Palladium-Catalyzed Dehydrogenative Fluoroalkoxylation of Benzaldehydes

Article abstract of DOI:10.1021/acs.orglett.1c00365

A direct and efficient palladium-catalyzed oxidative dehydrogenative fluoroalkoxylation of benzaldehydes is reported here for the first time. The method features mild reaction conditions, good tolerance of functional groups, and a broad substrate scope. The protocol employs the transient directing group strategy, thereby avoiding the additional installation and removal of directing groups, endowing the method with great advantages of atom and step economy. The approach should find broad applications in drug synthesis and discovery processes.

Full text of DOI:10.1021/acs.orglett.1c00365

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Dehydrogenative Fluoroalkoxylation of
Benzaldehydes
Long Jin, Xing-Long Zhang, Rui-Li Guo, Meng-Yue Wang, Ya-Ru Gao, and Yong-Qiang Wang*
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ABSTRACT: A direct and efficient palladium-catalyzed oxidative dehydrogenative fluoroalkoxylation of benzaldehydes is reported
here for the first time. The method features mild reaction conditions, good tolerance of functional groups, and a broad substrate
scope. The protocol employs the transient directing group strategy, thereby avoiding the additional installation and removal of
directing groups, endowing the method with great advantages of atom and step economy. The approach should find broad
applications in drug synthesis and discovery processes.
fluoroalkyl aryl ethers.4,5 Traditionally, fluoroalkyl aryl ethers
luorine-containing compounds, on the basis of their
have been prepared via nucleophilic substitution or transition-
Funique special pharmacokinetic and physicochemical
metal-mediated cross-coupling of phenols or aromatic halides
with fluorine partners (Figure 2a).4 Recently, Ji and Li et al.
realized the trifluoroethoxylation of benzamides through a C−
H bond activation strategy with amide groups as the directing
groups (Figure 2b).5 Compared with traditional methods,
direct C−H bond functionalization has obvious benefits in
terms of step and atom economy. However, the existing
methods require preinstallation of amide-based directing
groups. Furthermore, the amide groups are generally removed
under strong acid (e.g., aq. HCl5a) or base (e.g., NaOH,5c,d
LiOH5b,g) conditions, which greatly limits the application of
the method, in particular, in the late-stage transformation of
advanced synthetic intermediates.
properties, play important roles in the fields of pharmaceut-
icals, agrochemicals, and materials science.1 Among fluorine-
containing compounds, fluoroalkyl aryl ethers are widely used
in medicinal chemistry due to the high metabolic stability,
electron-withdrawing effect, and increasing lipophilicity of
fluoroalkoxy groups.2 Representative examples include the
multibillion-dollar proton pump inhibitor lansoprazole, the
antiarrhythmic flecainide, the antibenign prostatic hyperplasia
silodosin, and idalopirdine (Figure 1).3 Consequently, it is
highly desirable to develop an efficient synthetic method for
Benzaldehydes, as common organic chemicals, are the key
starting materials for the synthesis of many biologically active
compounds and functional materials.6 Therefore, the develop-
ment of the direct C−H functionalization of benzaldehydes is
extremely valuable. But such a promising transformation is a
challenge due to the aldehyde’s susceptibility toward
oxidation7 and undesired reactions of the acyl C−H bond
Received: January 31, 2021
Published: February 19, 2021
Figure 1. Drugs containing fluorinated alkyl aryl ethers.
https://dx.doi.org/10.1021/acs.orglett.1c00365
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1921−1927
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Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
Pd source
amino acid
oxidant
K2S2O8
yield (%)
c
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
A1
A1
A2
A3
A4
A5
A6
A7
A8
A6
A6
A6
A6
A6
A6
A6
A6
A6
A6
0
31
0
2
3
4
5
6
7
8
9
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
other oxidants
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Figure 2. Synthetic methods of the fluoroalkyl aryl ethers.
20
28
12
61
21
46
<32
62
36
15
0
21
0
38
71
72
(e.g., metal insertion).8 Herein we disclose an efficient
palladium-catalyzed direct C−H oxidative fluoroalkoxylation
of benzaldehydes (Figure 2c). This approach exploits a
transient directing group (TDG) strategy, thereby avoiding
additional installation and removal steps of the directing
group.9 To our knowledge, this is the first report of the
efficient dehydrogenative fluoroalkoxylation of benzaldehydes
with fluorinated alcohols.10
d
10
11
12
13
14
15
PdI2
Our study began with extensive transient directing amino
acid screening with benzaldehyde (1a) and trifluoroethanol
(TFE, 2) as the model substrates, Pd(OAc)2 as the catalyst,
and K2S2O8 as the oxidant (Table 1). First, 2-aminoisobutyric
acid was investigated at 80 °C. Unfortunately, no obvious
reaction was observed (entry 1). Considering that trifluoro-
acetic acid (TFA) and Pd(OAc)2 can facilely generate a more
active [Pd(II)O2CCF3]+ species,14a TFA (2.0 equiv) was
added to the reaction system. To our delight, the reaction gave
the desired trifluoroethoxylated product 3a in 31% isolated
yield (entry 2). Then, other amino acids were tested. No
reaction occurred with β-amino acid A2 (entry 3). All α-amino
acids A3−A8 could give the product 3a, and A6 afforded the
best result (entries 4−9). More amino acids and other types of
transient directing reagents were tested but gave inferior yields.
(See the Supporting Information (SI).) Then, we tested
different oxidants and found that K2S2O8 was still the best
(entry 10). Different types of palladium sources have been
examined successively (entries 11−15). Pd(TFA)2 and Pd-
(OAc)2 provided similar results. In view of the cost, we still
chose the more economical Pd(OAc)2. When TFA was
replaced by the same amount of AcOH, the reaction could
not proceed, demonstrating the importance of TFA (entry 16).
The amounts of A6 and TFA had a significant effect on the
reaction, and A6 (50 mol %) and TFA (2.0 equiv) were still
preferred. (See the SI.) Increases or decreases in the reaction
temperature led to an obvious drop in the yield. (See the SI.)
Finally, the amount of Pd(OAc)2 was investigated. Pd(OAc)2
(15 mol %) could provide the desired product 3a in 71%
isolated yield, and more Pd(OAc)2 loading did not lead to a
clear improvement in yield (entries 17−19). Accordingly, the
optimized reaction conditions were determined to be as
follows: Pd(OAc)2 (15 mol %), amino acid A6 (50 mol %),
K2S2O8 (2.0 equiv), and TFA (2.0 equiv) at 80 °C.
Pd(PPh3)2Cl2
Pd(OH)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
e
16
f
17
18
g
h
19
a
Reaction conditions: 1a (0.2 mmol), 2 (0.8 mL, 11 mmol), [Pd] (10
mol %), amino acid (50 mol %), oxidant (0.4 mmol), TFA (2 equiv),
b
c
d
and open to air for 12 h. Isolated yield. Without TFA. Other
oxidants: (NH4)2S2O8, Na2S2O8, p-benzoquinone (BQ), PhI(OAc)2,
Ag2CO3, and O2 (1 atm). 2.0 equiv of AcOH was added, without
TFA. Pd(OAc)2 (5 mol %). Pd(OAc)2 (15 mol %). Pd(OAc)2 (20
mol %).
e
f
g
h
benzaldehydes (Scheme 1). We were delighted to find that
various para substituents (alkyl groups, halides, phenyl, ether,
trifluoromethyl, and ester) with various steric and electronic
properties were well tolerated, affording the desired products
in good yields (3a−3l). It should be mentioned that
benzaldehydes with electron-withdrawing groups reacted faster
than those with electron-donating groups. Satisfactory results
were also obtained with Me, Cl, Br, CF3, NO2, and CO2Me
substituted at the meta position of benzaldehydes (3m−3r). It
is noteworthy that a derivative of the biologically active L-
menthol also afforded the corresponding product in good yield
(3s). Benzaldehydes substituted at the ortho position, which
usually were difficult substrates because of steric hindrance,
were also well tolerated, providing the products in 51−80%
yields (3t−3x). Gratifyingly, disubstituted and trisubstituted
benzaldehydes were also suitable substrates, affording corre-
sponding products in moderate to good yields (3y−3af).
Interestingly, 2-naphthylaldehydes gave normal 3-trifluoroe-
thoxylation products (3ag, 3ah), whereas 1-naphthylaldehyde
afforded 8-trifluoroethoxylation product (3ai). Both kinds of
naphthylaldehyde substrates presented complete respective
With the optimal reaction conditions in hand, the direct C−
H oxidative trifluoroethoxylation was applied to different
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a
a
Scheme 1. Scope of Aldehydes
Scheme 2. Difluoroalkoxylation
a
Reaction conditions: 1 (0.4 mmol), 2 (1.6 mL, 22 mmol), Pd(OAc)2
(0.06 mmol), amino acid (0.2 mmol), oxidant (0.8 mmol), and TFA
(0.8 mmol) under air at 80 °C for 24 h. All yields given are those for
the isolated products.
rich group; therefore, it is unfavorable for the second
fluoroalkoxylation.
Next, we moved on to test other fluorinated alcohols with
benzaldehyde, m-methylbenzaldehyde, and o-fluorobenzalde-
hyde as the partners (Scheme 3). To our delight, these
Scheme 3. Fluoroalkoxylation with Other Fluorinated
a
Alcohols
a
Reaction conditions: 1 (0.4 mmol), 4 (1.6 mL), Pd(OAc)2 (0.06
mmol), amino acid (0.2 mmol), oxidant (0.8 mmol), and TFA (0.8
mmol) under air at 80 °C for 12 h. All yields given are those for the
isolated products.
a
Reaction conditions: 1 (0.4 mmol), 2 (1.6 mL, 22 mmol), Pd(OAc)2
(0.06 mmol), amino acid (0.2 mmol), oxidant (0.8 mmol), and TFA
(0.8 mmol) under air at 80 °C for 12 h. All yields given are those for
the isolated products.
benzaldehydes could react smoothly with 2,2-difluoroethanol,
2,2,3,3-tetrafluoro-1-propanol, 1,1,1,3,3,3-hexafluoro-2-propa-
nol, and 2,2,3,3,4,4,4-heptafluoro-1-butanol under the optimal
reaction conditions, generating the corresponding fluoroal-
koxylated products in 53−76% yields (5a−5l). In these
reactions, we could not detect a difluoroalkoxylation product
in the reaction system. More valuable fluorinated alcohols,
such as 2,2,3,3-tetrafluoro-1-propanol and 2,2,3,3,4,4,4-hepta-
fluoro-1-butanol, possess higher boiling points, and their
amount could be decreased to 1.0 mL for 0.4 mmol of 1
without a reduction in yield. Note that nonafluoro-tert-butanol
was not a suitable substrate, probably due to the steric
hindrance effect. It should be mentioned that 2-fluoroethanol
and nonfluorinated alcohols, such as methanol and ethanol,
could not afford the corresponding alkoxylative products under
the current reaction conditions.12,13 Furthermore, it is
noteworthy that although the current reaction conditions
were oxidative, the oxidized product of fluorinated alcohols,
such as trifluoroacetaldehyde and heptafluorobutyraldehyde,
could not be detected in all reaction systems.
regioselectivity. The structures of 3r, 3ag, and 3ai were
confirmed by single-crystal X-ray diffraction. (See the SI.)
It is worth mentioning that ortho functionalization of arenes
generally suffers from poor mono- versus diselectivity.11 In this
dehydrogenative fluoroalkoxylation of benzaldehydes, we
found that the extension of the reaction time to 24 h would
lead to the formation of a small amount of the difluoroalkox-
ylation products 3a′−3f′ for substrates 1a−1f (Scheme 2; it
did not improve the yields of 3a′−3f′ for longer than 24 h),
and the yield of the monofluoroalkoxylation products 3a−3f
was decreased accordingly. For other substrates, difluoroalkox-
ylation products could not be detected, even when extending
the reaction time to 72 h. Moreover, we found that the
diarylation could not be improved by increasing the amount of
oxidant or alcohol, demonstrating that the approach possessed
good selectivity for the monoarylation. Although the exact
reason for the monofluoroalkoxylative selectivity was not clear,
we suspected that it might be ascribed to the reaction
mechanism of the concerted metalation−deprotonation
(CMD; see later). The fluoroalkoxyl group is an electron-
To test the practicality of the developed oxidative
dehydrogenative fluoroalkoxylation, we conducted the reaction
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on 15 mmol of 1a to couple to 2, and 1.78 g (58% yield) of
product 3a was isolated (eq 1).
To gain insight into the reaction mechanism, we
independently synthesized the putative palladacycle inter-
mediate (eq 2). Pleasingly, the cyclopalladium intermediate 6
was isolated from the reaction system of benzaldehyde with
stoichiometric Pd(OAc)2, pyridine, and A6.14d,15 Then, the
cyclopalladium intermediate 6 was treated with TFE, K2S2O8,
and TFA to give 3a in 55% yield (eq 3). Subsequently, kinetic
Figure 3. Proposed mechanism.
species is generated in situ from Pd(OAc)2 with TFA.14 The
coordination of an α-imino acid A to a Pd(II) species
generates a palladium complex B.17 The five-membered ring
intermediate C is formed by an intramolecular C−H bond
activation of the intermediate B, probably through a CMD
process.14b,18 The intermediate C is oxidized by persulfate to
generate the Pd(IV) species D, which is fluoroalkoxylated by
fluorinated alcohol to provide intermediate E;19 then, the
following reductive elimination results in product formation
and Pd catalyst regeneration.
In summary, an efficient protocol for the synthesis of
fluoroalkyl aryl ethers was developed by using the palladium-
catalyzed dehydrogenative fluoroalkoxylation of benzaldehydes
with fluorinated alcohols. The synthetic method features mild
reaction conditions, good tolerance of functional groups, and a
broad substrate scope. The approach employs a transient
directing group strategy, thereby possessing the advantages of
atom and step economy. Given the importance of the
fluoroalkyl aryl ether motif in medicinal chemistry, the
approach should find broad applications in drug synthesis
and discovery processes.20 Detailed mechanism and applica-
tion studies are currently ongoing in our laboratory.
isotope effect (KIE) experiments were performed (eqs 4 and
5). The KIE value of two parallel reactions of 1a with 2 and
ASSOCIATED CONTENT
[D3]-2 was found to be 1.1, and the intramolecular KIE value
for the reaction of [D]-1a was 3.8, indicating the cleavage of
the C−H bond of the aromatic ring involved in the rate-
determining step. As previously mentioned, electron-deficient
substrates 1 reacted faster than electron-rich substrates, and
only a few cases found a small amount of difluoroalkoxylation
products. These results and the intramolecular KIE value (3.8)
showed that the mechanism was likely a CMD process but not
an electrophilic aromatic palladation.14b
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00365.
Experimental details and characterization data (PDF)
Accession Codes
CCDC 2038545−2038547 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
On the basis of the above results and related literature,5g,15,16
a possible mechanism for the palladium-catalyzed C−H
oxidative fluoroalkoxylation of benzaldehydes was proposed
(Figure 3). First, benzaldehyde and amino acid A6 reversibly
form imine intermediate A.15 Meanwhile, the active Pd(II)
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Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−2506.
(k) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,
N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem.
2015, 58, 8315−8359. (l) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D.
Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and
Trifluoromethylation, and Trifluoromethylthiolation Reactions. Chem.
Rev. 2015, 115, 826−870. (m) Ahrens, T.; Kohlmann, J.; Ahrens, M.;
Braun, T. Functionalization of Fluorinated Molecules by Transition-
Metal-Mediated C−F Bond Activation To Access Fluorinated
Building Blocks. Chem. Rev. 2015, 115, 931−972. (n) Alonso, C.;
Martínez de Marigorta, E.; Rubiales, G.; Palacios, F. Carbon
Trifluoromethylation Reactions of Hydrocarbon Derivatives and
Heteroarenes. Chem. Rev. 2015, 115, 1847−1935.
(2) (a) Irurre, J.; Casas, J.; Messeguer, A. Resistance of the 2,2,2-
trifluoroethoxy aryl moiety to the cytochrome P-450 metabolism in
rat liver microsomes. Bioorg. Med. Chem. Lett. 1993, 3, 179−182.
(b) Reddy, M. R.; Shibata, N.; Kondo, Y.; Nakamura, S.; Toru, T.
Design, Synthesis, and Spectroscopic Investigation of Zinc Dodecakis
(trifluoroethoxy) phthalocyanines Conjugated with Deoxyribonucleo-
sides. Angew. Chem., Int. Ed. 2006, 45, 8163−8166. (c) Yoshiyama,
H.; Shibata, N.; Sato, T.; Nakamura, S.; Toru, T. Synthesis and
properties of trifluoroethoxy-coated binuclear phthalocyanine. Chem.
Commun. 2008, 1977−1979. (d) Begue, J.-P.; Bonnet-Delpon, D.
Bioorganic and Medicinal Chemistry of Fluorine; Wiley: Hoboken, NJ,
2008.
AUTHOR INFORMATION
■
Corresponding Author
Yong-Qiang Wang − Key Laboratory of Synthetic and
Natural Functional Molecule Chemistry of Ministry of
Education, Department of Chemistry & Materials Science,
Northwest University, Xi’an 710069, China; orcid.org/
0000-0002-2774-3248; Email: wangyq@nwu.edu.cn
Authors
Long Jin − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, China
Xing-Long Zhang − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, China
Rui-Li Guo − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, China
Meng-Yue Wang − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, China
(3) Legros, J.; Dehli, J. R.; Bolm, C. Applications of Catalytic
Asymmetric Sulfide Oxidations to the Syntheses of Biologically Active
Sulfoxides. Adv. Synth. Catal. 2005, 347, 19−31.
(4) (a) Nakai, T.; Tanaka, K.; Ishikawa, N. The reaction of 2,2,2-
trifluoroethyl iodide with sodium phenolate. A novel competition
between substitution and elimination reactions. J. Fluorine Chem.
Ya-Ru Gao − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, China; orcid.org/0000-0002-
6057-1652
̀
1977, 9, 89−93. (b) Camps, F.; Coll, J.; Messeguer, A.; Pericas, M. A.
A Simple Method for Preparation of Aryl 2,2,2-Trifluoroethyl Ethers.
Synthesis 1980, 1980, 727−728. (c) Idoux, J. P.; Gupton, J. T.;
McCurry, C. K.; Crews, A. D.; Jurss, C. D.; Colon, C.; Rampi, R. C.
Aromatic fluoroalkoxylation via direct aromatic nucleophilic sub-
stitution. J. Org. Chem. 1983, 48, 3771−3773. (d) Suzuki, H.;
Matuoka, T.; Ohtsuka, I.; Osuka, A. Copper(l)-Assisted Synthesis of
Aryl 2,2,2-Trifluoroethyl Ethers. Synthesis 1985, 1985, 499−500.
(e) Kamal, A.; Pratap, T. B.; Ramana, K. V.; Ramana, A. V.; Babu, A.
H. Facile and efficient synthesis of fluoroalkyl aryl ethers. Tetrahedron
Lett. 2002, 43, 7353−7355. (f) Quach, T. D.; Batey, R. A.
Copper(II)-Catalyzed Ether Synthesis from Aliphatic Alcohols and
Potassium Organotrifluoroborate Salts. Org. Lett. 2003, 5, 1381−
1384. (g) Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-Delpon, D.
Facile Access to Fluorinated Aryl and Vinyl Ethers through Copper-
Catalysed Reaction of Fluoro Alcohols. Eur. J. Org. Chem. 2009, 2009,
3513−3518. (h) Shen, X.; Neumann, C. N.; Kleinlein, C.; Goldberg,
N. W.; Ritter, T. Alkyl Aryl Ether Bond Formation with PhenoFluor.
Angew. Chem., Int. Ed. 2015, 54, 5662−5665. (i) Huang, R.; Huang,
Y.; Lin, X.; Rong, M.; Weng, Z. Well-Defined Copper(I)
Fluoroalkoxide Complexes for Trifluoroethoxylation of Aryl and
Heteroaryl Bromides. Angew. Chem., Int. Ed. 2015, 54, 5736−5739.
(j) Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D.
W. Switching on elusive organometallic mechanisms with photoredox
catalysis. Nature 2015, 524, 330−334. (k) Zhang, K.; Xu, X.-H.; Qing,
F.-L. Copper-catalyzed oxidative trifluoroethoxylation of aryl boronic
acids with CF3CH2OH. J. Fluorine Chem. 2017, 196, 24−31.
(l) Wang, D.-Y.; Yang, Z.-K.; Wang, C.; Zhang, A.; Uchiyama, M.
From Anilines to Aryl Ethers: A Facile, Efficient, and Versatile
Synthetic Method Employing Mild Conditions. Angew. Chem., Int. Ed.
2018, 57, 3641−3645. (m) Zhang, H.; Ruiz-Castillo, P.; Buchwald, S.
L. Palladium-Catalyzed C−O Cross-Coupling of Primary Alcohols.
Org. Lett. 2018, 20, 1580−1583. (n) Laffoon, S. D.; Chan, V. S.;
Fickes, M. G.; Kotecki, B.; Ickes, A. R.; Henle, J.; Napolitano, J. G.;
Franczyk, T. S.; Dunn, T. B.; Barnes, D. M.; Haight, A. R.; Henry, R.
F.; Shekhar, S. Pd-Catalyzed Cross-Coupling Reactions Promoted by
Biaryl Phosphorinane Ligands. ACS Catal. 2019, 9, 11691−11708.
(o) Chen, Z.; Jiang, Y.; Zhang, L.; Guo, Y.; Ma, D. Oxalic Diamides
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from National Natural
Science Foundation of China (nos. NSFC-21572178, NSFC-
21702162, and NSFC-21971206).
REFERENCES
■
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Fluorine in
Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317,
1881−1886. (b) Tressaud, A.; Haufe, G. Fluorine and Health:
Molecular Imaging, Biomedical Materials and Pharmaceuticals; Elsevier:
London, 2008. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320−
330. (d) Hagmann, W. K. The Many Roles for Fluorine in Medicinal
Chemistry. J. Med. Chem. 2008, 51, 4359−4369. (e) Ojima, I. Fluorine
in Medicinal Chemistry and Chemical Biology; Wiley: Hoboken, NJ,
2009. (f) Furuya, T.; Kamlet, A. S.; Ritter, T. Catalysis for fluorination
and trifluoromethylation. Nature 2011, 473, 470−477. (g) Berger, R.;
Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Organic fluorine
compounds: a great opportunity for enhanced materials properties.
Chem. Soc. Rev. 2011, 40, 3496−3508. (h) Tomashenko, O. A.;
Grushin, V. V. Aromatic Trifluoromethylation with Metal Complexes.
Chem. Rev. 2011, 111, 4475−4521. (i) Liang, T.; Neumann, C. N.;
Ritter, T. Introduction of Fluorine and Fluorine-Containing Func-
tional Groups. Angew. Chem., Int. Ed. 2013, 52, 8214−8264. (j) Wang,
́
̌
J.; Sanchez-Roselló, M.; Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.;
Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in Pharmaceutical
Industry: Fluorine-Containing Drugs Introduced to the Market in the
1925
https://dx.doi.org/10.1021/acs.orglett.1c00365
Org. Lett. 2021, 23, 1921−1927

Organic Letters
pubs.acs.org/OrgLett
Letter
and tert-Butoxide: Two Types of Ligands Enabling Practical Access to
Alkyl Aryl Ethers via Cu-Catalyzed Coupling Reaction. J. Am. Chem.
Soc. 2019, 141, 3541−3549. (p) Szpera, R.; Isenegger, P. G.; Ghosez,
M.; Straathof, N. J. W.; Cookson, R.; Blakemore, D. C.; Richardson,
P.; Gouverneur, V. Synthesis of Fluorinated Alkyl Aryl Ethers by
Palladium-Catalyzed C−O Cross-Coupling. Org. Lett. 2020, 22,
6573−6577.
Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Functionalization of C(sp3)−H
bonds using a transient directing group. Science 2016, 351, 252−256.
(d) Yang, K.; Li, Q.; Liu, Y.; Li, G.; Ge, H. Catalytic C−H Arylation
of Aliphatic Aldehydes Enabled by a Transient Ligand. J. Am. Chem.
Soc. 2016, 138, 12775−12778. (e) Wu, Y.; Chen, Y.-Q.; Liu, T.;
Eastgate, M. D.; Yu, J.-Q. Pd-Catalyzed γ-C(sp3)−H Arylation of Free
Amines Using a Transient Directing Group. J. Am. Chem. Soc. 2016,
138, 14554−14557. (f) Xu, Y.; Young, M. C.; Wang, C.; Magness, D.
M.; Dong, G. Catalytic C(sp3)−H Arylation of Free Primary Amines
with an exo Directing Group Generated In Situ. Angew. Chem., Int. Ed.
2016, 55, 9084−9087. (g) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.;
Yu, J.-Q. Palladium-Catalyzed Transformations of Alkyl C−H Bonds.
Chem. Rev. 2017, 117, 8754−8786. (h) Liu, X.-H.; Park, H.; Hu, J.-H.;
Hu, Y.; Zhang, Q.-L.; Wang, B.- L.; Sun, B.; Yeung, K.-S.; Zhang, F.-
L.; Yu, J.-Q. Diverse ortho-C(sp2)−H Functionalization of Benzalde-
hydes Using Transient Directing Groups. J. Am. Chem. Soc. 2017, 139,
888−896. (i) Zhu, R.-Y.; Liu, L.-Y.; Yu, J.-Q. Highly Versatile β-
C(sp3)−H Iodination of Ketones Using a Practical Auxiliary. J. Am.
Chem. Soc. 2017, 139, 12394−12397. (j) Park, H.; Verma, P.; Hong,
K.; Yu, J.-Q. Controlling Pd(IV) reductive elimination pathways
enables Pd(II)-catalysed enantioselective C(sp3)−H fluorination. Nat.
Chem. 2018, 10, 755−762. (k) Gandeepan, P.; Ackermann, L.
Transient Directing Groups for Transformative C−H Activation by
Synergistic Metal Catalysis. Chem. 2018, 4, 199−222. (l) Li, F.; Zhou,
Y.; Yang, H.; Wang, Z.; Yu, Q.; Zhang, F.-L. Monodentate Transient
Directing Group Enabled Pd-Catalyzed Ortho-C−H Methoxylation
and Chlorination of Benzaldehydes. Org. Lett. 2019, 21, 3692−3695.
(m) Chen, Y.-Q.; Wu, Y.; Wang, Z.; Qiao, J. X.; Yu, J.-Q. Transient
Directing Group Enabled Pd-Catalyzed γ-C(sp3)−H Oxygenation of
Alkyl Amines. ACS Catal. 2020, 10, 5657−5662. (n) Xiao, L.-J.;
Hong, K.; Luo, F.; Hu, L.; Ewing, W. R.; Yeung, K.-S.; Yu, J.-Q. PdII−
Catalyzed Enantioselective C(sp3)−H Arylation of Cyclobutyl
Ketones Using a Chiral Transient Directing Group. Angew. Chem.,
Int. Ed. 2020, 59, 9594−9600. (o) St John-Campbell, S.; White, A. J.
P.; Bull, J. A. Methylene C(sp3)−H β,β′-Diarylation of Cyclo-
hexanecarbaldehydes Promoted by a Transient Directing Group and
Pyridone Ligand. Org. Lett. 2020, 22, 1807−1812. (p) Higham, J. I.;
Bull, J. A. Transient imine directing groups for the C−H
functionalisation of aldehydes, ketones and amines: an update
2018−2020. Org. Biomol. Chem. 2020, 18, 7291−7315.
(5) (a) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.;
Chen, G. Efficient Alkyl Ether Synthesis via Palladium-Catalyzed,
Picolinamide-Directed Alkoxylation of Unactivated C(sp3)−H and
C(sp2)−H Bonds at Remote Positions. J. Am. Chem. Soc. 2012, 134,
7313−7316. (b) Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.;
Zhang, S.-Q.; Shi, B.-F. Pd(II)-catalyzed alkoxylation of unactivated
C(sp3)−H and C(sp2)−H bonds using a removable directing group:
efficient synthesis of alkyl ethers. Chem. Sci. 2013, 4, 4187−4192.
(c) Roane, J.; Daugulis, O. Copper-Catalyzed Etherification of Arene
C−H Bonds. Org. Lett. 2013, 15, 5842−5845. (d) Zhang, L.-B.; Hao,
X.-Q.; Zhang, S.-K.; Liu, Z.-J.; Zheng, X.-X.; Gong, J.-F.; Niu, J.-L.;
Song, M.-P. Cobalt-Catalyzed C(sp2)−H Alkoxylation of Aromatic
and OlefinicCarboxamides. Angew. Chem., Int. Ed. 2015, 54, 272−275.
(e) Guo, X.-K.; Zhang, L.-B.; Wei, D.; Niu, J.-L. Mechanistic insights
into cobalt(II/III)-catalyzed C−H oxidation: a combined theoretical
and experimental study. Chem. Sci. 2015, 6, 7059−7071. (f) Selvaku-
mar, J.; Grandhi, G. S.; Sahoo, H.; Baidya, M. Copper-mediated
etherification of arenes with alkoxysilanes directed by an (2-
aminophenyl) pyrazole group. RSC Adv. 2016, 6, 79361−79365.
(g) Yang, L.; Li, S.; Cai, L.; Ding, Y.; Fu, L.; Cai, Z.; Ji, H.; Li, G.
Palladium-Catalyzed C−H Trifluoroethoxylation of N-Sulfonylbenza-
mides. Org. Lett. 2017, 19, 2746−2749.
(6) Smith, M. B.; March, J. Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 6th ed.; Wiley-Interscience: New York,
2007.
(7) (a) Padala, K.; Jeganmohan, M. Highly Regio- and Stereo-
selective Ruthenium(II)-Catalyzed Direct ortho-Alkenylation of
Aromatic and Heteroaromatic Aldehydes with Activated Alkenes
under Open Atmosphere. Org. Lett. 2012, 14, 1134−1137. (b) Liu,
X.; Li, X.; Liu, H.; Guo, Q.; Lan, J.; Wang, R.; You, J. Aldehyde as a
Traceless Directing Group for Rh(III)-Catalyzed C−H Activation: A
Facile Access to Diverse Indolo[1,2-a]quinolones. Org. Lett. 2015, 17,
2936−2939. (c) Santhoshkumar, R.; Mannathan, S.; Cheng, C. H.
Ligand-Controlled Divergent C−H Functionalization of Aldehydes
with Enynes by Cobalt Catalysts. J. Am. Chem. Soc. 2015, 137,
16116−16120.
(8) (a) Bosnich, B. Asymmetric Catalysis. A Comparative Study of
the Mechanisms of Intramolecular Hydroacylation and Hydrosilation.
Acc. Chem. Res. 1998, 31, 667−674. (b) Jun, C.-H.; Jo, E.-A.; Park, J.-
W. Intermolecular Hydroacylation by Transition−Metal Complexes.
Eur. J. Org. Chem. 2007, 2007, 1869−1881. (c) Fristrup, P.; Kreis, M.;
Palmelund, A.; Norrby, P.-O.; Madsen, R. The Mechanism for the
Rhodium-Catalyzed Decarbonylation of Aldehydes: A Combined
Experimental and Theoretical Study. J. Am. Chem. Soc. 2008, 130,
5206−5215. (d) Garralda, M. A. Aldehyde C−H activation with late
transition metal organometallic compounds. Formation and reactivity
of acyl hydrido complexes. Dalton Trans. 2009, 3635−3645. (e) Willis,
M. C. Transition Metal Catalyzed Alkene and Alkyne Hydroacylation.
Chem. Rev. 2010, 110, 725−748. (f) Modak, A.; Deb, A.; Patra, T.;
Rana, S.; Maity, S.; Maiti, D. A general and efficient aldehyde
decarbonylation reaction by using a palladium catalyst. Chem.
Commun. 2012, 48, 4253−4255. (g) Leung, J. C.; Krische, M. J.
Catalytic intermolecular hydroacylation of C−C π-bonds in the
absence of chelation assistance. Chem. Sci. 2012, 3, 2202−2209.
(h) Murphy, S. K.; Dong, V. M. Enantioselective hydroacylation of
olefins with rhodium catalysts. Chem. Commun. 2014, 50, 13645−
13649.
(10) Chen, X.-Y.; Ozturk, S.; Sorensen, E. J. Pd-Catalyzed Ortho C−
H Hydroxylation of Benzaldehydes Using a Transient Directing
Group. Org. Lett. 2017, 19, 6280−6283. In the reference, Sorensen et
al. reported one example of the fluoroalkoxylation of 3,4-
dichlorobenzaldehyde with HFIP, but the yield was only 22%.
(11) Wang, J.; Li, R.; Dong, Z.; Liu, P.; Dong, G. Complementary
site-selectivity in arene functionalization enabled by overcoming the
ortho constraint in palladium/norbornene catalysis. Nat. Chem. 2018,
10, 866−872.
(12) Under the reaction conditions of ref 9l for the methoxylation of
benzaldehydes, we could repeat the reaction result of 2-cholobenzal-
dehyde (1v) with methanol, but with the same reaction conditions,
benzaldehyde (1a) reacted with trifluoroethanol (2) to afford 3a in
only 13% yield, and 1v reacted with 2 to give 3v in only 17% yield.
(13) The different reactivities of fluorinated and non-fluorinated
alcohols were partially attributed to their different pKa values, which
had a marked impact on the nucleophilicity of alcohol (e.g.
CF3CH2OH, pKa = 12.37; CH3OH, pKa = 15.09). For the concerted
pKa values, see: Takahashi, S.; Cohen, L. A.; Miller, H. K.; Peake, E.
G. Calculation of the pKa Values of Alcohols from σ* Constants and
from the Carbonyl Frequencies of Their Esters. J. Org. Chem. 1971,
36, 1205−1209.
(14) (a) Lu, W.; Yamaoka, Y.; Taniguchi, Y.; Kitamura, T.; Takaki,
K.; Fujiwara, Y. Palladium(II)-catalyzed carboxylation of benzene and
other aromatic compounds with carbon monoxide under very mild
(9) (a) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-
Directed C−H Functionalization Reactions. Chem. Rev. 2010, 110,
1147−1169. (b) Yang, F.; Rauch, K.; Kettelhoit, K.; Ackermann, L.
Aldehyde-Assisted Ruthenium(II)-Catalyzed C−H Oxygenations.
Angew. Chem., Int. Ed. 2014, 53, 11285−11288. (c) Zhang, F.-L.;
conditions. J. Organomet. Chem. 1999, 580, 290−294. (b) Wurtz, S.;
̈
̈
Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Palladium-
Catalyzed Oxidative Cyclization of N-Aryl Enamines: From Anilines
to Indoles. Angew. Chem., Int. Ed. 2008, 47, 7230−7233. (c) Chen,
1926
https://dx.doi.org/10.1021/acs.orglett.1c00365
Org. Lett. 2021, 23, 1921−1927

Organic Letters
pubs.acs.org/OrgLett
Letter
W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.; Wang, Y.-F.; Wang, Y.-Q.
Palladium-Catalyzed Intermolecular C3 Alkenylation of Indoles Using
Oxygen as the Oxidant. Org. Lett. 2012, 14, 5920−5923. (d) Wang,
D.-Yu.; Guo, S.-H.; Pan, G.-F.; Zhu, X.-Q.; Gao, Y.-R.; Wang, Y.-Q.
Direct Dehydrogenative Arylation of Benzaldehydes with Arenes
Using Transient Directing Groups. Org. Lett. 2018, 20, 1794−1797.
(15) (a) Liu, Y.; Ge, H. Site-selective C−H arylation of primary
aliphatic amines enabled by a catalytic transient directing group. Nat.
Chem. 2017, 9, 26−32. (b) Sathyamoorthi, S.; Banerjee, S.
Peroxydisulfate as an Oxidant in the Sit-Selective Functionalization
of sp3 C−H Bonds. ChemistrySelect 2017, 2, 10678−10688.
(16) Chen, X.-Y.; Ozturk, S.; Sorensen, E. J. Synthesis of
Fluorenones from Benzaldehydes and Aryl Iodides: Dual C−H
Functionalizations Using a Transient Directing Group. Org. Lett.
2017, 19, 1140−1143.
(17) Xu, J.; Liu, Y.; Wang, Y.; Li, Y.; Xu, X.; Jin, Z. Pd-Catalyzed
Direct ortho-C−H Arylation of Aromatic Ketones Enabled by a
Transient Directing Group. Org. Lett. 2017, 19, 1562−1565.
(18) Lapointe, D.; Fagnou, K. Overview of the Mechanistic Work on
the Concerted Metallation−Deprotonation Pathway. Chem. Lett.
2010, 39, 1118−1126.
(19) (a) Yang, Z.; Qiu, F.-C.; Gao, J.; Li, Z.-W.; Guan, B.-T.
Palladium-Catalyzed Oxidative Arylation of Tertiary Benzamides:
Para-Selectivity of Monosubstituted Arenes. Org. Lett. 2015, 17,
4316−4319. (b) Karthikeyan, J.; Cheng, C.-H. Synthesis of
Phenanthridinones from N−Methoxybenzamides and Arenes by
Multiple Palladium-Catalyzed C−H Activation Steps at Room
Temperature. Angew. Chem., Int. Ed. 2011, 50, 9880−9883.
(c) Thirunavukkarasu, V. S.; Cheng, C.-H. Pd-Catalyzed Multiple
C−H Functionalization to Construct Biologically Active Compounds
from Aryl Aldoxime Ethers with Arenes. Chem. - Eur. J. 2011, 17,
14723−14726.
(20) Chen, L.; Ding, Q.; Liu, J.-J.; Yang, S.; Zhang, Z.
Spiroindolinone Derivatives. U.S. Patent No. 2008/0009486 A1,
Jan. 10, 2008.
1927
https://dx.doi.org/10.1021/acs.orglett.1c00365
Org. Lett. 2021, 23, 1921−1927