Radical-Radical Cross-Coupling for C-S Bond Formation

Article abstract of DOI:10.1021/acs.orglett.6b00764

A new method was demonstrated to overcome the selectivity issue of radical-radical cross-coupling toward the synthesis of asymmetric diaryl thioethers. The preliminary mechanism was revealed by radical-trapping experiments, DFT calculations, and kinetics,

Full text of DOI:10.1021/acs.orglett.6b00764

Letter
pubs.acs.org/OrgLett
Radical−Radical Cross-Coupling for C−S Bond Formation
Zhiliang Huang,† Dongchao Zhang,† Xiaotian Qi,‡ Zhiyuan Yan,† Mengfan Wang,† Haiming Yan,|
and Aiwen Lei*,†,|
†College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, People’s
Republic of China
‡School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, People’ s Republic of China
|National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, People’ s Republic of China
S
* Supporting Information
ABSTRACT: A new method was demonstrated to overcome the selectivity issue of radical−radical cross-coupling toward the
synthesis of asymmetric diaryl thioethers. The preliminary mechanism was revealed by radical-trapping experiments, DFT
calculations, and kinetics, etc., indicating that the C−S bond formed through cross-coupling of a thiyl radical and an aryl radical
cation. Moreover, the formation of an aryl radical cation instead of the C−H bond cleavage was determined as the rate-limiting
step.
coupling reactions.3b,7 Nevertheless, these examples only
adicals have attracted a lot of attention due to their high
1
Rreactivity and strong tendency to form chemical bonds.
focused on the carbon- or nitrogen-centered radicals. Thus, it
is still highly important to develop new strategies for stabilizing
other reactive radicals, such as thiyl radicals, and make them
suitable for the radical−radical cross-coupling reaction.
In the last few decades, numerous effective processes, such as
radical addition, substitution, and cyclization, were successfully
demonstrated for the construction of C−X (X = C, N, O etc.)
bonds when radicals were utilized as the key intermediates.2
However, the radical−radical cross-coupling reaction, which
also emerged as a powerful tool for new chemical bonds, still
remains in its infancy when compared with those highly
developed reactions.3
Generally, the activation energy of the radical−radical
coupling reaction is nearly zero.4 Therefore, when two types
of reactive radicals are employed to couple with each other,
three pathways afford two homocoupling products and one
cross-coupling product; i.e., the poor selectivity is the main
issue for the radical−radical cross-coupling reaction.3c,5 Usually,
in order to control the selective bond formation, a persistent
radical and a transient radical should be engaged according to
the persistent radical effect.6 In this regard, if one of the reactive
radicals could be stabilized to a persistent one, selective cross-
coupling of two reactive radicals could succeed.3b Recently,
there have been some clues in the literature reporting the
stabilization of reactive radicals by using transition metals (Cu,
Ni, etc.) or molecular I2 in oxidative radical−radical cross-
It is well-known that the addition of thiyl radical to alkene is
fast and reversible.8 Therefore, we envisioned that it is possible
to transfer the reactive thiyl radical to a persistent one by
stabilizing it through radical addition to a unique alkene. Then,
once a transient carbon-centered radical is added, a selective
radical−radical cross-coupling reaction could be achieved.6a
DDQ is an excellent single-electron oxidant that could oxidize
thiol and electron-rich arene, etc., to the corresponding
radicals.9 Moreover, the unique quinone structure of DDQ
shows great potential in stabilizing the reactive thiyl radical.10
Regarding this information, a new DDQ-controlled selective
radical−radical cross-coupling between arene and thiol toward
C−S bond formation is proposed in this work (Scheme 1).
1,3,5-Trimethoxybenzene (1a) and 4-chlorobenzenethiol
(2a) were initially employed as the substrates to test the
proposal above. As expected, when DDQ was utilized, the
Received: March 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00764
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Mechanism for Selective Radical−Radical Cross-
Coupling between Arene and Thiol
Scheme 2. Oxidative C−H/S−H Cross-Coupling
cross-coupling product 3aa could be obtained in 84% yield (eq
1). To further identify the role of DDQ, a set of experiments
Table 1. Optimization for Oxidative Cross-Coupling of 1a
and 2a
a
a
In a Schlenk tube, a toluene solution of 2 (0.6 mmol, 2 mL) was
added to the mixture of 1a (0.3 mmol), DDQ (0.6 mmol), and toluene
(1 mL) by constant-flow pump in 10 min. Then, the mixture was
allowed to stir at rt for 2 h under N2. The yields were obtained by
b
entry
oxidant
solvent
yield (%)
1
2
3
K2S2O8
TBHP
chloranil
DDQ
toluene
toluene
toluene
toluene
CH3CN
trace
trace
trace
98
b
isolating the pure products. 4-Nitrobenzenethiol (0.6 mmol) was
c
added at once. CH3CN was used to replace toluene as the solvent.
d
c
DDQ (1.5 mmol), 2a (1.5 mmol).
4
c
5
DDQ
86
a
on the phenyl ring of benzenethiol are well tolerated, which
enables a potential application in further functionalization (3aa,
3ad, 3ae, and 3af). A mercapto group on the heteroaromatic
ring is also an effective S−H source for this oxidative C−H/S−
H cross-coupling reaction. For example, pyridine-2-thiol,
benzo[d]oxazole-2-thiol, 1-methyl-1H-tetrazole-5-thiol, and 5-
methyl-1,3,4-thiadiazole-2-thiol react with 1a successfully to
give the corresponding products in good to excellent yields
(3ah, 3ai, 3aj, and 3ak). 1,3-Dimethoxybenzene was also tested
for this reaction, which afforded the product in 71% yield (3al).
No desired product 3aa could be obtained when bis(4-
chlorophenyl) disulfide 4 was employed to react with 1a,
showing that 4 is not an intermediate in this cross-coupling
reaction (eq 2).
All of the reactions were performed with 1a (0.3 mmol), 2a (0.6
mmol), oxidant (0.6 mmol), and toluene (3.0 mL) in Schlenk tubes at
room temperature for 2 h under N2. Yield determined by GC analysis
with biphenyl as the internal standard. A toluene solution of 2a (0.6
mmol, 2 mL) was added to the mixture of 1a (0.3 mmol), DDQ (0.6
mmol), and toluene (1 mL) by constant-flow pump in 10 min. Yield
was obtained by isolating the pure product.
b
c
were carried out. As shown in Table 1, when K2S2O8 or TBHP,
which is a well-known single-electron oxidant but does not
stabilize radicals,11 was used instead of DDQ, only a trace
amount of 3aa could be produced (entries 1 and 2).
Meanwhile, chloranil was unable to oxidize 1a12 and could
only afford trace amounts of 3aa (entry 3). With the addition of
2a to the reaction mixture by constant-flow pump in 10 min, a
98% yield of 3aa was obtained (entry 4), indicating that excess
DDQ over thiol is beneficial for the cross-coupling reaction.
The transformation could also proceed very well in acetonitrile
(entry 5). All of these results are consistent with the proposed
radical−radical cross-coupling reaction mechanism in which
DDQ not only acts as a single-electron oxidant to produce the
relevant radicals but also might stabilize the reactive thiyl
radical.
The scope of this oxidative C−H/S−H cross-coupling
reaction was examined in detail under the optimized conditions.
As shown in Scheme 2, various thiols could react with 1a
smoothly to produce the desired products in good to excellent
yields. Thiols with electron-donating groups (−Me, −OMe) or
electron-withdrawing groups (−NO2) are suitable for this
transformation, and 70%−92% yields were obtained (3ab, 3ac,
and 3ag). It is noteworthy that −F, −Cl, and −Br substituents
Mechanistic investigations were carried out initially by
conducting radical inhibition experiments. Only a trace amount
of product 3aa was observed when the reaction was carried out
in the presence of radical scavenger TEMPO (eq 3), suggesting
that radicals might be the key intermediates in the trans-
formation. Hence, radical-trapping experiments were further
B
DOI: 10.1021/acs.orglett.6b00764
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
explored. As shown in Scheme 3, the product 5 (or 6) was
detected in the reaction of 1, 1-diphenylethylene, and 1a (or
the C−S bond formation were evaluated. As shown in Scheme
6, path A involving a radical addition step is initially considered
Scheme 3. Radical-Trapping Experiments
Scheme 6. Possible Reaction Pathways for C−S Bond
Formation
2a). Moreover, when 1,1-diphenylethylene was introduced into
the coupling reaction of 1a and 2a as the radical trapping
reagent under the standard conditions, 3aa, 5, and 6 were
produced. These results indicated that both the 1,3,5-
trimethoxyphenyl radical (or 1,3,5-trimethoxyphenyl radical
cation) and the 4-chlorobenzenethiyl radical might be involved
in this coupling reaction.
As a follow-up study, density functional theory (DFT)
calculations were carried out to study the formation of these
radicals using the M06 method. As shown in Scheme 4,
in calculation. However, neither the transition state nor the
addition intermediate was located after many attempts, which
implies the thiyl radical addition to 1a is unfavorable. In path B,
the combination of radical 7 with radical 8 is exothermic by
23.5 kcal/mol, followed by deprotonation of 9, which is also
exothermic by 16.3 kcal/mol. Consequently, the radical−radical
cross-coupling mechanism is finally recommended for this C−S
bond formation reaction.13
A kinetic isotope effect (KIE) experiment was also performed
to further study this oxidative C−H/S−H cross-coupling
reaction. As shown in Scheme 7, the KIE of 1.30 is observed
Scheme 4. Possible Pathway for the Formation of 4-
Chlorobenzenethiyl Radical
Scheme 7. Measurement of KIE
oxidizing 4-chlorobenzenethiol by DDQ to form the radical
through a hydrogen atom transfer (HAT) pathway (eq 4) is
favorable with an energy barrier of 4.3 kcal/mol (see the
Supporting Information for more details). In contrast, for the
formation of the 1,3,5-trimethoxyphenyl radical species, the
electron-transfer (ET) pathway (Scheme 5) was recommended,
since the energy barrier is only 11.2 or 12.0 kcal/mol, while the
energy barrier in HAT pathway is up to 40.3 kcal/mol (see the
SI for more details). Therefore, two competitive pathways for
from an intermolecular competition, suggesting that C−H
bond cleavage of 1a is not involved in the rate-limiting step.
Further detailed kinetic behavior of 1a was tested by utilizing in
situ IR. As illustrated in Figure 1, plotting initial rate vs [1a]
shows a linear relationship, indicating that the reaction is first
order on [1a]. These results are consistent with our DFT
calculations, suggesting the single-electron-transfer (SET)
process between 1a and DDQ (or HDDQ•) with a 11.2
kcal/mol (or 12.0 kcal/mol) barrier is the rate-determining
step, and the C−H bond cleavage is a facile process with a 16.3
kcal/mol exothermic barrier, which proceeds after radical−
radical cross-coupling of 7 and 8.
Scheme 5. Possible Pathways for the Formation of 1,3,5-
Trimethoxyphenyl Radical
On the basis of the above results, a putative mechanism was
proposed (see Scheme S1 for more details). For example, cross-
coupling between 1a and 2a begins with DDQ oxidizing 2a
through a HAT process to produce the thiyl radical 8, which
could be stabilized by forming the radical [DDQ−8]•.
Simultaneously, 1a undergoes a SET process to afford the
aryl radical cation 7. Thereafter, cross-coupling between 7 and
C
DOI: 10.1021/acs.orglett.6b00764
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00764.
General procedures, calculation details, kinetic studies,
and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: aiwenlei@whu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the 973 Program
(2012CB725302), the National Natural Science Foundation
of China (21390400, 21272180, 21302148, and 21372266), the
Research Fund for the Doctoral Program of Higher Education
of China (20120141130002), and the Ministry of Science and
Technology of China (2012YQ120060). The Program of
Introducing Talents of Discipline to Universities of China (111
Program) is also acknowledged.
D
DOI: 10.1021/acs.orglett.6b00764
Org. Lett. XXXX, XXX, XXX−XXX