One-step synthesis of N, N′-substituted 4-imidazolidinones by an isocyanide-based pseudo-five-multicomponent reaction

Article abstract of DOI:10.1039/c8ob02229a

A pseudo-five-multicomponent reaction involving an isocyanide, a primary amine, two molecules of formaldehyde and water is reported, which gives N,N′-substituted 4-imidazolidinones when trifluoroethanol is used as the solvent. The reaction proceeds with good yields and with a wide variety of amines and isocyanides, providing an efficient new entry to these heterocycles. A preliminary study of the reaction mechanism suggests that trifluoroethanol, although acting as the solvent, is directly involved as a reagent in the reaction pathway.

Full text of DOI:10.1039/c8ob02229a

Organic &
Biomolecular Chemistry
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One-step synthesis of N,N’-substituted
4-imidazolidinones by an isocyanide-based
pseudo-five-multicomponent reaction†
Cite this: Org. Biomol. Chem., 2018,
16, 8944
Received 10th September 2018,
Accepted 12th November 2018
Cecilia I. Attorresi,a,b Evelyn L. Bonifazi,a,b Javier A. Ramírez
*
a,b and Gabriel F. Golaa,b
DOI: 10.1039/c8ob02229a
rsc.li/obc
A pseudo-five-multicomponent reaction involving an isocyanide, a inducing profound changes in the reaction outcome. As an
primary amine, two molecules of formaldehyde and water is interesting example, when ammonia is added in a four-com-
reported, which gives N,N’-substituted 4-imidazolidinones when ponent Ugi reaction as the amine component, the use of
trifluoroethanol is used as the solvent. The reaction proceeds with methanol as the solvent leads to a six-component coupling
good yields and with a wide variety of amines and isocyanides, product with low yields, whereas TFE efficiently gives the
providing an efficient new entry to these heterocycles. A prelimi- expected α-aminoacylamide.2,3
nary study of the reaction mechanism suggests that trifluoroetha-
During our work on the use of MCRs as key synthetic steps
nol, although acting as the solvent, is directly involved as a reagent for the generation of bioactive molecules, we turned our atten-
in the reaction pathway.
tion toward the Ugi–Smiles reaction, which gives an N-aryl car-
boxamide 1 from an acidic phenol (2), an amine (3), an isocya-
nide (4) and an aldehyde (5).4 Preliminary optimization experi-
ments were performed using the particular components
shown in Scheme 1 and different solvents and reaction temp-
eratures. Taking into account the reports mentioned on the
use of TFE as a solvent for the classic Ugi reaction, we decided
to include it along with toluene and ethanol.
Unexpectedly, whereas the latter solvents yielded the
desired product 1, the use of TFE rendered the formation of
4-imidazolidinone 6a. To the best of our knowledge, and
although the synthesis of the 4-imidazolidinone ring has been
widely explored, no reports are available on the preparation of
this scaffold through a MCR.
The 4-imidazoline ring is a biologically relevant scaffold, as
it occurs in natural compounds such as oxaline, neoxaline5
and hetacillin,6 isolated from Penicillium spp., which exhibit
antibacterial, antifungal, and antitumoral activities. In
addition, this ring is present in some bioactive synthetic com-
pounds such as spiperone and mosapramine, which are
known to interact with the dopamine receptor7 and are clini-
cally useful antipsychotic agents8 (Fig. 1).
Numerous synthetic methods have been reported for
obtaining 4-imidazolidinones which are in general multistep
routes involving harsh conditions.9–17 A typical procedure
starts with the construction of a linear α-amino amide fol-
lowed by a cyclization reaction. In several cases, the use of a
protective group is needed. Furthermore, additional substi-
tution reactions are required if the target compound is an
N-substituted ring.
Multicomponent reactions (MCRs) have become increasingly
popular as powerful tools for the rapid generation of small-
molecule libraries. However, in further pursuit of molecular
diversity and complexity, novel and more versatile MCRs prove
necessary. Despite the existence of rational design strategies
for discovering new MCRs, serendipity continues to be an
important source.1 It is not surprising that MCRs, where three
or more molecules must react in sequential steps in a defined
succession, will be affected by changes in the conditions in
which they are performed. It is known, for example, that the
use of catalysts, solvents, or additives may redirect the course
of a reaction along different pathways, thus producing alterna-
tive scaffolds.1
In this context, several recent reports provide evidence on
the use of 2,2,2-trifluoroethanol (TFE) as a solvent in MCRs.
This highly fluorinated alcohol has several properties such as
low nucleophilicity, high ionizing power and high hydrogen
bonding ability, which make it a unique solvent capable of
aDepartamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Ciudad Universitaria,
Ciudad Autónoma de Buenos Aires, C1428EGA, Argentina
bCONICET – Universidad de Buenos Aires, Unidad de Microanálisis y Métodos
Físicos Aplicados a Química Orgánica (UMYMFOR), Ciudad Universitaria,
Ciudad Autónoma de Buenos Aires, C1428EGA, Argentina.
E-mail: jar@qo.fcen.uba.ar
†Electronic supplementary information (ESI) available: Detailed experimental
procedures and NMR spectra (1H, 13C, and 19F) for all the new compounds.
2D-NMR and mass spectra for selected compounds. See DOI: 10.1039/c8ob02229a
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Scheme 1 TFE induces a new multicomponent condensation.
whereas a lower yield and the formation of some by-products,
mainly the α-aminoamide Ugi-like intermediate 7, probably
originated by water attack on the intermediate nitrilium
ion,18,19 and 8, likely formed through an over-Ugi reaction,20
were observed at 90 °C (entry 3). Most importantly, we found
that 2-nitrophenol 2 was not required for the reaction to
proceed (entry 4).
In another set of experiments, and as two equivalents of
formaldehyde are required to give the cyclization product, an
experiment starting with an excess of this component was
attempted. In this case, the yield could be improved to reach
Fig. 1 Natural and synthetic compounds possessing the 4-imidazolidi-
none scaffold in their structures.
Table 1 Identification of the best-suited conditions for the synthesis 75% by the addition of five equivalents of formaldehyde (as
of 6a
formalin, a 37% aqueous solution, entry 5). Finally, the effect
of water on the outcome of the reaction was assessed by repla-
Entry
T (°C)
2-Nitrophenol
CH2Oa
H2Oa
Yieldb (%)
cing formalin with paraformaldehyde, and adding variable
amounts of water. When the quantity of water was reduced to
5 equivalents, to be equimolar to formaldehyde, the reaction
proceeded slowly and no completion of the reaction was
observed after 96 h (entry 6). On the other hand, an excess of
water (entry 7) does not prove to increase the yield. Thus, we
choose the conditions reported under entry 5 as the best-
suited for the formation of the 4-imidazolidinone 6a.
Having these improved conditions in hand, we tested the
reaction with different isocyanides and amines. Our prelimi-
nary assays confirmed that in these cases the N,N′-substituted
4-imidazolidinones 6b, 6c and 6d were also formed with good
yield (Fig. 2), suggesting that this procedure may have a broad
general scope.
1
2
3
4
5
6
7
25
60
90
60
60
60
60
1
1
1
0
0
0
0
1.1
1.1
1.1
1.1
5
5
5
3.6
3.6
3.6
3.6
15
5
100
15c
29
21d
31
75
41c
72
a Equivalents with respect to isocyanide 6a. b Isolated yields. c No com-
pletion of the reaction after 96 h by TLC. d By-products 7 and 8 were
also isolated (4% and 6%, respectively).
As in other isocyanide-based MCRs, we were limited by the
availability of this family of reactants. Furthermore, as isocya-
nides usually have unpleasant odors, we decided to overcome
these drawbacks by synthesizing them in situ from the corres-
ponding formylamides following Dömling’s procedure,21,22
In this context, and in light of our unexpected result, we which involves the slow addition of a triphosgene solution to a
decided to further identify the conditions leading, if possible, solution of formylamide 8 and triethylamine (TEA) in dichloro-
to an improvement of the reaction yield. Table 1 gives an over- methane at 0 °C (Scheme 2). In order to test this strategy, we
view of the most relevant screening results. Firstly, we deter- prepared compounds 6c and 6d starting from formylamides 9c
mined that the reaction was best performed at 60 °C, as the and 9d, which were converted into isocyanides and used
formation of 6a proceeded slowly at room temperature (entry 1), without prior isolation in our MCR. It is worth highlighting
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With this new, optimized procedure, a small library of
4-imidazolidinones was obtained with a variety of substitution
patterns (Scheme 2).
Various alkylamines, both linear and branched, including
sterically demanding tert-butylamine, reacted to afford the
corresponding 4-imidazolidinones in good to excellent yields
(6e–q). Amines with additional functional groups, such as pro-
pargylamine and benzylamines with different electrodemand-
ing substituents, also proved useful in this reaction. Moreover,
the fact that the isocyanides can be obtained from the corres-
ponding amines, allows the same substituent to be introduced
in each of the N atoms of the heterocycle (compare 6e and 6m,
or 6j and 6k). However, some amines, especially those with
lower nucleophilicity such as 4-nitroaniline, 3-aminopyridine
or 1-(3-aminophenyl)ethanone failed to give the corresponding
4-imidazolidinones, yielding α-hydroxy amides instead, which
are probably derived from the attack of the isocyanide on
formaldehyde.23,24
Fig. 2 Compounds obtained by the variation of the amine and the
isocyanide.
that both compounds were formed with similar yields when
compared to our previous experiments. Also of note is that the
presence of dichloromethane, which was the solvent used in
isocyanide synthesis, did not preclude the progress of this
reaction.
On the other hand, chemically diverse isocyanides reacted
correctly to provide the target compounds 6, irrespective of
their structure.
Scheme 2 4-Imidazolidinones obtained from isocyanides generated in situ. Reaction conditions: 9 (1.1 mmol), TEA (2.4 equiv.) and triphosgene
(0.4 equiv.) in CH2Cl2 (1.0 mL) were stirred at 0 °C for 2 h, then 5 (37% aq, 5 eq.) and 3 (1.1 eq.) in TFE (1.5 mL) were added. The reaction was kept at
60 °C for 3 days; isolated yields after purification. Following this procedure, compounds 6c and 6d were obtained in 74% and 81% yields, respectively.
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After having demonstrated the wide scope of this new MCR,
we performed additional experiments in order to establish a
preliminary proposal for its mechanism. Taking into account
previous reports on isocyanide-based reactions,25 and the fact
that the formation of the 4-imidazolidinones involved the par-
ticipation of two equivalents of aldehyde, we conducted the
reaction with a lower amount of this component (1 equivalent
with respect to amine), and at a lower temperature, with the
aim of detecting possible intermediates. Fortunately, it was
possible to isolate and fully characterize intermediate
imidate26 10 depicted in Scheme 3. This suggests that the
solvent does not only act as an acidic medium but also partici-
pates directly in the reaction as a reactant even when it is not
present in the final product.
Interestingly, Saya et al. have observed very recently the for-
mation of this kind of intermediate during a Passerini-type
reaction when 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was
present as a cosolvent.27 Thus, we performed some preliminary
experiments in order to verify if this alternative fluorinated
alcohol might also promote the formation of the 4-imidazolidi-
nones reported herein. To our delight, both compounds 6a
and 6b were obtained with good yields when TFE was replaced
by HFIP following the same procedures described before (see
the ESI† for details). Furthermore, when using the latter
solvent, a small amount of the corresponding imidate 11 was
also isolated at low temperatures.
At this point, a possible pathway for the transformation of
imidates such as 10 into the corresponding 4-imidazolidinone
could be thought to involve the hydrolysis of 10 to give an
α-aminoamide Ugi-like intermediate 12, which might further
react with formaldehyde to give the cyclic product. However,
when 10 was treated with water in TFE at 60 °C, the starting
material remained unchanged after 4 h of reaction. In con-
trast, when intermediate 10 was treated with an excess of
aqueous formaldehyde, the cyclic final compound 6d was
obtained in good yields (Scheme 4). These findings reinforce
Scheme 4 Preliminary studies on the mechanism of the reaction.
our hypothesis that the procedure reported in this work consti-
tutes a new MCR and not a combination of a previously known
Ugi-like reaction followed by a post cyclization reaction.
Altogether, this information made it possible to conceive a
reaction cycle leading to 4-imidazolidinone 6 (Fig. 3). This
cycle may be initiated by the protonation of the imine I gener-
ated in situ, which suffers the attack of the isocyanide to give a
nitrilium ion. This intermediate could be trapped by the
nucleophilic trifluoroethanol to give the imidate II, which is
stable enough to be isolated. We propose that II could react
with a second molecule of formaldehyde to give the enamine
III, which undergoes an intramolecular nucleophilic attack to
form the cyclic intermediate IV. Finally, water reacts with IV to
generate the hemi-orthoamide V, which in turn fragments to
4-imidazolidinone 6, regenerating the solvent molecule VI.
Scheme 3 Isolation of the reaction intermediates.
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Universidad de Buenos Aires) for kindly providing the HFIP
needed for our experiments.
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