* 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.
Reference：
[1] Synthesis, 2008, # 14 SPEC. ISS., p. 2199 - 2210
[2] Journal of the American Chemical Society, 2014, vol. 136, # 13, p. 4881 - 4884
[3] Inorganic Chemistry, 2015, vol. 54, # 16, p. 7873 - 7884
6
[ 3132-99-8 ]
[ 882772-99-8 ]
Yield
Reaction Conditions
Operation in experiment
48%
at 0 - 20℃; for 1.33333 h;
A solution of nitric acid (0.6mL), and concentrated sulfuric acid (8.1mL), was stirred at 0°C, then 6a (3.0g, 0.11mmol) was added over a period of 20min. The mixture was stirred at rt for 1h and then poured into ice. The white solid formed was filtered and washed with water. The crude product was purified by flash chromatography (1:4, EtOAc/n-hexane) to obtain title compound as white solid (yield 48percent). 1H NMR (300MHz, CDCl3) δ 7.60 (t, J=7.5Hz, 1H), 7.92 (d, J=2.4Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 9.87 (s, 1H).
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 70, p. 233 - 247
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 28, p. 5113 - 5118
7
[ 1261475-45-9 ]
[ 882772-99-8 ]
Yield
Reaction Conditions
Operation in experiment
67.7%
With manganese(IV) oxide In 1,2-dichloro-ethaneReflux
14.0 g of 3-bromo-2-nitrobenzyl alcohol and 150 mL of 1,2-dichloroethane were placed in a three-necked flask, and 42.0 g of manganese dioxide was added thereto, followed by heating to reflux. After the reaction was completed, it was added to Celite, and the filtrate was concentrated.Column was isolated to give 9.4 g (67.7percent) of 3-bromo-2-nitrobenzaldehyde.
With titanium(IV) tetraethanolate In tetrahydrofuran at 70℃; for 1h;
232
To a solution of 3-bromo-2-nitrobenzaldehyde (Tetrahedron 2008, 64, 856-865) (1.5 g, 6.5 mmol, 1.0 equiv) and (5)-2-methylpropane-2-sulfnamide (1.2 g, 9.8 mmol, 1.5 equiv) in THF (5.0 niL) was added Ti(OEt)4 (4.1 niL, 19.6 mmol, 3.0 equiv) and the resultant mixture was heated to 70 0C for 1 hour. After cooled at room temperature, the mixture was and poured into a solution of brine with rapid stirring. The resulting suspension was filtered and washed with EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried (over Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (heptane/EtOAc, 1/1) to give product 1.6 g. MS: 335 [M+H+].
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 4h;
A15.a
Example Al 5 a) Preparation of intermediate 35Sodium triacetoxyborohydride (1.17 g, 5.5 mmol) was added portionwise to a stirring solution of intermediate 20 (0.8 g, 3.69 mol), 4-fluorobenzylamine (0.46 g, 3.69 mmol) and AcOH (1.1 g, 18.48 mmol) in 1 ,2-dichloroethane (12 ml). The r.m. was stirred at r.t. for 4 h, washed with an aq. K2CO3 solution and brine. The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography over silica gel (eluent: n-heptane/DCM from 30/70 up to 0/100). The product fractions were collected and the solvent was evaporated. Yield: 0.70 g of intermediate 35 (41 %).
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 3h;
41%
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 4h;
A8.c
c) Preparation of intermediate 21Sodium triacetoxyborohydride (1.38 g, 6.5 mmol) was added portionwise to a stirring solution of intermediate 20 (1.0 g, 4.34 mol), 3-methoxyaniline (0.53 g, 4.34 mmol) and acetic acid (1.3 g, 21.7 mmol) in 1,2-dichloroethane (16 ml). The r.m. was stirred at r.t. for 4 h, washed with an aqueous K2CO3 solution and brine. The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography over silica gel (eluent: n-heptane/DCM isocratic 50/50). The product fractions were collected and the solvent was evaporated. Yield: 0.65 g of intermediate 21 (41 %).
With sodium periodate In water; N,N-dimethyl-formamide at 0 - 20℃; for 3h;
A8.b
b) Preparation of intermediate 20The crude solution from the previous reaction step, containing intermediate 19, was dropwise added at 0 0C to a stirring solution of sodium periodate (29.7 g, 139 mmol) in DMF (75 ml) and H2O (100 ml). The r.m. was then allowed to warm to r.t. and was stirred for 3 h. The suspension was filtered over diatomaceous earth which was extensively washed with EtOAc. The filtrate was washed with H2O and the organic phase was concentrated under reduced pressure. The residue was purified by chromatography over silica gel (eluent: n-heptane/DCM from 50/50 to 0/100). The product fractions were collected and the solvent was evaporated. Yield: 2.72 g of intermediate 20 (20 % yield over two reaction steps).
With sodium periodate In water; N,N-dimethyl-formamide at 0 - 20℃;
With sulfuric acid; nitric acid at 0 - 20℃; for 1.33333h; regioselective reaction;
4.1.2 3-Bromo-2-nitrobenzaldehyde (7a)
A solution of nitric acid (0.6mL), and concentrated sulfuric acid (8.1mL), was stirred at 0°C, then 6a (3.0g, 0.11mmol) was added over a period of 20min. The mixture was stirred at rt for 1h and then poured into ice. The white solid formed was filtered and washed with water. The crude product was purified by flash chromatography (1:4, EtOAc/n-hexane) to obtain title compound as white solid (yield 48%). 1H NMR (300MHz, CDCl3) δ 7.60 (t, J=7.5Hz, 1H), 7.92 (d, J=2.4Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 9.87 (s, 1H).
83 g
With sulfuric acid; nitric acid at 5 - 10℃; for 1.16667h;
With toluene-4-sulfonic acid Microwave irradiation;
4.1.4 2-(3-Bromo-2-nitrophenyl)-1,3-dioxolane (8a)
A mixture of 7a (45mg, 0.20mmol), ethylene glycol (163μL, 2.93mmol), and PTSA (29.30mmol) was submitted to MW irradiation. The reaction mixture was cooled to rt and water (1mL) was added. The aqueous phase was extracted with DCM (3×5mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (1:4, EtOAc/n-hexane) to obtain title compound as a colorless oil (yield 52%). 1H NMR (300MHz, CDCl3) δ 3.99 (s, 4H), 5.98 (s, 1H), 7.36 (t, J=8.1Hz, 1H), 7.60 (d, J=7.8Hz, 1H), 7.64 (d, J=8.1Hz, 1H).
With sodium tetrahydroborate; In tetrahydrofuran; water; at 25℃; for 0.333333h;
Sodium borohydride (37 mg, 0.98 mmol) was added to a solution of 3 (105 mg, 0.46 mmol) in THF (3mL) and H2O (1 mL). The resulting solution was stirred at ambient temperature (20 min), water was added (20 mL), and the mixture was extracted with EtOAc (320 mL). The combined organic phases were dried (MgSO4) and filtered, and the solvents were removed under reduced pressure to give 9 (87 mg, 0.37 mmol, 81%) as a pale yellow oil. No further purification was required. Spectral data were in accordance with literature data.
tert-butyl (R)-3-((3-bromo-2-nitrobenzyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.53 g
Stage #1: 3-bromo-2-nitrobenzaldehyde; (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester With acetic acid In dichloromethane at 20℃; for 0.5h;
Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 0 - 20℃; for 16h;
77.a Step a.
To a solution of 3-bromo-2-nitrobenzaldehyde (0.35 g, 1.52 mmol) in DCM (15 ml) was added acetic acid (10 drop) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (0.28 g, 1.52 mmol) at rt and stirred for 30 mm. The resulting reaction mixture was cooled to 0°C and treated with sodum triacetoxyborohydride (0.97 g, 4.58 mmol) in equal portions. The reaction mixture was stirred at rt for5 16 h. The resulting mixture was neutralized by saturated aqueous NaHCO3 solution (100 ml) and extracted with DCM (3 x 30 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (50-100% EtOAc in hexane) yielding tert-butyl (R)-3 -((3 -bromo-2-nitrobenzyl) amino) pyrrolidine-1-carboxylate (0.53 g, 1.32 mmol). LCMS: Method C, 1.93 mi MS: ES+ 344.6,10 346.30 [M-56j.
tert-butyl (R)-3-((2-amino-3-morpholinobenzyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 3 steps
1.1: acetic acid / dichloromethane / 0.5 h / 20 °C
1.2: 16 h / 0 - 20 °C
2.1: 16 h / 110 °C
3.1: acetic acid; iron / tetrahydrofuran; water / 1 h / 100 °C
tert-butyl (R)-3-(8-morpholino-2,2-dioxido-1,4-dihydro-3H-benzo[c][1,2,6]thiadiazin-3-yl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 4 steps
1.1: acetic acid / dichloromethane / 0.5 h / 20 °C
1.2: 16 h / 0 - 20 °C
2.1: 16 h / 110 °C
3.1: acetic acid; iron / tetrahydrofuran; water / 1 h / 100 °C
4.1: pyridine; SULFAMIDE / 48 h / 125 °C
With manganese(IV) oxide; In 1,2-dichloro-ethane;Reflux;
14.0 g of <strong>[1261475-45-9]3-bromo-2-nitrobenzyl alcohol</strong> and 150 mL of 1,2-dichloroethane were placed in a three-necked flask, and 42.0 g of manganese dioxide was added thereto, followed by heating to reflux. After the reaction was completed, it was added to Celite, and the filtrate was concentrated.Column was isolated to give 9.4 g (67.7%) of 3-bromo-2-nitrobenzaldehyde.
tert-butyl ((2-methyl-3,4-dihydroquinazolin-8-yl)methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 5 steps
1.1: iron; hydrogenchloride / water; ethanol / 3 h / 80 °C
2.1: sodium carbonate / ethanol / 96 h / 120 °C
3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 2.5 h / 160 °C / Microwave irradiation
4.1: hydrogen; ammonia / methanol; water / 2 h / 20 °C
5.1: sodium hydroxide / 1,4-dioxane / 72 h / 20 °C
5.2: 3 h / 60 °C
4-bromo-3-(2,2,2-trifluoroacetyl)-1H-indole-7-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 3 steps
1.1: toluene-4-sulfonic acid / toluene / 16 h / Reflux
2.1: tetrahydrofuran / 0.75 h / -45 °C
2.2: 0.75 h / 20 °C
3.1: N,N-dimethyl-formamide / 16 h
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