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

<A NAME="RG09409ST-1">1</A>

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

<A NAME="RG09409ST-2A">2a</A> O’Hagan D. Chem. Soc. Rev.  2008,  37:  308 

<A NAME="RG09409ST-2B">2b</A> Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev.  2008,  37:  320 

<A NAME="RG09409ST-2C">2c</A> Kirk KL. Org. Process Res. Dev.  2008,  12:  305 

<A NAME="RG09409ST-2D">2d</A> Müller K. Faeh C. Diederich F. Science  2007,  317:  1881 

<A NAME="RG09409ST-2E">2e</A> Isanbor C. O’Hagan D. J. Fluorine Chem.  2006,  127:  303 

<A NAME="RG09409ST-2F">2f</A> Bégué J.-P. Bonnet-Delpon D. J. Fluorine Chem.  2006,  127:  992 

<A NAME="RG09409ST-2G">2g</A> Kirk KL. J. Fluorine Chem.  2006,  127:  1013 

<A NAME="RG09409ST-3">3</A> De Matteis V. van Delft FL. Tiebes J. Rutjes FP. Eur. J. Org. Chem.  2006,  1166 

<A NAME="RG09409ST-4">4</A> Verniest G. Surmont R. Van Hende E. Deweweire A. Deroose F. Thuring JW. De Kimpe N. J. Org. Chem.  2008,  73:  5458 

<A NAME="RG09409ST-5">5</A> Allen JG, Krasutsky AP, Wallace OB, Xu Y, and York JS. inventors; WO  2007127693.  ; Chem. Abstr. 2007, 147, 522085

<A NAME="RG09409ST-6">6</A> Tai VW.-F. Sperandio D. Shelton EJ. Litvak J. Pararajasingham K. Cebon B. Lohman J. Eksterowicz J. Kantak S. Sabbatini P. Brown C. Zeitz J. Reed C. Maske B. Graupe D. Estevez A. Oeh J. Wong D. Ni Y. Sprengeler P. Yee R. Magill C. Neri A. Cai SX. Drewe J. Qiu L. Herich J. Tseng B. Kasibhatla S. Spencer JR. Bioorg. Med. Chem. Lett.  2006,  16:  4554 

<A NAME="RG09409ST-7">7</A> Norman MH, Pettus LH, Wang X, and Zhu J. inventors; US  2006058308.  ; Chem. Abstr. 2006, 144, 312100

<A NAME="RG09409ST-8">8</A> Micheli F. Pasquarello A. Tedesco G. Hamprecht D. Bonanomi G. Checchia A. Jaxa-Chamiec A. Damiani F. Davalli S. Donati D. Gallotti C. Petrone M. Rinaldi M. Riley G. Terreni S. Wood M. Bioorg. Med. Chem. Lett.  2006,  16:  3906 

<A NAME="RG09409ST-9A">9a</A> Berlin M. Ting PC. Vaccaro WD. Aslanian R. McCormick KD. Lee JF. Albanese MM. Mutahi MW. Piwinski JJ. Shih N.-Y. Duguma L. Solomon DM. Zhou W. Sher R. Favreau L. Bryant M. Korfmacher WA. Nardo C. West RE. Anthes JC. Williams SM. Wu R.-L. She HS. Rivelli MA. Corboz MR. Hey JA. Bioorg. Med. Chem. Lett.  2006,  16:  989 

<A NAME="RG09409ST-9B">9b</A> Davey D, Lee W, Lu S.-F, Phillips G, Wei GP, and Ye B. inventors; US  2005101644.  ; Chem. Abstr. 2005, 142, 463444

<A NAME="RG09409ST-9C">9c</A> Deshpande PK, Sindkhedkar MD, Phansalkar MS, Yeole RD, Gupte SV, Chugh Y, Shetty N, Bhagwat SS, De Souza NJ, and Patel MV. inventors; WO  2005054234.  ; Chem. Abstr. 2005, 143, 59964

<A NAME="RG09409ST-9D">9d</A> Blizzard TA. DiNinno F. Morgan JD. Wu JY. Chen HY. Kim S. Chan W. Birzin ET. Yang YT. Pai L.-Y. Zhang Z. Hayes EC. DaSilva CA. Tang W. Rohrer SP. Schaeffer JM. Hammond ML. Bioorg. Med. Chem. Lett.  2004,  14:  3865 

<A NAME="RG09409ST-10A">10a</A> Fatheree P, Gendron R, Goldblum AA, Long DD, Marquess D, Turner SD, and Choi S.-K. inventors; US  2006135764.  ; Chem. Abstr. 2006, 145, 83322

<A NAME="RG09409ST-10B">10b</A> John V, Moon JB, Pulley SR, Rich DH, Brown DL, Jagodzinska B, and Jacobs JS. inventors; WO  2003043987.  ; Chem. Abstr. 2003, 139, 6887

<A NAME="RG09409ST-10C">10c</A> Stanton MG, Munoz B, Sloman DL, Hubbs J, and Hamblett C. inventors; WO  2008030391.  ; Chem. Abstr. 2008, 148, 331574

<A NAME="RG09409ST-10D">10d</A> Burger M, Lindvall M, Han W, Lan J, Nishiguchi G, Shafer C, Bellamacina C, Huh K, Atallah G, McBride C, Antonios-McCrea W, Zavorotinskaya T, Walter A, and Garcia P. inventors; WO  2008106692.  ; Chem. Abstr. 2008, 149, 332352

<A NAME="RG09409ST-11">11</A> Zacuto MJ. Caia D. Tetrahedron Lett.  2005,  46:  447 

<A NAME="RG09409ST-12">12</A> Lal GS. Pez GP. Pesaresi RJ. Prozonic FM. Chem. Commun.  1999,  215 

<A NAME="RG09409ST-13">13</A>

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.

<A NAME="RG09409ST-14">14</A>

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.

<A NAME="RG09409ST-15">15</A>

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.

<A NAME="RG09409ST-16">16</A>

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.

<A NAME="RG09409ST-17">17</A> Bégué J.-P. Bonnet-Delpon D. Tetrahedron  1991,  47:  3207