Oxidative amidation of benzaldehyde using a quinone/DMSO system as the oxidizing agent

Article abstract of DOI:10.1039/c9ra02893e

An efficient transition-metal-based heterogeneous catalyst free procedure for obtaining the oxidative amidation of benzaldehyde using quinones as oxidizing agents in low molar proportions is described here. Pyrrolylquinones (PQ) proved to be more suitable

Full text of DOI:10.1039/c9ra02893e

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Oxidative amidation of benzaldehyde using
a quinone/DMSO system as the oxidizing agent†
Cite this: RSC Adv., 2019, 9, 18265
a
a
b
Itzel Mejıa-Farfan, Manuel Solıs-Hernandez,
Pedro Navarro-Santos,
´
´
´
´
a
a
Claudia A. Contreras-Celedon,
Carlos Jesus Cortes-Garcıa
and Luis Chacon-
´
´
´
´
a
Garcıa
*
´
An efficient transition-metal-based heterogeneous catalyst free procedure for obtaining the oxidative
amidation of benzaldehyde using quinones as oxidizing agents in low molar proportions is described
here. Pyrrolylquinones (PQ) proved to be more suitable than DDQ and 2,5-dimethylbenzoquinone to
conduct the oxidation process. Although the solvent itself acted as the oxidant with low to moderate
yields, PQ/DMSO provided an efficient system for carrying out the reaction under operational simplicity,
mild reaction conditions, short reaction times and high yields of the desired product. The scope of the
method was evaluated with substituted benzaldehydes and secondary amines. Theoretical foundations
are given to explain the participation of quinones as an oxidizing agent in the reaction.
Received 17th April 2019
Accepted 3rd June 2019
DOI: 10.1039/c9ra02893e
rsc.li/rsc-advances
important chemical linkage, essential for life because it
forms the structural backbones of proteins. Amides form
Introduction
5
Quinones, as for example 2,3-dichloro-5,6-dicyano-1,4- building blocks in organic synthetic chemistry and are
benzoquinone (DDQ), are used as oxidizing agents in prevalent in a variety of natural products, pharmaceuticals,
1
6
organic synthesis. However, quinones are used as oxidants agrochemicals, polymers, and materials. More than 25% of
in organic synthesis as well as in biological systems. For natural products and drug molecules possess an amide
7
example, 1,4-benzoquinone, that is, ubiquinone, couples bond. Conventional amide synthesis methods involve
NAD and electrons during oxidative phosphorylation in the coupling reactions between amines and carboxylic acids or
2
8
9
10
11
electron transfer chain, toward the synthesis of ATP.
acyl halides, anhydrides, esters, and acyl azides. Cata-
1
2
Hydroquinone, a reduced form of quinone obtained as lytic methods based on transition metals are considered to
a product of the oxidation process, is oxidized to regenerate be environmentally unfavorable. Aldehydes have become
quinone, oen in a simple step in the presence of oxygen. In important scaffolds for the synthesis of amides through
prior studies, we reported the attainment of a new group of oxidative amidation in recent years. Nakagawa et al. rst re-

uoride-recognizing quinone derivatives, the pyrrolyl ported the oxidative amidation of aldehydes with amines in
quinones, from the natural product perezone and from 2,6- the presence of ammonia and stoichiometric amounts of
3
4
dimethyl-1,4-dibenzoquinone 1. The anion recognition nickel peroxide as the oxidant. Recently, several groups re-
1
3
capabilities of these compounds suggested that in addition ported photocatalytic methods based on phenazinium,
to generating radicals, the pyrrolyl quinones were decient Rose Bengal, BODIPY, quinolizinium compounds, and
electron species capable of participating in oxidative addi- hemicyanine derivatives. This paper describes the use of
tion reactions. In this way, the pyrrolyl quinones could pyrrolyl quinones (Scheme 1) as efficient oxidant in the
participate in oxidative amidation, in which an aldehyde is oxidative amidation of benzaldehyde.
oxidized in the presence of an amine and an oxidizing agent
1
4
15
16
1
7
4
to give the amide. The functional group amide is an
Results and discussion
a
The pyrrolyl quinones were obtained from the corresponding
Laboratorio de Dise n˜ o Molecular, Instituto de Investigaciones Qu ´ı mico Biol ´o gicas,
Universidad Michoacana de San Nicol a´ s de Hidalgo, Edif. B-1, Ciudad quinones as summarized in Scheme 2.
Universitaria, Francisco J. M u´ gica, s/n, Morelia 58030, Michoac a´ n, Mexico. E-mail:
Table 1 summarizes the results of the oxidative amidation
lchaco@umich.mx
between 4-nitrobenzaldehyde and pyrrolidine using the
quinones, 1, 2, 4, 4a–4d, 5, 6, and DDQ. Both DDQ and 1,4-
benzoquinone have been tested previously for the same
purposes in comparison with other oxidizing without good
b
CONACYT-Universidad Michoacana de San Nicol a´ s de Hidalgo, Edif. B-1, Ciudad
Universitaria, Francisco J. M u´ gica, s/n, Morelia 58030, Michoac a´ n, Mexico
†
Electronic supplementary information (ESI) available: Spectroscopic
information of compounds and theoretical information. See DOI:
0.1039/c9ra02893e
1
2a,17,18
1
results.
The quantity of oxidizing agent used in this
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favour the reaction by facilitating the nucleophilic attack of
12a,13,14
amine on carbonyl.
We explored the effects of the benz-
aldehyde substituents by conducting the reaction under the
same conditions, but with various substituents at the benzal-
dehyde position 4 (–H, –NO , –OCH , –Cl, and –Br) using
2 3
compound 4c as the oxidizing agent. The results are summa-
rized in Table 2. For the halogen substituents, a change in
solvent from acetonitrile to dimethylsulfoxide provided
a marked yield increase, from 6 to 57% for 4-bromobenzalde-
hyde and from 8 to 71% for 4-chlorobenzaldehyde (Table 2).
In order to evaluate the extent of oxidation to other
secondary amines, the reaction was carried out with diethyl-
amine, dibutylamine, morpholine and piperazine (Table 3).
To give theoretical insights about the participation of
quinones as oxidizing agent, proper forms of the Fukui func-
20
tions, f(r), have been calculated to describe the local reactive
sites of the pyrrolyl quinones. The reactivity is characterized
through f(r), which describe the local changes occurring in the
electron density r(r) due to changes in the number of electrons
N.
Scheme 1 Quinones and pyrrolyl quinones used in this work.
work is very low. In a typical reaction, 0.02 mmol was reacted
with 0.66 mmol aldehyde. The addition of more quinone did
not increase the yield, and the use of less quinone reduced
the yield (Entry 6, 7 and 8, Table 1).
0
The f(r) form of the Fukui functions was used as a stability
descriptor pursuing zones within the pyrrolyl quinones that
0
could stabilize a free radical. The f(r) descriptor indicated
regions in the pyrrolyl quinones in which an unpaired electron
could potentially be localized aer redistribution of the initial
electronic density.
The reaction was carried out in acetonitrile and dime-
thylsulfoxide as both solvents are considered radical stabi-
1
9
lizers.
The change in solvent, from acetonitrile to
0
The highest values of f(r) suggested that the oxygen atoms
dimethylsulfoxide, clearly altered the reaction efficiency, and
the yield increased from 30–54% (input 4) to 85–98% (input
O and O of the quinones were the most favorable sites for
8
9
stabilizing a free radical, with a subtle preference for O
8
over O
9
.
6
) only by swapping acetonitrile with dimethylsulfoxide. For
O
9
participates in non-bonded interactions, whereas O
8
can
quinones 1, 4, 4a, 4b and 4c the advantages of DMSO were
evident.
The pyrrolyl quinones generally provided better yields
than the corresponding quinone parents 1 and 2. The best
performance was obtained from thiocyanate 4c with 98%
yield in very clean reaction (input 6).
The reaction yield obtained from 2.5-dimethyl-1.4-
dibenzoquinone was very low (26%, entry 1). DDQ provided
a 59% yield, but many by-products were produced, compli-
cating the reaction purication processes.
As has been described in previous oxidative amidation work,
the electroatractor groups substituted in the aromatic system
accept one electron to form a radical. Radical formation raises
an interesting question: Do the pyrrolyl quinones accept or
donate the electron? To address this question, we calculated the
+
À
values of f(r) and f(r) of the Fukui functions in the open shell
+
scheme (aer radical formation). The value f(r) provides
information about sites that stabilize incoming charges on the
À
PQs. The value of f(r) gives information about the electron
donor sites from which a charge may “exit” to stabilize the PQs
in a subsequent step.
Table 4 indicates that the highest values of the Fukui func-
+
tion occurred at O
8
, particularly for f(r) . Once the radical
formed, O8 preferably accepted the incoming charge. It is
Scheme 2 Synthesis of pyrrolyl quinones.
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a
Table 1 Oxidative amidation using quinones
b
Yield (%)
DMSO
Selectivity of
product (%)
Entry
Oxidant
R
1
R
2
R
3
CH
3
CN
DMSO
26
Conversion (%)
1
2
1
2
–H
–CH
3
___
___
18
85
52
30.5
55.7
–OH
68
29
3
4
5
6
7
8
4
–H
–H
–H
–H
–H
–H
–CH
–CH
–CH
–CH
–CH
–CH
3
3
3
3
3
3
–H
–Cl
–NO
–SCN
–SCN
–SCN
23
30
55
85
___
___
45
54
64
98
17
81
80
80
100
84
55.5
67.5
80
98
20
4a
4b
4c
2
c
4c
4c
d
e
41
100
41
9
4d
5
–H
–CH
3
42
73
25
33
79
66
31.6
50
1
0
–OH
–H
1
1
1
2
6
–OH
–H
58
21
27
59
78
34.6
DDQ
___
___
___
100
59
a
b
ꢀ
Reagents and conditions: aldehyde (0.66 mmol), pyrrolidine (0.79 mmol), oxidant (0.02 mmol) solvent 2 ml (CH
Isolated yields. Oxidant (0.01 mmol). Oxidant (0.04 mmol). Polar side products were found.
3
CN or DMSO), 70 C, 19 h.
c
d
e
+
important to note that f(r) increased in the presence of DMSO equivalent. Interestingly 1.2 molar equivalents of amine were
by up to 7.2%, in agreement with our proposed mechanism that used, unlike other methodologies, which used 3 molar
1
5,21
the quinones promoted radical formation in the presence of equivalents.
DMSO with synergic effects. reaction than the acetonitrile solvent by increasing the yield
Electron affinity (A), chemical potential (m), hardness (h) and making the reaction cleaner. In previous work, the
The DMSO solvent provided a more efficient
2
2
and electrophilicity (u) [in eV] of benzoquinones calculated oxidative amidation of 2-oxoaldehydes was reported to use
in the presence of CH CN and DMSO support the superiority dimethyl sulfoxide as both the solvent and the oxidizing
of one solvent over another (see ESI† for more details). agent. In this case, the 2-oxoaldehydes possessed a neigh-
3
Radicals are decient species of electrons that can be boring carbonyl group that acted as an electron attractor and
stabilized or destabilized by inductive effects. However, increased the reactivity of the aldehyde during the addition
according to the results, a direct relationship between the of the amine.
inductive capacity of the different substitutes of the pyrrolyl
The increased reactivity facilitated the formation of an
quinones and the yield of the amidation product is not imine intermediary that presumably was responsible for the
appreciable.
oxidation reaction, providing the corresponding amide and
2
2,23
The oxidation reaction was carried out with moderate to releasing dimethyl sulphide.
good yields under mild reaction conditions using very low
The same treatment was applied to the aldehydes in this
amounts of quinone (0.02 mmol equivalents) compared with work, revealing that the quinone addition improved the
the use of peroxide, which required more than 1 molar reaction efficiency and cleanliness in a fraction of the
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a
+
À
Table 2 Oxidative amidation of different aldehydes
Table 4 Condensed forms of f(r) and f(r) , calculated after the radical
formed in the PQs
Gas phase
DMSO
+
À
+
À
f(r)
f(r)
f(r)
f(r)
Compound
O
8
O
9
O
8
O
9
O
8
O
9
O
8
O
9
4
0.184 0.061 0.114 0.075 0.194 0.067 0.122 0.084
0.181 0.069 0.129 0.078 0.194 0.066 0.120 0.083
0.182 0.057 0.125 0.080 0.195 0.063 0.143 0.088
0.184 0.061 0.120 0.078 0.196 0.067 0.138 0.087
4
4
4
a
b
c
Yield (%)
Amide
R
1
DMSO
3
CH CN
7
7
7
7
7
a
b
c
d
e
–NO
–OCH
–H
–Cl
–Br
2
98
86
64
71
57
85
56
35
8
3
and vice versa. A mechanism involving cooperation between
DMSO and quinone is, therefore, feasible.
The mechanism proposed here for the reaction is analogous
to that proposed for a catalyst-free amidation assisted by an
oxidizing agent such as peroxide (Scheme 3).
6
a
Reagents and conditions: aldehyde (0.66 mmol), pyrrolidine (0.79
ꢀ
mmol), 4c (0.02 mmol), solvent (CH CN or DMSO) 70 C, 19 h.
3
Isolated yields.
To verify the participation of oxygen in the proposed mech-
anism, experiments were carried out on acetonitrile and DMSO
in open ask (presence of oxygen) and in argon atmosphere.
reaction time, providing higher amide yields. The results are The results summarized in Table 6 conrmed that oxygen is
summarized in Table 5.
indeed necessary to carry out the reaction. The 30% yield ob-
DMSO radicals have been shown to be stable upon exposure tained with DMSO in inert atmosphere is due to the fact that the
24
to strong Br ¨o nsted–Lowry bases. Although pyrrolidine is not solvent provides oxygen in the oxidation process by releasing
22
a strong base, quinone can promote radical formation in DMSO dimethyl sulphide.
a
Table 3 Reaction of 4-nitrobenzaldehyde with secondary amines
Compound
Amine
Product
Yield (%)
34
8
8
8
a
43
87
b
8
c
32
a
ꢀ
Reagents and conditions: aldehyde (0.66 mmol), amine (1.2 eq), 4c (0.02 mmol), DMSO 2 ml, 70 C, 19 h. Isolated yields.
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Table 5 Oxidative amidation in DMSO with and without quinone 4c
Conclusions
In conclusion, we have developed an efficient, metal-free
oxidative amidation method under moderate reaction condi-
tions with high yields which is, to our knowledge, the rst
report of this type of oxidation carried out by an organic
oxidizing compound that is neither photoinductive nor
peroxide. The solvents used in this work, acetonitrile and
dimethylsulfoxide, are considered radical stabilizers that favor
the formation of quinoid radicals generated by pyrrolylquinone
facilitating the course of the reaction. We found that unlike
acetonitrile, DMSO is able to carry out the oxidative amidation
reaction of benzaldehyde in the absence of additive or catalyst
although in low performance but interestingly, the reaction
carried out in the presence of pyrrolylquinone/DMSO makes the
Yield (%)
a
b
Entry
Amide
R
1
DMSO
DMSO/4c
1
2
3
4
5
7a
7b
7c
7d
7e
–NO
–OCH
–H
–Cl
–Br
2
30
21
16
19
14
98
86
64
71
57
3
a
Reagents and conditions: aldehyde (0.66 mmol), pyrrolidine (0.79 reaction highly efficient.
ꢀ
b
mmol), DMSO 2 ml, 70 C, 19 h. Reagents and conditions: aldehyde
(
7
0.66 mmol), pyrrolidine (0.79 mmol), 4c (0.02 mmol), DMSO 2 ml,
0 C, 19 h. Isolated yields.
ꢀ
Conflicts of interest
There are no conicts to declare.
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ꢀ
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