Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5-Hetero-Functionalized Triazoles

Article abstract of DOI:10.1002/anie.201509124

The 5-heterofunctionalized triazoles are important scaffolds in bioactive compounds, but current click reactions (CuAAC) cannot produce these core structures. A copper(I)-catalyzed interrupted click reaction to access diverse 5-functionalized triazoles is reported. Various 5-amino-, thio-, and selenotriazoles were readily assembled in one step in high yields. The reaction proceeds under mild conditions with complete regioselectivity. It also features a broad substrate scope and good functional group compatibility.

Full text of DOI:10.1002/anie.201509124

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International Edition: DOI: 10.1002/anie.201509124
German Edition: DOI: 10.1002/ange.201509124
1,2,3-Triazoles
Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of Diverse
5-Hetero-Functionalized Triazoles
Weiguo Wang, Xianglong Peng, Fang Wei, Chen-Ho Tung, and Zhenghu Xu*
Abstract: The 5-heterofunctionalized triazoles are important
scaffolds in bioactive compounds, but current click reactions
(CuAAC) cannot produce these core structures. A copper(I)-
catalyzed interrupted click reaction to access diverse 5-
functionalized triazoles is reported. Various 5-amino-, thio-,
and selenotriazoles were readily assembled in one step in high
yields. The reaction proceeds under mild conditions with
complete regioselectivity. It also features a broad substrate
scope and good functional group compatibility.
For instance, carboxylamidotriazole I (CAI) exhibits anti-
cancer activity,[4a] the triazole II is an active potassium
channel activator,[4b] the triazole III is a potent h-NK1
antagonist,[3b] the sulfur-containing triazole IV is a potential
herbicide with antifungal activity,[4c] and the triazole V is an
excellent chiral ligand used in asymmetric catalysis.[4d] How-
ever, the CuAAC reaction is limited to terminal alkynes and
cannot produce these functionalized structures. Conse-
quently, the development of an efficent strategy to access
diverse hetero-functionailized triazoles is of great impor-
tance.
In 2010, Fokin and co-workers reported a sequential
halide exchange and subsequent SNAr reaction to produce
various 5-functionalized triazoles.[5] This strategy requires
multiple reaction steps and a halide exchange step that
involves high temperatures. The recently reported RuAAC[6a]
and IrAAC[6b] reactions have partially addressed this chal-
lenge, and could afford trisubstituted triazoles with high
regioselectivity. However, these approaches need to use noble
metal catalysts and prepare the functionalized internal
alkynes in advance. To date, no widely applicable direct
synthesis of various heteroatom-functionalized triazoles from
easily available terminal alkynes has been reported.[7]
The CuAAC reaction shown in Scheme 2A is an effective
approach to triazoles. The Ackermann group reported
a copper-catalyzed one-pot reaction to introduce an aryl
group onto the triazole ring at elevated temperature.[8]
Herein, we proposed another interrupted click reaction
using a heteroatom electrophile to intercept the cuprate–
triazole intermediate M1 forming 5-hetero-functionalized
triazoles (Scheme 2B). Previously reported successful inter-
T
he copper(I)-catalyzed azide–alkyne cycloaddition
(CuAAC)[1] forming 1,2,3-triazoles has become a prime
example of click chemistry because of its reliability, specific-
ity, and biocompatability. Click chemistry has been widely
used in different areas of science, such as drug discovery,
bioconjugation, polymer and supermolecular chemistry.[2] The
triazole products of this reaction are more than simply
connecting linkers: they are very important pharmacophores,
widely used in medicinal chemistry.[3] Among them, the
multisubstituted 5-heterofunctionalized 1,2,3-triazoles are
a type of privileged triazoles, present in many synthetic
molecules with a variety of biological activitites (Scheme 1).
Scheme 1. Important 5-functionalized triazoles.
[*] W. Wang, X. Peng, F. Wei, Prof. C.-H. Tung, Prof. Z. Xu
Key Lab for Colloid and Interface Chemistry of Education Ministry
Department of Chemistry, Shandong University
No. 27 South Shanda Road, Jinan, 250100 (China)
E-mail: xuzh@sdu.edu.cn
Homepage: http://opcl.sdu.edu.cn/Teacher.aspx?tid=4
Prof. Z. Xu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (P.R. China)
Scheme 2. Copper(I)-catalyzed interrupted click reaction by electro-
philes to diverse 5-functionalized triazoles.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509124.
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ception of this intermediate with ICl or allyl iodide demon-
strated the feasibility of this method.[9–11] However, most
reactions require stoichiometric amounts of a copper(I)
catalyst. Realizing a catalytic reaction is highly desirable,
but completion of this catalytic cycle is challenging because of
two competing reactions: (1) protonation of the cuprate–
triazole intermediate M1 producing the undesired 1,4-disub-
stituted triazole; and (2) reaction of copper(I) acetylide with
the heteroatom electrophile generating a heteroatom-substi-
tuted internal alkyne, which is unreactive under click reaction
conditions. Therefore, choosing an appropriate heteroatom
electrophile with enough reactivity toward the vinyl copper
intermediate, rather than the copper acetylide, is critically
important.
(5a; Entries 2 and 3). Further screening of different bases
indicated that LiOtBu was crucial for the success of this
reaction (Entries 4–8). The highest isolated yield (90%;
Entry 10) was obtained by raising the temperature to 408C
and increasing the amount of 3a to two equivalents. Using an
electrophilic amination reagent (9a),[15] 5-amino triazole
(10a) could be obtained in 83% yield by a similar CuI-
catalyzed three-component reaction [Eq. (1)].
Previously, S-methyl benzenesulfonothioate 3a was used
successfully by Dai and Tang to introduce a sulfenyl group
into d-camphor, building a chiral sulfide.[12] Compound 3a
might be an excellent electrophilic sulfenylating reagent,
because the cleaved benzenesulphinate is a good leaving
group, with the pKa of phenylsulfinic acid being 2.76. To
validate this concept, the phenylacetylene 1a and the
benzylazide 2a were selected as model substrates with
which to optimize the reaction conditions (Table 1; see the
With the optimized conditions defined, we investigated
the scope of various alkyne structures (Table 2). Both
Table 2: Substrate scope of alkynes and azides.[a]
Table 1: Optimization of reaction conditions.[a]
Entry
Base
Temp [8C]
Electrophile
Yield [%][b]
4a
5a
1
2
LiOtBu
LiOtBu
25
25
3a
74
0[c]
8
66
3
LiOtBu
25
0
96
4
5
6
7
KOtBu
NaOMe
NaH
25
25
25
25
25
40
40
3a
3a
3a
3a
3a
3a
3a
<5
30
25
<5
<5
64
52
56
92
94
K2CO3
Et3N
8
9
LiOtBu
LiOtBu
81
95 (90)
5
10[d]
trace
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.3 mmol),
CuI (20 mol%), base (0.4 mmol), 4 Š molecular sieves (MS, 150 mg),
THF (1 mL) was stirred at room temperature under N2 atmosphere for
1
12 h. [b] Determined by H NMR using trimethoxybenzene as the
internal standard. The isolated yield is in parentheses. [c] 5-phenyl-
thiotriazole product was not detected. [d] 3a (0.4 mmol).
Supplementary Information for details). It was found that
benzenethiosulfonate (3a) serves as an efficient electrophile,
affording the desired 5-thiotriazole (4a) in 74% yield,
together with 8% of the 5-H-triazole (5a) in the presence
of 20 mol% CuI (Table 1, Entry 1). Almost no thioalkyne (6)
was observed in the reaction. Other electrophilic sulfenylat-
ing reagents (7, 8)[13,14] were also tested. The expected
thiotriazole was not observed, but only the click product
[a] Reaction conditions: Sulfenylation: (Condition A) 1 (0.2 mmol), 2
(0.3 mmol), 3a (0.4 mmol), CuI (20 mol%), base (0.4 mmol), 4 Š MS
(150 mg), THF (1 mL) was stirred at 408C under N2 atmosphere for 12 h;
Amination: (Condition B) 1 (0.2 mmol), 2 (0.3 mmol), 9a (0.3 mmol),
CuI (20 mol%), base (0.4 mmol), 4 Š MS (150 mg), pentane (1 mL) was
stirred at room temperature under N2 atmosphere for 12 h. Isolated
yields were reported.
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aromatic and aliphatic alkynes can participate in this three-
The construction of medium and large rings is always
component reaction to give the 5-thio- or 5-amino-triazoles in
good to excellent yields. Electron-donating groups, such as
methyl (4e and 10e) and methoxyl (4 f and 10 f), and
electron-withdrawing groups, such as halogen (4b,c and
10b,c) and cyano (4d and 10d) moieties, are compatible
with the reaction. Alkynes substituted by thienyl (4g,h and
10g,h), cyclopropyl (4i and 10i), and phenoxyl (4k and 10k)
are also suitable for this transformation, giving good yields of
the corresponding triazoles.
a challenge in the organic synthesis,[16] and we questioned
whether this copper-catalyzed reaction can be applied to an
intramolecular reaction to construct various ring systems. By
linking the thiosulfonyl and alkyne groups in the same
molecule, we synthesized the functionalized alkyne 12
(Supporting Information). The reaction of alkyne 12 with
azide 2a afforded the fused bicyclic triazole 13 in moderate to
good yields (Table 4). Many 5- and 6-membered rings, and
The reaction is also efficient with various alkyl and
aromatic azides (Table 2). All of the aliphatic azides tested
were effective substrates, giving the corresponding triazoles in
good to excellent yields under standard conditions. Cinnamyl
groups (4o and 10o), phthalimide-protected amines (4q and
10q), and indole skeletons (4r and 10r) are all tolerated
under these mild conditions. Furthermore, the reaction is also
efficient for aromatic azides, generating the 5-thio- and
aminotriazoles in good yields (4s and 10s).
Table 4: Intramolecular reaction to construct various-sized rings.[a]
We next examined the scope of this transformation with
respect to different heteroatom electrophiles (Table 3). For
Table 3: Substrate scope of hetero-atoms.[a]
[a] Isolated yields. [b] 12 was slowly injected in 5 h by syringe pump.
also 7- to 14-membered medium and large rings, can all be
synthesized in good yields. Notably, the catechol-derived 12-
membered ring 13h and 14-membered ring 13i can be formed
in 80% and 76% yield, respectively. The structure of 13h was
confirmed by single-crystal X-ray crystallography.[17] For
formation of 8–14-membered ring systems, a slow injection
of the alkyne substrate 12 into the reaction system was
necessary.
[a] Isolated yields. Condition A for sulfenylation, condition B for amina-
tion. [b] PhSO2SePh was slowly injected in 6 h by syringe pump. [c] at
408C.
The utility of this chemistry is demonstrated by its
application to a two-step synthesis of the antifungal thiotria-
zole IV (Scheme 3).[4d] This biologically active compound was
the sulfenylation reaction, a large variety of alkyl and
aromatic thio groups could be easily introduced onto the
triazole ring, giving 5-thiotriazoles (4t-ab), mostly in very
good yields, and functional groups such as allyl, halogen, and
nitro are well tolerated. Significantly, 5-phenylselenyl triazole
(11) could be produced in 71% yield by this approach under
very mild conditions. Various amines such as morpholine,
piperidine, diethyl amine, and diallyl amine can all be
installed on the triazole ring and give good yields (10t–w).
The structures of 4aa and 10n were unambiguously charac-
terized by single-crystal X-ray crystallography. All of these
heteroatom electrophiles can easily be prepared from readily
available starting materials (Supporting Information), thus
making this method a practical approach to various 5-hetero-
functionalized triazoles.
Scheme 3. Synthesis of antifungal active thiotriazole IV.
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originally prepared from highly toxic thiophosgene and ethyl
diazoacetate in multiple reaction steps with less than 15%
overall yield. However, it can be synthesized in 70% yield by
the standard three-component reaction of the azide 2a,
propiolic acid ethyl ester, and the sulfenylating reagent 14,
which can be easily prepared by the reaction of PhSO2SNa
with corresponding iodide.
The significance of this chemistry is seen in the late-stage
click/functionalization of bioactive natural compounds, sac-
charides, and amino acid derivatives shown in Scheme 4.
Treatment of oleanane-type triterpene-derived alkyne 15
Scheme 5. Proposed reaction mechanism.
triazole M1. This intermediate reacts with the heteroatom
electrophile E-LG to form the product 4, possibly through an
oxidative addition and reductive elimination sequence. The
recovered Cu-LG reacts with the alkyne in the presence of
base to form copper(I) acetylide M0, completing the catalytic
cycle.
In summary, we have developed a copper(I)-catalyzed
interrupted click reaction to access diverse 5-functionalized
triazoles. The reaction proceeds under very mild conditions,
with only catalytic amounts of an inexpensive copper catalyst
and no required ligands. This practical method exhibits a very
broad scope with respect to alkynes, azides, and also different
heteroatom electrophiles. The intramolecular reaction can be
used to construct bicyclic triazoles with various ring sizes. A
notable feature of this reaction is the late-stage functional-
ization of bioactive compounds, thus providing efficient and
practical synthetic routes for drug discovery and develop-
ment, which the current click reaction (CuAAC) is unable to
do. Further applications of this interrupted click reaction in
medicinal chemistry are in progress in our laboratory.
Scheme 4. Late-stage functionalization of biologically active molecules.
under standard reaction conditions afforded the correspond-
ing thiotriazole 16 in 91% yield. This reaction has great
potential for drug discovery and development. Furthermore,
the glucose derivative 17 and the amino acid derivative 19
were also amenable to this transformation giving desired
products 18 and 20 with good yields.
To gain an improved understanding of the reaction
mechanism, controlled experiments were conducted. The
reaction of phenylacetylene (1a) with 3a under standard
conditions afforded the thioalkyne (6) in 90% yield. How-
ever, the reaction of 6 with benzyl azide (2a) failed to afford
the target product (4a) [Eq. (2)]. Disubstituted triazole (5),
Acknowledgements
We are grateful for the financial support from Natural Science
Foundation of China and Shandong province (No. 21572118
and JQ201505), and subject construction funds of Shandong
University (104.205.2.5 and 2014JC008).
Keywords: aminations · click reactions · sulfenylation · triazoles
How to cite: Angew. Chem. Int. Ed. 2016, 55, 649–653
Angew. Chem. 2016, 128, 659–663
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