Tris(pentafluorophenyl)borane-Catalyzed Formal Cyanoalkylation of Indoles with Cyanohydrins

Article abstract of DOI:10.1021/acs.joc.1c00808

Despite the significant achievements related to the C3 functionalization of indoles, cyanoalkylation reactions continue to remain rather limited. We herein report on the formal C3 cyanoalkylation of indoles with cyanohydrins in the presence of a tris(pentafluorophenyl)borane (B(C6F5)3) catalyst. It is noteworthy that cyanohydrins are used as a cyanoalkylating reagent in the present reaction, even though they are usually used as only a HCN source. Mechanistic investigations revealed the unique reactivity of the B(C6F5)3 catalyst in promoting the decomposition of a cyanohydrin by a Lewis acidic activation through the coordination of the cyano group to the boron center. In addition, a catalytic three-component reaction using indoles, aldehydes as a carbon unit, and acetone cyanohydrin that avoids the discrete preparation of each aldehyde-derived cyanohydrin is also reported. The developed methods provide straightforward, highly efficient, and atom-economic access to various types of synthetically useful indole-3-acetonitrile derivatives containing α-tertiary or quaternary carbon centers.

Full text of DOI:10.1021/acs.joc.1c00808

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Article
Tris(pentafluorophenyl)borane-Catalyzed Formal Cyanoalkylation of
Indoles with Cyanohydrins
Kensuke Kiyokawa,* Naruyo Urashima, and Satoshi Minakata*
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ABSTRACT: Despite the significant achievements related to the
C3 functionalization of indoles, cyanoalkylation reactions continue
to remain rather limited. We herein report on the formal C3
cyanoalkylation of indoles with cyanohydrins in the presence of a
tris(pentafluorophenyl)borane (B(C6F5)3) catalyst. It is note-
worthy that cyanohydrins are used as a cyanoalkylating reagent in
the present reaction, even though they are usually used as only a HCN source. Mechanistic investigations revealed the unique
reactivity of the B(C6F5)3 catalyst in promoting the decomposition of a cyanohydrin by a Lewis acidic activation through the
coordination of the cyano group to the boron center. In addition, a catalytic three-component reaction using indoles, aldehydes as a
carbon unit, and acetone cyanohydrin that avoids the discrete preparation of each aldehyde-derived cyanohydrin is also reported.
The developed methods provide straightforward, highly efficient, and atom-economic access to various types of synthetically useful
indole-3-acetonitrile derivatives containing α-tertiary or quaternary carbon centers.
trimethylsilyl cyanide has been reported, which permits the
synthesis of nitriles containing a quaternary α-carbon center
(Scheme 1c).10 However, an excess of an indole substrate is
required, and this is a significant drawback from a synthetic point
of view. To develop a more efficient cyanoalkylation method, we
focused on the use of readily available cyanohydrins as an ideal
cyanoalkylating reagent, even though they are usually used only
the HCN source.11 The proposed reaction would involve not a
direct dehydrative substitution12 but a stepwise reaction, in
which the indole first reacts with a carbonyl compound that is
generated in situ from cyanohydrines, and the resulting alcohol
intermediate then undergoes substitution by HCN (Scheme
1d).13,14 Herein, we report that the use of a tris-
(pentafluorophenyl)borane (B(C6F5)3) catalyst permits this
formal C3 cyanoalkylation of indoles with cyanohydrins to
proceed, thus providing various indole-3-acetonitrile derivatives.
This unprecedented method is a highly efficient and atom-
economic process, in which cyanohydrins function as a source of
not only HCN but also carbonyl compounds, and only water is
generated as the byproduct.
INTRODUCTION
■
Indole derivatives exhibit unique chemical and biological
properties and find wide applications in the fields of organic,
medicinal, and pharmaceutical chemistry.1 Due to their great
importance, significant efforts have been devoted to the
development of new methodologies for the synthesis of these
types of derivatives in the past decades.2 As a result, two distinct
synthetic strategies have emerged for constructing indole cores
and for the functionalization of parent indoles. The vast majority
of the latter strategy involves the C3 functionalization of indoles
due to the nucleophilic reactivity of these molecules.3
Indole-3-acetonitriles comprise an important class of
compounds that can be readily converted into valuable
tryptamine derivatives, which are useful intermediates for the
synthesis of pharmaceutically important indole alkaloids.4−6
Despite the significant advancements that have been achieved in
the C3 functionalization of indoles, methods that enable the
straightforward C3 cyanoalkylation to provide indole-3-
acetonitriles remain scarce. The classical approach is three-
step synthesis, in which the Mannich reaction of indoles is
followed by quaternization of the amine moiety and subsequent
nucleophilic substitution by cyanide (Scheme 1a).7 In 2019, the
use of an iron porphyrin complex with diazoacetonitrile for
direct cyanomethylation was reported (Scheme 1b).8 However,
the method involves the preparation of a hazardous
diazoacetonitrile using a laborious flow system and poses
some safety concerns. In addition, the above two approaches
were only applied to the synthesis of simple indole-3-
acetonitriles.9 As a result, further transformations are required
to access derivatives that have α-tertiary and quaternary carbon
centers.7 Meanwhile, the indium-catalyzed three-component
reaction of N-methylindole, a ketone (or an alkyne), and
RESULTS AND DISCUSSION
■
Our group recently developed several electrophilic cyanation
reactions utilizing Lewis acidic boron compounds that can
Received: April 8, 2021
Published: June 2, 2021
https://doi.org/10.1021/acs.joc.1c00808
© 2021 American Chemical Society
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a
Scheme 1. Synthetic Approaches to the Production of Indole-
3-acetonitriles from Indoles
Table 1. Survey of Lewis Acid Catalysts and Solvents
b
entry
catalyst (mol %)
solvent
MeCN
yield (%)
c
1
2
3
4
5
6
7
8
B(C6F5)3 (5)
>95 (85)
<5
6
BF3·OEt2 (10)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeNO2
MeNO2
MeCN
MeNO2
1,4-dioxane
toluene
1,2-DCE
d
BCl3 (10)
BBr3 (10)
BPh3 (10)
InCl3 (10)
In(NTf2)3 (10)
Zn(OTf)2 (10)
Cu(OTf)2 (10)
Sc(OTf)3 (10)
Me3SiOTf (10)
TfOH (5)
TsOH (5)
none
B(C6F5)3 (5)
B(C6F5)3 (5)
B(C6F5)3 (5)
B(C6F5)3 (5)
<5
<5
10
29
9
<5
<5
<5
<5
<5
0
>95
>95
91
9
10
11
12
e
e
13
14
15
16
17
e
e
e
e
18
75
a
b
Reactions were performed on a 0.5 mmol scale. Determined by 1H
NMR analysis of the crude product using 1,1,2,2-tetrachloroethane as
c
d
e
an internal standard. Isolated yield. 1.0 M in heptane. 2a (2 equiv)
was used.
dioxane represented efficient alternatives to MeCN (entries 15
and 16), while the use of toluene and 1,2-dichloroethane (DCE)
resulted in slightly lower efficiencies (entries 17 and 18).
activate a cyano group of the cyanating reagent.15 In 2019,
Oestreich et al. reported on an intriguing approach for transfer
hydrocyanation using boron Lewis acids that enable isocyanide
to be captured from cyclohexa-1,4-diene-based HCN surro-
gates.16 Based on our previous studies and literature reports on
reactions that proceed via the activation of a cyano group by a
boron Lewis acid,17 we began our investigation by screening a
series of boron Lewis acid catalysts for the reaction of indole
(1a), which was used as the limiting reagent, with acetone
cyanohydrin (2a). The target reaction proceeded effectively
when 5 mol % B(C6F5)3 was added to the reaction mixture using
MeCN as the solvent at 80 °C, affording the desired
cyanoalkylated product 3aa in nearly quantitative yield (Table
1, entry 1). Meanwhile, strong but moisture-sensitive boron
Lewis acids such as BF3·OEt2, BCl3, and BBr3 as well as weak
Lewis acid BPh3 failed to promote the reaction (entries 2−5). In
the present reaction using 2a as an alkylating reagent, the use of
indium catalysts, InCl3 and In(NTf)3, resulted in low efficiency,
even though In(NTf)3 was successfully applied to a three-
component reaction, as described in Scheme 1c (entries 6 and
7).10 We also examined some commonly used Lewis acids, such
as Zn(OTf)2, Cu(OTf)2, Sc(OTf)3, and Me3SiOTf, but they
were ineffective for this reaction (entries 8−11). The product
3aa was not obtained when Brønsted acids such as
trifluoromethanesulfonic acid (TfOH) and p-toluenesulfonic
acid (TsOH) were used as catalysts (entries 12 and 13).18 No
reaction was observed in the absence of a catalyst (entry 14).
These results clearly demonstrate the unique and high catalytic
activity of B(C6F5)3 in this cyanoalkylation. In addition,
screening a series of solvents revealed that MeNO2 and 1,4-
With the optimized reaction conditions (Table 1, entry 1), we
next investigated the substrate scope of indoles in B(C6F5)3-
catalyzed cyanoalkylation with acetone cyanohydrin (2a)
(Scheme 2). A number of indoles bearing electron-donating
and -withdrawing groups at the 5-position were subjected to the
reaction, and all of the reactions proceeded smoothly to afford
high yields of the corresponding nitriles 3 bearing an α-
quaternary carbon center (3aa−3ia). The synthetic utility of this
cyanoalkylation was demonstrated by a gram-scale reaction
using 1a, which resulted in the formation of 3aa in excellent yield
(1.64 g, 89%). Although highly electron-deficient substrates
with ester, cyano, and nitro groups showed low reactivity,
increasing the catalyst loading to 10 mol % and the amount of 2a
was effective in improving the product yield (3ga−3ia). It is
noteworthy that this catalytic reaction was also compatible with
various functional groups, which include halogens (3da−3fa),
ester (3ga), cyano (3ha), and nitro (3ia) groups. The influence
of the substitution pattern of the indoles was also investigated.
Substituents at the 1-, 2-, 6-, and 7-positions had little effect on
reactivity, affording the corresponding products in high yields
(3ja−3pa). However, a 4-methyl substituent was found to have
a significant influence on reactivity. Interestingly, 4-methyl-1H-
indole preferentially underwent N-alkylation to give 3qa′,19
rather than 3-alkylation to give 3qa, probably due to steric
hindrance. We also tested the reactivity of 3-methyl-1H-indole
for this cyanoalkylation and found that the N-alkylated product
3ra′ was produced preferentially along with the 2-alkylated
product 3ra being produced in a lower yield.20,21 Unfortunately,
the method could not be successfully applied to reactions
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a
cyanohydrin (2a), various other types of ketone-derived
cyanohydrins, such as cyclohexanone-, 1,3-diphenylacetone-,
and acetophenone-derived reagents (2b−2d), were found to be
applicable to the reaction, providing the corresponding
cyanoalkylated products 3 in high yields. Mandelonitrile (2e)
was also found to be efficiently coupled with 1a, demonstrating
that the method can be used to prepare α-monosubstituted
nitrile 3. It is noteworthy that the present method allowed for the
synthesis of derivatives bearing an aryl group at the α-position
(products from 2d and 2e) that would be difficult to access by α-
arylation of indole-3-acetonitriles. However, the use of electron-
deficient 1,1,1-trifluoroacetone-derived cyanohydrin 2f24 as well
as glycolonitrile (2g) resulted in almost no desired product.
We then performed several experiments to gain insights into
the reaction mechanism (Scheme 5). Our hypothesis was that a
cyanohydrin is decomposed in situ to form HCN and the
corresponding carbonyl compounds in the initial step. To
confirm this, the reaction mixture, which was prepared by mixing
2a with 5 mol % of B(C6F5)3 in MeCN-d3 at 80 °C for 30 min,
Scheme 2. Scope and Limitation of Indoles
1
1
was monitored by H NMR (Scheme 5a). In the H NMR
spectrum of the mixture, signals corresponding to acetone and
HCN were observed with consumption of 2a,25 while most of 2a
remained in the absence of B(C6F5)3. These results clearly
demonstrate that B(C6F5)3 promotes the decomposition of
2a.26 In addition, the decomposition of mandelonitrile (2e) to
form benzaldehyde and HCN was also observed in the presence
of the B(C6F5)3 catalyst, even though the reaction rate was much
slower than that of 2a.27 Interestingly, B(C6F5)3 was found to
accelerate the decomposition of a cyanohydrin but not the
backward addition reaction.28 This is further supported by the
fact that mixing 2a with benzaldehyde in the presence of the
B(C6F5)3 catalyst at 80 °C led to the formation of acetone and
HCN with only trace amounts of 2e being produced (Scheme
5b). The use of indole, 2a, and acetone-d6 provided almost
equimolar amounts of 3aa and the deuterated product 3aa-d
(Scheme 5c), ruling out a mechanism involving the direct
substitution of the hydroxy group of 2a with 1a. This result also
indicates that the rate of decomposition of 2a would be faster
than that of the addition of 1a to the existing acetone-d6.
a
Reactions were performed on a 0.5 mmol scale. Yields are isolated
b
c
yields. Reaction was performed on a 10 mmol scale. B(C6F5)3 (10
mol %) and 2a (1.5 equiv) were used. The reaction was conducted for
20 h. B(C6F5)3 (10 mol %) and 2a (2 equiv) were used. MeNO2
d
e
f
was used as a solvent. B(C6F5)3 (10 mol %) and 2a (5 equiv) were
g
h
used. Determined by 1H NMR analysis of the crude product. 2a (5
equiv) was used.
To obtain more detailed insights into the activation mode of a
cyanohydrin with B(C6F5)3, a mixture of 2e and 1 equiv of
B(C6F5)3 in toluene was monitored by 13C{1H} NMR
spectroscopy (Scheme 5d).25 The addition of B(C6F5)3 to 2e
led to an upfield shift in the signal corresponding to the cyano
group (δ = 119.3 ppm for 2e to 114.4 ppm for 2e·B(C6F5)3).
This characteristic upfield shift strongly indicates that the cyano
group of 2e and not the hydroxyl group coordinates to
B(C6F5)3.16,29 Additional support for the coordination came
from the 11B NMR (δ = 58.9 ppm for B(C6F5)3 to −10.2 ppm for
2e·B(C6F5)3) and 19F{1H} NMR spectroscopy.25 These NMR
analyses indicate that the decomposition of a cyanohydrin is
promoted by unprecedented Lewis acidic activation that occurs
through the coordination of its cyano group to B(C6F5)3.16
Product analysis of the reaction of 1a with 2a for 1 h showed
that, in addition to 3aa, an alcohol intermediate is not generated
from the addition of 1a to acetone, but the formation of a small
amount of bis(indoyl)methane 6a was observed.30 To examine
its role as a potentially reactive intermediate, the reaction of 6a
with 2b in the presence of B(C6F5)3 was examined. This resulted
in the formation of 3aa, involving the release of one indole
moiety that undergoes cyanoalkylation with 2b to give 3ab
(Scheme 5e). This result suggests that bis(indoyl)methane 6 is
involving electron-deficient N-Boc- and N-Ts-protected indoles
and azaindoles.
The reactivity of pyrroles toward the present cyanoalkylation
was also investigated (Scheme 3). 1-Methylpyrrole and 2,5-
dimethylpyrrole underwent selective C3 cyanoalkylation under
the standard conditions to provide 4 and 5, respectively, in good
yields.22 The synthesized pyrrole derivatives are potentially
useful intermediates for the synthesis of pharmaceuticals.23
We next examined the scope of cyanohydrins for the
cyanoalkylation of 1a (Scheme 4). In addition to acetone
Scheme 3. Cyanoalkylation of Pyrroles
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a
Scheme 4. Scope and Limitation of Cyanohydrins
a
b
Reactions were performed on a 0.5 mmol scale. Yields are isolated yields. 2c (2 equiv) was used. The reaction was conducted at 100 °C.
c
d
e
Reaction was conducted for 24 h. 2g (ca. 52% in water) was used. Unreacted starting material 1a was recovered (>90%).
Scheme 5. Mechanistic Experiments
one of the intermediates that is produced in this cyanoalkyla-
tion.10
On the basis of the experimental results, a plausible reaction
pathway is depicted in Scheme 6. First, a cyanohydrin is
decomposed into HCN and the corresponding carbonyl
compound by Lewis acidic activation through the coordination
of its cyano group to B(C6F5)3. Indole 1 then attacks the
resulting carbonyl compound to provide alcohol 7, which is
followed by dehydration, leading to the formation of iminium
intermediate 8. The cyanide generated through the dehydration
step adds to 8 to afford cyanoalkylated product 3. When 1
participates in the addition step instead of cyanide, bis(indoyl)-
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Scheme 6. Plausible Reaction Pathway
Scheme 7. Cyanoalkylation of Indole Using Aldehydes as a
Carbon Unit
a
methane 6 is formed, but 6 can undergo a reverse reaction to 8
under the reaction conditions, leading to the formation of 3.
This reaction highlights the unique catalytic activity of B(C6F5)3
that participates in the activation of cyanohydrins, carbonyl
compounds, and alcohol intermediate 7.31
a
Reactions were performed on a 0.5 mmol scale. Yields are isolated
b
yields. 1,4-Dioxane was used as a solvent. The reaction was
conducted at 100 °C. Reaction was conducted for 24 h. MeNO2
was used as a solvent. 2b was used instead of 2a.
An aldehyde-derived cyanohydrin was found to be suitable for
use in this cyanoalkylation (Scheme 4, 2e), but the preparation
of cyanohydrins is somewhat laborious. We envisioned that a
more practical process that would avoid the preparation of each
cyanohydrin could be established by a three-component
reaction using indoles, aldehydes as a carbon unit, and 2a, in
which indoles would react selectively with aldehydes over the
acetone generated from 2a. We then examined the reaction
using 1a, benzaldehyde, and with 2a being added to a MeCN
solution of the B(C6F5)3 catalyst in succession and found that
the desired 10aa was selectively produced in 84% isolated yield,
along with a small amount of 3aa (<5%) (Scheme 7). A variety
of aromatic aldehydes containing electron-donating and -with-
drawing groups at the para, meta, and ortho positions were
suitable substrates, affording the corresponding 2-(1H-indol-3-
yl)-2-arylacetonitrile 5 in good to high yields (10ab−10ar).
Moreover, this practical process could also be applied to
aliphatic aldehydes. For example, butyraldehyde (9s) and 3-
methylbutanal (9t) smoothly reacted to afford the desired
products 10as and 10at, respectively. The use of the sterically
hindered pivalaldehyde (9u) also provided 10au albeit in a
somewhat low yield due to the competitive side reaction that
leads to the formation of 3aa.
c
d
e
EXPERIMENTAL SECTION
■
General Information. New compounds were characterized by 1H
NMR, 13C{1H} NMR, 11B NMR, 19F{1H} NMR, IR, mass spectrometry
(MS), and high-resolution mass spectrometry (HRMS). 1H, 13C{1H},
11B, and 19F{1H} NMR spectra were recorded on a JEOL JMTC-400/
54/SS spectrometer (1H NMR, 400 MHz; 13C{1H} NMR, 100 MHz;
11B NMR, 128 MHz; 19F{1H} NMR, 377 MHz). H NMR chemical
1
shifts were determined relative to Me4Si (0.0 ppm) in CDCl3, the
signals of residual undeuterated acetonitrile (1.94 ppm) in CD3CN,
undeuterated toluene (2.08 ppm for the methyl group) in toluene-d8, or
undeuterated acetone (2.05 ppm) in acetone-d6 as an internal standard.
13C{1H} NMR chemical shifts were determined relative to CDCl3 (77.0
ppm), CD3CN (118.20 ppm), CD3C6D5 (20.43 ppm), or (CD3)2CO
(29.84 ppm). 11B NMR chemical shifts were determined relative to
BF3·OEt2 (0.0 ppm in toluene-d8) as an external standard. 19F{1H}
NMR chemical shifts were determined relative to C6F6 (−164.9 ppm in
CDCl3) as an external standard. Infrared spectra were recorded on a
SHIMADZU IRAffinity-1 FT-IR spectrometer. Mass spectra were
obtained on a SHIMADZU GCMS-QP2010 mass spectrometer. High-
resolution mass spectra were obtained on a JEOL JMS-700 (magnetic
sector type mass spectrometer). Melting points were determined on a
Stanford Research Systems MPA100 OptiMelt Automated Melting
Point System. All reactions were carried out under nitrogen. Products
were purified by chromatography on silica gel BW-300 (Fuji Silysia
Chemical Ltd.) or Chromatorex NH (Fuji Silysia Chemical Ltd.).
Analytical thin-layer chromatography (TLC) was performed on pre-
coated silica gel glass plates (Merck silica gel 60 F254 and Fuji Silysia
Chromatorex NH, 0.25 mm thickness). Compounds were visualized
with a UV lamp or treatment with an ethanolic solution of
phosphomolybdic acid followed by heating.
CONCLUSIONS
■
In conclusion, we have developed the B(C6F5)3-catalyzed formal
C3 cyanoalkylation of indoles with cyanohydrins (and
aldehydes). The key to the success of the reaction was the use
of a B(C6F5)3 catalyst that has the ability to promote the
decomposition of a cyanohydrin through unique Lewis acidic
activation, which was supported by mechanistic investigations
including NMR spectroscopy analysis. This unprecedented
method has a broad substrate scope with high functional group
compatibility, thus offering a practical and general procedure for
the synthesis of potentially valuable indole-3-acetonitrile
derivatives.
Materials. 2-Benzyl-2-hydroxy-3-phenylpropionitrile (2c) is a
known compound and is prepared according to the reported
procedure.32 The H NMR data for 2c was in agreement with the
1
reported data.32 Dehydrated acetonitrile was used from a solvent
purification system. Nitromethane was distilled over calcium sulfate
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before use. Indoles, cyanohydrins, aldehydes, and all other reagents and
solvents were purchased and used as obtained.
111.6, 31.3, 27.9; IR: (ATR) 3406, 3360, 3348, 3130, 3057, 2980, 2934,
2234, 1458, 766 cm−1; MS (EI) m/z: 184 (M+, 41), 169 (100), 142
(40), 115 (27); HRMS (EI) m/z: [M]+ calcd for C12H12N2 184.1000;
found 184.0998.
Typical Procedure for the Reaction of Indoles with Cyanohydrins
(Typical Procedure A). In a glovebox, an oven-dried reaction vial
containing a magnetic stir bar was charged with B(C6F5)3 (0.025 mmol,
5 mol %). The vial was capped and removed from the glovebox. Then, a
solution of indoles (0.5 mmol, 1.0 equiv) in the indicated solvent (1
mL) and cyanohydrins (0.6 mmol, 1.2 equiv) were added to the vial,
which was then sealed and placed in an aluminum block, which was
preheated at 80 °C. After the mixture was stirred at 80 °C for 15 h, the
reaction was quenched by sat. NaHCO3 aq (10 mL), and the mixture
was extracted with Et2O (3 × 10 mL). The combined organic layers
were dried over Na2SO4. The solution was then concentrated under
reduced pressure to give the crude product, which was analyzed by 1H
NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal
standard. Purification by flash column chromatography on silica gel
(hexane/EtOAc) gave the product.
2-(5-Methoxy-1H-indol-3-yl)-2-methylpropanenitrile (3ba). Ac-
cording to the typical procedure A, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 5-methoxy-1H-indole (73.7 mg, 0.50 mmol,
1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol,
1.2 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
1
as a colorless liquid (102.5 mg, 96% yield). H NMR: (400 MHz,
CDCl3) δ 8.10 (brs, 1H), 7.30−7.21 (m, 2H), 7.06 (d, J = 2.8 Hz, 1H),
6.90 (dd, J = 8.8, 2.8 Hz, 1H), 3.88 (s, 3H), 1.83 (s, 6H); 13C{1H}
NMR: (100 MHz, CDCl3) δ 154.1, 132.1, 124.9, 124.5, 121.1, 116.6,
112.7, 112.3, 101.7, 56.0, 31.2, 27.8; IR: (ATR) 3040, 3391, 3325, 2984,
2938, 2830, 2232, 1483, 1458, 1439, 1217, 1153, 1036, 831, 800 cm−1;
MS (EI) m/z: 214 (M+, 54), 199 (100), 172 (40); HRMS (EI) m/z:
[M]+ calcd for C13H14N2O 214.1106; found 214.1107.
Typical Procedure for the Three-Component Reaction Using
Indole, Aldehydes, and Acetone Cyanohydrin (Typical Procedure B).
In a glovebox, an oven-dried reaction vial containing a magnetic stir bar
was charged with B(C6F5)3 (0.025 mmol, 5 mol %). The vial was
capped and removed from the glovebox. Then, a solution of 1H-indole
(0.50 mmol, 1.0 equiv) in the indicated solvent (1 mL), acetone
cyanohydrin (0.6 mmol, 1.2 equiv), and aldehydes (0.60 mmol, 1.2
equiv) were added to the vial, which was then sealed and placed in an
aluminum block, which was preheated at 80 °C. After the mixture was
stirred at 80 °C for 6 h, The reaction was quenched by sat. NaHCO3 aq
(10 mL), and the mixture was extracted with Et2O (3 × 10 mL). The
combined organic layers were dried over Na2SO4. The solution was
then concentrated under reduced pressure to give the crude product,
which was analyzed by 1H NMR spectroscopy using 1,1,2,2-
tetrachloroethane as an internal standard. Purification by flash column
chromatography on silica gel (hexane/EtOAc) gave the product.
Experimental Procedure for 1H NMR Monitoring of the
Decomposition of Cyanohydrins. Solutions of cyanohydrin (0.1
mmol, 1.0 equiv) in the presence and absence of B(C6F5)3 (0.005
mmol, 5 mol %) in MeCN-d3 (0.5 mL) were prepared and transferred
to a sealed NMR tube. After subjection of them to indicated conditions,
2-Methyl-2-(5-methyl-1H-indol-3-yl)propanenitrile (3ca). Ac-
cording to the typical procedure A, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 5-methyl-1H-indole (65.6 mg, 0.50 mmol,
1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol,
1.2 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a brown liquid (82.7 mg, 83% yield). 1H NMR: (400 MHz, CDCl3) δ
8.05 (brs, 1H), 7.60 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.07−7.04 (m,
2H), 2.47 (s, 3H), 1.84 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ
135.3, 129.3, 124.7, 124.6, 124.2, 120.5, 119.3, 116.5, 111.3, 31.3, 27.9,
21.6; IR: (ATR) 3408, 3399, 2980, 2924, 2870, 2232, 1483, 1458, 1438,
1419, 1340, 1146, 1107, 797, 760 cm−1; MS (EI) m/z: 198 (M+, 44),
183 (100), 156 (32); HRMS (EI) m/z: [M]+ calcd for C13H14N2
198.1157; found 198.1156.
2-(5-Fluoro-1H-indol-3-yl)-2-methylpropanenitrile (3da). Accord-
ing to the typical procedure A, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 5-fluoro-1H-indole (67.8 mg, 0.50 mmol, 1.0
equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol, 1.2
equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
1
1
the resulting H NMR spectra are shown in Figures S1 and S2. To
as a colorless liquid (93.5 mg, 92% yield). H NMR: (400 MHz,
CDCl3) δ 8.26 (brs, 1H), 7.47 (dd, J = 2.4 Hz, 3JH−F = 9.6 Hz, 1H), 7.30
(dd, J = 4.4 Hz, 4JH−F = 8.8 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.98 (ddd,
J = 8.8, 2.4 Hz, 3JH−F = 8.8 Hz, 1H), 1.82 (s, 6H); 13C{1H} NMR: (100
MHz, CDCl3) δ 157.6 (d, JC−F = 233.9 Hz), 133.4, 124.6 (d, JC−F = 9.9
Hz), 124.4, 122.2, 116.7 (d, JC−F = 4.1 Hz), 112.4 (d, JC−F = 9.8 Hz),
110.9 (d, JC−F = 26.3 Hz), 104.5 (d, JC−F = 23.9 Hz), 31.0, 27.6; 19F{1H}
NMR: (376 MHz, CDCl3) δ −123.7; IR: (ATR) 3447, 3404, 3379,
3364, 3347, 2982, 2938, 2234, 1487, 1460, 1146, 797 cm−1; MS (EI)
m/z: 202 (M+, 44), 187 (100), 160 (46), 133 (22); HRMS (EI) m/z:
[M]+ calcd for C12H11FN2 202.0906; found 202.0907.
confirm the generation of HCN, a 200 μL sample of the mixture was
added to 500 μL of CDCl3, and the resulting 1H NMR spectrum was
compared to the reported data.33
Experimental Procedure for NMR Monitoring of a Mixture of
Mandelonitrile (2e) and B(C6F5)3. A solution of mandelonitrile (2e)
(0.1 mmol, 1.0 equiv) and B(C6F5)3 (0.1 mmol, 1.0 equiv) in toluene-d8
(0.5 mL) was prepared and transferred into a sealed NMR tube. The
1
resulting H, 13C{1H}, 11B, and 19F{1H} NMR spectra are shown in
Figures S3−S6.34
2-(1H-Indol-3-yl)-2-methylpropanenitrile (3aa). According to the
typical procedure A, the reaction using B(C6F5)3 (12.8 mg, 0.025 mmol,
5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv), MeCN (1 mL),
and acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv) was conducted
at 80 °C for 15 h. Purification by flash column chromatography on silica
gel (hexane/EtOAc = 8:2) gave the product as a colorless liquid (78.2
mg, 85% yield). Gram-scale synthesis of 3aa: In a glovebox, an oven-
dried vial containing a magnetic stir bar was charged with B(C6F5)3
(256.0 mg, 0.5 mmol, 5 mol %). The vial was capped and removed from
the glovebox. Then, the B(C6F5)3, a solution of 1H-indole (1.17 g, 10.0
mmol, 1.0 equiv) in MeCN (10 mL), and acetone cyanohydrin (1.1
mL, 12.0 mmol, 1.2 equiv) were added to the sealed reaction tube. The
mixture was stirred at 80 °C for 15 h. The reaction was quenched by sat.
NaHCO3 aq (60 mL), and the mixture was extracted with Et2O (3 × 20
mL). The combined organic layers were dried over Na2SO4. The
solution was then concentrated under reduced pressure to give the
crude product. Purification by flash column chromatography on silica
gel (hexane/EtOAc = 8:2) gave the product as a colorless liquid (1.64 g,
89% yield). 1H NMR: (400 MHz, CDCl3) δ 8.11 (brs, 1H), 7.84 (d, J =
8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.27−7.22 (m, 1H), 7.22−7.17
(m, 1H), 7.14 (d, J = 2.4 Hz, 1H), 1.86 (s, 6H); 13C{1H} NMR: (100
MHz, CDCl3) δ 136.9, 124.6, 124.4, 122.5, 120.5, 120.0, 119.6, 116.9,
2-(5-Chloro-1H-indol-3-yl)-2-methylpropanenitrile (3ea). Accord-
ing to the typical procedure A, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 5-chloro-1H-indole (76.1 mg, 0.50 mmol, 1.0
equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol, 1.2
equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
1
as a colorless liquid (100.8 mg, 92% yield). H NMR: (400 MHz,
CDCl3) δ 8.25 (brs, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz,
1H), 7.19−7.13 (m, 2H), 1.83 (s, 6H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 135.3, 125.7, 125.4, 124.3, 123.0, 121.9, 119.1, 116.8, 112.7,
31.1, 27.8; IR: (ATR) 3417, 3408, 3358, 3350, 2981, 2938, 2234 cm−1;
MS (EI) m/z: 220 ([M + 2]+, 14), 218 (M+, 41), 205 (34), 203 (100),
176 (29); HRMS (EI) m/z: [M]+ calcd for C12H11ClN2 218.0611;
found 218.0613.
2-(5-Bromo-1H-indol-3-yl)-2-methylpropanenitrile (3fa). Accord-
ing to the typical procedure A, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 5-bromo-1H-indole (98.0 mg, 0.50 mmol, 1.0
equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol, 1.2
equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a brown liquid (110.7 mg, 84% yield). 1H NMR: (400 MHz, CDCl3)
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δ 8.26 (brs 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.8, 2.0 Hz, 1H),
7.24 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 3.2 Hz, 1H), 1.82 (s, 6H); 13C{1H}
NMR: (100 MHz, CDCl3) δ 135.6, 126.1, 125.6, 124.3, 122.1, 121.7,
116.7, 113.3, 113.1, 31.1, 27.8; IR: (ATR) 3429, 3420, 3350, 3339,
2982, 2932, 2234, 1458, 1418, 1335, 1192, 1165, 1109, 1059, 885, 797,
752, 731 cm−1; MS (EI) m/z: 264 ([M + 2]+, 40), 262 (M+, 40), 249
(98), 247 (100), 168 (77), 140 (29), 71 (18); HRMS (EI) m/z: [M]+
calcd for C12H11BrN2 262.0106; found 262.0101.
Methyl 3-(2-Cyanopropan-2-yl)-1H-indole-5-carboxylate (3ga).
According to the typical procedure A, the reaction using B(C6F5)3 (25.6
mg, 0.05 mmol, 10 mol %), methyl 1H-indole-5-carboxylate (87.5 mg,
0.50 mmol, 1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (69
μL, 0.75 mmol, 1.5 equiv) was conducted at 80 °C for 20 h. Purification
by flash column chromatography on silica gel (hexane/EtOAc = 8:2)
gave the product as a white solid (111.8 mg, 92% yield). Mp: 122.5−
123.4 °C; 1H NMR: (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.41 (brs, 1H),
7.96 (dd, J = 8.4, 1.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 2.4
Hz, 1H), 3.95 (s, 3H), 1.88 (s, 6H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 168.0, 139.6, 124.3, 123.98, 123.95, 122.4, 122.1, 122.0,
118.4, 111.5, 52.0, 31.3, 28.0; IR: (ATR) 3319, 3136, 2957, 2228, 1684,
1614, 1435, 1271, 1246, 1123, 982, 750 cm−1; MS (EI) m/z: 242 (M+,
46), 227 (100), 140 (24); HRMS (EI) m/z: [M]+ calcd for
C14H14N2O2 242.1055; found 242.1052.
1.2 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a white solid (115.2 mg, 88% yield). Mp: 167.1−168.0 °C; 1H NMR:
(400 MHz, CDCl3) δ 8.19 (brs 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.55 (d, J
= 1.6 Hz, 1H), 7.29 (dd, J = 8.8, 1.6 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H),
1.83 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 137.7, 124.3, 123.4,
121.0, 120.8, 117.3, 116.2, 114.5, 31.1, 27.8 (one sp2 signal was not
observed because of overlapping); IR: (ATR) 3410, 3123, 2986, 2934,
2230, 1659, 1614, 1539, 1456, 1387, 1366, 1329, 1294, 1229, 1109,
1028, 1016, 893, 854, 829, 793, 781 cm−1; MS (EI) m/z: 264 ([M + 2]+,
40), 262 (M+, 43), 249 (93), 247 (100), 168 (70), 141 (23), 140 (52),
114 (25), 71 (22), 63 (21); HRMS (EI) m/z: [M]+ calcd for
C12H11BrN2 262.0106; found 262.0109.
2-(7-Methoxy-1H-indol-3-yl)-2-methylpropanenitrile (3la). Ac-
cording to the typical procedure A, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 7-methoxy-1H-indole (73.6 mg, 0.50 mmol,
1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol,
1.2 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a white solid (98.5 mg, 92% yield). Mp: 148.6−150.2 °C; 1H NMR:
(400 MHz, CDCl3) δ 8.32 (brs, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.15−
7.06 (m, 2H), 6.68 (d, J = 8.0 Hz, 1H), 3.95 (s, 3H), 1.84 (s, 6H);
13C{1H} NMR: (100 MHz, CDCl3) δ 146.3, 127.6, 125.7, 124.6, 120.5,
119.9, 117.6, 112.4, 102.3, 55.3, 31.4, 28.0; IR: (ATR) 3314, 3005,
2984, 2938, 2237, 1580, 1450, 1429, 1331, 1267, 1254, 1179, 1103,
1030, 1016, 781, 735, 700 cm−1; MS (EI) m/z: 214 (M+, 61), 199
(100), 172 (52); HRMS (EI) m/z: [M]+ calcd for C13H14N2O
214.1106; found 214.1109.
2-Methyl-2-(2-methyl-1H-indol-3-yl)propanenitrile (3ma). Ac-
cording to the typical procedure A, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 2-methyl-1H-indole (65.6 mg, 0.50 mmol,
1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol,
1.2 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a brown liquid (92.0 mg, 93% yield). 1H NMR: (400 MHz, CDCl3) δ
7.92 (brs, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.17−
7.06 (m, 2H), 2.57 (s, 3H), 1.92 (s, 6H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 134.7, 130.6, 126.2, 125.3, 121.3, 119.7, 119.5, 110.6, 109.9,
32.4, 28.9, 14.0; IR: (ATR) 3391, 3356, 3339, 3321, 2980, 2932, 2232,
1460, 1425, 1194, 1078 cm−1; MS (EI) m/z: 198 (M+, 42), 183 (100),
156 (39); HRMS (EI) m/z: [M]+ calcd for C13H14N2 198.1157; found
198.1156.
3-(2-Cyanopropan-2-yl)-1H-indole-5-carbonitrile (3ha). Accord-
ing to the typical procedure A, the reaction using B(C6F5)3 (25.6 mg,
0.05 mmol, 10 mol %), 1H-indole-5-carbonitrile (71.1 mg, 0.50 mmol,
1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (92 μL, 1 mmol,
2.0 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
1
as a colorless liquid (91.0 mg, 86% yield). H NMR: (400 MHz,
CDCl3) δ 8.83 (brs, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.14 (dd, J = 9.2, 2.0
Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 1.89 (s, 6H);
13C{1H} NMR: (100 MHz, CDCl3) δ 138.6, 125.5, 125.3, 124.3, 123.9,
122.8, 120.3, 118.1, 112.6, 103.3, 31.1, 27.9; IR: (ATR) 3360, 2984,
2230, 2212, 1622, 1472, 1423, 1352, 1252, 1130, 1103, 876, 808, 760
cm−1; MS (EI) m/z: 209 (M+, 31), 194 (100), 167 (28), 140 (23);
HRMS (EI) m/z: [M]+ calcd for C13H11N3 209.0953; found 209.0954.
2-Methyl-2-(5-nitro-1H-indol-3-yl)propanenitrile (3ia). According
to the typical procedure A, the reaction using B(C6F5)3 (25.6 mg, 0.05
mmol, 10 mol %), 5-nitro-1H-indole (67.0 mg, 0.50 mmol, 1.0 equiv),
MeNO2 (1 mL), and acetone cyanohydrin (92 μL, 1 mmol, 2.0 equiv)
was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
2-Methyl-2-(1-methyl-1H-indol-3-yl)propanenitrile (3na). Ac-
cording to the typical procedure A, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 1-methyl-1H-indole (66.1 mg, 0.50 mmol,
1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol,
1.2 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
1
as a yellow solid (105.7 mg, 92% yield). Mp: 135.0−136.1 °C; H
NMR: (400 MHz, CDCl3) δ 8.80−8.70 (m, 2H), 8.14 (dd, J = 8.8, 2.0
Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 1.90 (s, 6H);
13C{1H} NMR: (100 MHz, CDCl3) δ 141.8, 140.0, 124.0, 123.9, 123.8,
119.5, 118.2, 116.7, 111.9, 31.2, 28.0; IR: (ATR) 3381, 3132, 3105,
3080, 2990, 2924, 2852, 2235, 1512, 1469, 1458, 1327, 1290, 1103,
1082, 839, 810, 737 cm−1; MS (EI) m/z: 229 (M+, 35), 214 (100), 168
(40); HRMS (EI) m/z: [M]+ calcd for C12H11N3O2 229.0851; found
229.0852.
1
as a colorless liquid (93.7 mg, 95% yield). H NMR: (400 MHz,
CDCl3) δ 7.82 (d, J = 7.6 Hz, 1H), 7.32−7.23 (m, 2H), 7.20−7.14 (m,
1H), 6.96 (s, 1H), 3.71 (s, 3H), 1.82 (s, 6H); 13C{1H} NMR: (100
MHz, CDCl3) δ 137.6, 125.1, 124.8, 124.6, 122.0, 119.7, 119.4, 115.2,
109.7, 32.6, 31.1, 27.9; IR: (ATR) 2980, 2934, 2232, 1464, 1331, 1229,
1107 cm−1; MS (EI) m/z: 198 (M+, 41), 183 (100), 156 (31); HRMS
(EI) m/z: [M]+ calcd for C13H14N2 198.1157; found 198.1153.
2-(1-Benzyl-1H-indol-3-yl)-2-methylpropanenitrile (3oa). Accord-
ing to the typical procedure A, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 1-benzyl-1H-indole (103.6 mg, 0.50 mmol, 1.0
equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol, 1.2
equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a white solid (124.1 mg, 90% yield). Mp: 130.0−130.9 °C; 1H NMR:
(400 MHz, CDCl3) δ 7.85 (d, J = 7.6 Hz, 1H), 7.37−7.27 (m, 4H),
7.25−7.15 (m, 2H), 7.12 (d, J = 7.6 Hz, 2H), 7.07 (s, 1H), 5.30 (s, 2H),
1.85 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 137.3, 137.0, 128.8,
127.8, 126.8, 125.1, 124.6, 124.5, 122.3, 120.0, 119.8, 116.1, 110.2, 50.1,
31.3, 28.0; IR: (ATR) 2978, 2224, 1618, 1549, 1497, 1472, 1443, 1391,
1375, 1339, 1238, 1196, 1182, 1155, 1074, 1016, 970, 770, 733 cm−1;
MS (EI) m/z: 274 (M+, 14), 259 (21), 91 (100); HRMS (EI) m/z:
[M]+ calcd for C19H18N2 274.1470; found 274.1468.
2-Methyl-2-(6-methyl-1H-indol-3-yl)propanenitrile (3ja). Accord-
ing to the typical procedure A, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 6-methyl-1H-indole (65.6 mg, 0.50 mmol, 1.0
equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol, 1.2
equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a brown liquid (93.4 mg, 94% yield). 1H NMR: (400 MHz, CDCl3) δ
7.99 (brs, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.07−6.98 (m,
2H), 2.46 (s, 3H), 1.83 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ
137.4, 132.5, 124.6, 122.3, 121.8, 119.8, 119.3, 116.9, 111.5, 31.3, 27.9,
21.6; IR: (ATR) 3360, 2984, 2938, 2862, 2232, 1653, 1628, 1549, 1456,
1387, 1366, 1341, 1109, 1032, 854, 827, 793 cm−1; MS (EI) m/z: 198
(M+, 47), 183 (100), 156 (29); HRMS (EI) m/z: [M]+ calcd for
C13H14N2 198.1157; found 198.1159.
2-(6-Bromo-1H-indol-3-yl)-2-methylpropanenitrile (3ka). Ac-
cording to the typical procedure A, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 6-bromo-1H-indole (98.0 mg, 0.50 mmol,
1.0 equiv), MeCN (1 mL), and acetone cyanohydrin (55 μL, 0.6 mmol,
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2-Methyl-2-(1-methyl-2-phenyl-1H-indol-3-yl)propanenitrile
(3pa). According to the typical procedure A, the reaction using
B(C6F5)3 (12.8 mg, 0.025 mmol, 5 mol %), 1-methyl-2-phenyl-1H-
indole (103.6 mg, 0.50 mmol, 1.0 equiv), MeCN (1 mL), and acetone
cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv) was conducted at 80 °C for
15 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc = 8:2) gave the product as a colorless solid (115.1 mg,
84% yield). Mp: 145.2−146.6 °C; 1H NMR: (400 MHz, CDCl3) δ 8.01
(d, J = 7.6 Hz, 1H), 7.53−7.43 (m, 3H), 7.37−7.27 (m, 4H), 7.25−7.20
(m, 1H), 3.37 (s, 3H), 1.65 (s, 6H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 136.8, 136.6, 132.9, 131.2, 129.2, 128.2, 125.3, 125.0, 122.2,
120.2, 119.9, 111.6, 109.6, 32.4, 30.1, 29.5; IR: (ATR) 3045, 2978,
2938, 2918, 2226, 1460, 1368 cm−1; MS (EI) m/z: 274 (M+, 45), 260
(22), 259 (100); HRMS (EI) m/z: [M]+ calcd for C19H18N2 274.1470;
found 274.1471.
mL), and 1-hydroxycyclohexane-1-carbonitrile (75.1 mg, 0.60 mmol,
1.2 equiv) was conducted at 80 °C for 15 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
1
as a colorless liquid (84.9 mg, 76% yield). H NMR: (400 MHz,
CDCl3) δ 8.14 (brs, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz,
1H), 7.25−7.20 (m, 1H), 7.20−7.13 (m, 1H), 7.12 (d, J = 2.4 Hz, 1H),
2.53−2.31 (m, 2H), 2.00−1.72 (m, 7H), 1.42−1.21 (m, 1H); 13C{1H}
NMR: (100 MHz, CDCl3) δ 136.9, 124.5, 122.9, 122.5, 120.5, 119.93,
119.87, 117.2, 111.6, 38.2, 36.3, 25.3, 23.3; IR: (ATR) 3348, 2930,
2860, 2232, 1630, 1547, 1493, 1450, 1433, 1260, 1242, 1113, 1096,
1028, 1013, 995, 903, 816, 799, 760, 735 cm−1; MS (EI) m/z: 224 (M+,
82), 182 (22), 181 (100), 168 (79), 155 (31), 154 (32), 141 (26), 140
(37), 130 (27), 127 (21), 117 (33), 115 (31), 114 (24); HRMS (EI)
m/z: [M]+ calcd for C15H16N2 224.1313; found 224.1309.
2-Benzyl-2-(1H-indol-3-yl)-3-phenylpropanenitrile (3ac). Accord-
ing to the typical procedure A, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol,
1.0 equiv) in 1,4-dioxane (1 mL), and 2-benzyl-2-hydroxy-3-phenyl-
propanenitrile (237.2 mg, 1.0 mmol, 2.0 equiv) was conducted at 100
°C for 15 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc = 8:2) gave the product as a white solid (149.9 mg,
2-Methyl-2-(4-methyl-1H-indol-3-yl)propanenitrile (3qa), 2-
Methyl-2-(4-methyl-1H-indol-1-yl)propanenitrile (3qa′). According
to the typical procedure A, the reaction using B(C6F5)3 (25.6 mg, 0.05
mmol, 5 mol %), 4-methyl-1H-indole (66.8 mg, 0.51 mmol, 1.0 equiv),
MeCN (1 mL), and acetone cyanohydrin (227 μL, 2.5 mmol, 5.0
equiv) was conducted at 80 °C for 15 h, providing the mixture of 3qa
and 3qa′ in 1:2.5 ratio, as determined by 1H NMR analysis. Purification
by flash column chromatography on silica gel (hexane/EtOAc = 8:2)
gave 3qa as a white solid (25.8 mg, 24% yield) and 3qa′ as a brown
liquid (55.8 mg, 52% yield). 3qa: mp: 146.5−147.7 °C; 1H NMR: (400
MHz, CDCl3) δ 8.13 (brs, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.14 (dd, J =
7.2, 7.2 Hz, 1H), 7.12 (d, J = 3.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 2.96
(s, 3H), 1.89 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 137.9,
130.2, 126.2, 124.2, 123.1, 122.8, 121.2, 118.2, 109.2, 30.9, 29.9, 23.2;
IR: (ATR) 3337, 3130, 2974, 2932, 2868, 2236, 1433, 1406, 1389,
1327, 1148, 1026, 831, 779, 745 cm−1; MS (EI) m/z: 198 (M+, 49), 183
(100), 156 (29), 154 (22), 129 (28), 128 (21), 77 (20); HRMS (EI)
1
89% yield). Mp: 194.0−195.3 °C; H NMR: (400 MHz, CDCl3) δ
7.95−7.87 (m, 2H), 7.43−7.36 (m, 1H), 7.33−7.22 (m, 2H), 7.19−
7.09 (m, 6H), 7.01−6.94 (m, 4H), 6.79 (d, J = 2.4 Hz, 1H), 3.63 (d, J =
13.2 Hz, 2H), 3.39 (d, J = 13.2 Hz, 2H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 137.2, 135.6, 130.2, 127.9, 127.1, 124.4, 124.0, 122.4, 121.7,
120.1, 119.9, 112.2, 112.1, 46.7, 44.2; IR: (ATR) 3325, 3053, 3030,
2934, 2245, 1668, 1601, 1551, 1495, 1437, 1331, 1254, 1227, 1134,
1113, 1096, 1061, 1032, 1015, 970, 839, 760, 741, 702 cm−1; MS (EI)
m/z: 336 (M+, 6), 245 (100), 91 (35); HRMS (EI) m/z: [M]+ calcd for
C24H20N2 336.1626; found 336.1623.
2-(1H-Indol-3-yl)-2-phenylpropanenitrile (3ad). According to the
typical procedure A, the reaction using B(C6F5)3 (12.8 mg, 0.025 mmol,
5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv), 1,4-dioxane (1
mL), and 2-hydroxy-2-phenylpropanenitrile (80 μL, 0.6 mmol, 1.2
equiv) was conducted at 80 °C for 24 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a white solid (93.4 mg, 76% yield). Mp: 162.5−163.6 °C; 1H NMR:
(400 MHz, CDCl3) δ 8.22 (brs, 1H), 7.49−7.43 (m, 2H), 7.39−7.23
(m, 5H), 7.21−7.15 (m, 2H), 7.00 (t, J = 7.4 Hz, 1H), 2.14 (s, 3H);
13C{1H} NMR: (100 MHz, CDCl3) δ 140.9, 136.9, 128.8, 127.7, 126.1,
124.7, 123.1, 122.7, 122.3, 120.1, 120.0, 116.1, 111.4, 40.5, 28.5; IR:
(ATR) 3348, 2940, 2932, 2862, 2234, 1632, 1547, 1493, 1450, 1433,
1341, 1260, 1242, 1134, 1113, 1096, 1030, 1013, 997, 903, 816, 795,
760, 735, 706 cm−1; MS (EI) m/z: 246 (M+, 40), 231 (100), 204 (21),
115 (27); HRMS (EI) m/z: [M]+ calcd for C17H14N2 246.1157; found
246.1155.
2-Methyl-2-(1-methyl-1H-pyrrol-3-yl)propanenitrile (4). In a
glovebox, an oven-dried reaction vial containing a magnetic stir bar
was charged with B(C6F5)3 (12.8 mg, 0.025 mmol, 5 mol %). The vial
was capped, removed from the glovebox. Then, a solution of 1-methyl-
1H-pyrrole (40.3 mg, 0.50 mmol, 1.0 equiv) in MeCN (1 mL) and
acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv) were added to the
vial. The mixture was stirred at 80 °C for 15 h. The reaction was
quenched by sat. NaHCO3 aq (10 mL), and the mixture was extracted
with Et2O (3 × 10 mL). The combined organic layers were dried over
Na2SO4. The solution was then under reduced pressure to give the
crude product. Purification by flash column chromatography on silica
gel (hexane/EtOAc = 8:2) gave the product as a colorless liquid (51.0
mg, 69% yield). 1H NMR: (400 MHz, CDCl3) δ 6.65−6.59 (m, 1H),
6.59−6.53 (m, 1H), 6.15−6.08 (m, 1H), 3.63 (s, 3H), 1.65 (s, 6H);
13C{1H} NMR: (100 MHz, CDCl3) δ 125.9, 125.4, 122.4, 118.1, 105.6,
36.2, 31.2, 29.1; IR: (ATR) 2980, 2938, 2232, 1551, 1508, 1466, 1458,
1422, 1387, 1366, 1346, 1207, 1190, 1119, 1086, 964, 777, 700 cm−1;
MS (EI) m/z: 148 (M+, 21), 133 (100), 106 (29); HRMS (EI) m/z:
[M]+ calcd for C9H12N2 148.1000; found 148.1001.
1
m/z: [M]+ calcd for C13H14N2 198.1157; found 198.1156. 3qa′: H
NMR: (400 MHz, CDCl3) δ 7.58 (d, J = 7.2 Hz, 1H), 7.21 (dd, J = 7.2,
7.2 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.58 (d, J
= 4.0 Hz, 1H), 2.55 (s, 3H), 2.06 (s, 6H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 134.3, 130.9, 129.7, 122.5, 122.4, 120.7, 120.2, 109.3, 101.3,
51.3, 27.8, 18.6; IR: (ATR) 3146, 3109, 3080, 3049, 2994, 2940, 2859,
2239, 1487, 1319, 1279, 1238, 748, 710 cm−1; MS (EI) m/z: 198 (M+,
37), 183 (24), 131 (25), 130 (100), 103 (20), 77 (29); HRMS (EI) m/
z: [M]+ calcd for C13H14N2 198.1157; found 198.1155.
2-Methyl-2-(3-methyl-1H-indol-2-yl)propanenitrile (3ra), 2-
Methyl-2-(3-methyl-1H-indol-1-yl)propanenitrile (3ra′). According
to the typical procedure A, the reaction using B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), 3-methyl-1H-indole (65.7 mg, 0.50 mmol, 1.0 equiv),
MeCN (1 mL), and acetone cyanohydrin (228 μL, 2.5 mmol, 5.0
equiv) was conducted at 80 °C for 15 h, providing the mixture of 3ra
and 3ra′ in 1:3.8 ratio, as determined by 1H NMR analysis. Purification
by flash column chromatography on silica gel (hexane/EtOAc = 8:2)
gave 3ra as a colorless liquid (15.9 mg, 16% yield) and 3ra′ as a colorless
liquid (60.2 mg, 61% yield). 3ra: 1H NMR: (400 MHz, CDCl3) δ 7.97
(brs, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.21 (dd, J
= 7.6, 7.6 Hz, 1H), 7.14 (dd, J = 7.6, 7.6 Hz, 1H), 2.44 (s, 3H), 1.86 (s,
6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 134.2, 130.8, 129.8, 123.1,
122.5, 119.8, 118.5, 110.7, 108.1, 32.5, 27.3, 9.4; IR: (ATR) 3366, 3059,
2984, 2932, 2868, 2237, 1653, 1585, 1524, 1458, 1333, 1306, 1240,
1200, 1180, 1007, 741, 719 cm−1; MS (EI) m/z: 198 (M+, 21), 183
(100), 154 (28), 129 (21), 128 (35), 102 (21), 77 (22), 52 (22), 51
(30), 50 (25); HRMS (EI) m/z: [M]+ calcd for C13H14N2 198.1157;
found 198.1160. 3ra′: 1H NMR: (400 MHz, CDCl3) δ 7.70 (d, J = 8.0
Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.34−7.26 (m, 1H), 7.23−7.15 (m,
1H), 6.96 (s, 1H), 2.31 (s, 3H), 2.04 (s, 6H); 13C{1H} NMR: (100
MHz, CDCl3) δ 135.0, 130.4, 122.3, 120.7, 120.4, 119.9, 119.5, 112.0,
111.5, 51.1, 27.8, 9.5; IR: (ATR) 3051, 2992, 2918, 2864, 2248, 1611,
1456, 1371, 1342, 1310, 1238, 1211, 1184, 1088, 1020, 762, 739 cm−1;
MS (EI) m/z: 198 (M+, 36), 183 (35), 130 (100), 77 (27); HRMS (EI)
m/z: [M]+ calcd for C13H14N2 198.1157; found 198.1157.
2-(2,5-Dimethyl-1H-pyrrol-3-yl)-2-methylpropanenitrile (5). In a
glovebox, an oven-dried reaction vial containing a magnetic stir bar was
charged with B(C6F5)3 (12.8 mg, 0.025 mmol, 5 mol %). The vial was
capped, removed from the glovebox. Then, a solution of 2,5-dimethyl-
1-(1H-Indol-3-yl)cyclohexane-1-carbonitrile (3ab). According to
the typical procedure A, the reaction using B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv), MeCN (1
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1H-pyrrole (47.4 mg, 0.50 mmol, 1.0 equiv) in MeCN (1 mL) and
acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv) were added to the
vial. The mixture was stirred at 80 °C for 15 h. The reaction was
quenched by sat. NaHCO3 aq (10 mL), and the mixture was extracted
with Et2O (3 × 10 mL). The combined organic layers were dried over
Na2SO4. The solution was then concentrated under reduced pressure to
give the crude product. Purification by flash column chromatography
on silica gel (hexane/EtOAc = 8:2) gave the product as a white solid
(63.3 mg, 78% yield). Mp: 74.9−76.3 °C; 1H NMR: (400 MHz,
CDCl3) δ 7.71 (brs, 1H), 5.71 (d, J = 2.8 Hz, 1H), 2.35 (s, 3H), 2.20 (s,
3H), 1.64 (s, 6H); 13C{1H} NMR: (100 MHz, CDCl3) δ 125.1, 124.7,
122.1, 119.0, 103.6, 30.4, 28.6, 12.7, 12.3; IR: (ATR) 3372, 2980, 2934,
2874, 2230, 1599, 1464, 1437, 1404, 1383, 1364, 1198, 1157, 775, 725
cm−1; MS (EI) m/z: 162 (M+, 29), 147 (100), 132 (37), 120 (27);
HRMS (EI) m/z: [M]+ calcd for C10H14N2 162.1157; found 162.1159.
2-(1H-Indol-3-yl)-2-phenylacetonitrile (3ae, 10aa). According to
the typical procedure A, the reaction usign B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol, 1.0
equiv) in MeNO2 (1 mL), and 2-hydroxy-2-phenylacetonitrile (79.3
mg, 0.60 mmol, 1.2 equiv) was conducted at 80 °C for 15 h. Purification
by flash column chromatography on silica gel (hexane/EtOAc = 8:2)
gave the product as a colorless liquid (84.5 mg, 73% yield). According
to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol, 1.0
equiv) in 1,4-dioxane (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol),
and benzaldehyde (63.2 mg, 0.60 mmol, 1.2 equiv) was conducted at
100 °C for 24 h. Purification by flash column chromatography on silica
gel (hexane/EtOAc = 8:2) gave the product as a colorless liquid (97.6
mg, 84% yield). 1H NMR: (400 MHz, CDCl3) δ 8.20 (brs, 1H), 7.48−
7.41 (m, 3H), 7.41−7.28 (m, 4H), 7.25−7.19 (m, 1H), 7.16 (d, J = 2.0
Hz, 1H), 7.13−7.07 (m, 1H), 5.39 (s, 1H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 136.5, 135.3, 129.0, 128.2, 127.7, 125.2, 123.2, 122.9, 120.3,
119.8, 118.8, 111.5, 111.0, 34.4; IR: (ATR) 3366, 3354, 3057, 2886,
2247, 1491, 1458, 1341, 1217, 1105, 789, 741, 702 cm−1; MS (EI) m/z:
232 (M+, 98), 231 (35), 204 (31), 155 (100), 102 (29), 101 (21);
HRMS (EI) m/z: [M]+ calcd for C16H12N2 232.1000; found 232.0998.
2-(4-Hydroxyphenyl)-2-(1H-indol-3-yl)acetonitrile (10ab). Ac-
cording to the typical procedure B, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50
mmol, 1.0 equiv) in MeCN (1 mL), acetone cyanohydrin (55 μL, 0.6
mmol, 1.2 equiv), and 4-hydroxybenzaldehyde (73.3 mg, 0.60 mmol,
1.2 equiv) was conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a pink solid (93.7 mg, 75% yield). Mp: 162.8−164.3 °C; 1H NMR:
(400 MHz, acetone-d6) δ 8.48 (brs, 1H), 7.55−7.40 (m, 2H), 7.40−
7.25 (m, 3H), 7.20−7.10 (m, 1H), 7.10−6.95 (m, 1H), 6.90−6.80 (m,
2H), 5.64 (s, 1H); 13C{1H} NMR: (100 MHz, acetone-d6) δ 157.9,
138.0, 129.7, 128.3, 126.3, 124.5, 122.9, 121.2, 120.2, 119.5, 116.5,
112.6, 111.9, 33.9; IR: (ATR) 3397, 3067, 3032, 2963, 2878, 2241,
1614, 1603, 1514, 1258, 1096, 1065, 1020, 1009, 820, 799, 783 cm−1;
HRMS (EI) m/z: [M]+ calcd for C16H12N2O 248.0950; found
248.0953.
mg, 0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
MeCN (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and
4-(tert-butyl)benzaldehyde (97.6 mg, 0.60 mmol, 1.2 equiv) was
conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a brown liquid (118.0 mg, 82% yield). 1H NMR: (400 MHz, CDCl3)
δ 8.20 (brs, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.41−7.34 (m, 5H), 7.22 (dd,
J = 8.0, 8.0 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.11 (dd, J = 8.0, 8.0 Hz,
1H), 5.36 (s, 1H), 1.30 (s, 9H); 13C{1H} NMR: (100 MHz, CDCl3) δ
151.1, 136.5, 132.3, 127.3, 125.9, 125.3, 123.2, 122.8, 120.2, 120.0,
118.8, 111.5, 111.1, 34.5, 34.0, 31.2; IR: (ATR) 3402, 3061, 3034, 2959,
2901, 2884, 2868, 2237, 1620, 1553, 1508, 1458, 1418, 1094, 1011, 853,
818, 789, 766, 737 cm−1; MS (EI) m/z: 288 (M+, 90), 273 (100), 231
(21), 208 (23), 207 (99), 156 (33), 155 (83), 128 (27), 122 (24), 117
(21); HRMS (EI) m/z: [M]+ calcd for C20H20N2 288.1626; found
288.1628.
2-(1H-Indol-3-yl)-2-(p-tolyl)acetonitrile (10ae). According to the
typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025 mmol,
5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv), MeCN (1 mL),
acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and 4-
methylbenzaldehyde (72.5 mg, 0.60 mmol, 1.2 equiv) was conducted
at 80 °C for 6 h. Purification by flash column chromatography on silica
gel (hexane/EtOAc = 8:2) gave the product as a brown liquid (95.3 mg,
77% yield). 1H NMR: (400 MHz, CDCl3) δ 8.20 (brs, 1H), 7.44 (d, J =
8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.24−
7.18 (m, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 2.8 Hz, 1H), 7.11−
7.06 (m, 1H), 5.33 (s, 1H), 2.33 (s, 3H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 137.9, 136.5, 132.3, 129.7, 127.5, 125.2, 123.2, 122.8, 120.2,
120.0, 118.8, 111.5, 111.0, 34.1, 21.0; IR: (ATR) 3408, 3053, 2961,
2920, 2872, 2243, 1620, 1549, 1512, 1456, 1418, 1339, 1098, 1011, 812,
772, 739 cm−1; MS (EI) m/z: 246 (M+, 100), 245 (33), 231 (30), 207
(23), 155 (82), 128 (23), 102 (20), 77 (20); HRMS (EI) m/z: [M]+
calcd for C17H14N2 246.1157; found 246.1159.
2-(4-Fluorophenyl)-2-(1H-indol-3-yl)acetonitrile (10af). Accord-
ing to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
MeCN (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and
4-fluorobenzaldehyde (74.2 mg, 0.60 mmol, 1.2 equiv) was conducted
at 80 °C for 6 h. Purification by flash column chromatography on silica
gel (hexane/EtOAc = 8:2) gave the product as a orange liquid (92.9 mg,
74% yield). 1H NMR: (400 MHz, CDCl3) δ 8.22 (brs, 1H), 7.44−7.36
(m, 4H), 7.27−7.22 (m, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.14−7.08 (m,
1H), 7.08−7.02 (m, 2H), 5.38 (s, 1H); 13C{1H} NMR: (100 MHz,
CDCl3) δ 162.4 (d, JC−F = 246.2 Hz), 136.5, 131.1 (d, JC−F = 3.3 Hz),
129.3 (d, JC−F = 8.2 Hz), 125.0, 123.3, 122.9, 120.3, 119.7, 118.6, 116.0
(d, JC−F = 22.3 Hz), 111.6, 110.4, 33.7; 19F{1H} NMR: (376 MHz,
CDCl3) δ −116.3; IR: (ATR) 3402, 2963, 2903, 2369, 2239, 1508,
1260, 1092, 1018, 793, 737 cm−1; MS (EI) m/z: 250 (M+, 92), 249
(31), 222 (34), 155 (100), 128 (26), 101 (28), 77 (23), 75 (35);
HRMS (EI) m/z: [M]+ calcd for C16H11FN2 250.0906; found
250.0910.
2-(4-Chlorophenyl)-2-(1H-indol-3-yl)acetonitrile (10ag). Accord-
ing to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
MeCN (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and
4-chlorobenzaldehyde (84.6 mg, 0.60 mmol, 1.2 equiv) was conducted
at 80 °C for 6 h. Purification by flash column chromatography on silica
gel (hexane/EtOAc = 8:2) gave the product as a brown liquid (95.8 mg,
72% yield). 1H NMR: (400 MHz, CDCl3) δ 8.24 (brs, 1H), 7.42−7.29
(m, 6H), 7.26−7.20 (m, 1H), 7.13−7.08 (m, 1H), 7.13−7.08 (m, 1H),
5.36 (s, 1H); 13C{1H} NMR: (100 MHz, CDCl3) δ 136.5, 134.1, 133.9,
129.2, 129.0, 125.0, 123.3, 123.0, 120.4, 119.4, 118.6, 111.6, 110.4,
33.9; IR: (ATR) 3410, 3059, 2905, 2245, 1896, 1724, 1711, 1618, 1595,
1578, 1547, 1489, 1092, 1015, 814, 775, 741 cm−1; MS (EI) m/z: 268
([M + 2]+, 31), 266 (M+, 82), 231 (29), 207 (51), 204 (26), 155 (100),
128 (22), 102 (31), 101 (34), 89 (22), 88 (28), 77 (23), 75 (40);
HRMS (EI) m/z: [M]+ calcd for C16H11ClN2 266.0611; found
266.0609.
2-(1H-Indol-3-yl)-2-(4-methoxyphenyl)acetonitrile (10ac). Ac-
cording to the typical procedure B, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
MeCN (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and
4-methoxybenzaldehyde (81.6 mg, 0.60 mmol, 1.2 equiv) was
conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a red liqud (125.0 mg, 95% yield). 1H NMR: (400 MHz, CDCl3) δ
8.20 (brs, 1H), 7.45−7.31 (m, 4H), 7.26−7.16 (m, 2H), 7.10 (dd, J =
8.8, 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 5.35 (s, 1H), 3.80 (s, 3H);
13C{1H} NMR: (100 MHz, CDCl3) δ 159.3, 136.6, 128.8, 127.4, 125.2,
123.1, 122.9, 120.2, 120.0, 118.8, 114.3, 111.5, 111.3, 55.3, 33.7; IR:
(ATR) 3408, 2963, 2837, 2359, 2243, 1611, 1508, 1258, 1096, 1069,
1026, 795, 779, 741 cm−1; MS (EI) m/z: 262 (M+, 100), 261 (27), 231
(20), 155 (57), 154 (20); HRMS (EI) m/z: [M]+ calcd for C17H14N2O
262.1106; found 262.1106.
2-(4-(tert-Butyl)phenyl)-2-(1H-indol-3-yl)acetonitrile (10ad). Ac-
cording to the typical procedure B, the reaction using B(C6F5)3 (12.8
4-(Cyano(1H-indol-3-yl)methyl)phenyl Acetate (10ah). According
to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025
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mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv), MeCN (1
mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and 4-
formylphenyl acetate (98.7 mg, 0.60 mmol, 1.2 equiv) was conducted at
80 °C for 6 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc = 8:2) gave the product as a brown liquid (110.5 mg,
76% yield). 1H NMR: (400 MHz, CDCl3) δ 8.27 (brs, 1H), 7.47−7.41
(m, 3H), 7.38 (d, J = 8.4 Hz, 1H), 7.26−7.20 (m, 1H), 7.13−7.06 (m,
4H), 5.38 (s, 1H), 2.30 (s, 3H); 13C{1H} NMR: (100 MHz, CDCl3) δ
169.4, 150.3, 136.5, 132.9, 128.8, 125.1, 123.3, 122.9, 122.2, 120.3,
119.6, 118.7, 111.6, 110.5, 33.8, 21.1; IR: (ATR) 3397, 2963, 2359,
2243, 1748, 1605, 1504, 1260, 1194, 1165, 1094, 1016, 858, 794, 741
cm−1; MS (EI) m/z: 290 (M+, 52), 249 (20), 248 (100), 247 (32), 207
(49), 155 (63); HRMS (EI) m/z: [M]+ calcd for C18H14N2O2
290.1055; found 290.1050.
2-(1H-Indol-3-yl)-2-(4-(trifluoromethyl)phenyl)acetonitrile
(10ai). According to the typical procedure B, the reaction using
B(C6F5)3 (12.8 mg, 0.025 mmol, 5 mol %), a solution of 1H-indole
(58.6 mg, 0.50 mmol, 1.0 equiv) in MeNO2 (1 mL), acetone
cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and 4-(trifluoromethyl)-
benzaldehyde (104.9 mg, 0.60 mmol, 1.2 equiv) was conducted at 80
°C for 6 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc = 8:2) gave the product as a white solid (103.2 mg,
69% yield). Mp: 121.9−123.1 °C; 1H NMR: (400 MHz, CDCl3) δ 8.28
(brs, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.45−7.36
(m, 2H), 7.28−7.21 (m, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.15−7.07 (m,
1H), 5.44 (s, 1H); 13C{1H} NMR: (100 MHz, CDCl3) δ 139.2, 136.5,
mmol, 1.2 equiv) and 3-hydroxybenzaldehyde (73.3 mg, 0.60 mmol, 1.2
equiv) was conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a red liquid (86.5 mg, 70% yield). 1H NMR: (400 MHz, CDCl3) δ
8.18 (brs, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.24−
7.15 (m, 2H), 7.14−7.04 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.88 (s,
1H), 6.77 (dd, J = 8.4, 1.4 Hz, 1H), 5.61 (brs, 1H), 5.30 (s, 1H);
13C{1H} NMR: (100 MHz, CDCl3) δ 156.2, 136.7, 136.4, 130.3, 125.1,
123.3, 122.9, 120.3, 120.0, 119.7, 118.7, 115.3, 114.6, 111.6, 110.4,
34.2; IR: (ATR) 3401, 3345, 2245, 1701, 1591, 1487, 1456, 1420, 1354,
1339, 1244, 1148, 1098, 1042, 770, 739 cm−1; HRMS (EI) m/z: [M]+
calcd for C16H12N2O 248.0950; found 248.0952.
2-(1H-Indol-3-yl)-2-(3-methoxyphenyl)acetonitrile (10am). Ac-
cording to the typical procedure B, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
MeCN (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and
3-methoxybenzaldehyde (81.9 mg, 0.60 mmol, 1.2 equiv) was
conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a yellow liquid (96.1 mg, 73% yield). 1H NMR: (400 MHz, CDCl3) δ
8.21 (brs, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.28
(dd, J = 8.0, 8.0 Hz, 1H), 7.22 (dd, J = 8.0, 8.0 Hz, 1H), 7.18 (d, J = 2.4
Hz, 1H), 7.11 (dd, J = 8.0, 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 7.00−
6.95 (m, 1H), 6.85 (dd, J = 8.0, 2.4 Hz, 1H), 5.36 (s, 1H), 3.77 (s, 3H);
13C{1H} NMR: (100 MHz, CDCl3) δ 160.0, 136.8, 136.5, 130.0, 125.2,
123.2, 122.9, 120.3, 120.0, 119.7, 118.8, 113.6, 113.4, 111.5, 110.8, 55.3,
34.4; IR: (ATR) 3402, 2963, 2835, 2243, 1599, 1585, 1487, 1456, 1433,
1260, 1096, 1036, 1013, 795, 741 cm−1; HRMS (EI) m/z: [M]+ calcd
for C17H14N2O 262.1106; found 262.1111.
2-(3-Chlorophenyl)-2-(1H-indol-3-yl)acetonitrile (10an). Accord-
ing to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
MeNO2 (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv),
and 3-chlorobenzaldehyde (84.5 mg, 0.60 mmol, 1.2 equiv) was
conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a brown liquid (93.1 mg, 70% yield). 1H NMR: (400 MHz, CDCl3) δ
8.24 (brs, 1H), 7.45−7.38 (m, 3H), 7.37−7.28 (m, 3H), 7.28−7.20 (m,
2H), 7.12 (dd, J = 7.4, 7.4 Hz, 1H), 5.37 (s, 1H); 13C{1H} NMR: (100
MHz, CDCl3) δ 137.3, 136.5, 134.9, 130.3, 128.5, 127.9, 125.9, 125.0,
123.3, 123.1, 120.5. 119.2, 118.6, 111.6, 110.2, 34.1; IR: (ATR) 3406,
3059, 2982, 2903, 2245, 1724, 1595, 1474, 1458, 1423, 1354, 1339,
1244, 1098, 1080, 1043, 1011, 739, 716, 702 cm−1; MS (EI) m/z: 268
([M + 2]+, 22), 266 (M+, 66), 231 (25), 155 (100), 128 (21), 102 (24),
101 (34), 88 (21), 75 (30); HRMS (EI) m/z: [M]+ calcd for
C16H11ClN2 266.0611; found 266.0615.
2-(1H-Indol-3-yl)-2-(2-methoxyphenyl)acetonitrile (10ao). Ac-
cording to the typical procedure B, the reaction using B(C6F5)3 (12.8
mg, 0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
1,4-dioxane (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv),
and 2-methoxybenzaldehyde (81.8 mg, 0.60 mmol, 1.2 equiv) was
conducted at 100 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a orange liquid (118.7 mg, 91% yield). 1H NMR: (400 MHz, CDCl3)
δ 8.20 (brs, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H),
7.32−7.16 (m, 4H), 7.11−7.06 (m, 1H), 6.98−6.86 (m, 2H), 5.77 (s,
1H), 3.90 (s, 3H); 13C{1H} NMR: (100 MHz, CDCl3) δ 156.3, 136.5,
129.5, 128.9, 125.5, 123.9, 123.3, 122.7, 120.9, 120.2, 120.1, 118.9,
111.4, 110.8, 110.5, 55.6, 27.9; IR: (ATR) 3404, 3057, 2965, 2938,
2837, 2243, 1489, 1456, 1437, 1246, 1101, 1047, 1024, 739 cm−1; MS
(EI) m/z: 262 (M+, 76), 247 (22), 155 (25), 131 (59), 130 (100);
HRMS (EI) m/z: [M]+ calcd for C17H14N2O 262.1106; found
262.1110.
130.4 (q, JC−F = 32.4 Hz), 128.1, 126.0 (br), 124.9, 123.8 (q, JC−F
=
270.8 Hz), 123.4, 123.1, 120.5, 119.1, 118.5, 111.7, 109.8, 34.2;
19F{1H} NMR: (376 MHz, CDCl3) δ −65.2; IR: (ATR) 3333, 2255,
1620, 1458, 1422, 1323, 1260, 1219, 1153, 1132, 1105, 1067, 1018,
1011, 964, 862, 824, 791, 766, 745 cm−1; MS (EI) m/z: 300 (M+, 83),
155 (100); HRMS (EI) m/z: [M]+ calcd for C17H11F3N2 300.0874;
found 300.0872.
4-(Cyano(1H-indol-3-yl)methyl)benzonitrile (10aj). According to
the typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol, 1.0
equiv) in MeNO2 (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2
equiv), and 4-formylbenzonitrile (78.7 mg, 0.60 mmol, 1.2 equiv) was
conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a brown liquid (106.8 mg, 83% yield). 1H NMR: (400 MHz, CDCl3)
δ 8.29 (brs, 1H), 7.70−7.62 (m, 2H), 7.62−7.52 (m, 2H), 7.42 (d, J =
8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29−7.22 (m, 2H), 7.16−7.08
(m, 1H), 5.45 (s, 1H); 13C{1H} NMR: (100 MHz, CDCl3) δ 140.6,
136.6, 132.8, 128.4, 124.8, 123.5, 123.2, 120.6, 118.7, 118.3, 118.2,
112.2, 111.8, 109.3, 34.4; IR: (ATR) 3404, 3057, 2924, 2849, 2228,
1724, 1707, 1607, 1551, 1501, 1458, 1414, 1339, 1244, 824, 777, 766,
743 cm−1; MS (EI) m/z: 257 (M+, 75), 256 (20), 229 (22), 155 (100),
128 (20), 101 (25); HRMS (EI) m/z: [M]+ calcd for C17H11N3
257.0953; found 257.0951.
2-(1H-Indol-3-yl)-2-(4-nitrophenyl)acetonitrile (10ak). According
to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv), 1,4-
dioxane (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv),
and 4-nitrobenzaldehyde (90.7 mg, 0.60 mmol, 1.2 equiv) was
conducted at 100 °C for 24 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
as a orange liquid (85.2 mg, 61% yield). 1H NMR: (400 MHz, CDCl3) δ
8.30 (brs, 1H), 8.25−8.20 (m, 2H), 7.63−7.60 (m, 2H), 7.43 (d, J = 8.4
Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.31−7.20 (m, 2H), 7.15−7.05 (m,
1H), 5.50 (s, 1H); 13C{1H} NMR: (100 MHz, CDCl3) δ 147.7, 142.5,
136.6, 128.6, 124.8, 124.2, 123.5, 123.3, 120.7, 118.6, 118.3, 111.8,
109.3, 34.2; IR: (ATR) 3401, 3111, 3078, 2963, 2924, 2853, 2245,
1705, 1597, 1516, 1458, 1420, 1342, 1260, 1098, 1015, 856, 845, 818,
795, 785, 743, 725, 716 cm−1; HRMS (EI) m/z: [M]+ calcd for
C16H11N3O2 277.0851; found 277.0846.
2-(2-Chlorophenyl)-2-(1H-indol-3-yl)acetonitrile (10ap). Accord-
ing to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv),
MeNO2 (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv),
and 2-chlorobenzaldehyde (84.3 mg, 0.60 mmol, 1.2 equiv) was
conducted at 80 °C for 6 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
2-(3-Hydroxyphenyl)-2-(1H-indol-3-yl)acetonitrile (10al). Accord-
ing to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol,
1.0 equiv) in MeCN (1 mL) and acetone cyanohydrin (55 μL, 0.6
8398
https://doi.org/10.1021/acs.joc.1c00808
J. Org. Chem. 2021, 86, 8389−8401

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
as a brown liquid (82.2 mg, 71% yield). 1H NMR: (400 MHz, CDCl3) δ
8.23 (brs, 1H), 7.50−7.42 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.32−7.18
(m, 4H), 7.11 (dd, J = 8.4, 8.4 Hz, 1H), 5.83 (s, 1H); 13C{1H} NMR:
(100 MHz, CDCl3) δ 136.6, 133.3, 133.1, 130.0, 129.74, 129.71, 127.6,
125.2, 123.6, 123.0, 120.4, 119.0, 118.7, 111.6, 109.7, 31.7; IR: (ATR)
3329, 3063, 2907, 2253, 1620, 1476, 1460, 1437, 1103, 1051, 1036,
1011, 945, 791, 735, 708 cm−1; MS (EI) m/z: 268 ([M + 2]+, 16), 266
(M+, 50), 230 (23), 229 (22), 204 (51), 155 (100), 128 (32), 102 (40),
101 (50), 89 (27), 88 (36), 87 (21), 77 (38), 76 (25), 75 (70), 74 (26),
63 (32), 51 (35), 50 (33); HRMS (EI) m/z: [M]+ calcd for
C16H11ClN2 266.0611; found 266.0607.
80 °C for 6 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc = 8:2) gave the product as a colorless liquid (75.4 mg,
71% yield). 1H NMR: (400 MHz, CDCl3) δ 8.24 (brs, 1H), 7.64 (d, J =
7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.26−7.20 (m, 1H), 7.19−7.14
(m, 1H), 7.12 (d, J = 2.4 Hz, 1H), 4.09 (dd, J = 9.6, 5.6 Hz, 1H), 2.11−
1.79 (m, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H);
13C{1H} NMR: (100 MHz, CDCl3) δ 136.3, 125.1, 122.6, 122.0, 121.4,
119.9, 118.3, 111.6, 110.6, 42.8, 26.8, 26.0, 22.5, 21.6; IR: (ATR) 3410,
3059, 2957, 2932, 2870, 2239, 1620, 1553, 1458, 1422, 1354, 1339,
1246, 1098, 1011, 816, 739 cm−1; MS (EI) m/z: 212 (M+, 26), 156
(38), 155 (100); HRMS (EI) m/z: [M]+ calcd for C14H16N2 212.1313;
found 212.1316.
2-(2-Bromophenyl)-2-(1H-indol-3-yl)acetonitrile (10aq). Accord-
ing to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg,
0.025 mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol,
1.0 equiv) in MeCN (1 mL), 1-hydroxycyclohexane-1-carbonitrile
(75.7 mg, 0.60 mmol, 1.2 equiv), and 2-bromobenzaldehyde (111.5 mg,
0.60 mmol, 1.2 equiv) was copnducted at 80 °C for 24 h. Purification by
flash column chromatography on silica gel (hexane/EtOAc = 8:2) gave
2-(1H-Indol-3-yl)-3,3-dimethylbutanenitrile (10au). According to
the typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol, 1.0
equiv) in MeCN (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2
equiv), and pivalaldehyde (51.9 mg, 0.60 mmol, 1.2 equiv) was
conducted at 80 °C for 24 h. Purification by flash column
chromatography on silica gel (hexane/EtOAc = 8:2) gave the product
1
the product as a brown liquid (69.1 mg, 45% yield). H NMR: (400
1
MHz, CDCl3) δ 8.23 (brs, 1H), 7.64 (dd, J = 7.6, 1.6 Hz, 1H), 7.50−
7.44 (m, 2H), 7.42−7.37 (m, 1H), 7.30 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H),
7.25−7.18 (m, 3H), 7.15−7.09 (m, 1H), 5.84 (s, 1H); 13C{1H} NMR:
(100 MHz, CDCl3) δ 136.5, 134.7, 133.3, 129.94, 129.85, 128.2, 125.1,
123.7, 123.6, 122.9, 120.3, 119.1, 118.8, 111.6, 109.7, 34.5; IR: (ATR)
3426, 2922, 2251, 1620, 1570, 1549, 1476, 1458, 1443, 1416, 1339,
1254, 1217, 1188, 1123, 1094, 1038, 1028, 1011, 970, 827, 799, 741
cm−1; MS (EI) m/z: 312 ([M + 2]+, 39), 310 (M+, 40), 231 (35), 230
(21), 229 (44), 204 (100), 203 (27), 176 (25), 155 (89), 128 (28), 127
(21), 102 (53), 101 (49), 89 (25), 88 (42), 77 (36), 76 (40), 75 (53),
74 (24), 63 (34), 51 (34), 50 (39); HRMS (EI) m/z: [M]+ calcd for
C16H11BrN2 310.0106; found 310.0113.
2-(1H-Indol-3-yl)-2-(2-nitrophenyl)acetonitrile (10ar). According
to the typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025
mmol, 5 mol %), 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv), MeNO2
(1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and 2-
nitrobenzaldehyde (90.7 mg, 0.60 mmol, 1.2 equiv) was conducted at
80 °C for 6 h. Purification by flash column chromatography on silica gel
(hexane/EtOAc = 8:2) gave the product as a brown liquid (97.9 mg,
71% yield). 1H NMR: (400 MHz, CDCl3) δ 8.23 (brs, 1H), 8.06 (dd, J
= 8.2, 1.4 Hz, 1H), 7.80 (dd, J = 8.2, 1.4 Hz, 1H), 7.64 (ddd, J = 8.2, 8.2,
1.4 Hz, 1H), 7.52 (ddd, J = 8.2, 8.2, 1.4 Hz, 1H), 7.44−7.35 (m, 2H),
7.31−7.18 (m, 2H), 7.13−7.08 (m, 1H), 6.37 (s, 1H); 13C{1H} NMR:
(100 MHz, CDCl3) δ 147.8, 136.4, 134.0, 130.5, 130.3, 129.5, 125.7,
124.9, 123.9, 123.1, 120.6, 118.5, 111.7, 108.8, 30.9 (one sp2 signal was
not observed because of overlapping); IR: (ATR) 3401, 2963, 2247,
2214, 1520, 1341, 1258, 1096, 1080, 1013, 785, 764, 741, 700 cm−1;
HRMS (EI) m/z: [M]+ calcd for C16H11N3O2 277.0851; found
277.0849.
2-(1H-Indol-3-yl)pentanenitrile (10as). According to the typical
procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025 mmol, 5 mol
%),1H-indole (58.8 mg, 0.50 mmol, 1.0 equiv), MeNO2 (1 mL),
acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv), and butyraldehyde
(43.7 mg, 0.61 mmol, 1.2 equiv) was conducted at 80 °C for 6 h.
Purification by flash column chromatography on silica gel (hexane/
EtOAc = 8:2) gave the product as a colorless liquid (56.2 mg, 57%
yield). 1H NMR: (400 MHz, CDCl3) δ 8.16 (brs, 1H), 7.64 (d, J = 8.4
Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.28−7.25 (m, 1H), 7.23 (d, J = 2.4
Hz, 1H), 7.22−7.14 (m, 1H), 4.10 (dd, J = 7.2, 7.2 Hz, 1H), 2.13−1.92
(m, 2H), 1.70−1.48 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR:
(100 MHz, CDCl3) δ 136.4, 125.2, 122.7, 122.2, 121.2, 120.0, 118.4,
111.6, 110.8, 35.9, 28.6, 20.4, 13.4; IR: (ATR) 3408, 3366, 2959, 2932,
2872, 2239, 1620, 1551, 1491, 1458, 1422, 1354, 1339, 1244, 1098,
1011, 822, 739 cm−1; MS (EI) m/z: 198 (M+, 12), 155 (100), 128 (24),
101 (30); HRMS (EI) m/z: [M]+ calcd for C13H14N2 198.1157; found
198.1161.
as a colorless liquid (37.7 mg, 36% yield). H NMR: (400 MHz,
CDCl3) δ 8.31 (brs, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz,
1H), 7.26−7.19 (m, 2H), 7.19−7.12 (m, 1H), 3.89 (s, 1H), 1.12 (s,
9H); 13C{1H} NMR: (100 MHz, CDCl3) δ 135.7, 126.7, 124.1, 122.4,
121.0, 120.1, 119.0, 111.4, 108.8, 40.7, 35.7, 27.5; IR: (ATR) 3406,
3366, 2963, 2936, 2907, 2891, 2870, 2236, 1620, 1543, 1458, 1422,
1368, 1354, 1339, 1219, 1099, 1013, 772, 739 cm−1; MS (EI) m/z: 212
(M+, 16), 156 (100), 155 (71), 130 (21), 128 (25), 101 (26), 57 (50);
HRMS (EI) m/z: [M]+ calcd for C14H16N2 212.1313; found 212.1316.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00808.
■
sı
Experimental procedures and copies of NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Kensuke Kiyokawa − Department of Applied Chemistry,
Graduate School of Engineering, Osaka University, Osaka
565-0871, Japan; orcid.org/0000-0001-6124-2861;
Email: kiyokawa@chem.eng.osaka-u.ac.jp
Satoshi Minakata − Department of Applied Chemistry,
Graduate School of Engineering, Osaka University, Osaka
565-0871, Japan; orcid.org/0000-0001-9619-445X;
Email: minakata@chem.eng.osaka-u.ac.jp
Author
Naruyo Urashima − Department of Applied Chemistry,
Graduate School of Engineering, Osaka University, Osaka
565-0871, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00808
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Numbers
JP19H02716 (S.M.) and JP20K05511 (K.K.).
■
2-(1H-Indol-3-yl)-4-methylpentanenitrile (10at). According to the
typical procedure B, the reaction using B(C6F5)3 (12.8 mg, 0.025 mmol,
5 mol %), a solution of 1H-indole (58.6 mg, 0.50 mmol, 1.0 equiv) in
MeNO2 (1 mL), acetone cyanohydrin (55 μL, 0.6 mmol, 1.2 equiv),
and 3-methylbutanal (51.7 mg, 0.60 mmol, 1.2 equiv) was conducted at
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