Palladium-catalyzed direct thiolation of ethers with sodium sulfinates

Article abstract of DOI:10.1016/j.tetlet.2014.09.098

A new method for palladium-catalyzed arylthiolation of ethers with sodium sulfinates is described. The CH bond in various ethers was successfully converted into CS bond to yield the corresponding sulfides in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2014.09.098

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed direct thiolation of ethers with sodium
sulfinates
b,
Shengrong Guo a,b, Weimin He a, Jiannan Xiang a, , Yanqin Yuan
⇑
⇑
a College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
b Department of Chemistry, Lishui University, 323000 Lishui, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for palladium-catalyzed arylthiolation of ethers with sodium sulfinates is described. The
CAH bond in various ethers was successfully converted into CAS bond to yield the corresponding sulfides
in moderate to good yields.
Received 5 August 2014
Revised 8 September 2014
Accepted 22 September 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Thiolation
Sodium sulfinates
Sulfides
Pd(OAc)2
Ethers
The direct functionalization of CAH bonds is of great impor-
tance to organic chemistry because of its high efficiency and high
atom-economy.1 Owing to their low reactivity, direct and selective
methods of C(sp3)AH bond functionalization are challenging.2 In
recent years, however, much progress has been made in the area
of oxidative functionalization of C(sp3)AH bonds to form CAC
and CAX (X = O, N, S) bonds.3
the best of our knowledge, no reports of oxidative, sp3 CAH thiola-
tion of ethers with sodium sulfinates are known. Herein, we have
reported a novel protocol to construct unsymmetrical sulfides
using sodium sulfinates as sulfur sources (Scheme 1b).
Inspired by our previous work,10 our initial attempt started with
the reaction of sodium p-tolylsulfinate 1a (1.0 mmol) and 1,4-diox-
ane 2a (4 mL) catalyzed with 2.0 mol % PdCl2 using di-tert-butyl per-
oxide (DTBP, 2.0 equiv) as the oxidant at 120 °C for 12 h (Table 1,
entry 1). By GC–MS, the reaction took place with a 35% yield. Efforts
were then made to get the optimized reaction conditions, the aryl-
thiolation of 1,4-dioxane with sodium p-tolylsulfinate (1a,
1.0 mmol) was selected as the model reaction, several palladium
catalysts such as Pd(OAc)2, PdBr2, (CH3CN)2PdCl2, and (Ph3P)4Pd
were investigated (Table 1, entries 2–5), and among them Pd(OAc)2
(2.0 mol %) showed the best efficiency to give the corresponding
Organosulfur compounds are of great importance to the phar-
maceutical industry, material science, and general organic synthe-
sis.4 With the development of direct CAH functionalization,
remarkable progress has been made in the area of CAS bond for-
mation.5 The first example of copper salt catalyzed thiolation of a
C(sp2)AH bond was reported by Yu in 2006,5a Subsequently, many
thiolating reagents like disulfides,5c–f S-arylthiophthalimides,6 sul-
fonyl hydrazides,7 sulfonyl chlorides,8 and mesitylphenyl sulfides9
have been used for direct arylthiolation of benzoxazole, benzothi-
azole, and indole in the presence of different metal catalysts. How-
ever, the selective thiolation of sp3-hybridized CAH bonds in
simple ethers has remained a challenging task.
(a) Previous work:
Ar
S
O
Recently, Deng5j reported thiolation of indoles using sodium
sulfinates, which are usually used in arylations, as an effective sul-
fur electrophiles and aryl thiol surrogate (Scheme 1a). Our group is
interested in arylthiolation of sp3-hybridized CAH bonds.5e,10 To
I2 , DMSO
S
+
Ar
ONa
anisole
diethyl phosphite
N
H
N
H
(b) Thiswork
O
S
S
O
H
O
Pd(II)
R
+
Ar
ONa
⇑
Corresponding authors.
E-mail addresses: jnxiang@hnu.edu.cn (J. Xiang), guosr9609@lsu.edu.cn
[O]
(Y. Yuan).
Scheme 1. Methods of CAS bond formation using sodium sulfinates.
http://dx.doi.org/10.1016/j.tetlet.2014.09.098
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
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2
S.-r. Guo et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
Table 2
Optimization of the reaction conditionsa
Thiolation of 1,4-dioxane with sodium sulfinatesa,b
O
S
O
S
S
H
O
O
O
H
O
O
S
O
2 mol % Pd(OAc)2
Ar
+
metal-cat.
oxidant
ONa
Ar
ONa
+
2eq.DTBP
O
CH3
O
120 oC, 12 h
H3C
1a-1l
2a
1a
3aa
3aa-3al
2a
S
O
O
S
O
O
S
O
O
Entry Oxidant (equiv.)
Catalyst (mol%)
Yield (%)b
H3C
H3CO
1
2
3
4
5
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
PdCl2(2.0)
Pd(OAc)2(2.0)
PdBr2(2.0)
(CH3CN)2PdCl2(2.0)
(Ph3P)4Pd(2.0)
35
81
30
61
56
entry 1, 3aa (81 %)
entry 2, 3ab (78 %)
entry 3, 3ac (72 %)
S
O
S
O
S
O
F3C
O
Cl
O
Br
O
entry 4, 3ad (73 %)
entry 5, 3ae (77 %)
entry 6, 3af (79 %)
c
6
7
8
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
CuBr(2.0)
N.D.
S
O
S
O
Br
S
O
c
Cu(OAc)2(2.0)
N.D.
S
entry 7, 3ag (72O%)
entry 8, 3ah (O59 %)
entry 9, 3ai (73O%)
c
Fe(acac)3(2.0)
N.D.
9
10
11
DCP (2.0)
TBPB (2.0)
TBHP (2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
70
61
51
OCH3
Br
S
O
S
O
S
O
CH3
O
c
O
O
12
13
14
15
16
CAN (2.0)
(NH4)2S2O8 (2.0)
K2S2O8 (2.0)
PhI(OAc)2 (2.0)
DDQ (2.0)
N.D.
entry 10, 3aj (73 %)
entry 11, 3ak (67 %)
entry 12, 3al (70 %)
c
N.D.
c
a
N.D.
Reaction condition:
(2 mol %) heated at 120 °C for 12 h.
1 (1.0 mmol), 2a (4.0 mL), DTBP (2.0 mmol), Pd(OAc)2
c
N.D.
b
Isolated yield based on 1.
c
N.D.
17
18
19
20
DTPB (1.0)
DTPB (3.0)
TBPB (2.0)
TBPB (2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(2.0)
Pd(OAc)2(1.0)
Pd(OAc)2(0.5)
65d
80e
78
products 3aa–3ac in 72–81% yields (Table 2, entries 1–3). The reac-
tion is also tolerant of electron-withdrawing substituents such as
chlorine, bromine, and trifluoromethyl groups on the aromatic ring
of sodium arenesulfinates and the products 3ad, 3ae, and 3ef were
observed in 73%, 77%, and 79% yields, respectively (Table 2, entries
4–6). The more bulky 2-naphthalenesulfinic acid sodium salt was a
good substrate for this thiolation reaction as shown for the suc-
cessful formation of 3ag in 72% yield (Table 2, entry 7). It is worth
noting that this protocol is also applicable to heterocyclic aromat-
ics such as thiophene with 59% yield (Table 2, entry 8). However,
51
a
Reaction conditions: 1a (1.0 mmol), 2a (4 mL), heated at 120 °C for 12 h with
2.0 mmol % catalyst.
b Isolated yield.
c Not detected by GC–MS.
d DTBP (1.0 equiv).
e DTBP (3.0 equiv).
product 3aa in 81% (Table 1, entry 2) yield at 120 °C under an argon
atmosphere (Table 1, entries 1–5). The formation of the desired
product halted with other metal catalysts, such as CuBr, Cu(OAc)2,
and FeCl3Á6H2O (Table 1, entries 6–8). Palladium plays a pivotal role
in the catalytic cycle, although the exact mechanism is unclear.
The oxidant plays another important role in the activation of
the inactive CAH bond. The reaction is less efficient and proceeds
with only a moderate yield when other oxidants were used such
as tert-butyl hydroperoxide (TBHP), dicumyl peroxide (DCP) and
tert-butyl perbenzoate (TBPB). DTBP proved to be the best oxidant
(Table 1, entries 9–11). Under the present reaction conditions,
other organic and inorganic oxidants, such as ceric ammonium
nitrate (CAN), (NH4)2S2O8, K2S2O8, PhI(OAc)2, and DDQ were also
examined and were found to impede the transformation (Table 1,
entries 12–16). The appropriate amount of DTBP was 2.0 equiv
and no significant increased yield of 3aa was observed with less
or more than 2.0 equiv of DTBP (Table 1, entries 17 and 18). It is
worth noting that a similar yield could still be achieved when
the amount of the catalyst loading was decreased to 1 mol %
(Table 1, entry 19). Further reduction of the catalyst loading to
0.5 mol % reduced the reaction yield (Table 1, entry 20).
Under optimized reaction conditions (2 mol % of Pd(OAc)2,
2 equiv of DTBP, 4 mL of 1,4-dioxane, 120 °C, 12 h), the scope of
the Pd-catalyzed direct arylthiolation using sodium sulfinates as
arylthiolation reagents was investigated. As can be seen from
Table 2, the reactions of a wide range of sodium arenesulfinates
with 1,4-dioxane generate the desired arylthiolated products in
moderate to good yields. The substituted sodium arenesulfinates
with electron-donating groups, such as methyl and methoxy
reacted with dioxane efficiently and afforded the corresponding
Table 3
Thiolation of ethers with sodium arenesulfinatesa,b
2 mol % Pd(OAc)2
O
S
3ba-3bi
3ca-3cc
3da-3dc
H
O
S
O
Ar
+
2eq.DTBP
Ar
ONa
120 oC, 12 h
2b-2d
1
S
O
S
O
S
O
H3CO
H3C
entry 1, 3ba (63 %)
entry 2, 3bb (65 %)
entry 3, 3bc (62 %)
S
O
S
O
S
O
F3C
Br
Cl
entry 4, 3bd (64 %)
entry 5, 3be (67 %)
entry 6, 3bf (61 %)
S
O
S
O
S
O
CH3
Cl
entry 7, 3bg (53 %)
entry 8, 3bh (54 %)
entry 9, 3bi (51 %)
O
S
S
O
S
O
H3CO
Br
entry 10, 3ca (34 %)
entry 11, 3cb (36 %)
entry 12, 3cc (40 %)
O
S
S
O
O
S
O
O
O
H3CO
Cl
entry 13, 3da (64 %)
entry 14, 3db (56 %)
entry 15, 3dc (65 %)
a
Reaction condition:
1 (1.0 mmol), 2a (4.0 mL), DTBP (2.0 mmol), Pd(OAc)2
(2 mol %) heated at 120 °C for 12 h.
b
Isolated yield based on 1.
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S.-r. Guo et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
when sodium arenesulfinate containing-nitro groups were used as
S
2
a substrate, no desired crosscoupling products were observed. This
reaction was not sensitive to steric hindrance (Table 2, entries
9–12), for example, when sodium arenesulfinate bearing an
ortho-substituent (sodium 2-methylbenzenesulfinate, 1j) was trea-
ted with 1,4-dioxane, and the desired product 3aj was obtained
with 73% yield.
H3CO
10mol% Pd(OAc)2
major, 95%
OCH3
SO Na
2
without DTBP
1,4-dioxane
O
O
H3CO
S
S
minor, 5%
H3CO
Subsequently, the scope of ethers in the present reaction was
also examined (Table 3). A variety of ethers including cyclic and
unsymmetrical linear ethers could couple with different sodium
arenesulfinates. Tetrahydrofuran (THF) was found to work effec-
tively with different kinds of sodium arenesulfinates and the corre-
sponding products were obtained in moderate yields (entries 1–9).
The electronic effects of the substituents on the aromatic ring of
sodium arenesulfinate did not substantially influence the reaction
reactivity, as both electron-rich and electron-deficient sodium
arenesulfinates worked. ortho-substituted sodium arenesulfinate
was tolerated, but the steric effects of the sodium arenesulfinate
did impact on the yields (entries 8 and 9). For example, the reaction
of sodium 2-chloro benzenesulfinate with THF proceeded only with
51% yield (entry 9). In addition, compared to the yield of 1,4-diox-
ane, one can conclude that the activity of THF is poorer than 1,4-
dioxane, which maybe influenced by the number of oxygen atoms
and the size of the cyclic ester. In the case of methyl tert-butyl ether
(MTBE), which has one CH3 group adjacent to the oxygen atom and a
sterically large group, the reaction proceeded with poor yields
(entries 10–12). Clearly, the sterically demanding tert-butyl had
an effect on the reaction. 1,2-dimethoxyethane (DME) furnished a
mixture of products with moderate yields, it’s very interesting that
the main thiolation reaction took place on the terminal methyl
group not the methylene (entry 13–15).
Scheme 2. Reaction of sodium arenesulfinates with 1,4-dioxane catalyzed by
Pd(OAc)2 without DTBP.
O
O
H
S
O
O
DTBP (2.0 equiv)
S
2
+
3ab
2.0 mmol%Pd(OAc)2
120 oC, 12h
H3CO
H3CO
yield 90 %
Scheme 3. Reaction of disulfide with 1,4-dioxane only using DTBP as oxidant with
2 mmol % Pd(OAc)2.
O
heat
Ethers
t-BuO-OBu-t
t-BuO
Ar SO2Na
Ar SO2Cl
Pd(OAc)2
S
Ar
Ar
S
O
S
O
S
Ar
+
Ar
Ar
Ar
S
+
+
ArS
Lastly, under optimal reaction conditions, the applicability of
this method to sulfonyl chlorides with 1,4-dioxane was tested
(Table 4). This procedure was found to be similarly compatible
with a broad range of substrates. Notably, substrates bearing both
electron-withdrawing and electron-donating groups were all suc-
cessfully tolerated in this reaction. However, the yields were lower
than those of sodium arenesulfinate. Unfortunately, similar to
sodium 4-nitrobenzenesulfinate, 4-nitrobenzenesulfonyl chloride
also failed to deliver the products.
O
S
O
Ar
S
Scheme 4. Plausible reaction mechanism.
To investigate the possible mechanism for this arylthiolation, a
series of experiments were carried out. The disulfide was the major
product when the model reaction was carried out with only using
10 mol % Pd(OAc)2 catalyst without DTBP (Scheme 2). The interme-
diate product of disulfide could react with dioxane smoothly under
the same conditions (Scheme 3). In a subsequent reaction, the for-
mation of the desired product 3aa was suppressed by addition of
TEMPO as a radial inhibitor, thus revealing that the mechanism
proceeds via a radical process.8–10
Table 4
Thiolation of 1,4-dioxane with sulfonyl chloridesa
H
O
S
O
O
O
O
2 mol % Pd(OAc)2
Ar
+
S
Ar
Cl
2eq.DTBP
O
120 oC, 12 h
1a'-1f'
As far as sodium aryl sulfinates are concerned, a plausible
mechanism is illustrated in Scheme 3. Similar to the metal-cata-
lyzed thiolation reaction of arenesulfonyl chlorides or sulfonyl
hydrazides, the plausible mechanism involves the following sev-
eral steps: (I) sodium aryl sulfonate is converted into the disulfide
by Pd(OAc)2; (II) the tert-butoxyl radical, which is formed by the
decomposition of DTBP under heat, can abstract hydrogen from
the ether to generate the corresponding alkyl radical intermediate;
(III) the radical intermediate reacts with disulfide affording the
product and ArSÅ free radical which is trapped by another alkyl rad-
ical (see Scheme 4).
In conclusion, we have developed an efficient Pd-catalyzed aryl-
thiolation using sodium sulfinates as sulfur sources. In the pres-
ence of 2.0 mol % of Pd(OAc)2 and DTBP as an oxidant, a broad
range of sodium sulfinates react with ethers smoothly giving aryl-
thiol substituted ethers in moderate to good yields. This finding
offers a new, simple, and mild method for the synthesis of aryl
alkyl sulfides.
Entry
Substrate
Product
Yield (%)b
H3C
SO2Cl
SO2Cl
SO2Cl
1
2
3
4
3aa
3ac
3ad
3af
54
45
48
35
Cl
F3C
SO2Cl
SO2Cl
5
6
3ag
3aj
33
42
SO2Cl
CH3
a
Reaction conditions: sulfonyl chlorides (1.0 mmol), 2a (4 mL), heated at 120 °C
for 12 h with 2.0 mmol % catalyst.
b Isolated yield.
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S.-r. Guo et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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This work was supported by the National Natural Science Foun-
dation of China (No. 21276068) and the Normal Foundation of Zhe-
jiang Education Department (No. Y201329988).
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