* 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] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 24, p. 5449 - 5460
[2] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 6, p. 705 - 710
[3] Heterocycles, 1987, vol. 26, # 11, p. 2805 - 2809
[4] Journal of the American Chemical Society, 1994, vol. 116, # 4, p. 1316 - 1323
[5] Journal of Organic Chemistry, 1992, vol. 57, # 1, p. 28 - 32
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 535 - 540
[7] European Journal of Organic Chemistry, 2018, vol. 2018, # 27, p. 3844 - 3852
2
[ 79-37-8 ]
[ 3182-95-4 ]
[ 59830-60-3 ]
Reference：
[1] Patent: US5362912, 1994, A,
3
[ 3182-95-4 ]
[ 28920-43-6 ]
[ 129397-83-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 20℃; for 0.0333333 h; Sonication; Irradiation; Green chemistry
General procedure: Amine (1 mmol) and Fmoc-Cl (1.1 mmol) were placed in a glass tube under neat conditions and were sonicated for a suitable time (as indicated in Tables 1, 2 and 3). All reactions were performed in a water bath at room temperature. After completion of the reaction (as indicated by TLC), 5 cm3 of diethyl ether was added to the mixture. The N-Fmoc derivatives were crystallized and were obtained in good to excellent yields. Purification of the product was accomplished by recrystallization from diethyl ether.
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 404 - 414
[2] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 3, p. 546 - 550
[3] Journal of Organic Chemistry, 1995, vol. 60, # 2, p. 405 - 410
[4] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
Reference：
[1] Advanced Synthesis and Catalysis, 2001, vol. 343, # 8, p. 802 - 808
9
[ 3182-95-4 ]
[ 108-24-7 ]
[ 52485-51-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 20℃; for 0.166667 h; Green chemistry
In a 50mL round-bottomed flask, a mixtureof amine or amino alcohol (1 mmol) and aceticanhydride (1.2 mmol) was stirred at roomtemperature for the appropriate time. Aftercompletion of the reaction, as monitored by TLC,the reaction mixture was dissolved in ether (5 mL)and was allowed to stand at room temperature for1 hour. During this time, crystal of product formed,which were collected by filtration.In the case of solid substrates(sulfonamides), the same protocol was used.However, the use of water was required for thesolubility of the mixture. The N-acylatedsulfonamides were collected by crystallization fromdiethyl ether.
78%
at -20℃; for 2 h;
To a solution of l-phenylalaninol (1 g, 6.6 mmol) in pyridine (20 mL) at -20 °C, acetic anhydride (0.7 mL, 7.26 mmol) was added dropwise, and the solution was stirred at -20 °C for 2 h after which TLC (EtOAc/CH2Cl2/MeOH 6:2:2) (stained with ninhydrin) showed no starting material. The reaction was quenched with methanol (3 mL) then evaporated in vacuo. The residue was dissolved in EtOAc (15 mL), washed with water (2 x 15 mL), brine (2 x 15 mL), dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness to afford 11 as white needles which was recrystallized from EtOAc, (1.1 g, 78percent); mp 98-99 °C; 1H NMR (270 MHz, CDCl3): δ 7.25-7.21 (m, 5H, Ar), δ 5.7 (br s, 1H, NH), δ 4.15-4.12 (m, 1H, CH-NH), δ 3.66-3.58 (m, 2H, CH2-OH), δ 2.87-2.84 (d, 2H, CH2-Ph), δ 2.64-2.62 (t, 1H, OH), δ 2.03 (s, 3H, Ac); HRMS (ESI+): (Mwt. 193); m/z found: 194.1168 [M+H]+, C11H16NO2 requires 194.1181 and 216.0987 [M+Na]+, C11H15NO2Na requires 216.1000.
75%
for 16 h;
To a stirred solution of L-phenylalaninol (228 mg, 1.51 mmol) in THF (5 mL) was added acetic anhydride (0.15 mL, 1.59 mmol) and the mixture stirred for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with 1 N HCL (15 mL), saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by column chromatography on silica gel afforded the N-acetylated alcohol (220 mg, 75percent) as a white solid. 1H NMR (CDCl3) δ 1.95 (s, 3H), 2.87 (d, 2H, J=6.0 Hz), 3.17 (br s, 1H), 3.56-3.68 (m, 2H), 4.13-4.21 (m, 1H), 5.97 (br d, 1H, J=6.0 Hz), 7.20-7.34 (m, 5H). The alcohol was then oxidized according to the general Dess-Martin procedure and the crude aldehyde used without further purification.
Reference：
[1] Chinese Chemical Letters, 2010, vol. 21, # 2, p. 155 - 158
[2] Oriental Journal of Chemistry, 2015, vol. 31, # 2, p. 913 - 919
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 10, p. 2742 - 2755
[4] Patent: US6750348, 2004, B1, . Location in patent: Page column 47
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2216 - 2220
Reference：
[1] Green Chemistry, 2012, vol. 14, # 8, p. 2251 - 2255
12
[ 3182-95-4 ]
[ 165727-45-7 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2010, vol. 53, # 3, p. 148 - 152
13
[ 75-15-0 ]
[ 3182-95-4 ]
[ 171877-39-7 ]
Reference：
[1] Tetrahedron, 2008, vol. 64, # 24, p. 5637 - 5644
[2] European Journal of Organic Chemistry, 2009, # 33, p. 5841 - 5846
[3] Organic Letters, 2008, vol. 10, # 13, p. 2821 - 2824
[4] Journal of Organic Chemistry, 1995, vol. 60, # 20, p. 6604 - 6607
[5] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 14, p. 2139 - 2145
[6] Organic Letters, 2000, vol. 2, # 6, p. 775 - 777
[7] Journal of Organic Chemistry, 2001, vol. 66, # 3, p. 894 - 902
[8] Journal of Organic Chemistry, 2001, vol. 66, # 3, p. 894 - 902
[9] Patent: WO2008/23336, 2008, A2, . Location in patent: Page/Page column 55
[10] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6156 - 6174
[11] Organic Syntheses, 2011, vol. 88, p. 364 - 376
[12] Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 1, p. 112 - 122
14
[ 3182-95-4 ]
[ 171877-39-7 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 14, p. 2139 - 2145
[2] Journal of Organic Chemistry, 1995, vol. 60, # 20, p. 6604 - 6607
[3] Organic Letters, 2012, vol. 14, # 21, p. 5396 - 5399
[4] Patent: WO2013/148324, 2013, A1,
15
[ 75-15-0 ]
[ 3182-95-4 ]
[ 131744-19-9 ]
[ 171877-39-7 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 14, p. 2139 - 2145
16
[ 3182-95-4 ]
[ 1088965-37-0 ]
Reference：
[1] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1254 - 1263
[2] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1254 - 1263
[3] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1254 - 1263
[4] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1254 - 1263
[5] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1254 - 1263
[6] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1254 - 1263
In neat (no solvent); at 20℃; for 0.0333333h;Sonication; Irradiation; Green chemistry;
General procedure: Amine (1 mmol) and Fmoc-Cl (1.1 mmol) were placed in a glass tube under neat conditions and were sonicated for a suitable time (as indicated in Tables 1, 2 and 3). All reactions were performed in a water bath at room temperature. After completion of the reaction (as indicated by TLC), 5 cm3 of diethyl ether was added to the mixture. The N-Fmoc derivatives were crystallized and were obtained in good to excellent yields. Purification of the product was accomplished by recrystallization from diethyl ether.
General procedure: A vial was charged with aldehyde or imidate (0.085 mmol), amine, amino alcohol or diamine or (0.085 mmol) and anhydrous toluene (0.4 mL). To this was added 4Å molecular sieves and the vial was sealed. The reaction was then stirred at 70 C for 12 h. Mixtures were then added directly to the catalytic reaction. In cases where ligands were synthesised prior to the reaction then the same procedure was followed, and ligands were purified by column chromatography prior to use.
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃;
L-phenylalaninol (5 g, 33.1 mmol) and Na2CO3 (7.01 g, 66.1 mmol) were dissolved in a mixture of H20 (31 mL) and dioxane (31 mL). The suspension was cooled to 0 C andCbz-Cl (7.08 mL, 49.6 mmol) was added dropwise. The reaction was stirred overnightat RT. After concentration under reduced pressure, the mixture was extracted withCH2C12 (2 x 40 mL) and the combined organic layers were washed with 5% citric acid(30 mL), sat. NaHCO3 (20 mL) and brine (20 mL), dried over Na2504 and filtered.Evaporation of the solvent and purification by flash column chromatography (PE -60% EA/PE, v/v) yielded 13 (8.54 g, 29.9 mmol, 91%) as a white solid.
85%
In neat (no solvent); at 50℃; for 0.05h;Microwave irradiation; Green chemistry;
General procedure: Benzylcholoroformate Cbz-Cl (1 mmol) was added to amine (1 mmol) and the mixture was subjected to the microwave irradiation (100W) for the appropriate time (tables 2, 3, 4 and 5). After completion of the reaction (monitored by TLC) dichloromethane: methanol (98/2), the reaction mixture was treating with n-hexane (15-20 mL) and was allowed to stand at room temperature overnight. The solid products were collected by filtration, washed with n-hexane and dried to give the N-Cbz derivatives in good to excellent yields. During the reaction, the formation of hydrogen chloride (gas) was observed, confirming the protection of all amines structures proposal.
76%
With hydrogenchloride; sodium carbonate; In 1,4-dioxane; water;
(1) To a mixture of L-phenylalaninol (20.2 g, 0.134 mol), sodium carbonate (21.1 g, 0.200 mol) and 1,4-dioxane (150 mL) was added a solution of benzyloxycarbonyl chloride (19.1 mL, 0.134 mol) in 1,4-dioxane (50 mL) and the mixture was stirred at room temperature for 3 hours. Water (300 mL) was added to the reaction mixture and the obtained mixture was added to ice-cooled 0.5 N hydrochloric acid (500 mL). The precipitated crystals were collected by filtration and washed with hexane and dried to give N-benzyloxycarbonyl-L-phenylalaninol as white crystals (28.8 g, 76%).
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 18h;
To a solution (250 mL) of L-phenylalaninol (25 g, 170 mmol) in tetrahydrofuran were added N-carbobenzoxyoxysuccinimide (41 g, 170 mmol) and triethylamine (25 g, 250 mmol) under ice-cooling. This solution was stirred at room temperature for 18 hr. This was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane to give Reference compound 7 (41 g, 87%) as colorless crystals. mp 90.2-91.0C. 1H-NMR (300 MHz, DMSO-d6)delta:2.58 (dd, 1H, J = 13.8, 9.3 Hz), 2.85 (dd, 1H, J = 13.8, 5.5 Hz), 3.27-3.42 (m, 2H), 3.66 (m, 1H) , 4.76 (t, 1H, J = 5.5 Hz), 4.91-5.00 (m, 2H), 7.12 (d, 1H, J = 8.4 Hz), 7.16-7.37 (m, 10H). Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.45; H, 6.72; N, 4.68.
With potassium hydroxide; In water; for 16h;Heating / reflux;
To a solution of compound (32.5 g) obtained in stepa above,in IN aqueous potassium hydroxide (1 lit), carbon disulphide(68 mL, 5.0 equiv.) was added and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, the aqueous solution was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography using 15% ethyl acetate in hexane to get the title compound (22.5 g).
1. (S)-2-Benzylaziridine A solution of sulfuric acid (181.8 ml, 95% purity; 3.41 mol) in water (260 ml) is added slowly to a stirred, cooled (5 C.) solution of L-phenylalaninol (500 g, 3.31 mol) in water (800 ml). After the addition is completed, the reaction mixture is stirred for a another hour. The water is removed in vacuo. The residue is then heated to 140 C. under vacuum (2 mm/Hg) for 2 days (the transformation of the hydroxy compound to the sulfate ester can be easily followed by 1H NMR spectroscopy). The solid is then allowed to cool to room temperature and 30% sodium hydroxide solution (1700 ml) is added. A reflux condenser is fitted to the flask and the solution is heated to 135 C for 6 hours. The mixture is allowed to cool before being extracted with diethyl ether (3*500 ml). The combined organic layers are dried over sodium hydroxide pellets (ca. 100 g) and filtered. The solvent is removed under reduced pressure and the product is purified by vacuum distillation off sodium hydroxide pellets (80-85 C./0.5 mm/Hg) to give 306 g (70.5%) of pure (S)-2-benzylaziridine (IVc) as a colorless liquid. Sodium hydroxide pellets are added as a preservative and the material is stored in the refrigerator. 1H NMR (CDCl3): 7.35-7.2 (m, 5H), 2.83, 2.77 (dd, J=6.07 Hz, 6.08 Hz, 1H), 2.68, 2.63 (dd, J=5.95 Hz, 5.93 Hz, 1H), 2.23-2.16 (m, 1H), 1.80 (d, J=5.76 Hz, 1H), 1.44 (d, J=3.49 Hz, 1H). 13C NMR (CDCl3): 139.6, 129.1, 128.7, 126.6, 40.4, 31.2, 25.1.
1) At room temperature, add 200 ml of 50% sulfuric acid to the toluene solution of the amino alcohol (4) obtained in Example 1, and stir for 30 minutes to fully form a salt;2) After refluxing and water separation, add 600 ml of a 25% sodium hydroxide solution at 80 C;3) Continue stirring and refluxing for 20 hours, cool to room temperature, and allow the layers to stand still;4) The organic layer was washed with a mixed solution of 200 ml of saturated saline and 200 ml of 10% sodium hydroxide;5) The separated organic phase is the toluene solution of the desired cycloethyleneimine (5), which is directly used in the next reaction.
(S)-N-(1-hydroxy-3-phenylpropan-2-yl)furan-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In tetrahydrofuran; at 23 - 25℃;Inert atmosphere;
General procedure: A round bottom centrifuge tube containing catalyst 4 (6.7 mol % based on the percent phosphorus determined by elemental analysis or as otherwise stated in the footnotes of the corresponding Tables) was equipped with a rubber septum and two magnetic stir bars for extra stirring efficiency. After flushing the tube with argon, it was charged via syringe with a higher ester (5 mmol) and MeOH (5 mL) for transesterifications. For amidations, the tube was similarly charged with an ester (2 mmol), amino alcohol (2 mmol), and THF (3 mL). The reaction mixture was vigorously stirred at room temperature (23-25 C) and progress of the reaction was monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture was filtered through Whatman No. 1 filter paper and washed with 3 × 10 mL of THF. The combined organics were subjected to short-path silica gel chromatography (0-20% ethyl acetate in hexanes v/v) to obtain an analytically pure product. In the case of amides, products were purified using a short-path silica gel column eluted with dichloromethane/methanol (95:5, v/v).
In neat (no solvent); at 20.0℃; for 0.166667h;Green chemistry;
In a 50mL round-bottomed flask, a mixtureof amine or amino alcohol (1 mmol) and aceticanhydride (1.2 mmol) was stirred at roomtemperature for the appropriate time. Aftercompletion of the reaction, as monitored by TLC,the reaction mixture was dissolved in ether (5 mL)and was allowed to stand at room temperature for1 hour. During this time, crystal of product formed,which were collected by filtration.In the case of solid substrates(sulfonamides), the same protocol was used.However, the use of water was required for thesolubility of the mixture. The N-acylatedsulfonamides were collected by crystallization fromdiethyl ether.
78%
With pyridine; at -20.0℃; for 2.0h;
To a solution of l-phenylalaninol (1 g, 6.6 mmol) in pyridine (20 mL) at -20 C, acetic anhydride (0.7 mL, 7.26 mmol) was added dropwise, and the solution was stirred at -20 C for 2 h after which TLC (EtOAc/CH2Cl2/MeOH 6:2:2) (stained with ninhydrin) showed no starting material. The reaction was quenched with methanol (3 mL) then evaporated in vacuo. The residue was dissolved in EtOAc (15 mL), washed with water (2 x 15 mL), brine (2 x 15 mL), dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness to afford 11 as white needles which was recrystallized from EtOAc, (1.1 g, 78%); mp 98-99 C; 1H NMR (270 MHz, CDCl3): delta 7.25-7.21 (m, 5H, Ar), delta 5.7 (br s, 1H, NH), delta 4.15-4.12 (m, 1H, CH-NH), delta 3.66-3.58 (m, 2H, CH2-OH), delta 2.87-2.84 (d, 2H, CH2-Ph), delta 2.64-2.62 (t, 1H, OH), delta 2.03 (s, 3H, Ac); HRMS (ESI+): (Mwt. 193); m/z found: 194.1168 [M+H]+, C11H16NO2 requires 194.1181 and 216.0987 [M+Na]+, C11H15NO2Na requires 216.1000.
75%
In tetrahydrofuran; for 16.0h;
To a stirred solution of L-phenylalaninol (228 mg, 1.51 mmol) in THF (5 mL) was added acetic anhydride (0.15 mL, 1.59 mmol) and the mixture stirred for 16 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with 1 N HCL (15 mL), saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by column chromatography on silica gel afforded the N-acetylated alcohol (220 mg, 75%) as a white solid. 1H NMR (CDCl3) delta 1.95 (s, 3H), 2.87 (d, 2H, J=6.0 Hz), 3.17 (br s, 1H), 3.56-3.68 (m, 2H), 4.13-4.21 (m, 1H), 5.97 (br d, 1H, J=6.0 Hz), 7.20-7.34 (m, 5H). The alcohol was then oxidized according to the general Dess-Martin procedure and the crude aldehyde used without further purification.
(S)-2-(6-methyl-5-nitro-pyridin-2-ylamino)-3-phenyl-propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With sodium acetate; In ethanol; at 130 - 150℃; for 0.666667h;Microwave irradiation;
Example 11 (S)-2- (6-Methyl-5-nitro-pyridin- 2-ylaminop3-phenyl-propan-l-ol. 6-Chloro-3-nitro-2-picoline (30 mg, 0.17 mmol) was coupled with (S)-2-amino-3-phenyl- propan-l-ol (32 mg, 0.21 mmol), sodium acetate (28 mg, 0.34 mmol) in EtOH (2 mL). The reaction was heated in a microwave oven for 20 min at 130 °C and then additionally 20 minutes at 150 °C. The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with EtOAc and evaporated. Purification on a silica column with a gradient solution of heptane : EtOAc gave 24 mg (48percent) of (S)-2-(6-methyl-5-nitro- pyridin-2-ylamino)-3-phenyl-propan-l-ol as a yellow solid.
(S)-β-[(9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-1H-purin-6-yl)amino]benzenepropanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine;
2.0 g of 2,6-dichloro-9-(2,3,5-tri-O -acetyl-beta-D-ribofuranosyl)-9H-purine was combined with 0.67 g of S-(-)-2-amino-3-phenyl-1-propanol, 0.67 ml triethylamine, and heated to reflux for 16 hours. The solvent was removed and the residue was purified by flash chromatography (5-10% methanol/trichloromethane) to yield 0.90 g of a foam. Less pure fractions were rechromatographed as above to provide a total of 1.81 g of (S)-beta-[(9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-2-chloro-1H-purin-6-yl)amino]benzenepropanol.
With sodium hydrogencarbonate; triethylamine; In sodium chloride; chloroform; water; sulfur trioxide pyridine complex; dimethyl sulfoxide;
Example 1-22 Synthesis of <strong>[118133-15-6]1-ethoxycarbonylpiperidine-4-carboxylic acid</strong>-(1S)-(1-formyl-2-phenyl)ethylamide (Compound No. 1-22): 50 ml of a chloroform solution containing 0.84 g (4.17 mmol) of <strong>[118133-15-6]1-ethoxycarbonylpiperidine-4-carboxylic acid</strong> synthesised in Reference Example 1-5 was cooled in an ice bath containing sodium chloride. 0.61 ml (4.36 mmol) of triethylamine and 0.38 ml (3.97 mmol) of ethyl chlorocarbonate were successively added to the above solution. After stirring for 30 minutes, a chloroform solution containing 0.6 g (3.97 mmol) of (2S)-2-amino-3-phenylpropanol synthesised in Reference Example 1-48 was added to the above prepared reaction mixture. The reaction mixture was stirred for one hour at -10C and further stirred overnight at room temperature. The reaction mixture was washed successively with a 1 N hydrochloric acid solution, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogencarbonate and then a saturated aqueous solution of sodium chloride. The solvent was distilled away under reduced pressure. The residue thus obtained was crystallized in isopropyl ether and then the crystals were separated by filtration. 0.95 g (2.84 mmol) of the thus obtained crystals was dissolved in 10 ml of dimethyl sulfoxide, 1.60 ml (11.4 mmol) of triethylamine was added thereto. Furthermore, 10 ml of a dimethyl sulfoxide solution in which 1.81 g (11.4 mmol) of pyridine sulfur trioxide was added dropwise to the above reaction mixture. After stirring for one hour, the reaction mixture was poured into 10 ml of iced water and extracted with ethyl acetate. The extract layer was washed successively with a 10% cirtic acid solution, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The resultant organic extract layer was dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. The residue thus obtained was chromatographed on a silica gel column for purification, whereby 0.53 g of the captioned Compound No. 1-22 was obtained as crystals in a yield of 41%.
(S)-2-Aminomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
a (S)-2-Aminomethyl-N-(3-phenylpropan-1-al-2-yl)benzamide 5 g (28.2 mmol) of <strong>[4692-99-3]5-methylisatoic anhydride</strong> and 4.3 g (28.5 mmol) of (S)-2-amino-3-phenyl-1-propanol in 150 ml of tetrahydrofuran were heated at reflux for about 8 h. The mixture was then concentrated under reduced pressure and the residue was distributed between ethyl acetate and 2M aqueous sodium hydroxide solution. The organic phase was dried and once again concentrated under reduced pressure. This residue was then treated with ether, affording 3.2 g (39%) of the product.
With PS-DCC; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 100℃; for 0.166667h;Microwave irradiation;
In a microwave vial containing 3 eq. of PS-DCC, 4-(pyridin-4-yl) benzoic acid (20 mg, 0.1 mmol) was added dissolved in DMA (1.0 ml). Then a solution of HOBT (14 mg, 0.1 mmol) dissolved in DMA (0.3 ml) was added followed by the addition of DIEA (36 mul, 0.2 mmol) dissolved in DMA (0.3 ml) and the addition of (S)-2-amino-3-phenylpropan- 1-ol (17 mg, 0.11 mmol) dissolved in DMA (0.6 ml). The mixture was heated in the mi- <n="186"/>crowave to 100 0C for 600 seconds. The reaction was filtered through Si-Carbonate, 6ml-1g supplied by Silicycle chemical Division and transferred to 20 ml vials. The reaction was checked by LC/MS and concentrated to dryness. The residues were dissolved in 1 :1 DMSO/MeOH and purified by reverse phase HPLC (TFA method). Product was characterized by 1H NMR, MS and LC/MS.1H NMR (500 MHz, DMSO-D6/D2O) delta = 2.71 - 2.86 (m, 1 H) 2.94 - 3.02 (m, 1 H) 3.42 -3.59 (m, 2 H) 4.15 - 4.27 (m, 1 H) 7.14 - 7.22 (m, 1 H) 7.23 - 7.33 (m, 4 H) 7.73 - 7.82 (m, 2 H) 7.84 - 7.97 (m, 4 H) 8.61 - 8.68 (m, 2 H);Formula: C21 H20 N2 O2 CaIc MW: 332,40MS (ESI) positive ion 333 (M+H); negative ion 331 (M-H).The following compounds were prepared in an analogous method:
With triethylamine; In N,N-dimethyl-formamide; at 23℃; for 2h;Darkness; Inert atmosphere;
To a vial containing NBD-F 2 (46.6 mg, 0.244 mmol, 1.0 equiv) was added L-phenylalaninol5 15 (45.0 mg, 0.298 mmol, 1.2 equiv), 0.5 mL DMF, and then triethylamine (0.07 mL, 0.502 mmol, 2.0 equiv), immediately producing a black reaction mixture. The reaction was allowed to stir in the dark at 23 C for 2 h. The solvent was removed in vacuo with gentle heating (from 23 C to 70 C) to yield a black sludge which was then loaded onto a silica column using the dry-loading technique (see above). Flash column chromatography of the residue on silica gel (1:2 hex/EtOAc, Rf = 0.52) afforded the desired product 21 as a red film (63 mg, 82%). 1H NMR (CDCl3, 400 MHz) delta: 8.29 (1H, d, J = 8.4 Hz), 7.24 (5H, m), 6.93 (1H, J = 8.6 Hz), 6.10 (1H, J = 8.9 Hz), 4.18 (1H, br s), 3.97 (1H, dd, J = 11.1, 3.0 Hz), 3.88 (1H, dd, J = 11.1, 4.4 Hz), 3.08 (1H, m). HRMS (ES+): calcd for C15H15N4O4 [M+H]+ 315.1093, found 315.1096.
With carbon tetrabromide; triethylamine; triphenylphosphine; In toluene; at 90℃; for 8h;Inert atmosphere;
General procedure: A 200-ml three-necked flask equipped with a condenser was charged with Ph3P (2.20 g, 8.4 mmol), Et3N (0.85 g, 8.4 mmol), CBr4 (16.8 g, 8.4 mmol), the substrate 1 (3.3 mmol), and fluorinated carboxylic acid (2.8 mmol) in toluene (15.0 ml) under a nitrogen atmosphere. After the solution was stirred for about 10 min at room temperature, the mixture was heated to 90 C by for 1-3 h with stirring. The solvent was evaporated under reduced pressure, and the residue was diluted with petroleum ether (60-90 C) and filtered. The residual solid Ph3PO and Et3N·HCl was washed with petroleum ether three times. The filtrate was concentrated, and the residue was purified by column chromatography to obtain product 3.
General procedure: Constant current electrolyses (I = 25 mA cm-2) were performed under a nitrogen atmosphere, at 20C, using an Amel Model 552 potentiostat equipped with an AmelModel 731 integrator. All the experiments were carried out in a divided glass cell separated through a porous glass plug filled up with a layer of gel (i.e., methylcellulose 0.5% vol dissolved in DMF-Et4NPF6 1.0 mol dm-3); Pt spirals (apparent areas 0.8 cm2) were used both as cathode and anode. MeCN-Et4NPF6 0.1 mol dm-3 was used as solvent-supporting electrolyte system (catholite: 20 cm3; anolite: 5 cm3).1 mmol of substrate was present in the catholyte (except for D-cycloserine, which was added to the catholyte after the end of the electrolysis). After 145 C (if not otherwise stated) were passed, the current was switched off and 1 mmol of alkylating agent was added to the catholyte. The solution was kept under stirring at room temperature for 2 hours, than the solvent was evaporated under reduced pressure and the residue was extracted three times with diethyl ether. The products were purified by flash column chromatography, using a mixture of ethyl acetate/light petroleum ether 2/8 in volume. The reactions on D-cycloserine were carried out following the general method, but the substrate was added to the catholyte after the end of the electrolysis. After 15 minutes at room temperature, the alkylating agent was added and the solution was kept under stirring at rt for 2 hours. The solvent was evaporated under reduced pressure and the residue was treated with 1 cm3 of saturated acqueous NaHCO3 and 1 mmol of ethyl chloroformate, at 0C, for 2 h. The solution was then acidified with diluted HCl (pH 4) and extracted with diethyl ether. The products were purified by flash column chromatography.
General procedure: To a cold solution of N-protected amino acid 2 (3 mmol) in dryTHF (8 ml) at -15C under N2 was added 4-methylmorpholine(0.33 mL, 3 mmol) followed by addition of isobutyl chloroformate (0.39mL, 3 mmol). The reaction mixture was allowed to stir for 5 minutes and then, aTHF solution of chiral amino alcohol 3 (3 mmol) was added to the reaction flask at -15C. The mixture was warmed to ambient temperature over 16 h. Then the reaction mixture was concentrated and dissolved in 13 mL of ethyl acetate and 3 mL of water. After separation of layers, the ethyl acetate layer was washed with 1N HCl (12 mL), water (5 mL ), 5% NaHCO3(12 mL ), water (6 mL ), and then with saturated NaCl (6 mL). The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo to afford chiral hydroxyldiamide 4 as a white solid after crystallization in ethylacetate / hexane.
82%
General procedure: To a cold solution of N-protected amino acid 7 (3 mmol) in dry THF (10 mL) at -15oC under N2 were added 4-methylmorpholine (0.33 mL, 3 mmol) followed by addition of isobutyl chloroformate (0.39 mL, 3 mmol). The reaction mixture was allowed to stir for 5 minutes and then, a THF solution of chiral amino alcohol 8 (3 mmol) was added to the reaction flask at -15 oC. The reaction was warmed to room temperature and stirred for 16 h at rt. The reaction mixture was concentered and dissolved in 15 mL of ethyl acetate and 3 mL of water. After separation of layers,The ethyl acetate layer was washed with 1 N HCl (12 mL), water (3 mL), 5% NaHCO3 (12 mL), water (6 mL), and then with saturated NaCl. The organic layer was concerted to afford chiral hydroxyldiamide 2 as a white solid after crystallization in ethylacetate/hexane.
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids.
(S,E)-N-(1-(4-bromophenyl)-3-((1-hydroxy-3-phenylpropan-2-yl)amino)-3-oxoprop-1-en-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With methylene chloride; at 0℃;
General procedure: Compounds 5 was obtained by the acylation reaction with glycine (0.01 mol) and benzoyl chloride or benzoyl chloride derivatives (0.02 mol) as the raw materials in sodium hydroxide solution, which was then reacted with benzaldehyde or benzaldehy dederivatives (0.01 mol) in the presence of acetic anhydride (Ac2O)(10 mL) and sodium acetate (AcONa) (0.01 mol) to obtain compounds 6. Next, the intermediate mentioned above was reacted with L-phenylalaninol (0.01mol). The crude product was purified bycolumn chromatography to yield the title compound 7a-g,respectively.
N-((S)-1-hydroxy-3-phenylpropan-2-yl)2,6-dimethoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: Benzoic acid derivatives (1 mmol) and heterogeneous catalyst (10 mg) were mixed for 5 min in 1 mL of anhydrous toluene. Then, the amine (1.2 mmol) was added and the mixture was reacted under ultrasound for about 15-60 min at room temperature. After completion of the reaction (monitored by TLC), the catalyst was separated through filtration and the solvent was removed in vacuo. The obtained residue was dissolved in chloroform (10 ml) and washed with 10% NaHCO3 (10 ml) and HCl (1 M, 10 ml). The organic layer was extracted and dried over Na2SO4 and concentrated under reduced pressure to afford the amide, which was purified by recrystallization or column chromatography.
benzyl ((S)-1-(((S)-1-(((S)-1-hydroxy-3-phenylpropan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; water; at 20℃; for 18h;
General procedure: To a stirred solution of the N-protected amino acid derivative (1.0 eq) in dry CH2Cl2 (50-75 mM)was added EDC (1.3 eq), HOBt·H2O (1.5 eq) and DIPEA (3.0 eq). The solution was stirred at rtovernight, diluted with CH2Cl2 and the organic layer washed twice with 1M HCl(aq), saturatedaqueous NaHCO3(aq) and brine. The organic layer was dried over MgSO4(s) and the solventremoved in vacuo. See individual experiments for details.
In ethanol; at 100℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: To the mixture of vicinal amino alcohol (1, 1.0 mmol, 1.0 equiv.) in absolute ethanol (2.0 mmol),potassium ethylxanthate (5.0 mmol, 5.0 equiv.) was added quickly. After flushed with N2 for 5 mins,the suspension was sealed and heated in an oil bath at 100 C for 24 hr. The it was cooled down toroom temperature, the mixture was transferred to a 50 mL-round bottom flask, and evaporated underreduced pressure to remove alcohol. Then water (10 mL) was added to the slurry and extracted withethyl acetate (30 mL*3). Combined organic phase was washed with brine (30 mL) and dried overanhydrous Na2SO4. After concentration, the crude product was obtained. Then it was applied onsilica gel for flash chromatography to afford corresponding 1,3-thiazolidine-2-thione (2). For somecases, 1,3-oxazolidine-2-thione (3) was obtained as side product.
In a sealed tube, a mixture of 1 (2.74 g, 10 mmol)and (S)-phenylalaninol (3.78 g, 25 mmol) in methanol (10 mL) was stirred at 115 C for 12 h. After cooling to ambient temperature, the crude product was poured into crushed ice (100 g), stirred for15 min, filtered, washed with water (20 mL 3) and the residues was dried under vacuum. The white product was used for the next step without further purification (4.50 g, 88%). 1H NMR (400 MHz,CDCl3): d 8.43 (s, 2 H), 7.94 (d, J 8 Hz, 2 H), 7.32e7.21 (m, 10 H),4.40e4.32 (m, 2 H), 3.83e3.74 (m, 4 H), 3.06e2.96 (m, 4 H), 2.59 (br,2 H). 13C NMR (150 MHz, CDCl3): d 162.6, 149.7, 137.5, 136.4, 129.4,128.8, 128.5, 126.9, 63.6, 53.1, 37.0. HRMS (MALDITOF) calcd forC25H27BrN3O4 [M H] 512.1179, found 512.1186.
(S)-6-(4-benzyl-1-(p-tolyl)-4,5-dihydro-1H-imidazol-2-yl)-2,2′-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
(1) Preparation of (S)-6-(4-benzyl-1-(p-tolyl)-4,5-dihydro-1H-imidazol-2-yl)-2,2'-bipyridine:2,2-bipyridyl-6-carboxylic acid (10 mmol) was refluxed in thionyl chloride solution (5 mL) for 8 h, and the excess thionyl group was removed by rotary distillation.Chlorine obtained as a pale yellow oil, which was dissolved in anhydrous methylene chloride, and then, in ice bath, was added dropwise to dissolve L-phenylalaninol (11 mmol, 1.82 g) and triethylamine (30 mmol, 4.2 In an anhydrous dichloromethane solution of mL), after the addition is completed,The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the reaction mixture was spun dry, ethyl acetate was added, and the insoluble material was removed by filtration, and the filtrate was dried.Continue to add thionyl chloride (5 mL) under reflux for 8 h, and remove excess thionyl chloride by rotary distillation to give a reddish brown oil.Dissolve it in an anhydrous dichloromethane solution and add dropwise p-toluidine (11 mmol, 1.2 g) in an ice bath.And triethylamine (60mmol, 8mL) in anhydrous dichloromethane, after working overnight at room temperature, then add 10% sodium hydroxideThe aqueous solution (35 mL) was stirred at room temperature for 8-12 h. After completion, the mixture was separated and the aqueous phase was extracted three times with dichloromethane.Add anhydrous magnesium sulfate, filter by suction, spin dry, and separate by column chromatography (eluent ratio PE/EA = 3/1~1/10) to obtain correspondingNNN' ligand. Brown solid; yield 56%;
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