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To a solution of 4-formylphenylboronic acid (4.11 g) in anhydrous tetrahydrofuran (THF) (40 ml_) was added 2,2-dimethyl-1 ,3-propanediol (3.14 g) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness. The residue was dissolved in dichloromethane (120 ml_), washed with water (80 ml_ x 3), dried and evaporated under vacuum to obtain 4-(5,5-dimethyl-[1 ,3,2]dioxaborinan-2-yl)-benzaldehyde (5.66 g, 95percent yield).
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.
In tetrahydrofuran; at 20℃; for 2h;Product distribution / selectivity;
To a solution of 4-formylphenylboronic acid (4.11 g) in anhydrous tetrahydrofuran (THF) (40 ml_) was added 2,2-dimethyl-1 ,3-propanediol (3.14 g) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness. The residue was dissolved in dichloromethane (120 ml_), washed with water (80 ml_ x 3), dried and evaporated under vacuum to obtain 4-(5,5-dimethyl-[1 ,3,2]dioxaborinan-2-yl)-benzaldehyde (5.66 g, 95% yield).
In toluene; for 2h;Heating / reflux;Product distribution / selectivity;
To a mixture of 4-formylphenylboronic acid (50 g) in toluene (250 ml_) was added 2,2-dimethyl-1 ,3-propanediol (34.39 g) and the dispersion was heated at reflux for 2 h. The water while formed was azeotropically separated and the residue (330 ml_) was used directly in the next step. 1H-NMR (400 MHz,CDCI3): delta 1.04 (s, 6 H, 2 CH3), 3.79 (s, 4 H, 2 CH2), 7.84 (d, J = 6.4 Hz, 2 H, H-Ar), 7.96 (d, J = 8 Hz, 2 H, H-Ar), 10.04 (s, 1 H, CHO) ppm.
In toluene; for 2h;Heating / reflux;
Example 1 : Preparation of 4-(5,5-dimethyl-H ,3,21dioxaborinan-2-yl)- benzaldehvde;To a mixture of 4-formylphenylboronic acid (50 g) in toluene (250 mL) was added 2,2-dimethyl-1 ,3-propanediol (34.39 g) and the dispersion was heated at reflux for 2 h. The water while formed was azeotropically separated and the residue (330 mL) was used directly in the next step.1H-NMR (400 MHz, CDCI3): delta 1.04 (s, 6 H, 2 CH3), 3.79 (s, 4 H, 2 CH2), 7.84 (d, J = 6.4 Hz, 2 H,H-Ar), 7.96 (d, J = 8 Hz, 2 H, H-Ar), 10.04 (s, 1 H, CHO) ppm.
tert-butyl N-{3-{[4-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)phenyl]methylidene}amino}propyl}-N-{4-[(tert-butyloxy)carbonyl]amino}butyl}carbamate[ No CAS ]
(5Z,10Z,14Z,19Z)-5-[4-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-15-[4-(5,5-dimethyl-[1,3]dioxan-2-yl)-phenyl]-2,8,12,18-tetrahexyl-3,7,13,17-tetramethyl-porphyrin[ No CAS ]
2-(2,5-di-<i>tert</i>-butyl-phenyl)-6-[2-(4-{15-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-2,8,12,18-tetrahexyl-3,7,13,17-tetramethyl-porphyrin-5-yl}-phenyl)-[1,3]dioxan-5-yl]-pyrrolo[3,4-<i>f</i>]isoindole-1,3,5,7-tetraone[ No CAS ]
In tetrahydrofuran; at 20℃; for 72h;Molecular sieve;Product distribution / selectivity;
A mixture of L-Valine methyl ester hydrochloride (548 mg), 4-(5,5-dimethyl- [1 ,3,2]dioxaborinan-2-yl)-benzaldehyde (476 mg) and molecular sieves in anhydrous THF (17 ml_) was stirred at room temperature for three days. Then, the mixture was cooled to O0C and a solution of NaBH3CN (155 mg) in dry MeOH (3 ml_) was added dropwise. The mixture was stirred at room temperature for 4 hours and the solids were removed by filtration. The filtrate was evaporated under vacuum to yield the desired product (632 mg) that was used in the next reaction without further purification.
With triethylamine; In toluene; for 1h;Heating / reflux;Product distribution / selectivity;
A mixture of L-Valine benzyl ester tosylate (132.7 g), 4-(5,5-dimethyl- [1 ,3,2]dioxaborinan-2-yl)-benzaldehyde (330 ml_), Et3N (48.4 ml_) and toluene (413 ml_) was heated at reflux temperature for 1 h. The water while formed was azeotropically separated. Then, the mixture was cooled to room temperature and the solution was washed with aqueous NaHCO3 (317 ml_ x 2) and water (317 ml_). The residual water was azeotropically removed. The toluene was partially distilled (134 ml_) and MeOH (134 ml_) was added. The solution was then cooled to 0-5 0C and NaBH4 (6.5 g) was slowly added. The reaction mixture was stirred at room temperature overnight. Then the solvent was partially distilled (half volume) and the residue was washed with aqueous NaHCO3 (270 ml_). The separated aqueous phase was extracted with toluene (135 ml_ x 2). The combined organic phases were then washed with water (135 ml_). The residual water in the organic layer was azeotropically removed and the residue (aprox. 730 ml_) was used directly in the next step. 1H-NMR (400 MHz, CDCI3): delta 0.91 and 1.02 (s and m, 12 H, CH3), 1.77 (bs, 1 H, NH), 1.93 (m, 1 H, CH(CH3)2), 1.82 (bs, 1 H, NH), 3.05 (d, 1 H, J = 6.4 Hz, CH-N), EPO <DP n="18"/>3.58 and 3.83 (2 d, J = 13.2 Hz, 1 H each, CH2-Ph), 5.16 (s, 2 H, CH2-Ph), 7.28 (d, 2 H, J = 8 Hz, H-Ar), 7.36 (bs, 5 H, H-Ar), 7.73 (d, 2 H, J = 8 Hz, H- Ar) ppm.
A mixture of L-Valine methyl ester hydrochloride (6.77 g), anhydrous MgSO4 (5.51 g) and Et3N (5.68 ml_) in anhydrous THF (40 ml_) was stirred for 15 minutes. To this solution was added while stirring at 0-50C 4-(5,5-dimethyl- [1 ,3,2]dioxaborinan-2-yl)-benzaldehyde (5.87 g) and the mixture was stirred at room temperature for 24 hours. The precipitated salts were removed by filtration and the filtrate evaporated under vacuum. The residue was dissolved in anhydrous methanol (120 ml_) and to this solution was added NaBH4 (1.59g) in small portions, for 1 h The resulting mixture was stirred at room temperature for 3 hours. Then, was cooled to O0C and water (10 ml_) was added dropwise. The reaction mixture was concentrated under vacuum, and the residue was partitioned between dichloromethane (100 ml_) and water (500 ml_). Extraction was carried with dichloromethane (2 x 50 ml_) followed by drying and evaporating to dryness to obtain 8.86 g of the desired product that was used in the next reaction without further purification. 1H-NMR (400 MHz, CDCI3): delta 0.92-0.96 (m, 6 H, 2 CH3 (1Pr)), 1.02 (s, 6 H, C(CH3J2), 1 -77 EPO <DP n="16"/>(bs, 1 H, NH), 1.91 (m, 1 H, CH(CH3)2), 3.01 (d, 1 H, J = 6.0 Hz, CH-N), 3.59 and 3.85 (2 d, 1 H each, J = 13 Hz, CH2-Ph), 3.71 (s, 3 H, CH3O), 3.76 (s, 4 H, 2CH2O), 7.32 (d, 2 H, J = 8 Hz, H-Ar), 7.75 (d, 2 H, J = 8 Hz, H-Ar) ppm.
A mixture of L-Valine benzyl ester tosylate (0.5 g), anhydrous MgSO4 (0.18 g) and Et3N (0.19 ml_) in anhydrous THF (6.6 ml_) was stirred for 15 minutes. To this solution was added while stirring at 0-50C 4-(5,5-dimethyl- [1 ,3,2]dioxaborinan-2-yl)-benzaldehyde (0.19 g) and the mixture was stirred at room temperature for 24 hours. The precipitated salts were removed by filtration and the filtrate evaporated under vacuum. The residue was dissolved in anhydrous methanol (6.6 ml_) and to this solution was added NaBH4 (52 mg) in small portions, for 1 h The resulting mixture was stirred at room temperature for 3 hours. Then, was cooled to O0C and water (2 ml_) was added dropwise. The reaction mixture was concentrated under vacuum, and the residue was partitioned between dichloromethane (15 ml_) and water (30 ml_). Extraction was carried with dichloromethane (2 x 5 ml_) followed by drying and evaporating to dryness to obtain 426 mg of the desired product that was used in the next reaction without further purification.
A mixture of L-Valine tert-butyl ester hydrochloride (1 g), anhydrous MgSO4 (732 mg) and Et3N (0.67 ml_) in anhydrous THF (24 ml_) was stirred for 15 minutes. To this solution was added while stirring at 0-50C 4- formylphenylboronic acid (799 mg) and the mixture was stirred at room temperature overnight. The precipitated salts were removed by filtration and the filtrate evaporated under vacuum. The residue was dissolved in anhydrous methanol (24 ml_) and to this solution was added NaBH4 (208 mg) in small portions, for 1 h The resulting mixture was stirred at room temperature for 3.5 h. Then, was cooled to O0C and water (8 ml_) was added dropwise. The reaction mixture was concentrated under vacuum, and the residue was partitioned between dichloromethane (35 ml_) and water (100 ml_). Extraction was carried with dichloromethane (4 x 15 ml_) followed by drying and evaporating to dryness to obtain 1.44 g of the desired product that was used in the next reaction without further purification. 1H-NMR (400 MHz, CDCI3): delta 0.94 and 0.95 (2 d, 3 H each, J = 6.8 Hz, 2 CH3 (1Pr)), 1.02 (s, 6 H, C(CHa)2), 1 -48 (s, 9 H, 'Bu), 1.94 (m, 1 H, CH(CH3)2), 2.89 (d, 1 H, J = 6.0 Hz, EPO <DP n="21"/>CH-N), 3.65 and 3.89 (2 d, 1 H each, J = 13.4 Hz, CH2-Ph), 3.76 (s, 4 H, 2 CH2O), 7.35 (d, 2 H, J = 8 Hz, H-Ar), 7.75 (d, 2 H, J = 8 Hz, H-Ar) ppm.
benzyl N-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl-4-yl-methyl]-L-valinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 3: Preparation of (benzyl N-r4-(5,5-dimethyl-H ,3,21dioxaborinan-2- yl)phenyl-4-yl-methyll-L-valinate); A mixture of L-Valine benzyl ester tosylate (132.7 g), 4-(5,5-dimethyl- <n="19"/>[1 ,3,2]dioxaborinan-2-yl)-benzaldehyde (330 ml_), Et3N (48.4 mL) and toluene (413 mL) was heated at reflux temperature for 1 h. The water while formed was azeotropically separated. Then, the mixture was cooled to room temperature and the solution was washed with aqueous NaHCO3 (317 mL x 2) and water (317 mL). The residual water was azeotropically removed. The toluene was partially distilled (134 mL) and MeOH (134 mL) was added. The solution was then cooled to 0-5 0C and NaBH4 (6.5 g) was slowly added. The reaction mixture was stirred at room temperature overnight. Then the solvent was partially distilled (half volume) and the residue was washed with aqueous NaHCO3 (270 mL). The separated aqueous phase was extracted with toluene (135 mL x 2). The combined organic phases were then washed with water (135 mL). The residual water in the organic layer was azeotropically removed and the residue (aprox. 730 mL) was used directly in the next step.
1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In toluene; at 100℃; for 18h;Product distribution / selectivity;
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; 10% 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 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.
4-(4-(trifluoromethoxy)phenyl)piperidine[ No CAS ]
[ 128376-65-8 ]
[ 1236001-10-7 ]
Yield
Reaction Conditions
Operation in experiment
Intermediate 71 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]methyl}-4-{4-[(trifluoromethyl)oxy]phenyl} piperidine Intermediate 71 was prepared according to a method similar to that described in WO 2006/067216 (page 41 ), as described below:A mixture of 4-{4-[(trifluoromethyl)oxy]phenyl}piperidine (4.91 g, 20.03 mmol) and N, N- diisopropylethylamine (5.95 ml, 33.4 mmol) in anhydrous THF (25ml) was stirred at room temp for 15 minutes. To this solution was added while stirring at 0-5C 4-(5,5-dimethyl- 1 ,3,2-dioxaborinan-2-yl)benzaldehyde (3.639 g, 16.69 mmol) and the mixture was stirred at 5O0C overnight. The residue was concentrated to dryness under vacuum and re- dissolved in anhydrous ethanol (25ml). To this solution previously cooled at O0C was added sodium borohydride (840 mg, 22.2 mmol) in small portions during 1 h. The resulting mixture was stirred at room temperature. After 3 hours the reaction was completed. Solvent was evaporated under vacuum and residue was cooled to O0C and partitioned between dichloromethane and water. Aqueous phase was extracted with dichloromethane (2x20ml). Combined organic phase was dried (Na2SO4), filtered and concentrated to dryness to give 5.25 g of a brown solid. Residue was triturated with few drops of methanol and acetonitrile. Solid was filtrated through a glass frited funnel and filtrate was concentrated under vacuum to dryness. 3.4 g of the title compound as an off-white solid were collected and dried under vacuum.1H-NMR(delta, ppm, CDCI3): 7.77(d, 2H); 7.35(d, 2H); 7.23(d, 2H); 7.12(d, 2H); 3.77(s, 4H); 3.59(d, 2H); 3.02(m, 2H); 2.50(s, 1H); 2.10(m,2H); 1.80(m, 2H); 1.66(m, 2H); 1.02(s, 3H).
In nitrobenzene; at 150℃; for 24h;Inert atmosphere;
General procedure: Into a two-neck round bottom flask equipped with a magnetic bar, the corresponding formyl phenylboronate ester (1 mmol) in nitrobenzene (25 mL) was added dropwise to a solution of 1,2-diamino-1,4-anthraquinone (1 mmol) in nitrobenzene (75 mL). (0021) The reaction mixture was slowly heated to 150 C for 1 day under nitrogen atmosphere. The solution was cooled to room temperature and then the precipitate slowly formed. The precipitate was filtered and washed with diethylether to give a brown solid of the protecting products (Boc-oHAQB=45%, Boc-pHAQB=60%). 1H NMR (DMSO, 400 MHz) Boc-oHAQB, delta (ppm): 13.56 (s, 1H), 8.41 (d, 1H, J=6.4 Hz), 8.25-8.13 (m, 4H), 7.94-7.92 (m, 2H), 7.57-7.50 (m, 3H), 3.70 (s, 4H), 1.07 (s, 6H). Boc-pHAQB, delta (ppm): 10.18 (s, 1H), 8.40 (t, 1H, J=8.2 Hz), 8.29-8.21 (m, 4H), 8.13-8.05 (m, 2H), 7.97-7.93 (m, 3H), 3.78 (s, 2H), 3.11 (s, 2H), 0.97 (s, 3H) 0.72 (s, 3H).
With tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In tetrahydrofuran; tetrahydrofuran-d8; at 100℃; for 5h;Inert atmosphere;
Example 31 [0317] In a glove box, a THF (0.4 mL)-THF-D8 (0.1 mL) solution of Pd2(dba)3 (5 mg, 0.005 mmol), PCy3 (5.6 mg, 0.02 mmol), and 5,5-dimethyl-2-(4-formyl)phenyl-1,3,2-dioxaborinane (21.8 mg, 0.1 mmol) was prepared in a pressure tube (capacity: 2 mL) under an inert atmosphere. alpha,alpha,alpha-Trifluorotoluene (12 muL, 0.097 mmol: internal standard for the 19F-NMR measurement) was added thereto. TFE (0.313 mmol: calculated from the container capacity described above and the applied pressure of 0.35 MPa) was further added thereto. This reaction solution was allowed to stand at 100 C. for 5 hours. The reaction was monitored by 19F-NMR. Based on the internal standard, it was confirmed that 1-(1,2,2-trifluoroethenyl)-4-(formyl)benzene was obtained at a yield of 41%. RRN 95 1-(1,2,2-Trifluoroethenyl)-4-(formyl)benzene [0318] 19F NMR(376 MHz, THF-d8, d/ppm): -180.0 (dd, JFF=32.8, 108.4 Hz, 1F), -114.3 (dd, JFF=63.5, 108.4 Hz, 1F), -100.4 (dd, JFF=32.8, 63.5 Hz, 1F)
68%Spectr.
General procedure: The reactions were conducted with a pressure-tight NMR tube (Wilmad-LabGlass, 524-PV-7). To a solution of CuOtBu (2.7 mg, 0.02 mmol) and ligand in THF/THF-d8 (v/v? = 4/1) (0.5 mL) was added arylboronic acids (0.022 mmol, 1.1 eq) and alpha,alpha,alpha-trifluorotoluene (2.4 L, 0.02 mmol; as an internal standard for 19F NMR). The resultant solution was transferred into the tube, and then TFE (3.5 atm, excess) was pressurized. After the reaction mixture was heated at 40 C for 24 h, Lewis acid (0.04 mmol, 2.0 eq) was added. Monitoring the reaction was performed by means of 19F NMR spectroscopy. The yields were determined by 19F NMR spectroscopy using alpha,alpha,alpha-trifluorotoluene as an internal standard.
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