* 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.
With N-Bromosuccinimide In methanol at 0 - 20℃; Inert atmosphere
To a mixture of 6-(trifluoromethyl)pyridin-2-amine (600 mg, 3.7mmol) in MeOH (10 mL) was added NBS (659 mg, 3.7mmol) in portions at 0oC. The reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE:EA = 4:1) to afford the title compound (650 mg, 73.1percent yield) as a white solid. Retention time (LC-MS): 1.33 min. MH+ 241.
44%
With N-Bromosuccinimide In chloroform for 2 h; Darkness
To a solution of 6-trifluoromethyl-pyridin-2-ylamine (10.0 g, 62.1 mmol, 1 eq) in CHCI3 (200 mL) was added NBS (12.0 g, 67.4 mmol, 1.08 eq). The solution was stirred in the dark for 2 h, at which time it was added to DCM (200 mL) and 1 N NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was dried and concentrated. The residue was purified by silica gel column (EA/PE = 1/1, v/v) to give 5-bromo-6- trifluoromethyl-pyridin-2-ylamine (6.5 g, 44percent) as an orange solid.
40.3%
at 0 - 20℃; for 3 h;
The 6 - (trifluoromethyl) pyridin -2 amine (972 mg, 6 . 0mmol) dissolved in chloroform (10 ml) in, cooling to 0 °C, adding N-bromo succinimide (1.28g, 7 . 2mmol), stir at room temperature 3 hours, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) purification, to obtain solid title compound (0.58g, yield 40.3percent).
Reference:
[1] Patent: WO2016/44792, 2016, A1, . Location in patent: Page/Page column 173
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 527 - 531
[3] Patent: WO2017/1926, 2017, A2, . Location in patent: Paragraph 00139
[4] Patent: CN105541792, 2016, A, . Location in patent: Paragraph 0242; 0243; 0244
In N,N-dimethyl-formamide; at 150℃; for 0.25h;Microwave irradiation; Inert atmosphere;
To <strong>[882500-21-2]5-bromo-6-(trifluoromethyl)pyridin-2-amine</strong> (3.0g, 12.45mmol, l .Oeq) in dimethylformamide (1ml) was added zinc cyanide (1.456g, 12.45mmol, l .Oeq). The reaction mixture was then heated in microwave at 150oC for 15min. After completion of reaction, water was added to reaction mixture and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain 92.1. (Yield: 68.69%). MS (ES): m/z 188.13 [M+H]+
38%
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 3.0h;
To a solution of 5-bromo-6-trifluoromethyl-pyridin-2-ylamine (6.5 g, 27.08 mmol, 1 eq) in DMF (70 mL) was added Zn(CN)2 (6.3 g, 54.16 mmol, 2 eq) and Pd(PPh3)4 (3.1 g, 2.71 mmol, 0.1 eq). The mixture was stirred at 100 C for 3 h and then cooled to rt. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography on a silica gel column (PE/EA = 1/1, v/v) to give 6-amino-2- trifluoromethyl-nicotinonitrile (1.9 g, 38%) as a yellow solid.
tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In ISOPROPYLAMIDE; at 160℃; for 20.0h;Sealed tube; Inert atmosphere;
A mixture of <strong>[882500-21-2]5-bromo-6-(trifluoromethyl)pyridin-2-amine</strong> (3.0 g, 12.3 mmol), Zn(CN)2 (0.81 g, 6.9 mmol), Pd2(dba)3 (0.57 g, 0.6 mmol), and Xantphos (0.72 g, 1.2 mmol) in DMA (12 mL) was placed in a sealed tube. The mixture was degassed with argon and stirred at 160C for 20h. The mixture was poured into water and extracted with EtOAc (2x). The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel eluting with 3: 1 EtOAc/hexanes to afford 1.9 g of 6-amino-2-(trifluoromethyl)nicotinonitrile as a solid. lR NMR (400 MHz, CDC13) delta 7.74 (d, 1H), 6.67 (d, 1H).
With N-Bromosuccinimide; In methanol; at 0 - 20℃;Inert atmosphere;
To a mixture of 6-(trifluoromethyl)pyridin-2-amine (600 mg, 3.7mmol) in MeOH (10 mL) was added NBS (659 mg, 3.7mmol) in portions at 0oC. The reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE:EA = 4:1) to afford the title compound (650 mg, 73.1% yield) as a white solid. Retention time (LC-MS): 1.33 min. MH+ 241.
48.2%
With N-Bromosuccinimide; In methanol; at 0 - 20℃; for 10.0h;
To a stirred solution of 6-(trifluoromethyl)pyridin-2-amine (2 g, 12.34 mmol) in methanol (20 ml.) was added N-bromosuccinamide (2.19 g, 12.34 mmol) in portions at 0 C. Reaction mixture was then stirred at rt for 10 h. After completion of reaction (monitored by TLC) evaporated the solvent invacuo to dryness. Crude compound was purified by column chromatography using 0-50% EtOAc in n-hexanes to afford title compound 1 .4 g (48.2%), Rf = 0.55 (20% EtOAc in n-Hexane). 1 H NMR (300 MHz, Chloroform-d) d 7.68 (d, J = 8.6 Hz, 1 H), 6.53 (d, J = 8.7 Hz, 1 H), 4.71 (s, 2H).
44%
With N-Bromosuccinimide; In chloroform; for 2.0h;Darkness;
To a solution of 6-trifluoromethyl-pyridin-2-ylamine (10.0 g, 62.1 mmol, 1 eq) in CHCI3 (200 mL) was added NBS (12.0 g, 67.4 mmol, 1.08 eq). The solution was stirred in the dark for 2 h, at which time it was added to DCM (200 mL) and 1 N NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was dried and concentrated. The residue was purified by silica gel column (EA/PE = 1/1, v/v) to give 5-bromo-6- trifluoromethyl-pyridin-2-ylamine (6.5 g, 44%) as an orange solid.
40.3%
With N-Bromosuccinimide; at 0 - 20℃; for 3.0h;
The 6 - (trifluoromethyl) pyridin -2 amine (972 mg, 6 . 0mmol) dissolved in chloroform (10 ml) in, cooling to 0 C, adding N-bromo succinimide (1.28g, 7 . 2mmol), stir at room temperature 3 hours, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) purification, to obtain solid title compound (0.58g, yield 40.3%).
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 105℃;Inert atmosphere;
Example 82 A suspension of <strong>[882500-21-2]2-amino-5-bromo-6-trifluoromethyl-pyridine</strong> (0.5 g, 2.075 mmol), PdCl2(dppf)-DCM adduct (0.085 g, 0.104 mmol), bis(pinacolato)diboron (0.685 g, 2.70 mmol) and KOAc (0.611 g, 6.22 mmol) in dioxane (8 mL) was sparged with Ar and heated at 105 C. overnight. The mixture was cooled to RT, treated with EtOAc, the solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and the filtrate concentrated to dryness to afford 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (100% yield assumed). MS (ESI) m/z: 289.1 (M+H+).
N-(5-bromo-6-(trifluoromethyl)pyridin-2-yl)-2-chloroacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.7%
In N,N-dimethyl-formamide; at 0 - 20℃; for 2.0h;Inert atmosphere;
To a solution of <strong>[882500-21-2]5-bromo-6-(trifluoromethyl)pyridin-2-amine</strong> (72mg, 0.3mmol) in DMF (2 mL) was added dropwise 2-chloroacetyl chloride (0.05 mL, 0.6 mmol) at 0oC. The reaction mixture was stirred at r.t. for 2 h and poured into EA. The mixture was washed with water and brine, dried over Na2SO4, and concentrated to give the title compound (85 mg, 89.7% yield) as yellow solid. Retention time (LC-MS): 1.64 min. MH+ 319.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 110℃; for 20.0h;Inert atmosphere;
To a solution of <strong>[882500-21-2]5-bromo-6-(trifluoromethyl)pyridin-2-amine</strong> (0.500, 2.07mmol, l .Oeq) in 1,4-dioxane (0.5mL) was added Tri methyl boroxine (0.520g, 4.14mmol, 2.0eq). The reaction mixture was degassed for 10 min. under argon atmosphere. Potassium carbonate (0.858g, 6.22mmol, 3.0eq) and tetrakis(triphenylphosphine)palladium(0) (0.239 g, 0.207mmol, O. leq), again reaction mixture was degassed for 10 min. under argon atmosphere. The reaction was stirred at 110C for 20h. After completion of reaction, reaction mixture was transferred in water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 15% ethyl acetate in hexane to obtain pure 189.1 (0.230g, 62.94%). MS(ES): m/z 177.14 [M+H]+
With zinc(II) cyanide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 0.25h;Microwave irradiation;
To <strong>[882500-21-2]5-bromo-6-(trifluoromethyl)pyridin-2-amine</strong> (3.Og,12.45mmol, 1.Oeq) in dimethylformamide (imi) was added zinc cyanide (1.456g, 12.45mmol, 1 .Oeq). The reaction mixture was then heated in microwave at 150 C for 15mm. After completion of reaction, water was added to reaction mixture and extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4 and concentrated in vacuo to obtain crude product. This was purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain 36.1. (Yield: 68.69%). MS (ES): m/z 188.13 [M+H]t
3-bromo-6-fluoro-2-(trifluoromethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine hydrogenfluoride; sodium nitrite; at 0℃; for 1.0h;
To a solution of amine precursor (300 mg, 1 .25 mmol) in HF-pyridine (3 ml.) was added sodium nitrite (103 mg, 1 .50 mmol) in portions at 0 C. Reaction mixture was stirred at 0 C for 1 h. Reaction mixture diluted with water and extracted with DCM (25 ml. X 2). The combined organic layer was dried over sodium sulphate and concentrated at reduced pressure (DCM was not evaporated completely due to low boiling point of compound) to get crude title compound (500 mg), which was used for next step without further purification. Rf = 0.4 (10% EtOAc in n-Hexane); 1 H NMR (400 MHz, Chloroform- d) d 8.29 - 7.97 (m, 1 H), 7.07 (ddd, J = 8.6, 3.7, 0.6 Hz, 1 H).