1
512
T. Balle et al.
PAPER
1
1
H NMR (CDCl ): = 6.77 (d, 1 H, J = 3.0 Hz), 7.20–7.30 (m, 3 H),
H NMR (CD Cl ): = 0.27 (s, 18 H), 6.55 (d, 1 H, J = 3.3 Hz), 7.20
3
2
2
7
.42 (dd, 1 H, J = 8.5, 1.9 Hz), 7.44–7.49 (m, 3 H), 7.57 (d, 1 H,
(d, 1 H, J = 8.0 Hz), 7.23 (d, 1 H, J = 8.0 Hz), 7.26 (d, 1 H, J = 3.3
Hz), 7.38 (d, 2 H, J = 4.7 Hz),7.73 (s, 1 H).
J = 8.5 Hz), 7.89 (d, 1 H, J = 1.4 Hz), 9.01 (s, 2 H), 9.18 (s, 1 H).
+
MS: m/z = 290 (MH , 18%).
Anal. Calcd for C H BrFNSi : C, 55.29; H, 5.80; N, 3.22. Found:
2
0
25
2
C, 55.22; H, 5.94; N, 3.08.
Anal. Calcd for C H FN : C, 74.73; H, 4.18; N, 14.52. Found: C,
1
8
12
3
7
4.59; H, 4.03; N, 14.35.
The last fraction gave 0.10 g (3%) of 12.
R 0.73 (EtOAc–heptane, 1:9); mp 62–63 °C (Et O).
f
2
1
5
-(4-Fluorophenyl)-5-(trimethylstannyl)-1H-indole (4)
-Bromo-1-(4-fluorophenyl)-1H-indole (1) (5 g, 17.2 mmol) in
1
2
H NMR (CD Cl ): = 0.26 (s, 9 H), 6,53 (d, 1 H, J = 2.8 Hz), 7.06
2 2
(
t, 1 H, J = 8.0 Hz), 7.19 (dd, 1 H, J = 8.7, 1.8 Hz), 7.22 (d, 1 H,
THF (20 mL) was added during 3 min to a soln of n-BuLi (1.6 M,
6 mmol) in THF (200 mL) at –78 °C. The soln was stirred for 4 min
J = 8.7 Hz), 7.24 (d, 1 H, J = 3.0 Hz), 7.32–7.35 (m, 1 H) 7.35–7.39
m, 1 H) 7.70 (d, 1 H, J = 1.4 Hz).
2
(
at –78 °C before addition of trimethylstannyl chloride (10 g, 50
mmol) in THF (10 mL). The reaction mixture was allowed to warm
up to r.t. and stirred for 1 h. H O (75 mL) was added and the aq
Anal. Calcd for C H BrFNSi: C, 56.36; H, 4.73; N, 3.87. Found:
1
7
17
2
C, 56.67; H, 4.84; N, 3.81.
phase extracted with EtOAc (3 75 mL). Evaporation of the solvent
and purification by flash chromatography (EtOAc–heptane, 5:100)
gave 3.6 g (56%) of 4; mp 61–63 °C (EtOAc–heptane).
In addition, several mixed fractions were obtained.
1H NMR (CDCl3): = 0.32 (td, 9 H, J = 26.8, 0.9 Hz), 6.50 (d, 1 H, References
J = 3.3 Hz), 7.17–7.25 (m, 2 H), 7.24 (d, 1 H, J = 3.3 Hz), 7.40–7.44
(
(
(
(
(
(
1) Current address: Medicinal Chemistry Research, Novo
(
m, 2 H), 7.47 (dt, 1 H, J = 8.0, 0.9 Hz), 7.82 (td, 1 H, J = 24.5, 0.9
Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark.
2) Perregaard, J.; Arnt, J.; Bøgesø, K. P.; Hyttel, J.; Sanchez, C.
J. Med. Chem. 1992, 35, 1092.
3) Perregaard, J.; Andersen, K.; Hyttel, J.; Sanchez, C. J. Med.
Chem. 1992, 35, 4813.
4) Andersen, K.; Liljefors, T.; Hyttel, J.; Perregaard, J. J. Med.
Chem. 1996, 39, 3723.
5) Carbonnelle, A.-C.; Zamora, E. G.; Beugelmans, R.; Roussi,
G. Tetrahedron Lett. 1998, 39, 4467.
Hz).
Anal. Calcd for C H FNSn: C, 54.59; H, 4.85; N, 3.74. Found: C,
17
18
5
4.98; H, 5.09; N, 3.85.
Procedure B
1
1
-(4-Fluorophenyl)-5-(1-methylpyrazol-3-yl)-1H-indole (5)
-(4-Fluorophenyl)-5-(trimethylstannyl)-1H-indole (4) (1 g, 2.7
mmol), Pd(PPh ) (62 mg, 0.05 mmol) and 3-iodo-1-methylpyra-
3
4
zole (0.6 g, 2.9 mmol) were dissolved in anhyd DMF (30 mL) and
6) Yang, Y.; Martin, A. R. Synth. Commun. 1992, 22, 1757.
stirred at 100 °C for 2 h. H O (50 mL) was added and the soln was
2
(7) Nielsen, S. F.; Peters, D.; Axelsson, O. Synth. Commun.
000, 30, 3501.
(8) Pearce, B. C. Synth. Commun. 1992, 22, 1627.
9) Hudkins, R. L.; Diebold, J. L.; Marsh, F. D. J. Org. Chem.
995, 60, 6218.
extracted with EtOAc (3 50 mL). The combined organic phases
2
were washed with a sat. soln of CaCl (3 50 mL), dried (MgSO4)
2
filtered and the solvent was evaporated in vacuo. The compound
was purified by preparative TLC (EtOAc–heptane, 1:10) to yield
(
1
0
.40 g (51%) of 5 identical to the material above.
(
(
10) Jensen, J.; Skjærbæk, N.; Vedsø, P. Synthesis 2001, 128.
11) Yang, Y.; Martin, A. R.; Nelson, D. L.; Regan, J.
Heterocycles 1992, 34, 1169.
The following derivative was prepared accordingly:
(
(
12) Yang, Y.; Martin, A. R. Heterocycles 1992, 34, 1395.
13) Chu, L.; Fisher, M. H.; Goulet, M. T.; Wyvratt, M. J.
Tetrahedron Lett. 1997, 38, 3871.
1
-(4-Fluorophenyl)-5-(1-methylpyrazol-4-yl)-1H-indole (6)
Aryl halide 4-bromo-1-methylpyrazole when reacted according to
procedure B gave the crude product which was purified by flash
chromatography (EtOAc–heptane–MeOH, 10:90:0 80:0:20) to
yield 0.40 g (39%) of 6 identical to the material above.
(
14) Baston, E.; Hartmann, R. W. Bioorg. Med. Chem. Lett. 1999,
9, 1601.
(
15) Meng, C. Q.; Rakhit, S.; Lee, D. K. H.; Kamboj, R.;
McCallum, K. L.; Mazzocco, L.; Dyne, K.; Slassi, A.
Bioorg. Med. Chem. Lett. 2000, 10, 903.
16) We performed Negishi cross-coupling reactions in 21 g (73
mmol) scale without encountering any problems. See
preparation of 11.
5
5
-Bromo-1-(4-fluoro-3-trimethylsilyl-phenyl)-1H-indole (12),
-Bromo-1-(4-fluoro-3,5-bis(trimethylsilyl)-phenyl)-1H-indole
(
(
13) and 5-bromo-1-(4-fluoro-3,5-bis(trimethylsilyl)-phenyl)-2-
trimethylsilyl-1H-indole (14)
To a soln of 1 (2 g, 6.9 mmol) in THF (70 mL) at –78 °C was added
TMSCl (2.99 g 27.6 mmol) and LDA (17.2 mmol 8.6 mL 2 M soln
in THF–heptane–ethylbenzene, 40:20:15). After stirring at –78 °C
for 10 min, H O (50 mL) was added and the aq phase extracted with
EtOAc (2 75 mL). Evaporation of the solvent gave 3 g of crude
(17) Takami, H.; Koshimura, H.; Kumazawa, T. Heterocycles
1999, 51, 1119.
(
18) Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J. J. Org.
Chem. 1994, 59, 10.
2
1
(19) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem.
986, 51, 5106.
product containing a 1:4:1 mixture of 12, 13, and 14 ( H NMR).
1
Flash chromatography (heptane) and evaporation of the fractions
containing the fastest eluting compound gave 0.50 g of a 3:7 mix-
ture of 13 and 14. Compound 14 was tentatively assigned as 5-bro-
mo-1-(4-fluoro-3,5-bis(trimethylsilyl)-phenyl)-2-trimethylsilyl-
(
(
(
20) Bridges, A. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E.
Tetrahedron Lett. 1992, 33, 7499.
21) Bridges, A. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E.
Tetrahedron Lett. 1992, 33, 7495.
1H-indole (14).
22) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105,
R 0.88 (EtOAc–heptane, 1:9).
f
6155.
1
H NMR (CD Cl ): = 0.05 (s, 9 H), 0.29 (s, 18 H), 6.74 (s, 1 H)
(23) Felding, J.; Uhlmann, P.; Kristensen, J.; Vedsø, P.; Begtrup,
M. Synthesis 1998, 1181.
2
2
6
.85 (d, 1 H, J = 8.6 Hz), 7.16 (dd, 1 H, J = 8.6, 1.9 Hz), 7.31 (d, 2
H, J = 4.9 Hz), 7.71 (d, 1 H, J = 1.8 Hz).
(24) Katrizky, A.; Lue, P.; Akutagawa, K. Tetrahedron 1989, 45,
4
253.
The next fraction contained 1.0 g (33%) of 13
(
25) Effenberger, F.; Krebs, A. J. Org. Chem. 1984, 49, 4687.
R 0.83 (EtOAc–heptane, 1:9); mp 104–105 °C (heptane).
f
Synthesis 2002, No. 11, 1509–1512 ISSN 0039-7881 © Thieme Stuttgart · New York