Abstract: Strong photoinduced oxidants are important to organic synthesis and solar energy conversion, to chemical fuels or electric. For these applications, visible light absorption is important to solar energy conversion and long-lived excited states are needed to drive catalysis. With respect to these desirable qualities, a series of five 5,6-dicyano[2,1,3]benzothiadiazole (DCBT) dyes are examined as organic chromophores that can serve as strong photooxidants in catalytic systems. The series utilizes a DCBT core with aryl groups on the periphery with varying electron donation strengths relative to the core. The dyes are studied via both steady-state and transient absorption and emission studies. Additionally, computational analysis, voltammetry, crystallography, and absorption spectroelectrochemistry are also used to better understand the behavior of these dyes. Ultimately, a strong photooxidant is arrived at with an exceptionally long excited state lifetime for an organic chromophore of 16 µs. The long-lived excited state photosensitizer is well-suited for use in catalysis, and visible light driven photosensitized water oxidation is demonstrated using a water-soluble photosensitizer.
* 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] Journal of the American Chemical Society, 2009, vol. 131, # 31, p. 11049 - 11061
3
[ 328-70-1 ]
[ 556-96-7 ]
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 9, p. 2852 - 2853
[2] Science, 2013, vol. 341, # 6152, p. 1374 - 1377
4
[ 67-56-1 ]
[ 201230-82-2 ]
[ 328-70-1 ]
[ 26107-80-2 ]
Reference：
[1] Patent: JP2015/105232, 2015, A, . Location in patent: Paragraph 0038
[2] Patent: JP2017/19733, 2017, A, . Location in patent: Paragraph 0034
5
[ 402-31-3 ]
[ 328-70-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 0 - 10℃; for 4 h;
EXAMPLE 1 1,3-Bis(trifluoromethyl)benzene (1 kg) was added to concentrated sulphuric acid (4 kg).The mixture was agitated and cooled to 5° C. DBDMH (668 g) was added over 4 hours keeping the temperature between 0° C. and 10° C. The mixture was allowed to separate and the organic phase washed with water and a dilute solution of sodium bisulphite.The product was fractionally distilled to give 3,5-bis(trifluoromethyl)bromobenzene 1100 g (80percent) of 99percent purity.
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 9, p. 3695 - 3698
[2] Journal of Organic Chemistry USSR (English Translation), 1991, vol. 27, # 1.2, p. 108 - 112[3] Zhurnal Organicheskoi Khimii, 1991, vol. 27, # 1, p. 125 - 129
[4] Tetrahedron Letters, 1998, vol. 39, # 52, p. 9621 - 9622
[5] Synlett, 1999, # 8, p. 1245 - 1246
[6] Patent: US2004/19243, 2004, A1, . Location in patent: Page 3
[7] Chemistry - A European Journal, 2012, vol. 18, # 52, p. 16938 - 16946
[8] Journal of the American Chemical Society, 1950, vol. 72, p. 1651
[9] Bulletin de la Societe Chimique de France, 1962, p. 587 - 593
6
[ 402-31-3 ]
[ 328-70-1 ]
Reference：
[1] Patent: US6350915, 2002, B1, . Location in patent: Example 1
[2] Chemische Berichte, 1996, vol. 129, # 2, p. 233 - 235
7
[ 69807-91-6 ]
[ 328-70-1 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 50, p. 15434 - 15435
8
[ 121-91-5 ]
[ 328-70-1 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1991, vol. 27, # 1.2, p. 108 - 112[2] Zhurnal Organicheskoi Khimii, 1991, vol. 27, # 1, p. 125 - 129
9
[ 109-65-9 ]
[ 402-31-3 ]
[ 328-70-1 ]
[ 118527-30-3 ]
[ 327-75-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
[2] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
[3] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
10
[ 479411-92-2 ]
[ 328-70-1 ]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 536 - 539
11
[ 328-74-5 ]
[ 328-70-1 ]
Reference：
[1] Patent: US2547679, 1950, ,
[2] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 5, p. 1340 - 1351
12
[ 328-70-1 ]
[ 349-58-6 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5804 - 5809
[2] Angewandte Chemie - International Edition, 2009, vol. 48, # 46, p. 8729 - 8732
[3] Chemische Berichte, 1996, vol. 129, # 2, p. 233 - 235
[4] Organic and Biomolecular Chemistry, 2014, vol. 12, # 26, p. 4747 - 4753
13
[ 328-70-1 ]
[ 30071-93-3 ]
Yield
Reaction Conditions
Operation in experiment
82%
With acetic anhydride; magnesium In tetrahydrofuran; water
EXAMPLE 3 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 h). The mixture was aged for 30 min at reflux, cooled to RT and added over 1 h to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C. The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added. The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL). The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr). The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.
82%
With acetic anhydride; magnesium In tetrahydrofuran; water
EXAMPLE 3 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 h). Alternatively, the Grignard initiation may be conducted at 0-20° C. to minimize the loss of solvent. The mixture was aged for 30 min at reflux, cooled to RT and added over 1 h to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C. The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added. The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL). The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr). The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.
82%
With acetic anhydride; magnesium In tetrahydrofuran; water
EXAMPLE 8 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 h). The mixture was aged for 30 min at reflux, cooled to RT and added over 1 h to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C. The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added. The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL). The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr). The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.
82%
With sodium hydroxide; iodine; acetic anhydride; magnesium In tetrahydrofuran; water; acetonitrile
EXAMPLE 2 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one To a 500 mL 3-neck round bottom flask equipped with an addition funnel, N2 inlet, and a Teflon coated thermocouple was added magnesium granules (5.10 g, 210 mmol) and THF (200 mL). The mixture was heated to reflux. 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g, 98 mmol) was dissolved in 30 mL of THF. Some bromide solution (5 mL) was added to the gently refluxing magnesium slurry over 2 minutes to initiate the Grignard reaction. Alternatively, the Grignard initiation may be conducted at 0-20° C. to minimize the loss of solvent. After Grignard initiation, the remaining bromide was added over 1 hour. An initial induction period of 5 minutes is generally permitted. If the reaction does not initiate, another 5percent charge of bromide solution is added. If the reaction still does not initiate after a bromide charge of 10percent, 100 mg of iodine is added. The reaction exotherm was controlled by slowing or stopping the bromide addition if the reaction appeared too violent. After complete bromide addition (~60 minutes), the dark brown solution was heated at gentle reflux for an additional 30 minutes. The reaction was monitored by HPLC (sample preparation: 100 μL sample quenched into 3.5 mL of 1:1 THF:2N HCl, then diluted to 100 mL in 65:35 acetonitrile:pH 6 buffer). Grignard formation was considered complete when the bromide level is less that 1 mol percent. After cooling to ambient temperature in a water bath, the mixture was transferred via cannula to a 1L addition funnel. THF (10 mL) was used as rinse. This solution was then added to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C. over 1 hr. The dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added over 3 minutes. The biphasic mixture was vigorously stirred while 50percent NaOH was added dropwise over 1 hr, until a pH of 8.0 was maintained for 5 minutes. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extraced with MTBE (3*150 mL). The organic layers were combined and assayed (22.4 g ketone), then concentrated in vacuo at bath temperature of 32° C. (50-80 torr). The concentrate was then distilled at atmospheric pressure and 20.7 g (82percent yield based on LC purity) of colorless oil was collected at 150-189° C., with the bulk collected at 187-189° C.
82%
With acetic anhydride; magnesium In tetrahydrofuran; water
EXAMPLE 3 1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 hour). The mixture was aged for 30 minutes at reflux, cooled to room temperature and added over 1 hour to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C. The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added. The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL). The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr). The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 26, p. 8328 - 8331
18
[ 328-70-1 ]
[ 124-41-4 ]
[ 349-60-0 ]
Yield
Reaction Conditions
Operation in experiment
79.4%
at 105℃; for 22 h;
EXAMPLE 3 Preparation of 3,5-bis(trifluoromethyl)anisole From 1-bromo-3,5-bis(trifluoromethyl)benzene. 25 g of 1-bromo-3,5-bis(trifluoromethyl)benzene (85 mmol) are introduced into a mixture of 366 mg of copper(I) bromide (CuBr, 3 mol percent), 1.57 g of 18-crown-6 (7 mol percent) and 92.3 g of sodium methanolate solution in methanol (30percent strength) (precursor concentration 21percent) and heated to 105° C. After the conversion, determined by GC, it is >97percent (total of 22 h), the reaction mixture is added to 175 g of water. The mixture is brought to pH 5-6 by metering in hydrochloric acid and is then filtered through decalite. The mixture if extracted twice with 150 g of dichloromethane each time. Vacuum fractionation of the combined organic phases results in 16.5 g of 3,5-bis(trifluoromethyl)anisole (68 mmol, 79.4percent), GC purity >98.5percent a/a.
With 5,5’-(1,2-phenylene)bis(1H-tetrazole); copper(I) iodide; caesium carbonate; potassium iodide In N,N-dimethyl-formamide at 130℃; for 10 h; Inert atmosphere
General procedure: A mixture of copper salt (0.3 mmol) and 2 (0.8 mmol) in DMF (2 mL)was stirred at room temperature under a dry nitrogen atmospherefor 10 min to give a homogeneous solution. Next the aryl bromide(1 mmol), base (1.0 mmol), KI (0.5 mmol), K4Fe(CN)6 (0.22 mmol)and DMF (2 mL) were added and the mixture stirred at 130 °C for 10 h(Table 2). After completion (as monitored by TLC), H2O (15 mL) was added and the organic layer was extracted with EtOAc (3 × 15 mL),washed with brine (15 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by columnchromatography. All the products are known and were characterisedby IR, NMR and melting points and their spectroscopic data identicalto that reported in the literature.
68%
With 1-methyl-1H-imidazole In toluene at 160℃; for 16 h;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
52%
With 1-Butylimidazole In toluene at 140 - 160℃; for 16 h;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
29%
With 1-Butylimidazole In toluene at 160℃; for 16 h;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
Reference：
[1] Journal of Chemical Research, 2014, vol. 38, # 5, p. 291 - 294
[2] Patent: US2009/62541, 2009, A1, . Location in patent: Page/Page column 3
[3] Patent: US2009/62541, 2009, A1, . Location in patent: Page/Page column 3-4
[4] Patent: US2009/62541, 2009, A1, . Location in patent: Page/Page column 3
[5] Synthesis, 2008, # 20, p. 3351 - 3355
20
[ 328-70-1 ]
[ 27126-93-8 ]
Reference：
[1] Chemistry - A European Journal, 2007, vol. 13, # 21, p. 6249 - 6254
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 16-17, p. 3419 - 3423
27
[ 13755-29-8 ]
[ 328-70-1 ]
[ 79060-88-1 ]
Yield
Reaction Conditions
Operation in experiment
82%
With magnesium; ethylene dibromide In diethyl ether at 20℃; Inert atmosphere; Heating
A three-neck round bottom flask fitted with a reflux condenser was evacuated, flame dried and filledwith argon prior to use. 1.01 g (41.7 mmol) magnesium, 0.72 g (6.4 mmol, 1 eq) NaBF4 and diethylether (150 mL) were added. To start to reaction 1.07 g (0.49 ml, 5.7 mmol, 0.9 eq) dibromoethanewere added and the flask was heated for several minutes followed by the dropwise addition of 1.71 g(6.25 ml, 36 mmol) 3,5-bis(trifluoromethyl)bromobenzene diluted with diethyl ether (50 mL) over30 min. When the exothermic reaction slowed the reaction mixture was heated for additional 30 min.The solution was then stirred over night at room temperature. The reaction mixture was quenched bythe addition of 16 g Na2CO3 in distilled water (200 mL), stirred for 30 min and filtered. The aqueousphase was extracted three times with diethyl ether (50 mL), the combined organic phases were driedover sodium sulfate and charcoal followed by filtration. The solvent was removed and the remainingcrude product was dissolved in toluene (200 mL) to remove the water with a Dean Stark trap byazeotropic distillation. The solvent was removed, the product filtered, washed with dry toluene anddried under vacuo. The product was observed as colorless solid (4.65 g, 5.3 mmol, 82 percent).m.p. decomposition >290 °C.1H-NMR (300 MHz, DMSO-d6): δ = 7.67 (s, 4H, B-p-CH), 7.61 (s, 8H, B-o-CH) ppm.13C-NMR (75.5 MHz, DMSO-d6): δ = 161.0 (q, JB = 50 Hz, 4 Ci-B), 134.0 (s, 8 B-o-CH), 128.5 (qq,JF = 31 Hz, JB = 2.7 Hz, 8 Ci-CF3), 124.0 (q, JF = 272 Hz, CF3), 117.6 (m, 4 B-p-CH) ppm.19F-NMR (283 MHz, DMSO-d6): δ = -57.6 (CF3) ppm.Elemental analysis for C32H12BF24Na*1.8 H2O: calcd. C = 41.61 H = 1.70, found C = 41.57, H = 1.66.
Reference：
[1] Inorganic Chemistry, 2014, vol. 54, # 1, p. 359 - 369
[2] Inorganic Chemistry, 2014, vol. 54, # 1, p. 359 - 369
[3] Tetrahedron Letters, 2016, vol. 57, # 31, p. 3453 - 3456
[4] Organic Syntheses, 2008, vol. 85, p. 248 - 266
[5] Journal of the American Chemical Society, 2001, vol. 123, # 44, p. 11020 - 11028
[6] Organometallics, 1992, vol. 11, p. 3920 - 3922
[7] Organometallics, 2005, vol. 24, # 14, p. 3579 - 3581
[8] Angewandte Chemie - International Edition, 2018, vol. 57, # 40, p. 13335 - 13338[9] Angew. Chem., 2018, vol. 130, p. 13519 - 13522,4
28
[ 328-70-1 ]
[ 497-19-8 ]
[ 79060-88-1 ]
Yield
Reaction Conditions
Operation in experiment
47%
Stage #1: With magnesium; ethylene dibromide In diethyl ether at 20℃; Heating / reflux Stage #2: for 0.5 h;
f) Preparation of Sodium tetrakis [3,5-bis-(trifluoromethyl)-phenyl]-borate (as described by D. L. Reger, T. D. Wright, C. A. Little, J. J. S. Lamba, M. D. Smith in Inorg. Chem., 2001, 40, 3810-3814); Step f-1: A total of 3.49 g (31.7 mmol, 1 eq.) of sodium tetrafluoroborate, 4.98 g (205 mmol, 6.45 eq.) and 600 mL of anhydrous ether were charged in a 2 L 4 neck round bottom flask, equipped with overhead stirrer, addition funnel, thermocouple, condenser, nitrogen line and heating mantle. Dibromoethane (1 mL) was added, and the flask was gently heated to initiate the reaction. The heat was removed, and a solution of 50.94 g (174 mmol, 5.47 eq.) of 3,5-bis-(trifluoromethyl)-bromobenzene in 100 mL of ether was added dropwise within 30 min, which caused the solution to gently reflux. Once all bromide was added, the reaction was heated with a heating mantle to continue the reflux for an additional 1 hour. The heat than was removed, and the resulted mixture stirred overnight at room temperature. After this period of time, the reaction mixture was poured on a cold solution of sodium carbonate (77 g of Na2CO3 in 950 mL of water) and stirred for 30 min. The top brown organic layer was separated, and the bottom milky aqueous layer was extracted with ether (2.x.300 mL). Combined organic phases were dried over sodium sulfate and stirred with 17 g of charcoal for 2 hours at room temperature. The mixture was filtered through the Celite pad, and the ether was removed on a rotovap to yield 32.4 g of brown semisolid. The obtained crude product was dissolved in 800 mL of benzene and water was removed with a Dean-Stark trap by azeotropic distillation for 3 hours. The solvent volume was reduced to about 200 mL and the residue was cooled on an ice bath to form a mixture of a solid and heavy brown oil. The heterogeneous mixture was filtered off, washed with benzene (3.x.50 mL) followed by hexane wash (1.x.100 mL). The isolated solid was dried under suction and nitrogen flow to yield 13.28 (47percent yield) of white solid with Rf=0.15 in EtOAc.
Reference：
[1] Journal of the American Chemical Society, 2001, vol. 123, # 44, p. 11020 - 11028
30
[ 328-70-1 ]
[ 109-63-7 ]
[ 497-19-8 ]
[ 79060-88-1 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 14, p. 4738 - 4742
31
[ 109-65-9 ]
[ 402-31-3 ]
[ 328-70-1 ]
[ 118527-30-3 ]
[ 327-75-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
[2] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
[3] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
32
[ 109-65-9 ]
[ 402-31-3 ]
[ 328-70-1 ]
[ 118527-30-3 ]
[ 327-75-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
[2] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
[3] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
33
[ 328-70-1 ]
[ 88444-81-9 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1625 - 1632
[2] Journal of Organic Chemistry, 1993, vol. 58, # 24, p. 6614 - 6619
[3] Journal of Fluorine Chemistry, 1983, vol. 23, p. 497
[4] Journal of Materials Chemistry C, 2017, vol. 5, # 31, p. 7977 - 7984
[5] Patent: US2018/290986, 2018, A1,
34
[ 121-43-7 ]
[ 328-70-1 ]
[ 7732-18-5 ]
[ 73852-19-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With magnesium In tetrahydrofuran at 0 - 20℃; for 17 h; Inert atmosphere Stage #2: at -70 - 20℃; for 12 h; Inert atmosphere Stage #3: at 0℃; for 25 h; Inert atmosphere
Bar magnet, 500 ml with a funnel, a condenser and a nitrogen inlet for adding three-neck dried round bottom flask, magnesium turning of 9.30 g in a nitrogen atmosphere under a reactor (Aldrich Co.) and purified by distillation in tetrahydrofuran (Fisher, Inc.) It was added to 220 ml. The temperature of the reaction was maintained by the ice into the range 0 to 5 . Keeping the temperature of the reaction and was added to the 3 ', 5'-bis (trifluoromethyl) bromobenzene (Aldrich (Aldrich) Co., Ltd.) 44.0 ml using a funnel and slowly added over 1 hour. The reaction solution was slowly allowed to reach room temperature after the addition was completed, and added for 16 hours reaction at room temperature reaction, to give a viscous solution of a dark brown. After using the viscous solution was cooled to -70 on a dry ice and acetone maintained , Dropwise using an addition funnel 28.97 ml of trimethyl borate (Aldrich Co.) to the viscous solution and allowed to react.After the addition was completed, the reaction was allowed to stand to reach room temperature and was added to the reaction at room temperature for 12 hours to obtain a viscous solution of the brown. While maintaining the viscous solution to below 0 using the ice, the aqueous hydrochloric acid solution (37 wtpercent) solution was mixed with 63.3 ml of distilled water 144.5 ml was added over 1 hour, followed by further reaction for 24 hours of the water-soluble gum to give a red organic compound separated using a separating funnel and after completion of the reaction mixture the organic layer was dried under reduced pressure. The residue obtained after drying the solid is purified by recrystallization in a solvent of distilled water, and the 3 'and then collecting the resulting white crystals were washed with petroleum ether and dried for 24 hours at ambient temperature / atmospheric pressure the desired compound, 5'-bis (trifluoromethyl) benzene boronic acid (6FBB) (19.44g, yield: 85percent).
Reference：
[1] Patent: KR2015/112649, 2015, A, . Location in patent: Paragraph 0089; 0093-0095
35
[ 328-70-1 ]
[ 73852-19-4 ]
Reference：
[1] Journal of Nanoscience and Nanotechnology, 2010, vol. 10, # 8, p. 5153 - 5160
[2] Chemistry - A European Journal, 2013, vol. 19, # 46, p. 15565 - 15571
36
[ 121-43-7 ]
[ 328-70-1 ]
[ 73852-19-4 ]
Reference：
[1] Journal of Materials Chemistry C, 2017, vol. 5, # 12, p. 3107 - 3111
37
[ 328-70-1 ]
[ 73183-34-3 ]
[ 69807-91-6 ]
Reference：
[1] ACS Catalysis, 2018, vol. 8, # 5, p. 4049 - 4054
[2] Journal of the American Chemical Society, 2018, vol. 140, # 27, p. 8429 - 8433
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid In acetic acid at 45℃; for 4h;
93%
With sulfur tetrafluoride; hydrogen fluoride; bromine at 120℃; for 12h;
84%
With N-Bromosuccinimide; sulfuric acid In trifluoroacetic acid for 51h; Ambient temperature;
84%
With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid at 25℃; for 51h;
80%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid at 0 - 10℃; for 4h;
1 EXAMPLE 1
EXAMPLE 1 1,3-Bis(trifluoromethyl)benzene (1 kg) was added to concentrated sulphuric acid (4 kg).The mixture was agitated and cooled to 5° C. DBDMH (668 g) was added over 4 hours keeping the temperature between 0° C. and 10° C. The mixture was allowed to separate and the organic phase washed with water and a dilute solution of sodium bisulphite.The product was fractionally distilled to give 3,5-bis(trifluoromethyl)bromobenzene 1100 g (80%) of 99% purity.
72%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; acetic acid In water at 5 - 45℃; for 4h;
With antimonypentachloride; bromine; chlorine at 125℃;
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With isopropylmagnesium bromide In tetrahydrofuran; diethyl ether at -10 - 20℃; for 4h; Inert atmosphere;
Stage #2: 1,2-bis(dichlorophosphino)ethane In tetrahydrofuran; diethyl ether at 0 - 20℃; for 16h; Inert atmosphere;
97%
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With isopropylmagnesium bromide In tetrahydrofuran; diethyl ether at -10 - 20℃; for 4h; Inert atmosphere;
Stage #2: 1,2-bis(dichlorophosphino)ethane In tetrahydrofuran; diethyl ether at 0 - 20℃; for 16h; Inert atmosphere;
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With magnesium In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Glovebox; Schlenk technique;
Stage #2: With diethylphosphoramidous dichloride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Glovebox; Schlenk technique;
Stage #3: With hydrogenchloride In diethyl ether at 20℃; for 2h; Inert atmosphere; Glovebox; Schlenk technique;
58%
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With magnesium In tetrahydrofuran at 20℃; for 8h;
Stage #2: With diethylphosphoramidous dichloride In tetrahydrofuran at 20℃;
Stage #3: With hydrogenchloride In diethyl ether at 20℃; for 1h; Further stages.;
55%
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With magnesium In diethyl ether
Stage #2: With diethylphosphoramidous dichloride In diethyl ether at -50 - 20℃; for 1h;
Stage #3: With hydrogenchloride at 0℃;
Multi-step reaction with 2 steps
1.1: magnesium; iodine / diethyl ether / 1 h / 80 °C
1.2: 4.5 h / 0 - 20 °C
2.1: phosphorus trichloride / dichloromethane / 20 °C
18-crown-6 ether; copper(I) bromide; In methanol; at 105℃; for 22.0h;
EXAMPLE 3 Preparation of 3,5-bis(trifluoromethyl)anisole From 1-bromo-3,5-bis(trifluoromethyl)benzene. 25 g of 1-bromo-3,5-bis(trifluoromethyl)benzene (85 mmol) are introduced into a mixture of 366 mg of copper(I) bromide (CuBr, 3 mol percent), 1.57 g of 18-crown-6 (7 mol percent) and 92.3 g of sodium methanolate solution in methanol (30percent strength) (precursor concentration 21percent) and heated to 105° C. After the conversion, determined by GC, it is >97percent (total of 22 h), the reaction mixture is added to 175 g of water. The mixture is brought to pH 5-6 by metering in hydrochloric acid and is then filtered through decalite. The mixture if extracted twice with 150 g of dichloromethane each time. Vacuum fractionation of the combined organic phases results in 16.5 g of 3,5-bis(trifluoromethyl)anisole (68 mmol, 79.4percent), GC purity >98.5percent a/a.
palladium diacetate; In tetrahydrofuran; ethyl acetate;
EXAMPLE 2 A 1000-ml autoclave made of stainless steel was charged with 350 g of 3,5-bis(trifluoromethyl)bromobenzene, 233 ml of tetrahydrofuran, 1.34 g of palladium acetate, 1.34 g of 1,4-bis(diphenylphosphino)butane (dppb), 325 g of 25percent ammonia water. Stirring for the content of the autoclave was started, upon which nitrogen gas displacement for the autoclave was made three times, and carbon monoxide gas displacement for the autoclave was made three times. Thereafter, the initial pressure of carbon monoxide gas was set at 4 kg/cm2, and then heating for the autoclave was started. After lapse of 1 hour, the inside temperature of the autoclave reached 85° C., at which the inside pressure of the autoclave was adjusted at 8 kg/cm2. During reaction, the inside temperature and pressure were respectively kept at 85° C. and 8 kg/cm2. After lapse of 7 hours, the autoclave was cooled, and the gas inside the autoclave was purged. A reaction mixture or liquid was taken out into a separatory funnel, in which the reaction liquid was separated into two (upper and lower) layers. The lower layer (organic layer) was sampled. Extraction was made on the upper layer (water layer) by using ethyl acetate to obtain an extract. The extract was mixed with the above organic layer to obtain a mixture. The mixture was dried over magnesium sulfate and subjected to suction filtration to obtain a filtrate. The filtrate was condensed by using an evaporator. n-Hexane was added to the condensed filtrate. Then, the condensed filtrate was subjected to suction filtration so as to filtrate precipitated crystals, thereby obtaining 101.3 g of 3,5-bis(trifluoromethyl)benzamide.
With triphenylphosphine;palladium diacetate; In hexane; ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 3 A 500-ml autoclave made of stainless steel was charged with 200 g of 3,5-bis(trifluoromethyl)bromobenzene, 200 ml of N,N-dimethylformamide (DMF), 0.763 g of palladium acetate, 3.57 g of triphenylphosphine, and 139 g of 25percent ammonia water. Stirring for the content of the autoclave was started, upon which nitrogen gas displacement for the autoclave was made three times, and carbon monoxide gas displacement for the autoclave was made three times. Thereafter, the initial pressure of carbon monoxide gas was set at 4 kg/cm2, and then heating for the autoclave was started. After lapse of 1 hour, the inside temperature of the autoclave reached 100° C., at which the inside pressure of the autoclave was adjusted at 10 kg/cm2. During reaction, the inside temperature and pressure were respectively kept at 100° C. and 10 kg/cm2. After lapse of 4.5 hours, the autoclave was cooled, and the gas inside the autoclave was purged. A reaction mixture or liquid was subjected to suction filtration so as to obtain a filtrate. Thereafter, 200 g of ice and 200 ml of ethyl acetate were added to the filtrate. The filtrate was then transferred into a separatory funnel thereby separating an organic layer from an aqueous layer. Extraction was made two times on the aqueous layer by using ethyl acetate so as to obtain an extract. The extract was added to the organic layer to obtain a mixture. The mixture was dried over magnesium sulfate anhydride and then subjected to suction filtration to obtain a filtrate. The filtrate was concentrated by using an evaporator. A mixture solvent of n-hexane and ethyl acetate was added to the concentrated filtrate to allow crystals to be precipitated. The precipitated crystals were filtered thereby to obtain 62.2 g of 3,5-bis(trifluoromethyl)benzamide.
(3ARS,4RS,7ASR)-2-benzyl-4-[3,5-bis(trifluoromethyl)phenyl]-4-perhydroisoindolol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; nitrogen; In tetrahydrofuran; hexane; cyclohexane; water; ethyl acetate;
To a solution of 3.06 cm3 of 3,5bis(trifluoromethyl)bromobenzene in 15 cm3 of dry tetrahydrofuran is added, at -78 C., a solution of 10.9 cm3 of 1.6M butyllithium in hexane. This solution is stirred for 30 minutes at -78 C., and a solution of 1 g of (3aRS,7aSR)-2-benzyl-4-perhydroisoindolone in 5 cm3 of tetrahydrofuran is then run in dropwise. The reaction mixture is subsequently stirred at room temperature for 18 hours, treated with 20 cm3 of water and then extracted with 20 cm3 of ethyl acetate. The organic phase is separated out after settling has taken place, washed with twice 20 cm3 of water, then with 20 cm3 of saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluding under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 20 cm3 fractions. Fractions 26 to 37 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.82 g of (3aRS,4RS,7aSR)-2-benzyl-4-[3,5-bis(trifluoromethyl)phenyl]-4-perhydroisoindolol is obtained in the form of an oil.
f) Preparation of Sodium tetrakis [3,5-bis-(trifluoromethyl)-phenyl]-borate (as described by D. L. Reger, T. D. Wright, C. A. Little, J. J. S. Lamba, M. D. Smith in Inorg. Chem., 2001, 40, 3810-3814); Step f-1: A total of 3.49 g (31.7 mmol, 1 eq.) of sodium tetrafluoroborate, 4.98 g (205 mmol, 6.45 eq.) and 600 mL of anhydrous ether were charged in a 2 L 4 neck round bottom flask, equipped with overhead stirrer, addition funnel, thermocouple, condenser, nitrogen line and heating mantle. Dibromoethane (1 mL) was added, and the flask was gently heated to initiate the reaction. The heat was removed, and a solution of 50.94 g (174 mmol, 5.47 eq.) of 3,5-bis-(trifluoromethyl)-bromobenzene in 100 mL of ether was added dropwise within 30 min, which caused the solution to gently reflux. Once all bromide was added, the reaction was heated with a heating mantle to continue the reflux for an additional 1 hour. The heat than was removed, and the resulted mixture stirred overnight at room temperature. After this period of time, the reaction mixture was poured on a cold solution of sodium carbonate (77 g of Na2CO3 in 950 mL of water) and stirred for 30 min. The top brown organic layer was separated, and the bottom milky aqueous layer was extracted with ether (2×300 mL). Combined organic phases were dried over sodium sulfate and stirred with 17 g of charcoal for 2 hours at room temperature. The mixture was filtered through the Celite pad, and the ether was removed on a rotovap to yield 32.4 g of brown semisolid. The obtained crude product was dissolved in 800 mL of benzene and water was removed with a Dean-Stark trap by azeotropic distillation for 3 hours. The solvent volume was reduced to about 200 mL and the residue was cooled on an ice bath to form a mixture of a solid and heavy brown oil. The heterogeneous mixture was filtered off, washed with benzene (3×50 mL) followed by hexane wash (1×100 mL). The isolated solid was dried under suction and nitrogen flow to yield 13.28 (47% yield) of white solid with Rf=0.15 in EtOAc.
With magnesium; ethylene dibromide; In diethyl ether; at 20℃;Inert atmosphere; Heating;
A three-neck round bottom flask fitted with a reflux condenser was evacuated, flame dried and filledwith argon prior to use. 1.01 g (41.7 mmol) magnesium, 0.72 g (6.4 mmol, 1 eq) NaBF4 and diethylether (150 mL) were added. To start to reaction 1.07 g (0.49 ml, 5.7 mmol, 0.9 eq) dibromoethanewere added and the flask was heated for several minutes followed by the dropwise addition of 1.71 g(6.25 ml, 36 mmol) 3,5-bis(trifluoromethyl)bromobenzene diluted with diethyl ether (50 mL) over30 min. When the exothermic reaction slowed the reaction mixture was heated for additional 30 min.The solution was then stirred over night at room temperature. The reaction mixture was quenched bythe addition of 16 g Na2CO3 in distilled water (200 mL), stirred for 30 min and filtered. The aqueousphase was extracted three times with diethyl ether (50 mL), the combined organic phases were driedover sodium sulfate and charcoal followed by filtration. The solvent was removed and the remainingcrude product was dissolved in toluene (200 mL) to remove the water with a Dean Stark trap byazeotropic distillation. The solvent was removed, the product filtered, washed with dry toluene anddried under vacuo. The product was observed as colorless solid (4.65 g, 5.3 mmol, 82 %).m.p. decomposition >290 C.1H-NMR (300 MHz, DMSO-d6): delta = 7.67 (s, 4H, B-p-CH), 7.61 (s, 8H, B-o-CH) ppm.13C-NMR (75.5 MHz, DMSO-d6): delta = 161.0 (q, JB = 50 Hz, 4 Ci-B), 134.0 (s, 8 B-o-CH), 128.5 (qq,JF = 31 Hz, JB = 2.7 Hz, 8 Ci-CF3), 124.0 (q, JF = 272 Hz, CF3), 117.6 (m, 4 B-p-CH) ppm.19F-NMR (283 MHz, DMSO-d6): delta = -57.6 (CF3) ppm.Elemental analysis for C32H12BF24Na*1.8 H2O: calcd. C = 41.61 H = 1.70, found C = 41.57, H = 1.66.
With 5,5?-(1,2-phenylene)bis(1H-tetrazole); copper(I) iodide; caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 10h;Inert atmosphere;
General procedure: A mixture of copper salt (0.3 mmol) and 2 (0.8 mmol) in DMF (2 mL)was stirred at room temperature under a dry nitrogen atmospherefor 10 min to give a homogeneous solution. Next the aryl bromide(1 mmol), base (1.0 mmol), KI (0.5 mmol), K4Fe(CN)6 (0.22 mmol)and DMF (2 mL) were added and the mixture stirred at 130 C for 10 h(Table 2). After completion (as monitored by TLC), H2O (15 mL) was added and the organic layer was extracted with EtOAc (3 × 15 mL),washed with brine (15 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by columnchromatography. All the products are known and were characterisedby IR, NMR and melting points and their spectroscopic data identicalto that reported in the literature.
68%
With 1-methyl-1H-imidazole;copper(l) iodide; In toluene; at 160℃; for 16h;Product distribution / selectivity;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
52 - 98%
With 1-Butylimidazole;copper(l) iodide; In toluene; at 140 - 160℃; for 16h;Product distribution / selectivity;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
29%
With 1-Butylimidazole;copper(I) bromide; In toluene; at 160℃; for 16h;Product distribution / selectivity;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With magnesium In tetrahydrofuran Inert atmosphere;
Stage #2: quinoline-2-carbonitrile In tetrahydrofuran; toluene at 0 - 20℃; Inert atmosphere;
Stage #3: With hydrogenchloride; water In diethyl ether for 0.333333h; Inert atmosphere;
4-ethenyl-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazolyl-3,5-bis(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
10 g of 3,5-bis(trifluoromethyl)bromobenzene are mixed with 11 ml of cyclohexyldimethylamine and 30 ml of dimethylacetamide and degassed. 38 mg of palladium acetate and 152 mg of di(tert-butyl)phenylphosphine are dissolved in 5 ml of dimethylacetamide and added to the mixture. The mixture is transferred to an autoclave and 30 bar of ethylene are injected. The mixture is then heated to 110 C. and stirred at this temperature for 3 hours. At the end of the reaction, the mixture is cooled and the pressure released. Subsequently, 8.3 g of 1,5-dimethyl-3-trifluoromethyl-1H-pyrazole are added to the reaction mixture and the mixture is heated to 130 C. for 12 h. Afterwards, the mixture is cooled, added to water and worked up with toluene. Yield over the two steps: 10.5 g (76%) of slightly brownish solid.
Synthesis of Di-(3,5-Bis(trifluoromethyl)phenyl)dithiophosphinic Acid; The following examples are by reference to the chemical reaction identified as Schemes 1 and 2 below. With reference to Scheme 1, an approximate 1.0 M solution of a starting Grignard reagent was synthesized (1). Magnesium metal shavings (Mg0, 4.9 g; 0.20 mol) were placed into a 250 mL round bottom flask. The flask was equipped with a gas inlet adapter and magnetic stir bar. This system was placed under vacuum and the system was then purged with nitrogen. First, 171 mL of an anhydrous diethyl ether was transferred to the flask by syringe, and then 50 g (0.171 mol) of 3,5-(CF3)2C6H3Br (2) was introduced by syringe. The solution was stirred during the reaction. An ice bath was needed to cool down the reaction as the magnesium was consumed. After most of the magnesium metal was consumed, the reaction mixture was allowed to set overnight under nitrogen.After the procedure discussed above, and by reference to Scheme 2, a 500-mL three-neck, round-bottom flask, equipped with a gas inlet; a 125 mL addition funnel; magnetic stir bar, and a rubber septum was charged with nitrogen, Cl2P-N(CH2CH3)2 (3) 10 g, 0.058 mol), and anhydrous diethyl ether (300 mL). The solution was cooled to 0 C., and a Grignard reagent [3,5-(CF3)2C6H3MgBr (2)] (1.0 M in diethyl ether, 117 mL, 0.117 mol) was added to the addition funnel via syringe. The compound (2) was added to the cooled solution. After finishing, the addition funnel was removed and replaced with a stopper. The ice bath was removed and the mixture was allowed to warm to room temperature while stirring overnight. The next day, approximately 75% of the ether was removed under reduced pressure, leaving behind a slurry. The slurry was washed three times with 200 mL of hexanes to precipitate the salts. The supernatant, (3,5-(CF3)2C6H3)2Cl2P-N(CH2CH3)2 (4), was decanted into a nitrogen-purged 1000-mL round-bottom flask equipped with a magnetic stir bar.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 16h;Inert atmosphere; Reflux;
Reference Example 18 (3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-ol; A solution of 3,5-bis(trifluoromethyl)phenyl bromide (44.0 g), <strong>[122536-94-1](S)-3-hydroxypyrrolidine hydrochloride</strong> (17.8 g), tris(dibenzylideneacetone)dipalladium(0) (5.88 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (8.00 g) and sodium tert-butoxide (36.0 g) in toluene (280 mL) was refluxed with stirring under an argon gas atmosphere for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1 - 2:1) to give the title compound (12.0 g, yield 28%) as a white solid. 1H-NMR (300 MHz, CDCl3)delta:1.67 (br, 1H), 2.08 - 2.36 (m, 2 H), 3.28 - 3.38 (m, 1 H), 3.38 - 3.50 (m, 1 H), 3.50 - 3.65 (m, 2 H), 4.55 - 4.81 (m, 1 H), 6.87 (s, 2 H), 7.13 (s, 1 H).
28%
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; for 16h;Inert atmosphere; Reflux;
A solution of 3,5-bis(trifluoromethyl)phenyl bromide (44.0 g), <strong>[122536-94-1](S)-3-hydroxypyrrolidine hydrochloride</strong> (17.8 g), tris(dibenzylideneacetone)dipalladium(0) (5.88 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (8.00 g) and sodium tert-butoxide (36.0 g) in toluene (280 ml) was refluxed with stirring under an argon gas atmosphere for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1-2:1) to give the title compound (12.0 g, yield 28%) as a white solid.1H-NMR (300 MHz, CDCl3) delta: 1.67 (br, 1H), 2.08-2.36 (m, 2H), 3.28-3.38 (m, 1H), 3.38-3.50 (m, 1H), 3.50-3.65 (m, 2H), 4.55-4.81 (m, 1H), 6.87 (s, 2H), 7.13 (s, 1H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 18.0h;Inert atmosphere;
Reference Example 1 1-[3,5-bis(trifluoromethyl)phenyl]<strong>[40499-83-0]pyrrolidin-3-ol</strong>; A solution of 3,5-bis(trifluoromethyl)phenyl bromide (21.1 g), 3-hydroxypyrrolidine (6.53 g), tris(dibenzylideneacetone)dipalladium(0) (1.47 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.99 g) and sodium tert-butoxide (10.6 g) in toluene (140 mL) was stirred under an argon gas atmosphere at 100C for 18 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 95:5 - 70:30) to give the title compound (13.2 g, yield 61%) as colorless crystals. 1H-NMR (300 MHz, CDCl3)delta:1.82 (br, 1 H), 2.08 - 2.25 (m, 2 H), 3.30 - 3.34 (m, 1 H), 3.39 - 3.46 (m, 1 H), 3.52 - 3.60 (m, 2 H), 4.64 - 4.68 (m, 1 H), 6.85 (s, 2 H), 7.11 (s, 1 H).
61%
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 18.0h;Inert atmosphere;
A solution of 3,5-bis(trifluoromethyl)phenyl bromide (21.1 g), 3-hydroxypyrrolidine (6.53 g), tris(dibenzylideneacetone)dipalladium(0) (1.47 g), (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.99 g) and sodium tert-butoxide (10.6 g) in toluene (140 ml) was stirred under an argon gas atmosphere at 100 C. for 18 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 95:5-70:30) to give the title compound (13.2 g, yield 61%) as colorless crystals.1H-NMR (300 MHz, CDCl3) delta:1.82 (br, 1H), 2.08-2.25 (m, 2H), 3.30-3.34 (m, 1H), 3.39-3.46 (m, 1H), 3.52-3.60 (m, 2H), 4.64-4.68 (m, 1H), 6.85 (s, 2H), 7.11 (s, 1H).
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With iodine; magnesium In tetrahydrofuran at 50℃; Cooling;
Stage #2: (-)-dimethy-2,3-O-isopropylidene-L-tartrate In tetrahydrofuran at 20℃; for 48h;
With aluminium; lithium chloride; In tetrahydrofuran; at 65℃; for 1h;
Example 10Preparation of ethyl 4-[3,5-6is(trifluoromethyl)phen-l-yl)benzoate (15a) via direct aluminium insertion and subsequent Pd-catalyzed cross-couplingsThe substrate l-bromo-fos(trifluoromethyl)benzene 4a is combined with 0.5 equivalent tributylb orate and 1.5 equivalent LiCl per equivalent of substrate 4a in THF and contacted with 3 equivalents aluminum metal per equivalent substrate 4a at 65C for 1 h to make the /s(trifluoromethyl)phenylborate 5a in ca. 90% yield.The arylborate 5a is then subjected to Pd-catalyzed cross-coupling with ethyl 4- iodobenzoate (7a); together with 2 equivalent cesium carbonate (base) per equivalent of 7a in a 1 : 1 mixture of THF and ethanol in the presence of 4 mol% Pd(PPh3)4 (catalyst) at 65 C for 12 h to produce the title polyfunctional arene 15a in 68% yield.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In ethanol at 80℃; for 2h; Inert atmosphere;
General procedure: General procedure: The synthetic procedure for pentafluorophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonate (a) is presented as an example (Scheme 1). 2,2'-Bis(1,3,2-benzodioxaborole) (cat2B2, 262 mg, 1.10 mmol), PdCl2(dppf) (25 mg, 0.030 mmol), AcOK (294 mg, 3.0 mmol), pentafluorophenyl 4-bromobenzenesulfonate (403 mg, 1.0 mmol), and EtOH (6.0 mL) were charged in a reaction vessel under an Ar atmosphere. The resulting mixture was stirred for 2 h at 80 °C. After cooling to room temperature, pinacol (260 mg, 2.20 mmol) was added to the mixture. The mixture was further stirred for 30 min at room temperature. H2O and n-hexane were added to the mixture and the product was extracted into the organic layer. After drying the organic layer with anhydrous MgSO4, solids were removed by filtration. The filtrate was concentrated. The product was obtained as a white solid by Kugelrohr distillation.
With copper(l) iodide; C37H51ClFeNPPd; cesium fluoride; In N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere;
General procedure: 4.3.15 3-[3,5-Bis(trifluoromethyl)phenyl]pyridine (3oa) Yellow solid, mp 62-63 C; 1H NMR (400 MHz, CDCl3): delta=8.89 (s, 1H), 8.72 (s, 1H), 8.01 (s, 2Aryl halide (0.5 mmol), base (1 mmol), CuI (20 mol %), alkylstannylpyridine(0.75 mmol), and catalyst (1 mol %) 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.H), 7.92 (s, 2H), 7.47-7.44 (m, 1H); 13C NMR (100 MHz, CDCl3): delta=29.7, 30.8, 119.1, 121.8, 123.9, 124.5, 127.3, 132.4, 132.7, 134.6, 140.1, 148.2, 150.1; HRMS-ESI (m/z): [M+H]+ calcd for C13H8F6N+: 292.0555, found: 292.0562.
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); potassium acetate; In N,N-dimethyl-formamide; at 150℃; for 72h;Inert atmosphere;
General procedure: In a typical experiment,the aryl bromide (3 mmol), heteroaromatic 1, 21 or 23 (1 mmol), KOAc(0.588 g, 6 mmol) and PdCl(C3H5)(dppb)16 (0.012 g, 0.02 mmol) were dissolvedin DMA (4 mL) under an argon atmosphere. The reaction mixture was stirred at 150 C for 72 h. Then, the solvent was evaporated and the product was purified by silica gel column chromatography.
tert-butyl 2-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carboxylate[ No CAS ]
C18H21F6NO2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%; 32%
To an oven-dried, septum-capped round bottom flask equipped with a stir bar, was added freshly distilled TMEDA (2 mL, 12 mmol, 1.2 equiv) and Et2O (20 mL) under argon. The mixture was cooled to -80 C and 1.0 M solution of s-BuLi in cyclohexane (11 mL, 11 mmol, 1.1 equiv) was added. A precooled solution of N-Boc-piperidine (1.85 g, 10.0 mmol, 1.0 equiv) in Et2O (5 mL)was added to the flask containing the TMEDA/s-BuLi/Et2O mixture. After 4 h at this temperature, a freshly prepared solution of ZnCl2 (6 mL, 1.0 M solution in THF, 0.6 equiv), was added slowly over a ten minute period and the mixture was stirred for 30 minutes, removed from the cold bath and warmed to room temperature. After 30 minutes, Pd(OAc)2 (100 mg, 4 mol%), t-Bu3P·HBF4 (230 mg, 8 mol%) and 1,3-Bis(trifluoromethyl)-5-bromobenzene (1.9 mL, 11mmol, 1.1 equiv) were added sequentially. The mixture was diluted with THF (50 mL) andheated to 40C. After stirring for 24 h at room temperature, NH4OH (20 mL, 10% aqueous solution) was added dropwise and the mixture was stirred for 30 minutes. The resulting slurry was filtered through Celite and rinsed with 50 mL Et2O. The filtrate was washed with 1 M HCl(aq) (50 mL), then with water (2 x 50 mL), dried over Na2SO4 and evaporated under reduced pressure to obtain the crude product. Purification by silica gel chromatography eluting with hexane-EtOAc (98:2) afforded 2.30 g of the 2-arylated product as an oil in 58% yield. Note: A significant amount of the 3-arylated piperidine (32%) was identified as a byproduct formed presumably via a 1,2-aryl migration. This byproduct was not observed when the arylation was performed at room temperature for 3 days.
5-(3,5-bis(trifluoromethyl)phenyl)-1-(4-methoxyphenyl)-imidazole[ No CAS ]
5-(3,5-bis(trifluoromethyl)phenyl)-1-(4-methoxyphenyl)-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 75%
2: 45%
With cesium acetate; palladium diacetate In N,N-dimethyl acetamide at 150℃; for 48h; Inert atmosphere; Schlenk technique;
4.1 General procedure
General procedure: In a typical experiment, the aryl bromide (3mmol), imidazole derivative (1mmol), CsOAc (1.303g, 4mmol) and Pd(OAc)2 (4.4mg, 0.02mmol), were dissolved in DMA (5mL) under an argon atmosphere. The reaction mixture was stirred at 150°C for 48h. After evaporation of the solvent, the product was purified by silica gel column chromatography.
2-(3,5-bis(trifluoromethyl)phenyl)-4-bromo-5-methylthiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: 3,5-dibromo-2-methylthiophene With n-butyllithium In tetrahydrofuran at -78℃; for 1.5h;
Stage #2: With boric acid tributyl ester In tetrahydrofuran at -78 - 20℃; for 2h;
Stage #3: 3,6-bis(trifluoromethyl)bromobenzene With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 85℃; for 18h;
84%
Stage #1: 3,5-dibromo-2-methylthiophene With n-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 1.5h;
Stage #2: With boric acid tributyl ester In tetrahydrofuran; cyclohexane at -78 - 20℃; for 2h;
Stage #3: 3,6-bis(trifluoromethyl)bromobenzene With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; cyclohexane; water at 85℃; for 18h; Reflux;
1,2-bis(5-(3,5-bis(trifluoromethyl)phenyl)-2-methylthien-3-yl)cyclopent-1-ene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
Stage #1: 1,2-bis(5-chloro-2-methylthien-3-yl)cyclopent-1-ene With n-butyllithium In tetrahydrofuran; cyclohexane at 20℃; for 0.5h;
Stage #2: With boric acid tributyl ester In tetrahydrofuran; cyclohexane at 20℃; for 1h;
Stage #3: 3,6-bis(trifluoromethyl)bromobenzene With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; cyclohexane; water at 20 - 80℃; for 16.25h;
nBuLi (2.5 muL of a 1.6 M soln in hexanes, 4 mumol) was added dropwise to a stirring solution of 1-bromo-3,5-bis(trifluoromethyl)benzene in 19 muL of Et2O at -40 C. The solution was warmed to room temperature andstirred for 4 hours. The solution was cooled to -40 C. The corresponding cyclopentenone was added and thesolution was warmed to room temperature. After stirring overnight, the solution was quenched with water andacidified with 1 mL conc. aq. HCl. The organic layer was dried over MgSO4 and concentrated. The crude liquid(>20:1 favoring endo isomer) was purified by column chromatography (petroleum ether) to provide a yellow oil(451 mg, 34%).
1-(3,4-dimethyl-1,3-cyclopentadien-1-yl)-3,5-bis(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
1-(3,4-Dimethyl-1,3-cyclopentadien-1-yl)-3,5-bis(trifluoromethyl)benzene The solution of 1-bromo-3,5-bis(trifluoromethyl)benzene (10 g, 34 mmol) in 50 mL of Et2O was cooled to -70 C., and BuLi (22 mL, 1.6 M in hexane, 35 mmol) was added. The mixture was stirred at this temperature for 1 h, 3,4-dimethylcyclopenen-2-one (3.3 g, 30 mmol) in 10 mL of ether was added, the mixture was stirred overnight, and treated by 20 mL of water. Organic layer was separated and washed by brine. TsOH (0.5 g) was added, and the mixture was refluxed for 3 min. After cooling the mixture was washed by 5% NaHCO3, brine, dried over MgSO4, solvent was evaporated and the residue was recrystallized from methanol, yielding 4.7 g (63%) of the product. 1H NMR (CDCl3): delta 7.81 (s, 2H); 3.61 (s, 1H); 6.87 (s, 1H); 3.32 (s, 2H); 2.03 (s, 3H); 1.94 (s, 3H).
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; for 0.25h;Inert atmosphere;
N1,N1,N4-triphenylbenzene-1,4-diamine (1.0 g, 3.0 mmol) and 1-bromo-3,5-bis(trifluoromethyl)benzene (1.15 g, 3.9mmol) to 70 mL of xylene were mixed in dry. The solution was bubbling with nitrogen for 15 minutes. Then, Pd2(dba)3 (0.29 g, 0.32 mmol), 2-dicyclohexylphosphino-2 ',6'-di-methoxy-biphenyl fertilization (0.58 g, 1.20 mmol) and tBuONa (0.44 g, 4.50 mmol) It was added to the solution. The mixture was refluxed overnight under a nitrogen atmosphere. After cooled, filtered through celite / silica pad to the reaction mixture, the filtrate was concentrated. Then, the residue as the eluant DCM: hexane (1: 4, v / v) and purified by column chromatography using compound 743 was collected in .1.3 g (80%).
Add 1 g of magnesium powder and 400 ml of tetrahydrofuran to 1 L, and add 1-2 tablets of elemental iodine with stirring.Under nitrogen protection, and about 5 ml of 3,5-bis-trifluoromethylbromobenzene was added dropwise to initiate the reaction. After the reaction was initiated,An additional 85 ml of 3,5-bis-trifluoromethylbromobenzene was slowly added dropwise, maintaining the temperature at 0-10 C, the addition was completed, stirring for about 1 hour, and the Grignard reagent was transferred to another 1 L reaction flask to separate Reactive magnesium powder.Under the protection of nitrogen, the temperature is controlled at 0-10 C, 60 ml of trimethyl borate is slowly added dropwise, and the temperature is slowly raised to 20 C for 16 h.After completion of the reaction, 250 ml of 4M hydrochloric acid was slowly added dropwise, and the obtained solid was filtered.The obtained solid was recrystallized from water, filtered and dried in vacuo.Obtained 121.2 g of a white solid with a molar yield of 90%.
85%
Bar magnet, 500 ml with a funnel, a condenser and a nitrogen inlet for adding three-neck dried round bottom flask, magnesium turning of 9.30 g in a nitrogen atmosphere under a reactor (Aldrich Co.) and purified by distillation in tetrahydrofuran (Fisher, Inc.) It was added to 220 ml. The temperature of the reaction was maintained by the ice into the range 0 to 5 . Keeping the temperature of the reaction and was added to the 3 ', 5'-bis (trifluoromethyl) bromobenzene (Aldrich (Aldrich) Co., Ltd.) 44.0 ml using a funnel and slowly added over 1 hour. The reaction solution was slowly allowed to reach room temperature after the addition was completed, and added for 16 hours reaction at room temperature reaction, to give a viscous solution of a dark brown. After using the viscous solution was cooled to -70 on a dry ice and acetone maintained , Dropwise using an addition funnel 28.97 ml of trimethyl borate (Aldrich Co.) to the viscous solution and allowed to react.After the addition was completed, the reaction was allowed to stand to reach room temperature and was added to the reaction at room temperature for 12 hours to obtain a viscous solution of the brown. While maintaining the viscous solution to below 0 using the ice, the aqueous hydrochloric acid solution (37 wt%) solution was mixed with 63.3 ml of distilled water 144.5 ml was added over 1 hour, followed by further reaction for 24 hours of the water-soluble gum to give a red organic compound separated using a separating funnel and after completion of the reaction mixture the organic layer was dried under reduced pressure. The residue obtained after drying the solid is purified by recrystallization in a solvent of distilled water, and the 3 'and then collecting the resulting white crystals were washed with petroleum ether and dried for 24 hours at ambient temperature / atmospheric pressure the desired compound, 5'-bis (trifluoromethyl) benzene boronic acid (6FBB) (19.44g, yield: 85%).
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 5,5-dimethyl-1,3-cyclohexadiene; at 145℃; for 20.0h;Inert atmosphere; Large scale;
5L glass kettle was washed and dried, 2 kg of xylene was added under nitrogen flow, stirring was started, and nitrogen gas was degassed for 15 minutes. Then 750 g of 3,5-bistrifluoromethylbromobenzene (2.56 mol), 300 g of cyano sodium acetate (2.8mol), 2.0g of tris (dibenzylideneacetone) dipalladium (2.18mmol, 0.17mol%), 6.2g9,9--dimethyl-4,5-bis (diphenylphosphino) oxy xanthene (13mmol, 0.51mol%); under nitrogen flow, the temperature of the reaction system was gradually raised to 145 20h the reaction, the reaction system was then lowered to room temperature, the reaction was filtered to remove sodium chloride, and the filtrate recovery spin dry mesitylene, the residue was concentrated to give 450g, 2- (3,5-bis-trifluoromethylphenyl) acetonitrile crude product, detecting the GC purity 90%, yield 63%.
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; 1,4-di(diphenylphosphino)-butane; In toluene; at 120℃; under 7500.75 Torr;
In a 200 mL dissolution tank, 14.70 g (0.05 mol) of 3,5-bis (trifluoromethyl) bromobenzene (substrate), dichlorobis (triphenylphosphine) palladium 0. 08 g (0.25 mol%), 0.22 g (1.0 mol%) of 1,4-bisdiphenylphosphinobutane, 6.07 g (0.06 mol) of triethylamine,25 g (500 g / mol) of methanol and 25 g (500 g / mol) of toluene were charged and dissolved. This was sucked into the syringe pump and 0.25 ml / min. (Residence time: 67 minutes). At the same time, carbon monoxide is brought to 4.2 ml / min with a mass flow controller. (1.2 equivalents) at a rate of 1: 1. While mixing these mixtures with a mixer, the reaction was started by a retention unit (inner diameter × length of the heating device: 2.17 mmphi × 10 m) set at a temperature of 120 C. The pressure was adjusted to 1 MPa with a back pressure valve. The obtained reaction solution was analyzed with a high-speed liquid chromatogram.Conversion rate 99.9%, selectivity: 99.6%.
With 5%-palladium/activated carbon; triethylamine; 1,4-di(diphenylphosphino)-butane; In toluene; at 120℃; under 7500.75 Torr;Flow reactor;
28.6 g of granular 5% palladium carbon (manufactured by N. E. Chemcat Corporation) was filled in a stainless steel pipe having an inner diameter of 10 mm and a length of 0.5 m,Both ends were connected to stainless steel piping with high-pressure compatible fittingsIn a 200 mL dissolution tank, 14.70 g (0.05 mol) of 3,5-bis (trifluoromethyl) bromobenzene, 0.22 g (1.0 mol%) of 1,4-bisdiphenylphosphinobutane, 6.07 g 0.06 mol), 25 g (500 g / mol) of methanol and 25 g (500 g / mol) of toluene were added and dissolved. This was sucked into a syringe pump and feeding was started at a rate of 0.5 ml every minute (residence time 36 minutes).At the same time, carbon monoxide was fed with a mass flow controller at a rate of 8.2 ml / minute (1.2 equivalent).The mixture was sent to a flow reactor filled with a transition metal catalyst set at a temperature of 120 C. while mixing with a mixer, and the reaction was started. The pressure was adjusted to 1 MPa with a back pressure valve. The obtained reaction solution was analyzed by high performance liquid chromatogram.Conversion: 99.9%, selectivity: 99.9%In addition, elution of palladium into the reaction solution was less than 1 ppm
2-dicyclohexylphosphino-2',6'-bis(3,5-ditrifluoromethylphenyl)biphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 150℃; for 36h;Schlenk technique; Inert atmosphere;
25 mL of Schlenk tube,And 70.1 mg of 2-dicyclohexylphosphino biphenyl (<strong>[247940-06-3]CyJohnPhos</strong>) was added (0.2 mmol), (1,5-cyclooctadiene) chlorideRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.3,5-Bistrifluoromethylchlorobenzene248.6 mg (1.0 mmol). 150 C for 36 hours, cooled to room temperature and evaporated under reduced pressure. The solvent was passed through a 200-300 mesh silica gel Column separation, petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 142.4 mg of product as a white solid in 94% yield,
2'-(dicyclohexylphosphino)-6-(3,5-bis(trifluoromethyl)phenyl)-N,N-dimethylbiphenyl-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere;
In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.3,5-Bis-trifluoromethyl bromobenzene87.9 mg (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was evaporated under reduced pressure and chromatographed on silica gel at 200-300 mesh Column separation, petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 100.8 mg of product as a white solid in 83% yield.
2-(3,5-bis(trifluoromethyl)phenyl)-1-methyl-1H-pyrrole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With pyrene; tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 25℃; for 5h; Inert atmosphere; Irradiation;
71%
With N-ethyl-N,N-diisopropylamine; cercosporin In acetonitrile at 20℃; Irradiation; Inert atmosphere; Schlenk technique;
2.5. Typical experimental procedure for photocatalytic test
General procedure: In a 10 mL schlenk tube with magnetic stirring bar, cercosporin(0.05 equiv), aryl halide 1 (0.2 mmol), arene 2 (20 equiv), DIPEA (4equiv) were dissolved in CH3CN (2 mL) and the resulting mixtures were placed under 23WCFL under N2 atmosphere. When the reaction was finished, the reaction mixture was washed with brine. The aqueous phase was reextracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, concentrated in vacuum,and the resulting residue was purified by silica gel column chromatographyto afford the desired product 3.
46%
With hypericin; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 25℃; for 48h; Inert atmosphere; Irradiation;
With N,N,N,N,-tetramethylethylenediamine; C39H46IrN4 In acetonitrile at 45℃; for 48h; Sealed tube; Glovebox; Inert atmosphere;
74%
With [2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine]ruthenium(II) chlorocarbonyl hydride; isopropyl alcohol; sodium t-butanolate at 100℃; for 18h; Inert atmosphere; Sealed tube; Green chemistry;
99 %Spectr.
With 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole; C39H45IrN4 In N,N-dimethyl-formamide at 45℃; for 24h; Irradiation; Glovebox;
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In neat (no solvent); at 110℃; for 24h;
General procedure: Under atmospheric conditions, a 10-mL screwcap vial equipped with a magnetic stir bar was charged with Pd source (0.01 mmol, 0.02 equiv), base (0.6 mmol, 1.2 equiv), bis(pinacolato)diboron (0.525 mmol, 1.05 equiv) and aryl halide (0.5 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 product yield was determined by GC-FID based on integration relative to hexamethylbenzene as an internal standard. The residue was purified by column chromatography on silica gel (eluting with 5:95 ethyl acetate in hexane) to give pure aryl boronic ester.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 10h;Inert atmosphere;
In step (a), 1-bromo 3,5-bis (trifluoromethyl) benzene (compound a, 1.10 mL, 6.35 mmol) and tetrakis (triphenylphosphine) palladium (0) (0 , 187 mg, 0.162 mmol) was dissolved in 1,2-dimethoxyethane under a nitrogen atmosphere and stirred at room temperature for 1 hour, which was designated as solution A. Thereafter, in a separate flask, (2-chloro-4-pyridyl) boronic acid (compound b, 1.0 g, 6.35 mmol) and sodium carbonate (1.21 g, 10.7 mmol) were dissolved in 10 mL of ion- While stirring, nitrogen flow was carried out for about 1 hour to replace oxygen in the ion exchanged water, and this solution was designated as solution B. Then, to the flask containing the solution A, the solution B was dropped with a pipette and mixed, and the mixture was heated at about 100 C. for 10 hours under nitrogen. After cooling to room temperature, the organic layer was concentrated under reduced pressure and filtered to obtain a white solid. The solid was dried and purified with a silica column using chloroform as a developing solvent to obtain about 860 mg of a white solid. This was designated Compound 1.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In dichloromethane; water; at 60℃;
General procedure: All liquids incorporated into the reaction were degassed prior to addition. To a solution of 1 (1 eq., 50.0 mg, 0.192 mmols) and PdCl2(dppf)•CH2Cl2 (20 mol%, 31.3 mg, 0.0384 mmols) in CH2Cl2 (0.1M, 1.6 mL) was added aryl bromide (1.1 eq., 0.211 mmols) and 3.33M K2CO3 solution (6 eq.,0.958 mmols, 0.27 mL). The mixture is quickly stirred and heated at 60. The mixture would go from a bright red solution to a darkened mixture within minutes of the reaction. Upon confirmation of completion by TLC (typically eluted with 40% to 50% MeCN/CH2Cl2), the mixture is immediately taken off the heat and diluted with 10 mL H2O. The organic mixture is extracted with 3 x 10 mL diethyl ether. The organic extracts are dried over Na2SO4, filtered then concentrated. The crude product is purified by silica gel column chromatography (gradient with ethylacetate/hexanes) to afford 3 as a resin or white powder.
((3,5-bis(trifluoromethyl)phenyl)methylenedisulfonyl)dibenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With palladium diacetate; triphenylphosphine; lithium tert-butoxide In 1,4-dioxane at 100℃; for 24h; Inert atmosphere;
4.2. General procedure for the synthesis of 3
General procedure: To a 25 mL reaction tube equipped with a magnetic stirrer was charged with Pd(OAc)2 (1.1 mg, 2.5 mol%), PPh3 (5.2 mg,10 mol%), t-BuOLi (40 mg, 0.5 mmol), 4-bromobenzonitrile 1a (36.4 mg, 0.2 mmol), bis(phenylsulfonyl)methane 2a (59.3 mg, 0.2 mmol), and 1,4-dioxane (2 mL). The mixture was stirred at 100 οC under N2 atmosphere for 24 h. The mixture was diluted with water (5 mL) and the pH value was adjusted to about 7 with dilute hydrochloric acid solution (2 M). The mixture was extracted with CH2Cl2 (10 mL x 3). The combined organic layer was filtered through a layer of celite and concentrated under reduced pressure. The crude product was purified by flash column chromatography using petroleum ether/ethyl acetate (3:1) as eluent to afford 3a (68.3 mg, 86 %) as a white solid. 4.2.1. 4-(Bis(phenylsulfonyl)methyl)benzonitrile (3a) White solid (68.3 mg, 86 % yield); Mp: 193-195 οC; 1H NMR( 400 MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 4H), 7.68 (t, J = 7.6 Hz, 2H), 7.57-7.49 (m, 8H), 5.48 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 137.42, 135.00, 132.22, 130.89, 129.63, 129.14, 117.77, 114.29, 87.56; HRMS (ESI): calculated for C20H16NO4S2 [M+H]+: 398.0515, found: 398.0529.
Stage #1: 3,6-bis(trifluoromethyl)bromobenzene With magnesium In tetrahydrofuran at 35 - 45℃; for 8h;
Stage #2: N-methyl-N-phenylformamide In tetrahydrofuran at 25 - 35℃;
1; 4-5 Example 5
In a reactor equipped with a stirring blade and a thermometer, 4400 g of cyclopentyl methyl ether and 96 g of magnesium powder were added. Add 590 g of 3,5-bistrifluoromethyl bromobenzene under stirring, and control the temperature at 35-45° C. to react for 8 hours. When the reaction is over, the temperature is controlled at 25-35°C and 408g of N-methyl-N-phenylformamide is added dropwise. When the reaction is over, 5000 g of water and 400 g of concentrated hydrochloric acid are added to the kettle, and after acidification, the liquids are separated. The aqueous phase was extracted twice with 8500 g of ethyl acetate. Combine the organic phases, add 750 g of 5% sodium carbonate solution, stir for 20 min, and separate the liquids. The organic phase was subjected to atmospheric distillation to remove most of the solvent, and then rectified under reduced pressure to obtain 3,5-bistrifluoromethylbenzaldehyde with a GC purity of 98.2% and a yield of 93%.
3,5-bis(trifluoromethyl)-4’-methoxybiphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 85℃; for 24h; Inert atmosphere;
1 Synthesis of 4'-Methoxy-3,5-bis(trifluoromethyl)-1,1'-biphenyl (compound a-2)
Compound a-1 (1.5 mmol, 351 mg) and 1-bromo-3,5-bis(trifluoromethyl)benzene (1.5 equiv.), Pd(PPh3)4 (5 mol%) in a two-necked round bottom flask ), Na2CO3 (8 equiv) was added, and nitrogen conditions were created. DME (10 mL), EtOH (5 mL), and H2O (10 mL) were added thereto in this order and heated to reflux at 85° C. for 24 hours. After the reaction was completed, the catalyst was removed through silica filtration after cooling to room temperature. Thereafter, compound a-2 as a white solid was obtained through column chromatography (eluent: Ether/n-Hex = 1/50 v/v) (336 mg, 70%).
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl-formamide at 100℃; for 24h;
4’-methyl-3,5-bis(trifluoromethyl)-1,1’-biphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With tetrabutyl ammonium fluoride; palladium diacetate; di(1-adamantyl)-N-butylphosphine hydroiodide at 80℃; for 24h; Inert atmosphere; Sealed tube; Green chemistry;
N1,N4-bis(3,5-bis(trifluoromethyl)phenyl)-N1,N4-di(naphthalen-2-yl)benzene-1,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With tri-tert-butyl phosphine; palladium diacetate; sodium tertiary butoxide In toluene at 110℃; for 14h; Schlenk technique; Inert atmosphere;
N1,N4-bis(3,5-bis(trifluoromethyl)phenyl)-N1,N4-diphenylbenzene-1,4-diamine (3,5-FTPB)
General procedure: To a Schlenk tube with a magnetic stirrer N1,N4-diphenylbenzene-1,4-diamine (0.5g, 1.9mmol), 1-bromo-3,5-bis(trifluoromethyl)benzene (0.74ml, 2.97mmol), t-BuONa (0.6g, 6.65mmol) and 15ml of anhydrous toluene were added. The reaction mixture was degassed by bubbling with argon for 15min under stirring. Then, Pd(OAc)2 (0.034g, 0.285mmol) and P(t-Bu)3 (0.036ml, 0.108mmol) were added and the reaction mixture was degassed for another 10min. The reaction mixture was stirred at 110°C under argon atmosphere. After 14h the reaction mixture was cooled down to room temperature and extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography using dichloromethane and hexane in a volume ratio of 1:5 as an eluent. The product was crystallized from the eluent giving yield of white crystals 45% (0.55g).
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