4-CARBOXY-2,6-DIFLUOROBENZALDEHYDE

To a solution of 3, 5-difluorobenzoic acid (20 g, 126.5 mmol) in 2- methyltetrahydrofuran (225 ml_) Ν, Ν, Ν', Ν'-tetramethylethylenediamine (TMEDA) (2.2 eq., 278.3 mmol, 43 ml_) was added at room temperature. The resulting solution was cooled to -78To a solution of 3, 5-difluorobenzoic acid (20 g, 126.5 mmol) in 2- methyltetrahydrofuran (225 ml_) Ν, Ν, Ν', Ν'-tetramethylethylenediamine (TMEDA), (2.2 eq., 278.3 mmol, 43 ml_) was added at room temperature. The resulting solution was cooled to -78Example 1. Preparation of 3, 5-difluoro-4-formylbenzoic acid.To a solution of 3, 5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran (4.35 L) was added TMEDA (604 mL, 4.03 mol) at room temperature. The resulting solution was cooled to -78°C. Afterward, w-BuLi (2.5 M in hexane) (1.77 L, 4.43 mol) was added drop-wise, during which the temperature of the mixture remained at less than -65 °C. The mixture was then stirred at -78 °C for 1.5 hr. Anhydrous MeOCHO (239 mL, 3.88 mol) was added dropwise at a rate that allowed the temperature to be maintained at less than -65 °C. The resulting solution was allowed to warm at room temperature, and then maintained a room temperature while being stirred for 18 hr. The mixture was then cooled to 0-5°C, and excess base was quenched with 6M aqueous HC1 (2.2 L, 13.2 mol). The phases were then separated, and the aqueous layer was extracted 3 times with 2- methyltetrahydrofuran (3 x 500 mL). The combined organic phases were washed with saturated brine, dried over MgS0Example 1. Preparation of 3, 5-difluoro-4-formylbenzoic acid.To a solution of 3, 5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran (4.35 L) was added TMEDA (604 mL, 4.03 mol) at room temperature. The resulting solution was cooled to -78°C. Afterward, BuLi (2.5 M in hexane) (1.77 L, 4.43 mol) was added drop-wise, during which the temperature of the mixture remained at less than -65 °C. The mixture was then stirred at -78 °C for 1.5 hr. Anhydrous MeOCHO (239 mL, 3.88 mol) was added dropwise at a rate that allowed the temperature to be maintained at less than -65 °C. The resulting solution was allowed to warm at room temperature, and then maintained a room temperature while being stirred for 18 hr. The mixture was then cooled to 0-5°C, and excess base was quenched with 6M aqueous HC1 (2.2 L, 13.2 mol). The phases were then separated, and the aqueous layer was extracted 3 times with 2- methyltetrahydrofuran (3 x 500 mL). The combined organic phases were washed with saturated brine, dried over MgS0To a solution of 3, 5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran(4.35 L) was added TMEDA (604 mL, 4.03 mol) at room temperature. The resultingsolution was cooled to -78°C. Afterward, n-BuLi (2.5 M in hexane) (1.77 L, 4.43 mol)was added drop-wise, during which the temperature of the mixture remained at less than-65 °C. The mixture was then stirred at -78 °C for 1.5 hr. Anhydrous MeOCHO (239 mL, 3.88 mol) was added dropwise at a rate that allowed the temperature to be maintained atless than -65 °C. The resulting solution was allowed to warm at room temperature, and then maintained a room temperature while being stirred for 18 hr. The mixture was then cooled to 0-5°C, and excess base was quenched with 6M aqueous HC1 (2.2 L, 13.2 mol). The phases were then separated, and the aqueous layer was extracted 3 times with 2- methyltetrahydrofuran (3 x 500 mL). The combined organic phases were washed withsaturated brine, dried over Mg504, filtered, and concentrated under vacuum. The residue was dissolved in ethyl acetate (350 mL) at reflux, and cooled to room temperature. Hexanes (480 mL) were then added, and the resulting mixture was further cooled to -15°C. The solid was collected by filtration, rinsed with hexanes, and dried under mechanical vacuum to form the title compound (122 g, 35percent) as a solid. ‘H NMR (300 MHz, DMSOd 6) ö ppm 7.63-7.70 (m, 2 H), 10.23 (s, 1 H); MS m/z (ESI) 187.17 [M+Hjb.full text is not avalable from articleGeneral procedure: Method 2: In order to increase the reaction ratio ofexo isomer a solution of methyl 4-formyl-3-methylbenzoate6 (5.61 mmol, 1 g) in anhydrous ACN(60 mL), p-toluidine (5.1 mmol, 547 mg), 3, 4-dihydro-2H-pyran (10.2 mmol, 0.93 mL) and TFA(1.12 mmol, 0.087mL) were added. The reactionmixture was stirred 16 h at RT. Solvent was evaporatedand purification of the crude material (60:40 mixtureof exo/endo diastereomers) by flash chromatographyover silica gel using an elution of 15% ethyl acetate inhexanes afforded 1 g (Yield 50%) of the title exoisomer(exo-1c) and 290 mg (Yield 14%) of the titleendo-isomer (endo-1c).General procedure: To a solution of 4-formylbenzoic acid(130.9 mmol, 19.6 g), 4-(difluoromethoxy)benzenamine(157.1 mmol, 25 g) and 3, 4-dihydro-2H-pyran (91.12mmol, 8.31 mL) in anhydrous ACN (91 mL), chlorotrimethylsilane(28.8 mmol, 3.75 mL) was added. Thereaction mixture was stirred 16 h at RT. The suspensionreaction (75:25 mixture of exo/endo diastereomers) wascooled, filtered and the solid washed with the minimumamount of cold acetonitrile and hexane gave 19.2 g (Yield39%) of the pure title compound exo-1m.full text is not avalable from articlefull text is not avalable from articlefull text is not avalable from article

Molecular Weight:186.11
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:186.01285031
Monoisotopic Mass:186.01285031
Topological Polar Surface Area:54.4
Heavy Atom Count:13
Complexity:207
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes