Metal–Organic Framework Based on Copper and Carboxylate-Imidazole as Robust and Effective Catalyst in the Oxidative Amidation of Carboxylic Acids and Formamides

Article abstract of DOI:10.1002/ejoc.201600991

A metal–organic framework (MOF) based on copper and 1,3-bis(carboxymethyl)imidazole (bcmim) was prepared on a gram scale by using a precipitation method at room temperature. The Cu(bcmim)₂MOF was shown to be an efficient catalyst for the preparation of amides through an oxidative coupling between carboxylic acids and formamides in the presence of an oxidant, such as tert-butyl hydroperoxide (TBHP). The method for the preparation of the amides is robust regardless of the carboxylic acid and gives good conversions with good selectivity. The heterogeneous catalyst was recovered unaltered after the reaction, was easily separated from the reaction mixture, and subsequently reactivated by suitable treatment. Moreover, the coupling reaction was scaled up to a gram scale, which allowed for the preparation of valuable products, such as fatty acid amides (i.e., 1-palmitoylpiperidine).

Full text of DOI:10.1002/ejoc.201600991

A Journal of
Accepted Article
Title: Metal-organic framework based on copper and carboxylate-imidazole as ro-
bust and effective catalyst in the oxidative amidation of carboxylic acids using
formamides
Authors: Mar´ıa Albert-Soriano; Isidro Manuel Pastor
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600991
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Metal-organic framework based on copper and carboxylate-
imidazole as robust and effective catalyst in the oxidative
amidation of carboxylic acids using formamides
María Albert-Soriano,[a] and Isidro M. Pastor*[a]
Abstract: A metal-organic framework (MOF) based on copper and
1,3-bis(carboxymethyl)imidazole [Cu(bcmim)2] has been prepared
up to gram-scale, using a precipitation methodology at room
temperature. The MOF-Cu(bcmim)2 has proved to be a very efficient
catalyst in the preparation of amides via an oxidative coupling
between carboxylic acids and formamides in the presence of an
oxidant, such as TBHP. The methodology for the preparation of
amides has shown to be very robust regardless of the carboxylic
acid, giving good conversions and selectivities. The heterogeneous
catalyst has been recovered unaltered after the reaction, being
easily separated from the reaction mixture and subsequently
reactivated by suitable treatment. Moreover, the coupling reaction
has been scaled up to gram-scale, being possible to prepare
valuable products, such as fatty acid amides (i.e. 1-
palmitoylpiperidine).
and industrial interest.[14] Among the functional group
transformations, the formation of amides[15] is highly relevant due
to their presence in several natural products and in many fine
chemicals, agrochemicals, and pharmaceuticals. Indeed,
a
quarter of drugs in the market presents at least an amide
bond.[16] The condensation between an amine and a carboxylic
acid is the most straightforward way of forming an amide,
although it needs harsh reaction conditions. The use of an
activating reagent, which transforms the carboxylic acid into a
more reactive species, is an interesting strategy in order to
soften the reaction conditions. In this sense, there is a plethora
of coupling reagents for carrying out the amide formation under
mild conditions in good yields, but it is necessary to use them in
stoichiometric amounts.[17] Alternative catalytic methods have
been developed for direct amidation, although the reported
protocols are still limited.[18] Nowadays, oxidative couplings have
emerged as a stimulating option to form C-N bonds,[19] among
others. Thus, the formation of amides have been accomplished
by coupling reactions between aldehydes or alcohols with
amines or formamides.[20] This type of coupling between
aldehydes and amines has been catalysed by a copper based
MOF.[21] The use of less conventional precursors, such as
carboxylic acids and formamides [mainly, dimethylformamide
(DMF) and diethylformamide (DEF)], have been also coupled in
the presence of homogeneous copper(II) salts [i.e. Cu(OAc)2,[22]
CuCl2,[23] Cu(OTf)2,[24] Cu(ClO4)2·6H2O][25] and heterogeneous
copper based nanoparticles [i.e. CuO,[26] γ-Fe2O3@SiO2–
Introduction
The imidazole derivatives bearing carboxylic moieties have been
employed both as N-heterocyclic carbene (NHC) precursors and
as ionic liquids (ILs), being applied to different catalytic
processes.[1] Recently, metal-organic frameworks (MOFs) have
been prepared employing carboxy-functionalised imidazoles due
to the excellent coordination ability of this type of substituents.
Indeed, metal-organic frameworks with ligands based on
carboxylate-imidazole salts (in zwitterion form) have been
prepared in combination with various metals, such as
strontium,[2] cesium,[3] cobalt,[4] lanthanum,[5] neodymium,[5]
copper[6] and manganese.[7] Moreover, zwitterion carboxylate-
imidazoles have been treated with an acid giving their
corresponding imidazolium salts,[8] which have been also linked
to metals in the preparation of MOFs. In particular, chloride and
bromide salts have been utilised in combination with cobalt,[9]
zinc,[9,10] calcium,[3] barium,[3] strontium,[3] lead,[11] lanthanum,[12]
europium,[12] praseodymium,[12] bismuth[13] and copper[6] for the
synthesis of this type of structures.
Cu(acac)2].[27] Hitherto, the oxidative coupling between
a
carboxylic acid and a formamide has not been described using
metal-organic frameworks as catalysts (Scheme 1). Our group
presents the first use of a MOF (based on copper), which is
straightforwardly prepared under mild conditions, as effective
catalyst in the synthesis of amides by oxidative coupling of
carboxylic acids and formamides. This work was inspired by
related C-H activation of formamides, aldehydes and ethers with
copper-MOFs.[28] The Cu(II) centres, in the MOF based on
copper and 1,3-bis(carboxymethyl)imidazole, are equivalent
among them and with a square planar environment provided by
four carboxylate oxygen donors.[6] As a result, we consider that
this geometry around the copper atom could allow this centre to
be active as catalyst in oxidative coupling reactions.
The formation of carbon–heteroatom bonds is an essential tool
for the preparation of chemical compounds of both academic
[a]
M. Albert-Soriano, I. M. Pastor
Organic Chemistry Dpt. and Instituto de Síntesis Orgánica (ISO)
University of Alicante
Apdo. 99, 03080, Alicante (Spain)
E-mail: ipastor@ua.es
http://orcid.org/0000-0002-8271-0641
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201600991
FULL PAPER
confirmed the presence of copper(II) in the MOF (see
Supporting Information).
Scheme 1. Oxidative coupling of carboxylic acids and formamides considered
in this work.
recycled
Results and Discussion
Cooper and 1,3-bis(carboxymethyl)imidazole based metal-
organic framework. Our study started with the preparation of
the ligand 1,3-bis(carboxymethyl)imidazole (bcmim, 1, see
Supporting Information), as described in the literature, by
reaction of glycine, glyoxal and formaldehyde (ratio 2:1:1).[1e,29]
Following, the metal-organic framework Cu(bcmim)2 was
precipitated from an aqueous solution of biscarboxylate 1 and
Cu(OAc)2 by adding methanol (Scheme 2). Accordingly, we
obtained MOF-[Cu(bcmim)2] as a blue solid following the
procedure described by Abrahams, Robson and co-workers,[6]
albeit we scaled efficiently up the procedure to multi-gram scale
(Scheme 2 and Supporting Information). The obtained blue solid
was treated with methanol for several hours in order to purify
and activate it.[30]
synthesized
simulated
10
20
30
2θ deg
Figure 1. PXRD patterns of MOF-[Cu(bcmim)2]: (a) simulated, (b) synthesized
and (c) recycled.
Scheme 2. Preparation of MOF-[Cu(bcmim)2].
The prepared MOF-[Cu(bcmim)2] was characterized by powder
X-ray diffraction (PXRD), scanning electron microscopy (SEM),
thermogravimetric analysis (TGA), elemental analysis, X-ray
photoelectron spectroscopy (XPS) and Fourier transform
infrared (FT-IR) spectrometry (Figures 1 and 2, and Supporting
Information). Thus, the MOF presents crystallinity after the
preparation and activation procedures, when compared with the
simulated pattern[6] (compare Figure 1a and Figure 1b). The
SEM images of the synthesised Cu(bcmim)2 are shown in Figure
2. The solid formed takes spherical form (Figure 2a), although
these patterns are formed by small slab-like crystals (Figure 2b).
In fact, after the treatment with methanol (washing/activation
process) the SEM image shows the lamellar morphology of the
small crystals but without any arrangement (Figure 2c). The
thermal stability of the MOF was measured by TG analysis:
Cu(bcmim)2 started to decompose ca. 275 ºC and a significant
loss of weight was observed around 290 ºC (see Supporting
Information), the material being decomposed. The XPS analysis
Figure 2. SEM of MOF-[Cu(bcmim)2]: (a) and (b) as precipitated using
Cu(OAc)2 and ligand 1 in a water/MeOH mixture, (c) after washing/activation
with MeOH for several hours, (d) after recycling.
Catalytic activity in oxidative coupling between carboxylic
acids and formamides: Optimisation. Following, we wondered
about its catalytic activity in oxidative cross-coupling processes.
Therefore, we were pleased to verify that the MOF-[Cu(bcmim)2]
catalyses the oxidative coupling between benzoic acid and 1-
formylpiperidine (2), in the presence of tert-butylhydroperoxide
(TBHP), giving 1-benzoylpiperidine (3) with 48% conversion
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European Journal of Organic Chemistry
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FULL PAPER
reaction towards the formation of the amide product is >99%. [f] TON =
9.9, TOF = 5.94 h–1. [g] In parentheses isolated yield of pure product.
(>99% selectivity, Table 1, entry 1). The absence of MOF gave
no conversion and the starting materials were recovered,
proving the need of the catalyst (Table 1, entry 2). Additionally,
the reaction did not proceed without the oxidant (Table 1, entry
3). Preliminary experiments showed better conversions when
the reaction is carried out with the flask open to the atmosphere
(see Supporting Information), probably due to the need of
releasing the pressure generated from gaseous by-products.
Consequently, the study was continued performing the assays in
open vessels. Furthermore, we proved temperature to be a
crucial factor, thus a conversion of 41% was achieved after 2
days of reaction by lowering the temperature to 70 ºC (although
the selectivity remained high, Table 1, entry 4, footnote b). In
order to improve the conversion, we modified the amounts of
catalyst and amide. The increase of catalyst amount to 20 mol%
produced practically no improvement in the conversion (Table 1,
entry 5). In relation to the quantity of amide, there is an evident
connection with the reaction progress. Indeed, employing 18
equivalents of amide gave a conversion of 77% whereas 33% of
conversion was obtained by reducing it to 2 equivalents (Table 1,
compare entries 7 and 8 with entry 1).
At this point, we postulated the decomposition of the oxidant in
the reaction media as a possible explanation for the incomplete
conversion. Thus, an experiment was performed under the
reaction conditions detailed in the entry 1 of Table 1, but adding
the whole amount of oxidant divided in 10 portions (1 portion
every 5 min). The conversion was slightly improved (Table 1,
entry 9), what led us to think about slowing the addition along
the reaction time. Therefore, the conversion was again improved
(Table 1, entry 10), and in combination with a higher amount of
amide resulted in complete conversion with an excellent
selectivity (Table 1, entry 11). In the last experiment, product 3
was isolated as a pure compound with 98% yield, verifying the
efficacy of the methodology.
Table 2. Oxidative coupling between benzoic acid and 1-formylpiperdine:
Oxidant.
Table 1. Oxidative coupling between benzoic acid and 1-formylpiperdine:
Optimisation.
Entry[a]
Oxidant[b]
Conversion (%)[c]
1
TBHP (water sol. 70%)
TBHP (decane sol. 5.5 M)
DTBP
70
46
0
2
Entry[a]
x
y
Oxid. Portions (lapse-time)[c]
Conversion (%)[e]
3
1
10
0
4.5
4.5
4.5
4.5
4.5
4.5
18
1
48
4
MCPBA
0
2
1
0
5
UHP
0
3
10
10
20
1
No oxidant
0
6
H2O2 (water sol. 33%)
TBHP (water sol. 70%)
8
4[b]
5
1
41
7[d]
53
1
55
[a] Reaction conditions: benzoic acid (0.25 mmol), 1-formylpiperidine (18
equiv., 4.5 mmol, 0.5 mL0), oxidant (1.5 equiv., 0.38 mmol), Cu(bcmim)2
(10 mol-% refer to Cu, 11 mg), 100 ºC, 100 min. [b] Oxidant: tert-butyl-
hydroperoxide (TBHP), di-tert-butylperoxide (DTBP, m-chloroperbenzoic
acid (MCPBA), Urea-H2O2 complex (UHP), hydrogen peroxide (H2O2). [c]
Conversion obtained by GC analysis. [d] 10 mol-% of MOF-[Cu(BTC)2]
(HKUST-1, Basolite C-300) was employed as catalyst.
6
1
37
7
10
10
10
10
10
1
77
8
2
1
33
9
4.5
4.5
18
10 (5 min.)
Slow addition[d]
Slow addition[d]
65
10
11
83
99[f] (98%)[g]
The use of TBHP as oxidant was initially stated based on similar
catalytic procedures.[23-26] However, we considered other
oxidants in order to validate it (Table 2). Thus, TBHP (both water
and decane solution), di-tert-butylperoxide (DTBP), meta-
chloroperbenzoic acid (MCPBA), and hydrogen peroxide (as an
aqueous solution and complexed with urea, UHP) were tested
under the optimal conditions adding the oxidant at the beginning
[a] Reaction conditions: benzoic acid (1 mmol), 1-formylpiperidine (2, 4.5 or
18 mmol), TBHP (70% water solution, 3 mmol), Cu(bcmim)2 (10 mol% refer
to copper, 43 mg), 100 ºC, 100 min. [b] Reaction performed at 70 ºC. [c]
Lapse-time, when indicated, is the time between each oxidant portion
added. [d] A syringe pump is used to add slowly the oxidant along 100 min.
[e] Conversion obtained by GC analysis. In all cases the selectivity of the
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European Journal of Organic Chemistry
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FULL PAPER
of the reaction (comparing with Table 1, entry 7), besides only
1.5 equivalents of oxidant were used to get margin for
comparison. Only TBHP and H2O2 gave conversion (Table 2,
entries 1, 2 and 6), being better the use of aqueous solution of
TBHP, as previously described.
300) under similar reaction conditions as described in Table 2
(compare entries 1 and 7, footnote [d]). The corresponding
amide 3 was obtained with a conversion of 53%, proving the
higher activity of the prepared Cu(bcmim)2.
For comparison, we performed the reaction with the
commercially available MOF-[Cu(BTC)2] (HKUST-1; Basolite C-
Table 3. Oxidative coupling of carboxylic acids with formamides.[a]
[a] Reaction conditions: carboxylic acid (1 mmol), formamide (2 mL), Cu(bcmim)2 (10 mol% Cu, 43 mg), TBHP (70% water solution, 3 mmol, 415 μL), 100 ºC,
100 min. Yields are of isolated products. In parentheses are the conversions by GC analysis. Generally, the selectivities to the formation of the amide are
>99%, being the only detected product. [b] Conversion using 5 mol% of Cu(bcmim)2. [c] Conversion using 1 mol% of Cu(bcmim)2. [d] Selectivity is ca. 80%. [e]
6% of N-ethyl-3,4-dimethoxybenzamide was obtained together with 22.
Catalytic activity in oxidative coupling between carboxylic
acids and formamides: Scope, scale-up and recyclability.
The general versatility of this methodology was further evaluated
for a variety of carboxylic acids under the optimised reaction
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European Journal of Organic Chemistry
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conditions. Thus, carboxylic acids underwent oxidative coupling
with 1-formylpiperidine catalysed by Cu(bcmim)2 (10 mol% Cu)
with the slow addition of TBHP as oxidant at 100 ºC in an open
vessel, and the results are shown in Table 3. In general,
excellent conversions with
a high selectivity towards the
formation of the corresponding amides 3-19 were observed,
being the conversions higher than 92% in all the cases (except
for 4-toluic acid). Regarding aromatic acids, both electron-rich
and electron-deficient benzoic derivatives and 2-naphthoic acid
formed neatly the corresponding amides 3-14 (Table 3), as the
only observed product (excellent selectivity in all cases).
Essentially, differences in the yield of pure product have to do
with the isolation process. Notably, benzoic acids bearing
halogen substituents (chloro, bromo and iodo), which can show
reactivity in the presence of transition metal based catalysts,
produced exclusively the expected amides 4-8 in yields from 86
to 93% (Table 3). Moreover, ortho-, meta- and para-
chlorobenzoylpiperidines (6-8, Table 3) were prepared without
any significant difference. Remarkably, sensitive groups, such
as hydroxyl (–OH) and amino (–NH2), were tolerated as
substituents and the corresponding products 11 and 12 (Table
3) were exclusively produced.
Scheme 3. Synthesis of 1-palmitoylpiperidine: gram scale.
The protocol described seems very robust regardless of the
carboxylic acid (substituted aromatics, aliphatics), thus we
coupled four different acids with other formamide derivatives in
order to broaden its applicability. As previously observed, the
catalyst performed correctly producing the amides 20-23 (Table
3), which could be isolated with yields in the range of 64-94%.
N-Acylmorpholine derivatives present different bioactivities,[33] so
the formation of this type of compounds (such as 20) is of
relevant interest. Additionally, the cyclic 1-formylpyrrolidine was
coupled with phenylacetic acid giving product 21 exclusively.
Moreover, the use of N,N-dialkyl formamides (such as diethyl or
diisopropyl) gave smoothly the oxidative coupling process, and
compounds 22 and 23 (Table 3) were isolated in excellent yields.
Of the latter, product 23 is formed by an oxidative dealkylation
process of the amide under the reaction conditions.[34]
Next, the study was extended to aliphatic carboxylic acids to
explore the potential of our methodology. Gratifyingly, different
acids were completely converted into the corresponding amides
15-19 (Table 3) with excellent conversions and selectivities.
Among the substrates,
a protected amino acid (i.e. N-
benzoylglycine) was converted into the corresponding amide 18
(high conversion, and isolated yield of 95%). In general, the
smaller the acid the more difficult the purification of the amide
derivative, so the cyclohexanecarboxamide derivative 17 was
isolated with 55% yield. Actually, butyric acid coupled efficiently
(97% conversion) under the described reaction conditions, but 1-
butyrylpiperidine could be only isolated with 5% yield.
Interestingly, palmitic acid was transformed into the piperidine
derivative 19, being obtained after purification in 97% yield. Fatty
acid amides, such as 19, have been described as
antituberculosis[31] and anticancer agents.[32] Thus, the protocol
described here represents an interesting procedure for the
preparation of this type of compounds. For that substrate, we
proved that the amount of catalyst can be reduced to 5 mol%
with a slight reduction in the conversion (93%, Table 3, footnote
b). Lessening the catalyst to 1 mol% produced a drop in the
conversion to almost half (55%, Table 3, footnote c). Next, we
proved that the reaction can be performed in gram scale without
losing the effectiveness of the heterogeneous catalyst. Thus, 1.8
grams of palmitic acid was reacted during 140 minutes with 1-
formylpiperidine in the presence of 10 mol% of catalyst, being
isolated 2.0 grams of 1-palmitoylpiperidine (90% yield, Scheme
3). The catalyst was removed by centrifugation, the excess of
the amide was distilled off and the product was purified by
filtration through a pad of silica gel (eluting with 1:1 ethyl
acetate/hexanes mixture).
Scheme 4. MOF-[Cu(bcmim)2] recyclability. Conversions by GC analysis.
Accumulative TON = 49.5.
The recovery of the heterogeneous catalyst MOF-[Cu(bcmim)2]
and its recyclability are points at issue. Thus, a study of catalyst
recyclability was carried out on the model reaction, i.e. the
oxidative coupling between benzoic acid and 1-formylpiperidine
using 10 mol% of copper-MOF. After the reaction, the catalyst
was easily separated from the reaction mixture by centrifugation.
We observed that simple washing of the catalyst with organic
solvents [i.e. stirring for 2 h in ethyl acetate (AcOEt), diethyl
ether (Et2O), acetone or methanol (MeOH)], was not enough to
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European Journal of Organic Chemistry
10.1002/ejoc.201600991
FULL PAPER
recover completely the catalyst activity, being the conversions in
the range of 60-80% in the second run. The partial deactivation
could be due to by-products of the reaction, which remain
attached to the catalyst. Indeed, a catalyst load (after the first
run) was washed with MeOH for 2 h giving 62% conversion in
acid is linearly decreasing with time, confirming order zero with
respect to the carboxylic acid.
Regarding the mechanism, oxidative coupling between acids
and amides using copper catalysts have been proposed to
proceed via radical intermediates.[25,27] The use of a radical
the second run, and then it was treated during 2 weeks in MeOH, scavenger, such as TEMPO, inhibited the reaction between
recovering its activity (99% conversion in the third run). Finally,
we found a shorter and straightforward protocol for recovering
the catalyst activity. Truly, treating the catalyst with water for 1
minute and adding then MeOH allowed the recovery of the
catalyst for the second run with the same activity (Scheme 4). It
was even more interesting that the catalyst do not suffer any
deactivation after 5 cycles (Scheme 4), following the same
protocol of recycling. After the recycling experiment, we verified
that the copper-MOF does not suffer any alteration during the
oxidative coupling reaction. At first sight, the external
appearance is similar to the fresh prepared and activated MOF
(see Supporting Information). Definitely, the PXRD analysis
proves the crystallinity of the recycled MOF to be intact (Figure
1c). The SEM image of the recycled Cu(bcmim)2 shows small
crystals with lamellar morphology (Figure 2d), which are similar
to the freshly prepared MOF after treatment with methanol
(Figure 2c). The thermal stability (TG analysis) is identical to the
MOF originally prepared (see Supporting Information). The XPS
analysis after the recycling experiments showed the presence of
copper(II) in the material (see Supporting Information). The
recovered MOF presents the same elemental analysis (see
Supporting Information) and similar percentage of copper
(14.2 % by ICP-OES, see Supporting Information), albeit the
material Cu(bcmim)2 is very slitghly soluble in the amide (i.e. 51
ppm of copper detected by reaction media ICP analysis after
separation of the MOF).
Oxidative coupling between carboxylic acids and
formamides: Kinetic and mechanistic considerations. Based
on our optimisation experiments, the amount of amide has
proved to be important in the process. We confirmed the optimal
amount (18 equiv.) of the amide, and we verified that higher
amounts of amide did not have any positive effect in the reaction
rate (see Supporting Information). Since structurally different
acids provided good results in the amidation reaction, we
wondered if the structure of the acid has any influence in the
reaction rate. Therefore, we set up a competitive experiment
with 4-cyanobenzoic acid and 4-methoxybenzoic acid. As can be
seen in Figure 3, both acids reacted to form the corresponding
amides 10 and 13, being the formation of both independently of
each other. Indeed, both profiles are nearly parallel even when
the concentration of 4-cyanobenzoic acid decreased sooner
than 3,4-dimethoxybenzoic acid. The same behaviour was
observed when 4-cyanobenzoic acid and 4-aminobenzoic acid
were compared in a competitive experiment (see Supporting
Information). This observation suggests that the carboxylic acid
is not involved in the rate of the reaction, but the formamide. To
confirm this proposition, the reaction profiles for different acids
(i.e. benzoic acid, 4-cyanobenzoic acid and 4-aminobenzoic
benzoic acid and 1-formylpiperidine, proving this pathway. Thus,
we set an experiment following the protocol described in Table 3,
and a sample was taken after 5 minutes, observing an 8%
conversion. At this moment in time, TEMPO was added what
produced the termination of the reaction (12% of conversion
after 50 minutes). Based on previous reports,[35] the oxidant
TBHP in the presence of the catalyst (Cu based MOF) forms
radical initiators (such as tert-butoxyl, tert-butylperoxyl, and
hydroxyl) which generate carbamoyl radical A (Scheme 5). Then,
intermediate A may lose CO to form aminyl radical B,[36] which
reacts directly with the acid to form the corresponding amide
product [Scheme 5, Path (a)].[35a] Other authors have proposed
that intermediate A can react with the acid to form intermediate
C, which produces the amide by releasing a CO2 molecule
[Scheme 5, Path (b)].[25,27] Anyway, the reaction starts with the
formation of radical intermediates from the formamide, which is
the rate determining step as it was evidenced.
100
80
60
40
20
0
0
20
40
60
80
100
t (min)
Figure 3. Reaction profile (competitive experiment) for two different carboxylic
acids: (●) 4-cyanobenzoic acid and (■) 3,4-dimethoxybenzoic acid. Reaction
conditions: 4-cyanobenzoic acid (1 mmol), 3,4-dimethoxybenzoic acid (1
mmol), 1-formylpiperidine (2 mL), MOF-[Cu(bcmim)2] (10 mol-%), 100 ºC,
TBHP (70% aqueous solution, 3 mmol).
acid) were recorded showing
a linear formation of the
corresponding amides during the first 60 minutes of the reaction
(see Supporting Information). Therefore, the concentration of the
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European Journal of Organic Chemistry
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FULL PAPER
Entry[a]
x
t (min)
Oxid. Portions (lapse-time)[c]
Yield (%)[d]
24
25
26
1
1.6
1.6
1.6
3.2
1.6
1.6
1.6
3.2
90
1
14
14
14
30
25
31
29
30
4
28
26
20
35
40
47
34
43
2[b]
3
90
1
4
240
270
270
360
600
270
1
3
4
1
10
6
5
5 (10 min)
5 (60 min)
5 (120 min)
10 (10 min)
Scheme 5. Proposed reaction mechanism.
6
5
7
4
Study on the oxidative coupling with dimethylformamide. As
commented in the introduction, the study of oxidative coupling of
carboxylic acids with formamides, mediated by copper catalysts,
have been generally performed with DMF. Thus, we wanted to
test the catalytic activity of MOF-Cu(bcmim)2 with DMF, for
comparison. The coupling reaction between 4-toluic acid and
dimethylformamide in the presence of an oxidant was taken as
model reaction (Table 4). The foreseen product N,N,4-
trimethylbenzamide (24), previously described employing other
copper catalysts,[22-27] was obtained together with N,4-
dimethylbenzamide (25) and N-formyl-N-methylaminomethyl 4-
toluate (26). The N-acyloxymethylamides, such as compound 26,
have been obtained in the oxidative coupling between
phenylglyoxylic acid and DMF using tetrabutylammoninum
iodide (TBAI) as catalyst,[37] but they have never been observed
by copper catalysts. Among the tested oxidants (TBHP, DTBP,
H2O2, UHP, MCPBA and sodium percarbonate) only the TBHP,
both in decane and aqueous solution, produced coupling
products (Table 4, entries 1 and 2). The rest of the oxidants did
not give almost any conversion even after 24 hours (see
Supporting Information), as previously observed for 1-
formylpiperidine. Consequently, the following optimisation steps
were performed using aqueous TBHP solution, since decane
was employed as internal standard. Extending reaction time had
no effect on the yield of products 24 and 25, although yield of
product 26 was slightly lower (Table 4, entry 3). An increase in
the yield of all products was observed when the amount of
oxidant was doubled, being the products in the same ratio
(Table 4, entry 4).
8
5
[a] Reaction conditions: 4-toluic acid (0.25 mmol), DMF (0.5 mL, 25.8
equiv.), TBHP (70% water solution), Cu(bcmim)2 (10 mol% refer to copper,
11 mg), 100 ºC. [b] Reaction performed with TBHP (5.5 m in decane). [c]
Lapse-time, when indicated, is the time between each oxidant portion added.
[d] Yield obtained by GC analysis, using decane as internal standard.
Previously, we evidenced that the addition of the oxidant in
different portions along the reaction time has influence in the
yield of the reaction. Thus, the yield of the products was
modified when the oxidant was added in 5 portions (0.32
equivalents each), being added a portion every 10 minutes
(Table 4, entry 5). Best yield (47%) for product 26 was obtained
when the oxidant was added in 5 portions with 60 minutes lapse-
time, albeit the yield of product 24 was also increased up to 31%
(Table 4, entry 6). Finally, it was observed that neither enlarging
the lapse-time nor the use of higher amount of oxidant had a
positive effect (Table 4, entries 7 and 8).
Additional studies were performed varying the amount of DMF,
and employing different solvents in combination with DMF (see
Supporting Information for further details). The reaction did not
work in polar protic solvents (i.e. methanol and water). The use
of toluene or ethers, such as tetrahydrofuran (THF),
dimethoxymethane (DMM), dimethoxyethane (DME) and tert-
butyl methyl ether (TBME), gave similar ratio of compounds 24
and 26, but with lower yields. The rest of tested solvents (i.e.
hexane, cyclohexane and acetonitrile) decreased drastically the
yield of all products (see Supporting Information for further
details). Undoubtedly, best results were obtained in the absence
of any additional solvent, apart from DMF.
Table 4. Oxidative coupling between 4-toluic acid and DMF: Optimisation.
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European Journal of Organic Chemistry
10.1002/ejoc.201600991
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Scheme 7. Oxidative coupling between 4-toluic acid and DMA.
Conclusions
In summary, we have optimised here the preparation in gram
scale of a metal-organic framework [Cu(bcmim)2] based on
copper and 1,3-bis(carboxymethyl)imidazole. The MOF
preparation is very easy (mild conditions) and with a quantitative
yield. The MOF-Cu(bcmim)2 is an efficient catalyst for the
oxidative coupling reaction between carboxylic acids and
formamides, being the first type of this heterogeneous catalyst
described for this amidation reaction. The optimised protocol
seems to be very robust regardless of the carboxylic acid,
providing the corresponding amides in good conversions and
selectivities. The oxidative coupling proceeds better in an
opened-vessel and with the slow addition of the oxidant.
Moreover, the amidation reaction can be performed in gram
scale, as proved for the preparation of a fatty acid amide (i.e. 1-
palmitoylpiperidine). The MOF is easily recovered at the end of
the reaction, and it has not suffered any modification in its
structure. Therefore, the catalyst can be reactivated by proper
treatment.
Scheme 6. Formation of different radical intermediates form DMF.
After testing different reaction conditions, a mixture of products
was obtained in all tests, being the ratio of the major products 24
and 26 ranging from 1:1.4 to 1:2. Certainly, the MOF-
Cu(bcmim)2 has different catalytic activity than copper salts,
which only produce the amide product 24.[22-27] Although, it has
not been observed previously under copper catalysis, the
formation of both radical intermediates A and D is possible
(Scheme 6)[38] and their formation is energetically comparable.[39]
Indeed, performing the oxidative coupling with N,N-
dimethylacetamide (DMA), instead of DMF, produced
exclusively the acyloxylation product 27 (Scheme 7), since the
Experimental Section
General. All commercially available reagents and solvents were
purchased (Acros, Aldrich, Fluka) and used without further purification.
Melting points were determined using a Gallenkamp capillary melting
1
point apparatus (model MPD 350 BM 2.5) and are uncorrected. H-NMR
and 13C-NMR spectra were recorded at the technical service of the
University of Alicante (SSTTI–UA), employing a Bruker AC-300 or a
Bruker Advance-400. Chemical shifts (δ) are given in ppm and the
coupling constants (J) in Hz. Low-resolution mass spectra (EI) were
obtained at 70 eV with an Agilent 5973 Network spectrometer, with
fragment ions m/z reported with relative intensities (%) in parentheses.
Low-resolution HPLC with electrospray ionization (HPLC-ESI) mass
spectra were recorded at the technical service of the University of
Alicante (SSTTI–UA), employing an Agilent 1100 series apparatus with
the possibility of MS/MS. Infrared spectra were recorded with an FT-IR
4100 LE (JASCO, Pike Miracle ATR) spectrometer. Spectra were
recorded from neat samples and results are given in cm-1. Analytical TLC
was performed on Merck aluminium sheets with silica gel 60 F254, 0.2
mm thick. Silica gel 60 (0.04-0.06 mm) was employed for column
chromatography. P/UV254 silica gel with CaSO4 supported on glass
plates was employed for preparative TLC. The conversion of the
reactions and purity of the products were determined by GC analysis
using a Younglin 6100GC, equipped with a flame ionization detector and
a Phenomenex ZB-5MS column (5% PH-ME siloxane): 30 m (length),
0.25 mm (inner diameter) and 0.25 μm (film). ICP-OES analysis were
performed at the technical service of the University of Alicante (SSTTI–
UA) employing a Perkin Elmer Optima 4300 DV or Perkin Elmer 7300 DV
apparatus. Powder DRX analysis were performed at the technical service
of the University of Alicante (SSTTI–UA) employing a Bruker D8-
Advance apparatus with Göebel Mirror and X-ray generator
KRISTALLOFLEX K 760-80F (Power: 3000 W, Voltage: 20-60 KV y
Current: 5-80 mA).1 DRX pattern simulation was performed with the
software Mercury 3.5.1 (Build RC5). Centrifugation was carried out with a
Nahita Model 2610 apparatus (4000 rpm). TGA analysis were performed
formation of intermediate
A from DMA is not possible.
Furthermore, the formation of a radical in αC to the carbonyl is
disfavoured, both kinetically and thermodynamically, compared
with the formation of a radical nearby the nitrogen.[36,39]
Regarding the mechanism, product 24 can be generated from
radical A as above mentioned in Scheme 5. On the other hand,
intermediate D, which is stabilised by the adjacent nitrogen, can
react with the acid giving the acyloxylation product 26 (Scheme
6).[37] Alternatively, the formation of an iminium intermediate E,
by a subsequent oxidation of D, cannot be completely ruled out
as possible pathway in the formation of 26 (Scheme 6).[40] Finally,
minority product 25 is formed by in situ oxidative demethylation
process.[34,41]
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European Journal of Organic Chemistry
10.1002/ejoc.201600991
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at the technical service of the University of Alicante (SSTTI–UA)
employing a Mettler Toledo TGA/SDTA851e/SF/1100 apparatus.
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General procedure for the synthesis of amides 3-23. The
corresponding acid (1 mmol) and MOF-[Cu(bcmim)2] (10 mol-%, 43 mg)
were placed in a vessel, followed by the addition of the corresponding
amide (2mL). The mixture was stirred at 100 °C while TBHP (70% in
water, 3 mmol, 415 µL) was added slowly over a period of 100 minutes
employing an addition pump. The mixture was allowed to cool down to
room temperature and it was filtered through a pad of silica, celite and
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to 4×10-4 mbar, 55-90 ºC). The corresponding products were obtained
after purification by preparative TLC or column chromatography.
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Keywords: Metal-organic framework • Copper • Carboxyl-
imidazole • Amides • Oxidative coupling
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Entry for the Table of Contents
FULL PAPER
Amide synthesis by oxidative coupling
between carboxylic acids and
formamides mediated by a metal-
organic framework based on copper
and in the presence of an oxidant.
Oxidative coupling
María Albert-Soriano, Isidro M. Pastor*
Page No. – Page No.
Metal-organic framework based on
copper and carboxylate-imidazole as
robust and effective catalyst in the
oxidative amidation of carboxylic
acids using formamides
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