The Biginelli Reaction with a Recyclable Iron Catalyst
FULL PAPER
Due to the possibility of charged and polar intermediates
in the Biginelli reaction pathways, it is reasonable to envis-
age ion-pairing formation of those species with ionic compo-
nents (cations and anions), thus accelerating the product for-
mation by lowering the activation barrier in the presence of
ILs[17] when compared with reactions carried out in classical
organic solvents. In other words, it is the so-called ionic-
liquid effect.
Despite advances observed in the scientific literature to
perform the Biginelli MCR,[18] there are still many questions
to be answered and improvements to be achieved.[19] For ex-
ample, the Biginelli mechanism is still under debate, with no
consensus reached about the preferred pathway. Because
there seems to be supporting evidence for the three mecha-
nistic proposals depicted in Scheme 3 (see later), with many
intermediates proposed, the discussion surrounding the
mechanism of the Biginelli reaction is highly controversial.
In the 1930s it was proposed that urea addition to the alde-
hyde was a key step for the synthesis of DHPs.[20] The Knoe-
venagel mechanism was later invoked.[21] Kappe then re-ex-
amined the Biginelli mechanism[22] and found that the exper-
imental evidence aligned with an iminium-like mechanism.
Due to our interest in the development of new ion-tagged
catalysts[23] in reaction mechanism investigations,[24] in ionic-
liquid effects on catalysis,[25] and on MCR reactions,[16] we
describe herein the synthesis, characterization, and applica-
tion of a new ion-tagged recyclable iron catalyst to the Bigi-
nelli reaction. Mass spectrometry, kinetics, and density func-
tional theory are employed to investigate the mechanism by
which the Biginelli reaction proceeds in the presence of the
catalyst. In addition, the antitumoral activity of selected
DHP derivatives synthesized in this work is described.
Scheme 2. Synthesis of the two ion-tagged iron catalysts.
Notably, in the gas phase, the anion
Fe2Cl7 loses neutral FeCl3 forming the anion
been recently demonstrated that in the presence of
[FeCl4]À, additional quantities of FeCl3 forces the formation
of
[Fe2Cl7]À.[31]
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Catalyst performance: Traditional conditions for the Biginel-
li reaction commonly require large excess of one of the re-
agents, large amounts of catalyst, high temperatures, several
hours of reaction, and occasionally the presence of a co-cat-
alyst.[32] In an attempt to find milder conditions, the activi-
ties of the new catalysts were tested in several organic sol-
vents and ILs. The reaction of urea (3.00 mmol), benzalde-
hyde (3.00 mmol), and ethyl acetoacetate (3 mmol) in the
presence of either MAI·FeCl4 (10 mol%) or MAI·Fe2Cl7
(10 mol%) at 808C for 1 h was used as a model reaction.
The results are summarized in Table 1.
As seen in Table 1, MAI·Fe2Cl7 is more active than MAI·-
FeCl4 in all cases. This reaction has already been described
with FeCl3 as the promoter,[33] and it required large excess
of one of the reagents (urea), iron (30 mol), additional cata-
lytic amounts of HCl, and at least four hours to achieve rea-
sonable yields. In the absence of solvent (Table 1, entries 1
and 2) the yields were comparable to reactions carried out
in the presence of classical solvents (Table 1, entries 3–14).
Conversely, reactions carried out in ionic media (Table 1,
Entries 15–22) provided higher yields than those performed
in organic solvents, except entries 15 and 16. To improve the
results, we optimized the reaction conditions by using MAI·-
Fe2Cl7 as the catalyst and the IL BMI BF4 as the reaction
medium (Table 1, entry 21). BMI·PF6 resulted in the same
yield as BMI·BF4 (Table 1, entries 19 and 20), but the re-
Results and Discussion
Catalyst synthesis and characterization: Aiming at a more
efficient support in the selected reaction media and envisag-
ing catalyst recyclability, two new ion-tagged iron catalysts
were synthesized (Scheme 2). The choice of iron as the
metal with the ionophilic ligand is compatible with green
and sustainable processes. The ion-tagged catalyst would
also allow an efficient support in the ionic media, thus im-
proving the solubility/stability[26] of the catalyst and its elec-
trostatic activation[27] favoring the ionic-liquid effect, that is,
an auto-organization forming well-ordered nano-organized
structures,[28] as discussed below. Moreover, ILs are regarded
as promising candidates for green and sustainable process-
es.[29] Hence, this unique combination of ILs and ion-tagged
iron catalysts is expected to be a powerful combination to-
wards eco-friendly catalytic processes.
The ionophilic ligand (MAI·Cl) was obtained as previous-
ly described.[30] MAI·Cl was directly treated with FeCl3, af-
fording the new catalysts in quantitative yields (MAI·FeCl4
and MAI·Fe2Cl7). Both catalysts were characterized by high-
resolution electrospray-ionization quadrupole time-of-flight
mass spectrometry (ESI-QTOF-MS and MS/MS) (Figure 2).
AHCTUNGTREGaNNUN ction medium turned dark, most probably due to anion
degradation, as previously reported.[34] It has been reported
À
that hexafluorophosphate (PF6 ) degradation may be more
pronounced in reactions involving metals, which can cata-
lyze this decomposition.[35]
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Ramos, Luciana M.
