Sodium Iodide (NaI)-Catalyzed Cross-Coupling for C?S Bond Formation via Oxidative Dehydrogenation: Cheap, Direct Access to Unsymmetrical Aryl Sulfides

Article abstract of DOI:10.1002/asia.201701163

A simple and practical NaI-catalyzed direct C?H sulfenylation of arenes has been developed under air. In this reaction, aryl sulfides were obtained in moderate to excellent yields with high regioselectivity from readily available aromatic compounds and aryl/alkyl thiols, even on gram scale. To demonstrate the practicability of this reaction, two bioactive compound skeletons were synthesized in good yields. This method can also be used to late-stage modification of curcumin.

Full text of DOI:10.1002/asia.201701163

DOI: 10.1002/asia.201701163
Communication
Sulfenylation
Sodium Iodide (NaI)-Catalyzed Cross-Coupling for CÀS Bond
Formation via Oxidative Dehydrogenation: Cheap, Direct Access
to Unsymmetrical Aryl Sulfides
Hui-Hong Wang+,[b] Tao Shi+,[b] Wei-Wei Gao,[b] Yong-Qiang Wang,[b] Jun-Fang Li,[b] Yi Jiang,[b]
Yong Sheng Hou,[b] Chen Chen,[b] Xue Peng,*[b] and Zhen Wang*[a, b]
Abstract: A simple and practical NaI-catalyzed direct CÀH
sulfenylation of arenes has been developed under air. In
this reaction, aryl sulfides were obtained in moderate to
excellent yields with high regioselectivity from readily
available aromatic compounds and aryl/alkyl thiols, even
on gram scale. To demonstrate the practicability of this re-
action, two bioactive compound skeletons were synthe-
sized in good yields. This method can also be used to
late-stage modification of curcumin.
Aryl sulfides are ubiquitous structural motifs existing in many
natural products, biologically active compounds, and organic
materials.[1] Thus, the formation of CÀS bonds has garnered
Scheme 1. Examples of CÀS bond formation reactions.
much attention.[2] Among them, C(sp2)ÀS bond formation is
one of the most important and fundamental reactions for the
synthesis of these sulfide compounds (Scheme 1). Classical
transition-metal-catalyzed cross-coupling reactions of prefunc-
tionalized arenes[1c,3] (e.g., aryl halides) with various sulfur-
based partners were mediated by palladium,[4] copper,[5]
nickel,[6] iron,[7] cobalt,[8] rhodium[9] and gold.[10] Subsequently,
direct CÀH thioarylation was also achieved in the presence of
suitable metal catalysts.[3c,11] Since thiol(ate) anions deactivate
the catalysts[12] and disulfide formation in the presence of oxi-
dants,[13] the general applicability of these metal-catalyzed pro-
cedures has been limited. Typically toxic matters[14] and heavy-
metal-salt waste produced were also serious problems in those
reactions. In recent years, with the emergence of the concepts
of “atom economy”and “green chemistry”, metal-free CÀH thio-
arylation of electron rich arenes and heteroarenes using (thio)-
succinimides,[15] sulfonyl hydrazines,[16] and other precursors[17]
can circumvent some of the problems of transition-metal-
mediated transformations. Considering the highly active oxi-
dants and intermediates, these methodologies, however, often
suffer from low functional-group tolerance and multistep prep-
arations of the coupling precursors. In addition, the direct
metal-free conversion of CÀH bonds into CÀS bonds using
thiols has been reported as an efficient alternative approach,[18]
but such approaches used toxic and volatile iodine, which lim-
ited the applicability. It is desirable in the medicinal industry
that reactions are conducted under metal-free and non-toxic
conditions. A metal-free electrophilic phosphination reaction
has been recently achieved.[19] Therefore, developing a practi-
cal and economic approach to aryl sulfides directly from
arenes and aryl/alkyl thiols is a challenging and urgent task.
Herein, we report an efficient, metal-free, practical, and simple
route for the synthesis of unsymmetrical aryl sulfides by oxida-
tive dehydrogenation in the presence of inexpensive and envi-
ronment friendly NaI, using air as the oxidant.
[a] Prof. Z. Wang
State Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering
Lanzhou University
Lanzhou 730000 (P.R. China)
E-mail: zhenw@lzu.edu.cn
[b] H.-H. Wang,+ T. Shi,+ W.-W. Gao, Y.-Q. Wang, J.-F. Li, Y. Jiang, Y. S. Hou,
C. Chen, X. Peng, Prof. Z. Wang
School of Pharmacy
Lanzhou University
West Dong gang Road. No. 199, Lanzhou 730000 (P.R. China)
E-mail: pengx13@lzu.edu.cn
According to our previous work,[20] the bromide anion can
be oxidized to bromine (Br2) under air, and subsequently oxi-
dize an SÀH bond to an SÀBr bond, while the umpolung of
aryl thiols could be attacked by the nitrogen atom of an intra-
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
asia.201701163.
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Table 1. Reaction optimizations.[a]
Table 2. Substrate scope of thiols.[a,b]
Entry
–
Thiol
Product
Yield[%][b]
–
Entry
Solvent
T [8C]
Catalyst [mol %]
Oxidant
Yield[a] [%]
1
2
3
4
5
6
7
8[b]
9[c]
10
11
12
13[d]
14
15
16
17
18
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
90
KBr (10)
NaI (10)
NaI (10)
No
NaI (10)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
KI (10)
CuI (10)
TBAI (10)
NaI (10)
NaI (20)
NaI (50)
NaI (20)
NaI (20)
NaI (20)
O2
O2
No
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
air
5
26
0
0
0
1[c]
2
3
4
5
6
7
8
R1 =H
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1m’
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3m’
93
80
90
87
70
94
93
87
84
76
86
78
71
75
NMP
R1 =2-Me
R1 =3-Me
R1 =4-Me
R1 =2,6-dimethyl
R1 =4-F
R1 =4-Cl
R1 =4-Br
R1 =4-OMe
R1 =4-tBu
R1 =2-Cl
R1 =2-NH2
R=Me
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
54
60
61
57
23
53
60
90
93
20
trace
85
9
10
11
12
13
14
R=Ph
120
15
16
17
1n
1o
1p
3n
3o
3p
83
86
92
[a] Unless otherwise noted, the reactions were performed in a Schlenk
tube with 1a (0.1 mmol), 2a (0.1 mmol), and O2 (balloon pressure) in
1 mL (0.10 mmolmLÀ1) solvent for 16 h. All yields listed are isolated
yields. [b] 0.2 mmolmLÀ1. [c] 0.5 mmolmLÀ1. [d] 24 h.
molecularly formed amide SÀN bond. Thus, 10 mol% KBr with
equal amounts of 1a and 2a as starting materials were tested
in DMF at 1208C (Table 1, entry 1). Only 5% of the desired pro-
duct 3a was obtained in this trial. Therefore, we chose the
more easily oxidized iodide as catalyst in this reaction. To our
delight, when the reaction was carried out in the presence of
10 mol% NaI in DMF at 1208C, the yield of 3a slightly im-
proved to 26%. The following control reactions in the absence
of O2 and NaI (Table 1, entries 3 and 4, respectively), showed
no traces of 3a, indicating that both NaI and oxygen are nec-
essary in these transformations. Then various solvents were
screened and the reaction proceeded well in highly polar
DMSO (Table 1, entry 7). Subsequently, we tried to increase the
yield of 3a by enhancing the concentration of the reaction
(Table 1, entries 8, 9) or prolonging the reaction time (Table 1,
entry 13), and only a slightly increase occurred. A series of
iodide salts (Table 1, entries 10, 11, 12) were also tested but
failed to provide more favorable outcomes. However, when in-
creasing the amount of NaI to 20 and 50 mol%, 3a was ob-
tained in 90 and 93% yield (Table 1, entries 14 and 15, respec-
tively); for environmental concerns, 20 mol% NaI was used.
The effect of temperature was also examined (Table 1, en-
tries 16 and 17) and 1208C was found to be the best. A similar
yield was observed when the reaction was carried out under
air (Table 1, entry 18).
[a] Conditions:1 (0.1 mmol), 2a (0.1 mmol), NaI (0.02 mmol), DMSO
(1.0 mL), 1208C, 16 h, under oxygen. [b] Isolated yield based on 2a.
[c] The reaction can also be performed on gram scale. 1a (1.10 g) with
2a (1.21 g) gave 3a 1.87 g (82% yield).
substituents, the yield of corresponding sulfenylated arene 3e
was 70%. Aryl thiols having electron-withdrawing halo groups
at the 2 or 4 position 1 f–h, 1k afforded the thiolated pro-
ducts 3 f–3h, 3k in 86–94% yields. However, those having
electron-donating groups at the 2 or 4 position 1i, 1j, and 1l
gave slightly lower yields than those with electron-withdraw-
ing groups, which might be caused by the lower reactivity of
sulfur cation intermediates. Moreover, alkylthiols 1m and 1n
reacted smoothly and provided the desired products 3m, 3m’
and 3n in 71, 75 and 83% yield, respectively. Further investiga-
tions showed that heterocyclic thiols such as pyridine-2-thiol
1o and benzo[d]thiazole-2-thiol 1p also reacted well. In addi-
tion, this reaction also proceeded well on gram scale for 3a
(82% yield).
On the basis of the results obtained in the case of carbon
nucleophile N,N-dimethylaniline 2a, we further extended this
strategy to investigate the nucleophile partners (Scheme 2).
For this purpose, the arylthiolation of pyrrole 2b was initially
carried out under the aforementioned conditions, providing
the corresponding sulfide 4b in 85% yield. In addition, it is
noteworthy that indoles could couple with aryl (alkyl) thiols,
giving the expected products 4ca and 4cb in excellent yield.
Furthermore, indoles with methyl group 2d and moderate
With the optimized reaction conditions in hand, a range of
arylthiols bearing an alkyl substituent were examined (Table 2)
giving the corresponding products 3b–3d in good to excellent
yields (80–93%). Notably, when the arenes had two ortho-alkyl
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as a potent inhibitor of tubulin polymerization.[23] Both of them
were synthesized previously in low yields and many steps.[17d,22]
Notably, by using the method we developed, the two bioactive
compounds were successfully prepared in 65 and 72% yield,
respectively. The metal-free protocol was also applied to late-
stage modification of curcumin, an extensive pharmacological-
ly active compound,[24] leading selectively to monosulfide 4j in
76% yield. In addition, when the reaction was conducted with
diphenyl diselenide 1q,[25] it proceeded smoothly and gave the
product in 89%.
A primary mechanism research was also conducted. Previous
results indicated NaI and oxygen are necessary in these trans-
formations. Then, to further elucidate the mechanism, some
control experiments were carried out (Scheme 4). Thiols could
Scheme 2. Substrate scope of the arene and heteroarene coupling partners.
Conditions: 1d (0.1 mmol), 2 (0.1 mmol), NaI (0.02 mmol), DMSO (1.0 mL),
1208C, 16 h, under oxygen. Isolated yields based on 1d or 1m.
electron-withdrawing acetyl group 2e substituents were toler-
ated and afforded the corresponding diaryl sulfides 4d and 4e
in 89 and 65% yield rather than a iodination products.[21] The
thiolation of 1,3,5-trimethoxybenzene 2 f and 2-naphthol 2g
also afforded the thiolated products 4 f and 4g in 82 and 87%
yield, respectively.
To demonstrate the practicability of this reaction, two com-
plex bioactive compounds were synthesized using our ap-
proach (Scheme 3). AZD4407 is a known 5-lipoxygenase inhibi-
tor.[22] Methyl 5-methoxy-3-((3,4,5-trimethoxyphenyl)thio)-1H-
indole-2-carboxylate (4h) shows excellent antitumor activities
Scheme 4. Control experiments.
be absolutely transferred to disulfide 5a in the absence of aro-
matics (Scheme 4a). Disulfide 5a reacted well with 2a giving
the product in 93% yield. However, the reaction could not
conduct in the absence of NaI (Scheme 4b). On the other
hand, when the reaction time was shortened to 6 h, disulfide
5a and product 3a were observed in 63 and 35% yield, re-
spectively (Scheme 4c). All of these reactions indicated that
both thiols and disulfides could be converted to the desired
products. Besides, when using I2 as oxidant or catalyst (Sche-
me 4d,e), 3a was obtained in a slightly lower yield (79 and
67% respectively), which uncovered that I2 is a very important
oxidant intermediate.
A proposed mechanism for the formation of sulfides is
shown as follows (Scheme 5): (1) IÀ is oxidized to I2 by molecu-
lar oxygen; (2) the nucleophilic arylthiol attacks the electrophil-
ic iodine leading to the formation of electrophilic intermediate
ArÀSI via elimination of one molecule of HI; (3) the species ArÀ
SI is attacked by electron-rich arenes or arylthiols forming de-
sired compounds or disulfides, upon elimination of HI; (4) the
disulfide is oxidized by I2 to an activated intermediate 4; (5) 4
Scheme 3. Syntheses of two bioactive compound skeletons.
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Scheme 5. Proposed mechanism.
is then converted into the desired product and 2 by a direct
nucleophilic substitution.
In summary, an operationally simple and environmentally
friendly method of direct CÀH thioarylation of arenes and het-
eroarenes with high regioselectivity was developed. In this re-
action, cheap and safe NaI was used as catalyst and air as oxi-
dant, affording sulfenylated arenes in good to excellent yields,
even on gram scale. The reaction had high functional group
tolerance and a broad substrate scope. The developed method
was also successfully utilized in the syntheses of two biologi-
cally active compounds and late-stage modification of the
pharmacologically active compound curcumin. Further studies
on sulfur cations and applications of this reaction are under in-
vestigation.
Experimental Section
General procedure for the synthesis of N,N-dimethyl-4-(phe-
nylthio)aniline (3a):
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A mixture of thiophenol (11.0 mg, 0.1 mmol) with N,N-dimethylani-
line (12.1 mg, 0.1 mmol), NaI (2.98 mg, 0.02 mmol) and DMSO
(1.0 mL) was stirred at 1208C in a Schlenk tube for 16 h under dry
air conditions. The mixture was then cooled to room temperature,
diluted with water, extracted with ethyl acetate, dried over sodium
sulfate and concentrated. The crude products were purified by
column chromatography on silica gel to give the corresponding
products.
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Acknowledgements
We thank Prof. Yong-Min Liang and Chun-An Fan for helpful
discussions. Financial support was provided by the Recruit-
ment Program of Global Experts (1000 Talents Plan) and Fun-
damental Research Funds for the Central Universities (lzujbky-
2016-153).
Keywords: aryl sulfides · CÀH sulfenylation · cross-coupling ·
regioselectivity · sodium iodide
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Manuscript received: August 12, 2017
Revised manuscript received: September 11, 2017
Version of record online: && &&, 0000
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