Facile synthesis of bromo- and iodo-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2017.07.016

Facile synthetic routes to bromo- and iodo-1,2,3-triazoles were achieved. Diiodo-1,2,3-triazole was directly obtained from 1,2,3-triazole, and dihalo-1,2,3-triazoles were converted to halo-1,2,3-triazoles in good yields without protection by NH. Unsymmetr

Full text of DOI:10.1016/j.tetlet.2017.07.016

Tetrahedron Letters 58 (2017) 3188–3190
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of bromo- and iodo-1,2,3-triazoles
⇑
Isao Sakurada
Discovery Research, Mochida Pharmaceutical Co. Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile synthetic routes to bromo- and iodo-1,2,3-triazoles were achieved. Diiodo-1,2,3-triazole was
directly obtained from 1,2,3-triazole, and dihalo-1,2,3-triazoles were converted to halo-1,2,3-triazoles
in good yields without protection by NH. Unsymmetrical 4-bromo-5-iodo-1,2,3-triazole was synthesized
from bromo-1,2,3-triazole. These halo-1,2,3-triazoles can be readily prepared using common reagents
and solvents and are useful building blocks for the analogous synthesis of 1,2,3-triazole derivatives.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 22 May 2017
Revised 26 June 2017
Accepted 3 July 2017
Available online 4 July 2017
Keywords:
1
,2,3-Triazole
Halogenation
Reduction
Deuterated 1,2,3-triazoles
Suzuki-Miyaura coupling
The 1,2,3-triazole moiety has been used as a heteroaryl ring in
medicinal chemistry, and its well-known click chemistry2 (Huis-
the reaction mixture at 60 °C for 2 h, 4,5-diiodo-1,2,3-triazole (5)
was observed as a major product in the LCMS data. Furthermore,
running the same reaction with NIS (3 eq.) in NMP at 100 °C for
30 min resulted in good conversion to give the desired product 5.
An equimolar amount of 1,3-diiodo-5,5-dimethylhydantoin
1
3
gen reaction ) has expanded the many pharmacological applica-
4
tions of N-1-substituted 1,2,3-triazoles. As synthons, bromo- and
iodo-1,2,3-triazoles are useful building blocks for metal-catalyzed
5
9
coupling reactions, such as Suzuki-Miyaura coupling. To the best
(DIH) in NMP also produced compound 5 as a major product.
of our knowledge, there are few known synthetic routes to prepare
bromo- and iodo-1,2,3-triazoles (Scheme 1). 4-Bromo-1,2,3-tria-
zole (2) is commercially available but expensive, and its known
synthetic method starting from compound 16 is not efficient in
terms of the atom economy. To prepare monobromo-1,2,3-tria-
zoles from dibromo-1,2,3-triazoles, halo-metal exchange reactions
Therefore, the two iodine atoms of DIH participated in the reaction.
Knownroute to prepare bromo-1,2,3-triazole
N
Br
N
N
N
2 steps
N
NH
7
were performed, but the NH group of the triazole moiety must be
masked. Regarding iodo-1,2,3-triazoles, direct diiodination of
OMe
1
1
1
,2,3-triazole has not been reported, even though 4,5-dibromo-
1
2
,2,3-triazole (3) can be easily prepared by dibromination of
6
7b
Known routesto prepare iodo-1,2,3-triazoles
Wang et al. (2010)
,2,3-triazole. Wang et al. reported that diiodo-1,2,3-triazole
(
(
5) was not obtained from 1,2,3-triazole using N-iodosuccinimide
NIS) in isopropyl acetate and that compound 5 was prepared
Br
Br
TMS
TMS
I
I
1) i-PrMgCl
NIS
TMSCl
from
bis(trimethylsilyl)-1,2,3-triazole
(4).
Recently,
the
N
N
N
N
N
N
2
) i-PrMgCl·LiCl
TMSCl
65%
IPAc
preparation of iodo-1,2,3-triazoles 5 and 7 was reported by
N
H
N
H
N
H
8
Shreeve et al., but high-pressure conditions were necessary.
3
4
77%
5
Herein, the facile synthesis of bromo- and iodo-1,2,3-triazoles
and the applications of halo-1,2,3-triazoles are discussed.
Initially, iodination of 1,2,3-triazole with NIS (1 eq.) in N-
methyl-2-pyrrolidone (NMP) was attempted, and almost no reac-
tion occurred at room temperature for 2 h. However, by heating
Shreeve et al. (2016)
15% aq. NH3
I
I
I
N
N
+
I
N
N
N
N
N
100 °C, 10-15 min
(pressure tube)
N
H
N
H
6
5 (25%)
7 (33%)
⇑
Address: 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan.
E-mail address: isao.sakurada@mochida.co.jp
Scheme 1. Known preparation methods for bromo- and iodo-1,2,3-triazoles.
http://dx.doi.org/10.1016/j.tetlet.2017.07.016
040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
0

I. Sakurada / Tetrahedron Letters 58 (2017) 3188–3190
3189
DIH (added portionwise)
NMP
I
X
X
Na SO
2
D
X
2
3
N
N
N
N
N
N
D O
HN
HN
HN
HN
8
0~88 °C
N
8
N
I
(
inner temperature)
5
,
3 5
,
9 10
4
.54 g
14.5 g
(
(
X = Br) 100 °C, 3 d, 64% yield
X = I) 80 °C, 2.5 h, 64% yield
6
5.8 mmol
68.7% yield
Scheme 2. Diiodination of 1,2,3-triazole.
Scheme 3. Preparation of deuterated 1,2,3-triazoles.
The product was precipitated after addition of water to the reac-
tion mixture, and the solid product was collected by filtration to
afford 5 in 65% yield (0.5 mmol scale). Since the DSC (differential
scanning calorimetry) data for 4-iodo-1,2,3-triazole (7) indicated
DIH, NMP
0 °C, 2 h
I
N
N
N
N
6
HN
HN
8
Br
Br
exothermal decomposition at approximately 150 °C and the diio-
77% yield
dination was exothermal, large-scale production of this compound
should be carefully conducted. A scaled-up reaction (65.8 mmol
scale) was performed by adding DIH portionwise to manage the
reaction temperature. As a result, the temperature of the reaction
mixture was maintained within 80–88 °C, and 14.5 grams of the
desired product 5 were obtained from 1,2,3-triazole (8) without
purification by column chromatography (Scheme 2).10
2
11
Scheme 4. Synthesis of 4-bromo-5-iodo-1,2,3-triazole.
The applications of halo-1,2,3-triazoles are described in
Scheme 5. Bromo- and iodo-1,2,3-triazoles 2 and 7 were reacted
with an epoxide 12 in the presence of a catalytic amount of cesium
carbonate to give N-1- and N-2-regioisomers (13–16). In general,
N-1-substituted triazoles are more polar than N-2-substituted tri-
Next, the conditions to prepare bromo- and iodo-1,2,3-triazoles
(2 and 7) were explored. Because the halogenation of 1,2,3-triazole
6
azoles because of their different dipole moments. Therefore, the
using one equivalent of bromine or NIS generated dihalo-1,2,3-tri-
azole as a major product, the direct preparation of monohalo-1,2,3-
triazoles 2 and 7 from 1,2,3-triazole was believed to be difficult.
Therefore, we investigated the removal of one halogen atom from
the dihalo-1,2,3-triazoles. 4,5-Dibromo-1,2,3-triazole (3) was
regioisomers were easily isolated by column chromatography.
The structures of the iodo-1,2,3-triazole analogs 15 and 16 were
confirmed by HMBC experiments with 15 and 16 and the NMR
1
13
spectra ( H and C) of the des-iodo compounds after hydrogena-
1
4
11
tion.
Suzuki-Miyaura coupling with 4-bromophenyl boronic acid (17)
was performed. Pd(Xantphos)Cl was selected as the catalyst
because it has been used for selective Suzuki-Miyaura coupling
with
heteroaryl halide rather than phenylbromide.15 The
Using N-2-substituted halo-1,2,3-triazoles 13 and 15,
treated with sodium sulfite in water at 110 °C, and the reaction
interestingly gave 4-bromo-1,2,3-triazole (2) without notable
over-reaction (Table 1, run 1). In addition, basic and acidic condi-
2
3 4
tions were examined. In the presence of K PO , no desired product
a
was observed (run 2). The addition of acetic acid did not affect the
reaction (run 3). To minimize the risk of thermal decomposition of
the desired product, the hot plate was set to 100 °C, at which
temperature the reaction took 3 days (run 4). For the reduction
of 4,5-diiodo-1,2,3-triazole (5), mild conditions (80 °C for 2.5 h)
produced the desired product 7 in good yield (run 5).
bromo-1,2,3-triazole analog 13 did not give the desired product,
and the starting material 17 was consumed. This result indicated
that compound 13 was less reactive than the bromophenyl analog
1
7, and homocoupling reaction of 17 proceeded. Conversely, the
iodo-1,2,3-triazole analog 15 was more reactive than 17, and the
reaction produced the desired product 18 in 63% yield. The
sequential reactions starting from 4-iodo-1,2,3-triazole (7) provide
a convenient strategy for the synthesis of a diverse library of
Reduction with sodium sulfite can be applied to prepare deuter-
1
2
ated compounds that are attractive for drug discovery. The
reduction of dibromo- and diiodo-1,2,3-triazoles (3 and 5) with
sodium sulfite in deuterium oxide gave the corresponding deuter-
ated bromo- and iodo-1,2,3-triazoles (9 and 10) under the same
conditions as for the reduction in water (Scheme 3).
1
,2,3-triazole derivatives.
Furthermore, iodination of 4-bromo-1,2,3-triazole (2) provided
the unsymmetrical 4-bromo-5-iodo-1,2,3-triazole (11) which can
Cs
2 3
CO (0.2 eq.)
N
N
O
NMP, 60 °C
HN
+
1
3
be used for regio-selective Suzuki-Miyaura coupling reaction.
X
Compound 2 was treated with DIH in NMP at 60 °C for 2 h and
the desired product 11 was obtained in a good yield (Scheme 4).
The iodination of 4-bromo-1,2,3-triazole was faster than that of
2, 7
12
HO
N
HO
N
N
+
N
N
1
,2,3-triazole.
N
X
X
1
3 (X = Br) 55% yield 14 (X = Br) 29% yield
5 (X = I) 49% yield
Table 1
1
16 (X = I) 26% yield
Conditions used to prepare monohalo-1,2,3-triazoles.
X
N
N
N
Conditions
2
Pd(Xantphos)Cl (5 mol%)
HN
HN
OH
B
3 4
K PO (2 eq.)
N
NMP-water(2:1), 50 °C
X
X
1
3
5
+
HO
3, 5
2, 7
almost no desired product
Br
17
Run
X
Conditions
Results
1
2
3
4
5
Br
Br
Br
Br
I
Na
Na
Na
Na
Na
2
2
2
2
2
SO
SO
SO
SO
SO
3
3
3
3
3
(3 eq.), water, 110 °C, 20 h
(3 eq.), K PO , water, 110 °C, 20 h
(3 eq.), AcOH, water, 110 °C, 17 h
(3 eq.), water, 100 °C, 3 d
3/2 ratioa = 6:94
No reaction
3/2 ratio = 9:91
67% isolated yield
72% isolated yield
HO
N
same as above
3% yield
N
3
4
1
+
17
a
N
6
Br
(3 eq.), water, 80 °C, 2.5 h
18
a
The ratio was calculated from the LCMS peak areas of PDA.
Scheme 5. Applications of halo-1,2,3-triazoles.

3
190
I. Sakurada / Tetrahedron Letters 58 (2017) 3188–3190
In summary, novel approaches to prepare 4,5-diiodo-1,2,3-tria-
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