Remote ether groups-directed regioselective and chemoselective cycloaddition of azides and alkynes

Article abstract of DOI:10.1016/j.cclet.2021.05.037

Remote ether groups could be used as directing groups to prepare fully substituted 5-ether-1,2,3-triazoles with exclusive 1,5-regioselectivities and excellent chemoselectivities. Ether group could coordinate with iridium catalyst by lone-pair electron at a distance (up to four σ bonds) away from alkyne to control the regioselectivity by weak coordination effect. The cycloaddition reaction chemoselectively occurred at the propargyl ether moiety of diyne to give unique fully substituted 4-alkynyl-triazole.

Full text of DOI:10.1016/j.cclet.2021.05.037

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Remote ether groups-directed regioselective and chemoselective
cycloaddition of azides and alkynes
Xuelun Duan, Nan Zheng∗, Ming Li, Xinhao Sun, Zhuye Lin, Pan Qiu, Wangze Song∗
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Department of Pharmaceutical Science, Dalian University of Technology, Dalian
116024, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Remote ether groups could be used as directing groups to prepare fully substituted 5-ether-1,2,3-triazoles
with exclusive 1,5-regioselectivities and excellent chemoselectivities. Ether group could coordinate with
iridium catalyst by lone-pair electron at a distance (up to four σ bonds) away from alkyne to control the
regioselectivity by weak coordination effect. The cycloaddition reaction chemoselectively occurred at the
propargyl ether moiety of diyne to give unique fully substituted 4-alkynyl-triazole.
Received 1 April 2021
Revised 16 May 2021
Accepted 16 May 2021
Available online xxx
Keywords:
© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia
Medica, Chinese Academy of Medical Sciences.
Remote ether
Directing group
Regioselectivity
Chemoselectivity
Triazole
Coordination of directing groups to metals usually play impor-
tant roles as driving force and control manner for various trans-
formations such as asymmetric hydrogenation, epoxidation and
triazoles [13-16]. However, most of the reactions are limited to
use terminal alkynes because of low reactivities and complicated
selectivities for electron-rich internal alkynes. Until recently, Mas-
careñas, López, Sun, Jia, Hong, Cui, our group and others have
successfully synthesized a series of 1,4,5-fully substituted 1,2,3-
triazoles starting from internal alkynes with excellent regioselec-
tivities using nitrogen-, sulfur- or seleno groups as proximal and
strong directing groups to coordinate with various transition met-
als including Ru, Ir, Rh and Ni (Scheme 1a1) [17-34]. Lin, Jia
and Fokin’s group used the hydroxyl group from internal propar-
gyl alcohol as directing group to accomplish 1,5-regioselectivities
by ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC) [35].
The hydroxyl group as hydrogen bond donor could coordinate
with ligating chloride from ruthenium catalyst to favor the 1,5-
regioselectivities (Scheme 1b2). Unfortunately, such RuAAC reac-
tion lacks both the regioselectivities and chemoselectivities if the
directing group was replaced by ether group, which was mainly
due to the weak coordination ability for ether as hydrogen bond
acceptor (Scheme 1b3) [36-37]. Moreover, remote directing group
has never been applied in tuning selectivity in cycloaddition,
which also significantly limited the further application of MAAC
reactions [38-42]. As known that ether is one of the most fun-
damental groups in natural products, drug molecules, polymers
and materials [43]. Numerous compounds with diverse biologi-
cal activities also contain the ether-substituted triazoles [44-46].
Therefore, it is of great significance and interest to develop a
direct approach to access fully substituted 5-ether-1,2,3-triazoles
with high regioselectivities and chemoselectivities by remote ether
–
C H activation [1-8]. However, the application of such coordina-
tion strategy is severely restricted by the following two key issues.
The nitrogen-, sulfur- or selenium-chelating groups owning strong
coordination abilities are more commonly used as directing groups
rather than oxygen, especially for ethers with poor coordination
to late transition metals, which lead to very limited methodolo-
gies for the ether-directed transformations [4]. In addition, most of
the current coordination strategies are based on proximal direct-
ing groups due to spatial and geometrical accessibility. It is still
distinct and longstanding challenge for controlling the selectivity
by remote directing groups [9-12]. Albeit some promising progress
have been accomplished in overcoming above-mentioned issues in
–
C H activation [1-12], achieving regioselective and chemoselective
cycloaddition of azides and inert alkynes remains undisclosed, es-
pecially when the cycloaddition site is far away from directing
groups. Herein, we set out to address above problems by apply-
ing the weak and remote coordination of ethers to the metals for
highly regioselective and chemoselective cycloaddition of azides
and alkynes.
Metal-catalyzed azide–alkyne cycloaddition (MAAC) has been
well-defined during the past decades to afford various 1,2,3-
∗
Corresponding authors.
E-mail addresses: nzheng@dlut.edu.cn (N. Zheng), wzsong@dlut.edu.cn (W.
Song).
https://doi.org/10.1016/j.cclet.2021.05.037
1001-8417/© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Please cite this article as: X. Duan, N. Zheng, M. Li et al., Remote ether groups-directed regioselective and chemoselective cycloaddition
of azides and alkynes, Chinese Chemical Letters, https://doi.org/10.1016/j.cclet.2021.05.037

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slightly lower yield (3h) compared to methyl ether. Subsequently,
the long-distance ether directing groups were explored by extend-
ing the σ bonds away from internal alkyne part. Encouragingly,
the remote directing groups with three σ bonds away from the
alkyne moieties remained well controlling the regioselectivities for
IrAAC reaction (more than 20:1), despite that the yields would de-
crease (3i-3l). Only moderate yields were acquired using remote
ethers with four σ bonds away from the alkynes (3m and 3n). Be-
sides various ethers, although the internal thioalkynes have already
been successfully used in MAAC process before [18,19, 25-31], we
further explored other kinds of alkynes with thio-functional moi-
eties using thioethers as directing groups for this transformation.
To our delight, good yields and regioselectivities were acquired
using thioethers as directing groups for various internal alkynes
without significant electronic effect (4a-4c).
Methyl ether has already been demonstrated to be the most
efficient directing group in the IrAAC process. Thus, we contin-
uously explored the substrate ranges of internal alkynes (1) and
azides (2) using methyl ethers as directing groups in Scheme 3.
Both electron-donating and electron-withdrawing internal alkynes
could participate in the cycloadditions with benzyl azide to afford
fully substituted 5-ether-1,2,3-triazoles with similar yields (3a, 3o-
3t). The electronic effect was not very obvious for para- and meta-
methyl, methoxy, chloro substituted internal alkynes (3o-3t). But
for the ortho-chloro substituted internal alkyne, the yield would
drop to 68% due to the steric hindrance (3u). Noticeably, hetero-
cyclic substrates such as benzothiazole, furan and pyridine could
be tolerated in this transformation despite the moderate yields
(3v-3x). In these cases, ether group could well control the regios-
electivites in a competitive manner with the heteroatoms exist-
ing in furan and pyridine, whose coordination abilities may be
weakened by aromaticity effect. Unfortunately, only trace amount
of product was observed using alkyl internal alkyne as substrate
(3y). Then the substrate scope of different azides was screened.
The IrAAC reaction could conduct smoothly with various alkyl
and aryl azides (3z-3ae). Both the electron-donating and electron-
withdrawing azides could provide the corresponding products with
similar yields (71%−75%), hinting the electronic effect was not ob-
vious for azides (3z-3ab). However, lower yield (3ac) was obtained
using phenyl azide instead of alkyl azide. To our delight, ethyl and
n-butyl azides could be used as substrates to give complicated fully
substituted 5-ether-1,2,3-triazoles with good yields (72% and 77%)
(3ad and 3ae). The TsN3 could also participate in this transforma-
tion albeit the low yield (3af).
Scheme 1. Coordination strategy for regioselective cycloaddition of azides and
alkynes.
groups-directed cycloaddition reaction. Considering that the fail-
ure for ether-directed AAC reactions, and as a continuation of our
pursuit of highly regioselective cycloaddition reaction, we hypothe-
sized that iridium(I) with stronger coordination ability to the lone-
pair electron of ether groups could potentially solve the remote-
controlled issues. Thus, we used ether group as directing group to
coordinate with iridium catalyst, which resulted in excellent 1,5-
regioselectivities and excellent chemoselectivities for the synthe-
sis of various fully substituted 5-ether-1,2,3-triazoles. Beyond that,
we found that even the remote ether group (up to four σ bonds
away from internal alkyne part) can also control the regioselectiv-
ities well during the IrAAC process (Scheme 1c).
After achieving remote ether groups-directed regioselective
cycloaddition of azides and alkynes, we turned to investi-
gate the chemoselective issues by ether groups-directed strategy
(Scheme 4). 1,3-Diynyl ethers (5) were designed as substrates
for the chemoselective synthesis of fully substituted 4-alkynyl-
triazoles (6) by discriminating two different internal alkynes at-
taching with/without ether groups. The IrAAC reaction only oc-
curred at the propargly ether moiety rather than outer inter-
nal alkyne to generate fully substituted 4-alkynyl-triazole, and
no any bis-1,2,3-triazole was isolated. Besides methyl-ether could
be used as directing group (6a), other ether groups including
benzyl-ether and bulky-ether could also promote the transforma-
tion well with excellent regioselectivities and chemoselectivities
(6b and 6c). For para-substituted diynes, both electron-donating
and electron-withdrawing diynes could supply fully substituted 4-
alkynyl-triazoles (6d-6f) with similar yields, even for using strong
electron-withdrawing nitro substrate (6f). The cycloaddition re-
action could proceed smoothly for meta- and ortho-substituted
diynes (6g-6i) in spite of lower yield for ortho-chloro substituted
diyne (6i). Encouragingly, the diyne with thiophene structure could
also be employed as substrate to give 4-alkynyl-triazole (6j) in
good yield, and excellent regioselectivity and chemoselectivity. The
With the optimized conditions in hand (For the details, please
see Supporting information), we next examined various substrates
with different directing groups in Scheme 2. Various internal
alkynes (1), and benzyl azide (2a) were used as substrates to
afford fully substituted 5-ether-1,2,3-triazoles (3) in good yields
(up to 80%), and excellent regioselectivities (more than 20:1). The
steric hindrance effect for ether directing groups was firstly inves-
tigated (3a-3d). The yield would dramatically decrease when the
steric hindrance was increased from proton (3a) to gem-dimethyl
group (3d) albeit with excellent 1,5-regioselectivities. Remarkably,
the secondary propargyl ethers could be used as directing groups
for IrAAC reactions (3b and 3c), which paved the route to access
chiral triazoles from chiral propargyl ethers later. When allyl ether
was used as directing group, the yield dropped significantly (3e),
which may be attributed to the side reactions involving Ir-π-allyl
intermediate [47,48]. If benzyl ethers were used instead of methyl
ether as directing groups, the moderate yields were obtained and
no obvious electronic effect was observed (3f and 3g). Aryl ether
could also be used as directing group for this transformation with
2

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Scheme 2. Substrate scope using various directing groups. Standard reaction conditions: 1 (1.0 equiv.), 2 (1.5 equiv.), [Ir(COD)Cl]2 (5 mol%), CHCl3 (0.1 mol/L), 60 °C for
12–24 h. Yield of isolated product. The regioisomeric ratios of all examples were more than 20:1, which were determined by 1H NMR of the crude mixture with an internal
standard.
Scheme 3. Substrate scope for methyl ether-directing regioselective cycloaddition. The reactions were set up in standard reaction conditions.
moderate yields were attributed to the low conversion of internal
alkynes.
which offers the unique and efficient way to access non-natural
glycosyl triazoles in glycomics study (Scheme 5a2). The chemos-
elective synthesis of bistriazoles from other types of diynes was
expanded (Scheme 2b). Using symmetric dipropargyl methyl ether
(5k) as substrate, fully substituted 5-ether-bistriazole (6k) was
acquired with excellent regioselectivity, which could be applied
in regiospecific polymerization in future (Scheme 5b3). Terminal
alkyne and internal alkyne could be successfully differentiated by
orthogonal CuAAC-IrAAC reaction with excellent chemoselectivity.
Benzyl azide (2a) and phenylethyl azide (2ad) were used in CuAAC
Subsequently, the applicability of ether-directing IrAAC reac-
tion was investigated in Scheme 5. The regioisomeric ratios of all
examples in Scheme 5 were more than 20:1, which were deter-
mined by 1H NMR of the crude mixture with an internal stan-
dard. Estrone as a steroidal estrogen could be efficiently modi-
fied by ether-directing IrAAC reaction to form derivate 3ag, which
provides a novel drug conjugate approach (Scheme 1a1). Glycosyl
azide (2ah) could be utilized to prepare carbohydrate derivate 3ah,
3

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Scheme 4. Substrate scope for chemoselective synthesis of fully substituted 4-alkynyl-triazoles. The reactions were set up in standard reaction conditions.
Scheme 5. The application of the regio- and chemoselectively ether groups-directing cycloaddition.
and IrAAC respectively. 1,6-Diyne (5i) was converted to bistriazole
(6l) without cross-reactivity, which could be sequentially modified
by mutually orthogonal MAAC approach to rapidly build multi-
functionalized molecular scaffolds (Scheme 5b4).
reaction in materials science, medicinal chemistry and polymer
chemistry are underway in our laboratory.
Declaration of competing interest
In summary, we have used ether group as directing group to co-
ordinate with iridium catalyst in the cycloaddition process, which
results in the excellent 1,5-regioselectivities and chemoselectivi-
ties for the synthesis of fully substituted 5-ether-1,2,3-triazoles.
We have also demonstrated the remote ether group (up to four
σ bonds away from alkyne) could well control the regioselectivi-
ties. The IrAAC reaction chemoselectively occurs at the propargyl
ether moiety of diynes to give unique fully substituted 4-alkynyl-
triazoles. Further applications of this ether groups-directed IrAAC
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
This work was supported by grants from the National Natu-
ral Science Foundation of China (No. 21978039), Special Funds of
4

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the Central Government Leading Local Government for the Tech-
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the Fundamental Research Funds for the Central Universities (Nos.
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