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CAS No. : | 1570-45-2 | MDL No. : | MFCD00006428 |
Formula : | C8H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MCRPKBUFXAKDKI-UHFFFAOYSA-N |
M.W : | 151.16 | Pubchem ID : | 15291 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.32 |
TPSA : | 39.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.21 cm/s |
Log Po/w (iLOGP) : | 1.88 |
Log Po/w (XLOGP3) : | 1.43 |
Log Po/w (WLOGP) : | 1.26 |
Log Po/w (MLOGP) : | 0.66 |
Log Po/w (SILICOS-IT) : | 1.51 |
Consensus Log Po/w : | 1.35 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.88 |
Solubility : | 1.98 mg/ml ; 0.0131 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.86 |
Solubility : | 2.1 mg/ml ; 0.0139 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.49 |
Solubility : | 0.491 mg/ml ; 0.00325 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.3 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H227-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
95% | for 4 h; Reflux | General procedure: The HT catalyst and substrate were added to MeOH and the mixture was refluxed with stirring. The reaction condition using HT and HT-like compounds as shown in Table 1 was carried out as follows: butyl decanoate 0.34 mmol, catalyst 5.2 mg, and MeOH 8 mL. After 8 h reaction, the amounts of the product and unreacted substrate were determined by GC using dichlorobenzene as an internal standard. Reaction condition in Table 2 was as follows: butyl decanoate 0.674 mmol, MeOH 16 mL, catalyst 10 mg(0.25 mmol of La/1 g HT). After 24 h reaction, the reaction mixture was analyzed by GC. Reaction condition in Table 3 was as follows: butyl dacanoate 0.674 mmol, MeOH 16 mL, catalyst 52 mg (0.25–1.00 mmol of La/1 g HT). After 8 h reaction, the reaction mixture was analyzed by GC. Reaction condition in Table 4 was as follows: substrate 0.674 mmol, MeOH 16 mL, catalyst La/HT-A 52 mg. The yields of products in the transesterification were determined by GC using dichlorobenzene or diethylene glycol dibutyl ether as an internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrazine hydrate In ethanol at 60℃; for 1 h; | Commercially available ethyl isonicotinate was refluxed with hydrazine hydrate. for 1 hr at 60° C. and the solvent was evaporated. Trituration of this solid with diethyl ether afforded pure hydrazide 2 in 86percent yield. The treatment of hydrazide 2 with CS2 and KOH in 60 ° C. for 18 hrs produced a solid upon concentration in vacuo. It was found that this material could be easily purified by trituration with H20 followed by filtration to give thiol 3 in 78percent yield, thus avoiding chromatography over the first two steps. This operationally simple procedure afforded multi-gram quantities of 3 for subsequence focused library synthesis. Finally, diversification of the aryl ring was achieved by nucleophilic displacement reaction of thiol 3 with substituted aryl bromides in room temperature DMF using K2C03 as base. |
86% | With hydrazine hydrate In ethanol at 60℃; for 1 h; | Commercially available ethyl isonicotinate was refluxed with hydrazine hydrate for 1 hr at 60° C. and the solvent was evaporated. Trituration of this solid with diethyl ether afforded pure hydrazide 2 in 86percent/o yield. The treatment of hydrazide 2 with CS2 and KOH in 60° C. for 18 hrs produced a solid upon concentration in vacuo. It was found that this material could be easily purified by trituration with H2O followed by filtration to give thiol 3 in 78percent yield, thus avoiding chromatography over the first two steps. This operationally simple procedure afforded multi-gram quantities of 3 for subsequence focused library synthesis. Finally, diversification of the aryl ring was achieved by nucleophilic displacement reaction of thiol 3 with substituted aryl bromides in room temperature DMF using K2CO3 as base. |
86% | With hydrazine hydrate In ethanol for 10.25 h; Cooling with ice; Reflux | Isonicotinicacid ethyl ester 1 (1.5g, 10mmol) was dissolved in 15mL of ethanol, then under ice-cooling was slowly added dropwise with hydrazine hydrate (2g, 40mmol), after the addition was complete, it was stirred at room temperature for 15min, then heated under reflux for 10h. After completion of the reaction, ethanol was removed by rotary evaporation, poured into water, extracted with ethyl acetate, the organic phase was dried and concentrated to give the desired product 2 (1.2g, 86percent), without purification into the next step. |
85% | With hydrazine hydrate In ethanol for 24 h; Reflux | Step 1: 15.12 g (0.1 mol) of ethyl pyridine-4-carboxylate and 10.00 g (0.2 mol) of hydrazine hydrate (NH 2 NH 2 · H 2 O) were added to 50 mL of ethanol, refluxed for 24 h, cooled to room temperature, and the solution was spun dry and recrystallized. The 11.62 g (0.085 mol) pyridine-4-formyl hydride was obtained in a yield of 85percent. |
73% | With hydrazine hydrate In ethanol for 6 h; Reflux | To a solution of ethyl isonicotinate (1.44 g, 10 mmol) inEtOH (10 mL), 85percent hydrazine hydrate (2 mL, 35 mmol)was added dropwise. The mixture was heated under refluxfor 6 h. After the reaction was over, the mixture was cooledto room temperature, filtered, washed with cool ethyl acetate,and then dried to give white solid isonicotinyi hydrazine 2,yield (1.0 g, 73percent). |
73% | With hydrazine hydrate In water for 6 h; | A mixture of ethyl isonicotinate (1.44 g, 10 mmol) and 85percent hydrazine hydrate (2 mL, 35 mmol) was heated under reflux for 6 h. The mixture was cooled to room temperature,filtered, washed with cool ethyl acetate, then dried to give white solid isonicotinohydrazide 2. Yield 1.0 g, 73percent. |
12.9 g | With hydrazine hydrate In ethanol for 3 h; Reflux | General procedure: An ethanol (300 ml) suspension of salicylic acid(13.8 g; 0.1 mol) and strongly acidic ion-exchange resin,Amberlyst-15 (5 g) were stirred with refluxing for three days.Insoluble catalyst was separated by filtration, and washed withethanol (3 20 ml). Combined ethanol filtrates were mixed with hydrazine hydrate (20 ml; 20.5 g; 0.4 mol) and refluxed with slowsolvent distillation using the modified Hickman still apparatus(Scheme 3). After 3 h of refluxing, the volume of the reaction mixturewas reduced to about 50 ml and white precipitate started toform. The white suspension was cooled to room temperature andthen left at 5 C for 1 h. Insoluble product was separated by filtration,washed with ice cold ethanol, and dried on air to give pureproduct (13.2 g; 87percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With lithium hexamethyldisilazane In tetrahydrofuran at -40℃; for 0.333333 h; Inert atmosphere | General procedure: To the solution of ester (10 mmol) in THF (20 mL) and ethyl acetate (70 mmol), LiHMDS (30 mmol) was added very quickly at -40 °C, and stirred at this temperature for 20 min. After completion of the reaction, reaction mixture was quenched with acetic acid (50 mmol) and then basified using 10percent NaHCO3 solution, extracted with ethyl acetate (2.x.100 mL), the combined organic layer was washed with water and brine solution and dried over Na2SO4. The specific purification procedure for each compound has been included along with their characterization data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: methyl (4-pyridyl) ketone With sodium hydride In tetrahydrofuran; paraffin oil at 20℃; for 1h; Inert atmosphere; Stage #2: isonicotinic acid ethylester In tetrahydrofuran; paraffin oil at 70℃; for 28h; Inert atmosphere; | |
75% | With sodium hydride In tetrahydrofuran; paraffin oil at 60℃; for 12h; | |
47% | Stage #1: methyl (4-pyridyl) ketone With sodium amide In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: isonicotinic acid ethylester In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere; Reflux; |
With sodium |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.2% | With pyrographite In toluene at 130℃; for 0.166667h; Irradiation; | 1.1; 2.1; 3.1 (1) Preparation of ethyl 4-pyridinecarboxylate 0.8 mol of isonicotinic acid was added in sequence to a 100 mL three-necked flask.0.64 mol of absolute ethanol, 2.0 g of activated powdered activated carbon was used as a catalyst, and toluene was used as a solvent.The microwave reaction time was 10 min (power 200 W; temperature 130 ° C).The reaction solution was neutralized with a saturated aqueous solution of Na 2 CO 3 until the pH was 7, and the layer was allowed to stand, and the upper layer was taken;The aqueous phase was extracted with 20 mL of chloroform and combined with organic layer.The chloroform was recovered by atmospheric distillation and then distilled under reduced pressure to give a colorless transparent liquid ethyl 4-pyridinecarboxylate with a purity of 96.3% (GC) and a yield of 97.2%. The activated powdery activated carbon was obtained by immersing the powdered activated carbon in 60 mL of a 25% aqueous solution of p-toluenesulfonic acid for 30 hours, suction filtration, and drying. |
90% | With N-dodecanoyl-N-methyl-1-glucamine In water at 45℃; for 5h; Green chemistry; | |
90% | With sulfuric acid for 12h; Reflux; | Synthesis of Ethyl Isonicotinate (1) To a solution of isonicotinic acid (1.23 g, 10 mmol) inethanol(20 mL), H2SO4(0.5 mL) was added dropwise. Thenthe mixture was fluxed for 12 h. When the reaction wascompleted, ethanol was evaporated, the mixture was washedby 20 mL of Na2CO3 solution, extracted with ether, and theethyl isonicotinate was obtained. Colorless liquid, yield:90%. |
90% | With sulfuric acid for 12h; Reflux; | Synthesis of Ethyl Isonicotinate A mixture of isonicotinic acid (1.23 g, 10 mmol), 20 mLof ethanol, and 0.5 mL of H2SO4 was refluxed for 12 h in a100 mL round-bottomed flask. After ethanol was evaporated under reduced pressure, about 20 mL of Na2CO3 solution (1M) was added into the mixture. Then the mixture was extracted with ether. After evaporation of the solvent, the product 1 was obtained. Colorless liquid, yield 90%. |
90% | With sulfuric acid for 6h; Reflux; | |
88.5% | With sulfuric acid for 5h; Reflux; | 1.1 Step 1: With stirring,In a 500ml three-necked flask for reflow and drying equipment,Add 50.5g of isonicotinic acid,Anhydrous ethanol 120ml,Add concentrated sulfuric acid,The mixture was heated under reflux with stirring for 3 hours.95% ethanol is recovered at atmospheric pressure,After cooling, add 50 ml of absolute ethanol.Continue the reflux reaction for 2 hours.After cooling, pour into 400ml of ice water.Neutralized to pH 7 with sodium bicarbonate,Then adjust the pH to concentrated ammonia.Extract three times with EtOAc.Combine organic layers,Washed to neutral,Washed with saturated saline,Dry over anhydrous sodium sulfate,Recovering the solvent under reduced pressure, Distilled under reduced pressure to give a colorless oily liquid isonicotinic acid ethyl ester 53.2g, yield 88.5% |
88% | With sulfuric acid at 80℃; for 4h; | |
82% | With sulfuric acid for 8h; Inert atmosphere; Reflux; | |
73% | With sulfuric acid In ethanol for 24h; Reflux; | |
67% | With sulfuric acid at 80℃; for 15h; | a (a) ethyl isonicotinate To a suspension of isonicotinic acid (5 g, 40.65 mmoL ) in EtOH ( 50 mL ) was added concentrated sulfuric acid (3.98 g, 40.65 mmol) dropwise. After the dropwise addition, the mixture was stirred at 80 °C for 15 hours. To this suspension were added water at 0 °C and adjusted pH=6.5 with NaHC03. The mixture was extracted with EA (150 mL x 3), the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to give ethyl isonicotinate (4 g, yield 67%). 1HNMR (300MHz, CHLOROFORM-d)5= 8.77 (d, J=5.5 Hz, 2H), 7.90 - 7.79 (m, 2H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). |
67% | With sulfuric acid In ethanol at 80℃; for 15h; | a (a)ethyl isonicotinate (a)ethyl isonicotinate To a suspension of isonicotinic acid (5 g, 40.65 mmoL) in EtOH (50 mL) was added concentrated sulfuric acid (3.98 g, 40.65 mmol) dropwise. After the dropwise addition, the mixture was stirred at 80° C. for 15 hours. To this suspension were added water at 0° C. and adjusted pH=6.5 with NaHCO3. The mixture was extracted with EA (150 mL*3), the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to give ethyl isonicotinate (4 g, yield 67%). 1H NMR (300 MHz, CHLOROFORM-d) δ=8.77 (d, J=5.5 Hz, 2H), 7.90-7.79 (m, 2H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). |
58% | With sulfuric acid | |
With sulfuric acid | ||
With sulfuric acid; benzene | ||
With chlorosulfonic acid | ||
With sulfuric acid for 240h; Heating; | ||
With sulfuric acid for 3h; Heating; | ||
With sulfuric acid | ||
With sulfuric acid for 8h; Reflux; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid | ||
With sulfuric acid for 8h; Reflux; | General method for the synthesis of hydrazides General procedure: Substituted aromatic acid (0.01 mol) was dissolved in 20 ml absolute ethanol added 1 ml conc. H2SO4 and refluxed for 8 h. The two third volume of reaction mixture was removed under reduced pressure and then poured into crushed ice and neutralized with sodium bicarbonate to obtain esters. In the subsequent step equimolar quantity of substituted ester (0.005 mol) and hydrazine hydrate (0.25 ml, 0.005 mol) in ethanol was refluxed for 24 h with stirring. The two third volume of alcohol was removed under reduced pressure and the reaction mixture was poured into the crushed ice. The resultant precipitate was filtered, washed with water and dried. The solid was recrystallized from 25 ml of 90 % ethanol. The purity of the compounds was checked by TLC using toluene-ethyl acetate-formic acid (5:4:1) as mobile phase. | |
With sulfuric acid Reflux; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid | ||
With thionyl chloride at 130℃; for 12h; | ||
With hydrogenchloride Reflux; | 4.2. General procedure for the synthesis of ethyl aromatic esters (8a-s) General procedure: Each substituted benzoic acid or aroyloxy acetic acid (7a-s) 0.088 mol was refluxed for 2-12 h in 2.4 mol of HCl gas saturated anhydrous ethanol. Then a hot solution was poured into 300 mL of water (no hydrochloride separates) to which solid Na2CO3 was added until the solution turns neutral. Precipitated ester was filtered by suction, dried and recrystallized from ethanol or methanol. In case of liquid esters, the neutralized solution was extracted with chloroform (25 mL x 3), the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear liquid. | |
With thionyl chloride for 6h; Reflux; | 2.5. General synthetic procedure for compound I General procedure: Aryl carboxylic esters (I) was synthesized from aromatic acids and ethanol. Thionyl chloride (32 mmol) was added dropwise to as tirred mixture of aromatic acids (8 mmol) and ethanol (70 mmol) at room temperature. After the reaction had been refluxed for 6 h, most of the ethanol was removed. The residue solution was poured into cold water (20 mL) and extracted with ethyl acetate (3 x 15 mL). Then, the organic layer was washed successively with water (3 x 10 mL). The organic layer was dried over an hydrous sodium sulfate. After filtration, the solvent was removed under vacuum to give the Compound I with high yield, which was not further purified. | |
With sulfuric acid at 110℃; | ||
With Amberlyst-15 | 1.1.4 3.1.1.1. Preparation of 2-Hydroxybenzohydrazide(HD2). General procedure: An ethanol (300 ml) suspension of salicylic acid(13.8 g; 0.1 mol) and strongly acidic ion-exchange resin,Amberlyst-15 (5 g) were stirred with refluxing for three days.Insoluble catalyst was separated by filtration, and washed withethanol (3 20 ml). Combined ethanol filtrates were mixed with hydrazine hydrate (20 ml; 20.5 g; 0.4 mol) and refluxed with slowsolvent distillation using the modified Hickman still apparatus(Scheme 3). After 3 h of refluxing, the volume of the reaction mixturewas reduced to about 50 ml and white precipitate started toform. The white suspension was cooled to room temperature andthen left at 5 C for 1 h. Insoluble product was separated by filtration,washed with ice cold ethanol, and dried on air to give pureproduct (13.2 g; 87%). | |
With sulfuric acid for 8 - 12h; Reflux; | ||
With thionyl chloride | ||
With sulfuric acid Reflux; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid | ||
With thionyl chloride; triethylamine at 5 - 25℃; for 22h; | 1-4 Example 2 Preparation of Isoniazid Add 200g (1 · 62mol) of isonicotinic acid to a 3000ml three-necked bottle.1600 g of ethanol, 16 · 4 g (0 · 162 mol) of triethylamine,Stir and cool to 5 °C ~ 10 °C,Slowly add 250g (2. lmol) of thionyl chloride,After the addition is completed, the temperature is controlled at 5 ° C ~ 10 ° C for 2 hours.Then heat up to 20 ° C ~ 25 ° C for 20 hours,After completion of the reaction, the oil was concentrated under reduced pressure, and 143 g (2.92 π ο1) hydrated hydrazine was added.Raise the temperature to 73 ° C ~ 76 ° C, after 10 hours of incubation,Add the diluent (350g of water), heat up and dissolve,To obtain an aqueous solution of the crude isoniazid, add activated carbon 10g,After holding at 70 ° C ~ 75 ° C for half an hour, filter, the filtrate is naturally cooled for 6 hours.Slowly cool to 0 ° C, filter, and dry to obtain the finished product of isoniazid.The purity was 99.95%, the single impurity was less than 0.10%, and the impurity J was not detected, and the total yield was 89%. | |
With sulfuric acid at 80℃; for 7h; | General synthetic procedure for intermediates 6a-6m General procedure: Taking 6a as an example, a mixture of benzoic acid (2.5 g,20.0 mmol), 4 mL sulfuric acid, and 50 mL ethanol was heated under reflux for 7 h (hour, h). After finishing the reaction, it was poured into water and extracted by ethylacetate, dried with anhydrous Na2SO4, and then the solventof the organic phase was evaporated under vacuum to give colorless liquid 4a. Then excess 80% N2H4·H2O and 15 mLof ethanol were added into the flask containing 4a, which was heated under reflux about 5 h. After the reaction was completed, it should be cooled into room temperature overnight and the white solid 5a was given after being filtered, washed with ethanol and dried in open air. Finally, 5a (1.4 g,8.0 mmol) was then subjected to substitution reaction with KOH (0.9 g, 15.6 mmol) and CS2(1.2 g, 15.0 mmol) togenerate intermediate 6a. At the same time, 6b-6m was synthesized by the methods described in the literature (Shi et al.2015; Du et al. 2013). | |
With sulfuric acid | ||
With thionyl chloride; triethylamine at 5 - 30℃; for 26h; | 1 Comparative Example 1 Add 200g (1.62mol) isonicotinic acid to a 3000ml three-necked bottle,1800g ethanol,16.4g (0.162mol) triethylamine,Stir to cool down to 510,Slowly add 295g (2.48mol) thionyl chloride,The addition is complete,Keep the temperature at 510 for 2 hours,Then heat up to 25 ~ 30 for 24 hours,After the reaction,Concentrate under reduced pressure to obtain an oil,Add 158g (3.2mol) hydrazine hydrate,Warm up to 7580,After holding for 10 hours,Add diluent (350g water),Appropriate temperature rise,Dissolve,Obtained the aqueous solution of crude isoniazid,Add 10g of activated carbon,After holding at 7075 for half an hour,filter,The filtrate is cooled naturally for 6 hours, And then slowly cooled to 0 ~ 5 ,filter,dry,To obtain the finished product of isoniazid,The yield is 87%,The purity is 99.91%. | |
With sulfuric acid Reflux; | - Route B (R1 = aryl) General procedure: Note: hydrazine and carbon disulphide used during this procedure have to be handled withcaution.The carboxylic compound was first converted into its ethyl ester by refluxing in absoluteethanol in the presence of a few drops of H2SO4. The ester was then treated overnight withhydrazine hydrate (2 to 4 equiv.) without solvent at 120 °C. Evaporation of excess hydrazineyielded the corresponding hydrazide compound. The hydrazide, solubilized in absolute ethanol,was treated with CS2 (5 equiv.) in the presence of KOH (1.7 equiv.) at 85 °C for 3 h. Water wasadded and pH was adjusted to 2-3 with 1N HCl. The formed precipitate was collected byfiltration and washed with water, yielding the 1,3,4-oxadiazol-thione, which was used withoutfurther purification. Finally, the preceding compound was treated with hydrazine hydrate (10equiv.) in absolute ethanol at 100 °C overnight in a sealed tube. After evaporation of excesshydrazine, the residue was purified on a silica gel column to yield the final compound. | |
With sulfuric acid at 78℃; for 2h; | ||
With sulfuric acid Reflux; | 3.3. General Procedure for the Synthesis of IsonicotinicAcid Hydrazide (3) The mixture of Isonicotinic acid (0.02mole) and absoluteethanol (0.20 M) with concentrated H2SO4 (1 mL) were gentlyrefluxed for an appropriate time. Then cooled the mixture,and the residue was poured into separating funnel containing200 ml of ice-cold water. Then ether was added andthe mixture was shaken vigorously. The ether layer waswashed with sodium bicarbonate solution for neutralizationof excess acid and water. Liquid ester was obtained by evaporationof ether. Then Hydrazine hydrate (0.01 M) and Isonicotinicethyl ester (0.01 M) were taken in a flat bottomflask. About 5 ml ethanol was added to make the mixture aclear solution. The reaction mixture was refluxed for completion,and the reaction was monitored through TLC plate.After the reflux, solid mass (compound-3) was filtered,washed with cold water, and recrystallized by ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 20 - 55℃; for 18h; | General procedure: For the synthesis of the hydroxylated precursors, ethanolamine (1.5 mmol) was added slowly to the esters (1 mmol) at 55°C and stirred for 3 h. The reaction mixture was stirred at room temperature for 15 h. The residue was purified by silica gel column chromatography (eluent/ethyl acetate/hexane 8:2) or recrystallized from ethyl acetate. The progress of the reaction was monitored by TLC.` |
In chloroform for 4h; Heating; | ||
1.04 g | at 55℃; for 21h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | With sodium ethanolate; at 25 - 105℃; for 4h; | The ethyl pyridine picoformate and ethyl acetate undergo a Claisen ester condensation reaction, and the other three bottles are equipped with a thermometer.Mechanically stirred, adding 76 g of 4-picolinic acid ethyl ester, 20.4 g of sodium ethoxide at room temperature, heating in an oil bath, and slowly heating the temperature in the reaction flask from 25 C to 105 C.50 g of ethyl acetate was added dropwise, and after completion of the dropwise addition, the reaction was completed in about 4 hours, and the system was thick.Cool to room temperature, dilute hydrochloric acid to adjust pH = 6.8, stir for half an hour, filter, and wash the solid with petroleum ether;The solid obtained by suction filtration was ethyl 3-oxo 3-(4-pyridyl)propanoate, purity 95.5% (GC), yield 93.5%. |
With sodium ethanolate; at 20 - 78℃; for 11h; | 2.15 g of sodium ethoxide was added to the vessel,Cooling to 0 ~ 5 ,A mixed solution of 3.17 g of ethyl isonicotinate and 3.5 g of ethyl acetate was added dropwise,After the reaction mixture was stirred at room temperature for 1 h,And then heated to 78 C reflux 10h,After cooling to 25 ; add water 21.6g, stirring clarification, the direct response to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With hydrazine hydrate monohydrate In methanol for 0.0333333h; Microwave irradiation; | |
88% | With hydrazine hydrate monohydrate In ethanol Reflux; | General procedure for the synthesis of 2a-2i, 2j-2l,2n-2r General procedure: To a solution of 100 mmol of ethyl picolinate (for 2a-2i),ethyl nicotinate (for 2j), ethyl isonicotinate (for 2k), ethylbenzoate (for 2l) or thiophene-2-carboxylate (for 2n-2r) inEtOH was added hydrazine monohydrate (400 mmol). Thereaction mixture was refluxed overnight and cooled to roomtemperature. Half of the solvent was removed underreduced pressure and the residue was poured into ice. Theprecipitate was filtered and washed with ice-cold EtOH togive a product. |
87% | Stage #1: isonicotinic acid ethylester With hydrazine hydrate monohydrate at 75 - 80℃; for 10h; Stage #2: With pyrographite In water monomer at 70 - 75℃; for 0.5h; | 12-3; 5-6; 8-9; 11-12; 1 Comparative Example 1 Add 200g (1.62mol) isonicotinic acid to a 3000ml three-necked bottle,1800g ethanol,16.4g (0.162mol) triethylamine,Stir to cool down to 510,Slowly add 295g (2.48mol) thionyl chloride,The addition is complete,Keep the temperature at 510 for 2 hours,Then heat up to 25 ~ 30 for 24 hours,After the reaction,Concentrate under reduced pressure to obtain an oil,Add 158g (3.2mol) hydrazine hydrate,Warm up to 7580,After holding for 10 hours,Add diluent (350g water),Appropriate temperature rise,Dissolve,Obtained the aqueous solution of crude isoniazid,Add 10g of activated carbon,After holding at 7075 for half an hour,filter,The filtrate is cooled naturally for 6 hours, And then slowly cooled to 0 ~ 5 ,filter,dry,To obtain the finished product of isoniazid,The yield is 87%,The purity is 99.91%. |
87% | With hydrazine hydrate monohydrate In ethanol for 3h; Reflux; | |
86% | With hydrazine hydrate monohydrate In ethanol at 60℃; for 1h; | |
86% | With hydrazine hydrate monohydrate In ethanol at 60℃; for 1h; | 1 Commercially available ethyl isonicotinate was refluxed with hydrazine hydrate. for 1 hr at 60° C. and the solvent was evaporated. Trituration of this solid with diethyl ether afforded pure hydrazide 2 in 86% yield. The treatment of hydrazide 2 with CS2 and KOH in 60 ° C. for 18 hrs produced a solid upon concentration in vacuo. It was found that this material could be easily purified by trituration with H20 followed by filtration to give thiol 3 in 78% yield, thus avoiding chromatography over the first two steps. This operationally simple procedure afforded multi-gram quantities of 3 for subsequence focused library synthesis. Finally, diversification of the aryl ring was achieved by nucleophilic displacement reaction of thiol 3 with substituted aryl bromides in room temperature DMF using K2C03 as base. |
86% | With hydrazine hydrate monohydrate In ethanol at 60℃; for 1h; | a Commercially available ethyl isonicotinate was refluxed with hydrazine hydrate for 1 hr at 60° C. and the solvent was evaporated. Trituration of this solid with diethyl ether afforded pure hydrazide 2 in 86%/o yield. The treatment of hydrazide 2 with CS2 and KOH in 60° C. for 18 hrs produced a solid upon concentration in vacuo. It was found that this material could be easily purified by trituration with H2O followed by filtration to give thiol 3 in 78% yield, thus avoiding chromatography over the first two steps. This operationally simple procedure afforded multi-gram quantities of 3 for subsequence focused library synthesis. Finally, diversification of the aryl ring was achieved by nucleophilic displacement reaction of thiol 3 with substituted aryl bromides in room temperature DMF using K2CO3 as base. |
86% | With hydrazine monohydrate In ethanol for 10.25h; Cooling with ice; Reflux; | 1 Isonicotinicacid ethyl ester 1 (1.5g, 10mmol) was dissolved in 15mL of ethanol, then under ice-cooling was slowly added dropwise with hydrazine hydrate (2g, 40mmol), after the addition was complete, it was stirred at room temperature for 15min, then heated under reflux for 10h. After completion of the reaction, ethanol was removed by rotary evaporation, poured into water, extracted with ethyl acetate, the organic phase was dried and concentrated to give the desired product 2 (1.2g, 86%), without purification into the next step. |
85% | With hydrazine monohydrate In ethanol for 24h; Reflux; | 19.1 3-(4-pyridyl)-6-(3-benzenesulfonate sodium)-[1,2,4]triazole [3,4-b][1,3,4]thiadi(SD-B-9) is exemplified by the synthesis (i.e., Preparation Example 19). Step 1: 15.12 g (0.1 mol) of ethyl pyridine-4-carboxylate and 10.00 g (0.2 mol) of hydrazine hydrate (NH 2 NH 2 · H 2 O) were added to 50 mL of ethanol, refluxed for 24 h, cooled to room temperature, and the solution was spun dry and recrystallized. The 11.62 g (0.085 mol) pyridine-4-formyl hydride was obtained in a yield of 85%. |
83% | With hydrazine hydrate monohydrate In ethanol | |
79.8% | With hydrazine hydrate monohydrate In ethanol for 8h; Reflux; | 1.2 Step 2: 30 g of ethyl isonicotinic acid is dissolved in 95% ethanol.Add 80% hydrazine hydrate,After the addition was completed, the mixture was heated to reflux for 8 hours.TLC detects the reaction completely,But condensed, concentrated under reduced pressure,Freezer in the refrigerator,Precipitating colorless needle crystals,Filter, wash twice, dryWhite crystal isoniazid 21.8g,The yield was 79.8% |
78% | With hydrazine In ethanol for 120h; Reflux; | |
76% | With hydrazine hydrate monohydrate In ethanol Reflux; | |
75% | With hydrazine hydrate monohydrate In ethanol at 20℃; | 6.1.1.3. General synthetic procedure for nicotinohydrazide derivatives(6 and 8). General procedure: The volume of 0.016 mol hydrazine hydrate was addedto a solution of ethyl nicotinate (5, 0.016 mol) in absolute ethanol(20 ml) and continuously stirred for 4-6 h at room tempera-ture. A solid was separated, quenched with water (50 ml), fil×20tered, and then washed with water (3ml). Finally, the solidhas been dried under the vacuum and recrystallized with ethanolto obtain nicotinohydrazide (6) . In the same way, isonicotinohy-drazide (8) was synthesized from ethyl isonicotinate ( 7 ). |
73% | With hydrazine hydrate monohydrate In ethanol for 6h; Reflux; | Synthesis of Isonicotinyi Hydrazine (2) To a solution of ethyl isonicotinate (1.44 g, 10 mmol) inEtOH (10 mL), 85% hydrazine hydrate (2 mL, 35 mmol)was added dropwise. The mixture was heated under refluxfor 6 h. After the reaction was over, the mixture was cooledto room temperature, filtered, washed with cool ethyl acetate,and then dried to give white solid isonicotinyi hydrazine 2,yield (1.0 g, 73%). |
73% | With hydrazine hydrate monohydrate In water monomer for 6h; | Synthesis of Isonicotinohydrazide A mixture of ethyl isonicotinate (1.44 g, 10 mmol) and 85% hydrazine hydrate (2 mL, 35 mmol) was heated under reflux for 6 h. The mixture was cooled to room temperature,filtered, washed with cool ethyl acetate, then dried to give white solid isonicotinohydrazide 2. Yield 1.0 g, 73%. |
With hydrazine hydrate monohydrate | ||
With methanol; hydrazine hydrate monohydrate | ||
With water monomer; hydrazine hydrate monohydrate | ||
With ethanol; hydrazine hydrate monohydrate | ||
With hydrazine In ethanol for 3h; Heating; | ||
With hydrazine hydrate monohydrate In ethanol for 2h; Heating; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate In ethanol Heating; | ||
With hydrazine hydrate monohydrate In ethanol; water monomer Reflux; | ||
With hydrazine In ethanol for 6h; Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate Reflux; Alcoholic solution; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate In ethanol for 24h; Reflux; | General method for the synthesis of hydrazides General procedure: Substituted aromatic acid (0.01 mol) was dissolved in 20 ml absolute ethanol added 1 ml conc. H2SO4 and refluxed for 8 h. The two third volume of reaction mixture was removed under reduced pressure and then poured into crushed ice and neutralized with sodium bicarbonate to obtain esters. In the subsequent step equimolar quantity of substituted ester (0.005 mol) and hydrazine hydrate (0.25 ml, 0.005 mol) in ethanol was refluxed for 24 h with stirring. The two third volume of alcohol was removed under reduced pressure and the reaction mixture was poured into the crushed ice. The resultant precipitate was filtered, washed with water and dried. The solid was recrystallized from 25 ml of 90 % ethanol. The purity of the compounds was checked by TLC using toluene-ethyl acetate-formic acid (5:4:1) as mobile phase. | |
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate Reflux; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine In ethanol at 130℃; for 12h; | ||
With hydrazine hydrate monohydrate Reflux; | 4.3. General procedure for the synthesis of acid hydrazides (9a-s) General procedure: The 0.015 mol of ethyl aromatic esters (8a-s) and 0.02 mol of hydrazine hydrate were dissolved in absolute ethanol or methanol (20 mL) to reflux the reaction mixture for 3-6 h for complete hydrazinolysis of ethyl aromatic esters. The product obtained was isolated after cooling as a white or yellow solid and recrystallized from ethanol or methanol. | |
With hydrazine hydrate monohydrate In ethanol Reflux; | 2.6. General synthetic procedure for compound II General procedure: A 5 mL absolute ethanol solution of hydrazine hydrate (80%) and Compound I (6 mmol) was refluxed for 4-6 h under severely stirring, the product being appeared as yellowish white solid. For purification of product, it was filtered and washed with 30 mL water and 30 mL ethanol pre-cooled by ice, and recrystallized from ethanol to yield the Compound II as white solid. | |
With hydrazine monohydrate In ethanol at 100℃; for 12h; | ||
12.9 g | With hydrazine hydrate monohydrate In ethanol for 3h; Reflux; | 3.1.1.1. Preparation of 2-Hydroxybenzohydrazide(HD2). General procedure: An ethanol (300 ml) suspension of salicylic acid(13.8 g; 0.1 mol) and strongly acidic ion-exchange resin,Amberlyst-15 (5 g) were stirred with refluxing for three days.Insoluble catalyst was separated by filtration, and washed withethanol (3 20 ml). Combined ethanol filtrates were mixed with hydrazine hydrate (20 ml; 20.5 g; 0.4 mol) and refluxed with slowsolvent distillation using the modified Hickman still apparatus(Scheme 3). After 3 h of refluxing, the volume of the reaction mixturewas reduced to about 50 ml and white precipitate started toform. The white suspension was cooled to room temperature andthen left at 5 C for 1 h. Insoluble product was separated by filtration,washed with ice cold ethanol, and dried on air to give pureproduct (13.2 g; 87%). |
With hydrazine In ethanol for 12h; Cooling with ice; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | Synthesis of the hydrazide ligands General procedure: Hydrazides were synthesized by reported methods [6, 9,10]. The appropriate hydrated hydrazine (2 mL, 40 mmol) was added to a solution of the ester (1 mmol) in ethanol (50 ml). The mixture was refluxed for 2-3 h to get a solid product. This was filtered off, washed with hexane and dried. The hydrazides were recrystallized from methanol. Analytical data for all the free ligands have been reported previously [19, 20]. | |
With hydrazine In ethanol for 15h; Reflux; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine monohydrate | ||
With hydrazine hydrate monohydrate In neat (no solvent) at 120℃; Sealed tube; | ||
With hydrazine hydrate monohydrate In ethanol at 30 - 100℃; for 8.5h; | 1.3 80% hydrated hydrazine 1.5 ml (0.03 mol) was dissolved in 10 ml of ethanol to form a mixed solution, and 4-picolinate (1.0 mol) was dissolved in 5 ml of ethanol and added dropwise to the mixture, reacted at 30 ° C for 0.5 h, and then raised to 100 ° C Should be 8h hydrazine hydrolysis intermediates, directly for the next step reaction; | |
With hydrazine hydrate monohydrate In ethanol | ||
With hydrazine monohydrate at 73 - 76℃; for 10h; | 1-4 Example 2 Preparation of Isoniazid Add 200g (1 · 62mol) of isonicotinic acid to a 3000ml three-necked bottle.1600 g of ethanol, 16 · 4 g (0 · 162 mol) of triethylamine,Stir and cool to 5 °C ~ 10 °C,Slowly add 250g (2. lmol) of thionyl chloride,After the addition is completed, the temperature is controlled at 5 ° C ~ 10 ° C for 2 hours.Then heat up to 20 ° C ~ 25 ° C for 20 hours,After completion of the reaction, the oil was concentrated under reduced pressure, and 143 g (2.92 π ο1) hydrated hydrazine was added.Raise the temperature to 73 ° C ~ 76 ° C, after 10 hours of incubation,Add the diluent (350g of water), heat up and dissolve,To obtain an aqueous solution of the crude isoniazid, add activated carbon 10g,After holding at 70 ° C ~ 75 ° C for half an hour, filter, the filtrate is naturally cooled for 6 hours.Slowly cool to 0 ° C, filter, and dry to obtain the finished product of isoniazid.The purity was 99.95%, the single impurity was less than 0.10%, and the impurity J was not detected, and the total yield was 89%. | |
With hydrazine Reflux; | ||
With hydrazine In ethanol | ||
With hydrazine In methanol for 7h; Reflux; | ||
With hydrazine hydrate monohydrate Reflux; | ||
With hydrazine monohydrate In ethanol | ||
With hydrazine monohydrate In ethanol for 5.25h; Reflux; | Hydrazides 1a-1l (general procedure). General procedure: A clean and dry 250-mL round-bottom flask was charged with 5 g of the corresponding ethyl ester and 50 mL of ethanol, and 5 g of hydrazine hydrate was added dropwise with stirring at room temperature over a period of 15 min. The mixture was then refluxed for 5 h (TLC) and concentrated, and the solid product was filtered off and recrystallized from methanol. | |
With hydrazine monohydrate In neat (no solvent) at 120℃; Sealed tube; | - Route B (R1 = aryl) General procedure: Note: hydrazine and carbon disulphide used during this procedure have to be handled withcaution.The carboxylic compound was first converted into its ethyl ester by refluxing in absoluteethanol in the presence of a few drops of H2SO4. The ester was then treated overnight withhydrazine hydrate (2 to 4 equiv.) without solvent at 120 °C. Evaporation of excess hydrazineyielded the corresponding hydrazide compound. The hydrazide, solubilized in absolute ethanol,was treated with CS2 (5 equiv.) in the presence of KOH (1.7 equiv.) at 85 °C for 3 h. Water wasadded and pH was adjusted to 2-3 with 1N HCl. The formed precipitate was collected byfiltration and washed with water, yielding the 1,3,4-oxadiazol-thione, which was used withoutfurther purification. Finally, the preceding compound was treated with hydrazine hydrate (10equiv.) in absolute ethanol at 100 °C overnight in a sealed tube. After evaporation of excesshydrazine, the residue was purified on a silica gel column to yield the final compound. | |
With hydrazine hydrate monohydrate In ethanol Reflux; | 4.1.1 General procedure for the synthesis of arylhydrazides 2 General procedure: The intermediate hydrazides 2 were prepared from appropriate esters 1 according to the reported method [31]. Briefly, to a solution of ethyl ester (1mmol) in EtOH, hydrazine hydrate (128mg, 4mmol) was added and the mixture was refluxed overnight. After evaporation of the solvent under reduced pressure, the residue was poured into ice. The precipitate was separated by filtration and washed with cold EtOH to give desired hydrazide compound. | |
With hydrazine hydrate monohydrate In ethanol at 78℃; for 6h; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | 3.3. General Procedure for the Synthesis of IsonicotinicAcid Hydrazide (3) The mixture of Isonicotinic acid (0.02mole) and absoluteethanol (0.20 M) with concentrated H2SO4 (1 mL) were gentlyrefluxed for an appropriate time. Then cooled the mixture,and the residue was poured into separating funnel containing200 ml of ice-cold water. Then ether was added andthe mixture was shaken vigorously. The ether layer waswashed with sodium bicarbonate solution for neutralizationof excess acid and water. Liquid ester was obtained by evaporationof ether. Then Hydrazine hydrate (0.01 M) and Isonicotinicethyl ester (0.01 M) were taken in a flat bottomflask. About 5 ml ethanol was added to make the mixture aclear solution. The reaction mixture was refluxed for completion,and the reaction was monitored through TLC plate.After the reflux, solid mass (compound-3) was filtered,washed with cold water, and recrystallized by ethanol | |
With hydrazine hydrate monohydrate In methanol Reflux; | 2.2. Synthesis and Characterization of Hydrazide Ligands General procedure: All the ligands (1-13) were synthesized by the reported method [31, 32]. Hydrazine hydrate (100 mmol) was added to the solution of ethyl benzoate in methanol (25 mmol) and then refluxed for 3-5 hours on a water bath. The resulting solid was washed with hexane to obtain pure hydrazide. Respective esters were used to prepare all the ligands. The synthesized ligands (1-13) were characterized with the help of elemental (C,Hand N) analysis, 1H NMR, 13C NMR, IR,and EI-Mass spectroscopy which was reported previously as well [31-33]. | |
With hydrazine hydrate monohydrate In methanol Reflux; | 2.2. Synthesis and Characterization of Hydrazide Ligands General procedure: All the ligands (1-13) were synthesized by the reported method [31, 32]. Hydrazine hydrate (100 mmol) was added to the solution of ethyl benzoate in methanol (25 mmol) and then refluxed for 3-5 hours on a water bath. The resulting solid was washed with hexane to obtain pure hydrazide. Respective esters were used to prepare all the ligands. The synthesized ligands (1-13) were characterized with the help of elemental (C,Hand N) analysis, 1H NMR, 13C NMR, IR,and EI-Mass spectroscopy which was reported previously as well [31-33]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dihydrogen peroxide In acetic acid at 70℃; Inert atmosphere; | |
93% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 10h; Sealed tube; | |
90% | With phthalic anhydride; urea-hydrogen peroxide In dichloromethane for 4h; Ambient temperature; |
83% | With urea hydrogen peroxide adduct; trifluoroacetic anhydride In acetonitrile at 0℃; for 0.166667h; | |
80% | R.51 4-Pyridinecarboxylic acid ethyl ester 1-oxide REFERENCE EXAMPLE 51 4-Pyridinecarboxylic acid ethyl ester 1-oxide The title compound was obtained from isonicotinic acid ethyl ester by the method similar to that in Reference Example 47. Yield: 80%. 1H NMR (CDCl3) δ 1.39 (3H, t, J = 7.0 Hz), 4.42 (2H, q, J = 7.0 Hz), 7.92-7.97 (2H, m), 8.33-8.39 (2H, m). | |
29% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 16h; | |
With phthalic anhydride; dihydrogen peroxide | ||
With dihydrogen peroxide; acetic acid | ||
10.5 g | With dihydrogen peroxide; acetic acid at 75℃; for 24h; | |
With dihydrogen peroxide; acetic acid In water at 75℃; for 24h; | 1 Ethyl-2-chloro-isonicotinate To a mixture of acetic acid and hydrogen peroxide (30%, 14 mi) was added ethyl isonicotinate (10 g). The solution was heated to 75°C for 24 h, then reduced to a third of the volume, made basic with aq K2C03 and extracted into dichloromethane. The CH2CI2 solution was dried and evaporated in vacuo to give the N- oxide as a white crystalline solid (10.5 g). The N-oxide (10.5 g) in chloroform (25 mi) was refluxed for 12 h with phosphorus oxychloride (25 ml), cooled, then poured onto ice. The product was extracted into dichloromethane, dried and evaporated to give ethyl-2-chloro- isonicotinate [Registry No. 54453-93-9] as a pale yellow liquid.'H NMR (300 MHz, CDCI3) 8.53 (1H, d, J 7Hz), 7.87 (1H, d, J 2Hz), 7.76 (1H, dd, J 2,7Hz), 4.42 (2H, q, J 8Hz) and 1. 40 (3H, t, J 8Hz). | |
Stage #1: isonicotinic acid ethylester With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 24℃; for 12h; Stage #2: With triphenylphosphine In dichloromethane for 4h; | ||
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 24h; | ||
Stage #1: isonicotinic acid ethylester With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 24h; Stage #2: With potassium carbonate In dichloromethane; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium hydroxide; hydroxylamine hydrochloride In methanol; water at 20℃; for 72h; | |
With hydrogenchloride; potassium hydroxide; hydroxylamine | ||
With hydrogenchloride; hydroxylamine; sodium methylate |
10.6 g | With hydroxylamine In methanol for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydride In 1,2-dimethoxyethane Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate for 2h; Ambient temperature; | |
44% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 8 - 10.5℃; for 2.41667h; Ice/methanol bath; | A.1; 6 A solution of ethyl isonicotinate (25.2 mL, 165 mmol) in formamide (200 niL) was stirred with ice/methanol bath cooling as concentrated sulfuric acid (8.80 mL, 165 mmol) was added. Ferrous sulfate heptahydrate (69 g, 248 mmol) and hydrogen peroxide (25.6 mL of 30% in water) were added slowly over 25 min in alternating portions such that the temperature of the mixture was kept between 8-10.5 °C. During this addition small pieces of dry ice were added to the bath to keep the reaction temperature in the desired range. After addition was complete, the ice bath was removed and the dark mixture was stirred for 2 h without cooling and then poured into a solution of trisodium citrate dihydrate (80.6 g) in water (700 mL) and then residues left in the reaction flask were washed out with a little methanol and water. The resulting mixture was rapidly stirred in a large flask as solid NaHCO3 was added slowly, portion-wise, until the mixture was basic. Some saturated aqueous NaHCO3 was added to make the mixture more basic and then it was vacuum filtered through Celite and the solids were washed down with three 200 mL portions of dichloromethane. The phases of the filtrate were separated and the aqueous layer was extracted twice with dichloromethane. The combined extract was dried (Na2SO4) and evaporated in vacuo. The resulting solid residue was washed with ether/hexane (200 mL, 1:30) twice with warming and sonication followed by cooling and filtration to yield 13.9 g (44%) of pure title compound. The wash solutions, which contained some highly contaminated desired product, were discarded.1H NMR (300 MHz, DMSO-J6) 5 8.83 (d, IH), 8.39 (d, IH, meta coupling), 8.24 (bs, IH), 8.00 (d, IH), 7.81 (bs, IH), 4.39 (q, 2H) and 1.37 ppm (t, 3H); ES-MS m/z 195.0 [M+H]+, HPLC RT (min) 1.83. |
44% | With dihydrogen peroxide; iron(II) sulfate at 8 - 10.5℃; for 2.41667h; | G.1 Intermediate G : Preparation of [2-(aminocarbonyl)pyridin-4-yl]methyl methanesulfonate; Step 1: Preparation of ethyl 2-(aminocarbonyl)isonicotinate; A solution of ethyl isonicotinate (25.2 mL, 165 mmol) in formamide (200 mL) was stirred with ice/methanol bath cooling as concentrated sulfuric acid (8.80 mL, 165 mmol) was added. Ferrous sulfate heptahydrate (69 g, 248 mmol) and hydrogen peroxide (25.6 mL of 30% in water) were added slowly over 25 min in alternating portions such that the temperature of the mixture was kept between 8-10.5 °C. During this addition small pieces of dry ice were added to the bath to keep the reaction temperature in the desired range. After addition was complete, the ice bath was removed and the dark mixture was stirred for 2 h without cooling and then poured into a solution of trisodium citrate dihydrate (80.6 g) in water (700 mL) and then residues left in the reaction flask were washed out with a little methanol and water. The resulting mixture was rapidly stirred in a large flask as solid NaHCOs was added slowly, portion-wise, until the mixture was basic. Some saturated aqueous NaHCOs was added to make the mixture more basic and then it was vacuum filtered through Celite and the solids were washed down with three 200 mL portions of dichloromethane. The phases of the filtrate were separated and the aqueous layer was extracted twice with dichloromethane. The combined extract was dried (Na2SC>4) and evaporated in vacuo. The resulting solid residue was washed with ether/hexane (200 mL, 1:30) twice with warming and sonication followed by cooling and filtration to yield 13.9 g (44%) of pure title compound. The wash solutions, which contained some highly contaminated desired product, were discarded.'H NMR (300 MHz, DMSO-4) & 8.83 (d, 1H), 8.39 (d, 1H, meta coupling), 8.24 (bs, 1H), 8.00 (d, 1H), 7.81 (bs, 1H), 4.39 (q, 2H) and 1.37 ppm (t, 3H); ES-MS m/z 195.0 [M+H]+, HPLC RT (min) 1.83. |
44% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In methanol; water at 0℃; for 0.416667h; | H.1 A solution of ethyl isonicotinate (25.2 niL, 165 mmol) in formamide (200 mL) was stirred with ice/methanol bath cooling as concentrated sulfuric acid (8.80 mL, 165 mmol) was added. Ferrous sulfate heptahydrate (69 g, 248 mmol) and hydrogen peroxide (25.6 mL of 30% in water) were added slowly over 25 min in alternating portions such that the temperature of the mixture was kept between 8-10.5 °C. During this addition small pieces of dry ice were added to the bath to keep the reaction temperature in the desired range. After addition was complete, the ice bath was removed and the dark mixture was stirred for 2 h without cooling and then poured into a solution of trisodium citrate dihydrate (80.6 g) in water (700 mL) and then residues left in the reaction flask were washed out with a little methanol and water. The resulting mixture was rapidly stirred in a large flask as solid NaHCO3 was added slowly, portion-wise, until the mixture was basic. Some saturated aqueous NaHCO3 was added to make the mixture more basic and then it was vacuum filtered through Celite and the solids were washed down with three 200 mL portions of dichloromethane. The phases of the filtrate were separated and the aqueous layer was extracted twice with dichloromethane. The combined extract was dried (Na2SO4) and evaporated in vacuo. The resulting solid residue was washed with ether/hexane (200 mL, 1:30) twice with warming and sonication followed by cooling and filtration to yield 13.9 g (44%) of pure title compound. The wash solutions, which contained some highly contaminated desired product, were discarded. 1H NMR (300 MHz, DMSO-J6) δ 8.83 (d, IH), 8.39 (d, IH, meta coupling), 8.24 (bs, IH), 8.00 (d, IH), 7.81 (bs, IH), 4.39 (q, 2H) and 1.37 ppm (t, 3H); ES-MS m/z 195.0 [M+H]+, HPLC RT (min) 1.83. |
44% | Stage #1: isonicotinic acid ethylester; formamide With sulfuric acid; dihydrogen peroxide at 8 - 20℃; for 2.5h; Stage #2: With sodium citrate In water | C.1 1: Preparation of ethyl 2-(aminocarbonyl)isonicotinateA solution of ethyl isonicotinate (25.2 mL, 165 mmol) in formamide (200 mL) was stirred with ice/methanol bath cooling as concentrated sulfuric acid (8.80 mL, 165 mmol) was added. Ferrous sulfate heptahydrate (69 g, 248 mmol) and hydrogen peroxide (25.6 mL of 30% in water) were added slowly over 25 min in alternating portions such that the temperature of the mixture was kept between 8-10.5 C. During this addition small pieces of dry ice were added to the bath to keep the reaction temperature in the desired range. After the addition was complete, the ice bath was removed and the dark mixture was stirred for 2 h without cooling. The mixture was then poured into a solution of trisodium citrate dihydrate (80.6 g) in water (700 mL) and then residues left in the reaction flask were washed out with a little methanol and water. The resulting mixture was rapidly stirred in a large flask as solid NaHCO3 was added slowly, portion- wise, until the mixture was basic. Some saturated aqueous NaHCO3 was added to make the mixture more basic and then it was vacuum filtered through Celite and the solids were washed down with three 200 mL portions of dichloromethane. The phases of the filtrate were separated and the aqueous layer was extracted twice with dichloromethane. The combined extract was dried(Na2SO4) and evaporated in vacuo. The resulting solid residue was washed with ether/hexane (200 niL, 1:30) twice with warming and sonication followed by cooling and filtration to yield 13.9 g (44%) of pure title compound. The wash solutions, which contained some highly contaminated desired product, were discarded.1H NMR (300 MHz, DMSO-J6) ? 8.83 (d, IH), 8.39 (d, IH, meta coupling), 8.24 (bs, IH), 8.00 (d, IH), 7.81 (bs, IH), 4.39 (q, 2H) and 1.37 ppm (t, 3H); ES-MS m/z 195.0 [M+H]+, HPLC RT (min) 1.83. |
40% | Stage #1: isonicotinic acid ethylester; formamide With ferrous(II) sulfate heptahydrate; sulfuric acid; dihydrogen peroxide In water Cooling; Stage #2: With sodium citrate; sodium hydrogencarbonate In water | 36.1 To a solution of ethyl isonicotinate (10 g, 66.15 mmol) and concentrated sulfuric acid (3.53 mL, 66.15 mmol) in formamide (80 mL, 2012.41 mmol), 30% hydrogen peroxide (2.399 mL, 99.23 mmol) and powdered iron(II) sulfate heptahydrate (27.6 g, 99.23 mmol) were separately and simultaneously added over 15 min with efficient stirring and cooling in an ice-bath. After complete addition the ice bath was removed and stirring was continued for 2 h. Sodium 2-hydroxypropane-1,2,3-tricarboxylate (132 mL, 132.31 mmol) (tris odium citrate) was added and the mixture was brought to pH 8 by addition of satd NaHCO3 The resultant mixture was extracted with DCM three times and the combined organic extracts were washed with cold water, dried over Na2SO4 and evaporated. The solid residue contained a minority of product. The crude product was subjected to the same treatment as above twice more before there was a majority of the desired product in the crude product which was recrystallised from EtOH. Yield: 4.3 g. The mother liquor was purified on Biotage using heptane/EtOAc 80/20-10/90 and gave another 0.8 g of product. Ethyl 2-carbamoylisonicotinate (5.1 g, 40%) was isolated. 1H NMR (400 MHz, dmso) δ 1.34 (t, 3H), 4.37 (q, 2H), 7.79 (s, 1H), 8.00 (d, 1H), 8.22 (s, 1H), 8.40 (s, 1H), 8.83 (d, 1H). MS m/z 195 (M+H)+ |
25% | With ferrous(II) sulfate heptahydrate; sulfuric acid; dihydrogen peroxide for 12h; Cooling with ice; | b (b) ethyl 2-carbamoylisonicotinate To a solution of ethyl isonicotinate (4 g, 26.46 mmol) and concentrated H2S04(2.6 g, 26.46 mmol)in formamide (32 mL), 30% H202(4.5 g, 39.69 mmol) and powdered FeS04.7H20(l lg, 39.69 mmol) were separately and simultaneously added over 10 min efficient stirring and cooling in an ice-bath. After complete addition the ice-bath was remove and stirred for 12h. Trisodium citrate(52.8 mL, 1M) was added and the mixture was brought to Ph=8 by addition of NaHC03. The mixture was extracted with DCM (100 mL x 5), the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product which was recrystallised from EtOH to give ethyl 2-carbamoylisonicotinate (1.3 g, yeild 25%). 1H NMR (400MHz, DMSO-d6)5 = 8.85 (dd, J=0.8, 4.8 Hz, 1H), 8.42 (dd, J=0.9, 1.6 Hz, 1H), 8.26 (br. s., 1H), 8.02 (dd, J=1.6, 4.9 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 4.43 - 4.34 (m, 2H), 1.36 (t, J=7.2 Hz, 3H). |
25% | With ferrous(II) sulfate heptahydrate; sulfuric acid; dihydrogen peroxide for 12h; Cooling with ice; | b (b)ethyl 2-carbamoylisonicotinate (b) ethyl 2-carbamoylisonicotinate To a solution of ethyl isonicotinate (4 g, 26.46 mmol) and concentrated H2SO4(2.6 g, 26.46 mmol) in formamide (32 mL), 30% H2O2(4.5 g, 39.69 mmol) and powdered FeSO4.7H2O (11 g, 39.69 mmol) were separately and simultaneously added over 10 min efficient stirring and cooling in an ice-bath. After complete addition the ice-bath was remove and stirred for 12 h. Trisodium citrate (52.8 mL, 1M) was added and the mixture was brought to Ph=8 by addition of NaHCO3. The mixture was extracted with DCM (100 mL*5), the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product which was recrystallised from EtOH to give ethyl 2-carbamoylisonicotinate (1.3 g, yield 25%). 1HNMR (400 MHz, DMSO-d6) δ=8.85 (dd, J=0.8, 4.8 Hz, 1H), 8.42 (dd, J=0.9, 1.6 Hz, 1H), 8.26 (br. s., 1H), 8.02 (dd, J=1.6, 4.9 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 4.43-4.34 (m, 2H), 1.36 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: isonicotinic acid ethylester With potassium <i>tert</i>-butylate In tetrahydrofuran; water Stage #2: phenylacetonitrile In tetrahydrofuran; water at 20℃; for 0.5h; | 4.5 Typical procedure for reaction of esters with cyanides to β-ketonitriles 9 under the optimized conditions General procedure: Ethyl ester 1 (6.65 mmol, 1 equiv) was dissolved in THF (30 mL, technical grade involving 0.2% water) with stirring (about 230rpm) at ambient temperature for 5min. Potassium tert-butoxide (1.57 g, 14.0 mmol, 95%, 2 equiv) was added immediately to the above THF solution. After stirring enough the flask, the corresponding cyanide 8 (6.65mmol, 1equiv) was then added. The resulting mixture was stirred at ambient temperature. The reaction mixture was quenched by addition of water (50mL) and then stirred for 5min. After adding ethyl acetate (40 mL) and then HCl solution (1 mL, 12 M), the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was applied to the top of an open-bed silica gel column (for 9a-e, 9g-j: 3×15cm, n-hexane/ethyl acetate (3:1, v/v); for 9f: 3.5×8 cm, CH2Cl2). Fractions containing the product were combined and evaporated under reduced pressure to give the corresponding β-ketonitriles. |
61% | With naphthalene; potassium In tetrahydrofuran; toluene at 5 - 10℃; for 1.5h; ultrasonic irradiation; | |
With sodium ethanolate for 2.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With silver(II) fluoride; In acetonitrile; at 50℃; for 1h;Sealed tube; Inert atmosphere; Glovebox; | General procedure: j0073j To an oven-dried vial was added the pyridine substrate (0.50 mmol, 1.0 equiv) and MeCN (5.0 - 20.0 mL). While the solution was stirring rapidly, AgF2 (219 mg, 1.50 mmol, 3.00 equiv) was added at once. The vial was sealed with a Teflon-lined cap and stirred at room temperature for 1 hour. The reaction was poured into a seperatory funnel containing 20 mL of saturated aqueous NaHCO3 and extracted with 30 mL of Et20. The organic layer was washed once with 20 mL of brine, dried over Mg504, and concentrated. The fluoropyridine product was purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | With sulfuric acid; dihydrogen peroxide In water at 6 - 22℃; for 0.5h; | H.1 A stirred solution of ethyl isonicotinate (250 mL, 1.64 mole) and concentrated sulfuric acid (92 mL, 1.64 mole) in N-methylformamide (2.0 L) was cooled to 6°C with an ice bath. Iron (II) sulfate heptahydrate (22.8 g, 0.0812 mole, milled with a mortar and pestle) was added, followed by the dropwise addition of 30% aqueous hydrogen peroxide (56 mL, 0.492 mole). The additions of iron (II) sulfate and hydrogen peroxide were repeated four additional times, while the reaction temperature was kept below 22°C. After the reaction mixture was stirred for thirty minutes, sodium citrate solution (2 L, 1 M) was added (pH of the resulting mixture was about 5). The mixture was extracted with dichloromethane (1L, 2 x 500 mL). The combined organic extracts were washed with water (2 x 500 mL), 5% aqueous sodium bicarbonate (3 x 100 mL), and brine (500 mL). The resulting organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. The crude solid was triturated with hexanes, filtered, washed with hexanes and dried under vacuum to give 270.35 g (79.2%) of pastel yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.9 (d, 1H), 8.3 (m, 1H), 8.0 (dd, 1H), 4.4 (q, 2H), 2.8 (d, 3H), 1.3 (t, 3H). |
79.2% | Stage #1: N-Methylformamide; isonicotinic acid ethylester With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 6 - 22℃; for 0.5h; Stage #2: With sodium citrate In water | H.1 A stirred solution of ethyl isonicotinate (250 mL, 1.64 mole) and concentrated sulfuric acid (92 mL, 1.64 mole) in N-methylformamide (2.0 L) was cooled to 6°C with an ice bath. Iron (IT) sulfate heptahydrate (22.8 g, 0.0812 mole, milled with a mortar and pestle) was added, followed by the dropwise addition of 30% aqueous hydrogen peroxide (56 mL, 0.492 mole). The additions of iron (H) sulfate and hydrogen peroxide were repeated four additional times, while the reaction temperature was kept below 22°C. After the reaction mixture was stirred for thirty minutes, sodium citrate solution (2 L, 1 M) was added (pH of the resulting mixture was about 5). The mixture was extracted with dichloromethane (IL, 2 x 500 mL). The combined organic extracts were washed with water (2 x 500 mL), 5% aqueous sodium bicarbonate (3 x 100 mL), and brine (500 mL). The resulting organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. The crude solid was triturated with hexanes, filtered, washed with hexanes and dried under vacuum to give 270.35 g (79.2%) of pastel yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.9 (d, IH), 8.3 (m, IH), 8.0 (dd, IH), 4.4 (q, 2H), 2.8 (d, 3H), 1.3 (t, 3H). |
79.2% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate In water at 6 - 22℃; for 0.5h; | H.1 Step 1 A stirred solution of ethyl isonicotinate (250 mL, 1.64 mole) and concentrated sulfuric acid (92 mL, 1.64 mole) in N-methylformamide (2.0 L) was cooled to 6° C. with an ice bath. Iron (II) sulfate heptahydrate (22.8 g, 0.0812 mole, milled with a mortar and pestle) was added, followed by the dropwise addition of 30% aqueous hydrogen peroxide (56 mL, 0.492 mole). The additions of iron (II) sulfate and hydrogen peroxide were repeated four additional times, while the reaction temperature was kept below 22° C. After the reaction mixture was stirred for thirty minutes, sodium citrate solution (2 L, 1 M) was added (pH of the resulting mixture was about 5). The mixture was extracted with dichloromethane (1L, 2×500 mL). The combined organic extracts were washed with water (2×500 mL), 5% aqueous sodium bicarbonate (3×100 mL), and brine (500 mL). The resulting organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. The crude solid was triturated with hexanes, filtered, washed with hexanes and dried under vacuum to give 270.35 g (79.2%) of pastel yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.9 (d, 1H), 8.3 (m, 1H), 8.0 (dd, 1H), 4.4 (q, 2H), 2.8 (d, 3H), 1.3 (t, 3H). |
58.64% | With sulfuric acid; dihydrogen peroxide; iron(II) sulfate at 5 - 15℃; | The commercially available ethyl isonicotinate 1 (5.00g, 33.08mmol) was dissolved in N-methylformamide (20mL), and cold 98% H2SO4 (3.24g, 33.08mmol) was added drop wise and the temperature was kept below 5°C. After the addition of H2SO4, 30% H2O2 and a saturated solution of FeSO4 were added to the reaction mixture at 10-15°C [9] until compound 1 disappeared. After extraction, washing, recrystallization, the pure compound 2 (4.04g, 19.40mmol, 58.64%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethanol; water at 150℃; for 96h; | 131 Reference Example 131: 1-(Pyridin-4-yl)piperidin-4-carboxylic acid 4-Chloropyridine hydrochloride (9.55 g) and triethylamine (26.0 ml) are dissolved in ethanol (10 ml) and water (30 ml), thereto is added ethyl isonicotinate (10.00 g), and then the reaction solution is heated at 150°C for 96 hours in a sealed tube. After allowing to cool, ethanol is added to the reaction solution and the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, the resulting residue is suspended in chloroform, the precipitates are collected by filtration and recrystallized from water-N,N-dimethylformamide to give the title compound (10.34 g). APCI-MS M/Z:207[M+H]+. | |
With triethylamine In ethanol; water at 150℃; for 96h; | 17 Reference Example 17: Reference Example 17: 1-Pyridin-4-ylpiperidin-4-carboxylic acid 4-Chloropyridine hydrochloride (9.55 g) and triethylamine (26.0 ml) are dissolved in ethanol (10 ml) and water (30 ml), and thereto is added ethyl isonicotinate (10.00 g). The reaction solution is then heated at 150°C for 96 hours in a sealed tube. After allowing to cool, ethanol is added to the reaction solution and the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, and the resulting residue is suspended in chloroform. The precipitates are collected by filtration and recrystallized from water/N,N-dimethylformamide to give the title compound (10.34 g). APCI-MS M/Z:207[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium tert-butylate; In water; tert-butyl alcohol; | REFERENCE EXAMPLE 20 2-[4-(1,1-Dimethylethyl)phenyl]-1-(4-pyridyl)ethanone To a solution of ethyl isonicotinate (12 g) and 4-(1,1-Dimethylethyl)phenylacetonitrile (9.1 g) in tert-butyl alcohol (36 mL), was added potassium tert-butoxide (7.3 g), and the mixture was stirred at 100 C. for 3 h. After cooling, the resulting mixture was dissolved in water and washed with isopropyl ether. The aqueous phase was adjusted to pH 7.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, And the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to obtain 2-cyano-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanone (5.09 g, yield 35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydride In tetrahydrofuran at 20℃; for 6h; Heating / reflux; | 50 In a solution of 2'-hydroxyacetophenone (10 g, 73.53 mmol) in 12 N HCI (160 mL) at room temperature was mixed with paraformaldehyde (2.43 g, 80.88 mmol) and stirred at 4O0C for 8 hours. The reaction was diluted with water, extracted with CH2CI2 (3χ100 mL), and concentrated using a rotary evaporator to provide 13 g of 5'-chloromethyl-2'-hydroxyacetophenone (98%). To a solution of 5'-chloromethyl-2'-hydroxyacetophenone (4 g, 21.74 mmol) in THF (50 mL) at EPO room temperature was added dimethylamine in THF (13 ml_, 26 mmol). The reaction mixture was stirred at 6O0C for 6 hours. It was quenched with water and neutralized with potassium carbonate to pH = 8. Extract with CH2CI2 (3x100 mL) followed by concentration using a rotary evaporator provided 3.86 g of 5'-(N, N- dimethylaminomethy)-2'-hydroxyacetophenone (92%). A solution of 5'-(N, N- dimethylaminomethy)-2'-hydroxyacetophenone (1.4 g, 7.25 mmol) and ethyl isonicotinate (1.1 g, 7.25 mmol) in THF (100 mL) at room temperature was mixed with NaH (1.02 g, 25.375 mmol) and was stirred at reflux for 6 hours. The reaction was quenched with water and extracted with CH2CI2 (3x100 mL). The volume was reduced using a rotary evaporator to minimal and triturated with hexanes. The solid was collected by filtration to afford 1.85 g of the corresponding diketone (86%). A solution of the above diketone (1.85 g,~6.19 mmol) in HOAc (100 mL) was stirred at reflux for 2 hours. All the solvent was removed using a rotary evaporator to afford a solid residue. It was then re-dissolved in CH2CI2, diluted with water and neutralized with potassium carbonate to pH = 8, extracted with CH2CI2 (3x100 mL) and concentrated using a rotary evaporator The solid residue was purified by column (SiO2, hexanes / EtOAc/ MeOH = 2:2:1) to afford 1.4 g of the intermediate (80%). A solution of the above intermediate (0.7 g, 2.34 mmol) in CH2CI2 (20 mL) was mixed with HCI in ether (10 mL, 20 mmol) and stirred at room temperature for 30 min. The solid was collected by filtration and washed with CH2CI2 and MeOH sequentially to obtain 0.48 g of the 6-((dimethylamino)methyl)- 2-(pyridin-4-yl)-4H-chromen-4-one hydrochloride (60%) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: isonicotinic acid ethylester With (TMP)3CdLi In tetrahydrofuran; hexane at 20℃; for 2h; Stage #2: With iodine In tetrahydrofuran; hexane | |
66% | Stage #1: isonicotinic acid ethylester In tetrahydrofuran at -40℃; for 12h; Stage #2: With iodine In tetrahydrofuran at -40 - 25℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In not given 1,3-diethynylbenzene treated by Ru-complex; resulting diruthenium complex treated with excess of isonicotinate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.9% | With sodium ethanolate In ethanol for 7h; Heating / reflux; | 324 2-Methyl-5-[2-(5-pyridin-4-yl-l,2,4-oxadiazol-3-yl)ethyl]-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole (G6-e). To sodium ethoxide (from 0.188g of Na and 25mL of anhydrous ethanol) was added ethyl isonicotinate (1.249g, 8.3mmol) and 5-a (1.336 g, 4.9 mmol). The mixture was heated under reflux for 7h. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (benzene/Et3N, 9:1) to yield 1.145g (64.9%) of G6-e, mp 110.5- 111.5°C (i-PrOH, -12°C). 1H NMR (DMSO-d6/CDC13, 2:1): 2.42 (3H,s), 2.64-2.90 (4H,m), 3.25 (2H,t), 3.51 (2H,s), 4.53 (2H,t), 6.90-7.12 (2H,m), 7.26-7.42 (2H,m), 7.98 (2H,d), 8.87 (2H,d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: isonicotinic acid ethylester; methyl iodide In ethyl acetate at 80℃; for 3h; Stage #2: With sodium tetrahydroborate In ethanol at -40 - 20℃; for 2h; | 1.1 (Step 1) To a solution of ethyl isonicotinate (151 g) in ethyl acetate (1000 mL) was added methyl iodide (126 mL), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was cooled, and the orange precipitate was collected by filtration. The precipitate was suspended in ethanol (1000 mL), sodium borohydride (37.8 g) was added with cooling at -40° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and ethanol was evaporated under reduced pressure. The resultant product was extracted with ethyl acetate-tetrahydrofuran, the organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to give ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (85.8 g, 51%) as a pale yellow oil.Boiling point: 64-77° C. (1 mmHg)1H-NMR (CDCl3) δ 1.29 (3H, t, J=7.2 Hz), 2.37 (3H, s), 2.40-2.50 (2H, m), 2.54 (2H, t, J=3.3 Hz), 3.09 (2H, q, J=3.0 Hz), 4.20 (2H, q, J=7.2 Hz), 6.86-6.91 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium methylate In tetrahydrofuran for 3.5h; Reflux; | 12.a Intermediate 12 3-(aminomethyl)-6-methyl-4,4'-bipyridin-2(1H)-one To a solution of ethyl 4-pyridinecarboxylate (30 g, 198 mmol) and acetone (34.58g, 595 mmol) in THF (150 mL) was slowly added NaOMe (12.87 g, 238 mmol) at 35-40 °C. The mixture was stirred at room temperature for 0.5 h, and then heated at reflux for 3h. The mixture was cooled to room temperature and filtered to give a solid, which waswashed with t-BuOMe, and dissolved in H20. The solution was acidified with acetic acid and the resulting oily product was extracted with CHCh. The solvent was removed invacuo, and the crude product was obtained (12 g, 37%) and used without furtherpurification. 1H NMR (400 MHz, DMSO-d6) 8 8.73 (d, 2H), 7.76 (d, 2H), 6.63 (s, 1H),2.21 (s, 3H); note: enolic OH does not appear |
With sodium methylate In tetrahydrofuran at 35℃; for 3.5h; Reflux; | 6.1 Step 1(Z)-3-hydroxy-l-(pyridin-4-y])but-2-en-l-oneTo a solution of ethyl 4-pyridinecarboxylate (30 g, 198 mmol) and acetone (34.58 g, 595 mmol) in THF (150 n L) was slowly added NaOMe (12.87 g, 238 mmol) at 35-40 °C. The mixture was stirred at room temperature for 0.5 h, and then heated at reflux for 3 h. The mixture was cooled to room temperature and filtered to give a solid, which was washed with M3uOMe, and dissolved in H20. The solution was acidified with acetic acid and the resulting oily product was extracted with CHC13. The solvent was removed in vacuo, and the crude product was obtained (12 g, 37%) and used without further purification. ¾ NMR (400 MHz, DMSO-d6) δ 8.73 (d, 2H), 7.76 (d, 2H), 6.63 (s, 1H), 2.21 (s, 3H); note: enolic OH does not appear. | |
In tetrahydrofuran; acetone at 35℃; for 3h; Inert atmosphere; Reflux; | 12a 12a) (2Z)-3-Hydroxy-1-(4-pyridinyl)-2-buten-1-one To a solution of ethyl 4-pyridinecarboxylate (30 g, 198 mmol) and acetone (34.58 g, 595 mmol) in THF (150 mL) was slowly added NaOMe (12.87 g, 238 mmol) at 35-40° C. The mixture was stirred at room temperature for 0.5 h, and then heated at reflux for 3 h. The mixture was cooled to room temperature and filtered to give a solid, which was washed with t-BuOMe, and dissolved in H2O. The solution was acidified with acetic acid and the resulting oily product was extracted with CHCl3. The solvent was removed in vacuo, and the crude product was obtained (12 g, 37%) and used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 2H), 7.76 (d, 2H), 6.63 (s, 1H), 2.21 (s, 3H); note: enolic OH does not appear. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With tert.-butylhydroperoxide; ferrous(II) sulfate heptahydrate; trifluoroacetic acid for 4h; Reflux; | Preparation of compound 1 CH3CN (180 mL), ethyl isonicotinate (19.2 g, 127 mmol)), paraldehyde (82 g, 620 mmol), FeSO4·7H2O (0.6 g, 2.16 mmol), TFA (14.86 g, 130 mmol), and 70% t-BuOOH (32 g, 252 mmol) was added into a 500 mL round bottom flask in sequence. The resulting mixture was heated to reflux for 4 h. After being cooled to room temperature, acetonitrile was removed in vacuum and the residue was neutralized. Then the as-obtained mixture was extracted with chloroform (3x100 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuum followed by column chromatography (SiO2), eluting with the mixture of petroleum ether and ethyl acetate (13:1) to obtain the pure product, collected as a white solid (16 g, 62% yield). |
61% | With tert.-butylhydroperoxide; ferrous(II) sulfate heptahydrate; trifluoroacetic acid In acetonitrile at 20℃; Reflux; | |
61% | With tert.-butylhydroperoxide; ferrous(II) sulfate heptahydrate; trifluoroacetic acid In acetonitrile for 4h; Reflux; |
56% | With tert.-butylhydroperoxide; iron(II) sulfate; trifluoroacetic acid In acetonitrile for 24h; Reflux; | |
53% | Stage #1: isonicotinic acid ethylester; paracetaldehyde In acetonitrile at 20℃; Stage #2: With tert.-butylhydroperoxide; ferrous(II) sulfate heptahydrate; trifluoroacetic acid In acetonitrile at 130℃; for 4h; | 1 The compounds of 10g (66.1mmol) it-1-4, by mixing paraldehyde 43.6mL (5eq) and acetonitrile 165 mL, was stirred at room temperature. Iron sulfate to there heptahydrate 305mg (0.0166eq), trifluoroacetic acid (TFA) 4.9mL (1eq) and t- butyl peroxide (2eq), and the mixture was heated to reflux for 4 hours at 130 . The reaction mixture was concentrated under reduced pressure after cooling. It was added a saturated aqueous solution of sodium carbonate in the concentrated residue was extracted and subjected to liquid separation with ethyl acetate. The extract was purified by alumina column chromatography to obtain Compound the I-1-5 as a yellow solid 6.77g (53% yield). The structures of the compounds the I-1-5 was confirmed by 1H-NMR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Acetonitrile (2.09 mL, 39.7 mM) was added to a solution of 18-crown-6 (875 mg, 3.31 mM) and potassium tert-butoxide (1M THF solution, 36.4 mL, 36.4 mM) in THF (10 mL) at 60 C. and then the mixture was stirred for 5 minutes. To this solution, there was added ethyl isonicotinate (5.00 g, 33.1 mM) and the mixture was then stirred for 30 minutes. This suspension was filtered and the resulting solid was washed with diethyl ether. The resulting solid was suspended in ethanol (60 mL), then concentrated hydrochloric acid (3.0 mL) and methyl carbazinate (3.61 g, 39.7 mM) were added to the suspension with ice-cooling and the mixture was stirred at room temperature for 20 hours. After the stirring operation, potassium carbonate (2.74 g, 19.8 mM) was added to this suspension and the mixture was stirred at 90 C. for one hour. This reaction solution was concentrated under reduced pressure, the concentrate was diluted with water and the mixture was then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was sufficiently washed with diethyl ether to thus give the title compound (1.33 g, yield: 25%). 1H-NMR (300 MHz, DMSO): δ 4.65-5.16 (br, 2H), 5.81 (br, 1H), 7.59-7.61 (m, 2H), 8.50-8.52 (m, 2H), 11.80 (br, 1H); MS (ESI) m/z 161 (M+H)+. | |
25% | Acetonitrile (2.09 mL, 39.7 mM) was added to a solution of 18-crown-6 (875 mg, 3.31 mM) and potassium tert-butoxide (1 M THF solution, 36.4 mL, 36.4 mM) in THF (10 mL) at 60 C, and the mixture was then stirred for 5 min. To this solution, ethyl isonicotinate (5.00 g, 33.1 mM) was added, and the mixture was stirred for 30 min. This suspension was filtered, and the resulting solid was washed with diethyl ether. The washed solid was suspended in ethanol (60 mL), then concentrated hydrochloric acid (3.0 mL) and methyl carbazinate (3.61 g, 39.7 mM) were added to the suspension with ice cooling, and the mixture was stirred at room temperature for 20 h. After stirring, potassium carbonate (2.74 g, 19.8 mM) was added to this suspension, and the mixture was stirred at 90 C for 1 h. This reaction solution was concentrated under reduced pressure, the concentrate was diluted with water, and the mixture was then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was removed by distillation, and the resulting solid was sufficiently washed with diethyl ether to give the title compound (1.33 g, yield: 25%). 1H-NMR (300 MHz, DMSO-d6): δ 4.65-5.16 (br, 2H), 5.81 (br, 1H), 7.59-7.61 (m, 2H), 8.50-8.52 (m, 2H), 11.80 (br, 1H); MS (ESI) m/z 161 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water at 20℃; for 4h; Inert atmosphere; | Compound 4: 2-Difluoromethyl-isonicotinic acid ethyl ester. General procedure: General procedure VIII: Formation of ester A via innate carbon-hydrogen functionalization. Under inert atmosphere, a mixture of ethyl isocotinate (1.0 equiv.) and sulfinate (2.0 equiv.)was suspended in a mixture of DCM:water (8:2 - C0.14 mol.L1). TEA (1.0 equiv.), thentertbutylhydroperoxide (3.0 equiv.) were added and the mixture was vigorously stirred. Whenthe starting material is consumed, the mixture was hydrolysed with a saturated aqueous NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, driedover MgSO4 or Na2SO4 and concentrated. Compounds were used in the next steps without further purification.:_Compound 4: 2-Difluoromethyl-isonicotinic acid ethyl ester.Compound 4 was obtained according to general procedure VIII using bis[(difluoromethyl)sulfonyl]oxy}zinc (DFMS). The reaction mixture was stirred for 4 hours atroom temperature. Compound 4 was isolated as a yellow oil in a quantitative yield. Tofacilitate the extraction step, EDTA (8% ww) was added to the NaHCO3 solution.1H-NMR (400 MHz, DMSO): 1.35 (t, 3H, J 7.1 Hz, OCH2CH3); 4.39 (q, 2H, J 7.1 Hz,OCH2CH3); 7.09 (t, J54.7 Hz, 1H, CHF2); 8.02 (d, J5.0 Hz, 1H, Ar); 8.06 (s, 1H, Ar); 8.92 (d, J5.0 Hz, 1H, Ar).MZ (M+H) = 202.0. |
66% | With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water at 23℃; for 1h; regioselective reaction; | |
66% | With tert.-butylhydroperoxide In dichloromethane; water at 25℃; |
66% | With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water for 1h; | 5 Difluoromethylation of Heterocycles Standard Procedures: Procedure A: General procedure: Difluoromethylation of Heterocycles Standard Procedures: Procedure A: To a solution of heterocycle (0.25 mmol,1.0 equiv) and zinc difluoromethanesulfinate (DFMS) (200 mg, 0.50 mmol, 2.7 equiv ‘calculated as anhydrous') in dichloromethane (1.0 inL) and water (0.4 mL) at room temperature was added trifluoroacetic acid (20 μL, 0.25 mmol, 1.0 equiv) followed by slow addition of tert-butyl hydroperoxide (70% solution in water, 0.17 mL, 1.25 mmol, 5.0 equiv) with vigorous stirring. The reaction was monitored by thin layer chromatography until completion. For substrates that do not react to completion in 24 hours, a second addition of DFMS (2.7 equiv) and tert-butyl hydroperoxide (5.0 equiv) may be added to drive the reaction further. Upon consumption of starting material, the reaction was partitioned between dichloromethane (2.0 mL) and saturated sodium bicarbonate (2.0 mL) . The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3 X 2.0 mL) . The combined organic layers were dried with sodium sulfate, concentrated and purified by column chromatography on silica gel. |
44% | With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With lithium hexamethyldisilazane; In tetrahydrofuran; at -40℃; for 0.333333h;Inert atmosphere; | General procedure: To the solution of ester (10 mmol) in THF (20 mL) and ethyl acetate (70 mmol), LiHMDS (30 mmol) was added very quickly at -40 C, and stirred at this temperature for 20 min. After completion of the reaction, reaction mixture was quenched with acetic acid (50 mmol) and then basified using 10% NaHCO3 solution, extracted with ethyl acetate (2×100 mL), the combined organic layer was washed with water and brine solution and dried over Na2SO4. The specific purification procedure for each compound has been included along with their characterization data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium hydride In tetrahydrofuran; mineral oil at 100℃; for 8h; | 60 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.66 g, 12 mmol) in 40 mL of THF was treated with NaH (60 percent, 0.7 g, 17 mmol). After the addition of Isonicotinic acid ethyl ester (0.3 g, 20 mmol), the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(Pyridine-4-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.78 g, 7.3 mmol) as red solid in 61% yield. |
61% | With sodium hydride In tetrahydrofuran; mineral oil at 100℃; for 8h; | 60 5,6-dihydro-cyclopenta [b] thiophen-4-one (1.66 g, 12 mmol) in 40 mL of THF was treated with NaH (60%, 0.7 g, 17 mmol). After addition of isonicotinic acid ethyl ester (0.3 g, 20 mmol), the reaction mixture was heated to 100 ° C and maintained for 8 hours. The solution was cooled to room temperature and poured into water. The product mixture was acidified with concentrated hydrochloric acid and ethyl acetate (80 mL) was added. Collecting organic layer,Treated with brine, dried over MgSO4 (s), and concentrated under reduced pressure. The resulting precipitate was collected and recrystallized from ethanol to give the corresponding 5- (pyridine-4-carbonyl) -5,6-dihydro-cyclopenta [b] thiophen-4-one (1.78 g, 7.3 mmol) The red solid,Yield 61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium <i>tert</i>-butylate In tetrahydrofuran; water Cooling with ice; | 4.7 General procedure for reaction of esters and acetylenes to biscarbinols 12 General procedure: Ethyl ester (1, 6.65 mmol) was dissolved in cold THF (30 mL, technical grade involving 0.2% water, cooling in ice bath for 5min). Potassium tert-butoxide (1.57 g, 14.0 mmol, 95%) and acetylene (10, 13.3 mmol) were added immediately. After the reaction was quenched by addition of water (20 mL) was then added. The reaction mixture was poured into the mixture of ethyl acetate (60 mL)/ice powder (25-30 g). The organic layerwas separated and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure at 60°C below, the residue was applied to the top of an open-bed silica gel column (for 12a, c, d: 4.5×15cm, n-hexane/ethyl acetate (3:1, v/v)) or washed with n-hexane (50 mL, for 12b) to give 12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lanthanum complex grafted upon hydrotalcite for 4h; Reflux; | 4.4. General procedure for transesterification General procedure: The HT catalyst and substrate were added to MeOH and the mixture was refluxed with stirring. The reaction condition using HT and HT-like compounds as shown in Table 1 was carried out as follows: butyl decanoate 0.34 mmol, catalyst 5.2 mg, and MeOH 8 mL. After 8 h reaction, the amounts of the product and unreacted substrate were determined by GC using dichlorobenzene as an internal standard. Reaction condition in Table 2 was as follows: butyl decanoate 0.674 mmol, MeOH 16 mL, catalyst 10 mg(0.25 mmol of La/1 g HT). After 24 h reaction, the reaction mixture was analyzed by GC. Reaction condition in Table 3 was as follows: butyl dacanoate 0.674 mmol, MeOH 16 mL, catalyst 52 mg (0.25-1.00 mmol of La/1 g HT). After 8 h reaction, the reaction mixture was analyzed by GC. Reaction condition in Table 4 was as follows: substrate 0.674 mmol, MeOH 16 mL, catalyst La/HT-A 52 mg. The yields of products in the transesterification were determined by GC using dichlorobenzene or diethylene glycol dibutyl ether as an internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium In ethanol for 8h; Reflux; | 2.54 3-(3'-lsopropoxyphenyl)-5-(4' ^yridyl)-3H-[1 ,2,3]triazolo[4,5-c(]pyrimidin- 7(6H)-one General procedure: To a solution of Na (5.00 mmol) in ethanol (10 mL/mmol), the carboxamide 15 (1 .00 mmol) and the appropriate ester (4.00 mmol) were added. The reaction mixture was heated at reflux for 1 to 8 hours. After cooling, the reaction was concentrated to dryness. The residue was dissolved in water, acidified by addition of acetic acid and the precipitate thus formed was isolated by filtration and purified as specified.Following the general procedure, to a solution of Na (33 mg, 1.45 mmol) in ethanol (2.9 mL), 15 (80 mg, 0.29 mmol) and methyl 4-pyridylacetate (159 μΙ_, 1.16 mmol) were added. The reaction mixture was refluxed for 5 hours to yield 80 mg (79%) of 16c as a beige solid. Mp: 259-260 °C. MS (ES, positive mode): m/z 349 (M+H)+. 1 H NMR (400 MHz, DMSO-d6): δ 1 .33 (d, J = 6.0 Hz, 6H, CH(CH3)2), 4.73 (hept, J = 6.0 Hz, 1 H, CH), 7.11 (d, J = 8.7 Hz, 1 H, H-4'), 7.56 (pt, J = 8.3 Hz, 1 H, H-5'), 7.66 (m, 2H, H-2', H-6'), 8.05 (d, J = 5.9 Hz, 2H, H- 2"), 8.83 (d, J = 5.7 Hz, 2H, H-3"). 13C NMR (100 MHz, DMSO-d6): δ 22.2 (CH3), 70.4 (CH), 109.4, 1 14.4, 117.0, 122.5 (Ar), 130.1 (C-7a), 131.2, 136.7, 139.5 (Ar), 148.7 (C-3a), 150.9, 156.4 (Ar), 156.6 (Ar, C-7), 158.6 (C-5). Anal, calc. for (Ci8Hi6N602): C, 62.06; H, 4.63; N, 24.12. Found: C, 61 .70; H, 4.61 ; N, 23.78. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 71.4% 2: 19.7% | With iron(II) oxalate; trifluoroacetic acid In dichloromethane at 25℃; for 24h; | Example 5 In a 50 ml three-port flask, add isonicotinic acid ethyl ester 4mmol (0.60g), phenylboronic acid 4.4mmol (0.54g), dichloromethane 10 ml, water 10 ml, ferroxalate 0.4mmol, trifluoroacetic acid 4mmol (0.46g; 306 μ L); the room temperature (25 °C) under stirring, by adding the second potassium sulfate 12mmol (3.24g). At this temperature, to continue stirring 24h. After the reaction, the resulting product to filter, with a small amount of dichloromethane wash residue 2-3 time (each about using 5 ml). The merger of the shall be dichloromethane layer solution, then with 5% aqueous solution of sodium bicarbonate wash two; reuse the 2g dry dichloromethane solution of anhydrous magnesium sulfate, the filtrate, the filtrate is rotary evaporated to remove the dichloromethane, to obtain crude products; the crude product is ordinary silica gel column (containing 200-300 mesh silica gel) column chromatography separation, in order to-hexane: ethyl acetate volume ratio of 85:15 eluting the mixed solvent, can get aromatise product, 2-phenyl-isonicotinic acid ethyl ester 0.65g, the yield is 71.4% ; 3-phenyl-isonicotinic acid ethyl ester 0.18g, to yield 19.7% |
With dipotassium peroxodisulfate; iron(II) oxalate; trifluoroacetic acid In dichloromethane; water at 20℃; for 48h; Overall yield = 62.4 %; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In 1,2-dimethoxyethane at 20℃; for 5h; | 4 Experimental section 4.1 General procedure for the preparation of spirooxindoles 1a-1d from three-component reactions of substituted pyridine, electron-deficient alkynes, and isatins General procedure: 4 Experimental section 4.1 General procedure for the preparation of spirooxindoles 1a-1d from three-component reactions of substituted pyridine, electron-deficient alkynes, and isatins (0010) A mixture of substituted pyridine (1.0mmol), electron-deficient alkyne (1.2mmol), and isatin (1.0mmol) in 15.0mL of dimethoxyethane was stirred at room temperature for 5h. The solvent was removed by evaporation and the residue was crystallized with a mixture of chloroform and ethanol to give the product for spectroscopic analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.5% | With sodium amide In benzene at 50℃; for 7h; | 4.1 Typical procedure for the synthesis of the pyridyl-b-diketones General procedure: To a suspension of sodium amide (1.4 g, 36 mmol) and ethyl isonicotinate(6.65 g, 44 mmol) in benzene (50 mL), A solution of the aryl methyl ketones(22 mmol) in benzene was added dropwise under stirring at 50 °C. The reactionmixture was refluxed for about 7 h until the dark yellow product precipitated.The precipitate was filtered off and washed with 5 % acetic acid until pH = 6.The crude products were recrystallized from ethanol (95 %) to give the pyridylb-diketones (1a-e).4.1.1 1-Phenyl-3-(4-pyridyl)-1,3-propandione (1a)Colorless needles, yield 70.5 %, mp 81-82 oC; 1H NMR (CDCl3, 300 MHz)d: 4.65 (s, 0.08H, keto CH2), 6.89 (s, 1H, enol CH), 7.50-7.63 (m, Ar-H, 3H),7.79 (d, 2H, Py-H, J = 5.7 Hz), 8.01 (d, 2H, Ar-H, J = 7.8 Hz), 8.80 (d, 2HPy-H, J = 5.7 Hz), 16.55 (br s, 1H, enol OH) ppm; IR (KBr) n: 3419 (w), 3089(m), 3040 (m), 2920 (m), 1591 (s), 1542 (s), 1480 (m), 1401 (m), 1290 (m),1228 (m), 1064 (m), 764 (s), 692 (s) cm-1; ESI-MS m/z: 226.13 [M+1]+. Anal.calcd. for C14H11NO2: C 74.65, H 4.92, N 6.22; found C 74.89, H 4.88, N 6.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.2% | With sodium amide In benzene at 50℃; for 7h; | 4.1 Typical procedure for the synthesis of the pyridyl-b-diketones General procedure: To a suspension of sodium amide (1.4 g, 36 mmol) and ethyl isonicotinate(6.65 g, 44 mmol) in benzene (50 mL), A solution of the aryl methyl ketones(22 mmol) in benzene was added dropwise under stirring at 50 °C. The reactionmixture was refluxed for about 7 h until the dark yellow product precipitated.The precipitate was filtered off and washed with 5 % acetic acid until pH = 6.The crude products were recrystallized from ethanol (95 %) to give the pyridylb-diketones (1a-e). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.6% | With sodium amide In benzene at 50℃; for 7h; | 4.1 Typical procedure for the synthesis of the pyridyl-b-diketones General procedure: To a suspension of sodium amide (1.4 g, 36 mmol) and ethyl isonicotinate(6.65 g, 44 mmol) in benzene (50 mL), A solution of the aryl methyl ketones(22 mmol) in benzene was added dropwise under stirring at 50 °C. The reactionmixture was refluxed for about 7 h until the dark yellow product precipitated.The precipitate was filtered off and washed with 5 % acetic acid until pH = 6.The crude products were recrystallized from ethanol (95 %) to give the pyridylb-diketones (1a-e). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.4% | With sodium amide In benzene at 50℃; for 7h; | 4.1 Typical procedure for the synthesis of the pyridyl-b-diketones General procedure: To a suspension of sodium amide (1.4 g, 36 mmol) and ethyl isonicotinate(6.65 g, 44 mmol) in benzene (50 mL), A solution of the aryl methyl ketones(22 mmol) in benzene was added dropwise under stirring at 50 °C. The reactionmixture was refluxed for about 7 h until the dark yellow product precipitated.The precipitate was filtered off and washed with 5 % acetic acid until pH = 6.The crude products were recrystallized from ethanol (95 %) to give the pyridylb-diketones (1a-e). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.1% | With sodium amide In benzene at 50℃; for 7h; | 4.1 Typical procedure for the synthesis of the pyridyl-b-diketones General procedure: To a suspension of sodium amide (1.4 g, 36 mmol) and ethyl isonicotinate(6.65 g, 44 mmol) in benzene (50 mL), A solution of the aryl methyl ketones(22 mmol) in benzene was added dropwise under stirring at 50 °C. The reactionmixture was refluxed for about 7 h until the dark yellow product precipitated.The precipitate was filtered off and washed with 5 % acetic acid until pH = 6.The crude products were recrystallized from ethanol (95 %) to give the pyridylb-diketones (1a-e). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium 2-methyl-2-butoxide In tetrahydrofuran at 20℃; for 18h; | A2.a a- Synthesis of intermediate 6: a- Synthesis of intermediate 6: To a solution of ACN (6 mL, 115 mmol) and ethyl isonicotinate (51.6 mL, 345 mmol) in dry THF (500mL) was slowly added potassium 2-methyl-2-butoxide (48.3 mL, 345mmo1). The reaction was stirred at r.t. for 1 8h, quenched with water and evaporated in vacuo. The solid was triturated with Et20, filtered on a glass fit and washed withEt20 (3 times) to give 17.3 g of intermediate 6, yellow solid (quantitative yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 20℃; for 0.666667h; | 2.1 Typical experimental procedure General procedure: To a stirred solution of 5-nitroquinoline (8a, 103 mg, 0.59 mmol) and 2,2-dimethyl-3-ethoxycyclobutanone (7a, 92.5 mg, 0.65 mmol) in dry acetonitrile (2 mL) was addedMe3SiOTf (0.12 mL, 0.65 mmol) at 24 °C and the mixture was stirred for 20 min at the sametemperature. The reaction was quenched by adding aqueous solution of potassium sodium(+)-tartrate and the resulting mixture was extracted with ethyl acetate (three times). The combinedorganic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude product was purified by column chromatography on silica gel (13.7 g,hexane/ethyl acetate = 3:1 to 1:1) to afford 9a (101.4 mg, 0.375 mmol, 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: isonicotinic acid ethylester; sodium cyanamide In methanol at 20℃; for 1.5h; Stage #2: With sodium methylate | 5.3.8 Compound 19h General procedure: (Method B) To a solution of 18h (27.96 g, 128 mmol) in MeOH (300 ml) was added sodium cyanamide (9.8 g, 148 mmol), followed by stirring at room temperature for 1.5 h. The mixture was concentrated to 50 ml, and then i-PrOH was added. The resulting precipitate was filtered and dried to give 19h (31.5 g, 82%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride In tetrahydrofuran at 1 - 5℃; for 3h; | 1 1-(5-bromo-2-hydroxyphenyl)-3-(4-pyridyl)propane-1,3-dione (M1) In a 100 mL three-necked flask was added 30 mL of tetrahydrofuran (anhydrous treatment)1.2 g (49 mmol) of NaH was added to the reaction solution,The reaction flask was placed in an ice bath,The temperature in the reaction flask was controlled at 1-5 ° C.562 mg (3.72 mmol) of ethyl isonicotinate was added.(12.25 mmol) of 2-hydroxy-5-bromoacetophenone (200 mg, 0.93 mmol) was diluted with 15 mL of THF,The reaction solution was added dropwise using a constant-pressure dropping funnel,The temperature in the reaction flask was controlled at 1-5 ° C.After stirring for 3 h, the reaction was monitored by TLC plate,Raw materials disappear,The reaction was stopped.The reaction solution was poured into ice water,The pH was adjusted to 6-7 with dilute hydrochloric acid,A large number of yellow solid precipitation,Filtration,The crude product was 223 mg, yield: 75%. Directly cast the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. 4-(Ethoxycarbonyl)-1-(2-oxo-2-phenylethyl)-pyridinium bromide (9a). Yield 69%, mp 189190°C.1H NMR spectrum (DMSO-d6), δ, ppm: 1.38 t (3H,CH2CH3, J = 7.1 Hz), 4.46 q (2H, CH2CH3, J =7.0 Hz), 6.67 s (2H, CH2CO), 7.66 t (2H, 3′-H, 5′-H,J = 7.6 Hz), 7.79 t (1H, 4′-H, J = 7.3 Hz), 8.07 d (2H,2′-H, 6′-H, J = 7.6 Hz), 8.65 d (2H, 3-H, 5-H, J =6.1 Hz), 9.25 d (2H, 2-H, 6-H, J = 6.2 Hz). 13C NMRspectrum (DMSO-d6), δC, ppm: 14.4 (CH2CH3), 63.5(CH2CH3), 67.2 (CH2CO), 127.4, 128.8, 129.6, 133.9,135.2, 145.1, 148.3, 162.3 (OCO), 190.8 (CH2CO).Found, %: C 54.72; H 4.63; N 3.97. C16H16BrNO3.Calculated, %: C 54.87; H 4.61; N 4.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In acetone at 20℃; for 24h; | Quaternary salts 9a-9h (general procedure). General procedure: A solutionof 11 mmol of substituted phenacyl bromide 8a-8h in 10 mL of acetone was added to a solution of10 mmol of ethyl pyridine-4-carboxylate (7) in 12 mLof acetone. The mixture was kept for 24 h at roomtemperature, and the precipitate was filtered off,washed with acetone, and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With lithium hexamethyldisilazane In tetrahydrofuran | Intermediate 213 2-methyl-3-oxo-3-(pyridin-4-yl)propanenitrile Ethyl pyridine-4-carboxylate (5.0 ml, 33 mmol) and propanenitrile (5.9 ml, 83 mmol) were dissolved in tetrahydrofuran (47 mL) and chilled with a waterbath. A solution of lithium bis(trimethylsilyl)amide (84 mL, 1.0 M, 84 mmol) was slowly added und vigorous stirring. A pale yellow solid starts precipitating immediately. After 30 min, the precipitated solid was collected by filtration, washed with with tetrahydrofuran and dried under vacuum. It was then suspended in ethyl acetate and aqueous ammonium chloride solution and adjusted to pH 4-5 with aqueous hydrochloric acid solution (1 M). After phase separation, the aqueous layer was extracted with ethyl acetate (2x). The combined organic phase extracts were dried over sodium sulfate and concentrated to yield the desired product (4.08 g, 75% yield). LC-MS (method 11): Rt = 0.53 min; MS (ESIpos): m/z = 161 [M+H]+1H-NMR (400 MHz, dimethylsulfoxide-d6) δ [ppm]: -0.149 (0.18), -0.008 (1.47), 0.008 (1.67), 0.146 (0.17), 1.085 (0.38), 1.104 (0.19), 1.471 (0.66), 1.484 (0.67), 1.564 (0.55), 1.676 (3.26), 1.884 (16.00), 2.328 (0.20), 2.367 (0.17), 2.523 (0.54), 2.670 (0.22), 2.711 (0.18), 5.143 (0.19), 7.412 (0.74), 7.416 (0.55), 7.427 (0.81), 7.523 (4.17), 7.538 (4.45), 7.874 (0.49), 8.694 (4.40), 8.708 (4.64), 8.873 (0.44), 11.166 (0.44). |
Stage #1: propiononitrile With lithium hexamethyldisilazane In tetrahydrofuran at -60 - 10℃; for 0.5h; Inert atmosphere; Stage #2: isonicotinic acid ethylester In tetrahydrofuran at -60 - 20℃; for 3h; | 1 Step 1: 2-Methyl-3-oxo-3-(pyridin-4-yl)propanenitrile. 2-Methyl-3-oxo-3-(pyridin-4-yl)propanenitrile. A solution of propiononitrile (2.0 g, 36 mmol, 1.0 equiv) in anhydrous THF (150 mL, 0.24 M) under at atmosphere of nitrogen was cooled to -60 °C. To the cold solution was then added LiHMDS (1.0 M in THF, 75 mL, 75 mmol, 2.1 equiv) dropwise. The resulting mixture was warmed to 10 °C and stirred for 30 min. The reaction mixture was cooled again to -60 °C, and ethyl isonicotinate (10 g, 73 mmol, 2.0 equiv) was added. After the addition, the resulting mixture was warmed to rt and stirred for 3 h. The suspension was then filtered, and the solid was collected and triturated with DCM (200 mL) to obtain crude 2-methyl-3-oxo-3-(pyridin-4-yl)propanenitrile (9.0 g, 34 mmol, 60% purity) as an off-white solid. The crude material was used on the next step without further purification. LCMS: ESI-MS m/z: 161.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With oxygen; copper dichloride In acetonitrile at 80℃; for 12h; Sealed tube; | 8 The synthesis method of I-8 is:Using CuCl2 as a catalyst,Acetonitrile as a solvent,To a solution of 3.0 mmol of 4-ethyl pyridine and 3.0 mmol of bromoacetophenone in acetonitrile, 0.2 mmol of CuCl 2 was added under an oxygen atmosphere.Sealing reaction,The reaction temperature is 80 ° C.The reaction time is 12h.Silica gel filtration removes CuCl2,The filtrate was concentrated in vacuo.The crude product was separated by column chromatography to give a yellow solid I-8.Yield: 62% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In tetrahydrofuran; hexane at -40 - 0℃; for 3h; Inert atmosphere; | Typical synthetic procedure of (Ligand)2Zn(CF2H)2 reagent from difluoroiodomethane General procedure: To a mixture of pyridine derivative (2.0mmol) in hexane (10mL) was added dropwise difluoroiodomethane (THF solution 1.0-1.5M, 290-440μL, 2.2mmol) at -40°C. Diethylzinc (1.0M in hexanes, 1.0mL, 1.0mmol) was added dropwise at -40°C under argon atmosphere. The reaction mixture was stirred at 0°C for 3h. After stirring, unreacted difluoroiodomethane and solvents were removed by decantation and in vacuo to give pure bis-difluoromethyl Zn reagent as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With copper(l) iodide; iodine; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h; | General Procedure for the Product General procedure: An test tube was charged with acetophenone (1a, 0.6 mmol, 72.1 mg), pyridine (2a, 0.6 mmol, 47.5 mg), methyl acrylate (3a, 0.3 mmol, 25.8 mg), K2CO3 (2.4 mmol, 331.7 mg) , I2 (1.2 mmol, 304.6 mg), CuI (0.06 mmol, 11.4 mg) and 1 mL DMF. The reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with EtOAc, and washed with 10% Na2S2O3 solution (50 mL). Then the mixture was extracted with EtOAc (20 mL×3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated invacuo. The remaining crude product was then purified through column chromatography using silica gel (EtOAc/petroleum ether = 1/10) to afford 4a as a yellow solid in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In water at 85 - 90℃; for 1h; | [RuNO(inicEt)2(NO2)2OH] (I). The mixture ofNa2[RuNO(NO2)4OH].2H2O (1 mmol) and NH2SO3H (2 mmol) wasdissolved in water (2-3 ml) and stirred at the room temperature(r.t.). The release of N2 usually active in the beginning of the reactionand since the reaction is exothermic cooling can be applied inthe first minutes. After 30 min the solution was neutralized with2 mmol of NaHCO3; 4 mmol of C5H4NCOOEt was added to the solutionand the reaction mixture was stirred at the water bath(85-90°C) for 1 h. The final reaction mixturewas evaporated underthe reduced pressure, resulted viscous solid phase was washedwith water several times and final product was extracted withdichloromethane. The desired complex was precipitated by hexaneor diethyl ether. Final yield is 78%. Single crystals suitable for X-rayanalyses were prepared by slow diffusion of diethyl ether todichloromethane solution. For C16H19N5O10Ru calculated %: C -35.4, N - 12.9,H - 3.5; found % C - 35.7, N - 13.05, H - 3.7. IR (cm-1):3504 ν(OH), 3107, 2985 ν(CH), 1863 ν(NO), 1728 ν(CO), 1413νas(NO2), 1336 νs(NO2), 966 dδ(RuOH), 823 δ(NO2). 1H NMR (ppm):1.37 (3H, t, J = 7.15 Hz), 4.37 (2H q, J= 7.15 Hz), 8.04 (2H, d,J = 6.69 Hz), 9.00 (2H, d, J = 6.69 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogenchloride; tetraethylammonium chloride In water; acetonitrile at 34 - 42℃; Electrochemical reaction; Irradiation; Inert atmosphere; | |
56% | With dipotassium peroxodisulfate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; trifluoroacetic acid In acetonitrile at 20℃; for 16h; Irradiation; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 4h; | 2.2 Synthesis and characterization of oxadiazoles (ODAs). General procedure 2 (GP2) General procedure: An amidoxime (30 mmol) and ester (36 mmol) was added to a suspension of powdered NaOH (36 mmol) in DMSO (10 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with cold water (100 mL), and resulted precipitate was filtered off, washed with cold water (50 mL) and dried in air at room temperature. 3-Phenyl-5-(pyridin-4-yl)-1,2,4-oxadiazole (ODA-4, according to GP2): white solid; 4.62 g (69%) yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.7% | With hydrogenchloride In ethanol; tert-butyl methyl ether at 50℃; for 1h; | 1; 4; 7; 10 Example 1 Preparation of ethyl isonicotinate hydrochloride Add 200g (1.62mol) of isonicotinic acid to a 3000ml four-necked bottle,1600ml of methylene chloride,N,N-dimethylformamide 10ml,Get a white suspension.Slowly add 620g (4.86mol) of oxalyl chloride,The addition is complete,Stir at 1050 for 4 hours,Then add 150.4g (3.24mol) of absolute ethanol dropwise,After the addition is complete, stir for 30 minutes to complete the reaction.The sodium carbonate aqueous solution prepared in advance (220g of sodium carbonate dissolved in 800ml of water) was added dropwise to pH=7-8, the liquid was separated, and the lower organic phase was washed with 600g of 15% aqueous sodium chloride solution. The organic phase was concentrated under reduced pressure at 45°C until no obvious fraction was added, and 400 ml of methyl tert-butyl ether was added, and concentrated at 50°C under reduced pressure until no obvious fraction was added, and the concentrate was diluted with 3200 ml of methyl tert-butyl ether, and the content of hydrogen chloride was 0.39 g 151.6g (1.62mol) of ethanol solution of hydrogen chloride per gram, stirred for 1 hour after dropping, filtered with suction, the filter cake was rinsed with 400ml of methyl tert-butyl ether, and the filter cake was blow-dried at 50°C for 3 hours to obtain 288.7g of different smoke Ethyl acetate hydrochloride white solid powder, yield 94.7%, purity 99.92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: isonicotinic acid ethylester; N,N-dimethyl (trimethylsilyl)methanamide In toluene at 110℃; for 28h; Inert atmosphere; Schlenk technique; Sealed tube; Cooling with ice; Stage #2: With hydrogenchloride In dichloromethane; water at 20℃; for 2h; Inert atmosphere; Schlenk technique; | 2. General procedure for aminocarbonylation of carboxylic esters with carbamoylsilane General procedure: A Schlenk tube fitted with a Teflon vacuum stopcock and micro stirbar was f lame-heatedunder vacuum and refilled with Ar. Carboxylic esters (0.5 mmol) and anhydrous toluene (1 .5mL) was added at ice bath temperature. After 20 min, N,N-dimethylcarbamoylsilane 2 (0 .6mmol) was added. The sealed reaction m ixture was stirred at 110 °C until no carbamoylsilane2 could be detected by TLC. For Table 1 and Table 2, the reaction mixture was addeddichloromethane (5 mL), water (2 mL) and concentrated hydrochloric acid (0.5 mL), thenstirred 2 hours at room temperature, the organic layer was decanted and the aqueous phaseextracted with dichloromethane (2 × 5 mL). The combined organic layers were dried overMgSO4 and evaporated to afford the crude product which was purif ied by columnchromatography on silica gel to afford α-ketoamides 3 or 5. For Table 3, entries 1-3, theresidue was directly isolated by Kugelrohr d istillation to give product 7a. For Table 3, entries4 and Scheme 2, volatiles were removed in vacuum, and the residue was chromatographedusing petroleum ether-EtOAc as eluent to yield products 7d and 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With iodine In acetonitrile at 90℃; for 12h; Sealed tube; | General Procedure for the preparation of 5 General procedure: Substituted pyridines 1 (1.5 mmol), methyl ketones 2 (0.6 mmol), 1,4-naphthoquinone 3(0.5 mmol) and iodine (1.0 mmol) were mixed in 10mL CH3CN and heated at 90oC for 12 h in a sealed tube.After completion of the reaction, chromatographic separation of the reaction mixture after removal of the solvent gave product 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With iodine In acetonitrile at 90℃; for 12h; Sealed tube; | General Procedure for the preparation of 5 General procedure: Substituted pyridines 1 (1.5 mmol), methyl ketones 2 (0.6 mmol), 1,4-naphthoquinone 3(0.5 mmol) and iodine (1.0 mmol) were mixed in 10mL CH3CN and heated at 90oC for 12 h in a sealed tube.After completion of the reaction, chromatographic separation of the reaction mixture after removal of the solvent gave product 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With iodine In acetonitrile at 90℃; for 12h; Sealed tube; | General Procedure for the preparation of 5 General procedure: Substituted pyridines 1 (1.5 mmol), methyl ketones 2 (0.6 mmol), 1,4-naphthoquinone 3(0.5 mmol) and iodine (1.0 mmol) were mixed in 10mL CH3CN and heated at 90oC for 12 h in a sealed tube.After completion of the reaction, chromatographic separation of the reaction mixture after removal of the solvent gave product 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In N,N-dimethyl-formamide; at 70℃; for 6h; | 9,10-bis-bromomethylanthracene (3.65 g, 10.00 mmol) was dis- solved in the dimethylformamide (DMF) and stirred at 70 C for 30 min. Then, the solution of ethyl isonicotinate (3.10 mL, 20.00 mmol) in DMF was added drop wise to the above solution and the reaction mixture was refluxed at 70 C for 6 h. The yel- low precipitate formed was filtered and washed three times with ethanol/water (EtOH/H 2 O) (3:1) mixture. The precipitate was dried in vacuum oven at 65 C (5.33 g, Yield 80%). 1 H NMR (600 MHz, CDCl 3 , 25 C, Si(CH 3 ) 4 ] 9.08 (d, 4H, Ar-H), 8.55 (m, 4H, Ar-H), 8.40 (d, 4H, Ar-H), 7.73 (m, 4H, Ar-H), 7.18 (s, 4H, -CH 2 -), 4.38 (m, 4H, - CH 2 -), 1.29 (t, 6H, -CH 3 ) (Fig. S1). 13 C NMR [125 MHz, d 6 - DMSO, 25 C, Si(CH 3 ) 4 ] 14.38 (-CH 3 ), 56.83 (-CH 2 -), 63.49 (-CH 2 - ), 125.22 (Ar-C), 126.24 (Ar-C), 128.02 (Ar-C), 128.84 (Ar-C), 132.01 (Ar-C), 145.15 (Ar-C), 146.21 (Ar-C), 162.36 (-CO-) (Fig. S2). ESI-MS m/z 585.15 (calcd for [M-Br] + m/z 585.14) (Fig. S3). Anal. Calcd (%) for C 32 H 30 Br 2 N 2 O 4 : C 57.68, H 4.54, N 4.20. Found (%): C 57.53, H 4.45, and N 4.06. IR (KBr, cm -1 ): 3581(s), 3417(w), 3107(s), 2981(s), 1722(s), 1635(s), 1575(s), 1452(s), 1301(m), 1118(s), 762(m), 674(m), 512(m) (Fig. S4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dipotassium peroxodisulfate; silver nitrate In water; 1,2-dichloro-ethane at 100℃; for 20h; Schlenk technique; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dipotassium peroxodisulfate; silver nitrate In water; acetonitrile at 80℃; for 20h; Schlenk technique; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With piperidine In ethanol for 4h; Reflux; | 1 Preparation of 3-(Pyridin-4-yl)-6-((4,7,7-trimethyl-3-carbonylbicyclo[2.2.1]heptane-2-ylidene)methyl)-2H-benzopyran-2-one: 1 mmol of 2-hydroxy-5-((4,7,7-trimethyl-3-carbonylbicyclo[2.2.1]hept-2-ylidene)methyl)benzaldehyde,1 mmol of ethyl 4-picolinate, 30 mL of absolute ethanol and 20 μL of piperidine were successively added to a dry three-necked flask, and the mixture was stirred and refluxed for 4 h. The reaction solution was cooled to room temperature, filtered, washed and dried to obtain pale yellow crystals 3-(pyridin-4-yl)-6-((4,7,7-trimethyl-3-carbonylbicyclo[2.2.1] Hept-2-ylidene)methyl)-2H-benzopyran-2-one in 78% yield and 99.8% purity. |
Tags: 1570-45-2 synthesis path| 1570-45-2 SDS| 1570-45-2 COA| 1570-45-2 purity| 1570-45-2 application| 1570-45-2 NMR| 1570-45-2 COA| 1570-45-2 structure
[ 14208-83-4 ]
Ethyl 3-amino-4-pyridinecarboxylate
Similarity: 0.90
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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