* 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 hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 125℃; for 48 h;
General procedure: Aldehyde (0.5mmol), NH2OH·HCl (0.6mmol) and Cs2CO3 (0.6mmol) were stirred at 125°C for 48h in a 3:1 mixture of DMSO–H2O (2mL) under air. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture was cooled to room temperature and treated with water (1mL). The resulting mixture was extracted with ethyl acetate (3×5mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica gel column chromatography using ethyl acetate and hexane. The purified products were identified by 1H NMR spectra and the melting points comparison with the literature data.
Reference：
[1] Tetrahedron, 2002, vol. 58, # 52, p. 10323 - 10328
[2] RSC Advances, 2014, vol. 4, # 27, p. 13782 - 13787
[3] RSC Advances, 2016, vol. 6, # 43, p. 37093 - 37098
[4] Synthesis, 2002, # 8, p. 1057 - 1060
[5] Journal of Chemical Research - Part S, 2003, # 3, p. 176 - 178
[6] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7590 - 7593
[7] Tetrahedron Letters, 2014, vol. 55, # 20, p. 3192 - 3194
[8] Applied Organometallic Chemistry, 2018, vol. 32, # 6,
2
[ 873-62-1 ]
[ 618-49-5 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: at 50℃; for 70 h; Stage #2: With hydrogenchloride In methanol; water
Example 49; 3-Hydroxybenzamide (49a). 3-Cyanophenol (295 mg, 2.48 mmol, 100 mol-percent) and NaBO3 - 4 H2O (1146 mg, 7.45 mmol, 300 mol-percent) in H2O (8 ml_) were heated to 50 0C and MeOH (14 ml_) was added until mixture was clear. The mixture was stirred at 50 0C for 70 hours and excess MeOH was evaporated and the pH of remaining mixture was adjusted to 5 with cone. HCI (aq). Mixture was extracted with CH2CI2 (12 ml_) and with EtOAc (5x15 ml_). Organic phases were combined, washed with brine (25 ml_) and dried over Na2SO4. Filtering and evaporation of solvents gave 49a as spectro- scopically pure white solid (183 mg, 54percent): mp 165-168 0C; Rf (50percent EtOAc in hex) 0.10.
With ammonium hydroxide In tetrahydrofuran at 20℃; Cooling with ice
To a solution of 3-hydroxybenzoic acid (1) (10.0 g, 72.41 mmol) in toluene (80 mL) at room temperature was slowly added thionyl chloride (7.71 mL, 108.62 mmol). The resulting solution was heated to reflux for 4.5 h and concentrated in vacuo to give crudeproduct of 3-hydroxybenzoyl chloride (2). The crude product was dissolved in THF (30 mL) in an ice-methanol bath and concentrated aqueous ammonia (28 mL) was dropwise added.The resulting reaction mixture was warmed slowly to room temperature and stirredfor 18 h at the same temperature. After concentrating in vacuo, the residue was suspended in water (20 mL) and filtered. The collected solid was washed with water (3 × 15 mL) and then dried in vacuo to give 3-hydroxybenzamide (3) (7.03g, 70.8percent) as anoff-white crystals. mp 160–163 °C, TLC Rf= 0.12 (petroleum ether/ethyl acetate, 1:2); IR (KBr): 2958, 2925, 2851, 1113, 638, 615 cm-1;1H NMR (600 MHz, DMSO-d6, FontSize="10" δppm): 9.60 (s, 1H), 7.86 (s,1H), 7.29–7.21 (m, 4H), 6.90 (dd, J =7.8 Hz, J = 1.8 Hz, 1H); MS(ESI) m/z calcd for C7H7NO2 137.0; found (M + H+) 138.3.
7.03 g
With ammonia In tetrahydrofuran; water at 20℃; for 18 h; Cooling with ice
To a solution of 3-hydroxybenzoic acid (1) (5.0 g, 36.21mmol) in toluene (40 mL) at room temperature was slowly added thionyl chloride (3.86 mL, 54.38 mmol). The reaction solution was heated to reflux for 4.5 h and concentrated invacuo to give 3-hydroxybenzoyl chloride (2). The crude product 2 was dissolved in THF (15 mL) in an ice bath and aqueous ammonia (14 mL) was dropwise added. The resulting mixture was slowly warmed to room temperature and stirred for 18 h at the same temperature. After concentrating in vacuo, the residue was suspended in water (10 mL) and filtered. The collected solid was washed with water (3 x10mL) and then dried in vacuo to give 3-hydroxybenzamide (3)(7.03 g, 70.8percent) as an off-white solid. mp 160–163°C, TLC Rf = 0.12 (petroleum ether/ethyl acetate, 1:2); IR (KBr):2958, 2925, 2851, 1113, 638, 615 cm-1; 1H NMR (600 MHz,DMSO-d6, ppm) 9.60 (s, 1H), 7.86 (s, 1H), 7.29–7.21 (m,4H), 6.90 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H); MS (ESI) m/z calcd for C7H7NO2 137.0; found [M+H]+ 138.3; Analysis calculated for C7H7NO2: C 61.31, H 5.14, N 10.21; Found: C61.42, H 5.12, N 10.22.
Reference：
[1] Justus Liebigs Annalen der Chemie, 1925, vol. 442, p. 41
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 2, p. 524 - 527
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 14, p. 4076 - 4079
[4] Letters in Drug Design and Discovery, 2013, vol. 10, # 4, p. 320 - 326
[5] Chemical Biology and Drug Design, 2016, vol. 87, # 2, p. 257 - 264
[6] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 667 - 672
[7] Patent: WO2007/107758, 2007, A1, . Location in patent: Page/Page column 21
4
[ 19438-10-9 ]
[ 618-49-5 ]
Yield
Reaction Conditions
Operation in experiment
10%
With ammonia In methanol at 50℃; for 16 h; Sealed tube
. Example 25 Synthesis of 3-hydroxybenzamideTo a reactor was charged methyl 3-hydroxybenzoate (160 mg) and 7N ammonia in methanol (4 ml). The reactor was then sealed, heated to 50 °C, and stirred for 16 hours. The reaction mixture was cooled to ambient temperature then reduced by rotary evaporation to yield an oil. This was purified by flashchromatography, eluting with n-hexane and ethyl acetate. Appropriate fractions were collected for the product peak and were reduced by rotary evaporation to obtain the desired product as yellow oil (15 mg, 10percent). The structure was confirmed as 3-hydroxybenzamide by 1H NMR.
With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); water; 3-cyano-1-methylquinolinium cation In acetonitrile at 20℃; for 5 h; Inert atmosphere; Irradiation; Green chemistry
Using 1-methyl-3-cyanoquinoline salt as photosensitizer, cobalt oxime complex 2 as cobalt catalyst and 5mL of acetonitrile, 2.69mg (1 × 10-2mmol) photosensitizer and 2.80mg ) Cobalt catalyst, the atmosphere was replaced with Ar atmosphere, Then 0.2 mmol of benzamide (R1 is CONH2, R2, R3, R4 are independently H) and 2 mmol H2O. Room temperature, high pressure mercury lamp irradiation 5h. After completion of the reaction, H2 production was detected by GC (TCD), benzene conversion by GC (FID) was detected, and then column separation was performed. Nuclear magnetic hydrogenSpectroscopy and mass spectrometry identified products as 2-hydroxybenzamide, 3-hydroxybenzamide,4-hydroxybenzamide and Ν- (3-carbamoylphenyl) benzamide. The conversion of benzamide was 63percent, the yields of 2-hydroxybenzamide, 3-hydroxybenzamide and 4-hydroxybenzamide were 35percent, 8percent, 11percentThe yield of N- (2-carbamoylphenyl) benzamide was 9percent and the yield of H2 was 58percent.
Reference：
[1] Patent: CN107324975, 2017, A, . Location in patent: Paragraph 0118-0119
[2] Journal of the American Chemical Society, 2016, vol. 138, # 32, p. 10080 - 10083
6
[ 99-06-9 ]
[ 618-49-5 ]
Yield
Reaction Conditions
Operation in experiment
64%
With thionyl chloride; ammonia In tetrahydrofuran; benzene
EXAMPLE 1 Preparation of 3-Hydroxybenzamide Ten g (72.4 mmol) of 3-hydroxybenzoic acid and 10 ml SOCl2 were mixed and allowed to stand for 1 hr, heated on a steam bath for 2 hr, and then cooled and diluted with 25 ml of benzene. The benzene was then evaporated in vacuo to dryness and the residue extracted with 2*50 ml benzene. The extracted residue was dissolved in 25 ml tetrahydrofuran (THF) and this solution added dropwise over a period of 15 min to a stirred, cold (-10° C.) 50 ml solution of concentrated ammonia. The mixture was stirred with cooling for an hour and then at room temperature overnight. The mixture was poured into an open dish and allowed to evaporate to a solid mass. The solid was triturated with 50 ml ice water, collected, and air dried to yield 6.4 g (64percent) of the desired product 3-hydroxybenzamide, mp 160°-162° C. The identity of the product with the desired 3-hydroxybenzamide was further confirmed using thin layer chromatography (TLC).
Reference：
[1] Journal of the Indian Chemical Society, 2005, vol. 82, # 7, p. 675 - 676
[2] Phosphorus and Sulfur and the Related Elements, 1980, vol. 9, p. 155 - 164
[3] Naunyn-Schmiedebergs Archiv fuer Experimentelle Pathologie und Pharmakologie, 1938, vol. 191, p. 55,57
[4] Patent: US5032617, 1991, A,
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 14, p. 4076 - 4079
[6] Letters in Drug Design and Discovery, 2013, vol. 10, # 4, p. 320 - 326
[7] Chemical Biology and Drug Design, 2016, vol. 87, # 2, p. 257 - 264
[8] Angewandte Chemie - International Edition, 2017, vol. 56, # 46, p. 14498 - 14501[9] Angew. Chem., 2017, vol. 129, p. 14690 - 14693,4
[10] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 884 - 891
[11] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 667 - 672
[12] Patent: WO2007/107758, 2007, A1,
7
[ 171861-74-8 ]
[ 618-49-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 884 - 891
8
[ 6304-89-8 ]
[ 618-49-5 ]
Reference：
[1] Chimica Therapeutica, 1967, vol. 2, p. 57 - 65
[2] Patent: US5756510, 1998, A,
With ammonium hydroxide; In tetrahydrofuran; at 20℃;Cooling with ice;
To a solution of 3-hydroxybenzoic acid (1) (10.0 g, 72.41 mmol) in toluene (80 mL) at room temperature was slowly added thionyl chloride (7.71 mL, 108.62 mmol). The resulting solution was heated to reflux for 4.5 h and concentrated in vacuo to give crudeproduct of 3-hydroxybenzoyl chloride (2). The crude product was dissolved in THF (30 mL) in an ice-methanol bath and concentrated aqueous ammonia (28 mL) was dropwise added.The resulting reaction mixture was warmed slowly to room temperature and stirredfor 18 h at the same temperature. After concentrating in vacuo, the residue was suspended in water (20 mL) and filtered. The collected solid was washed with water (3 × 15 mL) and then dried in vacuo to give 3-hydroxybenzamide (3) (7.03g, 70.8%) as anoff-white crystals. mp 160-163 C, TLC Rf= 0.12 (petroleum ether/ethyl acetate, 1:2); IR (KBr): 2958, 2925, 2851, 1113, 638, 615 cm-1;1H NMR (600 MHz, DMSO-d6, FontSize="10" deltappm): 9.60 (s, 1H), 7.86 (s,1H), 7.29-7.21 (m, 4H), 6.90 (dd, J =7.8 Hz, J = 1.8 Hz, 1H); MS(ESI) m/z calcd for C7H7NO2 137.0; found (M + H+) 138.3.
7.03 g
With ammonia; In tetrahydrofuran; water; at 20℃; for 18h;Cooling with ice;
To a solution of 3-hydroxybenzoic acid (1) (5.0 g, 36.21mmol) in toluene (40 mL) at room temperature was slowly added thionyl chloride (3.86 mL, 54.38 mmol). The reaction solution was heated to reflux for 4.5 h and concentrated invacuo to give 3-hydroxybenzoyl chloride (2). The crude product 2 was dissolved in THF (15 mL) in an ice bath and aqueous ammonia (14 mL) was dropwise added. The resulting mixture was slowly warmed to room temperature and stirred for 18 h at the same temperature. After concentrating in vacuo, the residue was suspended in water (10 mL) and filtered. The collected solid was washed with water (3 x10mL) and then dried in vacuo to give 3-hydroxybenzamide (3)(7.03 g, 70.8%) as an off-white solid. mp 160-163C, TLC Rf = 0.12 (petroleum ether/ethyl acetate, 1:2); IR (KBr):2958, 2925, 2851, 1113, 638, 615 cm-1; 1H NMR (600 MHz,DMSO-d6, ppm) 9.60 (s, 1H), 7.86 (s, 1H), 7.29-7.21 (m,4H), 6.90 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H); MS (ESI) m/z calcd for C7H7NO2 137.0; found [M+H]+ 138.3; Analysis calculated for C7H7NO2: C 61.31, H 5.14, N 10.21; Found: C61.42, H 5.12, N 10.22.
With ammonia; In tetrahydrofuran; water; at 20℃; for 16h;Ice-methanol bath;
3-Hydroxybenzoic acid (110.5 g, 0.8 mol, 1 equiv.) was suspended in toluene (500 ml) and thionyl chloride (88.0 ml, 1.2 mol, 1.5 equiv.) was added slowly, at room temperature. The solution was heated to reflux where it was maintained for 5 h. After this time, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (300 ml) and cooled in an ice-methanol bath. Concentrated aqueous ammonia solution (~300 ml) was added slowly, dropwise and the reaction mixture was warmed slowly to room temperature where it was stirred for 16 h. The reaction mixture was concentrated in vacuo and the resulting solid was suspended in water and filtered. The collected solid was washed with additional water (x3) and then dried in vacuo to give 3-hydroxybenzamide as an off-white solid (79.9 g, 72.8%) mp 167-1680C. HPLC-MS (method 1): m/z 136 [M-H] Rt = 1.21 min. 1H NMR (d6-DMSO) delta = 9.53 (s, 1H), 7.78 (s, 1H), 7.30-7.15 (m, 4H), 6.88 (d, J = 8 Hz, 1 H).
With ammonia; In methanol; at 50℃; for 16h;Sealed tube;
. Example 25 Synthesis of 3-hydroxybenzamideTo a reactor was charged methyl 3-hydroxybenzoate (160 mg) and 7N ammonia in methanol (4 ml). The reactor was then sealed, heated to 50 C, and stirred for 16 hours. The reaction mixture was cooled to ambient temperature then reduced by rotary evaporation to yield an oil. This was purified by flashchromatography, eluting with n-hexane and ethyl acetate. Appropriate fractions were collected for the product peak and were reduced by rotary evaporation to obtain the desired product as yellow oil (15 mg, 10%). The structure was confirmed as 3-hydroxybenzamide by 1H NMR.
Example 49; 3-Hydroxybenzamide (49a). 3-Cyanophenol (295 mg, 2.48 mmol, 100 mol-%) and NaBO3 - 4 H2O (1146 mg, 7.45 mmol, 300 mol-%) in H2O (8 ml_) were heated to 50 0C and MeOH (14 ml_) was added until mixture was clear. The mixture was stirred at 50 0C for 70 hours and excess MeOH was evaporated and the pH of remaining mixture was adjusted to 5 with cone. HCI (aq). Mixture was extracted with CH2CI2 (12 ml_) and with EtOAc (5x15 ml_). Organic phases were combined, washed with brine (25 ml_) and dried over Na2SO4. Filtering and evaporation of solvents gave 49a as spectro- scopically pure white solid (183 mg, 54%): mp 165-168 0C; Rf (50% EtOAc in hex) 0.10.
With thionyl chloride; ammonia; In tetrahydrofuran; benzene;
EXAMPLE 1 Preparation of 3-Hydroxybenzamide Ten g (72.4 mmol) of 3-hydroxybenzoic acid and 10 ml SOCl2 were mixed and allowed to stand for 1 hr, heated on a steam bath for 2 hr, and then cooled and diluted with 25 ml of benzene. The benzene was then evaporated in vacuo to dryness and the residue extracted with 2*50 ml benzene. The extracted residue was dissolved in 25 ml tetrahydrofuran (THF) and this solution added dropwise over a period of 15 min to a stirred, cold (-10 C.) 50 ml solution of concentrated ammonia. The mixture was stirred with cooling for an hour and then at room temperature overnight. The mixture was poured into an open dish and allowed to evaporate to a solid mass. The solid was triturated with 50 ml ice water, collected, and air dried to yield 6.4 g (64%) of the desired product 3-hydroxybenzamide, mp 160-162 C. The identity of the product with the desired 3-hydroxybenzamide was further confirmed using thin layer chromatography (TLC).
With di-isopropyl azodicarboxylate; triethylamine; In tetrahydrofuran; at 20℃; for 16.5h;
To a suspension of polymer-supported triphenyl phosphine (1.4 g, 3 mmol, based on a loading of 2.15 mmol/g [purchased from Argonaut], 1.5 equiv.) swollen in THF (20 ml) at room temperature was added diisopropylazodicarboxylate (0.47 ml, 2.4 mmol, 1.2 equiv.). The mixture was shaken for 5 min before <strong>[618-49-5]3-hydroxybenzamide</strong> (274 mg, 2 mmol, 1 equiv.), triethylamine (0.28 ml, 2 mmol, 1 equiv.) and cis-5-decenol (313 mg, 2 mmol, 1 equiv.) were added. The resulting suspension was shaken at room temperature for 16 h and then filtered. The resin was washed with additional <n="28"/>THF (x 3) and then the combined filtrate and washings were concentrated under reduced pressure, to give the crude product as a colourless semi-solid. It was purified by column chromatography on silica eluting with EtOAc/hexane (20%-40% gradient) to give the desired compound as a white solid (390 mg, 71%), mp 98- 1000C. HPLC-MS (method 1): m/z 276 [M+H]+, Rt = 5.00 min. 1H NMR (CDCI3) delta = 7.35 (s, 1 H), 7.32-7.28 (m, 2H), 7.08-7.02 (m, 1H), 6.18 (br, 2H), 5.41-5.32 (m, 2H), 3.98 (t, J = 6.4 Hz, 2H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.34-1.28 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H).
(Method D) K2CO3 (1.38 g, 10 mmol, 1 equiv.) was added to a suspension of 3- hydroxybenzamide (1.37 g, 10 mmol, 1 equiv.) in CH3CN (100 ml). The mixture stirred for 10 min at room temperature, before 1 ,6-dibromo-hexane (9.76 g, 40 mmol, 4 equiv.) was added. The resulting mixture was stirred at 600C for 16 h. After this time, the reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate evaporated under reduced pressure to dryness. The residue was taken-up in EtOAc and water. The organic phase was separated and washed consecutively with K2CO3 solution, water and brine. Dried with MgSO4 and evaporated under reduced pressure to a small volume. The precipitant solid was filtered and washed with EtOAc/pentane, to give the desired compound as a white solid (2.0 g, 67%), mp 115-1170C. HPLC-MS (method 1): m/z 300 [M]+, 302 [M+2H]+, Rt = 4.08 min.
55.4%
With potassium carbonate; In acetonitrile; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
In ethanol; for 2.5h;Heating / reflux;Product distribution / selectivity;
(Method G) A solution of commercially available 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran (1.0 g, 3.4 mmol, 1 equiv.) in DMSO (5 ml), was added, slowly, dropwise, at r.t., under N2, to a stirred suspension of lithium acetylide ethylenediamine complex (350 mg, 3.8 mmol, 1.1 equiv.) in DMSO (5 ml). The reaction mixture was stirred at r.t. for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1N HCI solution (2x20 ml) and water (2x20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated under reflux for 2.5 h. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient), to give the desired compound as a colourless oil (240 mg, overall yield 48%).
3-[(5-methyl-3-pyridinyl)methoxy]benzenecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;
N-Bromosuccinimide (2.13 g, 12 mmol) and subsequently alpha.alpha'-azoisobutyronitriie (16 mg, 0.1 mmol) were added to a solution of 3,5-lutidine (1.14 ml, 10 mmol) in CCI4 (40 ml). The reaction mixture was stirred at reflux for 2 hrs. After cooling, succinimide was removed by filtration and the filtrate was evaporated to smaller volume (10 ml). To this filtrate, a mixture of 3-hydroxybenzenecarboxamide (550 mg, 4 mmol) and K2CO3 (830 mg, 6 mmol) in DMF (5 ml) was added and the new reaction mixture was stirred at 60C for 24 h. After diluting with CH2CI2 (100 ml), the solution was washed with Na2CO3 solution (40 ml) and water (40 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The brown oil residue was extracted by trituration with Et2O (2x10 ml), and from the Et2O extracts, the precipitant solid was filtered and washed with pentane, to give 70 mg (7.2% yield) of the desired product. Mp 152- 154C, HPLC-MS: m/z 243 [M+H]+, Rt = 2.28 min.
(b) 2nd Stage--Preparation of 3-Hydroxybenzamide 3-Acetoxybenzoic acid (0.5 g;) from the first stage was dissolved in thionyl chloride (1.74 ml) and refluxed for 31/2 hours. Excess thionyl chloride was removed by distillation to yield a yellow oil, which was added dropwise to a cooled solution of ammonia (35% aq) and stirred for 30 minutes. The mixture was boiled to a reduced volume (50%) and left to cool. 3-hydroxybenzamide crystallized out of solution and was collected and then recrystallized from boiling water.
With potassium carbonate; In acetonitrile; for 120h;Heating / reflux;
A mixture of <strong>[618-49-5]3-hydroxybenzamide</strong> (2.7 g, 19.7 mmol, prepared by treatment of the methyl ester with aqueous ammonium hydroxide), 1,2-dichloroethane (50 mL) and anhydrous potassium carbonate (6 g, 43.5 mmol) in acetonitrile (150 mL) were heated at reflux for 5 days. The mixture was cooled to room temperature, insolubles removed by filtration and volatiles removed on a rotary evaporator. The product was precipitated from chloroform-ether to give 0.5 g of 3-(2-chloroethoxy)benzamide.
EXAMPLE 8 3-(4-Trifluoromethylbenzyloxy)benzamide (Compound NU1036) <strong>[618-49-5]3-hydroxybenzamide</strong> (0.137 g; 1 mmol) was dissolved in anhydrous acetonitrile (20 ml) under a nitrogen atmosphere. To this was added potassium carbonate (0.138 g; 1 mmol) and 4-(trifluoromethyl)benzyl bromide (0.155 ml; 1 mmol). This mixture was left to reflux for 17 hours. The reaction was followed by TLC. Upon completion the acetonitrile was removed under reduced pressure to leave a white solid which was dissolved in water. The organics were extracted into dichloromethane (3*30 ml), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to leave a white crystalline solid which was recrystallized from boiling ethyl acetate and petrol (60-80). M/Z (EI): 295 (35%; M+) 159 (100%)
EXAMPLE 3 3-(4-Bromobenzyloxy)benzamide (Compound NU1014) To <strong>[618-49-5]3-hydroxybenzamide</strong> (2.0 mM) under nitrogen was added anhydrous acetonitrile (20 ml), potassium carbonate (2.0 mM), and p-bromobenzyl bromide (2.0 mM). The mixture was refluxed for 3 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallized from hot dichloromethane (minimum amount). A white crystalline solid was isolated and dried. Melting point: 160-161 C. Infrared data: cm-1: KBr disc: 3323; 3146; 1670; 1622. 1 H NMR: d6 DMSO: delta=5.26 (s; 2H; CH2); 7.3 (dd; 1H: H4); 7.49-7.75 (m, 9H; PhBr; NH2; PhO) 13 C NMR: d6 DMSO: delta=114.031; 118.123; 120.402; 121.295; 129.704; 130.107; 131.690; 136.094; 136.723; 158.371; 167.843. Mass spectra: m/z: EI: 307 (M+1); 262; 212; 169 (100%) 101;90. Elemental analysis: Expect C: 55.26%; H: 3.29%; N: 4.61% Found C: 54.61%; H: 3.66%; N: 4.47%.
EXAMPLE 13 3-(Phenethyl)oxybenzamide (Compound NU1048) <strong>[618-49-5]3-Hydroxybenzamide</strong> (500 mg; 3.6 mM) was dissolved in dry acetonitrile (36 ml), and to this was added potassium carbonate (0.503 g; 3.6 mmol) and 2-(bromoethyl)benzene (0.498 ml; 3.6 mmol). The mixture was heated under reflux for two days. The acetonitrile was removed under reduced pressure to yield a white solid. This was dissolved in water and extracted into dichloromethane (3*30 ml). The organics were pooled, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to yield a white solid. This was recrystallized from boiling ethyl acetate and petrol (0.459 g; 12.51%). MPt: 132-136 C. 1 H: 200 MHz CDCl3 3.05 (2H, t, H8); 4.2 (2H, t, H7); 6.00 (1H, br s, NH); 7.04 (1H, m, H4); 7.27 (9H, m, NH; aromatic). IR cm-1 3300 (NH2); 1666 (CO); 2930 (C=C). M/Z (EI); 241 (M+; 18%); 105 (--COHN2; 100%). Elemental Analysis: Expected % C15 H15 O2 N C: 74.4, H: 6.20, N: 5.79; Found: % C: 74.7, H:6.2, N:5.8.
EXAMPLE 4 3-(4-Fluorobenzyloxy)benzamide (Compound NU1015) To <strong>[618-49-5]3-hydroxybenzamide</strong> (2.0 mM) under nitrogen was added anhydrous acetonitrile (30 ml), potassium carbonate (2.0 mM), and p-fluorobenzyl bromide (2.0 mM). The mixture was refluxed for 14 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallized from hot dichloromethane (minimum amount), and petrol ether 40/60. A white crystalline solid was isolated and dried. Melting point: 161-162 C. Infrared data: KBr disc: cm-1: 3366; 3171; 1 H NMR: d6 DMSO: delta=5.23 (s; 2H; CH2); 7.26-7.68 (m; 9H; NH; aromatics); 8.11 (s; 1H; H4) 13 C NMR: d6 DMSO: delta=68.914; 113.951; 115.405; 115.821; 118.124; 120.329; 129,329; 130.255; 130.421; 133.487; 136.056; 158.464; 159.692; 164.546; 167.853. Elemental analysis: Expect: C: 67.2; H: 4.8; N: 5.6 Found: C: 67.79; H: 4.81; N: 5.65
With potassium carbonate; In methanol; acetonitrile;
EXAMPLE 14 3-Allyloxybenzamide (Compound NU1031) To <strong>[618-49-5]3-hydroxybenzamide</strong> (274 mg; 2.0 mM) under a nitrogen atmosphere was added potassium carbonate (276 mg; 21.0 mM). This was dissolved in acetonitrile (20 ml) containing allyl bromide (169 ul; 2.0 mM). The mixture was refluxed for 5 hours, and the reaction followed by T.L.C.: 10% MeOH: 90% CH2 Cl2. The excess solvent was then removed under vacuum, the organics extracted into dichloromethane, dried, and the solvent removed, to yield a white solid. This was recrystallized from hot water to produce a white "needle" solid (63%) as the final productproduct. Melting point: 116-117 C. 1 H NMR: delta=4.7(m;2H:He,Hf); 5.5(m;2H;Hh,Hi); 6.2(m;1H;Hg); 7.2(m;1H;Hd); 7.6m;4H;Ha,Hb,Hc,NH); 8.1(s;1H;NH). 13 C NMR: delta=68.580, 113.821, 117.978, 129.661, 133.893, 136.025, 158.371, 167.892. Mass spectra: EI: 177 (M+); 41 (100%)
EXAMPLE 11 3-(2-Nitrobenzyloxy)benzamide (Compound NU1042) To <strong>[618-49-5]3-hydroxybenzamide</strong> (0.137 g; 1 mmol) was added potassium carbonate (0.138 g; 1 mmol) and 2-nitrobenzyl bromide (0.216 g; 1 mmol) in anhydrous acetonitrile (10 ml). The mixture was heated under reflux for 5 hours. The acetonitrile was removed under reduced pressure, and the solids dissolved in water. The organics were extracted into dichloromethane (3*20 ml) and pooled. The solvent was dried over magnesium sulfate and removed under reduced pressure. The solid was recrystallized from boiling ethyl acetate and petrol, collected and dried. IR cm-1: 3368; 3196, M/Z; 272 (3.8%; M+); 248; 217; 196; 181; 136 (100%). 1 H: d6 DMSO; delta=5.5 (2H; OCH2 Ph), 7.14 (1H; d, H4), 7.4 (4H; m; NH; H2 ', H5 '; H6), 7.26 (2H; m; H5 '; H4 '), 8.0 (1H; br; NH); 8.02 (1H; d; H3 '). 13 C: 66.783; 113.854; 118.172; 120.753; 125.183; 129.490; 129.549; 132.679; 132.339; 136.136.; 147.786; 158.112; 167.778. Elemental Analysis: Required C 61.76%; H 4.41% N 10.29%; Found C 61.49%; H 4.42%; N 10.11%.
EXAMPLE 5 3-(3-Nitrobenzyloxy)benzamide (Compound NU1017) To <strong>[618-49-5]3-hydroxybenzamide</strong> (2.0 mM) under nitrogen was added anhydrous acetonitrile (20 ml), potassium carbonate (2.0 mM), and m-nitrobenzyl bromide (2.0 mM). The mixture was refluxed for 3 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallized from hot dichloromethane (minimum amount). A white crystalline solid was isolated and dried. Melting point: 162-163 C. Infrared data: KBr disc: 3362; 3171; 1655; 1622. Mass spectrum: EI: m/z: 272(M+); 136(100%); 105;90;77. 1 H NMR: d6 DMSO: delta=5.42(s; 2H; CH2): 7.28-7.33 (m;1H;Halpha); 7.45-7.66 (m;4H;NH;H2;H5;H6); 7.8 (t;1H;H5 '); 8.0(m:2H;NH;H6 '); 8.3 (m:1H;H4 '): 8.4 (m;1H;H2 ') 13 C NMR: d6 DMSO: delta=68.354; 114.041; 118.124; 120.589; 122.317; 123.120; 129.812; 130.435; 134.406; 136.132; 139.661; 148.185; 158.185; 167.774. Elemental analysis: Expect: C: 61.76; H: 4.41; N: 10.11 Found: C: 61.53; H: 4.32; N: 10.01
2nd Stage Preparation of Piperonyl BOB To <strong>[618-49-5]3-hydroxybenzamide</strong> (137 mg; 1 mM) was added potassium carbonate (138 mg; 1 mM) and this was dissolved in anhydrous acetonitrile under a nitrogen atmosphere. To this was added piperonyl chloride (270 mg; 1 mM), and the mixture left to reflux for 15 hours. The organics were extracted into dichloromethane (3*20 ml), dried over magnesium sulphate, and the solvent removed under vacuum. The product was isolated using chromatographic techniques, with 20% petrol:80% ethyl acetate as eluant. A white solid was isolated which was recrystallized from hot water (97%). Melting point: 141-142 C. 1 H NMR: d6 DMSO: delta: 5.1 (s;2H;CH2); 6.1(s,2H; OCH2 O); 7.1 (m; 3H; H2 '; H5 '; H6 '); 7.25 (dd; 1H; H4); 7.5 (m; 4H; NH; N2; H5; H6); 8.05 (s; 1H; NH) 13C NMR: d6 DMSO: delta: 69.02; 101.36; 108.40; 108.80; 114.01; 118.12; 120.20; 121.89; 129.65; 136.00; 147.20; 146.62; 158.53; 167.84. Mass spectrum: EI: 271 (M+); 135 (100%) Elemental analysis: Expected C: 66.42; H: 4.79; N: 5.16 Found C: 66.18; H: 4.47; N: 4.94
With potassium carbonate; In acetonitrile; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; In methanol; acetonitrile;
EXAMPLE 21 3-(5-Bromopentyloxy)benzamide (Compound NU1019) A mixture of <strong>[618-49-5]3-hydroxybenzamide</strong> (0.5 g, 3.65 mmol), 1,5-dibromopentane (1.82 g, 1.1 ml, 7.3 mmol) and potassium carbonate (500 mg, 3.65 mmol) was refluxed (2h) in acetonitrile (18 ml) until the reaction was complete by TLC. The solvent was then removed by rotary evaporation to leave a white sticky solid which was chromatographed (10% methanol in dichloromethane on silica) to give a white solid. This was recrystallized from a mixture of petrol and ethyl acetate to give white flaky crystals (0.744 g, 2.6 mmol, 70% yield). mp 98-99 C. deltaH (200 MHz, d6 -DMSO): 8.09 (1H,s,NH), 7.49 (4H,m,H2,5, 6 and NH), 7.1 (1H,d,J 7.99,H4), 4.11 (2H,t,J 6.2,CH2 O), 3.67 (2H,t,J 6.6,2H), 1.90 (4H,m,CH2 CH2 CH2), 1.62 (2H,m,CH2); deltaC (200 MHz, d6 -DMSO): 168(CO), 158.85(C3), 129.63(C2), 120(C4), 117.79(C6), 113.53(C5), 67.73(OCH2), 35.36(CH2 Br), 32.30(CH2 CH2 O), 28.12 (CH2 CH2 Br), 24.63 (OCH2 CH2 CH2); M/Z (EI) 285(M+). Elemental Analysis: Found: C: 50.71%, H: 5.36%, N: 4.95%. C15 H22 NO2 Br Requires C: 50.366%, H: 5.636%, N: 4,895%.
With potassium carbonate; In dichloromethane; water; acetonitrile;
EXAMPLE 15 3-(Cinnamyloxy)benzamide (Compound NU1050) <strong>[618-49-5]3-hydroxybenzamide</strong> (0.5 g 3.6 mmol) was dissolved in dry acetonitrile (50 ml). To this was added potassium carbonate (0.503 g; 3.6 mmol) and cinnamyl chloride (0.5 ml; 3.6 mmol). This was left to reflux for 3.5 hours. The acetonitrile was removed under reduced pressure yielding a white sold which was dissolved in water (80 ml). The organics were extracted in dichloromethane (3*30 ml), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure leaving a white solid. The solid was recrystallized from ethyl acetate and petrol (45%). MPt: 131-138 C. M/Z 137 (36%); 165 (100%, cinnamyl+), 94 (48%); 77 (24%). IR cm-1 3400 & 3200 (NH2), 1600 (C=O). 1 H: 200 MHz d6 DMSO 4.88 (2H, d, H7); 6.65 (1H, m, H8); 6.94 (1H, m, H4); 7.24 (1H, m, H4); 7.5 (9H, m, aromatic & NH); 8.1 (1H, s, NH). Elemental Analysis: Expected C: 75.9%; H: 5.9%; N: 5.5%; Found C: 76.07%; H: 5.85%; N: 5.56%.
EXAMPLE 9 3- (4-Cyanobenzyloxy)benzamide (Compound NU1037) <strong>[618-49-5]3-hydroxybenzamide</strong> (0.137 g; 1 mmol) was dissolved in anhydrous acetonitrile (20 ml) under a nitrogen atmosphere. To this was added potassium carbonate (0.138 g; 1 mmol) and 4-cyanobenzyl bromide (0.138 g; 1 mmol). This was left to reflux for 5 hours. The reaction was followed by TLC. Upon completion the acetonitrile was removed under reduced pressure. Water was added to the remaining solid. The organics were extracted into dichloromethane (3*30 ml), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to leave a white crystalline solid which was recrystallized from boiling ethyl acetate and petrol (68%). M/Z (EI) 252 (18% M+); 153, 116 (75%); IR cm-1 3362, 3179 (amide NH2); 2228 (C?N)
(c) Final Stage--Preparation of p-Azidobenzyl-3-Oxybenzamide To <strong>[618-49-5]3-hydroxybenzamide</strong> (2.0 mM) under nitrogen was added anhydrous acetonitrile (20 ml), potassium carbonate (2.0 mM), and p-azidobenzyl bromide (2.0 mM). The mixture was refluxed for 3 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallized from hot dichloromethane (minimum amount). A pale yellow crystalline solid was isolated and dried. Melting point: 167-168 C. Infrared data: cm-1: 3341;3155;2121;2094;1631;1583. Mass spectra: m.backslash.z: 269 (M+1) 252;223;167;104 (100%); 93;77. 1 H NMR: d6 -DMSO delta=5.5 (s; 2H; CH2); 7.27 (m; 3H; H2 '; H6 '; H4); 7.41-7.6 (m: 6H; H3 '; H5 '; H2; H6; H5; NH); 8.0 (s; 1H; NH) 13 C NMR: delta=69.098; 114.049; 118.164; 119.528; 120.359; 129.735; 129.886; 134.188; 136.096; 139.332; 158.480; 167.889 Elemental Analysis: Expect C: 62.68%; H: 4.47%; N: 20.89% Found C: 62.18%; H: 4.30%; N: 20.70%
EXAMPLE 3 Preparation of 3-(2-Hydroxyethoxy)benzamide 1.0 g (4.5 mmol) of the 3-(2-acetoxyethoxy)benzamide prepared in Example 1 was mixed with 2 g Amberlyst 15 and 50 ml methanol. The mixture was stirred for 40 hr and filtered. The filtrate was evaporated in vacuo to dryness and the residue dissolved in 50 ml absolute ethanol and filtered to remove a small amount of insoluble material. The filtrate was evaporated in vacuo to obtain 750 mg of the white solid 3-(2-hydroxyethoxy)benzamide, representing 92% yield. The identity of the desired product was confirmed by TLC and elemental analysis: Calculated for C9 H11 NO3; C: 59.65; H: 6.11; N: 7.73; Found: C: 59.56; H: 6.05; N: 7.70.
With potassium carbonate; In methyl ethyl ketone ("MEK");
Preparation 1 3-(2-Chloroethoxy)benzamide STR61 To a solution of <strong>[618-49-5]3-hydroxybenzamide</strong> (21.6 g) in methyl ethyl ketone ("MEK") was added 2-chloroethyl p-toluenesulphonate (55.46 g) and potassium carbonate (16.0 g). After stirring at reflux for 6 hours, the resultant mixture was poured onto water and a colourless solid filtered off. Crystallisation from ethanol gave the title compound, (22.2 g), m.p. 125-126. Analysis %: Found: C,53.7; H,5.3; N,6.9; Calculated for C9 H10 clNO2: C,54.1; H,5.05; N,7.0.
With potassium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 2 Preparation of 3-(2-Acetoxyethoxy)benzamide 3.0 g (21.9 mmol) of the <strong>[618-49-5]3-hydroxybenzamide</strong> prepared in Example 1 and 5.7 g (41.2 mmol) of anhydrous potassium carbonate were added to a round bottom flask followed by 40 ml anhydrous DMF added by syringe. To this mixture was added 11.85 g (70.9 mmol, 7.8 cc) of 2-acetoyl ethyl bromide, also using a syringe to maintain anhydrous conditions. The suspension was stirred for 48 hr and the mixture filtered. The solid was washed with 6*5 ml DMF and the filtrate evaporated in vacuo to a solid. The resulting solid was recrystallized from 90% aqueous alcohol and the solid from the filtration was washed with cold 90% alcohol and ether. The desired product, 3-(2-acetoylethoxy)benzamide was obtained in 65% yield (3.2 g), mp 121-122 C. Identity of the product was confirmed by TLC and by elemental analysis. Calculated for C11 H13 NO4; C: 59.18; H: 5.87; N: 6.28; Found: C: 59.03; H: 5.83; N: 6.58.
With triphenylphosphine; In tetrahydrofuran; chloroform;
EXAMPLE W Preparation of 3-[2-(4-Piperidyloxy)ethoxy]benzamide N-Acetyl-4-(2-hydroxyethoxy)piperidine (5.0 g.), <strong>[618-49-5]3-hydroxybenzamide</strong> (4.4 g.), diethyl azodicarboxylate (5.6 g.) and triphenylphosphine (8.4 g.) in dry tetrahydrofuran (100 ml.) were stirred at 0 C. for 2 hours then at room temperature for 64 hours. The solvent was evaporated in vacuo, then the residue treated with refluxing ether (3*100 ml.) and the mother liquors decanted. The residual oil was taken up in chloroform and washed with dilute sodium hydroxide solution (40 ml.) and water (40 ml.). The chloroform layer was dried (MgSO4) then the solvent evaporated in vacuo. The residual oil was treated with ether (50 ml.) and set aside in the fridge. The resulting solid was collected, slurried with ether (30 ml.), filtered and the solid washed with ether (30 ml.) to give 4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (3.7 g.) containing some triphenylphosphine oxide (approximately 25% by n.m.r.).
b) To a solution of 13.7 g of <strong>[618-49-5]3-hydroxybenzamide</strong> and 25.6 of benzyl bromide in acetone (400 ml) were added 25.6 g of potassium carbonate at RT. The mixture was then refluxed for 6 h after which time the reaction was completed according to TLC analysis (CH2Cl2/MeOH: 20/1). The reaction mixture was cooled to RT and partitioned between EtOAc and water, the organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The crystalline residue obtained was suspended in n-hexane (200 ml), the crystals were filtered off under suction and dried in a vacuum to give 3-benzyloxy-benzamide as a white crystalline solid, mp 136-140 C.
To a solution of 3-hydroxybenzenecarboxamide (200 mg, 1.46 mmol, 1 equiv.) in DMF (3 ml) was added K2CO3 (302 mg, 2.19 mmol, 1.5 equiv.) and NaI (43.5 mg, 0.29 mmol, 0.2 equiv). The suspension was stirred for 5 min before n-nonyl chloride (0.32 ml, 1.61 mmol, 1.1 equiv) was introduced. The resulting mixture was warmed to 600C where it was maintained for 16 h. After this time, the reaction was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, washed with additional water (x 2), dried (MgSO4), filtered and concentrated in vacuo to reveal a colourless solid. In the case of 3-n- nonyloxybenzamide this colourless solid was stirred for 5 min with MeOH (~0.5 ml) [NB: 3-n-nonyloxybenzamide partially soluble in MeOH] and then filtered to reveal the desired compound as a colourless solid (116 mg, 30%). HPLC-MS (method 3): m/z 264 [M+H]+, Rt = 1.80 min. 1H NMR (d6-DMSO) delta = 7.95 (s, 1 H), 7.44-7.31 (m, 4H), 7.06 (ddd, J = 8 Hz, J = 2 Hz, J = 1 Hz, 1 H), 3.99 (t, J = 6.5 Hz, 2H), 1.72 (quintet, J = 6.5 Hz, 2H), 1.42 (m, 2H), 1.34-1.26 (m, 10H), 0.86 (t, J = 6.5 Hz, 3H).
With potassium carbonate; In acetonitrile; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
64.5%
With potassium carbonate; In acetonitrile; at 60℃; for 18h;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in CH3CN (75 mL)were added K2CO3 (1.80 g, 13 mmol) and 1,3-dibromopropane or 1,4-dibromobutane (30 mmol). The resulting mixture was warmed to 60C and stirred for 18 h at the same temperature. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to dryness. The residue was dissolved in ethyl acetate (60 mL) and the organic layer was washed consecutively with saturated K2CO3 solution (2 x 5mL), water (2 x 10 mL) and brine (2 x 10 mL). The washed organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to dryness. The residue was purified by flash chromatography (petroleum ether/ethylacetate, 1:1) to give compounds 9 and 10 in yields of 64.5% and 66.5%, respectively.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (for alkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyl dibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (for alkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyl dibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (for alkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyl dibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; In acetonitrile; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; In acetonitrile; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
58.6%
With potassium carbonate; In acetonitrile; at 60℃; for 18h;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in CH3CN (75 mL)were added K2CO3 (1.80 g, 13 mmol) and 1,3-dibromopropane or 1,4-dibromobutane (30 mmol). The resulting mixture was warmed to 60C and stirred for 18 h at the same temperature. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to dryness. The residue was dissolved in ethyl acetate (60 mL) and the organic layer was washed consecutively with saturated K2CO3 solution (2 x 5mL), water (2 x 10 mL) and brine (2 x 10 mL). The washed organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to dryness. The residue was purified by flash chromatography (petroleum ether/ethylacetate, 1:1) to give compounds 9 and 10 in yields of 64.5% and 66.5%, respectively.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
General procedure: To a solution of 3 (1.37 g, 10 mmol) in DMF (foralkyl dichloride) or CH3CN (for alkyl dibromide) (75 mL) were added K2CO3 (1.80 g, 13 mmol) and NaI (0.45 g, 3 mmol), CH3CN (for alkyldibromide) and then, saturated dihalide (30 mmol). The resulting reaction mixturewas warmed to 60 C and stirred for 16-20 h. After cooling to room temperature, the reaction mixturewas filtered and evaporated under reduced pressure to dryness. After theresidue was taken up in EtOAc (60 mL) and water (10 mL), the organic phase was separated and washed consecutively with saturated K2CO3 solution (2 × 4ml), water (10 mL) and brine (2 × 10 mL). After the washed organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, the residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give the target compounds 4-15 in yields ranging from 55.4% to 73.6%.
General procedure: To a solution of 3 (0.35 g, 2.5 mmol) in DMF (25 mL) at room temperature was added K2CO3 (0.48 g, 3.5 mmol) and NaI (0.11 g, 0.75 mmol) (NaI was not needed for the reaction with alkyl bromide). The suspension was stirred for 5 min and alkyl chloride or alkyl bromide (2.25 mmol) was added. The reaction mixture was warmed to 60-65 C andstirred for 16-18 h at the same temperature. After the reaction suspension was cooled to room temperature and filtered.The filtrate was evaporated under reduced pressure to dryness.The residue was dissolved in ethyl acetate (35 mL) and the organic layer was washed with saturated K2CO3 solution(2 x 7 mL), water (2 x 7 mL) and brine (2 x 7 mL), respectively.The washed organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to dryness. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give compounds 4-8 in yields ranging from 56.3-62.5%.
General procedure: To a solution of 3 (0.35 g, 2.5 mmol) in DMF (25 mL) at room temperature was added K2CO3 (0.48 g, 3.5 mmol) and NaI (0.11 g, 0.75 mmol) (NaI was not needed for the reaction with alkyl bromide). The suspension was stirred for 5 min and alkyl chloride or alkyl bromide (2.25 mmol) was added. The reaction mixture was warmed to 60-65 C andstirred for 16-18 h at the same temperature. After the reaction suspension was cooled to room temperature and filtered.The filtrate was evaporated under reduced pressure to dryness.The residue was dissolved in ethyl acetate (35 mL) and the organic layer was washed with saturated K2CO3 solution(2 x 7 mL), water (2 x 7 mL) and brine (2 x 7 mL), respectively.The washed organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to dryness. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give compounds 4-8 in yields ranging from 56.3-62.5%.
General procedure: To a solution of 3 (0.35 g, 2.5 mmol) in DMF (25 mL) at room temperature was added K2CO3 (0.48 g, 3.5 mmol) and NaI (0.11 g, 0.75 mmol) (NaI was not needed for the reaction with alkyl bromide). The suspension was stirred for 5 min and alkyl chloride or alkyl bromide (2.25 mmol) was added. The reaction mixture was warmed to 60-65 C andstirred for 16-18 h at the same temperature. After the reaction suspension was cooled to room temperature and filtered.The filtrate was evaporated under reduced pressure to dryness.The residue was dissolved in ethyl acetate (35 mL) and the organic layer was washed with saturated K2CO3 solution(2 x 7 mL), water (2 x 7 mL) and brine (2 x 7 mL), respectively.The washed organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to dryness. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give compounds 4-8 in yields ranging from 56.3-62.5%.
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