A solid-supported arylboronic acid catalyst for direct amidation

Article abstract of DOI:10.1039/c8cc09913h

An efficient heterogeneous amidation catalyst has been prepared by co-polymerisation of styrene, DVB with 4-styreneboronic acid, which shows wide substrate applicability and higher reactivity than the equivalent homogeneous phenylboronic acid, suggesting potential cooperative catalytic effects. The catalyst can be easily recovered and reused; suitable for use in packed bed flow reactors.

Full text of DOI:10.1039/c8cc09913h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Du, T. Barber, S.
E. Lim, H. S. Rzepa, I. R. Baxendale and A. Whiting, Chem. Commun., 2019, DOI: 10.1039/C8CC09913H.
Volume 52 Number
1
4
January 2016 Pages 1–216
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
www.rsc.org/chemcomm
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 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/C8CC09913H
ChemComm
COMMUNICATION
www.rsc.org/
Received 00th January 20xx,
Accepted 00th January 20xx
A solid-supported arylboronic acid catalyst for direct amidation
a
a
a
b
a
Yihao Du, Thomas Barber, Sol Ee Lim, Henry S. Rzepa, Ian R. Baxendale* and Andrew
DOI: 10.1039/x0xx00000x
a
Whiting*
An efficient heterogeneous amidation catalyst has been prepared reasonably stable, readily accessed and show good
by co-polymerisation of styrene, DVB with 4-styreneboronic acid, applicability and substrate scope when used in inert organic
which shows wide substrate applicability and higher reactivity than solvents and coupled with azeotropic water removal or
1
0
the equivalent homogeneous phenylboronic acid, suggesting molecular sieve drying. However, there are still major
potential cooperative catalytic effects. The catalyst can be easily challenges to be overcome before boron-based catalysts can
recovered and reused; suitable for use in packed bed flow reactors.
become the system of choice for routine amide formation,
including: 1) developing lower temperature reactions; 2)
efficient water removal; 3) low catalyst loading; and 4) simple
catalyst recovery and re-use. An approach targeted at
addressing all these issues is to employ a heterogeneous
catalyst and indeed, the Ishihara group have reported such
systems, including a polystyrene-bound borono-pyridinium salt
and supported ortho-fluorophenyl boronic acid, systems which
have shown good efficiency, yet both systems are non-trivial
The amide bond is by far the most widely occurring
structural motif incorporated into pharmaceutical compounds
with amide formation reactions constituting around 16% of all
1
reactions used by medicinal chemists. Most amidation
methods developed for amide bond formation between
carboxylic acids and amines, particularly those for peptide
2
,3
synthesis involve the use of carboxylic acid activating agents,
however, such approaches generate stoichiometric amounts of
waste, which has led to the development of more
13
to prepare. Based on our recent mechanistic proposals and
understanding about the way in which boronic acids form
reactive dimeric B-X-B species in situ, we surmised that the
inherent and facile drive for boronic acids to form B-O-B
bridged and boroxine systems could be used as a templating
effect to cluster boronate functions in close proximity within a
polymer matrix, making the resulting polymer pre-organised
towards amidation catalysis. In addition, the inherently
hydrophobic nature of the bulk polymer might render the
resulting supported catalyst system capable of not requiring
additional water removal from the reaction. Herein, we report
the realisation of this hypothesis through a simple and
inexpensive polystyrene-based phenylboronic acid catalyst
that is readily prepared, easily recycled and can even be
employed in a flow reactor.
4
,5
environmentally friendly processes and methods.
The
challenge for new, sustainable amidation is to achieve high
conversion and catalyst reactivity, coupled with recyclability.
Such developments in the direct amidation of carboxylic acids
and amines have been realised in recent years, enabling major
improvements in atom economy since water is the only by-
product, with particular success being derived from metal-
6
-9
catalysed direct amidations.
From as early as 1970, a role for boron-based catalysts in
direct amidation has been recognised, however, years have
seen a considerable number of new developments involving
borate and boronate systems, showing increasing generality
and utility.10 Our interests have involved developing new
1
1
generations of boron-based catalysts,
together with
The heterogeneous polymeric catalyst 1 was prepared by
mechanistic understanding of the likely role of these systems heating a mixture of 4-styreneboronic acid, styrene, DVB (1,4-
in direct amidation.1 Boronic acid are particularly attractive divinylbenzene) and AIBN in 1-dodecanol at 85 °C (Table 1).
2
14
The resulting white polymeric catalyst was washed, dried and
ground into a powder, and further treated through solvent
extraction to remove residual monomers and 1-dodecanol (see
for developing new amidation catalysts because they are
1
1
SI). The polymer was analysed by solid state B NMR and
showed a broad peak around  17 ppm, possibly related to a B-
O-B water complex species and hence, the boron functions
would be expected to be catalytically active due to their
a.
Centre for Sustainable Chemical Processes, Department of Chemistry, Durham
University, Science Laboratories, South Road, Durham, DH1 3QZ, UK, Email:
andy.whiting@durham.ac.uk
b.
Department of Chemistry, Imperial College, South Kensington Campus, London,
SW7 2AZ, UK.
1
5
proximal nature (see SI). Indeed, this proved to be the case
since application of catalyst 1 in direct amidation reactions (5%
catalyst loading, calculated according to the estimated
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
Journal Name
COMMUNICATION
theoretical maximum boron content of the catalyst, see SI) additional amines and comparative reactions werVeiewpAerrtifcolerOmnleinde
under azeotropic refluxing conditions in toluene with a range against phenylboronic acid, since this
D
h
O
a
I:
s
10
p
.1
r
0
e
3
v
9
i
/
o
C
u
8Csl
C
1
y
09
1d
b
9
e
1
e
3H
n
of different carboxylic acids and benzylamine (Table 1) showed demonstrated to not be a particularly effective catalyst. The
effective catalysis. Further reactions were also conducted with results are reported in Table 1.
Table 1 Substrate scope of the catalytic direct amide formation with application of the polystyrene-based boronic acid 1.
Entry
Carboxylic Acid
PhCO
Amine
Yield / %
Entry
Carboxylic Acid
Amine
Yield / %
c
d
1
2
H
BnNH
2
90 (25 22 )
13
BnNH
2
40
2
3
4
BnNH
BnNH
BnNH
2
2
2
2
5
25 (16d)
30
14
15
16
BnNH
BnNH
BnNH
2
2
2
2
70 (42c)
83b
NR
5
6
7
8
BnNH
BnNH
BnNH
BnNH
27
32
46
20
17
18
19
20
BnNH
BnNH
BnNH
BnNH
NR
82 (64c)
76
2
2
2
2
2
2
42
9
BnNH
2
2
NR
29
21
22
PhNH
PhNH
2
75
15
1
0
BnNH
2
PhCO H
2
1
1
1
2
BnNH
2
2
92 (75c)
67
23
24
morpholine
79
BnNH
NR
a
General conditions: 2.86 mmol (1 eq.) carboxylic acid, (1 eq.) amine, 75.8 mg (5 mol%) catalyst 1, 20 mL toluene, Dean-Stark reflux, 24 h. Purified by low pressure
b
Kügelrohr distillation. Benzylamine (2 eq.) was used due to both amidation and conjugate addition occurring to give a mixture of both PhCHCHCONHBn and
PhCH(NHBn)CH CONHBn. Homogeneous catalysis using 5 mol% phenylboronic acid (See SI). Reflux without azeotropic water removal. NR = No reaction.
2
c
d
a
As shown higher pK carboxylic acids were more reactive including bromine, methoxy and methyl (Entries 3-8, 10, Table
1
6
towards direct amide formation as discussed elsewhere, and 1). While some of the effects could be steric in nature 1-
importantly, the new heterogeneous catalyst 1 followed the naphthoic acid versus 2-naphthoic acid for example (Table 1,
same trend. The aromatic substrates benzoic, furoic, and 2- entries 13 and 14) and mesityl carboxylic acid (Table 1, entry
naphthoic acids showed excellent reactivity (Table 1, entries 1, 9), there are clearly other, more subtle effects at work.
1
2 and 14). However, a reduction in conversion was observed Furthermore, the more electron deficient aryl carboxylic acids
for those aryl carboxylic acids with a range of substituents were much less reactive, as seen with nitrobenzoic acid and 1
This journal is © The Royal Society of Chemistry 2018
Chem. Commun., 2018, 00, 1-3 | 2
Please do not adjust margins

Please do not adjust margins
Page 3 of 5
ChemComm
Journal Name
COMMUNICATION
nicotinic acid, both of which were unreactive (Table 1, entries resulting in incomplete conversion to the amide when
View Article Online
2
and 17). Nonetheless, the general utility of catalyst 1 was
DOI: 10.1039/C8CC09913H
equimolar quantities of the two substrates are used. Further
further demonstrated through amidation of cinnamic acid
demonstration that catalyst 1 comprises of proximal boroxine-
like species that can indeed form carboxylate complexes
resulting in catalytic reactivity was obtained through solid
state NMR experiments using a stoichiometric amidation
reaction. Hence, catalyst 1 was taken step-wise through the
amidation reaction of phenylacetic acid with benzylamine, as
shown in Scheme 1.
(
(
Table 1, entry 15) and several other alkyl carboxylic acids
Table 1, entries 11, and 18-20).
1
00
100
80
60
40
20
0
80
60
40
20
0
Scheme 1 Activation process of polymer catalyst 1.
0
6
12
18
24
0
18
36
54
72
Reaction time (h)
Reaction time (h)
Figure 1. Kinetic studies on the heterogeneous catalytic direct amide formation
between benzylamine and phenylacetic acid (left) or 4-bromobenzoic acid (right).
The less reactive amines such as aniline and morpholine,
also showed good reactivity with phenylacetic acid (Table 1,
entries 21 and 23), although the combination of benzoic acid
and aniline (Table 1, entry 22) gave low conversion, as might
be expected for a lower pKa carboxylic acid reacting with a less
nucleophilic amine. Unfortunately, the potential lactamisation
reaction of 5-aminovaleric acid failed (Table 1, entry 24).
In terms of heterogeneous versus homogeneous phase (See SI). Solid-state B NMR and in situ IR (ReactIR, see SI) was
catalyst, the solid catalyst 1 showed considerably improved carried out at each stage of the reaction. The catalyst showed
reactivity over phenylboronic acid. Hence, although catalyst 1 a broad   ppm B NMR shift after preparation and solvent
is electronically similar to phenylboronic acid, its reactivity was
shown to be considerably higher (Table 1, entries 1, 3, 14 and
Firstly, catalyst 1 was heated at reflux with the carboxylic
acid (1 equiv.), followed by 24 h reaction with benzylamine to
yield 92% of phenylacetamide. Most of the amide was
generated within 30 min of the addition of the benzylamine
1
1
1
1
extraction, which may be due to a B-O-B-like water-associated
complex (see ESI). After reaction with a carboxylic acid a
1
8). In addition, the recovery of catalyst 1 (vide infra) added to
12
species of type 2 was indicted by a  5 ppm shift relating to
the general utility of the solid supported system.
the reactive double acyl-bridged intermediate. The amount of
the reactive species 2 decreased after addition of benzylamine,
synchronised with the amide formation, and indicative of
partial consumption of the B-O-B coordinated bridged species
Further examination of the results Table 1, it is clear that
the reaction timescales varied considerably, depending upon
the substrate, which was further investigated. Therefore, two
amidation reactions involving phenylacetic and 4-
bromobenzoic acids (these reactions have quite different
reaction timescales. See entries 3 and 11, Table 1) were
repeated in parallel, under identical reaction conditions.
Individual reactions representing different reaction times were
terminated and their conversion determined (see the ESI). The
faster reaction of phenylacetic acid with benzylamine is shown
in Fig. 1. and shows a high conversion level within the first 3 h,
eventually yielding 80% amide formation. In contrast, the less
reactive combination of 4-bromobenzoic acid and benzylamine
only reached ~70% conversion even over a prolonged
timescale, i.e. 70 h (Fig. 1). These contrasting results
demonstrate the strong correlation between carboxylic acid
pKa and reactivity even using the solid phase catalyst 1 which
(See SI). The in situ IR helped unveil the amidation process
further, wherein the same solid phase reaction, addition of
carboxylic acid to the reaction mixture resulted in the
appearance of a peak at 1719 cm- (typical of phenylacetic
acid), which also reduced as the reaction proceeded after
benzylamine addition, and deriving a new C=O peak at 1686
1
-1
cm for the amide within 30 minutes.
1
6
mirrors the previously reported results of Loupy et al. for
homogeneous catalysis. However, these results also show that
both reactions, albeit on different timescales, stalled at a Figure 2. Catalyst recovery test of catalyst 1 in the reaction of phenylacetic acid with
maximum of 70-80% conversion. Based on recent mechanistic benzylamine.
studies,12 boronic acid-mediated catalysis is likely dependent
Catalyst recovery and re-use was demonstrated in a series
upon the formation of B-X-B-type intermediates, that react
of amidations, followed by filtration and recovery. The
with carboxylic acids to form doubly bridged carboxylate
recovered catalyst showed high, reproducible reactivity
complexes which are attacked by the amine nucleophiles.
through several cycles (Fig. 2). The first 3 reactions gave
However, the formation of such complexes necessarily means
essentially identical yields and although there was some drop-
that excess carboxylate is tied up through boron coordination
off in yield over later reactions (4th and 5th reactions, Fig.2),
and hence, not all the carboxylic acid can subsequently react,
this was minimal. Indeed, accounting for minor mass loss at
This journal is © The Royal Society of Chemistry 2018
Chem. Commun., 2018, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
Journal Name
COMMUNICATION
5
V. R. Pattabiraman and J. W. Bode, Nature, 20V1ie1w, A4r8tic0le, O4n7li1ne-
79.
each flitration of the catalyst explains the slight decline in
yield. These results show that the catalyst was robust, suitable
for repeated use, and importantly, for potential application in
a packed bed reactor as part of a flow system. Hence, a
4
DOI: 10.1039/C8CC09913H
6
7
H. Lundberg and H. Adolfsson, ACS Cat., 2015, 5, 3271-3277.
A. Correa and R. Martin, J. Am. Chem. Soc., 2014, 136, 7253-
7
256.
Y. Kawagoe, K. Moriyama and H. Togo, Tetrahedron, 2013,
9, 3971-3977.
S. Ghosh, A. Bhaumik, J. Mondal, A. Mallik, S. Sengupta
Bandyopadhyay) and C. Mukhopadhyay, Green Chem., 2012,
4, 3220-3229.
2
Vapourtec R +/R
4
flow reactor (see SI), consisting of a binary
8
9
6
pumping unit driving liquid flow through a reactor was utilised
to examine the feasibility of flow-based amidations. To
accomplish this, a heated column unit was loaded with catalyst
(
1
1
and the system pressure regulated (in-line 75-psi back-
1
0 a) A. Pelter, T. Levitt and P. Nelson, Tetrahedron, 1970, 26,
1539-1544; b) K. Ishihara, S. Ohara and H. Yamamoto, J. Org.
Chem., 1996, 61, 4196-4197; c) N. Gernigon, R. M. Al-Zoubi
and D. G. Hall, J. Org. Chem., 2012, 77, 8386; d) S. Fatemi, N.
Gernigon and D. G. Hall, Green. Chem., 2015, 17, 4016-4028;
e) M. T. Sabatini, L. T. Boulton and T. D. Sheppard, Sci. Adv.,
pressure regulator, BPR). A secondary digital pressure monitor
was added for precise pressure monitoring (sited before
column). Finally, a liquid handling robot allowing collection and
fractionation of the fluidic output. After safety checking and
reliability tests, the system was checked for precipitation and
blocking due to ammonium salt formation upon mixing the
carboxylic acid and amines which could limit this approach.
Prior substrate screening informed us that phenylbutyric acid
and benzylamine was a soluble pairing (57.2 mmol/L solution).
Fraction collection was set for 100 min intervals to allow NMR
analysis to determine conversion and estimation of catalytic
efficiency. The output pattern indicated rapid initial formation
of the amide product (as in batch) but delayed in the output
due to a chromatographic effect of the column (fractions 2 – 6,
see SI). In a typical run, this unoptimised reactor system was
run for 20 h reaching steady state at ~10 h, giving an output
comprising 17% conversion (31 min residence time). In total,
2
017, 3, e1701028; f) H. Noda, M. Furutachi, Y. Asada, M.
Shibasaki and N. Kumagai, Nature Chem., 2017, 9, 571-577;
g) H. Charville, D. Jackson and A. Whiting, Chem. Comm.,
2
010, 46, 1813-1823; h) K. Ishihara, Synthesis and
Application of Organoboron Compounds, 2015, 243-270; and
references therein.
1
1 a) S. Liu, Y. Yang and A. Whiting, Eur. J. Org. Chem., 2013, 25,
5692-5700; b) B. M. Monks and A. Whiting. Sustainable
Catalysis, 2013, 89-110; c) K. Arnold, B. Davies and A.
Whiting, Angew. Chem., 2008, 120, 2713; d) K. Arnold, A. S.
Batsanov and A. Whiting, Green Chem., 2008, 10, 124-134; e)
K. Arnold, B. Davies and A. Whiting, Adv. Syn. & Catal., 2006,
3
48, 813-820; f) I. Georgiou, G. Ilyashenko and A. Whiting,
Acc. Chem. Res., 2009, 42, 756-768.
1
1
1
2 S. Arkhipenko, M. T. Sabatini, A. S. Batsanov, V. Karaluka, T.
D. Sheppard, H. S. Rzepa and A. Whiting, Chem. Sci., 2018, 9,
-1
this reactor produced 1.80 g of amide over 116 h (15.5 mg h ),
with activity right to the end of this operational period.
1
058-1072.
3 a) F. Jäkle, Synthesis and Application of Organoboron
Compounds, 2015, 297-325; b) T. Maki, K. Ishihara and H.
Yamamoto, Org. Let., 2005, 7, 5043-5046.
In summary, a novel polystyrene-supported boronic acid
catalyst, prepared by co-polymerisation, shows the propensity
of boronic acids to form anhydrides, resulting in clustering of
the boronate sites within the catalyst, and hence, enabling
efficient catalytic amidation reactivity. Evidence for B-O-B
systems forming di-acyl bridged structures mirrors that of the
4 Examples of bespoke polymers as immobilized monolithic
reagents see: a) F. Svec and J. M. J. Frechet, Anal. Chem.,
1
992, 62, 820–822; b) F. Svec and J. M. J. Frechet, Chem.
Mater., 1995, 7, 707-715; c) P. Hodge, Curr. Opin. Chem.
Biol., 2003, 7, 362-373; d) G. Jas and A. Kirschning, Chem.
Eur. J., 2003, 9, 5708-5723; e) A. Kirschning,W. Solodenko
and K. Mennecke, Chem. Eur. J., 2006, 12, 5972–5990; f) K. F.
Bolton, A. J. Canty, J. A. Deverell, R. M. Guijt, E. F. Hilder, T.
Rodemann and J. A. Smith, Tetrahedron Lett., 2006, 47,
1
2
homogeneous systems previously reported. Application of
the heterogeneous catalyst under standard amidation
conditions (24 h, reflux) gave up to 92% of the amide products.
More than 20 substrates showed direct applicability including
aryl and aliphatic carboxylic acids, and alkyl and aryl amines.
The catalyst could also be recovered by filtration and reused
multiple times without loss of reactivity. This stability also
enabled the use of the catalyst in a flow reaction using a non-
precipitating substrate combination. The flow reaction
proceeded smoothly, maintaining catalytic activity for over 4.5
days of continuous operation.
9
321-9324; g) N. Nikbin, M. Ladlow and S. V. Ley, Org.
Process Res. Dev., 2007, 11, 458-462; h) M. Baumann, I. R.
Baxendale, S. V. Ley, N. Nikbin and C. D. Smith, Org. Biomol.
Chem. 2008, 6, 1587-1593; i) C. J. Smith, N. Nikbin, C. D.
Smith, S. V. Ley and I.R. Baxendale, Org. Biomol. Chem. 2011,
9
, 1927-1937; j) K. A. Roper, H. Lange, A. Polyzos, M. B.
Berry, I. R. Baxendale and S. V. Ley, Beilstein J. Org. Chem.
011, 7, 1648-1655; k) R. J. Ingham, E. Riva, N. Nikbin, I. R.
2
Baxendale and S. V. Ley, Org. Lett. 2012, 14, 3920-3923; l) M.
V. Rojo, L. Guetzoyan and I. R. Baxendale, Org. Biomol. Chem.
2
015, 13, 1768-1777.
1
5 H. S. Rzepa, S. Arkhipenko, E. Wan, M. T. Sabatini, V.
Karaluka, A. Whiting and T. D. Sheppard, J. Org. Chem., 2018,
83, 8020-8025.
Notes and references
1
S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54,
451-3479.
3
16 L. Perreux, A. Loupy and F. Volatron, Tetrahedron, 2002, 58,
2
3
S.-Y. Han and Y.-A. Kim, Tetrahedron, 2004, 60, 2447-2467.
C. A. G. N. Montalbetti and V. Falque, Tetrahedron, 2005, 61,
2155-2162.
1
0827-10852.
4
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.,
2
007, 9, 411-420.
Graphical abstract
This journal is © The Royal Society of Chemistry 2018
Chem. Commun., 2018, 00, 1-3 | 4
Please do not adjust margins

Please do not adjust margins
Page 5 of 5
ChemComm
Journal Name
COMMUNICATION
A solid-supported phenylboronic acid-based catalyst for direct
amidation
View Article Online
DOI: 10.1039/C8CC09913H
OH
B(OH)2
B
B
styrene,
solid-phase
catalyst
O
Yihao Du, Tom Barber, Sol Ee Lim, Henry S. Rzepa, Ian R.
Baxendale and Andrew Whiting
divinylbenzene,
co-polymerisation
OH
RCOOH , -H2O
O
O
R
R
B
R'NH2
R’
O
R
N
H
O
O
B
O
This journal is © The Royal Society of Chemistry 2018
Chem. Commun., 2018, 00, 1-3 | 5
Please do not adjust margins