Regioselective C-S Bond Formation between Flavones and Arylsulfonyl Chlorides through the Use of Ammonium Iodide

Article abstract of DOI:10.1002/cctc.201500673

A novel and regioselective ammonium iodide mediated C-S bond formation protocol involving flavones and sulfonyl chlorides to generate different ArS-substituted flavone derivatives in high yields was developed. Different from existing metal-free C-S bond formation protocols with the use of PPh₃ or I₂ as the catalyst, this method provides an alternative way of constructing C-S bonds through the use of NH₄I as a catalyst, which makes it highly valuable for the efficient synthesis of thioether compounds.

Full text of DOI:10.1002/cctc.201500673

DOI: 10.1002/cctc.201500673
Communications
Regioselective CÀS Bond Formation between Flavones and
Arylsulfonyl Chlorides through the Use of Ammonium
Iodide
Wannian Zhao and Aihua Zhou*[a]
A novel and regioselective ammonium iodide mediated CÀS
bond formation protocol involving flavones and sulfonyl chlor-
ides to generate different ArS-substituted flavone derivatives in
high yields was developed. Different from existing metal-free
CÀS bond formation protocols with the use of PPh3 or I2 as the
catalyst, this method provides an alternative way of construct-
ing CÀS bonds through the use of NH4I as a catalyst, which
makes it highly valuable for the efficient synthesis of thioether
compounds.
Thioethers exist widely in natural products,[1] and many drugs
also possess the thioether structure;[2] therefore, the develop-
ment of efficient methods to construct CÀS bonds is highly
desirable.
Scheme 1. Sulfenylation methods with the use of arylsulfonyl chlorides as
Traditionally, the construction of a C(sp3)ÀS bond is achieved
by reacting an alkyl halide with a metal thiolate.[3] Later, transi-
tion-metal-catalyzed couplings between aryl halides (or aryl
boronic acids, etc.) and various sulfenylating sources such as
thiols,[4] sulfonyl chlorides,[5] disulfides,[6] sodium sulfinates,[7]
and sulfonyl hydrazides[8] to generate C(sp2)ÀS bond were de-
veloped, and various transition metals such as ruthenium, pal-
ladium, copper, nickel, cobalt, and iron salts have been used as
efficient catalysts to generate thioethers.[9]
the sulfur source.
chlorides as sulfenylating agents. In this paper, we report
a new method to construct CÀS bond by using NH4I as a cata-
lyst to generate thioether flavone derivatives regioselectively
in good to excellent yields without using any oxidants. To the
best of our knowledge, there are no reports on such a -
reaction.
To find suitable reaction conditions for this sulfenylation re-
action between flavones and arylsulfonyl chlorides, flavone 1a
and sulfonyl chloride 2a were used as the representative reac-
tants (Table 1), and different catalysts, oxidants, temperature,
and solvents were screened. First, CuI and FeCl3 were used as
catalysts and tert-butyl hydroperoxide (TBHP, 70 wt% in water)
was employed as the oxidant in CH3CN; both reactions did not
give expected product 3a (Table 1, entries 1 and 2) at 908C in
CH3CN. The use of tetrabutylammonium iodide (TBAI) as a cata-
lyst with TBHP provided less than 5% yield of 3a (Table 1,
entry 3) in CH3CN. Upon using NaI or KI with TBHP, a trace
amount of 3a was produced (Table 1, entries 4 and 5). The I2/
TBHP combination in CH3CN afforded 3a in 60% yield (Table 1,
entry 6), whereas the combination of NH4I/TBHP in CH3CN af-
forded 3a in 65% yield (Table 1, entry 7). The combination of
NH4I/TBHP in DMF at 908C afforded 3a in 70% yield (Table 1,
entry 8). Upon increasing the temperature to 1308C, 3a was
obtained in 79% yield (Table 1, entry 9). Surprisingly, the use of
NH4I without TBHP in DMF also afforded 3a in 81% yield
(Table 1, entry 10). If NH4I was employed as the catalyst in ben-
zene or toluene, 3a was isolated in only 25 or 30% yield
(Table 1, entries 11 and 12). Using THF or dioxane as the sol-
vent generated 3a in 48 or 30% yield, respectively (Table 1, en-
tries 13 and 14). Decreasing the number of equivalents of NH4I
Recently, the transition-metal-catalyzed formation of CÀS
bonds through CÀH bond functionalization was proposed as
an alternative method to convert CÀH bonds directly into CÀS
bonds,[10] but these reactions still suffer from high loadings of
toxic transition-metal catalysts and some additives.
Very recently, metal-free CÀS bond-formation methods have
been successfully developed;[11] among these methods, the use
of arylsulfonyl chlorides as sulfenylating agents was also ach-
ieved (Scheme 1). Zheng and co-workers reported the visible-
light-induced sulfenylation of N-methylindoles with arylsulfonyl
chlorides,[5a] You and co-workers demonstrated CÀS bond for-
mation by directly using arylsulfonyl chlorides as a sulfur
source in the presence of triphenylphosphine,[12a] and Deng
et al. reported iodine-promoted 2-arylsulfanylphenol formation
by using cyclohexanones as the phenol source.[12b] All three re-
ported reactions generate CÀS bonds by using arylsulfonyl
[a] W. Zhao, Prof. A. Zhou
Pharmacy School
Jiangsu University
Xuefu Road 301, Zhenjiang, Jiangsu 212013 (P.R. China)
E-mail: ahz@ujs.edn.cn
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500673.
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Communications
Table 1. Screening for suitable reaction conditions.[a]
Table 2. Sulfenylation of flavones with arylsulfonyl chlorides.[a]
Entry
Catalyst
Oxidant
Solvent
T
[8C]
Yield[b]
[%]
1
2
3
4
5
6
7
8
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
–
–
–
–
–
–
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
90
90
90
90
90
90
90
90
130
130
130
130
130
130
130
130
0
0
5
FeCl3
TBAI
NaI
KI
I2
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I[c]
–
trace
trace
60
65
70
79
81
25
30
48
30
62
0
9
DMF
DMF
10
11
12
13
14
15
16
benzene
toluene
THF
dioxane
DMF
DMF
[a] Reaction conditions: Flavone (0.1 mmol, 1.0 equiv.), sulfonyl chloride
(1.5 equiv.), KI/I2 (1.0 equiv.), NH4I (4.0 equiv.), solvent (0.5 mL), metal cata-
lyst (20 mol%). All reactions were run for 20 h. [b] Yield of isolated prod-
uct based on reactant 1a. [c] NH4I (1.0 equiv.).
from four to one led to the isolation of 3a in 62% yield
(Table 1, entry 15). The reaction did not produce the expected
product (Table 1, entry 16) in the absence of NH4I. After the
above screening, the suitable conditions selected for the cou-
pling of flavone and arylsulfonyl chloride included flavone
(1.0 equiv.), arylsulfonyl chloride (1.5 equiv.), and NH4I
(4.0 equiv.) in DMF as the solvent at 1308C.
After suitable reaction conditions were determined, different
electron-withdrawing and electron-donating flavones were
synthesized on the basis of existing literature,[13] and they were
then treated with various arylsulfonyl chlorides; all sulfenyla-
tion reactions proceeded well and afforded good yields of ArS-
substituted flavone derivatives 3a–p (Table 2) with high regio-
selectivities. On the basis of the chemical shifts displayed in
[a] Reaction conditions: Flavone (1.0 equiv.), sulfonyl chloride (1.5 equiv.),
NH4I (4.0 equiv.), solvent (0.5 mL). All reactions were run for 20 h.
[b] Yields of isolated products 3a–p were based on the reactant flavones.
1
the H NMR and 13C NMR spectra of each ArS-substituted fla-
vone derivative, all substrates were bonded to the more elec-
tron-rich a positions of the flavone ketone functions.
To expand the sulfenylation reaction scope, an alkylsulfonyl
chloride was also tried, and methanesulfonyl chloride was used
as a representative to react with electron-deficient nitro-substi-
tuted flavone and electron-rich methyl-substituted flavone;
both reactions gave good yields of expected products 3q and
3r (Scheme 2).
Scheme 2. Sulfenylation reactions of flavones with methanesulfonyl chloride.
To provide further insight into the regioselectivity of this sul-
fenylation reaction, a-methyl-substituted and b-methyl-substi-
tuted flavones were synthesized and treated with benzenesul-
fonyl chloride (Scheme 3). If the preferred reaction site (a posi-
tion) was blocked by a methyl group, no desired product was
isolated. If the b position of the flavone was bonded to a ÀCH3
group, the sulfenylation reaction still proceeded, but because
of steric factors, the isolated yield was not high (42%). This
result indicates that the regioselectivity of this sulfenylation
reaction is very good.
To further explore the reaction mechanism, 2,2,6,6-tetrame-
thylpiperidin-1-oxyl (TEMPO) and butylated hydroxytoluene
(BHT) were used as radical scavengers in subsequent reactions
(Scheme 4). In the presence of TEMPO or BHT, the reaction pro-
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In summary, we developed a novel and regioselective am-
monium iodide mediated CÀS bond-formation protocol involv-
ing flavones and arylsulfonyl chlorides to generate different
ArS-substituted flavone derivatives in high yields. This method
can also be extended to alkylsulfonyl chlorides. This protocol
enriches current metal-free CÀS bond formation chemistry by
using sulfonyl chlorides as the sulfenylating agents, which
makes it a good choice for the efficient synthesis of thioether
compounds. This method is also suitable for the production of
a library of compounds as a result of its high regioselectivity
and efficiency.
Scheme 3. Control reactions.
Experimental Section
General procedure
Flavone 1a (0.5 mmol, 1.0 equiv.) was added to a dried sealed tube
containing DMF (0.5 mL), and this was followed by the addition of
NH4I (4.0 equiv.) and the sulfonyl chloride (1.5 equiv.). The mixture
was stirred at 1308C. After 20 h, the mixture was cooled to room
temperature, diluted with ethyl acetate, washed with brine, dried
with anhydrous Na2SO4, and concentrated under vacuum. The resi-
due was purified by flash chromatography (silica gel, petroleum
ether/EtOAc=15:1) to give desired product 3a (81%) as a colorless
oil. The same procedure was used to prepare compounds 3b–t.
Scheme 4. Radical trapping experiments.
ceeded well and afforded 3a in good yield, which indicates
that radical intermediates are not involved in either of these
couplings.
Acknowledgements
On the basis of these results, a plausible mechanism is pro-
posed (Scheme 5). Heat splits NH4I into HI and NH3, and then
HI reduces the sulfonyl chloride; after intermediates B, C, and
D and the loss of two H2O molecules, the electrophilic ArSÀCl
species is produced, which then continues to react with fla-
vone 1 to give intermediate E. The loss of a proton from E to
NH3 generates final product 3. The resultant iodine reacts with
the arylsulfonyl chloride to generate ArSÀCl and to release the
IOÀ ion.[12b]
A.Z. acknowledges Jiangsu University for financial support
(1281290006).
Keywords: CÀS bond formation
systems · sulfenylation · sulfur
· flavones · fused-ring
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Published online on September 17, 2015
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