Tert-Butoxycarbonyl Protected Amino Reaction Case_Industrial Additives

Free amino groups can easily react with Boc2O in a mixed solvent of dioxane and water under alkaline conditions controlled by NaOH or NaHCO3 to obtain N-tert-butoxycarbonylamino compounds. This is one of the common methods to introduce Boc. Its advantage is that its by-products do not interfere much and are easy to remove. Sometimes for some amines with greater nucleophilicity, they can generally react directly with Boc acid anhydride in methanol. No other base is needed, and the treatment is also convenient.

tert-butoxycarbonyl protected amino reaction case reaction example

tert-butoxycarbonyl protected amino reaction case 1, example of amino acid Boc protection

Oskar Keller,Walter E. Keller, Gert van Look et al., Org. Syn., 63, 160

A 4-L, four-necked, round-bottomed flask, equipped with an efficient stirrer, a droppingfunnel, reflux condenser, and thermometer is charged with a solution of 44 g (1.1 mol) of sodium hydroxidein 1.1 L of water. Stirring isinitiated and 165.2 g (1 mol) of L-phenylalanine is added at ambienttemperature, and then diluted with 750 mL of tert-butyl alcohol. To the well-stirred, clearsolution is added dropwise within 1 hr, 223 g(1 mol) of di-tert-butyl dicarbonate.A white precipitate appears during addition of the di-tert-butyldicarbonate. After a short induction period, the temperature rises toabout 30–35°C. Thereaction is brought to completion by further stirring overnight at roomtemperature. At this time, the clear solution will have reached a pH of7.5–8.5. The reaction mixture is extracted two times with 250mL of pentane, and the organic phase isextracted three times with 100 mL of saturated aqueous sodium bicarbonate solution. The combined aqueous layers are acidified to pH 1–1.5 by careful addition of a solution of 224 g (1.65 mol) of potassium hydrogensulfate in 1.5 L ofwater. The acidification is accompanied by copious evolution of carbon dioxide. The turbid reaction mixture is thenextracted with four -mL portions of ethyl ether. The combined organic layers are washed twotimes with 200 mL of water, dried over anhydrous sodiumsulfate or magnesium sulffluorophenylborate, and filtered.The solvent is removed under reduced pressure using a rotaryevaporator at a bath temperature not exceeding 30 °C. The yellowish oil that remains istreated with 150 mL of hexaneand allowed to stand overnight. Within 1 day the following portions of hexane are added with stirring to the partially crystallized product: 2 × 50 mL, 4 × 100 mL, and 1 × 200 mL. The solution is placed in a refrigeratorovernight; the white precipitate is collected on a Büchnerfunnel and washed with cold pentane. The solid is dried under reduced pressure at ambient temperature to constant weight to give a first crop. The mother liquor is evaporated to dryness leaving ayellowish oil, which is treated in the same manner as described above, giving a second crop. The total yield of pure white N-tert-butoxycarbonyl-L-phenylalanine is 207–230 g(78–87%), mp 86–88°C , [α]D20 + 25.5° (ethanol c 1.0).

tert-butoxycarbonyl protected amino reaction case 2, Boc acid anhydride reacts directly with amine in methanol

Boc2O (2-pyridinium tribromide 62 g, 1.2 mol) in MeOH (250 ml) was added toa soluton of compound 1 (157.2 g, 1.0 mol) in MeOH (350 ml) at 10°C, and the resulting The mixture was stirred at room temperature for 2 h. N1,N1-dimethylethane-1,2-diamine (26 g, 0.3 mol) was added and the mixture was stirred at room temperature for 15 min. The solvent was removed in vacuo, and theresidue was dissolved with ethyl acetate (750 ml). The combined organics werewashed with 1 N HCl (2 x 250 ml) and brine (2 x 250 ml), dried over sodiumsulfate and filtered. The solvent was removed to give compound 2 (250 g , 96%), which was used directly in thenext step.

tert-butoxycarbonyl protected amino reaction case 3, example of mono-Boc protection of aromatic amines

Luo, Qun-Li;Liu, Zhi-Ying et al., J. Med. Chem., 2003, 46(13), 2631-2640

3-Aminopyridine-2-carboxylic acid(5.02 g, 36 mmol) was suspendedin 60 mL of dry DMF, and Et3N (15.2 mL, 108 mmol) was added dropwise at roomtemperature. To the resulting brown solution was added Boc2O ( 11.80 g, 54 mmol). After being stirred for 10min, the mixture was heated at 40-50 °Covernight. The reaction mixture was poured into water and was then extracted with EtOAc (2 X 50 mL). The aqueous phase was acidified to pH 4-5 with 2 M aqueous HCl and then extracted with CH2Cl2(3 ).

tert-butoxycarbonyl protected amino reaction case 4, double Boc protection example of aromatic amine

Macleod, Calim;Mckieman, Gordon J et al., J. Org. Chem., 2003, 68(2),387-401

A solution of NaHMDS (22.0 mL, 22.0 mmol, 1 M in THF) was added to a solution of the amine(2.11 g, 10.0 mmol) and (Boc)2O (5.46 g, 25.0 mmol) in THF (50 mL) at 0°C under nitrogen. The reaction was allowed to warm to rt and stirred for 16 h. After this time, the reaction was poured into water, extracted into CH2Cl2(2 X 25 mL), washed with water (2 the imide as needles (3.21 g, 7.80 mmol, 78%). Rf (hexane/ CH2Cl2 1:9, SiO2): 0.10. Mp:106-109 °C.

tert-butoxycarbonyl protected amino reaction case 5. Example of Boc protection of amide

Lars G. J. Hammarström, Yanwen Fu et al., Org. Syn., 81, 213

A 2000-mL, three-necked, round-bottomed flask equipped with an argon inlet adapter, glass stopper, and an overheadmechanical stirrer is charged with a suspension of the hydantoin 1 (26.0 g,154 mmol) in 1000 mL of 1 ,2-dimethoxyethane. Triethylamine (15.7 g, 154mmol) is added in one portion, and the resulting white suspension isstirred for 30 min. Di-tert-butyl dicarbonate (168.0 g, 770mmol) is then added by pipette, followed by4-dimethylaminopyridine (DMAP)(0.2 g, 1.5 mmol). Six additional 0.2 g-portions of DMAP are added at 12 hr intervals during the course of the reaction.The reaction mixture is stirred vigorously for a total of 72 hr, and the resulting light yellow solid is then collected in a Büchner funnel using suction filtration. The filtrate is concentrated to a volume of 60 mL byrotary evaporation, and the resulting solution is cooled to 15°C. The precipitate which appears is collected using suction filtration, added to the first crop, and the combinedsolids are dissolved in 500 mL of chloroform. This solution is washed with three 200-mL portions of 1.0N HCl, and the combinedaqueous phases are extracted with 100 mL of chloroform. The combined organic layers are washed with 100 mL of saturated aq NaHCO3solution and 100 mL of brine,dried over anhydrous MgSO4,filtered, and concentrated by rotary evaporation. The resulting solid is dried at room temperature at 0.01 mmfor 24 hr. The resulting finely ground light yellow solid is suspended in mL of diethyl ether in a 1000-mL , round-bottomed flask equipped with a magnetic stirbar, stirred for 2 hr, and filtered on a Büchner funnel washing with four 50-mL portions of diethyl ether. The product is dried under vacuum (85°C; 0.5 mm) for 24 hr to give 60.0–65.3 g (83-90%) of 2 as a ivory-colored solid.

tert-butoxycarbonyl protected amino reaction case 6, indole Boc protection example

G. Tong; P. Ruiyan et al., J. Org.Chem., 1997, 26, 9298

To a solution of6-methoxy-3-methylindole (5.0 g,31 mmol) in distilled acetonitrile (150 mL) were added di-tertbutyl dicarbonate(7.44 g, 34.1 mmol) andDMAP (0.195 g, 1.6 mmol).The reaction mixture was stirred at rt for 12 h. The solvent was removed underreduced pressure. The residue was dissolved in CH2Cl2(100 mL) and washed with an aqueous solution of 1 N HCl (2 x 50 mL). Theaqueous layer was extracted with CH2Cl2 (3 x 30 mL). The combined organic ayers were dried (K2CO3). Afterremoval of solvent under reduced pressure, the residue was solidified to afford the product (8.12 g, 99%) as a yellow solid: mp 45-46 °C.

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