MCF-supported boronic acids as efficient catalysts for direct amide condensation of carboxylic acids and amines

Article abstract of DOI:10.1039/c4cc01148a

For efficient direct amide condensations, a new class of catalysts are developed by immobilizing boronic acids on mesocellular siliceous foam. Associated with their large pores, the microenvironments surrounding the immobilized active species greatly influence the catalytic activity. The fluoroalkyl moieties on the silica surface significantly enhance the catalytic performance along with easy recovery and reuse. This approach proposes a potential way to optimize various types of silica-supported catalysts. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01148a

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MCF-supported boronic acids as efficient catalysts
for direct amide condensation of carboxylic acids
and amines†
Cite this: Chem. Commun., 2014,
50, 7017
Received 13th February 2014,
Accepted 12th May 2014
Liuqun Gu,*‡ Jaehong Lim,‡ Jian Liang Cheong and Su Seong Lee*
DOI: 10.1039/c4cc01148a
www.rsc.org/chemcomm
For efficient direct amide condensations, a new class of catalysts are acid catalysts for direct amide condensations. Mesocellular siliceous
developed by immobilizing boronic acids on mesocellular siliceous foam (MCF) was mainly investigated as support material due to its
foam. Associated with their large pores, the microenvironments large (420 nm) and interconnected internal pores, which significantly
surrounding the immobilized active species greatly influence the facilitate the diffusion of substrates.13 Moreover, the two-dimensional
catalytic activity. The fluoroalkyl moieties on the silica surface signifi- silica surface of MCF can be easily manipulated to control the micro-
cantly enhance the catalytic performance along with easy recovery environments of immobilized catalysts. Indeed, we were delighted to
and reuse. This approach proposes a potential way to optimize observe that the MCF-supported boronic acids optimized with fluoro-
various types of silica-supported catalysts.
alkyl capping groups showed considerably enhanced catalytic activity
compared with their homogeneous counterparts, not to mention bare
Amide bond formation is frequently used in the synthesis of MCF and trimethylsilyl (TMS)-capped MCF alone.
pharmaceuticals and proteins.1,2 The current industrial synthetic
As depicted in Fig. 1, various silica-supported boronic acids
procedures usually involve the stoichiometric use of acylation were prepared by using our previously reported immobilization
reagents, such as thionyl chloride, or coupling agents, such as method (see ESI,† Scheme S1).13 The sequential treatments began
1-hydroxybenzotriazole (HOBt) and 1,10-carbonyldiimidazole (CDI), with the pre-capping of free silanol groups by a sub-stoichiometric use
for activation of carboxylic acids, from which a hefty amount of of hexamethyldisilazane (HMDS) or other dialkyltetramethyldi-
wastes are generated.3 Although much effort has been made to silazane, partially and uniformly. Into the remaining active silanol
develop alternative coupling agents for more efficient formation of groups, a desired amount of 3-aminopropyltriethoxysilane (APTES)
amide bonds, most methods still suffer from poor atom economy and was introduced in anhydrous toluene at 100 1C for 20 h to give
high costs.4 In search of novel methods that avoid employing such the amine-functionalized MCF. The degree of pre-capping was
reagents, boron-based organocatalysts5 as well as some metal-based determined depending on the amount of APTES to load. To
catalysts2,6 were investigated for direct amide condensations. These prepare 0.2 mmol gꢀ1 of the APTES moiety, for example, 0.8 mmol gꢀ1
methods are significantly more environmentally friendly and atom-
economical with only water produced as a co-product. However, the
drawbacks such as moderate reactivity and difficulty in catalyst
recovery hampered those methods for industrial application. Recently,
several inorganic heterogeneous catalysts7–12 and polystyrene-bound
4-boronopyridinium salts5b were reported for direct amide bond
formation. These findings indicate that heterogeneous catalysts are
promising candidates despite the remaining challenges such as high
reaction temperature, long reaction time and azeotropic removal of
in situ generated water. Herein, we report on silica-supported boronic
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669. E-mail: gulq@imre.a-star.edu.sg, sslee@ibn.a-star.edu.sg;
Fax: +65-6478-9080
† Electronic supplementary information (ESI) available: Experimental proce-
dures, results obtained from testing all the catalysts, BET data and NMR spectra.
See DOI: 10.1039/c4cc01148a
Fig. 1 Silica-supported boronic acids and their homogeneous counterparts.
‡ Both authors contributed equally to this work.
Commercial silica indicates Silica gel 60 (0.040–0.063 mm), Merck KGaA.
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of HMDS was used for pre-capping, which amounts to slightly more aromatic substituent of boronic acid. Supported on the identical
than half of the maximal TMS capping of ca. 1.5 mmol g
ꢀ1 13b After microenvironments, the fluoro-free catalyst 8d led to lower catalytic
.
complete anchoring of APTES, the 1H NMR spectrum of the concen- activity than the fluoroalkyl derivative 8a (entries 8 and 9). The
trated filtrate did not show any organic compound, which confirmed background reaction using bare MCF and 4 afforded the product
that the added APTES groups were completely incorporated. Cross- with 23% and 11% yield, respectively. These results firmly proved that
polarization magic angle spinning (CPMAS) 29Si NMR spectra clearly the boronic acid played a key role in the catalysis. It is noteworthy that
showed T2 and T3 peaks from the anchored APTES (see ESI,† Fig. S5). the homogeneous catalyst 5 was inhibited by the presence of TMS-
The still remaining silanol groups were thoroughly capped by further capped MCF (see ESI,† Table S3). The isolated yield (27%) became
treatment with the corresponding dialkyltetramethyldisilazane. only comparable to that of TMS-capped MCF alone (20%). These
Although these steps can be sequentially conducted in one pot, a phenomena might be attributed to strong interactions between free
vapour-phase reaction under reduced pressure at 80 1C is carried out boronic acid and the silica surface capped with the simple TMS group.
for the more efficient post-capping with HMDS.13 The resulting
The importance of post-capping is best demonstrated by the
amine-functionalized MCF then became available to immobilize significantly decreased catalytic activity resulting from a catalyst
carboxyphenylboronic acids through a typical coupling reaction. It is prepared by pre-capping with a slightly less amount of the fluoro-
apparent that the pre-capping method beneficially minimizes the alkyl moieties (0.5 mmol gꢀ1) and no post-capping (see ESI,† 8b in
adverse interactions between the amine groups of APTES and the Table S3). This might be caused by strong interactions between the
silica surface during the grafting step. The Kaiser test and CPMAS 13
C
anchored boronic acid and the silica surface. The loading density of
NMR spectra of the investigated catalysts showed successful coupling the boronic acid affected the catalytic activity. High loading signifi-
of the boronic acids to the amine groups on MCF (see ESI,† Fig. S2 cantly hampered the catalytic activity presumably due to the internal
and S5). The surface area and pore volume of MCF slightly decreased interactions amongst the immobilized boronic acids (see ESI,†
during the immobilization process, which also supports the success- Table S3). The pore size of the support material is another key
ful sequential anchoring of pre-capping agents, APTES and boronic factor affecting the catalytic activity. MCF with large pores (23.8 nm)
acid (see ESI,† Fig. S1 and Table S1).
showed much higher activity than SBA-16 (9) and commercial silica
The catalysts in Fig. 1 were investigated in amide condensation of (10) with smaller pores (3.7 nm and 4.7 nm, respectively) possibly
phenylacetic acid and benzylamine in a sealed tube using toluene as a due to the diffusion process (entries 11–13).15
solvent (Table 1). To our surprise, the MCF-supported boronic acid
Next, we examined the scope and limitations of the best
catalysts 8a capped with fluoroalkyl moieties showed the best perfor- catalyst 8a. In the presence of 5 mol% of 8a, various carboxylic
mance with even higher catalytic activity than the homogeneous acids reacted with benzylamine to produce the corresponding
counterparts 1 and 2 (entries 1, 2 and 8). Interestingly, the introduc- amides in good to excellent yields (Table 2). Aliphatic carboxylic
tion of the fluoroalkyl moiety in the capping propyl group significantly acids turned out to be more reactive than aromatic derivatives,
improved the catalytic efficiency. The isolated yield produced by 8a especially in the case of those containing electron-withdrawing
reached up to 82%, remarkably from 55% by the fluoro-free derivative groups. Functionalities including hydroxyl, alkene and furan
6 (entries 9 and 10), presumably due to the beneficial role of the groups were tolerant under these relatively mild conditions
fluoroalkyl group as a Lewis base14 or a better water-repelling agent (entries 3–5). A significant decrease in conversion was observed
(or both). Similar halogen group effects were also observed in the in the case of 4-cyanobenzoic acid compared to that with benzoic
acid (entries 6 and 7).
For amines, a similar trend was also observed that the
Table 1 Amide condensation of phenylacetic acid and benzylamine with
aliphatic amines reacted with phenylacetic acid faster than
the aromatic derivatives (entries 8–10). A sterically encumbered
substrate affected the reaction to result in only moderate yield
(68%) with N-methylbenzyl amine even with a prolonged reaction
time and azeotropic removal of water (entries 1 and 9). The less
reactive aniline was converted into the corresponding amide in a
relatively low yield, whereas nearly full conversion could be
achieved upon azeotropic removal of water (entry 10). With the
one-time recycled catalyst, an active pharmaceutical ingredient
(API) intermediate16 was synthesized in a moderate isolated yield
(entry 11) on a relatively large scale (10 mmol).
The catalyst 8a was successfully reused 5 times without any
substantial loss of catalytic activity (Table 3). The 13C solid-state
NMR spectrum of 8a after 6 repeated use revealed the increase
in the intensity of the peaks in the aromatic region, which we
speculate might be caused by strong interactions between the
aromatic boronic acid moiety and phenylacetic acid.17
various catalysts under sealed conditionsa
Entry
Catalyst (mol%)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1 (10)
2 (10)
Bare MCFc
4 (5)
5b (10)
6 (10)
7 (10)
8a (10)
8d (10)
6 (5)
2
2
2
2
2
2
2
2
2
1
1
1
1
74
78
23
11d
71
98
88
498
84
55
82
28
42
9
10
11
12
13
8a (5)
9 (5)
10 (5)
a
Conditions: catalyst (10 or 5 mol%), phenylacetic acid (0.5 mmol), benzyl-
amine (0.5 mmol), toluene (2 ml), 120 1C. b Isolated yield. 250 mg, dried
c
In summary, a new class of MCF-supported boronic acid
catalysts were developed in conjunction with a simple and
under high vacuum at 120 1C for 15 h. d Azeotropic removal of water.
7018 | Chem. Commun., 2014, 50, 7017--7019
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Table 2 Direct amide condensation of various carboxylic acids and
amines by 8aa
Table 3 Recycling use of the MCF-supported boronic acid catalyst 8a in
the amide condensations of phenylacetic acid and benzylaminea
Run
1
2
3
4
5
6
Yieldb
91%
94%
498%
498%
498%
498%
Entry Product
1
Solvent Temp. (1C) Time (h) Yieldb (%)
a
Conditions: catalyst 2 (5 mol%), phenylacetic acid (2.5 mmol), benzyl-
amine (2.5 mmol), toluene (5 ml), 120 1C, azeotropic removal of water, 2 h.
b Isolated yield.
Toluene 120
Toluene 120
2
3
498
heterogeneous catalysts could be easily recovered by simple
filtration and reused multiple times without loss of activity.
Although it is still a long and challenging way to apply these
catalysts to industrial production, the developed immobiliza-
tion strategy would provide an insight into the future develop-
ment of reusable heterogeneous catalysts.
2
89
3c
o-Xylene 155
5
94
This work was supported by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency for
Science, Technology and Research Singapore).
4
5
6
7
o-Xylene 155
o-Xylene 155
o-Xylene 155
o-Xylene 155
5
5
97
95
83
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a
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b
c
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d
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