* 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.
General procedure: Hydrazides (30–58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3–6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
91.9%
With hydrazine hydrate In ethanol at 80℃; for 6 h;
(10.83 mmol) of ethyl 4-chlorobenzoate and 50 mL of absolute ethanol were added to a 100 mL round-bottomed flask and 1.08 g (21.67 mmol) of 80percent hydrazine hydrate was added. The temperature of the oil bath was 80Othe C heated under reflux for 6 h, the end of the reaction by TLC, the solvent was distilled off under reduced pressure, to the system was added 30 mL of purified water, extracted with dichloromethane, and finally as a white solid 1.7 g, yield 91.9percent,
82%
With hydrazine hydrate In ethanolReflux
General procedure: Ethylbenzoates (11-15, 1.5g, 9.98 mmol)and ethyl-2-phenylacetates (16-20, 1.5g, 9.13 mmol)were dissolved in ethanol and then hydrazine-hydrate(99percent) was added and reux for 8-12h. Ethanol wasconcentrated and the resultant residue was pouredin ice cold water and stirred for 15 -20 min, the solidsthat were thrown out was fltered at the pump anddried to obtain the corresponding benzohydrazides(21-25) and 2-phenylacetohydrazides (26-30) in 80-82percent yield.
79.3%
With hydrazine hydrate In ethanolReflux
General procedure: A solution of the isolated esters 2a–e (10mmol) in ethanol (20mL), hydrazine hydrate (97percent, 3mL) was added and heated under reflux for 5–8h. After cooling, the formed precipitate was filtered off, washed with water, dried, and crystallized from ethanol.
79.3%
With hydrazine hydrate In ethanolReflux
General procedure: Hydrazine hydrate (97percent, 30 mmol, 1.5 mL) was added to a solutionof the isolated esters 2a–e (10 mmol) in ethanol (20 mL), and themixture was heated at reflux for 5–8 h. After cooling, the resultingprecipitate was filtered off, washed with water, dried, and crystallizedfrom ethanol.
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2
[ 64-17-5 ]
[ 74-11-3 ]
[ 7335-27-5 ]
[ 790-41-0 ]
Reference：
[1] Synthesis, 2007, # 22, p. 3489 - 3496
3
[ 541-41-3 ]
[ 74-11-3 ]
[ 7335-27-5 ]
[ 790-41-0 ]
Reference：
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2.3. Synthesis of 4-chlorobenzohydrazide (2)
Ethyl 4-chlorobenzoate (1; 9.8 mL, 0.05 mol) was taken in a250-mL round-bottom flask and 35 mL of hydrazine hydrate(80%) was added slowly on stirring and the mixture was furtherstirred for 5-6 h. Yellow precipitates were obtained onevaporation of solvent under vacuum. The precipitates werewashed with cold water and dried. The physical and spectroscopicdata of 2 is as follows:Yellow amorphous powder; Yield: 95%; M.P.: 164-166 C;IR (KBr, max, cm1): 3390, 3350 (N-H), 3030 (Ar-H), 2954 (CH),1673 (CO), 1613-1516 (Ar-CC); 1H-NMR (400 MHz,CDCl3, ppm): 7.49 (2H, d, J8.5 Hz, H-3,5), 8.10 (2H, d,J8.5 Hz, H-2,6); 13C-NMR (100 MHz, CD3OD): d 125.1 (C-3,5),128.9 (C-2,6), 131.0 (C-1), 134.9 (C-4), 168.9 (CO); HR-EI-MS(m/z): 170.0247. [M] calculated for C7H7ClN2O; 170.0238.
93.2%
With hydrazine hydrate monohydrate In ethanol at 80℃; for 4h; Reflux;
91%
With hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate Reflux;
Synthesis of benzohydrazides
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
91.9%
With hydrazine hydrate monohydrate In ethanol at 80℃; for 6h;
1.2 (2) Preparation of 4-chlorobenzohydrazide
(10.83 mmol) of ethyl 4-chlorobenzoate and 50 mL of absolute ethanol were added to a 100 mL round-bottomed flask and 1.08 g (21.67 mmol) of 80% hydrazine hydrate was added. The temperature of the oil bath was 80Othe C heated under reflux for 6 h, the end of the reaction by TLC, the solvent was distilled off under reduced pressure, to the system was added 30 mL of purified water, extracted with dichloromethane, and finally as a white solid 1.7 g, yield 91.9%,
88%
With hydrazine hydrate monohydrate In ethanol for 4h; Reflux;
87%
With hydrazine hydrate monohydrate In ethanol for 6h; Heating;
82%
With hydrazine hydrate monohydrate In ethanol Reflux;
General method for the preparation of benzohydrazides ( 21-25 ) and 2-henylbenzohydrazides (26-30)
General procedure: Ethylbenzoates (11-15, 1.5g, 9.98 mmol)and ethyl-2-phenylacetates (16-20, 1.5g, 9.13 mmol)were dissolved in ethanol and then hydrazine-hydrate(99%) was added and reux for 8-12h. Ethanol wasconcentrated and the resultant residue was pouredin ice cold water and stirred for 15 -20 min, the solidsthat were thrown out was fltered at the pump anddried to obtain the corresponding benzohydrazides(21-25) and 2-phenylacetohydrazides (26-30) in 80-82% yield.
79.3%
With hydrazine hydrate monohydrate In ethanol Reflux;
2 4.1.2 General procedure for the synthesis of substituted benzohydrazides 3a-e [58,59]
General procedure: A solution of the isolated esters 2a-e (10mmol) in ethanol (20mL), hydrazine hydrate (97%, 3mL) was added and heated under reflux for 5-8h. After cooling, the formed precipitate was filtered off, washed with water, dried, and crystallized from ethanol.
79.3%
With hydrazine hydrate monohydrate In ethanol Reflux;
4.1.2. General procedure for the synthesis of substitutedbenzohydrazides 3a-e
General procedure: Hydrazine hydrate (97%, 30 mmol, 1.5 mL) was added to a solutionof the isolated esters 2a-e (10 mmol) in ethanol (20 mL), and themixture was heated at reflux for 5-8 h. After cooling, the resultingprecipitate was filtered off, washed with water, dried, and crystallizedfrom ethanol.
76%
With hydrazine hydrate monohydrate In methanol
75%
With hydrazine hydrate monohydrate Reflux; Alcoholic solution;
With ethanol; hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate Yield given;
With hydrazine hydrate monohydrate In ethanol Heating;
With hydrazine hydrate monohydrate
With hydrazine In ethanol; lithium hydroxide monohydrate for 3h; Heating;
With hydrazine hydrate monohydrate In ethanol for 2h; Heating;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate for 8h; Heating;
With hydrazine hydrate monohydrate In ethanol
With hydrazine
With hydrazine hydrate monohydrate for 8h; Reflux;
With hydrazine hydrate monohydrate In ethanol for 8h; Reflux;
With hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate Reflux;
With hydrazine In lithium hydroxide monohydrate
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate for 0.05h; Microwave irradiation;
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux;
With hydrazine In ethanol for 16h; Reflux; Inert atmosphere;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate for 0.05h; Microwave irradiation;
With hydrazine hydrate monohydrate
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
With hydrazine monohydrate In ethanol Microwave irradiation;
With hydrazine hydrate monohydrate for 2h; Reflux;
With hydrazine hydrate monohydrate Microwave irradiation; Reflux;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux;
With hydrazine monohydrate for 2h; Reflux;
With hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate
With hydrazine hydrate monohydrate for 6h; Reflux;
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 at 80℃;
Preparation of acyl hydrazine B
General procedure: At firstseveral different acyl hydrazines Bwere synthesized. To do this, we have started with corresponding carboxylicacid A in solvent EtOH (2 mL/mmol), 4 equivalents ofthionyl chloride (SOCl2) was added dropwise at room temperature andrefluxed with stirring for 5-12 h (monitored by TLC). SOCl2 and EtOHwas evaporated. Water was added to the crude mixture, extracted withdichloromethane (DCM) and dried with anhydrous Na2SO4.Solvent DCM was evaporated and the residue was dried at high vacuum whichprovided the ethyl ester of the corresponding carboxylic acid A.The ester was added dropwise to hydrazinehydrate (NH2NH2,H2O) (5mmol/1mmol of ethylcarboxylate) and heated at 80 °C for 5-20 hours (monitored by TLC) and allowedto stand for 12 hours. If solid appeared it was filtered and the residue wasdissolved in DCM and dried with anhydrous Na2SO4, DCM wasthen evaporated and the solid was dried at high vacuum. If solid was notobserved then the reaction mixture was extracted several occasions by DCM, andthe combined organic layer was dried with anhydrous Na2SO4. DCM was evaporated and residue was dried at high vacuum that leads usdifferent acyl hydrazine Bcorresponding to the starting carboxylic acid A.
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. 4-chlorobenzohydrazide (II-1): yield (91.3%). Melting point: 143.6-144.1 °C. ESI-MS (m/z, [M+H]+) = 171.2.
With sodium tetrahydroborate; hafnium tetrachloride In tetrahydrofuran at 20℃; for 5.6h; Inert atmosphere; Cooling with ice;
98%
With phenylsilane; potassium <i>tert</i>-butylate; water; sodium triethylborohydride; cobalt(II) chloride In 1,4-dioxane; toluene at 60℃; for 15h; Inert atmosphere; Glovebox; Schlenk technique;
96%
With C30H34Cl2N2P2Ru; potassium methanolate; hydrogen In tetrahydrofuran at 100℃; for 15h; Glovebox; Autoclave;
27 Example 27: Hydrogenation of ester compounds catalyzed by ruthenium complex Ia
General procedure: In a glove box, add a ruthenium complex Ia (0.3 to 0.7 mg, 0.0002 to 0.001 mmol) to a 300 mL autoclave,Potassium methoxide (35-700 mg, 0.5-10 mmol), tetrahydrofuran (4-60 mL), and ester compounds (10-200 mmol).After sealing the autoclave, take it out of the glove box and fill it with 50 100atm of hydrogen.The reaction kettle was heated and stirred in an oil bath at 100 ° C for 10 to 336 hours.After the reaction kettle was cooled in an ice-water bath for 1.5 hours, the excess hydrogen was slowly released.The solvent was removed from the reaction solution under reduced pressure, and the residue was purified with a short silica gel column to obtain an alcohol compound. The results are shown in Table 5.
95%
With calcium borohydride In tetrahydrofuran; toluene at 100℃; for 1h;
92%
With sodium tetrahydroborate; C36H30F6N10Ni4O10(2+)*2C2F3O2(1-); zinc(II) chloride In tetrahydrofuran at 45℃; for 12h;
91%
With lithium borohydride In methanol; diethyl ether for 0.5h; Heating;
91%
With methanol; lithium borohydride In diethyl ether for 0.5h; Heating;
90%
With lithium borohydride In diethyl ether for 1h; Heating;
90%
With lithium borohydride In diethyl ether for 1h; Heating;
74%
With 15-crown-5; (1-(2-(2,3-diisopropyl-1-methylguanidino)ethyl)-3-mesityl-1,3-dihydro-2H-imidazol-2-ylidene)copper(I) chloride; hydrogen; sodium t-butanolate In 1,4-dioxane at 60℃; for 24h; Inert atmosphere;
With sodium tetrahydroborate; diethylene glycol dimethyl ether; lithium bromide
With lithium borohydride; aluminium trichloride; diethyl ether
With sodium tetrahydroborate; aluminium trichloride; diethylene glycol dimethyl ether
91 % Chromat.
With potassium borohydride; lithium chloride for 0.0833333h; microwave irradiation;
Multi-step reaction with 2 steps
1: lithium tert-butoxide / tetrahydrofuran / 0 - 20 °C
2: sodium hydroxide / water / 1 h / 20 °C
1.1 (1) Preparation of ethyl 4-chlorobenzoate
2 mL (12.77 mmol) of 4-chlorobenzoic acid was added to a 100 mL round-bottomed flask. 50 mL of ethanol was added and 1 mL (20.1 mmol) of concentrated sulfuric acid was added dropwise. The mixture was heated at reflux for 5 h. The reaction was terminated by TLC. Saturated sodium carbonate The solution was adjusted to pH 7 and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, stripped and column chromatographed (PE: EA = 10: 1, v / v) Liquid 2.0 g, yield 93.4%.
87%
With sulfuric acid for 3h; Heating;
82%
With fluorosulfonyl fluoride; N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; for 5h;
Esterification; General Procedure
General procedure: Carboxylic acid 1 (1.0 mmol, 1.0 equiv), alcohol 2 (2.0 mmol, 2.0 equiv), DIPEA (3.0 mmol, 3.0 equiv) and DCE (the reaction mixture was diluted to 0.2 M) were added to an oven-dried 25 mL reaction flask equipped with a stir bar and sealed with a rubber stopper. SO2F2 gas was introduced into the stirred reaction mixture by slowly bubbling from a balloon [the balloons were made from low-density polyethylene (LDPE) which it not reactive with SO2F2]. The reaction mixture was stirred at room temperature for 5 h. After the reaction was completed, the reaction mixture was directly concentrated under vacuum and was purified by column chromatography on silica gel using a mixture of petroleum ether and ethyl acetate as eluent to give the desired product 3. To confirm the amount of SO2F2 consumed in this transformation, 4-biphenylcarboxylic acid (1a) (10 mmol, 1.0 equiv), EtOH (2a) (20 mmol, 2.0 equiv), DIPEA (30 mmol, 3 equiv) and DCE (the reaction mixture was diluted to 0.2 M) were added to an oven-dried 100 mL reaction flask equipped with a stir bar and sealed with a rubber stopper. A balloon filled with SO2F2 gas was weighed before introduction of the SO2F2 gas into the stirring reaction mixture by slow bubbling at room temperature. After the reaction complete, the SO2F2 balloon was weighed again to measure the difference in weight. It was calculated that the SO2F2 consumption was about 3.26 g (31.9 mmol, 3.2 equiv) in this particular reaction (some of the gas dissolved in the DCE solvent can be considered as unreacted but consumed). The corresponding ester product 3a was obtained in 98% yield after work-up.
71%
With sulfuric acid In ethanol for 12h; Reflux;
9 Synthesis of XXXIX:
To a stirred solution of 4-chlorobenzoic acid (XXXVIII; 15 g; 9.61 mmol) in ethanol (150 mL) was added a catalytic quantity of sulfuric acid (3 mL). The reaction mixture was heated to areflux for 12 hours, whereupon it was cooled, concentrated under reduced pressure and diluted with water. The aqueous layer was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with successively with sodium bicarbonate and brine, followed by drying over Na2SO4, filtration and concentration under vacuum to afford ethyl 4- chlorobenzoate as a white solid (XXXIX; 12 g, 71% yield). ‘H NMR (400 MHz, CDC13): ö7.96-7.94 (d, J = 8.4 Hz, 2H), 7.60-7.58 (d, J = 8.4 Hz, 2H), 4.33-4.28 (q, J = 7.2 Hz, 2H),1.33-1.29 (t,J 7.2 Hz, 3H).
With thionyl chloride for 0.0666667h; Microwave irradiation;
With sulfuric acid In mineral acid Reflux;
With sulfuric acid Reflux;
With sulfuric acid
With thionyl chloride Microwave irradiation;
With thionyl chloride for 0.0666667h; Microwave irradiation;
With thionyl chloride
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 thionyl chloride Microwave irradiation;
With sulfuric acid
With sulfuric acid Reflux;
With sulfuric acid
With sulfuric acid Reflux;
99 %Chromat.
With poly(ethylene glycol) 1000 based dicationic acidic ionic liquid In toluene at 80℃; for 0.833333h; Ionic liquid;
General procedure for esterification in PEG1000-DAIL/toluene system
General procedure: Aromatic acids (2 mmol) and alcohols (3 mmol) were added into a 10 mL tube reactor preloaded with PEG1000-DAIL (2 mL) and toluene (2 mL). The reaction mixture was stirred thoroughly at 80C for 1 h. After the completion of reaction, the mixture separated into two phases at room temperature, the upper phase was decanted for analysis and the below phase was reused for the next time directly or after removing water under vacuum at 80C for 1 h.
With sulfuric acid
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 at 20℃; Reflux;
Preparation of acyl hydrazine B
General procedure: At firstseveral different acyl hydrazines Bwere synthesized. To do this, we have started with corresponding carboxylicacid A in solvent EtOH (2 mL/mmol), 4 equivalents ofthionyl chloride (SOCl2) was added dropwise at room temperature andrefluxed with stirring for 5-12 h (monitored by TLC). SOCl2 and EtOHwas evaporated. Water was added to the crude mixture, extracted withdichloromethane (DCM) and dried with anhydrous Na2SO4.Solvent DCM was evaporated and the residue was dried at high vacuum whichprovided the ethyl ester of the corresponding carboxylic acid A.The ester was added dropwise to hydrazinehydrate (NH2NH2,H2O) (5mmol/1mmol of ethylcarboxylate) and heated at 80 °C for 5-20 hours (monitored by TLC) and allowedto stand for 12 hours. If solid appeared it was filtered and the residue wasdissolved in DCM and dried with anhydrous Na2SO4, DCM wasthen evaporated and the solid was dried at high vacuum. If solid was notobserved then the reaction mixture was extracted several occasions by DCM, andthe combined organic layer was dried with anhydrous Na2SO4. DCM was evaporated and residue was dried at high vacuum that leads usdifferent acyl hydrazine Bcorresponding to the starting carboxylic acid A.
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 sulfuric acid Reflux;
With sulfuric acid
With sulfuric acid at 70 - 80℃; for 12h; Reflux;
General procedure: To a solution of the R-substituted aromatic acid (10 mmol) in 20 ml ethanol was added 5 ml concentrated sulfuric acid. The mixture was refluxed at 70-80 °C for 12 h. The reaction was concentrated and alkalized with saturated Na2CO3 solution to pH 6-7. The mixture was poured into 100 ml of ice-cold water and extracted with CH2Cl2 (3 50 ml). The organic layer was combined, washed with water, saturated NaHCO3 solution and brine, dried over anhydrous Mg2SO4 and concentrated to give a corresponding ester.
With sulfuric acid Reflux;
General Procedure for the Synthesis of Different Ethyl Esters (2a-k)
General procedure: The aryl/aralkyl organic acids (5.0 g, 1a-k), the absolute ethanol (20 mL), and conc.H2SO4 (1.5 mL) were taken in 250 mL round bottom flask fitted with reflux condenser. Thereaction mixture was refluxed for 3-4 h. TLC was used to check the completion of reactionby using a solvent system, n-hexane, and EtOAc. On completion, reaction contents were transferred to a separating funnel containing distilled H2O (20 mL). Sodium carbonate(Na2CO3) solution was added to neutralize the acidic pH. Diethyl ether was added to theseparating funnel followed by shaking and the contents were left to set up two layers. Thelower aqueous layer was discarded and the upper organic ether layer containing requiredester was taken into the distillation flask. The organic layer, diethyl ether was distilled offand the corresponding esters (2a-k) were collected from the flask to follow the furtherreaction.17-19
With sulfuric acid for 8 - 12h; Reflux;
With sulfuric acid In water for 6h; Reflux;
Synthesis of benzohydrazides
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
With thionyl chloride
With sulfuric acid Reflux;
General procedure for synthesis of benzohydrazidederivatives (4a-m):
General procedure: To a stirred solution of different benzoic acids (6.42 mmol) in ethanol (3 mL) was added H2SO4 (0.1mL) and heated to reflux for 6-10 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was washed with saturated NaHCO3 followed by water and brine solution. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain the respective ethyl benzoate derivatives.
With sulfuric acid for 10h; Reflux;
General procedure for the synthesis of benzohydrazides7a-k [12,13]
General procedure: A mixture of benzoic acid (6.42 mmol), catalytic quantity of conc. H2SO4 in ethanol was heated to reflux for 10 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was washed with saturated NaHCO3 followed by water and brine solution. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain respective ethyl benzoates.
With sulfuric acid at 70℃; for 3h;
With sulfuric acid for 10h; Reflux;
Experimental procedure for synthesis of benzohydrazides7a-j [34-35]
General procedure: Benzoic acids a-j(8.12 mmol) was dissolved in ethanol (15 mL) and added catalytic qty of conc.H2SO4and heated to reflux for 10 h. Ethanol was evaporated and the obtained residue was diluted with ethylacetate (25 mL). The organic layer was washed with aqueous saturated NaHCO3(3 X 15 mL) followed by water (2 X 15 mL) and brine solution (20 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to obtain respective ethyl benzoates.
With sulfuric acid for 8h; Reflux;
General methods for synthesis of substituted ethylbenzoates (16-30)24
General procedure: To a solution of substituted benzoic acid (1-15)(0.246 mol) in dry ethanol (2.5 mol), concentrated sulphuricacid (0.5 mL) was added. The reaction mixture was refluxedfor 8 h. Excess of ethanol was distilled off and the contentwas allowed to cool. The residue was poured into separatingfunnel containing 60 mL of water. Carbon-tetrachloride(5-10 mL) was added to obtain sharp separation of aqueousand ester layer. Ester layer was washed with sodiumhydrogen carbonate solution. The esters (16-30) were collected and recrystallized from ethanol. Details of thesecompounds are available in Supplementary Information.
With thionyl chloride for 2h; Reflux;
2.5 General procedure for synthesis of starting Materials 1a-p[1]-[3]
General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketoamides 1a-p, white solid compounds in 45% - 85% yields.
With sulfuric acid for 10h; Reflux;
With sulfuric acid for 0.25h;
With sulfuric acid In water for 12h; Reflux;
With sulfuric acid Reflux;
General procedure: We added dense H2SO4 (0.098g, 1mmol) to a solution of substituted benzoic acid (5mmol) in dry ethyl alcohol (10mL). The mixture was heated under reflux until completion (as monitored via TLC), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50mL) and washed with 0.1M Na2CO3, brine, dried and concentrated, respectively. The crude products (intermediate 3) were used directly for the next step.
With thionyl chloride Reflux;
With sulfuric acid Heating;
With sulfuric acid Reflux;
General method for the preparation ofethylbenzoates (11-15) and ethyl-2-phenylacetates(16-20)
General procedure: Benzoicacids (1-5, 2g, 16.40mmol) and2-phenylaceticacid (6-10, 2g, 14.69 mmol) wasdissolved in ethanol (25 mL) and then catalyticquantity of concentrated sulphuric acid was addedand reuxed for 10-12h. Ethanol was concentrated upto 80% and diluted with ethylacetate (50 mL) followedby water (25 mL). The organic layer was washedwith saturated NaHCO3solution (4 X 20 mL), waterand brine solution. The separated organic layer wasdried on sodium sulphate, fltered and concentratedto obtain the corresponding ethylbenzoates (11-15)and ethyl-2-phenylacetates (16-20) in 75-80% yield.The isolated compounds were utilized in the next stepwithout any further purifcation.
With sulfuric acid Inert atmosphere;
With sulfuric acid Reflux;
4.1.1 General procedure for the synthesis of substituted ethylbenzoate 2a-e [57]
General procedure: A mixture of the appropriate substituted benzoic acid 1a-e (10mmol), absolute ethanol (20mL) and concentrated sulfuric acid (2mL) was heated under reflux for 12-18h. Excess solvent was removed under reduced pressure; The residue extracted with ether (2×50mL) and washed with saturated NaHCO3 (2×20mL). The ether layer was dried over anhydrous magnesium sulphate, and the ether was evaporated under vacuum to give the ethyl ester derivatives 2a-e.
With sulfuric acid Reflux;
Synthesis of ethyl p-substituted benzoate:
General procedure: Esters of allderivatives were synthesized by the standard esterification methodvia Fischer esterification (McMurry, 2012) of correspondingp-substituted benzoic acids. The appropriate p-substitutedbenzoic acid (0.1 mol) was refluxed in 100 mL absolute ethanoland 14 mL conc. sulphuric acid. Completion of the reactions(2-8 h) was monitored by TLC using hexane:ethyl acetate asmobile phase. Solvent was evaporated and sodium bicarbonatesolution was added until the solution became neutral, the resultedsolution was subjected to extraction three times each of 20 mLdichloromethane. The extracts were collected and the solventwas evaporated, resulted esters were used in the second stepwithout further purification, (m.p. ethyl p-amino and p-nitrobenzoate were found to be 89 C and 58 C (lit. 88-90 C and55-59 C, respectively [6]
With sulfuric acid Reflux;
4.1.1. General procedure for the synthesis of substitutedethylbenzoate 2a-e
General procedure: A mixture of the appropriate substituted benzoic acid 1a-e(10 mmol), absolute ethanol (20 mL), and concentrated sulfuric acid(2 mL) was heated under reflux for 12-18 h. Excess solvent was removedunder reduced pressure. The residue was extracted with ether(2 X 50 mL) and washed with saturated NaHCO3 (2 X 20 mL). The etherlayer was dried over anhydrous magnesium sulfate, and ether wasevaporated under vacuum to produce the ethyl ester derivatives 2a-e.
With sulfuric acid at 20℃; for 16h; Reflux;
4.2.2. General procedure for preparation of substituted aromaticesters (4a-4e)
General procedure: To a solution of substituted aromatic benzoic acid (3a-3e)(1 mmol) in EtOH (15 ml), a catalytic amount of Conc. H2SO4 wasadded slowly at RT, then heated to reflux for 16 h with stirring. Aftercooling, EtOH was removed and concentrated in vacuum; the reactionmixture was diluted with ethyl acetate (30 mL) and washedwith sat.NaHCO3 and coldwater, followed by separating the organic layer. The combined organic layer was washed with brine, driedover anhydrous Na2SO4, filtered, concentrated, and dried undervacuum for 12 h.
With sulfuric acid Reflux;
General procedure for synthesis of ethyl (un)substituted benzoates (Va-n).
General procedure: (Un)Substituted benzoic acid (IVa-n) (0.02 mol) was refluxed with 60 mL EtOH for 4-5 h in the presence of conc. H2SO4 (1.25 mL) in around-bottom flask (250 mL). TLC plates were used to monitor the reaction. Excess distilled water (150 mL) was added after reaction completion and pH was adjusted to 8-10 by 20% aq. Na2CO3 solution. The product was collected through sequential extraction with CHCl3 (20 mL × 3). Chloroform was distilled off to collect the product. In some cases, the product was collected through filtration. Esters (Va-n) were used in further synthesis [18, 19].
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 Reflux;
With sulfuric acid
With thionyl chloride for 2h; Reflux;
With sulfuric acid at 120℃;
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 for 3h; Reflux;
With sulfuric acid Reflux;
With sulfuric acid at 78℃; for 2h;
With sulfuric acid for 24h; Reflux;
With sulfuric acid
With sulfuric acid for 5h; Reflux;
4.2.4. General synthetic procedures for the title compound I12-I15
General procedure: The acetonitrile (50 mL) containing 4-chlorobenzenethiol (20.74mmol), ethyl bromoacetate (24.89 mmol) and potassium carbonate(31.12 mmol) was stirred under reflux for 5 h. After filtration, the filterliquor containing the intermediate 14a was mixed with hydrazine hydrate(80%, 62.29 mmol), stirred under reflux for 3 h, and followed bythe removal of acetonitrile under vacuum to generate the intermediate15a emerging as white solids. Subsequently, the ethanol (50 mL) containingthe intermediate 15a (14.95 mmol) and potassium hydroxide(KOH, 17.94 mmol) was stirred in an ice-bath for 30 min. Then, theethanol (10 mL) containing carbon disulfide (CS2, 17.94 mmol) wasslowly added into the above mixture in an ice-bath. After stirring under80 C for 5 h, the obtained mixture was transferred to distilled water(300 mL), acidized by the 5% hydrochloric acid, and filtered to obtainthe intermediate 17a emerging as white solids. The reaction of the intermediate13a (2.40 mmol) with the intermediate 17a (2.40 mmol) wascatalyzed by potassium carbonate (7.19 mmol) in boiling acetonitrile(25 mL) for 3 h. After the obtained mixture was filtered and followed bythe removal of acetonitrile under vacuum, the resulting residue containingthe title compound I12 was purified by the silica gel that used theeluent containing petroleum ether and ethyl acetate (V:V = 3:1).The hydrogen peroxide (H2O2, 30%, 39.00 mmol) containingammonium molybdate (H8MoN2O4, 0.65 mmol) was slowly added intothe ethanol (40 mL) containing the intermediate 14a (13.00 mmol).After stirring for 3 h at room temperature, the resulting mixture wasfiltered, followed by the removal of acetonitrile under vacuum, andtransferred to distilled water (100 mL). After extraction by ethyl acetate,the organic phase was treated by anhydrous sodium sulfate, concentratedunder vacuum to generate the intermediate 14b emerging aswhite solids. The subsequent procedures used to generate the titlecompound I13 were similar with those that successfully constructed thetitle compound I12, in which the intermediate 14a was replaced by theintermediate 14b.The ethanol (50 mL) containing 4-chlorobenzoic acid (63.87 mmol)and concentrated sulfuric acid (6.39 mmol) was stirred for 5 h underreflux. After the removal of ethanol under vacuum, the resulting mixturewas transferred to distilled water (100 mL) and extracted by ethyl acetate.The obtained organic phase was treated by anhydrous sodiumsulfate and concentrated under vacuum to generate the intermediate14c emerging as colorless oleamen. The subsequent procedures used togenerate the title compound I14 were similar with those that successfullyconstructed the title compound I12, in which the intermediate 14a wasreplaced by the intermediate 14c.The synthetic procedures used to generate the title compound I15were similar with those that successfully constructed the title compoundI14, in which 4-chlorobenzoic acid (14c) was replaced by 2-(4-chlorophenyl)acetic acid (14d).
With sulfuric acid In water for 3h; Reflux;
General method for the synthesis of substituted esters(2a-c):
General procedure: Substituted aromatic acids (1a-c) (1 mmol) weredissolved in 5 mL of ethanol and refluxed for 3 h in the catalyticamount of concentrated sulfuric acid. Reaction completion wasobserved by TLC (toluene:ethyl acetate = 7:3). Ethanol wasevaporated and the resulting mass was neutralized with 5%NaHCO3. The product was extracted into ether, washed withwater and the ether was evaporated to get the product (2a-c),which was taken directly for the second step
Stage #1: p-chlorobenzyl cyanide With sodium hydride In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: ethyl 4-chlorobenzoate In tetrahydrofuran Reflux;
General Procedure for the Synthesis of Intermediates 3a-3d
General procedure: Sodium hydride (1.33 ml, 2.61 mmol) was added dropwise to a solution of phenyl acetonitrile (1.0 g, 8.5 mmol)) in anhydrous THF (30 mL), the mixture was stirred at R.T. for30 minutes, followed by adding a solution of ethyl 4-chlorobenzoate (1.78 g, 10.2 mmol) in anhydrous THF (30mL). The mixture was refluxed till the reaction was finished.The result mixture was quenched with water and extracted with ether. The aqueous layer was acidified with 10% HCl to filter out the white precipitation, which was recrystallized with ether to give a white solid. Yield: 76%-80%.
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 80℃; for 4h;
91%
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 80℃; for 6h;
Typical procedure for carbonylation reactions
General procedure: The catalytic reactions were carried out in a 10 mL reaction flask and fitted with condenser and carbon monoxide balloon. In a typical run, a catalyst containing 1.0 mol% Pd, aryl iodide (0.5 mmol) and DBU (1.5 mmol) were added to solvent and allowed to react under CO atmosphere at 80 °C temperature for 6-10 h. After the reaction,the flask was cooled to room temperature and carbon monoxide balloon was removed. The reaction mixture was then centrifuged and the clear supernatant was analyzed with GC by using n-butanol as an internal standard. For the study of substrate scope, after completion of the reaction, the catalyst was centrifuged and extracted with copious ethanol. The obtained liquid was concentrated. For phenoxycarbonylation, the obtained liquid was diluted with saturated NH4Cl and extracted with diethyl ether. The organic layer was dried over anhydrous Na2SO4 and then concentrated. The product was obtained by preparative thin-layer chromatography (PTLC) using petroleum ether and ethyl acetate (30:1, v/v) as eluting solvent. The purity of products was checked by NMR and yields were based on aryl iodides.
90%
With 4 A molecular sieve In tetrahydrofuran at 100℃; for 24h;
Stage #1: ethyl 4-chlorobenzoate With morpholine; diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 3.16667h; Inert atmosphere;
Stage #2: With diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 0.166667h; Inert atmosphere;
4.4 Partial reduction of aromatic esters to corresponding aldehydes (Table 4)
General procedure: The following experimental procedure for the partial reduction of ethyl benzoate to benzaldehyde is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (0.18mL, 2.1mmol) and THF (10mL). After cooling to 0°C, DIBALH (2.0mL, 1.0M in hexane, 2.0mmol) was added dropwise and the mixture was stirred for 3h at the same temperature. Ethyl benzoate (0.14g, 1.0mmol) was added slowly to the reaction mixture, which was stirred for 10min. Then, DIBALH (1.1mL, 1.0M in hexane, 1.1mmol) was added and the mixture was stirred for 10min again. The reaction was stopped aqueous 1N HCl (10mL) and extracted with diethyl ether (2×10mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by short column chromatography on silica gel using Et2O yielded benzaldehyde (106mg, 99%).
84%
With phenylsilane; cobalt(II) diacetate tetrahydrate; sodium triethylborohydride In 1,2-dimethoxyethane; toluene at 25℃; for 15h; Inert atmosphere; Schlenk technique;
83%
With n-butyllithium; diisobutylaluminium hydride; <i>tert</i>-butyl alcohol In tetrahydrofuran; hexane at 0℃;
79%
With sodium diethylpiperidinohydroaluminate In tetrahydrofuran at 0℃; for 0.5h;
83 % Chromat.
With naphthalene In tetrahydrofuran; hexane at 0℃; for 3h;
98 %Chromat.
With Na(1+)*C12H27AlNO5(1-) In tetrahydrofuran; toluene at 0 - 20℃; for 0.5h;
Partial Reduction of Esters to Corresponding Aldehydes.
General procedure: The following experimental procedure for the partial reduction of ethyl benzoate to benzaldehyde is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with ethyl benzoate (0.07 mL, 0.5 mmol) and THF (5 mL). After cooling to 0 °C, cis-2,6-dimethylmorpholine-modified Red-Al (2.5 mL, 0.4 M 1.0 mmol) was added dropwise and the mixture was stirred for 30 min at the room temperature. The reaction was stopped aqueous 1 N HCl (5 mL) and the product was extracted with diethyl ether (10 mL). The ether layer was dried over anhydrous magnesium sulfate. GC analysis showed a 98% yield of benzaldehyde. All products in Table 1 were confirmed through comparison with GC data of authentic sample.
Stage #1: ethyl 4-chlorobenzoate With triethylsilane; 1,2,3-trimethoxybenzene; C24H23ClCrIrNO3; sodium tetrakis[(3,5-di-trifluoromethyl)phenyl]borate In dichloromethane at 25℃; for 0.25h; Inert atmosphere; Glovebox; Schlenk technique;
Stage #2: In dichloromethane; water for 0.5h; Inert atmosphere; Glovebox; Schlenk technique;
With C22H29N2O(1+)*I(1-); caesium carbonate In toluene at 60℃; for 3h;
2.4 General Procedure forOxidative Esterication of Aldehydes and Alcohols
General procedure: A three-neck flask was charged with aldehyde 7a-7p(1.0mmol), camphor-based imidazolium salts (5mol%),Cs2CO3(163mg, 0.5mmol), alcohol (5mmol) and 10ml oftoluene in an air atmosphere, then the mixture was stirred for3h at 60°C. The reaction mixture was extracted with diethylether (3 × 30ml), concentrated under reduced pressure andthe residue was purified by flash column chromatography onsilica gel (PE (petroleum ether):EA (ethyl acetate) = 20:1)to give the desired product. All products were identified by1H and 13C NMR and in accord with literatures [42-52] (forspectra see Supplementary Data).
94%
With 3-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methyl-1-(2,6-diisopropylphenyl)-1H-imidazol-3-ium tetrafluoroborate; caesium carbonate In toluene at 60℃; for 3h;
2.5 5) Preparation of ethyl 4-chlorobenzoate:
Accurately weigh 0.1mol 4-chlorobenzaldehyde,Add to 500mL round bottom flask,Then add 0.5mol of ethanol,0.005mol of 1- (2,6-diisopropyl) phenyl-3- (7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methyl-1H- Imidazol-3-ium tetrafluoroborate,0.05mol of cesium carbonate, 150mL of toluene, put on an air balloon, and stir at 60 ° C for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated brine to neutrality, concentrated under reduced pressure, and subjected to column chromatography to obtain ethyl 4-chlorobenzoate. The yield was 94%.
92%
With potassium cyanide; oxygen at 70℃; for 2h; chemoselective reaction;
86%
With urea-2,2-dihydroperoxypropane; hydrogen bromide; acetic acid at 20℃; for 6h;
81%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; benzyl chloride at 90℃; for 0.5h; Microwave irradiation;
General procedure: A 10 mL reaction vessel was charged in air with Pd(PPh3)4 (6 mg, 1 mol %), aldehyde (0.5 mmol), K2CO3 (207 mg, 1.5 mmol), benzyl chloride (70 μL, 0.6 mmol) and EtOH (1 mL). The vessel was sealed and submitted to microwave irradiation for 30 min at 90 °C, using an initial power of 30 W. (Microwave reactions were carried out with a CEM Discover 300 W monomode microwave instrument. The closed vessels used were special glass tubes with self-sealing septa that controlled pressure with appropriate sensors on the top (outside the vial). The temperature was monitored through a non-contact infrared sensor centrally located beneath the cavity floor.) The mixture was then allowed to cool to room temperature, filtered over a pad of Celite and rinsed with EtOH (5 mL). The filtrate was concentrated in vacuo and the product was purified by flash chromatography on silica gel (CH2Cl2/hexane).
79%
With 1,3-dimethylbenzimidazolium Iodide; 4-nitro-aniline; 1,8-diazabicyclo[5.4.0]undec-7-ene for 4h; Heating;
79%
Stage #1: 4-chlorobenzaldehyde With hydroxylamine hydrochloride In dimethyl sulfoxide at 100℃; for 1h;
Stage #2: ethanol With sulfuric acid In dimethyl sulfoxide at 130℃; for 2.5h;
76%
Stage #1: ethanol; 4-chlorobenzaldehyde With tris(pentafluorophenyl)borate for 0.25h; Green chemistry;
Stage #2: With tert.-butylhydroperoxide In decane for 28h; Green chemistry;
Typical experimental procedure:
General procedure: B(C6F5)3 (1 mol %) was added to a stirringsolution of aldehyde (1 mmol) in MeOH (6 mL). After 15 min., 5.5 M TBHP indecane (3 mmol) was added slowly and reaction mixture was refluxed untilthe complete conversion of starting material (monitored by TLC). Aftercompletion of reaction, the methanol was evaporated in vacuo. Later, thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (3 15 mL). The organic layer was washed with cold saturated sodiumbicarbonate solution (2 20 mL) followed by brine. The organic layer wasdried over MgSO4 and concentrated under reduced pressure and products werepurified over silica gel column chromatography in ethyl acetate/hexane. Allcompounds were characterized and confirmed by comparison of their spectraldata and physical properties with reported literature.
75%
With bis(acetylacetonate)oxovanadium; dihydrogen peroxide at 60℃; for 2.5h;
5%
With palladium diacetate; potassium carbonate; XPhos In acetone at 50℃; Inert atmosphere; Glovebox;
With potassium cyanide; potassium iodide at 75 - 80℃; for 24h;
With dihydrogen peroxide at 60℃; for 3h;
2.3. Catalytic reaction
General procedure: The catalytic reactions were performed in a round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser. The oxidative esterification was carried out as follows: catalyst (20 mg), aldehyde (1 mmol) and alcohol (5 mmol) were magnetically stirred in the reaction flask at 60 °C. H2O2 (2 mmol) was progressively added to the reaction mixture using a syringe. The reactions were stopped after 3 h and the excess hydrogen peroxide was deactivated by the addition of aq. sodium bisulfite. The catalyst was separated from the reaction mixture by filtration. As a two-layer mixture was obtained (organic phase/water phase) after the reaction, the organic products were separated from the aqueous phase by ethyl acetate extractions. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, and then analyzed by GC-MS.
90 %Chromat.
With dihydrogen peroxide at 70℃; for 24h;
2.4. General procedure for one pot oxidative esterification of aldehydes tocorresponding methyl esters with PS-Zn-salen complex (1f) and H2O2
General procedure: The reaction of 3,4,5-trimethoxybenzaldehyde (0.01mol)withH2O2(0.04 mol) and methanolwas carried out in 100 mL round bottomflask.The reaction mixture was reflux for 24 h. After completion of the reaction,the reaction mixture pour in distilled water; the aqueous solutionwas the extracted with ethyl acetate (3 × 20 mL) and brine solution toget clear ethyl acetate layer. The organic layerwas driedwith anhydrous sodiumsulfate. It was filtered and vaporized to dryness at reduced pressureto obtained corresponding methyl etster.
Stage #1: ethyl 4-chlorobenzoate With potassium <i>tert</i>-butylate In tetrahydrofuran; water
Stage #2: acetonitrile 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.
67.5%
With sodium hydride In toluene at 90℃; for 24h;
With sodium hydride In tetrahydrofuran at 20℃;
With potassium <i>tert</i>-butylate In tetrahydrofuran at 17 - 19℃; for 0.583333h;
Stage #1: acetonitrile With sodium hydride In toluene at 0℃; for 0.5h;
Stage #2: ethyl 4-chlorobenzoate In toluene at 100℃; for 12h;
9 Synthesis of XL:
To a stirred solution of acetonitrile (10 mL) in toluene (100 mL) was added sodium hydride(3.26 g; 81 mmol) at 0°C. The stirring was continued for 30 minutes and then ethyl 4-chlorobenzoate (XXXIX; 5 g; 27 mmol) was added. The reaction mixture was stirred at 100°Cfor 12 hours. The reaction mixture was cooled, concentrated at reduced pressure and dilutedwith ice cold water. The reaction mixture was acidified using iN hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound 3-(4-chlorophenyl)-3-oxopropanenitrile as a crude light yellow solid (XL; 3 g,61%yield).
With sodium hydride In tetrahydrofuran; mineral oil at 70℃; for 5h;
5.1.2. General Procedure for the Preparation of 6a-c
General procedure: To a stirred suspension of sodium hydride (60% dispersionin mineral oil, 50 mmol) in THF (25 mL) was added a mixture of ethyl benzoate (5a-c, 33 mmol) and acetonitrile(50 mmol). The resulting pale yellow suspension was heated at 70 °C for 5h, monitoring by TLC. After cooling to rt, the reaction mixture was poured into water (150 mL), acidified to pH2 with aqueous 2M HCl and the resulting solution was extracted with diethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure to afford the title ketonitriles which were used without further purification.
With sodium hydride In tetrahydrofuran for 1h; Reflux;
2.5 General procedure for synthesis of starting Materials 1a-p[1]-[3]
General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product β-ketoamides 1a-p, white solid compounds in 45% - 85% yields.
With sodium hydride In tetrahydrofuran at 20℃;
With sodium hydride In N,N-dimethyl-formamide; benzene for 4h; Reflux;
With sodium hydride In N,N-dimethyl-formamide; benzene for 4h; Reflux;
With sodium hydride In toluene for 2h;
With sodium hydride In tetrahydrofuran; mineral oil at 50℃;
6.1.8 General procedure for the preparation of 10
General procedure: Step 1: A stirred suspension of NaH (15.6mmol, 60% dispersion in mineral oil) in THF was heated to 50°C. To this was added a mixture of ester 8 (10.40mmol) and acetonitrile (15.60mmol) dropwise over the course of 15min. The resulting suspension was heated at reflux temperature for a further 16h. After cooling to rt, the reaction mixture was poured into H2O and then the resulting solution was washed with diethyl ether (2x times) (ether extract discarded). The aqueous layer was separated, acidified to pH~2 with aqueous 2M HCl, and extracted with EtOAc (2x times). The combined EtOAc layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure to afford the title compounds 9, which is used for the next step without further purification.
With C55H46N4O4W; potassium carbonate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; Irradiation;
100 % Chromat.
With dimethylamine borane; potassium carbonate; triphenylphosphine In acetonitrile for 8h; Heating;
99 %Chromat.
With ammonium formate In water; toluene at 25℃; for 4h;
> 98 %Chromat.
With triethanolamine; water In methanol for 24h; Irradiation; Glovebox;
2.7 General procedure of photocatalytic reactions
General procedure: A silica tube containing the catalyst, substrate (0.2 mmol), TEOA (0.9 mL), H2O (8.1 mL) and ethanol (1 mL), was sealed in a glovebox and transferred outside. Then the mixture was irradiated under the LED light (427 nm) with stirring for 24 h. Ether acetate (5 mL) was added to the mixture and the upper organic phase was collected. The yield was calculated by GC-MS with the standard curve and by NMR. For photocatalytic stability evaluation, the catalyst was re-collected by centrifugation, washed with ethanol and dried under vacuum. For deuteration, D2O and CH2CH2OD were used instead of water and ethanol.
83 %Spectr.
With C41H40O16; N-ethyl-N,N-diisopropylamine In acetone at 20℃; for 40h; Schlenk technique; Inert atmosphere; Irradiation;
2.4. Typical experimental procedure for the photoreduction of arylhalides catalyzed by HARCP
General procedure: In a 10 mL schlenk tube with a magnetic stirring bar, aryl halide1 (0.1 mmol), HARCP (10 mol%), DIPEA (8 equiv) were dissolved inacetone (1 mL). The reaction mixtures were then irradiated with23 W CFL (at approximately 2 cm away from the light source)under nitrogen atmosphere. When the reaction finished, the solventin the reaction was removed with rotary evaporation andyields of photoreduction products 2 were calculated by 1H NMRwith hexamethyldisiloxane as the internal standard.
With bis(dicyclopentyl(2-methoxyphenyl)phosphine)dichloropalladium(II); Aliquat 336; sodium carbonate In water; toluene at 100℃; for 3h; Cooling;
30
10521] Into a glass reaction vessel equipped with a cooling apparatus were added 0.0075 mmol of bis(dicyclopentyl(2- methoxyphenyl)phosphine)dichioropalladium(II), 0.3 mmol of trioctylmethylammonium chloride, 1.5 mmol of a compound (1) shown in Table 6, 1.65 mmol of a compound (2) shown in Table 6, 3.0 mmol of sodium carbonate, 6 mE of toluene and 1.5 mE ofwater. The resultant mixture was stirred with heating at 100° C. for 3 hours. The resultant reaction mixture was cooled down to room temperature, 20 mE of water was added, and the mixture was extracted with 20 mE of diethyl ether twice. The resultant organic layers were mixed, and dried over anhydrous magnesium sulfate, then, filtrated, to obtain a solution containing the targeted compound (3). The yield of the compound (3) was determined by concentrating the resultant solution, and puriFying the resultant coarse product by silica gel column chromatography. The results are shown in Table 6.
66%
With potassium phosphate; 2-(dicyclohexylphosphino)biphenyl based D-gluconamide In water at 80℃; for 16h;
288.2 mg
With methanol; palladium diacetate; potassium carbonate; tricyclohexylphosphine tetrafluoroborate for 1.65h; Milling;
(-)-4-(3-methyl-2-oxo-tetrahydro-furan-3-yl)-benzoic acid ethyl ester[ No CAS ]
4-((R)-3-Methyl-2-oxo-tetrahydro-furan-3-yl)-benzoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hexamethyldisilazane; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); zinc dibromide In tetrahydrofuran; toluene at 60℃; for 20h;
Stage #1: triallyl(phenyl)silane With tetrabutyl ammonium fluoride In tetrahydrofuran; water at 20℃; for 1h;
Stage #2: ethyl 4-chlorobenzoate With XPhos In tetrahydrofuran; water at 80℃; for 4h;
With C33H49ClN2PdSi; potassium carbonate In ethanol at 20℃; for 24h;
3.4. Typical procedure for the Suzuki-Miyaura cross-coupling test reactions using complexes 1Pd-7Pd (and IPr-Pd ) as pre-catalysts
General procedure: The aryl chloride (0.5 mmol), arylboronic acid (0.5 mmol), inor- ganic base (0.55 mmol), and internal standard (80 μL) were placed into a vial, then the dry solvent (1 mL) was added, and a solu- tion of the pre-catalyst in toluene (25 μM; [Pd]: 1.5 μmol) was in- troduced into the vial. The mixture was then stirred at the preset temperature to initiate the catalytic test. The conversion of the aryl chloride and the yield of the coupling product were determined by GC analysis. 4- Tert -butyltoluene was used as the internal stan- dard in the test experiments in which CN -or NO 2 -group contain- ing products were formed, and dodecane was used as the inter- nal standard for all other experiments. All coupling products were identified from the GC-MS data.
98%
With 2-chloro-1,3-[di-(2,6-diisopropyl)phenyl]-1,3,2-diazaphospholidine; tris-(dibenzylideneacetone)dipalladium(0); cesium fluoride In 1,4-dioxane at 80℃; for 18h; Inert atmosphere;
98%
With potassium carbonate In toluene at 100℃; for 3h; Inert atmosphere;
94%
With caesium carbonate In N,N-dimethyl acetamide at 80℃; for 6h; Inert atmosphere;
Typical Procedure for the 7% Pd/WA30-Catalyzed Suzuki-Miyaura Reaction between Aryl Chlorides and Arylboronic Acids (Table 2 and Scheme 2)
General procedure: In the test tube were placed 7% Pd/WA30 (19.0 mg, 12.5 μmol), the aryl chloride (250 μmol), the arylboronic acid (375 μmol), Cs2CO3 (163 mg, 500 μmol), and DMA (1 mL). The mixture was stirred at 80 °C under an Ar atmosphere. The reaction progress was monitored by TLC analysis (hexane-EtOAc, 5:1). When the reaction was completed within 24 h, the mixture was cooled to r.t., diluted with Et2O (5 mL), and passed through a cotton filter. The catalyst on the filter was washed with Et2O (2 × 15 mL) and H2O (3 × 10 mL). The combined filtrate was separated into two layers. The aqueous layer was extracted with Et2O (20 mL), and the combined organic layers were washed with H2O (4 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. To the residue was added CDCl3 (ca. 1 mL) and 1,4-dioxane (8.53 μL, 100 μmol). After the determination of the reaction yield by 1H NMR, the product was purified by silicagel column chlomatography using hexane-EtOAc (10:1) as eluents to give the corresponding biaryl. When the reaction was incomplete after 24 h, the reaction mixture was treated in the same manner as described above.
94%
With caesium carbonate In N,N-dimethyl acetamide at 80℃; for 6h; Inert atmosphere; chemoselective reaction;
93%
With [(IPr)PdI]2; caesium carbonate In ethanol; toluene at 40℃; for 4h; Sealed tube; Inert atmosphere;
75%
Stage #1: phenylboronic acid With sodium hydride In 1,4-dioxane; mineral oil at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: ethyl 4-chlorobenzoate With C74H84N2O2P2Pd(2+)*2BF4(1-) In 1,4-dioxane; mineral oil at 130℃; for 1h; Inert atmosphere;
With potassium fluoride; potassium phosphate; p-(MeOPEG2000-OCH2)C6H4CH2P(1-adamantyl)2*HBr In dimethyl sulfoxide at 80℃; for 18h;
With N,N-dimethyl acetamide; sodium carbonate In water Inert atmosphere; Heating;
97 %Chromat.
With potassium phosphate In 1,4-dioxane at 100℃; for 20h; Schlenk technique; Inert atmosphere;
General procedure: a mixture of aryl chloride (3.0 mmol), phenylboronicacid (3.3 mmol), potassium phosphate (3.0 mmol), the catalyst(0.1-0.3 mol% with respect to palladium), and 4-tert-butyltoluene(430 mg) as an internal standard for gas chromatograph analysiswere stirred in 1,4-dioxane (3 mL) at 100C. The reaction mixturewas periodically sampled to follow the progress of the reaction bygas chromatography. After the reaction, the catalyst was separatedby centrifugation, and the supernatant was analyzed on a ShimadzuGC-14B gas chromatograph (GC) equipped with a thermal conduc-tivity detector and a column (2 mm × 3 m) packed with 3% OV-101on Chromosorb WHP (100/120 mesh) to determine the productyields.
Stage #1: ethyl 4-chlorobenzoate With sodium diisobutyl-tert-butoxyaluminium hydride In tetrahydrofuran at 0℃; for 4h; Inert atmosphere;
Stage #2: With ammonia; iodine In tetrahydrofuran; water at 0 - 20℃; for 3h;
4.2. Typical procedure for conversion of aromatic ethyl esters into aromatic nitriles
General procedure: NaOtBu (98% purity, 353 mg, 3.6 mmol) was dried by a vacuum pump for 30 min at room temperature. To a solution of NaOtBu in THF (3 mL) was added DIBAL-H (1.04 M, 3.27 mL, 3.4 mmol) at 0 °C under argon atmosphere and the obtained mixture was stirred for 1 h at room temperature. Then, ethyl benzoate (150.06 mg, 2.0 mmol) in THF (4 mL) was added to the solution at 0 °C, and the obtained mixture was stirred for 4 h. Finally, aq NH3 (concentration: 28.0%-30.0%, 4 mL) and I2 (2.08 g, 4.1 equiv) were added at 0 °C, and the obtained mixture was stirred for 3 h at room temperature. Then the reaction mixture was poured into saturated aq Na2SO3 solution (10 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent under reduced pressure, the residue was treated with flash short column chromatography on silica gel (eluent: hexane/ethyl acetate=9:1) to afford benzonitrile (156.7 mg, 76% yield)
Multi-step reaction with 2 steps
1: 82 percent / HONH2*HCl, KOH / methanol / 36 h / Ambient temperature
2: 83 percent / PBr3 / benzene / 5 h / Heating
226 mg
Stage #1: ethyl 4-chlorobenzoate With sodium diisobutyl-tert-butoxyaluminium hydride In tetrahydrofuran at -40 - 0℃; for 3h; Inert atmosphere;
Stage #2: With ammonium hydroxide; iodine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere;
Stage #1: ethyl 4-chlorobenzoate With bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium-bis(lithium chloride) complex; zinc(II) chloride In tetrahydrofuran at 25℃; for 12h; Inert atmosphere;
Stage #2: With 1,2-dibromo-1,1,2,2-tetrachloroethane In tetrahydrofuran at 25℃; for 1h; Inert atmosphere;
Stage #1: ethyl 4-chlorobenzoate With lithium diisobutyl-tert-butoxyaluminum hydride In tetrahydrofuran; hexane at 0℃;
Stage #2: vinyl magnesium bromide In tetrahydrofuran; diethyl ether; hexane at 20℃;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; hexane
The following experimental procedure for the synthesis of 1-phenylpentan-1-ol is representative
General procedure: To a solution of ethyl benzoate (0.14 g, 1.0 mmol) in THF (10 mL) was slowly added LDBBA (2.4 mL, 0.5 M in THF-hexane, 1.2 mmol) and the mixture was stirring for 3 h at 0 °C. To this was slowly added n-butylmagnesium chloride (0.94 mL, 1.6 M in Et2O, 1.5 mmol). After being stirred for 30 min at room temperature, the reaction mixture was quenched with aqueous 1 N HCl (10 mL) and extracted with diethyl ether (2 × 10 mL). The combined organic layers were dried over MgSO4 and filtered. After the removal of solvents in vacuo, purification of the residue by column chromatography on silica gel gave 1-phenylpentan-1-ol (108 mg, 66%). All products in this Letter were confirmed by comparison with data reported in the literatures.5
Stage #1: ethyl 4-chlorobenzoate With lithium diisobutyl-tert-butoxyaluminum hydride In tetrahydrofuran; hexane at 0℃;
Stage #2: butyl magnesium bromide In tetrahydrofuran; diethyl ether; hexane at 20℃;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; hexane
The following experimental procedure for the synthesis of 1-phenylpentan-1-ol is representative
General procedure: To a solution of ethyl benzoate (0.14 g, 1.0 mmol) in THF (10 mL) was slowly added LDBBA (2.4 mL, 0.5 M in THF-hexane, 1.2 mmol) and the mixture was stirring for 3 h at 0 °C. To this was slowly added n-butylmagnesium chloride (0.94 mL, 1.6 M in Et2O, 1.5 mmol). After being stirred for 30 min at room temperature, the reaction mixture was quenched with aqueous 1 N HCl (10 mL) and extracted with diethyl ether (2 × 10 mL). The combined organic layers were dried over MgSO4 and filtered. After the removal of solvents in vacuo, purification of the residue by column chromatography on silica gel gave 1-phenylpentan-1-ol (108 mg, 66%). All products in this Letter were confirmed by comparison with data reported in the literatures.5
With copper(II) ferrite; potassium tert-butylate; In N,N-dimethyl-formamide; at 155℃; for 24h;Inert atmosphere;
General procedure: To a solution of N-heterocycle (1 equiv), bromobenzene (1.02 equiv) and tBuOK (2 equiv) in dry DMF, CuFe2O4 (10 mol %) was added and heated at reflux for 24 h under N2 atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate and the catalyst was separated by a magnetic separator. The catalyst was washed with ethyl acetate. The combined ethyl acetate layer was washed with water (twice), dried over anhydrous Na2SO4, and concentrated to yield the crude product, which was further purified by silica gel column chromatography using petroleum ether/ethyl acetate to yield N-arylated product.
With di-tert-butyl{2′-isopropoxy-[1,1′-binaphthalen]-2-yl}phosphane; potassium phosphate; bis(dibenzylideneacetone)-palladium(0) In toluene at 110℃; for 18h; Inert atmosphere;
Typical procedure for the palladium-catalyzed the coupling reactions of aryl halides and phenols with K3PO4 as base and toluene as solvent
General procedure: An oven-dried Schlenk tube was evacuated and backfilled with nitrogen. The Schlenk tube was charged with Pd(bda)2 (11.5 mg,0.02 mmol), L1 (13.7 mg, 0.03 mmol), K3PO4 (424.5 mg, 2 mmol), and toluene (1.0 mL). After stirring for 15 min, the solution of arylhalide (1.0 mmol) and phenol (1.2 mmol) in toluene (1.5 mL) was added. The septum was replaced with an inside reflux condenser, and then the reaction mixture was stirred for 18 h at 110 C. Then,the reaction mixture was cooled to room temperature and quenched with water (5 mL). After separating the organic phase, the aqueous phase was extracted with ethyl acetate (3 mL3), and the combined organic phase was dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure, and then the crude material was purified by column chromatography on silica gel
91%
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 12h;
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 15h; Inert atmosphere;
General procedure for coupling reaction: An oven-dried resealable Schlenk tube were charged with Pd(OAc)2 (6.7 mg, 0.03 mmol), Xantphos (34.7 mg, 0.06 mmol), 2-methylpropane-2-sulfinamide (145 mg, 1.2 mmol) and Cs2CO3 (650 mg, 2.0 mmol). The Schlenk tube was evacuated and back-filled with argon. 4-bromo-2-methylbenzonitrile (196 mg, 1.0 mmol) and dioxane (3 ml) were added and the Schlenk tube was then sealed with a Teflon screw cap and placed in a preheated oil bath at 100oC for 15 h. After cooling of the reaction mixture to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by flash chromatography. Yield: 228 mg, 97 % [table-1, entry-5].
Stage #1: bromochlorobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: formic acid ethyl ester In tetrahydrofuran; hexane at -78℃; for 3h;
Stage #3: With ethanol; iodine; potassium carbonate In tetrahydrofuran; hexane at -78 - 20℃; for 14h;
4.2. Typical procedure for one-pot conversion of aromatic bromides into aromatic ethyl esters with ethyl formate
General procedure: n-BuLi (1.67 M solution in hexane, 1.32 mL, 2.2 mmol) was added dropwise into a solution of p-bromochlorobenzene (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, ethyl formate (1.6 mL, 20 mmol) was added to the mixture and the obtained mixture was stirred at -78 °C. After 3 h at the same temperature, I2 (1523 mg, 6 mmol), K2CO3 (1382 mg, 10 mmol) and EtOH (3 mL) were added at -78 °C and the mixture was stirred for 14 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide ethyl 4-chlorobenzoate in 77% yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure ethyl 4-chloro-1-benzoate as a colorless oil.
1.1 2-(4-Bromopyridin-2-yl)-1-(4-chlorophenyl)ethanone Under a stream of nitrogen, 5 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed in a round-bottomed flask and dissolved in 50 mL of anhydrous tetrahydrofuran. The solution is cooled to 5 C. and 70 mL (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5 C., and 100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, which is then concentrated under reduced pressure. The powder obtained is used as solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 8.4 g (93%) of compound are obtained in the faun of a yellow powder. LC-MS: M+H=310 1H NMR (DMSO) delta (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); from 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H) (ketone/enol mixture: 40/60).
93%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 5 - 20℃;Inert atmosphere;
1.1 2-(4-Bromopyridin-2-yl)-1-(4-chlorophenyl)ethanone 5 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 5 C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h and cooled to 5 C., and then 100 ml of water are gradually added. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate and the mixture is concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel, with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 8.4 g (93%) of compound are obtained in the form of a yellow powder. LC-MS: M+H=310 1H NMR (d6-DMSO) delta (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); from 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H). (Keto/enol mixture: 40/60).
93%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 5 - 20℃; for 2h;Inert atmosphere;
2.1 2-(4-bromopyridin-2-yl)-1-(4-chlorophenypethanone 5 g (29.07 mmol) of <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 5 C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h and cooled to 5 C., and then 100 ml of water are gradually added. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate and the mixture is concentrated under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel, with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 8.4 g (93%) of compound are obtained in the form of a yellow powder. LC-MS: M+H=310 1H NMR (d6-DMSO) delta (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); from 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H). (Keto/enol mixture: 40/60).
With palladium diacetate In 1-methyl-pyrrolidin-2-one at 20 - 140℃; for 24h; Inert atmosphere;
General experimental procedure.
General procedure: An oven-dried Schlenk-tube (10 mL) was charged with Pd source (1 mol %), and ethyl potassium oxalate (0.75 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). After that, iodobenzene (0.5 mmol) and NMP (1.0 mL) were added by syringe under a counter flow of argon at room temperature. The reaction vessel was closed and then placed under stirring in a preheated oil bath. The reaction mixture was stirred for 24 h. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate, and analyzed by gas chromatography.
With dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; C47H63NO2PPd(2+)*CH3O3S(1-); caesium carbonate In 1,4-dioxane at 100℃; for 24h;
87%
With dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; caesium carbonate In 1,4-dioxane at 100℃; for 24h; Inert atmosphere;
4 General Procedure for Catalyzed Arylation of Primary Amines
General procedure: An oven-dried, resealable tube equipped with a magnetic stir bar and Teflon septum was charged with OMsBrettPhos precatalyst (0.01-0.5 mol %), BrettPhos (0.01-0.5 mol %) NaOt-Bu (115 mg, 1.20 mmol, 1.20 eq), aryl halide (1.00 mmol, 1.00 eq) and amine (1.20 mmol, 1.20 eq) if they are solids. The tube was evacuated and backfilled with argon. This process was repeated three times. Then the aryl halide and amine were added if they are liquid, followed by dioxane (1 mL). The reaction was heated at 100° C. and monitored by thin-layer chromatography or gas chromatography, observing the disappearance of aryl halide. After completion the reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through a plug of Celite. The solvent was removed via rotary evaporation and the crude product was then purified by flash chromatography. See FIG. 14.
With hydrogen bromide; dihydrogen peroxide In water at 60℃; for 16h; Sealed tube;
80%
With C25H19BrMnN2O2P; potassium <i>tert</i>-butylate In toluene at 120℃; for 24h;
78.3%
With oxygen; potassium carbonate at 90℃; for 6h;
70%
With Oxone; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrabutylammomium bromide at 75℃; for 48h; Sealed tube;
87 %Chromat.
With oxygen; potassium carbonate In n-heptane at 70℃; for 24h; Schlenk technique; Green chemistry;
With gold supported on zirconium oxide; oxygen; caesium carbonate at 30℃; for 24h;
2.4. Activity test
General procedure: Known amounts of catalyst, base and alcohol (RCH2OH,2 mmol) were mixed with methanol in a round bottomed flask.The reaction device was sealed after having been filled with O2at ambient pressure and then kept at a specified temperature witha magnetic stirrer. During the reaction, the O2 was supplemented;a small amount of the mixture was extracted and filtered toremove the catalysts. The filtrate was analyzed using theGC-2014C.
Stage #1: ethyl 4-chlorobenzoate With potassium <i>tert</i>-butylate In tetrahydrofuran; water
Stage #2: propyl cyanide 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.
With potassium <i>tert</i>-butylate In tetrahydrofuran at 17 - 19℃; for 0.583333h;
Stage #1: morpholine With diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 3h; Inert atmosphere;
Stage #2: ethyl 4-chlorobenzoate In tetrahydrofuran; hexane at 0℃; for 0.166667h; Inert atmosphere;
4.2 Synthesis of morpholine amides from representative esters (Table 2)
General procedure: The following experimental procedure for the synthesis of morpholino(phenyl)-methanone is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (0.18 mL, 2.1 mmol) and 10 mL THF. After cooling to 0 °C, DIBALH (2.0 mL, 1.0 M in hexane, 2.0 mmol) was added dropwise and stirred for 3 h at same temperature. To a reaction mixture was slowly added ethyl benzoate (0.14 g, 1.0 mmol) and stirred for 10 min. The reaction was stopped by the aqueous 1 N HCl (10 mL) and extracted with diethyl ether (2*10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel yielded morpholino(phenyl)methanone (184 mg, 96%).
Stage #1: ethyl 4-chlorobenzoate With morpholine; diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 3.16667h; Inert atmosphere;
Stage #2: n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.166667h; Inert atmosphere;
4.3 Synthesis of ketones from representative esters in a one-pot reaction (Table 3)
General procedure: The following experimental procedure for the synthesis of 1-phenylpentanone is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (0.18mL, 2.1mmol) and 10mL THF. After cooling to 0°C, DIBALH (2.0mL, 1.0M in hexane, 2.0mmol) was added dropwise and stirred for 3h at same temperature. To a reaction mixture was slowly added ethyl benzoate (0.14g, 1.0mmol) and stirred for 10min. Then, n-BuLi (1.25mL, 1.6M in hexane, 2.0mmol) was added and the mixture was stirred for 10min again. The reaction was stopped by the aqueous 1N HCl (10mL) and extracted with diethyl ether (2×10mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel yielded 1-phenylpentanone (150mg, 92%).
With potassium <i>tert</i>-butylate In benzene at 20℃; for 24h;
Synthesis of bis-β-diketone ligands 1a-1f
General procedure: A suspension of freshly cut potassium (1.56 g, 40 mmol) in tert-butanol (30 mL) was placed in a 100 mL round bottom flask with stirring and the mixture was heated up to 80 °C. After the potassium was completely exhausted, the excess tert-butanol was evaporated under reduced pressure and the white residue was dissolved in benzene (20 mL). To this solution a mixture of 3,5-diacetyl-2,6-dimethyl-pyridine (1.19 g, 10 mmol) and the required ester (25 mmol) in benzene (30 mL) was slowly added. The mixture was stirred at room temperature for 24 h and then poured into 100 mL ice-water. The aqueous layer was adjusted to pH = 6 and the products were precipitated. The resulting precipitates were filtered and recrystallized from acetone to give bis-β-diketones (1a-1f).
With caesium carbonate In N,N-dimethyl acetamide at 80℃; for 4h; Inert atmosphere;
Typical Procedure for the 7% Pd/WA30-Catalyzed Suzuki-Miyaura Reaction between Aryl Chlorides and Arylboronic Acids (Table 2 and Scheme 2)
General procedure: In the test tube were placed 7% Pd/WA30 (19.0 mg, 12.5 μmol), the aryl chloride (250 μmol), the arylboronic acid (375 μmol), Cs2CO3 (163 mg, 500 μmol), and DMA (1 mL). The mixture was stirred at 80 °C under an Ar atmosphere. The reaction progress was monitored by TLC analysis (hexane-EtOAc, 5:1). When the reaction was completed within 24 h, the mixture was cooled to r.t., diluted with Et2O (5 mL), and passed through a cotton filter. The catalyst on the filter was washed with Et2O (2 × 15 mL) and H2O (3 × 10 mL). The combined filtrate was separated into two layers. The aqueous layer was extracted with Et2O (20 mL), and the combined organic layers were washed with H2O (4 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. To the residue was added CDCl3 (ca. 1 mL) and 1,4-dioxane (8.53 μL, 100 μmol). After the determination of the reaction yield by 1H NMR, the product was purified by silicagel column chlomatography using hexane-EtOAc (10:1) as eluents to give the corresponding biaryl. When the reaction was incomplete after 24 h, the reaction mixture was treated in the same manner as described above.
91%
With caesium carbonate In N,N-dimethyl acetamide at 80℃; for 4h; Inert atmosphere; chemoselective reaction;
254.1 mg
With methanol; palladium diacetate; potassium carbonate; tricyclohexylphosphine tetrafluoroborate for 1.65h; Milling;
With 1,3-diazido-propane In neat (no solvent) at 20℃; for 0.333333h;
General procedure forthe synthesis of alkyl esters from trialkylphosphite (3a-v)
General procedure: To a mixture oftrimethylphosphite/triethylphosphite (1.0mmol) and carboxylic acid (1.0mmol),1,3-diazidopropane (0.5mmol) was added slowly in a drop wise manner (to avoidaccumulation of azide) and the mixture was stirred at room temperature for10-20 minutes. (Caution As azides arepotentially explosive, all the reactions should be carried out behind a blastshield with personal protective equipment. In particular, the sequence of addition of thereactants should be strictly followed to avoid the accumulation of organicazides. This has been achieved in thepresent investigation by the slow drop wise addition of the bis azide to thereaction mixture containing trialkylphosphite during which the azide group isinstantaneously converted to iminophosphorane and hence no difficulty wasencountered). After the completion ofthe reaction (as monitored by TLC), the mixture was poured onto crushedice. Then the reaction mixture wasextracted with dichloromethane and the organic layer was dried over anhydrousNa2SO4. Thesolvent was removed and the residue was purified by column chromatography usingsilica gel as the adsorbent and petroleum ether: ethyl acetate (98:2) as themobile phase to afford the corresponding carboxylic esters (3a-v) as colourless oily liquids. Yield (71-80%)
Stage #1: phenylacetonitrile With sodium hydride In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: ethyl 4-chlorobenzoate In tetrahydrofuran Reflux;
General Procedure for the Synthesis of Intermediates 3a-3d
General procedure: Sodium hydride (1.33 ml, 2.61 mmol) was added dropwise to a solution of phenyl acetonitrile (1.0 g, 8.5 mmol)) in anhydrous THF (30 mL), the mixture was stirred at R.T. for30 minutes, followed by adding a solution of ethyl 4-chlorobenzoate (1.78 g, 10.2 mmol) in anhydrous THF (30mL). The mixture was refluxed till the reaction was finished.The result mixture was quenched with water and extracted with ether. The aqueous layer was acidified with 10% HCl to filter out the white precipitation, which was recrystallized with ether to give a white solid. Yield: 76%-80%.
Stage #1: phenylacetylene With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 1h; Inert atmosphere;
Stage #2: With morpholine In tetrahydrofuran; hexane at 0℃; for 0.5h; Inert atmosphere;
Stage #3: ethyl 4-chlorobenzoate In tetrahydrofuran; hexane at 0℃; for 6h; Inert atmosphere;
Partial Alkynylation of Esters to Corresponding Ynones
General procedure: The following experimental procedure for the partial alkynylation of ethyl benzoate to 1,3-diphenylprop-2-yn-1-one is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with phenyl acetylene (0.45 mL, 4.1 mmol) and THF (10 mL). After cooling to 0 °C, n-BuLi (1.6 mL, 2.5 M in hexane, 4.0 mmol) was added dropwise and stirred for 1 h at room temperature. To the reaction mixture was slowly added morpholine (0.08 mL, 1.0 mmol) and stirred for 30 min at 0 °C. Then, ethyl benzoate (0.14 mL, 1.0 mmol) was added and the mixture was stirred for 6 h again. The reaction was stopped by aqueous NH4Cl (aq) (10 mL) and extracted with diethyl ether (2 * 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel yielded 1,3-diphenylprop-2-yn-1-one (175 mg, 85%). All products in Table 2 were confirmed by comparison with NMR data reported of authentic sample.7
3-(4-chlorophenyl)-2-ethyl-3-hydroxy-2,3-dihydro-1H-isoindole-1-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: N-ethylbenzothioamide With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃;
Stage #2: ethyl 4-chlorobenzoate In tetrahydrofuran; hexane at -78 - 0℃;
3-(4-Chlorophenyl)-2-ethyl-3-hydroxy-2,3-dihydro-1H-isoindole-1-thione (3e)
General procedure: To a stirred solution of 1a (0.15 g, 1.0 mmol) in THF (8 mL) at -78 C was added n-BuLi (1.6 M in hexane; 2.0 mmol) dropwise.The temperature was gradually raised to 0 C and stirring was continued for 1.5 h. The mixture was cooled again to -78 C and ethyl benzoate (0.15 g, 1.0 mmol) was added dropwise. After the temperature was gradually raised to 0 C, saturated aqueous NH4Cl (20 mL) was added and the mixture was extracted with AcOEt (3 × 15 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on SiO2(AcOEt/hexane 1:5) to afford 3a (0.16 g, 63%); a yellow solid
With tetrabutyl ammonium fluoride; palladium diacetate; XPhos In tetrahydrofuran; toluene at 100℃; for 3h; Schlenk technique;
Typical Procedure for Cross-Coupling of Aryl Chlorides 1 with Arylsilatranes 2.
General procedure: Palladium(II) acetate (0.025 mmol, 5.6 mg), XPhos (0.0375 mmol, 17.9 mg), and phenylsilatrane (2a, 0.75 mmol, 188.5 mg) were added to a Schlenk flask. The flask was then purged with nitrogen. 4-Chloroanisole (1a) (0.50mmol, 71.3 mg), toluene (1.5 mL), and TBAF (0.75 mmol, 0.75 mL in ca. 1.0 M THF solution) were subsequently added. The mixture was stirred at 100 °C for 3 h, then quenched by addition of water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered,and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (hexane) to provide 3a (75.2 mg, 0.408 mmol) in 82% yield.
With dmap; 4,4'-diamino-2,2'-bipyridyl; magnesium chloride; nickel dichloride; zinc In N,N-dimethyl acetamide at 60℃; for 36h; Molecular sieve; Inert atmosphere;
123 Example 123
10g magnitude reaction:Add in a 350mL stoppered reaction bottleAryl chloride (11.1 g, 60 mmol, 1.0 eq.),NiCl2 (10mol%),Ligand 4,4'-diNH2-bpy (5 mol%),Zinc powder (3.0 equivalents),MgCl2 (4.0 equivalents),MS (10 g) and DMAP (20 mol%).Under an argon atmosphere,Add DMA (100mL)And ClCF2H solution (2.6 M, 240 mmol, 4 eq.).The reaction flask was stoppered and placed in a 60 ° C oil bath for 36 hours.After the reaction,Cool to room temperature,Dilute with 100 mL of ethyl acetate.Diatomaceous earth filtration,Extracted with petroleum ether,Washed with saturated saline,The organic phase is dried over anhydrous sodium sulfate.Filter and concentrate.Column chromatography separated the target product 8.8g,The yield was 74%.The purity was identified by hydrogen spectroscopy to be greater than 95%.
With manganese; 4,4'-Dimethoxy-2,2'-bipyridin; magnesium chloride; nickel dibromide; In 1-methyl-pyrrolidin-2-one; at 80℃; for 24h;Inert atmosphere; Sealed tube;
Under a nitrogen atmosphere, nickel bromide (4.4 mg, 0.02 mmol),4,4'-dimethoxy-2,2'-bipyridine (4.3 mg, 0.02 mmol), magnesium chloride (28.6 mg, 0.3 mmol), manganese powder (43.95 mg, 0.8 mmol), and a solvent NMP (0.5 mL) was added )And stir well. Weigh ethyl 4-chlorobenzoate (36.92mg, 0.2mmol)Dissolve in NMP (0.5mL), add <strong>[762-51-6]1-fluoro-2-iodoethane</strong> (26muL, 0.3mmol) after dissolutionAnd mix well, the solution is transferred to the sealed tube. After sealing, stir the reaction in an oil bath at 80 C. 24Hour, cool the reaction to room temperature, ether (5mL)Add an equal volume of saturated ammonium chloride solution to the diluted reaction solution.Filter through a diatomaceous sand core funnel, rinse with a small amount of ether, and collect the filtrate.The filtrate was extracted three times with diethyl ether, and the organic phases were combined (add internal standard dodecane,GC-MS determined crude yield). Dry over anhydrous sodium sulfate, filter, and remove the solvent by distillation under reduced pressure.After the residue was separated by silica gel column chromatography, the product was weighed, and the calculated yield was 72%.
With boron trifluoride In Hexadecane at 110℃; for 18h; Autoclave;
15 Example 1. Preparation of triethyl orthobenzoate
General procedure: In a 50ml stainless steel autoclave with a magnetic stir bar, add 1.50g (10mmol) ethyl benzoate,In 0.1g n-hexadecane (internal standard) and 7.40g (100mmol) ether solution containing 0.068g (1mmol) boron trifluoride, heat up to 110 and react for 6.0 hours. After the reaction is over, cool down to 0-5 .The sample was analyzed by gas phase, and the conversion rate of ethyl benzoate was 98%, and the yield of triethyl orthobenzoate was 95%.
Multi-step reaction with 2 steps
1: sodium hydride / mineral oil; tetrahydrofuran / 50 °C
2: sodium hydroxide; hydroxylamine hydrochloride / water / 100 °C
ethyl 4-[2-(4-chlorophenyl)-2-phenylethyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With [Pt(2-(4-(3,5-di-tert-butylphenyl)-6-(3-(pyridin-2-yl)phenyl)pyridin-2-yl)phenolate)]; caesium carbonate; N-ethyl-N,N-diisopropylamine In water; acetonitrile at 20℃; for 10h; Irradiation; Sealed tube; Inert atmosphere; regioselective reaction;
With n-butyllithium; lithium diisobutyl t-butoxyaluminum hydride In tetrahydrofuran; hexane at 0℃; for 3h; regioselective reaction;
General Procedure for the HWE Olefination of Esters.
General procedure: The following experimental procedure for the synthesis of α, β-unsaturated esters is representative. A dry and argon flushedflask, equipped with a magnetic stirring bar and septum, was charged with triethyl phosphonoacetate (0.11 mL, 0.55 mmol) and THF (5 mL). After cooling to 0 C, 2.5 M n-BuLi (in hexane, 0.22 mL, 0.55 mmol), the ester (0.5 mmol), and LDBBA (in THF, 2.0 mL,0.75 mmol) were added dropwise and the mixture was stirred for 3 h at 0 C. The reaction was subsequently quenched with 6 N HCl (5 mL). The crude mixture was extracted with diethyl ether and the combined organic layers were dried over MgSO4. The product was isolated by column chromatography (hexane:EA = 200:1).
With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; lithium iodide; zinc In N,N-dimethyl-formamide at 100℃; for 12h; Inert atmosphere;
21 Preparation Example 21
Add 0.3mmol of diphenyl antimony iodine XI (R1=n-Bu, R2, R3=H) containing bridge nitrogen atom ligand, 0.3mmol 4-ethoxycarbonylchlorobenzene, 0.03mmol 1, into a 25mL reaction tube, 2-bis(diphenylphosphine)ethane nickel chloride, 0.03mmol 1,1'-binaphthalene-2,2'-bisdiphenylphosphine, 0.6mmol zinc powder and 0.6mmol lithium iodide. For vacuum, backfill with nitrogen Three times, 3 mL of N,N-dimethylformamide (DMF) was added under a nitrogen atmosphere, and reacted at 100° C. for 12 h. After the reaction, it was washed three times with 9 mL of 1N dilute hydrochloric acid solution (3 mL each time), and then neutralized to pH=7 with saturated sodium bicarbonate solution. The organic phase was obtained by liquid separation, which was washed with water, dried, and concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography to obtain a pure compound with a yield of 85%.
4-chloro-N,N,N-trimethylanilinium triflate[ No CAS ]
[ 1906-57-6 ]
[ 7335-27-5 ]
Yield
Reaction Conditions
Operation in experiment
50%
With bathophenanthroline; tetra-n-butylammonium tetrafluoroborate; anhydrous Sodium acetate; nickel(II) bromide In N,N-dimethyl-formamide; acetonitrile at 50℃; for 6h; Inert atmosphere; Electrolysis;
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
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