* 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 ruthenium-carbon composite In ethanol at 20℃; for 15 h;
5.068 g (50 mmol) of 2-thiophenecarboxaldehyde (I-10) and 0.5 g (5 molar amount of Ru (I-10) of Ru/C catalyst) were added to the reaction flask.3.303 g (50 mmol) of malononitrile II and 100 mL of ethanol were stirred at room temperature for 15 h. The following procedure was the same as in Example 1.Finally, 7.769 g of solid was obtained, the yield was 97.0percent, and the purity of GC-MS was 98.0percent.
94%
With copolymer of allylamine and epichlorohydrin (11 molpercent) In water at 20℃; for 0.5 h; Green chemistry
General procedure: A 10 mL round-bottomed flask was charged with carbonyl compound (1 mmol), active methylene compound (1 mmol), S-4 (12 mg and 20 molpercent of the substrates), and water (3 mL). The reaction mixture was stirred at room temperature. The suspension was stirred at room temperature for the lengths of time shown in Table 4. The reaction progress was monitored by thin layer chromatography usingn-hexane–EtOAc (5:1) as eluent. After completing the reaction, the reaction mixture solidified in the round-bottomed flask. The solids were then dissolved in hot ethanol (30 mL). The catalyst was removed by filtration and washed with ethanol. The solid product was obtained after the ethanol was concentrated in vacuo.
91%
With 1,4-diaza-bicyclo[2.2.2]octane In water at 20℃; for 0.0166667 h; Green chemistry
General procedure: A mixture of 1a (232 mg, 2.0 mmol) and 2a (132 mg, 2.0 mmol) in H2O (0.5 mL) and DABCO (224 mg, 2.0mmol) was stirred at room temperature for 3 min until TLC showed complete disappearance of the starting materials. The mixture was extracted by EtOAc (5 mL) and the organic layer was washed with saturated solution of NaHCO3 and brine. The organic layer was dried over Na2SO4 . Product 3aa was obtained by evaporation of the volatile portion of the organic layer and was puried by recrystallization from EtOAc/hexane mixture. Product 3aa was obtained in 80percent yield (262 mg). The product was identied based on its physical and spectral characteristics. The remaining compounds 3ab-3db were synthesized in a similar manner.
91%
at 65℃; for 2 h;
General procedure: The mixture of aldehyde (10.0 mmol), malononitrile (15.0 mmol) was stirred in water (20 mL) at 65 °C for 2 h. Then after the reaction system was cooled to room temperature, the precipitate formed was filtered and washed with water to give the crude production. Further purication was achieved by recrystallization from methanol or ethanol to afford the pure product, except 2m which was isolated through column chromatograph (petroleum ether/ ethyl acetate).
88%
at 20℃; for 0.25 h;
General procedure: Benzaldehyde (1 mmol) and ethyl cyanoacetate (1 mmol) were mixedtogether in the presence of 20 molpercent DES and then stirred at roomtemperature. Upon completion of the reaction (monitored by TLC,solvent system: ethyl acetate and petroleum ether), water (2 mL) wasadded to the mixture. The product was filtered and the solid, was driedin vacuo at 60 °C for 10 h. This gave the desired product in high puritythat did not need further purification. The deep eutectic solvent wasrecovered by removing the aqueous layer using a rotary evaporator.All the products had the E‑geometry exclusively and no Z‑geometricalisomers were detected in the NMR.
87%
With Fe3O4(at)SiO2-N1-(3-trimethoxysilylpropyl)diethylenetriamine nanoparticles catalyst In toluene at 75℃; for 0.166667 h;
General procedure: A mixture of the aldehyde/ketone (0.1 mmol), compound of active methylene group (0.1 mmol), catalyst (5 mg)and solvent (toluene or water, 0.4 mL) was added in a glass tube and mechanically stirred at 75 °C. The reaction progress was monitored by Gas Cromatography with FID detector. After the completion of this reaction, the catalyst was removed by magnetic separation. For there actions in toluene, the mixture was purified by using column chromatography, and for the reactions in water, the product was precipitated with cool water, filtrated and dried under low pressure. All the products were characterized by 1H NMR, and 13C NMR.
85%
at 60℃; for 0.5 h; Microwave irradiation; Green chemistry
General procedure: A mixture of aldehyde (1.0 mmol), malononitrile (1.1 mmol) in methanol (3 mL) was put in the microwave reactor for 30 min at 60°C, 20W. The reaction progress was monitored by TLC. At end of the reaction, the solution was filtered out and washed with water (3×5mL). The product was recrystallized in a mixture of hexane–dichloromethane (1:1) to yield the pure compound.
84%
With iron-doped single walled carbon nanotubes In neat (no solvent) at 80℃; for 4 h; Green chemistry
General procedure: The required carbonyl compound (1 mmol) and malononitrile (1 mmol) were added to Fe/SWCNTs (0.05 g) and the mixture was heated in an oil bath at 80 °C for a certain period of time as required to complete the reaction (monitored by TLC against malononitrile with CH2Cl2 as eluent and KMnO4 as stain). The solid mass was then eluted with EtOAc (4×10 mL) and centrifuged to separate the catalyst. Evaporation of solvent furnished the corresponding practically pure product.
80%
With sodium hydrogencarbonate In ethanol at 20℃; for 2 h;
General procedure: A mixture of thiophene-2-carboxaldehyde (0.560 g, 5 mmol),malononitrile (0.330 g, 5 mmol), and sodium bicarbonate (0.055 g, 0.5 mmol) was dissolved inethanol (10 mL) and stirred at room temperature for 2 h. Ethanol was then removed under lowpressure and the residue was dissolved in a dichloromethane/pentane solution (1/10). An orangeprecipitate appears and, after filtration, product 1 was obtained in 80percent yield
55%
at 75℃; for 0.25 h;
General procedure: The aldehyde (0.2 mmol) and the compound with theactive methylene group (0.2 mmol) were added to a testtube followed by the addition of the solvent (ethanol/water 3:7, 0.8 mL). The system was maintained at 80 °Cand magnetically stirred until the reaction completed.The reaction progress was monitored by thin layerchromatography (TLC). The products were obtainedby precipitation with cooled water or by extractionwith ethyl acetate. The extract was purified by columnchromatography. All the products were characterizedby Fourier transform infrared spectroscopy (FTIR),gas‑chromatography mass spectrometry (GC-MS), 1Hand 13C nuclear magnetic resonance (NMR).
Reference：
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[2] Tetrahedron Letters, 1982, vol. 23, # 47, p. 4927 - 4928
[3] Green Chemistry, 2010, vol. 12, # 3, p. 514 - 517
[4] Patent: CN108383755, 2018, A, . Location in patent: Paragraph 0076-0079
[5] European Journal of Organic Chemistry, 2004, # 3, p. 546 - 551
[6] Applied Catalysis A: General, 2014, vol. 475, p. 140 - 146
[7] Chemistry Letters, 1998, # 8, p. 773 - 774
[8] Chinese Chemical Letters, 2014, vol. 25, # 8, p. 1141 - 1144
[9] Australian Journal of Chemistry, 2013, vol. 66, # 4, p. 500 - 504
[10] RSC Advances, 2015, vol. 5, # 99, p. 81415 - 81428
[11] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2801 - 2821
[12] European Journal of Organic Chemistry, 2006, # 16, p. 3767 - 3770
[13] Archiv der Pharmazie, 2004, vol. 337, # 9, p. 482 - 485
[14] Turkish Journal of Chemistry, 2014, vol. 38, # 4, p. 650 - 660
[15] Tetrahedron, 2018, vol. 74, # 29, p. 3996 - 4004
[16] Helvetica Chimica Acta, 2008, vol. 91, # 4, p. 715 - 724
[17] Crystal Growth and Design, 2016, vol. 16, # 5, p. 2874 - 2886
[18] Chinese Journal of Chemistry, 2014, vol. 32, # 4, p. 343 - 348
[19] Journal of Chemical Research, 2014, vol. 38, # 3, p. 186 - 188
[20] RSC Advances, 2017, vol. 7, # 76, p. 48214 - 48221
[21] Australian Journal of Chemistry, 2008, vol. 61, # 9, p. 700 - 703
[22] Journal of the Iranian Chemical Society, 2013, vol. 10, # 1, p. 141 - 149
[23] Catalysis Letters, 2017, vol. 147, # 1, p. 167 - 180
[24] Asian Journal of Chemistry, 2015, vol. 27, # 6, p. 2145 - 2148
[25] Tetrahedron, 2016, vol. 72, # 46, p. 7317 - 7322
[26] Tetrahedron, 2013, vol. 69, # 23, p. 4708 - 4724
[27] Synthetic Communications, 2004, vol. 34, # 16, p. 2893 - 2901
[28] Tetrahedron Letters, 2012, vol. 53, # 50, p. 6801 - 6805
[29] Beilstein Journal of Organic Chemistry, 2009, vol. 5,
[30] Chemistry - A European Journal, 2015, vol. 21, # 4, p. 1420 - 1424
[31] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 7, p. 1382 - 1387
[32] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4449 - 4455
[33] Journal of Organic Chemistry, 1949, vol. 14, p. 790,795
[34] Journal of the American Chemical Society, 1949, vol. 71, p. 2949
[35] Molecular Crystals and Liquid Crystals (1969-1991), 1990, vol. 182, p. 71 - 79
[36] Bulletin de la Societe Chimique de France, 1990, p. 129 - 131
[37] Tetrahedron, 1989, vol. 45, # 13, p. 4103 - 4112
[38] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 10, p. 1180 - 1189
[39] Heterocyclic Communications, 2002, vol. 8, # 6, p. 587 - 592
[40] Synthesis, 2008, # 2, p. 279 - 285
[41] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 5, p. 832 - 836
[42] Tetrahedron Asymmetry, 2010, vol. 21, # 11-12, p. 1569 - 1573
[43] Chemical Communications, 2011, vol. 47, # 3, p. 1045 - 1047
[44] Synlett, 2010, # 19, p. 2847 - 2852
[45] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 599 - 601
[46] Journal of Carbohydrate Chemistry, 2011, vol. 30, # 3, p. 132 - 146
[47] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5195 - 5198
[48] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5272 - 5278
[49] Monatshefte fur Chemie, 2012, vol. 143, # 8, p. 1175 - 1185
[50] Synthetic Communications, 2013, vol. 43, # 4, p. 465 - 475
[51] Journal of the Korean Chemical Society, 2012, vol. 56, # 6, p. 712 - 715
[52] Molecules, 2013, vol. 18, # 2, p. 2212 - 2221
[53] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 291 - 300
[54] Synlett, 2014, vol. 25, # 3, p. 359 - 364
[55] Asian Journal of Chemistry, 2014, vol. 26, # 13, p. 3896 - 3902
[56] Angewandte Chemie - International Edition, 2015, vol. 54, # 18, p. 5470 - 5473[57] Angew. Chem., 2015, vol. 54-127, # 18, p. 5560 - 5563,4
[58] Chemistry - A European Journal, 2015, vol. 21, # 42, p. 14862 - 14870
[59] Crystal Growth and Design, 2015, vol. 15, # 8, p. 4110 - 4122
[60] New Journal of Chemistry, 2016, vol. 40, # 2, p. 1535 - 1546
[61] Research on Chemical Intermediates, 2016, vol. 42, # 4, p. 2919 - 2935
[62] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1598 - 1603
[63] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 3, p. 1880 - 1886
[64] Tetrahedron Letters, 2017, vol. 58, # 29, p. 2865 - 2871
[65] Applied Organometallic Chemistry, 2017, vol. 31, # 7,
[66] Journal of Molecular Structure, 2017, vol. 1147, p. 682 - 696
[67] Dalton Transactions, 2018, vol. 47, # 9, p. 3059 - 3067
[68] Dalton Transactions, 2018, vol. 47, # 29, p. 9742 - 9754
[69] Synthetic Communications, 2018, vol. 48, # 17, p. 2169 - 2176
[70] Molecules, 2018, vol. 23, # 10,
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 972 - 986
19
[ 7647-01-0 ]
[ 850638-58-3 ]
[ 98-03-3 ]
[ 58255-18-8 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 3922,3923
20
[ 98-03-3 ]
[ 5402-55-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 32, p. 7009 - 7019
21
[ 636-72-6 ]
[ 98-03-3 ]
[ 7283-96-7 ]
Yield
Reaction Conditions
Operation in experiment
79 %Chromat.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite pentahydrate; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane at 5℃; for 3 h;
General procedure: NaOCl5H2O crystals (11.0e14.0 mmol) were added in one portion to a mixture of Bu4NHSO4 (0.170 g, 0.50 mmol), TEMPO(15.6 g, 0.10 mmol), alcohols (10.0 mmol), and 0.2 g of PCBTF (aninternal standard) in dichloromethane (15 or 30 mL) at 5 or 15 C.After stirring for an appropriate time, 0.5 mL of the organic layerwas added to 1 mL of CH2Cl2 for GC analysis. GCeMS analyses of theproducts were identical with authentic samples.
Reference：
[1] Synthesis, 1995, # 3, p. 248 - 250
[2] Synthesis, 1995, # 3, p. 248 - 250
[3] Synthesis, 1995, # 3, p. 248 - 250
23
[ 98-03-3 ]
[ 7283-96-7 ]
[ 67482-49-9 ]
[ 67482-50-2 ]
[ 57500-51-3 ]
Reference：
[1] Organic Preparations and Procedures International, 1995, vol. 27, # 2, p. 233 - 236
[2] Organic Preparations and Procedures International, 1995, vol. 27, # 2, p. 233 - 236
24
[ 98-03-3 ]
[ 4701-17-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-Bromosuccinimide In chloroform at 20℃;
2.1.1 Synthesis of 5-bromo-2-thiophenecarbaldehyde To a solution of 2-thiophenecarboxaldehyde (6.0 g, 53.5 mol) in anhydrous CHCl3 (125 mL), N-bromosuccinimide (10.4 g, 58.9 mmol) was slowly added, and then the reaction mixture was stirred for overnight at room temperature. The reaction mixture was extracted with CHCl3, and the organic phase was washed with deionized water, dried over Na2SO4, filtered, and evaporated to dryness to give the crude product. Column chromatography was performed on silica gel using CHCl3 as the eluent, which affords the pure product as a colorless oil (10.0 g, 98percent). 1H NMR (400 MHz, CDCl3): δ 7.20 (d, H, J = 4.0 Hz), 7.53 (d, H, J = 8.0 Hz), 9.79 (s, H).
35%
With acetic acid In chloroform at 0 - 20℃; for 13 h; Darkness
NBS (1.5 eq, 5.8g, 33 mmol) was added to a solution of thiophene-2-carbaldehyde (1.0 eq., 2 mL, 22 mmol) in a mixture of chloroform/AcOH (10:1, 22 mL) at 0 C in the absence of light. The reaction mixture was stirred at 0 C for 1h. Then the mixture was allowed to warm to rt for 12 hours. The reaction was quenched with an aqueous sat. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and the solvents were evaporated in vacuo. The crude product was purified (FCC, SiO2, 0-100 percent EtOAc in heptane) to provide the title compound (1.4 g, 35percent).1H NMR (300 MHz, CDCl3) δ 9.76 (s, 1H), 7.51 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H).
Reference：
[1] Physica B: Condensed Matter, 2017, vol. 519, p. 53 - 58
[2] Tetrahedron, 2007, vol. 63, # 37, p. 9188 - 9194
[3] Tetrahedron Letters, 2005, vol. 46, # 12, p. 1989 - 1992
[4] Patent: WO2018/67786, 2018, A1, . Location in patent: Page/Page column 134; 135
[5] Journal of the Chemical Society, 1958, p. 1721
[6] Arkiv foer Kemi, 1955, vol. 8, p. 87
[7] Journal of Materials Chemistry, 2000, vol. 10, # 9, p. 2069 - 2080
[8] Macromolecules, 2011, vol. 44, # 13, p. 5155 - 5167
[9] Molecular Crystals and Liquid Crystals, 2014, vol. 599, # 1, p. 157 - 162
25
[ 636-72-6 ]
[ 98-03-3 ]
[ 4701-17-1 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 13, p. 4112 - 4113
Reference：
[1] New Journal of Chemistry, 2002, vol. 26, # 4, p. 373 - 375
[2] New Journal of Chemistry, 2002, vol. 26, # 4, p. 373 - 375
32
[ 96-43-5 ]
[ 121-43-7 ]
[ 188290-36-0 ]
[ 98-03-3 ]
[ 6165-68-0 ]
Reference：
[1] New Journal of Chemistry, 2002, vol. 26, # 4, p. 373 - 375
33
[ 98-03-3 ]
[ 75-25-2 ]
[ 75-08-1 ]
[ 1918-77-0 ]
Yield
Reaction Conditions
Operation in experiment
58%
With potassium hydroxide In diethyl ether; water; dimethyl sulfoxide
EXAMPLE 2 To a 50percent dimethyl sulfoxide aqueous solution (50 ml) were added ethyl mercaptan (3.5 ml, 47 mmoles), an aqueous solution (10 ml) of potassium hydroxide (0.6 g, 10 mmoles), a solution of 2-thienyl aldehyde (1.12 g, 10 mmoles) in dimethyl sulfoxide (10 ml) and then bromoform (3.04 g, 12.2 mmoles) in an argon atmosphere under ice-water cooling with stirring, and the mixture was stirred for 1 hour. Potassium hydroxide (3.04 g, 46 mmoles) dissolved in a 50percent dimethyl sulfoxide aqueous solution (30 ml) was added dropwise to the reaction mixture. After completion of the addition, the mixture was stirred for 2 hours and then at room temperature for 3 hours. Water and diethyl ether were added to the reaction mixture and the ether-soluble material was removed. The aqueous layer was rendered acidic with dilute hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to afford 0.82 g of thienylacetic acid. Yield 58percent. m.p.: 60°-62° C. (Lit. 62°-64° C.) NMR (CDCl3, TMS): δ3.8 (s, 2H), 6.80-7.23 (m, 3H), 11.2 (bs, 1H).
Reference：
[1] Patent: US4268442, 1981, A,
34
[ 98-03-3 ]
[ 1918-77-0 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 20, p. 3566 - 3569
35
[ 98-03-3 ]
[ 4521-33-9 ]
[ 57500-53-5 ]
Yield
Reaction Conditions
Operation in experiment
40%
at -10℃; for 0.0833333 h;
Example 1a; (S)-1-(5-((2-amιnopropanamιdo)methyl)thιophen-3-yl)-N-(2-methoxybenzyl)-3- (trιfluoromethyl)-i H-pyrazole-5-carboxamιde (9a); Step 1 4-nιtrothιophene-2-carbaldehyde (1); [0170] A mixture of fuming HNO3 (4 0 ml_) in cone H2SO4 (3 1 ml_) was added to a solution of thιophene-2-carbaldehyde (2 O g, 17 8 mmol) in cone H2SO4 (4 7 mL) cooled in an ice-salt bath according to the procedure of Pierre Foumari and Jean Paul Chane (Bull Soc Chum Fr ,1963, 479-484) After completion of addition the mixture was stirred for 5 mm, then ice was added, and the mixture was extracted with ether The ether extracts were washed with sat'dNaHCO3, then with brine, dried over MgSO4, filtered and concentrated giving brown oilProton NMR of the crude showed a mixture of the two regioisomers in a ratio of almost 40 60 for 4-nιtrothιophene-2-carbaldehyde and 5-nιtrothιophene-2-carbaldehyde respectively The mixture was separated by column chromatography eluting with 30-50percent DCM/hexanes 4-Nιtrothιophene-2-carbaldehyde was obtained in 40percent yield as a light yellow solid1H NMR (CDCI3) δ(ppm) 9 95(s, 1 H), 8 63 (s, 1 H), 8 27 (s, 1 H)
Reference：
[1] Journal of Chemical Research, Miniprint, 1997, # 9, p. 2001 - 2013
[2] Patent: WO2008/104077, 2008, A1, . Location in patent: Page/Page column 46
[3] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 1, p. 162 - 165
[4] Bulletin de la Societe Chimique de France, 1963, p. 479 - 484
[5] Journal of the American Chemical Society, 1954, vol. 76, p. 1378
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 577
[7] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 8088 - 8094
36
[ 98-03-3 ]
[ 4521-33-9 ]
[ 57500-53-5 ]
[ 58963-75-0 ]
Reference：
[1] Synthesis, 2006, # 8, p. 1295 - 1300
37
[ 98-03-3 ]
[ 4521-33-9 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 2, p. 127 - 130[2] Khimiya Geterotsiklicheskikh Soedinenii, 1982, vol. 18, # 2, p. 167 - 170
38
[ 98-03-3 ]
[ 7664-93-9 ]
[ 7697-37-2 ]
[ 4521-33-9 ]
[ 57500-53-5 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1963, p. 479 - 484
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1956, vol. 243, p. 61,62[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 246, p. 2003,2004
[4] Journal of the American Chemical Society, 1954, vol. 76, p. 1378
[5] Journal of the American Chemical Society, 1955, vol. 77, p. 577
[6] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 246, p. 2003[7] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1959, vol. 248, p. 1182
39
[ 98-03-3 ]
[ 7697-37-2 ]
[ 108-24-7 ]
[ 64-19-7 ]
[ 4521-33-9 ]
[ 57500-53-5 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1963, p. 479 - 484
[2] Journal of the Chemical Society, 1958, p. 1721
[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1956, vol. 243, p. 61,62[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 246, p. 2003,2004
[5] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 246, p. 2003[6] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1959, vol. 248, p. 1182
40
[ 98-03-3 ]
[ 16689-02-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1955, p. 1614
[2] Bulletin de la Societe Chimique de France, 1963, p. 479 - 484
Reference：
[1] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 364, p. 303 - 308
43
[ 98-03-3 ]
[ 637-81-0 ]
[ 46193-76-4 ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: With sodium ethanolate In ethanol at -10 - 20℃; for 4 h; Inert atmosphere Stage #2: for 1 h; Reflux
General procedure: A solution of sodium ethoxide (8.17 g, 120 mmol, 20 wt percent in ethanol) was added dropwise into a mixture of 3a (2.8 mL, 30 mmol) and ethyl azidoacetate (15.4 g, 120 mmol) in anhydrous ethanol (50 mL) at -10 °C and stirred for 4 h at room temperature. Excess amount of saturated aqueous NH4Cl solution was added. The mixture was extracted with ethyl acetate (2*80 mL), the organic layer was washed with brine (2*60 mL), and dried over anhydrous Na2SO4. After removing the solvents by evaporation, the resulting residue was dissolved in toluene (30 mL) and heated to reflux for 1 h. After cooling, the solvent was evaporated. The residue was separated by column chromatography (n-hexane/CH2Cl2=2:1) to afford 4a as white solid (2.93 g, 50percent). 1H NMR (400 MHz, CDCl3) δ 9.26 (br s, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.14 (d, J=0.8 Hz, 1H), 6.96 (dd, J=5.2, J=0.8 Hz, 1H), 4.38 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 141.3, 129.4, 127.1, 124.8, 111.1, 107.5, 60.7, 14.5.
5%
With sodium ethanolate In ethanol at 0 - 20℃; for 14 h;
To a solution of thiophene-2-carbaldehyde (1.10 mL, 11.7 mmol) and ethyl azidoacetate (1.4 mL, 11.7 mmol) in EtOH (35 mL) cooled to 0° C. was added NaOEt (1.0 g, 14.7 mmol) in one portion. The mixture was allowed to reach room temperature over 14 h and was then poured into water (400 mL) and extracted with CH2Cl2 (3.x.50 mL). The combined organics were washed with water and brine, dried over Na2SO4, and concentrated. The residue was taken up in xylenes (10 mL), and the resulting solution was refluxed for 1 h. The solution was cooled and then loaded directly onto silica gel and purified (35 g SiO2, 10-20percent EtOAc/hexanes) to reveal 0.12 g (5percent) of a yellowish solid. 1H NMR (400 MHz, CDCl3): 9.06 (br s, 1H), 7.33 (d, J=5.3 Hz, 1H), 7.15-7.14 (m, 1H), 6.96 (dd, J=5.3, 0.8 Hz, 1H), 4.37 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.3Hz, 3H). 13C NMR (100 MHz, CDCl3): 161.3, 140.9, 129.2, 126.9, 124.6, 110.9, 107.3, 60.4, 14.2.
Reference：
[1] Russian Journal of Applied Chemistry, 2010, vol. 83, # 8, p. 1440 - 1443
49
[ 98-03-3 ]
[ 5650-52-2 ]
Reference：
[1] Patent: WO2016/44770, 2016, A1,
50
[ 98-03-3 ]
[ 81290-20-2 ]
[ 35304-68-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With cesium fluoride In 1,2-dimethoxyethane at 0 - 25℃; Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water for 0.5 h;
To a suspension of 125a (11.2 g, 0.1 mol) and CsF (1.52 g, 0.01 mol) in DME (70 mL) was added TMSCF3 (28.4 g, 0.2 mol) dropwise at 0 °C. Then the mixture was stirred at 25°C for 3 hours. The starting material was consumed up. After that, HC1 (3N) was added to quench the reaction and it was stirred for another 0.5 hours. The intermediate was used up and the desired product was formed. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated in vacuo and purified using Si02 chromatography (200 g, Petroleum Ether/EtOAc = 1percent to 2percent) to providel25b as a oil (17.2 g, 97percent yield). 1H NMR (CDC13): 7.39 - 7.38 (m, 1 H) , 7.19 - 7.18 d, 1 H, J=3.6Hz), 7.05 - 7.03 (m, 1 H), 5.29 - 5.23 (m, 1 H)
Reference：
[1] Patent: WO2014/110688, 2014, A1, . Location in patent: Page/Page column 154
[2] Tetrahedron, 2009, vol. 65, # 11, p. 2232 - 2238
[3] Chemical Communications, 2018, vol. 54, # 78, p. 11017 - 11020
Reference：
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[ 57500-51-3 ]
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[2] Patent: US2004/102450, 2004, A1, . Location in patent: Page/Page column 76
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[2] Organic Preparations and Procedures International, 1995, vol. 27, # 2, p. 233 - 236
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With potassium hydroxide; mesitylenesulfonylhydroxylamine;
EXAMPLE 70 7-Bromo-2-thiophen-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine The title compound, MS m/e (%): 297 (M++2, 100), was prepared in accordance with the general method of example 63 from <strong>[329974-09-6]4-bromo-pyridine-2,6-diamine</strong>, O-mesitylene-sulfonylhydroxylamine, and 2-thiophenecarboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
With 1,4-diaza-bicyclo[2.2.2]octane; In 1,4-dioxane; at 20℃;
General procedure: To a solution of piplartine (0.157 mmol) and aldehyde (0.189 mmol) in 1,4-dioxane (2 mL) 2 eq of DABCO was added at room temperature and the reaction allowed to stir for 72 h. Progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was partitioned with tert-butyl methyl ether (5 mL) and water (3 mL). The organic phase was washed with brine (2 × 3 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel, (60-120 mesh) using hexane/EtOAc (6:4) as eluent to give the desired product
With acetic acid; In tetrahydrofuran; at 60℃; for 4h;Inert atmosphere;
General procedure: Take preparation of SB1 for example: 4-amino-triphenylamine (A1) (0.5217 g, 0.0020 mol) was dissolved in 100 ml THF and the mixture was poured into a 100 ml, three-neck, round-bottom flask. 2-thiophenecarboxaldehyde (0.3017 g, 0.0027 mol) was added slowly into the mixture, then a drop of acetic acid was added. After that the solution was stirred at 60 C reflux temperature for 4 h under nitrogen atmosphere, it became transparent and orange. The solution was evaporated by rotary evaporation to powders in brown with the yield of 73.1% (0.5174 g). The other SBs were prepared in the same procedure, and the synthesis routes of SBs are showed Scheme 1.
7,7-dimethyl-10-(thiophen-2-yl)-1,5,6,7,8,10-hexahydropyrimido[5,4-b]quinoline-2,4,9(3H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With copper(I) iodide; In water; at 20℃; for 5h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
diphenyl (benzo[d]thiazol-5-ylamino)(thiophen-2-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
With ZnBr2/SiO2; In neat (no solvent); for 0.1h;Microwave irradiation; Green chemistry;
General procedure: The mixture of 4-(4-chlorophenoxy)aniline (2) (220 mg,1.0 mmol), 3-nitrobenzaldehyde (3e) (155mg, 1.03 mmol),diethyl phosphite (4) (0.13 mL, 1.0 mmol) and SiO2-ZnBr2 (17.1 mg, 6 molpercent) were taken into a flask. Thereaction mass was irradiated with microwave radiationsfor 4 min using Catalyst systems (CATA-4R,), percentpower is 65percent and 465Watts. Ethyl acetate (10 mL) wasadded to the reaction mixture and stirred for 10 min,after completion of the reaction as checked by TLC.The catalyst, SiO2-ZnBr2 was separated by filtrationas residue, washed with ethyl acetate (2×5mL) andcollected residue was dried under vacuum at 100°C toutilize in further reactions. The combined organic layerwas washed with water (10 mL), dried over anhydrousNa2SO4 and concentrated under vacuum at 50°C toobtain crude mass. The pure compound, diethyl (4-(4-chlorophenoxy)phenylamino)(3-nitrophenyl)methylphosphonate (5e) was isolated by column chromatographyusing 20?60percent ethyl acetate:n-hexane as a mobilephase.
4,5-diphenyl-1-[4-(1H-imidazol-1-yl)phenyl]-2-(thiophen-2-yl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With bismuth (III) nitrate pentahydrate; ammonium acetate; silica gel; In neat (no solvent); at 110℃; for 24h;
General procedure: A mixture of N-(4-aminophenyl) azoles 2a-d (1 mmol), benzil (1 mmol, 0.21 g), aromatic aldehyde (1 mmol), and ammonium acetate (1 mmol, 0.077 g) was stirred vigorously. Bi(NO3)3*5H2O (0.15 mmol, 0.073 g, 15 mol%) and SiO2 (0.5 g) were mixed effectively and added to the mixed reactants. The resulting mixture was heated at 110 C for 24 h. Acetone (50 mL) was then added and the mixture was stirred at 50 C for 10 min. Filtering the hot mixture and then concentration of the filtrate produced the crude product. Recrystallization of the crude products in 96% EtOH gave the desired product 3-5.
The compound 1-1 (17.1 g, 100 mmol) obtained in Example 1 was suspended in 200 mL of n-butanol,Piperidine (17.0 g, 200 mm & lt; 0 & gt; l)And 2-thiophenecarboxaldehyde (22.4 g, 200 mml)Reflux stirring overnight,The solvent was distilled off under reduced pressure,Add 500 mL of water,Fully agitated,The precipitated solid was filtered,Washed once with water and acetone, and dried to give compound 20-1,Yield 85%;
6-chloro-2-[(E)-2-(thiophen-2-yl)ethenyl]quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With sulfuric acid; at 190℃; under 750.075 - 5250.53 Torr; for 1.5h;Microwave irradiation;
General procedure: The 2-methylquinazolin-4(3H)-ones (1 mmol) were mixed with benzaldehydes (1.5 mmol) and 1 drop concentrated sulphuric acid was added to the mixtures. The reaction was carried out in microwave set (Personal Chemistry, Emrys Creator, heating power: 150 W, measured pressure 1-7 bar, reaction time: 1.5 hours) at 190 C. The crude product was washed with 5% sodium hydrogen carbonate and filtered out. The products were crystallized from dimethyl formamide and dried under vacuum.
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