Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from Carboxylic Acids and CF3SO2OCF3

Article abstract of DOI:10.1002/chem.202003756

A convenient method for deoxyfluorination of aromatic and aliphatic carboxylic acids with CF₃SO₂OCF₃ in the presence of a suitable base at room temperature has been developed. The reaction allows a straightforward access to a variety of acyl fluorides and proves that CF₃SO₂OCF₃ is an effective deoxyfluorination reagent for carboxylic acids. The method features simplicity, expeditiousness, high efficiency, ease of handling, good functional group tolerance, a wide range of substrates, excellent yields of products, compatibility of many amine initiators, use of environmentally friendly reagents, and effortless removal of byproducts. This reaction represents the first utilization of trifluoromethyl trifluoromethanesulfonate as a fluorination reagent.

Full text of DOI:10.1002/chem.202003756

Accepted Article
Accepted Article
Title: Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from
Carboxylic Acids and CF3SO2OCF3
Authors: Hai-Xia Song, Ze-Yu Tian, Ji-Chang Xiao, and Cheng-Pan
Zhang
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1/2020

Chemistry - A European Journal
10.1002/chem.202003756
COMMUNICATION
Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from
Carboxylic Acids and CF
3
SO
2
OCF
3
Hai-Xia Song,†,[a] Ze-Yu Tian,†,[a] Ji-Chang Xiao, and Cheng-Pan Zhang*,[a]
[b]
†
†
[
a]
Hai-Xia Song (co-first author), Ze-Yu Tian (co-first author), Prof. Dr. Cheng-Pan Zhang
School of Chemistry, Chemical Engineering and Life Science
Wuhan University of Technology
2
05 Luoshi Road, Wuhan 430070, China
E-mail: cpzhang@whut.edu.cn, zhangchengpan1982@hotmail.com.
Prof. Dr. Ji-Chang Xiao
[
b]
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
3
45 Lingling Road, Shanghai 200032, China
E-mail: jchxiao@sioc.ac.cn.
Supporting information for this article is given via a link at the end of the document
Abstract: A convenient method for deoxyfluorination of aromatic
and aliphatic carboxylic acids with CF SO OCF in the presence of a
3
2
3
suitable base at room temperature has been developed. The
reaction allows a straightforward access to a variety of acyl fluorides
3 2 3
and proves that CF SO OCF is an effective deoxyfluorination
reagent for carboxylic acids. The method features simplicity,
expeditiousness, high efficiency, ease of handling, good functional
group tolerance, a wide range of substrates, excellent yields of
products, compatibility of many amine initiators, use of
environmentally friendly reagents, and effortless removal of
byproducts. This reaction represents the first utilization of
trifluoromethyl trifluoromethanesulfonate as a fluorination reagent.
Scheme 1. Synthesis of acyl fluorides from carboxylic acids with different
fluorination reagents (selected).
Because of the unique properties imparted by fluorine,
fluorinated compounds have attracted great interest in the fields
Trifluoromethyl trifluoromethanesulfonate (CF
3
SO
2
OCF
in
3
) has
the
[1]
of chemistry, biology, and materials science. Acyl fluorides
RCOF), an intriguing class of carboxylic acid derivatives
bearing a fluorocarbonyl group, have played an increasingly
been
confirmed
as
a
versatile
reagent
(
trifluoromethoxylation
and
trifluoromethanesulfonylation
o
[7-9]
reactions, despite that it has a boiling point of 21 C.
nucleophilic trifluoromethoxy anion, derived from the breakage
of the S-OCF bond of CF SO OCF by diverse fluorides,
The
[2]
important role in organic synthesis. They can be used as
versatile “RCO” sources in acylation reactions, “R” sources in
decarbonylative coupling reactions, and “F” sources in
fluorination reactions. Acyl fluorides possess better stability than
the homologous acyl halides but much higher reactivity than the
analogous esters and amides, displaying a good balance
between stability and reactivity, due to the special electrostatic
3
3
2
3
represents the most prevalent trifluoromethoxylation reagent,
which reacted with organic halides, metal complexes, α-diazo
compounds, and alkenes under transition-metal-catalyzed or -
free conditions to form a variety of useful trifluoromethoxylated
[8]
3 2 3
compounds. Moreover, CF SO OCF can be employed as a
[2]
nature of the C-F bonds. So far methods for the synthesis of
acyl fluorides have included deoxyfluorination and halogen-
exchange reactions of carboxylic acids or their derivatives with
different types of fluorination reagents, e.g., MF (M = H, Na, K,
promising click ligation for primary and secondary amines in the
preparation of urea derivatives, heterocycles, and carbamoyl
fluorides under additive-free conditions.[10] In addition to these
achievements, application of CF
has rarely been explored. It was known that CF
3
SO
2
OCF
3
in other reactions
SO OCF is a
Cs, Bu
salts,
4
N), KHF
fluoro
2
, KSO
formamidinium
2
F, cyanuric fluoride, 2-fluoropyridinium
salts (e.g., TFFH),
, SF , R N-
(DAST, morpholinosulfur trifluoride and Deoxo-Fluor),
N=SF )BF (XtalFluor), ArSF (Me N)SCF and others
Scheme 1). These reagents enabled efficient and practical
3
2
3
low-cost, modest, bench-stable, air- and moisture-insensitive
reagent, and resistant to hydrolysis even in an aqueous NaOH
perfluoroalkylamines (e.g., Ishikawa’s reagent), BrF
SF
3
4
2
[7]
3
solution at
synthesized from CF
). The –OCF
3 3 2 3
anion originated in situ from CF SO OCF is
a
low temperature.
It can also be readily
in a large scale (Scheme
(R
2
2
4
3
,
4
3
,
3
SO H and P
3
2
O
5
[3-6]
(
2
fluorination of various carboxylic acids and their derivatives to
the corresponding acyl fluorides in satisfactory yields.
Nevertheless, application of many of these reagents was
restricted owing to their high toxicity, thermal instability, high
cost, air or moisture sensitivity, harsh reaction conditions,
difficulty to access or control, and/or release of vast hazardous
thermally unstable and quickly decomposes to form
fluorophosgene and fluoride ion at room temperature. In this
regard, CF
efficient reservoir of O=CF
3 2 3
SO OCF can be considered as a convenient and
–
[10]
2
and F anions.
Furthermore,
fluorophosgene and anhydrous fluorine anions have been
evidenced to be important condensation and nucleophilic
fluorination reagents, respectively.[11] We envisioned that
[
3-6]
byproducts.
In this context, the development of environmental
benign reagents for deoxyfluorination of carboxylic acids to acyl
fluorides is highly sought after.
3 2 3
decomposition of CF SO OCF by an appropriate initiator would
result in a viable fluorination reagent for organic synthetic
chemistry. In this article, the reaction of carboxylic acids with
1
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Chemistry - A European Journal
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COMMUNICATION
CF
3
SO
2
OCF
3
in the presence of a tertiary amine was explored,
(DBU), pyridine, 2,4,6-collidine, 2,6-bis(tert-butyl)pyridine, 1-
methylimidazole, and 4-dimethylaminopyridine (DMAP) proved
to be comparably effective for the reaction, giving 3a in 79-94%
yields (Table 1, entries 2-8). CsF was also a suitable initiator for
the deoxyfluorination, furnishing 3a in 87% yield (Table 1, entry
which provided exclusively acyl fluorides as the products via
deoxyfluorination.
9). Nevertheless, reaction of 1a and 2a with NaOH or without
bases provided no desired product (Table 1, entries 10-11),
suggesting that use of an appropriate base was very essential
for the transformation. Moreover, the equivalent of bases had an
influence on the reaction. When 1a reacted with 2a (2 equiv) and
DMAP (0.5 equiv) under the same conditions, 3a was formed in
3 2 3 3 3
Scheme 2. A facile synthesis of CF SO OCF from CF SO H.
78% yield (Table 1, entry 12). Further decreasing the amount of
3 2 3
Table 1. Deoxyfluorination of 1a with CF SO OCF under different reaction
conditions.
DMAP from 0.5 equiv to 0.2 equiv led to only 28% of 3a (Table
S2). Varying the molar ratios of 1a/2a/DMAP from 1:2:1 to
1
:1.5.1:5, 1:1.2:1.2 and 1:1:1 provided 3a in 98%, 94% and 80%
yield, respectively (Table 1, entries 13-15). If 1a was mixed with
a (1.2 equiv) and DMAP (1.2 equiv) at room temperature for 20
2
h, 3a was obtained in 95% yield (Table 1, entry 14), indicating
that lower reaction temperature was not necessary for the
deoxyfluorination. In addition, the reaction time could be
significantly shortened (Table S3). Reaction of 1a with 2a (1.2
equiv) and DMAP (1.2 equiv) at room temperature for 15 min
supplied 3a in 97% yield (92% isolated yield) (Table 1, entry 16).
Entry[a]
Base (x equiv)
NEt (1.0)
2a (y equiv)
2.0
Yield (3a, %)
1
2
3
4
5
6
7
8
9
3
86
DABCO (1.0)
DBU (1.0)
2.0
89
2.0
83
3 3
If 2a was replaced by TsOCF (2b) or PhCOOCF (2c) in the
pyridine (1.0)
2,4,6-collidine (1.0)
2,6-bis(tert-butyl)pyridine (1.0)
1-methylimidazole (1.0)
DMAP (1.0)
2.0
91
same reaction, 3a was formed in 94% or 91% yield, suggesting
that 2b-c were also efficient fluorination reagents for the
conversion (Table 1, entries 17-18, and Table S5).[12] Further
2.0
81
2.0
79
studies showed that Et
DME, diglyme, CH CN, DCE, and ethyl acetate were reliable
solvents for the reaction of 1a, 2a and DMAP, which gave similar
yields of 3a to that obtained in CH Cl (Table S4). The use of
2
O, toluene, hexane, 1,4-dioxane, THF,
3
2.0
84
2.0
94
2
2
hydrophobic solvents was beneficial for the purification of the
product by simply washing the reaction mixture with aqueous
HCl solution and water, which readily removed the byproduct
and afforded the pure acyl fluoride without using column
chromatography. Additionally, the present deoxyfluorination is
not sensitive to moisture as a mixture of 1a, 2a and DMAP
reacted in air at room temperature for 1 h to give 3a in 87% yield
CsF (1.0)
2.0
87
1
1
1
1
1
1
0
1
2
3
4
5
NaOH (1.0)
2.0
0
none
2.0
0
DMAP (0.5)
2.0
78
DMAP (1.5)
1.5
98
(Table S3).
DMAP (1.2)
1.2
94, 95[b]
80
DMAP (1.0)
1.0
1 [
1 [
1 [
6
b],[c]
DMAP (1.2)
1.2
97 (92)
94
b],[c],[d]
b],[c],[e]
7
DMAP (1.2)
1.2
8
DMAP (1.2)
1.2
91
[
a] Reaction conditions: 1a (0.2 mmol), base (0.2, 0.1, 0.24 or 0.3 mmol), 2a
o
(
0.4, 0.3, 0.24 or 0.2 mmol), CH
determined by HPLC using 3a as an external standard (t
60 nm, water/methanol (v/v) = 20 : 80). Isolated yield was depicted in the
parentheses. [b] The reaction was run at room temperature. [c] The reaction
was run for 15 min. [d] TsOCF (2b) was used instead of 2a. [e] PhCOOCF
2c) was used instead of 2a.
2
Cl
2
(2 mL), -20 C to rt, N
2
, 20 h. Yields were
R
= 9.457 min, λmax
=
2
3
3
(
The investigation started by using 4-phenylbenzic acid (1a) as
a model substrate to optimize the reaction conditions. It was
found that reaction of 1a and 2a (2 equiv) with triethylamine (1
o
equiv) in DCM at -20 C to room temperature under a N
2
atmosphere for 20 h afforded [1,1'-biphenyl]-4-carbonyl fluoride
3a) in 86% yield (Table 1, entry 1). A series of organic and
(
inorganic bases were evaluated in this deoxyfluorination. 1,4-
Diazabicyclo[2.2.2]octane (DABCO), diazabicycloundecene
2
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COMMUNICATION
Scheme 3. Deoxyfluorination of aromatic carboxylic acids (1) with
Furthermore, deoxyfluorination of alkyl carboxylic acids with 2a
initiated by DMAP could yield the respective acyl fluorides
Scheme 4). Reactions of 3-arylpropanoic acids (4a-e), palmitic
CF
mmol), 2a (0.24 mmol), DMAP (0.24 mmol), r.t., N
h. [c] 8 h.
3
SO
2
OCF
3
(2a) in the presence of DMAP. [a] Reaction conditions: 1 (0.2
2
, 15 min. Isolated yields. [b]
(
1
acid (4f), pentacosa-10,12-diynoic acid (4g) and (3r,5r,7r)-
adamantane-1-carboxylic acid (4h) with 2a (1.2 equiv)/DMAP
(
9
(
1.2 equiv) at room temperature for 1 h constructed 5a-h in up to
7% yield. The drug molecules like Indometacin (4i), Oxaprozin
4j), Naproxen (4k) and Loxoprofen (4l) were easily transformed
Taking an assembly of 1, 2a (1.2 equiv), DMAP (1.2 equiv),
DCM, room temperature, N , and 15 min as one of the optimal
reaction conditions, the substrate scope of the reaction was
2
under the same conditions to provide the acyl fluoride
derivatives (5i-l) in 69-93% yields. These observations
confirmed that the primary, secondary and tertiary carboxylic
acids were all suitable substrates in the reaction and that the
functional groups such as carbon-carbon triple bond, amide, and
oxazole were very compatible in this deoxyfluorination, which
hinted at good practicability of the approach.[13]
examined (Scheme 3). To our delight, a wide range of aromatic
carboxylic acids (ArCO H) were efficiently converted under the
2
standard conditions to form the corresponding ArCOF products
in good yields. Benzoic acids (1b-j) bearing either electron-
donating (e.g., OMe, t-Bu, Me) or electron-withdrawing
functionalities (e.g., CHO, NO
the desired products (3b-j) in 71-95% yields. The strong
electron-withdrawing groups like CHO, CN, and NO slowed
2
, F, CN) on the aryl rings provided
Since CF
cleavage rather than the O-CF
of nucleophiles,[
3
SO
2
OCF
3
always decomposes via the S-OCF
bond breakage in the presence
plausible reaction mechanism is
3
bond
2
3
down the transformation, which needed longer reaction times for
complete conversion of the starting acids. 4-Methoxybenzoic
acid (1c), 3-methoxybenzoic acid (1d), and 2-methoxybenzoic
acid (1e) reacted with 2a under the standard conditions to afford
7e,8]
a
suggested (Scheme 5) according to the above results. First,
fragmentation of trifluoromethyl trifluoromethanesulfonate (2a)
by DMAP through nucleophilic attack at the sulfur center in situ
90% of 3c, 86% of 3d, and 90% of 3e, respectively, implying that
generates a ‒OCF
degrades to difluorophosgene (COF
elimination. Then, carboxylic acid (RCO
COF in the presence of DMAP to yield an acyl carbonofluoridic
anion (path a). The ‒OCF
) and fluoride ion via α-F
H, 1 or 4) reacts with
3
3
anion rapidly
the position of the substituent on the aryl groups had few effects
on the reaction. The deoxyfluorination was also amenable to
heteroaromatic systems. Reactions of 1-phenyl-1H-imidazole-4-
carboxylic acid (1k), 4,5-dibromofuran-2-carboxylic acid (1l), 3-
bromothiophene-2-carboxylic acid (1m), 2-phenylquinoline-4-
carboxylic acid (1n), and 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-
pyrazole-4-carboxylic acid (1o) with 2a (1.2 equiv)/DMAP (1.2
equiv) at room temperature for 1 h supplied 3k-o in 51-95%
yields. Similarly, treatment of Febuxosta (1p, an agent to treat
gout), Telmisartan (1q, an antihypertensive drug), Probenecid
2
2
2
anhydride (II). The intermediate (II) undergoes an attack at the
carbonyl site of RCO group by fluorine anion to form an unstable
species (III). Finally, disassociation of III provides the desired
product (RCOF, 3 or 5) and releases the gaseous carbon
dioxide and the useful fluoride ions. The fluorides derived from
‒
degradation of OCF
3
, condensation of COF
2
with RCO
2
H, and
disassociation of intermediate III are also the possible initiators
(
(
1r, a uricosuric and renal tubular blocking agent), Adapalene
1s, an antiacne drug), and Bexarotene (1t, an anticancer drug)
for the decomposition of CF
3
SO
2
OCF
3
(2a), which produces the
‒
3
OCF anion again (path b) and sustains the subsequent
with 2a and DMAP furnished 3p-t in 83-95% yields. The results
demonstrated that heterocycles, sulfamide, and carbon-carbon
double bond were well tolerated in this transformation and that
the reaction was applicable to the late-stage functionalization of
fluorination of carboxylic acid. DMAP might play an essential
role in both initiation of CF SO OCF and activation of COF
2
3
2
3
during the fluorination as the reactions of 1a and 2a with
catalytic amounts of DMAP gave dramatically decreased yields
of 3a (Table S2).
complex
deoxyfluorination of (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid
1u) by 2a and DMAP under the standard reaction conditions
molecules
and
drug
agents.
Additionally,
(
produced 3u in 95% yield, indicating that alkenyl carboxylic acid
was the suitable substrate in the conversion. The good
functional group tolerance and the easily scale-up synthesis of
3
u (as an example) showcased the great synthetic potentials of
this deoxyfluorination method.
Scheme 5. A plausible reaction mechanism for the deoxyfluorination of
carboxylic acids with CF SO OCF (2a)
3 2 3
In summary, we have accomplished a convenient and efficient
deoxyfluorination of carboxylic acids with trifluoromethyl
trifluoromethanesulfonate and DMAP under mild conditions. The
reaction provides a powerful tool for the preparation of acyl
fluorides, which are very useful building blocks in organic
synthesis. Advantages of the method include simplicity,
speediness, high efficiency, ease of handling, transition-metal-
free conditions, good functional group tolerance, a wide range of
Scheme 4. Deoxyfluorination of aliphatic carboxylic acids (4) with
CF
3
SO
2
OCF
3
(2a) in the presence of DMAP. [a] Reaction conditions: 4 (0.2
, 1 h. Isolated yields.
mmol), 2a (0.24 mmol), DMAP (0.24 mmol), r.t., N
2
3
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Chemistry - A European Journal
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COMMUNICATION
substrates, excellent yields, with no use of air- and moisture-
sensitive reagents, and effortless purification of the products
because of the formation of easily removable byproducts. More
1663; c) J.-G. Kim, D. O. Jang, Synlett 2010, 3049-3052; d) G. Olah, I.
Kuhn, I. Beke, Chem. Ber. 1956, 89, 862-864; e) F. Seel, J. Langer,
Chem. Ber. 1958, 91, 2553-2557.
[
[
5]
Selected examples: a) G. A. Olah, M. Nojima, I. Kerekes, Synthesis
importantly, CF
3
SO
2
3 3
OCF (2a) and its analogues (e.g. TsOCF
1
3
5
973, 1973, 487-488; b) T. Mukaiyama, T. Tanaka, Chem. Lett. 1976, 5,
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(
2b) and PhCOOCF
3
(2c)) have been verified as safe precursors
or replacements for difluorophosgene and anhydrous fluoride
and as promising deoxyfluorination reagents for carboxylic acids,
only when appropriate initiators were employed. This reaction
Jpn. 1979, 52, 3377-3380; e) V. A. Petrov, S. Swearingen, W. Hong, W.
C. Petersen, J. Fluorine Chem. 2001, 109, 25-31; f) O. Cohen, R.
Sasson, S. Rozen, J. Fluorine Chem. 2006, 127, 433-436.
represents the first example of using CF
fluorination reagent. Application of CF
3
SO
2
OCF
3
as a viable
and its
6]
Selected examples: a) W. R. Hasek, W. C. Smith, V. A. Engelhardt, J.
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SO
2
OCF
3
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Acknowledgements
We thank Wuhan University of Technology, the “Hundred
Talent” Program of Hubei Province, the Fundamental Research
Funds for the Central Universities (2019-YB-002, 2020-YB-003),
and the Excellent Dissertation Cultivation Funds of Wuhan
University of Technology (2018-YS-082) for financial support.
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Keywords: acyl fluorides • carboxylic acids • trifluoromethyl
trifluoromethanesulfonate • deoxyfluorination
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[
13] Unfortunately, the reactions of ((benzyloxy)carbonyl)phenylalanine and
(
(
tert-butoxycarbonyl)alanine (as examples of amino acids) with TfOCF
3
2a) and DMAP under the standard conditions gave complicated
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[
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4
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Chemistry - A European Journal
10.1002/chem.202003756
COMMUNICATION
Entry for the Table of Contents
Amine-triggered deoxyfluorination of carboxylic acids with CF
3
SO
2
OCF
3
is described. The reaction proceeds rapidly at room
temperature under metal-free conditions to form various acyl fluorides in up to 97% yield. This protocol represents the first utilization
of trifluoromethyl trifluoromethanesulfonate as a convenient and efficient fluorination reagent.
5
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