AlCl3-promoted three-component cascade reaction for rapid access to [1,2,3]triazolo[5,1-a]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2019.151287

Novel AlCl₃-promoted, three component cascade Henry reaction-triazole formation-intramolecular 6-endo-dig cyclization reactions between 2-alkynylaryl aldehydes, nitroalkanes, and sodium azide for the assembly of [1,2,3]triazolo[5,1-a]isoquinolines have been developed. Further transformations of representative [1,2,3]triazolo[5,1-a]isoquinolines are also described.

Full text of DOI:10.1016/j.tetlet.2019.151287

Journal Pre-proofs
AlCl3-promoted three-component cascade reaction for rapid access to [1,2,3]tri-
azolo[5,1-a]isoquinolines
Yangang Wu, Yonggang Meng, Zibo Liu, Mengge Zhang, Chuanjun Song
PII:
S0040-4039(19)31067-6
DOI:
https://doi.org/10.1016/j.tetlet.2019.151287
TETL 151287
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 August 2019
11 October 2019
15 October 2019
Please cite this article as: Wu, Y., Meng, Y., Liu, Z., Zhang, M., Song, C., AlCl3-promoted three-component cascade
reaction for rapid access to [1,2,3]triazolo[5,1-a]isoquinolines, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.151287
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AlCl3-promoted three-component cascade reaction for rapid access to [1,2,3]triazolo[5,1-
a]isoquinolines
Yangang Wu, Yonggang Meng, Zibo Liu, Mengge Zhang, and Chuanjun Song*
College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
E-mail: chjsong@zzu.edu.cn; Phone: +86 (0)371 67781788
Abstract: Novel AlCl3-promoted, three component cascade Henry reaction‒triazole
formation‒intramolecular 6-endo-dig cyclization reactions between 2-alkynylaryl aldehydes,
nitroalkanes, and sodium azide for the assembly of [1,2,3]triazolo[5,1-a]isoquinolines have been
developed. Further transformations of representative [1,2,3]triazolo[5,1-a]isoquinolines are also
described.
R3
R3CH2NO2, NaN3
N
O
AlCl3, DMSO, 105 oC
R1
N
N
R1
X
20 examples
22-97% yield
R2
R2
X
R1 = H, Me, MeO, Cl, F;
R2 = aryl, hetero aryl, alkyl, TMS;
R3 = H, alkyl;
X = CH, N
Keywords: [1,2,3]triazolo[5,1-a]isoquinoline; cascade reaction; Henry reaction; triazole; 6-endo-dig
cyclization
Introduction
The [1,2,3]triazolo[5,1-a]isoquinolines are an important class of heterocyclic compounds
possessing a wide spectrum of biological activities1 and are also important building blocks in organic
synthesis.2 Like many other fused polyheterocyclic molecules, their assembly from simple starting
materials in a rapid and efficient manner remains a challenge.3-9 The traditional syntheses involve
hydrazone formation via the condensation of 2-acylpyridines with hydrazine, followed by oxidative
cyclization.3 Overall, this process requires harsh conditions and the desired products are usually
obtained in low yields. In recent years, a number of alternative approaches have been developed, based
on cascade reactions. For example, the cyclization of 1,2-diacetylenic benzenes with NaN3 (Scheme 1a)
gives the corresponding [1,2,3]triazolo[5,1-a]isoquinolines, but with low regioselectivity for substrates
bearing two different alkyne substituents (R1 ≠ R2).4 Alternatively, the target compounds could be
obtained via the transition-metal catalyzed annulation of acetylenes with (2-halo)phenyl-1,2,3-
triazoles5 (Scheme 1b) or 2-azido-3-(2-iodophenyl)acrylates6 (Scheme 1c). However, multiple steps
were needed to access the required substrates. In 2013, Kundu and co-workers reported a [3 + 2]
cycloaddition/6-endo cyclization sequence of (E)-1-(2-nitrovinyl)-2-(alkynyl)benzene species for the
synthesis of [1,2,3]triazolo[5,1-a]isoquinolines.7 Unfortunately, the requirement for the isolation of the
former was troublesome and the reactions could not be used to form 1-substituted products. In recent
years, we have become interested in the development of strategies toward the synthesis of biologically
active nitrogen-containing heterocyclic compounds.10 Herein, we report
a novel one-pot
AlCl3‒catalyzed, three-component Henry reaction‒triazole formation‒intramolecular 6-endo-dig
cyclization cascade for the rapid access to such [1,2,3]triazolo[5,1-a]isoquinolines.
1 / 8

R1
R1
R1
N
N
N
R2
NaN3
(a)
N
N
H
N
[M]
(b)
X
R2
R2
X = H, Halogen
CO2Et
N
CO2Et
R
N
(c)
N3
CuCl2, K2CO3
I
N
R
Scheme 1. Recent approaches for the synthesis of [1,2,3]triazolo[5,1-a]isoquinolines.
Results and Discussion
Our investigation started with the model reaction of 2-(phenylethynyl)benzaldehyde 1a,
nitromethane, and sodium azide. Initially, the reaction was carried out in the presence of 10 mol% of a
o
Lewis acid in DMF at 100 C, which resulted in the formation of a mixture of [1,2,3]triazolo[5,1-
a]isoquinoline 2a and isoquinoline 2aʹ (Table 1, entries 1‒5). Among those investigated, Sc(CF3SO3)3
and AlCl3 were superior to other Lewis acids tested to promote the formation of 2a. AlCl3 was selected
1
for further optimization since it is cheaper and gave higher 2a/2aʹ ratios as determined by H NMR
integration of the crude reaction mixtures. Our studies indicated that the amount of AlCl3 applied was
crucial to the products formed. To a certain extent, the formation of 2a was favored with higher catalyst
loading (Entries 5‒9). An 18:1 ratio of 2a:2aʹ was observed in the presence of 60 mol% AlCl3, in
which case 2a could be isolated in 85% yield (Entry 9). However, triazole 2aʺ predominated if the
amount of AlCl3 was further increased (Entries 10, 11). Next, the solvents and reaction temperatures
were screened. While the desired product 2a was isolated in 90% yield in DMSO (Entry 12), no
reaction occurred in other solvents including toluene, 1,4-dioxane and ethylene glycol (Entries 13‒15).
o
With DMSO as solvent, the yield of 2a could be improved to 97% at 105 C (Entry 17). However,
further raising (Entry 18) or lowering (Entry 16) the reaction temperature provided 2a in reduced yield.
Table 1. Optimization of reaction conditions for the synthesis of [1,2,3]triazolo[5,1-a]isoquinoline 2a.
N
N
N
CH3NO2 (3.0 equiv.)
NaN3 (2.5 equiv.)
O
N
N
N
N
H
+
+
Ph
Lewis acid
Ph
Ph
Ph
1a
Entry
2a
2a''
2aʹʹ
2a'
Lewis acid
(equiv.)
FeCl3 (0.1)
Temp
(oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
2a
2aʹ
Solvent
(% yield)
87a
90a
83a
87a
91a,b
87a
92a,c
94a,d
95a,e
42a
3a
(% yield)
13a
10a
17a
13a
9a
(% yield)
1
2
3
4
5
6
7
8
9
10
11
12
13h
14h
15h
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
0a
0a
Sc(CF3SO3)3 (0.1)
ZnCl2 (0.1)
Cu(OAc)2 (0.1)
AlCl3 (0.1)
AlCl3 (0.05)
AlCl3 (0.2)
AlCl3 (0.5)
AlCl3 (0.6)
AlCl3 (0.8)
AlCl3 (1.0)
AlCl3 (0.6)
AlCl3 (0.6)
AlCl3 (0.6)
AlCl3 (0.6)
0a
0a
0a
13a
8a
0a
0a
6a
0a
5a
0a
DMF
DMF
5a
53a
6a
91a
g
g
DMSO
toluene
1,4-dioxane
ethylene glycol
90f
0
0
0
-
-
0
0
0
0
0
0
2 / 8

g
g
g
g
g
g
16
17
18
AlCl3 (0.6)
AlCl3 (0.6)
AlCl3 (0.6)
DMSO
DMSO
DMSO
90
105
110
87f
97f
86f
-
-
-
-
-
-
a Yield determined based on 1H NMR integration of the crude reaction mixture; b 64% isolated yield of
2a; c 67% isolated yield of 2a; d 76% isolated yield of 2a; e 85% isolated yield of 2a; f isolated yield; g
not determined; h No reaction, 1a was recovered.
With the optimized reaction conditions in hand, we embarked on examining the scope of this
AlCl3-promoted three-component synthesis of various [1,2,3]triazolo[5,1-a]isoquinolines and
analogues. As shown in Table 2, [1,2,3]triazolo[5,1-a]isoquinolines 2b‒g with different substituents
(R1) on the phenyl ring could be obtained. In general, 2b‒e with electron-donating groups were isolated
in higher yields than 2f, g with electron-withdrawing groups. Under the reaction conditions, 2h with an
electron-deficient pyridine, as well as 2i with a more π-electron delocalized naphthalene in place of the
phenyl ring, could also be synthesized, albeit in moderate isolated yields. Replacing R2 on the alkyne
with a substituted phenyl ring, heterocycle, or alkyl group afforded 2j‒q as expected. The yields were
generally good to excellent except in the cases of 2l and 2m with a tethered heterocyclic ring.
Concomitant desilylation occurred during the reaction of 1r (R2 = TMS), which resulted in the
formation of 2r in 66% isolated yield. Finally, the developed method could also be applied to the
synthesis of 1-substituted [1,2,3]triazolo[5,1-a]isoquinolines 2s‒u and bis-[1,2,3]triazolo[5,1-
a]isoquinoline 2v.
Table 2. Substrate scope.
3 / 8

R3
N
N
O
R3CH2NO2 (3.0 equiv.)
NaN3 (2.5 equiv.)
R1
N
R1
X
X
R2
R2
AlCl3 (0.6 equiv.)
DMSO, 105 oC
1a v
-
2a v
-
N
N
N
N
N
N
N
N
N
N
N
N
MeO
2b
2a
, 72%
N
2d
2h
, 97%
2c
, 86%
, 90%
N
N
N
N
N
N
N
N
MeO
F
F
N
N
N
Cl
N
2e
2f
2g
, 83%
, 71%
, 42%
, 32%
N
N
N
N
N
N
N
N
N
N
N
N
S
Cl
2j
2k
2l
2i
, 80%
N
N
N
, 85%
N
N
N
, 45%
, 53%
N
N
N
N
N
N
N
OH
(CH2)5CH3
2m
2n
2o
2p
, 60%
, 22%
N
N
N
, 65%
, 72%
C2H5
N
N
N
N
N
N
N
N
N
HO
2r
2q
, 66%
2t
, 35%
, 91%
2s
, 40%
OMe
N
N
N
N
N
N
N
N
N
MeO
a
2v
2u
, 30%
, 95%
a DMF as solvent.
To determine the reaction mechanism, we carried out some control experiments (Scheme 2). First,
no reaction occurred in the absence of nitromethane, indicating that 2aʹ was not formed from the direct
reaction of 1a with sodium azide. Second, no trace of 2aʹ was detected when the isolated 2a was re-
subjected to the standard reaction conditions.
4 / 8

NaN3 (2.5 equiv.)
AlCl3 (0.6 equiv.)
O
no reaction
(1)
(2)
DMSO, 105 oC, 6 h
Ph
1a
2a
N
N
AlCl3 (0.6 equiv.)
N
N
DMSO, 105 oC, 10 h
Ph
Ph
2a'
Scheme 2. Control experiments.
Based on the results of these experiments and literature reports,11 a plausible mechanism is
depicted in Scheme 3. The coordination of 2-(phenylethynyl)benzaldehyde and nitromethane to
aluminium A could trigger a Henry reaction to provide 1-(2-nitrovinyl)-2-(alkynyl)benzene C.
Subsequent attack of intermediate C by azide would then provide intermediate D, the cyclization of
which gives intermediate E (path a). Proton transfer of E gives F, which undergoes aromatization upon
releasing
a molecule of nitrous acid and re-generating the aluminium catalyst to give
(phenylethynyl)phenyltriazole 2aʺ. The 6-endo-dig cyclization of 2aʺ then gives [1,2,3]triazolo[5,1-
a]isoquinoline 2a. On the other hand, nucleophilic attack of D with water gives G (path b). The Nef
reaction of G gives aldehyde H, which can then be oxidized to acid I under the reaction conditions.
Finally, the decarboxylation of I gives J, which leads to the formation of 2aʹ via denitrogenative ring
closure.
H
N
N
AlX3
N
AlX3
N
O
O
H+
N
N
HO
O
N
N
H
N
N
N
N
N
N
Ph
Ph
H+
2a''
2a
Ph
Ph
E
F
path a
H2O
X
X
N
N
X2Al
Al
N
AlX3
O
O
O
N
O
O
N
N
N
O
N
N
b
a
O
O
O
N
AlX3
H
O
Ph
Ph
Ph
Ph
B
C
A
D
path b
H
O
O
O
O
H
N
X3Al
Nef
N
O
OH2
N
N
N
N
N
N
N
N
N
N
air
N
N
Ph
H+
Ph
Ph
Ph
Ph
2a'
J
I
H
G
Scheme 3. Proposed mechanism.
Having established this new method for the synthesis of [1,2,3]triazolo[5,1-a]isoquinolines, we
then explored the feasibility of transforming these fused heterocycles into other useful molecules. Thus,
treatment of 2a, 2h, 2l, 2m and 2p with AcOH at reflux5b gave the corresponding denitrogenative ring-
opened products 3‒7, respectively, in good to excellent isolated yields (Scheme 4). Compounds
containing such structural motifs are ideal metal ligands.12 Some of them have also shown important
5 / 8

biological activities.13 However, the reported methods for their synthesis are tedious. Our approach
represents a novel and facile strategy towards these valuable molecules. As shown in Scheme 5,
hydrolysis of 3 provided alcohol 8, Parikh-Doering oxidation of which gave aldehyde 9 in excellent
combined yield over the two steps. Following a modified literature procedure,14 compound 9 could be
converted into pyrrolo[2,1-a]isoquinoline derivative 10 in 65% isolated yield upon treatment with
malononitrile in the presence of Hantzsch ester. On the other hand, Baylis-Hillman reaction between 9
and 2-cyclohexenone promoted by DMAP yielded 11, which could be transformed into
dihydroindolo[2,1-a]isoquinolinone 12 in good isolated yield upon treatment with acetic anhydride.
OAc
N
N
AcOH, reflux
N
N
R
X
R
X
2a
2h
3
4
5
6
7
, X = CH, R = Ph
, X = N, R = Ph
, 91%
, 95%
, 93%
, 92%
, 62%
2l
, X = CH, R = 2-thiophenyl
2m
2p
, X = CH, R = 2-pyridinyl
, X = CH, R = CH2OH
Scheme 4. Denitrogenative ring-opening for the synthesis of 3‒7.
OH
N
OAc
N
Py.SO3, Et3N, DMSO
r.t., 10 h, 75%
K2CO3, MeOH
r.t., 0.5 h, 92%
3
8
CN
CHO
EtO2C
CO2Et
NH2
N
CN
+
N
N
H
CN
PhMe, reflux
4 h, 65%
9
10
O
DMAP, THF/H2O
r.t., 80 h, 71%
O
O
HO
Ac2O
100 oC, 1 h, 75%
N
N
11
12
Scheme 5. Synthesis of pyrrolo[2,1-a]isoquinoline 10 and dihydroindolo[2,1-a]isoquinolinone 12.
Conclusion
In summary, we have developed a novel AlCl3-promoted, three-component cascade consisting of
a sequential Henry reaction‒triazole formation‒intramolecular 6-endo-dig cyclization combination for
the rapid, single-pot access to diversely substituted [1,2,3]triazolo[5,1-a]isoquinolines from simple and
readily available precursors. Cleavage of the triazole ring by loss of nitrogen gave the highly valuable
6 / 8

but difficult to prepare ring-opened products 3‒7. Compounds 3 could be further transformed into
pyrrolo[2,1-a]isoquinoline derivative 10 and dihydroindolo[2,1-a]isoquinolinone 12. Studies on the
biological properties of these molecules are underway in our laboratory.
Acknowledgement
We are grateful to NSFC-Henan (U1804283) for financial support.
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Declaration of interests
The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in
this paper.
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[1,2,3]triazolo[5,1-a]isoquinolines have been synthesized;
A three-component cascade reaction has been developed;
[1,2,3]triazolo[5,1-a]isoquinolines have been converted to other molecules.
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