2-bromo-5,8-dioxaspiro[3.4]octane

Conditions: temp:87.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-5,8-dioxa-spiro[3.4]octane (Compound 100F, 19 g, 100 mmol) and 4-iodopyrazole (38.6 g, 200 mmol) in DMF (100 mL) was added powdered K2CO3 (41.4 g, 300 mmol) and 18-crown-6 ether (5.3 g, 20 mmol). The reaction mixture was stirred at 85-90° C. for 2 days. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (4×100 mL). The combined organic layers were washed with brine and concentrated, the residue was purified by column chromatography (ethyl acetate/DCM: 5:95) to give 8.8 g (29%) of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole. 1H NMR (CDCl3, 300 MHz): δ=2.87-2.89 (m, 4 H), 3.92-3.96 (m, 4 H), 4.64-4.68 (m, 1 H), 7.53 (s, 2 H). washed with water (4×100 mL) The combined organic layers were washed with brine concentrated the residue was purified by column chromatography (ethyl acetate/DCM: 5:95)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromocyclobutanone (5.90 g, 39.6 mmol), 1,2-ethanediol (8.6 mL, 158 mmol, 4 eq.) and PPTS (1.90 g, 7.92 mmol) in benzene (40 mL) was heated to reflux using Dean-Stark assembly. After 12 h, the reaction mixture was allowed to cool and washed with water (2×30 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (ethyl acetate/hexanes 1:5) to give the title compound (51% yield starting from 3-oxocyclobutanecarboxylic acid). 1H NMR (300 MHz, CDCl3): δ=2.77-2.82 (m, 4H), 2.95-3.00 (m, 4H), 4.19-4.23 (m, 1H). was heated to reflux to cool washed with water (2×30 mL) The organic phase was dried (Na2SO4) concentrated The residue was purified

Conditions: temp:87.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-5,8-dioxa-spiro[3.4]octane (Compound 100F, 19 g, 100 mmol) and 4-iodopyrazole (38.6 g, 200 mmol) in DMF (100 mL) was added powdered K2CO3 (41.4 g, 300 mmol) and 18-crown-6 ether (5.3 g, 20 mmol). The reaction mixture was stirred at 85-90° C. for 2 days. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (4×100 mL). The combined organic layers were washed with brine and concentrated, the residue was purified by column chromatography (ethyl acetate/DCM: 5:95) to give 8.8 g (29%) of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole. 1H NMR (CDCl3, 300 MHz): δ=2.87-2.89 (m, 4H), 3.92-3.96 (m, 4H), 4.64-4.68 (m, 1H), 7.53 (s, 2H). washed with water (4×100 mL) The combined organic layers were washed with brine concentrated the residue was purified by column chromatography (ethyl acetate/DCM: 5:95)

Conditions: temp:87.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-5,8-dioxa-spiro[3.4]octane (Compound 100F, 19 g, 100 mmol) and 4-iodopyrazole (38.6 g, 200 mmol) in DMF (100 mL) was added powdered K2CO3 (41.4 g, 300 mmol) and 18-crown-6 ether (5.3 g, 20 mmol). The reaction mixture was stirred at 85-90° C. for 2 days. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (4×100 mL). The combined organic layers were washed with brine and concentrated, the residue was purified by column chromatography (ethyl acetate/DCM: 5:95) to give 8.8 g (29%) of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole. 1H NMR (CDCl3, 300 MHz): δ=2.87-2.89 (m, 4 H), 3.92-3.96 (m, 4 H), 4.64-4.68 (m, 1 H), 7.53 (s, 2 H). washed with water (4×100 mL) The combined organic layers were washed with brine concentrated the residue was purified by column chromatography (ethyl acetate/DCM: 5:95)