coupling8,10). We report herein mild and high-yielding cross-
coupling reactions of indolyl-2-silanols with aryl iodides and
bromides that proceed with both N-Boc and N-methylindole
precursors.
Table 1. Activator Optimization in the Cross-Coupling of 1
with 2a
For initial studies on the cross-coupling, N-Boc(2-indolyl)-
dimethylsilanol (1) was selected, because of the general
1
1,12
utility of the Boc protecting group.
In contrast to the
corresponding N-Boc(2-indolyl)boronic acid or -stannane, 1
is easily prepared, chromatographically stable, and can be
stored for extended periods at -20 °C. To develop a method
for the cross-coupling of 1, a set of conditions was developed
employing 4-nitroiodobenzene, allylpalladium chloride dimer
entrya
b
activator
product, % after 24 h
1
2
3
4
5
NaH
KH
LiOt-Bu
NaOt-Bu
KOt-Bu
47
30
0
46
3
(
2
[allylPdCl] ), and KH as the activator in toluene at room
1
3
temperature. Under these conditions, only N-Boc-indole,
the product of protiodesilylation, was observed and none of
the desired cross-coupling product was obtained.
a
Conditions: 1.2 equiv of 1, 2.0 equiv of activator, 1.0 equiv of CuI,
To overcome the problem of low reactivity and the
formation of undesired side-products, we next examined the
effect of copper salts that have a beneficial effect on the
0.05 equiv of APC, 0.5 M in 2a in toluene at room temperature.
Determined by HPLC analysis with an internal standard.
b
14
15
rate of cross-coupling of stannanes and silanes and may
Next, the influence of palladium source was surveyed
5
also inhibit protiodesilylation. The tetrameric copper trim-
(
Table 2). The use of PdCl
showed little product formation, (Table 3, entries 1-3).
Whereas PdBr and (CH CN) PdCl were more active
catalysts compared to [allylPdCl] , they were still inferior
to the chloroform solvate of Pd (dba) (entry 7). Although
2 2 3 2 2
, PdCl (PPh ) , and Pd(OAc)
ethylsilanolate16 afforded a small amount of the desired
product, whereas among other copper sources (CuCl
CuCN) only copper(I) iodide showed any salutary effect
30% conversion after 24 h) and thus was chosen for
2
, CuBr,
2
3
2
2
2
(
2
3
subsequent optimization studies.
this reaction reached completion within 12 h at room
temperature, 2a is a very reactive electrophile, and other less
reactive aryl halides might require more forcing conditions.
Simply doubling the concentration from 0.5 to 1.0 M in 2a
resulted in complete conversion of the iodide to the desired
product in 6 h in 92% yield (HPLC) along with only 3% of
the halide-homocoupling side product.
To find an optimal activator for this reaction, several
inorganic bases were surveyed in combination with copper-
(
I) iodide (Table 1). Although KH and NaH effected the
cross-coupling reaction (entries 1 and 2), they are too harsh
and would preclude the use of substrates bearing sensitive
functional groups. However, a dramatic cation dependence
was observed for the tert-butoxide bases where NaOt-Bu was
found to be optimal (entries 3-5). This behavior may result
1
7
from the greater solubility of the sodium silanolate.
Table 2. Catalyst Optimization of the Cross-Coupling of 1
with 2aa
(10) (a) N-Boc(2-indolyl)boronic acid reacts poorly with iodobenzene
under typical Suzuki conditions; see: Johnson, C. N.; Stemp, G.; Anand,
N.; Stephen, S. C.; Gallagher, T. Synlett 1998, 1025-1027. (b) Ishikura
and co-workers have demonstrated the cross-coupling of an in-situ-generated
N-Boc(2-indolyl)boronate with aryl bromides from a 2-lithated indolyl
species and triethylborane; see: Ishikura, M.; Agata, I.; Katagiri, N. J.
Heterocycl. Chem. 1999, 36, 873-879.
product (%)b
entry
Pd source
PdCl2
PdCl2(PPh3)2
Pd(OAc)2
[allylPdCl]2
PdBr2
(CH3CN)2PdCl2
Pd2(dba)3‚CHCl3
12 h
24 h
1
2
3
4
5
6
7
0
0
0
3
15
17
46
94
(
11) Hasan, I.; Marinelli, E. R.; Lin, L. C.; Fowler, F. W.; Levy, A. B.
J. Org. Chem. 1981, 46, 157-164.
12) Vazquez, E.; Davies, I. W.; Payack, J. F. J. Org. Chem. 2002, 67,
551-7552.
13) Preliminary experiments with KOTMS as the activator gave
(
22
55
57
87
7
(
98
protiodesilylation as the major product, so we surmised that using KH as
an activator would quickly and irreversibly deprotonate the silanol and
remove the only available proton source as H2.
>99
a
Conditions: 1.2 equiv of 1, 2.0 equiv of NaOt-Bu, 1.0 equiv of CuI,
.1 equiv Pd, 0.5 M in 2a in toluene at room temperature. b Determined by
HPLC analysis with an internal standard.
(
14) (a) Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-
0
5
364. (b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L.
S. J. Org. Chem. 1994, 59, 5905-5911. (c) Takeda, T.; Kabasawa, Y.;
Fujiwara, T. Tetrahedron 1995, 51, 2515-2524. (d) Han, X.; Stoltz, B.
M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605. (e) Casado, A.
L.; Casada, A. L.; Espinet, P. Organometallics 2003, 22, 1305-1309.
(15) (a) Taguchi, H.; Ghoroku, K.; Tadaki, M.; Tsubouchi, A.; Takeda,
Because Pd
catalysts surveyed, Pd
for this reaction (Table 3, entry 2). Surprisingly, Pd
CHCl was more active than Pd (dba) under these conditions
compare entries 1 and 2). To determine if the chloroform
2
(dba)
3
‚CHCl
3
was superior to the other
was also examined as a catalyst
(dba)
T. Org. Lett. 2001, 3, 3811-3814. (b) Taguchi, H.; Miyashita, H.;
Tsubouchi, A.; Takeda, T. Chem. Commun. 2002, 2218-2219. (c) Hana-
moto, T.; Kobayashi, T.; Kondo, M. Synlett. 2001, 281-283. (d) Taguchi,
H.; Ghoroku, K.; Tadaki, M.; Tsubouchi, A.; Takeda, T. J. Org. Chem.
2
(dba)
3
2
3
‚
3
2
3
2
2
2
002, 67, 8450-8456. (e) Denmark, S. E.; Kobayashi, T. J. Org. Chem.
003, 68, 5153-5159. (f) Denmark, S. E.; Tymonko, S. A. J. Org. Chem.
003, 68, 9151-9154.
(
(
16) Schmidbaur, H.; Adlkofer, J.; Shiotani, A. Chem. Ber. 1972, 105,
(17) Solubility in toluene (wt %) at 25 °C: NaOt-Bu, 6%; KOt-Bu, 2.3%.
LiOt-Bu is more soluble but less nucleophilic.
3
389-3396.
3650
Org. Lett., Vol. 6, No. 20, 2004