CuBr-NCS-mediated multicomponent azide-alkyne cycloaddition: Mild and efficient synthesis of 5-bromo-1,4-disubstituted-1,2,3-triazoles

Article abstract of DOI:10.1055/s-0030-1259908

CuBr-NCS was found to be a mild and efficient reaction system to promote the multicomponent azide-alkyne cycloaddition reactions. Under the reaction conditions, terminal alkynes and azides can react smoothly at ambient temperature to give the target produ

Full text of DOI:10.1055/s-0030-1259908

874
LETTER
CuBr–NCS-Mediated Multicomponent Azide–Alkyne Cycloaddition:
Mild and Efficient Synthesis of 5-Bromo-1,4-Disubstituted-1,2,3-Triazoles
S
ynthesis of 5-B
i
romo-
n
1,4-Disubstit
g
uted-1,2, 3-T
j
riazole
u
s
n Li,*a Ran Li,a Anlian Zhu,a Guisheng Zhang,a Lihe Zhangb
a
College of Chemistry and Environmental Science, Henan Normal University, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Xinxiang 453007, P. R. of China
Fax +86(373)3325250; E-mail: 031148@htu.cn; E-mail: zdszlh@bjmu.edu.cn
National Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100083, P. R. of China
b
Received 19 December 2010
activity relationship in the drug discovery,20,21 but only
very limited methods are available for the preparation of
5-bromo-1,4-substituted-1,2,3-triazole in literature. These
include (1) preparation from triazole boronic esters,22 (2)
Abstract: CuBr–NCS was found to be a mild and efficient reaction
system to promote the multicomponent azide–alkyne cycloaddition
reactions. Under the reaction conditions, terminal alkynes and
azides can react smoothly at ambient temperature to give the target
products 5-bromo-1,4-disubsituted-1,2,3-triazoles in moderate to preparation from the cycloaddition between bro-
moalkynes and azide,23 and (3) tandem azide–alkyne 1,3-
good yields with a wide tolerance of other sensitive functional
dipolar cycloaddition–electrophilic addition.17 These
groups. The further successful application of the CuBr–NCS reac-
tion system in sugar and cyclic adenosine 5¢-diphosphoribose
methods involved vigorous reaction conditions and the
(cADPR) analogues illustrated the value of this method in the syn-
active bromoalkynes or alkynylboronates have to be pre-
thesis of designed biomolecules.
pared in advance. There are no available methods for the
Key words: multicomponent azide–alkyne cycloaddition, 5-bromo-
efficient preparation of 5-bromo-1,2,3-triazole directly
1,4-disubstituted-1,2,3-triazole, click chemistry, copper catalysis
from the azide and terminal alkyne with good chemose-
lectivity. In this work, we found that a novel CuBr–NCS
system can mediate the multicomponent reaction of azide
The Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC
and alkyne with high efficiency for the preparation of 5-
reaction, also defined as ‘click reaction’) has recently pro-
bromo-1,4-disubstituted-1,2,3-triazole at ambient condi-
vided a promising synthetic protocol in the fields of
tions with good chemoselectivity.
organic chemistry and medicinal chemistry.1,2 The sim-
plicity and excellent functional-group tolerance of the
CuAAC reaction allow it to link two or more functional
O
X
N
N
O
N
H
R3
molecular entities with high efficiency during the synthe-
sis of libraries of compounds.3,4 Furthermore, 1,2,3-triaz-
ole has been explored as an efficient bioisostere in the
drug design. It can mimic the function of amide,5–7
acylphosphate8 trans-olefinic moiety,9 and other five-
membered rings containing two nitrogen atoms.10 As an
exploration, we have successfully applied 4-amide-1,2,3-
triazole moiety to mimic the purine nucleobase of cyclic
adenosine 5¢-diphosphoribose (cADPR), and have ob-
tained a novel structure-simplified, membrane-permeant,
calcium-releasing agonists cTDPRE (Figure 1).11,12
N
–O P O
O
O
N
N
R5
P
O–
O
N
O
R1
R4
R2
OH
OH
X = OCH2, CH2
cADPR triazole analogues: cTDPRE/cTDPRC
fipronil triazole analogues
Figure 1 Bioactive compounds containing 1,2,3-triazole moieties
as bioisosteres
As it has been shown in our previous work, the selection
of the proper oxidant is essential for the substitution on the
The diverse modifications on the 1,2,3-triazole moiety are
essential for the further application of 1,2,3-triazole moi- 5-carbon of the 1,4-disubstituted-1,2,3-triazole in the
ety as a potential bioisostere. Several groups have inde- CuAAC reactions.15 Therefore, different CuBr–oxidant
pendently taken up this challenge to explore the methods systems were investigated for the preparation of 5-bromo-
for the synthesis of 5-substituted-1,2,3-triazole based on 1,4-disubstituted-1,2,3-triazole in this work (Table 1). It
the classic CuAAC reactions.13–19 Most of these methods was found that the target product 3a was obtained in only
are focused on the synthesis of 5-iodo-1,2,3-triazoles13–16 25% yield in CuBr–NBS reaction system after 24 hours
and 5-alkyl-1,2,3-triazole derivatives.13,16,18 It is known (entries 1–3). CuBr–Ph3P–NBS reaction system was used
that bromo substitution is one of the important methods for the cycloaddition reaction between compound 1a and
for lead optimizations and investigations of structure– 2a. It was found that the yield of 3a increased a little per-
haps due to the phosphorous ligand that might stabilize
Cu+ and increase the solubility of CuBr in the organic so-
lution (entries 4 and 5).3 CuBr and iodosobenzene diace-
tate (CuBr–IBD) were also used as reaction system for
SYNLETT 2011, No. 6, pp 0874–0878
Advanced online publication: 15.03.2011
DOI: 10.1055/s-0030-1259908; Art ID: W19810ST
x
x.
x
x.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 5-Bromo-1,4-Disubstituted-1,2,3-Triazoles
875
this reaction, with 45% yield of 3a and 18% yield of 4 (en- 1,2,3-triazole derivatives by using different azides and
try 6). On the other hand, the combination of CuBr and alkynes (Table 2). It was found that various protective
pyridinium chlorochromate (CuBr–PCC) had no catalytic groups such as acetyl, methoxy, and TBDMS groups as
activity for this reaction (entry 7). It was worthy to note well as some widely used functional groups like ester,
that when CuBr–NCS was applied, the CuAAC reaction ether, and amide were well tolerated under the reaction
1
could proceed smoothly. ESI-MS and H NMR analyses conditions. Benzyl azides or other aliphatic azides also
revealed that the product obtained from the CuBr–NCS successfully reacted with corresponding alkynes to give
reaction system was identical and agreed well with 5-bro- 5-bromo-1,4-disubstituted-1,2,3-triazoles in moderate to
mo-1,4-disubstituted-1,2,3-triazole 3a, and no chloride good yields (entries 5–8). Furthermore, the reactivities of
1
compound was found in HPLC-MS and H NMR analy- the alkynes in the sugar building blocks and cADPR ana-
ses. Furthermore, no starting material 1a could be detect- logues were also investigated under the CuBr–NCS reac-
ed by TLC after the reaction proceeded for 8 hours at tion systems (entries 3, 4, and 9). The results showed that
ambient temperature, and the 5-bromo-1,4-disubstituted- the corresponding 5-bromo-1,4-disubstituted-1,2,3-triaz-
1,2,3-triazole 3a could be obtained with 81% isolated oles could be successfully obtained in good yields with in-
yield. This was much higher than the yields obtained in tact sugar and amino moieties, suggesting the promising
the other reaction systems (entry 8). The solvent effects on application of this method in the construction of designed
this CuBr–NCS-mediated azide–alkyne cycloaddition re- sugar and cADPR analogues.
action were also investigated (entry 8–11). It was found
A possible reaction mechanism of the CuBr–NCS-medi-
that THF was the best solvent for this reaction with 81%
ated azide–alkyne cycloaddition reactions was proposed
yield of 3a at ambient temperature within 8 hours. When
(Scheme 1). There is a competitive reaction between 5-H-
MeCN was used as the reaction solvent, 57% yield of 3a
was given with 18% yield of 4, and the reaction in dichlo-
romethane was sluggish due to the poor solubility, while
the reaction in methanol did not occur after 8 hours.
1,2,3-triazole and 5-bromo-1,2,3-triazole (Scheme 1).1
The H+ abstraction by carbanion intermediate 5 could pro-
duce 5-H-1,2,3-triazole, or the Br+ abstraction could give
5-bromo-1,2,3-triazole. In the CuBr–NCS reaction sys-
The application of this new synthetic protocol was then tem, Br– originating from CuBr might be oxidized by NCS
explored to construct various 5-bromo-1,4-disubstituted- to provide the Br+ resource. The change of the color after
Table 1 The Preparation of 5-Bromo-1,4-disubstituted-1,2,3-triazole 3a under Different Reaction Systems at Ambient Temperature
N
N
Br
N
N
N
N
AcO
AcO
AcO
N3
O
O
O
CuBr–X
+
+
OAc OAc
OAc OAc
OAc OAc
1a
2a
3a
5H-triazole
4
Entry
Catalyst systema
CuBr–NBS
Solvent
THF
Time (h)
Isolated yield (%) 3a (4)
1
2
24
24
24
12
10
8
25 (45)
20 (37)
15 (25)
30 (35)
36 (40)
45(35)
–
CuBr–NBS
MeCN
CH2Cl2
MeCN
THF
3
CuBr–NBS
4
CuBr–Ph3P–NBSb
CuBr–Ph3P–NBSb
CuBr–IBD
5
6
THF
7
CuBr–PCC
THF
8
8
CuBr–NCS
THF
8
81(10)
57(18)
25(10)
–
9
CuBr–NCS
MeCN
CH2Cl2
MeOH
8
10
11
CuBr–NCS
8
CuBr–NCS
8
a Molar ratio of alkyne/azide/CuBr/oxidant = 1.5:1:1.5:1.5, with 1.5 equiv of DIPEA added as the alkali.
b Molar ratio of alkyne/azide/CuBr/Ph3P/oxidant = 1.5:1:1.5:1.5:1.5 with 1.5 equiv of DIPEA added as the alkali.
Synlett 2011, No. 6, 874–878 © Thieme Stuttgart · New York

876
L. Li et al.
LETTER
In summary, the preparation of 5-bromo-1,4-disubstitut-
ed-1,2,3-triazole directly from alkyne and azide was real-
ized in this work, and the CuBr–NCS was found to be a
mild and efficient reaction system for this conversion.
With this novel reaction system, terminal alkynes and
azides could react smoothly to give 5-bromo-1,4-disubsti-
tuted-1,2,3-triazoles in moderate to good yields with good
functional-group tolerance, and the application of this
method in constructing sugar and cADPR analogues also
give positive results, suggesting this reaction system has
potential applications in the synthesis of designed biomol-
ecules and natural-product analogues.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Scheme 1 The plausible mechanism of preparation of 5-bromo-1,
4-disubstituted-1,2,3-triazole with CuBr–NCS reaction system
Acknowledgment
This study was supported by the National Natural Sciences Found-
ation of China (grant no. 20802017) and Innovation Scientists and
Technicians Troop Construction Projects of Henan Province
(084100510002).
mixing NCS and bromide salt in THF supported this pro-
posal.24 With the active Br+ resource, bromo-substitution
reaction would be more facile as compared to proton ab-
straction, and thus the bromo-substituted product will be
the major product in the competitive reaction procedure.
Table 2 The Preparations of 5-Bromo-1,4-disubstituted-1,2,3-triazoles through the Multicomponent Azide–Alkyne Cycladdtion Reaction
Mediated by CuBr–NCS Reaction Systema
Entry Azides
Alkynes
Products25
Time (h) Isolated yield (%)
AcO
N3
O
Br
N
1
8
81
AcO
N
N
O
OAc
OAc
2a
1a
OAc
OAc
3a
AcO
N3
O
2
8
76
Br
N
AcO
N
N
OAc
OAc
O
2b
1a
OAc
OAc
3b
OAc
O
AcO
AcO
OAc
OAc
N
O
N
OAc
3
AcO
AcO
Br
8
71
N
N3
1b
2a
3c
Synlett 2011, No. 6, 874–878 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Bromo-1,4-Disubstituted-1,2,3-Triazoles
877
Table 2 The Preparations of 5-Bromo-1,4-disubstituted-1,2,3-triazoles through the Multicomponent Azide–Alkyne Cycladdtion Reaction
Mediated by CuBr–NCS Reaction Systema (continued)
Entry Azides
Alkynes
Products25
Time (h) Isolated yield (%)
O
OTBDMS
AcO
N
N
Br
O
OTBDMS
AcO
N
4
13
65
N3
1c
2a
3d
N3
Br
5
10
12
70
65
N
N
1d
N
2a
2a
3e
N3
Br
6
N
N
N
1e
3f
MeO
AcO
N3
O
7
12
60
Br
N
AcO
MeO
OAc
OAc
N
N
O
2c
1a
OAc
F
OAc
3g
AcO
N3
O
8
14
55
Br
N
AcO
F
OAc
N
OAc
N
O
2d
1a
OAc
OAc
O
3h
AcO
AcO
AcO
O
N3
O
O
HN
9
8
71
N
Br
HN
OAc
OAc
AcO
N
O
N
1a
O
OAc
OAc
2e
3i
Synlett 2011, No. 6, 874–878 © Thieme Stuttgart · New York

878
L. Li et al.
LETTER
Table 2 The Preparations of 5-Bromo-1,4-disubstituted-1,2,3-triazoles through the Multicomponent Azide–Alkyne Cycladdtion Reaction
Mediated by CuBr–NCS Reaction Systema (continued)
Entry Azides
Alkynes
Products25
Time (h) Isolated yield (%)
AcO
AcO
O
AcO
O
N3
O
HN
O
10
12
46b
N
Br
HN
OAc
OAc
AcO
N
O
N
1a
O
OAc
OAc
2e
3i
a The reaction was performed under ambient temperature in dry THF. Molar ratio of alkyne/azide/CuBr/NCS = 1.5:1:1.5:1.5 with 1.5 equiv of
DIPEA added as the alkali.
b With the CuBr–NBS reaction system in THF.
(16) Wu, Y. M.; Deng, J.; Li, Y.; Chen, Q. Y. Synthesis 2005,
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in THF (1.5 mL), and a light yellow solution was obtained
immediately. The UV spectrum showed emax = 382 nm,
which agreed with the UV spectrum of active bromine
reagent BrCl.
(25) Representative Procedure
A mixture of 1 (0.048 mmol), 2 (0.072 mmol), CuBr (10 mg,
0.072 mmol), DIPEA (9 mg, 0.072 mmol), and NCS (9.5
mg, 0.072 mmol) in THF (3 mL) was stirred at r.t. The
reaction procedure was monitored by TLC. When the
reaction was completed, the mixture was evaporated, and the
residue was partitioned between EtOAc and H2O. The
organic layer was washed with brine, dried over anhyd
Na2SO4, and evaporated. The residue was purified by silica
130, 3630.
gel column chromatography to give compound 3.
Synlett 2011, No. 6, 874–878 © Thieme Stuttgart · New York

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