Visible-Light-Induced Direct Thiolation at α-C(sp3)-H of Ethers with Disulfides Using Acridine Red as Photocatalyst

Article abstract of DOI:10.1021/acs.orglett.6b00304

A simple and efficient method for the preparation of α-arylthioethers through a visible-light-induced direct thiolation at α-C(sp³)-H of ethers with diaryl disulfides was developed using acridine red as a novel photocatalyst. The reactions occurred at ambient conditions and generated the corresponding products in good to excellent yields, ignoring steric effect of disulfides.

Full text of DOI:10.1021/acs.orglett.6b00304

Letter
pubs.acs.org/OrgLett
Visible-Light-Induced Direct Thiolation at α‑C(sp3)−H of Ethers with
Disulfides Using Acridine Red as Photocatalyst
Xianjin Zhu,† Xiaoyu Xie, Pinhua Li,*,† Jianqi Guo,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P.R. China
S
* Supporting Information
ABSTRACT: A simple and efficient method for the preparation of α-arylthioethers through a visible-light-induced direct
thiolation at α-C(sp3)−H of ethers with diaryl disulfides was developed using acridine red as a novel photocatalyst. The reactions
occurred at ambient conditions and generated the corresponding products in good to excellent yields, ignoring steric effect of
disulfides.
he development of mild and efficient methods for the
formation of C−S bonds has received significant attention
inexpensive, and renewable energy source.13 Since the
disclosure of visible-light-induced organic reactions by
MacMillan,14 extensive efforts have been made, and it has
emerged as one of the most active research topics in organic
synthesis. After that, a number of efficient and versatile
protocols have been explored.15 More recently, Wang and co-
workers realized a relatively long-lived α-oxy radical species via
external oxidation of α-C(sp3)−H of ethers by visible light
stimulation and organic dye sensitization, subsequent radical
addition to alkyne.16 On the basis of our exploration in
photocatalysis and inspired by reported results,17 herein we
report a simple and efficient protocol to access α-arylthioethers
via visible-light-induced direct thiolation at α-C(sp3)−H of
ethers with diaryl disulfides in the presence of acridine red. To
the best of our knowledge, it is the first example of coupling
reaction through energy transfer pathway using acridine red as
photocatalyst under visible light irradiation and ambient
conditions.
Initially, diphenyl disulfide (1a) and THF (2a) were chosen
as substrates for the optimization of reaction conditions. It was
found that the reaction afforded the corresponding product 3a
in 18% yield in the presence of Ru(bpy)3Cl2 as photocatalyst,
and TBHP as oxidant under 3 W blue LED (530−535 nm)
irradiation for 12 h, but Ru(phen)3Cl2 failed (Table 1, entries 1
and 2). Organic dyes including eosin Y, rose bengal, fluorescein,
rhodamine B, and acridine red were employed in the reaction,
as shown in Table 1. Most of the selected organic dyes showed
catalytic reactivity, while rose bengal did not (entries 3−7).
Among the tested organic dyes, acridine red exhibited the
highest activity. Comparing with eosin Y, rose bengal,
fluorescein, and rhodamine B, the advantages of acridine red
T
because these bonds are widely found in many important
biological and pharmaceutical compounds.1 The classical
constructions of C−S bonds include direct coupling of organic
halides with thiols, and addition of thiols to unsaturated
carbon−carbon bonds.2 Recently, the direct C−H functional-
ization3 and decarboxylative C−S coupling reactions4 for their
construction have been developed. However, the synthesis of
C−S bonds through C(sp3)−H functionalization has been less
explored. It is well-known that transformation of the inert
C(sp3)−H bond into more useful molecules has attracted much
attention in the past years. Notably, great progress has been
achieved in the functionalization of α-C(sp3)−H bonds of
ethers, alcohols,5 and amines.6 In general, tetrahydrofuran
(THF) and its derivatives are usually accessible through their α-
C(sp3)−H functionalization, such as Fe-catalyzed CDC
reaction of THF with malonates,7 Ni-catalyzed arylation of
THF,8 TBHP-promoted reaction of phenylacetylene with
THF,9 and others.10 It was worth noting that the thiolation
of α-C(sp3)−H bond of ethers and amines has also been
achieved. Xiang and co-workers reported a TBHP-mediated
oxidative thiolation of α-C(sp3)−H bond of amide with
disulfides in 2011,11 and an oxidative α-C(sp3)−H thiolation
of ethers with disulfides under metal free conditions in 2013.12
However, harsh reaction conditions, overstoichiometric
amounts of oxidants, and high reaction temperature are
required in the most cases. It is desirable to develop more
practical methods for the synthesis of α-arylthioethers from
simple and readily available precursors under mild reaction
conditions.
Sunlight is a unique natural resource. Early in 1912, a
pioneering chemist Ciamician published a perspective of
converting solar energy into chemical energy for chemical
transformations by using sunlight as a safe, abundant,
Received: January 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00304
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Organic Letters
Letter
a
a,b
Table 1. Optimization of the Reaction Conditions
Scheme 1. Reactivity Screening on Disulfides
a
Reaction conditions: 1 (0.25 mmol), THF (2a, 2.0 mL), acridine red
a
Reaction conditions: 1a (0.25 mmol), THF (2a, 2.0 mL),
(2.0 mol %), 4 Å MS (80 mg), TBHP (70% solution in water, 1.0
mmol), rt, 3 W green LED (530−535 nm) for 12 h. Isolated yield.
b
photocatalyst (2.0 mol %), oxidant (1.0 mmol), rt, 3 W LED for 12
b
c
h. Isolated yield. n.r. = no reaction. Addition of 4 Å MS (80 mg).
d
e
TBHP (0.2 mL, 5.5 mol/L in decane). THF/CH3CN (1:1, 2.0 mL).
f
g
h
THF/acetone (1:1, 2.0 mL). THF/DMSO (1:1, 2.0 mL). THF/
disulfides attached an electron-poor group including F, Cl, Br,
CF3, and CN on the para-positions of benzene rings afforded
the corresponding products (3f−j) in excellent yields (83−
92%). In addition, diaryl disulfides with an electron-donating or
electron-withdrawing group on the meta-positions of benzene
rings gave high yields (82−95%) of the desired products (3k−
p). It should be noted that no ortho-position effect was
observed when (2-substituted diphenyl)-disulfides reacted with
THF, leading the products (3q−t) in 83−91% yields.
Di(disubstituted)phenyl disulfides, such as di(3,5-dimethyl-
phenyl)disulfide, di(3,5-dichlorophenyl)disulfide, di(3,4-
dichlorophenyl)disulfide, di(3-trifluoromethyl-4-chlorophenyl)-
disulfide, di(2,4-dichlorophenyl)disulfide, di(2,6-difluoro-
phenyl)disulfide, and di(2,6-dichlorophenyl)disulfide were
found to be applicable for this transformation (75−95% yields
of 3u−aa). It is important to note that diaryl disulfide with two
ortho-substitutes on the benzene ring underwent the reaction
smoothly to generate the anticipated products 3z and 3aa in
81% and 94% yields, respectively, ignoring steric effect. In
addition, the reactions of dinaphthyl disulfides with THF also
gave the desired products 3ab and 3ac in good yields. However,
dialkyl disulfides, such as dibenzyl disulfide, di(n-butyl)disulfide
failed under the present reaction conditions. The structure of
product 3e was further confirmed by X-ray single crystal
analysis (Supporting Information).
i
j
PhMe (1:1, 2.0 mL). THF/PhCl (1:1, 2.0 mL). Acridine red (1.0 mol
%). Acridine red (3.0 mol %). 10 h. 15 h.
k
l
m
as photocatalyst are highlighted in simple structure, novelty,
and high efficiency. In the absence of photocatalyst or visible-
light irradiation, no product was detected and the starting
material was recovered (entries 8 and 9). To our delight, a
significant improved yield (82%) of 3a was obtained when 4 Å
molecular sieve was added (entry 10). In addition, a variety of
oxidants were subjected to the reaction; TBHP (70% solution
in water) was the best one among the tested oxidants (entries
11−15). The effect of solvent was also examined, and THF
(also as substrate) was the best of choice (entries 16−20). The
loading of photocatalyst and the reaction time were also
optimized, which are presented in Table 1, entries 21 and 22.
Under the optimized reaction conditions, the generality of
this direct thiolation of THF was investigated, as shown in
Scheme 1. A variety of diaryl disulfides were subjected to the
reaction, and the corresponding products were obtained in high
yields with excellent functional group tolerance. Diaryl
t
disulfides with an electron-rich group such as MeO, Bu, Me,
and Ph on the para-positions of benzene rings reacted with
THF to generate the corresponding products (3b−e) in 73−
81% yields. Meanwhile, the reactions of THF with diaryl
B
DOI: 10.1021/acs.orglett.6b00304
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Organic Letters
Letter
On the other hand, the common used symmetrical ethers
except THF were also examined in this transformation. As
shown in Scheme 2, the direct thiolation at α-C(sp3)−H of 1,4-
total 80% yield), 3ao/3ao′ (58/31, 89% of total yield). This
protocol was further applied to 2-methyltetrahydrofuran with
diphenyl disulfide; the corresponding isomers 3ap and 3ap′
were isolated in 60% and 26% yields (total yield = 86%).
To elucidate the possible reaction mechanism, a series of
experiments were performed, as summarized in Scheme 4.
a,b
Scheme 2. Reactivity Screening on Ethers
Scheme 4. Control Experiment and KIE Determination
a
Reaction conditions: 1 (0.25 mmol), 2 (1.0 mL), acetone (1.0 mL),
acridine red (2.0 mol %), 4 Å MS (80 mg), TBHP (70% solution in
water, 1.0 mmol), rt, 3 W green LED (530−535 nm) for 12 h.
When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a radical
scavenger, was added into the reaction of THF with diphenyl
disulfide under the standard conditions, the reaction was
inhibited completely. It is suggested that a radical pathway
might be involved in this transformation. Moreover, a radical
intermediate (I) formed in situ was captured by TEMPO and
detected by high-resolution mass spectrum (HRMS) analysis.
To further illustrate C−H bond cleavage of THF might be a
rate-determining step, the kinetic isotope effect (KIE) was
implemented, and a significant KIE (KH/KD) was found to be
4:1 (Scheme 4). Finally, an energy transfer process between
acridine red and TBHP was confirmed by fluorescence
quenching experiments (Support Information (SI) for detail).
On the basis of the above observation and previous literature,
a proposed mechanism is shown in Scheme 5. At first, acridine
b
Isolated yield.
dioxane and diethyl ether with diphenyl disulfide, di(4-
chlorophenyl)disulfide, di(4-methylphenyl)disulfide, and di(4-
phenylphenyl)disulfide proceeded to afford the desired
products (3ad−al) in moderate to good yields (55−81%).
The results indicated that the reactivity of ethers is THF >
diethyl ether >1,4-dioxane > tetrahydropyran.
Subsequently, the synthetic application of this methodology
was further extended to unsymmetrical ethers, including 1,2-
dimethoxyethane (2e) and 2-methyltetrahydrofuran (2f). As
shown in Scheme 3, when 1,2-dimethoxyethane reacted with
diphenyl disulfide, a couple of regioisomers 3am and 3am′ were
obtained in 54% and 32% isolated yields by column
chromatography, showing a regioselectivity of 27/16. The
reactions of other di(substituted phenyl)disulfides, such as di(p-
tolyl)disulfide and di(p-chlorophenyl)disulfide with 1,2-dime-
thoxyethane proceeded smoothly to give 3an/3an′ (51/29,
Scheme 5. Plausible Mechanism
a,b
Scheme 3. Regioselectivity of Unsymmetrical Ethers
red (AR) changed to its excited state (AR)* under green LED
t
irradiation. Then, the formed (AR)* interacted with BuOOH
(TBHP) via an energy transfer to generate two crucial radical
species, a hydroxyl radical (HO•) and a tert-butoxy radical
(tBuO•) simultaneously, along with the formation of the
t
ground state AR from (AR)*. Subsequently, HO• or BuO•
abstracted hydrogen from α-C(sp3)−H of THF (1a), giving a
key alkoxyalkyl radical intermediate (I). The obtained I reacted
with PhSSPh (1a) to afford the desired product 2-(phenylthio)-
tetrahydrofuran (3a) and a new radical PhS•. On the other
hand, the PhS• would be trapped by another alkoxyalkyl radical.
Moreover, a tetrahydrofuran-2-ol (II) was confirmed by HRMS
a
Reaction conditions: 1 (0.25 mmol), 4 (1.0 mL), acetone (1.0 mL),
acridine red (2.0 mol %), 4 Å MS (80 mg), TBHP (70% solution in
water, 1.0 mmol), rt, 3 W green LED (530−535 nm) for 12 h.
b
Isolated yield.
C
DOI: 10.1021/acs.orglett.6b00304
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Organic Letters
Letter
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In summary, we have developed a simple and efficient
method for the preparation of α-arylthioethers through a
visible-light-induced direct thiolation at α-C(sp3)−H of ethers
with diaryl disulfides using acridine red as photocatalyst at
ambient conditions. A number of disulfides reacted with various
ethers to generate the corresponding 2-(arylthio)ethers in good
to excellent yields, ignoring steric effect of disulfides. The
reactions exhibited advantages including ambient conditions
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00304.
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Full experimental details and characterization data for all
products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: pphuali@126.com
*E-mail: leiwang88@hotmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 21572078 and 21372095).
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