Efficient Synthesis of 3-Alkoxy-4,4-difluoropiperidines

Abstract

Fluorinated piperidines bearing an additional functional group at the heterocyclic ring are important building blocks for use in agrochemical or pharmaceutical chemistry. Therefore, for the first time 3-alkoxy-4,4-difluoropiperidines were synthesized by deoxofluorination of 3-alkoxy-4-piperidinones with morpholinosulfur trifluoride and were selectively N- and O-deprotected. In ­addition, the oxidation of 4,4-difluoro-3-hydroxy-1-trifluoroacetylpiperidine resulted in the interesting 4,4-difluoro-3,3-dihydroxypiperidine.

piperidines - fluorine - ketones - deoxofluorination - ­4,4-difluoropiperidines

References and Notes

1

Aspirant of the Research Foundation - Flanders (FWO-Vlaanderen).

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13

3-Benzyloxy-4,4-difluoro-1-(trifluoroacetyl)piperidine (9a)
In a 25 mL flask, 3-benzyloxy-1-(trifluoroacetyl)-4-piperidinone (8a, 0.30 g, 1.00 mmol) was dissolved in anhyd CH₂Cl₂ (10 mL). The solution was cooled to -78 ˚C under nitrogen atmosphere and morpholinosulfur trifluoride (Morph-DAST; 0.53 g, 3.00 mmol, 3 equiv, 0.37 mL) was added dropwise. The reaction mixture was allowed to warm to r.t. over 1 h and was stirred for 2 h at the same temperature. The mixture was poured in CH₂Cl₂ (10 mL) and H₂O (10 mL). The separated aqueous phase was extracted twice with CH₂Cl₂ (10 mL), and the combined organic phases were dried over MgSO₄. After filtration, the solvent was evaporated in vacuo, and the concentrate was purified via flash chromatography over silica gel (hexane-EtOAc = 83:17, R _f  = 0.29) yielding 0.24 g of piperidine 9a (0.73 mmol, 73%). Ratio of rotamers = 3:2; colorless oil. ^¹H NMR (300 MHz, CDCl₃): δ_major = 1.88-2.05 (1 H, m, NCH₂CH _aH_b), 2.17-2.43 (1 H, m, NCH₂CH_a H _b), 3.21 (1 H, br d, J = 14.9 Hz, NCH _aH_bCH), 3.37 (1 H, ddd, J = 14.5, 11.4, 3.2 Hz, NCH _aH_bCH₂), 3.55-3.73 (1 H, m, OCH), 3.80-3.93 (1 H, m, NCH_a H _bCH₂), 4.44-4.53 (1 H, m, NCH_a H _bCH), 4.63 (1 H, d, J = 11.8 Hz, CH _aH_bPh), 4.71 (1 H, d, J = 11.8 Hz, CH_a H _bPh), 7.21-7.44 (5 H, m, 5 × CH_ar); δ_minor = 1.88-2.05 (1 H, m, NCH₂CH _aH_b), 2.17-2.43 (1 H, m, NCH₂CH_a H _b), 3.27 (1 H, ddd, J = 14.0, 10.5, 3.4 Hz, NCH _aH_bCH₂), 3.48 (1 H, br d, J = 14.3 Hz, NCH _aH_bCH), 3.55-3.73 (1 H, m, OCH), 3.80-3.93 (1 H, m, NCH_a H _bCH), 4.10-4.21 (1 H, m, NCH_a H _bCH₂), 4.64 (1 H, d, J = 11.6 Hz, CH _aH_bPh), 4.74 (1 H, d, J = 11.6 Hz, CH_a H _bPh), 7.21-7.44 (5 H, m, 5 × CH_ar). ^¹9F NMR (282 MHz, CDCl₃): δ = -67.8 and -68.8 (3 F, s, CF₃), -107.4 (1 F, dd, J = 247.6, 24.3 Hz, CF _aF_b,_rotamer1), -107.6 (1 F, br d, J = 247.6 Hz, CF _aF_b,_rotamer2), -108.5 (1 F, br d, J = 247.6 Hz, CF_a F _b,_rotamer1), -109.2 (1 F, br d, J = 247.6 Hz, CF_a F _b,_rotamer2). ^¹³C NMR (75 MHz, CDCl₃): δ = 30.3 and 31.1 (t, J = 22.8 Hz), 40.1 and 42.3, 44.1 and 47.0, 72.5 and 73.4, 73.1 and 73.5 (t, J = 20.5 Hz), 116.5 (q, J = 288.2 Hz), 120.0 (t, J = 246.9 Hz) and 120.6 (dd, J = 250.4, 244.6 Hz), 128.0, 128.1, 128.2, 128.4, 128.7, 136.9 and 137.1, 156.4 and 156.5 (q, J = 36.2 Hz). IR (NaCl): ν = 1699, 1203, 1116 cm^-¹. GC-MS (EI): m/z (%) = 323 (22) [M⁺], 107 (71) [C₇H₉O⁺], 91 (100) [C₇H₇ ⁺]. Anal. Calcd: C, 52.02; H, 4.37; N, 4.33. Found: C, 51.76; H, 4.11; N, 4.01.

14

3-Benzyloxy-4,4-difluoropiperidine (10) In a 25 mL flask, 3-benzyloxy-4,4-difluoro-1-(trifluoro- acetyl)piperidine (9a, 0.50 g, 1.55 mmol) was dissolved in MeOH (6 mL). A solution of K₂CO₃ (0.64 g, 4.64 mmol, 3 equiv) in H₂O (3 mL) was added, and the mixture was stirred for 12 h at r.t. After completion of the reaction, the solvent was evaporated in vacuo, and the residue was dissolved in CH₂Cl₂ (20 mL) and H₂O (20 mL). The separated aqueous phase was extracted twice with CH₂Cl₂ (20 mL) and the combined organic phases dried over MgSO₄. After filtration, the solvent was evaporated in vacuo, yielding 0.35 g of piperidine 10 (1.55 mmol, 100%, purity >92%). For analytical purposes a 50 mg sample of the compound was subjected to an acid-base extraction (30% yield), excluding the necessity of flash chromatography to yield pure compound 10 as a yellow oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.48-1.72 (1 H, br s, NH), 1.87 (1 H, dddt, J = 24.7, 13.0, 4.0, 1.3 Hz, CH _aH_b), 2.12 (1 H, dddd, J = 35.4, 13.0, 10.2, 5.0 Hz, CH_a H _b), 2.73-2.91 (2 H, m, NCH ₂CH₂), 2.91-3.10 (2 H, m, NCH ₂CH), 3.45-3.54 (1 H, m, OCH), 4.63 (1 H, d, J = 11.8 Hz, OCH _aH_b), 4.80 (1 H, d, J = 11.8 Hz, OCH_a H _b), 7.27-7.38 (5 H, m, 5 × CH_ar). ^¹9F NMR (282 MHz, CDCl₃): δ = -104.9 (1 F, br s),-105.7 (1 F, br s). ^¹³C NMR (75 MHz, CDCl₃): δ = 32.5 (t, J = 20.8 Hz), 42.8 (t, J = 4.0 Hz), 48.4 (t, J = 2.3 Hz), 72.8, 74.7 (t, J = 24.8 Hz), 121.6 (t, J = 247.5 Hz), 127.8, 127.9, 128.4, 137.7. IR (ATR): ν = 3324, 3032, 2930, 1454, 1351, 1200, 1111, 967, 737, 698 cm^-¹. MS (ES⁺): m/z (%) = 228 (100) [M + H⁺]. Anal. Calcd: C, 63.42; H, 6.65; N, 6.13. Found: C, 63.08; H, 6.01; N, 5.95.

15

4,4-Difluoro-3-hydroxy-1-(trifluoroacetyl)piperidine (11) In a dry pressure vessel, 3-benzyloxy-4,4-difluoro-1-(trifluoroacetyl)piperidine (9a, 1.10 g, 3.40 mmol) was dissolved in EtOAc (10 mL). After adding 10% Pd/C (0.22 g) at 0 ˚C, the mixture was stirred during 15 h at r.t. under hydrogen pressure of 4.75 bar. The mixture was filtered over Celite^®, and the filtrate was evaporated in vacuo to yield 0.75 g of pure piperidine 11 (3.20 mmol, 94%). Ratio of rotamers = 53:47; yellow oil. ^¹H NMR (300 MHz, CDCl₃): δ_major = 1.93-2.11 (1 H, m, NCH₂CH _aH_b), 2.18-2.48 (1 H, m, NCH₂CH_a H _b), 2.60-3.10 (1 H, br s, OH), 3.47 (1 H, d × m, J = 13.8 Hz, NCH _aH_bCH), 3.46-3.54 (1 H, m, NCH _aH_bCH₂), 3.81-3.95 (1 H, m, NCH_a H _bCH₂), 3.97-4.05 (1 H, m, OCH), 4.28 (1 H, d × m, J = 13.8 Hz, NCH_a H _bCH); δ_minor = 1.93-2.11 (1 H, m, NCH₂CH _aH_b), 2.18-2.48 (1 H, m, NCH₂CH_a H _b), 2.60-3.10 (1 H, br s, OH), 3.41 (1 H, ddd, J = 13.8, 10.0, 3.7 Hz, NCH _aH_bCH₂), 3.65 (1 H, d, J =
13.8 Hz, NCH _aH_bCH), 3.81-3.95 (2 H, m, OCH and NCH_a H _bCH), 4.14 (1 H, dt, J = 13.8, 4.8 Hz, NCH_a H _bCH₂). ^¹9F NMR (282 MHz, CDCl₃): δ = -67.8 and -68.9 (3 F, s, CF₃), -110.1 (1 F, dd, J = 246.0, 21.1 Hz, CF _aF_b,_rotamer1),
-110.4 (1 F, dd, J = 246.0, 23.7 Hz, CF _aF_b,_rotamer2), -111.2 (1 F, br d, J = 246.0 Hz, CF_a F _b,_rotamer1), -111.6 (1 F, br d, J = 246.0 Hz, CF_a F _b,_rotamer2). ^¹³C NMR (75 MHz, CDCl₃):
δ = 29.7 and 30.7 (t, J = 23.1 Hz), 40.2 (t, J = 5.2 Hz), 42.3 (d, J = 3.5 Hz), 46.3 (t, J = 3.5 Hz), 47.9 (d, J = 2.3 Hz), 67.5 (t, J = 26.5 Hz), 67.7 (t, J = 27.1 Hz), 116.3 (q, J = 287.7 Hz), 119.9 and 120.1 (t, J = 246.3 Hz), 156.7 (q, J = 36.5 Hz). IR (ATR): ν = 3444, 1683, 1464, 1185, 1111, 967
cm^-¹. MS (ES⁺): m/z (%) = 251 (100) [M + NH₄ ⁺]. Anal. Calcd: C, 36.06; H, 3.46; N, 6.01. Found: C, 35.79; H, 3.09; N, 5.88.

16

4,4-Difluoro-3,3-dihydroxy-1-(trifluoroacetyl)piper-idine (14)
In a 10 mL flask, 4,4-difluoro-3-hydroxy-1-(trifluoro-acetyl)piperidine (11, 0.10 g 0.43 mmol) was dissolved in anhyd CH₂Cl₂ (5 mL). After adding Dess-Martin periodinane (0.36 g, 0.86 mmol, 2.0 equiv), the solution was stirred for 15 h at r.t. The mixture was diluted with Et₂O (30 mL), and the organic phase was washed three times with a sat. aq NaHCO₃ solution (20 mL). The organic phase was dried over MgSO₄, and after filtration the solvent was evaporated in vacuo. The concentrate was dissolved in Et₂O (5 mL) and cooled to -40 ˚C to crystallize residues of the Dess-Martin periodinane reagent. After filtration of the solids, the filtrate was evaporated in vacuo to yield 0.06 g of piperidine 14 (0.26 mmol, 60%). Ratio of rotamers = 2:1; colorless oil. ^¹H NMR (300 MHz, CDCl₃): δ_major = 2.11-2.31 (2 H, m, NCH₂CH ₂), 3.71 (2 H, t, J = 6.1 Hz, NCH ₂CH₂), 3.83 [2 H, s, NCH ₂C(OH)₂], 5.52 (2 H, br s, 2 × OH);
δ_minor = 2.11-2.31 (2 H, m, NCH₂CH ₂), 3.67 [2 H, s, NCH ₂C(OH)₂], 3.78 (2 H, t, J = 6.1 Hz, NCH ₂CH₂), 5.52 (2 H, br s, 2 × OH). ^¹9F NMR (282 MHz, CDCl₃): δ = -67.2 and -68.9 (3 F, s, CF₃), -119.6 (2 F, t, J = 13.2 Hz, CF₂,_rotamer1), -119.7 (2 F, t, J = 13.2 Hz, CF₂,_rotamer2). ^¹³C NMR (75 MHz, CDCl₃): δ_major = 31.6 and 30.2 (t, J = 23.1 Hz), 40.2 (t, J = 4.6 Hz), 42.6 (m), 49.9 and 51.6, 90.8 and 91.5 (t, J = 24.2 Hz), 116.3 and 116.3 (q, J = 287.3 Hz), 118.7 and 119.0 (t, J = 250.9 Hz), 156.6 and 156.8 (q, J = 36.5 Hz). IR (ATR,): ν = 3410, 1685, 1461, 1187, 1112, 964 cm^-¹. MS (ES⁺): m/z (%) = 267 (100)[M + NH₄ ⁺]. Anal. Calcd: C, 33.75; H, 3.24; N, 5.62. Found: C, 33.41; H, 3.49; N, 5.43.

17 Bégué J.-P. Bonnet-Delpon D. Tetrahedron  1991,  47:  3207