5-FLUOROBENZO[D]OXAZOLE-2-THIOL

A solution of 2-amino-4-fluorophenol (10 g, 78.8 mmol), carbon disulfide (35 mL), and potassium hydroxide (5.3 g, 94.6 mmol) in ethanol (200 mL) was heated to reflux overnight. The reaction mixture was concentrated to dryness then diluted with water. This solution was neutralized with 1M HC1 then washed with ethyl acetate several times. The combined organicphases were washed with brine, dried over Na2SO4, and concentrated in vacuo giving 9.3 g (70percent yield) of the desired 5-fluorobenzo[dloxazole-2-thiol. ‘H NMR (300 MHz, DMSO-d6) ö 7.51 (ddd, J= 8.8, 4.2, 0.6 Hz, 1H), 7.15 —7.04 (m, 2H), 3.31 (brs, 1H). LC-MS (mlz): 170.2.General procedure: 2-Aminophenol (1.0 mmol), K2CO3 (3.0 mmol) was dissolved in DMF (3 mL) in a dried tube, equipped with a magnetic stirring bar and a septum. The mixture was stirred for 5 minutes, and then TMTD (0.6 mmol) was added. The reaction mixture was then heated at 120 °C and checked by TLC until the starting material was finished (around 12 hours). The reaction was cooled down to room temperature, and then quenched with sat. NH4Cl solution and extracted with ethyl acetate, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to afford the desired product.Example 32; (2S, 2'S)-Dimethyl 4, 4'-disulfanediyl-bis(2-(5-fluorobenzo[d]oxazol-2-ylamino) butanoate); Step 1. 5-Fluoro-2-mercaptobenzoxazole; A mixture of 2-amine-4-fluorophenol (5.0 g) and potassium ethyl xanthate (1.0 eq), dissolved in 100 mL ethanol was heated under reflux for 7 hrs. The solvent was removed in vacuum and the residue was dissolved in water. The solution was acidified to pH 5 with glacial acetic acid. The product was filtered and crystallized to obtain 5-fluoro-2-mercaptobenzoxazole (5.O g, 75percent).General procedure: A mixture of 4?-demethylepipodophyllotoxin (DMEP) (400mg 1mmol) and SH-containing building blocks in dichloromethane (15mL) at 0C was mixed with 1mL of TFA as the catalyst. After stirring the reaction mixture for 2-3hat room temperature and maximal conversion was reached (3h, monitored by TLC), the resultant mixture was washed with saturated NaHCO3 (20mL×2) and extracted with CH2Cl2 (45mL×2). The organic layer was dried over MgSO4, and the solvent was evaporated to give a crude residue, which was purified by flash column chromatography (petroleum ether: dichloromethane: ethyl acetate, 3:2:1) to afford the target compounds. The purity of compounds was determined by HPLC with a thermo-C18 (250mm×4.6mm, 5mum) column as the stationary phase and methanol-water (35:65) as the mobile phase at ambient temperature and a flow rate of 2.0mL/min.General procedure: 2-Aminophenol (1.0 mmol), K2CO3 (3.0 mmol) was dissolved in DMF (3 mL) in a dried tube, equipped with a magnetic stirring bar and a septum. The mixture was stirred for 5 minutes, and then TMTD (0.6 mmol) was added. The reaction mixture was then heated at 120 C and checked by TLC until the starting material was finished (around 12 hours). The reaction was cooled down to room temperature, and then quenched with sat. NH4Cl solution and extracted with ethyl acetate, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Molecular Weight:169.18
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:168.99976309
Monoisotopic Mass:168.99976309
Topological Polar Surface Area:53.4
Heavy Atom Count:11
Complexity:187
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes