5-Benzothiazolecarboxaldehyde

To a mixture of compound B-188 (2.8 g, 17 mmol) in anhydrous dichloromethane (20 mL) was added manganese dioxide (14 g, 0.16 mol) at room temperature. The mixture was stirred at room temperature for 16 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo to give compound B-189 (2.5 g, 93percent yield) as a yellow solid.Aldehyde preparation: To a solution of 4-chloro-3-nitrobeznoic acid (20 g, 99.2 mmol, 1.0 eq) in dimethylformamide (400 mL) was added potassium carbonate (35 g, 254 mmol, 2.55 eq). The mixture was stirred 30 min and ethyl iodide (18.6 g, 119 mmol, 1.20 eq) was added. The reaction mixture was stirred at 50 [°C] for 4h. Water (3 L) was added and the mixture was extracted with diethyl ether (2 x 500 mL). The organic extracts were combined, washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from hexanes to provide 19.7 g (86percent) of the ester. Data [: IH] NMR (500 MHz, CDC13) [8] 8.51 (d, 1H), 8.17 (dd, 1H), 7.65 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H). Sulfur (1.60 g, 49.9 mmol, 0.58 eq) was dissolved in a solution of sodium sulfide [NONAHYDRATE] (12.0 g, 50.0 mmol, 0.58 eq) in water (60 [ML).] This solution was combined with a solution of ethyl 4-chloro-3-nitrobenzoate (19.6 g, 85.4 mmol, 1.00 eq) in ethanol (100 mL). The resulting mixture was heated at reflux for 3 h. The hot reaction mixture was poured into water (600 mL) and stirred for 15 min. The product was isolated by filtration and recrystallized from ethanol to provide 16.45 g (77percent) of the disulfide. Data: [APOS;H NMR] (500 MHz, CDC13) [5] 8.96 (d, 1H), 8.19 (dd, 1H), 7.88 (d, 1H), 4.43 (q, 2H), 1.41 (t, 3H). A mixture of diethyl 4, 4'-dithiobis (3-nitrobenzoate) (11.2 g, 24.75 mmol, 1.00 eq) and zinc granules (15.0 g, 234 mmol, 9.47 eq) in formic acid (600 mL) was heated to reflux for 48 h. The mixture was cooled to room temperature and concentrated to dryness on vacuum rotary evaporator. The residue was partitioned between ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated on vacuum rotary evaporator. The residue was purified by chromatography on neutral Alumina (1/0 to 0/1 hexanes/dichloromethane) to provide 5.30 g (51percent) of the benzthiazole ester. Data: 1H NMR (500 MHz, [CDC13)] [8] [9. 08 (S, 1H), ] 8.83 (d, 1H), 8.14 (dd, 1H), 8.02 (d, 1H), 4.45 (q, 2H), 1.44 (t, 3H); MS [(EI)] m/z 208 [(M++1).] Diisobutylaluminum hydride (1.0 M in dichloromethane, 6.0 mL, 6 mmol, 1.05 eq) was added over 15 min to a solution of the ester (1.18 g, 5.70 mmol) in dichloromethane (40 mL) [AT-35] [°C.] The reaction mixture was allowed to warm to rt and was maintained overnight. Analysis of the reaction progress by thin layer chromatography revealed the presence of starting material. The reaction mixture was cooled to [0 °C] and was treated with additional diisobutylaluminum hydride (6.0 mL, 6 mmol). After 4 h at rt, the reaction was quenched by the addition of water (10 mL) and the slurry was poured onto 5percent sodium hydroxide and dichloromethane (200 mL) and maintained for 30 min with vigorous stirring. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated. The residue was dissolved in dichloromethane (100 mL) and was treated with manganese [(IV)] oxide (3.0 g) and powdered [4A] seives (3.0 g). The reaction mixture was filtered through Celite (100 mL dichloromethane rinse) after 14 h and the filtrate was extracted with 0.6 N aqueous sodium hydrogen sulite (2 x 150 mL). The combined aqueous layers were back-extracted with dichloromethane [(50] mL), were made basic (pH 11) by the addition of 50percent sodium hydroxide, and were extracted with ethyl acetate (2 x 100 mL). The ethyl acetate layers were dried (sodium sulfate) and concentrated to provide 268 mg (29percent) of the aldehyde as a tan solid. Data [: IHNMR (CDCL3) 6] 10.18 (s, 1H), 9.13 (s, [1H), ] 8.61 (d, J= 1.0, 1H), 8.11 (d, J= 8.0, 1H), 8.01 (dd, J= 8.5, 1.5, 1H). Condensation: According to procedure A. Data: Yield: 86percent. 1H NMR (CD30D) 8 8.97 (s, 1H), 8.75 (s, [1H), ] 8.60 (s, [1H), ] 8.06 (d, [J=] 0.6, [1H), ] 7. 87 (d, [J=] 8.4, [1H), ] 7.82 (dt, Jd = 7.8, Jt = 1. 8, 1H), 7.30 (dd, J= 7.8, 4.8, 1H), 7.26 (dd, J= 8.4, 1.6, 1H), 6.76 (s, 1H), 3.86 (t, J= 5.5, 2H), 2.85 (m, 2H), 1.79 (m, 2H); MS [(EL)] m/z 306 [(M+ +] 1).Triethylamine (0.098 mL, 0.70 mmol) was added to a stirred solution of intermediate 27 (50 mg, 0.18 mmol, bis HC1 salt) in DCM (0.84 mL) at rt. Then benzo[d]thiazole-5- carbaldehyde (CAS: 211915-60-7; 34.3 mg, 0.21 mmol) followed by sodium triacetoxyborohydride (56.3 mg, 0.27 mmol) were added. The mixture was further stirred at rt for 15 h. The reaction mixture was diluted with NaHC03 (aq. sat. soltn.) and DCM. The organic layer was separated, dried over MgS04, filtered and the filtrate was evaporated in vacuo. The residue thus obtained was purified by reverse phase HPLC (Stationary phase: CI 8 XBridge 30 x 100 mm 5 muiotaeta), mobile phase: gradient from 74% 10 mM NH4CO3H pH 9 solution in water, 26% CH3CN to 58% 10 mM NH4CO3H pH 9 solution in water, 42% CH3CN). The desired fractions were collected and extracted with EtOAc. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo to yield product 53 (16 mg, 25 % yield) as a yellow oil.The starting material cyclohexene-2-one (0.95 g, 10.0 mmol) was dissolved in 15 ml of anhydrous dichloromethane at a temperature of -50 CFollowed by addition of 200 mg of TiCl4 and PPh3 (2.62 g, 10.0 mmol). After 15 min, a) A dried vial was charged with copper(l) iodide (0.120 g, 0.630 mmol) and dichloromethane (7.93 g, 92.5 mmol, 5.99 mL). XANTPHOS (0.401 g, 0.693 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. The solvent was removed by bubbling through with argon. The remaining solid was directly used for the next step. b) A vial was set under argon and charged with Cu(Xantphos)l (0.0471 g, 0.0613 mmol) (procedure step a), dichloro-bis(tricyclohexylphosphine)palladium(ll) (0.119 g, 0.153 mmol), cesium carbonate (2.50 g, 7.66 mmol) and toluene (6.13 mL). To the resulting mixture was added 1 , 3-benzothiazole-5- carbaldehyde (0.500 g, 3.06 mmol) and 1 -bromo-4-(trifluoromethoxy)benzene (1 .11 g, 4.60 mmol, 0.683 mL). The reaction mixture was stirred at 100C overnight. After cooling to room temperature, it was diluted with ethyl acetate and quenched with a solution of ammonium chloride saturated/water (1/1 ). The resulting suspension was filtered over celite and washed several times with ethyl acetate. The organic layer was separated and washed with water, brine, dried over anhydrous magnesium sulfate, filtered of and evaporated. The crude product was purified over flash-chromatography to give 2-[4-(trifluoromethoxy)phenyl]-1 , 3-

Molecular Weight:163.20
XLogP3:1.5
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:163.00918496
Monoisotopic Mass:163.00918496
Topological Polar Surface Area:58.2
Heavy Atom Count:11
Complexity:162
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes