Difluoromethylthiolation of Phenols and Related Compounds with a HF2CSO2Na/Ph2PCl/Me3SiCl System

Article abstract of DOI:10.1021/acs.orglett.7b00113

A novel HF₂CSO₂Na/Ph₂PCl/Me₃SiCl system is disclosed for the late-stage direct difluoromethylthiolation of C_sp2 and C_sp3 nucleophiles. Difluoromethylthiolation of phenols and naphthols proceeded nicely under this system to regioselectively provide corresponding SCF₂H compounds in good yields. Other substrates such as indoles, pyrroles, pyrazoles, enamines, ketones, and β-keto esters were also transformed to corresponding SCF₂H products in good yields. The late-stage direct difluoromethylthiolation of a number of natural products and pharmaceutically attractive molecules was also achieved.

Full text of DOI:10.1021/acs.orglett.7b00113

Letter
pubs.acs.org/OrgLett
Difluoromethylthiolation of Phenols and Related Compounds with a
HF2CSO2Na/Ph2PCl/Me3SiCl System
Zhongyan Huang, Okiya Matsubara, Shichong Jia, Etsuko Tokunaga, and Norio Shibata*
Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
S
* Supporting Information
ABSTRACT: A novel HF2CSO2Na/Ph2PCl/Me3SiCl system is disclosed for the late-stage direct difluoromethylthiolation of
Csp2 and Csp3 nucleophiles. Difluoromethylthiolation of phenols and naphthols proceeded nicely under this system to
regioselectively provide corresponding SCF2H compounds in good yields. Other substrates such as indoles, pyrroles, pyrazoles,
enamines, ketones, and β-keto esters were also transformed to corresponding SCF2H products in good yields. The late-stage
direct difluoromethylthiolation of a number of natural products and pharmaceutically attractive molecules was also achieved.
luorine and sulfur have become crucial elements in the fields
F
of agrochemicals, pharmaceuticals, and material sciences.1
In the last two decades, the trifluoromethylthio (SCF3) group has
gained special attention as a potential functional group to
improve and/or alter the physical and biological properties of
original compounds.2 Thus, numerous methods for the direct
introduction of the SCF3 group into target compounds have been
actively developed worldwide.3−6 In this context, we are
interested in the difluoromethylthio (SCF2H) group.7−10 The
SCF2H group is generally considered as a weak lipophilic
hydrogen-bonding donor and has and may have more advantages
than the SCF3 group leading to the design of novel drug
candidates.11 The traditional strategy for the synthesis of SCF2H
compounds focuses on the difluoromethylation of thiols or
disulfides, while only a handful of studies have focused on the
direct introduction of the SCF2H unit, i.e., difluoromethylth-
iolation.12 The first direct electrophilic difluoromethylthiolation
reagent, N-difluoromethylthiophthalimide (1), was developed by
Shen and co-workers in 2015.12a We also reported difluor-
omethanesulfonyl hypervalent iodonium ylides 2 for electro-
philic difluoromethylthiolation (Figure 1a).12b Both reagents 1
and 2 are shelf-stable and have substrate generality, but they
require multiple steps for their preparation. Moreover, they are
not applicable for the difluoromethylthiolation of phenols and
naphthols, which are the ubiquitous structural units of
biologically active molecules and natural products. In this
context, we became interested in the use of HF2CSO2Na as a
direct electrophilic difluoromethylthiolation reagent via in situ
rearrangement and reduction.6,12b The HF2CSO2Na is reported
by Hu and co-workers to be an efficient CF2H radical precursor
under silver catalysis with SO2 extrusion.13 Herein, we disclose
the first direct difluoromethylthiolation of phenols and naphthols
using a novel HF2CSO2Na/Ph2PCl/Me3SiCl system. The
reaction proceeds very nicely for a wide range of phenols and
naphthols in good to high yields in the presence of trimethylsilyl
Figure 1. (a) Electrophilic difluoromethylthiolating reagents. (b) Novel
HF2CSO2Na/Ph2PCl/Me3SiCl system for electrophilic difluorome-
thylthiolation.
chloride (Me3SiCl). The reaction is carried out under mild, base-
free, and metal-free conditions. The method is applicable for the
electrophilic difluoromethylthiolation of several kinds of Csp2 and
Csp3 nucleophiles including anisoles, anilines, pyrroles, indoles,
coumarins, enamines, ketones, and β-keto esters. A pharmaceuti-
cally important natural product, thymol, and a pesticide, fipronil,
were directly functionalized by this system to regioselectively
provide their corresponding SCF2H analogues (Figure 1b).
During the preparation of this paper, another approach for
difluoromethylthiolation using HCF2SO2Cl was reported by the
Yi and Zhao groups independently, although the conditions,
reaction scope, and mechanism are very different.14
We selected 2-naphthol (3a) as a model substrate to optimize
the reaction conditions using the HF2CSO2Na/Ph2PCl combi-
nation (Table 1). We first attempted the reaction of 3a with
HF2CSO2Na/Ph2PCl in MeCN at 25 °C for 12 h, but a reaction
Received: January 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00113
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
screening was next carried out, but yields did not improve
(entries 8−11). The suitable choice of phosphine ligands was
crucial (for more details, see Table S1 in the Supporting
Information). The best result was obtained with a combination of
4.0 equiv of HCF2SO2Na and Ph2PCl with 1.5 equiv of Me3SiCl
in MeCN at 90 °C to furnish 4a in 83% yield (entry 13).
With optimized reaction conditions in hand, substrate
generality was investigated (Scheme 1). Naphthols 3a−c
smoothly and regioselectively transformed to corresponding
SCF2H products 4a−c in moderate to good yields (54−88%).
Phenols were also nicely difluoromethylthiolated under the same
conditions to provide the SCF2H phenols 4d−j regioselectively
with the exception of 4k. Difluoromethylthiolation of resorcinol
(3j) provided bis-SCF2H product 4j in 73% using 6.0 equiv of
HF2CSO2Na/Ph2PCl. Pyridine-2,4-diol (3l) also regioselectively
afforded the corresponding compound 4l in 49% yield.
Difluoromethylthiolation of chromane 3m provided correspond-
ing SCF2H product 4m in good yields. Iridol (3n), an
intermediate in the synthesis of ubiquinone, was directly
difluoromethylthiolated by this method, resulting in 4n as a
mixture of isomers in 87% yield. Direct difluoromethylthiolation
of other nucleophiles such as 1,3-dimethoxybenzene, 4-nitro-
benzenethiol, enamine, 5-aminoisozazole, 5-aminopyrazole, β-
keto ester, ketone, indoles, and pyrrole was efficiently
difluoromethylthiolated by the same system, yielding the
corresponding SCF2H products 4o−y in satisfactory to good
yields (Scheme 1).
Table 1. Optimization of Reaction Conditions
b
entry
additive (mol %)
solvent
yield (%)
c
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
0
2
14
3
AlCl3 (20)
<5
19
4
TsOH/H2O (20)
TfOH (100)
5
18
6
Me3SiOTf (100)
Me3SiCl (150)
Me3SiCl (150)
Me3SiCl (150)
Me3SiCl (150)
Me3SiCl (150)
Me3SiCl (150)
Me3SiCl (150)
33
7
50
8
26
9
EtOAc
dioxane
toluene
MeCN
MeCN
trace
trace
40
10
11
d
12
62
e
13
83
a
Reaction conditions: HF2CSO2Na (0.2 mmol) in 0.75 mL of solvent,
Ph2PCl (0.2 mmol) was added, stirred at room temperature for 30
min. Then, 2-naphthol (3a, 0.1 mmol) in 0.25 mL of solvent was
b
added in the presence of additives. Yields were determined by 19F
NMR spectroscopy with trifluoromethylbenzene as the internal
standard. The reaction was conducted at 25 °C. 3.0 equiv of
HF2CSO2Na/Ph2PCl was used. 4.0 equiv of HF2CSO2Na/Ph2PCl
c
d
e
was used.
Direct difluoromethylthiolation of natural products or
pharmaceutically important compounds is an ideal and practical
route to modify the molecules. The difluoromethylthiolation of
natural products, chromone 5a and coumarin 5b, 4-hydrox-
ycoumarin (5c), 2-aminochromone (5d), 3-indoleacetic acid
(5e), provided corresponding SCF2H products 6a−e in
satisfactory to good yields. Thymol (5f) is a natural product
did not take place (Table 1, entry 1). When the same reaction
was carried out at reflux temperature (bath temp, 90 °C), 14% of
1-((difluoromethyl)thio)naphthalen-2-ol (4a) was obtained
(entry 2). We next examined the effect of additives on yield.
After several additives were screened (entries 1−7), Me3SiCl was
found to be suitable, furnishing 4a in 50% yield (entry 7). Solvent
a
Scheme 1. Difluoromethylthiolation of Nucleophiles 3
a
Reaction conditions: HF2CSO2Na (0.8 mmol) in 1.0 mL of MeCN, Ph2PCl (0.8 mmol) was added, stirred at room temperature for 30 min; NuH
(0.2 mmol) in 0.5 mL of MeCN was added; after that, Me3SiCl (0.3 mmol) was added and then heated at 90 °C for 0.5−12 h. The position ratio was
b
c
d
calculated from 19F NMR. All yields given are isolated yields. At 90 °C for 2 h At 90 °C for 0.5 h. HF2CSO2Na (1.2 mmol) and Ph2PCl (1.2
e
f
mmol) were used. CSA (20 mol %) was used to replace Me3SiCl as catalyst in DMF, 100 °C for 2 h. HF2CSO2Na (0.4 mmol) and Ph2PCl (0.4
mmol) were used at 90 °C for 0.5 h.
B
DOI: 10.1021/acs.orglett.7b00113
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and has antibacterial and antifungal activities.15 The difluor-
omethylthiolation of 5f provided SCF2H-thymol (6f) in 83%
yield. Direct difluoromethylthiolation of pharmaceutically
important dopamine derivative 5g and pesticide fipronil 5h
furnished the SCF2H products 6g and 6h in 46% and 68% yields,
respectively. The results demonstrate the utility of the protocol.
The regioselectivity of the reaction is sometimes obvious but not
always (Schemes 1 and 2). It could be explained by the steric
and/or electronic effects, and further investigation is required.
highly activated in the presence of Me3SiCl as a Lewis acid when
heated (Scheme 3b). The formation of C is also strongly
supported by the literature data that the reaction of NaSO2Ar and
2 equiv of Ph2PCl gave Ph2P(O)SAr accompanied by Ph2P(O)-
Cl.17,18 The requirement of excess reagent can be explained by
the side reactions, such as the rearrangement of B to D followed
by radical decomposition6c with the elimination of E (Ph2P(O)-
OH was detected by LCMS).
In conclusion, we disclose a novel HF2CSO2Na/Ph2PCl/
Me3SiCl system for the direct difluoromethylthiolation of
phenols and naphthols. Corresponding SCF2H compounds are
regioselectively obtained in good yields under mild conditions.
Other Csp2 and Csp3 nucleophiles such as indoles, pyrroles,
pyrazoles, enamines, ketones, and β-keto esters were also
transformed to corresponding SCF2H products in good yields.
This system is effective for the late-stage direct difluoromethylth-
iolation of a number of natural products and pharmaceutically
attractive molecules without any pretreatment of the substrates.
Further potential of this system and the isolation and preparation
of the proposed reactive intermediate are under investigation.
Scheme 2. Difluoromethylthiolation of Natural Products or
a
Pharmaceutically Important Compounds
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00113.
Table S1, experimental procedures, and NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nozshiba@nitech.ac.jp.
ORCID
a
Reaction conditions: HF2CSO2Na (0.8 mmol) in 1.0 mL of MeCN;
Norio Shibata: 0000-0002-3742-4064
Notes
Ph2PCl (0.8 mmol) was added, stirred at room temperature for 30
min; NuH (0.2 mmol) in 0.5 mL of MeCN was added; after that,
Me3SiCl (0.3 mmol) was added and then heated at 90 °C for 12 h.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Although the reaction mechanism is not clear yet, we
hypothesize the generation of reactive SCF2H species C via A
and B under a substitution/rearrangement/reduction process
(Scheme 3a).6,16,17 First, HF2CSO2Na reacts with Ph2PCl to
afford intermediate A with the elimination of NaCl and converts
to intermediate B via an intramolecular rearrangement. B is
converted into a reactive species after reduction by a second
Ph2PCl to generate reactive species C for electrophilic
difluoromethylthiolation. C is rather unreactive and can be
This work was financially supported in part by the Platform for
Drug Discovery, Informatics, and Structural Life Science from
the Ministry of Education, Culture, Sports, Science and
Technology (MEXT) Japan, the Japan Agency for Medical
Research and Development (AMED), the Advanced Catalytic
Transformation (ACT-C) from the Japan Science and
Technology (JST) Agency, the Hoansha Foundation, and the
Kobayashi International Scholarship Foundation. Z.H. thanks
the Hori Sciences & Arts Foundation (Japan) for support.
Scheme 3. (a) Plausible Reaction Mechanism and (b)
Plausible Role of Me3SiCl
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Ph2P(O)Cl to give C with NaCl.
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D
DOI: 10.1021/acs.orglett.7b00113
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