Structure of TFB-2
CAS No.: 312-73-2
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| CAS No. : | 312-73-2 |
| Formula : | C8H5F3N2 |
| M.W : | 186.13 |
| SMILES Code : | FC(C1=NC2=CC=CC=C2N1)(F)F |
| English Name : | 2-(Trifluoromethyl)-1H-benzo[d]imidazole |
| MDL No. : | MFCD00022675 |
| InChI Key : | MXFMPTXDHSDMTI-UHFFFAOYSA-N |
| Pubchem ID : | 67560 |
| Num. heavy atoms | 13 |
| Num. arom. heavy atoms | 9 |
| Fraction Csp3 | 0.12 |
| Num. rotatable bonds | 1 |
| Num. H-bond acceptors | 4.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 41.1 |
| TPSA ? Topological Polar Surface Area: Calculated from |
28.68 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.29 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.85 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.73 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.06 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.98 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.58 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-3.24 |
| Solubility | 0.108 mg/ml ; 0.000581 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.11 |
| Solubility | 0.144 mg/ml ; 0.000775 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.8 |
| Solubility | 0.0296 mg/ml ; 0.000159 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.41 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.24 |
* 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 |
|---|---|---|
| With nitric acid |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | for 4h; Reflux; | 1 Example 1 Production of 2-trifluoromethylbenzimidazole To a 100 mL eggplant-shaped flask equipped with a magnetic stirrer, 10.8 g (100 mmol) of 1,2-phenylenediamine and 17.1 g (150 mmol) of trifluoroacetic acid were added. The mixture was heated to reflux for 4 hours. After cooling, the reaction mixture was poured into an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 18.7 g of gray crystals. Yield: 100%. 1H-NMR (400 MHz, CDCl3, relative to TMS) δ (ppm): 7.37-7.47 (m, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 9.96 (br, 1H). |
| 99% | at 70℃; for 16h; | 2. General Procedure A General procedure: In a screw-cap vial, the diamine or aminothiophenol (1 mmol) was dissolved in fluorinated carboxylic acid (2 mL, 0.5 M) and the reaction was stirred at 70 °C for 16 hours. The fluorinated carboxylic acid was then evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to yield the corresponding product. |
| 99.9% | at 70℃; for 0.5h; Microwave irradiation; | 1 1) Preparation of 2-trifluoromethyl--1H- benzimidazole (2) he o-phenylenediamine 1 (1.08g, 10mmol) was added to a 10mL microwave reaction tube was added trifluoroacetic acid (2mL), a stirring, the reaction 30min (70 , 100W, high speed).After the reaction was finished the mixture was poured into a round bottom flask was cooled rotary evaporation to remove excess trifluoroacetic acid to give 2-trifluoromethyl-benzimidazole 1.35 g of -1H-, yield 99.9% |
| 99.9% | at 70℃; for 0.5h; Microwave irradiation; | 1 1) 2 - trifluoromethyl - 1H - benzimidazole (2) preparation of The O-phenylene diamine 1 (1.08g, 10mmol) is added to 10 ml of in microwave reaction tube, adding trifluoroacetic acid (2 ml), added to the solder, reaction 30min (70 °C, 100W, high-speed). After cooling the reaction mixture is poured into the end of the in round bottomed flask, steaming and remove excess trifluoroacetic acid, to obtain 2 - trifluoromethyl - 1H - benzimidazole 1.35g, yield 99.9%. |
| 99.9% | at 70℃; for 0.5h; Microwave irradiation; | 1) Preparation of 2-trifluoromethyl-1H-benzimidazole (2) O-phenylenediamine 1 (1.08 g, 10 mmol) was added to a 10 mL microwave reaction tube,Trifluoroacetic acid (2 mL) was added,Add stirrups,Reaction 30min (70 , 100W, high speed).After completion of the reaction, the mixture was poured into a round bottom flask,Steamed to remove excess trifluoroacetic acid,To give 1.35 g of 2-trifluoromethyl-1H-benzimidazole,Yield 99.9%. |
| 97% | for 24h; Reflux; | 3 2-Trifluoromethyl-lH-benzo[d]imidazole (5 cxc). A mixture of ortho- phenylenediamine (1 g, 9.25 mmol) and trifluoroacetic acid TFA (1.581, 13.87 mmol, (0205) 1.5 eq.) was heated under reflux with vigorous magnetic stirring (500 rpm) for 24 hours. After cooling down to room temperature, the reaction mixture was transferred progressively with caution into a solution (100 ml) of saturated sodium carbonate. Extraction was conducted with ethyl acetate (3 x 50 ml) and the collected extracts were transferred into a separating funnel. The organic phase was washed with brine (3 x 50 ml). After decantation, the organic layer was dried over anhydrous MgSCU, filtered on a paper filter and the filtrate was concentrated in a rotary evaporator under reduced pressure. The resulting solid was further dried under high vacuum (103 Torr) and afforded the desired compound 5occ as brown powder in 97% yield. The compound 5occ is pure enough to be used later without further purification. Mp = 213-218°C. 7.38 (dd, / = 6.2, 3.2 Hz, 2H, H-5, H-6, Ar), 7.72 (dt, J = 6.7, 3.3 Hz, 2H, H-4, H-7, Ar), 12.53 (br s, 1H, NH). (0206) 13C NMR (75 MHz, DMSO -d6) d = 117.3 (C-4, C-7), 120.9 (CF3), 124.1 (C-5, C- 6), 139.8 (C-3a, C-7a), 140.3 (C-2). (0207) 19F NMR (282 MHz, DMSO -d6) d = - 62.8. (0208) HRMS, m/z = 209.0295 found (calculated for CxH3N2F3Na [M+Na]+ requires 209.0297). |
| 97% | for 24h; Reflux; | 3 2-Trifluoromethyl-lH-benzo[d]imidazole (5 cxc). A mixture of ortho- phenylenediamine (1 g, 9.25 mmol) and trifluoroacetic acid TFA (1.581, 13.87 mmol, (0205) 1.5 eq.) was heated under reflux with vigorous magnetic stirring (500 rpm) for 24 hours. After cooling down to room temperature, the reaction mixture was transferred progressively with caution into a solution (100 ml) of saturated sodium carbonate. Extraction was conducted with ethyl acetate (3 x 50 ml) and the collected extracts were transferred into a separating funnel. The organic phase was washed with brine (3 x 50 ml). After decantation, the organic layer was dried over anhydrous MgSCU, filtered on a paper filter and the filtrate was concentrated in a rotary evaporator under reduced pressure. The resulting solid was further dried under high vacuum (103 Torr) and afforded the desired compound 5occ as brown powder in 97% yield. The compound 5occ is pure enough to be used later without further purification. Mp = 213-218°C. 7.38 (dd, / = 6.2, 3.2 Hz, 2H, H-5, H-6, Ar), 7.72 (dt, J = 6.7, 3.3 Hz, 2H, H-4, H-7, Ar), 12.53 (br s, 1H, NH). (0206) 13C NMR (75 MHz, DMSO -d6) d = 117.3 (C-4, C-7), 120.9 (CF3), 124.1 (C-5, C- 6), 139.8 (C-3a, C-7a), 140.3 (C-2). (0207) 19F NMR (282 MHz, DMSO -d6) d = - 62.8. (0208) HRMS, m/z = 209.0295 found (calculated for CxH3N2F3Na [M+Na]+ requires 209.0297). |
| 95% | at 70℃; for 2h; | General procedure: Ortho-phenylenediamine was mixed with trifluoroacetic acid (TFA) at an equimolar concentration of 0.5M, at a reaction temperature of 70°C for 2h. The excess TFA was evaporated to get the desired product in a sufficient quantity/yield. The product was made purified by a silica gel chromatography column to obtain total free analytical yield (overall reaction is given below) [33] |
| 87% | With triethylamine; triphenylphosphine In tetrachloromethane Heating; | |
| 81% | With hydrogenchloride Heating; | |
| 80% | for 2h; Heating; | |
| 77% | In various solvent(s) at 70℃; for 12h; | |
| 73% | With hydrogenchloride Reflux; | Synthesis of 2-trifluoromethylo-1H-benzimidazole derivatives (3a-e) General procedure: Benzene-1,2-diamine derivative (2 mmol) was dissolved in trifluoroacetic acid (2 mL) anda catalytic amount of concentrated HCl was added. The reaction mixture was heated atreflux overnight. The reaction was quenched by the addition of 50 mL of concentratedNaHCO3 solution; afterwards, it was extracted by ethyl acetate (3 × 30 mL). Combinedorganic layers were dried by MgSO4, then the solvent was evaporated. The crude productwas purified by column chromatography on silica gel using 85:15 (hexane:AcOEt) aseluent (compounds 3d and 3e) or by recrystallization from hexane (compounds 3a, 3b,and 3c).2-trifluoromethylo-1H-benzimidazole (3a) Yield = 73%. 1H-NMR (500 MHz, d-DMSO) δ7.34-7.42(2H, m, ArH), 7.68-7.77(2H, m, ArH); 13C-NMR (125 MHz, d-DMSO) δ 115.88,118.02, 120.17, 122.32, 124.09, 139.90, 140.22; HRMS calcd. for C8H6F3N2 [M + H]+:187.04776, found: 187.04773. |
| 22% | In methanol at 20℃; Flow reactor; Inert atmosphere; | |
| With hydrogenchloride | ||
| In water Heating; | ||
| at 60℃; | ||
| With hydrogenchloride In water Reflux; | ||
| at 70℃; for 12h; | ||
| 93 % | Reflux; | 4.1.2.1. 2-(Trifluoromethyl)-1H-benzo[d]imidazole (1). A mixture of1,2-phenylene diamine (10 mmol, 1.08 g) in 40 mL trifluoroacetic acidwas refluxed for 4 h. The cooled reaction mixture was neutralized withsaturated NaHCO3 solution, and the crude product was extracted withEtOAc. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified byflash column chromatography with petroleum ether/EtOAc elution toafford compound 1 as a white solid in 93% yield. 1H NMR (400 MHz,CD3OD) δ 7.73-7.66 (m, 2H), 7.44-7.37 (m, 2H). ESI-MS m/z: 187.1[M+H]+. |
| 93 % | Reflux; | 4.1.2.1. 2-(Trifluoromethyl)-1H-benzo[d]imidazole (1). A mixture of1,2-phenylene diamine (10 mmol, 1.08 g) in 40 mL trifluoroacetic acidwas refluxed for 4 h. The cooled reaction mixture was neutralized withsaturated NaHCO3 solution, and the crude product was extracted withEtOAc. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified byflash column chromatography with petroleum ether/EtOAc elution toafford compound 1 as a white solid in 93% yield. 1H NMR (400 MHz,CD3OD) δ 7.73-7.66 (m, 2H), 7.44-7.37 (m, 2H). ESI-MS m/z: 187.1[M+H]+. |
| 100 % | at 180℃; | 2-(Trifluoromethyl)-1H-benzo[d]imidazol (S2b) Following a modified literature procedure,[5] a pressure vial was filled witho-phenylenediamine (S1, 1.62 g, 15.0 mmol) 2,2,2-trifluoroacetic acid (S3, 30 mL) andstirred for 11 h at 180 °C. The solvent was removed under reduced pressure, and theresidue was filtered through silica with EtOAc. The solution was washed with sat. aq.NaHCO3 solution (30 mL), brine (30 mL), dried over Na2SO4, filtered and the solvent wasremoved under reduced pressure to obtain 2-(trifluoromethyl)-1H-benzo[d]imidazole(S4, 2.79 g, 15.0 mmol, 100%) as a colorless solid.1H NMR (601 MHz, CDCl3) δ (ppm) 7.73 (dd, J = 6.1, 3.3 Hz, 2H), 7.42 (dd, J = 6.2, 3.1 Hz,2H). 13C NMR (151 MHz, CDCl3) δ (ppm) 140.7 (q, J = 40.5 Hz), 137.4, 125.1, 118.9 (q, J= 270.8 Hz), 116.7 ppm. 19F NMR (565 MHz, CDCl3) δ (ppm) -64.2. MS (ESI) m/z 187.1[M+H]+. IR (ATR) ν (cm-1) 2968, 2873, 2756, 2655, 1550, 1499, 1462, 1400, 1317, 1286,1129, 980, 739. MP (°C) 209. Analytical data is in accordance with those reported in theliterature.[6] |
| 77 % | With hydrogenchloride at 20 - 60℃; | General synthesis of 2-(trifluoromethyl)-benzo[d]imidazole precursors (10l-n) General procedure: 4-Substituted o-phenylenediamine (10 mmol) was stirred at room temperature, for 30 minutes, in the presencemixture of trifluoroacetic acid (10 mmol) and concentrated hydrochloric acid (25 mL). Thereafter, the reaction mixturewas refluxed for 12h at 60 and monitored to completion by TLC. Upon completion, the trifluoroacetic acid wasconcentrated under reduced pressure, and the resultant crude product was dissolved in ethyl acetate (15 mL), basifiedwith the addition of sodium hydrogen carbonate until alkaline (pH 8), and separated. The separated organic layer wasthen washed with water (3 x 15 mL), followed by brine solution, and concentrated under reduced pressure to yield 2-(trifluoromethyl)-1H-benzo[d]imidazole precursors in good yields:77-88%:2-(trifluoromethyl)-1H-benzo[d]imidazole (10l) as a light brown solid; Yield: 77%, mp: 190-192. 1H-NMR (DMSO-d6, 400 MHz, ppm): δH 7.33 (2H, m, H-5, and H-6), 7.69 (2H, m, H-4,and H-7). |
| 77 % | With hydrogenchloride at 20 - 60℃; | General synthesis of 2-(trifluoromethyl)-benzo[d]imidazole precursors (10l-n) General procedure: 4-Substituted o-phenylenediamine (10 mmol) was stirred at room temperature, for 30 minutes, in the presencemixture of trifluoroacetic acid (10 mmol) and concentrated hydrochloric acid (25 mL). Thereafter, the reaction mixturewas refluxed for 12h at 60 and monitored to completion by TLC. Upon completion, the trifluoroacetic acid wasconcentrated under reduced pressure, and the resultant crude product was dissolved in ethyl acetate (15 mL), basifiedwith the addition of sodium hydrogen carbonate until alkaline (pH 8), and separated. The separated organic layer wasthen washed with water (3 x 15 mL), followed by brine solution, and concentrated under reduced pressure to yield 2-(trifluoromethyl)-1H-benzo[d]imidazole precursors in good yields:77-88%:2-(trifluoromethyl)-1H-benzo[d]imidazole (10l) as a light brown solid; Yield: 77%, mp: 190-192. 1H-NMR (DMSO-d6, 400 MHz, ppm): δH 7.33 (2H, m, H-5, and H-6), 7.69 (2H, m, H-4,and H-7). |
| 78 % | at 100℃; | General procedure A - Synthesis of naphthoimidazoles (2a-d,34a-b) General procedure: Diamino naphthoquinone 1 or 1,2-diaminobenzene 33 (1.0equiv.) was dissolved in the corresponding acid (acid and volume specified in the individual protocol of each compound). The reactionmixture was heated at 100 °C with stirring for 10 h, then was allowed to cool to room temperature and concentrated under a stream of nitrogen. Water (volume specified) was then added to the residue to form a precipitate,which was collected by vacuum filtration and washed with water. The solid intermediates collected were dried under high vacuum. |
| 78 % | at 100℃; | General procedure A - Synthesis of naphthoimidazoles (2a-d,34a-b) General procedure: Diamino naphthoquinone 1 or 1,2-diaminobenzene 33 (1.0equiv.) was dissolved in the corresponding acid (acid and volume specified in the individual protocol of each compound). The reactionmixture was heated at 100 °C with stirring for 10 h, then was allowed to cool to room temperature and concentrated under a stream of nitrogen. Water (volume specified) was then added to the residue to form a precipitate,which was collected by vacuum filtration and washed with water. The solid intermediates collected were dried under high vacuum. |
| Reflux; | ||
| for 3h; Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 1: 3% 2: 35% 3: 2% | In methanol for 168h; Ambient temperature; Irradiation; Title compound not separated from byproducts; | |
| 1: 3% 2: 2% 3: 35% | In methanol for 168h; Ambient temperature; Irradiation; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With dihydrogen peroxide In sulfuric acid at 120℃; | |
| 82.2% | With sulfuric acid; dihydrogen peroxide at 0 - 120℃; for 3h; | 63.1 Step 1: 2-(Trifluoromethyl)-1H-imidazole-4,5-dicarboxylic acid To a solution of 2-(trifluoromethyl)-1H-benzo[d]imidazole (2 g, 10.7 mmol) in H2SO4 (55.2 g, 30 mL, 535 mmol) was added slowly hydrogen peroxide (35% solution, 10.4 g, 9.41 mL, 107 mmol) at 0-5° C. The reaction mixture was stirred at 120° C. for 3 h, cooled to RT, poured into water (80 mL) under ice bath cooling and extracted with diethyl ether (3*80 mL). The combined organic phase was dried over MgSO4, filtered and evaporated to give the product as colorless solid (1.98 g, 8.84 mmol, 82.2%) which was used without further purification for the next step. MS: M=225.4 (M+H)+ |
| 82.2% | With sulfuric acid; dihydrogen peroxide at 0 - 120℃; for 3h; | 63.1 Step 1: 2-(Trifluoromethyl)-lH-imidazole-4,5-dicarboxylic acid To a solution of 2-(trifluoromethyl)-lH-benzo[d]imidazole (2 g, 10.7 mmol) in H2S04 (55.2 g, 30 mL, 535 mmol) was added slowly hydrogen peroxide (35 % solution, 10.4 g, 9.41 mL, 107 mmol) at 0-5 °C. The reaction mixture was stirred at 120 °C for 3 h, cooled to RT, poured into water (80 mL) under ice bath cooling and extracted with diethyl ether (3 x 80 mL). The combined organic phase was dried over MgS04, filtered and evaporated to give the product as colorless solid (1.98 g, 8.84 mmol, 82.2 %) which was used without further purification for the next step.MS: M = 225.4 (M+H)+ |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With triethylamine In diethyl ether at 10℃; for 3h; | |
| 97% | With triethylamine In diethyl ether at 0℃; for 3h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With hydrogen In ethanol at 120℃; for 18h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With potassium carbonate In acetone for 3h; Reflux; | 2 Example 2 Production of 1-methyl-2-trifluoromethylbenzimidazole To a 200 mL eggplant-shaped flask equipped with a magnetic stirrer, 18.7 g (100 mmol) of 2-trifluoromethylbenzimidazole, 16.6 g (120 mmol) of potassium carbonate, 17.0 g (120 mmol) of methyl iodide and 100 mL of acetone were added. The mixture was heated to reflux for 3 hours. After the reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 19.7 g of gray crystals. Yield: 98%. 1H-NMR (400 MHz, CDCl3, relative to TMS) δ (ppm): 3.96 (s, 3H), 7.37-7.46 (m, 3H), 7.88 (d, J=6.0 Hz, 1H). |
| 97.1% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 25℃; for 1h; | 1; 2; 3 Preparation of Compound III-1 Compound II (60.00g, 0.322mol, 1.0eq.) And potassium carbonate (89.01g, 0.644mol, 2.0eq.) Were added to 600mL DMF, and iodomethane (91.4g, 0.644mol, 2.0eq) was added dropwise at 0 ° C. .), After the addition was completed, the reaction was performed at 25 ° C for 1h. TLC showed that the raw materials had reacted. The system was poured into 1L of ice water, washed with water (100mL * 2), filtered to obtain a white solid, washed with water (100mL * 2), white solid Dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to give compound III-1 as a white solid 62.00g, yield: 97.1% |
| Stage #1: 2-Trifluoromethylbenzimidazole With sodium hydroxide In tetrahydrofuran for 0.166667h; Stage #2: methyl iodide In tetrahydrofuran at 20℃; |
| With potassium carbonate In acetonitrile for 5h; Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium hydrogencarbonate In N,N-dimethyl acetamide at 160℃; for 5h; microwave irradiation; | 9 The 4-chloro-6-morpholino-2-(2-trifluoiOmethylbenzimidazol-l-yl)pyrimidine used as a starting material was prepared as follows :-; A mixture of 2-trifluoromethyl-lH-benzimidazole (0.358 g), 2,4-dichloro- 6-niorpholinopyrimidine (0.5 g), sodium bicarbonate (0.718 g) and DMA (5 ml) was heated to 160°C under nitrogen in a sealed vessel in a microwave oven for 5 hours. The resultant mixture was cooled and filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and methanol as eluent. There was thus obtained 4-chloro-6-morpholino- 2-(2-trifluoromethylbenzimidazol-l-yl)pyrimidine (0.21 g); Mass Spectrum: M+H1" 384. | |
| With sodium hydrogencarbonate In N,N-dimethyl acetamide at 110 - 160℃; for 96h; microwave irradiation; | 5 The 4-(4-aminopiperidin- 1 -yl)-6-morpholino-2-(2-trifluoromethylbenzimidazol- l-yl)pyrimidine dihydrochloride used as a starting material was prepared as follows :- Under an atmosphere of nitrogen, a mixture of 2-trifluoromethyl- 1 H-benzimidazole(2 g), 2,4-dichloro-6-morpholinopyrimidine (2.79 g), sodium bicarbonate (4 g) and DMA (28 ml) was heated to 110°C in a sealed vessel in a microwave oven for 18 hours. The reaction mixture was heated to 140°C for 20 hours and to 160°C for 48 hours. The solvent was evaporated from the resultant reaction mixture. The residue was partitioned between ethyl acetate and water. The organic solution was washed in turn with water and with a saturated aqueous sodium chloride solution. The organic solution was dried over anhydrous sodium sulphate and evaporated. The resultant product was purified using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of a 1% solution of ammonium hydroxide (d=0.88) in water and acetonitrile as eluent. There was thus obtained 4-chloro-6-morpholino-2-(2-trifluoromethylbenzimidazol-l-yl)pyrimidine (0.65 e): NMR Spectrum: (DMSOd6) 3.75 (s, 8H), 7.18 (s, IH), 7.5 (t, IH), 7.6 (t, IH), 7.94 (d, IH), 8.12 (d, IH): Mass Spectrum:M+H" 384. | |
| With sodium hydrogencarbonate In N,N-dimethyl acetamide at 110 - 160℃; for 86h; | 14 The 4-chloro-6-morpholino-2-(2-trifluoromethylbenzimidazol-l-yl)pyrimidine used as a starting material was prepared as follows :-; Under an atmosphere of nitrogen, a mixture of 2,4-dichloro-6-morpholinopyrimidine (2.79 g), 2-trifluoromethylbenzimidazole (2 g), sodium bicarbonate (4 g) and DMA (28 ml) was stirred and heated to 110°C for 18 hours. The reaction temperature was raised to 140°C and the mixture was stirred for 20 hours. The reaction temperature was raised to 160°C and the mixture was stirred for 48 hours. The resultant mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water and with brine, dried over anhydrous sodium sulphate and evaporated. The material so obtained was purified using a Waters 'Xbridge' preparative reversed-phase column using decreasingly polar mixtures of of water [containing 1% aqueous ammonium hydroxide (density 0.88 )] and acetonitrile as eluent. There was thus obtained 4-chloro-6-morpholino- 2-(2-trifluoromethylbenzimidazol-l-yl)pyrimidine (0.65 g); NMR Spectrum: (DMSOd6) 3.75 (s, 8H), 7.18 (s, IH), 7.5 (t, IH), 7.6 (t, IH), 7.94 (d, IH), 8.12 (d, IH); Mass Spectrum: M+H+ 384. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With trifluoroacetic acid; trifluoroacetic anhydride In concentrated NH4 OH | 162.1 Preparation of 1-N,N-Dimethylcarbamoyl-4-methoxycarbonyl-3-{4-[(1H-2-(trifluoromethyl)benzimidazolyl)methyl]benzoyl}indole Step 1: 1H-2-(Trifluoromethyl)benzimidazole. A mixture of 1,2-diaminobenzene (1.0 g), trifluoroacetic acid (1 mL) and trifluoroacetic anhydride (1 mL) was heated at 60° C. for 10 hours. The reaction mixture was then cooled in an ice bath and taken to pH=7-8 with concentrated NH4 OH. The resulting white solid was filtered and recrystallized from ethanol to give 400 mg of 1H-2-(trifluoromethyl)benzimidazole as colorless crystals. | |
| Multi-step reaction with 2 steps 1: acetonitrile / 6 h / 90 °C / Schlenk technique; Inert atmosphere 2: copper(I) oxide / acetonitrile; water / 12 h / 90 °C / Schlenk technique; Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 17h; | 1.B Ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate(371mg, lmmol) was dissolved in DMF (5ml) and K CO (552mg, 4mmol) was added followed by 2-trifluoromethyl benzimidazole (204mg, 1.1 mmol). The reaction mixture was heated to 6O0C for 17hrs. After the completion of the reaction, water was added and the product was extracted with Et O. The product was purified by column chromatography on silica gel using ethyl acetate and hexanes as solvent (333mg, 70%).[182][183] 1K NMR: (300MΗz, CDCl3): δ 7.92 (d, IH), 7.68 (d, IH), 7.53-7.40 (m, 2H), 7.14(d, 2H), 6.73 (d, IH), 4.46 (t, 2H), 4.34 (t, 2H), 4.18 (q, 2H), 3.95 (t, IH), 3.63-3.60 EPO (m, IH), 3.58-3.31 (m, IH), 2.95 (t, 2H), 1.26-1.14 (m, 6H).[ 184] Mass m/z: 451.7 (M+H) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 16h; | 1.G G. Synthesis of Compounds 46 and 47A stirred mixture of 2-Trifluoromethyl-I H-benzoimidazole (4.92g, 26.4 mmol), 4-fluorobenaldehyde (3.1 mL, 29.1 mmol), and K2CO3 (4.37g, 31.7 mmol) in DMF (50 mL) was heated to 150 0C for 16 h. After being cooled to room temperature, the reaction mixture was partitioned between H2O and EtOAC. After usual workup, the crude product was purified by silica gel chromatography (20% Hexane/EtOAc to 30% Hexane/EtOAc) to afford a yellow oil which was subjected to a second silica gel chromatography (DMC) to provide the aldehyde intermediate 4-(2-Trifluoromethyl-benzoimidazol-1-yl)- benzaldehyde as a white solid (4.0 g). | |
| With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 16h; | 1.G A stirred mixture of 2-Trifluoromethyl-1 H-benzoimidazole (4.92g, 26.4 mmol), 4-fluorobenaldehyde (3.1 mL, 29.1 mmol), and K2CO3 (4.37g, 31.7 mmol) in DMF (50 mL) was heated to 150 0C for 16 h. After being cooled to room temperature, the reaction mixture was partitioned between H2O and EtOAC. After usual workup, the crude product was purified by silica gel chromatography (20% Hexane/EtOAc to 30% Hexane/EtOAc) to afford a yellow oil which was subjected to a second silica gel chromatography (DMC) to provide the aldehyde intermediate 4-(2-Trifluoromethyl-benzoimidazol-1-yl)- benzaldehyde as a white solid (4.0 g).To a solution of the above 4-(2-Trifluoromethyl-benzoimidazol-1-yl)- benzaldehyde (0.155g, 0.53 mmol) and (2,3-Difluoro-phenyl)-acetonttrile (83 mg, 0.54 mmol) in EtOH (5 mL) was added a solution of KOH (0.2g) in H2O (0.5 mL). The mixture was then stirred at rt for 1h, partitioned between EtOAc/H2θ. The organic layer was dried and concentrated followed by silica gel chromatography (20% Hexane/EtOAc) to afford the product Compound 47 as a colorless oil.To a stirred solution of 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.58 g, 2 mmol) in acetone (25 mL) was added Jone's reagent (1.0 mL, 2.0 M) at O0C. After stirring at room temperature for 2h, the mixture was partitioned between EtOAc and saturated NaHCO3 solution. After usual workup, the crude material was separated by silica gel chromatography (50% Hexane/EtOAc to EtOAc) to afford the intermediate acid 4-(2-Trifluoromethyl- benzoimidazol-1-yl)-benzoic acid as a while solid (490 mg).To a stirred solution of 4-(2-Trifluoromethyl-benzoirnidazol-1-yl)-benzoic acid (102 mg, 0.33 mmol) in dry CHCI3 (15 mL) was added oxalyl chloride (0.09 mL) followed by one drop of DMF at room temperature. After 1h, the reaction pot was concentrated and vacuum dried. Dry chloroform (15 mL) and pyridine (0.1 mL) was then added followed by the addition of 2,3-difluoroaniHine (36 mg, 0.28 mmol). The reaction was monitored by TLC, after completion, the mixture was partitioned between 1 N HCI and DCM. Organic layer was separated and dried (Na2SO4). Removal of solvents followed silica gel chromatography (20% hexane/EtOAc) afforded the product Compound 46 as a white solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 2-Trifluoromethylbenzimidazole With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-Fluoronitrobenzene In N,N-dimethyl-formamide at 150℃; for 4h; | 1.A A suspension of a substituted benzoimidazole (27mmol) and potassium t-butoxide (3.6 g, 30 mmol) in DMF (50 ml_) was stirred at rt for 30 min. 1- Fluoro-4-nitro-benzene (4.2 g, 30 mmol) was added and the reaction mixture was heated to 15O0C for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (EtOAc). The organic extract was washed with water and dried. The oil obtained on concentration was flash chromatographed on silica gel to give 162 in 10-90% yields. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With di-tert-butyl peroxide; iron(II) chloride In toluene at 120℃; for 24h; Inert atmosphere; | |
| 73% | With tert.-butylhydroperoxide; iodine In neat (no solvent) at 100℃; for 8h; | The general procedure of the reaction between azoles and toluenes: General procedure: All reactions were performed on a 0.50mmol scale relative to azoles. The benzotriazole(1a) (0.50 mmol), toluene (2a) (1.50 mmol), I2 (0.050 mmol) and TBHP (2 eq) weretaken in a round bottom flask equipped with stirrer. The resulting mixture was stirred for8 h at 100 oC. After cooling to room temperature, to the reaction mixture was addedwater (2 mL), and extracted with ester (3×10 mL). The combined organic phases werewashed with brine (2×5 mL), dried over anhydrous MgSO4 and concentrated in vacuo.The residue was subjected to flash column chromatography with hexanes/EtOAc (10/1)as eluent to obtain the desired 3aa a light yellow solid( 90% yield). The identity andpurity of the products was confirmed by 1H and 13C NMR spectroscopic analysis. |
| 73% | With tert.-butylhydroperoxide; iron(III) chloride In neat (no solvent) at 100℃; for 10h; |
| 43% | With tert.-butylhydroperoxide; 1-methyl pyridinium iodide In neat (no solvent) at 75℃; for 12h; Green chemistry; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; | 7.2. General procedure for the synthesis of acids 3a-f General procedure: A solution of this chloromethyl ester (1.8 mmol) in N,N-dimethylformamide (4 ml) was treated with the 2-substituted benzimidazoles (1.8 mmol) and cesium carbonate (2.8 mmol). The mixture was stirred for 3 h at r.t. and partitioned with water and ethyl acetate (20 ml). The aqueous layer was further extracted with ethyl acetate (20 ml) and the combined organic layers washed with brine (20 ml), dried (sodium sulfate), filtered and concentrated. Flash chromatography with ethyl acetate provided the desired product as colored oil. |

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