Transition-Metal-Free Aerobic Oxidative Cross-Coupling of Indoles with Arylidenemalononitriles

Article abstract of DOI:10.1055/s-0039-1691532

An efficient method for the direct construction of C(sp ²)-C(sp ²) bonds by aerobic oxidative cross-coupling of indoles with arylidenemalononitriles is described. Various [aryl(1 H -indol-3-yl)methylene]malononitriles were efficientl

Full text of DOI:10.1055/s-0039-1691532

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
A. Yang, Z. Li
Letter
Synlett
Transition-Metal-Free Aerobic Oxidative Cross-Coupling of Indoles
with Arylidenemalononitriles
Aizhen Yang
R2
Zheng Li*
NH
R2
College of Chemistry and Chemical Engineering, Northwest
Normal University, Lanzhou, Gansu, 730070, P. R. of China
lizheng@nwnu.edu.cn
NH
H
KOH, air
+
CN
CN
1,4-dioxane, 60 °C, 2 h
H
R1
CN
CN
R1
No transition-metal catalyst
Air as an oxidant
Mild condition
High atom economy
22 examples
Up to 82% yield
Received: 09.10.2019
Accepted after revision: 01.12.2019
Published online: 10.12.2019
previously investigated, only Michael addition products
were obtained, and no oxidative cross-coupling reactions
were reported.5
DOI: 10.1055/s-0039-1691532; Art ID: st-2019-k0539-l
Here, we report an aerobic oxidative cross-coupling be-
tween the C(sp2)–H bond of arylidenemalononitriles and
the C(sp2)–H of indoles at the C3-position under transition-
metal-free conditions using air as an oxidant to give indole-
functionalized arylidenemalononitriles.
Abstract An efficient method for the direct construction of C(sp2)–
C(sp2) bonds by aerobic oxidative cross-coupling of indoles with
arylidenemalononitriles is described. Various [aryl(1H-indol-3-yl)methy-
lene]malononitriles were efficiently synthesized by using air as an oxi-
dant under mild conditions. The salient features for this protocol are no
transition-metal catalysts, no organometallic reagents, high atom
economy, high yield, mild conditions, and simple workup procedures.
Initially, we selected the reaction of benzylidenemalo-
nonitrile (1a) with unsubstituted indole under open-air
conditions as a model reaction to determine the optimal
conditions. Various bases and solvents were examined for
the reaction (Table 1). The reaction was first tested in MeCN
at room temperature in the absence of a base, but no prod-
uct was detected (Table 1, entry 1). When one equivalent of
KOH was used as a base and the mixture was stirred at
room temperature for two hours, [1H-indol-3-yl(phe-
nyl)methylene]malononitrile (2a) was isolated in 34% yield
(entry 2). This result implied that a cross-dehydrogenation
coupling reaction between 1a and indole had taken place
smoothly. Other inorganic bases (NaOH, Cs2CO3, K2CO3, and
NaOAc) were also tested, but no improvement in the yield
was achieved (entries 3–6). The organic bases Et3N, 1,8-diaz-
abicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]
octane (DABCO), and 4-(dimethylamino)pyridine (DMAP)
had no effect on the reaction (entries 7–10). However, we
found that increasing the amount of KOH significantly en-
hanced the yield of 2a (entry 11). In an attempt to improve
the yield of 2a, we also tested various solvents for the reac-
tion. Product 2a was obtained in trace or low yields in THF,
DCE, toluene, EtOH, DMSO, and DMF (entries 12–17). How-
ever, in 1,4-dioxane the reaction gave 2a in a moderate
yield (entry 18). Raising the temperature improved the
yield of 2a markedly (entries 19 and 20), the best yield of 2a
(82%) being obtained at 60 °C (entry 20).
Key words cross-coupling, indoles, arylidenemalononitriles, metal-
free synthesis
In oxidative cross-coupling reactions, C–H bonds in two
substrates form a new C–C bond under oxidative condi-
tions. This is one of the most atom-economical methods for
constructing a new chemical bond, and it eliminates the
need for the substrate prefunctionalization steps required
in conventional cross-coupling reactions.1
Reported methods for the formation of C(sp2)–C(sp2)
bonds through oxidative cross-coupling generally involve
two aromatic C–H nucleophiles.2 However, the method is
far from satisfactory in that transition-metal catalysts are
required for the reactions and, because of possible homo-
coupling of C(sp2)–H bonds, direct oxidative cross-coupling
between two C(sp2)–H bonds is challenging. In addition, no
examples of oxidative cross-couplings between alkene
C(sp2)–H and heteroarene C(sp2)–H bonds have been re-
ported.
The indole ring system is the most widely distributed
heterocycle found in nature. Functionalized indoles have a
wide range of physiological activities.3 In many synthetic
methods, cross-coupling of indoles at their C3-position is
an important route to functionalized indoles.4 Although re-
actions of indoles with arylidenemalononitriles have been
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Yang, Z. Li
Letter
Synlett
With the optimized reaction conditions in hand, we ex-
amined the scope of the formation of C(sp2)–C(sp2) bonds
through aerobic oxidative cross-coupling of indole or sub-
stituted indoles with various arylidenemalononitriles at
60 °C in the presence of two equivalents of KOH as a base
(Scheme 1).6 We found that for typical cases, a wide range
of substituents on the arylidenemalononitrile, including H,
Me, MeO, CF3, F, Cl, Br, and NO2 groups, were tolerated (2a–
n). The yield from the aerobic oxidative cross-coupling was
satisfactory for both electron-donating and electron-with-
drawing substituents. Due to the lower steric hindrance,
the yields from meta- and para-substituted substrates (2b,
2d–2g, 2i, 2j, 2m, and 2n) were slightly higher than those
from ortho-substituted substrates (2c, 2h, and 2l). A sub-
strate containing a hetaryl ring (thiophene) also gave the
corresponding product 2o in good yield. Furthermore, with
R2
NH
H
CN
CN
N
KOH, air
R2
R1
CN
1,4-dioxane, 60 °C, 2 h
R1
CN
2a–v
1
H
H
H
N
H
H
N
N
N
N
CN
CN
CN
CN
CN
CN
CN
CN
H3CO
CN
CN
OCH3
H3CO
H3C
2a 82%
2b 78%
2c 60%
2e 72%
2d 67%
H
N
H
N
H
H
N
H
N
N
CN
CN
CN
CN
CN
CN
CN
CN
CN
Cl
CN
Cl
Cl
F3C
F
2i 66%
2j 71%
2g 65%
2h 59%
2f 76%
H
N
H
N
H
H
N
H
N
N
CN
CN
CN
CN
CN
CN
CN
CN
CN
O2N
CN
Br
S
Cl
Br
Cl
2m 67%
2o 76%
2n 61%
2k 74%
2l 58%
H
H
N
H
H
N
N
N
H3CO
Cl
H3CO
H3CO
CN
CN
CN
CN
CN
CN
CN
CN
Cl
H3CO
2s 80%
2r 69%
2p 78%
2q 74%
H
N
H
N
H
N
Cl
CN
CN
Cl
Cl
CN
CN
CN
CN
H3CO
2v 38%
2u 73%
2t 62%
Scheme 1 Synthesis of [aryl(1H-indol-3-yl)methylene]malononitriles 2a–v. Reagents and conditions: 1 (0.5 mmol), indole (0.5 mmol), KOH (1.0 mmol),
1,4-dioxane (4 mL), under air, 60 °C, 2 h.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
A. Yang, Z. Li
Letter
Synlett
substituted indoles (R2 = 5-MeO, 5-Cl), the corresponding
aerobic oxidative cross-coupling products 2p–u were ob-
tained smoothly and in good yields. However, for a methyl-
substituted indole (R2 = 2-Me), the corresponding aerobic
oxidative cross-coupling product 2v was obtained in only
38% yield, possibly because of high steric hindrance. An at-
tempt to react N-methylindole was not successful.
Having successfully demonstrated the generality of our
protocol, we next examined the reaction of 1a with indole
on a gram scale. The reaction of 1.54 g of 1a with 1.17 g of
indole in the presence of 1.20 g of KOH in 1,4-dioxane (25
mL) under the optimized condition gave 1.69 g of 2a in 63%
isolated yield. The gram-scale reaction showed that the op-
timized conditions are suitable for a bulk process to a cer-
tain extent (Scheme 2).
Table 1 Optimization of the Reaction Conditionsa
NH
H
CN
N
base, solvent
+
CN
CN
CN
temperature
2a
1a
H
N
Entry
Base (equiv)
Temp (°C) Solvent
Yieldb (%)
H
CN
N
KOH, 1,4-dioxane
60 °C, 4 h
CN
CN
2a 1.69 g 63%
+
1
2
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
0
CN
KOH (1.0)
NaOH (1.0)
Cs2CO3 (1.0)
K2CO3 (1.0)
NaOAc (1.0)
Et3N (1.0)
DBU (1.0)
DABCO (1.0)
DMAP (1.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
34
1a 1.54 g
1.17 g
3
25
4
21
Scheme 2 Gram-scale experiment for 2a
5
27
To investigate the reaction mechanism, we performed
two control experiments (Scheme 3). When the reaction of
1a with indole was carried out under standard conditions
under an atmosphere of nitrogen instead of air, the Michael
addition product 3a was obtained in 65% yield, and only
traces of the oxidative cross-coupling product 2a were de-
tected. Moreover, 3a was readily converted into 2a in high
yield under the standard conditions. This implied that the
Michael addition product 3a is a possible intermediate for
the reaction of 1a with indole to produce 2a, and that air is
indispensable for the formation of 2a.
Based on the above experiments, a plausible mechanism
is proposed for the synthesis of 2a (Scheme 4). Benzyliden-
emalononitrile (1a) reacts with indole in the presence of
potassium hydroxide to give the Michael addition product
3a initially, as isolated and characterized in the control ex-
periments. 3a is subsequently oxidized by oxygen in the air
to give the hydroxylated intermediates A1 and A2. These in-
termediates then undergo dehydration in the presence of
potassium hydroxide to give 2a as the final product.
6
trace
0
7
8
0
9
0
10
11
12
13
14
15
16
17
18
19
20
0
48
0
DCE
trace
trace
trace
trace
15
PhMe
EtOH
DMSO
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
59
65
60
82
a Reaction conditions: 1a (0.5 mmol), indole (0.5 mmol), base, solvent (4
mL), open to air, 2 h.
b Isolated yield.
NH
NH
H
CN
N
KOH, N2
1,4-dioxane, 60 °C, 2 h
+
+
CN
CN
CN
CN
CN
3a 65%
1a
2a trace
Michael addition product
cross-coupling product
NH
CN
NH
KOH, air
CN
1,4-dioxane, 60 °C, 2 h
CN
CN
3a
2a 86%
Scheme 3 Control experiments
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

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A. Yang, Z. Li
Letter
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NH
H
CN
N
KOH
+
CN
CN
CN
Michael addition
1a
3a
KOH, air (O2)
oxidation
H
N
H
N
KOH
dehydration
NH
CN
CN
CN
OH
CN
+
HO
CN
CN
H2O
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RSC Adv. 2019, 9, 5870. (o) Guo, S.; Li, Y.; Wang, Y.; Guo, X.;
Meng, X.; Chen, B. Adv. Synth. Catal. 2015, 357, 950.
A2
[M + H]+ detectable
2a
A1
Scheme 4 Proposed mechanism for the formation of 2a
In conclusion, we have developed a simple method for
the direct construction of C(sp2)–C(sp2) bonds between in-
doles and 2-arylidenemalononitriles by using air as an oxi-
dant under transition-metal-free conditions. This method
provides an efficient and high-yielding route for the synthe-
sis of useful 2-[aryl(1H-indol-3-yl)methylene]malononi-
triles. This new processes is characterized by a high effi-
ciency, a short reaction time, and excellent functional-
group tolerance, and it provides a practical and versatile
strategy for obtaining various (indol-3-yl)methylene-func-
tionalized malononitriles.
Funding Information
The authors thank the National Natural Science Foundation of China
(21462038) for the financial support of this work.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691532.
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References and Notes
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2019, 119, 6769. (b) Tang, S.; Zeng, L.; Lei, A. J. Am. Chem. Soc.
2018, 140, 13128. (c) Tang, S.; Liu, Y.; Lei, A. Chem 2018, 4, 27.
(d) Morimoto, K.; Dohi, T.; Kita, Y. Synlett 2017, 28, 1680.
(e) Guo, S.; Kumar, P. S.; Yang, M. Adv. Synth. Catal. 2017, 359, 2.
(f) Dong, J.; Wu, Q.; You, J. Tetrahedron Lett. 2015, 56, 1591.
(g) Liu, C.; Liu, D.; Lei, A. Acc. Chem. Res. 2014, 47, 3459. (h) Shi,
W.; Liu, C.; Lei, A. Chem. Soc. Rev. 2011, 40, 2761. (i) Shao, Z.;
Peng, F. Angew. Chem. Int. Ed. 2010, 49, 9566. (j) Li, C.-J. Acc.
Chem. Res. 2009, 42, 335. (k) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005,
127, 3672.
(5) (a) Su, W.-Q.; Yang, C.; Xu, D.-Z. Catal. Commun. 2017, 100, 38.
(b) Desyatkin, V. G.; Beletskaya, I. P. Synthesis 2017, 49, 4327.
(c) Romanini, S.; Galletti, E.; Caruana, L.; Mazzanti, A.; Himo, F.;
Santoro, S.; Fochi, M.; Bernardi, L. Chem. Eur. J. 2015, 21, 17578.
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Chem. 2015, 146, 691. (e) Liu, R.; Zhang, J. Org. Lett. 2013, 15,
2266. (f) Singh, S. K.; Singh, K. N. J. Indian Chem. Soc. 2012, 89,
401. (g) Gupta, P.; Paul, S. J. Mol. Catal. A: Chem. 2012, 352, 75.
(h) Liu, X.-L.; Xue, D.; Zhang, Z.-T. J. Heterocycl. Chem. 2011, 48,
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© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

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A. Yang, Z. Li
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Synlett
(6) [Aryl(1H-indol-3-yl)methylene]malononitriles 2a–v; General
Procedure
 = 168.46, 137.58, 136.78, 134.99, 132.38, 130.30, 129.31,
126.13, 123.64, 122.15, 120.80, 116.75, 116.03, 113.52, 112.65,
72.09. HRMS (ESI): m/z [M + H]+ calcd for C18H12N3: 270.1026;
found: 270.1023.
[(5-Methoxy-1H-indol-3-yl)(phenyl)methylene]malononi-
trile (2p)
A mixture of the appropriate arylidenemalononitrile 1 (0.5
mmol), indole (0.5 mmol), and KOH (1.0 mmol) in 1,4-dioxane
(4 mL) was stirred at 60 °C for 2 h. When the reaction was com-
plete (TLC), the mixture was extracted with EtOAc (3 × 10 mL),
and the extracts were washed with sat. brine (3 × 10 mL). The
organic phase was dried (Na2SO4) and concentrated under
reduced pressure, and the residue was purified by column chro-
matography [silica gel, PE–EtOAc (2:1)].
[1H-Indol-3-yl(phenyl)methylene]malononitrile (2a)
Yellow solid; yield: 110 mg (82%); mp 166–170 °C. 1H NMR (600
MHz, DMSO-d6):  = 12.60 (s, 1 H), 8.34 (s, 1 H), 7.65 (t, J = 7.2
Hz, 1 H), 7.57–7.51 (m, 5 H), 7.19–7.15 (m, 1 H), 6.96–6.93 (m, 1
H), 6.38 (d, J = 8.1 Hz, 1 H). 13C NMR (150 MHz, DMSO-d6):
Yellow solid; yield: 117 mg (78%); mp 231–233 °C. 1H NMR (400
MHz, DMSO-d6):  = 12.56 (s, 1 H), 8.28 (s, 1 H), 7.69–7.64 (m, 1
H), 7.58 (t, J = 7.6 Hz, 2 H), 7.52 (dd, J = 8.4, 1.4 Hz, 2 H), 7.43 (d,
J = 8.8 Hz, 1 H), 6.82 (dd, J = 8.9, 2.4 Hz, 1 H), 5.79 (d, J = 2.4 Hz, 1
H), 3.43 (s, 3 H). 13C NMR (150 MHz, DMSO-d6):  = 168.32,
155.38, 136.90, 135.12, 132.35, 132.10, 130.17, 129.36, 126.98,
116.88, 116.18, 114.24, 113.28, 112.58, 103.37, 71.00, 55.27.
HRMS (ESI): m/z [M + H]+ calcd for C19H14N3O: 300.1131; found:
300.1132.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E