One-pot synthesis of 4-substituted 1H-[1,2,3]triazolo[4,5-c]quinolines through CuO-promoted tandem cyclization reactions of (e)-3-(2-bromoaryl)-1- arylprop-2-en-1-ones with Sodium Azide

Article abstract of DOI:10.1002/ejoc.201300924

A facile and efficient protocol for the synthesis of 4-substituted-1H-[1,2, 3]triazolo[4,5-c]quinolines through a CuO-promoted tandem cyclization reaction has been developed. This method allows for the construction of two heterocyclic rings in a one-pot reaction of readily available (E)-3-(2-bromoaryl)-1-arylprop- 2-en-1-ones and sodium azide without the addition of any additive. A series of triazole-fused N-heterocyclic compounds could be prepared in moderate to good yields. Copyright

Full text of DOI:10.1002/ejoc.201300924

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Date: 22-08-13 16:39:42
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300924
One-Pot Synthesis of 4-Substituted 1H-[1,2,3]triazolo[4,5-c]quinolines Through
CuO-Promoted Tandem Cyclization Reactions of (E)-3-(2-Bromoaryl)-1-
arylprop-2-en-1-ones with Sodium Azide
Kangning Li,[a,b] Jinying Chen,[a,b] Jihui Li,[a,b] Yongxin Chen,[a,b] Jinpeng Qu,[a,b]
Xin Guo,[a,b] Chunxia Chen,[a,b] and Baohua Chen*[a,b]
Keywords: Domino reactions / Nitrogen heterocycles / Copper / Azides / Cyclization
A facile and efficient protocol for the synthesis of 4-substi-
tuted-1H-[1,2,3]triazolo[4,5-c]quinolines through a CuO-pro-
moted tandem cyclization reaction has been developed. This
method allows for the construction of two heterocyclic rings
in a one-pot reaction of readily available (E)-3-(2-bromoaryl)-
1-arylprop-2-en-1-ones and sodium azide without the ad-
dition of any additive. A series of triazole-fused N-heterocy-
clic compounds could be prepared in moderate to good
yields.
Introduction
1H-[1,2,3]Triazolo[4,5-c]quinolines (Scheme 1) contain
the skeleton of 1,2,3-triazoles and quinolines. 1,2,3-Tri-
azoles derivatives are an important class of organic com-
pounds with regard to their various biological and pharma-
cological properties.[1] Moreover, they have wide applica-
tions in biological science, materials chemistry, medicinal
chemistry, and synthetic organic chemistry.[2] Quinoline de-
rivatives are also important biologically active motifs and
are ubiquitous in both natural products[3] and active phar-
maceutical ingredients (APIs).[4] However, molecules con-
taining both the 1,2,3-triazole and quinoline frameworks
have not been synthesized thus far. Additionally, it is highly
needed to develop novel, structurally diverse molecules for
drug discovery and related fields, and herein we want to
design and synthesize novel triazole-fused N-heterocyclic
compounds by using readily available starting materials.
In the past decade, azides have been used by us and
others in a diverse array of cycloaddition and multicompo-
nent reactions for the synthesis of various N-containing
compounds.[5,6] Our group has also been endeavoring to
synthesize 1,2,3-triazole derivatives by using sodium azide
to avoid the preparation of organic azides.[7] Inspired by
previous work,[5–8] we envisioned an efficient one-pot, cop-
per-promoted tandem cyclization reaction of readily avail-
Scheme 1. Structure of a fused compound containing the 1,2,3-tri-
azole and quinoline skeletons.
able (E)-3-(2-bromoaryl)-1-arylprop-2-en-1-ones with two
molecules of sodium azide to synthesize 4-substituted-1H-
[1,2,3]triazolo[4,5-c]quinolines by the formation of two het-
erocyclic rings without the addition of any additive. In this
system, the oxidative reaction and reductive amination
could proceed simultaneously.
Results and Discussion
In an initial attempt, we selected (E)-3-(2-bromophenyl)-
1-phenylprop-2-en-1-one (1a) as a model substrate to probe
the reaction conditions (Table 1). We were pleased to find
that product 2a was obtained in 67% yield in the presence
of NaN3 (2 equiv.) and CuO (1 equiv.) in DMF at 100 °C
for 24 h (Table 1, entry 1). To improve the reaction effi-
ciency, we first examined the influence of various copper
catalysts, but only a trace amount of the desired product
was detected (Table 1, entries 2–4). Subsequently, different
solvents such as DMSO, dimethylacetamide (DMA), and
THF were investigated, but they were less efficient than
DMF (Table 1, entries 5–7). The effect of the reaction tem-
perature was also tested, and 110 °C was found to be the
most effective. Although the yield decreased at lower tem-
peratures (80 °C), no improvement was achieved upon con-
ducting the reaction at higher temperatures (130 °C)
[a] State Key Laboratory of Organic Chemistry, Lanzhou Univer-
sity,
Lanzhou, 730000, P. R. China
E-mail: chbh@lzu.edu.cn
Homepage: http://www.lzu.edu.cn/
[b] Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province,
Lanzhou, 730000, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300924.
Eur. J. Org. Chem. 0000, 0–0
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K. Li, J. Chen, J. Li, Y. Chen, J. Qu, X. Guo, C. Chen, B. Chen
SHORT COMMUNICATION
(Table 1, entries 8–10). Gratifyingly, the yield was enhanced Table 2. Substrate scope of the (E)-3-(2-haloaryl)-1-arylprop-2-en-
1-ones.[a]
to 82% if 2 equiv. of CuO was added (Table 1, entries 11
and 12). Additionally, there was no clear change in the yield
of the product if 3 equiv. of NaN3 was employed (Table 1,
entry 13). Thus, the best result was obtained by stirring a
mixture of 1a (1.0 equiv.), NaN3 (2.0 equiv.), and CuO
(2.0 equiv.) in DMF at 110 °C for 24 h.
Entry R1
R2
X
Product
Yield
[%][b]
Table 1. Optimization of the reaction conditions.[a]
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl/F
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2a
82
73
72
32
0
73
85
60
61
76
43
55
75
68
0
4-CH3C6H4
4-OCH3C6H4
4-NH2C6H4
4-OHC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
Entry
Catalyst
Equiv.
T [°C]
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuO
1
1
1
1
1
1
1
1
1
100
100
100
100
100
100
100
80
110
130
110
110
110
DMF
DMF
DMF
DMF
DMSO
DMA
THF
DMF
DMF
DMF
DMF
DMF
DMF
67
9
Cu(OAc)2
Cu(OTf)2
CuBr
CuO
CuO
CuO
CuO
CuO
CuO
CuO
trace
trace
trace
65
trace
0
59
77
76
48
10
11
12
13
14
15
16
17
18
19
4-NO2C6H4
3-NO2C6H4
4-PhC6H4
naphthyl
6-methoxynaphthyl
isopropyl/ethyl
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
C6H5
5-OCH3
4-F
4-Cl
H
74
36
77
0
9
10
11
12
13
1
0.1
2
CuO
CuO
82
[a] Conditions:
1
(0.20 mmol), NaN3 (0.40 mmol), CuO
2
80[c]
(0.40 mmol), DMF (2 mL), 24 h, 110 °C. [b] Yield of isolated prod-
uct after column chromatography.
[a] Conditions: 1a (0.20 mmol), NaN3 (0.40 mmol), solvent (2 mL),
24 h. [b] Yield of isolated product after column chromatography.
[c] With NaN3 (0.60 mmol).
To demonstrate the efficiency and generality of this reac-
tion, a wide range of (E)-3-(2-haloaryl)-1-arylprop-2-en-1-
ones were examined under the optimized reaction condi-
tions (Table 2). Generally, 1-(2-bromoaryl)enones with vari-
ous R1 and/or R2 substituents were compatible with the
reaction conditions, and the desired products were afforded
in moderate to good yields. The structure of 2c was unam-
biguously confirmed by X-ray crystallographic analysis
(Figure 1). Substrates in which R1 = NH2 or OH were not
compatible with this reaction, and these substrates afforded
the desired product in only low yield or not at all (Table 2,
entries 4 and 5). Notably, halogen substituents, especially
Br and I, were also well tolerated, and these derivatives can
undergo further coupling reactions for the synthesis of
more complex molecules (Table 2, entries 6–9, 17, 18).
Upon reaction of 1-(2-bromoaryl)enones 1 with R1 = 3-
NO2, only 43% yield of the desired product was obtained
(Table 2, entry 11). Substrates with more bulky R1 substitu-
ents were also efficiently transformed and delivered the de-
Figure 1. X-ray crystal structure of 2c.
Conclusions
In conclusion, we have successfully demonstrated a facile
sired products in satisfactory yields (Table 2, entries 12–14). and efficient protocol for the synthesis of 4-substituted-1H-
Aliphatic R1 substituents, such as isopropyl and ethyl, were [1,2,3]triazolo[4,5-c]quinolines in moderate to good yields.
not suitable for this reaction (Table 2, entry 15). Further- This protocol allowed the formation of two heterocyclic
more, the substrate in which R2 = 4-F delivered a relatively rings in a one-pot reaction through the CuO-promoted tan-
low yield of the product, probably as a result of a strong dem cyclization of readily available (E)-3-(2-bromoaryl)-1-
electron-withdrawing effect. Unfortunately, upon replacing arylprop-2-en-1-ones with sodium azide. It will be a useful
the halide X by F or Cl, the reaction failed to give the strategy for the construction of novel and valuable N-het-
desired product (Table 2, entry 19).
erocyclic compounds in organic and medicinal chemistry.
2
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One-Pot Synthesis of Triazolo[4,5-c]quinolines
C. F. Ye, G. L. Gard, R. W. Winter, R. G. Syvret, B. Twamley,
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Experimental Section
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Typical Procedure for the Preparation of 4-Substituted-1H-[1,2,3]tri-
azolo[4,5-c]quinolines 2: (E)-3-(2-bromoaryl)-1-arylprop-2-en-1-one
1 (0.20 mmol), sodium azide (0.40 mmol, 26 mg), CuO (0.40 mmol,
32 mg), and DMF (2 mL) were added to a flask with a magnetic
stirring bar. The resulting mixture was stirred at 110 °C for 24 h.
After cooling to room temperature, water (20 mL) was added to
the mixture, and the organic material was extracted with EtOAc
(3ϫ 10 mL). The combined organic phase was washed with brine
(2ϫ 5 mL), dried with anhydrous MgSO4, and concentrated
in vacuo. The residue was subjected to flash column chromatog-
raphy (petroleum ether/EtOAc, 2:1) to give product 2.
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cle): Synthesis and characterization data and copies of the 1H
NMR and 13C NMR spectra.
Acknowledgments
The authors are grateful for support of this project by the National
Science Foundation of the P. R. China (NSFC) (grant number
J1103307) and the Science Foundation of Gansu Province (grant
number 1208RJZA266).
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Received: June 24, 2013
Published Online: ᭿
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Date: 22-08-13 16:39:42
Pages: 4
K. Li, J. Chen, J. Li, Y. Chen, J. Qu, X. Guo, C. Chen, B. Chen
SHORT COMMUNICATION
Heterocyclic Chemistry
K. Li, J. Chen, J. Li, Y. Chen, J. Qu,
X. Guo, C. Chen, B. Chen* ............... 1–4
One-Pot Synthesis of 4-Substituted 1H-
[1,2,3]triazolo[4,5-c]quinolines
Through
A facile and efficient protocol for the syn-
thesis of 4-substituted-1H-[1,2,3]triazolo-
[4,5-c]quinolines through a CuO-promoted
tandem cyclization reaction is reported.
Two heterocyclic rings are constructed in a
one-pot reaction involving readily available
CuO-Promoted Tandem Cyclization Reac-
tions of (E)-3-(2-Bromoaryl)-1-arylprop-2-
en-1-ones with Sodium Azide
(E)-3-(2-bromoaryl)-1-arylprop-2-en-1-
ones and sodium azide without the need
for the addition of any additive.
Keywords: Domino reactions / Nitrogen
heterocycles / Copper / Azides / Cyclization
4
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