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CAS No. : | 23165-29-9 | MDL No. : | MFCD00040838 |
Formula : | C9H3F6NS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FXOSSGVJGGNASE-UHFFFAOYSA-N |
M.W : | 271.18 | Pubchem ID : | 2733395 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 51.13 |
TPSA : | 44.45 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -3.94 cm/s |
Log Po/w (iLOGP) : | 2.56 |
Log Po/w (XLOGP3) : | 5.65 |
Log Po/w (WLOGP) : | 6.76 |
Log Po/w (MLOGP) : | 5.27 |
Log Po/w (SILICOS-IT) : | 5.61 |
Consensus Log Po/w : | 5.17 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.14 |
Solubility : | 0.00195 mg/ml ; 0.00000718 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.35 |
Solubility : | 0.000122 mg/ml ; 0.000000449 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -4.37 |
Solubility : | 0.0116 mg/ml ; 0.000043 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.21 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P280-P301+P310+P330-P304+P340+P312-P305+P351+P338-P337+P313 | UN#: | 2206 |
Hazard Statements: | H301-H315-H319-H335 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
187 mg | With triethylamine In dichloromethane; chloroform | General procedure: To a ice cooled solution of N-Boc-aminoacid (L-tertleucine, L-Leu, L-Val, L-Phe, L-Ala) 1mmol in DCM 10 ml, HOBt hydrate (0.153 g, 1 mmol) and DCC (0.205 g, 1 mmol) was added. Reaction mixture was stirred at 0°C through 30 minutes, and amine 7 a-g (2 mmol) was added. Resulting reaction mixture was stirred for 12 h and allowed to warm to room temperature. Then a few drops of acetic acid was added, solvents was removed under reduced pressure. Residue was dissolved in AcOEt and cooled to 4°C, precipitate of urea was removed by filtration. Organic phase was washed with aqueous solution of KHSO4 (10percent, 20ml) followed by aqueous solution of NaHCO3 (5percent, 20ml) and dried with MgSO4. Solvents were removed under reduced pressure and residue was dissolved in 10ml mixture of TFA:DCM (1:1). Progress of N-deprotection was monitored with TLC. Then mixture of TFA:DCM was evaporated and trifluoroacetate salt was dissolved in DCM 10 ml. To a resulted mixture NEt3 (0.303 g, 3 mmol) and chloroform solution of isothiocyanate 9a,b[2] was added dropwise. After completion of the reaction, the solvent was removed under vacuum, and the residue was purified with flash column chromatography. (S)-N-benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3,3-dimethylbutanamide (10a)Purification by flash column chromatography, (EtOAc/Hex, gradient elution 1:5 to 1:3),(187 mg, 38percent over two steps). white solid; mp 149–151 °C; [α]D26 −12.5° (c 0.4,CHCl3); 1H NMR (500 MHz, C6D6) δ 8.60 (s, 1H), 8.06 (d, J 9.2 Hz, 1H), 7.99 (s, 2H),7.42 (s, 1H), 6.96–6.90 (m, 4H), 6.89–6.84 (m, 1H), 5.51 (s, 1H), 5.02 (d, J 9.2 Hz,1H), 4.08 (dd, J2 14.7 Hz, J3 6.4 Hz, 1H), 3.88 (dd, J2 14.7 Hz, J3 5.3 Hz, 1H),0.97 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 181.9, 172.1, 139.9, 136.2, 131.7 (q, JC–F 33.3 Hz), 128.8, 127.9, 127.6, 124.2 (m), 123.0 (q, JC–F 271.1 Hz), 118.5 (m), 66.4, 44.2,35.1, 27.2; HRMS (ESI): m/z [MNa] calcd for C22H23F6N3OSNa: 514.1364; found:514.1368. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 20% | Stage #1: 2-(4-chlorobenzenesulfonyl)acetonitrile; 3,5-bistrifluoromethylphenylisothiocyanate With potassium carbonate In acetone at 20℃; for 2h; Stage #2: methyl iodide In acetone at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 2-(4-chlorobenzenesulfonyl)acetonitrile; 3,5-bistrifluoromethylphenylisothiocyanate With potassium carbonate In acetone at 20℃; for 4.5h; Stage #2: methyl iodide In acetone at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In tetrahydrofuran at 0 - 20℃; | |
88% | In dichloromethane at 20℃; | |
In tetrahydrofuran at 0 - 20℃; |
In dichloromethane at 20℃; | ||
In tetrahydrofuran for 0.5h; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In dichloromethane at 20℃; | |
92% | In tetrahydrofuran at 0 - 20℃; for 5.5h; | |
91% | In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
91% | In tetrahydrofuran at 0 - 20℃; for 4.75h; | 1 Preparation Example 1 The preparation method of hydrogen bond catalyst 1-((1R,2R)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (-1) includes the steps:(1R,2R)-1,2-cyclohexanediamine (910.0mg, 8.0mmol) was added to 40mL anhydrous tetrahydrofuran, and then at 0 , stirring conditions, 3,5-bis (three Fluoromethyl)phenyl isothiocyanate (1.46mL, 8.0mmol), the dripping time is 45 minutes; after the dripping is completed, the temperature is raised to room temperature, the reaction is stirred at room temperature for 4h, and the solvent is distilled off under reduced pressure. Purification is carried out by silica gel column chromatography, the eluent is a mixed solvent of dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is 100:1-20:1;A white flaky solid product (2.81g, yield 91%) was obtained, which was 1-((1R,2R)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl) ) Thiourea (-1). |
90% | In tetrahydrofuran at 0 - 20℃; for 2h; | |
85.7% | In dichloromethane at 0℃; for 20h; | |
85.7% | In dichloromethane at 0℃; for 20h; | |
73% | In dichloromethane at 20℃; for 10h; | 1 As shown in FIG. 4, 3,5-Bis(trifluoromethyl)-phenyl isothiocyanate (1.3 mL, 7.1 mmol, 1.0 equiv) was added to a solution of (R,R)-cyclohexanediamine (970 mg, 8.51 mmol, 1.2 equiv) in anhydrous dichloromethane (20 mL) at rt. The resulting solution was stirred at room temperature (“rt”) for 10 hours, then loaded onto a silica gel column and chromatographed (EtOAc/MeOH/NH4OH, 200:5:1→100:20:1) to afford 1-((1R,2R)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (2.0 g, 73% yield) as a yellow foam. Rf0.31 (EtOAc/MeOH/NH4OH, 100:5:1); [α]20D=+76.9 (c 1.7, CHCl3); 1H NMR (CDCl3, 300 MHz) δ=8.01 (s, 2H), 7.55 (s, 1H), 1H), 3.37 (br s, 1H), 2.69-2.65 (m, 1H), 2.04 (m, 2H, NH2), 1.98-1.91 (m, 2H), 1.80-1.65 (m, 2H), 1.40-1.20 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ=183.3, 142.0, 131.8 (q, JCF=33.9 Hz), 128.8, 125.2, 122.9, 121.5, 117.9, 117.7, 63.4, 56.8, 35.1, 32.3, 24.7; HRMS (FAB, NBA) Calcd. for C15H18N3SF6 [MH+] m/z 386.1125, found 386.1128. |
73% | In dichloromethane at 20℃; for 10h; | |
In dichloromethane at 0 - 20℃; for 15h; | ||
In dichloromethane at 0℃; for 20h; | ||
In dichloromethane at 0 - 20℃; | ||
In dichloromethane at 20℃; for 4h; | ||
In tetrahydrofuran at 0 - 24℃; for 16h; | ||
In dichloromethane at 0 - 20℃; for 1.5h; | ||
1.5 g | In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | |
In dichloromethane Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 0 - 20℃; | ||
In dichloromethane at 20℃; | ||
In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.65 g (99%) | With potassium carbonate; In dichloromethane; acetone; | 1 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile A solution of <strong>[120069-21-8]2-propanesulphonylacetonitrile</strong> (4.0 g, 27.2 mmol) in dry acetone (50 ml) was stirred while dry potassium carbonate (7.52 g, 54.4 mmol) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (7.72 g, 4.87 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 20 h. Excess of potassium carbonate was filtered off, methyl iodide (5.08 ml, 81.6 mmol) was added to the filtrate, and stirring was continued for 48 h. The mixture was evaporated and the residue was dissolved in dichloromethane and extracted with water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to afford 11.65 g (99%) of the title compound as yellowish brown crystals. Mp 130-133 C. 1H NMR (200 MHz, CDCl3): delta=1.47 (d, 6H), 2.35 (s, 3H), 3.44 (heptet, 1H), 7.73 (s, 2H), 7.80 (s, 1H), 10.10 (br s, 1H); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.52 g (20%) | With potassium carbonate In acetone | 11.1 1 1 3-[N-(3,5-Bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile To a solution of 4-chlorophenylsulfonylacetonitrile (1.10 g, 5.1 mmol) in dry acetone (12 ml) first dry potassium carbonate (1.41 g, 10.2 mmol) and then 3,5-bis(trifluoromethyl)phenyl isothiocyanate (1.44 g, 5.3 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen. After 2 h methyl iodide (3.86 ml, 61.2 mmol) was added. The mixture was stirred at room temperature for 18 h, followed by filtration and concentration. Crystallisation from ethyl acetate/heptane 1:3 gave 0.52 g (20%) of the title compound. 1H NMR (300 MHz, CDCl3): δ=2.40 (s, 3H), 3.65 (s, 3H), 7.36 (s, 2H), 7.42 (d, 2H), 7.58 (s, 1H), 7.65 (d, 2H);); El SP/MS: 514 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In dichloromethane; acetone; | 1 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile To a solution of methanesulfonylacetonitrile (0.55 g, 4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then 3,5bis(trifluoromethyl)phenyl isothio-cyanate (1.32 g, 4.7 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 4 h, and then filtered. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (sodium sulfate) and concentrated. The residue was recrystallized from ethyl acetate/heptane 1:2 to give the title compound (1.55 g, 83%). Mp 129-131 C. 1H NMR (200 MHz, CDCl3): delta=2.35 (s, 3H), 3.25 (s, 3H), 7.77 (s, 2H), 7.80 (s, 1H)H), 9.90 (brs, 1H); El SP/MS: 404 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
317 mg (12%) | With hydrogenchloride; magnesium sulfate; triethylamine In ice-water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; acetonitrile | 6 Synthesis of 3-[3,5-bis(trifluoromethyl)phenylamino]-3-(3-methylbutylamino)-2-(4-chlorophenylsulfonyl)-2-propenenitrile Example 6 Synthesis of 3-[3,5-bis(trifluoromethyl)phenylamino]-3-(3-methylbutylamino)-2-(4-chlorophenylsulfonyl)-2-propenenitrile To a solution of 3,5-bis(trifluoromethyl)phenylisothiocyanate (1,44 g, 5.31 mmol) in DCM (15 mL) and acetonitrile (5 mL) first 4-chlorophenylsulfonylacetonitrile (1.10 g, 5.10 mmol) and then triethylamine (1.0 mL) were added. The resulting mixture was stirred at room temperature for 2 h 15 min, and then isoamylamine (0.65 mL, 5.59 mmol), mercury(II) oxide (2.70 g, 12.47 mmol) and magnesium sulfate (0.8 g) were added. Stirring was continued for 2 d. The mixture was then filtered, poured into a mixture of ice-water (200 mL) and concentrated hydrochloric acid (2 mL), phases were separated, the aqueous layer was extracted twice with DCM (20 mL) and the combined extracts were dried (magnesium sulfate) and concentrated. Column chromatography of the residue (100 g silica gel, gradient elution with heptane/ethyl acetate 10:0 to 3:1) gave 317 mg (12%) of the title compound as an oil. 1 H NMR (300 MHz, DMSO-d6): δ=0.79 (d, J=7 Hz, 6H), 1.39 (q, J=7 Hz, 2H), 1.50 (nonett, J=7 Hz, 1H), 3.31 (m, 2H), 7.27 (s, 2H), 7.67-7.80 (m, 5H), 8.13 (s, br, 1H), 9.76 (s, 1H); LCMS: elution at 16.23 min, MH+: 540. |
317 mg (12%) | With hydrogenchloride; magnesium sulfate; triethylamine In ice-water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; acetonitrile | 6 Example 6. Example 6. Synthesis of 3-[3,5-bis(trifluoromethyl)phenylamino]-3-(3-methylbutylamino)-2-(4-chlorophenylsulfonyl)-2-propenenitrile To a solution of 3,5-bis(trifluoromethyl)phenylisothiocyanate (1,44 g, 5.31 mmol) in DCM (15 mL) and acetonitrile (5 mL) first 4-chlorophenylsulfonylacetonitrile (1.10 g, 5.10 mmol) and then triethylamine (1.0 mL) were added. The resulting mixture was stirred at room temperature for 2 h 15 min, and then isoamylamine (0.65 mL, 5.59 mmol), mercury(II) oxide (2.70 g, 12.47 mmol) and magnesium sulfate (0.8 g) were added. Stirring was continued for 2 d. The mixture was then filtered, poured into a mixture of ice-water (200 mL) and concentrated hydrochloric acid (2 mL), phases were separated, the aqueous layer was extracted twice with DCM (20 mL) and the combined extracts were dried (magnesium sulfate) and concentrated. Column chromatography of the residue (100 g silica gel, gradient elution with heptane/ethyl acetate 10:0 to 3:1) gave 317 mg (12%) of the title compound as an oil. 1H NMR (300 MHz, DMSO-d6): δ = 0.79 (d, J = 7 Hz, 6H), 1.39 (q, J = 7 Hz, 2H), 1.50 (nonett, J = 7 Hz, 1H), 3.31 (m, 2H), 7.27 (s, 2H), 7.67-7.80 (m, 5H), 8.13 (s, br, 1H), 9.76 (s, 1H); LCMS: elution at 16.23 min, MH+: 540. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 89 3-[3-(3,5-Bis-trifluoromethylphenyl)-thioureido]-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3,5-di(trifluoromethyl)phenyl isothiocyanate (1.08 g, 3.98 mmol) to afford the product (1.076 g); m.p. 192-193 C. Calculated for C23H17N3O2F6S: C, 53.80; H, 3.34; N, 8.18. Found: C, 53.71; H, 3.15; N, 8.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In dichloromethane at 20℃; | |
81% | In dichloromethane at 20℃; | |
61% | In tetrahydrofuran at 20℃; for 48h; Inert atmosphere; |
In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; for 24h; | 2 A solution of 2-(3,4-Dichloro-phenoxy)-ethylamine (1 mmol) and 3,5-bis-(trifluoromethyl)phenyl isothiocyanate (1 mmol) in CHCI2 (5 mL) was stirred at r.t. for 24 h. The precipitate was collected and washed with n-heptane, giving compound E as white crystals (425 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 24h; | A solution of 4-bromo-alfa-methylbenzylamine (1 mmol) and 3,5-bis-(trifluoromethyl)phenyl isothiocyanate (1 mmol) in CHCI2 (5 mL) was stirred at <n="25"/>r.t. for 24 h. The precipitate was collected and washed with n-heptane, giving compound C as white crystals (158 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In tetrahydrofuran at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.71 g | Stage #1: tert-butyl (S)-1-(N-benzyl-N-methylcarbamoyl)-2,2-dimethylpropylcarbamate With hydrogenchloride In 1,4-dioxane at 20℃; for 2h; Stage #2: 3,5-bistrifluoromethylphenylisothiocyanate With triethylamine In dichloromethane at 20℃; for 4h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: N-methyl-N-[(S)-1-phenylethyl]amine; N-tert-butyloxycarbonyl-L-tert-leucine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; Stage #3: 3,5-bistrifluoromethylphenylisothiocyanate With triethylamine In dichloromethane at 20℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 2-(4-chlorobenzenesulfonyl)acetonitrile; 3,5-bistrifluoromethylphenylisothiocyanate With potassium carbonate In acetone at 20℃; for 1h; Stage #2: methyl iodide With sodium hydrogencarbonate In water; acetone at 20℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Stage #1: 2-(4-chlorobenzenesulfonyl)acetonitrile; 3,5-bistrifluoromethylphenylisothiocyanate With potassium carbonate In acetone at 20℃; for 2h; Stage #2: methyl iodide In acetone at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In dichloromethane at 20℃; | |
86% | In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In tetrahydrofuran at 20℃; for 5h; | |
60% | In tetrahydrofuran Inert atmosphere; Reflux; | |
60% | In tetrahydrofuran | 1-(4-Vinylphenyl)-3-(3,5-bis(trifluromethyl)phenyl)-thiourea (3) 1-(4-Vinylphenyl)-3-(3,5-bis(trifluromethyl)phenyl)-thiourea (3) To a stirred solution of 4-aminostyrene (3.5 mmol) in dry THF (20 mL) under nitrogen was added 3,5-bis-(trifluoromethyl)phenyl isothiocyanate (3.5 mmol). The solution was refluxed overnight and then the solvent was evaporated under reduced pressure. The resulting solid residue was purified by column chromatography to yield the desired product in 60% yield. 1H NMR (DMSO-d6): 5.22 (d, 1H), 5.28 (d, 1H), 6.76 (dd, 1H), 7.51 (s, 4H), 7.77 (m, 1H), 8.34 (s, 2H), 9.47 (s, 1H), 9.56 (s, 1H). 13C NMR (DMSO-d6) 114.21, 117.18, 122.22, 123.7, 124.13, 124.24, 124.94, 126.87, 129.85, 130.17, 130.50, 130.82, 134.37, 136.33, 138.44, 142.04, 179.81. MS (FAB) m/z (M+) 390.0, ([M+H]+) 391.0. Calculated for C17H12F6N2S: C 52.31, H 3.10, N 7.18, S 8.21. Found: C 52.19, H 3.14, N 7.22, S 8.25. |
60% | In tetrahydrofuran Inert atmosphere; Reflux; | 1 -(4-Vinylphenyl)-3-(3,5-bis(trifluromethyl)phenyl)- thiourea (3) To a stirred solution of 4-aminostyrene (3.5 mmol) in dry THF (20 mE) under nitrogen was added 3,5-bis-(trifluorom- ethyl)phenyl isothiocyanate (3.5 mmol). The solution was refluxed overnight and then the solvent was evaporated under reduced pressure. The resulting solid residue was purified by column chromatography to yield the desired product in 60% yield.‘HNMR(DMSO-d5): 5.22(d, 1H), 5.28(d, 1H), 6.76(dd,1H), 7.51 (s, 4H), 7.77 (m, 1H), 8.34 (s, 2H), 9.47 (s, 1H), 9.56(s, 1H). ‘3CNMR(DMSO-d5) 114.21,117.18,122.22,123.7,124.13, 124.24, 124.94, 126.87, 129.85, 130.17, 130.50,130.82, 134.37, 136.33, 138.44, 142.04, 179.81. MS (FAB)mlz (M) 390.0, ([M+H]) 391.0. Calculated forC17H12F6N25: C, 52.31; H, 3.10;N, 7.18; S,8.21. Found: C,52.19; H, 3.14; N, 7.22; 5, 8.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
711 mg | In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24h; | |
Stage #1: (S)-2-phenylglycine With sodium hydroxide In tetrahydrofuran; water for 0.25h; Stage #2: 3,5-bistrifluoromethylphenylisothiocyanate In tetrahydrofuran; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24h; | |
Stage #1: 3,5-bistrifluoromethylphenylisothiocyanate With sodium hydroxide In tetrahydrofuran; water for 0.25h; Stage #2: (R)-phenylglycine In tetrahydrofuran; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In tetrahydrofuran at 20℃; | |
In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dichloromethane at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In tetrahydrofuran at 20℃; for 16h; | |
88% | In tetrahydrofuran at 0 - 20℃; | |
87% | In dichloromethane at 20℃; | Procedure for synthesis of thiourea-quinine catalyst General procedure: According to the literature 18c, to a solution of 9-aminoquinine (2 mmol) in CH2Cl2 (10 mL) was slowly added to a solution of isothiocyanate (2 mmol) in CH2Cl2 (5 mL). The mixture was stirred at ambient temperature until reaction completion. The pure product was obtained after purification by column chromatography on silica gel with EtOAc/CH3OH/Et3N (10:1:0.1) as eluant, affording the catalyst (Q1~Q6). |
85% | In methanol at 20℃; | |
80% | With di-isopropyl azodicarboxylate; diphenyl phosphoryl azide; triphenylphosphine In benzene at 22℃; for 12h; Inert atmosphere; | |
79% | In dichloromethane at 20℃; | 3.1 Preparation of catalyst 1c Quinine amine (500 mg 1.55 mmol 1 equiv) was dissolved in 20 ml methylenedichloride. 1-isothiocyanato-3,5-bis(trifluoromethyl) benzene (505 mg 1.86 mmol 1.2 equiv) was added. Stir at room temperature overnight. The mixture was concentrated under reduced pressure and purified by flash chromatography (CH2Cl2/MeOH = 30:1) to afford the desired product 1c. Light yellow solid, 79% yield, m.p.=110-111°C, [a]D20 =- 107.5 (c = 0.5, CHCl3). 1H NMR (300 MHz, CD3OD) δ 8.67 (d, J = 4.7 Hz, 1H), 8.07 (s, 3H), 7.93 (d, J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.43 (dd, J = 9.3, 2.7 Hz, 1H), 6.40 (d, J = 10.8 Hz, 1H), 5.94 - 5.72 (m, 1H), 5.14 - 5.05 (m, 1H), 4.98 (d, J = 1.2 Hz, 2H), 4.00 (s, 3H), 3.71 (brs, 1H), 3.52 (d, J = 6.0 Hz, 1H), 3.43 - 3.30 (m, 1H), 3.01 - 2.76 (m, 2H), 2.43 (brs, 1H), 1.81 - 1.64 (m, 3H), 1.53 (t, J = 10.8 Hz, 1H), 1.01 - 0.77 (m, 1H). 13C NMR (126 MHz, CD3OD_SPE) δ 158.40, 146.90, 145.60, 143.83, 141.57, 140.65, 131.47, 131.20, 130.94, 129.90, 128.69, 126.53, 124.37, 122.51, 122.35, 119.79, 116.56, 114.00, 102.74, 60.17, 55.18, 54.50, 54.42, 41.78, 38.98, 27.24, 26.72, 25.36. HRMS (ESI): calculated for C44H51F6N4OS [M+H]+: 595.6279, found 595.6274. |
76% | In tetrahydrofuran at 20℃; for 14h; Inert atmosphere; | |
69% | In dichloromethane at 20℃; for 24h; Inert atmosphere; | |
In tetrahydrofuran for 12h; Inert atmosphere; | ||
In tetrahydrofuran at 20℃; | ||
0.8 g | In tetrahydrofuran at 20℃; | |
In tetrahydrofuran at 20℃; | ||
In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; | ||
1093.7 g | In ethyl acetate at 0 - 20℃; for 1h; Inert atmosphere; Large scale; | 3; 4.B; 4.C B. The reaction mixture prepared in Paragraph A was cooled to 0 °C. A solution of 753.8 g (2779.7 mmol, 0.9 eq.) of 3,5-bis(trifluoromethyl)phenylisocyanate in 2000 mL (2 V) of ethyl acetate was prepared, and charged to the reaction mixture while keeping the reaction mixture temperature at 0 ± 10 °C. The reaction mixture was warmed to 20 °C and stirred for approximately 1 hour. The reaction was quenched with 3400 mL of 1 N HCI solution until the pH was adjusted to 2.43. After partition, the upper organic layer was washed with additional 3400 mL (3.4 V) of Dl water, and basified with 400 mL of ammonium hydroxide solution until the pH was 10.30. Approximately 3400 mL (3.4 V) of Dl water was added and the reaction mixture stirred for additional 15 minutes. The stirring was stopped and the bottom aqueous layer was drained. The remaining ethyl acetate solution was heated to 40 °C after a charge of 3500 mL (3.5 V) of Dl water. The batch was stirred for 15 minutes and held at the same temperature overnight without stirring. After complete separation of two layers, the bottom aqueous layer was drained, and vacuum distillation of the organic solution began. After approximately half the solvent was removed, the reaction mixture was cooled to 40 °C before charging additional 4 L of fresh acetonitrile. The distillation continued and the process was repeated until the residual water was below 700 ppm. C. The vacuum was removed, the reaction mixture prepared in Paragraph B was heated to 80 °C to achieve a clear solution before cooling back to 20°C in 1 hour. The product precipitated, and the batch was further cooled to 0 °C and stirring for additional 24 hours. The solids were filtered, washed with 575 mL of cold acetonitrile, and dried under a stream of nitrogen to furnish 1093.7 g of 1-(3,5-5/'s(trifluoromethyl)phenyl)-3-((1 S)-(6-methoxyquinolin-4-yl)((2f?)-8-vinylquinuclidin-2- yl)methyl)thiourea (compound of formula (Ha)), 59% yield, 97.1 A% purity. |
In tetrahydrofuran at 20℃; | General procedure for the preparation of bifunctional catalysts 3 General procedure: Bifunctional organocatalysts 3 were prepared by the literature procedure. A cinchona alkaloid (5 mmol) and triphenylphosphine (1.6 g, 6 mmol) were dissolved inTHF (25 ml), and the solution was cooled to 0 °C. Diethyl azodicarboxylate (1.0 g, 6 mmol) was subsequently added. To the resulting solution was added dropwise the solution of diphenyl phosphoryl azide (1.3 ml, 6 mmol) in THF (10 ml) at 0 °C. The mixture was allowed to warm to ambient temperature. After being stirred for 24 h, it was heated to 50 °C and stirred for 10 h. Triphenylphosphine (1.7 g, 6.5 mmol) was added again, and the mixture was stirred at 50 °C for additional 15 h. After the solution was cooled to ambient temperature, H2O (0.5 ml) was added, and the solution was stirred for 24 h. Solvents were removed in vacuo, and the residue was dissolved in CH2Cl2/10% aqueous HCl (25 ml/ 25 ml). The aqueous phase was separated and washed with CH2Cl2 (25 ml x 4). It was subsequently made alkaline with aqueous NH3, and the aqueous phase was extracted with CH2Cl2 (25ml x 4). The combined organic layers were dried over Na2SO4, and concentrated in vacuo. Purification by flash silica gel column chromatography using EtOAc/CH3OH (v/v = 9/1) then CHCl3/CH3OH (v/v = 8/2) as an eluent gave the corresponding 9-amino(9-deoxy)cinchona alkaloids. Next, to a solution of the obtained 9-amino(9-deoxy)cinchona alkaloid in THF (6 ml) was slowly added a solution of 3,5-bis(trifluoromethyl)phenyl isothiocyanate (1 equiv.) in THF (4 ml) at ambient temperature. The mixture was stirred overnight, and solvents were removed in vacuo. Purification by flash silica gel column chromatography using EtOAc/CH3OH (v/v =95/5-97.5/2.5) or EtOAc as an eluent gave the corresponding bifunctional organocatalyst 3. | |
In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: (S,S)-1,2-diphenyl-1,2-diaminoethane With hydrogenchloride In diethyl ether for 1h; Schlenk technique; Inert atmosphere; Stage #2: 3,5-bistrifluoromethylphenylisothiocyanate In diethyl ether at 20℃; for 48h; Schlenk technique; Inert atmosphere; | |
21% | In dichloromethane at 20℃; for 18h; | |
In dichloromethane at 0℃; for 20h; |
In dichloromethane at 0℃; | ||
In dichloromethane at 0℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In tetrahydrofuran at 0 - 20℃; for 2h; | |
In dichloromethane at 0℃; for 20h; | ||
In dichloromethane at 0℃; |
In dichloromethane at 0℃; for 20h; | ||
In dichloromethane for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In toluene at 0℃; for 1h; | 3.2.1. Synthesis of N-Mono-Thiourea Catalyst DPEN (0.5 g, 0.235 mmol) was dissolved in toluene (2.50 mL). Then, the solution wasadded with isothiocyanate (0.35 mL, 0.235 mmol) and stirred for 1 h at 0 °C, and the reactionwas terminated with distilled water. The mixture was extracted with ethyl acetate (20mL × 3 times), dehydrated using MgSO4, filtered, concentrated under reduced pressure,and purified using column chromatography (SiO2, CH2Cl2: n-hexane = 1:2) to isolate the product (Scheme 1). |
90% | In tetrahydrofuran at 0 - 20℃; for 5.5h; | |
83% | In tetrahydrofuran at 0 - 20℃; for 4.75h; | 3 Preparation Example 3 Hydrogen bond catalyst 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (-4) The preparation method includes the steps:(1R,2R)-1,2-Diphenylethylenediamine (910.0mg, 8.0mmol) was added to 10mL of tetrahydrofuran, and then 3,5-bis(trifluoromethyl) Phenyl isothiocyanate (1.46mL, 8.0mmol) was added dropwise under stirring at 0, the dripping time is 45 minutes; after the dripping is completed, the reaction system is raised to room temperature, and the reaction is stirred at room temperature for 4h; the reaction solution is distilled under reduced pressure to remove the solvent, and the product is obtained Purification was carried out by silica gel column chromatography. The eluent was a mixed solvent of dichloromethane and methanol, where the volume ratio of dichloromethane to methanol was 30:1-20:1 to obtain a white flaky solid (2.23g, yield Rate 83%), which is 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea ( -4) |
In dichloromethane at 0℃; for 20h; | ||
In dichloromethane at 0℃; | ||
In dichloromethane at 0℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | |
84% | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | General Procedure A5: Thiourea/urea formation from quinolone analogues General procedure: To an oven-dried round bottom flask flushed with argon for 10 min was added the respective quinolone analogue (250 mg, 1 eq), dry DMF (40 mL), NaHCO3 (1.2 eq) and the corresponding isothiocyanate or isocyanate (1 eq). The reaction flask was once again flushed with Argon then allowed to stir at RT overnight. Afterward, the reaction was quenched by addition of saturated NH4Cl solution (25 mL) then extracted with EtOAc. The organic phase was washed with 5% w/v LiCl (aq.), water and brine. The solvent was removed by vacuum and the residue was washed with water, followed by MeOH, and isolated by suction filtration. If precipitation occurred in the organic phase, the solid was collected by vacuum filtration, then washed with water and MeOH. |
18 2-(4-[(3,5-bis(trifluoromethyl)phenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid (18) Example 18 2-(4-[(3,5-bis(trifluoromethyl)phenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid (18) Pipemidic acid (40 mg, 0.132 mmol) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (20 μL, 0.110 mmol) were used. Purification on silica yielded compound 18 in Table 1, below (61 mg, 97%). 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 7.94 (s, 2H), 7.62 (s, 1H), 4.42-4.05 (m, 10H), 1.51 (t, J=7.07 Hz, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In tetrahydrofuran at 20℃; Inert atmosphere; | |
In dichloromethane at 20℃; for 2h; | ||
In dichloromethane at 20℃; |
0.44 g | In tetrahydrofuran at 0℃; | |
0.44 g | In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In dichloromethane at 40℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: (2R,3S)-3-amino-4-(diphenylphosphanyl)butan-2-ol; 3,5-bistrifluoromethylphenylisothiocyanate In dichloromethane at 20℃; for 2h; Stage #2: t-butyldimethylsiyl triflate With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
for 0.5h; neat (no solvent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In toluene at 20℃; for 0.0833333h; | 4.1.1 (S)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-(1-cyclohexylethyl) thiourea (S-5) The reaction mixture of (S)-1-cyclohexylethylamine (0.66g, 5mmol) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (1.36g, 5mmol) in toluene (10mL) was stirred at room temperature for 5min. The compound S-5 was obtained as a white solid (1.69g, 85%). mp: 167-168°C. 1H NMR (400MHz, CDCl3, δ):8.02 (s, 1H, NH), 7.72 (d, J= 7.4Hz, 2H, ArH), 7.25 (s, 1H, ArH), 5.97 (s, 1H, NH), 4.36 (s, 1H, CH), 1.79-0,97 (m, 11H, 5CH2+CH), 1.18 (d, J=6.6Hz, 3H, CH3). 13C NMR (100MHz, CDCl3, δ): 179.6, 138.8, 133.3, 133.0, 126.8, 124.2, 123.8, 121.4, 119.4, 118.6, 55.9, 42.9, 29.2, 29.1, 26.2, 26.0, 25.9, 17.1. The compound is enantiopure as determined by HPLC (see page S31 in supporting information), retention time: 14.5min (Column: Chiralpak IB; eluent: hexane:ethanol (95%:5%, v/v, flow rate:0.6mL/min). |
62% | In dichloromethane at 20℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In dichloromethane at 20℃; for 2h; | 1 (S)-N-benzhydryl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-trimethylbutanamide (4e) A 100-mL round-bottomed flask containing (S)-2-amino-N-benzhydryl-N,3,3-trimethylbutanamide (6b) (2.98 g, 9.60 mmol, 1.0 equiv) was charged with anhydrous CH2Cl2 (30 mL). 3,5-Bis(trifluoromethyl)phenylisothiocyanate (1.75 mL, 9.60 mmol, 1.0 equiv) was added in one portion via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred for 2 h at room temperature. The clear, yellow solution was concentrated using a rotary evaporator. The residue was subjected to purification by flash column chromatography on silica gel (gradient elution, hexanes→1:1 hexanes/Et2O, 100 g silica gel, 1.5 L solvent). The product (4e) was isolated as a white solid in ˜98% 1H-NMR purity (5.14 g, 8.83 mmol, 92% yield; 74% yield over three steps).The compound exists as a 15:1 mixture of amide rotamers in CDCl3. [α]=-83.4° (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3), major rotamer: δ 8.26 (1H, br s), 8.92 (1H, br s), 7.69 (2H, s), 7.59 (1H, s), 7.31-7.37 (3H, m), 7.13-7.16 (2H, m), 6.95-7.06 (5H, m), 5.65 (1H, d, J=9 Hz), 3.13 (3H, s), 1.13 (9H, s); selected minor rotamer resonances: δ 2.76 (3H, s), 0.92 (9H, s). 13C {1H} NMR, major rotamer: δ 182.5, 174.2, 139.7, 139.0, 137.3, 131.9 (q, JC-F=34 Hz), 129.8, 128.8, 128.7, 128.4, 128.2, 127.5, 127.2, 126.3 (m), 123.1 (q, JC-F=274 Hz), 119.3 (m), 62.4, 62.3, 36.5, 34.0, 27.6. IR (cm-1): 3313 (br m), 2967 (m), 1609 (m), 1529 (m), 1473 (m), 1380 (m), 1276 (s), 1172 (m), 1127 (s), 961 (m), 889 (w), 847 (w), 758 (w), 698 (m), 681 (m). LRMS (ESI): 582.2 (80%) [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In dichloromethane at 20℃; for 24h; | 4.3 General procedure 1 for the synthesis of thioureas 6, 7, and 8 General procedure: Amine (1.0 equiv) and isothiocyanate (1.3 equiv) were mixed in dichloromethane and stirred at rt for 24 h. Then, the solvent was evaporated and the residue was subjected to column chromatography on silica gel (hexanes/EtOAc, 1:1, v/v) that afforded the desired thiourea. |
92% | In dichloromethane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.818 % de | With triethylamine In acetonitrile at 20℃; Overall yield = 32 %; diastereoselective reaction; | General procedure for the preparation of quaternary α-amino acids via Edman degradation General procedure: To a solution of amino ester (1 equiv) in MeCN were added isothiocyanate (1.2 equiv), a β-nitrostyrene (1.2 equiv), and triethylamine (0.2 equiv). The solution was stirred for the indicated time and subsequently the solvent was removed by rotary evaporation. The reaction mixture was purified by column chromatography (hexane/acetone). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane for 72h; Inert atmosphere; | 1,10-((1S,2S)-Cyclohexane-1,2-diyl)bis(3-(3,5bis(trifluoromethyl)phenyl)thiourea) (4) 3,5-Bis(trifluoromethyl)phenyl isothiocyanate (0.66 mL,3.6 mmol) and (^)-trans -1,2 -diaminocyclohexane (0.21mL, 1.8mmol) were dissolved in DCM (40mL) and stirred for 72 h at rt under a nitrogen atmosphere. A white solid was collected and triturated in DCM (40 mL) at 408C for 2 h. The precipitate was isolated by filtration in a 98% yield after washing with excess DCM. 1HNMR (DMSO-d6,300 MHz): d 1.30 (brs,4H),1.71(br s, 2H), 2.18 (br s, 2H), 4.33 (br s, 2H), 7.70 (s, 2H), 8.17 (s, 6H), 10.14 (br s, 2H). 13C{1H} NMR (DMSO-d6, 75MHz): d 24.2 (CH2), 31.2 (CH2), 56.8 (CH), 116.2 (Ar CH), 122.0 (Ar CH), 123.2 (q, CF3, J 271.4Hz),130.0 (q, Ar CZCF3, J 33.0 Hz), 141.6 (Ar C), 180.1 (CvO). 19F{1H} NMR (DMSO-d6, 282 MHz): d 61.48. LR-MS ES (m/z): 657 [M H].HR-MS ES (m/z): Act. 679.0825 [M Na]. Calcd 679.0830 [M Na],err.(ppm) +0.8 m.p. (8C): 199.9 -200.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In dichloromethane; at 0℃; for 4h;Inert atmosphere; | To a solution of BINAM (360 mg, 1.3 mmol) was added 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (220 mg, 1.1 mmol) in DCM (anhydrous, 20 mL) at 0 oC. After stirring for 4 h, the reaction mixture was washed by 5percent HCl aq., dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel using hexane-EtOAc as the eluent, to give A-5; yield: 419 mg (93percent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In Isopropyl acetate; dimethyl sulfoxide Inert atmosphere; | Preparation of 4-(3-(3,5-bis(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide(54) Intermediate 53was prepared according to literature procedures.v53 (0.56 mmol),isothiocyanate 52 (1.12 mmol), DMSO(0.2 mL) and iPAc (0.4 mL) were charged in a round-bottom flask and stirred at84 °C for 18 h. The reaction mixture was then cooled to r.t. and partitionedbetween water and EtOAc. The organic phase was washed with brine, dried overMgSO4 and concentrated under vacuum. The residue was purified byflash column chromatography eluting with n-hexane/EtOAc100:0 v/v increasing to n-hexane/EtOAc50:50 v/v. Obtained in 67% yield as a white solid. 1H-NMR (CDCl3),δ: 8.29-8.26 (m, 1H), 7.96 (s, 1H), 7.93 (s, 2H), 7.26-7.25 (m, 1H), 7.17-7.15(m, 1H), 6.69 (bs, 1H), 3.06 (d, J= 4.1 Hz, 3H), 1.61 (s, 6H). 19F-NMR (CDCl3), δ:-62.9 (s, 6F), -110.8 (s, 1F). 13C-NMR (CDCl3), δ: 180.2,174.6, 162.7 (d,J= 5.3 Hz), 161.3, 159.4, 139.1 (d, J= 13.3 Hz), 134.2, 133.3 (d, J= 3.5 Hz),132.9, 132.5 (m), 129.0, 126.2 (m), 123.8, 123.0 (m), 122.5 (m), 121.6, 118.0(m), 66.5, 26.9, 23.8. Anal. Calcd for C21H16F6N3O2S:C, 49.71; H, 3.18; N, 8.28. Found: C, 49.96; H, 3.21; N, 8.23. MS [ESI, m/z]: 530.1 [M+H]+. EI-HMRS (M-H)-found 488.0899, calculated for C21H16F6N3O2S488.0873. HPLC (method 1): retention time = 22.89 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane for 4h; | 1 4.2 Preparation of catalysts General procedure: To a stirred solution of α-amino acid-derives phosphine (1.0 mmol) in CH2Cl2 (10 mL), isothiocyanatobenzene (2.0 mmol) was added. Then the reaction was vigorously stirred for 4 h. After removal of the solvent, direct purification by silica gel chromatography (15 % EtOAc-petroleum ether) provided products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | In dichloromethane Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In dichloromethane; at 20℃; for 18h; | To a solution of CH2Cl2 (5 mL), <strong>[4848-43-5]2-<strong>[4848-43-5](diphenylphosphino)ethylamine</strong></strong> (1.8mmol, 413.2mg)and 3,5-bis(triuoromethyl)phenyl isothiocyanate (2 mmol, 310 L) were added. The reactionwas carried out at room temperature during 18 h. After that, the solvent was partiallyevaporated, and the product was purified by precipitating with hexane, filtered and successivewashes with more hexane (3 5 mL). The final thiourea T1 was obtained as awhite solid in 80% yield [70]. 1H NMR (300 MHz, CD2Cl2) (ppm): 7.89 (br s, 1H, NHb),7.81 (s, 2H, H-C5), 7.72 (s, 1H, H-C7), 7.51-7.29 (m, 10H, H-C10-12), 6.46 (br s, 1H, NHa),3.79 (td, J = 12.5, 6.8 Hz, 2H, H-C2), 2.47 (t, J = 7.0 Hz, 2H, H-C1). 13C-APT NMR (101 MHz,CD2Cl2) (ppm): 181.1 (s, 1C, C3), 139.7 (s, 1C, C4), 137.9 (d, J = 11.4 Hz, 2C, C9), 133.2 (d,J = 19.0 Hz, 4C, C10), 132.9 (q, J = 32.0 Hz, 2C, C6), 129.6 (s, 2C, C12), 129.2 (d, J = 7.0 Hz, 4C,C11), 124.6 (m, 2C, C5), 123.5 (q, J = 273.7 Hz, 2C, C8), 119.8 (m, 1C, C7), 42.9 (d, J = 18.8 Hz,1C, C2), 28.1 (d, J = 13.0 Hz, 1C, C1). 31P{1H} NMR (162 MHz, CD2Cl2) (ppm): 21.83 (s,1P, P-Ph2). 19F NMR (377 MHz, CD2Cl2) (ppm): 63.25 (F-CF3). HRMS (ESI+) calculatedfor C23H19F6N2NaPS 523.0803, found 523.0803 [M + Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine In dichloromethane at 20℃; Inert atmosphere; | To a solution of V (0.2 g, 0.65 mmol) in CH2Cl2 (8.5 ml) under inert atmosphere was added TEA (0.3ml, 2.13 mmol), followed by 3,5-bis-(trifluoromethyl)phenyl-isothiocyanate (0.13 ml, 0.71 mmol).The reaction was stirred overnight at room temperature and then concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (ETP/AcOEt 7:3) to give catalystB (0.25 g, 66% yield) as a white solid.1H-NMR (300 MHz, CDCl3; compound exists as a 4:1 mixture of rotamers, only the major isindicated): δ 9.8 (br s, 1H); 8.12 (s, 3H); 7.58 (s, 1H); 7.24-7.14 (m, 5H); 5.55 (d, 1H, J = 3.3 Hz); 4.78(d, 1H, J = 14.4 Hz); 4.44 (d, 1H, J = 14.4 Hz); 3.31 (s, 3H); 1.14 (s, 9H) ppm. |
With triethylamine In dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In toluene at 20℃; for 0.0833333h; | 4.1.2 (S)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[1-(naphth-1-yl)ethyl]thiourea (S-6) The reaction mixture of (S)- 1-(naphth-1-yl)ethylamine (0.29g, 1.6mmol) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (0.45g, 1.6mmol) in toluene (5mL) was stirred at room temperature for 5min. The compound S-6 was obtained as a white solid. (0.62g, 87%). mp:130-131°C. 1H NMR (400MHz, CDCl3, δ): 8.18-7.17 (m, 10H, ArH), 6.28 (s, 2H, NH+CH), 2.40 (s, 1H, NH), 1.84 (d, J=6.5Hz, 3H, CH3). 13C NMR (100MHz, CDCl3, δ): 179.4, 138.8, 136.3, 134.0, 129.2, 127.2, 126.3, 125.3, 123.9, 123.7, 123.1, 121.2, 119.3, 119.2, 119.1, 118.5. The compound is enantiopure as determined by HPLC (see page S32 in supporting information), retention time: 33.2min (Column: Chiralpak IB; eluent: hexane:ethanol (95%:5%, v/v, flow rate:0.6mL/min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In dichloromethane at 20℃; for 16h; Inert atmosphere; | |
85% | With triethylamine In acetonitrile at 20℃; for 14h; Inert atmosphere; | 2V Example 2V: Synthesis of 1NT-H001 (0668) l-(3,5-Bis(trlfluoromethyl)phenyl)-3-(3-hydroxypropyl)thiourea (15): JZ-25-145 3-Aminopropanol (0.33 mL, 4.40 mmol, 1.10 equiv.) was added to a room temperature MeCN (8 mL) solution of 3,5-bis(trifluoromethyl]phenyl isothiocyanate (1.08 g, 4.00 mmol) and Et3N (0.61 mL, 4,40 equiv., 1.10 equiv.) in a round bottom flask under argon. After 14 h, the reaction mixture was diluted with H2O and extracted with EtOAc (3x15 mL). The combined organic layers were washed with H:0 (1x15 mL), brine, dried over Na2S04 and concentrated on a rotary evaporator under reduced pressure. The crude semi-solid was filtered through a plug of silica gel (75:25 EtOAc/hexanes), the filtrate concentrated under reduced pressure, then recrystallized from t-BuOMe/hexanes to afford thiourea 15 (1.18 g, 85% yield) as a white solid. (0670) ‘H NMR (300 MHz, DMSO-de): d 10.1 (br s, 1H), 8.26 (br s, 3H), 7.72 (br s, 1HJ, 4.59 (br s, 1H), 3.66-3.39 (m, 4H), 1.72 (quint., J = 6.4 Hz, 2H); (0671) 13C NMR (75.5 MHz, DMSO-ds): 6 180.4, 142.0, 130.1 (q, J = 34 Hz), 123.3 (q, J = 273 Hz), 121.7 (br), 115.9 (br), 58.7, 41.6, 31.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In acetonitrile at 60℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In dichloromethane at 20℃; Inert atmosphere; |
Tags: 23165-29-9 synthesis path| 23165-29-9 SDS| 23165-29-9 COA| 23165-29-9 purity| 23165-29-9 application| 23165-29-9 NMR| 23165-29-9 COA| 23165-29-9 structure
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