Regioselective Direct C-H Trifluoromethylation of Pyridine

Article abstract of DOI:10.1021/acs.orglett.0c02413

A highly efficient and regioselective direct C-H trifluoromethylation of pyridine based on an N-methylpyridine quaternary ammonium activation strategy has been developed. A variety of trifluoromethylpyridines can be obtained in good yield and excellent re

Full text of DOI:10.1021/acs.orglett.0c02413

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Letter
Regioselective Direct C−H Trifluoromethylation of Pyridine
Xiao Yang, Rui Sun, Shun Li, Xueli Zheng, Maolin Yuan, Bin Xu, Weidong Jiang, Hua Chen, Haiyan Fu,*
and Ruixiang Li*
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ABSTRACT: A highly efficient and regioselective direct C−H
trifluoromethylation of pyridine based on an N-methylpyridine
quaternary ammonium activation strategy has been developed. A variety
of trifluoromethylpyridines can be obtained in good yield and excellent
regioselectivity by treating the pyridinium iodide salts with trifluoro-
acetic acid in the presence of silver carbonate in N,N-dimethylforma-
mide. The protocol features good functional group compatibility, easily
available starting materials, and operational simplicity. Controlled
experiments showed that the reaction may involve a nucleophilic
trifluoromethylation mechanism.
rifluoromethyl has been proven to be an essential group
used a benchtop stable trifluoromethyl radical source, Langlois
reagent NaSO2CF3, to achieve direct pyridine trifluoromethy-
lation, which suffered from low regioselectivity and resulted in
mixed C2 and C3 trifluomethylation products. In the same year,
MacMillan7 reported the first example of a photoredox-based
method for direct C−H trifluoromethylation of pyridine using
triflyl chloride, TfCl, as the CF3 source. Togni8 later developed
a rhenium catalyzed electrophilic trifluoromethylation protocol
with the expensive hypervalent iodine reagent 1-(trifluor-
omethyl)-1,2-benziodoxol-3(1H)-one.
The system features a broad substrate scope, but the yields
and regioselectivities are generally low. In 2014, Kanai9 et al.
disclosed a direct pyridine C−H nucleophilic trifluoromethy-
lation with the Ruppert−Prakash reagent (MeSiCF3) by
employing pyridine N-oxides activated by trifluoromethyl-
difluoroborane (BF2CF3). Although the reaction exhibits
excellent regioselectivity, the activated substrate N-oxide−
BF2CF3 complex brought about inconvenient multiple
synthetic procedures. In the same year, the Larionov10 group
also used the MeSiCF3 reagent to carry out the trifluor-
omethylation reaction of quinoline on a quinoline nitrogen
oxide substrate, but in this nitrogen oxide compound system,
the reaction activity of pyridine is very low.
T
in pharmaceutical chemistry and material science.1 When
it is introduced into the molecule, it can significantly improve
the lipophilicity, metabolic stability, and bioavailability of
compounds.2 Pyridines are valuable pharmacophores, and the
development of methodology for introducing the trifluor-
omethyl and its related groups onto the pyridine has received
great interest.3
Traditionally, CF3 is installed by transitional metal mediated
or catalyzed cross-coupling reaction with prefunctionalized
pyridines (Scheme 1).4 From the viewpoint of step and atom
Scheme 1. Preparation of 2-Trifluoromethylpyridine from
Pyridine Derivatives
Despite these advancements in pyridine C−H direct
trifluoromethylation, a number of limitations still remain,
such as narrow substrate cope, low activity and regioselectivity,
or using expensive trifluoromethylating reagents. Thus, a
economy, direct C−H trifluoromethylation of pyridine would
be a more straightforward and efficient method for installing
the CF3 group to the pyridine ring.5 However, the direct C−H
trifluoromethylation of pyridine is a quite challenging task, and
only a handful of successful examples have been reported in
the literature to date. Among them, this transformation has
been achieved by using a radical, electrophilic, or nucleophilic
trifluoromethylating reagents. In 2011, Baran6 and co-workers
Received: July 21, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02413
© XXXX American Chemical Society
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simple protocol for the direct C−H trifluoromethylation of
pyridine with high site selectivity and activity is still desirable.
The cheap and easily available trifluoroacetic acid would be
an appealing trifluoromethylating reagent, which releases the
carbon dioxide as only a side product after the reaction.
However, to our surprise, only rare examples of pyridine
trifluoromethylation using trifluoroacetic acid has been
reported. Very recently, Li11 and Budnikova12 groups
independently achieved (hetero)arene trifluoromethylation
using trifluoroacetic acid, by means of photocatalysis and
Ag/SiO2-based heterogeneous catalysis, respectively. Nonethe-
less these systems suffered from the low reactivity and
regioselectivity, particularly for pyridine compounds. In recent
years, our group has developed a new activation strategy for
pyridine C−H functionalization by using pyridinium salts as
the pyridine surrogate.13,14 The formation of pyridinium salts
greatly increases the acidity of C−H bond ortho to the pyridine
nitrogen and, hence, improves the reaction reactivity and site
selectivity.15 We envision that an efficient and regioselective
pyridine trifluoromethylation would be achievable by using the
same strategy. Herein, we report a regioselective trifluorome-
thylation of pyridines by using N-methylpyridinium iodide salts
in combination with trifluoroacetic acid.
small amount of byproduct 2-phenylpyridine (resulted from
the N-demethylation of the substrate) being detected. The
structure of the product was fully characterized by NMR
spectra. Then, different silver sources such as CF3COOAg,
AgOAc, Ag2O, and Ag2CO3 were investigated, and Ag2CO3
afforded the desired product in the best yield (entries 2−5).
The most appropriate amount of Ag2CO3 was proven to be 2
equiv (entries 6−9). Either increasing or decreasing the
amount of Ag2CO3 decreased the yields gradually. The attempt
to make the reaction catalytic by using K2S2O8 also failed
(entries 10−11). Investigation of the solvent effect revealed
that the polar solvent DMA is the best one. The reaction also
occurs in N,N-dimethylformamide (DMF), but gave a
significantly lower yield of 57%. Whereas the use of nonpolar
or less polar solvent such as toluene, acetonitrile, dioxane, and
1,2-dichloroethane only led to a trace amount of products
(entries 12−16). In consideration of the good solubilities of
pyridinium salts in water, an aqueous system was also
employed, but still no reaction took place (entry 17). Using
the traditional Minisci reaction conditions, the reaction did not
occur (entry 18). In the case of CF3COOAg instead of
Ag2CO3/CF3COOH as the CF3 precursor, the desired
products were only obtained in moderate yields, which
highlights the high efficiency of the in situ generated silver
trifluoroacetate on this transformation (entry 19). Finally, the
optimal conditions were selected as follows: treatment of 0.25
mmol of N-methyl-2-phenylpyridinium iodide with 0.75 mmol
of trifluoroacetic acid in the presence of 2.0 equiv of Ag2CO3
in DMA (0.25 M) at 150 °C under air for 24 h.
We initiated our investigation by coupling N-methyl-2-
phenylpyridinium iodide (1a) with trifluoroacetic acid (2a) in
the presence of AgNO3 as an oxidant in N,N-dimethyl-
acetamide (0.25 M) at 150 °C under air for 24 h (Table 1).
Gratifyingly, the desired product 2-phenyl-6-trifluoromethyl-
pyridine was successfully obtained in 32% yield (entry 1), with
the majority of the substrate pyridinium salt recovered, and a
With the optimized reaction conditions in hand, we set out
to explore the scope of N-methylpyridinium iodide salts
(Scheme 2). For the 2-arylpyridinium salts with substituents at
the 3, 4, or 5 position of the pyridine ring, the corresponding
trifluoromethylated pyridine can be obtained in good yield
(2a−h). When the substituents are electron-donating groups
(EDGs), the corresponding products can be obtained in good
to excellent yields (2b, 2d−e), with the exception of the 3-
MeO substituent which only resulted in a low yield of 38%
(2c). However, the presence of electron-withdrawing groups
(EWGs) on the pyridine ring totally inhibited the reaction and
resulted in an unidentified complex mixture. For 2-arylpyr-
idinium salts, good yields of trifluoromethylation products
were obtained (2i−r) regardless of whether there are electron-
rich or electron-poor substituents on the 2-aryl ring. In general,
the substrates bearing the EDGs at its 2-aryl groups afforded a
slightly higher yield than those with EWGs. Importantly, the
heteroaryl substituted substrates were also compatible with this
protocol, delivering the products (2s−u) with moderate yields
of 44−67%. The pyridinium salts containing the branched alkyl
groups at the 2-position of the pyridine ring gave moderate to
good yields (2v−z), whereas those with straight alkyl groups,
such as 1-methyl-2-pentylpyridin-1-ium iodide, only gave a
trace amount of product.14 The present reaction protocol was
extremely effective for the 3-arylpyridinium salts which have
two ortho-C−H bonds available. For instance, yields higher
than 90% were obtained for products 2aa−ae. Importantly,
exclusive monoselectivity was observed in all cases without
ditrifluoromethylation products being detected, but the two
different monotrifluoromethylation products were produced
with nearly equal amounts. For example, the pyridinium salt of
an antiprostate cancer drug, abiraterone acetate,16 reacted
under the standard conditions to afford two trifluoromethy-
lated products (2af) in a total yield of 91% with a ratio of
a
Table 1. Optimization of the Reaction Conditions
b
entry
Ag salt (equiv)
solvent (1 mL)
yield (%)
1
2
3
4
5
6
7
8
9
AgNO3 (2)
CF3COOAg (2)
Ag2O (2)
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
toluene
CH3CN
dioxane
DCE
32
57
68
59
74
57
70
56
AgOAc (2)
Ag2CO3 (2)
Ag2CO3 (1)
Ag2CO3 (1.5)
Ag2CO3 (2.5)
Ag2CO3 (3)
Ag2CO3 (0.1)
Ag2CO3 (0.2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
AgNO3 (0.1)
CF3COOAg (3)
48
c
10
11
trace
trace
56
trace
trace
trace
trace
trace
N.R.
55%
c
12
13
14
15
16
17
H2O
DMA
DMA
d
18
19
e
a
Reaction conditions: 1a (0.25 mmol), CF3COOH (0.75 mmol), 24
b
c
h, 150 °C under air. Isolated yield. 4.0 equiv of K2S2O8 were used.
d
Conditions of Minisci reaction: AgNO3 (0.025 mmol), (NH4)2S2O8
e
(0.75 mmol), CF3COOH (0.75 mmol), H2SO4 (20 mol %). Without
CF3COOH. DMA = N,N-dimethylacetamide. DMF = N,N-
dimethylformamide. DCE = 1,2-dichloroethane.
B
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The newly developed reaction conditions were also
applicable for polyfluoroalkylation of pyridine (Scheme 2).
For example, both the pentafluoropropionic acid and
heptafluorobutyric acid could successfully react with N-
methyl-2-(hetero)arylpyridinium iodide to give the corre-
sponding polyfluoroalkylation products 3a−h in good to
excellent yields.
Scheme 2. Substrate Scope of N-Methylpyridinium Salts and
Perfluoroalkyl Carboxylic Acid
a b
,
Subsequently, the two independent parallel reactions and a
one-pot intermolecular competitive reaction between 1a and
1a-d1 or 1a-d4 were performed to determine the kinetic
isotopic effects (KIE) of this reaction (see Supporting
Information (SI) for details). The KIE values of 1.9 and 1.6
were obtained, respectively, suggesting that the cleavage of the
C−H bond might be the rate-determining step of the reaction.
In order to verify whether the reaction is a radical or an ionic
mechanism, we added the free radical inhibitors 2,2,6,6-
tetramethylpiperidinooxy (TEMPO) into the reaction system
under the standard conditions, and found that the reaction
proceeded equally efficiently without a significant decrease in
yield. In addition, the free radical trapping experiments by
reacting TEMPO, butylated hydroxytoluene (BHT), or 1,1-
diphenylethylene with trifluoroacetic acid under standard
conditions resulted in no formation of CF3 radical combined
products, which indicated that the reaction is not likely to
involve the radical mechanism (see the SI for details).
Of note, either 2-phenylpyridine itself or its N-oxide and N-
ylide failed to undergo the trifluoromethylation reaction under
the standard conditions (see the SI for details). In order to
further understand the advantages of the N-methylpyridinium
salt activation strategy, the energy of the LUMO of 2-
phenylpyridine, 2-phenylpyridine N-oxide, 2-phenylpyridinium
ylide, and N-methylpyridine quaternary ammonium salt were
calculated with the Gaussian algorithm. The calculated LUMO
energies are −1.14, −1.30, −1.89, and −6.19 eV, respectively
(Figure 1). Kuninobu and Kanai9 have reported that the N-
Figure 1. Comparison of LUMO levels of several pyridine derivatives.
rb3lyp/6-31g* for (A-C); rb3lyp/6-31+g* for (D). Bz = benzoxyl.
heteroaromatics with a lower LUMO level is more prone to
occur in the dearomatizing nucleophilic addition by the CF3
group. Accordingly, the trifluoromethylation of the N-
methylpyridinium salt, which has the lowest LUMO level,
most likely proceeds via dearomatizing nucleophilic addition of
the CF3 group to the pyridinium salt, followed by a
rearomatization mechanism. In addition, the comparison of
chemical shifts of protons at the 6-position of the
aforementioned four pyridine derivatives (see the SI for
details) revealed that N-methyl-2-phenylpyridinium iodide has
the lowest electron density at the C6−H bond. This
experimental evidence further supported that the prior
formation of the pyridinium salt is the most efficient activation
strategy for pyridine C−H bond functionalization.
a
Reaction conditions: 1a−z, 1aa-ai (0.25 mmol), CnF2n+1COOH
(0.75 mmol), Ag2CO3 (0.5 mmol), 24 h, 150 °C under air in a sealed
b
c
tube. Isolated yield. 1.0 mmol of N-methyl-2-phenylpyridinium
iodide was used.
48:43. Whereas the symmetrical 4-tert-butylpyridinium salt
gave rise to a very clean reaction, affording monotrifluoro-
methylated product 2ag in 92% yield. It should be noted that
quinolium and isoquinolinium iodide salts are less reactive
under the standard conditions. For instance, the 7-methyl N-
methylquinolinium iodide salt only delivered the desired
product 2ah1 in less than 16% yield, accompanied by a small
amount of quinolinium dearomatizating addition byproduct
1,7-dimethyl-2-(trifluoromethyl)-1,2-dihydroquinoline (2ah2).
Lindhardt’s group17 has developed a decarboxylative
trifluoromethylation of (iso)quinoline derivatives by using
methyltrifluoroacetate (MTFA) as the CF3 anion precursor,
wherein 2-methyl-(1-trifluoromethyl)-1,2-dihydro(iso)-
quinolines were produced as the product. The author
C
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attributed the reaction efficiency to the in situ formation of the
(iso)quinolinium trifluoroacetate, and the DMF solvent cage
stabilized (iso)quinolinium−CF3 anion ion pairs. In our
system, the in situ formed CF3COOAg by the reaction of
Ag2CO3 and CF3COOH in DMA could serve as a CF3 anion
precursor. The anion exchange between CF3COOAg and
pyridinium iodide salts would occur to produce pyridinium
trifluoroacetate. Indeed, the reaction of the preformed N-
methylpyridinium trifluoroacetate (4) under the standard
conditions in the absence of CF3COOH afforded the 2-
phenyl-6-trifluoromethylpyridine in a comparable yield of 68%
(Scheme 3a). By analogy, the reaction might also proceed via a
removed by the nucleophilic attack with the anion in the
system13,15 to give the final product (Scheme 4)
In summary, a highly selective direct C2−H trifluoromethy-
lation of pyridine using cheap and commercially available
trifluoroacetic acid has been developed by employing the N-
methylpyridinium salt activation strategy. Compared with the
reported pyridine trifluoromethylation system, the present
system features high reactivity, excellent regioselectivity, and
good functional group tolerance. The preliminary mechanism
studies showed that a nucleophilic trifluoromethylation process
might be involved.
ASSOCIATED CONTENT
■
Scheme 3. CF3 Anion Verification Experiment
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02413.
Experimental details and full spectroscopic data for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Haiyan Fu − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China; orcid.org/0000-0002-7185-
2062; Email: scufhy@scu.edu.cn
Ruixiang Li − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China;
orcid.org/0000-0003-0756-3722; Email: liruixiang@
scu.edu.cn
nucleophilic addition of the CF3 anion to the pyridinium salts
pathway.17,18 Although the corresponding CF3 anion adduct
product could not be detected, possibly due to its rapid
transformation to the trifluoromethylated pyridine, subjecting
the 1-methylquinolinium iodide (5) under the standard
conditions led to formation of 1-methyl-2-(trifluoromethyl)-
1,2-dihydroquinoline (6) in 29% isolated yield (Scheme 3b).
In addition, a CF3 anion captured product, 2,2,2-trifluoro-1-
phenylethanol, was detected by GC-MS in the CF3 anion
trapping experiment using benzaldehyde as the electrophile
(Scheme 3c). This result further indicated that the reaction
followed a nucleophilic trifluoromethylation pathway.
Authors
Xiao Yang − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
On the basis of the literature and our experimental results, a
plausible mechanism shown in Scheme 4 was proposed. First,
Rui Sun − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
Shun Li − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
Scheme 4. Proposed Reaction Mechanism
Xueli Zheng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China;
orcid.org/0000-0001-8394-0310
Maolin Yuan − Key Laboratory of Green Chemistry &
Technology, Ministry of Education College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China
Bin Xu − School of Chemistry and Environmental Engineering,
Sichuan University of Science & Engineering, Sichuan, Zigong
643000, P. R. China
Weidong Jiang − School of Chemistry and Environmental
Engineering, Sichuan University of Science & Engineering,
Sichuan, Zigong 643000, P. R. China
Hua Chen − Key Laboratory of Green Chemistry & Technology,
Ministry of Education College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China; orcid.org/0000-0003-4248-
8019
the reaction of trifluoroacetic acid with silver carbonate
produces silver trifluoroacetate, which undergoes the anion
exchange with substrate N-methyl-2-phenylpyridinium iodide
to give N-methylpyridinium trifluoroacetate (I). Then the
decarboxylation occurs on I under high temperature (150
°C)19 to form a solvent cage stabilized intermediate (II).17
Subsequently the CF3 anion nucleophilically attacks the
pyridinium salt in a regioselective manner to produce the
dearomatizated intermediate (III), which is then oxidized18b,20
by silver salt to afford the trifluoromethylated N-methylpyr-
idinium salts (IV), and then the methyl group might be
Complete contact information is available at:
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D
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Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21871187, 21572137) and the Opening Project of Key
Laboratory of Green Chemistry of Sichuan Institutes of Higher
Education (LZJ1901) and the Key Program of Sichuan Science
and Technology Project (2019YFG0146) for their financial
support. We also thank Chunchun Zhang from the Centre of
Testing & Analysis, Sichuan University, for NMR measure-
ments.
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