Synthesis of Imidazoles from Fatty 1,2-Diketones

Article abstract of DOI:10.1002/ejoc.202100053

Unsaturated vegetable oils and their corresponding fatty acid derivatives constitute interesting renewable platforms for the preparation of heterocycles, notably through the formation of oxygenated intermediates. In this work, fatty imidazoles were prepared from the corresponding 1,2-diketones through Debus-Radziszewski reaction. The reaction was optimized under microwave irradiation using a 1,2-diketone derived from methyl oleate and ammonium acetate as a nitrogen source. Using benzaldehyde as a model substrate, the reaction occurs at 180 °C for 5 min and the desired imidazole was formed in 96 % GC yield. A range of aldehydes was tested under the optimized conditions and the corresponding imidazoles were obtained in 33–99 % isolated yields (20 examples).

Full text of DOI:10.1002/ejoc.202100053

Communications
doi.org/10.1002/ejoc.202100053
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Synthesis of Imidazoles from Fatty 1,2-Diketones
Mansouria Bouchakour,[a, b] Mortada Daaou,[b] and Nicolas Duguet*[a]
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irradiation,[22] are particularly interesting considering that imida-
zoles are biologically-relevant targets that should be exempt of
any traces of metals.
Most of reported methods are only focussing on the
preparation of imidazoles from aromatic substrates such as
benzil or benzoin derivatives. In sharp contrast, the use of
aliphatic α-hydroxyketones or 1,2-diketones has been by far
less studied and it usually only concerns butanedione or
acetoin.
Unsaturated vegetable oils and their corresponding fatty acid
derivatives constitute interesting renewable platforms for the
preparation of heterocycles, notably through the formation of
oxygenated intermediates. In this work, fatty imidazoles were
prepared from the corresponding 1,2-diketones through Debus-
Radziszewski reaction. The reaction was optimized under micro-
wave irradiation using a 1,2-diketone derived from methyl
oleate and ammonium acetate as a nitrogen source. Using
benzaldehyde as a model substrate, the reaction occurs at
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Vegetable oils are interesting renewable resources for the
chemical industry. For example, they can be transformed to
biodiesel,[23] fine chemicals[24] and polymers.[25] Considering their
low environmental impact, they have already found numerous
applications in paints, packaging materials, lubricants, surfac-
tants, cosmetics and pharmaceuticals. Unsaturated fatty deriva-
tives are particularly interesting as they can be functionalized to
give a wide range of reactive groups such as aldehydes,
ketones, 1,2-diols, α-hydroxyketones and diketones.[24] More-
over, the double bond is an excellent site for the construction
of carbocycles such as cyclopropanes[26] and heterocycles such
as epoxides,[27] aziridines,[28] episulfides[29] and carbonates
(Scheme 1).[30] In particular, Fürmeier and Metzger have shown
that nitrogenated heterocycles can be produced from unsatu-
rated fatty acids such as tetrazoles, 4,5-dihydrooxazoles,
oxazolidines, oxazoles and imidazoline-thione.[31] To the best of
our knowledge, only one example of a fatty imidazole was
reported by the authors,[31] obtained by reacting a fatty α-
hydroxyketone with formamide through a Bredereck reaction.[32]
Within the frame of a research programme aiming at the
valorization of vegetable oil derivatives,[33] we have recently
reported a clean access to fatty α-hydroxyketones from the
corresponding 1,2-diols by either palladium-catalyzed selective
oxidation using oxygen as a clean oxidant or by ruthenium-
°
180 C for 5 min and the desired imidazole was formed in 96%
GC yield. A range of aldehydes was tested under the optimized
conditions and the corresponding imidazoles were obtained in
33–99% isolated yields (20 examples).
The imidazole core is naturally occurring in some molecules of
life such as histidine and histamine and is also present in a wide
range of natural products.[1] Moreover, it is encountered in
many biologically active molecules exhibiting a wide variety of
properties such as anti-inflammatory[2] and inhibition of p38
MAP kinase.[3] Furthermore, some of imidazole-containing
molecules have also antiviral,[4] antimicrobial,[5] antifungal[6] and
antitumoral[7] activities. In addition to these biologically-relevant
properties, imidazoles are also encountered in organic
chemistry such as in carbonyldiimidazole (CDI),[8] ionic liquids[9]
and N-hetererocyclic carbenes, that serve both as
organocatalysts[10] or ligands[11] for organometallic complexes.
The Debus–Radziszewski reaction allows the straightforward
synthesis of imidazoles from 1,2-diketones, aldehydes and a
source of ammonia such as ammonium acetate.[12] In this
respect, it is a useful multi-component reaction (MCR) that can
be used to generate libraries of compounds.[13] A large variety
of catalysts have been reported to promote the reaction
including organocatalysts,[14] (acidic) ionic liquids,[15] Brönsted
acids,[16] Lewis acids[17] and their supported versions,[18] and
metal oxides.[19] In this vast field, recent advances concern the
use magnetically recoverable catalytic systems.[20] Alternatively,
catalyst-free
conditions,[21]
notably
using
microwave
[a] M. Bouchakour, Dr. N. Duguet
Univ Lyon, CNRS, INSA-Lyon, CPE-Lyon, Institut de Chimie et Biochimie
Moléculaires et Supramoléculaires,
ICBMS, UMR 5246, Equipe CAtalyse, SYnthèse et ENvironnement (CASYEN),
Université Claude Bernard Lyon 1
Bâtiment Lederer, 1 rue Victor Grignard, 69100 Villeurbanne, France
E-mail: nicolas.duguet@univ-lyon1.fr
[b] M. Bouchakour, Prof. M. Daaou
Faculté de Chimie, Département de Chimie Organique lndustrielle
Laboratoire de Synthèse organique, Physico-chimie, Biomolécules et
Environnement (LSPBE)
Université des Sciences et de la Technologie d’Oran (USTO) Mohamed
Boudiaf
Scheme 1. Selected heterocycles from unsaturated fatty acids (represented
for methyl oleate, some are mixture of regioisomers).
BP 1505, El’Mnaouer, Oran, 31000, Algeria
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catalyzed dehydrogenation.[33b] Moreover, the corresponding
fatty 1,2-diketones were also prepared by oxidation of α-
hydroxyketones, using oxygen.[33f] With a clean access to fatty
1,2-diketones in hands, we now report the synthesis of
imidazoles from these starting materials through Debus–
Radziszewski reaction (Scheme 2).
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4
The 1,2-diketone derived from methyl oleate was selected a
model substrate for the optimization of the reaction parameters
considering that methyl oleate is by far the most available fatty
acid methyl esters. It was prepared through a four-step
sequence from commercially available methyl oleate (96%
purity) (Scheme 3). First, methyl oleate 1 was epoxidized using
H2O2 in the presence of formic acid to give epoxide 2 in 96%
yield. Next, hydrolysis of the epoxide gave the corresponding
1,2-diol 3 in 90% yield. Then, fatty α-hydroxyketone 4 was
prepared by selective oxidation using oxygen (3 bar) in the
presence of Pd(OAc)2 and neocuproine and was isolated in
80%. Finally, oxidation of the α-hydroxyketone under oxygen
(1 atm) in the presence of VOCl3 gave the desired 1,2-diketone
5 in 90% yield (62% overall yield over 4 steps).
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Scheme 2. Imidazoles from fatty 1,2-diketones through Debus-Radziszewski
reaction.
First, the reaction was carried out using benzaldehyde
(1 equiv) and 2 equivalents of ammonium acetate in acetic acid
°
(Table 1). After only 5 min at 180 C under microwave
irradiation,[22] the conversion of 5 reached 77% and the desired
imidazole 6 was obtained in 70% GC yield (Table 1, entry 1).
Progressively increasing the amount of NH4OAc from 2 to 5
equivalents led to an increase in both conversion and yield
(Table 1, entries 2–4). Satisfyingly, with 5 equivalents, the
conversion was complete and the yield of imidazole 6 reached
98% (Table 1, entry 4). Further increasing the amount to 10
equivalents led to a slight decrease of yield to 95%, probably
due to the formation of side-products (Table 1, entry 5). The
effect of the temperature was also studied using 5 equivalents
°
of NH4OAc. From 120 to 160 C, the conversion increased from
85 to >99% and the yield of 6 from 75 to 99% (Table 1, entries
6–8). This indicates that the reaction was also very efficient at
°
°
160 C, however, we preferred to select a temperature of 180 C
for further studies, notably for the conversion of less reactive
aldehydes.
Scheme 3. Preparation of fatty 1,2-diketone from methyl oleate.
Table 1. Optimization of reaction conditions.[a]
The scope was first investigated under the optimized
conditions using aromatic aldehydes [aldehyde (1 equiv),
°
NH4OAc (5 equiv), 180 C, 5 min)] (Figure 1). With benzaldehyde,
fatty imidazole 6 was obtained in 60% isolated yield, after
purification by column chromatography. The moderate yield
obtained is explained by the fact that the purification of such
species proved to be laborious, probably due to their
amphiphilic nature. Starting from 4-phenylbenzaldehyde and 4-
anisaldehyde, imidazoles 7 and 8 were obtained in 51 and 33%
yield. The influence of the substitution pattern of the aromatic
aldehydes was studied using ortho-, meta- and para-tolualde-
hyde. Expectedly, the yield of fatty imidazole 9 (with para-
tolualdehyde) was found to be superior to those of imidazoles
10 and 11 bearing meta- and ortho-methyl substituent,
probably for steric reasons.
Entry
NH4OAc
(equiv)
T
Conv.[b]
[%]
5
GC Yield[b]
[%]
6
°
[ C]
1
2
3
4
5
6
7
8
2
2.5
3
5
10
5
5
180
180
180
180
180
120
140
160
77
93
99
>99
>99
85
96
>99
70
83
91
98
95
75
91
99
Para-halogenated benzaldehydes were also considered.
With a bromine, chlorine and flurorine, the corresponding
imidazoles 12–14 were isolated in 50, 43 and 45% yield,
respectively. 1- and 2-naphthaldehyde gave imidazoles 15 and
16 in 45 and 47% yields, respectively. More challenging
5
[a] Reaction conditions: 10-mL microwave tube, diketone
5
(65 mg,
0.2 mmol), benzaldehyde (0.2 mmol, 1 equiv), NH4OAc (2-10 equiv), AcOH
°
(2 mL), 120–180 C, 5 min. [b] Conversion and yields were determined by
gas chromatography using hexadecane as an internal standard.
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indicating that the free hydroxyl group has a negative impact
on the reaction outcome. Finally, fatty imidazole 19, incorporat-
ing a furfural moiety, was isolated in 47% yield.
1
2
3
The scope of the reaction was also investigated with
diketone 5 using a range of aliphatic aldehydes (Figure 2).
Paraformaldehyde was used as a source of formaldehyde and
the desired imidazole 20 was obtained in an excellent 98%
yield. Linear aliphatic aldehydes were also considered such as
butanal, nonanal and dodecanal. Satisfyingly, the corresponding
products 21–23 were isolated in 77–99% yield. Using branched
aldehydes such as isobutyraldehyde and pivalaldehyde gave
fatty imidazoles 24 and 25 in 98 and 80% yield, respectively.
Overall, aliphatic aldehydes are giving better results than
aromatic aldehydes, due to the fact that they are more reactive.
Consequently, almost no by-product was formed when using
aliphatic aldehydes. In most cases, the crude product did not
require further purification by column chromatography after
the work-up of the reaction, so the desired fatty imidazoles
were isolated with high yields.
Considering that fatty diketone 5 was prepared from the
corresponding α-hydroxyketone 4, we envisioned that the
Debus–Radziszewski reaction could also be carried out from
this substrate (Table 2). The reaction was first performed under
an argon atmosphere, however, the desired product 6 was
obtained with only 17% GC ratio under these conditions
(Table 2, entry 1). Interestingly, fatty imidazole 26, bearing a N-
benzyl group, was formed in 78% GC ratio under these
conditions. Consequently, the reaction was repeated under
oxygen atmosphere, either to promote the initial oxidation of 4
to diketone 5 or to facilitate the final oxidation of an imidazo-
line to the imidazole core (Table 2, entry 2). However, the GC
ratio of imidazole 6 dropped to 6% under these conditions.
Nevertheless, N-benzylated imidazole 26 was still obtained as
the major product (80% GC ratio), along with an unidentified
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Figure 1. Scope of aromatic aldehydes for the synthesis of fatty imidazoles.
aldehydes, such as 4-(benzyloxy)benzaldehyde, 3-hydroxyben-
zaldehyde and furfural were considered. Imidazole 17 was only
formed in 48% yield due to the difficulty to fully convert the
aldehyde. Imidazole 18 was also obtained in only 41% yield,
Figure 2. Scope of aliphatic aldehydes for the synthesis of fatty imidazoles.
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Table 2. Debus–Radziszewski reaction from fatty α-hydroxyketones.[a]
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2
3
4
5
6
7
8
9
Entry
Atmosphere
ArCHO
(equiv)
Conv.[b] 4 (or 27)
[%]
GC ratio[b]
X:6(28):26(29) [%]
1[c]
2[c]
3[c]
4[d]
Ar
O2
Ar
Ar
Ph (1)
Ph (1)
Ph (2)
o-tol (2)
>99
>99
>99
>99
5:17: 78
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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43
44
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14:6:80
0:4:96 (59%)[e]
0:4:96
[a] Reaction conditions: 10-mL microwave tube, α-hydroxyketone 4 or 27 (0.4 mmol), benzaldehyde or ortho-tolualdehyde (1 or 2 equiv), NH4OAc (308 mg,
4 mmol, 10 equiv), AcOH (2 mL), 180 C, 5 min. [b] Conversion and GC ratio were determined by gas chromatography. X represents an unidentified
byproduct. [c] Using α-hydroxyketone 4. [d] Using α-hydroxyketone 27. [e] Isolated yield in brakets.
°
by-product. Considering that 26 is a compound of interest, the
reaction was repeated using 2 equivalents of benzaldehyde
under argon atmosphere (Table 2, entry 3). Under these con-
ditions, the product was obtained in 96% GC ratio and was
isolated in 59% after purification by column chromatography.
Finally, the reaction was also performed using α-hydroxyketone
27, derived from methyl erucate, and ortho-tolualdehyde as a
bulkier aldehyde (Table 2, entry 4). Satisfyingly, the desired
imidazole 29 was also obtained with 96% GC ratio. This result
shows that the use of a more sterically demanding aldehyde
does not affect the ratio between NH-free and N-benzyl
derivatives.
imine I that tautomerizes to II, then to an α-aminoketone III
(Scheme 4).
A second condensation with ammonia would give imine IV
that tautomerizes to diamine V. This diamine would form an
imine VI in the presence of benzaldehyde, followed by ring
closure to give a fatty imidazoline VII. Oxidation of intermediate
VII gives imidazole 6. Alternatively, imidazoline VII could react
with a second equivalent of benzaldehyde to form iminium VIII,
that tautomerizes to give N-benzylated imidazole 26 upon
dehydration. This final tautomerization is driven by the
aromatisation of the imidazoline to the imidazole. An alter-
native mechanism is also possible, in which benzaldehyde first
reacts with ammonium acetate to give benzylamine, that adds
onto either 4 or intermediate III to give the desired imidazole
The formation of 26 from α-hydroxyketone 4 would involve
a condensation with a first equivalent of ammonia to form an
Scheme 4. Mechanism proposal for the formation of N-benzylated fatty imidazole 26 using two equivalents of aldehydes under argon atmosphere.
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Conflict of Interest
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3
The authors declare no conflict of interest.
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Keywords: Aldehydes · Debus-Radziszewski reaction · 1,2-
Diketones · Fatty acids · Imidazoles
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Scheme 5. Complementarity between Debus-Radziszewski reactions using
fatty diketone or α-hydroxyketone.
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26, after addition of a second equivalent of benzaldehyde and
subsequent aromatisation. This would be similar to the reported
four-component reactions using benzaldehyde and benzyl-
amine to produce tetra-substituted imidazoles from α-
hydroxyketones.[15c,34] This alternative mechanism would require
the presence of oxygen or air for the final oxidation step.
However, it cannot be fully ruled out that the presence of
adventitious oxygen is involved.
Overall, Debus–Radziszewski reactions on either α-hydrox-
yketone or diketone are complementary considering that they
are giving the N-benzylated or the NH-free imidazole, respec-
tively (Scheme 5).
To conclude, we have reported here the preparation of fatty
imidazoles from a 1,2-diketone derived from methyl oleate
through a Debus–Radziszewski reaction. The reaction was
optimized under microwave irradiation using a stoichiometric
amount of aldehyde and an excess of ammonium acetate in
acetic acid. A range of aromatic and aliphatic aldehydes were
tested and the corresponding fatty imidazoles were obtained in
33–99% isolated yields (20 examples). Interestingly, the reaction
affords the N-benzylated imidazole when starting from the
corresponding α-hydroxyketone using 2 equivalents of benzal-
dehyde.
Acknowledgements
The authors thank the “Université des Sciences et de la
Technologie d’Oran (USTO) Mohamed Boudiaf“ (Algeria) for a
preliminary grant for M.B. The Algerian “Ministry of Higher
Education and Scientific Research” is also acknowledged for
further financial support to M.B. within the frame of the
“Programme National Exceptionnel“ (PNE, 2019–2020). “La Direc-
tion Générale de la Recherche Scientifique et du Développement
Technologique (DGRSDT)“ is also thanked for financial support. T.
De Dios Miguel (team CASYEN, ICBMS) is acknowledged for
sharing some fatty diketone.
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Manuscript received: January 18, 2021
Revised manuscript received: February 24, 2021
Accepted manuscript online: March 1, 2021
Eur. J. Org. Chem. 2021, 1647–1652
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