Catalytic cyclization of 2,3-dibromopropionates with benzyl azides to afford 1-benzyl-1,2,3-triazole-4-carboxylate: The use of A nontoxic bismuth catalyst

Article abstract of DOI:10.3987/COM-15-13371

We synthesized 1,2,3-triazoles via the cyclization of 2,3-dibromopropionates with benzyl azides. Bismuth chloride is an efficient catalyst, and the reaction is accelerated by weak bases such as sodium acetate. A variety of functional groups are compatible

Full text of DOI:10.3987/COM-15-13371

HETEROCYCLES, Vol. 92, No. 3, 2016
423
HETEROCYCLES, Vol. 92, No. 3, 2016, pp. 423 - 430. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 18th November, 2015, Accepted, 27th January, 2016, Published online, 5th February, 2016
DOI: 10.3987/COM-15-13371
CATALYTIC CYCLIZATION OF 2,3-DIBROMOPROPIONATES WITH
BENZYL
AZIDES
TO
AFFORD
1-BENZYL-1,2,3-
TRIAZOLE-4-CARBOXYLATE: THE USE OF A NONTOXIC BISMUTH
CATALYST
Hong-bin Sun,1* Dong Li,1 Weiping Xie,1,2 and Xinlin Deng1
1Department of Chemistry, Northeastern University, Shenyang 110819, P. R.
2
China, Ningbo Institute of Material Technology & Engineering, Chinese
Academy of Sciences Public Technical Service Center, Ningbo, P. R. China
E-mail: sunhb@mail.neu.edu.cn
Abstract
–
We synthesized 1,2,3-triazoles via the cyclization of
2,3-dibromopropionates with benzyl azides. Bismuth chloride is an efficient
catalyst, and the reaction is accelerated by weak bases such as sodium acetate. A
variety of functional groups are compatible with this catalytic protocol, and it
takes advantage of oxygen stable catalyst and substrates because the reactive
dibromides are saturated.
To expand the substrate scope of the known transformations is an attractive topic in organic synthesis.
The development of the new applications for existing catalysts is an important aspect of catalytic
chemistry. In recent years, bismuth compounds have been well developed as catalysts in various
transformations for their air-stability, bio-non-toxic nature and their tolerance to small amounts of
moisture.1 In previous work, we have reported several applications of bismuth catalyst,2 and now extend
our research to bismuth-catalyzed heterocycles of interest to pharmaceutical chemistry. In this paper, we
report new development in BiCl3-catalyzed synthesis of 1,2,3-triazoles.
The construction of 1,2,3-triazoles by alkyne-azide cycloaddition (AAC) has long been known as an
example of “click chemistry”.3 The copper-promoted AAC (CuAAC) has been applied in various field
including synthetic chemistry,4 medicinal chemistry,5 polymer/materials science6 and the life sciences.7 It
offers high yield and tolerance to many functional groups. However, the bio-toxicity of copper sometimes
limits applications in biological and clinical applications. In addition, the existence of residual copper
may cause unpredictable reactions.8 Many efforts have been devoted to eliminate the drawback of metal
residual by verifying the catalysts’ construction,9 and tremendous improvement have been achieved in

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HETEROCYCLES, Vol. 92, No. 3, 2016
recent years.10 Nevertheless, the development of copper-free synthetic methodology is still appealing.11
Alternatives such as palladium,12 ruthenium,13 silver14 and other metal compounds15 have been developed
to replace copper. Furthermore, metal-free catalysts16 and non-catalytic procedures17 are also emerging. In
addition, non-alkyne-based substrates have been applied to the synthesis of 1,2,3-triazoles12a,15,18 as an
alternative to the alkynes that are usually used in AAC reaction. Here, we investigated the cyclization of
non-alkyne-based substrates in the presence of catalytic amounts of BiCl3 to develop new synthetic
methods for 1,2,3-triazoles using simple and readily available catalysts and substrates. We found that the
1,2,3-triazoles could be obtained via cyclization of the azides with 2,3-dibromopropionates.
Table 1 shows that the catalytic activity of bismuth chloride is superior to other inorganic metal salt. Of
the tested catalysts, bismuth trichloride is the most appropriate although it does not provide the best yield.
For example, it is well-known that Cu(I) is active in AAC reaction, but surprisingly, the CuCl has no
obvious catalytic activity in this reaction. Both ZnSO4 and ZrOCl2 promote a reaction with slightly lower
yields than BiCl3, but their bio-capability is not as good as BiCl3 whose residue is harmless especially if
the product is prepared for pharmaceutical use. We also found that DMF is a better solvent than DMSO.
Moreover, bases bestow obvious benefits to catalytic reactions because they can absorb the resulting and
harmful HBr. It is interesting that the weak base produces better results than the strong one. Sodium
acetate is an excellent additive (Table 1, entry 15). The BiCl3 does not act as a simple Lewis acid for the
complexation of BiCl3 with Et3N and does not eliminate its catalytic activity19 (Table 1, entry 13). The
yield is 68% in the presence of triethylamine in contrast to 34% under base-free conditions (Table 1, entry
12).
Under the optimized conditions, a variety of reactions in which azides react with 2,3-dibromopropionates
are carried out using BiCl3 as a catalyst. The results are listed in Table 2. Of note, the acid and base-labile
ester group remains undisturbed. As the length of the ester's alkyl chain increases, the yield first increases
and then decreases. The electro-deficient 2,3-dibromopropanoic acid is low yield (Table 2, entry 9), and
the unhindered substrate 2,3-dibromopropanenitrile offers a standard yield (Table 2, entry 10). No
reaction occurred with 2,3-dibromopropanamide—neither did dibromides such as 2,3-dibromopropanol
nor styrene dibromide transform to 1,2,3-triazole.
Under our experimental conditions, the reaction exhibits excellent selectivity of 1,4-subtituted
1,2,3-triazole, and 1,5-isomer is detectable in no cases. We suspect that there should be a coordination
intermediate generated from the 2,3-dibromo ester with bismuth in the reaction pathway. The crowding of
bromo and ester groups restricts the closure of the azide group to the ester. The formation of the
1,5-isomer is then difficult. This hypothesis is based on the benzyl 2,3-dibromopropionate result, which is
a steric substrate and gives a low yield of triazole.

HETEROCYCLES, Vol. 92, No. 3, 2016
425
Table 1. The cyclization of benzyl azide with methyl 2,3–dibromopropionate to afford methyl
1-benzyl-1H-1,2,3-triazole-4-ylcarboxylate under different conditionsa,b
N
Br
cat.
N
N
N3
+
Br
O
80 oC, 20 h
O
O
O
2a
1a
3a
Entry
1
Catalyst
—
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Additive
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
Yield (%)
49
2
p-TSA
CuCl
BiCl3
57
3
40
4
78
5
FeCl3
AlCl3
48
6
43
7
ZnSO4
ZrOCl2
SrCl2
CoSO4
InCl3
71
8
72
9
52
10
11
12
13
14
15
55
46
BiCl3
34
BiCl3
Et3N
68
BiCl3
NaOAc
NaOAc
74
BiCl3
80
a
1 mmol benzyl azide, 1.2 mmol methyl 2,3-dibromopropionate, 2.4 mmol added base and 5 mol% catalyst are
b
charged in a sealed tube. The yield is calculated from LC. The full version of condition-optimized experiment is
available in supporting information.
Besides the benzyl azide, the substituted benzyl azides are investigated in this catalytic procedure. These
reactions provide a variety of 1, 4-substituted 1,2,3-triazoles with excellent tolerance to the tested
functionalities. It is clear from Table 2 that few substituents show significant impediment to this catalytic
protocol. Halogen atoms as well as alkyl, ether or nitro groups exhibit little influence on the yield. Benzyl
azides bearing electron sufficient group such as methoxy and tert-butyl react smoothly with the
2,3-dibromopropionate to give the corresponding triazoles; electron-deficient substrates also work well.

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HETEROCYCLES, Vol. 92, No. 3, 2016
Table 2. The synthesis of 1,2,3-triazoles via the cycloaddtion of benzyl azides with 2,3-dibromopropionic
acid esters catalyzed by bismuth trichloridea
Entry
1
R1
R2
Product
3a
3b
3c
3d
3e
3f
Yield (%)b
80 (78)
81 (74)
72 (73)
87 (83)
89 (82)
76 (64)
78 (72)
57 (48)
70 (60)
78 (65)
82 (57)
80 (61)
78 (75)
56 (50)
75 (66)
84 (73)
72 (66)
85 (84)
86 (82)
81 (76)
83 (78)
90 (78)
phenyl (1a)
methyl (2a)
2
phenyl (1a)
ethyl
(2b)
3
phenyl (1a)
2-propyl (2c)
2-butyl (2d)
1-butyl (2e)
1-pentyl (2f)
1-octyl (2g)
benzyl (2h)
4
phenyl (1a)
5
phenyl (1a)
6
phenyl (1a)
7
phenyl (1a)
3g
3h
3i
8
phenyl (1a)
9
phenyl (1a)
H
(2i)
10c
11
12
13
14
15
16
17
18
19
20
21
22
phenyl (1a)
2,3-dibromopropanenitrile (2j)
methyl (2a)
3j
4-chlorophenyl (1b)
2-chlorophenyl (1c)
2,4-dichlorophenyl (1d)
4-azidomethylphenyl (1e)
4-methoxyphenyl (1f)
3-fluorophenyl (1g)
4-nitrophenyl (1h)
4-tertbutylphenyl (1i)
4-bromophenyl (1j)
4-cyanophenyl (1k)
pyridin-2-yl (1l)
MeO2C- (1m)
3k
3l
methyl (2a)
methyl (2a)
3m
3n
3o
3p
3q
3r
methyl (2a)
methyl (2a)
methyl (2a)
methyl (2a)
methyl (2a)
methyl (2a)
3s
3t
methyl (2a)
methyl (2a)
3u
3v
methyl (2a)
a 1.0 mmol benzyl azide, 1.2 mmol dibromopropionate, 2.4 mmol NaOAc and 0.05 mmol BiCl3 are stirred with 1 mL
DMF at 80 oC for 20 hours. b The yield is determined by LC, and the number in parenthese is isolated yield. c The
nitrile substrate is examined instead of the ester.

HETEROCYCLES, Vol. 92, No. 3, 2016
427
The sterically strict ortho-substituted benzyl azides give average yields (Table 2, entry 12, 13), due to the
sufficient distance between the hindered group and the reacting moiety. Only strong electron withdrawing
group NO2 gives a slightly decreased yield of 72% (Table 2, entry 17). In another case, triazole is
produced efficiently from the cyclization of electro-deficient heterocyclic substrate pyridin-2-ylmethyl
azide (Table 2, entry 21). Once again, the reaction employed a non-aromatic substrate methyl
azidoacetate 1m and produces triazole 3v in very high yield (Table 2, entry 22).
Furthermore, reactive groups such as cyano survive the bismuth-catalyzed conditions. It is noticeable that
the mono cycloaddition product 3n is obtained when the 1,4-bis(azidomethyl)benzene reacted with
equivalent amount of dibromide. This means that the selectivity is readily controlled by simply adjusting
the amount of the other dibromide reactants.
The reaction mechanism of AAC is clear, but for this reaction of azide with 2,3-dibromopropionate, we
do not suggest that the propiolate should be considered as the intermediate according to the current
experimental result. The elimination of the first molecule of HBr from the dibromopropionate is
accessible with weak base, but it is implausible for the second HBr. A more plausible pathway of the
1,2,3-triazole formation is described below. Moreover, the weak base NaOAc shows better promotion
than K2CO3 or Et3N, and the reaction even occurred in the absence of base.
Scheme 1. The plausible pathway of the catalytic synthesis of 1,2,3-triazole via 2,3-dibromopropionate
with benzyl azide
As illustrated in Scheme 1, after the removal of one molecule of HBr, the BiCl3 catalyst reacts with
2-bromoacrylate to form a bismuth complex. This is nucleophilically attacked by the benzyl azide via
Michael addition-type reaction. The cycloaddition of 2-bromoacrylate with azide then occurs, and the
cyclization-aromatization by HBr elimination generates the 1,2,3-triazole. The ester group plays an
important role, and we have found that styrene dibromide does not react with benzyl azide. This explains
the product selectivity because bismuth reagents would activate the 1,4-addition of organic azides to
2-bromoacrylates.

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HETEROCYCLES, Vol. 92, No. 3, 2016
In conclusion, we have developed a novel copper free procedure for the synthesis of 1,2,3-triazole with
good to high yield. The BiCl3 catalyst and 2,3-dibromopropionate substrates are cheap and readily
available, and the reaction conditions are relatively mild and environmental friendly. This cyclization has
good selectivity, and is compatible with a variety of functional groups. Moreover, as an alternative to the
ordinary alkyne, the 2,3-dibromopropionates are relatively easy to handle.
EXPERIMENTAL
Typical
procedure
for
the
synthesis
of
1,2,3-triazole:
formation
of
methyl
1-benzyl-1,2,3,-triazole-4-carboxylate (3a): A mixture of 1 mmol benzyl azide, 1.2 mmol methyl
o
2,3-dibromopropionate, 2.4 mmol NaOAc, and 0.05 mol BiCl3 with 1 mL DMF is stirred at 80 C for 20
h. After cooling, 10 mg of the mixture is sampled and diluted to 5.0 mL with MeOH as determined by LC.
The others are poured into 10 mL water and then extracted with EtOAc. The product is purified on silica
gel by eluting with EtOAc and PE (2:3). The product 3a is obtained as a white solid with 78% yield.
ACKNOWLEDGEMENTS
Financial support from the National Natural Science Foundation of China (21003018) and the
Fundamental Research Funds for the Central Universities (N130405005) are gratefully acknowledged.
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