A convenient preparation of 5-iodo-1,4-disubstituted-1,2,3-triazole: Multicomponent one-pot reaction of azide and alkyne mediated by CuI-NBS

Article abstract of DOI:10.1021/jo800035v

(Chemical Equation Presented) The system of CuI and NBS was found to provide both I⁺ and Cu⁺ for the first time. An efficient method for preparation of 5-iodo-1,4-disubstituted-1,2,3-triazole was achieved by multicomponent one-pot re

Full text of DOI:10.1021/jo800035v

Currently, click chemistry has found applications in target-
oriented synthesis,3,4 building molecular library,5,6 and biological
conjugation.7,8 A large number of biological active molecules
have been discovered with this convenient chemical tool.9–11
Possible reasons for the good biological activity of 1,2,3-triazole
derivatives have been suggested.4,10,12 One is that 1,2,3-triazoles
can well mimic natural peptides and heterocycles in geometrical
shape and interaction function.12a,2c Moreover, some recent
research has begun to explore the activity of 5-substituted-1,2,3-
triazole derivatives.13 Therefore, diverse functionalities on the
5-position of 1,2,3-triazole will be another efficient method for
exploring functional molecules.
A number of useful methodologies have been developed for
the synthesis of 5-substituted-1,2,3-triazoles. These methods
were summarized as follows: (1) specific 1,3-dipolar cylcoad-
dition between substituted alkynes and azides,14,15 (2) substitu-
tion reactions based on the activity of 5-H in 1,2,3-triazoles,16
and (3) substitution by trapping the carbon anion intermediates.17
However, most current methods display very narrow structural
diversity on both reactants and substituents. Thus, it is still a
challenge to find new protocols for efficient preparation of 1,4,5-
trisubstituted-1,2,3-triazole derivatives with diverse structure.
Here, we report a convenient multicomponent one-pot method
for efficient preparation of 1,4,5-trisubstituted-1,2,3-triazole
A Convenient Preparation of
5-Iodo-1,4-disubstituted-1,2,3-triazole:
Multicomponent One-Pot Reaction of Azide and
Alkyne Mediated by CuI-NBS
Lingjun Li,†,‡ Guisheng Zhang,*,† Anlian Zhu,† and
Lihe Zhang*,‡
College of Chemistry and EnVironmental Science, Henan
Normal UniVersity, XinXiang 453007, P. R. China, and
National Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Sciences, Peking UniVersity,
Beijing 100083, P.R. China
zgs6668@yahoo.com
ReceiVed January 7, 2008
(5) (a) Lee, L. V.; Mitshell, M. L.; Huang, S.-J.; Fokin, V. V.; Sharpless,
K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588–9589. (b) Salama, I.;
Hocke, C.; Utz, W.; Prante, O.; Boeckler, F.; Hubner, H.; Kuwert, T.; Gmeiner,
P. J. Med. Chem. 2007, 50, 489–500. (c) Lee, T.; Cho, M.; Ko, S. Y.; Youn,
H. J.; Baek, D. J.; Cho, W. J.; Kang, C. Y.; Kim, S. J. Med. Chem. 2007, 50,
585–589.
The system of CuI and NBS was found to provide both I+
and Cu+ for the first time. An efficient method for preparation
of 5-iodo-1,4-disubstituted-1,2,3-triazole was achieved by
multicomponent one-pot reaction of azides with alkynes in
the presence of the novel CuI and NBS catalytic system.
The high tolerance of various sensitive groups revealed the
potential applications of this method in organic synthesis and
drug discovery.
(6) (a) O’Neil, E. J.; DiVittorio, K. M.; Smith, B. D. Org. Lett. 2007, 9,
199–202. (b) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653–
4655. (c) Gierlich, J.; Burley, G. A.; Gramlich, P. M. E.; Hammond, D. M.;
Carell, T. Org. Lett. 2006, 8, 3639–3642. (d) Kuijpers, B. H. M.; Groothuys, S.;
Keereweer, A. R.; Quaedflieg, P. J. L. M.; Blaauw, R. H.F.; Van Delft, L.; Rutjes,
F. P. J. T. Org. Lett. 2004, 6, 3123–3126.
(7) (a) Mindt, T. L.; Struthers, H.; Brans, L.; Anguelov, T.; Schweinsberg,
C.; Maes, V.; Tourwé, D.; Schibli, R. J. Am. Chem. Soc. 2006, 128, 15096–
15097. (b) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.;
Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192–3193. (c) Link, A. J.; Tirrell,
D. A. J. Am. Chem. Soc. 2003, 125, 11164–11165. (d) Deiters, A.; Cropp, T. A.;
Mukherji, M.; Chin, J. W.; Anderson, J. C.; Schultz, P. G. J. Am. Chem. Soc.
2003, 125, 11782–11783.
(8) Seo, T. S.; Li, Z.; Ruparel, H.; Ju, J. J. Org. Chem. 2003, 68, 609–612.
(9) Cosyn, L.; Palaniappan, K. K.; Kim, S.-K.; Duong, H. T.; Gao, Z.-G.;
Jacobson, K. A.; Van Calenbergh, S. J. Med. Chem. 2006, 49, 7373–7383.
(10) Moorhouse, A. D.; Santos, A. M.; Gunaratnam, M.; Moore, M.; Neidle,
S.; Moses, J. E. J. Am. Chem. Soc. 2006, 128, 15972–15973.
Although, the demand for new chemical materials and
biologically active molecules continues to grow, chemists have
hardly begun to explore the vast pool of potentially active
compounds.1 The emerging field of “click chemistry”, a newly
identified classification for a set of powerful and selective
reactions, offers a unique approach to this problem.2 The most
powerful click reaction to date arguably is the Cu(I)-catalyzed
Huisgen 1,3-dipolar cycloaddition of azides and terminal alkynes
to afford 1,2,3-triazoles.2
(11) (a) Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.;
Vullo, D.; Supuran, C. T.; Poulsen, S.-A. J. Med. Chem. 2007, 50, 1651–1657.
(b) Pagliai, F.; Pirali, T.; Del Grosso, E.; Di Brisco, R.; Tron, G. C.; Sorba, G.;
Genazzani, A. A. J. Med. Chem. 2006, 49, 467–470. (c) Zhang, G.; Fang, L.;
Zhu, L.; Sun, D.; Wang, P. G. Bioorg. Med. Chem. 2006, 14, 426–434.
(12) (a) Thibault, R. J.; Takizawa, K.; Lowenheilm, P.; Helms, B.; Mynar,
J. L.; Fréchet, J. M. J.; Hawker, C. J. J. Am. Chem. Soc. 2006, 128, 12084–
12085. (b) Brik, A.; Alexandratos, J.; Lin, Y.-C.; Elder, J. H.; Olson, A. J.;
Wlodawer, A.; Goodsell, D. S.; Wong, C.-H. ChemBioChem 2005, 6, 1167–
1169.
† Henan Normal University.
‡ Peking University.
(13) Whiting, M.; Tripp, J. C.; Lin, Y.-C.; Lindstrom, W.; Olson, A. J.; Elder,
J. H.; Sharpless, K. B.; Fokin, V. V. J. Med. Chem. 2006, 49, 7697–7710.
(14) For reviews on 1,3-dipolar cycloadditions, see: (a) Carruthers, W.
Cycloaddition Reactions in Organic Chemistry; Pergamon: Oxford, 1990; p 269.
(b) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863. (c) L’abbé, G.
Chem. ReV. 1969, 69, 345–363.
(1) Bohacek, R. S.; McMartin, C.; Guida, W. C. Med. Res. ReV. 1996, 16,
3–50.
(2) For reviews of click chemistry, see: (a) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B Angew Chem., Int. Ed. 2001, 40, 2004–2021. (b) Kolb, H. C.;
Sharpless, K. B. Drug DiscoV. Today 2003, 8, 1128–1137. (c) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H Eur. J. Org. Chem. 2006, 51–68.
(3) Mocharla, V. P.; Colasson, B.; Lee, L. V.; Röper, S.; Sharpless, K. B.;
Wong, C.-H.; C. Kolb, H. C. Angew. Chem., Int. Ed. 2005, 44, 116–120.
(4) Bourne, Y.; Kolb, H. C.; Radic, Z.; Sharpless, K. B.; Taylor, P.; Marchot,
P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1449–1454.
(15) (a) Štimac, A.; Leban, I.; Kobe, J. Synlett 1999, 1069–1073. (b) Joubert,
N.; Schinazi, R. F.; Agrofoglio, L. A. Tetrahedron 2005, 61, 11744–11750.
(16) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett.
2007, 9, 2333–2336.
(17) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 1314–1318.
3630 J. Org. Chem. 2008, 73, 3630–3633
10.1021/jo800035v CCC: $40.75 2008 American Chemical Society
Published on Web 03/22/2008

TABLE 2. Reactive Procedure under Different Catalyst Systemsa
catalyst
system
reaction
time (h)
yieldb
(%)
product
FIGURE 1. Structures of cADPR, cTDPRE, and 5-I-cTDPRE.
CuI-NBSc
1
2
3
1
2
3
1
2
10
3
3
3
4
4
4
50
81
90
32
85
91
0
TABLE 1. One-Pot Preparation of 5-Iodo-1,2,3-triazole under
Different Conditions and Reagents
CuId
e
CuI-I2
4 + 3
4 + 3
4 + 3
0
0
a The reaction was performed under room temperature in dry THF,
with 1 equiv of DIPEA added as the alkali. b Isolated yields. c The mole
ratio of alkyne, azide, CuI, and NBS was 1:1.1:1.1:1.2, and 5-iodo-
1,4-disubstituted-1,2,3-triazole was obtained. d The mole ratio of alkyne
and azide was 1:1.1, and 1,4-disubstituted-1,2,3-triazole was obtained.
e Tthe mole ratio of alkyne and azide was 1:1.1.
catalyst
system
yielda
(%)
solvent
T (°C)
time (h)
b
CuI/I2
CuI/I2
CuI/I2
CuI/I2
THF
r.t.
reflux
r.t.
reflux
r.t.
r.t.
48
10
48
10
3
b
CH3CN
CH3CN
THF
THF
THF
First, we selected I2, NIS, and NBS as the source of I+ or
Br+ for the halo substitution on the 5-position of 1,2,3-triazole
by multicomponent one-pot click reaction of azidosugar 1a with
terminal alkyne 2a using CuI as catalyst (Table 1). It was found
that when I2 was chosen as the source of I+, no desired results
were obtained. Under different temperatures in different sol-
vents, no product was observed, and reactants remained intact,
which suggested that the existence of excessive iodine could
reduce the capability of Cu+ to catalyze the click reaction. Then,
NIS, as the active source of I+, was chosen for the iodination.
The desired product was obtained with low yield. As a control
group, we applied NBS as the active source of Br+ for
bromination. The reaction proceeded smoothly under room
temperature, and no obvious reactants were detected by TLC
after 3 h. Very surprisingly, the ESI-MS revealed that the
product from the reaction using NBS was identical and agreed
with the 5-iodo-1,2,3-triazole. No bromide was found in ESI-
b
b
CuI/NISc
55
90
CuI/NBSd
3
a Isolated yields. b The mole ratio of alkyne, azide, CuI, and I2 was
1:1.1:1.1:1.5. c The mole ratio of alkyne, azide, CuI, and NIS was
1:1.1:1.1:1.2. d The mole ratio of alkyne, azide, CuI, and NBS was 1:1.1:1.
1:1.2.
derivatives using a novel CuI and NBS system. The high
tolerance of various sensitive groups revealed the potential
applications of this method for the diverse modification on 1,2,3-
triazoles.
Along with our research in cADPR binding protein with
cADPR structural mimics, 5-halo-cTDPRE is designed on the
basis of cTDPRE (Figure 1).18 Several methods have been
reported for the preparation of 5-halo-1,4-disubstituted-1,2,3-
triazoles: (1) transformations from 5-NH2-1,4-disubstituted-
1,2,3-triazoles,15b (2) specific cycloaddition reaction between
bromoalkynes and azides,19 (3) substitution by trapping the
carbon anion intermediate with I2 or ICl as electrophilic
reagents,17 and (4) byproducts from Cu(I)-catalyzed Huisgen
cycloaddition reactions.20a In our case, the synthesis of 5-halo-
1,4-disubstituted-1,2,3-triazoles by trapping the carbon anion
intermediate with electrophilic reagents is employed because
of its benefits in efficiency and convenience, which come from
the reactivity of negative carbon intermediates and the charac-
teristics of multicomponent one-pot reactions.
1
MS and H NMR. In addition, the reaction with CuI-NBS as
catalyst provided 5-iodo-1,2,3-triazole in much higher yield than
the reaction using the CuI-NIS system.
In order to explore the efficiency of this protocol for
preparation of 5-iodo-1,2,3-triazoles, we compared the click
reaction with three catalytic systems, NBS-CuI, CuI-I2, and
CuI, respectively (Table 2). It was found that the one-pot
iodination click reaction with the CuI-NBS catalytic system
had almost equivalent activity to the Cu+-catalyzed click
reaction in conversion rate of alkyne and azide. The reaction
catalyzed with NBS-CuI proceeded for 3 h to give 5-iodo-
SCHEME 1. Plausible Mechanism of Preparation of 5-Iodo-1,4-disubstituted-1,2,3-triazole with CuI and NBS
J. Org. Chem. Vol. 73, No. 9, 2008 3631

TABLE 3. One-Pot Preparations of 5-Iodo-1,4-disubstituted-1,2,3-triazoles with CuI and NBSa
a The reaction was performed under room temperature in dry THF. The mole ratio of alkyne, azide, CuI, and NBS was 1:1.1:1.1:1.2, with 1 equiv of
DIPEA added as the alkali. b Isolated yield.
1,4-disubstituted-1,2,3-triazole derivative in a yield of 90%, and
no bromide was observed. In the absence of NBS, the reaction
catalyzed with CuI gave 1,4-disubstituted-1,2,3-triazole deriva-
tive in a yield of 91% under the same conditions. The CuI-I2
catalytic system did not show any reactivity under the same
conditions; neither the 5-iodo-1,4-disubstituted-1,2,3-triazole
derivative nor 1,4-disubstituted-1,2,3-triazole derivative was
observed.
Different solvents were also applied for this one-pot iodination
reaction. This reaction proceeded well in several common
solvents, such as THF, CH3CN, and CH3COCH3, with more
than 89% yields, under room temperature within 3 h. But the
reaction could not take place in methanol. Meanwhile, the
reaction in dichloromethane was sluggish due to the poor
solubility of CuI in it.
Based on the mechanisms of the click reaction in the
literature,2c,20b two possible mechanisms (I and II) for the
preparation of 5-iodo-1,4-disubstituted-1,2,3-triazole with CuI
and NBS were proposed and are outlined in Scheme 1. In order
to explore the rational mechanism of this multicomponent one-
pot reaction, three reactions catalyzed by CuI/NBS were
terminated after 1, 2, and 3 h, respectively. The yields of 3a
were 50%, 81%, and 90%, respectively (Table 2), and the
intermediate 3a′ was not observed in all three cases. This result
indicated that the reaction might not proceed via the mechanism
I. This result also indicated the oxidation–reduction reaction
must take place efficiently between NBS and CuI during this
procedure. The in situ generated I+ was then trapped by the
carbon anion intermediate from the click reaction (mechanism
II). During these processes, the Cu+ did not suffer oxidation;
3632 J. Org. Chem. Vol. 73, No. 9, 2008

instead, it acted as catalyst for the click reaction. Consequently,
CuI played double roles during this reaction procedure: (1) to
provide Cu+ as catalyst for Huisgen cycloaddition, in which
catalytic amounts of CuI were enough, and (2) to provide iodo
atom for the delivery of halogen in the reaction, in which
stoichiometric amounts of CuI were needed. As to NBS, its
possible role was to oxidize I- to I+; thus, the stoichiometric
amounts were needed.
The application of this new synthetic protocol was explored
by using various alkynes and azides as building blocks to
construct 5-iodo-1,4-disubstituted-1,2,3-triazole derivatives (Table
3).Different types of protective groups, such as acid-sensitive
acetal and ketal, alkali-sensitive acetyl and S,S-diphenylphos-
phate, and TBDMS group could tolerate the reaction conditions.
Some widely used active groups, like PhS- and MsO-, and
functional groups like ester, ether, amide, and hydroxyl were
also found to be intact under the CuI-NBS catalytic system.
Moreover, benzyl azide or other aliphatic azides successfully
reacted with corresponding alkynes to give 5-iodo-1,4-disub-
stituted-1,2,3-triazoles in good yields.
1,4-disubstituted-1,2,3-triazole and its application on synthesis
of natural product mimetics are underway now.
Experimental Section
Typical Procedure for the One-Pot Multicomponent Click
Reaction. The Synthesis of N-[5′′-(Phenylthio)phosphorylethoxy
ethyl]-2′,3′-O-isopropylidene-5′-phosphoryl-5-I-1,2,3-triazole-4-
amide-1-ꢀ-D-ribofuranoside 3a. A mixture of 1a (12 mg, 0.053
mmol), 2a (20 mg, 0.048 mmol), CuI (10 mg, 0.053 mmol), DIPEA
(7 mg, 0.053 mmol), and NBS (10 mg, 0.058 mmol) in 3 mL of
THF was stirred at room temperature for 3 h. The mixture was
evaporated, and the residue was partitioned between ethyl acetate
and H2O. The organic layer was washed with brine, dried over
anhydrous Na2SO4, and evaporated. The residue was purified by
silica gel column chromatography (1:50 MeOH/CH2Cl2) to give
compound 3a (33 mg, 90%): 1H NMR (500 MHz, D2O) δ 7.50–7.34
(m, 10 H), 5. 94 (d, J ) 8.5 Hz, 1 H), 4.91–4.87 (m, 1 H), 4.79
(dd, J ) 7.5 Hz, 3.5 Hz, 1 H), 4.50–4.47 (m, 1 H), 4.35–4.31 (m,
2 H), 4.02 (dd, J ) 14 Hz, 3 Hz, 1 H), 3.80 (dd, J ) 14 Hz, 3 Hz,
1 H), 3.68–3.60 (m, 6 H), 2.82–2.80 (br, 1 H), 1.63, 1.44 (s, each
3 H); 13C NMR (75 MHz, CDCl3),δ 159.4, 142.7, 135.3, 129.5,
126.2, 110.7, 85.7, 82.8, 73.5, 73.1, 69.7, 66.9, 66.7, 64.7, 38.9,
29.7, 26.6, 25.1; HRMS (M + H)+ (FT-ICRMS) calcd for
In conclusion, we have developed an efficient method for
preparation of 5-iodo-1,4-disubstituted-1,2,3-triazole by a one-
pot trapping carbon anion intermediate in click chemistry. The
CuI-NBS system was found to be an effective source of I+
and catalytic Cu+ simultaneously. The further construction of
diverse 1,4,5-trisubstituted-1,2,3-triazoles based on the 5-iodo-
+
C27H33IN4O8PS2 763.0517, found 763.0519.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (20672031), the Program
for New Century Excellent Talents in University of Henan
Province (2006-HACET-06), and Innovation Scientists and
Technicians Troop Construction Projects of Henan Province to
G.Z.
(18) (a) Gu, X. F.; Yang, Z. J.; Zhang, L. R.; Kunerth, S.; Fliegert, R.; Weber,
K.; Guse, A. H.; Zhang, L. H J. Med. Chem. 2004, 47, 5674–5682. (b) Guse,
A.; Gu, X. F.; Zhang, L. R.; Weber, K.; Zhang, L. H J. Biol. Chem. 2005, 280,
15952–15959. (c) Huang, L. J.; Zhao, Y. Y.; Yuan, L.; Min, J. M.; Zhang, L. H.
J. Med. Chem. 2002, 45, 5340–5352. (d) Huang, L. J.; Zhou, Y. Y.; Yuan, L.;
Min, J. M.; Zhang, L. H. Bioorg. Med. Chem. Lett. 2002, 12, 887–889.
(19) Kuijpers, B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg,
P. J. L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Synlett 2005,
3059–3062.
Supporting Information Available: Experimental proce-
dures, characterization data, and copies of 1H and 13C NMR of
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) (a) Bock, V. D.; Perciaccante, R.; Jansen, T. P.; Hiemstra, H.; van
Maarseveen, J. H. Org. Lett. 2006, 8, 919–922. (b) Himo, F.; Lovell, T.; Hilgraf,
R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am.
Chem. Soc. 2005, 127, 210–216.
JO800035V
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