* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With hydrogen; sodium acetate; palladium dichloride In methanol at 35℃; for 12 h;
Typical procedures: 6-bromonicotinaldehyde (930 mg, 5.0 mmol), NaOAc (820 mg, 10.0 mmol), MeOH (30 mL), and PdCl2 (45 mg) were mixed in a glass bottle capped with a balloon filled with hydrogen. After stirred at 35 °C for 4 h, the mixture was filtered and washed with MeOH. The solvent was removed and the residue was dissolved in water, neutralized with solid NaHCO3, and extracted with ethyl acetate. The organic phase was dried over anhyd Na2SO4, and then filtered. The solvent was removed and the residue was subjected to chromatography to yield pyridin-3-ylmethanol (428 mg, 78percent).
With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 3 h;
To a solution of thiophene-3-carbaldehyde (10 g, 89.3 mmol) in THF (200 mL) at 0 °C was added NaBH4 (1.7 g, 45.0 mmol) in portions. After stirring at 0 °C for 3 h, The reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (9.7 g, 95percent).
70%
With sodium tetrahydroborate In ethanol; benzene at 0 - 20℃; for 4 h;
A solution of 3-thiophenecarboxaldehyde 11 (10 g, 89.3 mmol) in 20 mL of benzene and 20 mL of absolute ethyl alcohol was cooled to 0°C and then sodium borohydride (4.39 g, 116 mmol) was added in three portions to the solution over an hour. After the addition, the reaction mixture was warmed up to room temperature and stirred for anther 3 hours and quenched with 3 mL of water. The solvent was evaporated and the residue was taken by 300 mL of dichloromethane and washed with 2x100 mL of water. The organic layer was dried over NA2S04 and concentrated via rotary evaporation. The crude product was purified via a flash chromatography on silica gel with an eluent of dichloromethane/hexanes (1/1) to give 7.1 of pure product (70percent).APOS;H NMR (CDCL3) 8 7.28-7. 32 (m, 1H), 7.20-7. 22 (brm, 1H), 7.08 (dd, 4.4 Hz, 1.2 Hz, 1H), 4.68 (s, 2H), 1.74 (brm, 1H). Anal. CSH60S requires C, 52.60 ; H, 5.30. Found C, 53.89 ; H, 5.61.
61 %Chromat.
With formaldehyd; tricarbonyl(η4-1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-inden-2-one)iron; water; sodium carbonate In dimethyl sulfoxide at 120℃; for 24 h; Inert atmosphere; Sealed tube
General procedure: Knölker iron complex 2a (3 mol percent,12.6 mg), paraformaldehyde (300 mg, 10 mmol), and Na2CO3 (106 mg, 1 mmol,1.0 equiv) and a stirring bar were charged in a pressure tube and flushed withargon. DMSO (1.0 mL), degassed water (1.0 mL), and benzaldehyde (1 mmol)were added under an argon atmosphere to the pressure tube with a syringe.The pressure tube was placed in oil and heated at 120 C for 24 h, then cooledto room temperature. The reaction mixture was neutralized with HCl (1M) andstirred for 30 min. After extraction with EtOAc for 3 times, the combinedorganic layers were dried over MgSO4. The crude product was purified bycolumn chromatography (Heptane/EtOAc: 70:30). The reaction was cooled toroom temperature and hexadecane (100 lL) was added as a GC internalstandard.
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[4] Patent: WO2011/69063, 2011, A2, . Location in patent: Page/Page column 94
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[6] Magnetic Resonance in Chemistry, 1988, vol. 26, p. 129 - 133
[7] Macromolecules, 2013, vol. 46, # 3, p. 708 - 717
[8] Patent: WO2004/65384, 2004, A1, . Location in patent: Page 35-36; 16/19
[9] Molecular Crystals and Liquid Crystals (1969-1991), 1990, vol. 189, # 1, p. 155 - 168
[10] Chemistry - A European Journal, 2006, vol. 12, # 10, p. 2739 - 2744
[11] Electrochimica Acta, 2012, vol. 59, p. 270 - 278
[12] Chemistry - A European Journal, 2012, vol. 18, # 50, p. 15935 - 15939
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[14] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788
[15] Tetrahedron Letters, 2015, vol. 56, # 9, p. 1118 - 1121
[16] European Journal of Organic Chemistry, 2016, vol. 2016, # 12, p. 2207 - 2211
[17] Inorganic Chemistry, 2017, vol. 56, # 18, p. 11282 - 11298
3
[ 85719-70-6 ]
[ 71637-34-8 ]
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[3] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
[4] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
7
[ 872-31-1 ]
[ 71637-34-8 ]
Reference：
[1] Patent: US2005/23507, 2005, A1,
8
[ 117657-59-7 ]
[ 71637-34-8 ]
[ 117657-70-2 ]
[ 117657-74-6 ]
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[1] Tetrahedron Letters, 1987, vol. 28, # 48, p. 5965 - 5968
[2] Journal of Organic Chemistry, 1997, vol. 62, # 25, p. 8741 - 8749
9
[ 117657-61-1 ]
[ 71637-34-8 ]
[ 117657-72-4 ]
[ 117657-76-8 ]
Reference：
[1] Tetrahedron Letters, 1987, vol. 28, # 48, p. 5965 - 5968
[2] Journal of Organic Chemistry, 1997, vol. 62, # 25, p. 8741 - 8749
10
[ 117657-63-3 ]
[ 71637-34-8 ]
Reference：
[1] Tetrahedron Letters, 1987, vol. 28, # 48, p. 5965 - 5968
[2] Journal of Organic Chemistry, 1997, vol. 62, # 25, p. 8741 - 8749
11
[ 498-62-4 ]
[ 1192-58-1 ]
[ 71637-34-8 ]
[ 173276-64-7 ]
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[1] Journal of Organic Chemistry, 1999, vol. 64, # 2, p. 394 - 399
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 21, p. 2669 - 2672
12
[ 498-62-4 ]
[ 71637-34-8 ]
[ 173276-64-7 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 2, p. 394 - 399
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 21, p. 2669 - 2672
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[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
15
[ 98277-70-4 ]
[ 71637-34-8 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 3800,3803
16
[ 36157-41-2 ]
[ 71637-34-8 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
17
[ 36157-42-3 ]
[ 71637-34-8 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
18
[ 53935-71-0 ]
[ 71637-34-8 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 2445
19
[ 616-44-4 ]
[ 71637-34-8 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 3800,3803
20
[ 34846-44-1 ]
[ 71637-34-8 ]
Reference：
[1] Canadian Journal of Chemistry, 1989, vol. 67, p. 1071 - 1076
21
[ 17303-83-2 ]
[ 71637-34-8 ]
[ 222840-73-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 5, p. 2227 - 2238
22
[ 71637-34-8 ]
[ 1641-09-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
With ammonium hydroxide; copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N-Phenylglycine; sodium hydroxide In methanol at 50℃; for 24 h; Cooling with ice
General procedure: Benzyl alcohol was added in a 2L round-bottomed flask (108.02g, 1000mmol, i.e., of formula (I) wherein R is H, X = C, n = 1, m = 0),cuprous iodide (9.50g, 50mmol) , of N- phenylglycine (7.51g, 50mmol), TEMPO ( 7.80g, 50mmol),sodium carbonate (10.60g, 100mmol), aqueous ammonia (300mL, 25 ~ 28percent) ,800mL methanol, under ice-cooling, with the oxygen round bottom flask was evacuated of air ventilation 3 times, and then the system was stirred at 50 at 12h, after completion of the reaction, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure and dried to give the product benzonitrile 95.79g, yield 93percent. The reactants used is 2-thiophene methanol (57.12g, 500mmol, i.e., of formula (I) wherein R is H, X = S, n = 0, m = 0), experimental methods and procedures were the same as in Example 1, except that: cuprous iodide (4.76g, 25mmol), N- phenylglycine (3.79g, 25mmol), TEMPO ( 3.91g, 25mmol), sodium hydroxide (2.03g, 50mmol), aqueous ammonia (60mL, 25 ~ 28percent), methanol 160mL, stirred at at 50 24h, to give the final product 49.05g, yield 90percent.
Reference：
[1] Applied Organometallic Chemistry, 2018, vol. 32, # 4,
[2] Patent: CN105294646, 2016, A, . Location in patent: Paragraph 0041; 0064; 0065
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3349 - 3354
23
[ 71637-34-8 ]
[ 498-62-4 ]
[ 1641-09-4 ]
Reference：
[1] Angewandte Chemie, International Edition, 2009, vol. 48, # 34, p. 6286 - 6288[2] Angewandte Chemie, 2009, vol. 121, # 34, p. 6404 - 6406
24
[ 71637-34-8 ]
[ 67-56-1 ]
[ 22913-26-4 ]
Reference：
[1] Chinese Journal of Catalysis, 2018, vol. 39, # 7, p. 1249 - 1257
25
[ 71637-34-8 ]
[ 201230-82-2 ]
[ 6964-21-2 ]
[ 616-44-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 3, p. 723 - 734
[2] Tetrahedron Letters, 1997, vol. 38, # 21, p. 3747 - 3750
26
[ 71637-34-8 ]
[ 70260-16-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 20℃; for 0.75 h;
To a solution of 3-hydroxymethylthiophene 12 (4.06 g, 35.6 mmol) in 18 mL of acetic acid was added N-bromosuccinimide (6.34 g, 35.6 mol) at room temperature and stirred for 45 minutes. The resulting mixture was quenched with 1 mL of water, poured into 250 mL ether and washed with 100 mL of water, 100 mL of 10percent NAHC03 aq. respectively. The organic layer was dried over NA2S04 and concentrated. 6.25 G of crude product 13 (91 percent) was obtained and used for the subsequent reaction without further purification.
77%
With N-Bromosuccinimide In fluorobenzene at 20℃; for 24 h; Schlenk technique; Inert atmosphere
According to the reported procedure, 15 (2-bromothien-3-yl)methanol was prepared by the bromination of 3-thienylmethanol (1.37 g, 12.0 mmol) with N-bromosuccinimide (2.56 g, 14.4 mmol) in PhF (120 mL), and isolated in 77percent yield (1.80 g) as a light orange oil by column chromatography on silica gel (hexane/EtOAc = 3/1). Its spectral and analytical data are shown below because they were not provided in reference 15.
With [Ir(2,2':6',2'’-terpyridine)(1,10-phenanthroline)Cl](PF6)2; sodium formate In ethanol; water at 100℃; for 0.25h; Microwave irradiation; chemoselective reaction;
A typical procedure for TH reaction:
General procedure: An aldehyde (1 mmol),sodium formate (4.5 eq), and catalyst (0.2 mol%) were taken in70% ethanol in water (4 mL) in a microwave vial and vortexed togenerate a homogenous solution. The mixture was heated in MWat 100 °C using 150W of irradiation. Reaction progress was monitored by TLC. If complete conversion took place, the reaction colorturns to emerald green (color disappears after sometime) from paleyellow, and byproduct Na2CO3 precipitates. The Na2CO3 solid wasremoved by decanting the supernatant. The solid was washed withethyl acetate (20 mL). The combined decanted solution waswashed with water (5.0 mL), followed by brine solution (5.0 mL),dried over Na2SO4, filtered, and evaporated to dryness to affordthe desired alcohol as a pale-yellow liquid or off-white solid.
96%
With LaNi5 hydride In tetrahydrofuran; methanol for 14h; Ambient temperature;
96%
With LaNi5 hydride In tetrahydrofuran; methanol 1) 0 deg C, 6 h, 2) r.t., 14 h;
96%
With lithium aluminium tetrahydride In tetrahydrofuran
95%
With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 3h;
20.T.a
To a solution of thiophene-3-carbaldehyde (10 g, 89.3 mmol) in THF (200 mL) at 0 °C was added NaBH4 (1.7 g, 45.0 mmol) in portions. After stirring at 0 °C for 3 h, The reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (9.7 g, 95%).
90%
With methanol; sodium tetrahydroborate at 0 - 20℃; for 1h;
1.1 Step 1: Preparation of Thiophen-3-ylmethanol (2)
To the stirred solution of thiophene-3-carbaldehyde (1, 1 g, 8.92 mmol) in MeOH (10 mL), was added NaBH4(0.5 g, 13.3 mmol) portion wise at 0 °C and stirred at rt for 1 h (Reaction condition a). The reaction mixture was quenched with ice and the MeOH was evaporated. To the resulting crude added water (5 mL) and extracted with EtOAc (2 X 20 mL). Organic layer was washed with brine (5 mL) solution, dried over anhydrous Na2S04and evaporated under vacuum to give the product as brown oil (2) (0.9 g, 90%, Yield).XHNMR (400 MHz, DMSO-d6) δ (ppm): 7.45-7.43 (m, 1H), 7.26 (s, 1H), 7.03 (d, = 4.4 Hz, 1H), 5.05 (t, = 6.0 Hz, 1H), 4.45 (d, = 5.6 Hz, 2H).
83%
With lithium aluminium tetrahydride In diethyl ether for 6h; Ambient temperature;
83%
With methanol; sodium tetrahydroborate at 0 - 20℃; for 4h;
3.A Example 3: Synthesis of 2-amino-3- (2,5-dibromothiophen-3- yl) propanoic acid (Code 552)
A .Sodium borohydride (2.0 g, 53 mmol, 0.5 eq.) was added to a solution of aldehyde 1 (12.0 g, 107 mmol, 1 eq.) in methanol (150 ml) at 0°C. The reaction mixture was stirred 4 hours at room temperature and then partitioned in 5% HCl (300 mL) / and ethyl acetate (150 mL) . The aqueous layer was separated and extracted with ethyl acetate (2 x 150 ml) . The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness to give the product 2 (10.1 g, 83%)
80.7%
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; 3 h, rt;
74%
With aluminum (III) chloride; triethylamine; isopropyl alcohol In dichloromethane at 20℃; for 24h;
General experimental methods for AlCl3catalyzedMeerwein-Ponndorf-Verley (MPV) reactions
General procedure: A mixture of AlCl3(0.1-10 mmol), the aldehyde (10 mmol),triethylamine (10 mmol) and isopropanol (10 mmol) wasadded to 2 cm3of dried CH2Cl2and stirred for 2 days atroom temperature under argon atmosphere until the aldehydewas completely consumed. The reaction progress wasmonitored by TLC and GC/MS. The reaction mixture wasthen filtered, and treated with sodium bicarbonate solution,followed by isolating the organic phase via a separatory funnel.The aqueous phase washed several times with CH2Cl2toensure that all organic materials extracted. Then, the organicphase was dried over sodium sulfate, and subsequently analyzedby GC/MS and 1H NMR and validated using meltingor boiling point of the product.
72%
With lithium aluminium tetrahydride In tetrahydrofuran for 1h;
70%
With sodium tetrahydroborate In ethanol; benzene at 0 - 20℃; for 4h;
8 3-(HVDROXYMETHYL) THIOPHENE (12).
A solution of 3-thiophenecarboxaldehyde 11 (10 g, 89.3 mmol) in 20 mL of benzene and 20 mL of absolute ethyl alcohol was cooled to 0°C and then sodium borohydride (4.39 g, 116 mmol) was added in three portions to the solution over an hour. After the addition, the reaction mixture was warmed up to room temperature and stirred for anther 3 hours and quenched with 3 mL of water. The solvent was evaporated and the residue was taken by 300 mL of dichloromethane and washed with 2x100 mL of water. The organic layer was dried over NA2S04 and concentrated via rotary evaporation. The crude product was purified via a flash chromatography on silica gel with an eluent of dichloromethane/hexanes (1/1) to give 7.1 of pure product (70%).'H NMR (CDCL3) 8 7.28-7. 32 (m, 1H), 7.20-7. 22 (brm, 1H), 7.08 (dd, 4.4 Hz, 1.2 Hz, 1H), 4.68 (s, 2H), 1.74 (brm, 1H). Anal. CSH60S requires C, 52.60 ; H, 5.30. Found C, 53.89 ; H, 5.61.
5.6 g
With sodium hydroxide; sodium tetrahydroborate In methanol for 3h; Heating;
With sodium tetrahydroborate In methanol at 20℃;
98 %Chromat.
With water; ammonium chloride; fipronilβ-cyclodextrin nickel anode; Electrochemical reaction;
96 %Chromat.
With carbon monoxide; C12H10FeO4; potassium carbonate In water; dimethyl sulfoxide at 100℃; for 20h; Inert atmosphere;
With sodium tetrahydroborate In methanol for 0.166667h; Inert atmosphere;
With sodium tetrahydroborate; water In acetonitrile
61 %Chromat.
With formaldehyd; tricarbonyl(η4-1,3-bis(trimethylsilyl)-4,5,6,7-tetrahydro-2H-inden-2-one)iron; water; sodium carbonate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; Sealed tube;
Reduction of benzaldehyde to benzylalcohol
General procedure: Knölker iron complex 2a (3 mol %,12.6 mg), paraformaldehyde (300 mg, 10 mmol), and Na2CO3 (106 mg, 1 mmol,1.0 equiv) and a stirring bar were charged in a pressure tube and flushed withargon. DMSO (1.0 mL), degassed water (1.0 mL), and benzaldehyde (1 mmol)were added under an argon atmosphere to the pressure tube with a syringe.The pressure tube was placed in oil and heated at 120 C for 24 h, then cooledto room temperature. The reaction mixture was neutralized with HCl (1M) andstirred for 30 min. After extraction with EtOAc for 3 times, the combinedorganic layers were dried over MgSO4. The crude product was purified bycolumn chromatography (Heptane/EtOAc: 70:30). The reaction was cooled toroom temperature and hexadecane (100 lL) was added as a GC internalstandard.
98 %Chromat.
With 1-hydrosilatrane; sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.5h;
With C19H33ClIrN3O; sodium isopropylate In isopropyl alcohol for 3h; Inert atmosphere; Reflux;
With thionyl chloride In dichloromethane at 0 - 20℃; for 1h;
1.2 Step 2: Preparation of 3-(chloromethyl)thio hene (3)
To a stirred solution thiophen-3-ylmethanol (2, 0.5 g, 4.38 mmol) in DCM (5 mL), was added SOCl2(0.6 mL, 8.77 mmol) drop wise at 0 °C and the reaction mixture was stirred at rt for 1 h (Reaction condition b). The reaction mixture was evaporated under vacuum and dried to afford the product as brown oil (3) (0.5 g, 80%, Yield).XHNMR (400 MHz, DMSO-d6): δ 7.45-7.43 (m, 1H), 7.26 (s, 1H), 7.03 (d, = 4.4 Hz, 1H), 4.78 (s, 2H).
67%
With thionyl chloride In dichloromethane at 0 - 20℃; for 16.1667h;
67%
With thionyl chloride In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;
With thionyl chloride In chloroform for 0.166667h; Ambient temperature;
With 1,2,3-Benzotriazole; thionyl chloride In dichloromethane
With thionyl chloride In dichloromethane; water
R.26.1 Refeference Example 26
(1) A solution of 3-hydroxymethylthiophene and thionyl chloride in methylene chloride is stirred under ice-cooling for 30 minutes. To the reaction mixture is added water, and the mixture is extracted with chloroform. The organic layer is washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried. The residue is concentrated under reduced pressure to give 3-chloromethylthiophene (1.61 g).
Stage #1: 3-hydroxymethyl-thiophene With thionyl chloride In chloroform at 20℃; for 1h;
Stage #2: With thionyl chloride; water In chloroform
Precursor: Synthesis of 3-chloromethylthiophene (compound of formula II with X = CI)86 g thionyl chloride were metered into a solution of 65 g thiophen-3-yl methanol (commercially available) in 325 ml chloroform at room temperature. After stirring for one hour, the mixture was hydrolysed with 400 ml iced water, the phases separated and the aqueous phase extracted twice more with chloroform. The combined organic phases were washed withsodium bicarbonate solution and with water and dried over sodium sulfate. After filtering and evaporating the solution in vacuo, 75 g of the crude product of 3-chloromethylthiophene were obtained (purity >95%).
With thionyl chloride In tetrahydrofuran at 50℃; for 2h;
99
Production Example 99 Synthesis of (3-thienyl) methyl 3, 3-bis (4- fluorophenylthio) -N- (phenyl) thiopropionimidate (hereinafter referred to as the present compound 99)Thionyl chloride (0.29 mL) was added to a solution of (3-thienyl) methanol (0.23 g) in anhydrous THF (2 mL) . The mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added anhydrous DMF (3 mL) . Then, a solution of 3, 3-bis (4-fluorophenylthio) -N- (phenyl) thiopropionamide (0.84 g) in anhydrous DMF (1 mL) , sodium iodide (0.30 g) and potassium carbonate (0.28 g) were added thereto at room temperature, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added t-butyl methyl ether (50 mL) , which was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative liquid chromatography (Yamazen SI-40B, hexane : ethyl acetate = 92 : 8) to obtain the present compound 99 (0.46 g) as a yellow oil. 1H-NMR (CDCl3) δ ppm: 2.86 (1.62H, d, J=7.8Hz), 2.99(0.38H, brs), 4.35(O.81H, t, J=7.8Hz), 4.29(1.62H, s), 4.51(0.38H, s), 4.94(0.19H, brs), 6.66-7.46 (16H, m) .
With hydrogenchloride In dichloromethane
With thionyl chloride In dichloromethane
2
3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (80 mg, 220 μmol) was dissolved in N,N-dimethylformamide (4.0 ml) under a dry argon atmosphere. Potassium carbonate (85 mg, 618 μmol) and 3-chloromethylthiophene (112 mg, 845 μmol; prepared from 3-thiophenemethanol using SOCl2 in CH2Cl2) were subsequently added. The reaction mixture was stirred at 50° C. for 18 h overnight. When the reaction was complete, the mixture was poured into water (60 ml), stirred for 30 min and extracted twice with ethyl acetate (75 ml each time). The combined organic phases were washed with water (25 ml), subsequently dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue chromatographed over flash silica gel (solvent gradient ethyl acetate/0-17% by vol. of ethanol), giving 3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (64 mg, 139 μmol), as solid. MS: 461.1 (M+H+), TLC (HPTLC): Rf=0.33 (ethyl acetate/ethanol 5:1, parts by volume).
With thionyl chloride In dichloromethane at 20℃;
1-(Furan-3-ylmethyl)-1H-imidazole-2-carboxylic acid (34).
General procedure: To a solution of furan-3-ylmethanol (A18,143 mg, 1.46 mmol) inDCM (10 mL) was added thionyl chloride (344 mg, 2.92 mmol), andthe mixture was stirred at room temperature for 2 h. The reactionmixture was concentrated to give chlorinated compoundA19,which was used in the next step without purification. UsingA19thetarget compound 34 was then obtained byCs2CO3- catalyzednucleophilic substitution reaction and NaOH-mediated hydrolysis1Hreaction in tuin, 51% yield for three steps, 96.6% HPLC purity.
With N-Bromosuccinimide In tetrahydrofuran Inert atmosphere; Darkness;
86%
With N-Bromosuccinimide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Darkness;
85%
With N-Bromosuccinimide In tetrahydrofuran at 20℃; Inert atmosphere;
85%
With N-Bromosuccinimide In tetrahydrofuran at 20℃; Inert atmosphere;
85%
With N-Bromosuccinimide In tetrahydrofuran at 20℃; Inert atmosphere;
82%
With N-Bromosuccinimide In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Sealed tube;
80%
With N-Bromosuccinimide In tetrahydrofuran at 20℃;
77%
With N-Bromosuccinimide In tetrahydrofuran at 20℃;
3.B
B. NBS (30.7 g, 173 mmol, 1.95 eq.) was added gradually to compound 2 (10.1 g, 88 mmol, 1 eq. ) in THF (300 mL) and the mixture was kept at RT overnight, filtered, and then THF was removed by rotary evaporation. The product was dissolved in diethyl ether, then rinsed with 1M sodium hydroxide solution and water. The organic layer was dried over Na2S04 and the product was eluted over silica gel using hexane: ethyl acetate (80:20) . The solvent was removed by rotary evaporation to yield the desired product 3 (18.5 g, 77% yield) .
62%
With N-Bromosuccinimide In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
(2,5-dibromothiophen-3-yl)methanol(9).
N-Bromosuccinimide (NBS) (6.5g, 35mmol) was added in small portions to a solution of 3-thiophenemethanol (2g, 17.5mmol) in 150mL THF at 0°C. After stirring overnight at room temperature, the reaction mixture was poured into water (50mL) and extracted with diethyl ether. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent, the crude product was chromatographed on silica gel using petroleum ether/diethyl ether 2:1 as eluent to afford compound 9 (2.95g) as a transparent oil. Yield: 62%. 1H NMR (600MHz, CDCl3) δ (ppm): 7.02 (s, 1H), 4.56 (s, 2H).
With N-Bromosuccinimide In chloroform; acetic acid
With N-Bromosuccinimide In dichloromethane
With N-Bromosuccinimide
With N-Bromosuccinimide In tetrahydrofuran at 20℃; Sealed tube; Inert atmosphere;
With N-Bromosuccinimide In tetrahydrofuran at 20℃;
With phosphorus tribromide In dichloromethane at 20℃; for 16h; Inert atmosphere;
13; R
To a stirred solution of thiophen-3-ylmethanol (2 mmol, 0.29 g) in dry DCM (20 mL) under an inert atmosphere was added phosphorous tribromide (4 mmol, 0.38 mL). The reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo and partitioned between saturated sodium bicarbonate solution and DCM. The layers were separated and the aqueous was extracted twice more with DCM. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give a quantitative yield of 3-(bromomethyl)thiophene. 1H NMR (CDCl3): 7.09 (2H, m), 6.94 (1H, dd, J 4.9, 1.3 Hz), 4.33 (2H, s).
89%
With phosphorus tribromide In benzene for 3h; Ambient temperature;
89%
With 1H-imidazole; bromine; triphenylphosphine In dichloromethane at 0 - 20℃; Inert atmosphere;
73%
With pyridine; bromine; triphenylphosphine In dichloromethane at 0℃;
70%
With phosphorus tribromide In dichloromethane at 20℃; for 16h;
70%
With hydrogen bromide for 3h;
57.1; 58.1 First step: 3-(bromomethyl)thiophene (57B)
Thiophen-3-ylmethanol(28A) (3g, 43mmol) dissolved in hydrobromic acid(40ml, 48%), the reaction was 3h,Cool, add water (50 mL), extract with dichloromethane(50mL × 4), with saturated saline solution (150mL × 3)Washed, dried over anhydrous sodium sulfate, filtered, and concentrated.Separation and purification by column chromatography (hexane/ethyl acetate = 10:1),A yellow liquid 3-(bromomethyl)thiophene 57B (3 g, yield 70%)
23%
With phosphorus tribromide In dichloromethane at 20℃;
10
To a solution of thiophen-3-ylmethanol (1.0 g, 8.8 mmol) in anhydrous dichloromethane (80 mL) was added a phosphorus tribromide (1.7 mL, 17.9 mmol). The solution was stirred at room temperature overnight. Dichloromethane was evaporated. The residue was treated slowly with a saturated aqueous sodium bicarbonate solution (50 mL). The mixture was extracted with dichloromethane (3 x 50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% EtOAc/hexanes), affording 3-(bromomethyl)thiophene (360 mg, 23% yield).
With phosphorus tribromide In dichloromethane at 0 - 20℃; for 3h;
11.1
A solution of phosphorus tribromide (2.24 g, 8.23 mmol) in 10 mL DCM was added dropwise to a solution of 3-thiophenemethanol (0.66 g, 5.8 mmol) in DCM (30 mL) at 00C. The mixture was stirred at room temperature for 3 hours and then poured onto ice. The layers were separated and the organic phase was washed with saturated NaHCO3 solution, dried over sodium sulfate and concentrated to give 3-bromomethylthiophene (1.1 g) as a clear liquid, which was used in the next step without further purification.
With dibromotriphenylphosphorane Inert atmosphere;
With hydrogen bromide Cooling with ice;
50 Synthesis of 3-(bromomethyl)thiophene
Example 50 Synthesis of 3-(bromomethyl)thiophene 48% Hydrobromic acid (147.6 g) was cooled on ice, and 3-hydroxymethylthiophene (10 g) was added thereto, followed by stirring for 30 minutes. The organic layer was separated, and then washed with saturated aqueous sodium bicarbonate solution. The resultant mixture was subjected to vacuum distillation (4.5 mmHg) at 46-48°C, whereby the title compound (5.2 g) was yielded. Ms(FAB)m/z178(M+H)+ 1H-NMR(400MHz,DMSO-d6): δ(ppm)4.72(2H,s),7.16(1H,dd,J=1.0,5.0Hz),7.55(1H,J=3.0,5.0Hz),7.62(1H,d,J=3.0Hz).
With phosphorus tribromide In diethyl ether at 0℃; for 0.5h;
1.1 Step 1 : 3-(bromomethyl)thiophene
A cooled (0 °C) solution of 3-thiophenemethanol (5.00 g, 43.7mmol) in diethyl ether (40 mL) was treated with phosphorus tribromide (1.35 mL, 14.4 mmol) and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was then poured into ice and extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated to afford the title compound (5.23 g, 67%), which was used without further purification. 1H NMR (400MHz, CDCI3) δ 7.32-7.30 (m, 2H), 7.14 (d, J= 4.6 Hz, 2H), 4.54 (s, 1 H).
With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 3h;
With phosphorus tribromide In dichloromethane at 20℃; for 24h;
2.d; 3.d
Conditions: (d) PBr3, CH2Cl2, rt, 24 h
With phosphorus tribromide In diethyl ether at 25℃; for 12h;
With phosphorus tribromide In diethyl ether at 25℃; for 12h;
With phosphorus tribromide In diethyl ether at 20℃; for 12h;
With dmap; triethylamine In tetrahydrofuran; N,N-dimethyl-formamide for 1h; Ambient temperature;
1.6 g
With triethylamine In N,N-dimethyl-formamide at 60℃; for 3h;
213.A A) tert-Butyl (dimethyl) (3-thienylmethoxy) silane
Example 213 1- (2-Cyclopropyl-l-methyl-lH-benzimidazol-6-yl) -4- ( (5-methyl- 3-thienyl) methoxy) pyridin-2 ( 1H) -one A) tert-Butyl (dimethyl) (3-thienylmethoxy) silane A mixture of tert-butyldimethylchlorosilane (1.58 g) , triethylamine (2.44 ml), 3-thiophenemethanol (0.822 ml) and DMF (20 ml) was stirred at 60°C for 1 h. Additional DMF (20 ml) was added to the reaction mixture, and the mixture was stirred at 60°C for 2 h. The mixture was quenched with saturated NaHC03 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgS04, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane) to give the title compound (1.6 g) as a colorless oil. XH NMR (400 MHz, DMSO-cfe) : δ 0.00 (6H, s) , 0.83 (9H, s) , 4.62 (2H, s), 6.95-7.00 (lH, m), 7.22-7.28 (1H, m) , 7.41-7.46 (1H, m) .
With triethylamine In dichloromethane at 0 - 20℃; for 17h;
1-45.2 Step 2 Thiophen-3-ylmethyl methanesulfonate
Step 2 Thiophen-3-ylmethyl methanesulfonate To a mixture of thiophen-3-ylmethanol (500 mg, 4.38 mmol, 1.0 eq.) in DCM (10 mL) was added TEA (885 mg, 8.76 mmol, 2.0 eq.) and MsCl (754 mg, 6.58 mmol, 1.5 eq) dropwise at 0°C. The reaction mixture was stirred at 20 °C for 17 h. TLC showed that the starting material was consumed. The mixture was concentrated to give the crude, which was used for the next step directly.
Stage #1: 3-hydroxymethyl-thiophene; tert-butylchlorodiphenylsilane With 1H-imidazole In N,N-dimethyl-formamide at 0 - 25℃; for 6h;
Stage #2: With ammonium chloride In water; N,N-dimethyl-formamide
147
A solution of 3-thienylmethanol (5.0 g, 43.8 mmol) and imidazole (8.94 g, 131.4 mmol) in DMF (86 ml) was treated with terf-butylchlorodiphenylsilane (15.0 g, 54.7 mmol) at 0 °C. The reaction stirred for 6 h at 25 °C before being quenched by the addition of 250 ml 10 NH4Cl(sat). The resulting mixture was extracted with EtOAc. The combined organic phase was washed once with NaCl(sat) (100 ml), dried with MgSO4(s), and concentrated under reduced pressure. The crude reaction product was purified by column chromatography utilizing an ISCO system (hexanes-EtOAc, 10:1) giving 14.8 g of the title compound as a colourless oil (96 %); m/z 353.
96%
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 25℃; for 6h;
115
Method 115; tert-ButylfdiphenylX3-thienylmethoxy)silane; A solution of 3-thienylmethanol (5.0 g, 43.8 mmol) and imidazole (8.94 g, 131.4 mmol) in DMF (86 ml) was treated with terf-butylchlorodiphenylsilane (15.0 g, 54.7 mmol) at 0 0C. The reaction stirred for 6 h at 25 0C before being quenched by the addition of 250 ml saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc. The combined organic phase was washed once with NaCl (sat) (100 ml), dried with MgSO4 (s), and concentrated under reduced pressure. The crude reaction product was purified by column chromatography utilizing an ISCO system (hexanes/EtOAc 10:1) giving 14.8 g of the title compound as a colourless oil (96 %); m/z 353.
96%
With 1H-imidazole In DMF (N,N-dimethyl-formamide) at 0 - 25℃; for 6h;
23
Method 23; tert-Butyl(diphen,y,l)(3-thienylmethoxy)silane; Anhydrous DMF (86 ml) and imidazole (8.94 g, 131.4 mmol) were added to 3- thienylmethanol (5.0 g, 43.8 mmol). The reaction mixture was cooled to 0 °C and treated with tert-butylchlorodiphenylsilane (15.0 g, 54.7 mmol) and was allowed to stir 6 h. The reaction was warmed to 25 °C before being quenched by the addition of saturated aqueous NH4CI (250 ml). The resulting mixture was extracted with EtOAc (3 x 125 ml). The combined organic phase was washed with brine (1 x 100 ml), dried with MgS04, and concentrated in vacuo. The crude reaction product was purified on 120 g Si02 using hexanes-EtOAc 10:1 as eluent giving 14.8 g (96 %)
91%
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 24h;
With 1H-imidazole In DMF (N,N-dimethyl-formamide) at 20℃; for 24h;
8, 29 Example 29; Scheme 8
t-Butyldiphenylchlorosilane (11.3 mL, 43.3 mmol) was added to a stirred solution of 3-thiophenemethanol (4.5 g, 39.4 mmol) and imidazole (5.9 g, 86.7 mmol) in DMF at room temperature. After 24 h the reaction mixture was quenched with brine and worked up using EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified on a silica gel pad, eluting with ether and concentrating in vacuo to give the compound 29: 1HNMR (300 MHz, CDCl3) δ (ppm) 7.69 (m, 4H), 7.34-7.43 (m, 6H), 7.27 (dd, J=1.7 Hz, 3.1 Hz, 1H), 7.15 (dd, J=1.4 Hz, 2.6 Hz, 1H), 6.99 (dd, J=1.0 Hz, 3.6 Hz, 1H), 4.76 (s, 2H), 1.08 (s, 9H).
With pyridinium p-toluenesulfonate In dichloromethane at 20℃;
100%
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 0.5h;
1.1; 2.1; 3.1
EXAMPLE 1 Synthesis of kahweofuran (method 1) Kahweofuran (compound (e)) was produced from thiophene 3-methanol (compound (a)) according to the following formula. THP represents a tetrahydropyranyl group in the formula. [Show Image] (1) Step A: Protection of the hydroxy group of thiophene-3-methanol; Synthesis of-2-(3-thienylmethyloxy) tetrahydro-2H-pyrane (compound (b)) To 4.56 g (40 mmol) of thiophene-3-methanol (compound (a)) were added 3.36 g (40 mmol) of 3,4-dihydro-2H-pyrane, 80 ml of dichloromethane solution, and subsequently 0.25 g (1 mmol) of pyridinium p-toluenesulfonate. After stirring the resultant mixed liquid at room temperature for 30 minutes, the solution was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to yield, as a colorless oil-like substance, 2-(3-thienylmethyloxy) tetrahydro-2H-pyrane (compound (b), 7.92 g, 100% yield) in which the hydroxy group of thiophene-3-methanol was protected. The physical properties of the obtained 2-(3-thienylmethyloxy)tetrahydro-2H-pyrane are shown below: 1H NMR (CDCl3, 400 MHz, (ppm): 7.30 (dd, J=3.2, 4. 8 Hz, 1H), 7.25 (dd, J= 3.2, 1.2 Hz, 1H), 7.09 (dd, J=1.2, 4.8 Hz, 1H), 4.77 (d, J=12.4 Hz, 2H), 4.70 (t, J=4 Hz, 1H), 4.54 (d, J=12.4 Hz, 2H), 3. 91 (m, 1H), 1.88-1.51 (m, 6H); 13C NMR (CDCl3, 100 MHz, (ppm) 139.25, 127.35, 125.74, 122.67, 97.43, 66.99, 62.02, 30.44, 25.42, 19.25; MS (m/e) 198 (M+) ; IR(heat) (max 2945, 2872, 2247, 1466, 1454, 1440, 1120, 1030, 908, 736 cm-1.; Example 2 Synthesis of.kahweofuran (method 2) Kahweofuran (compound (e)) was produced from thiophene-3-methanol (compound (a)) according to the following scheme. [Show Image] (1) Step A: Protection of the hydroxy group of thiophene-3-methanol Synthesis of 2-(3-thienylmethyloxy)tetrahydro-2H-pyrane (Compound b) According to step A described in Example 1, 2-(3-thienylmethyloxy)tetrahydro-2H-pyrane (compound (b)) was synthesized from thiophene-3-methanol (compound (a)).; Example 3 Synthesis of 6-ethyl-2,3-dihydrothieno[2, 3c]furan 6-ethyl-2,3-dihydrothieno[2,3c]furan (compound (h)) was produced from thiophene-3-methanol (compound (a)) according to the following scheme. [Show Image] (1) Step A: Protection of the hydroxy group of thiophene-3-methanol Synthesis of 2-(3-thienylmethyloxy)tetrahydro-2H-pyrane (compound (b)) According to step A of Example 1, 2-(3-thienylmethyloxy)tetrahydro-2H-pyrane (compound (b)) was produced from 4.56 g (40 mmol) of thiophene-3-methanol (compound (a)).
100%
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 0.5h;
1.1.1 Step 1: Protection of the hydroxyl group of thiophene-3-methanol(Synthesis of 2- (3-thienylmethyloxy) tetrahydro-2H-pyran (compound (b)))
To 4.56 g (40 mmol) of thiophene-3-methanol (compound (a)), 3.36 g (40 mmol) of 3,4-dihydro-2H-pyran and 80 ml of dichloromethane solution were added,Next, 0.25 g of pyridinium p-toluenesulfonic acid(1 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes, and then the solution was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to protect the hydroxyl group of thiophene-3-methanol as a colorless oil.2- (3-thienylmethyloxy) tetrahydro-2H-pyran (compound (b),7.92 g, 100% yield).The physical properties of 2- (3-thienylmethyloxy) tetrahydro-2H-pyran are shown below.
90%
With hydrogenchloride In tetrahydrofuran for 3h;
37.1 First step: 2-(thiophen-3-ylmethoxy)tetrahydro-2H-pyran (37B)
Thiophen-3-ylmethanol(28A) (5g, 60mmol)Dissolved in tetrahydrofuran(40mL),Join in orderDihydropyran(5g, 60mmol), hydrochloric acid solution (0.5ml, 3N), reaction for 3h,Cooled, added water (50 mL), extracted with dichloromethane (50 mL×4).Washed with a saturated aqueous solution of brine (150 mL × 3), dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated and purified by column chromatography (hexane/ethyl acetate = 10:1).Light yellow liquid product2-(Thien-3-ylmethoxy)tetrahydro-2H-pyran (37B) (11 g, yield 90%).
45 Preparation of 3-hydroxymethyl-2-iodothiophene
Preparation of 3-hydroxymethyl-2-iodothiophene 3-Hydroxymethylthiophene (2.3 g, 20 mmole) (Aldrich Chem. Co., Milwaukee, Wis.) and iodine (2.39 g, 9.4 mmole) were dissolved in ethanol (15 ml). Iodic acid (1.09 g, 6.2 mmole) in water (2 ml) was added dropwisely at 0° C. and was further stirred for 1 hour at the same temperature. The reaction was monitored with thin layer chromatography until the reaction was completed. Sodium thiosulfate aqueous solution was added and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography, eluted with n-hexane/ethyl acetate (3:1) to give light yellowish oily product (3.9 g, 81%). Spectral Data: 1 H NMR (CDCl3), δ value 7.43 (d, 1H, J=5.2 Hz), 6.96 (d, 1H, J=5.2 Hz), 4.54 (s, 2H)
61%
With iodine; silver trifluoroacetate In chloroform at 0℃; for 0.5h;
With hydrogen bromide; oxygen In acetonitrile for 10h; Irradiation;
80%
With carbon tetrabromide; oxygen; triphenylphosphine In acetonitrile for 10h; fluorescent irradiation;
76%
With dichloro(1,5-cyclooctadiene)ruthenium(II); C30H30N3P2(1+)*Cl(1-); potassium hydroxide In toluene at 120℃; for 24h; Inert atmosphere; Schlenk technique;
15%
With N-Bromosuccinimide; oxygen In acetonitrile at 20℃; for 10h; Irradiation;
64 %Spectr.
With oxygen; potassium hydroxide In methanol; water at 50℃; for 8h;
Multi-step reaction with 2 steps
1: tert.-butylnitrite; oxygen / 1,4-dioxane / 24 h / 25 °C / 760.05 Torr / Green chemistry
2: oxygen / 1,4-dioxane / 24 h / 80 °C / 760.05 Torr / Green chemistry
With sodium hydride In tetrahydrofuran at 30℃; for 2h;
74
Example 74; In 1 ml of tetrahydrofuran was dissolved 0.23 g of 3- thiophenemethanol, 50 mg of sodium hydride (60% oily) was added, and the mixture was stirred at 30°C for 1 hour. To the solution was added 2ml of a tetrahydrofuran solution (0.5 M) of the compound represented by the formula (Ha-I), and the mixture was stirred at 300C for 2 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate, The organic layer was washed with water, dried with magnesium sulfate, centrifuged, and concentrated. The residue was subjected to medium pressure preparative liquid chromatography to obtain 67 mg of a compound represented by the formula (74) :(hereinafter, referred to as present compound (74)).1H-NMR (CDCl3, TMS) δ (ppm): 7.46 (IH, m) , 7.36 (IH, dd) ,7.18 (IH, dd) , 5.55 (2H, s), 3.05 (6H, br)
methyl 3-[2-chloro-4-[(thiophene-3-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 0 - 20℃; for 28h;
144.6 Preparation Example 144-6 Methyl 3-[2-chloro-4-[(thiophene-3-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
Preparation Example 144-6 methyl 3-[2-chloro-4-[(thiophene-3-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate To a suspension of methyl 3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (240 mg), 3-thiophenemethanol (68 mg) and triphenylphosphine (218 mg) in dry dichloromethane were added to diethyl azodicarboxylate (139 mg) under ice-cooling.. After 2 hr, the reaction mixture was stirred at room temperature.. After 6 hr, to a suspension of 3-thiophenemethanol (34 mg) and triphenylphosphine (109 mg) in dry dichloromethane was added diethyl azodicarboxylate (69 mg) under ice-cooling.. After 20 hr, the reaction mixture was subjected to flash silica gel chromatography (silica gel 60 ml, eluent: chloroform).. The elude was recrystallized from ethyl acetate to give the objective compound (143 mg) as colorless crystals. 1H-NMR (CDCl3): 2.54(3H, s), 4.00(3H, s), 5.02(2H, s), 5.62(2H, s), 6.64(1H, d, J=8 Hz), 6.72(1H, dd, J=8, 2 Hz), 7.05(1H, d, J=2 Hz), 7.12(1H, br d, J=5 Hz), 7.26-7.38(2H, m), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) Mass (ESI):m/z 428(M+1).
With N-Bromosuccinimide; acetic acid; at 20℃; for 0.75h;
To a solution of 3-hydroxymethylthiophene 12 (4.06 g, 35.6 mmol) in 18 mL of acetic acid was added N-bromosuccinimide (6.34 g, 35.6 mol) at room temperature and stirred for 45 minutes. The resulting mixture was quenched with 1 mL of water, poured into 250 mL ether and washed with 100 mL of water, 100 mL of 10% NAHC03 aq. respectively. The organic layer was dried over NA2S04 and concentrated. 6.25 G of crude product 13 (91 %) was obtained and used for the subsequent reaction without further purification.
77%
With N-Bromosuccinimide; In fluorobenzene; at 20℃; for 24.0h;Schlenk technique; Inert atmosphere;
According to the reported procedure, 15 (2-bromothien-3-yl)methanol was prepared by the bromination of 3-thienylmethanol (1.37 g, 12.0 mmol) with N-bromosuccinimide (2.56 g, 14.4 mmol) in PhF (120 mL), and isolated in 77% yield (1.80 g) as a light orange oil by column chromatography on silica gel (hexane/EtOAc = 3/1). Its spectral and analytical data are shown below because they were not provided in reference 15.
With N-Bromosuccinimide; In tetrahydrofuran; at 0 - 20℃; for 1.0h;
Example 1; 4-[l -({ [5-chloro-3-(3-chlorobenzyl)-2-thienyl]carbonyl}amino)ethyl]-benzoic acid; Step 1 : 2-bromo-3-hydroxymethylthiophene; To a solution of 3-thiophenemethanol (8.20 g, 71.8 mmol) in THF (150 mL) at O0C was added water (10 mL) followed by solid iV-bromosuccinimide (12.8 g, 71.8 mmol) and the solution was stirred at r.t. for Ih. Most of the solvent was evaporated in vacuo and the residue was redissolved in EtOAc and washed with water (3x) and brine. The organic layer was dried over MgStheta4, filtered and concentrated in vacuo to give the desired product as a yellowish oil. The crude product was used directly without further purification.
ethyl 3-[4-phenyl-1-[4-(3-thienylmethoxy)benzyl]-3-pyrrolyl]propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃;
21 Example 21
A toluene solution (1.74 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), 3-thiophenemethanol (0.236 ml), triphenyl phosphine (984 mg), and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred overnight at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(3-thienylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (629 mg, yield: 56%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR(CDCl3) δ: 1.19(3H, t, J=7.2 Hz), 2.51(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.0 Hz), 4.93(2H, s), 5.05(2H, s), 6.50(1H, d, J=2.2 Hz), 6.71(1H, d, J=2.2 Hz), 6.92(2H, d, J=8.8 Hz), 7.08-7.22(4H, m), 7.31-7.41(6H, m).
5-(thien-3-yl)methoxy-3-methylthio-1,2,4-thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 4.5h;
17
To 4 ml of N,N-dimethylformamide, 0.334 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 228 mg of 3-thiophenemethanol were dissolved, and added 0.084 g of sodium hydride (60 % in oil) at about 0 °C, followed by stirring at about 0 °C for 0.5 hours and at room temperature for 4 hours. Then, the reactionmixturewas addedto saturatedsodiumchloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 500 mg of 5-(3-thienyl)methoxy-3-methylthio-1,2,4-thiadiazole. 5-(3-thienyl)methoxy-3-methylthio-1,2,4-thiadiazole (which is reffered to as the compound of the present invention 17 hereinafter). 1H-NMR:7.43(m,1H) 7.35(m,1H) 7.17(m,1H) 5.49(s,2H) 2.61(s,3H)
With sodium hypochlorite; C8H18NPol; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5h;
7
EXAMPLE 7 5.00 g (0.0438 mol) of 3-thiophenemethanol, 0.138 g of PIPO obtained in Reference Example 1 (2,2,6,6-tetramethylpiperidine-1-oxyl-4-yl group: 0.000438 mol), 10.0 g of toluene and 5.0 g of a 5% by weight aqueous solution of sodium hydrogen carbonate (sodium hydrogen carbonate: 0.0030 mol) were placed in a 100 ml reaction vessel. Then, with maintaining the temperature at 15 to 20° C., reaction was conducted while 24.4 g of a 13.4% by weight aqueous solution of sodium hypochlorite (sodium hypochlorite: 0.0438 mol) was dropped over 4 hours by a microsyringe pump under stirring. Stirring was conducted for another 0.5 hour to complete the reaction. The reaction mixture after the reaction was completed was separated into the organic phase and the water phase and each phase was analyzed by liquid chromatography. By the reaction, 3-thiophenecarbaldehyde was produced with yield of 87.5% (based on 3-thiophenemethanol). As a by-product, 0.1% (based on 3-thiophenemethanol) of 3-thiophenecarboxylic acid was produced.
1: 65%
2: 18 %Spectr.
With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium chloride; oxygen In 1,2-dichloro-ethane at 25℃; for 48h; Schlenk technique;
General procedure: To a Schlenk tube were added Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol), TEMPO (15.8 mg, 0.1 mmol), KCl (7.5 mg, 0.1 mmol), 1a (108.5 mg, 1.0 mmol), and DCE (4.0 mL) sequentially under an atmosphere of oxygen (gas bag, commercial size: 2 L, which could be expanded to 5 L). The mixture was then stirred at 25 °C until completion of the reaction as monitored by TLC (petroleum ether/EtOAc = 5:1) (48h). The crude reaction mixture was filtered through a short column of silica gel (height: 2 cm, diameter: 3 cm) eluting with Et2O (3 × 25 mL). After evaporation, the residue was purified by chromatography on silica gel [petroleum ether/EtOAc = 15:1 (500 mL) to 2:1 (300 mL)] to afford benzoic acid (2a)14 (69.9 mg, 57%) as a pale yellow solid.
1: 52.3%
2: 2.3%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate In water; toluene at 15 - 20℃; for 4.5h;
3
COMPARATIVE EXAMPLE 3 The experiment was conducted in the same manner as in Example 7, except that 0.072 g (0.000458 mol) of 2,2,6,6-tetramethylpiperidine-1-oxyl was used instead of PIPO. As a result, by the reaction, 3-thiophenecarbaldehyde was produced with yield of 52.3% (based on 3-thiophenemethanol). As a by-product, 2.3% (based on 3-thiophenemethanol) of 3-thiophenecarboxylic acid was produced.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5 - 12h;
26
The title compound is formed by reacting a 0.1M solution of the title compound from Example 17 in DMF with thiophen-3-yl methanol (1.2 equiv.) in the presence of K2CO3 (2 equiv.) at room temperature for 5-12 hours. The resulting reaction mixture is then extracted with EtOAc, washed with NaHCO3, water, and brine, and the washed extract is concentrated in vacuo. The residue is then purified by silica chromatography to yield the ethyl ester of the title compound. The ethyl ester is then hydrolyzed to the free acid via treatment with LiOH to arrive upon the title compound.
5-(2,3-dichlorophenyl)-1-(thien-3-ylmethyl)-1H-tetraazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 6h;
77
Thien-3-ylmethanol (207 nig, 1.81 mmol) in THF (7 mL) was treated with 5-(2,3- dichlorophenyl)-lH-tetraazole (300 mg, 1.39 mmol), triphenylphosphine (475 mg, 1.81 mmol), and diethylazodicarboxylate (475 mg, 1.81 mmo). The solution was stirred at ambient temperature for 6 hours then partitioned between EtOAc (15 mL) and 10% HCl (10 mL). The organic phase was washed with brine (5 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution with 10-100% CH3CN containing 0.01M aq. NH4OAc) to provide the EPO desired product (51 mg). MS (DClTNH3) m/z 311 (M+H)+; 1H NMR (DMSOd6) δ 7.94 (dd, IH, J=7.0, 2.8 Hz), 7.62-7.53 (m, 2H), 7.48 (dd, IH, J=4.9, 2.8 Hz)5 7.28-7.26 (m, IH), 6.85 (dd, IH, J=4.9, 1.2 Hz), 4.58 (s, 2H); Anal, calcd for C12H8Cl2N4S: C, 46.32; H, 2.59; N, 18.00. Found: C5 46.29; H, 2.57; N, 18.07.
4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline[ No CAS ]
[ 1972-28-7 ]
4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With triphenylphosphine In dichloromethane
76 Example 76
The starting material was prepared as follows: Diethyl azodicarboxylate (274 μl, 1.7 mmol) was added dropwise to a solution of 4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (400 mg, 0.7 mmol), (prepared as described for the starting material in Example 33), 3-thiophenemethanol (119 mg, 1 mmol) triphenylphosphine (456 mg, 1.7 mmol) in methylene chloride (12 ml) cooled at 0° C. The mixture was stirred for 2 hours at ambient temperature, the solvent was removed by evaporation and the residue was purified by column chromatography eluding with methylene chloride/ether (95/5). The purified product was triturated with petroleum ether/ethyl acetate (8/2) and the solid product was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-5-diphenyl-t-butylsilyloxy-2-fluoroanilino)-6-methoxy-7-((3-thienyl)methoxy)quinazoline (223 mg, 47%). 1 H NMR Spectrum: (DMSOd6) 1.09(s, 9H); 3.85(s, 3H); 5.23(s, 2H); 7.04(d, 1H); 7.21(d, 1H); 7.25(s, 1H); 7.4-7.5(m, 6H); 7.58(m, 2H); 7.62-7.75(m, 6H); 8.1(s, 1H); 9.22(br s, 1H)
(1) Synthesis of an intermediate, 2-chloro-4-methoxy-6-(3-thienylmethyloxy)pyridine To a solution containing 3-thiophenemethanol (0.45 g, 0.0033*1.2 mol) and sodium hydride (0.14 g, (ca.60% in mineral oil), 0.033*1.05 mol) in tetrahydrofuran, 2,6- dichloro-4-methoxypyridine (0.59 g, 0.0033 mol) was added and the resultant solution was refluxed for about 2 hours. Then, the reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter, concentrated and purified on a silica gel column to obtain the end product. Yield: 0.64 g (76%). Oily product. 1 H-NMR (60 MHz, CDCl3, delta): 3.63(3H,s), 5.17(2H,s), 5.95(1H,d,J=2.0 Hz), 6.30(1H,d,J=2.0 Hz), 6.7-7.2(3H, complex).
(1) Synthesis of an intermediate, 2-chloro-4-methylamino-6-(3-thienylmethyloxy)pyridine To a solution of 3-thiophenemethanol (1.42 g, 0.0113*1.1 mol) in 20 ml of dry tetrahydrofuran, sodium hydride (1.35 g (ca.60% in mineral oil), 0.0113*3.0 mol) was added. After the bubbling ceased, a solution of <strong>[175461-33-3]2,6-dichloro-4-methylaminopyridine</strong> (2.0 g, 0.0113 mol) in 30 ml of dry tetrahydrofuran was added dropwise at room temperature. After the addition, the reaction solution was stirred for about 20 hours under reflux. Then, the solvent was distilled off and the residue was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified on a silica gel column to obtain the end product. Yield: 0.45 g (16%). Oily product. 1 H-NMR (60 MHz, CDCl3, delta): 2.64(3H,d,J=5 Hz), 4.2(1H,q, J=5 Hz), 5.2(2H,s), 5.6(1H,d,J=2 Hz), 6.0(1H,d,J=2 Hz), 6.9-7.3(3H, complex).
(1) Synthesis of an intermediate, 2-chloro-4-dimethylamino-6-(3-thienylmethyloxy)pyridine To a solution of 3-thiophenemethanol (0.526 g, 0.0042*1.1 mol) in 10 ml of dry tetrahydrofuran, sodium hydride (0.335 g, (ca.60% in mineral oil), 0.0042*2.0 mol) was added. After the bubbling ceased, a solution of <strong>[175461-34-4]2,6-dichloro-4-dimethylaminopyridine</strong> (0.8 g, 0.0042 mol) in 20 ml of dry tetrahydrofuran was added dropwise at room temperature. After the addition, the resultant solution was stirred for 24 hours under reflux. Then, the solvent was distilled off and the residue was partitioned between chloroform and water. The obtained organic layer was washed successively with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified on a silica gel column to obtain the end product. Yield: 0.63 g (56%). Solid. Melting point: 78-79 C. 1 H-NMR (60 MHz, CDCl3, delta): 2.86(6H,s), 5.20(2H,s), 5.73(1H,d,J=2 Hz), 6.15(1H,d,J=2 Hz), 7.0-7.3(3H, complex).
(1) Synthesis of an intermediate, 2-chloro-4-cyano-6-(3-thienylmethyloxy)pyridine Sodium hydride (0.24 g (ca.60% in mineral oil), 0.006*1.0 mol) was suspended in 20 ml of N-methyl-2-pyrrolidinone, and 3-thiophenemethanol (0.69 g, 0.006*1.0 mol) was added thereto and the resultant solution was stirred for about 30 minutes at room temperature. The resultant mixture was cooled to 4 C. with iced water, then 4-cyano-2,6-dichloropyridine (1.04 g, 0.006 mol) was added thereto and stirred for about 1.5 hour while cooling with iced water. After stirred for another about 1.5 hours, the reaction solution was partitioned between ethyl acetate and water. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter, concentrated and purified on a silica gel column to obtain the end product. Yield: 0.94 g (63%). Oily product. 1 H-NMR (60 MHz, CDCl3, delta): 5.30(2H,s), 6.78(1H, s), 6.97(1H,s), 6.9-7.4(3H, complex).
(1) Synthesis of an intermediate, 2-chloro-6-(3-thienylmethyloxy)-4-trifluoromethylpyridine To a mixture prepared by adding to 3-thiophenemethanol (1.27 g, 0.0093*1.2 mol) successively tetrahydrofuran and sodium hydride (0.39 g, (ca.60% in mineral oil), 0.0093*1.05 mol), <strong>[39890-98-7]2,6-dichloro-4-trifluoromethylpyridine</strong> (2.0 g, 0.0093 mol) was added, and the resultant solution was refluxed for about 1 hour. Then, the reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter concentrated. The concentrate was purified on a silica gel column and the starting material which was difficult to separate was distilled off by using a tubular oven, whereby the end produce was obtained. Yield: 2.42 g (89%). Oily product. 1 H-NMR (60 MHz, CDCl3, delta): 5.34(2H,s), 6.83(1H,s), 6.9-7.5 (4H, complex).
(1) Synthesis of an intermediate, 2-chloro-4-methyl-6-(3-thienylmethyloxy)pyridine To a solution containing 3-thiophenemethanol (0.78 g, 0.0062*1.1 mol) and sodium hydride (0.26 g, (ca.60% in mineral oil), 0.0062*1.05 mol) in tetrahydrofuran, <strong>[39621-00-6]2,6-dichloro-4-methylpyridine</strong> (1.0 g, 0.0062 mol) was added, and the resultant solution was refluxed for about 1 hour. Then, the reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter, concentrated and purified on silica gel column to obtain the end product. Yield: 1.21 g (82%). Oily product. 1 H-NMR (60 MHz, CDCl3, delta): 2.20(3H,s), 5.26(2H,s), 6.38(1H,s), 6.64(1H,s), 6.9-7.4(3H, complex).
5 EXAMPLE 5
EXAMPLE 5 This Example illustrates the preparation of (Z)- and (E)-isomers of methyl 3-methoxy-2-(3-phenoxymethyl-2thienyl)propenoate (compounds numbers 9 and 10 respectively of Table I). A solution of methanesulphonyl chloride (20.3 ml) in dichloromethane (20 ml) was added dropwise over 15 minutes to a stirred solution of 3-(hydroxymethyl)thiophene (20.0 g) and triethylamine (42.8 ml) in dichloromethane (150 ml), cooled in an ice bath. The solution, initially colourless, became yellow and a white solid precipitated. After 1 hour at ice bath temperatures the reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was then washed successively with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate and aqueous sodium chloride, then dried and concentrated to give 3-(chloromethyl)thiophene (14.50 g, 63% yield) as a yellow liquid, 1 H nmr: delta 4.62 (2H, s) ppm.
63%
With triethylamine In dichloromethane
5 EXAMPLE 5
EXAMPLE 5 This Example illustrates the preparation of (Z)- and (E)-isomers of methyl 3-methoxy-2-(3-phenoxymethyl-2-thienyl)propenoate (compounds numbers 9 and 10 respectively of table I). A solution of methanesulphonyl chloride (20.3 ml) in dichloromethane (20 ml) was added dropwise over 15 minutes to a stirred solution of 3-(hydroxymethyl)thiophene (20.0 g) and triethylamine (42.8 ml) in dichloromethane (150 ml), cooled in an ice bath. The solution, initially colourless, became yellow and a white solid precipitated. After 1 hour at ice bath temperatures the reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was then washed successively with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate and aqueous sodium chloride, then dried and concentrated to give 3-(chloromethyl)thiophene (14.50 g, 63% yield) as a yellow liquid, 1H nmr: delta 4.62 (2H,s) ppm.
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 0 - 20℃; for 18h;
Synthesis of Compound B (5- (4- (Thiophen-3-ylmethoxy) benzylidene) thiazolidine-2,4-dione
3-Thiophene methanol (600 mg, 5.76 mmol),P-Hydroxybenzaldehyde (0.78 g, 6.34 mM)And triphenylphosphine (1.6 g, 6.1 mmol) in THF (20 ml)To this mixed solution was added diethyl azodicarboxylate (40% in toluene)Was added at 0°C over 10 minutes with stirring.After that, for 18 hours at room temperature, a solution of 3-thiophene methanol and p-hydroxybenzaldehydeStir until the initial reaction material disappeared.The solution was concentrated and then purified by chromatography over silica gel,At this time, elution was carried out under the condition of hexane to ethyl acetate of 5: 1, 4- (thiophene-3-ylmethoxy) benzaldehyde (0.98 g, yield: 94%) was obtained (Step 1).
40%
With PS-triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 7h;
77.1.1
Manufacturing Example 77-1-1 4-(Thiophen-3-ylmethoxy)-benzaldehyde; To a tetrahydrofuran (250 mL) solution of diethylazodicarboxylate (16.1 mL, 40.9 mmol) were added 4hydroxybenzaldehyde (5 g, 40.9 mmol), 3-thiophene methanol (3.86 mL, 40.9 mmol) and PS-triphenylphosphine (29 g, 1.41 mmol/g, 40.9 mmol). This mixture was stirred for 7 hours at room temperature. This mixture was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (3.61 g, 40%).1H-NMR Spectrum (CDCl3) δ (ppm): 5.17 (2H, s), 7.07-7.09 (2H, m), 7.15-7.17 (1H, m), 7.35-7.39 (2H, m), 7.84-7.86 (2H, m), 9.90 (1H, s).
40%
With diethylazodicarboxylate In tetrahydrofuran at 20℃; for 7h;
77.1.1
To a tetrahydrofuran (250 mL) solution of diethylazodicarboxylate (16.1 mL, 40.9 mmol) were added 4-hydroxybenzaldehyde (5 g, 40.9 mmol), 3-thiophene methanol (3.86 mL, 40.9 mmol) and PS-triphenylphosphine (29 g, 1.41 mmol/g, 40.9 mmol). This mixture was stirred for 7 hours at room temperature. This mixture was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (3.61 g, 40%). 1H-NMR Spectrum (CDCl3) δ (ppm): 5.17 (2H, s), 7.07-7.09 (2H, m), 7.15-7.17 (1H, m), 7.35-7.39 (2H, m), 7.84-7.86 (2H, m), 9.90 (1H, s).
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 0 - 25℃;
With cynomethylene tri-n-butylphospholan In toluene at 20 - 110℃;
4
Production Example 4 A 500 mg portion of ethyl 2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 24 ml of toluene, and 0.39 ml of 3-thienylmethanol and 1.00 g of cynomethylene tri-N-butylphospholan were added at room temperature, followed by overnight stirring at 110°C. A 0.39 ml portion of 3-thienylmethanol and 1.00 g of cyanomethylene tri-N-butylphospholan were added to the reaction liquid, followed by stirring at 110°C for 8 hours. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:20 to 1:10) to obtain 378 mg of ethyl 2,3-dimethyl-1-(3-thienylmethyl)-1H-indole-5-carboxylate as a yellow solid.
Stage #1: 3-hydroxymethyl-thiophene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.25h;
Stage #2: With sulfur dioxide In tetrahydrofuran; hexane at 20℃; for 2h;
21
Reference Example 21; (2-hydrosulfonylthiophen-3-yl) Methanol; Into a solution of thiophen-3-methanol (14.5 ml, manufactured by AlfaAesar) in tetrahydrofuran (230 ml, manufactured by KANTO CHEMICAL CO., INC.), n-butyllithium (1.59M n-hexane solution, 212 ml, manufactured by KANTO CHEMICAL CO., INC.) was dripped over 45 minutes at -78° C. The resultant mixture was stirred for 30 minutes at the same temperature. Then sulfur dioxide (16 ml, manufactured by SUMITOMO SEIKA CHEMICALS CO., LTD.) was added thereto. While the temperature of the resultant mixture was gradually elevated to room temperature, the mixture was stirred for 2 hours. The reaction solution was distilled away to give the titled compound.
Stage #1: 3-hydroxymethyl-thiophene With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 1h;
Stage #2: 2,6 difluorobenzonitrile In DMF (N,N-dimethyl-formamide) at 0 - 20℃;
47.1
Example 47; 5-(Thiophen-3-ylmethoxy)quinazoline-2,4-diamine; [00160] Step 1; A solution of 3-thiophenemethanol (1.0 g; 8.76 mmol) in dimethylformamide was added to a cooled (0° C) slurry of sodium hydride (0.42 g; 10.51 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C), then a solution of 2,6-difluorobenzonitrile in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice- water, stirred, filtered, washed with water and dried to afford 600 milligrams of 2- fluoro-6- (thiophen-3-ylmethoxy)benzonitrile.
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; Cooling with ice;
7.a
The separately isolated Compound B (50 mg) was dissolved in THF (1.5 mL), and 3-thiophenemethanol (16.5 mg) and triphenylphosphine (38.0 mg) were added to the solution. Under cooling on ice, diethyl azodicarboxylate (ca. 2.2 mol/L toluene solution) (65.9 µL) was added dropwise thereto, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the reaction mixture for extraction, and the water layer was further subjected to extraction with ethyl acetate. The organic layers were combined, and the combined mixture was dried with sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform : methanol = 50 : 1), whereby the title compound (C) (48.2 mg) was yielded. Compound (A): MS(FAB)m/z382(M+H)+ 1H-NMR(400MHz,DMSO-d6): δ(ppm)1.41(9H,s),1.98-2.07(2H,m),2.46-2.56(2H,m),2.93-3.02(2H,m),3.71(2H,t,J=6.5Hz),4.07-4.18(1H,m),6.93(1H,t,J=8.0Hz),7.00-7.07(2H,m),7.31(1H,d,J=8.0Hz),9.37(1H,br s),9.58(1H,br s). Compound (B): MS(FAB)m/z346(M+H)+ 1H-NMR(400MHz,DMSO-d6): δ(ppm)1.41(9H,s),2.08-2.18(2H,m),2.36-2.43(2H,m),2.93-3.06(2H,m),3.56-3.62(2H,m),4.08-4.19(1H,m),6.95-7.07(2H,m),7.10(1H,d,J=7.5Hz),7.16(1H,d,J=7.5Hz),9.66(1H,s). Compound (C): MS(FAB)m/z442(M+H)+ 1H-NMR(400MHz,DMSO-d6,80°C): δ(ppm)1.41(9H,s),1.83-2.07(2H,m),2.25-2.36(2H,m),2.79-2.94(2H,m),3.13-3.40(1H,m),3.72-3.79(1H,m),4.08-4.17(1H,m),4.56(1H,d,J=15.5Hz),5.17(1H,d,J=15.5Hz),6.52-6.61(1H,m),6.79(1H,d,J=5.0Hz),7.00-7.04(1H,m),7.06-7.12(1H,m),7.13-7.18(2H,m),7.31(1H,dd,J=3.0,5.0Hz).
With ammonium hydroxide; manganese(IV) oxide; oxygen at 130℃; for 48h; Autoclave;
2.2. Catalytic evaluation
General procedure: The ammoxidation of alcohols and hydration of nitrileswere performed in a high-pressure steel autoclave reactorequipped with a PTFE bottle, magnetic stirrer (900 rpm), andan explosion-proof pressure sensor. For the ammoxidation ofalcohols, the as-prepared catalyst, aqueous ammonia(28%-30% NH3), and alcohols were added into a certainamount of t-amyl alcohol solvent in the reactor, then the autoclavewas sealed and purged with oxygen for two times to excludethe inside air. For the hydration of nitrile, the as-preparedcatalyst, nitrile, and water were added into a certain amount oft-amyl alcohol solvent in the reactor, then the autoclave wassealed and purged with N2 for two times to exclude the insideair. After that, the reactor was quickly heated to the desiredtemperature (the reaction temperature was measured by athermocouple in the autoclave) in an oil bath. After a desiredreaction time, the reactor was placed in an ice bath to quenchthe reaction. After separation of the solid catalyst by centrifugation,the liquid was analyzed with a Shimadzu GC-2014 gaschromatograph equipped with a flame ionization detector(FID) and an Agilent HP-6890 gas chromatograph-mass spectrometer,with ethylbenzene, bromobenzene, hexadecane, orbiphenyl used as internal standards. The gas-phase products,such as CO and CO2, were analyzed with a Fu Li-9790 gaschromatograph equipped with a thermal conductivity detector(TCD). Notably, no CO and CO2 signals were observed in TCDand total carbon balances were always >90.0% in this work.Safety Note: The high-pressure oxygen has been extensivelyused in the aerobic oxidations [21,22], and the reaction systemsin this work were out of the explosion limits of the reactants.For example, the explosion limit of benzyl alcohol is1.3%-13.0% in oxygen, and the concentration of benzyl alcoholin the gaseous phase in this work is in a 0-0.4% region, whichis out of the explosion limits. Furthermore, the fire and staticelectricity are not allowed to access the internal reactor forsafety reasons. In the kinetics study, the average reaction rateswere calculated from the moles of substrate converted pergram of catalyst in one hour (mmol gcat-1 h-1), with the conversionof substrate controlled to be lower than 20.0%.
71%
With tert.-butylhydroperoxide; ammonium hydroxide In water at 100℃; for 16h;
87 %Chromat.
With ammonia; water; oxygen In 1,4-dioxane at 130℃; for 3h; Autoclave;
87 %Chromat.
With ammonium hydroxide; cryptomelane; oxygen In 1,4-dioxane at 130℃; for 3h; Autoclave; Green chemistry;
54 %Chromat.
With ammonium acetate; oxygen In tert-Amyl alcohol at 130℃; for 18h; Autoclave;
With potassium carbonate In dimethyl sulfoxide at 20℃; for 168h; Inert atmosphere;
Stage #1: 3-hydroxymethyl-thiophene; 4-Nitrophthalonitrile In N,N-dimethyl-formamide at 40℃; for 1h; Inert atmosphere;
Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 30℃; for 72.5h; Inert atmosphere;
2.2.1. 3-(Thiophen-3-ylmethoxy)phthalonitrile (1) and 4-(thiophen-3 ylmethoxy)phthalonitrile(2)
General procedure: Thiophen-3-ylmethanol (1.15 g, 10.64 mmol) and 3- or 4-nitrophthalonitrile (1.00 g, 5.78 mmol) were dissolved in dry DMF (10 mL) and heated at 40 °C in N2 for 1 h. Then, finely ground anhydrous potassium carbonate (~1.0 g excess) was added portionwiseto mixture over the period of 0.5 h at 30 °C. After the reaction mixture was keptat this temperature under N2 for 3 days, it was cooled to room temperature (rt.) and pouredinto 200 mL ice-water. The creamy precipitate formed was filtered and dissolved in CHCl3and washed with % 5 NaHCO3 to remove starting unreacted compounds. The creamy solution was then dried with anhydrous Na2SO4 and filtered. It was chromatographed overa silica gel column using a mixture of CHCl3 : MeOH (100/5) as eluent, giving blue powder, 1. Finally, the pure powder was dried in a vacuum.
With 1.9 mol% Au/HT; potassium <i>tert</i>-butylate In o-xylene at 90℃; for 36h; Inert atmosphere;
General procedure for the dehydrogenative amide synthesis from amine and alcohol:
General procedure: All the reactions were carried out in a multi-reactor (Carousel 12 station, RADLEYS). Typically, 0.5 mmol morpholine (43 mg), 1.0 mmol benzyl alcohol (108 mg), 50 mg Au/HT (1.9 mol % Au), and 5 mL o-xylene were added to a 40 mL glass vessel. Then, the reaction mixture was stirred (310 rpm) at 90 °C under argon. After 24 h, it was cooled down to room temperature. ∼20 mL ethyl acetate was added to dissolve the reaction mixture and filtrated with celite to remove the solids. Then the ethyl acetate and solvent were removed under vacuum and a yellow liquid was obtained. It was further purified using column chromatography (ethyl acetate / petroleum ether = 2/3, v/v; Silica Gel: 200-300 mesh; Rf = 0.17) to obtain the pure product as a white solid.
With hydrogen; sodium acetate; palladium dichloride; In methanol; at 35℃; under 760.051 Torr; for 12h;
Typical procedures: 6-bromonicotinaldehyde (930 mg, 5.0 mmol), NaOAc (820 mg, 10.0 mmol), MeOH (30 mL), and PdCl2 (45 mg) were mixed in a glass bottle capped with a balloon filled with hydrogen. After stirred at 35 C for 4 h, the mixture was filtered and washed with MeOH. The solvent was removed and the residue was dissolved in water, neutralized with solid NaHCO3, and extracted with ethyl acetate. The organic phase was dried over anhyd Na2SO4, and then filtered. The solvent was removed and the residue was subjected to chromatography to yield pyridin-3-ylmethanol (428 mg, 78%).
3. General procedure for preparation of (hetero)benzyl acetates 5a-5l and 5q-5s
General procedure: To a solution of benzyl or hetero-benzyl alcohols (2.0 mmol) in CH2Cl2 (6 mL) was added acetyl chloride (173 mg, 2.2 mmol) and Et3N (202 mg, 2.0 mmol). The reaction mixture was stirred at room temperature until completion (monitored by TLC), and then water (30 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was puried by flash chromatography (petroleum ether/ethyl acetate 300:1 to 50:1) to give the products 5a-5l and 5q-5t.
85%
With dmap; triethylamine In dichloromethane for 3h; Inert atmosphere;
With ammonia; oxygen In tert-Amyl alcohol; water at 100℃; for 5h; Autoclave; High pressure;
95.4%
With ammonium hydroxide; manganese sesquioxide; oxygen at 130℃; for 48h; Autoclave;
2.2. Catalytic evaluation
General procedure: The ammoxidation of alcohols and hydration of nitrileswere performed in a high-pressure steel autoclave reactorequipped with a PTFE bottle, magnetic stirrer (900 rpm), andan explosion-proof pressure sensor. For the ammoxidation ofalcohols, the as-prepared catalyst, aqueous ammonia(28%-30% NH3), and alcohols were added into a certainamount of t-amyl alcohol solvent in the reactor, then the autoclavewas sealed and purged with oxygen for two times to excludethe inside air. For the hydration of nitrile, the as-preparedcatalyst, nitrile, and water were added into a certain amount oft-amyl alcohol solvent in the reactor, then the autoclave wassealed and purged with N2 for two times to exclude the insideair. After that, the reactor was quickly heated to the desiredtemperature (the reaction temperature was measured by athermocouple in the autoclave) in an oil bath. After a desiredreaction time, the reactor was placed in an ice bath to quenchthe reaction. After separation of the solid catalyst by centrifugation,the liquid was analyzed with a Shimadzu GC-2014 gaschromatograph equipped with a flame ionization detector(FID) and an Agilent HP-6890 gas chromatograph-mass spectrometer,with ethylbenzene, bromobenzene, hexadecane, orbiphenyl used as internal standards. The gas-phase products,such as CO and CO2, were analyzed with a Fu Li-9790 gaschromatograph equipped with a thermal conductivity detector(TCD). Notably, no CO and CO2 signals were observed in TCDand total carbon balances were always >90.0% in this work.Safety Note: The high-pressure oxygen has been extensivelyused in the aerobic oxidations [21,22], and the reaction systemsin this work were out of the explosion limits of the reactants.For example, the explosion limit of benzyl alcohol is1.3%-13.0% in oxygen, and the concentration of benzyl alcoholin the gaseous phase in this work is in a 0-0.4% region, whichis out of the explosion limits. Furthermore, the fire and staticelectricity are not allowed to access the internal reactor forsafety reasons. In the kinetics study, the average reaction rateswere calculated from the moles of substrate converted pergram of catalyst in one hour (mmol gcat-1 h-1), with the conversionof substrate controlled to be lower than 20.0%.
91%
With ammonia; oxygen In 1,4-dioxane for 3h; Reflux;
90%
With ammonium hydroxide; copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N-Phenylglycine; sodium hydroxide In methanol at 50℃; for 24h; Cooling with ice;
13
General procedure: Benzyl alcohol was added in a 2L round-bottomed flask (108.02g, 1000mmol, i.e., of formula (I) wherein R is H, X = C, n = 1, m = 0),cuprous iodide (9.50g, 50mmol) , of N- phenylglycine (7.51g, 50mmol), TEMPO ( 7.80g, 50mmol),sodium carbonate (10.60g, 100mmol), aqueous ammonia (300mL, 25 ~ 28%) ,800mL methanol, under ice-cooling, with the oxygen round bottom flask was evacuated of air ventilation 3 times, and then the system was stirred at 50 at 12h, after completion of the reaction, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure and dried to give the product benzonitrile 95.79g, yield 93%. The reactants used is 2-thiophene methanol (57.12g, 500mmol, i.e., of formula (I) wherein R is H, X = S, n = 0, m = 0), experimental methods and procedures were the same as in Example 1, except that: cuprous iodide (4.76g, 25mmol), N- phenylglycine (3.79g, 25mmol), TEMPO ( 3.91g, 25mmol), sodium hydroxide (2.03g, 50mmol), aqueous ammonia (60mL, 25 ~ 28%), methanol 160mL, stirred at at 50 24h, to give the final product 49.05g, yield 90%.
83%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; ammonia; oxygen; copper(II) nitrate In water; dimethyl sulfoxide at 80℃; for 5h;
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 60℃; for 4h; Sonication;
80 mg
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 60℃; for 4h; Sonication;
133 Example 133 1- (2-Cyclopropyl-3-methylimidazo [1, 2-a] pyridin-6-yl) -4- (3- thienylmethoxy) pyridin-2 ( 1H) -one
Example 133 1- (2-Cyclopropyl-3-methylimidazo [1, 2-a] pyridin-6-yl) -4- (3- thienylmethoxy) pyridin-2 ( 1H) -one To a solution of 1- (2-cyclopropyl-3-methylimidazo [1, 2- a] pyridin-6-yl ) -4-hydroxypyridin-2 ( 1H) -one (150 mg) , 3- thienylmethanol (121 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1, 1' - (azodicarbonyl) dipiperidine (401 mg) . The mixture was stirred under sonication at 60°C for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (80 mg) as a white solid. MS (ESI+) : [M+H]+ 378.3. XH NMR (400 MHz , DMSO-d6) : δ 0.88-0.94 (4H, m) , 2.04-2.10 (1H, m) , 2.47 (3H, s) , 5.15 (2H, s) , 6.02 (1H, d, J = 2.6 Hz), 6.10 (1H, dd, J = 2.6, 7.6 Hz), 7.07 (1H, dd, J = 1.8, 9.5 Hz), 7.19 (1H, d, J = 4.9 Hz), 7.43 (1H, d, J = 9.4 Hz), 7.59 (1H, dd, J = 2.9, 4.8 Hz), 7.64-7.66 (2H, m) , 8.37 (1H, s) .
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 60℃; for 3h;
27 5.1.23 4-[(2-Chlorobenzyl)oxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6n)
General procedure: To a suspension of 9a (100 mg, 0.36 mmol) and (2-chlorophenyl)methanol (101 mg, 0.71 mmol) in THF (2 mL) were added tributylphosphine (0.266 ml, 1.07 mmol) and ADDP (269 mg, 1.07 mmol) at 60 °C, and the mixture was stirred at the same temperature for 3 h. After solvent was removed by evaporation, the residue was purified by column chromatography (silica gel, hexane/EtOAc = 90/10 to 0/100, then EtOAc/MeOH = 100/0 to 85/15), followed by column chromatography (NH silica gel, hexane/EtOAc = 90/10 to 0/100, then EtOAc/MeOH = 100/0 to 85/15). The residual solid was recrystallized by EtOH-hexane to give the title compound (60.0 mg, 42%) as an off-white solid.
50 mg
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 50℃; for 1h; Sonication;
75 Example 75 1- (2-Cyclopropyl-l-methyl-lH-benzimidazol-6-yl ) -4- (3- thienylmethoxy) pyridin-2 ( 1H) -one
Example 75 1- (2-Cyclopropyl-l-methyl-lH-benzimidazol-6-yl ) -4- (3- thienylmethoxy) pyridin-2 ( 1H) -one To a solution of 1- (2-cyclopropyl-l-methyl-lH- benzimidazol-6-yl) -4-hydroxypyridin-2 ( 1H) -one (100 mg) , 3- thienylmethanol (67 μ) and tributylphosphine (258 μ) in THF (10 ml) was added 1, 1' - (azodicarbonyl) dipiperidine (264 mg) . The mixture was stirred under sonication at 50°C for 1 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM (100 ml), and the DCM layer was washed with water (100 ml), brine (30 ml), dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid. MS (ESI+) : [M+H]+ 378.2. XH NMR (400 MHz, DMSO-d6) : δ 1.02-1.09 (4H, m) , 2.24-2.28 (1H, m) , 3.85 (3H, s) , 5.13 (2H, s) , 5.99 (1H, d, J = 2.6 Hz), 6.06 (1H, dd, J = 2.6, 7.5 Hz), 7.04 (1H, dd, J = 1.7, 8.4 Hz), 7.19 (1H, d,. J = 4.2 Hz), 7.50-7.52 (2H, m) , 7.56-7.60 (2H, m) , 7.64 (1H, m) .
Synthesis of Tris(3-thiophenylmethyl)trimersic Ester (L1).
Triethylamine (16.5 mmol, 2.32 mL) was added to a stirred mixture of 1,3,5-benzenetricarbonyl trichloride (5mmol, 1.38 g) and 3-thiophenemethanol (15.8 mmol, 1.52mL) in chloroform (120 mL) at 60 °C. The reaction mixture was refluxed for 24 h. The solution was filtered, and added methanol (300 mL). Colorless crystals of L1 were obtained in 2 days in an 80 % yield.
3-thienylmethyl 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h;
9 Example P9: Preparation of 3-thienylmethyl 1-hydroxy-3H-2, 1-benzoxaborole-6-carboxylate:
To a stirred solution of 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid (0.150 g, 0.843 mmol) in dichloromethane (10 mL/g, 23.4 mmol) were added 3-thienylmethanol (0.106 g, 0.927 mmol) , 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (0.178 g, 0.927 mmol) and DMAP (0.002g, 0.0169 mmol) and the RM was stirred at ambient temperature for 5 h. Reaction mixture was diluted 10 ml water and then acidified with dil.HCI till pH~3. The aqueous layer was then extracted with dichloromethane (2X50ml). The combined organic layer was washed with brine solution (2X10 ml) and then dried over anhydrous sodium sulfate, filtered and evaporated completely to give crude compound. The crude mass thus obtained was purified by flash chromatography over silica gel with hexane / ethyl acetate 1 :0 to 70:30 as eluent to afford desired compound 3-thienylmethyl 1- hydroxy-3H-2, 1-benzoxaborole-6-carboxylate (0.120 g, 52% of theoretical yield). H NMR (400 MHz, DMSO-c/6) δ ppm 1.17 (s, 1 H) 1.22 (s, 1 H) 2.50 (dt, J=3.70, 1.79 Hz, 3 H) 3.34 (s, 1 H) 5.06 (s, 2 H) 5.54 (s, 2 H) 7.06 (t, J=4.41 Hz, 1 H) 7.28 (d, J=3.64 Hz, 1 H) 7.54 - 7.62 (m, 2 H) 8.06 (d, J=7.83 Hz, 1 H) 8.40 (s, 1 H) 9.42 (s, 1 H)
Stage #1: 3-hydroxymethyl-thiophene; 3-nitrobenzene-1,2-dicarbonitrile In N,N-dimethyl-formamide at 40℃; for 1h; Inert atmosphere;
Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 30℃; for 72.5h; Inert atmosphere;
2.2.1. 3-(Thiophen-3-ylmethoxy)phthalonitrile (1) and 4-(thiophen-3 ylmethoxy)phthalonitrile(2)
General procedure: Thiophen-3-ylmethanol (1.15 g, 10.64 mmol) and 3- or 4-nitrophthalonitrile (1.00 g, 5.78 mmol) were dissolved in dry DMF (10 mL) and heated at 40 °C in N2 for 1 h. Then, finely ground anhydrous potassium carbonate (~1.0 g excess) was added portionwiseto mixture over the period of 0.5 h at 30 °C. After the reaction mixture was keptat this temperature under N2 for 3 days, it was cooled to room temperature (rt.) and pouredinto 200 mL ice-water. The creamy precipitate formed was filtered and dissolved in CHCl3and washed with % 5 NaHCO3 to remove starting unreacted compounds. The creamy solution was then dried with anhydrous Na2SO4 and filtered. It was chromatographed overa silica gel column using a mixture of CHCl3 : MeOH (100/5) as eluent, giving blue powder, 1. Finally, the pure powder was dried in a vacuum.Yield of 1: 1.32 g (66%); m.p. = 96 °C; Anal. Calcd for C13H8N2OS (240 g mol-1): C,64.98; H, 3.36; N, 11.66. Found: C, 64.21; H, 3.32; N, 10.98. FT-IR (cm-1); 3084 (w,Ar-CH), 2887 (w, Alip-CH), 2227 (C≡N, st), 1604(C=C), 1591 (C=N), 1471(st), 1249(Ar-O-Alip-CH), 1266, 1184, 1035, 916, 858, 827, 800, 729, 768. 1H-NMR (DMSO-d6)Σ: 7.80 (t 1H, meta to Ar-OR and CN, Phenyl H5), 7.65 (d, 1H, ortho to Ar-OR, PhenylH4), 7.59 (d, 1H ortho to S, thiophene) 7.20 (d, 1H, ortho to CN, Ar-H6), 6.45, 6.44 (m2H ortho to S and meta to S thiophene) 5.21(s, 2H, CH2OAr). 13C-NMR (DMSO-d6) δ:192.38, 161.22, 116.45, 116.12, 136.77, 136.42, 128.07, 127.88, 125.65, 119.62, 103.84,67.26, 56.71, EI/MS m/z: 241.02 [M]+.
With N-iodo-succinimide; toluene-4-sulfonic acid In ethanol at 25℃; for 0.166667h; Green chemistry;
Monoiodothiophenes 2, 5, 7, 10, 13; General Procedure
General procedure: The thiophene derivative (1 mmol, 1 equiv) was dissolved in EtOH (2mL) at the temperature indicated in Tables 1-5. Then, NIS (1 or 1.1 equiv, see Tables 1-5) was added followed by PTSA (10% mol). The mixture was stirred for 10 min, then sat. Na2S2O3 (2 mL) was added. The mixture was diluted with EtOAc (3 mL). After phase separation, the organic phase was washed with 1 M Na2CO3 solution, dried (MgSO4), filtered through cotton, and evaporated to give the iodinated thiophene derivative.
With N-iodo-succinimide; toluene-4-sulfonic acid In ethanol at 50℃; for 0.166667h; Green chemistry; regioselective reaction;
Diiodothiophenes 3, 8, 11, 15; General Procedure
General procedure: The thiophene derivative (100 mg, 1 equiv) was dissolved in EtOH (4 mL) at the temperature indicated in Tables 1-5. Then, NIS (2.2 equiv, see Tables 1-5) was added followed by PTSA (10% mol). The mixture was stirred 10 min, then sat. Na2S2O3 (2 mL) was added. The mixture was diluted with EtOAc (3 mL). After phase separation, the organic phase was washed with 1 M Na2CO3 solution, dried (MgSO4), filtered through cotton, and evaporated to give the diiodinated thiophene derivative.
With dirhodium tetraacetate In dichloromethane at 0℃; for 1.5h; Molecular sieve; Inert atmosphere; diastereoselective reaction;
General procedure for the preparation of racemic products
General procedure: A mixture of Rh2(OAc)4 (0.002mmol), substituted alcohols 1 (0.3mmol), imine 3 (0.2mmol), 5 (10mol%), and 4 MS (100mg) in 2 mL of CH2Cl2 under an argon atmosphere was cooled to 0°C. Diazo compound 2 (0.3 mmol) in 1mL of CH2Cl2 was then added over 1h via a syringe pump. After completion of the addition, the reaction mixture was stirred for another 0.5 h, then filtrated and evaporated in vacuo to give the crude product. The crude products was purified by flash chromatography on silica gel (EtOAc/light petroleum ether=1:25∼1:10) to give the pure product.
With tert.-butylhydroperoxide; tetrabutyl phosphonium bromide In water; chlorobenzene at 80℃; for 3h; Sealed tube;
General procedure for the synthesis of benzoic anhydride (2a)
General procedure: In a 5 mL sealed tube, TBPB(30 mol%, 0.041 g), and TBHP (70 wt% in H2O, 1.0 mmol, 0.131 g) was added to a solution ofbenzyl alcohol 1a (0.4 mmol, 0.043 g) in chlorobenzene (1 mL). The resultant mixture washeated at 80 °C for 2.5 h. After completion of the reaction as was indicated by TLC monitoring,the reaction mixture was cooled to ambient temperature and saturated NaHCO3 (2 mL) wasadded. The product was extracted with ethyl acetate (2 × 3 mL). The combined organic phasewas dried over Na2SO4. The solvent was removed under the reduced pressure. The residue waspurified by column chromatography using n-hexane-EtOAc (15:1) as eluent to afford pureproduct 2a as a white solid.
tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-thienyl]azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: 3-hydroxymethyl-thiophene With n-butyllithium In tetrahydrofuran; hexane at -70 - -10℃; for 1.5h;
Stage #2: tert-butyl 3-oxoazetidine-1-carboxylate In tetrahydrofuran; hexane at -70 - 0℃;
1.1 Step 1 : tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-thienyl]azetidine-1-carboxylate
To a solution of 3-thiophenemethanol (10.0 g, 87.6 mmol, 1.00 equiv.) in THF (100 mL) at -70°C was added a solution of butyllithium (55.3 mL of a 1 .6 M solution in hexanes, 88.5 mmol, 1.01 equiv.) and stirred for 1 h. Additional butyllithium (52 mL of a 1.6 M solution in hexanes, 83 mmol, 0.95 equiv.) was added at this temperature. After 30 min, the mixture was allowed to warm to -10°C and recooled to -70°C. A solution of N-Boc-azetidinone ( 4.70 g, 85.8 mmol, 0.98 equiv.) in THF (15 mL) was added and the cooling bath was replaced with ice-cooling. The mixture was stirred at 0°C until completely dissolved. Saturated aqueous NH4CI solution was added and the pH of the mixture was adjusted to 6 by addition of 2 N HCI. Dilution with MTBE and extraction with EtOAc afforded an organic layer that was separated and washed with water and brine. Drying of the organic layer over Na2S04 and filtration gave a crude product which was chromatographed on silica gel to afford the title compound (16.6 g, 68%). 1H NMR (400 MHz, CDCb): δ = 1.41 (s, 9H), 4.20 (d, 2H), 4.30 (d, 2H), 4.65 (s, 2H), 6.91 (d, 1 H), 7.12 (d, 1 H).
With sodium hydride In tetrahydrofuran at 0 - 60℃; for 2h;
28.1 First step: 3-(methoxymethyl)thiophene (28B)
Sodium hydrogen at zero degrees(3.15 g, 131.3 mmol) was dissolved in tetrahydrofuran (40 mL).Adding backward solutionThiophene 3-ylmethanol(28A) (5g, 43.7mmol),After the addition, iodomethane (9.32 g, 65.69 mmol) was added dropwise, and the addition was completed.60 degree reaction for 2 h, cooling, adding water (30 mL),Extracted with ethyl acetate (50 mL×3), washed with water (50 mL×1), and combined organic phase.Wash with a saturated saline solution (50 mL × 1).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.Separation and purification by column chromatography (n-hexane / ethyl acetate = 10:1),Yellow liquid product 3-(methoxymethyl)thiophene(28B) (5.6 g, yield 100%).
With sodium hydride In tetrahydrofuran at 50℃; for 2h; Schlenk technique;
2-amino-4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-8-ol[ No CAS ]
4-(4-methylpiperazin-1-yl)-8-(thiophen-3-ylmethoxy)-5,6-dihydrobenzo[h]quinazolin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12.6 mg
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; for 1h;
3.b (b) 4-(4-methylpiperazin-1-yl)-8-(thiophen-3-ylmethoxy)-5, 6-dihydrobenzo[h]quinazolin-2-amine
The compound (30 mg, 0.096 mmol) obtained in Example 3 (a) was dissolved in THF (480 μL), and triphenylphosphine (50.5 mg, 0.193 mmol, 2.0 equivalents) and thiophen-3-yl methanol (13.6 μL, 0.145 mmol, 1.5 equivalents) were added, followed by stirring. Thereafter, diethyl azodicarboxylate (40% toluene solution, 2.2 mol/L) (88 μL, 0.193 mmol, 2.0 equivalents) was added, followed by stirring at room temperature for 1 hour. Water was added to the reaction liquid, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. This crude product was subjected to a silica gel column chromatography (eluent, chloroform : methanol) to obtain 12.6 mg of 4-(4-methylpiperazin-1-yl)-8-(thiophen-3-ylmethoxy)-5, 6-dihydrobenzo[h]quinazolin-2-amine.
With copper; potassium hydroxide In toluene at 180℃; for 48h; Inert atmosphere;
90%
With potassium <i>tert</i>-butylate; C17H19N5; molybdenum hexacarbonyl In toluene at 120℃; for 24h;
Synthetic Procedures for the Synthesis of Amines:
General procedure: A mixture ofaryl amines (0.5 mmol), benzyl alcohol (0.6 mmol), Mo(CO)6 (0.02mmol, 4 mol%), L1 (0.02 mmol, 4 mol%), and KOtBu (0.75 mmol) intoluene (2.0 mL) were allowed to react at 120 C for 24 h under a airatmosphere. The solvent was concentrated under vacuum, and theamines were isolated by flash chromatography.
78%
With dimanganese decacarbonyl; potassium <i>tert</i>-butylate In toluene at 20℃; for 48h; Inert atmosphere; Sealed tube;
63%
With cis-tetracarbonyl(1,1'-methylene-3,3'-dimethyl-4,4'-diimidazoline-2,2'-diylidene)molybdenum(0); potassium <i>tert</i>-butylate In hexane at 130℃; for 24h; Sealed tube;
With tetrabutylammomium bromide; potassium hydroxide at 20℃; for 10h;
Synthesis of S1, intermediate compound 3-[2-(2-methoxyethoxy)ethoxymethylthiophene
3-methanolthiophene (9.23 g, 80.8 mmol),Brominated diacryl ether (3) (23.2 g, 84.6 mmol),Tetrabutylammonium bromide (TBAB, 2.88 g, 8.08 mmol) and potassium hydroxide (10.1 g, 164 mmol) were placed in a three-necked flask and stirred at room temperature.After 10 h, then 4.32 g of water was added, the mixture was extracted several times with diethyl ether, and the extract was washed three times with water, then anhydrous sodium sulfateDry, filter and evaporate to remove the solvent. The crude product is purified by distillation (83 ° C / 0.1 mmHg).A whiteish yellow oily liquid was obtained
With triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 24.5h; Inert atmosphere;
1.1.3. General procedure for the Mitsunobu synthesis of amines 1
General procedure: To a stirred solution of the tert-butyl 4-hydroxybenzylcarbamate (5.0 mmol) in dry THF under nitrogen atmosphere, the corresponding benzyl alcohol (5.0 mmol) and PPh3 (5.0 mmol) were added at 0°C. Afterwards, DIAD or DEAD (5.0 mmol) was added dropwise for over 10 min. The reaction mixture was stirred at 0°C for 20 min and then at rt for 24 h. The solvent was removed under reduced pressure and the product was purified by flash chromatography (petroleum ether/EtOAc 5:1) giving the corresponding amines 1q-ad. The procedures above were used in order to further use the compound as free amine or its trifluoroacetic/hydrochloric salt.
Stage #1: 3-hydroxymethyl-thiophene With n-butyllithium In tetrahydrofuran; hexane at -5℃; for 0.5h; Inert atmosphere;
Stage #2: acetaldehyde In tetrahydrofuran; hexane at -5℃; for 0.5h;
1.1A Step A: Introduction of hydroxyalkyl group into thiophene-3-methanol(Synthesis of 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanol (Compound (2)))
Thiophene-3-methanol (11.2 g (98 mmol) of compound (1)) was dissolved in 970 ml of a tetrahydrofuran (THF) solution, which was then cooled at -5 ° C. under a nitrogen atmosphere.189 ml of n-butyllithium (1.55 M hexane solution,293 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes after the completion of the dropwise addition. 14.2 g (323 mmol) of acetaldehyde was added to the solution.And stirred at -5 ° C. for another 30 minutes,Saturated aqueous ammonium chloride solution was added to terminate the reaction.After separation, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue isPurification by silica gel column chromatography (hexane: ethyl acetate = 1: 1) gave a colorless oily substance.1- [3- (hydroxymethyl) -2-thienyl] -1-ethanol (compound (2),12.0 g, 77% yield).The physical properties of 1- [3- (hydroxymethyl) -2-thienyl] -1-ethanol are shown below.
With o-phenylenebis(diphenylphosphine); palladium diacetate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; <i>tert</i>-butyl alcohol at 100℃; for 12h; Sealed tube; Inert atmosphere;
General procedure
General procedure: A 15mL sealed tube containing phenylallene (0.5mmol) and 4-nitrotoluene (1.5mmol, 3 equiv), Pd(OAc)2 (2.5mol%), DPPBz (3mol%), Mo(CO)6 (0.5mmol, 1 equiv) and was evacuated and purged with nitrogen gas three times. Then, methanol (1mL) and DiPEA (2mmol, 4 equiv) was added to the reaction tube by syringe. The tube was sealed and the mixture was stirred at 100°C for 12h. After the reaction was completed, the reaction mixture was filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel to afford the corresponding product.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 12h; Reflux;
2.2a Synthesis of TTF-Th-1
TTF-acid (286 mg,0.5 mmol), DMAP (92 mg, 0.75 mmol), EDC (144 mg,0.75 mmol), and 3-Thienylmethanol (Th-1) (69 mg,0.6 mmol) was simultaneously dissolved into the freshdistilled DCM (30 mL). After 12 h stirring in refluxedtemperature, the mixture solution changed from dark yellow to dark red. Washed by 0.1 M HCl (50 mL), water (50 mL)and saturated brine (50 mL) in turn, the mixture wasdesiccated by anhydrous sodium sulfate overnight.Removing the solvent through the vacuum, the residuewas purified by column chromatography on silica gel(PE / DCM = 2:1), the orange oil (252 mg, 73.4%) wascollected in the second section.
With sodium carbonate In acetonitrile at 25℃; for 2h; Molecular sieve;
17 Example 17:
Add aniline (1.1 mmol), acetonitrile (2 mL), 3-thiophene methanol (1 mmol), sodium carbonate (1.5 mmol) to a 10 mL reaction tube, add molecular sieve HP-FeAlPO-5, and place the reaction mixture at 25 The reaction was carried out at for 120 min. After the reaction was completed, the target product XV was isolated by column chromatography with a yield of 84.6%.
3.2. Synthesis of monomer (MT) and alternating copolymer P(MT- alt -St)
In the first step of N-(4-(3-thienylmethylene)-oxycarbonyl phenyl)maleimide (MT) synthesis, 4-N-maleimidobenzoic acid was synthesized by condensation and cyclodehydration reaction of maleic anhydride with 4-aminobenzoic acid using the method adapted in the literature [ 23 , 24 ]. Then, 4-N-maleimidobenzoic acid was converted to its acid chloride in the presence of thionyl chloride in accordance with the procedure specified in the liter- ature [ 24 , 25 ]. Monomer MT was obtained by condensation reac- tion of synthesized acid chloride and 3-(2-hydroxyethyl)thiophene. For this purpose, 3-(2-hydroxyethyl)thiophene and triethyl amine mixture was added dropwise to the stoichiometric ratio of 4-N- maleimidobenzoic acid chloride in chloroform as in common pro- cedure in the literature [ 24 , 26 ]. After the reaction mixture was refluxed for 24 h, the mixture was washed with hydrochloric acid solution (1% w, w) and dried over calcium chloride. After removing the solvent under vacuum, the remaining solid was washed with hot methyl alcohol and crystallized using THF/hexane mixture fol- lowingly. The resulting product was dried under vacuum. Melting point: 85 °C Yield: 45%, FTIR (cm -1 ): 3020, 3110, 2900, 1767, 1710, 1690, 1270, 1210, 1365, 1132, 854, 762, 685; 1 H NMR (DMSO-ppm): 8.10-8.05 (d, 2H); 7.71-7.46 (m, 5H); 7.27-7.23 (s, 2H); 5.36 (s, 2H)
1,2-bis(thiophenemethoxydimethylsilyl)ethane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;
P.1 Synthesis Example
Triethylamine (9.4 ml, 0.0674 mol) was mixed with 3-thiophenemethanol (5.21 ml, 0.0553 mol) diluted with dichloromethane (15 ml) under a nitrogen atmosphere of 1,2-bis(thiophenemethoxydimethylsilyl)ethane. After the temperature was lowered to 0° C., 1,2-bis(chlorodimethylsilyl)ethane (5.81 g, 0.0270 mol) diluted with dichloromethane was added dropwise to the mixture, and then stirred at room temperature for 3 hours. Then, the stirred resultant was washed with water to remove triethylamine hydrochloride. The resultant was purified by column chromatography (EtOAc:Hexane=1:3) to obtain Compound 1 which is a transparent yellow liquid. (7.5 g, 75%); 1H NMR (400 MHz, CDCl3): δ 7.27 (s, 2H), 7.15 (d, 2H), 7.04 (d, 2H), 4.68 (s, 4H), 0.52 (s, 4H), 0.11 (s, 12H); 13C NMR (100 MHz, CDCl3): δ 7.27 (s, 2H), 7.15 (d, 2H), 7.04 (d, 2H), 4.68 (s, 4H), 0
2-fluoro-8-(thiophen-3-ylmethoxy)phenazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With diethyl diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 18h; Inert atmosphere;
Intermediate 24 2-fluoro-8-(thioohen-3-ylmethoxy)ohenazine
To intermediate 22 (200 mg, 0.934 mmol), triphenylphosphine (367 mg, 1.401 mmol) and thiophen-3-ylmethanol (0.106 ml, 1.120 mmol) in dry THF under nitrogen and at 0°C was added dropwise diethyl (E)-diazene-l ,2-dicarboxylate (0.238 ml, 1.401 mmol). After 18 hours at RT solvent was evaporated, to the remaining residue was then added DCM (25 ml_) and water (50 ml_). After prolonged mixing, the organic layer was separated, dried over anhydrous sodium sulphate and evaporated. The residue was purified by normal phase column chromatography on a Biotage HP-Sil 50g column eluting initially for 2CV with cHex/DCM 1 :1 and then changing to DCM only over 8CV and then eluting with DCM only. Yield 120mg (43%), yellow solid. (0286) ESI+ m/z 311 [M+H]
thiophen-3-ylmethyl 6-(4-ethoxyphenyl)picolinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 19h; Schlenk technique; Inert atmosphere;
197 General procedure D (DCC-mediated esterification)
General procedure: A 15 mL Schlenk-tube with magnetic stirring bar was evacuated and purged with Ar (repeated three times). The Schlenk tube was charged with a mixture of 71.7 mg (0.295 mmol, 1.0 eq) 6- (4-ethoxyphenyl)picoinic acid (see NG-384) and 3.0 eq of the corresponding alcohol in 1.5 mL CH2CI2 abs. The suspension was cooled to 0 °C and DMAP (3.6 mg, 29 pmol, 0.1 eq), followed by 84.8 mg (0.442 mmol, 1.5 eq) of EDC hydrochloride were added. The ice bath was removed and the pale-yellow solution was left to spontaneous warmup overnight (reaction control via TLC). The reaction mixture was diluted with 4.5 mL CH2CI2, and washed with H2O (3 x 3 mL). The phases were separated and the org. phase was dried over Na2SC>4, filtered, and the solvent was removed under reduced pressure. The crude product was purified via flash column chromatography (Si02, cyclohexane/EtOAc).
With ethylenediaminetetraacetic acid; cesium chloride; sulfur; sodium hydroxide at 60℃; for 10h; Inert atmosphere;
30
Under nitrogen protection, add 3-thiophene methanol (0.45g, 3.9mmol), sublimed sulfur (0.25g, 7.8mmol), sodium hydroxide (0.31g, 7.8mmol) to 4mL N,N-dimethylformamide Then, cesium chloride (0.20g, 1.17mmol) and ethylenediaminetetraacetic acid (0.35g, 1.17mmol) were added, and the reaction was stirred for 10 hours at a reaction temperature of 60°C.After the reaction, 4mL deionized water was added to the resulting reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (4mL×3) to obtain the aqueous phase and the organic phase respectively, and then use saturated brine (4mL×3) The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel (100-200 mesh) column chromatography, using a mixture of ethyl acetate/petroleum ether (1:7 volume ratio) as the elution The amount of the eluent is 280ml. Collect all the eluents and concentrate them by rotary evaporation; 0.54g of brown-yellow oil is obtained, which is N,N-dimethyl-3-thiothiophene carboxamide detected by NMR. , The yield is 81.2%.
thiophen-3-ylmethyl thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 63%
2: 7%
3: 7%
With aluminum (III) chloride; triethylamine In dichloromethane at 20℃; for 48h;
General experimental methods for AlCl3-catalyzedCannizzaro/Tishchenko reactions
General procedure: A mixture of AlCl3(0.5 mmol), the aldehyde (10 mmol),and triethylamine (5 mmol) was added to 2 cm3of driedCH2Cl2and stirred for 2 days at room temperature underargon atmosphere until the aldehyde was completelyconsumed. The reaction progress was probed by TLCand GC/MS (Agilent 6890 (GC)/5972A (MS)). The reactionmixture was then filtered through Whatman filterpaper (grade 2), and treated with sodium bicarbonatesolution, followed by isolating the organic phase via aseparatory funnel. The aqueous phase washed severaltimes with CH2Cl2to make sure that all organic materialsextracted. Then, the organic phase was dried usingsodium sulfate and subsequently analyzed by GC/MSand 1H NMR, and validated using melting or boilingpoint of the product.
1: 57%
2: 57%
3: 6%
With aluminum (III) chloride; triethylamine In dichloromethane at 20℃; for 48h;
General experimental methods for AlCl3-catalyzedCannizzaro/Tishchenko reactions
General procedure: A mixture of AlCl3(0.5 mmol), the aldehyde (10 mmol),and triethylamine (5 mmol) was added to 2 cm3of driedCH2Cl2and stirred for 2 days at room temperature underargon atmosphere until the aldehyde was completelyconsumed. The reaction progress was probed by TLCand GC/MS (Agilent 6890 (GC)/5972A (MS)). The reactionmixture was then filtered through Whatman filterpaper (grade 2), and treated with sodium bicarbonatesolution, followed by isolating the organic phase via aseparatory funnel. The aqueous phase washed severaltimes with CH2Cl2to make sure that all organic materialsextracted. Then, the organic phase was dried usingsodium sulfate and subsequently analyzed by GC/MSand 1H NMR, and validated using melting or boilingpoint of the product.
S-methyl O-(thiophen-3-ylmethyl) carbonodithioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: 3-hydroxymethyl-thiophene With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere;
Stage #2: carbon disulfide In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere;
Stage #3: methyl iodide In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere;
thiophen-3-ylmethyl (S)-5-fluoro-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-4-oxopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;
39 Example 39: Thiophen-3-ylmethyl (S)-5-fluoro-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-4-oxopentanoate
The compound of Formula 2 (500 mg, 1.20 mmol) was reacted with EDCI (277 mg, 1.44 mmol), DMAP (37 mg, 0.24 mmol) and thiophen-3-ylmethanol (550 mg, 4.81 mmol) in dichloromethane (4 mL) under room temperature condition for 12 hours. After adding water, the reaction mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated and purified by the use of MPLC to obtain the title compound (243 mg, 40%). 1H NMR (CDCl3) δ 9.14 (t, 1H), 8.54 (d, 1H), 7.87 ∼ 7.64 (m, 4H), 7.37 ∼ 7.17 (m, 4H), 5.15 ∼ 4.90 (m, 4H), 4.01 (dd, 1H), 3.78 (dd, 1H), 3.14 ∼ 2.87(m, 2H), 2.40 ∼ 2.33(m, 1H), 1.09 ∼ 1.02 (m, 6H)
40%
With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;
39 Example 39: Thiophen-3-ylmethyl (S)-5-fluoro-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-4-oxopentanoate
The compound of Formula 2 (500 mg, 1.20 mmol) was reacted with EDCI (277 mg, 1.44 mmol), DMAP (37 mg, 0.24 mmol) and thiophen-3-ylmethanol (550 mg, 4.81 mmol) in dichloromethane (4 mL) under room temperature condition for 12 hours. After adding water, the reaction mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated and purified by the use of MPLC to obtain the title compound (243 mg, 40%). 1H NMR (CDCl3) δ 9.14 (t, 1H), 8.54 (d, 1H), 7.87 ∼ 7.64 (m, 4H), 7.37 ∼ 7.17 (m, 4H), 5.15 ∼ 4.90 (m, 4H), 4.01 (dd, 1H), 3.78 (dd, 1H), 3.14 ∼ 2.87(m, 2H), 2.40 ∼ 2.33(m, 1H), 1.09 ∼ 1.02 (m, 6H)
40%
With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;
39 Example 39: Thiophen-3-ylmethyl (S)-5-fluoro-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4,5-dihydroisoxazole-5-carboxamido)-4-oxopentanoate
The compound of Formula 2 (500 mg, 1.20 mmol) was reacted with EDCI (277 mg, 1.44 mmol), DMAP (37 mg, 0.24 mmol) and thiophen-3-ylmethanol (550 mg, 4.81 mmol) in dichloromethane (4 mL) under room temperature condition for 12 hours. After adding water, the reaction mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated and purified by the use of MPLC to obtain the title compound (243 mg, 40%). 1H NMR (CDCl3) δ 9.14 (t, 1H), 8.54 (d, 1H), 7.87 ∼ 7.64 (m, 4H), 7.37 ∼ 7.17 (m, 4H), 5.15 ∼ 4.90 (m, 4H), 4.01 (dd, 1H), 3.78 (dd, 1H), 3.14 ∼ 2.87(m, 2H), 2.40 ∼ 2.33(m, 1H), 1.09 ∼ 1.02 (m, 6H)
1-(N-methyl-pyrrol-2-yl)-3-(thiophen-3-yl)propan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium-t-butoxide In 1,4-dioxane at 140℃; for 12h; Schlenk technique;
35 Example 35
The N-alkyl-substituted pyrrolone compound in this embodiment is 1-(N-methyl-pyrrol-2-yl)-3-(thiophen-3-yl)propan-1-one, For the preparation route of the N-alkyl-substituted pyrrolone compounds of the present embodiment, reference may be made to example 1, and the following steps are specifically adopted: 1) Take 0.2 mmol of 1-methyl-2-acetylpyrrole, 0.4 mmol of 3-thiophenemethanol and 0.2 mmol of potassium tert-butoxide, add 1 ml of 1,4-dioxane to prepare a mixture, and set the mixture to In a 5ml schlenk tube, put it in a heating module at 140 °C, react for 12 h, and then cool to room temperature to obtain a reaction solution; 2) Concentrate the reaction solution to obtain a concentrate, use the mixed solvent composed of petroleum ether and ethyl acetate by volume 5:1 as a developing solvent, and use silica gel as an adsorbent, carry out TLC separation, and obtain 26mg target product. The yield of the target product in this example is 60%.
In toluene at 100 - 140℃; for 24h; Schlenk technique;
23
(1) Take 3-thiophenemethanol 0.5mmol, benzoylnitrile 0.2mmol, add 0.5 ~ 1ml of toluene to make a mixture, the mixture is placed in a 5ml Schlenk tube, placed in an oil bath of 100 ~ 140 ° C for heating, after the reaction for 24h, cooled to room temperature, to give the reaction liquid;
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