* 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 [ReOCl2(1,2-bis(diphenylphosphino)ethane)]; hydrogen; potassium tetraphenylborate In toluene at 160℃; for 24 h; Autoclave; Inert atmosphere
General procedure: By the following method, it went 3-reduction of phenylpropionic acid (hydrogenation).Put a stir bar in a dry glass tube (25mL), further, 3-phenylpropionic acid (75.09mg, 0.5mmol), the rhenium complex 4 (7.07mg, 0.010mmol), potassium tetraphenylborate (17.92mg , accommodates 0.05 mmol), the tubes containing this mixture, was inserted into the autoclave. Then, after replacing the inside of the autoclave in an argon gas atmosphere was added while continuing flow of argon gas dehydration toluene (4.0mL). This autoclave through a stainless steel tube by introducing hydrogen gas from a hydrogen gas cylinder connected, the inside of the autoclave was replaced with hydrogen gas, then disconnect the hydrogen gas pressure from the leak valve. This operation - was repeated (substituted de substitution) five times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, using a constant temperature bath, and allowed to react for 12 hours at 180 ° C. After completion of the reaction, the autoclave was cooled by immersion in an ice bath, almost to room temperature. Then, carefully release the hydrogen gas that is inside in the draft. After removing the solvent, the reaction product was analyzed by 1H NMR using mesitylene (60.1 mg, 0.5 mmol) as an internal standard substance. As a result, 3-phenylpropyl alcohol, and 3-phenylpropionic acid 3-phenylpropyl The yield was 98percent and 1percent, respectively. In the above Examples 6-1,Substrate (carboxylic acid compounds), and hydrogenation conditions (hydrogen pressure),Except that to adopt the conditions described in Table 7-9,It has been reduced (hydrogenated) in the same manner as in Example 6-1.However,The entry 19-26 in Table 9,Using tetrahydrofuran (THF) as a solvent.The results are shown in Tables 7 to 9.
Reference：
[1] Journal of Organic Chemistry, 1994, vol. 59, # 14, p. 3933 - 3938
[2] Tetrahedron, 2006, vol. 62, # 29, p. 7056 - 7070
[3] Tetrahedron Letters, 2016, vol. 57, # 35, p. 3942 - 3944
[4] Canadian Journal of Chemistry, 2009, vol. 87, # 5, p. 650 - 661
[5] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 452 - 458
[6] Patent: JP2015/124156, 2015, A, . Location in patent: Paragraph 0117; 0118; 0127; 0129; 0131
[7] Steroids, 2007, vol. 72, # 4, p. 351 - 359
[8] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 11, p. 2003 - 2006
[9] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 7, p. 1757 - 1766
[10] Journal of Medicinal Chemistry, 2006, vol. 49, # 6, p. 2110 - 2116
[11] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 756 - 760
[12] Green Chemistry, 2018, vol. 20, # 10, p. 2242 - 2249
[13] Journal of the American Chemical Society, 1949, vol. 71, p. 1922,1924
[14] Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479
[15] Journal of medicinal chemistry, 1966, vol. 9, # 2, p. 172 - 176
[16] Bulletin de la Societe Chimique de France, 1973, p. 3427 - 3432
[17] Tetrahedron Letters, 1987, vol. 28, # 36, p. 4163 - 4164
[18] Tetrahedron: Asymmetry, 1992, vol. 3, # 6, p. 775 - 784
[19] Journal of Organic Chemistry, 1982, vol. 47, # 27, p. 5411 - 5413
[20] Journal of Organic Chemistry, 1993, vol. 58, # 26, p. 7507 - 7515
[21] Journal of the American Chemical Society, 1999, vol. 121, # 4, p. 710 - 714
[22] Journal of the American Chemical Society, 1949, vol. 71, p. 1922,1924
[23] Bulletin de la Societe Chimique de France, 1972, p. 306 - 317
[24] Patent: US5952350, 1999, A,
[25] Patent: WO2011/100838, 2011, A1, . Location in patent: Page/Page column 69; 70
[26] Tetrahedron, 2011, vol. 67, # 52, p. 10229 - 10233
[27] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2785 - 2788
[28] Angewandte Chemie - International Edition, 2015, vol. 54, # 45, p. 13357 - 13361[29] Angew. Chem., 2015, vol. 127, # 45, p. 13555 - 13559,5
[30] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
[31] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735
[32] Journal of the American Chemical Society, 2018, vol. 140, # 15, p. 5065 - 5068
2
[ 1798-09-0 ]
[ 5020-41-7 ]
Reference：
[1] Patent: EP838459, 1998, A1,
3
[ 1798-09-0 ]
[ 621-37-4 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 1373,1375, 1376
[2] Journal of the Chemical Society, 1927, p. 2412
4
[ 1798-09-0 ]
[ 32454-33-4 ]
Reference：
[1] Patent: US2004/209936, 2004, A1,
5
[ 1798-09-0 ]
[ 20876-29-3 ]
Reference：
[1] Archiv der Pharmazie, 1988, vol. 321, # 5, p. 265 - 272
6
[ 5020-41-7 ]
[ 1798-09-0 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 7, p. 2564 - 2566
[2] Organic Syntheses, 2005, vol. 81, p. 195 - 203
[3] Bulletin of the Chemical Society of Japan, 1993, vol. 66, # 5, p. 1511 - 1515
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 16, p. 5053 - 5057[2] Angew. Chem., 2016, vol. 128, # 16, p. 5137 - 5141,5
12
[ 124-38-9 ]
[ 1286023-66-2 ]
[ 1798-09-0 ]
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 3, p. 1062 - 1069
13
[ 66947-60-2 ]
[ 1798-09-0 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, # 12, p. 2393 - 2396
14
[ 626-20-0 ]
[ 1798-09-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 12, p. 2132 - 2141
15
[ 18927-05-4 ]
[ 1798-09-0 ]
Reference：
[1] Synthesis, 1981, # 2, p. 126 - 127
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 11, p. 2575 - 2582
16
[ 6971-51-3 ]
[ 1798-09-0 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1912, vol. 391, p. 44
[2] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 776 - 794
[3] Journal of the American Chemical Society, 2014, vol. 136, # 3, p. 1062 - 1069
17
[ 124-38-9 ]
[ 824-98-6 ]
[ 1798-09-0 ]
Reference：
[1] Synthesis, 2010, # 22, p. 3802 - 3810
18
[ 67-56-1 ]
[ 1878-65-5 ]
[ 103-82-2 ]
[ 1798-09-0 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 852 - 858
19
[ 5000-65-7 ]
[ 1798-09-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 11, p. 2575 - 2582
20
[ 84508-57-6 ]
[ 1798-09-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 11, p. 2575 - 2582
21
[ 221354-48-9 ]
[ 1798-09-0 ]
Reference：
[1] Journal of Organic Chemistry, 1952, vol. 17, p. 568,570
22
[ 5020-41-7 ]
[ 1798-09-0 ]
[ 91367-10-1 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 7, p. 2564 - 2566
Reference：
[1] Canadian Journal of Chemistry, 1992, vol. 70, # 3, p. 992 - 999
[2] Canadian Journal of Chemistry, 1992, vol. 70, # 3, p. 992 - 999
32
[ 82301-50-6 ]
[ 1798-09-0 ]
[ 65-85-0 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1912, vol. 391, p. 44
33
[ 3027-13-2 ]
[ 7553-56-2 ]
[ 75-47-8 ]
[ 1798-09-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1908, vol. <4> 3, p. 316[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1905, vol. 141, p. 597
34
[ 67-56-1 ]
[ 1798-09-0 ]
[ 18927-05-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
for 16 h; Heating / reflux
Methyl (3-methoxyphenyl)acetate; A solution of 25.0 g (150 ml) of (3-methoxyphenyl)acetic acid in dry methanol (250 ml) was mixed with 2 ml of cone, sulfuric acid and heated under reflux for 16 h. The cooled reaction solution was concentrated in vacuo, added to ice-water and extracted four times with 70 ml of ethyl acetate each time. The combined organic extracts were washed with saturated NaCI solution and dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 28.3 g (100percent) of colorless oil 1H-NMR (DMSOd6): 3.61 (s, 3H), 3.64 (s, 2H), 3.74 (s, 3H), 6.80-6.86 (m, 3H), 7.19- 7.25 (m, 1 H). MS (API-ES,pos) m/z = 181 [M+H]+
100%
Reflux
General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5percent NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2843 - 2866
[2] Patent: WO2008/25736, 2008, A1, . Location in patent: Page/Page column 64
[3] European Journal of Medicinal Chemistry, 2017, vol. 135, p. 117 - 124
[4] Organic Letters, 2017, vol. 19, # 17, p. 4632 - 4635
[5] Tetrahedron Letters, 2001, vol. 42, # 24, p. 3959 - 3961
[6] Journal of Physical Chemistry B, 2010, vol. 114, # 20, p. 6968 - 6972
[7] Tetrahedron, 1995, vol. 51, # 45, p. 12211 - 12216
[8] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 7, p. 1757 - 1766
[9] Tetrahedron Letters, 2003, vol. 44, # 2, p. 331 - 334
[10] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1998, vol. 340, # 6, p. 530 - 535
[11] Helvetica Chimica Acta, 1971, vol. 54, p. 868 - 897
[12] Tetrahedron, 2009, vol. 65, # 33, p. 6600 - 6610
[13] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1130 - 1135
[14] Journal of the Brazilian Chemical Society, 2012, vol. 23, # 5, p. 854 - 860
[15] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 8, p. 2741 - 2747
[16] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3885 - 3896
[17] Russian Journal of Bioorganic Chemistry, 2015, vol. 41, # 2, p. 170 - 177
[18] Australian Journal of Chemistry, 2012, vol. 65, # 10, p. 1413 - 1419,7
[19] Australian Journal of Chemistry, 2012, vol. 65, # 10, p. 1413 - 1419
[20] CrystEngComm, 2014, vol. 16, # 2, p. 164 - 174
[21] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2785 - 2788
[22] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3719 - 3735
35
[ 1798-09-0 ]
[ 18927-05-4 ]
Yield
Reaction Conditions
Operation in experiment
97%
With chloro-trimethyl-silane In methanol; ethyl acetate
Step 1. Preparation of Methyl 3-methoxyphenylacetate Trimethylsilyl chloride (182 g, 1.68 mol) was added dropwise to a solution of 3-methoxyphenylacetic acid (127 g, 0.77 mol) in methanol (1.0 L) over 1.1 hours. The reaction was stirred at room temperature for 17.25 hours, concentrated in vacuo, dissolved in ethyl acetate, dried over MgSO4, and concentrated in vacuo, to give a brown oil (133 g, 97percent): 1 H NMR (CDCl3 /300 MHz) 7.24 (t, 1H, J=7.5 Hz), 6.83 (m, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 3.60 (s, 2H).
(3-methoxy)phenylacetic acid (4.164 g, 25.06 mmol) was refluxed in EtOH in presence of catalytic amount of conc. H2SO4. The mixture was concentrated in vacuo, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine. It was dried over Na2SO4 and concentrated to give colorless oil (4.69 g, 97%).
93%
With sulfuric acid; for 6h;Reflux;
General procedure: Step 1: A mixture of appropriate carboxylic acid (1 equiv) in ethanol was refluxed for6 h in the presence of a catalytic amount of H2SO4. After the reaction was finished,the cooled mixture was concentrated in vacuo. The mixture was diluted with ethylacetate and washed with NaHCO3 1% aqueous solution (10 mlx3), and brine (10mlx3). The combined organic layers were dried over Na2SO4, and evaporated togive crude product. The pure crude product was used without further purification.
93%
With sulfuric acid; for 6h;Reflux;
General procedure: Step 1: A mixture of appropriate carboxylic acid (1 equiv) in ethanol was refluxed for6 h in the presence of a catalytic amount of H2SO4. After the reaction was finished,the cooled mixture was concentrated in vacuo. The mixture was diluted with ethylacetate and washed with NaHCO3 1% aqueous solution (10 mlx3), and brine (10mlx3). The combined organic layers were dried over Na2SO4, and evaporated togive crude product. The pure crude product was used without further purification.
81%
With sulfuric acid; at 0 - 70℃; for 2h;
To a stirred solution of 3-methoxy-2-phenylacetic acid (5 g, 30 mmol) in absolute ethanol (50 ml), sulfuric acid (0.3 ml) was added at 0 C and reaction mixture was refluxed at 70 C for 2 hours. Reaction progress was monitored by TLC. After completion of the reaction, ethanol was removed by evaporation under reduced pressure. Then reaction mixture was neutralized with saturated solution of sodium bicarbonate and extracted with DCM (2 x 15 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the title compound (3.82 g, 81 %) as colorless liquid. LCMS: m/z = 195.26 [M+l].
81%
With sulfuric acid; at 70℃; for 2h;
[00149] To a stirred solution of 3-methoxy-2-phenylacetic acid (5 g, 30 mmol) in absolute ethanol (50 ml), sulfuric acid (0.3 ml) was added at 0 C and reaction mixture was refluxed at 70 C for 2 hours. Reaction progress was monitored by TLC. After completion of the reaction, ethanol was removed by evaporation under reduced pressure. Then reaction mixture was neutralized with saturated solution of sodium bicarbonate and extracted with DCM (2 x 15 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (3.82 g, 81 %) as colorless liquid. LCMS: m/z = 195.26 [M+1].
With hydrogenchloride; In water monomer;Reflux;
To a solution of 3-methoxyphenylacetic acid (1 g, 6.02 mmol) in ethanol (10 mL) was added cHCl (5 drops) and the mixture heated at reflux overnight. The solvents were evaporated to give the target compound as a white solid. This compound was then dissolved in ethanol (10 mL) and hydrazine hydrate (5.86 mL, 120 mmol) was added and the mixture heated at reflux overnight. Solvents were evaporated and the product was purified by flash chromatography using a gradient mixture of ethyl acetate and hexanes to give the desire compound as a white solid (1.03 g, 94% over 2 steps). 1H NMR (CDCl3), δ 3.79 (s, 3H), 3.83 (s, 2H), 6.83 (m, 4H); MS m/z = 181.5 (M + H)+.
With hydrogenchloride; In water monomer; for 18h;Reflux;
General procedure: To a stirred solution of carboxylic acid 11j-r (1 mmol) in EtOH(3 mL) was added conc. HCl (1 drop), and the resulting mixturewas refluxed for 18 h. After cooling, the solvent was removed, andthen the residue was added sat. NaHCO3 aq., and the aqueous mixturewas extracted with CH2Cl2. The organic extracts were driedover Na2SO4, and the solvent was removed to afford the correspondingethyl ester, which was used for the next reaction withoutfurther purification. To a stirred solution of ethyl ester (1 mmol),obtained above, in EtOH (0.5 mL) was added hydrazine monohydrate(0.05 mL, 1 mmol), and the resulting mixture was refluxedfor 18 h. The solvent was removed to give the corresponding acylhydrazide, which was used for the next reaction without furtherpurification. To a stirred solution of acylhydrazide, obtained above,in CH2Cl2 (1 mL) was added a solution of isothiocyanate 8a-h or10c, i (1 mmol) in CH2Cl2 (5 mL), and the resulting mixture was stirredat room temperature for 18 h. The insoluble solid was correctedby filtration, and dried to give acyl hydrazino thiourea 13A-U.
With borane-THF; In tetrahydrofuran; at -78 - 20℃; for 4h;Inert atmosphere;
Following the acid reduction procedure as applied to 9b, 151 2-(3-methoxyphenyl)acetic acid (1.16 g, 7.0 mmol; Aldrich Chem. Co.) and 112 BH3.THF (1.0 M in 42 THF, 8.4 mL, 8.4 mmol) were reacted in THF (20 mL) for 4 h. Chromatographic purification of the crude product afforded 152 2-(3-methoxyphenyl)ethanol (9h) as a colorless oil (1.05 g, 98%) whose spectral data were in agreement with literature values in Gmez, et al., 2006. TLC: Rf?0.5 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) delta 7.30-7.19 (m, 1H), 6.87-6.73 (m, 3H), 3.89-3.82 (m, 2H), 3.80 (s, 3H), 2.84 (t, J=6.5 Hz, 2H), 1.59 (br s, 1H); 3C NMR (101 MHz, CDC3) 159.75, 140.08, 129.57, 121.33, 114.76, 111.75, 63.56, 55.15, 39.22.
95%
With [ReOCl2(1,2-bis(diphenylphosphino)ethane)]; hydrogen; potassium tetraphenylborate; In toluene; at 160℃; under 30003.0 Torr; for 24h;Autoclave; Inert atmosphere;
General procedure: By the following method, it went 3-reduction of phenylpropionic acid (hydrogenation).Put a stir bar in a dry glass tube (25mL), further, 3-phenylpropionic acid (75.09mg, 0.5mmol), the rhenium complex 4 (7.07mg, 0.010mmol), potassium tetraphenylborate (17.92mg , accommodates 0.05 mmol), the tubes containing this mixture, was inserted into the autoclave. Then, after replacing the inside of the autoclave in an argon gas atmosphere was added while continuing flow of argon gas dehydration toluene (4.0mL). This autoclave through a stainless steel tube by introducing hydrogen gas from a hydrogen gas cylinder connected, the inside of the autoclave was replaced with hydrogen gas, then disconnect the hydrogen gas pressure from the leak valve. This operation - was repeated (substituted de substitution) five times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, using a constant temperature bath, and allowed to react for 12 hours at 180 C. After completion of the reaction, the autoclave was cooled by immersion in an ice bath, almost to room temperature. Then, carefully release the hydrogen gas that is inside in the draft. After removing the solvent, the reaction product was analyzed by 1H NMR using mesitylene (60.1 mg, 0.5 mmol) as an internal standard substance. As a result, 3-phenylpropyl alcohol, and 3-phenylpropionic acid 3-phenylpropyl The yield was 98% and 1%, respectively. In the above Examples 6-1,Substrate (carboxylic acid compounds), and hydrogenation conditions (hydrogen pressure),Except that to adopt the conditions described in Table 7-9,It has been reduced (hydrogenated) in the same manner as in Example 6-1.However,The entry 19-26 in Table 9,Using tetrahydrofuran (THF) as a solvent.The results are shown in Tables 7 to 9.
With hydrogenchloride; LiAlH4; In tetrahydrofuran; methanol;
Preparation A 2-(3-Methoxyphenyl)ethanol 30 g (790 mmol) of LiAlH4 was slurried in 500 mL of THF and cooled to -70 C. 131 g (790 mmol) of 3-methoxyphenylacetic acid was dissolved in 600 mL of THF and slowly over a period of one hour to the reaction. After one hour, the reaction was allowed to warm to 0 C. and was quenched with the careful addition of MeOH. To the quenched reaction was added 1 L of 1 N HCl and the reaction was stirred. After several minutes an additional 300 mL of 5 N HCl was added, along with 600 mL of ether. The reaction was shaken and the layers allowed to separate. The organic layer was reduced in volume by evaporation in vacuo. The aqueous layer was extracted three times with ether and all the ether extracts were combined. The ether extract was washed twice with brine and dried by filtration through anhydrous Na2 SO4 and evaporated to a yellow oil. This yielded 115 g of the title compound. PMR: Consistent with the proposed structure. MS: m/e=152 (M) FD EA: Calc: C, 71.03; H, 7.95 Fd: C, 70.84; H, 7.75 C9 H12 O2
A solution of 7c1 (Lancaster; 10.0 g, 60.2 mmol) in THF (10 mL) is added to an ice- cold solution of LiAIH4 (4.71 g, 124 mmol) in THF (250 mL). The mixture is allowed to warm to RT and is stirred at RT for 24 h. The reaction mixture is carefully poured into an aqueous 0.1 N NaOH solution. The solution is extracted with Et20. The combined organic layers are washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to give compound 7c2.
With methanol; dimethylsulfide borane complex; In tetrahydrofuran;
To 3-methoxyphenylacetic acid 21 in 50 mL THF containing 10 drops of MeOH was added BH3·Me2S in portions (foams.). After the reaction had subsided, MeOH (20 mL) was added cautiously (foams.). The solvent was removed on the rotary evaporator, then the MeOH addition and evaporation were repeated two more times. The residue was then distilled bulb-to-bulb (pot=100-120 C, 1.0 mmHg) to give 5.47 g of crude 2-(3-methoxyphenyl)ethanol.Comment
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4.5h;Reflux;
General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.
With N-iodo-succinimide; trifluoroacetic acid In acetonitrile at 20℃;
65%
With iodine; Iodine monochloride In acetic acid
1 2-Iodo-5-methoxybenzeneacetic Acid
EXAMPLE 1 2-Iodo-5-methoxybenzeneacetic Acid A solution of 45 g (0.27 mole) of 3-methoxybenzeneacetic acid, 52.6 g (0.32 mole) of iodine monochloride and 1 g of iodine was allowed to stand in 500 ml of glacial acetic acid for six days at room temperature. The reaction was poured into water and the solid collected. It was recrystallized from toluene to give 51 g of crystalline 2-iodo-5-methoxybenzeneacetic acid, mp 133.5°-134.5° C. (65% yield).
62%
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 60℃; for 15h; Sealed tube; Darkness;
With Iodine monochloride; acetic acid
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 60℃; for 15h; Darkness;
With thionyl chloride In dichloromethane for 2h; Heating;
100%
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃; for 1h; Inert atmosphere;
100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 3h; Inert atmosphere;
xxxii.a a) 2-(3-Methoxyphenyl)acetyl chloride I93
To a solution of 2-(3-methoxyphenyl)acetic acid (10.0 g, 60.0 mmol) and DMF (3 drops) in DCM (100 mL) at 0 °C under N2 was added oxalyl chloride (23.0 g, 180 mmol) and the mixture was stirred for 3 h. The solvent was removed under reduced pressure to give the title compound (11.0 g, 100%) as a yellow oil. LCMS-D: Rt 2.17 min, m/z 181.0 [M- CI+MeO+H]+.
76%
With thionyl chloride In dichloromethane Heating;
60%
With thionyl chloride In benzene for 4h; Heating;
With thionyl chloride
With pyridine; thionyl chloride; benzene
With thionyl chloride In dichloromethane for 1h; Heating;
With oxalyl dichloride In benzene for 1h; Ambient temperature;
With thionyl chloride In benzene for 1h; Heating;
With thionyl chloride for 1h; Heating;
With thionyl chloride
With thionyl chloride for 0.25h; Heating;
With oxalyl dichloride In dichloromethane
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h;
With phosphorus(V) chloride In chloroform Heating;
With thionyl chloride In dichloromethane
With thionyl chloride for 1h; Heating;
With oxalyl dichloride; N,N-dimethyl-formamide In benzene for 1h;
With oxalyl dichloride In dichloromethane at 20℃; for 0.333333h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
With oxalyl dichloride In N,N-dimethyl-formamide; benzene at 20℃; for 0.5h;
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 5h;
75
The title compound was synthesized by referring to the synthetic method of EP285287. To a solution of (3-methoxyphenyl)acetic acid (16 g) in tetrahydrofuran (150 ml) were sequentially added N,N-dimethylformamide (0.1 ml) and oxalyl chloride (10 ml) under a nitrogen atmosphere, the solution was stirred for 5 hours at room temperature, and then the reaction mixture was concentrated in vacuo to provide (3-methoxyphenyl)acetyl chloride (18.8 g). To a solution of aminoacetaldehyde dimethylacetal (11 g) and triethylamine (11 g) in chloroform (150 ml) was added (3-methoxyphenyl)acetyl chloride (18.8 g) on an ice bath, and the solution was stirred for 9.5 hours at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), a solution ofN-(2,2-dimethoxyethyl)-2-(3-methoxyphenyl)acetamide (24.9 g) in acetic acid (75 ml) was added dropwise to concentrated hydrochloric acid (50 ml), and the solution was stirred overnight at room temperature. The reaction mixture was poured into an ice water, ethyl acetate and tetrahydrofuran were sequentially added thereto, insoluble material was removed by filtration, then the filtrate was concentrated in vacuo. To the residue was added water, the resulting solid was filtered and collected. To a solution of the resulting 8-methoxy-1,3-dihydrobenz[d]azepin-2-one (6.3 g) in acetic acid (100 ml) was added 10% palladium-activated charcoal (1.5 g), and the solution was stirred for 23 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solvent was evaporated in vacuo, was neutralized by sequentially adding water and aqueous ammonia. The resulting solid was filtered to provide 8-methoxy-1,3,4,5-tetrahydrobenz[d]azepin-2-one (5.6 g). To a suspension of this compound (1.5 g) in tetrahydrofuran (15 ml) was added dropwise borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (15 ml), and the solution was refluxed for 2 hours. 5N hydrochloric acid (5 ml) was added thereto on an ice bath, the solution was refluxed for 45 minutes, and then neutralized with aqueous ammonia. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (752 mg).1H-NMR (400MHz, CDCl3); δ (ppm): 2.84-2.98 (m, 8H), 3.78 (s, 3H), 6.64 (dd, 1H), 6.67 (d, 1H), 7.01 (d, 1H).
With thionyl chloride In N,N-dimethyl-formamide; toluene
1 EXAMPLE 1
EXAMPLE 1 A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was stirred for 16 hours at 25° and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride.
With phosgene In dichloromethane at 20℃; for 3h;
1
Separately, to 2-(3-methoxyphenyl)acetic acid (compound 1007, 1 g) in 25 mL of dichloromethane containing 0.1 mL of DMF was added 2.45 mL of 2M phosgene/CH2Cl2. The reaction mixture was stirred for 3 hours at room temperature and the volatiles were removed in vacuo. The residue was treated with 25 mL of THF and 1.82 g of thiourea, followed by heating at 80° C. for 3 hours. The mixture was cooled, poured into 20 mL of water, which was extracted with ethyl acetate (3×50 mL). The combined organics were concentrated and the residue recrystallized (ethyl acetate/hexanes) to provide 1-(2-(3-methoxyphenyl)acetyl)thiourea (compound 1008, 476 mg).
With thionyl chloride for 0.5h; Reflux;
With thionyl chloride at 80℃; for 1h;
With thionyl chloride
With oxalyl dichloride In dichloromethane at 20℃; for 6h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;
With thionyl chloride; N,N-dimethyl-formamide In toluene at 70℃; for 3h; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃; for 1h;
With thionyl chloride at 90℃;
With thionyl chloride In tetrahydrofuran for 1.5h; Reflux;
Diethyl 2-(2-(2-methoxyphenyl)acetamido)-4,5-dihydrothieno[2,3-c]pyridine-3,6(7H)-dicarboxylate 10i
General procedure: 2-Methoxyphenyl acetic acid (465 mg, 2.8 mmol) and thionyl chloride (204 µL, 2.8 mmol) were refluxed in anhydrous THF (1 mL) for 1.5 hours, and the resulting reaction solution was added to a solution containing 9d (200 mg, 0.67 mmol) and DIPEA (210 µL, 1.2 mmol) in THF (0.5 mL). After stirring for 1 day, the reaction mixture was taken up in EtOAc, washed with 1M aqueous HCl, washed with 5% aqueous Na2CO3, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 4:1) to yield an oil (161 mg, 54%). An 81 mg sample was further purified by HPLC (4.8 mg). 1H NMR (300 MHz, CDCl3) δ 11.2 (br s, 1H, NH), 7.31 (m, 2H, Ar-H), 6.95 (m, 2H, Ar-H), 4.53 (s, 2H, 7-CH2), 4.27 (q, J = 7.1 Hz, 2H, CH2CH3), 4.17 (q, J = 7.1 Hz, 2H, CH2CH3), 3.89 (s, 3H, OCH3), 3.82 (s, 2H, CH2Ar), 3.68 (m, 2H, 5-CH2), 2.86 (m, 2H, 4-CH2), 1.30 (t, J = 7.2 Hz, 3H, CH2CH3), 1.30 (t, J = 6.9 Hz, 3H, CH2CH3). ESI-MS m/z 447.3 [M + H]+.
With thionyl chloride In dichloromethane
With thionyl chloride; N,N-dimethyl-formamide In toluene at 20℃; for 15h;
(b). N-(2,2-Dimethoxyethyl)-2-(3-methoxyphenyl)acetamide (1)
Method A: Thionyl chloride (13.2 mL, 180.5 mmol) was added with stirring to a suspension of 3-methoxyphenylacetic acid (10.0 g, 60.2 mmol) in CH2Cl2 (15 mL) dropwise at room temperature (rt). The mixture was heated under reflux for 1 h and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was added as a solution in CH2Cl2 (40 mL) with stirring to a solution of aminoacetaldehyde dimethyl acetal (6.89 mL, 63.2 mmol) and trimethylamine (9.22 mL, 66.2 mmol) in CH2Cl2 (30 mL) dropwise at 0 °C. After stirring at rt for 1 h, the mixture was washed with water, 1.0 N HCl, brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100:2 CH2Cl2/MeOH) to afford 1 (13.1 g, 86%) as a yellow oil. Method B: Thionyl chloride (11.0 mL, 150.4 mmol) and DMF (6 drops) were added with stirring to a solution of 3-methoxyphenylacetic acid (10.0 g, 60.2 mmol) in toluene (100 mL) at rt. The mixture was stirred at rt for 15 h and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was added as a solution in CH2Cl2 (30 mL) with stirring to a solution of aminoacetaldehyde dimethyl acetal (7.01 mL, 64.4 mmol) and trimethylamine (9.31 mL, 66.8 mmol) in CH2Cl2 (30 mL) dropwise at 0 °C. After stirring at rt for overnight, the mixture was washed with water, 1.0 N HCl, brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100:2 CH2Cl2/MeOH) to afford 1 (15.0 g, 98%) as a yellow oil.
With oxalyl dichloride In benzene at 20℃; for 24h;
With thionyl chloride In dichloromethane for 0.25h;
With thionyl chloride at 80℃; for 3h;
General procedure: For the synthesis of compounds 4a-4h and 5a-5h was depicted in Scheme 2. Firstly, 2-phenylacetic acid (1 mmol) and SOCl2 (4-6 mL) were refluxed at 80 °C for 3 h. The reaction liquid was cooled to room temperature and then evaporated to give reactive acyl chloride. The product was obtained as an oil matter, which would be dissolved in acetone (5-6 mL) in the next step. Treatment of 3a (5-phenylthiazol-2-amine) with 2-phenylacetyl chloride in acetone for 5 h at ice-bath afforded the aimed amine. Meanwhile, K2CO3 (0.8 g) was added to the mixture. Then the mixture was evaporated under reduced pressure and the resulting solid was washed with diluted NaOH liquid. The aimed amide was extracted from the NaOH liquid with ethyl acetate for column chromatography. Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether to give the aimed amine (4a). Compounds of 4b-4h and 5a-5h could begot with corresponding acids by the procedures above.
With thionyl chloride at 80℃; for 6h;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20 - 50℃;
31.1 Example 31 3-(3-Hydroxyphenyl)-4-methyl-2-(4-(2-(3-methylazetidin-l-y])ethoxy)phenyl)-2H-chromen- -ol Step 1 : 2-(3-Methoxyphenyl)ac
Thionyl chloride (1L) was added over 30 min to a suspension of 2-(3- methoxyphenyl)acetic acid (530 g, 3.19 mol) and dry dichloromethane (3 L) in an ice bath. N,N- Dimethylformamide (15 mL) was added dropwise over 10 min keeping the internal temperature below 20 °C. The ice bath was removed, and the reaction mixture was stirred until gas evolution has ceased. The mixture was heated at reflux (-50 °C) for 3 h, stirred at room temperature overnight, and then concentrated to give a yellow oil which was used directly in the next step.
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 50℃; Cooling with ice;
1
Thionyl chloride (1L) was added over 30 min to a suspension of 2-(3- methoxyphenyl)acetic acid (530 g, 3.19 mol) and dry dichloromethane (3 L) in an ice bath. N,N- Dimethylformamide (1 mL) was added dropwise over 10 min keeping the internal temperature below 20 °C. The ice bath was removed, and the reaction mixture was stirred until gas evolution has ceased. The mixture was heated at reflux (-50 °C) for 3 h, stirred at room temperature overnight, and then concentrated to give a yellow oil which was used directly in the next step.
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;
General procedure: Aralkanoic acid chlorides 2a-g were synthesized by the reaction of aralkanoic acid 1a-g (1 mmol) in the presence of 1,2-dichloroethane (12 mL) solvent and phosphorous oxychloride(0.4 mL) chlorinating agent under reflux for 3hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressureto afford aralkanoic acid chloride 2a-g, which was directly used in the next step without further purification. Acid chloride 2a-g was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate(1 mmol), TEA (0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 hours with monitoring by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature. Evaporation of the solvent under reduced pressure yielded crude acid hydrazide 3a-g as a white solid on cooling, which was purified by column chromatography and crystallized in methanol [46].
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;
General procedure: To an over-dried 100 mL three-necked flask, the carboxylic acid (10 mmol), DMF (5 drops) and DCM (30 mL) were added under a N2 atmosphere. Oxalyl chloride (1.0 mL, 12 mmol) was added dropwise at 0 °C resulting in vigorous bubbling. The mixture was stirred for 3 h at room temperature, and the solvent was then removed in vacuo. The resulting acid chloride was used immediately without further purification. To a solution of the acid chloride in DCM (30 mL) ,a solution of 1,1,1,3,3,3-hexamethyldisilazane (30 mmol) in DCM (10 mL) was added dropwise at 0 °C, and the solution was then allowed to warm to room temperature. After stirring overnight, the reaction system was quenched with 1 M HCl aq. and saturated aqueous NH4Cl (excess amount) and the organic layer was separated. The aqueous layer was extracted with DCM (2x15 mL). The combined organic layers were washed with saturated aqueous NH4Cl (30 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated in vacuo. The resulting crude material was purified by recrystallization from EtOAc and hexane. The resulting product (5 mmol), 8-bromomethylquinoline (6 mmol), Al2O3 (50 mmol), KOH (25 mmol) and dioxane (30 mL) were added to an over-dried 100 mL three-necked flask. The mixture was stirred for 8 h at 60 °C and then was filtered through a celite pad. The filtrate was washed with H2O (30 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtrated and evaporated in vacuo. The resulting crude amide was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1).
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h;
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 3h;
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 21℃; Inert atmosphere;
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 50℃; Cooling with ice;
1.1 Step 1: 2-(3-methoxyphenyl)acetyl chloride
Thionyl chloride (1L, 13.7 mol) was added over 30 min to a suspension of 2-(3- methoxyphenyl)acetic acid (530 g, 3.19 mol) and dry dichloromethane (3 L) in an ice bath. N,N-Dimethylformamide (15 mL) was added drop wise over 10 min keeping the internal temperature below 20 °C. The ice bath was removed, and the reaction mixture was stirred until gas evolution has ceased. The mixture was heated at reflux (-50 °C) for 3 h, stirred at room temperature overnight, and then concentrated to give a yellow oil which was used directly in the next step.
With thionyl chloride In dichloromethane at 0℃; for 2h; Reflux;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 0.5h;
General procedure for the synthesis of α-bromo ketones 11g-j
General procedure: The appropriate phenylacetic acid (1.1 mmol) was dissolved in dry DCM (10 mL) and few drops ofDMF were added. The mixture was cooled to 0°C and thionyl chloride (160 μL, 2.2 mmol) was addeddropwise. Reaction mixture was stirred at r.t. for 30 minutes. Solvent was evaporated under reducedpressure to obtain the acyl chloride derivative. Acyl chloride (1.1 mmol) was dissolved in dry CH3CN(10 mL) and the solution was cooled to 0°C. 2M trimethylsilyl diazomethane (1.5 mL) was addeddropwise. Reaction mixture was allowed warm to room temperature and reaction was monitored withTLC. After disappearing of the starting material (0.5-1 h) the mixture was cooled to 0 °C and HBr 33%(1 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2h.The mixture was poured in water and extracted with AcOEt. The organic phase was washed with water,dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purifiedwith flash chromatography on silica gel, eluting with 30% AcOEt/Hex to give pure compound.
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;
2.3. General Procedure for the Synthesis of 2-(4-methoxyphenyl)acetohydrazide (3)
2-(3- methoxyphenyl)acetyl chloride (2) was synthesizedby the reaction of 2-(3-methoxyphenyl)acetic acid (1) (1mmol) in the presence of 1,2-dichloroethane (12 mL) solventand phosphorous oxychloride (0.4 mL) chlorinatingagent under reflux for 3 hrs. Then, the resulting solution wascooled to room temperature, and the solvent was removedunder reduced pressure to afford compound (2), which wasdirectly used in the next step without further purification.Compound (2) was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate (1 mmol), TEA (0.5 mL), acetonitrile (20 mL) and allowed toreflux for 3 hrs with monitoring by TLC. After consumptionof the starting material, the reaction mixture was cooled toroom temperature. Evaporation of the solvent under reducedpressure yielded crude 2-(3- methoxyphenyl)acetohydrazide(3) as a white solid on cooling, which was purified by columnchromatography if needed and crystallized on methanol.
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0 - 50℃; Inert atmosphere;
With oxalyl dichloride In N,N-dimethyl-formamide; toluene at 20℃; for 1h; Inert atmosphere; Schlenk technique;
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere;
With thionyl chloride at 90℃;
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 23℃; for 1h; Inert atmosphere;
General procedure A: synthesis of N-acyl 5,5-dimethyl oxazolidinones via acyl chloride
General procedure: Oxalyl chloride (1.65 equiv) was added to a solution of arylacetic acid (1.5 equiv), dimethylformamide (10 ml), anddichloromethane (2.0 M) at 0 °C. After 10 min, the solution was warmed to 23 °C and stirred for 1 h (bubbling stops). Thesolution was concentrated in vacuo. In a separate flask, n-butyllithium (1.1 equiv, 2.42 M in hexanes) was added to asolution of (S)-4-benzyl-5,5-dimethyloxazolidin-2-one (1.0 equiv) in THF (0.3 M) at -78 °C under argon. The solution wasstirred for 30 min at -78 °C. A solution of the crude acyl chloride in THF was added dropwise at -78 °C. After stirring at -78 °C for 2 h, the reaction mixture was quenched with saturated ammonium chloride. The aqueous layer was extractedwith ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine, dried with sodium sulfate andconcentrated in vacuo.
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;
1
2-(3-methoxyphenyl)acetyl chloride in 1,2-dichloroethane (12 mL) solvent under reflux with 2-(3-methoxyphenyl)acetic acid (1 mmol) and phosphorusoxychloride (0.4 mL) chlorinating agent It was synthesized by processing for 3 hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressure to obtain compound 2-(3-methoxyphenyl)acetylchloride, which was used directly in the next step without further purification. 2-(3-methoxyphenyl)acetylchloride was dissolved in acetonitrile (80 mL) and gradually added to a solution containing hydrazine hydrate (1 mmol), TEA (0.5 mL), and acetonitrile (20 mL) while monitoring by TLC. After refluxing for 3 hours, it was cooled to room temperature. The solvent was evaporated under reduced pressure to obtain crude 2-(3-methoxyphenyl)acetohydrazide as a white solid as shown below upon cooling, which was purified by column chromatography as necessary and crystallized in methanol.
With thionyl chloride In dichloromethane at 20℃;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 6h;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Inert atmosphere;
1.78 g
With thionyl chloride In N,N-dimethyl-formamide at 55 - 90℃; for 3h;
1-3 Example 1
Add 1.66g (10mmol) of 3-methoxyphenylacetic acid and a magnet in a 50mL three-necked flask, install a condenser and a dropping funnel,Place the instrument in an oil bath and set the temperature to 55, and turn on the stirring and condenser tube, then add 10mL thionyl chloride and 0.5mL N,N-dimethylformamide to the dropping funnel, and wait until the temperature rises to 55 , turn on the dripping, the solution is slowly dripped into the reactor, the dripping rate is controlled to 0.1mL/s, after the dripping is completed, reset the heating temperature to 90, stir the reaction for 3 hours, use TLC detection to confirm the reaction is complete and ready to start purification.After the liquid in the reactor is cooled to room temperature, take it out of the eggplant-shaped bottle,Rotate the contents of the eggplant-shaped flask under reduced pressure at 60°C to remove the excess thionyl chloride. After the rotary steaming is completed, add 30 mL of n-hexane to dissolve the product at 75°C. After all dissolved, cool down at 10°C to precipitate. A brown liquid was obtained from the liquid, weighing 1.78 g.
With thionyl chloride In benzene for 1h; Reflux;
With thionyl chloride In dichloromethane at 20℃; for 3h;
Stage #1: m-methoxyphenylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h;
Stage #2: 2-(3,4-dimethoxyphenyl)-ethylamine In dichloromethane at 20℃; for 8h;
6.4.1. N-(2-(4-(Benzyloxy)-3-methoxyphenyl)ethyl)-2-(3,5-dimethoxyphenyl)acetamide (15c)
General procedure: To a solution of 3,5-dimethoxyphenylacetic acid 14a (0.98 g, 5 mmol) in CH2Cl2 (10 mL), EDCI (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimidehydrochloride) (1.15 g, 6 mmol) was added. The mixture was stirred at room temperature for 0.5 h, and 2-(4-(benzyloxy)-3-methoxyphenyl)ethan-1-amine hydrochloride 13a (1.47 g, 5 mmol) was added. The mixture was stirred for another 8 h, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH = 80/1) to afford 15c (1.76 g, 81%) as a white solid.
Methyl (3-methoxyphenyl)acetate; A solution of 25.0 g (150 ml) of (3-methoxyphenyl)acetic acid in dry methanol (250 ml) was mixed with 2 ml of cone, sulfuric acid and heated under reflux for 16 h. The cooled reaction solution was concentrated in vacuo, added to ice-water and extracted four times with 70 ml of ethyl acetate each time. The combined organic extracts were washed with saturated NaCI solution and dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 28.3 g (100%) of colorless oil 1H-NMR (DMSOd6): 3.61 (s, 3H), 3.64 (s, 2H), 3.74 (s, 3H), 6.80-6.86 (m, 3H), 7.19- 7.25 (m, 1 H). MS (API-ES,pos) m/z = 181 [M+H]+
100%
With sulfuric acid;Reflux;
General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5% NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils.
With thionyl chloride; at 0 - 20℃; for 3h;
General procedure: 5.1.57.1. Step 1. To a solution of 3-fluorophenylacetic acid (24.85 g,158 mmol) in MeOH (200 mL) was added SOCl2 (4.00 mL,52.2 mmol) at 0 C with silica gel blue tube. After stirring at rtfor 3 h, the reaction mixture was concentrated under reduced pressure.The residue was partitioned between 1 N NaOH (250 mL) andEtOAc (250 mL). The separable organic layer was washed withbrine (100 mL), dried over MgSO4, filtered, concentrated underreduced pressure to obtain methyl (3-fluorophenyl)acetate(25.81 g, 97%) as colorless oil.
With N-Bromosuccinimide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;
22.1 Step 1: 2-(2-Bromo-5-methoxyphenyl)acetic acid
In a 250-mL round-bottom flask, 2-(3-methoxyphenyl)acetic acid (1.50 g, 9.00 mmol) was dissolved in CH2Cl2 (25 mL, 0.36M). N-Bromsuccinimid (1.80 g, 9.90 mmol) was added portionwise at 0 °C and under N2. The colorless solution was stirred at RT for 3 h. Water was added to the mixture and the layers were separated. The aqueous layer was washed with CH2Cl2. All the organic layers were combined and washed with brine, dried (Na2SO4), filtered and concentrated yielding 2-(2-bromo-5-methoxyphenyl)acetic acid as an orange solid (2.22 g, 100 %). C9H9BrO3; Mw = 245.07 g.mol-1; 1H NMR (400 MHz, CDCl3) d 7.46 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 3.0 Hz, 1H), 6.73 (dd, J = 8.8, 3.0 Hz, 1H), 3.81 (s, 2H), 3.79 (s, 3H).
95%
With bromine In dichloromethane at 20℃; for 2h;
92%
With bromine In dichloromethane
90%
With sodium hydroxide; bromine In water at 50℃; for 0.5h;
87.2%
With bromine In dichloromethane at 0℃; for 4h;
1 Step 1 : 2-(2-bromo-5-methoxyphenyl)acetic acid
[00156] To a solution of 2-(3-methoxyphenyl)acetic acid Core-1 a_E1 (7.0 g, 42.12 mmol) in DCM (50 ml.) was added Br2 (8.08 g, 50.55 mmol) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 4 h. TLC (DCM:MeOH (10:1), Rf 0.30) showed that the reaction was complete. The reaction was diluted with DCM (200 mL) and washed aqueous Na2S03 (100 mL). The organic layer was washed with brine, and concentrated to afford Core-1 a_E2, (9.0 g, yield 87.2%). 1H NMR (400 MHz, CDCI3) d 7.48 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 3.0 Hz, 1H), 6.75 (dd, J = 3.0, 8.8 Hz, 1H), 3.82 (s, 2H), 3.81 (s, 3H).
85%
With bromine In dichloromethane at 0 - 20℃; for 24h;
83%
With bromine
76%
With bromine; sodium acetate In acetic acid for 3h; ice-bath;
With bromine In dichloromethane at 20℃; for 2h;
With bromine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;
With bromine In dichloromethane at 0 - 20℃;
5
Example 5Synthesis of 2-(2-bromo-5-methoxyphenyl) acetic acid; To a solution of 2-(3-methoxyphenyl) acetic acid (4.50 g, 27.1 mmol) in DCM (25 ml), was added bromine (1.40 ml, 27.1 mmol) dropwise at 0 °C (ice-water bath). The mixture was stirred overnight at RT and quenched by addition of 5% sodium thiosulfate solution. The organic layer was washed with brine, dried with MgS04 and concentrated under a stream of nitrogen to give the titled compound, 2-(2-bromo-5-methoxyphenyl) acetic acid as white crystalline solid.
With potassium 12-tungstocobaltate(III) In water; acetonitrile for 0.166667h; Microwave irradiation;
85%
With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20 - 25℃; for 8h; Irradiation;
2
In a 25mL reaction tube, add photocatalyst 4CzIPN (0.1mol%), DBU (10mol%), solvent acetonitrile 1.5mL, 3-methoxyphenylacetic acid (0.2mmol), stir in air at room temperature 25 , under blue light After 8 hours of reaction,Silica gel column chromatography separated the final product, based on the molar amount of arylacetic acid as 100%,The yield of the final product is 85%.
82%
With mercury(II) fluoride; oxygen In acetonitrile at 25℃; for 24h; Irradiation;
65%
With dipotassium peroxodisulfate In water at 90℃; for 12h; Green chemistry;
General Procedure for the preparation of Aldehydes and Ketones from Aryl acetic acids
General procedure: In an oven dried tube containing a mixture of 4-methyl phenyl acetic acid 1a (200 mg, 1.33mmol) and potassium persulfate (360 mg, 2.66 mmol), water (2 mL) was added and heated at 90 °C for 12 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature (24°C) and it was extracted with ethyl acetate (3 x 5 mL). The crude product was purified by column chromatography to furnish compound 2a as colorless liquid (136 mg, 85% yield).
61%
With oxygen; mercury(II) oxide In methanol; acetonitrile at 25℃; UV-irradiation;
24%
With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; N,N,N',N'-tetramethylguanidine In acetonitrile at 20℃; for 6h; Irradiation;
2.1 Experimental procedure for synthesis of 2a-2q
General procedure: To a 25 mL reaction tube, arylacetic acid (0.2 mmol), 4CzIPN (1 mol%), TMG (50 mol%) were dissolved in CH3CN (1.5 mL), and then the tube was stirred in air at room temperature for 6 h with the irradiation of 25 W blue LEDs. After reaction, the mixture was collected, and the residue was purified by column chromatography on silica gel to afford the desired products.
With oxygen In N,N-dimethyl-formamide at 120℃; for 4h;
2.2 Catalytic studies
General procedure: In a typical experiment, a solution of phenylacetic acid (0.3mmol, 40.8mg) in DMF (0.5mL) was added to a 10mL vial with the VNU-21 catalyst (5.5mg, 5mol%). The mixture was stirred at 120°C for 4h under an oxygen atmosphere. After that, the catalyst was removed by filtration. A solution of 2-aminobenzamide (0.2mmol, 27.2mg) in DMSO (0.5mL) was then added to the reactor. The mixture was additionally stirred at 120°C for 5h under oxygen. The GC yield of benzaldehyde and 2-phenylquinazolin-2(3H)-one were monitored by withdrawing samples from the reaction mixture, quenching with brine (1mL), extracting with ethyl acetate (3×1mL), drying over anhydrous Na2SO4, and analyzing by GC regarding diphenyl ether as internal standard. After the completion of the second step, the reaction mixture was cooled to room temperature. Resulting solution was quenched with brine (5mL), extracted by ethyl acetate (3×5mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum. The crude product was purified by silica gel column chromatography using hexane and ethyl acetate (1:1, v/v) as eluent. The structure of 2-phenylquinazolin-4(3H)-one was verified by GC-MS, 1H NMR and 13C NMR. For the leaching test, after the first 4h reaction time, the catalyst was removed by filtration. The solution phase was transferred to a new and clean reactor. New phenylacetic acid was added, and the resulting mixture was subsequently stirred for additional 4h at 120°C under an oxygen atmosphere. The yield of benzaldehyde was monitored by GC.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 20h;
74%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; water at 20℃; for 24h; Inert atmosphere;
65%
Stage #1: m-methoxyphenylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine at 20℃; for 0.166667h;
Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane
Method B
General procedure: Diisopropylethylamine (4 equiv, 0.1 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 equivwere sequentially added to a dry solution of the correspondingcarboxylic acid (1 equiv) in CH2Cl2 and stirred for 10 min at r.t.N,O-Dimethylhydroxylamine hydrochloride (2 equiv) wasadded, and the resulting mixture was stirred until all startingmaterials were consumed (TLC and LC-MS monitoring). Thecrude reaction was quenched with a sat. aq NH4Cl solution andextracted with EtOAc. The organic layers were washed with asat. solution of NaCl, dried over anhydrous Na2SO4, and concentratedunder reduced pressure. The residue was purified byflash chromatography (gradient of eluent from 100% heptane to100% EtOAc) affording the desired Weinreb amides.
21%
Stage #1: N,O-dimethylhydroxylamine*hydrochloride With phosphorus trichloride at 0 - 20℃; Inert atmosphere;
Stage #2: m-methoxyphenylacetic acid In toluene Inert atmosphere;
Stage #1: m-methoxyphenylacetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃;
Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃;
Stage #1: m-methoxyphenylacetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 1h; Inert atmosphere;
Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 0 - 23℃; Inert atmosphere;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
2-(3-methoxyphenyl)-N-(4-pyridin-4-yl-thiazol-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
3- (3-METHOXY-PHENYL)-1- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-PIPERIDIN-2-ONE : 2- (3- METHOXY-PHENYL)-N- (4-PYRIDIN-4-YL-THIAZOL-2-YL)-ACETAMIDE (prepared according to General Method A from 4- (4-PYRIDYL)-2-AMINOTHIAZOLE and 3-methoxyphenylacetic acid: 1 mmol), triphenylphosphine (1.2 mmol), diisopropyl azodicarboxylate (1.2 mmol) and THF were were stirred overnight at room temperature. The mixture was then cooled to 0 C and NaH (1.2 mmol) added and reaction mixture was stirred at 0 C for 30 minutes. MEOH was added to quench the reaction. The solvent was evaporated and the residue dissolved in ethyl acetate and washed with H20 and dried over NA2SO4. The product was purified by flash column chromatography on silica gel to afford 3- (3-methoxyphenyl)-1- (4-pyridin-4-yl-thiazol-2-yl)- piperidin-2-one in 60% YIELD.'H NMR (500 MHz, DMSO-d6) 8 8.67 (d, 2H), 7.80 (d, 2H), 7.46 (s, 1H), 7.30 (m, 1H), 6.85 (m, 3H), 4.57 (m, 1H), 4.32 (m, 1H), 3.93 (m, 1H), 3.82 (s, 3H), 2.36 (m, 1H), 2.25 (m, 1H), 2.15 (m, 2H). LC-MS (10-90% CH3CN in H20), Rt = 2.40 min, [M+H] + = 366, [M-H]-= 364.
With chloro-trimethyl-silane; In methanol; ethyl acetate;
Step 1. Preparation of Methyl 3-methoxyphenylacetate Trimethylsilyl chloride (182 g, 1.68 mol) was added dropwise to a solution of 3-methoxyphenylacetic acid (127 g, 0.77 mol) in methanol (1.0 L) over 1.1 hours. The reaction was stirred at room temperature for 17.25 hours, concentrated in vacuo, dissolved in ethyl acetate, dried over MgSO4, and concentrated in vacuo, to give a brown oil (133 g, 97%): 1 H NMR (CDCl3 /300 MHz) 7.24 (t, 1H, J=7.5 Hz), 6.83 (m, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 3.60 (s, 2H).
Stage #1: m-methoxyphenylacetic acid With thionyl chloride In dichloromethane at 0℃; for 2h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 2h;
2- (3-Methoxyphenyl) acetamide (13a)
To a solution of 2-(3-methoxyphenyl)acetic acid (1.00 g, 6.00 mmol,1.00 equiv) in dry CH2C12 (20.0 ml, 0.300 M) was added thionyl chloride(5 mL, 69.0 mmol, 11.5 equiv) at 0 °C. The reaction mixture wasrefluxed for 2 h. The solvent was evaporated and the residue wasazeotroped with toluene (2 xlO.0 ml. THF (30.0 ml) was added to theresidue followed by a slow addition of NH3 H20 (7.00 mL, 28-30%) under vigorous stirring at 0 °C. After stirring at room temperature for 2 h, the solvent was removed, Water (10.0 mL) was added and the mixture was heated for 10 mm while stirring. The suspension was cooled to 0°c, filtered and the residue was washed with ice water. The product was dried overnight to afford the title compound as a white solid (580 mg, 3.51 mmcl, 59% yield) . NMR Spectroscopy: H NMR (700 MHz, (CD3)2S0, 25 °C, 5): 7.46 (s, 1H), 7.20 (t, J 7.8 Hz, lH), 6.87 (s, 1H), 6.83 (s, 1H), 6.82 (s, 1H), 6.79 (dd, J 1.9, 8.2 Hz, lH), 3.72 (s, 3H),3.32 (s, 2H) . ‘3C NMR (175 MHz, (CD3)2S0, 25 °C, 5): 172.1, 159.1,138.0, 129.1, 121.3, 114.8, 111.7, 54.9, 42.3. All the analytical data were in good agreement with values reported in the literature (Kaboudin, B. et al. 2009)
42%
Stage #1: m-methoxyphenylacetic acid With thionyl chloride In dichloromethane at 0℃; for 2.5h; Reflux; Inert atmosphere;
Stage #2: With ammonium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 16h; Inert atmosphere;
With thionyl chloride In chloroform
38 EXAMPLE 38
EXAMPLE 38 Thionyl chloride (650 ml) was added dropwise to a stirred suspension of 3-methoxyphenylacetic acid (500 g) in chloroform (650 ml) over ca 10 mins. The cloudy solution was heated to reflux for 41/2 hours and then allowed to cool to room temperature. The excess thionyl chloride and chloroform were removed by distillation. The cooled residue was dissolved in dry ether (1 liter) and poured onto iced aqueous ammonia solution (S.G. 0.880, 3.5 l). 3-Methoxyphenylacetamide (m.p. 124°-127° C.) was deposited.
With hydrogenchloride; In tetrahydrofuran; methanol;
Preparation A 2-(3-Methoxyphenyl)ethanol 30 g (790 mmol) of LiAlH4was slurried in 500 mL of THF and cooled to -70 C. 131 g (790 mmol) of 3methoxyphenylacetic acid was dissolved in 600 mL of THF and slowly over a period of one hour to the reaction. After one hour, the reaction was allowed to warm to 0 C and was quenched with the careful addition of MeOH. To the quenched reaction was added 1 L of 1 N HCl and the reaction was stirred. After several minutes an additional 300 mL of 5 N HCl was added, along with 600 mL of ether. The reaction was shaken and the layers allowed to separate. The organic layer was reduced in volume by evaporation in vacuo.The aqueous layer was extracted three times with ether and all the ether extracts were combined. The ether extract was washed twice with brine and dried by filtration through anhydrous Na2SO4and evaporated to a yellow oil. This yielded 115 g of the title compound.
Step 1. Preparation of 2-(3-Methoxy-phenyl)-2-methyl-propionic acid methyl ester (Compound 21A) 3-Methoxy phenyl acetic acid (10 g, 60 mmol) was dissolved in MeOH (100 mL) and was then treated with H2SO4 (5 muL). The reaction mixture was refluxed overnight. MeOH was evaporated and the residue was diluted with water and ether. The layers were separated and the aqueous layer was extracted with ether (2*30 mL). The combined organics were dried with MgSO4 and condensed to afford the product in quantitative yield (10.91 g) as a light yellow oil. MS m/z 181 (M+1).
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h;
53%
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h;
Synthesis of compounds 1-3
General procedure: A solution of 2-hydroxy-5-methylbenzaldehyde (7.34mmol) and the corresponding phenylacetic acid (9.18mmol) in dimethyl sulfoxide (15mL) was prepared. N,N’-Dicyclohexylcarbodiimide (11.46mmol) was added, and the mixture was heated in an oil bath at 110°C for 24h. Ice (100mL) and acetic acid (10mL) were added to the reaction mixture. After keeping it at room temperature for 2h, the mixture was extracted with ether (3×25mL). The organic layer was extracted with sodium bicarbonate solution (50mL, 5%) and then water (20mL). The solvent was evaporated under vacuum, and the dry residue was purified by flash chromatography (hexane/ethyl acetate 9:1). Colorless solids were obtained in a yield of 68%, 59% and 53%, respectively. Suitable crystals for X-ray studies were grown from slow evaporation from acetone/ethanol. 6-Methyl-3-(m-methoxyphenyl)coumarin (3). It was obtained a colorless solid with a yield of 53%. Mp 84-85 °C. 1H NMR: 2.44 (s, 3H, CH3), 3.88 (s, 1H, OCH3), 6.97 (m, 1H, H-4'), 7.26-7.42 (m, 6H, H-5, H-7, H-8, H-2', H-5' and H-6'), 7.78 (s, 1H, H-4). 13C NMR: 20.77 (CH3), 55.37 (OCH3), 114.15 (C-2'), 114.38 (C-4'), 116.10 (C-8), 119.28 (C-4a), 120.86 (C-6'), 127.70 (C-5), 129.43 (C-5'), 132.48 (C-7), 134.12 (C-3), 136.12 (C-1'), 139.91 (C-4), 140.10 (C-6), 151.60 (C-8a), 159.45 (C-3'), 160.66 (C-2). DEPT: 20.77 (CH3), 55.37 (OCH3), 114.15 (C-2'), 114.38 (C-4'), 116.10 (C-8), 120.86 (C-6'), 127.70 (C-35), 129.44 (C-5'), 132.48 (C-7), 139.91 (C-4). EI MS m/z (%): 267 (48), 266 (M+, 100), 239 (16), 238 (70), 237 (20), 195 (48), 194 (16), 166 (10), 165 (29), 152 (23). Anal. Calcd for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.76; H, 5.21.
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h;
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h;
2.1.1. General procedure for the preparation of methoxy-3-arylcoumarins
General procedure: To a solution of the conveniently substituted ortho-hydroxybenzaldehyde (7.34 mmol) and the corresponding phenylacetic acid (9.18 mmol) in dimethyl sulfoxide (15 mL), N,N'-dicyclohexylcarbodiimide (11.46 mmol) was added. The mixture was heated at 110°C for 24 h. Then, ice (100 mL) and acetic acid (10 mL) were added to the reaction mixture. After keeping it at room temperature for 2 h, the mixture was extracted with ether (3*25 mL).The organic layers were combined and washed with sodium bicarbonate solution (50 mL, 5%) and water (20 mL). Subsequently, the solvent was evaporated under vacuum and the dry residue was purified by flash chromatography (hexane/ethyl acetate 9:1), to give the desired methoxy-3-arylcoumarins.23,28
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h;
2-(3-methoxy-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: m-methoxyphenylacetic acid With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholin-4-ylethoxy)aniline In N,N-dimethyl-formamide at 20℃;
1.55
A solution of HATU (57.0 mg, 0.150 mmol), triethylamine (41.8 μl, 0.300 mmol) and 3-methoxy-phenylacetic acid (24.9 mg, 0.150 mmol) in DMF (0.3 mL) was stirred at room temperature. After 15 min, 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-aniline (30.2 mg, 0.100 mmol) was added, and the mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by RP-HPLC and lyophilized to give a TFA-salt as a yellow oil (57 mg, 80%). LCMS m/z (%)=451.2 (M+H 100). 1H NMR (500 MHz, MeOH-d4) δ 2.91-3.27 (m, 4 H), 3.50-3.55 (m, 2 H), 3.57-3.99 (m, 4 H), 3.64 (s, 2 H), 3.70 (s, 3 H), 3.77 (s, 3 H), 4.35-4.42 (m, 2 H), 6.31 (d, J=1.89 Hz, 1 H), 6.79-6.85 (m, 1 H), 6.89-6.95 (m, 2 H), 7.14 (d, J=8.83 Hz, 1 H), 7.22 (t, J=8.20 Hz, 1 H), 7.52 (d, J=1.89 Hz, 1 H), 7.56 (d, J=2.84 Hz, 1 H), 7.67 (dd, J=8.98, 2.68 Hz, 1 H).
syn-methyl 2-hydroxy-3-phenyl-3-(2,2,2-trifluoroethoxy)propanoate[ No CAS ]
[ 1798-09-0 ]
(2SR,3RS)-methyl 2-(2-(3-methoxyphenyl)acetoxy)-3-phenyl-3-(2,2,2-trifluoroethoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h;
4.3. General procedure for the esterification of alcohols syn-4b and anti-4b
General procedure: Alcohol syn-4b (500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), and DMAP (110 mg, 0.898 mmol, 0.5 equiv) were added to phenylacetic acid (294 mg, 2.16 mmol, 1.2 equiv) in CH2Cl2 (5 mL) at room temperature, under nitrogen. The mixture was stirred at room temperature for 12 h and the solvent was removed under reduced pressure. Et2O was added and the mixture was filtered. The filtrate was washed with sodium acetate buffer (pH=5) and the aqueous layer was extracted with Et2O. The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5% AcOEt/cyclohexane) to afford compound syn-9b (605 mg, 85%) as a colorless oil.
anti-methyl 2-hydroxy-3-phenyl-3-(2,2,2-trifluoroethoxy)propanoate[ No CAS ]
[ 1798-09-0 ]
(2RS,3RS)-methyl 2-(2-(3-methoxyphenyl)acetoxy)-3-phenyl-3-(2,2,2-trifluoroethoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h;
4.3. General procedure for the esterification of alcohols syn-4b and anti-4b
General procedure: Alcohol syn-4b (500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), and DMAP (110 mg, 0.898 mmol, 0.5 equiv) were added to phenylacetic acid (294 mg, 2.16 mmol, 1.2 equiv) in CH2Cl2 (5 mL) at room temperature, under nitrogen. The mixture was stirred at room temperature for 12 h and the solvent was removed under reduced pressure. Et2O was added and the mixture was filtered. The filtrate was washed with sodium acetate buffer (pH=5) and the aqueous layer was extracted with Et2O. The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5% AcOEt/cyclohexane) to afford compound syn-9b (605 mg, 85%) as a colorless oil.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: A mixture 2-amino-4,5-dimethylthiophene-3-carboxamide (340 mg, 2 mmol), 2-(1-naphthalen-1-yl)acetic acid (372 mg, 2 mol), EDC (458 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol), DIEA ( 1.1 mL, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into 100 mL of water then extracted with ethyl acetate (150 mL). The organic layer was washed with saturated NaHCO3 solution (3 x 50 mL), brine (3 x 50 mL), water (3 x 50 mL) respectively. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (30 to 40% ethyl acetate in haxane) to afford compound 1 (277 mg, 41%).
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere;
General procedure for amide coupling of 5 with carboxylic acids
General procedure: To a suspension of EDC*HCl (0.46 g, 2.4 mmol, 1.2 equiv.) and NMM (0.81 mL, 8 mmol, 4 equiv.) in DMF (10 mL) at rt were added successively HOBt (0.33 g, 2.4 mmol, 1.2 equiv.), appropriate carboxylic acid (1.2 mmol, 1.2 equiv.) and the free base of 2-benzofuranoylpiperazine hydrochloride (5*HCl, 0.46 g, 2 mmol, 1 equiv.). The reaction mixture was stirred at rt for 20 h and then diluted with H2O (50 mL) and then extracted with CHCl3:MeOH (9:1 v/v, 3 × 50 mL). The combined organic fractions were then washed with aqueous sodium hydroxide (1 M, 100 mL), dried (Na2SO4) and concentrated under reduced pressure to give a crude residue, which was triturated with cold EtOAc (ca. 10 mL).
Stage #1: m-methoxyphenylacetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h;
Stage #2: 4-hydroxy-5-methylisophthalaldehyde In N,N-dimethyl-formamide at 110℃; for 0.583333h;
95%
Stage #1: m-methoxyphenylacetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h;
Stage #2: 4-hydroxy-5-methylisophthalaldehyde In N,N-dimethyl-formamide at 110℃;
General synthesis of 3-aryl coumarins (9a-9p):
General procedure: To a mixture of cyanuric chloride (1.0 mmol), N-methyl morpholine (1.5 mmol) and substituted phenyl acetic acids (1.0 mmol) in DMF (5 mL), was stirred at room temperature for 10 min. after that 4-hydroxy-5-alkyl isophthalaldehyde (8a-8g, 1.0 mmol) was added. Subsequently, the resulting reaction mixture was refluxed for 30-90 min, after completion of the reaction (monitored by TLC) diluted with water (10 mL) and extracted 3-fold with EtOAc (15 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol, the resulted solid was filtered and dried under vacuums to provide the pure compounds (9a-9p).
2-Amino-5-(4-methyl-phenyl)-thiophene-3-carboxylic Acid Amide[ No CAS ]
[ 1798-09-0 ]
[ 1393911-82-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In chloroform at 120℃; Microwave irradiation;
General procedure: To a mixture of 2-amino-5-(4-methylphenyl) thiophene-3-carboxamide 1a (0.25 g, 0.107 mol) and 4-benzyloxy benzoic acid 4a (0.319 g, 0.140 mol) in anhydrous chloroform (4 ml) was added triethylamine (0.32 g, 0.323 mol) and phosphonic acid cyclic anhydride (1.02 g, 0.323 mol). The reaction mixture was irradiated at 120 °C in a microwave initiator for a given period of time (Table 1, entry 1). Once the substrate was completely consumed as monitored by TLC, the brown reaction mixture was cooled and poured into ice-cold water (10 ml). The product was extracted with ethyl acetate (2 × 25 ml) and the combined organic phase was washed with water, brine solution and dried over anhydrous sodium sulfite. The solvent was removed under vacuum and the brown residue was passed through a small plug of silica gel using petroleum ether/ethyl acetate (9/1) to afford 429 mg (94%) of 2a as a yellow solid.
Stage #1: m-methoxyphenylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h;
Stage #2: 2-(3,5-dimethoxyphenyl)ethan-1-amine hydrochloride In dichloromethane at 20℃; for 8h;
6.4.1. N-(2-(4-(Benzyloxy)-3-methoxyphenyl)ethyl)-2-(3,5-dimethoxyphenyl)acetamide (15c)
General procedure: To a solution of 3,5-dimethoxyphenylacetic acid 14a (0.98 g, 5 mmol) in CH2Cl2 (10 mL), EDCI (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimidehydrochloride) (1.15 g, 6 mmol) was added. The mixture was stirred at room temperature for 0.5 h, and 2-(4-(benzyloxy)-3-methoxyphenyl)ethan-1-amine hydrochloride 13a (1.47 g, 5 mmol) was added. The mixture was stirred for another 8 h, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH = 80/1) to afford 15c (1.76 g, 81%) as a white solid.
Stage #1: m-methoxyphenylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h;
Stage #2: [2-(4-benzyloxy-3-methoxyphenyl)ethyl]amine hydrochloride In dichloromethane at 20℃; for 8h;
6.4.1. N-(2-(4-(Benzyloxy)-3-methoxyphenyl)ethyl)-2-(3,5-dimethoxyphenyl)acetamide (15c)
General procedure: To a solution of 3,5-dimethoxyphenylacetic acid 14a (0.98 g, 5 mmol) in CH2Cl2 (10 mL), EDCI (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimidehydrochloride) (1.15 g, 6 mmol) was added. The mixture was stirred at room temperature for 0.5 h, and 2-(4-(benzyloxy)-3-methoxyphenyl)ethan-1-amine hydrochloride 13a (1.47 g, 5 mmol) was added. The mixture was stirred for another 8 h, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH = 80/1) to afford 15c (1.76 g, 81%) as a white solid.
Stage #1: m-methoxyphenylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h;
Stage #2: 3,4-methylenedioxyphenylethylamine In dichloromethane at 20℃; for 8h;
6.4.1. N-(2-(4-(Benzyloxy)-3-methoxyphenyl)ethyl)-2-(3,5-dimethoxyphenyl)acetamide (15c)
General procedure: To a solution of 3,5-dimethoxyphenylacetic acid 14a (0.98 g, 5 mmol) in CH2Cl2 (10 mL), EDCI (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimidehydrochloride) (1.15 g, 6 mmol) was added. The mixture was stirred at room temperature for 0.5 h, and 2-(4-(benzyloxy)-3-methoxyphenyl)ethan-1-amine hydrochloride 13a (1.47 g, 5 mmol) was added. The mixture was stirred for another 8 h, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH = 80/1) to afford 15c (1.76 g, 81%) as a white solid.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In acetonitrile; at 80℃; for 0.5h;Microwave;
N-(lH-indol-4-yl)-2-(3-methoxyphenyl)acetamide (26d) A mixture of 4-Aminoindole (0.150 g, 1.135 mmol), 3-methoxyphenyl acetic acid (260 g, 1.564 mmol), EDC hydrochloride (0.440 g, 2.26 mmol), 4-dimethylaminopyridine (0.050 g, 0.410 mmol) in acetonitrile (4mL) was heated in the Biotage Microwave for 30min at 80C. The solution was then washed with lOmL of IN HCl, extracted with ethyl acetate, and then washed with lOmL of a saturated NaHC03 solution. The organic phase was dried over Na2S04 and filtered. The solution was concentrated under reduced pressure to afford 26d as a dark brown solid (0.312 g, 1.114 mmol, 99%>). The crude material was used in the next step without purification. 1H NMR (400 MHz, CDC13) delta 8.22 (s, 1H), 7.79 (t, J = 4.4 Hz, 1H), 7.47 - 7.29 (m, 1H), 7.17 (d, J = 4.5 Hz, 2H), 7.11 (t, J = 2.9 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.94-6.92 (m, 1H), 5.99 (t, J= 2.2 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 2H).
With triethylamine; In toluene; at 80℃; for 3h;Inert atmosphere;
2.2.1 Synthesis of [Ti(eta5-C5H5)2(OOC-3-mpa)2] (1) NEt3 (0.57 mL, 4.00 mmol) was added dropwise to a suspension of 3-methoxyphenylacetic acid (0.60 g, 4.00 mmol) and [Ti(eta5-C5H5)2Cl2] (0.50 g, 2.00 mmol) in toluene (50 mL) at room temperature. The reaction mixture colour changed immediately from deep red to orange and was then stirred for 3 h at 80 C. The mixture was decanted and filtered to remove the triethylammonium chloride salt. The filtrate was then concentrated and cooled to -30 C to give orange crystals of the complex which were isolated by filtration. Yield: 1.64 g, 81%. 1H NMR (400 MHz, CDCl3, 25 C): delta 3.54 (s, 4H, -CH2-), 3.84 (s, 6H, -OMe), 6.28 (s, 10H, C5H5), 6.81 (d, 2H, Hpara of Ph), 6.89 (br m, 4H, Hortho and Hmeta of Ph) and 7.26 (d, 2H, Hortho of Ph) ppm. 13C{1H} NMR (100 MHz, CDCl3, 25 C): delta 43.3 (-CH2-), 55.3 (-OMe), 112.6 (Cpara of Ph), 115.4, 122.9 (Cortho of Ph), 118.2 (C5H5), 129.5, 159.7 (Cmeta of Ph), 137.5 (-CH2-C) and 188.5 (COO) ppm. FT-IR (KBr) = 1432 (nusym COO-) and 1644 (nuasym COO-) cm-1. FAB-MS: 343.2 (33) [M+ - OOC-CH2-C6H4-m-OMe], 208.0 (10) [MCp2O2-2H], 148.1 (99) [OC-CH2-C6H4-m-OMe] and 121.1 (100) [H3C-C6H4-m-OMe]. Elemental analysis (C28H28O6Ti, 508.14 g/mol) Calculated: C 66.15, H 5.55; Found: C 66.00, H 5.41%.
With triethylamine In toluene at 80℃; for 3h; Inert atmosphere;
2.2.1 Synthesis of [Ti(η5-C5H5)2(OOC-3-mpa)2] (1)
General procedure: NEt3 (0.57 mL, 4.00 mmol) was added dropwise to a suspension of 3-methoxyphenylacetic acid (0.60 g, 4.00 mmol) and [Ti(η5-C5H5)2Cl2] (0.50 g, 2.00 mmol) in toluene (50 mL) at room temperature. The reaction mixture colour changed immediately from deep red to orange and was then stirred for 3 h at 80 °C. The mixture was decanted and filtered to remove the triethylammonium chloride salt. The filtrate was then concentrated and cooled to -30 °C to give orange crystals of the complex which were isolated by filtration.
With sodium hydrogencarbonate; trifluoroacetic anhydride In dichloromethane at 20℃;
1 1-(Furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one
EXAMPLE 1 1-(Furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one 3-Methoxyphenylacetic acid (20 g, 120.35 mmol) was dissolved in CH2Cl2 (200 mL), and furan (24.6 g, 361.39 mmol) and trifluoroacetic anhydride (37.8 g, 180 mmol) were added to the solution. The reaction was kept being stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 to pH=6.9, and the organic reagent in the mixture was evaporated. The residue was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give 1-(furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one as yellow oil: 20 g (yield: 77%) 1H NMR (300 MHz, CDCl3) δ 3.76 (3H, s), 4.07 (2H, s), 6.50 (1H, dd, J=1.7, 3.6 Hz), 6.76-6.89 (3H, m), 7.19-7.26 (2H, m), 7.57 (1H, dd, J=0.7, 1.7 Hz).
77%
With trifluoroacetic anhydride In dichloromethane at 20℃;
1 1-(Furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one
3-Methoxyphenylacetic acid (20 g, 120.35 mmol) was dissolved in CH2Cl2 (200 mL), and furan (24.6 g, 361.39 mmol) and trifluoroacetic anhydride (37.8 g, 180 mmol) were added to the solution. The reaction was kept being stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 to pH=6.9, and the organic reagent in the mixture was evaporated. The residue was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give 1-(furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one as yellow oil: 20 g (yield: 77 %) 1H NMR (300 MHz, CDCl3) δ 3.76 (3H, s), 4.07 (2H, s), 6.50 (1H, dd, J = 1.7, 3.6 Hz), 6.76-6.89 (3H, m), 7.19 -7.26 (2H, m), 7.57 (1H, dd, J = 0.7, 1.7 Hz).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 23.5h;
3-Methoxy-4-oxazol-5-yl-phenylamine (Intermediate 1) (3.792 g, 19.9 mmol) and 2-(3-methoxyphenyl)acetic acid (5.3 g, 31.9 mmol) were combined with dichloromethane (200 ml).The mixture was cooled to 0C and treated with (3-dimethylamino-propyl)-ethyl-carbodiimide(6.12 g, 31.9 mmol). The mixture was stirred for 30min at 0C, then at RT for 23 h.The mixture was washed with saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting yellow solid (8.2 g) was suspended in ethyl acetate and the solid filtered and washed. The filtrate was evaporated and purified by flash chromatography (heptane/ethyl acetate) and combined with the solid to yield N-(3-methoxy-4- oxazol-5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide as a white solid (5.4 g. 80.3%). MS (ISN) mlz = 339.5 [(M+H)+].
Stage #1: m-methoxyphenylacetic acid With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: allyl iodid In tetrahydrofuran at -78 - 25℃; for 15h;
3.1 Step 1: 2-(3-Methoxyphenyl)pent-4-enoic acid
Step 1: 2-(3-Methoxyphenyl)pent-4-enoic acidTo a solution of 3-methoxyphenyl acetic acid (30.08 mmol) in THF (150 ml) at -78 °C was added LiHMDS (1M solution in THF; 66. 19m1, 66. l9mmol), and the reaction mixture was stirred at -78 °C for 0.5 h. Allyl iodide (2.75 ml, 30.08 mmol) was added to the reaction mixture at -78 °C, and the mixture was slowly allowed to warm to 25 °C over a period of 3 h, and then continued to stir at 25 °C for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution, acidified using iN aqueous HC1 solution, and extracted with EtOAc (2 x 130 ml). The combined organic layers were dried over anhydrous Na2504, filtered, and concentrated under reduced pressure. The resulting crude material was purified by column chromatography over silica gel (10-20 %EtOAc/hexane) to get 2-(3- methoxyphenyl) pent-4-enoic acid (5.3 g, 85.48 %) as light yellow oil.
85.48%
Stage #1: m-methoxyphenylacetic acid With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: allyl iodid In tetrahydrofuran at -78 - 25℃; for 15h;
3.1 Step 1: 2-(3-Methoxyphenyl)pent-4-enoic acid
To a solution of 3-methoxyphenyl acetic acid (30.08 mmol) in THF (150 ml) at -78° C. was added LiHMDS (1M solution in THF; 66.19 ml, 66.19 mmol), and the reaction mixture was stirred at -78° C. for 0.5 h. Allyl iodide (2.75 ml, 30.08 mmol) was added to the reaction mixture at -78° C., and the mixture was slowly allowed to warm to 25° C. over a period of 3 h, and then continued to stir at 25° C. for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution, acidified using 1N aqueous HCl solution, and extracted with EtOAc (2*130 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by column chromatography over silica gel (10-20% EtOAc/hexane) to get 2-(3-methoxyphenyl) pent-4-enoic acid (5.3 g, 85.48%) as light yellow oil.
2-(3-methoxyphenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In acetic anhydride; at 30℃; for 2h;
General procedure: General procedure A Step-a: Synthesis of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl) phenyl) acrylic acid (C). A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 ml). To this mixture diisopropylethylamine (DIPEA) (3.4 ml, 19.7 mmol) was added and stirred at 30 C for 2 h. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH was adjusted to 1 using dil. HClaq (1:1). The aqueous layer was extracted with ethyl acetate (2 * 150 ml). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a white solid. It was filtered and dried under vacuum to afford the title compound (2 g, 47%).
N-(4’-chlorophenyl)-2-(3-methoxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With 1,2-dichloro-ethane In dichloromethane at 20℃;
87%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 24℃; for 12h; Inert atmosphere;
General synthetic protocol for methoxyphenyl acetamides 36.
General procedure: To a mixture of N,N‘-dicyclohexylcarbodimide (220 mg, 1.08 mmol), DMAP (11.1 mg, 9.03 × 10-5 mmol) and 3-methoxyphenylacetic acid 31 (150 mg, 0.903 mmol) at 0 oC were added the respective amines (b-g) (0.903 mmol) in anhydrous CH2Cl2 (5.0 mL) and the resultant reaction mixture was stirred at 24 oC for 12 h. The suspension was filtered and the eluent concentrated under reduced pressure to yield a solid residue which was purified by flash chromatography (15:85 EtOAc/Hexane) to afford the products described below. The compounds were characterized by NMR spectroscopy (for some compounds HRMS too) and utilized directly in the next reduction step).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid.
2-(3-methoxyphenyl)-N-[2-(trifluoromethoxy)phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound.
2-(3-methoxyphenyl)-N-(2,3-difluorophenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; at 25℃; for 18h;Inert atmosphere;
General procedure: All the starting materials were purchased from Sigma-Aldrichand were used without further purification. All the compounds(Scheme 1) were synthesized from their corresponding aniline and3-methoxyphenylacetic acid initially following the procedure reportedby Nagarajan et al. [13], and later, on experiencing poor yieldof some of our target molecules we followed a different syntheticprocedure for better yield with the use of less hazardous chemicals[14]. 3-Methoxy-phenyl-acetic acid 1a (1.0 eqv), fluorinesubstituted aniline 1b (1.10 eqv), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) (1.10 eqv) andhydroxybenzotriazole (HOBt) (0.50 eqv) were mixed in a roundbottom flask and N-methylpyrrolidin-2-one (NMP) solvent wasadded at room temperature (25 °C) under N2 environment. Thereaction mixturewas stirred at room temperature for 18 h. After thereaction was over, water and ethyl acetate were added and themixture was stirred for 15 min. The mixture was then allowed tosettle in a separating funnel, and the lower aqueous phase wasremoved and discarded. The organic phasewas washed a few timeswith water and brine solution to remove the unreacted watersolublecompounds and to achieve better separation of organicand aqueous layers. Then the organic phase was collected overexcess anhydrous sodium sulfate to remove traces of moisture inthe organic phase. Then the organic solvent was removed underreduced pressure on a rotary evaporator to extract the solid targetcompound. The crude product was purified by column chromatographyusing ethyl acetate/hexane mixture as the mobile phase.All the pure compounds were characterized by 1H, 13C and 19F NMR(400 MHz, Bruker Biospin Avance-III NMR spectrometer), FTIR(Perkin Elmer Spectrum 2) and the melting point of all the compoundswere determined by differential scanning calorimetry(DSC) (Perkin Elmer Diamond 8000 DSC). All the characterizationdetails (NMR, IR, DSC and PXRD) are provided as electronicsupporting information (ESI).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; at 25℃; for 18h;Inert atmosphere;
General procedure: All the starting materials were purchased from Sigma-Aldrichand were used without further purification. All the compounds(Scheme 1) were synthesized from their corresponding aniline and3-methoxyphenylacetic acid initially following the procedure reportedby Nagarajan et al. [13], and later, on experiencing poor yieldof some of our target molecules we followed a different syntheticprocedure for better yield with the use of less hazardous chemicals[14]. 3-Methoxy-phenyl-acetic acid 1a (1.0 eqv), fluorinesubstituted aniline 1b (1.10 eqv), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) (1.10 eqv) andhydroxybenzotriazole (HOBt) (0.50 eqv) were mixed in a roundbottom flask and N-methylpyrrolidin-2-one (NMP) solvent wasadded at room temperature (25 C) under N2 environment. Thereaction mixturewas stirred at room temperature for 18 h. After thereaction was over, water and ethyl acetate were added and themixture was stirred for 15 min. The mixture was then allowed tosettle in a separating funnel, and the lower aqueous phase wasremoved and discarded. The organic phasewas washed a few timeswith water and brine solution to remove the unreacted watersolublecompounds and to achieve better separation of organicand aqueous layers. Then the organic phase was collected overexcess anhydrous sodium sulfate to remove traces of moisture inthe organic phase. Then the organic solvent was removed underreduced pressure on a rotary evaporator to extract the solid targetcompound. The crude product was purified by column chromatographyusing ethyl acetate/hexane mixture as the mobile phase.All the pure compounds were characterized by 1H, 13C and 19F NMR(400 MHz, Bruker Biospin Avance-III NMR spectrometer), FTIR(Perkin Elmer Spectrum 2) and the melting point of all the compoundswere determined by differential scanning calorimetry(DSC) (Perkin Elmer Diamond 8000 DSC). All the characterizationdetails (NMR, IR, DSC and PXRD) are provided as electronicsupporting information (ESI).
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 24℃; for 12h; Inert atmosphere;
General synthetic protocol for methoxyphenyl acetamides 36.
General procedure: To a mixture of N,N‘-dicyclohexylcarbodimide (220 mg, 1.08 mmol), DMAP (11.1 mg, 9.03 × 10-5 mmol) and 3-methoxyphenylacetic acid 31 (150 mg, 0.903 mmol) at 0 oC were added the respective amines (b-g) (0.903 mmol) in anhydrous CH2Cl2 (5.0 mL) and the resultant reaction mixture was stirred at 24 oC for 12 h. The suspension was filtered and the eluent concentrated under reduced pressure to yield a solid residue which was purified by flash chromatography (15:85 EtOAc/Hexane) to afford the products described below. The compounds were characterized by NMR spectroscopy (for some compounds HRMS too) and utilized directly in the next reduction step).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1-methyl-pyrrolidin-2-one at 25℃; for 18h; Inert atmosphere;
2. Experimental
General procedure: All the starting materials were purchased from Sigma-Aldrichand were used without further purification. All the compounds(Scheme 1) were synthesized from their corresponding aniline and3-methoxyphenylacetic acid initially following the procedure reportedby Nagarajan et al. [13], and later, on experiencing poor yieldof some of our target molecules we followed a different syntheticprocedure for better yield with the use of less hazardous chemicals[14]. 3-Methoxy-phenyl-acetic acid 1a (1.0 eqv), fluorinesubstituted aniline 1b (1.10 eqv), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) (1.10 eqv) andhydroxybenzotriazole (HOBt) (0.50 eqv) were mixed in a roundbottom flask and N-methylpyrrolidin-2-one (NMP) solvent wasadded at room temperature (25 °C) under N2 environment. Thereaction mixturewas stirred at room temperature for 18 h. After thereaction was over, water and ethyl acetate were added and themixture was stirred for 15 min. The mixture was then allowed tosettle in a separating funnel, and the lower aqueous phase wasremoved and discarded. The organic phasewas washed a few timeswith water and brine solution to remove the unreacted watersolublecompounds and to achieve better separation of organicand aqueous layers. Then the organic phase was collected overexcess anhydrous sodium sulfate to remove traces of moisture inthe organic phase. Then the organic solvent was removed underreduced pressure on a rotary evaporator to extract the solid targetcompound. The crude product was purified by column chromatographyusing ethyl acetate/hexane mixture as the mobile phase.All the pure compounds were characterized by 1H, 13C and 19F NMR(400 MHz, Bruker Biospin Avance-III NMR spectrometer), FTIR(Perkin Elmer Spectrum 2) and the melting point of all the compoundswere determined by differential scanning calorimetry(DSC) (Perkin Elmer Diamond 8000 DSC). All the characterizationdetails (NMR, IR, DSC and PXRD) are provided as electronicsupporting information (ESI).
10 General experimental procedure
General procedure: In 5mL thick wall glass tube (microwave tube) equipped with magnetic stirring bar, first dry toluene 1mL was added then 4-methylphenylacetic acid (1a, 0.50mmol) dissolved into toluene by stirring for 5min. Then benzylamine (2a, 0.55mmol) was added and stirred the reaction mixture for 5min. Finally, catalyst triphenyl borate (4mol%) was added and tube was closed with septum and placed into oil bath and magnetically stirred at 110°C for 3h under air atmosphere. After completion, the reaction mixture was cooled to room temperature. Then reaction mixture was transfer into conical flask and ethyl acetate or dichlormethane (10mL) was added. Then product is purified by acid base extraction using aqueous 1:1 HCl and 10% NaOH and finally washed with brine and water. The organic layer was dried over Na2SO4 and finally organic solvent evaporated on rota-evaporator to afford the pure product 3a. The product was confirmed by 1H and 13C NMR spectroscopic analysis. Same procedure is followed for synthesis of all other amides from 3b to 3q.
71%
With bis(cyclopentadienyl)titanium dichloride In tetrahydrofuran at 70℃; for 24h; Molecular sieve; Sealed tube; Inert atmosphere;
With triethylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 1h;Inert atmosphere;
A mixture of compound 48 (600 mg, 2.8 mmol, 1.0 eq), 2-(3- methoxyphenyl)acetic acid (465 mg, 2.8 mmol, 1.0 eq), HATU (1.1 g, 2.8 mmol, 1.0 eq), triethylamine (425 mg, 4.2 mmol, 1.5 eq) in 8 mL of DMF was stirred at 25C for 1 hour. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was diluted with 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combinedorganic layers were washed with three 20 mL portions of brine, dried over Na2504, filtered and concentrated under reduced pressure to give 1.08 g of compound 49 as a crude yellow oil.
4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl 2-(3-methoxyphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1.
methyl (2-(3-methoxyphenyl)acetyl)alaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 0 - 20℃; for 4h;
To a stirred solution of 2-(3-methoxyphenyl)acetic acid (5.0 g, 30.30 mmol), methyl alaninate hydrochloride (4.63 g, 33.15 mmol) and TEA (10.5 ml_, 75.38 mmol) added T3P (50% in EtOAc, 28.7 ml_, 45.21 mmol) at 0 C and stirred at RT for 4 h. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 ml_), extracted with EtOAc (3 x 50 ml_), and the combined organic layer was dried over Na2S04 and concentrated to give the tittle compound. Yield: 63% (4.7 g, pale brown gummy solid). LCMS: (Method A) 252.0 (M+H), Rt. 2.2 min, 90.7% (Max).
5-(3-methoxyphenyl)-3-phenyl-1,2,4-thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With sulfur; copper(l) iodide; sodium carbonate In dimethyl sulfoxide at 130℃; for 24h; Inert atmosphere;
69%
With sulfur; copper(l) iodide; sodium carbonate In dimethyl sulfoxide at 130℃; for 24h;
13
Preparation method: In a 25mL pressure tube, add 0.5mmol benzamidine hydrochloride, 1.0mmol 3-methoxyphenylacetic acid, 3.0mmol sulfur powder, 1.0mmol Na2CO3, 0.1mmol CuI, then add 2mL dimethyl sulfoxide, Stir at 130 ° C for 24 hours. The TLC plate detects that the reaction is complete and product is formed.The reaction solution was cooled, extracted, dried, evaporated under reduced pressure, filtered by column chromatography, and filtered to obtain a white solid.The yield was 69%.
(S)-N-methyl-7-nitro-1,2,3,4-tetrahydronaphthalen-1-amine[ No CAS ]
(S)-2-(3-methoxyphenyl)-N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;
2-(3-Methoxyphenyl)-N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (12)
General procedure: A mixture of 11 (199 mg, 0,965 mmol), 3-methoxyphenylacetic acid (483 mg, 2.91 mmol), Et3N (1.00 mL, 7.19 mmol), and HATU (1.10 g, 2.89 mmol) in DMF (5 mL) was stirred for 4 h at room temperature under an argon atmosphere. The reaction mixture was diluted with sat. NaHCO3 aq. (5 mL) and H2O (10 mL) and extracted with CHCl3 (20, 10, 10 mL). The organic layer was washed with 1 M HCl aq. (5 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (18-50% EtOAc in hexane and hexane:EtOAc:MeOH:28% NH3 aq.=20:10:0.9:0.1) and preparative TLC (33% EtOAc in hexane) to afford 12 (321 mg, 93%) as a yellow oil.
95%
With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;
2-(3-Methoxyphenyl)-N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (12)
General procedure: A mixture of 11 (199 mg, 0,965 mmol), 3-methoxyphenylacetic acid (483 mg, 2.91 mmol), Et3N (1.00 mL, 7.19 mmol), and HATU (1.10 g, 2.89 mmol) in DMF (5 mL) was stirred for 4 h at room temperature under an argon atmosphere. The reaction mixture was diluted with sat. NaHCO3 aq. (5 mL) and H2O (10 mL) and extracted with CHCl3 (20, 10, 10 mL). The organic layer was washed with 1 M HCl aq. (5 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (18-50% EtOAc in hexane and hexane:EtOAc:MeOH:28% NH3 aq.=20:10:0.9:0.1) and preparative TLC (33% EtOAc in hexane) to afford 12 (321 mg, 93%) as a yellow oil.
(R)-N-methyl-7-nitro-1,2,3,4-tetrahydronaphthalen-1-amine[ No CAS ]
(R)-2-(3-methoxyphenyl)-N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;
2-(3-Methoxyphenyl)-N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (12)
General procedure: A mixture of 11 (199 mg, 0,965 mmol), 3-methoxyphenylacetic acid (483 mg, 2.91 mmol), Et3N (1.00 mL, 7.19 mmol), and HATU (1.10 g, 2.89 mmol) in DMF (5 mL) was stirred for 4 h at room temperature under an argon atmosphere. The reaction mixture was diluted with sat. NaHCO3 aq. (5 mL) and H2O (10 mL) and extracted with CHCl3 (20, 10, 10 mL). The organic layer was washed with 1 M HCl aq. (5 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (18-50% EtOAc in hexane and hexane:EtOAc:MeOH:28% NH3 aq.=20:10:0.9:0.1) and preparative TLC (33% EtOAc in hexane) to afford 12 (321 mg, 93%) as a yellow oil.
98%
With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;
2-(3-Methoxyphenyl)-N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (12)
General procedure: A mixture of 11 (199 mg, 0,965 mmol), 3-methoxyphenylacetic acid (483 mg, 2.91 mmol), Et3N (1.00 mL, 7.19 mmol), and HATU (1.10 g, 2.89 mmol) in DMF (5 mL) was stirred for 4 h at room temperature under an argon atmosphere. The reaction mixture was diluted with sat. NaHCO3 aq. (5 mL) and H2O (10 mL) and extracted with CHCl3 (20, 10, 10 mL). The organic layer was washed with 1 M HCl aq. (5 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (18-50% EtOAc in hexane and hexane:EtOAc:MeOH:28% NH3 aq.=20:10:0.9:0.1) and preparative TLC (33% EtOAc in hexane) to afford 12 (321 mg, 93%) as a yellow oil.
With ammonium hydroxide; oxygen In neat (no solvent) at 120℃; for 6h; Sealed tube;
General Procedure for preparation of amides catalyzed by Fe3O4*SiO2-SMTU-Cu
General procedure: A sealed pressure vessel was charged with phenylacetic acids (68.0 mg, 0.5 mmol), Fe3O4*SiO2-SMTU-Cu catalyst (20 mg), and aqueous ammonia solution (28 wt% in H2O; 1.5 mL). The resulting solution was stirred at 120 °C under O2 (monitored by TLC and GC) for 6 hours. Upon completion of the reaction, the catalyst was separated using magnetic stirring bar and ethyl acetate (20 mL) was added, the organic layer was washed with saturate NaHCO3 (20 mL) solution twice, brine (20 mL) once, the combined aqueous layers was extracted with EtOAc (20 mL) twice. The combine organic layers were dried over anhydrous Na2SO4. The solvents were removed via rotary evaporator and the residue was purified with flash chromatography (silica gel, ethyl acetate: petroleum ether=2:1) to give amide products.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
