Iodine/DMSO-Promoted Selective Direct Arylthiation of Anilines with Thiols under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.0c02078

An iodine-promoted divergent thiolation of unprotected anilines with thiols for the synthesis of sulfide anilines has been described. The combinational use of I2 and DMSO played an important role to realize this kind of transformation without the aid of a

Full text of DOI:10.1021/acs.joc.0c02078

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Article
Iodine/DMSO-Promoted Selective Direct Arylthiation of Anilines
with Thiols under Metal-Free Conditions
Wenqi Zhao, Feng Zhang,* and Guo-Jun Deng*
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ABSTRACT: An iodine-promoted divergent thiolation of unpro-
tected anilines with thiols for the synthesis of sulfide anilines has been
described. The combinational use of I2 and DMSO played an
important role to realize this kind of transformation without the aid of
a metal catalyst and strong oxidants. The reaction selectivity was well
controlled to provide mono-, bis-, and trisubstituted diaryl sulfide
derivatives. More importantly, iodination and sulfenylation can occur
simultaneously to provide useful multifunctionalized iodoaniline
products. This method afforded an efficient protocol for the construct
C−S and C−I bonds from the C−H bond under mild reaction
conditions.
In spite of utilities, however, multiple steps are usually
indispensable to prepare these highly prefunctionalized
sulfenylating reagents. Therefore, the direct oxidative C−H/
S−H cross-dehydrogenative couplings (CDCs) of simple and
readily available thiols to form C−S bonds can provide an
efficient and environmentally benign synthetic approach.12 In
the past several years, some new methods have been developed
for the direct oxidative sulfenylation of electron-rich arenes
such as phenols,13 aryl ethers,14 indole derivatives,15 or
heterocycles16 under transition-metal-catalyzed or metal-free
conditions. Aromatic amines are widely found in drug
molecules, pesticides, functional materials, and natural
products. Furthermore, because of their active amino groups,
these compounds can be easily converted into other nitrogen-
containing functional molecules.17 Therefore, direct function-
alization reaction based on aromatic amines has been a hot
research field in organic synthesis. Among them, C−S bond
formation via C−H sulfenylation of anilines has also attracted
considerable interest. Arylsulfonyl hydrazides,18 arylthio-
pyrrolidine-2,5-diones,19 sulfinamides,20 disulfides,21 arylsul-
fonyl chlorides,22 and thioesters23 were successfully used as the
sulfenylation reagents. Furthermore, Wang and co-workers
developed an excellent protocol for direct sulfenylation of
substituted anilines with thiols under metal-free conditions.24
INTRODUCTION
■
Sulfur-containing compounds are crucial for the synthesis of
diverse compounds in pharmaceutical drugs, natural products,
pesticides, and material science.1 Among them, diaryl sulfides
have attracted much more attention because of their unique
biological activity. These compounds have therapeutic
potential for the treatment of breast cancer, HIV, diabetes,
and inflammatory diseases.2 In addition, these compounds also
act as important synthons for organic synthesis.3 Therefore,
efficient synthetic methods for the construction of various
diaryl sulfides have inspired great efforts. During the past
several decades, several significant synthetic methods for the
construction of diaryl sulfides have been reported. Among
these approaches, the transition-metal-catalyzed cross-coupling
of thiols, disulfides, or even elemental sulfur with aryl halides
and the reaction of organometals such as arylmagnesium
compounds and arylboronic acid derivatives with electrophilic
arylsulfur reagents are frequently used for the synthesis of
diverse diaryl sulfide compounds.4 However, these methods
are susceptible to the need for highly functionalized starting
materials, expensive metal catalysts, harsh reaction conditions,
and producing a large amount of waste.
Although there are many other alternative methods for the
construction of diaryl sulfide derivatives from various starting
materials,5 it is no doubt that the direct arylthiolation of widely
present C−H bonds with appropriate thiolating reagents is the
most economic and efficient approach.6 The synthesis of diaryl
sulfides via direct C−H sulfenylation under transition-metal-
catalyzed or metal-free conditions with diverse sulfur reagents
including disulfides,7 sulfonyl chlorides,8 sulfinates,9 sulfonyl
hydrazides,10 and others11 has attracted considerable attention.
Received: August 28, 2020
https://dx.doi.org/10.1021/acs.joc.0c02078
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

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a
̈
Noel and co-workers reported a one-pot Stadler−Ziegler
Table 1. Screening the Reaction Conditions
process to form C−S bonds by employing Ru(bpy)3Cl2·6H2O
as a photoredox catalyst.25 Lei and co-workers communicated
a progress on an electrocatalytic oxidant-free dehydrogenative
C−H/S−H cross-coupling in a simple undivided cell under
constant-current conditions.26 A catalytic amount of iodine is
crucial for this kind of transformation, and the strong oxidant
di-tert-butyl peroxide is necessary to get a satisfactory reaction
yield. Because the reaction tends to occur in the para and ortho
positions of the amino group, the selectivity control is critical
in this process. In our previous research, we found that
combined use of the iodide additive or iodine and DMSO
system could provide a mild oxidative reaction condition for
selective transformation.27 We speculate that such a system
may also be efficient for the oxidative sulfenylation of anilines
with good selectivity and compatible functional groups. As part
of our continuing efforts on C−S bond construction under
metal-free conditions,28 herein, we describe metal- and strong
oxidant-free direct C−H sulfenylation of anilines with thiols,
selectively providing mono-, bis-, and tri-sulfenylation products
in reasonable yields. More importantly, iodination and
sulfenylation reactions can occur simultaneously to provide
very useful multifunctionalized products.
b
yield (%)
3aa
entry I2 (equiv) DMSO (equiv)
solvent
4aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.5
2.0
1.5
2.0
2.0
1.0
1.0
1.0
1.5
2.0
1.5
1.5
4.0
4.0
4.0
4.0
4.0
4.0
6.0
8.0
6.0
6.0
6.0
0.0
6.0
6.0
4.0
4.0
8.0
4.0
4.0
8.0
8.0
o-xylene
toluene
dioxane
PhCl
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
40
42
50
51
50
60
47
45
46
53
60
28
65
55
62
68
74
nd
95 (90)
52
nd
nd
nd
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
NMP
DMF
DMF
DMF
DMF
DMF
DMF
c
d
e
f
RESULTS AND DISCUSSION
g
g
g
g
g
g
■
We commenced our investigation using aniline (1a) and 4-
methylbenzenethiol (2a) as the standard substrates to optimize
the reaction conditions (Table 1). To our delight, 2,4,6-
trisubstituted product 4aa was generated exclusively in o-
xylene at 120 °C when I2 (1 equiv) and DMSO (4 equiv) were
used (entry 1). The reaction yield did not increase when other
solvents such as toluene, dioxane, and PhCl were used (entries
2−4); however, a better yield could be obtained when ortho-
dichlorobenzene (o-DCB) was used (entry 5). The reaction
showed good reactivity under an air atmosphere, and a decline
in yield was observed under an O2 atmosphere (entry 6).
Increasing the amount of I2 or DMSO led to a better yield of
the product (entries 7−11). DMSO played a key role in the
present thiolation reaction, and no product was observed when
the coupling reaction was run in its absence (entry 12).
Furthermore, the addition of molecular sieves could further
increase the reaction yield to 95% (entry 13). For comparison,
when H2O was added, the reaction yield decreased to 52%
(entry 14). It was also interesting to find that 4-substituted
product 3aa was obtained as the major product when excess of
aniline was used and N-methyl-2-pyrrolidone (NMP) or DMF
was used as a solvent (entries 15 and 16). The reaction yield
could be slightly increased by increasing the amount of I2 or
DMSO (entries 17−20). The yield could also be enhanced by
adding molecular sieves to give the desired 3aa in 69% yield
(entry 21).
nd
nd
nd
nd
gh
,
e
69 (67)
a
Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), solvent (1.0
mL), air, 12 h. GC yield based on 1a. Under O2. 100 mg 4 Å MS.
Isolated yield based on 2. 1.5 equiv H2O. Substrate amounts: 1a
(0.4 mmol), 2a (0.2 mmol). GC yield based on 2a. 100 mg 4 Å MS.
b
c
d
e
f
g
h
Subsequently, the substrate scope for the synthesis of
trisubstituted products was investigated using different
arylthiols under the given reaction conditions. As presented
in Scheme 2, a variety of thiols were successfully coupled with
aniline (1a) to give the corresponding thiolation products in
good to high yields under the I2/DMSO system using o-DCB
as the solvent. The position of the methyl substituent did not
significantly affect the reaction yields, and all of them afforded
the desired products in more than 90% yield (4aa, 4ae, and
4af). Notably, when we used 3aa instead of 1a, we also
obtained 4aa in 95%. Halogen functional groups were well
accommodated to afford the desired products in reasonable
yields. Furthermore, 4ab was obtained in 97% yield when a
fluoro group was presented at the para position. The bromo
group located at the ortho position gave a slightly higher yield
(4ad and 4ah). Notably, N-methylaniline and formanilide
could also be involved in this kind of reaction to give the same
product 4aa, both of which lost the functional groups on amine
during the reaction.
With the optimized reaction conditions in hand, various aryl
thiols were investigated for the mono-sulfenylation, and the
results are summarized in Scheme 1. The model reaction of 1a
and 2a afforded 3aa in 67% isolated yield in the presence of I2/
DMSO using DMF as the solvent. In general, the reaction
between aniline (1a) and various thiol derivatives bearing
methyl and halogens such as F, Cl, and Br on the aromatic ring
led to good yields for the desired products. The position of
substituents on thiophenol affected the reaction yields
significantly (3aa, 3ae, and 3af). Notably, higher yields could
even be achieved when methyl and bromo substituents were
presented at the ortho position (3af and 3ah).
As noticed by others24 and us, the easiest place to reach for
this kind of arylthiation is the para position of the amino
group. Therefore, 4-substituted anilines are always used to
prepare ortho arylthiation products. To further explore this
method for diaryl sulfide preparation, we investigated several
para-substituted anilines for this kind of reaction. To our
delight, mono-arylthiation products could be obtained solely
B
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Scheme 1. Substrate Scope with Respect to the
Thiophenols
Scheme 3. Substrate Scope Based on 4-Substituted
Anilines
a
a
a
Reaction conditions: 1a (0.4 mmol), 2 ( 0.2 mmol), I2 (1.5 equiv),
DMSO (8 equiv), DMF (1.0 mL), 4 Å MS (100 mg). Air, 12 h.
Isolated yield based on 2.
a
Reaction conditions: 1 (0.4 mmol), 2 ( 0.2 mmol), I2 (1.5 equiv),
a
Scheme 2. Substrate Scope with Respect to Anilines
DMSO (8 equiv), DMF (1.0 mL), 4 Å MS (100 mg). Air, 12 h. Yield
based on 2. 6 mmol scale.
b
methyl and halogens at the para position could smoothly react
to furnish the desired products in excellent yields (5aa−5ad).
A better yield could be achieved when the methyl group was
located at the ortho position in aryl thiol. 2,3-Dichlorobenze-
nethiol could be used for this reaction to afford 5ai in 87%
yield. Notably, other para-substituted anilines could smoothly
react with para-toluenethiol to give the corresponding
products in high yields (5aj−5al). In addition, we could
know that 2-naphthylamine and 4-methylbenzenethiol react
with a yield of 77% (5am).
Furthermore, the bis-arylthiation product could be selec-
tively obtained by fine-tuning the reaction conditions as shown
in Scheme 4. A series of para-substituted anilines were used to
react with 2a to give the corresponding products in good to
high yields (6aa−6ad). At the same time, when we used 5aa
instead of 1a, we also obtained 6aa in 92%. However, the much
lower yield was obtained when 4-methoxyaniline was used
(6ae). Notably, halogens such as F and Cl were well tolerated
to give the desired product in moderate yields (6af and 6ag).
Furthermore, thiols with an electron-donating group reacted
smoothly to give products in moderate yields (6ah, 6am, and
6ap). When alkyls and halogens presented at different
positions, they all gave the desired products in good to
excellent yields. Notably, 6ar with an active bromo substituent
at the ortho position could be obtained in 94% yield, which
provides an opportunity for further conversion.
a
Reaction conditions: 1a (0.2 mmol), 2 (1.0 mmol), I2 (2.0 equiv),
DMSO (6 equiv), o-DCB (1.0 mL), 4 Å MS (100 mg), air, 16 h.
Isolated yield based on 1a. 3aa instead of 1a as the substrate.
b
Interestingly, when we altered the proportion of 1 and 2
under the standard reaction, we were surprised to obtain 2-
iodo-4-methyl-6-(p-tolylthio)aniline as the new outcome
(Scheme 5). We then slightly adjusted the condition of
reactions, and we finally got the optimized reaction conditions
by using an excess of anilines to give the corresponding
products in good to high yields (Scheme 3). For example,
when para-toluidine was used as the substrate, all thiols with
C
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conditions, 1 was smoothly reacted with several thiols to
give the corresponding products in moderate to good yields.
More importantly, halogens in thiols were well tolerated to
give the desired products with multi-halogen functional groups
(7ab−7ad, 7ag−7ah). No obvious substituent effect was
observed when the methyl substituent was located at different
positions. This reaction provided an efficient and facile
approach to anilines with various functional groups.
Scheme 4. Substrate Scope with Respect to the Anilines and
Thiophenols
a
As mentioned above, the most advantage of this method is
that the reaction conditions are very simple, and no transition-
metal catalyst or strong oxidant is needed. Therefore, the
reaction has very good functional group stability, which
provides a new opportunity for further transformation of the
product. We evaluated the transformation of 5ah and 6ar, both
of which have a reactive bromo group at the ortho position
(Scheme 6). When 5ah and 6ar were treated with Pd2dba3
Scheme 6. Further Transformation of Products
a
Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), I2 (1.5 equiv),
(2% mmol), SPhos (4% mmol), and t-BuONa (2.0 equiv)
under an argon atmosphere in NMP (0.6 mL) at 110 °C, both
of them smoothly gave the corresponding cyclized products
5ah′ and 6ar′ in 80 and 65% yields, respectively. This method
provides a convenient and concise way to synthesize the fused
heterocyclic compounds.
DMSO (4 equiv), o-DCB (1.0 mL), 4 Å MS (100 mg), air, 12 h.
Isolated yield based on 1. 5 mmol scale. 5aa instead of 1.
b
c
for iodination products: I2 (2.0 equiv), DMSO (4.0 equiv), and
o-DCB as the solvent. Under the optimized reaction
a
Scheme 5. Substrate Scope with Respect to Thiophenols
a
Reaction conditions: 1 (0.4 mmol), 2 ( 0.2 mmol), I2 (2.0 equiv), DMSO (4.0 equiv), o-DCB (1.0 mL), 4 Å MS (100 mg). Air, 12 h. Yield based
on 2.
D
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To understand the mechanism of the reaction, several
control experiments were performed (Scheme 7). 4-Iodoani-
Scheme 8. Possible Reaction Mechanism
Scheme 7. Control Experiments
and selectivity. Mono-, bis-, and tri-sulfenylation products were
selectively formed by fine-tuning the reaction conditions.
Synthetically useful functionalities such as halogens were
smoothly compatible with the DMSO-based oxidative reaction
conditions. Besides, iodination and sulfenylation reactions can
occur simultaneously to provide very useful multifunctional-
ized aniline products. This metal- and strong oxidant-free
method provides an efficient and selective alternative access to
diaryl sulfides with a free amino group, which may have
practical applications in organic and pharmaceutical fields.
EXPERIMENTAL SECTION
General Information. All reactions were carried out under an
■
line (1a′) was observed when 1a was treated under the
optimized reaction conditions in the absence of the thiol
substrate. p-Tolyl disulfide (2a′) could be obtained in 93%
yield from 2a under standard conditions. However, treatment
of 1a′ with 2a in the absence of I2 did not yield any desired
product, whereas the reaction of 1a with 2a′ yielded the
desired product 3aa in 60% yield. Hence, disulfides are
probably the intermediate products. Meanwhile, 2,2,4,4-
tetramethyl-1-piperidinyloxy (TEMPO) was added to the
standard reaction conditions, and the reaction was completely
inhibited by its 2 equiv. This indicates that a radical pathway
was probably involved in this kind of reaction.
When we probe the substrate scope, we also tried aliphatic
thiols, but we did not observe any corresponding products
under the standard conditions. These results may be
contributed to the high stability of aliphatic disulfide. Besides,
electron-deficient anilines also did not work, suggesting an
electrophilic sulfuration process in the C−S bond formation.
Based on the above observation and previous literature, a
possible reaction mechanism is illustrated in Scheme 8.
Initially, the oxidation of the thiol molecule by iodine generates
the thiyl radical A. Homo-coupling of two thiyl radicals affords
the disulfide intermediate 2a′. The reaction of 2a′ with I2
forms 2 equiv of electrophilic species p-MePhSI (B),29 which
attacks aniline to generate intermediate C. Finally, deprotona-
tion results in the desired product 3aa. Similarly, 4aa can be
obtained by repeating these steps. Treatment of HI with
DMSO could regenerate the important molecular iodine.
atmosphere of air unless otherwise noted. Column chromatography
was performed using silica gel (neutral) (200−300 mesh). H, 13C,
1
and 19F NMR spectra were recorded on a Bruker-AV (400, 100, and
376 MHz, respectively) instrument internally referenced to
tetramethylsilane (TMS) or chloroform signals. Mass spectra were
recorded on an Agilent 5975 gas chromatography−mass spectrometry
(GC−MS) instrument (EI). High-resolution mass spectra were
recorded at Beijing Forestry University. High-resolution mass
spectrometry (HRMS) was conducted using electrospray ionization
(ESI) or matrix-assisted laser desorption ionization (MALDI) and
was performed on an FTMS ICR MS BRUKER 7T. The structures of
known compounds were further corroborated by comparing their 1H,
13C, 19F NMR, and MS data with those of the literature. All reagents
were obtained from commercial suppliers and used without further
purification.
General Procedure for the Synthesis of 3. Aniline (38.0 μL,
0.4 mmol), 4-methylbenzenethiol (25.0 mg, 0.2 mmol), I2 (75.0 mg,
0.3 mmol), and molecular sieves (100.0 mg) were added to an oven-
dried reaction vessel (5 mL). The reaction vessel was sealed, and
DMSO (120.0 μL, 1.6 mmol) and DMF (1.0 mL) were added using a
syringe. The reaction vessel was stirred in an oil bath at 120 °C for 12
h under an air atmosphere. After cooling to room temperature, the
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with saturated saltwater. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate three times. The
combined organic layer was dried over sodium thiosulfate, and the
volatiles were removed under reduced pressure. The residue was
purified by column chromatography on silica gel (petroleum ether/
EtOAc = 20:1) to yield the desired product 3aa as a yellow liquid
(28.9 mg, 67% yield), Rf = 0.50 (petroleum ether/EtOAc = 20:1).
General Procedure for the Synthesis of 4. Aniline (19.0 μL,
0.2 mmol), 4-methylbenzenethiol (124.0 mg, 1.0 mmol), I2 (100.0
mg, 0.4 mmol), and molecular sieves (100.0 mg) were added to an
oven-dried reaction vessel (5 mL). The reaction vessel was sealed, and
DMSO (90.0 μL, 1.2 mmol) and o-DCB (1.0 mL) were added using a
syringe. The reaction vessel was stirred in an oil bath at 120 °C for 12
CONCLUSIONS
■
In summary, we have described a metal- and strong oxidant-
free C−S bond formation using anilines and aryl thiols as the
starting materials. The combinational use of molecular iodine
and DMSO could significantly improve the reaction efficiency
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h under an air atmosphere. After cooling to room temperature, the
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with saturated saltwater. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate three times. The
combined organic layer was dried over sodium thiosulfate, and the
volatiles were removed under reduced pressure. The residue was
purified by column chromatography on silica gel (petroleum ether/
EtOAc = 150:1) to yield the desired product 4aa as a yellow solid
(82.8 mg, 90% yield), mp 114−116 °C. Rf = 0.60 (petroleum ether/
EtOAc = 150:1).
product 6aa as a light-yellow solid (1.31 g, 75% yield), mp 102−104
°C. Rf = 0.60 (petroleum ether/EtOAc = 150:1).
4-(p-Tolylthio)aniline (3aa).29d Black liquid (petroleum ether/
EtOAc = 20:1); 67% (28.8 mg); 1H NMR (400 MHz, CDCl3): δ 7.27
(d, J = 8.4 Hz, 2H), 7.05 (q, J = 8.2 Hz, 4H), 6.65 (d, J = 8.4 Hz, 2H),
3.37 (s, 2H), 2.28 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ
146.4, 135.4, 135.3, 129.6, 128.2, 121.8, 115.9, 20.9; HRMS
(MALDI) m/z: [M]+ calcd for C13H13NS, 215.0769; found,
215.0765.
4-((4-Fluorophenyl)thio)aniline (3ab).29d Purple-black liquid
1
(petroleum ether/EtOAc = 20:1); 73% (32.0 mg); H NMR (400
General Procedure for the Synthesis of 5. p-Toluidine (43.0
mg, 0.4 mmol), 4-methylbenzenethiol (25.0 mg, 0.2 mmol), I2 (75.0
mg, 0.3 mmol), and molecular sieves (100.0 mg) were added to an
oven-dried reaction vessel (5 mL). The reaction vessel was sealed, and
DMSO (120.0 μL, 1.6 mmol) and DMF (1.0 mL) were added using a
syringe. The reaction vessel was stirred in an oil bath at 120 °C for 12
h under an air atmosphere. After cooling to room temperature, the
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with saturated saltwater. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate three times. The
combined organic layer was dried over sodium thiosulfate, and the
volatiles were removed under reduced pressure. The residue was
purified by column chromatography on silica gel (petroleum ether/
EtOAc = 50:1) to yield the desired product 5aa as a yellow liquid
(37.6 mg, 82% yield), Rf = 0.60 (petroleum ether/EtOAc = 50:1).
General Procedure for the Synthesis of 6. p-Toluidine (21.5
mg, 0.2 mmol), 4-methylbenzenethiol (63.5 mg, 0.5 mmol), I2 (75.0
mg, 0.3 mmol), and molecular sieves (100.0 mg) were added to an
oven-dried reaction vessel (5 mL). The reaction vessel was sealed, and
DMSO (60.0 μL, 0.8 mmol) and o-DCB (1.0 mL) were added using a
syringe. The reaction vessel was stirred in an oil bath at 120 °C for 12
h under an air atmosphere. After cooling to room temperature, the
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with saturated saltwater. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate three times. The
combined organic layer was dried over sodium thiosulfate, and the
volatiles were removed under reduced pressure. The residue was
purified by column chromatography on silica gel (petroleum ether/
EtOAc = 150:1) to yield the desired product 6aa as a light-yellow
solid (64.7 mg, 92% yield), mp 102−104 °C. Rf = 0.60 (petroleum
ether/EtOAc = 150:1).
Procedure for the Gram-Scale Reaction of 5ah. 2-
Bromobenzenethiol (1.2 g, 6 mmol), p-toluidine (1.3 g, 12 mmol),
I2 (2.3 g, 9 mmol), and molecular sieves (2.0 g) were added to a
round-bottomed flask (50 mL). DMSO (2.4 mL, 40 mmol) and DMF
(15 mL) were added using a measuring cylinder. The reaction vessel
was stirred in an oil bath at 130 °C for 16 h under an air atmosphere.
After cooling to room temperature, the reaction mixture was diluted
with ethyl acetate (25 mL) and washed with saturated saltwater. The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate three times. The combined organic layer was dried over
sodium sulfate, and the volatiles were removed under reduced
pressure. The residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc = 50:1) to yield the desired
product 5ah as a yellow liquid (1.38 g, 78% yield). Rf = 0.60
(petroleum ether/EtOAc = 50:1).
MHz, CDCl3): δ 7.28 (d, J = 8.6 Hz, 2H), 7.17−7.11 (m, 2H), 6.97−
6.89 (m, 2H), 6.67 (d, J = 8.2 Hz, 2H), 3.61 (s, 2H); 13C {1H} NMR
1
(100 MHz, CDCl3): δ 161.2 (C−F, JC−F = 245.1 Hz), 146.8, 135.4,
4
3
134.2 (C−F, JC−F = 3.2 Hz), 129.9 (C−F, JC−F = 7.9 Hz), 121.4,
116.0, 115.9 (C−F, 2JC−F = 21.9 Hz); 19F NMR (377 MHz, CDCl3):
δ −117.10; HRMS (MALDI) m/z: [M]+ calcd for C12H10FNS,
219.0518; found, 219.0514.
4-((4-Chlorophenyl)thio)aniline (3ac).29d Purple-black liquid
1
(petroleum ether/EtOAc = 20:1); 77% (36.2 mg); H NMR (400
MHz, CDCl3): δ 7.32−7.26 (m, 2H), 7.19−7.13 (m, 2H), 7.05−6.99
(m, 2H), 6.70−6.64 (m, 2H), 3.63 (s, 2H); 13C {1H} NMR (100
MHz, CDCl3): δ 147.1, 138.4, 136.1, 130.9, 128.8, 128.3, 119.8,
115.9; HRMS (MALDI) m/z: [M]+ calcd for C12H10ClNS, 235.0223;
found, 235.0219.
4-((4-Bromophenyl)thio)aniline (3ad).29d Purple liquid (petro-
1
leum ether/EtOAc = 20:1); 70% (39.1 mg); H NMR (400 MHz,
CDCl3): δ 7.34−7.28 (m, 4H), 6.97 (d, J = 8.6 Hz, 2H), 6.69 (d, J =
8.5 Hz, 2H), 3.77 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ
147.3, 139.2, 136.2, 131.7, 128.5, 119.0, 118.7, 115.9.
4-(m-Tolylthio)aniline (3ae).29d Light-pink liquid (petroleum
ether/EtOAc = 20:1); 70% (30.1 mg); 1H NMR (400 MHz,
CDCl3): δ 7.34−7.28 (m, 4H), 6.97 (d, J = 8.6 Hz, 2H), 6.69 (d, J =
8.5 Hz, 2H), 3.77 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ
146.7, 139.2, 138.6, 135.9, 128.6, 127.9, 126.2, 124.4, 120.7, 115.9,
21.3; HRMS (MALDI) m/z: [M]+ calcd for C13H13NS, 215.0769;
found, 215.0767.
4-(o-Tolylthio)aniline (3af).29d Light-pink liquid (petroleum
ether/EtOAc = 20:1); 86% (37.0 mg); 1H NMR (400 MHz,
CDCl3): δ 7.26−7.22 (m, 2H), 7.16−7.11 (m, 1H), 7.07−6.98 (m,
2H), 6.93−6.85 (m, 1H), 6.67 (d, J = 8.5 Hz, 2H), 3.62 (s, 2H), 2.37
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 146.7, 138.3, 135.9,
135.6, 123.0, 127.6, 126.3, 125.3, 120.4, 116.0, 20.1.
4-((2-Chlorophenyl)thio)aniline (3ag).29d Purple liquid (petro-
1
leum ether/EtOAc = 20:1); 60% (28.2 mg); H NMR (400 MHz,
CDCl3): δ 7.37−7.27 (m, 3H), 7.06−6.97 (m, 2H), 6.75−6.66 (m,
3H), 3.80 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ 147.7,
139.6, 137.2, 130.3, 129.2, 126.9, 126.8, 125.5, 117.7, 116.0; HRMS
(MALDI) m/z: [M]+ calcd for C12H10ClNS, 235.0223; found,
235.0221.
4-((2-Bromophenyl)thio)aniline (3ah). Purple liquid (petroleum
ether/EtOAc = 20:1); 87% (48.5 mg); 1H NMR (400 MHz, CDCl3):
δ 7.50−7.45 (m, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.10−7.04 (m, 1H),
6.95−6.89 (m, 1H), 6.71 (d, J = 8.5 Hz, 2H), 6.68−6.63 (m, 1H),
3.84 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ 147.8, 141.6,
137.3, 132.5, 127.5, 126.8, 125.7, 120.0, 118.2, 116.0; HRMS
(MALDI) m/z: [M]+ calcd for C12H10BrNS, 278.9717; found,
278.9713.
Procedure for the Gram-Scale Reaction of 6aa. p-Toluidine
(547.0 mg, 5 mmol), 4-methylbenzenethiol (1.9 g, 15 mmol), I2 (1.9
g, 7.5 mmol), and molecular sieves (2.0 g) were added to a round-
bottomed flask (50 mL). DMSO (1.2 mL, 20 mmol) and o-DCB (15
mL) were added using a measuring cylinder. The reaction vessel was
stirred in an oil bath at 130 °C for 18 h under an air atmosphere. After
cooling to room temperature, the reaction mixture was diluted with
ethyl acetate (25 mL) and washed with saturated saltwater. The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate three times. The combined organic layer was dried over
sodium sulfate, and the volatiles were removed under reduced
pressure. The residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc = 150:1) to yield the desired
2,4,6-Tris(p-tolylthio)aniline (4aa). Colorless solid (petroleum
1
ether/EtOAc = 150:1); 90% (82.6 mg); mp 114−116 °C; H NMR
(400 MHz, CDCl3): δ 7.60 (s, 2H), 7.12−7.09 (m, 2H), 7.06 (s, 2H),
7.02 (t, J = 8.4 Hz, 8H), 5.03 (s, 2H), 2.30 (s, 3H), 2.29 (s, 6H); 13C
{1H} NMR (100 MHz, CDCl3): δ 149.7, 142.9, 136.1, 136.0, 134.3,
131.7, 129.9, 129.8, 128.9, 127.5, 121.6, 116.9, 21.0, 21.0; HRMS
(MALDI) m/z: [M]+ calcd for C27H25NS3, 459.1150; found,
459.1149.
2,4,6-Tris((4-fluorophenyl)thio)aniline (4ab). Yellow solid (petro-
1
leum ether/EtOAc = 150:1); 97% (91.2 mg); mp 89−91 °C; H
NMR (400 MHz, CDCl3): δ 7.55 (s, 2H), 7.21−7.17 (m, 2H), 7.12−
7.06 (m, 4H), 6.95 (t, J = 8.4 Hz, 6H), 4.91 (s, 2H); 13C {1H} NMR
F
https://dx.doi.org/10.1021/acs.joc.0c02078
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(100 MHz, CDCl3): δ 161.71 (C−F, 1JC−F = 246.6 Hz), 161.64 (C−
2-((4-Chlorophenyl)thio)-4-methylaniline (5ac).31 Yellow liquid
(petroleum ether/EtOAc = 50:1); 93% (46.5 mg); H NMR (400
1
1
F, JC−F = 246.6 Hz), 149.48, 142.41, 132.56 (C−F, 4JC−F = 3.3 Hz),
131.17 (C−F, 3JC−F = 8.0 Hz), 130.04 (C−F, 4JC−F = 3.3 Hz), 129.58
MHz, CDCl3): δ 7.25 (s, 1H), 7.20−7.14 (m, 2H), 7.09−7.03 (m,
1H), 7.03−6.95 (m, 2H), 6.72 (d, J = 8.1 Hz, 1H), 4.13 (s, 2H), 2.24
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 146.3, 137.4, 135.6,
132.2, 131.1, 129.0, 128.2, 127.6, 115.6, 113.7, 20.2; HRMS (ESI) m/
z: [M + H]+ calcd for C13H13ClNS, 250.0452; found, 250.0441.
2-((4-Bromophenyl)thio)-4-methylaniline (5ad). Yellow liquid
3
2
(C−F, JC−F = 8.0 Hz), 122.12, 117.30, 116.35 (C−F, JC−F = 22.2
Hz), 116.17 (C−F, JC−F = 22.0 Hz); 19F NMR (376 MHz, CDCl3):
2
δ −115.40, −115.45; HRMS (MALDI) m/z: [M]+ calcd for
C24H16F3NS3, 471.0397; found, 471.0396.
2,4,6-Tris((4-chlorophenyl)thio)aniline (4ac). Yellow solid (petro-
1
1
(petroleum ether/EtOAc = 50:1); 97% (57.1 mg); H NMR (400
leum ether/EtOAc = 150:1); 82% (85.4 mg); mp 113−115 °C; H
MHz, CDCl3): δ 7.31 (d, J = 8.5 Hz, 2H), 7.25 (s, 1H), 7.08−7.02
(m, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.1 Hz, 1H), 3.99 (s,
2H), 2.24 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 146.3,
137.4, 136.3, 132.2, 131.9, 128.2, 127.8, 118.9, 115.6, 113.5, 20.2;
HRMS (MALDI) m/z: [M]+ calcd for C13H12BrNS, 292.9874; found,
292.9875.
NMR (400 MHz, CDCl3): δ 7.66 (s, 2H), 7.22 (d, J = 8.6 Hz, 6H),
7.10 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.6 Hz, 4H), 4.87 (s, 2H); 13C
{1H} NMR (100 MHz, CDCl3): δ 150.4, 144.2, 136.6, 133.7, 132.2,
132.0, 129.4, 129.3, 129.1, 128.3, 120.7, 116.2; HRMS (MALDI) m/
z: [M]+ calcd for C24H16Cl3NS3, 518.9511; found, 518.9515.
2,4,6-Tris((4-bromophenyl)thio)aniline (4ad). Yellow solid (pe-
troleum ether/EtOAc = 150:1); 67% (87.6 mg); mp 122−124 °C; 1H
NMR (400 MHz, CDCl3): δ 7.66 (s, 2H), 7.36 (d, J = 8.5 Hz, 6H),
7.02 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 4H), 5.08 (s, 2H); 13C
{1H} NMR (100 MHz, CDCl3): δ 150.5, 144.5, 137.4, 134.4, 132.2,
132.0, 129.6, 128.5, 120.5, 120.0, 119.9, 116.0; HRMS (MALDI) m/
z: [M]+ calcd for C24H16Br3NS3, 652.7975; found, 652.7977.
2,4,6-Tris(m-tolylthio)aniline (4ae). Yellow liquid (petroleum
ether/EtOAc = 150:1); 98% (90.0 mg); 1H NMR (400 MHz,
CDCl3): δ 7.70 (d, J = 1.3 Hz, 2H), 7.11 (t, J = 7.6 Hz, 3H), 6.98−
6.85 (m, 9H), 5.12 (s, 2H), 2.26 (s, 9H); 13C {1H} NMR (100 MHz,
CDCl3): δ 150.7, 144.7, 138.9, 138.7, 138.3, 135.2, 128.9, 128.8,
128.3, 127.4, 126.9, 126.6, 124.8, 123.9, 120.3, 116.1, 21.4, 21.3;
HRMS (MALDI) m/z: [M]+ calcd for C27H25NS3, 459.1150; found,
459.1162.
4-Methyl-2-(m-tolylthio)aniline (5ae).24 Colorless liquid (petro-
1
leum ether/EtOAc = 50:1); 83% (38.0 mg); H NMR (400 MHz,
CDCl3): δ 7.27 (s, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.06−7.02 (m, 1H),
6.92 (d, J = 9.6 Hz, 2H), 6.86 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.1 Hz,
1H), 3.81 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3): δ 146.2, 138.8, 137.4, 136.6, 131.8, 128.8, 128.1,
127.1, 126.3, 123.5, 115.5, 114.5, 21.4, 20.2.
4-Methyl-2-(o-tolylthio)aniline (5af).24 Colorless solid (petroleum
ether/EtOAc = 50:1); 95% (43.5 mg); mp 75−77 °C; 1H NMR (400
MHz, CDCl3): δ 7.22 (s, 1H), 7.16−7.12 (m, 1H), 7.08−6.98 (m,
3H), 6.76−6.68 (m, 2H), 3.93 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3): δ 146.2, 137.3, 135.8, 135.1,
131.7, 130.1, 128.4, 126.5, 125.3, 125.1, 115.5, 114.0, 20.2, 20.0.
2-((2-Chlorophenyl)thio)-4-methylaniline (5ag). Yellow solid
(petroleum ether/EtOAc = 50:1); 85% (42.2 mg); mp 81−83 °C;
1H NMR (400 MHz, CDCl3): δ 7.37−7.30 (m, 1H), 7.27 (s, 1H),
7.12−7.07 (m, 1H), 7.07−7.00 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H),
6.66−6.60 (m, 1H), 3.94 (s, 2H), 2.25 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3): δ 146.8, 137.9, 136.1, 132.5, 130.8, 129.4, 128.4,
127.1, 126.2, 125.9, 115.6, 112.4, 20.2; HRMS (ESI) m/z: [M + H]+
calcd for C13H13ClNS, 250.0452; found, 250.0442.
2,4,6-Tris(o-tolylthio)aniline (4af). Yellow solid (petroleum ether/
1
EtOAc = 150:1); 96% (88.1 mg); mp 114−116 °C; H NMR (400
MHz, CDCl3): δ 7.53 (s, 2H), 7.14 (t, J = 6.5 Hz, 3H), 7.10−7.03 (m,
6H), 7.00 (d, J = 6.0 Hz, 1H), 6.80 (d, J = 6.9 Hz, 2H), 4.85 (s, 2H),
2.37 (s, 6H), 2.34 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ
149.9, 143.0, 136.9, 136.7, 136.0, 134.2, 130.4, 130.2, 128.6, 126.6,
126.5, 126.2, 126.1, 126.0, 121.0, 116.2, 20.2, 20.1; HRMS (MALDI)
m/z: [M]+ calcd for C27H25NS3, 459.1150; found, 459.1167.
2-((2-Bromophenyl)thio)-4-methylaniline (5ah).32 Light-yellow
solid (petroleum ether/EtOAc = 50:1); 80% (47.1 mg); mp 82−84
°C; 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 7.9 Hz, 1H), 7.28 (s,
1H), 7.09 (t, J = 7.5 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 8.2
Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.87 (s, 2H), 2.25 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3): δ 146.7, 138.1, 137.8, 132.7, 132.6,
128.4, 127.7, 126.2, 126.1, 120.5, 115.6, 113.0, 20.2.
2-((2,3-Dichlorophenyl)thio)-4-methylaniline (5ai). White solid
(petroleum ether/EtOAc = 50:1); 87% (49.5 mg); mp 120−122 °C;
1H NMR (400 MHz, CDCl3): δ 7.25 (d, J = 2.4 Hz, 1H), 7.21−7.16
(m, 1H), 7.14−7.08 (m, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.2
Hz, 1H), 6.54−6.48 (m, 1H), 3.99 (s, 2H), 2.25 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3): δ 146.7, 139.0, 137.8, 133.2, 132.9, 128.5,
127.3, 126.4, 124.0, 115.7, 112.1, 20.2; HRMS (MALDI) m/z: [M]+
calcd for C13H11Cl2NS, 282.9989; found, 282.9990.
2-((4-Bromophenyl)thio)-4-ethylaniline (5aj). Yellow liquid (pe-
troleum ether/EtOAc = 50:1); 94% (57.9 mg); 1H NMR (400 MHz,
CDCl3): δ 7.34−7.29 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.11−7.06
(m, 1H), 6.95−6.89 (m, 2H), 6.74 (d, J = 8.2 Hz, 1H), 4.03 (s, 2H),
2.54 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H); 13C {1H} NMR
(100 MHz, CDCl3): δ 146.5, 136.3, 134.9, 131.9, 131.1, 127.7, 118.8,
115.6, 113.4, 27.7, 15.7; HRMS (MALDI) m/z: [M]+ calcd for
C14H14BrNS, 307.0030; found, 307.0026.
2-((4-Bromophenyl)thio)-4-isopropylaniline (5ak). Wine-red solid
(petroleum ether/EtOAc = 50:1); 92% (59.3 mg); mp 54−56 °C; 1H
NMR (400 MHz, CDCl3): δ 7.33 (s, 1H), 7.32−7.28 (m, 2H), 7.15−
7.11 (m, 1H), 6.92 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 4.04
(s, 2H), 2.87−2.74 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3): δ 146.5, 139.7, 136.3, 135.0, 131.9, 129.7,
127.7, 118.8, 115.6, 113.4, 33.0, 24.1; HRMS (MALDI) m/z: [M]+
calcd for C15H16BrNS, 321.0187; found, 321.0182.
2,4,6-Tris((2-chlorophenyl)thio)aniline (4ag). Yellow solid (petro-
1
leum ether/EtOAc = 150:1); 83% (86.5 mg); mp 133−135 °C; H
NMR (400 MHz, CDCl3): δ 7.75 (s, 2H), 7.37−7.31 (m, 3H), 7.14−
7.08 (m, 6H), 6.91−6.86 (m, 1H), 6.77−6.72 (m, 2H), 5.21 (s, 2H);
13C {1H} NMR (100 MHz, CDCl3): δ 151.8, 146.2, 137.9, 134.4,
131.9, 131.6, 129.8, 129.7, 128.0, 127.3, 127.1, 126.9, 126.9, 126.6,
118.9, 115.1; HRMS (MALDI) m/z: [M]+ calcd for C24H16Cl3NS3,
518.9511; found, 518.9515.
2,4,6-Tris((2-bromophenyl)thio)aniline (4ah). Yellow solid (pe-
troleum ether/EtOAc = 150:1); 70% (91.6 mg); mp 114−116 °C; 1H
NMR (400 MHz, CDCl3): δ 7.77 (s, 2H), 7.52 (t, J = 8.4 Hz, 3H),
7.18−7.13 (m, 3H), 7.05−6.97 (m, 3H), 6.86 (d, J = 7.9 Hz, 1H),
6.73 (d, J = 7.9 Hz, 2H), 5.20 (s, 2H); 13C {1H} NMR (100 MHz,
CDCl3): δ 151.6, 146.3, 139.9, 136.4, 133.1, 133.0, 127.9, 127.9,
127.7, 127.1, 126.8, 126.7, 121.6, 121.4, 119.4, 115.7; HRMS
(MALDI) m/z: [M]+ calcd for C24H16Br3NS3, 652.7975; found,
652.7977.
4-Methyl-2-(p-tolylthio)aniline (5aa).29d Yellow solid (petroleum
ether/EtOAc = 50:1); 82% (37.6 mg); mp 74−76 °C; 1H NMR (400
MHz, CDCl3): δ 7.26 (s, 1H), 7.06−6.97 (m, 5H), 6.70 (d, J = 8.1
Hz, 1H), 3.93 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3): δ 146.0, 137.1, 135.3, 133.1, 131.6, 129.7, 128.1,
126.9, 115.5, 115.2, 20.9, 20.1; HRMS (MALDI) m/z: [M]+ calcd for
C14H15NS, 229.0925; found, 229.0924.
2-((4-Fluorophenyl)thio)-4-methylaniline (5ab).30 Colorless
1
liquid (petroleum ether/EtOAc = 50:1); 90% (42.0 mg); H NMR
(400 MHz, CDCl3): δ 7.25 (s, 1H), 7.11−7.00 (m, 3H), 6.96−6.87
(m, 2H), 6.71 (d, J = 8.1 Hz, 1H), 3.95 (s, 2H), 2.23 (s, 3H); 13C
1
{1H} NMR (100 MHz, CDCl3): δ 161.2 (C−F, JC−F = 244.9 Hz),
4
3
146.1, 137.1, 131.9 (C−F, JC−F = 4.5 Hz), 128.6 (C−F, JC−F = 7.8
2
Hz), 128.2, 116.0 (C−F, JC−F = 22.1 Hz), 115.6, 114.7, 20.2; 19F
2-((4-Bromophenyl)thio)-4-(tert-butyl)aniline (5al). Yellow liquid
1
NMR (376 MHz, CDCl3): δ −117.2; HRMS (MALDI) m/z: [M]+
(petroleum ether/EtOAc = 50:1); 91% (61.2 mg); H NMR (400
calcd for C13H12FNS, 233.0675; found, 233.0674.
MHz, CDCl3): δ 7.44 (d, J = 2.3 Hz, 1H), 7.35−7.27 (m, 3H), 6.92
G
https://dx.doi.org/10.1021/acs.joc.0c02078
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 4.02 (s, 2H), 1.28 (s,
9H); 13C {1H} NMR (100 MHz, CDCl3): δ 146.2, 142.0, 136.4,
134.0, 131.9, 128.7, 127.6, 118.8, 115.3, 113.0, 34.0, 31.4; HRMS
(MALDI) m/z: [M]+ calcd for C16H18BrNS, 335.0343; found,
335.0347.
6.79 (d, J = 8.8 Hz, 4H), 4.78 (s, 2H), 3.75 (s, 6H), 2.18 (s, 3H); 13
C
{1H} NMR (100 MHz, CDCl3): δ 158.4, 147.0, 137.5, 129.8, 127.31,
126.4, 117.2, 114.7, 55.3, 20.0; HRMS (MALDI) m/z: [M]+ calcd for
C21H21NO2S2, 383.1014; found, 383.1012.
2,6-Bis((4-fluorophenyl)thio)-4-methylaniline (6ai). Dark-red
liquid (petroleum ether/EtOAc = 150:1); 80% (57.5 mg); 1H
NMR (400 MHz, CDCl3): δ 7.33 (s, 2H), 7.07 (m, J = 8.7, 5.1 Hz,
4H), 6.93 (t, J = 8.6 Hz, 4H), 4.80 (s, 2H), 2.22 (s, 3H); 13C {1H}
1-((4-Bromophenyl)thio)naphthalen-2-amine (5am).24 Black
1
liquid (petroleum ether/EtOAc = 10:1); 77% (40.8 mg); H NMR
(400 MHz, CDCl3): δ 8.31 (d, J = 8.5 Hz, 1H), 7.75 (m, J = 12.1, 8.5
Hz, 2H), 7.45 (m, J = 11.3, 4.1 Hz, 1H), 7.30−7.26 (m, 1H), 7.07 (d,
J = 8.8 Hz, 1H), 6.97 (q, J = 8.4 Hz, 4H), 4.42 (s, 2H), 2.26 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3): δ 148.2, 136.6, 134.8, 133.1,
131.6, 129.7, 128.4, 128.3, 127.7, 126.0, 124.3, 122.5, 117.6, 105.2,
20.8; HRMS (ESI) [M + H]+ m/z calcd for C17H16NS, 266.0998;
found, 266.1002.
4-Methyl-2,6-bis(p-tolylthio)aniline (6aa). Light-yellow solid
(petroleum ether/EtOAc = 150:1); 92% (64.7 mg); mp 102−104
°C; 1H NMR (400 MHz, CDCl3): δ 7.33 (s, 2H), 7.02 (q, J = 8.3 Hz,
8H), 4.79 (s, 2H), 2.28 (s, 6H), 2.22 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3): δ 148.0, 138.9, 135.6, 132.6, 129.8, 127.3, 127.0,
115.6, 20.9, 20; HRMS (MALDI) m/z: [M]+ calcd for C21H21NS2,
351.1115; found, 351.1111.
1
NMR (100 MHz, CDCl3): δ 161.3 (C−F, JC−F = 245.6 Hz), 147.9,
4
3
139.1, 131.1 (C−F, JC−F = 3.2 Hz), 128.82 (C−F, JC−F = 7.9 Hz),
2
127.6, 116.1 (C−F, JC−F = 22.1 Hz), 115.7, 20.0; 19F NMR (376
MHz, CDCl3): δ −116.5. HRMS (MALDI) m/z: [M]+ calcd for
359.0614; found, 359.0618.
2,6-Bis((4-chlorophenyl)thio)-4-methylaniline (6aj). White solid
(petroleum ether/EtOAc = 150:1); 90% (70.6 mg); mp 92−94 °C;
1H NMR (400 MHz, CDCl3): δ 7.36 (s, 2H), 7.22−7.16 (m, 4H),
7.03−6.96 (m, 4H), 4.76 (s, 2H), 2.24 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3): δ 148.3, 139.8, 134.8, 131.6, 129.1, 127.8, 127.7,
114.6, 20.0; HRMS (MALDI) m/z: [M]+ calcd for C19H15Cl2NS2,
391.0023; found, 391.0019.
2,6-Bis((4-bromophenyl)thio)-4-methylaniline (6ak). White solid
(petroleum ether/EtOAc = 150:1); 88% (84.7 mg); mp 94−96 °C;
1H NMR (400 MHz, CDCl3): δ 7.37 (s, 2H), 7.33 (d, J = 8.0 Hz,
4H), 6.93 (d, J = 7.9 Hz, 4H), 4.74 (s, 2H), 2.24 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3): δ 148.4, 139.9, 135.5, 132.0, 128.0, 127.7,
119.3, 114.4, 20.0; HRMS (MALDI) m/z: [M]+ calcd for
C19H15Br2NS2, 480.8992; found, 480.9004.
4-Ethyl-2,6-bis(p-tolylthio)aniline (6ab). Yellow solid (petroleum
1
ether/EtOAc = 150:1); 87% (63.6 mg); mp 86−88 °C; H NMR
(400 MHz, CDCl3): δ 7.36 (s, 2H), 7.01 (q, J = 8.2 Hz, 8H), 4.79 (s,
2H), 2.52 (q, J = 7.5 Hz, 2H), 2.28 (s, 6H), 1.18 (t, J = 7.6 Hz, 3H);
13C {1H} NMR (100 MHz, CDCl3): δ 148.3, 137.9, 135.5, 133.9,
132.6, 129.8, 126.9, 115.5, 27.5, 20.9, 15.6; HRMS (MALDI) m/z:
[M]+ calcd for C22H23NS2, 365.1272; found, 365.1266.
4-Methyl-2,6-bis(m-tolylthio)aniline (6al). Bright-yellow liquid
1
4-Isopropyl-2,6-bis(p-tolylthio)aniline (6ac). Deep-yellow solid
(petroleum ether/EtOAc = 150:1); 89% (67.5 mg); mp 68−70 °C;
1H NMR (400 MHz, CDCl3): δ 7.39 (s, 2H), 7.03 (d, J = 8.1 Hz,
4H), 6.98 (d, J = 8.3 Hz, 4H), 4.78 (s, 2H), 2.88−2.64 (m, 1H), 2.27
(s, 6H), 1.20 (d, J = 6.9 Hz, 6H); 13C {1H} NMR (100 MHz,
CDCl3): δ 148.4, 138.6, 136.6, 135.4, 132.6, 129.8, 126.8, 115.3, 32.9,
24.0, 20.9; HRMS (MALDI) m/z: [M]+ calcd for C23H25NS2,
379.1428; found, 379.1422.
(petroleum ether/EtOAc = 150:1); 84% (59.0 mg); H NMR (400
MHz, CDCl3): δ 7.37 (s, 2H), 7.10 (t, J = 7.8 Hz, 2H), 6.92 (d, J =
7.3 Hz, 4H), 6.86 (d, J = 7.9 Hz, 2H), 4.81 (s, 2H), 2.26 (s, 6H), 2.24
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 148.6, 139.5, 138.8,
136.1, 128.9, 127.3, 127.1, 126.5, 123.5, 114.8, 21.4, 20.0; HRMS
(MALDI) m/z: [M]+ calcd for C21H21NS2, 351.1115; found,
351.1111.
2,6-Bis((3-methoxyphenyl)thio)-4-methylaniline (6am). Light-
yellow liquid (petroleum ether/EtOAc = 150:1); 40% (30.6 mg);
1H NMR (400 MHz, CDCl3): δ 7.38 (s, 2H), 7.13 (t, J = 8.0 Hz,
2H), 6.70−6.59 (m, 6H), 4.72 (s, 2H), 3.71 (s, 6H), 2.23 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3): δ 160.0, 148.7, 139.9, 137.8,
129.8, 127.4, 118.6, 114.5, 111.9, 111.1, 55.1, 20.0; HRMS (MALDI)
m/z: [M]+ calcd for C21H21NO2S2, 383.1014; found, 383.1015.
4-Methyl-2,6-bis(o-tolylthio)aniline (6an). Light-yellow solid
(petroleum ether/EtOAc = 150:1); 92% (64.6 mg); mp 113−115
4-(tert-Butyl)-2,6-bis(p-tolylthio)aniline (6ad). Light-yellow liquid
1
(petroleum ether/EtOAc = 150:1); 95% (74.7 mg); H NMR (400
MHz, CDCl3): δ 7.55 (s, 2H), 7.04 (d, J = 8.1 Hz, 4H), 6.98 (d, J =
8.2 Hz, 4H), 4.77 (s, 2H), 2.28 (s, 6H), 1.27 (s, 9H); 13C {1H} NMR
(100 MHz, CDCl3): δ 148.1, 141.0, 135.8, 135.4, 132.6, 129.8, 126.7,
115.0, 34.0, 31.4, 20.9; HRMS (MALDI) m/z: [M]+ calcd for
C24H27NS2, 393.1585; found, 393.1582.
4-Methoxy-2,6-bis(p-tolylthio)aniline (6ae). Bright-yellow liquid
1
1
(petroleum ether/EtOAc = 150:1); 40% (29.4 mg); H NMR (400
°C; H NMR (400 MHz, CDCl3): δ 7.32 (s, 2H), 7.16−7.13 (m,
MHz, CDCl3): δ 7.26 (s, 2H), 7.06 (d, J = 6.7 Hz, 8H), 3.72 (s, 3H),
2.29 (s, 6H); 13C {1H} NMR (100 MHz, CDCl3): δ 151.4, 144.5,
143.4, 136.1, 131.9, 129.9, 127.8, 122.9, 117.7, 55.9, 21.0; HRMS
(ESI) m/z: [M + H]+ calcd for C21H22NOS2, 368.1137; found,
368.1122.
2H), 7.07−7.00 (m, 4H), 6.79−6.71 (m, 2H), 4.72 (s, 2H), 2.40 (s,
6H), 2.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 148.4,
139.2, 135.4, 135.2, 130.2, 127.7, 126.5, 125.5, 125.4, 114.5, 20.0;
HRMS (ESI) [M + H]+ m/z calcd for C21H22NS2, 352.1188; found,
352.1175.
4-Fluoro-2,6-bis(p-tolylthio)aniline (6af). Wine-red solid (petro-
2,6-Bis((2-ethylphenyl)thio)-4-methylaniline (6ao). Light-yellow
solid (petroleum ether/EtOAc = 150:1); 85% (64.5 mg); mp 53−55
°C; 1H NMR (400 MHz, CDCl3): δ 7.32 (s, 2H), 7.17 (d, J = 7.4 Hz,
2H), 7.09 (t, J = 7.4 Hz, 2H), 7.02 (t, J = 7.5 Hz, 2H), 6.76 (d, J = 7.8
Hz, 2H), 4.69 (s, 2H), 2.80 (q, J = 7.5 Hz, 4H), 2.23 (s, 3H), 1.29 (t,
J = 7.5 Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3): δ 148.4, 141.3,
139.2, 134.6, 128.5, 127.7, 126.5, 125.9, 125.7, 114.8, 26.6, 20.0, 14.2;
HRMS (MALDI) m/z: [M]+ calcd for C23H25NS2, 379.1428; found,
379.1427.
1
leum ether/EtOAc = 150:1); 62% (44.1 mg); mp 53−55 °C; H
NMR (400 MHz, CDCl3): δ 7.14 (d, J = 8.2 Hz, 2H), 7.07 (s, 8H),
4.70 (s, 2H), 2.30 (s, 6H); 13C {1H} NMR (100 MHz, CDCl3): δ
154.1 (C−F, 1JC−F = 240.5 Hz), 145.59 (C−F, 4JC−F = 2.1 Hz), 136.6,
2
131.1, 130.0, 128.4, 122.84 (C−F, JC−F = 22.7 Hz), 117.77 (C−F,
3JC−F = 7.9 Hz), 20.98; 19F NMR (376 MHz, CDCl3): δ −126.1;
HRMS (MALDI) m/z: [M]+ calcd for C20H18FNS2, 355.0865; found,
355.0859.
4-Chloro-2,6-bis(p-tolylthio)aniline (6ag). Light-yellow solid
(petroleum ether/EtOAc = 150:1); 77% (57.2 mg); mp 112−114
2,6-Bis((2-methoxyphenyl)thio)-4-methylaniline (6ap). White
solid (petroleum ether/EtOAc = 50:1); 64% (49.0 mg); mp 141−
142 °C; 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 2H), 7.11 (t, J = 7.7
Hz, 2H), 6.87−6.78 (m, 4H), 6.69 (d, J = 7.6 Hz, 2H), 4.87 (s, 2H),
3.91 (s, 6H), 2.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ
155.7, 149.4, 140.0, 127.4, 126.4, 124.5, 121.2, 113.5, 110.3, 55.8,
20.0; HRMS (MALDI) m/z: [M]+ calcd for C21H21NO2S2, 383.1014;
found, 383.1015.
1
°C; H NMR (400 MHz, CDCl3): δ 7.42 (s, 2H), 7.10−7.02 (m,
8H), 4.90 (s, 2H), 2.30 (s, 6H); 13C {1H} NMR (100 MHz, CDCl3):
δ 148.2, 136.5, 136.5, 131.2, 130.0, 128.0, 121.4, 117.7, 21.0; HRMS
(MALDI) m/z: [M]+ calcd for C20H18ClNS2, 371.0569; found,
371.0563.
2,6-Bis((4-methoxyphenyl)thio)-4-methylaniline (6ah). Light-yel-
1
low liquid (petroleum ether/EtOAc = 150:1); 69% (59.2 mg); H
2,6-Bis((2-chlorophenyl)thio)-4-methylaniline (6aq). White solid
(petroleum ether/EtOAc = 150:1); 83% (65.1 mg); mp 120−122 °C;
NMR (400 MHz, CDCl3): δ 7.24 (s, 2H), 7.11 (d, J = 8.8 Hz, 4H),
H
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1H NMR (400 MHz, CDCl3): δ 7.43 (s, 2H), 7.36−7.31 (m, 2H),
7.09−7.03 (m, 4H), 6.70−6.65 (m, 2H), 4.80 (s, 2H), 2.26 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3): δ 149.2, 140.6, 135.4, 131.2,
129.6, 127.9, 127.1, 126.3, 113.3, 20.0; HRMS (MALDI) m/z: [M]+
calcd for C19H15Cl2NS2, 391.0023; found, 391.0019.
2,6-Bis((2-bromophenyl)thio)-4-methylaniline (6ar). White solid
(petroleum ether/EtOAc = 150:1); 94% (90.4 mg); mp 137−139 °C;
1H NMR (400 MHz, CDCl3): δ 7.55−7.48 (m, 2H), 7.44 (s, 2H),
7.16−7.08 (m, 2H), 7.02−6.95 (m, 2H), 6.67−6.61 (m, 2H), 4.80 (s,
2H), 2.27 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 149.1,
140.6, 137.3, 132.9, 128.0, 127.7, 126.5, 126.3, 121.0, 113.9, 20.0;
HRMS (MALDI) m/z: [M]+ calcd for C19H15Br2NS2, 480.8992;
found, 480.9004.
2-Iodo-4-methyl-6-(p-tolylthio)aniline (7aa). Yellow liquid (pe-
troleum ether/EtOAc = 100:1); 62% (44.0 mg); 1H NMR (400 MHz,
CDCl3): δ 7.52 (d, J = 1.2 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.07−
7.00 (m, 4H), 4.42 (s, 2H), 2.28 (s, 3H), 2.19 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3): δ 146.2, 140.9, 137.5, 135.9, 132.3, 129.9,
129.2, 127.4, 115.1, 83.9, 20.9, 19.6; HRMS (MALDI) m/z: [M]+
calcd for C14H14INS, 354.9892; found, 354.9892.
2-((2-Bromophenyl)thio)-6-iodo-4-methylaniline (7ah). Yellow
liquid (petroleum ether/EtOAc = 100:1); 66% (55.4 mg); 1H
NMR (400 MHz, CDCl3): δ 7.60 (d, J = 1.7 Hz, 1H), 7.52 (m, J =
7.9, 1.1 Hz, 1H), 7.27 (d, J = 1.3 Hz, 1H), 7.14−7.09 (m, 1H), 6.98
(m, J = 7.7, 1.5 Hz, 1H), 6.60 (m, J = 8.0, 1.4 Hz, 1H), 4.31 (s, 2H),
2.22 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 146.8, 142.0,
138.4, 137.3, 132.8, 129.5, 127.9, 126.5, 126.3, 120.7, 112.6, 83.8,
19.6; HRMS (MALDI) m/z: [M]+ calcd for C13H11BrINS, 418.8840;
found, 418.8842.
3-Methyl-10H-phenothiazine (5ah′, CAS: 3939-47-7).33,34 1H
NMR (400 MHz, DMSO): δ 8.45 (s, 1H), 6.95 (t, J = 7.6 Hz, 1H),
6.88 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.70 (d, J = 12.2
Hz, 2H), 6.65 (d, J = 7.9 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 2.11 (s,
3H); 13C {1H} NMR (100 MHz, DMSO): δ 142.8, 140.0, 131.1,
128.4, 127.9, 126.9, 126.68, 121.9, 116.7, 116.6, 114.7, 20.4.
7-Methylbenzo[5,6][1,4]thiazino[2,3,4-kl]phenothiazine
(6ar′).33,34 White solid (petroleum ether/EtOAc = 100:1); 65% (41.5
mg); 1H NMR (400 MHz, CDCl3): δ 7.21−7.14 (m, 4H), 7.09 (t, J =
7.2 Hz, 2H), 7.01 (t, J = 7.4 Hz, 2H), 6.79 (s, 2H), 2.20 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3): δ 142.7, 136.8, 134.7, 127.9, 127.3,
126.9, 126.0, 125.4, 124.4, 120.4, 20.4; HRMS (MALDI) m/z: [M]+
calcd for C19H13NS2, 319.0489; found, 319.0492.
2-((4-Fluorophenyl)thio)-6-iodo-4-methylaniline (7ab). Yellow
liquid (petroleum ether/EtOAc = 100:1); 63% (45.2 mg); 1H
NMR (400 MHz, CDCl3): δ 7.56−7.52 (m, 1H), 7.24 (d, J = 1.2 Hz,
ASSOCIATED CONTENT
1H), 7.11−7.06 (m, 2H), 6.98−6.91 (m, 2H), 4.39 (s, 2H), 2.20 (s,
■
1
3H); 13C {1H} NMR (100 MHz, CDCl3): δ 161.4 (C−F, JC−F
=
sı
* Supporting Information
4
245.7 Hz), 146.1, 141.2, 137.6, 131.0 (C−F, JC−F = 3.2 Hz), 129.4,
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02078.
3
2
129.0 (C−F, JC−F = 7.9 Hz), 116.2 (C−F, JC−F = 22.1 Hz), 114.7,
83.9, 19.6; 19F NMR (377 MHz, CDCl3): δ −116.34; HRMS
(MALDI) m/z: [M]+ calcd for C13H11FINS, 358.9641; found,
358.9641.
Full characterization data and copies of NMR spectral
data (PDF)
2-((4-Chlorophenyl)thio)-6-iodo-4-methylaniline (7ac). Yellow
liquid (petroleum ether/EtOAc = 100:1); 60% (45.2 mg); 1H
NMR (400 MHz, CDCl3): δ 7.56 (d, J = 1.3 Hz, 1H), 7.25 (d, J = 1.3
Hz, 1H), 7.21−7.17 (m, 2H), 7.02−6.98 (m, 2H), 4.59 (s, 2H), 2.20
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 146.34, 141.6, 137.9,
134.7, 131.6, 129.4, 129.2, 127.9, 113.5, 83.9, 19.6; HRMS (MALDI)
m/z: [M]+ calcd for C13H11ClINS, 374.9345; found, 374.9346.
2-((4-Bromophenyl)thio)-6-iodo-4-methylaniline (7ad). Yellow
liquid (petroleum ether/EtOAc = 100:1); 50% (42.0 mg); 1H
NMR (400 MHz, CDCl3): δ 7.56 (d, J = 1.1 Hz, 1H), 7.33 (d, J = 8.5
Hz, 2H), 7.25 (d, J = 1.0 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 4.60 (s,
2H), 2.20 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 146.4,
141.6, 137.9, 135.4, 132.1, 129.4, 128.1, 119.4, 113.3, 83.9, 19.6;
HRMS (MALDI) m/z: [M]+ calcd for C13H11BrINS, 418.8840;
found, 418.8842.
2-Iodo-4-methyl-6-(m-tolylthio)aniline (7ae). Yellow liquid (pe-
troleum ether/EtOAc = 100:1); 70% (49.7 mg); 1H NMR (400 MHz,
CDCl3): δ 7.54 (d, J = 1.3 Hz, 1H), 7.26 (d, J = 1.3 Hz, 1H), 7.12 (t, J
= 7.9 Hz, 1H), 6.95 (d, J = 6.5 Hz, 2H), 6.86 (d, J = 7.9 Hz, 1H), 4.31
(s, 2H), 2.28 (s, 3H), 2.20 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3): δ 146.4, 141.2, 138.9, 137.9, 135.8, 129.2, 129.0, 127.4,
126.8, 123.9, 114.3, 83.8, 21.4, 19.7; HRMS (ESI) [M + H]+ m/z
calcd for C14H15INS, 355.9964; found, 355.9969.
AUTHOR INFORMATION
■
Corresponding Authors
Feng Zhang − Key Laboratory for Green Organic Synthesis
and Application of Hunan Province, Key Laboratory of
Environmentally Friendly Chemistry and Application of
Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China; School of Chemistry
and Materials Science, Hunan Agricultural University,
Changsha 410128, China; Email: zhangf@iccas.ac.cn
Guo-Jun Deng − Key Laboratory for Green Organic Synthesis
and Application of Hunan Province, Key Laboratory of
Environmentally Friendly Chemistry and Application of
Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China; orcid.org/0000-
0003-2759-0314; Email: gjdeng@xtu.edu.cn
Author
Wenqi Zhao − Key Laboratory for Green Organic Synthesis
and Application of Hunan Province, Key Laboratory of
Environmentally Friendly Chemistry and Application of
Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China
2-Iodo-4-methyl-6-(o-tolylthio)aniline (7af). Yellow liquid (petro-
1
leum ether/EtOAc = 100:1); 65% (46.2 mg); H NMR (400 MHz,
CDCl3): δ 7.55 (d, J = 1.3 Hz, 1H), 7.20 (d, J = 1.3 Hz, 1H), 7.18−
7.14 (m, 1H), 7.09−7.00 (m, 2H), 6.74−6.70 (m, 1H), 4.22 (s, 2H),
2.40 (s, 3H), 2.19 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ
146.3, 141.1, 137.7, 135.4, 135.0, 130.2, 129.4, 126.7, 125.8, 125.6,
113.8, 83.8, 20.0, 19.7; HRMS (MALDI) m/z: [M]+ calcd for
C14H14INS, 354.9892; found, 354.9892.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02078
Notes
The authors declare no competing financial interest.
2-((2-Chlorophenyl)thio)-6-iodo-4-methylaniline (7ag). Yellow
liquid (petroleum ether/EtOAc = 100:1); 67% (50.3 mg); 1H
NMR (400 MHz, CDCl3): δ 7.60 (d, J = 1.4 Hz, 1H), 7.36−7.32 (m,
1H), 7.27 (d, J = 1.3 Hz, 1H), 7.09−7.04 (m, 2H), 6.66−6.61 (m,
1H), 4.54 (s, 2H), 2.22 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3):
δ 146.9, 142.0, 138.5, 135.4, 131.0, 129.6, 129.5, 127.3, 126.4, 126.3,
112.1, 83.8, 19.6; HRMS (MALDI) m/z: [M]+ calcd for
C13H11ClINS, 374.9345; found, 374.9346.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21871226 and 21572194) and the
China Postdoctoral Science Foundation (2018M632976 and
2019T120709).
I
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Article
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