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DOI: 10.1055/s-2004-820026
Aromatic Substitution with Photochemically Generated Difluoromethyl Radicals Bearing Electron-Withdrawing Group
Publication History
Publication Date:
04 March 2004 (online)

Abstract
Novel and facile aromatic and heteroaromatic substitutions with difluoromethyl radicals bearing electron-withdrawing group generated by the photo-initiated Se-CF2 bond cleavage of ethyl α,α-difluoro-α-(phenylseleno)acetate and diethyl α,α-difluoromethyl-α-(phenylseleno)phosphonate were successfully carried out to provide the corresponding α-aryl-α,α-difluoroacetates and α-aryl-α,α-difluoromethylphosphonates in good to moderate yields.
Key words
radical aromatic substitution - photoreaction - α-aryl-α,α-difluoroacetate - α-aryl-α,α-difluoromethylphosphonate - selenide
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1a
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14a Ethyl α,α-difluoro-α-(phenyl)acetate (4): See ref.6
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14b
A mixture of ethyl α,α-difluoro-α-(o-, m-, and p-tolyl)acetates (5): 1H NMR: δ = 7.58-7.21 (m, 4 H), 4.32 (q, 0.9 H, J = 7.1 Hz), 4.30 (q, 0.7 H, J = 7.1 Hz), 4.29 (q, 0.4 H, J = 7.1 Hz), 2.42 (s, 1 H), 2.41 (s, 0.7 H), 2.40 (s, 1.3 H), 1.31 (t, 1.3 H, J = 7.1 Hz), 1.30 (t, 1.7 H, J = 7.1 Hz). 19F NMR: δ = -24.8 (s, 2 F), -26.9 (s, 2 F), -27.2 (s, 2 F). MS: m/z = 214 (M+), 141.
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14c
Ethyl α,α-difluoro-α-(o-fluorophenyl)acetate (6): 1H NMR: δ = 7.68-7.62 (m, 1 H), 7.54-7.46 (m, 1 H), 7.29-7.23 (m, 1 H), 7.17-7.10 (m, 1 H), 4.36 (q, 2 H, J = 7.0 Hz), 1.32 (t, 3 H, J = 7.0 Hz). 13C NMR: δ = 163.09 (t, J = 34.0 Hz), 132.93 (d, J = 8.4 Hz), 127.00 (dt, J = 7.3, 2.2 Hz), 124.17 (d, J = 3.4 Hz), 120.84 (dt, J = 25.7, 12.3 Hz), 116.34, 116.03, 115.52 (t, J = 251.0 Hz), 63.36, 13.90. 19F NMR: δ = -25.45 (d, 2 F, J = 5.6 Hz), -37.78-37.93 (m, 1 F). MS: m/z = 218 (M+), 145, 95. HRMS calcd for C10H9F3O2: m/z = 218.0555. Found: 218.0563.
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14d
Ethyl α,α-difluoro-α-(m-fluorophenyl)acetate (6): 1H NMR: δ = 7.48-7.11 (m, 4 H), 4.31 (q, 2 H, J = 7.0 Hz), 1.31 (t, 3 H, J = 7.0 Hz). 13C NMR: δ = 163.55 (t, J = 35.2 Hz), 130.41 (d, J = 8.4 Hz), 121.15 (dt, J = 6.1, 2.8 Hz), 118.22 (t, J = 3.7 Hz), 117.91 (t, J = 3.7 Hz), 115.92 (t, J = 22.4 Hz), 112.96 (dt, J = 24.1, 6.7 Hz), 112.15 (t, J = 252.7 Hz), 63.4, 14.2. 19F NMR: δ = -27.25 (s, 2 F), -34.63-35.54 (m, 1 F). MS: m/z = 218 (M+), 145, 95. HRMS calcd for C10H9F3O2: m/z = 218.0555. Found: 218.0538.
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14e
Ethyl α,α-difluoro-α-(p-fluorophenyl)acetate (6): 1H NMR: δ = 7.63-7.58 (m, 2 H), 7.17-7.11 (m, 2 H), 4.30 (q, 2 H, J = 7.3 Hz), 1.31 (t, 3 H, J = 7.1 Hz). 19F NMR: δ = -26.47 (s, 2 F), -32.41-32.49 (m, 1 F). MS: m/z = 218 (M+), 145, 95. HRMS calcd for C10H9F3O2: m/z = 218.0555. Found: 218.0560.
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14f
Ethyl α,α-difluoro-α-[2-(furyl)]acetate(7): 1H NMR: δ = 7.52 (dd, 1 H, J = 1.65, 0.8 Hz), 6.76 (dd, 1 H, J = 3.3, 0.8 Hz), 6.46 (dd, 1 H, J = 3.3, 1.7 Hz), 4.38 (q, 2 H, J = 7.0 Hz), 1.36 (t, 3 H, J = 7.0 Hz). 13C NMR: δ = 162.25 (t, J = 33.5 Hz), 144.73 (t, J = 2.2 Hz), 131.86, 111.56 (t, J = 3.4 Hz), 110.68 (t, J = 1.1 Hz), 108.59 (t, J = 248.2 Hz), 63.55, 14.00. 19F NMR: δ = -25.95 (s, 2 F). MS: m/z = 190 (M+), 117. HRMS calcd for C8H8F2O3: m/z = 190.0442. Found: 190.0424.
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14g
Ethyl α,α-difluoro-α-[2-(thienyl)]acetate (8): See ref. 3b.
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14h
Ethyl α,α-difluoro-α-[2-(pyrrolyl)]acetate (9): 1H NMR: δ = 9.03-8.55 (br. 1 H), 6.90 (dd, 1 H, J = 2.6, 1.8 Hz), 6.55 (dd, 1 H, J = 3.3, 1.8 Hz), 6.24 (dd, 1 H, J = 3.3, 2.6 Hz), 4.36 (q, 2 H, J = 7.3 Hz), 1.37 (t, 3 H, J = 7.3 Hz). 19F NMR: δ = -21.32 (s, 2 F). MS: m/z = 189 (M+), 116. HRMS calcd for C8H9F2NO2: m/z = 189.0601. Found: 189.0591.
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14i
Ethyl α,α-difluoro-α-[2-(1-methyl-pyrrolyl)]acetate (10):1H NMR: δ = 6.70 (dd, 1 H, J = 2.8, 2.0 Hz), 6.40 (dd, 1 H, J = 3.8, 2.0 Hz), 6.10 (dd, 1 H, J = 3.8, 2.8 Hz), 4.38 (q, 2 H, J = 7.0 Hz), 3.76 (s, 3 H), 1.37 (t, 3 H, J = 7.0 Hz). 13C NMR: δ = 163.28 (t, J = 34.1 Hz), 129.06, 126.98 (t, J = 2.2 Hz), 112.22 (t, J = 5.6 Hz), 111.16 (t, J = 245.9 Hz), 107.29, 63.22, 35.48 (t, J = 3.4 Hz), 14.03. 19F NMR: δ = -19.62 (s, 2 F). MS: m/z = 203 (M+), 130. HRMS calcd for C9H11F2NO2: m/z = 203.0758. Found: 203.0764.
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14j
Ethyl α,α-difluoro-α-[2-(1phenyl-pyrrolyl)]acetate (11):1H NMR: δ = 7.40-7.30 (m, 5 H), 6.90 (dd, 1 H, J = 2.6, 2.0 Hz), 6.60 (dd, 1 H, J = 3.6, 2.0 Hz), 6.30 (dd, 1 H, J = 3.6, 2.6 Hz), 4.13 (q, 2 H, J = 7.3 Hz), 1.21 (t, 3 H, J = 7.3 Hz). 13C NMR: δ = 162.95 (t, J = 34.1 Hz), 139.23, 132.42, 128.73, 128.27, 127.16 (t, J = 2.2 Hz), 126.86 (t, J = 1.6 Hz), 112.90 (t, J = 5.0 Hz), 110.62 (t, J = 245.4 Hz), 108.36, 63.09, 13.87. 19F NMR: δ = -15.65 (s, 2 F). MS: m/z = 265 (M+), 192, 77. HRMS calcd for C14H13F2NO2: m/z = 265.0914. Found: 265.0922.
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14k
Ethyl α,α-difluoro-α-[2-(indolyl)]acetate (12): 1H NMR: δ = 8.68-8.46 (br, 1 H), 7.66 (d, 1 H, J = 7.7 Hz), 7.43 (dd, 1 H, J = 8.1, 0.7 Hz), 7.30 (dt, 1 H, J = 7.7, 0.7 Hz), 7.16 (dt, 1 H, J = 8.1, 0.6 Hz), 6.89-6.86 (m, 1 H), 4.38 (q, 2 H, J = 7.0 Hz), 1.30 (t, 3 H, J = 7.0 Hz). 13C NMR: δ = 163.22 (t, J = 34.7 Hz), 136.36, 127.81 (t, J = 30.7 Hz), 126.18, 124.20, 121.69, 120.72, 111.56, 110.09 (t, J = 248.7 Hz), 104.17 (t, J = 5.0 Hz), 63.68, 13.99. 19F NMR: δ = -24.12 (s, 2 F). MS: m/z = 239 (M+), 166. HRMS calcd for C12H11F2NO2: m/z = 239.0758. Found: 239.0756.
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15a
Diethyl α,α-difluoromethyl-α-(phenyl)phosphonate(13): See ref.3a
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15b
Diethyl α,α-difluoromethyl-α-[1-(naphthyl)]phosphonate (14): See ref.3a
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15c
Diethyl α,α-difluoromethyl-α-[2-(furyl)]phosphonate (15):1H NMR: δ = 7.55 (dd, 1 H, J = 1.3, 1.0 Hz), 6.82 (dd, 1 H, J = 3.6, 1.0 Hz), 6.48 (dd, 1 H, J = 3.6, 1.3 Hz), 4.35-4.27 (m, 4 H), 1.36 (t, 6 H, J = 6.9 Hz). 19F NMR: δ = -110.97 (d, 2 F, J = 31.2 Hz). MS: m/z = 254 (M+), 117. HRMS calcd for C10H16F2NO3P: m/z = 254.0520. Found: 254.0539.
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15d
Diethyl α,α-difluoromethyl-α-[2-(1-methyl-pyrrolyl)]phosphonate (16): 1H NMR: δ = 6.69 (dd, 1 H, J = 2.6, 1.8 Hz), 6.56 (dd, 1 H, J = 3.4, 1.8 Hz), 6.10 (dd, 1 H, J = 3.4, 2.6 Hz), 4.33-4.09 (m, 4 H), 3.80 (s, 3 H), 1.34 (t, 6 H, J = 7.0 Hz). 19F NMR: δ = -24.48 (d, 2 F, J = 116.7 Hz). MS: m/z = 267 (M+), 130. HRMS calcd for C10H16F2NO3P: m/z = 267.0836. Found: 267.0823.
References
Typical Procedure for Photoreaction: A solution of 1 or 2 (0.17 mmol) and an aromatic compound (0.85 mmol) in CH2Cl2 (40 mL) or without solvent was bubbled with Ar at r.t. for 0.5 h and then photolyzed for 3 h with 100 W high-pressure mercury-vapor lamp. The reaction was conducted using pyrex vessel inside the light source. After the photoreaction, the resulting solution was evaporated under vacuum and the residue was purified by silica gel column chromatography (linear gradient of 0-20% EtOAc in hexane) or by HPLC (Develosil ODS-5, MeCN as eluent) to provide pure products.
13Ethyl α,α-difluoro-α-[1-(naphthyl)]acetate (3):1H NMR: δ = 8.19 (d, 1 H, J = 7.3 Hz), 7.99-7.84 (m, 3 H), 7.59-7.49 (m, 3 H), 4.28 (q, 2 H, J = 7.0 Hz), 1.23 (t, 3 H, J = 7.0 Hz). 13C NMR: δ = 164.25 (t, J = 34.6 Hz), 133.75, 131.83, 129.25 (t, J = 2.8 Hz), 128.74, 128.36, 127.21, 126.20, 124.79 (t, J = 11.5 Hz), 124.47, 124.14 (t, J = 3.3 Hz), 114.27 (t, J = 251.6 Hz), 63.27, 13.93. 19F NMR: δ = -23.49 (s, 2 F). MS: m/z = 250 (M+), 177. HRMS calcd for C14H12F2O2: m/z = 250.0805. Found: 250.0804.
16In support of this, Byers et al. detected a phenylselenyl transfer product as an intermediate in the photolysis of phenyl-selenomalonates in the presence of indoles.9 The inter-mediate adduct was too unstable to be isolated and the elimination of PhSeH provided the substituted indole derivatives.