* 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.
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 40℃; for 2.5 h; Stage #2: for 20 h;
A solution of 1,10-carbonyldiimidazole (130 g,0.81 mol), isonicotinic acid (100 g, 0.81 mol) and DMF (300 mL) was heated at 40 C for 2.5 h before aniline (100 g, 0.81 mol) was added in a single portion. After 20 h, water (1.2 L) was added. The resulting suspension was filtered andthe solids dried under vacuum to afford isonicotinanilide (39) (142.6 g, 89percent).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 976 - 981
2
[ 1126-46-1 ]
[ 536-40-3 ]
Yield
Reaction Conditions
Operation in experiment
93.4%
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.
92%
With hydrazine hydrate In methanolReflux
General procedure: Compound (2) (0.1 mol) was taken in a round-bottom flaskwith methanol (100 mL). Hydrazine hydrate (99percent) (0.15mol, 5.7 mL) was added drop wise with gentle stirring. Thereaction mixture was refluxed for 4–6 h. Excess of methanolwas distilled off under reduced pressure. The precipitatedhydrazide was dried and re-crystallized from methanol(Zamani and Faghihi 2003).
88%
With hydrazine hydrate In water at 50 - 60℃; for 0.166667 h;
General procedure: Pathway A-Hydrazine hydrate 64percent (v/v) (30.0 mL, 0.33 mol) was heated up to 50-60 °C. The methyl ester previously isolated (0.01 mol) was added and the mixture was refluxed during 10 min. The cooling down was proceeded sequentially in a water bath, followed by ice bath and dry ice - ethanol bath. The solid was filtered and washed with cold water. Different conditions were needed to obtain 4-nitro-3-(trifluoromethyl)benzhydrazide (3d) and 4-nitrobenzhydrazide (3 h). Hydrazine hydrate 64percent (v/v) (30.0 mL, 0.33 mol) was cooled down in ice bath to -3 to 2 °C. The respective methyl ester (0.01 mol) was added and the mixture was stirred during 1 hour. The cooling down was proceeded in dry ice - ethanol bath. The solid was filtered and washed with cold water. Pathway B-each substituted benzoic acid (0.01 mol) was refluxed during 4 h in 20.0 mL (0.50 mol) of anhydrous methanol and 0.5 mL (1.0 mmol) of sulfuric acid. The reaction mixture was cooled down to room temperature. and the hydrazine hydrate 80percent (v/v) (10.0 mL, 0.11 mol) was added. The system was maintained into vigorously stirring for more 30 minutes. In the case of compounds with 4-nitro and 4-nitro-3-trifluoromethyl substituent groups attached in the benzene moiety, after the addition of hydrazine hydrate 80percent (v/v) at room temperature, the reaction mixture was cooled down in ice bath and maintained into stirring during 1 hour. After these periods, the mixture was maintained at cold temperature to give 3.
82.4%
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.
Reference：
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Stage #1: Methyl 4-chlorobenzoate With lithium aluminium deuteride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: With acetic acid In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
97%
With Aluminum Chloride; deuterated sodium borohydride In tetrahydrofuran at 0 - 60℃; for 3.5h;
87%
With deuterated sodium borohydride In tetrahydrofuran; ethyl [2]alcohol at 3 - 20℃; for 26h;
4.1 Step 1. 4-Chlorophenyl)melhan- ol (41).
A solution of methyl 4- chlorobenzoate (40) in ethanol-d (100 mL, 99 atom% D, Sigma Aldrich) and anhydrous THF (100 mL) was cooled to 3 °C. Sodium borodeuteride (4.9 g, 117.2 mmol, 98 atom% D, Sigma Aldrich) was added, and the reaction mixture was warmed gradually to rt, then stirred for 26 h. The reaction mixture was poured into deuterium oxide (300 mL, 99 atom% D, Cambridge Isotopes) and extracted with diethyl ether (3x 300 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white solid. The residue was purified by chromatography (Biichi automated system, SorbTech 120 g silica column, 0-100% ethyl acetate/hexanes) to give 41 (7.3 g, 87% yield) as a white solid.
86%
With samarium diiodide; water-d2; triethylamine In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere;
Typical Procedure for the Preparation of Model Compound(4-Heptylphenyl)methan-d2-ol (2a)
General procedure: To a solution of samarium (II) iodide (0.10 M in THF; 12 mL, 1.2 mmol, 6.0 equiv), asolution of ester (0.200 mmol, 1.00 equiv) in THF (2.0 mL) was added, followed by Et3N (0.33 mL, 2.4 mmol, 12 equiv) and D2O (0.261 mL, 14.4 mmol, 72.0 equiv) under Ar atroom temperature and stirred vigorously. After 15 min, the excess of SmI2 was oxidized bybubbling air through the reaction mixture. The reaction mixture was diluted with CH2Cl2(10 mL) and NaOH (10 mL, 1 M, aq). The aqueous layer was extracted with CH2Cl2 (3 ×10 mL), organic layers were combined, washed with Na2S2O3 (2 × 20 mL, sat., aq) driedover MgSO4, filtered and concentrated. The crude product was purified by flashchromatography (silica, 15% EtOAc/hexane). Percentage of exchanged protons aredetermined by 1H NMR indicated in square brackets.
86%
With samarium diiodide; water-d2; triethylamine In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere;
12 Example 12
Into a 50 mL single-necked round bottom flask under the protection of argon, add 12 mL of a solution of samarium diiodide (SmI2) in tetrahydrofuran (0.1 mol/L), compound 11 34.1 mg (0.200 mmol), and triethylamine 0.33 mL (2.4 mmol) and 0.260 mL (14.4 mmol) of heavy water. The reaction mixture was stirred at room temperature for 15 min, after which air was passed through to quench the reaction. Dichloromethane and saturated sodium hydroxide solution were added for extraction, the organic phase was dried and concentrated, and 24.9 mg of the target compound was obtained by column chromatography. The yield was 86% and the deuteration rate was 97%.
79%
With deuterated sodium borohydride; deuteromethanol at 20℃; for 16h;
2.1
EXAMPLE 2; l-(4-Chloro-rf2-benzyl)-2-(pyrrolidin-l-ylmethyl)-lH-benzo[rf]-imidazole hydrochloride (rf2-clemizole hydrochloride)[00106] (ΦChlorophenyD-tfe-methanol: Sodium borodeuteride (2.96 mg, 70.4 mmol, 2.10 equiv.) was added in several batches to a stirred solution of methyl 4- chlorobenzoate (6.0 g, 33.6 mmol, 1.00 equiv.) in Ji-methanol (60 mL). The resulting solution was stirred at ambient temperature for about 16 hours, and then water was added (200 mL). Following standard extractive workup with ethyl acetate (3 x 300 mL), the resulting crude residue was purified by silica gel column chromotagraphy (ethyl acetate / petroleum ether (1:4)), to give the title product as a white solid (4.0 g; yield = 79 %). LC-MS: m/z = 168/170 (MH-H2O+CH3CN)+.
With lithium aluminium deuteride
With Aluminum Chloride; deuterated sodium borohydride In tetrahydrofuran at 0 - 60℃; for 3.3h; Inert atmosphere;
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).
93.4%
With hydrazine monohydrate In ethanol for 5h; Reflux;
1 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.
92%
With hydrazine monohydrate In methanol Reflux;
Synthesis of acid hydraz ide (3a-b)
General procedure: Compound (2) (0.1 mol) was taken in a round-bottom flaskwith methanol (100 mL). Hydrazine hydrate (99%) (0.15mol, 5.7 mL) was added drop wise with gentle stirring. Thereaction mixture was refluxed for 4-6 h. Excess of methanolwas distilled off under reduced pressure. The precipitatedhydrazide was dried and re-crystallized from methanol(Zamani and Faghihi 2003).
91.34%
With hydrazine hydrate monohydrate In ethanol Heating;
90%
With hydrazine hydrate monohydrate In methanol Reflux;
88%
With hydrazine hydrate monohydrate In lithium hydroxide monohydrate at 50 - 60℃; for 0.166667h;
5.1.2. General procedure for the preparation of benzhydrazides (3)
General procedure: Pathway A-Hydrazine hydrate 64% (v/v) (30.0 mL, 0.33 mol) was heated up to 50-60 °C. The methyl ester previously isolated (0.01 mol) was added and the mixture was refluxed during 10 min. The cooling down was proceeded sequentially in a water bath, followed by ice bath and dry ice - ethanol bath. The solid was filtered and washed with cold water. Different conditions were needed to obtain 4-nitro-3-(trifluoromethyl)benzhydrazide (3d) and 4-nitrobenzhydrazide (3 h). Hydrazine hydrate 64% (v/v) (30.0 mL, 0.33 mol) was cooled down in ice bath to -3 to 2 °C. The respective methyl ester (0.01 mol) was added and the mixture was stirred during 1 hour. The cooling down was proceeded in dry ice - ethanol bath. The solid was filtered and washed with cold water. Pathway B-each substituted benzoic acid (0.01 mol) was refluxed during 4 h in 20.0 mL (0.50 mol) of anhydrous methanol and 0.5 mL (1.0 mmol) of sulfuric acid. The reaction mixture was cooled down to room temperature. and the hydrazine hydrate 80% (v/v) (10.0 mL, 0.11 mol) was added. The system was maintained into vigorously stirring for more 30 minutes. In the case of compounds with 4-nitro and 4-nitro-3-trifluoromethyl substituent groups attached in 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 hour. After these periods, the mixture was maintained at cold temperature to give 3.
88%
With hydrazine hydrate monohydrate In ethanol for 10h; Reflux;
84%
With hydrazine hydrate monohydrate In ethanol at 70℃;
82.4%
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.
82%
With hydrazine In methanol for 12h; Reflux;
80%
With hydrazine hydrate monohydrate In ethanol for 8h; Reflux;
75%
With hydrazine hydrate monohydrate In ethanol for 18h; Reflux;
68%
With hydrazine hydrate monohydrate Ambient temperature;
64%
With hydrazine hydrate monohydrate In methanol at 60℃; for 1h;
4-chlorobenzohydrazide (22)
To a solution of methyl 4-chlorobenzoate (5.0 g, 29.3mmol) in MeOH (50 mL) was added N2H4.H20 (80%, 50 mL). The resulting solution was heated at 60 °C for 1 h. After concentration, the resulting solid was dissolved in EA (150 mL), washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated to dryness to afford desired product 4-chlorobenzohydrazide 22 (3.2 g, 64%). ‘H NMR (300 MHz, DMSO-d6): ö 9.83 (s, 1H),7.85-7.81 (dd, 2h), 7.54-7.51 (dd, 2H), 4.50 (s,2H). LCMS (TOF-ESI) for C7H7C1N2O, Calculated for [M+Hj:; Found [M+ Hj:171.
With hydrazine hydrate monohydrate In ethanol Heating;
With hydrazine In lithium hydroxide monohydrate Heating;
With hydrazine hydrate monohydrate for 0.5h; Heating;
With hydrazine hydrate monohydrate In ethanol Heating;
With hydrazine In lithium hydroxide monohydrate at 60℃;
With hydrazine hydrate monohydrate for 0.166667h; Reflux;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate In ethanol for 10h; Reflux; Inert atmosphere;
With hydrazine hydrate monohydrate Reflux;
With hydrazine hydrate monohydrate at 80℃; for 2h;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate In lithium hydroxide monohydrate 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 In methanol Reflux;
With hydrazine hydrate monohydrate Reflux;
With hydrazine hydrate monohydrate In ethanol for 6h; Reflux;
With hydrazine hydrate monohydrate In lithium hydroxide monohydrate 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
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 In ethanol for 16h; Reflux;
Synthesis of acid hydrazides (2-3)
General procedure: A solution of substituted benzoic acid 1 (0.083 mol) in 20 ml methanol containing 2-3 ml of sulfuric acid was refluxed for 12 h (Scheme 1). The mixture was then allowed to cool at room temperature. A saturated solution of sodium bicarbonate was added to neutralize the mixture. Prepared ester was extracted by using dichloromethane (DCM). The DCM layer was dried using anhydrous sodium sulfate. The solvent was removed to dryness to afford ester which was used without further purification. To a solution of acid methyl ester in 15 ml of ethanol, 5 ml hydrazine hydrate was added and the resulting solution was refluxed for 16 h. Excess ethanol was distilled off and the concentrated solution was cooled to obtain acid hydrazide which was used without further purification.
With hydrazine monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate In methanol for 8h; Reflux;
With hydrazine hydrate monohydrate
With hydrazine hydrate monohydrate for 0.0833333h; Microwave irradiation; Inert atmosphere;
With hydrazine hydrate monohydrate In methanol
With hydrazine hydrate monohydrate In ethanol Reflux;
With hydrazine hydrate monohydrate for 5h; Reflux;
10
To a solution of ester (5g, 29.4mmole), hydrazine hydrate (5.2m1, 102.9mmole, 3.Seq) was added dropwise. The mixture was refluxed for 5 hr, after completion of reaction the solid product (hydrazide) was formed and the excess solvent was removed under reduced pressure.To the slurry of hydrazide (5gm, 29 .3Ommole) in ethanolic potassium hydroxide (1.97gm, 35.l6mmole), carbon disulfide (2.14m1, 35.l6mmole) was added slowly followed by refluxfor 10 hrs. After completion of reaction solvent was evaporated. The reaction mixture was acidified with conc.H2S04. The precipitate was filtered, washed with water and dried. By using the above procedure the representative compounds viz., 45 ,46 etc were prepared.
With pyridine; hydrazine hydrate monohydrate In methanol Reflux;
With hydrazine hydrate monohydrate In ethanol Reflux;
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 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.
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux;
With hydrazine hydrate monohydrate at 80℃; for 5h;
6.1; 7.1; 8.1
1) In a 100 ml round bottom flask,To a solution of 15.12 g (80.0 mmol) of methyl p-chlorobenzoateAnd hydrazine hydrate 30ml (excess) at 80 for 5h,After the reaction was completely cooled, the solid was precipitated at low temperature,Filter,Dried to give p-chlorobenzoyl hydrazide.
With hydrazine In lithium hydroxide monohydrate
With hydrazine hydrate monohydrate In ethanol
With hydrazine hydrate monohydrate In methanol at 65 - 67℃; for 9h;
With hydrazine hydrate monohydrate In ethanol at 70℃;
With hydrazine monohydrate In ethanol
With hydrazine hydrate monohydrate Cooling with ice; Reflux;
General procedure for synthesis of hydrazides (5a-l)1
General procedure: Carboxylic acids (10 mmol) were refluxed for 1-2 h in methanol (5 mL) in presence of conc. H2SO4 (catalytic amount) with continuous stirring. The reaction was monitored by TLC till the acids were fully converted to the corresponding esters [Eluent: EtOAc/Hexanes (1:4)]. The reaction mixture was allowed to cool down to room temperature and hydrazine monohydrate 80% (40 mmol, 1.91 mL) was added slowly in an ice bath. The reaction was then warmed to room temperature and refluxed for another 1-2 h and followed by TLC till formation of hydrazide. The reaction mixture was kept at refrigerator till the product precipitated. All hydrazides were isolated in quantitative yields and in a pure form. There melting points were in full agreement with the literature melting points of the same compounds.
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 at 45℃; for 5h;
5.3.1. typical procedure for the synthesis of 1,3,4-oxadiazol-2(3H)-oneintermediates (18)
General procedure: The substituted benzoic acid 15 (6 mmol) was dissolved in 20 mL MeOH, SOCl2 (1.4 g, 12 mmol) was added slowly in ice-bath, then themixture was heated at 45 °C for 5 h. Upon completion, the mixture was concentrated, the residue was re-dissolved in EtOAc and washed with NaHCO3 and brine. The organic layer was dried with Na2SO4 and concentrated to give the desired ester intermediate 16, which was used in the next step without further purification.The above ester 16 was dissolved in 15 mL MeOH, hydrazine hydrate(2 mL, 32 mmol), then the mixture was heated at 45 °C for 5 h.Upon completion, the mixture was concentrated, the residue was redissolved in EtOAc and washed with brine. The organic layer was concentrated and purified by silica gel affording the desired acylhydrazine intermediate 17 as a white solid in good yield.Add benzhydrazide 17 (2 mmol), CH2Cl2 (20 mL) and DIPEA(0.52 g, 4 mmol) to a round bottomed flask under N2 protection.Triphosgene (0.3 g, 1 mmol) dissolved in DCM (4 mL) Using a syringe,the triphosgene/DCM solution was added dropwise to the stirred solutionof hydrazide, and stirred at room temperature for 1 h. The reactionmixture was concentrated by rotary evaporation, the crudeproduct was purified by chromatography on silica (DCM/MeOH=100:1) affording the desired products 18 as white solid (about70% yield for three steps). Example 18-D3, 1H NMR (600 MHz,DMSO-d6) δ 12.66 (s, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.6 Hz,2H). ESI-MS calcd for C8H4ClN2O2 [M-H]-, 195.0, found 195.2.
With hydrazine hydrate monohydrate In ethanol at 90℃;
44 General procedure E, Hydrazide Formation:
General procedure: To a suspension of the methyl ester (1 eq) in EtOH (0.25-0.1M) was added hydrazine hydrate (3-5 eq) and the reaction mixture was heated at 90 °C overnight. The reaction mixture was cooled to rt often causing the product to crystallize out of solution. This solid was collected by removal of the supernatant. If the product did not crystallize, the solution was concentrated, and the crude product was sufficiently pure to use in subsequent steps.
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 monohydrate In methanol at 65℃; for 4h;
General Procedure 2: The Formation of Hydrazide
General procedure: To a solution of esters (2a~2t, 1.0 equiv.), furan-2-carbonyl chloride (7a, 1.0 equiv.) orthiophene-2-carbonyl chloride (7b, 1.0 equiv.) in MeOH (2 mL/1 mmol) was added hydrazine hydrate(1 mL/1 mmol), then the mixture was allowed to reach 65 C and stirred for 4 h. After completion(monitored by TLC), the organic solvent was removed and extracted three times with ethyl acetate,the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to givethe corresponding hydrazides (3a~3t, 8a, or 8b) in high yields, which were taken up for the next stepwithout any purification.
With hydrazine
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 methanol at 0℃; Reflux;
4.1.1. General procedure for the preparation of hydrazides 8
General procedure: Carboxylic acids 1a-g (5 mmol) were heated under reflux in methanol(5 mL) for 2 h in presence of conc. H2SO4 (catalytic amount)with continuous stirring. The reaction was monitored by TLC till theacids were fully converted to the corresponding esters [Eluent: EtOAc/Hexanes (1:4)]. The reaction mixture was allowed to cool down to roomtemperature and hydrazine monohydrate 80% (20 mmol, 0.96 mL) wasadded slowly in an ice bath. The reaction was then warmed to roomtemperature and heated under reflux for another 1-2 h and followed byTLC till formation of hydrazide. The reaction mixture was kept at refrigeratortill the product precipitated. All hydrazides were isolated inquantitative yields and in a pure form. Their melting points were in fullagreement with the literature melting points of the same compounds.
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 methanol Reflux;
With hydrazine hydrate monohydrate In ethanol for 10h; Inert atmosphere; Sealed tube; Reflux;
With hydrazine monohydrate In methanol at 80℃;
1-6
Under stirring conditions, 120mmol of hydrazine hydrate was dropped into 30mL (20mmol) of methanol solution (80), refluxed for 3~6h, cooled to room temperature under stirring conditions, a solid was precipitated, and the solid was obtained
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.
With hydrazine hydrate monohydrate In ethanol at 60 - 70℃;
4.2.2. General procedure for synthesis of aromatic hydrazide (3a-3r)
General procedure: To a solution of substituted aromatic ester (1 mol) in ethanol,mixture of hydrazine hydrate (1.2 mol) in anhydrous ethanol was addeddropwise and refluxed at 60-70 C for 12-18 h. Upon completion of thereaction, excess of hydrazine hydrate was evaporated under vacuum andthe resulting mixture was allowed to cool, to yield the hydrazide derivatives[28].
With hydrazine hydrate monohydrate In methanol for 3h; Reflux;
With hydrazine In ethanol for 3h; Reflux;
With hydrazine hydrate monohydrate In ethanol for 3h; 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
With hydrazine hydrate monohydrate In ethanol at 90℃;
With C39H39N6ORu(1+)*Br(1-); potassium methanolate; hydrogen In tetrahydrofuran at 70℃; for 4h;
100%
With C56H70Cl3N10Ru2(1+)*F6P(1-); potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran; dodecane at 70℃; for 16h; Inert atmosphere; Glovebox; Autoclave;
99%
With C13H34BFeNOP2; hydrogen In tetrahydrofuran at 60℃; for 18h; Autoclave; Inert atmosphere;
99%
With ethanol; [bis({2‐[bis(propan‐2‐yl)phosphanyl]ethyl})amine](borohydride)(carbonyl)(hydride)iron(II) at 100℃; for 24h; Inert atmosphere; Sealed tube; Darkness;
98%
With 2-(Aminomethyl)pyridine; 1,3-bis-(diphenylphosphino)propane; potassium <i>tert</i>-butylate; hydrogen In 2-methyltetrahydrofuran at 50℃; for 16h; Autoclave;
98%
With 2-(Aminomethyl)pyridine; RuCl2(norbornadiene)(pyridine); 1,3-bis-(diphenylphosphino)propane; potassium <i>tert</i>-butylate; hydrogen In 2-methyltetrahydrofuran at 50℃; for 16h; Autoclave;
98%
Stage #1: Methyl 4-chlorobenzoate With diethylzinc; lithium chloride In tetrahydrofuran; hexane at 20℃; for 6h; Inert atmosphere;
Stage #2: With sodium hydroxide In tetrahydrofuran; hexane; water at 20℃; for 8h; Inert atmosphere; chemoselective reaction;
96%
With methanol; sodium tetrahydroborate In tetrahydrofuran at 65℃; for 2h;
96%
Stage #1: Methyl 4-chlorobenzoate With phenylsilane; potassium hydroxide at 20℃; for 0.75h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 20℃; for 1h;
96%
Stage #1: Methyl 4-chlorobenzoate With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; lithium tert-butoxide In tetrahydrofuran at 100℃; for 24h; Inert atmosphere;
Stage #2: With methanol; sodium hydroxide In tetrahydrofuran at 20℃; Inert atmosphere;
8 The preparation of 4-chlorobenzyl alcohol, the structural formula is as follows:
Under nitrogen protection, the raw materials methyl 4-chlorobenzoate (1 mmol) and pinacolborane (2.5 mmol) were added, the catalyst LiOtBu (0.05mol) and the solvent tetrahydrofuran (1.0mL) were reacted at 100°C for 24h, subsequently, 2 mol/L NaOH/MeOH solution (ie, 2 mol of sodium hydroxide per liter of methanol) was added, and the mixture was stirred at room temperature overnight, and the product separation yield was 96%.
94%
With C31H26ClN2OPRu; hydrogen; sodium methylate In tetrahydrofuran at 80℃; for 1h;
92%
With dichloro(benzene)ruthenium(II) dimer; 2-((di-p-tolylphosphino)methyl)-1-methyl-1H-imidazole; potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran at 100℃; for 4.5h;
91%
With hydrogen; sodium ethanolate In 1,4-dioxane at 80℃; for 16h;
91%
With phenylsilane; dimanganese decacarbonyl In tetrahydrofuran at 100℃; for 16h; Sealed tube;
90%
With sodium tetrahydroborate; [fac-8-(2-diphenylphosphinoethyl)amidotrihydroquinoline]RuH(PPh)3(CO); hydrogen In tetrahydrofuran at 120℃; for 8h; Inert atmosphere; Autoclave;
90%
With hydrogen; C28H25BrMnN2O2P; lithium tert-butoxide In propan-1-ol at 100℃; for 5h; Autoclave;
88%
With [iPrPN(H)P]2Fe(H)(CO)(BH4); hydrogen In toluene at 115℃; for 3h; Glovebox; Sealed tube;
88%
With [bis({2‐[bis(propan‐2‐yl)phosphanyl]ethyl})amine](borohydride)(carbonyl)(hydride)iron(II); hydrogen at 115℃; for 3h;
86%
With sodium tetrahydroborate; ethanol; cerium(III) chloride heptahydrate at 20℃; for 24h;
80%
With sodium tetrahydroborate In 1,4-dioxane; water for 6h; Ambient temperature;
80%
With C30H26Cl2N3PRu; hydrogen; sodium ethanolate In toluene at 80℃; for 16h; Autoclave; Inert atmosphere; Schlenk technique;
79%
With ethanol; potassium <i>tert</i>-butylate; C39H41FeMnN2O5P(1+)*Br(1-) In <i>tert</i>-butyl alcohol at 100℃; for 22h; Inert atmosphere; Schlenk technique; enantioselective reaction;
78%
With C17H16BrMnNO3P; potassium <i>tert</i>-butylate; hydrogen In 1,4-dioxane at 100℃; for 16h; Autoclave;
75%
With C15H29MnNO3P2(1+)*Br(1-); potassium <i>tert</i>-butylate; hydrogen In 1,4-dioxane at 110℃; for 24h; Inert atmosphere; Autoclave;
73%
With n-butyllithium; [(1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene)FeCl2] In hexane; toluene at 100℃; for 20h; Inert atmosphere; Schlenk technique; Glovebox; Sealed tube;
67%
With hydrogen; sodium methylate In tetrahydrofuran at 100℃; for 2.5h;
2.8
Several others esters (see Table 3) were hydrogenated under identical conditions as reported in Table 4 with RuCl2(L-I)2. The reaction conditions were identical to those reported above for methyl benzoate.Table 3: Structure and name of substrates used EPO Table 4: Results obtained using the general conditions described above EPO Conversion: (in %, analysed by GC after silylation) of ester to alcohol after 2h 30min. Reaction conditions: Substrate (20 mmol), H2 gas (50 bars), RuCl2(L-I)2 0.05 mol%, NaOMe 10 mol%, THF (14 mL) at 1000C during 2h 30min.
67%
With hydrogen; sodium methylate In tetrahydrofuran at 100℃; for 2.5h;
2.8
Several others esters (see Table 3) were hydrogenated under identical conditions as reported in Table 4 with RuCl2(L-1)2. The reaction conditions were identical to those reported above for methyl benzoate.
65%
With sodium tetrahydroborate; sodium methylate In methanol at 25℃; for 3h; Inert atmosphere;
With zinc(II) tetrahydroborate; <i>N</i>,<i>N</i>-dimethyl-aniline In 1,2-dimethoxyethane for 24h; sonication;
Stage #1: Methyl 4-chlorobenzoate With C33H58FeN3PSi2; phenylsilane In toluene at 20℃; for 4h; Inert atmosphere; Glovebox; Green chemistry;
Stage #2: With sodium hydroxide In toluene for 1h; Green chemistry;
85 %Chromat.
With [bis({2‐[bis(propan‐2‐yl)phosphanyl]ethyl})amine](borohydride)(carbonyl)(hydride)iron(II); hydrogen In tetrahydrofuran at 120℃; for 19h; Autoclave;
77 %Chromat.
With 1,1'-methylene-bis(3-benzyl-1H-imidazol-3-ium) diiodide; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; potassium <i>tert</i>-butylate; hydrogen In 1,4-dioxane at 100℃; for 6h;
> 99 %Chromat.
With [RuCl2(2-(diphenylphosphino)-N-((6-((diphenylphosphino)methyl)pyridin-2-yl)methyl)ethan-1-amine)]; potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran at 80℃; for 5h; Autoclave;
With C23H29Cl2N2OPRuS; potassium <i>tert</i>-butylate; hydrogen at 50℃; for 16h; Inert atmosphere; Schlenk technique;
91 %Chromat.
With hydrogen; sodium ethanolate In 1,4-dioxane at 80℃; for 16h; Autoclave;
10
Being placed in a magnetic sub 5ml glass bottle, washed added NaOEt (17mg, 0.25mmol), Catalyst E (0.38mg, 0.001mmol), methyl p-chlorobenzoate (0.8529g, 5mmol, S / C = 10000: 1 ), dioxane 2.5mL solvent, the reaction system mentioned above into the autoclave, washed three times with hydrogen exchange, 50atm filled with hydrogen, the reactor was placed in an oil bath at 80 deg.] C pot and heated with stirring 16h, the reaction the autoclave was cooled in an ice bath.Analysis by gas chromatography of the reaction system (SPBTM-5, FUSED SILICA Capillary Column, 30m × 0.25mm × 0.25μm, filmthickness), injection temperature 250°C, detector temperature 260°C, temperature program 120°C (0°C) -20°C/min-240°C (0min).Gas chromatographic analysis of the yield of 91%.
Multi-step reaction with 2 steps
1: sodium tetrakis[(3,5-di-trifluoromethyl)phenyl]borate; C24H23ClCrIrNO3 / dichloromethane / 1 h / 25 °C / Schlenk technique; Glovebox; Inert atmosphere
2: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / Inert atmosphere
With diisobutylaluminium hydride In diethyl ether; toluene at -70 - 20℃;
> 92 %Chromat.
Stage #1: Methyl 4-chlorobenzoate With phenylsilane; [(k2-P,N)Mn(N(SiMe3)2)] In benzene-d6 at 25℃; for 4h; Inert atmosphere; Glovebox; Sealed tube;
Stage #2: With sodium hydroxide In benzene-d6; water for 18h; Inert atmosphere; Glovebox;
Multi-step reaction with 2 steps
1: 3C7H21Si3(1-)*La(3+) / benzene / 0.5 h / 25 °C / Inert atmosphere
2: sodium hydroxide; water / Inert atmosphere
68 %Chromat.
With HN(CH2CH2C3H3N2Mes)2Cl2; potassium <i>tert</i>-butylate; hydrogen; cobalt(II) chloride In tetrahydrofuran at 100℃; for 16h; Autoclave; Glovebox;
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere;
General procedure for the synthesis of aldehyde intermediates
General procedure: To a solution of methyl phenyl acetates (1.0 eq.) in dry THF (5mL) was added LiAlH4 (2 eq.) at 0°C under N2 atmosphere, and the resulting mixture was stirred at room temperature for 1h [23]. After complete consumption of starting material, the reaction mixture was quenched with Na+/K+ tartrate solution (∼10mL), and the mixture was filtered after being stirred at room temperature overnight. The collected filtrate was dried and concentrated to afford crude alcohol intermediate, which was oxidized by PCC (2 eq.) for 2h in CH2Cl2 (5-10mL) [24,25]. The reaction mixture was filtered through short silica column to remove brown side-product. The collected filtrate was concentrated in vacuo for next step without any purification.
With C22H14MnN2O4(1+)*BF4(1-); potassium hydride In tetrahydrofuran at 50℃; Inert atmosphere; Glovebox; Sealed tube;
With tris(trimethylphosphine)nickel(II) chloride; (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride In tetrahydrofuran at 100℃; for 12h; Inert atmosphere;
99%
With (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride; dichlorobis(trimethylphosphine)nickel In tetrahydrofuran at 100℃; for 12h; Inert atmosphere; Sealed tube;
10; 11; 12; 3; 4; 5; 6; 13; 14; 15; 41 Example-10
Under an argon atmosphere, 1.4 mg (0.005 mmol) of dichlorobis (trimethylphosphine) nickel, 85.0 mg (0.5 mmol) of methyl 4-chlorobenzoate, 152 mg (1.0 mmol) of cesium fluoride, , 140 mg (0.55 mmol) of 5,5,4 ', 4', 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolanyl) , 2-trifluoroethoxy) silane (180 mg, 1.05 mmol) and tetrahydrofuran (0.5 mL) were added and the mixture was sealed and stirred at 100 ° C. for 12 hours. After the reaction vessel was cooled to room temperature, 1 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 8 mL of ethyl acetate, and the obtained organic phases were combined. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: chloroform: ethyl acetate = 16: 4: 0 to 16: 4: 1)129 mg (white solid, yield 99%) of methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate was obtained.
96%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); potassium acetate In 1,4-dioxane for 0.25h; Reflux; Inert atmosphere;
96%
With potassium acetate; palladium diacetate; (1R,3S,5S,7R)-8-([1,1'-biphenyl]-2-yl)-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phospha-adamantane In tetrahydrofuran at 25℃; for 12h; Inert atmosphere; Sealed tube;
General procedure for room temperature borylation (A).
General procedure: An oven-dried ace pressure tube was evacuated and backfilled with argon. Pd(OAc)2 (0.005 - 0.02 mmol, 0.5 - 2 mol%) and ligand (0.0125 - 0.05 mmol, 1.25 - 5 mol%), were added and the tube was evacuated and backfilled with argon. THF (2.00 mL), aryl halide (1mmol), bis(pinacolato)diboron (2 - 3 mmol), KOAc (3 mmol), and n-decane (0.5 mmol, internal standard), were added to the tube. The tube underwent a final evacuation/backfill cycle, sealed with a screw cap, and allowed to stir at room temperature (25 °C) for the specified times (1 - 12 h). Conversion, selectivity and GC yield were quantified from an aliquot (0.20 mL) of the reaction mixture using GC-FID. Upon completion, the GC sample was transferred back into the main reaction mixture, an aqueous work-up was performed (EtOAc:H2O, 1:1). The organic layer was dried over MgSO4, filtered through a cotton wool plug and concentrated on a rotary evaporator. The isolated yield was obtained by purification of the crude product through column chromatography using silica gel (EtOAc-hexane).
92%
With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; XPhos In ethanol at 20℃; for 15h;
6.1 Example 1: Synthesis of 4-tert-butylphenylboronic acid pinacol ester
General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98%
91%
Stage #1: Methyl 4-chlorobenzoate; bis(pinacol)diborane With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos at 110℃; for 6h; Schlenk technique; Inert atmosphere;
Stage #2: Inert atmosphere;
Palladium-Catalyzed Borylation of Aryl Chlorides in PEG-2000;General Procedure
General procedure: To a dried Schlenk tube were added Pd2dba3 (4.6 mg, 0.005 mmol),XPhos (9.6 mg, 0.02 mmol), bis(pinacolato)diboron (190 mg, 0.75mmol), PEG-2000 (1.0 g), and KOAc (147 mg, 1.5 mmol). The Schlenktube was evacuated and backfilled with argon. The reaction mixturewas heated to 50 °C, followed by the addition of the aryl chloride (0.5mmol) via syringe (aryl chlorides that were solid were added withother reagents before evacuation). The reaction mixture was thenstirred at 110 °C under Ar for 6 h. After being cooled to 45 °C, the resultingmixture was extracted with cyclohexane (3 × 5 mL). The residueof the extraction was subjected to a second run of the borylationreaction by charging with the same substrates (aryl chloride, bis(pinacolato)diboron and KOAc) under the same conditions without furtheraddition of Pd2dba3 and XPhos. The combined cyclohexane layerwas concentrated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel using a mixture of petroleumether and EtOAc as eluent or by recrystallization from hexaneto afford the desired aryl boronates 2.
90%
With p-phenylpyridine; sodium methylate In acetonitrile at 20℃; for 12h; Sealed tube; Inert atmosphere; Irradiation;
88%
With 10H-phenothiazine; caesium carbonate In acetonitrile for 48h; Irradiation; Sealed tube; Inert atmosphere;
86%
With tris-(dibenzylideneacetone)dipalladium(0); rac-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole; potassium acetate In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere;
85%
With potassium acetate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In tetrahydrofuran for 6h; Heating;
83%
With 3,7-di([1,1'-biphenyl]-4-yl)-10-(4-(trifluoromethyl)phenyl)-10H-phenoxazine; 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 20℃; for 12h; Inert atmosphere; Irradiation; chemoselective reaction;
75%
With potassium acetate; palladium diacetate In benzene at 60℃; for 10h; Inert atmosphere;
75%
With catalyst: silica-SMAP/Pd(CH3COO)2; K(CH3COO) In benzene soln. of Pd complex in benzene and aryl halide added to mixt. of silica-SMAP, B compd., and KOAc in degassed benzene in glass tube with stirrer,tube sealed with screw cap, removed from glove box, mixt. stirred at 60 °C for 10 h; soln. filtered through Celite pad, filtrate evapd. under vac., column chromy. (silica gel, EtOAc/hexane 1/9);
70%
With pyridine-4-carbonitrile; potassium phosphate; sodium oxalate; 2,4,5-tri(9H-carbazol-9-yl)-6-(ethyl(phenyl)amino)isophthalonitrile In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube;
61%
With p-phenylpyridine; potassium methanolate In tert-butyl methyl ether at 85℃; for 12h; Sealed tube;
61%
With p-phenylpyridine; potassium methanolate In tert-butyl methyl ether at 85℃; for 12h;
60%
With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; potassium acetate In benzene at 25℃; for 10h; Inert atmosphere; Sealed tube;
Typical Procedure for Miyaura Borylation of Chloroarenes (Figure 1 and Table 1)
General procedure: In a nitrogen-filled glove box, Silica-3p-TPP ([P] 0.11 mmol/g, 45.5 mg, 0.005 mmol P, 1 mol % P), anhydrous, degassed benzene (0.8 mL), and a solution of [PdCl(η3-cinnamyl)]2 (0.65 mg, 0.00125 mmol, 0.5 mol % Pd) in benzene (0.2 mL) were placed in an oven-dried, 10-mL glass tube containing a magnetic stirring bar. After stirring of the mixture for 5 min, KOAc (147 mg, 1.5 mmol), bis(pinacolato)diboron (2, 140 mg, 0.55 mmol), and p-chlorotoluene (1a, 63.3 mg, 0.50 mmol) were added. The tube was sealed with a screw cap and was removed from the glove box. The mixture was stirred at 25 °C for 10 h, and was filtered through a Celite pad (eluting with Et2O). Solvent was removed under reduced pressure. An internal standard (1,1,2,2-tetrachloroethane) was added to a residue to determine the yield of the product by 1H NMR (95%). The crude material was then purified by silica gel chromatography to give arylboronate 3a (87.0 mg, 0.40 mmol, 80% yield).
36%
With cerium(III) chloride; tetraethylammonium chloride In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube;
27%
With C20H28Cl2CoFeNOP; potassium methanolate; methyllithium In tert-butyl methyl ether at 50℃; for 24h; Inert atmosphere; Schlenk technique; Sealed tube;
20%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In acetonitrile at 25℃; for 8h; Irradiation; Inert atmosphere;
87 % Chromat.
With potassium acetate; bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine In 1,4-dioxane at 80℃; for 6h;
Stage #1: Methyl 4-chlorobenzoate With tetrabutylammonium tetrafluoroborate; zinc(II) chloride In pyridine; acetonitrile Electrochemical reaction;
Stage #2: 3-penten-2-one In pyridine; acetonitrile at 50℃; for 15h;
With (3-phenylallyl)(chloro)-[1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II); potassium carbonate In ethanol; water at 80℃; for 4h; Sealed tube; Green chemistry;
95%
With cesium fluoride In 1,4-dioxane at 130℃; for 27h;
92%
With potassium fluoride; monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 100℃; for 20h;
92%
With KF In tetrahydrofuran
105 4-methyloxycarbonyl-2'-methyl-1,1'-biphenyl (Table 15, Entry 7)
Example 105 4-methyloxycarbonyl-2'-methyl-1,1'-biphenyl (Table 15, Entry 7) Methyl 4-chlorobenzoate (172 mg, 1.01 mmol) reacted with 2-methylphenylboronic acid (210 mg, 1.54 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (190 mg, 3.39 mmol) in THF at 100° C. to give the title compound (209 mg, 92%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 8.13 (d, 2H, J=8.24 Hz), 7.44 (d, 2H, J=8.20 Hz), 7.33-7.25 (m, 4H), 3.98 (s, 3H), 2.30 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 166.98, 146.69, 140.79, 135.10, 130.44, 129.47, 129.36, 129.21, 128.53, 127.78, 125.85, 52.06, 20.33. GC/MS(EI): m/z 226 (M+), 195, 165, 152. Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found C, 79.33; H, 6.26.
86%
With potassium phosphate In tetrahydrofuran at 100℃; for 24h;
With manganese;cobalt(II) bromide; iron(II) bromide; In pyridine; acetonitrile; at 50℃;
[0266] Allyl acetate (10 mmol) and aryl chloride (5 mmol) are introduced into a pyridine acetonitrile solution (AN=20 ml/Py=2 ml) that contains manganese dust (50 mmol), cobalt bromide dust (2 mmol), and ferrous bromide dust (5 mmol). The reaction mixture is brought to 50 C. and is stirred until aryl chloride completely disappears (not detectable in gas chromatography).
Stage #1: Methyl 4-chlorobenzoate With zinc bis[bis(trimethylsilyl)amide]; tri-tert-butyl phosphine; lithium chloride In tetrahydrofuran at 90℃; for 18h;
Stage #2: With hydrogenchloride In tetrahydrofuran; diethyl ether
79%
With tripotassium phosphate tribasic; bis(tri-o-tolylphosphine)palladium(0); (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine; ammonia In 1,4-dioxane at 70℃; for 12h; Inert atmosphere;
53%
With dicyclohexyl(2',4',6'-triisopropyl-5-methoxy-3,4,6-trimethyl-[1,1'-biphenyl]-2-yl)phosphine; C50H70NO4PPdS; C50H70NO4PPdS; dicyclohexyl(2',4',6'-triisopropyl-4-methoxy-3,5,6-trimethyl-[1,1'-biphenyl]-2-yl)phosphine; ammonia; sodium tertiary butoxide In 1,4-dioxane at 50℃; for 24h; Inert atmosphere;
51%
With C46H71Cl3N2Pd; ammonia; sodium tertiary butoxide In 1,4-dioxane at 80℃; for 2h; Inert atmosphere; Schlenk technique;
With Caswell No. 744A; lithium hydroxide monohydrate; triethylamine In methanol at 60℃; for 60h; Inert atmosphere; Irradiation;
With sodium methylate for 6h; Inert atmosphere; Reflux;
a 3-(4-chlorophenyl)-3-oxopropanenitrile
To a solution of 59.0 g (346 mmol) of methyl 4-chlorobenzoate in 690 mL of acetonitrile 37.37 g ( 692 mmol) sodium methyiate was added in nitrogen athmosphere and the mixture was refluxed for 6 h. The reaction mixture was cooled and poured into 500 mL of water. The pH of the mixture was adjusted to 3 by the addition of 2M hydrochloric acid. The precipitated product was filtered off and washed with water to yield 60.66 g (97.6 %) of the title compound. Mp. : 130-143 °C.
74%
Stage #1: acetonitrile With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1h;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 20℃;
70%
With sodium methylate for 6h; Reflux; Inert atmosphere;
64%
Stage #1: acetonitrile With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -78 - -60℃; for 1h; Inert atmosphere;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran; toluene at -78 - 20℃; for 16h; Inert atmosphere;
62%
With sodium hydride In toluene at 100℃; for 15h;
Synthesis of 3-(4-Chlorophenyl)-3-oxopropanenitrile
To a stirred solution of methyl 4-chlorobenzoate (5 g, 29.41 mmol) in toluene (50 mL), ACN (4.6 mL, 88.23 mmol) and NaH (60%, 3.3 g, 88.23 mmol) were added and stirred at 100 °C for 15 h. Progress of the reaction was monitored by TLC. Upon completion the reaction mixture was diluted with ice cold water, quenched with 2N HC1 up to pH=2 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure resulting in a crude compound which was purified by column chromatography to afford the title compound (3.2 g, 62%)
53%
With potassium <i>tert</i>-butylate; isopropyl alcohol In 2-methyltetrahydrofuran at 20℃; for 1h; Inert atmosphere;
General procedure for the synthesis of the β-ketonitriles
General procedure: To a solution of methyl/ethyl ester (1.0 equiv) in 20 mL 2-MeTHF under N2 was added IPA (0.2 equiv),CH3CN (1.0 equiv), followed by KOt-Bu (1.0 equiv). The reaction mixture was stirred at room temperaturefor an hour under N2 atmosphere, then dosed-up with an additional 1.0 mol equiv of CH3CN and KOt-Bu,respectively. The reaction mixture was stirred for another hour, quenched with 200 mL of saturated NH4Cl solution and the layers separated. The aqueous layer was extracted with 200 mL DCM. The combinedorganic layer was dried over Na2SO4, filtered and the solvents removed in vacuo by roto-evaporation. Theresulting residue was purified by SiO2 gel column chromatography using EtOAc/hexane mixtures as mobilephases.
43%
With sodium methylate for 2h; Reflux; Inert atmosphere;
20%
With sodium methylate at 20 - 100℃; for 19h;
12
3-(4-Chlorophenyl)-3-oxopropanenitrile; Methyl 4-chlorobenzoate (3.40 g, 20 mmol) was dissolved in toluene (16 niL). Acetonitrile (1.32 mL, 25 mmol) and NaOCH3 (1.08 g, 20 mmol) were added and the reaction was stirred at room temperature under argon for 18h. The reaction was heated to 1000C for Ih, and the reaction mixture was cooled to ambient temperature and the volatiles were removed by rotary evaporation leaving a residue. The residue was dissolved in water (10 mL) and washed with diether (3 times). The aqueous layer was then acidified to pH 6.4 with citric acid. The resulting precipitate was collected on fritted glass, washed with water, saturated aqueous NaHCO3, and water. The solid on the filter was dried under high vacuum over night to provide the beta-ketonitrile (692 mg, 20% yield).
With sodium hydride In toluene; mineral oil for 24h;
0.7 g
Stage #1: acetonitrile With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78℃; for 0.5h;
B Step-B: Synthesis of 3-(4-chlorophenyl)-3-oxopropanenitrile (Compound B)
To a stirred solution of dry CH3CN (14.5 g, 35 mmol) and dry tetrahydrofuran (300 mL) was added lithium diisopropylamide (220 mL, 441 mmol, 2M solution, in tetrahydrofuran) at -78°C, and the mixture was stirred at the same temperature for 1 hour under nitrogen atmosphere. Compound A (50 g, 29.4 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Next, the reaction mixture was allowed to cool at room temperature, and quenched with an ammonium chloride solution. The precipitated solid was filtered, washed with water, ether and pentane, and dried to obtain Compound B (0.7 g, 63.1%). The same batch was repeated with the scales of 50 g x 20. 1H-NMR (400 MHz, CDCl3): δ7.89 (d, 2H), 7.45 (d, 1H), 4.02 (s, 2H); LCMS: 180.1 (M+1).
Stage #1: acetonitrile With sodium hydride In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at 66℃; for 12h;
With sodium hydride In toluene for 4h; Reflux;
With sodium hydride In tetrahydrofuran for 5h; Reflux; Inert atmosphere;
With tBu2P-N=P(iBuPCH2CH2)3N; tetrabutyl ammonium fluoride; palladium diacetate In 1,4-dioxane at 80℃; for 2h; Inert atmosphere;
86%
With 3-(dicyclohexylphosphino)-2-(2-methoxyphenyl)-1-methyl-1-H-indole; tetrabutyl ammonium fluoride; palladium diacetate; acetic acid In toluene at 110℃; for 3h; Schlenk technique; Inert atmosphere; Sealed tube;
83%
With NHC-Pd(II)-Im; tetrabutyl ammonium fluoride In toluene at 120℃; for 3h; Inert atmosphere;
2.2. General procedure for the NHC-Pd(II)-Im complex 1 catalyzed Hiyama reaction of aryl chlorides with aryltrimethoxysilanes
General procedure: Under N2 atmosphere, NHC-Pd(II)-Im 1 (1.0 mol%), dry toluene (2.0 mL), aryl chlorides 2 (0.81 mmol), aryltrimethoxysilanes 3 (2.0 equiv) and TBAF•3H2O (2.0 equiv) were successively added into a Schlenk reaction tube. Then the tube was placed in a 120 °C oil bath and stirred for 3 h. The mixture was then allowed to cool to room temperature, diluted with ethyl acetate and washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and then purified by flash chromatography to give the pure products 4.
68%
With tetrabutyl ammonium fluoride In 1,4-dioxane at 80℃; for 17h;
The other compounds of Example 3 were prepared by essentially the same procedure using the corresponding carboxamide and acyl hydrazide. Acetonitrile was used as solvent in the preparation of 3-2. Compound [3-19] was isolated as a byproduct in the synthesis of 3-18. The methyl amides were prepared from their corresponding methyl esters and [METHYLAMINE] using well established protocols. The other amides were conveniently prepared from commercially available carboxylic acids and amines using 1- (dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as the reagent and published procedures. Preparation of the acyl hydrazides was described in Procedures 3A, 3B, 3C and 3D.
methyl 3'-acetyl-[1,1'-biphenyl]-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
229 mg (90%)
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
EXAMPLE 31 Synthesis of 4-carbomethoxy-3'-acetylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 3-acetylphenyl boronic acid (246 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and methyl-4-chlorobenzoate (171 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 229 mg (90%) of the title compound.
229 mg (90%)
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
Example 31 Synthesis of 4-carbomethoxy-3'-acetylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 3-acetylphenyl boronic acid (246 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and methyl-4-chlorobenzoate (171 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 229 mg (90%) of the title compound.
from <strong>[13925-00-3]2-<strong>[13925-00-3]ethylpyrazine</strong></strong> and methyl 4-chlorobenzoate there is obtained 4'-chloro-2-(2-pyrazinyl)-propiophenone, m.p. 85°;
EXAMPLE 7 Potassium 4-chlorobenzoate The procedure of Example 1 was followed using methyl 4-chlorobenzoate (13.65 g, 80 mmol), <strong>[10519-96-7]potassium trimethylsilanolate</strong> (10.26 g, 80 mmol), dry ether (500 mL) and a 4 h reaction time. Potassium 4-chlorobenzoate (13.1 g, 84% yield) was isolated as a white solid: 1 H NMR (D2 O, DSS, 80 MHz) delta 7.68 ppm (ABq, Deltanu1-3 =29 Hz, J=8.5 Hz, Ar--H's, 4H). Anal. Calcd. for C7 H4 ClKO2: C, 43.19; H, 2.07. Found: C, 43.27; H, 2.33.
8 Sodium 4-chlorobenzoate
EXAMPLE 8 Sodium 4-chlorobenzoate The procedure of Example 1 was followed using methyl 4-chlorobenzoate (4.55 g, 26.6 mmol), sodium trimethylsilanolate (2.99 g, 26.6 mmol), dry toluene (150 mL), and 4 h of heating at 80°. Sodium 4-chlorobenzoate (4.50 g, 86% yield) was isolated as a white solid: 1 H NMR (D2 O, DSS, 80 MHz) δ 7.65 ppm (ABq, Δν1-3 =29 Hz, J=8 Hz, Ar--H's, 4H).
EXAMPLE 8 Cross Coupling with a Zincate as the Nucleophile A solution of EtMgBr (3 M in Et2O, 0.9 mL) is added to a solution of Et2Zn (3 M in toluene, 1 mL) at -78 C. After stirring for 15 min, the resulting cold solution of the zincate is added dropwise to a solution of methyl 4-chlorobenzoate (354 mg, 2.10 mmol) and Fe(acac)3 (36 mg, 0.1 mmol) in THF (6 mL) and NMP (0.5 mL) at 0 C. causing a spontaneous color change from yellow to brown-black. Standard extractive work up followed by flash chromatography affords 4-ethylbenzoic acid methyl ester (93%) the analytical and spectroscopic data of which are identical to those of a commercial sample.
With potassium phosphate tribasic hydrate; NiIICl(1-naphthyl)(tricyclohexylphosphine)2; tricyclohexylphosphine; In tetrahydrofuran; at 23℃; for 2h;Inert atmosphere; Glovebox; Sealed tube;
General procedure: Cross-Coupling of ortho-, meta-, and para-Substituted, Electron-Rich and Electron-Deficient Aryl Halides and Aryl Mesylates with Aryl Neopentylglycolboronates Catalyzed by NiIICl(1-naph-thyl)(PCy3)2/PCy3 in Anhydrous THF at 23 °C; General Procedure 2In an oven-dried test tube charged with a Teflon coated stirring barwere added aryl halide or aryl mesylate (0.3 mmol), aryl neopentyl-glycolboronates (0.315 mmol), K3PO4(H2O)3.2 (191.00 ± 1.00 mg, 0.9mmol), and NiIICl(1-naphthyl)(PCy3)2 (11.73 ± 0.0510 mg, 0.015mmol, 5percent catalyst loading). The test tube was brought into a N2 filledglove box (moisture level <2 ppm) through three degassing cycles andPCy3 (8.4 mg, 0.03 mmol, 10percent loading) ligand was added. Distilled sol-vent (1 mL) was added inside the glove box and the test tube wassealed by a rubber septum and left stirring at 23 °C. A sample was tak-en by syringe and transferred outside the glove box. The sample wasdiluted by distilled THF (0.2 mL) and filtered through a short columnof Al2O3. The filtrate was concentrated and the GC analysis was car-ried out. The reaction mixture was diluted with CH2Cl2 (2 mL), filteredthrough a layer of Al2O3, and washed with CH2Cl2 (3 1 mL). The fil-trate was collected and concentrated under vacuum. The crude prod-uct was purified by column chromatography on silica gel with EtO-Ac/hexane mixture as eluent. The reductive elimination side-productwas also isolated and characterized.
96%
With cesium fluoride;palladium diacetate; CyJohnPhos; In 1,4-dioxane; at 25℃; for 18h;Product distribution / selectivity;
A Schlenk tube was charged with aryl halide (0.67 mmol, 1.0 equiv), aryl boronate ester (0.81 mmol, 1.2 equiv), potassium phosphate or CsF (3.0 equiv), Pd catalyst (0.1 equiv), 2-(dicyclohexylphosphino)biphenyl (0.2 equiv) (co-ligand was used in the presence of Pd(OAc)2 as catalyst and CsF as base (see Table 8, entries 13-15); reaction was performed at rt) and a Teflon coated stirbar. The reaction mixture was evacuated three times for ten minutes under high vacuum and backfilled with N2. Dry dioxane was added via the T-neck and the reaction mixture was heated to 110 0C for 18 h. The reaction mixture was cooled to room <n="24"/>temperature and diluted with DCM (10 rnL). The solution was filtered and the filtrated washed with DCM (100 mL). The filtrate was concentrated and purified by silica gel chromatography.
With triethylamine;1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In toluene; at 100℃; for 18h;Inert atmosphere;Product distribution / selectivity;
A round-bottom flask charged with the aryl halide (5.0 mmol, 1.0 equiv), Ni (For exact amount of catalyst and co-ligand see Table 8; 10% loading was used for Ni catalysts not specified in Table 8). (NiCl2(L)x , Ni(COD)2) or Pd (No co-ligand was used for Pd catalyst) catalysts (PdCl2(dppf)) (0.5 mmol, 0.1 to 0.02 equiv), ligand (L: dppp, dppe, dppf, PPh3, Et3N, bpy, PCy3) (0.5 mmol, 0.1 equiv), and a Teflon coated stir bar was evacuated three times for 10 min under high vacuum and backfilled with N2. Toluene (5 mL) and base (Et3N or (i-Pr)2EtN (15.0 mmol, 3.0 equiv) were added to the reaction mixture at rt. Freshly prepared neopentylglycolborane (10.0 mmol, 2.0 equiv in 5 ml toluene) was added to the red colored suspension via syringe at 23 0C. The reaction mixture was heated to 100 0C and the conversion was followed by GC. After 2 h-12 h (reaction time depends on the type of the aryl halide; iodo derivatives were found to react faster, in 2-4 h , while bromo derivatives in 8-12h), the reaction mixture was quenched via slow addition of saturated aqueous ammonium chloride (10 mL). The quenched reaction mixture was three times washed with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography or recrystallization.
Stage #1: Methyl 4-chlorobenzoate; fluoromethyl phenyl sulfone With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; Inert atmosphere;
Stage #2: With hydrogenchloride In tetrahydrofuran; water at -78℃; Inert atmosphere;
n-Butyl lithium (2.5M solution, 5.27 mL, 13.18 mmol) was added to a stirred solution of diisopropylamine (1.93 mL, 13.75 mmol) in anhydrous THF (25 mL) at -75 C. under a nitrogen atmosphere, and maintained at -30 C. for a further 1 h to produce lithium diisopropylamide (LDA). After re-cooling to -75 C., a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (1 g, 5.73 mmol) in THF (20 mL) was added over 1 h, and stirring continued overnight at -75 C. under nitrogen. A solution of methyl 4-chlorobenzoate (1.95 g, 11.46 mmol) in THF (20 mL) was added over 10 min, stirring was continued at -70 C. for 2 h and then at RT for 4 h. Water (30 mL) was added and the aqueous layer was washed with ether (3×50 mL), acidified with 1M HCl, extracted with DCM (3×50 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow solid. Partial purification was attempted with chromatography (Biotage, silica, 50% EtOAc/petrol to 20% MeOH/EtOAc). The crude product (0.60 g, 34%) was used in the next step without further purification. Rf=0.05 (50:50 EtOAc:petrol). mp=188-190 C. lambdamax (CH3OH)/nm=260. IR: 706, 749, 785, 843, 901, 958, 987, 1003, 1090, 1166, 1254, 1395, 1487, 1562, 1586, 1671, 1770, 2855, 2924, 3398 cm-1.1H NMR: (300 MHz, MeOD) delta 7.27-7.32 (dd AB, J=8.5 Hz, 2H, CC2H2C2H2C(Cl)), 7.39-7.42 (m, 1H, CHC(F)C(Cl)), 7.60-7.66 (dd AB, J=8.5 Hz, 2H, CC2H2C2H2C(Cl)), 8.17 (d, J=8.30 Hz, 1H, CHCHC(F)C(Cl), 13.60 (br s, 1H, CO2H). 13C NMR (MeOD, 75 MHz), delta 119.90, 124.16, 132.022, 132.46, 133.89, 134.91, 135.87, 139.02, 163.04, 165.05, 197.46. LCMS (DMSO): RT=3.43 min (on 5 min column), m/z=311 ES-.
With NHC-Pd(II)-Im; tetrabutyl ammonium fluoride In toluene at 120℃; for 3h; Inert atmosphere;
General procedure for the NHC-Pd(II)-Im complex 1 catalyzed Hiyama reaction of aryl chlorides with aryltrimethoxysilanes
General procedure: Under N2 atmosphere, NHC-Pd(II)-Im 1 (1.0 mol%), dry toluene (2.0 mL), aryl chlorides 2 (0.81 mmol), aryltrimethoxysilanes 3 (2.0 equiv) and TBAF•3H2O (2.0 equiv) were successively added into a Schlenk reaction tube. Then the tube was placed in a 120 °C oil bath and stirred for 3 h. The mixture was then allowed to cool to room temperature, diluted with ethyl acetate and washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and then purified by flash chromatography to give the pure products 4.
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82% yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil.
Example 10: Borylation with tetrakis - aryl chlorides KOAc (1.84 g, 18.8 mmol, 3.0 eq.), neopentyl glycol (1.56 g, 15.0 mmol, 2.4 eq.) and tetrakis (1 .48 g, 7.50 mmol, 1 .2 eq.) were suspended in toluene (25 ml) and heated to 80C for 30 min. Afterwards a solution of the corresponding aryl chloride (see Table 9) and Pd-catalyst (see Table 9) in toluene (5 ml) was added and stirred at 80C for 22 h. The conversion of the reaction was followed by GC. The final product was identified by its mass using GC-MS-technology. Table 9: Borylation of arylchlorides3'a> other Pd-catalysts (2 mol-%) gave lower yields: Pd(PPh3)4: 18.1 % after 22 h; PdC (dppf): 55.3%.- after 22 h.Table 10: Retention times of aryl chlorides and their borylation products
With (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; palladium diacetate; caesium carbonate; In dimethyl sulfoxide; at 130℃; for 12h;
General procedure: Alkynyl carboxylic acid (1.0 mmol), aryl chloride (1.0 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), L5 (17.5 mg, 0.03 mmol), Cs2CO3 (391 mg, 2.4 mmol), and DMSO (5.0 mL) were added to the reaction vial. The mixture was stirred at 130 C for 12 h, after which the mixture was extracted with Et2O and the organic layer was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the crude product, which was purified by column chromatography on silica gel.
Stage #1: Methyl 4-chlorobenzoate With tetrahydroxydiboron; 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); N-ethyl-N,N-diisopropylamine; triphenylphosphine In ethanol at 20℃; for 12h; Inert atmosphere; Sealed tube;
Stage #2: With potassium hydrogen difluoride In methanol; ethanol; water at 0 - 20℃; for 0.5h;
With palladium diacetate; sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 24h;
General procedure for the Suzuki reaction of aryl halide witharylboronic acids
General procedure: A mixture of aryl halide (1 mmol), arylboronic acid (1.5 mmol), Pd(OAc)2 (for aryl bromide 1 mol%, for aryl chloride 2 mol%), and Na2CO3 (2 mmol) was stirred in the mixture of H2O/DMF (3.5: 3 mL) at suitable temperature for indicated time in air. The reaction mixture was cooled to room temperature, and extracted by Et2O (10 mL) for three times. And then the organic phase was combined and evaporated under reduced pressure. The residue was purified on a silica gel (300-400 mesh) column to afford the desired product.
A solution of 1,10-carbonyldiimidazole (130 g,0.81 mol), isonicotinic acid (100 g, 0.81 mol) and DMF (300 mL) was heated at 40 C for 2.5 h before aniline (100 g, 0.81 mol) was added in a single portion. After 20 h, water (1.2 L) was added. The resulting suspension was filtered andthe solids dried under vacuum to afford isonicotinanilide (39) (142.6 g, 89%).
In an acetone/dry ice bath, a solution of isonicotinanilide (39) (150 g, 0.76 mol) and TMEDA (228 mL, 1.51 mol) in THF (2.25 L) was maintained at 45 C whileit was treated with 2.37 M n-BuLi in hexane (637 mL, 1.51 mol), stirred for 1hour, treated with a solution of methyl 4-chlorobenzoate (129.1 g, 1.51 mol) inTHF (260 mL) and finally stirred for a further 1.5 h. Water (750 mL) was slowlyadded and the biphasic mixture allowed to warm to room temperature withstirring for 18 h. While cooling in ice/water, the aqueous layer was adjusted topH 7 by addition of HCl (conc., 300 mL). The organic layer was washed withwater (650 mL), concentrated to 1 L and filtered. The solid was dried undervacuum to afford 41 (62.9 g, 25%). Further concentration of the filtrate andwashing with isopropanol (150 mL) yielded additional product (70 g, 28%).
General procedure: A mixture of 2-oxoacids 2/2-oxoaldehydes 3/2-oxoesters 4 (0.5mmol), oxone (1.25mmol) and alcohol (1.5mL) in round bottomed flask was stirred at 65C. After completion of the reaction that was confirmed by thin layer chromatography, the crude mixture was cooled to room temperature, filtered and purified by column chromatography using silica gel (100-200 ) with ethyl acetate and hexane as an eluent to afford the desired product 5 in 70-99 % yields.
With potassium phosphate tribasic hydrate; NiIICl(1-naphthyl)(tricyclohexylphosphine)2; tricyclohexylphosphine; In tetrahydrofuran; at 23℃; for 4h;Inert atmosphere; Glovebox; Sealed tube;
General procedure: Cross-Coupling of ortho-, meta-, and para-Substituted, Electron-Rich and Electron-Deficient Aryl Halides and Aryl Mesylates with Aryl Neopentylglycolboronates Catalyzed by NiIICl(1-naph-thyl)(PCy3)2/PCy3 in Anhydrous THF at 23 C; General Procedure 2In an oven-dried test tube charged with a Teflon coated stirring barwere added aryl halide or aryl mesylate (0.3 mmol), aryl neopentyl-glycolboronates (0.315 mmol), K3PO4(H2O)3.2 (191.00 ± 1.00 mg, 0.9mmol), and NiIICl(1-naphthyl)(PCy3)2 (11.73 ± 0.0510 mg, 0.015mmol, 5% catalyst loading). The test tube was brought into a N2 filledglove box (moisture level <2 ppm) through three degassing cycles andPCy3 (8.4 mg, 0.03 mmol, 10% loading) ligand was added. Distilled sol-vent (1 mL) was added inside the glove box and the test tube wassealed by a rubber septum and left stirring at 23 C. A sample was tak-en by syringe and transferred outside the glove box. The sample wasdiluted by distilled THF (0.2 mL) and filtered through a short columnof Al2O3. The filtrate was concentrated and the GC analysis was car-ried out. The reaction mixture was diluted with CH2Cl2 (2 mL), filteredthrough a layer of Al2O3, and washed with CH2Cl2 (3 1 mL). The fil-trate was collected and concentrated under vacuum. The crude prod-uct was purified by column chromatography on silica gel with EtO-Ac/hexane mixture as eluent. The reductive elimination side-productwas also isolated and characterized.
With potassium phosphate tribasic hydrate; Ni<SUP>II</SUP>Cl(1-naphthyl)(tricyclohexylphosphine)<SUB>2</SUB>; tricyclohexylphosphine In tetrahydrofuran at 23℃; for 4h; Inert atmosphere; Glovebox; Sealed tube;
Cross-Coupling of ortho-, meta-, and para-Substituted, Electron-Rich and Electron-Deficient Aryl Halides and Aryl Mesylates with Aryl Neopentylglycolboronates Catalyzed by NiIICl(1-naph-thyl)(PCy3)2/PCy3 in Anhydrous THF at 23 °C; General Procedure 2
General procedure: Cross-Coupling of ortho-, meta-, and para-Substituted, Electron-Rich and Electron-Deficient Aryl Halides and Aryl Mesylates with Aryl Neopentylglycolboronates Catalyzed by NiIICl(1-naph-thyl)(PCy3)2/PCy3 in Anhydrous THF at 23 °C; General Procedure 2In an oven-dried test tube charged with a Teflon coated stirring barwere added aryl halide or aryl mesylate (0.3 mmol), aryl neopentyl-glycolboronates (0.315 mmol), K3PO4(H2O)3.2 (191.00 ± 1.00 mg, 0.9mmol), and NiIICl(1-naphthyl)(PCy3)2 (11.73 ± 0.0510 mg, 0.015mmol, 5% catalyst loading). The test tube was brought into a N2 filledglove box (moisture level <2 ppm) through three degassing cycles andPCy3 (8.4 mg, 0.03 mmol, 10% loading) ligand was added. Distilled sol-vent (1 mL) was added inside the glove box and the test tube wassealed by a rubber septum and left stirring at 23 °C. A sample was tak-en by syringe and transferred outside the glove box. The sample wasdiluted by distilled THF (0.2 mL) and filtered through a short columnof Al2O3. The filtrate was concentrated and the GC analysis was car-ried out. The reaction mixture was diluted with CH2Cl2 (2 mL), filteredthrough a layer of Al2O3, and washed with CH2Cl2 (3 1 mL). The fil-trate was collected and concentrated under vacuum. The crude prod-uct was purified by column chromatography on silica gel with EtO-Ac/hexane mixture as eluent. The reductive elimination side-productwas also isolated and characterized.
With dicyclohexyl(2',4',6'-triisopropyl-[1,1':3',1''-terphenyl]-2-yl)phosphane; tetrabutylammomium bromide; palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h;
3-(4-chlorophenyl)-1,1-difluoro-1H-benzo[4,5]oxazolo[3,2-c][1,3,2]oxazaborinine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
NaH (60percent, 0.28 g, 7.03 mmol) was added to a solution of 2-methylbenzoxazole (0.61 mL, 7.03 mmol) in dry THF (30 mL) at 0 °C. Then, methyl 4-chlorobenzoate (1.12 g, 8.44 mmol) was added and the mixture was stirred at room temperature for 30 min. After that, the mixture was refluxed under an atmosphere of nitrogen for 24 h and cooled to room temperature and acidified with HCl (0.1 mol/L). A white cotton-like solid was collected by filtration and dried under vacuum. The intermediate of beta-ketoiminate was not purified and dissolved in DCM (30 mL), in which boron trifluoride ether complex (0.93 mL, 7.80 mmol) and triethylamine (1.09 mL 7.80 mmol) were added. The mixture was refluxed under an atmosphere of nitrogen for another 2 h. After that, the mixture was poured into water (200 mL), and was extracted with DCM, followed by dried over anhydrous Na2SO4. After removal of the solvent, the crude product was purified by column chromatography (silica gel) using petroleum ether/ethyl acetate (v/v = 5/1) as eluate to afford CBO (1.76 g) as a white solid in 76percent yield. m.p.: 250 °C (obtained from DSC); 1H NMR (400 MHz, DMSO-d6) delta 8.13 (d, J = 8.0 Hz, 2H), 7.96-7.94 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.60-7.57 (m, 2H), 7.25 (s, 1H) (Fig. S10). 13C NMR (100 MHz, DMSO-d6) delta 169.33, 164.94,148.50, 137.90, 131.94, 130.07, 129.57, 129.29, 127.45, 126.99,114.94, 112.53, 82.56 (Fig. S11). FT-IR (KBr, cm?1) nu 659, 697, 724,740, 752, 786, 838, 886, 1008, 1034, 1092, 1115, 1132, 1171, 1222,1270, 1280, 1297, 1339, 1372, 1394, 1421, 1462, 1487, 1554, 1593,1630. MALDI-TOF MS: m/z: calculated for C15H9O2NBF2Cl: 319.5;found: 320.9 ([M+H]+) (Fig. S12). Elemental analysis (percent): C 56.39, H2.84, N 4.38; found: C 56.29, H 3.13, N 4.32.
Typical alcoholysis procedure.
General procedure: A mixture of the amide (1, 1 mmol), alcohol (15 mL), and pulverized potassium bisulfate (1.1 g, 8 mmol) was refluxed for the specified time. The alcohol was removed in vacuo and the residue was triturated with hexanes (or other appropriate solvent such as DCM or ethyl acetate to dissolve the product). Removal of hexanes in vacuo provided the following pure products
With nickel(II) bromide dimethoxyethane; pyridine-2,6-bis(N-cyanocarboxamidine); lithium chloride; zinc In 1-methyl-pyrrolidin-2-one at 80℃; for 24h; Inert atmosphere;
With N-iodo-succinimide; 1,10-Phenanthroline; oxygen; potassium carbonate; copper dichloride In dimethyl sulfoxide at 140℃; for 12h; Molecular sieve;
General procedure for aerobic esterification
General procedure: In a typical experiemnt, 0.2 mmol alcohol substrate, 100 μL MeOH, 0.08 mmol CuCl2 ,0.08 mmol phen, 0.4 mmol NIS, 1 mmol K2CO3, 100 mg 4Å, 0.2 mmol n-decane asinternal standard, and 2 mL DMSO were added into a Teflon-lined stainless-steelreactor, followed by chaging 0.5 MPa O2. Then the mixture was heated to 140 °C for adesired period of time. After reaction, the reactor was quenched in ice-water bath,followed by addition of sodium hyposulfide, and extraction using ethyl acetate andsaturated aqueous NH4Cl to separate the products. Subsequently, the organic matterwas extracted with ethyl acetate twice, and combined for qualitative and quantitativeanalysis. For aerobic oxidative conversion of eucalyptus lignin, 40 mg eucalyptus lignin, 100 μLMeOH, 0.08 mmol CuCl2 , 0.08 mmol phen, 0.4 mmol NIS, 1 mmol K2CO3, 100 mg4Å, and 2 mL DMSO-d6 were added into a Teflon-lined stainless-steel reactor, followedby charging 5 MPa O2. After reaction, the reaction mixture was concentrated in vacuoto remove the excess MeOH before 2D Short-range 13C-1H correlation (HSQC)measurement.
93 %Chromat.
With oxygen; potassium carbonate at 150℃; for 24h; Autoclave;
86 %Chromat.
With oxygen; potassium carbonate at 130℃; for 12h; Autoclave;
12 Example 12
Add Co-NC (5mol%), 1-(4-chlorophenyl)-1-ethanol (1mmol), K2CO3 (20mol%), and 4mL methanol to a 25mL polytetrafluoroethylene lined autoclave and seal it. Fill the reactor with oxygen pressure to 0.4MPa, put the reactor into an oil bath at 130°C, and stir for 12h at 400 speed. After the reaction, the reactor is cooled to room temperature, the reactor is opened, and the internal standard biphenyl (60mg ), the qualitative products were detected by gas chromatography-mass spectrometry, and the yields of the substrate 1-(4-chlorophenyl)-1-ethanol and the product methyl 4-chlorobenzoate by gas chromatography internal standard method are shown in Table 1.
With N-iodo-succinimide; 1,10-Phenanthroline; oxygen; potassium carbonate; copper dichloride In dimethyl sulfoxide at 140℃; for 24h; Molecular sieve;
General procedure for aerobic esterification
General procedure: In a typical experiemnt, 0.2 mmol alcohol substrate, 100 μL MeOH, 0.08 mmol CuCl2 ,0.08 mmol phen, 0.4 mmol NIS, 1 mmol K2CO3, 100 mg 4Å, 0.2 mmol n-decane asinternal standard, and 2 mL DMSO were added into a Teflon-lined stainless-steelreactor, followed by chaging 0.5 MPa O2. Then the mixture was heated to 140 °C for adesired period of time. After reaction, the reactor was quenched in ice-water bath,followed by addition of sodium hyposulfide, and extraction using ethyl acetate andsaturated aqueous NH4Cl to separate the products. Subsequently, the organic matterwas extracted with ethyl acetate twice, and combined for qualitative and quantitativeanalysis. For aerobic oxidative conversion of eucalyptus lignin, 40 mg eucalyptus lignin, 100 μLMeOH, 0.08 mmol CuCl2 , 0.08 mmol phen, 0.4 mmol NIS, 1 mmol K2CO3, 100 mg4Å, and 2 mL DMSO-d6 were added into a Teflon-lined stainless-steel reactor, followedby charging 5 MPa O2. After reaction, the reaction mixture was concentrated in vacuoto remove the excess MeOH before 2D Short-range 13C-1H correlation (HSQC)measurement.
Stage #1: 2,5-Dihydroxyacetophenone With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 10℃; for 3h; Inert atmosphere;
Stage #2: Methyl 4-chlorobenzoate In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
5.2 General procedure for the synthesis of 12a-e
General procedure: A solution of LiHMDS in THF (1M, 4 equiv) was added to a well-stirred solution of 2,5-dihydroxyacetophenone (9, 1 equiv) in anhydrous THF (20mL) under argon at-78°C over 15min. The reaction mixture was stirred at-78°C for 1h and at-10°C for 2h and was cooled again to-78°C, and a solution of 10a-e (1 equiv) in THF (5mL) was added in one portion. The mixture was stirred at-78°C for 1h and at room temperature overnight. The reaction mixture was poured into a mixture of ice and neutralized with conc. HCl (6.5mL) and extracted with dichloromethane. The combined organic layer was washed with brine and dried over sodium sulfate, filtered, and evaporated to give crude 11a-e. Crude 11a-e were dissolved in glacial acetic acid (20mL) and concentrated sulfuric acid (0.2mL). The reaction was stirred at room temperature for 4h. H2O (20mL) was added to the reaction mixture, and the resulting solid was filtered, washed with water, and dried to afford 12a-e.
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