* 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.
A mixture of 1 , 1 ,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-lH-pyrazole (25 g, 89percent yield). 1H NMR (400 MHz, OMSO-Cl6): δl.n (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
89%
With hydrogenchloride In ethanol; waterReflux
A mixture of 1,1,3,3-tetramethoxypropane (3.7 g, 22.6 mmol), tert-butylhydrazinehydrochloride (2.8 g, 22.6 mmol), and conc. HCl (6 mL, 72 mmol) in EtOH (30 mL) was heated at reflux overnight. The reaction mixture was poured into water and the resulting mixture wasextracted with ether (30 mL x 3). The combined organics was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to afford 1-tert-butyl-1H-pyrazole as awhite solid (2.5 g, 89percent). MS (ESI) m/z: 125 [M+H].
72%
Stage #1: With hydrogenchloride In ethanol; water at 50℃; for 2 h; Reflux; Industry scale Stage #2: With sodium hydroxide In water
To a mixture of 1 ,1 ,3,3-tetramethoxypropane (3.82kg, 23.27mol) and tert- butylhydrazine hydrochloride (2.9kg, 23.27mol) in ethanol (24.54kg), cone HCI (4.72kg ,46.55mol) was added, keeping the temperature below 50°C. The reaction mixture was then rapidly heated to reflux. After ca. 2h the reaction was sampled and analysed by NMR. Pass criteria was <3.0percent starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29kg) and evaporated in vacuo (T<50°C, p<-0.08MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (1 1 .1 1 kgx2) and the organic phase washed with saturated ammonium chloride solution (4.3ml/g x 2) and brine (4.3ml/g), then evaporated to give the title compound (2.08kg, 72percentyield) as a brown liquid (GC purity 99.70percenta/a).
72%
With hydrogenchloride In ethanol; water at 50℃; for 0.2 h; Reflux; Industrial scale
Stage a) Preparation of 1-(1,1-Dimethylethyl)-1H-pyrazole (Intermediate 9) To a mixture of 1,1,3,3-tetramethoxypropane (3.82 kg, 23.27 mol) and tert-butylhydrazine hydrochloride (2.9 kg, 23.27 mol) in ethanol (24.54 kg), conc HCl (4.72 kg, 46.55 mol) was added, keeping the temperature below 50° C. The reaction mixture was then rapidly heated to reflux. After ca. 2 h the reaction was sampled and analysed by NMR. Pass criteria was <3.0percent starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29 kg) and evaporated in vacuo (T<50° C., p<-0.08 MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (11.11 kg*2) and the organic phase washed with saturated ammonium chloride solution (4.3 ml/g*2) and brine (4.3 ml/g), then evaporated to give the title compound (2.08 kg, 72percent yield) as a brown liquid (GC purity 99.70percent a/a).
21.9 g
With hydrogenchloride In ethanol for 2 h; Reflux
To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and 26.20 g tert.butyihydrazine hydrochloride in 230 mL ethanol was added 40.0 mL conc. hydrochloric acid dropwise below 50 00, then the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with water. The solvent was almost removed by destillation and the aqueous residue extracted with diethylether. The combined aqueous phases were basified with iON sodium hydroxide solution and extracted with diethylether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 0.412 mm (method A), M+H = 125
Reference：
[1] Bulletin de la Societe Chimique de France, 1986, # 1, p. 129 - 132
3
[ 15754-60-6 ]
[ 70951-85-8 ]
Yield
Reaction Conditions
Operation in experiment
93.4%
With N-Bromosuccinimide In dichloromethane at 0 - 20℃; Industry scale
To an ice cooled solution (0°C to 10°C) of 1 -(tert-butyl)pyrazole (1.75kg, 14.09mol) in dichloromethane (12.9kg) was added NBS (2.63kg ,14.79mol) portionwise. The solution was stirred at 0°C until the content of 1-(ie f-butyl)pyrazole <30percent (GC), then warmed to RT and stirred until the sample taken shows <1.0percent by GC. On receipt of a pass result, 10percent sodium bisulfite aqueous was added to the reaction mixture until Kl-starch did not turn to blue. The organic phase was then washed with 5percent NaCI solution and brine in sequence, then evaporated to give the title compound as a brown liquid (2.67kg, 93.4percentyield; GC purity 99.1 percenta/a).
85%
With bromine; sodium carbonate In dichloromethane at 20℃;
To a suspension OfNa2CO3 (36 g, 339 mmol) in CH2Cl2 (300 mL) was added l-t- butyl-lH-pyrazoIe from Example B19 (21 g, 170 mmol) and Br2 (9 mL), and the resulting mixture was stirred at RT overnight. The solid was removed by Filtration and the filter cake was washed with CH2Cl2. The filtrates were washed with water and brine, dried (MgSO4), and concentrated to give crude 4-bromo-l- λ-butyl-lH-pyrazole (29 g, 85percent), used without further purification. 1H NMR (300 MHz, CDC13): δ 7.49 (s, 1 H), 7.45 (s, 1 H), 1.53 (s, 9 H); MS (ESI) m/z: 203 [M+H]+.
85%
With sodium carbonate decahydrate; bromine In dichloromethane at 20℃;
To a suspension of Na2CO3 (3.6 g, 33.9 mmol) in CH2Cl2 (30 mL) was added 1-tert-butyl-1H-pyrazole (2.1 g, 17 mmol) and Br2 (0.9 mL). The mixture was stirred at roomtemperature overnight. The formed solid was removed by filtration and the filter cake waswashed with CH2Cl2 (30 mL). The filtrates were washed with water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude 4-bromo-1-tert-butyl-1H-pyrazole (2.9 g, 85percent), which was used in next step without further purification. MS (ESI)m/z: 203 [M+H]+.
7.402 g
With N-Bromosuccinimide In dichloromethane at 20℃; for 18 h;
Intermediate 10: 4-Bromo-1-(1,1-dimethylethyl)-1H-pyrazole[0393]1-(1,1-dimethylethyl)-1H-pyrazole (6.1 g, 49.1 mmol) in dichloromethane (DCM) (200 ml) was added N-bromosuccinimde (8.74 g, 49.1 mmol). This was warmed to ambient temperature and stirred for 18 h. There was no starting material present and so the reaction mixture was quenched with aqueous sodium thiosulfate. The organics were washed with water (2×500 ml) and passed through a hydrophobic frit. The filtrate was concentrated in vacuo to yield an orange-brown oil which turned purple on standing (7.402 g).[0395]LCMS (Method B): Rt=1.03 min, MH+=203, 205
34 g
With N-Bromosuccinimide In dichloromethane at 0 - 10℃; for 0.5 h;
To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 mL DOM was added 31.5 g Nbromosuccinimide in portions between 0 and 10 00 The resulting mixture was stirred for 30 mm. The reaction mixture was allowed to reach ambient temperature. The precipitate was filtered off and washed with DOM. The combined organic extracts were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 34.0 g of 4-bromo-1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 1 .35 mm (method B), M+H = 203 I 205
Example 12 As in Example 2, the column was charged with 30 g of glass rings of diameter 3 mm, 16.4 g (0.24 mol) of pyrazole and 1.02 g (0.01 mol) of 96% by weight sulfuric acid, heated to 195 C. and reacted over the course of 7 hours with 703 g (9.5 mol) of tert-butanol vaporized at 180 C. 21.7 g of N-tert-butylpyrazole were obtained, boiling point 103 C., with a content of 99.4% (GC), which corresponds to a yield of 72.5%.
Example 14 6.8 g (0.1 mol) of pyrazole, 23.7 g (0.32 mol) of tert-butanol and 0.51 g (0.005 mol) of 96% by weight sulfuric acid were stirred in an autoclave at 200 C. and 35 bar for 3 hours. After cooling, decompression (expulsion of isobutylene) and phase separation, 6.5 g of an aqueous pyrazole solution, which was 10.2% by weight according to GC analysis, were obtained, and distillation thereof yielded 0.66 g of pyrazole. 10.5 g (83.6%) of N-tert-butylpyrazole were obtained from the organic phase, boiling point 102 C., with a content of 98.8% (GC).
4
[ 102-52-3 ]
[ 7400-27-3 ]
[ 15754-60-6 ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrogenchloride; In ethanol;Heating / reflux;
A mixture of 1 , 1 ,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-lH-pyrazole (25 g, 89% yield). 1H NMR (400 MHz, OMSO-Cl6): deltal.n (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
89%
With hydrogenchloride; In ethanol; water;Reflux;
A mixture of 1,1,3,3-tetramethoxypropane (3.7 g, 22.6 mmol), tert-butylhydrazinehydrochloride (2.8 g, 22.6 mmol), and conc. HCl (6 mL, 72 mmol) in EtOH (30 mL) was heated at reflux overnight. The reaction mixture was poured into water and the resulting mixture wasextracted with ether (30 mL x 3). The combined organics was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to afford 1-tert-butyl-1H-pyrazole as awhite solid (2.5 g, 89%). MS (ESI) m/z: 125 [M+H].
72%
To a mixture of 1 ,1 ,3,3-tetramethoxypropane (3.82kg, 23.27mol) and tert- butylhydrazine hydrochloride (2.9kg, 23.27mol) in ethanol (24.54kg), cone HCI (4.72kg ,46.55mol) was added, keeping the temperature below 50C. The reaction mixture was then rapidly heated to reflux. After ca. 2h the reaction was sampled and analysed by NMR. Pass criteria was <3.0% starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29kg) and evaporated in vacuo (T<50C, p<-0.08MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (1 1 .1 1 kgx2) and the organic phase washed with saturated ammonium chloride solution (4.3ml/g x 2) and brine (4.3ml/g), then evaporated to give the title compound (2.08kg, 72%yield) as a brown liquid (GC purity 99.70%a/a).
72%
With hydrogenchloride; In ethanol; water; at 50℃; for 0.2h;Reflux; Industrial scale;
Stage a) Preparation of 1-(1,1-Dimethylethyl)-1H-pyrazole (Intermediate 9) To a mixture of 1,1,3,3-tetramethoxypropane (3.82 kg, 23.27 mol) and tert-butylhydrazine hydrochloride (2.9 kg, 23.27 mol) in ethanol (24.54 kg), conc HCl (4.72 kg, 46.55 mol) was added, keeping the temperature below 50 C. The reaction mixture was then rapidly heated to reflux. After ca. 2 h the reaction was sampled and analysed by NMR. Pass criteria was <3.0% starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29 kg) and evaporated in vacuo (T<50 C., p<-0.08 MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (11.11 kg*2) and the organic phase washed with saturated ammonium chloride solution (4.3 ml/g*2) and brine (4.3 ml/g), then evaporated to give the title compound (2.08 kg, 72% yield) as a brown liquid (GC purity 99.70% a/a).
21.9 g
With hydrogenchloride; In ethanol; for 2.0h;Reflux;
To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and 26.20 g tert.butyihydrazine hydrochloride in 230 mL ethanol was added 40.0 mL conc. hydrochloric acid dropwise below 50 00, then the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with water. The solvent was almost removed by destillation and the aqueous residue extracted with diethylether. The combined aqueous phases were basified with iON sodium hydroxide solution and extracted with diethylether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 0.412 mm (method A), M+H = 125
With nitric acid; In sulfuric acid; at 0℃; for 0.5h;
HNO3 (11.7 g, 185 mmol)was added dropwise to a mixture of 1-tert-butyHH-pyrazole (23 g, 185 mmol) in cone. H2SO4 (30 mL) at O0C. The resulting mixture was stirred at O0C for 30 min and was poured onto crashed ice. The aqueous mixture was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1- tert-butyI-4-nitro-lH-pyrazole (2Og, 64 % yield). 1H NMR (400 MHz, DMSO-rffi):
With N-Bromosuccinimide; In dichloromethane; at 0 - 20℃;Industry scale;Product distribution / selectivity;
To an ice cooled solution (0C to 10C) of 1 -(tert-butyl)pyrazole (1.75kg, 14.09mol) in dichloromethane (12.9kg) was added NBS (2.63kg ,14.79mol) portionwise. The solution was stirred at 0C until the content of 1-(ie f-butyl)pyrazole <30% (GC), then warmed to RT and stirred until the sample taken shows <1.0% by GC. On receipt of a pass result, 10% sodium bisulfite aqueous was added to the reaction mixture until Kl-starch did not turn to blue. The organic phase was then washed with 5% NaCI solution and brine in sequence, then evaporated to give the title compound as a brown liquid (2.67kg, 93.4%yield; GC purity 99.1 %a/a).
85%
With bromine; sodium carbonate; In dichloromethane; at 20℃;
To a suspension OfNa2CO3 (36 g, 339 mmol) in CH2Cl2 (300 mL) was added l-t- butyl-lH-pyrazoIe from Example B19 (21 g, 170 mmol) and Br2 (9 mL), and the resulting mixture was stirred at RT overnight. The solid was removed by Filtration and the filter cake was washed with CH2Cl2. The filtrates were washed with water and brine, dried (MgSO4), and concentrated to give crude 4-bromo-l- lambda-butyl-lH-pyrazole (29 g, 85%), used without further purification. 1H NMR (300 MHz, CDC13): delta 7.49 (s, 1 H), 7.45 (s, 1 H), 1.53 (s, 9 H); MS (ESI) m/z: 203 [M+H]+.
85%
With sodium carbonate decahydrate; bromine; In dichloromethane; at 20℃;
To a suspension of Na2CO3 (3.6 g, 33.9 mmol) in CH2Cl2 (30 mL) was added 1-tert-butyl-1H-pyrazole (2.1 g, 17 mmol) and Br2 (0.9 mL). The mixture was stirred at roomtemperature overnight. The formed solid was removed by filtration and the filter cake waswashed with CH2Cl2 (30 mL). The filtrates were washed with water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude 4-bromo-1-tert-butyl-1H-pyrazole (2.9 g, 85%), which was used in next step without further purification. MS (ESI)m/z: 203 [M+H]+.
7.402 g
With N-Bromosuccinimide; In dichloromethane; at 20℃; for 18.0h;
Intermediate 10: 4-Bromo-1-(1,1-dimethylethyl)-1H-pyrazole[0393]1-(1,1-dimethylethyl)-1H-pyrazole (6.1 g, 49.1 mmol) in dichloromethane (DCM) (200 ml) was added N-bromosuccinimde (8.74 g, 49.1 mmol). This was warmed to ambient temperature and stirred for 18 h. There was no starting material present and so the reaction mixture was quenched with aqueous sodium thiosulfate. The organics were washed with water (2×500 ml) and passed through a hydrophobic frit. The filtrate was concentrated in vacuo to yield an orange-brown oil which turned purple on standing (7.402 g).[0395]LCMS (Method B): Rt=1.03 min, MH+=203, 205
34 g
With N-Bromosuccinimide; In dichloromethane; at 0 - 10℃; for 0.5h;
To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 mL DOM was added 31.5 g Nbromosuccinimide in portions between 0 and 10 00 The resulting mixture was stirred for 30 mm. The reaction mixture was allowed to reach ambient temperature. The precipitate was filtered off and washed with DOM. The combined organic extracts were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 34.0 g of 4-bromo-1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 1 .35 mm (method B), M+H = 203 I 205
Flash vacuum pyrolysis reactions were carried out by distillation of the substrate in vacuo through an electrically heated silica furnace tube (35 × 2.5 cm). Products were trapped in a U-tube situated at the exit point of the furnace and cooled with liquid N2. Conditions were first established on a small scale (20 mg) where the product(s) were dissolved in a deuterated solvent and analyzed directly by 1H NMR spectroscopy. Larger-scale pyrolyses, involving 0.1 g or more of substrate, were usually removed from the trap by solution in CH2Cl2 (30mL). The precursors and pyrolysis conditions [quantity of precursor, inlet temperature (Ti), furnace temperature (Tf), pressure range (P), and pyrolysis time (t)] and yields are stated. This compound was too volatile for normal inlet conditions. It was therefore cooled in an acetone-dry ice bath, which was slowly removed to allow sublimation (20 mg, Ti acetone/dry ice bath, Tf 600-850 C, P 0.03 Torr, t 15 min).
With ammonium cerium (IV) nitrate; iodine; In acetonitrile; at 20℃; for 2.0h;
0481-1 Iodine (1.59 g) and ammonium cerium nitrate (3.45 g) were added to a solution of <strong>[15754-60-6]1-(tert-butyl)-1H-pyrazole</strong> (1.30 g) in acetonitrile (6 mL), followed by stirring at room temperature for 2 hours. After ethyl acetate and water were added to the reaction mixture, the organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(tert-butyl)-4-iodo-1H-pyrazole (487 mg). MS m/z (M+H): 251.
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