Visible-light-promotedE-selective synthesis of α-fluoro-β-arylalkenyl sulfidesviathe deoxygenation/isomerization process

Article abstract of DOI:10.1039/d0cc08254f

Regioselective synthesis of α-fluoro-β-arylalkenyl sulfides has been established withgem-difluoroalkenes and sodium sulfinates in a transition-metal-free manner. A series of control experiments were executed to demonstrate thiol radicals and anions as the proposed intermediates. Notably, regioselectiveZ→Eisomerization was achieved under green light irradiation in the absence of a photoinitiator.

Full text of DOI:10.1039/d0cc08254f

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Visible-light-promoted E-selective synthesis
of a-fluoro-b-arylalkenyl sulfides via the
deoxygenation/isomerization process†
Cite this: Chem. Commun., 2021,
57, 2152
Received 20th December 2020,
Accepted 18th January 2021
a
Yuxiu Li,
Xiangqian Li,a Xiaowei Lia and Dayong Shi*ab
DOI: 10.1039/d0cc08254f
rsc.li/chemcomm
Regioselective synthesis of a-fluoro-b-arylalkenyl sulfides has been
Over the past decade, not only has visible-light-induced
established with gem-difluoroalkenes and sodium sulfinates in a photocatalysis been demonstrated as one of the most powerful
transition-metal-free manner. A series of control experiments were and straightforward tools for new chemical bond formation7
executed to demonstrate thiol radicals and anions as the proposed due to its appealing features such as environmental friendli-
intermediates. Notably, regioselective Z - E isomerization was ness, mild reaction conditions, and excellent functional group
achieved under green light irradiation in the absence of
photoinitiator.
a
compatibility, but it also offers a valid route to perform geome-
trical isomerization of alkenyl derivatives (Scheme 2A).8 In
2020, the group of Rossi–Ashton reported a visible-light-
Vinylsulfides are widely present in natural products, bioactive induced photocatalytic deoxygenation reaction of sulfoxides
compounds and functional materials, and also serve as important to produce a wide array of functionalized sulfides reduced by
building blocks for the synthetic community.1 Due to the influence PPh3 (Scheme 2B).9 Moreover, sodium sulfinates are odorless,
on the lipophilicity, metabolic stability, and biopotency by fluorine stable and commercially available sulfur compounds that have
substitution, the incorporation of fluorine and fluorine-containing been widely implemented as sulfuration agents.10 However, to
functional groups into organic molecules has beneficial advantages the best of our knowledge, a phosphine-associated photoredox
in drug design.2 In particular, monofluoroalkenes can serve as approach for the deoxygenative functionalization11 of sodium
peptide bond isosteres and skeleton of drug molecules, which have sulfinates is still unknown. Herein, we report a method to
attracted substantial attention from medicinal chemists.3 Given the synthesize highly E-selective a-fluoro-b-arylalkenyl sulfides
significantly potential medicinal value of a-fluoro-b-arylalkenyl from gem-difluoroalkenes and sodium sulfinates via visible-
sulfides, considerable efforts have been put into developing varied light-induced deoxygenation of S–O bonds and isomerization of
strategies to generate the functionalized molecules (Scheme 1).4 alkenes (Scheme 2C).
However, the exploration of efficient methodologies to produce
The initial investigations commenced with 2-(2,2-difluo-
highly stereoselective a-fluoro-b-arylalkenyl sulfides utilizing sim- rovinyl)naphthalene 1a and sodium benzenesulfinate 2a as
ple, bench-stable and odorless precursors under mild conditions is model substrates (see more details in the ESI†). Gratefully,
still eagerly anticipated and challenging.
the desired product 3aa was isolated in 94% yield with good
Recently, gem-difluoroalkenes have been employed as a
synthon to fabricate mono-fluoroalkenes.5 On account of the
strong electron-withdrawing capability of fluorine atoms and
the repulsion effect from its lone-pair electrons, the difluoro-
methylene carbon of gem-difluoroalkenes is attacked by nucleo-
philes to construct heterogeneous C–C and C–X bonds.5d,6
a State Key Laboratory of Microbial Technology, and Marine Biotechnology Research
Center, Shandong University, 72 Binhai Road, Qingdao 266237,
Shandong, P. R. China. E-mail: shidayong@sdu.edu.cn
b Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for
Marine Science and Technology, 168 Wenhai Road, Qingdao 266237,
Shandong, P. R. China
Scheme 1 Previous strategies for the synthesis of a-fluoro-b-arylalkenyl
sulfides.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0cc08254f
2152 | Chem. Commun., 2021, 57, 2152À2155
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ratios. In particular, the sodium arylsulfinates bearing reactive
functional groups, such as OMe (2c), ester group (2f) and halide
groups (2g–j), were adapted to this reaction system. And meta-
and ortho-substituted sodium arylsulfinates (2k–n) show simi-
lar reactivities, but a slightly dropped E/Z ratio. Moreover,
reaction of both 2- and 1-naphthylsulfinate salts could proceed
smoothly providing 3ao and 3ap in 86% and 73% yields with
89 : 11 and 76 : 24 E/Z selectivities, respectively. Notably, 2,4,6-
tri-substituted sodium arylsulfinate was facile to deliver the
desired product 3aq in 66% yield with poor E/Z selectivity, due
to the bulky groups. Heteroaromatic sulfinate salt, sodium
thiophene-2-sulfinate, also successfully produced the desired
products (3ar) in 58% yield with substandard E/Z selectivity.
Subsequently, the scope of the reaction with respect to gem-
difluoroalkenes was examined. As summarized in Table 2, we
found that this mild protocol was applicable to most substrates,
Scheme 2 Photocatalytic geometrical isomerization of alkenes, deoxy- including both mono-substituted and multi-substituted gem-
genative reaction and our work.
difluorostyrenes in moderate to good yields with a good E/Z
ratio (3bh–ih). The gem-difluorostyrenes attached with either
stereoselectivity (E/Z = 92.5 : 7.5) with 2.2 equiv. PPh3 as a
reductant and 5 mol% Na2(Eosin Y) as a photosensitizer with
exposure to a 6 W green LED at ambient temperature under a
Table 2 Substrate scope of gem-difluorostyrene with sodium arylsulfi-
nate 2h
N2 atmosphere in DMSO for 36 h.
With the optimal conditions in hand, an array of sodium
sulfinates was explored (Table 1). Either electron-rich or
electron-deficient substitution at the para-position of the
sodium arylsulfinates could be well tolerated in this process
to afford the desired products (3aa-aj) in good yields and E/Z
Table
1
Substrate scope of sodium arylsulfinates with gem-
difluoroalkene 1a
Reaction conditions: all reactions were performed with 1a (0.10 mmol),
2 (2 equiv.), Na2(Eosin Y) (5 mol%), PPh3 (2.2 equiv.) and DMSO
(0.5 mL) with 6 W green LED irradiation for 36 h under N2 at rt unless
otherwise noted. The E/Z ratio was determined by 19F NMR.
(a) 2.2 equiv. P(4-OMePh)3. (b) The E/Z ratio was determined by isolated
yield.
Reaction conditions: all reactions were performed with 1 (0.10 mmol),
2h (2 equiv.), Na2(Eosin Y) (5 mol%), PPh3 (2.2 equiv.) and DMSO
(0.5 mL) with 6 W green LED irradiation for 36 h under N2 at rt unless
otherwise noted. The E/Z ratio was determined by 19F NMR.
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electron-donating or electron-withdrawing groups on benzene conditions, ring-opened products 4 were obtained in 15% yield
could react with 2h to generate the expected products with good and product 3vh was also detected by GC-MS (Scheme 3,
yields and E/Z selectivities (3bh–ch). What’s more, halogen eqn (3)). As is well known, vinylcyclopropanes conduct ring-
groups were also well-tolerated (3dh, 3ih). Remarkably, the steric opening in the presence of a carbon-centered radical.12 Thus,
hindrance decreased the reactivity and selectivity (3hh-ih). It was these findings confirmed that the thiol anion and thiol radical
noteworthy that a range of polycyclic aromatic gem-difluo- originating from sodium sulfinate were produced under stan-
roalkenes could be efficiently converted to the desired products dard conditions (see the ESI† for more details, eqn (S1)–(S13)).
in good yields with moderate to good stereoselectivities
During the procedure of this transformation, the regioselec-
(3jh–mh). Interestingly, heteroaromatic difluoroalkenes contain- tive Z - E isomerization of a-fluoro-b-arylalkenyl sulfide was
ing N, O or S that were of significant utility to medicinal investigated simultaneously (see Table S5 in the ESI†). Thus,
chemists were also extended as suitable candidates, giving the control experiments were conducted to validate the role of
corresponding adducts (3nh–qh) in 42–85% yields and Na2(Eosin Y), resulting in the fact that the photosensitizer
87.5: 12.5–94: 6 E/Z selectivities. It was noted that when difluo- didn’t seem to actually engage in the Z - E isomerization
roalkene bearing two different substituents 1r was used, a target (Scheme 3, eqn (4) and (5)). Therefore we expected that a-fluoro-
product 3rh was isolated in 74% yield without stereoselectivity. b-arylalkenyl sulfide itself might act as a photosensitizer for
And (2,2-difluoroethene-1,1-diyl)dibenzene 1s was also a compe- this photochemical isomerization (Scheme 3, eqn (5)).
tent substrate to produce product 3sh in 76% yield. Finally, we
On the basis of the above results and previous studies on the
applied the protocol in the late-stage modification of complex reduction of sodium sulfinates10c–e,13 and regioselective isomeriza-
natural products and drugs. A small molecule drug, mexiletine tion of alkenes,8,14 a conceivable mechanism is presented in
derivative, and natural product, fructose derivative, were reacted Scheme 4. First, the ground state of [Na2(Eosin Y)] was irradiated
with 2h to get desired products 3th and 3uh with 62% and 50% to generate excited [Na2(Eosin Y)]*, which could undergo SET with
ox
yields, respectively.
sodium benzenesulfinate 2a [E = À0.34 V versus SCE]15 to afford
1/2
To shed light on the mechanism of this protocol, we an oxygen-centered sulfinic radical A and [Na2(Eosin Y)]À. Then
designed a series of experiments. First, radical inhibition intermediate A reacted with PPh3 [E = + 0.98 V versus SCE]9 to
ox
/2
experiments were carried out with different radical inhibitors, deliver a phosphoranyl radical B, following through b-scission
such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 1,4- giving rise to sulfoxide radical C and phosphine oxide. Repeating
dinitrobenzene (Scheme 3, eqn (1)), and the reactions were the operation, the radical intermediate C would release thiyl radical
suppressed, indicating that the transformation might rely on D [Er1e/2d = +0.16 V versus SCE],16 and by a single electron reduction
red
an SET-involved radical pathway. In order to acquire more with reduced [Na2(Eosin Y)]À [E = À1.06 V versus SCE],7c,17 thiyl
1/2
evidence of the reaction intermediates, control experiments anion E was produced and the ground state [Na2(Eosin Y)] was also
were also conducted (see the ESI† for more details). When regenerated to close the photocatalytic cycle (Scheme 4, path a).
sodium benzenethiolate PhSNa (1.2 equiv.) was used in the
system, a good yield of 3aa was achieved (Scheme 3, eqn (2)),
suggesting that the thiol anion was probably the key intermedi-
ate. Additionally, to verify the conjecture that thiol radicals
could be produced in the reaction system, when (1-cyclopropyl-
2,2-difluorovinyl)benzene (1v) was subjected to the standard
Scheme 3 Control experiments.
Scheme 4 A proposal mechanism.
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addition/b-F elimination reaction with gem-difluoroalkene 1a to
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(see eqn (S14) in the ESI†) due to the electronic repulsion between
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(Scheme 2A).8b,14a In this reaction system, path b (Scheme 4) might
also be valid.4f The thiyl radical D was added to 1a, providing the
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photocatalyst. The following transformation was the same as path
a. As an alternative, radical C might disproportionate into radical
A and radical D. While the free energy barrier of disproportionation
was much higher than that of the PPh3-associated procedure, the
disproportionation was unfavorable.10e
In summary, we have disclosed a method to acquire various
a-fluoro-b-arylalkenyl sulfides in good yields and stereoselectiv-
ities. The reactions perform well under mild conditions and are
tolerant of wide varieties of functional groups. Control experi-
ments illustrate that the deoxygenation of S–O bonds refers to
the SET approach by photocatalysis. Importantly, the rare
visible-light-promoted regioselective Z - E isomerization of
a-fluoro-b-arylalkenyl sulfides does not require any photosen-
sitizers. Further mechanistic studies and the application to
pharmaceuticals are underway in our laboratory.
This work was funded by the National Program for Support
of Top-notch Young Professionals, Fund of Taishan scholar
project, Shandong Provincial Natural Science Foundation for
Distinguished Young Scholars (JQ201722), the Qingdao Science
and Technology Benefit People Demonstration Guide Special
Project (20-3-4-20-nsh), and the Fundamental Research Funds
of Shandong University. The Postdoctoral Science Foundation
of China (2019M662377) is also acknowledged. Haiyan Sui and
Xiaoju Li from Shangdong University Core Facilities for Life
and Environmental Sciences are thanked for their help with
the NMR.
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