min, before warming to room temperaure. The solution was washedwith sat. NH4Cl solution and brine, then dried over MgSO4,filtered and concentrated to give the following amides, which were used withoutfurther purification.
With dichlorosulfoxide at 80 - 90℃; for 1h;
With oxalyl dichloride In dichloromethane at 0℃;
With dichlorosulfoxide In N,N-dimethyl-formamide for 1h; Reflux;
General procedure: It was prepared by two-step process. In a typical experiment, 2-thiophene carboxylicacid was placed in a 100 ml single-necked round-bottom flask fitted with a double wallreflux condenser and a calcium chloride guard tube. Thionyl chloride (1.09 ml, 0.0075 mol)and few drops of N,N-dimethylformamide were added to the flask and refluxed for 1 hour.The excess thionyl chloride was removed by vacuum pump. Then it was dissolved in ethylmethyl ketone (50 ml) and added dropwise through pressure equalizing dropping funnelfor 45 minutes at 0C to the mixture of 4-hydoxy phenyl 4-(dodecyloxy) benzoate (2 g,0.005 mol) and triethylamine (0.84 ml, 0.006 mol) in ethyl methyl ketone. The reactionmixture was allowed for stirring for 5 hours. Then the flask was taken out, the triethylaminesalt was filtered, and the solvent was removed from solution under reduced pressure. Thesolid obtained was washed twice with 2% potassium hydroxide solution followed by waterand then dried, recrystallized from isopropyl alcohol and methanol.Similar protocols were used for synthesizing other homologues of the series.
With dichlorosulfoxide for 3h; Reflux;
With dichlorosulfoxide In N,N-dimethyl-formamide; toluene at 20℃;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; Schlenk technique;
With dichlorosulfoxide; N,N-dimethyl-formamide for 1h; Reflux;
Synthesis of 3- thiophene carbonyl chloride
General procedure: Synthesis of 2 or 3- thiophene carbonyl chloride (6). 2 (or) 3- thiophene carboxylicacid (3 g, 0.0234 mol) which was placed in a 100 ml single neck round bottomed flask fittedwith a double wall reflux condenser and a calcium chloride guard tube. Thionyl chloride(2.13 ml, 0.0292 mol) and a few drops of DMF were added to the flask. The reactionmixture was refluxed for about one hour and the excess SOCl2 was removed by vacuumpump.
With dichlorosulfoxide In dichloromethane; N,N-dimethyl-formamide at 60℃; for 5h; Inert atmosphere;
With oxalyl dichloride In dichloromethane at 20℃;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃;
With N-chloro-succinimide; In acetic acid; for 4h;Reflux; Inert atmosphere;
In a 1 L round-bottomed flask, N-chlorosuccinimide (23.5 g, 176 mmol, Eq: 1.00) and thiophene-3-carboxylic acid (17.5 g, 137 mmol, Eq: 0.776) were combined with acetic acid (200 mL) to give a white suspension. The reaction mixture was refluxed for 4 hours. After this time, the reaction mixture was cooled to room temperature. The reaction mixture was combined with ice water. The resulting mixture was extracted several times with methylene chloride. The combined organic extracts were then treated with an equal volume of 1.0 N aqueous sodium hydroxide solution. This aqueous mixture was washed once with methylene chloride. The aqueous phase was acidified with concentrated HC1 to precipitate a white solid. This precipitate was filtered, and then thoroughly dried under vaccum with heating at 65 C to afford 5- chlorothiophene-3-carboxylic acid (14 g, 49%) as a cream colored powder
With N-chloro-succinimide; In acetic acid; for 4h;Heating / reflux;
Thiophene-3-carboxylic acid (17.51 g, 136.6 mmol) and 1-chloro-pyrrolidine-2, 5-dione (23.7 g) was refluxed in acetic acid (200 ml) for 4 h under argon before pouring onto water (700 ml). Repeated extraction with several small portions of DCM, followed by back extraction from the combined organics with several small portions [OF 2 M] aqueous sodium hydroxide, gave a combined alkaline aqueous solution that was washed with DCM before acidified with cone. [HC1] to precipitate the crude material. This precipitate was recrystallized from water to yield 14.98 g of the title compound as a grey solid contaminated with approximately 20 mol% of a dichlorinated byproduct as judged from MS and [1H-NMR.] 1H NMR (DMSO-d6) d (ppm): 8.15 (d, 1H), 7.37 (d, 1H).
100 g
With sulfuryl dichloride; In dichloromethane; at -15 - 10℃; for 2h;
In a 1000 ml three-necked flask were placed 128 g of 3-thiophenecarboxylic acid and 600 g of dichloromethane,The temperature dropped to -15 or so,To three-necked flask, 140 g of sulfuryl chloride was added dropwise,After completion of the dropwise addition,The reaction was allowed to proceed for 2 hours by slowly raising the temperature to 10 C or higher.After completion of the reaction,The reaction solution was poured into about 1,000 ml of ice water,The reaction solution was layered,The organic layer was separated, the organic layer was dried,filter,Concentrated to give 165 g of crude 5-chloro-3-thiophenecarboxylic acid;The resulting crude 5-chloro-3-thiophenecarboxylic acid was recrystallized from 800 ml of methyl t-butyl ether,Crystalline solid was obtained by filtration, and the crystal solid was dried to obtain 100 g of pure product of 5-chloro-3-thiophenecarboxylic acid of 97% purity.
(d) 5-bromo-3-thiophenecarboxylic acid A solution containing 16 g of Br2 (0.1 mol) in glacial acetic acid (200 ml) is added slowly to a solution of 3-thiophenecarboxylic acid (12.8 g; 0.1 mol) in 100 ml of glacial acetic acid. The mixture is stirred for 20' and then poured into water and ice. The white precipitate is filtered, washed and crystallized from water. Yield, 70%.
50%
With bromine; In acetic acid; at 20℃; for 0.25h;
A. To a stirred solution of 3-thiophenecarboxylic acid (1.00 g, 7.80 mmol) in glacial acetic acid (9 mL) at ambient temperature under nitrogen atmosphere was slowly added bromine (0.39 mL, 7.53 mmol) in glacial acetic acid (6 mL). The reaction mixture was stirred for 15 minutes, then quenched with cold water (50 mL). The precipitate was filtered, washed with water and dried in vacuum oven at 50 C. to afford 5-bromo-3-thiophenecarboxylic acid as a colorless solid (0.78 g, 50%): mp 133-135 C.; 1H NMR (300 MHz, CDCl3) delta 8.12 (d, J=1.5 Hi, 1H), 7.51 (d, J=1.5 Hz, 1H).
46%
With bromine; In acetic acid; at 0 - 20℃;
A solution of bromine (2 mL, 39.06 mmol) in glacial acetic acid (64 mL) was added slowly to a stirred solution of Int-1 (5 g, 39.06 mmol) in glacial acetic acid (37 mL) at 0 C. and stirred at room temperature for 20 minutes. The reaction mixture was then poured into ice water while stirring vigorously. The white precipitated solid was filtered, washed with water and recrystallised from hot water to afford pure Int-2 as white solid (3.68 g, 46%). 1H NMR (200 MHz, dmso-d6): delta 7.55 (s, 1H), 8.17 (s, 1H). To a stirred solution of Int-2 (3.4 g, 16.42 mmol) in methanol (40 mL) was added H2SO4 (321 mg, 3.28 mmol) and stirred under reflux for 12 hours. Volatiles from the reaction mixture were distilled off under reduced pressure and the resulting residue was extracted with DCM (75 mL). The organic extract was washed with water (40 mL), saturated aqueous NaHCO3 solution (40 mL), brine (40 mL) and dried over Na2SO4, filtered and concentrated under vacuum to afford pure Int-3 as colorless viscous oil (3.3 g, 91%). 1H NMR (200 MHz, dmso-d6): delta 7.98 (s, 1H), 7.44 (s, 1H), 3.87 (s, 3H). To a stirred solution of Int-3 (0.5 g, 2.26 mmol) in dioxane (25 mL) was added Int-4 (0.51 g, 2.26 mmol) followed by Pd (OAc) 2 (105 mg, 0.45 mmol), xanthpos (265 mg, 0.497 mmol) and CS2CO3 (1.18 g, 3.62 mmol). The reaction mixture was degassed under vacuum, bubbled with N2 for 10 minutes and stirred under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure and was purified by column chromatography to isolate product and a very close spot together eluting with EtOAc. This mixture (140 mg) was further purified with preparative HPLC to obtain pure Int-5 as a yellow solid (80 mg, 10%). Mass (m/z): 366.0 [M++1]. 1H NMR (200 MHz, dmso-d6): 9.50 (d, J=7 Hz, 1H), 8.51 (d, J=7 Hz, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.74 (brs, 1H), 7.66 (d, J=11.8 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=5.6 Hz, 1H), 6.87 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.73 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.91 mmol) in THF: MeOH: H2O (2:1:2) (50 ml) was added LiOH (0.24 g, 5.74 mmol) at room temperature and stirred while heating at 50 C. for 16 hours. Volatiles from the reaction mixture were distilled off under reduced pressure, the reaction mixture was acidified to about pH 5-6 with 2N HCl. The precipitated solid was filtered and dried under vacuum to afford pure Int-6 (0.51 g, 76%). Mass (m/z): 352.0 [M++1]. 1H NMR (200 MHz, dmso-d6): delta 12.45 (brs, 1H), 10.87 (s, 1H), 9.70 ((brs, 1H), 8.60 (d, J=4.68 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (t, J=8.4 Hz, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.04 (s, 2H), 2.65 (s, 3H).
26%
With bromine; In acetic acid; for 0.5h;
To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0 mmol) in acetic acid(140 mL), was added dropwise, a solution of bromine (6.60 g, 40.0 mmol) in acetic acid (40 mL). The reaction mixture was stirred for 30 minutes and then poured into water. The resultant solid was collected by filtration to afford the title compound as a grey solid (2.07g, 26%). LCMS (Method B): RT = 2.9 min, M+H+ = 208.
In acetic acid;
(d) 5-bromo-3-thiophenecarboxylic acid. A solution containing 16 g of Br2(0.1 mol) in glacial acetic acid (200 ml) is added slowly to a solution of 3-thiophenecarboxylic acid (12.8 g; 0.1 mol) in 100 ml of glacial acetic acid. The mixture is stirred for 20' and then poured into water and ice. The white precipitate is filtered, washed and crystallized from water. Yield, 70%.
With bromine; acetic acid; at 20℃; for 0.5h;
Step; 5-Bromo-thiophene-3-carboxylic acid; To a solution of thiophene-3-carboxylic acid (25 g, 195 mmol) in AcOH (700 ml) was added bromine (10.6 ml) in AcOH (200 ml) dropwise. After the addition, the reaction was stirred for 30 minutes at room temperature and poured onto water. A white precipitate was formed, which was filtered and dried to obtain 5-bromo-thiophene-3-carboxylic acid (14.5 g) as a white solid after crystallization (water).
With bromine; In acetic acid;
a) To a solution of 3-thiophenecarboxylic acid (7.7 g, 60 mmol) in 70 mL acetic acid was added a solution of 9.6 g bromine in 50 mL acetic acid at RT and stirring was continued at RT for 0.5 h. After that, the reaction mixture was poured into 600 mL ice-water. The precipitate was filtered, washed with water and air-dried to give 7.9 g of 5-bromo-3-thiophenecarboxylic acid.
With pyridinium hydrobromide perbromide; acetic acid; In ethyl acetate;
Reference Example 124 5-Bromo-3-thiophenecarboxylic Acid A mixture of 3-thiophenecarboxylic acid (12.81 g), pyridinium bromide perbromide (35.54 g) and acetic acid (50 ml) was stirred at 45 C. for 48 hours. The mixture was poured into ice-water and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-3-thiophenecarboxylic acid (19.78 g) as crystals. mp 137-138 C.
With pyridinium hydrobromide perbromide; hydrogen bromide; In acetic acid; at 20℃;
To a solution of thiophene-3-carboxylic acid (12.6 g, 0.1 mol) in AcOH (96 ml), being stirred at room temperature, HBr solution (8 ml) was added, and the stirring continued until the color of mixture turned to yellow. Pyridinium bromide perbromide (27 g) was then sequentially added. The mixture was poured into ice-water, stirred for about 30 minutes. A white precipitate was formed, which was filtered and dried to obtain 5-bromo-thiophene-3-carboxylic acid (10.8 g) as a white solid after crystallization in hot water. HPLC: 92%.
With 2-(4-bromo-3-oxobutyl)isoindoline-1,3-dione; In acetic acid; at 20℃; for 0.25h;
Prepare a solution of thiophene carboxylic acid (500 mg, 3.90 mmol) in HOAC (5 mL). Add Br2 (0.17 mL, 0. 85 MMOL), in HOAc (3 mL), dropwise. Then stir the mixture for 15 minutes at room temperature under nitrogen. Quench the reaction with ice cold water and stir for an additional 10 minutes. Cool the SOLUTION-10C when the product will precipitate out. Filter the solution, rinse the filter cake with ice cold water, and dry the product to afford 473 mg of 5-BROMOTHIOPHENE-3-CARBOXYLIC acid as a white solids NMR (dimethylsulfoxide-d6) S 12.90 (br s, 1H), 8.18 (d, J = 1. 5 Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H).
With bromine; acetic acid; for 1h;
5-Bromo-thiophene-3-carboxylic acid Thiophene-3-carboxylic acid (25 g, 195 mmol) was dissolved in acetic acid (200 mL). Bromine (10.4 mL, 200 mmol) was added slowly over the course of 0.5 hour. The mixture was stirred for a further 0.5 hour and then poured onto ice. After 0.5 hours the white precipitate that formed was collected by filtration. Recrystallisation from water gave the title compound as a white solid (13.7 g). 1H NMR (400 MHz, d6-DMSO): delta 8.25 (s, 1 H), 7.45 (s, 1 H).
With bromine; In acetic acid;
(A) 5-Bromothiophene-3-carboxylic Acid Bromine (46.5 g) in acetic acid (200 mL) was added dropwise to a solution of thiophene-3-carboxylic acid (38 g) in acetic acid (300 mL). After the addition was complete, stirring was continued at room temperature for 30 min. The reaction mixture was poured into 2000 mL of ice/water and the precipitated solid was collected and recrystallized from water to give a colourless solid; MS (ES-) 205, 207 (MH+).
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃;
PREPARATION EXAMPLE 118; 5-Bromo-thiophene-3-carboxylic acid [2-(4-fluorophenyl)-ethyl]-amide; a) 5-Bromo-thiophene-3-carboxylic acid; To a solution of thiophene-3-carboxylic acid (18.2 g) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (27.8 g) in small amounts on an ice bath. After stirring at room temperature overnight, the reaction solution was poured into water (1.5 L), and the resulting solid was collected by filtration and washed with water. After dissolving in ethyl acetate, and dried with anhydrous magnesium sulfate, the drying agent was removed by filtration, and evaporation in vacuo was carried out. The solid that was generated by dissolving the residue in ethyl acetate, and adding hexane were collected by filtration, and the crude product (16 g) of 5-bromo-thiophene-3-carboxylic acid was obtained as a colorless solid.
Step 1: Synthesis of 5-bromo-thiophene-3-formic acid Thiophene-3-formic acid (12.6g) and AcOH (96ml) are added to a reaction flask (250ml), to dissolved after stirred at room temperature, HBr solution (8ml) is then added to the reaction flask, and the reaction is rapidly changed to a light yellow. Pyridinium bromide perbromide (27g) is then added to the flask in batches at room temperature. After addition, the reaction is stirred at room temperature, and the reaction is tracked by HPLC. The above mixture is poured into ice-water after reaction, stirred for about 30 minutes, filtered to form a white powder solid, the white powder solid is crystallized with hot water, filtered and dried to obtain a crystal of 5-bromo-thiophene-3- formic acid (10.8g), content of 92% meastured by HPLC.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 50℃; for 18h;Darkness;
3-Thenoic acid (1.49 g, 11.7 mmol) and N-bromosuccinimide (NBS) (4.60 g, 25.8 mmol) were added to degassed DMF (24 mL). The flask was then wrapped with aluminum foil to shield the reaction mixture from light. The mixture was then stirred at 50 C for 28 h. The mixture was allowed to cool to room temperature, after which it was poured into water (300 mL). The resulting precipitate was collected by filtration and washed with saturated NaCl aq., dried over anhydrous MgSO4, and then filtrated to afford 2,5-dibromo-3-thenoic acid as a white dasolid in 88% yield.
80.7%
With bromine; acetic acid; at 60℃; for 24h;
Compound 1 (2.00 g, 15.6 mmol) was dissolved in glacial acetic acid (25.0 mL) and Br2 (12.4 g, 78.0 mmol) was added to the above solution dropwise at room temperature. The mixture was heated and stirred at 60 C for 24 h. After the reaction was completed, the mixture was poured into 200 mL of deionized water to quench the reaction. The precipitate was filtered and dissolved in ethyl acetate(EA). The solution in EA was dried with Na2SO4. After evaporation of the solvent, the crude product was purified by recrystallization from EtOH-H2O to give the product as a white powder (3.60 g, yield 80.7%; 1H NMR (500 MHz, CDCl3; d (ppm)): 13.29 (s, 1H), 7.44(s, 1H)).
31%
With bromine; acetic acid; at 50℃; for 24h;
To a solution of 3-thiophenecarboxylic acid (25.3 g) in acetic acid (200 mL) was added dropwise bromine (21.3 mL), and the mixture was stirred at 50C for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (17.3 g, 31%) as a white solid. 1H NMR(300MHz, CDCl3) delta ppm 7.40(m,1H)
R.133 5-Nitro-3-thiophenecarboxylic Acid
Reference Example 133 5-Nitro-3-thiophenecarboxylic Acid 3-Thiophenecarboxylic acid (5.12 g) was added portionwise to a mixture of nitric acid (20 ml) and sulfuric acid (11.5 ml) below 5° C. The mixture was stirred at the same temperature for 30 minutes, and poured into ice water. The mixture was alkalified with 1N sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 5-nitro-3-thiophenecarboxylic acid (4.45 g) as crystals. mp 117°-118° C.
An ethereal solution of diazomethane (prepared by literature methods) [27] was slowly added to a cold mixture of 3-thiophenecarboxylic acid (5.0 g, 39 mmol) in ether (10 mL) (caution: diazomethane is explosive and highly toxic. Avoid using sharp materials). When the evolution of the nitrogen liberated in the reaction finished and the excess of diazomethane was noted (yellow color), no more diazomethane was added. The reaction mixture was stirred for 2 h in an ice-water bath and for 2 h at room temperature to insure complete reaction. The solution was filtered and the ether and excess of diazomethane were evaporated under reduced pressure. The viscous residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to give an oil. The complete disappearance of the substrate was checked by silica gel TLC. In the TLC plate the product was visualized by UV light and also by p-dimethylaminobenzaldehyde solution [30] (color of the spot: reddish); Rf (hexane/ethyl acetate 2:1) = 0.72. Identification data: IR (KBr) nu (cm-1): 1718, 1352; 1H NMR (300 MHz, Cl3CD) delta (ppm): 8.10 (dd, 1H, J = 3.0, 1.2 Hz), 7.52 (dd, 1H, J = 5.1, 1.2 Hz), 7.30 (dd, 1H, J = 5.1, 3.1 Hz); 3.87 (s, 3H). 13C NMR (200 MHz, Cl3CD) delta (ppm): 163.2, 132.6, 130.8, 128.8, 127.8, 52.8.
Compound 9 was synthesized as reported previously [24]. To a solution of diisopropylamine (233g, 2.30mol) in THF (2.3L), a solution of n-BuLi (1.6M in n-hexane, 1.50L, 2.40mol) was added dropwise at 0C. After stirring at the same temperature for 40min, the reaction mixture was cooled to-60C, compound 8 (223g, 1.74mol) in THF (500mL) added dropwise, and stirred at the same temperature for 1h. After the addition of MeI (254g, 1.79mol), the reaction mixture was allowed to warm to room temperature and stirred for 1h. Next, the mixture was concentrated under reduced pressure, acidified with 6N aqueous HCl (to pH 1), and extracted with AcOEt. The organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure and the residue was crystallized with H2O/AcOH to give 209g (85%) of 9 as a pale-yellow solid: 1H NMR (400MHz, CDCl3) delta 7.45 (d, J=5.4Hz, 1H), 7.01 (d, J=5.4Hz, 1H), 2.78 (s, 3H); MS (ESI) m/z: 143 (M+H)+, 141 (M-H)-.
82.1%
1 (15.00 g, 0.12 mol) was dissolved in THF (50ml). Under argon protection, n-butyl lithium (2.0 M THF solution, 120 ml) wasadded dropwise at -78 C. The reaction mixture was stirred for 1 h at -78 C.To this mixture was added CH3I (8.7 ml, 0.14 mol), then the reactionmixture was allowed to warm to room temperature and stirred for 2 hours. Slowlyquenched the reaction with hydrogen chloride (2.0 M ethyl acetate solution), thenstirred the mixture at room temperature for 30 min before concentrating in vacuo. The residue was diluted with H2O(100 ml) and extracted with ethyl acetate (200 ml). The combined organic layerswere washed with H2O (50 ml ×2) and brine (50 ml ×2), dried overanhydrous Na2SO4, and filtrated, then the solvent wasevaporated under reduced pressure to give a yellow crude solid, which waspurified by recrystallization from acetic acid/H2O to afford 2 (14.00 g, 82.1% ) as a white solid:mp 108-110 C. 1H NMR (400 MHz, CDCl3)delta 7.45 (d, J = 5.5 Hz, 1H), 7.01 (d, J = 5.5, 1H), 2.73 (s, 3H). MS (EI) m/z: 142 (M+).
Diisopropylamine (233 g) was dissolved in tetrahydrofuran (2.3 L), a solution of n-butyllithium in hexane (1.50 L) was added dropwise thereto at 0 C., and stirring was conducted for 40 minutes. The reaction liquid was cooled to from -68 to -60 C., a solution of thiophene-3-carboxylic acid (223 g) in tetrahydrofuran (500 mL) was added dropwise thereto, and the reaction liquid was stirred for 1 hour. Methyl iodide (254 g) was then added thereto, the temperature was raised to room temperature, and the reaction liquid was further stirred for 1 hour. The reaction liquid was concentrated under a reduced pressure, 6 N hydrochloric acid was added to the obtained residue to adjust the pH to 1, and extraction was conducted by using ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration was conducted, the filtrate was then concentrated under a reduced pressure, and the obtained residue was recrystallized with water/acetic acid to give the title compound (209 g).1H-NMR (CDCl3) delta (ppm): 2.78 (3H, s), 7.01 (1H, d, J=5.5 Hz), 7.45 (1H, d, J=5.5 Hz).ESI/MS (m/z): 141 (M-H)-.
An oven-dried 100 mL round bottom flask was charged with compound 1 (2.00 g, 15.6 mmol) and tetrahydrofuran (THF; 30 mL). The solution was cooled to -78.0 C and 2.50 M n-butyllithium in hexane (12.6 mL, 31.5 mmol) was slowly added dropwise. The reaction mixture was stirred for 30 min at -78.0 C and bromine (0.86 mL, 16.4 mmol) was added dropwise. Stirring was continued for 1 h at -78.0 C and the mixture was heated to room temperature. After stirring the mixture overnight, a small amount of dilute 1M HCl (50.0 mL) was added to quench the reaction and the solution was then concentrated. After extracting the resultant mixture using ether and water, the organic layer was dried with Na2SO4. The compound was recrystallized twice using a H2O/ether mixture to furnish the compound as faint yellow needles (2.13 g, yield 66.0%; 1H NMR (500 MHz, DMSO-d6, d (ppm)): 7.63-7.62 (d,J 5.8 Hz, 1H), 7.32-7.31 (d, J 5.8 Hz, 1H)).
Ca. 50%
With carbon tetrabromide; lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 2h;
The reaction temperature was -78 , the reaction time was 2h, the yield was about 50%. In a 1 L two-necked flask, 24.5 g of 3-methylthiophene (98 g mol-1,24.5 g, 250 mmol) was added and 400 mL of chloroform / glacial acetic acid (V: V = 1: / L,Favoring the inhibition of the bis-brominated product), 44.5 g of NBS (178 g mol-1, 44.5 g, 250 mmol) were added in portions in an ice-water bath.After the addition of NBS to continue stirring for 2-3 hours, TLC monitoring. After treatment: deionized water to quench the reaction, liquid separation, the organic phase was NaOH solution, washed with water, dried, concentrated vacuum pump with fractional distillation.
At low temperature (-78C), n-BuLi (24.99 g, 390.16 mmol) was slowly added dropwise to a solution of diisopropylamine (39.48 g, 390.16 mmol) in tetrahydrofuran (250 mL). After completion of addition, the reaction solution was slowly warmed up to 0C, stirred for half an hour and then cooled to -78C. A solution of thiophene-3-carboxylic acid (25 g, 195.08 mmol) in tetrahydrofuran (100 mL) was added dropwise. After completion of dropwise addition, the reaction solution was slowly warmed up to 20C with stirring for half an hour, and added with CBr4 (64.69 g, 195.08 mmol) with stirring for 1h. TLC showed complete reaction, the reaction solution was quenched with saturated NH4Cl (20 mL), then added with 1N HCl (300mL) to acidize, and extracted with DCM (300 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized in 50% ethanol (500 mL) to give the title compound (40 g, crude), which was used directly in the next step. 1H NMR (400MHz, DMSO-d6) delta = 7.64 - 7.60 (m, 1H), 7.31 (d, J=5.8 Hz, 1H).
With hydrogen bromide; oxygen In acetonitrile for 10h; Irradiation;
80%
With carbon tetrabromide; oxygen; triphenylphosphine In acetonitrile for 10h; fluorescent irradiation;
76%
With dichloro(1,5-cyclooctadiene)ruthenium(II); C30H30N3P2(1+)*Cl(1-); potassium hydroxide In toluene at 120℃; for 24h; Inert atmosphere; Schlenk technique;
15%
With N-Bromosuccinimide; oxygen In acetonitrile at 20℃; for 10h; Irradiation;
64 %Spectr.
With oxygen; potassium hydroxide In methanol; water at 50℃; for 8h;
Multi-step reaction with 2 steps
1: tert.-butylnitrite; oxygen / 1,4-dioxane / 24 h / 25 °C / 760.05 Torr / Green chemistry
2: oxygen / 1,4-dioxane / 24 h / 80 °C / 760.05 Torr / Green chemistry
Stage #1: 5,5-dimethyl-2-(thiophen-3-yl)-1,3,2-dioxaborinane; carbon dioxide With [Ni(N,N'-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]imidazole-2-ylidene)(allyl)Cl]; potassium <i>tert</i>-butylate In toluene at 100℃; for 15h; Schlenk technique; Inert atmosphere;
Stage #2: With hydrogenchloride In water; ethyl acetate; toluene at 20℃;
83%
Stage #1: 5,5-dimethyl-2-(thiophen-3-yl)-1,3,2-dioxaborinane; carbon dioxide With potassium <i>tert</i>-butylate; silver(I) acetate; triphenylphosphine In 1,4-dioxane at 100℃; for 8h; Inert atmosphere; Autoclave;
Stage #2: With hydrogenchloride In tetrahydrofuran; water Inert atmosphere;
64%
With 1,3-bis-(diphenylphosphino)propane; cesium fluoride In 1,4-dioxane at 60℃;
Preparation Example U-1. Thiophen-3-yl-carbamic acid tert-butyl ester Thiophene-3-carboxylic acid (2.50g, 19.5mmol), diphenylphosphoryl azide (4.62mL, 21.5mmol), triethylamine (3.26mL,23.4mmol) were dissolved in tert-butanol (50mL), and the solution was stirred for 3.5 hours under reflux. Water was added to the reaction solution at 0C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the title compound (3.33g, 16.7mmol,86%) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) delta (ppm):1.46 (9H, s), 6.97 (1H, d, J=5.2Hz), 7.16 (1H, s), 7.38 (1 H, m), 9.61 (1H, s).
86%
With diphenyl phosphoryl azide; triethylamine; for 3.5h;Heating / reflux;
Thiophene-3-carboxylic acid (2.50g, 19.5mmol), diphenylphosphoryl azide (4.62mL, 21.5mmol), triethylamine (3.26mL, 23.4mmol) were dissolved in tert-butanol (50mL), and the solution was stirred for 3.5 hours under reflux. Water was added to the reaction solution at 0C, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and the title compound (3.33g, 16.7mmol,86%) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) delta(ppm) :1.46 (9H, s), 6.97 (1H, d, J=5.2Hz), 7.16 (1H, s), 7.38 (1 H, m), 9.61 (1 H, s).
69%
With diphenyl phosphoryl azide; triethylamine; for 22h;Heating / reflux;
3-Thiophenecarboxylic acid (31 g, 0.24 mol), Diphenylphosphoryl azide (57 mL, 0.26 mol) and triethylamine (36 mL, 0.26 mol) were combined in dry tert-butanol (450 mL) and the resulting solution was heated to reflux. After 22 h the cooled solution was concentrated in vacuo to remove solvent. The residue was taken up in diethyl ether (1.5 L) and washed with 5% aqueous citric acid, water and brine (1.5 L each), dried (Na2SO4), and concentrated in vacuo to give the crude product as a tacky tan solid (51 g). Recrystallization from hot ethyl acetate-hexane gave the title compound (33 g, 69%, m.p. 139-41 C.) as shiny off-white needles. 1H NMR delta 1.45 (s, 9 H, (CH3)3), 6.97 (m, 1 H, ArH), 7.16 (broad s, 1 H, ArH), 7.37 (m, 1 H, ArH), 9.60 (broad s, 1 H, NH). MS (ESI) m/z 198 [M-H]- Analysis calc. for C18H13FO3S: C, 54.25; H, 6.58; N, 7.03 Found: C, 54.26; H, 6.48; N, 6.99
Step 1: Into a 100 mL round bottom flask containing a solution of thiophene-3-carboxylic acid (4.0 g, 31 mmol) in toluene (40 mL) were added diphenylphosphoryl azide (9.5 g, 34 mmol) andN,N-diisopropylethylamine (6.7 mL, 38 mmol) at 0 C and the reaction was stirred at roomtemperature for 1 h. The reaction mixture was cooled to 0 C, treated with tert-butanol (12 mL,124 mmol) and heated to 120 C for 5 h. The reaction mixture was concentrated under reducedpressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (2-5%) to afford tert-butyl thiophen-3-ylcarbamate as a solid. ?H NMR (CDC13, 400 MHz): 5 7.23-7.21 (m, 2H), 6.93 (d, J 5.6 Hz, 1H), 6.71 (brs, 1H), 1.54 (s, 9H).
Step 1: Into a 100 mL round bottom flask containing a solution of thiophene-3-carboxylic acid(4.0 g, 31 mmol) in toluene (40 mL) were added diphenylphosphoryl azide (9.5 g, 34 mmol) andN,N-diisopropylethylamine (6.7 mL, 38 mmol) at 0 C and the reaction was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 C, treated with tert-butanol (12 mL, 124 mmol) and heated to 120 C for 5 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (2-5%) to afford tert-butyl thiophen-3-ylcarbamate as a solid. ?H NMR (CDC13, 400 MHz): 5 7.23-7.21 (m, 2H), 6.93 (d, J 5.6 Hz, 1H), 6.71 (brs, 1H), 1.54 (s, 9H).
Step 1: Into a 100 mL round bottom flask containing a solution of thiophene-3-carboxylic acid (4.0 g, 31 mmol) in toluene (40 mL) were added diphenylphosphoryl azide (9.5 g, 34 mmol) and NN-diisopropylethylamine (6.7 mL, 38 mmol) at 0 C and the reaction was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 C, treated with fert-butanol (12 mL, 124 mmol) and heated to 120 C for 5 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (2- 5%) to afford fert-butyl thiophen-3-ylcarbamate as a solid. 1 NMR (CDC13, 400 MHz): delta 7.23- 7.21 (m, 2H), 6.93 (d, J= 5.6 Hz, 1H), 6.71 (brs, 1H), 1.54 (s, 9H).
Step 1: Into a 100 mL round bottom flask containing a solution of thiophene-3-carboxylic acid (4.0 g, 31 mmol) in toluene (40 mL) were added diphenylphosphoryl azide (9.5 g, 34 mmol) and N,N-diisopropylethylamine (6.7 mL, 38 mmol) at 0 oC and the reaction was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 oC, treated with tert-butanol (12 mL, 124 mmol) and heated to 120 oC for 5 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (2- 5%) to afford tert-butyl thiophen-3-ylcarbamate as a solid. 1H NMR (CDCl3, 400 MHz): delta 7.23- 7.21 (m, 2H), 6.93 (d, J = 5.6 Hz, 1H), 6.71 (brs, 1H), 1.54 (s, 9H).
With oxalyl dichloride; potassium carbonate;pyridine; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 19h;
3-Thiophenecarboxylic acid (2.0 g, 15.6 mmol) was dissolved in methylene chloride (100 mL) and 2 drops of DMF were added. The mixture was cooled to 0 0C and oxalyl chloride (1.5 mL, 17.1 mmol) was added slowly and allowed to warm to room temperature. Gas evolution was observed during warming. 3-Methyl-4-iodoaniline (5.45 g, 23.5 mmol), 4 drops of pyridine and K2CO3 (2.58 g, 18.7 mmol) are dissolved in CH2Cl2 (10 mL) and <n="112"/>cooled to about 0 0C. After about Ih, the acid chloride mixture is slowly added to the cooled aniline mixture and allowed to warm to room temperature and stirred for about 18h. The resulting mixture is filtered, washed with ethyl acetate and the filtrate is concentrated to a brown oil. The crude material was purified via flash chromatography (10-30% ethyl acetate in hexanes) to afford the title compound (1.56 g, 29%) as an off-white solid.
Stage #1: 3-Thiophene carboxylic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5h;
4.2.15 4.2. Typical procedure for the primary amidation of 3-phenylpropanoic acid 1a with NH4Cl
General procedure: To a colorless solution of 75mg (0.50mmol) of 3-phenylpropanoic acid 1a in 10mL of THF were added at 0°C 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) was added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 72mg (96% yield) of 3-phenylpropanamide 2a. 4.2.15 Thiophene-3-carboxamide 2o 29 mg (45%); colorless powder; mp: 178-180 °C; 1H NMR (400 MHz, MeOD-d4): δ 7.46, 7.50, 8.08 (dd, dd, dd, J = 2.9, 5.1, 1.4, 5.1, 1.4, 2.9 Hz, 1H, 1H, 1H, thiophenyl); 13C NMR (100 MHz, MeOD-d4): δ 127.5, 127.9, 130.6, 138.1, 167.8; IR (KBr, vmax/cm-1) = 3359 (CONH), 1622 (CON); HRMS (ESI-TOF): Calcd for C5H5NOSNa (M+Na)+: 149.9984, found: 150.0010.
Multi-step reaction with 2 steps
1: thionyl chloride / 0.5 h / 85 °C / Reflux
2: ammonium hydroxide / dichloromethane / 0.5 h / Cooling with ice
With ammonia at 155℃; for 0.5h;
A Amide Intermediate Preparation Example A
General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1% by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min).
Multi-step reaction with 2 steps
1: thionyl chloride / toluene / 2 h / Reflux
2: ammonium hydroxide / water; dichloromethane / 1 h / 0 - 20 °C
Stage #1: 3-Thiophene carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.333333h; Inert atmosphere;
Stage #2: With ammonium hydroxide In dichloromethane at 20℃; for 3h; Inert atmosphere;
With dmap; benzotriazol-1-ol; 1,2-dichloro-ethane; In dichloromethane; for 8h;
To a solution of 3-fluoro-4- [piperazinyl-4-yl]-phenyl]-2-oxazolidin-5- yl] methyl] acetamide (prepared according to the procedure described in preparation 9) in DMF (5 ml), thiophene 3-carboxylic acid (160 mg, 1.25 mmol), 1-hydroxybenztriazole hydrate (HOBt) (202.7 mg, 1.5 mmol), dichloroethane, (EDC) (597 mg, 3.12 mmol) and DMAP (50 mg) were added and the resulting mixture was stirred for 8 hrs. The product was extracted with EtOAc and water. The organic layer was separated, dried over Na2S04 and solvent was removed under vacuum. The product was purified onto a silica gel column using 20 % MeOH in EtOAc to afford the title compound (302 mg, yield 54%). H-NMR (CDCl3): delta 2.0 (3H, s), 3.0 (4H, m), 3.8 (1H, m),] 3.9 (4H, m), 4.3 (3H, m), 5.0 (1H, m), 6.8-7. 3 (6H,m, aromatic). Mass: M+1= 447
13 ml (200 mmol) of thionyl chloride are added dropwise, at 0oC, to a solution of 9 g (70 mmol) of 3-thiophenecarboxylic acid and 86 mg (0.7 mmol) of 4-dimethylaminopyridine in 100 ml of ethanol. The reaction medium is stirred from 0oC to room temperature over 48 hours and then evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 1/1 heptane/dichloro- methane mixture. 10 g (91%) of ethyl thiophene-3- carboxylate are obtained.
With sulfuric acid;Reflux;
To a solution of thiophene-3-carboxylic acid (12.8 g, 100 mmol) in 250 mL ethanol was added 3 mL sulfuric acid. Then the reaction mixture was refluxed overnight. After cooling to room temperature, the solvent was removed using rotary evaporator. The resulting yellow oil was purified by column chromatography on silica gel using dichloromethane as the eluent to give ethyl thiophene-3-carboxylate as a colorless oil. To a solution of diisopropyl amine (2.88 mL, 20 mmol) in 100 mL dry ether at -78 , n-BuLi (2.4 M in hexane, 8.3 mL, 20 mmol) was added dropwise under argon to form lithiumdiisopropylamide (LDA). A solution of ethyl thiophene-3-carboxylate (3.12 g, 20 mmol) in 10 mL dry ether was then added dropwise to the formed LDA over the period of 20 min. The resulting solution was stirred at -78 for 1 h. To the reaction mixture was added trimethyltinchloride (44 mL, 44 mmol) in one portion via syringe injection at -78 . Then the cooling bath was removed and the mixture was gradually warmed to room temperature. After stirring for 4 h at room temperature, the reaction solution was quenched with H 2O. The solvent was then evaporated under reduced pressure, and the crude product was purified by column chromatography on silica gel using dichloromethane as the eluent to give 18 as a colorless oil (5.4 g, 84.6 %). 1H NMR (400 MH Z, CDCl 3) delta 7.72-7.70 (d, 1H), 7.58-7.56 (d, 1H), 4.39-4.34 (q, 2H), 1.42-1.39 (t, 3H), 0.49-0.35 (t, 9H). 13C NMR (100 MHz, CDCl 3) delta 164.28, 150.81, 139.74, 131.21, 129.58, 60.65, 14.47, -7.19.
With sodium hypochlorite; C8H18NPol; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5h;
7
EXAMPLE 7 5.00 g (0.0438 mol) of 3-thiophenemethanol, 0.138 g of PIPO obtained in Reference Example 1 (2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl group: 0.000438 mol), 10.0 g of toluene and 5.0 g of a 5% by weight aqueous solution of sodium hydrogen carbonate (sodium hydrogen carbonate: 0.0030 mol) were placed in a 100 ml reaction vessel. Then, with maintaining the temperature at 15 to 20° C., reaction was conducted while 24.4 g of a 13.4% by weight aqueous solution of sodium hypochlorite (sodium hypochlorite: 0.0438 mol) was dropped over 4 hours by a microsyringe pump under stirring. Stirring was conducted for another 0.5 hour to complete the reaction. The reaction mixture after the reaction was completed was separated into the organic phase and the water phase and each phase was analyzed by liquid chromatography. By the reaction, 3-thiophenecarbaldehyde was produced with yield of 87.5% (based on 3-thiophenemethanol). As a by-product, 0.1% (based on 3-thiophenemethanol) of 3-thiophenecarboxylic acid was produced.
1: 65%
2: 18 %Spectr.
With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium chloride; oxygen In 1,2-dichloro-ethane at 25℃; for 48h; Schlenk technique;
General procedure: To a Schlenk tube were added Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol), TEMPO (15.8 mg, 0.1 mmol), KCl (7.5 mg, 0.1 mmol), 1a (108.5 mg, 1.0 mmol), and DCE (4.0 mL) sequentially under an atmosphere of oxygen (gas bag, commercial size: 2 L, which could be expanded to 5 L). The mixture was then stirred at 25 °C until completion of the reaction as monitored by TLC (petroleum ether/EtOAc = 5:1) (48h). The crude reaction mixture was filtered through a short column of silica gel (height: 2 cm, diameter: 3 cm) eluting with Et2O (3 × 25 mL). After evaporation, the residue was purified by chromatography on silica gel [petroleum ether/EtOAc = 15:1 (500 mL) to 2:1 (300 mL)] to afford benzoic acid (2a)14 (69.9 mg, 57%) as a pale yellow solid.
1: 52.3%
2: 2.3%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5h;
3
COMPARATIVE EXAMPLE 3 The experiment was conducted in the same manner as in Example 7, except that 0.072 g (0.000458 mol) of 2,2,6,6-tetramethylpiperidine-1-oxyl was used instead of PIPO. As a result, by the reaction, 3-thiophenecarbaldehyde was produced with yield of 52.3% (based on 3-thiophenemethanol). As a by-product, 2.3% (based on 3-thiophenemethanol) of 3-thiophenecarboxylic acid was produced.
Preparation of N-(3-methoxybenzyl)-5-{IH-pyrrolo[2,3-b]pyridin-3- yl)thiophene-3-carboxamide; [00263] 5-Bromothiophene-3-carboxylic acid:; Thiophene-3-carboxylic acid (0.51 g, 4 mmol) was dissolved in HOAc (5 mL) and Br2 (0.21 mL, 4 mmol) was added in 1 mL HOAc. The reaction mixture was stirred for 40 minutes, poured into water and a white precipitate formed, which was filtered and dried to 0.70 g grams of product that contains about 30 % 2,5-dibromothiophane- 3-carboxylic acid.
With bromine; In acetic acid; at 20℃; for 7.5h;
(Step 1) A solution of bromine (4.4 mL) in acetic acid (30 mL) was added to a solution of thiophene-3-carboxylic acid (9.8 g) in acetic acid (40 mL) at room temperature for as long as 30 minutes. The reaction solution was stirred at room temperature for 7 hours, and water (200 mL) was added. The deposited precipitate was filtrated to obtain a mixture of 2-bromothiophene-4-carboxylic acid and 2.5-dibromothiophene-3-carboxylic acid (approximately 5:1).
furan-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-yl-methyl]-amide[ No CAS ]
furan-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
furan-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
furan-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
N-[4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-nicotin amide[ No CAS ]
pyrazine-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
isoxazole-5-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
1-methyl-1H-pyrrole-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
isoxazole-5-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
thiophene-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
N-[4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-nicotinamide[ No CAS ]
pyrazine-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
thiophene-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
1-methyl-1H-pyrrole-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
5-methyl-isoxazole-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
5-methyl-isoxazole-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
1,5-dimethyl-1H-pyrazole-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
5-oxo-pyrrolidine-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
[1,2,3]-thiadazole-4-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
N-[4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-1-hydroxyisonicotin amide N-oxide[ No CAS ]
tetrahydro-furan-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
tetrahydro-furan-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
5-methyl-pyrazine-2-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
2,5-dimethyl-furan-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-3-ylmethyl]-amide[ No CAS ]
2,5-dimethyl-furan-3-carboxylic acid [4'-(1,1-dimethyl-6-morpholin-4-yl-6-oxo-hexyl)-2'-hydroxy-biphenyl-2-ylmethyl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Compounds 41-70 were part of a parallel set prepared in library plate format according to General Procedure L, outlined below. ; L. General Procedure for Plate Preparation-Amide Formation XXI: Resin bound deprotected biarylphenol XVII (prepared from intermediate XII, boronates XIVd and XIVe, following general procedures D-F) was distributed into a 96 well plate, 10 mg of resin (0.013 mmol) per well. To the resin 400 mul of dichloromethane was added, followed by 100 mul of DIEA, followed by 0.13 mmol (10 equiv) of heterocyclic carboxylic acid XXa-XXn was added followed by 61 mg (0.13 mmol, 10 equiv) of PyBrop. The plate was shaken at room temperature for 24 hours, then drained and washed with dichloromethane, methanol/dichloromethane, dimethylformamide, methanol/dichloromethane and dichloromethane. The compounds were cleaved with TFA/dichloromethane (600 mul, 1:1) into a 96 deep well plate and submitted for testing without further purification. (Mass spec results obtained are shown in Table 4). Carboxylic Acids Het-COOH XX:
(a) Methyl thiophene-3-carboxylate: 19.85 g (154.9 mmol) of thiophene-3-carboxylic acid and 700 ml of methanol are introduced into a two-liter three-necked flask under a stream of nitrogen. 7 ml of concentrated sulphuric acid are added dropwise and the mixture is refluxed for sixteen hours. The mixture is cooled, the methanol is evaporated off, water is added, the mixture is extracted with ethyl ether, the organic phase is washed with water to neutral pH, dried over magnesium sulphate and filtered and the solvents are evaporated off. 20.26 g (92%) of the expected compound are collected in the form of a pale yellow oil. 1 H NMR (CDCl3) delta 3.87 (s, 3H), 7.30 (dd, 1H, J=3.1/5.0 Hz), 7.53 (dd, 1H, J=1.1/5.1 Hz), 8.10 (dd, 1H, J=1.1/3.0 Hz).
With n-butyllithium; In tetrahydrofuran; hexane; ethyl acetate;
2-Methyl-3-thiophenecarboxylic acid To a suspension of 5.32 g (41.5 mmol) of 3-thiophenecarboxylic acid in 100 ml of anhydrous tetrahydrofuran (chilled to -78 C.) was added 57.1 ml (91.4 mmol) of 1.6M n-BuLi in hexanes. The cloudy suspension was stirred at -78 C. under a blanket of argon for 40 minutes, and was then transfered via canulla onto a solution of 59.05 g (25.9 ml, 416 mmol) of methyl iodide dissolved in 20 ml of anhydrous tetrahydrofuran (chilled to -78 C.). The resulting clear, colorless solution was allowed to warm to room temperature and stirred for 20 hours. A white solid was formed. The reaction mixture was concentrated in vacuo, partitioned between 75 ml of sat. NH4 Cl solution and 150 ml of ethyl ether, and the layers separated. The aqueous phase was washed with 100 ml of ethyl ether and layered with 100 ml of ethyl ether and acidified with 1N sulfuric acid solution until all of the yellow emulsion dissapated. All organic phases were combined, washed with brine solution, dried over MgSO4, filtered and concentrated in vacuo to yield an off-white solid. Purification by flash chromatography (silica gel, 75% ethyl acetate in hexane) yielded the title compound as an off white solid. PMR (CDCl3): d 2.78 (3H, s), 7.01 (1H, d, J=5.4 Hz), 7.45 (1H, d, 5.4 Hz).
Reference Example 127 2-Methyl-3-thiophenecarboxylic Acid 3-Thiophenecarboxylic acid (3.84 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78 C. n-Butyllithium (1.6M in hexane, 41.3 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Iodomethane (3.7 ml) in tetrahydrofuran (10 ml) was added dropwise. The resulting mixture was heated to room temperature and stirred for 15 hours. The mixture was poured into water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid (3.98 g) as crystals. mp 71-73 C.
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; hexane; N,N-dimethyl-formamide;
Reference Example 132 2-Difluoromethyl-3-thiphenecarboxylic Acid 3-Thiophenecarboxylic acid (3.48 g) was dissolved in tetrahydrofuran (50 ml), and N,N,N',N'-tetramethylethylenediamine (10 ml) was added. The mixture was cooled to -78 C., and n-butyllithium (1.6M in hexane, 41.3 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (4.6 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a mixture of 2-formyl-3-thiophenecarboxylic acid and 5-formyl-3-thiophenecarboxylic acid (2.11 g).
Example 26 N,N-Diethyl-3-thiophenecarboxamide To a 0oC nitrogen flushed solution of 7.5 g of thiophene 3-carboxylic acid, 6.44 ml of N -methylmorpholine, and 150 ml of tetrahydrofuran was added 7.3 ml of trimethylacetyl chloride. The mixture was stirred at 0oC for 1 hour followed by the addition of 6.04 ml of diethylamine in 40 ml of tetrahydrofuran. The reaction was stirred at room temperature for 16 hours, concentrated in vacuo and dissolved in dichloromethane. The organic layer was washed with 10% NaOH, 10% HCl, water and a saturated brine solution. The dichloromethane solution was dried over sodium sulfate, concentrated in vacuo and purified by column chromatography giving 6.59 g of a yellow oil.
Thiophene-3-carboxylic acid (2.75g, 21.45mmol) and HATU (8.15g, 21.45mmol) in DMF (25ml) were stirred at room temperature for 15mins. HOBT (2.9g, 21. 45mmol), 3- iodo-4-methylaniline (5. Og, 21. 45mmol) and DIPEA (11. 2ml, 64.35mmol) were added and the reaction stirred at room temperature for 16hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (4: 1). The solvent was evaporated from the product fractions under vacuum to give N- (3-iodo-4-methylphenyl) thiophene-3-amide. LCMS: retention time 3. 69min, MH+ 344. NMR: No.H [2H6]-DMSO 10.06, (1H, b), 8.34, (1H, m), 8.29, (1H, d), 7.70, (1H, dd), 7.66, (1H, dd), 7.62, (1H, dd), 7.30, (1H, d), 2.34, (3H, s).
Thiophene-3-carboxylic acid (2.75g) and HATU (8.15g) in DMF (25ml) were stirred at room temp for 15min. HOBT (2.9g), <strong>[35944-64-0]3-iodo-4-methylaniline</strong> (5. 0g) and DIPEA (11.2ml, 64. 35mmol) were added and the reaction was stirred at room temp for 16h. The solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a silica column and eluted with cyclohexane/ethyl acetate (4: 1). The solvent was evaporated from the product fractions under vacuum to the title compound. NMR: 8H [d6-DMSO] 10.06, (1H, b), 8.34, (1H, m), 8.29, (1H, d), 7.70, (1H, dd), 7.66, (1H, dd), 7.62, (1H, dd), 7.30, (1H, d), 2.34, (3H, s). LCMS: Rt 3.69min, MH+ 344.
With 14C2H7N*14H(1+)*2H2O*2Hf(4+)*2O(2-)*O122P4W34(18-) In dimethyl sulfoxide at 90℃;
89%
Stage #1: 3-Thiophene carboxylic acid With niobium pentachloride; 1-n-butyl-3-methylimidazolim bromide In toluene at 20℃; for 0.5h; Molecular sieve;
Stage #2: benzylamine In toluene for 24h; Reflux; Molecular sieve;
3 Example 3
Add 3-thiophenecarboxylic acid (256mg, 2mmol), niobium pentachloride (11mg, 0.08mmol), ionic liquid 5 (22mg, 0.05mmol) and 4A molecular sieve (122mg, 50%, w/w%) into a round bottom flask After adding toluene (4 mL, 2 mL/mmol), stirring at room temperature for 30 minutes, then adding benzylamine (214 mg, 2 mmol), heating to reflux, and reacting for 24 hours. After the reaction is complete, flash column chromatography (petroleum ether→ethyl acetate:triethylamine (200:1, v/v)) to pass the column to obtain 386 mg of white solid with a yield of 89%.
85%
at 160℃; for 7h; Molecular sieve; Neat (no solvent);
To a solution of thiophene-3-carboxylic acid (26.65g) in THF (300 ml) was added 2M lithium DIISOPROPYLAMIDE (229 ml) dropwise at 0-5C with stirring under nitrogen, and the resulting mixture stirred for 15 min. A solution of N-methoxy-N, 2- dimethylpropanamide (30 g) in THF (150 ml) was added dropwise over a period of 1 hr. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hr. It was poured onto water, the layers separated and the aqueous washed with ether. The aqueous was acidified with CONC. hydrochloric acid and extracted with ethyl acetate, the organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound as a solid (38. 91 g). HDMSO 1.10 (6H, d), 3.30 (1H, m), 7.37 (1H, d), 7.85 (1H, d)
Stage #1: carbon dioxide With o-phenylenebis(diphenylphosphine); copper(II) acetate monohydrate In 1,4-dioxane at 65℃; for 0.333333h; Schlenk technique;
Stage #2: 3-Bromothiophene With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane; toluene at 100℃; for 7h; Schlenk technique; Sealed tube;
94%
Stage #1: carbon dioxide With o-phenylenebis(diphenylphosphine); copper(II) acetate monohydrate In 1,4-dioxane at 60℃; for 0.416667h; Schlenk technique;
Stage #2: 3-Bromothiophene With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane; toluene at 100℃; for 7h; Schlenk technique;
5 Preparation of benzoic acid
General procedure: In a Schlenk (50 mL) reaction flask with a carbon dioxide balloon attached to a branch tube, add Cu (OAc) 2.H2O (0.0125 mmol), 1,2-bis (diphenylphosphine) benzene (0.018 mmol), and 1,4 -Dioxane (2.0mL), PMHS (2.5mmol) was added under stirring, and then the reaction flask was placed in an oil bath at 60 ° C for 25min to react under carbon dioxide atmosphere, followed by toluene (8mL) and bromobenzene (1.0 mmol), Pd (OAc) 2 (0.03 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.06 mmol), Et3N (2.5 mmol, 2.5 equiva.), The carbon dioxide was then removed and reacted at 100 ° C until the raw bromobenzene disappeared. After cooling to room temperature, sodium hydroxide solution (1M, 10.0mL) was added, stirred for 10min, and filtered. The solid was washed three times with water, and the filtrate was washed with ethyl acetate ( 2 × 10mL) left after extraction, the aqueous layer was adjusted to pH 1-2 with hydrochloric acid solution (1M), extracted with ethyl acetate (3 × 15mL), dried over anhydrous sodium sulfate,The solvent was removed to give benzoic acid. Yield, 65%.
65%
With manganese; 2.9-dimethyl-1,10-phenanthroline; lithium acetate; cobalt(II) bromide In N,N-dimethyl acetamide at 20℃; for 12h; Inert atmosphere; Schlenk technique;
62%
With diethylzinc; palladium diacetate; tert-butyl XPhos In hexanes; N,N-dimethyl acetamide at 40℃; Automated synthesizer;
42%
With tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 4h; Electrolysis;
40%
With [2,2]bipyridinyl; lithium chloride; cobalt(II) iodide; zinc In N,N-dimethyl-formamide; acetonitrile at 40℃; for 14h; Sealed tube;
With (2’,4’,6’-triisopropyl-[1,1’-biphenyl]-2-yl)-diphenylphosphine; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; palladium diacetate; caesium carbonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 6h; Irradiation;
Stage #1: [(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-(3-amino)tetrahydro-2H-pyran-2,4,5-triyl]triacetate hydrochloride With triethylamine In dichloromethane at 20℃; Cooling with ice;
Stage #2: 3-Thiophene carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;
With diethyl cyanophosphonate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;Cooling;
General procedure: To a cooled and stirred solution of the appropriate acid (3-methoxybenzoic acid, thiophene 3-carboxylic acid and piperonylic acid) (0.42 mmol) and a catalytic amount of Et3N (0.05 mL) in anhydrous DMF (1-2 mL), diethylcyanophosphonate (DCF) (1.68 mmol) and 1H-indazole-3-carboxylic acid phenylamide 234 (0.42 mmol) were added. The mixture was stirred at room temperature for 12 h. After dilution with cold water, the suspension was extracted with CH2Cl2 (3 × 15 mL), and the solvent was evaporated in vacuo, resulting in a residue oil, which was purified by column chromatography using toluene/ethyl acetate (8:2) as eluent.
Stage #1: 3-Thiophene carboxylic acid; β-naphthol With dmap In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;
Stage #2: With dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 24h; Inert atmosphere;
2.4.3 Synthesis of monomer 3
The Steglich esterification between 3-thiophenecarboxylic acid and 2-naphthol was performed in a one pot reaction and illustrated in Scheme 3. The 3-thiophenecarboxylic acid (1 mmol) was reacted with the terminal hydroxyl group of naphthol (1 mmol) in the presence of N,N-dimethylaminopyridine (DMAP) (2 mmol) in CH2Cl2/DMF (10 ml/2 ml). The reaction mixture was cooled to 0 °C and stirred vigorously under N2 for 30 min prior to addition of DCC to increase its reactivity. Dicyclohexylcarbodiimide (DCC) (2 mmol) was dissolved in 1-2 ml of CH2Cl2 and added to the stirring mixture at 0 °C. The solution was stirred at room temperature under N2 for 24 h. The solvent was evaporated in vacuo. Dicyclohexyl urea (DCU) was removed by dissolving the crude product in CH2Cl2 and placed in the freezer for 30 min and filtered through a crucible. The crude product was purified with column chromatography (chloroform) to afford pure thiophene-naphthalene (ThN) compound as an off-white solid. The monomer was obtained in a 56% yield.
Stage #1: 3-Thiophene carboxylic acid With lithium diisopropyl amide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide at -78℃; for 1h;
Stage #2: N-methyl-N-methoxyisonicotinamide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide at -78 - 20℃;
2.1 2.1 2-Isonicotinoylthiophene-3-carboxylic acid
2.1 2-Isonicotinoylthiophene-3-carboxylic acid To a solution of diisopropylamine (5.2 g, 51 5 mmol) in anhydrous THF (40 mL) at -30° C. was added n-BuLi (23.2 mL, 56.2 mmol, 2.5M in THF) dropwise. The mixture was stirred at the same temperature for 0.5 h, then cooled to -78° C. and HMPA (0.8 g, 4.7 mmol) was added slowly. Then a solution of thiophene-3-carboxylic acid (3.0 g, 23.4 mmol) in anhydrous THF (50 mL) was added slowly. The mixture was stirred at the same temperature for 1 h, N-methoxy-N-methyl-4-pyridinecarboxamide (5.0 g, 46.9 mmol) was added drop wise into the stirring mixture at -78° C. The reaction mixture was stirred for another 1 h at room temperature and was then quenched with H2O (10 mL). The aqueous layer was acidified with 5% aq. HCl to pH 1-2, the precipitate was collected by filtration. The filter cake wash with DCM and the filtrate was extracted with DCM (3*200 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with DCM to give the title product (2.2 g, yield 40%) as a white solid. LC-MS (ESI+): m/e 234 (M+H)+, Rt: 0.57 min.
40%
Stage #1: 3-Thiophene carboxylic acid With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1h;
Stage #2: N-methyl-N-methoxyisonicotinamide at -78 - 20℃;
II.1.1 1.1 2-Isonicotinoylthiophene-3-carboxylic acid
1.1 2-Isonicotinoylthiophene-3-carboxylic acid n-BuLi (23.2 mL, 56.2 mmol, 2.5M in THF) was added dropwise to a solution of diisopropylamine (5.2 g, 51.5 mmol) in anhydrous THF (40 mL) at -30°C. The mixture was stirred at the same temperature for 0.5 h and then cooled to -78°C and HMPA (0.8 g, 4.7 mmol) was added slowly. Then a solution of thiophene-3-carboxylic acid (3.0 g, 23.4 mmol) in anhydrous THF (50 mL) was added slowly. The mixture was stirred at the same temperature for 1 h. Then N-methoxy-N-methyl-4-pyridinecarboxamide (5.0 g, 46.9 mmol) was added dropwise to the stirring mixture at -78°C. The reaction mixture was stirred for another 1 h at room temperature and was then quenched with H20 (10 mL). The aqueous layer was acidified with 5% aq. HC1 to pH 1-2 and the resulting precipitate collected by filtration. The filter cake was washed with DCM and the filtrate was extracted with DCM (3x200 mL). The organic layers were dried over Na2S04 and concentrated under reduced pressure. The crude product was washed with DCM to give the title product (2.2 g, 40% yield) as a white solid. LC-MS (Method A): m/z 234 (M+H)+, Rt: 0.57 min.
N-[4-(2-pyridinyl)-1,3-thiazol-2-yl]thiophene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
General procedure: 5.1.3. General procedure C. To the carboxylic acid substrate (0.42 mmol, 1.2 equiv) in DMF (1.5 mL) was added CDI (0.50 mmol, 1.1equiv) and DBU (0.67 mmol, 1.9 equiv). The reaction was stirred for 30 min at 23 C. Next, 2-amino-4-(2-pyridyl)thiazole 20 (0.35 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 16 h at 23 C. A small amount of silica gel was added to the reaction mixture, which was concentrated in vacuo under reduced pressure. The crude product impregnated on the silica gel was purified by silica gel flash chromatography (0-10% MeOH-CH2Cl2) to afford the title compound.
Stage #1: 3-Thiophene carboxylic acid With dmap In dichloromethane at 0℃; Inert atmosphere; Schlenk technique;
Stage #2: 1-bromo-6-hexanol With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique;
Synthesis of 6-bromohexyl thiophene 3-carboxylate
In a 50 mL Schlenk flask fitted with argoninlet was added 3-thiophene carboxylic acid (0.5 g, 3.9 mmol), 4-dimethylaminopyridine (0.48g, 3.9 mmol) was added and evacuated 3 times and backfilled with argon. 25 mL of dichloromethane was added to this mixture and stirred for a few min with 0 °C. Then 1-bromo-6hexanol (0.7 g, 3.9 mmol) was added via syringe to this. A solution of DCC (0.8 g, 3.9 mmol) in 10 mL of dichloromethane was added and this solution was allowed to warm up to room temperature and stirred overnight. The product was filtered and purified by column chromatography on silica gel using hexane/EA (8.5/1.5). Yield: 0.7 g, 83%. 1H NMR: (CDCl3, ppm, JHz), 8.09 (d-d, 1H, J = 4.25), 7.53 (m, 1H, J = 4.25), 7.27-7.33 (m, 1H, J = 12), 4.28 (t,2H, OCH2 J = 8.75), 3.42 (t, 2H, CH2Br, J = 13.5), 1.82 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.44(broad, 4H, CH2). 13C NMR: (CDCl3, ppm, JHz) 162.70 (C=O), 133.79 (C-quaternary), 132.40(C-aromatic), 127.81 (C-aromatic), 125.89 (C-aromatic), 64.53 (O-CH2), 34.9-25.3 (C alkylchain). Mass spectrum: [M+] = 289.99. Elemental analysis: C11H15O2BrS calcd. C, 45.37; H,5.19; S, 11.01; found, C, 45.18; H, 5.34; S, 10.94.
A 250 mL round bottom flask charged with 3-thiophenecarboxylic acid (10.0 g, 78 mmol) was evacuated andrefilled with N2 gas for three times followed by the addition of150 mL anhydrous CH2Cl2. To this solution, anhydrous dimethylformamide(15 drops) was added and the reaction temperaturewas cooled down to 0 C. Oxalyl chloride (11.1 g, 87 mmol) wasadded to the reaction mixture and the mixturewas stirred for 2 h at0 C. The solvent was removed under reduced pressure and thereaction mixture was re-dissolved in CH2Cl2 (150 mL). To the abovesolution, diethylamine (11.4 g, 156 mmol) was added at 0 C andstirred for 16 h at room temperature. The reaction mixture waspoured into 1M aqueous HCl (200 mL) and extracted with CH2Cl2(200 mL). The organic extract was washed with saturated aqueouspotassium chloride (1 20 mL) and brine (1 20 mL) and driedover anhydrous Na2SO4. The solvent was removed under reducedpressure and crude product obtained was purified on silica gelcolumn chromatography (50% ethyl acetate and hexane eluent) toobtain the title compound as a pale yellow oil (yield 90%).1H NMR (500 MHz, CDCl3, d ppm): 1.20 (t, J 8.5 Hz, 6H), 3.45(bs, 4H), 7.19 (dd, J1 2.0 Hz and J2 4.5 Hz, 1H), 7.31e7.33 (m, 1H),7.46e7.48 (m, 1H).
With water; palladium diacetate; potassium carbonate at 20℃; for 12h;
4-Nitrobenzoic Acid (2a)
General procedure: A 25-mL flask was charged with Pd(OAc)2 (1.2 mg, 0.005 mmol), 1-iodo-4-nitrobenzene (1a, 127.0 mg, 0.5 mmol), K2CO3 (141.0 mg, 1.0 mmol), H2O (0.5 mL), and PEG 400 (2.0 mL); the flask was subjected to standard cycles (3 ×) of evacuation and back-filling with dry and pure CO. The mixture was stirred at r.t. for the indicated time. The mixture was poured into sat. aq NaCl (15 mL), acidified to pH 3 with 3 M aq HCl, and extracted with EtOAc (3 × 15 mL). The solvent was removed from the combined organic phases on a rotary evaporator. The crude product was purified by column chromatography (silica gel, PE-EtOAc-HCO2H, 25:1:1) to afford 2a as a light yellow solid; yield: 75mg (90%); mp 238.0-239.3 °C. 1H NMR (400 MHz, DMSO-d6): δ = 13.68 (br s, 1 H), 8.30 (d, J = 8.0 Hz,2 H), 8.14 (d, J = 8.0 Hz, 2 H). 13C NMR (100 MHz, DMSO-d6): δ = 165.9, 150.0, 136.4, 130.7, 123.8.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 18h;
Intermediate 4-9-A. W-(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)thiophene-3- carboxamideA mixture of thiophene-3-carboxylic acid (CAS 88-13-1 , 2.24 g, 17.5 mmol), T3P (2 M in DMF, 12.5 mL, 25 mmol), DIPEA (6.2 mL, 35.5 mmol) and 2,3,5,6-tetrafluoro-4- (trifluoromethyl)aniline (4.45 g, 19.1 mmol) was stirred at 100 C for 18 h, and then cooled to room temperature. The reaction mixture was then poured into sat. aq. NH4CI, and then stirred for 0.5 h. Resulting precipitate was collected by filtration. The precipitate was then triturated with CH2CI2 (ca. 60 mL). The solid was collected by filtration, rinsed with CH2CI2, to afford the title compound. MS (ESI+) m/z 344.0 (M+H).
4-(pyren-1-yl)butyl thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12.5h; Inert atmosphere;
3.4. Synthesis of the Monomers
General procedure: General SynthesisThe appropriate thiophene alcohol (0.82 mmol), the selected carboxylic acid (1.23 mmol), DCC(2.46 mmol) and DMAP (2.05 mmol) were dissolved in CH2Cl2 (15 mL) at 0 °C for 30 min. The resultingmixture was stirred at room temperature for 12 h under inert atmosphere. The suspension was filteredin order to remove DCU formed during the reaction, and the filtrates were concentrated under reducedpressure at 45 °C. The crude product was purified by column chromatography in silica gel, usingn-hexane/CH2Cl2 (2:5) and then pure CH2Cl2 as eluent to give the desired product TPM1 (Figure 1).All monomers were characterized by 1H- and 13C-NMR spectroscopy and the spectra are included inthe Supplementary Materials.
4-bromo-N'-(thiophene-3-carbonyloxy)benzimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 3-Thiophene carboxylic acid With 1,2-dichloro-ethane In acetone at 20℃; for 0.5h;
Stage #2: p-bromobenzamidoxime In acetone at 20℃; for 12h;
Typical proceduresfor the synthesis of O-acylamidoximes1a-w
General procedure: a) To a mixture of the carboxylic acid (5 mmol) in acetone (20 mL) was added EDC (5.5 mmol). The reaction mixture was stirred at room temperature for 30 min, then the amidoxime (5 mmol) was added. The resulting mixture was stirred at room temperature for 12 h. Acetone was evaporated at reduced pressure and to the residue was added water (100 mL). The resulting precipitate was filtered off, washed with water (50 ml) and dried under vacuum at rt.
With hydrogenchloride; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In 1,4-dioxane at 120℃; for 6h;
N,N-Dimethylthiophene-3-carboxamide (12)
General procedure: A 20 mL Radleys Carousel screw-capped glass tube was charged with carboxylic acid (2 mmol, 1.0 equiv), DMF (1.2 mL), T3P in DMF 50%(1.28 mL, 1.4 g, 1.1 equiv) and HCl (4 M in dioxane, 0.25 mL, 1.0mmol, 0.5 equiv) at r.t. The mixture was heated to 130 °C (ca. 120 °C internal) and stirred until the conversion according to LC-MS or TLCwas ≥95%. The solution was quenched at 10 °C with aq half-saturated Na2CO3 (5 mL; caution: gas evolution) and extracted with i-PrOAc (10mL and 2 × 5 mL or until no product was present in the aqueousphase). Combined organic phases were dried over MgSO4 and concentratedunder reduced pressure. The crude product was purified bychromatography on silica gel as described below. N,N-Dimethylthiophene-3-carboxamide (12) The reaction was performed according to the general procedure with3-thiophenecarboxylic acid as starting material. After work-up, thecrude material was absorbed on Celite, concentrated to dryness andpurified by chromatography on silica gel (5 g Isolute SPE column,Flash Si II; heptane-EtOAc, 4:1 to 1:2) to give 12.Yield: 283 mg (91%); colorless oil. 1H NMR (500 MHz, CDCl3): δ = 7.49 (dd, J = 1.2, 3.0 Hz, 1 H), 7.28 (dd,J = 3.0, 5.0 Hz, 1 H), 7.19 (dd, J = 1.2, 5.0 Hz, 1 H), 3.05 (s, 6 H).13C NMR (125 MHz, CDCl3): δ = 166.87, 136.80, 127.28, 126.42,125.62, 39.37, 35.54.MS: m/z = 156.09 [M + 1]+.
79%
With tert.-butylhydroperoxide; iron(III) chloride In pyridine; water; toluene at 85℃; for 8h; Inert atmosphere; Sealed tube;
10 Example 10: Synthesis of N,N-dimethyl-3-carboxamidothiophene from 3-thiophenecarboxylic acid and DMF
In the reaction flask equipped with a magnetic 20mL of a solution of 3-thiophenecarboxylic acid (0.038g, 0.3mmol),FeCl3 (0.0049 g, 0.03 mmol),TBHP (0.116 g, 0.9 mmol, 70% aqueous solution),DMF (1 mL),Toluene (1 mL),Pyridine (0.118 g, 1.5 mmol),Fill it with argon,Tighten the cap,External temperature 85 ° C closed reaction 8h;Gas chromatography monitoring;After the reaction is completed,Rotary evaporation to remove the solvent,After column chromatography (ethyl acetate: petroleum ether = 4:1), an oily liquid was obtained.Yield 79%.
N-(prop-2-yn-1-yl)thiophene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: 3-Thiophene carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;
Stage #2: Propargylamine With triethylamine In dichloromethane at 20℃; Cooling with ice;
Method B (from carboxylic acid).
General procedure: To a stirred solution of corresponding carboxylic acid (10 mmol) in dichloromethane (20 mL) was added oxalyl chloride (10 mmol, 1.269 g) and DMF (1drop). The mixture was stirred at room temperature during 2 h. After that reaction mass was cooled in an ice bath and solution of propargylamine (10 mmol, 0.551 g) and triethylamine (30 mmol, 3.036 g) in dichloromethane (5 mL) was added with stirring. The mixture was stirred atroom temperature overnight, washed with water (20 mL), brine (20 mL) and sat. aq. NaHCO3(20 mL). The solvent was removed in vacuo and the residue was purified by columnchromatography on silica gel using appropriate eluent.
With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 18h;
6,6-dimethylthieno[2,3-c]furan-4(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
Stage #1: 3-Thiophene carboxylic acid With n-butyllithium In tetrahydrofuran; hexane at -70 - -55℃; for 1h;
Stage #2: acetone In tetrahydrofuran; hexane at -70 - 0℃; for 3h;
Stage #3: With toluene-4-sulfonic acid In water; toluene at 100℃; for 16h;
10 6,6-Dimethyithieno [2,3 -cjfuran-4-one
Cool a solution of 3-thiophenecarboxyhc acid (250 g, 1,95 mol) inTHF (9750 mL) to -70 °C in a 20 L 3-neck flask. To this solution, add n-butyi lithium (2.5 M in hexane, 1872 mL, 4,68 mol) slowly while maintaining the temperature below -55 °C. Stir the reaction mixture for one hour at -70 Oc;. Add acetone (187 mL, 2.55 mol) slowly at - 70 °C. Allow the reaction mixture to warm to 0 °C and stir for three hours at 0 °C. Tothe resulting solution, add 4 M hydrochloric acid (1500 mL) at 0 °C and allow the reaction mixture to warm to room temperature. Stir the resulting mixture overnight. Filter the reaction mixture through a diatomaceous earth pad and wash the pad with toluene (3 x 500 mL). Concentrate the filtrate under reduced pressure. Dissolve the resulting crude residue in toluene (3750 mL) and water (250 mL) and add p1oiuenesulfonic acid (100,1 g, 0.526 mol) at room temperature. Refiux the reaction mixture for16 hours at 100 °C. Cool the reaction to room temperature and concentrate under reduced pressure at 50 °C. Dissolve the resulting residue in water and extract with EtOAc (2 x 10L). Wash the organic layer with saturated aqueous sodium bicarbonate and water. Drythe combined organic extracts over anhydrous sodium sulfate, filter and concentrate under reduced pressure at 50 °C to provide the title compound 200 g (61%) as brown viscousliquid. MS mIz): 169 (M÷1).
61%
Stage #1: 3-Thiophene carboxylic acid With n-butyllithium In tetrahydrofuran; hexane at -70 - -55℃; for 1h;
Stage #2: acetone In tetrahydrofuran; hexane at -70 - 0℃; for 3h; Further stages;
1 6,6-Dimethylthieno[2,3-c]furan-4-one
Cool a solution of 3-thiophenecarboxylic acid (250 g, 1.95 mol) in THF (9750 mL) to -70° C. in a 20 L 3-neck flask. To this solution, add n-butyl lithium (2.5 M in hexane, 1872 mL, 4.68 mol) slowly while maintaining the temperature below -55° C. Stir the reaction mixture for one hour at -70° C. Add acetone (187 mL, 2.55 mol) slowly at -70° C. Allow the reaction mixture to warm to 0° C. and stir for three hours at 0° C. To the resulting solution, add 4 M HCl (1500 mL) at 0° C. and allow the reaction mixture to warm to room temperature. Stir the resulting mixture overnight. Filter the reaction mixture through a diatomaceous earth pad and wash the pad with toluene (3×500 mL). Concentrate the filtrate under reduced pressure. Dissolve the resulting crude residue in toluene (3750 mL) and water (250 mL) and add p-toluene sulfonic acid (100.1 g, 0.526 mol) at room temperature. Reflux the reaction mixture for 16 hours at 100° C. Cool the reaction to room temperature and concentrate under reduced pressure at 50° C. Dissolve the resulting residue in water and extract with EtOAc (2×10 L). Wash the organic layer with saturated aqueous sodium bicarbonate and water. Dry the organic layer over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure at 50° C. to provide the title compound 200 g (61%) as brown viscous liquid. MS (m/z): 169 (M+1).
61%
Stage #1: 3-Thiophene carboxylic acid With n-butyllithium In tetrahydrofuran; hexane at -70 - -55℃; for 1h;
Stage #2: acetone In tetrahydrofuran; hexane at -70 - 0℃; for 3h;
Stage #3: With toluene-4-sulfonic acid In tetrahydrofuran; toluene at 100℃; for 16h;
1 6,6-Dimethylthieno[2,3-c]furan-4-one
Cool a solution of 3-thiophenecarboxylic acid (250 g, 1.95 mol) in THF (9750 mL) to -70 °C in a 20 L 3-neck flask. To this solution, add n-butyl lithium (2.5 M in hexane, 1872 mL, 4.68 mol) slowly while maintaining the temperature below -55 °C. Stir the reaction mixture for one hour at -70 °C. Add acetone (187 mL, 2.55 mol) slowly at -70 °C. Allow the reaction mixture to warm to 0 °C and stir for three hours at 0 °C. To the resulting solution, add 4 M HCl (1500 mL) at 0 °C and allow the reaction mixture to warm to room temperature. Stir the resulting mixture overnight. Filter the reaction mixture through a diatomaceous earth pad and wash the pad with toluene (3 x 500 mL). Concentrate the filtrate under reduced pressure. Dissolve the resulting crude residue in toluene (3750 mL) and water (250 mL) and add p-toluene sulfonic acid (100.1 g, 0.526 mol) at room temperature. Reflux the reaction mixture for 16 hours at 100 °C. Cool the reaction to room temperature and concentrate under reduced pressure at 50 °C. Dissolve the resulting residue in water and extract with EtOAc (2 x 10 L). Wash the organic layer with saturated aqueous sodium bicarbonate and water. Dry the organic layer over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure at 50 °C to provide the title compound 200 g (61%) as brown viscous liquid. MS (m/z): 169 (M+1).
General procedure: To a solution of 3a (1 g) in ethanol was added Pd/C (5%, 0.1 g) and the mixture was stirred for 24 hrs at room temperature in a hydrogen atmosphere under atmospheric pressure. Insoluble matters were removed using Celite, and the filtrate was concentrated in vacuo to give the desired product 4a (0.76 g) as a yellow solid. To a solution of carboxylic acid (1 equiv) in CH2Cl2 (15 mL) at 0 C was added DMAP (1 equiv) and EDCI (1 equiv). The reaction mixture was stirred at 0 C for 45 minutes. At this time 4a (1 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo, partitioned between 1.0 M HCl (20 ml) and ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 × 15 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 5, v/v) as eluent to afford the product as a white solid. To a solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 2-17 as white solid.
A 2M solution of LDA in THF/heptane/benzene (7.6 mL) was added dropwiseto a stirred solution of thiophene-3-carboxylic acid (6.8 mmol) in anhydrousTHF (30 mL) at 0 C under nitrogen atmosphere. The resulting mixture wasstirred for 15 min and then, after cooling to 0 C, a solution of the <strong>[104863-65-2]N-methoxy-N-methylpropanamide</strong> (8.89 mmol) was dropwise added. The reaction mixture was allowed to warm to rtand stirred for 4 h. The resulting suspension was diluted with iced water (40mL) and washed with Et2O (20 mL). The aqueous layer was acidifiedwith 3M HCl and then extracted with EtOAc (70 mL x 3), anhydrified (Na2SO4)and evaporated under reduced pressure to yield a solid which was used for thenext step without further purification.70% yield. 1H NMR (DMSO-d6) delta: 1.07 (t, 3H, CH3,J = 7.2 Hz), 2.95 (q, 2H, CH2, J = 7.2 Hz), 7.37 (d, 1H, Ar, J = 5.0Hz), 7.86 (d, 1H, Ar, J = 5.0 Hz),13.38 (br s, 1H, OH).
With potassium carbonate In dimethyl sulfoxide at 130℃; for 5h;
General procedure for synthesis of Dichloromethyl Esters under metal-free conditions.
General procedure: An oven-dried Schlenk tube equipped with a stir bar was charged with carboxylic acid (0.2 mmol) and K2CO3 (55.3 mg, 0.4 mmol, 2 equiv.). The tube was fitted with a rubber septum, DMSO (1 mL) and CH2Cl2 (1 mL) was added via syringe at air. With stirring, the reaction mixtures were heated at 130 °C for 5 h (unless otherwise specified), and then cooled down to room temperature. The resultant mixture was filtered through a short plug of silica gel and then concentrated in vacuo. The residue was then purified by flash chromatography on silica gel to provide the corresponding product. For the substrates 26, 31 were heated at 140 °C for 8 h under otherwise identical conditions.
amino(hydrazinyl)methaniminium thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
In methanol; at 50℃;
General procedure: General procedures: A commercial availabe organic acid (1 mmol) was added to a solution of aminoguanidinium bicarbonate (1 mmol) in 30 mL methanol. The reaction mixture was stirred with heating (50 oC) untila transparent solution was formed. If not, more methanol was added to the mixture. Then, methanol was slowlyevaporated at ambient pressure and temperature, giving the corresponding product in good yields. Most ofas-synthesized simple aminoguanidinium salts with various organic anions have been characterized by IR, 1H and13C NMR. Since some of these salts have been previously reported, they are been mainly characterized by TLC and melting points.
To a solution of compound 2-1 (10.00 g, 78.03 mmol, 1.00 eq) and diphenyl azidophosphate (25.77 g, 93.64mmol, 20.29 mL, 1.20 eq) in toluene (150.00 mL) was added Triethylamine (23.69 g, 234.09 mmol, 32.45 mL, 3.00 eq)at 15C. The reaction solution was stirred under nitrogen atmosphere at 15C for 1.5 hours, then the reaction solutionwas heated to 80C and stirred for 7 hours, 2-Methoxy-5-trifluoromethyl aniline (15.66 g, 81.93 mmol, 1.05 eq) wasadded to the reaction solution and the reaction solution was stirred for 12 hours. Then the reaction solution was concentratedunder reduced pressure and the residue was poured into HCl (1 N, 300 mL), the mixture was extracted withethyl acetate (200 mL) twice. The combined organic phases werewashed with brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure, the residue was washed with PE:EtOAc (2:1) to give 2-2 (10.00 g, 24.41mmol, yield 31.28%).1HNMR (400 MHz, DMSO-d6) delta 9.72 (s, 1 H), 8.58 (s, 1 H), 8.47 (s, 1H), 7.47-7.48 (m, 1H),7.33-7.35 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 5.2 Hz, 1H), 3.92 (s, 3H).
Stage #1: 3-Thiophene carboxylic acid With N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃; for 0.166667h;
Stage #2: With n-butyllithium In tetrahydrofuran for 1h;
Stage #3: N,N-dimethyl-formamide In tetrahydrofuran for 0.5h;
95.A Step A: 2-Formylthiophene-3-carboxylic acid (Compound 95.1)
Dissolve the raw material thiophene-3-carboxylic acid (3.48g, 27.16mmol) in 50mL of tetrahydrofuran, add 10mL of tetramethylethylenediamine under a nitrogen atmosphere of -78 degrees, stir for 10 minutes, and then add dropwise n-butyl lithium ( 2.5M, 27mL), and stirred for one hour. Finally, 4.6mL of N,N-dimethylformamide was added dropwise and stirred for 30 minutes. The reaction solution was quenched by adding dilute hydrochloric acid solution and extracted three times with 30 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and spin-dried to obtain the product 95.1 (4.17g, yield 98.3%)
98.3%
Stage #1: 3-Thiophene carboxylic acid With N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃; for 0.166667h; Inert atmosphere;
Stage #2: With n-butyllithium In tetrahydrofuran for 1h;
Stage #3: N,N-dimethyl-formamide In tetrahydrofuran for 0.5h;
36.A Step A: 2-Formylthiophene-3-carboxylic acid (Compound 36.1)
The raw material thiophene-3-carboxylic acid (3.48g, 27.16mmol) was dissolved in 50mL of tetrahydrofuran,Add 10 mL of tetramethylethylenediamine under a nitrogen atmosphere at -78 degrees and stir for 10 minutes.Then add dropwise n-butyl lithium (2.5M, 27mL) and stir for one hour,Finally, 4.6 mL of N,N-dimethylformamide was added dropwise and stirred for 30 minutes.The reaction solution was quenched by adding dilute hydrochloric acid solution, and extracted three times with 30 mL of ethyl acetate.The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the product 36.1 (4.17 g, yield 98.3%).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 6h;
3.3. General Synthetic Procedures for Target Compounds 1-20
General procedure: Intermediate d (10 mmol), EDCI (10 mmol), DMAP (0.1 mmol), and aromatic acid (10 mmol)were dissolved in DCM (CH2Cl2, 30 mL). The mixture was stirred at room temperature for 6 h.The target compounds 1-10 were purified via column chromatography. Similarly, the intermediateb, e, f, and target compounds 11-20 were synthesized by using the same methods. The spectrogram oftarget compounds 1-20 are presented as Supporting Information.
51
Dissolve 3-thiophenecarboxylic acid 51a (1g, 7.80mmol) in ethanol (15mL), add dropwise concentrated sulfuric acid (2 drops), heat to reflux at 78°C until TLC detects the completion of the reaction, cool to room temperature, evaporate the solvent under reduced pressure Add ethyl acetate (30mL) to reconstitute, wash with saturated sodium bicarbonate solution (30mL), water (30mL) and saturated brine (30mL) successively, dry with anhydrous sodium sulfate, filter, concentrate and dry to obtain compound 51b( Pale yellow oily liquid, 1.07g, yield 88%):
thiophen-3-ylmethyl thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 63%
2: 7%
3: 7%
With aluminum (III) chloride; triethylamine In dichloromethane at 20℃; for 48h;
General experimental methods for AlCl3-catalyzedCannizzaro/Tishchenko reactions
General procedure: A mixture of AlCl3(0.5 mmol), the aldehyde (10 mmol),and triethylamine (5 mmol) was added to 2 cm3of driedCH2Cl2and stirred for 2 days at room temperature underargon atmosphere until the aldehyde was completelyconsumed. The reaction progress was probed by TLCand GC/MS (Agilent 6890 (GC)/5972A (MS)). The reactionmixture was then filtered through Whatman filterpaper (grade 2), and treated with sodium bicarbonatesolution, followed by isolating the organic phase via aseparatory funnel. The aqueous phase washed severaltimes with CH2Cl2to make sure that all organic materialsextracted. Then, the organic phase was dried usingsodium sulfate and subsequently analyzed by GC/MSand 1H NMR, and validated using melting or boilingpoint of the product.
1: 57%
2: 57%
3: 6%
With aluminum (III) chloride; triethylamine In dichloromethane at 20℃; for 48h;
General experimental methods for AlCl3-catalyzedCannizzaro/Tishchenko reactions
General procedure: A mixture of AlCl3(0.5 mmol), the aldehyde (10 mmol),and triethylamine (5 mmol) was added to 2 cm3of driedCH2Cl2and stirred for 2 days at room temperature underargon atmosphere until the aldehyde was completelyconsumed. The reaction progress was probed by TLCand GC/MS (Agilent 6890 (GC)/5972A (MS)). The reactionmixture was then filtered through Whatman filterpaper (grade 2), and treated with sodium bicarbonatesolution, followed by isolating the organic phase via aseparatory funnel. The aqueous phase washed severaltimes with CH2Cl2to make sure that all organic materialsextracted. Then, the organic phase was dried usingsodium sulfate and subsequently analyzed by GC/MSand 1H NMR, and validated using melting or boilingpoint of the product.
(3-(thiophene-3-carboxamido)phenyl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;
General Method for the Synthesis of Amide Analogues (7a-f).
3-Aminophenylboronic acid (0.10 g, 0.65 mmol, 1 equiv), the corresponding carboxylic acid (0.71 mmol, 1.1 equiv) and HBTU (0.25 g, 0.65 mmol, 1 equiv) were dissolved into anhydrous N,N-dimethylformamide (2.5 mL). To this solution diisopropylethylamine (0.7 mL, 3.87 mmol, 3 equiv) was added dropwise. The reaction mixture was stirred vigorously for 3 hours at room temperature, after which time the starting material had been analyzed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), and then washed with water (100 mL) and brine (aq) (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The filtrate was further purified by RP column chromatography and preparative HPLC as necessary.
Chemistry
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