Multicomponent Aqueous Synthesis of Iodo-1,2,3-triazoles: Single-Step Models for Dual Modification of Free Peptide and Radioactive Iodo Labeling

Article abstract of DOI:10.1002/chem.201605034

Iodo-1,2,3-triazoles are of considerable interest for chemical and biomedical applications. However, current synthetic methods for preparing iodo-1,2,3-triazoles cannot easily be applied to the direct modification of bioactive molecules in water. Through

Full text of DOI:10.1002/chem.201605034

A Journal of
Accepted Article
Title: Multi-component Aqueous Synthesis of Iodo-1,2,3-triazoles: A
Single-step Model for Iodine and Fluorescent Dual-modification of
Free Peptide
Authors: Lingjun Li, Shengqiang Ding, Yanping Yang, Anlian Zhu,
Xincui Fan, Mengchao Cui, Changpo Chen, and guisheng
Zhang
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To be cited as: Chem. Eur. J. 10.1002/chem.201605034
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Multi-component Aqueous Synthesis of Iodo-1,2,3-triazoles: A
Single-step Model for Iodine and Fluorescent Dual-modification of
Free Peptide
Lingjun Li,*[a] Shengqiang Ding,[a] Yanping Yang,[b] Anlian Zhu,[a] Xincui Fan,[a] Mengchao Cui*[b]
Changpo Chen,[a] and Guisheng Zhang*[a]
Abstract: Iodo-1,2,3-triazoles are of considerable interest
for chemical and biomedical applications. However, current
synthetic methods of iodo-1,2,3-triazoles can be hardly
applied into direct modifications of bioactive molecules in
water solvent. In this work, through novel combination of
water-compatible oxidative iodination and CuAAC reaction,
we developed a novel copper-catalyzed aqueous multi-
component synthetic method of 5-iodo-1,2,3-triazoles. The
method shows to be highly effective and selective for
substrates including biologically relevant compounds
bearing nucleoside, sugar and amino acid moieties.
Dramatically, based on this aqueous tandem reaction, a
direct single-step multi-component dual-modification of
peptide is developed from readily available starting
materials. Furthermore, the method could also be applied
radio-active isomer of iodine, iodo-1,2,3-triazole has offered
an intriguing moiety for the labeling of bioactive molecules,
with excellent resistances to in vivo deiodination and
compatibilities to different imaging groups (Figure 1).4,5
Many efforts have been made for the synthesis of iodo-
1,2,3-triazoles,6 however, most of them are not proper to
direct radioactive iodo-labeling procedures. Generally,
radioactive sodium iodide aqueous solution was the main
resource of iodine in the labeling, and less steps of reaction
and isolation procedure are required due to the radioactive
decay. For example, copper-catalyzed cycloaddition of 1-
iodo-alkyne and organic azide is one of the efficient way to
prepare 5-iodo-1,2,3-triazoles.6c However, this method
could not use simple iodide as iodine resource, and
involved pre-preparation of active 1-iodo-alkynes. Therefore,
atom- and step-economic multi-component reactions
allowing sodium iodide as main iodine resource are highly
appreciated in this field.
into concise and fast multi-component radioactive I125
-
labelings from commercial sodium [125I]iodide aqueous
solution as starting materials.
Introduction
Recently, iodo-1,2,3-triazoles have attracted great interest
in the wide scope of chemistry and biomedical science.1,2
Beyond a synthetic intermediate to structurally diverse
1,2,3-triazole derivatives, the unique properties of iodine
atom enable iodo-1,2,3-triazoles a valuable platform for
design of functional molecules.3,4,5 Especially, utilizing
Figure 1. Iodine-labeled and Iodine-modified compounds.4, 5
On the other hand, the solvent plays important role for
direct modifications of bioactive molecules. Highly polar
molecules including free peptides and nucleosides are
hardly soluble in low polar organic solvents, which
particularly require to develop aqueous reactions under mild
[a] Prof. L. Li, Mr. S. Ding, Dr. A. Zhu, X. Fan, Dr. C. Chen and Prof. G.
Zhang
Collaborative Innovation Center of Henan Province for
Green Manufacturing of Fine Chemicals, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education, School of
Chemistry and Chemical Engineering,
conditions for their post-modifications. We have developed
Henan Normal University
Xinxiang, Henan 453007, P. R.
E-mail: lingjunleelingjunlee@htu.edu.cn, zgs6668@yahoo.com.
a multi-component tandem protocol for combination of
oxidative iodination and copper-catalyzed alkyne and azide
cycloaddition (CuAAC), in which the “I+” in situ produced by
oxidation can effectively attack triazolyl copper(I)
intermediate to give 5-iodo-1,2,3-triazole with excellent
selectivity.6a Recently, Å stad and coworkers invented a new
CuCl2/NaI tandem oxidative iodination and CuAAC system,
by which labeling of peptides via 5-iodo-1,2,3-triazole
[b] Mr. Y. Yang and Prof. M. Cui
Key Laboratory of Radiopharmaceuticals, Ministry of Education,
College of Chemistry, Beijing Normal University,
Beijing 100875, People's Republic of China
E-mail: cmc@bnu.edu.cn
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moiety was efficiently accomplished in a step-economic
manner.5a,5b However, both of these systems are highly
sensitive to water. For instance, over 12% moisture in
CuCl2/NaI system was found to result a sharp decrease of
target I125-1,2,3-triazole.5b
(Table 1). In the presence of 0.1 equiv CuI as catalyst, and
1.2 equiv NaI, Selectfluor and TBACl, benzyl azide and
phenylacetylene reacted smoothly to give 5-iodo-1,2,3-
triazole 3a in the yield of 83% at 37 oC (Entry 16 in Table 1).
While raising temperature to 50oC, 5-iodo-1,2,3-triazole was
obtained in a little higher yield of 86% within 6 hours (Entry
30 in Table 1). The discovery of NaI/Selectfluor/TBACl
system firstly realize an aqueous multi-component
preparation of 5-iodo-1,2,3-triazole with readily accessible
terminal alkyne, azide and NaI as starting materials, which
can also proceed sufficiently under mild conditions with
catalytic amount of copper salts.
Scheme 1. Copper-catalyzed aqueous multi-component preparation of iodo-
1,2,3-triazole
Table 1 Screening the reaction systems for the synthesis of 3a in water
In this paper, we reported the first aqueous multi-
component synthetic method of 5-iodo-1,2,3-triazoles
directly from terminal alkynes, organic azides and NaI
under the catalytic amount of copper (Scheme 1). The
elaborate combination of water-compatible oxidative
iodination and CuAAC reaction in this reaction system
allows of this reaction being conducted in water under very
mild conditions. A wide range of structurally diverse fully
substituted 5-iodo-1,2,3-triazoles, including those bearing
bioactive molecules such as amino acids, sugars and
nucleosides, or photosensitive groups could be prepared
efficiently with good to excellent yields. Furthermore, the
high compatibility to water and mild conditions enables this
method to be utilized effectively in bioconjugation and
radioactive iodo-labeling. A single-step model for multi-
component iodine/fluorescent dual-modification of free
peptide was build up. Besides, a concise and fast multi-
component radioactive I125-labelling could be achieved with
commercial sodium [125I]iodide aqueous solution as starting
materials.
Entrya
Oxidant
(equiv.)
Catalyst
(10mol%)
Iodide
(equiv.)
Addtive
(1.2equiv.)
Yieldb
(%)
0
0
0
1
2
3
4
5
6
7
8
NBS(1.2)
NCS(1.2)
CuCl2(1.2)
H2O2(1.2)
TBHP(1.2)
NaClO(1.2)
Na(ClO4)2(1.2)
NaNO2(1.2)
CuCl2(1.2)
--
--
--
CuI(1.2)
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
CuI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
KI(1.2)
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
0
10
10
15
0
0
0
0
0
0
0
35
83
72
60
80
79
55
83
82
43
20
43
55
71
30
86
71
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30d
31e
FeCl3(1.2)
SnCl4(1.2)
PCC(1.2)
DDQ(1.2)
IBDc(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectflour(1.2)
Selectfluor(2.4)
Selectfluor(4.8)
Selectfluor(0.6)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
Selectfluor(1.2)
TBACl
TBABr
TBAF
TBACl
NH4I(1.2)
I2(1.2)
TBACl
TBACl
TBACl
TBACl
TBACl
TBACl
TBACl
TBACl
TBACl
TBACl
TBACl
TBACl
NaI(2.4)
NaI(4.8)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
NaI(1.2)
Results and Discussion
CuCN
CuBr
CuPF6
CuCl
Cu2O
CuI
Oxidants play key roles to provide electrophilic iodine
resource and keep the catalytic ability of copper salts in the
tandem oxidative iodination and CuAAC reaction.6b,7
Rational groups of oxidants and copper salts could
dramatically enhance reaction efficiency and selectivity.5a, 6b
In this work, we systemically screened oxidants in the
combination of various iodide, copper salts and additives
under water-phase conditions. All the reported oxidative
iodination system such as NBS/CuI, NCS/CuI, and
CuCl2/NaI did not work under the water-phase conditions.
Besides, other commercial iodination reagents such as
iodine and ICl were also ineffective due to low solubility in
water. Finally, a new NaI/Selectfluor/TBACl system was
found as the potent one from the over 20 combinations
CuI
[a] 0.12 mmol alkyne 1a, 0.1 mmol of azide 2a and 1.2 mmol DIPEA
were used as substrates; [b] isolated yields; [c] IBD is iodosobenzene
diacetate; [d] reaction was run at 50 oC; [e] reaction was run at 70 oC.
The scope of the substrates was then investigated with
the novel reaction system. It was found that
phenylacetylenes and benzyl azides with various
substituted groups could react well with NaI under the
optimized reaction conditions (Table 2). Phenylacetylenes
with electron-rich and electron-withdrawing substituent
groups reacted to give corresponding 5-iodo-1,2,3-triazoles
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(
3a
-
d
in Table 2) in 83% to 86% yields. Benzyl azides with
although they very easily suffered iodination with other
oxidative iodination reagents.9 The applications in bioactive
molecules further indicated a wide scope of reactants and
desirable chemoselectivity of this aqueous reaction system.
The other intriguing aspect of this reaction system is its
high tolerance to functional groups. The functional groups
such as fluorophores, photoaffinity tags, bioconjugation
groups are well used for preparation of biology relative
materials and biconjugations.10 Fluorescent alkyne 1h and
florescent azide 2h reacted effectively under the optimized
electron-rich and electron-withdrawing substituent groups
were the effective substrates for the reaction, in which the
corresponding 5-iodo-1,2,3-triazoles
(
3e
-h)
could be
obtained in the yields of 86-81%. Besides, aryl and alkyl
azides were also effective to this reaction to give 5-iodo-
1,2,3-triazoles with 72% to 85% yields (3i-j). These results
suggested that this reaction was very useful in the small
organic molecules for the preparation of their 5-iodo-1,2,3-
triazole derivatives.
conditions to produce 5-iodo-1,2,3-triazole 3l, 3r and 3v in
the yields of 81%, 77% and 88%. Alkynyl donor containing
photoaffinity tag 1g reacted effectively with azides 2j and 2k
to give products 3o and 3t with 84% and 90% yields. N-
Hydroxyl succinimidyl (NHS) ester is one of the classic
functional groups using in the bioconjugation of nucleic
acids and proteins.11 Azide donor bearing NHS ester group
2m was also investigated as the substrate for the water-
phase reaction system. Excitingly, NHS ester was found
intact during the reaction procedure after 12 hours to give
Table 2 Synthesis of 5-iodo-1,2,3-triazoles from alkynes and azides.
Entry[a]
R1
R2
Product Time
(h)
Yieldb
1
2
3
4
5
6
7
8
9
10
Ph
PhCH2
PhCH2
PhCH2
PhCH2
p-Cl(C6H4)CH2
p-Br(C6H4)CH2
p-NO2(C6H4)CH2
p-CH3O(C6H4)CH2
p-CH3O C6H4
n-hexyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
12
12
12
12
12
12
12
12
24
24
86
88
89
83
86
82
81
86
72
85
p-CH3(C6H4)
p-F(C6H4)
p-CH3O(C6H4)
Ph
Ph
Ph
Ph
Ph
Ph
desirable products 3u and 3v
.
3j
[a] 0.12 mmol alkyne and 0.1 mmol of azide were used as substrates
[b] isolated yields.
;
Nucleosides, sugars and amino acids containing 1,2,3-
triazole motifs present a class of interesting structures for
multi-purpose applications in drug design.8 However, the
delicate structures of these compounds require more mild
reagents, close to neutral pH for their late-stage
modifications. The current methods involved pre-
preparations of 1-iodo-alkyne or harsh reaction reagents
were not applicable to this kind of reactants. Following with
the utilizations in simple small organic molecules, we then
investigated the applications of the current reaction system
in nucleosides, sugars and amino acids derivatives bearing
alkyne and azide donors (Table 3). The nucleoside moieties
Figure 2. Strategies for dual-modification of bio-molecules.12
Inspired by the successful utilization of this method in
bioactive molecules, photosensitive functional groups, plus
the moderate reaction conditions, we next explored its
application in the bioconjugation of peptides. As we know,
dual function labeling of bioactive molecules is a practical
tool in the bioconjugation and medical imaging.13,6
Traditionally, these dual-modifications require the use of
sequential click reactions or combination of different types
of click reactions such as CuAAC and SPAAC,12 in which
multi-step reaction routes and different types of reaction are
involved (Figure 2A). Comparedly, one-pot multi-component
reactions can provide a fairly convenient tool to realized
such procedures (Figure 2B). However, most multi-
component reactions that involved active intermediates can
not proceed in water solvents under the close to neutral pH
scope,14 which make them hardly utilize in the direct
modifications on water-soluble biomolecules. Herein, we
would like to provide an example for the application of our
(1e and 1f) were the effective substrates for the reaction
under the optimized conditions. Protected ribosyl and free
deoxy-ribosyl were intact under this conditions to give 5-
iodo-1,2,3-triazoles with 80% to 81% yields. Azides bearing
D-ribose and D-glucose moieties (2i and 2j) were also used
as azide donors. Both of furanoid and pyranoid sugars
reacted smoothly to give corresponding 5-iodo-1,2,3-
triazoles in good yields. Besides, azides deriving from
natural amino acid esters could effectively produce 5-iodo-
1,2,3-triazoles 3p, 3q, 3r and 3t with desirable yields.
aqueous
fluorescent/iodine dual-modification of free peptides. The
reaction of pentapeptide bearing azide group 2n
multi-component
reaction
system
in
Surprisingly, even no iodination occurred on the electro-rich
phenol moieties of 3q and 3r under the current conditions,
,
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Scheme 2 Dual-modification of peptide by three-component (A) or four-component (B) assembly in water.
fluorescent alkyne 1h and NaI under the optimized
conditions could proceed effectively to give the target
product 3w with 81% yield in 24 h (Scheme 2A). Since we
have noticed that NHS ester group can be intact under the
current reaction system (3u and 3v in Table 3), we
supposed that the connection of NHS to peptide, iodination
and CuAAC could complete in one pot. Thus, a four-
component assembly was then investigated with the
pentapeptide, azide donor bearing NHS, alkyne donor
bearing fluorescent group and NaI as starting materials
Scheme 3 Radioactive multi-component iodination in water. a RCY
(Scheme 2B). To our delight, the double-modified peptide
3w with iodine and fluorescent group was finally obtained in
67% yields within 24 h. This example illustrated a promising
perspective of our reaction system in the direct multi-
component labelling on water-soluble biomolecules.
was calcuated by analytic HPLC.
(Scheme 4).15 In order to detailedly understand the reaction
mechanism, control reactions were conducted (Scheme 5).
In situ electrophilic trapping with allyl bromide is an effective
approach to detect triazolyl copper intermediate.6c,16 After
the addition of 2.2 equiv allyl bromide, 5-allyl-1,2,3-triazole
was obtained in 55% yield under the current reaction
conditions. Increasing the amount of alkyl bromide to 5.0
equiv, 86% yield of 5-allyl-1,2,3-triazole was obtained (Eq-1
in Scheme 5). The high yield of 5-alkyl-1,2,3-triazole
indicated triazolyl copper existed in the reaction procedure
as the main intermediate. Besides, no 1-iodo-alkyne was
detected during the reaction conditions. Instead, an additive
product 1,2-diiodoalkene was isolated in 71% yield in the
absence of azide, however, it failed to react with benzyl
azide to give 5-iodo-1,2,3-triazole under the standard
reaction conditions (Eq-3 and Eq-4 in Scheme 5). Therefore,
in this aqueous system, current evidences support the route
A in which the iodination occurs on triazolyl copper
intermediate.
Advantages of the current aqueous reaction system were
also investigated in the radioactive I-125 labeling. Direct
preparation of I125-1,2,3-triazole reaction in water is still a
challenging due to high sensitivity of water in the multi-
component radioactive iodination.5b In this paper, taking the
reaction of 1-ethynyl-4-fluorobenzene and benzyl azide as
an example, in the presence of CuCl, [125I]NaI, Selectfluor,
TBACl and water as the only solvent, 78% radiochemical
yield (RCY) of the triazole [125I]3c was obtained (Scheme
3). 100 μCi of sodium [125I]iodide aqueous solution could be
directly used as the iodine source without any pre-
concentration for the reaction. Further time-course
experiments indicated 70% RCY of triazole [125I]3c could be
achieved even within 10min. In this regards, the current
aqueous multi-component synthetic methodology provides
an attractive perspective for the development of concise
and fast radioactive I125-labelling.
Two separated reaction mechanistic pathways via 1-iodo-
alkyne or triazolide copper for the formation of 5-iodo-1,2,3-
triazole are suggested based on the recent research
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Table 3 Synthesis of 5-iodo-1,2,3-triazoles containing bioactive moieties and functional groups.
Entry
Alkyne
Azide
Product
Isolated Yield
1
BnN3 2a
80
1e
1e
3k
2
81
2h
3l
3
4
BnN3 2a
80
1f
1a
3m
81
2i
3n
5
84
2j
1g
3o
6
7
86
1a
2k
3p
79
1a
2l
2l
3q
8
77
1h
1i
3r
9
BnN3 2a
91
3s
10
90
1g
2k
3t
11
12
91
1a
1h
2m
2m
3u
88
3v
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Scheme 5 Control experiments (I)
Scheme 4 Plausible mechanistic pathways
During the route A, the oxidation of iodide with selectfluor
was identified by potassium iodide starch papers test. A
blue spot appeared immediately when dropping the
aqueous solution of selectfluor onto the test paper, which
indicated selectfluor rapidly oxidated iodide in water. The
oxidation product then provided electrophilic “I+” to trap
triazolide copper intermediate. The roles of TBACl were
investigated by another two groups of control experiments
in Scheme 6. As shown by Eq-5 in Scheme 6, only 35%
yield of 5-iodo-1,2,3-triazole was given with NaI/Selectfluor.
Compared with the combination of NaI/Selectfluor/TBACl,
86% yield of 5-iodo-1,2,3-triazole could be obtained (Eq-6
in Scheme 6). Therefore, one of the roles of TBACl in the
reaction is to assist NaI/Selectfluor to provide more efficient
iodination reagents. Replacing NaI and TBACl with TBAI,
85% yield of 5-iodo-1,2,3-triazole were obtained (Eq-7),
almost equal to the yield of the reaction with
NaI/Selectfluor/TBACl (Eq-6). Thus, it is reasonable that
NaI and TBACl might form TBAI tight ion pair17 in the
current aqueous reaction. Free iodide in the solvent could
retain a low concentration due to the formation of TBAI tight
ion pair, which would prevent the electrophilic oxidation
product of iodide and selectfluor (“I+”) to react further with
iodide to form less reactive molecular iodine or triiodide,
and thus keep a high reactivity for the following iodination
on triazolyl copper intermediate. The effects of TBACl on
the trapping experiments were also investigated as shown
in Eq-8 and Eq-9 in Scheme 6. In the presence of
selectfluor and TBACl, 5-allyl-1,2,3-triazole was produced in
51% yield (Eq-8). At the same condition but in absence of
TBACl, 5-allyl-1,2,3-triazole was obtained in 46% yield (Eq-
9). No dramatic decrease of trapping yields implied that
there might be not significant effects of TBACl on the
reactivity of copper triazolide in the current reaction system.
Scheme 6 Control experiments (II)
Conclusions
In summary, a copper-catalyzed aqueous multi-component
reaction to prepare 5-iodo-1,2,3-triazole from readily
accessible terminal alkynes, organic azides and NaI was
developed for the first time. In the presence of catalytic
copper salt, a wide scope of substrates bearing sensitive
functional groups and delicate structures such as sugar,
nucleoside and amino acid moieties can react smoothly
under the optimized conditions to give desirable yields with
high selectivity. Furthermore, the aqueous solvent, mild
reaction conditions, high tolerance of sensitive functional
groups and bio-compatible starting materials of this reaction
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enabled the method to successfully apply in the direct multi-
component dual-modification of the free peptide.
Additionally, the current method was applied into I-125
labeling. In the model reaction, 70% RCY could be
achieved within 10 min using water as the solvent and
commercial 100 μCi sodium [125I]iodide aqueous solution as
the radioactive starting material, which provided an
attractive perspective for the development of concise and
fast multi-component radioactive I125-labelling.
on a C18-bonded silica column. After the reaction was completed, the
solvent was evaporated, and the residue was dissolved in 10% CH3CN
water solution, which was applied to a C18 reversed-phase column
(9.4×250mm). The column was eluted using a linear gradient of 10–85%
CH3CN containing 0.1% TFA over 50 min to give 3w (2.6 mg, 67 %) after
lyophilization.
Acknowledgements
This work provided a novel protocol to resolve the
problems of the high sensitivity to water in this type of
reactions and requirements of stoichiometric copper salt
existed in known methods. Besides, it also presents a rare
Financial support from NSFC (21172058, 21472036, and
21372065) and PCSIRT (IRT1061).
example for efficient tandem of
a water-compatible
Keywords: Aqueous reaction • Iodination • triazole • Click
chemistry • Peptide
iodination and copper-catalyzed alkyne-azide cycloaddition
(CuAAC), which is expected to further expand the usages
of 5-iodo-1,2,3-triazole in the post-modifications of bioactive
molecules, and enrich the toolbox of current CuAAC
systems. The further applications of this method in the
medicinal radiochemistry and multi-purpose bioconjugation
are still undergoing in our lab.
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Experimental Section
Synthesis of Compound 3a to 3v Azides (0.1 mmol), terminal alkynes
(0.12 mmol), Selectflour (0.12 mmol), NaI (0.12 mmol), TBACl (0.12
mmol), DIPEA (0.12 mmol), and CuI (0.01 mmol) were added in H2O (1
mL) and stirred for 6 h at 50℃ (oil bath) in air. The reaction was
monitored by TLC analysis. After the reaction was completed, the mixture
was extracted with ethyl acetate ( 3×10 mL).The organic layer dried over
Na2SO4. The filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel, eluting with
petroleum ether/ethyl acetate to afford the pure compounds.
[3]
[4]
[5]
Synthesis of dual-labeling pentapeptide 3w
Route A: Pentapeptide bearing azide group 2n (2 mg), fluorescent
alkyne 1h (1mg, 1.5 equiv.), Selectflour (2mg, 1.5 equiv), NaI (2 mg, 1.5
equiv), TBACl (1mg, 1.5 equiv), DIPEA (0.5 mg, 1.5 equiv), and CuI (0.1
mg, 0.15 equiv) were added in H2O (150μL) and stirred for 24 h at 37 oC.
The reaction was monitored by analytical RP-HPLC chromatogram in a
linear gradient of 10-85% of CH3CN in water containing 0.1% TFA over
20 min on a C18-bonded silica column. After the reaction was completed,
the solvent was evaporated, and the residue was dissolved in 10%
CH3CN water solution, which was applied to a C18 reversed-phase
column (9.4×250mm). The column was eluted using a linear gradient of
10–85% CH3CN containing 0.1% TFA over 50 min to give 3w (2.3 mg,
81 %) after lyophilization.
[6]
[7]
[8]
[9]
Route B: Pentapeptide 4 (2 mg), azide 2m (7mg, 6 equiv), fluorescent
alkyne 1h (6mg, 6 equiv), Selectflour (8.5 mg, 7 equiv), NaI (3.6 mg, 7
equiv), TBACl (6.7 mg, 7 equiv), DIPEA (3 mg, 7 equiv), and CuI (0.6 mg,
a) F. Amblard, J. H. Cho, R. F. Schinazi, Chem. Rev. 2009, 109, 4207-
4220.
o
0.7 equiv) were added in H2O (150μL) and stirred for 24 h at 37 C. The
A. Podgoršek, M. Zupan, J. Iskra, Angew. Chem. Int. Ed. 2009, 48,
8424-8450.
reaction was monitored by analytical RP-HPLC chromatogram in a linear
gradient of 10-85% of CH3CN in water containing 0.1% TFA over 20 min
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Chemistry - A European Journal
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Entry for the Table of Contents
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Lingjun Li,* Shengqiang Ding, Yanping
Yang, Anlian Zhu, Xincui Fan,
Mengchao Cui,* Changpo Chen and
Guisheng Zhang*
Page No. – Page No.
Multi-component Aqueous Synthesis
of Iodo-1,2,3-triazoles: A Single-step
Model for Iodine and Fluorescent
Dual-modification of Free Peptide
Multi-component dual-labelling of free peptide in water
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