* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With ammonium chloride In ethanol for 0.5 h; Reflux
General procedure: To asolution of hydrazide (0.73 mmol) in 10 mL of anhydrous ethanol, added triethyl orthoester (0.81 mmol) and ammonium chloride (0.219 mmol). The solution was stirred and heated to reflux until it complete (0.5-18 h). The reaction mass was cooled to room temperature and concentrated under vacuum. The crude product was made into slurry in a mixture of hexanes and ether (3:1), filtered,washed with deionized water or purified by column chromatography.
92%
at 100 - 110℃; for 12 h;
To a mixture of 3 (18.0 g, 0.1083 mol) and triethyl orthoformate (80.3 g, 0.541 mol) was heated to 100-110 °C and maintained for 12 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated to syrup. Traces triethyl orthoformate was removed by azeotropic distillation with toluene. The residue was purified by column chromatography on silica gel using eluent 0-5percent ethyl acetate in petroleum ether. The title compound was yielded as pale yellow liquid (Yield: 17.55 g, 92percent).
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2
[ 3290-99-1 ]
[ 829-35-6 ]
Yield
Reaction Conditions
Operation in experiment
67%
With trifluoroacetic acid In toluene at 130℃; for 12 h;
General procedure: A 25 mL pressure tube was charged with arylhydrazide 1 (0.5 mmol), TFBen (53 mg, 0.25 mmol, white solid, mp 57.2-58.5 °C), TFA (38 μL, 1.0 equiv), and toluene (4 mL). The tube was then heated by stirring the contents at 130 °C for 12 h. Afterwards, the mixture was cooled to r.t., quenched with sat. aq NaHCO3 (3 mL), and extracted with EtOAc (3 4 mL). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. The pure product 2 was obtained after purification by column chromatography (EtOAc/ pentane 1:3).
With Al3+-K10 montmorillonite clay In neat (no solvent) at 55℃; for 0.25 h; Microwave irradiation
General procedure: A 5 mL microwave vial was charged with acidhydrazide (100 mg, 1 eq), trimethyl orthoester (2 eq) and Al3+-K10 clay (75 mg). The resulting mixture was kept under microwave irradiation maintaining the temperature at 55 °C for 15 min (Microwave irradiations were performed on CEM-discover model No. 908010). The reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with ethyl acetate stirred well, filtered, washed well with ethyl acetate. Filtrate was evaporated under reduced pressure to obtain highly pure product. In some cases, products were purified by column chromatography using 60-120 mesh silica with 20-100 percent ethyl acetate in pet ether as eluting solvents. The catalyst recovered by filtration was reused for another 5 more times.
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4-Methoxybenzohydrazide was synthesized according to the literature[22]. A mixture of methylmethoxybenzoate (1.66 g, 0.01 mol) andhydrazine hydrate (3.6 ml, 0.06 mol) in ethanol (20 mL) was heatedunder reflux for 6 h. The solvent was removed and the precipitate wasobtained. The solid product was recrystallized with ethanol to give 4-methoxybenzohydrazide as colorless crystals. Yield 96percent, mp 138–139 °C.
90%
With hydrazine In methanol; water at 45℃; for 24 h;
Example I 4-methoxy-benzoic acid hydrazide A solution of methyl 4-methoxybenzoate, (5.0 g, 0.03 mol) in methanol (20 mL) was treated with hydrazine hydrate (12.0 g, 0.24 mol) and the mixture stirred at 45° C. for 24 hours. The reaction mixture was concentrated and the residue partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (3.x.20 mL), and the combined organic extracts washed with brine (20 mL), dried over Na2SO4, and concentrated to give the desired hydrazide (compound 2) as solid which was crystallized by EtOAc giving white solid 4.50 g in 90percent yield, mp: 134.3° C. (Aldrich, mp: 136-140° C.). 1H NMR (CDCl3) δ 7.73 (d, 2H), 7.38 (s, 1H), 6.94 (d, 2H), 3.85 (s, 3H), 1.69 (s, 2H). 13C NMR (CDCl3) δ 165.5, 159.6, 125.7, 122.0, 111.1, 52.5. Anal. Calcd for C8H10N2O2.1/2H2O: C, 54.84; H, 5.75; N, 15.99. Found: C, 54.57; H, 5.59; N, 15.53.
88%
for 4 h; Reflux
In the 500 ml round bottom flask is added 53.15g (0.32 µM) 4 - methoxybenzoic acid methyl ester, 300ml50percent hydrazine hydrate reflux 4h, changing device, for the majority of the solvent water pump by reducing pressure, the residual liquid is separated out light yellow crystal after cooling, filtering, drying, and for using ethanol to recrystallize the decolorize with active carbon, to obtain white crystal, yield 88percent
87%
With hydrazine hydrate In ethanolReflux
General procedure: To a solution of the appropriate methyl benzoate ester (1.0 mmol) in ethanol (30 mL), hydrazine monohydrate (0.15 g, 3.0 mmol) was added. The reaction mixture was heated under reflux overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was washed with water (2 x 3 mL), and the obtained solid was filtered and dried to give benzohydrazide derivatives 3a-c.
85%
With hydrazine hydrate In methanol for 5 h; Reflux
General procedure: To a solution of an appropriate methyl esters17(a–j) (1.0 mmol) in 50 mL of methanol was added 99 percenthydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
70%
With hydrazine hydrate In ethanol for 5 h; Reflux
General procedure: A solution of hydrazine hydrate (20.00 mmol) in 2 mL EtOH was added dropwise to the ester 2 (5.00 mmol). The mixture was refluxed for 5 h and filtered, and the corresponding acid hydrazide 3 was obtained by washing the residue with ice water.
69%
With hydrazine hydrate In ethanol for 5 h; Reflux
General procedure: Compound 12 (0.013 mol) and 80percent NH2NH2H2O (5 mL) wereadded to EtOH (10 mL), the mixturewas stirred under reflux for 5 h.After being cooled to room temperature, the precipitate was obtainedby filtration, and was dried to give the title compounds,respectively.
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10
[ 94-30-4 ]
[ 3290-99-1 ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrazine hydrate In ethanol; waterReflux
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).
88%
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.
80%
With hydrazine hydrate In ethanol at 0℃; for 3 h;
To a mixture of 2 (25.0 g, 0.1387 mol) in ethanol (200mL) at 0-5 °C, hydrazine hydrate (13.87 mL, 0.2774 mol) was added. The reaction mass was heated to reflux for 2.0 h. The reaction completion was monitored by TLC. The reactionmixture was cooled to 0-5 °C stirred for 60 min. The solid formed was filtered and dried to get compound 3 as white solid (Yield: 18.4 g, 80percent).
80.2%
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.
80.2%
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.
70%
With hydrazine hydrate In ethanol for 12 h; Reflux; Inert atmosphere; Schlenk technique
General procedure: Hydrazine monohydrate (5 mmol) was added dropwise to a solution of compounds 1A-C (1mmol) in EtOH. The mixture was refluxed for 12 h, and then the solvent was removed by rotary evaporation. The residue was treated with water and extracted with CH2Cl2. The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed by rotary evaporation. The residue was purified by recrystallization.
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11
[ 100-09-4 ]
[ 3290-99-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 250℃; Microwave irradiation
General procedure: Acyl hydrazides were synthesized in excellent yields from thereaction of substituted aryl acids (0.010 mol) with hydrazine hydrate(0.012 mol) in absence of organic solvents under microwaveirradiation (300 W, 250 C) for 4e8 min. Spectral analysis of thesynthesized hydrazides are consistent with the proposed structuresand with those reported [58].
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12
[ 100-07-2 ]
[ 3290-99-1 ]
Yield
Reaction Conditions
Operation in experiment
84%
With hydrazine hydrate; triethylamine In acetonitrile for 3 h;
Compound 1b is prepared by reacting compound 1a (1 mmol), 1,2-dichloroethane (DEC) (12 mL) and chlorinating agent (0.4 mL) while refluxing for 3 hours. Then, the obtained solution was cooled at room temperature After removal of the solvent under reduced pressure, compound 1b is obtained, which is subjected to the next step without further purification . The compound Compound 1b was dissolved in acetonitrile (80 mL), and hydrazine hydrate (1 mmol), Was added dropwise to a solution containing TEA (0.5 mL) and acetonitrile (20 mL), which was monitored by TLC, Respectively. After the reactants were exhausted, the reaction mixture was cooled to room temperature. Subsequently, the solvent was evaporated under reduced pressure to give To give crude 4-methoxybenzohydrazide (Compound 1c) as a white solid, which was purified by column chromatography Purification by column chromatography and crystallization in methanol gives the product (Compound 1c).
Reference:
[1] Patent: KR101697220, 2017, B1, . Location in patent: Paragraph 0099-0100
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2521 - 2526
[3] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 2, p. 436 - 440
[4] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 8, p. 2271 - 2276
[5] Chemistry - A European Journal, 2015, vol. 21, # 26, p. 9550 - 9555
[6] RSC Advances, 2015, vol. 5, # 80, p. 65351 - 65357
[7] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 270 - 283
[8] Journal of Molecular Structure, 2017, vol. 1138, p. 177 - 191
13
[ 3424-93-9 ]
[ 3290-99-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
With silica gel; hydrazine In neat (no solvent) at 130℃; for 20 h; Inert atmosphere; Sealed tube
General procedure: These compounds were prepared using the standard procedure at 130°C for 20–24h. For each reaction, the crude product was adsorbed onto silica gel and purified on a 15cm×2.5cm silica gel column eluted with 80percent EtOAc in hexanes. The isolated yields are given in Table 7.
With hydrazine hydrate monohydrate In ethanol at 100℃; for 31h; Inert atmosphere;
97%
With hydrazine hydrate monohydrate In ethanol at 100℃; for 30h;
91%
With hydrazine hydrate monohydrate In 2-methoxy-ethanol at 100℃; for 4h;
90%
With hydrazine hydrate monohydrate In ethanol at 80℃;
89%
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).
88%
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.
86%
With hydrazine hydrate monohydrate In ethanol for 4h; Reflux;
84%
With hydrazine monohydrate In ethanol; lithium hydroxide monohydrate for 12h; Reflux;
Synthesis of 4-amino-3-(4-methoxyphenyl)-1H-1,2,4-triazole-5(4H)-thione
Substituted aromatic acid was esterified by refluxing in ethanol in the presence of catalytic amount of sulfuric acid. Substituted aromatic esters were converted into their corresponding acid hydrazides by refluxing in hydrazine hydrate using ethanol. The potassium hydroxide (0.125 mol) was dissolved in dry methanol (50 ml). To the above solution, the substituted acid hydrazide (0.125 mol) was added and cooled the solution in ice. To this, carbon disulfide (0.125 mol) was added slowly with constant stirring. The solid product of potassium dithiocarbazate formed, was filtered, washed with chilled diethyl ether and used in the next step by taking in water (20 mL), mixed with hydrazine hydrate and allowed to reflux for 10-12 hours. The reaction mixture turned to green with evolution of hydrogen sulphide and finally it became homogeneous. It was then poured in crushed ice and neutralized with concentrated hydrochloric acid. The white precipitates appeared on acidic induction was filtered, washed with chilled water and recrystallized from aqueous methanol.
80%
With hydrazine hydrate monohydrate Reflux; Alcoholic solution;
80%
With hydrazine hydrate monohydrate In ethanol at 0℃; for 3h;
4.1.2. Preparation of 4-methoxybenzohydrazide (3)
To a mixture of 2 (25.0 g, 0.1387 mol) in ethanol (200mL) at 0-5 °C, hydrazine hydrate (13.87 mL, 0.2774 mol) was added. The reaction mass was heated to reflux for 2.0 h. The reaction completion was monitored by TLC. The reactionmixture was cooled to 0-5 °C stirred for 60 min. The solid formed was filtered and dried to get compound 3 as white solid (Yield: 18.4 g, 80%).
80.2%
With hydrazine hydrate monohydrate In ethanol Reflux;
1 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.
80.2%
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.
70%
With hydrazine hydrate monohydrate In ethanol for 12h; Reflux; Inert atmosphere; Schlenk technique;
General Procedure for the synthesis of the compounds 2A.
General procedure: Hydrazine monohydrate (5 mmol) was added dropwise to a solution of compounds 1A-C (1mmol) in EtOH. The mixture was refluxed for 12 h, and then the solvent was removed by rotary evaporation. The residue was treated with water and extracted with CH2Cl2. The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed by rotary evaporation. The residue was purified by recrystallization.
65%
With hydrazine monohydrate In ethanol for 20h; Reflux;
2 4.5. General procedure for the synthesis of N-acylhydrazides 31-33
General procedure: Benzoic acid 27, p-methoxybenzoic acid 28 and p-nitrobenzoicacid 29 (40 mmol) were treated with a sulfuric acid-ethanol solution.The resulting mixture was allowed to reflux with stirring for 20 h. Ethanol was removed under reduced pressure and the mixture was extracted with Et2O and H2O and washed with saturated NaHCO3 solution. The organic layer was dried with Na2SO4, filtrated and concentrated, furnishing the esters derivatives. Then, a mixture of the appropriated aromatic esters and 2.0 equivalents of hydrazine hydrated (69% m/v) were reacted in an ethanol solution.The resulting mixture was allowed under reflux with stirring for 20 h. The reaction was cooled and the precipitated formed was washed with ethanol and filtrated. The solid obtained was recrystallized under ethanol solution affording the desired products.
55%
With hydrazine
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate Yield given;
With hydrazine hydrate monohydrate In ethanol for 6h; Heating;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate In ethanol for 2h; Heating;
With hydrazine hydrate monohydrate In methanol for 6h; Heating;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate In ethanol for 17h; Heating;
With hydrazine
With hydrazine In lithium hydroxide monohydrate
With hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate Reflux;
With hydrazine hydrate monohydrate In ethanol
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 Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In ethanol Inert atmosphere;
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 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
With hydrazine monohydrate for 2h; Reflux;
With hydrazine In ethanol at 70℃;
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 at 85℃;
With hydrazine monohydrate In ethanol at 100℃; for 12h;
With hydrazine monohydrate In methanol for 3h; Reflux;
With hydrazine hydrate monohydrate Reflux;
With hydrazine In methanol at 5 - 20℃;
General Procedure for the Synthesis of Different Aryl/aralkyl AcidHydrazides (3a-k)
General procedure: Amixture of ethyl esters (25 mmol, 3a-k) and methanol (20mL)was taken in 100 mLround bottom flask and cooled up to 5C. Hydrazine hydrate (80%, 0.05-0.07 mol) wasadded gradually to the reaction mixture and kept stirring for 4-6 h at room temperature.Some of the hydrazide products were formed at room temperature while some esters gotaltered on refluxing with continuous stirring. The reaction completion was monitored byTLC using n-hexane and ethyl acetate as solvent system. After completion of reaction, colddistilled water was added to acquire the precipitates. Precipitates of consequent aryl/aralkylacid hydrazides (3a-k) were filtered, washed with distilled water, and dried to follow thefurther reaction.17-19
With hydrazine In ethanol for 12h; Cooling with ice;
With hydrazine hydrate monohydrate In ethanol for 8h; 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. To a stirred solution of ethyl benzoates (5 mmol) in ethanol was added hydrazine-hydrate (12.5 mmol) and refluxed for 8 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain respective benzohydrazides 7a-k.
With H4N2*5H2O In ethanol at 70℃; for 6h;
With hydrazine monohydrate In ethanol at 60℃; for 30h;
With hydrazine hydrate monohydrate In ethanol for 8h; 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.To the above prepared respective ethyl benzoates (6.65 mmol) in ethanol was added hydrazine-hydrate (40.0 mmol) and refluxed for 8 h. Ethanol was evaporated from the reaction mixture and the precipitated solids were slurred with petether (5 times) and filtered at the pump and dried to obtain benzohydrazides7a-7j.
With hydrazine hydrate monohydrate In ethanol for 10h; Reflux;
With hydrazine hydrate monohydrate In ethanol
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux;
5.4 General procedure for preparation of 4
General procedure: 5mL of hydrazine monohydrate (80%) was added to a solution of intermediate 3 (5mmol) in ethanol (5mL). The reaction mixture was maintained under reflux for 5h. was then concentrated under reduced pressure and the resulting solid was collected by filtration, washed with cold water and dried to give the desired intermediate 4 as a white solid.
With hydrazine monohydrate In ethanol Reflux;
With hydrazine monohydrate In ethanol Reflux;
With hydrazine In ethanol Inert atmosphere;
With hydrazine hydrate monohydrate In ethanol for 48h; Reflux;
4 4.5. Synthesis of acid hydrazides (29-33):
General procedure: A mixture of an ester 24-28 (15 mmol each) and hydrazine hydrate(15 mmol) were refluxed in ethanol (30 mL), for 48 h. Reaction was monitored through TLC. After completion of reaction the excess of solvent was distilled out. The resulting precipitates were then filtered and thoroughly washed with solvent.
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine monohydrate In ethanol for 12h; Reflux;
With hydrazine hydrate monohydrate for 1h; Reflux;
4.2.3. General procedure for preparation of aromatic acidhydrazides (5a-5e)
General procedure: Substituted aromatic ester (1 mmol) was heated to reflux withhydrazine hydrate (2 mL) for 1 h. Upon completion of the reaction,the reaction mixture was quenched with water and extracted withethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
With hydrazine hydrate monohydrate Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In ethanol for 6h; Reflux;
12.30 g
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine monohydrate In ethanol Reflux;
2.1.1.2. General procedure for the synthesis of (2/3/4) un/substitutedbenzhydrazides (3a-3g).
General procedure: As displayed in Scheme 2, the un/substitutedester derivative (2a-2g, 1.0 mmol), hydrazine hydrate (1.2 mmol)were taken in ethyl alcohol (10 mL) and the reaction mixture washeated to reflux temperature and maintained until the reaction wascompleted (Checked by TLC) [50a]. After achievement of the reaction,the reaction was progressively cooled to room temperature. Slowly,solid precipitated out in the reaction mass, was filtered, washed withcold ethanol, and dried to afford a product (2/3/4) un/substituted-Benz hydrazides with 80-87% yield (3a-3g).
With hydrazine monohydrate In ethanol for 5.25h; Reflux;
Hydrazides 1a-1l (general procedure).
General procedure: A clean and dry 250-mL round-bottom flask was charged with 5 g of the corresponding ethyl ester and 50 mL of ethanol, and 5 g of hydrazine hydrate was added dropwise with stirring at room temperature over a period of 15 min. The mixture was then refluxed for 5 h (TLC) and concentrated, and the solid product was filtered off and recrystallized from methanol.
With hydrazine hydrate monohydrate In ethanol at 78℃; for 6h;
With hydrazine hydrate monohydrate In ethanol for 4h; Reflux;
With hydrazine monohydrate In ethanol Reflux;
General method for the synthesis of substituted hydrazide(3a-c):
General procedure: Aromatic esters (2a-c) (1 mmol) and hydrazine hydrate(1 mmol) were dissolved in ethanol and the mixture was refluxedfor 3-4 h. After the completion of the reaction by TLC (toluene:ethyl acetate = 7: 3), the mass was cooled and solid separatedwas filtered to give hydrazides (3a-c)
With hydrazine hydrate monohydrate at 80℃; for 12h;
With hydrazine hydrate monohydrate In methanol Reflux;
2.2. Synthesis and Characterization of Hydrazide Ligands
General procedure: All the ligands (1-13) were synthesized by the reported method [31, 32]. Hydrazine hydrate (100 mmol) was added to the solution of ethyl benzoate in methanol (25 mmol) and then refluxed for 3-5 hours on a water bath. The resulting solid was washed with hexane to obtain pure hydrazide. Respective esters were used to prepare all the ligands. The synthesized ligands (1-13) were characterized with the help of elemental (C,Hand N) analysis, 1H NMR, 13C NMR, IR,and EI-Mass spectroscopy which was reported previously as well [31-33].
With hydrazine hydrate monohydrate In methanol Reflux;
2.2. Synthesis and Characterization of Hydrazide Ligands
General procedure: All the ligands (1-13) were synthesized by the reported method [31, 32]. Hydrazine hydrate (100 mmol) was added to the solution of ethyl benzoate in methanol (25 mmol) and then refluxed for 3-5 hours on a water bath. The resulting solid was washed with hexane to obtain pure hydrazide. Respective esters were used to prepare all the ligands. The synthesized ligands (1-13) were characterized with the help of elemental (C,Hand N) analysis, 1H NMR, 13C NMR, IR,and EI-Mass spectroscopy which was reported previously as well [31-33].
With hydrazine hydrate monohydrate In ethanol at 85℃; for 6h;
1.1 1. Preparation of p-methoxybenzoic acid hydrazide:
add 14.3 mL of ethyl p-methoxybenzoate to 30 mL of ethanol, stir until the ethyl benzoate is completely dissolved, and then use a constant pressure dropping funnel under stirring conditions Add 14.6 mL of hydrazine hydrate dropwise at a rate of 1 mL/min. After the hydrazine hydrate is completely added dropwise, it is heated to the reflux temperature, the reflux temperature is 85 °C, and then refluxed for 6 h, cooled to room temperature, and left to stand for 18 h (until no crystals are precipitated). ), and then suction filtered to obtain filter cake I, washed filter cake I with distilled water, washed 3 times to obtain washed filter cake I, and vacuum-dried the washed filter cake I for 5h at a temperature of 60 ° C to obtain p-methoxyl Benzoic hydrazide; The volume ratio of the quality of filter cake 1 and distilled water is 1g:40mL when distilled water single washing filter cake 1 in step 1;
With ammonium chloride; In ethanol; for 0.5h;Reflux;
General procedure: To asolution of hydrazide (0.73 mmol) in 10 mL of anhydrous ethanol, added triethyl orthoester (0.81 mmol) and ammonium chloride (0.219 mmol). The solution was stirred and heated to reflux until it complete (0.5-18 h). The reaction mass was cooled to room temperature and concentrated under vacuum. The crude product was made into slurry in a mixture of hexanes and ether (3:1), filtered,washed with deionized water or purified by column chromatography.
92%
at 100 - 110℃; for 12h;
To a mixture of 3 (18.0 g, 0.1083 mol) and triethyl orthoformate (80.3 g, 0.541 mol) was heated to 100-110 C and maintained for 12 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated to syrup. Traces triethyl orthoformate was removed by azeotropic distillation with toluene. The residue was purified by column chromatography on silica gel using eluent 0-5% ethyl acetate in petroleum ether. The title compound was yielded as pale yellow liquid (Yield: 17.55 g, 92%).
at 120℃;
General procedure: Benzhydrazide (2 g, 14.6 mmol) and triethyl orthoformate (10 mL) were placed in a 50 mL round bottom flask, and the mixture was vigorously stirred at 120C over night. The excess triethyl orthoformate was removed by evaporation under reduced pressure. The resulting oil was purified by column chromatography (hexane: ethyl acetate = 70:30) to afford 2-phenyl-1, 3, 4-oxadiazole (1a, 2 g, 10 mmol) in 96% yield.
In neat (no solvent); at 120℃;
General procedure: Benzhydrazide (2 g, 14.6 mmol) and triethyl orthoformate (10 mL) were placed in a 50 mL round bottom flask, and the mixture was vigorously stirred at 120C over night. The excess triethyl orthoformate was removed by evaporation under reduced pressure. The resulting oil was purified by column chromatography (hexane: ethyl acetate = 70:30) to afford 2-phenyl-1, 3, 4-oxadiazole (1a, 2 g, 10 mmol) in 96% yield.
With hydrazine hydrate monohydrate In methanol for 2h; Inert atmosphere; Reflux;
96%
With hydrazine monohydrate In ethanol for 0.183333h; Reflux; Microwave irradiation;
96%
With hydrazine hydrate monohydrate In ethanol for 6h; Reflux;
4-Methoxybenzohydrazide was synthesized according to the literature[22]. A mixture of methylmethoxybenzoate (1.66 g, 0.01 mol) andhydrazine hydrate (3.6 ml, 0.06 mol) in ethanol (20 mL) was heatedunder reflux for 6 h. The solvent was removed and the precipitate wasobtained. The solid product was recrystallized with ethanol to give 4-methoxybenzohydrazide as colorless crystals. Yield 96%, mp 138-139 °C.
95%
With hydrazine
95%
With hydrazine hydrate monohydrate In ethanol
95.2%
With hydrazine hydrate monohydrate In methanol for 0.0666667h; Microwave irradiation;
General procedure for synthesis of substituted acid hydrazide:
General procedure: The benzoic acid hydrazides, 3a-h were prepared accordingto reported method in literature28,29 with some desirablemodifications. The ester (2a-h, 0.1 mol) dissolved inappropriate volume of methanol was transferred to a flaskwith a reflux condenser. Hydrazine hydrate (99%, 0.15 mol) was slowly added to the mixture and then kept on reflux forabout 5-6 h. The excess of solvent and hydrazine hydratewere distilled off. On addition of water the product separatedout which was washed several times with distilled water anddried. The product was recrystallized from 80% aqueous ethanoland melting points determined (Table 2).Microwave method: The same procedure as stated abovewas adopted using 100 ml methanol following the other conditionsof microwave in a microwave reactor at 350 Watt(power) for 3-5 min. Precipitation and separation of precipitatewas done as for conventional method (Table 2).
92%
With hydrazine hydrate monohydrate In methanol for 6h; Reflux;
92%
With hydrazine hydrate monohydrate In methanol for 48h;
Preparation of hydrazide: A typical procedure 1
General procedure: A solution of methyl 4-tert-butylbenzoate (5.15 g, 26.8 mmol) and hydrazine monohydrate (1.50 ml, 30.0 mmol) in MeOH (15 mL) was stirred for 2 d. After the removal of the solvent in vacuo, the residue was recrystallized from MeOH to give 4-tert-butylbenzohydrazide (1b) (2.94 g, 15.3 mmol, 57%) as a colorless crystal. 1 H-NMR (300 MHz, DMSO-d 6 ): δ 9.68 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 4.44 (s, 2H), 1.28 (s, 9H) ppm.
92%
With hydrazine hydrate monohydrate In methanol for 6h; Reflux;
4.2. General procedure for the synthesis of thiadiazole derivatives 1-25
Methyl-4-methoxybenzoate (i) was refluxed with 5 mL of hydrazine hydrate solution in 15 mL of methanol for 6 h. The excess hydrazine and methanol was then removed in vacuo to obtain crude product which was then recrystallized from methanol to afford pure 4-methoxybenzohydrazide in 92% yield. Pure 4-methoxybenzohydrazide(20 mmol, 3.32 g) were refluxed with Lawesson's reagent (20 mmol,8.09 g) of in dry toluene for 8 h to get corresponding 4-methoxybenzothiohydrazide. The crude product was washed with diethyl ether and crystallized from methanol to get pure 4-methoxybenzothiohydrazide in 91% yield. In order to get thiadiazole derivatives 1-25, a mixture of 4-methoxybenzothiohydrazide (0.5 mmol) and the corresponding aromatic aldehyde (0.5 mmol) were taken together in around-bottomed flask and was then added drop wise POCl3 (5 mL) carefully. The reaction mixture was heated to reflux for 4-6 h, then cooled to room temperature and poured onto crushed ice. NaHCO3 solution was added and the resulting solid mass precipitated out was filtered, dried, and crystallized from methanol in good to excellent yields.
90%
With hydrazine In methanol; water monomer at 45℃; for 24h;
I 4-methoxy-benzoic acid hydrazide
Example I 4-methoxy-benzoic acid hydrazide A solution of methyl 4-methoxybenzoate, (5.0 g, 0.03 mol) in methanol (20 mL) was treated with hydrazine hydrate (12.0 g, 0.24 mol) and the mixture stirred at 45° C. for 24 hours. The reaction mixture was concentrated and the residue partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL), and the combined organic extracts washed with brine (20 mL), dried over Na2SO4, and concentrated to give the desired hydrazide (compound 2) as solid which was crystallized by EtOAc giving white solid 4.50 g in 90% yield, mp: 134.3° C. (Aldrich, mp: 136-140° C.). 1H NMR (CDCl3) δ 7.73 (d, 2H), 7.38 (s, 1H), 6.94 (d, 2H), 3.85 (s, 3H), 1.69 (s, 2H). 13C NMR (CDCl3) δ 165.5, 159.6, 125.7, 122.0, 111.1, 52.5. Anal. Calcd for C8H10N2O2.½H2O: C, 54.84; H, 5.75; N, 15.99. Found: C, 54.57; H, 5.59; N, 15.53.
90%
With hydrazine hydrate monohydrate In methanol Reflux;
89%
With hydrazine hydrate monohydrate at 120℃; for 3h;
88%
With hydrazine hydrate monohydrate In ethanol at 70℃;
88%
With hydrazine hydrate monohydrate for 4h; Reflux;
1.2 Intermediate 2; Synthesis of 4 - Methoxybenzohydrazide
In the 500 ml round bottom flask is added 53.15g (0.32 µM) 4 - methoxybenzoic acid methyl ester, 300ml50% hydrazine hydrate reflux 4h, changing device, for the majority of the solvent water pump by reducing pressure, the residual liquid is separated out light yellow crystal after cooling, filtering, drying, and for using ethanol to recrystallize the decolorize with active carbon, to obtain white crystal, yield 88%
88%
With hydrazine hydrate monohydrate In ethanol for 18h; Reflux;
87%
With hydrazine hydrate monohydrate In ethanol Reflux;
4.2. Synthesis of benzohydrazide derivatives 3a-c [23]
General procedure: To a solution of the appropriate methyl benzoate ester (1.0 mmol) in ethanol (30 mL), hydrazine monohydrate (0.15 g, 3.0 mmol) was added. The reaction mixture was heated under reflux overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was washed with water (2 x 3 mL), and the obtained solid was filtered and dried to give benzohydrazide derivatives 3a-c.
87%
With hydrazine In ethanol for 3h; Reflux;
General procedure: Brief, a round bottom flask (25 mL) equipped with a condenser has addeda mixture of ester 1a-b (10 mmol), hydrazine hydrate (11 mmol, 0.5 ml)and ethanol (5 ml). The mixture was refluxed for 3 hours. The solvent wasevaporated under vacuum and the hydrazide was recrystallized using ethanolto afford the desired product with 70% for 2a and 87% for 2b. Then,chloroacetic acid (11 mmol, 1,04 g), phosphorus oxychloride (30 mmol,2.8 ml) and DCE (20 ml) were mixed in 100 ml round bottom flask andheated at 80 °C for 2 hours. After, carboxylic acid hydrazide (2a or 2b) wasadded to the mixture and heated for 12 hours. After completion of thereaction, water (40 ml) was added and the pH was adjusted to 7-8 withsodium hydrogen carbonate and extracted with dichloromethane. Theorganic layer was dried (Na2SO4), evaporated, and purified by columnchromatography (silica gel, 5% EtOAc in hexane) to give 3a in 68% and 3bin 74%.
85%
With hydrazine monohydrate In methanol for 5h; Reflux;
General procedure for the preparation of acid hydrazides(18a-j)
General procedure: To a solution of an appropriate methyl esters17(a-j) (1.0 mmol) in 50 mL of methanol was added 99 %hydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
85%
With hydrazine hydrate monohydrate In methanol for 48h; Reflux;
2. General procedure for the synthesis of benzoic acid hydrazides 4b-c
General procedure: The synthesis procedure was adapted from the literature [7]. To a solution of substituted benzoicacid methyl ester (10 mmol) in dry CH3OH (25 mL), H2NNH2 × H2O (98%, 1.0 mL, 20 mmol) wasadded. The reaction mixture was stirred and carried out under gentle reflux for two days. Reactionmixture was concentrated before crystallization to obtain the hydrazides 4b-c.
77%
With hydrazine hydrate monohydrate In ethanol for 12h; Reflux;
75%
With hydrazine hydrate monohydrate In methanol
70%
With hydrazine monohydrate In ethanol for 5h; Reflux;
2 4.1.3 General procedure for synthesis of 4-substituted benzohydrazide 3a-3c
General procedure: A solution of hydrazine hydrate (20.00 mmol) in 2 mL EtOH was added dropwise to the ester 2 (5.00 mmol). The mixture was refluxed for 5 h and filtered, and the corresponding acid hydrazide 3 was obtained by washing the residue with ice water.
69%
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux;
2 4.1.7. General procedure for preparation of compounds (13a-b)
General procedure: Compound 12 (0.013 mol) and 80% NH2NH2H2O (5 mL) wereadded to EtOH (10 mL), the mixturewas stirred under reflux for 5 h.After being cooled to room temperature, the precipitate was obtainedby filtration, and was dried to give the title compounds,respectively.
65.2%
With hydrazine monohydrate In methanol at 20 - 70℃;
2
Methyl 4-methoxybenzoate (500mg, 3.01mmol) was dissolved in 10ml methanol at room temperature, and hydrazine hydrate (354mg, 6.02mmol, 85% v/v) was added dropwise to the stirred solution,The mixture was heated to reflux overnight. After the detection reaction is completed, the reaction liquid is cooled,The resulting precipitate was collected by filtration, washed with 10 ml of water and 10 ml of ethyl acetate successively,And vacuum dry. Compound II-3 (326 mg, yield 65.2%) was obtained.
60%
With hydrazine hydrate monohydrate In ethanol for 40h; Reflux;
53%
With hydrazine hydrate monohydrate Ambient temperature;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate In ethanol for 96h; Heating;
With hydrazine In water monomer Heating;
With hydrazine hydrate monohydrate for 28h; Heating;
With hydrazine In ethanol for 12h; Heating;
With hydrazine hydrate monohydrate
With hydrazine In water monomer at 60℃;
With hydrazine hydrate monohydrate for 0.166667h; Reflux;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate at 80℃; for 2h;
With hydrazine hydrate monohydrate Reflux;
With hydrazine hydrate monohydrate at 120℃; for 3h;
With hydrazine hydrate monohydrate In water monomer at 75℃; for 0.166667h;
4.1.2. General procedure for the synthesis of benzhydrazides (3a-o)
General procedure: Hydrazine hydrate 64% (v/v) (30.0 mL, 0.33 mol) was heated up to 50-60 °C. The methyl ester 3 (0.01 mol) was added and the mixture was heated at reflux for 10 min. The cooling was performed sequentially in water bath, followed by ice bath and dry ice-ethanol bath. The precipitate was filtered and washed with cold water.
With hydrazine hydrate monohydrate In methanol Reflux;
2.2.2. Synthesis of p-substituted benzoic hydrazides
General procedure: Methyl benzoates were synthesized from their respective p-substituted benzoic acids, using excess dry methanol in the presence of H2SO4. para-Substituted benzoic hydrazides (2a-i) were prepared by reaction of the corresponding methyl benzoates (10 mmol) with hydrazine hydrate 99% (50 mmol) in methanol under reflux for 4-6 h. The excess solvent was removed under vacuum and the residue was filtered under suction, washed with water, and dried. The spectral and analytical data of benzoic hydrazide (2a) [26], 4-bromobenzoic hydrazide (2b) [27], 4-chlorobenzoic hydrazide (2c) [28], 4-fluorobenzoic hydrazide (2d) [26], 4-hydroxybenzoic hydrazide (2e) [29], 4-methoxybenzoic hydrazide (2f) [30], 4-methylbenzoic hydrazide (2g) [28], 4-nitrobenzoic hydrazide (2h) [28] and 4-aminobenzoic hydrazide (2i)[28] are in good agreement with literature values.
With hydrazine
With hydrazine hydrate monohydrate In methanol Reflux;
2.2.2. Synthesis of p-substituted benzoic hydrazides 2a-i
General procedure: Methyl benzoates were synthesized from their respective p-substituted benzoic acids, using excess of dry methanol in presence of H2SO4. p-Substituted benzoic acid hydrazides (2a-i) were prepared by reaction of the corresponding methyl benzoates (10 mmol) with hydrazine hydrate 99% (50 mmol) in methanol under reflux for 4-6 h. The excess solvent was removed under vacuum and the residue was filtered under suction, washed with water and dried. The spectral and analytical data of benzoic hydrazide (2a) [35], 4-bromobenzoic hydrazide (2b) [36], 4-chlorobenzoic hydrazide (2c) [37], 4-fluorobenzoic hydrazide (2d) [35], 4-hydroxybenzoic hydrazide (2e) [38], 4-methoxybenzoic hydrazide (2f) [39], 4-methylbenzoic hydrazide (2g) [37], 4-nitrobenzoic hydrazide (2h) [37] and 4-aminobenzoic hydrazide (2i) [38] are in good agreement with literature values.
With hydrazine hydrate monohydrate Reflux;
With hydrazine hydrate monohydrate at 80℃; for 2h;
With hydrazine hydrate monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate In ethanol at 70℃; for 3h;
With hydrazine hydrate monohydrate for 10h;
With hydrazine hydrate monohydrate In ethanol for 48h; Reflux;
5.3 2,3-Dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (3a)
General procedure: To a solution of 2a (1.16 g, 6.0 mmol) in EtOH (30 mL) was added hydrazine hydrate (2.91 mL, 60 mmol) and the mixture was heated at reflux for 2 days. After cooling to room temperature pure crystals are formed, collected by filtration and washed several times with EtOH to give compound 3a (0.87 g, 75%) as a light yellow solid.
With hydrazine hydrate monohydrate In water monomer for 0.5h; Reflux;
4.1.1. General procedure for the synthesis of benzhydrazides (2a-j)
General procedure: Each substituted benzoic acid (1) (0.02 mol) was refluxed for 4 h in 20.0 mL (0.49 mol) of anhydrous methanol and 0.5 mL (0.01 mol) of sulphuric acid. The reaction mixture was cooled down to room temperature and the hydrazine hydrate 80% (v/v) (10.0 mL, 0.13 mol) was added. The system was maintained by vigorously stirring for more 30 min in reflux. In the case of compound with 4-nitro substituent group attached to the benzene moiety, after the addition of hydrazine hydrate 80% (v/v) at room temperature, the reaction mixture was cooled down in ice bath and maintained into stirring during 1 h. After this period, the mixture was maintained at low temperature to give 2.19,22
With hydrazine hydrate monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
General procedure for the synthesis of the hydrazide ligands
General procedure: Different substituted carboxylic acids (20 mmol) (A) were stirred with thionyl chloride (100 mmol) in dry methanol (75 ml) or 5-6 h to synthesize corresponding methyl esters (B) (Scheme1). After extraction of esters in chloroform, solvent was evaporated and esters (66 mmol) were refluxed with hydrazine hydrate(330 mmol) in ethanol (75 ml) for 4-5 h. A solid was obtained upon removal of the solvent by rotary evaporation. The resulting solid was washed with hexane to afford hydrazide ligand (C). The spectral and analytical data are given below.
With hydrazine hydrate monohydrate In methanol
With hydrazine hydrate monohydrate In methanol for 5h; Reflux;
General procedure: Compounds 6a-t were synthesized from substituted benzoic acid via six steps according to the literature method as described. Various substituted benzoic acids 1a-t were treated with SOCl2 to give compounds 2a-t, which were reacted with CH3OH and EtN3 in CH2Cl2 at 0 to afford compounds 3a-t. Compounds 4a-t were prepared by the reaction of compounds 3a-t, hydrazine hydrate in CH3OH under reflux condition about 5h. Subsequently, compounds 5a-t were obtained by reaction of compounds 4a-t with CS2 and KOH in CH3OH. Compounds 6a-t were obtained by the cyclization reaction of compounds 5a-t in the presence of HCl at 0-5°C.
With hydrazine monohydrate In methanol
With hydrazine hydrate monohydrate for 1h; Reflux;
With sulfuryl dichloride; hydrazine hydrate monohydrate Reflux;
With hydrazine monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate In methanol for 8h; Reflux;
With hydrazine monohydrate In methanol for 3h; Reflux;
With hydrazine at 140℃; for 0.5h; Inert atmosphere;
19 Preparation of Intermediate 19:
The mixture of 4-methoxy methyl benzoate (33 g, 0.2 mol) and anhydrous hydrazine (7.7 g, 0.24 mmol) was heated to 140° C. under nitrogen atmosphere, and reacted at the said temperature for 30 minutes. After cooled to the room temperature, the mixture was extracted with ethyl acetate (3×100 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered, then concentrated under reduced pressure to give a crude product of intermediate compound 19 (30 g), which can be used for the next reaction step directly.
With hydrazine hydrate monohydrate at 65℃; for 4h;
With hydrazine at 140℃; for 0.5h; Inert atmosphere;
19 Preparation of Intermediate 19:
The mixture of 4-methoxy methyl benzoate (33 g, 0.2 mol) and anhydrous hydrazine (7.7 g, 0.24 mmol) was heated to 140 °C under nitrogen atmosphere, and reacted at the said temperature for 30 minutes. After cooled to the room temperature, the mixture was extracted with ethyl acetate (3×100 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered, then concentrated under reduced pressure to give a crude product of intermediate compound 19 (30 g), which can be used for the next reaction step directly.
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine In ethanol for 5h; Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate at 20℃;
With hydrazine hydrate monohydrate In methanol for 8h; Reflux;
General Procedure for the Synthesis of Acid Hydrazides (3a-t)
General procedure: To a solution of methyl ester of aromatic carboxylic acid 2 (0.1 mol) in methanol (30 mL), hydrazine hydrate (0.2 mol) was added drop wise with stirring. The resulting mixture was allowed to reflux for 8 h. After the completion of the reaction as monitored by TLC, the excess methanol was distilled off under reduced pressure. The resulting acid hydrazide 3 was washed with cold water, dried and recrystallized from ethanol.
With hydrazine hydrate monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In ethanol for 10h; Reflux;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate In methanol
General procedure for the synthesis ofbenzohydrazides (3a-e)
General procedure: The substituted benzoic acid (2.46 m mol)was reuxed with methanol in sulphuric acid for 4h.The ester formed reacts with hydrazine and getsconverted to benzohydrazides by hydrozinolysis22.
Stage #1: methyl 4-methoxybenzoate In methanol at 0℃; for 0.166667h;
Stage #2: With hydrazine monohydrate In methanol for 8h; Reflux;
Step 2. General Procedure for Preparation of the Benzoyl Hydrazines
General procedure: A mixture of methyl benzoates (15.0 mmol), CH3OH (30.0 mL) wereplaced in a 100mL round-bottomed flask equipped with a magnetic stirrer.Stirring for 10 minutes in 0 °C. Then hydrazine hydrate (4.0 eq.) was added to the flask. Afterword the mixture was stirred under reflux 8 h, the reaction system was concentrated to remove CH3OH and most of hydrazine hydrate. After cooling, the contents were added petroleum-ether (50 mL) by stirring, then the white solids would be separated, washed with water and dried under vacuum. The yield was 65%~80%.
With hydrazine In water monomer
With hydrazine hydrate monohydrate In methanol at 65 - 67℃; for 9h;
With hydrazine hydrate monohydrate In ethanol at 70℃;
With hydrazine hydrate monohydrate Reflux;
With hydrazine monohydrate In ethanol
With pyridine; hydrazine hydrate monohydrate In ethanol for 10h; Reflux;
Preparation of intermediate hydrazide (10a-n)
General procedure: To a mixture corresponding ester (9a-n, 5.0 mmol) and hydrazine monohydrate (15.0 mmol) in ethanol, catalytic amount of pyridine (0.5 mL) was added and refluxed for 10 h. The reaction was monitored by TLC. After the completion of the reaction, ethanol was evaporated from the mixture, water was added and extracted using ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum to get the crude mass. Finally, the products 10a-n were purified using column chromatography. (Yield 80-85%).
With hydrazine In ethanol for 4h; Reflux;
General procedure: Synthesis of triazoles: Substituted benzoic acid (0.01mol) in 0.2 mol of anhydrous methanol and 0.5 mL of conc. H2SO4 was added in a round bottom flask and then refluxed for 5 h. The resultant compound was confirmed by TLC (hexane:ethyl acetate) in the ratio 80:20 and then required compound was isolated by treating with NaOH. Then 0.01 mol of substituted methyl benzoate in 25 mL of ethanol was taken in a round bottom flask. The solution was refluxed for 4 h by adding 0.7 mL of 0.15 mol N2H4. The product was confirmed by TLC (hexane:ethyl acetate) in the ratio 80:20 and distilled off ethanol and it is cooled in ice water. The resultant compound was recrystallized with EtOH (78 % yield).
With hydrazine hydrate monohydrate In methanol at 85℃; for 14h;
With hydrazine hydrate monohydrate In methanol Reflux;
General procedure: Carboxylic acid hydrazides are synthesized following a modifiedprocedure from one already reported in the literature [22]. Hydrazinehydrate (80%, 0.06 mol) is added slowly to a solution ofcarboxylate esters (0.02 mol) in methanol (30 mL). The reactionmixture is subjected to reflux for 6-8 h. Upon completion of reaction,the mixture is cooled down to the room temperature and icewater is added. The precipitated solid product obtained wasfiltered, dried and recrystallized from methanol.
With hydrazine hydrate monohydrate In methanol Reflux;
With hydrazine monohydrate Reflux;
Synthesis of acid hydrazide derivatives (3) from esters (2)
General procedure: One millimole of the corresponding ester was added insmall portion to a round bottom flask containing solution ofhydrazine hydrate (10 ml) and followed by stirring themixture under reflux conditions. When completion of thereaction was monitored by TLC, the media was poured ontoice bath and the resulting precipitation was isolated by filtration.The corresponding acid hydrazide was afforded andrecrystallized from ethanol and water.
With hydrazine hydrate monohydrate In methanol Reflux; Inert atmosphere;
2.1.1. General procedure for the synthesis of hydrazides 2
General procedure: Hydrazine hydrate (5 mL, 40%) was added to a solution of requiredester (5.0 mmol) in methanol (20 mL). The solution was refluxed for12-24 h and monitored by TLC until starting material was completelyconsumed. After that, solvent was evaporated under reduced pressureand a small amount of water (5 mL) was added to precipitate the hydrazide,which was filtered and dried in vacuum to give a shiny white toyellow solid in excellent yields, without further purification.
With hydrazine hydrate monohydrate In ethanol for 6h; Reflux;
With hydrazine monohydrate
With hydrazine monohydrate at 120℃; for 2h;
1.1 Step 1: Synthesis of Compound WX004-2
A liquid mixture of a compound WX004-1 (4.70g, 28.28mmol) and hydrazine hydrate (20.00ml) was stirred at 120 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target compound WX004-2 which was directly used in the next reaction step without purification, MS m/z: 167.2 [M+H]+.
With hydrazine hydrate monohydrate for 4h; Reflux;
4.2.1. General procedure for the synthesis of hydrazides 2
General procedure: Hydrazides 2 were obtained in reaction of methyl esters 1 (1 mmol), which synthesized from corresponding acids [61], and hydrazine monohydrate (6 mmol) by heating under reflux for 4 h [62].
With hydrazine hydrate monohydrate In ethanol for 10h; Inert atmosphere; Reflux; Sealed tube;
With hydrazine hydrate monohydrate In methanol at 80℃; for 4h;
preparation of intermediate 2
General procedure: At the 250 cm3double-mouth bottle, 13.5 mmol of themethyl benzoate derivatives was added to 100 cm3of methanol,added 6.75 cm3of hydrazine hydrate (108 mmol) tothe reaction mixture slowly. After that warming to 80 °Cand reflux for 4 h until the reaction was completed, thenconcentrated under reducing pressure to remove methanol,filtering and drying to get white solid 2.
With hydrazine hydrate monohydrate In methanol at 0 - 20℃; for 4h;
4.3 General procedure for the synthesis of compounds 3a-3q
General procedure: Compound 2a was dissolved in methanol and the mixture was cooled in an ice bath. Hydrazine hydrate (3 eq.) was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 4h. The reaction progress was monitored by TLC (MeOH/DCM=1:20) until it was completed. A crude solid 3a was obtained by filtering and washing with ice methanol, which was used to the next step without further purification. Preparation method of 3b∼3q was same as 3a.
With hydrazine hydrate monohydrate In ethanol Reflux;
Synthesis of benzohydrazide derivatives (4a-m)
General procedure: Method A Methyl benzoate derivatives (2, 1 eq) and 85% hydrazine hydrate (10 eq) were dissolved in ethanol (45 mL). The mixture was refluxed overnight. After cooling, the solvent was removed in vacuo and the residue was separated on the Biotage SNAP Cartridge KP-Sil 100 g eluting with 0-60 % ethyl acetate/petroleum ether to afford compound 4.
1.42 g
With hydrazine hydrate monohydrate In methanol for 16h; Reflux;
1.49 g
With hydrazine monohydrate In methanol for 16h; Reflux;
With hydrazine hydrate monohydrate for 5h; Reflux;
Substituted benzohydrazides 3a-3d (generalproce dure).
General procedure: A 100-mL round-bottom flask was chargedwith 25 mL of methanol, ester 2a-2d (0.01 mol) wasadded, 4.0 mL of 80% hydrazine hydrate was thenadded, and the mixture was refluxed for 5 h (TLC,ethyl acetate-hexane, 30:70). The mixture was cooledand diluted with excess distilled water, and the solidproduct was filtered off and washed with distilledwater.
With hydrazine hydrate monohydrate In ethanol for 12h; Reflux;
With hydrazine hydrate monohydrate In ethanol at 80℃; for 6h;
General procedure: The crude methyl ester (1 mmol) was dissolved in anhydrous methanol and hydrazine hydrate (1.5 mmol) was added. Then, the mixture was refluxed for about 6 h. After completion of the reaction as monitored by TLC, the mixture was cooled to room temperature. Upon cooling the precipitate, it was filtered and dried to give the aryl hydrazide product 3
Stage #1: ethyl acetimidate hydrochloride With ethanol at 20℃;
Stage #2: 4-methoxybenzoic acid hydrazide at 20℃;
a
Intermediate product 9: 3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine a) 4-methoxy-benzoic acid N'-(1-imino-ethyl)-hydrazide: 4.6 g (0.20 mol) sodium in 200 mL ethanol are combined at ambient temperature with a solution of 25 g (0.20 mol) ethylacetimidate hydrochloride in 200 mL ethanol. The sodium chloride precipitated is suction filtered and 33.2 g (0.20 mol) 4-methoxybenzoic acid hydrazide are added to the filtrate. The reaction mixture is stirred overnight at ambient temperature and then cooled. The precipitate formed is separated off and washed with ethanol and diethyl ether.Yield: 33.6 g (81%); melting range=179-181° C.
4-methoxy-N’-((5-nitrofuran-2-yl)methylene)benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sulfuric acid; acetic acid; In methanol; water; for 1h;Reflux;
General procedure: Compounds of series I were synthesized by refluxing <strong>[92-55-7]5-nitro-2-furaldehyde diacetate</strong> 98% (5 mmol) and benzhydrazides (3) (5 mmol) in water, sulphuric acid, acetic acid, and methanol (8:7:8:20 v/v) for 1 h. After cooling, the mixture was poured into cold water to precipitate the azomethine derivatives 20(see structural elucidation of the compounds of series I in Supplementary data, p. S2).
With Al3+-K10 montmorillonite clay; In neat (no solvent); at 55℃; for 0.25h;Microwave irradiation;Catalytic behavior;
General procedure: A 5 mL microwave vial was charged with acidhydrazide (100 mg, 1 eq), trimethyl orthoester (2 eq) and Al3+-K10 clay (75 mg). The resulting mixture was kept under microwave irradiation maintaining the temperature at 55 C for 15 min (Microwave irradiations were performed on CEM-discover model No. 908010). The reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with ethyl acetate stirred well, filtered, washed well with ethyl acetate. Filtrate was evaporated under reduced pressure to obtain highly pure product. In some cases, products were purified by column chromatography using 60-120 mesh silica with 20-100 % ethyl acetate in pet ether as eluting solvents. The catalyst recovered by filtration was reused for another 5 more times.
With ammonium chloride In ethanol for 0.75h; Reflux;
Representative procedure for the 1,3,4-oxadiazoles synthesis:
General procedure: To asolution of hydrazide (0.73 mmol) in 10 mL of anhydrous ethanol, added triethyl orthoester (0.81 mmol) and ammonium chloride (0.219 mmol). The solution was stirred and heated to reflux until it complete (0.5-18 h). The reaction mass was cooled to room temperature and concentrated under vacuum. The crude product was made into slurry in a mixture of hexanes and ether (3:1), filtered,washed with deionized water or purified by column chromatography.
76%
In o-xylene for 6h; Reflux;
5-Methyl-2-phenyl-1,3,4-oxadiazole (3a).
General procedure: Triethyl orthoacetate2 (1.8 mL, 0.01 mol) in anhydrous o-xylene (10 mL) wasadded by small portions with stirring to a solution of benzhydrazide1a (1.36 g, 0.01 mol) in anhydrous o-xylene (50 mL) at~20 °C. The reaction mixture was refl uxed for 6 h monitoringthe formation of the reaction product by TLC. The solvent wasremoved in vacuo, and the product was isolated by column chromatographyon silica (0.063-0.200 mm, ethyl acetate-petroleumether (1 : 10) as eluent) collecting the fraction with Rf = 0.80.The yield was 1.46 g (83%)
66%
at 120 - 140℃;
at 120 - 140℃; for 5h;
at 120℃; for 2h;
1.2 Step 2: Synthesis of Compound WX004-3
A solution of the compound WX004-2 (3.20 g, 19.26 mmol) and triethyl orthoacetate (32.08 g, 197.76 mmol, 36.05 mL) was stirred at 120 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by a chromatography column (developing agent: petroleum ether/ethyl acetate=2:1) to obtain the target compound WX004-3. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.95-8.00 (m, 2H), 6.99-7.04 (m, 2H), 3.89 (s, 3H), 2.58-2.64 (m, 3H), MS m/z: 191.2 [M+H]+.
With acetic acid; acetic acid hydrazide for 0.166667h; Microwave irradiation;
89%
Stage #1: 4-methoxybenzoic acid With sulfuric acid In ethanol for 6h; Reflux;
Stage #2: With hydrazine monohydrate; Sodium hydrogenocarbonate; acetic acid Reflux;
87%
With hydrazine hydrate monohydrate for 0.0277778h; Microwave irradiation;
87%
With hydrazine at 250℃; Microwave irradiation;
2 6.2.1. Microwave assisted synthesis of acyl hydrazides
General procedure: Acyl hydrazides were synthesized in excellent yields from thereaction of substituted aryl acids (0.010 mol) with hydrazine hydrate(0.012 mol) in absence of organic solvents under microwaveirradiation (300 W, 250 C) for 4e8 min. Spectral analysis of thesynthesized hydrazides are consistent with the proposed structuresand with those reported [58].
83%
Stage #1: 4-methoxybenzoic acid With dicyclohexyl-carbodiimide In acetonitrile at 0 - 20℃;
Stage #2: With benzotriazol-1-ol In acetonitrile at 0 - 20℃;
Stage #3: With hydrazine hydrate monohydrate In acetonitrile at 0 - 20℃; for 5h;
Stage #1: 4-methoxybenzoic acid With thionyl chloride
Stage #2: With hydrazine hydrate monohydrate; ethyl acetate
With hydrazine hydrate monohydrate Microwave irradiation;
A. 4-Methoxy-benzoic acid N'-(4-amino-3-nitrobenzoyl)-hydrazide; To a solution of <strong>[1588-83-6]4-amino-3-nitrobenzoic acid</strong> (3.64 g, 20 mmol) in DMF (50 mL) was added HOBT (2.70 g, 20 mmol) and EDCI (3.83 g, 20 mmol). After the addition, the solution was stirred at 25 0C for 10 min then 4-methoxybenzoic acid hydrazide (3.32 g, 20 mmol) was added and followed by the addition of NEt3 (8.35 mL, 60 mmol). The solution was stirred at 25 0C overnight and water was added. The resulting suspension was filtered and the solid was washed with water. The yellow solid was dried under reduced pressure and was purified by flash chromatography (heptane/EtOAc = 1 :3) to give the title compound. MS: m/z 331 (M+1).
General procedure: Tripod (1) (0.106 g, 0.24 mmol) was added to a solution of benzoic hydrazide (2a) (0.109 g, 0.8 mmol) in tetrahydrofuran (75 mL) and the reaction mixture was stirred under reflux for 15-18 h. The solvent was removed by evaporation under reduced pressure. The residue was filtered under suction and washed several times withhot tetrahydrofuran. The resulting solid (3a) was dried in vacuo at 40 C for 4 h. The same general procedure was followed for the compounds 3b-i.
General procedure: General procedure: A mixture of 8 (1mmol) and aromatic acid hydrazide was refluxed in absolute ethanol for 3-4h. After the completion of the reaction the solid precipitated was filtered off, washed with cold ethanol, dried and recrystallized from ethanol which afforded the pure products 9a-9g.
Example 1. N-(4-methoxybenzo[d]thiazol-2-yl)-5-(4-methoxyphenyl)-l,3,4- oxadiazol-2-amine 4-Methoxybenzhydrazide (0.332 mg, 2.0 mmol) was dissolved in acetonitrile (10 mL) and to this mixture was added 1 , l'-thiocarbonyldiimidazole (445 mg, 2.5 mmol). After stirring at rt for 3 hours, <strong>[5464-79-9]2-amino-4-methoxy-benzothiazole</strong> (450 mg, 2.5 mmol) was added and the temperature raised to 85 C with stirring continued for 20 hours. After cooling, the acetonitrile was removed by rotary evaporator. Water was added (100 mL) and this mixture was extracted with 3 volumes of ethyl acetate (50 mL). The organic layers were collected and solvent removed en vacuo. To this thiosemicarbazide intermediate was added tosyl chloride (393 mg, 2.1 mmol) and pyridine (0.29 mL, 3.6 mmol) in THF (20 mL). The solution was heated to 70 C, bringing the mixture to reflux for 20 h, then cooled. Ethyl acetate (10 mL) and HC1 (1.0 M, 10 mL) were added and the mixture was vigorously stirred for 10 minutes. The aqueous layer was removed and extracted with EtOAc (20 mL), and the combined organic layers were flushed with concentrated to a slurry. After purification via reverse-phase HPLC (water/acetonitrile, 10-95%), the product fractions were collected, concentrated and lyophilized to furnish a white solid. ESI-MS m/z 355 [M+H]+.
2,6-Di-tert-butyl-4-[5-(4-methox yphenyl)-1,3,4-oxadiazol-2-yl]phenol (5b).
General procedure: To a mixture of (0.31 g, 1.24 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 1.24 mmolearyl acid hydrazide in a 50 mL round bottom flask, 5 mL of phosphorus oxychloride was added in a fewportions at room temperature. The mixture was refluxed for 3 h with stirring on water bath 80-90 °C.After cooling, the mixture poured onto 100 mL crushed ice and stirred for 15 min. Sodium bicarbonatewas added in a few portions until the pH was around to 7-8. The precipitate was filtered, washed withwater and dried then purified either by column chromatography or by crystallization from suitable solvent
N'-(3,4-di-benzyloxybenzylidene)-2-(4-methoxyphenyl)acetyl hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethanol at 80℃; Inert atmosphere;
2 General synthetic procedure for acylhydrazone Schiff bases
General procedure: An esterification procedure devised by Park et al. was used to synthesize methyl eater I [22], as follows: 4-methoxy benzene acetic acid (10.0 g, 60.0 mmol) was suspended in methanol (100 mL) and thionyl chloride (26 mL, 361.1 mmol) was added into the solution placed over an ice bath (10 C). The reaction mixture was refluxed at 90°C for 3 h under argon, and then excess methanol and thionyl chloride were evaporated. The crude product was purified by crystallization (methanol/ethylacetate) and 4-methoxybenzene methyl acetate (9.84 g), with a yield of 90%, was obtained. Further, 4-methoxy benzene methyl acetate (9.84 g, 54 mmol) and hydrazine hydrate (27 mL, 300 mmol) were dissolved in methanol(100 mL). The mixture was refluxed at 80°C for 5 h. After cooling down to room temperature, the white crystal was filtered and washed with cold methanol. 4-Methoxy phenylacetyl hydrazine (4.66 g), with yield of 43.0% was obtained as a white crystal by crystallization using methanol. Another compound named 4-chlorobenzene oxygen acetyl hydrazine (white needle like crystals) was synthesized by the same procedure with a final yield of 73.1%. Twenty acylhydrazone Schiff bases were synthesized asdescribed previously [21,24]. Under an argon atmosphere, a solution of 2-hydroxybenzaldehyde (5 mmol) in 20 mL anhydrous ethanol was added in acylhydrazine II (5 mmol; suspended in 30 mL anhydrous ethanol). The mixture was then refluxed for 48 h at 80°C and monitored by TLC. The resulting solid was filtered and washed with cold ethanol after cooling down to room temperature. Recrystallization in ethanol provided the final derivatives 2a-2t.
N'1,N'<SUP>3</SUP>,N'<SUP>5</SUP>-tris(4-methoxybenzylidene)benzene-1,3,5-tricarbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With trifluoroacetic acid; In chloroform; for 4h;Reflux;
General procedure: Aldehyde (1.5 mmol, 1 eq.) and the corresponding hydrazide (1.5 mmol/3 mmol/4.5 mmol, 1eq.) were dissolved in chloroform (50 mL). Trifluoroacetic acid (30 muL) was added, then heated to reflux for 4 h and left to cool to room temperature. The resulted solid was filtered, washed with cold diethyl ether and further used without any other purification.
N'-[2,6-dinitro-4-(trifluoromethyl)phenyl]-4-methoxybenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine; In 1,2-dimethoxyethane; at 20 - 40℃;
General procedure: A solution of 1-chloro-2,6-dinitro-4-(trifluoromethyl)benzene (10 mmol) in 1,2-dimethoxyethane(20 mL) was added dropwise to a stirred solution of of N?-substituted hydrazide 1a, 1b, 1c (10 mmol)and triethylamine (10 mmol) in anhydrous dimethoxyethane (40 mL) over a period of 30 min at 20-25 C.Then reaction mixture was heated to 40 C and stirred for 2-3 h. The reaction was monitored by TLC.The reaction mixture was poured on ice water (200 mL). The obtained solid product was filtered off,washed with water and recrystallized from 80% acetic acid.
With silica gel; hydrazine In neat (no solvent) at 130℃; for 20h; Inert atmosphere; Sealed tube;
3 Conversion of benzamides to benzhydrazides
General procedure: These compounds were prepared using the standard procedure at 130°C for 20-24h. For each reaction, the crude product was adsorbed onto silica gel and purified on a 15cm×2.5cm silica gel column eluted with 80% EtOAc in hexanes. The isolated yields are given in Table 7.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate Reflux; Inert atmosphere;
1 General procedure for two steps synthesis of 1,3,4-oxadiazole derivatives 8-17 (Method A) and general procedure for one-step synthesis of 1,3,4-oxadiazole derivatives 8-28 (Method B)
General procedure: Method A; To a stirred solution of acrylic acid (200mg, 1 eq) and substituted hydrazide (1 eq) in dry ethyl acetate (5-10mL) were added dropwise T3P (2.5 eq, 50% solution in EtOAc) and triethylamine (3 eq), and the mixture was refluxed under argon atmosphere for 1h-24h. The completion of reaction was confirmed by TLC. The mixture was cooled to room temperature, and poured into ice/water. The precipitating solid was filtered off, washed with water, cyclohexan and dried under pressure to give the pure diacylhydrazine derivative.; The corresponding diacylhydrazine derivative was placed under argon atmosphere and POCl3 was added dropwise (10 mL). The mixture was refluxed for 1h30. The mixture was cooled to room temperature, and poured into ice/water. The precipitating solid was filtered off, washed with water, cyclohexane and dried under pressure to give the desired 1,3,4-oxadiazole derivative.
2-[(E)-2-(5-bromothiophen-2-yl)ethenyl]-5-(4-methoxyphenyl)-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate at 160℃; Sealed tube; Inert atmosphere; Microwave irradiation;
9 General procedure for two steps synthesis of 1,3,4-oxadiazole derivatives 8-17 (Method A) and general procedure for one-step synthesis of 1,3,4-oxadiazole derivatives 8-28 (Method B)
General procedure: Method B; To a stirred solution of acrylic acid (200mg, 1 eq) and substituted hydrazide (1 eq) in dry ethyl acetate (5-10mL) were added dropwise T3P (3 eq, 50% solution in EtOAc) and triethylamine (5 eq). The reaction vessel was sealed under argon atmosphere and the mixture was heated under microwave conditions at 160°C for 20min to 30min. The completion of reaction was confirmed by TLC. The mixture was cooled to room temperature. The organic layer was washed twice with 1N HCl, once with H2O and once with brine. The organic layer was dried under Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (cyclohexan/EtOAc or DCM/Methanol) to afford the desired 1,3,4-oxadiazole derivative.; 4.1.2.9 2-[(E)-2-(5-bromothiophen-2-yl)ethenyl]-5-(4-methoxyphenyl)-1,3,4-oxadiazole 14 1H NMR (DMSO-d6, 250 MHz): δ = 8.03 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 16.2 Hz, 1H), 7.41 (d, J = 3.5 Hz, 1H), 7.32 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 16.2 Hz, 1H), 3.88 (s, 3H); 13C NMR (DMSO-d6, 101 MHz): δ = 163.78, 163.67, 162.68, 141.99, 132.41, 131.66, 131.08, 129.05, 116.13, 115.44, 115.08, 109.67, 56.10; LC/MS (ESI): 362.86 [M+H]+ and isotopic peak: 364.89; HRMS (TOF, ESI+) cald for C15H12N2O2SBr (M + H)+ 362.9803, found 362.9804; beige powder.
With trichlorophosphate; In toluene; at 100℃; for 2h;
General procedure: A mixture of benzoylhydrazine 23 (0.68 g, 5 mmol), 3-<strong>[590-92-1]bromopropionic acid</strong> (1.2 g, 7.5 mmol), POCl3 (4 mL) in toluene (20 mL) was stirred at 100 C for 2 h. After cooling to room temperature, the mixture was poured into ice water slowly, and extracted with ethyl acetate (20 mL* 3). The organic layer was combined, dried over Na2SO4, and concentrated to afford crude 2-(2-bromoethyl)-5-phenyl-1,3,4- oxadiazole 19o as a yellow solid in 41% of yield. This crude product was used without purification. Following the same procedure for the synthesis of 17a, targetcompound 17o was obtained using crude 2-(2-bromoethyl)-5-phenyl-1,3,4-oxadiazole 19o as halide.
With tetrabutylammonium acetate In methanol at 20℃; for 3h; Electrochemical reaction; Inert atmosphere;
83%
With tert.-butylhydroperoxide; sodium carbonate; potassium iodide In 1,4-dioxane at 120℃; for 5h; Sealed tube;
2.Experimental Procedures
General procedure: In a 35 mL sealed tube, a solution of 3 mL of 1,4-dioxane, acyhydrazines 1 (0.5mmol), α-ketoacids 2 (0.5 mmol) , Na2CO3 (0.6 mmol), KI (0.05 mmol) and TBHP (2.0 mmol) was sequentially added. The reaction mixture was stirred at 120 °C for 5 h and then cooled to room temperature. Then, the mixture extracted with ethyl acetate (2 × 10 mL), and the organic layer was combined and dried with anhydrous Na2SO4. After removal of the solvent under reduced pressure, the residue was separated by flash column chromatography to afford the pure product 3 (PE:EA = 20:1).
82%
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 24h; Sealed tube; Irradiation;
General procedure for synthesis of 2,5-diaryl 1,3,4-oxadiazoles and reuse of the catalyst:
General procedure: A sealed tube equipped with a magnetic stir bar was charged with acylhydrazine 1 (0.5 mmol), α-keto acid 2 (0.5 mmol), K2CO3 (1 mmol), PANI-g-C3N4-TiO2 (40 mg) and DMF (5.0 mL). The mixture was then irradiated with a 14 W CFL and stirred at room temperature (25 °C) for 24 h. The distance of the reaction vial from the light is about 5 centimeters. After reaction, the mixture was diluted with EtOAc (10 mL) and H2O (5 mL), and the solid catalyst was recovered by centrifugation. The aqueous phase was extracted with EtOAc (5 mL × 3). The collected organic extracts were dried on Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel using a mixture of PE/EA (20:1) to give the pure product 3.
67%
With Eosin Y In N,N-dimethyl-formamide at 45℃; for 12h; Sealed tube; Irradiation;
Experimental Procedures for the Synthesis of 3aa-3ak, 3ba-3ga, 5a-5k.
General procedure: In sealed tube, a solution of 3 mL solvent (DMSO or DMF) of hydrazines 1 (0.5mmol), diketones 2 or 4 (0.5mmol), K2CO3 (1mmol), eosin Y (0.025mmol) was sequentially added. The reaction mixture was stirred under incandescent light (0.4 Wcm-2) irradiation at 45 °C for 24 h. Then, the mixture extracted with ethyl acetate (3 × 10 mL), and the organic layer was combined and dried with anhydrous Na2SO4. After removal of the solvent under reduced pressure, the residue was separated by flash column chromatography to afford the pure product 3 or 5 (PE: EA = 20:1).
With tert.-butylhydroperoxide; iron(III) chloride; In acetonitrile; at 80℃;
With 4-methoxybenzohydrazide and aniline as raw material, the reaction steps are as follows: In the reaction flask was added 0.083 g (0.5 mmol) of 4-methoxybenzohydrazide, 0.0465 g (0.5 mmol) of aniline, 0.0081 g (0.05 mmol) of ferric chloride and 0.3 mL (3 mmol) of tert-butyl hydroperoxide and 5 ml of acetonitrile at 80 C. TLC followed the reaction until complete. The crude product obtained after the end of the reaction was separated by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the desired product (yield 85% ).
75%
With tert.-butylhydroperoxide; iron(III) chloride; In water; acetonitrile; at 80℃; for 2h;Inert atmosphere;
General procedure: To a Schlenk tube equipped with a rubber septum was successively added acylhydrazine 1 (1 mmol), amine 2 (1 mmol), FeCl3 (16.2 mg, 10 mol %) and acetonitrile (10 mL). The tube was evacuated and purged with argon three times. Then TBHP (70% in H2O (6 mmol), was slowly added and the mixture allowed to stir for 2 hours at 80 oC. After the completion of reaction (indicated by TLC), the reaction mixture was concentrated under reduced pressure and the crude mixture was purified by column chromatography using acetone/petroleum ether (v/v 1:10) as eluent to obtain the pure products 3 or 4.
4.2.3. Synthesis of substitutedbenzoyl hydrazides (III)
General procedure: The substituted phenyl benzoate (II) (0.01 mol)was reacted withhydrazine hydrate (0.02 mol) in methanol. The mixture wasrefluxed and monitored by TLC. The crude product was washedwith water and recrystallized from ethanol [12,20].
With hydrazine monohydrate In methanol for 0.5h; Reflux;
Synthesis of substituted benzoic acid hydrazide (5a-m)
General procedure: 0.05 mol of substituted benzaldehyde in 3 mL of methanol is mixed with 0.1 mol of 99% hydrazine hydrate, the rinsing isrefluxed for 30 min, the mixture is allowed to cool once the product formed, and the precipitated solid is filtered off. Theproduct obtained is purified by washing with plenty of water and crystallizing from ethanol [27, 28].
With hydrazine monohydrate In methanol for 0.5h; Reflux;
Synthesis of substituted benzoic acid hydrazide (5a-m)
General procedure: 0.05 mol of substituted benzaldehyde in 3 mL of methanol is mixed with 0.1 mol of 99% hydrazine hydrate, the rinsing isrefluxed for 30 min, the mixture is allowed to cool once the product formed, and the precipitated solid is filtered off. Theproduct obtained is purified by washing with plenty of water and crystallizing from ethanol [27, 28].
N′-[(E)-2H-chromen-3-ylmethylidene]-4-methoxybenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
In ethanol at 20℃;
General synthetic procedure for compounds 7a-q
General procedure: To a stirred solution of 2H-chromene-3-carbaldehydes (2 mmol) 3a-c in 10-20 ml abs. ethanol appropriate hydrazide 6a-f (2 mmol) was added. The reaction mixture was vigorously stirred at room temperature for 15 min until TLC showed reaction completion. After 15 min - 2 h the clusters of yellow crystalline compounds 7a-q deposited from the solution. Upon filtration the crystals were washed with aqueous ethanol and recrystallized from EtOH to give TLC pure crystals.
62%
In ethanol at 20℃;
General synthetic procedure for compounds (4a-c) and(8a-d)
General procedure: The compounds were prepared by an established procedure(Angelova et al. 2016b, 2017). An appropriate hydrazide3a-d (2 mmol) was added to a stirred solution of4-chlorocoumarin-3-carbaldehyde 2 or 2H-chromene-3-carbaldehydes (2 mmol) 7: in 10-20 mL anhydr. ethanol.The reaction mixture was vigorously stirred at room temperaturefor 15 min. After 15 min to 1 h the clusters ofyellow crystalline compounds 4a-c and 8a-d depositedfrom the solution. Upon filtration the crystals were washedwith aqueous ethanol to give TLC pure crystals.
N'-[(E)-2-methyl-2H-chromen-3-ylmethylidene]-4-methoxybenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
In ethanol at 20℃;
General synthetic procedure for compounds 7a-q
General procedure: To a stirred solution of 2H-chromene-3-carbaldehydes (2 mmol) 3a-c in 10-20 ml abs. ethanol appropriate hydrazide 6a-f (2 mmol) was added. The reaction mixture was vigorously stirred at room temperature for 15 min until TLC showed reaction completion. After 15 min - 2 h the clusters of yellow crystalline compounds 7a-q deposited from the solution. Upon filtration the crystals were washed with aqueous ethanol and recrystallized from EtOH to give TLC pure crystals.
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 24h;Sealed tube; Irradiation;
General procedure: A sealed tube equipped with a magnetic stir bar was charged with acylhydrazine 1 (0.5 mmol), alpha-keto acid 2 (0.5 mmol), K2CO3 (1 mmol), PANI-g-C3N4-TiO2 (40 mg) and DMF (5.0 mL). The mixture was then irradiated with a 14 W CFL and stirred at room temperature (25 C) for 24 h. The distance of the reaction vial from the light is about 5 centimeters. After reaction, the mixture was diluted with EtOAc (10 mL) and H2O (5 mL), and the solid catalyst was recovered by centrifugation. The aqueous phase was extracted with EtOAc (5 mL × 3). The collected organic extracts were dried on Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel using a mixture of PE/EA (20:1) to give the pure product 3.
4-methoxy-N'-(4-phenylbutanoyl)benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0℃; for 2h;
General procedure: To a cooled solution of the 10a-n (3.0 mmol) in dichloromethane, triethylamine (3.0 mmol) was added at 0 C followed by the addition of the corresponding 12a-c (3.0 mmol). The reaction mixture was stirred at 0 C for 2 h. After the completion of the reaction, water was added and the reaction mixture was extracted using ethyl acetate. The organic layer was washed with 10% sodium bicarbonate solution and finally with brine solution. It was dried over anhydrous sodium sulfate and evaporated under vacuum. The products 13a-q was purified by column chromatography.
General procedure: 8-Methoxyquinoline-2-carbaldehyde (25, 0.534 mmol) was refluxedwith various substituted acylhydrazines (0.587 mmol, 1.1 eq) in ethanol(5-10 mL) to get acyl hydrazides of 8-hydroxyquinoline. After completionof reaction, quinoline acyl hydrazides were found as precipitateson cooling to -15 C. Precipitates were washed with coldethanol and dried under vacuum. These acyl hydrazides were used directlyfor one pot synthesis of 2,5-disubstituted-1,3,4-oxadiazole usingiodine/K2CO3 catalysed oxidative cyclization. To the acyl hydrazides(1.0 eq) in DMSO (5-10 mL), K2CO3 (3.0 eq) and iodine (1.2 eq) wereadded in sequence and refluxed at 110 C. After the completion, thereaction mixture was cooled and saturated solution of sodium thiosulfatewas added. The precipitates were collected and dried under highvacuum to get the respective compounds (33-50).
With trifluoroacetic acid; In toluene; at 130℃; for 12h;
General procedure: A 25 mL pressure tube was charged with arylhydrazide 1 (0.5 mmol), TFBen (53 mg, 0.25 mmol, white solid, mp 57.2-58.5 C), TFA (38 muL, 1.0 equiv), and toluene (4 mL). The tube was then heated by stirring the contents at 130 C for 12 h. Afterwards, the mixture was cooled to r.t., quenched with sat. aq NaHCO3 (3 mL), and extracted with EtOAc (3 4 mL). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. The pure product 2 was obtained after purification by column chromatography (EtOAc/ pentane 1:3).
With dipotassium peroxodisulfate; copper(l) iodide; at 120℃;Green chemistry;
Add p-methoxybenzoyl hydrazide 0.2 mmol in a 25 mL tube.Cuprous iodide 0.05 mmol,Potassium persulfate 0.2 mmol,Adding DMF (N,N-dimethylformamide) as a solvent,Stir at 120 C.After TLC (thin layer chromatography) detection, the reaction solution is cooled to room temperature, the reaction solution is filtered, extracted, and the filtrate is evaporated under reduced pressure to remove the solvent, and then purified by column chromatography.The target product 2-(4-methoxyphenyl)-1,3,4-oxadiazole is obtained.The column chromatography eluate used was a petroleum ether:ethyl acetate mixture of 3:1 by volume.The yield was 64%.
3,5-diiodosalicylaldehyde-4-methoxybenzoylhydrazone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In N,N-dimethyl-formamide; for 2h;Reflux;
The aroylhydrazone H2DSMB was prepared by refluxingequimolar N,N-dimethylformamide solutions of 4-methoxybenzhydrazide(0.166 g, 1 mmol) and 3,5-diiodosalicyaldehyde(0.374 g, 1 mmol) for 2 h. The resulting solution was allowed toevaporate at room temperature. Single crystals suitable for X-rayanalysis were obtained within a period of 2-3 days. The productobtained was filtered and dried.Yield: 0.4332 g (83%) Color: Yellow. Anal. Calc. for C15H12I2N2O3(M.W.: 522.07 g mol1): C, 34.51; H, 2.32; N, 5.37. Found: C, 34.09;H, 1.96; N, 5.11%.
In methanol; for 2h;Heating;
General procedure: Briefly, 4-substituted benzohydrazides (1 mmol) were treated with 2- or 4-hydroxy-3,5-diiodobenzaldehyde (for hydrazones 1 and 2, respectively; 1.1 mmol; 411.3 mg) in boiling methanol for 2 h. The hydrazide-hydrazones spontaneously precipitated were crystallized from MeOH if necessary.29
General procedure: The ligands L3, L4, L5 and L6 were synthesized using <strong>[65-22-5]pyridoxal hydrochloride</strong> (0.180g, 8mmol) solubilized in methanol (15mL). Then 4-hydroxybenzoic hydrazide (L3), 4-methoxybenzoic hydrazide (L4), 4-aminobenzoic hydrazide (L5), and 4-nitrobenzoic hydrazide (L6) were added (0.134g, 0.146g, 0.133g, 0.160g, 8mmol each, respectively). The reaction solution remained at 50C and constant stirring, with reaction time of 2h (L3-L4) and 3h (L5-L6). After this period, the reaction mixture was cooled to room temperature and the methanol was then evaporated under reduced pressure, whereby a yellow solid was obtained (Scheme 2 ). Thin-layer chromatography plates monitored the reactions (Hex/Ac 80-20). The synthetic route used to obtain the L4 ligand is similar to that proposed by K. Ramdasand and co-workers [29].
(E)-4-methoxy-N'-(2,3,4-trihydroxybenzylidene)benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.9%
In methanol at 20℃; for 12h; Inert atmosphere;
2.1.2. General procedure for the synthesis of hydrazides 3a-3z
General procedure: 2,3,4-Trihydroxybenzaldehyde (0.55 g, 3.6 mmol) was added to asolution of hydrazides (3.0 mmol) in methanol (20 mL). The solutionwas stirred for 12 h under room temperature, which was then filteredand finally recrystallized from ethanol, to give the target hydrazonederivatives as white to gray powdered solid.
N'-((4-hydroxynaphthalen-1-yl)methylene)-4-methoxybenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogenchloride; In 1,4-dioxane; dimethyl sulfoxide; at 20℃;
General procedure: To a stirring mixture of 4-methoxybenzoic acid hydrazide (668 mg, 4.02 mmol) and 8-hydroxyquinoline-5-carbaldehyde (583 mg, 3.37 mmol) was added a catalytic amount of HCl (0.09 mL of a 4 N solution in 1,4-dioxane, 0.36 mmol) in 10mL of DMSO, then the reaction was left to stir at rt overnight. The following day, the reaction was diluted with distilled water and the precipitate was filtered, rinsed with distilled water, collected, and dried to afford 1 as a yellow solid (1.07 g, 99 % yield).
Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.5h;
Stage #2: 4-methoxybenzoic acid hydrazide With triethylamine In dichloromethane at 20℃; for 12h;
4.1.1. General synthetic procedure for intermediates 3a, 6a and 9a
General procedure: The substituted benzoic acid (1 equiv) and EDCI (1.2 equiv) weredissolved in dichloromethane, and stirred for 30 min. To a stirred abovesolution added substituted benzoyl hydrazine (1 equiv) and Et3N (2equiv). The mixture was stirred at room temperature for 12 h. Theorganic layers were washed with brine (25 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated to give intermediates3a, 6a and 9a, which was used for the next reactionwithout further purification.
2.1.2.1 Synthesis of hydrazide-hydrazones 1 and 2
General procedure: Briefly, 4-substituted benzohydrazides (1 mmol) were treated with 2- or 4-hydroxy-3,5-diiodobenzaldehyde (for hydrazones 1 and 2, respectively; 1.1 mmol; 411.3 mg) in boiling methanol for 2 h. The hydrazide-hydrazones spontaneously precipitated were crystallized from MeOH if necessary.29
With potassium phosphate In acetonitrile at 100℃; for 1h; Sealed tube; Inert atmosphere;
2. General procedure for the synthesis of 3
General procedure: CH3CN (2 mL) was added to a mixture of ClCF2COONa 2a (0.3 mmol, 1.5 equiv) and hydrazides 1 (0.2 mmol, 1 equiv) in the presence of K3PO4 (0.3 mmol, 1.5 equiv). Then the sealed tube was stirred at 100 °C under N2 for 1 h. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatograph (silica gel, petroleum ether:EtOAc = 2:1, v/v) to give the desired product 3.
(E)-4-methoxy-N'-((2-(piperidin-1-yl)pyridin-3-yl)methylene)benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With acetic acid In ethanol at 20℃;
General experimental procedure for the preparationof (E)-N'-(pyridin-3-ylmethylene) benzohydrazides, 3a-y
General procedure: Glacial acetic acid (0.2 mL) was added to a stirredsolution of nicotinaldehyde 1a (1.0 mmol), benzohydrazide 2a (1.0 mmol) in absolute ethanol (3 mL) at RT and the contents were stirred at the same temperature. After completion of the reaction (TLC, 1h), the reaction mixture was filtered through Whatman filter paper and compound wasrecrystallized from ethanol to afford (E)-N'-(pyridin-3-ylmethylene)benzohydrazide 3a as colourless solid.The compounds 3b-y were prepared by the reaction ofnicotinaldehydes 1a-b with benzohydrazides 2a-eunder above conditions. All the prepare compoundsare unknown and well characterized by spectral data.