| 99% |
With triethylamine In tetrahydrofuran at 20℃; for 48h; |
Synthesis of 4-chloro-N-tert-butoxycarbonylaniline (1)
To a solution of 4-chloroaniline (1 g, 7.84 mmol) in dry tetrahydrofurane (THF) (65 mL), tert-butyl dicarbonate (1.88 g, 8.62 mmol) and triethylamine (872 mg, 1.2 mL, 8.62 mmol) were added. The reaction mixture was stirred at room temperature for 48 h, after then solvent was evaporated and ethyl acetate (300 mL) was added. The solution was washed with saturated NH4Cl (2 × 100 mL) and water (2 × 100 mL). The organic layer was dried over MgSO4, filtered and evaporated, obtaining a solid white showing spectral data according to 1 (yield 99%) (Roosen et al., 2012). It was used with no further purification. |
| 99% |
In neat (no solvent) at 80℃; for 0.166667h; Green chemistry; chemoselective reaction; |
General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80°C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions. |
| 99% |
In neat (no solvent, solid phase) at 80℃; for 0.166667h; |
2.1.1 1) Synthesis of (4-chlorophenyl)carbamic acid tert-butyl ester compound 14
The weighed p-chloroaniline (2 g, 16.3 mmol) was placed in a round bottom flask of appropriate size. An equivalent amount of di-tert-butyl dicarbonate (3.54 g, 16.3 mmol) was weighed into a flask. The mixed reactant was placed on a vacuum distillation apparatus and reacted at 80 ° C for 10 minutes. When the solid formation is completely completed, it is completed. Made directly without purification tert-Butyl (4-chlorophenyl)carbamate 14 (3.6 g, yield 99%). |
| 99% |
With sulfated polyborate In neat (no solvent) at 20℃; for 0.166667h; Sonication; Green chemistry; chemoselective reaction; |
1.2. Representative procedure for the synthesis of N-tert-butyl carbamate under ultrasonic irradiation.
General procedure: A mixture of amine (2 mmol) and Boc2O (2 mmol), and sulfated polyborate (10 wt%) was sonicated using 20 kHz frequency and 35W power at room temperature in 25mL round bottom flask for stipulated time (progress was monitored by TLC). After complete consumption of the starting materials (TLC), the reaction mixture was cooled to room temperature. The crude mixture was dissolved in the ethyl acetate and the insoluble catalyst was separated using simple filtration then dried and reused. The filtrate was washed with water, dried over sodium sulfate, and concentrated in vacuo to furnish the corresponding N-tert-butyl carbamate derivatives of amines in excellent (87-99%) yields. |
| 98% |
at 25 - 28℃; for 0.0833333h; ultrasound; |
|
| 98% |
With 1-n-butyl-3-methylimidazolium bistrifluoromethylsulfonylamide at 30 - 35℃; for 0.166667h; neat (no solvent); chemoselective reaction; |
|
| 98% |
In tetrahydrofuran at 20℃; for 12h; |
|
| 98% |
With sulfated tungstate 10 wt % In neat (no solvent) at 20℃; for 0.333333h; chemoselective reaction; |
2. General procedure for N-Boc protection of amines
General procedure: A mixture of amine (1mmol), (Boc)2O (1mmol) and sulfated tungstate (10wt%) was vigorously stirred at room temperature for appropriate time until complete disappearance of amines was observed in the TLC monitoring. After the completion of reactions, the reaction mixture was diluted with diethyl ether and the catalyst was isolated by simple filtration. After drying catalyst, it is reused for N-Boc protection of amines. The product was isolated in purified form by evaporating the diethyl ether at room temperature. After the evaporation of diethyl ether solvent, the pure products were obtained and no recrystallization or column chromatography was needed for the purification of products. |
| 98% |
With thiamine chloride hydrochloride In neat (no solvent) at 20℃; for 0.25h; |
General procedure for N-Boc protection of amines
General procedure: A mixture of amine (1 mmol), (Boc)2O (1 mmol) and VB1 (2 mol%) was vigorously stirred at room temperature for appropriate time until complete disappearance of amines was observed in the TLC monitoring. After the completion of reactions, the reaction mixture was diluted with ethyl acetate and the VB1 catalyst was isolated by simple filtration. After drying catalyst, it is reused for N-Boc protection of amines. The product in ethyl acetate was washed with water and excess of solvent removed under reduced pressure. The pure products N-tert-butylcarbamate derivatives of amines were obtained in 83-99% yield. The structure of synthesized compounds analyzed by 1H NMR, 13C NMR and mass spectrometry. |
| 97% |
With iron(III) trifluoromethanesulfonate In neat (no solvent) at 20℃; for 0.133333h; Green chemistry; |
N-Boc protection of amines
General procedure: Fe(OTf)3 (1 mol%) was added to a magnetically stirred mixture of anamine (1 mmol) and Boc2O (1 mmol) at room temperature. The mixturewas stirred until completion of the reaction (TLC), then diluted withEtOAc and washed with water. The organic layer was dried overanhydrous MgSO4, then the solvent was distillated off under vacuum toyield the highly pure N-Boc derivatives |
| 97% |
With 1,4-disulfopiperazine-1,4-diium chloride In neat (no solvent) at 20℃; for 0.5h; Green chemistry; chemoselective reaction; |
|
| 96% |
In ethanol at 30℃; for 6h; |
|
| 96% |
at 20℃; for 6h; |
|
| 96% |
With guanidinium monohydrochloride In water monomer at 35 - 40℃; for 0.916667h; |
2.1. General procedure for N-tert-butoxycarbonylation of amines:
General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 mol%) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent. |
| 96% |
With γ-Fe2O3@SiO2 nanoparticles at 20℃; for 0.333333h; chemoselective reaction; |
|
| 96% |
In neat (no solvent) at 100℃; for 0.0833333h; Microwave irradiation; Green chemistry; chemoselective reaction; |
(General procedure for the N-tert-butoxycarbonylation of amines:
General procedure: Amine (1 mmol) and di-tert-butyl dicarbonate [(Boc)2O] (1.1 mmol) were placed in a microwave reaction vial. The LG microwave oven MG 555f was programmed to 300 W at 100 °C. The reaction was monitored using TLC. After the reaction, ice water was added to the reaction mixture which resulted in the precipitation of the product. The solid product was merely filtered off and washed with excess cold water. The product was pure enough for all practical purposes. For characterization purpose, it was further purified by column chromatography (Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate (7.5:2.5)). |
| 95% |
With amberlyst-15 at 20℃; for 0.05h; Neat (no solvent); |
|
| 95% |
With nanocerium oxide In neat (no solvent) at 20℃; for 0.416667h; |
2. General procedure for N-Boc protection of amines
General procedure: To a mixture of amines (1mmol) and Boc2O (1mmol), 10mol% nanocerium oxidewas added wit h vigorous stirring at room temperature for stipulated time. Aftercompletion of reaction as monitored by TLC, diethyl ether was added and the catalyst wasremoved by simple filtration. After removal of the solvent, the pure products wereobtained and no recrystallization or column chromatography was needed. |
| 94% |
With N-ethyl-N,N-diisopropylamine In toluene at 20℃; |
|
| 94% |
With N-ethyl-N,N-diisopropylamine In toluene at 20℃; |
|
| 94% |
With Amberlyst A21 In neat (no solvent) at 20℃; for 0.05h; Green chemistry; |
General experimental procedure for the N-Boc protection of amines using Amberlyst A21 catalyst
General procedure: Amberlyst A21 (20 wt %) was added to a mixture of amine (1 mmole) and (Boc)2O (1 mmole) and the mixture was stirred for the appropriate reaction time as specified in (Table 1). The progress of reaction was monitored by Thin layer chromatography (10-20% ethyl acetate: hexane) on TLC plates (Merck) precoated with silica. After completion of reaction, the reaction mass was diluted with methanol, filtered off the catalyst which was washed for several times and then dried at 800 °C under reduced pressure for 1 hour and subjected to further recycle study (Table 4). It showed no much more decrease in the product yield indicating high activity of the catalyst. The filtrate was concentrated on rotavacc and the product was purified by column chromatography to afford pure products. |
| 94% |
With pyridinium trifluoroacetate In neat (no solvent) at 20℃; for 1h; Green chemistry; |
General procedure for the N-Boc protection of amines
General procedure: To a magnetically stirred mixture of amine (1mmol) and (Boc)2O (1mmol) a catalytic amount of ionic liquid (0.2mmol) was added under solvent-free conditions at room temperature for the specified period of time. The progress of the reaction was monitored by TLC and GC-MS. The mixture extraction was carried out using ethyl acetate (2×5mL). The organic layer was washed with water (2×10mL) and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum to yield highly pure N-Boc derivatives. In some cases, the purification was done by column chromatography using silica gel (60-120) by hexane-ethyl acetate as eluent to get a pure product. |
| 94% |
Stage #1: di-<i>tert</i>-butyl dicarbonate With C12H24KO6(1+)*Br3H(1-) In ethanol at 20℃; for 0.0166667h;
Stage #2: 4-chloro-aniline In ethanol at 20℃; for 7h; |
For the N-boc protection of amines, to solution of diboc (1 mmol) in ethanol (5 ml) was added {K*18-crown-6]Br3}n (0.001 mmol). The solution was stirred at room temperature for 1 min. The amine (1 mmol) was then added and solution as stirred at room temperature for an appropriate time (table 1). After completion of the reaction, the solvent was removed by water bath distillation. To the residue was added ethyl acetate (5 ml) and the mixture was filtered (the catalyst is insoluble in n-hexane and ethyl acetate). The solid was washed with ethyl acetate ()10 ml*2) amd combined filtrates were reduced to dryness to yield the pure products. |
| 93% |
at 20℃; for 0.25h; Green chemistry; |
General Procedure for the Boc Protection of Amines
General procedure: To (Boc)2O (1.0 mmol), was added an amine (1.0 mmol)and the mixture was stirred at room temperature for the time indicated in Table 1. The progress of the reaction was monitored by TLC. In most cases, the BOC protected product was found to be sufficiently pure and did not require any further purification. In some cases the product was purified by silica gel column chromatography (1:2; EtOAc/ Petrolium ether).All products were characterized by IR, 1H NMR and their physical properties. |
| 92% |
In <i>tert</i>-butyl alcohol at 20℃; for 3h; |
|
| 92% |
|
|
| 92% |
With PEG-400 at 20℃; for 2.5h; Neat (no solvent); |
|
| 92% |
With phenylsulfonic acid supported on mesoporous silica SBA-15 In neat (no solvent) at 20℃; for 0.25h; Green chemistry; |
General procedure for the N-Boc protection of amines and amino acidsin presence of SBA-15-Ph-SO3H under solvent-free condition
General procedure: An amine (1 mmol) was added to a magnetically stirred mixture of SBA-15-Ph-SO3H (1 mol %, 4 mg) and (Boc)2O (1.1 mmol) at room temperature. The progressof the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with EtOH (5 mL)and centrifuged. Then the clear liquid was separated, and the residue containing the catalyst was kept for recovery. EtOH was distilled off under vacuum to yield the highly pure N-Boc derivative. |
| 92% |
In tetrahydrofuran; water monomer at 20℃; for 3h; |
5.b b) Method B
4-Chloroaniline 68 (5 g, 39.3 mmol) was added into a 100 mL round bottom flask charged with a 1:1 ratio of THF and water (50 ml) and stirred until the compound dissolved, to this di-tert-butyl dicarbamate (9.13 mL, 43.3 mmol) was added dropwise and stirred for 3 hours at room temperature. The completion of the reaction was monitored by TLC (20% ethyl acetate in hexane) and GC. After completion, the reaction mixture extracted with ethyl acetate (3x50 mL), washed with water (50 mL) and brine solution (50 mL). The resulting organic layer dried over anhydrous Na2SO4 and evaporated under reduced pressure to get product as white coloured solid (8.1 g, 92%) which was analytically compared with Method A results. |
| 91% |
In water monomer at 20℃; for 24h; |
|
| 90% |
With iodine at 20℃; for 2.5h; |
|
| 90% |
With thioglycoluril In ethanol at 30 - 40℃; for 1h; chemoselective reaction; |
|
| 90% |
With trimethyl-(2-hydroxyethyl)ammonium chloride; urea at 50℃; Green chemistry; |
General procedure
General procedure: A dried test tube, equipped with a magnetic stir bar, wascharged with 0.5 cm3 DES, amine derivatives(0.5 mmol), and Boc2O (0.5 mmol) and the mixture washeated at 50 C until the reaction was complete (monitoredby TLC and IR). After this time, 5 cm3 water wasadded and in the most cases a white solid was obtained.The solid product was collected by filtration and washedsuccessively with water and recrystallized from ethanolto get the pure final product [51-60]. The viscousproducts extracted with ethyl acetate and were purifiedby column chromatography, using ethyl acetate-petroleumether. |
| 90% |
With 3a,6a-diphenylglycoluril In ethanol at 25 - 30℃; for 1h; |
6. General procedure of diphenylglycoluril catalyzed N-tertbutoxycarbonylationof amines 3a-y
General procedure: In a 25 mL of round bottom flask, a solution of di-tert-butyldicarbonate (1 mmol) and Diphenyglycouril (10 mol %) were addedin 10 mL of ethanol. A turbid solutionwas obtained. In that solution1 mmol of Amine (1a-y) was added. Reaction mixture was stirredfor 30 min at room temperature. After total consumption of thestarting material (determination by TLC), the solvent was removedin vacuo, and the residue was isolated by column chromatographyon silica gel to get the pure product 3a-y as solid or oil. |
| 89% |
With glycerol at 20℃; for 0.916667h; Green chemistry; chemoselective reaction; |
|
| 87% |
With sulfonic-acid-functionalized silica In dichloromethane at 20℃; for 1.5h; |
|
| 85% |
With triethylamine In N,N-dimethyl-formamide at 20℃; |
|
| 83% |
With triethylamine In tetrahydrofuran at 25 - 40℃; for 42h; Inert atmosphere; |
1-3 Production Example 1-3:
Synthesis of p-chloro-N-t-butoxycarbonylaniline
0.20 g (1.6 mmol) of p-chloroaniline, 0.17 g (1.7 mmol) of triethylamine, and 1 mL of THF were placed in a 15-mL test tube purged with nitrogen. While stirring the mixture, 0.38 g (1.7 mmol) of di-t-butyl dicarbonate/1 mL of THF solution was added dropwise. The resulting mixture was stirred at 25° C. for 24 hours, and then further stirred at 40° C. for 18 hours. The obtained reaction mixture was cooled to 25° C., and dried under reduced pressure, thereby obtaining 0.30 g of a compound represented by the above formula (p-chloro-N-t-butoxycarbonylaniline) (yield: 83%). The 1H-NMR analysis results of the compound represented by the above formula are shown below. 1H-NMR (CDCl3) δ (ppm)=7.31 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 1.51 (s, 9H) |
| 83% |
With triethylamine In tetrahydrofuran at 25 - 40℃; for 42h; Inert atmosphere; |
2-3 Production Example 2-3: Synthesis of p-chloro-N-t-butoxycarbonylaniline
0.20 g (1.6 mmol) of p-chloroaniline, 0.17 g (1.7 mmol) of triethylamine, and 1 mL of tetrahydrofuran (THF) were placed in a 15-mL test tube purged with nitrogen. While stirring the mixture, 0.38 g (1.7 mmol) of di-t-butyl dicarbonate/1 mL of THF solution was added dropwise. The obtained mixture was stirred at 25° C. for 24 hours, and then further stirred at 40° C. for 18 hours. The obtained reaction mixture was cooled to 25° C., and dried under reduced pressure, thereby obtaining 0.30 g of a compound represented by the above formula (p-chloro-N-t-butoxycarbonylaniline) (yield: 83%). The 1H-NMR analysis results of the compound represented by the above formula are shown below. 1H-NMR (CDCl3) δ (ppm)=7.31 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 1.51 (s, 9H) |
| 81% |
With dmap; triethylamine In dichloromethane at 20℃; for 8h; |
79.1 Step 1: tert-Butyl (4-chlorophenyl)carbamate:
To a solution of 4-chloroaniline (3.0 g, 24 mmol, 1.0 equiv) in DCM (30 mL, 0.80 M) was added triethylamine (6.0 g, 59 mmol, 2.5 equiv), DMAP (290 mg, 2.4 mmol, 0.10 equiv)02and Boc anhydride (5.7 g, 26 mmol, 1.1 equiv). After the addition, the mixture was stirred at rt for 8 h. The mixture was washed with water (15 mL), brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (20-90% EtOAc in hexanes) to afford tert-butyl (4-chlorophenyl)carbamate (4.3 g, 19 mmol, 81% yield) as a light yellow liquid. LCMS: ESI-MS m/z: 172.1 [M-55]+. |
| 80% |
With [H2-cryptand 222](Br3)2 In acetonitrile at 20℃; for 4h; chemoselective reaction; |
|
| 80% |
With nano-sphere silica sulfuric acid In neat (no solvent) at 20℃; for 0.166667h; chemoselective reaction; |
2.2.1. General procedure for the protection of amines
General procedure: An amine (5 mmol) was added to a magnetically stirred mixture of NS-SSA (5 mg) and di-tert-butyl dicarbonate (5.5 mmol, 1.19 g) at room temperature. After completion of the reaction (as monitored by TLC), the reaction mixture was diluted with EtOH (5 mL) and centrifuged for 3 minutes. Then, the clear liquid was separated, and the residue containing the catalyst was kept for recovery. EtOH was distillated off under vacuum to yield the highly pure N-Boc derivative. |
| 51.6% |
With sodium hydroxide In 1,4-dioxane at 20℃; for 15h; |
|
| 48% |
In toluene Reflux; |
6.1 Step 1
Step 1 The solution of 4-chloro-phenylamine (12.0 g, 94.1 mmol), Boc2O (30.5 g, 141 mmol) in toluene (100 mL) was stirred at reflux overnight. After cooled to room temperature, the solution was concentrated to dryness in vacuum. The residue was purified by silica gel column (PE) to afford (4-chloro-phenyl)-carbamic acid tert-butyl ester (21.0 g, yield: 48%) as white solid. 1H NMR (400MHz, DMSO-d6): δ=7.29 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.47 (s, 1H), 1.51 (9H, s). |
|
With triethylamine In tetrahydrofuran at 20℃; for 14h; |
|
|
In 1,4-dioxane at 20℃; for 24h; |
1.32.B.a
A mixture of 12.7 g of 4-chloroaniline and 22 g of di-tert-butyl dicarbonate in 60 ml of dioxane is stirred at RT for 24 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in pentane and the precipitate formed is filtered off by suction and dried. 22.5 g of the expected product are obtained. |
|
In tetrahydrofuran at 20℃; |
|
|
In ethanol at 20℃; |
|
|
In <i>tert</i>-butyl alcohol at 40℃; for 24h; Inert atmosphere; Schlenk technique; |
|
|
In methanol at 100℃; |
|
|
In tetrahydrofuran |
|
|
In ethanol; water monomer at 20℃; for 3h; |
|
|
In <i>tert</i>-butyl alcohol at 0 - 20℃; for 2.5h; |
78
Referential Example 78; tert-Butyl 4-chlorophenylcarbamate [Show Image] [Show Image] To a tert-butanol solution (200 mL) of 4-chloroaniline (30.1 g) was added di-tert-butyl dicarbonate (77.2 g) at 0°C. The resulting mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure. To the residue was added hexane (200 ml) and crystals were filtered to give the title compound (45.7 g). 1H-NMR(CDCl3)δ:1.51(9H,s),6.45(1H,s),7.24(2H,dd,J=6.8,2.2Hz),7 .28-7.33(2H,m). |
|
With dmap; triethylamine In dichloromethane at 20℃; for 6h; |
|
|
In tetrahydrofuran at 20℃; for 12h; |
|
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