Synthesis of Precursors of gem-Difluorodiols and Amino Alcohols Using Electrochemical and Photochemical Reactions

Satoru Murakami; Toshio Fuchigami

doi:10.1055/s-2006-939079

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Synlett 2006(7): 1015-1020
DOI: 10.1055/s-2006-939079

LETTER

Synthesis of Precursors of gem-Difluorodiols and Amino Alcohols Using Electrochemical and Photochemical Reactions

Satoru Murakami, Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502 Japan
Fax: +81(45)9245406; e-Mail: fuchi@echem.titech.ac.jp;

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Publication History

Received 13 February 2006
Publication Date:
24 April 2006 (online)

Abstract
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Abstract

Photo-initiated S-CF₂ bond cleavage of electrochemically prepared 4-[difluoro(phenylthio)methyl]-1,3-dioxolanone and 4-[difluoro(phenylthio)methyl]-1,3-oxazolidinone in the presence of olefins provided the corresponding radical addition products, while the photolysis in the presence of aromatics and heteroaromatics provided radical substitution products in moderate yields.

Key words

radical addition - radical aromatic substitution - photoreaction - difluoromethyl radical - sulfide

References and Notes

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Typical Procedure for Photochemical Reaction. A solution of 2 or 11 (0.17 mmol) and olefin (3.40 mmol) in CH₂Cl₂ (40 mL) or aromatic compounds (40 mL) without any solvents was bubbled with Ar at r.t. for 0.5 h and then photolyzed for 2 h or 4 h with 6-W low-pressure mercury-vapor lamp. The reaction was conducted using a quartz vessel inside the light source. After the photolysis, the resulting solution was evaporated under vacuum and the residue was purified by preparative thin-layer chromato-graphy (MERCK Silica gel 60 GF₂₅₄, 33% or 50% EtOAc in hexane) and by HPLC (Develosil ODS-5, MeCN as eluent) to provide pure products.

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(a) 4-[Difluoro-(3-tetrahydrofuryl)methyl]-1,3-dioxolan-2-one ( 4): ¹H NMR (270 MHz, CDCl₃): δ = 4.86-4.54 (m, 3 H), 4.02-3.74 (m, 4 H), 3.09-2.83 (m, 1 H), 2.20-1.89 (m, 2 H). ¹⁹F NMR (254 MHz, CDCl₃): δ = -41.91 to -44.34 (m, 2 F). MS: m/z = 207 [M⁺ - H], 189 [M⁺ - F], 87 [M⁺ - F₂C - C₄H₇O].
(b) 4-[(3- tert -Butoxy-1,1-difluoro)propyl]-1,3-dioxolan-2-one ( 5): ¹H NMR (270 MHz, CDCl₃): δ = 5.10-4.97 (m, 1 H), 4.59-4.48 (m, 2 H), 3.55 (t, 2 H, J = 5.8 Hz), 2.44-2.09 (m, 2 H), 1.19 (s, 9H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 153.82, 120.56 (dd, J = 247.0, 243.1 Hz), 74.89 (dd, J = 34.7, 26.3 Hz), 73.63, 64.26 (dd, J = 5.0, 2.8 Hz), 54.76 (t, J = 6.7 Hz), 34.54 (dd, J = 23.5, 22.9 Hz), 27.41. ¹⁹F NMR (254 MHz, CDCl₃): δ = -33.90 to -35.17 (m, 1 F), -36.78 to -37.93 (m, 1 F). FAB-MS: m/z = 239 [M⁺ + H]. FAB-HRMS: m/z calcd for C₁₀H₁₇F₂O₄: 239.1095; found: 239.1091.
(c) 4-[(Cyclohexyl)difluoromethyl]-1,3-dioxolan-2-one ( 6): ¹H NMR (270 MHz, CDCl₃): δ = 4.92-4.78 (m, 1 H), 4.69-4.50 (m, 2 H), 2.01-1.74 (m, 6 H), 1.31-1.24 (m, 5 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 153.61, 121.25 (dd, J = 249.8, 243.7 Hz), 72.36 (dd, J = 41.4, 28.5 Hz), 64.02 (dd, J = 5.6, 3.9 Hz), 40.80 (t, J = 21.8 Hz), 25.76 (dd, J = 5.6, 2.8 Hz), 25.69, 25.46 (d, J = 1.1 Hz), 25.29, 24.04 (dd, J = 4.5, 3.9 Hz). ¹⁹F NMR (254 MHz, CDCl₃): δ =
-54.11 (ddd, 1 F, J = 303.3, 53.6, 3.7 Hz), -59.75 (ddd, 1 F, J = 303.3, 55.5, 16.6 Hz). FAB-MS: m/z = 221 [M⁺ + H]. FAB-HRMS: m/z calcd for C₁₀H₁₅F₂O₃: 221.0989; found: 221.0986.
(d) 4-(1,1-Difluorooctyl)-1,3-dioxolan-2-one ( 7): ¹H NMR (270 MHz, CDCl₃): δ = 4.80-4.51 (m, 3 H), 2.18-1.81 (m, 2 H), 1.60-1.48 (m, 2 H), 1.39-1.23 (m, 8 H), 0.89 (t, 3 H, J = 7.1 Hz). ¹³C NMR (67.8 MHz, CDCl₃): δ = 153.49, 120.72 (dd, J = 249.3, 241.5 Hz), 74.16 (dd, J = 40.8, 27.9 Hz), 63.96 (dd, J = 5.0, 3.4 Hz), 33.11 (dd, J = 23.5, 22.4 Hz), 31.65, 29.18, 28.98, 22.65, 21.25 (dd, J = 5.6, 2.8 Hz), 14.41. ¹⁹F NMR (254 MHz, CDCl₃): δ = -35.57 to -36.76 (m, 1 F), -40.22 to -41.43 (m, 1 F). MS: m/z = 236 [M⁺], 149. HRMS: m/z calcd for C₁₁H₁₈F₂O₃: 236.1224; found: 236.1232.
(e) 4-[Difluoro(phenyl)methyl]-1,3-dioxlan-2-one ( 8): ¹H NMR (270 MHz, CDCl₃): δ = 7.56-7.45 (m, 5 H), 5.04-4.92 (m, 1 H), 4.68-4.43 (m, 2 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 153.32, 131.36 (dd, J = 25.2, 24.6 Hz), 131.21 (dd, J = 2.2, 1.7 Hz), 128.83, 125.59 (t, J = 6.1 Hz), 118.15 (dd, J = 249.3, 244.3 Hz), 75.88 (dd, J = 39.7, 32.4 Hz), 64.21 (t, J = 3.3 Hz). ¹⁹F NMR (254 MHz, CDCl₃): δ =
-30.95 (dd, 1 F, J = 262.6, 5.5 Hz), -37.90 (dd, 1 F, J = 262.6, 12.9 Hz). MS: m/z = 214 [M⁺], 127. HRMS: m/z calcd for C₁₀H₈F₂O₃: 214.0442; found: 214.0443.
(f) 4-[Difluoro(2-furyl)methyl]-1,3-dioxolan-2-one ( 9): ¹H NMR (270 MHz, CDCl₃): δ = 7.55-7.54 (m, 1 H), 6.83-6.81 (m, 1 H), 6.51-6.50 (m, 1 H), 5.23-5.11 (m, 1 H), 4.72-4.56 (m, 2 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 153.24, 144.97 (dd, J = 2.2, 1.7 Hz), 143.58 (dd, J = 37.4, 33.0 Hz), 113.82 (dd, J = 243.7, 240.3 Hz), 112.33 (dd, J = 3.4, 2.8 Hz), 111.00 (t, J = 1.1 Hz), 74.21 (dd, J = 37.4, 29.6 Hz), 63.94 (t, J = 3.4 Hz). ¹⁹F NMR (254 MHz, CDCl₃): δ =
-28.80 (dd, 1 F, J = 280.0, 5.5 Hz), -38.17 (dd, 1 F, J = 280.0, 11.1 Hz). MS: m/z = 204 [M⁺], 117. HRMS:
m/z calcd for C₈H₆F₂O₄: 204.0234; found: 204.0237.

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(a) 5-[Difluoro(3-tetrahydrofuryl)methyl]-3-methyl-oxazolidinone ( 12): ¹H NMR (270 MHz, CDCl₃): δ = 4.67-4.44 (m, 1 H), 4.01-3.63 (m, 6 H), 3.18-2.92 (m, 4 H), 2.22-1.87 (m, 2 H). ¹⁹F NMR (254 MHz, CDCl₃): δ = -43.16 (ddd, 1 F, J = 262.6, 18.5, 12.9 Hz), -44.43 (ddd, 1 F, J = 262.4, 20.2, 3.7 Hz). MS: m/z = 222 [M⁺ + H]. FAB-HRMS:
m/z calcd for C₉H₁₄F₂NO₃: 222.0942; found: 222.0945.
(b) 5-[(3- tert- Butoxy-1,1-difluoro)propyl]-3-methyl-oxazol-idinone ( 13): ¹H NMR (270 MHz, CDCl₃): δ = 4.81-4.67 (m, 1 H), 3.64-3.54 (m, 4 H), 2.90 (s, 3 H), 2.44-2.06 (m, 2 H), 1.19 (s, 9 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 156.82, 121.00 (dd, J = 246.5, 244.3 Hz), 73.36, 71.69 (dd, J = 34.1, 30.2 Hz), 54.91 (dd, J = 6.7, 6.1 Hz), 46.10 (dd, J = 4.5, 3.4 Hz), 34.37 (dd, J = 23.5, 22.9 Hz), 30.95, 27.45. ¹⁹F NMR (254 MHz, CDCl₃): δ = -35.48 to -37.81 (m, 2 F).
FAB-MS: m/z 252 [M⁺ + H]. FAB-HRMS: m/z calcd for C₁₁H₂₀F₂NO₃: 252.1411; found: 252.1407.
(c) 5-[(Cyclohexyl)difluoromethyl]-3-methyloxazol-idinone ( 14): ¹H NMR (270 MHz, CDCl₃): δ = 4.73-4.59 (m, 1 H), 3.74-3.58 (m, 2 H), 2.91 (s, 3 H), 2.14-1.62 (m, 6 H), 1.33-1.13 (m, 5 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 156.69, 121.84 (dd, J = 250.1, 244.3 Hz), 69.41 (dd, J = 39.17, 29.1 Hz), 45.79 (dd, J = 5.3, 3.4 Hz), 40.66 (t, J = 21.8 Hz), 30.94, 29.77, 25.95 (dd, J = 6.1, 2.8 Hz), 25.84, 25.43, 24.06 (dd, J = 5.0, 3.9 Hz). ¹⁹F NMR (254 MHz, CDCl₃): δ = -45.35 (ddd, 1 F, J = 258.9, 20.3, 3.7 Hz), -46.72 (ddd, 1 F, J = 258.9, 18.5, 9.2 Hz). MS: m/z = 233 [M⁺], 100. HRMS: m/z calcd for C₁₁H₁₇F₂NO₂: 233.1227; found: 233.1222.
(d) 5-(1,1-Difluorooctyl) - 3-methyloxazolidinone ( 15): ¹H NMR (270 MHz, CDCl₃): δ = 4.60-4.446 (m, 1 H), 3.71-3.60 (m, 2 H), 2.91 (s, 3 H), 2.17-1.84 (m, 2 H), 1.58-1.46 (m, 2 H), 1.37-1.25 (m, 8 H), 0.89 (t, 3 H, J = 6.8 Hz). ¹³C NMR (67.8 MHz, CDCl₃): δ = 156.65, 121.36 (dd, J = 248.2, 239.8 Hz), 71.22 (dd, J = 40.2, 27.9 Hz), 45.81 (dd, J = 4.5, 3.4 Hz), 33.07 (dd, J = 23.5, 22.9 Hz), 31.67, 30.94, 29.25, 29.03, 22.65, 21.36 (dd, J = 5.6, 2.8 Hz), 14.14. ¹⁹F NMR (254 MHz, CDCl₃): δ = -35.55 to -36.72 (m, 1 F), -40.22 to 41.43 (m, 1 F). MS: m/z = 249 [M⁺], 149, 100. HRMS: m/z calcd for C₁₂H₂₁F₂NO₂: 249.1540; found: 249.1539.
(e) 5-[Difluoro(phenyl)methyl]-3-methyloxazolidinone ( 16): ¹H NMR (270 MHz, CDCl₃): δ = 7.55-7.42 (m, 5 H), 4.85-4.73 (m, 1 H), 3.67 (d, 2 H, J = 7.4 Hz), 2.82 (s, 3H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 156.45, 132.20 (dd, J = 25.7, 25.2 Hz), 130.72 (t, J = 1.7 Hz), 128.51, 125.69 (t, J = 6.1 Hz), 118.65 (dd, J = 248.7, 244.3 Hz), 72.93 (dd, J = 39.13, 32.42 Hz), 46.32 (t, J = 3.35 Hz), 30.83. ¹⁹F NMR (254 MHz, CDCl₃): δ -30.25 (dd, 1 F, J = 258.9, 5.5 Hz), -38.53 (dd, 1 F, J = 258.9, 14.8 Hz). MS: m/z = 227 [M⁺]. HRMS: m/z calcd for C₁₁H₁₁F₂NO₂: 227.0758; found: 227.0748.
(f) 5-[Difluoro(2-furyl)methyl]-3-methyloxazolidinone ( 17): ¹H NMR (270 MHz, CDCl₃): δ = 7.52-7.49 (m, 1 H), 6.79-6.76 (m, 1 H), 6.48-6.45 (m, 1 H), 5.04-4.91 (m, 1 H), 3.73 (d, 2 H, J = 7.6 Hz), 2.89 (s, 3 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 156.36, 144.31 (dd, J = 2.2, 1.7 Hz), 144.45 (dd, J = 35.8, 33.0 Hz), 114.38 (dd, J = 243.7, 240.3 Hz), 111.78 (dd, J = 3.9, 2.8 Hz), 110.78 (t, J = 1.1 Hz), 71.22 (dd, J = 36.3, 29.6 Hz), 45.97 (t, J = 3.4 Hz), 30.87. ¹⁹F NMR (254 MHz, CDCl₃): δ = -28.77 (dd, 1 F, J = 277.4, 5.5 Hz), -39.12 (dd, 1 F, J = 277.4, 12.9 Hz). MS: m/z = 217 [M⁺], 117, 100. HRMS: m/z calcd for C₉H₉F₂NO₃: 217.0550; found: 217.0551.

20

Electrochemical Difluorination of 5-(Phenylthio)methyl-3-methyloxazolidinone ( 10): Constant current electrolysis (40 mA/cm^-2) of 10 was carried out at platinum electrodes (2 × 2 cm²) at 40 °C in DME-MeCN (5 mL each) containing 0.3 M Et₃N·3HF using undivided cell. After electrolysis, the supporting electrolyte was removed by silica gel short column chromatography. The product 11 was isolated by silica gel column chromato-graphy (EtOAc-hexane, 1:3).
5-[Difluoro(phenylthio)methyl]-3-methyloxazolidinone ( 11): ¹H NMR (270 MHz, CDCl₃): δ = 7.63-7.60 (m, 2 H), 7.49-7.35 (m, 3 H), 4.71-4.57 (m, 1 H), 3.74-3.61 (m, 2 H), 2.88 (s, 3 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 156.09, 138.46 (dd, J = 8.9, 0.6 Hz), 136.34, 130.23, 129.11, 126.41 (dd, J = 282.3, 280.6 Hz), 71.86 (dd, J = 31.9, 27.9 Hz), 46.48 (t, J = 2.8 Hz), 30.67. ¹⁹F NMR (254 MHz, CDCl₃): δ = -11.22 (dd, 1 F, J = 218.2, 9.2 Hz), -12.91 (dd, 1 F, J = 218.2, 9.2 Hz). MS: m/z = 259 [M⁺], 159, 77. HRMS: m/z calcd for C₁₁H₁₁F₂NO₂S: 259.0479; found: 259.0485.

21

3,3-Difluoro-3-phenylpropan-1,2-diol (8′): ¹H NMR (270 MHz, CDCl₃): δ = 7.55-7.45 (m, 5 H), 4.14-4.02 (m, 1 H), 3.78-3.64 (m, 2 H), 3.22-1.93 (br, 2 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 133.98 (t, J = 25.7 Hz), 130.23 (t, J = 1.7 Hz), 128.40, 125.50 (t, J = 6.7 Hz), 120.72 (t, J = 247.0 Hz), 74.23 (dd, J = 30.2, 29.1 Hz), 61.14 (t, J = 3.4 Hz). ¹⁹F NMR (254 MHz, CDCl₃): δ = -29.62 (dd, 1 F, J = 253.4, 9.2 Hz), -32.57 (dd, 1 F, J = 253.4, 12.9 Hz). MS: m/z = 188 [M⁺], 127, 77. HRMS: m/z calcd for C₉H₁₀F₂O₂: 188.0649; found: 188.0652.