The synthesis of 3-sulfenylflavones via FeCl3-promoted regioselective cyclization of alkynyl aryl ketones with N-arylthiobenzamides

Article abstract of DOI:10.1016/j.tet.2016.11.034

A FeCl₃-promoted regioselective cyclization of alkynyl aryl ketones with N-arylthiobenzamides had been developed for the synthesis of 3-sulfenylflavones derivatives. Various alkynyl aryl ketones and N-arylthiobenzamides with a number of functional groups were compatible in this reaction to afford the corresponding 3-sulfenylflavones in moderate to good yields. The mechanism was described in detail.

Full text of DOI:10.1016/j.tet.2016.11.034

Tetrahedron xxx (2016) 1e6
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Tetrahedron
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The synthesis of 3-sulfenylflavones via FeCl -promoted regioselective
3
cyclization of alkynyl aryl ketones with N-arylthiobenzamides
*
Lin-Feng Shi, Xing-Guo Zhang, Xiao-Hong Zhang
College of Chemical and Materials Engineering, Wenzhou University, Wenzhou 325035, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 September 2016
Received in revised form
A FeCl -promoted regioselective cyclization of alkynyl aryl ketones with N-arylthiobenzamides had been
developed for the synthesis of 3-sulfenylflavones derivatives. Various alkynyl aryl ketones and N-
arylthiobenzamides with a number of functional groups were compatible in this reaction to afford the
corresponding 3-sulfenylflavones in moderate to good yields. The mechanism was described in detail.
3
8
November 2016
Accepted 14 November 2016
Available online xxx
©
2016 Elsevier Ltd. All rights reserved.
Keywords:
FeCl -promoted
3
Cyclization
N-arylthiobenzamides
3-sulfenylflavones
1
. Introduction
had shown to be other efficient protocols for the synthesis of fla-
16
vones (eq. (2)). However, to the best of our knowledge, no 3-
sulfenylflavones had been reported so far although the introduc-
tion of sulfur moiety can greatly enhance the biological activity. In
the course of our ongoing efforts directed toward the synthesis of
1
2
Flavones are frequently found in numerous natural products
and are well known for their beneficial effects on human health.
Many flavone derivatives show a wide range of biological activ-
ities and have been already/potentially identified as tankyrase in-
17
3
sulfenylated aromatic cyclics, we wished to report a FeCl -pro-
hibitors,3 aglucosidase inhibitors,
4
gastroprotective agents,
5
moted 6-endo-dig regioselective cyclization of alkynyl aryl ketones
with N-arylthiobenzamides, leading to 3-sulfenylflavones in mod-
erate to good yields under mild conditions (eq. (3)).
6
7
antihypertensive agents, anti-inflammatory drugs, anticancer
agents and so on.
8
These wide applications greatly promoted the development of
several strategies for the construction of flavone derivatives.9 At
early time, Miranda and co-authors developed an esterification,
rearrangement and the subsequent 6-endo-dig ring cyclization of
phenylpropynoic acids with phenols to give flavones as well as the
1
0
11
5
-exo-dig ring by-products. Subsequently, Lewis acid-catalyzed,
12
13
LiOtBu/air-mediated or ultrasonic-assisted intramolecular an-
nulations of 2-hydroxyphenyl carbonyl compounds or their
equivalents1 provided powerful methods for the construction of
flavones (Scheme 1, eq. (1)). For example, Zeni and co-workers
4
3 2
reported a FeCl /(PhSe) -promoted cyclization of alkynyl aryl ke-
15
tones for the synthesis of 3-organoselenyl flavones. Recently, the
direct palladium-catalyzed carbonylative annulations of o-halo-
genphenols (or o-halogenphenol acetates) with terminal acetylenes
Scheme 1. Construction of flavones.
*
Corresponding author.
E-mail address: kamenzxh@wzu.edu.cn (X.-H. Zhang).
http://dx.doi.org/10.1016/j.tet.2016.11.034
040-4020/© 2016 Elsevier Ltd. All rights reserved.
0
3
Please cite this article in press as: Shi L-F, et al., The synthesis of 3-sulfenylflavones via FeCl -promoted regioselective cyclization of alkynyl aryl
ketones with N-arylthiobenzamides, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.034

2
L.-F. Shi et al. / Tetrahedron xxx (2016) 1e6
2
. Results and discussion
detail in the mechanism part. When the reaction temperature was
enhanced to 50 C or the reaction time was shortened to 15 h, the
ꢀ
The reaction between 1-(2-methoxyphenyl)-3-phenylprop-2-
yield was reduced to 80% or 78%, respectively (entries 22e23). It is
worth noting that only 35% and 45% yield were obtained when
diphenyl disulfide or N-phenylthiosuccimimide was used as thio-
yn-1-one (1a) and N-(phenylthio)benzamide (2a) was chosen as a
model reaction to optimize the reaction conditions, and the results
were listed in Table 1. Initially, the reaction of substrate 1a with N-
2
lation reagents (entries 24e26). The reaction of PhSSPh with I was
(
phenylthio)benzamide 2a and 1.0 equiv FeCl
3
was performed in
also evaluated, only giving compound 3 in 10% yield (entry 25).
These results suggested that N-(phenylthio) benzamide 2a with
NeS bond was greatly superior to diphenyl disulfide and N-phe-
nylthiosuccimimide in view of the 3-sulfenylflavone yields.
With the optimal conditions in hand, we next investigated the
substrate scope of various alkynyl 2-methoxyaryl ketones and N-
arylthiobenzamides (Table 2). Initially, a wide variety of N-
arylthiobenzamides were tested, and the results demonstrated
that N-arylthiobenzamides bearing both the electron-donating
and electron-withdrawing groups on arylthio moiety underwent
the cyclization reaction smoothly. In general, N-arylth-
iobenzamides with electron-rich groups gave the products in
higher yields than those bearing electron-deficient groups. Methyl
and methoxyl substituted benzamides afforded products 4 and 5
in 80% and 81% yield, respectively. Fluoride product 6 was isolated
in 63% yield. o, m, p-(Chlorophenylthio) benzamides gave the
corresponding products 7e9 in 54e80% yields while 3,5-dichloro
product 10 was obtained in 42% yield. Substrate bearing a strong
electron-withdrawing nitro group afforded product 11 only in 31%
yield.
CH Cl at room temperature, giving the desired 3-sulfenylflavone 3
2
2
in 40% yield (entry 1). When the amount of N-(phenylthio) ben-
zamide 2a was increased to 1.2 or 1.5 equiv, an obvious yield
improvement can be observed (entries 2, 3). It was noted that the
reagents 1a and 2a were kept intact in the absence of FeCl
). The findings promoted us to explore the FeCl amount and the
results showed that 2.0 equiv FeCl was enough to give a good yield
entries 5e7). Moreover, various promoters, such as CuBr , AlCl
CuCl , Cu(OAc) , ZnCl and FeBr were investigated, but all were
less effective than FeCl (entries 8e13). Subsequently, we further
investigated the reaction conditions by examining different sol-
vents, including DCE, THF, DMSO, CHCl , CCl , DMF, CH CN and
3
(entry
4
3
3
(
2
3
,
2
2
2
3
3
3
4
3
dioxane (entries 14e21). The results showed that the reaction can
undergo smoothly in some solvents bearing chlorine atom, such as
CH
was yielded possibly owing to the poor solubility of the reaction
4
mixture in CCl (entry 18). The solvent effect will be discussed in
2 2 3
Cl , DCE and CHCl . Meanwhile, trace of targeted molecule 3
During the examination of substitution effect on alkynyl (R
moiety), the results showed that the cyclization reaction seemed to
be sensitive to the electronic effects of R group. For example,
alkynyl 2-methoxyaryl ketones with methyl, ethyl, n-propyl, n-
butyl and methoxyl moieties gave higher yields than their F, Cl, Br,
Table 1
Screening conditions.a
2 3
NO and CF equivalents. Methyl, ethyl and n-propyl substituted 3-
(phenylthio) flavones 12e15 were isolated in 85e87% yields except
the lower yield of methoxyl derivative 17. The alkynyl 2-
methoxyaryl ketone with bulky n-butyl was also converted
smoothly to product 16 in 87% yield. Fluoride, chloride and bromide
products 18e23 were isolated in 41e81% yields under the optimal
conditions. To determine whether the reaction proceeded via
whether 6-endo-dig or 5-exo-dig cyclization process, 3-(4-
Yieldb
Entry
Additive (equiv.)
2a (equiv.)
Solvent
1
2
3
4
5
6
7
8
9
FeCl
FeCl
FeCl
e
3
3
3
(1.0)
(1.0)
(1.0)
1.0
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
e
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
40%
46%
47%
NR
69%
84%
85%
15%
55%
NR
chlorophenyl)-1-(2-methoxyphenyl)prop-2-yn-1-one
1b was
FeCl
FeCl
FeCl
3
3
3
(1.5)
(2.0)
(2.5)
(2.0)
(2.0)
(2.0)
reacted with N-(phenylthio) benzamide 2a under the standard
conditions. The regioselective 6-endo-dig cyclization product 21
was isolated in 65% while the 5-exo-dig ring product was not
observed. Moreover, the structure of product 21 was confirmed by
X-ray crystallography (Scheme 2 and Fig. 1). However, alkynyl 2-
CuBr
AlCl
CuCl
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2
Cu(OAc)
ZnCl
FeBr
2
(2.0)
NR
2 3
methoxyaryl ketones bearing NO and CF underwent the cycliza-
2
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
15%
75%
80%
NR
tion reaction, giving their corresponding products 24e25 in 42%
and 40% yields, respectively. It was notable that an acceptable 51%
yield of 26 could be obtained when alkynyl was an aliphatic 1-
hexyne.
3
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
3
DCE
THF
3
3
3
3
3
3
3
3
3
3
3
3
DMSO
CHCl
CCl
DMF
CH CN
dioxane
NR
3
79%
trace
NR
4
3
NR
NR
80%
c
CH
CH
CH
CH
CH
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
d
78%
e
35
10
45
f
e
g
e
a
3
Reaction conditions: 1a (0.2 mmol), 2a, FeCl in solvent (2 mL) at room tem-
perature for 20 h.
b
Isolated yields.
At 50 C.
c
d
e
f
ꢀ
1
0
0
0
5 h.
.24 mmol PhSSPh.
.24 mmol PhSSPh with 0.24 mmol I
.24 mmol N-phenylthiosuccimimide.
2
.
Scheme 2. Regioselective Cyclization.
g
Please cite this article in press as: Shi L-F, et al., The synthesis of 3-sulfenylflavones via FeCl
3
-promoted regioselective cyclization of alkynyl aryl
ketones with N-arylthiobenzamides, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.034

L.-F. Shi et al. / Tetrahedron xxx (2016) 1e6
3
Table 2
a,b
Scope of the cyclization reaction.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), FeCl
Isolated yields.
3
(2.0 equiv) in CH
Cl
2 2
(2 mL) at room temperature for 20 h.
b
To understand the mechanism of this reaction, the substrate 1a
with N-(phenylthio) benzamide 2a was performed in FeCl /DMF
using 0.3 equiv HCl and 34% yield of product 3 was isolated (eq. (4),
from the reaction of PhCH
2
Cl with N-(phenylthio) benzamide 2a
3
(see supporting information). Based on the experimental results
18
and previous reports, a possible mechanism for the cyclization
Scheme 3), whereas no reaction can be observed when using 1.0
was proposed as outlined in Scheme 4. Initially, the NeS bond
equiv HCl in the absence of FeCl
3
or in the presence of Cu(OAc)
or
2
cleavage of N-(phenylthio) benzamide with FeCl
3
generated the
þ
ꢁ
(
eqs. (5) and (6), Scheme 3). The results demonstrated that FeCl
3
PhS cation and the anion [FeCl (NHCOPh)] , which undergoes
3
ꢁ
Cl played an important role in the electrophilic cyclization reac-
protonation to release benzamide detected by GC-MS. Subse-
quently, the selectively electrophilic addition of PhS cation to the
þ
tion. Moreover, the reaction of substrate 1c and N-(phenylthio)
benzamide 2a was selected to show the role of FeCl
the left of alkoxy group under the optimal reaction conditions. It
was found that the by-product PhCH Cl was observed by GC-MS
accompanied with a small amount of PhCH SPh, which generated
3
/solvent and
triple bond of substrate 1c afforded intermediate A. Then the ox-
ygen atom attacked the cyclo-sulfur cation to provide the targeted
ꢁ
2
product 3 associated with the left of benzyl group by Cl yielded
19
2
3 2 2
from the interaction of FeCl and solvent CH Cl .
3
Please cite this article in press as: Shi L-F, et al., The synthesis of 3-sulfenylflavones via FeCl -promoted regioselective cyclization of alkynyl aryl
ketones with N-arylthiobenzamides, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.034

4
L.-F. Shi et al. / Tetrahedron xxx (2016) 1e6
room temperature. Chemical shifts are given in
d relative to TMS,
and the coupling constants J are given in hertz. High-resolution
mass spectra were recorded on an ESI-Q-TOF mass spectrometer.
Melting point data are uncorrected. Column chromatography was
performed using EM silica gel 60 (300e400 mesh).
4.2. General procedure for the synthesis of 3-sulfenylflavones
derivative 3-26
To a flame-dried Schlenk tube with a magnetic stirring bar was
charged with 1a (0.2 mmol), 2a (0.24 mmol), FeCl
3
(66 mg,
0
.4 mmol) in CH Cl (2 mL) under air atmosphere. The reaction
2
2
mixture was stirred at room temperature until complete con-
sumption of starting material as detected by TLC or GC-MS analysis.
After the reaction was finished, brine and ethyl acetate were added
to the reaction mixture. The mixture was extracted with ethyl ac-
etate three times, and the combined organic layer was dried over
Fig. 1. X-ray structure of compound 21.
4
MgSO . After removal of the solvent under reduced pressure, the
residue was purified by silica-gel column chromatography to give
the products 3e26.
4
4
.3. Characterization data
.3.1. 2-phenyl-3-(phenylthio)-4H-chromen-4-one (3)
Yellow solid (55.4 mg, 84% yield), m.p. 129e131 C; 1H NMR
ꢀ
(
7
500 MHz, CDCl
3
)
d
8.26 (d, J ¼ 7.0 Hz, 1H), 7.78 (d, J ¼ 7.5 Hz, 2H),
.73 (t, J ¼ 7.0 Hz, 1H), 7.54e7.51 (m, 2H), 7.49e7.44 (m, 3H), 7.21 (d,
1
3
J ¼ 4.5 Hz, 4H), 7.14e7.11 (m, 1H); C NMR (125 MHz, CDCl
3
)
d
176.0, 168.8, 156.0, 136.3, 134.3, 133.2, 131.2, 129.3, 129.1, 128.3,
1
C
27.3, 126.8, 126.0, 125.9, 122.9, 118.1, 115.3; HRMS (ESI) Calcd for
þ
þ
21
H
15
O
2
S
([MþH] ) 331.0787, Found: 331.0779.
4
.3.2. 2-phenyl-3-(p-tolylthio)-4H-chromen-4-one (4)
Yellow solid (55.1 mg, 80% yield), m.p. 104e106 C; 1H NMR
500 MHz, CDCl
8.26 (d, J ¼ 8.0 Hz, 1H), 7.81e7.79 (m, 2H), 7.70
t, J ¼ 8.5 Hz, 1H), 7.54e7.51 (m, 2H), 7.49e7.46 (m, 2H), 7.43 (t,
ꢀ
Scheme 3. Control Experiments.
(
(
3
) d
J ¼ 8.0 Hz,1H), 7.15 (d, J ¼ 8.5 Hz, 2H), 7.03 (d, J ¼ 8.0 Hz, 2H), 2.27 (s,
13
3
3
H); C NMR (125 MHz, CDCl ) d 175.9, 168.4, 155.9, 135.9, 134.1,
1
33.1, 132.5,131.0,129.8,129.3,128.1, 127.8, 126.6,125.7, 122.9,118.0,
þ
þ
115.8, 21.0; HRMS (ESI) Calcd for C21
H
17
O
2
S
([MþH] ) 345.0944,
Found: 345.0944.
4
.3.3. 3-((4-methoxyphenyl)thio)-2-phenyl-4H-chromen-4-one (5)
ꢀ
1
Yellow soild (58.3 mg, 81% yield), m.p. 117e119 C; H NMR
500 MHz, CDCl
8.24 (d, J ¼ 8.0 Hz, 1H), 7.78 (d, J ¼ 7.5 Hz, 2H),
.69 (t, J ¼ 7.5 Hz, 1H), 7.55e7.48 (m, 4H), 7.42 (t, J ¼ 7.5 Hz, 1H), 7.21
Scheme 4. Possible Mechanism.
(
7
3
) d
3
. Conclusions
13
(
(
d, J ¼ 8.5 Hz, 2H), 6.74 (d, J ¼ 8.5 Hz, 2H), 3.73 (s, 3H); C NMR
125 MHz, CDCl 176.2, 168.1, 158.8, 156.0, 134.1, 133.4, 131.1, 131.
, 129.5, 128.2, 126.7, 126.6, 125.7, 123.1, 118.1, 117.2, 114.7, 55.4;
3
) d
In conclusion, we have developed an effective protocol for the
synthesis of 3-sulfenylflavones via FeCl -promoted regioselective
0
3
þ
þ
HRMS (ESI) Calcd for C22
3
H
16
O
3
S
([MþNa] ) 383.0712, Found:
cyclization. A variety of alkynyl aryl ketones bearing 2-methoxy
groups and N-arylthiobenzamides underwent the reaction suc-
cessfully to give the corresponding 3-sulfenylflavones in moderate
to good yields. The present method would serve as a good route for
the synthesis of 3-sulfenylflavone derivatives. Moreover, the
mechanism was described in detail.
83.0725.
4
.3.4. 3-((2-fluorophenyl)thio)-2-phenyl-4H-chromen-4-one (6)
ꢀ
1
Yellow soild (43.9 mg, 63% yield), m.p. 120e121 C; H NMR
500 MHz, CDCl
8.24 (d, J ¼ 8.0 Hz, 1H), 7.78 (d, J ¼ 7.5 Hz, 2H),
.73e7.69 (m, 1H), 7.54e7.51 (m, 2H), 7.49e7.42 (m, 3H), 7.17 (t,
(
7
3
) d
13
J ¼ 7.5 Hz, 1H), 7.13e7.09 (m, 1H), 7.02e6.93 (m, 2H); C NMR
4
. Experimental section
(125 MHz, CDCl
3
) d
175.7, 168.3, 160.6 (d, JC-F ¼ 243.8 Hz), 155.9,
1
34.3, 133.0, 131.2, 129.8, 129.3, 128.2, 127.8 (d, JC-F ¼ 7.5 Hz), 126.6,
4.1. General
125.8, 124.5 (d, JC-F ¼ 3.8 Hz), 123.0 (d, JC-F ¼ 16.3 Hz), 122.7, 118.1,
þ
1
15.7 (d, JC-F ¼ 21.3 Hz), 114.1; HRMS (ESI) Calcd for C21
2
H13FO S
þ
Chemicals were either purchased or purified by standard tech-
([MþNa] ) 371.0512, Found: 371.0525.
1
13
niques. H NMR and C NMR spectra were measured on a 500 MHz
1
13
spectrometer ( H at 500 MHz, C at 125 MHz), using CDCl
3
as the
4.3.5. 3-((2-chlorophenyl)thio)-2-phenyl-4H-chromen-4-one (7)
ꢀ
1
solvent with tetramethylsilane (TMS) as an internal standard at
Yellow soild (39.2 mg, 54% yield), m.p. 163e164 C; H NMR
Please cite this article in press as: Shi L-F, et al., The synthesis of 3-sulfenylflavones via FeCl
3
-promoted regioselective cyclization of alkynyl aryl
ketones with N-arylthiobenzamides, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.034

L.-F. Shi et al. / Tetrahedron xxx (2016) 1e6
5
(
7
7
1
500 MHz, CDCl
.56e7.51 (m, 2H), 7.49e7.45 (m, 3H), 7.32 (d, J ¼ 8.0 Hz, 1H),
.11e7.02 (m, 3H); 13C NMR (125 MHz, CDCl
175.6, 169.2, 156.0,
35.5, 134.4, 132.9, 131.9, 131.4, 129.8, 129.2, 128.3, 127.3, 127.1,
3
)
d
8.26 (d, J ¼ 8.0 Hz, 1H), 7.76e7.73 (m, 3H),
(d, J ¼ 8.0 Hz, 1H), 7.74e7.70 (m, 3H), 7.52 (d, J ¼ 8.0 Hz, 1H), 7.44 (t,
J ¼ 7.5 Hz, 1H), 7.30 (d, J ¼ 8.0 Hz, 2H), 7.22e7.20 (m, 4H), 7.14e7.10
13
3
)
d
(m, 1H), 2.73 (q, J ¼ 7.5 Hz, 2H), 1.28 (t, J ¼ 7.5 Hz, 3H); C NMR
3
(125 MHz, CDCl ) d 176.0, 169.0, 156.0, 147.9, 136.4, 134.2, 130.5,
1
C
26.8, 126.5, 126.0, 122.7, 118.2, 113.9; HRMS (ESI) Calcd for
129.4, 129.1, 127.8, 127.2, 126.8, 125.8, 125.7, 122.9, 118.1, 114.7, 29.0,
þ
þ
þ
þ
21
H13ClO
2
S
([MþNa] ) 387.0217, Found: 387.0232.
15.3; HRMS (ESI) Calcd for C23
59.1107.
19
H O
2
S
([MþH] ) 359.1100, Found:
3
4
.3.6. 3-((3-chlorophenyl)thio)-2-phenyl-4H-chromen-4-one (8)
ꢀ
1
Yellow soild (54.0 mg, 74% yield), m.p. 143e145 C; H NMR
500 MHz, CDCl
8.26 (dd, J ¼ 8.0, 1.5 Hz, 1H), 7.76e7.73 (m, 3H),
.56e7.53 (m, 2H), 7.50e7.46 (m, 3H), 7.16e7.13 (m, 2H), 7.10e7.08
m, 2H); 13C NMR (125 MHz, CDCl
175.8, 169.1, 156.0, 138.4,
34.9, 134.4, 132.9, 131.4, 130.1, 129.3, 128.4, 126.8, 126.2, 126.0,
4.3.13. 3-(phenylthio)-2-(4-propylphenyl)-4H-chromen-4-one (15)
1
(
7
(
1
3
)
d
3
Yellow oil (63.2 mg, 85% yield); H NMR (500 MHz, CDCl ) d 8.26
(d, J ¼ 8.0 Hz, 1H), 7.74 (d, J ¼ 8.0 Hz, 2H), 7.70 (t, J ¼ 7.0 Hz, 1H), 7.52
3
) d
(d, J ¼ 8.5 Hz, 1H), 7.43 (t, J ¼ 7.5 Hz, 1H), 7.28 (d, J ¼ 8.5 Hz, 2H),
7.25e7.20 (m, 4H), 7.12 (m,1H), 2.66 (t, J ¼ 7.5 Hz, 2H),1.75e1.65 (m,
þ
13
125.3, 122.9, 118.2, 114.5; HRMS (ESI) Calcd for C21
H13ClO
2
S
2H), 0.98 (t, J ¼ 8.0 Hz, 3H); C NMR (125 MHz, CDCl
3
) d 175.9,
þ
(
[MþNa] ) 387.0217, Found: 387.0235.
168.8, 155.9, 146.3, 136.4, 134.1, 130.4, 129.3, 129.0, 128.2, 127.2,
1
26.6, 125.8, 125.6, 122.8, 118.0, 114.7, 38.0, 24.2, 13.9; HRMS (ESI)
þ
þ
4
.3.7. 3-((4-chlorophenyl)thio)-2-phenyl-4H-chromen-4-one (9)
Calcd for C24
H
21
O
2
S
([MþH] ) 373.1257, Found: 373.1265.
ꢀ
1
Yellow soild (58.2 mg, 80% yield), m.p. 161e162 C; H NMR
500 MHz, CDCl
8.25 (d, J ¼ 7.0 Hz, 1H), 7.76e7.71 (m, 3H),
.54e7.52 (m, 2H), 7.50e7.46 (m, 3H), 7.19e7.12 (m, 4H); C NMR
125 MHz, CDCl 175.8, 168.9, 156.0, 134.8, 134.4, 133.0, 132.0,
(
3
)
d
4.3.14. 2-(4-butylphenyl)-3-(phenylthio)-4H-chromen-4-one (16)
13
ꢀ
1
7
Yellow soild (67.2 mg, 87% yield), m.p. 84e85 C; H NMR
(500 MHz, CDCl
(
3
)
d
3
)
d
8.26 (d, J ¼ 8.0 Hz, 1H), 7.76e7.67 (m, 3H), 7.52
1
31.3, 129.3, 129.2, 128.9, 128.3, 126.7, 126.0, 122.9, 118.2, 115.1;
(d, J ¼ 8.0 Hz, 1H), 7.43 (t, J ¼ 8.0 Hz, 1H), 7.28 (d, J ¼ 8.5 Hz, 2H),
7.25e7.19 (m, 4H), 7.14e7.10 (m, 1H), 2.68 (t, J ¼ 7.5 Hz, 2H),
þ
þ
HRMS (ESI) Calcd for C21
H13ClO
2
S
([MþNa] ) 387.0217, Found:
1
3
3
87.0236.
1.68e1.62 (m, 2H), 1.44e1.33 (m, 2H), 0.96 (t, J ¼ 7.4 Hz, 3H);
C
3
NMR (125 MHz, CDCl ) d 175.9, 168.9, 155.9, 146.6, 136.4, 134.1,
4
.3.8. 3-((3,5-dichlorophenyl)thio)-2-phenyl-4H-chromen-4-one
130.4, 129.3, 129.0, 128.2, 127.2, 126.7, 125.8, 125.7, 122.8, 118.0,
þ
(
10)
Yellow soild (33.4 mg, 42% yield), m.p. 116e117 C; 1H NMR
500 MHz, CDCl
8.26 (dd, J ¼ 8.0, 1.5 Hz, 1H), 7.78e7.73 (m, 3H),
.57e7.54 (m, 2H), 7.51e7.47 (m, 3H), 7.10 (t, J ¼ 1.8 Hz, 1H), 7.04 (d,
114.7, 35.7, 33.3, 22.4, 14.0; HRMS (ESI) Calcd for C25
([MþH] ) 387.1413, Found: 387.1421.
23
H O
2
S
ꢀ
þ
(
7
3
) d
4.3.15. 2-(4-methoxyphenyl)-3-(phenylthio)-4H-chromen-4-one
13
J ¼ 1.8 Hz, 2H); C NMR (125 MHz, CDCl
3
)
d
175.5, 169.4, 156.0,
(17)
1
40.1, 135.4, 134.6, 132.7, 131.6, 129.2, 128.4, 126.8, 126.2, 124.9,
Yellow soild (48.3 mg, 67% yield), m.p. 99e100 C; 1H NMR
ꢀ
þ
þ
122.8, 118.3, 113.6; HRMS (ESI) Calcd for C21
H12Cl
2
O
2
S
([MþNa] )
(500 MHz, CDCl
7.71 (t, J ¼ 7.5 Hz, 1H), 7.52 (d, J ¼ 8.5 Hz, 1H), 7.43 (d, J ¼ 7.5 Hz, 1H),
.21 (d, J ¼ 4.5 Hz, 4H), 7.13e7.10 (m, 1H), 6.97 (d, J ¼ 8.5 Hz, 2H),
3
)
d
8.24 (d, J ¼ 7.5 Hz, 1H), 7.80 (d, J ¼ 7.5 Hz, 2H),
4
20.9827, Found: 420.9834.
7
13
4
.3.9. 3-((3-nitrophenyl)thio)-2-phenyl-4H-chromen-4-one (11)
3
3.87 (s, 3H); C NMR (125 MHz, CDCl ) d 176.1, 168.6, 162.0, 155.9,
ꢀ
1
Yellow soild (23.3 mg, 31% yield), m.p. 114e115 C; H NMR
500 MHz, CDCl
8.24 (d, J ¼ 8.0 Hz, 1H), 8.00e7.94 (m, 2H),
.78e7.75 (m, 3H), 7.58e7.54 (m, 3H), 7.52e7.47 (m, 3H), 7.38 (t,
136.5,134.1,131.3,129.1,127.0,126.8,125.8,125.7,125.3,122.9,118.0,
þ
þ
(
7
3
)
d
114.0, 113.6, 55.6; HRMS (ESI) Calcd for C22
383.0712, Found: 383.0726.
H
16
O
3
S
([MþNa] )
13
J ¼ 8.0 Hz, 1H); C NMR (125 MHz, CDCl
3
) d 175.5, 169.4, 156.0,
148.7, 139.1, 134.7, 132.8, 132.7, 131.6, 129.8, 129.2, 128.5, 126.7,
4.3.16. 2-(4-fluorophenyl)-3-(phenylthio)-4H-chromen-4-one (18)
ꢀ
1
126.2, 122.7, 121.5, 120.8, 118.3, 113.7; HRMS (ESI) Calcd for
Yellow soild (56.5 mg, 81% yield), m.p. 123e124 C; H NMR
(500 MHz, CDCl
8.26 (d, J ¼ 8.0 Hz, 1H), 7.84e7.77 (m, 2H), 7.73
t, J ¼ 8.0 Hz, 1H), 7.52 (d, J ¼ 8.0 Hz, 1H), 7.46 (t, J ¼ 8.0 Hz, 1H),
þ
þ
C
21
H13NO
4
S
([MþNa] ) 398.0457, Found: 398.0455.
3
) d
(
1
3
4
.3.10. 3-(phenylthio)-2-(p-tolyl)-4H-chromen-4-one (12)
7.24e7.18 (m, 4H), 7.18e7.09 (m, 3H); C NMR (125 MHz, CDCl
175.9, 167.7, 164.3 (d, JC-F ¼ 251.2 Hz), 155.9, 136.1, 134.3, 131.8 (d,
C-F ¼ 8.8 Hz), 129.24 (d, JC-F ¼ 2.5 Hz), 129.20, 127.3, 126.8, 126.1,
3
)
Yellow soild (58.5 mg, 85% yield), m.p. 118e119 C; 1H NMR
ꢀ
d
(
500 MHz, CDCl
3
)
d
8.26 (d, J ¼ 8.0 Hz,1H), 7.72e7.70 (m, 3H), 7.52 (d,
J
J ¼ 7.5 Hz, 1H), 7.44 (t, J ¼ 7.0 Hz, 1H), 7.28 (d, J ¼ 7.0 Hz, 2H),
125.9, 122.9, 118.1, 115.5 (d, JC-F ¼ 22.5 Hz), 115.3; HRMS (ESI) Calcd
13
þ
þ
7
(
1
.24e7.20 (m, 4H), 7.14e7.10 (m, 1H), 2.43 (s, 3H); C NMR
125 MHz, CDCl 176.0,169.0, 156.0, 141.7, 136.4, 134.1, 130.3, 129.3,
29.0, 128.9, 127.2, 126.7, 125.9, 125.7, 122.9, 118.1, 114.7, 21.7; HRMS
for C21
H13FO
2
S
([MþNa] ) 371.0512, Found: 371.0528.
3
) d
4.3.17. 2-(2-fluorophenyl)-3-(phenylthio)-4H-chromen-4-one (19)
þ
þ
ꢀ
1
(
ESI) Calcd for C21
17 2
H O S
([MþH] ) 345.0944, Found: 345.0947.
Yellow soild (43.8 mg, 63% yield), m.p. 107e108 C; H NMR
500 MHz, CDCl
8.29 (d, J ¼ 8.0 Hz, 1H), 7.74 (t, J ¼ 8.0 Hz, 1H),
7.56e7.51 (m, 3H), 7.48 (t, J ¼ 7.5 Hz, 1H), 7.28 (d, J ¼ 7.5 Hz, 1H),
(
3
) d
4
.3.11. 3-(phenylthio)-2-(m-tolyl)-4H-chromen-4-one (13)
Yellow soild (59.9 mg, 87% yield), m.p. 126e127 C; 1H NMR
ꢀ
7.25e7.20 (m, 5H), 7.14 (t, J ¼ 6.5 Hz,1H); C NMR (125 MHz, CDCl
175.4, 164.3, 159.7 (d, JC-F ¼ 250.0 Hz), 156.2, 135.4, 134.3, 132.7 (d,
C-F ¼ 8.8 Hz), 130.7, 128.9, 128.3, 126.7, 126.3, 125.9, 124.1 (d, JC-
13
)
3
(
500 MHz, CDCl
3
)
d
8.14 (d, J ¼ 8.0 Hz, 1H), 7.57 (t, J ¼ 8.0 Hz, 1H),
d
7
.45 (d, J ¼ 8.5 Hz, 2H), 7.40 (d, J ¼ 8.5 Hz, 1H), 7.31 (t, J ¼ 7.5 Hz,1H),
J
7.25e7.18 (m, 2H), 7.14e7.06 (m, 4H), 7.01e6.98 (m, 1H), 2.28 (s,
F
¼ 3.75 Hz), 123.1, 121.6 (d, JC-F ¼ 15.0 Hz), 118.6, 118.2, 116.2 (d, JC-
13
þ
þ
3
H); C NMR (125 MHz, CDCl
3
)
d
175.9, 169.0, 155.9, 137.9, 136.4,
F
¼ 20.0 Hz); HRMS (ESI) Calcd for C21
H13FO
2
S
([MþNa] )
134.1, 133.0, 131.8, 129.7, 128.9, 128.0, 127.4, 126.6, 126.4, 125.8,
371.0512, Found: 371.0527.
þ
125.7, 122.8, 118.0, 115.2, 21.4; HRMS (ESI) Calcd for C21
H
17
O
2
S
þ
(
[MþH] ) 345.0944, Found: 345.0949.
4.3.18. 2-(3-fluorophenyl)-3-(phenylthio)-4H-chromen-4-one (20)
ꢀ
1
Yellow soild (28.5 mg, 41% yield), m.p. 129e130 C; H NMR
(500 MHz, CDCl
8.26 (d, J ¼ 7.0 Hz, 1H), 7.73 (t, J ¼ 7.5 Hz, 1H),
7.58 (d, J ¼ 8.0 Hz, 1H), 7.53 (d, J ¼ 8.5 Hz, 1H), 7.50e7.41 (m, 3H),
4
.3.12. 2-(4-ethylphenyl)-3-(phenylthio)-4H-chromen-4-one (14)
3
) d
1
3
Yellow oil (60.9 mg, 85% yield); H NMR (500 MHz, CDCl ) d 8.25
3
Please cite this article in press as: Shi L-F, et al., The synthesis of 3-sulfenylflavones via FeCl -promoted regioselective cyclization of alkynyl aryl
ketones with N-arylthiobenzamides, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.034

6
L.-F. Shi et al. / Tetrahedron xxx (2016) 1e6
7
.24e7.21 (m, 5H), 7.16e7.11 (m, 1H); 13C NMR (125 MHz, CDCl
3
)
(d, J ¼ 8.0 Hz,1H), 7.67 (t, J ¼ 8.0 Hz, 1H), 7.46 (d, J ¼ 8.5 Hz, 1H), 7.40
(t, J ¼ 7.5 Hz,1H), 7.26e7.19 (m, 4H), 7.13e7.10 (t, J ¼ 6.6 Hz,1H), 3.10
(t, J ¼ 7.5 Hz, 2H), 1.77e1.71 (m, 2H), 1.46e1.39 (m, 2H), 0.94 (t,
d
175.8,167.0 (d, JC-F ¼ 2.5 Hz),162.2 (d, JC-F ¼ 246.3 Hz),155.9,135.9,
34.9 (d, JC-F ¼ 7.5 Hz), 134.4, 130.0 (d, JC-F ¼ 7.5 Hz), 129.2, 127.6,
26.8, 126.2, 126.0, 125.3 (d, JC-F ¼ 3.8 Hz), 122.8, 118.13 (d, JC-
1
1
13
J ¼ 7.5 Hz, 3H); C NMR (125 MHz, CDCl
3
) d 175.4, 174.9, 155.8,
F
¼ 21.0 Hz), 118.12, 116.5 (d, JC-F ¼ 23.8 Hz), 116.0; HRMS (ESI) Calcd
136.2, 133.9, 129.0, 127.5, 126.8, 126.0, 125.6, 123.1, 117.8, 115.1, 33.9,
þ
þ
þ
þ
for C21
H13FO
2
S
([MþNa] ) 371.0512, Found: 371.0526.
29.8, 22.6, 13.8; HRMS (ESI) Calcd for C19
11.1100, Found: 311.1111.
H
19
O
2
S
([M þ H] )
3
4
.3.19. 2-(4-chlorophenyl)-3-(phenylthio)-4H-chromen-4-one (21)
ꢀ
1
Yellow soild (47.2 mg, 65% yield), m.p. 136e137 C; H NMR
500 MHz, CDCl
8.25 (d, J ¼ 8.0 Hz, 1H), 7.72 (t, J ¼ 8.5 Hz, 3H),
.52 (d, J ¼ 8.5 Hz, 1H), 7.45 (t, J ¼ 8.5 Hz, 3H), 7.23e7.19 (m, 4H),
Acknowledgements
We thank the National Natural Science Foundation of China (No.
(
3
) d
7
7
.14e7.12 (m, 1H); 1 C NMR (125 MHz, CDCl
3
3
) d 175.8, 167.5, 155.9,
2
1302144 and 21272177) for financial support.
1
37.4, 136.0, 134.4, 131.5, 130.8, 129.2, 128.6, 127.4, 126.8, 126.2,
þ
126.0, 122.9, 118.1, 115.5; HRMS (ESI) Calcd for C21
H13ClO
2
S
þ
(
[MþNa] ) 387.0217, Found: 387.0234.
Appendix A. Supplementary data
4
.3.20. 2-(3-chlorophenyl)-3-(phenylthio)-4H-chromen-4-one (22)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2016.11.034.
ꢀ
1
Yellow soild (45.1 mg, 62% yield), m.p. 119e120 C; H NMR
500 MHz, CDCl
8.25 (d, J ¼ 8.0 Hz, 1H), 7.78e7.69 (m, 2H), 7.66
d, J ¼ 7.5 Hz, 1H), 7.52 (d, J ¼ 8.5 Hz, 1H), 7.49e7.44 (m, 2H), 7.39 (t,
(
(
3
) d
13
References
J ¼ 8.0 Hz, 1H), 7.22e7.19 (m, 4H), 7.15e7.11 (m, 1H); C NMR
125 MHz, CDCl 175.8, 166.9, 155.9, 135.9, 134.7, 134.4, 134.3,
31.1, 129.5, 129.2, 129.1, 127.7, 127.6, 126.8, 126.2, 126.0, 122.8, 118.1,
(
1
3
) d
1
. (a) Sritularak B, Likhitwitayawuid K, Conrad J, et al. J Nat Prod. 2002;65:589;
b) Wang Y-H, Hou A-J, Chen L, et al. J Nat Prod. 2004;67:757;
(c) Lin C-N, Kuo S-H, Chung M-I. J Nat Prod. 1997;60:851;
(
þ
þ
116.1; HRMS (ESI) Calcd for C21
H13ClO
2
S
([MþNa] ) 387.0217,
(
(
d) Hakim EH, Fahriyati A, Kau MS, et al. J Nat Prod. 1999;62:613;
e) Jones JR, Lebar MD, Jinwal UK, et al. J Nat Prod. 2011;74:38.
Found: 387.0237.
2
3
4
. (a) Losiewicz MD, Carlson BA, Kaur G, Sausville EA, Worland PJ. Biochem Bio-
phys Res Commun. 1994;201:589;
(b) Minagawa A, Otani Y, Kubota T, et al. M Jpn J Cancer Res. 2001;92:1322.
. (a) Narwal M, Haikarainen T, Fallarero A, Vuorela PM, Lehtio L. J Med Chem.
4
.3.21. 2-(4-bromophenyl)-3-(phenylthio)-4H-chromen-4-one (23)
ꢀ
1
Yellow soild (57.9 mg, 71% yield), m.p. 154e155 C; H NMR
500 MHz, CDCl
8.25 (d, J ¼ 8.0 Hz, 1H), 7.73 (t, J ¼ 8.0 Hz, 1H),
(
7
3
) d
2013;56:3507;
.66 (d, J ¼ 8.5 Hz, 2H), 7.60 (d, J ¼ 8.0 Hz, 2H), 7.51 (d, J ¼ 8.5 Hz,
(b) Narwal M, Koivunen J, Haikarainen T, et al. J Med Chem. 2013;56:7880.
. (a) Imran S, Taha M, Ismail NH, et al. Eur J Med Chem. 2015;105:156;
13
1
H), 7.46 (t, J ¼ 7.5 Hz, 1H), 7.23e7.19 (m, 4H), 7.15e7.12 (m, 1H);
175.8, 167.6, 155.9, 136.0, 134.4, 131.9,
31.6, 130.9, 129.2, 127.3, 126.8, 126.1, 126.0, 125.9, 122.9, 118.1,
C
(
(
b) Lebovitz HE. Endocrinol Metab Clin N Am. 1997;26:539;
c) Lebovitz HE. Drugs. 1992;44:21;
3
NMR (125 MHz, CDCl ) d
1
(d) Inui Y, Kawata S, Matsuzawa Y, et al. J Hepatol. 1990;10:62;
e) Giorgino R, Damato A. Ann Ital Med Int. 1995;10:61.
þ
þ
(
115.5; HRMS (ESI) Calcd for C21
H13BrO
2
S
([MþNa] ) 430.9712,
5
6
7
. Ares JJ, Outt PE, Randall JL, et al. J Med Chem. 1995;38:4937.
. Wu ESC, Cole TE, Davidson TA, et al. J Med Chem. 1989;32:183.
. (a) Freitas M, Ribeiro D, Tome SM, Silva AMS, Fernandes E. Eur J Med Chem.
2014;86:153;
Found: 430.9710.
4
.3.22. 2-(4-nitrophenyl)-3-(phenylthio)-4H-chromen-4-one (24)
ꢀ
1
(b) Ballesteros JF, Sanz MJ, Ubeda A, et al. J Med Chem. 1995;38:2794.
. (a) Shobeiri N, Rashedi M, Mosaffa F, et al. Eur J Med Chem. 2016;114:14;
Yellow soild (31.5 mg, 42% yield), m.p. 155e156 C; H NMR
500 MHz, CDCl
8.31 (d, J ¼ 8.5 Hz, 2H), 8.27 (d, J ¼ 8.0 Hz, 1H),
8
(
7
3
) d
(b) Zemanova L, Hofman J, Novotna E, et al. J Nat Prod. 2015;78:2666.
.94 (d, J ¼ 9.0 Hz, 2H), 7.76 (t, J ¼ 8.5 Hz,1H), 7.53 (d, J ¼ 8.5 Hz,1H),
9. (a) Klier L, Bresser T, Nigst TA, Karaghiosoff K, Knochel P. J Am Chem Soc.
13
2012;134:13584;
7.49 (t, J ¼ 7.5 Hz, 1H), 7.24e7.20 (m, 4H), 7.15 (t, J ¼ 7.0 Hz, 1H);
C
(
(
b) Banerjee D, Kayal U, Maiti G. Tetrahedron Lett. 2016;57:1667;
c) Liu J, Song W, Yue Y, et al. Chem Commun. 2015;51:17576.
3
NMR (125 MHz, CDCl ) d 175.6, 165.9, 155.9, 149.1, 138.9, 135.4,
1
34.7, 130.5, 129.3, 127.6, 126.9, 126.5, 126.3, 123.5, 122.9, 118.2,
10. Garcia H, Iborra S, Primo J, Miranda MA. J Org Chem. 1986;51:4432.
11. (a) Huang X, Tang E, Xu W-M, Cao J. J Comb Chem. 2005;7:802;
þ
þ
116.9; HRMS (ESI) Calcd for C21
H13NO
4
S
([MþNa] ) 398.0457,
(b) Perez M, Ruiz D, Autino J, Sathicq A, Romanelli G. Chimie. 2016;19:551;
(c) Sashidhara KV, Kumar M, Kumar A. Tetrahedron Lett. 2012;53:2355;
(d) Wen S-S, Wang J, Luo Y-M, Yang H. Tetrahedron. 2014;70:9314.
Found: 398.0460.
1
1
1
2. Zhang S, Wan C, Wang Q, et al. Eur J Org Chem. 2013:2080.
3. Lahyani A, Trabelsi M. Ultrason Sonochem. 2016;31:626.
4. (a) Zhou C, Dubrovsky AV, Larock RC. J Org Chem. 2006;71:1626;
(b) Zhao J, Zhao Y, Fu H. Org Lett. 2012;14:2710.
4
4
.3.23. 3-(phenylthio)-2-(4-(trifluoromethyl)phenyl)-4H-chromen-
-one (25)
Yellow soild (31.8 mg, 40% yield), m.p. 149e150 C; 1H NMR
ꢀ
(
7
7
d
500 MHz, CDCl
3
)
d
8.27 (d, J ¼ 8.0 Hz, 1H), 7.89 (d, J ¼ 8.0 Hz, 2H),
15. Godoi B, SperanÅa A, Bruning CA, et al. Adv Synth Catal. 2011;353:2042.
6. (a) Liu J, Liu M, Yue Y, Zhang N, Zhang Y, Zhuo K. Tetrahedron Lett. 2013;54:
802;
1
.76e7.72 (m, 3H), 7.53 (d, J ¼ 8.5 Hz, 1H), 7.47 (t, J ¼ 7.5 Hz, 1H),
1
13
.23e7.19 (m, 4H), 7.15e7.12 (m, 1H); C NMR (125 MHz, CDCl
3
)
(b) Liang B, Huang M, You Z, et al. J Org Chem. 2005;70:6097;
(c) Yang Q, Alper H. J Org Chem. 2010;75:948;
175.7, 167.0, 156.0, 136.5, 135.8, 134.5, 132.8 (q, J ¼ 32.5 Hz), 129.8,
(
(
(
d) Xue L, Shi L, Han Y, Xia C, Huynh HV, Li F. Dalton Trans. 2011;40:7632;
e) Miao H, Yang Z. Org Lett. 2000;2:1765;
f) Wu X-F, Neumann H, Beller M. Chem Eur J. 2012;18:12595.
1
29.2, 127.6, 126.8, 126.3, 126.1, 125.3 (q, J ¼ 3.7 Hz), 123.8 (q,
þ
2
O S
J ¼ 270.0 Hz), 122.9, 118.1, 116.3; HRMS (ESI) Calcd for C22
H
14
F
3
þ
(
[M þ H] ) 399.0661, Found: 399.0661.
17. (a) Zhang X-S, Li G, Zhang X-G, Zhang X-H. Tetrahedron. 2015;71:5458;
b) Zhang X-S, Jiao J-Y, Zhang X-H, Hu B-L, Zhang X-G. J Org Chem. 2016;81:
710.
8. Yang Z-J, Hu B-L, Deng C-L, Zhang X-G. Adv Synth Catal. 2014;356:1962.
19. Chen X, Hao X-S, Goodhue CE, Yu J-Q. J Am Chem Soc. 2006;128:6790.
(
5
4
.3.24. 2-butyl-3-(phenylthio)-4H-chromen-4-one (26)
Yellow oil (31.7 mg, 51% yield); H NMR (500 MHz, CDCl
1
1
3
)
d
8.21
Please cite this article in press as: Shi L-F, et al., The synthesis of 3-sulfenylflavones via FeCl
3
-promoted regioselective cyclization of alkynyl aryl
ketones with N-arylthiobenzamides, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.034