Transition-Metal-Free and Oxidant-Free Cross-Coupling of Arylhydrazines with Disulfides: Base-Promoted Synthesis of Unsymmetrical Aryl Sulfides

Article abstract of DOI:10.1021/acs.joc.7b00767

A novel synthesis of unsymmetrical aryl sulfides, which requires no transition metal catalyst and no oxidant, was developed. This base-promoted cross-coupling reaction proceeded using arylhydrazines and 1 equiv amount of disulfides under inert gas conditions to afford the unsymmetrical aryl sulfides in good yields.

Full text of DOI:10.1021/acs.joc.7b00767

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Article
Transition-Metal-Free and Oxidant-Free Cross-Coupling of Arylhydrazines
with Disulfides: Base-Promoted Synthesis of Unsymmetrical Aryl Sulfides
Toshihide Taniguchi, Takuya Naka, Mitsutaka Imoto, Motonori Takeda, Takeo
Nakai, Masatoshi Mihara, Takumi Mizuno, Akihiro Nomoto, and Akiya Ogawa
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 15 Jun 2017
Downloaded from http://pubs.acs.org on June 15, 2017
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Transition-Metal-Free and Oxidant-Free Cross-Coupling of Arylhydrazines
with Disulfides: Base-Promoted Synthesis of Unsymmetrical Aryl Sulfides
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Toshihide Taniguchi,*,†,§ Takuya Naka,† Mitsutaka Imoto,† Motonori Takeda,† Takeo
Nakai,‡ Masatoshi Mihara,‡ Takumi Mizuno,*,‡ Akihiro Nomoto,§ and Akiya Ogawa§
† Seika Corporation, 1-1-82 Kozaika, Wakayama 641-0007, Japan
‡ Morinomiya Center, Osaka Research Institute of Industrial Science and Technology,
1-6-50 Morinomiya, Joto-ku, Osaka 536-8553, Japan
§ Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture
University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
Abstract Graphic
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ABSTRACT: A novel synthesis of unsymmetrical aryl sulfides, which requires no
transition metal catalyst and no oxidant, was developed. This base-promoted
cross-coupling reaction proceeded using arylhydrazines and one equivalent amount of
disulfides under inert gas conditions to afford the unsymmetrical aryl sulfides in good
yields.
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INTRODUCTION
Diaryl sulfides, which are used as pharmaceuticals, bioactive compounds, functional
polymer materials,1 and synthetic chemicals,2 have received considerable attention. In
particular, unsymmetrical aryl sulfides are of great importance as medicines for the
treatment of various medical conditions such as cancer, Alzheimer's, Parkinson's, AIDS,
neoplastic, HCV, diabetic, and parasitic diseases.3 The importance of diaryl sulfides in
biologically and pharmaceutically active compounds has sparked an increased interest
toward improving methodologies to form these unsymmetrical compounds.
One of the most popular synthetic methods of unsymmetrical diaryl sulfides is the
traditional Stadler−Ziegler reaction (Scheme 1),4 where aryl amines are converted into
the corresponding diazonium salts. These salts react with thiolates to yield
unsymmetrical diaryl sulfides. The Stadler−Ziegler reaction has also been applied to the
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industrial manufacturing of diaryl sulfides.5 Recently, a cross-coupling reaction of
diazonium salts with thiols using a SET photoredox catalyst was reported.6 In this
reaction, diazonium salts and diazosulfides are formed as key intermediates, which are
explosive and therefore their use is better avoided. 7
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Among the numerous synthetic methods for the aryl C−S bond formation, a powerful
approach is the transition-metal-catalyzed C−S coupling reaction. Hitherto, many
transition-metal-catalyzed systems including palladium,8 nickel,9 zinc,10 copper,11 iron,12
rhodium,13 silver,14 and iridium15 have been reported (Scheme 1). Although these
reports were great breakthroughs for the synthesis of unsymmetrical sulfides, these
transition-metal-catalyzed reactions usually need harsh conditions such as high
temperatures8−14 and microwave irradiation.11f Furthermore, high loadings of catalysts
bearing specially designed ligands and/or strong bases are often required, because the
strong coordination of thiolates to transition metal catalysts causes deactivation of the
catalysts.1b,16,17 Also, the tolerance of functional groups is limited due to the high
temperatures and strong bases required in these reactions.
Moreover, to apply these reactions to industrial scale production, researchers often
face the following problems: 1) Most of the transition metal catalysts, e.g., palladium
catalysts, are very expensive, and some of them are toxic; and 2) The removal of
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transition metal residues from the target products is very costly. Therefore, the
development of diaryl sulfide synthetic methods in the absence of transition metal
catalysts is strongly desired from a practical perspective.
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The formation of unsymmetrical aryl sulfides from diaryl disulfides, which are easy
to handle, and aryl radicals generated from diazonium salts under reducing conditions is
well-known.14,18 Moreover, the generation of aryl radicals from arylhydrazines under
oxidative conditions has been reported (homolytic aromatic substitution (HAS)
reaction),19 although, excess amounts of radical acceptors are generally required.
Furthermore, diaryl disulfides are easily oxidized under air in the presence of a base and
converted into benzenesulfonic acids.20
Herein, we report a transition-metal-free and oxidant-free cross-coupling reaction of
arylhydrazines with diaryl disulfides overcoming the above difficulties. To the best of
our knowledge, this is the first example of the synthesis of unsymmetrical diaryl sulfide
using arylhydrazines and one equivalent of diaryl disulfides under oxidant-free
conditions.
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Scheme 1. Synthesis of Unsymmetrical Diaryl Sulfides
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RESULTS AND DISCUSSION
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In the course of our previous studies on the cross-coupling of arylhydrazines with
aminoheterocycles21 and aromatic diamines,22 we examined the cross-coupling reaction
of 4-chlorophenylhydrazine hydrochloride (1a) with 4,4-dinitrodiphenyl disulfide (2a)
(Table 1). The coupling reaction of 1a with one equivalent of 2a in the presence of
potassium carbonate (2.0 equiv) in dimethyl sulfoxide (DMSO) occurred to afford
4-chlorophenyl 4-nitrophenyl sulfide (3aa) in 75% yield (Table 1, entry 1).
A shorter reaction time slightly lowered the yield of 3aa (Table 1, entry 1, footnote b).
When the amounts of 2a were decreased to 0.5 mmol and 0.75 mmol, the yields of 3aa
were lowered (Table 1, entry 1, footnotes c and d). However, increasing the amounts of
2a to 1.5 mmol and 2.0 mmol, the similar yields of 3aa were obtained (Table 1, entry 1,
footnotes e and f). Another solvents (DMF, DMA, MeCN, and MeOH) gave 3aa in
reduced yields (Table 1, entries 2-5).
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Using rubidium carbonate or cesium carbonate as base, 3aa was formed in similar
yields (Table 1, entries 6 and 7). However, the use of lithium carbonate or sodium
carbonate resulted in poor yields of 3aa (Table 1, entries 8 and 9).
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Table 1. Optimization of Synthesis of 3aa
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NO2
S
NHNH2
HCl
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Conditions
S
S
+
25 oC, 24 h
under air
Cl
NO2
Cl
O2N
1a, 1.0 mmol
3aa
2a, 1.0 mmol
entry
1
solvent (mL)
DMSO (10)
base (equiv)
K2CO3 (2.0)
yield (%)a
75, 42b, 44c, 63d,
77e, 74f
2
DMF (10)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
Rb2CO3 (2.0)
Cs2CO3 (2.0)
Li2CO3 (2.0)
Na2CO3 (2.0)
DBU (2.0)
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DMA (10)
MeCN (10)
MeOH (10)
DMSO (10)
DMSO (10)
DMSO (10)
DMSO (10)
DMSO (10)
DMSO (10)
DMSO (10)
DMSO (10)
DMSO (5)
DMSO (5)
DMSO (10)
DMSO (5)
DMSO (3)
DMSO (3)
DMSO (2)
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17
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74
7
73, 67g, 61h
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54
DABCO (2.0)
Et3N (2.0)
16
7
none
trace
69
K2CO3 (1.0)
Rb2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (0.5)
Cs2CO3 (1.0)
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72
79
82, 82i
5
81
Reaction conditions: 1a (1.0 mmol) and 2a (1.0 mmol) at 25 °C for 24 h under air.
aHPLC yields, calibration curve was shown in Figure S23. bReaction time was 18 h. c2a
(0.5 mmol). d2a (0.75 mmol). e2a (1.5 mmol), f2a (2.0 mmol). gReaction temperature was
35 °C. hReaction temperature was 80 °C for 1 hour. iIsolated yield.
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Higher reaction temperatures (35 °C and 80 °C for 1 hour) in the presence of cesium
carbonate as base gave slightly lowered the yields of 3aa (Table 1, entry 7, footnotes g
and h). When the reaction time was longer than 1 hour at 80 °C, a complex mixture such
as tar was formed.
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As to organic bases, DBU was effective in this cross-coupling reaction and gave 3aa
in 54% yield (Table 1, entry 10). The use of DABCO or triethylamine was ineffective
(Table 1, entries 11 and 12). In the absence of a base, 3aa was not obtained (Table 1,
entry 13).
The yields of 3aa decreased when one equivalent of K2CO3 or Rb2CO3 in 5 mL of
DMSO were used (Table 1, entries 14 and 15). Instead, in the presence of one
equivalent of Cs2CO3, desired 3aa was synthesized in good yield (Table 1, entry 17).
The best result was obtained under high concentrated conditions (DMSO, 3 mL), and
product 3aa was generated in 82% yield (Table 1, entry 18). Using 0.5 equivalent of
base resulted in a remarkable decrease of yield of 3aa (Table 1, entry 19). These results
show that the base plays an important role in this cross-coupling reaction. Reducing the
volume of solvent to 2 mL did not improve further the yield of 3aa (Table1, entry 20).
Surprisingly, 3aa was formed in 41% yield under an atmosphere of nitrogen (Table 2,
entry 1). Under these conditions the yield was further increased when the amount of
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DMSO was increased to 5mL, 7.5 mL, and 10 mL (Table 2, entries 2, 3, and 4), and
improved to 78% when the reaction time was increased (45 h) (Table 2, entry 4,
footnote b). A similar yield of 3aa was observed under an argon atmosphere (Table 2,
entry 4, footnote c) and the reaction also proceeded smoothly in DMF or DMA
(N,N-dimethylacetamide) under nitrogen or argon atmospheres (Table 2, entries 5 and 6).
These results strongly suggest that oxidants are not necessary for this cross-coupling
reaction. However, 3aa was hardly obtained when other solvents such as MeCN or
MeOH were employed under an argon atmosphere (Table 2, entries 7 and 8). These low
yields might be attributable to the very low solubility of 2a in MeCN or MeOH.
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Table 2. Synthesis of 3aa under Inert Gas
NO2
S
NHNH2
HCl
Conditions
S
S
+
25 oC, 24 h
Cl
NO2
Cl
O2N
under inert gas
1a, 1.0 mmol
3aa
2a, 1.0 mmol
entry
solvent (mL)
base (equiv)
yield (%)a
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8
DMSO (3)
DMSO (5)
DMSO (7.5)
DMSO (10)
DMF (10)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
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59
64, 78b, 70c
70b
65c
2c
Tracec
DMA (10)
MeCN (10)
MeOH (10)
Reaction conditions: 1a (1.0 mmol) and 2a (1.0 mmol) at 25 °C for 24 h under N2.
aHPLC yields. bReaction time was 45 h. cUnder argon atmosphere.
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With the optimized conditions in hand, the scope and limitations of the
cross-coupling reaction of 4-chlorophenylhydrazine hydrochloride (1a) with a series of
disulfides (2a−2k) were investigated (Table 3). The reaction of 1a with
3,3-dinitrodiphenyl disulfide (2b) provided compound 3ab in 75% yield. In the case of
2,2-dinitrodiphenyl disulfide (2c), the yield of 3ac was lower probably due to steric
effects. The reaction of 1a with a diaryl disulfide bearing an electron-donating group
such as methyl group provided 3ad in 30% yield under air. A similar yield of 3ad was
also observed under an argon atmosphere.
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The coupling reaction of 1a with 4,4-dihydroxydiphenyl disulfide (2e) having acidic
protons using 1.0 equiv or 3.0 equiv of cesium carbonate was performed to afford the
corresponding 3ae in moderate yields. However, the coupling reaction of 1a with
4,4-diaminodiphenyl disulfide gave a complicated mixture.
Additionally, the cross-coupling with heteroaryl disulfides was successful. Thus,
2,2-dibenzothiazolyl disulfide (2f) gave 3af in high yield (76%) and with 4,4-dipyridyl
disulfide (2g) 3ag was obtained in good yield. Instead, the use of 2,2-dipyridyl
disulfide (2h) resulted in a low yield (20%) of 3ah. Interestingly, in the case of the
2,2-dipyridyl disulfide derivative bearing a nitro group (2i), the coupling reaction
provided 3ai in excellent yield (93%). In addition, the coupling reactions with alkyl
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disulfides gave the corresponding unsymmetrical sulfides in good to high yields (3aj
and 3ak).
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Table 3. Cross-Coupling Reaction of 1a with Disulfides 2
Reaction conditions: 1a (1.0 mmol) and 2 (1.0 mmol) at 25 °C for 24 h under air.
aIsolated yields. bUnder argon atmosphere. cCesium carbonate (3.0 mmol) was used.
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Next, the cross-coupling between a variety of arylhydrazine hydrochlorides (1b−1k)
and several disulfides (2a, 2j, 2l, and 2m) was examined, and the results are
summarized in Table 4. The cross-coupling reaction of arylhydrazine hydrochlorides
bearing either electron-withdrawing groups (i.e., fluoro, bromo, cyano, and nitro
groups) or electron-donating groups (i.e., methyl group) with 4,4-dinitrodiphenyl
disulfide (2a) successfully afforded 3ba−3ga in good to excellent yields (55−94%).
However, the reaction of 4-methoxyphenylhydrazine hydrochloride having an
electron-donating group with 2a gave a complex mixture. Sulfide 3aa was synthesized
from 4-nitrophenylhydrazine hydrochloride (1h) and 4,4-dichlorodiphenyl disulfide
(2l) (67% under air and 59% under argon). Compound 1h was allowed to react with
diphenyl disulfide (2m) to afford 3da in good yield (62%).
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Using 4-nitrophenylhydrazine hydrochloride (1h) and dimethyl disulfide (2j), 3hj
was obtained in good yield (62%). Finally, the cross-coupling reaction could be applied
to more hindered dichlorophenylhydrazine hydrochlorides (1i−1k) with
4,4-dinitrodiphenyl disulfide (2a), giving the corresponding products (3ia−3ka) in good
yields.
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Table 4. Reaction of Arylhydrazines 1b−1k with Disulfides 2a, 2j, 2l, and 2m
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Reaction conditions: 1a (1.0 mmol) and 2 (1.0 mmol) at 25 °C for 24 h under air.
Isolated yields are shown. aUnder argon atmosphere.
Even in a large-scale reaction (20 mmol), the cross-coupling of 1a with 2a proceeded
smoothly to afford 3aa in 79% yield (Scheme 2).
Scheme 2. Large-Scale Reaction
To clarify the mechanistic pathway for the cross-coupling reaction of arylhydrazines
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with disulfides, a radical trapping experiment was performed. Thus, using
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) under argon in DMF, the 4-chlorophenyl
radical was trapped to afford 4 in 15% yield. Also, 3aa was formed in a reduced yield
(Scheme 3).
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Scheme 3. Radical Trapping Experiment with TEMPO
Next, the reaction of 4-chlorophenylhydrazine hydrochloride (1a) with two
equivalents of 4-nitrobenzenethiol (2a) instead of 4,4-nitrodiphenyl disulfide (2a) was
investigated (Scheme 4). The desired product 3aa was formed in a low yield (12%)
under argon atmosphere. This result suggests that disulfide 2a may formally act as an
oxidant.
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Scheme 4. Reaction of 4-Nitrobenzenethiol with 1a
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In summary, the generation of aryl radicals from arylhydrazines (HAS-type reaction)
was successfully achieved in the absence of any oxidant. The base-promoted
cross-coupling reaction of arylhydrazines with one equivalent of disulfides under inert
gas provides unsymmetrical aryl sulfides in good yields. This rare HAS-type reaction
provides a practical synthesis of unsymmetrical aryl sulfides.
EXPERIMENTAL SECTION
General Information. All the starting materials were purchased from commercial
sources and used without further purification. IR spectra were reported in wave numbers
1
(cm−1). H NMR spectra were recorded on a 400 MHz spectrometer using CDCl3 or
DMSO-d6 as solvent referenced to TMS (0 ppm) and CHCl3 (7.26 ppm) or DMSO (2.50
ppm). 13C NMR spectra were recorded at 100 MHz in CDCl3 and DMSO-d6 using
CDCl3 (77.0 ppm) and DMSO-d6 (39.5 ppm) as standards. Chemical shifts are reported
in parts per million (ppm). Coupling constants are in reported in hertz (J, Hz). The
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following abbreviations are used for the description of signals: s (singlet), d (doublet), t
(triplet), q (quadruplet), and m (multiplet). Exact mass spectra were recorded using
direct analysis in real time (DART-TOFMS). Analytical TLC was carried out on silica
gel plates using short wave (254 nm) UV light. Silica gel (230−400 mesh) was used for
column chromatography.
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General Procedure for the Synthesis of Unsymmetrical Aryl Sulfide 3. A
mixture of arylhydrazine hydrochlorides 1 (1.0 mmol), disulfides 2 (1.0 mmol), and
cesium carbonate (326 mg, 1.0 mmol) in DMSO (3.0 mL) was stirred at 25 °C in air.
The reactions were monitored by thin layer chromatography (TLC) and upon
completion (24 h) quenched by the addition of water. Then, the reaction mixtures were
extracted with ethyl acetate. The organic layer was washed with water and brine and
dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give
crude products, which were purified by column chromatography (inner diameter: 3.0 cm
and length: 30 cm) over silica gel (hexane/AcOEt) to afford pure products.
4-Chlorophenyl 4-nitrophenyl sulfide (3aa). Compound 3aa was synthesized
from 4-chlorophenylhydrazine hydrochloride (1a) (179 mg, 1.0 mmol) and
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4,4-dinitrodiphenyl disulfide (2a) (308 mg, 1.0 mmol) according to the general
procedure. Purification by column chromatography (hexane/AcOEt = 95:5) and
recrystallization from hexane/AcOEt (9:1) gave 3aa (218 mg, 0.82 mmol, 82%) as a
pale yellow block crystal; Rf = 0.44 (hexane/AcOEt = 95:5) (UV); mp 84.5−85.5 °C
(Lit.23 83−84 °C); FT-IR (neat) 3091, 3059, 1502, 1331, 1078, 845 cm−1; 1H NMR (400
MHz, DMSO-d6) 7.32 (d, J = 8.9 Hz, 2H), 7.59 (s, 4H), 8.14 (d, J = 8.9 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) 124.4, 127.3, 129.0, 130.3, 134.8, 136.0, 145.3, 146.7;
HRMS (DART-TOFMS) calcd for C12H8ClNO2S [M+]: 264.9964, found: 264.9944.
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4-Chlorophenyl 3-nitrophenyl sulfide (3ab). Compound 3ab was prepared from
4-chlorophenylhydrazine hydrochloride (1a) (179 mg, 1.0 mmol) and
3,3-dinitrodiphenyl disulfide (2b) (308 mg, 1.0 mmol) according to the general
procedure. Purification by column chromatography (hexane/AcOEt = 95:5) and
recrystallization from hexane/AcOEt (9:1) gave 3ab (198 mg, 0.75 mmol, 75%) as a
pale yellow needle; Rf = 0.34 (hexane/AcOEt = 95:5) (UV); mp 70.5−71.5 °C
(Lit.2470−71 °C); FT-IR (neat) 3083, 3066, 1521, 1343, 727 cm−1; 1H NMR (400 MHz,
DMSO-d6)  7.50-7.55 (m, 4H), 7.64 (t, J = 8.2 Hz, 1H), 7.69 (td, J = 1.6 Hz, J = 8.2 Hz,
13
1H), 7.97 (t, J = 1.6 Hz, 1H), 8.10 (ddd, J = 1.6 Hz, J = 2.3 Hz, J = 8.2 Hz, 1H); C
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NMR (100 MHz, DMSO-d6)  121.8, 123.0, 130.0, 130.9, 131.1, 133.8, 134.3, 135.3,
138.2, 148.4; HRMS (DART-TOFMS) calcd for C12H8ClNO2S [M+]: 264.9964, found:
264.9943.
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4-Chlorophenyl 2-nitrophenyl sulfide (3ac). Compound 3ac was prepared
according to the general procedure using 4-chlorophenylhydrazine hydrochloride (1a)
(179 mg, 1.0 mmol) and 2,2-dinitrodiphenyl disulfide (2c) (308 mg, 1.0 mmol).
Purification by column chromatography (hexane/AcOEt = 95:5) and recrystallization
from hexane/AcOEt (9:1) gave 3ac (105 mg, 0.40 mmol, 40%) as a pale orange needle.
Rf = 0.22 (hexane/AcOEt = 95:5) (UV); mp 96.0−97.0 °C (Lit.25 94−96 °C); FT-IR
(neat) 3100, 1504, 1303, 1091 cm−1; 1H NMR (400 MHz, DMSO-d6)  6.91 (dd, J = 1.4
Hz, J = 8.2 Hz, 1H), 7.42 (dt, J = 1.4 Hz, J = 8.2 Hz, 1H), 7.58−7.65 (m, 5H), 8.25 (dd,
13
J = 1.4 Hz, J = 8.2 Hz, 1H); C NMR (100 MHz, DMSO-d6)  125.8, 126.4, 128.5,
129.4, 130.4, 134.5, 135.3, 136.6, 137.0, 145.0; HRMS (DART-TOFMS) calcd for
C12H8ClNO2S [M+]: 264.9964, found: 264.9947.
4-Chlorophenyl 4-tolyl sulfide (3ad). The mixture of 4-chlorophenylhydrazine
hydrochloride (1a) (179 mg, 1.0 mmol), 4,4-ditolyl disulfide (2d) (246 mg, 1.0 mmol),
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and cesium carbonate (1.0 equiv) in DMSO (3 mL) provided the desired 3ad (71 mg,
0.30 mmol, 30% in air, and 86 mg, 0.37 mmol, 37% under argon). Recrystallization
from hexane, gave 3ad as a white solid; Rf = 0.40 (hexane) (UV); mp 71.5−72.5 °C
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(Lit.24 70−71 °C); FT-IR (neat) 2917, 1472, 1085, 804 cm−1; H NMR (400 MHz,
DMSO-d6)  2.31 (s, 3H), 7.20 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.31 (d, J =
13
8.0 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H); C NMR (100 MHz, DMSO-d6)  20.7, 129.3,
129.4, 130.5, 130.5, 131.2, 132.5, 135.7, 138.2; HRMS (DART-TOFMS) calcd for
C13H11ClS [M+]: 234.0270, found: 234.0255.
4-Chlorophenyl 4-hydroxyphenyl sulfide (3ae). Following the general procedure,
compound 3ae was synthesized from 4-chlorophenylhydrazine hydrochloride (1a) (179
mg, 1.0 mmol) and 4,4-dihydroxydiphenyl disulfide (2e) (250 mg, 1.0 mmol).
Purification by column chromatography (hexane/AcOEt = 2:1) afforded 3ae (138 mg,
0.58 mmol, 58%) as an orange solid; Rf = 0.50 (hexane/AcOEt = 2:1) (UV); mp
1
66.0−67.5 °C (Lit.26 54−55 °C); FT-IR (neat) 3283, 1582, 1489, 1092, 810 cm−1; H
NMR (400 MHz, DMSO-d6) 6.85 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.33
(d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 9.95 (bs, 1H); 13C NMR (100 MHz,
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DMSO-d6)  116.9, 119.6, 128.4, 129.0, 130.1, 136.3, 138.0, 158.6; HRMS
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(DART-TOFMS) calcd for C12H9ClOS [M+]: 236.0063, found: 236.0039.
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2-[(4-Chlorophenyl)thio]benzothiazole (3af). The desired product 3af was
synthesized from 4-chlorophenylhydrazine hydrochloride (1a) (179 mg, 1.0 mmol) and
2,2'-dibenzothiazolyl disulfide (2f) (332 mg, 1.0 mmol) according to the general
procedure. Purification by column chromatography (hexane/AcOEt = 4:1) and
recrystallization form hexane/AcOEt (9:1), gave 3af (211 mg, 0.76 mmol, 76%) as a
colorless plate crystal; Rf = 0.60 (hexane/AcOEt=4:1) (UV); mp 59.0−60.0 °C (Lit.27
1
60−61 °C); FT-IR (neat) 3079, 3058, 1454, 1390, 747, 723 cm−1; H NMR (400 MHz,
DMSO-d6)  7.36 (dt, J = 1.2 Hz, J = 7.6 Hz, 1H), 7.47 (dt, J = 1.2 Hz, J = 7.6 Hz, 1H),
7.65 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 7.84−7.87 (m, 1H), 7.96 (dd, J = 1.2
Hz, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) 121.5, 121.8, 124.7, 126.5,
127.9, 130.3, 134.9, 137.0, 153.3; HRMS (DART-TOFMS) calcd for C13H9ClNS2 [M +
H+]: 277.9859, found: 277.9839.
4-[(4'-Chlorophenyl)thio]pyridine (3ag). Compound 3ag was obtained from
4-chlorophenylhydrazine hydrochloride (1a) (179 mg, 1.0 mmol) and 4,4-dipyridyl
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disulfide (2g) (220 mg, 1.0 mmol) according to the general procedure. Purification by
column chromatography (hexane/AcOEt = 2:3) gave 3ag (144 mg, 0.65 mmol, 65%) as
a brown solid; Rf = 0.40 (hexane/AcOEt = 2:3) (UV); mp 56.5−57.5 °C; FT-IR (neat)
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3035, 1567, 1474, 1403, 1087, 822, 802 cm−1; H NMR (400 MHz, DMSO-d6) 7.04
(dd, J = 1.6 Hz, J = 4.6 Hz, 2H), 7.59 (s, 4H), 8.38 (dd, J = 1.6 Hz, J = 4.6 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) ; HRMS
(DART-TOFMS) calcd for C11H9ClNS [M + H+]: 222.0139, found: 222.0126.
2-[(4'-Chlorophenyl)thio]pyridine (3ah). Following the general procedure,
compound 3ah was synthesized from 4-chlorophenylhydrazine hydrochloride (1a) (179
mg, 1.0 mmol) and 2,2-dipyridyl disulfide (2h) (220 mg, 1.0 mmol). Purification by
column chromatography (hexane/AcOEt = 4:1) afforded 3ah (44 mg, 0.20 mmol, 20%)
as a brown oil; Rf = 0.50 (hexane/AcOEt = 4:1) (UV); FT-IR (neat) 3044, 2987, 1572,
1415, 1085, 755, 746 cm−1; 1H NMR (400 MHz, DMSO-d6) 7.04 (td, J = 0.8 Hz, J =
8.0 Hz, 1H), 7.17 (ddd, J = 0.8 Hz, J = 4.4 Hz, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H),
7.58 (d, J = 8.4 Hz, 2H), 7.67 (dt, J = 2.0 Hz, J = 8.0 Hz, 1H), 8.40 (ddd, J = 0.8 Hz, J =
2.0 Hz, J = 4.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) 120.8, 121.5, 129.3, 129.8,
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134.1, 136.2, 137.5, 149.7, 158.9; HRMS (DART-TOFMS) calcd for C11H9ClNS [M +
H+]: 222.0139, found: 222.0120.
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2-[(4'-Chlorophenyl)thio]-5-nitropyridine
(3ai).
The
reaction
of
4-chlorophenylhydrazine hydrochloride (1a) (179 mg, 1.0 mmol) with
2,2-dithiobis(5-nitropyridine) (2i) (310 mg, 1.0 mmol) was performed according to the
general procedure to afford compound 3ai. Purification by column chromatography
(hexane/AcOEt = 4:1) and recrystallization from hexane/AcOEt (9:1) gave 3ai (249 mg,
0.93 mmol, 93%) as white needles; Rf = 0.50 (hexane/AcOEt = 4:1) (UV); mp
136.0−137.5 °C (Lit.28 136−138 °C); FT-IR (neat) 3053, 1568, 1508, 1343, 1089, 822,
1
747 cm−1; H NMR (400 MHz, DMSO-d6)  7.21 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 8.7
Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 8.40 (dd, J = 2.8 Hz, J = 9.0 Hz, 1H), 9.18 (d, J = 2.8
13
Hz, 1H); C NMR (100 MHz, DMSO-d6)  120.5, 127.0, 130.2, 132.3, 135.4, 137.1,
141.6, 145.0, 167.5; HRMS (DART-TOFMS) calcd for C11H8ClN2O2S [M + H+]:
266.9990, found: 266.9968.
1-Chloro-4-(methylthio)benzene (3aj). Compound 3aj was obtained from
4-chlorophenylhydrazine hydrochloride (1a) (179 mg, 1.0 mmol) and dimethyl disulfide
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(2j) (94 mg, 1.0 mmol) according to the general procedure. The crude product was
purified by column chromatography using hexane and 3aj (128 mg, 0.81 mmol, 81%)
was obtained as a colorless oil; Rf = 0.30 (hexane) (UV); FT-IR (neat) 2984, 2919, 1474,
1093, 1010, 806 cm−1; 1H NMR (400 MHz, CDCl3)  2.47 (s, 3H), 7.18 (d, J = 8.5 Hz,
2H), 7.25 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) 16.1, 127.9, 128.9, 130.9,
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137.0; HRMS (DART-TOFMS) calcd for C7H7ClS [M+]: 157.9957, found: 157.9960.
1-Chloro-4-(ethylthio)benzene (3ak). Compound 3ak was prepared from
4-chlorophenylhydrazine hydrochloride (1a) (179 mg, 1.0 mmol) and diethyl disulfide
(2k) (122 mg, 1.0 mmol) according to the general procedure. The resulting crude
reaction mixture was purified by column chromatography using hexane to give the
corresponding product 3ak (107 mg, 0.62 mmol, 62%) as a colorless oil; Rf = 0.36
1
(hexane) (UV); FT-IR (neat) 2973, 2927, 2870, 1474, 1093, 1010, 809 cm−1; H NMR
(400 MHz, CDCl3) 1.30 (t, J = 7.4 Hz, 3H), 2.92 (q, J = 7.4 Hz, 2H), 7.25 (s, 4H); 13C
NMR (100 MHz, CDCl3)  14.2, 27.9, 128.9, 130.3, 131.7, 135.1; HRMS
(DART-TOFMS) calcd for C8H9ClS [M+]: 172.0113, found: 172.0113.
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4-Fluorophenyl 4-nitrophenyl sulfide (3ba). According to the general procedure,
compound 3ba was synthesized from 4-fluorophenylhydrazine hydrochloride (1b) (163
mg, 1.0 mmol) and 4,4-dinitrodiphenyl disulfide (2a) (308 mg, 1.0 mmol). The crude
mixture was purified by column chromatography (hexane/AcOEt = 95:5) and
recrystallized from hexane to give 3ba (206 mg, 0.83 mmol, 83%) as a pale yellow
sticky crystal; Rf = 0.32 (hexane/AcOEt = 95:5) (UV); mp 97.4−98.4 °C (Lit.29
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97−99 °C); FT-IR (neat) 3091, 1502, 1332, 1077, 831 cm−1; H NMR (400 MHz,
DMSO-d6) 7.26 (d, J = 9.0 Hz, 2H), 7.40 (dd, JHF = 9.0 Hz, J = 9.0 Hz, 2H), 7.68 (dd,
JHF = 5.4 Hz, J = 9.0 Hz, 2H), 8.13 (d, J = 9.0 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) 117.5 (d, JCF = 22.9 Hz), 124.3, 125.1, 126.5, 137.4 (d, JCF = 8.6 Hz),
145.0, 147.7, 163.1 (d, JCF = 246.9 Hz); HRMS (DART-TOFMS) calcd for
C12H8FNO2S [M+]: 249.0260, found: 249.0237.
4-Bromophenyl
4-nitrophenyl
sulfide
(3ca).
The
reaction
of
4-bromophenylhydrazine hydrochloride (1c) (224 mg, 1.0 mmol) with
4,4-dinitrodiphenyl disulfide (2a) (308 mg, 1.0 mmol) was carried out according to the
general procedure to provide the desired compound 3ca (220 mg, 0.71 mmol, 71%) as a
pale yellow block crystal after column chromatography (hexane) and recrystallization
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from hexane; Rf = 0.22 (hexane) (UV); mp 94.0−95.0 °C (Lit.30 94−96 °C); FT-IR (neat)
3092, 1504, 1334, 1008, 845, 742 cm−1; 1H NMR (400 MHz, DMSO-d6)  7.33 (d, J =
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9.2 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 9.2 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) d 123.4, 124.4, 127.4, 129.6, 133.2, 136.1, 145.3,
146.5; HRMS (DART-TOFMS) calcd for C12H8BrNO2S [M+]: 308.9459, found:
308.9447.
4-Nitrophenyl phenyl sulfide (3da). Compound 3da was prepared from
phenylhydrazine hydrochloride (1d) (145 mg, 1.0 mmol) and 4,4-dinitrodiphenyl
disulfide (2a) (308 mg, 1.0 mmol) according to the general procedure. Purification by
column chromatography (hexane) and recrystallization from hexane/AcOEt (9:1) gave
3da (196 mg, 0.85 mmol, 85%) as a pale orange plate crystal; Rf = 0.18 (hexane) (UV);
mp 55.0−56.0 °C (Lit.23 54−55 °C); FT-IR (neat) 3096, 3052, 1501, 1333, 741 cm−1; 1H
NMR (400 MHz, DMSO-d6)  7.27 (d, J = 8.9 Hz, 2H), 7.52-7.59 (m, 5H), 8.12 (d, J =
8.9 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)  124.3, 126.8, 129.7, 129.9, 130.3, 134.4,
145.0, 147.5; HRMS (DART-TOFMS) calcd for C12H10NO2S [M+H+]: 232.0427,
found: 232.0408.
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4-Nitrophenyl 4-tolyl sulfide (3ea). Compound 3ea was synthesized from
4-tolylhydrazine hydrochloride (1e) (159 mg, 1.0 mmol) and 4,4-dinitrodiphenyl
disulfide (2a) (308 mg, 1.0 mmol) according to the general procedure. Purification by
column chromatography (hexane) and recrystallization from hexane/AcOEt (9:1) gave
3ea (188 mg, 0.77 mmol, 77%) as pale yellow needles; Rf = 0.30 (hexane) (UV); mp
80.0−81.0 °C (Lit.24 78−79 °C); FT-IR (neat) 1508, 1338, 811, 738 cm−1; 1H NMR (400
MHz, DMSO-d6)  7.23 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.8
Hz, 2H), 8.12 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)  20.8, 124.3, 125.8,
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126.2, 131.0, 134.9, 140.1, 144.8, 148.4; HRMS (DART-TOFMS) calcd for
C13H11NO2S [M+]: 245.0510, found: 245.0507.
4-Cyanophenyl 4-nitrophenyl sulfide (3fa). Following the general procedure,
compound 3fa was obtained from 4-cyanophenylhydrazine hydrochloride (1f) (170 mg,
1.0 mmol) and 4,4-dinitrodiphenyl disulfide (2a) (308 mg, 1.0 mmol). The crude
mixture was purified by column chromatography with hexane/AcOEt = 4:1 to afford the
desired compound 3fa (140 mg, 0.55 mmol, 55%). Recrystallization from
hexane/AcOEt (9:1) afforded 3fa as pale yellow needles; Rf = 0.46 (hexane/AcOEt =
4:1) (UV); mp 153.5−154.5 °C (Lit.31 153−154 °C); FT-IR (neat) 3086, 2227, 1572,
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1499, 1336, 825 cm−1; 1H NMR (400 MHz, DMSO-d6)  7.55 (d, J = 9.2 Hz, 2H), 7.60
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(d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 9.2 Hz, 2H); C NMR (100
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MHz, DMSO-d6)  110.8, 118.3, 124.6, 130.5, 131.9, 133.5, 139.2, 142.9, 146.4;
HRMS (DART-TOFMS) calcd for C13H8N2O2S [M+]: 256.0306, found: 256.0288.
3-Nitrophenyl 4-nitrophenyl sulfide (3ga).18a Compound 3ga was obtained from
3-nitrophenylhydrazine hydrochloride (1g) (190 mg, 1.0 mmol) and 4,4-dinitrodiphenyl
disulfide (2a) (308 mg, 1.0 mmol) according to the general procedure. Purification by
column chromatography (hexane/AcOEt = 7:1) afforded the desired product 3ga (258
mg, 0.94 mmol, 94%) as a yellow powder; Rf = 0.23 (hexane/AcOEt = 7:1) (UV); mp
122.0−123.0 °C (decomp.); FT-IR (neat) 3088, 1540, 1512, 1337, 1315, 850, 841, 738
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cm−1; H NMR (400 MHz, DMSO-d6)  7.84 (t, J = 7.9 Hz, 1H), 8.06 (d, J = 9.2 Hz,
2H), 8.11 (ddd, J = 0.8 Hz, J = 2.0 Hz, J = 7.9 Hz, 1H), 8.31 (t, J = 2.0 Hz, 1H),
8.34−8.38 (m, 3H); 13C NMR (100 MHz, DMSO-d6)  115.8, 124.4, 125.2, 128.1, 128.5,
131.2, 142.1, 147.2, 148.6, 151.3; HRMS (DART-TOFMS, neg) calcd for C12H7N2O4S
[M − H+]: 275.0132, found: 275.0149.
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4-(Methylthio)nitrobenzene (3hj). Following the general procedure, compound 3hj
was synthesized from 4-nitrophenylhydrazine hydrochloride (1h) (190 mg, 1.0 mmol)
and dimethyl disulfide (2j) (94 mg, 1.0 mmol). Purification by column chromatography
(hexane/AcOEt =9:1) and recrystallization from hexane gave 3hj (105 mg, 0.62 mmol,
62%) as a pale brown plate crystal; Rf = 0.30 (hexane/AcOEt = 9:1) (UV); mp
69.4−70.4 °C (Lit.32 65−67 °C); FT-IR (neat) 3092, 3001, 2915, 1583, 1505, 1330, 1092,
829, 737 cm−1; 1H NMR (400 MHz, DMSO-d6)  2.59 (s, 3H), 7.47 (d, J = 8.7 Hz, 2H),
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8.14 (d, J = 8.7 Hz, 2H); C NMR (100 MHz, DMSO-d6)  14.0, 123.8, 125.3, 144.1,
149.0; HRMS (DART-TOFMS) calcd for C7H7NO2S [M+]: 169.0197, found: 169.0195.
3,4-Dichlorophenyl 4-nitrophenyl sulfide (3ia). Compound 3ia was obtained
from 3,4-dichlorophenylhydrazine hydrochloride (1i) (214 mg, 1.0 mmol) and
4,4-dinitrodiphenyl disulfide (2a) (308 mg, 1.0 mmol) according to the general
procedure. The crude product was purified by column chromatography (hexane/AcOEt
= 95:5) and recrystallized from hexane/AcOEt (9:1) to give 3ia (251 mg, 0.84 mmol,
84%) as white needles; Rf = 0.22 (hexane/AcOEt = 95:5) (UV); mp 110.0−111.0 °C;
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(400 MHz, DMSO-d6)  7.41 (d, J = 8.9 Hz, 2H), 7.53 (dd, J = 2.3 Hz, J = 8.2 Hz, 1H),
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145.6; HRMS (DART-TOFMS) calcd for C12H7Cl2NO2S [M+]: 298.9575, found:
298.9550.
2,4-Dichlorophenyl 4-nitrophenyl sulfide (3ja). Compound 3ja was synthesized
from 2,4-dichlorophenylhydrazine hydrochloride (1j) (214 mg, 1.0 mmol) and
4,4-dinitrodiphenyl disulfide (2a) (308 mg, 1.0 mmol) according to the general
procedure. Purification by column chromatography (hexane/AcOEt = 95:5) and
recrystallization from hexane/AcOEt (9:1) gave 3ja (198 mg, 0.66 mmol, 66%) as a
pale brown block crystal; Rf = 0.20 (hexane/AcOEt = 95:5) (UV); mp 76.0−77.0 °C;
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MHz, DMSO-d6)  7.35 (d, J = 8.9 Hz, 2H), 7.56 (dd, J = 2.3 Hz, J = 8.5 Hz, 1H), 7.66
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(d, J = 8.5 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 8.9 Hz, 2H); C NMR (100
MHz, DMSO-d6)  124.5, 127.9, 128.5, 128.9, 130.3, 135.6, 137.2, 138.0, 144.3, 145.7;
HRMS (DART-TOFMS) calcd for C12H7Cl2NO2S [M+]: 298.9575, found: 298.9549.
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