DBU catalyzed metal free synthesis of fused 1,2,3-triazoles through [3+2] cycloaddition of aryl azides with activated cyclic C–H acids

Article abstract of DOI:10.1016/j.tetlet.2016.05.082

DBU catalyzed synthesis of fused 1,2,3-triazoles by [3+2] cycloaddition of aryl azides with activated cyclic C–H acids such as dimedone, cyclohexane-1,3-dione, 5-methylcyclohexane-1,3-dione, and 2-hydroxynaphthalene-1,4-dione in PEG-400 has been reported

Full text of DOI:10.1016/j.tetlet.2016.05.082

Accepted Manuscript
DBU catalyzed metal free synthesis of fused 1,2,3-triazoles through [3+2] cy-
cloaddition of aryl azides with activated cyclic C-H acids
Harjinder Singh, Garima Khanna, Jitender M. Khurana
PII:
S0040-4039(16)30615-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.082
TETL 47701
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 March 2016
14 May 2016
21 May 2016
Please cite this article as: Singh, H., Khanna, G., Khurana, J.M., DBU catalyzed metal free synthesis of fused 1,2,3-
triazoles through [3+2] cycloaddition of aryl azides with activated cyclic C-H acids, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.082
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DBU catalyzed metal free synthesis of fused 1,2,3-triazoles through [3+2] cycloaddition of
aryl azides with activated cyclic C-H acids
Harjinder Singh, Garima Khanna and Jitender M. Khurana*
Department of Chemistry, University of Delhi, Delhi-110007, India
Email: jmkhurana@chemistry.du.ac.in
* Corresponding author. Tel. +91 11 27667725-1384; fax: +91 11 27666605
Abstract
DBU catalyzed synthesis of fused 1,2,3-triazoles by [3+2] cycloaddition of aryl azides with
activated cyclic C-H acids such as dimedone, cyclohexane-1,3-dione, 5-methylcyclohexane-1,3-
dione and 2-hydroxynaphthalene-1,4-dione in PEG-400 has been reported under heating. The
important features of this reaction are high yield products, short reaction times, easy availability
of starting materials and recyclability of both reaction medium and catalyst.
Keywords
DBU, Triazoles, PEG-400, Cycloaddition
1,2,3-Triazoles represent an important class of biologically active nitrogen containing
heterocyclic compounds with numerous biological activities such as, antibacterial, anticancer,
antivirus, antiHIV, and antituberculosis.1 Compounds containing 1,2,3-triazole ring fused with
various carbocycles exhibited significant biological activities e.g. they act as benzodiazepine and
adenosine receptors2,3 , γ-secretase modulator (GSM) for the treatment of Alzheimer’s disease.4
Some of the biologically active compounds containing fused 1,2,3-triazole ring are shown in
Figure 1.
1

N
O
H
H
N
N
N
N
N
N
N
HN
2,8-Dihydro-indeno[1,2-d]-1,2,3-
triazole (Chemotherapeutic)5
N
6-{2-[4-(4-Methyl-piperazin-1-yl)-phenyl]-
5-pyridin-4-yl-3H-imidazol-4-yl}-
2,4-dihydro-indeno[1,2-c]pyrazole (Chemotherapeutic)7
N
HN
N
O
Me
N
Cl
N
N
CN
N
()
6
O
2-[6-[(1E)-2-[(5S,6R,7S)-4,5,6,7-Tetrahydro-5,6-
dimethyl-1H-benzotriazol-7-yl]ethenyl]-3-pyridinyl]-
benzonitrile
1-Octyl-3-methyl-1H-naphtho[2,3-d]triazole-
4,9-dione chloride (antibacterial)6b
(Cardiovascular agent)6a
Figure 1: Examples of some biologically active fused 1,2,3-triazoles.
The Cu (I)-catalyzed azide−alkyne cycloaddition (CuAAC) has been extensively used for the
synthesis of 1,4-disubstituted 1,2,3-triazoles with high regioselectivity and with huge
implications in organic synthesis.8 Subsequently, the synthesis of 1,5-disubstituted 1,2,3-triazoles
were achieved by the RuAAC reaction.9 Several other methods including the IrAAC reaction and
Pd-catalyzed alkenyl bromide-azide cycloaddition have been developed for the regioselective
synthesis of substituted triazoles.10-12 All these reactions employ heavy metals as catalysts, which
restrict their application in biological sciences. Moreover, these methods cannot be employed for
the synthesis of fused 1,2,3-triazoles because of the non-availability of smaller cyclic alkynes as
the smallest cyclic alkyne isolated is cyclooctyne and also because of their low reactivity. The
metal free procedure for synthesis of substituted 1,2,3-triazoles such as enamine/dienamine-azide
cycloaddition, enolate-azide cycloaddition, strained alkyne-azide cycloaddition13-16 have also
been reported in literature, but have not been explored for the synthesis of fused 1,2,3-triazoles.
Methods such as Pd-catalyzed cyclization of 5-iodotriazoles17, oxidative alcohol–azide
cycloaddition18, cycloaddition of unactivated ketones/activated ketones to aryl azides19,20 for the
2

synthesis of fused 1,2,3-triazoles, have disadvantages such as poor yield of products, use of
expensive catalyst, and volatile organic solvents, long reaction times, severe reaction conditions
etc.
The development of new strategies to synthesize fused 1,2,3-triazoles is highly desirable in view
of their importance. Therefore, in continuation of our research interest for the synthesis of
variously substituted 1,2,3-triazoles21 and to investigate a novel methodology for the synthesis of
fused 1,2,3-triazoles, we attempted reactions of aryl azides with cyclic C-H acids, using
organobases (metal free conditions) in environmentally benign solvents like PEG-400.
In this paper, we wish to report for the first time the synthesis of fused 1,2,3-triazoles by
cycloaddition of various aryl azides with cyclic 1,3-dicarbonyl compounds such as dimedone
(1a), cyclohexane-1,3-dione (1b), 5-methylcyclohexane-1,3-dione (1c) and 2-hydroxy-1,4-
naphthoquinone (1d) using catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
o
PEG-400 at 80 C. Different aryl azides were prepared from corresponding aryl amines by
reported procedure 22.
The reaction conditions were optimized after attempting reactions of 1a (1.0 mmol) with 4-
bromophenyl azide (1.0 mmol) under different reaction conditions as listed in Table 1. Firstly,
the model reaction was attempted using a catalytic amount of the tertiary amine base Et3N (10
o
mol%) in PEG-400 at 80 C. The reaction was complete after 240 min as indicated by TLC.
After workup, the desired product 6,6-dimethyl-1-(4-bromophenyl)-6,7-dihydro-1H-
benzo[d][1,2,3]triazol-4(5H)-one (2a) was obtained in 74% yield (eq. 1) (Entry 1, Table 1). The
above reaction was then examined by using different nitrogenous organic base catalysts such as
o
DABCO, DBU, pyrrolidine and piperidine (10 mol%) in PEG-400 at 80 C (Entries 2-5, Table
3

1). Among all these bases, DBU was found to exhibit best catalytic activity as it gave the product
2a in 89% yield after 60 min (Entry 3, Table 1) unlike other base catalysts which gave product
2a in inferior yields and required longer reaction for completion (Entries 2-5 Table 1).
Therefore, we decided to attempt reactions with DBU in different solvents such as ethanol,
o
DMSO, water and acetonitrile using DBU (10 mol%) as catalyst at 80 C (Entries 6-9, Table 1).
The reaction was incomplete when attempted in ethanol even after 240 min with 60% yield of
desired product 2a (Entry 6, Table 1). Reactions using DMSO, water, and acetonitrile as solvent
required longer reaction times and gave inferior yields (Entries 7-9, Table 1) compared to PEG-
400 (Entry 3, Table 1). The reaction of 1a and 4-bromophenyl azide in PEG-400 was then
attempted at lower temperature and also with lower catalyst loading. The reactions at lower
o
temperature (60 C) and with lower catalyst loading (5 mol%) resulted in increase in reaction
time and decrease in product yield (Entries 10-11, Table 1).
Table 1. Optimization of reaction conditions for synthesis of fused 1,2,3-triazoles by reaction of
1a (1 mmol) with 4-bromophenylazide (1 mmol) under different conditions
Entry
Solvent
Base
Temp.
(oC)
80
Time
(min)
240
180
60
Yield
(%)
74
1.
2.
3.
4.
PEG-400
PEG-400
PEG-400
Et3N (10 mol %)
DABCO (10 mol%)
DBU (10 mol%)
80
78
80
89
PEG-400 Pyrrolidine (10 mol%)
80
180
76
4

5.
6.
PEG-400
Ethanol
Piperidine (10 mol%)
DBU (10 mol%)
DBU (10 mol%)
DBU (10 mol%)
DBU (10 mol%)
DBU (10 mol%)
DBU ( 5 mol%)
80
80
80
80
80
60
80
180
240
150
180
120
90
72
60a
74
79
80
82
79
7.
DMSO
8.
Water
9.
Acetonitrile
PEG-400
PEG-400
10.
11.
90
a Incomplete reaction
It can be inferred from above results that reaction of dimedone and 4-bromophenyl azide gave
the highest yield of the desired [3+2] cycloaddition product using DBU (10 mol%) as a base
o
catalyst in PEG-400 at 80 C. The probable mechanism of cycloaddition of dimedone and 4-
bromophenyl azide in presence of DBU is shown in Scheme 1. Firstly, reaction of DBU with
dimedone results in the formation of enolate (A), which undergoes 1,3-dipolar cycloaddition
with 4-bromophenyl azide, leading to the formation of triazoline intermediate (B) and
regeneration of DBU. This triazoline intermediate (B) undergoes elimination of water to give
6,6-dimethyl-1-(4-bromophenyl)-6,7-dihydro-1H-benzo[d][1,2,3]triazol-4(5H)-one (2a).
5

Scheme 1 Mechanism for synthesis of fused 1,2,3-triazole 2a in presence of DBU as catalyst.
With the optimized reaction conditions in hand, the scope of this DBU catalyzed [3+2]
cycloaddition reaction was further investigated. The reactions of different aryl azides (1 mmol)
such as 4-nitrophenylazide, 4-fluorophenylazide, 4-fluoro-3-chlorophenylazide, 4-azido-7-
chloroquinoline, 4-chloro-3-nitrophenyl azide, 3-nitrophenylazide and phenyl azide were carried
out with 1a (1.0 mmol) in PEG-400 using DBU (10 mol%) as catalyst at 80 oC. All the reactions
proceeded smoothly and were complete in 20 min to 240 min yielding corresponding fused
1,2,3-triazoles i.e. 1-aryl-6,6-dimethyl-6,7-dihydro-1H-benzo[d][1,2,3]triazol-4(5H)-ones (2b-
2h) in high yields (Entries 2- 8, Table 2, Scheme 1). Similarly the reaction of aryl azides (1.0
mmol) with 1b (1.0 mmol) and 1c (1.0 mmol) instead of 1a under otherwise identical conditions
gave corresponding 1-aryl-6,7-dihydro-1H-benzo[d][1,2,3]triazol-4(5H)-ones (2i-2m, Entries 9-
13, Table 2) and 6-methyl-1-aryl-6,7-dihydro-1H-benzo[d][1,2,3]triazol-4(5H)-ones (2n-2o,
Entries 14-15, Table 2)24, respectively, in high yields. The generalized equation for cycloaddition
is shown in Scheme 2.
Scheme 2: Synthesis of fused 1,2,3-triazoles (2a-2o).
6

Table 2. Synthesis of fused 1,2,3-triazoles (2a-2o)
S.No
ArN3
Product
Time (min)
60
Yield (%)
90
1
1.
1a
2.
1a
20
92
60
60
30
25
87
88
81
90
3.
4.
5.
6.
1a
1a
1a
1a
7

45
78a
7.
1a
240
80
8.
9.
1a
1b
20
86
60
40
50
30
84
87
10.
11.
1b
1b
80a
12.
13.
1b
1b
82
8

14.
15.
1c
1c
30
35
90
82
aYield after column chromatography
1
The structures of all new products were confirmed by IR, H NMR, 13C NMR and HRMS
spectra. Structure of compound 2b was further confirmed by single crystal X-ray
crystallography. The single crystal X-ray structure of compound 2b is shown in Figure 2.
Figure 2: Single crystal X-ray structure of compound 2b (CCDC No. 1452232)
Subsequently activated cyclic C-H acid 2-hydroxynaphthalene-1,4-dione was also investigated
for this cycloaddition reaction with various aryl azides. All the reactions proceeded smoothly and
gave the desired products in good yields (Scheme 3) (entries 1-8, Table 3).
Scheme 3. Synthesis of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-diones (3a-3h)
9

Table 3. Synthesis of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-diones (3a-3h)
Entry
ArN3
Product
Time (Min)
Yield (%)
1.
90
81
2.
3.
4.
60
45
30
86
81
87
5.
6.
45
90
86
83
10

7.
8.
90
90
86
87
All our efforts to prepare fused triazoles with 4-hydroxycoumarin under a variety of conditions
were unsuccessful (eq. 2).
The reaction was also tried with aryl azides bearing electron donating groups such as 4-
methylphenyl azide and 4-methoxyphenyl azide but the reaction did not proceed even after 12 h.
This different reactivity toward aryl azides with electron donating groups can be explained on the
basis of mechanism involved in cycloaddition reaction. 1,3-Cycloaddition takes place by
overlapping of frontier molecular orbitals of the 1,3-dipole and the dipolaraphile, such orbital
overlap may be HOMO controlled dipole or HOMO-LUMO controlled dipole or LUMO
controlled dipole. Since in present case reaction does not take place when 1,3-dipole i.e. aryl
azide bears an electron releasing groups this indicates that reaction take place by LUMO
controlled dipole mechanism in which LUMO of 1,3-dipole overlap with HOMO of
dipolaraphile. The presence of electron releasing functional group on aryl azide (1,3-dipole)
11

raises the energy of LUMO thus increasing HOMO – LUMO energy gap which make the
reaction difficult to proceed even after 12 h.
Recently, Bazgir et. al.20 also reported the synthesis of four fused 1,2,3-triazoles by cycloaddition
reaction of dimedone/ 2-hydroxynaphthalene-1,4-dione with meta and para- nitrophenylazide
o
using TMG as a catalyst in ethanol at 30 C. The comparison of our method with this reported
procedure is shown in Table 4. As it can be seen from Table 4 our method found to be much
more efficient in terms of both yield and reaction time.
Table 4. Comparison of our method with method reported in literature by Bazgir et. al.
Yield (%)b
72
S.No.
1.
Product
Yield (%)a
86
Timea
45 min
Timeb
3 h
2.
3.
92
78
20 min
7 h
62
60
45 min
7 h
aYield and time by our method. bYield and time by method reported bys Bazgir et. al
12

The recyclability of the catalyst and solvent i.e. DBU-PEG system was also examined by using
model reaction of 1a (1.0 mmol) with 4-nitrophenyl azide (1.0 mmol) at 80 oC. After completion
of the reaction as indicated by TLC, it was cooled and quenched with water (5 mL). The
precipitate formed was collected by filtration at pump. The filtrate was concentrated under
reduced pressure and dried under vaccum to recover DBU-PEG for the subsequent use. No
significant loss in the yield of 2b was observed after three cycles as 2b was obtained in 92%,
90% and 86% yield after first, second and third cycle, respectively. Therefore, this catalytic
system acts as an excellent recyclable reaction medium for synthesis of fused 1,2,3-triazoles in
good yield.
The purity of the recovered DBU-PEG has been confirmed using TLC analysis, which showed
the spot corresponding to DBU only. During the recyclability of DBU-PEG water was removed
completely. The effect of water on the reaction was also investigated. The aqueous extract
obtained after filtration of 2b was used as such for the next reaction. The reaction was
incomplete even after 8 h and the desired product was separated in 38% yield. Thus, removal of
water by concentration is essential to reuse the DBU•PEG for a next reaction.
In summary, we have described an efficient synthesis of biologically important fused 1,2,3-
triazoles by DBU catalyzed [3 + 2] cycloaddition of aryl azides with activated cyclic C-H acids
such as dimedone, cyclohexane-1,3-dione, 5-methylcyclohexane-1,3-dione and 2-
hydroxynaphthalene-1,4-dione in PEG-400. All products were obtained in good yields. Metal
free experimental procedure, easy available starting materials, short reaction time, recyclability
of both catalyst and solvent are major advantages of the present procedure.
Supplementary Material
1
Spectral data and copies of H NMR and 13C NMR spectra are available on the Journal’s
website.
13

Acknowledgements:
G.K. thanks the Council of Scientific and Industrial Research, New Delhi, India and H.S. thanks
UGC, New Delhi, India for the grant of junior and senior research fellowship. The authors also
acknowledge DU-DST for providing HRMS-LC analysis.
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24. General procedure for the synthesis of fused 1,2,3-triazoles (2a-2o and 3a-3h): A
mixture of aryl azide (1.0 mmol), activated cyclic C-H acid such as dimedone/
cyclohexane-1,3-dione/ 5-methylcyclohexane-1,3-dione/ 2-hydroxynaphthalene-1,4-
16

dione (1.0 mmol), DBU (10 mol%) and PEG-400 (3 mL) was placed in a 50 mL round–
bottomed flask. The reaction contents were stirred magnetically in an oil-bath maintained
at 80 oC for appropriate time as mentioned in Table 2 and 3. The progress of the reaction
was monitored by TLC (eluent: ethyl acetate : petroleum ether, 50 : 50, v/v). After
completion of the reaction, the reaction mixture was allowed to cool to room temperature
and was quenched with water (5 mL). The precipitate formed was collected by filtration
at the pump and washed with water. Products 2g and 2l were further purified by flash
column chromatography using ethyl acetate : petroleum ether (80 : 20 v/v) as eluent.
17

Highlights
 DBU catalysed synthesis of fused triazoles
 High yield of products, short reaction time
 Recyclability of both reaction medium and catalyst
18

Graphical Abstract
DBU catalyzed metal free synthesis of fused 1,2,3-triazoles through [3+2] cycloaddition of
aryl azides with activated cyclic C-H acids
Harjinder Singh, Garima Khanna and Jitender M. Khurana*
Department of Chemistry, University of Delhi, Delhi-110007, India
Email: jmkhurana@chemistry.du.ac.in
* Corresponding author. Tel. +91 11 27667725-1384; fax: +91 11 27666605
19