Catalytic direct amidations in: Tert -butyl acetate using B(OCH2CF3)3

Article abstract of DOI:10.1039/c9ob01012b

Catalytic direct amidation reactions have been the focus of considerable recent research effort, due to the widespread use of amide formation processes in pharmaceutical synthesis. However, the vast majority of catalytic amidations are performed in non-polar solvents (aromatic hydrocarbons, ethers) which are typically undesirable from a sustainability perspective, and are often poor at solubilising polar carboxylic acid and amine substrates. As a consequence, most catalytic amidation protocols are unsuccessful when applied to polar and/or functionalised substrates of the kind commonly used in medicinal chemistry. In this paper we report a practical and useful catalytic direct amidation reaction using tert-butyl acetate as the reaction solvent. The use of an ester solvent offers improvements in terms of safety and sustainability, but also leads to an improved reaction scope with regard to polar substrates and less nucleophilic anilines, both of which are important components of amides used in medicinal chemistry. An amidation reaction was scaled up to 100 mmol and proceeded with excellent yield and efficiency, with a measured process mass intensity of 8.

Full text of DOI:10.1039/c9ob01012b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: C. Coomber, V.
Laserna, L. T. Martin, P. D. Smith, H. Hailes, M. J. Porter and T. Sheppard, Org. Biomol. Chem., 2019, DOI:
10.1039/C9OB01012B.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C9OB01012B
ARTICLE
Catalytic Direct Amidations in tert-Butyl Acetate using
B(OCH2CF3)3
Charlotte E. Coomber,a Victor Laserna,a Liam T. Martin,a Peter D. Smith,b Helen C. Hailes,a Michael
Received 00th January 20xx,
Accepted 00th January 20xx
J. Portera and Tom D. Sheppard*a
DOI: 10.1039/x0xx00000x
Catalytic direct amidation reactions have been the focus of considerable recent research effort, due to the widespread use
of amide formation processes in pharmaceutical synthesis. However, the vast majority of catalytic amidations are performed
in non-polar solvents (aromatic hydrocarbons, ethers) which are typically undesirable from a sustainability perspective, and
are often poor at solubilising polar carboxylic acid and amine substrates. As a consequence, most catalytic amidation
protocols are unsuccessful when applied to polar and/or functionalised substrates of the kind commonly used in medicinal
chemistry. In this paper we report a practical and useful catalytic direct amidation reaction using tert-butyl acetate as the
reaction solvent. The use of an ester solvent offers improvements in terms of safety and sustainability, but also leads to an
improved reaction scope with regard to polar substrates and less nucleophilic anilines, both of which are important
components of amides used in medicinal chemistry. An amidation reaction was scaled up to 100 mmol and proceeded with
excellent yield and efficency, with a measured process mass intensity of 8.
mixture exacerbates these problems as higher dilution reaction
conditions are normally required, along with excess solvent
during work-up for washing the molecular sieves to recover the
Introduction
The direct amidation reaction between carboxylic acids and
amines is one of the most common processes employed in the
synthesis of organic molecules in both academic and industrial
organisations. It remains a highly inefficient reaction, however,
due to the widespread use of stoichiometric activating agents
that leads to the generation of high molecular weight
byproducts as well as increased solvent use during both work-
up and purification.1-2 There has consequently been
considerable interest in recent years in the development of
catalytic direct amidation reactions which enable amides to be
produced from carboxylic acids and amines with a molecule of
water as the only stoichiometric by-product. Common catalytic
systems include those based around boronic acids,3 boric acid
derivatives4 or boron heterocycles,5 as well as salts of the
group(IV) metals titanium, zirconium or hafnium.6 However, to
date these catalytic amidation methods have failed to become
widely adopted.7 This is partly due to the fact that they cannot
often be applied to common amide targets which incorporate
polar functional groups such as heterocyclic rings. It is also a
consequence of the poor efficiency of many catalytic amidation
reactions due to the large quantities of solvents employed both
in the reaction itself and in the work-up procedure.7 The use of
molecular sieves to efficiently remove water from the reaction
amide product. For larger scale reactions, Dean-Stark water
removal is employed as this is considerably more efficient in
terms of solvent usage and scalability, and there are a few
reports of direct amidation reactions catalysed by boric acid or
simple boronic acids being employed on an industrial scale.8 The
solvents used for catalytic amidation reactions are typically
aromatic hydrocarbons (toluene,3a,4a fluorobenzene3b),
chlorinated solvents (1,2-dichloroethane3i) or ethers (Et2O,6d
THF,5a-5b CPME,4e TAME4g-4h), and these are often sub-optimal
Previous work (refs 3-6)
O
O
R2
Cat. (B, Ti, Zr, Hf)
 Non-polar solvents
R2
HN
R1
N
 Few polar substrates
-H2O
R1
OH R3
R3
THF, Et2O, CPME, TAME,
DCE, PhMe, PhF
OH
ref 8a
NH2
O
O
N
OR
HO2C
Cat. BuB(OH)2
OH
77%
OR
nPrOAc
CO2H
then ZnCl2/HMDS
This work
O
 1 M concentration
 Polar substrates
 Scalable
O
R2 Cat. B(OCH2CF3)3
R2
HN
OH R3
R1
N
R3
-H2O
tBuOAc
R1
a. Department of Chemistry, University College London, 20 Gordon St, London,
WC1H 0AJ, UK. Tom.sheppard@ucl.ac.uk
Scheme 1: Solvents previously employed in catalytic amidation reactions and our
new approach using tert-butyl acetate. CPME = cyclopentyl methyl ether; TAME =
tert-amyl methyl ether; DCE = 1,2-dichloroethane.
b. Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit,
AstraZeneca, Macclesfield SK10 2NA, UK..
Electronic Supplementary Information (ESI) available: [Experimental procedures
and data for all compounds, along with 1H and 13C NMR spectra for all amides]. See
DOI: 10.1039/x0xx00000x
from a safety and/or sustainability perspective.9 In addition,
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
ARTICLE
Journal Name
these relatively non-polar solvents do not effectively solubilise Aside from this, esters have not been explored as solvents for
View Article Online
DOI: 10.1039/C9OB01012B
many polar functionalised carboxylic acids or amines.
catalytic amidation reactions.
In this paper, we outline a highly effective and scalable method
for performing catalytic direct amidation reactions in an ester Reaction Optimisation
solvent, and demonstrate its application to challenging
substrates including polar heterocycles and poorly nucleophilic
anilines.
We selected the synthesis of amide 1 as a test reaction for
evaluating a range of ester solvents. Using 10 mol% B(OCH2CF3)3
catalyst, the reaction could be performed in a range of ester
solvents under Dean-Stark reaction conditions though the yields
were somewhat variable (Table 1, entries 2-7). A very low yield
was obtained in ethyl acetate (entry 2), and n-propyl acetate
(entry 3) or n-butyl acetate (entry 4) offered relatively little
improvement. Pleasingly, iso-propyl acetate (entry 5) and tert-
butyl acetate (entry 6) gave significantly improved yields with
the latter being particularly effective, even though these
solvents have lower boiling points than their unbranched
isomers. The yield of amide 1 could be further improved in tert-
butyl acetate by increasing the concentration of the reaction
mixture to 1 M, leading to a reduction in the solvent
requirements of the process. Finally, the nitrile solvents
propionitrile (entry 8) and butyronitrile (entry 9) were also
effective for the amidation reaction, potentially offering useful
more-polar alternative solvents.11 It should be noted that the
most effective solvents have relatively low boiling points and
form azeotropes with a high proportion of water present, with
tert-butyl acetate (bp 97 °C; 22 wt% H2O in azeotrope) and
propionitrile (bp 97 °C; 24 wt% H2O in azeotrope) being most
effective.12 This may reflect a balance between the need for
efficient water removal from the reaction and the greater levels
of catalyst decomposition which may take place at higher
reaction temperatures.§ A selection of other simple amidation
Results & Discussion
Background
We have recently reported that B(OCH2CF3)3 can be employed
as a very effective catalyst for direct amidation reactions which
is applicable to a wide range of substrates.4g Remarkably, it can
also be used for the catalytic direct amidation of many
unprotected amino acids.4h The reactions were largely
performed in tert-amyl methyl ether (TAME) as solvent,
although selected reactions involving less nucleophilic but
relatively apolar amines were more efficient in toluene.
Important advantages of this catalytic system include an
extremely wide substrate scope, together with a relatively high
reaction concentration (0.5 M) which leads to efficient and
scalable reactions. B(OCH2CF3)3 is available commercially, or can
be synthesised on a large scale from B2O3 and CF3CH2OH.4d, 4g
During the course of an ongoing research project on Pd-
catalysed direct C-H arylation reactions,10 we needed to prepare
a series of amides derived from picolinic acid such as 1. Initial
evaluation of our catalytic amidation method using TAME as a
solvent led to a moderate 71% yield of the desired amide 1 with
20 mol% catalyst (Table 1, entry 1).
t
catalysts (entries 10-13) were also evaluated in BuOAc, with
only an arylboronic acid being effective.
H2N
O
Cat. B(OCH2CF3)3
O
Table 1: Optimisation of reaction solvent and conditions for the synthesis of amide 1.
Reaction conditions: 5 mmol scale, 0.5 M concentration in indicated solvent, 10 mol%
B(OCH2CF3)3, reflux, Dean-Stark. 24 h.
N
H
Dean-Stark
OH
Solvent
N
1
N
Entry Catalyst
Solvent
TAME
EtOAc
Bp
Yielda
71%
9%
27%
20%
52%
75%
91%
76%
64%
8%
Scheme 1: Preparation of amide 1 via B(OCH2CF3)3-catalysed amidation.
1b
2
B(OCH2CF3)3
86 °C
77 °C
102 °C
126 °C
89 °C
97 °C
97 °C
97 °C
117 °C
97 °C
97 °C
97 °C
97 °C
B(OCH2CF3)3
B(OCH2CF3)3
B(OCH2CF3)3
B(OCH2CF3)3
B(OCH2CF3)3
B(OCH2CF3)3
B(OCH2CF3)3
B(OCH2CF3)3
B(OMe)3
We hypothesised that this was due to the relatively poor
solubility of picolinic acid (and the corresponding ammonium
salt) in TAME. We therefore decided to explore other reaction
solvents which might circumvent these problems. Esters were
identified as potentially suitable, as they are typically greener
and more sustainable solvents than ethers or aromatic
hydrocarbons, and offer a better safety profile (i.e they are
typically not prone to peroxide formation).9 They are also
considerably more polar so should be much more effective at
solubilising polar substrates and/or ammonium salts derived
from them. Importantly, we had previously observed that
stoichiometric amidation mediated by B(OCH2CF3)3 could be
carried out in ethyl acetate as a solvent without any significant
amidation of the ester being observed.4e To date, there is only
a single report of a catalytic amidation reaction performed in an
ester solvent, using BuB(OH)2 as a catalyst in n-propyl acetate.8a
3c
4
nPrOAc
nBuOAc
iPrOAc
tBuOAc
tBuOAc
EtCN
5
6
7c
8c
9c
10d
11
12c
13e
nPrCN
tBuOAc
tBuOAc
tBuOAc
tBuOAc
B(OEt)3
Ti(OiPr)4
ArB(OH)2
10%
14%
73%
aIsolated yields. b20 mol% B(OCH2CF3)3. c1 M concentration. d0.75 M concentration.
eAr=3,5-bis-(trifluoromethyl)phenyl.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 5
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C9OB01012B
O
O
R2
10 mol% B(OCH2CF3)3
Amberlyst 15
R2
HN
OH R3
R1
N
R1
Dean-Stark
tBuOAc
Amberlyst A26
R3
Amberlite IRA743
H
O
N
PMP
O
O
S
O
Ph
H
H
N
N
N
N
N
N
N
N
N
H
O
NBoc
Ph
O
O
O
O
N
1 92% (71%a)
2 91% (23%a)
3 90%
36 h
4 93%
5 85%
1 h
6 96%
24 h
7 63
2 h
48 h
H
H
H
N
H
N
CF3
H
N
H
N
Cl
N
CF3
N
N
Ph
Ph
Ph
Ph
O
O
O
OMe
O
O
O
HO
CF3
8 96%
40 h
9 65%
10 74% [74%]
11 78%
nC4H9
12 41%
48 h
O
13 71% Cl
20 h
OH
F
H
H
H
Ph
N
N
N
Ph
H
Ph Ph
N
Ph
N
N
O
N
Ph
N
O
O
H
O
Cl
O
14 73% (63%)
15 63%
16 81%
17 91%
18 h
18 92%
20 h
19 38%
48 h
40 h
OH
O
MeO
MeO
Ph
Ph
O
O
N
Ph
N
H
HN
nC5H11
BocHN
OtBu BocHN
OtBu
HN
nC5H11
N
H
N
N
N
H
24 45%a
O
O
O
O
Granisetron
72 h
20 70%, 20 h
(97%, 18 h)
21 54%, 20 h
(50%, 18 h)
22 95% (96%)
23 79%
16 h
16 h
Scheme 2: Scope of the catalytic amidation reaction in tert-butyl acetate. All reactions were run for 24 h unless otherwise indicated. Yields given in parentheses/brackets
are for the synthesis of the same amide in TAME/PhMe. a20 mol% B(OCH2CF3)3 used.
Reaction Scope
catalyst. Notably, in several cases amides were prepared from
reactants where both the carboxylic acid and the amine can be
considered as challenging substrates for catalytic amidation (5,
7, 13, 22-24).‡ As can be seen in Scheme 2, with the exception
of amide 20, tert-butyl acetate offers comparable or improved
amide yields over amide syntheses previously performed in
TAME or toluene (1, 2, 10, 14, 21). In most cases, the amides
could be purified using a solid-phase work-up procedure
employing scavenger resins to remove unreacted amine
(Amberlyst 15), carboxylic acid (Amberlyst A-26) and boron
compounds (Amberlite IRA743), with no requirement for
aqueous work-up or chromatography.4d
With optimised conditions in hand, we evaluated them in the
synthesis of a selection of challenging amides 1-24. We were
particularly interested in examining the reactivity of medicinally
relevant substrates such as polar heterocycles and poorly
nucleophilic amines. Pleasingly, amides could be prepared
effectively from heterocyclic carboxylic acids, containing a
pyridine (1-2, 7), a quinoline (3), a tetrahydrofuran (4-5), and a
thiophene (6). A range of anilines and related derivatives could
also be employed including indoline (7), electron-rich anilines
(8-10),
electron-deficient
anilines
(11-13)
and
aminoheterocycles (14-15). Aliphatic amines including simple
alkylamines (1-4), electron-deficient benzylamines (16),
secondary amines (5-6, 17), and branched systems (18, 22-24)
were also good substrates. The amide 19 derived from 2-
chloromandelic acid was obtained in only 38% yield,
demonstrating the challenging nature of this particular
substrate. Amides derived from hexanoic acid and
dimethyldopamine (20) or 1-phenylethanolamine (21) were
synthesised effectively, with the latter reaction demonstrating
that the amidation reaction is chemoselective for acylation of
the amine over the alcohol. Dipeptide synthesis from Boc-
protected D- or L-alanine and L-phenylalanine tert-butyl ester
proceeded efficiently, giving diastereomeric amides 22/23 with
no observable epimerisation. Finally, the serotonin 5-HT3
receptor antagonist Granisetron 24 (used commonly as an
antiemetic)13 could be prepared in 45% yield using only 20 mol%
H2N
10 mol%
O
B(OCH2CF3)3
O
N
H
Dean-Stark
tBuOAc
OH
N
1 97%
21.23 g
PMI: 8
N
100 mmol
Scheme 3: Large scale synthesis of amide 1
Multigram scale reaction
To demonstrate the efficiency of our protocol, amide 1 was
prepared on a 100 mmol scale (Scheme 3), using the solid-phase
work-up procedure to purify the amide. This gave 21.23 g of
amide 1 in 97% overall yield. The process mass intensity14 for
the reaction was calculated to be 8, showing that this catalytic
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
ARTICLE
Journal Name
amidation method is extremely competitive for use in large
scale preparations (e.g. a typical PMI for stoichiometric
amidation reactions used in the synthesis of pharmaceutical
intermediates is ~437a).
Notes and references
View Article Online
DOI: 10.1039/C9OB01012B
§Analysis of the reaction mixture and Dean-Stark trap by 19F NMR
indicated that in tBuOAc, 49% of the CF3CH2OR group remained in
the reaction mixture after 24 h (cf 78% in TAME4g). In contrast,
n
analysis of an amidation performed in BuOAc showed that only
16% of the CF3CH2OR group remained in the reaction mixture
after 24 h. Minor additional signals could be seen in the 19F NMR
Conclusions
t
n
spectrum of the BuOAc reaction, whereas in BuOAc multiple
species were present at significant concentration. See
supplementary information for further details.
We have demonstrated that tert-butyl acetate is a very effective
solvent for B(OCH2CF3)3-catalysed direct amidation reactions.
These conditions were found to be particularly effective for
challenging pharmaceutically relevant substrates including
carboxylic acids containing polar heterocycles, as well as
electron-deficient anilines and aminoheterocycles. The
reactions can be run at 1 M concentration, and the amides can
typically be purified using a simple resin-based filtration process
which has low solvent requirements. A 100 mmol synthesis of
an amide yielded >20 g of product with process mass intensity
of 8. tert-Butyl acetate is a readily available low-cost solvent,
produced industrially from acetic acid and isobutylene, which
has a good safety profile9 making it potentially suitable for
widespread use in catalytic direct amidation reactions.
‡We have previously noted that 2-aminopyridine (amide 14)
shows low reactivity in stoichiometric BOCH2CF3)3 amidation
reactions.4e Others have recently noted that sterically
encumbered (amides 8-10) or electron-deficient (amides 11-13)
anilines were particularly challenging substrates for catalytic
amidation reactions.5a
1
(a) J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
Biomol. Chem., 2006, 4, 2337; (b) L. Amarnath, I. Andrews, R.
Bandichhor, A. Bhattacharya, P. Dunn, J. Hayler, W. Hinkley,
N. Holub, D. Hughes, L. Humphreys, B. Kaptein, H. Krishnen, K.
Lorenz, S. Mathew, G. Nagaraju, T. Rammeloo, P. Richardson,
L. Wang, A. Wells and T. White, Org. Process Res. Dev., 2012,
16, 535; (c) M. C. Bryan, P. J. Dunn, D. Entwistle, F. Gallou, S.
G. Koenig, J. D. Hayler, M. R. Hickey, S. Hughes, M. E. Kopach,
G. Moine, P. Richardson, F. Roschangar, A. Steven and F. J.
Weiberth, Green Chem., 2018, 20, 5082; (d) D. J. C. Constable,
P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L. Leazer Jr., R. J.
Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A.
Zaks and T. Y. Zhang, Green Chem., 2007, 9, 411.
For recently reported stoichiometric amidation methods, see:
(a) T. Krause, S. Baader, B. Erb, L. J. Gooen, Nat. Commun.,
2016, 7, 11732; (b) L. Hu, S. Xu, Z. Zhao, Y. Yang, Z. Peng, M.
Yang, C. Wang, J. Zhao, J. Am. Chem. Soc., 2016, 138, 13135;
(c) X. Xu, H. Feng, L. Huang, X. Liu, J. Org. Chem., 2018, 83,
7962; (d) D. C. Braddock, P. D. Lickiss, B. C. Rowley, D. Pugh, T.
Purnomo, G. Santhakumar, S. J. Fussel, Org. Lett., 2018, 20,
950; (e) S.-M. Wang, C. Zhao, X. Zhang, H.-L. Qin, Org. Biomol.
Chem., 2019, 17, 4087; (f) M. Cortes-Clerget, N. R. Lee, B. H.
Lipshutz, Nat. Protoc., 2019, 14. 1108.
(a) K. Ishihara, S. Ohara and H. Yamamoto, J. Org. Chem.,
1996, 61, 4196; (b) K. Arnold, B. Davies, R. L. Giles, C. Grosjean,
G. E. Smith and A. Whiting, Adv. Synth. Catal., 2006, 348, 813;
(c) R. M. Al-Zoubi, O. Marion and D. G. Hall, Angew. Chem. Int.
Ed., 2008, 47, 2876; (d) K. Arnold, A. S. Batsanov, B. Davies and
A. Whiting, Green Chem., 2008, 10, 124; (e) K. Arnold, B.
Davies, D. Herault and A. Whiting, Angew. Chem., Int. Ed.,
2008, 47, 2673; (f) (a) N. Gernigon, R. M. Al-Zoubi and D. G.
Hall, J. Org. Chem., 2012, 77, 8386; (g) S. Fatemi, N. Gernigon
and D. G. Hall, Green Chem., 2015, 17, 4016; (h) S. Arkhipenko,
M. T. Sabatini, A. S. Batsanov, V. Karaluka, T. D. Sheppard, H.
S. Rzepa and A. Whiting, Chem. Sci., 2018, 9, 1058; (i) K. Wang,
Y. Lu and K. Ishihara, Chem. Commun., 2018, 54, 5410; (j) Y.
Du, T. Barber, S. E. Lim, H. S. Rzepa, I. R. Baxendale and A.
Whiting, Chem. Commun., 2019, 55, 2916.
(a) P. Tang, Org. Syn., 2005, 81, 262; (b) R. Yamashita, A.
Sakakura and K. Ishihara, Org. Lett., 2013, 15, 3654; (c) P.
Starkov, T. D. Sheppard, Org. Biomol. Chem., 2011, 9, 1320;
(d) R. M. Lanigan, P. Starkov and T. D. Sheppard, J. Org. Chem.,
2013, 78, 4512; (e) V. Karaluka, R. M. Lanigan, P. M. Murray,
M. Badland and T. D. Sheppard, Org. Biomol. Chem., 2015, 13,
10888; (f) R. M. Lanigan, V. Karaluka, M. T. Sabatini, P. Starkov,
M. Badland, L. Boulton and T. D. Sheppard, Chem. Commun.,
2016, 52, 8846; (g) M. T. Sabatini, L. T. Boulton and T. D.
Sheppard, Sci. Adv., 2017, 3, e1701028; (h) M. T. Sabatini, V.
Karaluka, R. M. Lanigan, L. T. Boulton, M. Badland and T. D.
Sheppard, Chem. Eur. J., 2018, 24, 7033; (i) D. N. Sawant, D. B.
Bagal, S. Ogawa, K. Selvam, S. Saito, Org. Lett., 2018, 20, 4397.
Experimental Section
General Amidation Procedure
2
A suspension of carboxylic acid (5 mmol, 1 equiv.), amine (5
mmol, 1 equiv.) and B(OCH2CF3)3 (108 µL, 0.5 mmol, 10 mol%)
t
in BuOAc (5 mL, 1 M) with a Dean-Stark trap (side arm filled
with tBuOAc) was heated to reflux. An air condenser was fitted
and the reaction mixture heated for 1–48 h (see Scheme 2). The
reaction was cooled to room temperature and water (0.5 mL),
dimethyl carbonate (5 mL), Amberlite IRA-743 (0.25 g),
Amberlyst A15 (0.5 g) and A-26(OH) (0.5 g) resins were added
and the resulting suspension was stirred for 30 min. Anhydrous
magnesium sulfate (~0.5 g) was added, the mixture filtered, and
the resins/solids washed with ethyl acetate (2 × 5 mL). The
combined filtrates were concentrated in vacuo to yield the pure
amide.
3
Further Experimental Details
Characeterisation data for all amides 1-24, together with 1H and
13C spectra can be found in the supplementary information.
Conflicts of interest
There are no conflicts to declare.
4
Acknowledgements
We would like to thank AstraZeneca and the UCL MAPS faculty
for providing an EPSRC CASE award to support a Ph.D.
studentship for CEC, the Leverhulme Trust for providing a grant
(RPG-2017-221) to support VL, and the Wellcome Trust
(105342/Z/14/Z) for providing a PhD studentship to support
LTM.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
5
(a) H. Noda, M. Furutachi, Y. Asada, M. Shibasaki and N.
View Article Online
DOI: 10.1039/C9OB01012B
Kumagai, Nature Chem., 2017, 9, 571; (b) H. Noda, Y. Asada,
M. Shibasaki and N. Kumagai, J. Am Chem. Soc, 2019, 141,
1546.
6
(a) H. Lundberg, F. Tinnis and H. Adolfsson, Synlett, 2012,
2201; (b) H. Lundberg, F. Tinnis and H. Adolfsson, Chem. – Eur.
J., 2012, 18, 3822; (c) C. L. Allen, A. R. Chhatwal and J. M. J.
Williams, Chem. Commun., 2012, 48, 666; (d) H. Lundberg and
H. Adolfsson, ACS Catal., 2015, 5, 3271.
7
(a) M. T. Sabatini, L. T. Boulton, H. F. Sneddon and T. D.
Sheppard, Nature Catal., 2019, 2, 10. (b) X. Wang, Nature
Catal., 2019, 2, 98; (c) B. M. Monks and A. Whiting,
Sustainable Catalysis: Challenges and Practices for the
Pharmaceutical and Fine Chemical Industries, ed. P. J. Dunn,
K. K. Hii, M. J. Krische and M. T. Williams, Wiley, Hobokon, NJ,
USA, 2013, ch. 5; (d) F. Ferdousi and A. Whiting, Green
Catalytic Direct Amide Bond Formation in Green and
Sustainable Medicinal Chemistry: Methods, Tools and
Strategies for the 21st Century Pharmaceutical Industry, ed. L.
Summerton, H. F. Sneddon, L. C. Jones and J. H. Clark, RSC
Green Chemistry series, Cambridge, 2016, ch. 13; (e) R. M.
Lanigan and T. D. Sheppard, Eur. J. Org. Chem., 2013, 7453; (f)
K. Ishihara, Tetrahedron, 2009, 65,1085; (g) H. Lundberg, F.
Tinnis, N. Selander and H. Adolfsson, Chem. Soc. Rev., 2014,
43, 2714.
8
9
(a) J. Limanto, E. R. Ashley, J. Yin, G. L. Beutner, B. T. Grau, A.
M. Kassim, M. M. Kim, A. Klapars, Z. Liu, H. R. Strotman, M. D.
Truppo, Org. Lett., 2014, 16, 2716; (b) J. R. Dunetz,. J. Magano
and G. A. Weisenburger, Org. Process Res. Dev., 2016, 20, 140;
(c) R. M. Bannister, M. H. Brookes, G. R. Evans, R. B. Katz, and
N. D. Tyrrell, Org. Process Res. Dev., 2000, 4, 467; (d) R. Kumar
Mylavarapu, K. GCM, N. Kolla, R. Veeramalla, P. Koilkonda,
Apurba Bhattacharya, and Rakeshwar Bandichhor, Org.
Process Res. Dev., 2007, 11, 1065.
D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S. Abou-
Shehada, and P. J. Dunn, Green Chem., 2016, 18, 288; (b) C.
M. Alder, J. D. Hayler, R. K. Henderson, A. M. Redman, L.
Shukla, L. E. Shuster and H. F. Sneddon, Green Chem., 2016,
18, 3879.
10 C. E. Coomber, L. Benhamou, D. -K. Bucar, P. D. Smith, M. J.
Porter and T. D. Sheppard, J. Org. Chem., 2018, 83, 2495.
11 P. M. Murray, F. Bellany, L. Benhamou, D. -K, Bučar, A. B.
Tabor and T. D. Sheppard, Org. Biomol Chem., 2016, 14, 2373.
12 http://www.homepages.ed.ac.uk/jwp/Chemeng/azeotrope/
hetero.html, Last accessed 11th April 2019. The azeotropes
contain the following quantities of water (wt%): EtOAc (8);
nPrOAc (14); nBuOAc (27); iPrOAc (11); tBuOAc (22); EtCN (24);
nPrCN (33).
13 J. Cassidy, V. Raina, C. Lewis, L. Adams, M. Soukop, W. G.
Rapeport, B.D. Zussman, E. M. Rankin and S. B. Kaye, Brit. J.
Cancer, 1988, 58, 651.
14 C. Jimenez-Gonzalez, C. S. Ponder, Q. B. Broxterman, J. B.
Manley, Org. Process Res. Dev., 2011, 15, 912.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins