Generation of ArS-substituted flavone derivatives using aryl thiols as sulfenylating agents

Article abstract of DOI:10.1039/c5ra10763f

The regioselective and metal-free sulfenylation of flavones was achieved under aerobic conditions with ammonium iodide salt as an inducer instead of traditional iodine/oxidant combinations. This method enables the generation of various ArS-substituted flavone derivatives in good to excellent yields under environmentally friendly conditions, which significantly enriches current flavone chemistry.

Full text of DOI:10.1039/c5ra10763f

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DOI: 10.1039/C5RA10763F
Journal Name
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Generation of ArS‐substituted Flavone Derivatives Using Aryl
Thiols as Sulfenylating Agents
Wannian Zhao,a Ping Xie,b Zhaogang Bian,a Aihua Zhou,a Haibo Ge,c Ben Niu,a and Yingcai Dinga
Received 00th January 20xx,
Accepted 00th January 20xx
*
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The regioselective and metal‐free sulfenylation of flavones was
achieved under aerobic conditions with ammonium iodide salt as
an inducer instead of traditional iodine/oxidant combinations.
This method enables the generation of various ArS‐substituted
flavone derivatives in good to excellent yields under
environmentally friendly conditions, which significantly enriches
current flavone chemistry.
this significant progress, the development of a new metal‐free
sulfenylation method is still highly desirable.
Herein, we developed a new and regioselective sulfenylation
method in which a clean and colorless ammonium iodide salt was
used as an reaction inducer instead of direct usage of purple iodine.
In this study, air was used as the oxidant instead of pure oxygen and
some oxidants (Scheme 1)12; and cheap aryl thiols were used as
sulfenylating agents. To the best of our knowledge, there are no
such reports to date. In this paper, this ammonium iodide‐induced
sulfenylation method was directly applied to electron‐rich flavones
to generate flavone derivatives which may be potentially valuable in
drug discovery.
The construction of C‐S bond is a very important transformation in
organic synthesis,1 because C‐S bond is widely present in natural
products and drug molecules.2 Therefore, many researchers have
devoted their efforts on developing highly efficient, regioselective,
and environmentally friendly C‐S bond formation methods.3
Traditionally, C(sp3)‐S bond can be constructed easily by the
condensation of an alkyl halide with a metal thiolate.4 Recently,
transition metal catalyzed C(sp2)‐S bond formation were
successfully developed via cross couplings between aryl halides and
various sulfenylating reagents such as thiols (Scheme 1),5 sulfonyl
chlorides,6 disulfides,7 sodium sulfinates,8 and sulfonyl hydrazides.9
However, these processes require the use of prefunctionalized
halides and expensive catalysts.10
Recently, transition metal‐catalyzed C‐S bond formation via
direct C‐H bond functionalization has risen as an efficient
alternative method, which allows direct conversion of C‐H into C‐S
bonds. Although this method is highly efficient and atom‐economic,
these reactions still suffer from the high loading of transition metal
catalysts, additives and harsh reaction conditions sometimes.11
Very recently, metal‐free iodine‐induced sulfenylation method to
construct C(sp2)‐S bond was successfully developed (Scheme 1).12
This method doesn’t need the use of any toxic and transitional
metal catalysts, and proceeded well under environmentally friendly
reaction conditions, generating thioesters in good yields. Despite
Scheme 1 Previously reported sulfenylation methods with arylthiols
a.Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang, Jiangsu 212013,
People’s Republic of China, Email: ahz@ujs.edn.cn.
as sulfenylating agents.
b.Scientific Information Research Institute, Jiangsu University (Library), Xuefu Road
301, Zhenjiang, Jiangsu 212013, People’s Republic of China.
c Department of Chemistry and Chemical Biology, Indiana University Purdue
University Indianapolis, Indianapolis IN 46202 (USA), Email: geh@iupui.edu
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/c000000x/
To find the suitable reaction conditions for the ammonium
iodide‐induced sulfenylation between flavones and aryl thiols,
flavone 1a and thiol 2a were used as the representative reactants.
Different catalysts/inducers, oxidants, and solvents were screened
This journal is © The Royal Society of Chemistry 20xx
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under different reaction temperature (Table 1). First, CuCl2 and NH4I in DMF didn’t produce any product (entry 18). Using H2O2
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DOI: 10.1039/C5RA10763F
FeCl3 were used as catalysts, and TBHP (tert‐butyl hydroperoxide, instead of TBHP as an oxidant in the presence of NH4I afforded 3a in
70 wt % in water) was employed as an oxidant. Both reactions gave a 65% yield (entry 19). While the combination of I2/H2O2 gave a 70%
a less than 5% yield or trace amount of expected product 3a yield of 3a (entry 20). After the above screening, the suitable
o
(entries 1 and 2) at 80 C in CH3CN. Using CuI as a catalyst with conditions selected for the coupling of flavone and aryl thiol are:
TBHP also provided a less than 5% yield of 3a (entry 3) in CH3CN. flavone (1.0 equiv.), thiols (1.2 equiv.), NH4I (2.0 equiv.), DMF is
The combination of KI and TBHP only produced a 20% yield of 3a used as a solvent and temperature: 135oC.
(entry 4). When I2 was employed with TBHP in CH3CN, 45% of 3a
After suitable reaction conditions have been obtained, different
was observed (entry 5). The TBAI/TBHP combination in CH3CN aryl thiols were reacted with different flavones which were
didn’t afford 3a at all (entry 6), while the combination of NH4I/TBHP synthesized based on existing literature13. From Table 2, it can be
in CH3CN afforded a 53% yield of 3a (entry 7). The combination of found that all flavones with electron‐donating functions gave better
I2/TBHP or I2/DTBP afforded 3a in 70% and 65% yields, respectively yields, while flavones with electron‐deficient functions gave a little
(entries 8 and 9). When the reaction temperature was raised to 135 bit lower yields. Based on 1H and 13C‐NMR spectra of all products, it
oC, the combination of NH4I/TBHP in CH3CN gave a 78% yield (entry was found that ‐SAr was regioselectively added to the α‐position of
10). By converting NH4I into I2, the reaction afforded 75% yield of 3a
(entry 11). Using DMF instead of CH3CN afforded 83% yield of 3a Table 2 Ammonium iodide‐mediated sulfenylation reactions using
(entry 12). Surprisingly, when NH4I was used without TBHP, the thiols as sulfenylating agentsa
reaction also gave an 86% yield of 3a (entry 13). Decreasing the __________________________________________________
amount of NH4I from 2.0 to 1.2 equivalents led to 64% yield (entry
14). Using CH3CN or THF as a solvent generated 55% yield or trace
amount of product (entries 15 and 16). When toluene was used as a
solvent, 73% yield of 3a (entry 17) was obtained. No presence of
Table 1 Screening of reaction conditionsa
_____________________________________________________
Yieldb
(%)
Entry
Reactant 1
Product 3
1
85
86
80
82
Entry
Catalyst
/Inducer
CuCl2
FeCl3
CuI
KI
I2
TBAI
NH4I
I2
I2
NH4I
I2
NH4I
NH4I
NH4Ic
NH4I
NH4I
NH4I
‐‐
Reagent Temp.
(oC)
Solvent
Yieldb
(%)
5
trace
<5
20
45
0
53
70
65
78
75
83
86
64
55
trace
73
0
2
3
4
1
2
3
4
5
6
7
8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DCP
DTBP
TBHP
TBHP
TBHP
‐‐
80
80
80
80
80
80
80
80
80
135
135
135
135
135
135
135
135
135
135
135
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
CH3CN
THF
Toluene
DMF
9
10
11
12
13
14
15
16
17
18
19
20
5
6
7
84
81
83
‐‐
‐‐
‐‐
‐‐
‐‐
H2O2
H2O2
NH4I
I2
DMF
DMF
65
70
a Reaction conditions: flavone (1 equiv.), aryl thiol (1.2 equiv.), NH4I
(2.0 equiv.), aqueous TBHP (70 wt % in water, 2.0 equiv.), metal
catalyst (10 mol%), DMF (0.5 mL). b Isolated yields are based on
8
81
c
reactant 1a, the reaction was run for 15 hours with air. NH4I (1.2
equiv.)
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2 | J. Name., 2012, 00, 1‐3
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9
85
83
10
O
O
S
11
12
13
82
79
Br
3k
O
O
NC
Scheme 2 Control reactions and radical trapping experiments.
_____________________________________________________
77
84
82
135 oC, NH4I was split into NH3 and HI, and the resulting HI was
further oxidized by air to generate iodine. Thiophenol was then
reacted with iodine to form electrophilic species ArS‐I, which
reacted further with electron‐rich flavone 1 to give reaction
intermediate A. After the loss of a proton from intermediate A, final
product 3 was obtained.
O
Br
Br
S
S
14
O
O
3n
I
I
NH4I
HI
+
NH3
H2O
HI
I2
HI
+
Ar
S
I
Ar
S
2
H
15
air
4
O
+
O
3o
R
a Reaction conditions: flavone (1.0 equiv.), aryl thiol (1.2 equiv.),
NH4I (2.0 equiv.). b Isolated yields are based on reactant 1a, the
reaction was run for 15 hours.
O
1
I
O
O
O
Ar
S
O
S
S
H
Ar
Ar
_______________________________________________________
R
R
R
O
3
O
NH3
the ketone function of flavones, and no β‐substituted products
were isolated.
A
Scheme 3 Proposed reaction mechanism
To further explore how the substituents on α and β‐position of
flavones influence the regioselective sulfenylation, two methyl‐
substituted flavones were synthesized with methyl function on α
and β‐position of the flavone (see Scheme 2, entries 1 and 2). When
the α‐position reaction site was blocked, no any expected product
was isolated, indicating that the regioselectivity of this sulfenylation
is very good, and the reaction only happened on the α‐position of
flavone. When the methyl group on the β‐position of flavone, a
decreased sulfenylation yield was observed, possibly due to the
steric effects caused by neighbouring methyl function.
_______________________________________________________
Conclusion
In summary, an efficient and regioselective ammonium iodide‐
induced sulfenylation of flavones is herein reported with different
thiophenols as sulfenylating agents, generating various ArS‐
substituted flavone derivatives in good to excellent yields under
metal‐free conditions. This method has improved the current
reported protocol represented by using iodine as a catalyst. This
method enriches current flavone chemistry, making it a highly
valuable and practical approach in pharmaceutical industry.
Investigation on biological activities of flavone derivatives is
currently underway. The method is also quite suitable for
compound library production.
To determine if a radical process is involved in this sulfenylation
protocol, TEMPO (2,2,6,6‐tetramethypiperidine) and BHT (butylated
hydroxytoluene) were used as radical scavengers in the reaction of
producing 3a. In the presence of TEMPO or BHT, 3a was still
produced in good yields (Scheme 2). This fact indicated that radical
intermediate is not involved in the sulfenylation process. Based on
the above results and existing literature,12a,14
a plausible
Acknowledgment
nucleophilic substitution reaction mechanism is proposed below. At
Aihua Zhou acknowledge Jiangsu University for financial support
(1281290006 and PAPD).
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Graphic abstract:
The regioselective and metal-free sulfenylation of flavones was achieved under aerobic conditions with
ammonium iodide as an inducer