Iodine-Mediated Synthesis of 2-(Methylthio)-4 H-chromen-4-ones and Study of Their Halogenation Reactions

Article abstract of DOI:10.1021/acs.joc.1c00788

An efficient iodine-mediated method is developed for the synthesis of functionalized 2-(methylthio)-4H-chromen-4-ones by intramolecular cyclization of easily accessible 1-(2-benzyloxy-aryl)-3,3-bis-methylsulfanyl-propenones. The synthesized chromen-4-ones turn out to be a key precursor for various kinds of chemical reactions. Mechanistically, we observed that iodine-mediated intramolecular cyclization of ketene dithioacetal proceeded through a radical pathway. 3-Halo-2-(methylthio)-4H-chromen-4-ones were achieved via various two- or one-pot halogenation approaches.

Full text of DOI:10.1021/acs.joc.1c00788

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Article
Iodine-Mediated Synthesis of 2‑(Methylthio)‑4H‑chromen-4-ones
and Study of Their Halogenation Reactions
Amr Elagamy, Ranjay Shaw, Chandan Shah, and Ramendra Pratap*
Cite This: J. Org. Chem. 2021, 86, 9478−9489
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sı Supporting Information
ABSTRACT: An efficient iodine-mediated method is developed for the synthesis of functionalized 2-(methylthio)-4H-chromen-4-
ones by intramolecular cyclization of easily accessible 1-(2-benzyloxy-aryl)-3,3-bis-methylsulfanyl-propenones. The synthesized
chromen-4-ones turn out to be a key precursor for various kinds of chemical reactions. Mechanistically, we observed that iodine-
mediated intramolecular cyclization of ketene dithioacetal proceeded through a radical pathway. 3-Halo-2-(methylthio)-4H-
chromen-4-ones were achieved via various two- or one-pot halogenation approaches.
INTRODUCTION
3-bromo-chromone from chromone) has been accomplished
■
+
−
using a mixture of DMP and Et N Br or NBS−Et N·3HBr
4
3
Chromone skeleton is present in many naturally occurring
16,17
1
and K CO in dry DCM.
However, there is no particular
compounds, and its derivatives exhibit a broad range of
2
3
study established for the halogenation of chromone derivatives.
So far, very limited literature studies for the synthesis of 2/3-
important biological activities such as anti-inflammatory,
antiallergic, antitumor, anticancer, and antimicrobial. Chro-
mones are privileged structures and valuable intermediates in
the synthesis of new heterocyclic compounds.
2
(
methylthio)-4H-chromen-4-ones are reported. In 2015,
2
c,3
sulfenylation of chromones was first reported by Zheng and
The most
18
4
co-workers via C−H functionalization. Zhou and co-workers
well-known synthetic routes enclose Claisen condensation,
5
Vilsmeier−Haack reaction, Baker−Venkataraman rearrange-
reported another sulfenylation method by using alkyl halides
6
3,7
19
ment, Simonis and Ruhemann reactions, catalytic reactions
and Na
2
S O
2
.
3
These methods provide 3-alkylthio- or 3-
8
mediated by palladium, and the oxidative cyclization of 2′-
arylthio-chromones, while no substitution occurs at the C-2
position even if the reaction site C-3 is blocked. Lee and Pak
have reported the one-pot synthesis of 2-(methylthio)-4H-
chromen-4-ones from 2-hydroxyacetophenones through a
9
10
hydroxychalcones, 2′-allyloxychalcones, or 2′-benzyloxy-6′-
1
1
hydroxychalcone using a catalytic amount of iodine in
DMSO. Yang et al. reported a green approach for the synthesis
of 3-thiocyanated chromones from o-hydroxyaryl enaminones
20
ketene dithioacetal intermediate. Although this method
provides direct preparation of 2-(methylthio)-4H-chromen-4-
ones, it requires very low reaction temperature (−78 °C) and
the use of strong and moisture sensitive base lithium
bis(trimethylsilyl)amide (LiHMDS), and the generality of
protocol was not tested. We have tried to obtain the desired
product under the same reaction conditions, but we got low
yield. Apart from this, there are no other specific methods
12
under electrochemical thiocyanation conditions. In recent
years, C−H activation and annulation methodologies based on
salicylaldehyde derivatives have been developed for the
synthesis of chromones employing substrates such as alkynes,
1
3
alkynoic acids, diazo compounds, and sulfoxonium ylides.
Larock and co-workers described the successful use of iodine
monochloride for the synthesis of chromones, benzo[b]furans,
and α-pyrones via electrophilic cyclization reaction of o-
alkoxyalkynones, o-alkoxyalkynes, and alkynyl ester, respec-
1
4
Received: April 4, 2021
Published: July 7, 2021
tively.
On the other hand, α-aroyl-α-bromoketene dithioacetals
have been synthesized via direct bromination of the
corresponding α-aroylketene dithioacetals using NBS in
1
5
CCl4. Besides, a study for the synthesis of α-bromo-α,β-
unsaturated ketones from α,β-unsaturated ketones (including
©
2021 American Chemical Society
https://doi.org/10.1021/acs.joc.1c00788
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known for the synthesis of 2-(methylthio)-4H-chromen-4-
ones.
Table 1. Exploration and Optimization Studies for the
Synthesis of 2-(Methylthio)-4H-chromen-4-one
a
Functionalized ketene dithioacetals are versatile intermedi-
ates in the synthesis of various classes of heterocyclic
compounds such as furans, thiophenes, pyrroles, pyridines,
2
1
and lactones. Herein, we reported a synthetic route to 2-
methylthio)-4H-chromen-4-ones via iodine-mediated cycliza-
tion of α-aroylketene dithioacetals. In addition, a survey for the
(
b
entry
reagent
50 mol % CuI
solvent, time
yield
halogenation of chromones was accomplished.
1
2
3
4
5
6
7
1 mL DMSO, 24 h
1 mL DMSO, 24 h
1 mL DMSO, 24 h
1 mL DCE, 24 h
0
0
0
0
c
50 mol % Cu(OAc)2
50 mol % PIDA
50 mol % PIDA
10 mol % CuI, 4 equiv TBHP
10 mol % CuI, 4 equiv TBHP
100 mol % DDQ
13 mmol TFA
50 mol % I2
50 mol % I2
50 mol % I2
50 mol % I2
RESULT AND DISCUSSION
■
The required precursors 1a−k were synthesized by reaction of
functionalized acetophenones, carbon disulfide, and methyl
iodide under basic conditions at low temperature (Scheme
1 mL DMSO, 24 h
c
1 mL CH CN, 24 h
2
2
3
1
). This method failed to provide precursor 1l using 1,2-
1 mL CH CN, 24 h
0
73%
e
3
d
8
2 mL DCE, 24 h
1 mL DMSO, 24 h
1 mL benzene, 3 h
1 mL THF, 3 h
1 mL DCE, 3 h
1 mL DCE, 3 h
Scheme 1. Synthesis of 1-(2-Benzyloxy-aryl)-3,3-bis-
9
a
methylsulfanyl-propenones 1a−k and 1-(2-
1
1
1
0
1
2
f
0
(
1
Benzyloxy)phenyl)-2-(1,3-dithiolan-2-ylidene)ethan-1-one
l
e
trace
95%
81%
b
1
3
50 mol % I2
a
Unless noted otherwise, reactions were performed on a 0.30 mmol
b
scale using 1a as a starting material at 80 °C. Isolated yield.
c
d
Complex mixture formation. The reaction was run at room
e
f
temperature. Decomposition of the starting material. The reaction
was run at 60 °C.
benzene as an oxidizing agent in DMSO or DCE did not
produce the compound 2a (entries 3 and 4). It was also found
that using tert-butyl hydroperoxide along with CuI in DMSO
or CH CN gives a complex mixture and the use of DDQ in
3
CH CN provided no desired product (entries 5−7). The use
3
of trifluoroacetic acid in DCE at room temperature provides
the desired chromone in 73% yield (entry 8), while increasing
the temperature up to 80 °C does not provide better yield. The
treatment of 1a with DMSO-I reagent commonly used for the
2
oxidative cyclization of 2′-hydroxychalcones to flavones results
in decomposition of the starting material (entry 9).
Furthermore, the use of iodine catalyst in benzene and THF
provides no product and only a trace amount of 2a,
respectively (entries 10 and 11). When iodine catalyst was
used in DCE solvent at 80 °C, the reaction proceeded well and
we successfully achieved the desired chromone in 95% yield
within 3 h (entry 12). Lowering the temperature from 80 to 60
°
C dropped the yield to 81% (entry 13).
To study the effect of a protecting group at the ortho
a
Precursors 1a−k were synthesized by stirring functionalized
acetophenones (2.0 mmol), carbon disulfide (2.40 mmol), methyl
hydroxyl group of α-aroylketene dithioacetal, other protecting
groups such as allyl, methoxymethyl, and methyl were used
instead of the benzyl group (Scheme 2). When the ortho
hydroxyl group was protected with allyl, methoxymethyl, and
methyl group, 74%, 70%, and 0% yields of 2-(methylthio)-4H-
chromen-4-one 2a were obtained, respectively. Therefore,
further synthesis was carried out with 1-(2-benzyloxy-aryl)-3,3-
bis-methylsulfanyl-propenones as precursor following the
optimal condition (entry 12).
Initially, we examined the scope of the oxidative cyclization
reaction with respect to various 1-(2-(benzyloxy)aryl)-3,3-
bis(methylthio)prop-2-en-1-ones. The reaction proceeded well
and the desired chromones were achieved in good to excellent
yields as illustrated in Scheme 3. The structure of 2g was
confirmed using single-crystal X-ray diffraction (see Figure S1,
Supporting Information (SI)). It was noticed that 1-(2/1-
benzyloxy-naphthalen-1/2-yl)-3,3-bis-methylsulfanyl-prope-
iodide (4.40 mmol), and NaH (8 mmol) in dry THF (10.0 mL) at 0
b
°
C for 5−6 h. Precursor 1l was synthesized by stirring 1-(2-
(
benzyloxy)phenyl)ethan-1-one (2.0 mmol), carbon disulfide (2.40
mmol), 1,2-dibromoethane (4.40 mmol), and potassium tert-butoxide
(8.0 mmol) in dry THF (8.0 mL) at 0 °C for 6 h.
dibromoethane in lieu of methyl iodide under the same
reaction conditions. Therefore, we have tried another
procedure, and we successfully achieved the desired
precursor 1l in 52% yield (Scheme 1).
To find optimal reaction conditions for intramolecular
oxidative cyclization, 1-(2-(benzyloxy)phenyl)-3,3-bis-
2
3
(
methylthio)prop-2-en-1-one 1a was selected as a model
substrate. The results are presented in Table 1. Treatment of
a with CuI or Cu(OAc) as a catalyst in DMSO provided no
1
2
desired product (entries 1 and 2). The use of (diacetoxyiodo)-
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a
Scheme 2. Examination of Various Protecting Groups for the Synthesis of 2-(Methylthio)-4H-chromen-4-one
a
All reactions were performed by stirring 1 (0.50 mmol) and I (0.25 mmol) in DCE (1 mL) at 80 °C for 3 h.
2
Scheme 3. Synthesis of 2-(Methylthio)-4H-chromen-4-ones
developed the practical synthesis of some chromone
derivatives via conducting scale-up experiments. Thusly,
chromone products 2a and 2f were obtained in yields of
from 1-(2-Benzyloxy-aryl)-3,3-bis-methylsulfanyl-
a
propenones
89% (0.52 g) and 86% (1.06 g), respectively.
Next, we have synthesized 3-chloro/bromo-chromones in
high yields using NCS/NBS at 80 °C. A trial using NIS also
provides the corresponding iodinated product in a competitive
yield. Since NIS is quite an expensive reagent as compared to
NCS and NBS, a new method for the synthesis of 3-iodo-
chromones was established by heating 2a−h with DDQ and
iodine in DCE for 2 h at 80 °C (Scheme 4).
Further, we investigated the halogenation under a one-pot
approach from 1-(2-benzyloxy-aryl)-3,3-bis-methylsulfanyl-
propenones. After monitoring the complete formation of 2-
(
methylthio)-4H-chromen-4-ones, NBS was added to the
reaction mixture under the same reaction condition, and
surprisingly, major 3-bromo-chromone along with minor 3-
iodo-chromone was observed. An attempt to quench the excess
of iodine prior to addition of NBS using sodium thiosulfate
was unsuccessful. Moreover, addition of NCS under similar
reaction conditions provides 3-iodo-chromone along with a
trace of 3-chloro-chromone. However, 3-iodo-chromones were
selectively afforded by addition of iodine, followed by dropwise
addition of a solution of NCS in DCE (Scheme 5).
a
All reactions were performed by stirring 1 (1.0 mmol) and I (0.50
2
b
mmol) in DCE (2 mL) at 80 °C for 3 h. The procedure was scaled
up to a gram scale.
In order to study the effect of iodine during one-pot
halogenation, we independently carried out the reaction of 6-
methyl-2-(methylthio)-4H-chromen-4-one 2c with 1 equiv of
iodine and 0.5 equiv of NCS/NBS at room temperature and
afforded 3-iodo-6-methyl-2-(methylthio)-4H-chromen-4-one
3i selectively (Scheme 6).
nones 1g and 1h provided relatively lower yields of the desired
products as compared to 1-(2-benzyloxyphenyl)-3,3-bis-
methylsulfanyl-propenones 1a−f and 1i, probably due to
involvement of an additional electronic factor. Then, we have
Scheme 4. Scope of Synthesis of 3-Halo-2-(methylthio)-4H-chromen-4-onesa,b
a
Bromination and chlorination reactions were performed by stirring 2 (0.30 mmol) and (NBS or NCS) (0.36 mmol) in DCE (1 mL) at 80 °C for
b
3
0 min. Iodination reaction was performed by stirring 2 (0.30 mmol), DDQ (0.36 mmol), and I (0.36 mmol) in DCE (1 mL) at 80 °C for 2 h.
2
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Scheme 5. Scope of One-Pot Synthesis of 3-Iodo-2-
The mechanism of the oxidative cyclization was investigated
and established by the control experiments (Scheme 7, eqs 1
and 2). Initially, we performed the cyclization reaction in the
presence of a radical scavenger, (2,2,6,6-tetramethylpiperidin-
a
(methylthio)-4H-chromen-4-ones
1-yl)oxyl (TEMPO) or butylated hydroxytoluene (BHT),
under standard conditions. The reaction was completely
inhibited in the presence of TEMPO, whereas the product
yield was significantly lowered in the presence of BHT
(
Scheme 7, eqs 1 and 2). In addition, we have identified the
BHT-trapped chromone compound 4a, indicating that a
radical pathway might be involved in this transformation.
Therefore, the free radical mechanism starts with abstraction of
one electron from the ethereal oxygen lone pair of compound
1
to form intermediate I, which undergoes cyclization to
generate radical cation II, followed by deprotection of the
benzyl group to provide radical intermediate III and benzyl
iodide. The removal of the SMe radical from intermediate III
results in the formation of chromone 2, and the SMe radical
reacts with benzyl iodide to form benzyl(methyl)sulfane
(Scheme 8).
To probe the mechanism, starting material 1l was used and
we have isolated 2-(1,3-dithiolan-2-ylidene)-1-(2-hydroxy-
phenyl)ethan-1-one 5 in 79% yield within 2 h. Although,
when the reaction was carried out for a longer time (12 h), 2-
a
The reaction was performed by stirring 1 (0.30 mmol) and I (0.15
2
mmol) in DCE (1 mL) at 80 °C for 3 h, and subsequent treatment
with I (0.15 mmol) and a solution of NCS (0.22 mmol) in DCE (0.5
mL) at 80 °C for 30 min.
2
Scheme 6. Iodination Using NCS/NBS and Iodine at Room
Temperature (Synthesis of 3-Iodo-6-methyl-2-
a
(methylthio)-4H-chromen-4-one)
(
(2-(benzylthio)ethyl)thio)-4H-chromen-4-one 2l was isolated
in 19% yield. This result confirms that the SMe group was
eliminated as benzyl(methyl)sulfane.
The mechanism of the halogenation reaction was established
by the control experiments (Scheme 7, eqs 3−5). Radical
scavenger experiment of 2a with TEMPO or BHT using NXS
in DCE at 80 °C provide the desired products 3a−b in high
yields (Scheme 7, eq 3), indicating that radical species is not
involved and the reaction proceeds via an electrophilic
substitution pathway. The halogenation reactions of com-
pound 2f using DDQ/I2 at 80 °C or NXS/I2 at room
a
Iodination reaction was performed by stirring 2c (0.30 mmol), I2
(
0.30 mmol), and NXS (0.15 mmol) in DCE (1 mL) at room
temperature for 1 h.
Scheme 7. Control Experiments
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Scheme 8. Proposed Reaction Mechanism for Intramolecular Cyclization of 1-(2-Benzyloxy-aryl)-3,3-bis-methylsulfanyl-
propenones Using Iodine in DCE
Scheme 9. Proposed Reaction Mechanism for Iodination of 2-(Methylthio)-4H-chromen-4-ones Using I and DDQ
2
Scheme 10. Synthetic Utility of 2-(Methylthio)-4H-chromen-4-ones
temperature were totally inhibited in the presence of TEMPO
or BHT. We have also identified the BHT-trapped chromone
compound in all cases (Scheme 7, eqs 4 and 5), indicating that
a radical pathway might be involved in this reaction.
mechanism is proposed for iodination using NXS and I (see
Scheme S1, SI).
To demonstrate the utility of 2-(methylthio)-4H-chromen-
2
4-ones, various kinds of chemical reactions were conducted as
shown in Scheme 10. Synthesis of halogenated chromones 3a−
x is considered to be an example of an electrophilic
substitution reaction at the C-3 position of chromones. The
Liebeskind−Srogl coupling reaction was carried out using the
A plausible reaction mechanism for the iodination of 2-
(
methylthio)-4H-chromen-4-ones with DDQ and I is shown
2
in (Scheme 9). A single electron transfer from 2 to DDQ
results in the formation of radical cation I, which reacts with
iodine to generate the cation intermediate II, followed by
proton transfer to provide product 3. A similar reaction
24
previously reported literature to provide 4′-ethylflavone 6 in
92% yield. Nucleophilic substitution reaction at the C-2
position was performed using primary and secondary amines to
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provide the corresponding aminated chromones in very good
yields. Deprotection of the benzyl group from compound 8b
and 2b was carried out in the presence of an excess amount of
TFA to give 3-chloro-7-hydroxy-2-(phenylamino)-4H-chro-
men-4-one 9 and 7-hydroxy-2-(methylthio)-4H-chromen-4-
one 10 in 93% and 95% yields, respectively. On the basis of a
previously reported procedure, we have achieved reductive
desulfuration of 2-(methylthio)-4H-chromen-4-one 2a and 3-
methyl-2-(methylthio)-4H-chromen-4-one 2i in very good
yields through refluxing with freshly prepared Raney nickel
in ethanol for 12 h.
and was washed with water (20.0 mL × 2), dried, and recrystallized
from hexane.
Synthetic Procedure for 1-(2-(Benzyloxy)phenyl)-2-(1,3-
dithiolan-2-ylidene)ethan-1-one 1l. To a stirred suspension of
potassium tert-butoxide (898 mg, 8.0 mmol) in dry THF (3.0 mL) at
0
°C was dropwise added a dry THF solution (3.0 mL) of 1-(2-
(benzyloxy)phenyl)ethan-1-one (453 mg, 2.0 mmol) and carbon
25
disulfide (145 mg, 2.40 mmol). The reaction mixture was vigorously
stirred at 0 °C for 90 min. To this suspension was added a dry THF
solution (2 mL) of 1,2-dibromoethane (379 mg, 4.40 mmol)
dropwise within 10 min at 0 °C. The reaction mixture was stirred
for 6 h. After completion of the reaction, the mixture was poured into
a saturated aqueous solution of ammonium chloride with crushed ice.
Then, the aqueous solution was extracted with ethyl acetate (3 × 20
mL). The combined organic extracts were washed with brine (1 × 20
mL), dried, and then concentrated under vacuum to obtain the crude
product. Pure product was obtained by silica gel column
chromatography using 10% EtOAc/hexane.
CONCLUSION
■
In summary, we have developed an efficient method for the
synthesis of 2-(methylthio)-4H-chromen-4-ones via oxidative
cyclization of easily accessible precursors 1-(2-benzyloxy-aryl)-
General Procedure for the Synthesis of 2-(Methylthio)-4H-
chromen-4-ones (2a−i). A 10 mL Schlenk tube equipped with a
magnetic stirring bar was charged with 1-(2-benzyloxy-aryl)-3,3-bis-
methylsulfanyl-propenones 1a−i (1 mmol) and DCE (2 mL),
followed by addition of iodine (0.50 mmol). The reaction mixture
was stirred at 80 °C (oil bath) for 3 h. After completion, the reaction
mixture was quenched with 3% Na S O (5 mL), diluted with brine
3
,3-bis-methylsulfanyl-propenones under mild conditions in
high yields. Bromination and chlorination of 4H-chromen-4-
ones at the C-3 position proceeded through an electrophilic
substitution reaction. Iodination was achieved through a free
radical pathway. One- and two-pot approaches were developed
to access iodinated chromones using I /NCS and I /DDQ,
2
2
3
2
2
(
10 mL), and extracted with DCM (15 mL × 3). The combined
respectively, at 80 °C. Iodination using I /NXS at room
2
organic layer was dried over anhydrous Na SO , concentrated, and
2
4
temperature was the most interesting finding, where no
chlorination or bromination occurs as side reaction and
selective iodination was achieved. Various kinds of chemical
reactions were conducted to demonstrate the synthetic
potential of 2-(methylthio)-4H-chromen-4-ones. During syn-
thetic applicability, we have achieved 3-methyl-4H-chromen-4-
one (CAS No. 85-90-5) in good yield by simple reductive
desulfuration, which is an expensive reagent.
purified through silica gel column chromatography using 10% EtOAc/
hexane to afford the desired chromones.
Gram-Scale Procedure for the Synthesis of 2-(Methylthio)-
4H-chromen-4-ones 2a. A 50 mL round-bottom flask equipped
with a magnetic stirring bar was charged with 1-(2-(benzyloxy)-
phenyl)-3,3-bis(methylthio)prop-2-en-1-one 1a (1 g, 3.02 mmol) and
DCE (6 mL), followed by addition of iodine (1.5 mmol). The
reaction mixture was stirred at 80 °C (oil bath) for 4−5 h. After
completion, the reaction mixture was quenched with 3% Na S O (50
2
2
3
mL), diluted with brine (50 mL), and extracted with DCM (50 mL ×
EXPERIMENTAL SECTION
3). The combined organic layer was dried over anhydrous Na SO
2
,
4
■
concentrated, and purified through silica gel column chromatography
using 10% EtOAc/hexane to afford the desired chromone 2a in 89%
yield (0.52 g).
General Information. Commercially available reagent and
solvent purchased by Sigma-Aldrich and Alfa Aesar were used directly
without further purification. Reactions were monitored by analytical
thin-layer chromatography (TLC). All reactions were conducted
using dried glassware. IR spectra were recorded on an IR
spectrophotometer, and stretching frequencies were reported in
Gram-Scale Procedure for the Synthesis of 6-Methoxy-2-
methylthio)-4H-chromen-4-one 2f. A 50 mL round-bottom flask
(
equipped with a magnetic stirring bar was charged with 1-(2-
benzyloxy)-5-methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one
f (2 g, 5.5 mmol) and DCE (10 mL), followed by addition of iodine
2.7 mmol). The reaction mixture was stirred at 80 °C (oil bath) for
−5 h. After completion, the reaction mixture was quenched with 6%
Na S O (100 mL), diluted with brine (100 mL), and extracted with
(
1
(
4
−
1
1
13
wavenumber (cm ). The H NMR (400 MHz) and C NMR (100
MHz) spectra were recorded in CDCl solution using chloroform
3
1
13
peak (7.24 ppm for H and 77.0 ppm for C) as reference. Only
spectra of compounds 9 and 10 were recorded in DMSO-d solution
6
1
13
2
2
3
using the DMSO peak (2.50 ppm for H and 39.52 ppm for C) as
DCM (75 mL × 3). The combined organic layer was dried over
26
27
28
29
reference. Compounds 2a, 6, 7a,b, and 11a,b are known; the
remaining compounds are newly synthesized. The coupling constants
J are reported in Hz, and signal patterns are reported as s, singlet; br,
broad; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet
doublets. High-resolution mass spectra were recorded on a quadru-
pole-time-of-flight (Q-TOF) mass spectrometer equipped with an
electrospray ion source (ESI-TOF).
anhydrous Na SO , concentrated, and purified through silica gel
2
4
column chromatography using 10% EtOAc/hexane to afford the
desired chromone 2f in 86% yield (1.06 g).
General Procedure for the Synthesis of 3-Chloro/bromo-2-
methylthio)-4H-chromen-4-ones (3a,b, 3d,e, 3g,h, 3j,k, 3m,n,
(
3p,q, 3s,t, and 3v,w). A solution of 2-(methylthio)-4H-chromen-4-
ones 2a−h (0.30 mmol) in DCE (1 mL) was treated with NBS or
NCS (0.36 mmol) and then stirred at 80 °C (oil bath) for 30 min.
Completion of the reaction was monitored by TLC. After completion,
DCE was removed under vacuum, and the crude 3-chloro and 3-
bromo-chromones were purified by column chromatography using 5%
EtOAc/hexane.
General Procedure for the Synthesis of 1-(2-Benzyloxy-
aryl)-3,3-bis-methylsulfanyl-propenones (1a−k). To a stirred
suspension of NaH (8.0 mmol) (previously washed with hexane in
order to remove mineral oil) in THF (8.0 mL) was added a solution
of functionalized acetophenones (2.0 mmol) in THF (2.0 mL)
dropwise within 15 min at 0 °C. The reaction mixture was stirred for
General Procedure for the Synthesis of 3-Iodo-2-(methyl-
2
0 min at 0 °C; then carbon disulfide (2.40 mmol) was added
dropwise within 15 min at 0 °C. The reaction mixture was stirred for
0 min at 0 °C; then methyl iodide (4.40 mmol) was added dropwise
during 15 min at 0 °C. The reaction mixture was stirred for 15 min at
thio)-4H-chromen-4-ones (3c, 3f, 3i, 3l, 3o, 3r, 3u, and 3x)
Using I /DDQ. A solution of 2-(methylthio)-4H-chromen-4-ones
2
3
2a−h (0.30 mmol) in DCE (1 mL) was treated with DDQ (0.36
mmol) and I (0.36 mmol) in sequence and then stirred at 80 °C (oil
2
0
°C, then warmed to room temperature, and stirred for 5−6 h.
bath) for 2 h. After completion, the reaction mixture was quenched
with 5% Na S O (5 mL), diluted with brine (10 mL), and extracted
Completion of the reaction was monitored by TLC. After completion,
THF was removed under vacuum, and ice-cold water (20.0 mL) was
added to the mixture and stirred well. The formed solid was filtered
2
2
3
with DCM (15 mL × 3). The combined organic layer was dried over
anhydrous Na SO , concentrated, and purified through silica gel
2
4
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column chromatography using 5% EtOAc/hexane to afford 3-iodo-2-
156.7, 136.2, 132.5, 131.4, 129.5, 128.5, 128.2, 128.0, 121.1, 114.9,
(
methylthio)-4H-chromen-4-ones.
General Procedure for the One-Pot Synthesis of 3-Iodo-2-
112.5, 70.6, 16.3, 15.0; HRMS (ESI) m/z calcd for C H O S [M +
1
8
19
2 2
+
H] 331.0821, found 331.0825.
(methylthio)-4H-chromen-4-ones (3c, 3f, 3i, 3l, 3u, and 3x). A
1-(2,4-Bis(benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-
one (1b). Yield: 90% (812 mg), white solid (recrystallized from
hexane), mp: 135−137 °C; IR (KBr): 3031, 2921, 1589, 1478, 757
solution of 1-(2-benzyloxy-aryl)-3,3-bis-methylsulfanyl-propenones 1
0.30 mmol) in DCE (1 mL) was treated with iodine (0.15 mmol)
(
−
1
1
and then stirred at 80 °C (oil bath) for 3 h. The complete formation
of chromones 2 was monitored by TLC. Thereafter, I (0.15 mmol)
cm ; H NMR (CDCl , 400 MHz): δ 7.94 (d, 1H, J = 8.8 Hz),
3
2
7.43−7.33 (m, 10H), 6.95 (s, 1H), 6.64 (d, 1H, J = 8.8 Hz), 6.62 (s,
1
3
1
was added to the reaction mixture, followed by dropwise addition of a
solution of NCS (0.22 mmol) in DCE (0.5 mL) at 80 °C (oil bath).
The reaction mixture was stirred for 30 min. Upon completion, it was
quenched with 3−5% Na S O (5 mL), diluted with brine (10 mL),
1H), 5.08 (s, 2H), 5.01 (s, 2H), 2.43 (s, 3H), 1.78 (s, 3H); C{ H}
NMR (CDCl , 100 MHz): δ 184.1, 163.0, 162.6, 158.5, 136.3, 136.0,
3
133.5, 128.6, 128.5, 128.4, 128.1, 127.5, 122.6, 115.1, 106.4, 100.2,
2
2
3
70.8, 70.1, 16.2, 15.1; HRMS (ESI) m/z calcd for C H O S [M +
25 25
3 2
+
and extracted with DCM (15 mL × 3). The combined organic layer
was dried over anhydrous Na SO , concentrated, and purified through
H] 437.1240, found 437.1237.
2
4
1-(2-(Benzyloxy)-5-methylphenyl)-3,3-bis(methylthio)prop-2-en-
silica gel column chromatography using 5% EtOAc/hexane to afford
the desired products.
1-one (1c). Yield: 93% (640 mg), white solid (recrystallized from
−
1
hexane), mp: 117−119 °C; IR (KBr): 3030, 1593, 1483, 762 cm ;
1
Synthetic Procedure for 3-Iodo-6-methyl-2-(methylthio)-
H NMR (CDCl , 400 MHz): δ 7.65 (s, 1H), 7.42−7.31 (m, 5H),
3
4
H-chromen-4-one (3i) Using NXS and Iodine at Room
7
3
.19 (d, 1H, J = 7.6 Hz), 6.92−6.89 (m, 2H), 5.04 (s, 2H), 2.46 (s,
Temperature. A solution of 6-methyl-2-(methylthio)-4H-chromen-
-one 2c (62 mg, 0.30 mmol) in DCE (1 mL) was treated with I (76
13 1
H), 2.29 (s, 3H), 1.91 (s, 3H); C{ H} NMR (CDCl , 100 MHz):
3
4
2
δ 185.7, 163.8, 154.7, 136.5, 133.0, 131.8, 130.6, 129.3, 128.6, 128.2,
28.0, 115.0, 112.8, 70.9, 20.3, 16.4, 15.1; HRMS (ESI) m/z calcd for
mg, 0.30 mmol), followed by addition of NCS or NBS (0.5 equiv,
.15 mmol), and then stirred at room temperaturefor 1 h. After
completion, the reaction mixture was quenched with 5% Na S O (5
1
0
+
C H O S [M + H] 345.0977, found 345.0968.
1
9
21
2 2
2
2
3
1
-(2-(Benzyloxy)-5-chlorophenyl)-3,3-bis(methylthio)prop-2-en-
mL), diluted with brine (10 mL), and extracted with DCM (15 mL ×
1
-one (1d). Yield: 95% (693 mg), yellow solid (recrystallized from
3
). The combined organic layer was dried over anhydrous Na SO ,
2
4
hexane), mp: 112−113 °C; IR (KBr): 3032, 2918, 1606, 1485, 750
concentrated, and purified through silica gel column chromatography
using 5% EtOAc/hexane to afford compound 3i.
−1
1
cm ; H NMR (CDCl , 400 MHz): δ 7.80 (d, 1H, J = 2.4 Hz),
3
7
2
.41−7.30 (m, 6H), 6.93 (d, 1H, J = 8.8 Hz), 6.84 (s, 1H), 5.04 (s,
The presence of only the iodinated product was confirmed using a
C NMR spectrum to prove the selectivity of this method.
13 1
H), 2.45 (s, 3H), 1.88 (s, 3H); C{ H} NMR (CDCl , 100 MHz):
13
3
δ 183.7, 165.7, 155.2, 135.9, 131.9, 131.2, 130.9, 128.7, 128.4, 128.1,
26.5, 114.3, 114.2, 71.2, 16.4, 15.1; HRMS (ESI) m/z calcd for
1
+
C H ClO S [M + H] 365.0431, found 365.0435.
1
8
18
2 2
1
-(2-(Benzyloxy)-5-bromophenyl)-3,3-bis(methylthio)prop-2-en-
1
-one (1e). Yield: 89% (729 mg), yellow solid (recrystallized from
hexane), mp: 106−108 °C; IR (KBr): 3057, 2910, 1573, 1456, 746
−
1 1
cm ; H NMR (CDCl , 400 MHz): δ 7.94 (d, 1H, J = 2.0 Hz), 7.45
3
(
dd, 1H, J = 8.4, 2.0 Hz), 7.40−7.31 (m, 5H), 6.88 (d, 1H, J = 8.4
13 1
Hz), 6.83 (s, 1H), 5.04 (s, 2H), 2.45 (s, 3H), 1.90 (s, 3H); C{ H}
NMR (CDCl , 100 MHz): δ 183.6, 165.6, 155.7, 135.8, 134.8, 134.0,
3
1
31.3, 128.7, 128.4, 128.1, 114.7, 114.3, 113.8, 71.2, 16.5, 15.1;
+
HRMS (ESI) m/z calcd for C H BrO S [M + H] 408.9926, found
1
8
18
2 2
4
08.9920.
General Procedure for the Synthesis of 2-sec-Amino-4H-
1
-(2-(Benzyloxy)-5-methoxyphenyl)-3,3-bis(methylthio)prop-2-
chromen-4-ones (7a,b). A mixture of 2-(methylthio)-4H-chromen-
4
en-1-one (1f). Yield: 90% (649 mg), yellow solid (recrystallized from
hexane), mp: 96−98 °C; IR (KBr): 3032, 2914, 1597, 1479, 1278,
-one 2a (0.20 mmol) and pyrrolidine/piperidine (0.15 mL) was
stirred at 60 °C (oil bath) for 2 h. Completion of the reaction was
monitored by TLC. After completion, the excess of secondary amine
was removed under vacuum and recrystallized from methanol to
afford 2-sec-amino-4H-chromen-4-ones.
General Procedure for the Synthesis of 2-(Phenylamino)-
H-chromen-4-ones (8a,b). A mixture of 2-(methylthio)-4H-
chromen-4-one/7-(benzyloxy)-3-chloro-2-(methylthio)-4H-chromen-
-one 2a/3d (0.20 mmol) and aniline (1 mL) was stirred at 90 °C
oil bath) for 24 h. Completion of the reaction was monitored by
TLC. After completion, the excess of aniline was removed through
silica gel column chromatography using DCM; then the desired
product was collected using 20% MeOH/DCM.
General Procedure for the Synthesis of 7-Hydroxy-4H-
chromen-4-ones (9 and 10). A mixture of 7-(benzyloxy)-2-
methylthio)-4H-chromen-4-one/7-(benzyloxy)-3-chloro-2-(phenyla-
mino)-4H-chromen-4-one 2b/8b (0.20 mmol) and TFA (1 mL) was
stirred at 90 °C (oil bath) for 6 h. Completion of the reaction was
monitored by TLC. After completion, the excess of TFA was removed
under vacuum and the obtained precipitate was washed with water,
filtered, and dried to afford the desired products without further
purification.
−
1 1
1
6
1
1
1
037, 761 cm ; H NMR (CDCl , 400 MHz): δ 7.43−7.29 (m, 6H),
3
.98 (s, 1H), 6.94 (s, 2H), 5.00 (s, 2H), 3.78 (s, 3H), 2.46 (s, 3H),
1
3
1
.91 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 184.9, 164.4,
54.0, 151.2, 136.6, 130.3, 128.5, 128.2, 128.1, 119.3, 115.0, 114.9,
14.7, 71.9, 55.7, 16.5, 15.1; HRMS (ESI) m/z calcd for C H O S
3
4
19 21
3 2
+
[
M + H] 361.0927, found 361.0933.
-(2-(Benzyloxy)naphthalen-1-yl)-3,3-bis(methylthio)prop-2-en-
-one (1g). Yield: 96% (728 mg), white solid (recrystallized from
1
4
(
1
hexane), mp: 113−115 °C; IR (KBr): 3028, 2922, 1623, 1469, 748
cm ; H NMR (CDCl , 400 MHz): δ 7.83 (d, 1H, J = 8.4 Hz), 7.72
−
1 1
3
(
6
d, 1H, J = 8.4 Hz), 7.68 (d, 1H, J = 7.6 Hz), 7.38−7.17 (m, 8H),
13 1
.35 (s, 1H), 5.13 (s, 2H), 2.47 (s, 3H), 2.15 (s, 3H); C{ H} NMR
(
CDCl , 100 MHz): δ 189.0, 163.7, 152.8, 137.0, 131.5, 130.8, 129.2,
3
(
128.4, 127.8, 127.7, 127.1, 127.0, 126.8, 124.7, 124.1, 116.1, 115.1,
71.5, 16.9, 14.9; HRMS (ESI) m/z calcd for C22H O S
381.0977, found 381.0987.
[M + H]+
21 2 2
1-(1-(Benzyloxy)naphthalen-2-yl)-3,3-bis(methylthio)prop-2-en-
-one (1h). Yield: 89% (676 mg), brown viscous liquid (recrystallized
1
−
1 1
from hexane); IR (KBr): 3060, 2922, 1613, 1476, 758 cm ; H NMR
CDCl , 400 MHz): δ 8.29 (m, 1H), 7.89−7.82 (m, 2H), 7.66 (d,
(
1
3
H, J = 8.8 Hz), 7.55−7.48 (m, 4H), 7.42−7.33 (m, 3H), 7.13 (s,
1
-(2-(Benzyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one
13 1
(
1a). Yield: 97% (641 mg), yellow solid (recrystallized from hexane),
1H), 4.96 (s, 2H), 2.53 (s, 3H), 2.11 (s, 3H); C{ H} NMR (CDCl ,
3
−
1 1
mp: 126−128 °C; IR (KBr): 3030, 2918, 1585, 1476, 752 cm ; H
100 MHz): δ 186.0, 165.0, 154.0, 136.6, 136.1, 129.3, 128.4, 128.2,
128.1, 128.0, 127.8, 127.6, 126.5, 126.3, 124.2, 122.9, 114.0, 78.3,
16.6, 14.9; HRMS (ESI) m/z calcd for C H O S [M + H]+
NMR (CDCl , 400 MHz): δ 7.84 (d, 1H, J = 7.6 Hz), 7.42−7.29 (m,
3
6
1
H), 7.04−6.99 (m, 2H), 6.91 (s, 1H), 5.06 (s, 2H), 2.44 (s, 3H),
2
2
21
2 2
.88 (s, 3H); 13C{ H} NMR (CDCl , 100 MHz): δ 185.4, 163.9,
1
381.0977, found 381.0962.
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−
1 1
1
-(2-(Benzyloxy)phenyl)-2-methyl-3,3-bis(methylthio)prop-2-en-
cm ; H NMR (CDCl , 400 MHz): δ 8.29 (d, 1H, J = 2.0 Hz), 7.71
3
1
-one (1i). Yield: 51% (348 mg), yellow viscous liquid (recrystallized
(dd, 1H, J = 8.8, 2.0 Hz), 7.30 (d, 1H, J = 8.8 Hz), 6.21 (s, 1H), 2.56
(s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 174.1, 170.4, 155.5,
136.2, 128.5, 124.9, 119.1, 118.6, 107.3, 13.8; HRMS (ESI) m/z calcd
for C H BrO S [M + H] 270.9423, found 270.9425.
−
1
1
13
1
from hexane); IR (KBr): 3030, 2919, 1593, 1449, 752 cm ; H NMR
3
(
CDCl , 400 MHz): δ 7.75 (d, 1H, J = 7.6 Hz), 7.42−7.29 (m, 6H),
3
+
7
3
1
7
.03−6.95 (m, 2H), 5.04 (s, 2H), 2.21 (s, 3H), 2.00 (s, 3H), 1.89 (s,
1
0
8
2
H); 13C{ H} NMR (CDCl , 100 MHz): δ 196.7, 157.7, 147.1,
1
3
6-Methoxy-2-(methylthio)-4H-chromen-4-one (2f). Yield: 91%
(202 mg), yellow solid, eluent (hexane/EtOAc = 9:1), mp: 100−101
°C; IR (KBr): 2943, 1612, 1544, 1427, 1338, 1134, 1244, 1070, 805
36.0, 133.3, 132.3, 131.6, 128.7, 128.6, 128.2, 127.8, 120.8, 112.4,
0.7, 20.1, 16.9, 16.1; HRMS (ESI) m/z calcd for C H O S [M +
1
9
21
2 2
+
−1 1
H] 345.0977, found 345.0972.
-(2-(Allyloxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-one (1j).
Yield: 92% (516 mg), white solid (recrystallized from hexane), mp:
cm ; H NMR (CDCl , 400 MHz): δ 7.50 (d, 1H, J = 2.8 Hz), 7.29
3
1
(d, 1H, J = 9.2 Hz), 7.17 (dd, 1H, J = 9.2, 2.8 Hz), 6.16 (s, 1H), 3.86
(s, 3H), 2.51 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 175.4,
169.3, 156.8, 151.5, 124.0, 122.8, 118.5, 106.7, 105.2, 55.8, 13.7;
HRMS (ESI) m/z calcd for C H O S [M + H] 223.0423, found
1
3
1
3
−
1 1
5
(
0−52 °C; IR (KBr): 3072, 2920, 1598, 1478, 760 cm ; H NMR
CDCl , 400 MHz): δ 7.73 (d, 1H, J = 8.0 Hz), 7.35 (t, 1H, J = 7.6
+
3
11 11
3
Hz), 6.98 (t, 1H, J = 7.6 Hz), 6.91 (s, 1H), 6.88 (d, 1H, J = 8.4 Hz),
223.0428.
6
.08−5.98 (m, 1H), 5.39 (d, 1H, J = 17.2 Hz), 5.26 (d, 1H, J = 10.4
3-(Methylthio)-1H-benzo[f ]chromen-1-one (2g). Yield: 79% (192
mg), white solid, eluent (hexane/EtOAc = 9:1), mp: 144−146 °C; IR
(KBr): 2923, 1630, 1561, 1438, 1317, 1139, 955, 823, 755 cm ; H
1
3
1
Hz), 4.55 (d, 2H, J = 5.2 Hz), 2.47 (s, 3H), 2.42 (s, 3H); C{ H}
−1 1
NMR (CDCl , 100 MHz): δ 185.9, 163.5, 156.3, 132.8, 132.2, 131.1,
3
1
30.0, 121.0, 117.9, 114.9, 112.6, 69.2, 17.1, 15.0; HRMS (ESI) m/z
NMR (CDCl , 400 MHz): δ 9.98 (d, 1H, J = 8.8 Hz), 8.00 (d, 1H, J =
9.2 Hz), 7.84 (d, 1H, J = 7.6 Hz), 7.71 (t, 1H, J = 7.6 Hz), 7.57 (t,
3
+
calcd for C H O S [M + H] 281.0664, found 281.0651.
14
17
2 2
1
-(2-(Methoxymethoxy)phenyl)-3,3-bis(methylthio)prop-2-en-1-
1H, J = 7.6 Hz), 7.41 (d, 1H, J = 9.2 Hz), 6.32 (s, 1H), 2.53 (s, 3H);
1
3
1
one (1k). Yield: 86% (488 mg), white solid (recrystallized from
C{ H} NMR (CDCl , 100 MHz): δ 177.8, 166.7, 157.9, 135.0,
3
−
1 1
hexane), mp: 55−57 °C; IR (KBr): 2921, 1597, 1479, 761 cm ; H
NMR (CDCl , 400 MHz): δ 7.68 (d, 1H, J = 7.2 Hz), 7.35 (s, 1H),
.13−7.02 (m, 2H), 6.82 (s, 1H), 5.20 (s, 2H), 3.46 (s, 3H), 2.49 (s,
H), 2.46 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 186.1,
63.9, 154.9, 132.1, 130.9, 130.6, 122.1, 115.3, 114.5, 95.1, 56.3, 17.2,
5.0; HRMS (ESI) m/z calcd for C H O S [M + H] 285.0614,
1
30.6, 130.5, 129.1, 128.1, 127.1, 126.5, 116.8, 116.6, 110.5, 13.8;
+
3
HRMS (ESI) m/z calcd for C H O S [M + H] 243.0474, found
1
4
11
2
7
3
1
1
2
43.0482.
1
3
1
3
2-(Methylthio)-4H-benzo[h]chromen-4-one (2h). Yield: 63%
(152 mg), yellow solid, eluent (hexane/EtOAc = 9:1), mp: 100−
102 °C; IR (KBr): 2924, 1621, 1548, 1437, 1343, 1164, 914, 824, 757
+
1
3
17
3 2
−
1 1
found 285.0611.
1
cm ; H NMR (CDCl , 400 MHz): δ 8.31 (d, 1H, J = 7.2 Hz), 8.06
3
-(2-(Benzyloxy)phenyl)-2-(1,3-dithiolan-2-ylidene)ethanone
(d, 1H, J = 8.4 Hz), 7.85 (d, 1H, J = 7.2 Hz), 7.70−7.60 (m, 3H),
(
1l). Yield: 52% (342 mg), white solid, eluent (hexane/EtOAc = 9:1),
13
1
6
.34 (s, 1H), 2.63 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ
3
−
1 1
mp: 101−102 °C; IR (KBr): 3065, 2924, 1595, 1483, 753 cm ; H
NMR (CDCl , 400 MHz): δ 7.80 (dd, 1H, J = 7.8, 1.8 Hz), 7.49 (s,
H), 7.44−7.29 (m, 6H), 7.03−6.96 (m, 2H), 5.15 (s, 2H), 3.42 (t,
H, J = 6.2 Hz), 3.32 (t, 2H, J = 6.2 Hz); C{ H} NMR (CDCl , 100
MHz): δ 186.3, 165.5, 157.0, 136.4, 132.6, 131.2, 129.1, 128.6, 127.8,
27.1, 121.1, 113.8, 113.0, 70.6, 38.8, 35.3; HRMS (ESI) m/z calcd
for C H O S [M + H] 329.0664, found 329.0657.
1
75.5, 168.6, 153.8, 135.5, 129.0, 127.9, 127.0, 125.1, 123.1, 121.7,
3
120.5, 119.4, 108.6, 13.8; HRMS (ESI) m/z calcd for C H O S [M
14 11 2
1
2
+
+
H] 243.0474, found 243.0478.
3-Methyl-2-(methylthio)-4H-chromen-4-one (2i). Yield: 86%
178 mg), white solid, eluent (hexane/EtOAc = 9:1), mp: 100−102
1
3
1
3
(
−
1
1
1
°
C; IR (KBr): 3012, 1617, 1551, 1466, 1366, 1216, 751 cm ; H
+
18
17
2
2
NMR (CDCl , 400 MHz): δ 8.18 (dd, 1H, J = 7.6, 1.2 Hz), 7.57 (t,
3
2
-(Methylthio)-4H-chromen-4-one (2a). Yield: 95% (182 mg),
1
H, J = 7.8 Hz), 7.38−7.33 (m, 2H), 2.62 (s, 3H), 2.05 (s, 3H);
1
1
3
1
eluent (hexane/EtOAc = 9:1); H NMR (CDCl , 400 MHz): δ 8.13
d, 1H, J = 8.0 Hz), 7.60 (t, 1H, J = 7.8 Hz), 7.36 (t, 2H, J = 8.8 Hz),
.19 (s, 1H), 2.52 (s, 3H); HRMS (ESI) m/z calcd for C H O S [M
3
C{ H} NMR (CDCl , 100 MHz): δ 175.0, 162.7, 156.5, 132.6,
3
(
6
+
1
26.2, 125.0, 122.6, 116.8, 116.3, 13.2, 10.3; HRMS (ESI) m/z calcd
+
1
0
9
2
for C H O S [M + H] 207.0474, found 207.0476.
1
1
11
2
+
H] 193.0318, found 193.0320.
-(Benzyloxy)-2-(methylthio)-4H-chromen-4-one (2b). Yield:
2
-((2-(Benzylthio)ethyl)thio)-4H-chromen-4-one (2l). Yield: 19%
7
(
2
4
62 mg), viscous liquid, eluent (hexane/EtOAc = 9:1); IR (KBr):
923, 1649, 1550, 1461, 1348, 1130, 758 cm ; H NMR (CDCl ,
00 MHz): δ 8.12 (dd, 1H, J = 8.4, 2.0 Hz), 7.49 (t, 1H, J = 8.0 Hz),
9
1
6% (286 mg), white solid, eluent (hexane/EtOAc = 9:1), mp:
−1 1
3
50−152 °C; IR (KBr): 2925, 1622, 1548, 1439, 1337, 1163, 757
−
1 1
cm ; H NMR (CDCl , 400 MHz): δ 8.03 (dd, 1H, J = 8.8 Hz),
3
7.32−7.06 (m, 8H), 3.85 (s, 2H), 3.40 (t, 2H, J = 7.6 Hz), 2.93 (t,
7
1
(
.42−7.32 (m, 5H), 6.97 (dd, 1H, J = 8.8, 1.6 Hz), 6.84 (d, 1H, J =
.6 Hz), 6.10 (s, 1H), 5.10 (s, 2H), 2.47 (s, 3H); C{ H} NMR
CDCl , 100 MHz): δ 175.2, 169.5, 162.9, 158.3, 135.6, 128.7, 128.3,
27.4, 127.1, 117.2, 114.7, 107.1, 101.0, 70.5, 13.8; HRMS (ESI) m/z
calcd for C H O S [M + H] 299.0736, found 299.0747.
6
188 mg), white solid, eluent (hexane/EtOAc = 9:1), mp: 96−98
C; IR (KBr): 2924, 1651, 1548, 1463, 1356, 1131, 753 cm ; H
NMR (CDCl , 400 MHz): δ 7.92 (s, 1H), 7.40 (d, 1H, J = 8.4 Hz),
.27 (d, 1H, J = 8.4 Hz), 6.17 (s, 1H), 2.51 (s, 3H), 2.41 (s, 3H);
C{ H} NMR (CDCl , 100 MHz): δ 175.8, 169.8, 155.0, 135.2,
34.5, 125.1, 123.0, 116.9, 107.1, 20.8, 13.7; HRMS (ESI) m/z calcd
for C H O S [M + H] 207.0474, found 207.0482.
6
193 mg), white solid, eluent (hexane/EtOAc = 9:1), mp: 126−128
C; IR (KBr): 2920, 1647, 1541, 1429, 1323, 1143, 723 cm ; H
13
1
2
H, J = 7.6 Hz); C{ H} NMR (CDCl , 100 MHz): δ 174.8, 162.3,
3
1
3
1
1
56.3, 139.1, 133.1, 128.7, 128.3, 126.4, 126.2, 125.3, 122.9, 121.7,
3
116.7, 38.6, 31.0, 30.1; HRMS (ESI) m/z calcd for C H O S [M +
H] 329.0664, found 329.0671.
18 17 2 2
+
1
+
17
15
3
3-Chloro-2-(methylthio)-4H-chromen-4-one (3a). Yield: 80% (55
mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 144−146 °C;
IR (KBr): 2925, 2854, 1644, 1525, 1463, 1353, 1320, 1215, 960, 750
-Methyl-2-(methylthio)-4H-chromen-4-one (2c). Yield: 91%
(
°
−1
1
−
1 1
cm ; H NMR (CDCl , 400 MHz): δ 8.18 (d, 1H, J = 8.0 Hz), 7.63
3
1
3
1
3
(t, 1H, J = 7.8 Hz), 7.40 (t, 2H, J = 4.4 Hz), 2.64 (s, 3H); C{ H}
7
NMR (CDCl , 100 MHz): δ 169.5, 164.8, 156.0, 133.3, 126.4, 125.7,
3
13
1
3
122.3, 116.7, 115.0, 13.3; HRMS (ESI) m/z calcd for C H ClO S
10
8
2
+
1
[M + H] 226.9928, found 226.9930.
+
11
11
2
3-Bromo-2-(methylthio)-4H-chromen-4-one (3b). Yield: 90% (73
-Chloro-2-(methylthio)-4H-chromen-4-one (2d). Yield: 85%
mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 175−177 °C;
−
1
(
°
IR (KBr): 2924, 2854, 1646, 1516, 1463, 1352, 1320, 950, 756 cm ;
−1
1
1
H NMR (CDCl , 400 MHz): δ 8.18 (d, 1H, J = 7.2 Hz), 7.62 (t, 1H,
3
1
3
1
NMR (CDCl , 400 MHz): δ 8.08 (d, 1H, J = 2.8 Hz), 7.53 (dd, 1H, J
8.8, 2.8 Hz), 7.32 (d, 1H, J = 8.8 Hz), 6.16 (s, 1H), 2.51 (s, 3H);
C{ H} NMR (CDCl , 100 MHz): δ 174.3, 170.5, 155.0, 133.5,
31.2, 125.3, 124.5, 118.9, 107.2, 13.8; HRMS (ESI) m/z calcd for
J = 7.4 Hz), 7.39 (t, 2H, J = 7.2 Hz), 2.64 (s, 3H); C{ H} NMR
3
=
(CDCl , 100 MHz): δ 169.7, 166.0, 156.1, 133.3, 126.6, 125.9, 121.9,
3
13
1
3
116.8, 105.7, 14.1; HRMS (ESI) m/z calcd for C H BrO S [M +
10
8
2
+
1
H] 270.9423, found 270.9426.
+
C H ClO S [M + H] 226.9928, found 226.9936.
0
3-Iodo-2-(methylthio)-4H-chromen-4-one (3c). Yield: 87% (83
1
8
2
6
-Bromo-2-(methylthio)-4H-chromen-4-one (2e). Yield: 83%
mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 200−202 °C;
−
1
(
1
225 mg), pale yellow solid, eluent (hexane/EtOAc = 9:1), mp:
13−115 °C; IR (KBr): 2926, 1656, 1544, 1460, 1327, 1141, 765
IR (KBr): 2924, 2852, 1637, 1504, 1463, 1347, 1317, 938, 757 cm ;
1
H NMR (CDCl , 400 MHz): δ 8.20 (dd, 1H, J = 8.4, 1.6 Hz), 7.64
3
9
485
https://doi.org/10.1021/acs.joc.1c00788
J. Org. Chem. 2021, 86, 9478−9489

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
3
1
3H); 13C{ H} NMR (CDCl , 100 MHz): δ 168.5, 166.4, 154.4,
1
(
(
1
3
t, 1H, J = 7.2 Hz), 7.43−7.40 (m, 2H), 2.64 (s, 3H); C{ H} NMR
CDCl , 100 MHz): δ 171.2, 168.2, 156.2, 133.3, 126.8, 125.9, 119.9,
3
133.5, 131.8, 126.0, 122.9, 118.6, 105.6, 14.2; HRMS (ESI) m/z calcd
for C H BrClO S [M + H] 304.9033, found 304.9024.
3
+
+
16.6, 83.2, 15.7; HRMS (ESI) m/z calcd for C H IO S [M + H]
18.9284, found 318.9284.
-(Benzyloxy)-3-chloro-2-(methylthio)-4H-chromen-4-one (3d).
Yield: 76% (76 mg), white solid, eluent (hexane/EtOAc = 19:1),
mp: 162−164 °C; IR (KBr): 2925, 2854, 1644, 1620, 1436, 1311,
268, 1101, 763 cm ; H NMR (CDCl , 400 MHz): δ 8.05 (d, 1H, J
8.8 Hz), 7.43−7.32 (m, 5H), 6.99 (dd, 1H, J = 8.8, 1.6 Hz), 6.85 (d,
H, J = 1.6 Hz), 5.11 (s, 2H), 2.60 (s, 3H); C{ H} NMR (CDCl ,
00 MHz): δ 169.0, 163.9, 162.7, 157.4, 135.4, 128.7, 128.4, 127.5,
27.5, 116.1, 115.1, 114.7, 100.6, 70.6, 13.3; HRMS (ESI) m/z calcd
for C H ClO S [M + H] 333.0347, found 333.0350.
-(Benzyloxy)-3-bromo-2-(methylthio)-4H-chromen-4-one (3e).
Yield: 86% (97 mg), white solid, eluent (hexane/EtOAc = 19:1),
1
0
8
2
10
7
2
6-Chloro-3-iodo-2-(methylthio)-4H-chromen-4-one (3l). Yield:
95% (101 mg), white solid, eluent (hexane/EtOAc = 19:1), mp:
218−220 °C; IR (KBr): 2927, 2850, 1635, 1498, 1456, 1334, 1298,
7
−
1 1
1242, 937, 767 cm ; H NMR (CDCl , 400 MHz): δ 8.16 (d, 1H, J
3
−
1 1
1
=
1
1
1
= 2.4 Hz), 7.58 (dd, 1H, J = 9.2, 2.4 Hz), 7.38 (d, 1H, J = 9.2 Hz),
2.64 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 170.0, 168.6,
154.7, 133.5, 131.8, 126.2, 121.1, 118.4, 83.0, 15.7; HRMS (ESI) m/z
3
1
3
1
3
1
3
1
3
+
calcd for C H ClIO S [M + H] 352.8894, found 352.8899.
1
0
7
2
6-Bromo-3-chloro-2-(methylthio)-4H-chromen-4-one (3m).
Yield: 92% (84 mg), white solid, eluent (hexane/EtOAc = 19:1),
mp: 195−197 °C; IR (KBr): 2951, 2920, 1649, 1510, 1429, 1340,
+
17
14
3
7
−
1 1
1301, 1205, 954, 765 cm ; H NMR (CDCl , 400 MHz): δ 8.32 (d,
3
mp: 143−144 °C; IR (KBr): 2925, 2855, 1642, 1618, 1436, 1308,
1H, J = 2.4 Hz), 7.71 (dd, 1H, J = 9.2, 2.4 Hz), 7.32 (d, 1H, J = 9.2
−
1
1
13
1
1
271, 1099, 760 cm ; H NMR (CDCl , 400 MHz): δ 8.11 (d, 1H, J
Hz), 2.65 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 168.2, 165.4,
3
3
=
9.2 Hz), 7.43−7.33 (m, 5H), 7.04 (dd, 1H, J = 9.2, 2.4 Hz), 6.89 (d,
154.7, 136.2, 129.0, 123.8, 119.2, 118.9, 115.1, 13.4; HRMS (ESI) m/
1
3
1
+
1
1
1
H, J = 2.4 Hz), 5.13 (s, 2H), 2.62 (s, 3H); C{ H} NMR (CDCl ,
00 MHz): δ 169.2, 165.0, 162.7, 157.5, 135.4, 128.7, 128.4, 127.8,
27.5, 115.7, 115.1, 105.5, 100.6, 70.6, 14.1; HRMS (ESI) m/z calcd
z calcd for C H BrClO S [M + H] 304.9033, found 304.9039.
3
10
7
2
3,6-Dibromo-2-(methylthio)-4H-chromen-4-one (3n). Yield: 94%
(99 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 224−225
°C; IR (KBr): 2929, 2854, 1645, 1504, 1417, 1336, 1296,1203, 948,
+
for C H BrO S [M + H] 376.9847, found 376.9858.
17
14
3
−
1 1
7
-(Benzyloxy)-3-iodo-2-(methylthio)-4H-chromen-4-one (3f).
763 cm ; H NMR (CDCl , 400 MHz): δ 8.33 (d, 1H, J = 2.4 Hz),
3
Yield: 73% (93 mg), white solid, eluent (hexane/EtOAc = 19:1),
mp: 152−154 °C; IR (KBr): 2923, 2854, 1617, 1585, 1493, 1434,
7.72 (dd, 1H, J = 9.2, 2.4 Hz), 7.32 (d, 1H, J = 9.2 Hz), 2.65 (s, 3H);
1
3
1
C{ H} NMR (CDCl , 100 MHz): δ 168.4, 166.5, 154.9, 136.3,
3
−
1 1
1
1
6
304, 1270, 1092, 754 cm ; H NMR (CDCl , 400 MHz): δ 8.09 (d,
H, J = 9.2 Hz), 7.43−7.33 (m, 5H), 7.02 (dd, 1H, J = 9.2, 2.4 Hz),
.88 (d, 1H, J = 2.4 Hz), 5.13 (s, 2H), 2.61 (s, 3H); C{ H} NMR
129.1, 123.2, 119.3, 118.8, 105.6, 14.2; HRMS (ESI) m/z calcd for
3
+
C H Br O S [M + H] 348.8528, found 348.8537.
1
0
7
2
2
1
3
1
6-Bromo-3-iodo-2-(methylthio)-4H-chromen-4-one (3o). Yield:
(CDCl , 100 MHz): δ 170.7, 167.3, 162.8, 157.9, 135.5, 128.8, 128.5,
91% (108 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 200−
3
1
28.2, 127.5, 115.1, 114.1, 100.5, 83.3, 70.8, 15.6; HRMS (ESI) m/z
202 °C; IR (KBr): 3007, 2912, 1635, 1494, 1456, 1379, 1338, 1292,
+
−1 1
calcd for C H IO S [M + H] 424.9703, found 424.9696.
931, 763 cm ; H NMR (CDCl , 400 MHz): δ 8.32 (d, 1H, J = 2.4
17
14
3
3
3
-Chloro-6-methyl-2-(methylthio)-4H-chromen-4-one (3g).
Hz), 7.72 (dd, 1H, J = 8.4, 2.4 Hz), 7.31 (d, 1H, J = 8.4 Hz), 2.64 (s,
1
3
1
Yield: 79% (57 mg), white solid, eluent (hexane/EtOAc = 19:1),
mp: 154−155 °C; IR (KBr): 2925, 2852, 1644, 1527, 1481, 1317,
3H); C{ H} NMR (CDCl , 100 MHz): δ 169.9, 168.6, 155.2,
3
136.3, 129.3, 121.5, 119.2, 118.6, 83.0, 15.7; HRMS (ESI) m/z calcd
−1
1
+
1
7
2
1
102, 963, 762 cm ; H NMR (CDCl , 400 MHz): δ 7.99 (s, 1H),
for C H BrIO S [M + H] 396.8389, found 396.8382.
3
10
7
2
.44 (dd, 1H, J = 8.8, 2.0 Hz), 7.32 (d, 1H, J = 8.8 Hz), 2.64 (s, 3H),
3-Chloro-6-methoxy-2-(methylthio)-4H-chromen-4-one (3p).
Yield: 91% (70 mg), white solid, eluent (hexane/EtOAc = 19:1),
mp: 196−170 °C; IR (KBr): 2956, 2929, 1633, 1514, 1438, 1333,
.43 (s, 3H); 13C{ H} NMR (CDCl , 100 MHz): δ 169.6, 164.7,
1
3
54.4, 135.9, 134.4, 125.7, 122.0, 116.7, 114.8, 20.9, 13.3; HRMS
+
−1 1
(ESI) m/z calcd for C H ClO S [M + H] 241.0085, found
1307, 1240, 1095, 950, 744 cm ; H NMR (CDCl , 400 MHz): δ
1
1
10
2
3
2
7.55 (d, 1H, J = 3.2 Hz), 7.34 (d, 1H, J = 9.2 Hz), 7.20 (dd, 1H, J =
1
3
1
9.2, 3.2 Hz), 3.87 (s, 3H), 2.64 (s, 3H); C{ H} NMR (CDCl , 100
3
Yield: 90% (78 mg), white solid, eluent (hexane/EtOAc = 19:1),
MHz): δ 169.4, 164.5, 157.3, 151.0, 123.2, 123.0, 118.3, 114.5, 105.7,
+
mp: 167−169 °C; IR (KBr): 2924, 2855, 1642, 1520, 1478, 1312,
56.0, 13.3; HRMS (ESI) m/z calcd for C H ClO S [M + H]
1
1
10
3
−1 1
1
095, 950, 764 cm ; H NMR (CDCl , 400 MHz): δ 7.98 (d, 1H, J
257.0034, found 257.0040.
3
2.0 Hz), 7.43 (dd, 1H, J = 8.8, 2.0 Hz), 7.31 (d, 1H, J = 8.8 Hz),
3-Bromo-6-methoxy-2-(methylthio)-4H-chromen-4-one (3q).
Yield: 93% (84 mg), white solid, eluent (hexane/EtOAc = 19:1),
mp: 164−166 °C; IR (KBr): 2999, 2933, 1624, 1506, 1471, 1328,
1
3
1
3
+
−1
1
1301, 1290, 1193, 1020, 948, 736 cm ; H NMR (CDCl , 400
1
1
10
2
3
MHz): δ 7.46 (d, 1H, J = 3.2 Hz), 7.27 (d, 1H, J = 9.2 Hz), 7.14 (dd,
1H, J = 9.2, 3.2 Hz), 3.83 (s, 3H), 2.59 (s, 3H); 1 C{ H} NMR
3
1
8
1
9
9% (89 mg), white solid, eluent (hexane/EtOAc = 19:1), mp:
(CDCl , 100 MHz): δ 169.4, 165.5, 157.2, 150.9, 122.8, 122.4, 118.2,
3
74−175 °C; IR (KBr): 2924, 2854, 1640, 1512, 1467, 1307, 1086,
105.7, 104.9, 55.9, 14.0; HRMS (ESI) m/z calcd for C H BrO S [M
11
10
3
−1
1
+
42, 760 cm ; H NMR (CDCl , 400 MHz): δ 7.95 (s, 1H), 7.43
+ H] 300.9529, found 300.9525.
3
(
(
1
dd, 1H, J = 8.4, 2.0 Hz), 7.29 (d, 1H, J = 8.8 Hz), 2.62 (s, 3H), 2.42
3-Iodo-6-methoxy-2-(methylthio)-4H-chromen-4-one (3r). Yield:
90% (94 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 180−
182 °C; IR (KBr): 2999, 2924, 1610, 1502, 1467, 1325, 1294, 1259,
s, 3H); 13C{ H} NMR (CDCl , 100 MHz): δ 171.2, 168.0, 154.7,
1
3
36.0, 134.5, 126.0, 119.8, 116.4, 83.1, 21.0, 15.6; HRMS (ESI) m/z
+
−1 1
calcd for C H IO S [M + H] 332.9441, found 332.9431.
1020, 941, 732 cm ; H NMR (CDCl , 400 MHz): δ 7.51 (d, 1H, J
11
10
2
3
3
,6-Dichloro-2-(methylthio)-4H-chromen-4-one (3j). Yield: 92%
= 3.2 Hz), 7.31 (d, 1H, J = 9.2 Hz), 7.17 (dd, 1H, J = 9.2, 3.2 Hz),
1
3
1
(
°
7
7
72 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 196−198
C; IR (KBr): 2961, 2918, 1645, 1514, 1423, 1340, 1303, 1207, 956,
63 cm ; H NMR (CDCl , 400 MHz): δ 8.16 (d, 1H, J = 2.8 Hz),
.57 (dd, 1H, J = 8.8, 2.8 Hz), 7.38 (d, 1H, J = 8.8 Hz), 2.65 (s, 3H);
C{ H} NMR (CDCl , 100 MHz): δ 168.3, 165.4, 154.3, 133.5,
31.8, 125.8, 123.5, 118.6, 115.1, 13.4; HRMS (ESI) m/z calcd for
3.85 (s, 3H), 2.61 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ
3
171.0, 167.8, 157.3, 151.3, 122.9, 120.8, 118.0, 106.1, 82.6, 55.9, 15.6;
−
1
1
+
HRMS (ESI) m/z calcd for C H IO S [M + H] 348.9390, found
3
11 10
3
348.9394.
1
3
1
2-Chloro-3-(methylthio)-1H-benzo[f ]chromen-1-one (3s). Yield:
71% (59 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 158−
160 °C; IR (KBr): 2924, 2855, 1629, 1540, 1461, 1384, 1262, 1010,
3
1
+
C H Cl O S [M + H] 260.9538, found 260.9545.
1
0
7
2
2
−
1 1
3
-Bromo-6-chloro-2-(methylthio)-4H-chromen-4-one (3k). Yield:
757 cm ; H NMR (CDCl , 400 MHz): δ 10.01 (d, 1H, J = 8.8 Hz),
3
9
2
9
6% (88 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 220−
8.04 (d, 1H, J = 8.8 Hz), 7.87 (d, 1H, J = 8.4 Hz), 7.75 (t, 1H, J = 8.0
Hz), 7.61 (t, 1H, J = 7.6 Hz), 7.44 (d, 1H, J = 9.2 Hz), 2.68 (s, 3H);
22 °C; IR (KBr): 2927, 2848, 1641, 1510, 1417, 1311, 1307, 1298,
−
1
1
13
1
37, 767 cm ; H NMR (CDCl , 400 MHz): δ 8.17 (d, 1H, J = 2.4
C{ H} NMR (CDCl , 100 MHz): δ 171.2, 161.7, 157.2, 135.2,
3
3
Hz), 7.58 (dd, 1H, J = 9.2, 2.4 Hz), 7.38 (d, 1H, J = 9.2 Hz), 2.65 (s,
130.8, 130.4, 129.5, 128.2, 127.2, 126.9, 117.7, 116.3, 115.6, 13.3;
9
486
https://doi.org/10.1021/acs.joc.1c00788
J. Org. Chem. 2021, 86, 9478−9489

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
+
HRMS (ESI) m/z calcd for C H ClO S [M + H] 277.0085, found
2-(1,3-Dithiolan-2-ylidene)-1-(2-hydroxyphenyl)ethanone (5).
Yield: 79% (188 mg), yellow solid, eluent (hexane/EtOAc = 9:1),
mp: 90−92 °C; IR (KBr): 2924, 2856, 1620, 1492, 1206, 1041, 759
1
4
10
2
2
77.0094.
2
-Bromo-3-(methylthio)-1H-benzo[f]chromen-1-one (3t). Yield:
−
1 1
8
1
8
4% (81 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 196−
cm ; H NMR (CDCl , 400 MHz): δ 12.79 (s, 1H), 7.68 (d, 1H, J =
3
98 °C; IR (KBr): 2923, 2855, 1629, 1530, 1461, 1377, 1288, 990,
7.6 Hz), 7.41−7.35 (m, 2H), 6.95 (d, 1H, J = 8.8 Hz), 6.84 (t, 1H, J =
−1
1
13
1
13, 759 cm ; H NMR (CDCl , 400 MHz): δ 10.01 (d, 1H, J = 8.8
7.2 Hz), 3.50 (t, 2H, J = 6.4 Hz), 3.39 (t, 2H, J = 6.4 Hz); C{ H}
3
Hz), 8.05 (d, 1H, J = 8.8 Hz), 7.87 (d, 1H, J = 7.6 Hz), 7.74 (t, 1H, J
NMR (CDCl , 100 MHz): δ 189.5, 170.0, 163.0, 135.2, 128.4, 119.7,
3
=
8.0 Hz), 7.61 (t, 1H, J = 7.6 Hz), 7.45 (d, 1H, J = 9.2 Hz), 2.68 (s,
118.6, 118.4, 107.1, 39.2, 35.5; HRMS (ESI) m/z calcd for
H); 13C{ H} NMR (CDCl , 100 MHz): δ 171.2, 163.0, 157.2,
1
C H O S [M + H] 239.0195, found 239.0186.
+
3
3
11 11
2 2
1
35.2, 130.7, 130.2, 129.3, 128.2, 127.2, 126.8, 116.1, 114.8, 108.8,
2-(4-Ethylphenyl)-4H-chromen-4-one (6). Yield: 92% (46 mg),
+
1
14.0; HRMS (ESI) m/z calcd for C H BrO S [M + H] 320.9585,
eluent (hexane/EtOAc = 19:1); H NMR (CDCl , 400 MHz): δ 8.20
1
4
10
2
3
found 320.9594.
(dd, 1H, J = 8.0, 1.6 Hz), 7.82 (d, 2H, J = 8.0 Hz), 7.68−7.64 (m,
1H), 7.53 (d, 1H, J = 8.4 Hz), 7.38 (t, 1H, J = 7.2 Hz), 7.32 (d, 2H, J
= 8.4 Hz), 6.77 (s, 1H), 2.70 (q, 2H, J = 7.6 Hz), 1.25 (t, 3H, J = 7.6
2
-Iodo-3-(methylthio)-1H-benzo[f ]chromen-1-one (3u). Yield:
7
2
9
8
1
2
1
8
3
5% (83 mg), white solid, eluent (hexane/EtOAc = 19:1), mp:
09−210 °C; IR (KBr): 2925, 2855, 1626, 1518, 1438, 1377, 1288,
79, 810, 761 cm ; H NMR (CDCl , 400 MHz): δ 9.99 (d, 1H, J =
+
Hz); HRMS (ESI) m/z calcd for C H O [M + H] 251.1067,
1
7
15
2
−
1 1
found 251.1062.
3
.4 Hz), 8.02 (d, 1H, J = 8.8 Hz), 7.85 (d, 1H, J = 7.6 Hz), 7.72 (t,
H, J = 7.6 Hz), 7.59 (t, 1H, J = 7.6 Hz), 7.42 (d, 1H, J = 9.2 Hz),
2-(Pyrrolidin-1-yl)-4H-chromen-4-one (7a). Yield: 81% (35 mg)
1
(recrystallized from methanol); H NMR (CDCl , 400 MHz): δ 8.09
3
.66 (s, 3H); 13C{ H} NMR (CDCl , 100 MHz): δ 172.6, 165.5,
1
(dd, 1H, J = 7.6, 1.6 Hz), 7.46−7.42 (m, 1H), 7.26−7.19 (m, 2H),
3
57.5, 135.2, 130.8, 130.1, 129.4, 128.2, 127.3, 126.8, 116.0, 113.3,
7.7, 15.6; HRMS (ESI) m/z calcd for C H IO S [M + H]
68.9441, found 368.9439.
-Chloro-2-(methylthio)-4H-benzo[h]chromen-4-one (3v). Yield:
5.24 (s, 1H), 3.44 (br, 4H), 1.98 (t, 4H, J = 6.8 Hz); HRMS (ESI) m/
+
+
z calcd for C H NO [M + H] 216.1019, found 216.1025.
1
4
10
2
13 14
2
2-(Piperidin-1-yl)-4H-chromen-4-one (7b). Yield: 85% (39 mg)
1
3
(recrystallized from methanol); H NMR (CDCl , 400 MHz): δ 8.05
3
7
2
6% (63 mg), white solid, eluent (hexane/EtOAc = 19:1), mp: 208−
(dd, 1H, J = 7.6, 1.2 Hz), 7.47−7.43 (m, 1H), 7.26−7.19 (m, 2H),
09 °C; IR (KBr): 2924, 2854, 1637, 1530, 1436, 1218, 979, 760
5.55 (s, 1H), 3.45 (br, 4H), 1.62 (br, 6H); HRMS (ESI) m/z calcd
−
1
1
+
cm ; H NMR (CDCl , 400 MHz): δ 8.31 (d, 1H, J = 8.8 Hz), 8.14
for C14H
16NO
2
[M + H] 230.1176, found 230.1159.
3
(
d, 1H, J = 8.8 Hz), 7.93 (d, 1H, J = 7.6 Hz), 7.79−7.62 (m, 3H),
2-(Phenylamino)-4H-chromen-4-one (8a). Yield: 84% (40 mg),
white solid, eluent (DCM/MeOH = 4:1), mp: 205−207 °C; IR
.85 (s, 3H); 13C{ H} NMR (CDCl , 100 MHz): δ 169.7, 163.6,
1
2
1
1
2
3
−
1 1
53.3, 135.5, 129.4, 128.3, 127.5, 125.9, 123.2, 121.3, 121.1, 118.7,
(KBr): 3165, 2926, 1615, 1553, 1240, 758 cm ; H NMR (CDCl ,
3
+
16.4, 13.6; HRMS (ESI) m/z calcd for C H ClO S [M + H]
400 MHz): δ 8.14 (d, 1H, J = 8.0 Hz), 7.56−7.51 (m, 2H), 7.38−7.27
3 1
1
4
10
2
(m, 6H), 7.19 (t, 1H, J = 7.2 Hz), 5.79 (s, 1H); 1 C{ H} NMR
(CDCl , 100 MHz): δ 177.5, 161.4, 153.9, 136.3, 132.5, 129.6, 125.8,
125.7, 124.9, 123.3, 122.9, 116.3, 88.0; HRMS (ESI) m/z calcd for
77.0085, found 277.0087.
-Bromo-2-(methylthio)-4H-benzo[h]chromen-4-one (3w).
3
3
Yield: 75% (72 mg), yellow solid, eluent (hexane/EtOAc = 19:1),
mp: 194−196 °C; IR (KBr): 2927, 2856, 1634, 1524, 1436, 1215,
9
+
C
H
12NO
[M + H] 238.0863, found 238.0871.
7-(Benzyloxy)-3-chloro-2-(phenylamino)-4H-chromen-4-one
8b). Yield: 82% (101 mg), white solid, eluent (DCM/MeOH = 4:1),
mp: 179−181 °C; IR (KBr): 2925, 2857, 1610, 1554, 1423, 1275, 758
15
2
−
1 1
78, 759 cm ; H NMR (CDCl , 400 MHz): δ 8.27 (d, 1H, J = 8.0
3
(
Hz), 8.11 (d, 1H, J = 8.4 Hz), 7.90 (d, 1H, J = 7.6 Hz), 7.76−7.61 (m,
1
3
1
3
1
1
H), 2.82 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 169.7,
3
−
1
1
64.6, 153.2, 135.7, 129.3, 128.3, 127.5, 125.9, 123.2, 121.4, 121.3,
cm ; H NMR (CDCl
3
, 400 MHz): δ 8.10 (d, 1H, J = 8.8 Hz),
7
2
1
1
.44−7.26 (m, 11H), 6.99 (dd, 1H, J = 8.8, 2.0 Hz), 6.80 (d, 1H, J =
18.2, 107.1, 14.4; HRMS (ESI) m/z calcd for C H BrO S [M +
1
4
10
2
1
3
1
+
.0 Hz), 5.08 (s, 2H); C{ H} NMR (CDCl , 100 MHz): δ 170.3,
H] 320.9585, found 320.9581.
-Iodo-2-(methylthio)-4H-benzo[h]chromen-4-one (3x). Yield:
3
62.4, 156.4, 153.4, 136.0, 135.6, 129.4, 128.7, 128.4, 127.5, 127.3,
3
25.6, 122.3, 116.3, 114.1, 101.1, 95.2, 70.5; HRMS (ESI) m/z calcd
7
2
7
8
3
1
1
3
4% (82 mg), white solid, eluent (hexane/EtOAc = 19:1), mp:
+
for C H ClNO [M + H] 378.0891, found 378.0890.
04−205 °C; IR (KBr): 2928, 2856, 1631, 1518, 1429, 1211, 975,
22 17
3
−
1 1
3
-Chloro-7-hydroxy-2-(phenylamino)-4H-chromen-4-one (9).
60 cm ; H NMR (CDCl , 400 MHz): δ 8.23 (d, 1H, J = 7.6 Hz),
3
Yield: 93% (54 mg), white solid, mp: 238−240 °C; IR (KBr):
.08 (d, 1H, J = 8.8 Hz), 7.90 (d, 1H, J = 8.0 Hz), 7.73−7.61 (m,
−
1 1
1
3
1
2
4
7
925, 2857, 1609, 1556, 1432, 1250, 761 cm ; H NMR (DMSO-d ,
H), 2.80 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 171.2,
6
3
00 MHz): δ 10.66 (s, 1H), 9.70 (s, 1H), 7.82 (d, 1H, J = 8.4 Hz),
.45−7.39 (m, 4H), 7.24−7.20 (m, 1H), 6.86 (dd, 1H, J = 8.8, 2.0
Hz), 6.61 (d, 1H, J = 2.0 Hz); C{ H} NMR (DMSO-d , 100 MHz):
67.1, 153.5, 135.6, 129.4, 128.4, 127.5, 126.0, 123.0, 121.6, 121.4,
+
16.4, 85.0, 16.0; HRMS (ESI) m/z calcd for C H IO S [M + H]
1
4
10
2
1
3
1
68.9441, found 368.9449.
-(3,5-Di-tert-butyl-4-hydroxybenzyl)-2-(methylthio)-4H-chro-
6
δ 169.5, 161.8, 156.6, 153.4, 136.9, 129.0, 128.0, 126.6, 125.1, 123.4,
3
men-4-one (4a). Yield: 13% (26 mg), white solid, eluent (hexane/
EtOAc = 19:1), mp: 180−181 °C; IR (KBr): 3435, 2919, 2865, 1723,
114.5, 101.8, 93.8; HRMS (ESI) m/z calcd for C15
H] 288.0422, found 288.0426.
H
11ClNO
3
[M +
+
−
1 1
1
4
7
1
1
3
619, 1546, 1490, 1340, 1219, 1025, 768 cm ; H NMR (CDCl ,
7-Hydroxy-2-(methylthio)-4H-chromen-4-one (10). Yield: 95%
(40 mg), white solid, mp: 200−202 °C; IR (KBr): 2926, 2857, 1612,
3
00 MHz): δ 8.18 (dd, 1H, J = 8.0, 1.6 Hz), 7.60−7.55 (m, 1H),
−
1 1
.37−7.32 (m, 4H), 5.00 (s, 1H), 3.82 (s, 2H), 2.63 (s, 3H), 1.39 (s,
1567, 1375, 764 cm ; H NMR (DMSO-d , 400 MHz): δ 7.81 (d,
6
8H); 13C{ H} NMR (CDCl , 100 MHz): δ 174.8, 163.6, 157.1,
1
1H, J = 8.4 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.82 (s, 1H), 6.13 (s, 1H),
3
1
3
1
52.4, 135.8, 133.3, 130.4, 126.0, 125.7, 124.0, 122.8, 120.9, 118.5,
4.77 (br, 1H), 2.56 (s, 3H); C{ H} NMR (DMSO-d
6
, 100 MHz): δ
4.6, 31.2, 30.6, 13.7; HRMS (ESI) m/z calcd for C H O S [M +
173.9, 169.1, 162.6, 158.0, 126.7, 115.5, 114.8, 106.4, 102.0, 13.4;
2
5
31
3
+
+
H] 411.1988, found 411.1982.
HRMS (ESI) m/z calcd for C10H O S [M + H] 209.0267, found
9 3
3
-(3,5-Di-tert-butyl-4-hydroxybenzyl)-6-methoxy-2-(methyl-
209.0278.
thio)-4H-chromen-4-one (4b). Yield: 41% (54 mg), white solid,
eluent (hexane/EtOAc = 19:1), mp: 175−177 °C; IR (KBr): 3426,
2
NMR (CDCl , 400 MHz): δ 7.57 (d, 1H, J = 2.8 Hz), 7.30 (d, 1H, J =
9
3
4H-Chromen-4-one (11a). Yield: 92% (27 mg), eluent (hexane/
1
EtOAc = 9:1); H NMR (CDCl , 400 MHz): δ 8.18 (d, 1H, J = 7.6
3
−
1 1
926, 2872, 1718, 1612, 1552, 1487, 1355, 1232, 1029, 779 cm ; H
Hz), 7.83 (d, 1H, J = 6.0 Hz), 7.65 (t, 1H, J = 7.6 Hz), 7.44−7.36 (m,
2H), 6.32 (d, 1H, J = 6.0 Hz); HRMS (ESI) m/z calcd for C H O
2
3
9
7
+
.2 Hz), 7.25 (s, 2H), 7.16 (dd, 1H, J = 9.2, 2.8 Hz), 5.01 (s, 1H),
[M + H] 147.0441, found 147.0436.
1
3
1
.87 (s, 3H), 3.83 (s, 2H), 2.62 (s, 3H), 1.40 (s, 18H); C{ H}
3-Methyl-4H-chromen-4-one (11b). Yield: 81% (26 mg), eluent
1
NMR (CDCl , 100 MHz): δ 174.5, 163.3, 156.7, 152.1, 151.4, 135.4,
(hexane/EtOAc = 9:1); H NMR (CDCl , 400 MHz): δ 8.21 (d, 1H,
3
3
1
30.1, 125.7, 123.7, 122.5, 120.5, 118.2, 105.6, 55.9, 34.2, 30.9, 30.3,
J = 8.4 Hz), 7.77 (s, 1H), 7.61 (t, 1H, J = 6.8 Hz), 7.41−7.34 (m,
+
+
13.5; HRMS (ESI) m/z calcd for C H O S [M + H] 441.2094,
2H), 2.01 (s, 3H); HRMS (ESI) m/z calcd for C H O [M + H]
2
6
33
4
10
9
2
found 441.2089.
161.0597, found 161.0602.
9
487
https://doi.org/10.1021/acs.joc.1c00788
J. Org. Chem. 2021, 86, 9478−9489

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00788.
■
part 11. Synthesis and Electron Impact Mass Spectrometric Study of
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Spectral data for all new compounds (PDF)
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
(7) Ellis, G. P.; Barker, G. Chromones-2- and −3-carboxylic acids
■
and Their Derivatives. Prog. Med. Chem. 1973, 9, 65−116.
Corresponding Author
Ramendra Pratap − Department of Chemistry, University of
Delhi, Delhi, India 110007; orcid.org/0000-0003-1846-
(
8) (a) Yue, Y.; Peng, J.; Wang, D.; Bian, Y.; Sun, P.; Chen, C. J.
Synthesis of 4H-Chromen-4-one Derivatives by Intramolecular
Palladium-Catalyzed Acylation of Alkenyl Bromides with Aldehydes.
J. Org. Chem. 2017, 82, 5481−5486. (b) Zhao, X.; Zhou, J.; Lin, S.;
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Elimination: Palladium Catalyzed Dehydrogenation of ortho-Acyl
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1
561; Phone: +911127666646; Email: rpratap@
chemistry.du.ac.in, ramendrapratap@gmail.com
Authors
Amr Elagamy − Department of Chemistry, University of Delhi,
Delhi, India 110007; orcid.org/0000-0002-5035-8479
Ranjay Shaw − Department of Chemistry, University of Delhi,
Delhi, India 110007
Chandan Shah − Department of Chemistry, University of
Delhi, Delhi, India 110007
(d) Liu, J.; Song, w.; Yue, Y.; Liu, R.; Yi, H.; Zhuo, K.; Lei, A.
Pd(OAc) /S=PPh Accelerated Activation of gem-Dichloroalkenes for
2
3
the Construction of 3-arylchromones. Chem. Commun. 2015, 51,
7576−17579.
9) Kausar, H.; Khan, M. U.; Begum, S. N.; Baig, M. M. V.; Baseer,
1
(
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00788
M. A. Synthesis of Some New Halogen Substituted Flavone
Derivatives. Inter. J. Pharm. Sci. Res. 2013, 5, 76−79.
Notes
(10) Lokhande, P. D.; Sakate, S. S.; Taksande, K. N.; Navghare, B.
The authors declare no competing financial interest.
Dimethylsulfoxide-Iodine Catalysed Deprotection of 2′-Allyloxychal-
cones: Synthesis of Flavones. Tetrahedron Lett. 2005, 46, 1573.
(11) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. Synthesis
of 5-Hydroxy-2-(phenyl or styryl)chromones and of Some Halo
Derivatives. J. Heterocycl. Chem. 1996, 33, 1887−1893.
ACKNOWLEDGMENTS
■
A.E. thanks the Department of Biotechnology (DBT), Ministry
of Science and Technology, India, and The World Academy of
Science (TWAS) for the research fellowship. R.P. thanks
University of Delhi for providing research funding under IoE
scheme and USIC, Delhi University, for the instrumentation
facility. R.P. thanks ICMR and CSIR for providing the research
funding.
(12) Yang, Z.; Wang, Y.; Hu, L.; Yu, J.; Li, A.; Li, L.; Yang, T.; Zhou,
C. Electrochemically Induced Thiocyanation of Enaminones: Syn-
thesis of Functionalized Alkenes and Chromones. Synthesis 2020, 52,
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