Selective synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines via copper-catalyzed tandem annulation of alkynylbenzonitriles with 2-Iodoanilines

Article abstract of DOI:10.1016/j.tetlet.2018.06.030

An efficient copper-catalyzed cascade cyclization reaction for selectively synthesizing a variety of benzo[4,5]imidazo[2,1-a]isoquinoline derivatives has been developed. The reaction features the formation of three different C–N bonds in sequence. In the

Full text of DOI:10.1016/j.tetlet.2018.06.030

Accepted Manuscript
Selective Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines via Copper-cat-
alyzed Tandem Annulation of Alkynylbenzonitriles with 2-Iodoanilines
Xiaodong Liu, Guobo Deng, Yun Liang
PII:
S0040-4039(18)30772-X
https://doi.org/10.1016/j.tetlet.2018.06.030
TETL 50068
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
12 April 2018
8 June 2018
11 June 2018
Please cite this article as: Liu, X., Deng, G., Liang, Y., Selective Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines
via Copper-catalyzed Tandem Annulation of Alkynylbenzonitriles with 2-Iodoanilines, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.06.030
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Tetrahedron Letters
Selective Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines via Copper-catalyzed Tandem Annulation of
Alkynylbenzonitriles with 2-Iodoanilines
Xiaodong Liu, Guobo Deng* and Yun Liang*
National & Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of the Assembly and Application of Organic Functional Molecules, Hunan
Normal University, Changsha, Hunan 410081, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient copper-catalyzed cascade cyclization reaction for selectively synthesizing a variety of
benzo[4,5]imidazo[2,1-a]isoquinoline derivatives has been developed. The reaction features the
formation of three different C−N bonds in sequence. In the presence of Cu(OAc)2 and KOtBu, o-
alkynylbenzonitriles and 2-iodoanilines proceeded smoothly to obtain the corresponding
benzo[4,5]imidazo[2,1-a]isoquinolines in moderate to good yields.
Available online
Keywords:
2-iodoaniline
2018 Elsevier Ltd. All rights reserved
o-alkynylbenzonitrile
Nitrogen heterocycles
cycloaddition
tandem reaction
development of novel and expeditious methods for selectively
synthesizing benzo[4,5]imidazo[2,1-a]isoquinolines is also a big
challenge at present. Herein, we describe a copper-catalyzed C–N
bond formation reaction for the selective synthesis of substituted
benzimidazo[2,1-a]isoquinolines using 2-iodoanilines and o-
alkynylbenzonitriles as substrates.
Isoquinoline-fused benzimidazoles are an important class of
heterocycles due to their widespread application in natural
products,1 pharmaceuticals,2 and synthetic materials.3 Therefore,
great efforts have been made to develop methods for the effective
synthesis of this useful structural skeleton in recent years.4
Benzo[4,5]imidazo[2,1-a]isoquinolines5 are an important
member of this tetracyclic heterocycle family and cyclization of
the o-alkynyladehyde with o-phenylenediamine in the presence
of various catalysts is the most common method for the
preparation of this useful structural core.6 Beyond that, there are
alternative powerful approaches for synthesizing such dominant
structural frameworks. For example, Yanada and co-workers
have reported a one-pot method for the construction of
benzimidazo[2,1-a]isoquinolines
bromoarylaldehydes, terminal
starting
alkynes,
from
and
2-
1,2-
phenylenediamines by a microwave-promoted tandem process
(Scheme 1 a).7 Li and co-workers also have developed a one-pot
route for the synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines
via nucleophilic addition of 2-aryl benzimidazoles to
alkynylbromides (Scheme 1 b).8 More recently, Wang and co-
workers have demonstrated that copper-catalyzed C-C coupling
and deacylative cyclization can be a powerful tool for the
synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines (Scheme 1
c).9 These methods afford good progress in the synthesis of
benzo[4,5]imidazo[2,1-a]isoquinolines. However, two isomers of
isoquinoline-fused benzimidazoles were obtained when there are
asymmetric substituents on the benzene ring of the
benzimidazoles in these previous methods. Therefore,
Scheme 1 Synthesis of Benzo[4,5]imidazo[2,1-a] isoquinolines
Our investigation began with the reaction of o-
alkynylbenzonitrile 1a with 2-iodoaniline 2a to determine the
optimal reaction conditions, and the results are summarized in
Table 1. Intriguingly, in the presence of KOtBu, substrates 1a and
2a were converted into the desired product, 6-
phenylbenzo[4,5]imidazo[2,1-a]isoquinoline 3a, in 68% yield
(entry 1). Subsequently, some copper catalysts, such as CuI,
CuBr, CuCl and Cu(OAc)2 were tested (entries 2-5). The result
indicated that Cu(OAc)2 was the best catalyst for this cascade
cyclization reaction, and desired product 3a was obtained in 81%
----------------
* Corresponding author.
E-mail address: gbdeng@hunnu.edu.cn (G. Deng);
yliang@hunnu.edu.cn (Y. Liang)

2
Tetrahedron Letters
yield (entry 5). To improve the reaction performance, the
reactions. Furthermore, 3-iodopyridin-2-amine was also tolerated
under the reaction conditions, affording the corresponding
product 3i in 62% yield. It was noteworthy that 1-
iodonaphthalen-2-amine 2j performed well under the standard
conditions, giving the corresponding poly cyclic ring product 3j
in 77% yield, which makes an aryne mechanism in these cases
unlikely.10 Fortunately, when the halogen atom on the aromatic
ring was replaced with F, Cl and Br, the reaction proceeded
effects of the ligands were evaluated, however, they all gave
slightly lower yield (entries 6-9). Then, reaction conditions were
further investigated and the influences of different solvents on
the outcome of the model reaction were screened (entries 10-13).
We found that DMAc (N, N-dimethylacetamide) was the best
solvent. The yield was decreased significantly when other bases
were used (entries 14-16). To our delight, when we increased the
amount of 1a to 1.2 equiv, the yield of 3a increased to 86%
(entries 17). In the end, temperature screening indicated that
120°C was the most suitable temperature for this reaction (entries
17, 18 and 19).
smoothly
to
obtain
the
corresponding
6-
arylbenzo[4,5]imidazo[2,1-a] isoquinoline 3a in 64%, 62%, 60%
yield, respectively.
Table 2. Substrate Scope of the 2-Halogenoaniline a
Table 1. Optimization of Reaction Conditions a
Entry
Base
Yield(%)b
Additive
-
Ligand
-
Solvent
DMAc
1
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
68
64
65
70
81
76
73
66
78
43
2
CuI,
CuBr
-
-
-
-
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
3
4
CuCl
5
Cu(OAc)2
6
Cu(OAc)2 L-Proline
Cu(OAc)2 TEMED
Cu(OAc)2 DEMED
Cu(OAc)2 1,10-Phen
7
8
9
a Reaction conditions: 1a (0.36mmol), 2 (0.3 mmol), Cu(OAc)2 (10 mmol %),
10
Cu(OAc)2
-
KOtBu (0.9 mmol), DMAc (1 mL), under the N2 atmosphere in a sealed
11
12
13
14
15
16
17c
18d
19e
a
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
-
-
-
-
-
-
-
-
-
NMSO
NMP
KOtBu
KOtBu
KOtBu
LiOtBu
Cs2CO3
KOH
51
70
0
c
Schlenk tube, at 120 oC for 12 h. b The substrate = 2-fluoroaniline, The
substrate = 2-chloroaniline, d The substrate = 2-bromoaniline.
Toluene
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
0
Inspired by the above results, we turned our attention to
exploring the scope of the 2-(phenylethynyl)benzonitriles in the
presence of o-iodoaniline 2a (0.3 mmol), Cu(OAc)2 (10 mol%)
and KOtBu (0.9 mmol) in DMAc (1 mL) under N2 atmosphere at
120 °C for 12 hours. The results are summarized in table 3. First,
we investigated the scope of substituents on the aryl ring of the
terminal alkyne. The results showed that substrates bearing either
electron-donating (R = Me, namyl, OMe) or electron-withdrawing
groups (R = F, Cl) furnished the transformation, producing the
desired benzo[4,5]imidazo[2,1-a]isoquinolines in good to
excellent yields (3k-3o). Notably, thiophen-3-yl-substituted
alkyne and pyridine-3-yl-substituted alkyne were also suitable for
the tandem cyclization reaction, affording the corresponding
products in 96% and 98% yields, respectively (3p and 3q). As for
low activity aliphatic alkyne substituted substrate 1r and 1s, the
corresponding product 3r and 3s could also successfully be
obtained, albeit in a low yield. Next, substrates with Me, two
OMe or Cl on the aryl ring linked to cyano group were
compatible with the standard conditions, producing 3t, 3u and 3v
in moderate yield. Finally, we examined the substrate 1-
(phenylethynyl)-2-naphthonitrile 1w, affording the poly-cyclic
ring product in 72% yield.
41
35
86
77
72
KOtBu
KOtBu
KOtBu
Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), [Cu] (10 mmol %),
ligand (20 mol%), base (0.9 mmol), solvent (1 mL), under a N2 atmosphere in
a sealed Schlenk tube, at 120 C for 12 h. b Isolated yield. 1a (0.36 mmol).
d At 100 oC. e At 140 oC.
o
c
With the optimized reaction conditions in hand, we proceeded
to explore the scope of 2-iodoanilines and the results are
summarized in Table 2. To our delight, not only were functional
groups such as methyl, fluoro and chloro groups compatible with
the
reaction,
but
also
the
corresponding
single
benzo[4,5]imidazo[2,1-a]isoquinolines were selectively obtained
in all of those reactions. For example, 4- or 5-methyl substituted
o-iodoanilines both showed high reactivity and selectively giving
3b and 3c both in 70% yield. The absolute configuration of 3c
was unambiguously established by X-ray crystallographic
analysis (CCDC 1817529). In addition, substrate 2d with two
methyl substituents at the 4- and 6- positions were also viable for
producing 3d in 88% yield. Notably, 4- or 5-chloro substituent on
the phenyl ring were well tolerated, affording 3g and 3h in 68%
and 97% yield, respectively, which gave the chance for futher
functionlization through transition-metal-catalyzed coupling
Table 3. Substrate Scope of the o-Alkynylbenzonitrile a

According to the literature,10 a plausible reaction mechanism
is outlined in Scheme 2. First, the alkynylbenzonitrile 1a is
activated by copper catalyst to form the Cu(Ⅱ) complex A. Then,
2-iodo-5-methylaniline 2c reacts with the activated
alkynylbenzonitrile to produce the intermediate
B
via
nucleophilic addition reaction.11 The intermediate B undergoes an
intramolecular nucleophilic addition on the copper-activated
triple bond, giving rise to the cyclic intermediate C. Finally, the
intermediate C undergoes a KOtBu-initiated deprotonation to
generate carbanion D,12 which leads to the desired product 3c via
a nucleophilic aromatic substitution reaction.
a Reaction conditions: 1 (0.36 mmol), 2a (0.3 mmol), Cu(OAc)2 (10 mmol
%), KOtBu (0.9 mmol), DMAc (1 mL), under the N2 atmosphere in a sealed
Schlenk tube, at 120 oC for 12 h.
Spectroscopic
properties
of
benzo[4,5]imidazo[2,1-
Scheme 2. Plausible Mechanism
a]isoquinolines were further investigated by measurements of
three representative compounds 3a, 3w, and 3j. Photochemical
data shown in Table 4 revealed that, due to structure hybrid
characteristic, typical absorption of both isoquinoline and
benzimidazoles could not be found in the absorption spectra, but
they possessed absorption bands centered at about 338-375 nm.
Moreover, as depicted in Figure 1, in comparison with the
maximum emission peaked at 386 nm of isoquinoline in DCM
solution, the bathochromic-shift fluorescence appeared for these
derivatives, which would be attributed to their improved
conjugate structure.
In summary, we have demonstrated a novel copper-catalyzed
method for the synthesis of benzo[4,5]imidazo[2,1-
a]isoquinolines from o-alkynylbenzonitriles and 2-iodoanilines.
In this reaction, three different C−N bonds are sequentially
formed through the cleavage of one C-I bond and two N-H
bonds. Notably, this project can selectively synthesize a series of
isoquinoline-fused benzimidazoles, which make it appealing for
application to the synthesis of important natural products,
pharmaceuticals, and functional materials.
Acknowledgments
Table 4. Spectroscopic Properties of 6-Phenylbenzo[4,5]-
imidazo[2,1-a]isoquinolines a
This work was supported by the Natural Science Foundation of
China (21572051, 21602057), Education Department of Hunan
Province (15A109), Opening Fund of Key Laboratory of
Chemical Biology and Traditional Chinese Medicine Research
(Ministry of Education of China), Hunan Normal University
(KLCBTCMR201707, KLCBTCMR201708), Hong Kong
Scholars program (XJ2017009) for financial support.
Stokes
shift(nm)
φf b
Absmax ε×103(L·mol- Emission
Compd
(nm)
1·cm-1)
max(nm)
3a
3w
3j
308
348
375
290
309
338
237
241
6.90
6.77
6.10
6.52
8.29
8.14
6.82
7.03
431
83
74
0.584
449
455
0.778
0.578
117
References and notes
4
5
386
-
-
-
-
-
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Selective Synthesis of Benzo[4,5]imidazo[2,1-
Leave this area blank for abstract info.
a]isoquinolines
via
Copper-catalyzed
Tandem Annulation of Alkynylbenzonitriles
with 2-Iodoanilines
Xiaodong Liu, Guobo Deng* and Yun Liang*
or alte
Highlights
· Broad substrate scope.
· Simple operation and mild conditions.
· Selective synthesis of a series of benzo[4,5]imidazo[2,1-
a]isoquinoline derivatives in moderate to good yields.