Pd(OAc)2-catalyzed regioselective arylation of indoles with arylsiloxane in acidic medium

Article abstract of DOI:10.1021/ol101147b

(Figure Presented) Mild conditions have been developed to achieve a Pd(OAc)₂-catalyzed cross-coupling between indoles and arylsiloxanes in the presence of TBAF and Ag₂O in acidic medium. Electron-deficient arylsiloxanes presented high efficiency in this system to give the arylated indoles in excellent yields.

Full text of DOI:10.1021/ol101147b

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3185-3187
Pd(OAc)2-Catalyzed Regioselective
Arylation of Indoles with Arylsiloxane in
Acidic Medium
Zunjun Liang, Bangben Yao, and Yuhong Zhang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P. R. China
yhzhang@zju.edu.cn
Received May 18, 2010
ABSTRACT
Mild conditions have been developed to achieve a Pd(OAc)2-catalyzed cross-coupling between indoles and arylsiloxanes in the presence of TBAF
and Ag2O in acidic medium. Electron-deficient arylsiloxanes presented high efficiency in this system to give the arylated indoles in excellent yields.
Transition-metal-catalyzed C-H bond activation has become
an extremely powerful tool for the construction of C-C
bonds in modern organic synthesis.1 In particular, the direct
arylation of indoles received considerable attention over the
past decades because arylated indoles are important building
blocks of natural products, materials, and pharmaceuticals.2
Apart from aryl halides,3 a variety of coupling species, including
hypervalent iodine arylating agents4 and organoboranes,5 have
been exploited in the direct C-H bond activation reactions of
indoles. Compared with these coupling partners, organosilanes
possess advantages such as good stability to reaction conditions
and environmental benignity. The pioneering work of Hiyama
has demonstrated that organosilanes are distinguished reagents
for effecting a cross-coupling reaction (the Hiyama reaction).6
Subsequent investigations led to the utility of various organosi-
lanes as versatile cross-coupling partners with a variety of
electrophiles.7 However, the application of organosilanes in the
reactions of direct C-H bond functionalizations is very limited,8
and the corresponding direct coupling with indoles is still
unexplored. Herein, we report a new palladium-catalysis system
for the arylation of indoles by arylsiloxanes in acidic medium
under very mild conditions (at room temperature). Electron-
deficient arylsiloxanes presented high efficiency in this system
to give the arylated indoles in excellent yields.
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Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998;
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10.1021/ol101147b  2010 American Chemical Society
Published on Web 06/21/2010

Initially, we chose N-methylindole 1a and trimethoxyphe-
nyl-silane 2a as the model substrates for surveying the
reaction parameters (Table 1). It was found that the nature
With the identification of the optimal reaction conditions,
the scope of the reaction was investigated as shown in Table
2. It can be seen that a range of arylsiloxanes participate in
Table 1. Effects of Metals and Oxidants on the Arylationa
Table 2. Arylation of N-MethylIndole with Various Organosilanesa
entry
catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(TFA)2
Pd(CH3CN)2Cl2
Pd(PPh3)4
Pd (dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
oxidant
yield (%)b
1
2
3
4
5
6
7
8
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2CO3
AgOAc
AgF
0c
0d
64
13
44
47
9
11
57
48
32
0
9
10
11
12
13
14
15
Ag2O
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
tr
Ag2O
Ag2O
85e
53f
a Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), catalyst (0.05
mmol), Ag2O (1.5 mmol), TBAF (1.5 mL, 1 M in THF), AcOH (10 mmol),
EtOH (4 mL), rt, 18 h, N2. b GC yields based on N-methyl indole. c NaOH
(2 mmol) instead of AcOH. d In the absence of AcOH. e 2a (0.5 mmol ×
3), TBAF (0.5 mL × 3, 1 M in THF). f 60 °C.
a Reaction conditions: indoles 1a (0.5 mmol), 2 (0.5 mmol × 3),
Pd(OAc)2 (0.05 mmol), Ag2O (1.5 mmol), TBAF (0.5 mL × 3), AcOH
(10 mmol), EtOH (4 mL), rt, 18 h, N2. b Isolated yields.
of oxidants, additives, and solvent play a critical role on the
reaction efficiency. On the basis of the observation that basic
conditions are preferred for reactions involving organosilanes,
we performed the reaction under basic or neutral conditions.
Unfortunately, the desired cross-coupling was not observed
(Table 1, entries 1 and 2). It is important to note that the
addition of AcOH led to the formation of cross-coupling
product 3aa and the best result was obtained when the
amount of AcOH was 10 mmol (Table 1, entry 3). A trace
of C3 arylated product was observed, showing the same high
regioselectivity as observed for organoboranes.5 Other pal-
ladium species, such as PdCl2, Pd(TFA)2, Pd(CH3CN)2Cl2,
Pd(PPh3)4, and Pd(dba)2, were substantially less effective
(Table 1, entries 4-8). Among the oxidants tested, the best
result was obtained by the use of Ag2O (Table 1, entry 3).
A comparable reaction efficiency was presented by Ag2CO3
(Table 1, entry 9), while AgOAc and AgF showed poor
reactivity (Table 1, entries 10 and 11). No reaction took place
without catalysts or oxidants in this acidic system (Table 1,
entries 12 and 13). The different solvents were also screened,
and ethanol is the most suitable for this transformation. Slow
addition of trimethoxyphenylsilane 2a was found to further
improve the reaction to give 3aa in 85% GC yield (Table 1,
entry 14. For details, see the Supporting Information). Increasing
reaction temperature led to the low conversion (Table 1, entry
15). Thus, the reaction efficiently proceeded when 10 mol %
of Pd(OAc)2 was used in combination with Ag2O (3 equiv)
and TBAF (3 equiv) in ethanol at room temperature.
the regioselective coupling reaction efficiently. Triethoxy-
phenylsilane 2b and dimethoxydiphenylsilane 2c showed the
similar efficiency as with trimethoxyphenylsilane 2a to give
the arylated indole 3aa in good yields (Table 2, entries 1-3).
Notably, the reaction tolerated the electron-deficient arylsi-
loxanes, as trimethoxy (4-(trifluoromethyl) phenyl)silane 2d
coupled efficiently with indole 1a to give 3ad in 90% yield
(Table 2, entry 4). Excellent yields were also obtained for
other electron-deficient arylsilanes such as (4-fluorophenyl)
trimethoxysilane 2e and (4-chlorophenyl)trimethoxysilane 2f
(Table 2, entries 5 and 6). In contrast, arylsilanes with an
electron-donating group in the aromatic ring presented
relatively lower reactivity (Table 2, entries 7 and 8). This results
are different from the reaction of indoles with organoboranes,5
in which the electron-rich aryl boronic acids are more active.
It should be noted that the tolerance of the reaction for C-Cl
bond in indole made it attractive for the further assembly
through the cross-coupling reactions. Arylsilanes with an ortho-
substitutent delivered the corresponding arylated indole in lower
yield (Table 2, entry 9), illustrating that the steric hindrance
played the role to the reaction.
This arylation reaction also demonstrated a remarkable
tolerance toward functional groups at the indoles as shown in
Figure 1, and the substituent groups on the indoles influenced
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Org. Lett., Vol. 12, No. 14, 2010

of the indole ring at the C3-position followed by a C3fC2
migration10 was the most possible pathway for the selective
C2-arylation (Scheme 1, intermediate 1 to 2). In our ex-
periment, the electron-rich indoles are more reactive than the
Scheme 1. Plausible Catalytic Cycle
electron-deficient indoles, which is consistent with the electrophilic
substitution mechanism. In addition, it is well-known that the
fluoride plays a role in the activation of tetracoordinated silanes
via the in situ formation of pentacoordinate silicate anion.11 On
the basis of these previous studies and our experimental results, a
plausible mechanism for the arylation of indoles was proposed as
shown in Scheme 1. First, the electrophilic palladation occurs at
preferential C3-position of indole, which undergoes a 1,2-migration
to form intermediate 2. The subsequent deprotonation leads to the
production of intermediate 3, which reacts with the in situ generated
pentavalent silicate to afford the (aryl)(indole)palladium(II) species
4. The subsequent reductive elimination liberates the arylated
indoles with the regenerate of the Pd(0), which is oxidated in the
presence of the oxidant to complete the catalytic cycle.
In summary, we have developed a new catalytic system for
the arylation of indoles with arylsiloxanes through the C-H
functionalization reaction under mild conditions. This transfor-
mation represents rare examples of organosilanes applied to
C-H bond activations in acidic medium, which allows efficient
synthesis of a variety of C2-arylated indoles. Further develop-
ment of other C-H functionalizations by the use of organosi-
lanes is in progress in our laboratories.
Figure 1. Arylation of various substituted indoles. Reaction
conditions: indoles 1 (0.5 mmol), 2a (0.5 mmol × 3), Pd(OAc)2
(0.05 mmol), Ag2O (1.5 mmol), TBAF (0.5 mL × 3), AcOH (10
mmol), EtOH (4 mL), rt, 18 h, N2. Isolated yields.
the reactivity of this direct arylation reaction. The electron-rich
indoles showed the better reactivity and furnished the products in
moderate to good yields (3ba-3fa, 3ma, and 3na). The sterically
demanding 3-methyl-N-methylindole 1g delivered relatively
lower yield (3ga). The reaction of 6-methoxy-N-methylindoles
and 6-methoxy-N-benzylindole showed relatively lower reactiv-
ity with the analogous tendency as in the direct arylation of
indoles with organoboranes5b and afforded low yields (3ha and
3oa). The electron-deficient indoles participated in the reaction
to give the corresponding cross-coupling products, but they are
less active and displayed low yields (3ia-3ka and 3pa).
Notably, the free (N-H) indoles could also tolerate the reaction
to give a 50% yield (3qa). N-Benzylindoles were good sub-
strates for this arylation reaction as shown for the synthesis of
3la-3na and afforded higher yields than N-phenylindole (3ra).
Acknowledgment. Funding from Natural Science Founda-
tion of China (No. 20872126) and Zhejiang Provincial Natural
Science Foundation of China (R407106) is acknowledged.
Supporting Information Available: General experimental
procedures and spectroscopic data (1H NMR, 13C NMR, HRMS,
and MS) for the corresponding products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL101147B
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