Trifluoromethylation of Benzoic Acids: An Access to Aryl Trifluoromethyl Ketones

Article abstract of DOI:10.1021/acs.orglett.1c01720

The trifluoromethylation of benzoic acids with TMSCF3 was achieved through nucleophilic substitution with the use of anhydrides as an in situ activating reagent. Under the reaction conditions, a wide range of carboxylic acids including the bioactive ones worked well, thus providing a facile and efficient method for preparing aryl trifluoromethyl ketones from the readily available starting materials.

Full text of DOI:10.1021/acs.orglett.1c01720

pubs.acs.org/OrgLett
Letter
Trifluoromethylation of Benzoic Acids: An Access to Aryl
Trifluoromethyl Ketones
Xue Liu, Long Liu, Tianzeng Huang, Jingjing Zhang, Zhi Tang, Chunya Li, and Tieqiao Chen*
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ABSTRACT: The trifluoromethylation of benzoic acids with
TMSCF3 was achieved through nucleophilic substitution with the
use of anhydrides as an in situ activating reagent. Under the
reaction conditions, a wide range of carboxylic acids including the
bioactive ones worked well, thus providing a facile and efficient
method for preparing aryl trifluoromethyl ketones from the readily
available starting materials.
used;11 however, the alcohols should be presynthesized from
he introduction of fluorine is a strategy to enhance or
Tchange the physical and chemical performance of the unstable aldehydes; overstoichiometric special oxidants are
functional molecules in chemical science,1 material science,2
also required.
and biological science.3 In particular, it is reported that ca. 20%
Herein we report a trifluoromethylation of benzoic acids
with TMSCF3 to produce aryl trifluoromethyl ketones in good
to high yields (Scheme 1). Carboxylic acids are abundant and
readily available raw chemicals. Compared with the aromatic
aldehydes and aryl halides used in the established reactions,
they are cheaper and environmentally benign. To our
knowledge, the synthesis of trifluoromethyl ketones through
the direct trifluoromethylation of carboxylic acids has never
been achieved. It should be noted that carboxylic derivatives
such as acyl halides,12 esters,13 and Weinreb amides14 can also
produce trifluoromethyl ketones through the addition with
TMSCF3 and the subsequent H3O+/F− treatment (Scheme 1).
The multistep operation, that is, the presynthesis of starting
materials and the two-step reaction process, reduces the step
efficiency and atomic utilization.
A mixture of 4-phenyl benzoic acid and TMSCF3 (3 equiv)
dissolved in PhOMe was allowed to react at 120 °C for 15 h in
the presence of TFAA (2 equiv) and DMAP (2.5 equiv), and
the corresponding aryl trifluoromethyl ketone (3a) was
produced in 80% yield (Table 1, entry 1). By adding 2.5
equiv of CsF to the reaction mixture, the yield of 3a was
increased to 90% (Table 1, entry 2). Lowering the reaction
temperature to 100 °C led to a slight decrease in the yield,
whereas the reaction efficiency was also not enhanced when
the reaction was conducted at 140 °C (Table 1, entries 3 and
4). The choice of an in situ activating reagent was essential to
of medicines and 30% of pesticides contain at least one fluorine
atom.4 Trifluoromethyl ketones are a kind of important
organofluorine compound. In addition to the lipophilicity
and metabolic stability,5 these compounds also exhibit strong
electron-withdrawing ability and are capable of forming stable
hydrates.6 These specific properties have lead to their wide
application in drug design and development. Trifluoromethyl
ketones are also important building blocks for other fluorine-
containing functional molecules due to the diverse reactivity of
the carbonyl group. Traditionally, the nucleophilic substitution
of aryl metals (Li or Mg) with trifluoroacetyl derivatives can
produce trifluoromethyl ketones;7 however, the harsh reaction
conditions limit the application. The Friedel−Crafts acylation
of electron-rich arenes is also used despite the narrow substrate
scope and issues of regioselectivity.8 Thus the development of
more efficient methods for their preparation is of current
concern (Scheme 1).9 Nowadays, the transition-metal-
catalyzed trifluoroacetylation of aryl halides/pseudohalides
has been developed for preparing these compounds.10 The
oxidation of α-trifluoromethyl alcohols is also extensively
Scheme 1. Synthesis of Aryl Trifluoromethyl Ketones
Received: May 22, 2021
Published: June 10, 2021
https://doi.org/10.1021/acs.orglett.1c01720
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4930−4934
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Table 1. Trifluoromethylation of 4-Phenyl Benzoic Acid
with TMSCF3
Table 2. Trifluoromethylation of Carboxylic Acids with
a
a
TMSCF3
b
entry
anhydride
base
solvent
yield (%)
c
1
TFAA
TFAA
TFAA
TFAA
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
THF
80
90
57
80
N.D.
N.D.
N.D.
N.D.
19
2
d
3
e
4
5
6
7
8
Piv2O
Ac2O
Boc2O
Ms2O
Tf2O
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
9
10
11
12
13
14
15
16
17
18
19
20
21
22
41
N.D.
N.D.
trace
trace
trace
trace
60
71
28
77
64
NaHCO3
Na2CO3
Et3N
DBU
pyridine
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
cyclohexane
NMP
CH3CN
toluene
1,4-dioxane
72
a
Reaction conditions: 4-phenyl benzoic acid 1a (0.2 mmol), TMSCF3
(2, 3.0 equiv), anhydride (2.0 equiv), CsF (2.5 equiv), base (2.5
equiv), solvent (2.0 mL), N2, 120 °C, 15 h. TFAA, trifluoroacetic
anhydride; DMAP, 4-dimethylaminopyridine. DBU, 1,8-
b
diazabicyclo[5.4.0]undec-7-ene. NMP, N-methyl pyrrolidone. GC
c
d
yields using dodecane as an internal standard. Without CsF. 140 °C.
e
100 °C.
this reaction. No product was detected without anhydride or
with Piv2O, Ac2O, or Boc2O (Table 1, entries 5−8). Low
yields were also given when Ms2O and Tf2O were used instead
(Table 1, entries 9 and 10). The base was also an important
factor for this reaction. No reaction took place in its absence
(Table 1, entry 11). No or only a trace amount of 3a was
obtained with the use of NaHCO3, Na2CO3, Et3N, DBU, or
pyridine under similar reaction conditions (Table 1, entries
12−16). Finally, this reaction could also occur in other
selected solvents such as THF, cyclohexane, NMP, CH3CN,
toluene, and 1,4-dioxane, but the yields decreased to some
extent (Table 1, entries 17−22).
With the optimal reaction conditions in hand, we
subsequently investigated the substrate scope of this
trifluoromethylation reaction. As compiled in Table 2, various
carboxylic acids worked well under the present reaction
conditions to produce the corresponding trifluoromethyl
ketones in good to high yields. Thus in addition to 1a, a
high yield was obtained from 3-phenyl benzoic acid (Table 2,
entry 2). Probably because of the steric hindrance, the yield
slightly decreased with 2-phenyl benzoic acid (Table 2, entry
3). Other substrates with electron-donating groups such as
cyclohexyl, tert-butyl, and methoxy groups, the easily hydro-
lytic phenoxy groups, and the alkaline dimethylamino groups
were also smoothly transformed into the expected products in
high yields (Table 2, entry 4−8). Halo iodine survived well in
a
Reaction conditions: acid 1 (0.2 mmol), TMSCF3 (2, 3.0 equiv),
TFAA (2.0 equiv), CsF (2.5 equiv), DMAP (2.5 equiv), PhOMe (2.0
mL), N2, 120 °C, 15 h. GC yields using dodecane as an internal
b
standard. The data in parentheses are the isolated yields. GC yield
c
d
using tridecane as an internal standard. 80 °C. Product is a mixture
e
of 3w and its hydration 3w′. (See the SI.) 19F NMR yield using 4-
f
fluorobenzoic acid as an internal standard. TMSCF3 (2, 1.0 equiv),
TFAA (1.5 equiv), 100 °C.
the current reaction system, facilitating the further function-
alization of the products via cross-coupling (Table 2, entries 9
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and 10). The electron-deficient substrates were also applicable
to this reaction. For example, benzoic acids bearing electron-
withdrawing groups such as NO2, CN, and PhC(O) worked
well, producing the trifluoromethylating products in high yields
(Table 2, entries 11−13). Under the present reaction
conditions, the di- and trisubstituted benzoic acids proved to
be the right substrate (Table 2, entries 14−17). It is worth
noting that piperic acid and trimethylgallic acid are important
medicinal intermediates, and they were readily trifluoromethy-
lated by the strategy (Table 2, entries 16 and 17). Good to
high yields of trifluoromethyl ketones were obtained from the
polycyclic and heterocyclic aromatic carboxylic acids (Table 2,
entries 18−26). Aliphatic carboxylic acids, exemplified as
stearic acid and oleic acid, were also applicable to this reaction,
although relatively low yields were given (Table 2, entries 27
and 28).15 The low yields might be ascribed to the relatively
high electron density of the carbonyl carbon, which is not
beneficial for the nucleophilic addition.
three reactions. The results well demonstrated the practicality
of this new reaction in organic synthesis.
On the basis of previous literature,12−14,16 a plausible
mechanism for this trifluoromethylation reaction is proposed
in Scheme 4. Initially, the carboxylic acid 1 was activated in
Scheme 4. Proposed Mechanism
situ by TFAA to produce a mixing anhydride A.16 By the aid of
CsF and DMAP, the resulting mixing anhydride A underwent
nucleophilic addition with TMSCF312−14 and then elimination
to give the corresponding product 3.
In summary, we have disclosed an efficient synthesis of the
value-added trifluoromethyl ketones from the environmental
benign and readily available carboxylic acids. The reaction
conditions were facile and relatively mild. A wide substrate
scope and high functional group tolerance were demonstrated.
The bioactive functional molecules such as adapalin,
probenecid, 3-methylflavone-8-carboxylic acid, and telmisartan
were also smoothly trifluoromethylated to produce the
corresponding products. In addition, this reaction is scalable.
These results showed the potential synthetic value of this new
reaction in organic synthesis.
Interestingly, this reaction was applicable to the direct
modification of bioactive carboxylic acids, generating the
corresponding trifluoromethyl ketones (Scheme 2). For
a
Scheme 2. Modification of Bioactive Molecules
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01720.
a
Reaction conditions: acid 1 (0.2 mmol), TMSCF3 (2, 3.0 equiv),
TFAA (2.0 equiv), CsF (2.5 equiv), DMAP (2.5 equiv), PhOMe (2.0
mL), N2, 120 °C, 15 h. GC yields using dodecane as an internal
standard. The data in parentheses are the isolated yields.
General information, experimental procedures, charac-
1
terized data, and copies of H and 13C NMR and 19F
NMR spectroscopies (PDF)
AUTHOR INFORMATION
Corresponding Author
example, adapalin, a clinical drug for skin disease, was readily
trifluoromethylated to produce 3ac in 80% yield. Probenecid is
used as an antigout drug and an antibiotic adjuvant. It also
worked well to give the target product 3ad in 90% yield under
the reaction conditions. 3-Methylflavone-8-carboxylic acid is a
clinical drug for the treatment of coronary heart disease. It was
also transformed into the expected product 3ae in 80% yield.
By this strategy, telmisartan, a kind of antihypertensive drug,
was also proved to be the right substrate (3af).
■
Tieqiao Chen − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China; orcid.org/0000-0002-9787-
9538; Email: chentieqiao@hnu.edu.cn
Practically, this reaction was scalable. As shown in Scheme 3,
we chose the drug probenecid as the model substrate and
carried out three trifluoromethylation reactions on a 1, 2, and 5
mmol scale. After work up and isolation through a SiO2
chromatographic column, high yields were obtained for all
Authors
Xue Liu − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Long Liu − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Scheme 3. Gram-Scale Experiments
Tianzeng Huang − Key Laboratory of Ministry of Education
for Advanced Materials in Tropical Island Resources,
Hainan Provincial Key Lab of Fine Chem, Hainan
Provincial Fine Chemical Engineering Research Center,
Hainan University, Haikou 570228, China
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Jingjing Zhang − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Zhi Tang − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Chunya Li − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chem, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Partial financial support from the Key R&D project of Hainan
province (no. ZDYF2020168) and National Natural Science
Foundation of China (no. 21871070) is gratefully acknowl-
edged. We also thank Miss Mengjie Cen for reproducing 3f
and 3y by the strategy.
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