Rhodium acetate/base-catalyzed N-silylation of indole derivatives with hydrosilanes

Article abstract of DOI:10.1039/c2cc34381a

In the presence of Rh₂(OAc)₄ (OAc = acetate) and TBA₂WO₄ (TBA = tetra-n-butylammonium), the N-silylation of indole derivatives with hydrosilanes efficiently proceeded to give the corresponding N-silylated indole

Full text of DOI:10.1039/c2cc34381a

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Rhodium acetate/base-catalyzed N-silylation of indole derivatives with
hydrosilanesw
Shintaro Itagaki, Keigo Kamata, Kazuya Yamaguchi and Noritaka Mizuno*
Received 19th June 2012, Accepted 26th July 2012
DOI: 10.1039/c2cc34381a
In the presence of Rh2(OAc)4 (OAc = acetate) and TBA2WO4
(TBA = tetra-n-butylammonium), the N-silylation of indole
derivatives with hydrosilanes efficiently proceeded to give the
corresponding N-silylated indoles in high yields. Pyrrole and
carbazole were also N-silylated with the combined catalysts.
procedures for the catalytic synthesis of silylated indoles with
hydrosilanes have been reported.9–11 Lu and Falck9 reported
the Ir(I)-catalyzed C2-silylation of indoles with hydrosilanes.
Tatsumi and co-workers10 reported the Ru(II)-catalyzed
C3-silylation of N-protected indoles with hydrosilanes. To
date there have been only a few reports on the N-silylation
of indoles with hydrosilanes,6,11 z as far as we know, due to
their strong N–H bonds in comparison with common
amines.12 Herein, we demonstrate the N-silylation of indoles
with hydrosilanes using simple Rh2(OAc)4 and O-donor bases,
especially TBA2WO4 [eqn (1)].13
Heteroarenes have been utilized as intermediates in a wide
range of organic syntheses,1 and they are essentially pharma-
cophores.2 In particular, much attention has been paid to the
development of efficient procedures for synthesis and functio-
nalization of indoles3 because the indole rings are some of the
most important skeletons ubiquitously found in many natural
products and biologically active compounds.4 N-Silylated
indoles have been recognized as very important synthons
and widely utilized for synthesis of indole-based natural
products and drug candidates.5 In addition, Hartwig and
co-workers have recently reported the site-selective borylation
of indoles using in situ generated N-silylated indoles as synthetic
intermediates.6 Up to the present, the vast majority have generally
utilized activated indoles and halosilanes for synthesis of silylated
indoles; for example, N-silylation has been performed by
activation (deprotonation) of indoles, followed by coupling
with chlorosilanes.7 However, this antiquated N-silylation
requires stoichiometric reagents such as alkyl lithium and
sodium hydride for pre-activation of indoles, and at least
equimolar amounts of by-products are formed during not
only the N-silylation but also the pre-activation of indoles.
Thus, the development of efficient procedures instead of the
above-mentioned antiquated silylations, i.e., the direct use of
indoles without pre-activation using stoichiometric reagents
and the replacement of halosilanes with hydrosilanes or their
surrogates, is an important subject in modern organic synthesis.
Hydrosilanes are readily available, easy-to-handle, nontoxic,
and inexpensive silylating reagents.8 Therefore, catalytic direct
cross-coupling of indoles with hydrosilanes is the most attractive
alternative for the synthesis of silylated indoles. To date, several
ð1Þ
Initially, the N-silylation of indole (1a) with dimethylphenyl-
silane (2a, five equivalents with respect to 1a) was carried out in
the presence of catalytic amounts of various metal salts and
complexes (e.g., Rh, Pd, Ru, Pt, Ir, Cu, Ag, Au, Co, Ni, and Zn,
2 mol% with respect to 1a) and TBA2WO4 (2 mol% with
respect to 1a) (Table S1, ESIw). No reaction proceeded in the
absence of metal catalysts and/or bases. Among the metal
catalysts examined, only Rh2(OAc)4 gave the corresponding
N-silylated indole in a high yield; for example, when the
silylation was carried out with Rh2(OAc)4 (1 mol% with respect
to 1a) and TBA2WO4 (2 mol% with respect to 1a) at 50 1C for
2 h, the corresponding N-silylated indole (3aa) was obtained
in >99% yield (Table 1, entry 1). In this case, no C2- and
C3-silylated indoles were produced. Notably, the N-silylation of
1a efficiently proceeded even with two equivalents of 2a, affording
3aa in 83% yield. Rh2(pfb)4 (pfb = perfluorobutyrate, analogue
of Rh2(OAc)4) also gave 3aa in a moderate yield (Table S2, ESIw).
Other rhodium complexes such as [RhCl2Cp*]2 (Cp* =
pentamethylcyclopentadienyl), [Rh(cod)Cl]2 (cod = 1,5-cy-
clooctadiene), and Rh(PPh3)3Cl were not effective (Table S2,
ESIw), while these complexes have been reported to be active
for dehydrosilylation of alcohols14 and hydrosilylation of
alkenes and alkynes.15
Department of Applied Chemistry, School of Engineering,
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656,
Japan. E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp;
Fax: +81-3-5841-7220; Tel: +81-3-5841-7272
Kinds of bases were also crucial for the N-silylation of 1a.
Among the bases examined, TBA2WO4 was the most suitable
for the N-silylation of 1a (Table S3, ESIw). Other O-donor
w Electronic supplementary information (ESI) available: Experimental
details, data of N-silylated products, and Tables S1–S4, Fig. S1–S3,
and Scheme S1. See DOI: 10.1039/c2cc34381a
c
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Chem. Commun., 2012, 48, 9269–9271 9269

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Table 1 N-silylation of 1a with various hydrosilanesa
Table 2 N-silylation of various heterocycles with 2aa
Entry Substrate
Time/h Silylated product
Yield (%)
>99 (79)
1
2
Entry Hydrosilane
Temp./1C Time/h Conv. (%) Yield (%)
2
4
4
92
1
PhMe2Si–H (2a) 50
Ph2MeSi–H (2b) 80
2
3
24
12
24
24
>99
95
63
87
66
1
>99 (77)
79
46
85 (76)
66
Nd
2b
3b
4c
5b,c
6
Ph3Si–H (2c)
Et3Si–H (2d)
80
80
3b
73 (78)
t-BuMe2Si–H (2e) 80
i-Pr3Si–H (2f) 80
a
Reaction conditions: Rh2(OAc)4 (1 mol% with respect to 1a),
TBA2WO4 (2 mol% with respect to 1a), 1a (0.5 mmol), hydrosilane
(2.5 mmol), CH3CN (2 mL), Ar (1 atm). Conversions and yields are
based on 1a and determined by GC analysis. Values in the parentheses
4
2
97 (88)
b
are the yields of isolated products. Nd = not detected. Rh2(OAc)4
(2 mol% with respect to 1a), TBA2WO4 (4 mol% with respect to 1a).
5
6
7
8
2
4
4
2
4
99 (76)
>99
c
CH3CN (1 mL).
bases such as KOt-Bu, K2CO3, TBAOH, K3PO4, and Cs2CO3
also gave 3aa in moderate to high yields, while N-donor bases such
as triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
were not effective (Table S3, ESIw). The selection of solvents
was also very important; the reaction efficiently proceeded in
acetonitrile and benzonitrile, while the reaction hardly proceeded
using other solvents such as DMSO, DMF, and acetone
(Table S4, ESIw). Not only 2a but also various structurally
diverse hydrosilanes could be utilized as silylating reagents.
The N-silylation with diphenylmethylsilane (2b), triphenylsilane
(2c), triethylsilane (2d), and tert-butyldimethylsilane (2e) afforded
the corresponding N-silylated indoles in moderate to high yields
(Table 1, entries 2–5). On the other hand, the reaction with
triisopropylsilane (2f) hardly proceeded likely due to the steric
hindrance of the isopropyl groups (Table 1, entry 6).
82 (55)
>99
9
88 (78)
10
2
6
98 (74)
98
11c
Next, the N-silylation of various indoles with 2a was carried out
(Table 2). Methyl substitutions at C3 and C5 positions of indole
rings did not affect the reaction rates (Table 2, entries 4 and 5),
while substitutions at C2 and C7 positions required longer reaction
times due to the steric effect of the methyl groups (Table 2, entries
2 and 9). Similarly, the N-silylation of 2-phenylindole (1c) required
a longer reaction time and a large amount of Rh2(OAc)4 and
TBA2WO4 to attain a high yield of the corresponding N-silylated
indole (Table 2, entry 3). The N-silylation of indoles with
electron-donating as well as electron-withdrawing substituents
at C5 positions efficiently proceeded to give the corresponding
substituted N-silylated indoles in high yields ( Z 82% yields)
(Table 2, entries 5–8). In the case of halo-substituted indoles,
the desired N-silylated indoles were obtained without dehalogena-
tion. Thus, it would be possible to utilize these halo-functionalities
for further modification of the indole molecules.5,11 Besides
indole derivatives, pyrrole (4a) and carbazole (6a) were
also silylated to afford the corresponding N-silylated products
in Z 98% yields (Table 2, entries 10 and 11).
a
Reaction conditions: Rh2(OAc)4 (1 mol% with respect to nitrogen
heterocycles), TBA2WO4 (2 mol% with respect to nitrogen hetero-
cycles), nitrogen heterocycles (0.5 mmol), 2a (2.5 mmol), CH3CN
(2 mL), Ar (1 atm), 50 1C. Yields are based on nitrogen heterocycles
and determined by GC analysis. Values in the parentheses are the
b
yields of isolated products. Rh2(OAc)4 (2 mol% with respect to
nitrogen heterocycles), TBA2WO4 (4 mol% with respect to nitrogen
c
heterocycles). 80 1C.
to the TBA2WO4 solution, a new set of signals appeared,
which agrees with the pattern calculated for [TBA2(PhMe2Si)-
WO4(PhMe2SiOAc)]+ (Fig. S1b, ESIw). The new set of signals
did not appear in the absence of Rh2(OAc)4. In addition, the
1H NMR spectrum of Rh2(OAc)4 (25 mM) and 2a (10 mM) in
acetonitrile-d3 showed signals due to dimethylphenylsilanol
and H2 (Fig. S2, ESIw), suggesting that Rh2(OAc)4 can activate
2a. Dimethylphenylsilanol and H2 are probably produced
through the activation of 2a by Rh2(OAc)4,y followed by the
reaction with water (including in Rh2(OAc)4 and/or the solvent).
Thus, the Si–H bond of 2a is initially activated by Rh2(OAc)4
The positive-ion cold-spray ionization mass (CSI-MS) spectrum
of an acetonitrile solution of TBA2WO4 showed a set of signals
due to [TBA3WO4]+ (Fig. S1a, ESIw). Upon the addition of
Rh2(OAc)4 and 2a (Rh2(OAc)4 : TBA2WO4 : 2a = 1 : 1 : 40)
c
9270 Chem. Commun., 2012, 48, 9269–9271
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(step 1 in Scheme S1, ESIw), and then a silicon electrophile
stabilized on TBA2WO4 is possibly formed (step 2 in Scheme S1,
ESIw). In the dehydrosilylation of alcohols with hydrosilanes
using Rh2(pfb)4 (analogue of Rh2(OAc)4), the reaction mechanism
of the coordination (not oxidative addition) of Si–H bonds to the
Rh sites for backside nucleophilic attack by alcohols has been
proposed.16 In addition, it has been reported that a silicon
electrophile can be stabilized on polyoxotungstates.17
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The H NMR spectrum of 1a in acetonitrile-d3 showed the
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signal of the NH proton at 9.4 ppm (Fig. S3a, ESIw). A
significant downfield shift (from 9.4 ppm to 13.6 ppm) was
observed upon addition of one equivalent of TBA2WO4 with
respect to 1a (Fig. S3b, ESIw). These results indicate the
hydrogen-bonding interaction between TBA2WO4 and 1a
that could weaken the N–H bond of 1a and facilitate the
electrophilic attack of activated hydrosilanes on the nitrogen
atom of 1a. In contrast, significant downfield shifts of the NH
proton of 1a were not observed with N-donor bases such as
triethylamine and DBU. Thus, these bases were not effective for
the present Rh2(OAc)4-catalyzed N-silylation, as mentioned
above (Table S3, ESIw).
Therefore, both activated hydrosilanes and indoles likely
co-existed on the TBA2WO4 molecules, resulting in efficient
promotion of the present N-silylation (step 3 in Scheme S1,
ESIw). Acetonitrile (solvent) also takes part in the catalytic
cycle; rhodium species and bases are regenerated by the
hydrogenation of acetonitrile (step 4 in Scheme S1, ESIw),z
and the catalytic cycle is complete. The present Rh2(OAc)4/
base-catalyzed N-silylation of indoles with hydrosilanes
likely proceeds via the ionic silylation mechanism shown in
Scheme S1 (ESIw). In the hydrosilylation of ketones, a similar
ionic hydrosilylation mechanism has been proposed.18
This work was supported in part by Grants-in-Aid for
Scientific Researches from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
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Notes and references
z During the review process of this manuscript, Tsuchimoto and
co-workers have reported the efficient zinc-catalyzed N-silylation of
indoles with hydrosilanes in the presence of nitrogen bases.11
y In the CSI-MS as well as 1H and 29Si NMR spectra of Rh2(OAc)4
(25 mM) and 2a (10 mM) in acetonitrile, no signals due to the
corresponding silyl metal hydride species were detected. Rh(PPh3)3Cl
and [RuCl2(p-cymene)]2, which are well known to form silyl metal
hydride species by oxidative addition of hydrosilanes,14 were not
effective for the N-silylation. Thus, the oxidative addition mechanism
can likely be excluded for the present N-silylation.
z During the present N-silylation, dimethylphenylsilylethylamine
formed as a co-product in all cases, which likely formed through the
hydrogenation of acetonitrile followed by hydrosilylation. For example,
dimethylphenylsilylethylamine formed in 95% yield (based on 1a)
during the N-silylation of 1a with 2a under the conditions described
in Table 2. Although silylamines formed from nitriles (solvents) as
co-products during the present N-silylation of indoles, silylamines can
be further converted into the corresponding primary amines by simple
hydrolysis.
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c
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Chem. Commun., 2012, 48, 9269–9271 9271