S. Debarge et al. / Tetrahedron Letters 45 (2004) 21–23
23
+
+
+
"CCl3
"
H
H
H
N
N
N
+
Cl3C
Cl3C
+
+
N
N
N
H
H
OH
OH
OH
+
+
+
Scheme 1.
7. Typical experiment: To HF (6 mL) and SbF5 (3 mL) at
)20 °C in a Teflon reactor, the substrate (2 mmol) then
CCl4 (0.58 mL, 3 equiv) were successively added. The
mixture was maintained at a given temperature for 0.25–
2 h, according to the substrate (see Table 1). The mixture
was then cooled to )78 °C and HF/pyridine 70:30 (v/v)
(2 mL) was added. The reaction mixture was kept at 0 °C
overnight, then very carefully poured into a vigorously
stirred mixture of Na2CO3, H2O and ice. After extraction
with ethyl acetate (three times) and usual work-up, the
reaction mixture was evaporated to dryness and purified
on SiO2.
8. (a) Tischler, A. N.; Lanza, T. J. Tetrahedron Lett. 1986,
27, 1653–1656; (b) Bromidge, S. M.; Dabbs, S.; Davies, D.
T.; Duckworth, D. M.; Forbes, I. T.; Ham, P.; Jones, G.
E.; King, F. D.; Saunders, D. V.; Starr, S.; Thewlis, K.
M.; Wyman, P. A.; Blaney, F. E.; Naylor, C. B.; Bailey,
F.; Blackburn, T. P.; Holland, V.; Kennett, G. A.; Riley,
G. J.; Wood, M. D. J. Med. Chem. 1998, 41, 1598–1612.
9. Kametani, T.; Tetsuji, O.; Tatsuschi, I. M. J. Chem. Soc.,
Perkin Trans. 1 1981, 290–294.
It should be pointed out that compound 14b is unreac-
tive, the diprotonation at the carbonyl group and at the
carbon atom a to nitrogen deactivating this compound.
Surprisingly, tetrahydrocarbolines 16 are unreactive
under the reaction conditions, the possible diprotona-
tion on both nitrogen atoms perhaps making the sub-
stitution very difficult. On the other hand, the N-acetyl
derivative 17 yields trifluoro derivative 18a which is
deacetylated to 18b.15 This result can be explained by the
O-protonated enamide system being less deactivating
than the protonated indole nucleus. Trichloromethyl-
ation meta to the nitrogen atom leads through a stabi-
lized intermediate to the product 18a (Scheme 1).
This reaction has been successfully applied to the tri-
fluoromethylation of vinburnine CERVOXANâ 19, a
vasodilator, to its analogue 20.
To conclude, it should be pointed out that the reported
reaction constitutes an efficient and convenient access to
trifluoromethylated indoles either directly from substi-
tuted indoles to give the 5-trifluoro derivatives, or by
reacting indolines, followed by aromatization to give the
6-trifluoro analogues.
10. Berrier, C.; Jacquesy, J. C.; Jouannetaud, M. P.; Morellet,
G. Bull. Soc. Chim. Fr. 1986, 158–164.
11. (a) Hardtmann, G. E.; Schilling, U.S. Patent 4,160,032,
1979; Chem. Abstr. 1979, 91, 107890; (b) Rewcastle,
G. W.; Palmer, B. D.; Dobrusin, E. M.; Fry, D. W.;
Kraker, A. J.; Denny, W. A. J. Med. Chem. 1994, 37,
2033–2042.
1
12. All new compounds have been characterized by H, 13C
1
NMR and HRMS (EI). Selected data: Compound 4: H
NMR (300 MHz, CDCl3): d 7.17 (d, J ¼ 7:7 Hz, H-4),
6.96 (d, J ¼ 7:7 Hz, H-5), 6.88 (s, H-7); 13C NMR
Acknowledgements
2
(75 MHz, CDCl3): d 130.4 (q, JCF ¼ 31 Hz, C-6), 126.2
(q, 1JCF ¼ 282 Hz, CF3), 115.5 (q, 3JCF ¼ 4 Hz, C-5), 105.6
We thank CNRS and Ligue Nationale contre le Cancer
ꢀ
ꢀ
and Region Poitou-Charentes for a grant (to S.D.).
3
(q, JCF ¼ 3:8 Hz, C-7); MS C13H15N2OF3: calcd
(Comite de Charente Maritime) for financial support
272.1137, found 272.1142; Compound 10: 1H NMR
(300 MHz, CDCl3): d 7.55 (br s, H-4), 7.48 (br d,
J ¼ 8:2 Hz, H-6), 6.98 (d, J ¼ 8:2 Hz, H-7); 13C NMR
3
(75 MHz, CDCl3): d 125.7 (q, JCF ¼ 3:8 Hz, C-4), 124.5
2
1
(q, JCF ¼ 32:4 Hz, C-5), 124.3 (q, JCF ¼ 267 Hz, CF3),
3
References and Notes
121.0 (q, JCF ¼ 3:8 Hz, C-6); MS C13H13F3N2O2: calcd
286.1055, found 286.1045; Compound 18b: 1H NMR
(300 MHz, CDCl3): d 7.59 (br s, H-8), 7.49 (d, J ¼ 8:2 Hz,
H-5), 7.28 (br d, J ¼ 8:2 Hz, H-6); 13C NMR (75 MHz,
1. McClinton, M. A.; McClinton, D. A. Tetrahedron 1992,
48, 6555–6666, and references cited therein.
2. Langlois, B. R.; Billard, T. Synthesis 2003, 185–194.
3. Umemoto, T.; Ishihara, S. Tetrahedron Lett. 1990, 31,
3579–3582.
1
CDCl3): d 122.1 (q, JCF ¼ 270 Hz, CF3), 119.3 (q,
2JCF ¼ 31:7 Hz, C-7), 115.9 (q, JCF ¼ 4:9 Hz, C-6), 108.4
3
3
(q, JCF ¼ 4:9 Hz, C-8); MS C15H17N2F3: calcd 282.1344,
found 282.1371; Compound 20: 1H NMR (300 MHz,
CDCl3): d 8.65 (s, H-16), 7.51 (s, H-13, H-14); 13C NMR
(75 MHz, CDCl3): d 126.5 (q, 2JCF ¼ 32:2 Hz, C-15), 124.7
4. Yang, J. J.; Kierchmeier, R. L.; Schreeve, J. J. J. Org.
Chem. 1998, 63, 2656–2660.
5. (a) Benning, A. F.; Gottlieb, H. B. U.S. Patent 2,273,922,
1942; Chem. Abstr. 1942, 36, 3812; (b) Opie, T. R. U.S.
Patent 4,207,266, 1980; Chem. Abstr. 1980, 93, 167863r;
(c) Marhold, A.; Klauke, E. Gen Offen. DE 2928745,
1981; Chem. Abstr. 1981, 94, 192005r; (d) Marhold, A.;
Klauke, E. J. Fluorine Chem. 1981, 18, 281–291; (e)
Desbois, M. Fr. Demande FR Patent 2538380, 1985;
Chem. Abstr. 1985, 102, 61914x; (f) Nasu, R.; Shigehara,
I.; Kawashima, J.; Maeda, M. Eur. Patent Appl. EP
137424, 1985; Chem. Abstr. 1985, 103, 104684n.
6. Debarge, S.; Violeau, B.; Bendaoud, N.; Jouannetaud, M.
P.; Jacquesy, J. C. Tetrahedron Lett. 2003, 44, 1747–1750.
1
3
(q, JCF ¼ 272 Hz, C-22), 120.7 (q, JCF ¼ 3:7 Hz, C-14),
3
113.5 (q, JCF ¼ 4:1 Hz, C-16); MS C20H21N2OF3: calcd
362.1606, found 362.1598.
13. Berrier, C.; Jacquesy, J. C.; Jouannetaud, M. P.; Renoux,
A. New J. Chem. 1987, 11, 611–615.
14. (a) Hary, U.; Roettig, U.; Paal, M. Tetrahedron Lett.
2001, 42, 5187–5189; (b) Forbes, E. J.; Stacey, M.;
Tatlow, J. C.; Wragg, R. T. Tetrahedron 1960, 8, 67–
72.
15. The compound 18a is unstable and decomposed rapidly
to give the compound 18b.