Converting (E)-(Hetero)arylethanesulfonyl Fluorides to (Z)-(Hetero)arylethanesulfonyl Fluorides Under Light Irradiation

Article abstract of DOI:10.1002/ejoc.201900799

The construction of (Z)-(hetero)arylethenesulfonyl fluorides was achieved utilizing Iridium photoredox catalysis under UV-light irradiation. This protocol provided a diverse range of (Z)-(hetero)arylethenesulfonyl fluorides in moderate to good yields under mild conditions without external additives. The late-stage transformation of the (Z)-(hetero)arylethenesulfonyl fluorides comparing with their E-configuration counterparts was also studied.

Full text of DOI:10.1002/ejoc.201900799

A Journal of
Accepted Article
Title: Converting (E)-(Hetero)arylethanesulfonyl Fluorides to (Z)-
(Hetero)arylethanesulfonyl Fluorides under Light Irradiation
Authors: Yu-Mei Huang, Shi-Meng Wang, Jing Leng, Balakrishna
Moku, Chuang Zhao, Njud S. Alharbi, and Hua-Li Qin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900799
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900799
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201900799
COMMUNICATION
Converting (E)-(Hetero)arylethanesulfonyl Fluorides to (Z)-
Hetero)arylethanesulfonyl Fluorides under Light Irradiation
(
[
a]
[a]
[a]
[a]
[a]
[b]
Yu-Mei Huang , Shi-Meng Wang , Jing Leng , Balakrishna Moku , Chuang Zhao , Njud S. Alharbi
and Hua-Li Qin*[a]
Abstract: The construction of (Z)-(hetero)arylethenesulfonyl
fluorides was achieved utilizing Iridium photoredox catalysis under
UV-light irradiation. This protocol provided a diverse range of (Z)-
(hetero)arylethenesulfonyl fluorides in moderate to good yields under
mild conditions without external additives. The late-stage
transformation of the (Z)-(hetero)arylethenesulfonyl fluorides
comparing with their E-configuration counterparts was also studied.
Introduction
Figure 1. Covalent inhibitors containing sulfonyl fluoride moieties.
Sulfur (VI) fluoride exchange (SuFEx), a new category of
rapidly developing click reactions was introduced by Professor K.
B. Sharpless and co-workers for the construction of molecular
the conjugated olefins as Michael acceptors possess a robust
and broad spectrum of bioactivity, which are among the
prominent biological probes and covalent protein inhibitors for
addressing the sulfydryl of cysteine and the ε-amino group of
lysines[8] (Figure 2).
connectivity based on the unique reactivity of S(VI)-F bonds to
react with suitable nucleophiles under appropriate conditions.[1]
Several features of sulfonyl fluoride motifs, such as their strong
electron withdrawing nature, stability against hydrolysis,
resistance to reduction at sulfur, and crisp preference for two-
electron processes over radical processes, have made this
“
grabber” group applicable to several productive fields.[2] In the
field of chemical biology, sulfonyl fluoride moiety was found to
be one of the most prominent covalent inhibitor warheads for
addressing the ε-amino group of lysines, and for targeting
tyrosine, activated serine, or threonine residues, and also
reactive toward cysteine and histidine side chains.[3] For
example, phenylmethanesulfonyl fluoride (PMSF), was found to
act as covalent inhibitors of serine proteases with widespread
use in protein chemistry and as reactive probes in the routine
preparation of cell lysates.[4] Sulfonyl fluoride based-probes have
enabled rational targeting of non-serine residues, which was
exemplified by a recent report of covalent modification of SF-p1-
yne of tyrosine residues in protein binding sites[5] (Figure 1).
On the other hand, the alkenes conjugated with electron-
withdrawing groups have played a significant role for drug
discovery.[ Many compounds containing conjugated olefins
have been successfully developed as drugs or drug candidates
for the treatment of a variety of diseases, for example, afatinib, a
compound designed to proceed a Michael addition with Cys797
in the active site of epidermal growth factor receptor at the
nanomolar level against mutated lung cancer cells.[7] Moreover,
Figure 2. Covalent inhibitors containing conjugated olefins.
2-Arylethenesulfonyl fluorides are
a special family of
[9]
selectively addressable bis-electrophiles, which contain both
conjugated olefins and sulfonyl fluoride moieties that can
undergo either a Michael addition for the assembly of diversified
sulfonyl fluorides, or a SuFEx click reaction for the construction
of S(VI) containing molecules such as vinyl sulfonates and
sulfonyl amides, prevalent in more than 150 FDA approved
drugs.[10] Considering both the conjugated olefins and the
sulfonyl fluoride moieties as structurally ubiquitous motifs in
many important areas, such as, chemical biology and drug
discovery, the 2-arylethenesulfonyl fluorides are undoubtedly of
great value for organic synthesis and the discovery of new
covalent drugs.[11]
6]
[
a]
Y.-M. Huang, S.-M. Wang, J. Leng, B. Moku, C. Zhao, Prof. H.-L.
Qin
State Key Laboratory of Silicate Materials for Architectures; and
School of Chemistry, Chemical Engineering and Life Science
Wuhan University of Technology
Wuhan, Hubei Province 430070, People’s Republic of China
E-mail: qinhuali@whut.edu.cn
The development of methods for the synthesis of 2-
arylethenesulfonyl fluorides have gained significant attention due
to their unique reactivity and wide applications. The synthesis
Homepage: http://www.qin-group.com
Njud S. Alharbi
Biotechnology Research group, Deportment of Biological Sciences,
Faculty of Science
King Abdulaziz University,
Jeddah, Saudi Arabia
was first reported by Truce and Hoerger half a century ago using
styrylsulfonyl chloride as starting material (Scheme 1a).[12] Since
the year of 2016, a series of Heck-type coupling reactions for the
synthesis of 2-arylethenesulfonyl fluorides from ethenesulfonyl
fluoride have been reported[9a,9d,13] (scheme 1b left). Lately, the
[
b]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
10.1002/ejoc.201900799
COMMUNICATION
o
constructions
of
2-arylethenesulfonyl
fluorides
were
reactions were operated at an elevated temperature of 70 C or
accomplished through either directing group assisted Rh(III)-
catalyzed[14] or ligand-accelerated Pd-catalyzed nondirected C-H
bond activation strategy[15] (Scheme 1b right). However, all the
a reduced temperature of -10 oC, the desired products were
obtained in nearly the same yields indicating that the reaction
temperature had very limited effects for this isomerization (Table
1, entries 6 and 7). Excitingly, reducing the loading of the
photocatalyst from 5% to 1% afforded a slightly better yield (63%,
Table 1, entry 8). Furthermore, the yield was almost unaffected
under air atmosphere (Table 1, entry 9). Interestingly, prolonging
the reaction time to 72 hours or reducing the reaction to 36
hours have little impact on the yield of 2a (Table 1, entries 9-11).
However, the yield of 2a was decreased obviously when the
reaction time was further reduced to 24 hours (Table 1, entries
9-12). The control experiments revealed that no desired product
was generated in the absence of light or photocatalyst (Table 1,
entries 13 and 14). Accordingly, the reaction conditions of Table
1, entry 11 was chosen as the standard conditions for further
above
methods
exclusively
afforded
the
(E)-
(
hetero)arylethenesulfonyl fluorides, the constructions of the
corresponding (Z)-configurations remain mysterious, and thus
the activity and application of the (Z)-configurations in drug
discovery, material science and chemical biology need to be
revealed, which has inspired us to explore the synthesis and
reactivity of the (Z)-2-arylethenesulfonyl fluoride. Most of the
current methods for the construction of new olefin bonds
provided the thermodynamically more stable E-alkenes, while
methods to access the less stable Z-alkene remained far less
developed. [16] Viewing on the recent success of photoredox
[
17]
catalysis mediated chemical transformations
continuing efforts on SuFEx click chemistry, herein, we reported
photoredox mediated preparation of the (Z)-2-
and our
Table 1 Impact of reaction parameters on the configuration reversal of 1aa
a
arylethenesulfonyl fluorides, which, to the best of knowledge,
provided the first example for the assembly of this class of
molecules.
Yield
b
Entry
Catalyst
t (h)
(
2a %)
1d
2d
3d
4
[Ir(ppy)
5.0 mol%)
Ru(bpy) (PF
5.0 mol%)
2
(bpy)]PF
6
48
48
48
48
48
48
48
48
48
72
36
24
7 (72c)
(
3
6 2
)
trace
(
[
3
Ir{dF(CF )ppy}
2
2
2
2
2
(dtb-bpy)]PF
(dtb-bpy)]PF
(dtb-bpy)]PF
(dtb-bpy)]PF
(dtb-bpy)]PF
6
6
6
6
6
6
6
6
11 (93c)
27 (99c)
57 (99c)
60 (88c)
59 (93c)
63 (98c)
65 (99c)
67 (95c)
63 (96c)
48 (95c)
(5.0 mol%)
[
3
Ir{dF(CF )ppy}
(5.0 mol%)
[
3
Ir{dF(CF )ppy}
5
5.0 mol%
6e
7f
8
3
[Ir{dF(CF )ppy}
(
[
(
5.0 mol%)
Ir{dF(CF )ppy}
5.0 mol%)
3
Scheme 1. Representative strategies for the synthesis of 2-arylethenesulfonyl
fluoride.
[Ir{dF(CF )ppy} (dtb-bpy)]PF
3
2
2
2
(1.0 mol%)
9g
3
[Ir{dF(CF )ppy}
(dtb-bpy)]PF
(dtb-bpy)]PF
(1.0 mol%)
[
3
Ir{dF(CF )ppy}
1
0g
Results and Discussion
(1.0 mol%)
[
(
Ir{dF(CF
1.0 mol%)
)ppy}
1.0 mol%)
)ppy}
1.0 mol%)
3
)ppy}
2
(dtb-bpy)]PF
6
1
1g
[
Ir{dF(CF
3
2
2
(dtb-bpy)]PF
6
6
12g
Initially, (E)-2-phenylethene-1-sulfonyl fluoride 1a was used
as a model substrate to investigate the feasibility of the
configuration reversal of (E)-2-arylethenesulfonyl fluorides.
When the reaction was carried out in the presence of
(
[Ir{dF(CF
(
3
(dtb-bpy)]PF
1
3gh
4g
36
36
trace
trace
1
No photocatalyst
a)
[
Ir(ppy)
2
(bpy)]PF
6
under blue LED irradiation in 1,4-dioxane, the
Reaction conditions: (E)-2-phenylethene-1-sulfonyl fluoride (1a, 0.1 mmol),
desired (Z)-2-phenylethene-1-sulfonyl fluoride 2a was obtained
in 7% yield (Table 1, entry 1). Several different photocatalysts
photocatalyst, solvent (2 mL) were added in a sealed tube (20 mL) and the
reaction mixture was irradiated with a 18W-light bulb under Argon atmosphere
at room temperature. b) The yield was determined by HPLC using 2a as the
(
Table 1, entries 1-3) were tested subsequently and
18]
[
Ir{dF(CF
3
)ppy}
2
(dtb-bpy)]PF [
6
promoted
the
desired
R
external standard (t = 4.9 min, λmax = 265.4 nm, water / acetonitrile = 40 : 60
(v / v)). c) The yields were based on the conversion of the starting material 1a.
transformation a little more effectively to provide the Z-isomer 2a
in 11% yield. Next, we turned to explore the influence of different
light wavelengths, and the 365 nm UV irradiation was found to
be the most suitable one for this isomerization formating 2a in
d)
the reaction mixture was irradiated with a 80W blue light and the solvent was
e)
The reaction temperature was 70 oC.
f)
1,4-dioxane.
The reaction
temperature was -10 C. Operated under air atmosphere. h) In dark.
o
g)
2
7% isolated yield (99% yield based on recovered starting
material, Table 1, entry 4). To our delight, switching the solvent
from 1,4-dioxane to CH CN resulted in a significantly improved
3
examination of substrate scope and functional group
compatibility.
yield (57% isolated yield, 99% yield based on recovered starting
material, Table 1, entry 5). It is worth noting that when the
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European Journal of Organic Chemistry
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COMMUNICATION
Table 2 Substrate scope examination of 2-(Z) -arylethenesulfonyl fluorides
Interestingly, when the phenol was transformed to the
corresponding fluorosulfate derivate 1t, the desired Z-
configuration product 2t was successfully generated in 55%
yield. It is interesting to observe that the transforming of (E)-2-
formation
arylethenesulfonyl fluorides 1x bearing
a strong electron-
withdrawing group (CN), at the ortho-position of the aromatic
ring, to the corresponding Z-counterparty 2x was not
accomplished using this method. In addition, the (E)-2-
arylethenesulfonyl fluorides, 1y and 1z, bearing multi-substituted
aromatic rings, were also smoothly converted into their
corresponding products 2y and 2z in 58% and 61% yields,
respectively.
Excitingly,
the
construction
of
(Z)-2-
arylethenesulfonyl fluorides containing heterocyclic aromatic
rings such as thiophene (2aa), especially pyridines (2ab and
2ac) were achieved in moderate to good yields from their E-
counterparties (1aa, 1ab, 1ac), which indicated the potential
authentic value of this method for the synthesis of bioactive
heterocycles-containing molecules.
a)
Reaction conditions: (E)-2-arylethenesulfonyl fluoride (1,
)ppy} (dtb-bpy)]PF (1.0 mol%, 0.01 mmol), acetonitrile (5 mL, 0.2 M)
were added in a reaction tube (30 mL) and the mixture was irradiated with
8W-ultraviolet light bulb at room temperature for 36 h. b)The yields in
1 mmol),
[
Ir{dF(CF
3
2
6
1
parentheses were based on the recovery of the starting material 1.
With the optimized conditions in hand, we next explored the
substrate scope of the photocatalytic configuration reversal of
various substituted (E)-2-(hetero)arylethenesulfonyl fluorides 1
and the results were illustrated in Table 2. Substrates
functionalized with both electron-donating groups, such as
phenyl group (1b), methyl group (1c-1e), ethyl group (1f) and
methoxyl group (1g and 1h) and electron-withdrawing groups,
such as nitro group (1i), cyano group (1j), halogens (1k-1p) and
trifluoromethyl group (1q and 1r) at ortho-, meta- and para-
positions of the aromatic rings tolerated smoothly under the
standard reaction conditions and the corresponding products 2a-
Scheme 2 Transformations of (Z)-2-arylethenesulfonyl fluorides
Compared with their E-configuration counterparts, the (Z)-
(
hetero) arylethenesulfonyl fluorides typically have much lower
melting points, many of which even exist as oil at room
temperature. The reactivity of these novel (Z)-
hetero)arylethenesulfonyl fluorides were explored as illustrated
(
in Scheme 2. The DBU-catalyzed annulation of (Z)-2-
phenylethenesulfonyl fluoride 2a with enolizable pyrazolone 3
provided the corresponding δ-sultone-fused pyrazolone 4 in
quantitative yield, which was very similar to what the (E)-2-
phenylethenesulfonyl fluoride behaved[9b] (Scheme 2a). In
addition, the annulative reaction (Z)-2-phenylethenesulfonyl
fluoride 2a with 2-acetyl pyridine 5 afforded 6 in 69% yield
2ac were obtained in moderate to good isolated yields (28% to
67%). It was worth noting that the products were obtained in
excellent to quantitative yields (89% to 99%) based on the
recovery of the starting materials (the E-olefins).
The substrates containing ortho-substituted methyl or
chlorine (1e and 1n) were compatible under this condition,
providing their corresponding Z-configration products 2e and 2n
in 67% yield and 56% yield respectively. It was worth noting that
when a hydroxyl group was present on aromatic rings of (E)-2-
arylethenesulfonyl fluorides (1u-1w), the desired products (2u-
(
Scheme 2b) while the reaction of (E)-configuration of
phenylethenesulfonyl fluoride 1a with 5 afforded 6 in 90%
yield.[
9c]
Surprisingly, silyl ether
7
reacted with (Z)-2-
phenylethenesulfonyl fluoride 2a provided (E)-phenyl 2-
phenylethenesulfonate in quantitative yield while no
corresponding (Z)-configuration product was observed
8
9
2w) were not obtained under the standard conditions.
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European Journal of Organic Chemistry
10.1002/ejoc.201900799
COMMUNICATION
(
Scheme 2c). In addition, the reaction of (Z)-2- Experimental Section
phenylethenesulfonyl fluoride 2a with methylhydrazine 10 did not
form the desired cyclic sulfonohydrazide 11 as what the (E)-2-
phenylethenesulfonyl fluoride did [9a] (Scheme 2d). The para-
nitro substituted (Z)-2- phenylethenesulfonyl fluoride reacted
with methylamine in the presence of DBU did not generate β-
sultam 13 as what the E-configuration did [9d] (Scheme 2e).
1. General procedure.
An oven-dried reaction tube (30 mL) was charged with (hetero)
arylethenesulfonyl fluoride (1, 1.0 mmol), [Ir{dF(CF )ppy} (dtb-bpy)]PF
6
3
2
(1.0 mol%, 0.01 mmol，9.1 mg), acetonitrile (10 mL). The resulting
mixture was irradiated under ultraviolet light bulb (18W, λmax = 365 nm)
and stirred at room temperature under air atmosphere for 36-48 h. The
crude mixture was purified through column chromatography on silica gel
to give the desired product 2 and recycle the starting material 1.
Scheme 3 Converting (Z)- arylethanesulfonyl fluorides to (E)-
(hetero)arylethanesulfonyl fluorides
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150), the Wuhan Applied Fundamental
Research Program of Wuhan Science and Technology Bureau
(Grant NO. 2017060201010216), the 111 Project (Grant No.
B18038) and Wuhan University of Technology for their financial
support.
Remarkably, the Z-configuration of arylethenesulfonyl fluoride 2
could also be successfully converted back to the E-isomer 1
either through the promotion of base catalyst (1 mol% DBU) at
room temperature within 30 minutes or after being heated up at
o
6
0 C for 6 hours in CH
3
CN (Scheme 3), both of these two
methods provided the corresponding E-isomer 1 in nearly
quantitative yield (see Supporting Information for details).
Keywords: (Z)-(hetero)arylethenesulfonyl fluorides • Sulfur (VI)
fluoride exchange (SuFEx) • click chemistry
[
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In conclusion, we have developed a method providing a
portal to a class of novel (Z)-(hetero)arylethenesulfonyl fluorides
through utilizing photoredox catalysis strategy. The reactivities of
this category of molecules were examined comparing with their
E-configuration counterparts. Further studies on applications of
these molecules in chemical biology and medicinal chemistry
are undergoing in our laboratory.
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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.201900799
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
The construction of (Z)-(hetero)aryl
ethenesulfonyl fluorides was achieved
utilizing Iridium photoredox catalysis
under UV-light irradiation. This
protocol provided a diverse range of
Key Topic*
Yu-Mei Huang, Shi-Meng Wang, Jing
Leng, Balakrishna Moku, Chuang Zhao,
Njud S. Alharbi and Hua-Li Qin*
(
Z)-(hetero)
arylethenesulfonyl
Page No. – Page No.
fluorides in moderate to good yields
under mild conditions without external
additives.
transformation
(
Converting (E)-(Hetero)aryl
ethanesulfonyl Fluorides to (Z)-
(Hetero)arylethanesulfonyl Fluorides
under Light Irradiation
The
of
late-stage
the
(Z)-
hetero)arylethenesulfonyl
fluorides
comparing with their E-configuration
counterparts was also studied.
(Z)-(Hetero)arylethanesulfonyl Fluorides
This article is protected by copyright. All rights reserved.