Mechanochemical Synthesis of N-Aryl Amides from O-Protected Hydroxamic Acids

Article abstract of DOI:10.1002/cplu.202000451

Two robust and efficient mechanochemical protocols for the synthesis of an array of N-arylamides have been developed. This was achieved by a C?N cross-coupling between O-pivaloyl hydroxamic acids and aryl iodides or aryl boronic acids, in the presence of a stoichiometric amount of a copper mediator. The effectiveness of this method is highlighted by the high-yielding (up to 94 %), scalable (up to 8 mmol), and rapid (20 minutes) synthesis of N-aryl amides (15 examples), using a variety of deactivated and sterically encumbered substrates, whilst employing mild conditions and in the absence of solvents. In addition, it was determined that whilst the O-pivaloyl hydroxamic acid precursors can be synthesised mechanochemically, iron contamination originating from the steel jars was found to occur which can hinder the efficacy of this process. Furthermore, 3D printing was used to produce custom milling jars that could successfully accommodate a scaled-up version of the two protocols.

Full text of DOI:10.1002/cplu.202000451

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Mechanochemical Synthesis of N-Aryl Amides from
O-Protected Hydroxamic Acids
Emmanouil Broumidis,[a] Mary C. Jones,[a] Filipe Vilela,*[a] and Gareth O. Lloyd*[b]
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Dedicated to Prof. Len Barbour, Prof. Jon Steed, Prof. Bill Jones, and the many young talents they have mentored.
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Two robust and efficient mechanochemical protocols for the
synthesis of an array of N-arylamides have been developed. This
was achieved by a CÀ N cross-coupling between O-pivaloyl
hydroxamic acids and aryl iodides or aryl boronic acids, in the
presence of a stoichiometric amount of a copper mediator. The
effectiveness of this method is highlighted by the high-yielding
(up to 94%), scalable (up to 8 mmol), and rapid (20 minutes)
synthesis of N-aryl amides (15 examples), using a variety of
deactivated and sterically encumbered substrates, whilst em-
ploying mild conditions and in the absence of solvents. In
addition, it was determined that whilst the O-pivaloyl hydroxa-
mic acid precursors can be synthesised mechanochemically,
iron contamination originating from the steel jars was found to
occur which can hinder the efficacy of this process. Further-
more, 3D printing was used to produce custom milling jars that
could successfully accommodate a scaled-up version of the two
protocols.
Introduction
database searches have revealed that the most prevalent
solvents employed in amide couplings are dichloromethane
(DCM) and N,N-dimethylformamide (DMF), used in 36% and
47% of the reactions respectively.[7] It is widely accepted that
both of these solvents pose issues,[8] both in handling them and
discarding them to the environment.[9,10] Thus, it is now
becoming increasingly important for chemists to seriously
consider implementing alternative and greener methods for
synthesising compounds and mechanochemistry is a great
means to achieve this. Traditionally, mechanochemistry was
considered as a technique of less versatility and scope for
chemists, and as a result, it hasn’t been widely accepted by the
synthetic community as a plausible method of inducing
chemical reactions. However, this is now rapidly changing, as
researchers are starting to recognise the versatility and
potential mechanochemistry has to offer, mainly due to the
advent of green chemistry and the need to find more environ-
mentally friendly and sustainable methods of producing
chemicals, both in research laboratories[11–13] and on an
industrial scale.[14] These realisations have led to rapid develop-
ments in key areas of synthetic organic chemistry spanning
from catalysis and coupling reactions[15] to more niche topics
such as fullerene chemistry,[16] photocatalysis, and
supramolecular chemistry.[17] Through this apparent era of
’mechanochemical enlightenment’, it has become clear that an
optimised mechanochemical protocol can not only provide
improved performance compared to equivalent batch reactions
but it can also unlock new mechanistic pathways which lead to
products previously unattainable through batch techniques.[18,19]
Amides have understandably been a target for mechanochem-
ical synthesis with activated carboxylic acids (carbodiimides, for
example), peptides, and materials being common themes.20
Herein we describe two mechanochemical protocols for the
high yielding N-amidation of aryl iodides (protocol A) and aryl
boronic acids (protocol B) by O-protected hydroxamic acids,
The amide functionality has proven to be extremely important
in most areas of organic chemistry and is present in a vast
number of contemporary pharmaceuticals, agrochemicals, poly-
mers, as well as natural products and biological molecules.[1–3]
Since there is an intrinsic need for large scale production of
amide-bearing compounds, it is imperative that improved and
sustainable methods are developed to provide high atom
efficiency, low energy consumption, and minimal waste, whilst
maintaining acceptable yields.[4] It is noted that within the
pharmaceutical industry alone, amides constitute by far the
most abundant functionality (16% of all reactions within the
sector), and subsequently, synthetic routes that provide access
to this moiety are the most commonly used in the sector.[5,6]
Aryl amides can be problematic to synthesise due to the
reduced reactivity/nucleophilicity of the amine. Furthermore, it
has been reported that around 85% of the chemicals that are
being used are solvents,[4] of which a large percentage are never
recycled, ending up in the environment as pollutants. Large
[a] E. Broumidis, M. C. Jones, F. Vilela
Institute of Chemical Sciences
School of Engineering & Physical Sciences
Heriot-Watt University
Edinburgh EH14 4AS (United Kingdom)
E-mail: F.Vilela@hw.ac.uk
[b] G. O. Lloyd
School of Chemistry
Joseph Banks Laboratories
University of Lincoln
Lincoln LN6 7TS (United Kingdom)
E-mail: glloyd@lincoln.ac.uk
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cplu.202000451
This article is part of a Special Collection on “Supramolecular Chemistry:
Young Talents and their Mentors”. More articles can be found under https://
onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)2192-6506.Supramolecular-
Chemistry.
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mediated by the stoichiometric presence of a Cu(I/II) species
(Scheme 1).
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Results and Discussion
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There are several examples in the literature[21–23] (see Scheme 1
for comparison of literature methods and work presented here)
where protected hydroxamic acids are converted into amides,
and it is clear that high temperatures, inert atmospheres, harsh
solvents and moderate to long reaction times are in most cases
indispensable to achieve the desired outcome. Additionally,
only one of the reports[21] employs aryl halides, where the
starting reagent N-methoxybenzamide undergoes a double
oxidative CÀ C and CÀ N bond formation to afford a cyclic
phenanthridinone, circumventing the formation of a secondary
amide. The most common coupling partners used in those
reactions are boronic acids. Our main goal for this study was to
find a set of more benign and sustainable reaction conditions
that could be implemented with mechanochemistry. Initially,
the possibility of using ball milling as a means to gain access to
the O-pivaloyl protected hydroxamic acids starting materials
was examined (Scheme 2).
It was found, that although it was possible to achieve
comparable yields with reduced reaction times by applying the
mainstream solution-based conditions[23,24] to the ball mill, in
the absence of a solvent, iron leaching from the steel jars occurs
during the milling process. It has been shown that iron particles
which become dislodged during the milling process can then
be oxidised to form Fe(II) and Fe(III) species.[25] We found that
when this occurs, the Fe-hydroxamate complex becomes
unreactive and due to the paramagnetic nature of Fe(III), during
NMR analysis we observed reduced relaxation times, which
causes an extreme broadening of the NMR peaks (Figure 1 and
Supporting Information S1.3). Furthermore, energy dispersive x-
ray spectroscopy (EDX) analysis with a scanning electron
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Figure 1. a) SEM/EDX analysis of pristine and milled benzohydroxamic acid
clearly shows that iron and chromium leaches from the steel jars to the
sample. Spectra and images are representative of the entire sample (nine
images and spectra recorded). b) Pre-milled and post-milled 1H-NMR spectra
of benzohydroxamic acid illustrating peak broadening due to the presence
of paramagnetic Fe(III).
microscope (SEM) of pristine and milled benzohydroxamic acid
samples confirmed the presence of iron and chromium in the
latter sample, both of which are contained within the steel jars
that were used (Figure 1). It is interesting to note that Mocci
et al.[26] do not mention leaching of iron during their hydroxa-
mic acid mechanochemical synthesis. We can only speculate
Filipe Vilela completed his PhD in the field of
polymer chemistry under the supervision of
Professor David C. Sherrington at the Univer-
sity of Strathclyde, Glasgow, Scotland, UK. A
postdoctoral position followed with Professor
Pete J. Skabara. Independence began as a
research group leader at the Max Planck
Institute of Colloids and Interfaces (MPI),
Potsdam, Germany. A move back to Scotland
as an assistant professor at Heriot-Watt Uni-
versity resulted in the establishment of the
Vilela lab.
north to Scotland and Heriot-Watt University
as a Research Fellow. Gareth recently moved
to the new School of Chemistry at the
University of Lincoln.
Len, Jon, Bill, Dave and Pete inspired an
interdisciplinary and collaborative work envi-
ronment. Mary Jones and Emmanouil Broumi-
dis are co-supervised by Gareth and Filipe,
and work across a number of teams. The
researchers within the teams, who bring this
scientific effort to fruition, are continuously
inspiring new ideas and projects, like this one.
This paper is the brainchild of Emmanouil, and
couples the Vilela group interests of polyaryls
and photocatalysis with the Lloyd group
interests of mechanochemistry and hydroxa-
mic acids.
Gareth Lloyd completed his MSc at Stellen-
bosch University, South Africa under the
supervision of Len Barbour. A PhD followed at
Durham, UK under the supervision of Jon
Steed. An independent position as a Herchel
Smith Fellow at Cambridge, UK under the
mentorship of Bill Jones began his interest in
mechanochemistry. The Lloyd/Vilela collabora-
tion ensued upon a move for Gareth further
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Scheme 1. Comparison between previous N-benzamide synthetic contributions using O-protected hydroxamic acids and current work.
inconsistent results, as hydroxamic acids and their derivatives
are well-known siderophores and iron sequesters.[29,30] As such,
in order to reliable obtain the desired O-protected hydroxamic
acids we opted to use traditional batch procedures, although
we believe that future research endeavours focusing on
addressing this issue are required to allow iron sensitive
chemistries to work reliably under mechanochemical conditions
using steel grinding jars. Use of jars made out of different
materials such as Teflon (PTFE) may be a way to circumvent this
issue, however, the aforementioned reaction did not work,
perhaps due to the softness of PTFE in comparison to steel.
For the optimisation of the Ullmann coupling (protocol A,
Scheme 1), we were interested in determining the optimal
conditions for the preparation of N-phenylbenzamide (2a).
Although this compound is trivial, the starting materials are
relatively cheap, easily available, and allow for ease of testing
and optimisation of the initial reaction conditions. These
include the determination of an appropriate catalyst/promoter,
base (if required), ligand, and protecting group for the
hydroxamic acid. It was found that by using 3 equivalents (eq.)
of copper (I) thiophene-2-carboxylate (CuTC), N,N’-dimeth-
ylethylenediamine (DMEDA) (6 eq.), O-pivaloyl protected benzo-
hydroxamic acid and iodobenzene the Ullmann-type trans-
formation (protocol A) proceeded to give the best results under
liquid-assisted grinding (LAG, EtOH, η=0.16 μL/mg)[31] mecha-
Scheme 2. Most common synthesis conditions of various O-protected
hydroxamic acids involves the use of solvents such as diethyl ether (Et2O) or
tetrahydrofuran (THF).
that ageing of the steel-constructed jars may be the cause of
our observation of leaching and we advise when using
mechanochemistry to be aware of this issue with steel grinding
jars, as leaching of iron or chromium may not only interfere
with the reactants but also catalyse reactions[27,28] both of which
may lead to inaccurate results. Unsurprisingly, this leaching
occasionally caused interference with the reaction leading to
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nochemical transformations. No other additives were deemed
necessary. All mechanochemical reactions were carried out
using a 10 mL steel jar with 2 steel balls (8 mm in diameter),
and the optimised reaction was complete in under 20 minutes,
which is significantly less than comparable batch reactions
(Scheme 1). With these optimal conditions in hand, we
proceeded to investigate whether the use of LAG is necessary
(Table 1).
A range of solvents was tested spanning a wide spectrum of
polarities. It immediately became obvious that using small
amounts of EtOH has a profound effect on the efficiency of the
reaction (entry 3). When the reaction was performed without
any solvent, (entry 1) the yield dropped significantly, high-
lighting the importance of LAG in this mechanochemical
synthesis.[32] The use of water as a LAG additive (entry 2) further
In order to extend the utility of the O-protected hydroxamic
acid starting materials, and inspired by previously reported[31]
solution-based N-amidations, we developed a separate, mecha-
nochemical Chan-Lam type coupling procedure (protocol B),
which uses arylboronic acids as the coupling partner together
with a stoichiometric amount of Cu(OAc)2 as a mediator. We
initiated our optimisation (Scheme 3), by adopting the con-
ditions that were developed for solution-based chemistry by
Zhang et al.[36] We found that both acetyl (1a) and pivaloyl (1d)
O-protected hydroxamic acids were effective coupling partners
affording 2a in a 90% and 92% yield, respectively. The
presence of a base was deemed necessary for the reaction to
proceed to completion and after a base screening, 2 equivalents
of potassium tert-butoxide (t-BuOK) was found to be the best
choice (SI S1.1).
In contrast with the Ullmann protocol A, the addition of a
LAG solvent did not improve the reaction efficacy with a
reduction in the overall yield when EtOH was used as a LAG
component (SI S1.1). The minimum amount of time for the
reaction to go to completion was determined to be 20 minutes,
which is comparable with the corresponding time for protocol
A. It was observed that when the Cu(OAc)2 equivalents were
less than one, the reaction did not proceed to completion. This
result is in line with most Chan-Lam coupling procedures in the
literature,[37] where a stoichiometric amount of copper is
required. Overall, the optimised conditions were determined to
be 1 eq. of 1d, 1 eq. of Cu(OAc)2 and 2 eq. of t-BuOK which
afforded product 2a in high yield (92%) after 20 minutes of
milling. For comparison, when applying these conditions to a
solution-based set-up using various solvents and heating the
reaction mixture we found that even after 16 hours the reaction
was not complete and thin-layer chromatography (TLC) analysis
revealed many side-products and unreacted starting material
(SI, S1.6). Finally, the optimised protocols (A and B) were
applied to a range of different aryl iodides and aryl boronic
acids to explore their effectiveness and versatility (Scheme 4).
Overall, both protocols A and B proved to be highly efficient
and provided access to moderate to high yielding N-arylamides.
Compounds bearing electron-deficient functional groups (2d,
2f, 2g, 2i, 2j, 2l, 2m) and sterically encumbering functional
groups (2e, 2h, 2i, 2o) were accessed, although 2m and 2o
only in trace amounts. Furthermore, protocol A also works by
varying the starting O-protected hydroxamic acid, as demon-
strated by the use of N-(pivaloyloxy)acetamide 1e and N-
(pivaloyloxy)picolinamide 1f to give the commercial pharma-
ceutical paracetamol, 2k, in moderate yield and traces of 2m.
Interestingly, when diiodo aryl starting materials were used only
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reduced the overall yield, while DMF (entry 4) offers
a
substantial conversion but lower than EtOH. Non-polar solvent
LAG did not affect the yield. Olefins and alkynes are known to
act as π-Lewis base ligands that can coordinate with various
copper species and enhance the yields of Ullmann oxidative
couplings.[33] Moreover, it was recently found[12,34] that olefins
can be used as effective molecular dispersants for solid-state Pd
promoted cross-coupling reactions. For those reasons 3-hexyne
was used to test whether any enhancement could be observed.
The overall yield of the reaction (entry 5) was no different than
the LAG-free benchmark. We also noticed that the two best
LAG additives (EtOH and DMF) were found to dissolve all
components of the mixture fairly well, albeit when we tried
applying the same reaction protocol in solution the reactivity
was reduced significantly (Supporting Information S1.6). After
establishing that EtOH is the most efficient LAG additive, we
wanted to examine the respective reactivity of bromo- and
chloro-benzene as coupling partners. It was found that under
the aforementioned optimal reaction conditions bromobenzene
only afforded 2a at a yield of 16% while chlorobenzene was
completely unreactive (SI, S1.2). This was not unexpected, as
aryl iodides are known to be the most reactive aryl halides
towards Ullmann couplings.[35] Commercial grinding jars are
available in a range of materials therefore further optimisation
may be achieved by changing the jars used. The reaction was
repeated for jars and 8 mm balls made out of Teflon (PTFE) and
poly(methyl methacrylate) (PMMA). It was found that stainless
steel and Teflon had comparable performances, and the acrylic
jars and balls did not perform as well (SI S1.7).
Table 1. Investigation of LAG effects on the yield of 2a.[a]
Entry
LAG[b]
Yield [%][c]
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Neat
Water
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46
94
88
66
65
Ethanol
Dimethylformamide (DMF)
3-Hexyne
Toluene
[a] 10 mL stainless-steel jar with two 8 mm diameter stainless-steel balls
were used for the ball-milling reactions. An average of two runs is reported
for the ball-milling reactions. [b] η=0.16 μL/mg, based on adding 100 μL
of solvent in 618 mg of reactants. [c] Yield of isolated product.
Scheme 3. Chan-Lam reaction parameters that were explored for optimisa-
tion under mechanochemical conditions (protocol B).
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Scheme 4. Reaction scope using the optimised protocols A and B.
the monosubstituted compounds were formed (2i, 2l, 2m, 2l),
even when the CuTC and DMEDA equivalents were doubled.
Similar results were observed under solution conditions.
inertness of 2n towards protocol A’s Ullmann-like conditions
was further established when we used a pure sample of 2n as
the halide source and it did not react with 1d. Similar results
were observed when 1,4-dibromobenzene and 4,7-diiodobenzo
[c][1,2,5]thiadiazole were used for the formation of 2c and 2l,
respectively. Overall, this selective reactivity towards aryl
dihalides expands the scope of the method and makes it
possible to synthesise halogen bearing N-benzamides which
can be then used for further synthetic modifications.
Heteroaryl 1f was used to afford compound 2m, but only a
trace amount (<5% yield) was isolated and when N-(pivaloy-
loxy)isonicotinamide (1g) was used the reaction failed. Similarly,
when these heteroaryl starting materials were used in con-
junction with protocol B conditions, the reaction did not work.
We postulate that this lack of reactivity stems from the pyridyl
moiety binding to the copper mediator. Interestingly, when 1,4-
diiodobenzene was used under protocol A conditions, com-
pound 2n was isolated (27% yield) and no traces of diamide
were detected in the reaction mixture. Even when we used
2 eq. of 1d only the monoamide 2n formed, despite having a
second iodine available for further cross-coupling. This apparent
We postulated that the donor-acceptor (DÀ A) type com-
pound, 2l, could be used for photochemical applications. This
was demonstrated by using it as a photosensitiser for the
mechanochemically-assisted
solid-state
photocatalytic
(MASSPC)[38] conversion of anthracene to anthracene-endoper-
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oxide (SI S1.8, S1.9) which was subsequently catalytically
decomposed to anthraquinone.[39]
since we know that side-reactions such as protodeboronations
may occur, under protocol’s B conditions.
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Since polycyclic aromatic hydrocarbons (PAHs) are known
for their low solubility in most organic solvents, due to strong
intermolecular π-π interactions which stem from their extended
planar structures,[40] we decided to use pyrene-1-boronic acid as
a coupling partner to 1d to gain access the corresponding N-
benzamide 2o via protocol B. Unexpectedly, after 20 minutes of
milling, TLC analysis of the reaction mixture showed a multitude
of trailing spots, indicating a deviation from the expected
outcome. Upon subjecting the reaction mixture to mass
spectrometry (MS) analysis, it was revealed that the target
amide 2o was present amongst other side-products. Purifica-
tion of the crude reaction mixture via preparative thin layer
chromatography, afforded 27 mg of a yellow solid (13% yield),
however, we were not able to isolate amide 2o. Interestingly,
upon analysis, the isolated yellow solid was found to be
primarily pyrene and although it was contaminated with other
by-products it was reasonably pure (Scheme 5).
We postulate that the formation of pyrene can be the result
of a protodeboronation side-reaction which may have been
catalysed by the presence of Cu(OAc)2. A solution-based copper
catalysed protodeboronation procedure under basic conditions
was reported in 2014,[41] however, to the best of our knowledge,
this is the first example of a mechanochemical protodeborona-
tion reaction. Although historically protodeboronations have
been considered of lesser importance by organic chemists,
recently this reaction has found a variety of applications in
synthetic procedures[42,43] and thus the aforementioned example
may form a stepping stone for further development of such
solventless protodeboronations. In general, protocol B gave
slightly lower yields than protocol A, which can be rationalised
We found that both protocols are scalable up to the gram
scale with only slight modifications (Scheme 6). Machining[44]
and 3D printing of custom milling jars[45] are examples of
customisation techniques mechanochemists have used in the
past to adjust the milling jars to their needs. To accommodate
the large quantity of reactants, custom milling jars were made
using a commercial 3D printer that uses methacrylate photo-
polymers to produce the desired object via a stereolithographic
(SLA) printing technique.[46] The 3D printed jar that was used
was printed using a commercial form 2 SLA printer along with
tough v5 resin, both made by Formlabs. The jars had an internal
volume of 70 mL, a wall thickness of 10 mm and could easily
accommodate the reactants, which combined had a mass of
12.75 g and 6.49 g for protocols A and B, respectively. The
milling frequency was reduced to 20 Hz in order to ensure that
the printed jars could withstand the prolonged milling forces,
as it was found that at 25 Hz cracks would form on the inner
surface of the jars after about 30–45 minutes of milling. As a
result of the lower milling frequency, the reaction time to
completion increased from 20 minutes to about 90 minutes, for
both protocols.
Initially, 25×8 mm Teflon balls with a total mass of 6 g were
used (protocol A), but the mixture remained unreactive.
However, when 6 ZrO2 balls of variable diameter (6–15 mm)
were used with a total mass of 16.11 g, the reaction gave
product 2d at 72% yield. This agrees with the studies made by
Fischer et al.,[47] which showed that the total energy input of
each collision during the milling process has a higher impact on
the reactivity than the number of collisions during the milling
process. Similarly, by using the mixed ZrO2 balls, protocol B was
successfully used at gram scale and afforded 2b at 61%. In
both cases, the yield diminished slightly, as would be expected
for a scaled reaction.
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Scheme 5. Mechanochemical reaction between 1d and pyrene-1-boronic
acid under protocol B conditions leads to the formation of pyrene as the
major isolatable product.
Scheme 6. Gram-scale synthesis using protocols A and B. The scaling of the
reaction reduces the yield slightly.
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Conclusion
Experimental Section
Preparation of N-aryl benzamides
Mechanochemical preparation
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We report here the synthesis of amides using two mechano-
chemical protocols. As a comparison to previously reported
methodologies, we believe that these methods add to the
current knowledge base. As early as 2008, Gao and Wang[48]
used potassium peroxymonosulfate, also known as oxone, as an
environmentally friendly non-toxic oxidant to synthesise a
range of aromatic benzamides by oxidative amidation of
aldehydes with anilines under mechanochemical, solvent-free
conditions. Other notable amide synthesis examples include
mechanochemically activating carboxylic acids using N-ethyl-N’-
(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl)
for the chemoselective and high yielding synthesis of aromatic
amides and dipeptides, developed by Štrukil et al.[49] A similarly
enticing report emerged in 2013 by Bonnamour et al.[50]
demonstrating a method that uses EtOAc LAG mechanochemis-
try to access a variety of peptides in high yields after 20
minutes of milling, compared to traditional solution syntheses
which primarily use harsh solvents such as DMF. Finally, a more
recent example from 2020 by Dayaker et al.,[11] introduced a
copper-catalysed milling synthesis affording a plethora of
carbamoyl-amides in high yields, whilst analogous batch experi-
ments required high temperatures to work, while producing
unwanted by-products not seen under mechanochemical
conditions. These examples are a small part of an ongoing
effort[20] for utilising mechanochemical techniques to form
amide and peptide bonds and they all operate under the same
principles as our study, offering high yielding amide syntheses,
minimal ecological impact, chemoselectivity, minimisation of
unwanted by-products, and synthesis of difficult-to-access
amides (e.g. aryl amides).
Protocol A: To a stainless steel ball mill jar (10 mL internal volume)
N-(pivaloyloxy)benzamide (88.5 mg, 0.400 mmol, 1 eq.) was added,
followed by the corresponding phenyl iodide (0.44 mmol, 1.1 eq.),
copper (I) thiophene-2-carboxylate (228.2 mg, 1.200 mmol, 3 eq.)
and N,N’-dimethylethylenediamine (211.6 mg, 2.400 mmol, 6 eq.). In
addition to these reagents, EtOH (η=0.16 μL/mg) was added to the
jar, along with two steel balls (8 mm in diameter). The jar was
sealed and milled for 20 minutes at 25 Hz. After the completion of
the reaction was confirmed by TLC (CHCl3 :EtOAc, 90:10), the jar
was opened and the reaction mixture was passed through a short
silica plug (eluted with 5 mL CHCl3 :EtOAc, 80:20). The resulting
solution was evaporated under reduced pressure, and the residue
was recrystallised to afford the title compound (2_).
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Protocol B: To a stainless steel ball mill jar (10 mL internal volume)
N-(pivaloyloxy)benzamide (88.5 mg, 0.400 mmol, 1 eq.) was added,
followed by the corresponding phenyl boronic acid (0.48 mmol,
1.2 eq.), copper(II) acetate (72.7 mg, 0.400 mmol, 1 eq.) and potas-
sium tert-butoxide (89.77 mg, 0.800 mmol, 2 eq.). In addition to
these reagents, two steel balls were added to the jar (8 mm in
diameter). The jar was then sealed and milled for 20 minutes at
25 Hz. After the completion of the reaction which was confirmed by
TLC (CHCl3 :EtOAc, 90:10), the jar was opened and the reaction
mixture was passed through a short silica plug (eluted with 5 mL
CHCl3 :EtOAc, 80:20). The resulting solution was evaporated under
reduced pressure, and the residue was recrystallised to afford the
title compound (2_).
Gram scale mechanochemical preparations
Protocol A: To an SLA 3D printed milling jar (70 mL internal volume)
N-(pivaloyloxy)benzamide (1.77 g, 8.00 mmol, 1 eq.) was added,
followed by 1-iodo-4-nitrobenzene (2.19 g, 8.80 mmol, 1.1 eq.),
copper (I) thiophene-2-carboxylate (4.56 g, 24.0 mmol, 3 eq.) and
N,N’-dimethylethylenediamine (4.23 g, 48.0 mmol, 6 eq.), along with
4 ZrO2 balls of variable diameter (6–15 mm) with a total mass of
16.11 g. The jar was sealed and milled for 90 minutes at 20 Hz. After
the completion of the reaction was confirmed by TLC (CHCl3 :EtOAc,
90:10), the jar was opened and the reaction mixture was passed
through a short silica plug (eluted with 10 mL CHCl3 :EtOAc, 80:20).
The resulting solution was evaporated under reduced pressure, and
the residue was recrystallised to afford 2d as a yellow powder
(1.39 g, 72%).
In summary, we developed two high yielding and scalable
mechanochemical protocols that provide access to various
secondary N-arylamides from readily available O-protected
hydroxamic acids, iodoaryls, and arylboronic acids. As the
industrial community recognises the need for the development
for new and sustainable amidation methodologies, this work
acts as
a proof of concept that may encourage other
researchers to delve into solvent-free syntheses of amides and
utilise the many benefits mechanochemistry has to offer
compared to the traditional batch-based chemistries. Protocol B
produced lower yields than protocol A, most likely due to
protodeboronation acting as a side-reaction. In addition, we
identified and highlighted the fact that iron leaching originating
from the steel milling jars should be taken into account when
using reactants with high affinity for iron such as hydroxamic
acids or when iron contamination may alter the reaction
outcome. Moreover, we utilised SLA 3D printing to produce jars
that were suitable for scaling up the new synthetic protocols.
Finally, in order to expand the scope of the methodology that
was developed, further work is currently underway that aims to
synthesise efficient BTZ-containing N-arylamides for MASSPC
singlet oxygen generation.
Protocol B: To an SLA 3D printed milling jar (70 mL internal volume)
N-(pivaloyloxy)benzamide (1.77 g, 8.00 mmol, 1 eq.) was added,
followed by 4-methoxyphenylboronic acid (1.47 g, 9.60 mmol, 1.2
eq), copper(II) acetate (1.45 g, 8.00 mmol, 1 eq.) and potassium tert-
butoxide (1.80 g, 16.0 mmol, 2 eq). In addition to these reagents, 4
ZrO2 balls of variable diameter (6–15 mm) with a total mass of
16.11 g were added. The jar was sealed and milled for 90 minutes
at 20 Hz. After the completion of the reaction was confirmed by
TLC (CHCl3 :EtOAc, 90:10), the jar was opened and the reaction
mixture was passed through a short silica plug (eluted with 10
mLCHCl3 :EtOAc, 80:20). The resulting solution was evaporated
under reduced pressure, and the residue was recrystallised to afford
2b as a white powder (1.10 g, 61%).
ChemPlusChem 2020, 85, 1754–1761
www.chempluschem.org
1760
© 2020 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/cplu.202000451
ChemPlusChem
[20] For selected examples on mechanochemical syntheses of aromatic
Acknowledgements
1
2
3
4
5
6
7
8
9
amides and peptides, see: a) T. X. Métro, J. Martinez, F. Lamaty, ACS
Sustainable Chem. Eng. 2017, 5, 9599–9602; b) C. Bolm, J. G. Hernández,
ChemSusChem, 2018, 11, 1410–1420; c) V. Kumar, S. K. Giri, P. Venugo-
palan, K. P. R. Kartha, ChemPlusChem, 2014, 79, 1605–1613; d) Y. Yang, F.
Bu, J. Liu, I. Shakirb, Y. Xu, Chem. Commun. 2017, 53, 7481–7484; e) J. G.
Hernández, K. J. Ardila-Fierro, D. Crawford, S. L. James, C. Bolm, Green
Chem. 2017,19, 2620–2625; f) I. Dokli, M. Gredičak, Eur. J. Org. Chem.
2015, 12, 2727–2732; g) J. M. Landeros, E. Juaristi, Eur. J. Org. Chem.
2017, 3, 687–694; h) S. Jaita, W. Phakhodee, N. Chairungsi, M.
Pattarawarapan, Tetrahedron Lett. 2018, 59, 3571–3573; i) L. Rajput, R.
Banerjee, Cryst. Growth Des. 2014, 14, 2729–2732; j) C. Duangkamol, S.
Jaita, S. Wangngae, W. Phakhodeea, M. Pattarawarapan, RSC Adv. 2015,
5, 52624–52628.
The University of Edinburgh Mass Spectrometry Service is acknowl-
edged for acquiring invaluable mass spectra. Sam Goldwater
(Lincoln) is thanked for assistance with SEM and EDX. E.B. would
like to thank Heriot-Watt University (HWU) and the CRITICAT
EPSRC Centre for Doctoral Training for funding. G.O.L. would like
to thank the Royal Society of Edinburgh/Scottish Government
Personal Research Fellowship scheme. M.J. would like to thank
HWU and EPSRC for PhD funding from the EPSRC DTP. This project
has been supported by the HWU Energy Academy 2016 Fledge
Award (Dr. Susana Garcia-Lopez (HWU) is thanked for being a co-I
on this grant).
10
11
12
13
14
15
16
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[21] G.-W. Wang, T.-T. Yuan, D.-D. Li, Angew. Chem. Int. Ed. 2011, 50, 1380–
1383; Angew. Chem. 2011, 123, 1416–1419.
[22] T. Yasuhisa, K. Hirano, M. Miura, Chem. Lett. 2017, 46, 463–465.
[23] Z. Zhang, Y. Yu, L. S. Liebeskind, Org. Lett. 2008, 10, 3005–3008.
[24] N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011, 133,
6449–6457.
[25] G. Štefanić, S. Krehula, I. Štefanić, Chem. Commun. 2013, 49, 9245–9247.
[26] R. Mocci, L. De Luca, F. Delogu, A. Porcheddu, Adv. Synth. Catal. 2016,
358, 3135–3144.
[27] T. L. Mako, J. A. Byers, Inorg. Chem. Front. 2016, 3, 766–790.
[28] J. Muzart, Chem. Rev. 1992, 92, 113–140.
[29] R. Codd, Coord. Chem. Rev. 2008, 252, 1387–1408.
[30] B. J. Brennan, J. Chen, B. Rudshteyn, S. Chaudhuri, B. Q. Mercado, V. S.
Batista, R. H. Crabtree, G. W. Brudvig, Chem. Commun. 2016, 52, 2972–
2975.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Amidation · cross-coupling · mechanochemistry ·
solvent-free synthesis · sustainable chemistry
[31] T. Friščić, S. L. Childs, S. A. A. Rizvi, W. Jones, CrystEngComm. 2009, 11,
418–426.
[1] G. Li, M. Szostak, Nat. Commun. 2018, 9, 1–8.
[2] P. R. Bradshaw, I. D. Wilson, R. U. Gill, P. J. Butler, C. Dilworth, T. J.
Athersuch, Sci. Rep. 2018, 8, 1–8.
[3] C. W. Cheung, M. L. Ploeger, X. Hu, Nat. Commun. 2017, 8, 1–10.
[4] M. T. Sabatini, L. T. Boulton, H. F. Sneddon, T. D. Sheppard, Nat. Can.
2019, 2, 10–17.
[32] T. Friščić, D. G. Reid, I. Halasz, R. S. Stein, R. E. Dinnebier, M. J. Duer,
Angew. Chem. Int. Ed. 2010, 49, 712–715.
[33] D. Winternheimer, C. Merlic, Org. Lett. 2010, 12, 2508–2510.
[34] T. Seo, T. Ishiyama, K. Kubota, H. Ito, Chem. Sci. 2019, 10, 8202–8210.
[35] H. Rao, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2005, 70, 8107–8109.
[36] Z. Zhang, Y. Yu, L. S. Liebeskind, Org. Lett. 2008, 10, 3005–3008.
[37] I. Munir, A. F. Zahoor, N. Rasool, S. A. R. Naqvi, K. M. Zia, R. Ahmad, Mol.
Diversity 2019, 23, 215–259.
[38] V. Štrukil, I. Sajko, Chem. Commun. 2017, 53, 9101–9104.
[39] M. Klaper, P. Wessig, T. Linker, Chem. Commun. 2016, 52, 1210–1213.
[40] G. Shixiang, W. Liansheng, H. Qingguo, H. Sukui, Chemosphere 1998, 37,
1299–1305.
[41] C. Liu, X. Li, Y. Wu, J. Qiu, RSC Adv. 2014, 4, 54307–54311.
[42] C. Y. Lee, S. J. Ahn, C. H. Cheon, J. Org. Chem. 2013, 78, 12154–12160.
[43] M. Veguillas, M. Ribagorda, M. C. Carreño, Org. Lett. 2011, 13, 656–659.
[44] I. Halasz, S. A. J. Kimber, P. J. Beldon, A. M. Belenguer, F. Adams, V.
Honkimäki, R. C. Nightingale, R. E. Dinnebier, T. Friščić, Nat. Protoc. 2013,
8, 1718–1729.
[5] J. R. Dunetz, J. Magano, G. A. Weisenburger, Org. Process Res. Dev. 2016,
20, 140–177.
[6] D. G. Brown, J. Boström, J. Med. Chem. 2016, 59, 4443–4458.
[7] H. F. Sneddon, J. Murray, D. S. MacMillan, A. J. B. Watson, C. Jamieson,
Green Chem. 2012, 15, 596–600.
[8] C. Gonzalez, C. S. Ponder, Q. B. Broxterman, J. B. Manley, Org. Process
Res. Dev. 2011, 15, 912–917.
[9] J. P. Rioux, R. A. M. Myers, J. Emerg. Med. 1988, 6, 227–238.
[10] C. A. Redlich, W. S. Beckett, J. Sparer, K. W. Barwick, C. A. Riely, H. Miller,
S. L. Shalat, M. R. Cullen, Ann. Intern. Med. 1988, 108, 680–686.
[11] G. Dayaker, D. Tan, N. Biggins, A. Shelam, J.-L. Do, A. D. Katsenis, T.
Friščić, ChemSusChem. 2020, 13, 2966–2972.
[12] K. Kubota, T. Seo, K. Koide, Y. Hasegawa, H. Ito, Nat. Commun. 2019, 10,
[45] N. Tumanov, V. Ban, A. Poulain, Y. Filinchuk, J. Appl. Crystallogr. 2017,
50, 994–999.
[46] https://formlabs.com/materials/.
1–11.
[13] Q. Cao, W. I. Nicholson, A. C. Jones, D. L. Browne, Org. Biomol. Chem.
2018, 17, 1722–1726.
[14] S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić, F.
Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini,
A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed, D. C. Waddell,
Chem. Soc. Rev. 2012, 41, 413–447.
[15] a) G. W. Wang, Chem. Soc. Rev. 2013, 42, 7668–7700; b) T. K. Achar, A.
Bose, P. Mal, Beilstein J. Org. Chem. 2017, 13, 1907–1931.
[16] S. E. Zhu, F. Li, G. W. Wang, Chem. Soc. Rev. 2013, 42, 7535–7570.
[17] T. Friščić, C. Mottillo, H. M. Titi, Angew. Chem. Int. Ed. 2020, 59, 1018–
1029.
[47] F. Fischer, N. Fendel, S. Greiser, K. Rademann, F. Emmerling, Org. Process
Res. Dev. 2017, 21, 655–659.
[48] J. Gao, G. W. Wang, J. Org. Chem. 2008, 73, 2955–2958.
[49] V. Štrukil, B. Bartolec, T. Portada, I. Đilović, I. Halasz, D. Margetić, Chem.
Commun. 2012, 48, 12100–12102.
[50] J. Bonnamour, T. X. Métro, J. Martinez, F. Lamaty, Green Chem. 2013, 15,
1116–1120.
[18] Z. V. Todres, Organic Mechanochemistry and Its Practical Applications,
CRC Press, Boca Raton, 2006.
[19] C. E. Diesendruck in Mechanochemistry in Materials. (Eds.: Y. C. Simon,
S. L. Craig), The Royal Society Of Chemistry, Croydon, 2018, pp. 36–52.
Manuscript received: June 8, 2020
Revised manuscript received: July 27, 2020
Accepted manuscript online: July 28, 2020
ChemPlusChem 2020, 85, 1754–1761
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© 2020 Wiley-VCH GmbH