Synthesis of novel fluorinated building blocks via halofluorination and related reactions

A study exploring halofluorination and fluoroselenation of some cyclic olefins, such as diesters, imides, and lactams with varied functionalization patterns and different structural architectures is described. The synthetic methodologies were based on electrophilic activation through halonium ions of the ring olefin bonds, followed by nucleophilic fluorination with Deoxo-Fluor®. The fluorine-containing products thus obtained were subjected to elimination reactions, yielding various fluorine-containing small-molecular entities.

volatile, the mixture was stirred at rt for 18 h to allow the half-amide intermediate to form.
Then, the mixture was treated at reflux temperature for 15 h to facilitate ring-closing. After cooling, it was washed with 3×40 mL 10% aqueous HCl solution, and then with 3×30 mL saturated aqueous NaCl solution. The organic layer was dried (Na 2 SO 4 ), slightly concentrated, and titurated with hexane to obtain the product 24 as a white solid (yield of 50%).

Synthesis of the tricyclic cyclopropane (rac)-28:
To a solution of 0.29 mmol of the starting compound in 10 mL THF, 2.1 equiv DBU was added.

General procedure for the fluoroselenation:
To a solution of 1.00 mmol of the starting olefin in 10 mL anhydrous MeCN, 2 equiv Deoxo-Fluor ® and 1 equiv PhSeBr were added. The reaction mixture was stirred at rt for the time given in the Scheme. Then, it was diluted with 20 mL EtOAc and washed with 2×10 mL of a saturated aqueous NaHCO 3 solution. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude product was purified by column chromatography on silica gel (n-hexane/EtOAc or nhexane/acetone).
Alternative procedure for the fluoroselenation of the diester (rac)-1: To a solution of 1.00 mmol of dimethyl trans-cyclohex-4-ene-1,2-dicarboxylate ((rac)-1) in 10 mL anhydrous MeCN, 4 equiv Et 3 N×3HF and 1 equiv PhSeBr were added. The reaction mixture was stirred at rt for 24 h. After adding 1 equivalent of PhSeBr again, the mixture was stirred at 55 °C for further 8 h. After diluting with 20 mL EtOAc, it was washed with 2×10 mL of a saturated aqueous NaHCO 3 solution. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude product was purified by column chromatography on silica gel (nhexane/acetone 18:1) to obtain 35% of the product (rac)-30 as a pale yellow oil.

Alternative procedure for the fluoroselenation of the diester 4:
To a solution of 1.00 mmol of dimethyl cis-cyclohex-4-ene-1,2-dicarboxylate (4) in 10 mL anhydrous MeCN, 4 equiv Et 3 N×3HF and 1 equiv PhSeBr were added. The reaction mixture was stirred at rt for 21 h. Then, after the addition of another equivalent of PhSeBr, the mixture was stirred at rt for further 10 h. Next, the mixture was diluted with 20 mL EtOAc and washed with 2×10 mL saturated aqueous NaHCO 3 solution. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude product was purified by column chromatography on silica gel (nhexane/acetone 17:1) to obtain 32% of the product (rac)-31 as a pale brown oil. Notably, the purification of this mixture was easier than the purification of reaction mixtures obtained via the general fluoroselenation procedure.
Alternative preparation of the lactone (rac)-32: To a solution of 1.00 mmol of the starting compound 16 in 10 mL anhydrous MeCN, 1 equiv PhSeBr was added, and the reaction mixture was stirred at rt for the time given in the Scheme.
Then, it was diluted with 20 mL EtOAc and washed with 2×10 mL of a saturated aqueous NaHCO 3 solution. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude product was purified by column chromatography on silica gel (n-hexane/acetone 6:1) to obtain 93% of the product (rac)-32 as a yellowish solid.

Oxidative elimination of the phenylselenyl group under acidic conditions:
0.32 mmol of the starting compound ((rac)-30 or (rac)-31) was dissolved in 8 mL THF. After cooling to 0 °C, 5 equiv H 2 O 2 (as a 30 wt % aqueous solution) and 1.1 equiv trifluoroacetic acid were added, and the mixture was allowed to warm up to rt upon stirring for the time given in the Scheme. Then, it was diluted with 30 mL EtOAc and washed with 2×10 mL of a saturated aqueous NaHCO 3 solution. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude product was purified by column chromatography on silica gel ((rac)-30: n-hexane/EtOAc 6:1, (rac)-31: n-hexane/EtOAc 9:1).

Oxidative elimination of the phenylselenyl group under basic conditions:
0.33 mmol of the starting compound ((rac)-30 or (rac)-31) was dissolved in 8 mL THF. After cooling to 0 °C, 2 equiv NaHCO 3 and 5 equiv H 2 O 2 (as 30 wt % aqueous solution) were added and the mixture was stirred at 0 °C for 30 min. Then 2.5 equiv Et 3 N was added and the mixture was allowed to warm up to rt while it was stirred for a day. Then, it was diluted with 30 mL EtOAc and washed with 2×10 mL water. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude product was purified by column chromatography on silica gel (nhexane/EtOAc 9:1 → 7:1).

Hydrogenation of (rac)-35:
To a solution of 0.25 mmol (rac)-35 in 5 mL EtOAc, 15 mg Pd/C (10 wt %) was added, and the reaction mixture was stirred at 10 °C under a hydrogen atmosphere (1 bar) for 4 days. The reaction mixture was then filtered on a fritted glass filter covered with Celite ® . The filtrate was dried (Na 2 SO 4 ) and concentrated. The crude product was purified by column chromatography on silica gel (n-hexane/EtOAc 5:1) to obtain 88% of the product (rac)-36 as a colorless oil. Prepared according to General procedures for halofluorination, Method A (eluent gradient for column chromatography: n-hexane/acetone 6:1→5:1). White solid; yield 66% (7:5 mixture of 2 diastereomers).