Aerobic Oxidative Sulfenylation of Pyrazolones and Pyrazoles Catalyzed by Metal-Free Flavin-Iodine Catalysis

Article abstract of DOI:10.1021/acs.joc.9b02422

Two-component metal-free catalytic oxidative sulfenylation of pyrazolones with thiols has been achieved using the biomimetic flavin and iodine. The methodology is mild and eco-friendly, proceeds in the presence of air or molecular oxygen (1 atm) as the sole sacrificial reagent, and generates water as the only byproduct. The methodology was also extended to the sulfenylation of pyrazoles and electron-rich benzenes and afforded a series of thioethers in good yields.

Full text of DOI:10.1021/acs.joc.9b02422

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Note
Aerobic Oxidative Sulfenylation of Pyrazolones and
Pyrazoles Catalyzed by Metal-Free Flavin–Iodine Catalysis
Kazumasa Tanimoto, Ryoma Ohkado, and Hiroki Iida
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02422 • Publication Date (Web): 22 Oct 2019
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The Journal of Organic Chemistry
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Aerobic Oxidative Sulfenylation of Pyrazolones and Pyrazoles
Catalyzed by Metal-Free Flavin–Iodine Catalysis
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Kazumasa Tanimoto, Ryoma Ohkado, and Hiroki Iida*
Department of Chemistry, Graduate School of Natural Science and Technology, Shimane
University, 1060 Nishikawatsu, Matsue 690-8504, Japan
ABSTRACT: Two-component metal-free catalytic oxidative sulfenylation of pyrazolones with
thiols has been achieved using the biomimetic flavin and iodine. The methodology is mild and
eco-friendly, and proceeds in the presence of air or molecular oxygen (1 atm) as the sole
sacrificial reagent, and generates water as the only by-product. The methodology was also
extended to the sulfenylation of pyrazoles and electron-rich benzenes and afforded a series of
thioethers in good yields.
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Pyrazoles and their derivatives are an important class of aza-heterocycles, which
display a wide range of pharmacological and biological activities.1 Notably, commercially
available drugs and agrochemicals such as Crizotinib (anticancer),2 Sildenafil (erectile
dysfunction therapeutic),3 Celecoxib (anti-inflammatory),4 and Fipronil (agricultural
insecticide)5 contain the pyrazole skeleton (Figure 1). Due to their widespread applications in
medicinal chemistry, considerable efforts have been devoted toward the synthesis and
functionalization of pyrazoles.6,7 Among them, the sulfenylation of pyrazolones and pyrazoles
by direct C-H functionalization has attracted increasing attention, due to the crucial
contribution of C-S bond incorporation toward imparting diversity to pharmaceutical and
material science-relevant molecules.8 Indeed, sulfur-containing pyrazole derivatives have been
recognized as promising candidates for medicinal and agrochemical compounds,9 e.g.
Sildenafil,3 Celecoxib,4 Fipronil,5 potent anti-inflammatory agent I,9d and fungicidal active agent
II9e (Figure 1).
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Figure 1. Biologically active pyrazole derivatives.
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Several reagents have been reported for the direct sulfenylation of C-H bonds, such as
thiols, disulfides, sulfenyl halides, sulfonyl hydrazides, sulfonyl cyanides, sulfinates, sulfinic
acid, and 1-(substituted phenylthio)pyrrolidine-2,5-dione.8,10 However, most of these C-H
sulfenylation reagents require moisture-free reaction conditions or involve multiple synthetic
manipulations. Since thiols are the simplest, most atom-economical, and readily available
sulfenylation reagents, the thiol-mediated oxidative sulfenylation has emerged as a highly
reliable strategy for a variety of substrates. However, methods for the sulfenylation of
pyrazolones11 and pyrazoles12 with thiols have been rather limited. Despite their potential
advantages, these reported methods typically involve harsh reaction conditions and may
require the use of expensive transition metal catalysts, and/or a stoichiometric amount of a base
or oxidant.11,12 The use of ambient molecular oxygen as the sole sacrificial reagent for oxidative
sulfenylation would be an ideal approach because molecular oxygen is an atom-economical and
low-polluting green oxidant which generates the non-hazardous water as the byproduct.13 The
recent demand for green and sustainable oxidative transformations has driven the use of
ambient molecular oxygen in these processes. However, to the best of our knowledge, eco-
friendly approaches to oxidative pyrazolone and pyrazole sulfenylation using molecular
oxygen have not been reported.
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Recently, we reported the development of a novel strategy for green metal-free
oxidation by coupling flavin and iodine catalysis, which enabled the use of molecular oxygen
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15,16
as a terminal oxidant.14 By the activation of O2
under biomimetic flavin organocatalysis,
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formation thiadiazole rings by the reaction of N-tosylhydrazones with sulfur14a was successfully
achieved using the two-component catalysis system under aerobic conditions, and the
sulfenylation was further extended to the reaction of indole analogs with thiols.14b,c Building on
the successes of these flavin-iodine coupled catalyses, we report herein, the first examples of the
oxidative sulfenylations of pyrazolones and pyrazoles using molecular oxygen as the sole
sacrificial reagent. Importantly, this methodology meets the growing demand for the
development of green chemical transformations.
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We began our study by probing the sulfenylation of 3-methyl-1-phenyl pyrazolone 1a
with p-tolyl thiol (2a) in the presence of I2 and a flavin catalyst, and found that the I2 and
riboflavin-derived alloxazinium salt (4•TfO) smoothly promoted the catalytic oxidative
sulfenylation of 1a in CH3CN, under an atmosphere of molecular oxygen to furnish the
corresponding sulfenyl pyrazole 3a (the effect of solvents and iodine sources was summarized
in Table S1, Supporting Information). Further optimization of the reaction conditions revealed
that the sulfenylation proceeded in excellent yield in the presence of 3 mol% of 4•TfO and 5
mol% of I2 in CH3CN at 25 ˚C and afforded the products in an excellent yield after 8 h (Table 1,
entry 1). To our delight, a 90% yield of the products was obtained by using air (1 atm) as the
terminal oxidant (entry 2), which indicated that the concentration of molecular oxygen in air
was sufficient for this sulfenylation to proceed at a reasonable rate under the present mild
condition.
Table 1. Catalytic sulfenylation of 1a with 2a under various conditionsa
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iodine
source
(mol%)
I2 (5)
I2 (5)
I2 (5)
None
I2 (5)
I2 (120)
I2 (5)
flavin
(mol%)
atmospher
e
entry
time (h) yield (%)
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4•TfO
4•TfO
None
O2
air
O2
O2
N2
N2
air
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94
90
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4•TfO
4•TfO
None
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0.5
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9 (91) b
(3)
8 c
4•TfO
I2 (5)
air
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93
(3)
aConditions: 1a (1.0 M), 2a (1.1 M), 4•TfO, I2, and CH3CN under air, O2, or N2 atmosphere (1 atm) at 25 °C. Yield was
determined by 1H NMR using 1,3,5-trioxane as an internal standard. bYield of disulfide 5a calculated on the bases of 2a. c5a
(0.55 M) was used instead of 2a.
Having optimized the reaction conditions, we surveyed the substrate scope and
limitations of the present methodology (Table 2). A series of aryl thiols bearing electron
donating and withdrawing groups successfully reacted with pyrazolone generally at 25 ˚C
under air and provided the corresponding sulfenylated products (3a-3g) in 85-98% yields, while
the synthesis of 3d was performed at 40 ˚C under molecular oxygen (1 atm) due to the poor
solubility of 2d. Because the sulfenylation with electron rich thiols such as benzyl thiol (2h) was
relatively slower than that with electron poor thiols, slightly higher temperature (40 ˚C) and
molecular oxygen (1 atm) was used to promote the sulfenylation, thus gave the corresponding
product 3f in 71% yield. On the other hand, the reaction with alkyl thiol (2i) was sluggish (3i)
probably due to the poor electrophilicity of the corresponding iodine adduct as described later.
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Pyrazolones bearing various substituents also underwent the sulfenylation to yield the desired
products (3j-3n) in 89-98% yields. It is noteworthy that amino, chloro, and bromo functional
groups are tolerated (3c, 3e, 3f, and 3m) under the present reaction condition. The
chemoselectivity of the transformation results from the efficient O2-activation catalysis of flavin,
that enables mild oxidative sulfenylation in the absence of stoichiometric quantities of strong
oxidants.
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Table 2. Aerobic sulfenylation of pyrazolonesa
aConditions: 1 (1.0 M), 2 (1.1 M), 4•TfO (3 mol%), I2 (5 mol%), and CH3CN under air or O2 (1 atm) at 25 °C. bAt 40 °C.
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With the assessment of the scope and limitations of the developed process complete,
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we conducted a series of control experiments to gain insight into the sulfenylation reaction. The
reaction of 1a with 2a in the absence of 4·TfO, I2, or molecular oxygen was studied, and the
sulfenylated product 3a was obtained only in a trace quantity in each of these conditions, which
indicated that the three components are essential for the desired outcome (Table 1, entries 3−5).
The use of a super-stoichiometric quantity of I2 (120 mol%) led to a lower yield of 3a (entry 6),
which further revealed the distinct advantage of the present dual catalytic system. To gain
further insight, we analyzed the reaction mixture at 0.5 h and found the formation of the
disulfide 5a, which results from the oxidation of 2a, in 91% yield along with the formation of 3a
in 9% yield (entry 7). Importantly, when 5a (0.55 equiv) was used instead of 2a, the sulfenylation
occurred smoothly in good yield (entry 8). These results suggest that the sulfenylation of
pyrazolones under the developed reaction conditions proceeds via generation of the disulfide.
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On the basis of these preliminary results along with related literature,11e,12,14a,b
a
tentative reaction mechanism is shown in Scheme 1. The basic mechanism of the flavin-iodine
catalytic system is almost identical to that reported previously for indole sulfenylation.14b In this
mechanism, the thiol is oxidatively converted to the corresponding disulfide, which reacts with
I2 to form the corresponding sulfenyl iodide (R-SI). The ensuing nucleophilic attack of
pyrazolone onto R-SI provides the desired product. This is supported by the fact that the
sulfenylation using relatively electron rich pyrazolones smoothly proceeded in the present
reaction. In this system, the flavin catalyst oxidizes the thiol and I– under aerobic conditions to
generate disulfide and I2, respectively. Although conventional conditions for sulfenylation of
pyrazolones with thiols require heating,11a-e the developed pyrazolone sulfenylation occurs at
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ambient temperature (25 ˚C) due to the multiple beneficial roles of flavin catalysis which include
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O2-activation and the oxidations of thiol and I–.
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Scheme 1. Proposed mechanism for aerobic sulfenylation catalyzed by flavin–iodine-catalyst.
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We explored next, the sulfenylation of pyrazoles, which seem to be less reactive than
pyrazolones. Indeed, the sulfenylation of pyrazoles with thiols has been limited to a single
recent example, where DMSO was used as the oxidant.12 We were pleased to find the successful
sulfenylation of pyrazole 6a using 4·TfO and I2 at 80 ˚C under a molecular oxygen atmosphere,
and the desired thioether 7a was obtained in 85% yield (Table 3). A series of thiols and pyrazoles
were tested under these conditions, and the corresponding sulfenylated pyrazoles(7b-7g) were
obtained in 81-88% yields, while the combination of the relatively electron-rich thiol with the
relatively electron-deficient pyrazoles, which would decelerate the nucleophilic attack of
pyrazole onto R-SI intermediate, required 5 d to yield the products (7d and 7e) in 82% yields. In
contrast to the result of the flavin-catalyzed system, the sulfenylated product 7b was not
obtained in the absence of 4·TfO. To extend the scope of the sulfenylation system, electron-rich
benzenes such as 1,3,5-trimethoxybenzene (8a) and 4-(methylthio)aniline (8b), which are
expected to be nucleophilic towards R-SI, were also evaluated under the developed conditions.
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As a result, the sulfenylation was successfully performed, thus gave the corresponding
sulfenylated products (9a and 9b) in good yields (Scheme S1, Supporting Information). These
results demonstrate the facile applicability of the developed flavin-iodine catalytic system for
the development of metal-free O2-driven reactions.
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Table 3. Aerobic sulfenylation of pyrazolesa
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aConditions: 6 (1.0 M), 2 (1.1 M), 4•TfO (10 mol%), I2 (10 mol%), and CH3CN under O2 (1 atm) at 80 °C. bWithout
4•TfO.
The first aerobic oxidative sulfenylation of pyrazolones and pyrazoles with thiols
mediated by the flavin-iodine dual catalytic system has been developed. The combination of
biomimetic flavin with iodine enabled the catalytic sulfenylation to be driven by molecular
oxygen, which is recognized as the ideal oxidant. Further, the molecular oxygen present in the
air is sufficient to catalyze the reaction. Overall, the present method provides a green synthetic
route with good economic advantages to access diverse sulfur-containing pyrazole derivatives,
which are promising candidates for medicinal and agrochemical applications. Extension of this
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methodology to diverse C-S bond formations, and related C-N and C-C bond formations is
currently under investigation.
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Experimental Section
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General Information. The NMR spectra were measured using JEOL JNM-L400 and JNM
ECX-500 spectrometers (JEOL, Akishima, Japan) operating at 400 and 500 MHz, respectively,
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for H and 100 and 126 MHz, respectively, for C using tetramethylsilane (TMS) or a solvent
residual peak as the internal standard. The electrospray ionization mass (ESI-MS) spectra were
recorded using a Bruker microTOFII-SHIY3 mass spectrometer (Bruker, Billerica, MA). All
starting materials were purchased from Aldrich (Milwaukee, WI), FUJIFILM Wako Pure Chemical
Industries (Osaka, Japan), Nacalai tesque (Kyoto, Japan), HYDRUS CHEMICAL INC. (Tokyo, Japan),
and Tokyo Kasei (TCI, Tokyo, Japan) and were used as received. 5-Ethyl-1,3,7,8-
tetramethylalloxazinium triflate (4·TfO) was synthesized according to the previously reported methods.17
Typical Procedure for Catalytic Sulfenylation of Pyrazolones. A mixture of 1a (174 mg, 1.0
mmol), 2a (137 mg, 1.1 mmol), I2 (12.7 mg, 0.050 mmol), 4·TfO (13.5 mg, 0.030 mmol), and
CH3CN (1.0 mL) was stirred at 25 °C for 12 h under air (1 atm). Evaporation of the solvent and
purification of the residue by column chromatography (SiO2, chloroform/methanol = 100/0 to
99/1, v/v) afforded 3a (272 mg, 92%) as a white solid. The results for the sulfenylation of
pyrazolones are summarized in Table 2.
Spectroscopic data of 3-methyl-1-phenyl-4-(p-tolylthio)-1H-pyrazol-5-ol (3a).18 1H NMR (500 MHz,
DMSO-d6, 25 °C, δ): 12.12 (br s, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.27 (t, J =
7.4 Hz, 1H), 7.09 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H). 13C{1H}
NMR (126 MHz, DMSO-d6, 25 °C, δ): 155.5, 151.8, 138.3, 134.8, 134.3, 129.7, 128.9, 125.7, 125.3,
120.8, 87.3, 20.4, 12.3.
Spectroscopic data of 3-methyl-1-phenyl-4-(phenylthio)-1H-pyrazol-5-ol (3b).18 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
(159 mg, 94%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 12.18 (br s, 1H),
7.76 (d, J = 7.8 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.6 Hz, 3H), 7.15−7.03 (m, 3H), 2.14 (s,
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3H). C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ): 155.6, 152.0, 138.4, 138.1, 129.1, 129.0, 125.8,
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124.94, 124.89, 120.8, 86.9, 12.3.
Spectroscopic data of 4-(4-chlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-5-ol (3c).19 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
(176 mg, 93%) as a white solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 12.27 (br s, 1H), 7.75 (d,
J = 7.7 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.09 (d, J =
8.5 Hz, 2H), 2.13 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ): 155.9, 151.8, 138.1, 137.6,
129.5, 129.0, 126.6, 125.8, 120.8, 86.5, 12.3.
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Spectroscopic data of 3-methyl-4-(4-nitrophenylthio)-1-phenyl-1H-pyrazol-5-ol (3d). Column
chromatography (SiO2, chloroform/methanol = 100/0 to 9/1, v/v) afforded the desired product
(190 mg, 97%) as a yellow solid. Mp: 215.1-216.3 ˚C. IR (KBr, cm–1): 1620, 1504, 1399, 1340, 1089.
1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 8.13 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 7.7 Hz, 2H), 7.49 (t, J
= 7.9 Hz, 2H), 7.34−7.25 (m, 3H), 2.14 (s, 3H). C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ):
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156.9, 151.9, 148.9, 144.7, 138.0, 129.0, 126.0, 124.9, 124.2, 120.9, 85.2, 12.2. HRMS (ESI+) (m/z): (M
+ Na+) calculated for C16H13N3O3SNa, 350.0570; found, 350.0565.
Spectroscopic data of 4-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-5-ol (3e).20 Column
chromatography (SiO2, hexane/ethyl acetate = 2/1, v/v) afforded the desired product (178 mg,
85%) as a white solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 7.76 (d, J = 7.6 Hz, 2H), 7.47 (t, J =
8.0 Hz, 2H), 7.33−7.25 (m, 2H), 7.07 (d, J = 1.7 Hz, 2H), 2.15 (s, 3H). C{1H} NMR (126 MHz,
13
DMSO-d6, 25 °C, δ): 157.1, 151.9, 143.5, 137.9, 134.7, 129.0, 125.9, 124.6, 122.9, 120.9, 85.8, 12.2.
Spectroscopic data of 4-(2-aminophenylthio)-3-methyl-1-phenyl-1H-pyrazol-5-ol (3f).21 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
(158 mg, 89%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 7.70 (d, J = 7.7 Hz,
2H), 7.46 (t, J = 7.8 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.15 (d, J = 5.4 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H),
6.68 (d, J = 7.8 Hz, 1H), 6.50 (t, J = 7.2 Hz, 1H), 2.20 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6,
25 °C, δ): 159.3, 152.1, 147.8, 137.6, 132.3, 129.0, 128.4, 125.5, 120.2, 118.6, 116.7, 114.9, 92.5, 12.1.
Spectroscopic data of 3-methyl-4-((1-methyl-1H-tetrazol-5-yl)thio)-1-phenyl-1H-pyrazol-5-ol (3g).18
Column chromatography (SiO2, chloroform/methanol = 99/1 to 9/1, v/v) afforded the desired
product (170 mg, 98%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 12.48 (br
s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 4.05 (s, 3H), 2.24 (s,
13
3H). C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ): 156.8, 153.7, 152.0, 137.7, 129.0, 126.0, 120.8,
83.1, 33.9, 12.3.
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Spectroscopic data of 4-(benzylthio)-3-methyl-1-phenyl-1H-pyrazol-5-ol (3h).18 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
(126 mg, 71%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 11.73 (br s, 1H),
7.70 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.9 Hz, 2H), 7.29−7.19 (m, 4H), 7.15 (d, J = 6.7 Hz, 2H), 3.75 (s,
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2H), 1.74 (s, 3H). C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ): 155.0, 152.0, 138.5, 138.1, 129.0,
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128.9, 128.1, 126.7, 125.4, 120.6, 89.4, 11.8.
Spectroscopic data of 3-methyl-1-p-tolyl-4-(p-tolylthio)-1H-pyrazol-5-ol (3j).19 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
(169 mg, 91%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 12.01 (br s, 1H),
7.62 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H),
2.32 (s, 3H), 2.23 (s, 3H), 2.11 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ): 154.9, 151.2,
136.0, 135.0, 134.8, 134.3, 129.6, 129.3, 125.3, 120.9, 86.7, 20.5, 20.4, 12.3.
Spectroscopic data of 1-(4-chlorophenyl)-3-methyl-4-(p-tolylthio)-1H-pyrazol-5-ol (3k).19 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
(186 mg, 94%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 12.35 (br s, 1H),
7.79 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H),
2.22 (s, 3H), 2.11 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ): 156.4, 152.3, 137.1, 134.6,
134.4, 129.7, 128.9, 128.3, 125.3, 122.0, 87.9, 20.4, 12.3.
Spectroscopic data of 1,3-dimethyl-4-((1-methyl-1H-tetrazol-5-yl)thio)-1H-pyrazol-5-ol (3l). Column
chromatography (SiO2, chloroform/methanol = 100/0 to 10/1, v/v) afforded the desired product
(122 mg, 90%) as a white solid. Mp: 185.6-186.5 ˚C. IR (KBr, cm–1): 3448, 1559, 1057. 1H NMR (500
MHz, DMSO-d6, 25 ˚C): δ 3.99 (s, 3H), 3.45 (s, 3H), 2.09 (s, 3H); 13C{1H} NMR (126 MHz, DMSO-
d6, 25 °C): δ 155.6, 154.0, 149.4, 80.0, 33.8, 33.0, 12.1. HRMS (ESI+) (m/z): (M + Na+) calculated for
C7H10N6SONa, 249.0529; found, 249.0527.
Spectroscopic data of 4-((4-bromophenyl)thio)-1,3-dimethyl-1H-pyrazol-5-ol (3m).20 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 9/1, v/v) afforded the desired product
(159 mg, 89%) as a white solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 11.51 (br s, 1H), 7.43 (d,
J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 3.49 (s, 3H), 1.98 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-
d6, 25 °C, δ): 155.0, 149.3, 138.9, 131.7, 126.6, 117.4, 83.4, 33.3, 12.1. HRMS (ESI+) (m/z): (M + Na+)
calculated for C11H11BrN2OSNa, 320.9668; found, 320.9668.
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Spectroscopic data of 3-tert-butyl-1-phenyl-4-(p-tolylthio)-1H-pyrazol-5-ol (3n).19 Column
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chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
(200 mg, 98%) as a beige solid. 1H NMR (500 MHz, DMSO-d6, 25 °C, δ): 11.91 (br s, 1H), 7.78 (d,
J = 7.7 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 6.95 (d, J =
8.1 Hz, 2H), 2.22 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (126 MHz, DMSO-d6, 25 °C, δ): 160.6, 156.6,
138.6, 135.6, 133.8, 129.5, 128.9, 125.8, 124.6, 121.2, 84.4, 33.6, 28.9, 20.4.
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Typical Procedure for Catalytic Sulfenylation of Pyrazoles.
A mixture of 1,3,5-
trimethylpyrazole (6b, 110 mg, 1.0 mmol), 2a (137 mg, 1.1 mmol), I2 (25.4 mg, 0.10 mmol), 4·TfO
(44.9 mg, 0.10 mmol), and CH3CN (1.0 mL) was stirred at 80 °C for 12 h under an O2 atmosphere
(1 atm). Evaporation of the solvent and purification of the residue by column chromatography
(SiO2, hexane/chloroform = 1/10, v/v) afforded 7b (201 mg, 87%) as a yellow oil. The results for
the sulfenylation of pyrazoles are summarized in Table 3.
Spectroscopic data of 1,3,5-trimethyl-4-(phenylthio)-1H-pyrazole (7a).22 Column chromatography
(SiO2, hexane/ethyl acetate = 2/1, v/v) afforded the desired product (112 mg, 85%) as a yellow
oil. 1H NMR (500 MHz, CDCl3, 25 °C, δ): 7.19 (t, J = 7.7 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.98 (d, J
13
= 7.4 Hz, 2H), 3.80 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H). C{1H} NMR (126 MHz, CDCl3, 25 °C, δ):
151.9, 144.0, 138.9, 128.9, 125.3, 124.8, 103.8, 36.8, 12.0, 10.2.
Spectroscopic
data
of
1,3,5-trimethyl-4-(p-tolylthio)-1H-pyrazole
(7b).
Column
chromatography (SiO2, hexane/chloroform = 1/10, v/v) afforded the desired product (201 mg,
87%) as a yellow oil. IR (neat, cm-1): 2922, 1492, 1384, 1084, 805. 1H NMR (500 MHz, CDCl3, 25
°C, δ): 7.00 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 3.78 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.20
(s, 3H).13C{1H} NMR (126 MHz, CDCl3, 25 °C, δ): 151.7, 143.8, 135.2, 134.6, 129.6, 125.6, 104.2,
36.7, 20.9, 12.0, 10.1. HRMS (ESI+) (m/z): (M + H+) calculated for C13H17N2S, 233.1107; found,
233.1111.
Spectroscopic data of 4-(4-chlorophenylthio)-1,3,5-trimethyl-1H-pyrazole (7c). Column
chromatography (SiO2, hexane/ethyl acetate = 2/1, v/v) afforded the desired product (134 mg,
88%) as a yellow oil. IR (neat, cm-1): 2925, 1474, 1090, 1010, 815. 1H NMR (500 MHz, CDCl3, 25
°C, δ): 7.12 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.76 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3, 25 °C, δ): 151.6, 143.8, 137.5, 130.5, 128.9, 126.4, 103.3, 36.7, 11.9, 10.0.
HRMS (ESI+) (m/z): (M + H+) calculated for C12H14ClN2S, 253.0561; found, 253.0566.
Spectroscopic data of 3,5-dimethyl-1-phenyl-4-(p-tolylthio)-1H-pyrazole (7d).23 Column
chromatography (SiO2, chloroform/methanol = 100/0 to 99/1, v/v) afforded the desired product
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(145 mg, 82%) as a yellow oil. 1H NMR (500 MHz, CDCl3, 25 °C, δ): 7.52-7.45 (m, 4H), 7.42-7.36
(m, 1H), 7.06 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3, 25 °C, δ): 153.2, 144.0, 139.8, 134.8, 134.7, 129.7, 129.2, 127.8,
125.8, 124.7, 106.8, 20.9, 12.1, 11.6.
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Spectroscopic data of 3,5-dimethyl-4-(p-tolylthio)-1H-pyrazole (7e). Column chromatography
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(SiO2, chloroform/methanol = 95/5, v/v) afforded the desired product (107 mg, 82%) as a pale
yellow solid. 1H NMR (500 MHz, CDCl3, 25 °C, δ): 10.55 (br s, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.94
13
(d, J = 8.0 Hz, 2H), 2.33 (s, 6H), 2.29 (s, 3H). C{1H} NMR (126 MHz, CDCl3, 25 °C, δ): 148.8,
135.0, 134.7, 129.7, 125.7, 104.4, 20.9, 11.2.
Spectroscopic data of 3,5-dimethyl-4-((1-methyl-1H-tetrazol-5-yl)thio)-1-phenyl-1H-pyrazole (7f).
Column chromatography (SiO2, hexane/ethyl acetate = 2/1, v/v) afforded the desired product
(150 mg, 88%) as a yellow oil. IR (neat, cm-1): 2927, 1597, 1505, 1388, 1022. 1H NMR (500 MHz,
CDCl3, 25 °C, δ): 7.47-7.39 (m, 4H), 7.36 (tt, J = 1.7, 7.0 Hz, 1H), 4.00 (s, 3H), 2.37 (s, 3H), 2.31 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3, 25 °C, δ): 153.5, 152.4, 144.8, 139.4, 129.2, 128.2, 124.9, 99.8,
33.8, 12.2, 11.7. HRMS (ESI+) (m/z): (M + H+) calculated for C13H15N6S, 287.1073; found, 287.1074.
Spectroscopic data of 4-(1-methyl-tetrazol-5-ylthio)-3,5-dimethyl-1H-pyrazole (7g).24 Column
chromatography (SiO2, hexane/ethyl acetate = 1/5, v/v) afforded the desired product (102 mg,
1
13
81%) as a white solid. H NMR (500 MHz, CDCl3, 25 °C, δ): 4.01 (s, 3H), 2.25 (s, 6H). C{1H}
NMR (126 MHz, CDCl3, 25 °C, δ): 154.6, 148.9, 96.7, 33.8, 11.2.
Typical Procedure for Catalytic Sulfenylation of Electron-Rich Benzenes. A mixture of 8a
(202 mg, 1.2 mmol), 2a (74.9 mg, 0.60 mmol), I2 (15.2 mg, 0.060 mmol), 4·TfO (13.4 mg, 0.030
mmol), and pyridine (0.60 mL) was stirred at 100 °C for 24 h under an O2 atmosphere (1 atm).
Evaporation of the solvent and purification of the residue by column chromatography (SiO2,
hexane/ethyl acetate = 8/1 to 4/1, v/v) afforded p-tolyl(2,4,6-trimethoxyphenyl)sulfane (9a, 160
mg, 91%) as a white solid. The results for the sulfenylation of benzenes are summarized in
Scheme S1.
Spectroscopic data of p-tolyl(2,4,6-trimethoxyphenyl)sulfane (9a).25 1H NMR (500 MHz, CDCl3, 25
°C, δ): 7.00−6.92 (m, 4H), 6.21 (s, 2H), 3.86 (s, 3H), 3.80 (s, 6H), 2.25 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3, 25 °C, δ): 162.9, 162.6, 135.2, 134.2, 129.4, 126.1, 99.5, 91.3, 56.4, 55.5, 21.0.
Spectroscopic data of 4-(methylthio)-2-(p-tolylthio)aniline (9b).25 Column chromatography (SiO2,
hexane/ethyl acetate = 8/1 to 4/1, v/v) afforded the desired product (135 mg, 86%) as a brown
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oil. 1H NMR (500 MHz, CDCl3, 25 °C, δ): 7.48 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 2.3, 8.4 Hz, 1H),
7.09−7.03 (m, 4H), 6.72 (d, J = 8.3 Hz, 1H), 4.27 (s, 2H), 2.43 (s, 3H), 2.30 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3, 25 °C, δ): 147.1, 137.7, 135.8, 132.5, 129.9, 127.3, 126.0, 116.3, 116.0, 21.0, 18.7.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Results of Catalytic Sulfenylation and NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: iida@riko.shimane-u.ac.jp
ORCID
Hiroki Iida: 0000-0002-7114-0364
ACKNOWLEDGMENT
This work was supported in part by JSPS KAKENHI (Grant-in-Aid for Scientific
Research (C), no. 16K05797 and 19K05617).
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