Pentafluorosulfanyldifluoroacetic acid: Rebirth of a promising building block

Article abstract of DOI:10.1021/ol500766v

Three novel, easily scalable routes for the synthesis of pentafluorosulfanyldifluoroacetic acid, SF₅CF₂C(O)OH, are described. Reactions of its acid chloride with amines and alcohols led to a small library of 15 amides and five esters

Full text of DOI:10.1021/ol500766v

Letter
pubs.acs.org/OrgLett
Pentafluorosulfanyldifluoroacetic Acid: Rebirth of a Promising
Building Block
Andrej V. Matsnev,*,† Si-Yan Qing,† Mark A. Stanton,† Kyle A. Berger,† Gunter Haufe,‡
̈
and Joseph S. Thrasher*,†
†Department of Chemistry, Advanced Materials Research Laboratory, Clemson University, 91 Technology Drive, Anderson, South
Carolina 29625, United States
‡Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraße 40, D-48149 Munster, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: Three novel, easily scalable routes for the synthesis of pentafluoro-
sulfanyldifluoroacetic acid, SF5CF2C(O)OH, are described. Reactions of its acid chloride
with amines and alcohols led to a small library of 15 amides and five esters, respectively.
The reaction of the acid chloride with phenylmagnesium bromide gave the
corresponding acetophenone. Pentafluorosulfanyldifluoroacetonitrile was obtained from
pentafluorosulfanyldifluoroacetamide by dehydration with diphosphorus pentoxide.
special place. The pentafluorosulfanyl group brings unique
t is well-known that fluorinated molecules play an important
Irole in human everyday life. Currently, about 30% of whole properties to organic compounds and often improves their
biological activities because of the group’s high chemical and
metabolic stability, significant lipophilicity, substantial steric
effect, and low surface energy.2 Compounds with an SF5 group
have been attracting great interest over the last six decades since
the first organic SF5-containing molecules were synthesized.
However, for a long time, the development of SF5 chemistry
has been quite slow, primarily due to the lack of pentafluoro-
sulfanyl-containing building blocks and/or useful synthetic
methods for their preparation. Pentafluorosulfanyldifluoroacetic
acid, SF5CF2C(O)OH, might be another interesting reagent
serving as a key starting material for the synthesis of
compounds bearing the SF5CF2 moiety that might be of
interest for medicinal and agrochemistry, materials science, etc.,
but all known methods for its preparation are either unsafe or
produce the acid in extremely low yield.
Scheme 1. Preparation of Pentafluorosulfanyldifluoroacetic
Acid Based on Hexafluoropropylene Oxide
Scheme 2. Preparation of Pentafluorosulfanyldifluoroacetic
Acid from Pentafluorosulfanyl Bromide and
Chlorotrifluoroethylene
Pentafluorosulfanyldifluoroacetic acid was synthesized for the
first time in 1956 by Haszeldine and Nyman via electrochemical
fluorination of thioglycolic acid with low yield.3 Several years
later, Young et al. tried to improve Haszeldine’s method, but
unfortunately, the target compound was not even isolated.4 In
1970, Knunyants and co-workers synthesized esters of
SF5CF2C(O)OH from alkyl trifluorovinyl ether and penta-
fluorosulfanyl chloride in several steps.5 Subsequent hydrolysis
of the ester gave the desired acid in 70% yield. Unfortunately,
Knunyants’ method also could not be widely used, basically
because of limited availability of the starting vinyl ether and the
substrate needed for its synthesis. Alkyltrifluorovinyl ethers are
known as highly reactive compounds that have a tendency to
self-polymerize even when stored at low temperature.6 At the
same time, the preparation of such ethers requires the use of
Scheme 3. Synthesis of Pentafluorosulfanyldifluoroacetic
Acid from 1:1 TFE/CO2 Mixture
agrochemicals and nearly 25% of drugs have one or more
fluorine atoms.1 Among the fluorine-containing molecules,
those with a pentafluorosulfanyl (SF5) substituent occupy a
Received: March 13, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Table 1. Synthesis of SF5CF2-Containing Amides
a
b
Isolated yield. NMR yield.
neat tetrafluoroethylene (TFE), a known deflagrant.7 In 2007,
DesMarteau et al. described the preparation of pentafluoro-
sulfanyldifluoroacetyl fluoride via an elegant rearrangement of
pentafluorosulfanyltrifluorovinyl ether.8 Pentafluorosulfanyl-
oxofluoride (SF5OF) was used as the starting material in this
route. Since the preparation of the SF5OF requires the use of
elemental fluorine, which has its own associated hazards, the
aforementioned method does not look attractive or easily
scalable.
Now we developed three convenient routes for the synthesis
of SF5CF2C(O)OH, starting from either hexafluoropropylene
oxide (HFPO), chlorotrifluoroethylene (CTE), or a mixture of
tetrafluoroethylene and carbon dioxide.7
corresponding adducts 3a and 3b. This addition reaction is
exothermic, and thus the reaction temperature should be
increased slowly. Hydrolysis of the formed adducts with
concentrated sulfuric acid in the presence of glass beads gave
SF5CF2C(O)OH in 45 or 83% yields, respectively.
Route B: SF5CF2C(O)OH from CTE
In this approach, we used SF5Br instead of SF5Cl, which reacted
with chlorotrifluoroethylene in the presence of a radical
initiator. The obtained 1-pentafluorosulfanyl-1,1-difluoro-
2,2,2-fluorochlorobromoethane (5) was then oxidized into
pentafluorosulfanyldifluoroacetyl fluoride with 60% oleum.
Subsequent hydrolysis resulted in the desired SF5CF2C(O)OH
(4) in 82% yield (Scheme 2).
Route A: SF5CF2C(O)OH from HFPO
Although both of these routes delivered pentafluorosulfanyl-
difluoroacetic acid 4 without the use of TFE, the results were
not completely satisfying. The disadvantage of the first route is
the high price of HFPO compared to that of TFE. At the same
time, SF5Br used in the second route is less available than
SF5Cl, and the same is true for the chlorotrifluoroethylene
compared to TFE. Therefore, we returned to the original work
of Knunyants, and finally came up with a process that not only
First a substrate more stable than alkyltrifluorovinyl ethers was
to be found. In 2010, Zeyfman et al. described the synthesis of
aryl- and polyfluoroalkyltrifluorovinyl ethers from HFPO and
the corresponding alcohol.9 As shown in Scheme 1, we
followed this method to obtain via acids 1 the 1,1,1-
trifluoroethyl- and phenyltrifluorovinyl ethers 2, which were
used in further reactions with SF5Cl in the presence of a radical
initiator, such as benzoyl peroxide, for example, to give the
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The anhydrous acid can be recovered from its hydrate by
distillation from concentrated sulfuric acid. To explore the
chemical properties of SF5CF2C(O)OH, initially some very
basic reactions, such as preparation of the corresponding
amides and esters, were investigated. Amides can be further
used for the synthesis of imidoyl chlorides, amidines,
heterocycles, and amines, while esters are also versatile
functionalities for subsequent conversions. All of these
compounds may be of interest for agro- and medicinal
chemistry.
Table 2. Synthesis of SF5CF2-Containing Esters
In the initial attempt to prepare an amide, SF5CF2C(O)OH
and 4-trifluoromethylaniline were mixed in CH2Cl2 in the
presence of DCC and DMAP. The expected amide 7j was
obtained in only 67% yield. Therefore, we decided to transform
the SF5CF2C(O)OH into the pentafluorosulfanyldifluoroacetyl
chloride (6) by heating with excess PCl5. The acyl chloride 6
obtained in 94% yield had been prepared earlier in situ in 42%
yield from the acid and benzoyl chloride.13 Subsequently, 6 was
reacted with 4-trifluoromethylaniline in dichloromethane in the
presence of Et3N, and the corresponding amide 7j was obtained
in 93% yield. Therefore, the acid chloride 6 was applied for
further preparation of amides and esters.
In all cases (except entry 1 when ammonia gas was used and
entry 4 when an excess of diethylamine was used), the
amidation was performed in dichloromethane in the presence
of triethylamine, and the yields of the formed products were up
to 93%. The yield of the product was lowest for o-nitroaniline
(entry 14, Table 1), presumably due to steric effects.
Furthermore, isolation of the lower molecular weight amides
(e.g., 7d and 7e) was difficult due to their high volatility. The
same issue was faced in the preparation of esters. Compound
8a could not be isolated, and its yield was determined only by
NMR spectroscopy. Higher molecular weight aliphatic esters
(i.e., 8b−d) were isolated. In contrast, all attempts to purify
aromatic ester 8e failed due to its instability on a silica gel
column (Table 2).
Pentafluorosulfanyldifluoroacetyl-containing ketones might
be another group of important compounds that should be
directly available from pentafluorosulfanyldifluoroacetyl chlor-
ide by reaction with corresponding Grignard reagents. The
stability of the SF5 group bonded to aromatic or heteroaromatic
rings toward strong nucleophiles is well-documented.14
However, it was unclear whether the SF5 group incorporated
into an aliphatic moiety will demonstrate the same stability. In
order to ascertain this, SF5CF2C(O)Cl was reacted with
PhMgBr at −95 °C. The expected fluorinated acetophenone
PhC(O)CF2SF5 9 was obtained in 63% (NMR yield) (Scheme
4) as a yellowish oil, which was difficult to isolate because of its
volatility. Compound 9 had been previously prepared in 36%
yield by Gard et al.15
a
b
Isolated yield. NMR yield.
Scheme 4. Synthesis of SF5CF2-Containing Ketone 9 and
Nitrile 10
allows for the safe use of tetrafluoroethylene but also can be
carried out with SF5Cl.
Route C: SF5CF2C(O)OH from TFE/CO2
In 1998, Rozen et al. described the preparation of phenyltri-
fluorovinyl ether from the potassium salt of 2-phenoxy-1,1,2,2-
tetrafluoropropionic acid, which was prepared from the
corresponding ethyl ester and potassium trimethylsilanolate.10
The preparation of the starting ester was described in 1984 by
Krespan et al.11 These authors used a mixture of commercially
available “neat” TFE, carbon dioxide, and sodium phenoxide.
The product of the reaction was then alkylated to give the ethyl
ester of 2-phenoxytetrafluoropropionic acid.
We found that in 1951 Hals et al. described the preparation
of tetrafluoroethylene as a 50:50 mol % mixture with carbon
dioxide via pyrolysis of the potassium salt of pentafluoro-
propionic acid.12 Following this procedure, we obtained a
mixture of TFE/CO2, which was reacted with potassium
phenoxide to give in one step the potassium salt of 2-
phenoxytetrafluoropropionic acid. The latter was then
pyrolyzed, giving phenyltrifluorovinyl ether 2b in 76−85%
yield depending upon the scale of the reaction. Along with the
target ether, pyrolysis of the potassium 2-phenoxytetrafluoro-
propionate generates potassium fluoride and carbon dioxide as
side products.
Finally, dehydration of amide 7a by heating with P2O5 at
140−170 °C gave pentafluorosulfanyldifluoroacetonitrile 10 in
75% yield.
In conclusion, three different, easily scalable routes for the
synthesis of pentafluorosulfanyldifluoroacetic acid (4) were
developed. This acid, or its acyl chloride 6, can be used to
introduce the SF5CF2 moiety into a variety of organic
substrates. The preparation of SF5CF2-containing compounds
that may be of practical interest will be reported in a later
publication.
Pentafluorosulfanyldifluoroacetic acid was obtained from
ether 2b in the same way as described earlier in route A with
slight modification (Scheme 3).
Pentafluorosulfanyldifluoroacetic acid 4 is an extremely
hygroscopic solid that liquefies even with traces of moisture.
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Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
compounds are available. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: a.v.matsnev@gmail.com.
*E-mail: thrash5@clemson.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the U.S. National Science Foundation (CHE-
1124859) and Deutsche Forschungsgemeinschaft (Ha 2145/
12-1, AOBJ 588585) for financial support. We are thankful to
Dr. Alfred Waterfeld for valuable discussions, and to Dr. Qiaoli
Liang for great help with HRMS, both are with the Department
of Chemistry at the University of Alabama.
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