B. Yin et al. / Tetrahedron 66 (2010) 6820e6825
6825
(d, J¼6.44, 3.86 Hz), 134.19 (CH), 125.40, 143.40 (C), 169.07 (d,
J¼2.78 Hz), 169.40 (d, J¼3.39 Hz) (C]O); MS (m/z) 269(Mþ), 249,
227, 207, 189, 148, 130; HRMS (ESI-TOF): m/z [MþNaþ] calcd for
C13H13F2NO3Na, 292.0761; found, 292.0756.
removed through filtration, almost pure product 6e was obtained in
good yield. Regrettably, it was difficult to further purify the crude
due to conversion to compound 6e00. In the case of utilizing alcohol
(MeOH) as solvent in dehydrofluorination reaction, compound 6e0
was obtained in 61 or 71% yield.
3.3.10. Benzyl (1-acetyl-2,3-difluoro-2,3-dihydro-3-indolyl)acetate
(4f) trans-form. Colorless oil; 1H NMR (270 MHz, CDCl3)
d
2.41 (s,
3.5.1. Methyl 2-(1-acetyl-2-fluoroindolin-3-ylidene)acetate 6e. Yel-
Ace3H), 3.12 (ddd, 1H, J¼17.28, 35.92, 4.32 Hz), 3.55 (ddd, J¼17.55,
8.91, 4.59 Hz), 5.24 (dd, 2H, J¼17.28, 12.42 Hz), 6.56 (dd, 1H,
J¼58.87, 11.07 Hz), 7.18 (tt, Are1H, J¼7.56, 0.81 Hz), 7.38 (m,
Are6H), 7.47 (m, Are1H), 8.22 (d, Are1H, J¼8.10 Hz); 19F NMR
lowoil; 1HNMR(270 MHz,CDCl3)
d2.48(s, Ace3H), 3.85(s, OMee3H),
6.48 (dd,1H, J¼5.95,1.35 Hz), 7.14(td,1H, J¼7.56, 0.81 Hz), 7.32(dd,1H,
J¼60.76, 1.08 Hz), 7.43 (dt, 1H, J¼15.66, 1.08), 7.54 (d, 1H, J¼7.83 Hz),
8.24 (d, 1H, J¼8.10 Hz); 19F NMR (254 MHz, CDCl3)
d
ꢀ53.35 (dd,
(254 MHz, CDCl3)
d
ꢀ63.45 (m, 1F), ꢀ67.46 (dd, 1F, J¼59.19,
26.52 (d, CH3, J¼440.70 Hz),
J¼59.19, 5.59 Hz); MS (m/z) 249 (Mþ), 231, 207, 189, 172, 148, 130. El-
14.73 Hz); 13C NMR (68 MHz, CDCl3)
d
emental analysis could not carried out because of its instability.
36.42 (dd, CH2, J¼26.24, 4.47 Hz), 67.18 (CH2), 99.39 (d, J¼43.53 Hz),
102.56 (d, J¼42.99 Hz) (CeF), 124.70 (d, J¼3.32 Hz), 128.23, 128.46,
128.60, 132.60 (d, J¼3.93 Hz), 135.12 (CH), 117.48 (d, J¼2.85 Hz),
123.76 (d, J¼1.70 Hz), 143 (C), 167.91, 168.89 (d, J¼2.78 Hz) (C]O);
MS (m/z) 220(MþꢀOBz, eF), 205; HRMS (EI): m/z calcd for
C19H17F2NO3, 345.1176; found, 345.1162.
3.6. Defluorination of difluorinated compound 3d and 3e
To a solution of the compounds 3d and 3e in dry solvent (MeOH,
DMF, etc.) was added appropriate bases, respectively. The reaction
mixture was stirred at room temperature for 1e13.5 h. The reaction
was halted once starting substrates were completely consumed
(checked by TLC). After taking off extra solvent through evaporation
under reduced pressure, compound 7 and 8 were determined by 19F
NMR and GCeMS.
3.3.11. 1-Acetyl-2-fluoro-3-hydroxy-2,3-dihydroindole (5c) trans-
form. 19F NMR (254 MHz, CDCl3)
d
ꢀ65.13 (d, J¼62.75 Hz); MS (m/z)
236 (Mþþ2H), 194, 154. Pure adduct could not be obtained because
of its instability.
3.6.1. 1-Acetyl-3-fluoroindole (7). White solid: mp 52e53 ꢁC; 1H
3.3.12. Benzyl
(2-fluoro-3-hydroxy-2,3-dihydro-3-indolyl)acetate
NMR (270 MHz, CDCl3)
d
2.58 (s, Ace3H), 7.20 (d, 1H, J¼2.70 Hz), 7.32
(5f) trans-form. Yellow oil; 19F NMR (254 MHz, CDCl3)
d
ꢀ61.83 (dt,
(td, Are1H, J¼7.56,1.08 Hz), 7.41 (td, Are1H, J¼7.29,1.08 Hz), 7.59(dd,
J¼62.75, 5.59 Hz); MS (m/z) 234 (MþþH, eCH2Ph, eOH); HRMS (ESI-
TOF): m/z[MþNaþ]calcdforC19H18FNO4Na, 366.1118; found, 366.1102.
Are1H, J¼7.83, 2.70 Hz), 8.43 (d, Are1H, J¼8.10 Hz); 19F NMR
(254 MHz, CDCl3)
d
ꢀ90.48 (s, 1F); 13C NMR (68 MHz, CDCl3) 23.85
(CH3), 107.27 (d, J¼27.80 Hz), 116.75, 117.08 (d, J¼2.71 Hz), 123.87,
126.54(CH),121.00(d,J¼18.31 Hz),132.93(C),148.79(d, J¼254.25 Hz)
(CeF), 168.39 (C]O); MS (m/z) 177 (Mþ), 135. HRMS (ESI-TOF): m/z
[MþNaþ] calcd for C10H8FNONa, 200.0488; found, 200.0482.
3.3.13. (1-Acetyl-2-fluoro-2,3-hydroindol-3-ylidene)acetonitrile
(6c). 19F NMR (254 MHz, CDCl3)
d
ꢀ71.30 (dd, J¼22.36, 9.15 Hz); MS
(m/z) 216 (Mþ), 172, 154, 145; HRMS [(EI): m/z calcd for C12H9FN2O,
216.0699; found, 216.0694.
References and notes
3.4. Direct anodic synthesis of compound 5e in the presence
of a few drops of water
1. (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y., Eds.; Ko-
dansha and Elsevier Biomedical: Tokyo, 1982; (b) Purrington, S. T.; Kagen, B. S.;
Partrik, T. B. Chem. Rev. 1986, 86, 997e1018; (c) Fluorine in Bioorganic Chemistry;
Welch, J. T., Eswarakrishnan, S., Eds.; Wiley: New York, NY, 1991; (d) Silvester, M. J.
Aldrichimica Acta 1991, 24, 31e38; (e) Selective Fluorination in Organic and Bio-
organic Chemistry; Welch, J. T., Ed.; American Chemical Society: Washington, DC,
1991; (f) Erian, A. W. J. Heterocycl. Chem. 2001, 38, 793e808; (g) Kirsch, p. Modern
Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH: Weinheim,
2004; (h) Uneyama, K. Organofluorine Chemistry; Oxford: Blackwell, 2006.
2. (a) Katayama, H.; Tagawa, N.; Kawada, Y.; Shiobara, K.; Kaneko, K.; Honda, Y.;
Kondo, N.; Ikeda, Y. Chem. Pharm. Bull. 1997, 45, 143e147; (b) Ma, J.; Hecht, S.
M. Chem. Commun. 2004, 1190e1191; (c) Suzuki, H.; Morita, H.; Shiro, M.;
Kobayashi, J. Tetrahedron 2004, 60, 2489e2495; (d) Cai, X. W.; Snieckus, V. Org.
Lett. 2004, 6, 2293e2295; (e) Kagata, T.; Saito, S.; Shigemori, H.; Ohsaki, A.;
Ishiyama, H.; Kubota, T.; Kobayashi, J. J. Nat. Prod. 2006, 69, 1517e1521; (f)
Matsuda, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 125e128.
3. (a) Takeuchi, Y.; Tarui, T.; Shibata, N. Org. Lett. 2000, 2, 639e642; (b) Baudoux, J.;
Salit, A. F.; Cahard, D.; Plaquevent, J. C. Tetrahedron Lett. 2002, 43, 6573e6574.
4. Barton, D. H. R.; Hesse, R. H.; Jackman, G. P.; Pechet, M. M. J. Chem. Soc., Perkin
Trans. 1 1977, 2604e2608.
5. Dawood, K. M.; Fuchigami, T. J. Org. Chem. 2004, 69, 5302e5306.
6. Compound 6e0 was also provided according to the reported methods. See: (a)
Kawasaki, T.; Nonaka, Y.; Uemura, M.; Sakamoto, M. Synthesis 1991, 9, 701e702; (b)
Kouko, T.; Kobayashi, J.; Ohta, A.; Sakamoto, M.; Kawasaki, T. Synthesis 2004, 15,
2463e2470; (c) Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.; Inagawa, M.;
Sakamoto, M. Org. Lett. 2000, 2, 3027e3029; (d) Kawasaki, T.; Nonaka, Y.; Ohtsuka,
H.; Sato, H.; Sakamoto, M. J. Chem. Soc., Perkin Trans. 1 1990, 1101e1106.
7. Compound 6e00 was also prepared according to the reported method Kawasaki, T.;
Ohtsuka, H.; Chien, C. S.; Omata, M.; Sakamoto, M. Chem. Pharm. Bull. 1987, 35,
1339e1346.
Electrolysis of compound 2e (0.2 mmol) was carried out in
a 0.3 M solution of Et4NF-4HF in acetonitrile (4 ml) containing dis-
tilled water (0.1 ml). The electrolysis was performed in an undivided
cell at room temperature until the starting substrate was completely
consumed that was monitored by TLC. Following short column first,
the reaction mixture was purified by chromatography on silica gel
using hexane/AcOEt (5/1, v/v) to simply give compound 5e.
3.4.1. Methyl
(1-acetyl-2-fluoro-3-hydroxy-2,3-dihydro-3-indolyl)
acetate (5e) trans-form. Colorless oil; 1H NMR (270 MHz, CDCl3)
d
2.41 (s, Ace3H), 2.96 (dd, 1H, J¼17.55, 4.86 Hz), 3.20 (dd, 1H,
J¼17.28, 6.75 Hz), 3.84 (s, OMee3H), 4.38 (s, OH), 6.21 (d, 1H,
J¼62.65 Hz), 7.17 (td, Are1H, J¼7.56, 0.81 Hz), 7.32e7.43 (m,
Are2H), 8.20 (d, Are1H, J¼8.10 Hz); 19F NMR (254 MHz, CDCl3)
d
61.67 (d, 1F, J¼62.75 Hz); 13C NMR (68 MHz, CDCl3)
d 23.29 (d,
CH3, J¼42.38 Hz), 49.57 (d, CH2, J¼32.88 Hz), 51.43 (CH3), 53.52 (C),
102.66 (d, CeF, J¼167.87 Hz), 123.52, 125.86, 130.20, 132.12 (CH),
129.87, 141.75 (C), 169.33, 173.18 (d, J¼2.78 Hz) (C]O); MS (m/z)
267 (Mþ), 247 (Mþ, eF), 225, 205, 173, 145, 130, 117; HRMS (EI): m/z
calcd for C13H14FNO4, 267.0907; found, 267.0923.
8. Compound 8 was also obtained according to the reported methods. See: (a)
Ermolenko, M. S.; Budylin, V. A.; Kost, A. N. Chem. Heterocycl. Compd. 1978, 14,
752e754; (b) Torres, J. C.; Garden, S. J.; Pinto, A. C.; Sliva, F. S. Q.; Boechat, N.
Tetrahedron 1999, 55, 1881e1892.
3.5. Dehydrofluorination of trans-2,3-difluoro-2,3-
dihydroindole derivative 4e
9. (a) Takechi, H.; Machida, M.; Kanaoka, Y. Chem. Pharm. Bull. 1988, 36, 3770e3779;
(b) Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639e2641;
(c) Torisu, K.; Kobayashi, K.; Iwahashi, M.; Egashima, H.; Nakai, Y.; Okada, Y.;
Nanbu, F.; Ohuchida, S.; Nakai, H.; Toda, M. Eur. J. Med. Chem. 2005, 40, 505e519;
(d) Brown, J. B.; Henbest, H. B.; Jones, E. R. H. J. Chem. Soc. 1952, 3172e3176.
To a stirring solution of the compound 4e (1 mmol) in dry solvent
(DMF, MeCN, etc.) (10 ml) was added various bases with 10 mmol
(10 equiv). The reaction mixturewas stirred at room temperature for
some hours. Following produced piperidyl hydrofluoride salt was