First regioselective iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles

Article abstract of DOI:10.1016/j.tetlet.2015.07.006

The regioselective iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles is described for the first time. The iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles using molecular iodine afforded diiodo-compound which on CuI-catalyzed intramolecular C-N coupling reaction gave six-membered 2-aryl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazines, whereas, the five membered 3-aryl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazoles were obtained exclusively when the iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles was carried out using NIS.

Full text of DOI:10.1016/j.tetlet.2015.07.006

Tetrahedron Letters 56 (2015) 5140–5144
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First regioselective iodocyclization reaction of 3-aryl-5-(prop-2-
ynylthio)-1H-1,2,4-triazoles
a,
a
Navnath D. Rode a, Amol D. Sonawane a, Dinesh R. Garud b, , , Rohini R. Joshi , Ramesh A. Joshi ,
⇑
⇑
Anjali P. Likhite a
a Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
b Department of Chemistry, Sir Parashurambhau College, Sadashiv Peth, Tilak Road, Pune 411030, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles is described
for the first time. The iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles using
molecular iodine afforded diiodo-compound which on CuI-catalyzed intramolecular C–N coupling
reaction gave six-membered 2-aryl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazines, whereas, the five membered
3-aryl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazoles were obtained exclusively when the iodocyclization
reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles was carried out using NIS.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 5 June 2015
Revised 26 June 2015
Accepted 1 July 2015
Available online 7 July 2015
Keywords:
Regioselective
Iodocyclization
Triazole
Thiazine
In recent decades, the chemistry of 1,2,4-triazoles and their
fused heterocyclic derivatives has received considerable attention
due to their interesting biological activities.1 However, systems
containing both nitrogen and sulfur atoms in the same heterocy-
cles showed remarkable properties and have proved to be suitable
for the development of functional organic materials as well as
pharmaceutically important molecules.2 In view of this, the thia-
zolo[3,2-b]-[1,2,4]triazole core is found in biologically active com-
pounds possessing antimicrobial,3 antibacterial,4 G-quadruplex
stabilizing,5 and anti-inflammatory6 activities whereas, thiazine
compounds are found to show a number of biological activities
such as anticancer,7 antileukemic,8 antibacterial,9 and antihyper-
tensive10 activities. In contrast, few articles devoted to the synthe-
sis of 2-aryl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine11 as compared
to 3-aryl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazole have been
published.12
containing heteroatom using N-nucleophiles for example, iodocy-
clization reaction of 2-anilino-3-(prop-2-ynyl)-l-imidazolinone,14
alkynyl-sulfonamides,15 N-protected o-(alkynyl)anilines,16 N,N-di-
alkyl-2-(1-alkynyl)anilines,17 2-alkynylbenzaldoximes,18 2-alkynyl
benzyl azides,19 or (pyridinyl)propynyl acetates.20 To the best of
our knowledge, no reports can be found in the literature for the
iodocyclization reaction in which 1,2,4-triazolyl nitrogen acts as
an internal nucleophile on alkynyl-carbon for the synthesis of
fused heterocyclic derivatives. Very recently, we reported the syn-
thesis of bicyclic-b-lactams via the regioselective iodocyclization
reaction of allene-thioureas.21 In continuation with our ongoing
project based on the development of efficient methodologies to
explore the new type of heterocyclic compounds which might have
potential biological activities, herein for the first time, in this Letter
we describe the regioselective iodocyclization reaction of 3-aryl-5-
(prop-2-ynylthio)-1H-1,2,4-triazoles for the synthesis of 2-aryl-
5H-[1,2,4]triazolo[5,1-b][1,3]thiazines and 3-aryl-5,6-dihydrothia-
zolo[2,3-c][1,2,4]triazoles.
Recently, electrophilic cyclization of an unsaturated C–C bond
with a wide variety of nucleophiles, including C, N, O, S, and Se
nucleophiles has emerged as versatile tool for the synthesis of var-
ious heterocycles.13 Reports are available in the literature for the
synthesis of heterocycles via iodocyclization reaction of alkynes
Our synthetic approach begun with triazolethiones 1, which
were readily prepared from aromatic carboxylic acids by the pre-
viously known procedure in three steps.22 Further, the selective
monoalkylation of triazolethiones
1 with propargyl bromide
under neutral condition resulted in the formation of 3-aryl-5-
(prop-2-ynylthio)-1H-1,2,4-triazoles 2 in good yields (Table 1,
entries 1–9). The structure of the 3-aryl-5-(prop-2-ynylthio)-1H-
⇑
Corresponding authors. Tel.: +91 9689647768; fax: +91 20 2433 2479 (D.R.G.);
tel.: +91 20 25902283; fax: +91 20 2590 2629 (R.R.J.).
E-mail addresses: ddgarud@gmail.com (D.R. Garud), rr.joshi@ncl.res.in
(R.R. Joshi).
1,2,4-triazoles
2 was confirmed by the studies of spectral
analysis.23
Affiliated to Savitribai Phule Pune University (formerly University of Pune).
http://dx.doi.org/10.1016/j.tetlet.2015.07.006
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

N. D. Rode et al. / Tetrahedron Letters 56 (2015) 5140–5144
5141
Table 1
Synthesis of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles 2a
N
NH
N
NH
Propargyl bromide
EtOH, 14 h, r.t
S
S
N
N
H
R
R
1
2
Entry
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
Me
H
CF3
OH
OMe
NH2
F
2a
2b
2c
2d
2e
2f
2g
2h
2i
69
74
62
69
70
77
68
72
69
Cl
NO2
a
The reaction was carried out as follows, 1.0 equiv of triazolethiones (1), 1.0 equiv of propargyl bromide in ethanol at 25 °C.
Isolated yields.
b
Table 2
Optimization conditions for the iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles 2a
I
N
N
N
NH
N
NH
I2
N
S
S
S
Me
N
N
I
Me
Me
3a
4a
2a
I
Entry
I2 (equiv)
Base
Solvent
Time (h)
Yieldb (%)
3a
4a
1
2
3
4
5
6
7
8
1.5
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
—
—
—
—
—
—
—
—
DCM
DCM
DCM
Methanol
THF
Toluene
DMF
CHCl3
THF
18
12
10
48
36
36
48
12
3
79
92
81
37
74
69
25
87
Traces
Traces
Traces
22
9
7
15
7
9
16
40
9
10
11
K2CO3
K2CO3
K2CO3
29
60
Traces
DCM
DMF
6
3
a
Iodocyclization reactions were conducted using 0.437 mmol of 2a at rt.
Isolated yields.
b
The key starting materials 2 in hand, we turned out attention
dihydrothiazolo[2,3-c][1,2,4]triazole 4a was improved to 40%
when the reaction was carried out in DMF using K2CO3 as a base
(entry 11).
toward the iodocyclization reaction. Firstly, the iodocyclization
reaction of compound 2a was carried out using 1.5 equiv of iodine
in DCM at room temperature (Table 2, entry 1). The reaction took
place readily and the diiodo-compound 3a was formed in 79% yield
with traces of five-membered compound 4a (entry 1). As shown in
Table 2, different reaction conditions were screened to improve the
yield of diiodo-compound 3a. Best result was obtained when the
reaction was carried out using 2 equiv of iodine in DCM to afford
diiodo-compound compound 3a in 92% yield along with traces of
five-membered compound 3-(p-tolyl)-5,6-dihydrothiazolo[2,3-
c][1,2,4]triazole 4a (entry 2).24 When the polar solvents were used
in the reaction, the diiodo-compound 3a was formed in low yields
along with five-membered compound 4a (entries 4–5 and 8–9). In
methanol the compound 4a was formed in 22% yield (entry 5).
Further, to improve the yield of five-membered 3-(p-tolyl)-5,6-di-
hydrothiazolo[2,3-c][1,2,4]-triazole 4a the iodocyclization reac-
tions was carried out under basic condition using K2CO3 as a
base (entries 9–11). The yield of the product 3-(p-tolyl)-5,6-
Next, we focused our attention toward the synthesis of diiodo-
compound 3 (Table 3). The reaction of various 3-aryl-5-(prop-2-
ynylthio)-1H-1,2,4-triazoles 2 was carried out under optimal con-
ditions (Table 3). The diiodo-compound 2-aryl-5H-[1,2,4]tria-
zolo[5,1-b][1,3]thiazines 3 were formed in good to excellent
yields (Table 3, entries 1–9). A variety of functional groups such
as electron donating as well as electron withdrawing groups were
well tolerated under the present reaction conditions (entries 1–9).
The structure of compounds 3 was confirmed by the studies of IR,
1H NMR, 13C NMR, NOESY, and HRMS spectral analysis.24 Finally,
the structure of the diiodo-compound 3h was confirmed by X-
ray crystallography (see Supporting information).
In recent years, the copper-mediated Ullmann-type intramolec-
ular C–N coupling reactions have developed as an important
approach to heterocyclic compounds.25 The intramolecular C–N
coupling reaction of diiodo-compound 3a using 20 mol % of CuI,

5142
N. D. Rode et al. / Tetrahedron Letters 56 (2015) 5140–5144
Table 3
Table 4
Synthesis of 2-aryl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazines 5a–ia
Synthesis of 3-aryl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazoles via iodocyclization reac-
tion of 2a
I
I
N
N
N
NH
N
NH
N
NH
I2 (2 equiv)
DCM, rt
NIS (1.5 equiv)
DCM
S
N
I
S
S
S
N
N
N
R
R
R
R
3
2
2
4
I
N
N
Entry
R
Time (min)
Product
Yieldb (%)
CuI, TMEDA, K3PO4
Toluene, 80oC, 10 h
S
N
1
2
3
4
5
6
7
8
Me
H
CF3
OMe
F
Cl
NO2
NH2
20
20
20
20
20
20
20
2 h
4a
4b
4c
4d
4e
4f
55
48
58
59
49
51
44
Traces
R
5
Entry
R
Time (h)
% yieldb,c (3)
% yieldb,d (5)
1
2
3
4
5
6
7
8
9
Me
H
12
12
12
12
12
13
12
11
13
92 (3a)
81 (3b)
83 (3c)
81 (3d)
89 (3e)
75 (3f)
77 (3g)
82 (3h)
83 (3i)
72 (5a)
67 (5b)
58 (5c)
— (5d)e
62 (5e)
— (5f)e
65 (5g)
63 (5h)
48 (5i)
4g
4h
CF3
OH
OMe
NH2
F
a
The reaction was carried using out using 0.437 mmol of 2 and 1.5 equiv of NIS in
DCM at rt.
b
Isolated yields.
Cl
NO2
a
Reaction was carried out using 0.437 mmol of 2 and 2 equiv of iodine in DCM at
rt.
b
c
Isolated yields.
Five-membered 3-aryl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazoles
4
were
formed in traces.
d
Reaction was carried out using 0.20 mmol of 3, 20 mol % of CuI, 40 mol % of
TMEDA, and 2 equiv of K3PO4 in Toluene at 80 °C for 10 h.
e
Reaction not resulted in the formation of required product whereas, longer
reaction time resulted in the decomposition of starting material.
Figure 2. The X-ray crystallographic structure of 4c.
The present Cu-catalyzed intramolecular C–N coupling reaction is
highly regioselective and the regioisomers, five-membered 3-
aryl-5,6-dihydro thiazolo[3,2-b]-[1,2,4]triazole or six-membered
3-aryl-7H-[1,2,4]triazolo[3,4-b][1,3]thiazine were never formed
under these reaction conditions. Finally, the structure of the repre-
sentative six-membered compound 5e was confirmed by X-ray
crystallography (Fig. 1).29
Encouraged by this finding, we searched for another catalyst
which would allow us to access the 3-aryl-5,6-dihydrothia-
zolo[2,3-c][1,2,4]triazoles 4 as major products. Interestingly, when
the iodocyclization reaction of compound 2a was carried out using
1.5 equiv of NIS as catalyst in DCM at room temperature the five-
membered compound 4a was formed exclusively in 55% yield
(Table 4, entry 1).30,31 Under this reaction condition the cyclization
of other 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles 2b–h was
carried out to afford 4b–h (entries 2–9). Functional groups such
as alkyl, methoxy, halogens, trifluoromethyl, and nitro were well
tolerated under the present reaction conditions (entries 1–7).
When the electron donating amine compound 2f was used in the
reaction, the required compound 4h was formed in traces (entry
8). This approach is highly regioselective for five-membered 3-
aryl-5,6-dihydrothiazolo[2,3-c][1,2,4]triazoles 4. The compounds
4a–h were formed with E-configuration whereas, compounds with
Z-configuration were not formed under these reaction conditions.
The structure of the compounds 4 was confirmed by the studies
of IR, 1H NMR, 13C NMR, NOESY, and HRMS spectral analysis.
Finally, the molecular structure of the representative compound
4c was determined by the X-ray crystallography (Fig. 2).32
Figure 1. The X-ray crystallographic structure of 5e.
40 mol % of TMEDA, and 2 equiv of K2CO3 in toluene at 80 °C read-
ily afforded the six-membered 2-aryl-5H-[1,2,4]triazolo[5,1-
b][1,3]thiazine 5a in 35% yield (see Supporting information). To
improve the yield of coupling reaction, different conditions were
then screened. We found that the reaction was highly dependent
on the type of base used26 and the best result was obtained when
the reaction was carried out using 2.0 equiv of K3PO4 (Table 3,
entry 1, 72% yield).27 Inspired by this result, the intramolecular
C–N coupling reaction of other diiodo-compounds 3 was carried
out under above conditions (Table 3, entries 1–9). The variety of
functional groups such as –Me, –CF3, –OMe, –F, Cl, and –NO2 at
the aromatic ring was well tolerated under the reaction conditions
and afforded the desired six-membered 2-aryl-5H-[1,2,4]tria-
zolo[5,1-b][1,3]thiazines 5 in good to moderate yields (entries 1–
3, 4, and 7–9). The intramolecular C–N coupling reactions failed
when –OH and –NH2 groups were at aromatic ring (entries 4 and
6). The structure of compounds 5 was confirmed by the studies
of IR, 1H NMR, 13C NMR, NOESY, and HRMS spectral analysis.28

N. D. Rode et al. / Tetrahedron Letters 56 (2015) 5140–5144
5143
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In conclusion, the first regioselective iodocyclization reaction of
3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-triazoles is described. The
iodocyclization reaction of 3-aryl-5-(prop-2-ynylthio)-1H-1,2,4-
triazoles using molecular iodine afforded the diiodo-compound
which on CuI-catalyzed intramolecular C–N coupling reaction gave
six-membered 2-aryl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazines whereas,
the use of NIS in the reaction afforded the five membered 3-aryl-
5,6-dihydrothiazolo[2,3-c][1,2,4]triazoles. The present approach
provides access to a substituted fused heterocycles. Further inves-
tigation on the application of this reaction is in progress.
Acknowledgments
Author (R.R.J.) thanks CSIR, New Delhi, India, for a financial sup-
port (BSC0103). Authors also are thankful to Dr. P.R. Rajamohanan,
NCL, Pune for his help on spectral analysis and Rajesh Gonade, NCL
Pune for X-ray crystallography.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
006.
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23. General procedure for the propargylation reaction of 1: To
a solution of
triazolethiones (5.23 mmol) in ethanol (10 mL), propargyl bromide
(0.396 mL, 5.23 mmol) was added and allowed to stir for 12 h at rt. The
reaction mixture was concentrated and the residue was extracted with ethyl
acetate and organic phase washed was with brine, dried over Na2SO4, filtered
and evaporated in vacuo. The residue was purified by column chromatography
on silica gel using ethyl acetate:pet ether (1.5:8.5) as eluent to give the
corresponding products 2a–2i.
24. General procedure for the iodocyclization reaction of 3: To
a solution of 2
(100 mg, 0.436 mmol) in CH2Cl2 (5 mL) was added I2 (223 mg, 0.873 mmol) at
room temperature. After stirring at this temperature (12 h), the reaction
mixture was extracted with CH2Cl2 and washed with saturated Na2S2O3 and
NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered
and evaporated in vacuo. The residue was chromatographed on silica gel using
ethyl acetate:pet ether (1:9) as eluent to give corresponding product (3a–3i).
25. (a) Jiang, B.; Tian, H.; Huang, Z. G.; Xu, M. Org. Lett. 2008, 10, 2737–2740; (b)
Zhang, Y.; Yang, X.; Yao, Q.; Ma, D. Org. Lett. 2012, 14, 3056–3059.
26. Ouyang, K.; Xi, Z. Acta Chim. Sinica 2013, 71, 13–25.
27. For optimization conditions see Supporting information.
6. (a) Tozkoparan, B.; Aytaç, S.; Gürsoy, S.; Aktay, G. Med. Chem. Res. 2012, 21,
192–201; (b) Uzgören-Baran, A. Eur. J. Med. Chem. 2012, 57, 398–406.
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106330082, 1987.
9. Sharma, R.; Goyal, R. D.; Prakash, L. Phosphorus, Sulfur Silicon Relat. Elem. 1993,
80, 23.
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Jones, H.; Neiss, E. S.; Schwah, A.; Mann, V. S.; Khandwala, A.; Wolf, P. S.;
Weinrybt, I. J. Med. Chem. 1986, 29, 784–796.
28. General procedure for the synthesis of 5: A round bottom flask was charged with
3 (0.20 mmol), TMEDA (40 mol %), K3PO4 (0.41 mmol), CuI (20 mol %) and
toluene (5 mL). The reaction mixture was stirred at 80 °C for 10 h, then
aqueous solution of sodium thiosulfate was added and the mixture was
extracted with ethyl acetate. The combined organic phase was washed with
brine and dried over Na2SO4. Purification of the crude mixture by flash
chromatography on silica gel using ethyl acetate:pet ether (1:9) as eluent to
afford the product 5.
29. CCDC 1043642 for 5e contains the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
30. For optimization conditions see Supporting information.
11. (a) Montazeri, N.; Pourshamsian, K.; Divsalar, A.; Ghoorchi-Beigi, M. Asian J.
Chem. 2012, 24, 2802–2804; (b) Heravi, M. M.; Montazeri, N.; Rahimizadeh, M.;
Bakavoli, M.; Ghassemzadeh, M. Monatsh. Chem. 2001, 132, 1225; (c) Nayak, J.;
Girisha, K. S.; Kalluraya, B.; Shenoy, S. Phosphorus, Sulfur Silicon Relat. Elem.
31. General procedure for the iodocyclization reaction of 4: To
a solution of 2
(100 mg, 0.436 mmol) in CH2Cl2 (5 mL) was added NIS (147 mg, 0.655 mmol)

5144
N. D. Rode et al. / Tetrahedron Letters 56 (2015) 5140–5144
at room temperature. After stirring at this temperature (20 min), the reaction
32. CCDC 1043644 for 4c contains the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
mixture was extracted with CH2Cl2 and washed with saturated Na2S2O3 and
NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered,
and evaporated in vacuo. The residue was chromatographed on silica gel using
ethyl acetate:pet ether (1:9) as eluent to give corresponding product (4a–4g).