* 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.
Reference：
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 5, p. 870 - 878
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4242 - 4247
7
[ 110-91-8 ]
[ 1122-91-4 ]
[ 1204-86-0 ]
Yield
Reaction Conditions
Operation in experiment
64%
With tetrabutylammomium bromide; palladium diacetate; potassium carbonate; 2,6-bis(diphenylphosphino)pyridine In N,N-dimethyl acetamide at 135℃; for 4 h; Inert atmosphere
General procedure: A round bottomedflask was charged with bromobenzene (4 mmol), aniline (4 mmol),TBAB (3 mmol), and K2CO3 (4 mmol) under a dry nitrogen atmosphere. A solution of (Ph2P)2py (0.05 mol percent in 2 mL of DMAc) and a solution of palladiumacetate (0.025 mol percent in 2 mL of DMAc) was added through a rubber septum,and the resulting mixture was heated at 135 C for the appropriate time. Uponcompletion of the reaction, the mixture was cooled to room temperature and quenched with H2O. After extraction with CH2Cl2 (3 20 mL), the combinedorganic layer was dried over MgSO4. The solvent was evaporated and the cruderesidue was purified by silica gel chromatography, using n-hexane/EtOAc aseluent to provide the desired product. The products were characterized byNMR spectroscopy
Reference：
[1] Journal of Organometallic Chemistry, 2009, vol. 694, # 9-10, p. 1473 - 1481
[2] Tetrahedron, 2008, vol. 64, # 40, p. 9507 - 9514
[3] Applied Organometallic Chemistry, 2018, vol. 32, # 1,
[4] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4098 - 4101
[5] Advanced Synthesis and Catalysis, 2008, vol. 350, # 17, p. 2767 - 2777
[6] Inorganica Chimica Acta, 2010, vol. 363, # 6, p. 1262 - 1268
[7] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8049 - 8065
8
[ 1122-91-4 ]
[ 103858-53-3 ]
Reference：
[1] Patent: US2002/68756, 2002, A1,
9
[ 288-32-4 ]
[ 1122-91-4 ]
[ 10040-98-9 ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium carbonate In N,N-dimethyl-formamide at 152℃; for 26 h;
General procedure: To a vigorously stirred suspension of the CuNPs/MagSilica catalyst (100 mg) in DMF (6 mL) under air, K2CO3 (276 mg, 2.0 mmol) and imidazole (136 mg, 2.0 mmol) were added. The reaction mixture was stirred for 30 min and then the corresponding aryl halide (1.0 mmol) was added and the reaction flask was immersed in an oil bath at the reflux temperature of DMF (152 °C). The reaction mixture was stirred at this temperature until no further conversion of the starting aryl halide was observed (TLC, GC). The catalyst was immobilized by means of a permanent magnet placed on the outer wall of the reaction flask, and washed twice with Et2O (10 mL each). Finally, the catalyst was dried under vacuum (5 Torr) for its recovery and reuse. The crude reaction mixture was evaporated under vacuum (15 Torr) and the resulting residue was purified by flash column chromatography (silica gel, hexane/AcOEt) to afford the corresponding N-aryl imidazoles (2a-j). All known compounds included in Table 1 were characterized by comparison of their chromatographic and spectroscopic data (1H, 13C NMR, and MS) either with those of the corresponding commercially available pure samples (2g) or with those described in the literature (2a,21 2b,212c,22 2d,21 2e,11a 2f,11a 2h,23 2i,24 2j25).
85 %Chromat.
With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference：
[1] Tetrahedron, 2008, vol. 64, # 19, p. 4254 - 4259
[2] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[3] Tetrahedron Letters, 2006, vol. 47, # 23, p. 3897 - 3899
[4] Synthetic Communications, 2012, vol. 42, # 1, p. 114 - 121
[5] Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2394 - 2400
[6] RSC Advances, 2015, vol. 5, # 12, p. 8571 - 8578
[7] Synthetic Communications, 2012, vol. 42, # 2, p. 279 - 284
[8] Research on Chemical Intermediates, 2016, vol. 42, # 10, p. 7501 - 7511
[9] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 4, p. 515 - 517
[10] Tetrahedron, 2014, vol. 70, # 36, p. 6082 - 6087
[11] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[12] Inorganic Chemistry, 2010, vol. 49, # 1, p. 331 - 338
[13] Tetrahedron, 2008, vol. 64, # 7, p. 1383 - 1387
[14] European Journal of Medicinal Chemistry, 2009, vol. 44, # 11, p. 4654 - 4660
[15] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
With copper(II) acetate monohydrate; sodium carbonate In toluene at 100℃; for 24 h;
General procedure: A mixture ofaldehyde 1 (6.8 mmol), amidine hydrochloride 2 (2 g,11.4 mmol), Na2CO3 (1.21 g, 11.4 mmol, 1.0 equiv) andCu(OAc)2 (10 molpercent) was stirred in toluene (20 mL) under100 °C in air for 24 h. After completion of the reaction, themixture was cooled to room temperature. The water wasadded to the reaction system and atmospheric distillation untiltoluene was evaporated. The resulting solution was filteredand residue with hot water washed 3 times. The crude productwas purified by column chromatography on silica gel usingpetroleum ether/EtOAc (100:1) as an eluent to give the correspondingproducts 7a-7x.
Reference：
[1] Journal of Fluorescence, 2018, vol. 28, # 2, p. 707 - 723
12
[ 1122-91-4 ]
[ 534-85-0 ]
[ 2620-76-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium hydrogensulfite In N,N-dimethyl-formamide for 1 h;
A solution of Ν-(4-phenyl)benzene-1,2-diamine (3.68 g, 20 mmol), 4-bromobenzaldehyde (3.70 g, 20 mmol) and sodium bisulfite (2.04 g, 10mmol) was dissolved in DMF (80 mL) and stirred in air for 1 h. After the completion of the reaction, the reaction solution was poured into water to precipitate the product. After standing for some time, the product was filtered and washed with a small amount of methanol. Finally, the crude product was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (1: 5) as eluent to give a white powdery solid product. Yield: 6.40 g, 92percent.
89%
With sodium hydrogensulfite In N,N-dimethyl-formamide for 1 h; Reflux
willN- (4-phenyl) benzene-1,2-diamine(3.68 g, 20 mmol),4-bromobenzaldehyde (3.70 g, 20 mmol) and sodium bisulfite (2.04 g, 10 mmol)Of the mixture was dissolved in DMF (80 mL)Mix in air for 1 h.Point plate test After the end of the reaction cooled to room temperature,The reaction solution was poured into water,Precipitation products.After standing for some time,Filter out the product,Wash with a small amount of methanol.At last,The crude product was mixed with n-hexane and ethyl acetate (1: 3)As a eluent by silica gel column chromatography to obtain a white powder solid product.Yield: 6.18 g, 89percent.
60%
at 180℃; for 6 h;
4-bromo-benzaldehyde (8.3g, 45mmol) was dispersed in the benzene in 10ml of N-phenyl-1,2-phenylenediamine (N-phenyl-1,2-phenylenediamine, 8.3g, 45mmol ), which was heated at 180 °C for 6 hours. After cooling to room temperature, and then removed by distillation under reduced pressure to nitrobenzene, the resulting solid was filtered and dried in vacuo, washed with ethyl ether to obtain a compound A.
57.71%
With toluene-4-sulfonic acid In toluene for 16 h; Heating / reflux
Synthesis of 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazoleN-Phenyl-o-phenylenediamine 13.27 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 14.51 g of product (yield=57.71percent).
49%
for 12 h; Reflux
Acetic acid (20 mL) was added to a flask containing N-phenyl-o-phenylenediamine (1.50 g, 8.14 mmol) and 4-bromobenzaldehyde (1.66 g, 8.96 mmol). After the mixture was refluxed for 12 h, distilled water was added and the organic layer was extracted with dichloromethane. The organic layer was washed with sodium bicarbonate and brine and dried using anhydrous sodium sulfate. The filtrate was concentrated in vacuo to give a crude mixture, which was then subjected to column chromatography on silica gel using ethyl acetate and hexane (v/v 1:20) as the eluent. Analytically pure 2-(4-bromophenyl)-1-phenyl-1H-benz[d]imidazole was isolated as a white solid (1.39 g, 49percent). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 1H), 7.53-7.42 (m, 7 H), 7.35-7.21 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ 151.21, 142.90, 137.25, 136.75, 131.55, 130.84, 130.01, 128.90, 128.77, 127.37, 124.04, 123.58, 123.15, 119.90, 110.48. MALDI-TOF MS: calcd for C19H13BrN2 348.03, found 349.20.
35%
With Oxone In N,N-dimethyl-formamide at 20 - 40℃; Inert atmosphere
c) 2-(4-Bromophenyl)-1-phenyl-1H-benzimidazole N-Phenyl-o-phenylenediamine (50 g, 0.27 mol) is dissolved in anhydrous DMF (400 ml) under N2, and 4-bromobenzaldehyde (45.5 g, 0.25 mol) is added dropwise. The reaction mixture is warmed to 40° C., and Oxone (potassium hydrogen monopersulfate, 98.1 g, 0.16 mol) is added in portions. After the mixture has been stirred at room temperature for 120 min., 1 l of water is added. The precipitated product is filtered off, washed with water and dried in vacuo. Recrystallisation from acetonitrile gives a cream-coloured solid (31 g, 35percent).
23.6%
at 140℃; Inert atmosphere
2.1Weigh 7.36 g of 4-bromobenzaldehyde and 7.3 g of o-aminodiphenylamine in 200 mL of acetic acid.After charging and discharging nitrogen for 3 times, the temperature was set to 140 ° C to start the reaction;2.2After the reaction, the temperature was lowered to room temperature, and a large amount of gray solid was precipitated after pouring into water, and filtered.After the filter cake was added with 5 g of silica gel, the column was passed to obtain 3.2 g of a white solid powder, the yield was 23.6percent, HPLC 99.7percent;
General procedure: An oven dried pressure tube was chargedwith aryl bromide (1 mmol), CuI (1 mmol), DABCO (2 mmol) and dry DMSO (5 mL).Then the tube was sealed with a teflon cap and heated with stirring at 130 Cin N2 atmosphere for 12 – 36 h. The completions of reactions weremonitored by TLC. The reaction mixture was then cooled to room temperature. Themass was passed through celite bed, packed in a sinter funnel. Then thefiltered reaction mixture was extracted with ethyl acetate (3 X 20) washed withwater (3 X 20) and brine solution (3 X 10). Ethyl acetate part were collectedand dried over Na2SO4, and then evaporated under reducedpressure. The crude products were purified by column chromatography on silicagel to obtain pure product.
70%
at 135℃; for 36 h;
General procedure: An oven dried pressure tube was charged with aryl halide (0.5mmol), CuI (10–25molpercent), anhydrous Zn(OAc)2 (1.5–2equiv) and anhydrous DMSO (1.6mL). The tube was sealed with a Teflon screw cap and stirred at 135°C for 24–36h. The reaction mixture was then cooled to room temperature and stirred in 10mL of diethyl ether for 5min. It is filtered through a sintered funnel and the filtrate is washed with excess ice cold water and further extracted with diethyl ether (3×10mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using 200–400 mesh silica gel and a mixture of diethyl ether and hexane (or pentane, for Table 2, entries 2, 8, 10, 14, 16 and 24) as eluents to afford the desired products in good yields.
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 37, p. 5199 - 5202
[2] Chemical Communications, 2011, vol. 47, # 18, p. 5304 - 5306
[3] Tetrahedron, 2013, vol. 69, # 38, p. 8276 - 8283
14
[ 624-92-0 ]
[ 1122-91-4 ]
[ 3446-89-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2006, vol. 348, # 1-2, p. 236 - 242
With hemicucurbituril supported [Bmim]Cl In toluene for 10 h; Reflux
General procedure: A mixture of aryl halide (1 mmol) and sodium alkoxide(3.0 mmol) was refluxed in the presence of 200 mg ofHmCucSILP catalyst in toluene (5 mL) for an appropriatetime as indicated in Table 2. After completion of thereaction, the reaction mixture was filtered and solvent wasevaporated in vacuo to give the crude product, which waspurified by column chromatography over silica gel usinghexane/EtOAc as the eluent.
Stage #1: for 12 h; Reflux; Dean-Stark Stage #2: With chloroformic acid ethyl ester In tetrahydrofuran at -10℃; for 0.166667 h;
A mixture of 4-bromobenzaldehyde (300.0 g, 1620.0 mmol) and amino acetaldehyde dimethyl acetal (170.4 g, 1620 mmol) in anhydrous toluene (1.5 L) was refluxed under a Dean-Stark condenser for 12 h. The solution was concentrated under vacuum. The residue was dissolved in anhydrous THF and cooled to -10 °C. Ethyl chloroformate (193.3 ml_, 1782 mmol) was added and stirred for 10 min at -10 °C, and then allowed to warm to room temperature. Subsequently trimethyl phosphite (249.6 ml_, 1782.0 mmol) was added dropwise to the reaction mixture and stirred for 10 h at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in anhydrous DCM (1.5 L) and stirred for 30 minutes. The reaction mixture was cooled to 0 °C, and titanium tetrachloride (1.2 L, 6480 mmol) was added dropwise. The reaction mixture was stirred at 40 °C for 6 days. The reaction mixture was poured into ice and pH was adjusted to 8 - 9 with aqueous 6N NaOH solution. The suspension was extracted three times with EtOAc. The organic layer was extracted with 3 M HCI. The acidic aqueous solution was adjusted to pH to 7 - 8 with 3N NaOH solutions and extracted two times with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the product. Crude compound was dissolved in minimum amount of DCM and mixed with pentane to get compound A1 as light brown solid. Yield: 90 g (35percent). Rf: 0.6 (30percent EtOAc in petroleum ether). LCMS m/z = 209 (M + 1 ). 1H NMR (400 MHz, cf6-DMSO): δ 7.82 (m, 2H), 8.1 1 (d, J = 8.8 Hz, 2H), 8.30 (br s, 1 H), 8.56 (d, J = 6.0 Hz, 1 H), 9.35 (s, 1 H).
14%
Stage #1: at 120℃; Dean-Stark Stage #2: at 160℃; for 0.5 h;
General procedure: Aminoacetaldehyde dimethylacetal (3.0 eq.) was added to a solution of bromobenzaldehyde13b or 13c (1.0 eq.) in toluene (30 mL). Each reaction mixture was refluxed (Dean–Stark apparatus)at 120 °C. After consumption of the starting material, each reaction mixture was concentrated todryness, then dissolved in conc. H2SO4 (2 mL) and added to a cold solution of P2O5 in conc. H2SO4(0.5 mL). Each reaction mixture was heated at 160 °C for 30 min, allowed to cool to RT, neutralizedwith NaOH (10 M), extracted with EtOAc, and concentrated to dryness. Each residue was subjected toFCC to afford 6-bromoisoquinoline (14b, 30 mg, 0.14 mmol, 14percent) and 7-bromoisoquinoline (14c, 99 mg,0.47 mmol, 22percent) [20,21]. Ethylchloroformate (1.0 eq.) was added to a solution of isoquinoline 14b or14c (1.0 eq.) in DCM at 0 °C and stirred at the same temperature for 30 min, followed by additionof 2-trimethylsilylthiazole (1.0 eq.). Each reaction mixture was stirred at RT for 3 h, concentratedto dryness, and each residue was subjected to FCC. Each product was dissolved in benzene (5 mL),o-chloranil (1.0 eq.) was added, and each reaction mixture was refluxed for 5 h. Each reaction mixturewas diluted with 5percent NaOH (10 mL), extracted with DCM, and concentrated to dryness. Each reactionmixture residue was subjected to FCC to afford the products 9b and 9c.6-Bromo-1-(2-thiazolyl)isoquinoline (9b): 6-Bromoisoquinoline (14b, 30 mg, 0.14 mmol) was synthesizedstarting from 4-bromobenzaldehyde (13c, 200 mg, 1.08 mmol) in 14percent yield. Compound 9b wassynthesized starting from 6-bromoisoquinoline (14b, 100 mg, 0.48 mmol) in 15percent yield over two steps(21 mg, 0.07 mmol), obtained as an orange powder, m.p. 103–105 °C.
Reference：
[1] Patent: WO2015/181676, 2015, A1, . Location in patent: Page/Page column 132-133
[2] Dalton Transactions, 2015, vol. 44, # 18, p. 8552 - 8563
[3] Molecules, 2017, vol. 22, # 8,
[4] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 2, p. 437 - 447
22
[ 1122-91-4 ]
[ 34784-05-9 ]
Reference：
[1] Patent: WO2011/103196, 2011, A1,
23
[ 110-89-4 ]
[ 1122-91-4 ]
[ 10338-57-5 ]
Yield
Reaction Conditions
Operation in experiment
92%
With water; sodium t-butanolate In toluene at 105℃; for 4 h; Schlenk technique
General procedure: An oven-dried Schlenk tube was charged with the aryl halide (2 mmol) and amine (2.5 mmol), FeOA–Pd (0.05 g, 0.04 mmol, 1.5 molpercent), base (3 mmol), solvent (5 mL) and additive. The resulting mixture was stirred for the appropriate time and temperature. After reaction completion the reaction mixture was then cooled to room temperature and the catalyst separated using a magnet, taken up in Et2O (4 mL), and washed with brine (5 mL). The resulting solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel.
Step 1. 4-Bromo-3-nitrobenzaldehyde; A 100-mL 3-necked round-bottom flask was charged with NaNO3 (5.48 g, 64.47 mmol, 1.19 equiv). To this was added H2SO4 (60 mL, 98percent). The resulting solution was stirred for 1.5 hours at 10° C. To the mixture was added 4-bromobenzaldehyde (10 g, 54.05 mmol, 1.00 equiv). The resulting solution was stirred for an additional 2 hours at 10° C. The reaction progress was monitored by TLC (EtOAc: PE=1:5). Upon completion, the reaction was then quenched by the addition of 200 g of ice. The solids were collected by filtration and washed with water (3.x.200 mL) affording 4-bromo-3-nitrobenzaldehyde as white solid (11.72 g, 94percent).
55%
at 0 - 40℃; for 1 h;
General procedure: The nitration of aldehydes was carried out in a three-neckedflask of 50 ml with magnetic stirrer. H2SO4 25 ml (0.47 M)were cooled to 0 °C, 3.1 ml (0.070 M) of HNO3 were added,and then the aldehyde (0.06 M) was slowly added. Thereaction was carried out at a temperature of 0–5 °C. Then,the mixture was heated at 40 °C for 1 h. The reaction waspoured into ice water and filtered under a vacuum; thenitrobenzaldehydes were purified by recrystallization. Thescheme of reaction is showed in Fig. 1 (Furniss et al. 1989).The spectrums of 1H NMR of nitrobenzaldehydes wereobtained in CDCl3 and TMS as reference.
Reference：
[1] Patent: US8080566, 2011, B1, . Location in patent: Page/Page column 65
[2] Medicinal Chemistry Research, 2018, vol. 27, # 7, p. 1782 - 1791
[3] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 694[4] Recueil des Travaux Chimiques des Pays-Bas, 1929, vol. 48, p. 1137
[5] Journal of the Chemical Society, 1927, p. 25
[6] Chemische Berichte, 1891, vol. 24, p. 3768
[7] Patent: US2002/7059, 2002, A1,
[8] Patent: US6642222, 2003, B2,
[9] Patent: US6593335, 2003, B1,
[10] European Journal of Medicinal Chemistry, 2015, vol. 100, p. 162 - 175
[11] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 261 - 265
35
[ 1122-91-4 ]
[ 4654-39-1 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 31, p. 4308 - 4311
36
[ 56985-67-2 ]
[ 49660-93-7 ]
[ 1122-91-4 ]
Yield
Reaction Conditions
Operation in experiment
46%
With chromium(VI) oxide; sulfuric acid In water; acetone for 2 h;
15.4 mi of a solution of Jones'reagent, prepared by dissolving 35 g of Cr03 in 98percent H2SO4 (31.6 ml), in 100 ml of water are added to a solution of 4.7 g (about 20.5 MMOL) of the alcohol obtained in preparation 4 (in a purity of 60percent, as results from the reaction for carrying out preparation 4) in 61 ml of acetone. After two hours, an analysis by thin layer chromatography shows that all the starting material has been consumed. The reaction medium is then filtered and concentrated under reduced pressure. The residue is taken up diethyl ether, washed with 1 N NAOH (twice), with water and with saturated aqueous salt SOLU- tion. The organic phase is then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.85 g (about 46percent of 4-bromo- BENZALDEHYDE). The product is pure enough to be used without further purification.
Reference：
[1] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 972 - 979
[2] Organic Letters, 2018, vol. 20, # 10, p. 2906 - 2910
39
[ 1122-91-4 ]
[ 23703-22-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 2233 - 2237
40
[ 85462-16-4 ]
[ 1122-91-4 ]
[ 27466-83-7 ]
[ 35452-54-1 ]
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 16, p. 4487 - 4490
41
[ 1122-91-4 ]
[ 51554-93-9 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 2233 - 2237
[2] Journal of the American Chemical Society, 1937, vol. 59, p. 1176
42
[ 1122-91-4 ]
[ 35656-89-4 ]
Reference：
[1] Journal of Organometallic Chemistry, 2002, vol. 657, # 1-2, p. 129 - 135
43
[ 1122-91-4 ]
[ 77047-87-1 ]
[ 28785-06-0 ]
[ 122-03-2 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 18, p. 5181 - 5183
44
[ 1122-91-4 ]
[ 40640-98-0 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 14, p. 4738 - 4742
[2] Chemical Communications, 2017, vol. 53, # 4, p. 732 - 735
45
[ 27329-60-8 ]
[ 1122-91-4 ]
[ 18648-66-3 ]
Reference：
[1] Patent: JP2005/298421, 2005, A, . Location in patent: Page/Page column 27-28
[2] Chemistry Letters, 2016, vol. 45, # 5, p. 517 - 519
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 20, p. 5695 - 5698[4] Angew. Chem., 2018, vol. 130, # 20, p. 5797 - 5800,4
46
[ 1122-91-4 ]
[ 411235-57-9 ]
[ 20034-50-8 ]
Yield
Reaction Conditions
Operation in experiment
93.2%
With potassium phosphate tribasic trihydrate; palladium diacetate; tricyclohexylphosphine In water; toluene at 80℃; for 15 h; Inert atmosphere
[0188] To a mixture of 4-bromobenzaldehyde (13.5 g,0.0734 mol), cyclopropylboronic acid (6.3 g, 0.0734 mol),K3P04 .3H20 (33.3 g, 0.147 mol) and PCy3 (20.5 g, 0.0734mol) in toluene/H20 (180 mL, 5:1) was added Pd(OAc )2 (500mg) under N2 . The reaction was heated at 80° C. for 15 hrsunder N2 . The reaction was complete detected by LCMS.Toluene and H20 were removed by vacuum. The crude productwas purified by colunm chromatography on silica gel(eluted with PE:Et0Ac=20: 1) to give the title compound (5.0g, yield: 93.2percent) as a yellow oil. 1 H-NMR ( 400 MHz, CDC13 )oppm 9.94 (s, lH), 7.76 (d, 2H, 1=7.6 Hz), 7.18 (d, 2H, 1=7.6Hz), 2.00-1.94 (m, lH), 1.11-1.07 (m, 2H), 0.82-0.80 (m,2H).
80%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; toluene at 110℃; for 16 h; Inert atmosphere; Microwave irradiation
4-Cyclopropylbenzaldehyde was prepared in 80percent yield according to the Example 8, Step A substituting cyclohex-l-en-l-ylboronic acid for cyclopropylboronic acid and 6-(4-bromophenyl)-3-((2-chlorophenyl)thio)-6-(thiophen-3-yl) piperidine -2,4-dione for 4-bromobenzaldehyde
61%
With potassium phosphate; palladium diacetate; tricyclohexylphosphine In toluene at 20 - 100℃; Inert atmosphere
[0721] Synthesis of 4-cyclopropylbe yde: [0722] To a stirred solution of 4-bromobenzaldehyde (500 mg, 2.70 mmol) in toluene (20 mL) under argon atmosphere were added cyclopropyl boronic acid (300 mg, 3.51 mmol), potassium phosphate (1.72 g, 8.10 mmol) and tricyclohexyl phosphine (38 mg, 0.13 mmol) at RT and purged under argon for 30 min. Then palladium acetate (30 mg, 0.13 mmol) was added to the reaction mass; heated to 100 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was diluted with ice cold water (25 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with saturated NaHC03 solution (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10percent EtOAc/ Hexanes to afford 4- cyclopropylbenzaldehyde (240 mg, 61percent) as pale yellow liquid. [0723] 1H-NMR (CDC13, 400 MHz): δ 9.94 (s, 1H), 7.78 (d, 2H), 7.20 (d, 2H), 2.00-1.95 (m, 1H), 1.12-1.07 (m, 2H), 0.84-0.78 (m, 2H); TLC: 20percent EtOAc/ Hexanes (R 0.5).
1.70 g
With potassium phosphate; triphenylphosphine In water; toluene at 100℃; for 18 h;
To a solution of 4-bromobenzaldehyde (3.4 g, 0.0 180 mmol) in mixture of toluene:water (40 mL: 3.0 mL) was added tripotassium phosphate (9.5 g, 0.045 mmol), triphenylphosphine (0.719 g, 0.002 mmol) and cyclopropylboronic acid (2.3 g, 0.027 mmol). The reaction mixture was heated at 100°C for 18 h. The reaction mass wasquenched with water and extracted with EtOAc. The organic layer were washed with water and brine, dried over Na2504 and concentrated. The obtained solid was purified by column chromatography to afford 1.70 g of the title product. ‘H NMR (300 IVIHz, DMSO d6): 9.94 (s, 1H), 7.77-7.75 (d, J = 8.4 Hz, 2H), 7.20-7.17 (d, J = 7.8 Hz, 2H), 1.97 (m, 1H), 1.11-1.08 (m, 2H), 0.82-0.80 (m, 2H).
With ammonium acetate In ethanol at 75 - 80℃; for 10 h;
To 30 mL of ethanol were added 5.00 g (27.0 mmol) of 4-bromobenzaldehyde, 2.80 g (27.0 mmol) of malonic acid and 3.10 g (40.2 mmol) of ammonium acetate, and the mixture was reacted while stirring under reflux (75 to 80°C) for 10 hours. After completion of the reaction, the obtained reaction mixture was stirred at room temperature for 1 hour and then filtered to give 4.8 g of 3-amino-3-(4-bromophenyl)propionic acid (racemic mixtures) (isolation yield based on 4-bromobenzaldehyde: 72.2percent) as white powder. Incidentally, physical properties of the 3-amino-3-(4-bromophenyl)propionic acid (racemic mixtures) were as follows. 1H-NMR (δ (ppm), D2O) : 2.93 (dd, 1H, J=17.1, 6.8Hz), 3.04 (dd, 1H, J=17.1, 7.8Hz), 4.63 (dd, 1H, J=7.8, 6.8Hz), 7.22 (s, 1H), 7.24 (s, 1H), 7.47 (s, 1H), 7.49 (s, 1H) 13C-NMR (δ (ppm), D2O) : 40.4, 53. 9, 126.0, 131.9, 135.3, 137.1, 175.9
72%
With ammonium acetate In butan-1-olReflux
General procedure: A mixture of appropriate aldehyde 2.40 g (1-15), 2.44 g ofmalonic acid and 3.54 g of ammonium acetate (1:1.1:2.3), in 200mLof the 1-butanol was refluxed for 1.5-2 h until the evolution of CO2ceased. The precipitate formed was filtered and washed withboiling 1-butanol (2 x 50 mL), boiling ethanol (2 x 50 mL) and100mL of water. Precipitates were dried at 80-100 °C for 8-10 h.Purity of product was checked by TLC, and yield obtained about65-80percent in each reaction.
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 395 - 406
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
[3] Patent: EP1621529, 2006, A1, . Location in patent: Page/Page column 33
[4] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 252 - 268
[5] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 14, p. 1673 - 1695
[6] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9152 - 9157
General procedure: To a solution of the appropriate benzaldehyde (3.6 mmol) in glacial acetic acid (4 mL) was added the nitroalkane (7.2mmol) followed by cyclohexylamine (3.6 mmol, 0.4 mL). The reaction mixture was heated under microwave irradiation at 120 °C for 30 min. After cooling, water (10 mL) was added to the reaction and it was allowed to stand. The precipitated nitroethene was isolated by filtration. The filtrate was further diluted with water (20 mL) and extracted with dichloromethane (3 x 10 mL). The organic phases were combined and washed with saturated aqueous NaHCO3 (3 x10 mL). The solution was dried over anhydrous Na2SO4, filtered and all solvent removed in vacuo, to give an oil which was purified by flash column chromatography over silica gel (eluent: dichloromethane/hexane) and recrystallised from ethanol.
47%
With ammonium acetate; sulfuric acid In toluene
Preparation 37 2-(4-bromophenyl)-1-nitro-1-methylethylene A solution of 30.0 g (162 mmol) of 4-bromobenzaldehyde, 116 mL (1.6 mole) of nitroethane, and 37.5 g (486 mmol) of ammonium acetate in 200 mL of toluene was heated under a Dean and Stark trap for 18 hours. The mixture was then cooled to 80° C., 1 mL of concentrated sulfuric acid was added, and the mixture was stirred at 80° C. for 2 hours. The mixture was then cooled to ambient temperature and washed with 200 mL of brine. The organic layer was separated and the aqueous layer was extracted three times with 60 mL of diethyl ether. The combined organics were dried (MgSO4), filtered and coincentrated in vacuo. The residue was recrystallized from methanol to afford 18.7 g (47percent) of the title compound.
Reference：
[1] Tetrahedron, 2008, vol. 64, # 27, p. 6294 - 6299
[2] Tetrahedron Letters, 1986, vol. 27, # 33, p. 3843 - 3844
[3] Chemical Communications, 2016, vol. 52, # 65, p. 10060 - 10063
[4] Medicinal Chemistry, 2018, vol. 14, # 2, p. 181 - 199
[5] Patent: US6303816, 2001, B1,
[6] Angewandte Chemie - International Edition, 2013, vol. 52, # 15, p. 4235 - 4238[7] Angew. Chem., 2013, vol. 125, # 15, p. 4329 - 4332,4
[8] Chemical Communications, 2014, vol. 50, # 64, p. 8878 - 8881
55
[ 79-24-3 ]
[ 1122-91-4 ]
[ 623-00-7 ]
[ 25062-46-8 ]
[ 131981-75-4 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1991, vol. 40, # 2.2, p. 366 - 372[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1991, # 2, p. 426 - 433
56
[ 1122-91-4 ]
[ 1208-87-3 ]
Reference：
[1] Patent: CN107573288, 2018, A,
[2] Patent: CN107652238, 2018, A,
57
[ 1122-91-4 ]
[ 122-52-1 ]
[ 38186-51-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 15, p. 2934 - 2936
58
[ 1122-91-4 ]
[ 38186-51-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 14-15, p. 2659 - 2664
[2] Tetrahedron, 2013, vol. 69, # 3, p. 1065 - 1068
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 22, p. 6624 - 6628[4] Angew. Chem., 2018, vol. 130, # 22, p. 6734 - 6738,5
59
[ 1122-91-4 ]
[ 41841-16-1 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 8673 - 8695
60
[ 1122-91-4 ]
[ 122-39-4 ]
[ 4181-05-9 ]
Reference：
[1] Dyes and Pigments, 2012, vol. 95, # 2, p. 229 - 235
61
[ 1450-14-2 ]
[ 1122-91-4 ]
[ 2199-32-8 ]
Reference：
[1] Chemical Communications, 2000, # 19, p. 1895 - 1896
62
[ 1122-91-4 ]
[ 107859-98-3 ]
Reference：
[1] Patent: WO2014/131855, 2014, A1,
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
With C7H10N2*Pd(2+)*2Cl(1-); potassium carbonate In ethanol; water for 0.166667 h; Reflux; Schlenk technique
General procedure: A 20mL Schlenk tube with a magnetic stir bar was charged with aryl halide (2mmol), arylboronic acid (2.4mmol), K2CO3 (5mmol), 10mL of solvent [H2O, H2O–MeOH (1:1), H2O–EtOH (1:1), H2O–EG (1:1)] and an aliquot of 0.01M solution of palladium complexes PdCl2(L)2 or Pd[(L)4]Cl2 in MeOH (0.001–0.2molpercent) under air atmosphere. The reaction mixture was placed in a preheated oil bath: at 100°C for MeOH–H2O, at 110°C for EtOH–H2O, at 140°C for H2O and at 160°C for EG–H2O; and stirred under reflux for the given time. After this time, the mixture was cooled, acidified by 5M HCl (in the case of acids) and diluted with 10mL of H2O and 10mL of Et2O (or EtOAc). The organic phase was separated, and the aqueous layer was extracted with Et2O EtOAc) (2×10mL). The combined organic layers were washed with H2O (10mL), brine (10mL), and dried over Na2SO4. The pure products were obtained by a simple filtration of ether solution through silica gel pad and evaporation of a solvent.
40%
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In ethanol; water; tolueneReflux
General procedure: Tetrakis(triphenylphosphine)palladium(0) (0.0168 mmol) was added to a solution of 4-bromobenzaldehyde (50, 5.6 mmol) in ethanol-toluene (40 mL, 1:1). After 15 min, the appropriate boronic acid 51b-m (6.75 mmol) was added, followed by sodium hydrogen carbonate (22.4 mmol) and water (11 mL). The resulting mixture was heated under reflux for 9-15 hours. After cooling, the reaction mixture was filtered through Celite.(R)., the organic phase was separated, washed with brine (2x20 mL), dried and the solvent evaporated in vacuo. The residue thus obtained was purified by flash-chromatography. Elution by light petroleum-ethyl acetate mixtures afforded the desired compounds.
Reference：
[1] Chemistry of Heterocyclic Compounds, 2014, vol. 50, # 1, p. 19 - 25[2] Khim. Geterotsikl. Soedin., 2014, vol. 50, # 1, p. 24 - 31,7
[3] Russian Journal of General Chemistry, 2014, vol. 84, # 9, p. 1782 - 1792[4] Zh. Obshch. Khim., 2014, vol. 84, # 9, p. 1546 - 1556,11
[5] RSC Advances, 2015, vol. 5, # 85, p. 69776 - 69781
[6] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1918 - 1930
[7] Catalysis Communications, 2016, vol. 79, p. 17 - 20
[8] European Journal of Organic Chemistry, 2006, # 17, p. 3938 - 3946
[9] Macromolecules, 2011, vol. 44, # 13, p. 5155 - 5167
[10] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6379 - 6397
[11] Advanced Synthesis and Catalysis, 2008, vol. 350, # 14-15, p. 2391 - 2400
[12] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3429 - 3445
[13] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8445 - 8458
[14] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 453 - 462
67
[ 188290-36-0 ]
[ 1122-91-4 ]
[ 107834-03-7 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 8138 - 8142
[2] Synthetic Communications, 2011, vol. 41, # 23, p. 3524 - 3531
[3] European Journal of Organic Chemistry, 2017, vol. 2017, # 1, p. 111 - 123
[4] Heterocycles, 1990, vol. 31, # 11, p. 1951 - 1958
68
[ 14221-01-3 ]
[ 1122-91-4 ]
[ 107834-03-7 ]
Reference：
[1] Patent: US5849911, 1998, A,
69
[ 1264696-96-9 ]
[ 1122-91-4 ]
[ 107834-03-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2011, # 1, p. 143 - 149
70
[ 54663-78-4 ]
[ 1122-91-4 ]
[ 107834-03-7 ]
Reference：
[1] Journal of Materials Chemistry A, 2013, vol. 1, # 38, p. 11909 - 11921
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In toluene at 90 - 100℃; for 6 h; Sealed tube
Pd(dppf)Cl2.CH2Cl2 (0.48 g, 0.0005 mole) was added to a sealed tube containing a mixture of 4-bromobenzaldehyde (1 g, 0.005 mole), potassium acetate (1.31 g, 0.013 mole) and bis(pinacolato)diboron (1.6 g, 0.006 mole) in toluene (20 mL) and the contents were heated at 90 - 100 °C for 6 hours and then cooled to room temperature. The reaction mass filtered through a pad of celite and washed with ethyl acetate (20 mL x 2). The filtrate was concentrated under vacuum to obtain the crude compound that was further purified by flash chromatography using ethyl acetate:hexanes (10:90) to obtain 4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)benzaldehyde. Yield: 1.12 g; l - NMR (CDC13, 400 MHz) δ ppm: 1.36 (s, 12H), 7.85 - 7.87 (d, J = 7.72 Hz, 2H), 7.95 - 7.97 (d, J = 7.8 Hz, 2H), 10.05 (s, 1H); Mass (m/z): 233.0 (M+H)+.
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 6, p. 977 - 983
[2] Patent: WO2013/170165, 2013, A1, . Location in patent: Page/Page column 93
[3] Applied Organometallic Chemistry, 2011, vol. 25, # 7, p. 537 - 541
[4] Organic Letters, 2016, vol. 18, # 20, p. 5248 - 5251
[5] Journal of the American Chemical Society, 2016, vol. 138, # 1, p. 84 - 87
[6] Synthetic Communications, 2007, vol. 37, # 5, p. 667 - 674
[7] Journal of Materials Chemistry, 2011, vol. 21, # 14, p. 5451 - 5456
[8] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 536 - 539
[9] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 51
[10] Patent: WO2018/195321, 2018, A1, . Location in patent: Page/Page column 493; 494
74
[ 61676-62-8 ]
[ 1122-91-4 ]
[ 128376-64-7 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 1, p. 263 - 271
75
[ 1122-91-4 ]
[ 73183-34-3 ]
[ 100-52-7 ]
[ 128376-64-7 ]
Reference：
[1] Green Chemistry, 2012, vol. 14, # 3, p. 661 - 667
76
[ 1122-91-4 ]
[ 215453-51-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
77
[ 1122-91-4 ]
[ 223671-15-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[2] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10464 - 10467
78
[ 668987-38-0 ]
[ 1122-91-4 ]
[ 128376-65-8 ]
Yield
Reaction Conditions
Operation in experiment
10%
at 100℃; for 18 h;
A round-bottom flask charged with the aryl halide (5.0 mmol, 1.0 equiv), Ni (For exact amount of catalyst and co-ligand see Table 8; 10percent loading was used for Ni catalysts not specified in Table 8). (NiCl2(L)x , Ni(COD)2) or Pd (No co-ligand was used for Pd catalyst) catalysts (PdCl2(dppf)) (0.5 mmol, 0.1 to 0.02 equiv), ligand (L: dppp, dppe, dppf, PPh3, Et3N, bpy, PCy3) (0.5 mmol, 0.1 equiv), and a Teflon.(R). coated stir bar was evacuated three times for 10 min under high vacuum and backfilled with N2. Toluene (5 mL) and base (Et3N or (i-Pr)2EtN (15.0 mmol, 3.0 equiv) were added to the reaction mixture at rt. Freshly prepared neopentylglycolborane (10.0 mmol, 2.0 equiv in 5 ml toluene) was added to the red colored suspension via syringe at 23 0C. The reaction mixture was heated to 100 0C and the conversion was followed by GC. After 2 h-12 h (reaction time depends on the type of the aryl halide; iodo derivatives were found to react faster, in 2-4 h , while bromo derivatives in 8-12h), the reaction mixture was quenched via slow addition of saturated aqueous ammonium chloride (10 mL). The quenched reaction mixture was three times washed with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography or recrystallization.
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 2, p. 888 - 896
82
[ 1122-91-4 ]
[ 206055-91-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 2, p. 284 - 302
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 3, p. 765 - 781
[3] Patent: WO2014/117090, 2014, A1,
[4] Chemical Papers, 2015, vol. 69, # 11, p. 1500 - 1511
[5] Ultrasonics Sonochemistry, 2017, vol. 36, p. 343 - 353
[6] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 929 - 936
[7] Patent: WO2008/108602, 2008, A1,
83
[ 1122-91-4 ]
[ 364794-79-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
84
[ 59020-10-9 ]
[ 1122-91-4 ]
[ 127406-55-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
With copper(l) iodide; C37H51ClFeNPPd; cesium fluoride In N,N-dimethyl-formamide at 80℃; for 12 h; Inert atmosphere
General procedure: 4.3.10 4-(Pyridin-3-yl)benzaldehyde (3ja) White solid, mp 50-51 °C; 1H NMR (400 MHz, CDCl3): δ=10.09 (s, 1H), 8.90 (d, J=1.76 Hz, 1HAryl halide (0.5 mmol), base (1 mmol), CuI (20 mol percent), alkylstannylpyridine(0.75 mmol), and catalyst (1 mol percent) were dissolvedin DMF (2 mL) in a 10 mL vial and heated at a specific temperatureunder N2 for 12 h. After the reaction was complete, and thenquenched with water. The mixture was diluted with ethyl acetate(10 mL), filtered through a pad of Celite, and followed by extractionwith ethyl acetate for three times. The combined organic layer wasdried over anhydrous Na2SO4, filtered, and evaporated under reducedpressure. The residual was purified by flash chromatographyon silica gel (ethyl acetate/hexane) to give the desired product.), 8.68-8.66 (m, 1H), 8.00 (d, J=8.24 Hz, 2H), 7.93 (d, J=7.88 Hz, 1H), 7.76 (d, J=8.20 Hz, 2H), 7.41-7.44 (m, 1H); 13C NMR (100 MHz, CDCl3): δ=123.8, 127.8, 127.8, 130.5, 130.5, 134.6, 135.3, 135.8, 143.8, 148.4, 149.6, 191.8; HRMS-ESI (m/z): [M+H]+ calcd for C12H10NO+: 184.0757, found: 184.0758.
Reference：
[1] European Journal of Organic Chemistry, 2009, # 13, p. 2051 - 2054
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[3] Dalton Transactions, 2007, # 35, p. 3952 - 3958
[4] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 453 - 462
86
[ 16518-17-5 ]
[ 1122-91-4 ]
[ 127406-55-7 ]
Yield
Reaction Conditions
Operation in experiment
45%
With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); 1,10-Phenanthroline In N,N-dimethyl acetamide at 60 - 180℃; for 4 h; Inert atmosphere; Glovebox; Microwave irradiation
General procedure: In an argon-filled glovebox, a 10 mL microwave vial was charged with Pd(PPh3)4 (14.35 mg,0.0125 mmol), Cu2O (21.3 mg, 0.15 mmol), 1,10-phenanthroline (8.95 mg,0.05 mmol), the potassium pyridylcarboxylate (0.50 mmol), aryl bromide(0.75 mmol) and anhydrous DMA (3.0 mL). The resulting solution wasirradiated in a microwave reactor (Biotage Initiator Eight EXP) with a 2 minprestirring period, followed by 10 min at 60 C. The reaction was then heatedat 180 C for 3 h 50 min. The maximum pressure noted was 3 bar. Aftercompletion of the reaction, H2O was added to the mixture which was thenextracted with EtOAc (3 10 mL). The combined organic layers were washedwith brine (5 mL), dried over Na2SO4, filtered, and the volatiles removed invacuo. The residue was purified by column chromatography on silica gel,yielding the corresponding biaryl product.
With sodium carbonate In methanol at 20℃; for 3 h; Sealed tube; Inert atmosphere
General procedure: To a round bottom flask with stir bar were added phenylboronic acid (275 mmol), 1-bromo-4-nitrobenzene (250 mmol), base (375 mmol), 1.0 molpercent catalyst 6 (9.2 mg), and solvent 4mL. The entrance was sealed with septum, and inside air was was exchanged with N2. After the mixture was stirred at room temperature for a certain period, the mixture was diluted with H2O (5ml) and Et2O (5 ml). Organic layer was concentrated in vacuo.
Reference：
[1] Journal of Chemical Research, 2004, # 9, p. 593 - 595
[2] Advanced Synthesis and Catalysis, 2004, vol. 346, # 13-15, p. 1669 - 1673
[3] Synthesis, 2005, # 4, p. 537 - 542
[4] Tetrahedron Letters, 2018, vol. 59, # 31, p. 2989 - 2993
[5] ChemCatChem, 2016, vol. 8, # 4, p. 743 - 750
[6] Organometallics, 2011, vol. 30, # 8, p. 2411 - 2417
[7] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3429 - 3445
[8] Tetrahedron, 2017, vol. 73, # 1, p. 64 - 69
With caesium carbonate In 1,4-dioxane at 110℃; Inert atmosphere
Compound B6.1 (1.00 g; 2.721 mmol), 4-bromobenzaldehyde (0.604 g;3.266 mmol) and cesium carbonate (0.436 ml; 5.443 mmol) weresuspended in dry 1,4-dioxane (10.0 mL) under argon atmosphere. The mixture was heated to 110 °C and stirred overnight at this temperature. The reaction mixture was cooled to room temperature, quenched with water (30 mL) and extracted with MTB-ether. The combined organic layerswere washed with 5percent citric acid solution, saturated NaHCO3 solution and brine, dried with sodium sulfate, filtered by suction and evaporated to dryness. The solid residue was triturated with petrolether/MTB-ether (1:1), filtered by suction, washed with petrolether/MTB-ether (3:1) and dried.From the filtrate further product was isolated by flash chromatography (Companion RF; 40 g Si50 silica gel column). Yield: 657 mg (66percent) colorless solid; LC/MS (A), Rt: 2.72 mm; (M+H-t-Bu) 312.0/314.0
Reference：
[1] Applied Organometallic Chemistry, 2017, vol. 31, # 4,
[2] Journal of Mass Spectrometry, 2008, vol. 43, # 4, p. 542 - 546
97
[ 1122-91-4 ]
[ 1088410-99-4 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 12, p. 1702 - 1713
[2] Organic Process Research and Development, 2014, vol. 18, # 12, p. 1702 - 1713
98
[ 1122-91-4 ]
[ 1088410-99-4 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 12, p. 1702 - 1713
[2] Organic Process Research and Development, 2014, vol. 18, # 12, p. 1702 - 1713
With tetrabutylammomium bromide; potassium carbonate; In methanol; water; at 80℃; for 0.25h;Reflux;
General procedure: A mixture of hetarylboronic acid 4a-d(1.2 mmol), aryl(hetaryl) bromide 5a-h or hetaryl chloride7a,b (1 mmol), Bu4NBr (3 mg, 1 mol %, for water-insolublearyl(hetaryl) halides 5b-g and 7a,b), and K2CO3 (346 mg,2.5 mmol) in 2 (5 ml) was heated to 80 and treated byadding 0.1-1 mol % of Pd-Ni(Co)-B-L (an aliquot of0.1 M solution of bimetallic catalyst in MeOH-H2Omixture). The reactor was fitted with a reflux condenserand placed in a hot silicone oil bath (150). The reactionmixture was vigorously stirred at reflux until completeconversion of the starting materials was achieved. Thereaction progress was controlled by TLC method (eluenthexane-Et2O, 3:1). The amount of catalyst, reactionduration and yields of the target compounds 6a-k are listedin Table 4. In the case of the activated aryl bromides5a,b,d,f, the reaction was highly exothermic, therefore aneffective reflux condenser was essential for scaling up thissynthesis.After the reaction was complete, the mixture was dilutedwith H2O (10 ml), heated to 80C, and filtered while hotthrough a Whatman autovial syringeless filter (pore size0.45 mum). The filtrate was diluted with 10-15 vol % ofEtOH, heated to ~50C, stirred, and slowly acidified with5% HCl to pH 2-3. The resulting precipitate was easy tofilter, and analytically pure products 6a,h,k were obtainedwithout chromatographic purification. In the case of thewater-insoluble heterobiaryls 6b-g,i,j, the reaction mixturewas diluted with saturated solution of NaCl (10 ml) andextracted with Et2O or EtOAc (3×5 ml). The obtainedextract was dried over anhydrous Na2SO4, filtered througha silica gel layer, and the solvent was evaporated at reducedpressure. The residues in all cases were >99% pureproducts (according to the results of elemental analysis).Analytically pure samples were obtained by recrystallizationof heterobiaryls 6a-k from a minimal amount ofaqueous EtOH (10-20% 2) or by converting amines intothe respective hydrochlorides. The residual metal content inthe isolated heterobiaryls 6a-k did not exceed 1 ppmaccording to the results of atomic absorption spectrometry.
87%
With C7H10N2*Pd(2+)*2Cl(1-); potassium carbonate; In ethanol; water; for 0.166667h;Reflux; Schlenk technique;
General procedure: A 20mL Schlenk tube with a magnetic stir bar was charged with aryl halide (2mmol), arylboronic acid (2.4mmol), K2CO3 (5mmol), 10mL of solvent [H2O, H2O-MeOH (1:1), H2O-EtOH (1:1), H2O-EG (1:1)] and an aliquot of 0.01M solution of palladium complexes PdCl2(L)2 or Pd[(L)4]Cl2 in MeOH (0.001-0.2mol%) under air atmosphere. The reaction mixture was placed in a preheated oil bath: at 100C for MeOH-H2O, at 110C for EtOH-H2O, at 140C for H2O and at 160C for EG-H2O; and stirred under reflux for the given time. After this time, the mixture was cooled, acidified by 5M HCl (in the case of acids) and diluted with 10mL of H2O and 10mL of Et2O (or EtOAc). The organic phase was separated, and the aqueous layer was extracted with Et2O EtOAc) (2×10mL). The combined organic layers were washed with H2O (10mL), brine (10mL), and dried over Na2SO4. The pure products were obtained by a simple filtration of ether solution through silica gel pad and evaporation of a solvent.
40%
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene;Reflux;
General procedure: Tetrakis(triphenylphosphine)palladium(0) (0.0168 mmol) was added to a solution of 4-bromobenzaldehyde (50, 5.6 mmol) in ethanol-toluene (40 mL, 1:1). After 15 min, the appropriate boronic acid 51b-m (6.75 mmol) was added, followed by sodium hydrogen carbonate (22.4 mmol) and water (11 mL). The resulting mixture was heated under reflux for 9-15 hours. After cooling, the reaction mixture was filtered through Celite, the organic phase was separated, washed with brine (2x20 mL), dried and the solvent evaporated in vacuo. The residue thus obtained was purified by flash-chromatography. Elution by light petroleum-ethyl acetate mixtures afforded the desired compounds.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 130℃;Microwave irradiation; Sealed tube;
General procedure: To a solution of a 3- or 4-bromobenzaldehyde in a mixture DMF/water (3:1; 14.8mL/mmol) were added boronic acid derivative (1.5 equiv.), Pd(PPh3)4 (5mol%), and K2CO3 (2 equiv.). The reaction mixture was heated under microwave irradiation (130C) until TLC showed complete conversion of the starting material (0.5-1h). After cooling, the mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered off, and concentrated under reduced pressure to afford the corresponding crude product 2. (0027) Compounds 2a-2p were synthesized following the procedure described above from the corresponding boronic acids.
With hydrogenchloride; sodium hydroxide; zinc diiodide; trifluoroacetic acid; lithium diisopropyl amide; In tetrahydrofuran; n-heptane; dichloromethane; water;
Step 1. Preparation of 1-(4-bromophenyl)-2-phenylethan-1-one. 4-Bromobenzaldehyde (10.0 g, 54 mmol), dichloromethane (100 mL), and zinc iodide (5 mg) were stirred at 0° C. under nitrogen and treated with trimethylsilylcyanide (5.95 g, 60 mmol) dropwise. The reaction was stirred for 16 hours, then water (5 mL) was added dropwise. The mixture was washed with brine (2*30 mL), dried over MgSO4, and concentrated under high vacuum. The resulting oily residue was dissolved in tetrahydrofuran (150 mL) and cooled to -78° C. under nitrogen. Lithium diisopropylamide (2.0M solution in heptane/tetrahydrofuran/ethylbenzene, 30 mL, 60 mmol) was added dropwise, maintaining the temperature below -60° C. This solution was stirred for 0.5 hour then treated with benzyl bromide (10.26 g, 60 mmol). The solution was warmed to -15° C. and poured into a stirred solution of 1N hydrochloric acid (150 mL) and trifluoroacetic acid (10 mL). After stirring for 1 hour, the mixture was extracted with ethyl acetate (2*50 mL). The combined extract was washed with brine (2*50 mL) and concentrated. The resulting dark oily residue was treated with 2.5N sodium hydroxide, filtered and recrystallized from acetone/ethanol/water to afford a light brown solid (11.5 g, 77percent): mp 111.4-111.5.
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
EXAMPLE 33 Synthesis of 4-formyl-4'-ethoxybiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (1.1 mg, 0.005 mmol, 0.5 mol %), 2-(di-tert-butylphosphino)biphenyl (3.0 mg, 0.01 mmol, 1.0 mol %), 4-ethoxyphenylboronic acid (249 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4-bromobenzaldehyde (185 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 203 mg (90%) of the title compound.
203 mg (90%)
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
Example 33 Synthesis of 4-formyl-4'-ethoxybiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (1.1 mg, 0.005 mmol, 0.5 mol %), 2-(di-tert-butylphosphino)biphenyl (3.0 mg, 0.01 mmol, 1.0 mol %), 4-ethoxyphenylboronic acid (249 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0 mmol), and 4-bromobenzaldehyde (185 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) was added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 203 mg (90%) of the title compound.
With potassium acetate; In thiophene; ISOPROPYLAMIDE; water;
45a 4-(Thiophen-2-yl)-benzaldehyde ?see Heterocycles 31, 1951[(1990)] 3.7 g (20 mmol) of 4-bromobenzaldehyde, 9.5 ml (120 mmol) of thiophene, 2.94 g (30 mmol) of potassium acetate and 1.16 g (1 mmol) of tetrakis(triphenylphosphine)-palladium (Fluka, Buchs, Switzerland) in 50 ml of dimethylacetamide are placed in a pressure reactor and stirred at 150 C. under nitrogen for 16 hours. The reaction mixture is concentrated by evaporation; the residue is taken up in water and extracted three times with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of a yellow solid. TLC: Rt 0.36 (hexane/ethyl acetate 4:1). HPLC20-100: tRet =15.26. 1H-NMR (CD3 OD; 200 MHz): 9.98/s (1H); 7.93 and 7.85/each d, J=9.5 (2*2H); 7.60/d, J=2.5 (1H); 7.52/d, J=5 (1H); 7.17/d*d, J=2.5 and 5 (1H).
2-(4-{3-[3,5-bis(trifluoromethyl)phenoxy]prop-1-ynyl}benzyl)-1,2,4-oxadiazolidine-3,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 61: Synthesis of 2- (4- {3- [3, 5-bis (TRIFLUOROMETHYL) PHENOXY] PROP-1- YNYL} BENZYL)-1, 2, 4-oxadiazolidine-3, 5-dione.[0270] Step 1.4-bromobenzaldehyde (20 mmole) was taken in 1 : 1 DIEMTHOXYETHANE and water (50 ML). To it was added 50 mmole of potassium carbonate was added followed by triphenyl phosphine (1. 6 mmole), 0.4 mmole of 10percent Palladium on Carbon and 0. 8 mmole of copper (I) iodide at room temperature. The mixture was stirred at room temperature for 1 hour.To it was added propargyl alcohol (50 mmole) and the reaction mixture was heated overnight.The reaction mixture was cooled to room temperature and filtered through a pad of celite anc concentrated. The residual oil was purified by flash column chromatography using 10percent EtOAc in hexane.[0271] Step 2. The alcohol (LMMOLE) from step 1 was dissolved in THF and treated with triphenyl phosphine (1 mmole), DIETHYLAZODICARBOXYLATE (1 mmole) and 3,5-bistrifluoromethyl phenol and stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash column chromatography (20percent EtOAc in hexane).[0272] Step 3. To a solution of the aldehyde from step 2 (0.5 mmol) dissolved in pyridine (0.5 ML) and ETOH (4.5 ml) was added hydroxylamine hydrochloride (17.4 mg, 0.25 MMOL). The reaction was heated to 60 C for 2 hours. The solvent was evaporated in VACUO.[0273] Step 4. To a solution of oxime (0.5 mmol) obtained from step 3 dissolved in MEOH (1 ML) was added 8M solution of borane/pyridine complex (0.313 ml, 2.5 mmol) and 10percent HC1 (0.5 ml). The reaction was shaken for 3 hours. The solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was dried with MGS04 and concentrated in VACUO.[0274] Step 5. To a solution of hydroxylamine (0. 5 MMOL) obtained from step 4 in anhydrous THF (2 ml) was added N- (chlorocarbonyl) isocyanate (0.527 g, 5 MMOL). The reaction was shaken at room temperature for 3 hours. To the reaction was added 10percent HC1. The solvent was evaporated in vacuo. The crude product was purified by RP-HPLC to give example 6. MS: (M-H) 457.
Example 1; Preparation of 2-(4-bromophenyl)cyclopropanecarboxylic acid (4); Example 1a; Preparation of (E)-tert-butyl 3-(4-bromophenyl)acrylate (2); To a three-necked flask was charged with NaH (95percent, 2.6 g, 103 mmol) followed by Toluene (250 ml). The suspension was cooled to 5° C. and to the mixture was added the t-butyldimethylphosphonoacetate (95percent, 25.5 ml, 103 mmol) slowly keeping the temperature below 5° C. (very little exotherm observed and H2 gas generated), the resulting mixture was stirred at 5° C. for NLT20 min until no more H2 gas was generated). To the above mixture was then added the aldehyde (17.6 g, 94.2 mmol) and the resulting mixture was stirred at 10° C. for 2 hours and then at room temperature overnight. The reaction was monitored by HPLC until the starting material is consumed (<1.0 pa percent of aldehyde). The reaction mixture was poured into 400 ml of water and the organic layer was separated and washed with brine (400 ml), dried with Na2SO4 and concentrated to give an oil, which solidified upon standing to give crude product which was purified by crystallization from ethanol/water water (1:1, 30 mL/g) to give 25 g of product. 1H NMR (400 MHz, DMSO-d6) delta 1.47 (s, 9H), 6.53 (d, 1H, J=15.92), 7.50 (d, 1H, J=16.05), 7.57 (d, 2H, J=8.51), 7.63 (d, 2H, J=8.51). 13C NMR (100 MHz, DMSO-d6) delta 27.8, 79.8, 120.3, 123.0, 129.6, 131.3, 132.9, 141.6 164.6 with 4 peaks overlapping. A sample of the isolated product was purified by crystallization from ethanol/water (1:1, 30 mL/g). 1H NMR (400 MHz, DMSO-d6) delta 1.47 (s, 9H), 6.53 (d, 1H, J=15.92), 7.50 (d, 1H, J=16.05), 7.57 (d, 2H, J=8.51), 7.63 (d, 2H, J=8.51). 13C NMR (100 MHz, DMSO-d6) delta 27.8, 79.8, 120.3, 123.0, 129.6, 131.3, 132.9, 141.6 164.6 with 4 peaks overlapping.
4-((E)-3,3,4,4,5,5,6,6,6-Nonafluoro-hex-1-enyl)-benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; C30H25ClN2P2Pd; In N,N-dimethyl-formamide; at 130℃; for 12h;Sealed tube;
General procedure: A sealed tube was charged with aryl halide (1.0 mmol), fluoroalkyl-substituted ethylenes (1.1 mmol), K3PO4 (1.0 mmol), DMF (2 mL) and catalyst (1 molpercent Pd), the mixture was stirred at a certain temperature for a certain time. After being cooled to room temperature, the mixture was filtered. The solvent and excess fluoroalkyl-substituted ethylenes were removed under reduced pressure and the residue was purified by F-SPE technique. Menthol and H2O (v/v = 8:2) were used as fluorophobic elution, while H2O were used as fluorophilic elution. The product was obtained from fluorous phase in high purity.
4-bromobenzaldehyde (7.40g, 40 mmol) and 4-acetyl-4'-bromobiphenyl (11.01, 40 mmol) were dissolved in ethanol (80 mL), and sodium hydroxide (0.16g, 4 mmol) was added. The resulting solution was stirred at room temperature for 8 hours. Then, benzamidine hydrochloride (4.70g, 30 mmol), sodium hydroxide (1.60g, 40 mmol) and ethanol (40 mL) were added, and the resulting solution was reacted while heating under reflux for 8 hours. White powder generated was filtered off and washed with ethanol until the liquid became colorless. The powder was further washed with water and ethanol. 200 mL of ethanol was added again, and then heated under reflux for an hour, followed by filtering. The filtered matter was dried in vacuum to obtain an intended intermediate O (9.32g, yield: 86%).
2-(2-(4-bromobenzylidene)hydrazino)-6-fluorobenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized to give compounds 3-29.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 130℃;Microwave irradiation; Sealed tube;
General procedure: To a solution of a 3- or 4-bromobenzaldehyde in a mixture DMF/water (3:1; 14.8mL/mmol) were added boronic acid derivative (1.5 equiv.), Pd(PPh3)4 (5molpercent), and K2CO3 (2 equiv.). The reaction mixture was heated under microwave irradiation (130°C) until TLC showed complete conversion of the starting material (0.5?1h). After cooling, the mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered off, and concentrated under reduced pressure to afford the corresponding crude product 2. (0027) Compounds 2a-2p were synthesized following the procedure described above from the corresponding boronic acids.
4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With dichlorobis(triphenylphosphine)palladium(II); sodium carbonate; In 1,2-dimethoxyethane; at 80℃; for 16h;Sealed tube; Inert atmosphere;
4-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)benzaldehyde In a 30 mL sealed tube purged and maintained with an inert atmosphere of argon, 4-bromobenzaldehyde (500 mg, 2.70 mmol, 1.00 equiv), <strong>[454482-11-2]1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (723.6 mg, 3.24 mmol, 1.20 equiv), Pd(PPh3)2Cl2 (189.7 mg, 0.27 mmol, 0.10 equiv) and a solution of sodium carbonate (572.8 mg, 5.40 mmol, 2.00 equiv) were mixed in a mixture of ethylene glycol dimethyl ether/water (10:3, 13 mL) at room temperature. The resulting mixture was stirred for 16 h at 80 C. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in (10% to 30% gradient) petroleum ether to afford 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzaldehyde (490 mg, 86%) as a yellow solid.
General procedure: Ammonium salt 6 (1 equiv.) was suspended in dry THF (0.05 M) andstirred at 40 °C. t-BuOK (4 equiv.) was added and the mixture was stirred vigorously. After 10 minutes 2 equiv. of aldehyde 2 were added and the mixture was stirred for 3 hours at 40 °C. The reaction was then quenched by addition of a half-saturated NaCl solution. After phase separation, the aqueous phase was extracted three times with DCM and the combined organic phases were dried with Na2SO4 and evaporated to dryness. Purification by columnchromatography (gradient of heptanes and EtOAc) gave the corresponding epoxides in the reported yields as a mixture of diastereomers.
With 4,4-bis(2-naphthyl)-1,3,5,7,8-pentamethyl-2,4-diethyl-4-bora-3a,4a-diaza-s-indacene; N,N-dicyclohexylmethylamine; nickel dibromide; In N,N-dimethyl-formamide; at 40℃; for 48h;Inert atmosphere;
Example 3: In this embodiment,The photocatalyst 1a in Example 1 was replaced with an equimolar photocatalyst 1c,The other steps are the same as in the first embodiment,4- [2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde 969 mg was obtained.The yield was 95%.:_Example 1: Under a nitrogen atmosphere,5-Ethyl-2-(2-hydroxyethyl)pyridine (1.21 g, 8 mmol)And 4-bromobenzaldehyde (0.74 g, 4 mmol) was added to a 25 mL reaction flask containing 5 mL of N,N-dimethylformamide.NiBr2 (0.043 g, 0.2 mmol) was added in that order.Photocatalyst 1a (1.3 mg, 0.002 mmol),N,N-Dicyclohexylmethylamine (1.41 g, 7.2 mmol),The reaction solution was heated to 40 C.Reaction under white light for 48 hours,After the reaction,Stop lighting,heating,Allow the reaction flask to cool to room temperature,The reaction solution is distilled under reduced pressure.Removal of N,N-dimethylformamide,N,N-dicyclohexylmethylamine,Column chromatography (using a 3:1 mixture of petroleum ether and ethyl acetate as the eluent)get4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde 918 mg,The yield was 90%.
General procedure: A mixture of 2-bromobenzoic acid (1.0 mmol), propargylamine (1.0 mmol), 4-methlyl benzaaldehyde (1.0 mmol) and cyclohexyl isocyanides (1.1 mmol) in methanol (4.0 mL) was stirred for 24 hours at room temperature. After completion of the reaction as indicated by TLC, a mixture of ice and water (4.0 mL) added to the reaction to form a yellowish precipitate. Then, the prepared precipitate washed with cold water and dried to produce the desired compound 5a.
A solution of 4-bromobenzaldehyde (0.654 mmol), 3-[(tert- butoxycarbonyl)amino]phenylboronic acid (0.719 mmol) and potassium carbonate (1.96 mmol) in a 0.1 M solvent mixture of ethanol:toluene:water (9:3:1) was stirred at room temperature for 5 minutes under N2. Tetrakis(triphenylphosphine)pallaidum(0) (0.0654 mmol) was then added and the mixture was stirred under microwave irradiation at 100 C for 20 minutes. The mixture was then filtered through a pad of celite and concentrated in vacuo. The crude sample was redissolved in DCM and water, and transferred to a separatory funnel. The two layers were partitioned and the aqueous layer was extracted with DCM (3X). The collected organic layers were then washed once with saturated NaCl solution, dried over MgSO4 and concentrated in vacuo. The crude sample was absorbed onto a small amount of silica and purified using flash chromatography using a Hexane:EtOAc gradient. tert-butyl (4'-formyl-[1,1'-biphenyl]-3-yl)carbamate was isolated as an oil (58%).1H NMR (400 MHz, CDCl3) delta 10.07 (s, 1H), 7.94 (d, J = 2.6Hz, 2H), 7.81 (s, 1H), 7.77 (d, J = 2.9 Hz, 2H), 7.43- 7.29 (m, 3H) ,6.76 (s, 1H), 1.56 (s, 9H).
With triphenylphosphine; In 1-methyl-pyrrolidin-2-one; at 100℃;Sealed tube; Inert atmosphere;
General procedure: An oven-dried 3-neck round-bottomed ask equipped with amagnetic stir bar was charged with aryl aldehyde (1.0 equiv.) andtriphenylphosphine (1.2 or 1.5 equiv.). The system was sealed withthree PFTE septa, and subsequently evacuated and backlled withN2 three times. Dry NMP was added via syringe transfer (PTFE sy-ringe with oven-dried stainless-steel needle), and the system wasimmersed in a preheated 100C oil bath. Once no solid reagentsremained (approximately 2 min of heating), potassium bromodi-uoroacetate (1.5 or 1.8 equiv.) was added portionwise over 0.5 h,with the rate of addition controlling the evolution of CO2 gas. Onceall of the potassium bromodiuoroacetate was added, the solutionwas allowed to stir for 0.5e1 h. Upon completion, the reaction wascooled to room temperature and then quenched with H2O. Subse-quently, Et2O was added to the reaction, and the mixture waswashed with H2O (ve times), and the aqueous layer was back-extracted with Et2O (two times). The combined organic layerswere dried over Na2SO4 and concentrated. The crude material wasdry-packed onto silica gel and then eluted through a plug of silicagel with EtOAc:hexanes (1:1) to remove triphenylphosphine oxide.Subsequently, H2O2 (30% in H2O) was added to the mother liquorand allowed to react for 30 min to oxidize the residual triphenyl-phosphine. The organic layer was washed with H2O (three times),dried over Na2SO4, concentrated, and subjected to normal phaseash chromatography using EtOAc and hexanes.
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