Three-component assembly of 5-halo-1,2,3-triazoles via aerobic oxidative halogenation

Article abstract of DOI:10.1016/j.tetlet.2013.08.089

An effective synthetic protocol for 5-halo-1,2,3-triazoles was developed by novel TBDMSCl (tert-butyldimethylsilyl chloride)-activated aerobic oxidative halogenations in this Letter. TBDMSCl, for the first time, was found to activate aerobic oxidation of

Full text of DOI:10.1016/j.tetlet.2013.08.089

Accepted Manuscript
Three-component Assembly of 5-Halo-1,2,3-triazoles via Aerobic Oxidative
Halogenation
Lingjun Li, Guoliang Hao, Anlian Zhu, Sangui Liu, Guisheng Zhang
PII:
S0040-4039(13)01475-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.089
TETL 43452
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 July 2013
16 August 2013
24 August 2013
Please cite this article as: Li, L., Hao, G., Zhu, A., Liu, S., Zhang, G., Three-component Assembly of 5-Halo-1,2,3-
triazoles via Aerobic Oxidative Halogenation, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.08.089
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Three-component Assembly of 5-Halo-1,2,3-triazoles via Aerobic
Oxidative Halogenation
Lingjun Li,* Guoliang Hao, Anlian Zhu, Sangui Liu, Guisheng Zhang*
School of Chemistry and Chemical Engineering, Henan Normal University, Key
Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Xinxiang 453007, P. R. China
Lingjunlee@htu.cn, zgs@htu.cn
Abstract: An effective synthetic protocol for 5-halo-1,2,3-triazoles was developed by
novel TBDMSCl (tert-Butyldimethylsilyl chloride)-activated aerobic oxidative
halogenations in this paper. TBDMSCl, for the first time, was found to activate
aerobic oxidation of CuX to produce X2 with Cu+ which then could effectively
promote one-pot syntheses of 5-halo-1,2,3-triazole from alkyne, azide and CuX (X = I,
Br) under O2 atmosphere at room temperature. The advantages in this method include
inexpensive and green O2 as oxidant, use of mild and non-oxidative additive, and
wide scope of substrates.
Keyword: aerobic oxidative halogenations, 5-halo-1,2,3-triazole, nucleoside
1

Recently, 1,2,3-triazole derivatives not only provide a desirable class of linkage,[1] but
also represent useful functional moieties including peptide bond mimics,[2] nucleobase
bioisosteres,[3] ligands in metal complex[4] and so on[5]. In this regard,
5-halo-1,2,3-triazoles are valuable structural derivatives of 1,2,3-triazole because they
are established precursors to other functional groups,[6] as well as widely-used
analogues for the SAR investigation.[7] Unfortunately, direct halogenation on
1,2,3-trizole ring is unsuccessful due to the electron deficiency of 1,2,3-triazoles.
Diazotization of 5-NH2-1,2,3-triazole was initially used to incorporation of iodine into
1,2,3-triazole.[8] Then the cycloaddition reactions of alkynyl-iodine and
alkynyl-bromide with azide were developed to preparation of 5-halo-1,2,3-trizoles by
Sharpless groups [9a], García-Álvarez[9b] and Rutjes groups[10]. Meanwhile, an
alternative tandem oxidative halogenation and Husigen cycloadditon protocol has
stepwise developed for the preparation of 5-iodo-1,2,3-triazole directly from the
multi-component reaction of iodide, alkyne and azide [11a, 12, 13]. This protocol allows
the reactions proceed under mild conditions without the pre-prepared active
alkynyl-halogen and complex ligands, which has been used in the preparation of the
sugar drugs [14] and I125-labled peptides [15]. However, the metal or organic oxidants are
still involved in this protocol. O2 as an oxidant has attracted interest in both of
academic research and industry due to its natural, inexpensive, and environmentally
friendly characters [16]. Herein, we reported the first effective tandem aerobic
oxidative halogenation and Husigen cycoladditon reaction for the preparation of
5-iodo-1,2,3-triazole and 5-bromo-1,2,3-triazole via an in situ activated procedure
2

(Scheme 1).
Scheme 1 Tandem halogenation and Husigen cycloaddition reaction via in situ
chlorosilane-activated aerobic oxidative procedure
5-Halo-1,2,3-triazoles are firstly found as trace by-products in CuAAC reaction[17]
.
These compounds are considered to be produced from trapping of Cu-triazolyl
intermediate with electrophilic halogen. But this aerobic oxidative halogenation in
CuAAC reaction is very sluggish. For example, van Maarseveen et al. found
5-iodo-1,2,3-triazole analogues in cyclic tetrapeptide could be obtained under CuI
(2.0 equvi)/2,4-ludtidine/DIPEA systems with 14% yield after 3 days.[18] In fact, it is
still a challenge to improve the efficiency of the aerobic oxidative halogenation for a
long time, because direct activation of O2 at mild conditions is very difficult.[19]
Several methods have been developed in this field. For example, MX/TFA/NOBF4/O2
[21]
[20], MX/RuCl3/O2
HX/[bmim][NO3][22] and HX/[BMIM(SO3H)][NO3][23] have
been reported to effectively promote aerobic oxidative halogenation. The systems,
however, often require strong acidic condition, co-oxidant or high reaction
temperature, which is hard to be compatible to the copper(I) catalyst and
copper-triazolyl complex in CuAAC reaction. Therefore, the goal of this work was to
3

find a mild and facile method for activation of the aerobic oxidative halogenation
during CuAAC procedure, then to develop an aerobic oxidative one-pot assembly of
terminal alkyne, azide and CuX to 5-halo-1,2,3-triazole.
Table 1. The effect of additives on one-pot synthesis of 5-iodo-1,2,3-triazole.
Isolated yield
Entrya Additive (equiv.) Oxidant
Base
Solvent
3a (%) 4a (%)
TMSCl (1.1)
TBDMSCl (1.1)
TBDMSCl (0.5)
TBDMSCl (0.1)
--
Air
Air
Air
Air
Air
O2
O2
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
TEA
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
65
81
78
49
9
22
4
1
2
11
20
83
5
3
4
5
6
TBDMSCl (0.5)
NaNO2 (0.5)
93
--b
--b
66
78
50
--b
89
6
7
TBDMSCl (0.5)
TBDMSCl (0.5)
TBDMSCl (0.5)
TBDMSCl (0.5)
N2
8
O2
9
O2
CH3CN
CH3CN
20
46
10
11
O2
K2CO3
a
Reaction conditions: A mixture of 1a (17 mg, 0.17mmol), 2a (23 mg, 0.17mmol),
CuI (32 mg, 0.17mmol), and DIPEA (30 μL, 0.17 mmol) with different additives and
oxidants was stirred in 3 mL solvent at room temperature for 18 h.b No product were
detected.
The investigation for activation of the aerobic oxidative halogenation in CuAAC was
4

carried out in Table 1. Firstly, we found increase of the amount of CuI could not
improve the yield of 5-iodo-1,2,3-triazole. In presence of 1.1 equiv. CuI, the yield of
3a was still 9% after 18 hours, with 83% 1,2,3-triazole 4a. Then 0.5 equiv. NaNO2 as
co-oxidant was tried, but neither of 1,2,3-triazole and 5-iodo-1,2,3-triazole could be
obtained under these conditions with total recovery of starting materials. To our
delight, the activation effects of chlorosilan on the aerobic oxidative iodination was
found by accidently when addition of TMSCl into the reaction of CuI, 1a and 2a in
presence of DIPEA. Unexpectedly, no 5-TMS-1,2,3-triazole was found, instead,
5-iodo-1,2,3-triazole 3a was obtained in 65%. With this result in hand, we continued
to optimize silica reagents, solvents and reaction temperature. With 0.5 equiv.
TBDMSCl, 1.1 equiv. DIPEA under O2 atmosphere, product 3a was obtained in 93%
yield after 18 hours at room temperature in CH3CN as solvent (Entry 6 in Table 1).
Having optimized reaction conditions, we next investigated the substrate scope of this
one-pot preparation of 5-iodo-1,2,3-triazole in Table 2. It was found that substituted
aromatic alkynes carrying electron-withdrawing or electron-donating groups reacted
smoothly with benzyl azide to produce 5-iodo-1,2,3-triazoles with excellent yields
(85%-93%). Aliphatic terminal alkynes also reacted well with benzyl azide to give
target compounds with 68%-78% yields. Even the bulky 9-ethynyl-9H-fluoren-9-ol
could condense smoothly to give a yield of 75% of desired product. Various azides
were used. Phenyl azide and phenethyl azide reacted with terminal alkyne to produce
5-iodo-1,2,3-triazoles with 69%-87% yields. Various acidic and basic sensitive groups
like ketal, methoxyl, ribosyl, trimethyl and ether were tolerated under the reaction
5

conditions. For example, ribosyl azides, alkyne and CuX were condensed to give
5-iodo-1,2,3-triazoles with 71% and 66% yields, which provided very useful
intermediates for the preparations of unnatural base nucleosides.[24]
Trimethylsilyacetylene
reacted
smoothly
with
azide
to
give
4-TMS-5-iodo-1,2,3-triazole, which could be conveniently converted into
1,5-disubstituted-1,2,3-triazole after deprotection of trimethylsilyl protective group [25]
Furthermore, preparations of 5-bromo-1,2,3-triazole were also investigated with
CuBr-TBDMSCl systems. It was expected to be more difficult to activate the areobic
oxidative bromination due to the higher standard electrode potential of Br2 compared
to that of I2. To our delight, however, under the current conditions,
.
5-bromo-1,2,3-triazoles
could
also
be
obtained
effectively
from
TBDMSCl/CuBr/Alkyne/Azide reaction system with 62%-69% yields (3l-3n, 3p in
Table 2).
6

Table 2 Substrate scope of TBDMSCl-promoted one-pot alkyne/azide/CuX reaction
Reaction conditions: A mixture of azide 1 (0.17mmol), alkyne 2 (0.17mmol), CuI
(32mg, 0.17mmol), DIPEA (30 μL, 0.17 mmol) and TBDMSCl (12mg, 0.08 mmol)
was stirred in 3 mL CH3CN under O2 atmosphere at room temperature for 18 h.
To gain some insight of the reaction mechanism, the possible roles of TBDMSCl in
the aerobic oxidative one-pot synthesis of 5-halo-1,2,3-triazole were investigated.
Firstly, an evident dissolution process of CuI was observed after addition of
TBDMSCl under the present conditions. A possible mechanism involved in this
procedure was that TBDMSCl and CuI reacted to produce CuCl and soluble
TBDMSI[26], by which the effective concentration of iodide was expected to
dramatically increase in organic phase. Secondly, additional two reactions (Eq-1 and
Eq-2 in Figure 1) were designed. Reaction mixture of Eq-1 turned into a light purple
7

after being stirred under air atmosphere for 18 hours at room temperature. This light
purple solution can make 0.5% soluble starch solution into deep blue (solution C).
Comparedly, the reaction mixture of Eq-2 after being stirred under same conditions in
absence of TBDMSCl for 18 hours could not make soluble starch solution blue.
Thirdly, UV spectrums of the Eq-1 reaction mixture and control groups were also
investigated as shown in Figure 2. The solution of I2 in CH3CN showed two
absorption bands at 294 nm, 367 nm (purple trace in Figure 2) which were consistent
to the reported data in literature. [27] Absorption spectrum of reaction mixture of Eq-1
contained two bands at 294 nm and 367 nm (green trace in Figure 2), which perfectly
agreed with the two absorption bonds of iodine in CH3CN solution. But in the
absorption spectrum of TBDMSCl and CuI, the corresponding bonds at 294 nm and
367 nm were not observed. These experiments indicated that I2 could be effectively
produced from reaction of CuI and oxygen in air in presence of TBDMSCl (Eq-1),
while in absence of TBDMSCl, I2 could hardly be detected from the reaction of CuI
and oxygen in the reaction of Eq-2. Thus, a key promotion of TBDMSCl on the
aerobic oxidative iodination could be concluded from the results. To our best
knowledge, this is the first report about the activation of chlorosilane on aerobic
oxidative iodination reaction. Moreover, no appearance of a copper (II) d-d transition
bond in the 700 nm range also suggested that this TBDMSCl-activated aerobic
oxidative iodination didn’t cause the oxidation of Cu(I) to Cu(II). The presence of
sufficient Cu (I) could provide effective catalyst for the following Husigen
cycloaddition.
8

Figure 1. (A) Adding reaction mixture of Eq-2 solution (0.06 mol/L) into 0.5%
soluble starch solution; (B) Adding 0.06 mol/L TBDMSCl (CH3CN) into 0.5%
soluble starch solution; (C) Adding resulting reaction mixture of Eq-1 solution (0.06
mol/L) into 0.5% soluble starch solution; (D) Adding 0.03 mol/L I2 (CH3CN) into
0.5% soluble starch solution; (E) Blank control: 0.5% soluble starch solution.
2.0
CuI
TBDMSCl
1.8
CuI+TBDMSCl
I
1.6
2
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
250
300
350
400
450
500
550
600
650
700
750
Wavelength(nm)
Figure 2. Absorption spectra of solution of CuI ( 0.2 mM, blue), TBDMSCl (2 mM,
red), Resulting reaction mixture of Eq-1 (0.2 mM green), and iodine (0.2 mM) in
CH3CN.
On the basis of the above preliminary results and the known nucleophilic trapping
mechanism models of 5-iodotriazoles[28], a possible reaction mechanism of the
TBDMSCl-CuX promoted one-pot reaction of terminal alkyne and azide was
proposed in Scheme 2. The X2 produced in situ from the TBDMSCl-activated aerobic
9

oxidative halogenation attacked the copper-triazolyl complex 5 to form the sp2 C-X
bond on the 5-carbon of 1,2,3-triaozle. During the reaction procedure, two main roles
of TBDMSCl could be suggested, (1) enhancing the effective concentration of
halogen in organic solvent through conversion of halide anion to TBDMSX, (2)
promoting the aerobic oxidation of halide to produce reactive X2 in situ. However, the
detailed mechanism of TBDMSCl-activated aerobic oxidative halogenation reaction
such as the TBDMSCl-O2-X- intermediate was still not clear at present.
Scheme 2. The possible reaction mechanism of the tandem aerobic oxidative
halogenation and Huisgen cycloaddition reaction
In brief, an effective synthetic protocol for 5-halo-1,2,3-triazoles was developed by a
novel TBDMSCl-activated aerobic oxidative halogenation in this paper.
5-iodo-1,4-disubstituted-1,2,3-triazole and 5-bromo-1,4-disubstituted-1,2,3-triazole
can be effectively prepared from terminal alkyne, organic azide and CuI or CuBr in
the presence of 0.5 equiv. TBDMSCl. The advantages in the current work include
inexpensive and green O2 as oxidant, use of mild and non-oxidative additive, and
10

wider scope of substrate compared to the existing methods. The high tolerance of
sensitive groups and successful application on nucleoside analogues make potential of
this method for design and synthesis of biomolecules and their mimics. The further
mechanism studies on chlorosilane-activated aerobic oxidative halogenation and
application of this new pathway for the preparation of natural product analogues are
underway in our lab.
Experimental Section
Typical Procedure for the One-pot Tricomponent Reaction for the Synthesis of
5-Halo-1,2,3-triazole. A mixture of 1 (0.17 mmol), 2 (0.17mmol), CuX (0.17mmol),
DIPEA (0.17 mmol), and TBDMSCl (0.08 mmol) in 3 mL of anhydrous CH3CN was
stirred at room temperature under dry air atmosphere for 18 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 to give compound 3.
Acknowledgments
This study was supported by the National Natural Sciences Foundation of China
(21172056, 21172058, 20802017), HASTIT (2012HASTIT10), and PCSIRT
(IRT1061).
Supporting Information Available: Characterization of compounds 3a-3q and full
11

spectroscopic data for all new compounds.
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