An integration of condensation/Ullmann-type coupling/bicyclization sequences: Copper-catalyzed three-component direct synthesis of [1,2,4]triazolo[1,5-b]isoquinolin-5(1H)-ones

Article abstract of DOI:10.1039/c4cc03420a

A highly efficient three-component domino protocol has been developed for the synthesis of [1,2,4]triazolo[1,5-b]isoquinolin-5(1H)-ones from simple and readily available o-halogenated benzohydrazides, aldehydes and nitriles. This domino process involves sequential selective condensation, copper-catalyzed intermolecular C-arylation and bicyclization. Notably, the use of ligands and anaerobic conditions can be avoided in this reaction.

Full text of DOI:10.1039/c4cc03420a

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An integration of condensation/Ullmann-type
coupling/bicyclization sequences: copper-
catalyzed three-component direct synthesis of
[1,2,4]triazolo[1,5-b]isoquinolin-5(1H)-ones†
Cite this: Chem. Commun., 2014,
50, 9914
Received 7th May 2014,
Accepted 23rd June 2014
Feng-Cheng Jia, Cheng Xu, Qun Cai and An-Xin Wu*
DOI: 10.1039/c4cc03420a
www.rsc.org/chemcomm
A highly efficient three-component domino protocol has been
developed for the synthesis of [1,2,4]triazolo[1,5-b]isoquinolin-5(1H)-
ones from simple and readily available o-halogenated benzohydrazides,
aldehydes and nitriles. This domino process involves sequential
selective condensation, copper-catalyzed intermolecular C-arylation
and bicyclization. Notably, the use of ligands and anaerobic conditions
can be avoided in this reaction.
Up to now, the major goal of synthetic chemists has been to design
an elegant and efficient synthetic route for the construction of
desired products from simple molecules.1 So maximizing efficiency
and minimizing steps in the synthesis of target molecules is where
synthetic chemists concentrate their efforts in the integration of
some organic unit reactions by a domino or self-sequence strategy.2
Recently, great progress has been achieved in Ullmann-type coupling
reactions.3 Notably, many types of fused N-heterocycles have
also been constructed via elegant domino processes driven by
copper-catalyzed cross-coupling, as reported by Fu’s group4 and
others.5 These routes, however, implied a multistep process since
the starting materials were not readily available and needed to be
prefabricated (Scheme 1a). Herein, we report a direct and efficient
synthesis of novel fused N-heterocycles via an integration of
condensation/Ullmann-type coupling/bicyclization sequences
from simple and readily available o-halogenated benzohydrazides,
aldehydes and nitriles (Scheme 1b).
Isoquinolinones and 1,2,4-triazolo[1,5-a]pyridines are two
important subclasses of N-heterocycles. Many compounds containing
isoquinolinone6 or 1,2,4-triazolo[1,5-a]pyridine7 motifs exhibit
various biological and medicinal activities. It is assumed that the
hybrid structure containing both isoquinolinone and 1,2,4-triazolo-
[1,5-a]pyridine motifs may feature promising bioactivity for screening.
To the best of our knowledge, there is no report on direct
construction of this novel skeleton via a domino strategy from
Scheme 1 Synthesis of fused N-heterocycles via a copper-catalyzed
domino strategy involving nitriles.
simple materials in one-pot. We herein envision a concise three-
component domino strategy to synthesize [1,2,4]triazolo[1,5-b]isoqui-
nolin-5(1H)-ones through a rational design using o-halogenated
benzohydrazides as the initial building blocks. In our hypoth-
esis, o-halogenated benzohydrazides could react preferentially
with aldehydes over nitriles to afford o-halogenated benzoyl
hydrazones I, and then skeleton I might serve as a novel coupling
partner trapped by nitriles to provide the key intermediate II.
Intermediate II would undergo a facile cyclization to generate
intermediate III. The desirable target molecules would be
obtained after another cyclization (Scheme 2).
To test the above hypothesis, our investigation was initiated
with 2-bromobenzohydrazide (1a), benzaldehyde (2a) and methyl
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Wuhan 430079,
P. R. China. E-mail: chwuax@mail.ccnu.edu.cn
Scheme 2 Rational design for synthesis of [1,2,4]triazolo[1,5-b]isoquino-
lin-5(1H)-ones via a domino strategy.
† Electronic supplementary information (ESI) available. CCDC 972885 (4ga). For ESI and
crystallographic data in CIF or other electronic format. See DOI: 10.1039/c4cc03420a
9914 | Chem. Commun., 2014, 50, 9914--9916
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Table 1 Optimization of the reaction conditionsa,b
Table 2 Scope of aldehydes, 2-halobenzohydrazides and nitrilesa,b
Entry Catalyst
Base
Sovlent
Temp. (8C) Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
K2CO3
Cs2CO3
NaHCO3 DMSO
KOH
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
100
100
100
100
100
100
100
100
100
100
100
100
100
84
83
80
76
74
86
86
91
62
68
67
80
88
Trace
48
88
90
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Toluene 100
Dioxane 100
DMSO
DMSO
CuI
CuCl
CuBr
Cu2O
CuCl2
CuBr2
9
10
11
12
13
14
15
16
17
Cu(OAc)2ÁH2O K2CO3
Cu(OTf)2
Cu2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cu2O
Cu2O
Cu2O
Cu2O
80
110
a
Reactions conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
catalyst (10%) and base (0.75 mmol) were heated in 4 mL solvent in a
b
sealed vessel under air for 10 h. Isolated yields.
2-cyanoacetate (3a) as the model substrates for the optimization of
the reaction conditions (Table 1). Various catalysts, bases, tempera-
tures and solvents were examined, and all cases are shown in Table 1.
To our delight, the reaction of 2-bromobenzohydrazide (1a) with
benzaldehyde (2a) and methyl 2-cyanoacetate (3a) proceeded
smoothly with 84% yield in the presence of CuI (0.1 equiv.) and
K2CO3 (1.5 equiv.) at 100 1C in DMSO in a sealed vessel under air for
10 hours (Table 1, entry 1). Then, a series of bases was screened for
this reaction, such as Cs2CO3, NaHCO3, KOH, and K3PO4 (Table 1,
entries 2–5), and the desired product 4aa was also obtained in a good
yield (74–83%). Next, various copper salts were screened against
the reaction (Table 1, entries 6–12), and Cu2O showed the
highest activity (entry 8). Moreover, several solvents were tested
(Table 1, entries 13–15), and DMSO was proved to be the most
effective solvent (compare entries 8 and 13–15). Increasing or
decreasing the temperature of the reaction did not lead to any
further improvements in the yield (Table 1, entries 16 and 17).
Under the optimal conditions, the scope of aldehydes was
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol) Cu2O
(0.05 mmol) and K2CO3 (0.75 mmol) in DMSO (4 mL) at 100 1C in a
sealed vessel under air for 6–10 h; 1a–1g (2-bromobenzohydrazides).
b
c
Isolated yields. Reaction conditions: 1a (0.5 mmol) and 2p
(0.5 mmol) were heated in DMSO (4 mL) at 100 1C in a sealed vessel
under air for 1 h and then 3a (0.5 mmol), Cu2O (0.05 mmol) and K2CO3
(0.75 mmol) were added and the resulting mixture was stirred for
another 6 h.
investigated. As shown in Table 2, the reaction demonstrated good could transform into the desired product 4ap in 63% yield
compatibility with various aldehydes. Reactions with aromatic alde- when a one-pot two-step procedure was adopted.
hydes containing electron-neutral (H) and electron-donating (2-Me,
To further expand the scope of the substrates, a variety of
4-Me, 4-OEt, 4-OMe, and 4-(N-Me)2) groups proceeded smoothly to 2-halobenzohydrazides and nitriles were examined. Gratifyingly, the
afford the corresponding products in good to excellent yields attachment of an electron-donating or electron-withdrawing group to
(Table 2, 4aa–4af, 70–91%). Halo-substituted aldehydes also gave the phenyl group of 1 was well tolerated, with the corresponding
target products 4ag–4ai in 45% to 87% yields. To our delight, products being obtained in good yields (Table 2, 4ba–4fa, 76–88%).
other representative aromatic aldehydes such as 1-naphthaldehyde, Moreover, ethyl 2-cyanoacetate (3b) and malononitrile (3c)
2-naphthaldehyde and thiophene-2-carbaldehyde were also found could also be successfully applied to the transformation to
to be suitable for this transformation and the desired products generate target products in 86% and 87% yields, respectively
were obtained in satisfactory yields (Table 2, 4aj–4al, 76–85%). (Table 2, 4ga and 4ha). In addition, 2-chlorobenzohydrazide
Alkyl and conjugated aldehydes, including propaldehyde (2m), (1g) and 2-iodobenzohydrazide (1h) also exhibit good reactivity
isovaleraldehyde (2n) and cinnamaldehyde (2o), also performed under the optimized conditions (Table 2, 4ia and 4ja, 84% and
well to give the corresponding products in good yields (Table 2, 90%). Furthermore, the structure of 4ga was unambiguously
4am–4ao, 54–82%). In addition, sensitive 4-hydroxybenzaldehyde determined by X-ray crystallographic analysis (see ESI†).
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B leads to C, and transfer of the double bond in C affords D. Next,
another nucleophilic attack of nitrogen to imine afforded E (inter-
mediate E was detected by MS, see the ESI†). Finally, the target
product 4aa was obtained after final oxidative dehydrogenation.
In conclusion, we have developed a highly efficient three-
component domino protocol for the synthesis of [1,2,4]triazolo[1,5-b]-
isoquinolin-5(1H)-ones using readily available o-halogenated
benzohydrazides, aldehydes and nitriles as basic building blocks.
This domino process involves sequential selective condensation,
copper-catalyzed intermolecular C-arylation, intramolecular addi-
tion of NH with CN, nucleophilic attack of amino to imine and
final oxidative dehydrogenation. It is notable that the reaction
performs well with varying functional group tolerance in the
absence of a ligand under air. Due to the above mentioned
characteristics of this reaction, it should be of great utility for
concise construction of complex and diverse fused N-heterocycles
for organic chemistry and medicinal chemistry. Further studies on
the applications of this strategy will be reported in due course.
We are grateful for financial support from the National Natural
Science Foundation of China (Grant 21032001, 21272085).
Scheme 3 Control experiments.
To gain some insight into the mechanism of the domino process,
several control experiments were performed as shown in Scheme 3.
A one-pot two-step strategy was initially adopted in which 2-bromo-
benzohydrazide (1a) and benzaldehyde (2a) were heated in DMSO at
100 1C until disappearance of reactants (monitored by TLC), then
methyl 2-cyanoacetate (3a), Cu2O and K2CO3 were added and the
resulting mixture was stirred for another 6 h to give the target
product in 93% yield (Scheme 3(a)). This clearly demonstrated that
hydrazone A may be a key intermediate in this transformation.
When reaction of 2-bromobenzohydrazide (1a) and methyl 2-cyano-
acetate (3a) was investigated under standard conditions, the reaction
turned out to be a complex one with none of the desired coupling
products being observed (Scheme 3(b)). Furthermore, a competi-
tion experiment was also conducted to clarify the reactivity of
2-bromobenzohydrazide (1a) and methyl 2-cyanoacetate (3a) towards
benzaldehyde (2a), where benzohydrazide was reacted with methyl
2-cyanoacetate (3a) and benzaldehyde (2a) under standard condi-
tions. To our surprise, 2,5-diphenyl-1,3,4-oxadiazole was obtained in
82% yield (Scheme 3(c)).8 The results of these two control experi-
ments indicate that the reaction was initiated by the condensation of
aldehydes and o-halogenated benzohydrazides, rather than the
cross-coupling between o-halogenated benzohydrazides and nitriles.
On the basis of the above results, a possible mechanism of the
present reaction was proposed using 2-bromobenzohydrazide (1a),
benzaldehyde (2a) and methyl 2-cyanoacetate (3a) as an example
(Scheme 4). Initially, substrate 2-bromobenzohydrazide (1a) prefer-
entially condensed with benzaldehyde (2a) to afford intermediate
hydrazone A. Subsequently, copper-catalyzed Ullmann-type coupling
of hydrazone A and methyl 2-cyanoacetate (3a) would proceed easily
to give B in the presence of a base (K2CO3) in the light of the ortho-
substituent effect,4a,d then intramolecular addition of NH with CN in
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Scheme 4 Possible mechanism.
9916 | Chem. Commun., 2014, 50, 9914--9916
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