Visible-Light-Driven Halogen-Bond-Assisted Direct Synthesis of Heteroaryl Thioethers Using Transition-Metal-Free One-Pot C-I Bond Formation/C-S Cross-Coupling Reaction

Article abstract of DOI:10.1021/acs.joc.0c02672

An efficient protocol for the synthesis of thioether directly from heteroarenes has been developed in the presence of visible light in a one-pot manner at room temperature. This method involves two sequential reactions in a single pot where the formation of the iodinated heteroarene is followed by a transition-metal-free C-S coupling reaction. A wide range of heteroarene and thiol partners (including aliphatic thiols) have been used for the synthesis of thioethers. NMR studies and DFT calculations revealed the presence of a halogen bond between the thiolate anion (halogen bond acceptor) and iodoheteroarene (halogen bond donor). This halogen bonded complex on photoexcitation facilitates the electron transfer from the thiolate anion to the iodoheteroarene at room temperature.

Full text of DOI:10.1021/acs.joc.0c02672

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Article
Visible-Light-Driven Halogen-Bond-Assisted Direct Synthesis of
Heteroaryl Thioethers Using Transition-Metal-Free One-Pot C−I
Bond Formation/C−S Cross-Coupling Reaction
Anuradha Nandy, Imran Kazi, Somraj Guha, and Govindasamy Sekar*
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ABSTRACT: An efficient protocol for the synthesis of thioether directly from heteroarenes has been developed in the presence of
visible light in a one-pot manner at room temperature. This method involves two sequential reactions in a single pot where the
formation of the iodinated heteroarene is followed by a transition-metal-free C−S coupling reaction. A wide range of heteroarene
and thiol partners (including aliphatic thiols) have been used for the synthesis of thioethers. NMR studies and DFT calculations
revealed the presence of a halogen bond between the thiolate anion (halogen bond acceptor) and iodoheteroarene (halogen bond
donor). This halogen bonded complex on photoexcitation facilitates the electron transfer from the thiolate anion to the
iodoheteroarene at room temperature.
Of late, photoredox catalysis is being used as a powerful tool
to develop a wide variety of reactions under mild conditions.
The application of visible light as a renewable source of energy
has garnered much interest from organic chemists in the past
decade for the formation of the C−S bond. A one-pot Stadler−
Ziegler process for C−S bond formation was developed by
Noel and co-workers using [Ru(bpy)3Cl2]·6H2O as the
photocatalyst in 2013.8 In 2016, Molander and co-workers
carried out the thioetherification of aryl bromides using
photoredox/Ni-dual catalysis.9 Fu et al. have developed a
general and efficient visible-light photoredox cross-coupling of
aryl halides with arenethiols at room temperature using [fac-
Ir(ppy)3] as the photocatalyst.10 More recently, a visible-light
photoredox catalysis for the synthesis of 2-substituted
benzothiazoles was reported by Natarajan et al. using Eosin
Y as a photocatalyst.11
INTRODUCTION
■
Organosulfur compounds are immensely important due to
their omnipresence. They are widely available in our bodies
and the natural environment.1 Heteroaryl thioethers, a class of
organosulfur compounds, are of great significance owing to
their role in pharmaceutical, medicinal, and biological
compounds. Quinoline-based thioethers are known to show
CB2 agonist activity and have a therapeutic effect in
osteoporosis, inflammation, pain relief, and cancer treatment
(Figure 1A).2 Also, certain N-alkylated 3-phenyl thioquinoli-
nium salts show enhanced activity against fungal pathogens
that are associated with AIDS.3 Moreover, thioether moieties
also act as important structural scaffolds for the synthesis of
higher-oxidation-state derivatives such as sulfones and
sulfoxides.4
Considering various utilities of these thioethers, umpteen
efforts have been made to synthesize these moieties.5
Conventional methods of synthesis employ precious transition
metal catalysts for the cross-coupling reactions of aryl halides
with thiols.6 On top of that, these methods require specific
costly ligands, high temperature, and high catalyst loading to
overcome the deactivation of catalyst due to strong
coordination of the thiolates to transition metal catalysts
(Figure 1B).6,7 Thus, there arises a need to develop alternative
approaches for the C−S bond formation.
However, a visible-light-mediated reaction does not
necessarily need a photocatalyst. The ground-state association
Received: November 9, 2020
Published: January 25, 2021
https://dx.doi.org/10.1021/acs.joc.0c02672
© 2021 American Chemical Society
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Figure 1. Visible-light-mediated one-pot thioether formation.
between the electron-rich donor (a nucleophile or reducing
agent) and an electron-poor acceptor (an electrophile or
oxidizing agent) can generate an electron donor−acceptor
(EDA) or charge-transfer (CT) complex which can absorb the
visible light and undergo photoexcitation to transfer an
electron.12 The ground-state association of the donor and
acceptor to form the EDA or CT complex can be aided by
several noncovalent interactions and one of these is halogen
bond.13 A halogen-bonded EDA complex can thus facilitate the
electron-transfer in its excited state in the presence of visible
light.14 The halogen bond (XB) is an attractive noncovalent
interaction between an electrophilic region of a halogen atom
and nucleophilic region of a molecule. It has found its
utilization in fields such as medicinal chemistry,15 supra-
molecular chemistry,16 and crystal engineering17 and most
importantly in organic synthesis as organocatalysts.18 In the
past demidecade, our research group has delved in probing the
application of XB in organic synthesis and in transition-metal-
free organocatalysis.19 Recently, an atom economic XB-assisted
electron-catalyzed iodination of heteroarene has also been
developed by our group.18e Taking this a step further, we
wanted to attempt a visible-light-driven halogen-bond-assisted
one-pot synthesis of thioether from heteroarenes at room
temperature wherein it was presumed that the thiolate anion
might act as the electron donor (XB acceptor) and the
heteroaryl iodide as the electron acceptor (XB donor). Hence,
an intermolecular charge transfer within the thiolate anion−
heteroaryl iodide might permit the reaction to take place even
in the absence of a photocatalyst.
reaction takes place in a one-pot fashion avoiding lengthy
separation processes associated with the intermediate isolation,
thus, saving time and resources.21 Hence, this new protocol
provides a mild and step economic synthesis of heteroaryl
thioethers.
RESULTS AND DISCUSSION
■
Initially, a trial reaction was kept with 1 equiv of isoquinoline
1a, 55 mol % of iodine, 50 mol % of TBHP in decane, and 10
mol % water at room temperature. After 18 h, on formation of
the iodinated product, 2 equiv of potassium tert-butoxide as
the base and 1.1 equiv of thiophenol were added to the
reaction mixture in 1 mL of DMSO.
Gratifyingly, the C−S cross-coupled product 2a was
obtained in 24 h with high yields (75%) on irradiating the
reaction mixture with visible light at room temperature (Table
1, entry 1).
Thus, further optimization was carried out. Increasing the
amount of TBHP showed a drastic decline in the yield of 2a
(entry 2). Other oxidizing agents like aqueous TBHP and
hydrogen peroxide were unable to give better results (entries 3
and 4). Eventually, it was observed that iodine (55 mol %),
TBHP in decane (50 mol %) as the oxidant, and H2O (10 mol
%) was the best suited condition for the iodination step. Focus
was thus shifted to the second step of this transformation.
Other bases were found to be inferior in comparison to
potassium tert-butoxide for carrying out the C−S bond
formation (entries 5−9). Later, different solvents were
evaluated; however, solvents other than DMSO could not
provide better results (entries 10−12). Further, on increasing
the amount of solvent to 2 mL, an appreciable hike in the yield
to 90% was observed (entry 13). However, the yield remained
constant on further increasing the quantity of solvent (entry
14). Also, varying the amount of base did not improve the
yield of the reaction (entries 15 and 16). Without base, the
product 2a was not obtained, and only the iodinated product
was isolated (entry 17). Importantly, the reaction also failed in
Thus, an effort was undertaken to synthesize heteroaryl
thioethers in a one-pot manner where, first, the iodination step
takes place,19e and the second C−S bond formation takes place
between the thiolate anion and the heteroaryl iodide. The
advantage of the current protocol is as enlisted: (1) The use of
transition metal catalyst has been eluded which is often
expensive and necessitates complete removal from products
particularly in the production of synthetic drugs.20 (2) The
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a
a
Table 1. Optimization for Thioether Formation
Table 2. Scope for Thioether Formation of Isoquinoline
b
entry
oxidant (equiv)
base (equiv)
solvent (mL)
yield (%)
1
2
3
4
5
6
7
8
TBHP (0.5)
TBHP (0.75)
TBHPaq (0.5)
H2O2 (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
LiOtBu (2)
NaOtBu (2)
NaOEt (2)
Cs2CO3 (2)
KOH (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (2)
KOtBu (1)
KOtBu (3)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMF (1)
MeCN (1)
tBuOH (1)
DMSO (2)
DMSO (3)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
75
47
40
c
35
63
70
51
64
55
45
50
23
9
10
11
12
13
14
15
16
17
18
d
90 (89)
89
55
84
trace
e
KOtBu (2)
0
a
Reaction conducted in 1 mmol scale at room temperature under the
b
irradiation of 450 W visible light. Yield calculated by 1H NMR
analysis using 1,3,5-trimethoxybenzene as the internal standard. 70%
c
d
aqueous TBHP was used. Isolated yield (yield in parentheses).
e
Reaction kept in the dark.
a
Reaction conducted in 1 mmol scale at room temperature under the
b
dark conditions (entry 18). Thus, light is indispensable for the
C−S cross-coupling reaction. Also, an on−off experiment was
conducted to validate the significance of light (Figure 2).
irradiation of 450 W visible light. Isolated yield.
electron-donating methyl and methoxy group underwent the
reaction smoothly and provided the corresponding thioether in
excellent yields (Table 2, 2b−2f). The structure of the product
was established by single-crystal XRD analysis of 2d (CCDC
1914361).22 In contrast, moderate to good yields were
observed with the thiophenol moiety containing a weak
electron-withdrawing group (2g−2j). In the presence of a
strong electron-withdrawing nitro group, even a trace amount
of product formation was not observed (2k).
The reaction worked well with heterocyclic thiophenol
giving 90% yield of the desired product (2l). Thiol having a
bulky group like naphthalene also provided an excellent yield
of product (2m). Importantly, aliphatic thiols like cyclo-
hexanethiol, ethanethiol, and tert-butylthiol also worked well
indicating that π−π interaction is not responsible for the
charge transfer (2n−2p).
Also, several quinolines were subjected to a C−S bond
forming reaction with thiols. Quinoline with thiophenol as its
coupling partner gave 83% yield of the thioether in 48 h (Table
3, 4a). Methyl- and methoxy-group-containing thiophenol
worked well under the optimized reaction condition (4b−4f).
A slight decrement in yield was observed in the case of thiol
containing a weak electron-withdrawing group like bromo,
chloro, and fluoro (4g−4j). Notably, the reaction gave
excellent yields of the corresponding thioether with 2-
mercaptopyridine (4k) and 2-naphthalene thiol (4l) as the
coupling partner. Aliphatic thiols also worked well to provide
Figure 2. Light on−off experiment.
Finally, the optimized reaction condition was obtained with 1.1
equiv of thiophenol, 2 equiv of potassium tert-butoxide as the
base, and 2 mL of DMSO as the solvent under the irradiation
of visible light to yield 90% of the desired product 2a.
To probe the scope of the reaction, the methodology was
examined with isoquinoline 1a and several types of thiols, and
the results are summarized in Table 2. Substrates with the
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a
Table 3. Scope for Thioether Formation of Quinoline
a
b
c
Reaction conducted in 1 mmol scale at room temperature under the irradiation of 450 W visible light. Isolated yield. 2 equiv of pyridine used for
d
iodination. 3 equiv of pyridine used for iodination.
a
Table 4. Scope for Thioether Formation of Azaindole
a
b
Reaction conducted in 1 mmol scale at room temperature under the irradiation of 450 W visible light. Isolated yield.
the corresponding heteroaryl thioethers (4m−4o). However,
the 8-substituted quinoline molecule gave low conversion to
the iodinated product, thus resulting in low thioether
formation (4p−4r). In 8-aminoquinoline (4s), the benzene
ring substituted with amine is more electron-rich in
comparison to the pyridine ring, and hence, the substitution
takes place at the para position of the amino-substituted ring.
Thus, the C-5 position of 8-aminoquinoline is more activated
for functionalization.23 Therefore, when the quinoline moiety
bearing an amino functional group was subjected to the
optimized reaction condition, 5-(phenylthio)quinolin-8-amine
was obtained in 82% yield (4s). Further, the weakly electron-
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withdrawing 8-benzamide-substituted quinoline molecule was
subjected to thioether formation. The corresponding N-(5-
(phenylthio)quinolin-8-yl)benzamide (4t) was attained in 35%
yield since the conversion to the iodinated product itself was
observed to be less.
Various substituted 7-azaindoles were also examined to
undergo the C−S cross-coupling reactions under the optimized
conditions (Table 4). 7-Azaindole with thiophenol as its
coupling partner gave 90% yield of the thioether in 30 h (Table
4, 6a). The electron-withdrawing-group-containing 7-azain-
doles, 4-chloro-7-azaindole, underwent the optimized reaction
conditions smoothly and provided the C−S cross-coupled
product in good yields (6b).
coupling partner, the reaction gave 90% yield of 2a, and with
benzeneselenol, the reaction gave 2ac in 89% yield. This is in
accordance to the fact that thiol and benzeneselenol are better
XB acceptors in comparison to aniline and phenol.24
Further, to verify the presence of radical intermediates in the
reaction mixture, radical scavenger (2,2,6,6-tetramethylpiper-
idin-1-yl)oxidanyl (TEMPO) or 2,6-di-tert-butyl-4-methylphe-
nol (BHT) was added to the reaction mixture under optimized
conditions, and a drastic decline in the yield of the product was
observed (Figure 3B). Also, the presence of the TEMPO
adduct with the thiophenol radical was confirmed with
HRMS.22 Additionally, the EPR experiment gave a radical
signal with g value 1.9974 which falls in the range for organic
radicals (Figure 3C).25 Thus, EPR studies also corroborate a
radical process.
A slight decrement in the yield was observed for N-methyl 7-
azaindole in comparison to 7-azaindole (6c). The reaction also
worked well for 7-azaindole with 4-mercaptoanisole as its
coupling partner which gave 88% yield of the thioether in 28 h
(6d).
NMR studies were performed to substantiate the presence of
XB interaction between 4-iodoisoquinoline and the thiolate
anion (Figure 4). 13C NMR for iodoisoquinoline was recorded
To exhibit the practical utility of light-mediated thioether
synthesis, a scaled-up reaction (10 mmol, 1.29 g) was
performed under the standard conditions. To our delight,
this transformation gave 88% isolated yield of the thioether 2a
in 46 h (Scheme 1).
Scheme 1. Gram Scale Reaction
To probe into the reaction mechanism, a series of control
experiments were conducted. The reaction was carried out
using other halogen bond acceptors. The reaction failed to give
the coupled product 2aa using aniline and 2ab using phenol as
the coupling partner (Figure 3A). With thiophenol as the
Figure 4. Cutouts of 13C NMR spectra of (a) iodoisoquinoline, (b)
iodoisoquinoline and KOtBu, and (c) iodoisoquinoline, KOtBu, and
thiophenol (1:1:1 ratio) in DMSO-d6.
Figure 3. (A) Controlled experiments with different coupling partners. (B) Radical scavenger experiment. (C) Electron paramagnetic resonance
(EPR) spectra (X band, room temperature).
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in DMSO-d6, and peak for the carbon atom adjacent to the
iodine was observed at 97.02 ppm. On addition of potassium
tert-butoxide, a significant shift in the peak was not observed.
However, on further adding thiophenol, the peak shifted
downfield (ca. 1 ppm). This increase in chemical shift indicates
a presence of halogen-bonding between iodoisoquinoline and
the thiolate anion due to the lengthening of the C−I bond
upon donation of the halogen bond acceptor electrons into
orbitals of iodine.26
The density functional theory (DFT) calculations also
verified the presence of the halogen bond. The distance
between the iodine atom of 4-iodoisoquinoline and the sulfur
atom of the benzenethiolate anion in the XB complex was
found to be 3.38 Å which is less than the sum of van der Waals
radii of S and I (3.78 Å) (Figure 5A). The C−I−S bond angle
(in decane).19e This is followed by the generation of the
thiolate anion in the presence of potassium tert-butoxide
(KOtBu) as the base. The thiolate anion and A form a halogen-
bonded complex B which on photoexcitation facilitates an
electron transfer.14a
The thiolate anion transfers an electron to carry out the
formation of intermediate C.27 Elimination of the iodide ion
leads to the generation of isoquinoline radical D, followed by
the formation of radical anion intermediate E on coupling with
the thiolate anion. Consequent oxidation of the intermediate E
by another molecule of 4-iodoisoquinoline A gives the C−S
cross-coupled product 2a. Alternatively, the thiyl radical thus
generated (after electron transfer from the thiolate anion to 4-
iodoisoquinoline A in the XB complex B) can couple with
isoquinoline radical D to give 2a.
CONCLUSION
■
In conclusion, we have developed an efficacious methodology
for thioether formation directly from heteroarenes at room
temperature under visible-light-mediated conditions in a one-
pot manner. The protocol involves the in situ formation of
iodinated heteroarenes followed by a C−S coupling reaction
with thiophenol under transition-metal-free conditions. The
reaction worked well for a wide array of thiol coupling partners
including aliphatic and heteroaromatic thiols to give heteroaryl
thioethers in good to excellent yields. NMR spectroscopic
analysis and DFT studies support the formation of a halogen-
bonded complex between the iodinated heteroarene and the
thiolate anion for facilitating the electron transfer.
Figure 5. (A) XB complex between 4-iodoisoquinoline and the
benzenethiolate anion optimized with DFT using the ωB97X-D
functional and 6-311G(d,p) for C, H; 6-311+G(d,p) for N, S; and
Def2TZV for I in a vacuum. (B) Calculated electrostatic potential
(blue = positive electrostatic potential) on the 0.0004 au isodensity
surface (ωB97X-D/Def2TZV).
of the XB complex is 174° which is in accordance with the
approximate linearity that is generally observed in XB
complexes. Figure 5B displays the mapped electrostatic
potential of the XB complex.
A plausible reaction mechanism for the thioether formation
from isoquinoline 1a is delineated in Scheme 2. The iodinated
heteroarene A forms on reaction of 1a with iodine and TBHP
EXPERIMENTAL SECTION
■
All reactions were carried out in oven-dried reaction tubes. TBHP in
decane, di-tert-butyl peroxide, hydrogen peroxide, tert-butyl peroxy
benzoate, and aqueous TBHP were purchased from Sigma-Aldrich
and Fisher Scientific. Iodine was purchased from Avra Synthesis Pvt.,
Ltd. Various isoquinolines, quinolines, and azaindoles were purchased
Scheme 2. Plausible Reaction Mechanism
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from Alfa Aesar, Sigma-Aldrich, TCI, Avra Synthesis, and
Spectrochem Pvt., Ltd., and used directly as received. Various thiols
were purchased from Alfa Aesar, Sigma-Aldrich, TCI, Avra Synthesis,
and Spectrochem Pvt., Ltd., and used directly. Iodomethane was
purchased from Avra Synthesis Pvt., Ltd. DMSO was purchased from
Qualigens. Potassium tert-butoxide, lithium tert-butoxide, sodium tert-
butoxide, cesium carbonate, potassium carbonate, sodium carbonate,
sodium hydroxide, and potassium hydroxide were purchased from
Avra Synthesis and Fisher Scientific. All the starting materials were
synthesized according to the reported procedures. Reactions were
monitored by thin layer chromatography (TLC) using Merck silica
gel 60 F254 precoated plates (0.25 mm) and visualized by UV
fluorescence quenching using an appropriate mixture of ethyl acetate
and hexanes as eluting solvent mixtures. Silica gel for column
chromatography (particle size 100−200 mesh) was purchased from
Avra Synthesis Pvt., Ltd., and used for column chromatography using
hexanes and ethyl acetate mixture as the eluent. Organic solutions
extracted with ethyl acetate (15 mL) and water (2× 10 mL). The
combined organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The reaction mixture was purified
by silica gel column chromatography (hexanes/ethyl acetate) to give
8-methoxy-3-(phenylthio)quinoline 4m (118 mg, 44% yield).
Experimental Procedure for Synthesis of 5-(Phenylthio)-
quinolin-8-amine (4p) from 8-Aminoquinoline (3c). 8-Amino-
quinoline 3c (244 mg, 1 mmol), molecular iodine (140 mg, 0.55
mmol), and 0.5 mmol of TBHP (6 M in decane) were taken in an
oven-dried reaction tube. Pyridine (242 μL, 3 mmol) and H2O (2 μL,
0.1 mmol) were added into the reaction tube. The reaction mixture
was stirred at rt until the disappearance of starting material on the
TLC plate, followed by the addition of potassium tert-butoxide (224
mg, 2 mmol) and thiophenol (112 μL, 1.1 mmol) in DMSO (2 mL)
as the solvent. The reaction was kept for continuous stirring under the
irradiation of 450 W visible light. After completion of the reaction, the
reaction was quenched with aqueous saturated Na2S2O3 solution (10
mL). The reaction mixture was extracted with ethyl acetate (15 mL)
and water (2× 10 mL). The combined organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pressure. The
reaction mixture was purified by silica gel column chromatography
(hexanes/ethyl acetate) to give 5-(phenylthio)quinolin-8-amine 4p
(206 mg, 82% yield).
Experimental Procedure for Synthesis of 3-(Phenylthio)-7-
azaindole (6a) from 7-Azaindole (5a). 7-Azaindole 5a (118 mg, 1
mmol), molecular iodine (140 mg, 0.55 mmol), and 0.5 mmol of
TBHP (6 M in decane) were taken in an oven-dried reaction tube.
Pyridine (242 μL, 3 mmol) and H2O (2 μL, 0.1 mmol) were added
into the reaction tube, and the reaction was stirred at room
temperature until the disappearance of starting material on the
TLC plate, followed by the addition of potassium tert-butoxide (224
mg, 2 mmol) and thiophenol (112 μL, 1.1 mmol) in DMSO (2 mL)
as the solvent. The reaction was kept for continuous stirring under the
irradiation of 450 W visible light. After completion of the reaction, the
reaction was quenched with aqueous saturated Na2S2O3 solution (10
mL). The reaction mixture was extracted with ethyl acetate (15 mL)
and water (2× 10 mL). The combined organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pressure. The
reaction mixture was purified by silica gel column chromatography
(hexanes/ethyl acetate) to give 3-(phenylthio)-7-azaindole 6a (203
mg, 90% yield).
were concentrated under reduced pressure on a Buchi rotary
̈
evaporator using a water bath. A multitube photoreactor was
purchased from Lelesil Innovative Systems which was equipped
with a 450 W light, a 250 W light, and a 15 W light. The 450 W light
has been used as a visible light source emitting in the region 420−700
nm.
1H and 13C NMR spectra were recorded on a Bruker 400 or 500
1
MHz instrument. H NMR is reported relative to residual CDCl3 (δ
7.26 ppm) or DMSO-d6 (δ 2.50 ppm). 13C NMR is reported relative
to residual CDCl3 (δ 77.16 ppm) or DMSO-d6 (δ 39.52 ppm).
Chemical shifts were recorded in parts per million (ppm), and
multiplicities are as indicated: s (singlet,) d (doublet), t (triplet), q
(quartet), quint (quintet), sext (sextet), dd (doublet of doublet), m
(multiplet), tt (triplet of triplet), and td (triplet of doublet). The
coupling constant, J, is reported in Hertz. Melting points were
recorded on a Guna capillary melting point apparatus and are
corrected with benzoic acid as the reference. FTIR spectra were
recorded on a JASCO spectrometer and are reported in frequency of
absorption (cm−1) using a dry KBr pellet. The UV−vis spectra were
recorded with a JASCO V-650 UV−vis spectrophotometer. High-
resolution mass spectra (HRMS) were recorded on a Q-Tof Micro
mass spectrometer.
Experimental Procedure for the Synthesis of 4-
(Phenylthio)isoquinoline (2a) from Isoquinoline (1a). In an
oven-dried reaction tube, isoquinoline 1a (129 mg, 1 mmol),
molecular iodine (140 mg, 0.55 mmol), 0.5 mmol of TBHP (6 M
in decane), and H2O (2 μL, 0.1 mmol) were taken. The reaction
mixture was stirred at room temperature until the disappearance of
starting material on the TLC plate, followed by the addition of
potassium tert-butoxide (224 mg, 2 mmol) and thiophenol (112 μL,
1.1 mmol) in DMSO (2 mL) as the solvent. The reaction was kept for
continuous stirring under the irradiation of 450 W visible light. After
the completion of the reaction, it was quenched with aqueous
saturated Na2S2O3 solution (10 mL). The reaction mixture was
extracted with ethyl acetate. The combined organic layer was washed
with water (2× 10 mL) and dried over anhydrous Na2SO4. The
organic layer was evaporated under reduced pressure to produce
crude product which was purified by silica gel column chromatog-
raphy (hexanes/ethyl acetate) to give 4-(phenylthio)isoquinoline 2a
(211 mg, 89% yield).
Experimental Procedure for the Synthesis of 8-Methoxy-3-
(phenylthio)quinoline (4m) from 8-Methoxyquinoline (3b). 8-
Methoxyquinoline 3b (159 mg, 1 mmol), molecular iodine (140 mg,
0.55 mmol), and 0.5 mmol of TBHP (6 M in decane) were taken in
an oven-dried reaction tube. Pyridine (161 μL, 2 mmol) and H2O (2
μL, 0.1 mmol) were added into the reaction tube. The reaction
mixture was stirred at room temperature (rt) until the disappearance
of starting material on the TLC plate, followed by the addition of
potassium tert-butoxide (224 mg, 2 mmol) and thiophenol (112 μL,
1.1 mmol) in DMSO (2 mL) as the solvent. The reaction was kept for
continuous stirring under the irradiation of 450 W visible light. After
completion of the reaction, the reaction was quenched with aqueous
saturated Na2S2O3 solution (10 mL). The reaction mixture was
4-(Phenylthio)isoquinoline (2a). 211 mg, 89% yield; cream
colored solid. mp 59−60 °C [57−58 °C, lit.].28 Rf = 0.30 (10%
ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3054, 1570, 1481,
1
1378, 1228, 981, 743. H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H),
8.65 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.76−
7.67 (m, 1H), 7.67−7.58 (m, 1H), 7.26−7.13 (m, 5H). 13C{1H}
NMR (100 MHz, CDCl3): δ 153.4, 148.1, 136.4, 135.8, 131.4, 129.3,
129.2, 129.1, 128.3, 127.9, 126.7, 126.4, 124.8. HRMS (TOF MS ES
+) m/z: [M + H]+ calcd for C15H12NS, 238.0690; found, 238.0702.
4-(p-Tolylthio)isoquinoline (2b). 222 mg, 88% yield; yellow liquid.
Rf = 0.30 (10% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3029,
1564, 1491, 1378, 980, 750. 1H NMR (400 MHz, CDCl3): δ 9.19 (s,
1H), 8.56 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H),
7.76−7.69 (m, 1H), 7.67−7.60 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H),
7.07 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 152.8, 147.0, 137.2, 136.1, 131.5, 131.3, 130.3, 130.2,
128.9, 128.3, 127.9, 127.6, 124.7, 21.2. HRMS (TOF MS ES+) m/z:
[M + H]+ calcd for C16H14NS, 252.0847; found, 252.0836.
4-(o-Tolylthio)isoquinoline (2c). 216 mg, 86% yield; orange liquid.
Rf = 0.29 (10% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3060,
1564, 1468, 1378, 982, 748. 1H NMR (400 MHz, CDCl3): δ 9.19 (s,
1H), 8.42 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H),
7.76−7.69 (m, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H),
7.14 (t, J = 7.2 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz,
1H), 2.48 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 152.6,
146.4, 138.2, 135.9, 133.9, 131.3, 130.7, 130.6, 128.9, 128.3, 127.9,
127.3, 127.0, 126.9, 124.5, 20.5. HRMS (TOF MS ES+) m/z: [M +
H]+ calcd for C16H14NS, 252.0847; found, 252.0852.
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J. Org. Chem. 2021, 86, 2570−2581

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Article
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4-((4-Methoxyphenyl)thio)isoquinoline (2d). 246 mg, 92% yield;
yellow solid. mp 79−80 °C. Rf = 0.17 (10% ethyl acetate in hexane).
FTIR (neat) ν (cm−1): 3054, 1593, 1494, 1257, 1030, 736. 1H NMR
(400 MHz, CDCl3): δ 9.13 (s, 1H), 8.39 (s, 1H), 8.28 (d, J = 8.4 Hz,
1H), 7.98 (d, J = 8.0 Hz, 1H), 7.77−7.71 (m, 1H), 7.67−7.59 (m,
2H), 7.38−7.31 (m, 2H), 6.89−6.82 (m, 2H), 3.78 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 159.7, 151.9, 145.2, 135.3, 133.7, 131.1,
129.4, 128.8, 128.2, 127.8, 124.3, 115.2. HRMS (TOF MS ES+) m/z:
[M + H]+ calcd for C16H14NOS, 268.0796; found, 268.0794.
(cm−1): 3048, 1568, 1450, 1122, 762. H NMR (400 MHz, CDCl3):
δ 9.34 (s, 1H), 8.87 (s, 1H), 8.39 (dt, J1 = 0.8 Hz, J2 = 4.8 Hz, 1H),
8.26 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.78−7.71 (m,
1H), 7.70−7.64 (m, 1H), 7.36 (td, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H),
7.02−6.95 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 160.3, 154.8, 150.4, 149.8, 137.4, 136.9, 131.9,
129.3, 128.4, 128.2, 125.2, 123.3, 121.1, 120.2. HRMS (TOF MS ES
+) m/z: [M + H]+ calcd for C14H11N2S, 239.0642; found, 239.0640.
4-(Naphthalen-2-ylthio)isoquinoline (2m). 248 mg, 86% yield;
orange liquid. Rf = 0.38 (15% ethyl acetate in hexane). FTIR (neat) ν
4-((3-Methoxyphenyl)thio)isoquinoline (2e). 244 mg, 91% yield;
orange liquid. Rf = 0.20 (10% ethyl acetate in hexane). FTIR (neat) ν
1
(cm−1): 3053, 1620, 1564, 1378, 746. H NMR (400 MHz, CDCl3):
1
(cm−1): 3059, 1582, 1477, 1239, 1040, 773. H NMR (400 MHz,
δ 9.27 (s, 1H), 8.76−8.70 (m, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.01 (d,
J = 8.0 Hz, 1H), 7.78−7.73 (m, 1H), 7.72−7.66 (m, 3H), 7.65−7.59
(m, 2H), 7.46−7.39 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 153.5, 148.1, 136.4, 133.8, 133.2, 132.1,
131.5, 129.1, 129.0, 128.3, 128.0, 127.8, 127.7, 127.3, 126.9, 126.8,
126.4, 126.1, 124.8. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C19H14NS, 288.0847; found, 288.0878.
CDCl3): δ 9.24 (s, 1H), 8.68 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.01
(d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.69−7.61 (m, 1H), 7.14
(t, J = 8.0 Hz, 1H), 6.79−6.67 (m, 3H), 3.70 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 160.2, 153.6, 148.4, 137.2, 136.6, 131.6, 130.1,
129.1, 128.3, 128.0, 126.0, 124.9, 121.3, 114.5, 112.2, 53.4. HRMS
(TOF MS ES+) m/z: [M + H]+ calcd for C16H14NOS, 268.0796;
found, 268.0791.
4-(Cyclohexylthio)isoquinoline (2n). 204 mg, 84% yield; orange
solid. mp 58−60 °C. Rf = 0.33 (10% ethyl acetate in hexane). FTIR
4-((2-Methoxyphenyl)thio)isoquinoline (2f). 240 mg, 90% yield;
yellow liquid. Rf = 0.33 (20% ethyl acetate in hexane). FTIR (neat) ν
(neat) ν (cm−1): 3058, 2929, 1620, 1564, 1446, 1258, 989, 753. H
1
1
(cm−1): 3057, 1573, 1471, 1245, 749. H NMR (400 MHz, CDCl3):
NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.67 (s, 1H), 8.44 (d, J =
8.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.82−7.75 (m, 1H), 7.64 (t, J =
7.6 Hz, 1H), 2.01−1.90 (m, 2H), 1.81−1.70 (m, 2H), 1.63−1.54 (m,
1H), 1.49−1.36 (m, 2H), 1.31−1.22 (m, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 152.4, 147.9, 137.5, 131.0, 128.9, 128.2, 127.7,
127.1, 125.1, 47.6, 33.7, 26.1, 25.8. HRMS (TOF MS ES+) m/z: [M
+ H]+ calcd for C15H18NS, 244.1160; found, 244.1142.
δ 9.22 (s, 1H), 8.60 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.0
Hz, 1H), 7.75−7.67 (m, 1H), 7.66−7.58 (m, 1H), 7.20−7.14 (m,
1H), 6.89 (d, J = 8.4 Hz, 1H), 6.77−6.69 (m, 2H), 3.90 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 156.8, 153.0, 147.7, 136.6,
131.3, 129.9, 128.9 (2C), 128.2, 127.9, 125.7, 124.8, 123.8, 121.4,
110.9, 55.9. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C16H14NOS, 268.0796; found, 268.0808.
4-(Ethylthio)isoquinoline (2o). 156 mg, 82% yield; orange liquid.
Rf = 0.23 (10% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3049,
4-((4-Bromophenyl)thio)isoquinoline (2g). 212 mg, 67% yield;
orange solid. mp 63−64 °C. Rf = 0.27 (10% ethyl acetate in hexane).
FTIR (neat) ν (cm−1): 3051, 1564, 1474, 1379, 1081, 751. 1H NMR
(400 MHz, CDCl3): δ 9.26 (s, 1H), 8.69 (s, 1H), 8.21 (d, J = 8.4 Hz,
1H), 8.02 (d, J = 8.0 Hz, 1H), 7.77−7.70 (m, 1H), 7.69−7.62 (m,
1H), 7.37−7.29 (m, 2H), 7.03 (d, J = 8.4 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 153.9, 148.7, 136.5, 135.4, 132.4, 131.7, 130.3,
129.2, 128.5, 128.1, 125.5, 124.7, 120.4. HRMS (TOF MS ES+) m/z:
[M + H]+ calcd for C15H11BrNS, 317.9796; found, 317.9783.
4-((2,4-Dichlorophenyl)thio)isoquinoline (2h). 200 mg, 65% yield;
yellow solid. mp 74−75 °C. Rf = 0.37 (10% ethyl acetate in hexane).
1
1619, 1564, 1378, 1264, 985, 741. H NMR (400 MHz, CDCl3): δ
9.11 (s, 1H), 8.56 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0
Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 3.00 (q, J =
7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 151.5, 144.5, 136.0, 130.8, 128.6, 128.5, 128.2, 127.7,
124.3, 28.5, 14.6. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C11H12NS, 190.0676; found, 190.0690.
4-(tert-Butylthio)isoquinoline (2p). 176 mg, 81% yield; yellow
solid. mp 58−60 °C. Rf = 0.20 (5% ethyl acetate in hexane). FTIR
(neat) ν (cm−1): 2959, 1563, 1459, 1159, 754. H NMR (400 MHz,
1
1
FTIR (neat) ν (cm−1): 3065, 1564, 1444, 1373, 1094, 807, 752. H
CDCl3): δ 9.21 (s, 1H), 8.72 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 7.95
(d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H),
1.28 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.6, 151.9,
139.5, 130.9, 128.9, 127.9, 31.3, 47.9, 125.6, 127.5, 126.2, 125.6, 47.9,
31.3. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for C13H16NS,
218.1003; found, 218.1023.
4-(Phenylselanyl)isoquinoline (2ac). 252 mg, 89% yield; yellow
liquid. Rf = 0.33 (10% ethyl acetate in hexane). FTIR (neat) ν
(cm−1): 3055, 1574, 1478, 1265, 897, 743. 1H NMR (400 MHz,
CDCl3): δ 9.22 (s, 1H), 8.77 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.95
(d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H),
7.40−7.32 (m, 2H), 7.22−7.14 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 153.5, 149.2, 137.0, 131.7, 131.4, 130.7, 129.5, 129.2,
128.3, 127.9, 127.2, 126.8, 124.4. HRMS (TOF MS ES+) m/z: [M +
H]+ calcd for C15H12NSe, 286.0135; found, 286.0135.
3-(Phenylthio)quinoline (4a). 196 mg, 83% yield; yellow liquid. Rf
= 0.40 (10% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3056,
1578, 1484, 1265, 741. 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H),
8.13−8.02 (m, 2H), 7.74−7.65 (m, 2H), 7.53 (t, J = 7.2 Hz, 1H),
7.43−7.37 (m, 2H), 7.37−7.27 (m, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 152.3, 146.7, 137.2, 134.4, 131.5, 130.1, 129.7, 129.6,
129.4, 128.3, 127.9, 127.4, 127.3. HRMS (TOF MS ES+) m/z: [M +
H]+ calcd for C15H12NS, 238.0690; found, 238.0686.
3-(p-Tolylthio)quinoline (4b). 204 mg, 81% yield; yellow liquid. Rf
= 0.40 (10% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3052,
1579, 1491, 1263, 957, 746. 1H NMR (400 MHz, CDCl3): δ 8.78 (s,
1H), 8.06 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.71−7.61 (m, 2H), 7.52
(t, J = 7.2 Hz, 1H), 7.35 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H),
2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 151.6, 146.5,
138.5, 135.8, 132.5 (2C), 131.4, 130.5, 130.0, 129.4, 128.4, 127.3,
NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.78 (s, 1H), 8.17 (d, J =
8.4 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.69
(t, J = 7.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H),
6.45 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.1, 150.2,
138.3, 136.9, 133.3, 132.2, 130.7, 130.0, 129.3, 128.6, 128.5, 127.5,
126.9, 124.6, 123.0. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C15H10NSCl2, 305.9911; found, 305.9906.
4-((4-Chlorophenyl)thio)isoquinoline (2i). 188 mg, 69% yield;
orange solid. mp 54−55 °C. Rf = 0.27 (10% ethyl acetate in hexane).
FTIR (neat) ν (cm−1): 3051, 1567, 1480, 1382, 1094, 741. 1H NMR
(400 MHz, CDCl3): δ 9.25 (s, 1H), 8.68 (s, 1H), 8.22 (d, J = 8.4 Hz,
1H), 8.02 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6
Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 153.9, 148.5, 136.4, 134.6, 132.6, 131.7,
130.2, 129.5, 129.2, 128.4, 128.1, 125.8, 124.7. HRMS (TOF MS ES
+) m/z: [M + H]+ calcd for C15H11ClNS, 272.0301; found, 272.0308.
4-((4-Fluorophenyl)thio)isoquinoline (2j). 166 mg, 65% yield;
yellowish orange liquid. Rf = 0.23 (10% ethyl acetate in hexane). FTIR
1
(neat) ν (cm−1): 3053, 1490, 1379, 1226, 1090, 744. H NMR (400
MHz, CDCl3): δ 9.38 (s, 1H), 8.74 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H),
8.17 (d, J = 8.0 Hz, 1H), 7.91 (t, J = 7.2 Hz, 1H), 7.81 (t, J = 7.6 Hz,
1H), 7.45−7.40 (m, 2H), 7.16−7.09 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 162.1 (C−F, 1JC−F = 245.8 Hz), 153.2, 147.2,
136.0, 132.1 (C−F, 3JC−F = 8.0 Hz), 131.5, 130.3 (C−F, 4JC−F =
3.7 Hz), 129.0, 128.4, 128.0, 127.3, 124.5, 116.6 (C−F, 2JC−F = 22.0
Hz). HRMS (TOF MS ES+) m/z: [M + H]+ calcd for Molecular
formula: C15H11FNS, 256.0596; found, 256.0589.
4-(Pyridin-2-ylthio)isoquinoline (2l). 214 mg, 90% yield; orange
liquid. Rf = 0.20 (20% ethyl acetate in hexane). FTIR (neat) ν
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J. Org. Chem. 2021, 86, 2570−2581

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127.2, 21.3. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C16H14NS, 252.0847; found, 252.0844.
(cm−1): 3055, 1586, 1488, 1266, 1229, 746. H NMR (400 MHz,
CDCl3): δ 8.77 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.71−
7.62 (m, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.46−7.38 (m, 2H), 7.10−
7.00 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.8 (C−F,
1JC−F = 247.5 Hz), 151.5, 146.6, 136.1, 134.4 (C−F, 3JC−F = 8.3
Hz), 130.8, 129.6, 129.3, 128.9 (C−F, 4JC−F = 3.4 Hz), 128.2, 127.4,
127.2, 116.9 (C−F, 2JC−F = 21.9 Hz). HRMS (TOF MS ES+) m/z:
[M + H]+ calcd for C15H11NSF, 256.0596; found, 256.0599.
3-(o-Tolylthio)quinoline (4c). 202 mg, 80% yield; yellow liquid. Rf
= 0.33 (5% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3060,
1
1582, 1490, 1355, 956, 751. H NMR (400 MHz, CDCl3): δ 8.77−
8.69 (m, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.69−7.61 (m,
2H), 7.54−7.47 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.31−7.23 (m,
2H), 7.20−7.14 (m, 1H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 151.3, 146.5, 140.3, 135.3, 133.5, 132.3, 131.1, 130.6,
129.4, 129.3, 128.7, 128.4, 127.3, 127.2 (2C), 20.7. HRMS (TOF MS
ES+) m/z: [M + H]+ calcd for C16H14NS, 252.0847; found, 252.0859.
3-((4-Methoxyphenyl)thio)quinoline (4d). 222 mg, 83% yield; pale
yellow liquid. Rf = 0.28 (10% ethyl acetate in hexane). FTIR (neat) ν
3-(Pyridin-2-ylthio)quinoline (4k). 196 mg, 82% yield; yellow
liquid. Rf = 0.33 (20% ethyl acetate in hexane). FTIR (neat) ν
(cm−1): 3052, 1570, 1415, 1122, 757. H NMR (400 MHz, CDCl3):
1
δ 9.01−8.91 (m, 1H), 8.44−8.37 (m, 2H), 8.13 (d, J = 8.4 Hz, 1H),
7.81 (d, J = 8.0 Hz, 1H), 7.79−7.72 (m, 1H), 7.63−7.54 (m, 1H),
7.53−7.45 (m, 1H), 7.07−7.00 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 159.4, 154.8, 150.0, 147.5, 141.9, 137.0, 130.5, 129.5,
128.4, 127.8, 127.4, 125.2, 122.0, 120.7. HRMS (TOF MS ES+) m/z:
[M + H]+ calcd for C14H11N2S, 239.0643; found, 239.0639.
1
(cm−1): 3061, 1588, 1492, 1253, 803. H NMR (400 MHz, CDCl3):
δ 8.73 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.68−7.62 (m,
2H), 7.51 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 6.97−6.90
(m, 2H), 3.84 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.4,
150.7, 146.3, 135.6, 134.0, 132.9, 129.4, 129.1, 128.4, 127.3, 127.1,
123.1, 115.5, 55.6. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C16H14NOS, 268.0796; found, 268.0797.
3-(Naphthalen-2-ylthio)quinoline (4l). 228 mg, 79% yield; white
solid. mp 70−72 °C. Rf = 0.27 (5% ethyl acetate in hexane). FTIR
(neat) ν (cm−1): 3054, 1583, 1493, 1358, 956, 744. H NMR (400
1
3-((3-Methoxyphenyl)thio)quinoline (4e). 220 mg, 82% yield;
yellow liquid. Rf = 0.30 (10% ethyl acetate in hexane). FTIR (neat) ν
MHz, CDCl3): δ 8.90 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H),
7.91 (s, 1H), 7.84−7.76 (m, 2H), 7.75−7.63 (m, 3H), 7.55−7.41 (m,
4H). 13C{1H} NMR (100 MHz, CDCl3): δ 152.1, 146.7, 137.0, 133.8,
132.5, 131.5, 130.5, 130.1, 129.6, 129.4, 128.6, 128.3, 127.8, 127.5,
127.4, 127.3, 126.9, 126.6. HRMS (TOF MS ES+) m/z: [M + H]+
calcd for C19H14NS, 288.0847; found, 288.0850.
1
(cm−1): 3061, 1584, 1476, 1241, 1040, 759. H NMR (400 MHz,
CDCl3): δ 8.88−8.77 (m, 1H), 8.13−8.04 (m, 2H), 7.76−7.65 (m,
2H), 7.54 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.98−6.90 (m,
2H), 6.86−6.79 (m, 1H), 3.76 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 160.3, 152.4, 146.8, 137.5, 135.7, 130.4, 129.8, 129.7,
129.4, 128.3 (2C), 127.4, 123.4, 116.5, 113.6, 55.4. HRMS (TOF MS
ES+) m/z: [M + H]+ calcd for C16H14NOS, 268.0796; found,
268.0801.
3-(Ethylthio)quinoline (4m). 134 mg, 71% yield; brown liquid. Rf =
0.33 (10% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3054,
1
2974, 1578, 1491, 1264, 958, 748. H NMR (400 MHz, CDCl3): δ
8.81 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.68 (d, J = 8.0
Hz, 1H), 7.65−7.58 (m, 1H), 7.53−7.46 (m, 1H), 3.00 (q, J = 7.2 Hz,
2H), 1.32 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
151.6, 146.3, 134.8, 130.7, 129.3, 129.0, 128.2, 127.2, 126.9, 28.0,
14.3. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for C11H12NS,
190.0690; found, 190.0694.
3-((2-Methoxyphenyl)thio)quinoline (4f). 216 mg, 81% yield;
yellow liquid. Rf = 0.20 (10% ethyl acetate in hexane). FTIR (neat) ν
1
(cm−1): 3061, 1578, 1472, 1251, 1022, 750. H NMR (400 MHz,
CDCl3): δ 8.80 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.72−
7.64 (m, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23
(d, J = 7.6 Hz, 1H), 6.96−6.88 (m, 2H), 3.84 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 158.1, 152.1, 146.5, 137.1, 132.9, 129.7 (2C),
129.5, 129.2, 128.4 (2C), 127.3, 122.0, 121.6, 111.4, 56.0. HRMS
(TOF MS ES+) m/z: [M + H]+ calcd for C16H14NOS, 268.0796;
found, 268.0801.
3-(tert-Butylthio)quinoline (4n). 156 mg, 72% yield; yellow liquid.
Rf = 0.37 (5% ethyl acetate in hexane). FTIR (neat) ν (cm−1): 3060,
1
2965, 1564, 1487, 1364, 1166, 959, 912, 751. H NMR (400 MHz,
CDCl3): δ 8.94 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.09 (d,
J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.74−7.68 (m, 1H), 7.53 (t,
J = 8.0 Hz, 1H), 1.30 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ
156.9, 147.5, 144.5, 130.3, 129.3, 128.0, 127.8, 127.1, 126.8, 46.9,
31.0. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for C13H16NS,
218.1003; found, 218.1013.
3-(Cyclohexylthio)quinoline (4o). 182 mg, 75% yield; pale yellow
liquid. Rf = 0.42 (10% ethyl acetate in hexane). FTIR (neat) ν
(cm−1): 3057, 2928, 1489, 1448, 1259, 1078, 958, 900, 750. 1H NMR
(400 MHz, CDCl3): δ 8.95−8.85 (m, 1H), 8.19−8.11 (m, 1H), 8.07
(d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H),
7.53 (t, J = 7.6 Hz, 1H), 3.24−3.13 (s, 1H), 2.05−1.93 (m, 2H),
1.83−1.72 (m, 2H), 1.65−1.56 (m, 1H), 1.49−1.21 (m, 5H).
13C{1H} NMR (100 MHz, CDCl3): δ 153.8, 146.8, 138.7, 129.5,
129.4, 129.1, 128.2, 127.3, 127.2, 47.3, 33.5, 26.1, 25.7. HRMS (TOF
MS ES+) m/z: [M + H]+ calcd for C15H18NS, 244.1160; found,
244.1153
3-((4-Bromophenyl)thio)quinoline (4g). 184 mg, 58% yield; light
yellow solid. mp 58−60 °C. Rf = 0.42 (10% ethyl acetate in hexane).
1
FTIR (neat) ν (cm−1): 3052, 1572, 1473, 1324, 1078, 814, 752. H
NMR (400 MHz, CDCl3): δ 8.85−8.76 (m, 1H), 8.17−8.01 (m, 2H),
7.75−7.67 (m, 2H), 7.58−7.51 (m, 1H), 7.47−7.39 (m, 2H), 7.24−
7.19 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 152.4, 146.9,
137.9, 134.0, 132.7, 132.5, 130.0, 129.4, 129.1, 128.2, 127.5, 127.4,
121.8. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for C15H11NSBr,
317.9796; found, 317.9777.
3-((2,4-Dichlorophenyl)thio)quinoline (4h). 180 mg, 59% yield;
pale yellow liquid. Rf = 0.37 (5% ethyl acetate in hexane). FTIR
1
(neat) ν (cm−1): 3061, 1568, 1446, 1364, 1093, 808, 752. H NMR
(400 MHz, CDCl3): δ 8.86 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.0 Hz,
1H), 8.13 (d, J = 8.4 Hz, 1H), 7.81−7.73 (m, 2H), 7.59 (t, J = 7.6 Hz,
1H), 7.31 (d, J = 8.8 Hz, 1H), 7.10 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz 1H),
6.90 (d, J = 2.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.6,
147.5, 141.0, 137.5, 133.5, 131.5, 130.9, 130.7, 129.6, 129.3, 128.3,
127.9, 127.7, 127.6, 125.6. HRMS (TOF MS ES+) m/z: [M + H]+
calcd for C15H10NSCl2, 305.9911; found, 305.9900.
8-Methoxy-3-(phenylthio)quinoline (4p). 118 mg, 44% yield; pale
yellow solid. mp 94−96 °C. Rf = 0.15 (20% ethyl acetate in hexane).
FTIR (neat) ν (cm−1): 3060, 2936, 1570, 1479, 1370, 1260, 1124,
1
911, 753. H NMR (400 MHz, CDCl3): δ 8.81 (d, J = 2.0 Hz, 1H),
3-((4-Chlorophenyl)thio)quinoline (4i). 160 mg, 59% yield; light
yellow solid. mp 52−54 °C. Rf = 0.42 (10% ethyl acetate in hexane).
FTIR (neat) ν (cm−1): 3060, 1573, 1480, 1358, 1089, 752. 1H NMR
(400 MHz, CDCl3): δ 8.83−8.78 (m, 1H), 8.11−8.05 (m, 2H),
7.74−7.68 (m, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.32−7.27 (m, 4H).
13C{1H} NMR (100 MHz, CDCl3): δ 152.3, 146.9, 137.7, 133.9,
133.2, 132.5, 129.9, 129.8, 129.5, 129.4, 128.3, 127.5, 127.4. HRMS
(TOF MS ES+) m/z: [M + H]+ calcd for C15H11NSCl, 272.0301;
found, 272.0300.
7.99 (d, J = 2.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 6.8 Hz,
2H), 7.34−7.27 (m, 3H), 7.24 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 7.6
Hz, 1H), 4.06 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.5,
150.8, 138.4, 136.7, 134.2, 131.4, 130.9, 129.5, 129.4, 127.8, 127.7,
119.0, 107.8, 56.0. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C16H14NOS, 268.0796; found, 268.0800.
8-Methoxy-3-(p-tolylthio)quinoline (4q). 106 mg, 38% yield; pale
yellow liquid. Rf = 0.27 (20% ethyl acetate in hexane). FTIR (neat) ν
1
(cm−1): 3050, 2929, 1565, 1485, 1373, 1318, 1124, 756. H NMR
3-((4-Fluorophenyl)thio)quinoline (4j). 142 mg, 56% yield; brown
liquid. Rf = 0.33 (10% ethyl acetate in hexane). FTIR (neat) ν
(400 MHz, CDCl3): δ 8.78 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 1.6 Hz,
1H), 7.43 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4
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J. Org. Chem. 2021, 86, 2570−2581

The Journal of Organic Chemistry
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Article
Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 4.07 (s,
3H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.6,
150.2, 138.4, 138.3, 135.5, 132.5, 132.3, 130.5, 129.9, 129.5, 127.6,
119.0, 107.7, 56.1, 21.3. HRMS (TOF MS ES+) m/z: [M + H]+ calcd
for C17H16NOS, 282.0952; found, 282.0960.
114.7, 103.5, 55.5. HRMS (TOF MS ES+) m/z: [M + H]+ calcd for
C14H13N2OS, 257.0749; found, 257.0744.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02672.
■
sı
8-Methoxy-3-((4-methoxyphenyl)thio)quinoline (4r). 118 mg,
40% yield; pale yellow liquid. Rf = 0.15 (20% ethyl acetate in
hexane). FTIR (neat) ν (cm−1): 3058, 2940, 1579, 1492, 1374, 1250,
1174, 757. 1H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 2.0 Hz, 1H),
7.75 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.40 (t, J = 8.0 Hz,
1H), 7.19 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.92 (d, J =
8.8 Hz, 2H), 4.06 (s, 3H), 3.82 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 160.4, 155.6, 149.2, 138.1, 135.5, 133.7, 133.6, 129.6,
127.6, 122.9, 118.9, 115.4, 107.4, 56.1, 55.6. HRMS (TOF MS ES+)
m/z: [M + H]+ calcd for C17H16NO2S, 298.0901; found, 298.0895.
5-(Phenylthio)quinolin-8-amine (4s). 206 mg, 82% yield; dark
brown solid. mp 74−76 °C. Rf = 0.29 (10% ethyl acetate in hexane).
FTIR (neat) ν (cm−1): 3477, 3369, 3053, 1601, 1499, 1199, 949, 739.
1H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 4.0 Hz, 1H), 8.59 (d, J =
8.8 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.39 (dd, J1= 4.0 Hz, J2= 8.8
Hz, 1H), 7.14 (t, J = 7.2 Hz, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.99 (d, J =
7.6 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 147.7, 146.3, 139.7, 139.1, 137.8, 134.8, 130.8,
128.9, 126.1, 125.0, 122.6, 114.2, 109.5. HRMS (TOF MS ES+) m/z:
[M + H]+ calcd for C15H13N2S, 253.0799; found, 253.0801.
N-(5-(Phenylthio)quinolin-8-yl)benzamide (4t). 125 mg, 35%
yield; yellow solid. mp 132−134 °C. Rf = 0.54 (10% ethyl acetate
in hexane). FTIR (neat) ν (cm−1): 3427, 3355, 3058, 1675, 1522,
1476, 1183, 943, 740. 1H NMR (400 MHz, CDCl3): δ 10.86 (s, 1H),
8.95 (d, J = 8.0 Hz, 1H), 8.89−8.83 (m, 1H), 8.70 (d, J = 8.4 Hz,
1H), 8.10 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.64−7.53
(m, 3H), 7.52−7.46 (m, 1H), 7.24−7.16 (m, 2H), 7.15−1.06 (m,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.7, 148.6, 139.6, 137.8,
136.2, 136.1, 135.1, 135.0, 132.2, 129.5, 129.2, 129.0, 127.7, 127.5,
125.9, 123.3, 122.6, 116.5. HRMS (TOF MS ES+) m/z: [M + H]+
calcd for C22H17N2OS, 357.1062; found, 357.1066.
1
Computational details, H and 13C{1H} NMR spectra
for all compounds, and X-ray structure and brief crystal
data of compound 2d (PDF)
Accession Codes
CCDC 1914361 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Govindasamy Sekar − Department of Chemistry, Indian
Institute of Technology Madras, Chennai 600 036, Tamil
Nadu, India; orcid.org/0000-0003-2294-0485;
Email: gsekar@iitm.ac.in
Authors
Anuradha Nandy − Department of Chemistry, Indian Institute
of Technology Madras, Chennai 600 036, Tamil Nadu,
India
Imran Kazi − Department of Chemistry, Indian Institute of
Technology Madras, Chennai 600 036, Tamil Nadu, India
Somraj Guha − Department of Chemistry, Indian Institute of
Technology Madras, Chennai 600 036, Tamil Nadu, India
3-(Phenylthio)-7-azaindole (6a). 203 mg, 90% yield; cream solid.
mp 176−178 °C. Rf = 0.62 (50% ethyl acetate in hexane). FTIR
1
(neat) ν (cm−1): 3011, 2991, 1580, 1473, 1413, 1283, 740, 736. H
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02672
NMR (400 MHz, CDCl3): δ 11.03 (s, 1H), 8.40 (d, J = 4.8 Hz, 1H),
7.94 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.21−7.13 (m, 3H), 7.12−7.05
(m, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 149.4, 143.4, 138.9,
132.1, 128.9, 128.6, 126.1, 125.2, 122.3, 116.9, 101.5. HRMS (TOF
MS ES+) m/z: [M + H]+ calcd for C13H11N2S, 227.0643; found,
227.0642.
4-Chloro-3-(phenylthio)-7-azaindole (6b). 219 mg, 84% yield;
white solid. mp 208−210 °C. Rf = 0.65 (50% ethyl acetate in hexane).
FTIR (neat) ν (cm−1): 3031, 2948, 1585, 1477, 1437, 1269, 793, 738.
1H NMR (400 MHz, CDCl3): δ 11.02 (s, 1H), 8.30−8.20 (m, 1H),
7.67 (s, 1H), 7.24−7.17 (m, 2H), 7.16−7.06 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ 150.1, 144.0, 140.0, 137.9, 133.3, 128.9, 126.3,
125.3, 119.1, 118.5, 102.2. HRMS (TOF MS ES+) m/z: [M + H]+
calcd for C13H10ClN2S, 261.0253, found 261.0248.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST-SERB, New Delhi (EMR/2017/00/001700)
for financial support. A.N., I.K., and S.G. thank IIT Madras for
the fellowship. High-performance computing centre at IIT
Madras is gratefully acknowledged for providing the computing
facility.
DEDICATION
■
1-Methyl-3-(phenylthio)-7-azaindole (6c). 206 mg, 86% yield;
Dedicated to Prof. Sundarababu Baskaran on the occasion of
his 60th birthday
brown solid. mp 88−90 °C. Rf = 0.38 (15% ethyl acetate in hexane).
1
FTIR (neat) ν (cm−1): 3046, 2945, 1568, 1405, 1300, 772, 743. H
NMR (400 MHz, CDCl3): δ 8.43−8.36 (m, 1H), 7.88 (d, J = 7.6 Hz,
1H), 7.48 (s, 1H), 7.21−7.14 (m, 2H), 7.13−7.02 (m, 4H), 3.95 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 148.5, 143.9, 139.1, 135.3,
128.9, 128.1, 126.1, 125.1, 122.3, 116.7, 99.8, 31.6. HRMS (TOF MS
ES+) m/z: [M + H]+ calcd for C14H13N2S, 241.0799; found,
241.0796.
3-((4-Methoxyphenyl)thio)-7-azaindole (6d). 226 mg, 88% yield;
cream solid. mp 146−148 °C. Rf = 0.55 (50% ethyl acetate in
hexane). FTIR (neat) ν (cm−1): 3061, 2919, 1588, 1445, 1410, 1283,
806, 763. 1H NMR (400 MHz, CDCl3): δ 11.47 (s, 1H), 8.38 (d, J =
4.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.20−7.10 (m,
3H), 6.80−6.70 (m, 2H), 3.74 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 158.2, 149.3, 143.5, 131.1, 129.1 (2C), 128.5, 122.1, 116.8,
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