Ammonium Iodide Induced Nonradical Regioselective Sulfenylation of Flavones via a C-H Functionalization Process

Article abstract of DOI:10.1021/acs.joc.5b01602

A novel and highly regioselective ammonium iodide-induced nonradical sulfenylation method for the construction of a C-S bond was developed via C-H functionalization. With DMSO or R¹SO₂NHNH₂ as a sulfenylating agent, MeS- and R¹S-substituted flavone derivatives were obtained in good yields. This method enriches current C-S bond formation chemistry, making it a highly valuable and practical method in pharmaceutical industry.

Full text of DOI:10.1021/acs.joc.5b01602

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Article
Ammonium Iodide-induced Non-radical Regioselective
Sulfenylation of Flavones via a C-H Functionalization Process
Wannian Zhao, Ping Xie, Zhaogang Bian, Aihua Zhou, Haibo Ge, Min Zhang, Yingcai Ding, and Lian Zheng
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 20 Aug 2015
Downloaded from http://pubs.acs.org on August 20, 2015
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Ammonium Iodide-induced Non-radical Regioselective
Sulfenylation of Flavones via a C-H Functionalization
Process
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Wannian Zhao,† Ping Xie,§ Zhaogang Bian,† Aihua Zhou,*† Haibo Ge,*‡
Min Zhang,† Yingcai Ding† and Lian Zheng†
† Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu, 212013, China;
§ Scientific Information Research Institute, Jiangsu University (Library), Xuefu Road 301, Zhenjiang City, Jiangsu, 212013, China;
‡ Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis IN 46202 (USA)
Abstract: A novel and highly regioselective ammonium iodideꢀinduced nonꢀradical sulfenylation method for the construction of
CꢀS bond was developed via CꢀH functionalization. With DMSO or R1SO2NHNH2 as a sulfenylating agent, MeSꢀ and R1Sꢀ
substituted flavone derivatives were obtained in good yields. This method enriches current CꢀS bond formation chemistry,
making it a highly valuable and practical method in pharmaceutical industry.
Introduction
Organic molecules containing a CꢀS bond widely exist in nature, possessing a variety of valuable biological activities.1 Therefore,
considerable efforts have been devoted to the development of efficient synthetic methods of constructing CꢀS bond between
biologically relevant molecules and sulfenylating sources.2
Traditionally, a CꢀS bond is achieved by the condensation of an alkyl halide with a metal thiolate.3 Later, transition metalꢀ
catalyzed couplings between vinyl/aryl halides and sulfenylating sources such as thiols, sulfonyl chlorides, and disulfides have
been developed.4 One shortcoming of these methods is that prefunctionalized reactants are needed for these reactions.
Recently, direct formation of CꢀS bond via CꢀH bond functionalization has emerged as an efficient method which enables
superior step and atomꢀeconomic transformations (see DMSO example in Scheme 1).5 Although no prefunctionalized reactants
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are needed, these reactions often suffer from the high loading of transition metal catalysts, additives and harsh reaction conditions
sometimes.
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Very recently, metalꢀfree sulfenylation processes via direct functionalization of unreactive CꢀH bonds were also developed,6
DMSO, R1SO2NHNH2, R1SO2Na and R1SO2H were often used as sulfenylating agents in these processes (Scheme 1).7,8
Compared with smelly and unstable thiols, these sulfenylating agents are stable, odorless and readily available.
Scheme 1. Representative sulfenylation methods
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In this paper, we reported a novel and regioselective sulfenylation method via direct CꢀH functionalization, in which
ammonium iodide (NH4I) was employed as a catalyst instead of previously reported iodine (I2) (Scheme 1). Both DMSO and
alkyl/arylsulfonyl hydrazines were used as sulfenylating agents. Although TBAI(Bu4NI)/TBHP(tꢀBuOOH)ꢀmediated
sulfonylation methods have been reported to construct (CꢀSO2R) bond recently,9 sulfonylation is different from sulfenylation (Cꢀ
S bond construction) in which no oxygen atoms are connected with sulfur atom. More importantly, no oxidants were needed in
our sulfenylation approach.
Flavone is a wellꢀknown natural product class in drug discovery with carbonylꢀconjugated olefin function in its structure, its
electronꢀrich ring enables it to undergo direct CꢀH bond functionalization with electrophiles (DMSO or R1SO2NHNH2) to form
MeSꢀ and R1Sꢀsubstituted flavone derivatives. To the best of our knowledgement, there are no reports until now.
Results and Discussion
Based on previous reports of CꢀS bond construction,10 we first investigated suitable reaction conditions for the couplings of
flavone with DMSO. Flavone 1a and DMSO were used as the representative reactants, and different catalysts and solvents were
screened for the reaction. (Table 1).
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First, CuI, CuBr2 or FeCl3 was used as a catalyst for the coupling, and none of these reactions gave the expected product 2a
(entries 1ꢀ3) at 95 oC. Using NaI or TBAI as a catalyst didn’t generate product 2a (entries 4 and 5) either. When I2 was selected
as a catalyst, the reaction product 2a was obtained in 10% yield (entry 6). When NH4I (1.0 equiv.) was employed with water as a
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Table 1. Screening reactions for the sulfenylationa
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Entry
1
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Catalyst
CuI
CuBr2
FeCl3
NaI
Solvent
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
Temp.(oC)
95
Yield (%)
0
95
95
95
95
95
0
0
0
TBAI
I2
0
ꢀꢀꢀ
10
trace
<5
79
25
65
0
65
81
trace
50
65
NH4Ib
NH4I
I2
H2O
H2O
MeCN
ꢀꢀꢀ
H2O
H2O
DCE
MeCN
EtOAc
THF
Toluene
95
95
135
135
135
135
135
135
135
135
135
NH4I
NH4I
NH4Cl
NH4I
NH4I
NH4I
NH4I
NH4I
a Reaction conditions: flavone 1a (0.5 mmol, 1.0 equiv.), DMSO (0.3 mL), NaI/TBAI/I2 (20 mol%), NH4I/NH4Cl (4.0 equiv.),
metal catalyst (20 mol%), solvent (0.5 mL); yield is based on reactant 1a. All reactions were run for 24 h. bNH4I (1.0 equiv.).
solvent, trace amount of 2a was produced (entry 7). Increasing NH4I (4.0 equiv.) to four equivalents gave 2a in less than 5%
o
yield (entry 8). Elevating reaction temperature to 135 C in the presence of iodine led to a 79% yield of expected product 2a
(entry 9). Using NH4I as a catalyst only afforded 25% yield of product 2a (entry 10). When water was used as a solvent, a 65%
yield of 2a was obtained (entry 11). When NH4Cl was used instead of NH4I as a catalyst at 135 oC, no expected product 2a was
isolated (entry 12). When DCE was used as the solvent, the reaction gave a 65 % yield of 2a (entry 13). Using CH3CN as the
solvent gave 2a in an 81% yield (entry 14). Interestingly, changing DCE to EtOAc didn’t generate 2a (entry 15), but with THF or
toluene as a solvent, a moderate yield of product 2a (entries 16 and 17) was produced. After the screening, the suitable
sulfenylation reaction conditions selected for the couplings of flavone with DMSO are: NH4I (4.0 equiv.), DMSO (0.3 mL),
flavone (0.5mmol, 1.0 equiv.), with CH3CN as the solvent at 135oC.
After suitable reaction conditions were obtained, different flavones were reacted with DMSO. Eleven different flavones with
electronꢀdeficient and electronꢀdonating substituents were synthesized based on existing methods11 and used as the coupling
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reactant partners. From the Table 2, it can be found that all flavones with electronꢀdonating functions (H, CH3, ꢀOH) gave good
yields of desired products, while flavones with electronꢀdeficient functions (ꢀCN, ꢀNO2) gave moderate yields of desired products.
All reactions selectively occurred on the αꢀpositions of ketone function of flavones, while only trace amount of βꢀposition
products were isolated.
Table 2. Regioselective sulfenylation of flavones with DMSOa
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O
Cl
S
O
2e, 72%
O
O2N
S
O
2h, 55%
a Reaction conditions: flavone (1.0 equiv.), DMSO (0.3 mL), NH4I (4.0 equiv.), CH3CN (0.5 mL), isolated yield is
based on reactant 1. All reactions were run for 24 h at 135 oC.
To further study the application scope of this ammonium iodideꢀinduced sulfenylation method, instead of using DMSO,
another important sulfenylating agent R1SO2NHNH2 was also employed under the same reaction conditions. It was found that 4a
was obtained in a 48% yield (entry 1, Table 3). To further explore this reaction, the molar amount of NH4I was decreased from
four equivalent to one equivalent, the reaction only afforded 5% isolated yield of the desired product (entry 2). Using THF or
toluene as a solvent also gave low yields of 4a respectively (entries 3 and 4). When DCE was selected as a solvent, trace amount
of 4a was produced (entry 5). But using DMF as a solvent afforded a 78% yield of expected product 4a (entry 6). When DMAC
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(dimethyl acetamide) was used as a solvent, an 83% yield was obtained (entry 7). After the screening, the suitable sulfenylation
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conditions are: flavone (0.5mmol, 1.0 equiv.), temperature: 135 C, R1SO2NHNH2 (1.2 equiv.), NH4I (4.0 equiv.) and DMAC
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(0.5 mL) is used as a solvent.
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Table 3. Screening reactions for the sulfenylation via using benzenesulfonyl hydrazine a
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Entry
Catalyst
Solvent
Yield (%)
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NH4I
NH4Ib
NH4I
NH4I
NH4I
NH4I
NH4I
MeCN
MeCN
THF
Toluene
DCE
48
5
30
25
trace
78
DMF
DMAC
83
a Reaction conditions: flavone (0.1 mmol, 1.0 equiv.), benzenesulfonyl hydrazine 3a (1.2 equiv.), NH4I, (4.0 equiv.),
solvent (0.5 mL); All reactions were run for 24 h. bNH4I (1.0 equiv.).
After the optimal reaction conditions were obtained, different flavones were reacted with arylsulfonyl hydrazines. It was found
that a majority of reactions proceeded well, and all CꢀH bonds on αꢀpositions of flavones were regioselectively functionalized
and replaced by ArSꢀ functions to give products 4a-m in good yields. As shown in the Table 4, different flavones and
arylsulfonyl hydrazines were used for these regioselective sulfenylation reactions of flavones. Flavones with electronꢀ
withdrawing functions (such as ꢀCN, ꢀNO2) gave relatively lower yields compared with other flavones.
Table 4. Regioselective sulfenylation reactions of flavones with arylsulfonyl hydrazines a
O
O
S
S
O
Br
O
t-Bu
4d, 79%
4e, 65%
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O
S
O
Cl
4m, 78%
a
Reaction conditions: flavone (0.5 mmol, 1.0 equiv.), arylsulfonyl hydrazine (1.2 equiv.), NH4I (4.0 equiv.),
DMAC (0.5 mL), All reactions were run for 24 h at 135 oC.
To explore if alkylsulfonyl hydrazine is also suitable for this sulfenylation method, herein, aliphatic methylsulfonyl hydrazine
(CH3SO2NHNH2) was selected as a sulfenylating agent and two flavones were used as representative reactants, under the same
reaction condition, both reactions afforded good yields of expected products 4n-o (Scheme 2).
Scheme 2. Regioselective sulfenylation of flavones with methylsulfonyl hydrazine
To determine if a common sulfenylating agentꢀꢀaromatic thiol is also suitable for this sulfenylation method, instead of using
alkyl/aryl sulfonyl hydrazines, pꢀtoluenethiol was tested for this sulfenylation reaction, it was found that the reaction also
proceeded well under the same condition, generating a good yield of 4b. To further extend application scope of this method, three
different electronꢀrich compounds were selected as reaction partners for this sulfenylation reaction instead of using flavones
(Scheme 3), these selected reactants were indole 7, 2ꢀphenylimidazo[1,2ꢀa]pyridine 9 and benzofurazan 11 which all included
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electronꢀrich double bonds in their structures. After the reactions with pꢀtoluenesulfonyl hydrazine under the same condition,
respectively, two reactions gave good yields of regioselctive sulfenylated products 8 and 10. While the reaction of benzofurazan
11 with pꢀtoluenesulfonyl hydrazine didn’t generate sulfenylated product 12, so further exploration was still needed, but this fact
would not devalue promising application of this ammonium iodideꢀinduced sulfenylation reaction.
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Scheme 3. Extension of this regioselective sulfenylation reactions
1
Despite H and 13CꢀNMR spectra have obviously confirmed the structures of products 2a-k and 4a-m, a chemical method to
prove chemical structure was still carried out(Scheme 4). Herein, MeSꢀsubstituted flavone 2a was selected as a representative
product, it was easily oxidized by H2O2 (30 wt% in water) to give sulfoxideꢀsubstituted flavone 13, while the oxidation by excess
mꢀCPBA generated methylsulfonylꢀsubstituted flavone 14. The same result was also achieved when flavone derivative 4a was
used as a reactant.
Scheme 4. The oxidation of flavone 2a with H2O2 and m-CPBA
To further study how the substituents on αꢀ and βꢀposition of flavones influenced the regioselectivity of this sulfenylation
reaction, two methylꢀsubstituted flavones with methyl functions on α and βꢀposition were synthesized. When the reaction sites on
αꢀpositions were blocked by methyl function (Scheme 5, entries 1 and 3), both reactions didn’t give CH3Sꢀ or PhSꢀsubstituted
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products 2l/4p on βꢀpositions, indicating that these sulfenylation reactions only regioselectively happened on αꢀposition reaction
sites. When the methyl function was on the βꢀposition of flavone, the sulfenylation with DMSO as a sulfenylating agent
proceeded well and gave a good yield of 2m, while a decreased yield was observed when benzenesulfonyl hydrazide was used as
a sulfenylating agent, possibly due to the steric effects caused by neighbouring methyl function.
Scheme 5. Control reactions
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O
O
O
NH4I, MeCN
S
1:
2:
+
+
135 o
C
O
2l
S
O
O
0%
O
S
O
NH4I, MeCN
135 o
S
C
O
O
O
2m
79%
O
O O
S
NH2
NH4I, DMAC
135 o
N
3:
4:
H
+
+
C
O
S
O
O
4p
0%
O
O O
S
S
NH2
NH4I, DMAC
135 oC
N
H
O
O
4q
45%
The reaction mechanisms were also explored. To determine if radical intermediates are involved in both sulfenylations, TEMPO
(2,2,6,6ꢀTetramethylpiperidinooxy) and BHT (butylated hydroxytoluene) were used as radical scavengers in these reactions
(Scheme 6). In the presence of TEMPO and BHT, both expected products 2a and 4b were still produced in good yields,
indicating that radical intermediates were not involved in both sulfenylation reactions. Based on the above observations and some
previous reports,12 it is believed that nucleophilic substitution reactions might occur via the following processes (Scheme 7).
Scheme 6 Radical trapping experiments.
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O
O
O
S
O
TEMPO
S
1:
NH4I, CH3CN, 135 o
C
C
+
+
O
2a
80%
S
O
O
O
S
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BHT
2:
3:
NH4I, CH3CN, 135 o
O
O
2a
81%
S
O O
S
O
O
NH2
TEMPO
N
H
NH4I, DMAC, 135 o
C
+
O
4a
O
82%
S
O
O O
S
O
NH2
BHT
NH4I, DMAC,135 o
N
H
4:
+
C
O
4a
O
81%
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For DMSO case, at 135 C, NH4I was split into HI and NH3, and the resultant HI reduced DMSO to give electrophilic
intermediate B, which easily reacted with nucleophilic flavone to generate intermediate C. Intermediate C underwent subsequent
Scheme 7. Proposed sulfenylation mechanisms
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attacks from Iꢀ and NH3 to give final product 2. For sulfonyl hydrazine case, the. ꢀSO2NHNH2 function was first reduced by HI,
followed by the loss of H2O to generate intermediate G, which again underwent HI reductive dehydration to give the
thiodiazonium 15. As a good electrophile, it regioselectively reacted with flavone 1 on α position to afford R1Sꢀsubstituted
flavone derivative 4 finally. Alternatively, thiodiazonium 15 could be converted into R1SI by the loss of N2, the reaction of R1SI
with flavone also generated flavone derivative 4.
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CONCLUSIONS
In summary, a novel and efficient ammonium iodideꢀinduced sulfenylation method to construct CꢀS bond via regioselective CꢀH
functionalization was developed, in which DMSO and alkyl/arylsulfonyl hydrazines were used as sulfenylating agents,
generating MeSꢀ and ArSꢀsubstituted flavone derivatives in good yields. Besides this sulfenylation method also works well when
aryl thiol was used as a sulfenylating agent and electronꢀrich heterocycles can also be sulfenylated by this method. The method
greatly enriches current CꢀS bond formation chemistry, making it a highly valuable and practical method in pharmaceutical
industry despite a high temperature and excess of ammonium iodide were used. Investigation on biological activities of flavone
derivatives is currently underway. The method is also quite suitable for compound library production.
EXPERIMENTAL SECTION
General experimental procedures. All reactions were carried out in sealed pressure tubes; stirring was achieved with an
ovenꢀdried magnetic stirring bar. Solvents were purified by standard methods unless otherwise noted. Commercially available
reagents were 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. 1Hꢀ and 13CꢀNMR spectra were recorded
on a spectrometer operating at 400 MHz and 100 MHz respectively. HRMS spectrometry (LCꢀHRMS) was recorded on a
Spectrometer operating on ESIꢀTOF (MeOH as a solvent). Flavones derivatives were synthesized according to existing literature.
General procedure for the syntheses of compounds 2a-m. Flavone 1a (0.5 mmol, 1.0 equiv.) was added to a dried sealed
tube with MeCN (0.5 mL), followed by the addition of NH4I (4.0 equiv.). Then DMSO (0.3 mL) was added to the sealed tube.
o
The mixture was stirred 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 =15:1) on silica gel to give the desired product 2a as a colorless oil in an 81% yield.
The same procedure was applied to the production of other compounds 2b-m.
General procedure for the synthesis of compounds 4a-q, 8, 10. Flavone 1a (0.5 mmol, 1.0 equiv.) was added to a dried
sealed tube with DMAC (0.5 mL), followed by the addition of NH4I (4.0 equiv.) and benzenesulfonyl hydrazide (0.6 mmol, 1.2
o
equiv.). The mixture was stirred at 135 C (monitored by TLC). 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
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purified by flash chromatography (Petroleum ether : EtOAc =15:1) on silica gel to give the desired product 4a in a 83% yield as
colorless oil. The same procedure was applied for producing other compounds 4b-q, 8, 10.
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3-(Methylthio)-4H-chromen-4-one (2a). Following the general procedure, isolated yield (77.8 mg, 81%) as colorless oil;
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FTIR: 3072, 2922，1628, 1466, 1357, 1084, 792 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.24 (dd, J=8.0, 1.6 Hz, 1H), 8.05 (s,
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1H), 7.69ꢀ7.65 (m, 1H), 7.45ꢀ7.40 (m, 1H), 2.40 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 175.6, 156.3, 153.9, 133.8, 126.1,
125.5, 123.1, 121.9, 118.1, 16.3; HRMS (ESIꢀTOF) m/z calculated for C10H8NaO2S+ 215.0137 (M+Na)+, found 215.0132.
6-Methyl-3-(methylthio)-4H-chromen-4-one (2b). Following the general procedure, isolated yield (84.5 mg, 82%) as colorless
oil; FTIR: 3064, 2920, 1639, 1486，1149, 1082, 872 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.04 (s, 1H), 8.02 (d, J=1.2 Hz, 1H),
7.48 (dd, J=8.8, 2.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 2.46 (s, 3H), 2.40 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 175.7, 154.6,
154.0, 135.5, 135.1, 125.3, 122.8, 121.5, 117.8, 21.0, 16.4; HRMS (ESIꢀTOF) m/z calculated for C11H10NaO2S+ 229.0294
(M+Na)+, found 229.0292.
6-Chloro-3-(methylthio)-4H-chromen-4-one (2c). Following the general procedure, isolated yield (82.5 mg, 73%) as colorless
oil; FTIR: 3083, 2917, 1629，1467, 1122, 1086, 818, 651 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.21 (d, J=2.4 Hz, 1H), 8.04 (s,
1H), 7.63 (dd, J=8.8, 2.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 2.41 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 174.5, 154.6, 153.7,
134.0, 131.4, 125.4, 124.0, 122.2, 119.9, 16.1; HRMS (ESIꢀTOF) m/z calculated for C10H7ClNaO2S+ 248.9747 (M+Na)+, found
248.9739.
7-Hydroxy-3-(methylthio)-4H-chromen-4-one (2d). Following the general procedure, isolated yield (83.2 mg, 80%) as
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colorless oil; FTIR: 3117, 2924, 1607, 1571, 1242, 1087, 901, 851 cmꢀ1; H-NMR (MeOD, 400 MHz): δ 8.17(s, 1H), 8.01 (d,
J=8.8 Hz, 1H), 6.94 (dd, J=8.8, 2.0 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 2.37 (s, 3H); 13C-NMR (MeOD, 100 MHz): δ 175.6, 163.4,
158.5, 153.9, 126.8, 121.4, 115.4, 115.3, 101.9, 14.6; HRMS (ESIꢀTOF) m/z calculated for C10H8NaO3S+ 231.0086 (M+H)+,
found 231.0082.
6-Chloro-7-methyl-3-(methylthio)-4H-chromen-4-one (2e). Following the general procedure, isolated yield (86.4 mg, 72%)
as colorless oil; FTIR: 2923, 1633, 1365, 1128, 1090, 911, 874, 644 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.17 (s, 1H), 7.99 (s,
1H), 7.33 (s, 1H), 2.49 (s, 3H), 2.40 (s, 3H); 13CꢀNMR (CDCl3, 100 MHz): δ 174.5, 154.5, 153.6, 143.2, 132.1, 125.6, 122.1,
121.9, 119.9, 20.8, 16.2; HRMS (ESIꢀTOF) m/z calculated for C11H9ClNaO2S+ 262.9904 (M+Na)+, found 262.9898.
3-(Methylthio)-4-oxo-4H-chromene-6-carbonitrile (2f). Following the general procedure, isolated yield (62.9 mg, 58%) as
colorless oil; FTIR: 3104, 2917, 1685, 1366, 1128, 1090, 912, 644 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.60 (d, J=2.0 Hz, 1H),
8.04 (s, 1H), 7.92 (dd, J=8.8, 2.0 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 2.44 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 173.8, 157.9,
153.0, 136.0, 131.9, 123.8, 123.3, 119.9, 117.4, 15.8; HRMS (ESIꢀTOF) m/z calculated for C11H7NNaO2S+ 240.0090 (M+Na)+,
found 240.0089.
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3-(Methylthio)-4H-benzo[h]chromen-4-one (2g). Following the general procedure, isolated yield (94.4 mg, 78%) as colorless
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oil; FTIR: 3067, 2922, 1624, 1392, 1211, 1110, 892, 766 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.48 (dd, J=8.0, 0.8 Hz, 1H),
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8.18 (m, 2H), 7.94 (t, J=8.8 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.75ꢀ7.67 (m, 2H), 2.48 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ
175.4, 153.8, 152.1, 135.8, 129.5, 128.1, 127.3, 125.6, 123.9, 123.8, 122.2,120.9, 119.2, 15.9; HRMS (ESIꢀTOF) m/z calculated
for C14H10NaO2S+ 265.0294 (M+Na)+, found 265.0289.
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3-(Methylthio)-6-nitro-4H-chromen-4-one (2h). Following the general procedure, isolated yield (65.3 mg, 55%) as colorless
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oil; FTIR: 3093, 2920, 1642, 1513, 1342, 1094, 1057, 887, 651 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 9.13 (d, J=2.8 Hz, 1H),
8.52 (dd, J=9.2, 2.8 Hz, 1H), 8.04 (s, 1H), 7.64 (d, J=9.2 Hz, 1H), 2.44 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 174.2, 159.0,
152.8, 144.9, 128.1, 123.8, 123.0, 122.9, 120.0, 15.7; HRMS (ESIꢀTOF) m/z calculated for C10H8NO4S+ 238.0169 (M+H)+,
found 238.0171.
6-Bromo-3-(methylthio)-4H-chromen-4-one (2i). Following the general procedure, isolated yield (98.9 mg, 72%) as colorless
oil; FTIR: 2917, 1628，1464, 1121, 1084, 917, 818 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.38 (d, J=2.4 Hz, 1H), 8.05 (s, 1H),
7.76 (dd, J=8.8, 2.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 2.42 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 174.4, 155.0, 153.7, 136.8,
128.7, 124.4, 122.3, 120.1, 118.8, 16.2; HRMS (ESIꢀTOF) m/z calculated for C10H7BrNaO2S+ 292.9242 (M+Na)+, found
292.9245.
8-Bromo-6-methyl-3-(methylthio)-4H-chromen-4-one (2j). Following the general procedure, isolated yield (92.7mg, 65%) as
colorless oil; FTIR: 3080, 2919, 1645, 1610, 1465, 1327, 1089, 957, 827 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.07 (s, 1H), 7.98
(dd, J=1.6, 0.8 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 2.45 (s, 3H), 2.41 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 175.1, 153.2, 151.1,
138.3, 136.5, 125.0, 123.8, 122.3, 111.1, 20.8, 16.0; HRMS (ESIꢀTOF) m/z calculated for C11H9BrNaO2S+ 306.9399 (M+Na)+,
found 306.9395.
7-Methyl-3-(methylthio)-4H-chromen-4-one (2k) Following the general procedure, isolated yield (84.6 mg, 82%) as
.
colorless oil; FTIR: 3072, 2914, 1622, 1427, 1085, 899, 772, 575 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.11 (d, J=8.4 Hz, 1H),
8.00 (s, 1H), 7.22 (t, J=6.8 Hz, 2H), 2.48 (s, 3H), 2.39 (s, 3H); 13CꢀNMR (CDCl3, 100 MHz): δ 175.5, 156.4, 153.7, 145.2, 127.0,
125.8, 121.6, 120.9, 117.8, 21.8, 16.3; HRMS (ESIꢀTOF) m/z calculated for C11H10NaO2S+ 229.0294 (M+Na)+, found 229.0292.
2-Methyl-3-(methylthio)-4H-chromen-4-one (2m). Following the general procedure, isolated yield (81.5 mg, 79%) as
colorless oil; FTIR: 2924, 1645, 1614, 1558, 1466, 1423, 1349, 1121, 760 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.21 (dd, J=8.0,
1.6 Hz, 1H), 7.67ꢀ7.63 (m, 1H), 7.42ꢀ7.37 (m, 2H), 2.72 (s, 3H), 2.38 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 175.6, 168.7,
155.5, 133.5, 126.2, 125.2, 122.7, 117.7, 117.6, 20.5, 17.1; HRMS (ESIꢀTOF) m/z calculated for C11H10NaO2S+ 229.0294
(M+Na)+, found 229.0289.
3-(Phenylthio)-4H-chromen-4-one (4a). Following the general procedure, isolated yield (105.5 mg, 83%) as colorless oil;
FTIR: 3058, 2925，1653, 1612, 1464, 1309, 1113, 760 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.27 (dd, J=8.0, 1.6 Hz, 1H), 8.18
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(s, 1H), 7.74ꢀ7.70 (m, 1H), 7.51ꢀ7.40 (m, 4H), 7.33ꢀ7.22 (m, 3H); 13C-NMR (CDCl3, 100 MHz): δ 175.1, 157.4, 156.4, 134.0,
129.9, 129.2, 127.1, 126.5, 125.8, 123.7, 120.0, 118.2; HRMS (ESIꢀTOF) m/z calculated for C15H11O2S+ 255.0474 (M+H)+,
found 255.0476.
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3-(p-Tolylthio)-4H-chromen-4-one (4b). Following the general procedure, isolated yield (99.36 mg, 78%) as colorless oil;
FTIR: 3075, 2923, 1647, 1464, 1114, 892, 758 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.25 (dd, J=8.0, 1.6 Hz, 1H), 8.06 (s, 1H),
7.72ꢀ7.67 (m, 1H), 7.49ꢀ7.42 (m, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 2.33 (s, 3H); 13C-NMR (CDCl3, 100
MHz): δ 175.1, 156.3, 156.2, 137.6, 133.9, 131.0, 130.1, 129.8, 126.4, 125.4, 123.6, 121.1, 118.1, 21.1; HRMS (ESIꢀTOF) m/z
calculated for C16H12NaO2S+ 291.0450 (M+Na)+, found 291.0447.
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3-((4-Chlorophenyl)thio)-4H-chromen-4-one (4c). Following the general procedure, isolated yield (116.9 mg, 81%) as
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colorless oil; FTIR: 3051, 1648, 1478，1465, 1313, 1091, 827, 758 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.25 (t, J = 3.2 Hz,
2H), 7.75ꢀ7.71 (m, 1H), 7.52ꢀ7.45 (m, 2H), 7.35ꢀ7.25 (m, 4H); 13C-NMR (CDCl3, 100 MHz): δ 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; HRMS (ESIꢀTOF) m/z calculated for C15H9ClNaO2S+ 310.9904
(M+Na)+, found 310.9894.
3-((4-Bromophenyl)thio)-4H-chromen-4-one (4d). Following the general procedure, isolated yield (131.6 mg, 79%) as
colorless oil; FTIR: 3061, 2925, 1641, 1463, 1086, 901, 798 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.27 (s, 1H), 8.25 (d, J = 1.4
Hz, 1H),7.76ꢀ7.71 (m, 1H), 7.52ꢀ7.45 (m, 2H), 7.41 (dd, J=6.8, 2.0 Hz, 2H), 7.26 (dd, J=8.8, 6.8 Hz, 2H); 13C-NMR (CDCl3, 100
MHz): δ 174.9, 158.1, 156.4, 134.2, 133.6, 132.2, 131.0, 126.5, 126.0, 123.7, 121.0, 119.0, 118.2; HRMS (ESIꢀTOF) m/z
calculated for C15H9BrNaO2S+ 354.9399 (M+Na)+, found 354.9394.
3-((4-(tert-Butyl)phenyl)thio)-4H-chromen-4-one (4e). Following the general procedure, isolated yield (100.9 mg, 65%) as
colorless oil; FTIR: 3070, 2963, 1649, 1611, 1560, 1462, 1115, 846, 764 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.27 (dd, J=8.0,
1.2 Hz, 1H), 8.09 (s, 1H), 7.73ꢀ7.68 (s, 1H), 7.49ꢀ7.43 (m, 2H), 7.40ꢀ7.33 (m, 4H), 1.30 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ
175.2, 156.6, 156.3, 150.7, 133.9, 130.5, 130.0, 126.7, 126.4, 126.3, 125.7, 123.6, 118.1, 34.6, 31.2; HRMS (ESIꢀTOF) m/z
calculated for C19H18NaO2S+ 333. 0920 (M+Na)+, found 333. 0917.
3-(p-Tolylthio)-4H-benzo[h]chromen-4-one (4f). Following the general procedure, isolated yield (119.4 mg, 75%) as colorless
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oil; FTIR: 3057, 2920, 2361, 1650, 1633, 1384, 1113, 886, 765 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.40 (d, J=8.0 Hz, 1H),
8.16 (d, J=8.8 Hz, 1H), 8.08 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.77ꢀ7.64 (m, 3H), 7.43 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H),
2.35 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 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, 123.4, 122.2, 121.0, 119.6, 21.2; HRMS (ESIꢀTOF) m/z calculated for C20H14NaO2S+ 341.0607 (M+Na)+, found
341.0603.
6-Chloro-3-(phenylthio)-4H-chromen-4-one (4g). Following the general procedure, isolated yield (118.4 mg, 82%) as
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colorless oil; FTIR: 3068, 2925, 2360, 1653, 1466, 1303, 1122, 918, 821, 755 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.22 (d,
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J=2.8 Hz, 1H), 8.12 (s, 1H), 7.65 (dd, J=9.2, 2.8 Hz, 1H), 7.47ꢀ7.40 (m, 3H), 7.34ꢀ7.25 (m, 3H); 13C-NMR (CDCl3, 100 MHz):
δ 174.0, 157.0, 154.7, 134.2, 133.4, 131.7, 130.3, 129.3, 127.5, 125.7, 124.5, 120.5, 120.0; HRMS (ESIꢀTOF) m/z calculated for
C15H9ClNaO2S+ 310.9904 (M+Na)+, found 310.9914.
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6-Chloro-7-methyl-3-(p-tolylthio)-4H-chromen-4-one (4h). Following the general procedure, isolated yield (121.9 mg, 77%)
as colorless oil; FTIR: 3060, 2924, 1651，1412, 1097, 899, 786 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.19 (s, 1H), 7.98 (s, 1H),
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7.35 (d, J=8.0 Hz, 3H), 7.13 (d, J=8.0 Hz, 2H), 2.51 (s, 3H), 2.33 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 174.0, 155.9, 154.6,
143.3, 137.8, 132.3, 131.2, 130.1, 129.5, 122.5, 121.2, 119.9, 21.1, 20.9; HRMS (ESIꢀTOF) m/z calculated for C17H13ClNaO2S+
339.0217 (M+Na)+, found 339.0213.
8-Bromo-6-methyl-3-(phenylthio)-4H-chromen-4-one (4i). Following the general procedure, isolated yield (118.1 mg, 68%)
as colorless oil; FTIR: 3054, 2925, 2360, 1660, 1463, 1299, 1090, 785, 691 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H),
7.98 (d, J=1.2 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.43 (d, J=3.6, 1.6 Hz, 2H), 7.34ꢀ7.24 (m, 3H), 2.45 (s, 3H); 13C-NMR (CDCl3,
100 MHz): δ 174.5, 156.4, 151.2, 138.5, 136.8, 133.2, 130.5, 129.3, 127.5, 125.3, 124.3, 120.8, 111.2, 20.8; HRMS (ESIꢀTOF)
m/z calculated for C16H11BrNaO2S+ 368.9555 (M+Na)+, found 368. 9553.
3-((4-Chlorophenyl)thio)-4-oxo-4H-chromene-6-carbonitrile (4j). Following the general procedure, isolated yield (101.6 mg,
65%) as colorless oil; FTIR: 3054, 2924, 2361, 1654, 1475, 1313, 815, 670 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.58 (d, J=2.0
Hz, 1H), 8.16 (s, 1H), 7.94 (dd, J=8.8, 2.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H); 13C-
NMR (CDCl3, 100 MHz): δ 173.2, 158.0, 156.7, 136.3, 134.1, 132.2, 132.1, 131.1, 129.6, 123.9, 121.7, 120.0, 117.2, 110.2;
HRMS (ESIꢀTOF) m/z calculated for C16H8ClNNaO2S+ 335.9856 (M+Na)+, found 335.9853.
6-Nitro-3-(phenylthio)-4H-chromen-4-one (4k). Following the general procedure, isolated yield (103.3 mg, 69%) as colorless
oil; FTIR: 3061, 2342, 1655, 1524, 1346, 1105, 835, 738 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 9.12 (d, J=2.8 Hz, 1H), 8.52 (dd,
J=9.2, 2.8 Hz,1H), 8.04 (s, 1H), 7.60 (d, J=9.2 Hz, 1H),7.48 (dd, J=8.0, 1.6 Hz, 2H), 7.38ꢀ7.32 (m, 3H); 13C-NMR (CDCl3, 100
MHz): δ 173.6, 159.0, 155.7, 145.0, 132.1, 131.4, 129.5, 128.2, 128.1, 123.4, 123.2, 122.7, 120.0; HRMS (ESIꢀTOF) m/z
calculated for C15H9NNaO4S+ 322.0144 (M+Na)+, found 322.0143.
6-Bromo-3-(phenylthio)-4H-chromen-4-one (4l). Following the general procedure, isolated yield (121.6 mg, 73%) as
colorless oil; FTIR: 3058, 2923, 1652, 1548, 1462, 1121, 908, 818, 735 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.38 (d, J=2.4 Hz,
1H), 8.12 (s, 1H), 7.78 (q, J=2.4, 1H), 7.43ꢀ7.38 (m, 3H),7.34ꢀ7.24 (m, 3H); 13C-NMR (CDCl3, 100 MHz): δ 173.8, 157.0, 155.1,
137.0, 133.4, 130.3, 129.3, 129.0, 127.5, 124.8, 120.6, 120.2, 119.2; HRMS (ESIꢀTOF) m/z calculated for C15H9BrNaO2S+
354.9399 (M+Na)+, found 354.9394.
3-((4-Chlorophenyl)thio)-6-methyl-4H-chromen-4-one (4m). Following the general procedure, isolated yield (118.1 mg,
78%) as colorless oil; FTIR: 3053, 2922, 1639, 1478, 1311, 1091, 812, 789 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.24 (s, 1H),
8.03 (d, J=1.2 Hz, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.33ꢀ7.22 (m, 4H); 13C-NMR (CDCl3, 100 MHz): δ
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175.1, 158.1, 154.7, 136.1, 135.4, 133.1, 132.9, 130.7, 129.2, 125.7, 123.4, 118.8, 118.0, 21.0; HRMS (ESIꢀTOF) m/z calculated
for C16H11ClNaO2S+ 325.0060 (M+Na)+, found 325.0049.
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1H), 7.64ꢀ7.60 (m, 1H), 7.40ꢀ7.34 (m, 1H), 2.35 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 175.6, 156.3, 153.9, 133.8, 126.1,
125.5, 123.1, 121.9, 118.1, 16.3; HRMS (ESIꢀTOF) m/z calculated for C10H8NaO2S+ 215.0137 (M+Na)+, found 215.0137.
3-(Methylthio)-6-nitro-4H-chromen-4-one (4o). Following the general procedure, isolated yield (93.7 mg, 79%) as colorless
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oil; FTIR: 3093, 2920, 1642, 1513, 1342, 1094, 1057, 887, 651 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 9.10 (d, J=2.8 Hz, 1H),
8.51 (dd, J=9.2, 2.8 Hz, 1H), 8.03 (s, 1H), 7.64 (d, J=9.2 Hz, 1H), 2.43 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 174.2, 159.0,
152.8, 144.9, 128.1, 123.8, 123.0, 122.9, 120.0, 15.7; HRMS (ESIꢀTOF) m/z calculated for C10H8NO4S+ 238.0169 (M+H)+,
found 238.0171.
2-Methyl-3-(phenylthio)-4H-chromen-4-one (4q). Following the general procedure, isolated yield (60.4 mg, 45%) as colorless
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oil; FTIR: 3050, 2924, 1647, 1465, 1120, 982, 764, 691 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.23 (dd, J=7.6, 1.2 Hz, 1H),
7.71ꢀ7.67 (m, 1H), 7.47ꢀ7.40 (m, 2H), 7.28ꢀ7.25 (m, 4H), 7.24ꢀ7.12 (m, 1H), 2.74 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 175.3,
171.5, 155.6, 135.7, 133.8, 129.3, 129.0, 127.5, 126.6, 126.0, 125.5, 122.9, 117.7, 115.3, 20.8; HRMS (ESIꢀTOF) m/z calculated
for C16H12NaO2S+ 291.0450 (M+Na)+, found 291.0451.
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3-(p-Tolylthio)-1H-indole (8).12b Following the general procedure, isolated yield (99.2 mg, 83%) as colorless oil; H-NMR
(CDCl3, 400 MHz): δ 8.23 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.45ꢀ7.43 (m, 2H), 7.38ꢀ7.34 (m, 1H), 7.29ꢀ7.25 (m, 1H), 7.15 (d,
J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 2.35 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 136.5, 135.6, 134.9, 130.7, 129.7, 129.2,
126.4, 123.1, 120.9, 119.7, 111.8, 103.2, 21.0.
2-Phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (10).13a Following the general procedure, isolated yield (134.3 mg, 85%) as
1
colorless oil; H-NMR (CDCl3, 400 MHz): δ 8.29ꢀ8.26 (m, 3H), 7.74 (d, J=9.2 Hz, 1H), 7.48ꢀ7.45 (m, 2H), 7.39 (t, J=7.2 Hz,
4H), 7.31ꢀ7.27 (m, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.82 (t, J=6.8 Hz, 1H), 2.26 (s, 3H); 13C-NMR (CDCl3,
100 MHz): δ 151.2, 147.0, 136.0, 133.5, 131.5, 130.2, 128.6, 128.5, 128.4, 126.6, 125.8, 124.5, 117.6, 113.0, 106.9, 20.9.
3-(Methylsulfinyl)-4H-chromen-4-one (13).13b Following the general procedure, isolated yield (93.6 mg, 90%) as colorless
1
oil; FTIR: 3070, 2921, 1642, 1611 1072, 827 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.31 (s, 1H), 8.23 (dd, J=9.6, 1.6 Hz, 1H),
7.82ꢀ7.78 (m, 1H),7.60 (d, J=8.0 Hz, 1H), 7.55ꢀ7.51(m, 1H), 3.02 (s, 3H); HRMS (ESIꢀTOF) m/z calculated for C10H8NaO3S+
231.0086 (M+Na)+, found 231.0083.
3-(Methylsulfonyl)-4H-chromen-4-one (14). Following the general procedure, isolated yield (98.6 mg, 88%) as colorless oil;
FTIR: 3082 2965, 1678, 1527, 1285, 889, 782 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.75 (s, 1H), 8.30 (dd, J=8.0, 1.2 Hz, 1H),
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7.84ꢀ7.80 (m, 1H), 7.61ꢀ7.54 (m, 1H), 3.37 (s, 3H); HRMS (ESIꢀTOF) m/z calculated for C10H8NaO4S+ 247.0036 (M+Na)+,
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found 247.0031.
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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, geh@iupui.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This investigation was generously supported by the funding (1281290006) provided by Jiangsu University.
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