* 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 potassium hydroxide; sodium hydroxide In neat (no solvent)Heating
General procedure: Potassium hydroxide (3.6 g, 64 mmol) and sodium hydroxide (2.4 g, 60 mmol) weremixed and quickly crushed in a porcelain dish. Then the corresponding aldehyde(15 mmol) was added and the mixture was heated on a hot-plate under stirring until thealdehyde melted and additionally 5 minutes. When liquid aldehydes were used, heatingwas continued until temperature reached 140C. After cooling, the crude solid productmixture was added to water (100 mL) and ice (30 g) and acidified with hydrochloric acidto pH 4. The precipitate was collected, dried and recrystallized from ethanol.
Reference：
[1] Organic Preparations and Procedures International, 2017, vol. 49, # 1, p. 45 - 52
2
[ 110-89-4 ]
[ 459-57-4 ]
[ 10338-57-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
With Aliquat(at)366; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h;
General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a–g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia–g. 4-(Piperidin-1-yl) benzaldehyde Ic Yield 98percent as yellow crystals, mp 64 °C, (as reported) [47,48].
90%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.5 h; Stage #2: at 80℃; for 6 h;
In 4.0ml of DMF of piperidine (0.0gm, 0.001mol) was dissolved. To this solution K2CO3 (0.27gm, 0.002mol) was added and heated at 80 °C with stirring. After 30 min 4-fluorobenzaldehyde 0.175 gm, 0.001mol) was added and heating was continued for six hours. On completion of reaction, the reaction mixture was cooled and added drop wise to ice water. The separated product was filtered and dried. The product obtained was pure and used further without any purification. (M.P.-289°C)
Reference：
[1] Bioorganic Chemistry, 2014, vol. 57, p. 65 - 82
[2] Russian Journal of General Chemistry, 2013, vol. 83, # 10, p. 1864 - 1868[3] Zh. Obshch. Khim., 2013, vol. 83, # 10, p. 1654 - 1659,6
[4] Oriental Journal of Chemistry, 2013, vol. 29, # 4, p. 1531 - 1534
[5] European Journal of Organic Chemistry, 2017, vol. 2017, # 35, p. 5219 - 5224
[6] Tetrahedron, 2001, vol. 57, # 22, p. 4781 - 4785
[7] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 44 - 60
[9] Tetrahedron Letters, 1998, vol. 39, # 17, p. 2471 - 2474
[10] Journal of Materials Chemistry, 1999, vol. 9, # 9, p. 2251 - 2258
[11] Monatshefte fur Chemie, 2009, vol. 140, # 4, p. 431 - 437
[12] Phosphorus, Sulfur and Silicon and the Related Elements, 2011, vol. 186, # 1, p. 149 - 158
[13] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3741 - 3749
[14] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1365 - 1369
[15] Tetrahedron, 2013, vol. 69, # 26, p. 5355 - 5366
[16] Medicinal Chemistry Research, 2013, vol. 22, # 10, p. 4610 - 4614
[17] Journal of Chemical Research, 2014, vol. 38, # 8, p. 498 - 501
[18] Russian Journal of General Chemistry, 2014, vol. 84, # 10, p. 2058 - 2059[19] Zh. Obshch. Khim., 2014, vol. 84, # 10, p. 1757 - 1758,2
[20] Journal of the Brazilian Chemical Society, 2015, vol. 26, # 6, p. 1086 - 1097
[21] Biochemical and Biophysical Research Communications, 2017, vol. 482, # 4, p. 615 - 624
[22] Biological and Pharmaceutical Bulletin, 2017, vol. 40, # 11, p. 1883 - 1893
[23] Molecules, 2018, vol. 23, # 1,
[24] Tetrahedron, 2018, vol. 74, # 6, p. 652 - 660
[25] Research on Chemical Intermediates, 2018, vol. 44, # 4, p. 2779 - 2805
[26] Molecules, 2018, vol. 23, # 4,
[27] Molecules, 2018, vol. 23, # 5,
3
[ 110-89-4 ]
[ 104-88-1 ]
[ 10338-57-5 ]
Yield
Reaction Conditions
Operation in experiment
83%
With water; sodium t-butanolate In toluene at 105℃; for 5 h; Schlenk technique
General procedure: An oven-dried Schlenk tube was charged with the aryl halide (2 mmol) and amine (2.5 mmol), FeOA–Pd (0.05 g, 0.04 mmol, 1.5 molpercent), base (3 mmol), solvent (5 mL) and additive. The resulting mixture was stirred for the appropriate time and temperature. After reaction completion the reaction mixture was then cooled to room temperature and the catalyst separated using a magnet, taken up in Et2O (4 mL), and washed with brine (5 mL). The resulting solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel.
With water; sodium t-butanolate In toluene at 105℃; for 4 h; Schlenk technique
General procedure: An oven-dried Schlenk tube was charged with the aryl halide (2 mmol) and amine (2.5 mmol), FeOA–Pd (0.05 g, 0.04 mmol, 1.5 molpercent), base (3 mmol), solvent (5 mL) and additive. The resulting mixture was stirred for the appropriate time and temperature. After reaction completion the reaction mixture was then cooled to room temperature and the catalyst separated using a magnet, taken up in Et2O (4 mL), and washed with brine (5 mL). The resulting solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel.
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 25, p. 8747 - 8757
6
[ 110-89-4 ]
[ 15164-44-0 ]
[ 10338-57-5 ]
Yield
Reaction Conditions
Operation in experiment
81 %Chromat.
With C35H34N3OP2PdS(1+)*NO3(1-); sodium t-butanolate In 1,4-dioxane at 100℃; for 6 h;
General procedure: In a typical run, an oven-dried 10 ml round bottom flask was charged with a known mole percent of catalyst, NaOtBu (1.3 mmol), amine (1.2 mmol) and aryl halide (1 mmol) with the appropriate solvent(s) (4 ml). The flask was placed in a preheated oil bath at required temp. After the specified time the flask was removed from the oil bath, water (20 ml) was added, and extraction with ether (4×10 ml) was done. The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in acetonitrile and analyzed by GC–MS.
With aliquat 336; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24h;
3 General method for preparation of 4-(substituted) benzaldehyde
General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a-g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia-g. 4-(Piperidin-1-yl) benzaldehyde Ic Yield 98% as yellow crystals, mp 64 °C, (as reported) [47,48].
95%
With potassium carbonate In N,N-dimethyl-formamide for 20h; Reflux;
90%
Stage #1: piperidine With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.5h;
Stage #2: para-fluorobenzaldehyde In N,N-dimethyl-formamide at 80℃; for 6h;
Synthesis of (4-piperidine-1-yl)benzaldehyde [1c]
In 4.0ml of DMF of piperidine (0.0gm, 0.001mol) was dissolved. To this solution K2CO3 (0.27gm, 0.002mol) was added and heated at 80 °C with stirring. After 30 min 4-fluorobenzaldehyde 0.175 gm, 0.001mol) was added and heating was continued for six hours. On completion of reaction, the reaction mixture was cooled and added drop wise to ice water. The separated product was filtered and dried. The product obtained was pure and used further without any purification. (M.P.-289°C)
90%
With tetrabutylammonium bromide; potassium carbonate In dimethyl sulfoxide at 90℃; for 48h;
85%
With potassium carbonate In dimethyl sulfoxide for 0.25h; ultrasound;
85%
With potassium carbonate In dimethyl sulfoxide for 0.25h; ultrasonic irradiation;
78.2%
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 135℃; for 12h; Inert atmosphere;
74%
In dimethyl sulfoxide for 0.583333h; Heating; Irradiation;
69.99%
With potassium carbonate In dimethyl sulfoxide for 6h; Reflux;
66.7%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24h;
64%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere;
4.1.4 General procedure for the synthesis of 2-1i-m
General procedure: p-Fluorobenzaldehyde (0.86mL, 8.06mmol), corresponding secondary amines (9.67mmol), anhydrous K2CO3 (2.23g, 16.12mmol) and DMF (10mL) were added to the reaction bottle. The mixture was stirred at 100°C for 4-6h under argon. After the reaction was completed, the mixture was poured into ice water and the corresponding solid was precipitated. The solid was filtered and washed with ice water. And then the solid was collected and dried at room temperature to obtain the corresponding substituted benzaldehydes (2-1i-m).
40%
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
With lithium carbonate In N,N-dimethyl-formamide at 50℃; for 10h;
With potassium carbonate In dimethyl sulfoxide
In N,N-dimethyl-formamide Reflux;
With N-hexadecyl-N,N,N-trimethylammonium bromide; potassium carbonate In N,N-dimethyl-formamide at 100℃;
Stage #1: piperidine With potassium carbonate In N,N-dimethyl-formamide for 0.25h;
Stage #2: para-fluorobenzaldehyde In N,N-dimethyl-formamide at 80℃;
Typical procedure for synthesis of 4-(pyrrolidin-1-yl)benzaldehyde (7a) and related compounds (7b-7d)
General procedure: To a solution of pyrrolidine (1.7 g, 24 mmol) in dry DMF (15 mL), anhydrous K2CO3 (3.3 g, 24 mmol) was added and strired for 15 min (Scheme 2). To this, 4-fluorobenzadehyde (1 g, 8 mmol) was added and stirred at 80 oC for 8-10 h. After completion of the reaction, water was added to the reaction mixture and extracted with CHCl3. The organic layer was dried over sodium sulphate, filtered and solvent removed. The crude thus obtained was purified by column chromatography.
at 80 - 90℃;
With potassium carbonate In lithium hydroxide monohydrate at 80℃;
With N-hexadecyl-N,N,N-trimethylammonium bromide; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24h;
With potassium carbonate In N,N-dimethyl-formamide at 140℃; Microwave irradiation;
With potassium carbonate In dimethyl sulfoxide
With N-hexadecyl-N,N,N-trimethylammonium bromide
With potassium carbonate In dimethyl sulfoxide for 6h; Reflux;
With potassium carbonate In N,N-dimethyl-formamide Reflux;
3.2.2. Synthesis of 4-Substituted Benzaldehyde Derivatives 3-16
General procedure: Appropriate seconder amines (5 mmol) or 4-substituted phenol/thiophenol derivatives (5 mmol)were refluxed with 4-fluorobenzaldehyde (5 mmol, 0.62 g) in dimethylformamide (10 mL) with thepresence of potassium carbonate (6 mmol, 0.83 g). After TLC screening, the mixture was poured intoice water and filtered. The products were recrystallized from ethanol.
With potassium carbonate In N,N-dimethyl-formamide
With potassium carbonate In propan-2-one for 8h; Reflux;
With potassium carbonate In N,N-dimethyl-formamide for 36h; Reflux;
3.1.2. Synthesis of Four Substituted Benzaldehydes (2a-2o)
General procedure: A mixture of 4-fluoro benzaldehyde (0.259 mL, 0.002 mol), corresponding phenol, thiophenol,or amine (0.002 mol), and a catalytic quantity of potassium carbonate (K2CO3) was refluxed in DMF(20 mL) for 36 h. After completion of the reaction, the mixture was poured into ice water (50 mL),and the precipitated product was filtered, washed with deionized water, dried, and recrystallizedfrom ethanol.
With potassium carbonate In N,N-dimethyl-formamide for 10h; Reflux;
General Synthesis Procedure for 4-Substitutebenzaldehyde Derivatives (1a-1e)
General procedure: Appropriate secondary amine (0.007 mol), 4-fluorobenzaldehyde (0.007 mol, 0.75 mL) and K2CO3 (0.007 mol, 0.96 g) were refluxed in DMF (10 mL) for 10 h. The mixture was cooled with ice-water (50 mL), a precipitated product was filtered, washed with deionised water, dried, and recrystallized from EtOH to give compounds 1a-1e in the yields range of 63 to 72%.
With potassium carbonate In methanol at 130℃;
With potassium carbonate In dimethyl sulfoxide Reflux;
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;
General procedure for the synthesis of 4-amino-substituted benzaldehyde (3a-e)
General procedure: A mixture of 4-fluorobenzaldehyde (1) (0.25 g, 2 mmol), appropriate amines (2a-e) (3 mmol) and anhydrous potassium carbonate (0.4 g) was stirred in DMF (5 mL) for 24 h at 80 °C. The mixture was concentrated under low pressure and left to cool. The mixture was then poured into ice water and left overnight. The formed solid was filtered, washed with water and crystallized with methanol to yield compounds 3a-e [13].
With potassium carbonate In N,N-dimethyl-formamide Reflux;
4.1.11 General procedure for the preparation of compounds (XIVa-i.)
General procedure: A mixture of equimolar amount of 4-hydrazinyl derivative X and appropriate aldehyde (1.6 mmol) was stirred under reflux in absolute ethanol (10 ml) for 7-18 h. The obtained solid was filtered off, washed with absolute ethanol and crystallized from ethanol to afford the corresponding XIVa-i.
With potassium carbonate In dimethyl sulfoxide for 6h; Reflux;
With potassium carbonate In N,N-dimethyl-formamide for 24h; Reflux;
Synthesis of benzaldehyde derivatives (4a-4m)
General procedure: Appropriate seconder amines (5 mmol) and 4-fluorobenzaldehyde (5 mmol, 0.62 g) were refluxed in dimethylformamide (10 mL) with the presence of potassium carbonate (6 mmol, 0.83 g). After TLC screening, the mixture was poured into ice water and filtered. The products were recrystallized from ethanol (Osmaniye et al. 2019).
With potassium carbonate In N,N-dimethyl-formamide
With aluminum oxide for 0.0208333h; microwave irradiation;
90%
With potassium phosphate; benzoin oxime; copper diacetate In dimethyl sulfoxide at 80℃; Inert atmosphere;
General Procedure for Catalytic Experiments
General procedure: K3PO4 (5.62 mmol) in DMSO (4 mL), were added Cu(OAc)2 (0.28 mmol). The flask was evacuatedand backfilled with argon for three times. The resulting suspension was heated in a 80 °C oil bathwith stirring for the indicated time. The reactor was cooled to r.t., the flask was opened to air and thereaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), andorganic layer was washed with water (20 mL × 2) and once with brine (25 mL), dried overmagnesium sulfate and concentrated in vacuo. The product was purified by column chromatographyon silica gel using petroleum ether and ethyl acetate as eluent.1-(2-Methoxyphenyl)-1H-pyrrole (3a) [30]: colorless oil (0.43 g, 88%). 1H-NMR (400 MHz, CDCl3) δ (ppm):7.30-7.23 (2H, m), 7.03-6.98 (4H, m), 6.30 (2H,
83%
With water; sodium t-butanolate In toluene at 105℃; for 5h; Schlenk technique;
Palladium-catalyzed amination of aryl chlorides
General procedure: An oven-dried Schlenk tube was charged with the aryl halide (2 mmol) and amine (2.5 mmol), FeOA-Pd (0.05 g, 0.04 mmol, 1.5 mol%), base (3 mmol), solvent (5 mL) and additive. The resulting mixture was stirred for the appropriate time and temperature. After reaction completion the reaction mixture was then cooled to room temperature and the catalyst separated using a magnet, taken up in Et2O (4 mL), and washed with brine (5 mL). The resulting solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel.
76%
With copper; caesium carbonate; methyl-alpha-D-glucopyranoside In water; dimethyl sulfoxide at 110℃; for 14h; Sealed tube; Green chemistry;
General Procedure
General procedure: All the reactions were carried out in DMSO-H 2 O (1:1, 2 mL) in asealed vessel. To a 10 mL hydrothermal synthesis reactor was chargedCu powder (6 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), Cs 2 CO 3 (980 mg,3.0 mmol), nitrogen-containing heterocycle (1.5 mmol), amine (3.0mmol), and aryl halide (0.8 mmol). The reaction mixture was stirredfor a specified time at 100-110 °C. After TLC analysis confirmed thecomplete consumption of aryl halides, the mixture was cooled to r.t.(the pH was adjusted if the product was acidic), diluted with EtOAc(10 mL), filtered through a Celite pad, and washed with EtOAc (20-30mL). The organic layer was dried and concentrated. The residue waspurified by silica gel column chromatography to give the product.
58%
In dimethyl sulfoxide for 7h; Heating; Irradiation;
ethyl 2-(4-(piperidin-1-yl) phenyl)-1H-benzo[d]imidazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogensulfite; In ethanol; at 65℃; for 3h;
Preparation of ethyl 2-(4-(piperidin-1 -yl)phenyl)-1 H-benzo[d] imidazole-5-carboxylate (BZD9L 1 ) The synthetic scheme is depicted in F igure 4. 4-fluoro-3-nitrobenzoic acid (0.05 g, 0.27 mmol) was esterified in the presence of catalytic H2S O4 in E tOH (10 mL) by refluxing at 65 C for 6 h, with the reaction monitored by thin layer chromatography (TLC). U pon completion of the reaction, ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 h, treated with S nC (190 mg, 1 mmol) and stirred for a further 0.5 h. The resulting mixture was then treated with 4-(1 - piperidinyl)benzaldehyde (0.3 mmol) and NaHS 03 (57 mg, 0.3 mmol) and left to stir for another 3 h. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. The residue was resuspended in E tOAc (10 mL), washed with 10% a2C 03 (20 mL) and water (20 mL x 2), dried over a2S 04 and concentrated under reduced pressure. The crude products were purified by column chromatography (silica gel, 70-230 mesh; C HC I3-MeOH 9:1 ) to obtain the final product BZD9L1 (75% from starting material).
N-cyclohexyl-2-[4-(piperidin-1-yl)benzylidene]hydrazine-1-carbothioamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
In ethanol Reflux;
3.2.3. Synthesis of 2-(4-Substituted Benzylidene)-N-phenyl/cyclohexylhydrazine-1-carbothioamideDerivatives B1-B26
General procedure: Equal amounts of N-phenyl/cyclohexylhydrazinecarbothioamides 1,2 (2 mmol) and the synthesized4-substituted benzaldehyde (2 mmol) derivatives 3-16 were refluxed in ethanol (40 mL). Aftercompletion of the reaction, the product was filtered and recrystallized from ethanol.
1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium hydroxide In methanol for 10h;
3.1.3. General Procedure for the Synthesis of Target Compounds (3a-3o)
General procedure: 1-(4-(1H-imidazol-1-yl)phenyl)ethan-1-one (1) (0.316 g, 0.0017 mol) and appropriate 4-substitutedbenzaldehydes (2a-2o) derivatives (0.0017 mol) in methanol were stirred for 10 h in the presence ofpotassium hydroxide. The precipitated product was washed with water, dried, and recrystallizedfrom ethanol.
(E)-1-(4-(methylsulfonyl)phenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydroxide In methanol; water at 20℃;
General procedure: Chalcones analogs were synthesized by Claisen-Schmidt condensation reaction using appropriate equimolar amounts of substituted acetophenones and benzaldehydes in MeOH. NaOH was dissolved in the least amount of water and added dropwise (3mmol) (Scheme 1). Reactions were stirred overnight. All reactions were monitored by TLC using appropriate solvent or mixture of solvents. When the reaction was complete, the obtained precipitate was filtered, washed with cold methanol and dried under vacuum. The crude products were crystallized from different solvent systems based on their solubility or purified by column chromatography to give pure crystalline compounds.
(E)-1-(4-(methylthio)phenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium hydroxide In methanol; water at 20℃;
General procedure: Chalcones analogs were synthesized by Claisen-Schmidt condensation reaction using appropriate equimolar amounts of substituted acetophenones and benzaldehydes in MeOH. NaOH was dissolved in the least amount of water and added dropwise (3mmol) (Scheme 1). Reactions were stirred overnight. All reactions were monitored by TLC using appropriate solvent or mixture of solvents. When the reaction was complete, the obtained precipitate was filtered, washed with cold methanol and dried under vacuum. The crude products were crystallized from different solvent systems based on their solubility or purified by column chromatography to give pure crystalline compounds.
Stage #1: diazomethyl-trimethyl-silane With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: 4-(piperidin-1-yl)benzaldehyde In tetrahydrofuran at -78℃; for 1h;
B2.1 Step 1 : l-(4-ethynylphenyl)piperidine
To a solution of TMS-diazomethane (6.3 mL, 12.6 mmol) in THF (20 mL) was added BuLi (6.3 mL, 12.6 mmol, 2 M in THF) at -78 °C. The reaction was stirred for 30 min at - 78 °C. Then 4-(piperidin-l-yl)benzaldehyde (1.89 g, 10 mmol) was added in THF. The reaction was stirred for another 1 h at -78 °C. The mixture was quenched with sat. NH4CI (100 mL) and then extracted with ethyl acetate (100 mLx3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography to give the desired product (1.42 g, 77% yield).
4.1.3. General method for the synthesis of compounds 7a-i
General procedure: To a solution of 1,3-diphenyl-1H-pyrazol-5-amine (2) (1.17 g,5 mmol) in absolute ethanol (20 mL), the corresponding 3-oxo-3-un/substituted phenylpropanenitrile (1a-c) (5 mmol) and theappropriate 4-(un/substituted-1-yl)benzaldehyde (6a-c) (5 mmol)were added. 3 Drops of triethylamine were added as a catalyst, thenthe mixturewas refluxed for 10 h. The reaction mixturewas cooled,and the precipitated crystalline product was filtered, dried, andrecrystallized from ethanol 4.1.3.1. 1,3,6-Triphenyl-4-[4-(piperidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (7a)
4.1.3. General method for the synthesis of compounds 7a-i
General procedure: To a solution of 1,3-diphenyl-1H-pyrazol-5-amine (2) (1.17 g,5 mmol) in absolute ethanol (20 mL), the corresponding 3-oxo-3-un/substituted phenylpropanenitrile (1a-c) (5 mmol) and theappropriate 4-(un/substituted-1-yl)benzaldehyde (6a-c) (5 mmol)were added. 3 Drops of triethylamine were added as a catalyst, thenthe mixturewas refluxed for 10 h. The reaction mixturewas cooled,and the precipitated crystalline product was filtered, dried, andrecrystallized from ethanol 4.1.3.1. 1,3,6-Triphenyl-4-[4-(piperidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (7a)
With manganese(IV) oxide In dichloromethane at 20℃;
110.2 Step 2: 4-(piperidin-1-yl)benzaldehyde (INT-160)
(4-(piperidin-1-yl)phenyl)methanol 159 (90.5 mg, 0.473 mmol) and manganese dioxide (411 mg, 4.73 mmol) were suspended in DCM (2 mL). The reaction stirred at room temperature overnight. The reaction was filtered through Celite and rinsed with dichloromethane. The filtrate was concentrated in-vacuo. The crude material was purified by silica gel chromatography (0-60% EtOAc in heptane) to afford 4-(piperidin-1-yl)benzaldehyde INT-160 (73.9 mg, 0.387 mmol, 82 % yield) as a clear liquid that crystalized into a white solid. LCMS [M+H]+: 190.0.1H NMR (400 MHz, CD2Cl2) δ 9.74 (s, 1H), 7.81 - 7.66 (m, 2H), 7.01 (d, J = 8.5 Hz, 2H), 3.47 - 3.33 (m, 4H), 1.80 - 1.61 (m, 6H).
With piperidine In methanol at 20℃; for 12h; Darkness;
General procedure:
General procedure: Piperidine (0.06 g, 0.7 mmol) was added to amixture of Rofecoxib (0.2 g, 0.65 mmol) and either 4- or 2-piperidinobenzaldehyde(2.6 mmol) in methanol (15 mL) was stirred, and themixture was stirred at room temperature for 12 h in dark atmosphere.The resulting precipitate was collected by filtration and washed withmethanol to afford the products with high purity. The structure of ROF1and ROF2 were characterized and confirmed by 1H NMR, 13C NMR,HRMS and X-ray structural analysis (Figs. S1-S6). (Z)-4-(4-(methylsulfionyl)phenyl)-3-phenyl-5-(4-(piperidin-1-yl)benzylidene)furan-2(5H)-one (ROF1)ROF1 was prepared using the general procedure described above,the red powder of ROF1 (0.14 g) was obtained with the yield 86%. Mp:218-220 C. IR (KBr, cm 1): 846, 857, 919, 945, 970, 980, 1021, 1089,1126, 1148, 1159, 1188, 1220, 1248, 1287, 1311, 1356, 1390, 1445,1465, 1518, 1569,1582, 1596, 1754, 2850, 2925.1H NMR (600 MHz,DMSO-d6) 8.06 (d, J = 8.5 Hz, 2H), 7.71-7.63 (m, 4H), 7.35-7.28 (m,5H), 6.98 (d, J = 9.1 Hz, 2H), 5.97 (s, 1H), 3.34 (s, 4H), 3.31 (s, 3H),1.59 (s, 6H). 13C NMR (151 MHz, DMSO-d6) 184.8, 180.3, 168.2,151.8, 149.3, 144.9, 141.9, 135.9, 132.8, 130.7, 129.7, 129.4, 129.0,128.8, 128.0, 123.3, 122.2, 114.8, 114.7, 48.3, 43.7, 25.4, 24.4.HRMS-ESI (m/z): [M+H]+ calcd for C29H27NO4S, 486.1734; found,486.1733.
With potassium hydroxide In ethanol; water monomer at 20℃; for 3h;
6.1 Example 6
(1) Dissolve 1 mmol of p-dimethylaminoacetophenone in 3 mL of ethanol, then add 1 mmol of 4-(1-piperidinyl)benzoin aldehyde (p-dimethylaminoacetophenone and 4-(1-piperidine) Base) the ratio of the amount of benzoin aldehyde is 1:1), then add 3 mL of potassium hydroxide aqueous solution with a mass concentration of 10%, after stirring at room temperature for 3h, there is solid precipitation, use TLC to detect that the reaction is complete and stop the reaction to obtain the reaction mother liquor The above-mentioned reaction mother liquor is subjected to suction filtration, the filter cake is washed with water many times, dried, and subjected to column chromatography, and gradient elution is carried out according to the proportion of petroleum ether: ethyl acetate=30:13:1, and the particles of silica gel The diameter is 200-300 mesh, and the intermediate 6a is obtained through the column; the structural formula of the intermediate 6a is as follows:
With tetrahydropyrrole In methanol at 40℃; for 8h;
5
Weigh compound a-1 and compound b-2 with a molar ratio of 1:1, dissolve them in methanol, add a catalytic amount of tetrahydropyrrole catalyst, heat to 40°C for 8 hours, cool and filter to obtain orange-red intermediate c-4 .Weigh c-4 (1eq.) and dissolve it in acetonitrile, add d, e, f, or g (2eq.) and heat to 80°C for 8 hours,Cool, filter, recrystallize and wash with acetonitrile/ethyl acetate to obtain dark red compounds AD-17-AD-20.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
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