Synthesis of [1,2,3]Triazolo[5,1- a]isoquinoline Derivatives via a Selective Cascade Cyclization Sequence of 1,2-bis(Phenylethynyl)benzene Derivatives

Article abstract of DOI:10.1080/00397911.2015.1020952

(Graphical Presented). A direct, concise, synthetic method for the generation of [1,2,3]triazolo[5,1-a]isoquinoline derivatives, using a selective cascade cyclization of unsymmetrical substituted 1,2-bis(phenylethynyl)benzene derivatives with NaN₃, has been developed. The reaction gave different substituted [1,2,3]triazolo[5,1-a]isoquinolines in moderate to good yields. It was found that the substituents on the alkynes were important for the selectivities of the cascade cyclization sequences.

Full text of DOI:10.1080/00397911.2015.1020952

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Synthesis of [1,2,3]Triazolo[5,1-a]isoquinoline
Derivatives via a Selective Cascade Cyclization
Sequence of 1,2-bis(Phenylethynyl)benzene
Derivatives
Shipeng Taoa, Qinquan Hua, Huan Lia, Shan Maa & Yunfeng Chena
a School of Chemical and Environmental Engineering, Wuhan Institute of Technology, Wuhan,
P. R. China
Accepted author version posted online: 25 Feb 2015.
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To cite this article: Shipeng Tao, Qinquan Hu, Huan Li, Shan Ma & Yunfeng Chen (2015): Synthesis of [1,2,3]Triazolo[5,1-
a]isoquinoline Derivatives via a Selective Cascade Cyclization Sequence of 1,2-bis(Phenylethynyl)benzene Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2015.1020952
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Synthesis of [1,2,3]triazolo[5,1-a]isoquinoline derivatives via a selective cascade
cyclization sequence of 1,2-bis(phenylethynyl)benzene derivatives
Shipeng Tao1, Qinquan Hu1, Huan Li1, Shan Ma1, Yunfeng Chen1
1School of Chemical and Environmental Engineering, Wuhan Institute of Technology,
Wuhan, P. R. China
Address correspondence to Yunfeng Chen, E-mail: chyfch@hotmail.com
Abstract
A
direct,
concise,
synthetic
method
for
the
generation
of
[1,2,3]triazolo[5,1-a]isoquinoline derivatives, using a selective cascade cyclization of
unsymmetrical substituted 1,2-bis(phenylethynyl)benzene derivatives with NaN3, has
been
developed.
The
reaction
gave
different
substituted
[1,2,3]triazolo[5,1-a]isoquinolines in moderate to good yields. It was found that the
substituents on the alkynes were important for the selectivities of the cascade cyclization
sequences.
KEYWORDS: [1,2,3]triazolo[5,1-a]isoquinoline, 1,2,3-triazole, cascade reaction,
cyclization
1

INTRODUCTION
With the development of copper-catalyzed azide-alkyne “click” reaction, 1,2,3-triazoles
became useful building blocks in medicinal, material, transition metal chemistry and
others.[1-4] It was found that some compounds containing the 1,2,3-triazole ring system
have shown a broad spectrum of biological activities including antifungal, antiviral,
anti-allergic, anti-HIV, and antimicrobial activities.[5-8] By contrast with numbers of
substituted 1,2,3-traizole compounds, 1,2,3-triazole-annulated polyheterocycles were
scare. Even so, some of them have shown potential applications in various fields.[9-13]
Recently, many approaches have been developed to synthesize 1,2,3-triazole- fused
N-heterocycle.[14-18] However, most of the methods are mainly based on intramolecular
azide-alkyne cycloaddition reactions (Scheme 1a).[19-24] In these methods, many efforts
and steps need be done on the synthesis of precursors with azide and alkyne moieties in
one molecule. There is a potential intermolecular 1,3-dipolar cyclization for these
substrates, which will induce the formation of oligmers or polymers.
[1,2,3]triazolo[5,1-a]isoquinoline is a new kinds of 1,2,3-triazole fused heterocycle.[25-26]
Previously, we have already developed a NH-1,2,3-triazoles post-annulation strategy for
the synthesis of 5-NH2-[1,2,3]triazolo[5,1-a]isoquinolines with high effectiveness.[27]
Another direct method to construct [1,2,3]triazolo[5,1-a]isoquinoline core structure is
intermolecular cascade cyclization of enediynes with NaN3. Recently, Gulevskaya group
reinvestigated the cyclization reactions of enediynes with NaN3.[28] They found
2

(Z)-hexa-3-en-1,5-diynes gave corresponding [1,2,3]triazolo[1,5-a]pyridines and other
fused heterocycles rather than 1-aryl-1H-benzotriazoles (Scheme 1b). [29] However, these
reactions need high reaction temperature and long reaction time, the yields and
selectivities were not very high. Inspired by this, we introduced a carbonyl group to
1,5-diynes which could activate the alkyne towards “N3” attack, which maybe lower the
reaction temperature and improve the selectivity of cyclization (Scheme 1c), Herein, we
report a selective cascade cyclization reaction of 1,2-diethynylbenzene derivatives with
NaN3 for the synthesis of [1,2,3]triazolo[5,1-a]isoquinoline compounds.
RESULT AND DISCUSSION
There were two reaction sequences for the cascade cyclization reactions of unsymmetric
1,2- bis(phenylethynyl)benzene derivatives and NaN3. According to the calculated
results,[28] the rate-determining step of cascade cyclization of enediynes with NaN3 was
the [3+2] cyclization reaction, so the reaction sequence could be adjusted by the
reactivity of the alkyne towards NaN3. In general, the cyclization reactions of more
electron-deficient alkynes with NaN3 were easier than electron-rich alkynes.[30] Firstly,
we tested the 1,2-bis(phenylethynyl)benzene derivative 2 in which one p-OMe phenyl
group was installed on one of the alkyne moiety. When it reacted with NaN3 (Scheme 2a),
the obtained products were mixtures, which cannot be separated by simple silica column
chromatography. The 1H NMR spectrum of products showed the ratio of two isomers was
about 3:5 (see supporting information). Interestingly, we have also obtained the crystal
3

structures of the products, which showed the cocrystallization of two isomers (3 and 4,
1:1) (Figure 1a). We proposed that the substituent effect was not obvious under high
reaction temperature, and attempts to reduce the reaction temperature (140 ℃) gave the
same ratio of the isomers and lower conversion.
Then we investigated the cyclization reactions of other different kind of substituted
unsymmetrical 1,2-bis(phenylethynyl)benzene derivatives with NaN3. It's gratifying that
the enediyne 5 reacting with NaN3 gave the 6 as the major product (Scheme 2b) and the
yield was up to 64%. The structure was also characterized by
single-crystal X-ray diffraction (Figure 1b), in this case, the first cyclization step
happened in the two aromatic substituted alkyne, then N-attack cyclization happened in
another alkyne moiety. And we also checked other alkyl substituted diynes (Scheme 3),
intermediates 7 and 8 could give the major products 9 and 10 in 60% and 57% yields (for
two steps). Interestingly, the diyne 11 gave the product 13 in which the 2-hydroxypropyl
group was cleaved, while intermediate diyne 12 in which 2-hydroxypropyl protecting
group was first removed by potassium hydroxide gave other mixtures under the same
condition, so the 2-hydroxypropyl group should be cleaved after the cascade cyclization.
Although the cyclization reaction of aromatic and alkyl substituted
1,2-bis(phenylethynyl)benzene derivatives with NaN3 gave corresponding products via
selective cyclization, it was regretful that these reactions also need high temperature and
4

long reaction time, and much excess NaN3 were needed to improve the conversion,
furthermore, the yields were not very high.
The electron-withdrawing group substituted alkynes were more active towards Nu attack
under mild conditions, such as the carbonyl group activated alkynes could be easy
attacked by “N3” to form 1,2,3-triazoles.[31-35] Inspired by this, the carbonyl groups
substituted 1,2-diethynylbenzene derivatives were synthesized by the Sonogashira
reactions of the acyl chloride with terminal alkynes.[36,37] Satisfactorily, their cascade
cyclization reactions with NaN3 could be conducted at 60 ℃, and different substituens all
gave the products in high total yields (two steps). The results were shown in Table 1, and
the product 15a was identified by X-ray crystal structure analysis (Figure 2).
2-hydroxypropyl substituted alkynes gave the deprotected products (15e and 15f) under
this condition. It was revealed that the cascade cyclization sequences were conducted by
the designed method, the first cycloaddition happened in the carbonyl activated alkyne,
which was the rate-determining step, and then 6-endo-dig cyclization step happened
quickly, overall, the cascade reaction showed high selectivity.
In conclusion, we developed a method for the synthesis of the
[1,2,3]triazolo[5,1-a]isoquinoline derivatives by the treatment of the substituted
1,2-diethynylbenzene derivatives with NaN3 in DMSO. It was found that the
regioselectivities of the reactions were decided by two substituents in the alkynes of
5

1,2-diethynylbenzenes. For the acyl-substituted 1,2-diethynylbenzenes, the cascade
cyclizations with NaN3 could happen under mild conditions and give the corresponding
products in high yields. Further investigation for the application of this strategy in the
synthesis of other N-heterocycle and the properties of the [1,2,3]triazolo[5,1-a]
isoquinoline derivatives are underway.
EXPERIMENTAL
General Methods and materials: All of the reactions were carried out in 25 mL
round-bottom flasks with air condensers. Unless otherwise noted, all commercial reagents
and solvents were obtained from the commercial provider and used without further
purification. 1H NMR and 13C NMR spectra were recorded on Varian 600 MHz and 400
MHz spectrometers. Chemical shifts were reported relative to internal tetramethylsilane
(TMS) (0.00 ppm) or CDCl3 (7.26 ppm) for 1H, CDCl3 (77.0 ppm) for 13C and d6-DMSO
(2.5 ppm) for 1H, (39.5 ppm) for 13C. Flash column chromatography was performed on
200-300 mesh silica gel. Analytical thin layer chromatography was performed with
precoated glass baked plates (250 μ) and visualized by fluorescence. MS were measured
on a Bruker Apex IV FTMS spectrometer. Melting points were measured on a melting
point tester RY-1G apparatus and uncorrected. All the products had passed the infrared
detector.
6

Typical Procedure For Preparation Of [1,2,3]Triazolo[5,1-A]Isoquinoline
Derivatives (15a-F)
1-ethynyl-2-(phenylethynyl)benzene (202 mg, 1 mmol), PdCl2(PPh3)2 (35 mg, 0.05
mmol), CuI (19 mg, 0.1 mmol) were added to a pear-shaped Schlenk tube charged with a
magnetic stirrer. The tube was evacuated and backfilled with argon and then degassed
Et3N and THF (6 mL, V/V, 1:1) was introduced, then the 2-chlorobenzoyl chloride (262
mg, 1.5 mmol) was introduced. The mixtures were heating at 60℃ for 2 hours. Then the
reaction mixture cooled to room temperature, next filtrated with short flash column
chromatography (silica gel), and eluted with EtOAc. The combined solution was removed
the solvent under reduced pressure to give an oil, which redissolved in DMSO (5 mL)
without further purification, and then NaN3 (98 mg, 1.5 mmol) was added. The mixture
was heated at 60 ℃. The reaction was monitored by TLC. After the completion of the
reaction, the mixture was poured into water and extracted with EtOAc. The organic layer
was washed with brine and dried with anhydrous Na2SO4. Concentration under reduced
pressure and purification of the residue by flash chromatography on silica gel gave 15a as
white solid (82% yield for two steps).
(2-chlorophenyl)(5-phenyl-[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)methanone (15a).
IR(KBr): νmax= 1656, 1521, 1064, 941, 858㎝-1. 1H NMR (600 MHz, CDCl3) δ = 9.94 (d,
J = 3.0 Hz, 1H), 7.88-7.95 (m, 3H), 7.80-7.82 (m, 2H), 7.59-7.62 (m, 1H), 7.52 (s, 3H),
7.41-7.50 (m, 3H), 7.24-7.40 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 188.7,
139.9, 139.8, 136.0, 134.8, 131.72, 131.67, 131.6, 131.3, 131.1, 130.1, 123.0, 129.8,
7

129.7, 128.9, 128.5, 128.3, 127.3, 126.4, 122.3, 118.0 ppm; ESI-MS(m/z):
383.1[C23H1435ClN3O]+, 385.1[C23H1437ClN3O]+ (3:1); HRMS(ESI):
calcd.[C23H14ClN3O+H]+: 384.0898, found: 384.0902.
FUNDING
We are grateful to National Natural Science Foundation of China (21002076), the
Scientific Research Foundation for the Returned Overseas Chinese Scholars, and Wuhan
“Youth Chenguang Program” of Science and Technology (201271031374) for financial
support.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra and X-ray data for this article can be
accessed on the publisher’s website. Please make the words “publisher’s website” a live
DOI link.
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Table 1.
12

Scheme 1. Strategies for the synthesis of fused 1,2,3-triazole heterocycles.
13

Scheme 2. Reagent and conditions: (i) 1-ethynyl-4-methoxybenzene or ((prop-2-ynyloxy)
methyl)benzene (1.2 eq), PdCl2(PPh3)2 (0.05 eq), CuI (0.06 eq), Et3N/THF(0.5 M, V/V,
1:1), 80 ℃; (ii) NaN3(3-5 eq), DMSO, 160 ℃, 48 h.
14

Scheme 3. The cascade cyclization of 1,2-bis(phenylethynyl)benzene with NaN3
15

Figure 1. The crystal structures of compound 3 and 4 (cocrystallization) and 6 (ellipsoids
at 30% of probability).
(a)
(b)
16

Figure 2. The crystal structure of compound 15a (ellipsoids at 30% of probability).
17