* 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.
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.25 h; Inert atmosphere Stage #2: at -78℃; for 2 h; Inert atmosphere
[00457] To a stirred solution of 1.3 M LHMDS (25 mL, 32.7 mmol) in THF (10 mL) was added EtOAc (1.9 g, 21.8 mmol) at -78 °C under inert atmosphere. After being stirred for 15 min, ethyl- 3-bromo benzoate (5 g, 21.8 mmol) was added and stirring was continued for 2 h; progress of the reaction was monitored by TLC. The reaction was quenched with aq. NH4C1 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography eluting with 4percent EtOAc/Hexane to afford compound G (4.5 g, 76.9percent) as a mixture with its enolic form as a brown oil. 1H NMR (500 MHz, CDCls): δ 8.07 (s, 1H), 7.86 (d, J= 7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.37 (t, J= 7.0 Hz, 1H), 4.28-4.26 (m, 2H), 3.92 (s, 2H), 1.24 (t, J= 6.2 Hz, 3H). MS (ESI): m/z 298.8 [M-l].
Reference：
[1] Patent: WO2015/191630, 2015, A1, . Location in patent: Paragraph 00457
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2991 - 3013
2
[ 24398-88-7 ]
[ 22726-00-7 ]
Reference：
[1] Chemische Berichte, 1871, vol. 4, p. 707
3
[ 24398-88-7 ]
[ 39115-96-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrazine hydrate In ethanol; waterReflux
General procedure: Hydrazides (30–58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3–6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
86%
With hydrazine In ethanol; water at 78℃; for 5 h;
Embodiment 9; SYNTHESIS EXAMPLE 4; Synthesis Example 4 will specifically show a synthesis example of 2-(3-{N-[4-(carbazol-9-yl)phenyl]-N-phenylamino}phenyl)-5-phenyl-1,3,4-oxadiazole (abbreviation: mYGAO11) that is the oxadiazole derivative of the present invention represented by the structural formula (68) of Embodiment Mode 1.; Step 1: Synthesis of 2-(3-bromophenyl)-5-phenyl-1,3,4-oxadiazole (abbreviation: mO11Br); In Step 1, mO11Br was synthesized according to (i) to (iii) shown below.; (i) Synthesis of 3-bromobenzoylhydrazine; First, 10 g (44 mmol) of ethyl-3-bromobenzoate was put in a 200-mL three-neck flask, 50 mL of ethanol was added therein, and the mixture was stirred. Thereafter, 12 mL of hydrazine monohydrate was added therein, and the mixture was stirred at 78° C. for 5 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration. The obtained solid was put in approximately 500 mL of water, washed, and again collected by suction filtration; thus, 8.1 g of a white solid that was an object was obtained (yield: 86percent).
86%
With hydrazine In ethanol at 78℃; for 5 h;
Synthesis Example 1 In the present Synthesis Example 1, a synthesis example of the oxadiazole derivative, 2-[3-(carbazol-9-yl)phenyl]-5-phenyl-1,3,4-oxadiazole (abbreviated designation: mCO11), of the present invention that is represented by the Structural Formula (G1) of Embodiment Mode 1 will be presented in concrete terms. <Step 1: Synthesis of 2-(3-bromophenyl)-5-phenyl-1,3,4-oxadiazole (abbreviated designation: mO11Br)> In the present Step 1, mO11Br was synthesized according to processes (i) to (iii) as given below. (i) Synthesis of 3-bromobenzoylhydrazine; After 10 grams (44 mmol) of ethyl-3-bromobenzoate were placed into a 200 mL, three-neck flask, 50 mL of ethanol was added thereto and the mixture was stirred; 12 mL of hydrazine monohydrate was added, this mixture was stirred at 78°C for 5 hours, and the contents of the flask were reacted together. After the reaction was completed, a solid was precipitated out with the addition of water to the reaction solution. The precipitate solid was removed by suction filtration. With the suction-filtered solid being placed into approximately 500 mL of water and washed and a solid removed by suction filtration, 8.1 grams of a white-colored solid, which was the objective of the synthesis process, were obtained at a yield of 86percent.
78%
With hydrazine hydrate In ethanol for 10.25 h; Cooling with ice; Reflux
3-bromobenzoicacid ethyl ester 25 (1.5g, 6.6mmol) was dissolved in 15mL of ethanol, then under ice-cooling was slowly added dropwise with hydrazine hydrate (1.3g,26mmol), after the addition was complete, it was stirred at room temperaturefor 15min, then heated under reflux for 10h. After completion of the reaction, ethanol was removed by rotary evaporation, poured into water, extracted with ethyl acetate, the organic phase was dried and concentrated to give the desired product 26 (1.1g, 78percent), without purification into the next step.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[2] Patent: US2007/149784, 2007, A1, . Location in patent: Page/Page column 80-81
[3] Patent: EP1972625, 2008, A1, . Location in patent: Page/Page column 19-20
[4] Patent: CN105481765, 2016, A, . Location in patent: Paragraph 0090; 0091; 0092
[5] Journal of the Chinese Chemical Society (Peking), 1936, vol. 4, p. 69,72[6] Sci.Rep.Tsing Hua Univ.<A>, 1936, vol. 3, p. 555,558
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 9, p. 2079 - 2087
[8] Letters in Drug Design and Discovery, 2012, vol. 9, # 2, p. 135 - 139
[9] Archives of Pharmacal Research, 2014, vol. 37, # 7, p. 852 - 861
[10] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3052 - 3056
[11] Medicinal Chemistry, 2015, vol. 11, # 8, p. 798 - 806
[12] European Journal of Medicinal Chemistry, 2016, vol. 120, p. 134 - 147
[13] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 11, p. 1998 - 2010
[14] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
[15] Chemical Biology and Drug Design, 2017, vol. 90, # 2, p. 236 - 243
[16] Organic Preparations and Procedures International, 2017, vol. 49, # 4, p. 370 - 376
[17] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5652 - 5661
[18] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
[19] Monatshefte fur Chemie, 2018, vol. 149, # 12, p. 2349 - 2358
4
[ 24398-88-7 ]
[ 2463-16-3 ]
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[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2541 - 2545
5
[ 24398-88-7 ]
[ 58313-23-8 ]
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[1] Tetrahedron Letters, 2002, vol. 43, # 20, p. 3645 - 3648
[2] Journal of the American Chemical Society, 2002, vol. 124, # 17, p. 4874 - 4880
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[ 24398-88-7 ]
[ 15852-73-0 ]
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[1] Journal of Organic Chemistry, 1982, vol. 47, # 24, p. 4702 - 4708
[2] Tetrahedron Letters, 2010, vol. 51, # 46, p. 5973 - 5976
7
[ 24398-88-7 ]
[ 7664-93-9 ]
[ 15852-73-0 ]
[ 95068-01-2 ]
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[1] Chemische Berichte, 1904, vol. 37, p. 3695[2] Chem. Zentralbl., 1906, vol. 77, # I, p. 615
8
[ 24398-88-7 ]
[ 30951-66-7 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 1906,1909
9
[ 24398-88-7 ]
[ 676-58-4 ]
[ 30951-66-7 ]
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[1] Chinese Chemical Letters, 2011, vol. 22, # 10, p. 1215 - 1218
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[ 24398-88-7 ]
[ 10601-99-7 ]
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[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7186 - 7194
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[ 24398-88-7 ]
[ 76008-73-6 ]
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[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 16, p. 4440 - 4444[2] Angew. Chem., 2013, vol. 125, # 16, p. 4536 - 4540,5
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
86%
With hydrazine; In ethanol; water; at 78℃; for 5h;
Embodiment 9; SYNTHESIS EXAMPLE 4; Synthesis Example 4 will specifically show a synthesis example of 2-(3-{N-[4-(carbazol-9-yl)phenyl]-N-phenylamino}phenyl)-5-phenyl-1,3,4-oxadiazole (abbreviation: mYGAO11) that is the oxadiazole derivative of the present invention represented by the structural formula (68) of Embodiment Mode 1.; Step 1: Synthesis of 2-(3-bromophenyl)-5-phenyl-1,3,4-oxadiazole (abbreviation: mO11Br); In Step 1, mO11Br was synthesized according to (i) to (iii) shown below.; (i) Synthesis of 3-bromobenzoylhydrazine; First, 10 g (44 mmol) of ethyl-3-bromobenzoate was put in a 200-mL three-neck flask, 50 mL of ethanol was added therein, and the mixture was stirred. Thereafter, 12 mL of hydrazine monohydrate was added therein, and the mixture was stirred at 78 C. for 5 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration. The obtained solid was put in approximately 500 mL of water, washed, and again collected by suction filtration; thus, 8.1 g of a white solid that was an object was obtained (yield: 86%).
86%
With hydrazine; In ethanol; at 78℃; for 5h;
Synthesis Example 1» In the present Synthesis Example 1, a synthesis example of the oxadiazole derivative, 2-[3-(carbazol-9-yl)phenyl]-5-phenyl-1,3,4-oxadiazole (abbreviated designation: mCO11), of the present invention that is represented by the Structural Formula (G1) of Embodiment Mode 1 will be presented in concrete terms. <Step 1: Synthesis of 2-(3-bromophenyl)-5-phenyl-1,3,4-oxadiazole (abbreviated designation: mO11Br)> In the present Step 1, mO11Br was synthesized according to processes (i) to (iii) as given below. (i) Synthesis of 3-bromobenzoylhydrazine; After 10 grams (44 mmol) of ethyl-3-bromobenzoate were placed into a 200 mL, three-neck flask, 50 mL of ethanol was added thereto and the mixture was stirred; 12 mL of hydrazine monohydrate was added, this mixture was stirred at 78C for 5 hours, and the contents of the flask were reacted together. After the reaction was completed, a solid was precipitated out with the addition of water to the reaction solution. The precipitate solid was removed by suction filtration. With the suction-filtered solid being placed into approximately 500 mL of water and washed and a solid removed by suction filtration, 8.1 grams of a white-colored solid, which was the objective of the synthesis process, were obtained at a yield of 86%.
80%
With hydrazine hydrate; In ethanol; for 7h;Reflux;
A mixture ofethyl-3-bromobenzoate (1) (2 mmol) and hydrazine hydrate(2) (80 %) (3 mmol) was refluxed for 7 h. The progress of reactionwas monitored by TLC using 20 % EtOAc:n-hexane. Aftercompletion of reaction; the reaction mixture was cooled, theprecipitated solid was filtered off, recrystallized from ethanoland confirmed by 1H NMR as the pure hydrazide (3a) (Scheme-I). Yield = 80 %, Colour-White, solid, m.p. 158 C; 1H NMR(200 MHz, DMSO-d6) ppm 4.54 (br., s., 2 H, NH2), 7.37 - 7.47(dd, J = 8.5, 8 Hz, 1H), 7.67 - 7.86 (m, 2 H), 7.98 (dd, J = 1.83,1.71 Hz, 1H), 9.89 (br., s., 1 H, NH).
78%
With hydrazine hydrate; In ethanol; for 10.25h;Cooling with ice; Reflux;
3-bromobenzoicacid ethyl ester 25 (1.5g, 6.6mmol) was dissolved in 15mL of ethanol, then under ice-cooling was slowly added dropwise with hydrazine hydrate (1.3g,26mmol), after the addition was complete, it was stirred at room temperaturefor 15min, then heated under reflux for 10h. After completion of the reaction, ethanol was removed by rotary evaporation, poured into water, extracted with ethyl acetate, the organic phase was dried and concentrated to give the desired product 26 (1.1g, 78%), without purification into the next step.
With hydrazine hydrate; In ethanol;Reflux;
General procedure: Then, the corresponding ester was refluxed with 85% hydrazine monohydrate in ethanol to get hydrazide 1.
With hydrazine hydrate; In ethanol;Reflux;
General procedure: Hydrazide ligands (1-12) were synthesized by reportedmethod [28,29]. Ethylbenzoate (25 mmol) was dissolved inethanol (75 mL), and then hydrazine hydrate (100 mmol)was added and the mixture refluxed for 5 h. The solid obtainedwas washed with hexane to afford the hydrazide.Other ligands were prepared from their respective esters. Theanalytical data of benzohydrazide (1), M.P. 116 C; 2-fluorobenzohydrazide (2), M.P. 74 C; 2-methoxybenzohydrazide(3), M.P. 83 C; 2-aminobenzohydrazide (4), M.P.124 C; 4-phenylsemicarbazide (5), M.P. 125 C; 3-aminobenzohydrazide(6), M.P. 79C; 4-aminobenzohydrazide (7),M.P. 229 C; 3-methoxybenzohydrazide (8), M.P. 94 C; 3-fluorobenzohydrazide (9), M.P. 138 C; 3-iodobenzohydrazide(10), M.P. 141 C; 4-iodobenzohydrazide (11) M.P.170 C and 3-bromobenzohydrazide (12) M.P. 160 C; werereported previously [28,30].
With hydrazine hydrate; In ethanol; for 6h;Reflux;
General procedure: The substituted ethyl benzoates (16-30) (0.01 mol)dissolved in dry ethanol (25 mL), hydrazine hydrate (99%,0.01 mol) was added and the mixture was reuxed for 6 h.The reaction mixture was cooled and the solid obtained wasltered and recrystallized from dilute ethanol or from water.Details of these compounds are available in SupplementaryInformation.
With hydrazine hydrate; In ethanol; for 5h;Reflux;
General procedure: 5mL of hydrazine monohydrate (80%) was added to a solution of intermediate 3 (5mmol) in ethanol (5mL). The reaction mixture was maintained under reflux for 5h. was then concentrated under reduced pressure and the resulting solid was collected by filtration, washed with cold water and dried to give the desired intermediate 4 as a white solid.
With sodium carbonate; triphenylphosphine;copper(l) iodide; palladium diacetate; In tetrahydrofuran; water; at 65℃;
A solution of 4-methylbenzeneboronic acid (4.45 g, 32.75 mmol, 1.5 eq. ) and ethyl 3- bromobenzoate (5.0 g, 21.83 mmol, 1 eq. ) in THF (100 mL) was treated with 2M aqueous sodium carbonate (24 mL, 48.03 mmol, 2.2 eq. ) followed by palladium (II) acetate (0.49 g, 2.18 mmol, 10 mol%), triphenylphosphine (2.52 g, 9.59 mmol, 4.4xPd eq. ), and copper (I) iodide (catalyst, 0.13 g, 0.68 mmol) as solids. The solution was then heated to 65C overnight. The dark reaction was cooled and diluted with water and extracted 2X200 mL with EtOAc. The organic layers were combined, dried over MGS04, filtered, and the solvent removed in vacuo leaving a dark oil. The oil was purified by preparative HPLC (Waters LC-2000) using a gradient starting with 100% hexane and going to 5% EtOAc in hexane over 30 minutes. Fractions containing the product were pooled and the solvent removed leaving 4'-methyl-biphenyl- 3-carboxylic acid ethyl ester as a faint yellow oil (5.01 g, 95% yield). 'H NMR (DMSO-d6) O8. 17 (M, 1H), 7.92 (m, 2H), 7.61 (M, 3H), 7.30 (d, 2H, J=8 Hz), 4.35 (q, 2H, 7 Hz), 2.36 (s, 3H), and 1.35 (t, 3H, J=7 Hz). IR (CHC13, CM 1) 1715, 1369,1310, 1300,1249, 1110. MS (ES+) M/Z 241. Anal. Calcd for C16HL6O2 C, 79.97 ; H, 6.71 ; N, 0.00. Found C, 79.84 ; H, 6.48 ; N, 0.14.
71%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water;Reflux; Inert atmosphere;
Ethyl 3-bromobenzoate (2.43 g) was mixed with p-methylphenylboronic acid (1.50 g), 2.12 g of sodium carbonate, 2.31 g of tetrakis(triphenylphosphine)palladium and 30 mL of water were added, and the mixture was stirred at reflux under nitrogen and stirred overnight. After cooling, the solution was evaporated by evaporation and the mixture was separated on a silica gel column (isolation system: petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain 1.61 g of a coupling product in a yield of 71%. 2.26 g of the product in the previous step was added to a mixed solution of 20 mL of tetrahydrofuran and 5 mL of methanol. 100 mL of a 20% aqueous lithium hydroxide solution was added to the solution, and the mixture was stirred at room temperature overnight. After the completion of the process, the pH is adjusted to 2 with concentrated hydrochloric acid and the solvent is distilled off. The mixture was separated on a silica gel column (isolation system: petroleum ether:ethyl acetate=10:1 to 100% ethyl acetate) to obtain 1.59 g of a hydrolyzed product with a yield of 75%. The product of the previous step was directly added with 50 mL of thionyl chloride and stirred at reflux for 2 h. Thionyl chloride was distilled off to obtain the product of the acid chloride, which was used directly in the next step. 3.46 g of the acid chloride product and 2.29 g of the intermediate compound were mixed and 50 mL of pyridine was added. 100C, stirred at reflux overnight. After cooling, the solvent was distilled off and the mixture was separated on a silica gel column (isolation system: petroleum ether:ethyl acetate=10:1 to 100% ethyl acetate) to give a crude product. The crude product was purified by preparative chromatography (mobile phase: water (0.05% aqueous ammonia)-acetonitrile; B 40%-80%, 50 minutes) to give a pale orange solid 0.85 g, yield 20%.
Ethyl 3-bromobenzoate (1.601 ml, 10 mmol), Chlorodiphenylphosphine (1.85 ml, 10 mmol) and NiBr2 (bpy) (93 mg) were mixed in 5 ml of N-methyl-2-pyrrolidone(NMP).After stirring for 1 hour at room temperature, Zn (1.16 g, 16 mmol) was added,and stirred at 105 (100-110 ), under N2 (g) air stream for 3 hours. After stirring, the mixture was cooled to room temperature,After filtration, it was separated into H2O layer and CHCl3 layer using H2O,The CHCl3 layer alone was collected and the solvent was evaporated using an evaporator,CHCl3 layer only separately collected by evaporating the solvent in evaporator was synthesized Ethyl 3- (diphenylphosphino) benzoate.
With nickel(II)-2,2'-bipyridine bromide; zinc; In 1-methyl-pyrrolidin-2-one; at 110℃; for 3h;Inert atmosphere;
NiBr2(bpy) was prepared according to a previously reported method.13 A mixture of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong>(1.601 ml, 10 mmol), chlorodiphenylphosphine (1.85 ml,10 mmol) and NiBr2(bpy) were dissolved in 5 ml NMP(N-methyl-2-pyrrolidone). Zinc dust (1.1 g, 16 mmol) wasadded portion-wise in a few minutes. The solution was heated under nitrogen to 110 C, and after 3 hours, the reaction was finished. The solution was then allowed to cool at room temperature and was subsequently filtered.The filtered solution was evaporated and dried undera vacuum, and the dried precipitate was dissolved in10 mL CH2Cl2. Then, H2O2 (2 mL, 30%) was added dropwisewhile stirring at room temperature. The solution wasextracted 3 times with water, and then the organic layerwas collected and evaporated.FT-IR (KBr, cm-1) 3057 (stretch, -CH3, 2991(stretch, -CH2-), 1717 (C O), 1436 (bend, -CH2-),1113 (bend, -CH3).
Stage #1: ethyl 3-bromobenzoate With tBu2Zn(TMP)Li In tetrahydrofuran at 20℃; for 3h;
Stage #2: With iodine In tetrahydrofuran at 20℃; Further stages.;
Stage #1: ethyl 3-bromobenzoate In tetrahydrofuran; hexane; pentane at 20℃; for 3h;
Stage #2: With iodine In tetrahydrofuran; hexane; pentane at 20℃; for 1h; Further stages.;
[00457] To a stirred solution of 1.3 M LHMDS (25 mL, 32.7 mmol) in THF (10 mL) was added EtOAc (1.9 g, 21.8 mmol) at -78 C under inert atmosphere. After being stirred for 15 min, ethyl- 3-bromo benzoate (5 g, 21.8 mmol) was added and stirring was continued for 2 h; progress of the reaction was monitored by TLC. The reaction was quenched with aq. NH4C1 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography eluting with 4% EtOAc/Hexane to afford compound G (4.5 g, 76.9%) as a mixture with its enolic form as a brown oil. 1H NMR (500 MHz, CDCls): delta 8.07 (s, 1H), 7.86 (d, J= 7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.37 (t, J= 7.0 Hz, 1H), 4.28-4.26 (m, 2H), 3.92 (s, 2H), 1.24 (t, J= 6.2 Hz, 3H). MS (ESI): m/z 298.8 [M-l].
With potassium phosphate; benzoin oxime; copper diacetate; In dimethyl sulfoxide; at 80℃;Inert atmosphere;
General procedure: K3PO4 (5.62 mmol) in DMSO (4 mL), were added Cu(OAc)2 (0.28 mmol). The flask was evacuatedand backfilled with argon for three times. The resulting suspension was heated in a 80 C oil bathwith stirring for the indicated time. The reactor was cooled to r.t., the flask was opened to air and thereaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), andorganic layer was washed with water (20 mL × 2) and once with brine (25 mL), dried overmagnesium sulfate and concentrated in vacuo. The product was purified by column chromatographyon silica gel using petroleum ether and ethyl acetate as eluent.1-(2-Methoxyphenyl)-1H-pyrrole (3a) [30]: colorless oil (0.43 g, 88%). 1H-NMR (400 MHz, CDCl3) delta (ppm):7.30-7.23 (2H, m), 7.03-6.98 (4H, m), 6.30 (2H,
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 5h;
EXAMPLE 11. Synthesis of Ethyl 3-(5-Aminopyrimidin-2-ylamino)Benzoate(Intermediate 6); <n="51"/>[0140] To a solution of <strong>[3073-77-6]2-amino-5-nitropyrimidine</strong> (550 mg, 3.9 mmol) in 35 mL anhydrous 1,4-dioxane were added ethyl 3-bromobenzoate (1.8 g, 7.9 mmol), Xantphos, (230 mg, 0.4 mmol), Pd2(dba)3 (180 mg, 0.2 mmol) and Cs2CO3 (2.6 g, 8 mmol). The reaction mixture was stirred at 1000C for 5 h under argon. The solvent was removed under reduced pressure. The resulting solution was extracted with CHCl3 (3 x 50 mL) and saturated NaHCO3 (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and filtered. The organic solvent was removed and the crude product was purified by silica gel column with CHCl3 as an eluent. The precipitated yellow solid was isolated by washed with chloroform and dried in vacuo (700 mg, 62%). 1H NMR (DMSO- de): delta 1.33 (t, J= 7.1 Hz, 3H), 4.33 (q, J = 7.1 Hz, 2H), 7.54 (t, J = 8.0 Hz, IH), 7.60-7.90 (m, IH), 7.95-8.10 (m, IH), 8.37 (t, J= 1.9 Hz, IH)3 9.26 (s, 2H)5 11.00 (s, IH).[0141] The above product was hydrogenated in 100 mL methanol/ethyl acetate (v/v: 1:1) using Pd/C (10%, 1 g) for 2 h. The palladium catalyst was removed by filtration, and the solvent was evaporated. The crude product was purified by silica gel column with 5% CH3OH / CHCl3 as an eluent to yield an off-white solid. MS (ES+): m/z 259 (M+H)+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 20℃; for 18h;Heating / reflux;
To a solution of 0.94 g (4.58 mmol) OF ETHYL-3-BROMOBENZOATE in 14. 5 Ml of toluene at RT was added 0. 25 g (0. 218 mmol) OF TETRAKISFTRIPHENYLPHOSPHINE) PALLADIUM (0), 0. 94 g (4. 58 mmol) of 2-trifluoromethoxyphenylboronic acid, 2.22 Ml (4.45 mmol) of 2M aqueous sodium carbonate solution and 7 Ml of ethanol. The reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled and diluted with ethyl acetate and water. The organic fraction was separated and washed with saturated NaCl solution (brine), dried over MgSO4, filtered and the filtrate was concentrated to an oil which was purified by chromatography (silica, 1%, 5%, 30% successively ethyl acetate : hexanes) to give the title COMPOUND. H NMR (CD30D) (5, ppm): 8.02 (s, 1H), 7.97 (dd, J = 7. 8, 1.2 Hz, 1H), 7.60 (dd, J = 7.7, 1.3 Hz, 1H), 7.50-7. 33 (m, 5H), 4. 31 (q, 2H), 1.31 (t, 3H).. Mass Spectrum (ESI) m/e (M+1) : 311.2.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 18h;Heating / reflux;
Step B: Ethyl-3- (2-Trifluoromethoxvphenyl)-benzoate To a solution of 0.94 g (4.58 mmol) of <strong>[24398-88-7]ethyl-3-bromobenzoate</strong> in 14.5 mL of toluene at RT was added 0.25 g (0.218 mmol) of tetrakis (triphenylphosphine) palladium (0), 0.94 g (4.58 mmol) of 2-trifluoromethoxyphenylboronic acid, 2.22 mL (4.45 mmol) of 2M aqueous sodium carbonate solution and 7 mL of ethanol. The reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled and diluted with ethyl acetate and water. The organic fraction was separated and washed with saturated NaCI solution (brine), dried over MgS04, and filtered. The filtrate was concentrated to an oil which was purified by chromatography (silica, 1%, 5%, 30% successively ethyl acetate: hexanes) to give the title compound. XH NMR (CD30D) (8, ppm): 8.02 (s, 1H), 7.97 (dd, J = 7.8, 1.2 Hz, 1H), 7.60 (dd, J = 7.7, 1.3 Hz, 1H), 7.50-7. 33 (m, 5H), 4.31 (q, 2H), 1.31 (t, 3H). Mass Spectrum (ESI) m/e (M+1) : 311.2.
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 70℃; for 18h;
ethyl 2', 4'-dimethylbiphenyl-3-carboxylate (2, 4-Dimethylphenyl) boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol) and cesium carbonate (9. 8 g, 30.0 mmol) were added to a mixture of ethanol (20 mL) and toluene (80 mL), and after argon substitution, tetrakis (triphenylphosphine) palladium (0) (0.30 g, 0.26 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70C for 18 hrs. The reaction mixture was cooled and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: hexane=1 : 10) to give the title compound (5.0 g, yield 100%) as a colorless oil. 1H NMR (CDC13) 8 : 1.39 (3H, t, J=7. 0Hz), 2.23 (3H, s), 2.37 (3H, s), 4.38 (2H, q, J=7. 0Hz), 7.02-7. 54 (5H, m), 8.00-8. 05 (2H, m).
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In methanol; toluene; at 80℃; for 18h;
A mixture of <strong>[24398-88-7]ethyl-3-bromobenzoate</strong> (3 g, 13.1 mmol), [3-(hydroxymethyl)phenyl]-boronic acid (3 g, 19.6 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol),and potassium carbonate (3.6 g, 26.2 mmol) in Toluene/MeOH (10:1, 40 mL) was stirred at80 C for 18 h. The resulting black mixture was cooled to room temperature, filtered throughcelite, and poured into a EtOAc/brine mixture. The two layers were separated and theaqueous was extracted with EtOAc (3x). The organics were combined, dried over sodiumsulfate, filtered, and evaporated to dryness. The residue was purified by flashchromatography on silica gel eluting with a mixture of EtOAc/Hexane to yield 3 g of ethyl 3'-(hydroxymethyl)biphenyl-3-carboxylate as an orange oil.
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In methanol; toluene; at 80℃; for 18h;
A mixture of <strong>[24398-88-7]ethyl-3-bromobenzoate</strong> (3.0 g, 13 mmol), [3-(hydroxymethyl)- phenyl]boronic acid (3.0 g, 20 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), K2CO3 (3.6 g, 26 mmol), methanol (4 mL), and toluene (36 mL) was heated at 80 0C for 18 h under N2 and then allowed to cool to rt. The reaction mixture was filtered through Celite and then poured into a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted with ethyl acetate (x 3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give ethyl 3'- (hydroxymethyl)biphenyl-3-carboxylate as an orange oil. A solution Of CBr4 (5.8 g, 17 mmol) and CH2Cl2 (20 mL) was added dropwise to a solution of the above alcohol, PPh3 (4.6 g, 18 mmol), and CH2Cl2 (50 mL) at 0 0C under N2. The reaction was allowed to warm to rt, maintained for 2 h, concentrated, and purified by silica gel chromatography to give ethyl 3'- (bromomethyl)biphenyl-3-carboxylate as a clear oil. Ethyl 3'-(bromomethyl)biphenyl-3- carboxylate was used to alkylate l-(2,2-dimethylpropyl)-4-propyl-lH-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (0.66 g, 1.4 mmol), 1 N LiOH (8 mL), and TEtaF (8 mL) was heated at 40 0C for 2 d and then cooled to 0 C- acetone can used in place of TEtaF if faster reaction rates are desired. The reaction was acidified to pEta = 1 with cone. HCl and extracted with ethyl acetate (x 3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give a yellow oil. 1H NMR (CDCl3, 500 MHz) delta 8.39 (s, IH), 8.11 (d, IH), 7.85 (d, IH), 7.76 (s, IH), 7.59- 7.48 (m, 4H), 7.12 (d, IH), 7.05 (d, IH), 6.96 (d, IH), 6.46 (d, IH), 5.16 (s, 2H), 3.84 (s, 2H), 2.95 (t, 2H), 1.76 (m, 2H), 1.01 (t, 3H), 0.99 (s, 9H). MS (ESI): 456 (M+H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene;
The N-(3-amino4-methylphenyl)-3-morpholinobenzamide used as a starting material was prepared as follows: A mixture of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (1.92 ml), morpholine (1.25 ml), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.336 g), sodium tert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladium(0) (0.33 g) and toluene (25 ml) was stirred and heated to 90 C. for 18 hours under argon. The reaction mixture was allowed to cool to ambient temperature and extracted with 1N aqueous hydrochloric acid. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 47:3 mixture of methylene chloride and methanol as eluent. There was thus obtained N-(3-morpholinobenzoyl)morpholine (0.45 g).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene;
The 3-morpholinobenzoyl chloride used as a starting material was prepared as follows: A mixture of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (1.92 ml), morpholine (1.25 ml), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.336 g), sodium tert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladium(0) (0.33 g) and toluene (25 ml) was stirred and heated to 90 C. for 18 hours under argon. The reaction mixture was allowed to cool to ambient temperature and extracted with 1M hydrochloric acid. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 47:3 mixtute of methylene chloride and methanol as eluent. There was thus obtained N-(3-morpholinobenzoyl)morpholine (0.45 g).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene;
The N-(3-amino-4-methylphenyl)-3-morpholinobenzamide used as a starting material was prepared as follows: A mixture of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (1.92 ml), morpholine (1.25 ml), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.336 g), sodium tert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladium(0) (0.33 g) and toluene (25 ml) was stirred and heated to 90 C. for 18 hours under argon. The reaction mixture was allowed to cool to ambient temperature and extracted with 1M hydrochloric acid. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residual oil was purified by column chromatography on silica gel using a 47:3 mixture of methylene chloride and methanol as eluent to yield N-(3-morpholinobenzoyl)morpholine (0.45 g).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene;
The 3-morpholinobenzoyl chloride used as a starting material was prepared as follows: A mixture of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (1.92 ml), morpholine (1.25 ml), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.336 g), sodium tert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladium(0) (0.33 g) and toluene (25 ml) was stirred and heated to 90 C. for 18 hours under argon. The reaction mixture was allowed to cool to ambient temperature and extracted with 1N aqueous hydrochloric acid. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 47:3 mixture of methylene chloride and methanol as eluent. There was thus obtained N-(3-morpholinobenzoyl)morpholine (0.45 g).
With triethylamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 60℃; for 4h;
Ethyl 3-bromobenzoate (0.500 g, 2.18 mmol) was dissolved in CH3CN ( 8.70 ml). Triethylamine (1.53 ml, 10.9 mmol) was added followed by 3,3-dimethylbut-l-yne (0.27 g, 3.27 mmol). With stirring Pd(PPh3)4 (0.25 g, 0.21 mmol) and CuI (0.083 g, 0.436 mmol) were added and the reaction was warmed to 60 C for 4 h. The reaction was then diluted with EtOAc (~ 50 ml), filtered through a pad of SiO2, and concentrated in vacuo. The crude product was purified on 40 g SiO2 using hexanes-EtOAc (10:1) as eluent giving 0.45 g of the title compound as a colourless oil (91 %); m/z 231.
91%
With triethylamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 60℃; for 4h;
Method 107; Ethyl 3 -(3.3 -dimethylbut- 1 -vn- 1 -vDbenzoate; Ethyl 3-bromobenzoate (0.500 g, 2.18 mmol), 3 ,3 -dimethylbut- 1-yne (0.27 g, 3.27 mmol) and triethylamine (1.53 ml, 10.9 mmol) in acetonitrile (8.70 ml) were treated with Pd(PPh3)4 (0.25 g, 0.21 mmol) and CuI (0.083 g, 0.436 mmol). The reaction was warmed to 60 0C for 4 h. The reaction was then diluted with EtOAc, filtered through a pad of SiO2, and concentrated in vacuo. The crude reaction product was purified by column chromatography utilizing an ISCO system (hexanes/EtOAc 10:1) giving 0,45 g of the title compound as a colourless oil (91 %); m/z 231.
Step 1 : Ethyl 3-(3-methoxypropyl)benzoateTo a THF solution (0.1 M) of allyl methyl ether (1.4 eq.) was added, at 0 0C, 9- borabicyclo[3.3.1]nonane (2.4 eq.) over a period of 30 min. The solution was stirred at 0 0C for 1 h and then warmed slowly to RT over 16 h. To the resulting clear solution was then added sodium methoxide (2.4 eq.), Cl2Pd(dppf)-dichloromethane complex (5% loading) and <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (1 eq.). The now brown suspension was heated to reflux for 16 h. The reaction mixture was cooled to RT, quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex -^ 4: 1 (v/v) Hex : EtOAc) afforded the title compound as a light yellow oil.
3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidine-4-amino}-benzoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 0.25h;Microwave irradiation;
[0221] A suspension of intermediate 32 (0.10 g, 0.33 lmnol), <strong>[24398-88-7]3-bromo-benzoic acid ethyl ester</strong> (0.07 mL, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 10% MeOH/DCM) to afford the title compound (0.10 g, 68%). MS (ES+): m/? AAl (M+H)+.
With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane; In tert-butyl methyl ether; at -10 - 0℃; for 0.916667h;
To a stirred mixture of a compound of formula V (1 eq), a boronic acid derivative of general formula VI (1.1 eq) and tetrakis(triphenylphosphine)palladium (0.03 eq) in an organic solvent (e.g. 1,2-dimethoxy-ethane) is added at room temperature aqueous 1 M sodium carbonate solution (2.5 eq), the reaction mixture is heated at 80 to 90 C. for around 18 h, cooled, poured into ice-water and extracted two times with ethyl acetate. The combined organic layers are washed two times with brine, dried (e.g. MgSO4) and evaporated. The crude product is further purified by flash chromatography on silica gel (ethyl acetate/n-heptane) and crystallization (e.g. dichloromethane/diethyl ether/n-heptane) to give compounds of general formulae Ia or Ib.Prepared from hexamethyldisilizane (16.5 mL, 79 mmol) and n-BuLi (48.4 mL, 77 mmol) in TBME (40 mL), then commercially available <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (7.55 g, 33 mmol) and tert-butyl acetate (4.86 mL, 36 mmol) in TBME (80 mL) according to the general procedure III. Obtained as a light yellow oil (9.934 g, 101%; 95% purity).
Preparation of ethyl-3-isopropylthiobenzoate [formula 6] A solution of palladium acetate (4.5 mg, 0.02 mmol) and Xantphos (12.7 mg, 0.022 mmol) in DMF (1 mL) was stirred for 5 minutes under a nitrogen atmosphere. To this solution was added <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (1 14.5 mg, 0.5 mmol) dissolved in 0.5 mL of DMF and then the reaction mixture was stirred for 10 minutes at room temperature. In(SPr')3 (57 mg, 0.168 mmol) in DMF ( 1 mL) and diisopropylethyl amine (65 mg, 0.5 mmol) were added to this reaction mixture. The reaction mixture was stirred for 2 hours at 100 degrees Celsius. The solution was cooled to room temperature and then 1 mL of hydrochloric acid (5 % of aqueous solution) was added to stop the reaction. The crude product was extracted with diethyl ether (15 mL, 3 times) and sequentially washed with 10 mL of water, a saturated NaHCO3 (10 mL) solution and a saturated NaCl (20 mL) solution. The extracted organic compound was dried over anhydrous MgSO4 and then filtered. After evaporation of solvents, the crude product was purified by column chromatography to give ethyl-3-isopropylthio benzoate (102 mg, 91 %) (formula 6).1H-NMR (400 MHz, CDCl3, 25 degrees Celsius) delta 8.06(s, IH), 7.89(d, J=7.8Hz, IH), 7.56(d, J=7.8Hz, IH), 7.36(t, J=7.8Hz, IH), 4.38(q, J=7.1Hz, 2H), 3.44(sep, J=6.7Hz, IH), 1.40(t, J =7. IHz, 3H), 1.31(d, J =6.7Hz, 6H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; for 6h;Reflux;
3'-Aminomethyl-biphenyl-3-carboxylic acid ethyl ester: To a stirred solution of 3-bromo-ethyl benzoate (500 mg, 2.18 mmol) in DME (20 mL) was added 3-cyano-phenyl-boronic acid (320 mg, 2.18 mmol), 2 N K2CO3 (1.9 mL) followed by tetrakistriphenylphosphine palladium (125 mg) and heated at reflux for 6 hrs. After cooling to room temperature, the reaction mixture was diluted with EtOAc (25 mL) and washed with H2O (10 mL×2). The organic layer was dried over Na2SO4, concentrated, and the residue purified by silica gel column chromatography with EtOAc and hexane as eluents to give 3'-cyano-biphenyl-3-carboxylic acid ethyl ester (383 mg, 70% yield).
Method A; Step e: 1-(3-bromophenyl)-2-pyridin-4-ylethanone; To 66 ml (0.066 mol) of sodium 1,1,1,3,3,3-hexamethyldisilazane 1M in THF under nitrogen atmosphere at 00C, 3.2 ml (0.033 mol) of 4-picoline were added. After stirring for 60 minutes 5 ml (7.15 g; 0.03 mol) of ethyl 3-bromo benzoate were added and the mixture maintained in the same conditions for 1.5 hours. HCI 2N was then added, the mixture made basic with NaOH 2N and extracted with ethyl acetate. The organic phase was dried over Na?SCM and the solvent evaporated. 7.5 g (82% yield) of the title compound were obtained by crystallization from AcOEt-Et2U. 1H NMR (401 MHz, DMSO-d6) delta = 8.52 (d, J = 6.0 Hz, 2 H), 8.19 (t, J = 1.7 Hz, 1 H), 8.05 (ddd, J = 1.0, 1.6, 7.8 Hz, 1 H), 7.89 (ddd, J = 1.0, 2.0, 8.0 Hz, 1 H), 7.54 (t, J = 7.9 Hz, 1 H), 7.19 - 7.33 (m, 2 H), 4.53 (s, 2 H). MS-ESI (M+H) calc. 276.0019 found 276.0023 (C13HIOBrNO)
82%
To 66 ml (0.066 mol) of sodium hexamethyldisilazane 1M in tetrahydrofuran under nitrogen atmosphere and 00C, 3.2 ml (0.033 mol) of 4-picoline were added. After 60 minutes of stirring 5 ml (7.15 g; 0.03 mol) of ethyl 3-bromo benzoate were added and the mixture maintained in the same conditions for 1.5 hours. HCI 2N was then added, the mixture made basic with NaOH 2N and extracted with ethylacetate. The organic phase was dried over Na?SCM and the solvent evaporated. 7.5 g (82% yield) of the title compound crystallized from AcOEt-Et2U. HPLC (254 nm): R1: 4.79 min.1H NMR (401 MHz, DMSOd6) delta = 8.52 (d, J = 6.0 Hz, 2 H), 8.19 (t, J = 1.7 Hz, 1 H), 8.05 (ddd, J = 1.0, 1.6, 7.8 Hz, 1 H), 7.89 (ddd, J = 1.0, 2.0, 8.0 Hz, 1 H), 7.54 (t, J = 7.9 Hz, 1 H), 7.19 - 7.33 (m, 2 H), 4.53 (s, 2 H). HRMS (ESI) calcd for C13H11 BrNO [M+H]+ 276.0019, found 276.0023.
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 16h;
Step II: Synthesis of ethyl 3-{(T i?.5£6sV6-[bis(fer^butoxycarbonyl)amino"|-3- azabicyclo[3.1.01hex-3-yl}benzoate:A mixture of di-tert-buty (liJ^^^-S-azabicyclofS.l.OJhex-delta-ylimidodicarbonate(0.1 g, 0.33 mmol), cesium carbonate (0.13 g, 0.405 mmol), <strong>[24398-88-7]ethyl-3-bromobenzoate</strong> (0.064 g, 0.27 mmol) and 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (0.02 g, 0.027 mmol) in dry toluene was degassed and treated with palladium(II) acetate (0.003 g 0.0315 mmol). The reaction mixture was heated at about 80 0C for about 16 hours. The reaction mixture was concentrated under vacuum, diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silicon dioxide (100-200) using hexane/ethyl acetate system as eluent to afford the title compound (100 mg).EIMS m/z 447.29 [M+H]+
100 mg
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; at 0.8℃; for 0.16h;
[0493] A mixture of di-tert-butyl (1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-ylimidodicarbonate (0.1 g, 0.33 mmol), cesium carbonate (0.13 g, 0.405 mmol), <strong>[24398-88-7]ethyl-3-bromobenzoate</strong> (0.064 g, 0.27 mmol) and 2,2?-bis(diphenylphosphino)-1,1?-binaphthyl (0.02 g, 0.027 mmol) in dry toluene was degassed and treated with palladium(II) acetate (0.003 g 0.0315 mmol). The reaction mixture was heated at about 80 C. for about 16 hours. The reaction mixture was concentrated under vacuum, diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silicon dioxide (100-200) using hexane/ethyl acetate system as eluent to afford the title compound (100 mg). [0494] EIMS m/z 447.29 [M+H]+
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 110℃; for 5h;
Production Example 13 To a mixture of 85 mg of palladium acetate, 350 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 15 mL of toluene were added 1.8 mL of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong>, 1.02 g of 2-nitroaniline and 4.81 g of cesium carbonate, followed by stirring at 110C for 5 hours. The reaction solution was allowed to cool, 50 mL of ethyl acetate was added thereto to remove insoluble materials, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1:9) to obtain 2.10 g of ethyl 3-[(2-nitrophenyl)amino] benzoate as an light orange oily susbstance.
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 5h;
Production Example 13 To a mixture of 85 mg of palladium acetate, 350 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 15 mL of toluene were added 1.8 mL of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong>, 1.02 g of 2-nitroaniline and 4.81 g of cesium carbonate, followed by stirring at 110 C. for 5 hours. The reaction solution was allowed to cool, 50 mL of ethyl acetate was added thereto to remove insoluble materials, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1:9) to obtain 2.10 g of ethyl 3-[(2-nitrophenyl)amino]benzoate as an light orange oily substance.
With trimethylsilylazide; copper; ethanolamine; In N,N-dimethyl acetamide; at 95℃; for 24h;Inert atmosphere;
General procedure: A mixture of copper powder (63.5 mg, 1.00 mmol), the aryl halide (500 mumol), 2-aminoethanol (74.9 muL, 1.25 mmol), and TMSN3 (133 muL, 1.00 mmol) in DMA (1 mL) in a 15 mL test tube was stirred under an Ar atmosphere (balloon) at 95 C using a Chemistation personal organic synthesizer (EYELA, Tokyo). After complete consumption of the aryl halide was confirmed by TLC analyses or after 24 h (if the reaction was incomplete within 24 h), the mixture was diluted with EtOAc (10 mL) and then filtered through a Celite pad. The pad was successively washed with EtOAc (20 mL), H2O (25 mL), and concd aq ammonia solution (5 mL). After the two layers were separated, the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography with n-hexane/EtOAc or n-pentane/Et2O as the eluent.
Stage #1: cyclohex-1-enecarbonitrile With zinc chloride-2,2,6,6-tetramethylpiperidin-1-ide lithium chloride complex In tetrahydrofuran at 25℃; Inert atmosphere;
Stage #2: ethyl 3-bromobenzoate With palladium diacetate In tetrahydrofuran at 50℃; for 3h; Inert atmosphere; regioselective reaction;
With potassium carbonate; tris-(o-tolyl)phosphine;palladium diacetate; In ethanol; water; toluene; at 80℃; for 5h;Inert atmosphere;
First, 7.98 g of phenylboronic acid, 15 g of 3-bromoethyl benzoate, 0.265 g of tri(ori/zo-tolyl)phosphine, 200 mL of toluene, 30 mL of ethanol, and 65 mL of 2.0M aqueous solution of potassium carbonate were put in a 500 mL three-neck flask, and the air in the flask was replaced with nitrogen. Then, 0.147 g of palladium(II) acetate (Pd(OAc)2) was added to this mixed solution, and heated and stirred at 80 C for 5 hours. After a certain time, an aqueous layer of this mixture was extracted with toluene. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate and then saturated saline. Anhydrate magnesium sulfate was added to the organic layer for drying, and the resulting mixture was subjected to gravity filtration to give a filtrate. This filtrate was concentrated to give an oily substance. The given oily substance was purified using silica gel column chromatography. As developing solvents, first, hexane was used, and then a mixed solvent of hexane:ethyl acetate = 9:1 was used. The resulting fraction was concentrated, so that 3-phenylethyl benzoate was prepared (a colorless oily substance, yield: 88 %). The synthetic scheme of Step 1 is shown by (a-16).
Intermediate 8benzoate ethyl 3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]- Under a nitrogen atmosphere 1.06 g (4.32 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 2.15 g (6.60 mmol) caesium carbonate, 100 mg (0.45 mmol) palladium-(II)-acetate and 280 mg (0.45 mmol) BINAP were stirred in 40 mL xylene for 10 min at RT. 850 muL (5.20 mmol) of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> were added and the mixture was stirred overnight at 120 C. Then the insoluble solid was suction filtered and the filtrate was evaporated down i. vac. The residue was purified by flash chromatography. The combined product fractions were evaporated down i. vac. The residue was stirred with diisopropylether and suction filtered. The solid was dried at 50 C. in the CAD.Yield: 650 mg (38% of theoretical)ESI-MS: m/z=394 (M+H)+ Rf: 0.81 (silica gel, eluant A)
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃;
A mixture of 3- bromo-benzoic acid ethyl ester (229 mg, 1 mmol), 4-methylpiperidine ( 120 mg, 1 .2 mmol ), Pd2(dba)3 (25 mg ), BINAP (25 mg), and fBuONa ( 130 mg ) in toluene (6 mL) was heated at 90 C overnight. After the reaction was completed as indicated by TLC, the mixture was filtered and the filtrate was concentrated in vacuo. Ethyl acetate (50 mL) and aq. HC1 ( I , 20 mL) were then added. The aqueous portion was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered, concentrated, and purified by chromatography to give the title compound (76 mg, 3 1 %).
31%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃;
Step A. 3-(4-Methyl-piperidin-1-yl)-benzoic acid ethyl ester. A mixture of <strong>[24398-88-7]3-bromo-benzoic acid ethyl ester</strong> (229 mg, 1 mmol), 4-methylpiperidine (120 mg, 1.2 mmol), Pd2(dba)3 (25 mg), BINAP (25 mg), and tBuONa (130 mg) in toluene (6 mL) was heated at 90 C. overnight. After the reaction was completed as indicated by TLC, the mixture was filtered and the filtrate was concentrated in vacuo. Ethyl acetate (50 mL) and aq. HCl (1N, mL) were then added. The aqueous portion was extracted with ethyl acetate (2*50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered, concentrated, and purified by chromatography to give the title compound (76 mg, 31%).
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; Selectfluor; trifluoroacetic acid; trifluoroacetic anhydride at 105℃; for 10h;
3,3''-diethyl 4'-methyl [1,1':2',1''-terphenyl]-3,3'',4'-tricarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
The zinc reagent 2c was prepared according to TP1 from methyl3-bromo-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (1c,7.26 g, 20 mmol), Zn-powder (3.92 g, 60 mmol) and InCl3(0.33 g, 1.5 mmol). The reaction mixture was stirred in DMPU(20 mL) at 50 C for 2 h. Iodolysis indicated a yield of 70% bimetallic reagent (14 mmol). The solution containing the zinc reagent was separated from the remaining zinc powder and transferred to a new flask containing a solution of <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (3e, 9.16 g, 40 mmol) and PEPPSI-iPr (0.19 g,0.28 mmol) in THF (20 mL). The reaction mixture was stirred at 50 C for 12 h before being quenched with HCl (2 M, 50 mL). Flash column chromatographical purification on silica gel(pentane/diethyl ether = 4:1) afforded 4e as a colorless oil (3.82 g, 8.83 mmol, 63%).
With bis(bipyridine)nickel(II) bromide; tetrabutylammomium bromide; In ethylene dibromide; N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Electrochemical reaction;
General procedure: To an undivided electrochemical cell, fitted with an iron/nickel (64/36) rod as the anode and surroundedby a nickel foam as the cathode, were added DMF (50 mL), tetrabutylammonium bromide (1.2 mmol, 400mg), and 1,2-dibromoethane (2.5 mmol, 215 muL). The mixture was electrolyzed under argon at a constantcurrent intensity of 0.2 A at room temperature for 15 min. The current was then stopped, and the NiBr2bpycomplex (0.4 mmol, 150 mg), 3-amino- or 3-alkoxy/aryloxy-6-chloropyridazine (4 mmol), and aromatic orheteroaromatic halides (8 mmol) were sequentially added. The solution was electrolyzed at 0.2 A at roomtemperature until one of the starting materials was totally consumed. A saturated aqueous solution of EDTAsodium salt (100 mL) was added to the mixture, and the solution was extracted with dichloromethanecontaining 2-5% methanol (3 × 100 mL). The combined organic layers were dried over MgSO4, filtered,and evaporated under vacuum. The crude product was purified by flash chromatography on silica, elutedwith a gradient of solvents (pentane/acetone). For some polar cross-coupling compounds, a mixture ofacetone/methanol (95/5) was necessary.
With C24H23ClN6O2; In tetrahydrofuran; water; at 20 - 85℃; for 13.5h;Inert atmosphere;
30.1: 6-Cyclopentyl-benzoic acid ethyl ester To 1.00 mL (6.24 mmol) <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> was added 13.0 mL (6.50 mmol) 0.5 M cyclopentylzinc bromide solution in THF followed by 100 mg (0.137 mmol) 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) under argon atmosphere. The reaction mixture was stirred at 85 C. for 1.5 h, then diluted with water and stirred at RT for 12 h. The suspension was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was filtered through Alox (EtOAC) and concentrated in vacuo. yield: 1.10 g (81%) ESI-MS: m/z=219 (M+H)+ Rt(HPLC): 1.73 min (method 7)
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 85℃; for 1.5h;Inert atmosphere;
30.1 : 6-Cyclopentyl-benzoic acid eth l ester To 1.00 mL (6.24 mmol) <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> was added 13.0 mL (6.50 mmol) 0.5 M cyclopentylzinc bromide solution in THF followed by 100 mg (0.137 mmol) Iota , Gamma- bis(diphenylphosphino)ferrocenedichloropalladium(II) under argon atmosphere. The reaction mixture was stirred at 85 C for 1.5 h, then diluted with water and stirred at RT for 12 h. The suspension was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was filtered through Alox (EtOAC) and concentrated in vacuo. yield: 1.10 g (81 %) ESI-MS: m/z = 219 (M+H)+ Rt(HPLC): 1.73 min (method 7)
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 6h;Inert atmosphere;
General procedure: A round-bottomed flask was charged with Pd2(dba)3 (5 mol percent ), ligand (10 molpercent), aryl halide (1mmol), appropriate isoquinolinamine (1 mmol), base (1.5 mmol) and dry solvent (5 mL). Theflask was flushed with argon for 5 min. The mixture was heated at reflux under magnetic stirring.After cooling down to room temperature, the reaction mixture was concentrated and the residuewas purified by flash column chromatography on silica gel.
2-bromo-4-(1,3-dioxolan-2-yl)phenyl trifluoromethanesulfonate[ No CAS ]
[ 1621227-71-1 ]
Yield
Reaction Conditions
Operation in experiment
58%
The zinc reagent 2e was prepared according to TP1 from 2-bromo-4-(1,3-dioxolan-2-yl)phenyl trifluoromethanesulfonate (1e, 5.66 g, 15 mmol), Zn-powder (2.94 mg, 45 mmol) and InCl3(0.25 g, 1.13 mmol). The reaction mixture was stirred in DMPU (15 mL) at 50 C for 2 h. Iodolysis indicated a yield of 60% bimetallic reagent (9.0 mmol). The solution containing the zinc reagent was separated from the remaining zinc powder and transferred to a new flask containing a solution of 1-(4-bromophenyl)ethanone (3h, 5.97 g, 30 mmol) and PEPPSI-iPr(0.14 g, 0.21 mmol) in THF (15 mL). The reaction mixture was stirred at 50 C for 12 h before being quenched with HCl (2 M,30 mL). Flash column chromatographical purification on silica gel (isohexane/diethyl ether = 4:1) afforded 4j as a colorless oil (2.10 g, 5.21 mmol, 58%).
ethyl 3-(1-methyl-3-phenylpyrrolo[1,2-a]pyrazin-6-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 16h;
General procedure: A mixture of 3a (0.26 mmol), 4-bromonitrobenzene (2.5 equiv), (PPh3)2PdCl2 (5 mol %), and KOAc (2 equiv) in DMA (1 mL) was stirred at 150 C for 16 h. After the reaction was complete, the residue was diluted with ethyl acetate (2 mL) and washed with water (2 mL). The water layer was extracted with ethyl acetate (2 mL) one more time. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane=30:1:2 to 10:1:2) to give 4a (71.3 mg, 87%).
ethyl 3-(3-phenylpyrrolo[1,2-a]pyrazin-6-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 16h;
General procedure: A mixture of 3a (0.26 mmol), 4-bromonitrobenzene (2.5 equiv), (PPh3)2PdCl2 (5 mol %), and KOAc (2 equiv) in DMA (1 mL) was stirred at 150 C for 16 h. After the reaction was complete, the residue was diluted with ethyl acetate (2 mL) and washed with water (2 mL). The water layer was extracted with ethyl acetate (2 mL) one more time. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane=30:1:2 to 10:1:2) to give 4a (71.3 mg, 87%).
3-(4-methoxyphenyl)pyrrolo[1,2-a]pyrazine[ No CAS ]
ethyl 3-(3-(4-methoxyphenyl)pyrrolo[1,2-a]pyrazin-6-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 16h;
General procedure: A mixture of 3a (0.26 mmol), 4-bromonitrobenzene (2.5 equiv), (PPh3)2PdCl2 (5 mol %), and KOAc (2 equiv) in DMA (1 mL) was stirred at 150 C for 16 h. After the reaction was complete, the residue was diluted with ethyl acetate (2 mL) and washed with water (2 mL). The water layer was extracted with ethyl acetate (2 mL) one more time. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane=30:1:2 to 10:1:2) to give 4a (71.3 mg, 87%).
3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazine[ No CAS ]
ethyl 3-(3-(4-fluorophenyl)pyrrolo[1,2-a]pyrazin-6-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 16h;
General procedure: A mixture of 3a (0.26 mmol), 4-bromonitrobenzene (2.5 equiv), (PPh3)2PdCl2 (5 mol %), and KOAc (2 equiv) in DMA (1 mL) was stirred at 150 C for 16 h. After the reaction was complete, the residue was diluted with ethyl acetate (2 mL) and washed with water (2 mL). The water layer was extracted with ethyl acetate (2 mL) one more time. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane=30:1:2 to 10:1:2) to give 4a (71.3 mg, 87%).
3-(4-chlorophenyl)pyrrolo[1,2-a]pyrazine[ No CAS ]
ethyl 3-(3-(4-chlorophenyl)pyrrolo[1,2-a]pyrazin-6-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 16h;
General procedure: A mixture of 3a (0.26 mmol), 4-bromonitrobenzene (2.5 equiv), (PPh3)2PdCl2 (5 mol %), and KOAc (2 equiv) in DMA (1 mL) was stirred at 150 C for 16 h. After the reaction was complete, the residue was diluted with ethyl acetate (2 mL) and washed with water (2 mL). The water layer was extracted with ethyl acetate (2 mL) one more time. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane=30:1:2 to 10:1:2) to give 4a (71.3 mg, 87%).
With N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 80℃; for 1h;
A solution of 1, 4-dioxane (250 mL) was degassed for 30 mm and to this were added <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> A-2 (6.7 g, 43.6 mmol) in 1, 4-dioxane (30 mL), (4-methoxyphenyl) methanethiol A-i (10 g, 43.6 mmol), xantphos (1.2 g, 2.18 mmol), Pd2(dba)3 (990 mg, 1.09 mmol), DIPEA (16 mL, 87.3 mmol) at RT. The reaction was heated to 80 C and stirred for 1 h. The reaction progress was monitored by TLC. After reaction completion, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude material. The crude material was purified through silica gel flash column chromatography using 3% EtOAc/ Hexanes to afford compound A-3 (10 g, 77%) as pale green semi-solid. 1H NMR (500 MHz, CDC13): oe 7.98 (s, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.44-7.41 (m, 1H), 7.32-7.28 (m, 1H), 7.25-7.10 (m, 2H), 6.81 (d, J= 9.0 Hz, 2H), 4.38-4.34 (m, 2H), 4.11 (s, 2H), 3.80 (s, 3H), 1.38 (t,J 7.0 Hz, 3H).
1-(6-(dibutyl(3-(ethoxycarbonyl)phenyl)stannyl)hexyl)-3-ethyl-1H-imidazol-3-ium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
1-(6-(dibutyl(3-(ethoxycarbonyl)phenyl)stannyl)hexyl)-3-ethyl-1H-imidazol-3-ium bromide I'a-14(Br-) A dried 50 mL Schlenk tube was flushed with argon and charged with zinc dust (1.36 g, 20.8 mmol, 5 eq) and cobalt(II) bromide (0.095 g, 0.4190.434 mmol, 0.1 eq). The mixture was activated under vacuum at 150C during 4 h. Acetonitrile (5 mL) was added to the cooled mixture then trifluoroacetic acid (0.15 mL) and 1,2-dibromoethane (0.1 mL) were added and the resulting solution stirred for additional 15 minutes (an increase of temperature was observed). Then <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (1.46 g, 6.36 mmol, 6.3 eq) was introduced to the mixture which was stirred at room temperature for 12 h. The resulting solution of arylzinc reagent was introduced dropwise to the ionic liquid (Va-1) (529 mg, 1.0 mmol, 1 eq) in solution in THF (6 mL). After 18 h of stirring at room temperature, the resulting mixture was filtered through a short pad of silica gel then extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (CH2Cl2 to CH2Cl2/MeOH 90:10) to afford compound I'a-14(Br-) as viscous yellow oil (450 mg, 70 %). 1H NMR (CDCl3): delta 10.17 (s, 1H), 8.14 (bs, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.39 (dd, J = 7.5 Hz, J = 7.5 Hz, 1H), 7.30 (bs, 1H), 7.23 (bs, 1H), 4.48-4.33 (m, 4H), 4.32 (t, 2H, J = 7.2 Hz), 1.89-1.78 (m, 2H), 1.61-1.47 (m, 9H), 1.42-1.24 (m, 11H), 1.13-1.00 (m, 6H), 0.87 (t, J = 7.2 Hz, 6H). 13C NMR 75 MHz (CDCl3) delta (ppm): 166.8, 141.9, 140.6, 136.9, 135.9, 129.4, 128.8, 127.5, 122.0, 121.8, 60.6, 49.8, 45.1, 33.4, 30.0, 28.7, 27.0, 26.3, 25.5, 15.5, 14.4, 13.4, 9.4, 9.3. HRMS (FAB) calcd. for C28H47N2O2Sn 563.2654 [M-Br]+; found 563.2675.
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; In tetrahydrofuran; diethyl ether; decane; at 60℃; for 12h;Inert atmosphere; Schlenk technique;
General procedure: PEPPSI-IPr10 (27 mg, 4 mol%) and aryl halide or acid chloride (0.6-0.7 equiv) were added sequentially to the prepared arylzinc reagent and the reaction mixture was stirred at 60 C under nitrogen. After 12 h, the reaction mixture was quenched with sat. aq NH4Cl (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EtOAc and isohexane) to give the analytically pure product.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; cesium fluoride; In 1,2-dimethoxyethane; at 80℃; for 7h;Inert atmosphere; Schlenk technique;
Ethyl 4'-ethoxybiphenyl-3-carboxylate (3) A 20 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged consecutively with 100.0 mg (70 muL, 0.437 mmol, 1.0 eq) <strong>[24398-88-7]ethyl-3-bromobenzoate</strong>, 72.5 mg (0.437 mmol, 1.0 eq) 4-ethoxyphenylboronic acid, 139.3 mg (0.917 mmol, 2.1 eq) CsF, 17.8 mg (0.022 mmol, 0.05 eq) PdCl2(dppf)*DCM and 5.0 mL DME. The orange suspension was degassed by vacuum/N2 cycles and stirred at 80 C. for 7 h. GC-MS analysis indicated full conversion (98% product) of the starting material. The reaction mixture was filtered through a pad of celite which was rinsed with EtOAc. The solvent from the filtrate was removed under reduced pressure and final purification by column chromatography (CH/EtOAc 15:1, size: 12.5*2.0 cm, 15 g silica gel) yielded the pure product. yield: 109.5 mg (93%); colorless solid; M.p.: 46-47 C.; Rf (CH/EtOAc 15:1): 0.40; 1H-NMR (300 MHz, CDCl3): delta (ppm)=delta (ppm)=8.25 (t, 4J=1.5 Hz, 1H, Ar-H), 7.98 (d, 3J=7.8 Hz, 1H, Ar-H), 7.74 (d, 3J=7.8 Hz, 1H, Ar-H), 7.56 (d, 3J=9.0 Hz, 2H, Ar-H), 7.48 (t, 3J=7.8 Hz, 1H, Ar-H), 6.98 (d, 3J=9.0 Hz, 2H, Ar-H), 4.41 (q, 3J=7.2 Hz, 2H, CH2), 4.09 (q, 3J=6.9 Hz, 2H, CH2), 1.47-1.39 (m, 6H, 2 CH3); 13C-NMR (75.5 MHz, CDCl3): delta (ppm)=166.6 (C=O), 158.8 (Cq), 141.0 (Cq), 132.5 (Cq), 131.0 (Cq), 130.9 (CHAr), 128.7 (CHAr), 128.2 (2 CHAr), 127.7 (CHAr), 127.6 (CHAr), 114.8 (2 CHAr), 63.8 (CH2), 61.0 (CH2), 14.8 (CH3), 14.3 (CH3); GC-MS (NM-50_S2): tR=7.796 min (m/z=270.1, 99% M+, BP); HRMS (EI+): m/z: calcd for C17H18O3 [M]+: 270.1256; found 270.1260.
ethyl 3-[4-(dimethylamino)phenyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; cesium fluoride; In 1,2-dimethoxyethane; at 80℃; for 26h;Inert atmosphere; Schlenk technique;
Ethyl 4?-(dimethylamino)biphenyl-3-carboxylate (4) (0159) (0160) A 25 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged consecutively with 150.0 mg (0.1 mL, 0.655 mmol, 1.0 eq) <strong>[24398-88-7]ethyl-3-bromobenzoate</strong>, 107.9 mg (0.655 mmol, 1.0 eq) 4-(dimethylamino)phenylboronic acid, 208.9 mg (1.375 mmol, 2.1 eq) CsF, 26.7 mg (0.033 mmol, 0.05 eq) PdCl2(dppf)*DCM and 7.5 mL DME. The orange suspension was degassed by vacuum/N2 cycles and stirred at 80 C. for 26 h. GC-MS analysis indicated full conversion (86% product) of the starting material. The reaction mixture was filtered through a pad of celite which was rinsed with EtOAc. The solvent from the filtrate was removed under reduced pressure and final purification by column chromatography (CH/EtOAc 19:1, size: 14.0×2.0 cm, 25 g silica gel) yielded the pure product. (0161) yield: 135.9 mg (77%); colorless solid; M.p.: 79-81 C.; Rf (CH/EtOAc 19:1): 0.24; 1H-NMR (300 MHz, CDCl3): delta (ppm)=8.26 (s, 1H, Ar-H), 7.94 (d, 3J=7.8 Hz, 1H, Ar-H), 7.74 (d, 3J=7.8 Hz, 1H, Ar-H), 7.55 (d, 3J=9.0 Hz, 2H, Ar-H), 7.46 (t, 3J=7.8 Hz, 1H, Ar-H), 6.82 (d, 3J=9.0 Hz, 2H, Ar-H), 4.41 (q, 3J=7.2 Hz, 2H, CH2), 3.01 (s, 6H, 2 CH3), 1.42 (t, 3J=7.2 Hz, 3H, CH3); 13C-NMR (75.5 MHz, CDCl3): delta (ppm)=166.8 (C?O), 150.2 (Cq-N(CH3)2), 141.4 (Cq), 130.8 (Cq), 130.4 (CHAr), 128.6 (CHAr), 128.0 (Cq), 127.7 (2 CHAr), 127.2 (CHAr), 127.0 (CHAr), 112.7 (2 CHAr), 60.9 (CH2), 40.5 (N(CH3)2), 14.4 (CH3); GC-MS (NM-50_S2): tR=8.288 min (m/z=269.1, 99% M+, BP).
With sodium carbonate; tris-(o-tolyl)phosphine; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran; water at 20℃; for 18h; Sealed tube; Inert atmosphere;
Under nitrogen, 1,3-dibromobenzene (30.0 g, 127 mmol)Was dissolved in THF (tetrahydrofuran)After dissolving in 300 mL, nBuLi (2.5M) 140 mmol, 56.0 mL was added and stirred at -78 C for 1 hourEthyl-3-bromobenzoate (26.2 g, 114 mmol) is added with a small amount of solvent. After 10 hours, the reaction mixture was slowly warmed to room temperature, quenched with NH4Cl, and extracted with ethyl acetate.The resulting organic solvent layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. This was subjected to column chromatography using ethyl acetate: hexane (EA: Hx) to obtain 21.0 g of [intermediate 1-1] (yield = 49%).
49%
1,3-Dibromobenzene (30.0 g, 127 mmol) was dissolved in 300 mL of THF (tetrahydrofuran) under nitrogen, 140 mmol of nBuLi (2.5 M) (56.0 mL) was added and stirred at -78 C for 1 hour. Ethyl 3-Bromobenzoate (26.2 g, 114 mmol) was added with a small amount of solvent. After 10 hours, the temperature was gradually raised to room temperature, and the residue was extracted with NH4Cl and extracted with ethyl acetate (EA). The resulting organic solvent layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. This was subjected to column chromatography with EA: Hx to obtain 21.0 g (yield = 49%) of [intermediate 1-1].
ethyl 3-[6-(diethylamino)pyridazin-3-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With bis(bipyridine)nickel(II) bromide; tetrabutylammomium bromide; In ethylene dibromide; N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Electrochemical reaction;
General procedure: To an undivided electrochemical cell, fitted with an iron/nickel (64/36) rod as the anode and surroundedby a nickel foam as the cathode, were added DMF (50 mL), tetrabutylammonium bromide (1.2 mmol, 400mg), and 1,2-dibromoethane (2.5 mmol, 215 muL). The mixture was electrolyzed under argon at a constantcurrent intensity of 0.2 A at room temperature for 15 min. The current was then stopped, and the NiBr2bpycomplex (0.4 mmol, 150 mg), 3-amino- or 3-alkoxy/aryloxy-6-chloropyridazine (4 mmol), and aromatic orheteroaromatic halides (8 mmol) were sequentially added. The solution was electrolyzed at 0.2 A at roomtemperature until one of the starting materials was totally consumed. A saturated aqueous solution of EDTAsodium salt (100 mL) was added to the mixture, and the solution was extracted with dichloromethanecontaining 2-5% methanol (3 × 100 mL). The combined organic layers were dried over MgSO4, filtered,and evaporated under vacuum. The crude product was purified by flash chromatography on silica, elutedwith a gradient of solvents (pentane/acetone). For some polar cross-coupling compounds, a mixture ofacetone/methanol (95/5) was necessary.
(1-vinyl-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate[ No CAS ]
[ 24398-88-7 ]
(E)-ethyl 3-(2-(4-(acetoxymethyl)-2-oxabicyclo[2.2.2]octan-1-yl)vinyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; potassium acetate; In N,N-dimethyl-formamide; at 110℃; for 18h;Inert atmosphere; Sealed tube;
To a stirred solution of (1-vinyl-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (60 mg, 0.19 mmol) (ACS Med Chem. Lett., 2014, 5, 609-614) in DMF (2 mL) were added <strong>[24398-88-7]ethyl 3-bromobenzoate</strong> (47 mg, 0.21 mmol), potassium acetate (46 mg, 0.47 mmol) and tetrabutylammonium bromide (60 mg, 0.19 mmol). The reaction mixture was purged with nitrogen for 10 min, after which time tetrakis(triphenylphosphine) palladium(0) (22 mg, 0.019 mmol) was added. The vial was sealed and the mixture was stirred at 110 C. After 18 h, the reaction mixture was cooled to rt and concentrated. The crude product was purified by flash column chromatography (24 g silica gel cartridge; A=Hex, B=EtOAc; 15 min grad.; 0% B to 40% B; flow rate=24 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (50 mg, 0.13 mmol, 71% yield, colorless semisolid). 1H NMR (300 MHz, CHLOROFORM-d) delta 8.05 (s, 1H), 7.89 (d, J=7.80 Hz, 1H), 7.53 (d, J=8.10 Hz, 1H), 7.39-7.34 (m, 1H), 6.57 (d, J=16.20 Hz, 1H), 6.26 (d, J=16.20 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 2H), 2.07 (s, 3H), 2.07-1.61 (m, 6H), 1.40-1.26 (m, 4H). MS (ESI) 359 (M+H).
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