A Selective Single Step Amidation of Polyfluoroarenes

Article abstract of DOI:10.1016/j.jfluchem.2021.109821

This chemistry establishes a method for the synthesis of per- and poly-fluoroaryl acid amides, utilizing nucleophilic aromatic substitution. Traditionally, such amides are constructed in a two-step process, namely, ammonolysis and then N-acylation. Herein, good yields of N-polyfluoroaryl acid amides were achieved in a single step under mild reaction conditions. Key to achieving optimal yields is the use of two equivalents of the nucleophile. In addition, the mechanism of the reaction is discussed which has implications for other related nucleophilic substitutions.

Full text of DOI:10.1016/j.jfluchem.2021.109821

Journal of Fluorine Chemistry 248 (2021) 109821
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A Selective Single Step Amidation of Polyfluoroarenes
Alyssa M. Noel, Matthew Hamilton, Brockton Keen, Megan Despain, Jon Day,
Jimmie D. Weaver*
Department of Chemistry, Oklahoma State University
A R T I C L E I N F O
A B S T R A C T
Edited by Prof Joseph Thrasher
This chemistry establishes a method for the synthesis of per- and poly-fluoroaryl acid amides, utilizing nucleo-
philic aromatic substitution. Traditionally, such amides are constructed in a two-step process, namely, ammo-
nolysis and then N-acylation. Herein, good yields of N-polyfluoroaryl acid amides were achieved in a single step
under mild reaction conditions. Key to achieving optimal yields is the use of two equivalents of the nucleophile.
In addition, the mechanism of the reaction is discussed which has implications for other related nucleophilic
substitutions.
Keywords:
Fluorination
Polyfluoroarylation
Amide
Organofluorines
and SNAr chemistry
1. Introduction
difficult to install C–F bonds are already in place, and are readily
available as building blocks. Novel substrates can then be reached
Per- and polyfluoroarenes are important targets because they are
active components in many agrichemicals, pharmaceuticals, and in-
dustrial manufacturing products [1]. More specifically, polyfluoroaryl
amides are a common subclass found within polyfluoroarenes as seen in
the insecticide Teflubenzuron [2] and the cystic fibrosis drug Tezacaftor
[3] (Fig. 1). Many of the current methods of synthesizing these poly-
fluoroarenes involve selective fluorine installation. Traditional proced-
ures for direct fluorine installation such as halex, Balz-Scheiman, and
C–H fluorination have significant drawbacks including harsh reaction
conditions and/or low selectivity which often result in poor yields [4,5,
6]. Perhaps more concerning, these methods often only allow limited
exploration of fluorinated space which pertains to the number, location
and directionality of fluorine atoms within a molecule. Furthermore,
due to the functional group incompatibility of these reactions, the
exploration of the fluorinated space must be accomplished at an early
stage before the molecules become too structurally complex and pos-
sesses incompatible functionality. Arguably, as a result of these diffi-
culties discovery programs investigating polyfluoroaryl chemical space
are often left with incomplete understanding. Consequently, methods
that enable exploration of fluorinated space at a late-stage are valuable.
An alternative approach to exploration of organofluorine space in-
volves the selective defluorination [7,8,9,10,11] and substitution of
highly fluorinated organofluorines, a process akin to sculpting. The
advantage being two-fold. Namely, within perfluoroarenes all the
through selective hydrodefluorination or functionalization [12]. Thus,
our lab and many others have explored the development of such re-
actions in hopes of developing sufficient tools that enable discovery
programs to more fully explore organofluorine space, which is expected
to positively impact the discovery of molecules with enhanced
properties.
Nucleophilic aromatic substitution using nitrogen-based nucleo-
philes has been previously investigated on highly fluorinated pyrimi-
dines and pyridines [13,14] with azides. More recently, azides of highly
fluorinated arenes have been shown to be readily coupled with alde-
hydes to make the corresponding acid amide [15,16]. Further, the re-
action of hexafluorobenzene with amine based nucleophiles has also
been studied [17], as well as N-silyl amides [18]. Indeed, previous
methods for the synthesis of N-polyfluoroaryl acid amides build from
this methodology. Typically, the synthesis involves two steps starting
from the commercially available perfluoroarene (Scheme 1A). The first
step usually involves the addition of ammonium hydroxide to make the
C–N bond, followed by an isolation step, and then formation of the
N-amide in a second step via treatment with the acid anhydride and an
acid [12]. In particular, perchloric acid has been used, and is corrosive
and can produce explosive salts as side products or on metal surfaces
with which it comes in contact. Thus, there are significant handling
concerns, and as a result, it has become a less accessible reagent in many
labs.
* Corresponding author.
E-mail address: jimmie.weaver@okstate.edu (J.D. Weaver).
https://doi.org/10.1016/j.jfluchem.2021.109821
Received 12 January 2021; Received in revised form 21 May 2021; Accepted 22 May 2021
Available online 30 May 2021
0022-1139/© 2021 Elsevier B.V. All rights reserved.

A.M. Noel et al.
Journal of Fluorine Chemistry 248 (2021) 109821
Thus, we set out to develop reaction conditions for the direct C–F sub-
stitution of polyfluoroarenes with deprotonated acid amide
nucleophiles.
2. Results and Discussion
Neutral amides are not generally strong enough nucleophiles to un-
dergo SNAr with the polyfluoroarenes, but upon deprotonation their
nucleophilicity is significantly enhanced [19,20]. Therefore, our syn-
thetic plan involved the use of a base to deprotonate the amide N–H,
followed by the addition of the polyfluorinated arene to yield the desired
N-polyfluoroaryl amide in a single step. We first observed that the use of
just one equivalent of strong base (vide infra), or alternatively the use of
weaker bases such as tertiary amines, led to nitrogen di-arylation or very
low conversions altogether in the case of amine bases (Scheme 2). The
di-arylation result can be understood to arise from the NH acidity of the
product. Because the highly electron withdrawing fluoroarene is ex-
pected to stabilize the charge of the incipient aza-anion formed upon
deprotonation, the polyfluoroarylation results in a significant acidifi-
cation of the N–H bond. In the presence of weak bases, the product N–H
is therefore selectively deprotonated. In the presence of one equivalent
of strong base, K1 may be adequately shifted towards the aza-anion, but
the formation of product serves to protonate the initial amide. In both
cases, the result is formation of a second N-arylation event. We reasoned
that this could be avoided by using two equivalents of strong base that
would fully deprotonate both the initial amide and the product amide.
With both amides present during the reaction, the initial amide would
outcompete the product amide for bond formation.
Based on our predictions, we attempted to synthesize N-(4-cyano-
2,3,5,6-tetrafluorophenyl)-2,2,2-trifluoroacetamide (3a, Scheme 3)
from pentafluorobenzonitrile using 2.15 equivalents of NaH and 2.15
equivalents of trifluoroacetamide, and we found that it indeed selec-
tively produces the mono-arylated amide product (Table 1, entry 1). We
then reduced the NaH loading such that only an equimolar amount of
nucleophile would be generated. As anticipated, we observed a 2:1
diarylation to intended product ratio (entry 2). This result confirmed
that adding sufficient base to account for the formation of the acidic
product was key to avoiding the N,N-diaryl amide product (3a’). We
next explored the effect of temperature on the reaction. When we ran the
reaction at -10◦C, we only achieved 61% conversion (entry 3). However,
as we increased the temperature the conversion increased (entries 2, 3,
and 4). Unfortunately, as the temperature increased we observed the
formation of a side product that appeared to arise from hydroxide
addition [21]. This assignment was supported by GC-MS. Suspecting
that this was due to adventitious water, we began using a modified
Schlenk technique in which more rigorously anhydrous conditions were
achieved. As a consequence, the hydroxide addition product was
completely suppressed and resulted in a 99% assay yield of 3a as
determined by 19F NMR.
Fig. 1. Bioactive compounds containing polyfluoroaryl amides or dericatives.
After achieving excellent NMR assay yields we turned our attention
to developing workup and purification conditions. Since we expected
this reaction to be used in a preparative manner, we sought to avoid the
need for column chromatography altogether. After quenching the re-
actions with a dilute HCl solution, we expected the reaction mixture to
contain our intended product, 3a, a minimal amount of the di-arylated
product, 3a’, excess trifluoroacetamide, and fluoride salts. We
believed that the product amide, 3a, along with any undesired 3a’ could
be extracted into 10:1 hexanes:ethyl acetate mixture. Meanwhile, excess
trifluoroacetamide and fluoride salts could be rejected by aqueous
washes. 3a treated in this way was a solid, and recrystallization from
hexanes allowed removal of any trace diarylated product, 3a’. Indeed,
by this method, we were able to achieve an 86% isolated yield with
better than 99% purity on a 500 mg scale without the aid of column
chromatography.
Scheme 1. A comparison of the proposed work with the traditional route.
We speculated that the amide motif could be synthesized more
directly, by adding it as an entire nucleophilic unit. Further, doing so
had the potential to take place under milder reaction conditions which
could allow a greater degree of functional group tolerance (Scheme 1B).
2

A.M. Noel et al.
Journal of Fluorine Chemistry 248 (2021) 109821
Scheme 2. Mechanistic rational for the formation of N-monoaryl- and N-diaryl amides.
Scheme 3. Optimization of reaction conditions.
evidenced in the fluorine and proton NMR spectra. Importantly, reaction
Table 1
of the trifluoronitrobenzene shows that perfluorination is not a hard
requirement, though it clearly facilitates the reaction. Attempts to utilize
the procedure to directly amidate minimally fluorinated 2-fluoropyri-
dine resulted in 80% conversion in 1 h at 160 ◦C. Evidence for the
product was seen in the crude 1H NMR and GCMS. The crude GCMS
gave 2 well resolved signals consistent with the expected molecular ion
(M+ = 136). They are consistent with N- and O-substitution products,
suggesting the reaction may be possible even with monofluorinated
pyridines. However, isolation of the products proved challenging. Pen-
tafluoropyridine similarly underwent smooth reaction at room temper-
ature to give selective amidation at the C4 position. Lastly,
perfluoronapthalene, devoid of other activating functional groups,
cleanly afforded product 4c, but required an increased temperature (70
◦C) and elongated reaction time.
Pentafluorobenzonitrile optimization. aRigorously anhydrous and air-free
Entry
X equiv
T◦C
% Conversion
Scale (mg)
3a/3a’
1a
2.1
1.0
2.1
2.1
2.1
2.1
10
27
-10
-5
99
99
61
73
85
98
500
50
50
50
50
50
>20/1
0.33
2
3
>20/1
>20/1
>20/1
>20/1
4
5
0
6a
-5
2.3. Scope
We next sought to evaluate the scope. Prior to campus closure [22],
we assessed five additional compounds both in terms of the fluoroarene
and the nature of the amide (Scheme 4). While the optimal equivalents
of the base and the amide varied subtly (among the trifluoroacetamide
products), the optimal reaction temperature varied significantly among
the substrates. We found that the highly activated penta-
fluorobenzonitrile (3a and 4b) went to >99% conversion at 10◦C, but
the less activated compounds octafluoronapthalene (4e) and per-
fluorobenzene (4f) required much higher temperatures of 70◦C and
140◦C, respectively. Moving from the trifluoroacetamide to the simple
acetamide nucleophile (compound 4b), we found that the optimal
temperature was the same as the reaction with trifluoroacetamide (4a).
However, the NaH and the acetamide equivalents had to be quadrupled.
This may have reflected the increased tendency of this amide to carry
water into the reaction mixture. In previous reports of nucleophilic
addition to 2,3,4-trifluoronitrobenzene (4d) with nitromethonate and
Meldrum’s acid anion the ortho substitution product was the primary or
exclusive product formed [23,24]. Instead, we observed complete con-
version within 1 h and amidation exclusively at the 4-position, as
The relatively low isolated yield is believed to be due to the
incomplete development of workup conditions [22]. Similarly, N-(per-
fluorophenyl)acetamide (4f) could be synthesized from hexa-
fluorobenzene, but required even higher temperatures (140 ◦C) due to
the absence of additional electron withdrawing groups in the substrate.
We accomplished this by use of microwave vial that could maintain the
volatile hexafluorobenzene even at the elevated temperatures.
3. Conclusions
In conclusion, we have explored the preparative single step synthesis
of polyfluoroarylated amides. This method allows the expedited syn-
thesis of N-polyfluoroaryl amides in a single step in high yields and
purities, which should enable faster production of these compounds and
inherently increase accessibility of fluorinated compounds. Importantly,
we found that product inhibition was a key complicating factor that
3

A.M. Noel et al.
Journal of Fluorine Chemistry 248 (2021) 109821
Scheme 4. Evaluation of the scope of the 1-step amidation. Assay yields were determined using 19F NMR and were based on the observed product distributions.
Isolated yields are based off the mass of the isolated material.
could be circumvented by using sufficient amount of nucleophile such
that the acidic product did not interfere with the desired reaction. This is
a general strategy that is common to polyfluoroarylation owing to the
aryl group’s tendency to acidify nearby protons.
flask containing the NaH which had been placed in an ice bath to cool
under positive Ar pressure which allowed venting of the H2 pressure
formed upon addition of the acetamide. The mixture was allowed to stir
for 20 minutes before the temperature was adjusted to the reaction
temperature. Finally, the fluoroarene was added to the flask and the
temperature was maintained. After 3 hours, the reaction was quenched
by the addition of 0.1 M HCl. Workup: The reaction mixture was
extracted 3 times with a hexanes: ethyl acetate mixture (3x reaction
volume). The organic layer was washed with H2O (3x) with 10x reaction
volume. Finally, the organic layer was dried with MgSO4, concentrated,
and purified via recrystallization or column chromatography.
4. Experimental
4.1. General Experimental
All reagents were obtained from commercial suppliers (Aldrich,
VWR, TCI Chemicals, and Oakwood Chemicals) and used without
further purification unless otherwise noted. Dry tetrahydrofuran (THF)
was distilled after refluxing over sodium until dry as indicated by the
benzophenone ketyl radical. Reactions were monitored by a combina-
tion of thin layer chromatography (TLC), (obtained from sorbent tech-
nologies Silica XHL TLC Plates, w/UV254, glass backed, 250 µm, 20×20
cm) and were visualized with ultraviolet light, potassium permanganate
stain, GC-MS (QP 2010S, Shimadzu equipped with auto sampler), 19F
NMR and 1H NMR (vide infra). Isolations were carried out using Tele-
dyne Isco Combiflash Rf 200i flash chromatograph with Redisep Rf
normal phase silica (4 g, 12 g, 24 g, 40 g) with product detection at 254
and 288 nm and by ELSD (evaporative light scattering detection). NMR
spectra were obtained on a 400 MHz Bruker Avance III spectrometer and
Neo 600 MHz. 1H, 19F and 13C NMR chemical shifts are reported in ppm
relative to the residual proteo solvent peak (1H, 19F, 13C). Reactions
were set up in oil baths at various temperatures that are indicated below.
Alternatively, reactions performed above their atmospheric boiling
points were performed in a Biotage Initiator Microwave Synthesizer
using 0.5- 2 mL vials with penetrable septa at the indicated
temperatures.
4a. N-(4-cyano-2,3,5,6-tetrafluorophenyl)-2,2,2-trifluoroacetamide
was prepared via the general procedure described above, using 1.0 equiv
of pentafluorobenzonitrile (500 mg), 2.1 equiv trifluoroacetamide, and
2.15 equiv of NaH. The reaction temperature was maintained at 10 ◦C
for 3 h. Mass isolated 636.6 mg, 85.83% isolated yield, mp 95-95◦C,
yellow solid. Yellow solid; mp 95-96◦C. 19F NMR (376 MHz, Chloro-
form-d) δ -74.8, -130.8 – -130.9 (m), -140.0 – -140.2 (m). 1H NMR (400
MHz, Chloroform-d) δ 8.26 (s, 1H). 13C NMR (151 MHz, Chloroform-d) δ
154.8 (q, J = 40.1 Hz), 147.5 (ddt, J = 263.5, 14.7, 4.3 Hz), 142.1 (dddd,
J = 256.8, 13.6, 4.5, 3.0 Hz), 119.4 (tt, J = 13.7, 2.7 Hz), 115.1 (q, J =
287.9 Hz), 106.7 (t, J = 3.5 Hz), 93.7 (t, J = 17.2 Hz).
4b N-(4-cyano-2,3,5,6-tetrafluorophenyl)acetamide was prepared
via the general procedure described above, using 1.0 equiv of penta-
fluorobenzonitrile (50 mg), 8.4 equiv acetamide, and 8.6 equiv of NaH.
The reaction temperature was maintained at 10 ◦C for 4.5 h. The crude
product was purified via column chromatography. Mass isolated: 30.0
mg, 60% isolated yield, white solid; mp 148-152◦C. The compound
matches the previously reported spectra [26].
4c. N-(2,3-difluoro-4-nitrophenyl)-2,2,2-trifluoroacetamide was
prepared via the general procedure described above, using 1.0 equiv of
pentafluorobenzonitrile (500 mg), 1.3 equiv trifluoroacetamide, and 2.4
equiv of NaH. The reaction temperature was maintained at 60 ◦C for 1 h.
Mass isolated: 652 mg; 85.6% yield, mp 123-126 ◦C. 19F NMR (376 MHz,
Chloroform-d) δ -75.4 (d, J = 1.1 Hz), -121.3 (ddd, J = 19.9, 8.4, 4.8 Hz),
-130.9 (ddd, J = 19.9, 7.1, 2.2 Hz). 1H NMR (400 MHz, Chloroform-d) δ
9.31 (s, 1H), 8.09 (ddd, J = 9.4, 4.8, 2.2 Hz, 1H), 7.37 (ddd, J = 9.4, 8.4,
7.1 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 155.8 (q, J = 38.5 Hz), 153.4
4.2. General procedure for the one-step amidation of fluoroarene
NaH (stored in a glovebox) was added into a flame-dried round
bottom flask with a stir bar. The flask was capped and the atmosphere
exchanged with Ar (3x). Then trifluoroacetamide was dissolved in dry
THF (previously dried by refluxing over Na) in a flame-dried flask with a
rubber septum. The amide solution was transferred using a syringe to the
4

A.M. Noel et al.
Journal of Fluorine Chemistry 248 (2021) 109821
(dd, J = 257.0, 11.9 Hz), 145.9 (dd, J = 254.5, 14.9 Hz), 142.0 (d, J =
3.4 Hz), 122.3 (dd, J = 9.1, 3.8 Hz), 120.2 (dd, J = 13.5, 2.5 Hz), 117.2
(d, J = 19.0 Hz), δ 116.0 (d, J = 287.9 Hz).
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Appendix Supplementary data
Contains further reaction details and spectra.
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Declaration of Competing Interest
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The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper
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We thank the National Institutes of Health NIGMS (5R01GM115697)
and the Herman Frasch Fund for Chemical Research for support of this
work, MD thanks the NSF (1946093) for support.
[22] Campus was closed in spring 2020 due to the COVID-19 pandemic.
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