Metal-free regioselective direct thiolation of 2-pyridones

Article abstract of DOI:10.1039/c9ob01061k

A highly regioselective metal-free direct C-H thiolation of 2-pyridones with disulfides or thiols has been developed. A combination of persulfate and a commercially available halide source such as LiCl, NCS or I₂ enables the successful direct incorporation of a sulfide moiety into the 5-position of pyridone under mild conditions, providing a useful and convenient approach for the preparation of a diverse array of 5-thio-substituted pyridones in moderate to excellent yields.

Full text of DOI:10.1039/c9ob01061k

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DOI: 10.1039/C9OB01061K
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ARTICLE
Metal-Free Regioselective Direct Thiolation of 2-Pyridones
Kunita Phakdeeyothin and Sirilata Yotphan*
Received 00th January 20xx,
Accepted 00th January 20xx
A highly regioselective metal-free direct C−H thiolation of 2-pyridones with disulfides or thiols has been developed. A
combination of persulfate and a commercially available halide source such as LiCl, NCS or I2 enables the successful direct
incorporation of a sulfide moiety into the 5-position of pyridone under mild conditions, providing a useful and convenient
approach for the preparation of a diverse array of 5-thio-substituted pyridones in moderate to excellent yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
direct carbon−hydrogen (C−H) bond functionalization,11 which
emerged as one of the most efficient transformations in
modern synthetic chemistry as it bypasses the requirement for
Introduction
Carbon−sulfur (C−S) bonds are widely distributed in a large
number of naturally occurring compounds, bioactive molecules,
pharmaceutical agents, and functional materials.1 The thio-
substituted scaffolds are also important building blocks in
organic synthesis, material science, coordination chemistry and
pharmaceutical research.2 As the incorporation of sulfur
moieties into organic molecules can partially modify the
physical and biological properties of the molecules,3 there has
been a great effort to develop new and efficient methods for
the construction of C−S bonds in the past few decades,4 for
instance, metal-catalyzed cross C−S bond coupling reactions,5
nucleophilic addition reactions,6 and electrophilic sulfenylation
reactions.7 These findings become highly efficient tools and
have a great benefit to chemists and other researchers in both
academia and industry.
substrate prefunctionalization, has been mainly employed to
manipulate 2-pyridone cores, particularly for the site-selective
direct C−C bond coupling.12 On the other hand, only a few
examples exist in the literature for the regioselective direct
carbon−heteroatom bond formation.13 To date, the direct C−H
thiolation of 2-pyridones has been disclosed by Jiang and Liu in
2016.14 Under a catalytic amount of Cu(OAc)2 and o-PBA, a
successful direct C6-thiolation with disulfides was reported
(Scheme 1a). In addition, Zhu and co-workers recently
discovered a silver-mediated C5-selective thiolation of 2-
pyridones and other related bicyclic compounds (Scheme 1b).15
Pyridone is considered as one of the privileged
heteroaromatic skeletons found in several natural products,
bioactive molecules, and pharmaceutical agents.8 2-Pyridones,
in particular, exhibit remarkably interesting physical properties
and chemical reactivities due to the presence of the amide
group as well as the conjugated enone-like structure.9 Many
compounds in this class often display promising biological and
pharmacological applications, such as antifungal, antibacterial,
antiepileptic, and antitumor activities.10 Therefore, the
development of synthetic methods to rapidly access pyridones
bearing substituents at specific positions is of great interest to
synthetic, medicinal chemistry and other related research
areas. To date, numerous synthetic methodologies have been
developed for the above purpose. Among those strategies,
Department of Chemistry and Center of Excellence for Innovation in Chemistry,
Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Scheme 1 Direct C−H Thiolation 2-Pyridones.
E
-
mail: sirilata
.yot@mahidol.ac.th
†
Electronic Supplementary Information (ESI) available
.
See DOI: 10.1039/x0xx00000x
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Based on our research interests in the oxidative C−H bond equivalent of LiCl or NCS was sufficient to giveVieawvAertircyle Ohnilginhe
DOI: 10.1039/C9OB01061K
functionalization strategies to manipulate various N-containing quantity of the desired product (entries 14 and 15).
compounds,16 we recently reported useful and convenient Nonetheless, other persulfate oxidants (entries 16−17), as well
protocols for direct C−H thiolation of N-heterocycles such as as a change in reaction temperature, led to a decrease in yield.
pyrazolones17 and uracils18 with disulfides as sulfur precursors. Lastly, only a trace amount or no reaction was observed in the
Herein, we report a straightforward approach for a highly absence of persulfate or halogen source (entries 18 and 19),
regioselective direct C−H thiolation of 2-pyridones with which indicated
a necessity of both reagents in this
disulfide or thiol precursors under metal-free conditions transformation.
(Scheme 1c). This present strategy offers an alternative and
Next, we surveyed a substrate scope of the metal-free direct
expedient method for the direct installation of sulfur moiety thiolation of 2-pyridones under the established reaction
into the C5 position of pyridone substrates, resulting in 5- conditions (LiCl or NCS 0.5 equiv., K2S2O8 3 equiv. in CH3CN at 70
thiosubstituted derivatives in moderate to excellent yields °C). In general, this method can accommodate a variety of N-
under relatively mild conditions.
protected pyridones and NH-pyridones, furnishing the
corresponding 5-thio-substituted products in moderate to
excellent yields. As illustrated in Table 3, many N-alkylated
pyridone substrates can undergo direct thiolation smoothly
with p-tolyldisulfide (2a), giving good quantities of products
Results and discussion
We initiated our studies on a metal-free direct thiolation of
2-pyridones by examining a reaction between N-methyl-2-
pyridone (1a) and p-tolyl disulfide (2a) under various conditions.
To our delight, when employing molecular iodine (I2) and
potassium persulfate (K2S2O8) in CH3CN, a 5-thio-substituted
product 3a was obtained in 75% (Table 1, entry 1). No other
regioisomers were observed. Meanwhile, testing reactions in
other solvents resulted in much lower yields or no reaction
(entries 2−5). Further screening of reaction conditions revealed
that a halogen source played a role in this reaction, and lithium
chloride (LiCl) and N-chlorosuccinimide (NCS) were found to be
suitable in this transformation (entries 6−13). Noteworthy, 0.5
(3a−3e). The reaction of 2-pyridone (2-hydroxypyridine) also
proceeded smoothly giving the desired product (3f) in a
satisfactory amount. Other regioisomers or side reactions due
to the presence of the NH group were not observed.
Remarkably, the N-2-ethoxy-2-oxoethyl pyridone with an ester
functionality was compatible and afforded the product 3g in
gratifying quantity. We also tested the reactions with N-
arylated
Entry
1
2
3
4
5
6
7
8
Reagent(equiv.)
I2 (1)
Oxidant
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
-
Solvent
CH3CN
Toluene
DMSO
MeOH
H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Yield(%)b
75
29
2
I2 (1)
I2 (1)
I2 (1)
I2 (1)
trace
no reaction
30
(nBu)4NI (1)
KI (1)
LiI (1)
25
56
49
78
64
39
80
82
84(84c)
30
31
trace
9
KBr (1)
LiCl (1)
NIS (1)
NBS (1)
NCS (1)
NCS (0.5)
LiCl (0.5)
LiCl (0.5)
LiCl (0.5)
LiCl (0.5)
-
10
11
12
13
14
15
16
17
18
19
K2S2O8
no reaction
a Conditions: pyridone 1 (1 mmol, 1 equiv.), di-p-tolyl-disulfide 2a (1.5 mmol,
1.5 equiv.), LiCl (0.5 mmol, 0.5 equiv.), K2S2O8 (3 mmol, 3 equiv.), CH3CN
(2 ml), 70 °C, under air, 16−24 h as monitored by TLC. Isolated yields after
chromatography purification. b Using NCS instead of LiCl.
a Conditions: pyridone 1a (0.25 mmol, 1 equiv.), di-p-tolyl-disulfide 2a
(0.375 mmol, 1.5 equiv.), oxidant (0.75 mmol, 3 equiv.), solvent (0.5
mL), 70 ˚C, 16 h, under air atmosphere. b GC yield. c Isolated yield.
2 | J. Name., 2012, 00, 1-3
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pyridones such as N-phenyl or N-pyridyl substrates (3h and 3i), substituted pyridone compounds. Reactions ofViepwhAernticylel Oannlinde
DOI: 10.1039/C9OB01061K
and we found that they underwent smooth transformations electron rich arene disulfides proceeded without difficulty,
although using NCS as a halide source appeared to have affording products 4a and 4b in reasonable amounts.
somewhat better results than using LiCl. The effect of Surprisingly, the hydroxyl moiety was tolerated under the
substituents on carbon atoms of pyridone rings was established conditions (4c). However, no reaction was detected
investigated, and the results revealed that both electronic and in the case of diaryl disulfides bearing strong electron
steric effects have an impact on the efficiency of the withdrawing groups (such as 4-nitro or 4-cyanophenyl
transformation. In the case of electron rich group or halogen disulfides, 4d and 4e), suggesting that the electronic
substitution at C3 position, very high yields of 5-thiosubstituted contribution from disulfides is crucial for the efficiency of the
products were obtained (3j−3m). However, for the substrates transformation. Meanwhile, phenyl disulfide substrates with
with an electron withdrawing group such as NO2 or cyano chloro substitutions were compatible, giving corresponding
groups, significantly lower yields of products were isolated products, 4f and 4g, in good yields.19 The direct thiolation
(3n−3p). The conversions to these products could be improved reaction was also applicable to aryl disulfide bearing amide (CO-
by using NCS instead of LiCl. Nonetheless, the pyridone NH) functionality (4h). In addition, we examined the reactions
substrates bearing substituents at C6 position were with heteroaryl and dialkyl disulfides, unfortunately, only fair to
incompatible with the thiolation reaction (3q and 3r). These modest yields of the corresponding 5-thiosubstituted products
outcomes suggested that steric encumbrance at the 6 position were obtained (4i−4k). These outcomes suggested that the
could possibly impede the transformation. Interestingly, the sulfur species from heteroaryl or alkyl disulfides are somewhat
carbostyril (2-quinolone), which is an important structural less stable than those sulfur species from the diaryl disulfide
constituent frequently found in natural products, drugs and sources. Finally, we further tested the reactions with diphenyl
physiologically active substances, was found to exhibit a very diselenide under the established conditions and the direct
good reactivity towards the direct thiolation, producing the selenylation could be achieved in good yields (4l and 4m).19
excellent quantity of the product (3s).
Apart from disulfides, the optimized reaction systems also
We also explored the effect of disulfide substrates toward proved applicable to arene thiols in the direct C−H thiolation.
the direct C−S bond construction, and results are shown in Table Comparable yields of C5-thiolated products were obtained in all
3. A range of disulfides were viable in this metal-free direct cases (Scheme 2).20
thiolation reaction, providing fair to good yields of 5-thio-
Scheme 2 Direct Thiolation with Arene Thiols.
To test the practicality of the developed method, we
conducted a gram scale reaction (10 mmol scale) under the
optimal conditions and the pyridone products could be
obtained with similar efficacy to small scale reactions (Scheme
3), suggesting a possibility of industrialized synthesis and
potential utilization of this synthetic approach.
Scheme 3 Gram-Scale Reactions.
a Conditions: pyridone
1
(1 mmol, 1 equiv.), disulfide
2
(1.5 mmol, 1.5
To gain insight into the reaction mechanism, we conducted
some control experiments as shown in Scheme 4.21 When a
radical scavenger (such as TEMPO and BHT) was employed in
the reaction, the direct thiolation was suppressed (Scheme 4a),
suggesting that the reaction possibly involves a radical or single
equiv.), LiCl (0.50 mmol, 0.5 equiv.), K2S2O8 (3 mmol, 3 equiv.), CH3CN
(2 ml), 70 °C, under air, 16−24 h as monitored by TLC. Isolated yields after
chromatography purification. bUsing I2 instead of LiCl.
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electron transfer process. Given the possibility that aryl Considering the supportive evidence from the conViterwoAlrtsictleuOdnielinse,
DOI: 10.1039/C9OB01061K
disulfides might be oxidized to thiosulfonate prior to reacting the latter pathway is more likely to proceed than the former.
with pyridone substrate in the reaction, we subjected However, we still could not rule out the possibility of pathway
thiosulfonate to test the reactions under standard conditions,
nonetheless, no product was obtained. Thus, this particular
sulfur species might not be formed in the reaction (Scheme 4b).
In addition, no reaction occurred when replacing 2-pyridone
with 5-chloro 1-methylpyridone (Scheme 4c), indicating that
this transformation takes place solely at the 5-position, and the
5-chloropyridone is not a likely intermediate in this reaction.
Nevertheless, we found that the thiol precursor can be
converted to a disulfide compound under the standard
conditions (Scheme 4d).22
A at this moment.
Scheme 5 Tentative Reaction Mechanism.
Conclusions
In summary, the metal-free approach for
a highly
regioselective direct C−H thiolation of 2-pyridones at the C5
position with aromatic disulfides or arene thiols has been
successfully accomplished. A combination of a simple halogen
source such as LiCl, NCS or I2, and K2S2O8 enables the C−S bond
formation to proceed smoothly, providing an effective and
convenient method to access a series of 5-thiosubstituted
pyridones in moderated to excellent quantities under relatively
mild and easy-to-operate conditions. This method should find
practical applications in the diversification of pyridones and
other related nitrogen-containing compounds. Further
mechanistic investigations, expansion of the synthetic
application, and utilization of such compounds in organic
synthesis and biological studies are currently ongoing in our
laboratory.
Scheme 4 Control Experiments.
Based on these preliminary mechanistic studies and
relevant reports,15,23 we proposed a reaction mechanism as
depicted in Scheme 5. This transformation presumably involves
an initial reaction of halide or halogen source with persulfate
(S2O82-) or SO4▪– to form an electrophilic halogen (X+) or halogen
radical (X▪) species.24 Next, the reaction of disulfide or thiol with
these reactive halogen species would produce intermediate
I
(RS−X) or intermediate II (RS•).25 Then, the corresponding 5-
Experimental section
thiosubstituted product can be generated from two possible
paths. In pathway A, pyridone substrate can directly react with General Information
RS−X (intermediate ), leading to a formation of iminium
I
Unless otherwise noted, all reagents were used as received from
commercial suppliers. All experiments were carried out under air
atmosphere, and oven-dried glasswares were used in all cases.
Column chromatography was performed over silica gel (SiO2; 60Å
silica gel, 70–230 Mesh). GC experiments were carried out with a GC-
FID on chromatograph equipped with HP-1 polydimethylsiloxane
intermediate III. Finally, the final product can be obtained upon
losing a proton. In pathway B, the RS• (radical intermediate II) is
captured by pyridone substrate to form the radical intermediate
IV, which can be further oxidized by sulfate radical anion via a
SET process to form cationic intermediate
elimination of a proton would furnish the final product.
V. A subsequent
1
column (30.0 m × 0.25 mm ID × 0.25 µm). H and 13C NMR spectra
4 | J. Name., 2012, 00, 1-3
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were recorded on a Bruker-AV400 spectrometers in CDCl3 or DMSO- 556; HRMS (ESI): calcd for C15H17NOSNa [M+Na]+ 28V2i.e0w9A2rt3ic,lefOounlninde
DOI: 10.1039/C9OB01061K
d6 solution, at 400 and 100 MHz, respectively. NMR chemical shifts 282.0927.
are reported in ppm, and were measured relative to CHCl3 (7.26 ppm
1
1
1-Pentyl-5-(p-tolylthio)pyridin-2(1H)-one (3d). Brown oil (166 mg,
58% yield); 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 2.5 Hz, 1H), 7.30
(dd, J = 9.4, 2.5 Hz, 1H), 7.097.05 (m, 4H), 6.51 (d, J = 9.4 Hz, 1H),
3.89 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 1.73 (quin, J = 7.3 Hz, 3H), 1.39 –
1.25 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
161.7, 144.8, 142.4, 136.5, 133.6, 130.0, 128.3, 121.7, 110.3, 50.1,
28.9, 28.8, 22.3, 21.0, 14.0; IR (neat, cm-1): ν = 3043, 2954, 2926,
2858, 1651, 1586, 1523, 1490, 1435, 1380, 1157, 828, 802, 664, 554;
HRMS (ESI): calcd for C17H21NOSNa [M+Na]+ 310.1236, found
310.1230.
for H and 77.16 ppm for 13C) or DMSO (2.50 ppm for H and 39.52
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
1
were corroborated by comparing their H NMR and 13C NMR data
with those of literature.12b,15
Typical Procedure for a metal-free promoted direct thiolation of 2-
pyridones: synthesis of compounds 3a ̶ 3s and 4a ̶ 4m. To a 2-dram
1-Benzyl-5-(p-tolylthio)pyridin-2(1H)-one (3e). Brown solid (214 mg,
1
70% yield); mp = 73.0
̶
74.0 °C; H NMR (400 MHz, CDCl3): δ 7.54 (d,
vial equipped with a magnetic stir bar, pyridone 1 (1 mmol, 1 equiv.),
disulfide 2 (1.5 mmol, 1.5 equiv.) or thiol (3 mmol, 3 equiv.), LiCl or
N-chlorosuccinamide (NCS) (0.5 mmol, 0.5 equiv.), potassium
persulfate (K2S2O8) (3.0 mmol, 3.0 equiv.) and acetonitrile (CH3CN) (2
mL) were added, respectively. The reaction mixture was stirred at 70
°C for 16−24 h. Upon completion (monitored by TLC), saturated
NaHCO3 (20 mL) was added, and the mixture was extracted with
ethyl acetate (EtOAc) (2 × 40 mL). The combined organic layer was
washed with distilled deionized H2O, saturated NaCl, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product
was purified by SiO2 column chromatography to afford the 5-
thiolated pyridone products.
J = 2.0 Hz, 1H), 7.38 – 7.30 (m, 6H), 7.097.06 (m, 4H), 6.58 (d, J = 9.5
Hz, 1H), 5.13 (s, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.8,
144.9, 141.8, 136.7, 136.0, 133.2, 130.1, 129.1, 128.5, 128.4, 128.3,
122.0, 111.0, 52.2, 21.0; IR (neat, cm-1): ν = 3056, 3028, 2917, 2851,
1655, 1582, 1521, 1489, 1245, 1160, 849, 797, 693, 665, 543; HRMS
(ESI): calcd for C19H17NOSNa [M+Na]+ 330.0923, found 330.0925.
5-(p-Tolylthio)pyridin-2(1H)-one (3f).15 Brown solid (122 mg, 56%
yield); mp = 146.6 ̶
147.6 °C; 1H NMR (400 MHz, CDCl3): δ 13.33 (s,
1H), 7.56 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 9.4, 2.5 Hz, 1H), 7.14 (d, J =
8.3 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 9.4 Hz, 1H), 2.31 (s,
3H) 13C NMR (100 MHz, CDCl3): δ 164.8, 147.2, 139.1, 137.0, 132.9,
130.2, 129.2, 121.2, 112.9, 21.1; IR (neat, cm-1): ν = 3042, 2923, 2850,
1724, 1645, 1594, 1538, 1465, 1415, 1122, 895, 833, 800, 672, 528;
HRMS (ESI): calcd for C12H11NOSNa [M+Na]+ 240.0454, found
240.0458.
1-Methyl-5-(p-tolylthio)pyridin-2(1H)-one (3a).15 White solid (194
mg, 84% yield); mp = 101.2 ̶
102.2 °C; 1H NMR (400 MHz, CDCl3): δ
7.56 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 9.4, 2.6 Hz, 1H), 7.127.07 (m,
4H), 6.55 (d, J = 9.6 Hz, 1H), 3.54 (s, 3H), 2.30 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 162.3, 145.2, 143.1, 136.7, 133.5, 130.1, 128.5, 121.5,
110.6, 37.9, 21.1; IR (neat, cm-1): ν = 3037, 2945, 2912, 1649, 1585,
1522, 1488, 1423, 1322, 927, 906, 827, 794, 665, 551; HRMS (ESI):
calcd for C13H13NOSNa [M+Na]+ 254.0610, found 254.0609.
Ethyl 2-(2-oxo-5-(p-tolylthio)pyridin-1(2H)-yl)acetate (3g). Brown
1
oil (154 mg, 51% yield); H NMR (400 MHz, CDCl3): δ 7.49 (d, J = 2.5
Hz, 1H), 7.34 (dd, J = 9.6, 2.0 Hz, 1H), 7.12 – 7.06 (m, 4H), 6.54 (d, J =
9.5 Hz, 1H), 4.61 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.28 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.4, 161.6, 145.7,
142.6, 136.7, 133.1, 130.1, 128.6, 121.7, 111.0, 62.1, 50.5, 21.0, 14.2;
IR (neat, cm-1): ν = 3050, 2980, 2922, 1744, 1656, 1587, 1524, 1374,
1208, 1190, 1170, 1017, 829, 803, 547; HRMS (ESI): calcd for
C16H17NO3SNa [M+Na]+ 326.0821, found 326.0821.
1-Ethyl-5-(p-tolylthio)pyridin-2(1H)-one (3b). Brown solid (162 mg,
66% yield); mp = 78.0 ̶
79.0 °C; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J
= 2.5 Hz, 1H), 7.29 (d, J = 9.6 Hz, 1H), 7.097.04 (m, 4H), 6.51 (d, J =
9.6 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.35 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 161.5, 144.8, 141.9, 136.5, 133.5,
130.0, 128.2, 121.7, 110.5, 45.1, 21.0, 14.7; IR (neat, cm-1): ν = 3031,
2976, 2930, 2871, 1710, 1648, 1583, 1490, 1397, 1263, 1160, 1082,
825, 797, 553; HRMS (ESI): calcd for C14H16NOS [M+H]+ 246.0947,
found 246.0950.
1-Phenyl-5-(p-tolylthio)pyridin-2(1H)-one (3h). Yellow pale solid
(222 mg, 76% yield); mp = 166.9 ̶
167.9 °C; 1H NMR (400 MHz, CDCl3):
δ 7.63−7.62 (m, 1H), 7.53 – 7.48 (m, 2H), 7.46 – 7.42 (m, 1H), 7.41 –
7.38 (m, 3H), 7.19 – 7.16 (m, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.66 – 6.62
(m, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.6, 145.3,
142.2, 140.5, 137.0, 133.1, 130.2, 129.6, 129.0, 128.9, 126.6, 122.6,
111.2, 21.1; IR (neat, cm-1): ν = 3039, 2915, 2861, 1713, 1664, 1597,
1580, 1517, 1488, 1272, 1235, 830, 782, 694, 564; HRMS (ESI): calcd
for C18H16NOS [M+H]+ 294.0947, found 294.0947.
1-Isopropyl-5-(p-tolylthio)pyridin-2(1H)-one (3c). Brown oil (163
mg, 63% yield); 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 2.5 Hz, 1H),
7.29 (dd, J = 9.4, 2.6 Hz, 1H), 7.107.06 (m, 4H), 6.53 (d, J = 9.6 Hz,
1H), 5.23 (sep, J = 6.8 Hz, 1H), 2.30 (s, 3H), 1.37 (d, J = 6.8 Hz, 6H); 13
C
NMR (100 MHz, CDCl3): δ 161.5, 144.2, 138.0, 136.5, 133.6, 130.1,
128.1, 121.6, 110.6, 46.9, 22.1, 21.1; IR (neat, cm-1): ν = 2975, 2921,
2870, 1648, 1582, 1592, 1490, 1418, 1256, 1180, 1148, 828, 802, 657,
5-(p-Tolylthio)-2H-[1,2'-bipyridin]-2-one (3i). Yellow solid (180 mg,
61% yield); mp = 100.5
̶
101.5 °C; 1H NMR (400 MHz, CDCl3): δ 8.58
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(ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 8.0, 3-Nitro-5-(p-tolylthio)pyridin-2(1H)-one (3o). OrangeVsieowlidArt(ic6le3Omnligne,
1
DOI: 10.1039/C9OB01061K
1.0 Hz, 1H), 7.85 (ddd, J = 8.7, 6.8, 1.9 Hz, 1H), 7.38 (dd, J = 9.5, 2.6 24% yield); mp = 159.7 ̶ 160.7 °C H NMR (400 MHz, CDCl3): δ 8.43
Hz, 1H), 7.34 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 7.21 – 7.19 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.13
(d, J = 8.0 Hz, 2H), 6.62 (d, J = 9.5 Hz, 1H), 2.32 (s, 3H); 13C NMR (100 (d, J = 8.2 Hz, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.6,
MHz, CDCl3): δ 161.4, 151.5, 149.1, 145.4, 140.2, 138.0, 136.9, 133.0, 146.5, 144.7, 138.5, 137.7, 131.0, 130.8, 130.6, 114.1, 21.2; IR (neat,
130.14, 129.1, 123.5, 122.9, 121.4, 111.9, 21.1; IR (neat, cm-1): ν = cm-1): ν = 3468, 3101, 3055, 2946, 2916, 1708, 1648, 1584, 1527,
3096, 3053, 2918, 2850, 1657, 1591, 1463, 1431, 1268, 1237, 858, 1515, 1490, 1381, 1277, 1205, 556; HRMS (ESI): calcd for
808, 798, 763, 687; HRMS (ESI): calcd for C17H15N2OS [M+H]+ C12H10N2O3SNa [M+Na]+ 285.0304, found 285.0305.
295.0900, found 295.0903.
1-Ethyl-4-methoxy-2-oxo-5-(p-tolylthio)-1,2-dihydropyridine-3-
1-Ethyl-3-methyl-5-(p-tolylthio)pyridin-2(1H)-one (3j). Yellow oil carbonitrile (3p). White solid (238 mg, 79% yield); mp = 166.1 ̶ 167.1
(194 mg, 75% yield); 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 2.5 Hz, °C; 1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.12 (d, J = 8.0 Hz, 2H),
1H), 7.20 (s, 1H), 7.10 – 7.06 (m, 4H), 3.98 (d, J = 7.0 Hz, 2H), 2.30 (s, 7.04 – 7.02 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 2.32 (s, 3H),
3H), 2.10 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 159.6, 156.8,
162.1, 141.9, 139.4, 136.3, 133.9, 131.0, 130.0, 128.1, 109.7, 45.2, 152.1, 137.3, 132.2, 130.5, 128.5, 115.4, 110.5, 103.1, 42.3, 21.1,
21.0, 17.3, 14.7; IR (neat, cm-1): ν = 3019, 2975, 2918, 1642, 1596, 18.9, 13.4; IR (neat, cm-1): ν = 3052, 2987, 2954, 2870, 2217, 1650,
1547, 1490, 1439, 1394, 1376, 1225, 1205, 802, 768, 603; HRMS (ESI): 1601, 1517, 1468, 1371, 1313, 1194, 1133, 799, 770; HRMS (ESI):
calcd for C15H17NOSNa [M+Na]+ 282.0923, found 282.0925.
calcd for C16H16N2O2SNa [M+Na]+ 323.0825, found 323.0829.
3-Methyl-5-(p-tolylthio)pyridin-2(1H)-one (3k). White solid (188 4-(p-Tolylthio)isoquinolin-1(2H)-one (3s).15 White solid (262 mg,
mg, 81% yield); mp = 184.8
185.8 °C; 1H NMR (400 MHz, CDCl3): δ 98% yield); mp = 215.1 216.1 °C; 1H NMR (400 MHz, DMSO-d6): δ
̶
̶
13.21 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 1.3, 1.0 Hz, 1H), 11.72 (d, J = 6.4 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.7 Hz,
7.14−7.07 (m, 4H), 2.31 (s, 3H), 2.12 (s, 3H); 13C NMR (100 MHz, 1H), 7.71 (td, J = 7.0, 1.3 Hz, 1H), 7.68 (d, J = 6.1 Hz, 1H), 7.55 – 7.51
CDCl3): δ 165.0, 144.4, 136.8, 136.7, 133.5, 130.4, 130.1, 128.9, (m, 1H), 7.08−7.04 (m, 4H), 2.20 (s, 3H); 13C NMR (100 MHz, DMSO-
112.1, 21.1, 16.7; IR (neat, cm-1): ν = 3291, 3135, 3068, 2847, 2686, d6): δ 161.8, 137.5, 137.3, 135.2, 133.4, 133.0, 129.9, 127.4, 127.1,
1884, 1641, 1607, 1477, 1252, 961, 878, 800, 657, 566; HRMS (ESI): 126.6, 126.5, 124.7, 104.7, 20.4; IR (neat, cm-1): ν = 3303, 3159, 3011,
calcd for C13H13NOSNa [M+Na]+ 254.0610, found 254.0610.
2947, 2815, 1650, 1613, 1468, 1334, 874, 1019, 787, 768, 686, 515;
HRMS (ESI): calcd for C16H14NOS [M+H]+ 268.0791, found 268.0788.
3-Chloro-1-ethyl-5-(p-tolylthio)pyridin-2(1H)-one (3l). White solid
(242 mg, 87% yield); mp = 87.5 ̶
88.5 °C; 1H NMR (400 MHz, CDCl3) δ
1-Ethyl-3-methyl-5-(phenylthio)pyridin-2(1H)-one (4a). White solid
(103 mg, 42% yield); mp = 96.4 ̶
97.4 °C; 1H NMR (400 MHz, CDCl3): δ
7.53 – 7.52 (m, 2H), 7.13 – 7.09 (m, 4H), 4.03 (q, J = 7.2 Hz, 2H), 2.31
(s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.9,
142.3, 140.0, 137.2, 132.7, 130.2, 129.0, 127.1, 110.5, 46.4, 21.1,
14.6; IR (neat, cm-1): ν = 3067, 3052, 2973, 2929, 2868, 1704, 1643,
1591, 1488, 1378, 1249, 1149, 800, 764, 582; HRMS (ESI): calcd for
C14H14ClNOSNa [M+Na]+ 302.0377, found 302.0376.
7.47 (d, J = 2.5 Hz, 1H), 7.28 – 7.25 (m, 2H), 7.24 – 7.23 (m, 1H), 7.18
– 7.15 (m, 3H), 4.00 (q, J = 7.2 Hz, 2H), 2.12 (s, 3H), 1.38 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 162.2, 142.1, 140.1, 137.9, 131.2,
129.3, 127.4, 126.2, 108.9, 45.3, 17.3, 14.8; IR (neat, cm-1): ν = 3052,
2980, 2931, 2852, 1638, 1590, 1578, 1547, 1474, 1229, 1209, 940,
739, 689, 586; HRMS (ESI): calcd for C14H16NOS [M+H]+ 246.0947,
found 246.0947.
3-Chloro-5-(p-tolylthio)pyridin-2(1H)-one (3m). White solid (216
mg, 86% yield); mp = 213.5
13.16 (br s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.18
̶
214.5 °C; 1H NMR (400 MHz, CDCl3) δ
1-Ethyl-5-((4-methoxyphenyl)thio)-3-methylpyridin-2(1H)-one
(d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 2.33 (s, 3H); 13C NMR (100 (4b). White solid (176 mg, 64% yield); mp = 95.8 96.8 °C; 1H NMR
̶
MHz, CDCl3) δ 160.7, 144.5, 137.8, 136.8, 131.9, 130.4, 130.1, 126.4, (400 MHz, CDCl3): δ 7.40 (d, J = 2.5 Hz, 1H), 7.22 – 7.17 (m, 3H), 6.83
113.9, 21.2; IR (neat, cm-1): ν = 3256, 3162, 3128, 3044, 3000, 1642,
1603, 1518, 1115, 1051, 955, 878, 803, 646, 565; HRMS (ESI): calcd
for C12H11ClNOS [M+H]+ 252.0244, found 252.0247.
– 6.80 (m, 2H), 3.96 (q, J = 9.0 Hz, 2H), 3.77 (s, 3H), 2.08 (s, 3H), 1.34
(t, J = 9.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.0, 159.0, 141.3,
138.3, 131.2, 130.8, 127.4, 115.0, 111.3, 55.5, 45.2, 17.3, 14.7; IR
(neat, cm-1): ν = 3049, 2979, 2918, 2850, 1727, 1636, 1578, 1545,
1473, 1437, 1208, 770, 735, 688, 585; HRMS (ESI): calcd for
C15H18NO2S [M+H]+ 276.1053, found 276.1052.
1-Ethyl-3-nitro-5-(p-tolylthio)pyridin-2(1H)-one (3n). Yellow solid
(214 mg, 74% yield); mp = 125.6
δ 8.28 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.19 – 7.17 (m, 2H),
7.15 – 7.13 (m, 2H), 4.11 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.43 (t, J = 1-Ethyl-5-((4-hydroxyphenyl)thio)-3-methylpyridin-2(1H)-one (4c).
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 153.5, 146.8, 143.0, 138.2 Brown oil (146 mg, 56% yield); mp = 63.6 64.5 °C; 1H NMR (400 MHz,
̶
126.6 °C; 1H NMR (400 MHz, CDCl3):
̶
(2C), 131.6, 130.6, 129.9, 110.2, 46.7, 21.2, 14.7; IR (neat, cm-1): ν = DMSO-d6): δ 9.62 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 2.5, 1.1
3043, 2922, 2852, 1676, 1591, 1498, 1442, 1334, 1292, 1245, 986, Hz, 1H), 7.15 – 7.13 (m, 2H), 6.74 – 6.72 (m, 2H), 3.94 – 3.89 (m, 2H),
912, 814, 773, 568; HRMS (ESI): calcd for C14H14N2O3SNa [M+Na]+ 1.95 (s, 3H), 1.21 (s, 3H); 13C NMR (100 MHz DMSO-d6): δ 160.9,
313.0617, found 313.0619.
156.9, 141.1, 140.0, 131.3, 129.2, 124.8, 116.3, 109.6, 44.1, 16.7,
6 | J. Name., 2012, 00, 1-3
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14.4; IR (neat, cm-1): ν = 3152, 2979, 2921, 1632, 1569, 1541, 1491, 1612, 1561, 1317, 1146, 1129, 1014, 713, 666, 606, 585, 520; HRMS
View Article Online
+
DOI: 10.1039/C9OB01061K
1433, 1372, 1265, 1213, 1166, 826, 767, 541; HRMS (ESI): calcd for (ESI): calcd for C12H13NOS2Na [M+Na] 274.0331, found 274.0335.
C14H16NO2S [M+H]+ 262.0896, found 262.0897.
5-((4-Chlorophenyl)thio)-1-ethyl-3-methylpyridin-2(1H)-one (4f).
Yellow oil (246 mg, 88% yield); 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J
= 2.3 Hz, 1H), 7.22 – 7.18 (m, 2H), 7.17 (dd, J = 2.4, 1.2 Hz, 1H), 7.07
– 7.03 (m, 2H), 3.98 (q, J = 7.2 Hz, 2H), 2.10 (s, 3H), 1.35 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 162.0, 141.7, 140.2, 136.4, 132.0,
131.3, 129.3, 128.6, 108.3, 45.3, 17.3, 14.7; IR (neat, cm-1): ν = 3056,
2976, 2932, 1642, 1598, 1548, 1473, 1389, 1353, 1204, 1089, 1009,
812, 769, 538; HRMS (ESI): calcd for C14H15ClNOS [M+H]+ 280.0557,
found 280.0557.
1-Ethyl-3-methyl-5-(propylthio)pyridin-2(1H)-one (4k). Yellow oil
(70 mg, 33% yield); H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 2.4 Hz,
1
1H), 7.25 – 7.24 (m, 1H), 3.94 (qd, J = 7.2, 0.7 Hz, 2H), 2.62 (td, J = 7.2,
1.0 Hz, 2H), 2.10 (s, 3H), 1.58 – 1.49 (m, 2H), 1.31 (td, J = 7.2, 1.0 Hz,
3H), 0.95 (td, J = 7.3, 1.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.0,
141.9, 138.6, 130.2, 111.1, 45.1, 38.7, 22.7, 17.3, 14.7, 13.2; IR (neat,
cm-1): ν = 3057, 2961, 2931, 2871, 1640, 1595, 1546, 1439, 1376,
1224, 1206, 937, 733, 573, 551; HRMS (ESI): calcd for C11H18NOSH
[M+H]+ 212.1104, found 212.1105.
1-Ethyl-3-methyl-5-((2,4,5-trichlorophenyl)thio)pyridin-2(1H)-one
(4g). White solid (184 mg, 53% yield); mp = 174.6 ̶
175.6 °C; 1H NMR
1-Ethyl-3-methyl-5-(phenylselanyl)pyridin-2(1H)-one (4l). Brown oil
(190 mg, 65% yield); mp = 78.4 ̶
79.8 °C; 1H NMR (400 MHz, CDCl3): δ
(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.50 (s, 1H),
7.12 (dd, J = 2.8, 1.2 Hz, 1H), 4.10−3.97 (m, 2H), 2.10 (s, 3H), 1.38 (t,
J = 7.2 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 162.2, 141.5, 137.5,
136.4, 133.5, 132.6, 131.8, 130.4, 129.0, 127.3, 119.2, 45.7, 17.5,
14.6; IR (neat, cm-1): ν = 3076, 3054, 2977, 2917, 1657, 1616, 1564,
1429, 1404, 1323, 1194, 1041, 857, 768, 557; HRMS (ESI): calcd for
C14H12Cl3NOSNa [M+Na]+ 369.9597, found 369.9590.
7.53 (d, J = 2.4 Hz, 1H), 7.34 – 7.29 (m, 3H), 7.27 – 7.19 (m, 3H), 3.99
(q, J = 7.2 Hz, 2H), 2.12 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 162.1, 143.3, 140.7, 132.5, 131.1, 130.2, 129.5, 126.9,
104.0, 45.2, 17.3, 14.8; IR (neat, cm-1): ν = 3049, 2981, 2957, 2916,
1633, 1586, 1573, 1542, 1473, 1437, 1208, 1048, 907, 735, 689;
HRMS (ESI): calcd for C14H15NOSeNa [M+Na]+ 316.0211, found
316.0214.
N-(2-((1-Ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-
yl)thio)phenyl)benzamide (4h). White solid (247 mg, 68% yield); mp
= 136.6 ̶
137.6 °C; 1H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.45 (d, J
2-Benzyl-4-(phenylselanyl)isoquinolin-1(2H)-one (4m). Yellow solid
(231 mg, 59% yield); mp = 115.7 ̶
116.7.6 °C; 1H NMR (400 MHz,
CDCl3): δ 8.49 (dd, J = 8.0, 0.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.71 (s,
1H), 7.65 – 7.61 (m, 1H), 7.53 – 7.49 (m, 1H), 7.36 – 7.29 (m, 5H), 7.24
– 7.20 (m, 2H), 7.19 – 7.14 (m, 3H), 5.25 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 162.4, 139.9, 137.8, 136.6, 133.1, 132.2, 129.4, 129.3,
129.1, 128.6, 128.2, 128.1, 127.7, 127.5, 126.8, 126.5, 104.9, 52.0; IR
(neat, cm-1): ν = 3056, 2947, 2850, 1741, 1646, 1607, 1476, 1365, 763,
738, 702, 693, 611, 509, 469; HRMS (ESI): calcd for C22H18NOSe
[M+H]+ 392.0548, found 392.0545.
= 8.2 Hz, 1H), 7.92 – 7.90 (m, 2H), 7.61 – 7.57 (m, 1H), 7.54 – 7.50 (m,
2H), 7.46 – 7.39 (m, 2H), 7.13 (td, J = 7.6, 1.4 Hz, 1H), 7.06 (dd, J = 2.5,
1.1 Hz, 1H), 3.85 (q, J = 7.2 Hz, 2H), 2.04 (s, 3H), 1.23 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 165.3, 161.8, 139.5, 138.3, 137.2,
134.9, 133.5, 132.3, 131.6, 130.0, 129.1, 127.2, 125.1, 124.1, 121.8,
109.7, 45.3, 17.4, 14.6; IR (neat, cm-1): ν = 3208, 3061, 3020, 2954,
1725, 1649, 1633, 1603, 1576, 1513, 1468, 1294, 1201, 743, 711;
HRMS (ESI): calcd for C21H21N2O2S [M+H]+ 365.1318, found 365.1328.
5-((4-Bromophenyl)thio)-1-ethyl-3-methylpyridin-2(1H)-one (4n).
Brown oil (174 mg, 54% yield); 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J
= 2.4 Hz, 1H), 7.39 – 7.36 (m, 2H), 7.20 (dd, J = 2.5, 1.2 Hz, 1H), 7.03
– 7.00 (m, 2H), 4.00 (q, J = 7.2 Hz, 2H), 2.12 (s, 3H), 1.38 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 162.1, 141.9, 140.3, 137.2, 132.3,
131.5, 128.9, 119.9, 108.3, 45.4, 17.4, 14.8; IR (neat, cm-1): ν = 3056,
2961, 2928, 2870, 1645, 1601, 1547, 1469, 1377, 1198, 1083, 1002,
805, 765, 580; HRMS (ESI): calcd for C14H14BrNOSNa [M+Na]+
347.9851, found 347.9844.
5-(Benzo[d]thiazol-2-ylthio)-1-ethyl-3-methylpyridin-2(1H)-one
(4i). Colorless solid (166 mg, 55% yield); mp = 121.4 ̶
122.4 °C; 1H
NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.6 Hz,
1H), 7.68 (d, J = 2.5 Hz, 1H), 7.45 – 7.40 (m, 2H), 7.32 – 7.28 (m, 1H),
4.06 (q, J = 7.2 Hz, 2H), 2.19 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 170.1, 162.2, 154.4, 142.3, 141.8 135.6, 131.7,
126.5, 124.6, 122.2, 121.1, 105.7, 45.6, 17.4, 14.8; IR (neat, cm-1): ν =
3051, 2977, 2934, 1642, 1597, 1546, 1453, 1421, 1232, 1200, 1006,
935, 753, 725, 570; HRMS (ESI): calcd for C15H15N2OS2 [M+H]+
303.0620, found 303.0618.
Conflicts of interest
1-Ethyl-3-methyl-5-(thiophen-2-ylthio)pyridin-2(1H)-one
(4j).
There are no conflicts to declare.
Colorless solid (30 mg, 12% yield); mp = 150.0
̶
151.0 °C; 1H NMR
(400 MHz, CDCl3): δ 8.06 (d, J = 2.6 Hz, 1H), 7.69 – 7.66 (m, 2H), 7.47
(dd, J = 2.5, 1.2 Hz, 1H), 7.11 (dd, J = 4.8, 4.0 Hz, 1H), 4.03 (q, J = 7.2
Hz, 2H), 2.13 (s, 3H), 1.38 (t, J = 7.2 Hz, 4H); 13C NMR (100 MHz,
CDCl3): δ 162.1, 143.0, 138.3, 133.9, 133.3, 132.2, 131.1, 128.1,
120.4, 46.2, 17.5, 14.6; IR (neat, cm-1): ν = 3078, 2922, 2851, 1646,
Acknowledgements
This work was supported by Thailand Research Fund
(RSA6280024 and DBG6080007), the Center of Excellence for
Innovation in Chemistry (PERCH-CIC), Ministry of Higher
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Education, Science, Research and Innovation, Central
Instrument Facility (CIF), Faculty of Science, Mahidol University
and the Science Achievement Scholarship of Thailand (to K. P.).
131, 8754; (c) Y. Luo, Y. Ma, Z. Hou, J. Am. CheVmie.wSAortcic.le2O0n1lin8e,
140, 114.
DOI: 10.1039/C9OB01061K
7
For selected examples: (a) K. M. Schlosser, A. P. Krasutsky, H.
W. Hamilton, J. E. Reed, and K. Sexton, Org. Lett., 2004,
819; (b) C. D. Prasad, S. J. Balkrishna, A. Kumar, B. S. Bhakuni,
K. Shrimali, S. Biswas and S. Kumar, J. Org. Chem., 2013, 78
6,
,
Notes and references
1434; (c) A. M. Wagner and M. S. Sanford, J. Org. Chem.,
2014, 79, 2263; (d) E. V. Vinogradova, P. Mꢀller, S. L. Angew.
Chem., Int. Ed. 2014, 53, 3125; (e) S. E. Denmark, S. Rossi, M.
P. Webster and H. Wang, J. Am. Chem. Soc. 2014, 136, 13016;
(f) L. Huang, J. Li, Y. Zhao, X. Ye, Y. Liu, L. Yan, C.-H. Tan, H. Liu
and Z. Jiang, J. Org. Chem. 2015, 80, 8933; (g) T. Hostier, V.
1
For selected references: (a) A. Gangjee, Y. Zeng, T. Talreja, J.
J. McGuire, R. L. Kisliuk and S. F. Queener, J. Med. Chem.,
2007, 50, 3046; (b) S. Pasquini, C. Mugnaini, C. Tintori, M.
Botta, A. Trejos, R. K. Arvela, M. Larhed, M. Witvrouw, M.
Michiels, F. Christ, Z. Debyser and F. Corelli, J. Med. Chem.,
2008, 51, 5125; (c) F. V. Singh, A. Parihar, S. Chaurasia, A. B.
Singh, S. P. Singh, A. K. Tamrakar, A. K. Srivastava and A. Goel,
Bioorg. Med. Chem. Lett., 2009, 19, 2158; (d) H. Yamaguchi
and Y. Minoura, J. Appl. Polym. Sci., 2003, 15, 1869; (e) I. P.
Beletskaya and V. P. Ananikov, Chem. Rev., 2011, 111, 1596;
(f) R. G. Arrayas and J. C. Carretero, Chem. Commun., 2011,
47, 2207; (g) E. A. Ilardi, E. Vitaku and J. T. Njardarson, J. Med.
Chem. 2014, 57, 2832.
Ferey, G. Ricci, D. G. Pardo and J. Cossy, Org. Lett., 2015, 17
,
3898.
8
For selected examples: (a) R. Misra, R. C. Pandey and J.
Silverton, J. Am. Chem. Soc., 1982, 104, 4478; (b) W. Adam,
J. Hartung, H. Okamoto, S. Marquardt, W. M. Nau, U. Pischel,
C. R. Saha-Möller and K. Spehar, J. Org. Chem., 2002, 67
,
6041; (c) F. Surup, O. Wagner, J. Frieling, M. Schleicher, S.
Oess, P. M€uller and S. Grond, J. Org. Chem., 2007, 72, 5085.
(d) C. L. Yeates, J. F. Batchelor, E. C. Capon, N. J. Cheesman,
M. Fry, A. T. Hudson, M. Pudney, H. Trimming, J. Woolven
and J. M. Bueno, J. Med. Chem., 2008, 51, 2845; (e) M. C.
Bryan, D. J. Burdick, B. K. Chan, Y. Chen, S. Clausen, J. Dotson,
C. Eigenbrot, R. Elliott, E. J. Hanan, R. Heald, P. Jackson, H. La,
M. Lainchbury, S. Malek, S. E. Mann, H. E. Purkey, G.
Schaefer, S. Schmidt, E. Seward, S. Sideris, S. Wang, I. Yen, C.
2
3
4
For selected references: (a) B. M. Trost and R. F. Hammen, J.
Am. Chem. Soc., 1973, 95, 962; (b) T. Kondo and T. Mitsudo,
Chem. Rev., 2000, 100, 3205; (c) Z.-Y. Gu, J.-J. Cao, S.-Y. Wang
and S.-J. Ji, Chem. Sci., 2016, 7, 4067; (d) F.-L. Liu, J.-R. Chen,
Y.-Q. Zou, Q. Wei and W.-J. Xiao, Org. Lett., 2014, 16, 3768;
(e) M. Feng, B. Tang, S. H. Liang and X. Jiang, Curr. Top. Med.
Chem., 2016, 16, 1200; (f) C. Zhang, J. McClure and C. J. Chou,
J. Org. Chem., 2015, 80, 4919.
For selected references: (a) J. Zhao and X. Jiang, Chinese
Chem. Lett., 2018, 29, 1079; (b) C. B. Mishra, S. Kumari and
M. Tiwari, Eur. J. Med. Chem., 2015, 92, 1; (c) A. Ayati, S.
Emami, A. Asadipour, A. Shafiee and A. Foroumadi, Eur. J.
Med. Chem., 2015, 97, 699; (d) P. Sun, D. Yang, W. Wei, L.
Jiang, Y. Wang, T. Dai and H. Wang, Org. Chem. Front., 2017,
Yu and T. P. Heffron, ACS Med. Chem. Lett., 2016, 7, 100; (f)
J. M. Bueno, F. Calderon, J. Chicharro, J. C. De la Rosa, B. Diaz,
J. Fernandez, J. M. Fiandor, M. T. Fraile, M. Garcia, E.
Herreros, A. Garcia-Perez, M. Lorenzo, A. Mallo, M. Puente,
A. Saadeddin, S. Ferrer, I. Angulo-Barturen, J. N. Burrows and
M. L. Leon, J. Med. Chem., 2018, 61, 3422.
(a) P. S. Dragovich, T. J. Prins, R. Zhou, E. L. Brown, F. C.
Maldonado, S. A. Fuhrman, L. S. Zalman, T. Tuntland, C. A.
Lee and A. K. Patick, J. Med. Chem., 2002, 45, 1607; (b) M.
9
4
, 1367; (e) M. Klečka, R. Pohl, J. Čej and M. Hocek, Org.
Biomol. Chem., 2013, 11, 5189.
(a) C. M. Rayner, in Organosulfur Chemistry: Synthetic
Aspects; Ed.; Page, P., Academic Press: London, 1995; p 89;
(b) A. N. Abeywickrema and A. L. J. Beckwith, J. Am. Chem.
Soc., 1986, 108, 8227; (c) P. Bakuzis and M. L. F. Bakuzis, J.
Org. Chem., 1985, 50, 2569; (d) C. Dell’Erba, A. Houmam, M.
Novi, G. Petrillo and J. Pinson, J. Org. Chem., 1993, 58, 2670;
(e) X. Wang, G. D. Cuny and T. Noel, Angew. Chem., Int. Ed.,
2013, 52, 7860; (e) H. Cui, X. Liu, W. Wei, D. Yang, C. He, T.
Zhang and H. Wang, J. Org. Chem., 2016, 81, 2252; (f) W. Wei,
H. Cui, D. Yang, H. Yue, C. He, Y. Zhang and H. Wang, Green
Chem., 2017, 19, 5608; (g) A. Mandal, H. Sahoo and M.
Baidya, Org. Lett., 2016, 18, 3202.
Torres, S. Gil and M. Parra, Curr. Org. Chem., 2005,
9, 1757;
(c) I. M. Lagoja, Chem. Biodiversity, 2005, , 1; (d) A. D.
2
Fotiadou and A. L. Zografos, Org. Lett., 2011, 13, 4592; (e) S.
Hibi, K. Ueno, S. Nagato, K. Kawano, K. Ito, Y. Norimine, O.
Takenaka, T. Hanada and M. Yonaga, J. Med. Chem., 2012,
55, 10584; (f) S. Mizutani, K. Komori, T. Taniguchi, K. Monde,
K. Kuramochi and K. Tsubaki, Angew. Chem., Int. Ed., 2016,
55, 9553; (g) G. Mata, V. E. do Rosario, J. Iley, L. Constantino
and R. Moreira, Bioorg. Med. Chem., 2012, 20, 886.
10 For selected examples: (a) H. J. Jessen and K. Gademann, Nat.
Prod. Rep., 2010, 27, 1168; (b) C. Tohda, T. Kuboyama and K.
Komatsu, Neurosignals, 2005, 14, 34; (c) R. M. Wilson and S.
J. Danishefsky, Acc. Chem. Res., 2006, 39; (d) M. Métifiot, B.
Johnson, S. Smith, X. Z. Zhao, C. Marchand, T. Burke, S.
Hughes and Y. Pommier, Antimicrob. Agents Chemother.,
2011, 55, 5127; (e) G. Manfroni, F. Meschini, M. L. Barreca,
P. Leyssen, A. Samuele, N. Iraci, S. Sabatini, S. Massari, G.
Maga, J. Neyts and V. Cecchetti, Bioorg. Med. Chem., 2012,
20, 866; (f) J. S. Scott, F. W. Goldberg and A. V. Turnbull, J.
Med. Chem., 2014, 57, 4466.
5
For selected examples: (a) E. Alvaro and J. F. Hartwig, J. Am.
Chem. Soc., 2009, 131, 7858; (b) J.-Y. Lee and P. H. Lee, J. Org.
Chem., 2008, 73, 7413; (c) C. C. Eichmann and J. P. Stambuli,
J. Org. Chem., 2009, 74, 4005; (d) S. L. Buchwald and C. Bolm,
Angew. Chem., Int. Ed., 2009, 48, 5586; (e) C. B. Jouffroy, M.
Kelly and G. A. Molander, Org. Lett. 2016, 18, 876; (f) M. S.
Oderinde, M. Frenette, D. W. Robbins, B. Aquila, J. W.
Johannes, J. Am. Chem. Soc., 2016, 138, 1760; (g) M. Arisawa,
T. Tazawa, S. Tanii, K. Horiuchi, and M. Yamaguchi, J. Org.
Chem., 2017, 82, 804; (h) H. L. Li, Y. Kuninobu and M. Kanai,
Angew. Chem., Int. Ed., 2017, 56, 1495.
11 K. Hirano and M. Miura, Chem. Sci., 2018, 9, 22.
12 For selected examples: (a) A. Nakatani, K. Hirano, T. Satoh
and M. Miura, J. Org. Chem., 2014, 79, 1377; (b) A. Modak, S.
Rana and D. Maiti, J. Org. Chem., 2015, 80, 296; (c) Y. Chen,
6
For selected examples: (a) D. Leow, S. Lin, S. K. Chittimalla, X.
Fu, C.-H. Tan, Angew. Chem., Int. Ed. 2008, 47, 5641; (b) K. L.
Kimmel, M. T. Robak, J. A. Ellman, J. Am. Chem. Soc. 2009,
F. Wang, A. Jia and X. Li, Chem. Sci., 2012, 3, 3231; (d) D.
Conreaux, E. Bossharth, N. Monteiro, P. Desbordes, J.-P. Vors
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
and G. Balme, Org. Lett., 2007,
ARTICLE
9
, 271; (e) Y. Li, F. Xie and X.
View Article Online
Li, J. Org. Chem., 2016, 81, 715; (f) S. Maity, D. Das, S. Sarkar
and R. Samanta, Org. Lett., 2018, 20, 5167; (g) W. Miura, K.
Hirano and M. Miura, J. Org. Chem., 2017, 82, 5337; (h) D.
Das, P. Poddar, S. Maity and R. Samanta, J. Org. Chem., 2017,
82, 3612.
DOI: 10.1039/C9OB01061K
13 (a) W. Miura, K. Hirano and M. Miura, Org. Lett., 2016, 18
,
3742; (b) W. Miura, K. Hirano and M. Miura, Synthesis, 2017,
49, 4745; (c) L. Zhang, X. Zheng, J. Chen, K. Cheng, L. Jin, X.
Jiang and C. Yu, Org. Chem. Front., 2018,
14 P. Peng, J. Wang, C. Li, W. Zhu, H. Jiang and H. Liu, RSC Adv.,
2016, , 57441.
5, 2969.
6
15 Y. Q. Zhu, J. L. He, Y. X. Niu, H. Y. Kang, T. F. Han and H. Y. Li,
J. Org. Chem., 2018, 83, 9958.
16 For recent examples: (a) T. Kittikool, A. Thupyai, K.
Phomphrai and S. Yotphan, Adv. Synth. Catal., 2018, 360
3345; (b) S. Toonchue, L. Sumunnee, K. Phomphrai and S.
Yotphan, Org. Chem. Front., 2018, , 1928; (c) L. Sumunnee,
,
5
C. Pimpasri, M. Noikham and S. Yotphan, Org. Biomol. Chem.,
2018, 16, 2697; (d) M. Noikham, T. Kittikool and S. Yotphan,
Synthesis, 2018, 50, 2337; (e) L. Sumunnee, C. Buathongjan,
C. Pimpasri and S. Yotphan. Eur. J. Org. Chem., 2017, 1025;
(f) D. Beukeaw, K. Udomsasporn and S. Yotphan. J. Org.
Chem., 2015, 80, 3447.
17 A. Thupyai, C. Pimpasri and S. Yotphan, Org. Biomol. Chem.,
2018, 16, 424.
18 M. Noikham and S. Yotphan, Eur. J. Org. Chem. 2019, 2759.
19 Higher yields of products could be obtained when using I2
instead of LiCl.
20 For the direct thiolation using thiols, we found that NCS gave
somewhat better results than LiCl.
21 See ESI for additional control experiments.
22 A. D. Hudwekar, P. K. Verma, J. Kour, S. Balgotra and S. D.
Sawant, Eur. J. Org. Chem., 2019, 1242.
23 (a) L. T. Silva, J. B. Azeredo, S. Saba, J. Rafique, A. J. Bortoluzzi,
A. L. Braga, Eur. J. Org. Chem., 2017, 4740; (b) J.-D. Fang, X.-
B. Yan, L. Zhou, Y.-Z. Wang and X.-Y. Liu, Adv. Synth. Catal.,
2019, 361, 1985; (c) H. Wang, Y. Li, Q. Lu, M. Yu, X. Bai, S.
Wang, H. Cong, H. Zhang and A. Lei, ACS Catal., 2019, 9, 1888;
(d) Y. Liu, Y. Hu, Z. Cao, X. Zhan, W. Luo, Q. Liu and C. Guo,
Adv. Synth. Catal., 2019, 361, 1084; (e) K. D. Mane, A.
Mukherjee, K. Vanka and G. Suryavanshi, J. Org. Chem., 2019,
84, 2039; (f) S. Guo, K. Jie, Z. Zhang, Z. Fu and H. Cai, Eur. J.
Org. Chem., 2019, 1808.
24 (a) U. Dutta, A. Deb, D. W. Lupton and D. Maiti, Chem.
Commun., 2015, 51, 17744; (b) R. Semwal, C. Ravi, R. Kumar,
R. Meena and S. Adimurthy, J. Org. Chem., 2019, 84, 792.
25 (a) B. Hu, P. Zhou, Q. Zhang, Y. Wang, S. Zhao, L. Lu, S. Yan
and F. Yu, J. Org. Chem., 2018, 83, 14978; (b) B. Hu, Q. Zhang,
S. Zhao, Y. Wang, L. Xu, S. Yan, and F. Yu, Adv. Synth. Catal.,
2019, 361, 49; (c) Y. Zheng, Y. He, G. Rong, X. Zhang, Y. Weng,
K. Dong, X. Xu and J. Mao, Org. Lett., 2015, 17, 5444.
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