Copper(I)-catalyzed tandem reaction: Synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl diacyl peroxides, azidotrimethylsilane, and alkynes

Article abstract of DOI:10.3762/bjoc.14.270

A copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction for the synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl diacyl peroxides, azidotrimethylsilane, and terminal alkynes is reported. The alkyl carboxylic acids is for the first time being used as the alkyl azide precursors in the form of alkyl diacyl peroxides. This method avoids the necessity to handle organic azides, as they are generated in situ, making this protocol operationally simple. The Cu(I) catalyst not only participates in the alkyl diacyl peroxides decomposition to afford alkyl azides but also catalyzes the subsequent CuAAC reaction to produce the 1,2,3-triazoles.

Full text of DOI:10.3762/bjoc.14.270

Copper(I)-catalyzed tandem reaction: synthesis of
1,4-disubstituted 1,2,3-triazoles from alkyl diacyl
peroxides, azidotrimethylsilane, and alkynes
Muhammad Israr1,2, Changqing Ye1,2, Munira Taj Muhammad1, Yajun Li1
and Hongli Bao*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2916–2922.
1Key Laboratory of Coal to Ethylene Glycol and Its Related
Technology, State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Center for Excellence
in Molecular Synthesis, Chinese Academy of Sciences, 155 Yangqiao
Road West, Fuzhou, Fujian 350002, P. R. China and 2University of
Chinese academy of Science (UCAS), Beijing 100190, P. R. China
doi:10.3762/bjoc.14.270
Received: 01 September 2018
Accepted: 07 November 2018
Published: 23 November 2018
This article is part of the thematic issue "Reactive intermediates part I:
radicals".
Email:
Hongli Bao* - hlbao@fjirsm.ac.cn
Guest Editor: T. P. Yoon
* Corresponding author
© 2018 Israr et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkyl diacyl peroxides; azidotrimethylsilane; click reaction; copper
catalysis; radical; 1,2,3-triazoles
Abstract
A copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction for the synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl
diacyl peroxides, azidotrimethylsilane, and terminal alkynes is reported. The alkyl carboxylic acids is for the first time being used
as the alkyl azide precursors in the form of alkyl diacyl peroxides. This method avoids the necessity to handle organic azides, as
they are generated in situ, making this protocol operationally simple. The Cu(I) catalyst not only participates in the alkyl diacyl
peroxides decomposition to afford alkyl azides but also catalyzes the subsequent CuAAC reaction to produce the 1,2,3-triazoles.
Introduction
The “click chemistry”, coined by K. B. Sharpless in 2001 [1], is The copper-catalyzed azide–alkyne cycloaddition (CuAAC)
a powerful chemical transformation that has rapidly orthogonal- reaction [13-21], derived from the Huisgen’s 1,3-dipolar cyclo-
ized traditional disciplinary boundaries. With the discovery of addition of azides and alkynes [22], has conceivably emerged as
“click chemistry”, new fields have been opened for the research the premier example of click chemistry. Generally, organic
and synthesis of functionalized compounds that have applica- azides are used as the azido source in most of the CuAAC reac-
tions in medicinal chemistry, drug discovery, materials chem- tions (Scheme 1a) [23]. However, the organic azides with low
istry, and as well as in bioconjugates [2-12].
molecular weight are considered to be unstable moieties that
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Scheme 1: General methods for the synthesis of triazoles.
can decompose spontaneously, with which the reactions are Results and Discussion
difficult or dangerous to handle [16]. Thus, a one-pot two-step Based on our unpublished work, we found that alkyl azide has
process for the in situ generation of organic azides is highly re- always appeared as a side product when the reaction involved
quired. A frequently used method to in situ generate organic TMSN3 and alkyl diacyl peroxide, easily available compounds
azides is the azidation of organic halides, such as aliphatic derived from aliphatic carboxylic acids. With this information
halides, vinyl halides, or aromatic halides with sodium azide in mind, initially, we started our investigation with phenylacety-
[24-27]. Organic triflates [28] and organic boronic acids [29-31] lene (1a), commercially available lauroyl peroxide (2a), and
can also be used as alternative precursors for organic azides, TMSN3 (Table 1). In a preliminary experiment, the reaction of
when reacted with sodium azide.
1a with 2a in the presence of 10 mol % of CuCl in THF at
50 °C afforded 1,4-disubstituted 1,2,3-triazole 3a in 65% isolat-
However, sodium azide is a highly toxic compound and has the ed yield (Table 1, entry 1). Surprisingly, under these conditions
potential to explode. Azidotrimethylsilane (TMSN3) has been no CuAAC product between TMSN3 and phenylacetylene was
considered as a safer azide source, which actually has been suc- detected. This result encouraged us to further exploit the optimi-
cessfully used in the CuAAC reaction directly [32-35], but zation of the reaction conditions. Afterwards, the effect of the
rarely been used as an azido precursor to enrich the function- solvent was also investigated (Table 1, entries 2−8). Dichloro-
ality of organic azide source. Moreover, as one of the most methane could afford the best result and the yield of the desired
commonly appearing compounds in nature, carboxylic acids product 3a could be as high as 97% (Table 1, entry 2). Other
have rarely been directly used as the organic azide precursors metal salts of copper, such as Cu(OAc)2, CuI, and CuBr were
for CuAAC reactions, considering the frequent involvement of then examined and they showed lower catalytic efficiencies
organic halides. Thus, new methods with non or less toxic than that of CuCl (Table 1, entries 9−11). Moreover, a reduced
reagents and enriched organic azide sources for CuAAC reac- amount of the catalyst loading leads to lower yields of product
tion are still highly required.
3a (Table 1, entries 12–14).
Herein, we report a novel CuAAC reaction, using aliphatic With the optimized reaction conditions in hand, the scope of the
carboxylic acids as the alkyl source [36], and TMSN3 as the terminal alkynes was screened and the results are depicted in
azide source (Scheme 1b). Because TMSN3 can react with Scheme 2. First, the reactivity of various substituted terminal
alkynes to form the CuAAC reaction product [32-35], there is arylalkynes was examined. Only 1,4-regioisomeric products
one significant challenge of this method that need to be empha- were formed with good to excellent yields. Phenylacetylene
sized: how to control the reaction to generate the alkyl azides with an electron-withdrawing bromo-, chloro-, or fluoro substit-
from aliphatic carboxylic acids and TMSN3, before TMSN3 uent afforded the corresponding products 3h–n in up to
directly reacting with alkynes.
92% yield, while phenylacetylenes with electron-donating
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Table 1: Optimization of the reaction conditionsa.
entry
catalyst (mol %)
solvent
yield (%)b
1
2
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuI (10)
THF
CH2Cl2
EtOH
(65)c
96 (97)c
53
3
4
DMF
13
5
MeOH
7
6
1,4-dioxane
MeCN
trace
trace
trace
52
7
8
acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
12
13
14
CuBr (10)
Cu(OAc)2 (10)
CuCl (7.5)
CuCl (5)
48
64
84
70
CuCl (2)
54
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), TMSN3 (0.75 mmol), catalyst (mol %), solvent (2 mL), 50 °C, 10 h. bYield was determined by
1H NMR analysis. cIsolated yield in parentheses.
groups gave the corresponding products 3b–g and 3o–q in up to Tertiary alkyl diacyl peroxides are relatively more reactive than
86% yield. Instead of a six-membered ring, five-membered primary and secondary alkyl diacyl peroxides, but they are not
heteroaromatics (ethynylthiophenes) have also been used, and stable enough for the simple filtration separation at room tem-
afforded the desired products 3s and 3t in up to 76% yield. Ter- perature. Thus, we have not tried the reactions with tertiary
minal aliphatic alkynes were then examined and it was found alkyl diacyl peroxides.
that they could smoothly deliver the corresponding 1,2,3-tri-
azoles 3u–z with high yields.
In order to understand the mechanism of this reaction, we per-
formed a set of experiments (Scheme 4). Firstly a radical
Furthermore, the scope of the alkyl diacyl peroxides was then capturing reaction was carried out with the addition of a radical
studied (Scheme 3). The alkyl diacyl peroxides 2 were synthe- trapping reagent (tetramethylpiperdinyloxy, TEMPO) [38,39] to
sized from the corresponding aliphatic carboxylic acids in a the standard reaction system, no product 3a was obtained; only
single step by DCC-mediated dehydrative condensation with the radical trapped product 4 was detected by GC–MS
hydrogen peroxide, and were used directly after simple filtra- (Scheme 4a).
tion without further treatment; see Supporting Information
File 1 for details [37]. The alkyl diacyl peroxides with long- To further investigate this phenomenon, we synthesized a sub-
chain alkyl groups and methyl-substituted long-chain alkyl strate bearing a cyclopropylmethyl moiety, diacyl peroxide 2p,
groups afforded the corresponding 1,4-disubstituted 1,2,3-tri- which is a radical-clock [40,41]. The reaction of phenylacety-
azoles with good to excellent yields (3aa, 3bb, 3dd, 3ff, 3hh, lene with the diacyl peroxide 2p afforded a ring-opened prod-
3ii, and 3ll). Remarkably, the chlorodiacyl peroxide also toler- uct 3pp in 88% yield. This result suggested the engagement of
ated the reaction conditions to afford chloro-substituted triazole radical species in the reaction (Scheme 4b).
3ee with good yield. Moreover, alkyl diacyl peroxides bearing a
phenyl group, cyclopentyl group, or a cyclohexyl group also Based on the previous literature [16,42,43] and the above exper-
afforded good yields (3cc, 3mm, and 3nn). Significantly, diacyl imental findings, a possible reaction mechanism is suggested as
peroxides with cyclic secondary alkanyl and alkenyl groups can shown in Scheme 5. In the presence of the Cu(I) catalyst, alkyl
also gave the corresponding 1,2,3-triazoles 3gg, 3jj, and 3kk. diacyl peroxide decomposes into an alkyl radical, CO2, and
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Scheme 2: Substrate scope of the terminal alkynes. Conditions: 1 (0.5 mmol), 2a (0.75 mmol), TMSN3 (0.75 mmol), CuCl (10 mol %), DCM (2 mL),
50 °C, 10 h. Yields of the isolated products are given.
releases a carboxyl–Cu(II) complex, which undergoes a ligand Conclusion
exchange with azidomethylsilane to form azido–Cu(II) species. In summary, we have established an efficient, ligand- and addi-
The alkyl radical then abstracts the azido moiety from the tive-free CuAAC reaction for the synthesis of 1,4-disubstituted
azido–Cu(II) species to afford an alkyl azide and the regener- 1,2,3-triazoles directly from a variety of readily accessible sub-
ated Cu(I) catalyst. Then, a conventional CuAAC process strates such as alkyl diacyl peroxides, azidotrimethylsilane, and
delivers the desired cycloaddition product 3.
terminal alkynes. The alkyl carboxylic acids are for the first
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Beilstein J. Org. Chem. 2018, 14, 2916–2922.
Scheme 3: Substrate scope of the alkyl diacyl peroxides. Conditions: 1a (0.5 mmol), 2 (0.75 mmol), TMSN3 (0.75 mmol), CuCl (10 mol %), DCM
(2 mL), 50 °C, 10 h. Yields of the isolated products are given.
Scheme 4: Preliminary mechanistic studies.
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Beilstein J. Org. Chem. 2018, 14, 2916–2922.
Scheme 5: Plausible reaction mechanism.
time being used as the alkyl azide precursors in the form of 21672213), the Strategic Priority Research Program of the
alkyl diacyl peroxides. This method avoids the necessity to Chinese Academy of Sciences (Grant No. XDB20000000), the
handle organic azides, as they are generated in situ, making this Haixi Institute of CAS (Grant No. CXZX-2017-P01) and CAS-
protocol operationally simple. This reaction features a wide TWAS president program of the UCAS for financial support.
substrate scope, good functional group tolerance, high yields,
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