The three-component biginelli reaction: A combined experimental and theoretical mechanistic investigation

Article abstract of DOI:10.1002/chem.200900470

Biginelli reactions have been monitored by direct infusion electrospray ionization mass spectrometry (ESI-MS) and key cationic intermediates involved in this three-component reaction have been intercepted and further characterized by tandem MS experiments

Full text of DOI:10.1002/chem.200900470

FULL PAPER
DOI: 10.1002/chem.200900470
The Three-Component Biginelli Reaction: A Combined Experimental and
Theoretical Mechanistic Investigation
Rodrigo O. M. A. De Souza,*[a] Eduardo T. da Penha,[a] Humberto M. S. Milagre,[b]
Simon J. Garden,[a] Pierre M. Esteves,[a] Marcos N. Eberlin,[c] and
Octavio A. C. Antunes[a]
Dedicated to the memory of Professor Octavio A. C. Antunes for his friendship, leadership, and inspiring life and career.
Professor Octavio A. C. Antunes, his wife Patricia, and their son Mateus were victims of the tragic accident involving
flight AF 447 on May 31, 2009.
Abstract: Biginelli reactions have been monitored by direct infusion electrospray
ionization mass spectrometry (ESI-MS) and key cationic intermediates involved in
this three-component reaction have been intercepted and further characterized by
tandem MS experiments (ESI-MS/MS). Density functional theory calculations
were also used to investigate the feasibility of the major competing mechanisms
proposed for the Biginelli reaction. The experimental and theoretical results were
found to corroborate the iminium mechanism proposed by Folkers and Johnson,
whereas no intermediates directly associated with either the more energy demand-
ing Knoevenagel or enamine mechanisms could be intercepted.
Keywords: Biginelli reaction · den-
sity functional calculations · electro-
spray mass spectrometry · heterocy-
clic
compounds
·
reaction
mechanisms
Introduction
iations in all three components leading therefore to a
myriad of dihydropyrimidines (Scheme 1).[2–12]
In 1893, Pietro Biginelli published his pioneering findings
on a three-component reaction that has become known as
the Biginelli reaction. This three-component one-pot reac-
tion leads to the synthesis of dihydropyrimidines (1) typical-
ly by the reaction of a benzaldehyde (2), an acetoacetate
(3), and an (thio)urea (4) under acid catalysis.[1] The Biginel-
li reaction is quite versatile as it can be performed with var-
Bignelli reactions can be performed under a variety of
conditions, and several improvements of the experimental
procedures have been reported in recent years. Although it
has been traditionally catalyzed by strong Brønsted acids,
Lewis acids such as LiClO4, LaCl3, InCl3, BiACHTNUGTRENUNG(OTf)3, BiCl3,
[13–17]
Mn
G
(OTf)2, FeCl3, ZrCl4, or SnCl2
are now
being increasingly used. The use of ionic liquids,[18–20] micro-
wave irradiation,[7,21–31] solid-phase reagents,[12,32,33] and poly-
mer-supported catalysts have also been reported.[34,35] Two
asymmetric versions of Biginelli reactions using CeCl3/InCl3
[a] Prof. Dr. R. O. M. A. De Souza, E. T. da Penha, S. J. Garden,
P. M. Esteves, O. A. C. Antunes
Institute of Chemistry, Federal University of Rio de Janeiro
Cidade Universitꢀria CT bloco A, RJ 21941-909 (Brazil)
Fax : (+55)21-2562-7559
or YbACTHNUTRGNE(NUG OTF)3 in the presence of chiral ligands have also
been recently reported.[3,36–39] A driving force in developing
synthetic methodologies for Bignelli products 1 is their simi-
lar pharmacological profile with analogous drugs, such as ni-
fedipine (Scheme 1) which act as calcium channel modula-
tors.[40]
E-mail: rodrigosouza@iq.ufrj.br
[b] Prof. Dr. H. M. S. Milagre
Department of Biochemistry and Microbiology
S¼o Poulo State University
13506-900, Rio-Claro SP (Brazil)
Since its first report in 1893, a number of mechanisms
have been forwarded for the Biginelli reaction. During the
1930s, Folkers and Johnson proposed that 5a, 6a, and 7a
(Scheme 2) could be involved.[41] The N,N-benzylidenebis-
[c] Prof. Dr. M. N. Eberlin
ThoMSon Mass Spectrometry Laboratory
Institute of Chemistry, State University of Campinas—UNICAMP
13084-971, Campinas SP (Brazil)
AHCTUNGTREGuNNNU rea (5a) would result from intermolecular condensation of
benzaldehyde (2a) and two equivalents of urea (4a). Inter-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900470.
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Biginelli reaction conditions, he
found that the equilibrium lies
to the side of the reagents, that
is, 3a and 4a.
Recently, intermediates 13
and 14 (Scheme 4) were isolat-
ed employing sterically bulky[44]
or electron-deficient acetoace-
tates ,[45] respectively, and dehy-
dration of 14 gave 1b using p-
toluenesulfonic acid. A number
of hexahydropyrimidines close-
ly related to 1b have been pre-
pared by using perfluorinated
1,3-dicarbonyl compounds or b-
Scheme 1. The one-pot three-component Biginelli reaction.
keto esters as building blocks in
the Biginelli condensation.[46,47]
Recently, direct infusion elec-
trospray ionization mass spectrometry (ESI-MS) has been
incorporated to the set of major techniques for mechanistic
studies of organic and inorganic reactions.[48,49] Owing to its
outstanding ability to “fish” ionic or ionized intermediates
directly from reaction solutions into the gas phase, with high
sensitivity, speed and gentleness, ESI-MS and its tandem
version ESI-MS/MS have provided continuous snapshots of
the ionic composition of reaction solutions with on-line MS
and MS/MS characterization of the intercepted intermedi-
ates. We rationalized therefore that ESI-MS and ESI-MS/
MS, by its outstanding ability to intercept intermediates
(even transient species) could provide a detailed picture of
the Biginelli mechanism in light of its three alternative
mechanisms (Scheme 3). Additionally, a theoretical investi-
gation using DFT calculations to evaluate the feasibility of
the three competing mechanisms was undertaken.
The Bignelli intermediates were expected to be trans-
ferred directly from solution to the gas phase and detected
by ESI-MS in the positive-ion mode either in their natural
cationic forms (such as 12a and 9a) or in protonated forms
(Scheme 3). In ESI-MS/MS experiments, the structures of
these gaseous cationic intermediates could then be investi-
gated by collision-induced dissociation (CID) with argon.
Scheme 2. Intermediates proposed by Folkers and Johnson for the Bigi-
nelli reaction.[41]
mediate 6a is an enamine formed by condensation of 3a
and 4a, whereas intermediate 7a is known as the Knoevena-
gel adduct formed by condensation of 2a and 3a.
In 1973, Sweet and Fissekis[42] proposed a more detailed
mechanistic interpretation for the Biginelli reaction, which
has became known as the Knoevenagel mechanism (mecha-
nism C in Scheme 3). Their mechanism is based on the for-
mation of a carbenium ion (9a) in the rate-limiting step of
an acid-catalyzed Knoevenagel reaction between 2a and 3a.
Intermediate 9a was proposed to react with 4a forming
adduct 10a (via 21a), which would undergo an intramolecu-
lar condensation reaction to give the Biginelli dihydropyri-
midine 1a.
More recently, Kappe[43] used NMR to investigate Biginel-
li intermediates. Monitoring the reaction of benzaldehyde
1
(2a) and ethyl acetoacetate (3a) in CD3OH/HCl by H and
Results and Discussion
13C NMR spectroscopy, he found no evidence for an aldol
reaction or any other reaction between the two components
at room temperature. Further, Kappe also observed the for-
Based on the overall mechanistic view of Scheme 3, we first
investigated the formation of the dormant bisureide 5a.
Benzaldehyde (2a, 1 mmol) and urea (4a, 2 mmol) were
mixed in aqueous methanol (1:1 v/v, 5 mL) in the presence
of a catalytic quantity of formic acid (0.1 mol%) and, most
importantly, in the absence of ethyl acetoacetate (3a). After
5 min, a sample of the reaction solution was taken and its
ESI(+)-MS recorded.
Figure 1 shows that ESI(+)-MS was able to intercept key
cationic species: protonated bisureide [5a+H+] of m/z 209;
the iminium ion 12a of m/z 149; its hydrated precursor 11a
of m/z 167 as well as the reagents, protonated benzaldehyde
1
mation of bisureide 5a (Scheme 3) by H NMR spectroscopy
(CD3OH, HCl), but no other intermediate (11a or 12a) was
detected (Scheme 3). Kappe assumed that the first addition
step (2a + 4a to give 11a) is the rate-determining step and
that both the subsequent acid-catalyzed dehydration (11a to
12a) and the addition of a second equivalent of urea to the
iminium ion (12a + 4a to give 5a) are fast steps, and there-
fore do not allow 11a or 12a to accumulate.
The presence of an enamine intermediate 6a (mechanism
B in Scheme 3) was also investigated by Kappe. Under the
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The Three-Component Biginelli Reaction
FULL PAPER
Scheme 3. The iminium (A), enamine (B), and Knoevenagel (C) mechanisms for the Biginelli reaction.
of formic acid (0.1 mol%) as catalyst. Figure 2 shows the
ESI(+)-MS collected after 5 min of reaction. Ions that were
previously detected in the absence of 3a (Figure 1) were
again detected, but now three novel ions appeared which
correspond to: a) intermediate 18a of m/z 191; b) the final
Biginelli product in its protonated form
[1a+H+] of m/z 261
ACHTUNGTRENNUNG
and c)
AHCTUNGTRENNUNG
Scheme 3 (perhaps in equilibrium with its isomeric form
21a). These key ions were also characterized by ESI(+)-
MS/MS (see the Supporting Information) and their dissocia-
tion chemistry was found to agree with the proposed struc-
tures.
Scheme 4. Intermediates 13 and 14 obtained from electron-deficient or
sterically bulky acetoacetates.
Ions for the Knoevenagel mechanism such as the carbeni-
um ion 9a of m/z 219 or its isomer 19a (Scheme 3) were not
detected by ESI-MS (Figure 2), even after a reaction time of
ACHTUNGTRENNUNG
[2a+H]+ of m/z 107 and the protonated urea dimer 16a of
m/z 121. The intermediates intercepted by ESI-MS were
then selected for further ESI(+)-MS/MS characterization
which, by showing predictable dissociation routes, provided
evidence for the proposed structures, see the Supporting In-
formation.
2 h with continuous monitoring. However, the ion ACHTUNGTRENNUNG[8a+H]
of m/z 237 was observed. The ESI(+)-MS interception of
11a, 12a and [10a+H+] are therefore more consistent with
the iminium mechanism (Scheme 3).
We then performed the Biginelli reaction under the usual
conditions with 2a, 3a, and 4a (1 mmol each) in aqueous
methanol (1:1 v/v, 5 mL) with a sub-stoichiometric amount
Kappe has questioned the participation of enamine 6a
(Scheme 3) arguing that the equilibrium for its formation
lies far to the side of the reactants 3a and 4a. By ESI(+)-
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R. O. M. A. De Souza et al.
Figure 3. ESI(+)-MS for the reaction between 3a and 4a.
Figure 1. ESI(+)-MS for the reaction of 2a with 4a.
Figure 4. ESI(+) MS of the Knoevenagel condensation between 2a and
3a after a reaction period of 24 h.
Figure 2. ESI(+)-MS for the three-component Biginelli reaction of 2a,
3a and 4a.
The Knoevenagel mechanism, evidenced by the detection of
the intermediate 7a (detected as its protonated form 19a)
after a reaction period of 24 h, seems to be feasible but too
slow in comparison to the much shorter time scale of the Bi-
ginelli reaction to contribute significantly to product forma-
tion under the conditions used in this study.
To evaluate possible intermediates and transition states,
and to compare the energetics of the proposed mechanisms:
Folkers and Johnson (A), enamine (B), and Sweet and Fis-
sekis (C) (see Scheme 3), DFT B3LYP/6-31G* calculations
were performed. The effect of solvation was also investigat-
ed by use of the IEFPCM solvation model and single-point
energies were calculated by using MP2/6-311++G**. The
polarizable continuum model (PCM)[50,51] was chosen so as
to mimic the effect of solvent. This model uses the physical
properties of the solvent to simulate an artificial solvation
environment without the explicit incorporation of solvent
molecules on the structures calculated. Recently, Zhou and
co-workers reported a short DFT study where they analyzed
the iminium mechanism as proposed by Kappe.[52]
MS monitoring we detected and characterized 18a but
failed to detect the enamine 6a in its protonated form 23a
of m/z 173. To verify whether the failure to detect 6a could
be due to its transient nature (fast formation and/or con-
sumption), 4a (2 mmol) and 3a (1 mmol) were mixed in
aqueous methanol (1:1 v/v, 5 mL) in the absence of 2a and
in the presence of formic acid (0.1 mol%), as above. After
5 min, analysis by ESI(+)-MS (Figure 3) was unable to
detect the protonated enamine 23a although its postulated
immediate precursor 18a of m/z 191 was readily detected as
an abundant ion.
We then monitored, by ESI(+)-MS, the Knoevenagel con-
densation between 2a (1 mmol) and 3a (1 mmol) in aqueous
methanol (1:1 v/v, 5 mL) leading to 8a in the presence of
formic acid (0.1 mol%) and in the absence of 4a. The reac-
tion was monitored periodically and after 6 h only the pro-
tonated reactants were detected. The reaction solution was
left stirring overnight and, after 24 h, the ESI(+)-MS was
collected (see Figure 4). Analysis reveals that the protonat-
ed Knoevenagel adduct 19a of m/z 219 and its protonated
Figure 5 presents a potential energy surface for the three
mechanisms and Figure 6 shows the calculated structures for
the lowest energy pathway. Figure 5 shows that the forma-
tion of intermediates 11a and 18a, through the transition
aldolic precursor
ACHTUNGTRENNUNG
[8a+H+] of m/z 237 were finally detected.
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The Three-Component Biginelli Reaction
FULL PAPER
311++G** (values in parenthesis in Figure 5). The calcula-
tions that Figure 5 summarizes reveal that the iminium
mechanism is kinetically and thermodynamically favored for
the Biginelli reaction. This prediction is consistent with the
experimental ESI(+)-MS/MS data.
Conclusions
ESI(+)-MS monitoring of the Biginelli reaction under
three- and two-component conditions indicate that the
Knoevenagel pathway is too slow and should not significant-
ly contribute to formation of the Bignelli product. In accord
with this finding, DFT calculations of the Knoevenagel path-
way revealed a step with the largest activation barrier for
the proposed mechanisms. A single early intermediate (18a)
associated with the enamine mechanism was intercepted,
but it is postulated to be a dormant species that reverts to
reagents during the course of reaction. Several intermedi-
ates associated with the iminium mechanism were intercept-
Figure 5. Potential energy surfaces for the three alternative Biginelli reac-
tion mechanisms (routes A–C). Note that the energies of TS1A, TS1B,
and TS1C are lower in energy than the reactants, but this is a conse-
quence of the method of comparison of the relative energies (see the
Supporting Information). The values in parentheses refer to MP2/6-311+
+GACHTUNGTRENNUNG(d,p)//B3LYP/6-31+G(d) IEPFPCM calculations.
ed and characterized by ESI(+)-MSACTHUNTGRNEUNG(/MS). DFT calculations,
including solvent effects, have
also indicated that the iminium
mechanism is the kinetically
and thermodynamically fa-
vored route to the Biginelli
product. Therefore, the com-
bined experimental and theo-
retical results support that the
iminium mechanism (A in
Scheme 3) is favored in Bigi-
nelli reactions. The most rea-
sonable mechanistic interpre-
tation would therefore assume
three principal steps for the
Biginelli reaction: 1) conden-
sation of aldehyde 2 with the
(thio)urea 4 in acidic media to
form iminium ion 12 as the
key intermediate; 2) addition
of enolic acetoacetate 3 to 12
to form 10, the immediate acy-
Figure 6. Optimized structures for key intermediates and transition states for the iminium mechanism of the
Biginelli reaction with selected bond lengths [ꢂ].
sates TS1A and TS1B, that is, the iminium (A) and enamine
clic precursor of the final product and; 3) intramolecular ad-
dition leading to analogs of cyclized 14 and the formation of
the final heterocyclic dihydropyrimidine product 1 via dehy-
dration (Scheme 3).
(B) mechanisms, respectively, are much more favored in
comparison with the formation of ACHTUNGTRNEUNG
[8a+H+] via TS1C for
the Knoevenagel mechanism (C). Intermediate 11a readily
undergoes dehydration to give the iminium ion 12a. Note
that both 12a and 18a were intercepted by ESI(+)-MS.
Kappe,[43] as already mentioned, has shown that 12a is in
equilibrium with the diureide 5a. Intermediate 12a subse-
quently undergoes addition of enolic 3a to give 22a (via
TS2A), which cyclizes to the final Biginelli product 1a. The
alternative enamine pathway via enamine 6a passes through
TS2B, which is 4.7 kcalmolÀ1 higher in energy than TS2A.
Note that similar energy profiles were obtained when con-
sidering solvation effects via the IEFPCM solvation model
or via the single point energies calculated using MP2/6-
Acknowledgements
We thank the following Brazilian science foundations for financial assis-
tance: CNPq, FAPESP, FAPERJ, and FINEP.
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Received: February 20, 2009
Published online: August 7, 2009
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