B(C6F5)3-Catalyzed (Convergent) Disproportionation Reaction of Indoles

Article abstract of DOI:10.1021/jacs.7b03534

A metal-free B(C₆F₅)₃-catalyzed approach is developed for the disproportionation reaction of a series of indoles with various hydrosilanes, without any additives such as base and production of any small molecule such as dihydrogen. This boron catalyst system also exhibits excellent catalytic performance for practical application, such as catalyst loading as low as 0.01 mol % under solvent-free conditions, and a long-life catalytic performance highlighted by a constant catalytic activity being maintained and excellent yields being achieved for the desired products over 10 sequential additions of starting materials. On the basis of characterization of key intermediates through a series of in situ NMR reactions and detailed experimental data, we proposed a reaction mechanism which illustrated pathways for the formation of different products, including both major products and byproducts. Additional control experiments were conducted to support our proposed mechanism. Understanding the mechanism enables us to successfully suppress side reactions by choosing appropriate substrates and hydrosilanes. More importantly, the use of an elevated reaction temperature for continuous oxidation of the resulting indoline to indole makes the convergent disproportionation reaction an ideal atom-economical process. Near-quantitative conversions and up to 99% yields of C3-silylated indoles were achieved for various indoles with trisubstituted silanes, Ph₃SiH (2b) or Ph₂MeSiH (2d).

Full text of DOI:10.1021/jacs.7b03534

Article
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B(CF)–catalyzed (Convergent) Disproportionation Reaction of Indoles
Yuxi Han, Sutao Zhang, Jianghua He, and Yuetao Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 May 2017
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Journal of the American Chemical Society
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B(C6F5)3–catalyzed (Convergent) Disproportionation Reaction of In-
doles
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Yuxi Han, Sutao Zhang, Jianghua He, and Yuetao Zhang*
State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun,
Jilin, 130012, China.
ABSTRACT: A metal free B(C6F5)3–catalyzed approach is developed for disproportionation reaction of a series of indoles
with various hydrosilanes, without any additives such as base and production of any small molecule such as dihydrogen.
This boron catalyst system also exhibits excellent catalytic performance for practical application, such as catalyst loading
as low as 0.01 mol% under solvent free condition, and a long life catalytic performance highlighted by maintaining a con-
stant catalytic activity and achieving excellent yields for desired products over ten sequential addition of starting materi-
als. Based on characterization of key intermediates through a series of in–situ NMR reactions and detailed experimental data,
we proposed reaction mechanism which illustrated pathways for the formation of different products, including both ma-
jor products and byproducts. Additional control experiments were conducted to support our proposed mechanism. Understand-
ing of mechanism enable us to successfully suppress side reactions by choosing appropriate substrates and hydrosilanes.
More importantly, the use of elevated reaction temperature for continuous oxidation of resulted indoline to indole makes
the convergent disproportionation reaction an ideal atom-economical process. Near quantitative conversions and up to
99% yields of C3-silylated indoles were achieved for various indoles with trisubstituted silanes, Ph3SiH(2b) or Ph2MeSiH
(2d).
INTRODUCTION
Scheme 1. B(C6F5)3-catalyzed (convergent) dispropor-
tionation reaction of indoles
As an important family of bioactive natural products,
indole and its derivatives have attracted considerable at-
tention in the fields of synthetic chemistry,1 material sci-
ence2 and medicinal chemistry.3 Owning to the very useful
physicochemical properties of silylated indoles, various
synthetic strategies have been developed to synthesize
regioselective silylated indoles in last few decades,4 in-
cluding stoichiometric silylation reactions between het-
eroaryl organometallic species and silicon electrophiles5
or direct, transition metal catalyzed intermolecular C–H
silylation using rhodium or iridium complexes,6 and the
transition–metal–free C–H silylation as well.7 In general,
metal-based catalyst is required for C–H silylation or ex-
cessive hydrogen acceptors or additives is necessary for
achieving enhanced catalyst turnover,6b, 6c which restricts
these synthetic methods from their practical applications.
Therefore, it remains as challenging task for people to
develop a general synthetic method to overcome such
limitations for preparation of silylated indoles.
B(C6F5)3 catalyst is required. They also proposed that
there exist competing reaction pathways between dehy-
drogenative coupling vs hydrosilylation and hydrogena-
tion in the C–H silylation of heteroarenes with hy-
drosilanes. By adding steric bulky base, 2, 6-
dichloropyridin, they were able to suppress these side
reactions to certain extent and achieved the C3-silylated
indole and indoline in 59% and 19% yield, respectively.11
In 2016, Hou and co-workers reported the effective C–H
silylation of a broad range of anilines by B(C6F5)3 at 120 °C,
which indicated that high temperature promote the C–H
silylation and release molecular hydrogen.While for 1-
methylindole, C5-silylated indole is isolated in 34% yield
As
the
potent
Boron
Lewis
acid
tris(pentafluorophenyl)borane, B(C6F5)3, and related elec-
tron-deficient boron catalysts often served as powerful
metal free tools for activation of dihydrogen and related
transformations,8 such as the seminal work reported by
Stephan and Erker.9 More recently, great advancements
have also been achieved in the boron catalyzed hydrosi-
lylation and hydrogenation.10 In 2014, Ingleson and co-
workers has achieved silylated indole and indoline in 30%
and 21% yield in the same reaction but the equal molar
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Page 2 of 10
plus a small amount of C3, C5-disilylated indole.12 Later,
Table 1. With a fixed 2:1 indole/2a ratio, we observed 93%
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Grimme and Paradies discovered that at 120 °C, B(C6F5)3
could catalyze the dehydrogenative oxidation of a series
of N-protected indolines into indoles, with concomitant
liberation of molecular hydrogen.13 It is noted that indo-
line is always observed as byproducts in the C–H silyla-
tion of indoles as reported by Ostreich and co-workers in
the the Brønsted acid [H(OEt)2]+[BArF4]– catalyzed C–H
of 1a was converted into 4aa in 43% yield and 5a in 45%
yield (Table 1, entry1). Indoles bearing electron-donating
methyl group at C4-C7 positions furnished with 4ba-4ea
in 43–49% yield and corresponding transfer hydrogenated
products 5b–5e in 41–48% yield (Table 1, entry 2–5), re-
spectively. While indoles bearing electron-withdrawing
substituents such as halogen-containing motifs (F, Cl, and
Br) at C5 or C6 position all steered the reaction toward
the highly selective production of 4fa-4ja in 41–48% yield
and 5f–5j in 42–47% yield without dehalogenation (Table
1, entry 6–11). These reactive halogen substituents leave
the further derivation potential to form diverse silylated
products. With a phenyl substituent at C5 position, 1-
methyl-5-phenyl-indole (1l) afforded 45% yield of 4la and
47% yield of 5l (Table 1, entry 12). It is noted that the con-
versions of these indoles remained unchanged even with
prolonged reaction time to 24 h. These results suggested
such disproportionation of indole is a reversible reaction
and reached equilibrium under these conditions. There-
fore, adding more starting material of 2a is expected to
shift equilibrium toward the right direction. To our de-
light, near quantitative conversion are achieved for all
indoles with 1:2 indole/2a ratio. However, in addition to
silylated indoles and substituted indolines, the presence
of excess amount of reducing agent 2a also led to the
formation of C5-silylated indolines. It is noted that the
corresponding C5-silylated indoline yield for C6-
substituted indoles follows the increasing order of elec-
tron–withdrawing power of C6 substituent: Me (1d, 3%
yield of 6da) < Br (1k, 9% yield of 6ka) < Cl (1i, 15%
yield of 6ia) < F (1g, 52% yield of 6ga). The molecular
structure of 6ga is confirmed by single–crystal X–ray dif-
fraction analysis (Figure 1). Interestingly, if the C5 posi-
tion is occupied, this side reaction could be completely
suppressed and thus near quantitative conversion of such
indoles and near 50% yield for both silylated indole and
indoline are successfully achieved (Table 1, entry 15, 18, 20,
22, 24). For example, 99% conversion is achieved for 5-Me
substituted indole (1c) and 4ca and 5c is produced in 49%
and 49% yield, respectively. Similar results were also
achieved for 5-F (1f), 5-Cl (1h), 5-Br (1j), 5-Ph (1l) with 99%
conversion and 49% yield for both C3-silylated indole and
indoline.
silylation
of
heteroarenes.14
Interestingly,
with
9
B(C6F5)3/diphenylhydrosilane (Ph2SiH2), Zhang and co-
workers successfully achieved indoline in 75% yield from
the reduction of indole at 75 °C.15 As shown by the above
overview, there are still several undressed key issues in
the C–H silylation of indoles by B(C6F5)3. First, atom eco-
nomical process without adding additives is needed. Sec-
ond, green and practical synthetic method is desirable.
Third, detailed mechanistic studies of B(C6F5)3–catalyzed
silylation or reduction of indoles are lacking. To this end,
this contribution revealed the disproportionation nature
of the B(C6F5)3–catalyzed C–H silylation (oxidation reac-
tion) and transfer hydrogenation (reduction reaction) of
indoles at room temperature (Scheme 1a), which produces
C3-silylated indoles (oxidation products) and indolines
(reduction products), respectively. This catalyst systems
exhibited green chemistry features, such as low catalyst
loading of 0.01 mol%, solvent free, and most notably a
long life catalytic performance over ten sequential addi-
tion of starting materials. Based on the characterization of
key reaction intermediates through a series of in–situ
NMR reactions and detailed experimental data, we pro-
posed mechanism for the disproportionation reaction of
indoles to describe the pathway for the formation of si-
lylated indoles and indolines, including both major prod-
ucts and byproducts. Additional control experiments were
conducted to support our proposed mechanism. With the
understanding of mechanism, we could successfully sup-
press side reactions by choosing appropriate substrates
and hydrosilanes. More importantly, with increased reac-
tion temperature, we successfully realize the B(C6F5)3 cat-
alyzed–convergent disproportionation reaction with ideal
atom economy such that indolines are continuously con-
verted back to indole starting materials, which proceed
with disproportionation reaction to afford C3-silylated
indoles and indolines for the next catalytic cycle, and thus
up to 99% yield of C3-selective silylation products is
achieved (Scheme 1b).
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RESULTS AND DISCUSSION
We initiated our studies with the reaction of 1-
methylindole (1a) with Ph2SiH2 (2a) by various electron–
deficient boron catalyst and found that B(C6F5)3 is the
only one but highly effective catalyst for the reaction (Ta-
ble S1). Combined with the screening results of the other
parameters (solvent, temperature, reaction time, catalyst
loading, and substrate ratio), the reaction was carried out
with 1 mol% catalyst loading of B(C6F5)3 to expand the
scope of indoles in deuterated benzene at room tempera-
ture for about 10 min, affording C3-silylated indoles and
indolines. Some representative results are summarized in
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Figure 1. X–ray crystal structure of 6ga. Hydrogen atoms are
omitted for clarity and ellipsoids drawn at 50% probability.
Figure 2. Long life catalytic performance of B(C6F5)3–
catalyzed disproportionation reaction of 1f.
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Table 1. Disproportionation Reaction of Indoles with
Diphenylsilanea
The preparative scale (13 g) and enviromental friendly
feature of this new method has been demonstrated by
performing this disproportionation reaction under
solvent–free condition. With 0.01 mol% catalyst loading
and 2:1 1a/2a ratio, we are greatly gratified to see 97% of
1a was converted into 4aa in 46% yield and 5a in 45%
yield. It is also noteworthy that the separation of 4aa and
5a is very convenient (check supporting information for
details). More significantly, the practicability of this new
method was also verified by the reuse experiments of this
borane catalyst. In order to shift the equilibrium but
avoid the formation of 6fa, we use 2:1.2 1f/2a ratio instead
of 2:1 to repeat reaction for 10 times at room temperature,
it is striking to see such borane catalyst has a long life
catalytic performance and maintains a constant catalytic
activity. The conversion remained unchanged around 96%
and the excellent yield of more than 47% was achieved for
both 4fa and 5f (Figure 2).
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Entry
1
Conv.
(%)b
4
(%)b
5
6
(%)b
(%)b
1
1a, R = H
93
85
97
97
91
4aa, 43
4ba, 43
4ca, 49
4da, 49
4ea, 46
4fa, 45
4ga, 41
4ha, 46
4ia, 47
4ja, 45
4ka, 48
4la, 45
4aa, 41
4ba, 46
4ca, 49
4da, 49
4ea, 46
4fa, 49
4ga, 20
4ha, 49
4ia, 41
5a, 45
5b, 41
5c, 48
5d, 47
5e, 43
5f, 45
5g, 42
5h, 46
5i, 46
5j, 46
5k, 47
5l, 47
5a, 41
5b, 45
5c, 49
5d, 47
5e, 43
5f, 49
5g, 26
5h, 49
5i, 44
5j, 49
5k, 46
5l, 49
6aa, 2
6ba, 1
6ca, 0
6da, 0
6ea, 2
6fa, 0
6ga, 12
6ha, 0
6ia, 1
2
1b, R = 4–Me
1c, R = 5–Me
1d, R = 6–Me
1e, R = 7–Me
1f, R = 5–F
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7
1g, R = 6–F
1h, R = 5–Cl
1i, R = 6–Cl
1j, R = 5–Br
1k, R = 6–Br
1l, R = 5–Ph
1a, R = H
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9
10
11
6ja, 0
6ka, 1
6la, 0
6aa, 18
6ba, 7
6ca, 0
6da, 3
6ea, 10
6fa, 0
6ga, 52
6ha, 0
6ia, 15
6ja, 0
6ka, 9
6la, 0
Next, using 1a as model substrate, we examined the
scope of hydrosilanes for the reaction with a 2:1 1a/silane
ratio in deuterated benzene at room temperature (Table
2). It turned out that a much wider range of hydrosilanes
could be employed and no specific substituent at the sili-
con atom of hydrosilanes is required. Good to high con-
versions are achieved for hydrosilanes with either alkyl-
or phenyl-substituents. More remarkably, chlorohy-
drosilanes containing a highly reactive Si–Cl bond, such
as Me2SiHCl (2h, Table 2, entry 4) and Ph2SiHCl (2i, Table
2, entry 5), could also selectively undergo the silylation
and transfer hydrogenation of indoles, leaving the reac-
tive chloride intact. The excellent Si–Cl compatibility of
the present borane catalyst should enable the synthesis of
further functionalized silylated organic compounds. It is
also notable that sterically encumbered Ph3SiH (2b, Table
2, entry 6) achieved 91% conversion and high yield of 4ab
of 48% and 5a of 42%, which is typically either ineffective
or inactive for the silylation of indoles.6c, 16 The molecular
structure of 4ab was further confirmed by single–crystal
X–ray diffraction analysis (Figure 3). Based on these re-
sults, we investigated the disproportionation reaction of
2b with a series of indoles, there is no observation for the
formation of C5-silylated indoline at all (Table S3). How-
ever, it took 2b more than 14 h to reach around 90% con-
version for most reactions with 2:1 indole/2b ratio, which
indicated 2b is less effective than 2a, probably due to its
steric hindrance. With a 1:2 indole/2b ratio, near quanti-
tative conversion was achieved for most reaction at room
temperature for 18 h, except for 1,4-dimethylindole (Table
S3, entry 40, 1b, 23% conversion) and 1,7-dimethylindole
(Table S3, entry 47, 1e, 55% conversion). The correspond-
ing yield (Table S3) for C3-silylated products and transfer
hydrogenated products is 47–49% and 45–48%, respec-
tively. While with the less sterically crowded phenylsilane,
PhSiH3 (2c, Table 2, entry 7), and a 2:1 1a/2c ratio, the ma-
jor product is achieved as bis(indol-3-yl)substituted prod-
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24
1b, R = 4–Me
1c, R = 5–Me
1d, R = 6–Me
1e, R = 7–Me
1f, R = 5–F
1g, R = 6–F
1h, R = 5–Cl
1i, R = 6–Cl
1j, R = 5–Br
1k, R = 6–Br
1l, R = 5–Ph
4ja, 49
4ka, 44
4la, 49
a Entry 1–12, [1]/[2a] = 2:1, Entry 13–24, [1]/[2a] = 1:2. b Conversion and yield
determined by 1H NMR analysis.
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uct 7ac in 29 % yield instead of 4ac as expected (11%
yield), along with 5a in 40% yield. In order to improve the
yield of 7ac, we employed a 4:1 1a/2c ratio to achieve the
enhanced yield of 7ac in 44% along with 5a in 45% yield
and trace amount of 4ac. It is noted that 2c is effective for
various indoles and a series bis(indol-3-yl) substituted
products 7bc–7lc were achieved in high yields (Figure 4).
Page 4 of 10
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Table 2. Screening of Hydrosilane Scopes in the Dis-
proportionation Reaction of Indoles a
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Entry
hydrosilane
Time
(h)
Conv.
(%)[b]
4
(%)b
5a
(%)b
Figure 4. Various bis(indol-3-yl)substituted products
1
MePh2SiH
Me2PhSiH
Et2SiH2
3
96
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93
85
98
91
4ad, 49
4ae, 45
4af, 42
4ah, 28
4ai, 43
4ab, 48
7ac, 29
4ac, 11
46
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42
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40
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5
6
7
3
Understanding the mechanism will enable us to make
advancements in the catalyst development. We initially
examined the above–mentioned disproportionation
reaction of 1a, 2a, and 3a with 10:5:1 ratio. In addition to
corresponding disproportionation products 4aa and 5a,
3
Me2SiHCl
Ph2SiHCl
Ph3SiH
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14
3
1
PhSiH3
88
the H NMR spectrum consisted a group of unknown
peaks (Figure 5a), while the 19F NMR spectrum clearly
a
b
exhibited
a four–coordinated borohydride analogue
Reaction condition: [1a]/[hydrosilane] = 2:1. 1–5 mol% B(C6F5)3. Conversion
and yield determined by 1H NMR analysis.
(Figure 5a),17 which might be ascribed to the reaction
intermediate. In order to determine its structure, at first,
we conducted a series of in–situ NMR reaction with either
two of 1a, 2a, 3a and 5a and found there is no obvious
interaction observed in the different combinations of
either two species (Figure S2 and S3), except for the
reaction of 3a and 5a.13 It is clear that the intermediate is
not resulted from such combination. While the reaction
of 3a, 5a and 2a with 1:1:1 ratio afforded complex 3e as
major product (Figure 5b) and the reaction of 3a, 5a, and
4aa with 1:1:1 ratio yielded complex 3f as major product
(Figure 5c). 19F NMR spectra indicated that both of them
are ion pairs composed of silylindolinium ion and a
borohydride. Prof. Oestreich discovered unexpected
intermediates of free amine and N-silylated enamine in
equimolar ratio instead of ion pair in the borane–
18
catalyzed Si–N hydrosilylation of imine,
while
Figure 3. X–ray crystal structure of 4ab. Hydrogen atoms are
omitted for clarity and ellipsoids drawn at 50% probability
borohydride species was proposed for the Si–N
hydrosilylation of indoles.19 However, there is no
characterization of such ion pair intermediate up to date.
Adding 1 equiv. of 4aa to complex 3e shifted the
equilibrium towards the partial conversion of 3e into 3f
(Figure 5d vs Figure 5b). In addition, according to the
charaterization of 3f, those small unknown peaks
observed in the reaction of 1a, 2a, and 3a with 10:5:1 ratio
could be assigned to complex 3f (Figure 5c vs Figure 5a).
Notably, 19F NMR spectra of these above–mentioned
reactions all contained the same species (borohydride).
These results strongly suggested that complex 3e and 3f
are very important key intermediates for the dispropor-
tionation reaction. The equilibrium between complex 3e
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and 3f could be disturbed by changing of reactants, and
thus yielded different products and byproducts.
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With successful characterization of key intermediates
and detailed experimental data, we proposed the
following reaction mechanism (Scheme 2) in that 3a
activated 2a through a B···H interaction to form the weak
adduct 3b, which is nucleophilic attacked by the electron–
rich indole 1a to yield highly Brønsted–acidic Wheland
9
complex 3c along with
a borohydride, which was
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subsequently nucleophilic attacked by another unreacted
molecule of 1a to form the desired C3-silylated product
4aa and the Wheland complex 3d. The hydride is trans-
ferred onto 3d to form indoline 5a and regenerate the
catalyst 3a. In the presence of hydrosilane 2a, the equilib-
rium reaction between 3a and 5a is shifted to produce 3e
as major borohydride intermediate, which is nucleophilic
attacked by 1a to yield 5a and reform the Wheland com-
plex 3c that re-enters into the next catalytic cycle (cycle 1,
black); while the attack of complex 3e by 5a produced
another molecule of 5a and Wheland complex 3h, which
is subsequently attacked by 1a to form a byproduct 6aa
and regenerate Wheland complex 3d that re-enters into
the next catalytic cycle (cycle 2, red). With C-5 substitut-
ed indoles, the C–H silylation occurring at C5 position
was inhibited, and thus no C5-silylated indoline is formed,
which also confirmed the cycle 2 of proposed mechanism.
We also verified cycle 2 by conducting the following con-
trol reaction of 1, 3-dimethyl-indole (1m), 1–methyl–6–
fluoro–indoline (5g) and 2a with 1:1:2 ratio at room tem-
perature: similar to cycle 2, 5g took place C5-silylation to
afford 5-(diphenylsilyl)-6-fluoro-1-methylindoline 6ga in
32% yield while 1m was completely consumed but only 38%
yield of 1, 3-dimethyl-indoline (5m) and 16% yield of 5-
(diphenylsilyl)-1,3-dimethylindoline (6ma) was observed,
which implied that partial 5m consumed 1m for C5-
silylation, and thus resulted in around 14% of 5g re-
mained unreacted (Figure S11). In the late stage of the
reaction, with increased amounts of 4aa, the equilibrium
reaction between 3a and 5a is shifted to form complex 3f,
which is attacked by another 1a to produce reduced prod-
uct 5a and Wheland complex 3g, followed by attack of
another molecular 1a to yield bis(indol-3-yl)substituted
byproduct 7aa and regenerate complex 3d (cycle 3, blue).
We also run the following control experiment to test cycle
3: to our expected, 4aa serving as silane to react with 1a in
1:2 ratio at room temperature afforded both 7aa and 5a in
41% yield (Figure S12). Furthermore, we have successful
isolated and characterized 7aa from the above-described
reaction. The molecular structure of 7aa was also con-
firmed by single crystal X–ray diffraction analysis (Figure
7), which provided additional evidence to support the
cycle 3 of proposed mechanism. Therefore, by choosing
appropriate reactants, we could verify the reaction path-
ways as shown in cycle 2 and cycle 3 of proposed mecha-
nism.
1
Figure 5. Overlay of H NMR spectra for (a) reaction with
1:10:5 3a:1a:2a ratio, (b) complex 3e as major product ob-
tained in the reaction with 1:1:1 2a:3a:5a ratio, (c) complex 3f
as major product obtained in the reaction with 1:1:1 3a:4aa:5a
ratio, (d) adding one more equiv. 4aa to the reaction with
1:1:1 2a:3a:5a ratio (CD2Cl2, 500 MHz).
Figure 6. Overlay of 19F NMR spectra for reaction with (a)
1:10:5 3a:1a:2a ratio, (b) 1:1:1 2a:3a:5a ratio, (c) 1:1:1 3a:4aa:5a
ratio, (d) add one more equiv. 4aa to the in–situ NMR reac-
tion with 1:1:1 2a:3a:5a ratio (CD2Cl2, 471 MHz).
Figure 7. X–ray crystal structure of 7aa. Hydrogen atoms are
omitted for clarity and ellipsoids drawn at 50% probability.
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Scheme 2. Possible mechanism for B(C6F5)3–Catalyzed After thorough investigation of disproportionation re-
1
2
3
4
5
6
7
8
disproportionation reaction of indoles
action, we turned our attention to improve the atom
economy of the reaction, which is not very good for dis-
proportionation reaction in general because the reaction
simultaneously produces an oxidation product and a re-
duction product, and thus the ideal yield for each product
is only 50%. However, a convergent disproportionation
reaction usually exhibits higher atom economy as it will
initially convert one of the resulted products back to
starting materials, which subsequently undergo the dis-
proportionation reaction to give the desired products. 20
As reported by Professor Grimme and Paradies, Borane
served as a highly effective catalyst to oxidize indoline to
9
10
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12
13
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60
13
indole in excellent yield at 120 °C. Therefore, we envi-
sioned that with increased temperature of the above–
mentioned disproportionation reaction, the resulted in-
dolines could be continuously converted back to indoles,
which proceed with disproportionation reaction to repro-
duce C3-silylated indole and indoline again, and thus the
enhanced yield of the C3-selective silylation will be
achieved (scheme 1b). Obviously, such goal could not be
accomplished by the reaction of 1a with 2a, as we have
demonstrated that at room temperature 6aa and 7aa al-
ways existed as byproducts (vide supra) while elevated
temperature facilitate dehydrogenative oxidation of in-
dolines, and thus yielded 7aa and C3,C5-disilylated prod-
uct, which makes the silylation of indole more complicat-
ed. Similar result was observed by Hou.12 According to the
mechanism, we should be able to prevent or suppress
these side reactions by choosing appropriate reactants.
1,5-dimethyl indole 1c was employed as substrate to react
with different silanes to prevent formation of C-5 silylated
indoline. Disubstituted silane, 2a, furnished C3-silylated
indole product 4ca in 69% yield and bis(indol-3-
yl)substituted byproduct 7ca in 22% yield without for-
mation of indolines (Table 3, entry 1). This results indicat-
ed that we are heading to the right direction. As 7ca is
clearly produced from the side reaction as shown in cycle
3 (Scheme 2), to prevent the formation of such byprod-
ucts, we choose trisubstituted silanes, 2b (Ph3SiH) and 2d
(Ph2MeSiH), as silicon sources for the reaction. Highly
C3-selective silylation products were achieved in excellent
yield for 2b (4cb, 93%) and 2d (4cd, 95%) (Table 3, en-
tries 2 and 3). These results encouraged us to further ex-
amine the reaction of trisubstituted silane with the other
C-5 substituted indoles (Table 3, entries 4–11). To our
great delight, 2b afforded near quantitative conversion
and more than 91% yield of C3-silylated indole for almost
all C5 substituted indoles (1f, 92%; 1h, 91%; 1l, 99%), ex-
cept for 1j (83%), while 2d achieved 100% conversion and
excellent yield of C3-silylated indole in the range of 95–99%
(1f, 99%; 1h, 99%; 1j, 95%; 1l, 99%). As shown in the dis-
proportionation reaction of indoles (Table S3), 2b exhibit-
ed excellent C3-silylation selectivity without formation of
C5-silylated indolines for all indoles, probably due to its
large steric hindrance. Therefore, we also examined the
convergent disproportionation reaction of 2b or 2d with
non-C5 substituted indoles. For 2d with smaller steric
hindrance (Table 3, entries 12–18), quantitative conversion
of indole and high yield of C3-silylated product is
Table 3. Convergent Disproportionation Reaction of
Indoles a
En-
try
Substrate
hydrosilane
Time
(h)
Conv.
(%)b
4
(%)b
other
(%)b
1c
1c, R = 5–Me
1c, R = 5–Me
1c, R = 5–Me
1f, R = 5–F
Ph2SiH2
Ph3SiH
48
100
100
100
96
4ca, 69
4cb, 93
4cd, 95
4fb, 92
4hb, 91
4jb, 83
4lb, 99
4fd, 99
4hd, 99
4jd, 95
4ld, 99
4ad, 86
4bd, 79
4dd, 93
4ed, 90
4gd, 79
4id, 95
4kd, 98
4ab, 94
4bb, 75
4db, 93
4eb, 98
4gb, 94
4ib, 94
4kb, 94
9
2.5
2
7
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
14
3
Ph2MeSiH
Ph3SiH
5
4
4
Ph3SiH
Ph3SiH
5
1h, R = 5–Cl
1j, R = 5–Br
1l, R = 5–Ph
1f, R = 5–F
96
5
6
97
14
1
7
Ph3SiH
100
100
100
100
100
100
88
Ph2MeSiH
8
1
Ph2MeSiH
9
1h, R = 5–Cl
1j, R = 5–Br
1l, R = 5–Ph
1a, R = H
1
10
11
Ph2MeSiH
5
Ph2MeSiH
1
Ph2MeSiH
12
13
14
15
16
17
18
19
20
21
22
23
24
25
14d
9d
7d
10d
21d
4d
2d
2
1b, R = 4–Me
1d, R = 6–Me
1e, R = 7–Me
1g, R = 6–F
1i, R = 6–Cl
1k, R = 6–Br
1a, R = H
Ph2MeSiH
Ph2MeSiH
2.5
2.5
2.5
2.5
2.5
9
100
100
100
99
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
100
96
Ph3SiH
14
1b, R = 4–Me
1d, R = 6–Me
1e, R = 7–Me
1g, R = 6–F
1i, R = 6–Cl
1k, R = 6–Br
Ph3SiH
Ph3SiH
76
1
2.5
2.5
2.5
2.5
2.5
100
100
99
7
Ph3SiH
Ph3SiH
Ph3SiH
Ph3SiH
2
5
98
4
98
4
a Reaction condition: [1]/[hydrosilane] = 1:2. b Conversion and yield determined
by 1H NMR analysis. c Yield of 7ca is 22%. d C3,C5-disilylated products.
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Journal of the American Chemical Society
achieved for most indoles (such as 1d, 93%; 1e, 90%; 1i, indoline and one C3,C5-disilylated indole in total. These
1
2
3
4
5
6
7
8
95%; 1k, 98%), except for 1a (86%), 1b (79%) and 1g (79%).
However, C3,C5-disilylated byproduct is always observed
for all non C5-substituted indoles (up to 21% yield). Such
byproduct is probably resulted from the C5-silylation of
indolines, followed by dehydrogenation to form C5-
silylated indole and then C3-silylation to afford the C3,
C5-disilylated products. It worth noting that more steri-
findings also enable us to synthesize various regioselec-
tive silylated products through such green and highly
efficient methodology on the expanding the substrates
and hydrosilanes. Relevant research work is in progress.
EXPERIMENTAL SECTION
General Information. All syntheses and manipulations
of air- and moisture–sensitive materials were carried out
in flamed Schlenk–type glassware on a dual-manifold
Schlenk line, a high-vacuum line, or an argon-filled
glovebox. Toluene, benzene, THF, hexane and dichloro-
methane, acetonitrile, dimethylacetamide were refluxed
over sodium/potassium alloy and CaH2 distilled under
nitrogen atmosphere, then stored over molecular sieves 4
Å . C6D6, C7D8, CDCl3, CD2Cl2 was dried over molecular
sieves 4 Å . NMR spectra were recorded on a Varian Inova
cally hindered 2b, which is typically either ineffective or
6c, 16
9
inactive for the C3-silylation of indoles,
exhibited
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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58
59
60
highly selectivity for C3-silylation in the convergent dis-
proportionation reaction of indoles without formation of
C5-silylated products and C3,C5-disilylated products.
Near quantitative conversion and excellent yield of C3-
silylated indole in the range of 93–98% for most non C5-
substituted indoles (1a, 94%; 1d, 93%; 1e, 98%; 1g, 94%; 1i,
94%; 1k, 94%). The yield of C3-silylation product for 1b
(74%) and 1e (98%) obtained in convergent dispropor-
tionation is also significantly enhanced, while it is only 19%
for 1b and 38% for 1e obtained in disproportionation reac-
tion. Similar to disproportionation reaction, the conver-
gent disproportionation reaction of 2d with 1c also exhib-
ited a long life performance and maintains a constant
catalytic activity. The conversion remained unchanged
and the excellent yield of more than 93% was achieved for
4cd. (Figure S13).
1
300 (300 MHz, H; 75 MHz, 13C; 282 MHz, 19F) or Bruker
1
Avance II 500 (500 MHz, H; 126 MHz, 13C; 471 MHz, 19F)
1
instrument at room temperature. Chemical shifts for H
and 13C spectra were referenced to internal solvent reso-
nances and are reported as parts per million relative to
SiMe4, whereas 19F NMR spectra were referenced to exter-
13
nal CFCl3. 1H and C NMR chemical shifts are reported in
ppm relative to the residual solvent. Air sensitive NMR
samples were conducted in Teflon-valve sealed J. Young-
type NMR tubes.
CONCLUSIONS
Ph2SiH2 and 5-phenyl-1H-indole were purchased from
J&K. Cyclohexane, Et3N(TEA), methyl tert-butyl ether
(TBME), PhSiH3, PhMe2SiH and BF3.Et2O were purchased
from Titan. Tribromoborane, boron trichloride (1.0 M
solution in hexanes), 4-methyl-1H-indole, 5-methyl-1H-
indole, 6-methyl-1H-indole, 7-methyl-1H-indole, 5-fluoro-
1H-indole, 6-fluoro-1H-indole, 5-chloro-1H-indole, 6-
chloro-1H-indole, 5-bromo-1H-indole and 6-bromo-1H-
indole were purchased from Energy Chemical.
Fluorodimesitylborane, Ph3SiH, Ph2MeSiH and B(C6H5)3
was purchased from TCI. Et2SiH2, Me2SiHCl, Ph2SiHCl
and 1-methylindole were purchased from Alfa Aesar. All
of Chemicals were used as received unless otherwise spec-
ified as follows. Tris(pentafluorophenyl)borane, B(C6F5)3,
was prepared according to literature procedures.21 Methyl-
indole was prepared according to literature procedures.13
In summary, we have reported here an efficient, metal-
free B(C6F5)3-catalyzed method for rapid access to C3-
silylated indoles and transfer hydrogenated products in-
dolines in the disproportionation reaction, with a catalyst
loading as low as 0.01 mol%. In addition to its feature of
green chemistry and long life catalytic performance, this
method could also be applied to a series of indoles with a
variety of hydrosilanes under mild condition, without
adding any additives and production of any small mole-
cules. Characterization of key reaction intermediates
through a series of in–situ NMR reactions and detailed
experimental data led to the proposed reaction mecha-
nism which illustrated the pathways for the formation of
different silylated indoles and indolines, including both
major products and byproducts. Additional control exper-
iments were conducted to support our proposed mecha-
nism. Understanding the mechanism of disproportiona-
tion reaction enable us to successfully suppress side reac-
tions by choosing appropriate substrates and hydrosilanes.
More importantly, the use of elevated reaction tempera-
ture for continuous oxidation of resulted indoline to in-
dole makes the convergent disproportionation reaction
an ideal atom economical process in which B(C6F5)3 could
continuously catalyze the oxidation of resulted indoline
to indole, which proceeded with disproportionation reac-
tion to reproduce C3-silylated indole and indoline that re-
enters next catalytic cycle, and thus achieving C3-silylated
indoles in up to 99% yield. To this end, with twelve in-
doles as substrate, we have successfully isolated thirty
eight C3-silylated indoles, fourteen bis(indol-3-
yl)substituted indoles, twelve indolines, one C5-silylated
Typical Procedure for Disproportionation Reaction
of Indoles
Method A: In a glovebox, indole (0.25 mmol) was add-
ed to a 0.5 mL C6D6 solution of B(C6F5)3 (3a) (1 mol% or 5
mol%) in a 2-mL NMR tube. Then the hydrosilane (62.5
μmol or 0.125 mmol or 0.5 mmol) was added. After com-
pletion of the reaction and measurement of NMR, the
reaction mixture is quenched with Et3N (0.5 mL). The
mixture is further purified by flash column chromatog-
raphy on silica gel using the solvents of cyclohex-
ane/Et3N/TBME (100/10/1 as eluent).
Method B: In a glovebox, indole (0.25 mmol) was add-
ed to a 0.5 mL C6D6 solution of 3a (1 mol% or 5 mol%) in a
2-mL NMR tube. Then the hydrosilane (62.5 μmol or 0.125
mmol or 0.5 mmol) was added. After completion of the
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Org. Prep. Proc. Int. 1995, 27, 1–31. (d) Dewick, P. M. Medicinal
reaction and measurement of NMR, the reaction mixture
was concentrated under vacuum to give the white precipi-
tate. The solid was collected by filtration, then washed
with hexane and dried in vacuo to afford the C-3 silylated
indole. The filtrate was concentrated in vacuo and the
residue was further purified by flash column chromatog-
raphy on silica gel using cyclohexane/TBME (100/1) as
eluent to give the indoline.
1
2
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5
6
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tion Reaction of Indoles
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Method C: In a glovebox, indole (0.25 mmol) was add-
ed to a 0.5 mL C6D6 solution of 3a (5.0 mol%) in a J.
Young-type NMR tube. Then the Hydrosilane (0.5 mmol)
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to 120 °C. After completion of the reaction and measure-
ment of NMR, the reaction mixture was concentrated
under vacuum to give the white precipitate. The solid was
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in vacuo to afford the C-3 silylated indole.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental details, NMR spectra, crystal data, bond
lengths and angles, and further tabular data (PDF)
Cif data for 4ab (C27H23NSi) (CIF)
Cif data for 6ga (C21H20FNSi) (CIF)
Cif data for 7aa (C30H26N2Si) (CIF)
AUTHOR INFORMATION
Corresponding Author
* ytzhang2009@jlu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (Grant no. 21374040, 21422401), 1000
Young Talent Plan of China funds, the startup funds from
Jilin University.
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