A Series of Deoxyfluorination Reagents Featuring OCF2Functional Groups

Article abstract of DOI:10.1021/acs.orglett.0c03238

Research on perfluoroalkyl ether carboxylic acids (PFECAs) as alternatives for perfluoroalkyl substances continues with the goal of protecting the environment. However, very little is known about the utilization of decomposition products of PFECAs. We report herein a new series of deoxyfluorination reagents featuring OCF2 functional groups derived from certain PFECAs. Alkyl fluorides were generated from various alcohols in ≤97% yield by these novel reagents. The mechanistic experiment verified in situ generation of carbonic difluoride (COF2).

Full text of DOI:10.1021/acs.orglett.0c03238

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Letter
A Series of Deoxyfluorination Reagents Featuring OCF2 Functional
Groups
Shiyu Zhao, Yong Guo,* Zhaoben Su, Wei Cao, Chengying Wu, and Qing-Yun Chen*
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ABSTRACT: Research on perfluoroalkyl ether carboxylic acids
(PFECAs) as alternatives for perfluoroalkyl substances continues with
the goal of protecting the environment. However, very little is known
about the utilization of decomposition products of PFECAs. We report
herein a new series of deoxyfluorination reagents featuring OCF2
functional groups derived from certain PFECAs. Alkyl fluorides were
generated from various alcohols in ≤97% yield by these novel reagents.
The mechanistic experiment verified in situ generation of carbonic
difluoride (COF2).
ecause of the unique properties of per- and polyfluoroalkyl
substances (PFASs) (e.g., hydrophobicity, lipophobicity,
will reduce the amount of fluorinated byproducts that are
disposed and create new economic value.
B
and thermal stability), they have been extensively used in a
wide range of applications, such as the production of
fluoropolymers, surface repellent coatings, metal plating, and
firefighting foam.1 The very strong C−F bond makes PFAS
substances unable to easily degrade naturally, which in turn
leads to global PFAS persistent pollution [e.g., perfluoroocta-
noic acid (PFOA) and perfluorooctanesulfonate (PFOS)].2
Perfluoroalkyl ether carboxylic acids (PFECAs), upon insertion
of oxygen atoms into perfluoroalkyl chains, have been
developed as “environmentally friendly” alternatives to full-
carbon-chain predecessor PFASs. However, toxicological
studies have revealed an even higher bioaccumulation potential
and toxicity of some PFECAs compared to those of PFOA, and
PFECAs have been recognized as a new class of contaminants
of emerging concern.3 A few studies have investigated the
destruction of these PFASs and PFECAs, including thermal
and nonthermal destruction, advanced oxidation or reduction
processes, sorption using activated carbon, and other treatment
processes.4 However, few studies have focused on the
utilization of decomposition products of PFECAs.
PFECAs are basic starting materials for designing a variety of
fluorinated surfactants and functional materials.5 PFECAs
featuring OCF2 functional groups [structure of
CF3(OCF2)nCOOH] are generated mainly as byproducts in
the manufacture of hexafluoropropene oxide (HFO) by
oxidation of hexafluoropropene (HFP) with oxygen. The
amounts of several key PFECA precursors with a general
structure of CF3(OCF2)nCOF would reach 30−100 tons in the
production of 1000 tons of HFO normally, depending on
different oxidation conditions.6 CF3OCF2COOH,
CF3(OCF2)2COOH (PFO2HxA), and their salts are prom-
inent among the derivatives of CF3(OCF2)nCOF. The
reclaiming of these PFECAs featuring OCF2 functional groups
Palmer reported the trifluoromethylation of aryl iodide using
−
the trifluoromethyl anion (CF3 ) liberated from thermal
destruction of PFO2HxA salts in 1995.7 Since then, there
has been no progress in the utilization of decomposition
products of PFECAs. We supposed that PFO2HxA salts might
release carbonic difluoride (COF2) when it generated
−
trifluoromethyl anion (CF3 ) through thermal degradation.
As the most promising semiconductor equipment cleaning and
etching material, COF2 is an important fluorinated material.8
However, its application in synthetic chemistry remains largely
unexplored because special safety precautions must be taken
during storage and transfer of COF2 [e.g., high toxicity and low
boiling point (−84 °C)]. We envisioned that we might utilize
COF2 generated in situ from the thermal degradation of
PFO2HxA salts for organic transformations.
Alkyl fluorides are common components in the field of
medicinal chemistry and drug design because of the unique
properties of fluorine.9 The high electronegativity of fluorine
atoms can regulate the lipophilicity, binding affinity, and
metabolic stability of pharmaceutical candidates. Therefore,
various synthetic methods have been used for the synthesis of
alkyl fluorides, such as nucleophilic, electrophilic, and radical
fluorination.10 Among them, deoxyfluorination has been
considered as one of most effective methods for the
introduction of fluorine atoms into organic molecules due to
Received: September 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03238
© XXXX American Chemical Society
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the abundance of both natural and synthetic alcohols.11 As a
consequence, several deoxyfluorination reagents have been
developed in recent years, ensuring the efficient synthesis of
alkyl fluorides from alcohols, such as DAST,11a Deoxo-
Fluor,11b XtalFluor,11c Fluolead,11d Ishikawa’s reagent,11e
PhenoFluor,11f AlkylFluor,11g PBSF,11h PyFluor,11i
CpFluors,11j and N-tosyl-4-chlorobenzenesulfonimidoyl fluo-
ride (SulfoxFluor).11k However, most of these deoxyfluorina-
tion reagents have some limitations, such as complicated
synthesis steps, high cost, or low stability, and there are also
certain risks in large-scale industrial use for some of the
deoxyfluorination reagents mentioned above. To overcome the
high cost and poor stability of existing deoxyfluorination
reagents, more efforts are needed in this field.
Herein, we report a new series of deoxyfluorination reagents
[CF3(OCF2)nCO2M], which can generate COF2 in situ.
Olofson and co-workers reported that alcohols reacted with
COF2, which was produced in situ via triphosgene and KF, to
produce alkyl fluoroformates. Most of the neat fluoroformates
were distilled in pure form and subsequently cleaved to the
alkyl fluorides by being heated at 120−125 °C using
hexabutylguanidinium fluoride (HBGF) as the catalyst.12
However, the fluoroformate needs to be purified before further
fluorination reaction to obtain alkyl fluorides. We assume that
the concise conversion of alkyl alcohols to alkyl fluorides can
be achieved through a one-pot process via COF2 generated in
situ from the thermal degradation of CF3(OCF2)nCO2M
(Scheme 1). The conversion of alcohol to alkyl fluoride is
a
Table 1. Screening of the Reaction Conditions
T
yield of yield of yield of
c c c
b
entry
ratio
2
[F−]
(°C) 3a (%) 4 (%)
5 (%)
1
2
3
4
5
1:1.5:0
1:1.5:0
1:1.5:0
1:1.5:0
1:1.5:0
1:1.5:1
1:1.5:1
1:1.5:1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
−
−
−
−
−
CsF
KF
KHF2
TMAF
TMAF
TMAF
TMAF
TMAF
TMAF
TMAF
TMAF
TMAF
TMAF
100
120
140
150
160
150
150
150
150
150
130
150
150
150
150
150
150
150
12
32
56
70
69
75
45
43
97
95
91
46
71
88
66
81
65
60
48
25
20
9
3
4
4
1
1
0
4
5
0
0
0
1
0
1
3
0
1
2
8
d
6
14
32
31
0
d
7
d
8
d
9
1:1.5:1
d
10
11
12
13
14
15
16
17
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:1.5:0.5
1:3:0.5
1:1:0.5
1:0.75:0.5
1:0.6:0.5
0
0
5
7
d
d
d
d
4
d
17
3
d
d
2g
2h
5
3
d
18
Scheme 1. Direct Deoxyfluorination by PFECAs Featuring
OCF2 Functional Groups
a
Reaction conditions: 4-phenylbutan-1-ol (1a, 0.2 mmol),
CF3(OCF2)nCO2M (as indicated), fluorides (as indicated), at the
indicated reaction temperatures in DMPU solvent (2 mL) under a
b
nitrogen atmosphere for 24 h. 1a:CF3(OCF2)nCO2M:[F−] ratio.
c
The yields were determined by 19F NMR analysis of crude reaction
d
mixtures using benzotrifluoride as the internal standard. Reaction
time of 5 h.
of added fluoride salts and found that the addition of fluoride
salt could increase the yield of the reaction and the use of
tetramethylammonium fluoride (TMAF) was able to increase
the yield to 95% (Table 1, entries 6−9). When the amount of
fluoride salt was reduced to 0.5 equiv or the reaction
temperature was reduced to 130 °C, the target product was
obtained in a yield of >90% (Table 1, entries 10 and 11).
Furthermore, we explored the effect of the cation species of the
fluorination reagent on the reaction. We found that regardless
of whether we used ammonium salt (CF3OCF2OCF2CO2-
NH4), sodium salt (CF3OCF2OCF2CO2Na), or cesium salt
(CF3OCF2OCF2CO2Cs), good yields were obtained (Table 1,
entries 12−14). Finally, we examined the reactivity of other
reagents. We found that the use of CF3OCF2CO2K,
CF3OCF2OCF2OCF2CO2K, CF3OCF2OCF2OCF2OCF2-
CO2K, and CF3OCF2OCF2OCF2OCF2OCF2CO2K gave
yields of 66%, 81%, 65%, and 60%, respectively (Table 1,
entries 15−18, respectively).
simple and efficient through the one-pot method via the
fluoroformate intermediate. More importantly, the synthesis of
alkyl fluorides was realized by using CF3(OCF2)nCO2M
compounds, which are generated mainly as byproducts in the
manufacture of hexafluoropropene oxide (HFO).
Following this design, 4-phenyl-1-butanol (1a) was chosen
as the model substrate to optimize the reaction conditions (see
the Supporting Information). At 100 °C in N,N-dimethyl-
trimethyleneurea (DMPU) under a nitrogen atmosphere for
24 h, we obtained (4-fluorobutyl)benzene (3a), [4-
(trifluoromethoxy)butyl]benzene (4), and [4-(perfluoro-
ethoxy)butyl]benzene (5) in yields of 12%, 48%, and 3%,
respectively (Table 1, entry 1). We investigated the temper-
ature effect and found that the yield gradually increased as the
temperature increased, reaching 70% at 150 °C (Table 1,
entries 2−5). To our delight, we further screened various types
We further focused on increasing the yield of deoxytri-
fluoromethoxylation product 4. Unfortunately, 4 was obtained
in an optimum yield of 58% with the generation of 3% of 3a,
9% of 5, 3% of 6, and 12% of 7 (Scheme 2). These byproducts
(3a and 5−7) were similar in polarity to the trifluoromethoxy-
lated product (4), and we failed to obtain pure 4 because of
the difficulty of separation.
B
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Moreover, the deoxyfluorination reaction of 4-iodobenzyl
alcohol (3c) on a gram scale was carried out to study the
possible scalability of the reactions. It was found that the
reaction proceeded smoothly and yielded the desired product
(1.15 g) in 81% yield. Second, we investigated some secondary
alcohol substrates and found that the target products (3n−3r
and 3ab) were obtained in moderate to good yields (57−97%).
Third, for tertiary alcohols, we found that 1-fluoroadamantane
was obtained in a yield of 93% from 1-adamantanol. However,
for general tertiary alcohols, the reaction gave rise to the target
products in only low yields (see the Supporting Information).
This may be due to the SN2 mechanism of the reaction (see
Scheme 4c). This may also be the reason for the low yield of
Scheme 2. An Optimum Example of
Deoxytrifluoromethoxylation Reaction via PFO2HxA-K
Having established optimized reaction conditions (Table 1,
entry 10), we then explored the scope of the deoxyfluorination
of alcohols (Scheme 3). We have found that the reaction could
Scheme 4. Control Experiments and Mechanistic Studies
Scheme 3. Substrate Scope for Deoxyfluorination of
a
Alcohols
cyclic secondary alcohols (3ac−3ae). Considering the
applications of heterocycles in drug molecules, we explored
alcohols bearing heterocycles. We found that the target
product could be obtained in moderate to excellent yields
(79−94%) in most heterocyclic substrates (3t−3x). Also, we
examined the substrate containing two hydroxyl groups, which
also gave the difluoro target product (3y) in 79% yield. Finally,
we selected rosuvastatin sodium drug molecular intermediates
(3z) and steroid alcohols (3aa) as reaction substrates and
obtained the target products in 57% and 19% yields,
respectively. Note that products 3aa were obtained with
retention of the configuration because the reaction may include
special carbocation intermediates involving the participation of
homoallylic olefin so that the inversion did not occur.11j,13
To gain more insight into the reaction mechanism, several
control experiments were conducted (Scheme 4). First, we
investigated the generation of COF2 from the decomposition
of PFO2HxA-K. COF2 could be produced by simply heating
PFO2HxA-K in ethyl acetate (EA), as confirmed by using gas
chromatography−mass spectrometry. Through the two-cham-
ber reaction, COF2 entered the B chamber from the A
chamber through the pipeline, thereby yielding bis(4-phenyl-
butyl) carbonate (70%) by the reaction of one molecule of
COF2 with two molecules of the alcohol. Both experiments
demonstrated the production of COF2. With regard to whether
the substitution reaction undergoes SN1 or SN2 reaction, we
selected (S)-4-phenyl-2-butanol as the reaction substrate and
carried out the reaction under the optimal reaction conditions;
(R)-(3-fluorobutyl)benzene (>99% ee) was obtained in an
isolated yield of 81%, and the configuration was completely
reversed, indicating that the reaction was more likely to
undergo the SN2 reaction process.11i
a
Reaction conditions: alkyl alcohol (0.3 mmol), PFO2HXA-K (0.45
mol), TMAF (0.15 mol), at 150 °C in DMPU (3 mL) under a
b
nitrogen atmosphere for 5 h. The yields were determined by 19F
NMR analysis of crude reaction mixtures using benzotrifluoride as the
internal standard. Reaction conditions: alkyl alcohol (0.3 mmol),
PFO2HXA-K (0.45 mol), TMAF (0.3 mol), at 150 °C in DMPU (3
mL) under a nitrogen atmosphere for 5 h. Reaction conditions: alkyl
alcohol (0.3 mmol), PFO2HXA-K (0.9 mol), TMAF (0.3 mol), at
150 °C in DMPU (3 mL) under a nitrogen atmosphere for 5 h.
c
d
produce the target product in moderate to excellent yields for
diverse alcohols. First, we investigated primary alcohols. The
yields were in the range of 70−97%. We found the reactions
were tolerant of a series of functional groups, including cyano,
ester, carbonyl, methoxy, methylthio, sulfone, iodine, bromo,
olefin, and alkyne, under the reaction conditions (3a−3m).
C
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105317.
In conclusion, we have described deoxyfluorination of
alcohols with a new series of deoxyfluorination reagents
[CF3(OCF2)nCO2M], which can generate COF2 in situ. This
method enables the transformation of various primary and
secondary alcohols into the corresponding fluorides and
tolerates a wide range of functional groups. The mechanistic
experiment verifies the production of carbonic difluoride
(COF2), and the reaction may undergo the SN2 process.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03238.
Experimental procedures, data for experimental design,
and spectral data (PDF)
(6) (a) Sianesi, D.; Bernardi, G.; Moggi, G. U.S. Patent 3721696,
1973. (b) Resnick, P. R. U.S. Patent 3817960, 1974.
AUTHOR INFORMATION
Corresponding Authors
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Yong Guo − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China; orcid.org/0000-
0002-5534-0091; Email: yguo@sioc.ac.cn
Qing-Yun Chen − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China; Email: chenqy@
sioc.ac.cn
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Authors
Shiyu Zhao − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China
Zhaoben Su − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China
Wei Cao − Sanming Hexafluo Chemicals Company, Ltd.,
Mingxi, Fujian 365200, P. R. China
Chengying Wu − Sanming Hexafluo Chemicals Company, Ltd.,
Mingxi, Fujian 365200, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03238
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The support to our work by the National Natural Science
Foundation of China (21737004, 21672239, and 21421002)
and the Chinese Academy of Science (KF-STS-QYZX-068) is
gratefully acknowledged.
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