Carboxylic Acid Deoxyfluorination and One-Pot Amide Bond Formation Using Pentafluoropyridine (PFP)

Article abstract of DOI:10.1021/acs.orglett.1c01953

This work describes the application of pentafluoropyridine (PFP), a cheap commercially available reagent, in the deoxyfluorination of carboxylic acids to acyl fluorides. The acyl fluorides can be formed from a range of acids under mild conditions. We also demonstrate that PFP can be utilized in a one-pot amide bond formation via in situ generation of acyl fluorides. This one-pot deoxyfluorination amide bond-forming reaction gives ready access to amides in yields of ≤94%.

Full text of DOI:10.1021/acs.orglett.1c01953

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Letter
Carboxylic Acid Deoxyfluorination and One-Pot Amide Bond
Formation Using Pentafluoropyridine (PFP)
William D. G. Brittain* and Steven L. Cobb*
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ABSTRACT: This work describes the application of pentafluoropyr-
idine (PFP), a cheap commercially available reagent, in the
deoxyfluorination of carboxylic acids to acyl fluorides. The acyl
fluorides can be formed from a range of acids under mild conditions.
We also demonstrate that PFP can be utilized in a one-pot amide
bond formation via in situ generation of acyl fluorides. This one-pot
deoxyfluorination amide bond-forming reaction gives ready access to
amides in yields of ≤94%.
cyl fluorides have emerged as a highly valuable class of
molecules in the field of synthetic organic chemistry, and
revolving around the corrosive nature of the reagents needed
and their incompatibility with other desirable one-pot
processes such as amide or ester synthesis.
A
they can be applied in a wide variety of useful transformations.1
Acyl fluorides have been used as key reagents in challenging
amidations/esterifications and coupling reactions,2 as a source
of anhydrous fluoride ions,3 and more recently in nickel-
catalyzed decarbonylative borylations.4 Despite the clear
interest within the synthetic community to utilize acyl
fluorides, access to this class of molecule may require the use
of toxic reagents, harsh reaction conditions, or the application
of approaches that have limited substrate tolerance in some
cases.1a
As part of an ongoing program of work to investigate the
synthetic applications of pentafluoropyridine (PFP) 2, we
hypothesized that this reagent might be capable of delivering
acyl fluorides under mild reaction conditions. In this regard, it
is worth noting that Crimmin has successfully generated acyl
fluorides in the reaction of acetic anhydrides with PFP and
DMAP.16 However, in this reaction sequence, addition of
DMAP is required and acyl fluoride generation was not the
primary focus of the work. PFP (2) also shares some structural
similarities with other deoxyfluorination reagents, for example,
cyuranic fluoride.17 Both PFP (2) and cyanuric fluoride
possess aromatic fluorines that are highly susceptible to
displacement via SNAr reactions. Previously, the ability to
undergo SNAr reactions has led to applications for PFP (2) in
protecting group chemistry,18 peptide modification,19 unsym-
metrical biaryl synthesis,20 polymer chemistry,21 and macro-
cycle synthesis.22 We speculated that PFP (2) could be reactive
enough to generate acyl fluorides directly from carboxylic acids
through an SNAr, deoxyfluorination sequence. In such a
sequence, the PFP reagent would be acting in a dual role,
providing a way to initially activate the carboxylic acid toward
The synthesis of acyl fluorides5 was pioneered by Olah with
his use of cyanuric fluoride and SeF4·pyridine complexes.6
Ishikawa and Petrov followed this with the development of
their related α-fluoroamine reagents (Scheme 1a).7 Issues
associated with preparation and toxicity led to the develop-
ment of new sulfur-based deoxyfluorination alternatives
(Scheme 1a), such as DAST,8 XtalFluor-E,2a,9 and more
recently (Me4N)SCF3,10 SO2F2,11 and others.12 However, as
with the α-fluoroamines, these reagents can require bespoke
synthesis, have narrow substrate tolerance, or are toxic and/or
corrosive. More recently, Prakash disclosed the synthesis of
acyl fluorides using triphenylphosphine, NBS, and Et3N·3HF.13
This approach used readily available commercial reagents;
however, the fluoride source (HF) is toxic and corrosive. Other
notable advances in the area include the work of Hu (Scheme
1b, CpFluor)14 and Shibata, who recently disclosed the
synthesis of acyl fluorides from carboxylic acids, aldehydes,
and alcohols through oxidative fluorination using trichlor-
oisocyanuric acid (TCCA).15 Despite these advances in the
generation of acyl fluorides, challenges remain, mostly
Received: June 11, 2021
Published: July 12, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c01953
Org. Lett. 2021, 23, 5793−5798
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DIPEA and stirred it at room temperature for 16 h in dry
MeCN. Using 19F NMR analysis (see pages S-123 and S-124 of
the Supporting Information) of the crude reaction mixtures, we
were able to determine that acyl fluoride 3 had been
successfully generated (18.1 ppm). We were then able to use
these reaction conditions to prepare acyl fluorides 3a−3h in
yields that were comparable to those obtained using previously
reported methods (Scheme 2).13 We were also able to apply
Scheme 1. Acyl Fluoride Synthesis and Amide Bond
Formation
Scheme 2. Synthesis of Acyl Fluorides from Carboxylic
Acids
the PFP methodology to access biologically relevant substrates
such as ibuprofen (3g) and naproxen (3h), giving the acyl
fluoride analogues in 93% and 94% yields, respectively. These
findings confirmed our initial hypothesis that PFP (2) could be
used as a mild deoxyfluorination reagent to generate acyl
fluorides. Following the successful generation of 3a−3h, we
turned our attention toward investigating the application of
PFP (2) for the in situ generation of acyl fluorides in amide
bond formations.
To start our optimization of the proposed one-pot
deoxyfluorination, amide bond-forming reaction, we picked a
benchmark reaction of benzoic acid (1a) and benzylamine.
With our first set of reaction conditions (PFP 2 and DIPEA)
(Table 1, entry 1), all reagents were added simultaneously,
including the benzylamine; this reaction led to a 32% yield
(isolated) of the desired amide 4a. The low yield was
attributed to the formation of a byproduct that had arisen due
to the unwanted SNAr reaction that had occurred between PFP
(2) and benzylamine; a similar byproduct had been observed
previously in the crude LCMS of a test reaction using aniline as
the amine component (see page S-127 of the Supporting
Information). To minimize this side reaction, an activation
period of 30 min was included to allow the generation of the
acyl fluoride prior to amine addition (Table 1, entry 2). In
addition, the numbers of equivalents of PFP (2) and base were
nucleophilic attack and acting as a fluoride source to generate
the desired acyl fluorides.
On the basis of our previous studies with PFP (2),19b we
also assumed that the most likely byproduct from the proposed
acyl fluoride preparation would be tetrafluorohydroxypyridine
(5). This compound has, in our experience, been shown to be
largely unreactive (at room temperature) to a wide variety of
other reagents. This is due to the p-hydoxyl moiety on the
pyridine ring deactivating the system toward additional SNAr
reactions. This led us to consider if PFP (2) could also be
utilized as a one-pot amide bond-forming reagent via an in situ
acyl fluoride generation type mechanism.2a,c,e,23 In this
capacity, PFP (2) would offer enhanced atom economy over
coupling reagents such as HATU and PyBOP (Scheme 1c)
and offer an alternative to pyridine-based agents such as 2-
chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) or 2-fluoro-1-
ethylpyridinium tetrafluoroborate (FEP) (Scheme 1c).24
Herein, we report the use of PFP (2) for the generation of
acyl fluorides from carboxylic acids and in the one-pot
preparation of amides via an in situ acyl fluoride generation
(Scheme 1d).
To initially evaluate PFP as a deoxyfluorination reagent, we
took a 1:1:1 mixture of benzoic acid (1a), PFP (2), and
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Table 1. Optimization of a Tandem Deoxyfluorination
Amidation Sequence
Scheme 3. (a) 19F NMR Study of Acyl Fluoride Formation
and (b) Proposed Mechanism for the Deoxyfluorination
Amidation One-Pot Reaction
a
entry
PFP (equiv)
base (equiv)
solvent
MeCN
yield (%)
b
1
3.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
DIPEA (3)
DIPEA (2)
DIPEA (1)
none
32
94
44
−
14
4
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
1,4-dioxane
THF
DMF
TEA (2)
K2CO3 (2)
pyridine (2)
DIPEA (2)
DIPEA (2)
DIPEA (2)
DIPEA (2)
DIPEA (2)
7
16
−
−
2
10
11
12
NMP
−
a
b
Isolated yield following column chromatography. No activation
period; i.e., amine was added at the same time as PFP.
decreased to help minimize byproduct formation. This led to a
greatly increased yield of 94% of the desired amide product 4a.
Decreasing the amount of based used, i.e., to 1.1 equiv, had a
deleterious effect on the product yield (Table 1, entry 3), and
when no base was included, no reaction was observed (Table
1, entry 4). Changing the identity of the base (Table 1, entries
5−7) or the solvent (Table 1, entries 9−12) was found not to
improve the observed amide yield. This led us to taking the
conditions from entry 2 of Table 1 forward for further
exploitation and substrate scope evaluation.
We then probed the mechanism of amide bond formation to
confirm that in situ acyl fluoride generation was occurring. To
do this, we employed both LCMS and 19F NMR techniques to
probe the makeup of the species present within the reaction
mixture at various times. After obtaining a 19F NMR spectrum
of the activated mixture, we performed spiking experiments
with reference compounds, including isolated benzoyl fluoride
(3) and 2,3,5,6-tetrafluoro-4-hydroxypyridine (5) (see pages S-
123 and S-124 of the Supporting Information). From this, we
were able to unambiguously confirm the presence of
compounds 3 and 5 after the initial activation period (30
min) (Scheme 3a). The 19F NMR observations were
confirmed by LCMS analysis of a crude reaction mixture
(see pages S-125−S-127 of the Supporting Information). From
the analysis, we were able to propose a mechanism for the one-
pot deoxyfluorination amide bond-forming reaction (Scheme
3b). This mechanism also considers the need for a minimum of
2.0 equiv of base that was seen in the optimization experiments
(Table 1).
at room temperature. The methodology was also found to be
applicable for the preparation of both secondary and tertiary
amides with both aliphatic and aromatic amines.
Electron deficient anilines and aminopyridines, which are
less nucleophilic entities, did require heating in a sealed tube
following acyl fluoride formation to generate the target amides.
Under these reaction conditions, 4-(trifluoromethyl)aniline
(4f), 2-aminopyridine (4aa), and 3-nitroaniline (4z) gave the
corresponding amines in 87%, 86%, and 73% yields,
respectively. The use of 4-nitroaniline was also attempted;
however, this gave very poor conversion (>5%) even under
sealed tube conditions. 19F NMR monitoring of the reaction
with 4-nitroaniline showed that the intermediate acyl fluoride
was still present in the reaction mixture even after heating (see
pages S-128 and S-129 of the Supporting Information). This
confirmed that as expected the inherent lack of nucleophilicity
of the amine was the reason for the poor observed reaction
conversion. This result mirrors previous observations in this
area that showed that increased temperatures are required for
electron poor or highly sterically hindered amine substrates.2c
From the differences seen in the amide yields obtained
among the various acid substrates used, we also hypothesized
that the activation time for acyl fluoride formation may also be
important. To this end, we selected a representative example
from the substrate scope study and increased the activation
time from 30 min to 3 h. In addition, to show the applicability
of the methodology to gram scale synthesis we also increased
the scale of the reaction. We chose to repeat the synthesis of 4y
using 1 g of trans-cinnamic acid. Increasing the initial
activation period to 3 h was found, in this specific case, to
increase the yield, and 4y was isolated in 90% yield (Scheme
4). However, it should be noted that increasing the activation
Following confirmation that PFP (2) could readily generate
acyl fluorides in situ for amidation reactions, we explored the
substrate scope of the process. A range of aliphatic and
aromatic carboxylic acids and amines were employed using the
developed conditions (Scheme 4).
It was found that amides 4a−4ad were isolated in good to
excellent yields with electron rich amines (e.g., 4-methoxyani-
line and 3,5-dimethylaniline) in general giving the best yields
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In addition to amide bond formation, we were interested in
seeing if this in situ acyl fluoride generation method was
applicable to other nucleophilic addition/elimination processes
such as ester formation. In a small scale proof of principle
study, we were able to generate esters from both electron poor
and electron rich phenols with benzoic acid such as 6a (68%)
and 6b (50%) (Scheme 5). We were also able to demonstrate
Scheme 4. Scope of One-Pot Deoxyfluorination Amidation
Scheme 5. PFP-Enabled One-Pot Synthesis of Esters
the synthesis of esters from aliphatic acids to generate
compounds 6c and 6d in 23% and 24% yields, respectively.
It should be noted that the reaction conditions used were
directly transferred from the amide bond formation protocols,
and thus, further optimization for ester formation is required.
In addition to optimizing the reaction conditions for accessing
esters, we are currently studying other addition/elimination
processes and will look to report the outcomes from this work
in due course.
In conclusion, PFP (2) has been shown to function as a
deoxyfluorination reagent allowing the generation of acyl
fluorides from a range of carboxylic acids under mild reaction
conditions. Given that PFP is cheap, commercially available,
non-corrosive, and bench stable, we see it as a useful alternative
to other reagents currently used in the field. In addition, we
have demonstrated that PFP can be utilized in a one-pot amide
bond formation process via the in situ formation of acyl
fluorides. This reaction between unactivated carboxylic acids
and amines gives ready access to amides in good to excellent
yields. The application of the methodology to ester formation
is reported, but further optimization is required.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01953.
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
a
After the activation period, the reaction mixture was heated to 100
°C in a sealed tube for 16 h.
William D. G. Brittain − Department of Chemistry, Durham
University, Durham DH1 3LE, United Kingdom;
orcid.org/0000-0002-2876-5895;
period for all substrates may not increase the amide yield as
there is a balance to be struck between acyl fluoride formation
and acyl fluoride degradation. Therefore, it is suggested that a
30 min activation should be tried in the first instance before
increasing the activation window.
Email: william.d.brittain@durham.ac.uk
Steven L. Cobb − Department of Chemistry, Durham
University, Durham DH1 3LE, United Kingdom;
orcid.org/0000-0002-3790-7023; Email: s.l.cobb@
durham.ac.uk
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01953
Notes
The authors declare the following competing financial
interest(s): S.L.C. is a founder and a current Director of the
company Pepmotec Ltd.
ACKNOWLEDGMENTS
■
This work was supported by funding from the Medical
Research Council (MRC) Global Challenges Research Fund
(GCRF) (Grant MR/P027989/1A) and via a Leverhulme
Trust Early Career Fellowship (ECF-2020-454 and Durham
University).
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