Silver-catalyzed three-component reaction: synthesis of N 2-substituted 1,2,3-triazoles via direct benzylic amination

Article abstract of DOI:10.1007/s11426-019-9455-0

A novel Ag(I)-catalyzed benzylic amination reaction with in situ generation of NH-1,2,3-triazoles for N²-substituted 1,2,3-triazole scaffolds is described. This protocol is achieved with easily accessible substrate, broad functional group, good regioselectivity, thus providing the efficient and practical method to diverse N²-substituted 1,2,3-triazole rings with moderate to good yields.

Full text of DOI:10.1007/s11426-019-9455-0

SCIENCE CHINA
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•ARTICLES•
https://doi.org/10.1007/s11426-019-9455-0
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Silver-catalyzed three-component reaction: synthesis of
N2-substituted 1,2,3-triazoles via direct benzylic amination
Zhenhua Liu†, Wenjing Hao†, Wen Gao*, Guangyu Zhu, Xiang Li, Lili Tong & Bo Tang*
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical
Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key
Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
Received January 22, 2019; accepted March 4, 2019; published online April 25, 2019
A novel Ag(I)-catalyzed benzylic amination reaction with in situ generation of NH-1,2,3-triazoles for N2-substituted 1,2,3-
triazole scaffolds is described. This protocol is achieved with easily accessible substrate, broad functional group, good re-
gioselectivity, thus providing the efficient and practical method to diverse N2-substituted 1,2,3-triazole rings with moderate to
good yields.
silver-catalyzed, alkynes, 1,2,3-triazoles, amination
Citation:
Liu Z, Hao W, Gao W, Zhu G, Li X, Tong L, Tang B. Silver-catalyzed three-component reaction: synthesis of N2-substituted 1,2,3-triazoles via direct
benzylic amination. Sci China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-9455-0
1 Introduction
water (Figure 1(a)). Compared with well developed methods
for synthesis of N1-substituted triazoles, available approaches
for N2-substituted ones were nearly all limited to two-step
strategy via presynthesis and post-functionalization of NH-
1,2,3-triazoles with suitable electrophiles as the reactant [10]
(Figure 1(b)). Another common route to the N2-substituted
triazoles [11] was obtained by the oxidative cyclization of
bishydrazones or bissemicarbazones. However, tedious pre-
modified process of the substrates was pre-requisite in those
reactions, which severely hampered a broader utility of N2-
substituted triazoles in different fields of chemical science.
Recently, Yamamoto et al. [12] and Fokin et al. [13] have
made good progress toward the synthesis of N2-allyl and N2-
hydroxymethyl triazoles via the elegant three-component
coupling by the restrictive electrophiles (Figure 1(c)).
Therefore, novel method for synthesis of N2-substituted
triazoles with diverse substitution patterns of commodity
chemicals under simple and mild conditions is still rare and
sorely needed so far.
1,2,3-Triazoles with interesting properties have been omni-
present in organic synthesis [1], medicinal chemistry [2],
chemical biology [3] and materials science [4]. The pio-
neered synthesis of 1,2,3-triazoles by Huisgen 1,3-dipolar
cycloaddition reaction [5] suffered from elevated tempera-
ture and poor regioselectivity. This smaller heterocyclic unit
has drawn little attention as “sleeper” until the premier
copper(I)-catalyzed examples of “click chemistry” [6] by
Sharpless and Meldal’s groups [7]. Nowadays, the copper(I)-
catalyzed azide-alkyne cycloaddition (CuAAC) and sub-
sequent ruthenium(II)-catalyzed azide-alkyne cycloaddition
(RuAAC) (Figure 1(a)) [8] have been established as reliable
strategies for the efficient and regioselective assembly of N1-
substituted 1,2,3-triazoles. Recently, Hong and co-workes
[9] introduced alternatively synthetic route to access 1,5-
substituted 1,2,3-triazoles using complex Ni(II) catalyst in
The carbon-carbon triple bonds of alkynes are among the
most valuable chemical skeletons because of their abundance
†These authors contributed equally to this work.
*Corresponding authors (email: gaowen@sdnu.edu.cn; tangb@sdnu.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

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Liu et al. Sci China Chem
was consumed. The resulting reaction mixture was cooled to
room temperature and extracted by dichloromethane
(3×15 mL). The organic layer was washed with brine
(3×40 mL), dried over MgSO4 and concentrated. Purification
of the crude product via flash column chromatography (silica
gel; petroleum ether) and concentratinon in vacuo afforded
the desired product of 3a-N2/3a-N1 in 91% yield.
3 Results and discussion
Based on our continuous interest in alkyne reactions, our
investigation began with the reaction of two easily accessible
phenylacetylene 1a and BHT 2a as the model substrates to
verify our hypothesis of the extensive screening of transi-
tion-metal catalysts and solvents (Table 1 and Supporting
Information online). Gratifyingly, we could obtain the de-
sired isomeric triazole 3a with 65% yield in 3.3:1 ratio of 3a-
N2 and 3a-N1 by employing AgCl as the catalyst and DMF as
the solvent (Table 1, entry 1). The two isomers were clearly
confirmed by single-crystal X-ray analysis [18a] of 1,4-dis-
ubstituted product 3a-N1 (see Supporting Information on-
line), assisted by the 13C chemical shifts of the triazole CH
[19]. Guided by this exciting result, other silver salts such as
AgF, AgNO3 and Ag2CO3 were then examined using model
substrates for 1,2,3-triazoles by in-situ C(sp3) –H/N–H cross-
coupling (Table 1, entries 2–4). A good yield of product 3a
was achieved with Ag2CO3 as catalyst under air atmosphere.
Diminished or no catalytic activity was exhibited when the
reaction was performed with other commercially available
metal sources such as CuI, Cu(OAc)2, NiCl2 (Table 1, entries
5–7). The click/coupling tandem reaction employing DCE,
EG, H2O, DMSO and toluene as solvent was investigated
and furnished 3a in the unsatisfactory outcome (Table 1,
entries 8–12). We further examined base as additives in the
tandem reaction (Table 1, entries 13, 14). KF was proved to
be beneficial for the reaction and delivered 1,2,3-triazole
product 3a in the highest yield with a ratio of N2-substituted/
N1-substituted (N2/N1) 1,2,3-triazoles up to 9.1:1.
Having identified optimal reaction conditions, we next
turned our attention to evaluate the scope of various terminal
alkynes for this sequential reaction. As shown in Scheme 1,
diverse electron-deficient or -rich aromatic alkynes pro-
ceeded smoothly under the optimization conditions, afford-
ing the desired 1,2,3-triazoles with moderate to good yields.
For instance, arylacetylenes with various para-substituted
groups such as alkyl, alkoxyl, halogen (1b–1j) were suitable
for this silver-catalyzed click/amination cascade reaction,
generating the corresponding N2/N1-substituted 1,2,3-tria-
zoles (3b–3j) in 70%–85% yields. The structure of 3f-N2 was
confirmed by single-crystal X-ray [18b] (see more details in
Supporting Information online). We were pleased to find that
regioselectivity was significantly increased when fluoro,
Figure 1 Synthesis of disubstituted 1,2,3-triazoles (color online).
and rich reactivities [9,14]. These fundamental chemicals
have been disclosed as significant and extensive applications
in organic transformations. Especially, “Silver Rush” in the
various transformations of alkynes and their derivatives has
flourished gradually over the past decade [15]. Meanwhile,
2,6-di-tert-butyl-4-methylphenol (BHT) was all restricted to
radical scavenger [16] and has been ignored in organic
synthesis [17]. Herein, we reported a silver-catalyzed click/
alkylation sequence reaction by direct benzylic amination for
N2-substituted 1,2,3-triazoles with easily available substrates
through three-component reaction in one-pot (Figure 1(d)),
in which amination source and the electrophile were both
generated in situ.
2 Experimental
Typical synthetic procedure for compounds 3, 4 (with 3a as
an example): to a solution of phenylacetylene (1a)
(0.055 mL, 0.5 mmol), 2,6-di-tert-butyl-4-methylphenol
(BHT) (2a) (133 mg, 0.6 mmol), NaN3 (39 mg, 0.6 mmol)
and KF (58 mg, 1.0 mmol) in DMF (1 mL) at 50 °C, Ag2CO3
(41 mg, 0.15 mmol) was added. The reaction mixture was
then stirred for 6 h when TLC conformed that substrate 1a

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Liu et al. Sci China Chem
Table 1 Optimization of the reaction conditionsa)
Entry
1
Cat.
AgCl
Sol.
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
3a (N2/N1) (%)b)
50:15
trace
50:15
70:10
30:0
33:0
0
2
AgF
3
AgNO3
Ag2CO3
CuI
4
5
6
Cu(OAc)2
NiCl2
7
8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
trace
30:55
trace
57:21
0
80:10c)
82:9d)
9
EG
10
11
12
13
14
H2O
Scheme 1 Scope of alkynes. Reaction conditions: 1a (0.5 mmol), 2a
(0.6 mmol.), NaN3 (0.6 mmol), Ag2CO3 (0.3 eq.), KF (2.0 eq.), DMF
(1 mL), 50 °C, 6 h, and isolated yield (color online).
DMSO
Toluene
DMF
DMF
a) Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol.), NaN3
(0.6 mmol), Cat. (0.3 eq.), Sol. (1 mL), 50 °C, 6 h. b) Isolated yield. c) 2.0
eq. NaHCO3 was added. d) 2.0 eq. KF was added. DMF=N,N-di-
methylformamide; DCE=1,2-dichloroethane; EG=ethylene glycol;
DMSO=dimethyl sulfoxide.
acetyl and ester group on benzene ring (1k–1m) were used,
delivering the sole N2-substituted products in moderate
yields. This could be attributed to the stabilization of the
proposed intermediates C with electron effect. Similarly,
meta-substituted groups including methyl, ethynyl and
chloro on the benzene ring (1n–1p) also gave the desired
triazoles (3n–3p) in a good regioselective manner with 64%–
75% yields. Fused or heteroaryl alkynes (1q–1t) were also
compatible with corresponding products (3q–3t) in a 57%–
65% yields under the optimized reaction conditions. Fur-
thermore, a variety of aliphatic alkynes (1v–1z) could be
used in the reaction to the sole triazoles (3v–3z) in moderate
yields. The structure of 3x was confirmed by single-crystal
X-ray [18c] (see more details in Supporting Information
online).
Subsequently, the range of multisubstituted phenols 2 was
estimated and summarized in Scheme 2. 2,4,6-trimethyl-
phenol 2b with 1a as reaction partner smoothly generated the
desired product 4a in 76% yield. Other electron-deficient or
-rich aromatic alkynes were also examined and afforded
corresponding products 4b–4h in 55%–74% yields. The
structure of 4h was verified by single-crystal X-ray [18d]
(see Supporting Information online). The reaction using
other ortho-disubstituted p-cresols with electron-deficient
Scheme 2 Scopes of trisubstituted phenol. Reaction conditions:
1 (0.5 mmol), 2 (0.6 mmol.), NaN3 (0.6 mmol), Ag2CO3 (0.3 eq.), KF (2.0
eq.), DMF (1 mL), 50 °C, 6 h, and isolated yield (color online).
and -rich aromatic acetylenes analogously showed good re-
activity and delivered the products 4i–4r with 60%–80%
yields, in which 4n was verified by single-crystal [18e] (see
more details in Supporting Information online). It is worth
noting that replacement of para-methyl with ethyl on the 2a

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Liu et al. Sci China Chem
also worked well by constructing a chiral center in the tar-
geted product, which was potential for asymmetric amination
in one-pot. Subsequently, other para-substituent groups such
as n-propyl (2u), aryl (2v–2x), naphthyl (2y) were con-
sidered and the corresponding desired products (4u–4y) were
successfully obtained by this three-component reaction.
Regretfully, when electron-deficient group such as acetyl or
nitryl was introduced into the substrate of trisubstituted
phenol, no corresponding product was isolated (4ya–4yb).
To further demonstrate the practicality of this methodol-
ogy, we carried out the gram-scale reaction in Scheme 3. The
efficiency was not significantly affected by scaling up, and
the corresponding product 3a-N2 and 3a-N1 was obtained in
one-pot with 75% and 9% yield, respectively.
Scheme 3 Gram-scale of the Ag(I)-catalyzed reaction (color online).
To learn more about the mechanism of tandem reaction,
several control experiments were performed as Scheme 4.
Firstly, increasing the loading of 2a to 3.2 equiv. decreased
the yield of 3a to 75%. While 0.5 equiv. 2,2,6,6-tetra-
methylpiperidinooxy (TEMPO) was added as additives, the
reaction yielded 1,2,3-triazole 3a in 72% (Eq. (1)). When 2.0
equiv. ethene-1,1-diyldibenzene (EDB) as radical scavenger
was used under the standard conditions, the yield of the
desired product was obtained in 78%. These results sug-
gested that the transformation did not involve a radical
process. In the absence of 1.2 equiv. 2a, the reaction gave the
phenyl-1H-1,2,3-triazole 5 (Eq. (2)) [20]. While 5 was used
as the substrate, the desired product 3a was yielded in 35%
with 60% recovery of the reactant 5 (Eq. (3)). It meant that 5
could be a key intermediate in the reaction. When the reac-
tion was conducted in the absence of 1a, the presupposed
product 6 was not detected (Eq. (4)). It indicated that the
silver-catalyzed click reaction between 1a and 6 in cascade
reaction was excluded. Silver acetylide 7 [21] was in-
troduced into the reaction with 2a under the standard con-
ditions. In the presence of 0.3 equiv. Ag2CO3, product 3a was
obtained in 86% yield. In the absence of 0.3 equiv. Ag2CO3, a
lower yield was afforded (Eq. (5)). These results implied that
7 was an intermediate in the reaction. 1a-D was subjected to
the cascade reaction as the reactant and product 3a was
isolated without D atom (Eq. (6)). This indicated that Ag-
catalyst activated the triple bond by the generation of silver
acetylide 7.
Scheme 4 Mechanistic investigations.
Scheme 5 Possible mechanism for the reaction.
On the basis of the above results and precedent literature
[17], a preliminary catalytic cycle for click/alkylation cas-
cade reaction was illustrated in Scheme 5. Initially, the ac-
tivation of alkyne 1a took place by producing acetylene
silver 7, and subsequently the 1,3-dipolar cycloaddition
proceeded between Ag(I)-species 7 and AgN3, which was
generated in situ by anion exchange of NaN3 with Ag2CO3
[15c]. This resulted in the formation of Ag(I) complex A
[8b], which would be in dynamic equilibrium with the
thermodynamically more stable intermediate [13] C through
intervention of complex B. The intermediates A and C were
rapidly captured by H2O to deliver D and E, respectively.
The coupling reaction subsequently underwent between D/E
and quinone methide F from oxidation of 2a by Ag+ and
oxygen to generate isomer 3a-N1/3a-N2 by consecutive loss
of Ag+ for the next cycle.
4 Conclusions
In summary, we have developed a novel and efficient Ag-
catalyzed tandem reaction for the preparation of diverse N2-

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Liu et al. Sci China Chem
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substituted 1,2,3-triazoles under simple and mild reaction
conditions. This reaction involved the click reaction for NH-
1,2,3-triazoles in situ and subsequently participated in
benzylic C(sp3)–H amination of easily accessible p-cresol
derivatives without further isolation. This regioselective and
practical protocol enabled operational simplicity, good
functional group tolerance and broad substrate scope with
simple silver catalyst by three-component reaction in one-
pot. The practicality and the synthetic application of this
reaction were demonstrated by the large-scale experiments.
Meanwhile, a speculated reaction pathway was tentatively
proposed based on our preliminary tests and reported lit-
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reaction are ongoing in our laboratory.
5
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Acknowledgements This work was supported by the National Natural
Science Foundation of China (21535004, 91753111, 21605097, 21775092,
21390411), the Key Research and Development Program of Shandong
Province (2018YFJH0502), the Natural Science Foundation of Shandong
Province of China (ZR2016BQ01, ZR2018JL008) and the China Post-
doctoral Science Foundation (2017M610442).
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Conflict of interest The authors declare that they have no conflict of
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Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
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All the supplementary crystallographic data for this paper are from
Cambridge Crystallographic Data Centre http://www.ccdc.cam.ac.uk/
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