Making flavone thioethers using halides and powdered sulfur or Na2S2O3

Article abstract of DOI:10.1021/acs.joc.7b01320

The method for constructing C-S bonds is very important in organic synthesis. Here a new sulfenylation method to generate flavone thioether derivatives was developed by employing aromatic or alkyl halides, S powder and Na₂S₂O₃ as reactants. Good yields of regioselective Calkyl-S and Caryl-S-substituted flavones were generated under relatively environmentally friendly and simple conditions. This method might be potentially applicable to large scale production, and it enriches current sulfenylation methods.

Full text of DOI:10.1021/acs.joc.7b01320

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Note
Making Flavone Thioethers Using Halides and Powdered Sulfur or Na2S2O3
Qiujie Tang, zhaogang bian, Wei Wu, Jin Wang, Ping Xie, Charles U. Pittman, and Aihua Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01320 • Publication Date (Web): 29 Aug 2017
Downloaded from http://pubs.acs.org on August 30, 2017
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Making Flavone Thioethers Using Halides and Powdered
Sulfur or Na2S2O3
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Qiujie Tang,a Zhaogang Bian,a Wei Wu,a Jin Wang,a Ping Xie,b Charles U. Pittman,
Jr.c Aihua Zhou*a
a
Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang city, Jiangsu, China 212013.
b
Scientific Information Research Institute, Jiangsu University (Library), Xuefu Road 301, Zhenjiang city, Jiangsu, China 212013.
c
Mississippi State University, Mississippi State, MS 39762, USA.
Abstract: The method for constructing CꢀS bonds is very important in organic synthesis. Here a new sulfenylation method to
generate flavone thioether derivatives was developed by employing aromatic or alkyl halides, S powder and Na2S2O3 as
reactants. Good yields of regioselective CalkylꢀS and CarylꢀSꢀsubstituted flavones were generated under relatively environmentally
friendly and simple conditions. This method might be potentially applicable to large scale production, and it enriches current
sulfenylation methods.
Flavones are popular natural products in drug discovery1 and their derivatives possess many important biological activities.
Some bioactive flavone derivatives are listed in figure 1.2 Flavone derivatives have been used as marketed drugs for a long time,
so their derivatives for new drug discovery are attractive to many medicinal chemists.3 Different valuable flavone derivatives
have been synthesized and reported including flavone thioethers in scheme 1.4 To make flavone thioethers, the construction of Cꢀ
S bonds directly from inactive CꢀH bonds of flavone skeletons is still a challenge to many medicinal chemists.5 Until now, they
have devoted their efforts to developing highly efficient CꢀS bond construction (sulfenylation) methods via CꢀH bond
functionalization,6 because sulfenylation is highly efficient and environmentally friendly.
Recently, our group also reported several ammonium iodideꢀinduced sulfenylation methods to make flavone derivatives by
coupling flavones with different sulfenylating reagents such as thiols, sulfonyl chlorides, disulfides, sodium sulfinates, and
sulfonyl hydrazides under similar reaction conditions shown in scheme 1.7 However, these methods still have a common
shortcoming with which we are not satisfied, they still require the use of prefunctionalized sulfur agents which are expensive or
not easy to make. These methods are not economical for large scale production. To overcome this shortcoming, we have
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developed a new and practical method to make both CalkylꢀS and CarylꢀSꢀsubstituted flavone derivatives out of odorless S powder
or inorganic Na2S2O3 along with easily available alkyl and aryl halides via direct CꢀH functionalization. This method is far more
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Figure 1. Biologically active flavone derivatives
practical and convienent than our previously reported methods, and it has the potential possibility for use in large scale
production. All reactions proceeded as expected under relatively simple and environmentally friendly condtions, affording
regioselective CalkylꢀS and CarylꢀSꢀsubstituted flavone derivatives in good yields.
Scheme 1. Previously reported sulfenylation methods of flavones versus this new method
To find an optimal reaction condition for this CꢀS construction reaction, flavone 1a was used as a representative reactant; S
powder was used as a sulfur agent, and iodobenzene was selected as a representative halide. To catalyze the reaction, different
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copper, iron, cobalt and nickel catalysts were screened. Different solvents, temperatures, S sources and reaction time were also
tried. The results are presented in Table 1.
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Table 1. Screening for suitable reaction conditionsa
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Entry
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7
Cat.
CuI
CuI
CuI
Temp (oC)
95
S source
S
Solvent
DMF
Yield (%)b
10
115
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
Dioxane
Toluene
EtOAc
CH3CN
DMSO
THF
45
90
63
50
45
43
85
55
31
65
23
0
14
0
0
5
15
6
Cu(OAc)2 H2O
Cu(NO3)2
Cu
CuBr2
CuCl
8
9
CuCN
FeCl2 4H2O
Fe(NO3) 9H2O
CoCl2 6H2O
NiCl2
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21
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23
24c
25d
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
S
S
S
Na2S 9H2O
Thiourea
NH4SCN
S
63
0
52
5
52
76
DMF
DMF
DMF
DMF
DMF
S
a Reaction conditions: flavone (0.5 mmol, 1.0 equiv.), iodobenzene (4.0 equiv.), S (4.0 equiv.), CuI (0.4 equiv.), DMF (0.5
mL), reaction time 24h. b Isolated yield of product 3a was based on the reactant flavone 1a. c Reaction time: 12h. d Reaction
time:18h.
When CuI was used in DMF at 95 oC, it was found that the reaction gave a 10% yield of product 2a (Table 1, entry 1). As the
reaction temperature was raised to 115 oC, the product was isolated in a 45% yield (entry 2). When the temperature was increased
further to 135 oC, the reaction proceeded well and afforded a 90% yield of PhSꢀsubstituted flavone derivative (entry 3). Therefore,
the reaction temperature was set up at 135 oC after entry 3. The use of Cu(OAc)2 H2O as a catalyst in DMF afforded a 63% yield
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(entry 4). When Cu(NO3)2 was used as a catalyst in DMF at 135 C, a 50% yield of product 2a was generated (entry 5). Using
copper only as the catalyst gave product 2a in a 45% yield (entry 6). When CuBr2 was used as a catalyst, a 43% yield of the
expected product 2a was isolated (entry 7). Using CuCl or CuCN as catalysts gave a good yield of 85% and a moderate yield of
55%, respectively (entries 8 and 9). The iron catalysts FeCl2 4H2O and Fe(NO3) 9H2O gave 31% and 65% yields, respectively
(entries 10 and 11). When CoCl2 6H2O and NiCl2 were employed as catalysts, the reaction afforded a 23% yield and no product,
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respectively (entries 12 and 13). Changing solvent from DMF to DCE dropped the yield to 14% (entry 14). Using dioxane and
toluene didn’t produce any of 2a (entries 15 and 16). Several solvents such as EtOAc, CH3CN, DMSO and THF were also
screened, but the yields were lower compared with using DMF (entries 17ꢀ20). A couple of other easily available sulfur sources
were also screened, including Na2S 9H2O, thiourea and NH4SCN. It was found that using Na2S 9H2O gave no expected product
(entry 21). When thiourea was used as a S source, the reaction afforded a moderate yield of 52% (entry 22). Using NH4SCN only
generated a 5% yield of 3a (entry 23). Decreasing the reaction time to 12 h and 18 h decrease in the yield from 90 to 52% and
Table 2. Sulfenylation of flavones with different iodobenzene analogs a,b
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a Reaction conditions: flavone (0.5 mmol, 1.0 equiv.), iodobenzene (4.0 equiv.), S (4.0 equiv.), CuI (0.4 equiv.), DMF (0.5 mL). b
Isolated yields are based on reactant 1a, all reactions were run for 24 h at 135 oC
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72%, respectively, (entries 24 and 25). From these screening reactions, the optimal reaction conditions for the sulfenylation of
flavone using S and iodobenzene as reactants are: flavone (1.0 equiv.), S (4.0 equiv.), iodobenzene (4.0 equiv.) and CuI (0.4
equiv.). DMF is a suitable solvent at 135 oC for 24 h.
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Flavone sulfenylation was then explored under the optimal reaction conditions. In table 2, several flavone analogs with
different functional groups were synthesized and several aromatic iodobenzene homologues with electronꢀdonating and electronꢀ
withdrawing substituents were used for exploring the sulfenylation reaction scope. Most reactions proceeded well, giving
regioselective CarylꢀS substituted flavone derivatives via CꢀH functionalization. Even orthoꢀfluorobenzene iodide gave a good
yield of 3f. It was also found that strong electronꢀwithdrawing functional groups (ꢀNO2 and ꢀCN) on flavone benzene rings had a
big impact on the yields, and none of the expected products 3p and 3q were obtained. All NMR spectra indicated that thioether
Table 3. Sulfenylation of flavones with alkyl halides a,b
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a Reaction conditions: flavone (0.5 mmol, 1.0 equiv), alkyl halide (4.0 equiv.), Na2S2O3 (2.0 equiv.), CuI (0.4 equiv.), DMF (0.5
mL). b Isolated yields are based on reactant 1a, all reactions were run for 24 h at 135 oC.
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substituents were added to the αꢀposition of flavone ketone functions. This regioselectivity was also proved by a designed
chemical method. When the αꢀposition of flavone ketone function was intentionally blocked by a methyl function (3o), no
reaction occured. This chemical verification further proved that the reaction only occured at the αꢀposition of flavone ketone
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function
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To further extend this sulfenylation scope to alkyl halides, several alkyl halides were also reacted under the same conditions in
table 3. The reaction didn’t proceed well when S powder was used as sulphur source. By changing from S powder to the cheap
and inorganic sulphur agent Na2S2O3, the reaction also proceeded quite well, giving good yields of expected CalkylꢀSꢀsubstituted
products. Here, several halides including CH3ꢀI, CH3CH2ꢀBr, CH3CH2BrCH3, CH3CH2CH2ꢀBr, BnꢀCl and BnꢀBr were used as
representative alkyl halides. All these primary alkyl halides (I, Br and Cl halides) were feasible for the reaction under the same
catalyst and solvent conditions. However, when the secondary halide, 2ꢀbromopropane was employed, this reaction didn’t
generate the expected product 5j. An elimination of 2ꢀbromopropane to give propene may have occurred during the reaction.
When a flavone with the αꢀposition of the ketone function blocked by methyl group was reacted with CH3CH2ꢀBr, no product
was isolated. Thus, the reaction happened regioselectively only at the αꢀposition. We have used two strong electronꢀwithdrawing
flavones analogs (ꢀCN, ꢀNO2) as starting materials for the reaction. Neither of these reactions proceeded.
Scheme 2. Control experiment
To explore the reaction mechanism, a control reaction of diphenyl disulfide with flavone was also conducted under the
standard conditions (Scheme 2). When flavone was reacted with diphenyl disulfide, the PhSꢀsubstitued product 3r was afforded
in an 83% yield. This result indicated that disulfides could be a possible intermediate species involved in the reaction.
Based on both literatures8 and the above experimental results, a plausible mechanism was proposed in scheme 3. The reaction
between sulphur agents (S powder or Na2S2O3) and alkyl and aromatic halides could have generated disulfides catalyzed by CuI
in DMF. The resulting disulfide intermediate reacted with CuI to give [RSCuI]ꢀ and the RS+ cation. Then RS+ continued to react
with the flavone to generate the αꢀsubstitued flavone thioether derivatives. The oxidation of RSH by air regenrates disulfides
which recycle in the process.
Scheme 3. Proposed reaction mechanism
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R-X
S powder or Na2S2O3
R=Ar or alkyl
CuI
RSSR
RS+
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9
O
O
H2O
[RSCuI]-
1
CuI
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O2
O
O
SR
RSH
3 or 5
CONCLUSIONS
In summary, a new method using cheap inorganic S powder or Na2S2O3 as sulfur agents, iodobenzenes/alkyl halides and
flavones as starting materials to make Calkyl/CarylꢀSꢀsubstituted flavone derivatives was developed. All reactions were carried out
under relatively practical and simple conditions, generating regioselective products in good yields. Compared with previously
available methods, this method is unique and more useful because it is practical and has the potential to be used on an industrial
scale. Also, this method is environmentally friendly, quite attractive and enriches current sulfenylation methods.
EXPERIMENTAL SECTION
General: All reactions were carried out in sealed tubes; stirring was achieved with an ovenꢀdried magnetic stirring bar. Solvents
were purified by standard methods unless otherwise noted. Commercially available reagents were purchased from Aladdin
Company in China and used throughout without further purification other than those detailed below. Flash column
chromatography was performed on silica gel (200ꢀ300 mesh). All reactions were monitored by TLC analysis. Deuterated solvents
were purchased from Cambridge Isotope laboratories. 1H and 13C NMR spectra were recorded on a Bruker DRXꢀ400
spectrometer operating at 400 MHz and 100 MHz respectively. HRMS spectrometry (LCꢀHRMS) was recorded on a LXQ
Spectrometer (Thermo Scientific) operating on ESIꢀTOF (MeOH as a solvent).
General procedure for the synthesis of compounds 3a-n. Flavone 1a (0.5 mmol, 1.0 equiv.), sulfur (4.0 equiv.) and
iodobenzene (4.0 equiv.) were added to a dried flask with DMF (0.5 mL), followed by the addition of CuI (0.4 equiv.). The
o
mixture was stirred at 135 C. After 24 h, the reaction was cooled to room temperature, diluted with ethyl acetate, washed with
brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography
(petroleum ether : EtOAc = 60:1) on silica gel to give the desired product 3a as a colorless oil in a 90% yield. The same
procedure was applied to the production of other compounds 3b-n.
The procedure for the synthesis of compound 3r. Flavone (0.5 mmol, 1.0 equiv.) and disulfide (2.0 equiv.) were added to a
dried flask with DMF (0.5 mL), followed by the addition of CuI (0.4 equiv.). The mixture was stirred at 135 oC. After 24 h, the
reaction was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and
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concentrated under vacuum. The residue was purified by flash chromatography (petroleum ether : EtOAc = 65:1) on silica gel to
give the desired product 3r as a colorless oil in a 83% yield.
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General procedure for the synthesis of compounds 5a-i. Flavone 1a (0.5 mmol, 1.0 equiv.), Na2S2O3 (2.0 equiv.) and halide
(4.0 equiv.) were added to a dried flask with DMF (0.5 mL), followed by the addition of CuI (0.4 equiv.). The mixture was stirred
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at 135 C. After 24 h, the reaction was cooled down to room temperature, diluted with ethyl acetate, washed with brine, dried
over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (petroleum ether :
EtOAc =80:1) on silica gel to give the desired product 5a as a colorless oil in a 65% yield. The same procedure was applied to the
production of other compounds 5b-i.
3-(Phenylthio)-4H-chromen-4-one (3a)
1
Following the general procedure, isolated yield (114.3 mg, 90%) as a colorless oil; H-NMR (CDCl3, 400 MHz): δ (ppm) 8.27
(dd, J = 8.0, 1.7 Hz, 1H), 8.18 (s, 1H), 7.72 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.45 – 7.40 (m, 2H), 7.34 – 7.28
(m, 2H), 7.27 – 7.21 (m, 1H). 13C-NMR (CDCl3, 100 MHz): 175.1, 157.4, 156.4, 134.0 (2 C), 129.9, 129.2, 127.1, 126.5, 125.8,
123.7, 120.0, 118.2. FTIR: 3057, 2925, 1652, 1612, 1464, 1301, 1113, 760 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for
C15H10NaO2S+ 277.0294 (M+Na)+, found 277.0293.
3-(p-Tolylthio)-4H-chromen-4-one (3b).
Following the general procedure, isolated yield (100.5 mg, 75%) as a colorless oil; 1H-NMR (CDCl3, 400 MHz): δ (ppm) 8.26
(dd, J = 8.0, 1.7 Hz, 1H), 8.07 (s, 1H), 7.70 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.52 – 7.41 (m, 2H), 7.41 – 7.34 (m, 2H), 7.13 (d, J =
7.9 Hz, 2H), 2.33 (s, 3H). 13C-NMR (CDCl3, 100 MHz): 175.1, 156.3 (2 C), 137.6, 133.9, 131.0, 130.1, 129.8, 126.4, 125.6,
123.6, 121.1, 118.1, 21.1. FTIR: 3075, 2921, 2359, 1647, 1463, 1115, 758 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for
C16H12NaO2S+ 291.0450 (M+Na)+, found 291.0453.
3-((4-(Tert-butyl)phenyl)thio)-4H-chromen-4-one (3c).
1
Following the general procedure, isolated yield (113.1mg, 73%) as a colorless oil; H-NMR (400 MHz, Chloroformꢀd) δ 8.27
(dd, J = 8.0, 1.7 Hz, 1H), 8.09 (s, 1H), 7.71 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.41 – 7.32 (m, 4H), 1.30 (s,
9H). 13C-NMR (CDCl3, 100 MHz): 175.2, 156.6, 156.3, 150.7, 133.9, 130.5, 130.0, 126.4 (2 C), 125.6, 123.6, 120.8, 118.2, 34.6,
31.2. FTIR: 3070, 2963, 1648, 1611, 1560, 1462, 1113, 846, 765 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C19H18NaO2S+
333.0920 (M+Na)+, found 333.0921.
3-((4-Chlorophenyl)thio)-4H-chromen-4-one (3d).
1
Following the general procedure, isolated yield (97.9 mg, 68%) as a colorless oil; H-NMR (400 MHz, Chloroformꢀd) δ 8.31 –
8.21 (m, 2H), 7.73 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 7.54 – 7.43 (m, 2H), 7.39 – 7.30 (m, 2H), 7.29 – 7.23 (m, 2H). 13C-NMR
(CDCl3, 100 MHz): 175.0, 157.9, 156.4 , 134.2, 133.1, 132.8, 130.9, 129.3, 126.5, 125.9, 123.7, 119.2, 118.2 . FTIR: 3050, 1648,
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1478, 1465, 1313, 1090, 827, 758 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C15H9ClNaO2S+ 310.9904 (M+Na)+, found
310.9903.
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3-((4-Bromophenyl)thio)-4H-chromen-4-one (3e).
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Following the general procedure, isolated yield (114.5 mg, 60%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.26 (d,
J = 7.0 Hz, 2H), 7.74 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.54 – 7.44 (m, 2H), 7.44 – 7.37 (m, 2H), 7.26 (d, J = 8.6 Hz, 2H). 13C-
NMR (CDCl3, 100 MHz): 174.9, 158.0, 156.4, 134.2, 133.6, 132.2, 131.0, 126.5, 125.9, 123.7, 121.0, 119.0, 118.2. FTIR: 3061,
2925, 1641, 1462, 1086, 902, 798 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C15H9BrNaO2S+ 354.9399 (M+Na)+, found
354.9396.
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3-((2-Fluorophenyl)thio)-6-methyl-4H-chromen-4-one (3f).
Following the general procedure, isolated yield (111.5 mg, 78%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.20 (s,
1H), 8.04 – 7.97 (m, 1H), 7.49 (dd, J = 8.6, 2.2 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.22 (tdd, J = 7.0, 6.0, 1.7 Hz, 1H), 7.10 – 7.00 (m,
2H), 2.44 (s, 3H). 13C-NMR (CDCl3,100 MHz): 175.1, 161.1 (d, JCꢀF = 245 Hz), 157.7, 154.6, 135.9, 135.3, 132.5, 129.2 (d, JCꢀF
= 8 Hz), 125.6, 124.6 (d, JCꢀF = 4 Hz), 123.3, 121.1 (d, JCꢀF = 17 Hz), 117.9, 117.8, 115.9 (d, JCꢀF = 22 Hz), 21.0. FTIR: 3054,
2921, 1644, 1474, 1210, 1114, 812, 743; HRMS (ESIꢀTOF) m/z calculated for C16H11FNaO2S+ 309.0356. (M+Na)+, found
309.0355.
3-((4-Chlorophenyl)thio)-6-methyl-4H-chromen-4-one (3g).
Following the general procedure, isolated yield (111.7 mg, 74%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.24 (s,
1H), 8.03 (dd, J = 2.2, 1.1 Hz, 1H), 7.53 (dd, J = 8.6, 2.3 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.27 – 7.22 (m,
2H), 2.47 (s, 3H). 13C-NMR (CDCl3, 100 MHz): 175.1, 158.0, 154.7, 136.1, 135.4, 133.1, 132.9, 130.7, 129.2, 125.7, 123.4,
118.8, 118.0, 21.0. FTIR: 3053, 2922, 1638, 1478, 1311, 1091, 812, 788 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for
C16H11ClNaO2S+ 325.0060 (M+Na)+, found 325.0066.
6-Chloro-3-(p-tolylthio)-4H-chromen-4-one (3h).
Following the general procedure, isolated yield (105.7 mg, 70%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.20 (d,
J = 2.6 Hz, 1H), 8.00 (s, 1H), 7.63 (dd, J = 9.0, 2.6 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.39 – 7.35 (m, 2H), 7.14 (d, J = 7.9 Hz,
2H), 2.34 (s, 3H). 13C-NMR (CDCl3, 100 MHz): 174.0, 155.8, 154.6, 138.0, 134.1, 131.5, 131.4, 130.2, 129.2, 125.7, 124.3,
121.7, 119.9, 21.1. FTIR: 3065, 2923, 1657, 1468, 1305, 1112, 817, 736 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for
C16H11ClNaO2S+ 325.0060 (M+Na)+, found 325.0058.
3-((4-Bromophenyl)thio)-6-chloro-4H-chromen-4-one (3i).
Following the general procedure, isolated yield (117.3 mg, 65%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.29 –
8.15 (m, 2H), 7.67 (dd, J = 9.0, 2.6 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.45 – 7.40 (m, 2H), 7.28 (s, 2H). 13C-NMR (CDCl3, 100
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MHz): 173.8, 157.7, 154.7, 134.4, 133.0, 132.3, 131.9, 131.4, 125.8, 124.6, 121.4, 120.0, 119.6. FTIR: 3055, 2923, 1653, 1468,
1301, 907, 765 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C15H8BrClNaO2S+ 388.9009 (M+Na)+, found 388.9001
6-Chloro-3-(phenylthio)-4H-chromen-4-one (3j).
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Following the general procedure, isolated yield (103.6 mg, 72%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.22 (d,
J = 2.6 Hz, 1H), 8.12 (s, 1H), 7.65 (dd, J = 8.9, 2.6 Hz, 1H), 7.50 – 7.40 (m, 3H), 7.34 – 7.24 (m, 3H). 13C-NMR (CDCl3, 100
MHz): 174.0, 157.0, 154.7, 134.2, 133.4, 131.7, 130.3, 129.3, 127.4, 125.7, 124.5, 120.5, 120.0. FTIR: 3068, 2925, 2360, 1652,
1466, 1303, 1122, 918, 821, 755 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C15H9ClNaO2S+ 310.9904 (M+Na)+, found
310.9902.
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6-Chloro-7-methyl-3-(p-tolylthio)-4H-chromen-4-one (3k).
Following the general procedure, isolated yield (124.8 mg, 79%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.19 (s,
1H), 7.98 (s, 1H), 7.36 (d, J = 8.3 Hz, 3H), 7.13 (d, J = 8.0 Hz, 2H), 2.53 – 2.48 (m, 3H), 2.33 (s, 3H). 13C-NMR (CDCl3, 100
MHz): 174.0, 155.9, 154.6, 143.3, 137.8, 132.3, 131.2, 130.1, 129.5, 125.9, 122.5, 121.3, 119.9, 21.1, 20.9. FTIR: 3060, 2925,
1651, 1413, 1097, 899, 786 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C17H13ClNaO2S+ 339.0217 (M+Na)+, found 339.0215.
8-Bromo-6-methyl-3-(phenylthio)-4H-chromen-4-one (3l).
Following the general procedure, isolated yield (77.8 mg, 45%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.11 (s,
1H), 7.98 (dd, J = 2.1, 1.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.35 – 7.23 (m, 3H), 2.45 (s, 3H). 13C-NMR
(CDCl3, 100 MHz): 174.5, 156.3, 151.2, 138. 5, 136.8, 133.2, 130.5, 129.3, 127.5, 125.3, 124.3, 120.8, 111.2, 20.8. FTIR: 3054,
2925, 2360, 1660, 1462, 1299, 1090, 785, 690 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C16H11BrNaO2S+ 368.9555 (M+Na)+,
found 368. 9552.
6-Bromo-3-(phenylthio)-4H-chromen-4-one (3m).
Following the general procedure, isolated yield (91.3 mg, 55%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.38 (d,
J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.78 (dd, J = 8.9, 2.5 Hz, 1H), 7.47 – 7.36 (m, 3H), 7.36 – 7.23 (m, 3H). 13C-NMR (CDCl3, 100
MHz): 173.8, 156.9, 155.1, 137.0, 133.4, 130.3, 129.3, 129.0, 127.5, 124.8, 120.7, 120.1, 119.2. FTIR: 3058, 2923, 1651, 1548,
1462, 1120, 908, 817, 735 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C15H9BrNaO2S+ 354.9399 (M+Na)+, found 354.9398.
3-(p-Tolylthio)-4H-benzo[h]chromen-4-one (3n).
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Following the general procedure, isolated yield (138.3 mg, 87%) as a colorless oil; H-NMR (400 MHz, Chloroformꢀd) δ 8.40
(dd, J = 8.1, 1.4 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.92 (dd, J = 7.7, 1.4 Hz, 1H), 7.78 – 7.63 (m, 3H), 7.43 (d, J =
8.2 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 2.35 (s, 3H). 13C-NMR (CDCl3, 100 MHz): 174.8, 154.3, 153.7, 138.0, 135. 8, 131.7,
130.2, 129.5, 129.1, 128.1, 127.3, 125.7, 123.8, 123.5, 122.2, 121.0, 119.6, 21.2. FTIR: 3056, 2920, 2362, 1650, 1633, 1384,
1113, 886, 765 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C20H14NaO2S+ 341.0607 (M+Na)+, found 341.0602
6-Chloro-7-methyl-3-(phenylthio)-4H-chromen-4-one (3r)
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Following the general procedure, isolated yield (125.3 mg, 83%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.19 (s,
1H), 8.10 (s, 1H), 7.44 – 7.38 (m, 2H), 7.37 (d, J = 0.9 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.28 – 7.22 (m, 1H), 2.51 (d, J = 0.8 Hz,
3H). 13C-NMR (CDCl3, 100 MHz,) δ 173.9, 157.0, 154.6, 143.4, 133.7, 132.4, 130.0, 129.2, 127.3, 126.0, 122.6, 120.1, 119.9,
20.9. FTIR: 3066, 2922, 1655, 1432, 1108, 918, 795 cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C16H11ClNaO2S+ 325.0060
(M+Na)+, found 325.0061.
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3-(Methylthio)-4H-chromen-4-one (5a)
Following the general procedure, isolated yield (62.4 mg, 65%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.24 (dd,
J = 8.0, 1.7 Hz, 1H), 8.05 (s, 1H), 7.67 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.49 – 7.37 (m, 2H), 2.40 (s, 3H). 13C-NMR (CDCl3, 100
MHz): 175.6, 156.3, 153.9, 133.8, 126.1, 125. 5, 123.1, 121.9, 118.1, 16.3. FTIR: 3072, 2923, 1628, 1466, 1357, 1084, 792 cmꢀ1;
HRMS (ESIꢀTOF) m/z calculated for C10H8NaO2S+ 215.0137 (M+Na)+, found215.0136.
3-(Ethylthio)-4H-chromen-4-one (5b).
Following the general procedure, isolated yield (61.8 mg, 60%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.26 (dd,
J = 8.2, 1.7 Hz, 1H), 8.17 (s, 1H), 7.69 (ddd, J = 8.6, 7.1, 1.7 Hz, 1H), 7.51 – 7.40 (m, 2H), 2.89 (q, J = 7.4 Hz, 2H), 1.26 (t, J =
7.4 Hz, 3H). 13C-NMR (CDCl3, 100 MHz): 175.9, 156.3, 156.3, 133.8, 126.2, 125.6, 123.5, 119.3, 118.1, 26.8, 14.56. FTIR:
2925, 2857, 1636, 1459, 1344, 1076, 887, 754cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C11H10NaO2S+ 229.0294 (M+Na)+,
found 229.0295.
3-(Benzylthio)-6-chloro-4H-chromen-4-one (5c).
Following the general procedure, isolated yield (135 mg, 90%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.24 (d, J
= 2.6 Hz, 1H), 7.82 (s, 1H), 7.62 (dd, J = 8.9, 2.6 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.29 – 7.17 (m, 5H), 4.07 (s, 2H). 13C-NMR
(CDCl3, 100 MHz): 174.8, 157.2, 154.6, 137.5, 134.1, 131.6, 129.0, 128.5, 127.2, 125.6, 124.3, 119.9, 118.6, 37.0. FTIR: 3029,
2923, 2359, 1626, 1466, 1020, 819, 692cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C16H11ClNaO2S+ 325.0060 (M+Na)+, found
325.0062.
3-(Benzylthio)-6-methyl-4H-chromen-4-one (5d).
Following the general procedure, isolated yield (97.3 mg, 69%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.08 (dd,
J = 2.1, 1.1 Hz, 1H), 7.81 (s, 1H), 7.49 (dd, J = 8.6, 2.3 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.28 – 7.18 (m, 5H), 4.07 (s, 2H), 2.49
(s, 3H). 13C-NMR (CDCl3, 100 MHz): 176.0, 157.3, 154.6, 137.8, 135.7, 135.1, 129.0, 128.4, 127.1, 125.5, 123.2, 117.9 (2 C),
37.1, 22.0. FTIR: 3475, 3415, 2918, 2359, 1620, 1482, 697cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C17H14NaO2S+ 305.0607
(M+Na)+, found 305.0612.
6-Chloro-3-(methylthio)-4H-chromen-4-one (5e).
Following the general procedure, isolated yield (85.8 mg, 76%) as a colorless oil; 1H-NMR (400 MHz, Chloroformꢀd) δ 8.21 (d,
J = 2.6 Hz, 1H), 8.04 (s, 1H), 7.63 (dd, J = 8.9, 2.6 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 2.41 (s, 3H). 13C-NMR (CDCl3, 100 MHz):
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174.5, 154.6, 153.7, 134.0, 131.4, 125.4, 124.0, 122.2, 119.9, 16.1. FTIR: 3083, 2915, 1629, 1467, 1123, 1086, 818, 651cmꢀ1;
HRMS (ESIꢀTOF) m/z calculated for C10H7ClNaO2S+ 248.9747 (M+Na)+, found 248.9744.
6-Methyl-3-(methylthio)-4H-chromen-4-one (5f).
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Following the general procedure, isolated yield (79.3 mg, 77%) as a colorless oil; H-NMR (400 MHz, Chloroformꢀd) δ 8.04 (s,
1H), 8.03 – 8.01 (m, 1H), 7.52 – 7.45 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 2.46 (s, 3H), 2.40 (s, 3H). 13C-NMR (CDCl3, 100 MHz):
175.7, 154.6, 154.0, 135.5, 135.1, 125.3, 122.8, 121.5, 117.8, 21.0, 16.4. FTIR: 3065, 2920, 1639, 1486, 1149, 1082, 873cmꢀ1;
HRMS (ESIꢀTOF) m/z calculated for C11H10NaO2S+ 229.0294 (M+Na)+, found 229.0294.
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6-Chloro-7-methyl-3-(methylthio)-4H-chromen-4-one (5g)
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Following the general procedure, isolated yield (78mg, 65%) as a colorless oil; H-NMR (400 MHz, Chloroformꢀd) δ 8.17 (s,
1H), 8.00 (s, 1H), 7.33 (d, J = 0.9 Hz, 1H), 2.49 (d, J = 0.9 Hz, 3H), 2.40 (s, 3H). 13C-NMR (CDCl3, 100 MHz): 174.4, 154.5,
153.6, 143.2, 132.1, 125.6, 122.1, 121.9, 119.9, 20.8, 16.2. FTIR: 2923, 1633, 1365, 1128, 1091, 911, 645 cmꢀ1; HRMS (ESIꢀ
TOF) m/z calculated for C11H9ClNaO2S+ 262.9904 (M+Na)+, found 262.9901.
6-Chloro-7-methyl-3-(propylthio)-4H-chromen-4-one (5h).
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Following the general procedure, isolated yield (97.8 mg, 73%) as a colorless oil; H-NMR (400 MHz, Chloroformꢀd) δ 8.19 (s,
1H), 8.11 (s, 1H), 7.34 (d, J = 1.0 Hz, 1H), 2.86 – 2.79 (m, 2H), 2.50 (d, J = 0.9 Hz, 3H), 1.60 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4
Hz, 3H). 13C-NMR (CDCl3, 100 MHz): 174.8, 155.8, 154.6, 143.1, 132.2, 125.8, 122.5, 119.9, 119.7, 34.7, 22.6, 20.8, 13.2.
FTIR: 3075, 2955, 1631, 1124,1087, 859,646cmꢀ1; HRMS (ESIꢀTOF) m/z calculated for C13H13ClNaO2S+ 291.0217 (M+Na)+,
found 291.0217
6-Bromo-3-(methylthio)-4H-chromen-4-one (5i)
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Following the general procedure, isolated yield (70.2 mg, 52%) as a colorless oil; H-NMR (400 MHz, Chloroformꢀd) δ 8.38 (d,
J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.77 (dd, J = 8.9, 2.5 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 2.42 (s, 3H). 13C-NMR (CDCl3, 100 MHz):
174.3, 155.0, 153.7, 136.8, 128.7, 124.3, 122.3, 120.1, 118.8, 16.2. FTIR: 2917, 1628, 1122, 1084, 917, 818 cmꢀ1; HRMS (ESIꢀ
TOF) m/z calculated for C10H7BrNaO2S+ 292.9242 (M+Na)+, found 292.9241
ASSOCIATED CONTENT
Supporting Information Available
Spectral characterization for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: ahz@ujs.edu.cn.
Author Contributions
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Q.T. and J.W. contributed equally.
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This investigation was generously supported by the funding (1281290006) provided by Jiangsu University.
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