Efficient C?S Bond Formation by Direct Functionalization of C(sp3)?H Bond Adjacent to Heteroatoms under Metal-Free Conditions

Article abstract of DOI:10.1002/adsc.201900666

A simple and efficient method for the formation of C?S bond via direct functionalization of C(sp³)?H bond adjacent to heteroatoms was described under metal-free conditions. In this work, stable and easily accessible sodium sulfinates were used as the thiolating agents to afford various aryl thioethers in moderate to excellent yields. Mechanistic explorations show that a radical pathyway is possibly involved during the transformations. (Figure presented.).

Full text of DOI:10.1002/adsc.201900666

Title: Efficient C-S Bond Formation by Direct Functionalization of
C(sp3)-H Bond Adjacent to Heteroatoms under Metal-Free
Conditions
Authors: Feng Zhao, Qi Tan, Dahan Wang, Jinjin Chen, and Guojun
Deng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900666
Link to VoR: http://dx.doi.org/10.1002/adsc.201900666

10.1002/adsc.201900666
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Efficient C-S Bond Formation by Direct Functionalization of
C(sp3)-H Bond Adjacent to Heteroatoms under Metal-Free
Conditions
Feng Zhao,a,b,* Qi Tan,a Dahan Wang,b Jinjin Chen,b and Guo-Jun Dengb,c,*
a
Key Laboratory of Dong Medicine of Hunan Province, School of Pharmaceutical Sciences, Hunan University of
Medicine, Huaihua 418000, China
E-mail: zhaofenghnmu@163.com
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, Key Laboratory for
b
Green Organic Synthesis and Application of Hunan Province, College of Chemistry, Xiangtan University, Xiangtan
411105, China
Beijing National Laboratory for Molecular Sciences, Chinese Academy of Sciences (CAS), Beijing 100190, China
c
E-mail: gjdeng@xtu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A simple and efficient method for the formation of explorations show that a radical pathyway is possibly
C-S bond via direct functionalization of C(sp3)-H bond involved during the transformations.
adjacent to heteroatoms was described under metal-free
Keywords: C(sp3)-H functionalization; C-S bond
formation; heteroatoms; sodium sulfinates; metal-free
conditions. In this work, stable and easily accessible sodium
sulfinates were used as the thiolating agents to afford various
aryl thioethers in moderate to excellent yields. Mechanistic
functionalization to form C-S bond. Direct and
selective functionalization of inert C(sp3)-H bond is a
challenging task due to its lower reactivity.
Introduction
Highly selective and efficient functionalization of C-
H bonds has attracted intensive attention in academic
and industrial chemistry in recent years. The
advantages of this strategy include high efficiency,
low cost, and slight environmental influence.[1,2] On
the other hand, it is well-known that heteroatom-
containing molecules widely exist in natural products,
pharmaceuticals and materials. Thus, it is highly
desirable to develop direct C-H functionalization of
these compounds.
In the past years, the transformation of C(sp3)-H
bond into more valuable structures has received
intensive attention. Particularly, great achievements
have been gained in the direct functionalization of
C(sp3)-H bond adjacent to heteroatoms.[10,11] However,
the formation of C-S bonds from C(sp3)-H bonds has
been less reported. Recently, Xiang and coworkers
realized a series of C-S formation reactions via direct
functionalization of C(sp3)-H bonds using
disulfides,[7e,h] sulfonyl chlorides[8a] and sulfonyl
hydrazides[9c] as thiolating reagents. Then, Wang and
coworkers disclosed a visible-light-induced direct
thiolation at α-C(sp3)-H of ethers with disulfides.[7b]
Organosulfur compounds play important roles in
organic synthesis, medicinal chemistry and material
science.[3] Among them, aryl sulfides have drawn
much attention because of their pivotal drug activities, However, these reactions suffer from the requirement
such as antibacterial, antifungal and antitumoral
activities.[4] Recently, considerable efforts have been
afforded on the selective and effcient construction of
C-S bonds.[5] From the viewpoint of green and
environmentally friendly chemistry, selective
oxidative coupling of C-H bond has demonstrated as
an efficient protocol for C-S bond construction.
Among those transformations, various thiolating or
sulfenylating reagents, for instance, arylthiols,[6]
disulfides,[7] sulfonyl chloride,[8] and sulfonyl
hydrazides,[9] were well developed. Nevertheless,
most of these methodologies limited to C(sp2)-H
of metal catalysts or/and overstoichiometric amounts
of oxidants. Owing to the threshold residual tolerance
of metals for drugs synthesis, direct functionalization
of C(sp3)-H bond to construct C-S bond under metal-
free conditions is quite desirable.
Sodium sulfinates are stable, readily accessible and
easy to handle to be generally served as sulfonylating
agents.[12] We and others have depicted a variety of
methodologies for direct thiolation of C-H bond using
sodium sulfinates as the reliable starting materials
under metal-free conditions.[13] As our continuing
interest in employing sodium sulfinates for the
1
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10.1002/adsc.201900666
Advanced Synthesis & Catalysis
construction of C-S bonds via C-H bond
functionalization, herein, we report an iodine-
mediated direct thiolation of C(sp3)-H bond adjacent
to heteroatoms with sodium sulfinates, which
provides efficient access to aryl thioethers in
moderate to excellent yields.
exhibited the best efficiency (Table 1, entries 5-8).
Other oxidants such as dicumyl peroxide (DCP), tert-
butyl peroxide (TBHP), hydrogen peroxide (H2O2)
and oxygen were less effective for this transformation
(Table 1, entries 9-12). Higher reaction temperature
and the amount of I2 were both beneficial to form the
target product (Table 1, entries 13 and 14). When
increasing the amount of (EtO)2P(O)H to 2.5
equivalents, 3aa was acquired in a yield of 84%
(Table 1, entry 15). As the control experiments
shown, when the reaction was conducted without I2,
only little amount of 3aa was obtained. If no any
oxidant was added to the reaction system, no desired
product was detected by TLC and GC-MS methods,
indicating that the oxidant is necessary for this kind
of transformation (Table 1, entries 16 and 17).
Results and Discussion
In order to obtain the optimal reaction conditions for
C-S bond formation, sodium p-tolylsulfinate (1a, 0.2
mmol) and 1,4-dioxane (2a, 0.4 mL) were chosen as
the model substrates using di-tert-butyl peroxide
(TBP, 0.4 mmol) as the oxidant. In the absence of any
metal catalyst, several iodine additives (10 mol%)
o
were examined at 120 C under air. Among them, I2
was the best choice to afford the desired thiolating
product 3aa in 18% yield (Table 1, entries 1-4). To
our delight, the addition of two equivalents
phosphorus reagent could improve the reaction yield
and diethyl phosphite ((EtO)2P(O)H)
Table 2. Reaction of 1,4-dioxane with various sodium
sulfinates.[a]
Table 1. Optimization of the reaction conditions.[a]
[a]
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mL), I2 (20
mol%), (EtO)2P(O)H (0.5 mmol), TBP (0.4 mmol), 130
oC, air, 16 h; isolated yield based on 1.
With the optimal reaction conditions established,
we next explored the substrate scope of this method.
As shown in Table 2, a variety of sodium sulfinates
were successfully performed with 1,4-dioxane (2a) to
provide corresponding thioethers in moderate to
excellent yields. In general, no or alkyl substituents at
the para position of sodium sulfinate slightly
influenced the yield (Table 2, 3aa-3ac). Functional
groups such as methoxy, trifluoromethoxy,
trifluoromethyl and halogens were well tolerated
under the optimized reaction conditions (Table 2,
3ad-3ai). Notably, the cleavage of C-halogen bond
was not observed during the reaction process. More
bulky substrate, for instance, 1-naphthyl sulfinic acid
sodium salt was also smoothly reacted with 1,4-
dioxane, where relatively lower yield was gained
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mL),
additive 1 (10 mol%), additive 2 (0.4 mmol), oxidant (0.4
o
[b]
mmol), 120 C, air, 16 h.
GC yield based on 1a. n.d. =
not detected. [c] I2 (20 mol%).
(0.5 mmol).
130 C.
(EtO)2P(O)H
[d]
o
[e]
2
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10.1002/adsc.201900666
Advanced Synthesis & Catalysis
probably because of the steric effect of the substituent
reaction. When treating sodium p-tolylsulfinate with
1,2-dimethoxyethane (DME), the terminal methyl
group was prefered to be thiolated (Table 3, 3ea). It
was found that tetrahydropyran (THP) was
compatible with this transformation and providing the
target sulfide in 70% yield (Table 3, 3fa). Besides,
this approach could also be applied to the direct
thiolation of C(sp3)-H bond adjacent to a sulfur atom
or nitrogen atom, such as tetrahydrothiophene or N,N-
dimethylformamide (DMF), respectively (Scheme 1).
Interestingly, when employing DMF as the substrate,
it is the C-H bond of formamide not the C-H bond of
-NCH3 to form C-S bond with sodium p-tolylsulfinate.
(Table 2, 3aj).
Table 3. Substrate scope.[a]
Table 4. Substrate scope.[a]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mL), I2 (20
mol%), (EtO)2P(O)H (0.5 mmol), TBP (0.4 mmol), 130
oC, 16 h under air unless otherwise noted; isolated yield
[a]
[b]
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mL), I2 (20
based on 1.
1 (0.5 mmol), 2 (1.0 mL), I2 (20 mol%),
o
mol%), (EtO)2P(O)H (0.5 mmol), TBP (0.4 mmol), 130
(EtO)2P(O)H (1.25 mmol), TBP (1.0 mmol), 130 C, 16 h
under air.
oC, 16 h under air unless otherwise noted; isolated yield
[b]
based on 1.
1 (0.5 mmol), 2 (1.0 mL), I2 (20 mol%),
o
(EtO)2P(O)H (1.25 mmol), TBP (1.0 mmol), 130 C, 16 h
under air.
To further investigate the scope as well as
limitation of the methodology, we examined various
substrates which contain C-H bonds adjacent to
heteroatoms, including ether, thioether and amide
(Table 3 and Scheme 1). To our delight, a variety of
ethers including cyclic, symmetric and unsymmetric
linear ethers could be well worked with different
sodium sulfinates. Firstly, tetrahydrofuran (THF),
similar to dioxane, was selected to deal with several
kinds of sodium sulfinates and gave the
corresponding products in moderate to high yields.
Both electron-withdrawing and electron-donating
groups could be well tolerated in this transformation
(Table 3, 3ba-3bf). Fortunately, methyl tert-butyl
ether (MTBE), which has a methyl group adjacent to
the oxygen atom and a sterically large group, could
also afford the desired thioethers in moderate to good
yields (Table 3, 3ca-3ce). To our surprise, the larger
steric hindrance substrate, cyclopentyl methyl ether
(CPME), was found to couple with sodium sulfinates,
even though leading to the corresponding products
with relatively lower yields (Table 3, 3da-3dd).
Obviously, the sterically hindered effect of tert-butyl
and cyclopentyl had a negative influence on the
Scheme 1. The reaction of tetrahydrothiophene and DMF.
Furthermore, sulfonyl hydrazides, as common
thiolating reagents, were subjected to the reaction
system to examine the applicability of this protocol.
Luckily, as presented in Table 4, positive results were
achieved under the optimized reaction conditions. A
series of thioethers were synthesized even though
relatively lower yields were acquired compared to
3
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10.1002/adsc.201900666
Advanced Synthesis & Catalysis
sodium sulfinates. There is no doubt that it will
broaden the utilization of this metal-free
methodology.
As summerized in Table 5, we also probed several
other common thiolating reagents such as sulfonyl
To get preliminary insight into the reaction
mechanism, some control experiments were carried
out and the results were shown in Scheme 2. If the
model reaction was conducted without TBP, the
desired product 3aa was not detected along with the
disulfide 5a as a major product (Scheme 2a). The
treatment of 5a as the substrate with 1,4-dioxane (2a)
afforded the desired thiolating product 3aa in a high
yield under optimal reaction conditions (Scheme 2b).
Subsequently, the addition of 2,2,4,4-tetramethyl-1-
chloride,
thiophenol
and
sulfonothioate.
Unfortunately, these reagents did not show good
performance and only trace amount of desired
product was obtained. When sodium 4-nitrobenzene
sulfinate, sodium methanesulfinate and sodium
trifluoromethanesulfinate were subjected to the
optimal reaction conditions respectively, no
corresponding products were detected by TLC and
GC-MS methods. We also tried some examples of
heteroaromatic sulfinate sodium salt and sulfonyl
hydrazide, however, the results are not satisfactory.
Other compounds which contained α-C(sp3)-H bond,
for instance, butyl ether, benzyl ether, ethyl tert-butyl
ether, diglyme, hexamethylphosphoric triamide
(HMPA), 1,3-dimethylpropyleneurea (DMPU), N,N-
dimethylacetamide (DMA), 1-methyl-2-pyrrolidone
(NMP), tetrahydropyrrole, N-methylpiperidine and
cyclohexane were not successful to deal with sodium
sulfinates under the optimized reaction conditions.
piperidinyloxy (TEMPO),
a
radical scavenger,
evidently suppressed the reaction under standard
conditions (Scheme 2c), suggesting that a radical
procedure was probably involved in the reaction
mechanism. In addition, a free radical intermediate
generated in situ was captured by TEMPO and this
species was detected by GC-MS analysis.
Based on the above observation and previous
literature, a possible reaction mechanism was
illustrated in Scheme 3. Initially, a tert-butoxy radical,
formed by the decomposition of TBP under heat, can
grasp hydrogen from α-C(sp3)-H of 1,4-dioxane to
provide tert-butanol and a pivatol alkyl radical
intermediate. On the other hand, aryl disulfide was
generated from aryl sulfinic sodium salt under the
promotion of I2 and diethyl phosphite.[13c,14] Then, the
key radical intermediate coupled with aryl disulfide
to afford the final thiolation product 3aa as well as a
new aryl sulfur free radical which could be trapped
by another alkyl radical.
Table 5. Unsuccsessful substrates.
Scheme 2. Control experiments.
Scheme 3. A possible reaction mechanism.
4
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10.1002/adsc.201900666
Advanced Synthesis & Catalysis
Conclusion
Brancale, E. Hamel, M. Artico, R. Silvestri, J. Med.
Chem. 2006, 49, 947.
In summary, we have described a metal-free C-S
bond formation by the direct functionalization of
C(sp3)-H bonds adjacent to heteroatoms. Various aryl
sodium sulfinates were treated with different ethers,
thioethers and amides to afford a number of aromatic
sulfides in moderate to excellent yields. Functional
groups were well tolerated under the optimized
reaction conditions. Mechanistic studies indicate that
the transformation probably undergo a radical
pathway. This metal-free method provides an
efficient and selective alternative access to thiothers,
which might have wide applications in organic and
pharmaceutical fields.
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Experimental Section
Sodium p-tolsulfinate (1a, 0.2 mmol), 1,4-dioxane (2a, 0.4
mL), I2 (20 mol%), TBP (0.4 mmol) and (EtO)2P(O)H (0.5
mmol) were added to an oven-dried reaction vessel
equipped with a magnetic stirring bar, then the vessel was
stirred at 130 oC for 16 h. After the reaction was completed,
the reaction mixture was filtered through a pad of silica gel
and the filtrate was concentrated under reduced pressure to
yield the crude product, which was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate =
50:1) to give the desired product 3aa in 72% yield as a
pale-yellow oil.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21801076), Hunan Provincial Natural
Science Foundation of China (2019JJ50415) and Scientific
Reseach Program of Huaihua (2018N2204).
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10.1002/adsc.201900666
Advanced Synthesis & Catalysis
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