Synthesis of triazolidines and triazole using DMAP

Article abstract of DOI:10.1080/00397911.2016.1263338

An efficient methodology has been developed for the synthesis of 1,2,4-triazolidine-3-thione and 3-ethoxy-5-phenyl-4H-1,2,4 triazole using N,N-dimethylpyridine-4-amine (DMAP). Aldehydes and thiosemicarbazide were reacted in water at ambient temperature in

Full text of DOI:10.1080/00397911.2016.1263338

Synthesis of triazolidines and triazole using DMAP
1
1
Devidas A. Mali , Vikas N. Telvekar
1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical
Technology, Matunga, Mumbai, India
Corresponding author: Vikas N. Telvekar, E-mail: vikastelvekar@rediffmail.com
Abstract
An efficient methodology has been developed for the synthesis of 1, 2, 4-triazolidine-3-
thione and 3-ethoxy-5-phenyl-4H-1, 2, 4 triazole using N, N-dimethylpyridine-4-amine
(DMAP). Aldehydes and thiosemicarbazide reacted in water at ambient temperature in
presence of DMAP and provided corresponding products in good to moderate yield.
GRAPHICAL ABSTRACT:
KEYWORDS: Aldehyde, Thiosemicarbazide/semicarbazide, Thiazolidine-3-thione,
Triazole, DMAP
INTRODUCTION
1

Triazoles are important class of nitrogen containing heterocycles, because many of them
[
1]
[2]
exhibit interesting biological activities, such as anti-inflammatory, antidepressant,
[
3,4]
[5,6]
[7]
[8]
antifungal,
anticancer, anti-TB,
analgesic and hypoglycemic. Sulfur-linked
1
2
,2,4-triazoles represent an important group in lead discovery. Also many sulfur-linked 1,
[
9–11]
[12]
, 4-triazole have been reported, as antibacterial,
antitumor, anti-HIV, and anti-
[
13]
TMV (tobacco mosaic virus) activities. Thus pharmacologically important sulfur-
linked 1,2,4-triazole have attracted attention of many researchers to pursue novel, and
easy synthetic routes. There are very few routes available for synthesis of these
molecules. Recently, the synthesis of 1,2,4-triazolidine-3-thiones has been reported using
[
14]
[
C MPy]AlCl Br as reusable ionic liquid catalyst. In another multi-component
16 3
reaction 1,2,4-triazolidine-3-thione was synthesized from aldehyde, hydrazine hydrate,
[
15]
and trimethylsilyl isothiocyanate (TMSNCS) using sulphamic acid as a catalyst. In
continuation to our research work on synthesis of heterocyclic molecules using novel
methodology, herein we report a novel system for the synthesis of 1,2,4-triazolidine-3-
thiones which involves the reaction between aldehydes, thiosemicarbazides in the
presence of catalyst N, N-dimethylpyridine-4-amine (DMAP) in water.
RESULT AND DISCUSSION
For our initial study we carried out reaction between anisaldehyde (1) and
thisemicarbazide (2) in presence of N, N-dimethylpyridine-4-amine (DMAP) as a catalyst
at room temperature in water (Scheme 1). After completion of reaction the desired
product 5-(4-methoxyphenyl)-1, 2, 4-triazolidine-3-thione (3e) was isolated by filtration.
2

The reaction was also carried out, using different catalysts and results are summarized in
Table 1.
It was observed that DMAP and PPTSA (p-toluenesulphonic acid pyridinium salt) are
suitable catalyst for this reaction 20 mole %, DMAP is sufficient for this reaction. Further
this reaction was also carried out in different solvents using 20 mole %, DMAP as a
catalyst and it was noted that the reaction did not occur in toluene, dioxane,
dichloromethane and chloroform but lower yield was observed when the reaction was
carried out in ethanol. In the presence of DMF, THF and acetonitirle only Schiff base was
isolated. Thus 20 mole %, DMAP as a catalyst and water as a solvent is optimal
condition required for this reaction. As the product was isolated by just filtration, we tried
to recycle the filtrate for above reaction and it was observed that the filtrate could be
recycled up to five times and at the same time efficiency of the product also decreased as
shown in Table 2.
This optimal reaction conditions were applied for the synthesis of various 1,2,4-
triazolidine-3-thiones derivatives (3a-i) and results are summarized in Table 3.
It was observed that both electron withdrawing and donating substituted aryl aldehydes
are suitable substrates for this reaction (Table 3, compounds 3b-3e). Heterocyclic
aldehydes also undergo this transformation and gives corresponding products in high
yield (Table 3, compounds 3g, 3h).
3

Further to extend the application of this methodology, we have taken semicarbazides (4)
instead of thiosemicarbazide (2) and carried out the reaction but only Schiff base was
isolated. It was observed that in the presence of ethanol and equivalent moles of DMAP,
reaction yielded 3-ethoxy-5-phenyl-4H-1, 2, 4 triazole (5e) at reflux temperature after
long reaction time (Scheme 2). We also tried other solvents instead of ethanol but no
desired product was isolated.
This methodology is applicable for various aldehydes and results are summarized in
Table 4.
CONCLUSION
In summary, we have successfully developed a novel, simple and efficient methodology
for synthesis of 1,2,4-triazolidine-3-thiones and 1,2,4 triazoles. In this system, easily
available aldehydes and thiosemicarbazide/semicarbazide were utilized in presence of
DMAP in water/ethanol, to give good yields of the desired products after easy workup
procedure
EXPERIMENTAL
General Procedure for Synthesis of 1, 2, 4-Triazolidine-3-Thione Derivatives (3a-i)
A mixture of (1 equiv.) aryl aldehyde, (1 equiv.) thiosemicarbazide and (20 mol %)
DMAP in water were stirred at room temperature for 20-30 min. The progress of the
reaction was monitored by TLC, and after completion of the reaction, the product is in the
4

form of precipitate was filtered and further purified by recrystalisation using EtOH as
solvent or using silica gel column chromatography (EtOAc–Hexane).
[15]
5
-Phenyl-1,2,4-Triazolidine-3-Thione (3a)
o
o
1
White solid; m.p : 153-155 C (lit. 154 C); H NMR (400 MHz, CDCl ) δppm 11.49 (s,
3
1
H),9.47 (s, 1H), 7.83 (s, 1H), 7.63 (dd, J = 7.3, 2.2 Hz, 2H), 7.47 – 7.35 (m, 3H), 6.34
−
1
(
s, 1H); FT-IR (KBr, cm ) 3388, 3232, 3149, 1597, 1532, 1460, 1444, 1368, 1289, 1226,
+
1
1
098, 1059, 943, 870, 843, 759, 752 MS : 179(M) (m/z).
General Procedure for Synthesis Of 3-Ethoxy-5-Phenyl-4H-1,2,4 Triazole
Derivatives (5a-e)
A mixture of (1 equiv.) aryl aldehyde, (1 equiv.) semicarbazide (1.1 equiv) DMAP was
stirred in EtOH at reflux temperature for 24-30 hr. The progress of reaction was
monitored by TLC and after completion of the reaction, reaction mixture was
concentrated under reduced pressure to give the crude product. The product was then
purified using silica gel column chromatography (MeOH-DCM).
[17
3
-Ethoxy-5-Phenyl-4H-1,2,4-Triazole (5a) ]
o
o
1
White solid; m.p : 120 C (lit. 121 C); H NMR (400 MHz, CDCl ) δ 7.84 (s, 1H), 7.69 –
3
7
6
1
.64 (m, 2H), 7.36 (dd, J = 4.9, 1.7 Hz, 3H), 4.29 (q, J = 12.9, 6.3 Hz, 2H), 1.32 (t, J =
−
1
.1 Hz, 3H); FT-IR (KBr, cm ) 3178, 3051, 1691, 1551, 1484, 1447, 1368, 1247, 1145,
+
047, 1013, 953, 916, 875, 758, 690. MS : 190(M) (m/z).
5

ACKNOWLEDEMENT
DAM thankful to University Grant Commission (UGC), and VNT thankful to Science
and Engineering Research Board (SERB), New Delhi, India for providing financial
support.
SUPPLEMENTARY DATA
1
13
The supporting material contains the spectral characterization data and copy H and C
NMR spectra’s. This material can be found via the “Supplementary Content” section of
this article’s webpage.
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[
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[
[
[
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Geterotsiklicheskikh Soedinenii, 1968, 11, 1258.
7

a
Table 1. Synthesis of 1,2,4-triazolidine-3-thione (3e) using various catalyst
b
Entry
Catalyst
Catalyst (moles
Yield (%)
%)
1
2
3
4
5
6
7
8
DMAP
10
20
30
10
20
30
10
20
30
82
95
95
85
87
90
60
65
67
DMAP
DMAP
PPTSA
PPTSA
PPTSA
L-Proline
L-Proline
L-Proline
9
a
Reaction conditions: 1.0 moles of anisaldehyde, 1.1 moles of thisemicarbazide in water
b
at room temperature for 2 hrs. Isolated yields after column chromatography.
8

a
Table 2. Recycling of filtrate of DMAP
b
c
Entry
No of Recycles
Recycle 1
Recycle 2
Recycle 3
Recycle 4
Recycle 5
Yield (%)
1
2
3
4
90
90
85
80
70
5
a
Reaction conditions: 1.0 mole of anisaldehyde, 1.1 moles of thiosemicarbazide, 20 mole
b
%
DMAP in water at room temperature for 2hrs. Product separated by filtration and in
c
filtrate the reaction was carried without adding DMAP for 2hrs. Isolated yields after
column chromatography
9

a
Table 3. Synthesis of 1,2,4-triazolidine-3-thiones using DMAP
b
Compound Aldehyde
Product
Time (Min)
20
Yield (%)
3
3
a
92
b
25
25
90
85
3
3
c
d
30
90
3
3
e
f
20
25
95
88
1
0

3
3
g
h
20
90
85
2
5
CHO
3
i
30
87
a
Reaction conditions: 1.0 mole of aldehyde, 1.1 moles of thiosemicarbazide, 20 mole %
b
DMAP in water at room temperature. Isolated yields after column chromatography, and
1
structures were confirmed by comparison of IR, H NMR and mp. with literature reports
[
14-15]
1
1

Table 4. Synthesis of various 3-ethoxy-5-phenyl-4H-1,2,4 triazole using DMAP in
a
ethanol
b
Compound Aldehyde
Product
Yield (%)
5
a
78
7
6
5
8
5
5
b
c
7
8
2
0
5
d
e
5
a
Reaction conditions: 1.0 mole of aldehyde, 1.1 moles of semicarbazide, 1.1 mol of
b
DMAP in ethanol at reflux temperature. Isolated yields after column chromatography,
1
2

1
and structures were confirmed by comparison of IR, H NMR and mp. with literature
[
16–17]
reports
1
3

Scheme 1. Synthesis of 5-(4-methoxyphenyl)-1,2,4 triazolidine-3-thione using DMAP as
catalyst
1
4

Scheme 2. Synthesis of 3-ethoxy-5-phenyl-4H-1,2,4 triazole using DMAP in ethanol
1
5