* 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.
Stage #1: With ethylmagnesium chloride; N-cyclohexyl-cyclohexanamine In tetrahydrofuran at 60℃; for 24 h; Inert atmosphere Stage #2: at 20℃; for 1 h;
General procedure: To a solution of 0.99 M EtMgCl (0.61 mL, 0.6 mmol) in THF were added dicyclohexylamine (0.01 mL, 0.05 mmol), and 2-methylthiophene (1a, 0.048 mL, 0.50 mmol) dropwise under an nitrogen atmosphere. After stirring at 60 °C for 24 h, 1.4 mL of THF and N,N-dimethylformamide (0.5 mL, 6.46 mmol) were successively added and stirring was continued for further 1 h. The mixture was quenched by saturated aqueous solution of ammonium chloride (1.0 mL) and the solution was poured into the mixture of diethyl ether/water to result in separation into two phases. Aqueous was extracted with diethyl ether twice and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to leave a crude oil, which was purified by column chromatography on silica gel (hexane/EtOAc = 20/1) to afford 62.3 mg of 2-formyl-5-methylthiophene (1a-CHO, colorless oil, 99percent).
80.2%
Stage #1: at 0 - 35℃; for 18 h; Stage #2: With sodium hydroxide; water In diethyl ether
Reference Example 1: Synthesis of 2-formyl-5-methylthiophene Into a 50 ml, three-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were added 10.9 g (0.15 mol) of dimethylformamide and 15.3 g (0.15 mol) of phosphorus oxychloride. The mixture was cooled to 0 °C with stirring. Then, 9.8 g (0.1 mol) of 2-methylthiophene was added to the system, followed by stirring at 25 to 35°C for 18 hours. To the reaction mixture were added 30 ml of water and 50 ml of ether. Further, an aqueous solution containing 23percent of sodium hydroxide was added carefully until a pH of >11 was reached. The mixture was subjected to phase separation. Then, there were conducted washing with a saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, and distillation under reduced pressure for ether removal. The residue was subjected to Kugel-rohr distillation to obtain 10.1 g of a colorless oil. The oil contained, as a component, >99.9percent (in terms of areal ratio of gas chromatography) (yield: 80.2percent) of 2-formyl-5-methylthiophene. Gas mass chromatography was conducted to confirm a molecular ion peak [M+] of 126.
Reference：
[1] Tetrahedron Letters, 2012, vol. 53, # 9, p. 1173 - 1176
[2] Dyes and Pigments, 2014, vol. 106, p. 154 - 160
[3] Patent: EP1555257, 2005, A1, . Location in patent: Page/Page column 25-26
[4] Pharmaceutical Chemistry Journal, 1989, vol. 23, # 7, p. 592 - 596[5] Khimiko-Farmatsevticheskii Zhurnal, 1989, vol. 23, # 7, p. 840 - 843
[6] Journal of Organic Chemistry, 2010, vol. 75, # 4, p. 1047 - 1060
[7] Journal of Materials Chemistry, 2007, vol. 17, # 12, p. 1166 - 1177
[8] Journal of the American Chemical Society, 1953, vol. 75, p. 989
[9] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 1221 - 1230
[10] Advanced Synthesis and Catalysis, 2010, vol. 352, # 13, p. 2116 - 2120
[11] Dyes and Pigments, 2011, vol. 91, # 3, p. 404 - 412
[12] Applied Organometallic Chemistry, 2013, vol. 27, # 5, p. 283 - 289
[13] Chemical Communications, 2015, vol. 51, # 18, p. 3842 - 3845
2
[ 638-02-8 ]
[ 13679-70-4 ]
Yield
Reaction Conditions
Operation in experiment
84%
With trichlorophosphate In N,N-dimethyl-formamide at 100℃; for 8 h; Cooling with ice
General procedure: To a stirred solution of 9ha–9hd (200 mmol) in dried DMF (43.86 g, 600 mmol) cooled in anice-water bath was added dropwise POCl3 (46.00 g, 300 mmol). The resulting mixture was stirred atthis temperature for 30 min and then at 100 °C for another 5 h. After cooling to room temperature,the reaction mixture was poured carefully into ice-water (300 mL). The mixture thus obtained wasextracted with CH2Cl2 (300 mL × 3), and the combined extracts were washed successively with 5percentbrine (200 mL), 10percent aqueous K2CO3 (200 mL) and 5percent brine (200 mL), dried (Na2SO4) and evaporatedon a rotary evaporator to afford a residue, which was purified by column chromatography to yield10ha–10hd.
Reference：
[1] Molecules, 2018, vol. 23, # 2,
3
[ 554-14-3 ]
[ 75-27-4 ]
[ 13679-70-4 ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; palladium diacetate; acetic anhydride; silver carbonate In acetonitrile at 60℃; for 24 h; Schlenk technique; Inert atmosphere Stage #2: With hydrogenchloride In dichloromethane at 30℃;
General procedure: To a 50 mL of Schlenk tube were added 1 or 3 (0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 molpercent), dppf (10 molpercent) under air, followed by K3PO4·3H2O (0.3 mmol, 1.5 equiv) and Ag2CO3 (0.3 mmol, 1.5 equiv) . The mixture was then evacuated and back filled with N2 (3 times). Bromodichoromethane (0.4 mmol, 2.0 equiv), Ac2O (2 mmol, 190 uL) and CH3CN (1 mL) were added subsequently. The Schlenk tube was screw capped and put into a preheated oil bath (60 °C). After stirring for 24 hours, the reaction mixture was cooled to room temperature, diluted with CH2Cl2 and Ethyl Acetate, then filtered with a pad of silica gel. The isolated yield was given by a hydrolysis pathway, in which the concentrated reaction mixture was diluted with 5 mL CH2Cl2 and 10 mL 3 N HCl and stirred over night. The reaction mixture was extracted with dichloromethane (3 times) and the solvent was removed under rotary evaporation. The residue was then purified by a preparative TLC to give product 2 or 4.
Reference：
[1] Journal of the Chemical Society, 1950, p. 2130,2134
[2] Journal of Organic Chemistry, 1949, vol. 14, p. 790,795
[3] Journal of the American Chemical Society, 1950, vol. 72, p. 1422
[4] Journal of Organic Chemistry, 1948, vol. 13, p. 635,637
7
[ 638-02-8 ]
[ 13679-70-4 ]
[ 31819-38-2 ]
[ 72306-62-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 11, p. 2817 - 2820
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 11, p. 2817 - 2820
21
[ 554-14-3 ]
[ 96-43-5 ]
[ 68-12-2 ]
[ 13679-70-4 ]
[ 7283-96-7 ]
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 4, p. 1047 - 1060
22
[ 13679-70-4 ]
[ 26421-44-3 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 638,639
23
[ 13679-70-4 ]
[ 72835-25-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: With sodium bromate; ammonia In water at 80℃; for 4 h; Stage #2: With sodium hydroxide In diethyl ether; water
Into a 50 ml, three-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were added 6.3 g (50 mmol) of 2-formyl-5-methylthiophene, 3.0 g (20 mmol) of sodium bromate, 10 ml (174 mmol) of acetic acid and 5 g (74 mmol) of 25percent aqueous ammonia, followed by stirring at 80°C for 4 hours. To the reaction mixture were added 30 ml of water and 50 ml of ether. Further, an aqueous solution containing 23percent of sodium hydroxide was added carefully until a pH of >11 was reached. The mixture was subjected to phase separation. Then, there were conducted washing with water and a saturated aqueous sodium chloride solution in this order, drying over anhydrous sodium sulfate, and distillation under reduced pressure for ether removal, to obtain 6.5 g of an oil as a residue. The oil was subjected to Kugel-rohr distillation to obtain 5.9 g of a colorless oil. The oil contained, as a component, 94.0percent (in terms of areal ratio of liquid chromatography) (yield: 96.0percent) of 2-cyano-5-methylthiophene. Liquid mass chromatography was conducted to confirm a molecular ion peak [(M-1)+] of 122.
Stage #1: 2-Methylthiophene With ethylmagnesium chloride; N-cyclohexyl-cyclohexanamine In tetrahydrofuran at 60℃; for 24h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 1h;
General procedure: To a solution of 0.99 M EtMgCl (0.61 mL, 0.6 mmol) in THF were added dicyclohexylamine (0.01 mL, 0.05 mmol), and 2-methylthiophene (1a, 0.048 mL, 0.50 mmol) dropwise under an nitrogen atmosphere. After stirring at 60 °C for 24 h, 1.4 mL of THF and N,N-dimethylformamide (0.5 mL, 6.46 mmol) were successively added and stirring was continued for further 1 h. The mixture was quenched by saturated aqueous solution of ammonium chloride (1.0 mL) and the solution was poured into the mixture of diethyl ether/water to result in separation into two phases. Aqueous was extracted with diethyl ether twice and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to leave a crude oil, which was purified by column chromatography on silica gel (hexane/EtOAc = 20/1) to afford 62.3 mg of 2-formyl-5-methylthiophene (1a-CHO, colorless oil, 99%).
92%
With trichlorophosphate at 20℃;
80.2%
Stage #1: 2-Methylthiophene; N,N-dimethyl-formamide With trichlorophosphate at 0 - 35℃; for 18h;
Stage #2: With sodium hydroxide; water In diethyl ether
1
Reference Example 1: Synthesis of 2-formyl-5-methylthiophene Into a 50 ml, three-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were added 10.9 g (0.15 mol) of dimethylformamide and 15.3 g (0.15 mol) of phosphorus oxychloride. The mixture was cooled to 0 °C with stirring. Then, 9.8 g (0.1 mol) of 2-methylthiophene was added to the system, followed by stirring at 25 to 35°C for 18 hours. To the reaction mixture were added 30 ml of water and 50 ml of ether. Further, an aqueous solution containing 23% of sodium hydroxide was added carefully until a pH of >11 was reached. The mixture was subjected to phase separation. Then, there were conducted washing with a saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, and distillation under reduced pressure for ether removal. The residue was subjected to Kugel-rohr distillation to obtain 10.1 g of a colorless oil. The oil contained, as a component, >99.9% (in terms of areal ratio of gas chromatography) (yield: 80.2%) of 2-formyl-5-methylthiophene. Gas mass chromatography was conducted to confirm a molecular ion peak [M+] of 126.
75%
With trichlorophosphate
34%
With trichlorophosphate at 0 - 100℃; Inert atmosphere;
25%
Stage #1: N,N-dimethyl-formamide With phosphorus trichloride at 0℃; for 0.333333h;
Stage #2: 2-Methylthiophene at 50℃; for 3h; Further stages.;
With trichlorophosphate anschliessend Hydrolysieren;
With trichlorophosphate Heating;
With trichlorophosphate
With trichlorophosphate
Stage #1: N,N-dimethyl-formamide With trichlorophosphate In dichloromethane at 0℃; for 0.5h;
Stage #2: 2-Methylthiophene In dichloromethane at 0 - 110℃;
With trichlorophosphate In 1,2-dichloro-ethane Reflux; Inert atmosphere;
With sodium hydroxide at 50℃; for 4h;
3.A-3.G
A: Put N,N-dimethylformamide in a container at 10-15 for low-temperature treatment for 1-2h for later use.B: Place 2-methylthiophene in an environment with a pH value of 7-8.5 at room temperature for 1-4 hours for use.C: Add the processed 2-methylthiophene slowly to the container containing N,N-dimethylformamide.D: Raise the temperature to 45-60°C, stir well, keep the reaction temperature for 3-5h, and absorb the tail gas generated during the reaction with sodium hydroxide.E; After the reaction is completed, the temperature is lowered and the temperature is controlled at 20-30°C.F; After cooling, use organic solvent extraction, the water layer to recover dimethylamine hydrochloride, the organic phases are combined, washed with lye, and the organic phase is desolventized to obtain crude 5-methyl-2-thiophene formaldehyde.G: Steam distillation of the crude 5-methyl-2-thiophenecarboxaldehyde to obtain the finished product of 5-methyl-2-thiophenecarboxaldehyde.In step A, keep the temperature at 12°C and treat at low temperature for 1.5h.In step B, it is processed for 3 hours in an environment with a pH value of 7-8.5 for standby.In step D, the temperature is raised to 50°C, fully stirred, and the reaction is kept for 4 hours.In step F, the organic solvent is chloroform, and the lye is sodium bicarbonate solution.
With sodium tetrahydroborate In ethanol; toluene at 0 - 20℃;
33.1
Step 1 : (5-Methyl-thiophen-2-yl)-methanolSodium borohydride (720 mg, 19.02 mmol) was added to a solution of 5-methyl- thiophene-2-carbaldehyde (2.0 g, 15.85 mmol) in a mixture of ethanol and toluene (1 : 1, 12 mL) at 0°C. The reaction mixture was stirred 2 hours at room temperature and then partitioned between water (15 mL) and ethyl acetate (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with a saturated solution of sodium chloride (20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title product was obtained as a yellow oil (2.01 g, 99%).*H NMR (CDCI3, 400 MHz) : δ (ppm) : 6.79 (d, J = 2.8 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 4.73 (S, 2H), 2.47 (s, 3H).
95%
With sodium tetrahydroborate In water at 0℃;
92%
With lithium aluminium tetrahydride In diethyl ether for 0.5h; Ambient temperature;
86%
With sodium tetrahydroborate In ethanol for 2h;
76.63%
With methanol; sodium tetrahydroborate; sodium methylate Cooling;
33.6%
With sodium tetrahydroborate; sodium methylate In methanol
33.6%
With methanol; sodium tetrahydroborate; sodium methylate Cooling;
1 (5-methylthiophen-2-yl)methanol (2B)
A solution containing 1.50 g of sodium methylate, 3.0 g of sodium borohydride and 25 ml of methanol was slowly added to a mixture containing 13.5 g (0.107 mol) of 5-methyl thiophenecarboxaldehyde and 50.0 mL of methanol with stirring and cooling. The reaction mixture was acidified over crushed ice with 6 M HCl. The mixture was then extracted with anhydrous ether several times, combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to afford 4.6 g (33.6%). 1H-NMR (300 MHz, CD3COCD3) d 6.7 (1H, d), 6.6 (1H, d), 4.6 (2H, s), 4.4 (1H, bs), 2.4 (3H, s).
32.2%
With sodium tetrahydroborate In methanol at -78℃; for 0.166667h; Inert atmosphere;
With iron; acetic acid; nickel dichloride
With sodium tetrahydroborate
With lithium aluminium tetrahydride In diethyl ether for 3h; Heating;
With sodium formate; N-tosylethylenediamine at 80℃; for 2h;
50.3 g (86%)
With sodium borohydrid In ethanol
3.1 3.1.
3.1. 2-Hydroxymethyl-5-methylthiophene (10) STR20 A solution of 50 ml (456 mmol) of 5-methylthiophene-2-carbaldehyde in 350 ml of ethanol was admixed with 13.2 g (347 mmol) of sodium borohydride a little at a time, with ice cooling and stirring. After addition was complete, the mixture was further stirred for another 2 h and the reaction solution was then poured into a mixture of 400 g of ice and 200 ml of saturated ammonium chloride solution. After gas formation was complete, the solution was freed from ethanol in vacuo. The aqueous residue was extracted repeatedly with ether, the combined ether phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The solvent was distilled off. An oily residue remained behind which was distilled at a pressure of 20 mbar. 1st fraction: 55-100° C. 0.3 g 2nd fraction: 101-99° C. 50.0 g The product was unstable even when stored in a refrigerator, and should therefore be reacted as soon as possible. Yield: 50.3 g (86%), colourless liquid Rf =0.512 (petroleum ether:ether=1:1). 1 H-NMR (CDCl3): δ=6.81 (d; 1H, CH), 6.63 (d; 1H, CH), 4.74 (s; 2H, --CH2 --), 2.50 (s; 3H, CH3), 1.75 (bs; 1H, OH). 13 C-NMR (CDCl3): δ=141.70 (s; C), 140.24 (s; C), 125.54 (d; C), 124.82 (d; C), 59.86 (t; CH2), 15.39 (q; CH3).
With sodium tetrahydroborate In methanol Sealed tube;
With sodium tetrahydroborate In methanol at 0 - 20℃; Inert atmosphere;
(4Z)-4-((5-methylthiophen-2-yl)methylene)-2-phenyloxazol-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With 1-butyl-3-methylimidazolium phosphotungstate; acetic anhydride at 80℃; for 0.333333h;
93%
With acetic anhydride at 20℃; for 0.2h; Neat (no solvent); Sonication;
83%
With sodium acetate; acetic anhydride at 100℃; for 2h;
80%
With acetic anhydride; 4-aminobenzene sulfonic acid In water at 20℃; for 0.833333h; Green chemistry;
General procedure for the synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones (4a-r)
General procedure: Theappropriate aldehyde (1, 1 mmol), hippurric acid (2, 1 mmol), acetic anhydride (3, 1 mmol), water (5 mL), and SA as a catalyst (20 mol%) was stirred at rt. After completion of the reaction as indicated by TLC (hexane:EtOAc; 70:30) analysis, the reaction mixture allowed to stand for 5 h at rt. The resulting precipitated products were filtered off, washed with ice water and dried at rt. The crude products were purified by recrystallization from absolute EtOH, if required. The filtrate containing the catalyst was usedas such for exploring the reusability of the catalyst. Representative spectral date is as follows:
With bromine In glacial acetic acid at 0 - 20℃; Darkness;
98%
With bromine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
95%
With bromine; glacial acetic acid at 20℃;
86.4%
With bromine; glacial acetic acid for 8.5h; Cooling with ice;
1 3-Bromo-2-methyl-5-aldehyde thiophene (2):
A solution of 2-methyl-5-aldehyde thiophene (1) (25. 2 g, 200 mmol) was dissolved in 200 mL of acetic acid in a 500 mL single-necked flask under ice-cooling. Bromine and 60 mL of glacial acetic acid were placed in a constant-pressure funnel and slowly added dropwise. The mixed solution of liquid bromine and glacial acetic acid was dripped in 0.5 h and continued ice bath reaction for 8 h. The water phase was separated by adding NaOH After neutralization, extraction with dichloromethane, combined organic phases, washed successively with saturated Na2C03 and aq., Dried over anhydrous MgSO ?, decanted, and evaporated to remove the solvent. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate To obtain 35 g of a pale yellow solid, 4g, yield: 86.4%;
80%
With bromine; glacial acetic acid at 20℃; for 25h;
1.1.1 (1) Synthesis of 5-methyl-4-bromo-2-thiophenecarboxaldehyde
In a 1000 mL three-necked flask, 0.4 mmol of 5-methyl-2-thiophenecarboxaldehyde was dissolved in 400 mL of glacial acetic acid.At room temperature, a solution of 0.5 mmol of bromine in 200 mL of glacial acetic acid was slowly added dropwise.After 9 hours of dropwise addition, the reaction was stirred for 16 hours at room temperature.The reaction solution thus obtained was poured into a 3 L saturated sodium carbonate solution and extracted three times with diethyl ether.The combined ether layers were washed three times with water, dried over anhydrous magnesium sulfate and filtered and evaporated.Obtaining a yellow-brown solid 5-methyl-4-bromo-2-thiophenecarboxaldehyde in a yield of 80%;
76%
With bromine; glacial acetic acid at 25℃; for 20h;
74%
With bromine In glacial acetic acid
74%
With bromine In glacial acetic acid for 36h; Ambient temperature;
73%
With bromine; glacial acetic acid at 20 - 30℃; for 72h; Cooling with ice; Darkness;
2 4-Bromo-5-methylthiophene-2-carboxaldehyde
A solution of bromine (19.18 g; 0.12 mol) in acetic acid (50 ml) was added dropwise to a solution of 5-methyl- 2-thiophenecarboxaldehyde (12.62 g; 97.9 mmol) in acetic acid (80 ml) under exclusion of light. The temperature was kept below 30° C. by cooling in a water bath. The reaction mixture was stirred for 72 h at RT and then carefully poured into saturated aqueous Na2CO3 solution (500 ml). Afier the gas evolution had abated, diethyl ether (400 ml) was added and the phases were separated. The aqueous phase was extracted with diethyl ether (2x100 ml). The combined organic phases were washed with saturated aqueous NaRCO3 solution (150 ml), dried over Na2504, filtered and concentrated on a rotary evaporatot The crude product was purified by means of column chromatography (5i02, n-hexane/ethyl acetate 9:1; R1=0.47). 14.67 g (71.5 mmol; 73%) of a yellowish solid was obtained. ‘R-NMR (CDC13, 400 MHz): ö=2.48 (s, 3H; CR3),7.59 (s, 1R, =CR), 9.77 (s, 1R, CR0). ‘3C-NMR (CDC13, 100.6 MHz): ö=15.9 (CR3),111.2 (=C), 138.7 (=CR), 140.1 (=C), 145.8 (=C), 181.6 (C=O).
68%
Stage #1: 5-methylthiophene-2-carboxaldehyde With bromine; glacial acetic acid for 55h; Absence of light;
Stage #2: With anhydrous sodium carbonate In lithium hydroxide monohydrate for 1h;
384
Example 384; Preparation of 4-bromo-5-methyIthiophene-2-carbaldehydeA solution of 5-methylthiophene-2-carbaldehyde (1Og5 79 mmol) in 30 ml of AcOH was added over a 7-hour period, with a syringe pump, to a stirring mixture of bromine (4.9 ml, 95 mmol) and 30 ml of AcOH, while the reaction was kept in the dark. The reaction was allowed to stir for 2 days and then poured slowly in 600 ml of 2M sodium carbonate. The mixture was stirred for 1 hour and extracted (3x) with ether. The organic layer was washed (2x) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, loaded unto silica and purified by column chromatography on silica gel using a gradient of 5 to 25 % EtOAc in hexanes to give 4-bromo-5-methylthioρhene-2-carbaldehyde (11 g, 68% yield) as yellow solid. MP 58 0C as reported in literature.
67%
With bromine; glacial acetic acid at 20℃; for 16h; Darkness;
51.5%
With bromine; glacial acetic acid for 8h; Cooling with ice;
1 1,4-bromo-5-methylthiophene-2-carbaldehyde (3):
Under ice bath conditions,2-Methyl-5-aldehydethiophene (1) (12.6 g, 100.0 mmol) was dissolved in 120.0 mL of glacial acetic acid,Acetic acid containing liquid bromine is added dropwise with stirring,Continue ice bath reaction for 8 hours,Add 80.0 mL of water to terminate the reaction, separate the phases, neutralize the aqueous phase to neutral with NaOH solution, and extract with ether. Combine the organic phases,And Na2CO3 and aqueous solution were washed successively, and dried over anhydrous MgSO4 overnight. The solvent was evaporated and the solvent was evaporated to dryness. The residue was eluted with petroleum ether and ethyl acetate (V petroleum ether: V ethyl acetate = 5: 1) Silica gel column chromatography gave 10.5 g of a pale yellow solid, yield: 51.5%;
50%
With bromine In glacial acetic acid at 20℃; for 6h;
2 4-bromo-5-methylthiophene-2-carbaldehyde
To a solution of 5-methylthiophene-2-carbaldehyde (50.0 g) in acetic acid (400 mL) was added dropwise a solution of bromine (25 mL) in acetic acid (200 mL) at room temperature over 6 hr. After the dropwise addition, the reaction mixture was stirred overnight, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in toluene (50 mL), and the mixture was stirred at 110°C for 2 hr and concentrated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (1:5, volume ratio) and concentrated to give 4-bromo-5-methylthiophene-2-carbaldehyde (40.0 g, yield 50%) as yellow crystals. melting point 60°C.
42%
With bromine
30%
With bromine; glacial acetic acid at 20℃; for 24h;
1.1 Preparation of 4-bromo-5-methyl-2-thiophenecarboxaldehyde
5-methyl-2-thiophenecarboxaldehyde (6.3 g, 50.0 mmol) and 50 mL of acetic acid were added to a 100 mL round bottom flask and Br2 (8.78 g, 55.0 mmol) was then weighed in an appropriate amount of acetic acid using a constant pressure dropping funnel. At room temperature slowly add bromine acetic acid solution, room temperature stirring 24h, TLC tracking reaction after the end of the water to stop the reaction. The reaction mixture was neutralized to neutral with anhydrous sodium carbonate. The product was extracted with ether three times and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a black liquid which was chromatographed on petroleum ether: ethyl acetate = 40: 3 (ν: ν). The solvent was evaporated to give 3.1 g of a white solid in 30% yield.
30.1%
With bromine; glacial acetic acid at 20℃; for 24h;
1.1.1 1.1 Preparation of 4-bromo-5-methyl-2-thienaldehyde
Add to 100mL round bottom flask5-methyl-2-thiophene formaldehyde (6.3 g, 50.0 mmol) and 50 mL of acetic acid,Then use a constant pressure dropping funnel to weigh Br2 (8.78g, 55.0mmol) and dissolve it in an appropriate amount of acetic acid.Add bromine acetic acid solution slowly at room temperature and stir for 24h at room temperature.After TLC followed the reaction, water was added to stop the reaction.The reaction mixture was neutralized to neutrality with anhydrous sodium carbonate.The product was extracted three times with ether, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a black liquid. Column chromatography was eluted with petroleum ether: ethyl acetate = 40: 3 (v: v).Evaporated solvent3.1g was obtained as a white solid,The yield was 30.1%.
16%
With bromine In tetrahydrofuran at 0℃; for 25h;
With bromine In tetrahydrofuran Yield given;
With bromine In glacial acetic acid at 20℃; for 18h;
With NBS; glacial acetic acid; dibenzoyl peroxide at 70℃; for 7h;
With bromine In tetrahydrofuran Inert atmosphere;
11.44 g
With phosphorus tribromide; glacial acetic acid at 40℃; for 24h;
1.1 Step 1: 4-Bromo-5-methyl-2-thiophenecarbaldehyde
Step 1: 4-Bromo-5-methyl-2-thiophenecarbaldehyde [00296] A l OOOmL round bottom flask was charged with 5-methyl-2-thiophenecarboxaldehyde ( 15 g, 120 mmol) and acetic acid (200 mL, 4000 mmol). Added pyridinium tribromide (48.5 g, 137 mmol). Heated in a 40 °C oil bath for 24 h. Reaction mixture was cooled to rt and poured into water ( 1 L). Layers were separated, and the aqueous layer was extracted three times with EtOAc. Combined organics were washed with saturated NaHC03 and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Subjected to ISCO chromatography eluting with a hexane / EtOAc gradient to afford the title compound as a white solid (yield = 1 1 .44g). NMR (400 MHz, Acetone-d6) δ 9.87 (s, 1 H), 7.88 (s, 1 H), 2.52 (s, 3H).
40 g
With bromine; glacial acetic acid at 20℃; for 50h;
1.1 Step 1 4-Bromo-5-methyl-thiophene-2-carbaldehyde
The title compound was prepared according to the procedure described in ). To a solution of 40 g of 2-methyl-2-carbaldehyde in 320 ml of AcOH was added a solution of bromine (20 ml) in 150 ml of AcOH over a period of 6h. After reaction mixture was stirred for 20 h at room temperature, a solution 8 mL of bromine in 50 ml of AcOH was added and stirring was continued for another 24 h. The mixture was then concentrated under vacuum. The residue was treated with 300 ml of saturated aqueous solution of Na2CO3 and extracted with 2 X 500 ml of ether. The combined ether extracts was dried over Na2SO4, filtered and concentrated. The crude product was swished from 100 ml of 10:1 hexane/ether to give 40 g of the title compound. 1H NMR (500 MHz, acetone-d6): δ 9.88 (s, 1H), 7.90 (s, 1H), 2.53 (s, 3H).
With bromine; glacial acetic acid In lithium hydroxide monohydrate at 20℃; for 48h;
1.2; 3 Synthesis of 5-methyl-4-bromo-2-thiophenecarbaldehyde
The mixed solution of bromine water (1.2eq.) and glacial acetic acid was added dropwise to the glacial acetic acid solution containing 5-methyl-2-thiophenecarbaldehyde (1eq.) under stirring. After stirring for 48h at room temperature, the reaction mixture was added to cold water, it was filtered and purified using a hexane/ethyl acetate (50:1) column to obtain a pale yellow solid.
8-Amino-2-(5-methyl-thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
Stage #1: 5,6-diamino-nicotinic acid methyl ester With N-hydroxy-2,4,6-trimethylbenzensulfonamide In 1,4-dioxane at 20℃; for 1h;
Stage #2: 5-methylthiophene-2-carboxaldehyde In 1,4-dioxane at 100℃; for 4h;
Stage #3: With potassium hydroxide In 1,4-dioxane; methanol at 70℃; for 2h;
Multi-step reaction with 2 steps
1.1: triphenylphosphine / dichloromethane / 0.25 h / 0 °C
1.2: 0.55 h / 0 °C
2.1: n-butyllithium / tetrahydrofuran / 0.67 h / -78 °C / Inert atmosphere
Multi-step reaction with 2 steps
1: triphenylphosphine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere
2: n-butyllithium / diethyl ether; hexane / 3.5 h / -78 - 20 °C / Inert atmosphere
7-bromo-2-(5-methylthiophen-2-yl)[1,2,4]triazolo[1,5-a]pyridin-5-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; mesitylenesulfonylhydroxylamine;
EXAMPLE 82 7-Bromo-2-(5-methyl-thiophen-2-yl)-[1,2,4]triazolo[, 1,5-a]pyridin-5-ylamine The title compound, MS m/e (%): 311 (M++2, 100), was prepared in accordance with the general method of example 63 from <strong>[329974-09-6]4-bromo-pyridine-2,6-diamine</strong>, O-mesitylene-sulfonylhydroxylamine, and 5-methyl-2-thiophenecarboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Into a 50 ml, three-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were added 6.3 g (50 mmol) of 2-formyl-5-methylthiophene, 3.0 g (20 mmol) of sodium bromate, 10 ml (174 mmol) of acetic acid and 5 g (74 mmol) of 25% aqueous ammonia, followed by stirring at 80C for 4 hours. To the reaction mixture were added 30 ml of water and 50 ml of ether. Further, an aqueous solution containing 23% of sodium hydroxide was added carefully until a pH of >11 was reached. The mixture was subjected to phase separation. Then, there were conducted washing with water and a saturated aqueous sodium chloride solution in this order, drying over anhydrous sodium sulfate, and distillation under reduced pressure for ether removal, to obtain 6.5 g of an oil as a residue. The oil was subjected to Kugel-rohr distillation to obtain 5.9 g of a colorless oil. The oil contained, as a component, 94.0% (in terms of areal ratio of liquid chromatography) (yield: 96.0%) of 2-cyano-5-methylthiophene. Liquid mass chromatography was conducted to confirm a molecular ion peak [(M-1)+] of 122.
60%
REFERENCE EXAMPLE 68 5-Methyl-2-thiophenecarbonitrile The title compound was obtained employing 5-methyl-2-thiophenecarboxaldehyde by the method similar to that in Reference Example 65. Yield: 60%. An oil. 1H NMR (CDCl3) delta 2.46 (3H, s), 6.95 (1H, d, J = 5.0 Hz), 7.47 (1H, d, J = 5.0 Hz).
With pyridine; hydrogenchloride; sodium borohydrid; trifluoroacetic acid In tetrahydrofuran; methanol; diethyl ether
C.C.1 5-Methyl-2-thienyl-methylamine
Preparation CC1 5-Methyl-2-thienyl-methylamine Methoxylamine hydochloride (3.5 g, 41.7 mmol) and pyridine (6.75 mL, 83.5 mmol) was added to a solution of 5-methylthiophene-2-carboxaldehyde (3.5 g, 27.8 mmol) in methanol (20 mL) at room temperature. After 3 h, the mixture was concentrated in vacuo, diluted with ethyl acetate (100 mL) and washed with 1 N HCl (3*) and brine (1*), dried (Na2 SO4), filtered and concentrated in vacuo to give a mixture of oxime isomers. Trifluoroacetic acid (4.97 mL, 65 mmol) was added dropwise to a suspension of sodium borohydride (2.44 g, 65 mmol) in THF (40 mL) at 0° C. A solution of the oxime prepared above (2.0 g, 13 mmol) in THF (5 mL) was then added dropwise. After 2 h, the reaction was heated to a gentle reflux for 2 h, cooled, and quenched by the addition of water (10 mL). The mixture was diluted with methylene chloride (50 mL) and washed with brine (2*) and dried (MgSO4) filtered and concentrated in vacuo. The residue was dissolved in 100 mL of diethyl ether and treated with sat HCl in ether (3 mL). The precipitate was collected by vacuum filtration and washed with ether and dried to afford the titled amine as a white solid as its hydrochloride salt (1.2 g). 1 H NMR (250 MHz, d6 DMSO) δ 8.5 (bs, 3H); 7.0 (d, 1H, J=2.0 Hz); 6.7 (m, 1H); 4.1 (bs, 2H); 2.4 (s, 3H).
Multi-step reaction with 2 steps
1: hydroxylamine hydrochloride; sodium acetate / ethanol / 6 h / 20 °C
2: zinc; acetic acid / 6 h / 20 °C
Multi-step reaction with 2 steps
1: hydroxylamine hydrochloride; sodium acetate / ethanol / 6 h / 20 °C
2: zinc; acetic acid / 6 h / 20 °C
Multi-step reaction with 2 steps
1: hydroxylamine hydrochloride; sodium acetate / methanol / 8 h / 25 °C
2: lithium aluminium tetrahydride; water / tetrahydrofuran / 12 h / 0 - 25 °C
Multi-step reaction with 2 steps
1: hydroxylamine hydrochloride; sodium acetate / ethanol / 6 h / 20 °C
2: acetic acid; zinc / 6 h / 20 °C
Multi-step reaction with 2 steps
1: hydroxylamine hydrochloride; sodium acetate / ethanol; water / 1 h / Heating / reflux
2: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Heating / reflux
With piperidine In pyridine at 100℃; for 13h; Reflux;
2
[00176] The nucleobase analogs 4a, 4b, 4c and 4d were synthesized based on literature methods 1,2 as shown in Scheme SI . Briefly, condensation of the aldehyde (la-d) with malonic acid at 100 °C in pyridine as a solvent and piperidine as a catalyst for 12 h, followed by a reflux for 1 h, yielded the corresponding acrylic acid intermediates (2a-d).
With pyridine at 80 - 90℃; for 2h;
With piperidine; pyridine for 6h; Reflux;
3.2. General Procedure for the Synthesis of I
General procedure: A mixture of benzaldehyde (30 mmol), malonic acid (120 mmol), and piperidine (2 mL) in pyridine was refluxed in a 250 mL single neck round bottomed flask (SNRB) for 6 h. Upon completion, the reaction mixture was poured into a 1 L Erlenmeyer flask (EF) containing cold, dilute HCl (200 mL) and stirred for 10 min. The resulting precipitate was filtered and washed with cold water to afford I.
With ammonium acetate; acetic acid; In cyclohexane; at 110℃; for 17h;
Example 1: Synthesis of dye; The Ru-type dye of the present invention, DCSC l(Chemical Formula 1-1) andDCSC(Chemical Formula 1-2) were synthesized by the reaction as shown in the above Reaction Formula 1. All the reactions were conducted under argon gas, and the used solvent was distilled with sodium. As starting material, Aldrich and Strem reagents were used without purification. (1) Preparation of compound (1); Cyano-acetic acid benzyl ester (8.4 g, 47.95 mmol) and ammonium acetate (0.709 g, 9.2 mmol) were dissolved in 25 mL of cyclohexane, and acetic acid (2.5 g,41.75 mmol) was slowly added thereto dropwise. The reaction mixture was agitated for15 minutes, and then 5-methyl-thiophene-2-carbaldehyde (6.05 g, 47.95 mmol) was added thereto, and the reaction mixture was agitated under nitrogen gas at 110C for 5 hours. After the agitation, ammonium acetate (0.709 g, 9.2 mmol) was added at room temperature and the reaction mixture was agitated at 110C for 12 hours. Then, an organic layer was extracted with 200 mL of ethylene acetate and water, and separated by recrystallization under ethylene acetate.
Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.5h;
Stage #2: 5-methylthiophene-2-carboxaldehyde In tetrahydrofuran at 0 - 20℃; for 5h;
92 (Example 92), Synthesis of ethyl (2Z)-2-methyl-3-[5-methylthiophen-2-yl]-2-propenoate
Under nitrogen atmosphere, a reactor was loaded with 60% sodium hydride (87.1 g, 2.15 mol) and dry THF (130 mL). A solution of triethyl 2-phosphonopropionate (239 mL, 1.54 mol) in dry THF(160 mL) was added dropwise into the reactor in an ice bath. The mixture was stirred at room temperature for 1.5 hours, and successively, in an ice bath, a solution of 5-methylthiophene-2-carboxyaldehyde (180.0 g, 1.43 mol) in dry THF (430 mL) was added dropwise thereto under ice bath cooling and stirred at room temperature for 5 hours. An aqueous saturated ammonium chloride solution was added to the resulting reaction mixture and the mixture was extracted with diethyl ether to obtain an organic layer. The organic layer was washed with a saturated brine and dried over magnesium sulfate anhydride. The solvent was distilled off under reduced pressure to obtain ethyl (2Z)-2-methyl-3-[5-methylthiophen-2-yl]-2-propenoate (291.8 g, 97.0%) as a dark red liquid
Stage #1: 5-methylthiophene-2-carboxaldehyde; cyclohexylamine In methanol at 20℃; for 1h;
Stage #2: Isopropyl fumarate; 1-(isocyanomethyl)-4-methoxybenzene In methanol at 20℃;
General procedure: A mixture of appropriate heterocyclic amine (1.0 mmol) (3) and aromatic aldehyde (1.2 mmol) (4) were stirred in tetrahydrofuran under ice-cold condition for 5 min, followed by addition of the thioglycolic acid (2.0 mmol). After 5 min, dicyclohexylcarbodiimide(1.2 mmol) was added to the reaction mixture at 0 C and the reaction mixture was stirred for an additional 3-5 h at room temperature to complete the reaction. Progresses of the reactions were monitored by TLC using acetone:chloroform (7:3) as mobile phase. The precipitated dicyclohexylurea was filtered off; the filtrate was concentrated to drynessunder reduced pressure. Deionized water was added to the residueand extracted with ethylacetate. The organic layer was successively washed with 5% aqueous sodium hydrogen carbonate and sodium chloride. Finally organic layer was dried over anhydrous sodium sulfate. The crude solid obtained on evaporation of the solvent under reduced pressure was subjected for column chromatography using silica gel 100-200 mesh using n-hexane:ethyl acetate (7:3) as the solvent system and further recrystallized in acetone to yield white/yellowish-white products[42].
General procedure: The mixture of the compound 15 (190.2 mg, 1.0 mmol) and 2-thiophenecarboxaldehyde (123.4 mg, 1.1 mol) in anhydrous ethanol (3.0 mL) was stirred over night at room temperature or reflux temperature. The corresponding imine was reduced with solid sodium borohydride (75.7 mg, 2.0 mmol) which was added slowly, the mixture was further stirred over night at room temperature. An additional ethanol (2.0 mL) was added to the reaction vessel after which 10% hydrochloric acid aqueous solution was added to quench excess sodium borohydride. The acidic mixture was basified with 25% aqueous ammonia solution. The desired product was extracted with dichloromethane (3 20 mL) and the solution was dried over sodium sulphate anhydrous. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with a gradient of 40-60% ethyl acetate in petroleum ether to give the title compound 17a1 [164.9 mg, 57.6% (from 15)] as a white solid, mp 100-101 C.
Synthesis of Retro-2 and Retro-2cycl [00281] To a stirring solution of 2-aminobenzanilide was added 5-methyl-2- thiophenecarboxaldehyde (86.3 mu, .80 mmol). After 24 hours, the reaction was concentrated and then chromatographed on silica gel with 20-40% ethyl acetate in hexanes. Retro-2 and Retro-2cycl were cleanly separated and then further purified by recrystalization from ethanol and ethyl acetate respectively. Yields: Retro-2 47.2 mg (36%), Retro-2cycl 78.0 mg (59.4%). Characterization: Retro-2 FAB HRMS: Ci9Hi6N2OSNa+ Predicted: 343.0881 Found:
3-hydroxy-3-(5-methylthiophen-2-yl)-2-(naphthalen-2-yl)propanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31.6%
Stage #1: 2-naphthaleneacetonitrile With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: 5-methylthiophene-2-carboxaldehyde In tetrahydrofuran for 0.166667h;
44 Example 44 - Synthesis of Compound ID No. 44 (CS -N-methyl-3-(5-methylthiophen- 2-yl)-2-fnaphthalen-2-yl)propan- 1 -amine) 4i/-3-hydroxy-3-(5-methylthiophen-2-yl)-2-(naphthalen-2-yl)propanenitrile:
Diisopropylamine (4.02 mL, 28.7 mmol) was added to a solution of 2- naphthylacetonitrile (4 g, 23.92 mmol) in 150 mL of dry THF under nitrogen. The mixture was stirred and cooled to -78 °C for 20 minutes before adding 2.5M n- butyllithium (1 1.48 mL, 28.7 mmol) in a dropwise fashion via a syringe. After 30 minutes of stirring at -78 °C, 5-methylthiophene-2-carboxaldehyde (3.07 mL, 28.7 mmol) was added slowly via a cannula. After 10 minutes, the reaction was quickly quenched with 25 mL 2: 1 THF/acetic acid. Cold bath was removed and the reaction was allowed to reach r.t slowly. Water was added and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with water and brine, dried over MgS04, and concentrated using a rotary evaporator. The resulting residue was dissolved in 5 mL of DCM. Hexane was slowly added till the solution turned turbid. This product was allowed to crystallize overnight at room temperature. Light brown crystals of the n/z'-adduct were filtered and washed with hexane and dried (2.5 g, 31.6%). 1H NMR (CDCl3) δ 7.86-7.79 (m, 4 H), 7.56-7.46 (m, 2 H), 7.34 (dd, 1 H, J= 8.7, 1.5 Hz), 6.68 (d, 1 H, J= 3.6 Hz), 6.55 (m, 1 H), 5.27 (dd, 1 H, J= 5.4, 5.4 Hz), 4.29 (d, 1 H, J= 6.0 Hz), 2.55 (d, 1 H, J= 5.4 Hz), 2.48 (s, 3 H). MS m/z (ESI) 316.08 (MNa+). The relative anti configuration of this compound was confirmed after borane reduction.
3-(5-methyl-thiophene-2-carbonyl)-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With tert.-butylhydroperoxide; iron(III) chloride hexahydrate In N,N-dimethyl-formamide at 90℃; for 10h;
3 Example 3. Preparation of 3- (5-methylthiophene-2-formyl) coumarin derivative when X = S, R1 = R2 = -H
To the 25 mL reaction flask was added coumarin (0.5 mmol, 73 mg) and 5-methylthiophene-2-carbaldehyde (1.5 mmol,189 mg) was dissolved in 5.0 mL of DMF and then FeCl3 6H2O (0.05 mmol, 13.5 mg) and t-BuOOH (1.5 mmol, 195 mg) were added. The reaction was carried out under heating with stirring in an oil bath at a reaction temperature of 90 ° C. The reaction was carried out by TLC. The reaction time was 10 h. After the reaction, the solvent was distilled off under reduced pressure. Ten mL of ethyl acetate was added to the residue, washed twice with 20 mL of saturated NaHCO3 and once with 10 mL of saturated brine. The mixture was dried over anhydrous Na2SO4 and the solution was concentrated and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/8) to give 0.092 g of a white solid in 68.0% yield.
63%
With tert.-butylhydroperoxide; iron(II) chloride In chlorobenzene at 120℃; for 12h; Schlenk technique; Inert atmosphere; regioselective reaction;
61%
With tert.-butylhydroperoxide In water; chlorobenzene at 100℃; for 20h; Sealed tube; regioselective reaction;
1,3:2,4-di(5-methyl-2-thenylidene)-D-sorbitol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.8%
Stage #1: 5-methylthiophene-2-carboxaldehyde; D-sorbitol With methanesulfonic acid In methanol at 20℃; for 48h;
Stage #2: With methanol; potassium borohydride for 0.5h;
1 Example 1 Preparation of pure 1,3:2,4-di(5-methyl-2-thenylidene)-D-sorbitol
Example 1 Preparation of pure 1,3:2,4-di(5-methyl-2-thenylidene)-D-sorbitol (0054) AIL four-necked cylindrical shaped reaction flask equipped with a thermometer, a nitrogen inlet, and a mechanical stirrer was charged with D-sorbitol (20.0 g, 0.110 moles), methanesulfonic acid (1.00 g), 5-methyl-2-thiophenecarboxaldehyde (25.0 g, 0.198 moles) and methanol (200 ml) and then reacted at room temperature for 48 hours, so as to form a first reaction mixture. (0055) Then potassium borohydride powders (1 g, purity>96%) were added in the first reaction mixture and stirred for 30 minutes to obtain a precipitated product. The precipitated product was filtered and washed with a 40 wt% methanol solution to obtain a second reaction mixture. (0056) After that, the second reaction mixture was filtered to collect the solid substance therefrom, dried and ground to give 1,3:2,4-di(5-methyl-2-thenylidene)-D-sorbitol as fine white powders (29.5 g, yield 74.8%) having a melting point of 210.2°C to 210.9°C and a LC purity of 97.3%. No 5-methyl-2-thiophenecarboxaldehyde was detected by the GC analysis, and the fine white powders did not release any odor.
Multi-step reaction with 10 steps
1.1: phosphorus tribromide; acetic acid / 24 h / 40 °C
2.1: toluene-4-sulfonic acid / toluene / Dean-Stark; Reflux
3.1: n-butyllithium / tetrahydrofuran; hexane / 0.08 h / -74 - -70 °C / Inert atmosphere
3.2: -30 - 0 °C / Inert atmosphere
4.1: dmap; triethylamine / dichloromethane / 1 h / 20 °C
5.1: hydrogenchloride / methanol; water / 1 h / 20 °C
6.1: n-butyllithium / hexane; 2-methyltetrahydrofuran / -75 - -70 °C / Inert atmosphere
7.1: manganese(IV) oxide / dichloromethane / 18 h / 20 °C
8.1: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere
9.1: N,N-dimethyl-formamide / 0.08 h / 0 - 20 °C
9.2: 2 h / 40 °C
10.1: trifluoroacetic acid / dichloromethane / 1 h / 0 - 20 °C
Multi-step reaction with 10 steps
1.1: phosphorus tribromide; acetic acid / 24 h / 40 °C
2.1: toluene-4-sulfonic acid / toluene / Dean-Stark; Reflux
3.1: n-butyllithium / tetrahydrofuran; hexane / 0.08 h / -74 - -70 °C / Inert atmosphere
3.2: -30 - 0 °C / Inert atmosphere
4.1: dmap; triethylamine / dichloromethane / 1 h / 20 °C
5.1: hydrogenchloride / methanol; water / 1 h / 20 °C
6.1: n-butyllithium / hexane; 2-methyltetrahydrofuran / -75 - -70 °C / Inert atmosphere
7.1: manganese(IV) oxide / dichloromethane / 18 h / 20 °C
8.1: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere
9.1: pyridine / 1-methyl-pyrrolidin-2-one / 10 - 15 °C / Inert atmosphere
10.1: phosphoric acid / acetonitrile / 4 h / 1 - 20 °C
Multi-step reaction with 9 steps
1.1: phosphorus tribromide; acetic acid / 24 h / 40 °C
2.1: toluene-4-sulfonic acid / toluene / Dean-Stark; Reflux
3.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 °C / Inert atmosphere
3.2: 1.67 h / -30 - 0 °C / Inert atmosphere
3.3: CHIRALPAK AD / Resolution of racemate
4.1: dichloromethane / 3 h / 20 °C
5.1: hydrogenchloride / tetrahydrofuran; water / 1 h / 20 °C
6.1: n-butyllithium / tetrahydrofuran; hexane / 0.25 h / -78 °C
6.2: 0.67 h / -75 - 26 °C
6.3: 4 h / 30 °C
7.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 20 °C
8.1: pyridine / 1-methyl-pyrrolidin-2-one / 10 - 15 °C / Inert atmosphere
9.1: phosphoric acid / acetonitrile / 4 h / 1 - 20 °C
Multi-step reaction with 9 steps
1.1: phosphorus tribromide; acetic acid / 24 h / 40 °C
2.1: toluene-4-sulfonic acid / toluene / Dean-Stark; Reflux
3.1: n-butyllithium / tetrahydrofuran / 0.33 h / -78 °C / Inert atmosphere
3.2: 1.67 h / -30 - 0 °C / Inert atmosphere
3.3: CHIRALPAK AD / Resolution of racemate
4.1: dichloromethane / 3 h / 20 °C
5.1: hydrogenchloride / tetrahydrofuran; water / 1 h / 20 °C
6.1: n-butyllithium / tetrahydrofuran; hexane / 0.25 h / -78 °C
6.2: 0.67 h / -75 - 26 °C
6.3: 4 h / 30 °C
7.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 20 °C
8.1: N,N-dimethyl-formamide / 0.08 h / 0 - 20 °C
8.2: 2 h / 40 °C
9.1: trifluoroacetic acid / dichloromethane / 1 h / 0 - 20 °C
3-[2,3-dihydro-2-(5-methylthiophen-2-yl)-1H-1,5-benzodiazepin-4-yl]-4-hydroxy-2H-1-benzopyran-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With nano silica-bonded N-propylsulfamic acid In water at 80℃; for 0.116667h; Microwave irradiation; Green chemistry;
General procedure for the synthesis of 1,5-benzodiazepines 4a-4p
General procedure: In a G30 vial equipped with a magnetic stir bar, a mixture of o-phenylenediamine 1a-1c, 3-acetyl-4-hydroxycoumarin (2, 1 mmol), aromatic/heterocyclic aldehyde 3a-3l (1 mmol), and 30-mg catalyst (NSBNPSA) in 10 cm3 water was taken and irradiated with microwaves at 80 C until the completion of the reaction (Table 5). After completion as monitored by TLC using chloroform-methanol (3:1) mixture as solvent, ethyl acetate was added to the resulting mixture to extract the product. The catalyst was separated by filtration, washed with ethyl acetate(3 9 10 cm3), dried, and reused. The organic layer was evaporated under reduced pressure, and the resulting product was further purified by recrystallization using ethyl acetate/ethanol to afford the pure products.
With N-Bromosuccinimide; palladium diacetate; silver trifluoroacetate; toluene-4-sulfonic acid; trifluoroacetic acid; 4-Nitroanthranilic acid In 1,2-dichloro-ethane at 90℃; for 24h; Sealed tube;
30%
With N-Bromosuccinimide; 4-chloro-2-(trifluoromethyl)aniline; palladium diacetate In 1,2-dichloro-ethane; trifluoroacetic acid at 60℃; for 24h;
1.2 General procedure for the synthesis of 3a-3w
General procedure: Compound 1 (0.4 mol), N-bromosuccinimide (NBS) (0.48 mol, 85.4 mg), and Pd(OAc)2(10 mol%, 8.9 mg), 2-Amino-5-chlorobenzotrifluoride (20 mol%, 15.6 mg) were mixed withDCE (2.5 mL) and TFA (0.5 mL) solvent. The reaction mixture was stirred 24 h at 60 °C. Aftercompletion of the reaction, the solution was concentrated in vacuo and purified by columnchromatography on silica gel using PE/DCM/EtOAc as eluent to give the desired product.
(6-bromo-2-methoxyquinolin-3-yl)(5-methylthiophen-2-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 2-methoxy-6-bromoquinoline With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78 - -40℃; for 1.5h;
Stage #2: 5-methylthiophene-2-carboxaldehyde In tetrahydrofuran; hexane at -78℃; for 3h;
Stage #3: With acetic acid In tetrahydrofuran; hexane at 20℃;
(6-Bromo-2-methoxyquinolin-3-yl)(5-meth lthiophen-2-yl)methanol (15)
A solution of 2,2,6,6-tetramethylpiperidine (3.5 mL, 20.6 mmol) in dry THF (20 mL) was cooled to -40 °C, and -BuLi (8.0 mL of a 2.5N solution in hexanes, 20 mmol) was added and the solution was stirred at -40 °C for 15 min, then cooled to -78 °C. A solution of 6-bromo-2- methoxyquinoline (4.00 g, 16.8 mmol) in THF (20 mL) was added dropwise and the orange solution was stirred at -78 °C for 1.5 h. A solution of 5-methylthiophene-2-carbaldehyde (1.12 g, 16.8 mmol) in THF (10 mL) was added. The mixture was stirred at -78 °C for 3 h, then acetic acid (2.9 mL, 50.7 mmol) was added and the solution was allowed to warm to r. . The mixture was partitioned between EtOAc and water and the organic fraction was dried and evaporated. Chromatography with DGVLhexanes (1 :3) eluted unreacted starting materials, then elution with DCM:hexanes (1 : 1) gave 15 as a white solid (3.37 g, 55%).1H MR (CDC13) δ 8.00 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 2.1 Hz, 1H), 6.72 (d, J = 3.4 Hz, 1H), 6.59 (dd, J = 3.4, 1.0 Hz, 1H), 6.18 (s, 1H), 4.07 (s, 3H), 3.03 (bs, 1H), 2.44 (s, 3H)Found: [M+H]=364.1
55%
Stage #1: 2-methoxy-6-bromoquinoline With 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran; hexane at -78℃; for 1.5h;
Stage #2: 5-methylthiophene-2-carboxaldehyde In tetrahydrofuran; hexane at -78℃; for 3h;
General procedure: Asolution of 2,2,6,6-tetramethylpiperidine (1.89 mL, 11.1 mmol) in dryTHF (12 mL) was cooled to -40 °C, n-BuLi(4.45 mL of a 2.5N solution in hexane, 11.1 mmol) was added and the solutionwas stirred at -40 °C for 15 min, then cooled to -78 °C. A solution of 6-bromo-2-methoxyquinoline(51) (2.20 g, 9.28 mmol) in THF (10mL) was added dropwise, the orange solution was stirred at -78 °C for 1.5 h,then a solution of 2,5-dimethylthiophene-3-carbaldehyde (52) (1.30 g, 9.27 mmol) in THF (10 mL) was added. The mixture was stirred at -78 °C for 3 h,then acetic acid (1.60 mL, 28.0 mmol) was added and the solution was allowed towarm to r.t.. The mixture waspartitioned between EtOAc and water, and the organic fraction was dried andevaporated. Chromatography with DCM:hexanes (1:3) eluted starting materials,then elution with DCM:hexanes (1:1) gave6-bromo-2-methoxyquinolin-3-yl)(2,5-dimethylthiophen-3-yl)methanol (53) as a white solid (1.97 g, 56%).
With sodium hydride; In tetrahydrofuran; at 35 - 80℃; for 8h;
General procedure: Anhydrous tetrahydrofuran (50 mL) was added into a round-bottomed flask (100 mL) containing<strong>[6882-68-4]sophoridine</strong> (0.005 mol) and sodium hydride (0.1 mol). The solution was stirred, and aldehyde(0.02 mol) was added at 35-40 C. The solution was then refluxed for 8 h. After cooling to roomtemperature, the mixture was treated with hydrochloric acid (5%, 20 mL) to hydrolyze the excesssodium hydride and then extracted with chloroform (3 x 20 mL). The combined organic layer wasconcentrated, and the residue was purified in a reverse-phase silica gel column (CH2Cl2:MeOH = 20:1,v/v) to give compounds 2a-2k.
With trichlorophosphate; In N,N-dimethyl-formamide; at 100℃; for 8h;Cooling with ice;
General procedure: To a stirred solution of 9ha-9hd (200 mmol) in dried DMF (43.86 g, 600 mmol) cooled in anice-water bath was added dropwise POCl3 (46.00 g, 300 mmol). The resulting mixture was stirred atthis temperature for 30 min and then at 100 C for another 5 h. After cooling to room temperature,the reaction mixture was poured carefully into ice-water (300 mL). The mixture thus obtained wasextracted with CH2Cl2 (300 mL × 3), and the combined extracts were washed successively with 5%brine (200 mL), 10% aqueous K2CO3 (200 mL) and 5% brine (200 mL), dried (Na2SO4) and evaporatedon a rotary evaporator to afford a residue, which was purified by column chromatography to yield10ha-10hd.
Grinding method
General procedure: Equimolar amounts of thiophene-2-carbaldehyde (1), substituted pyrazolone (2) (0.011 mol) and 2 gm of citric acid were taken in mortar and the whole reaction mixture was ground with the help of pestle for 8 min. Progress ofthe reaction was monitored by TLC. After completion of reaction, the reaction mixture was poured over ice cold water, the solid obtained was filtered, dried and purified by recrystallization from acetic acid to get pure compound 3.
1,4-dihydroxy-2-(hydroxy(5-methylthiophen-2-yl)methyl)anthracene-9,10-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: 1,4-dihydroxy-9,10-anthracenedione With potassium hydroxide In methanol; water for 0.5h; Inert atmosphere; Cooling with ice;
Stage #2: 5-methylthiophene-2-carboxaldehyde With sodium dithionite In methanol; water
1.12; 2.12; 3.12 (12) 2-((5-Methyl-2thienyl)hydroxymethyl)-1,4 dihydroxy-9,10anthraquinonePreparation of (LYH12):
Add 0.5 kg of 1,4-dihydroxyanthraquinone and 1 kg of potassium hydroxide in the glass-lined reaction tank.Add 50L of methanol and 10L of water as solvent.Protected by nitrogen and reacted under ice bath conditions.After 30 minutes, 1.5 kg of sodium dithionite was dissolved in 5 L of water to be added dropwise to the reaction system.After changing the color of the solution, slowly add 1 kg of excess reaction material 5-methylthiophene-2-carbaldehyde.After the reaction,Add 20 L of 3% hydrogen peroxide solution diluted 5 times, and continue stirring for 120 min.Finally, 10 L of a 1 mol/L hydrochloric acid solution was added for acidification, and the solid powder product was obtained after filtration.The solid yield was 93%.
38%
Stage #1: 1,4-dihydroxy-9,10-anthracenedione With sodium dithionite; potassium hydroxide In methanol; water for 0.25h; Inert atmosphere; Cooling with ice;
Stage #2: 5-methylthiophene-2-carboxaldehyde In methanol; water at 0℃; for 4h; Inert atmosphere;
Stage #3: With dihydrogen peroxide In water for 0.333333h;
2.1 General procedures for the synthesis of compounds A1-A14.
General procedure: In an ice bath,the solution of quinizarin (1 mmol) in MeOH (20 ml) and aqueous KOH (1 N, 6 ml) was added a solution of Na2S2O4 (1.0 mmol) in water under N2. After 15 min, the aldehyde (4 mmol) was added via syringe. The reaction mixture was stirred for 4 h at 0 °C. The solution was poured into 20 ml of cold water, which contained 4 ml of 30% H2O2 and stirred for 20 min. The mixture was acidified by addition of HCl (3 N, 2 ml) and extracted with CH2Cl2, dried and concentrated. The residue was purified by flash column chromatography to afford A1-14 as an orange solid. The yields of the derivatives (A1-A14) were 20-80%.
1,3:2,4-di-O-(5-methyl-2-thenylidene)-D-sorbitol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.1%
With methanesulfonic acid In methanol at 20℃; for 45h; Inert atmosphere;
1 Example 1
In the instant example, a powdery diacetal clarifying agent of 1,3:2,4-di(5-methyl-2-thenylidene)-D-sorbitol was prepared through the following steps. (0143) (a) A 500 ml four-necked cylindrical shaped reaction flask equipped with a thermometer, a nitrogen inlet, and a mechanical stirrer was charged with D-sorbitol (19.0 grams, 0.104 moles), methanesulfonic acid (0.4 grams), 5-methyl-2-thiophenecarboxaldehyde (25.0 grams, 0.198 moles), and methanol (150 grams) and then reacted at room temperature for 45 hours, so as to form a first reaction mixture. (0144) (b) The first reaction mixture was filtered to remove the mother liquor, and then added with new 100 grams of methanol and 10% of sodium hydroxide solution into the reaction flask slowly to neutralize the solution to pH>7. Subsequently, potassium borohydride powders (0.3 grams, purity>96%) and Ultramarine Blue (0.15 grams, CAS No. 57455-37-5) were added in the first reaction mixture and stirred for 1 hour to obtain a second reaction solution. (0145) (c) The second reaction solution was filtered to collect the solid precipitate from the second reaction solution. Then the solid precipitate was washed with 40 wt % methanol solution, and then dried and ground to obtain nearly white powdery diacetal clarifying agent of 1,3:2,4-di(5-methyl-2-thenylidene)-D-sorbitol (28.4 grams, yield 72.1% calculated from 39.4 grams of theoretical mass). Based on the total weight of the produced powdery diacetal clarifying agent, the amount of the Ultramarine Blue was about 0.5 wt %. The produced powdery diacetal clarifying agent of Example 1 had the following characteristics: (0146) i. Melting point: 198.78° C. (0147) ii. Data of 1H-NMR spectrum (400 MHz, d6-DMSO): δ6.89 (d, 2H), 6.69 (d, 2H), 5.79 (s, 2H), 4.79 (d, 1H), 4.41 (t, 1H), 4.17-4.00 (m, 3H), 3.88 (s, 1H), 3.80-3.78 (m, 1H), 3.75-3.65 (m, 1H), 3.60-3.55 (m, 1H), 3.50-3.40 (m, 1H), 2.42 (s, 6H). (0148) iii. Data of FTIR spectrum: λ3222, 2918, 2866, 1497, 1449, 1398, 1371, 1341, 1266, 1227, 1164, 1133, 1110, 1081, 1167, 1021, 1000, 960, 884, 858, 802, 769, 667, 614, 570, 544, 486 cm-1. (0149) iv. Data of UV/VIS spectrum: absorbance at 262 nm: 2.1820; absorbance at 292 nm: 1.0658; absorbance at 649 nm: 0.0036. (0150) v. Ash content: 0.51%. (0151) vi. Purity determined by LC: 99.6%. (0152) vii. GC analysis result of the residue of aromatic aldehyde: no 5-methyl-2-thiophenecarboxaldehyde was detected.
3-amino-N5-(2-methoxyphenyl)-6-methyl-4-(5-methylthiophen-2-yl)-N2-phenylthieno[2,3-b]pyridine-2,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
General procedure: Three drops of triethylamine were added at 20C to a mixture of 10 mmol of the corresponding aldehyde 1 and cyanothioacetamide 2 in 40 mL of ethanol. The mixture was stirred for 30 min, 10 mmol of acetoacetanilide 3a-3d and 1.4 mL (10 mmol) of triethylamine were added, and the mixture was stirred for 30 min and left to stand for 24 h. Alkylating agent 4i, 16a, or 19a-19i, was then added, the mixture was stirred for 4 h and diluted with 20 mL of DMF, 5.6 mL (10 mmol) of 10% aqueous potassium hydroxide was added, and the mixture was stirred for 2 h, left to stand for 24 h, and diluted with an equal volume of water.
3-amino-N2-(4-bromophenyl)-N5-(2-methoxyphenyl)-6-methyl-4-(5-methylthiophen-2-yl)-thieno[2,3-b]pyridine-2,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
General procedure: Three drops of triethylamine were added at 20C to a mixture of 10 mmol of the corresponding aldehyde 1 and cyanothioacetamide 2 in 40 mL of ethanol. The mixture was stirred for 30 min, 10 mmol of acetoacetanilide 3a-3d and 1.4 mL (10 mmol) of triethylamine were added, and the mixture was stirred for 30 min and left to stand for 24 h. Alkylating agent 4i, 16a, or 19a-19i, was then added, the mixture was stirred for 4 h and diluted with 20 mL of DMF, 5.6 mL (10 mmol) of 10% aqueous potassium hydroxide was added, and the mixture was stirred for 2 h, left to stand for 24 h, and diluted with an equal volume of water.
(E)-5-methyl-N’-((5-methylthiophen-2-yl)methylene)-1H-pyrazole-3-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.3%
In methanol for 4h; Reflux;
Synthesis of the compound (MTA)
The sulphur containing compound MTA was synthesized byrefluxing a methanolic solution (30ml) of 5-methylpyrazole-3-carbohydrazide(1.40g, 10mmol) with 2-Thiophenecarboxaldehyde(1.12g, 10mmol), also taken in methanol (20ml) (Scheme 1).Reflux was continued for ca. 4 h at water bath temperature. Afterslow evaporation of the respective reaction mixture a solidmicrocrystalline compound separated. It was filtered off, washedseveral times with cold methanol and dried in vacuo over fused CaCl2. Single crystal of MTA, suitable for X-ray diffraction wasobtained by slow evaporation of the methanolic solution of thecompound. Yield: 71.30%; Anal. Calc. for C10H10N4OS: C, 51.27; H,4.30; N, 23.91. Found: C, 51.23; H, 4.21; N, 23.94%. 1H NMR(DMSO-d6, 600MHz): d (ppm): 13.085 (s, 1H, pyrazole-NH), 11.688(s, 1H, hydrazide-NH), 8.689 (s, 1H, imine-CH), 7.635 (d, 1H,J4.8Hz), 7.366 (d, 1H, J3Hz), 7.115 (t, 1H, J4.2Hz), 6.490(s, 1H), 2.390 (s, 3H) (Figure S1).
S-(trifluoromethyl) 5-methylthiophene-2-carbothioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With disodium hydrogenphosphate; tetrakis(tetrabutylammonium)decatungstate(VI); In acetonitrile; at 20.0℃; for 96.0h;Inert atmosphere; Sealed tube; Irradiation;
General procedure: To a 8 mL glass vial was added TBADT (54.4 mg, 0.016 mmol, 8 mol %), aldehydes (0.2 mmol, 1.0 equiv), 6a (148.3 mg, 0.6 mmol, 3.0 equiv), Na2HPO4 (42.6 mg, 0.3 mmol, 1.5 equiv) and 0.5mL of CH3CN. The reaction mixture was degassed by bubbling with Ar for 15 s with an outlet needle and the vial was sealed with PTFE cap. The mixture was then stirred rapidly and irradiated with a 390 nm Blue LED (approximately 2 cm away from the light source) at room temperature for 96 h. Purification of the crude product by flash chromatography on silica gelusing the indicated solvent system afforded the desired product.
5-(4-((5-methylthiophen-2-yl)methyleneamino)phenyl)-1,3,4-oxadiazole-2-thiol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 80℃;
General procedure: A solution of <strong>[32058-82-5]5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol</strong>(0.107 g, 0.5 mmol) in 5 ml ethanol was added drop-wise to the solution of substituted aldehydes (0.5 mmol) in ethanol. Thereaction mixture was refluxed at 80 C for 30 min to 22 h. Tomonitor the reaction progress and purity of compounds TLC wasused in ethyl acetate and hexane (1:3). The coloured precipitateswere filtered, washed with ethanol and then dry in vaccum dessicator over fused CaCl2. The synthetic route for the heterocyclicderivatives 2a-2l is shown in the Scheme 1.
6-chloro-2-(5-methylthiophen-2-yl)quinazoline-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper chloride (II) In ethanol at 70℃;
2.2. Synthesis of resveratrol analogs
General procedure: The synthesis of the resveratrol analogs was performed in two steps.First, the intermediate was obtained by the amidation reaction of 2-amino-polysubstituted-benzoic acid (1 eq) with ammonia under thecatalysts including EDCI (1.5 eq), HOBT (1.5 eq) and NMM (1.5 eq).Then, resveratrol analogs were achieved by Cyclization of the intermediate(1 eq) with different aldehyde (1.1 eq) in the presence of a catalystCuCl2 (1.7 eq). The synthetic route to resveratrol analogs was shown inScheme 1.
General procedure of the Seyferth-Gilbert Homologation for the synthesis of compounds S9-S14
General procedure: To a solution of the required aryl aldehyde (1.0 mmol) and Bestmann-Ohira Reagent (288.2 mg, 1.5 mmol) in dry MeOH (15 mL) was added K2CO3 (276.4 mg, 2.0 mmol). The resulting mixture was stirred at rt overnight and then concentrated. The residue was purified on silica gel with petroleum ether to give the corresponding substituted acetylene 6.
3-(adamantan-1-yl)-5-methylthiophene-2-carboxaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With tris(2-phenylpyridinato-N,C2′)iridium(III) In dimethyl sulfoxide Irradiation;
General Procedure for the Syntheses of Alkylated Heteroarenes (1-39).
General procedure: In a 4 mL oven-driedvial, redox-active ester (0.2 mmol, 1.0 equiv.), photocatalyst Ir(ppy)3(0.5 mol%), heteroarene (2.0mmol, 10.0 equiv.) were added to degassed DMSO (2 mL). The mixture was stirred overnight (12-24 h) at room temperature under two 25W white LED irradiation. The reaction process wasmonitored by thin layer chromatography (TLC). After redox-active ester was consumed, themixture was quenched with water, extracted three times with ethyl acetate, and concentrated invacuo. Purification of the crude products by silica gel column chromatography (eluent: PE/EA orPE/DCM) gave the desired products.
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