Structure of 3132-99-8
                                
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Nitrothiazole-Thiazolidinone Hybrids: Synthesis and in Vitro Antimicrobial Evaluation
Dylan Hart ; Lesetja J. Legoabe ; Omobolanle J. Jesumoroti ; Audrey Jordaan ; Digby F. Warner ; Rebecca Steventon , et al.
Abstract: Herein we report the synthesis of novel compounds inspired by the antimicrobial activities of nitroazole and thiazolidin-4-one based compounds reported in the literature. Target compounds were investigated in vitro for antitubercular, antibacterial, antifungal, and overt cell toxicity properties. All compounds exhibited potent antitubercular activity. Most compounds exhibited low micromolar activity against S. aureus and C. albicans with no overt cell toxicity against HEK-293 cells nor haemolysis against human red blood cells. Notably, compound 3b exhibited low to sub-micromolar activities against Mtb, MRSA, and C. albicans. 3b showed superior activity (0.25 μg/ml) against MRSA compared to vancomycin (1 μg/ml).
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                        | CAS No. : | 3132-99-8 | 
| Formula : | C7H5BrO | 
| M.W : | 185.02 | 
| SMILES Code : | O=CC1=CC=CC(Br)=C1 | 
| MDL No. : | MFCD00003345 | 
| InChI Key : | SUISZCALMBHJQX-UHFFFAOYSA-N | 
| Pubchem ID : | 76583 | 
| GHS Pictogram: | 
                                
                                
                                     
                                
                                
                             | 
| Signal Word: | Warning | 
| Hazard Statements: | H302-H315-H319-H335 | 
| Precautionary Statements: | P261-P305+P351+P338 | 
| Num. heavy atoms | 9 | 
| Num. arom. heavy atoms | 6 | 
| Fraction Csp3 | 0.0 | 
| Num. rotatable bonds | 1 | 
| Num. H-bond acceptors | 1.0 | 
| Num. H-bond donors | 0.0 | 
| Molar Refractivity | 39.53 | 
| TPSA ? Topological Polar Surface Area: Calculated from   | 
                                            17.07 Ų | 
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from   | 
                                            1.68 | 
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by   | 
                                            2.34 | 
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from   | 
                                            2.26 | 
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from   | 
                                            2.21 | 
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by   | 
                                            2.68 | 
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions  | 
                                            2.23 | 
| Log S (ESOL):? ESOL: Topological method implemented from   | 
                                            -2.89 | 
| Solubility | 0.239 mg/ml ; 0.00129 mol/l | 
| Class? Solubility class: Log S scale   | 
                                            Soluble | 
| Log S (Ali)? Ali: Topological method implemented from   | 
                                            -2.34 | 
| Solubility | 0.85 mg/ml ; 0.00459 mol/l | 
| Class? Solubility class: Log S scale   | 
                                            Soluble | 
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by   | 
                                            -3.2 | 
| Solubility | 0.117 mg/ml ; 0.000634 mol/l | 
| Class? Solubility class: Log S scale   | 
                                            Soluble | 
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg  | 
                                            High | 
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg  | 
                                            Yes | 
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set)   | 
                                            No | 
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)  | 
                                            Yes | 
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)  | 
                                            No | 
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)  | 
                                            No | 
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)  | 
                                            No | 
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)  | 
                                            No | 
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from   | 
                                            -5.77 cm/s | 
| Lipinski? Lipinski (Pfizer) filter: implemented from   | 
                                            0.0 | 
| Ghose? Ghose filter: implemented from   | 
                                            None | 
| Veber? Veber (GSK) filter: implemented from   | 
                                            0.0 | 
| Egan? Egan (Pharmacia) filter: implemented from   | 
                                            0.0 | 
| Muegge? Muegge (Bayer) filter: implemented from   | 
                                            2.0 | 
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat   | 
                                            0.55 | 
| PAINS? Pan Assay Interference Structures: implemented from   | 
                                            0.0 alert | 
| Brenk? Structural Alert: implemented from   | 
                                            1.0 alert: heavy_metal | 
| Leadlikeness? Leadlikeness: implemented from   | 
                                            No; 1 violation:MW<1.0 | 
| Synthetic accessibility? Synthetic accessibility score:  from 1 (very easy) to 10 (very difficult)  | 
                                            1.12 | 
* 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.

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 26% | Stage #1: With sodium methylate In methanol; ethanol at 20℃; for 9 h; Inert atmosphere; Reflux Stage #2: With sodium hydroxide In methanol; ethanol at 70℃; for 5 h;  | 
                                                        3-bromobenzaldehyde (18.5 g, 100 mmol), acetophenone (12.0 g, 100 mmol), 1N-sadium methoxide/methanol solution (10 ml) and ethanol (200 ml) were stirred for five hours at the room temperature under an Ar gas atmosphere. Subsequently, the reactant mixture was heated and stirred for another four hours at a reflux temperature. Next, benzamidine hydrochloride (9.4 g, 60 mmol) and sodium hydroxide (8.0 g, 200 mmol) were added thereto and stirred for five hours at 70 degrees C. After the reaction, the reactant mixture was filtered to separate an extract. The extract was refined by silica-gel column chromatography (a developing solvent: dichloromethane) to provide an intermediate body X6 as a white solid. A yield of the intermediate body X6 was 10.1 g and a yield rate thereof was 26percent. | 

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 97% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 20h; | 3-Bromobenzaldehyde (18.5 g, 100 mmol) and 2,6-dimethylphenylboronic acid (21.0 g, 140 mmol) were dissolved in a mixture of 1 M aqueous sodium carbonate solution (200 mL), ethanol (100 mL) and toluene (200 mL). The air was substituted with argon gas, and tetrakis(triphenylphosphine)palladium(0) (5.78 g, 5.00 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 80C for 20 hr. After cooling the reaction mixture, water was added and the mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite. The organic layer in the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound (20.4 g, yield 97%) as a colorless oil. MS m/z 211 (MH+). | 
| 96% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃;Inert atmosphere; | 3-Bromobenzaldehyde (1.8 g, 10 mmol) and (2,6-dimethylphenyl)boronic acid (2.1 g, 14 mmol) were dissolved in a mixture of 1 M aqueous sodium carbonate solution (20 mL), EtOH (10 mL), and toluene (20 mL). After argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.5 mmol) was added. The reaction mixture was stirred under argon atmosphere at 80 C for 20 h. The reaction mixture was cooled, and water was added to the reaction mixture. The mixture was diluted with AcOEt, and the insoluble material was filtered through Celite. The organic layer of the filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 1, v/v) as eluent to afford the product 7a (2.1 g, 96%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ: 10.06 (s, 1H), 7.86-7.90 (m, 1H), 7.67-7.69 (m, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.42-7.46 (m, 1H), 7.11-7.23 (m, 3H), 2.02 (s, 6H). | 
| 83% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; toluene; at 80℃; for 22h;Inert atmosphere; | 3-bromo-benzaldehyde (370.4 mg, 2.002 mmol), 2,6- dimethyl phenyl boronic acid (420.5 mg, 2.804 mmol), saturated aqueous sodium hydrogen carbonate solution (1M solution, 4 mL, 4.001 mmol) ethanol (2.2 mL) of and in a mixed solution of toluene (4 mL), tetrakis (triphenylphosphine) palladium (0) (114.9 mg, 0.099 mmol) was added, under an argon atmosphere and stirred for 22 hours at 80 C.. The reaction mixture was cooled, water (5 mL) and ethyl acetate (10 mL) was added and filtered over Celite (registered trademark). Was separated into aqueous and organic layers, the aqueous layer was extracted twice with ethyl acetate (20 mL), the combined organic layers were extracted with brine (30 mL), further sedge aqueous layer of ethyl acetate (20 and extracted with mL). The combined organic layers were dried over sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography to give the title compound (hexane: diethyl ether = 60:: 1 ~ 50 1) (347.8 mg, 1.655 mmol, 83 %, to give a colorless oil). | 
| 83% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene; at 80℃; for 22h;Inert atmosphere; | 3-bromobenzaldehyde (370.4 mg, 2.002 mmol), 2,6- dimethyl phenyl boronic acid (420.5 mg, 2.804 mmol), saturated aqueous sodium hydrogen carbonate solution (1M solution, 4 mL, 4.001 mmol) ethanol (2.2 mL) of and in a mixed solution of toluene (4 mL), tetrakis (triphenylphosphine) palladium (0) (114.9 mg, 0.099 mmol) was added, under an argon atmosphere and stirred for 22 hours at 80 C.. The reaction mixture was cooled, water (5 mL) and ethyl acetate (10 mL) was added and filtered over Celite (registered trademark). Was separated into aqueous and organic layers, the aqueous layer was extracted twice with ethyl acetate (20 mL), the combined organic layers were extracted with brine (30 mL), further sedge aqueous layer of ethyl acetate (20 and extracted with mL). The combined organic layers were dried over sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography (hexane: diethyl ether = 60: 1 to 50: 1) toRi purified title compound (347.8 mg, 1.655 mmol, 83%, colorless oil) was obtained. | 
| With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100℃; for 16h; | To a degassed solution of 3-bromobenzaldehyde (500 mg, 2.70 mmol) , (2, 6-dimethylphenyl) boronic acid (608 mg, 4.05 mmol) , and Pd (PPh3) 4 (156 mg, 0.14 mmol) in dioxane (5 mL) was added K2CO3 (2N, 4.05 mL, 8.11 mmol) . The reaction was heated to 100. After 16 h, the mixture was poured into NH4Cl (sat, 25 mL) and extracted with EtOAc (2 x 25 mL) . The combined organic layers were dried over MgSO4 and concentrated. The resulting residue was purified by HPLC (ISCO 40 gram silica gel cartridge, 0 to 40EtOAc/Hex) to give the title compound. | 

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 82% | With potassium carbonate; In 1,2-dimethoxyethane; ethanol; water; for 20h;Heating / reflux; | (d) 3-('3-Formvlphenyl)-5-/.siotao-butyl-Lambda^-fer/-butylthiophene-2-sulfonamide; Palladium acetate (84.6 mg, 0.38 mmol) and triphenylphosphine (0.40 g, 1.52 mmol) in DME (5 mL) were stirred for 30 min under N2(g). The catalyst was then transferred into a nitrogen-flushed mixture of 5-iso-butyl-2-(N-tert- butylaminosulfonyl)tbiophene-3-boronic acid (4.0 g, 12.56 mmol, see step (c) above), 3-bromobenzaldehyde (2.96 g, 25.12 mmol) and potassium carbonate (5.21 g, 37.7 mmol) in a solvent mixture of DME (28 mL), ethanol (8 mL), and water (12 mL). After stirring for 20 h at reflux under a N2 atmosphere, the reaction mixture was diluted with NaOH (IM solution, 50 mL) followed by ethyl acetate (150 mL). The organic layer was washed with water, and brine, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue subjected to flash chromatography (20% ethyl acetate in petroleum ether, 230-400 mesh) to afford the title compound as colourless solid (3.9 g, 10.3 mmol, 82%). m.p. 96-98 0C.IR (neat, cm"1) v 2960, 1701, 1391, 1319, 1144, 10521H NMR (CDCl3) delta 0.98 (d, 6H, J= 6.6 Hz)5 1.03 (s, 9H), 1.93 (m, IH), 2.69 (d, 2H5 J= 6.6 Hz)5 4.22 (br s, IH), 6.79 (s, IH), 7.61 (t, IH, J= 7.92 Hz)5 7.88-7.98 (m, 2H),.8.04 (t, IH, J= 1.65 Hz)5 10.05 (s, IH).13C NMR (CDCl3) delta 22.12, 29.58, 30.52, 39.14, 54.75, 128.89, 129.10, 129.39, 130.01, 135.18, 135.88, 136.31, 137.04, 141.82, 148.90, 191.95. EPO <DP n="39"/>MS (ESI+) m/z: 380.0 (M+ +1).Anal. Calcd for C19H25NO3S2: C5 60.1; H5 6.6, N, 3.7; Found C5 60.4; H5 6.7; N5 3.7. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 96% | With Amino glucose-functionalized silica-coated NiFe2O4 nanoparticles; at 20℃; for 0.133333h; | General procedure: A mixture of aldehyde 1 (1.0 mmol), 1,2-aminophenol (1 mmol)and 0.05 g of NiFe2O4(at)SiO2(at)aminoglucose were stirred at roomtemperature under solvent free condition for the required reactiontime according to Table 6 and 7 After completion of the reaction, asindicated by TLC (TLC Silica gel 60 F, ethyl acetate: n-hexane 1: 4),the resulting mixture was diluted with hot ethanol (10 mL) and thecatalyst separated by the external magnet and washed with hotdistilledwater (5 mL) and ethanol (3 mL) two times. The filtratewascooled down to room temperature and the precipitated crudeproduct was recrystallized from ethanol if necessary. | 
| 92% | With oxygen; potassium carbonate; at 80℃; for 6h; | General procedure: In a 25 mL round bottomed flask, a mixture of 2-aminophenol,2-aminothiol (1.2 mmol), aldehyde (1 mmol),K2CO3(1.5 mmol), and MNPs-phenanthroline-Pd catalyst(25 mg) was stirred in PEG (3 ml) at 80 C for 6 h. Theprogress of the reaction was monitored by thin-layer chromatography(TLC). After completion of the reaction, catalystwas separated by an external magnet and the reactionmixture was extracted with H2Oand ethyl acetate and driedover anhydrous Na2SO4.After evaporation of the solvent,the desired product was isolated by silica gel flash columnchromatography with a mixture of petroleum ether/ethylacetate as eluent. | 
| 90% | With dodeca-tungstophosphoric acid; In neat (no solvent); at 20℃;Green chemistry; | General procedure: To a mixture of aromatic aldehyde/s(0.01mol) and 2-aminophenol/substituted 2aminophenol(0.01mol)solid phosphotungesticacid (0.020 g) was added and the whole reactionmixture was blended thoroughly in pestle and mortarwhich subsequently was allowed to grind vigorously with thehelp of mortar for appropriate time(15-25min) at room temperature.The progress of the reaction was monitored by TLC(eluent phase = n-hexane: EtOAc= 1:9). After the completionof the reaction, ethyl acetate was added to this reactionmixture in the pestle to dissolve the organic compound PTAcatalyst was precipitated out. The whole solution was filteredand solvent was removed on rotator evaporator under reducedpressure. The benzoxazole crude product was separatedand purified through the column chromatography usingn-hexane/ethyl acetate (1:9) as an eluent system | 
| 83% | With cerium(IV) oxide; In water monomer; at 30℃; for 0.416667h; | General procedure: A mixture of 2-aminothiophenol (1mmol) and benzaldehyde (1 mmol) was stirred in presence of Nano CeO2(5 mol %) in water at room temperature for 20 minutes. After completion, thereaction mixture was diluted with ethyl acetate and subsequently centrifuged to get the catalyst. Further the reactionmixture was extracted with ethyl acetate (10 x 3mL) and dried over Na2SO4. The solvent was evaporated under reducedpressure to obtain product. The crude product was purified on silica gel columnby using pet ether and ethyl acetate as solvent to get the pure product | 
| 72% | With silica chloride; In neat (no solvent); at 120℃; for 4h; | General procedure: To the flask containing a mixture of substituted benzaldehyde (1mmole) and 2-aminophenol (1mmole) was added silica chloride(1 eq) and was heated on a sand bath at 120 C, TLC was taken afterevery 1 h. After 4 h, TLC showed appearance of new spot. The productwas isolated by first separating out the catalyst by filtration using organicsolvent; the organic layer was dried using anhydrous sodiumsulfate and evaporated under vacuum. The solid thus obtained was recrystallized using petroleum ether and its % yield and melting pointswere determined. The results are tabulated in Table 1 and Table 2. | 

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 81% | at 90℃; for 10h;Neat (no solvent); | Aldehyde 1 (1 mmol), dihydrothiophen-3(2H)-one-1,1-dioxide 2 (0.134 g, 1 mmol), enaminone 3 (1 mmol) and were triturated together in an agate mortar for 5 minutes. Then the mixture was kept at 90 C for a certain time (monitored by TLC). The result mixture was washed with water and recrystallized from ethanol (95 %) to give pure product 4. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 100% | toluene-4-sulfonic acid; In toluene; for 12h;Reflux; | A mixture solution of <strong>[369-26-6]3-amino-4-fluoro-benzoic acid methyl ester</strong> (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-4-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 338.0 | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| In ethanol; at 60℃; for 0.5h; | General procedure: A mixture of corresponding hydrazinylpyridazine 1 or 5 (1 mmol) and aldehyde 2 (1.1 mmol) in ethanol (5 mL) was heated at 60 oC for 0.5 h. The formation of hydrazone was checked by TLC and the reaction mixture was cooled to rt. Oxone (1.5 mmol) was added to the mixture at rt followed by tetramethyl ammonium bromide (0.2 mmol) and the resulting mixture was heated at 60 oC for another 5 h. The mixture was cooled to rt and extracted with dichloromethane (2 × 25 mL), dried over anhydrous sodium sulphate and concentrated to obtain a residue which was purified by column chromatography using hexane/ethyl acetate as eluent to furnish the desired triazolopyridazines 4 and 7. | |
| In ethanol; at 60℃; for 0.5h; | General procedure: A mixture of corresponding hydrazinylpyridazine 1 or 5 (1 mmol) and aldehyde 2 (1.1 mmol) in ethanol (5 mL) was heated at 60 C for 0.5 h. The formation of hydrazone was checked by TLC and the reaction mixture was cooled to rt. Oxone (1.5 mmol) was added to the mixture at rt followed by tetramethyl ammonium bromide (0.2 mmol) and the resulting mixture was heated at 60 C for another 5 h. The mixture was cooled to rt and extracted with dichloromethane (2 × 25 mL), dried over anhydrous sodium sulfate and concentrated to obtain a residue which was purified by column chromatography using hexane/ethyl acetate as eluent to furnish the desired triazolopyridazines 4 and 7 (See reference no; 7 for supporting information). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 39% | General procedure: All materials were dried for one day at 120 C. Chloride and carbonyl derivatives were introduced into a Schlenk of 30 mL. Products were put in vacuo, then under nitrogen. An appropriate volume of anhydrous DMF was added after 10 min of nitrogen bubbling. The solution was vigorously stirred for 20 min at -20 C. TDAE was added slowly under inert atmosphere. The reaction was stirred for one hour. The second reaction phase was performed at rt or at temperature according to procedure of synthesis. The reaction was hydrolysed with distilled water after TLC analysis clearly showed that the chloride 1 had been totally consumed. The aqueous solution was extracted with dichloromethane and the combined organic layers washed with brine then dried on MgSO4. | 
                                                    
                                                    [ 3132-99-8 ]
                                                    
                                                    [ 34800-90-3 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 69.2% | In ethanol;Reflux; | General procedure: solutionof acid hydrazide (0.01 mol) and appropriate benzaldehyde/acetophenone (0.01 mol) in ethanol was refluxed for 5-6 h. The precipitated title compounds were then filtered off, washed with water and recrystallized from ethanol. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 42% | A 300 mL three-necked flask was charged with 1.21 ml (9.96 mmol) of the compound f,150 ml of dehydrated diethyl ether was added, and under a nitrogen atmosphereAnd the mixture was stirred at -70 C. or lower. N-Butyl lithium 6.0 ml (1.65 mol / l n-hexane solution,9.90 mmol) was added at -70 C. or less within 60 minutes, and the mixture was stirred for 2 hours.A solution of 0.29 ml (11.0 mmol) of compound g in 30 ml of dehydrated diethyl etherThe solution was added all at once and then stirred for a further 2 hours. After returning the reaction mixture to room temperature,100 ml of methanol was added to terminate the reaction. After distilling off the solvent,The obtained viscous substance was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 1.44 g (4.21 mmol) of the objective compound h,It was obtained in a yield of 42%. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 83% | In water; dimethyl sulfoxide; at 100 - 140℃; | (1036) A 25 mL pear-shaped flask with stir bar was charged with 49 (0.30 g, 2.0 mmol, 1 eq) and 3-bromobenzaldehyde (Aldrich, 0.37 g, 2.0 mmol, 1 eq). DMSO (2 mL) was added followed by a couple of drops of water. The resulting stirred solution, open to the air, was heated to 100 C. overnight. LCMS indicated the reaction was not complete. The temperature was increased to 140 C. After 3 h the reaction was cooled to room temperature and diluted with water. The solids were collected via vacuum filtration. The filter cake was rinsed with water followed by 20% DCM/hexanes and air dried. 0.523 g (1.7 mmol, 83% yield) of 72 was collected as an off-white solid. Mass spectrum (ESI+): m/z=315 [M+1]. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 69% | With potassium carbonate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; | 3-Bromobenzaldehyde (i85 mg, i.0 mmol) was suspended in dioxane (2 mL) and potassium carbonate (207 mg, i .5 mmol) was added. The solution was purged with nitrogen for 5 mm and vinylboronic anhydride pyridine complex (240.7 mg, i.0 mmol) and PdCI2(dppf)•CH2CI2 (40.8 mg, 0.05 mmol) were added. The reaction mixture was stirred for 2 h.at iOO 00 The reaction mixture was added to a stirred mixture of 5% citric acid solution/brine/ethyl acetate = i/i/i v/v% (30 mL). The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure The crude residue was purified by column chromatography (heptane to ethyl acetate = iO/0 to i/i v/v%) to afford the title compound (9i mg, yield: 69%). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 7% | 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. | 
                                                    
                                                    [ 120315-65-3 ]
                                                    
                                                    [ 3132-99-8 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 59% | Isopropylmagnesium chloride lithium chloride complex(1.3 M in THF,8.34 mL,10.85mmol)was added drop-wise to a 0-5 °C solution of <strong>[120315-65-3]4-bromo-3-methoxybenzonitrile</strong>(2 g,9.43 mmol)inTHF(21 mL). The reaction was stirred for 5h,whereupon a solution of 3-bromobenzaldehyde(1.979 g,10.38 mmol)in THF(10.5 mL)was added drop-wise,maintaining a temperature of <10°C. The reactionwas permitted to slowly warm to room temperature overnight. The reaction quenched with a saturatedaqueous solution ofNH4Cl(25 mL)and extracted with MTBE(50 mL X 3). The combined organics werewashed with brine(20 mL),dried(Na2S04),and solvents were removed under reduced pressure. Purification by chromatography(80 g silica)eluting with a gradient of 0-10percent MTBEheptanes gave thetitle compound(1.77 g,5.56 mmol,59percent yield)as a beige syrup/oil. LCMS(Method r,Table 7)R1 = 0.86min; MS(ESI-)m/z = 315.7 [M-H+]. 1H NMR(501 MHz,DMSO-d6)8 7.67(d,J = 7.8 Hz,1H),7.47(t,J = 1.8 Hz,1H),7.43(dd,J = 7.8,1.5 Hz,1H),7.41(d,J = 1.4 Hz,1H),7.40- 7.36(m,1H),7.28(dt,J =7.8,1.5 Hz,1H),7.23(d,J = 7.8 Hz,1H),6.10(d,J = 4.4 Hz,1H),5.94(d,J = 4.1 Hz,1H),3.80(s,3H). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 63.05% | With palladium diacetate; sodium carbonate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere; | 3-Bromobenzaldehyde (1g, 5.40mmol), pinacolato-4,4,5,5-tetramethyl-2-vinyl-1,3,2-borate (1.2g, 8.10mmol),Pd(OAc)2 (121.24mg, 0.54mmol) and PPh3 (283.27mg, 1.08mmol) and Na2CO3 (1.14mg, 10.80mmol) were dissolvedin a mixture of water (3mL) and DMF (9mL), the mixture was reacted at 80C under nitrogen atmosphere for 12 hours.Thin layer chromatography (petroleum ether: ethyl acetate = 2/1) indicated that the starting material was completelyreacted. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate = 40/1 to 30/1) to give the title compound (as a yellowish oil, 540.00mg,3.40mmol, yield 63.05%). 1H NMR (400 MHz, METHANOL-d4) 9.99-10.05 (m, 1H), 7.98 (s, 1H), 7.71-7.86 (m, 2H),7.48-7.60 (m, 1H), 6.78-6.90 (m, 1H), 5.93 (d, J=17.57 Hz, 1H), 5.38 (d, J=11.04 Hz, 1H) | 
                                                    
                                                    [ 3132-99-8 ]
                                                    
                                                    [ 13338-63-1 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 49.3% | With sodium methylate; In methanol; at 60℃; | Using the method of synthesizing an intermediate similar to that of Example 1,Take 0.01 mol of <strong>[13338-63-1]3,4,5-trimethoxyphenylacetonitrile</strong> (5), 0.01 mol of 3-bromobenzaldehyde and 20 mL of methanol into a 50 mL three-necked flask.Stirring to 60 C, adding 0.005 mol of sodium methoxide, constant temperature reaction 4-6 h,TLC scanning and detection, after the reaction is completed, it is cooled to room temperature, filtered, washed with water, dried, and recrystallized from methanol to obtain a pale yellow solid. Yield: 49.3%, | 
                                                    
                                                    [ 28710-97-6 ]
                                                    
                                                    [ 3132-99-8 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 80% | With toluene-4-sulfonic acid; In methanol; for 4.0h;Reflux; | General procedure: p-Toluenesulfonic acid (PTSA) (0.1mmol, 10mol%) was added to a mixture of aminopyrazolone 1 (1mmol) and benzaldehyde 2a (2.5mmol) in methanol (5mL) and the mixture was stirred at reflux for 4h. Upon reaction completion (TLC), the solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (n-hexane/EtOAc, 3:1). (3aR*,4S*,8aR*,9S*)-2,4,7,9,11-Pentaphenyl-5,7,9,10-tetrahydro-3a,8a-methanodipyrazolo[3,4-b:3?,4?-f][1,5]diazocine-3,8(2H,4H)-dione (3a). | 
                                                    
                                                    [ 3132-99-8 ]
                                                    
                                                    [ 62-53-3 ]
                                                    
                                                    [ 446065-11-8 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 64% | for 0.2h;Microwave irradiation; | General procedure: Second step consists of condensation of <strong>[6761-52-0]3-aminopyrazine-2-carbohydrazide</strong> (0.5 gm, 0.003 mol) with aromatic aldehydes (0.5 gm, 0.008 mol) using microwaveirradiation (8 - 10 min, 350 W). After cooling and filtration,the product was recrystallized using ethanol [6, 9] (Fig. 1). | 
Tags: 3132-99-8 synthesis path| 3132-99-8 SDS| 3132-99-8 COA| 3132-99-8 purity| 3132-99-8 application| 3132-99-8 NMR| 3132-99-8 COA| 3132-99-8 structure
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