| 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 |
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