Synthesis of Difluoromethanesulfinate Esters by the Difluoromethanesulfinylation of Alcohols

Article abstract of DOI:10.1021/acs.orglett.1c00688

Herein, we report the first synthesis of difluoromethanesulfinate esters via the direct difluoromethanesulfinylation of alcohols with HCF2SO2Na/Ph2P(O)Cl. Primary, secondary, and tertiary alcohols were converted to the corresponding difluoromethanesulfinate esters in good to excellent yields under mild conditions. The late-stage functionalization of complexed biologically active natural products was also demonstrated. The method was extended to the trifluoromethanesulfinylation of alcohols using CF3SO2Na in the presence of a catalytic amount of Me3SiCl to provide trifluoromethanesulfinate esters.

Full text of DOI:10.1021/acs.orglett.1c00688

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Letter
Synthesis of Difluoromethanesulfinate Esters by the
Difluoromethanesulfinylation of Alcohols
Yuji Sumii,∥ Kenta Sasaki,∥ Okiya Matsubara, and Norio Shibata*
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ABSTRACT: Herein, we report the first synthesis of difluoromethanesulfinate esters via the direct difluoromethanesulfinylation of
alcohols with HCF2SO2Na/Ph2P(O)Cl. Primary, secondary, and tertiary alcohols were converted to the corresponding
difluoromethanesulfinate esters in good to excellent yields under mild conditions. The late-stage functionalization of complexed
biologically active natural products was also demonstrated. The method was extended to the trifluoromethanesulfinylation of
alcohols using CF3SO2Na in the presence of a catalytic amount of Me3SiCl to provide trifluoromethanesulfinate esters.
rganofluorine compounds have gained significant
Oattention in recent decades in the fields of pharmaceut-
icals and agrochemicals. Although more than 325 fluoro-
pharmaceuticals1 and 424 fluoro-agrochemicals2 have been
registered globally since the 1950s, organofluorine compounds
are relatively scarce in nature.3 In contrast, organosulfur
compounds have a long history as components of pharma-
ceuticals and agrochemicals due to their abundance in natural
products.4 As a result, the trifluoromethylthio (SCF3) group
has become an attractive motif in drug design.5 Although many
SCF3-containing biologically active compounds have been
patented, drug marketing has been limited to agrochemicals,
such as monepantel, cefazaflur, toltrazuril, and vaniliprole.2
Figure 1. Examples of biologically active SCF2H- and SO2CF2H-
containing compounds.
Indeed, currently, no SCF3-containing pharmaceuticals have
been approved for human use. This can be partly attributed to
in a new motif, viz., the difluoromethanesulfinyl (S(O)CF2H)
the high lipophilicity of the SCF3 group (π = 1.44)6 because
group. Due to the presence of a characteristic ionic sulfinyl
lipophilicity plays a critical role in determining the absorption,
(S+−O−) unit, the S(O)CF2H group possesses a different
distribution, metabolism, excretion, and toxicity (ADMET)
balance of lipophilicity and hydrophilicity. The estimated log P
properties of a drug. Although high lipophilicity contributes to
and pKa values9 of PhCH2O-SCF2H, PhCH2O-S(O)CF2H,
good permeability, broad absorption, and good distribution, it
and PhCH2O-SO2CF2H are shown in Table S1. It therefore
also results in low solubility, poor pharmacokinetics, and high
has potential as a novel tool for fine-tuning the ADMET
toxicity.7 Thus, the fine-tuning of the lipophilicity of a drug
properties of drug candidates. Although various methods have
candidate with minimum structural alterations is of great
been reported for the preparation of compounds containing
importance to improving the prospects of clinical success. In
the SCF3,5,10 SCF2H,11 and SO2CF2H12 groups, the prepara-
this context, difluoromethylthio (SCF2H) and difluorometha-
nesulfonyl (SO2CF2H) groups have been considered useful
tools for the fine adjustment of ADMET properties because
both units are hybrids of SCF3, in addition to being hydrogen-
Received: February 26, 2021
Published: March 19, 2021
bond donor motifs. Some examples of drug candidates
containing SCF2H/SO2CF2H units are shown in Figure 1.1,2,8
Inspired by the advantages that the SCF3/SCF2H/SO2CF2H
units can bring to medicinal chemistry, we became interested
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© 2021 American Chemical Society
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a
tion of S(O)CF2H-containing compounds has received little
attention,13 as has the direct introduction of the S(O)CF2H
group.14 Recently, we achieved the difluoromethylthiolation of
carbon nucleophiles through the use of sodium difluorome-
thanesulfinate (HCF2SO2Na) and chlorodiphenylphosphine
(Ph2PCl) in the presence of chlorotrimethylsilane (Me3SiCl)
at a high reaction temperature (Figure 2a).15 A variety of Csp2
Scheme 1. Generation of Active Species
a
An expected reactive species II was generated from HCF2SO2Na and
Ph2P(O)Cl for the difluoromethanesulfinylation process to yield
difluoromethanesulfinate esters 2.
Table 1. Optimization of the Difluoromethanesulfinylation
a
of 1a
b
run
solvent
additive
X (equiv)
Y (equiv)
yield (%)
Figure 2. Difluoromethanethiolation vs difluoromethanesulfinylation
with HCF2SO2Na. (a) Reaction of C-nucleophiles including phenols
(previous work). (b) Reaction of alcohols 1 (this work).
1
2
3
4
5
6
7
8
MeCN
DCE
THF
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
2.0
1.5
1.2
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
1.0
1.0
1.0
69
89
57
50
93
98
88
62
DMF
and Csp3 nucleophiles, such as indoles, pyrroles, pyrazoles,
enamines, ketones, and β-keto esters, were transformed to the
corresponding Csp2 and Csp3 SCF2H products in good yields.
Even phenols and naphthols, possessing a free OH moiety,
were also selectively Csp2-difluoromethylthiolated on the
aromatic ring, while the corresponding O-SCF2H products
were not detected. This reaction required two moles of both
HCF2SO2Na and Ph2PCl to generate S-(difluoromethyl)-
diphenylphosphinothioate (Ph2P(O)-SCF2H, I), which is the
actual reagent involved in the difluoromethylthiolation
reaction.
Thus, we herein report a new system for the difluorome-
thanesulfinylation of alcohols to provide previously unknown
difluoromethanesulfinate esters (Figure 2b). In the presence of
HCF2SO2Na and Ph2P(O)Cl, a wide variety of alcohols 1,
including primary, secondary, and tertiary alcohols, are
efficiently converted to the corresponding difluoromethane-
sulfinate esters 2 (R-OS(O)CF2H) at room temperature in
good to excellent yields (Figure 2b). Although trifluorome-
thanesulfinate esters (R-OS(O)CF3)13f,16 and difluorometha-
nesulfonate esters (R-OS(O)2CF2H)8a,c,13f,17 have been
previously reported, to the best of our knowledge, this is the
first example of the synthesis of difluoromethanesulfinate
esters. The mechanistic details of this transformation are
revealed by NMR and LC-MS analyses of the reaction
mixtures. The developed method is then extended to the
trifluoromethanesulfinylation of alcohols 1 using sodium
trifluoromethanesulfinate (CF3SO2Na) instead of HCF2SO2Na
to provide trifluoromethanesulfinate esters 3.
Based on reactive species I determined in our previous
study15 (Figure 2a), we initially envisaged that the ideal
reactive species II for the difluoromethanesulfinylation reaction
could be generated by a 1:1 combination of HCF2SO2Na and
Ph2P(O)Cl, which subsequently reacts with alcohols 1 to
provide difluoromethanesulfinate esters 2 (Scheme 1).
We thus attempted the reaction of alcohol 1a under the
optimal conditions for the difluoromethylthiolation reaction in
the presence of Me3SiCl in MeCN but using Ph2P(O)Cl
instead of Ph2PCl (Table 1). As expected, the desired
difluoromethanesulfinate ester, 4-phenylbutyl difluorometha-
nesulfinate (2a), was obtained in 69% yield (run 1).
Subsequent solvent screening (runs 2−5) indicated that
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Me3SiCl
-
-
-
-
-
-
c
9
10
11
90 (89%)
78
64
a
Ph2P(O)Cl was added to a solution of HCF2SO2Na in the desired
solvent (1.0 mL). The mixture was stirred at rt for 30 min. A solution
of 4-phenyl-1-butanol (1a, 0.2 mmol) in the desired solvent (1.0 mL)
and Me3SiCl (0.02 mmol, 0.1 equiv) were added separately to the
b
mixture and stirred at rt. Yields were determined by 19F NMR
c
spectroscopy using fluorobenzene as an internal standard. Isolated
yield.
toluene (run 5) was the best solvent for this transformation,
while DCE (run 2, 89%) is not attractive from the view of
green chemistry. Interestingly, the reaction did not require the
addition of Me3SiCl, with the desired compound being
obtained in 98% yield in the absence of this reagent (run 6).
Although the number of equivalents of both HCF2SO2Na and
Ph2P(O)Cl could be reduced to 1.5 and 1.0, the yields also
reduced gradually (i.e., 88 and 62%, respectively). The molar
ratio of HCF2SO2Na to Ph2P(O)Cl was also varied, and it was
found that a high yield was maintained using a 2:1 molar ratio
(run 9).
With the optimized conditions in hand (run 9, Table 1), the
substrate scope of the reaction was investigated (Scheme 2).
Benzyl alcohols (1b−1e) were converted to the corresponding
difluoromethanesulfinate esters (2b−2e) in good to excellent
yields (80−88%). The presence of electron-donating (Me, 1c),
halogen (Br, 2d), and electron-withdrawing (NO2, 1e)
substituents was also supported. Primary alcohols (1f, 1g), a
secondary alcohol (L-menthol (1h)), and a tertiary alcohol (1-
adamantanol (1i)) were also nicely converted to the
corresponding esters (2f−2i) in high yields (79−98%).
Interestingly, the alkene moiety in 9-decen-1-ol (1g) remained
intact under the conditions employed, and the desired
difluoromethanesulfinate ester (2g) was obtained in 98% yield.
Late-stage selective functionalization of complexed mole-
cules without an adverse effect on other functional groups in
the molecule is a challenge. We thus attempted the
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optimization of reaction conditions (Table S2), we found the
reaction in the presence of a catalytic amount of Me3SiCl to be
suitable.
Scheme 2. Substrate Scope for the
Difluoromethanesulfinylation of Alcohol 1
a
The substrate scope of the difluoromethanesulfinylation was
then examined for the same series of alcohols 1 to afford the
corresponding trifluoromethylsulfinate esters 3 in good to
excellent yields (Scheme 3). Primary, secondary, and tertiary
Scheme 3. Substrate Scope for the
Trifluoromethylsulfinylation of Alcohols 1
a
a
Reaction conditions: Ph2P(O)Cl (0.2 mmol, 1.0 equiv) was added to
a solution of HCF2SO2Na (0.4 mmol, 2.0 equiv) in toluene (1.0 mL),
and the mixture was stirred at rt for 30 min. A solution of 2 (0.2
mmol) in toluene (1.0 mL) was then added to the mixture and stirred
a
Reaction conditions: Ph2P(O)Cl (0.2 mmol, 1.0 equiv) was added to
a solution of CF3SO2Na (0.4 mmol, 2.0 equiv) in toluene (1.0 mL),
and the mixture was stirred at rt for 30 min. A solution of 2 (0.2
mmol) in toluene (1.0 mL) and Me3SiCl (0.02 mmol, 0.1 equiv) were
b
at rt for 3 h. Reaction was conducted with 1.0 g (7.7 mmol) of 1f.
b
c
then added to the mixture and stirred at rt for 3 h. Yield of 3c was
4.0 equiv of Ph2P(O)Cl and 4.0 equiv of HCF2SO2Na were used.
determined by 19F NMR of the crude product.
d
2.0 equiv of Ph2P(O)Cl and 2.0 equiv of HCF2SO2Na were used.
e
Yield was determined by 19F NMR of the crude product, due to the
instability of 2m.
alcohols, including steroid 1j and diterpenoid 1k, were
efficiently converted to the desired esters (3h−3k) over a
reaction time of 3 h. The structure of 3e was also determined
unequivocally by X-ray crystallography.
difluoromethanesulfinylation of several biologically active
complexed molecules under the optimized conditions. Steroid
(1j) was first examined. The corresponding difluoromethane-
sulfinate ester 2j was obtained in good yield without any
damage to the multiple stereocenters. 4-Hydroxy-N-Boc-
proline (1k) was next converted to the corresponding sulfinyl
ester (2k) in 48% yield. For antitumor diterpenoid
andrographolide (1l), double difluoromethanesulfinylation
was observed in two secondary alcohol moieties to furnish
the difluoromethanesulfinate diester of andrographolide (2l) in
49% yield. The tertiary alcohol of 10-deacetylbaccatin III
(1m), a synthetic intermediate of anticancer drug Paclitaxel,
was converted to the sulfinyl ester (2m) in 54% yield.
Antiangiogenic fumagillol (1n) gave the corresponding
difluoromethanesulfinyl ester (2n) in 40% yield without
opening of the reactive epoxy groups. As indicated, a variety
of functional groups such as amino, alkene, conjugated alkene,
ketone, oxetane, and epoxide were accommodated in the
substrates without affecting the sulfinylation process.
19F NMR spectroscopy (Figure 3 and Figure S1 of the
Supporting Information (SI)) was then carried out for
HCF2SO2Na; no peak was observed due to its low solubility
in d-toluene (Figure 2a). When Ph2P(O)Cl was added to the
solution, a sharp doublet appeared at −118.2 ppm (J = 56.4
Hz) within 10 min (Figure 2b), although this signal
disappeared upon the addition of alcohol 1a. At this point,
product 2a was newly detected as a clear AB quartet (−123.5
and −125.9 ppm, J = 272.1 and 53.6 Hz) (Figure 2c). The
sharp doublet observed at −118.2 ppm was therefore
considered the active species for this transformation.
Furthermore, a new doublet appeared at −125.3 ppm (J =
56.4 Hz), which was confirmed to be HCF2S(O)OH 4 by
further 19F NMR experiments (Figures S2 and S3 in the SI).
Interestingly, the doublet at −125.3 ppm then slowly
disappeared spontaneously over several hours, as discussed
later.
We subsequently considered the syntheses of trifluorome-
thanesulfinate esters 3. While the trifluoromethanesulfinylation
of alcohols was seminally reported by Hendrickson and co-
workers in 197616a and improved by Billard and Langlois et al.
in 1999,16b we wished to consider our protocol for the
trifluoromethanesulfinylation of alcohols 1. After the brief
Based on the 19F NMR analysis and an additional LC-ESI-
MS (Figure S4 in the SI), a plausible reaction mechanism was
determined, as shown in Figure 3. More specifically, in this
mechanism, the first mole of HF2CSO2Na reacts with Ph2P(O)
Cl to form the initial intermediate Ph2P−O−S(O)CF2H II
(detected by LC-ESI-MS) and eliminate NaCl, as detected
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anhydride III (presumably corresponding to the signal at
−118.2 ppm) reacts with alcohols 1 at room temperature to
furnish the desired sulfinate esters 2 with the release of sulfinic
acid, HCF2S(O)OH 4. The unstable HCF2S(O)OH 4
(observed at −125.3 ppm, as confirmed by 19F NMR
experiments) slowly decomposes into gaseous SO2 and
H2CF2, resulting in the disappearance of the doublet at
−125.3 ppm. The observation of >50% of 1a when only 1 mol
of HF2CSO2Na was employed (i.e., 62%, run 8, Table 1) could
be explained by the contribution of path A, which cannot be
fully ruled out. However, the use of 2 equiv of HF2CSO2Na
promotes the complete transformation. Finally, we note that in
the trifluoromethanesulfinylation of 1 Me3SiCl catalytically
activates the symmetrical anhydride, (CF3S(O))2O, which is
generated from Ph2P(O)Cl and 2 equiv of CF3SO2Na.
In conclusion, we developed a novel difluoromethanesulfi-
nylation of alcohols based on the HF2CSO2Na/Ph2P(O)Cl
system. A variety of previously known difluoromethanesulfi-
nate esters, ROS(O)CF2H, were synthesized in good to
excellent yields under mild reaction conditions. The late-stage
functionalization of biologically active natural products was
also demonstrated. This protocol is the first example of the
preparation of difluoromethanesulfinate esters. Our method
was also extended to the trifluoromethylsulfinylation trans-
formation using CF3SO2Na in the presence of a catalytic
amount of Me3SiCl to afford the corresponding trifluorome-
thanesulfinate esters, ROS(O)CF3, in good to excellent yields.
These systems should be considered novel tools for the direct
transformation of biologically attractive alcohols into their di-
and trifluoromethanesulfinate esters. Application of this
method for the preparation of a drug library is currently
under investigation, and the results will be presented in due
course.
Figure 3. 19F NMR experiments in toluene-d6. (a) HCF2SO2Na (2
equiv). (b) The solution of (a) 10 min after the addition of Ph2P(O)
Cl (1 equiv). (c) The solution of (a) 30 min after the addition of
alcohol 1a. (d) The solution of (a) 7 h after the addition of alcohol
1a.
visually. Although intermediate II could be considered the
reactive species for the difluoromethanesulfinylation of
alcohols 1 (path A), this is not the main pathway because
the reaction requires 2 equiv of HF2CSO2Na for a quantitative
conversion. Thus, intermediate II rapidly reacts with the
second mole of HF2CSO2Na to form a more reactive,
symmetrical anhydride (HCF2S(O))2O III (detected by LC-
ESI-MS) with the release of Ph2P(O)ONa (detected as
Ph2P(O)O− by LC-ESI-MS) via path B (Scheme 4). Finally,
ASSOCIATED CONTENT
■
Scheme 4. Plausible Reaction Pathway for the
Difluoromethanesulfinylation of Alcohols 1 to Esters 2
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00688.
Tables S1 and S2, Figures S1−S4, experimental
procedures, characterization data, and copies of the
NMR spectra for products 2 and 3 (PDF)
Accession Codes
CCDC 2056418 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Norio Shibata − Department of Life Science and Applied
Chemistry and Department of Nanopharmaceutical Sciences,
Nagoya Institute of Technology, Nagoya 466-5888, Japan;
Institute of Advanced Fluorine-Containing Materials,
Zhejiang Normal University, 321004 Jinhua, China;
orcid.org/0000-0002-3742-4064; Email: nozshiba@
nitech.ac.jp
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Authors
pubs.acs.org/OrgLett
Letter
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Lipophilicity on Potency and Pharmacokinetic Parameters Enables
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Yuji Sumii − Department of Life Science and Applied
Chemistry, Nagoya Institute of Technology, Nagoya 466-
5888, Japan; orcid.org/0000-0003-3900-1089
Kenta Sasaki − Department of Life Science and Applied
Chemistry, Nagoya Institute of Technology, Nagoya 466-
5888, Japan
Okiya Matsubara − Department of Life Science and Applied
Chemistry, Nagoya Institute of Technology, Nagoya 466-
5888, Japan
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Author Contributions
∥Y.S. and K.S. contributed equally to this work. All authors
have approved the final version of the manuscript.
Notes
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J.-P. Holistic Prediction of pKa in Diverse Solvents Based on Machine
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This research was supported by a JSPS KAKENHI Grant-in-
Aid for Scientific Research (B) (Grant Number 18H02553).
Sodium difluoromethanesulfinate was provided from Juhua
Group Ltd. (China), and sodium trifluoromethanesulfinate was
provided from Central Glass, Inc. (Japan). We thank Mr.
Satoshi Gondo (Nagoya Institute of Technology) for the initial
studies.
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