Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate

Article abstract of DOI:10.1039/c5ob01244a

The copper-mediated cyanation of indoles with DMF as a single surrogate has been realized. This approach could be applied for the cyanation of some electron-rich arenes and aryl aldehydes as well. Aryl aldehydes were demonstrated to be the key intermediates in the cascade process of cyanation of indoles and electron-rich arenes.

Full text of DOI:10.1039/c5ob01244a

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Copper-Mediated Cyanation of Indols and Electron-Rich Arenes
Using DMF as a Single Surrogate
Received 00th January 20xx,
Accepted 00th January 20xx
Lianpeng Zhang, Ping Lu*, and Yanguang Wang*
DOI: 10.1039/x0xx00000x
The copper-mediated cyanation of indols with DMF as a single surrogate has been realized. This approach could be applied
for the cyanation of some electron-rich arenes and aryl aldehydes as well. Aryl aldehyde was demonstrated to be the key
intermediate in the cascade process of cyanations of indoles and electron-rich arenes.
www.rsc.org/
1
3
importance (Scheme 2, D). However, the large affinity of
cyanide anion to palladium center inevitably results in the
overloading of cyanide anions on palladium and directly
Introduction
Aryl nitriles are an important class of compounds in medicinal
1
4
inhibits the catalyst activity . Three strategies could be
applied to avoid this drawback. Those are selecting suitable
ligands, releasing or forming “CN” during the reaction
science. For example, therapeutic estrogen receptor ligand A,
which shows activity in treatment of diseases associated with
the estrogen receptor such as depressive disorders, anxiety
1
disorders, and Alzheimer’s diseases (Scheme 1). Taranabant is
15
16
process, and changing the metal. Altering palladium to zinc,
1
7
18
ferrous, and copper is of economic value no matter what
kind mechanism is followed. To the surrogates of “CN” applied
in the wealthy studied copper-catalyzed C3-cyanation of
a cannabinoid receptor type 1 inverse agonist investigated as a
potential treatment for obesity, it contains a cyano group on
2
its phenyl ring. Moreover, the cyano group on aryl nitriles
1
9
indole, “CN” released from benzyl cyanide and “CN” forming
could be transferred into various functional groups, such as
carboxylic acids, amides, amidines, amines, imidazoles,
triazoles, and tetrazoles. Therefore, aryl nitriles are important
intermediates both in organic synthesis and in pharmaceutical
2
0
21
from DMF/NH
Scheme 2, E). As our ongoing research towards the
development of the copper-mediated cyanation of aryl halides
4
I
or TMEDA/(NH
4
)
2
CO
3
have been disclosed
(
2
2
using DMF as a single source, we recently found that this
approach could be applied to the cyanations of indoles and
some other electron-rich arenes. Herein, we report our results
on this subject.
industry. For instance, Nortopsentins
antimicrobial, anti-inflammatory, and anticancer activities,
were synthesized from 3-cyanoindoles. Forasartan,
A-D, exhibiting antiviral,
3
a
nonpeptide angiotensin II receptor antagonist and clinically
4
used for the treatment of hypertension, was prepared from 2-
CN
bromobenzonitrile.
CN
Among aryl nitriles, 3-cyanoindoles have attracted much
more attentions due to their importance. The published
strategies for the preparation of 3-cyanoindoles include the
construction of the indole ring and the functionalization of
indoles. The former one is seldom utilized because specified
N
Cl
N
F3C
N
H
N
O
O
OH
5
Therapeutic estrogen
receptor ligand A
taranabant
substrates are required in those cases (Scheme 2, A). Classical
approaches for the functionalization of indoles include the
6
N
-8
N
N
NH
electrophilic aromatic substitution of indoles (Scheme 2, B)
and the functional transformations of 3-substituted indoles
X
Y
N
N
N
N
9
-11
(Scheme 2, C).
The modern approaches to 3-cyanoindoles
N
HN
H
NH
are the metal-mediated direct cyanation of indoles, which has
emerged as a powerful tool because of easily available starting
nortopsentins A-D
Forasartan
1
2
materials and mild reaction conditions. In this blooming field,
the palladium-catalyzed C3-cyanation of indoles is of particular
Scheme 1 Structures of representative drugs prepared from aryl
nitriles.
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
*
†
pinglu@zju.edu.cn; orgwyg@zju.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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With the optimized reaction conditions in hand, we tested the
substrate diversity of this reaction (Table 2). Lots of functional
groups were compatible and tolerated reaction conditions.
When the NH of indole was protected with methyl, ethyl, allyl,
phenyl, 4- methoxyphenyl, and benzyl, 2b
-
g
were prepared at
o
30 C in 55-80% yields. The oxidation of C-H bond in either N-
1
3
CH or allylic/benzylic was not observed. Cyanation exclusively
occurred on 3-position of indoles without the contaminant
derived from the cyanation on 2-position of indoles or on the
phenyl ring of 1-(4-methoxyphenyl)-1H-indole. tert-Butyl
indole-1-carboxylate afforded 2a in 73% yield. In this case,
tert-butyl group was removed. Whereas, the cyanation of 1-
tosyl-1H-indole did not occur, implying that decreased electron
density of the substrate influenced the reactivity. 2-
Substituted indoles such as 2-phenylindole and 2-(4-
a
Table 1 Screening of the reaction conditions
Entry
[Cu] (equiv)
HOAc
equiv)
TBHP
Temp Yield
o
b
(
(equiv)
( C)
(%)
1
2
3
4
5
6
7
8
9
CuI(1.2)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
12
4
2
—
4
4
4
4
4
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
1
—
2
2
2
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
110
130
120
64
35
25
40
Scheme 2 Published methods for preparation of 3-cyanoindoles.
CuBr(1.2)
CuCl(1.2)
Results and discussion
Cu
CuBr
Cu(OAc)
CuSO (1.2)
Cu(NO ·3H
CuCl •2H O(1.2)
CuO(1.2)
2
O(1.2)
(1.2)
(1.2)
2
trace
41
Our initial attempt was launched with the cyanation of indole
(
1a). To our delight, when the mixture of 1a, CuI, HOAc, and
2
o
TBHP in DMF (in 1:1.2:8:2 ratio) was stirred in air at 120 C for
8 h, 3-cyanoindole (2a) was isolated in 64% yield (Table 1,
entry 1). Altering Cu(I) source to others, such as CuBr, CuCl,
and Cu O, decreased yields were observed (Table 1, entries 2-
). The Cu(II) sources, such as CuBr , Cu(OAc) , CuSO
Cu(NO 3H O, CuCl 2H O, CuO, and Cu(OTf) gave poor
4
trace
39
4
3
)
2
2
O (1.2)
2
2
trace
trace
trace
trace
45
2
1
1
1
1
0
1
2
3
4
2
2
4
,
Cu(OTf)
Cu(1.2)
2
(1.2)
3
)
2
•
2
2
•
2
2
yields (Table 1, entries 5-11). Some of them did not afford the
CuI (1.0)
CuI (1.5)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
expected product. 2a could only be detected in trace by TLC
when copper powder was used (Table 1, entry 12). Decreasing 14
64
the amount of CuI led to a decrease in the yield of 2a, while 15
60
increasing the amount of CuI to 1.5 equivalents did not
improve the yield (Table 1, entries 1 and 13-14). However, 3-
formylindole instead of obtaining 2a was obtained in 78% yield
when 0.3 equivalents of CuI were used. The optimal amount of
HOAc was determined to be 4 equivalents to the amount of 1a
1
1
1
1
2
2
6
7
8
9
0
1
68
48
45
62
47
(Table 1, entries 1 and 15-17). In the absence of HOAc, 2a was
41
isolated in 45% yield (Table 1, entry 18). The optimal TBHP was
determined to be 2 equivalents (Table 1, entries, 16 and 19- 22
0). Without TBHP, 2a was obtained in 41% yield (Table 1, 23
46
2
51
entry 21). The optimal reaction temperature was determined
o
to be 120 C (Table 1, entries 16, 22 and 23). When the
c
2
4
trace
a
Reaction conditions: 1a (0.5 mmol), [Cu] source, HOAc, TBHP, DMF
reaction was carried out in nitrogen, trace of 2a was detected
b
(
3.0 mL), air, 48 h.
Yield of isolated product after column
by TLC (Table 1, entry 24).
c
chromatography on silica gel. Dry N atmosphere.
2
2
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fluorophenyl)indole were also examined and the desired demethylation, and amination, therapeutic estrogen receptor
products 2h and 2i were isolated in 86% and 66% yields, ligand was successfully afforded in 35% total yield.
respectively. 5-Substituted indoles provided 2j in relatively
lower yields. With phenyl blocked on the 2-position of indole,
was prepared in 80% yield. When NH of indole was
A
-l
2m
protected by ethyl group, 2n and 2o were produced in 65%
and 30% yields, respectively. Instead of indoles, 9H-carbazole
and 1-ethyl-1H-pyrrolo[2,3-b]pyridine could also work as the
substrate to furnish the corresponding cyanation products 2p
and 2q in 38% and 60% yields, respectively. Under the
standard reaction conditions, some electron-rich carbocyclic
arenes,
dimethoxybenzene, and 3,4,5-trimethoxytoluene could also be
cyanated to give 2r 2s, and 2t in 80%, 51%, and 35% yields,
such
as
1,3,5-trimethoxybenzene,
1,3-
,
respectively. However, without any electron-donating group
on the arenes, naphthalene, anthracene, and pyrene did not
afford any desired products. Moreover, benzothiophene and
benzofuran also didn’t work for this transformation, and the
starting materials were recovered after reaction.
Scheme 3 Preparation of therapeutic estrogen receptor ligand A.
a
Table 2 Copper-mediated cyanation of indoles and arenes
In order to have a deep insight into the reaction mechanism,
we tracked the reaction with carbon-13 labeled on carbonyl
carbon of DMF. 3-Cyanoindole (2a) was obtained without the
appearance of carbon-13 (Scheme 4). To our surprise, when 3-
CuI(1.2 equiv)
HOAc (4 equiv)
H3C
H3C
O
H
Ar-H
+
N
Ar-CN
TBHP (2 equiv)
air, 48 h
2
1
1
3
formylindole (3a- C), the carbonyl carbon labelled with
13
carbon-13, was used as substrate, 2a- C was obtained.
b
1
CN
2a : R = H, 68%
b : R = Me, 80%
c : R = Et, 55%
d : R = Allyl, 65%
CN
c
1
2
R2
Moreover, the results of the screening of the reaction
conditions (Table 2, entries 18 and 21) indicated that the
carbon of “CN” in 3-cyanoindole could not come from HOAc or
TBHP. Based on these experiments, it could be concluded that
carbon of “CN” came from the methyl of DMF. Without any
other choices, nitrogen of “CN” came from DMF. Thus, both
carbon and nitrogen of “CN” in the final product came from a
single DMF. It is also noticeable that 3-formylindole (3a) was
isolated in 72% yield when N,N-dimethylacetamide (DMA) was
used instead of DMF. Furthermore, 2a could also be prepared
c
1
2
2
2
2
2
N
c
1
N
H
R1
c
1
e : R = Ph, 64%
c
2
2
h : R = Ph, 86%
c
1
f : R = 4-MeOC H , 66%
2i : R = 4-FC H , 66%
6 4
c
2
6
4
c
1
g : R =Bn, 75%
CN
CN
R3
jb: R3 = OCH3, 49%
kb: R = NO2, 38%
lc: R3 = Cl, 58%
MeO
2
2
2
3
Ph
N
N
Me
Me
m : 80%
c
2
CN
CN
CN
from 3-(N,N-dimethylamino)methylindole (4).
R2
N
Et
N
N
N
H
Et
nc: R = Ph, 65%
2
d
d
2
2
2p , 38%
2q , 60%
oc: R2 = CH3, 30%
CH3
CN
OCH3
CN
OCH3
CN
H3CO
OCH3
OCH3
H3CO
OCH3
rd, 80%
OCH3
d
d
2
2s , 51%
2t , 35%
a
Reaction conditions: 1 (0.5 mmol), CuI (0.6 mmol), HOAc (2.0
b
o
c
o
mmol), TBHP (1.0 mmol), DMF (3 mL), air, 48 h. 120 C. 130 C.
d
1
o
40 C.
This protocol could be scaled up and of practical usage in
the preparation of therapeutic estrogen receptor ligand A
Scheme 3). Thus, 1.489 g of 2f was prepared in 75% yield by
using this protocol. After sequential bromination, Scheme 4 Mechanistic study.
(
a
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The reaction profile using 1a under the standard reaction reaction. It should be indicated that 2y
Journal Name
,
2z and 2A could not be
conditions is shown in Figure S1 (see supporting Information). directly cyanated from corresponding arenes using the
As the reaction underwent, 1a was completely consumed at aforementioned standard reaction conditions established for
the beginning 5 h and transferred into 3a as the key cyanation of indole.
intermediate. A steady increment of 2a was observed after the
a
reaction was carried out from 10 h to 40 h.
Table 3 Copper-mediated cyanation of aryl aldehydes
On the basis of these results, we proposed a possible
mechanism for this cascade transformation (Scheme 5). In the
presence of Cu(I) and oxidant, DMF is oxidized into electron-
2
0
deficient iminium species. Then, electrophilic aromatic
substitution on electron-rich indole (1a) occurs to form
intermediate
A
. Further copper-catalyzed oxidation, followed
3a as the key
condenses with
dimethylamine which is decomposed from DMF to generate
iminium intermediate . A sequential demethylation, oxidation,
and demethylation through intermediates and furnish 2a
Effective transformation from to 2a is indicative for the
formation of intermediate
by hydrolysis, forms 3-formylindole
(
)
1
3c
intermediate.
Subsequently,
3a
2
3
C
D
E
.
4
C
.
a
Reaction conditions: 3 (0.5 mmol), Cu(NO
3
)
2
2
⋅3H O (0.5 mmol),
o
HOAc (4.0 mmol), TBHP (1.0 mmol), DMF (3.0 mL) , air, 130 C, 48
h.
As an exception, 5-methoxy-2-methylisoindoline-1,3-dione
(
5a
subjected to this reaction under the standard reaction
conditions (Scheme 6). Similarly, 5b 5c, and 5d were isolated.
)
was obtained when 3-methoxybenzaldehyde was
Scheme 5 Postulated mechanism
,
Since 3-formylindole (3a) is the key intermediate for the In the preparation of this manuscript, Ge reported a direct
formation of 2a from 1a, we were encouraged to develop a carbonylation from benzamide to isoindoline-1,3-dione using
preparation of aryl nitriles from aldehydes using DMF as a the methyl of DMF as the carbonyl source in the presence of
2
4
single surrogate. After screened the reaction conditions by Cu(acac) , NiBr , and O .
using the cyanation of 3a as the model reaction (see
2
2
2
Supporting Information, Table S1), the best result was
obtained when the mixture of 3a (0.5 mmol), Cu(NO
3 2 2
) .3H O
(
1.0 equiv), HOAc (8 equiv) and TBHP (2 equiv) in DMF (3.0 mL)
o
was stirred under air atmosphere, at 130 C for 48 h.
With the optimized reaction conditions, we tested the
diversity of aryl aldehydes
3
(Table 3). Without the protecting
group on N-H of indole, 2u
-2x were obtained in yields ranging
from 52% to 75%. By blocking 2-position of indole with aryl
group, 2h and 2i were isolated in yields of 85% and 75% yields,
respectively. 1-Methylindole-3-carbaldehyde gave 2b in 82% Scheme 6 Preparation of 5a-d
yield. Furthermore, a variety of aryl aldehydes were converted
into the corresponding aryl nitriles 2y, 2z and 2A-G via this
4
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An oven-dried 25 mL eggplant-shaped bottle equipped with a
magnetic stir bar was charged with Cu(NO •3H O (0.5 mmol, 1.0
3
)
2
2
equiv), aromatic aldehyde (0.5 mmol), HOAc (4.0 mmol), t-BuOOH
Conclusions
(1.0 mmol, 70% aq.) and DMF (3.0 mL). The mixture was stirred
o
under air at 130-140 C (oil bath temperature) for about 48 hours
In conclusion, we developed a copper-mediated cyanation
reaction of indoles using DMF as a single surrogate of “CN”.
This protocol could be scaled up and of practical usage in the
(
checked by TLC). After the aromatic aldehyde completely
consumed, the reaction mixture was cooled to room temperature,
quenched with 10 mL of water, and extracted with DCM (3×10 mL).
preparation of therapeutic estrogen receptor ligand A.
A
variety of electron-rich arenes and aryl aldehydes could also be The organic layer was washed with saturated salt water and then
converted into the corresponding aryl nitriles by this approach. concentrated under reduced pressure. The residue was purified
Based on the isotope labelling and the controlled experiments, through a silica gel column to afford pure product.
aryl aldehyde was believed to be the key intermediate for the
1
9a
o
1
cyanation of arene. Moreover, isoindoline-1,3-diones were 1H-Indole-3-carbonitrile (2a) Yellow solid, m.p. 178-180 C. H
eventually obtained in which C-H activation and subsequent NMR (400 MHz, CDCl ) δ 8.80 (s, 1H), 7.89 (d, J =7.6 Hz, 1H), 7.75 (s,
carbonylation were observed although the mechanism is 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.35 (td, J = 7.2Hz, 1.2 Hz, 1H), 7.31 (td,
3
1
3
unclear at this stage.
3
J = 7.2 Hz, 1.2Hz, 1H). C NMR (100 MHz, CDCl ) δ 135.2, 132.2,
1
27.3, 124.7, 122.7, 120.0, 116.2, 112.4, 87.8.
1
9a
1
-Methyl-1H-indole-3-carbonitrile (2b) White solid, m.p. 53-55
o
1
Experimental
C. H NMR (400 MHz, CDCl
3
) δ 7.71 (d, J = 7.6Hz, 1H), 7.48 (s, 1H),
7
1
1
.35 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.27 (t, J = 8.2 Hz,
1
3
H), 3.79 (s, 3H). C NMR (100 MHz, CDCl ) δ 136.2, 135.8, 127.9,
3
General methods and materials
24.0, 122.3, 119.9, 116.2, 110.6, 85.5, 33.8.
Unless stated otherwise, reactions were conducted in flame-
o
1
dried glassware. Commercially available reagents and solvents 1-Ethyl-1H-indole-3-carbonitrile (2c) Brown solid, m.p. 88-90 C. H
were used as received. 300-400 Mesh silica gel was used for NMR (400 MHz, CDCl ) δ 7.64 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.32
3
flash column chromatography. Visualization on TLC was (d, J = 8.2 Hz, 1H), 7.24 (t, J = 6.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H),
13
achieved by the use of UV light (254 nm). 400 MHz and 100 4.10 (q, J = 7.3 Hz, 2H), 1.40 (t, J = 7.3 Hz, 3H). C NMR (100 MHz,
1
13
MHz were used for the record of H NMR and C NMR spectra,
respectively. Chemical shifts ( ) were reported in parts per
million referring to either the internal standard of TMS or the
residue of the deuterated solvents. Splitting pattern was 1-Allyl-1H-indole-3-carbonitrile (2d) Brown oil H NMR (400 MHz,
CDCl ) δ 135.3, 134.2, 128.2, 123.9, 122.3, 120.1, 116.3, 110.7, 85.6,
3
δ
4
2.1, 15.4.
1
described as follows: s for singlet, d for doublet, t for triplet, q
for quartet, and m for multiplet. Coupling constants were
reported in Hz. The high-resolution mass spectrum (HRMS)
was recorded on GCT premier instrument.
CDCl ) δ 7.74 (dd, J = 7.2, 1.0 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J = 7.9 Hz,
3
1
H), 7.36 -7.23 (m, 2H), 5.97 (ddd, J = 22.5, 10.6, 5.5 Hz, 1H), 5.28
(
d, J = 10.4 Hz, 1H), 5.14 (dd, J = 17.0, 0.6 Hz, 1H), 4.75 (d, J = 5.5 Hz,
13
2
1
H). C NMR (100 MHz, CDCl
3
) δ 135.6, 135.0, 131.9, 128.1, 124.1,
22.4, 120.1, 119.2, 116.1, 111.0, 86.1, 49.7.
2
0b
1
-Phenyl-1H-indole-3-carbonitrile (2e) White solid, m.p. 116-118
Typical procedure for Cu-mediated cyanation of
arenes
o
1
C. H NMR (400 MHz, CDCl
3
) δ 7.85-7.83 (m, 1H), 7.81 (s, 1H), 7.58
13
(
t, J = 8.0 Hz, 2H), 7.53-7.47 (m, 4H), 7.37-7.34 (m, 2H). C NMR (100
An oven-dried 25 mL eggplant-shaped bottle equipped with a MHz, CDCl ) δ 138.2, 136.0, 135.0, 130.4, 128.7, 128.3, 125.3, 124.9,
3
magnetic stir bar was charged with CuI (0.6 mmol), arene (0.5 123.2, 120.4, 115.9, 111.9, 88.5.
mmol), HOAc (2.0 mmol), t-BuOOH (1.0 mmol, 70% aq.) and DMF
o
1
-(4-Methoxyphenyl)-1H-indole-3-carbonitrile (2f ) White solid,
(
3.0 mL). The mixture was stirred under air at 120-140 C (oil bath
o
1
m.p. 126-128 C. H NMR (400 MHz, CDCl
3
) δ 7.80 (dd, J = 6.4, 2.7
temperature) for about 48 hours (checked by TLC). After the arene
was completely consumed, the reaction mixture was cooled to
room temperature, quenched with 10 mL of water, and extracted
with DCM (3×10 mL). The organic layer was washed with saturated
salt water and concentrated under reduced pressure. The residue
was purified by column chromatography to afford pure product.
Hz, 1H), 7.73 (s, 1H), 7.44 - 7.40 (m, 1H), 7.37 (d, J = 8.8 Hz, 2H),
13
7
.34 - 7.30 (m, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H). C NMR
100 MHz, CDCl ) δ 159.8, 136.3, 135.3, 130.9, 128.2, 128.0, 126.7,
24.7, 122.9, 120.2, 115.4, 111.8, 87.7, 56.0.
(
3
1
o
1
-Benzyl-1H-indole-3-carbonitrile (2g ) Yellow solid, m.p. 70-72 C.
1
H NMR (400 MHz, CDCl
3
) δ 7.64 - 7.55 (m, 1H), 7.40 (s, 1H), 7.26 -
13
7
.08 (m, 6H), 6.98 (dd, J = 7.2, 1.8 Hz, 2H), 5.14 (s, 2H). C NMR
Typical procedure for Cu-mediated cyanation of
aromatic aldehydes
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DOI: 10.1039/C5OB01244A
ARTICLE
100 MHz, CDCl ) δ 135.7, 135.5, 135.3, 129.2, 128.5, 128.1, 127.3,
Journal Name
o
1
(
9H-Carbazole-3-carbonitrile (2p) White solid, m.p. 180-181 C. H
NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 8.85(s, 1H), 8.27 (d, J = 7.8
Hz, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d,
3
124.2, 122.4, 112.0, 116.1, 111.1, 86.2, 51.0.
1
3
2
-Phenyl-1H-indole-3-carbonitrile (2h ) White solid, m.p. 245-247
J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H). C
o
1
C. H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 8.03 (d, J = 7.2 Hz,
NMR (100 MHz, DMSO) δ 142.6, 141.2, 129.5, 127.9, 126.5, 123.6,
2
H), 7.72 - 7.63 (m, 3H), 7.62 -7.56 (m, 2H), 7.35 (dd, J = 8.1, 1.1 Hz,
1
22.5, 121.9, 121.5, 120.8, 113.0, 112.5, 101.1.
1
3
1H), 7.31 (dd, J = 8.1, 1.1 Hz, 1H). C NMR (100 MHz, DMSO) δ
145.7, 136.5, 130.9, 130.3, 130.3, 129.2, 127.9, 124.9, 123.0, 119.3,
118.0, 113.6, 82.3.
1-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (2q) Yellow solid,
o
1
m.p. 72-74 C. H NMR (400 MHz, CDCl
3
) δ 8.47 (dd, J = 4.7, 1.4 Hz,
1
1
H), 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.80 (s, 1H), 7.28 (t, J = 4.0 Hz,
1
3
2
-(4-Fluorophenyl)-1H-indole-3-carbonitrile (2i ) White solid, m.p.
H), 4.43 (q, J = 7.3 Hz, 2H), 1.55 (t, J = 7.3 Hz, 3H). C NMR (100
o
1
239- 241 C. H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 8.11- 8.00
MHz, CDCl
3
) δ 146.6, 145.4, 134.8, 128.7, 120.6, 118.4, 115.5, 84.6,
+
(m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.53 (t, J =
4
1
0.8, 15.8. HRMS: Calcd. for C10
71.0794.
9 3
H N .[M] , 171.0796; found,
13
8.9 Hz, 2H), 7.36 (td, J = 7.2, 0.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H). C
NMR (100 MHz, DMSO) δ 162.8 (d, JC-F = 247.0 Hz), 143.8, 135.5,
2
0a
o
129.4(d, JC-F = 8.0 Hz), 128.2, 125.9(d, JC-F = 3.0 Hz), 123.9, 122.1,
18.3, 116.9, 116.4 (d, JC-F = 21.0 Hz), 112.6, 81.4.
2,4,6-Trimethoxybenzonitrile (2r) White solid, m.p. 139-140 C.
1
13
1
H NMR (400 MHz, CDCl
3
) δ 6.07 (s, 2H), 3.88 (s, 6H), 3.86 (s, 3H). C
NMR (100 MHz, CDCl ) δ 165.7, 164.1, 114.9, 90.7, 84.4, 56.4, 56.0.
3
19a
5
-Methoxy-1-methyl-1H-indole-3-carbonitrile (2j) Yellow solid,
o
1
20a
o
1
m.p. 103-105 C. H NMR (400 MHz, CDCl ) δ 7.47 (s, 1H), 7.25 (d, J
2,4-Dimethoxybenzonitrile (2s) White solid, m.p. 93-94 C. H
3
=
3
1
9.1 Hz, 1H), 7.13 (s, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.9, 2.4 Hz, 1H),
NMR (400 MHz, CDCl ) δ 7.47 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6, 1H),
3
1
3
13
.86 (s, 3H), 3.80 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 156.2, 135.7,
6.46 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H). C NMR (100 MHz, CDCl
3
) δ
31.3, 128.9, 116.5, 114.8, 111.5, 101.0, 85.0, 56.0, 34.0.
165.0, 163.2, 135.2, 117.3, 106.1, 98.8, 94.3, 56.3, 56.0.
1
9a
1
1
-Methyl-5-nitro-1H-indole-3-carbonitrile (2k) Yellow solid,
2,3,4-Trimethoxy-6-methylbenzonitrile (2t) Colorless oil H NMR
o
1
3 3
m.p.159- 160 C. H NMR (400 MHz, CDCl ) δ 8.66 (s, 1H), 8.24 (dd, J (400 MHz, CDCl ) δ 6.53 (s, 1H), 4.03 (s, 3H), 3.89 (s, 3H), 3.83 (s,
13
=
9.1, 1.8 Hz, 1H), 7.78 (s, 1H), 7.51 (d, J = 9.1 Hz, 1H), 3.97 (s, 3H).
3H), 2.46 (s, 3H). C NMR (100 MHz, CDCl ) δ 157.5, 139.3, 116.2,
3
1
3
C NMR (100 MHz, DMSO) δ 143.6, 142.5, 139.7, 127.1, 119.4,
16.1, 115.6, 113.5, 86.7, 34.9.
109.0, 100.2, 62.1, 61.5, 56.5, 30.0. HRMS: Calcd. for
+
1
C
11
H
13NO
3
.[M] , 207.0895; found, 207.0896.
1
9a
5
9
1
1
-Chloro-1-methyl-1H-indole-3-carbonitrile (2l) Yellow solid, m.p.
5-Methoxy-1H-indole-3-carbonitrile (2u) White solid, m.p. 154-
o
1
o
1
7-99 C. H NMR (400 MHz, CDCl
H), 7.31 – 7.24 (m, 2H), 3.83 (s, 3H). C NMR (100 MHz, CDCl
36.8, 134.7, 128.9, 128.5, 124.6, 119.5, 111.8, 85.4, 34.2. HRMS:
3
) δ 7.66 (d, J = 0.8 Hz, 1H), 7.54 (s, 156 C. H NMR (400 MHz, CDCl
3
) δ 12.10 (s, 1H), 8.20 (s, 1H), 7.48
13
3
) δ
(d, J = 8.9 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.9, 2.4 Hz,
13
1H), 3.85 (s, 3H). C NMR (100 MHz, DMSO) δ 156.2, 135.3, 131.0,
+
Calcd. for C10
7 2
H ClN .[M] , 190.0298; found, 190.0296.
128.5, 117.6, 114.8, 100.7, 84.9, 56.4.
o
1
5
-Methoxy-1-methyl-2-phenyl-1H-indole-3-carbonitrile (2m)
1H-Indole-3,5-dicarbonitrile (2v) Yellow solid, m.p. 257-259 C. H
o
1
Canary yellow solid, m.p. 253-255 C. H NMR (400 MHz, DMSO) δ
NMR (400 MHz, DMSO) δ 12.73 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H),
1
3
7
1
1
1
.81-7.47 (m, 6H), 7.15 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 9.0, 2.4 Hz,
7.76 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H). C NMR (100 MHz,
DMSO) δ 138.3, 138.0, 127.3, 127.2, 125.0, 120.6, 116.1, 115.3,
105.1, 86.4.
1
3
H), 3.88 (s, 3H), 3.77 (s, 3H). C NMR (100 MHz, DMSO) δ 156.7,
48.5, 132.5, 130.8, 130.7, 129.9, 129.4, 128.5, 117.6, 114.9, 113.7,
00.7, 84.4, 56.4, 32.8.
5
-Chloro-1H-indole-3-carbonitrile (2w) White solid, m.p. 165-167
1
9a
o
1
1
1
7
1
7
1
-Ethyl-2-phenyl-1H-indole-3-carbonitrile (2n) Yellow solid, m.p.
C. H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 8.36 (s, 1H), 7.70 (s,
o
1
13
08-110 C. H NMR (400 MHz, CDCl
3
) δ 7.79 (d, J = 7.0 Hz, 1H),
1H), 7.61 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H). C NMR (100
.62-7.52 (m, 5H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (td, J = 7.2, 1.2 Hz,
MHz, DMSO) δ 137.1, 134.7, 128.8, 127.5, 124.6, 118.7, 116.7,
115.6, 85.1.
H), 7.32 (td, J = 8.0, 1.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.37 (t, J =
13
3
.2 Hz, 3H). C NMR (100 MHz, CDCl ) δ 148.1, 135.9, 130.2, 130.0,
4
-Chloro-1H-indole-3-carbonitrile (2x) Yellow solid, m.p. 223-225
29.4, 128.2, 124.1, 122.6, 120.0, 116.9, 111.1, 86.3,39.9, 15.6.
o
1
C. H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 8.41 (s, 1H), 7.62 -
1
3
1-Ethyl-2-methyl-1H-indole-3-carbonitrile (2o) Brown solid, m.p.
7.47 (m, 1H), 7.38 - 7.10 (m, 2H). C NMR (100 MHz, DMSO) δ
o
1
3
89-91 C. H NMR (400 MHz, CDCl ) δ 7.67 (d, J = 7.6 Hz, 1H), 7.33
137.6, 137.4, 125.3, 125.2, 124.5, 122.8, 117.2, 113.2, 84.6.
(
d, J = 7.6 Hz, 1H), 7.30 -7.22 (m, 2H), 4.16 (q, J = 7.3 Hz, 2H), 2.58 (s,
o
1
3
Benzo[b]thiophene-3-carbonitrile (2y) White solid, m.p. 72-74 C.
3
1
1
3
H), 1.38 (t, J = 7.3 Hz, 3H). C NMR (100 MHz, CDCl ) δ 145.2,
1
3
H NMR (400 MHz, CDCl ) δ 8.12 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92
35.5, 127.5, 123.2, 122.1, 119.4, 117.0, 110.1, 85.2, 39.0, 15.2,
2.0.
6
| J. Name., 2012, 00, 1-3
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Organic & B molecula hemistry
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DOI: 10.1039/C5OB01244A
Journal Name
d, J = 7.9 Hz, 1H), 7.59 - 7.46 (m, 2H). C NMR (100 MHz, CDCl ) δ
ARTICLE
1
3
13
(
3H). C NMR (100 MHz, CDCl ) δ 168.7, 168.6, 164.9, 135.1, 125.2,
3
3
138.8, 137.9, 137.6, 126.5, 126.3, 123.2, 122.9, 114.7, 107.4.
124.4, 119.8, 108.4, 56.4, 24.3.
2
,3-Dihydrobenzofuran-5-carbonitrile (2z) White solid, m.p.68- 70
5-Ethoxy-2-methylisoindoline-1,3-dione (5b) White solid, m.p. 109-
o
1
o
1
C. H NMR (400 MHz, CDCl ) δ 7.46 -7.44 (m, 2H), 6.82 (d, J = 8.2
111 C. H NMR (400 MHz, CDCl ) δ 7.73 (d, J = 8.3 Hz, 1H), 7.30 (d, J
3
3
1
3
Hz, 1H), 4.66 (t, J = 8.8 Hz, 2H), 3.25 (t, J = 8.8 Hz, 2H). C NMR (100
= 2.2 Hz, 1H), 7.12 (dd, J = 8.3, 2.3 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H),
1
3
MHz, CDCl
9.3.
3
) δ 164.1, 133.9, 129.2, 128.9, 119.9, 110.6, 103.9, 72.4,
3.15 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl
168.8, 168.7, 164.3, 135.1, 125.2, 124.2, 120.3, 108.8, 64.8, 24.3,
4.9.
3
) δ
2
1
o
Benzo[d][1,3]dioxole-5-carbonitrile (2A) White solid, m.p.91- 93 C.
1
H NMR (400 MHz, CDCl
.5 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.06 (s, 2H). C NMR (100 MHz,
CDCl ) δ 151.8, 148.3, 128.5, 119.2, 111.7, 109.4, 105.2, 102.5.
3
) δ 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 7.03 (d, J =
5-Isopropoxy-2-methylisoindoline-1,3-dione (5c) White solid, m.p.
1
3
o
1
1
93-95 C H NMR (400 MHz, CDCl
3
) δ 7.70 (d, J = 8.3 Hz, 1H), 7.27 (d,
3
J = 2.2 Hz, 1H), 7.09 (dd, J = 8.3, 2.2 Hz, 1H), 4.67 (dt, J = 12.1, 6.0
13
Hz, 1H), 3.14 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H). C NMR (100 MHz,
o
1
3,4,5-trimethoxybenzonitrile (2B) White solid, m.p.92- 94 C. H
CDCl ) δ 168.8, 168.7, 163.4, 135.1, 125.2, 123.9, 121.3, 109.5, 71.3,
3
13
+
NMR (400 MHz, CDCl
NMR (100 MHz, CDCl
3
3
) δ 6.79 (s, 1H), 3.83 (s, 3H), 3.81 (s, 6H).
C
2
2
4.2, 22.1. HRMS: Calcd. for C12
19.0893.
3
H13NO .[M] , 219.0895; found,
) δ 153.8, 142.6, 119.3, 109.7, 107.0, 61.3,
56.7.
5
-(Benzyloxy)-2-methylisoindoline-1,3-dione
(
5d) White solid,
1
5b
o
1
4
-Methoxybenzonitrile (2C) White solid, m.p. 57-58 C. H NMR
o
1
m.p.123-125 C. H NMR (400 MHz, CDCl
3
) δ 7.75 (d, J = 8.3 Hz,
(
400 MHz, CDCl ) δ 7.58 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 9.2Hz, 2H),
3
1H), 7.45 – 7.38 (m, 6H), 7.22 (dd, J = 8.3, 2.3 Hz, 1H), 5.18 (s,
1
3
1
3
H), 3.15 (s, 3H). C NMR (100 MHz, CDCl
3
3
.85 (s, 3H). C NMR (100 MHz, CDCl ) δ 163.2, 134.3, 119.5, 115.1,
2
3
) δ 168.63, 168.60,
1
04.3, 55.9.
164.0, 135.8, 135.1, 129.1, 128.8, 127.9, 125.3, 124.7, 120.7,
+
1
3
09.3, 24.3. HRMS: Calcd. for C16H13NO .[M] , 267.0895;
2
0a
o
1
4
-Chlorobenzonitrile (2D) White solid, m.p. 90-91 C. H NMR
) δ 7.60 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz,
H). C NMR (100 MHz, CDCl ) δ 139.9, 133.7, 130.1, 118.3, 111.2.
found, 267.0897.
(400 MHz, CDCl
3
1
3
2
3
Acknowledgements
2
0a
o
1
4
-Nitrobenzonitrile (2E) Yellow solid, m.p. 140-141 C. H NMR
) δ 8.36 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H).
C NMR (100 MHz, CDCl ) δ 133.8, 128.7, 124.6, 118.7, 117.1.
The authors thank the National Natural Science Foundation of
China (Nos. 21472173, 21272203) for the financial support.
(
400 MHz, CDCl
3
1
3
3
1
5b
o
1
1
-Naphthonitrile (2F) White solid, m.p. 55-56 C. H NMR (400
MHz, CDCl ) δ 8.24 (d, J =8.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.98 (d,
J = 8.0 Hz, 2H), 7.70 (dd, J = 8.4, 7.0 Hz, 1H), 7.62 (dd, J = 8.4, 7.0 Hz,
Notes and references
3
1
P. Rhoennstad, E. Kallin, T. Apelqvist, M. Wennerstaal, A.
Cheng, PCT Int. Appl., 2009, WO 2009127686 A1.
1
3
1
1
1
H), 7.52 (dd, J = 8.4, 7.0 Hz, 1H). C NMR (100 MHz, CDCl ) δ
2
H. E. Armstrong, A. Galka, L. S. Lin, T. J. Lanza, Jr., J. P. Jewell,
S. K. Shah, R. Guthikonda, Q. Truong, L. L. Chang, G. Quaker,
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A. Strack, S. Ha, L. V. Ploeg, M. T. Gouleta, W. K. Hagmann,
Bioorg. Med. Chem. Lett., 2007, 17, 2184.
3
33.6, 133.3, 133.0, 132.7, 129.0, 128.9, 127.9, 125.5, 125.3, 118.1,
10.5.
o
1
Pyrene-1-carbonitrile (2G) White solid, m.p. 152-154 C. H NMR
400 MHz, CDCl ) δ 8.33 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 7.6 Hz, 2H),
.17 (dd, J = 13.1, 5.9 Hz, 3H), 8.07 (t, J = 7.6 Hz, 2H), 8.00 (d, J = 9.0
(
3
3
4
5
(a) X.-H. Gu, X.-Z. Wan, B. Jiang, Bioorg. Med. Chem. Lett.,
1
K. Shah, Bioorg. Med. Chem. Lett., 2011, 21, 5897.
M. Hagmann, J. Nussberger, R. B. Naudin, T. S. Burns, A.
Karim, B. Waeber, H. R. Brunner, J. Cardiovasc. Pharmacol.,
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999, 9, 569; (b) D. Kumar, M. Kumar, K.-H. Chang, R. Gupta,
8
1
3
Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 134.4, 133.1, 131.0, 130.72,
1
1
30.69, 129.8, 127.3, 127.24, 127.21, 127.1, 124.6, 124.14, 124.12,
23.7, 119.1, 105.8.
2
-(Dimethylamino)-1-(4-hydroxyphenyl)-1H-indole-3-carbonitrile
o
1
Yellow solid, m.p. 223-225 C. H NMR (400 MHz, DMSO) δ 9.98 (s,
H), 7.41 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.19 (t, J = 7.4
Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.92 (d, J =
Org. Lett., 2006, 8, 5919.
1
6
7
Y. Yang, Y. Zhang, J. Wang, Org. Lett., 2011, 13, 5608.
R. V. Smaliy, A. A. Chaikovskaya, A. M. Pinchuk, A. A.
Tolmachev, Synthesis, 2002, 2416.
8.0 Hz, 1H), 2.89 (s, 6H).
8
9
S. Ushijima, K. Moriyama, H. Togo, Tetrahedron, 2012, 68
588.
,
4
5
-Methoxy-2-methylisoindoline-1,3-dione (5a) White solid, m.p.
(a) J. R. Hwu, F. F. Wong, Eur. J. Org. Chem., 2006, 2513; (b)
L. M. Dornan, Q. Cao, J. C. A. Flanagan, J. J. Crawford, M. J.
Cook, M. J. Muldoon, Chem. Commun., 2013, 49, 6030; (c) A.
o
1
3
155-157 C. H NMR (400 MHz, CDCl ) δ 7.73 (d, J = 8.3 Hz, 1H), 7.31
(d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.3, 2.3 Hz, 1H), 3.91 (s, 3H), 3.14 (s,
Khalafi-Nezhad, S. Mohammadi, RSC Adv., 2014, 4, 13782.
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C5OB01244A
ARTICLE
Journal Name
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(b) Q. Wen, J. Jin, L. Zhang, Y. Luo, P. Lu, Y. Wang,
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(a) B. V. S. Reddy, Z. Begum, Y. J. Reddy, J. S. Yadav,
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