The palladium-catalyzed direct C3-cyanation of indoles using acetonitrile as the cyanide source

Article abstract of DOI:10.1039/d0ob00485e

The ligand-free palladium-catalyzed C3-cyanation of indoles via direct C-H functionalization was achieved. This protocol, utilizing CH3CN as a green and readily available cyanide source, produced the desired products in moderate to good yields through transition-metal-catalyzed C-CN bond cleavage. This journal is

Full text of DOI:10.1039/d0ob00485e

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DOI: 10.1039/D0OB00485E
ARTICLE
Palladium Catalyzed Direct C3-Cyanation of Indoles Using
Acetonitrile as the Cyanide Source
Bifu Liu,a Min Liu,*a,d Qiang Li,b,c Yuanhua Li,a Kejun Feng a and Yongbo Zhou c
Received 00th January 20xx,
Accepted 00th January 20xx
A ligand free palladium catalyzed C3-cyanation of indole via direct C-H functionalization was achieved. This protocol utilizing
CH3CN as green and readily available cyanide source obtaining the desired product in moderate to good yield through
transition metal catalyzed C-CN bond cleavage.
DOI: 10.1039/x0xx00000x
classified as nucleophilic CN- sources,6 electrophilic CN+
sources,7 combined cyano group8 and organic R-CN units.9
Among then, cyano anions like the metallic cyanides used to be
Introduction
Indole nitrile especially 3-cyanoindole moiety is a value-
added basic unit in organic synthesis, pharmaceutic science,
material preparation and anti-virus/bacteria natural products
(Figure 1).1 In which, the versatile cyano group can realize its
late-stage functionalization in suitable conditions transformed
frequently applied representatives. Nevertheless, the metallic
cyanides like CuCN, NaCN or KCN are highly toxic to human and
environment, and TMSCN suffers the same drawback. However,
in which, the relatively environment-benign K4[Fe(CN)6] shows
weak solubility in organic solvent thus suppressed its further
applications.9b Elegant progresses have been developed with
the versatile combined cyanide sources exhibiting good
feasibility constructing 3-cyanoindole.8
to carboxyl derivatives, amides, aldehydes and so on.2
t-Bu
Me
R
N
O
O
N
CN
S
EtO
CN
HOOC
H
CN
N
catalytic C-H bond
O
S
R2
functionalization
HN
R2
N
Me
N
R1
various "CN" sources
N
R1
O
Acatyl-CoA carboxylase inhibitors
Xanthine oxidase inhibitors
nucleophilic CN- sources:
electrophilic CN+ sources:
combined [CN] group:
CuCN; NaCN; K4[Fe(CN)6]; TMSCN
NCTs; BrCN
Figure 1. Representatives containing 3-cyanoindole block
A comprehensive research has been conducted for the
preparation of 3-cyanoindole.3,6-9 The Sandmeyer and
Rosenmund-von Braun reactions represents the most typically
conventional method.4 Significant efforts have been devoted to
develop a more efficient and greener cyanation protocol to
meet the modern organic synthesis demands.5 Various cyano
sources have been evolved (Scheme 1), which could be
DMF/NH4I; TMEDA/(NH4)2CO3;
DMF; NH4HCO3/DMSO
organic R-CN units:
t-BuNC; BnCN; CH3CN
Scheme 1. Catalytic synthesis of 3-cyano indoles with various “CN” sources
Concerning the economic and environmentally friendly
properties, acetonitrile would be an ideal alternative. While the
C-CN bond activation in acetonitrile is of particularly difficult
because it has a higher bond energy (133 Kcal mol-1) than the
average alkane C-C bond energy (approximate 83 Kcal mol-1).10
Few examples have been reported realizing the cyanation of
aromatic compounds using CH3CN as the sole cyano source.9a,11
In which, Shen group reported an indole C3-cyanation protocol
via the C-H bond activation catalysed by Cu/Si/TEMPO
activation system gaining the target product in moderate to
good yields with broad substrate scope application (Scheme
2a).9a Nevertheless, a ligand assistance and NIS promoted pre-
iodination of indole C-H bond are essential to furnish the further
cyanation consuming a lengthy reaction time (2-5 days). Herein,
a. School of Chemistry and Materials Engineering, Huizhou University, Huizhou,
516007, Guangdong, China.
b. College of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng,
Shandong 252059, China.
c. College of Chemistry and Chemical Engineering, Hunan University, Changsha
410082, China.
d. Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources
Recycle, Nanchang Hangkong University, Nanchang 330063, China
E-mail: minliu1018@163.com
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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we report a palladium catalysed ligand-free direct C3-cyanation
protocol of indoles using acetonitrile as the green cyanide
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DOI: 10.1039/D0OB00485E
2 | J. Name., 2012, 00, 1-3
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Table 1 Oxidative C-3 cyanation of N-benzyl indole with CH3CN a
source via C-H bond activation and C-CN bond cleavage
(Scheme 2b).
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DOI: 10.1039/D0OB00485E
H
CN
PdCl2/5 mol%
a: Previous work:
Cu(OAc)2/1.5 equiv.
CN
H
I
+
CN
CH3
acid, additive
N
N
Bn
NIS
CN
CH3
Bn
R'
R'
R'
ligand free
N
N
N
1a
3a
2
R
R
R
involving an pre-iodination pathway
lengthy reaction time: 2-5 days
Ru
n
1
2
3
4
5
6
7
Cat. [Pd]
mol %
PdCl2/5
Cu salt
1.5 eq.
Acid
(1 eq.)
/
/
/
/
/
/
/
/
/
/
Additive
(1 eq.)
3aa
Yield %b
16
11
13
b: This work:
H
CN
Cat. [Pd]/O2
ligand free
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuBr2
CuBr
CuI
Cu2O
Cu(TFA)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
PdCl2(PPh)3/5
Pd(OAc)2/5
PdBr2/5
Pd(PPh3)4/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
PdCl2/5
/
R'
R'
CN
CH3
+
direct C-H cyanation
N
N
R
R
9
R = Aryl; alkyl
C-CN bond cleavage
up to 88%
26 examples
trace
trace
trace
trace
N.D
15
20
15
26
16
10
45
trace
45
47
17
58
38c
Scheme 2. Pd-catalysed preparation of 3-cyanoindole with acetonitrile
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Results and discussion
Ph2POOH
PhCOOH
We initiated our study from utilizing N-Benzyl indole (1a) as the
model substrate, acetonitrile as both the cyanide source and
solvent in the presence of PdCl2 (5 mol %) and Cu(OAc)2 (1.5
equiv.) under O2 atmosphere at 135oC for 24 h, the desired
product 3-cyanoindole (3a) was obtained in 16% yield (Table 1,
run 1). And screening of other Pd-catalyst showed inferior
efficiency in this transformation (run 2-5). Then we optimized
the copper species, the results contained indicated that cupric
halide or Cu2O showed no reactivity (run 6-9) while Cu(TFA)2
exhibited almost the same reactivity to Cu(OAc)2 (Run 10). With
a screening of acids (run 11-15), a slight promotion was
observed and 4-nitrobenzoic acid showed better performance
gaining the desired product in 26% yield (run 13). When we
further introduced the AgOAc as additive, which might be a role
of co-oxidant, yield of the desired product was increased to 45%
(run 16). While trace amount of product was observed without
the loading of acid (run 17). Encouraged by the effect of AgOAc,
we further optimized a serial of Ag salts (run 18-21), and AgOTf
contributed the best reactivity promotion producing the
desired product in 58% yield (run 21). Either further elevating
the temperature to 150 oC or down to 100 oC showed no
promotion (run 22-23). As we screening the solvent effect, we
found that Cu(OAc)2 showed good solubility in DMF.
Gratifyingly, the mixed solvent (CH3CN/DMF = 3.5 mL/1.5 mL)
indeed exhibited good preference obtaining the desired
product in 73% yield (run 24). Further considering that DMF
could also act as an internal combined cyanide source,8a we
applied DMF as the sole solvent but only trace amount of the
desired product was observed (run 25) that indicated the
cyanide source mainly formed from acetonitrile. Selected
control experiments conducted showed that catalytic loading of
palladium and the O2 atmosphere were essential to this
oxidative cross-coupling system (run 26-27). Meanwhile, once
we decreased the Cu(OAc)2 or AgOTf to catalytic amount of 20%,
the reactivity were dramatically depressed (run 28-29).
4-NO2-PhCOOH
4-MeO-PhCOOH
(CH3)3CCOOH
4-NO2-PhCOOH
/
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
4-NO2-PhCOOH
AgOAc
AgOAc
AgClO4
Ag2CO3
AgNO3
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
traced
73e
tracef
N.Dg
N.De
N.De,h
N.De,i
PdCl2/5
PdCl2/5
Reaction condition: N-benzyl indole (0.2 mmol, 41.4 mg), PdCl2 (0.01 mmol, 1.8 mg),
Cu(OAc)2 (0.3 mmol, 54.3 mg), AgSO3CF3 (0.2 mmol, 51.4 mg), 4-NO2-PhCOOH (0.2
mmol, 33.4 mg ) in CH3CN/5 mL, O2 (1 atm, 25 mL), 135oC, 24 h. GC yields using
b
dodecane as the internal stander. 150 oC was used; 100 oC was used; Solvent
c
d
e
f
g
(CH3CN/3.5 mL, DMF/1.5 mL) was used. Solvent (DMF/5 mL) was used. Under the
atmosphere of N2 or air. h 20 mol % Cu(OAc)2 was used. i 20 mol % AgOTf was used.
With the optimizing condition in hand, the palladium catalysed
direct indole C3-cyanation strategy was applied to other indole
substrates. The N-aryl substituted and N-alkyl substituted
indoles both exhibited good feasibility in this catalytic
transformation. As displayed in Table 2, the N- aryl substituted
indoles with electronic donating group like MeO- substitution
could be well fitted gaining the yield of 59% (Table 2, 3b).
Meanwhile, the electronic withdrawing group substitutions also
exhibited good compatibility in this catalytic system. Such as the
simple halogen substitutions (F-, Cl-) at 5-position of indole ring,
ideal yields could be obtained in 79% (3c) and 88% (3d),
respectively. Besides, the strong electronic withdrawing groups
like -CHO and -NO2, could also well featured in this protocol
generating the desired cyanation products in good yields (3e
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and 3f, 75% and 65%, respectively). However, complicated electron-deficient group like F- at its 4- position, trace amount
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target product was produced when the 5- position of indole ring of cyanation product was observed (3p), DwOhIi:l1e0t.1h0e39e/lDe0cOtrBo0n0-4r8ic5hE
was occupied by -CN group. Furthermore, not only for the 5- substitution (MeO-) showed no influence to the reactivity (3o,
position substitutions could be adapted to this transformation, 76% yield).
functionalization of other positions could also be well
accommodated. In which, the selected simple bromide and the
strong electronic withdrawing ester group substitutions
distributed at 4-, 6-, 7- positions all exhibited good reactivity
obtaining the desired products in 72%-83% yields (3h-3k).
Meantime, a brief control experiment was conducted indicated
that the reactivity of 3- position was far more active than 2-
position. For which, trace amount of the 2-cyanation product
was obtained (GC-MS detected) when the 3- position was
occupied by methyl group (3l).
Table 3 C-3 cyanation of N-alkyl indoles with acetonitrile a
CN
H
PdCl2 /Cu(OAc)2 /AgOTf /4-NO2-PhCOOH
CH3CN/DMF, O2 (1 atm), 135 oC, 24 h.
R'
R'
CN
CH3
+
N
N
R
R
R = Alkyl
3
1
2
For alkyl substitutions:
CN
CN
CN
CN
F
MeO
N
Me
N
Me
N
N
Me
i-Pr
Table 2 C-3 cyanation of N-aryl indoles with acetonitrile a
c
d
f
e
3q
, 30%
3r
, 43%
3t
3s
, 72% (81 )
CN
, 8%
CN
CN
CN
CN
H
Me
F
F
PdCl2/Cu(OAc)2 /AgOTf /4-NO2-PhCOOH
CH3CN/DMF, O2 (1 atm), 135 oC, 24 h.
R'
R'
CN
CH3
+
N
N
N
N
N
N
R
i-Pr
i-Pr
n-Bu
n-Bu
R
3
R =Bn, Aryl
1
2
3u
3v
3w
3x
, 75%
, 71%
, 35%
, 83%
For aryl substitutions:
CN
CN
CN
CN
CN
CN
F
MeO
Cl
Me
N
Bn
N
Bn
N
Bn
N
N
N
Bn
3d
, 88%
n-Octyl
3z
, 56%
n-Bu
3a
3b
3c
, 63%
, 59%
, 79%
3y
, 39%
CN
CN
CN
CN
NC
O2N
OHC
a Reaction condition: indoles (0.2 mmol), PdCl2 (0.01 mmol), Cu(OAc)2 (0.3 mmol),
AgOTf (0.2 mmol), 4-nitrobenzoic acid (0.2 mmol) in CH3CN (3.5 mL) and DMF (1.5
mL) were stirred under O2 atmosphere (1 atm) at 135oC in the Schlenk tube (25
mL) for the indicated time. Isolated yield. AgSO3C8F17 was used. PdCl2 (0.02
mmol), Cu(OAc)2 (0.04 mmol) was used. e GC yield using dodecane as the internal
standard, no further purification. f 3,5-dinitrobenzoic acid was used.
N
Bn
N
Bn
N
N
Bn
MeOOC
Bn
, 65%
Br
b
c
d
3e
3f
, 75%
3h
, 83%
Me
3g
, complicated
CN
CN
CN
CN
N
Bn
N
Bn
Encouraged by the good performance of this catalytic cyanation
protocol of N-aryl indoles, we further explored the feasibility of
N-alkyl indoles. However, N-alkyl substitutions of indole
exhibited relatively defective reactivity furnishing this catalytic
system obtaining the desired product in moderate to good yield.
In which, methyl, iso-propyl (for 3t, 3u and 3v, in 81%, 71% and
35% yield, respectively), butyl (for 3w, 3x and 3y, in 83%, 75%
and 39% yield, respectively) and even octyl group (3z, 56%)
substitution could be applied in this palladium catalysed direct
C3-cyanation of indole. Meanwhile, it compiled to the regularity
of electrophilic attack, that is, the electronic donating
substitution on the phenyl ring of indole showed poorer
reactivity (3s in 8% yield, 3v in 35% yield, 3y in 42% yield).
Among then, N-methyl protection derivatives (for 3q, 3r and 3s
in 30%, 43% and 8% yield, respectively) displayed inferior
performance for the reason of the probably easier
decomposition compared thus suppressed the reactivity. We
also applied our catalytic system to other heteroaromatic
N
Bn
N
Br
Bn
Br
3l
, trace
CN
3i
3j
3k
, 82%
, 72%
, 80%
CN
CN
CN
N
N
N
N
Me
F
OMe
3m
3n
3o
3p
, trace
, 68%
, 78%
, 76%
a Reaction condition: indoles (0.2 mmol), PdCl2 (0.01 mmol), Cu(OAc)2 (0.3 mmol),
AgOTf (0.2 mmol), 4-nitrobenzoic acid (0.2 mmol) in CH3CN (3.5 mL) and DMF (1.5
mL) were stirred under O2 atmosphere (1 atm) at 135oC in the Schlenk tube (25
mL) for the indicated time. b Isolated yield.
Furthermore, benzyl (Me- functionalization on the phenyl group
of benzyl unit) substitutions could also well promote this
catalytic transformation gaining the desired product in 68%
yield (3m). Given that serials of indole C-H functionalization has
been performed mainly focused on the substitution effect to
the phenyl ring of indole. We tended to consider the influence
of various N-protection concerning to the reactivity of
cyanation. Except for the benzyl substitution, other aryl group
like phenyl block could also be served in this system (3n-3p).
Interestingly, when the phenyl group was substituted with an
substrates
for
cyanation,
however,
benzofuran,
benzothiophene, benzoxazole, and benzothiazole exhibited low
efficiency in this transformation and no corresponding products
were detected.
According to the precedent literature6b,10a,11a, and experimental
observation, a tentative mechanism for this C3-cyanylation of
4 | J. Name., 2012, 00, 1-3
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indoles is depicted in Scheme 3. Initially, C3-H activation of pure products were obtained by column chromatography using
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indole substrates took place with Pd(II) catalyst to afford aryl- ethyl acetate/petroleum ether as an elDuOenI:t10a.1n0d39d/De0tOecBt0e0d48b5Ey
Pd(II)-X species A. On the other hand (path a), oxidation of NMR using CDCl3 as the deuterium reagent. GC analysis was
acetonitrile gave cyanide anion, which further reacted to performed on GC 7820A (Shimadzu). GC-MS results were
1
copper salt to give cuprous cyanide B. Subsequent recorded on GC-MS QP2010 (Shimadzu). The H NMR and 13C
transmetalation followed by reductive elimination to release NMR data were data were acquired on a Brucker ADVANCE III
the desired C3-cyanylation indole products 3 and Pd(0), which spectrometer (400 MHz for 1H NMR spectroscopy and 100 MHz
underwent further oxidation to generate reactive Pd(II) catalyst for 13C NMR spectroscopy). Exact mass was conducted by the
and restart the catalytic cycle.
College of Chemistry and Materials Engineering, Wenzhou
Alternatively (path b), migratory insertion of C-N triple bond University, Wenzhou, 325000, China
General Procedure for the preparation of 1-Benzyl-1H-indole-3-
carbonitrile (3a):
of acetonitrile into the aryl-Pd(II)-X species A might take place
to give iminyl palladium complex D. Upon transmetalation to
copper or silver salt, which followed by β-methyl elimination,
the desired nitrile products 3 were obtained, with the release of
A mixture of N-benzyl indole (0.2 mmol, 41.4 mg), PdCl2 (0.01
mmol, 1.8 mg), Cu(OAc)2 (0.3 mmol, 54.3 mg), AgSO3CF3 (0.2
mmol, 51.4 mg) and 4-NO2-PhCOOH (0.2 mmol, 33.4 mg ) was
added to a 25 mL Schleck tube with a combined solvent
(CH3CN/DMF = 3.5 mL/1.5 mL), the solution was then vigorously
CH3-M-X byproduct.
H
Pd(II)X2
1
N
R
[O]
Oxidation
-HX
o
stirred at 135 C under O2 atmosphere (1 atm) for 24 h. After
C-H Activation
cooling the mixture to ambient temperature, the reaction
mixture was filtrated and evaporated to remove the solvent and
the crude product was purified by column chromatography on
silica gel (DCM/hexane = 1:1, Rf = 0.5) to afforded the desired
product 3a (63%, 29.2 mg) in white solid.
PdX
Pd(0)
A
(
)
N
R
Reductive elimination
path a
Transmetalation
CN
Characterization and analytical data of products
[Cu]
NC
CuCN
Pd
H3C
N
N
R
B
(
)
Oxidation
1-Benzyl-1H-indole-3-carbonitrile (3a). Following the general
procedure, 3a was obtained in 63% yield as a white solid
(reacting for 24 h). 1H NMR (CDCl3, 400 MHz, TMS) δ7.80-7.76
(m, 1H), 7.61 (s, 1H), 7.38-7.29 (m, 6H), 7.15 (d, J = 8.0 Hz, 2H),
5.34 (s, 2H); 13C NMR (CDCl3, 100 MHz, TMS) δ 135.6, 135.2,
135.0, 129.2, 128.5, 128.0, 127.1, 124.0, 122.3, 120.0, 115.8,
110.9, 86.3, 50.9.
3
C
)
(
N
R
X
X
path b
M
Pd
migratory
insertion
N
N
CH3
CH3
-methyl elimination
transmetalation
A
3
- CH3-M-X
N
N
H3C CN
R
R
E
D
(M = Cu or Ag)
Scheme 3. Proposed mechanism for the C3-H cyanylation of indoles
1-Benzyl-5-methoxy-1H-indole-3-carbonitrile (3b). Following
the general procedure, 3b was obtained in 59% yield as a white
solid (reacting for 36 h). 1H NMR(CDCl3, 400 MHz, TMS) δ7.55
(s, 1H), 7.37-7.32 (m, 3H), 7.22 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4
Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.94-6.91 (m, 1H), 5.29 (s, 2H),
3.86 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) δ 156.1, 135.3,
134.9, 130.6, 129.1, 128.9, 128.4, 127.1, 116.1, 114.8, 111.8,
100.9, 85.7, 55.8, 51.1.
Conclusions
In summary, we have explored a ligand free direct C3-cyanation
methodology of indole via palladium catalysed applying
acetonitrile as the green and readily available cyanide source
obtaining the desired product in moderate to good yields. In
which, the pre-functionalization of indole C-H bond wasn’t
essential and a transition catalysed C-CN bond cleavage was
involved in this protocol.
1-benzyl-5-fluoro-1H-indole-3-carbonitrile (3c). Following the
general procedure, 3c was obtained in 79% yield as a white solid
1
(reacting for 36 h). H NMR (CDCl3, 400 MHz, TMS) δ 7.64 (s,
1H), 7.44-7.41 (m, 1H), 7.38-7.34 (m, 3H), 7.29-7.26 (m, 1H),
7.14 (d, J = 8.0 Hz, 2H), 7.07-7.02 (m, 1H), 5.33 (s, 2H); 13C NMR
(CDCl3, 100 MHz, TMS) δ 160.5 (d, JF-C = 240.5 Hz), 136.2, 134.8,
Experimental
General information
132.1, 129.2, 128.6, 127.1, 115.3, 113.0, 112.7, 112.0 (d, JF-C
9.6 Hz), 105.5 (d, JF-C = 24.8 Hz), 86.4 (d, JF-C = 4.5 Hz), 51.3
=
All reactions were carried out under O2 atmosphere (1 atm)
using standard Schlenk technique in the parallel synthesizer. All
reagent/reactant were commercially available except other
noted. The substituted indole substrates were prepared
according to the known methods. DMF and CH3CN were
purified according to the <Purification of Laboratory Chemicals:
The Six Edition > before being used. Column chromatography
was performed using Silica Gel 60 (particle size 37-54 μm). The
1-benzyl-5-chloro-1H-indole-3-carbonitrile (3d). Following the
general procedure, 3d was obtained in 88% yield as a yellow
solid (reacting for 36 h). 1H NMR (CDCl3, 400 MHz, TMS) δ 7.74
(s, 1H), 7.64 (s, 1H), 7.42-7.38 (m, 3H), 7.32-7.25 (m, 2H), 7.18-
7.16 (m, 2H), 5.36 (s, 2H); 13C NMR (CDCl3, 100 MHz, TMS) δ
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J. Name., 2013, 00, 1-3 | 5
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136.1, 134.8, 134.0, 129.3, 129.0, 128.7, 128.5, 127.1, 124.6, 134.9, 132.1, 129.8, 128.0, 127.2, 123.9, 122.3, 120.0, 115.8,
View Article Online
DOI: 10.1039/D0OB00485E
119.5, 115.2, 112.1, 86.0, 51.2.
110.8, 86.1, 50.7, 21.1.
1-benzyl-5-formyl-1H-indole-3-carbonitrile (3e). Following the 1-phenyl-1H-indole-3-carbonitrile. (3n) Following the general
general procedure, 3e was obtained in 88% yield as a light procedure, 3n was obtained in 78% yield as a white solid
1
yellow solid (reacting for 36 h). 1H NMR (CDCl3, 400 MHz, TMS) (reacting for 24 h). H NMR(CDCl3, 400 MHz, TMS) δ 7.85-7.81
δ 10.44 (s, 1H), 8.63 (s, 1H), 8.23 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), (m, 2H), 7.60-7.56 (m, 2H), 7.53-7.48 (m, 4H), 7.38-7.33 (m, 2H);
7.88-7.65 (m, 4H), 7.56 (s, 2H), 5.78 (s, 2H); 13C NMR (CDCl3, 100 13C NMR (CDCl3, 100 MHz, TMS) δ 137.8, 135.6, 134.7, 130.0,
MHz, TMS) δ 192.0, 139.1, 137.2, 134.9, 131.9, 129.7, 129.2, 128.4, 128.0, 124.9, 124.6, 122.8, 120.1, 115.6, 111.5, 88.1.
128.2, 127.6, 125.1, 124.2, 115.1, 112.1, 88.7, 51.7
1-(4-methoxyphenyl)-1H-indole-3-carbonitrile. (3o) Following
1-benzyl-5-nitro-1H-indole-3-carbonitrile. (3f) Following the the general procedure, 3o was obtained in 76% yield as a white
general procedure, 3f was obtained in 88% yield as a yellow solid (reacting for 36 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.83-
solid (reacting for 36 h). 1H NMR (DMSO, 400 MHz, TMS) δ 8.79 7.81 (m, 1H), 7.75 (s, 1H), 7.44-7.41 (m, 1H), 7.38 (d, J = 8.8 Hz,
(s, 1H), 8.54 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.36 (m, 5H), 5.66 2H), 7.34-7.32 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H); 13
C
(s, 2H); 13C NMR (DMSO, 100 MHz, TMS) δ 143.4, 141.6, 138.5, NMR (CDCl3, 100 MHz, TMS) δ 159.5, 136.1, 135.0, 130.6, 127.8,
136.6, 129.3, 128.6, 127.9, 127.0, 119.3, 116.0, 113.3, 100.0, 126.4, 122.6, 120.0, 115.7, 115.1, 111.5, 87.4, 55.7.
87.2, 50.8
1-Methyl-1H-indole-3-carbonitrile. (3q) Following the general
1-benzyl-3-cyano-1H-indole-6-carboxylate. (3h) Following the procedure, 3q was obtained with 30% in as a brown liquid
general procedure, 3h was obtained in 88% yield as a yellow (reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.76 (d, J =
solid (reacting for 36 h). 1H NMR (DMSO, 400 MHz, TMS) δ 8.66 8.0 Hz, 1H), 7.57 (s, 1H), 7.26-7.41 (m, 3H), 3.86 (s, 3H); 13C NMR
(s, 1H), 8.25 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, (CDCl3, 100 MHz, TMS) δ 135.9, 135.6, 127.7, 123.8, 122.1,
1H), 7.37-7.27 (m, 5H), 5.65 (s, 2H), 3.86 (s, 3H); 13C NMR 119.9, 116.0, 110.3, 85.4, 33.7.
(DMSO, 100 MHz, TMS) δ 166.8, 140.7, 136.9, 135.1, 131.4,
129.3, 128.4, 127.5, 125.4, 123.0, 119.5, 115.7, 114.0, 85.2, 5-Fluoro-1-methyl-1H-indole-3-carbonitrile. (3r) Following the
52.6, 50.5
general procedure, 3r was obtained in 43% yield as a yellow
liquid (reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.57
1-benzyl-6-bromo-1H-indole-3-carbonitrile. (3i) Following the (s, 1H), 7.41 (dd, J = 2.4, 2.4 Hz, 1H), 7.35-7.31 (m, 1H), 7.13-7.08
general procedure, 3i was obtained in 88% yield as a yellow (m, 1H), 3.86 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) δ 160.5 (d,
solid (reacting for 36 h). 1H NMR (CDCl3, 400 MHz, TMS) δ 7.68 J = 238.2 Hz), 136.6, 132.6, 128.5 (d, J = 10.7 Hz), 115.4, 112.8
(d, 3H), 7.39 (m, 4H), 7.2 (m 2H), 5.30 (s, 2H); 13C NMR (CDCl3, (d, J = 26.4 Hz), 111.4 (d, J = 3.8 Hz), 105.3 (d, J = 24.8 Hz), 85.6
100 MHz, TMS) δ 136.4, 135.8, 134.9, 129.3, 128.7, 127.3, (d, J = 4.7 Hz), 33.9.
126.8, 125.7, 121.2, 117,7, 115.4, 114.0, 86.6, 51.0
1-isopropyl-1H-indole-3-carbonitrile. (3t) Following the general
1-benzyl-4-bromo-1H-indole-3-carbonitrile. (3j) Following the procedure, 3t was obtained in 81% yield as a yellow liquid
general procedure, 3j was obtained in 88% yield as a yellow (reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.76 (d, J =
solid (reacting for 36 h). 1H NMR (CDCl3, 400 MHz, TMS) δ 7.68 7.2 Hz, 1H), 7.71 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.36-7.26 (m,
(d, J = 7.2 Hz, 1H), 7.45-7.34 (m, 5H) 7.38-7.34 (m, 5H), 7.18-7.14 2H), 4.76-4.66 (m, 1H), 1.56 (d, J = 7.2 Hz, 6H); 13C NMR (CDCl3,
(m 3H), 5.37 (s, 2H); 13C NMR (CDCl3, 100 MHz, TMS) δ 137.1, 100 MHz, TMS) δ 134.9, 131.1, 128.0, 123.6, 122.1, 120.0,
136.3, 134.7, 129.3, 128.7, 127.2, 126.4, 126.2, 124.9, 115.7, 116.2, 110.6, 85.7, 48.3, 22.6.
114.7, 110.3, 87.1, 51.3
5-fluoro-1-isopropyl-1H-indole-3-carbonitrile. (3u) Following
1-benzyl-7-bromo-1H-indole-3-carbonitrile. (3k) Following the the general procedure, 3u was obtained in 71% yield as a yellow
general procedure, 3k was obtained in 88% yield as a yellow liquid (reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.74
solid (reacting for 36 h). 1H NMR (CDCl3, 400 MHz, TMS) δ 7.77- (s, 1H), 7.42-7.36 (m, 2H), 7.11-7.06 (m, 1H), 4.73-4.63 (m, 1H),
7.75 (m, 1H), 7.60-7.49 (m, 2H), 7.38-7.36 (m 3H), 7.19-7.11 (m, 1.57 (d, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz, TMS) δ 160.3
3H), 5.86 (s, 2H); 13C NMR (CDCl3, 100 MHz, TMS) δ 137.7, 136.8, (d, JF-C = 238.2 Hz), 132.2, 131.5, 128.6 (d, JF-C = 10.7 Hz), 115.6,
132.2, 130.9, 129.5, 129.1, 128.2, 126.6, 123.5, 119.5, 115.0, 112.5 (d, JF-C = 26.3 Hz), 111.7 (d, JF-C = 11.5 Hz), 105.3 (d, JF-C
=
104.8, 87.0, 52.4
24.6 Hz), 85.8, 48.7, 22.6. HRMS-ESI (m/z) [M + H+]: Calcd for
+
C12H12FN2 , 202.0906; found, 202.0912.
1-(4-methylbenzyl)-1H-indole-3-carbonitrile. (3m) Following
the general procedure, 3m was obtained in 68% yield as a 1-isopropyl-5-methyl-1H-indole-3-carbonitrile. (3v) Following
yellow solid (reacting for 36 h). 1H NMR (CDCl3, 400 MHz, TMS) the general procedure, 3v was obtained in 35% yield as a yellow
δ 7.70-7.68 (m, 1H), 7.50 (s, 1H), 7.31-7.28 (m, 1H), 7.24-7.21 liquid (reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.66
(m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 5.21 (s, (s, 1H), 7.55 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.4 Hz,
2H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) δ 138.4, 135.6, 1H), 4.72-4.61 (m, 1H), 2.48 (s, 3H), 1.55 (d, J = 7.2 Hz, 6H); 13
C
6 | J. Name., 2012, 00, 1-3
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ARTICLE
NMR (CDCl3, 100 MHz, TMS) δ 133.3, 131.8, 131.0, 128.3, 125.2, Guangdong Province (2019KQNCX154), and the Open Fund of
View Article Online
119.6, 116.4, 110.3, 85.0, 48.3, 22.6, 21.4.
the Key Laboratory of Functional MolDeOcuI:l1a0r.10E3n9g/iDn0eOeBr0in0g485oEf
Guangdong Province (No.2018kf02, South China University of
1-butyl-1H-indole-3-carbonitrile. (3w) Following the general Technology).
procedure, 3w was obtained in 83% yield as a brown liquid
(reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.76 (d, J =
Notes and references
7.6 Hz, 1H), 7.59 (s, 1H), 7.35-7.32 (m, 1H), 7.41 (d, J = 8.0 Hz),
7.36-7.26 (m, 2H), 4.15 (t, J = 7.2 Hz, 2H), 1.88-1.81 (m, 2H),
1.39-1.30 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100
MHz, TMS) δ 135.3, 134.7, 128.0, 123.7, 122.0, 120.0, 116.1,
110.5, 85.5, 47.0, 31.9, 20.0, 13.6.
1
For selected reviews: (a) A. J. Kochanowska-Karamyan and M.
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1-Butyl-5-fluoro-1H-indole-3-carbonitrile. (3x) Following the
general procedure, 3x was obtained in 75% yield as a brown
liquid (reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.62
(s, 1H), 7.40 (dd, J = 2.4, 2.4 Hz, 1H), 7.35-7.32 (m, 1H), 7.11-7.06
(m, 1H), 4.14 (t, J = 7.2 Hz, 2H), 1.88-1.80 (m, 2H), 1.39-1.30 (m,
2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS) δ
160.3 (d, J = 231 Hz), 135.7, 131.94, 128.62 (d, J = 10.8 Hz),
115.4, 112.6 (d, J = 26.3 Hz), 111.5 (d, J = 9.6 Hz), 105.4 (d, J =
24.6 Hz), 85.6, 47.3, 31.8, 19.9, 13.5. HRMS-ESI (m/z) [M + H+]:
+
Calcd for C13H14FN2 , 216.1063; found, 216.1071.
1-butyl-5-methyl-1H-indole-3-carbonitrile. (3y) Following the
general procedure, 3y was obtained in 39% yield as a yellow
liquid (reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.55
(s, 1H), 7.54 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.16-7.14 (m, 1H),
4.12 (t, J = 6.0 Hz, 2H), 2.48 (s, 3H), 1.87-1.79 (m, 2H), 1.38-1.26
(m, 2H), 0.94 (t, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS)
δ 134.5, 133.7, 131.8, 128.3, 125.3, 119.6, 116.2, 110.2, 84.8,
47.0, 31.9, 21.4, 20.0, 13.6.
2
3
For selected examples: (a) D. Zhao, P. Xu and T. Ritter, Chem,
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1-octyl-1H-indole-3-carbonitrile. (3z) Following the general
procedure, 3z was obtained in 56% yield as a brown liquid
(reacting for 24 h). 1H NMR(CDCl3, 400 MHz, TMS) δ 7.76 (d, J =
7.6 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.35-3.26 (m,
2H), 4.14 (t, J = 7.2 Hz, 2H), 1.89-1.83 (m, 2H), 1.31-1.25 (m,
10H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS) δ
135.4, 134.6, 128.0, 123.7, 122.0, 120.0, 116.0, 110.5, 85.5,
47.3, 31.7, 29.8, 29.1, 29.1, 26.8, 22.6, 14.0. HRMS-ESI (m/z) [M
4
5
6
(a) K. W. Rosenmund and E. Struck, Ber. Dtsch. Chem. Ges.,
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+
+ H+]: Calcd for C17H23FN2 , 254.1783; found, 254.1791.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for the financial support by the National Natural
Science Foundation of China (21502066), the Natural Science
Foundation of Guangdong Province (No. 2014a030310113), the
Program for Innovative Research Team of Huizhou University
(cxtd2019002), the Professorial and Doctoral Scientific Research
Foundation of Huizhou University (2018JB011), Youth
Innovative Talents Project in Colleges and Universities in
7
(a) Y. Yang, Y. Zhang and J. Wang, Org. Lett., 2011, 13, 5608;
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Ohe, Chem. Commun., 2012, 48, 3127.
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