* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 14, p. 3359 - 3368
[2] Journal of the American Chemical Society, 1981, vol. 103, # 17, p. 5176 - 5179
2
[ 3218-36-8 ]
[ 37729-18-3 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 31, p. 4308 - 4311
3
[ 64-19-7 ]
[ 3218-36-8 ]
[ 13026-23-8 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With titanium tetrachloride In dichloromethane at 25℃; for 0.333333 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; Inert atmosphere
General procedure: To a mixture of an aldehyde (0.1 mol) and acetic acid(0.1 mol) in dichloromethane (15 mL) was added TiCl4 (0.21 mol). The resulting reaction mixture was stirred at room temperature for 20 min under nitrogen atmosphere. To this was added Et3N (0.25 mol) dropwise over aperiod of 10 min and the mixture was stirred for further 3-4 h at room temperature. When the reaction was complete as confirmed by TLC, the mixture was diluted with water (25 mL) and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford the corresponding (E)-α,β-unsaturated carboxylicacid (1) in excellent yield and purity.
General procedure: A solution of suitably substituted carbaldehyde (200mmol), propenedioic acid (20.8g, 200mmol) in pyridine (10mL, 120mmol) and piperidine (1mL) was warmed at reflux for 2h. The resultant solution was poured into 2M HCl aq. and cooled to room temperature. The solid was filtered, washed with water and recrystallized in ethanol/water
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 149, p. 56 - 68
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 20, p. 5479 - 5493
[3] Journal of the American Chemical Society, 1957, vol. 79, p. 3514,3516
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 5, p. 1333 - 1336
[5] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 14, p. 4991 - 4996
[6] Journal of Organic Chemistry, 2018, vol. 83, # 7, p. 4190 - 4196
Reference：
[1] Journal of the Chemical Society, 1931, p. 2476,2477
[2] RSC Advances, 2017, vol. 7, # 19, p. 11233 - 11243
7
[ 108-24-7 ]
[ 3218-36-8 ]
[ 13026-23-8 ]
[ 79913-05-6 ]
Reference：
[1] Journal of the Chemical Society, 1931, p. 2476,2477
[2] Chemische Berichte, 1939, vol. 72, p. 1064,1067
8
[ 141-78-6 ]
[ 3218-36-8 ]
[ 13026-23-8 ]
Reference：
[1] Chemische Berichte, 1935, vol. 68, p. 453
9
[ 141-97-9 ]
[ 126-81-8 ]
[ 3218-36-8 ]
[ 1099644-42-4 ]
Yield
Reaction Conditions
Operation in experiment
97%
With ammonium acetate In neat (no solvent) at 80℃; for 0.166667 h; Green chemistry
General procedure: A mixture of aromatic aldehyde (1 mmol), dimedone (0.14 g, 1 mmol), ethyl acetoacetate (0.13 g, 1 mmol), ammonium acetate (0.115 g, 1.5 mmol), and Fe2O3(at)HAP(at)Melamine (0.15 g) was heated at for 80 °C. Completion of the reactions was monitored by TLC (n-hexan/ethyl acetate 10:3). After satisfactory completion of the reaction and cooling, the reaction mixture was washed with hot ethel acetate and the catalyst was removed by a magnetic field. The solid residue was isolated and purified by recrystallization in hot EtOH.
96%
With ammonium acetate In neat (no solvent) at 20℃; for 0.166667 h; Green chemistry
General procedure: The nickel(II) Schiff base complex immobilized on MWCNTs as a heterogeneous catalyst (0.005 g) was added to a mixture of aromatic aldehyde (1 mmol), 1,3-dione (1 mmol), ethyl acetoacetate (1 mmol), and ammonium acetate (1.5 mmol) in a round bottom flask and the resulting mixture was stirred magnetically under solvent-free conditions at room temperature. After reaction, as observed by TLC (n-hexane/ethyl acetate: 5/2), ethyl acetate (5 mL) was added to the reaction mixture, stirred and refluxed for 10 min, washed with ethanol (5 mL) and decanted to separate catalyst from other materials (the reaction mixture was soluble in hot ethyl acetate and nanocatalyst was insoluble). The solvent of organic layer was evaporated and the crude product was purified by recrystallization from ethanol. In this study, nanoheterogeneous catalyst was recycled and reused for seven times without significant loss of its catalytic activity.
96%
With ammonium acetate; ascorbic acid In neat (no solvent) at 80℃; for 5 h; Green chemistry
General procedure: A mixture of aldehyde (1 mmol), cyclic 1,3-diketone (1 mmol), ethyl acetoacetate (1 mmol), ammonium acetate (1 mmol), and ascorbic acid (5percent mol) was stirred at 80 °C under solvent-free conditions for appropriate time (Table 3). After complete conversion as indicated by TLC, the reaction mixture was cooled to room temperature, poured onto ice-cold water (10 mL), and stirred for about 10 min. The formed solid was filtered off, washed with cold water, and purified by simple crystallization in ethanol.
88%
With bismuth(III) bromide; ammonium acetate In ethanol at 20℃; for 3 h;
General procedure: A homogeneous mixture of p-tolualdehyde (0.5000 g,4.16 mmol), dimedone (0.6417 g, 4.58 mmol, 1.1 equiv), ethyl acetoacetate(0.5968 g, 0.58 mL, 4.58 mmol, 1.1 equiv), and ammonium acetate (0.3528 g,4.58 mmol, 1.1 equiv) was stirred in anhydrous ethanol (10.0 mL) at roomtemperature as BiBr3 (0.0373 g, 2.0 mol percent) was added. The reaction progresswas monitored by TLC (2,4-DNP stain). After 1.5 h, the reaction mixture waspoured onto 20 g of ice and the resulting yellow precipitate was collected viasuction filtration. The crude product was recrystallized using anhydrousethanol (approximately 30 mL) to yield 1.2694 g (86percent yield) of a slightly offwhite,powdery compound. Mpt: 258–259 C (Lit: 258–259 C).
38%
With ammonium acetate; iodine In ethanol at 20℃;
General procedure: 1 eq. of a cyclic 1,3-dicarbonyl compound 2, 1 eq. of the desired aldehyde 5, 1 eq. of a 1,3-dicarbonyl compound 3, 1 eq. of dried NH4OAc and 0.3 eq. of iodine were stirred in EtOH (2.5 mL/mmol) overnight at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed twice with a saturated solution of NaS2O3 and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by recrystallization or flash chromatography.
Reference：
[1] RSC Advances, 2014, vol. 4, # 101, p. 57662 - 57670
[2] Research on Chemical Intermediates, 2015, vol. 41, # 10, p. 7227 - 7244
[3] Applied Organometallic Chemistry, 2016, vol. 30, # 5, p. 311 - 317
[4] Journal of Coordination Chemistry, 2017, vol. 70, # 2, p. 340 - 360
[5] Synthetic Communications, 2017, vol. 47, # 12, p. 1185 - 1191
[6] RSC Advances, 2016, vol. 6, # 110, p. 108896 - 108907
[7] RSC Advances, 2015, vol. 5, # 68, p. 55303 - 55312
[8] Tetrahedron Letters, 2015, vol. 56, # 27, p. 4060 - 4062
[9] Chemical Communications, 2011, vol. 47, # 1, p. 529 - 531
[10] RSC Advances, 2017, vol. 7, # 89, p. 56764 - 56770
[11] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 249 - 266
10
[ 126-81-8 ]
[ 105-45-3 ]
[ 3218-36-8 ]
[ 1099644-42-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9946 - 9957
General procedure: A mixture of malonic acid (1.61g, 11.5 mmol), the desired aldehyde 2a-d (5.7 mmol) and a catalytic amount of piperidine (0.1 mL) was heated in a solution of pyridine (5 mL) at reflux for 2 h. The resultant mixture was poured into ice and a solution of 2 M HCl aq. was added dropwise. The formed solid was collected by filtration, washed with water and purified by flash column chromatography eluting with n-hexane:EtOAc 100:0 v/v, increasing to 80:20 v/v to give the title compound.
75%
With piperidine; pyridine;Reflux;
General procedure: A solution of suitably substituted carbaldehyde (200mmol), propenedioic acid (20.8g, 200mmol) in pyridine (10mL, 120mmol) and piperidine (1mL) was warmed at reflux for 2h. The resultant solution was poured into 2M HCl aq. and cooled to room temperature. The solid was filtered, washed with water and recrystallized in ethanol/water
With hydrogenchloride; sodium hydroxide; sodium borohydrid; In methanol; tert-butyl methyl ether; water;
Example 33 7.06 g (37.1 mol) of (R)-2,4-dichloro-alpha-methylbenzylamine and 8.13 g (44.6 mmol) of 4-phenylbenzaldehyde were mixed in 50 ml of t-butyl methyl ether and stirred at room temperature for 1 hour. After ascertaining the disappearance of the amine, 30 ml of methanol was added thereto and 2.60 g (68.7 mmol) of sodium borohydride was gradually added at room temperature and stirred at room temperature for 16 hours. After the reaction, 13 ml of 36% hydrochloric acid and 10 ml of water were added at room temperature and evaporated under reduced pressure to yield crystals. To the obtained crystals was added 25 ml of t-butyl methyl ether, stirred and separated the crystals by filtration. The crystals were washed with 50 ml of t-butyl methyl ether and then mixed with alkaline solution containing 2.87 g of sodium hydroxide in 100 ml of water and extracted with 800 ml of t-butyl methyl ether under alkaline condition. The extract was evaporated under reduced pressure to yield 9.65 g (27.1 mmol) of (R)-N-(4-phenylbenzyl)-2,4dichloro-alpha-methylbenzylamine. (Yield: 72.9%, Purity 99.1%); NMR spectrum data (delta ppm, CDCl3); 1.34 (d) 3H; 1.60 (s) 1H; 3.64 (s) 2H; 4.32 (q) 1H; 7.25-7.62 (m) 12H.
(S)-[1-{Biphenyl-4-ylmethyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
EXAMPLE 51 (S)-[1-{Biphenyl-4-ylmethyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic Acid Benzyl Ester The title compound can be prepared according to Example 15, Step 1, by substituting p-phenyl-benzaldehyde for 4-benzyloxy-benzaldehyde and in Step 5, by substituting beta-methyl-phenethylamine hydrochloride for beta,beta-dimethylphenethylamine hydrochloride. The title compound was obtained as a white foam (33%); ES-MS 630 (m+1).
3-[(Biphenyl-4-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 236 3-[(Biphenyl-4-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-phenylbenzaldehyde as starting materials, which are commercially available from Aldrich; m.p. 222-223 C.
General Procedure (E): Ester Method Step A: To w-N-protected amino acid methyl ester hydrochloride (10 mmol) and aldehyde (10.3 mmol) in THF (80 ml) is added at room temperature sodium triacetoxyborohydride (11 mmol) and the mixture is stirred overnight. Sat. aq. potassium carbonate (100 ml) is added and the mixture is stirred for 1 h. The layers are separated and the aq. layer is extracted with ethyl acetate (3×100 ml). The combined org. layers are dried over sodium sulfate and evaporated in vacuo. Flash chromatography (silica, dichloromethane) afforded the product.
With ammonium acetate; In neat (no solvent); at 80℃; for 0.166667h;Green chemistry;
General procedure: A mixture of aromatic aldehyde (1 mmol), dimedone (0.14 g, 1 mmol), ethyl acetoacetate (0.13 g, 1 mmol), ammonium acetate (0.115 g, 1.5 mmol), and Fe2O3(at)HAP(at)Melamine (0.15 g) was heated at for 80 C. Completion of the reactions was monitored by TLC (n-hexan/ethyl acetate 10:3). After satisfactory completion of the reaction and cooling, the reaction mixture was washed with hot ethel acetate and the catalyst was removed by a magnetic field. The solid residue was isolated and purified by recrystallization in hot EtOH.
96%
With ammonium acetate; In neat (no solvent); at 20℃; for 0.166667h;Green chemistry;
General procedure: The nickel(II) Schiff base complex immobilized on MWCNTs as a heterogeneous catalyst (0.005 g) was added to a mixture of aromatic aldehyde (1 mmol), 1,3-dione (1 mmol), ethyl acetoacetate (1 mmol), and ammonium acetate (1.5 mmol) in a round bottom flask and the resulting mixture was stirred magnetically under solvent-free conditions at room temperature. After reaction, as observed by TLC (n-hexane/ethyl acetate: 5/2), ethyl acetate (5 mL) was added to the reaction mixture, stirred and refluxed for 10 min, washed with ethanol (5 mL) and decanted to separate catalyst from other materials (the reaction mixture was soluble in hot ethyl acetate and nanocatalyst was insoluble). The solvent of organic layer was evaporated and the crude product was purified by recrystallization from ethanol. In this study, nanoheterogeneous catalyst was recycled and reused for seven times without significant loss of its catalytic activity.
96%
With ammonium acetate; ascorbic acid; In neat (no solvent); at 80℃; for 5.0h;Green chemistry;
General procedure: A mixture of aldehyde (1 mmol), cyclic 1,3-diketone (1 mmol), ethyl acetoacetate (1 mmol), ammonium acetate (1 mmol), and ascorbic acid (5% mol) was stirred at 80 C under solvent-free conditions for appropriate time (Table 3). After complete conversion as indicated by TLC, the reaction mixture was cooled to room temperature, poured onto ice-cold water (10 mL), and stirred for about 10 min. The formed solid was filtered off, washed with cold water, and purified by simple crystallization in ethanol.
88%
With bismuth(III) bromide; ammonium acetate; In ethanol; at 20℃; for 3.0h;
General procedure: A homogeneous mixture of p-tolualdehyde (0.5000 g,4.16 mmol), dimedone (0.6417 g, 4.58 mmol, 1.1 equiv), ethyl acetoacetate(0.5968 g, 0.58 mL, 4.58 mmol, 1.1 equiv), and ammonium acetate (0.3528 g,4.58 mmol, 1.1 equiv) was stirred in anhydrous ethanol (10.0 mL) at roomtemperature as BiBr3 (0.0373 g, 2.0 mol %) was added. The reaction progresswas monitored by TLC (2,4-DNP stain). After 1.5 h, the reaction mixture waspoured onto 20 g of ice and the resulting yellow precipitate was collected viasuction filtration. The crude product was recrystallized using anhydrousethanol (approximately 30 mL) to yield 1.2694 g (86% yield) of a slightly offwhite,powdery compound. Mpt: 258-259 C (Lit: 258-259 C).
38%
With ammonium acetate; iodine; In ethanol; at 20℃;
General procedure: 1 eq. of a cyclic 1,3-dicarbonyl compound 2, 1 eq. of the desired aldehyde 5, 1 eq. of a 1,3-dicarbonyl compound 3, 1 eq. of dried NH4OAc and 0.3 eq. of iodine were stirred in EtOH (2.5 mL/mmol) overnight at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed twice with a saturated solution of NaS2O3 and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by recrystallization or flash chromatography.
[0206] Biphenyl carboxaldehyde (2.82 g, 15.5 mmol) was added to a stirred solution of (IR, 35)-3-aminocyclopentanecarboxylic acid (2.0g, 15.5 mmol) in anhydrous methanol (50 mL) and acetic acid (2 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (6.57 g, 31 mmol) was added portion wise over 10 minutes and the reaction was stirred at room temperature for 4 hours, diluted with saturated aqueous sodium chloride, and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give crude (li?,35)-3-(biphen-4-ylmethyl-amino)- cyclopentane carboxylic acid, which was used in the next step without further purification;
With sodium sulfate; triethylamine; In dichloromethane; at 20℃; for 16h;
Compound (R)-5 .HCl (1g, 5.06mmol) was dissolved in CH2Cl2 abs. (15ml) and triethylamine (0.74ml, 5.06mmol) and biphenyl-4-carbaldehyde (6, 0.92g, 5.06mmol) were added slowly. Then Na2SO4 was added and the mixture was stirred for 16h at room temperature. For work-up, the suspension was filtered, the precipitate was washed with CH2Cl2 and the filtrate was concentrated in vacuo. Diethyl ether was added to the resulting residue and the mixture was filtered again. Evaporation of the filtrate gave the imine (760mg, 2.34mmol) as a colorless solid, which was dissolved in diethyl ether (15ml) and reduced directly by addition of NaBH4 (150.8mg, 3.98mmol) over 40min under ice cooling. The mixture was stirred at room temperature for another 5min, before the solvent was evaporated in vacuo. Water (15ml) was added to the residue and the aqueous layer was extracted with diethyl ether (5×10ml). The combined organic layers were dried (K2CO3), filtered and the solvent was removed under reduced pressure. The oily residue of the resulting amine (725.6mg, 2.22mmol) was dissolved in CH2Cl2 abs. (10ml). Triethylamine (0.25ml, 1.78mmol) and chloroacetyl chloride (0.28ml, 3.56mmol) were added dropwise under N2-atmosphere and ice cooling. The mixture was stirred for 2.5h at room temperature. The solvent was removed in vacuo and diethyl ether (50ml) was added to the resulting residue. The suspension was filtered, washed and the filtrate was concentrated in vacuo. Purification of the residue was performed by fc ( 3cm, h=19cm, v=30ml, cyclohexane/ethyl acetate=4/1, Rf=0.26). Colorless oil, yield 360mg (15% over 3 steps). C21H22ClNO5, Mr=403.9. HPLC (method ACN): tR=21.0min, purity 93.9%. Specific rotation: [alpha]20D[alpha]D20 +26.8 (c=0.97; EtOAc). MS (EM, APCI): m/z=calcd for C21H23ClNO5 404.1265 (M+H), found 404.1212.
With sodium hydroxide; In dichloromethane; water; at 20℃; for 3h;
[001621 To a solution of [1,1?-biphenylj-4-carbaldehyde (1.82 g, 10.0 mmol) and <strong>[1779-58-4](carbomethoxymethyl)-triphenylphosphonium bromide</strong> (8.30 g, 20.0 mmol) in DCM (100 mL) and water (80 mL) was added NaOH (2 N, 10 mL, 20 mmol). After the mixture wasstirred at room temperature for 3 h, the organic layer was collected and the aqueous was extracted with DCM (2 x 30 mL). The combined extract was dried over anhydrous Na2504. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (DCM/hexanes, 1:2 to 2:1) to afford (E)-methyl 3-([1,1?-biphenylj-4-yl)acrylate as a white solid (2.00 g, 84percent). ?H NMR(500 MHz, CDC13) oe 7.74 (d, J= 16.0 Hz, 1H), 7.64 ? 7.59 (m, 6H), 7.48 ? 7.44 (m, 2H),7.40? 7.36 (m, 1H), 6.48 (d, J 16.0 Hz, 1H), 3.83 (s, 3H).
General procedure: To a mixture of an aldehyde (0.1 mol) and acetic acid(0.1 mol) in dichloromethane (15 mL) was added TiCl4 (0.21 mol). The resulting reaction mixture was stirred at room temperature for 20 min under nitrogen atmosphere. To this was added Et3N (0.25 mol) dropwise over aperiod of 10 min and the mixture was stirred for further 3-4 h at room temperature. When the reaction was complete as confirmed by TLC, the mixture was diluted with water (25 mL) and the organic layer was separated. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford the corresponding (E)-alpha,beta-unsaturated carboxylicacid (1) in excellent yield and purity.
With potassium carbonate; In acetonitrile; for 1h;Reflux;
General procedure: A mixture of intermediate Ml 1 (1.26 g, 1 equiv), intermediate C2 (396 mg, 1 equiv) and anhydrous K2C03 (830 mg, 1.5 equiv) in acetonitrile (10 ml) was refluxed for 1 h. TLC detection showed that the reaction was complete. The mixture was filtered to remove the insoluble substances and washed with EA. The filtrate was concentrated and then purified by colunm chromatography (PE/EA=2: 1) to give the title compound as a white solid (1.14 g). ?H-NMR (CDC13, 300 MHz) oe5.67 (s, 2H), 7.20 (s, 1H), 7.30 (d, 2H, J=8.4), 7.33 (s, 1H), 7.57 (d, 2H, J=8.4), 7.67 (q, 4H), 9.86 (s, 1H); MS (ESI):331 (M+H).
ethyl 2-amino-4-(biphenyl-4-yl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With sodium ethanolate; In ethanol; at 80℃; for 0.833333h;
General procedure: In a round bottom flask 1 eq. of dimedone, 1 eq of the desired aldehyde and 1 eq of <strong>[57508-48-2]ethyl 3-amino-3-iminopropionate hydrochloride</strong> were suspended in dry EtOH (2.5 mL/mmol) and heated at 80 C. To this solution 1 eq of a 0.5 M sodium ethanolate solution was added over the period of 20 min. After heating for further 30 min under reflux the reaction was cooled to 0 C and water (40 mL/mmol) was added. The aqueous solution was extracted with EtOAc (5×20 mL/mmol). The combined organic layers were washed with brine, dried with MgSO4 and the solvent was evaporated under reduced pressure. The crude material was purified by recrystallization from ethanol.
ethyl 4-(biphenyl-4-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydro[1,6]naphthyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With ammonium acetate; iodine; acetic acid; In ethanol; at 60 - 80℃; for 72h;Inert atmosphere;
General procedure: 1 eq. of a cyclic 1,3-dicarbonyl compound 2, 1 eq. of the desired aldehyde 5, 1.2 eq. of a 1,3-dicarbonyl compound 3, 1.5 eq. of dried NH4OAc, 0.3 eq. of iodine and a few drops of concentrated acetic acid were stirred in EtOH (2.5 mL/mmol) under Ar at 60?80 °C. The progress of the reaction was monitored via TLC. Upon completion of the reaction the solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed twice with a saturated NaS2O3 solution and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by recrystallization or flash chromatography.
A container having an internal volume of 100 mL equipped with a stirrer, a cooling tube, and a buret was chargedwith a solution obtained by dissolving 3.20 g (20 mmol) of 2,6-naphthalenediol (reagent manufactured by Sigma-AldrichCorporation) and 1.82 g (10 mmol) of 4-biphenylcarboxaldehyde (manufactured by Mitsubishi Gas Chemical Company,Inc.) in 30 ml of methyl isobutyl ketone, and 5 ml of 95% sulfuric acid was further added. The obtained reaction liquidwas stirred at 100C for 6 hours for reaction. Next, the reaction liquid was concentrated, and 50 g of pure water wasadded to precipitate the reaction products. The reaction liquid was cooled to room temperature. Then, the reaction liquidwas filtered to separate the reaction liquid into a filtrate and solids. The obtained solids were dried and then subjectedto separation and purification by column chromatography, and 3.05 g of a compound represented by the following formula(3) was obtained. The fact that the obtained compound had the chemical structure of the following formula (3) wasconfirmed by 400 MHz 1H-NMR as follows, 1H-NMR: (d-DMSO, internal standard TMS)delta (ppm) 9.7 (2H, O-H), 7.2-8.5 (19H, Ph-H), 6.6 (1H, C-H)
3.05 g
With sulfuric acid; In butanone; at 100℃; for 6h;
In a container (internal capacity: 100 ml) equipped with a stirrer, a condenser tube, and a burette, 3.20 g (20 mmol) of 2,6-naphthalenediol (reagent manufactured by Sigma-Aldrich Corporation) and 1.82 g (10 mmol) of 4-biphenylcarboxaldehyde (manufactured by Mitsubishi Gas Chemical Company, Inc.) were charged to 30 ml of methyl isobutyl ketone, and 5 ml of 95% sulfuric acid was further added thereto. The reaction solution was stirred at 100 C. for 6 hours to perform reaction. Next, the reaction solution was concentrated. The reaction product was precipitated by the addition of 50 g of pure water. After cooling to room temperature, the precipitates were separated by filtration. The obtained solid matter was filtered, dried, and then separated and purified by column chromatography to obtain 3.05 g of the objective compound (XBisN-1) represented by the following formula. As a result of measuring the molecular weight of the obtained compound by the above method, it was 466. The obtained compound was subjected to NMR measurement under the above measurement conditions. The following peaks were found, and the compound was confirmed to have a chemical structure of the following formula. (0419) delta (ppm) 9.7 (2H, O-H), 7.2-8.5 (19H, Ph-H), 6.6 (1H, C-H) . The signals of protons at positions 3 and 4 were found as a doublet, thereby confirming that the substitution position of 2,6-naphthalenediol was position 1 The compound had the thermal decomposition temperature of 410 C. and the glass transition point of 152 C. and could thereby be confirmed to have high heat resistance. The solubility in MEK was evaluated by the above method. The compound was evaluated as excellence with evaluation A (50% by weight or more). The solubility in a safe solvent was further evaluated by the above method. The results are shown in Table 1.
3.05 g
With sulfuric acid; at 100℃; for 6h;
To a container having an inner volume of 100 mL, equipped with a stirrer, a condenser and a burette, were charged 1.60 g (10 mmol) of 2,6-naphthalenediol (reagent produced by Sigma-Aldrich Co., LLC.), 1.82 g (10 mmol) of 4-biphenylaldehyde (produced by Mitsubishi Gas Chemical Company, Inc.) and 30 mL of methyl isobutyl ketone, 5 mL of 95% sulfuric acid was added thereto, and a reaction liquid was stirred at 100 C. for 6 hours to perform a reaction. Then, the reaction liquid was concentrated, 50 g of pure water was added thereto to precipitate a reaction product, and the resultant was cooled to room temperature followed by filtration for separation. A solid obtained by filtration was dried, and separated and purified by column chromatography to thereby provide 3.05 g of an objective compound (BisN-1) represented by the following formula. (0105) Herein, the following peaks were observed by 400 MHz-1H-NMR, and it was confirmed that the compound had a chemical structure of the following formula. In addition, it was confirmed from a doublet signal of protons at 3- and 4-positions that 2,6-dihydroxynaphthol was substituted at 1-position. (0106) 1H-NMR: (d-DMSO, Internal reference TMS) (0107) delta (ppm) 9.7 (2H, O-H), 7.2-8.5 (19H, Ph-H), 6.6 (1H, C-H)
3.05 g
With sulfuric acid; at 100℃; for 6h;
To a container (internal capacity: 100 mL) equipped with a stirrer, a condenser tube, and a burette, 1.60 g (10 mmol) of 2,6-dihydroxynaphthalene (a reagent manufactured by Sigma-Aldrich), 1.82 g (10 mmol) of 4-biphenylaldehyde (manufactured by Mitsubishi Gas Chemical Company Inc.), and 30 mL of methyl isobutyl ketone were added, and 5 mL of 95% sulfuric acid was added. The reaction solution was stirred at 100 C. for 6 hours and reacted. Next, the reaction solution was concentrated. The reaction product was precipitated by the addition of 50 g of pure water. After cooling to room temperature, the precipitates were separated by filtration. The solid matter obtained by filtration was dried and then separated and purified by column chromatography to obtain 3.05 g of the compound (BisN-1) represented by the following formula. The following peaks were found by 1H-NMR, and the compound was confirmed to have a chemical structure of the following formula. 1H-NMR: (d-DMSO, Internal standard TMS) delta (ppm) 9.7 (2H, O-H), 7.2-8.5 (19H, Ph-H), 6.6 (1H, C-H)
6-fluoro-2-[2-((1,1'-biphenyl)-4-ylmethylene)hydrazino]benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized to give compounds 3-29.
(E)-4-[(1,1'-biphenyl)-4-yl]but-3-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With sodium hydride; In toluene; at 70 - 100℃;
182 mg of (1,1'-biphenyl)-formaldehyde intermediate was dissolved in 10 ml of toluene,457 mg of 2-carboxyethyltriphenylphosphonium bromide and 53 mg of sodium hydride were added in portions.The reaction is carried out at 70 to 100 ° C for 1 to 3 hours. After the reaction is completed, the reaction system is added.Into the water, extracted three times with ethyl acetate, washed with saturated brine,Dry over anhydrous sodium sulfate, filter, concentrate, 90 mg white solid.The yield was 38percent, and the product was used in the next step without being treated.
N'-[biphenyl-4-ylmethylidene]-2-(naphthalen-1-yl)acetohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
In ethanol; for 3h;Reflux;
General procedure: These compounds were prepared by refluxing substituted acetohydrazides 3(a-b) with 4-(benzyloxy) benzaldehyde (0.01 mol) in 20 mL of ethanol for 3 h. On cooling the reaction mixture to room temperature, a solid product appeared. The respective crude product was recrystallized using ethanol. N'-[Biphenyl-4-ylmethylidene]-<strong>[34800-90-3]2-(naphthalen-1-yl)acetohydrazide</strong> (5d). The final product was obtained as a white solid with 76% yield. m.p. 210-212 C. IR (KBr): numax (cm-1), 3228 (NH), 3037 (Ar C-H), 2897 (C-H), 1656 (C=O), 1610 (C=N), 1534(C=C). 1H-NMR (400 MHz, DMSO-d6): delta ppm, 4.97 (2H, s,H-1), 7.03-8.00 (16H, m, Ar-H), 8.11 (1H, s, H-5), 12.57 (1H, s, H-3). 13C-NMR (100 MHz, DMSO): delta ppm, 174.06 (amide C=O, C-2), 148.35 (N=CH, C-5), (aromatic C?s), 28.74 (naphthyl-CH2, C-1). LCMS (m/z): 365(M++1). Calcd. for C25H20N2O: C, 82.39; H, 5.53; N, 7.69; Found: C, 82.37; H, 5.55; N, 7.67 %.
76%
In ethanol; for 3h;Reflux;
General procedure: These compounds were prepared by refluxing substituted acetohydrazides 3(a-b) with 4-(benzyloxy) benzaldehyde (0.01 mol) in 20 mL of ethanol for 3 h. On cooling the reaction mixture to room temperature, a solid product appeared. The respective crude product was recrystallized using ethanol.
41.6 g (160 mmol) of N-(4-chlorophenyl)-1,2-phenylene diamine and 33 g (180 mmol) of biphenyl-4-carboxaldehyde was agitated with 300 mL of 2-methoxy ethanol in a 2000 mL round flask, and the agitated mixture was agitated for 24 hours afier increasing the temperature of the reaction vessel to a reflux temperature. The reaction solution was treatedwith methylene chloride to obtain an organic layer, andanhydrous magnesium sulfate was used to remove moisturefrom the organic layet 30 g of a compound (A) (40% yield) was obtained by columnizing the reactant afier removing the solvent therefrom.The compound (A) was atomically analyzed, and theresults are provided.calcd. C25H17C1N2: C, 78.84; H, 4.50; N, 7.36. found: C, 78.80; H, 4.52; N, 7.40.
(4-([1,1'-biphenyl]-4-yl)-2-amino-5-benzoyl-1H-pyrrol-3-yl)(3-chlorophenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With potassium carbonate; In ethanol;Reflux;
General procedure: The synthesis of 2-aminopyrrole analogues was based on a multicomponent reaction by refluxing a solution of three reactants including a methylsulfonamidoacetophenone, an aldehydes and acyanoacetic acid with 0.6 equiv of K2CO3 in ethanol. This reaction results in three substituted 2-aminopyrroles [35]. Compounds1-30 in Tables 1 and 2, and Fig. 3 were synthesized as shown in Scheme 1.
(1S*,2R*)-N-([1,1’-biphenyl]-4-ylmethyl)-2-phenylcyclopropan-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
General procedure: Trans-2-phenylcyclopropylamine hydrochloride (1.0 eq.), acetic acid (1.0eq.) and the appropriate aldehyde (0.9 eq.) were dissolved in around bottom flask in 10 mL dry DCE. The reaction mixture was stirred gently at room temperature for 2 h before sodium triacetoxyborohydride (3.0 eq.) was added in small portions to the reaction vessel. The reaction was monitored by TLC and quenched using 10 mL of an aqueous (5%) NaHCO3 solution. The organic layer was separated and the aqueous layer extracted three times with10 mL of DCE. All organic layers were combined, dried over anhydrous Na2SO4, concentrated in vacuo and purified using flash chromatography (silica gel; cyclohexane/ethyl acetate) to give the desired compound.
To a stirred solution of 5-bromopyrazin-2-amine (300 mg, 1.26 mmol) in DCE (5 mL), [1, 1'-biphenyl]-4-carbaldehyde (230 mg, 1.26 mmol), and AcOH (0.1 mL) were added at rt and the reaction mixture was stirredfor 30 min. Then, Na(OAc)3BH (9 mg, 3.78 mmol} was added and stirred for 16 h. The reaction mixture wasdiluted with DCM and washed with sat.NaHC03, water. The organic layers were dried over anhydrous Na2S04and the organic ayers were evaporated to dryness. The crude compound was purified by flash columnchromatography using 30% EtOAc: Pet ether as the eluent to get the title compound (260 mg, 60%). LC-MS (method 21): Rt = 2.46 min; m/z = 340.30 (M+H+).
General procedure: The aromatic aldehydes (14.0mmol) and starting compound 1 (1.65g, 11.0mmol) were dissolved in EtOH (20mL) and cooled in ice bath, then 50% KOH/EtOH (15mL) was added dropwise and the mixture was stirred in ice bath for 15min and then overnight at room temperature. Additional 50% KOH/EtOH (5mL) was added and stirred for 30min. Then the solution was cooled in ice bath and 10mL 30% H2O2 was added under vigorous stirring condition for 30min. After stirring overnight at room temperature, the mixture was poured into 200mL crushed ice water and acidified with dilute hydrochloric acid. The bright yellow precipitate was filtered and washed with small portions of cold EtOH to give the intermediates 2a and 2b.
In methanol;Inert atmosphere; Reflux; Green chemistry;
General procedure: The oxocomponent(i.e. the aldehyde or the ketone) (0.5 mmol, 1 eq.), the amine (0.5 mmol, 1 eq.), theisocyanide (0.5 mmol, 1 eq.), and <strong>[612-20-4]2-hydroxymethylbenzoic acid</strong> (0.5 mmol, 1 eq.) were one-potmixed in methanol (2 M, 250 muL) and stirred at reflux temperature under a nitrogen atmosphere for3-4h. The formation of the Ugi alpha-acylamino amide was monitored by TLC, and the crude reactionmixture was evaporated and filtered through a pad of silica gel (n-hexane/ EtOAc). The Ugi alpha-acylamino amide (0.15 mmol) was then stirred for 10 minutes at room temperature in 4N HClsolution in 1,4-dioxan (1 mL). The reaction was then evaporated to dryness and triturated with nhexaneto give the hydrochloride salt of the corresponding N,N?-substituted alpha-amino amide.
(Z)-3-(5-([1,1'-biphenyl]-4-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium acetate; acetic acid; at 105℃;Inert atmosphere;
General procedure: To a mixture of aldehyde (1.0 mmol), <strong>[7025-19-6]3-(4-oxo-2-thioxothiazolidin-3-yl)propanoic acid</strong> (205 mg,1.0 mmol) or 3-(2-(1H-tetrazol-5-yl)ethyl)-2-thioxothiazolidin-4-one (229 mg, 1.0 mmol) and NaOAc (820 mg, 10.0 mmol) was added acetic acid (5.0 mL). The reaction was allowed to stir at 105 C for 0.5h - 12h, then cooled to room temperature. To the reaction was added water (15mL). The resulting mixture was sonicated to give yellow-orange slurry. After filtration, the solid was washed with water (75 mL) and dried under high vacuum to yield the corresponding product as a red fine powder.
ethyl 4-([1,1’-biphenyl]-4-yl)-2-((2-(1,3-dioxoisoindolin-2-yl)ethoxy)-methyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate[ No CAS ]
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