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Synlett 2006(7): 1015-1020  
DOI: 10.1055/s-2006-939079
LETTER
© Georg Thieme Verlag Stuttgart · New York

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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Publikationsverlauf

Received 13 February 2006
Publikationsdatum:
24. April 2006 (online)

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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

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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.

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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.

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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.