Iodine/persulfate-promoted site-selective direct thiolation of quinolones and uracils

Article abstract of DOI:10.1016/j.tet.2019.130537

A simple and general method for direct thiolation of 4-quinolones with disulfides or thiols under I₂/K₂S₂O₈ system has been developed. Under the optimal conditions, the C–S bond coupling can take place effectively with good to decent yields and excellent regioselectivity of the S-linked products. The established metal-free site-selective approach was also applicable to transform a range of uracil substrates to the thio-substituted products under mild conditions. Further transformation to the sulfone derivatives can be conveniently performed in one-pot. These easy-to-handle protocols represent a useful and interesting synthetic alternative with good substrate scope and functional group compatibility.

Full text of DOI:10.1016/j.tet.2019.130537

Tetrahedron 75 (2019) 130537
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iodine/persulfate-promoted site-selective direct thiolation of
quinolones and uracils
Danupat Beukeaw, Medena Noikham, Sirilata Yotphan*
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400,
Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and general method for direct thiolation of 4-quinolones with disulfides or thiols under I2/
K2S2O8 system has been developed. Under the optimal conditions, the CeS bond coupling can take place
effectively with good to decent yields and excellent regioselectivity of the S-linked products. The
established metal-free site-selective approach was also applicable to transform a range of uracil sub-
strates to the thio-substituted products under mild conditions. Further transformation to the sulfone
derivatives can be conveniently performed in one-pot. These easy-to-handle protocols represent a useful
and interesting synthetic alternative with good substrate scope and functional group compatibility.
© 2019 Elsevier Ltd. All rights reserved.
Received 5 July 2019
Received in revised form
9 August 2019
Accepted 19 August 2019
Available online 22 August 2019
Keywords:
Iodine
Direct thiolation
Quinolone
Uracil
Sulfone
1. Introduction
enones found in a number of bioactive compounds and pharma-
ceutical agents. Many of these quinolone and uracil analogues are
Organic sulfur-containing compounds are widely present in a
large number of bioactive natural products, synthetic drugs, agro-
chemicals and functional materials [1]. Among various organo-
sulfur compounds, thioethers (sulfide group) had found extensive
applications in the field of medicine, biology, organic synthesis,
catalysis, coordination chemistry, polymers, and other related ap-
plications, as they can serve as an important auxiliary function in
molecules [2]. The incorporation of thioether moieties into the
organic compounds through CeS bond forming reactions has al-
ways been an attractive interest to researchers. Much of the early
work on CeS bond construction involved a classical cross-coupling
of organic halides with thiols or metal thiolates [3]. With sub-
stantial progress in a field of CeH bond functionalization, a direct
formation of CeS bond through CeH functionalization reactions
have recently received considerable attention [4]. Despite several
examples of metal-catalyzed or metal-free transformations have
been reported, the site-selective transformations still remain open
to study.
also known to display a broad spectrum of activities such as anti-
bacterial, antiviral, antitumor, antimalarial as well as herbicidal and
insecticidal properties [5,6]. Owing to their fascinating profiles,
they have been extensively manipulated in several areas including
organic synthesis, medicinal and pharmacological chemistry, agri-
cultural science and material chemistry [7]. In recent years,
tremendous efforts have been devoted to the site-selective syn-
thesis and modification of these heterocycles in order to increase
their structural diversity and utilization. Particularly, incorporation
of bioactive moieties or functional groups into their skeletons could
modify their reactivity, thereby leading to further applications.
In the context of direct construction of CeS bond linkage, the
thioether functionality can be directly introduced into the 4-
quinolone core via Pd-catalyzed decarboxylative CeS bond
coupling reaction (Scheme 1a) [8]. In addition, the metal-free sys-
tems to mediate thiolation process (using NH4I or NaI/TBHP) were
subsequently reported (Schemes 1b and 1c) [9,10]. Despite their
usefulness in forming CeS bonds, these methods still have some
limitations, such as high temperature, toxic solvent, using a large
excess of halogen, a requirement of a blocking or directing group
and narrow substrate scope. Therefore, alternative protocols to
access these compounds efficiently under mild conditions are
highly desirable.
Quinolones and uracils are privileged classes of N-heterocyclic
* Corresponding author.
E-mail address: sirilata.yot@mahidol.ac.th (S. Yotphan).
https://doi.org/10.1016/j.tet.2019.130537
0040-4020/© 2019 Elsevier Ltd. All rights reserved.

2
D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
Table 1
Optimization of reaction conditions.a
Entry
Reagent
Oxidant
Solvent
Yieldb
1
2
3
4
5
6
7
8
NCS
NBS
NIS
I2
NaCl
NaBr
NaI
NH4I
I2
I2
I2
I2
I2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
e
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
MeOH
H2O
21
47
42
84 (84c)
57
60
78
76
34
60
66
20
32
6
49
23
9
10
11
12
13
14
15
16
17
18
I2
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
I
I
2 (50%)
2 (20%)
e
no reaction
28
I2
1a ¼ quinolone, 2a ¼ disulfide, entry 4 ¼ optimal condition.
a
Conditions: 1a (0.25 mmol), 2a (0.38 mmol, 1.5 equiv), reagent (0.25 mmol, 1
equiv), oxidant (0.5 mmol, 2 equiv), solvent (0.5 mL), 70 ꢀC, 12 h.
b
GC yield.
Isolated yield.
c
Scheme 1. Synthesis of thioether derivatives of 4-quinolone.
yield. We also found that the thiolation was much less effective as
carrying out this reaction in other solvents (entries 11e14).
Employing catalytic amounts of I2 resulted in lower yields and
conversions (entries 15 and 16) [14]. Lastly, no reaction was
observed in the absence of I2 (entry 17), and only 28% yield of the
product 3a was obtained when the oxidant was omitted from the
reaction (entry 18). These results highlight the importance of both
I2 and K2S2O8 in this transformation. Overall, the optimal condi-
tions for the metal-free regioselective direct thiolation was estab-
lished (Table 1, entry 4; 1 equiv of quinolone,1.5 equiv of disulfide,1
equiv of I2, 3 equiv of K2S2O8, CH3CN, 80 ꢀC, 12 h).
Next, the scope of this transformation was examined in detail
under the optimized conditions. As shown in Table 2, several diaryl
disulfides could react with quinolone 1a smoothly to produce the
desired products (3aꢁ3i) in good to excellent yields. In general, aryl
disulfides with electron-donating groups (ꢁMe, ꢁOMe, eOH)
proceeded very well, and high yields of the products were obtained
(3a, 3c and 3d). Disulfides bearing electron-withdrawing group
(ꢁNO2) is also suitable for this transformation (3e, 50%). Pleasingly,
the chloro substituents on the phenyl ring of disulfides are well
tolerated, which enable a potential application in further func-
tionalization (3fꢁ3h). The amide group (COeNH) on diaryl disul-
fide was also a viable coupling partner for this CeS cross-coupling
reaction. Meanwhile, heteroaromatic disulfide as well as dialkyl
disulfide was less effective in this transformation and quite low
yields of products (3j and 3k) were found, indicating a less stability
of the sulfur intermediate species. Nevertheless, upon switching to
diphenyl diselenide, the direct CeSe bond formation was achieved
in decent quantity under the established conditions (3l, 95%). We
next turned our attention toward the reactions of other quinolone
substrates. For other N-alkylated 4-quinolones substrates, good to
excellent amounts of products were isolated from the reactions. In
particular, the N-2-ethoxy-2-oxoethyl (with ester functionality) 4-
With our interests toward the development of improved syn-
thetic routes to chemically modify various N-heterocyclic com-
pounds [11], herein, we disclose a convenient metal-free approach
for site-selective direct thiolation of quinolones with disulfides or
thiols using iodine/persulfate-promoted CeS bond coupling reac-
tion. This metal-free method offers a very simple and general
protocol to access the S-linked products of 4-quinolone compounds
regioselectively under relatively mild conditions. The established
thiolation method is also applicable to deliver the sulfide moiety to
uracil substrates effectively (Scheme 1d) [12,13]. In addition, the
optimized conditions are compatible with further oxidation reac-
tion, resulting in a conversion to sulfone derivatives in one-pot.
Other benefits of our strategies are air-tolerant, employing readily
accessible starting materials, giving high yields of products, and
avoiding the use of expensive or a large excess amount of halogen
inducing reagents.
2. Results and discussion
We began our study on the direct thiolation of quinolone with
optimization of reaction conditions between N-ethyl 4-quinolone
(1a) and p-tolyl disulfide (2a). Upon testing a reaction in acetoni-
trile (CH3CN) solvent, the presence of halogen source and potas-
sium persulfate (K2S2O8) as the oxidant allowed the direct CeS
bond coupling to occur and only 3-thiosubstituted product was
formed in this reaction at 80 ꢀC (Table 1). Among various choices of
halogen inducers, molecular iodine (I2) delivered the highest
amount of the corresponding 3-thio substituted product (entry 4),
while other halogen sources provided lower quantities (entries 1e3
and 5e8). In addition, replacing K2S2O8 by other persulfate salts
(entries 9 and 10) or peroxide oxidants resulted in a reduction of

D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
3
Table 2
Table 3
Substrate scope of I2/K2S2O8-promoted site-selective direct thiolation of quinolone.
Direct thiolation of uracils.
quinolone was compatible and afforded the product 3q in gratified
quantities. Furthermore, quinolone substrates bearing the methoxy
or chloro substituted on benzene ring worked well and provided
the desired compounds (3r and 3s) in high yields. On the other
hand, a somewhat smaller amount of product 3t was observed in
case of NH-quinolone, though using 1.5 equivalent of iodine could
help to enhance the yield from this transformation. Nonetheless,
the presence of the methyl substitution at C3 position showed a
deleterious effect on the conversion, and much lower yield of
coupling product 3u was found, suggesting that the steric hin-
drance from the substituent at the C3 position of quinolone is likely
to impede with the product formation.
For this present strategy, thiophenols could also be employed as
an alternate sulfur precursor instead of disulfides in the direct
thiolation reaction. As shown in Scheme 2, comparable yields with
excellent site-selectivity of the products were accomplished in all
cases. Other regioisomers of products were not detected under
standard conditions.
position to the amide carbonyl group of uracil (C5 position) in all
cases. Various aryldisulfides and thiols including electron-rich,
halogen, amide or heteroaryl substitution reacted readily with
1,3-dimethyluracil under the I2/K2S2O8-promoted system and gave
the products in good to excellent yields (5aꢁ5i), with the exception
of the nitro substitution (5d) which exhibited a considerably
decreased reactivity toward this reaction. Similar to quinolone
substrate, direct selenylation of uracil with diphenyl diselenide was
achievable under the standard conditions (70%). Apart from 1.3-
dimethyluracil, other N-protect uracils were feasible, and excel-
lent yields of CeS coupling products were obtained (5k and 5l). To
our surprise, the uracil substrates with the substitution at C6 po-
sition did not appear to interrupt the incorporation of the thiol
moiety, and good to high yields of products were received
(5mꢁ5o). Remarkably, no side reactions due to the presence of the
chloro or amino group at C6 position were detected under the
optimal conditions (5n and 5o). Finally, the NH-uracil substrates
were also amendable to convert to desired products 5p and 5q in
satisfying quantities.
With the success of direct CeS bond coupling of quinolones, we
extended this protocol to uracil substrates, and we found that they
also underwent thiolation with no difficulty and produced the
uracil derivatives under similar conditions [15]. As shown in
Table 3, the thiol moieties were installed exclusively at the
a
To gain insight into the reaction mechanism, we conducted
control experiments as shown in Scheme 3. Adding 1 or 3 equiv of
radical inhibitors, such as 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and 2,6-di-tert-butylphenol (BHT), to the standard reac-
tion, the yield of the coupled product was decreased (Scheme 3a),
which is indicative of partial inhibition of the reaction. These out-
comes suggested that the transformation is likely to operate under
a radical process. However, these observations cannot completely
rule out the possibility of a non-radical pathway. When employing
Scheme 2. Direct thiolation using thiols.

4
D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
Scheme 5. Gram-scale reaction and further transformation to sulfones in one-pot.
Scheme 3. Control experiments.
(RSꢁI) are initially generated from a series of reactions of I2, di-
sulfide (or thiol) and persulfate anion (S2O28ꢁ) or sulfate radical
anion (SO▪4ꢁ) and the final product could be formed by two possible
pathways [11h,18]. In pathway I, a radical triggered process, the RSꢂ
radical intermediate reacts with the substrate to form the radical
3-methyl substituted quinolone or 5-methyl substituted uracil as a
substrate of this transformation, no reactions were found (Scheme
3b). These results confirmed the regioselectivity of this metal-free
reaction as the direct CeS bond coupling takes place solely at the
intermediate C, in which a thiol group is installed at the
a position
to the carbonyl moiety. Then, this intermediate is further oxidized
by a sulfate radical anion via a SET process to form the carbocation
intermediate D. A subsequent loss of a proton would furnish the
final product [19]. In pathway II, a non-radical process, a reaction
between RSꢁI and substrate could result in a formation of iminium
intermediate E, which can undergo elimination to deliver the
product [9,10,20].
Furthermore, it is noteworthy that this I2/K2S2O8-mediated
direct thiolation protocol could be effectively and practically scaled
up to the gram scale (10 mmol) with similar efficacy to the small
scale reactions. As shown in Scheme 5a, the S-linked products 3b
and 5a could be conveniently prepared under the standard condi-
tions in high yields, 81% (2.27 g) and 90% (2.25 g), respectively.
Lastly, the optimal systems were compatible with further oxidation
reaction, resulting in a successful conversion to sulfone analogues
in one-pot (Scheme 5b and 5c). These outcomes suggested a useful
and promising application in the industry.
a
position to the carbonyl moiety. Besides, when subjecting the
iodo quinolone or iodo uracil substrate to reaction, no reaction was
detected (Scheme 3c). Therefore, these iodo species might not be
intermediates in this transformation. Nonetheless, we found that
the thiol precursor can be converted to the disulfide compound
under the standard conditions (Scheme 3d) [16].
Although some detail reaction mechanism is still unclear at this
stage, plausible mechanistic processes were proposed as depicted
in Scheme 4. Based on our observation and other relevant literature
[11h,17,18], we believed that both intermediates A (RSꢂ) and B
3. Conclusion
In summary, a simple and inexpensive I2/K2S2O8-induced sys-
tem was developed for a direct thiolation of 4-quinolones and
uracils. Using disulfides or thiols as a thiolating agent, these metal-
free approaches enable the CeS bond coupling to occur effectively
under relatively mild conditions. Further transformation to the
sulfone derivatives can be conveniently accomplished in one-pot
process. Additional advantages of these methods include high
regioselectivity, accommodating broad scope, avoiding the
requirement of large excess amount of halide reagent, and
providing moderate to excellent yields of products with good
scalability and simple experimental procedure, which are useful for
a modification of N- heterocycles for medicinal chemistry, drug
discovery research, and other related areas. Further expansion of
the synthetic utility and study of potential biological applications of
these synthesized compounds are currently in progress in our
laboratory.
Scheme 4. Possible reaction mechanism.

D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
5
4. Experimental section
3031, 2978, 1581, 1542, 1487, 1233, 1172, 1083, 804, 771, 703 cmꢁ1
;
1H NMR (DMSO‑d6, 400 MHz):
d
8.60 (s, 1H), 8.22 (dd, J ¼ 8.0, 1.4 Hz,
4.1. General methods
1H), 7.84e7.78 (m, 2H), 7.48e7.44 (m, 1H), 7.25e7.22 (m, 2H),
7.13e7.09 (m, 3H), 4.38 (q, J ¼ 7.1 Hz, 2H), 1.38 (t, J ¼ 7.0 Hz, 3H)
Unless otherwise noted, all reagents were obtained from com-
mercial suppliers and used without further purification. All ex-
periments were carried out under air atmosphere, and oven-dried
glasswares were used in all cases. Column chromatography was
performed over silica gel (SiO2; 60 Å silica gel, Merck Grade,
70e230 Mesh). GC experiments were carried out with an Agilent
6890N GC-FID on chromatograph equipped with Agilent column
ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.4, 150.0, 139.3, 137.6,
132.6, 128.8, 126.4, 126.2, 126.1, 125.1, 124.3, 117.0, 109.5, 47.4,
14.5 ppm; HRMS (ESI): m/z [MþNa]þ calcd for C17H15NOSNa:
304.0767; found: 304.0768.
4.3.3. 1-Ethyl-3-((4-methoxyphenyl)thio)quinolin-4(1H)-one (3c)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a yellow solid in (112 mg, 72% yield); mp ¼ 151.0e152.8 ꢀC; IR
(neat): 3023, 2974, 1724, 1581, 1460, 1384, 1241, 1171, 1032, 771,
HP-1,
ID ꢃ 0.25
dimethylpolysiloxane
m
column
(30 m ꢃ 0.25 mm
m). 1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively, in DMSO‑d6 and CDCl3 solutions. NMR
chemical shifts are reported in ppm and were measured relative to
DMSO to DMSO (2.50 ppm for 1H and 39.52 ppm for 13C) and CHCl3
(7.26 ppm for 1H and 77.16 ppm for 13C). IR spectra were recorded
on Bruker FT-IR Spectrometer Model ALPHA by neat method, and
only partial data are listed. Melting points were determined on
Buchi Melting Point M ꢁ 565 apparatus. High-resolution mass
spectroscopy (HRMS) data were analyzed by a high-resolution
micrOTOF instrument with electrospray ionization (ESI). The
structures of known compounds were corroborated by comparing
their 1H NMR, 13C NMR data with those of literature [12e,13,21].
627 cmꢁ1 1H NMR (DMSO‑d6, 400 MHz):
; d 8.47 (s, 1H), 8.20 (d,
J ¼ 8.4 Hz,1H), 7.81e7.75 (m, 2H), 7.46e7.42 (m, 1H), 7.22e7.18 (m,
2H), 6.87e6.84 (m, 2H), 4.36 (q, J ¼ 7.2 Hz, 2H), 3.70 (s, 3H), 1.35 (t,
J ¼ 7.2 Hz, 3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.2, 158.0,
148.2, 139.1, 132.4, 130.1, 127.2, 126.3, 126.0, 124.1, 116.8, 114.7, 112.4,
55.2, 47.3, 14.4 ppm; HRMS (ESI): m/z [MþNa]þ calcd for
C18H17NO2SNa: 334.0872; found: 334.0875.
4.3.4. 1-Ethyl-3-((4-hydroxyphenyl)thio)quinolin-4(1H)-one (3d)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a brown solid in (105 mg, 71% yield); mp ¼ 197.6e199.9 ꢀC; IR
(neat): 2921, 1598, 1581, 1488, 1266, 1223, 1168, 1086, 832, 755, 695,
4.2. Preparation of the starting materials
516 cmꢁ1; 1H NMR (DMSO‑d6, 400 MHz):
d 9.47 (s, 1H), 8.36 (s, 1H),
8.20 (d, J ¼ 7.6 Hz, 1H), 7.80e7.76 (m, 2H), 7.45e7.41 (m, 1H), 7.14 (d,
The N-alkylated quinolone and uracil substrates were synthe-
sized from the NH-quinolones and NH-uracils and the corre-
sponding alkylhalides via standard alkylation reactions according
to the literature procedures [22,23].
J ¼ 8.8 Hz, 2H), 6.69 (d, J ¼ 8.4 Hz, 2H), 4.33 (d, J ¼ 7.2 Hz, 2H),1.34 (t,
J ¼ 7.2 Hz, 3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.2, 156.4,
147.5, 139.0, 132.4, 131.0, 126.3, 125.9, 124.6, 124.0, 116.8, 116.0,
113.4, 47.3, 14.4 ppm; HRMS (ESI): m/z [MþNa]þ calcd for
C17H15NO2SNa: 320.0716; found: 320.0720.
4.3. Typical experimental procedure for the I2/K2S2O8-promoted
direct thiolation of quinolones and uracils: synthesis of compounds
3ae3v and 5a‒5q
4.3.5. 1-Ethyl-3-((4-nitrophenyl)thio)quinolin-4(1H)-one (3e)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a yellow solid (82 mg, 50% yield); mp ¼ 164.5e166.5 ꢀC; IR (neat):
1571, 1543, 1510, 1368, 1330, 1085, 839, 765, 740, 700, 535,
An 8 mL oven-dried scintillation vial equipped with a magnetic
stir bar was charged with a mixture of 4-quinolone or uracil
(0.50 mmol, 1.0 equiv), disulfide or thiol (0.75 mmol, 1.5 equiv),
molecular iodine (I2) (128 mg, 0.50 mmol, 1.0 equiv), K2S2O8
(1.00e1.50 mmol, 2.0e3.0 equiv), and acetonitrile (CH3CN) (1 mL).
The vial was capped, and the reaction mixture was stirred at 60 or
80 ꢀC for 12e16 h. Upon completion, saturated Na2S2O3 (5 mL) and
distilled deionized H2O (10 mL) was added, and the mixture was
extracted with ethyl acetate (3 ꢃ 25 mL). The combined organic
layer was washed with saturated NaCl, dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was purified
by SiO2 column chromatography to afford the desired thioether
products.
520 cmꢁ1 1H NMR (DMSO‑d6, 400 MHz):
; d 8.72 (s, 1H), 8.24 (dd,
J ¼ 8.1, 1.5 Hz, 1H), 8.09e8.06 (m, 2H), 7.89e7.82 (m, 2H), 7.52e7.49
(m, 1H), 7.30e7.27 (m, 2H), 4.41 (q, J ¼ 7.1 Hz, 2H), 1.40 (t, J ¼ 7.1 Hz,
3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.0, 150.5, 148.2, 144.5,
139.3, 132.8, 126.4, 126.2, 125.5, 124.6, 123.8, 117.1, 106.9, 47.5,
14.4 ppm; HRMS (ESI): m/z [MþH]þ calcd for C17H15N2O3S,
327.0798; found: 327.0799.
4.3.6. 3-((4-Chlorophenyl)thio)-1-ethylquinolin-4(1H)-one (3f)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a yellow solid (153 mg, 97% yield); mp ¼ 148.8e151.5 ꢀC; IR (neat):
3411, 2924, 1574, 1502, 1331, 1224, 1172, 1086, 853, 759, 737 cmꢁ1
;
1H NMR (DMSO‑d6, 400 MHz):
d
8.64 (s, 1H), 8.21 (dd, J ¼ 7.7, 1.4 Hz,
4.3.1. 1-Ethyl-3-(p-tolylthio)quinolin-4(1H)-one (3a)
1H), 7.85e7.79 (m, 2H), 7.49e7.45 (m, 1H), 7.31e7.28 (m, 2H),
7.15e7.11 (m, 2H), 4.39 (q, J ¼ 7.1 Hz, 2H),1.38 (t, J ¼ 7.1 Hz, 3H) ppm;
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a light yellow solid (123 mg, 84% yield); mp ¼ 176.0e177.4 ꢀC; IR
(neat): 3032, 2977, 2916, 1598, 1487, 1384, 1181, 1082, 804, 771, 702,
13C NMR (DMSO‑d6, 100 MHz):
d 174.1, 150.6, 148.2, 144.5, 139.4,
132.9, 126.5, 126.3, 125.5, 124.7, 123.9, 117.2, 106.9, 47.6, 14.5 ppm;
HRMS (ESI): m/z [MþNa]þ calcd for C17H14ClNOSNa: 338.0377;
found: 338.0372.
637 cmꢁ1 1H NMR (DMSO‑d6, 400 MHz):
; d 8.54 (s, 1H), 8.21 (d,
J ¼ 7.6 Hz, 1H), 7.83e7.76 (m, 2H), 7.47e7.43 (m, 1H), 7.08e7.01 (m,
4H), 4.37 (q, J ¼ 7.2 Hz, 2H), 2.22 (s, 3H), 1.36 (t, J ¼ 7.2 Hz, 3H) ppm;
13C NMR (DMSO‑d6, 100 MHz):
d
174.3, 149.3, 139.2, 134.6, 133.7,
4.3.7. 3-((3,5-Dichlorophenyl)thio)-1-ethylquinolin-4(1H)-one (3g)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a white solid (130 mg, 75% yield); mp ¼ 174.0e175.8 ꢀC; IR (neat):
3064, 3017, 1587, 1580, 1542, 1401, 1365, 1228, 757 cmꢁ1.1H NMR
132.4, 129.4, 126.9, 126.3, 126.1, 124.2, 116.8, 110.6, 47.3, 20.4,
14.4 ppm; HRMS (ESI): m/z [MþNa]þ calcd for C18H17NOSNa:
318.0923; found: 318.0927.
(DMSO‑d6, 400 MHz):
d
8.67 (s, 1H), 8.23 (dd, J ¼ 8.0, 1.4 Hz, 1H),
4.3.2. 1-Ethyl-3-(phenylthio)quinolin-4(1H)-one (3b)
7.87e7.80 (m, 2H), 7.51e7.47 (m, 1H), 7.34e7.33 (m, 1H), 7.12 (d,
J ¼ 2.0 Hz, 2H), 4.39 (q, J ¼ 7.2 Hz, 2H), 1.39 (t, J ¼ 7.1 Hz, 3H) ppm;
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a yellow solid (113 mg, 80% yield); mp ¼ 165.5e166.5 ꢀC; IR (neat):
13C NMR (DMSO‑d6, 100 MHz):
d 174.1, 150.6, 142.5, 139.4, 134.3,

6
D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
132.8, 126.4, 126.2, 124.7, 124.6, 123.9, 117.2, 107.2, 47.6, 14.4 ppm;
HRMS (ESI): m/z [MþNa]þ calcd for C17H13Cl2NOSNa: 371.9987;
found: 371.9988.
C17H15NOSeNa: 352.0211; found: 352.0212.
4.3.13. 1-Methyl-3-(p-tolylthio)quinolin-4(1H)-one (3m)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
4.3.8. 1-Ethyl-3-((2,4,5-trichlorophenyl)thio)quinolin-4(1H)-one
(3h)
a
brown solid (140 mg, 99% yield); mp ¼ 164.7e166.1 ꢀC; IR
(neat):2917, 2855, 1722, 1592,1469, 1279, 1154, 787, 756,
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
an orange solid (174 mg, 90% yield); mp ¼ 193.3e194.9 ꢀC; IR
(neat): 3045, 2980, 2930, 1599, 1427, 1221, 1109, 1051, 918, 906, 757,
693 cmꢁ1.1H NMR (DMSO‑d6, 400 MHz):
d 8.53 (s, 1H), 8.20 (dd,
J ¼ 8.0, 1.6 Hz, 1H), 7.83e7.78 (m, 1H), 7.72 (d, J ¼ 8.5 Hz, 1H),
7.49e7.45 (m, 1H), 7.08e7.03 (m, 4H), 3.89 (s, 3H), 2.22 (s, 3H) ppm;
639 cmꢁ1.1H NMR (DMSO‑d6, 400 MHz)
d 8.70 (s, 1H), 8.25 (d,
13C NMR (DMSO‑d6, 100 MHz):
d 174.4, 150.5, 140.4, 134.6, 133.9,
J ¼ 8.0 Hz, 1H), 7.90e7.83 (m, 3H), 7.54e7.50 (m, 1H), 6.90 (s, 1H),
132.4, 129.4, 126.8, 126.0, 125.8, 124.3, 117.1, 110.0, 40.2, 20.5 ppm;
HRMS (ESI): m/z [MþNa]þ calcd for C17H15NOSNa: 304.0767;
found: 304.0770.
4.40 (q, J ¼ 7.1 Hz, 2H), 1.40 (t, J ¼ 7.1 Hz, 3H) ppm.13C NMR
(DMSO‑d6, 100 MHz)
d 174.0, 150.9, 139.4, 137.9, 132.9, 130.5, 130.4,
128.6, 127.8, 127.0, 126.4, 126.2, 124.8, 117.3, 105.9, 47.7, 14.4 ppm;
HRMS (ESI): m/z [MþNa]þ calcd for C17H12Cl3NOSNa: 405.9597;
found: 405.9592.
4.3.14. 1-Pentyl-3-(p-tolylthio)quinolin-4(1H)-one (3n)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a brown solid (160 mg, 95% yield); mp ¼ 83.1e85.9 ꢀC; IR (neat):
4.3.9. N-(2-((1-Ethyl-4-oxo-1,4-dihydroquinolin-3-yl)thio)phenyl)
benzamide (3i)
2954, 2919, 2854, 1598, 1484, 1222, 1083, 847, 760, 697 cmꢁ1 1H
;
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
an orange solid (152 mg, 76% yield); mp ¼ 203.1e204.6 ꢀC; IR
(neat): 3058, 2978, 1665, 1598, 1567, 1518, 1486, 1432, 1308, 763,
NMR (DMSO‑d6, 400 MHz):
d 8.51 (s, 1H), 8.22e8.20 (m, 1H),
7.81e7.75 (m, 2H), 7.46e7.42 (m, 1H), 7.07e7.03 (m, 4H), 4.32 (t,
J ¼ 7.2 Hz, 2H), 2.22 (s, 3H), 1.78e1.71 (m, 2H), 1.31e1.25 (m, 4H),
688 cmꢁ1.1H NMR (DMSO‑d6, 400 MHz):
d 11.41 (s, 1H), 8.82 (s, 1H),
0.83 (t, J ¼ 7.2 Hz, 3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.3,
8.28e8.24 (m, 3H), 7.91e7.89 (m, 1H), 7.84e7.78 (m, 2H), 7.66e7.58
(m, 4H), 7.48e7.45 (m, 1H), 7.38e7.34 (m, 1H), 7.14 (td, J ¼ 7.6,
1.4 Hz, 1H), 4.42 (q, J ¼ 7.1 Hz, 2H), 1.39 (t, J ¼ 7.1 Hz, 3H) ppm; 13C
149.8, 139.3, 134.7, 133.8, 132.4, 129.5, 126.9, 126.3, 126.1, 124.2,
117.0, 110.3, 52.1, 28.1, 28.0, 21.7, 20.5, 13.9 ppm; HRMS (ESI): m/z
[MþNa]þ calcd for C21H23NOSNa: 360.1393; found: 360.1396.
NMR (DMSO‑d6, 100 MHz):
d 175.6, 164.7, 149.3, 139.4 (2C), 139.1,
134.8, 134.4, 132.8, 131.8, 128.9, 128.6, 127.9, 127.6, 126.4, 125.4,
124.6, 124.4, 117.0, 113.4, 47.6, 14.4 ppm; HRMS (ESI): m/z [MþH]þ
calcd for C24H21N2O2S: 401.1318; found: 401.1314.
4.3.15. 1-Isopropyl-3-(p-tolylthio)quinolin-4(1H)-one (3o)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a white solid (94 mg, 60% yield); mp ¼ 130.7e132.3 ꢀC; IR (neat):
2976, 2919, 2852, 1574, 1542, 1488, 1463, 761, 695, 507 cmꢁ1 1H
;
4.3.10. 3-(Benzo[d]thiazol-2-ylthio)-1-ethylquinolin-4(1H)-one
(3j)
NMR (DMSO‑d6, 400 MHz)
d
8.39e8.38 (m, 1H), 8.24 (dd, J ¼ 7.9,
1.7 Hz, 1H), 7.96 (d, J ¼ 7.2 Hz, 1H), 7.79 (ddd, J ¼ 8.7, 6.9, 1.7 Hz, 1H),
7.47e7.44 (m, 1H), 7.08e7.06 (m, 4H), 5.09 (sep, J ¼ 6.6 Hz, 1H), 2.23
(s, 3H), 1.49 (d, J ¼ 6.5 Hz, 6H) ppm; 13C NMR (DMSO‑d6, 100 MHz)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
an orange solid (60 mg, 35% yield); mp ¼ 118.3e120.5 ꢀC; IR (neat):
3358, 3030, 2920, 1600, 1580, 1459, 1424, 1009, 760, 698 cmꢁ1 1H
;
d
173.9, 144.0, 139.6, 134.8, 133.5, 132.4, 129.5, 127.2, 126.4, 126.0,
NMR (400 MHz, DMSO‑d6):
d
8.91 (s, 1H), 8.29 (dd, J ¼ 8.0, 1.5 Hz,
124.1, 116.3, 111.4, 50.6, 21.4, 20.4 ppm; HRMS (ESI): m/z [MþH]þ
1H), 7.92e7.84 (m, 3H), 7.82e7.80 (m, 1H), 7.55e7.51 (m, 1H),
7.45e7.41 (m, 1H), 7.32e7.27 (m, 1H), 4.45 (q, J ¼ 7.1 Hz, 2H), 1.42 (t,
calcd for C19H20NOS, 310.1260; found: 310.1266.
J ¼ 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO‑d6):
d 173.8, 170.9,
153.9, 151.4, 139.3, 134.8, 133.0, 126.5, 126.5, 126.2, 124.9, 124.0,
121.5, 121.1, 117.2, 107.3, 47.6, 14.5 ppm; HRMS (ESI): m/z [MþH]þ
calcd for C18H15N2OS2: 339.0620; found: 339.0619.
4.3.16. 1-Benzyl-3-(p-tolylthio)quinolin-4(1H)-one (3p)
Purification by column chromatography (Hexanes/EtOAc, 3/2) as
a light yellow solid (178 mg, 99% yield); mp ¼ 165.3e166.2 ꢀC; IR
(neat): 3031, 2915, 2861, 1622, 1596, 1481, 1227, 757, 693, 541 cmꢁ1
;
4.3.11. 1-Ethyl-3-(propylthio)quinolin-4(1H)-one (3k)
1H NMR (DMSO‑d6, 400 MHz):
d
8.76 (s, 1H), 8.20 (dd, J ¼ 8.0, 1.4 Hz,
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a yellow oil (41 mg, 33% yield); IR (neat): 3437, 2960, 2927, 1596,
1H), 7.69e7.62 (m, 2H), 7.43e7.33 (m, 3H), 7.30e7.24 (m, 3H),
7.12e7.07 (m, 4H), 5.62 (s, 2H), 2.24 (s, 3H) ppm.; 13C NMR
1581, 1483, 1223, 1169, 868, 757, 698 cmꢁ1 1H NMR (DMSO‑d6,
;
(DMSO‑d6, 100 MHz): d 174.4, 150.3, 139.6, 136.3, 134.8, 133.6, 132.4,
400 MHz):
d
8.27 (s, 1H), 8.21 (d, J ¼ 8.0 Hz, 1H), 7.76e7.73 (m, 2H),
129.5, 128.9, 127.8, 127.0, 126.4, 126.3, 126.2, 124.4, 117.6, 111.0, 55.0,
20.5 ppm; HRMS (ESI): m/z [MþNa]þ calcd for C23H19NOSNa:
380.1080; found: 380.1081.
7.43e7.39 (m, 1H), 4.35 (q, J ¼ 7.1 Hz, 2H), 2.78 (t, J ¼ 7.1 Hz, 2H),
1.54e1.45 (m, 2H), 1.34 (t, J ¼ 7.1 Hz, 3H), 0.94 (t, J ¼ 7.0 Hz, 3H)
ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.5, 145.3, 138.8, 132.1,
126.1,125.2,123.7,116.6,113.4, 47.1, 33.6, 22.0,14.4,13.2 ppm; HRMS
(ESI): m/z [MþH]þ calcd for C14H18NOS: 248.1104; found: 248.1102.
4.3.17. Ethyl 2-(4-oxo-3-(p-tolylthio)quinolin-1(4H)-yl)acetate
(3q)
4.3.12. 1-Ethyl-3-(phenylselanyl)quinolin-4(1H)-one (3l)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
Purification by column chromatography (Hexanes/EtOAc,3/2) as
a white solid (155 mg, 95% yield); mp ¼ 177.8e179.3 ꢀC; IR (neat):
3032, 2980, 1617, 1598, 1579, 1471, 1366, 1171, 1087, 910, 770,
a dark brown solid (114 mg, 65% yield); mp ¼ 152.0e153.4 ꢀC; IR
(neat):3033, 2920, 1736, 1579, 1543, 1235, 796, 762, 691,511 cmꢁ1
;
1H NMR (DMSO‑d6, 400 MHz):
d
8.53 (s, 1H), 8.21 (dd, J ¼ 8.0, 1.6 Hz,
702 cmꢁ1
;
1H NMR (DMSO‑d6, 400 MHz):
d
8.63 (s, 1H), 8.23e8.21
1H), 7.78e7.74 (m, 1H), 7.55 (d, J ¼ 8.6 Hz, 1H), 7.48e7.44 (m, 1H),
(m, 1H), 7.85e7.78 (m, 2H), 7.47 (ddd, J ¼ 8.0, 6.2, 1.7 Hz, 1H),
7.09e7.05 (m, 4H), 5.30 (s, 2H), 4.18 (q, J ¼ 7.1 Hz, 2H), 2.23 (s, 3H),
7.31e7.27 (m, 2H), 7.15e7.11 (m, 2H), 4.39 (q, J ¼ 7.1 Hz, 2H), 1.38 (t,
1.21 (t, J ¼ 7.1 Hz, 3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.5,
J ¼ 7.1 Hz, 3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d
174.2, 150.0,
168.0, 150.5, 140.1, 134.8, 133.4, 132.6, 129.5, 126.9, 126.2, 125.6,
124.4, 116.6, 110.9, 61.5, 52.7, 20.5, 14.0 ppm; HRMS (ESI): m/z
[MþNa]þ calcd for C20H19NO3SNa: 376.0978; found: 376.0979.
139.3, 136.7, 132.6, 129.6, 128.7, 127.8, 126.4, 126.2, 124.4, 117.0,
109.0, 47.4, 14.4 ppm; HRMS (ESI): m/z [MþNa]þ calcd for

D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
7
4.3.18. 1-Ethyl-6,7-dimethoxy-3-(p-tolylthio)quinolin-4(1H)-one
(3r)
(s, 1H), 7.28e7.24 (m, 4H), 7.20e7.19 (m, 1H), 3.41 (s, 3H), 3.36 (s,
3H) ppm; 13C NMR (CDCl3, 100 MHz)
d 161.7, 151.5, 147.5, 135.1,
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a brown solid in (147 mg, 83% yield); mp ¼ 167.8e169.7 ꢀC; IR
(neat): 3045, 2919, 1723, 1580, 1488, 1254, 1079, 997, 899, 803,
129.1, 128.7, 126.8, 106.0, 37.2, 28.6 ppm; HRMS (ESI): m/z [MþNa]þ
calcd for C12H12N2O2SNa: 271.0512; found: 271.0516.
579 cmꢁ1; 1H NMR (DMSO‑d6, 400 MHz):
d
8.41 (s, 1H), 7.57 (s, 1H),
4.3.24. 1,3-Dimethyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione
(5b) [13]
7.10 (s, 1H), 7.10e7.01 (m, 4H), 4.37 (q, J ¼ 7.1 Hz, 2H), 3.97 (s, 3H),
3.84 (s, 3H), 2.22 (s, 3H), 1.37 (t, J ¼ 7.0 Hz, 3H) ppm; 13C NMR
Purification by column chromatography (Hexanes/EtOAc,1/1) as
(DMSO‑d6, 100 MHz):
d
173.2, 153.2, 147.8, 147.0, 134.8, 134.4, 134.2,
a yellow solid (115 mg, 87% yield); 1H NMR (CDCl3, 400 MHz):
d
7.51
(s, 1H), 7.25e7.23 (m, 2H), 7.09e7.07 (m, 2H), 3.39 (s, 3H), 3.35 (s,
3H), 2.29 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
161.9, 151.6,
129.4,126.7,120.2,109.6,105.7, 98.5, 56.2, 55.5, 47.4, 20.5,14.5 ppm;
HRMS (ESI): m/z [MþNa]þ calcd for C20H21NO3SNa: 378.1134;
found: 378.1138.
d
146.5, 137.4, 131.2, 130.0, 129.9, 107.4, 37.3, 28.7, 21.1 ppm; HRMS
(ESI): m/z [MþNa]þ calcd for C13H14N2O2SNa: 285.0668; found:
285.0665.
4.3.19. 7-Chloro-1-ethyl-3-(p-tolylthio)quinolin-4(1H)-one (3s)
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a light yellow solid (126 mg, 76% yield); mp ¼ 150.0e151.0 ꢀC; IR
4.3.25. 5-((4-Methoxyphenyl)thio)-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (5c) [13]
(neat): 3024, 2977, 2921, 1585, 1453, 1221, 1077, 887, 778, 677 cmꢁ1
;
1H NMR (DMSO‑d6, 400 MHz):
d
8.53 (s, 1H), 8.19 (d, J ¼ 8.4 Hz, 1H),
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
7.93 (d, J ¼ 1.6 Hz, 1H), 7.47 (dd, J ¼ 8.6, 1.8 Hz, 1H), 7.09e7.04 (m,
4H), 4.36 (q, J ¼ 7.1 Hz, 2H), 2.23 (s, 3H), 1.34 (t, J ¼ 7.1 Hz, 3H) ppm;
a white solid (118 mg, 85% yield); 1H NMR (CDCl3, 400 MHz):
d
7.39e7.35 (m, 3H), 6.84e6.80 (m, 2H), 3.76 (s, 3H), 3.37 (s, 3H),
13C NMR (DMSO‑d6, 100 MHz):
d
173.7, 149.6, 140.1, 137.6, 134.8,
3.33 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
d
161.8, 159.7, 151.5,
133.3, 129.5, 128.5, 127.1, 124.7, 124.6, 116.5, 111.7, 47.4, 20.5,
14.4 ppm; HRMS (ESI): m/z [MþNa]þ calcd for C18H16ClNOSNa:
352.0533; found: 352.0537.
145.1, 133.3, 124.5,114.9, 108.9, 55.4, 37.2, 28.6 ppm; HRMS (ESI): m/
z [MþNa]þ calcd for C13H14N2O3SNa: 301.0617; found: 301.0612.
4.3.26. 1,3-Dimethyl-5-((4-nitrophenyl)thio)pyrimidine-
2,4(1H,3H)-dione (5d)
4.3.20. 3-(p-Tolylthio)quinolin-4(1H)-one (3t)
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a light yellow solid (45 mg, 34% yield); mp. ¼ 218.4e220.8 ꢀC; IR
(neat): 3055, 2993, 2914, 2858, 1623, 1556, 1502, 1347, 753, 688,
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a yellow solid (19 mg, 13% yield); mp ¼ 185.5e186.4 ꢀC; IR (neat):
3056, 2920, 1708, 1644, 1614, 1434, 1329, 1086, 851, 840, 740 cmꢁ1
;
586 cmꢁ1; 1H NMR (DMSO‑d6, 400 MHz):
d
12.23 (d, J ¼ 6.3 Hz, 1H),
1H NMR (CDCl3, 400 MHz):
7.79 (s, 1H), 7.29e7.28 (m, 1H), 7.27e7.25 (m, 1H), 3.51 (s, 3H), 3.41
d 8.12e8.11 (m, 1H), 8.10e8.09 (m, 1H),
8.30 (d, J ¼ 6.4 Hz, 1H), 8.11 (dd, J ¼ 8.1, 1.4 Hz, 1H), 7.72e7.68 (m,
1H), 7.61e7.59 (m,1H), 7.40e7.36 (m,1H), 7.12e7.01 (m, 4H), 2.23 (s,
(s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
d 161.4, 151.5, 149.7, 146.0,
3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d
174.8, 144.7, 139.7, 134.7,
145.7, 126.5, 124.3, 102.6, 37.7, 29.0 ppm; HRMS (ESI): m/z [MþNa]þ
133.7, 132.1, 129.5, 127.2, 125.4, 125.0, 124.0, 118.6, 110.7, 20.5 ppm;
HRMS (ESI): m/z [MþNa]þ calcd for C16H13NOSNa: 290.0610;
found: 290.0609.
calcd for C12H11N3O4SNa: 316.0362; found: 316.0368.
4.3.27. 5-((4-Chlorophenyl)thio)-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (5e) [13]
4.3.21. 2-Methyl-3-(p-tolylthio)quinolin-4(1H)-one (3u)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a light yellow solid (22 mg, 16% yield); mp ¼ 218.4e220.8 ꢀC; IR
(neat): 2921, 2853, 1724, 1489, 1472, 1342, 1145, 797, 754, 696,
a yellow solid (106 mg, 75% yield); 1H NMR (400 MHz, CDCl3):
d
7.65
(s, 1H), 7.24e7.17 (m, 4H), 3.42 (s, 3H), 3.35 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3):
d 161.7, 151.5, 148.0, 133.9, 132.9, 130.1, 129.3,
581 cmꢁ1
;
1H NMR (DMSO‑d6, 400 MHz):
d
12.09 (s, 1H), 8.05 (dd,
105.5, 37.4, 28.8 ppm; HRMS (ESI): m/z [MþNa]þ calcd for
J ¼ 8.1, 1.5 Hz, 1H), 7.70e7.67 (m, 1H), 7.57e7.55 (m, 1H), 7.37e7.34
C12H11ClN2O2SNa: 305.0122; found: 305.0121.
(m, 1H), 7.03e7.01 (m, 2H), 6.96e6.94 (m, 2H), 2.58 (s, 3H), 2.20 (s,
3H) ppm; 13C NMR (DMSO‑d6, 100 MHz):
d
174.7, 155.4, 139.1, 134.3,
4.3.28. 5-((4-Bromophenyl)thio)-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (5f)
133.9, 132.0, 129.4, 125.9, 125.5, 124.0, 123.7, 117.9, 109.0, 20.4,
19.9 ppm; HRMS (ESI): m/z [MþH]þ calcd for C17H16NOS: 282.0947;
found: 282.0945.
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a white solid (99 mg, 61% yield); mp ¼ 159.0e159.9 ꢀC; IR (KBr):
3445, 3061, 3042, 1716, 1667, 1614, 1472, 1440,1342, 767 cmꢁ1 1H
;
4.3.22. 3-((4-Bromophenyl)thio)-1-ethylquinolin-4(1H)-one (3v)
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a yellow solid (154.2 mg, 86% yield); mp ¼ 159.6e162.3 ꢀC; IR
NMR (CDCl3, 400 MHz)
d 7.65 (s, 1H), 7.38e7.35 (m, 2H), 7.17e7.13
(m, 2H), 3.43 (s, 3H), 3.36 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
d
161.7, 151.6, 148.1, 134.7, 132.2, 130.3, 120.9, 105.4, 37.4, 28.8 ppm;
(neat): 2918,1616,1593,1485,1223,1084,1006, 810, 756, 695 cmꢁ1
;
HRMS (ESI): m/z [MþNa]þ calcd for C12H11BrN2O2SNa: 348.9617;
1H NMR (DMSO‑d6, 400 MHz):
d
8.63 (s, 1H), 8.23e8.21 (m, 1H),
found: 348.9618.
7.85e7.79 (m, 2H), 7.47 (ddd, J ¼ 8.0, 6.5, 1.5 Hz, 1H), 7.43e7.40 (m,
2H), 7.08e7.05 (m, 2H), 4.39 (q, J ¼ 7.1 Hz, 2H), 1.38 (t, J ¼ 7.1 Hz, 3H)
4.3.29. 1,3-Dimethyl-5-((2,4,5-trichlorophenyl)thio)pyrimidine-
2,4(1H,3H)-dione (5g)
ppm; 13C NMR (DMSO‑d6, 100 MHz):
d 174.2, 149.9, 139.3, 137.3,
132.6, 131.5, 128.1, 126.4, 126.2, 124.4, 117.8, 117.0, 109.0, 47.4,
14.4 ppm; HRMS (ESI): m/z [MþNa]þ calcd for C17H14BrNOSNa:
381.9872; found: 381.9873.
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a yellow solid (86 mg, 49% yield); mp ¼ 198.3e200.3 ꢀC; IR (KBr):
3451, 3080, 3066, 2920, 1714, 1651, 1431, 1347, 1056, 766 cmꢁ1 1H
;
NMR (CDCl3, 400 MHz):
d
7.76 (s, 1H), 7.44 (s, 1H), 7.07 (s, 1H), 3.49
161.4, 151.5,
4.3.23. 1,3-Dimethyl-5-(phenylthio)pyrimidine-2,4(1H,3H)-dione
(5a) [13]
(s, 3H), 3.40 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
d
149.7, 135.3, 132.4, 131.8, 131.3, 131.0, 129.2, 102.5, 37.7, 29.0 ppm;
HRMS (ESI): m/z [MþH]þ calcd for C12H10Cl3N2O2S: 350.9523;
found: 350.9522.
Purification by column chromatography (Hexanes/EtOAc,1/1) as
a white solid (102 mg, 82% yield); 1H NMR (CDCl3, 400 MHz)
d 7.60

8
D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
4.3.30. N-(2-((1,3-Dimethyl-2,4-dioxo-1,2,3,4-
a yellow solid (106 mg, 72% yield); 1H NMR (CDCl3, 400 MHz):
7.27e7.25 (m, 2H), 7.07 (d, J ¼ 8.0 Hz, 2H), 3.65 (s, 3H), 3.36 (s, 3H),
2.29 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
160.3, 152.0, 150.6,
tetrahydropyrimidin-5-yl)thio)phenyl)benzamide (5h) [13]
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a white solid (138 mg, 76% yield); 1H NMR (CDCl3, 400 MHz):
d
d
137.3, 131.2, 130.0, 129.8, 107.5, 35.5, 29.5, 21.2; HRMS (ESI): m/z
d
10.52 (s, 1H), 8.29 (dd, J ¼ 8.3, 1.3 Hz, 1H), 8.23e8.20 (m, 2H), 7.71
[MþNa]þ calcd for C13H13ClN2O2SNa: 319.0278; found: 319.0277.
(s, 1H), 7.58e7.50 (m, 4H), 7.44e7.40 (m, 1H), 7.09 (td, J ¼ 7.6, 1.4 Hz,
1H), 3.41 (s, 3H), 3.31 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
4.3.37. 6-Amino-1,3-dimethyl-5-(p-tolylthio)pyrimidine-
2,4(1H,3H)-dione (5o) [12e]
d
165.8,163.2,151.3,147.0,140.8 (2C),136.5,134.9,131.9,130.9,128.7,
127.9, 125.1, 123.7, 108.7, 37.5, 29.0 ppm; HRMS (ESI): m/z [MþNa]þ
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
calcd for C19H17N3O3SNa: 390.0883; found: 390.0886.
a white solid (169 mg, 61% yield); 1H (DMSO‑d6, 400 MHz):
d
7.26 (s,
2H), 7.07e7.00 (m, 4H), 3.36 (s, 3H), 3.32 (s, 3H), 2.23 (s, 3H) ppm;
4.3.31. 5-(Benzo[d]thiazol-2-ylthio)-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (5i) [13]
13C NMR (DMSO‑d6, 100 MHz):
d 161.1, 157.6, 150.8, 134.4, 134.1,
129.4, 125.5, 74.9, 28.2, 20.4 ppm; HRMS (ESI): m/z [MþH]þ calcd
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
for C13H16N3O2S, 278.0958; found: 278.0958.
an orange solid (113 mg, 74% yield); 1H NMR (CDCl3, 400 MHz):
d
7.90 (s, 1H), 7.87e7.85 (m, 1H), 7.73e7.71 (m, 1H), 7.43e7.39 (m,
4.3.38. 5-(p-Tolylthio)pyrimidine-2,4(1H,3H)-dione (5p) [21]
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a light yellow solid (28 mg, 24% yield); 1H NMR (DMSO‑d6,
1H), 7.32e7.27 (m, 1H), 3.50 (s, 3H), 3.42 (s, 3H) ppm; 13C NMR
(CDCl3, 100 MHz):
d 166.6, 161.2, 153.8, 151.5, 150.3, 135.8, 126.4,
124.8, 122.3, 121.1, 102.5, 37.7, 29.1 ppm; HRMS (ESI): m/z [MþH]þ
400 MHz):
d
11.36 (s, 1H), 11.32 (d, J ¼ 6.0 Hz, 1H), 7.84 (d, J ¼ 6.0 Hz,
calcd for C13H12N3O2S2: 306.0365; found: 306.0369.
1H), 7.16e7.01 (m, 4H), 2.24 (s, 3H); 13C NMR (DMSO‑d6, 100 MHz):
d
162.2, 151.2, 148.1, 135.2, 132.8, 129.6, 127.1, 103.0, 20.4 ppm;
4.3.32. 1,3-Dimethyl-5-(phenylselanyl)pyrimidine-2,4(1H,3H)-
dione (5j) [13]
HRMS (ESI): m/z [MþNa]þ calcd for C11H10N2O2SNa: 257.0355;
found: 257.0359.
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a white solid (102 mg, 70% yield); 1H NMR (CDCl3, 400 MHz):
d
4.3.39. 6-Chloro-3-methyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-
dione (5q)
7.50e7.47 (m, 2H), 7.41 (s, 1H), 7.27e7.23 (m, 3H), 3.35 (s, 3H), 3.34
(s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
d
162.0, 151.7, 147.5, 146.4,
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
a light yellow solid (96 mg, 68% yield); mp ¼ 218.0e220.8 ꢀC; IR
(KBr): 3448, 3042, 2917, 2895, 1717, 1654, 1588, 1012, 759,
132.8, 129.5, 127.9, 103.3, 37.2, 28.6 ppm; HRMS (ESI): m/z [MþNa]þ
calcd for C12H12N2O2SeNa: 318.9956; found: 318.9953.
452 cmꢁ1
;
1H NMR (DMSO‑d6, 400 MHz):
d
12.88 (s, 1H),7.14e7.09
4.3.33. 1,3-Diethyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione
(5k) [13]
(m, 4H), 3.15 (s, 3H), 2.26 (s, 3H) ppm; 13C NMR (DMSO‑d6,
100 MHz): d 160.8, 150.5, 149.8, 135.2, 132.0, 129.6, 126.7, 101.9, 27.8,
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
20.4 ppm; HRMS (ESI): m/z [MþNa]þ calcd for C12H11ClN2O2SNa:
a yellow oil (139 mg, 95% yield); 1H NMR (CDCl3, 400 MHz):
d
7.49
305.0122; found: 305.0124.
(s, 1H), 7.25e7.22 (m, 2H), 7.09e7.07 (m, 2H), 4.00 (q, J ¼ 7.1 Hz, 2H),
3.80 (q, J ¼ 7.2 Hz, 2H), 2.29 (s, 3H), 1.30 (t, J ¼ 7.2 Hz, 3H), 1.19 (t,
4.4. Typical experimental procedure for the one-pot conversion to
sulfones: synthesis of compounds 6 and 7
J ¼ 7.1 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz):
d
161.4, 150.8, 145.4,
137.3, 131.2, 130.0,129.9,107.7, 45.2, 37.4, 21.1,14.5, 12.8 ppm; HRMS
(ESI): m/z [MþNa]þ calcd for C15H18N2O2SNa: 313.0981; found:
313.0987.
Following the typical procedure for the synthesis of compounds
3 and 5, after the reaction mixture was stirred at 60 or 80 ꢀC for
12e16 h, the resulting mixture was cooled down to room temper-
ature and m-CPBA (172 mg, 1.0 mmol, 2 equiv) was added. The re-
action mixture was stirred for an additional 2e6 h. Upon
completion, saturated Na2S2O3 (5 mL) and distilled deionized H2O
(10 mL) was added, and the mixture was extracted with ethyl ac-
etate (3 ꢃ 25 mL). The combined organic layer was washed with
saturated NaCl, saturated NaHCO3, dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude product was purified by SiO2
column chromatography to afford the desired thioether products.
4.3.34. 1,3-Dibenzyl-5-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione
(5l) [13]
Purification by column chromatography (Hexanes/EtOAc, 3/2) as
a yellow solid (178 mg, 86% yield); 1H NMR (CDCl3, 400 MHz):
d
7.50e7.45 (m, 2H), 7.40 (s, 1H), 7.38e7.32 (m, 3H), 7.31e7.22 (m,
5H), 7.21e7.16 (m, 2H), 7.06 (d, J ¼ 7.9 Hz, 2H), 5.14 (s, 2H), 4.89 (s,
2H), 2.30 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz):
161.4, 151.4,
d
144.9, 137.4, 136.6, 135.0, 130.8, 130.1, 130.0, 129.4, 129.2, 128.7,
128.5, 128.2, 127.8, 108.6, 52.7, 45.5, 21.2 ppm; HRMS (ESI): m/z
[MþNa]þ calcd for C25H22N2O2SNa: 437.1294; found: 437.1305.
4.4.1. 1-Ethyl-3-tosylquinolin-4(1H)-one (6)
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
4.3.35. 1,3-Diethyl-6-methyl-5-(p-tolylthio)pyrimidine-
2,4(1H,3H)-dione (5m)
a white solid (98 mg, 60% yield); mp ¼ 145.4e147.5 ꢀC; IR (KBr):
3417, 3071, 3051, 2972, 1631, 1609, 1289, 1140, 698, 667, 543 cmꢁ1
;
Purification by column chromatography (Hexanes/EtOAc, 1/1) as
1H NMR (400 MHz, DMSO‑d6)
d
8.88 (s, 1H), 8.14 (dd, J ¼ 8.0, 1.5 Hz,
a light yellow solid (135 mg, 89% yield); 1H NMR (CDCl3, 400 MHz):
1H), 7.92e7.81 (m, 4H), 7.52e7.48 (m, 1H), 7.37 (d, J ¼ 8.1 Hz, 2H),
d
7.12e7.10 (m, 2H), 7.05e7.03 (m, 2H), 4.04e3.98 (m, 4H), 2.66 (s,
3H), 2.27 (s, 3H), 1.31 (t, J ¼ 7.2 Hz, 3H), 1.20 (t, J ¼ 7.2 Hz, 3H) ppm;
13C NMR (CDCl3, 100 MHz):
161.1, 157.1, 151.0, 136.1, 132.9, 129.9,
4.51 (q, J ¼ 7.1 Hz, 2H), 2.36 (s, 3H), 1.41 (t, J ¼ 7.1 Hz, 3H) ppm; 13
C
NMR (100 MHz, DMSO‑d6)
d 171.3, 147.4, 143.9, 139.6, 138.9, 134.0,
d
129.6, 128.4, 128.2, 126.4, 125.9, 119.5, 118.1, 48.9, 21.5, 14.8 ppm;
HRMS (ESI): m/z [MþNa]þ calcd for C18H17NO3SNa: 328.1002;
found: 328.1015.
127.8, 105.7, 42.0, 37.7, 21.0, 18.5, 14.2, 12.8 ppm; HRMS (ESI): m/z
[MþH]þ calcd for C16H21N2O2S: 305.1318; found: 305.1321.
4.3.36. 6-Chloro-1,3-dimethyl-5-(p-tolylthio)pyrimidine-
2,4(1H,3H)-dione (5n) [13]
4.4.2. 1,3-Dimethyl-5-tosylpyrimidine-2,4(1H,3H)-dione (7)
Purification by column chromatography (Hexanes/EtOAc, 1/1)
white solid (130 mg, 88% yield); mp ¼ 132.4e134.9 ꢀC; IR (KBr):
Purification by column chromatography (Hexanes/EtOAc, 1/1) as

D. Beukeaw et al. / Tetrahedron 75 (2019) 130537
9
3414, 3289, 3068, 2952, 1725, 1672, 1660, 1627, 1303, 608 cmꢁ1; 1H
4396;
(c) V. Cecchetti, C. Parolin, S. Moro, T. Pecere, E. Filipponi, A. Calistri,
O. Tabarrini, B. Gatto, M. Palumbo, A. Fravolini, G. Palu, J. Med. Chem. 43
(2000) 3799;
(d) M. Sato, T. Motomura, H. Aramaki, T. Matsuda, M. Yamashita, Y. Ito,
H. Kawakami, Y. Matsuzaki, W. Watanabe, K. Yamataka, S. Ikeda, E. Kodama,
M. Matsuoka, H. Shinkai, J. Med. Chem. 49 (2006) 1506;
NMR (400 MHz, DMSO‑d6)
d
8.70 (s,1H), 7.84 (d, J ¼ 8.3 Hz, 2H), 7.40
(d, J ¼ 8.0 Hz, 2H), 3.44 (s, 3H), 3.06 (s, 3H), 2.38 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO‑d6)
d 157.3, 150.7, 150.2, 144.0, 137.5, 129.3,
127.9, 111.9, 37.4, 27.5, 21.0 ppm; HRMS (ESI): m/z [MþNa]þ calcd
for C13H14N2O4SNa: 317.0566; found: 317.0568.
(e) R.M. Cross, A. Monastyrskyi, T.S. Mutka, J.N. Burrows, D.E. Kyle,
R. Manetsch, J. Med. Chem. 53 (2010) 7076.
_
[6] For selected references, see: (a) A. Pałasz, D. Ciez, Eur. J. Med. Chem. 97 (2015)
Acknowledgments
582;
(b) C. Chen, D. Wu, Z. Guo, Q. Xie, G.J. Reinhart, A. Madan, J. Wen, T. Chen,
C.Q. Huang, M. Chen, Y. Chen, F.C. Tucci, M. Rowbottom, J. Pontillo, Y.-F. Zhu,
W. Wade, J. Saunders, H. Bozigian, R.S. Struthers, J. Med. Chem. 51 (2008)
7478;
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This work was supported by Thailand Research Fund
(RSA6280024 and DBG6080007), the Center of Excellence for
Innovation in Chemistry (PERCH-CIC), Ministry of Higher Educa-
tion, Science, Research and Innovation, Central Instrument Facility
(CIF), Faculty of Science, Mahidol University, and the Royal Golden
Jubilee Ph.D. Program for supporting student scholarship to D.B.
(Grant No. PHD/0141/2560).
(g) F. Medda, R.J.M. Russell, M. Higgins, A.R. McCarthy, J. Campbell,
A.M.Z. Slawin, D.P. Lane, S. Lain, N.J. Westwood, J. Med. Chem. 52 (2009) 2673.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.130537.
(c) N.F. Smith, W.D. Figg, A. Sparreboom, Drug Dev. Res. 62 (2004) 233;
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