* 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 N-ethyl-N,N-diisopropylamine In dichloromethane at -60℃; Inert atmosphere Stage #2: With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran-d8 for 8 h; Inert atmosphere; Reflux
Example 1 Compound 3 (36.0 g, 0.19 mol) was dissolved in 190 mL of methylene chloride under a nitrogen atmosphere,Diisopropylethylamine (27.0 g, 0.21 mol) was added and the temperature was lowered to -60 ° C. Trifluoromethanesulfonic anhydride (59.2 g,0.21 mol) was added and reacted at this temperature. After the reaction, water was added, the temperature was raised to room temperature, the mixture was extracted with ethyl acetate, and saturated sodium bicarbonateAfter washing and drying of the organic phase, the solvent was distilled off under reduced pressure to give 44.5 g of compound 3 as a light yellow solid. Example 2 A mixture of compound 3 (39.0 g, 0.12 p-nitrophenyl boronate mol) under nitrogen was added 130 mL of tetrahydrofuranAfter dissolution, (31.4 g, 0.13 mol), palladium tetrakistriphenylphosphine (6.9 g, 6.0 mmol), potassium carbonate(33.1 g, 0.13 mol) and heated to reflux temperature and reacted at this temperature for 8 hours, after which time the system was lowered to roomThe reaction solution was filtered through celite and the filtrate was evaporated under reduced pressure to a partial solvent, the crystals precipitated at low temperature, filtered to give a mixture of compounds 5,6The compound was 37.5 g as a light brown solid. Example 3 In an autoclave, 110 mL of methanol was added to a mixture of compounds 5 and 6 (19.0 g, 0.065 mol), 30 mL of acetic acid was added, 1.5 g of palladium hydroxide was added,After the introduction of hydrogen, after 12 at atmospheric pressure for 24 hours, after the reaction,The solid was filtered off and most of the methanol in the filtrate was evaporated under reduced pressure. 130 mL of 1 mL sodium hydroxide solution was added and the mixture was stirred for 20 minutes.The mixture was extracted twice with ethyl acetate (2 * 100 mL), the organic phase was washed once with saturated citric acid (100 mL) and the organic phase was washed with anhydrous sodium sulfateDrying, the organic phase pressure steaming to give a pale yellow solid 9.3g.
Reference：
[1] Patent: CN106749180, 2017, A, . Location in patent: Paragraph 0042; 0043; 0044; 0045; 0046; 0047
2
[ 624-38-4 ]
[ 171364-83-3 ]
[ 29170-08-9 ]
[ 3282-11-9 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 9, p. 3730 - 3733
3
[ 100-01-6 ]
[ 73183-34-3 ]
[ 171364-83-3 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With hydrogenchloride; methanol; sodium nitrite In water at 0 - 5℃; for 0.5 h; Green chemistry Stage #2: at 20℃; for 1 h; Green chemistry
General procedure: To a solution of arylamine (0.5 mmol, 1.0 equiv) in MeOH(1.0 mL) was added HCl (0.5 mL, 1.5 mmol, 3.0 equiv) followed by H2O (0.5 ml). This mixture was stirred 2 min, and the NaNO2 solution (0.25 mL) was then added. The NaNO2 solution was prepared by dissolving 35 mg of NaNO2 in H2O (0.25 mL). This mixture was stirred 30 minat 0–5 °C followed by B2pin2 (2, 381 mg, 1.5 mmol, 3.0equiv) in MeOH (1.0 mL). This mixture was stirred 60 min.H2O (10 mL) was added to the reaction mixture, then extracted with CH2Cl2 (50 mL, 3×). The combined organic layers were washed with sat. NaHCO3, dried over Na2SO4, followed by evaporation, and the crude residue was purified by flash chromatography.
91%
With tert.-butylnitrite; eosin In acetonitrile at 20℃; for 2 h; Irradiation
General procedure: tert-Butyl nitrite (155 mg, 1.1 mmol) wasadded drop wise to a mixture of bis(pinacolato)diborane (127 mg, 0.5 mmol),4-anisidine (61 mg, 0.5 mmol) and eosin Y (0.01 mmol) in acetonitrile (3 mL).The resulting mixture was stirred at room temperature under irradiation withblue LED for 2 h (TLC). This mixture after being diluted with ethyl acetate(5 mL) was ltered through celite and the ltrate was extracted with ethylacetate (3 10 mL). The extract was washed with brine, dried over anhydrousNa 2 SO 4 , and evaporated to leave the crude product which was puried bycolumn chromatography over silica gel with hexane–ethyl acetate (98:2) aseluent to furnish pure 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a light yellow viscous liquid (3d, 208 mg, 88percent); IR (neat)2978, 2933, 2839, 2526, 2050, 1950, 1911, 1724, 1605, 1570 cm1;1H NMR(500 MHz, CDCl 3 ) d 1.33 (s, 12H), 7.82 (s, 3H), 6.89 (d, J = 8.0 Hz, 2H), 7.75 (d,J = 8.0 Hz, 2H);13C NMR (125 MHz, CDCl 3 ) d 24.9 (4C), 55.2, 83.6 (2C), 113.4(2C), 136.6 (2C), 162.3. The spectroscopic data is in full agreement with thosereported for an authentic sample.14This procedure was followed for all thereactions listed in Table 2. All of these products (3a,143b,143c,16a3d,143e,143f,8a3g,143h,143i,143j,8a3k,8a3l,8a3m,143n,8c3o,16b) are known compounds,and their spectroscopic data are in agreement with those previously reported.
73%
Stage #1: With fluoroboric acid; sodium nitrite In water at 0℃; for 1 h; Inert atmosphere; Schlenk technique Stage #2: at 22 - 25℃; for 36 h; Inert atmosphere; Schlenk technique; Sealed tube
General procedure: An arylamine (50 mmol) was dissolved in 50percent hydrofluoroboric acid(17 mL) and water (20 mL). After cooling the reaction mixture to 0 °C, a solution of sodium nitrite (3.4 g in 7.5 mL water) was added dropwise to the reaction system (over 5 min). The resulting mixture was stirred for 1h and the precipitate was collected by filtration. It was redissolved in the minimum amount of acetone and then diethyl ether was added to precipitate the aryl diazonium tetrafluoroborate. The product was filtered, washed with diethyl ether and dried under reduced pressure. Borylation of aryldiazonium salts; general procedure The aryldiazonium salt (0.5 mmol) and (Bpin)2 (0.75 mmol) were added to an oven-dried Schlenk tube. The tube was evacuated and backfilled with argon (three times). CH3OH (0.8 mL) was added to this Schlenk tube. The tube was sealed and the mixture was stirred at room temperature (22–25 °C) for 36 h. After evaporation of the solvent, the residue was purified by column chromatography to afford the product.The arylboronates were purified by chromatography on a silica column eluting with petroleum ether (boiling range 60–90 °C) or a petroleumether/ethyl acetate mixture (ca. 60:1) by volume giving Rf values for the boronates of ca. 0.2–0.3.
66%
Stage #1: With tetrafluoroboric acid; sodium nitrite In water at 0℃; for 1 h; Stage #2: at 20℃; Sealed tube
General procedure: Aryl amine (10 mmol) was dissolved in a mixture of 5 mL of distilled water and 3.4 mL of 50percent hydrofluoroboric acid. After cooling the reaction mixture to 0 °C using ice bath and the sodium nitrite (0.69 g in 2 mL distilled water), was added dropwise in 5 min interval of time. The resulting mixture was stirred for 1 h and the precipitate was collected by filtration and redissolved in minimum amount of acetone. Diethylether was added until precipitation of aryl diazonium tetrafluoroborate, which is filtered, washed several times with diethyl ether and dried under vacuum. Typical reaction procedure: General procedure: Diazonium tetrafluoroborate salts (0.5 mmol) and B2pin2 (1.5 mmol) were transferred into an oven-dried tube under air. Then acetone/H2O (2/1, 4 mL) were added into the tube via syringe. The sealed tube was keep at 20 °C and stirred for 1-2 h. After the reaction was complete, dichloromethane was added to extract the product and the combined organic solution was dried by Na2SO4. The pure product was isolated after column chromatography on silica gel (petroleum ether/ethyl acetate).
65%
Stage #1: With tetrafluoroboric acid; sodium nitrite In water at 0℃; for 1.08333 h; Stage #2: With triphenylphosphine In acetonitrile at 20℃; for 18 h; Inert atmosphere; Schlenk technique
The arylamine (10 mmol) was dissolved in a mixture of 5 mL of distilled water and 3:4 mL of 50percent tetrafluoroboric acid. After cooling the reaction mixture to 0 °C in an ice bath, sodium nitrite (0:69 g in 2 mL of distilled water ) was added dropwise within 5 min. The resulting mixture was stirred for 1 h, and the precipitate was collected by filtration and redissolved in the minimum amount of acetone. Diethyl ether was added until precipitation of the arenediazonium tetrafluoroborate, which was filtered, washed several times with diethylether, and dried under vacuum. An arenediazonium salt (1:5 mmol), bis(pinacolato)diborane(1 mmol) and PPh3 (2:0 eq.) were weighed in a 25 LSchlenk round bottom flask under nitrogen atmosphere. Then 3 mL of acetonitrile was added by syringe. The resulting solution was stirred at room temperature. The reaction progress was monitored by GC-MS. After the completion of the reaction,the solution was filtered though a short column of silica gel and the column washed with ethyl acetate. The filtrate was concentrated under reduced pressure to leave a crude product, which was purified by flash column chromatography on silica gel to afford the final products.
1.4 g
With tert.-butylnitrite; dibenzoyl peroxide In acetonitrile at 25℃; for 4 h; Inert atmosphere
Under argon, 1.38 g p-nitroaniline, 2.54 gBoronic acid pinacol ester and49 mg of benzoyl peroxide The acid was added to 60 mL of acetonitrile at a controlled temperature of 25 ° C,Then, 1.55 g of t-butyl nitrite was dissolved in 10 mL of acetonitrile and added dropwise to the above system. After 4 h reaction, the reaction was carried out and dried to petroleum ether: ethyl acetate = 20: 1 as developing solvent Column chromatography to give pale yellow solid 11 (1.4 g); 1 g of the above pale yellow solid was added to a 25 mL shurenk Followed by the addition of 2.24 g of 9,9 dioctane dibromofluorene, 6 mL of potassium carbonate solution (2 mol / L), 20 mg of tetrakis (triphenylphosphine) palladium And 9 mL of tetrahydrofuran, followed by double-tube freezing - pumping - inflated three times, at 80 for 12 h reaction, after the end of the reaction, Extraction with methylene chloride followed by column chromatography using pure petroleum ether as developing solvent gave a yellow solid, compound E (1.95g)
Reference：
[1] Synlett, 2014, vol. 25, # 11, p. 1577 - 1584
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 10, p. 1846 - 1849
[3] Angewandte Chemie - International Edition, 2010, vol. 49, # 10, p. 1846 - 1849
[4] Tetrahedron Letters, 2016, vol. 57, # 14, p. 1551 - 1554
[5] Synlett, 2012, vol. 23, # 9, p. 1394 - 1396
[6] Journal of Organic Chemistry, 2013, vol. 78, # 5, p. 1923 - 1933
[7] Journal of Organic Chemistry, 2014, vol. 79, # 5, p. 1979 - 1988
[8] Journal of Chemical Research, 2018, vol. 42, # 9, p. 481 - 485
[9] Tetrahedron Letters, 2017, vol. 58, # 40, p. 3851 - 3853
[10] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2014, vol. 69, # 9-10, p. 982 - 986
[11] Organic Syntheses, 2014, vol. 91, p. 106 - 115
[12] Patent: CN107253920, 2017, A, . Location in patent: Paragraph 0022; 0027
4
[ 456-27-9 ]
[ 73183-34-3 ]
[ 171364-83-3 ]
Yield
Reaction Conditions
Operation in experiment
49%
With eosin y In neat (no solvent, solid phase) for 2 h; Milling; Irradiation
General procedure: A mixture of 1 (0.369 mmol), 2 (0.369 or 0.554 mmol) and eosin Y (11.96 mg; 5 mol percent)was mixed in a 25 mL PMMA milling jar with 15 ZrO2 balls of 5 mm in diameter at 25 Hz.Irradiation of the reaction mixture was achieved by wrapping the milling jar with a greenLED strip (90 cm; see picture in section 2). After the milling was stopped, the reactionmixture was recovered from the milling jar and the product was purified by columnchromatography (SiO2, eluent 100:1 n-pentane/ethyl acetate).
Reference：
[1] ChemistryOpen, 2017, vol. 6, # 3, p. 345 - 349
[2] Organic Letters, 2003, vol. 5, # 24, p. 4635 - 4638
[3] Advanced Synthesis and Catalysis, 2012, vol. 354, # 14-15, p. 2625 - 2628
[4] Tetrahedron Letters, 2000, vol. 41, # 45, p. 8683 - 8686
[5] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 1463 - 1469
5
[ 636-98-6 ]
[ 73183-34-3 ]
[ 171364-83-3 ]
Yield
Reaction Conditions
Operation in experiment
45%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; triethylamine In 1,4-dioxane at 80℃; for 48 h; Inert atmosphere; High pressure
4-Iodo-nitrobenzene (4 mmol) was added into a high pressure bottle containing the catalyst of bis(triphenylphosphine) palladium(II) chloride (50 mg), followed by the addition of 35 mL of dioxane 12 mmol of CH3COOK and bis(pinacolato)diboron (4.8 mmol). The bottle was sealed after bubbling for 10 min with nitrogen. After keeping the system under ~80 C for 48 h, the system was cooled to room temperature and then extracted twice with CH2Cl2/H2O. The solvent was dried using MgSO4 and then evaporated in vacuum.The residue was chromatographed on silica gel by hexane/ethylacetate 4:1 (Rf ~0.5) and recrystallized from acetone/hexane to produce a yellow solid (yield: 45percent). Data for 2a: 1H NMR (400 Hz,CDCl3): d 8.20 (d, J 8 Hz, 2H), 7.97 (d, J 8 Hz, 2H), 1.23 (s, 12H).
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1381 - 1385
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1381 - 1385
[3] Dyes and Pigments, 2015, vol. 112, p. 34 - 41
6
[ 586-78-7 ]
[ 73183-34-3 ]
[ 171364-83-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With meso-tetra(p-tolyl)porphinato-palladium(II); potassium acetate In 1,4-dioxane at 110℃; for 5 h;
General procedure: Aryl/heteroaryl bromide 1 (1 mmol), B2pin2(2), B2npg2(4) orBpin (6, 1.2 mmol), and dioxane (5 mL) are taken into a 25 mLround-bottomed flask. KOAc (2 mmol) was added and stirredthe resultant mixture at room temperature for 5 min, PdII-TpTP(0.15 molpercent) was added, and the contents were refluxed on preheatedoil bath at 110 °C under constant stirring in open-air.The reaction progress was ensured by TLC. After completion ofthe reaction, the mixture was cooled, dilute with water (20 mL)and extracted with tertbutylmethyl ether (3 × 10 mL). The combinedn-hexane layers were concentrated, and the crudeproduct obtained was purified by column chromatography (CC)on silica gel using a mixture of ethyl acetate and hexane (1:30)as eluent.
66%
With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 80℃; for 2 h;
1-bromo-4-nitrobenzene (1equi), Bis-pinacoloto Diborane(1.2equi), potassium acetate (3equi) and Pd (OAc)2 (0.05equi) were taken in DMF. Resulting reaction mixture was heated at 80 0C for 2 h and progress of reaction monitored by TLC in ethyl acetate- petroleum ether mixture. Resulting reaction mixture was poured in ice cold water and extracted with ethyl acetate. Organic layer washed by fresh water and brine, dried on Na2SO4 and concentrated under reduced pressure to afford crude product, which was purified by silica gel (100-200 No.) column chromatography in 10percent ethyl acetate petroleum ether as eluent to obtain a title compound as yellow solid. Yield 66percent, mp 118-120 0C; 1H NMR (DMSO-d6, 300MHz, δ ppm): 8.22 (d, 2H, J = 5.1 Hz), 7.92 (d, 2H, J = 4.8 Hz), 1.32 (s, 12H); MS (APCI); m/z 250 [M+1] +; HPLC; 96percent.
65%
With potassium acetate In dimethyl sulfoxide at 90℃; for 19 h;
In air, a vial was charged with Ih (10.2 mg, 0.015 mmol, 3 mol percent), bis(pinacolato)diboron (0.1397 g, 0.55 mmol) and KOAc (0.147 g, 1.5 mmol). The vial was sealed and purged with argon. Bromobenzene (52 μL, 0.5 mmol) and 3 mL of DMSO were then added. The resulting mixture was then stirred at 90° C. until the reaction was complete. The product was extracted into ether, separated and dried over MgSO4. The product was purified by column chromatography. Results for various substrate scope and reaction conditions are presented in Table 9.
54%
With potassium acetate; palladium diacetate In N,N-dimethyl-formamide at 80℃; for 2 h; Inert atmosphere
Under N2 atmosphere, bis(pinacolato)diboron (4.53g, 17.82mmol), potassium acetate (4.37g, 44.55mmol) andpalladium acetate (0.17g, 0.74mmol) were added respectively to a solution of 1-bromo-4-nitrobenzene (3.0g, 14.85mmol)in DMF (10mL). The mixture was stirred at 80°C for 2hrs, followed by adding water (20mL) and EA (20mL), the organicphase was in turn washed with water (10mL33) and saturated brine (lOmL), dried over anhydrous magnesium sulfate,filtered, concentrated under reduced pressure. The residue was purified by silica column chromatography (PE:EA =10:1) to give compound 13-e (2g, yield 54percent). LC-MS (ESI): m/z = 250 [M+H]+.
48%
With potassium acetate; palladium diacetate In 1,4-dioxane at 50℃; Inert atmosphere
In the reaction flask was added 250mL of starting material 4-nitro-bromobenzene (2.029,10.0mmol), with 70mL of 1,4-dioxane was dissolved completely, adding borate pinacol ester-linked (2.9g, 11.4mmol), acetic acid palladium (71mg, 0.3mmol) and potassium acetate (3.01 g, 30.6mmol); N2Replacement.The mixture was stirred and heated to 50 , maintained at this temperature, the reaction overnight.End of the reaction monitored by TLC. After completion of the reaction, subjected to suction filtration with Celite bedding.Was added to the filtrate, 50mL water and 120mL ethyl acetate extract separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure after column chromatography, to obtain the TM1 intermediate 1.2g, 48percent yield.
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 6, p. 977 - 983
[2] ChemCatChem, 2014, vol. 6, # 5, p. 1340 - 1348
[3] Synlett, 2018, vol. 29, # 8, p. 1055 - 1060
[4] Advanced Synthesis and Catalysis, 2010, vol. 352, # 11-12, p. 2002 - 2010
[5] Applied Organometallic Chemistry, 2011, vol. 25, # 7, p. 537 - 541
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 10, p. 3445 - 3448
[7] Patent: US2007/73055, 2007, A1, . Location in patent: Page/Page column 15; 25
[8] Patent: EP3275867, 2018, A1, . Location in patent: Paragraph 0161
[9] Patent: CN103848814, 2016, B, . Location in patent: Paragraph 0320-0322
[10] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 536 - 539
7
[ 98-74-8 ]
[ 73183-34-3 ]
[ 171364-83-3 ]
Yield
Reaction Conditions
Operation in experiment
78%
With dipotassium hydrogenphosphate In acetonitrile at 20℃; for 24 h; UV-irradiation
To a 25 mL reaction tube was added 2 mL of acetonitrile, 4-methylbenzenesulfonyl chloride (66.3 mg, 0.3 mmol), boronic acid pinacol ester (114.3 mg, 0.45 mmol), dipotassium hydrogen phosphate (104.4 mg, 2.0 eq.) , And the reaction tube was irradiated with an ultraviolet lamp, and the reaction was carried out by stirring at room temperature for 24 hours.After the reaction was completed, most of the solvent was distilled off under reduced pressure, and the remaining mixture was purified by column chromatography on petroleum ether / ethyl acetate (10: 1) as eluent to obtain the desired product as a yellow solid , 58.3 mg, yield 78percent.
Reference：
[1] Patent: CN105859761, 2016, A, . Location in patent: Paragraph 0029-0031
8
[ 76-09-5 ]
[ 22092-92-8 ]
[ 456-27-9 ]
[ 171364-83-3 ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: With ferrocene In acetonitrile at 20℃; for 2.5 h; Stage #2: With methanol In acetonitrile at 0 - 20℃; for 1 h; Stage #3: at 20℃; for 4 h;
Example 3: General procedure D for the synthesis of the arylpinacolboronates by arylation of diisopropylaminoborane, catalysed by ferrocene (1percent), followed by methanolysis and transesterification In a dried tube reactor under argon as described in example 2, the arenediazonium salt (1 mmol) and the ferrocene (ΙΟμιηοΙ, 1.8mg) were dissolved in 2mL of anhydrous CH3CN. Diisopropylaminoborane (2mmol, 226mg) was then added to the solution and the mixture was stirred for 2h30 at room temperature. The reaction mixture was quenched by a slow addition of anhydrous MeOH at 0°C (2mL) and stirred for an additional hour at room temperature. After removal of all the volatiles, 1.3eq of pinacol was added in Et20 (2mL), the mixture was stirred 4h at room temperature. The crude mixture was washed with a 50g/L CuCl2 solution (2 x 5mL). The organic layer were separated, dried over Na2S04, filtered and concentrated to dryness. The resulted oil was dissolved with CH2C12 and filtered of a pad of silica gel, eluting with CH2C12 to afford the corresponding boronate. Example 9: synthesis of 2-(4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [CAS 171364-83-3], compound VI6. 176 mg of 2-(3-iodophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane were obtained following the general procedure D according to example 3, using 237 mg of 4-nitrobenzenediazonium tetrafluoroborate as a pale yellow oil, with an isolated yield of 71percent. 1H NMR (300 MHz, CDC13) δ 8.19 (d, J = 8.7 Hz, 2H) 7.96 (d, J = 8.7 Hz, 2H) 1.37 (s, 12H) 11Β NMR (100 MHz, CDC13) δ 30.87 13C NMR (75 MHz, CDC13) δ 135.80; 122.56; 84.78; 25.02 MS (EI) tR = 10.31 min; m/z: 249 (Μ+', 100percent)
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1.5h;
3-Chloro-5-(4-nitrophenyl)isonicotinonitrile Prepared According to Scheme 8 To a solution of 1.73 g of commercial 3,5-dichloroisonicotinonitrile in 120 ml of dioxane are added 2.74 g of <strong>[171364-83-3]4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane</strong>, 2.31 g of sodium bicarbonate in 70 ml of water and 1.16 g of tetrakis(triphenylphosphine)palladium (0). The suspension is heated at 100 C. for 1 hour 30 minutes. After cooling, the reaction mixture is poured into 40 ml of water and extracted with three times 100 ml of ethyl acetate. The combined organic phases are washed with 50 ml of water, 50 ml of brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residual brown gum is purified by chromatography on a prepacked Merck cartridge of 70 g of silica 15-40 mum, eluding with dichloromethane. 1.58 g of a yellow solid of 3-chloro-5-(4-nitrophenyl)isonicotinonitrile are obtained, the characteristics of which are as follows: MS-EI: 259 (+) 1H NMR spectrum (400 MHz, (CD3)2SO, delta in ppm): 8.02 (d, J=9.0 Hz, 2H); 8.43 (d, J=9.0 Hz, 2H); 8.91 (s, 1H); 9.09 (s, 1H)
6,7-bis-benzyloxy-1-{4'-[4-(3-hexyl-ureido)-benzenesulfonylamino]-biphenyl-4-ylmethyl}-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
6,7-bis-benzyloxy-1-{4'-[4-(3-hexyl-ureido)-benzenesulfonylamino]-biphenyl-3-ylmethyl}-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 20h;
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 : 1) (250mg) was added to a degassed mixture of <strong>[171364-83-3]4,4,5,5-tetramethyl-2-(4-nitro-phenyl)-[1,3,2]dioxaborolane</strong> (1.67g, 6.70mmoles), 1-difluoromethoxy-4-iodo-benzene (2.17g, 8.04mmoles) and 2M aqueous cesium carbonate (10.05ml) in 1,4-dioxan (120ml). The mixture was placed under an argon atmosphere and was heated at 80C for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between dichloromethane (2 x 200ml) and water (100ml). The combined extracts were washed with brine (150ml) and dried (MgSO4). After evaporation of the solvent, the residue was purified by flash chromatography, using petrol (60-80)/diethyl ether 19 : 1v/v as eluent, to afford compound 168 (1.15g) as a beige coloured solid.
With meso-tetra(p-tolyl)porphinato-palladium(II); potassium acetate; In 1,4-dioxane; at 110℃; for 5h;
General procedure: Aryl/heteroaryl bromide 1 (1 mmol), B2pin2(2), B2npg2(4) orBpin (6, 1.2 mmol), and dioxane (5 mL) are taken into a 25 mLround-bottomed flask. KOAc (2 mmol) was added and stirredthe resultant mixture at room temperature for 5 min, PdII-TpTP(0.15 mol%) was added, and the contents were refluxed on preheatedoil bath at 110 C under constant stirring in open-air.The reaction progress was ensured by TLC. After completion ofthe reaction, the mixture was cooled, dilute with water (20 mL)and extracted with tertbutylmethyl ether (3 × 10 mL). The combinedn-hexane layers were concentrated, and the crudeproduct obtained was purified by column chromatography (CC)on silica gel using a mixture of ethyl acetate and hexane (1:30)as eluent.
82%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In neat (no solvent); at 110℃; for 24h;Green chemistry;
Under atmospheric conditions, a 25-mL round-bottom flaske quipped with a magnetic stir bar was charged with PdCl2(PPh3)2 (0.099 mmol, 0.02 equiv), KOAc (5.94 mmol, 1.2 equiv), bis(pinacolato)diboron (5.20 mmol, 1.05 equiv) and 1-bromo-4-nitrobenzene (4.95 mmol, 1 equiv). The reaction vial was transferred to a preheated oil bath. The reaction was stirred at 110 C for the desired time to give a grey mixture. The reaction mixture was extracted with 10 mL of ethyl acetate, washed with water (2 × 15 mL), brine (10 mL), and dried over Na2SO4. The solvent was evaporated in vacuo to afford the crude product. The residue was purified by column chromatography on silica gel(eluting with 5:95 ethyl acetate in hexane) to give 8a in 79%.
73%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane;Reflux;
A mixture of l-bromo-4-nitrobenzene (2.02 g, 0.01 mol, 1 eq.), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.54 g, 0.01 mol, 1 eq.), potassium acetate (2.88 g, 0.03 mol, 1 eq.), and PdCl2(dppf) (0.82 g, 1 .0 mmol, 0.1 eq.) in dioxane (35 mL) was refluxed overnight. The mixture was cooled to rt, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20: l to 5: 1) to give the product (1.83 g, 73% yield).
73%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane;Reflux;
A mixture of l-bromo-4-nitrobenzene (2.02 g, 0.01 mol, 1 eq.), 4, 4, 4', 4', 5, 5, 5', 5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.54 g, 0.01 mol, 1 eq.), potassium acetate (2.88 g, 0.03 mol, 1 eq.), and PdCl2(dppf) (0.82 g, 1 .0 mmol, 0.1 eq.) in dioxane (35 mL) was refluxed overnight. The mixture was cooled to rt, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20: 1 to 5:1) to give the product (1.83 g, 73% yield).
66%
With potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; at 80℃; for 2h;
1-bromo-4-nitrobenzene (1equi), Bis-pinacoloto Diborane (1.2equi), potassium acetate (3equi) and Pd (OAc)2 (0.05equi) were taken in DMF. Resulting reaction mixture was heated at 80 0C for 2 h and progress of reaction monitored by TLC in ethyl acetate- petroleum ether mixture. Resulting reaction mixture was poured in ice cold water and extracted with ethyl acetate. Organic layer washed by fresh water and brine, dried on Na2SO4 and concentrated under reduced pressure to afford crude product, which was purified by silica gel (100-200 No.) column chromatography in 10% ethyl acetate petroleum ether as eluent to obtain a title compound as yellow solid. Yield 66%, mp 118-120 0C; 1H NMR (DMSO-d6, 300MHz, delta ppm): 8.22 (d, 2H, J = 5.1 Hz), 7.92 (d, 2H, J = 4.8 Hz), 1.32 (s, 12H); MS (APCI); m/z 250 [M+1] +; HPLC; 96%.
65%
With potassium acetate;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃; for 19h;Product distribution / selectivity;
In air, a vial was charged with Ih (10.2 mg, 0.015 mmol, 3 mol %), bis(pinacolato)diboron (0.1397 g, 0.55 mmol) and KOAc (0.147 g, 1.5 mmol). The vial was sealed and purged with argon. Bromobenzene (52 muL, 0.5 mmol) and 3 mL of DMSO were then added. The resulting mixture was then stirred at 90 C. until the reaction was complete. The product was extracted into ether, separated and dried over MgSO4. The product was purified by column chromatography. Results for various substrate scope and reaction conditions are presented in Table 9.
54%
With potassium acetate; palladium diacetate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;
Under N2 atmosphere, bis(pinacolato)diboron (4.53g, 17.82mmol), potassium acetate (4.37g, 44.55mmol) andpalladium acetate (0.17g, 0.74mmol) were added respectively to a solution of 1-bromo-4-nitrobenzene (3.0g, 14.85mmol)in DMF (10mL). The mixture was stirred at 80C for 2hrs, followed by adding water (20mL) and EA (20mL), the organicphase was in turn washed with water (10mL33) and saturated brine (lOmL), dried over anhydrous magnesium sulfate,filtered, concentrated under reduced pressure. The residue was purified by silica column chromatography (PE:EA =10:1) to give compound 13-e (2g, yield 54%). LC-MS (ESI): m/z = 250 [M+H]+.
48%
With potassium acetate; palladium diacetate; In 1,4-dioxane; at 50℃;Inert atmosphere;
In the reaction flask was added 250mL of starting material 4-nitro-bromobenzene (2.029,10.0mmol), with 70mL of 1,4-dioxane was dissolved completely, adding borate pinacol ester-linked (2.9g, 11.4mmol), acetic acid palladium (71mg, 0.3mmol) and potassium acetate (3.01 g, 30.6mmol); N2Replacement.The mixture was stirred and heated to 50 , maintained at this temperature, the reaction overnight.End of the reaction monitored by TLC. After completion of the reaction, subjected to suction filtration with Celite bedding.Was added to the filtrate, 50mL water and 120mL ethyl acetate extract separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure after column chromatography, to obtain the TM1 intermediate 1.2g, 48% yield.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 10h;Inert atmosphere;
(1) Add 3.5 g of 4-bromonitrobenzene to a round bottom flask, and add 3.62 g of divaleryl diboron, 4.1 g of potassium acetate,0.5 g of 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride,Add 40 ml of 1,4-dioxane, and pass in argon for 10 minutes while stirring.The reaction was performed at 80 degrees Celsius for 10 hours, and the obtained product was obtained through column chromatography;
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 8h;Heating / reflux;
Example 49: 4-Methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)-N-[3-(trifluoromethyl)phenyl]- benzamideStepl: 6-Methyl-4'-nitro-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide4,4,5,5-Tetramethyl-2-(4-nitrophenyl)-l,3,2-dioxaborolane (0.35 g, 0.0014 mol) was mixed with 3-iodo-4-methyl-lambdaf-[3-(trifluoromethyl)phenyl]benzamide (0.73 g, 0.0018 mol) and potassium carbonate (0.50 g, 0.0036 mol) in toluene (15.00 mL), ethanol (2.10 mL) and water (2.00 mL) and the mixture was degassed. To the reaction was added tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.000086 mol) and the mixture was heated to reflux for 8 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 30% EtOAc/hexanes to give the product (0.32 g, 57% yield). 1H NMR(CDCl3): delta8.33 (dd, 2H), 7.76-7.93 (m, 5H), 7.43- 7.54 (m, 5H), 2.35 (s, 3H). MS (EI) m/z = 401 (M+H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 90℃; for 16h;Heating / reflux;
Step 1 N-(6-Methyl-4'-niotatrobpsihenyl-3-yl)-3-(triotafluoromethyl)benzamiotadeTo N-(3-iodo-4-methylphenyl)-3-(t?fluoromethyl)benzamide (400.0 mg, 0.99 mmol) was added 4,4,5,5-tetramethyl-2-(4-mtrophenyl)-l,3,2-dioxaborolane (270 mg, 1.1 mmol) followed by <n="65"/>toluene (8.2 mL) , then ethanol (1.15 niL), and K2CO3 (270 mg, 2.0 mmol in 1.1 niL water). The reaction was degassed with N2, then tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was added. The reaction was degassed again, and then heated at reflux under N2 atmosphere at 90 0C until LCMS and TLC indicated complete reaction, about 16 hours. The reaction was then cooled to ambient temperature, transferred to a separatory funnel and partitioned between water and EtOAc. The phases were separated and the organic phase was washed with water, then saturated aqueous NaCl, dried (MgSO4) and then evaporated to dryness to leave the crude product, which was purified by column chromatography to give the product (379 mg, 95.79%). 1H NMR (400 MHz, CDCl3): delta 8.29 (m, 2H), 8.12 (s, IH), 8.07 (d, IH), 7.82 (m, 2H), 7.5-7.7 (m, 5H), 7.33 (d, IH), 2.26 (s, 3H). MS (EI) m/z = 401 (M+H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.166667h;Microwave irradiation;
Example 23; Preparation of ethyl 4-(4-morpholino-6-(4-(3-phenylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (Scheme 22); tert-Butyl 4-(6-chloro-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is coupled to 4-nitrophenylboronic acid pinacol ester (1.5 eq) with tetrakis(triphenylphosphine) palladium (0) (10 mol %), 2 M aqueous sodium carbonate solution (4 eq), and ethylene glycol dimethyl ether (DME), under microwave irradiation (150 C., 10 min). Following filtration over celite and subjection of the filtrate to aqueous workup, flash chromatography provides tert-butyl 4-(4-morpholino-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In toluene; at 90℃; for 24h;Sealed tube;
Under anhydrous and anaerobic conditions, 2'-bromoacetanilide and 4-nitrophenylboronic acid pinacol ester were dissolved in solvent toluene, followed by anhydrous potassium phosphate, Pd(OAc)2 and SPhOS. ,Sealed, oil bath to control the reaction temperature at about 90 C, after 24 hours of reaction, the reaction solution was extracted, washed with water, dried, spin-dried, and passed through a column (PE: EA = 4:1) to obtain a yellow solid product.That is, compound 5. Among them, the mass of anhydrous potassium phosphate is about twice the mass of 2'-bromoacetanilide, and the amount of the catalyst Pd(OAc) 2 is about 8% of 2'-bromoacetanilide.The amount of SPhOS is about 16% of 2'-bromoacetanilide.
To a cold (-20 0C) solution of 5-bromo-2-iodopyridine (10 g, 35.22 mmol) in tetrahydrofuran (50 mL) was added isopropylmagnesium chloride (20 mL, 38.74 mmol, 2 M solution in tetrahydrofuran) dropwise over 10 minutes. The reaction was allowed to warm to 0 0C over 1 hour and then cooled to -15 0C. A solution of cyclopentanone (2.7 mL, 30 mmol) in tetrahydrofuran (25 mL) was added dropwise, and the reaction was warmed to 15 0C over 3 hours. The reaction was then quenched by the dropwise addition of saturated aqueous NH4Cl. The layers were separated, and the aqueous was extracted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure to provide a crude alcohol, which was used in the subsequent step without further purification.A mixture of the crude alcohol (1.05 g, 4.34 mmol), 4-nitrophenyl boronic acid pinacol ester (1.4 g, 5.64 mmol), potassium fluoride (0.76 g, 13 mmol) and tetrakis(triphenylphosphine) palladium (0.87 g, 0.43 mmol) in a solvent mixture(dimethoxyethane:ethanol:water:toluene, 10:6:3:1, 50 mL) was heated to 90 0C for 10 hours. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water, brine, dried with <n="86"/>anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (30 % ethyl acetate in hexane) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.70-1.82 (m, 4H), 1.84-1.93 (m, 2 H), 2.08-2.18 (m, 2 H), 5.15 (s, 1 H), 7.81 (m, 1 H), 8.02 (m, 2 H), 8.17 (m, 1 H), 8.32 (m, 2 H), 8.91 (m, 1 H).
General procedure: To a solution of arylamine (0.5 mmol, 1.0 equiv) in MeOH(1.0 mL) was added HCl (0.5 mL, 1.5 mmol, 3.0 equiv) followed by H2O (0.5 ml). This mixture was stirred 2 min, and the NaNO2 solution (0.25 mL) was then added. The NaNO2 solution was prepared by dissolving 35 mg of NaNO2 in H2O (0.25 mL). This mixture was stirred 30 minat 0-5 C followed by B2pin2 (2, 381 mg, 1.5 mmol, 3.0equiv) in MeOH (1.0 mL). This mixture was stirred 60 min.H2O (10 mL) was added to the reaction mixture, then extracted with CH2Cl2 (50 mL, 3×). The combined organic layers were washed with sat. NaHCO3, dried over Na2SO4, followed by evaporation, and the crude residue was purified by flash chromatography.
91%
With tert.-butylnitrite; eosin; In acetonitrile; at 20℃; for 2h;Irradiation;
General procedure: tert-Butyl nitrite (155 mg, 1.1 mmol) wasadded drop wise to a mixture of bis(pinacolato)diborane (127 mg, 0.5 mmol),4-anisidine (61 mg, 0.5 mmol) and eosin Y (0.01 mmol) in acetonitrile (3 mL).The resulting mixture was stirred at room temperature under irradiation withblue LED for 2 h (TLC). This mixture after being diluted with ethyl acetate(5 mL) was ltered through celite and the ltrate was extracted with ethylacetate (3 10 mL). The extract was washed with brine, dried over anhydrousNa 2 SO 4 , and evaporated to leave the crude product which was puried bycolumn chromatography over silica gel with hexane-ethyl acetate (98:2) aseluent to furnish pure 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a light yellow viscous liquid (3d, 208 mg, 88%); IR (neat)2978, 2933, 2839, 2526, 2050, 1950, 1911, 1724, 1605, 1570 cm1;1H NMR(500 MHz, CDCl 3 ) d 1.33 (s, 12H), 7.82 (s, 3H), 6.89 (d, J = 8.0 Hz, 2H), 7.75 (d,J = 8.0 Hz, 2H);13C NMR (125 MHz, CDCl 3 ) d 24.9 (4C), 55.2, 83.6 (2C), 113.4(2C), 136.6 (2C), 162.3. The spectroscopic data is in full agreement with thosereported for an authentic sample.14This procedure was followed for all thereactions listed in Table 2. All of these products (3a,143b,143c,16a3d,143e,143f,8a3g,143h,143i,143j,8a3k,8a3l,8a3m,143n,8c3o,16b) are known compounds,and their spectroscopic data are in agreement with those previously reported.
73%
General procedure: An arylamine (50 mmol) was dissolved in 50% hydrofluoroboric acid(17 mL) and water (20 mL). After cooling the reaction mixture to 0 C, a solution of sodium nitrite (3.4 g in 7.5 mL water) was added dropwise to the reaction system (over 5 min). The resulting mixture was stirred for 1h and the precipitate was collected by filtration. It was redissolved in the minimum amount of acetone and then diethyl ether was added to precipitate the aryl diazonium tetrafluoroborate. The product was filtered, washed with diethyl ether and dried under reduced pressure. Borylation of aryldiazonium salts; general procedure The aryldiazonium salt (0.5 mmol) and (Bpin)2 (0.75 mmol) were added to an oven-dried Schlenk tube. The tube was evacuated and backfilled with argon (three times). CH3OH (0.8 mL) was added to this Schlenk tube. The tube was sealed and the mixture was stirred at room temperature (22-25 C) for 36 h. After evaporation of the solvent, the residue was purified by column chromatography to afford the product.The arylboronates were purified by chromatography on a silica column eluting with petroleum ether (boiling range 60-90 C) or a petroleumether/ethyl acetate mixture (ca. 60:1) by volume giving Rf values for the boronates of ca. 0.2-0.3.
66%
General procedure: Aryl amine (10 mmol) was dissolved in a mixture of 5 mL of distilled water and 3.4 mL of 50% hydrofluoroboric acid. After cooling the reaction mixture to 0 C using ice bath and the sodium nitrite (0.69 g in 2 mL distilled water), was added dropwise in 5 min interval of time. The resulting mixture was stirred for 1 h and the precipitate was collected by filtration and redissolved in minimum amount of acetone. Diethylether was added until precipitation of aryl diazonium tetrafluoroborate, which is filtered, washed several times with diethyl ether and dried under vacuum. Typical reaction procedure: General procedure: Diazonium tetrafluoroborate salts (0.5 mmol) and B2pin2 (1.5 mmol) were transferred into an oven-dried tube under air. Then acetone/H2O (2/1, 4 mL) were added into the tube via syringe. The sealed tube was keep at 20 C and stirred for 1-2 h. After the reaction was complete, dichloromethane was added to extract the product and the combined organic solution was dried by Na2SO4. The pure product was isolated after column chromatography on silica gel (petroleum ether/ethyl acetate).
65%
The arylamine (10 mmol) was dissolved in a mixture of 5 mL of distilled water and 3:4 mL of 50% tetrafluoroboric acid. After cooling the reaction mixture to 0 C in an ice bath, sodium nitrite (0:69 g in 2 mL of distilled water ) was added dropwise within 5 min. The resulting mixture was stirred for 1 h, and the precipitate was collected by filtration and redissolved in the minimum amount of acetone. Diethyl ether was added until precipitation of the arenediazonium tetrafluoroborate, which was filtered, washed several times with diethylether, and dried under vacuum. An arenediazonium salt (1:5 mmol), bis(pinacolato)diborane(1 mmol) and PPh3 (2:0 eq.) were weighed in a 25 LSchlenk round bottom flask under nitrogen atmosphere. Then 3 mL of acetonitrile was added by syringe. The resulting solution was stirred at room temperature. The reaction progress was monitored by GC-MS. After the completion of the reaction,the solution was filtered though a short column of silica gel and the column washed with ethyl acetate. The filtrate was concentrated under reduced pressure to leave a crude product, which was purified by flash column chromatography on silica gel to afford the final products.
1.4 g
With tert.-butylnitrite; dibenzoyl peroxide; In acetonitrile; at 25℃; for 4h;Inert atmosphere;
Under argon, 1.38 g p-nitroaniline, 2.54 gBoronic acid pinacol ester and49 mg of benzoyl peroxide The acid was added to 60 mL of acetonitrile at a controlled temperature of 25 C,Then, 1.55 g of t-butyl nitrite was dissolved in 10 mL of acetonitrile and added dropwise to the above system. After 4 h reaction, the reaction was carried out and dried to petroleum ether: ethyl acetate = 20: 1 as developing solvent Column chromatography to give pale yellow solid 11 (1.4 g); 1 g of the above pale yellow solid was added to a 25 mL shurenk Followed by the addition of 2.24 g of 9,9 dioctane dibromofluorene, 6 mL of potassium carbonate solution (2 mol / L), 20 mg of tetrakis (triphenylphosphine) palladium And 9 mL of tetrahydrofuran, followed by double-tube freezing - pumping - inflated three times, at 80 for 12 h reaction, after the end of the reaction, Extraction with methylene chloride followed by column chromatography using pure petroleum ether as developing solvent gave a yellow solid, compound E (1.95g)
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 1h;Inert atmosphere; microwave irradiation;
In a 0.5 -2 mL microwave vial was placed 3-(6-chloro-2-iodopyrimidin-4-yl)-8-oxa-3- azabicyclo[3.2.1]octane (16, 50 mg, 0.142 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)- 1 ,3,2-dioxaborolane (35.4 mg, 0.142 mmol) in DME (1.5 ml) to give an orange solution. Na2CO3 (2M solution in water) (0.284 ml, 0.569 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution. Pd(PPh3)4 (16.43 mg, 0.014 mmol) was added and the mixture was heated under microwave irradiation for 60 min at 100C. The mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCO3. The organic phase was dried (MgSO4) and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-25%). Collected fractions were concentrated to give 39 mg (0.1 1 mmol, 79%) of the title compound as an off-white/yellow solid. The thus obtained compound was identical to the same compound prepared according to Scheme 5.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux;
In a 250 ml. round-bottomed flask was placed 8-(6-chloro-2-iodopyrimidin-4-yl)-3-oxa-8- azabicyclo[3.2.1]octane (35, 627 mg, 1.783 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)- 1 ,3,2-dioxaborolane (444 mg, 1.783 mmol) in DME (20 ml) to give an orange solution. Na2CO3 (2M solution in water) (3.57 ml, 7.13 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution. Pd(PPh3)4 (206 mg, 0.178 mmol) was added and the mixture was heated to reflux and stirred overnight. The mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCtheta3. The solids between the organic and aqueous phase were collected by filtration and washed with dichloromethane. The combined organic phases were dried (MgSO4) and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (5-20%). Collected fractions were concentrated to give the title compound (428 mg, 69%) as a yellow solid, containing some dichloride (34, -20% by UV) and a trace of OPPh3. The mixture was used without further purification in the next step.
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 85℃;Inert atmosphere;
To a degassed mixture of N-(4-bromo-3-methoxyphenethyl)-2-(3,4- dimethoxyphenyl)acetamide (200 mg, 0.489 mmol) and 4,4,5, 5-tetramethyl-2-(4-nitrophenyl)- 1,3,2- dioxaborolane (180 mg, 0.73 mmol) in DMF (5 ml) was added K3PO4 (310 mg, 1.5 mmol), followed by addition of tetrakis(triphenylphosphine)-palladium ( 18 mg, 0.016 mmol). The resulting mixture was stirred at 85 0C under nitrogen overnight. The reaction mixture was diluted with EtOAc to 60 mL and washed with aq NaHCO3 solution twice and 10% lithium chloride solution once. The EtOAc solution was dried over Na2SO4 and concentrated under reduced pressure and the reaction mixture was purified on silica gel eluting with 10-90% EtOAc/hexane to give the title compound as a solid (180 mg, 82%). 1H NMR (CDCl3) delta 8.18 (d, 2H, J = 8 Hz), 7.60 (d, 2H, J = 8 Hz), 7.12 (d, IH, J = 8 Hz), 6.70 (d, IH, J = 8 Hz), 6.67-6.64 (m, 4H), 5.43-5.38 (m, IH), 3.76 (s, 3H), 3.75(s, 3H), 3.71 (s, 3H), 3.44 (t, 2H, J = 8 Hz), 3.43 (s, 2H), 2.73 (t, 2H, J = 8 Hz).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; at 130℃; under 760.051 Torr; for 0.5h;Microwave irradiation; Inert atmosphere;
Step 1-Synthesis of (5)-4-(3-methylmorpholino)-2-(4-nitrophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (bj): (S)-2-chloro-4-(3-methylmorpholino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (bf) (287.1 mg, 1.064 mmol), 4-nitrophenylboronic acid pinacol ester (314.1 mg, 1.261 mmol), sodium carbonate (338.4 mg, 3.193 mmol) and tetrakis(triphenylphosphine)palladium(0) (71.5 mg, 0.0619 mmol) were weighed into a microwave vial equipped with a stirbar. The vial was placed under atmospheric nitrogen pressure. Acetonitrile (3.0 mL, 58 mmol) and degassed water (3.0 mL, 170 mmol) were added and the mixture microwaved at 130 C. for 30 min. The reaction was diluted with 25 ml water and extracted with EtOAc (3×25 ml). The combined organics were dried with MgSO4, filtered and concentrated onto silica gel. This crude material was purified by column chromatography using a 12 g column, with a gradient of 0% to 100% ethyl acetate in hexanes. The product-containing fractions were combined and evaporated under reduced pressure to give (5)-4-(3-methylmorpholino)-2-(4-nitrophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (bj) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.57-8.52 (m, 2H), 8.29 (d, J=8.9, 2H), 4.63 (q, J=14.4, 2H), 4.21-3.67 (m, 7H), 3.56-3.49 (m, 2H), 3.08-2.99 (m, 2H), 1.36 (d, J=6.7, 3H).
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 80 - 85℃;Inert atmosphere;
Example 220:; Methyl 3-methyl-4'-nitrobiphenyl-4-carboxylate; The compound of example 219 (10 g, 0.044 mol), 4,4,5, 5-tetramethyl-2-(4- nitrophenyl)-1 ,3,2-dioxaborolane (13.16 gm, 0.0528 mole) and Pd(dppf)CI2: CH2CI2 (1 .07 g, 0.00132 mol) were taken in DMF (250 mL) under an argon atmosphere. To this reaction mixture, degassed 2M solution of Na2C03 (14 g, 0.132 mol, 66.5 mL) was added. The reaction mixture was stirred at 80-85 C for 1 to 1 .5 h. After completion of the reaction, water was added and the product obtained was extracted with ether. The combined ether layer was washed with brine and dried over anhydrous Na2S04 or MgS04. The solvent was evaporated and the product was purified by column (silica gel, 20 % ethyl acetate in petroleum ether) to obtain the title compound.Yield: 1 1 .3 g (95 %); 1 H NMR (DMSO-d6, 300MHz): delta 8.298-8.280 (d, J=9Hz, 2H), 7.998-7.981 (d, J=8.5Hz, 2H), 7.928-7.912 (d, J=8Hz, 1 H), 7.744 (s, 1 H), 7.702- 7.684 (dd, J=1 .8 Hz, 1 H), 3.827 (s, 3H), 2.577 (s, 3H); MS (ESI): m/z 272 (M+H).
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In water; N,N-dimethyl-formamide; at 160℃; for 1h;Microwave irradiation; Inert atmosphere;
Step 1: Preparation of tert-butyl (1-{4-[2-(4-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (250 mg, 0.486 mmol), 4-nitrophenylboronic acid pinacol ester (152 mg, 0.730 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (34.4 mg, 0.0486 mmol) and 2M Na2CO3 aq. (0.485 mL, 0.970 mmol) in DMF (1.00 mL) was heated at 160 C. under microwave irradiation for 1 hour under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (*3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=1:4?1:2) and TLC (EtOAc/hexane=1:1, DCM/EtOAc=1:1) to afford desired product (51.4 mg, 17.6%) as yellow solid. 1HNMR (CDCl3) 400 MHz delta: 8.19-8.08 (m, 3H), 8.06-8.01 (m, 1H), 7.80-7.70 (m, 2H), 7.47-7.40 (m, 2H), 7.36-7.30 (m, 1H), 7.22-7.14 (m, 3H), 7.00-6.93 (m, 1H), 6.85-6.78 (m, 1H), 6.65-6.58 (m, 1H), 6.38 (s, 1H), 5.19 (s, 1H), 2.67-2.30 (m, 4H), 2.25-2.09 (m, 1H), 1.98-1.84 (m, 1H), 1.39 (br s, 9H).
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 120℃; for 0.333333h;Microwave irradiation;
(4, 4, 5, 5-tetramethyl-2-(4-nitrophenyl)-1, 3, 2-dioxaborolane (1) (1equi), 4, 6-dichloropyrimidine (1.2equi), sodium carbonate (3equi) and Pd (pph3)2Cl2 (0.05equi) were taken in 15ml of DME, 2ml of EtOH & 3ml water. Resulting reaction mixture was heated in microwave at 120 0C for 20 min and progress of reaction monitored by TLC in ethyl acetate- petroleum ether mixture. Resulting reaction mixture was poured in ice cold water and extracted with ethyl acetate. Organic layer washed by fresh water and brine, dried on Na2SO4 and concentrated under reduced pressure to afford crude product, which was purified by silica gel (100-200 No.) column chromatography in 10% ethyl acetate petroleum ether as eluent to obtain a title compound as yellow solid. Yield 53%, mp 141-143 0C; 1H NMR (CDCl3, 300 MHz, delta ppm): 9.12 (s, 1H), 8.41 (d, 2H, J = 8.1 Hz), 8.27 (d, 2H, J = 6.9 Hz), 7.84 (s, 1H); MS (APCI); m/z 237 [M+1] +; HPLC; 96%.
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