Multicomponent Synthesis of Structurally Diverse Imidazoles Featuring Azirines, Amines and Aldehydes

Article abstract of DOI:10.1002/ejoc.201800687

A novel and efficient method for the synthesis of structurally diverse imidazoles through a multicomponent reaction involving an azirine, an amine, and an aldehyde is described. The method is simple and environmentally benign, producing multifunctionalized imidazoles in moderate-to-good yields and in a regioselective manner, which was demonstrated by NMR experiments and X-ray analysis. A mechanism is proposed in which the amine participates not only as a reactant, but also as a nucleophilic reaction promoter.

Full text of DOI:10.1002/ejoc.201800687

A Journal of
Accepted Article
Title: Multicomponent Synthesis of Structurally Diverse Imidazoles
Featuring Azirines, Amines and Aldehydes
Authors: Thaís Andreia Rossa, Mariane Fantinel, Adailton João
Bortoluzzi, and Marcus Mandolesi Sa
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800687
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800687
Supported by

10.1002/ejoc.201800687
European Journal of Organic Chemistry
FULL PAPER
Multicomponent Synthesis of Structurally Diverse Imidazoles
Featuring Azirines, Amines and Aldehydes
Thaís A. Rossa,[a] Mariane Fantinel,[a] Adailton J. Bortoluzzi,[a] Marcus M. Sá*[a]
Abstract: A novel and efficient method for the synthesis of structurally
diverse imidazoles through a multicomponent reaction involving an
azirine, an amine, and an aldehyde is described. The method is
simple and environmentally benign, producing multifunctionalized
imidazoles in moderate-to-good yields and in a regioselective manner,
which was demonstrated by NMR experiments and X-ray analysis. A
mechanism is proposed where the amine participates not only as a
reactant, but also as a nucleophilic reaction promoter.
trisubstituted imidazoles and lack of structural diversity,motivates
the development of green and efficient methods.17,18
In recent years, the synthesis of imidazoles employing
azirines or their precursors as starting materials has been actively
pursued. Pusch & Opatz proposed the intermediacy of acyl azirine
I in the synthesis of tetrasubstituted imidazoles through a
photochemical one-pot reaction between isoxazole II, an -
aminonitrile, and an aldehyde (Scheme 1).19 The synthesis of tri-
and tetrasubstituted imidazoles from vinyl azides III and amines
under oxidative conditions was independently reported by the
research groups of Maurya20,21 and Yan.22 Both authors proposed
the in situ generation of azirines IV through thermolysis or
photolysis of the corresponding vinyl azides III. Similarly, Yu and
co-workers developed a method for the synthesis of trisubstituted
imidazoles from activated imidates and -azido enoates or
enones (III, R1 = electron-withdrawing group, EWG), possibly
involving the intermediacy of azirine IV.23
Introduction
The increasing environmental awareness of the chemical
community within the past two decades has boosted the
development of reliable synthetic strategies to produce useful
chemicals in a simple and sustainable way.1 In this context,
azirines have been recognized as versatile building blocks in
organic synthesis, being able to undergo ring expansion reactions
under mild conditions, mainly due to the ring strain of the
unsaturated three-membered ring.2 Nevertheless, substituted
azirines are usually stable and can be stored for long periods.
Over the years, significant studies have been reported on the
synthesis of N-heterocycles from azirines,3-8 including, among
others, pyrazines, pyrroles, oxazoles, indoles, and imidazoles.9-11
Imidazoles are a major class of heterocyclic compounds,
being highly relevant in medicinal chemistry and materials
science. Imidazoles and analogues are related to a broad
spectrum of biological properties, such as anti-inflammatory,
antitumor, antifungal, antimicrobial, and antiparasitic activity.12-14
Due to its unique acid-base character, the imidazole scaffold is
also very useful for the creation of advanced materials, including
ionic liquids15 and functionalized catalysts.16 The substitution
pattern of the imidazole ring is frequently associated with the
chemical, physical, and biological properties of the resultant
compound and can modulate its potential application. Thus, the
development of simple and efficient strategies for the selective
preparation of structurally diverse imidazoles is highly desirable.
The conventional approach for the synthesis of
tetrasubstituted imidazoles usually employs a 1,2-diketone, an
aldehyde, an amine and an ammonia source. However,
significant limitations, such as competitive formation of
R3
O
R2
R3
R2
O
N
N
h
H2N
CN
O
R1
N
N
R4CHO
R1
R2
II
I
R1
R4
Opatz (ref. 19)
R4
R3
N
R3
N3
R1
N
R4
or h
 N2
H
N
N
R1
R2
R2
Ag2CO3, 
or [Ru]/h
IV
R1
R2
III
V
Maurya (ref. 20 & 21)
R3
NH
R3
R3 NH2 (3 equiv)
R3 LG, 
N
NH
EWG
N
N
R3
I2/TBHP, R2 = H)
Yan (ref. 22)
(R1 = EWG)
R2
R1
Yu (ref. 23)
Scheme 1. Previous synthesis of imidazoles from isoxazoles II or vinyl azides
III through the possible intermediacy of azirines I or IV.
The direct synthesis of imidazoles from azirines can be
achieved by treating IV with imines in the presence of
stoichiometric amounts of Lewis acids, as demonstrated by
Auricchio24 and later by Pinho e Melo25 (Scheme 2). Although the
expected imidazole V has been obtained as a sole product in a
number of cases, the regioselectivity is strongly dependent on the
substitution pattern at the azirine ring25 as well as on the reaction
conditions.24 Therefore, further progress in the selective synthesis
of imidazoles from azirines is needed in order for this to be
considered a simple and reliable process.
[a]
Departamento de Química, Universidade Federal de Santa
Catarina, Florianópolis, SC 88040-900, Brazil. E-mail address:
marcus.sa@ufsc.br
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800687
European Journal of Organic Chemistry
FULL PAPER
R3
R3
After defining the best conditions (Table 1, entries 6, 7, 11),
the scope of the multicomponent transformation was investigated
in detail. The reactions were carried out using representative
aromatic as well as aliphatic aldehydes and primary amines
containing several functionalities, evidencing the broad scope of
this method (Scheme 3).
R3
N
R4
N
R4
R4
N
N
N
N
vs
R2
Lewisacid
R1
Auricchio (ref. 24)
IV
R1
R2
R1
R2
Pinho e Melo
(ref. 25)
V
V'
- Multicomponenttransformation
- Catalyst-free and metal-free
(solvent-free in several cases)
- Ambient conditions
- Moisture-insensitive
- High atom economy
O
R3
Table 1. Optimization of reaction conditionsa
R4
R3
R4NH2
H
N
N
R1
R2
NH2
This work
V
- Functional group tolerance
2a
O
N
Scheme 2. Synthesis of imidazoles from azirines IV.
25 °C
4a
N
N
+
CO2Me
H
Ph
The development of a simple, yet efficient, protocol for the
synthesis of imidazoles from azirines requires readily available
starting materials. In addition, the procedure should involve mild
and environmentally friendly conditions, offer high atom economy
and excellent tolerance to functional groups, and possibly
generate structurally diverse imidazoles in a single synthetic
operation.
While the participation of small-ring heterocycles in domino
and multicomponent transformations has been recently
reviewed,26 only one report on the multicomponent reaction
involving azirines could be found in the literature.7 Herein, we
report a novel and straightforward procedure for the synthesis of
type V tetrasubstituted imidazoles through a three-component
reaction involving azirines IV, aldehydes and amines at room
temperature (Scheme 2). The conditions employed here are
extremely simple, without any addition of Lewis acid, additive or
oxidant agent, and is solvent-free in several cases.
1a
3a
CO2Me
Yield (%)b
Ph
Entry
2a (equiv)
3a (equiv)
Solvent
Time (h)
c
1
2
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.0
1.1
1.5
1.3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.3
1.1
1.1
EtOAc
CH3CN
PEG
24
7
-
67
51
52
56
74
60
3
7
4
H2O
7
5
tBuOH
iPrOH
-
iPrOH
iPrOH
iPrOH
iPrOHd
7
6
7
7
7
c
8
24
24
7
-
c
9
-
10
11
73
80
24
[a] The reaction was monitored by TLC until the total consumption of azirine 1a.
[b] Yields of isolated imidazole 4a after column chromatography. [c] Incomplete
conversion to 4a (< 80%, measured by 1H NMR). [d] Na2SO4 (350 mg/mmol 1a)
was added to the reaction.
The reactions using aromatic aldehydes performed
satisfactorily under neat conditions as well as with PrOH as the
Results and Discussion
i
solvent. For the aliphatic aldehydes, however, the solvent-free
conditions were generally inefficient and the best yields were
achieved in alcoholic medium. The reaction also worked well with
substituted azirines 1b and 1c, giving the expected imidazoles 4o-
q in moderate-to-good yields.
Azirine 1a, benzylamine (2a) and tolualdehyde (3a) were
used as model substrates for the initial experiments. Several
environmentally benign solvents27,28 were evaluated (Table 1,
i
entries 1-6), with the most effective being PrOH, which gave
imidazole 4a in 74% isolated yield (entry 6). The reaction under
neat conditions also showed encouraging results, furnishing
imidazole 4a in fair isolated yield (entry 7).
For the preparative synthesis of imidazoles 4, the
multicomponent reaction starting from
3
mmol of the
corresponding azirine 1 was carried out to give the expected
product in yield and purity comparable to those obtained from a
0.5-mmol scale.
Remarkably, the reaction is strongly dependent on the
amine/aldehyde ratio (Table 1, entries 6, 8-10), with the optimal
results being observed when amine 2a is in slight excess relative
to the aldehyde 3a (entries 6 and 10). Conversely, the use of
equal amounts of 2:3 (entry 8) or an incremental excess of
aldehyde 3a (entry 9) was detrimental to the reaction rate. Several
additives were also tested, but, as a rule, they exerted little or no
influence on the outcome of the reaction (results not shown). The
only notable result was that the use of anhydrous Na2SO4, which
possibly acts as a desiccant agent, provided the expected
imidazole 4a in slightly better yield, but at the expense of a
prolonged reaction time (entry 11).
Imidazole-4-acetates
4
were fully characterized by
spectroscopic analysis, including 2D NMR techniques, which
confirmed the proposed structure and ruled out the formation of
the regioisomeric imidazole-5-acetate (Supp Info: Fig. S52 and
S53). The unequivocal structural determination of multisubstituted
imidazoles 4 was also achieved by single crystal X-ray methods
after crystallizing 4a in methanol and 4l in ether/hexane (Fig. 1).29
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10.1002/ejoc.201800687
European Journal of Organic Chemistry
FULL PAPER
R3
N
R = Ph, R1 = CO2Me
O
R2
Neat or iPrOH
1-24 h, 25 °C
1a
1b
N
N
R1
R = Ph, R1 = OH
R2NH2
+
+
R
R3
H
1c R = Et, R1 = CO2Me
R1
R
2
1
3
4
F
O
OMe
O
Br
N
N
N
N
N
N
N
N
N
N
N
N
CO2Me
CO2Me
4a
60% (7 h)a
74% (7 h)b
80% (24 h)c
CO2Me
CO2Me
4d
51% (3 h)b
CO2Me
CO2Me
4c
50% (24 h)a
69% (24 h)b
47% (24 h)c
4b
4e
4f
64% (2 h)b
64% (3 h)a
62% (24 h)b
63% (24 h)c
64% (5 h)a
NO2
N
NH
N
N
N
N
N
N
CO2Me
N
N
CO2Me
CO2Me
N
N
N
N
4l
4j
4k
CO2Me
32% (3 h)a
83% (3 h)b
31% (1 h)a
70% (1 h)c
33% (3 h)a
70% (3 h)b
CO2Me
CO2Me
4h
51% (4 h)b
4i
47% (19 h)a
4g
39% (24 h)c
HN
O
N
O
N
N
N
N
N
N
N
N
N
N
OH
CO2Me
4m
53% (3 h)a
CO2Me
OH
CO2Me
4n
66% (1 h)b
4o
70% (24 h)b
4p
55% (1 h)b
4q
40% (3 h)b
b
a Reaction conducted without solvent (neat conditions); Using iPrOH as the solvent; c Using iPrOH as the solvent with addition of Na2SO4.
Scheme 3. Multicomponent synthesis of tetrasubstituted imidazoles 4.
(Scheme 4). In fact, imine 6a (prepared from amine 2a and
aldehyde 3a through conventional methods)30 was found to react
with azirine 1a to give the expected imidazole 4a. However, the
reaction rate was much slower (24 h, 55%) than the
multicomponent reaction starting from the precursors 2a and 3a.
Repeating the reaction between equimolar amounts of azirine 1a
and imine 6a, but in the presence of 0.2 equiv of amine 2a, led to
a complete conversion to imidazole 4a with a reaction rate
comparable to that observed for the multicomponent process.
This result is in line with the previous observation that a slight
excess of amine is highly beneficial in terms of the reaction rate
(see Table 1, entries 6, 8-10).
Therefore, it seems clear that amine 2 exerts a dual role,
Figure 1. ORTEP plots of imidazoles 4a and 4l; ellipsoids are drawn at
acting not only as a reagent but also as a reaction promoter. In
the 40% probability level
fact, when azirine 1a is treated with amine 2 in the absence of
aldehyde, both starting materials are rapidly consumed to give
To rationalize the mechanism of this multicomponent
rise to a -imino--enamino ester 7 as the major product (Scheme
process, the reaction profile was studied in more detail.
4). This transformation can be rationalized by considering an
Monitoring the reaction by NMR and LC-MS revealed, as
initial attack of amine 2 on the electrophilic C=N bond in azirine 1
expected, the presence of imine 6 as an intermediate, originating
to generate the addition adduct 8, which could be evidenced by
from a fast condensation involving amine 2 and aldehyde 3
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10.1002/ejoc.201800687
European Journal of Organic Chemistry
FULL PAPER
monitoring the reaction profile by mass spectrometry (R = Ph, R1
= CO2Me, R2 = Bn: MH+, m/z = 297). Subsequent ring opening of
aziridine 8 followed by spontaneous air oxidation of 9 would lead
to 7, which had its structure assigned through 1H NMR, 13C NMR,
IR, and HRMS analyses. However, full characterization was
precluded due to its partial decomposition on attempted
purification by chromatography.
All of these observations are interconnected and support the
following mechanistic pathway (Scheme 4). Initially, there is
competition between the reversible nucleophilic attack of amine 2
on aldehyde 3 (to form imine 6) and that on azirine 1 (to generate
adduct 8). Once they are formed, these two intermediates react
with each other in the next step through nucleophilic addition to
furnish the tetracomponent adduct 10, which may isomerize to the
ring-opening forms 11 followed by the elimination of amine 2,
which gives rise to one or more of the isomers 12, as noted from
the MS analysis (R = Ph, R1 = CO2Me, R2 = Bn, R3 = 4-MePh:
MH+, m/z = 399). Subsequent air oxidation in the last step
provides the aromatic imidazole framework 4.
O
O
N
N
R3
H
base
Ph
OMe
Ph
CO2Me
Ref. 31
1a
13
R3
R3
This work
R2
R3
O
N
N
N
N
O
R2
6
CO2Me
(not observed)
CO2Me
14 (50-75%)
Ph
Ph
+
R2NH2
R3
H
5
Scheme 5. Proposed base-mediated mechanism for the ring-opening of azirine
1
.
The tetrasubstituted imidazoles 4 obtained by this method are
structurally diverse scaffolds that can be readily manipulated to
improve the chemical complexity. To further demonstrate the
synthetic potential of imidazoles 4 as useful building blocks, we
designed an intramolecular palladium-catalyzed Heck reaction32
for the synthesis of an analogue of zolpidem,33 a sedative used
for the treatment of sleep disturbances. Accordingly, starting from
imidazole 4c, the microwave-assisted intramolecular coupling
was successfully achieved in a short time to give the expected
fused tricycle 15 in good isolated yield (Scheme 6).
R2
H
R3
N
O
R2NH2
+
H
+
HN
R1
R3
H
R2 NH NH
2
R
1
3
11'
R2NH2
R
R1
R3
H
N
H
N
R2
R3
NR2
H
R2
HN
N
6
H
PdCl2(PPh3)2
Br
H
(10 mol%)
R3
H
H
N
R2 N
R2
N
R2
11
NH
H
H
N
N
N
N
NaOAc, DMF
100-120 °C, MW
1.5 h (74%)
R1
R1
R
R
10
8
R
R1
CO2Me
CO2Me
- R2NH2
4c
15
R2
N
R
NH2
H
R3
N
H
R3
12
NH
12'
Scheme 6. Synthesis of imidazo[2,1-a]isoquinoline 15 from 4c through
H
R1
R2N
2 NH
R
intramolecular Pd-catalyzed coupling.
9
R1 = CO2Me
R = Ph
R1
R1
[O]
R
R
R2
N
NH2
O
R3
Conclusions
4
[O]
R2
N
N
We have developed a simple and straightforward procedure
to access structurally diverse imidazoles 4 through a three-
component process involving the reaction of azirines 1 with
aldehydes and amines in the absence of any additive or metallic
catalyst. The key features of this environmentally friendly method
include the use of readily available starting materials, together
with high atom economy, good yields, and excellent functional
group tolerance, leading to multisubstituted imidazoles 4 in a
single step. The proposed reaction mechanism through
nucleophilic catalysis described here is novel and conceptually
different from the known Lewis acid-mediated preparation of
imidazoles from azirines.24,25 The synthetic usefulness of
imidazoles 4 was verified by direct post-transformation to an
exquisite fused tricyclic scaffold. Although being broad in scope,
one limitation of this multicomponent reaction concerns the use of
aromatic amines, such as substituted anilines, which did not work
under the conditions presented here. Nevertheless, further
studies are currently being carried out to expand this methodology
to other classes of compounds, as well as to uncover its
mechanistic intricacies, which will be reported in due course.
OMe
7 (R2 = Bn, nBu)
R1
R
Scheme 4. Proposed mechanism for the multicomponent synthesis of
tetrasubstituted imidazoles 4.
As reported previously,31 azirine-2-acetate 1a was
employed in a two-step synthesis of oxazole-5-acetates 14. In this
particular case, the presence of an activated methylene group
adjacent to the azirine ring enabled a base-mediated ring-opening
process with the formation of a stabilized iminyl anion 13, which
reacts with aldehydes to furnish oxazoles 14 after a subsequent
oxidation step (Scheme 5). However, this mechanism is ruled out
in the present case because a pre-formed imine 6 would lead to
the regioisomeric imidazole-5-acetate 5, which was not observed
in the crude reaction. In addition, the formation of the expected
imidazole-4-methanol 4o,p from the cinnamyl-derived azirine 1b
also excludes the involvement of an enolate-type intermediate 13.
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10.1002/ejoc.201800687
European Journal of Organic Chemistry
FULL PAPER
Method C: Identical to method B, but with the addition of
anhydrous Na2SO4 (350 mg/mmol azirine) in the beginning of the
reaction.
Experimental Section
General Experimental Methods
All chemicals were of reagent grade and were used as received.
Melting points were determined using a hot plate apparatus and
are uncorrected. Infrared spectra were acquired with a FT-IR
spectrometer (range 4000-400 cm-1) using KBr. 1H NMR spectra
were recorded at 400 MHz or at 200 MHz and 13C NMR spectra
(fully decoupled) were recorded at 100 MHz or at 50 MHz.
Splitting patterns are designated as s (singlet), br s (broad
singlet), d (doublet), dd (doublet of doublet), ddd (doublet of
doublet of doublet), ddt (doublet of doublet of triplet), t (triplet), tt
(triplet of triplet), q (quartet), qt (quintet), sx (sextet), m (multiplet),
apt (apparent triplet), apdt (apparent doublet of triplet). Coupling
constants (J) are measured in Hertz (Hz). Chemical shifts were
recorded in parts per million (ppm, ) relative to TMS or solvent
Methyl 1-benzyl-5-phenyl-2-(4-tolyl)-1H-imidazole-4-acetate (4a).
Method A: yield 60% (119 mg); method B: yield 74% (147 mg);
method C: yield 80% (159 mg); yellow solid, mp 135.5-136.0 °C.
1H NMR (200 MHz, CDCl3):  2.32 (s, 3H), 3.63 (s, 2H), 3.66 (s,
3H), 5.13 (s, 2H), 6.75-6.80 (m, 2H), 7.12-7.35 (m, 10H), 7.47 (d,
J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3):  21.3 (CH3), 33.6
(CH2), 48.5 (CH2), 51.9 (CH3), 125.9 (2  CH), 127.3 (CH), 127.9
(C), 128.4 (CH), 128.5 (2  CH), 128.6 (2  CH), 128.9 (2  CH),
129.2 (2  CH), 129.8 (C), 130.4 (2  CH), 131.9 (C), 132.5 (C),
137.7 (C), 138.7 (C), 148.1 (C), 172.0 (C). IR (KBr, cm-1):  = 3029,
2949, 1738, 1605, 1450, 1201, 1158, 732, 702. HRMS (ESI+):
calcd. for C26H25N2O2+ [M+H]+ 397.1911; found 397.1906.
1
peak (CDCl3 at 7.26 ppm for H NMR, and CDCl3 at 77.16 ppm
for 13C NMR) as the internal standard. Column chromatography
was performed using silica gel (70-230 mesh) as the stationary
phase and hexane/ethyl acetate as the eluent, except for the
indole-substituted imidazole 4n, which was purified by
chromatography using alumina (neutral, ~150 mesh) instead of
silica gel. TLC analysis was performed in silica gel plates. The
ESI-QTOF mass spectrometer was operated in the positive ion
mode at 4.5 kV and at a desolvation temperature of 180 °C. The
standard electrospray ion (ESI) source was used to generate the
ions. The instrument was calibrated in the range m/z 50-3000
using a calibration standard (low concentration tuning mix
solution) and data were processed with the aid of computer
software. Microwave assisted reactions were performed in 10 mL
sealed tubes in a monomode microwave CEM Explorer reactor
Methyl
1-allyl-2-(4-fluorophenyl)-5-phenyl-1H-imidazole-4-
acetate (4b). Method A: yield 64% (112 mg); method B: yield 62%
(109 mg); method C: yield 63% (110 mg); yellow solid, mp 76.3-
77.6 °C. 1H NMR (400 MHz, CDCl3):  3.59 (s, 2H), 3.67 (s, 3H),
4.47-4.49 (m, 2H), 4.83 (d, J = 17.1 Hz, 1H), 5.15 (d, J = 10.5 Hz,
1H), 5.74 (ddt, J = 17.1, 10.5, 4.4 Hz, 1H), 7.09-7.14 (m, 2H),
7.40-7.44 (m, 5H), 7.64-7.69 (m, 2H). 13C NMR (100 MHz, CDCl3):
 33.6 (CH2), 47.2 (CH2), 51.9 (CH3), 115.5 (d, J = 20.5 Hz, 2 
CH), 117.2 (CH2), 127.1 (d, J = 4.4 Hz, C), 128.65 (2  CH),
128.68 (CH), 129.8 (C), 130.6 (2  CH), 130.9 (d, J = 8.8 Hz, 2 
CH), 132.0 (C), 132.4 (C), 133.8 (CH), 146.6 (C), 163.2 (d, J =
249.4 Hz, C), 172.0 (C). IR (KBr, cm-1):  = 3057, 2953, 1734,
1605, 1530, 1352, 1212, 1163, 991, 848, 785, 708. HRMS (ESI+):
calcd. for C21H20FN2O2+ [M+H]+ 351.1503; found 351.1505.
instrument with infrared temperature monitoring and
a
Methyl
1-allyl-2-(2-bromophenyl)-5-phenyl-1H-imidazole-4-
noninvasive pressure transducer (maximum pressure = 200 psi, t
= 1 min ramp, 1 min cooling, stirring mode “on”). Complete
experimental procedure for the preparation of azirines 1a-c is
described in the Supporting Information.
acetate (4c). Method A: yield 50% (103 mg); method B: yield 69%
(144 mg); method C: yield 47% (97 mg); yellow oil. 1H NMR (400
MHz, CDCl3):  3.62 (s, 2H), 3.67 (s, 3H), 4.34-4.36 (m, 2H), 4.62
(dd, J = 17.1, 1.0 Hz, 1H), 4.93 (dd, J = 10.3, 1.0 Hz, 1H), 5.53
(ddt, J = 17.1, 10.3, 4.9 Hz, 1H), 7.28-7.45 (m, 7H), 7.49 (dd, J =
7.7, 1.7 Hz, 1H), 7.65 (dd, J = 7.7, 1.2 Hz, 1H). 13C NMR (50 MHz,
CDCl3):  33.7 (CH2), 47.2 (CH2), 52.0 (CH3), 116.9 (CH2), 124.6
(C), 127.3 (CH), 128.5 (CH), 128.7 (2  CH), 129.7 (C), 130.4 (2
 CH), 130.9 (CH), 131.1 (C), 132.1 (C), 132.7 (C), 132.8 (CH),
132.9 (CH), 133.0 (CH), 146.0 (C), 172.0 (C). IR (KBr, cm-1):  =
3059, 2949, 1740, 1607, 1452, 1399, 1201, 1161, 1026, 757, 704.
HRMS (ESI+): calcd. for C21H20BrN2O2+ [M+H]+ 411.0703; found
411.0702.
General Procedure for the Synthesis of Imidazoles 4
Method A (solvent-free): To a flask containing azirine 1 (0.5 mmol)
was added an aldehyde (0.50-0.55 mmol) and an amine (0.60-
0.65 mmol) then the mixture was stirred at 25 °C. The reaction
was accompanied by TLC until consumption of the starting azirine
(1-24 h). Then, the volatile components were evaporated under
reduced pressure and the crude product was directly purified by
column chromatography (gradient: hexane/EtOAc 8:2

hexane/EtOAc 1:1 or hexane/EtOAc 8:2  100% EtOAc).
Methyl
1-allyl-2-(3,4-methylenedioxyphenyl)-5-phenyl-1H-
i
imidazole-4-acetate (4d). Method B: yield 51% (96 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  3.56 (s, 2H), 3.65 (s, 3H), 4.46-4.48
(m, 2H), 4.81 (d, J = 17.1 Hz, 1H), 5.12 (d, J = 10.5 Hz, 1H), 5.71
(ddt, J = 17.1, 10.5, 4.4 Hz, 1H), 5.98 (s, 2H), 6.84 (d, J = 9.0 Hz,
1H), 7.12-7.15 (m, 2H), 7.37-7.42 (m, 5H). 13C NMR (100 MHz,
CDCl3):  33.7 (CH2), 47.2 (CH2), 51.9 (CH3), 101.4 (CH2), 108.3
(CH), 109.6 (CH), 117.1 (CH2), 123.2 (CH), 124.9 (C), 128.57
(CH), 128.61 (2  CH), 130.0 (C), 130.6 (2  CH), 131.7 (C), 132.2
(C), 134.0 (CH), 147.3 (C), 147.8 (C), 148.3 (C), 172.0 (C). IR
Method B: To a stirred solution of azirine 1 (0.5 mmol) in PrOH
(1.0 mL) was added an aldehyde (0.50-0.55 mmol) and an amine
(0.60-0.65 mmol) then the mixture was stirred at 25 °C. The
reaction was accompanied by TLC until consumption of the
starting azirine (1-24 h). Then, the volatile components were
evaporated under reduced pressure and the crude product was
purified by column chromatography as described for method A.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800687
European Journal of Organic Chemistry
FULL PAPER
(KBr, cm-1):  = 3079, 2951, 2898, 1738, 1471, 1250, 1167, 1038,
Methyl (E)-1-butyl-5-phenyl-2-styryl-1H-imidazole-4-acetate (4i).
Method A: yield 47% (88 mg); yellow solid, mp 82.3-83.7 °C. H
+
1
932, 820, 704. HRMS (ESI+): calcd. for C22H21N2O4 [M+H]+
377.1496; found 377.1497.
NMR (200 MHz, CDCl3):  0.78 (t, J = 7.3 Hz, 3H), 1.09-1.28 (m,
2H), 1.50-1.65 (m, 2H), 3.58 (s, 2H), 3.65 (s, 3H), 3.90 (t, J = 7.6
Hz, 2H), 6.91 (d, J = 15.7 Hz, 1H), 7.25-7.55 (m, 10H), 7.66 (d, J
= 15.7 Hz, 1H). 13C NMR (50 MHz, CDCl3):  13.6 (CH3), 19.8
(CH2), 33.4 (CH2), 33.7 (CH2), 43.6 (CH2), 52.0 (CH3), 113.8 (CH),
126.8 (2  CH), 128.2 (CH), 128.5 (CH), 128.8 (4  CH), 129.9
(C), 130.5 (2  CH), 131.5 (C), 132.6 (CH), 132.7 (C), 137.0 (C),
144.7 (C), 172.0 (C). IR (KBr, cm-1):  = 3029, 2957, 1730, 1687,
1420, 1269, 1240, 1156, 1020, 957, 753, 704. HRMS (ESI+):
calcd. for C24H27N2O2+ [M+H]+ 375.2067; found 375.2065.
Methyl 1-butyl-5-phenyl-2-(4-tolyl)-1H-imidazole-4-acetate (4e).
Method A: yield 64% (115 mg); yellow oil. 1H NMR (400 MHz,
CDCl3):  0.60 (t, J = 7.4 Hz, 3H), 0.94 (sx, J = 7.4 Hz, 2H), 1.28
(qt, J = 7.4 Hz, 2H), 2.39 (s, 3H), 3.59 (s, 2H), 3.64 (s, 3H), 3.94
(t, J = 7.4 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.38-7.53 (m, 7H). 13
C
NMR (50 MHz, CDCl3):  13.2 (CH3), 19.4 (CH2), 21.3 (CH3), 32.4
(CH2), 33.5 (CH2), 44.8 (CH2), 51.8 (CH3), 128.3 (CH), 128.5 (C),
128.7 (2  CH), 129.0 (2  CH), 129.2 (2  CH), 130.3 (2  CH),
130.4 (C), 131.4 (C), 132.0 (C), 138.6 (C), 147.7 (C), 172.0 (C).
IR (KBr, cm-1):  = 3028, 2957, 2931, 2872, 1740, 1607, 1471,
Methyl 1-benzyl-2-ethyl-5-phenyl-1H-imidazole-4-acetate (4j).
Method A: yield 33% (55 mg); method B: yield 70% (119 mg);
yellow solid, mp 82.5-88.2 °C. 1H NMR (400 MHz, CDCl3):  1.26
(t, J = 7.6 Hz, 3H), 2.59 (q, J = 7.6, 2H), 3.59 (s, 2H), 3.67 (s, 3H),
4.99 (s, 2H), 6.90 (d, J = 7.3 Hz, 2H), 7.23-7.34 (m, 8H). 13C NMR
(100 MHz, CDCl3):  12.2 (CH3), 20.8 (CH2), 33.7 (CH2), 47.3
(CH2), 51.9 (CH3), 125.9 (2  CH), 127.5 (CH), 128.3 (CH), 128.7
(2  CH), 128.9 (2  CH), 130.0 (C), 130.4 (2  CH), 130.8 (C),
131.0 (C), 137.4 (C), 149.5 (C), 172.2 (C). IR (KBr, cm-1):  = 3059,
2976, 2933, 1734, 1605, 1495, 1450, 1358, 1201, 1161, 738, 704.
+
1436, 1158, 1020, 826, 704. HRMS (ESI+): calcd. for C23H27N2O2
[M+H]+ 363.2067; found 363.2072.
Methyl
1-butyl-2-(4-methoxyphenyl)-5-phenyl-1H-imidazole-4-
1
acetate (4f). Method B: yield 64% (121 mg); brown oil. H NMR
(400 MHz, CDCl3):  0.60 (t, J = 7.3 Hz, 3H), 0.95 (sx, J = 7.3 Hz,
2H), 1.24-1.32 (m, 2H), 3.59 (s, 2H), 3.65 (s, 3H), 3.84 (s, 3H),
3.92 (t, J = 7.6 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 7.40-7.48 (m,
5H), 7.56 (d, J = 9.0 Hz, 2H). 13C NMR (100 MHz, CDCl3):  13.3
(CH3), 19.4 (CH2), 32.4 (CH2), 33.5 (CH2), 44.8 (CH2), 51.9
(OCH3), 55.3 (CH3), 114.0 (2  CH), 123.7 (C), 128.3 (CH), 128.7
(2  CH), 130.3 (2  CH), 130.4 (C), 130.5 (2  CH), 131.3 (C),
131.8 (C), 147.7 (C), 160.0 (C), 172.1 (C). IR (KBr, cm-1):  =3033,
2957, 1740, 1611, 1534, 1469, 1250, 1175, 1028, 838, 704.
+
HRMS (ESI+): calcd. for C21H23N2O2 [M+H]+ 335.1754; found
335.1754.
Methyl 1-allyl-2-ethyl-5-phenyl-1H-imidazole-4-acetate (4k).
Method A: yield 32% (46 mg); method B: yield 83% (118 mg);
yellow oil. 1H NMR (200 MHz, CDCl3):  1.29 (t, J = 7.6 Hz, 3H),
2.62 (q, J = 7.6 Hz, 2H), 3.47 (s, 2H), 3.59 (s, 3H), 4.27-4.31 (m,
2H), 4.79 (d, J = 17.0 Hz, 1H), 5.11 (d, J = 10.5 Hz, 1H), 5.75 (ddt,
J = 17.0, 10.5, 4.4 Hz, 1H), 7.24-7.35 (m, 5H). 13C NMR (100 MHz,
HRMS (ESI+): calcd. for C23H27N2O3 [M+H]+ 379.2016; found
379.2015.
+
Methyl 1-butyl-2-(4-nitrophenyl)-5-phenyl-1H-imidazole-4-acetate
(4g). Method C: yield 39% (77 mg); orange solid, mp 69.3-73.2 °C. CDCl3):  12.2 (CH3), 20.4 (CH2), 33.4 (CH2), 45.9 (CH2), 51.8
1H NMR (400 MHz, CDCl3):  0.63 (t, J = 7.3 Hz, 3H), 0.98 (sx, J
= 7.3 Hz, 2H), 1.33 (qt, J = 7.3 Hz, 2H), 3.60 (s, 2H), 3.67(s, 3H),
4.02 (t, J = 7.3 Hz, 2H), 7.42-7.53 (m, 5H), 7.87 (d, J = 8.6 Hz,
2H), 8.32 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3):  13.2
(CH3), 19.4 (CH2), 32.5 (CH2), 33.5 (CH2), 45.3 (CH2), 51.9 (CH3)
123.9 (2  CH), 128.87 (CH), 128.93 (2  CH), 129.5 (2  CH),
129.6 (C), 130.4 (2  CH), 133.4 (C), 133.5 (C), 137.6 (C), 145.0
(C), 147.7 (C), 171.7 (C). IR (KBr, cm-1):  = 3059, 2962, 2929,
1736, 1599, 1522, 1348, 1210, 1148, 863, 708. HRMS (ESI+):
calcd. for C22H24N3O4+ [M+H]+ 374.1761; found 394.1759.
(CH3), 116.5 (CH2), 128.1 (CH), 128.5 (2  CH), 129.8 (C), 130.0
(2  CH), 130.2 (C), 130.3 (C), 133.3 (CH), 149.1 (C), 172.2 (C).
IR (KBr, cm-1):  =, 3057, 2980, 1738, 1644, 1609, 1436, 1199,
1161, 1020, 761, 704. HRMS (ESI+): calcd. for C17H21N2O2
[M+H]+ 285.15975; found 285.15977.
+
Methyl 1-butyl-2-ethyl-5-phenyl-1H-imidazole-4-acetate (4l).
Method A: yield 31% (47 mg); method C: yield 70% (105 mg);
yellow solid, mp 81.5-83.0 °C. 1H NMR (400 MHz, CDCl3):  0.76
(t, J = 7.3 Hz, 3H), 1.14 (sx, J = 7.3 Hz, 2H), 1.39 (t, J = 7.6 Hz,
3H), 1.42-1.49 (m, 2H), 2.74 (q, J = 7.6, 2H), 3.50 (s, 2H), 3.64 (s,
3H), 3.74 (t, J = 7.8 Hz, 2H), 7.30-7.45 (m, 5H). 13C NMR (100
MHz, CDCl3):  12.4 (CH3), 13.4 (CH3), 19.6 (CH2), 20.6 (CH2),
32.6 (CH2), 33.3 (CH2), 43.5 (CH2), 51.7 (CH3), 128.0 (CH), 128.5
(2  CH), 129.9 (C), 130.2 (2  CH), 130.33 (C), 130.34 (C), 148.6
(C), 172.1 (C). IR (KBr, cm-1):  = 3029, 2947, 2872, 1746, 1611,
1428, 1350, 1187, 1163, 765, 712. HRMS (ESI+): calcd. for
C18H25N2O2+ [M+H]+ 301.1911; found 301.1908.
Methyl
1-butyl-2-[4(5)-imidazoyl]-5-phenyl-1H-imidazole-4-
acetate (4h). Method B: yield 51% (86 mg); white solid, mp 170.6-
1
173.7 °C. H NMR (400 MHz, CDCl3):  0.67 (t, J = 7.3 Hz, 3H),
1.07 (sx, J = 7.3, 2H), 1.45 (qt, J = 7.3 Hz, 2H), 3.54 (s, 2H), 3.60
(s, 3H), 4.28 (t, J = 7.3 Hz, 2H), 7.36-7.50 (m, 6H), 7.68 (d, J =
1.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):  13.5 (CH3), 19.6 (CH2),
32.6 (CH2), 33.3 (CH2), 44.8 (CH2), 52.0 (CH3), 118.9 (C), 128.6
(CH), 128.8 (2  CH), 129.8 (C), 130.6 (2  CH), 131.0 (C), 131.5
(C), 136.2 (2  CH), 141.7 (C), 172.0 (C). IR (KBr, cm-1):  = 3068,
2964, 2900-2500, 1742, 1415, 1348, 1197, 1165, 828, 706.
Methyl 1-(1-ethoxycarbonylpiperidin-4-yl)-2-ethyl-5-phenyl-1H-
imidazole-4-acetate (4m). Method A: yield 53% (106 mg); yellow
oil. 1H NMR (400 MHz, CDCl3):  1.23 (t, J = 7.1 Hz, 3H), 1.39 (t,
J = 7.6 Hz, 3H), 1.80-1.82 (m, 2H), 1.92-1.96 (m, 2H), 2.61-2.67
(m, 2H), 2.80 (q, J = 7.6 Hz, 2H) 3.40 (s, 2H), 3.62 (s, 3H), 3.96
+
HRMS (ESI+): calcd. for C19H23N4O2 [M+H]+ 339.1816; found
339.1819.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800687
European Journal of Organic Chemistry
FULL PAPER
(tt, J = 12.4, 3.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 4.15-4.32 (m,
2H), 7.26-7.30 (m, 2H), 7.40-7.46 (m, 3H). 13C NMR (100 MHz,
CDCl3):  13.0 (CH3), 14.6 (CH3), 22.2 (CH2), 31.7 (2  CH2), 33.2
(CH2), 43.8 (2  CH2), 51.7 (CH3), 54.8 (CH), 61.5 (CH2), 128.5 (2
 CH), 128.6 (CH), 129.9 (C), 130.7 (C), 131.06 (C), 131.11 (2 
CH), 148.3 (C), 155.2 (C), 171.9 (C). IR (KBr, cm-1):  = 3055,
2978, 2937, 1740, 1697, 1611, 1434, 1238, 1150, 1016, 767, 706.
3029, 2950, 1740, 1673, 1634, 1454, 1356, 1197, 1159, 1016,
824, 734. HRMS (ESI+): calcd. for C22H25N2O2+ [M+H]+ 349.1911;
found 349.1913.
Methyl
2-(6-methyl-3-phenylimidazo[2,1-a]isoquinolin-2-
yl)acetate (15). To a solution of imidazole 4c (82 mg, 0.20 mmol)
in DMF (1.0 mL), placed into a microwave tube, was added
NaOAc (20 mg, 0.24 mmol) and PdCl2(PPh3)2 (14 mg, 10 mol%).
After degassing the mixture under N2, the sealed tube was heated
under microwave radiation (100-120 °C, 50 W) for 90 min. Next,
the mixture was treated with 6 M NH4Cl and extracted with EtOAc,
the organic extract was dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was
purified by column chromatography (hexane/EtOAc 8:2) to give
tricycle 15 as a yellow solid (49 mg, 74%), mp 135.7-138.2 °C. 1H
NMR (200 MHz, CDCl3):  2.44 (d, J = 1.0 Hz, 3H), 3.71 (s, 3H),
3.87 (s, 2H), 7.47-7.78 (m, 9H), 8.70-8.72 (m, 1H). 13C NMR (100
MHz, CDCl3):  16.5 (CH3), 34.2 (CH2), 52.2 (CH3), 119.2 (CH),
119.3 (C), 123.8 (CH), 124.0 (CH), 124.9 (C), 127.9 (CH), 128.2
(CH), 128.7 (CH), 129.0 (C), 129.3 (CH), 129.8 (C), 130.1 (CH),
130.3 (C), 134.9 (C), 142.3 (C), 171.8 (C). IR (KBr, cm-1):  = 3027,
2947, 2916, 1724, 1601, 1450, 1389, 1261, 1008, 765, 708.
+
HRMS (ESI+): calcd. for C22H30N3O4 [M+H]+ 400.2231; found
400.2227.
Methyl 1-(2-(1H-indol-3-yl)ethyl)-2-ethyl-5-phenyl-1H-imidazole-
4-acetate (4n). Method B: yield 66% (128 mg); brown solid, mp
155.3-158.6 °C. 1H NMR (400 MHz, CDCl3):  1.27 (t, J = 7.6 Hz,
3H), 2.56 (q, J = 7.6, 2H), 2.83 (t, J = 7.6 Hz, 2H), 3.53 (s, 2H),
3.62 (s, 3H), 4.03 (t, J = 7.6 Hz, 2H), 6.73 (d, J = 2.2, 1H), 6.97-
7.45 (m, 9H), 8.73 (s, 1H). 13C NMR (100 MHz, CDCl3):  12.6
(CH3), 20.6 (CH2), 26.7 (CH2), 33.5 (CH2), 44.8 (CH2), 51.9 (CH3),
111.4 (C + CH), 118.2 (CH), 119.5 (CH), 122.1 (CH), 122.4 (CH),
127.1 (C), 128.3 (CH), 128.9 (2  CH), 130.0 (C), 130.55 (2  CH),
130.63 (C), 130.9 (C), 136.4 (C), 149.3 (C), 172.4 (C). IR (KBr,
cm-1):  = 3184, 3057, 2978, 2925, 1748, 1615, 1436, 1344, 1205,
+
1159, 744, 704. HRMS (ESI+): calcd. for C24H26N3O2 [M+H]+
+
388.2020; found 388.2018.
HRMS (ESI+): calcd. for C21H19N2O2 [M+H]+ 331.1441; found
331.1442.
1-Benzyl-5-phenyl-2-(4-tolyl)-1H-imidazole-4-methanol
(4o).
Method B: yield 70% (124 mg); white solid, mp 149.0-152.2 °C.
1H NMR (200 MHz, CDCl3):  2.33 (s, 3H), 4.60 (s, 2H), 4.98 (br
s, 1H), 5.15 (s, 2H), 6.74-6.78 (m, 2H), 7.13-7.33 (m, 10H), 7.44
(d, J = 8.1 Hz, 2H). 13C NMR (50 MHz, CDCl3):  21.4 (CH3),
48.6 (CH2), 57.2 (CH2), 126.1 (2  CH), 127.4 (CH), 127.6 (C),
128.4 (CH), 128.6 (2  CH), 128.7 (2  CH), 128.9 (2  CH), 129.4
(2  CH), 129.5 (C), 130.5 (2  CH), 131.4 (C), 137.5 (C), 139.0
(C), 139.1 (C), 148.3 (C). IR (KBr, cm-1):  = 3200, 3029, 2919,
2860, 1448, 1354, 1026, 728, 698. HRMS (ESI+): calcd. for
C24H23N2O+ [M+H]+ 355.1805; found 355.1802.
Acknowledgements
We are grateful to the Central de Análises de Química
(UFSC) for the spectroscopic analysis. Special thanks are due to
CEBIME (Laboratorio Central de Biologia Molecular e Estrutural,
UFSC) for providing the mass spectra and to Prof. Gustavo Micke
(UFSC) for the LC-MS analysis. The authors are grateful to FINEP
(Financiadora de Estudos e Projetos) and CNPq (Conselho
Nacional de Desenvolvimento Científico e Tecnológico) for
fellowships. Support from INCT-Catalysis (Brazilian Research
Council) is also gratefully acknowledged.
1-Butyl-2-ethyl-5-phenyl-1H-imidazole-4-methanol (4p). Method
1
B: yield 55% (71 mg); white solid, mp 117.8-118.2 °C. H NMR
(400 MHz, CDCl3):  0.76 (t, J = 7.3 Hz, 3H), 1.15 (sx, J = 7.3 Hz,
2H), 1.37 (t, J = 7.6 Hz, 3H), 1.41-1.49 (m, 2H), 2.74 (q, J = 7.6,
Keywords: azirines • imidazoles • green chemistry •
multicomponent reactions • structural diversity
2H), 3.78 (t, J = 7.8 Hz, 2H), 4.50 (s, 2H), 7.35-7.46 (m, 5H). 13
C
NMR (100 MHz, CDCl3):  12.5 (CH3), 13.5 (CH3), 19.8 (CH2),
20.6 (CH2), 32.8 (CH2), 43.6 (CH2), 56.5 (CH2), 128.1 (CH), 128.6
(2  CH), 129.6 (C), 130.2 (C), 130.4 (2  CH), 137.6 (C), 149.0
(C). IR (KBr, cm-1):  = 3170, 3051, 2976, 2937, 2876, 1509, 1422,
1026, 1004, 779, 710. HRMS (ESI+): calcd. for C16H23N2O+
[M+H]+ 259.1805; found 259.1807.
__________________
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2H), 3.69 (s, 2H), 3.71 (s, 3H), 5.17 (s, 2H), 6.98 (d, J = 7.1 Hz,
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47.9 (CH2), 52.0 (CH3), 125.7 (2  CH), 127.6 (CH), 128.1 (C),
128.8 (2  CH), 129.0 (2  CH), 129.2 (2  CH), 130.7 (C), 131.5
(C), 137.6 (C), 138.5 (C), 147.1 (C), 172.0 (C). IR (KBr, cm-1):  =
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Green Synthesis*
Thaís A. Rossa, Mariane Fantinel,
Adailton J. Bortoluzzi, Marcus M. Sá*
Pages 1 – 8
Multicomponent Synthesis of
Structurally Diverse Imidazoles
Featuring Azirines, Amines and
Aldehydes
A straightforward method for the synthesis of tetrasubstituted imidazoles
was developed, employing readily available starting materials and
environmentally benign conditions.
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