Semi-Industrial Fluorination of β-Keto Esters with SF₄: Safety vs Efficacy

Dedicated to 60th anniversary of Dr. Yurii Pustovit
Published as part of the ISySyCat2019 Special Issue

Abstract

The possibility of deoxofluorination of β-keto esters using SF₄ was investigated. The scope and limitation of the reaction were determined. The efficient method for the synthesis of β,β-difluorocarboxylic acids was elaborated based on the reaction. The set of mentioned acids, being the perspective building blocks for medicinal chemistry, were synthesized on multigram scale. The safety of SF₄ use was discussed. The described method does not improve upon the safety of using SF₄, but practical recommendations for working with the reagent are proposed. Despite the hazards of using toxic SF₄, a significant increase of efficacy in the synthesis of medicinal-chemistry-relevant building blocks, based on the reaction, in comparison with earlier described approaches is shown.

Key words

organofluorine compounds - deoxofluorination - sulfur tetrafluoride - β-keto esters - β,β-difluorocarboxylic acids - building blocks

• References and Notes

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• 19 Deoxofluorination Protocol А1 The keto ester 1 (1 mol) was placed in a Hastelloy autoclave (1200 mL) and cooled with liquid nitrogen. Anhydrous hydrogen fluoride (1 mL per 0.01 mol of the keto ester) was added. The autoclave was evacuated and SF₄ (about 1.7 equiv) was condensed into it. The autoclave was warmed up to room temperature and was stirred on a magnetic stirrer overnight. Gaseous products were released, the solution was removed from the autoclave and poured onto ice, the oil obtained was extracted with MTBE, the extracts were combined and washed with aqueous solution of Na₂CO₃, dried, evaporated and distilled. In the case of obtaining an admixture of monofluoroalkene during the fluorination (substrates 1a–c,h,i,u), the crude product was dissolved in dichloromethane/water mixture before purification (100 g of product per 1 L of dichloromethane and water), and KMnO₄ was added in portions under stirring until the boiling was ceased and the raspberry color was stabilized for 1 h (usually 0.3–0.7 g of potassium permanganate per 1 g of the mixture). Excess of potassium permanganate was quenched with Na₂S₂O₃, the precipitate was filtered and washed with dichloromethane. The organic phase was separated, dried, and distilled. The bp and yields for products 2 are given in Table 1. Bp (14a) = 105–108°C/0.3 mmHg. Bp (14c) = 65–67°C/0.3 mmHg. The compound 14b was purified by recrystallization from hexane mp 64 °C; bp (22a) 49–51 °C/20 mmHg; bp (22j) 55–59 °C/0.3 mmHg; bp (22t) 69–71 °C/20 mmHg. Representative Examples Ethyl 1-Benzyl-4,4-difluoropiperidine-3-carboxylate (14a) ¹H NMR (400 MHz, CDCl₃): δ = 7.52–7.04 (m, 5 H), 4.16 (qd, J = 7.1, 4.2 Hz, 2 H), 3.76–3.35 (m, 2 H), 2.96 (tt, J = 12.0, 5.6 Hz, 1 H), 2.86–2.61 (m, 3 H), 2.50 (t, J = 9.6 Hz, 1 H), 2.39–2.23 (m, 1 H), 2.09–1.90 (m, 1 H), 1.22 (t, J = 7.2 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 168.2, 138.0, 128.7, 128.3, 127.3, 120.51 (t, J = 246.3 Hz), 61.7, 61.0, 52.3, 49.8 (t, J = 5.3 Hz), 48.6 (t, J = 21.9 Hz), 33.3 (t, J = 22.2 Hz), 14.0. ¹⁹F NMR (376 MHz, CDCl₃): δ = –97.3 (d, J = 239.1 Hz). LC–MS (positive mode): m/z = 284 [M + H]⁺. 3,3-Difluorobutanenitrile (22a) ¹H NMR (400 MHz, CDCl₃): δ = 2.95 (t, J = 11.0 Hz, 2 H), 1.78 (t, J = 18.5, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 119.4 (t, J = 243.8 Hz), 113.6 (t, J = 4.8 Hz), 28.3 (t, J = 40.2 Hz), 22.9 (t, J = 25.1 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –88.7.
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• 21 Deoxofluorination Protocol B1 The keto ester 1 (1 equiv) was placed in a Hastelloy autoclave (1200 mL), cooled with liquid nitrogen, vacuumed, and SF₄ was condensed into it (about 1.7 equiv). The autoclave was warmed up to room temperature and stirred at 60 °C on a magnetic stirrer for 48 h. Gaseous products were released, the solution was poured from the autoclave onto ice, and the oil formed was extracted with MTBE. The extracts were washed with aqueous solution of Na₂CO₃ and dried. The residue was evaporated and purified with potassium permanganate (as in protocol A) and distilled. The bp and yields of products 2 are given in Table 1. Representative Examples Ethyl 3,3-Difluorobutanoate (2a) ¹H NMR (500 MHz, CDCl₃): δ = 4.20 (qd, J = 7.2, 3.4 Hz, 2 H), 2.92 (td, J = 14.1, 3.3 Hz, 2 H), 1.78 (td, J = 18.8, 3.3 Hz, 3 H), 1.29 (td, J = 7.2, 3.3 Hz, 3 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –87.0 Ethyl 4-Chloro-3,3-difluorobutanoate (2q) ¹H NMR (400 MHz, CDCl₃): δ = 4.18 (q, J = 7.1 Hz, 2 H), 3.93 (t, J = 12.7 Hz, 2 H), 3.09 (t, J = 14.2 Hz, 2 H), 1.26 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 166.4 (t, J = 8.4 Hz), 119.5 (t, J = 244.4 Hz), 61.5, 43.6 (t, J = 33.4 Hz), 38.9 (t, J = 27.6 Hz), 14.0. ¹⁹F NMR (376 MHz, CDCl₃): δ = –97.9. EIMS (70eV): m/z (%) = 186 [M – H]⁺ (1), 161 (15), 159 (49), 143 (30), 141 (100), 113 (24), 99 (14), 94 (15), 77 (17), 64 (15), 77 (17), 64 (150), 59 (11), 45 (14), 42 (12) Ethyl 2,2-Difluorocyclohexanecarboxylate (2u) ¹H NMR (400 MHz, CDCl₃): δ = 4.17 (qd, J = 7.2, 2.7 Hz, 2 H), 2.81 (dq, J = 19.3, 6.9 Hz, 1 H), 2.30–2.11 (m, 1 H), 1.89 (q, J = 6.9, 6.5 Hz, 2 H), 1.83–1.53 (m, 4 H), 1.46–1.30 (m, 1 H), 1.25 (t, J = 7.1 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 169.8 (d, J = 6.1 Hz), 121.7 (dd, J = 246.9, 244.6 Hz), 60.9, 48.8 (t, J = 23.0 Hz), 33.2 (t, J = 23.0 Hz), 26.5 (t, J = 3.3 Hz), 22.3–22.2, 22.2, 14.1. ¹⁹F NMR (376 MHz, CDCl₃): δ = –94.6 (d, J = 240.3 Hz). EIMS (70eV): m/z (%) = 192 [M]⁺ (2), 172 (21), 147 (59), 145 (13), 100 (42), 99 (100), 98 (14), 97 (11), 85 (20), 80 (41), 77 (26), 72 (16), 55 (22).
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• 24 Hydrolysis Protocol А2 A mixture of the ester 2 (1 equiv), formic acid (4 equiv), and 20% hydrochloric acid (3 equiv of HCl) was stirred at 100°C with 10 cm Vigreux column for 2 days. The reaction mixture was saturated with NaCl, and the product was extracted with dichloromethane (for the substance 2p, the precipitated product was filtered off and washed with cold water). The extracts were dried, evaporated, and distilled. The bp and yields of products 10 are given in Table 1. Representative Examples 3,3-Difluorobutanoic Acid (10a) ¹H NMR (400 MHz, CDCl₃): δ = 9.70 (br, 1 H), 2.97 (t, J = 13.9 Hz, 2 H), 1.77 (t, J = 18.7 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 173.2 (t, J = 7.8 Hz), 120.7 (t, J = 239.9 Hz), 42.9 (t, J = 29.3 Hz), 23.2 (t, J = 26.4 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –87.2. EIMS (70eV): m/z (%) = 122 (1), 107 (12), 104 (21), 89 (41), 76 (12), 65 (100), 64 (11), 63 (10), 60 (62), 59 (23), 45 (44), 43 (14), 42 (23), 40 (12), 39 (10) 2,2-Difluorocyclopentanecarboxylic Acid (10t) ¹H NMR (400 MHz, CDCl₃): δ = 11.20 (br, 1 H), 3.00–3.20 (m, 1 H), 2.40–2.00 (m, 4 H), 2.00–1.80 (m, 1 H), 1.80–1.60 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 175.8, 130.6 (t, J = 266.6 Hz), 51.4 (t, J = 24.1 Hz), 35.4 (t, J = 23.6 Hz), 26.3, 20.6. ¹⁹F NMR (376 MHz, CDCl₃): δ = –92.6 (d, J = 229.7 Hz), –100.8 (d, J = 229.7 Hz). EIMS (70eV): m/z (%) = 150 [M]⁺ (1), 130 (7), 115 (11), 110 (13), 109 (17), 91 (10), 82 (14), 77 (21), 73 (100), 66 (13), 65 (11), 59 (11), 55 (33), 51 (14), 45 (15), 41 (20), 39 (20).
• 25 Hydrolysis Protocol B2 A mixture of the ester 2 (1 equiv) and sodium hydroxide (1.5 equiv) in 50% aqueous ethanol (2 L per 1 mol) was boiled until the reaction was completed (from 1 night to 3 days). The reaction mixture was evaporated, acidified with hydrochloric acid, and the product was extracted with dichloromethane. The extracts were combined, dried, evaporated, and distilled. The bp and yields of products 10 are given in Table 1. Representative Examples 3,3-Difluoro-2,2-dimethylbutanoic Acid (10l) ¹H NMR (400 MHz, CDCl₃): δ = 11.51 (br, 1 H), 1.71 (t, J = 19.2 Hz, 3 H), 1.35 (s, 6 H). ¹³C NMR (151 MHz, CDCl₃): δ = 179.8, 123.9 (t, J = 246.1 Hz), 49.7 (t, J = 24.7 Hz), 20.3 (t, J = 27.7 Hz), 20.0 (t, J = 4.2 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –98.1. EIMS (70eV): m/z (%) = 154 [M + 2H]⁺ (1), 145 (1), 88 [M – CF₂CH₃]⁺ (94), 87 (25), 73 (100), 70 (31), 65 (49), 59 (17), 45 (16), 42 (11), 41 (23), 39 (15) 1-(1,1-Difluoroethyl)cyclopropanecarboxylic Acid (10m) ¹H NMR (400 MHz, CDCl₃): δ = 11.07 (s, 1 H), 1.88 (t, J = 18.7 Hz, 3 H), 1.41–1.32 (m, 2 H), 1.35–1.26 (m, 2 H). ¹³C NMR (151 MHz, CDCl₃): δ = 177.6, 120.8 (t, J = 240.4 Hz), 28.9 (t, J = 29.4 Hz), 22.9 (t, J = 28.3 Hz), 13.8 (t, J = 3.5 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –94.7. LC–MS (negative mode): m/z = 149 [M – H]^–.
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• 29 Hydrolysis Protocol C2 A mixture of the ester 14, acetic acid (2 mL per 1 g of ether) and 20% hydrochloric acid (2 mL per 1 g of ether) was stirred overnight at 110 °C with 10 cm Vigreux column. The resulting mixture was evaporated. The solid residue was washed with MTBE to obtain hydrochloride of the acid 16; mp (16a·HCl) 199 °C (with decomposition); mp (16b·HCl) 200 °C (with decomposition). Representative Examples 1-Benzyl-4,4-difluoropiperidine-3-carboxylic Acid Hydrochloride (16a·HCl) H NMR (400 MHz, DMSO-d ₆): δ = 13.47 (s, 1 H), 12.13 (s, 1 H), 7.64 (dd, J = 6.7, 2.9 Hz, 2 H), 7.51–7.40 (m, 3 H), 4.41 (s, 2 H), 3.88–3.66 (m, 1 H), 3.54 (d, J = 12.8 Hz, 1 H), 3.37 (s, 1 H), 3.28 (t, J = 12.7 Hz, 1 H), 3.16 (t, J = 12.4 Hz, 1 H), 2.72–2.52 (m, 1 H), 2.39 (t, J = 14.8 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 167.3, 131.8, 130.2, 130.0, 129.3, 119.5 (t, J = 247.6 Hz), 58.8, 49.4, 48.0, 45.2, 31.2. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –98.9 (d, J = 237.1 Hz), –110.0 (d, J = 237.1 Hz). LC–MS (negative mode): m/z = 254 [M – HCl – H]^– 1-Benzyl-3,3-difluoropiperidine-4-carboxylic Acid Hydrochloride (16b·HCl) ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.81 (br, 2 H), 7.63 (s, 2 H), 7.53–7.36 (m, 3 H), 4.55–4.17 (m, 2 H), 3.74–2.94 (m, 5 H), 2.18 (s, 2 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 169.0, 132.2, 130.1, 129.4, 129.2, 118.4 (t, J = 246.2 Hz), 59.4, 53.1, 49.6, 45.0, 22.4. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –100.9 (d, J = 243.0 Hz), –106.3 (d, J = 255.7 Hz). LC–MS (positive mode): m/z = 256 [M – HCl + H]⁺.
• 30 Debenzylation Protocol A3 10% Pd on carbon (0.1g for 1 g of 16) was added to the solution of a compound 16 in MeOH–H₂O (2:1, 10 mL of mixture for 1g of 16), and the mixture was hydrogenated at room temperature and atmospheric pressure until the reaction was completed (check by NMR). The catalyst was filtered off, and the filtrate was evaporated dry. The crude product was washed by MTBE–acetone mixture affording the desired compounds 11, which were then treated by a saturated solution of HCl in dioxane and isolated in pure form as hydrochloride; mp (11a·HCl) 185 °C; mp (11b·HCl) 188 °C. Representative Examples 4,4-Difluoropiperidine-3-carboxylic Acid Hydrochloride (11a·HCl) ¹H NMR (400 MHz, D₂O): δ = 3.56–3.18 (m, 5 H), 2.48–2.12 (m, 2 H); NH, OH not observed due to exchange. ¹³C NMR (151 MHz, D₂O): δ = 170.2, 118.2 (t, J = 247.6 Hz), 45.4 (t, J = 23.8 Hz), 42.7, 41.0, 29.7 (t, J = 25.3 Hz). ¹⁹F NMR (376 MHz, D₂O): δ = –98.9 (d, J = 244.7 Hz), –106.7 (d, J = 247.6 Hz). LC–MS (positive mode): m/z = 166 [M – HCl + H]⁺. 3,3-Difluoropiperidine-4-carboxylic Acid Hydrochloride (11b·HCl) ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.56 (br, 3 H), 3.64 (dt, J = 17.1, 9.3 Hz, 1 H), 3.47 (dd, J = 27.4, 12.9 Hz, 1 H), 3.38–3.22 (m, 1 H), 3.18 (d, J = 12.6 Hz, 1 H), 3.01 (t, J = 12.1 Hz, 1 H), 2.12 (d, J = 14.9 Hz, 1 H), 1.99 (q, J = 12.4, 11.9 Hz, 1 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 169.4, 118.3 (t, J = 247.4 Hz), 46.2 (dd, J = 36.1, 28.6 Hz), 45.2 (t, J = 21.1 Hz), 41.0, 22.9 (d, J = 5.2 Hz). ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –101.4 (d, J = 251.5 Hz), –108.0 (d, J = 251.9 Hz). LC–MS (positive mode): m/z = 166 [M – HCl + H]⁺.
• 31 Boc-Protection Protocol A4 The Boc₂O (1.2 equiv) was added to the stirred mixture of compound 11 (1 equiv), NaHCO₃ (3.5 equiv) in THF–H₂O (1:1, 10 mL of mixture for 1g of 11). The resulting suspension was stirred at room temperature overnight. The THF was distilled at rotor evaporator (20 mmHg, 40 °C). The suspension formed was filtered, and the mother liquor was extracted with MTBE. The water phase was acidified with citric acid, the product was extracted with EtOAc. The combined extracts were dried with Na₂SO₄ and evaporated to give the desired Boc-protected product 18; mp (18a) 185 °C; mp (18b) 188 °C. Representative Examples 4,4-Difluoropiperidine-3-carboxylic Acid Hydrochloride (11a·HCl) 1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-3-carboxylic acid (18a) ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 12.95 (s, 1 H), 3.86–3.41 (m, 4 H), 3.05–2.90 (m, 1 H), 2.36–2.17 (m, 1 H), 1.91 (q, J = 9.8, 6.1 Hz, 1 H), 1.39 (s, 9 H). ¹³C NMR (126 MHz, DMSO-d ₆ ): δ = 169.5, 153.8, 125.5–117.2 (m), 79.9, 47.6, 44.0, 43.2, 32.1, 28.3. ¹⁹F NMR (376 MHz, DMSO-d₆ ): δ = 95.9 (dm, J = 238.8 Hz), –100.1 (dm, J = 242.1 Hz), –103.3 (dm, J = 245.8 Hz). LCMS, negative mode, m/z: 264 [M–H]^–. 1-(tert-butoxycarbonyl)-3,3-difluoropiperidine-4-carboxylic acid (18b) ¹H NMR (400 MHz, DMSO-d₆ ): δ = 12.86 (s, 1 H), 4.02 (s, 1 H), 3.77 (d, J = 13.8 Hz, 1 H), 3.45–3.37 (m, 1 H), 3.18–2.98 (m, 2 H), 1.89 (dt, J = 13.6, 4.1 Hz, 1 H), 1.80–1.66 (m, 1 H), 1.40 (s, 9 H). ¹³C NMR (126 MHz, chloroform-d): δ = 170.2 (d, J = 2.4 Hz), 154.2, 119.1 (t, J = 249.7 Hz), 80.1, 49.2, 48.2, 46.8 (t, J = 21.5 Hz), 28.4, 25.7. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –103.3 (dd, J = 239.2, 172.0 Hz), -112.5 (dd, J = 239.6, 101.1 Hz). LCMS, negative mode, m/z: 264 [M–H]^–.
• 32 Debenzylation Protocol D2 10% Pd on carbon (0.1g for 1 g of 14c) was added to the solution of compound 14c (as hydrochloride) in EtOH (10 mL for 1g of 14c), and the mixture was hydrogenated at room temperature and atmospheric pressure until the consumption of hydrogen ceased. The catalyst was filtered off, and the filtrate was evaporated and dried. The crude product was washed by MTBE affording the desired compound 15c. Then crude compound 15c was treated by a saturated solution of HCl in dioxane and isolated in pure form as hydrochloride; mp (15c·HCl) 95 °C. Representative Example Ethyl 3,3-Difluoropyrrolidine-2-carboxylate Hydrochloride (15c·HCl) ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.76 (s, 2 H), 4.94 (dd, J = 17.4, 9.2 Hz, 1 H), 4.44–4.19 (m, 2 H), 3.55–3.36 (m, 2 H), 2.78–2.52 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 163.3 (d, J = 2.7 Hz), 126.9 (dd, J = 257.5, 250.4 Hz), 63.4, 62.7 (dd, J = 33.1, 28.7 Hz), 42.3 (d, J = 5.8 Hz), 33.4 (t, J = 24.1 Hz), 14.3. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –98.3 (d, J = 234.8 Hz), –100.7 (d, J = 234.8 Hz). LC–MS (positive mode): m/z = 180 [M – HCl + H]⁺.
• 33 Bogolubsky AV, Ryabukhin SV, Stetsenko SV, Chupryna AA, Volochnyuk DM, Tolmachev AA. J. Comb. Chem. 2007; 9: 661
• 34 TFA-Deprotection Protocol E2 A solution of 20d (1 equiv) in 1 M HCl in EtOH (prepared from AcCl (4 equiv) and EtOH) was stirred at 40 °C for 4 h. The solution was evaporated dry, and the crude product was washed by MTBE affording the desired compound 15d. Then crude compound 15d was treated by a saturated solution of HCl in dioxane and isolated in pure form as hydrochloride; mp (15d·HCl) 116 °C. Representative Example Ethyl 4,4-Difluoro-pyrrolidine-3-carboxylate Hydrochloride (15d·HCl) ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.40 (s, 2 H), 4.28–4.11 (m, 2 H), 4.00–3.83 (m, 1 H), 3.84–3.66 (m, 3 H), 3.55 (dd, J = 12.1, 10.1 Hz, 1 H), 1.22 (t, J = 7.1 Hz, 3 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 165.6, 126.2 (t, J = 253.2 Hz), 62.2, 50.4 (t, J = 32.5 Hz), 49.0 (t, J = 22.8 Hz), 44.8, 14.4. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –102.3. LC–MS (positive mode): m/z = 180 [M – HCl + H]⁺.
• 35 Hydrolysis Protocol F2 A mixture of nitrile 22j (1 mol) and conc sulfuric acid (3 mL per 1 g of nitrile) was heated to 90 °C and stirred for 1 h, diluted with water (10 mL per 1 g of nitrile), and boiled overnight. After cooling, the product was extracted with dichloromethane, the extracts were dried, evaporated, and distilled; bp (10j) 91–92 °C/0.3 mmHg. Representative Example 3,3-Difluoro-2-phenylbutanoic Acid (10j) ¹H NMR (400 MHz, CDCl₃): δ = 10.56 (br, 1 H), 7.43 (dd, J = 6.7, 3.0 Hz, 2 H), 7.37 (d, J = 3.6 Hz, 3 H), 4.15 (t, J = 12.2 Hz, 1 H), 1.65 (t, J = 19.0 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 174.5 (d, J = 7.0 Hz), 131.4 (t, J = 3.5 Hz), 129.5, 128.8, 128.7, 122.04 (t, J = 244.6 Hz), 58.4 (t, J = 26.9 Hz), 21.6 (t, J = 26.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –89.7 (d, J = 248.0 Hz), –92.4 (d, J = 248.0 Hz). LCMS (negative mode): m/z = 199 [M – H]^–.