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Synlett 2004(5): 0815-0818  
DOI: 10.1055/s-2004-820026
LETTER
© Georg Thieme Verlag Stuttgart · New York

Aromatic Substitution with Photochemically Generated Difluoromethyl ­Radicals Bearing Electron-Withdrawing Group

Satoru Murakami, Shokaku Kim, Hideki Ishii, 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 20 January 2004
Publication Date:
04 March 2004 (online)

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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

    References

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  • 14a Ethyl α,α-difluoro-α-(phenyl)acetate (4): See ref.6
  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 14g

    Ethyl α,α-difluoro-α-[2-(thienyl)]acetate (8): See ref. 3b.

  • 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.

  • 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.

  • 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.

  • 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.

  • 15a

    Diethyl α,α-difluoromethyl-α-(phenyl)phosphonate(13): See ref.3a

  • 15b

    Diethyl α,α-difluoromethyl-α-[1-(naphthyl)]phosphonate (14): See ref.3a

  • 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.

  • 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.

12

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.

13

Ethyl 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.

16

In 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.