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Structure of 104-86-9 * Storage: {[proInfo.prStorage]}
* 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.
With C25H19N3ORuS; potassium <i>tert</i>-butylate In iso-butanol at 120℃; for 0.5 h; Inert atmosphere
General procedure: A flask (25 mL) containing ruthenium(II) complex (1 Mpercent) and 2-butanol (5 mL) was stirredfor 5 min under an argon atmosphere at room temperature. Afterwards, KOtBu(0.05 mM) was added and the mixture was stirred for another 5 min. Then, the nitrile(0.5 mM) was added and placed on a hot plate at 120 °C for 30 min. After completion ofthe reaction, the catalyst was removed from the reaction mixture by addition of petroleumether followed by filtration and subsequent neutralization with 1 M HCl. The ether layerwas filtered through a short path of silica gel by column chromatography. To the filtrate,hexadecane was added as a standard and the yield was determined by GC.
86%
With sodium tetrahydroborate; iron(III) oxide In methanol at 40℃; for 0.666667 h; Sonication
General procedure: To the solution of substrate (10 mmol) in dry methanol (25 mL), Fe3O4 nanoparticles (50 mg) were added and the solution was sonicated for 10 min and then vigorously stirred at 40 °C. Sodium borohydride (30 mmol) was added in small lots cautiously while stirring the solution for 30 min and the progress of the reaction was monitored by thin layer chromatography (TLC). After the completion of reaction, the catalyst was separated by using external magnet and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and then separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography over silica gel (100–200 mesh) using ethyl acetate-hexane mixture (varying concentration) as the eluent. All products were analyzed by IR and NMR spectra which were in good agreement with the reported values [5, 10].
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 14, p. 4991 - 5002
[2] Journal of the American Chemical Society, 2015, vol. 137, # 28, p. 8888 - 8891
[3] Journal of Coordination Chemistry, 2015, vol. 68, # 2, p. 321 - 334
[4] Synlett, 2001, # 10, p. 1623 - 1625
[5] Catalysis Letters, 2016, vol. 146, # 10, p. 2149 - 2156
[6] Angewandte Chemie - International Edition, 2016, vol. 55, # 47, p. 14653 - 14657[7] Angew. Chem., 2016, vol. 128, # 47, p. 14873 - 14877,5
[8] Tetrahedron, 1992, vol. 48, # 21, p. 4301 - 4312
[9] Tetrahedron, 2002, vol. 58, # 11, p. 2211 - 2213
[10] Journal of the Chemical Society, 1946, p. 466
[11] Journal of the American Chemical Society, 1951, vol. 73, p. 242
[12] Synthesis, 1981, # 8, p. 605 - 606
[13] European Journal of Inorganic Chemistry, 2011, # 22, p. 3381 - 3386
[14] Chemistry - A European Journal, 2013, vol. 19, # 14, p. 4437 - 4440
[15] Patent: US8563753, 2013, B2, . Location in patent: Page/Page column 17; 18; 19; 20
[16] European Journal of Organic Chemistry, 2015, vol. 2015, # 27, p. 5944 - 5948
[17] Chemical Communications, 2016, vol. 52, # 9, p. 1812 - 1815
[18] Journal of the American Chemical Society, 2016, vol. 138, # 28, p. 8781 - 8788
[19] Journal of the American Chemical Society, 2016, vol. 138, # 28, p. 8809 - 8814
[20] ChemCatChem, 2016, vol. 8, # 7, p. 1329 - 1334
[21] ACS Catalysis, 2017, vol. 7, # 1, p. 275 - 284
[22] Catalysis Science and Technology, 2018, vol. 8, # 2, p. 499 - 507
3
[ 3848-36-0 ]
[ 104-86-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
With iron oxide; zirconium(IV) chloride; sodium cyanoborohydride In neat (no solvent) at 75 - 80℃; for 2 h;
A mixture of benzaldehyde oxime (0.121 g, 1 mmol) and nano Fe3O4 (0.046 g, 0.2 mmol) (nano particle size≈70 nm) was ground in a porcelain mortar. ZrCl4 (0.233 g,1 mmol) was then added and grinding the mixture was continued for a moment at room temperature. The mortar was heated in an oil bath until the temperature of reaction mixture reaches 75–80 °C. NaBH3CN (0.314 g, 5 mmol) wasthen added portion wisely and the mixture was ground for15 min at 75–80 °C. After completion of the reaction, H2O(5 mL) was added and the mixture was stirred for 5 min. The mixture was extracted with EtOAc (2 × 5 mL) and then dried over anhydrous Na2SO4. Evaporation of the solvent affords the pure liquid benzylamine in 93 percent yield (0.1 g, Table 2, entry 1). 1H NMR (CDCl3, 300 MHz): δ7.25–7.33 (m, 5H), 3.83 (s, 2H), 2.04 (s, 2H). 13C NMR(CDCl3, 75.5 MHz): δ 140.06, 128.56, 128.41, 128.20,127.65, 127.00, 53.05. FT-IR (KBr, υ cm−1): 3,368, 3,292,3,061, 3,026, 2,920, 2,858, 1,605, 1,585, 1,511, 1,494,1,452, 1,246, 1,026, 866, 736, 698.
86%
With sodium tetrahydroborate; iron(III) oxide In methanol at 40℃; for 0.5 h; Sonication
General procedure: To the solution of substrate (10 mmol) in dry methanol (25 mL), Fe3O4 nanoparticles (50 mg) were added and the solution was sonicated for 10 min and then vigorously stirred at 40 °C. Sodium borohydride (30 mmol) was added in small lots cautiously while stirring the solution for 30 min and the progress of the reaction was monitored by thin layer chromatography (TLC). After the completion of reaction, the catalyst was separated by using external magnet and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution and then separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography over silica gel (100–200 mesh) using ethyl acetate-hexane mixture (varying concentration) as the eluent. All products were analyzed by IR and NMR spectra which were in good agreement with the reported values [5, 10].
1.25 g
at 20℃; for 6 h;
Second step, p-chlorobenzaldehyde oxime (2.45 g) and zinc dust (6.15 g) in HOAc (25 ml) was stirred at room temperature for 6 h. The reaction solution was filtered to remove the excess zinc dust and ZnOAc residue, and the filtrate was concentrated to yield p-chlorolbenzylamine (1.25 g) as a yellowish oil.
1.25 g
at 20℃; for 6 h;
weigh precisely 2.45 g of p-dichlorobenzene oxime, dissolve in HOAc (25 mL), add 6.15 g of Zn powder, stir at room temperature for 6 hours, filter the reaction solution, remove excess Zn powder And ZnOAc precipitation are removed, and the HOAc is evaporated with the filtrate to give 1.25 g of yellow oily p-dichlorobenzene methylamine.
Reference：
[1] Journal of the Chinese Chemical Society, 2005, vol. 52, # 1, p. 109 - 112
[2] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 9, p. 3323 - 3326
[3] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 9, p. 3448 - 3452
[4] Journal of Chemical Research - Part S, 2003, # 6, p. 332 - 334
[5] Synthetic Communications, 2004, vol. 34, # 4, p. 599 - 605
[6] Journal of the Iranian Chemical Society, 2015, vol. 12, # 5, p. 873 - 878
[7] Catalysis Letters, 2016, vol. 146, # 10, p. 2149 - 2156
[8] Organic and Biomolecular Chemistry, 2016, vol. 14, # 45, p. 10599 - 10619
[9] Patent: EP2511283, 2012, A1, . Location in patent: Page/Page column 18
[10] Organic and Biomolecular Chemistry, 2013, vol. 11, # 3, p. 407 - 411
[11] Patent: US2013/45942, 2013, A1, . Location in patent: Paragraph 0114
[12] Patent: JP2015/172077, 2015, A, . Location in patent: Paragraph 0102
4
[ 27032-10-6 ]
[ 104-86-9 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1101 - 1107
[2] Green Chemistry, 2009, vol. 11, # 12, p. 1973 - 1978
[3] Tetrahedron Letters, 2016, vol. 57, # 37, p. 4183 - 4186
5
[ 131523-32-5 ]
[ 104-86-9 ]
Reference：
[1] RSC Advances, 2014, vol. 4, # 66, p. 34764 - 34767
[2] Polish Journal of Chemistry, 2001, vol. 75, # 3, p. 429 - 441
[3] Journal of the Chemical Society, 1931, p. 1225,1232
[4] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 1, p. 204 - 212
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6415 - 6420
6
[ 623-03-0 ]
[ 21913-13-3 ]
[ 104-86-9 ]
Reference：
[1] Synthetic Communications, 2002, vol. 32, # 8, p. 1265 - 1269
[2] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 3, p. 808 - 810
[3] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 3, p. 808 - 810
[4] Justus Liebigs Annalen der Chemie, 1926, vol. 449, p. 264
[5] Journal of the American Chemical Society, 1939, vol. 61, p. 3564
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 1999 - 2004
22
[ 623-03-0 ]
[ 21913-13-3 ]
[ 104-86-9 ]
[ 873-76-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 8, p. 2097 - 2101
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 8, p. 2097 - 2101
23
[ 67-56-1 ]
[ 27032-10-6 ]
[ 15184-98-2 ]
[ 104-86-9 ]
[ 104-11-0 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 14, p. 3339 - 3345
Reference：
[1] Polish Journal of Chemistry, 1984, vol. 58, # 10-12, p. 1025 - 1034
36
[ 130517-96-3 ]
[ 104-86-9 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 12, p. 2598 - 2600
37
[ 33499-37-5 ]
[ 104-86-9 ]
Reference：
[1] Journal of Organic Chemistry, 1969, vol. 34, # 6, p. 1817 - 1821
38
[ 57058-33-0 ]
[ 64-19-7 ]
[ 104-86-9 ]
Reference：
[1] Canadian Journal of Chemistry, 1984, vol. 62, p. 2401 - 2414
39
[ 104-83-6 ]
[ 104-86-9 ]
Reference：
[1] Journal of the Chemical Society, 1961, p. 1414 - 1416
[2] Synthesis, 1995, # 2, p. 150 - 152
[3] Journal of Organic Chemistry, 2011, vol. 76, # 5, p. 1425 - 1435
40
[ 540-69-2 ]
[ 104-88-1 ]
[ 104-86-9 ]
Reference：
[1] Journal of the Karnatak University, 1957, vol. 2, p. 19,26
41
[ 6342-46-7 ]
[ 586-95-8 ]
[ 104-86-9 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, p. 1397 - 1398
42
[ 3717-23-5 ]
[ 104-86-9 ]
Reference：
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1985, vol. 24, # 3, p. 252 - 253
43
[ 3717-24-6 ]
[ 104-86-9 ]
Reference：
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1985, vol. 24, # 3, p. 252 - 253
44
[ 100-46-9 ]
[ 104-86-9 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3804 - 3809
45
[ 109-73-9 ]
[ 104-86-9 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3804 - 3809
46
[ 67-56-1 ]
[ 27032-10-6 ]
[ 15184-98-2 ]
[ 104-86-9 ]
[ 104-11-0 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 14, p. 3339 - 3345
47
[ 6214-20-6 ]
[ 104-86-9 ]
[ 104-11-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
48
[ 15481-45-5 ]
[ 104-86-9 ]
[ 104-11-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
49
[ 104-86-9 ]
[ 80-48-8 ]
[ 104-11-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
50
[ 104-86-9 ]
[ 80-18-2 ]
[ 96982-27-3 ]
[ 104-11-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
51
[ 104-86-9 ]
[ 14123-76-3 ]
Reference：
[1] Patent: WO2016/83816, 2016, A1,
52
[ 6342-56-9 ]
[ 104-86-9 ]
[ 14123-76-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 17, p. 7412 - 7424
Example 6 [Show Image] (Experimental No.17) 5-Hydroxy-2-adamantanone (0.99 g, 6 mmol) was dissolved in dichloromethane (15 ml), a compound (I-4) (content 98%) (0.82 ml, 6.6 mmol) and acetic acid (0.45 ml, 7.8 mmol) were added thereto, the mixture was stirred at room temperature for 20 minutes, sodium borohydride (0.25 g, 6.6 mmol) was then added under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction solution was ice-cooled, 2M hydrochloric acid (8 ml) and water (15 ml) were added thereto, and the mixture was stirred for a while. The aqueous layer was washed with chloroform (15 ml and 10 ml), and the organic layer was extracted with water (15 ml). The aqueous layers were combined, 2M aqueous sodium hydroxide solution (9 ml) was added to adjust to pH = 8 to 9, and the combined aqueous layer was extracted with chloroform (15 ml). The aqueous layer was extracted again with chloroform (10 ml), and the organic layer was washed with saturated brine (15 ml). The organic layers were combined and then dried with sodium sulfate, and the organic solvent was evaporated under reduced pressure to obtain a colorless oil (1.35 g, crude yield = 77.1%). This oil was a mixture (II-4) in which an objective anti isomer and a syn isomer were present at a ratio of about 3 : 1, by NMR analysis (300 MHz). This oil was dissolved in warm ethyl acetate (2 ml), then heptane (30 ml) was added thereto, and then the mixture was stirred, and the resulting crystal was then filtered to obtain a crystal (0.31 g, crude yield = 17.7%). This crystal was a mixture in which an anti isomer [compound (III-4)] and a syn isomer were present at a ratio of about 14 : 1, by NMR analysis (300 MHz), and the purification effect by crystallization was identified. Compound (III-4) 1H NMR (300 MHz, CDCl3): d 1.34 - 2.05 (m, 13H), 2.75 (s, 1H), 3.74 (s, 2H), 7.27 - 7.29 (m, 4H). m.p.: 91 C
With triethylamine; In isopropyl alcohol; at 150℃; for 0.333333h;Microwave irradiation;
To a solution of compound 9-3 (50 mg, 0.27 mmol) and (4-chlorophenyl)methan- amine (47 mg, 0.33 mmol) in isopropyl alcohol (5 mL) was added Et3N (46 muL, 0.33 mmol). The solution was microwaved for 20 min at 1500C. TLC showed the reaction was completed. The mixture was concentrated and purified by flash chromatography to give A9 as a light yellow solid (52 mg, yield: 67 %, confirmed by 1H NMR, and LC-MS). The 1H NMR is shown in Figure 23.
67%
With triethylamine; In isopropyl alcohol; at 150℃; for 0.333333h;Microwave irradiation; Inert atmosphere;
To a solution of compound 9-3 (50 mg, 0.27 mmol) and (4-chlorophenyl)methan- amine (47 mg, 0.33 mmol) in isopropyl alcohol (5 mL) was added Et3N (46 mu, 0.33 mmol). The solution was microwaved for 20 min at 150C. TLC showed the reaction was completed. The mixture was concentrated and purified by flash chromatography to give A9 as a light yellow solid (52 mg, yield: 67 %, confirmed by 1H NMR, and LC-MS). The 1H NMR is shown in Figure 22. Preparation of A30
65%
With triethylamine; In N,N-dimethyl-formamide; for 4.0h;Reflux;
General procedure: Compound 4 (1.84 g, 0.01 mol) was mixed with (1.06 g, 0.01 mol) of trimethylamine and (0.01 mol)of the appropriate aromatic amine in 5 mL of dimethylformamide (DMF). The mixture was refluxedfor 4 h, cooled, and poured on crushed ice. The crystals were collected and crystallized from ethylalcohol. The melting points for all synthesized compounds were above 300 C.
. N,N'-bis(4-chlorobenzyl)pyrido[2,3-d]pyrimidine-2,4-diamine sesquihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
General procedure: A mixture of 5 (5.0 mmol), the respective amine (12 mmol), equimolecular amounts of triethylamine, and ethanol (15 mL) was heated at 70 C for 5 h with stirring. The solvent was removed under vacuum and the residue was dissolved in water (30 mL); the mixture was extracted with chloroform (3 × 25 mL) and the organic extracts were dried over anhydrous sodium sulfate and the solvent was removed in vacuum. For compounds 6t-y the resulting solid was purified by recrystallization as indicated in Table 1. For compounds 6z-ai the residual material isolated after removal of the solvent was washed with 5% HCl (25 mL) and the resulting solid was isolated and purified as indicated in Table 1.
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃;
GSK2945 was synthesized as described previously (Trump et al., 2013). The reductiveamination of <strong>[40137-29-9]4-chloro-2-methylbenzaldehyde</strong> (1) with 4-chlorobenzylamine (2) andsodium triacetoxyborohydride gave secondary amine 2 (3).
To a solution <strong>[1472104-49-6]4-bromo-2-fluoro-6-methoxy-benzoic acid</strong> (2.5 g, 10.0 mmol) in dichloromethane (30 ml) is added oxalyl chloride (1.04 ml, 12.0 mmol) added drop wise at 0 oC followed by addition of a catalytic amount of dimethylformamide. The mixture is stirred at the same temperature for 2 h. The solution is added via a cannula to a mixture of 4-chloro benzyl amine (1.7 g, 12.0 mmol) and triethyl amine (4.2 ml, 30.0 mmol) in dry tetrahydrofuran (50 ml) at 0 oC. After stirring at room temperature for 16 h the mixture is diluted with dichloromethane (50 ml) and washed with water (50 ml), brine (50 ml), dried over sodium sulfate and evaporated in vacuo. The crude product is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]- 2-fluoro-6-methoxy-benzamide (2.8 g, 7.52 mmol, 74%).
74%
d) Synthesis of 4-bromo-N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-benzamide To a solution <strong>[1472104-49-6]4-bromo-2-fluoro-6-methoxy-benzoic acid</strong> (2.5 g, 10.0 mmol) in dichloromethane (30 ml) is added oxalyl chloride (1.04 ml, 12.0 mmol) added drop wise at 0 C. followed by addition of a catalytic amount of dimethylformamide. The mixture is stirred at the same temperature for 2 h. The solution is added via a cannula to a mixture of 4-chloro benzyl amine (1.7 g, 12.0 mmol) and triethyl amine (4.2 ml, 30.0 mmol) in dry tetrahydrofuran (50 ml) at 0 C. After stirring at room temperature for 16 h the mixture is diluted with dichloromethane (50 ml) and washed with water (50 ml), brine (50 ml), dried over sodium sulfate and evaporated in vacuo. The crude product is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-benzamide (2.8 g, 7.52 mmol, 74%).
ethyl 2-tert-butoxycarbonylamino-3-(4-chlorobenzylamino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -10 - 20℃; for 16h;
General procedure: To a stirring solution of carboxylic acid (10 mmol, 1.0equiv) in dry DMF (10 mL) in a two-neck flask under argon atmosphere at -10 oC, HOBt (hydrate form, 1.76 g, 13 mmol,1.3 equiv) was added followed by the addition of DIPEA (2.26 mL, 13 mmol, 1.3 equiv) and EDCI (2.02 g, 13 mmol, 1.3equiv). The reaction mixture was stirred at -10 oC for 30 min before an appropriate amine (10 mmol, 1.0 equiv) was addedand allowed to warm to room temperature. After 16 h, the reaction mixture was treated with 10% citric acid solution (25mL) and extracted with DCM. The organic phase was washed with saturated NaHCO3 solution (2 ×), followed with waterand brine, dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to remove solvents. The crude product waspurified by silica gel flash chromatography (EtOAc-Heptane).
With sulfur; In neat (no solvent); at 130℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of 2-chloronitrobenzene (1 mmol), amine (3 mmol), and elemental sulfur (2 mmol) was stirred in a sealed tube under nitrogen atmosphere at indicated temperature for 24 h (See Table 2). After being cooled to room temperature, the crude reaction mixture was triturated and dissolved in ethylacetate, then filtered and the filtrate was concentrated, and the residue was purified by column chromatography on silica gel to afford the desired product.
General procedure: To a solution of <strong>[1458-18-0]methyl 3-amino-5,6-dichloro-2-pyrazinecarboxylate</strong> (1.0 eq.) in 2-propanol (5 mL/mmol), an appropriate primary or secondary amine(3-6 eq.) was added, and the reaction mixture wasrefluxed for 2 h.10) The solution was cooled to roomtemperature, concentrated under reduced pressure, andthe residue was purified by silica-gel column chromatography(Wako gel C-200, 30-40% ethyl acetate/n-hexane) to afford the series 1 intermediate (yield:32-95%). The regioselectivity of the nucleophilicsubstitution at the 5-position of the pyrazine ring wasconfirmed by an X-ray structural analysis (Fig. S1).
5-bromo-2-chloro-N-(4-chlorobenzyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With silica gel; In neat (no solvent); at 100℃; for 12h;Inert atmosphere; Sealed tube;
General procedure: These compounds were prepared using the same procedure as reported above, but at 100C for 6-28h. Following workup, the products (all solids) were recrystallized from EtOH to afford the isolated yields shown in Table 4. For analytical samples, purification was achieved by chromatography on a 15cm×2.5cm silica gel column eluted with 40-60% EtOAc in hexanes.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 2h;Inert atmosphere;
<strong>[20776-63-0]2-Amino-4,6-dichlorobenzoic acid</strong> (0.5 g; 2.427 mmol), 5 ml of dry DCM, and TEA (1.353 ml; 9.71 mmol) were placed in a reaction flask under nitrogen. 4-Chlorobenzylamine (0.384 ml; 3.15 mmol) was added slowly and then T3P (2.86 ml; 4.85 mmol; 50 % in EtOAc) was added keeping the temperature at rt. The mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM and washed three times with water. The organic phase was dried with a phase separator and evaporated to dryness to yield 0.814 g of 2-amino-4,6- dichloro-N-(4-chlorobenzyl)benzamide. 1H-NMR (400 MHz, --DMSO): delta 4.42 (d, 2H), 5.56 (br s, 2H), 6.69 (dd, 2H), 7.31-7.45 (m, 4H), 8.99 (t, 1H).
Bromo maleic anhydride 0.6mmol weighed into three neck round bottom flask, 10ml of acetone was dissolved, 4-chloro-benzylamine 0.5mmol dissolved by acetone 10ml was slowly dropped into a constant pressure funnel three-neck flask with magnetic stirring reaction at room temperature for IH, the acetone solvent was removed by rotary evaporation, 15ml of toluene as a solvent instead, 0.02g of anhydrous sodium acetate were added to the reaction system, 0.2ml of triethylamine, 0.05 g of hydroquinone was slowly warmed to 115 reflux 2.5h, the reaction is tracked by thin layer chromatography on silica gel.After the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, to obtain a concentrate, the concentrate was subjected to silica gel column chromatography (eluent: VPetroleum ether: VEthyl acetate= 12: 1), and collecting the target fluid, the rotation solvent in vacuo to give the desired product.Yield 53.3.
Phenyl maleic anhydride 0.6mmol weighed into three round-bottomed flask, dissolved in 5ml of acetone, 4-chloro-benzylamine 0.9mmol 5ml of acetone was dissolved dropping funnel was slowly added dropwise three-necked flask, with magnetic stirring constant voltage, after reaction at room temperature IH, solvent was removed by rotary evaporation acetone as solvent instead of toluene 6ml, 0.012g of anhydrous sodium acetate were added to the reaction system, 0.2ml of triethylamine, 0.018 g of hydroquinone was slowly warmed to 115 The reaction was refluxed for 2.5h, the reaction is tracked by thin layer chromatography on silica gel.After the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, to obtain a concentrate, the concentrate was subjected to silica gel column chromatography (eluent: VPetroleum ether: VEthyl acetate= 10: 1), and collecting the target fluid, the rotation solvent in vacuo to give the desired product.Yield 35.9.
In methanol;Inert atmosphere; Reflux; Green chemistry;
General procedure: The oxocomponent(i.e. the aldehyde or the ketone) (0.5 mmol, 1 eq.), the amine (0.5 mmol, 1 eq.), theisocyanide (0.5 mmol, 1 eq.), and <strong>[612-20-4]2-hydroxymethylbenzoic acid</strong> (0.5 mmol, 1 eq.) were one-potmixed in methanol (2 M, 250 muL) and stirred at reflux temperature under a nitrogen atmosphere for3-4h. The formation of the Ugi alpha-acylamino amide was monitored by TLC, and the crude reactionmixture was evaporated and filtered through a pad of silica gel (n-hexane/ EtOAc). The Ugi alpha-acylamino amide (0.15 mmol) was then stirred for 10 minutes at room temperature in 4N HClsolution in 1,4-dioxan (1 mL). The reaction was then evaporated to dryness and triturated with nhexaneto give the hydrochloride salt of the corresponding N,N?-substituted alpha-amino amide.
In methanol;Inert atmosphere; Reflux; Green chemistry;
General procedure: The oxocomponent(i.e. the aldehyde or the ketone) (0.5 mmol, 1 eq.), the amine (0.5 mmol, 1 eq.), theisocyanide (0.5 mmol, 1 eq.), and <strong>[612-20-4]2-hydroxymethylbenzoic acid</strong> (0.5 mmol, 1 eq.) were one-potmixed in methanol (2 M, 250 muL) and stirred at reflux temperature under a nitrogen atmosphere for3-4h. The formation of the Ugi alpha-acylamino amide was monitored by TLC, and the crude reactionmixture was evaporated and filtered through a pad of silica gel (n-hexane/ EtOAc). The Ugi alpha-acylamino amide (0.15 mmol) was then stirred for 10 minutes at room temperature in 4N HClsolution in 1,4-dioxan (1 mL). The reaction was then evaporated to dryness and triturated with nhexaneto give the hydrochloride salt of the corresponding N,N?-substituted alpha-amino amide.
6-bromo-N-(4-chlorobenzyl)quinazolin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;
To a solution of <strong>[882672-05-1]6-bromo-2-chloroquinazoline</strong> (200 mg, 0.821 mmol) in N,N- dimethylformamide (DMF) (1 mL) was added (4-chlorophenyl)methanamine (233 mg, 1 .643 mmol) and K2C03 (341 mg, 2.464 mmol). The reaction mixture was stirred at 100 C for 16h. The reaction mixture was cooled to rt and diluted with dichloromethane (50 mL). The mixture was filtered and concentrated under reduced pressure to afford crude product. The crude product was triturated with diethyl ether (20 mL). The mixture was filtered and the filter cake was washed with diethyl ether (20 mL). Then the filter cake was dried under vacuum to afford the title compound as a yellow solid (200 mg, 98% pure, 68% yield).
methyl 6-chloro-4-((4-chlorobenzyl)amino)pyridazine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 1h;
(4-Chlorophenyl)methanamine (1.95 mL, 15.94 mmol) and DIPEA (2.78 mL, 15.94 mmol) were added to a stirred solution of <strong>[372118-01-9]methyl 4,6-dichloropyridazine-3-carboxylate</strong>(3.0 g, 14.49 mmol) in MeCN (48.3 mL, 0.925 mol) at rt. After lh of stirring the precipitate formed was isolated by filtration. The powder was triturated with Et20 containing small amount of DMF to afford the title compound as off-white powder (3.8 g, yield: 84 %).
2-(4-chlorobenzyl)-5-methoxyisoindolin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With triethylamine; In toluene; at 110℃; for 4h;
The reactants <strong>[56427-63-5]ethyl 2-bromomethyl-4-methoxybenzoate</strong> (500 mg, 1.93 mmol), para-chlorobenzylamine (272 mg, 1.93 mmol) and triethylamine (585 mg, 5.79 mmol) were dissolved in toluene (3 mL), then sealed and heated at 110 C for 4 hours. After the completion of the reaction, the reaction solution was concentrated, then was extracted with water and ethyl acetate. The organic phases were combined, washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica column chromatograph to afford the product 21-1 (275 mg, 50%).
General procedure: In this work, previously reported N-benzyl-2-bromo-4-(1,3-dioxoisoindolin-2-yl)butanamide derivatives (25a-e) [44] were obtained by activating the carboxylic acid group of 24 (1 eqv) by using n-propanephosphonic acid anhydride (T3P, 50% in EtOAc, 1 eqv). The reaction was carried out under argon atmosphere for 2hat 0C in dry methylene chloride. Then, distilled triethylamine (1.2 eqv) and the appropriate N-benzylamine (1.1 eqv) were added to the reaction mixture [57]. The reaction was continued at room temperature for 12h. The products were purified by column chromatography over silica gel (DCM/acetone=9:1) to yield 25a-e as a white solid.
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