* 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] Organic Letters, 2016, vol. 18, # 11, p. 2576 - 2579
[2] Bulletin of the Chemical Society of Japan, 2012, vol. 85, # 3, p. 369 - 371
[3] RSC Advances, 2014, vol. 4, # 26, p. 13430 - 13433
[4] Molecular Crystals and Liquid Crystals (1969-1991), 1990, vol. 193, p. 167 - 170
2
[ 13679-74-8 ]
[ 1918-79-2 ]
Yield
Reaction Conditions
Operation in experiment
70%
With Oxone; trifluoroacetic acid In 1,4-dioxane for 10 h; Reflux; Green chemistry
General procedure: To a mixture of acetophenone (100 mg, 1 equiv) or phenylacetylene (1 equiv) in dioxane (5 mL), Oxone (2 equiv) and TFA (2 equiv) were added. The mixture was then heated to reflux for 10 h and then cooled to r.t. H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were treated with sat. NaHCO3 solution and the aqueous layer was poured onto crushed ice and treated with 2 M HCl; a colorless solid precipitated out. The precipitate was filtered off and dried in vacuo to give benzoic acid (3a) after column chromatography (silica gel; EtOAc–hexane, 1:9) as a white crystalline solid; yield: 0.096 g (95percent) from 1a; mp 122–123 °C.
Reference：
[1] Synthesis (Germany), 2015, vol. 47, # 20, p. 3161 - 3168
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 3096
[3] Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 5,29
3
[ 765-58-2 ]
[ 201230-82-2 ]
[ 1918-79-2 ]
[ 19432-69-0 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
4
[ 1430823-64-5 ]
[ 1918-79-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 32, p. 5377 - 5385
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 29, p. 7973 - 7978
5
[ 765-58-2 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 1918-79-2 ]
[ 19432-69-0 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 26, p. 8336 - 8340
6
[ 554-14-3 ]
[ 1918-79-2 ]
Reference：
[1] Chemistry Letters, 1983, p. 127 - 128
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 1646
[3] Journal of the American Chemical Society, 1934, vol. 56, p. 1127
[4] Journal of Organic Chemistry, 1948, vol. 13, p. 635,637
[5] Journal of the American Chemical Society, 1950, vol. 72, p. 3695,3696, 3697
[6] Journal of the American Chemical Society, 1950, vol. 72, p. 3695,3696, 3697
7
[ 63273-26-7 ]
[ 123-56-8 ]
[ 1918-79-2 ]
Reference：
[1] Patent: US5773411, 1998, A,
8
[ 13679-70-4 ]
[ 1918-79-2 ]
Reference：
[1] Journal of Organic Chemistry, 1948, vol. 13, p. 635,637
[2] Green Chemistry, 2018, vol. 20, # 17, p. 3931 - 3943
9
[ 554-14-3 ]
[ 108-24-7 ]
[ 1918-79-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 1221 - 1230
10
[ 59303-13-8 ]
[ 1918-79-2 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 3695,3696, 3697
11
[ 79852-26-9 ]
[ 1918-79-2 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 3695,3696, 3697
With iron(III) chloride; bromine In acetic acid at 25℃; for 5 h;
A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 ml.) was added dropwise to δ-methyl^-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCI3 (456 mg, 2.81 mmol) in AcOH (28 ml.) at 25 0C. After 5h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)+.
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 2 h;
To a solution of commercially available 5-methylthiophene-2-carboxylic acid (SI-13) (1.0g, 7.04 mmol) and K2CO3 (1.94 g, 14.08 mmol) in DMF (10 mL), CH3CH2I (1.65 g, 10.56mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2hours. Then, the reaction was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated togive compound SI-14 (400 mg, 34percent) as a pale yellow oil. ESI-MS m/z 171 [M+H]+ calc.for C8H10O2S. This intermediate was used in the next step without further purification orcharacterization.
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524
[2] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 63; 64
[3] Patent: WO2016/20307, 2016, A1, . Location in patent: Page/Page column 45
23
[ 1918-79-2 ]
[ 5751-81-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
With sulfuric acid In ethanol
Part 1 5-methyl-thiophene-2-carboxylic acid ethyl ester A solution of 5-methyl-thiophene-2-carboxylic acid (25.2 g, 177 mmol) in EtOH (500 mL) is treated with conc. H2SO4 (15 mL) and heated to a gentle reflux for 72 h. The solution is partially concentrated and poured into water (500 mL) and extracted with Et2O (3*). The combined extracts are washed with aq Na2CO3, water, dried over Na2SO4, filtered and concentrated in vacuo. Vacuum distillation of the residue afforded 5-methyl-thiophene-2-carboxylic acid ethyl ester (25.6 g, 85percent): bp 98-99° C./9-10 mbar; 1H NMR (CDCl3, 300 MHz) δ7.6 (s, 1 H), 6.78 (s, 1 H), 4.30 (q, J=6.0 Hz, 2 H), 2.50 (s, 3 H), 1.34 (t, J=6.0 Hz, 3 H).
Reference：
[1] Patent: US2003/166668, 2003, A1,
24
[ 1918-79-2 ]
[ 64-17-5 ]
[ 5751-81-5 ]
Yield
Reaction Conditions
Operation in experiment
67%
for 72 h; Reflux
δ-Methyl-thiophene^-carboxylic acid (30.5 mmol) is dissolved in Ethanol (53 ml), H2SO4 (0.5 eq) is added and the reaction is heated to reflux for 3 days. The solvent is removed in vacuo and the remaining material dissolved in Dichloromethane. The organic layer is extracted with saturated NaHCO3 and washed with brine. The organic layer is dried over IS^SO4 and the solvent removed in vacuo. 5-Methyl- thiophene-2-carboxylic acid ethyl ester is obtained as brown oil in a yield of 67 percent. HPLC (Method A): 3.36 min, LCMS (Method A): 2.20 min, 171.2 m/z (MH+)
Reference：
[1] Patent: WO2009/106203, 2009, A1, . Location in patent: Page/Page column 63
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 3258
With Oxone; trifluoroacetic acid; In 1,4-dioxane; for 10h;Reflux; Green chemistry;
General procedure: To a mixture of acetophenone (100 mg, 1 equiv) or phenylacetylene (1 equiv) in dioxane (5 mL), Oxone (2 equiv) and TFA (2 equiv) were added. The mixture was then heated to reflux for 10 h and then cooled to r.t. H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were treated with sat. NaHCO3 solution and the aqueous layer was poured onto crushed ice and treated with 2 M HCl; a colorless solid precipitated out. The precipitate was filtered off and dried in vacuo to give benzoic acid (3a) after column chromatography (silica gel; EtOAc-hexane, 1:9) as a white crystalline solid; yield: 0.096 g (95%) from 1a; mp 122-123 C.
5.1
To a solution of 5-methylthiophene-2-carboxylic acid (100 g, 703 mmol) in methanol (1.0 L) was added conc. sulfuric acid (10 ml) and the mixture was heated under reflux for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Diethyl ether (1.0 L) was added to the residue. The mixture was washed successively with water (500 ml×4) and saturated brine (500 ml), and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave methyl 5-methylthiophene-2-carboxylate (109 g, yield 100%). 1H-NMR (400 MHz, δppm, CDCl3) 7.61(1H, d, J=3.6 Hz,), 6.76(1H, d, J=3.6 Hz), 3.85(3H, s), 2.52(3H, s).
100%
With thionyl chloride at 0 - 25℃; for 12h;
Methyl 5-(bromomethyl)thiophene-2-carboxylate (21)
To a stirred solution of compound 20 (2.50 g, 17.58 mmol) in MeOH (30.00 mL) cooled to 0 °C, SOCl2 (5.11 mL, 7.32 mmol) was added and the reaction was stirred at 25 °C for 12 h. A 2 N solution of NaOH was added and volatiles were removed under reduced pressure. The aqueous phase was extracted with DCM (3 x 25.00 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. Methyl 5-methylthiophene-2-carboxylate was obtained in quantitative yield without any further purification. ESI-MS m/z 179 [M+Na]+; 1H NMR (300 MHz, CDCl3) δ 2.51 (s, 3H), 3.84 (s, 3H), 6.75 (d, J =3.1 Hz, 1H), 7.60 (d, J = 3.1 Hz, 1H). To a solution of the previously synthesized ester (3.00 g, 16.85 mmol) in CCl4 (15.00 mL), N-bromosuccinimide (2.70 g, 15.17 mmol)and azobisisobutyronitrile (catalytic amount) were added, and the reaction was stirred at 80 °C for 2 h. The reaction was cooled to 25 °C and filtered on asmall plug of Celite. Volatiles were removed under reduced pressure and the crude was purified by means of chromatography on silica gel (5 % diethyl ether in petroleum ether) to afford title compound (85 % yield) as a transparent oil. ESI-MS m/z 233-235 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 3.87 (s, 3H), 4.66 (s, 2H), 7.08 (d, J = 3.8Hz, 1H), 7.62 (d, J = 3.8 Hz, 1H).
100%
With thionyl chloride at 0 - 25℃; for 12h;
98%
Stage #1: methanol; 2-methylthiophene-5-carboxylic acid With sulfuric acid at 0 - 30℃;
Stage #2: With sodium carbonate In water
61.a
Compound 1 (5 g, 35 mmol) was dissolved in MeOH (50 ml). The mixture was cooled to O0C and H2SO4 (3 ml) was added drop wise. Then the mixture was stirred at 3O0C for 4 days. The mixture was treated with aqueous Na2CO3 and adjusted to pH=8, followed by extraction with EA. The organic layer was concentrated and purified with column chromatography (PE: EA=IO: 1) to give compound 2 as a yellow oil (5.4g). Yield: 98%.
97%
With thionyl chloride at 0℃; for 3.5h; Reflux;
3 Preparation 3 Methyl-5-methylthiophene-2-carboxylate
Add thionyl chloride (153 ml, 2.1 mol) dropwise over 20 min to a solution of 5- methylthiophene-2-carboxylic acid (100 g, 0.703 mol) in MeOH (1 L) at 0 °C and stir. After the addition is complete, heat the reaction mixture to reflux for 3.5 hours. Cool and concentrate in vacuo to give a thick oil. Dilute the oil with EtOAc (500 ml) and sequentially wash with water (300 ml) then brine (300 ml). Dry the organic layer over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give the title compound (106 g, 97%), which is used without further purification. ESI (m/z) 156(M+H).
97%
With thionyl chloride
92%
Stage #1: 2-methylthiophene-5-carboxylic acid With thionyl chloride In N,N-dimethyl-formamide for 3h; Inert atmosphere; Reflux;
Stage #2: methanol With triethylamine In diethyl ether at 0℃; for 1h; Inert atmosphere;
90.9%
With thionyl chloride at 0 - 80℃; for 3.5h; Inert atmosphere;
89%
With sulfuric acid for 6h; Reflux;
3 Methyl 5-methyl-2-thiophenecarboxylate (13) :
5-Methyl-thiophene-2- carboxylic acid (5 g, 35 mmol) was refluxed in H2SO1 in MeOH (2 M) for 6 h. The reaction was neutralized with NaOH (10 N) at 0 °C, and the methyl ester was extracted with DCM affording 4.85 g (89%) of 5~ methylthiophene-2-carboxylic acid methyl ester. NMR (CHClj, 400 MHz): δ 7.78 (d, J=3.8, 1H) , 6.82 (d, J-3.8, 1H) , 3.90 (s, 3H) , 2.21 (s, 3H) ; "C NMR (CHC13, 100 MHz) : δ 162.1, 144.2, 137.5, 132.2, 129.2, 53.0, 18.9; [M+H] ' = 157.12 (APCI+) .
87%
With sulfuric acid for 24h; Reflux;
86%
With sulfuric acid for 60h; Reflux;
71%
With toluene-4-sulfonic acid at 80℃; Inert atmosphere; Microwave irradiation;
With sulfuric acid
With hydrogenchloride
With sulfuric acid for 6h; Heating;
With sulfuric acid for 60h; Reflux;
To a solution of 5-methylthiophene-2-carboxylic acid (F-1) (14.0 g, 0.1 mol) in MeOH (250 mL) was added concentrated H2SO4 (2.0 mL). The reaction mixture was stirred under reflux for 60h. The solvent was removed in vacuo. Ethyl acetate was added to dilute the reaction mixture. Then the organic solution was washed with a saturated aqueous Na2C03 solution, and dried over Na2S04. The solvent was removed to afford the title compound (13.4 g).
With sulfuric acid
25.8 g
With sulfuric acid for 60h; Reflux;
6.1 Step 1: Methyl 5-methylthiophene-2-carboxylate (S2)
[0510] To a solution of 5-methylthiophene-2-carboxylic acid (25 g, 0.176 mol) in 300 mL of anhydrous methanol was added concentrated H2S04 (3 mL). The mixture was refluxed for 60 h. The reaction was cooled to rt and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and quenched carefully with saturated aq. sodium bicarbonate (adjust pH> 7). The organic layer was collected and the aqueous phase was extracted with ethyl acetate twice. The combined organic solution was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated to afford 25.8 g of the title compound as a pale yellow oil. LC (method A): tR = 1.70 mi LC/MS (El) m/z. [M + H] 156.9.
25.8 g
With sulfuric acid for 60h; Reflux;
12.1 Step 1 : Methyl 5-methylthiophene-2-carboxylate (161)
To a solution of 5-methylthiophene-2-carboxylic acid (25 g, 0.176 mol) in 300 mL of anhydrous methanol was added concentrated H2SO4 (3 mL). The mixture was heated at reflux for 60 h. The reaction was cooled to rt and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and quenched carefully with saturated aq. sodium bicarbonate (adjust pH > 7). The organic layer was collected and the aqueous phase was extracted with ethyl acetate twice. The combined organic solution was washed with brine, dried over MgS04, and filtered. The filtrate was concentrated to afford 25.8 g of the title compound as a pale yellow oil. LC (method A): fe = 1.70 min. LC/MS (EI) mlz: [M + H]+ 156.9.
With sulfuric acid for 18h; Reflux;
12 (1-hydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)(5- methylthiophen-2-yl)methanone
To a solution of 5-methylthiophene-2-carboxylic acid (1.42 g, 10 mmol) in MeOH (25 mL) was added conc.H2SO4 (0.8 mL) dropwise at room temperature; the resulting reaction mixture was heated to reflux overnight (about 18 hours). Then the reaction mixture was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with EtOAc (30 mL). The organic phase was washed with sat. NaHCO3 (30 mL), dried over Na2SO4, and concentrated in vacuo to give the crude methyl 5-methylthiophene-2-carboxylate (910 mg, yield 58%). The crude product was used to the next step without further purification. 1H NMRH NMR (400 MHz, DMSO-d6) d 7.63 (d, J = 3.7 Hz, 1H), 6.96-6.91 (m, 1H), 3.79 (s, 3H), 2.51 (s, 3H) ppm.
delta-Methyl-thiophene^-carboxylic acid (30.5 mmol) is dissolved in Ethanol (53 ml), H2SO4 (0.5 eq) is added and the reaction is heated to reflux for 3 days. The solvent is removed in vacuo and the remaining material dissolved in Dichloromethane. The organic layer is extracted with saturated NaHCO3 and washed with brine. The organic layer is dried over IS^SO4 and the solvent removed in vacuo. 5-Methyl- thiophene-2-carboxylic acid ethyl ester is obtained as brown oil in a yield of 67 percent. HPLC (Method A): 3.36 min, LCMS (Method A): 2.20 min, 171.2 m/z (MH+)
B METHOD 5-METHYL-2-THIOPHENE-CARBONYL-CHLORIDE 50 g 5-methyl-2-thiophene carboxylic acid (0.352 moles) are mixed, in a dry apparatus under a stream of nitrogen, with 125.6 g of freshly distilled thionyl chloride (1.055 moles). The apparatus is heated under reflux for 7 hrs. After cooling, the excess thionyl chloride is distilled off under the suction of a water pump, while the residue is distilled under high vacuum (e.g. at 73-74 C. under 10-1 mmHg). 54 g 5-methyl-2-thiophen-carbonyl chloride are obtained. (yield: 95.6%; Cl- 99.7%)
95.6%
With thionyl chloride;
B METHOD 5-METHYL-2-THIOPHENE-CARBONYL-CHLORIDE 50 g 5-methyl-2-thiophene carboxylic acid (0.352 moles) are mixed, in a dry apparatus under a stream of nitrogen, with 125.6 g of freshly distilled thionyl chloride (1.055 moles). The apparatus is heated under reflux for 7 hrs. After cooling, the excess thionyl chloride is distilled off under the suction of a water pump, while the residue is distilled under high vacuum (e.g. at 73-74C under 10min1 mmHg). 54 g 5-methyl-2-thiophen-carbonyl chloride are obtained. (yield: 95.6%; Clmin 99.7%)
With oxalyl dichloride; In dichloromethane; at 0℃; for 1h;Product distribution / selectivity;
Step A:; To an ice-cold suspension of 5-methyl-2-thiophenecaboxylic acid (304 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.18 mL, 2.14 mmol) dropwise. Then the ice-water bath was removed and the mixture was stirred for 1 h. To the above solution was added 2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.14 mmol) followed by triethylamine (1.20 mL, 8.56 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL). The reaction mixture was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford a yellow solid. The crude was dissolved in toluene (5 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (464 mg, 2.44 mmol). The reaction mixture was then heated at 95 C. under nitrogen for 5 h. The reaction was cooled down to room temperature, poured into water and extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated to a yellow solid. The crude material was purified by recrystallization from methanol to afford the desired product (111 mg, 26%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) delta 7.83-7.80 (m, 1H), 7.75-7.70 (m, 2H), 7.58-7.55 (m, 1H), 7.37-7.32 (m, 1H), MS (ESI+) m/z 260 (M+H).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 1h;Product distribution / selectivity;
Step A:; To an ice-cold suspension of 5-methyl-2-thiophenecarboxyl acid (400 mg, 2.14 mmol) in dichloromethane (20 mL) was added oxalyl chloride (0.21 mL, 2.14 mmol) dropwise followed by a few drops of DMF. Then the ice-water bath was removed and the reaction mixture was stirred for 1 h. To the above solution was added 2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.14 mmol) followed by triethylamine (1.19 mL, 8.56 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with 1 N HCl (20 mL). The reaction mixture was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford a yellow solid. The crude was dissolved in toluene (5 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (619 mg, 3.25 mmol). The reaction mixture was then heated to reflux under nitrogen for 3 h. The reaction was cooled down to room temperature, poured into water and extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated to a yellow solid. The crude material was recrystallized from methanol to afford the desired product (198 mg, 48%) as an off-white solid (78 mg, 12%): 1H NMR (500 MHz, DMSO-d6) delta 8.20 (d, J=2.1 Hz, 1H), 7.84 (d, J=3.7 Hz, 1H), 7.83 (d, J=2.2 Hz, 1H), 7.06 (dd, J=3.7, 1.1 Hz, 1H), 3.17 (s, 3H), MS (ESI+) m/z 293 (M+H).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;
5-Methylthiophene-2-carboxylic acid (2,4-diphenylthiazol-5-yl)amide (1 r).5-Methylthiophene-2-carboxylic acid (213 mg, 1 .50 mmol) was suspended in DCM (5.0 mL) then oxalyl chloride (131 muL, 1 .50 mmol) and DMF-DCM (1 :9, 20 muL) was added. After stirring at ambient temperature for 1 h, a solution of 2,4-diphenyl-5-aminothiazole (252 mg, 1 .00 mmol) in pyridine (5.0 mL) was added and stirring of the resultant mixture continued at ambient temperature for 18 hours. The reaction mixture was diluted with DCM (60 mL) and washed successively with 1 M HCI (4 x 40 mL) and sat. NaHCO3 (2 x 40 mL). The organic layer was dried over MgSO4, filtered and evaporated giving crude material, which was purified by flash column chromatography on silica gel, eluted with 60-75% DCM-hexane, yielding 1 r as an off-white solid (252 mg, 67%). mp 1900 C; m/z (El), 376 (M+); HRMS, found 376.0695 (C21 H16N2OS2, M+, requires 376.0704).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;
To a stirred solution of oxalyl chloride (2M solution in dichloromethane, 15 mL) was added 5-methylthiophene-2-carboxylic acid (2.8 g) in one lot followed by a drop of DMF. The reaction was continuously stirred at room temperature for 4 h and concentrated in vacuo. The residue was dissolved in toluene (20 mL) and the solvent removed to afford 5-methylthiophene-2-carbonyl chloride, which was used in the subsequent step without purification. To a stirred mixture of TMSCH2N2 (15 mL of 2M solution in hexanes) and triethylamine (3.5 mL) in THF (30 mL) and acetonitrile (30 mL) at 0 C. was added 5-methylthiophene-2-carbonyl chloride, which was stirred continuously at 0 C. for 30 h. The reaction mixture was concentrated in vacuo. Benzyl alcohol (10 mL) and 2,4,6-trimethylpyridine (10 mL) were added to the evaporated residue and the mixture was stirred at 180-185 C. for 10 minutes. The reaction mixture was cooled to room temperature, diluted with ether and washed successively with 10% aqueous citric acid, water and saturated aqueous sodium chloride. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 15 mL of 2M solution potassium hydroxide in methanol, stirred at room temperature for 18 h and concentrated in vacuo. The residue was suspended in water and the aqueous layer extracted with ether, and the organic layer discarded. The aqueous layer was acidified to pH 34 with 6N hydrochloric acid, then extracted with ether to obtain (5-methylthiophen-2-yl)acetic acid (1.8 g, 62% yield).
With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 16h;
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 thionyl chloride; In chloroform; for 8h;Reflux;
General procedure: To a solution of an appropriate substituted carboxylic acid (10 mmol) in CHCl3 (50 mL) was added thionyl chloride (3.6 mL, 50 mmol), dropwise over 10 min. The resulting solution was refluxed for 8 h and then concentrated in vacuo. The residual light brown oil was dissolved in THF (50 mL), diluted with a solution of 30% NH4OH (6 mL), and stirred at room temperature for an additional 2 h. At that point, saturated aqueous NaHCO3 (10 mL) was added and the reaction mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude amide was carried directly to the next step without further purification.
With thionyl chloride; In toluene;
Step 5 involves converting the commercially available starting material 5-methylthiophene-2-carboxylic acid to its isopropyl 5-methylthiophene-2-carboxylate making the acid chloride in situ and then reacting it with IPA.
With thionyl chloride; In toluene;
Step 5 involves converting the commercially available starting material 5- methylthiophene-2-carboxylic acid to its isopropyl 5-methylthiophene-2-carboxylate making the acid chloride in situ and then reacting it with IPA. Step 6 converts 5-methylthiophene-2- carboxylate to isopropyl 5-(bromomethyl)thiophene-2-carboxylate by radical reaction with NBS (N-bromosuccinimide) and peroxide in perchloroethylene followed by re-crystallization from heptane to yield pure the product.
With thionyl chloride; at 80℃; for 2h;Inert atmosphere;
Step 1: Preparation of 5-methylthiophene-2-carbonyl chloride (55) (0842) (0843) A solution of 5-methylthiophene-2-carboxylic acid (3.0 g, 21.1 mmol, 1.0 eq) in SOCl2 (7.5 g, 63.4 mmol, 3.0 eq) was stirred at 80 C. for 2 hours. The reaction mixture was concentrated to give the crude product (3.4 g) which was used in the following step without further purification.
With thionyl chloride; In benzene; for 4h;Heating / reflux;
5-Methyl-thiophene-2-carboxylic acid (25.00 g, 0.18 mol) was dissolved in benzene (150 mL), and sulfonyl chloride (30.00 mL, 0.41 mol) was added. The resulting reaction mixture was refluxed for 4 hours, then concentrated to afford the crude acid chloride. This crude acid chloride was then mixed in dichloromethane with N,O-dimethyl-hydroxylamine (1.3 eq) and a catalytic amount of DMAP and cooled to 0 C. Et3N (4.0 eq) was added. The resulting mixture was stirred for 14 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (2×200 mL) and brine (1×200 mL), then dried over MgSO4 and concentrated to give the desired Weinreb's amide. This amide was then dissolved in THF at 0 C. and 3-methylphenylmagnesium bromide (1.5 eq) was added. The resulting mixture was stirred for 3 hours. It was quenched with 5% HCl and extracted with Et2O (3×200 mL). The combined organic extracts were washed with H2O (2×200 mL) and brine (1×200 mL), then dried over MgSO4 and concentrated to give the crude ketone. The pure title ketone was obtained from column chromatography using hex:EtOAc (10:1) as the eluant. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) delta ppm 2.38 (s, 3H) 2.54 (s, 3H) 6.91-7.05 (m, 1H) 7.06-7.29 (m, 1H) 7.37-7.49 (m, 2H) 7.50-7.68 (m, 2H).
With 2,6-Dibromopyridine; ethylaluminum dichloride In hexane; toluene at 60℃; for 3h; Autoclave; Inert atmosphere;
79%
With ethylaluminum dichloride In hexane; toluene at 100℃; for 3h; Autoclave; Inert atmosphere; regioselective reaction;
48%
Stage #1: 2-Methylthiophene With lithium diisopropyl amide In tetrahydrofuran at 20℃; for 0.000833333h; Flow reactor;
Stage #2: carbon dioxide In tetrahydrofuran at 20℃; for 0.000138889h; Flow reactor;
Stage #3: With water; acetic acid In tetrahydrofuran at 20℃; Flow reactor;
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h;
N-(3,4-dimethoxyphenethyl)benzo[b]thiophene-2-carboxamide (7)
General procedure: A solution of compound 4b (0.4 g, 2.25 mmol),compound 3 (0.45 g, 2.47 mmol), HBTU (1.01 g, 2.69 mmol) and Et3N (0.48 mL, 3.37 mmol) in DMF (10 mL) was stirred at room temperature for 2 h.Then, the mixture was diluted with water (100 mL), and extracted with EtOAc (50mL × 3). The combined organic layers were dried over MgSO4, concentrated and purified by silica gel column chromatography (CH2Cl2: MeOH = 100:2) to give compound 7 (0.63 g, 73%) as a yellow solid, mp: 93-96 C.
With water; 1,1'-carbonyldiimidazole 1.) THF, RT, 2 h, 2.) THF, a) RT, 18-24 h, b) reflux, 3-6 h; Yield given. Multistep reaction;
In methanol; hexanes; dichloromethane at 20℃; for 3h;
26
To 5-methyl-thiophene-2-carboxylic acid (2.5 g, 17.6 mmol) in CH2Cl2 and MeOH (50 niL, 4:1) was added (trimethylsilyl)diazomethane (9.24 mL, 18.5 mmol, 2.0 M in hexanes) slowly at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Removal of the solvents under reduced pressure provided compound 26.1 (17.95 mmol, 98%) as a white solid. The crude product was used for next step without purification.
5-Bromomethyl-2-carbomethoxythiophene (III-3). This compound was prepared from 5-methylthiophene-2-carboxylic acid by the method of Gogte et al, Tetrahedron, 23, 2443-51 (1967).
Synthesis Example 14-1: Synthesis of 2-bromomethyl-5-methoxy carbonylthiophene (Compound IV-4) 2.05 g of commercially available 5-methylthiophene carboxylic acid was dissolved in 60 ml of methanol, and then a hydrochloric acid gas was brown into the solution for 5 minutes. After 23 hours, the reaction solution was concentrated, and then a 1 mol/l sodium hydroxide aqueous solution was added thereto, followedbyextractionwithchloroform. An organic layer was washed with a saturated salt solution and was then dried with anhydrous sodium sulfate and concentrated. 500 mg of the resulting residue was dissolved in 10 ml of carbon tetrachloride, followed by the addition of 570 mg of N-bromosuccinimide and 53 mg of azobisisobutyronitrile. After the resultant solution was stirred in oil bath for 20 hours at 70C, the reaction solution was filtrated, and then the filtrate thereof was then concentrated. The resulting residue was purified by means of silica gel column chromatography (15 g, hexane/ethyl acetate = 8/1). Consequently, 516.1 mg of the above-mentioned compound was obtained as light-yellow syrup. MS(EI,Pos.):m/z=233,235[M+1]+ 1H-NMR(500MHz,CDCl3):delta=3.89(3H,s),4.68(2H,s),7.10(1H,d,J=3.7Hz),7.64(1H,d,J=3.7Hz).
With N-Bromosuccinimide; dibenzoyl peroxide; In methanol; tetrachloromethane; methyl 5-methylthiophene-2-carboxylate;
(ii) 5-bromomethyl-2-carbomethoxythiophene A solution of 5-methyl-2-thiophene carboxylic acid (25 g, 0.176 mol) in 500 ml of methanol was saturated with gaseous hydrochloric acid at 0 C. The reaction mixture was stirred at room temperature for 18 hours and then refluxed for 48 hours. The solvent was removed in vacuo and the crude methyl 5-methyl-2-thiophene carboxylate was used without further purification. The methyl ester prepared above (11.07 g, 0.071 mol) was dissolved in 200 ml of carbon tetrachloride under argon. N-bromosuccinimide (13.25 g, 0.074 mol) and dibenzoyl peroxide were then added. The reaction mixture was refluxed for 2 hours and allowed to stand at room temperature for 18 hours. The solids were collected and the filtrate was concentrated in vacuo to give 19 g of 5-bromomethyl-2-carbomethoxythiophene.
Stage #1: 2-methylthiophene-5-carboxylic acid With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 4h;
Stage #2: With water; potassium carbonate
117.a
LiAlH4 (IM in THF, 5.6 niL) was added dropwise to a solution of 5-metliyl-2-tliioplieiiecarboxylic acid (0.4 g, 2.8 mmol) in THF (10 mL) at 0 0C under a N2 atmosphere. After stirring for 4 h, saturated K2CO3 was added slowly, and Hie mixture was filtered through a pad of Celite. The filtrate was partitioned between EtOAc and H2O, and the organic layer was dried over Na2SO4, filt δ : 2.495 (s, 3H,), 4.761 (s, 2H), 6.636 (m, IH), 6.818 (d, IH, J =3.2 Hz).
Multi-step reaction with 2 steps
2: LiAlH4 / diethyl ether
Methyl 5-methylthiophene-2-carboxylate (F-2) To a solution of 5-methylthiophene-2-carboxylic acid (F-1) (14.0 g, 0.1 mol) in MeOH (250 mL) was added concentrated H2SO4 (2.0 mL). The reaction mixture was stirred under reflux for 60 h. The solvent was removed in vacuo. Ethyl acetate was added to dilute the reaction mixture. Then the organic solution was washed with a saturated aqueous Na2CO3 solution, and dried over Na2SO4. The solvent was removed to afford the title compound (13.4 g).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;
1.1
To a solution of 5-methylthiophene-2-carboxylic acid (40.3 g, 282 mmol) in N,N-dimethylformamide (500 ml) were added potassium carbonate (43 g, 310 mmol) and methyl iodide (19.3 ml, 310 mmol). After stirring at room temperature for 4 hr, diethyl ether (1.0 L) was added, and the organic layer was washed successively with water (500 ml×3) and saturated brine (200 ml) and dried over magnesium sulfate. After filtration and concentration, methyl 5-methylthiophene-2-carboxylate (40.8 g, yield 93%) was obtained. 1H-NMR (300 MHz, δppm, CDCl3) 7.61(1H, d, J=3.6 Hz), 6.76(1H, d, J=3.6 Hz), 3.85(3H, s), 2.52(3H, s).
93%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;
9.1
Step 1: Production of methyl 5-methylthiophene-2-carboxylate To a solution of 5-methylthiophene-2-carboxylic acid (40.3 g, 282 mmol) in N,N-dimethylformamide (500 ml) were added potassium carbonate (43 g, 310 mmol) and methyl iodide (19.3 ml, 310 mmol). The mixture was stirred at room temperature for 4 hr and diethyl ether (1.0 L) was added. The organic layer was washed successively with water (500 ml x 3) and saturated brine (200 ml) and dried over magnesium sulfate. Filtration and concentration gave methyl 5-methylthiophene-2-carboxylate (40.8 g, yield 93%). 1H-NMR(300MHz, δppm, CDCl3): 7.61(1H, d, J=3.6Hz), 6.76(1H, d, J=3.6Hz), 3.85(3H, s), 2.52(3H, s).
Part 1 5-methyl-thiophene-2-carboxylic acid ethyl ester A solution of 5-methyl-thiophene-2-carboxylic acid (25.2 g, 177 mmol) in EtOH (500 mL) is treated with conc. H2SO4 (15 mL) and heated to a gentle reflux for 72 h. The solution is partially concentrated and poured into water (500 mL) and extracted with Et2O (3*). The combined extracts are washed with aq Na2CO3, water, dried over Na2SO4, filtered and concentrated in vacuo. Vacuum distillation of the residue afforded 5-methyl-thiophene-2-carboxylic acid ethyl ester (25.6 g, 85percent): bp 98-99° C./9-10 mbar; 1H NMR (CDCl3, 300 MHz) delta7.6 (s, 1 H), 6.78 (s, 1 H), 4.30 (q, J=6.0 Hz, 2 H), 2.50 (s, 3 H), 1.34 (t, J=6.0 Hz, 3 H).
With potassium carbonate; In N,N-dimethyl-formamide;
Reference Example 144 4-Chloro-5-methyl-2-thiophenecarboxylic Acid 5-Methyl-2-thiophenecarboxylic acid (2.84 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.68 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid ethyl ester (1.84 g).
2-[(5-Methyl-thiophene-2-carbonyl)-amino]-succinic acid 4-methyl Ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine In tetrahydrofuran; water
88.A 2-[(5-Methyl-thiophene-2-carbonyl)-amino]-succinic acid 4-methyl Ester
Step A 2-[(5-Methyl-thiophene-2-carbonyl)-amino]-succinic acid 4-methyl Ester A mixture of 5-methyl-2-thiophenecarboxylic acid (6.44 g, 45.4 mmol), N-methyl-morpholine (4.82 g, 47.7 mmol), and 2-chloro-4,6-dimethyl-1,3,5-triazine (8.2 g, 46.7 mmol) in THF (100 mL) was stirred at ambient temperature for 90 min. β-Methyl L-aspartate (8.6 g, 46.7 mmol), N-methylmorpholine (9.64 g, 95.3 mmol), and distilled water (10 mL) were added and the mixture was stirred 3 h. The reaction was partitioned between CH2Cl2 and 1N HCl. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The clear, colorless oil was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=3.6 Hz, 1H), 7.09 (br d, J=7.6 Hz, 1H), 6.74 (dd, J=3.6, 0.8 Hz, 1H), 5.00 (m, 1H), 4.07 (s, 3H), 3.06 (A of ABX, JAB=17.6 Hz, JAX=4.4 Hz, 1H), 3.05 (B of ABX, JBA=17.6 Hz, JBX=4.8 Hz, 1H), 2.51 (s, 3H).
With iron(III) chloride; bromine; In acetic acid; at 25℃; for 5h;
A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 ml.) was added dropwise to delta-methyl^-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCI3 (456 mg, 2.81 mmol) in AcOH (28 ml.) at 25 0C. After 5h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)+.
With iron(III) chloride; bromine; acetic acid; at 25℃;
Preparation 2; Preparation of 4-bromo-5-methyl-2-thiophenecarboxylic acid; A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 ml.) was added dropwise to delta-methyl^-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCI3 (456 mg, 2.81 mmol) in AcOH (28 ml.) at 25 0C. After 5h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)+.
With iron(III) chloride; bromine; In acetic acid; at 25℃; for 5h;
To a mixture of 5-methylthiophene-2-carboxylic acid (2 g, 14.1 mmol) and FeCl3 (456 mg, 2.81 mmol) in AcOH (28 mL) was added a solution of Br2 (725 uL, 14.1 mmol) in AcOH (2.8 mL) at 25 C. After 5 h, the mixture was poured into ice and the precipitate was filtered and washed with water affording 4-bromo-5-methylthiophene-2-carboxylic acid (2.7 g, 87 %) as a yellow solid.1H NMR (500 MHz, CDCl3) delta 13.33 (s, 1H), 7.61 (s, 1H), 2.41 (s, 3H). LC-MS m/z: 220.9 [M+H]+. LCMS: Purity (254nm): 92.7%; tR = 1.76 min.
Stage #1: acetyl chloride With methanol at 0 - 20℃;
Stage #2: 2-methylthiophene-5-carboxylic acid In methanol at 20℃;
7.1
Acetyl chloride (5 mL) was added to a 0° C. solution of methanol (40 mL) and the solution was allowed to warm to room temperature. 5-Methyl-thiophene-2-carboxylic acid (Lancaster; 1.58 g, 11.1 mmol) was added and the solution was allowed to stir at room temperature over the weekend. The solvents were evaporated under reduced pressure and ethyl acetate was added. The solution was extracted with aqueous sodium hydrogen carbonate and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give 5-methyl-thiophene-2-carboxylic acid methyl ester (1.40 g, 81%) as a yellow oil.
To a solution of methylthiophene carboxylic acid (20 g, 0.14 mol) in DMF (30 mL) was added at 0°C carbonyldimimidazole (23 g, 0.14 mol) in portions of 10 g. After stirring at 0°C for 1 hour, a solution of ethyl 3-aminopropionate hydrochloride (21 g, 0.14 mol) in DMF (30 mL) was added followed by triethylamine (20 mL, 0.14 mol). The mixture was stirred at ambient temperature for 16 hours, filtered by suction, and the filtrate was concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with water (2 x 50 mL), 1N hydrochloric acid (2 x 50 mL), sodium bicarbonate solution (2 x 50 mL), brine (50 mL), dried (MgSO4), and concentrated. Addition of hexane to the residue induced the crystallization of ethyl 3-([(5-methyl-2-thienyl)carbonyl]amino}propionate (27 g, 80percent).1H NMR (CDCl3): delta 1.28 (t, 3H), 2.50 (s, 3H), 2.62 (t, 2H), 3.68 (q, 2H), 4.17 (q, 2H), 6.60 (brd s, 1H), 6.66 (d, 1H), 7.30 (d, 1H).
Copper(II) nitrate (2.5 mmol), 5-methyl-2-thiophenecarboxylic acid (5 mmol) as well as equimolar quantity of sodium hydroxide and N-methylnicotinamide (5 mmol) were dissolved in 50 cm3 of methanol. The resulting solution was refluxed for 2 h and then left to slowly evaporate at ambient temperature. Well shaped green crystals of complex (1) suitable for single crystal X-ray structure analysis were collected after a few days by filtration, washed with methanol and finally dried at ambient temperature (yield 43%). Blue crystals of (2) were separated from above methanolic filtrate after a few days (yield 35%).
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 2h;
To a solution of commercially available 5-methylthiophene-2-carboxylic acid (SI-13) (1.0g, 7.04 mmol) and K2CO3 (1.94 g, 14.08 mmol) in DMF (10 mL), CH3CH2I (1.65 g, 10.56mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2hours. Then, the reaction was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated togive compound SI-14 (400 mg, 34percent) as a pale yellow oil. ESI-MS m/z 171 [M+H]+ calc.for C8H10O2S. This intermediate was used in the next step without further purification orcharacterization.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of commercially available 5-methylthiophene-2-carboxylic acid(9.2 g, 0.065 mol) in DMF (80 mL) was added K2003 (17.9 g, 0.13 mol), thencompound CH3CH2I (15.2 g, 0.98 mol) was added slowly. The reactionmixture was stirred at room temperature overnight. After TLC ( PE/ EtOAc =2:1 ) showed the starting material was consumed completely, the mixture was quenched with water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude reagent KR-39 (9.5 g, 86.3percent) as a pale yellow oil which was used for the next step without further purification. ESI-MS (Mi-i): 171.0 calc. forC8H1002S:170.0.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Preparation of reagent KR-5: ethyl 5-methylthiophene-2-carboxylate To a solution of commercially available 5-methylthiophene-2-carboxylic acid (9.2 g, 0.065 mol) in DMF (80 ml_) was added K2CO3 (17.9 g, 0.13 mol), then compound CH3CH2I (15.2 g, 0.98 mol) was added slowly. The reaction mixture was stirred at room temperature overnight. After TLC (PE/ EtOAc = 2:1 ) showed the starting material was consumed completely, the mixture was quenched with water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude reagent KR-5 (9.5 g, 86.3percent) as a pale yellow oil which was used for the next step without further purification. ESI-MS (M+1 ): 171 .0 calc. for C8H10O2S:170.0.
5-(2-tert-butoxycarbonyl-2-methylpropyl)thiophene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42.9%
Example 3 Synthesis of 5-(2-tert-butoxycarbonyl-2-methylpropyl)thiophene-2-carboxylic acid (0132) (0133) A mineral oil dispersion of NaH (NaH concentration 60 mass %, 840 mg) was suspended in THF (19.9 mL), and a solution of 5-methylthiophene-2-carboxylic acid (2.84 g, 20.0 mmol) in THF (11.3 mL) was added dropwise at room temperature. The mixture was heated to 60 C. and stirred for 10 min, cooled again to room temperature, and diisopropylamine (3.1 mL, 1.1 eq) was added. After cooling to 0 C., n-BuLi (10.5 mL, 1.05 eq, in 2.0 M cyclohexane) was added dropwise, and the mixture was directly stirred for 10 min. After cooling to -78 C., 2-bromoisobutyric acid tert-butyl ester (3.72 mL, 20.0 mol) was added and the mixture was stirred for 30 min. After warming to 0 C., 6 N HCl (11.7 mL, 3.5 eq) and heptane (28.4 mL) were added, and the mixture was stirred at 0 C. for 1 hr. The resulting solid was collected by filtration, the mother liquor was washed with water (17 mL), and the solvent (about 25 mL) was evaporated under reduced pressure. Heptane (28.4 mL) was added, and the mixture was washed with methanol/water=2/3 (volume ratio, 17 mL) and methanol/water=7/8 (volume ratio, 17 mL), and the solvent (about 60 mL) was evaporated under reduced pressure. Heptane (28.4 mL) and activated carbon (142 mg) were added, and the mixture was heated to 60 C. and stirred for 1 hr. Activated carbon was removed by celite filtration, and the filtrate was concentrated under reduced pressure to give about 30 mL of a solution, which was stirred at room temperature for 1 hr. Thereafter, the solution was cooled to 10 C., and stirred for 16 hr. The precipitated crystals were collected by filtration, washed with cold heptane (2.8 mL, 10 C.), and dried under reduced pressure at 40 C. for 6 hr to give the title compound (2.44 g) (yield 42.9%). (0134) 1H NMR (400 MHz, Chloroform-d) delta 7.71 (d, J=3.8 Hz, 1H), 6.83 (d, J=3.8 Hz, 1H), 3.06 (s, 2H), 1.46 (s, 9H), 1.19 (s, 6H).
(S)-ethyl (5-methylthiophene-2-carbonyl)alaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two-necked flask, an amino acid ester hydrochloride (1.1 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
(S)-ethyl (5-methylthiophene-2-carbonyl)tryptophanate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two-necked flask, an amino acid ester hydrochloride (1.1 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium 5-methylthiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; water; at 59.84℃; for 0.5h;
General procedure: Compounds (I)-(V) were prepared by mixing hot methanol-water (1:1 v/v) solutions (total volume 30 ml) of trimethoprim(72 mg) with 2,5-dichlorothiophene-3-carboxylic acid (49 mg)[for (I)], 3-bromothiophene-2-carboxylic acid (40 mg) [for(II)], 3-chlorothiophene-2-carboxylic acid (52 mg) [for (III)],5-methylthiophene-2-carboxylic acid (35 mg) [for (IV)] andanthracene-9-carboxylic acid (55 mg) [for (V)]. The solutionswere warmed to 333 K over a water bath for 30 min and thencooled slowly to room temperature after filtration. Colourlessneedle-shaped crystals were collected from the respectivemother liquors after a week.
2-(5-methylthiophen-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 25℃;
General procedure: In a three neck round bottom flask (50 mL in volume) along with guard tube was charged with carboxylic acid (1.0 equiv) in 5 ml solvent combination of CH2Cl2: DMF (4:1). After few minutes stirring at room temperature the resulting suspension was cooled with an ice-water bath prior to the addition of the bis(2-oxo-3-oxazolidinyl)phosphonic chloride (1.5 equiv) and the starting compound 1a (1.0 equiv). The resulting mixture was stirred again for few minutes and then DIPEA (3.0 equiv) was added. The mixture was kept at 0 C for 30-60 min and then stirred at room temperature until the starting material was consumed as monitored by TLC analysis. Ice-water (20 mL) was added while maintaining vigorous stirring. In the cases when the indole precipitated upon addition of water, the solid was filtered off and dissolved in EtOAc (20 mL). In all other cases, the aqueous layer was extracted with EtOAc (3 × 20 mL). The extracts were combined and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified either by silica gel chromatography.
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