2-Azidoethane-1-sulfonylfluoride (ASF): A Versatile Bis-clickable Reagent for SuFEx and CuAAC Click Reactions

Article abstract of DOI:10.1002/ejoc.201801825

A new reagent, 2-azidoethane-1-sulfonylfluoride (ASF), was synthesized from 2-chloroethane-1-sulfonyl fluoride in 50g-scale with 87 % yield. This novel reagent possesses two selectively clickable functionalities to be used for both CuAAC and SuFEx click reactions. The application of this reagent ASF to the construction of a class of novel 1,2,3-triazole derived S(VI)-F analogs was achieved in a quick, efficient and atom-economical manner. Orthogonally clickable construction of a new class of dendrimers was also accomplished.

Full text of DOI:10.1002/ejoc.201801825

A Journal of
Accepted Article
Title: 2-Azidoethane-1-sulfonylfluoride (ASF), a Versatile Bis‐clickable
Reagent for SuFEx and CuAAC Click Reactions
Authors: Xu Zhang, Balakrishna Moku, Jing Leng, K. P. Rakesh, and
Hua-Li Qin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801825
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European Journal of Organic Chemistry
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COMMUNICATION
2
-Azidoethane-1-sulfonylfluoride (ASF), a Versatile Bis‐clickable
Reagent for SuFEx and CuAAC Click Reactions
Xu Zhang,† Balakrishna Moku,
[a]
† [a]
Jing Leng, K. P. Rakesh and Hua-Li Qin *
[a]
[a]
[a]
Abstract:
A
new reagent, 2-azidoethane-1-sulfonylfluoride
and CuAAC click chemistries for the orthogonal synthesis of
dendrimers has rare been explored due to the very limited and
available reagents suitable for both types of click reactions.
(ASF), was synthesized from 2-chloroethane-1-sulfonyl fluoride
in 50g-scale with 87% yield. This novel reagent possesses two
selectively clickable functionalities to be used for both CuAAC
and SuFEx click reactions. The application of this reagent ASF
to the construction of a class of novel 1,2,3-triazole derived
S(VI)-F analogues was achieved in a quick, efficient and atom-
economical manner. Orthogonally clickable construction of a
new class of dendrimers was also accomplished.
VI
To date, several S -F reagents have been developed as
SuFEx clickable hubs (Figure 1). Arylfluorosulfates (Ar-O-SO
and iminosulfur oxydifluorides (R-N═SOF are accessible
through the reactions of two gases, sulfuryl fluoride (SO
)[3,8]
), with oxygen or nitrogen
2
-F)
2
)
2 2
F
[9]
and thionyl tetrafluoride (SOF
4
nucleophiles respectively under appropriate conditions to
provide robust click connecters for further SuFEx manifestation
(
Figure 1a, 1b). 2-Heteroaryl ethenesulfonyl fluorides (Figure 1c),
Introduction
a class of selectively addressable bis-electrophiles for SuFEx
transformations can be readily synthesized through manipulating
Click chemistry has been widely applied as a powerful tool in
a large variety of fields because of its unique features of
operational simplicity, mild conditions, substrate scopes, bio-
orthogonality, favorable kinetics, and high yields.[1] Among the
available clickable reactions, the copper catalyzed azide−alkyne
another excellent SuFEx reagent, the ethenesulfonyl fluoride
[10]
(
ESF)
using
Heck-type
couplings
or
direct
[11]
fluorosulfonylvinylation of aryl C-H bonds.
cycloaddition (CuAAC), had
a profound influence on the
evolution of click chemistry since the first reports by the groups
of Sharpless and Meldal.[ Sulfur(VI) Fluoride Exchange
2]
(
SuFEx), a rapidly developing new family of click chemistry
transformations, was introduced by professor Sharpless in 2014,
encompassing those reactions that facilitate the modular
VI
1
2
synthesis of S -X (where X can be NR R or OR) connections
VI
from
a
parent S -F containing compound under defined
[
3]
conditions. Many attractive features such as strong electron
withdrawing nature, stability against hydrolysis, resistance to
reduction at sulfur, and crisp preference for two-electron
processes over radical processes, have already made this
“
grabber” group applicable to many productive fields within a
short period.[ Dendrimers are a class of macromolecules with a
well-defined globular structure possessing a large number of
peripheral functional groups of numerous specific characteristics
for a wide range of applications.[5] Typically, the synthesis of
dendrimers requires a large excess of monomers, and/or the
protection-deprotection procedures, or implements at least two
orthogonal chemistries together with purification steps, all of
which suffer from low atom efficiency.[6] Therefore, orthogonal
click chemistries with high reaction enthalpy, high chemo-
selectivity and atom-economy has been widely investigated for
dendrimer synthesis. [7] However, the utilization of both SuFEx
4]
Figure
1 Evolution of Sulfur (VI) fluoride exchange (SuFEx) click
chemistry.
Recently, the constructions of fluorosulfonyl isoxazoles and
†
†
fluorosulfonyl 1,2,3-triazoles (Figure 1d) were accomplished by
[
a]
Xu Zhang. Balakrishna Moku, Jing Leng, K. P. Rakesh and Prof
Hua-Li Qin
using 1-bromoethene-1-sulfonyl fluoride (1-Br-ESF).[
12]
It
State Key Laboratory of Silicate Materials for Architectures; and
School of Chemistry, Chemical Engineering and Life Science
Wuhan University of Technology
provided two classes of novel heterocycles-functionalized
sulfur(VI)-F motifs for SuFEx click chemistry as robust tools.
These approaches to preparation of diverse compound libraries
205 Luoshi Road, Wuhan, 430070, China
VI
E-mail: qinhuali@whut.edu.cn.
Homepage: http://www.qin-group.com
bearing S -F increased the chance of identifying lead
[13]
compounds
and synthesizing new materials, especially
dendrimers. Therefore, design and synthesis of S(VI)-F new
reagents to enrich SuFEx cabinet for a quick access to S(VI)-F
[†]
These authors contributed equally to this work
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European Journal of Organic Chemistry
10.1002/ejoc.201801825
COMMUNICATION
containing molecules are highly desirable. Herein, we report the
unique structure of ASF 1 provides an azide functionality and a
development of 2-azidoethane-1-sulfonylfluoride (ASF) (Figure
sulfonyl fluoride motif to be selectively clickable for furnishing
both 1,2,3-triazoles and S derivatives linked by two adjacent
VI
1e) as a new portal to both azide-alkyne and SuFEx click
reactions allowing quick, efficient and atom-economical
synthesis of 1,2,3-triazole derived S(VI)-F libraries and as a
versatile bis‐clickable reagent for orthogonal synthesis of
dendrimers.
carbons (sulfamates, sulfonic acids, sulfones, sulfates et al.)
though azide−alkyne click, SuFEx click and other reactions.
Therefore, libraries of molecules (3) bearing both ethylsulfonyl
VI
(S ) and triazoles can be easily accessed for drug discovery
using reliable and robust click reactions, in which Tazobactam
Accordingly, after screening a variety of conditions, we
(
Figure 2) is a good example to show the value of this class of
achieved the synthesis of 2-azidoethane-1-sulfonylfluoride
motifs.
VI
(
ASF) (Figure 1e) bearing an S -F motif and an azide
functionality connected to two vicinal carbon atoms, from the
[
10]
readily accessible 2-chloroethane-1-sulfonyl fluoride
by
Results and Discussion
substituting chloride with azide anion in a reasonable scale (50 g)
with 87% yield. It is very interesting to note that unlike sulfonyl
chloride which can be easily converted to sulfonylazide in the
Based on the potential significance of this designed 2-
azidoethane-1-sulfonylfluoride (ASF) for medicinal chemistry
and pharmaceutical industry, we started our initial investigation
of application of this new clickable hub in copper(I)-catalyzed
azide-alkyne cycloaddition (CuAAC) click chemistry to testify the
robustness of this reagent for constructing a class of novel 1,4-
presence of NaN
the presence of NaN
construction through Michael addition of hydrazoic acid (HN
situ generated from NaN and H O) to ESF in a small scale (1.1
g) with 78% yield minimizing the effect of high explosibility of
HN
.[15] It is worth noting that when Michael addition was carried
3
, [14] the sulfonyl fluoride remains untouched in
. Alternatively, we also accomplished ASF
, in
3
3
3
2
disubsituted 1,2,3-triazoles bearing
functionality for further addressing.
a
sulfonyl fluoride
3
out in the presence of a strong base, the azide group of ASF
might undergo a β-elimination (or retro-Michael) process, to
regenerate ESF, and some strong base may even cause a
hydrolysis of the sulfonyl fluoride moiety to destroy ASF.[16]
Therefore, the substitution reaction between 2-chloroethane-1-
Table 1: Substrates scope of (CuAAC) click chemistry of ASF with terminal
alkynes. [
a]
sulfonyl fluoride and NaN
ASF preparation.
3
in DMSO is the preferred method for
Figure 2 Representative drugs bearing ethylsulfonyl (VI) moieties or/and
,2,3-triazoles.
1
VI
The sulfonyl (S ) moieties have significant impact in the fields
[
a] Isolated yields, ASF (1, 1 mmol), terminal alkynes (2, 1 mmol), 5 mol% of
CuSO .
5H O and 10 mol% of Na ascorbate were added into DMSO (3 mL),
the mixture was stirred at room temperature for 12 h; [b] 10 mol% of
CuSO .
5H O was used.
of pharmaceutical and medicinal chemistry, and there are more
than 150 drugs bearing SVI motif, which include some
blockbuster drugs, such as Tindamax (Tinidazole), Relpax
4
2
4
2
(
Eletriptan), Zonegran (Zonisamide), Campral (Acamprosate)
VI
and Trusopt (Dorzolamide), possess ethylsulfonyl (S )
functionality (Figure 2).[17] On the other hand, 1,2,3-triazoles
also play irreplaceably important roles in medicinal chemistry
and drug discovery, and a few triazole-containing drugs have
been approved, such as Cefatrizine and Tazobactam.[1,18] The
As illustrated in Table 1, examination of ASF (1) with various
structurally and electronically diverse terminal alkynes
revealed that this click reaction is compatible with a broad scope
of substrates. Not surprisingly, all of the 1,4-disubstituted 1,2,3-
2
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European Journal of Organic Chemistry
10.1002/ejoc.201801825
COMMUNICATION
triazoles were obtained in excellent yields regardless the
electron-donating or electron-withdrawing groups, such as
methyl, methoxyl, amine, halogen, nitro and amide moieties
[a] Isolated yield, cesium carbonate (1 mmol) and phenol (7, 1 mmol) were
added to
a stirred solution of triazolo sulfonyl fluoride (4a, 1 mmol) in
acetonitrile (2 mL) at room temperature and stirred for 12 h.
(
Table 1, 4a-4l). Heteroaryl and aliphatic alkynes were also
transformed into their corresponding products in good to nearly
quantitative yields (Table 1, 4m-4q).
yields (Table 3, 6a-6c) where 2-azido-N-phenylethane-1-
sulfonamide 6c was obtained in slightly lower yield than its
counterparts attributing to the sluggish reactivity of aniline. In
To further demonstrate the practicality of the new reagent ASF
addition, 4a, a representative of the new class of 1,4-
1
in drug derivatization, steroidal drugs (2r and 2s) and
disubstituted 1,2,3-triazoles 4 was smoothly converted to the
corresponding sulfonates 8 (Table 4, 8a-8c) in excellent yields
upon reacting with phenols 7 via a SuFEx process.
antineoplastic drug (2t) were chosen as the representative
examples, and much to our delight, their corresponding modified
products were smoothly furnished in good to excellent yields
(
Table 2, 4r-4t).
As illustrated in Scheme 1, ASF (1) also exhibited good
reactivity toward cyclohexanone 9 for generation of a unique
seven-membered lactam 10 bearing ethyl sulfonyl fluoride
moiety in moderate yield.
Table 2: Application of ASF for drug derivatization. [a]
Scheme 1 synthesis of cyclic lactam.[a]
[
a] Isolated yield, cyclohexanone (9, 1 mmol) and ASF (1, 1 mmol) were added
to a stirred solution in dichloromethane (3 mL), then TiCl
and recovered to room temperature for 20 h.
4
was dropwise at 0℃
[
a] Isolated yields, ASF (1, 1 mmol), terminal alkynes (2, 1 mmol), 5 mol% of
CuSO O and 10 mol% of Na ascorbate were added into DMSO (3 mL),
.5H
the mixture was stirred at room temperature for 12 h; [b] 10 mol% of
CuSO O was used.
.5H
4
2
Utilization of bis-clickable reagent through orthogonal CuAAC
and SuFEx click reactions for chemoselective assembly of
dendrimers was investigated to demonstrate the versatility of
this novel reagent. As shown in Scheme 2, dendrimers 15 was
successfully synthesized from versatile bis-clickable reagent
ASF in 54% overall isolated yield in a three-step sequence
4
2
Table 3: SuFEx of ASF with amines for construction of sulfonyl amides.[a]
(
Scheme 2) without requiring any protecting-deprotecting
processes. This new class of dendrimers allow controlled
molecular weight building, controlled branching and versatility in
design and modification of the terminal end groups. Therefore,
with this novel reagent (ASF), the highly efficient and orthogonal
SuFEx and CuAAC click reactions have provided promising
possibilities for the preparation of unique polymers.
[
a] 2-azidoethane-1-sulfonyl fluoride (1, 1 mmol) reacted with amine (5, 1.0
eq.) in the presence of triethylamine (1.1 eq.) in acetonitrile (1 M) at room
temperature for 12 h, followed by sonication at 45 oC for 4 h. The yields were
based on the amounts of isolated products.
Scheme 2 synthesis of dendrimers using SuFEx and CuAAC click reactions.
In view of the potential application of ASF 1 in SuFEx click
reactions, two representative aliphatic (primary and secondary)
amines and an aromatic amine were selected to test the
feasibility of our proposed SuFEx reaction. Gratifyingly, their
corresponding amides were successfully generated in moderate
Table 4: Synthesis of triazolo sulfonates.[a]
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European Journal of Organic Chemistry
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COMMUNICATION
Reaction conditions: (a) 1,3,5-triethynylbenzene (11, 1 mmol), ASF (6 eq.),
Cyclohexanone (9, 1 mmol) and ASF (1, 1 mmol) were added to a stirred
CuSO
2 h (90 %); (b) 3,5-diethynylphenol (12, 5 eq.), Cs
mL), H O (5 mol %), room temperature, 12 h (61 %); (c) ASF (12 eq.),
CuSO O (1 eq.), Na ascorbate (1 eq.), DMSO (3 mL), room temperature,
.5H
2 h (98 %).
4
.5H
2
O (1 eq.), Na ascorbate (1 eq.), DMSO (0.3 M), room temperature,
solution in dichloromethane (3 mL), then TiCl
recovered to room temperature for 20 h.
4
was dropwise at 0℃ and
1
2
CO (5 eq.), CH CN (5
3
3
2
4
2
General procedure for dendrimers.
1
(
a) 1,3,5-triethynylbenzene (11, 1 mmol), CuSO .
5H O (1 eq.) and Na
4 2
ascorbate (1 eq.) were added to a stirred solution of ASF (1, 6 eq.) in
DMSO (3 mL) and stirred at room temperature for 12 h. After completion
of reaction, the mixture was purified by recrystallization to get the
corresponding compound 13.
Conclusions
We have developed
a new reagent, 2-azidoethane-1-
sulfonylfluoride (ASF), which possesses two selectively clickable
functionalities for both sulfur(VI) fluoride exchange (SuFEx) and
CuAAC click reactions. This new molecule has great potential
for quick introducing sulfonyl fluoride into biological systems to
develop new covalent enzyme inhibitors through versatile,
reliable and robust click chemistry. The utilization of ASF for
(
b) 13 (1 mmol), 3,5-diethynylphenol (12, 5 eq.) and Cs
2 3
CO (5 eq.) were
added to a stirred solution of H O (5 mol %) in CH CN (5 mL) and stirred
2
3
at room temperature for 12 h. After completion of reaction, the mixture
was concentrated to dryness and purified by column chromatography to
obtain the corresponding compound 14.
orthogonally clickable construction of a new class of dendrimers
c) 14 (1 mmol), CuSO .
4 2
5H O (1 eq.) and Na ascorbate (1 eq.) were
(
was accomplished. The possible future wide applications of ASF
added to a stirred solution of ASF (1, 12 eq.) in DMSO (3 mL) and stirred
at room temperature for 12 h. After completion of reaction, the mixture
was purified by recrystallization to get the corresponding compound 15.
will significantly accelerate the preparation of diverse compound
VI
libraries bearing S -F moieties to increase the chance of
identifying new targeted covalent inhibitors.
Experimental Section
Acknowledgments
General procedure for compound 4.
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150), the Wuhan applied fundamental
research plan of Wuhan Science and Technology Bureau (grant
NO. 2017060201010216) and Wuhan University of Technology
2
-azidoethane-1-sulfonyl fluoride (1, 1.0 mmol, 153.1 mg), acetylene (2,
.0 mmol, 1.0 eq.), CuSO .
5H O (5 mol%, 13 mg), Na ascorbate (10
1
4
2
mol%, 20 mg), DMSO (3.0 mL) were added in a reaction tube (10 mL)
and stirred at room temperature for 12 h. Then the reaction mixture was
extracted with ethyl acetate (3×10 mL) and the combined organic layers
were washed with brine, dried over anhydrous sodium sulfate and
concentrated to dryness under reduced pressure. The crude product was
further purified by column chromatography on silica gel using petroleum
ether / ethyl acetate (v / v) as eluent to get desired compound 4.
(
2017-YS-084) for the financial support.
Keywords: Click chemistry • SuFEx • Azides • Dendrimers
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European Journal of Organic Chemistry
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COMMUNICATION
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801825
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A
novel unique reagent, 2-
azidoethane-1-sulfonylfluoride
ASF), which can be used for both
SuFEx and CuAAC
(
azide-alkyne and SuFEx click
reactions, was developed to
provide a portal to unique 1,2,3-
triazole derived S(VI)-F libraries for
Xu Zhang,† Balakrishna Moku,† Jing
Leng, K. P. Rakesh and Hua-Li Qin*
medicinal
biology and drug discovery in a
quick, efficient and atom-
chemistry,
chemical
Page No. 1 – Page No.6
Title: 2-Azidoethane-1-sulfonylfluoride
economical manner using a robust
click chemistry strategy. A new
class of dendrimers was developed
(ASF), a Versatile Bis‐clickable Reagent
for SuFEx and CuAAC Click Reactions
using
this
reagent
through
orthogonal CuAAC and SuFEx click
reactions.
This article is protected by copyright. All rights reserved.