Isolable Pyridinium Trifluoromethoxide Salt for Nucleophilic Trifluoromethoxylation

Article abstract of DOI:10.1021/acs.orglett.1c01664

An isolable pyridinium trifluoromethoxide salt is prepared from the reaction of 4-dimethylaminopyridine with the commercially available liquid 2,4-dinitro(trifluoromethoxy)benzene. The salt is an effective trifluoromethoxide source for SN2 reactions to form trifluoromethyl ethers.

Full text of DOI:10.1021/acs.orglett.1c01664

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Letter
Isolable Pyridinium Trifluoromethoxide Salt for Nucleophilic
Trifluoromethoxylation
Geraldo Duran-Camacho, Devin M. Ferguson, Jeff W. Kampf, Douglas C. Bland,
and Melanie S. Sanford*
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ABSTRACT: An isolable pyridinium trifluoromethoxide salt is
prepared from the reaction of 4-dimethylaminopyridine with the
commercially available liquid 2,4-dinitro(trifluoromethoxy)-
benzene. The salt is an effective trifluoromethoxide source for
SN2 reactions to form trifluoromethyl ethers.
omethyl arylsulfonate (TFMS),14 trifluoromethyl benzoate
(TFBz),23 or trifluoromethyl methyl ether (MeOCF3).24 The
practicality and scalability of these in situ protocols are limited
by the OCF3-containing electrophiles, of which many are gases
at room temperature (TFMT and MeOCF3), are expensive/
require costly reagents (TFMT and TFMS), and/or require
multi-step syntheses (TFMS and TFBz), often involving highly
toxic fluorophosgene (TFBz).
Many of these limitations could be addressed by leveraging
commercially available 2,4-dinitro(trifluoromethoxy)benzene
(DNTFB) as an OCF3 electrophile. In contrast to the reagents
in Figure 1B, DNTFB is a convenient-to-handle high boiling
liquid that is relatively inexpensive.25 In 2010, Langlois and co-
workers reported that the SNAr reaction between DNTFB and
tetrabutylammonium triphenyldifluorosilicate (TBAT) releases
Bu4NOCF3.19 This in situ generated trifluoromethoxide salt
was then used as a nucleophile for SN2 reactions (Scheme 1A).
We noted that DNTFB shares the dinitrobenzene moiety with
2,4-dinitrochlorobenzene, which is the reagent used for the
formation of pyridinium salts in the Zincke reaction.26 As such,
we hypothesized that pyridine nucleophiles could undergo
SNAr with DNTFB to afford isolable trifluoromethoxide salts
with a highly delocalized pyridinium countercation (PyOCF3;
Scheme 1B). The advantages of this approach are 2-fold: (1)
the trifluoromethoxide salt would be generated from two easy-
to-handle, commercially available, and inexpensive precursors,
and (2) the isolation of the salt would enable structural
characterization as well as deployment under a variety of
he trifluoromethoxy group (OCF3) has emerged as an
Timportant structural motif in scaffolds relevant to both
agrochemical and pharmaceutical development.1 The intro-
duction of an OCF3 substituent has been shown to enhance
the lipophilicity2,3 [Hansch parameter (π) = 1.04], bioavail-
ability, and metabolic stability4,5 of biologically active
molecules.6,7 As a result of the increasing importance of this
functional group, considerable recent attention has been
focused on developing practical and convenient reagents for
introducing OCF3 groups into organic molecules.8−11
Nucleophilic trifluoromethoxide reagents are widely used for
the construction of carbon−OCF3 bonds.12−17 As one
example, SN2 reactions between alkyl electrophiles and
trifluoromethoxide salts serve as an effective route to alkyl
trifluoromethyl ethers (Figure 1A).7,18−20 However, at present,
no trifluoromethoxide salts are commercially available.7,21
Instead, these reagents are typically formed in situ through the
reaction of fluoride or amine nucleophiles with OCF3-
containing electrophiles (Figure 1B), of which common
examples are trifluoromethyl triflate (TFMT),7,22 trifluor-
Received: May 17, 2021
Published: June 17, 2021
Figure 1. (A) SN2 reactions using in situ generated trifluoromethoxide
salts. (B) General procedure for in situ activation of trifluorometh-
oxide electrophiles with nucleophiles to form trifluoromethoxide salts.
https://doi.org/10.1021/acs.orglett.1c01664
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5138−5142
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Letter
Scheme 1. DNTFB as a Trifluoromethoxide Source
conditions (without limitations to the reaction media required
for salt formation).
Our initial studies explored the reaction of 1 equiv of
DNTFB with 1 equiv of various pyridine derivatives in MeCN
for 1 h at room temperature. As shown in Scheme 2, the
Scheme 2. Conversion of DNTFB Using Different Pyridine
Derivatives
Figure 2. (A) Synthesis of PyOCF3. (B) ORTEP diagram of PyOCF3
(ellipsoids at 50% probability). Selected bond distances (Å): C(1)−
O(1), 1.216; C(1)−F(1), 1.406; C(1)−F(2), 1.402; and C(1)−F(3),
1.408 (hydrogen atoms are omitted for clarity). (C) Electrostatic
potential map of PyOCF3. (D) Decomposition of an 8.0 mM solution
of PyOCF3 in MeCN-d3 at room temperature. Concentrations
1
determined by H NMR spectroscopy with benzene as an internal
standard.
X-ray quality crystals were obtained by slow diffusion of
diethyl ether into a MeCN solution of PyOCF3 at −35 °C. An
Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagram is shown
in Figure 2B. The bond distances and angles for PyOCF3 are
similar to those reported in the literature for tris-
(dimethylamino)sulfonium trifluoromethoxide (TASOCF3).28
In both structures, the C−O single bond is relatively short
(1.216 Å in PyOCF3 and 1.227 Å in TASOCF3), which is
consistent with significant hyperconjugation. An electrostatic
potential map for this salt (Figure 2C) illustrates that the
conjugated nature of the cation results in substantial
delocalization of the positive charge.29
percent conversion of DNTFB under these conditions tracks
closely with the nucleophilicity of the pyridine. For example,
while unsubstituted pyridine affords only 25% conversion, the
more nucleophilic 4-dimethylaminopyridine (DMAP) and 4-
pyrrolidinopyridine result in quantitative conversion of
DNTFB. This is accompanied by the formation of a broad
19F nuclear magnetic resonance (NMR) resonance at −22
ppm, which is consistent with the generation of a
trifluoromethoxide salt.17 DMAP was ultimately selected as
the optimal activator for DNTFB as a result of its low cost27
and ease of handling as a free-flowing solid.
The reaction between DNTFB and DMAP proceeds to high
(>99%) conversion in a variety of polar aprotic solvents,
including N,N-dimethylformamide (DMF), N-methylpyrroli-
done (NMP), and N,N′-dimethylpropyleneurea (DMPU), to
afford soluble PyOCF3. In contrast, when the reaction is
conducted in tetrahydrofuran (THF), PyOCF3 forms as a
yellow precipitate after 30 min at room temperature (Figure
2A). This solid can be collected by filtration and isolated in
90% yield and 94% purity. The major impurities are 1-fluoro-
2,4-dinitrobenzene and DMAP. These arise from decom-
position of trifluoromethoxide to fluorophosgene and fluoride
followed by SNAr reaction of the latter with the pyridinium
cation (Figure S1 of the Supporting Information).
The stability of PyOCF3 was evaluated in two different ways.
First, a sample of solid PyOCF3 was stored at −35 °C under
nitrogen and periodically assayed by 19F and 1H NMR
spectroscopy. No decomposition of this material was detected
over 1 month. Second, the decomposition of an 8.0 mM
1
solution of PyOCF3 in MeCN was monitored via H NMR
spectroscopy at room temperature. As shown in Figure 2D,
after 30 h, approximately 50% of the salt remained, while full
decomposition was observed after 48 h. These data indicate
that the solution stability of PyOCF3 is considerably lower
than that of the quaternary ammonium trifluoromethoxide
salts reported by Friesen and co-workers.24
Finally, PyOCF3 was employed as a nucleophilic trifluor-
omethoxide source for SN2 reactions (Table 1). We first
examined benzyl bromide as the substrate under conditions
reported by Langlois and co-workers19 [using 2 equiv of
PyOCF3 (generated ex situ from DNTFB and DMAP as a 0.4
M solution in MeCN) at room temperature for 4 days]. This
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Table 1. Optimization of Nucleophilic Substitution of
Scheme 3. Trifluoromethoxylation of Benzyl and Alkyl
a
Benzyl Bromide (1a) with Trifluoromethoxide Salt
Bromides with PyOCF3
a
(PyOCF3)
b
c
entry
temperature (°C)
time (h)
additive
yield (%)
1
2
3
4
rt
96
24
24
5
5
5
none
none
AgOTf
AgOTf
AgOTf
AgOTf
38
58
70
74
76
20
40
40
40
40
40
d
5
e
6
a
Conditions: 0.05 mmol of compound 1a and 0.1 mmol of PyOCF3
b
(generated ex situ as a solution in MeCN). A total of 1.1 equiv of
c
silver salt. Yields determined by 19F NMR spectroscopy using
d
trifluorotoluene (PhCF3) as an internal standard. Using isolated
PyOCF3. In situ generation of PyOCF3 in a single pot.
e
reaction afforded compound 2a in 38% yield (entry 1 in Table
1). Increasing the temperature to 40 °C and lowering the
reaction time to 24 h resulted in a 58% yield of compound 2a.
The addition of 1.1 equiv of AgOTf led to a further
enhancement in the yield to 70%, likely driving the reaction
by the precipitation of AgBr7,24 (entries 2 and 3 in Table 1).
Under the optimal conditions (1 equiv of benzyl bromide, 2
equiv of ex situ generated PyOCF3 as a 0.4 M solution in
MeCN, and 1.1 equiv of AgOTf at 40 °C for 5 h), product 2a
was formed in 74% yield (entry 4 in Table 1) and only traces
(<5%) of benzyl fluoride were detected.30 Notably, benzyl
fluoride is a common byproduct in other SN2 reactions with
trifluoromethoxide, and it derives from decomposition of
trifluoromethoxide to fluorophosgene and fluoride, followed by
SN2 by the latter.7 We hypothesize that the high chemo-
selectivity with PyOCF3 is due to the cation serving as a
fluoride sponge via SNAr (see the Supporting Information for
further details). Consistent with this proposal, the reaction of
PyOCF3 with 1 equiv of anhydrous NMe4F afforded 1-fluoro-
2,4-dinitrobenzene in 63% yield.31
We evaluated the scope of this reaction with respect to the
alkyl halide electrophile (Scheme 3).32 A variety of
functionalities, including methoxy, nitro, ester, amide, and
nitrile groups, were well-tolerated. We note that the yields with
PyOCF3 under these conditions are comparable to or slightly
lower than those reported with other trifluoromethoxide
salts.33 However, the practicality and synthetic accessibility of
PyOCF3 render it an attractive alternative. In addition, only
traces of benzyl and alkyl fluorides were observed in these
systems, which demonstrates a higher selectivity for trifluor-
omethoxylation over nucleophilic fluorination.
a
Conditions: 1.0 equiv of alkyl halide, 2.0 equiv of PyOCF3 (0.4 M
b
solution in MeCN), 1.1 equiv of AgOTf, 40 °C, and 5 h. A 1.0 mmol
c
scale reaction. Reaction time = 20 h. Yields were determined by 19F
NMR spectroscopy using trifluorotoluene (PhCF3) as an internal
standard and represent an average of three runs. Isolated yields are in
parentheses.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01664.
Experimental procedures, optimization details, X-ray
crystallographic data, and NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1k, 1l, 2b−2i, 2k, 2l, and PyOCF3 (ZIP)
Accession Codes
CCDC 2080854 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Melanie S. Sanford − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0001-9342-9436; Email: mssanfor@
umich.edu
In conclusion, this report describes the synthesis and
characterization of a new pyridinium trifluoromethoxide salt
that is easily prepared from inexpensive and readily available
starting materials. This salt serves as an effective reagent for
SN2 reactions, and we anticipate that it should find broader use
as a practical trifluoromethoxide source for other trans-
formations.
Authors
Geraldo Duran-Camacho − Department of Chemistry,
University of Michigan, Ann Arbor, Michigan 48109, United
States
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Letter
synthesized using Togni’s reagent (∼$28 000/mol14c). For example,
trifluoromethyl benzenesulfonate can be purchased from 1Click
Chemistry (∼$19 000/mol, based on the largest amount available, 25
g). (a) Guo, S.; Cong, F.; Guo, R.; Wang, L.; Tang, P. Asymmetric
Silver-Catalysed Intermolecular Bromotrifluoromethoxylation of
Alkenes with a New Trifluoromethoxylation Reagent. Nat. Chem.
2017, 9, 546. (b) Fiederling, N.; Haller, J.; Schramm, H. Notification
about the Explosive Properties of Togni’s Reagent II and One of Its
Precursors. Org. Process Res. Dev. 2013, 17, 318. (c) Pricing from TCI
is based on the largest amount available to purchase (1 g).
Devin M. Ferguson − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States
Jeff W. Kampf − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0003-1314-8541
Douglas C. Bland − Product & Process Technology R&D,
Corteva Agriscience, Indianapolis, Indiana 46268, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01664
(15) Jiang, X.; Deng, Z.; Tang, P. Direct Dehydroxytrifluoromethox-
ylation of Alcohols. Angew. Chem., Int. Ed. 2018, 57, 292.
(16) Zha, G. F.; Han, J. B.; Hu, X. Q.; Qin, H. L.; Fang, W. Y.;
Zhang, C. P. Silver-Mediated Direct Trifluoromethoxylation of α-
Diazo Esters via the OCF3 Anion. Chem. Commun. 2016, 52, 7458.
Notes
The authors declare no competing financial interest.
−
(17) Huang, C.; Liang, T.; Harada, S.; Lee, E.; Ritter, T. Silver-
Mediated Trifluoromethoxylation of Aryl Stannanes and Arylboronic
Acids. J. Am. Chem. Soc. 2011, 133, 13308.
(18) Nishida, M.; Vij, A.; Kirchmeier, R. L.; Shreeve, J. M. Synthesis
of Polyfluoro Aromatic Ethers: A Facile Route Using Polyfluoroalk-
oxides Generated from Carbonyl and Trimethylsilyl Compounds.
Inorg. Chem. 1995, 34, 6085.
(19) Marrec, O.; Billard, T.; Vors, J.-P.; Pazenok, S.; Langlois, B. R.
A New and Direct Trifluoromethoxylation of Aliphatic Substrates
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Stable Nucleophilic Reagent for Chemoselective and Stereospecific
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Front. 2019, 6, 1801.
(22) The use of trifluoromethyl triflate (TFMT) is limited by its
high cost (∼$5000/mol) and volatility (bp = 19 °C). (a) Kolomeitsev,
A. A.; Vorobyev, M.; Gillandt, H. Versatile Application of
Trifluoromethyl Triflate. Tetrahedron Lett. 2008, 49, 449. (b) Pricing
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purchase (5 g).
(23) Trifluoromethyl benzoate (TFBz) requires the use of
fluorophosgene as an intermediate for its synthesis. Zhou, M.; Ni,
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(25) At $500/mol, with pricing from Oakwood Chemical based on
the largest amount available to purchase (100 g).
ACKNOWLEDGMENTS
■
The authors thank Dr. James R. Bour (currently at the
Department of Chemistry, Wayne State University, Detroit,
MI, U.S.A.) for helpful insights and discussions. Corteva
Agriscience is acknowledged for supporting this work. Geraldo
Duran-Camacho acknowledges support from a Rackham Merit
Fellowship (RMF) and a National Science Foundation (NSF)
Graduate Research Fellowship.
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calculation of the PyOCF3 crystal structure geometry at the PM3 level
of theory using Spartan Student (Wavefunction, Inc., version 8.0.4).
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and Ag salt, is described in the Supporting Information.
(31) The reaction of 0.05 mmol of PyOCF3 with 0.05 mmol of
anhydrous Me4NF in MeCN-d3 at room temperature for 1 h resulted
in complete decay of the trifluoromethoxide signal, and the formation
of 1-fluoro-2,4-dinitrobenzene as the major product in 63% yield, as
determined by 19F NMR spectroscopy using trifluorotoluene as an
internal standard.
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(32) Secondary alkyl bromides, including bromodiphenylmethane,
1-bromoethylbenzene, and 2-bromopentane, were also evaluated as
substrates for this transformation and yielded trifluoromethoxylated
products 2m, 2n and 2o in 58, 51, and 40% 19F NMR yield,
respectively. The isolation of these products proved difficult as a result
of their volatility and the modest stability of the products to the
isolation conditions (see the Supporting Information for details).
(33) For example, product 2e was formed in 87% yield using
AgOCF3 (generated from TFMT; ref 22a), 78% yield using TFMS
(ref 15), and 73% yield using 1,1-dimethylpyrrolidinium trifluor-
omethoxide (generated from MeOCF3; ref 24).
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