Direct Amidation of Esters by Ball Milling**

Article abstract of DOI:10.1002/anie.202106412

The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.

Full text of DOI:10.1002/anie.202106412

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Accepted Article
Title: Direct Amidation of Esters via Ball Milling
Authors: Williams Nicholson, Fabien Barreteau, Jamie Leitch, Riley
Payne, Ian Priestley, Edouard Godineau, Claudio Battilocchio,
and Duncan L. Browne
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202106412
Link to VoR: https://doi.org/10.1002/anie.202106412

10.1002/anie.202106412
Angewandte Chemie International Edition
RESEARCH ARTICLE
Direct Amidation of Esters via Ball Milling
William I. Nicholson,[b] Fabien Barreteau,[c] Jamie A. Leitch,[a] Riley Payne,[a] Ian Priestley,[d] Edouard
Godineau,[c] Claudio Battilocchio,*[c] and Duncan L. Browne*[a]
[a]
Dr. Jamie A. Leitch, Riley Payne, Dr. Duncan L. Browne
Department of Pharmaceutical and Biological Chemistry, University College London (UCL), School of Pharmacy, 29-39 Brunswick Square, Bloomsbury,
London, WC1N 1AX, United Kingdom
E-mail: duncan.browne@ucl.ac.uk
[b]
[c]
William I. Nicholson
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, United Kingdom
Dr. Fabien Barreteau, Dr. Edouard Godineau, Dr. Claudio Battilocchio
Syngenta Crop Protection AG, Rosentalstrasse 67, 4002 Basel, Switzerland
Email: claudio.battilocchio@syngenta.com
[d]
Ian Priestley
Syngenta Ltd., Huddersfield Manufacturing Centre, Huddersfield, HD2 1FF, United Kingdom
Abstract: The direct mechanochemical amidation of esters – enabled
by ball-milling – is herein described. The operationally simple
procedure requires inputs of ester, amine, and sub-stoichiometric
KOtBu and is applicable to a preparation of a large and diverse library
of 78 amide structures with modest to excellent efficiency.
Heteroaromatic and heterocyclic components are specifically shown
to be amenable to this mechanochemical protocol. This direct
synthesis platform has been applied to the synthesis of API’s,
agrochemicals, and its ability to deliver gram-scale synthesis of active
pharmaceuticals and building blocks is demonstrated, all in the
absence of a reaction solvent.
whole reveal the synthetic opportunities enabled by the unique
reactor environment of a milling-jar.[9] Examples of these benefits
include solvent-free reactions, reduced reaction times,
alternative/improved reaction selectivity, and augmented/
complementary reaction efficiency. In the context of amidation by
ball-milling whilst several protocols have already been reported,
these methods centre around the translation of classical amide
coupling reactions using diimide and uronium coupling reagents
or activated starting materials in
environment.[10]
Accordingly, we
a
mechanochemical
recognized that
a
mechanochemical manifold – exploiting beneficial mass transfer
afforded by ball-milling – that could enable the direct amidation of
esters, negating the need for reaction solvent, transition-metal
catalysts, or activating reagents could unveil significant and
sustainable opportunities in synthetic route design, especially in
industrial settings, and herein we wish to report our findings.
Introduction
Despite the ubiquity of the amide linkage in biological,
pharmaceutical, agrochemical, and natural product chemistry, the
direct, efficient, and sustainable construction of amide bonds
remains an often-overlooked synthetic challenge.[1] As highlighted
in a study by Brown in 2014, as many as 50% of all medicinal Results and Discussion
chemistry routes contain at least one amide bond forming step.[2]
However the vast majority of these amides are constructed
through the coupling of an amine with a carboxylic acid enabled
by use of an activating reagent such as EDC, HATU, or oxalyl
chloride (Scheme 1A).[3] These established amidation protocols
generate stoichiometric quantities of often toxic waste by-
products.[4] This dichotomy has led the ACS green chemistry
roundtable – initially in 2007, and again in 2018 – to highlight the
requirement for more atom-economical approaches for forging
this high-demand functional group i.e. without the need for
stoichiometric reagents. A range of possible alternatives for the
synthesis of amides have been developed utilizing
organocatalysis, oxidative amidation, and the catalytic generation
of activated carboxylates.[5] To this end, one such avenue that has
flourished is the direct amidation of carboxylic esters.[6] Examples
of powerful contemporary methods include – among many others
– Newman and co-workers’ Ni0-catalyzed direct and redox-neutral
amidation of esters using NHC ligands,[6m,n] which can also be
achieved by Pd catalysed processes,[6o-q] and Szostak and co-
workers’ direct amidation of simple esters using stoichiometric
quantities of LHMDS (Scheme 1B).[6r-t]
Our initial investigation into the mechanochemical direct
amidation of esters employed ethyl benzoate (1a) and morpholine
(2a) as model coupling partners (Scheme 1C). Using a mixer mill
at 30 Hz for 1 hour, a survey of bases, of increasing strength,
highlighted the notable activity of alkoxide bases in this reaction
system (for full optimization details, see supporting information).
Notably, no formation of the amide product was observed in the
absence of base (entry 1). Potassium tert-butoxide was shown to
be the most effective, leading to a promising 75% yield of the
desired amide product (Scheme 1C, entry 3). Careful fine-tuning
of the stoichiometry of base used in the reaction methodology
(entries 4-6) revealed 85 mol% of KOtBu to be the optimal
balance (85% yield).[11] Finally, increasing the equivalents of the
ester from 1.0 to 1.2 provided complete conversion to the amide
product in 1 hour with an almost quantitative isolated yield of 98%
(entry 7). Notably, control experiments outside of the
mechanochemical environment demonstrated substantially lower
conversions in the same timeframe (entries 8-10).[12]
With optimal conditions in hand, the scope of ester starting
materials was explored using morpholine as the amine
component (Scheme 2A). Variation of the substitution pattern of
the benzoate esters provided good to excellent yields for both
electron-rich and -poor examples (55-98% yield, 3a-j). Notably,
and in stark difference to solvent based methods, the physical
form of the starting material drastically alters the rate of reaction.
Recently our group have embarked on a synthesis programme
centered around exploring concepts and opportunities offered by
ball-milling.[7][8] Through this strategy, there have been a wide
array of synthetic organic transformations which have been
explored by mechanochemistry, which, when analyzed as a
1
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10.1002/anie.202106412
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RESEARCH ARTICLE
Scheme 1. Synthesis of amides via (A) amide coupling manifolds, (B) direct amidation of esters, (C) mechanochemical amidation of esters
For example, 4-bromo benzoate methyl ester, a solid at room
temperature, and, 4-bromo benzoate ethyl ester, a liquid at room
temperature, afforded the product in 42% and 80% respectively
after 1 hour of reaction. Despite this, almost quantitative yield of
the amide product was achieved when the reaction was carried
out for 2 hours in the mill. In addition to simple aromatic esters, a
range of alkyl esters including simple benzyl (3k), heterobenzyl
(3l), and linear alkyl systems such as fatty acid derivatives
proceeded with good efficiency (3m-3q). Furthermore, esters
derived from amino acids – Boc-(L)-proline (3r, 26%)[13] and
diethyl glycinate (3s, 82%) were compatible. A range of small
carbocyclic and heterocyclic ring systems were smoothly
introduced in the reaction system with modest to excellent
efficiency enabling the introduction of cyclobutyl (3t, 68%),
azetidine (3y, 80%), and protected isonipecotic acid derivatives
(3w-x, 62-68%). Interestingly, the successful ring opening of the
lactone, benzofuran-2(3H)-one was also demonstrated in good
yield (3z, 73%). Amidation of vinylic esters produced moderate to
excellent yields (3aa-ab, 35-95%).
which all delivered the corresponding amide products in good to
excellent yields (Scheme 2B, 3ac-ah, 49-98%). Acyclic
secondary amines also proved good coupling partners, although
milling times were extended in this case to two hours to afford
improved yields (3ai-ak). Primary aliphatic and benzylic amines
also participate well in this direct transformation for example
butylamine (3ar, 72% yield) and 2-morpholinoethan-1-amine (3ap,
85% yield) provided the amide structure in good yields. More
sterically demanding primary amine examples required increased
reaction times (Scheme 2B, 3al 22% and 3am 41%). Additionally,
a selection of aniline and amino-pyridine examples were also
successfully coupled with ethyl benzoate (Scheme 2B, 3as-ba,
11-79% yield) including challenging bulky derivatives which often
struggle under conditions using activated carboxylic acids.[14]
Given the potential implications of this discovered reaction
process to industrial discovery projects, we also looked to explore
heteroaromatic ester and amine substrates. A range of ethyl or
methyl esters containing pyridine, pyrazine, thiophene and
benzofuran rings were all successfully coupled with morpholine
(3bb-bh). Furthermore, in order to showcase the potential of this
mechanochemical method in amide synthesis, a reactivity matrix
was constructed using amine/aniline feedstocks and heteroaryl
esters including pyridine and pyrazine (Scheme 2C).
The nature of the amine fragment was also studied using ethyl
benzoate as the model ester and commenced by assessing cyclic
secondary amines, similar to morpholine, including piperazine,
piperidine, pyrrolidine, azepane and tetrahydroquiniline examples
2
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10.1002/anie.202106412
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 2: Mechanochemical ester amidation via ball-milling. Reactions were carried out on 1 mmol scale using a 14/15 mL stainless steel jar and a 4 g stainless
steel ball (see supporting information for more details). Yields based on amine component. a Ethyl ester used. b Methyl ester used. c Reaction time 2 hours
3
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10.1002/anie.202106412
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RESEARCH ARTICLE
In total, a collection of 12 compounds were prepared using this
matrix manifold (3bi-3ct) in good to great yields, with higher
efficiency observed with the pyrazine-containing structures.
reaction could be successfully scaled (10-fold) to produce 2.4 g
(90% yield) of moclobemide in one hour. Further expanding this,
using two 30 mL jars with a 16 g ball in each, the model reaction
between ethyl benzoate and morpholine delivered 3.21 g (83%)
of the corresponding amide (3a) in 2 hours of milling, representing
a 20-fold scale up.
Whilst ammonium salts are invariably solid, salts of this type are
also often used as a stable equivalent for the long-term storage
and/or transportation of amines. Conveniently it was found that
ammonium salts were effective substrates for the direct amidation
of esters by ball-milling, as long as an extra equivalent of
potassium tert-butoxide base was added to the reaction mixture,
with the resulting yields being on par or better than the free amine
versions (Scheme 3A). Notably, application of ammonium
With regards to assessing the green metrics of our reaction
process compared to more traditional approaches, a simple atom
economy calculation (Mr of inputs/Mr of the product) demonstrates
the process to be quite favourable at 55%, compared to a
phosgene activation of carboxylic acids at 47% (Scheme 3D, see
supporting information for further details).[15] Process Mass
Intensity (PMI) – which is made up of two key components, the
PMI of the reaction (PMIreaction) and the PMI of the workup
(PMIworkup) – should also be considered.[16] Whilst comparing non-
optimized work-up procedures (PMIworkup) is non-productive,[17]
when studying PMIreaction, our mechanochemical methodology is
favorable (PMIreaction = 1.94 g g-1, see supporting information for
more details) when contrasted to the closest solution-phase
chloride to these reaction conditions led to
a promising
unoptimized 16% isolated yield of primary amide 3bu.
This reaction was also effective in the context of the direct
synthesis of biologically relevant compounds including active
pharmaceuticals and agrochemicals (Scheme 3B). In exploring
these reactions, good to excellent yields were achieved for a
broad
range
of compounds
including, moclobemide
(antidepressant, 3bv), lidocaine (anaesthetic, 3bz), coramine
(stimulant, 3), fenfuram (fungicide, 3by), and an analogue of CL-
82198, an MMP13 inhibitor (3ca).
counterpart reported by Yoon and co-workers[6d] (PMIreaction
=
59.28 g g-1). These metrics prove to highlight the beneficial
process mass intensity profiles that solvent-free ball-milling
processes can offer industrial route design.
This mechanochemical strategy was also directly scalable; use
of a larger jar (25 mL) and heavier milling ball (12 g) and utilizing
the capability of milling two reaction jars simultaneously the
Scheme 3: Mechanochemical ester amidation. (A) use of ammonium salts in the reaction methodology. (B) Synthesis of biologically-relevant amides, (C) scale-up
procedures, (D) atom economy calculations. a Reaction time 2 hours. b From Scheme 2. c 2a (1 eq), NH4Cl (2 eq), KOtBu (2.85 eq). d Ethyl ester was used. e Methyl
ester was used. f Two jars with half material in each.
4
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10.1002/anie.202106412
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RESEARCH ARTICLE
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Acknowledgements
W.I.N. thanks Cardiff University for a studentship. J.A.L. thanks
the Leverhulme Trust for a research fellowship (RPG-2019-260).
We thank Prof. Tom Sheppard (UCL) for helpful discussions. The
authors would like to thank Gavin Bluck, Andrei Iosub, George
Hodges, Faima Lazreg, Jean-Philippe Krieger, Kenneth Ling,
Christophe Grojean, Alan Robinson, and Maria Ciaccia for
valuable discussion.
Keywords: mechanochemistry • amides • amidation • ball-
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Entry for the Table of Contents
Insert graphic for Table of Contents here
The direct amidation of esters via mechanochemical ball-milling has been described. Through simple coupling under basic
conditions, a reaction system without the need for bulk solvent, catalysts, or additives has been designed and successfully
developed.
Institute and/or researcher Twitter usernames:, @WillNicholson18, @JamieLeitch165, @DuncanLBrowne @Syngenta,
@ChemistryCU, @School_Pharmacy
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