Solid-supported ortho-iodoarylboronic acid catalyst for direct amidation of carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2013.06.043

Amides are a ubiquitous class of organic compounds endowed with great utility. There is a need for simple and effective catalytic methods for their direct formation from carboxylic acids and amines as a way to avoid the use of coupling reagents. We have designed a recyclable resin-supported derivative of 5-methoxy-2-iodophenylboronic acid as a heterogeneous catalyst active in ambient conditions for promoting direct amidations of aliphatic carboxylic acids and amines. The optimal, practical procedure involves a simple double-filtration to isolate the amide product while separating the catalyst from residual molecular sieves.

Full text of DOI:10.1016/j.tetlet.2013.06.043

Tetrahedron Letters 54 (2013) 4475–4478
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solid-supported ortho-iodoarylboronic acid catalyst for direct
amidation of carboxylic acids
⇑
Nicolas Gernigon, Hongchao Zheng, Dennis G. Hall
Department of Chemistry, Gunning-Lemieux, Chemistry Centre, 4-010 Centennial Centre for Interdisciplinary Science, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Amides are a ubiquitous class of organic compounds endowed with great utility. There is a need for sim-
ple and effective catalytic methods for their direct formation from carboxylic acids and amines as a way
to avoid the use of coupling reagents. We have designed a recyclable resin-supported derivative of 5-
methoxy-2-iodophenylboronic acid as a heterogeneous catalyst active in ambient conditions for promot-
ing direct amidations of aliphatic carboxylic acids and amines. The optimal, practical procedure involves a
simple double-filtration to isolate the amide product while separating the catalyst from residual molec-
ular sieves.
Received 28 April 2013
Revised 4 June 2013
Accepted 11 June 2013
Available online 18 June 2013
Keywords:
Amides
Boronic acids
Heterogeneous catalysis
Solid-phase
Ó 2013 Elsevier Ltd. All rights reserved.
Because of the great importance of amides as a ubiquitous class
of compounds,1,2 there is significant interest in the development of
simple methods for their direct formation from carboxylic acids
and amines.3–5 A large number of sophisticated methods employ-
ing dehydrating-activating reagents have been developed for direct
(‘in situ’) coupling of carboxylic acids and amines.3–5 Common cou-
pling reagents such as carbodiimides, phosphonium or uronium
salts are expensive, provide poor atom-economy, and are often
toxic. All of these stoichiometric reagents and other additives, such
as bases and supernucleophiles, are often required in a molar ex-
cess and generate large amounts of wasteful by-products that com-
plicate the isolation of the desired amide product. An ideal direct
amidation reaction between carboxylic acids and amines would
be a waste-free, catalytic, and operationally simple process occur-
ring at or near the ambient temperature. In this regard, boronic
acids constitute an attractive alternative as catalysts for direct ami-
dation reactions.6 Some of the most efficient boronic acid catalysts
reported, such as 3,4,5-trifluorophenylboronic acid (1, Fig. 1),7,8 2-
diisopropylaminomethylphenylboronic acid (2),9 and the 3-10 and
4-pyridiniumboronic acids11 (3 and 4) tend to require high reac-
tion temperatures. In contrast, we recently reported that ortho-
iodophenylboronic acid (5) is a very efficient catalyst for direct
amidation reactions under ambient conditions (Fig. 1).12 Following
this discovery, 5-methoxy 2-iodophenylboronic acid (6) was iden-
tified as a second-generation catalyst.13 Catalyst 6 was found to
give higher yields within shorter reaction times for a wide range
of aliphatic carboxylic acids and amines.13
The prospect of immobilizing a boronic acid catalyst could
make this direct amidation methodology even more attractive.
By allowing the rapid separation and recycling of the supported
catalyst by a simple filtration, this boronic acid catalyzed amida-
tion would afford a simple isolation of amide products after evap-
oration of the reaction solvent and the water by-product. Although
pyridiniumboronic acid catalysts have previously been immobi-
lized onto a solid support,10,11 we anticipated several benefits in
immobilizing a derivative of catalyst 6 because of its high activity
under practical conditions at ambient temperatures.13
⇑
Corresponding author. Tel.: +1 780 492 3141; fax: +1 780 492 8231.
E-mail address: dennis.hall@ualberta.ca (D.G. Hall).
Figure 1. Known boronic acid catalysts for direct amidation reactions.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.043

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N. Gernigon et al. / Tetrahedron Letters 54 (2013) 4475–4478
the carboxylic acid group from the carboxyethyl polystyrene resin
(12) using our reported process in the presence of molecular
sieves.13 Unfortunately after many attempts it appeared extremely
difficult to isolate the desired product 7 (R = H) with the free amine
group. Then we switched to a one-pot sequence initiated by the use
of TBSOTf and 2,6-lutidine, followed by a solid-phase amidation
reaction using classical conditions with HOAt and HBTU to obtain
the desired functionalized resin 13. Finally, simple deprotection in
the presence of HCl 6 N in THF furnished the new solid-supported
boronic acid catalyst 14 (0.1 mmol/g theoretical loading based
on mass increase and analytical %N). Although only a fraction
(ꢀ10%) of the sites of resin 12 were effectively functionalized, the
final boronic acid loading of resin 14 was found to be sufficient
for providing good catalytic activity. The large degree of incomplete
functionalization implies that the heterogeneous support is
probably functionalized with boronic acid units mainly at the
surface of the resin beads. The internal carboxylic acid sites are
less available for sequestering the amine reagent through salt
formation, which avoids a decrease of amide product yields by
depleting the amine. Moreover, the resulting salt interaction is
reversible thus those amines could still be consumed.
As a preliminary test, we then evaluated solid-supported cata-
lyst 14 with a number of model substrates that were previously
tested with homogeneous catalyst 6.13 Similar conditions were
employed with the solid-supported catalyst 14, including the use
of 4A molecular sieves as water-trapping agent.16 Knowing that
Table 1
Substrate scope for the direct amide bond formation of carboxylic acids catalyzed by
solid-supported catalyst 14a
supported boronic acid 14
O
O
(10 mol%)
H2NR2
+
NHR2
amide product
R1
4A mol. sieves
CH2Cl2 [0.1M],
rt, time
R1
OH
Scheme 1. Synthesis of solid-supported boronic acid catalyst 14.
(1.1 equiv)
(1.0 equiv)
In designing a suitable linker for attachment to solid supports, it
was important to preserve the high activity of catalyst 6. To this
end, we realized that the 5-alkoxy substituent of 6 provides an
opportunity for attachment to a solid support without modifying
the optimal electronic characteristics of the catalytic unit. We opted
for a 5-alkoxy linker functionalized with a terminal amine, which
could be conjugated to carboxy-functionalized solid supports. The
desired catalytic construct 7 (Fig. 1) was prepared using a sequence
of chemoselective reactions made difficult by the presence of the
boronyl group. Thus, according to a protocol previously reported
by our group,14 commercially available 3-methoxyphenylboronic
acid was first iodinated to give 6 using a combination of AgNO3
and I2. This was followed by a demethylation with boron tribromide
(BBr3) at À78 °C, giving phenol 8 in 68% yield over two steps
(Scheme 1). Due to the basic conditions required for the alkylation
step, the boronic acid moiety was protected. Several protecting
groups were tested (n-butyldiethanolamine, pinacol ester, MIDA),
and the 1,8-diaminonaphthalene unit reported by Suginome and
coworkers was found to be the most efficient one.15 Easily
introduced, stable under basic conditions and cleavable with
aqueous acid, it furnished adduct 9, which was easily purified by
silica gel column chromatography. Compound 9 was thus obtained
after a reaction time of 12 h under azeotropic water removal
conditions in 95% yield. The linker arm 10 was prepared in one step
by simple BOC protection of the corresponding free amine. It was
then engaged in the alkylation step with phenol derivative 9 in
the presence of K2CO3 and KI in DMF at 60 °C to furnish the desired
Boc-protected construct 11 in 60% yield after purification. At
that stage, the initial idea was to deprotect both amine and boronic
acid, and perform a simple autocatalytic amidation reaction with
Entry
1
Product
Time (h)
Yieldb (%)
O
15
16
17
18
48
48
96
48
90
N
H
O
N
2
3
4
32c
79d
72
H
N
N
O
O
N
N
H
CONHCH2Ph
H3CO
5
19
48
86
N
O
Cl
a
Reaction conditions: carboxylic acid (0.55 mmol, 1.1 equiv), solid-supported
catalyst 14 (500 mg, 0.0485 mmol, ꢀ10 mol %), and the amine (0.5 mmol, 1.0 equiv)
were stirred at room temperature (25 °C) in dry DCM (5 mL) containing powdered
activated 4A molecular sieves (1.0 g).
Isolated yields following the simple filtration protocol and evaporation.
29% of the desired product was obtained when the reaction time was extended
to 6 days using DCM as solvent; 30% of the desired product was obtained after 48 h
when the reaction was performed in toluene. Other compounds obtained are left-
over starting materials.
b
c
d
Purified by silica gel column chromatography.

N. Gernigon et al. / Tetrahedron Letters 54 (2013) 4475–4478
4477
second filtration
(through fritted glass)
first filtration
(through PP filter)
4A MS
filtrate
(containing 4A MS)
reaction mixture
filtrate containing
amide product
recovered resin-supported catalyst
(for further use)
Figure 2. Two-step double-filtration process to separate 4A molecular sieves, recover resin-supported catalyst 14, and isolate amide product. PP: polypropylene.
the rate of heterogeneous reactions is usually slower, we elected to
increase the reaction times compared to the homogeneous variants
catalyzed by catalyst 6. To our satisfaction, it was found that the
reaction between phenylacetic acid and benzylamine went
smoothly and gave the desired amide 15 in 90% yield within 48 h
at room temperature (Table 1, entry 1).16 Encouraged by this prom-
ising result, the supported catalyst was evaluated with a more
challenging cyclic secondary amine substrate, pyrrolidine. How-
ever, only a moderate yield of the desired amide 16 could be ob-
tained (Table 1, entry 2), and the yield could not be improved by
employing a longer reaction time or another solvent (Table 1, entry
2). Considering that catalyst 6 provided a 91% yield of amide prod-
uct (rt, 6 h)13 this result confirmed that heterogeneous catalyst 14
is less active that its homogeneous congener 6. Nonetheless, de-
spite its restriction to the use of primary amines, the substrate
scope of this simple protocol is not limited to simple carboxylic
acids and amines. Thus, highly functionalized substrates bearing
pyridine and indole units were well tolerated in this highly
atom-economical process as exemplified with amide products 17
and 18, which were obtained with a good efficiency (Table 1, en-
tries 3 and 4). Remarkably, indomethacin amide 19, which is
known to exhibit potent biological activity,17,18 can be prepared
effectively using the new solid-supported boronic acid catalyst
14 (Table 1, entry 5). With the exception of the cyclic secondary
amine of entry 2, isolated yields of these heterogeneous catalytic
amidations are comparable to that of the homogeneous variant
with catalyst 6.13 Moreover, in contrast with previously reported
resin-supported boronic acids,10,11 which are employed at high
temperatures (e.g., refluxing toluene), amidations catalyzed by 14
proceed at room temperature. As depicted in Figure 2, it is note-
worthy that the solid-supported boronic acid catalyst 14 can be
easily separated from the 4A molecular sieves, and recovered by
a simple double-filtration strategy. This protocol provides essen-
tially pure amide product after evaporation and straightforward
acid–base extractions to eliminate the small excess of carboxylic
acid. It is also remarkable that all reactions listed in Table 1 were
performed sequentially using the same batch of recovered catalyst
14. This observation demonstrates that catalyst 14 is stable to
protodeboronation under the reaction conditions. Although a
systematic study of the catalyst’s reusability has not been per-
formed at this preliminary stage, our results indicate that sup-
ported catalyst 14 can be reused several times without an
appreciable loss of catalytic efficiency. This sort of process is highly
desirable in terms of atom- and step-economy and is potentially
attractive toward application in process chemistry.
In summary, we have designed and successfully prepared an
effective solid-supported 5-alkoxy-2-iodophenylboronic acid as a
recyclable catalyst for direct amidation reactions between carbox-
ylic acids and amines. Although the catalyst was found to be less
active than its homogeneous analogue, it does provide pure amide
products between aliphatic carboxylic acids and aliphatic primary
amines at room temperature. The optimal, practical procedure in-
volves a simple double-filtration to separate the catalyst and the
molecular sieves, and isolate the amide product after a simple
evaporation of the filtrate and straightforward acid–base extrac-
tions. The catalyst was recycled several times to demonstrate a
good substrate scope for the preparation of secondary aliphatic
amides containing various functional groups.
Acknowledgments
Acknowledgment for financial support of this research is made
to the Natural Sciences and Engineering Research Council (NSERC)
of Canada (Steacie Memorial Fellowship and Idea-to-Innovation
grants to D.G.H.), and the University of Alberta.
Supplementary data
Supplementary data (full experimental procedures, compound
characterization, NMR spectra) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.06.043.
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catalyzed by solid-supported catalyst 14 (N-benzylphenylacetamide 15, Table 1,
entry 1): A 50-mL plastic vessel was charged with phenylacetic acid (75 mg,
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and Et2O (3 Â 5 mL). The recovered solid-supported boronic acid catalyst 14
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containing 4A molecular sieves was filtered through a pad of Celite 545. The
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basic solution (pH 10–11), and brine. The organic layer was collected, dried
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product 15 as a white solid (101 mg, 90%). The characterization data for this
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synthesized using this procedure using recycled catalyst 14. Characterization
data for these compounds matched that of a previous report.13
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