* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: Hydrazides (30–58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3–6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
Reference：
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2
[ 348-52-7 ]
[ 1906-57-6 ]
[ 443-26-5 ]
Yield
Reaction Conditions
Operation in experiment
44%
With palladium diacetate In 1-methyl-pyrrolidin-2-one at 20 - 140℃; for 24 h; Inert atmosphere
General procedure: An oven-dried Schlenk-tube (10 mL) was charged with Pd source (1 mol percent), and ethyl potassium oxalate (0.75 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). After that, iodobenzene (0.5 mmol) and NMP (1.0 mL) were added by syringe under a counter flow of argon at room temperature. The reaction vessel was closed and then placed under stirring in a preheated oil bath. The reaction mixture was stirred for 24 h. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate, and analyzed by gas chromatography.
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
With hydrazine hydrate; at 80℃;
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; In ethanol;Reflux;
General procedure: Hydrazides were synthesized by reported methods [6, 9,10]. The appropriate hydrated hydrazine (2 mL, 40 mmol) was added to a solution of the ester (1 mmol) in ethanol (50 ml). The mixture was refluxed for 2-3 h to get a solid product. This was filtered off, washed with hexane and dried. The hydrazides were recrystallized from methanol. Analytical data for all the free ligands have been reported previously [19, 20].
With hydrazine hydrate; In ethanol;Reflux;
General procedure: Hydrazide ligands (1-12) were synthesized by reportedmethod [28,29]. Ethylbenzoate (25 mmol) was dissolved inethanol (75 mL), and then hydrazine hydrate (100 mmol)was added and the mixture refluxed for 5 h. The solid obtainedwas washed with hexane to afford the hydrazide.Other ligands were prepared from their respective esters. Theanalytical data of benzohydrazide (1), M.P. 116 C; 2-fluorobenzohydrazide (2), M.P. 74 C; 2-methoxybenzohydrazide(3), M.P. 83 C; 2-aminobenzohydrazide (4), M.P.124 C; 4-phenylsemicarbazide (5), M.P. 125 C; 3-aminobenzohydrazide(6), M.P. 79C; 4-aminobenzohydrazide (7),M.P. 229 C; 3-methoxybenzohydrazide (8), M.P. 94 C; 3-fluorobenzohydrazide (9), M.P. 138 C; 3-iodobenzohydrazide(10), M.P. 141 C; 4-iodobenzohydrazide (11) M.P.170 C and 3-bromobenzohydrazide (12) M.P. 160 C; werereported previously [28,30].
With hydrazine hydrate; In ethanol; at 20℃; for 3h;
General procedure: A mixture of substituted ethyl benzoate 2 (10 mmol) and hydrazinehydrate (20 mmol) in ethanol was stirred at room temperaturefor 3 h and then filtered. The crude product recrystallizedfrom absolute alcohol to give 3a-l, which were used directly forthe next step. Under this same condition, the intermediate compounds 8a-d were also prepared.
With hydrazine hydrate; In ethanol; for 6h;Reflux;
General procedure: The substituted ethyl benzoates (16-30) (0.01 mol)dissolved in dry ethanol (25 mL), hydrazine hydrate (99%,0.01 mol) was added and the mixture was reuxed for 6 h.The reaction mixture was cooled and the solid obtained wasltered and recrystallized from dilute ethanol or from water.Details of these compounds are available in SupplementaryInformation.
As described for the general reaction of <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> with amines set forth in Tetrahedron, 53, 7557-7576 (1997), <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(1-pyrazolyl)-benzoate, as a thick yellow oil. Anal. Calc'd: for C12H12N2O2: C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2:1) was refluxed for 2 hrs and the solvent removed.The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 3.7g of product. The pH of the filtrate was adjusted to 4.5 and extracted with ethyl acetate. The extract was concentrated to dryness to give 1.5g of product. The two crops were combined to give 5.2g of 2-(1-pyrazolyl)benzoic acid, mp 140-142C. To the preceding compound (2.07 g) in 5 ml CH2Cl2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2Cl2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2-(1-pyrazolyl)benzoyl chloride as a yellow solid.
ethyl 2-{3'-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yloxy}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With potassium carbonate; In ISOPROPYLAMIDE; for 48h;Heating / reflux;
2.15 g (12.8 mmol) of <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> and 1.9 g (14 mmol) of potassium carbonate are successively added to a solution of 4 g (12.8 mmol) of tert-butyl (4'-HYDROXYBIPHENYL-3-YLMETHYL) methyl- carbamate in 45 ml of dimethylacetamide. The reaction medium is refluxed for 48 hours, cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 3.1 g of ethyl 2-{3'-[(TERT-BUTOXYCARBONYLMETHYLAMINO) METHYL]- BIPHENYL-4-YLOXY} BENZOATE are obtained in the form of a colourless oil, in a yield of 53%.
With copper; potassium carbonate; In DMF (N,N-dimethyl-formamide); at 185℃;Heating / reflux;
A mixture of compound 20-1 (2 g, . 0535 mol), Boc piperazine 20-2 (3.32 g, . 017F mol, Aldrich), K2CO3 (7.39 g, . 0535 mol) and copper (. 0756 g, . 00119 mmol) in DMF (25 ML) was refluxed at 185 C overnight. The solution was cooled to room temperature, poured into 50 ML of ice water (50 ML) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried and concentrated in vacuo to give compound 20-3.
REFERENCE EXAMPLE 191 Methyl 4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate As described for the general reaction of <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> with amines set forth in Tetrahedron, 53, 7557-7576 (1997), <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C12H12 N2O2: C, 66.7,H, 5.6; N 13.0: Found: C, 66.5:H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H).
With NH-pyrazole;
REFERENCE EXAMPLE 191 Methyl 4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate As described for the general reaction of <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> with amines set forth in Tetrahedron, 53:7557-7576 (1997), <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> was reacted with pyrazole by refluxing N,N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C12 H12 N2 O2: C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H).
With NH-pyrazole;
EXAMPLE 63 4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide As described for the general reaction of <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> with amines set forth in Tetrahedron, 53, 7557-7576 (1997), <strong>[443-26-5]ethyl 2-fluorobenzoate</strong> was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C12 H12 N2 O2: C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H).
(1) 24.2 g of <strong>[443-26-5]ethyl o-fluorobenzoate</strong> and 9.8 g of imidazole are heated in the presence of sodium hydride, whereby 23 g of ethyl o-imidazolylbenzoate are obtained. B.p. 165 to 167 C. (2 mmHg).
EXAMPLE 15 0-(4-nitro-2-ethoxycarbonyl-phenyl)-hydroxylamine A mixture of 35 g of 2-fluoro-benzoyl chloride and 400 ml of ethanol was stirred for three hours and was allowed to stand overnight. The mixture was distilled to dryness at 50 C. and 30-40 mm Hg and the residue was taken up in methylene chloride The solution was washed with 5% aqueous sodium bicarbonate and then with water, dried and evaporated to dryness under reduced pressure. The product was rectified at 14 mm Hg to obtain 34 g of ethyl 2-fluoro-benzoate with a boiling point of 90-91 C. at 14 mm Hg.
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 sulfuric acid; In water; for 6h;Reflux;
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
With sulfuric acid; for 8h;Reflux;
General procedure: To a solution of substituted benzoic acid (1-15)(0.246 mol) in dry ethanol (2.5 mol), concentrated sulphuricacid (0.5 mL) was added. The reaction mixture was refluxedfor 8 h. Excess of ethanol was distilled off and the contentwas allowed to cool. The residue was poured into separatingfunnel containing 60 mL of water. Carbon-tetrachloride(5-10 mL) was added to obtain sharp separation of aqueousand ester layer. Ester layer was washed with sodiumhydrogen carbonate solution. The esters (16-30) were collected and recrystallized from ethanol. Details of thesecompounds are available in Supplementary Information.
4.9 g
With sulfuric acid;Reflux;
O-fluorobenzoic acid (5g, 35.7mmol) was dissolved in 20mL of ethanol, a catalytic amount of concentrated sulfuric acid was added dropwise, and the mixture was stirred at reflux overnight. After the reaction was completed, the ethanol was rotated.Extracted with ethyl acetate (25 mL × 3),The organic phase is combined, washed with saturated sodium hydrogen carbonate solution, washed with saturated brine and dried over anhydrous sodium sulfate.Concentrated to give a colorless oily productEthyl fluorobenzoate 4.9g;Ethyl fluorobenzoate (4.9 g, 29.1 mmol) was dissolved in 20 mL of DMSO, and morpholine (12.7 mL, 145.7 mmol) was added dropwise and stirred at 120 overnight.After the reaction, ethyl acetate was extracted (25 mL×3), and the organic phase was combined, washed with water (25 mL×3),After concentration, the oily product was 4.5 g;The above product (4.5 g, 19.1 mmol) was dissolved in 10 mL of methanol.Add 10 mL of 10% aqueous NaOH solution.After stirring at 80 C for 2 h, the methanol was rotated, and the pH was adjusted to 4 with 10% dilute hydrochloric acid.Solid precipitated and filtered to obtain 3.2 g of 2-morpholinylbenzoic acid.Three-step yield of 43.2%;The o-fluorobenzoic acid (50 mg, 0.24 mmol) was obtained in the same manner as in Example 1 to obtain 45g, two-step yield 54.9% of the product.
With palladium diacetate; In 1-methyl-pyrrolidin-2-one; at 20 - 140℃; for 24h;Inert atmosphere;
General procedure: An oven-dried Schlenk-tube (10 mL) was charged with Pd source (1 mol %), and ethyl potassium oxalate (0.75 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). After that, iodobenzene (0.5 mmol) and NMP (1.0 mL) were added by syringe under a counter flow of argon at room temperature. The reaction vessel was closed and then placed under stirring in a preheated oil bath. The reaction mixture was stirred for 24 h. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate, and analyzed by gas chromatography.
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;
A mixture of <strong>[443-26-5]2-fluoro-benzoic acid ethyl ester</strong> (200 mg; 1.19 mmol; 10 eq.), (1 H-imidazol- 2-ylmethyl)-dimethyl-amine (149 mg; 1.19 mmol; 1 eq.) and cesium carbonate (775 mg; 2.38 mmol; 2 eq.) in DMSO (3 mL) was stirred at 120C for 16 hours. The mixture was diluted with EA, washed with water (3x), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (58 mg, 18%) as a white solid. HPLC (max plot) 95.7%; RM .80 min.
With sodium hydride; In tetrahydrofuran; mineral oil; at 100℃; for 8h;
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 3-Fluoro-benzoic acid ethyl ester, the reaction mixture was heated at 100 C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2-Fluoro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol) as brown solid in 14% yield.
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