Bifunctional acid-base ionic liquid for the one-pot synthesis of fine chemicals: Thioethers, 2H-chromenes and 2H-quinoline derivatives

Article abstract of DOI:10.1016/j.apcata.2014.05.004

A bifunctional organocatalyst with ionic liquid properties and with an optimized distance between the acid and basic sites efficiently activates electron deficient olefins for 1,4 conjugated addition, which can be incorporated in different one-pot transformations for the preparation of cyclic and acyclic compounds of biological and synthetic interest. More specifically, the catalyst can be successfully applied for different carbon-carbon (CC) and carbon-heteroatom (C-N, C-O, C-S) bond forming reactions integrated in a cascade sequence. The activity of the organocatalyst has been compared with that of structurally related monofunctional and bifunctional catalysts. The most attractive features of this procedure are the high atom economy and the use of inexpensive starting materials as well as the use of an environmentally friendly catalyst that can be easily recovered due to its ionic liquid properties.

Full text of DOI:10.1016/j.apcata.2014.05.004

Accepted Manuscript
Title: Bifunctional acid-base ionic liquid for the one-pot
synthesis of fine chemicals: thioethers, 2H-chromenes and
2H-quinoline derivatives
Author: Maria J. Climent Sara Iborra Maria J. Sabater Juan D.
Vidal
PII:
S0926-860X(14)00315-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2014.05.004
APCATA 14824
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
13-2-2014
30-4-2014
2-5-2014
Please cite this article as: M.J. Climent, S. Iborra, M.J. Sabater, J.D. Vidal, Bifunctional
acid-base ionic liquid for the one-pot synthesis of fine chemicals: thioethers, 2H-
chromenes and 2H-quinoline derivatives, Applied Catalysis A, General (2014),
http://dx.doi.org/10.1016/j.apcata.2014.05.004
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1
Bifunctional acid-base ionic liquid for the one-pot synthesis of
fine chemicals: thioethers, 2H-chromenes and 2H-quinoline
derivatives
Maria J. Climent, Sara Iborra, Maria J. Sabater, * Juan D. Vidal
Instituto de Tecnología Química (UPV-CSIC), Universitat Politècnica de València,
Consejo Superior de Investigaciones Científicas, Av. de los Naranjos s/n,
46022 Valencia, Spain.
Fax: 34 96 387 7809
E-mail: mjsabate@itq.upv.es
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Abstract
A bifunctional organocatalyst with ionic liquid properties and with an optimized
distance between the acid and basic sites efficiently activates electron deficient olefins
for 1,4 conjugated addition, which can be incorporated in different one-pot
transformations for the preparation of cyclic and acyclic compounds of biological and
synthetic interest.
More specifically, the catalyst can be successfully applied for different carbon-carbon
(C-C) and carbon-heteroatom (C-N, C-O, C-S) bond forming reactions integrated in a
cascade sequence. The activity of the organocatalyst has been compared with that of
structurally related monofunctional and bifunctional catalysts.
The most attractive features of this procedure are the high atom economy and the
use of inexpensive starting materials as well as the use of an environmentally friendly
catalyst that can be easily recovered thanks to its ionic liquid properties.
Keywords: organocatalysis, bifunctional, acid-base, one-pot, Michael addition,
condensation, fine chemicals, chromenes, quinolines
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1. Introduction
One possibility to improve activity and selectivity of chemical processes is the design of
multisite catalysts that can jointly act and minimize the energy of the reaction transition
state. The cooperative interactions occurring between two different catalytic centers and
a given reaction transition state enable transformations that are not possible, or are done
less efficiently, by using each catalyst separately. [1-3] For example a dual cooperation
between acid and base centers placed on the same support and between complexes has
been described. [1-3] In those cases where both active sites intervene in the transition
state, the distance between the centers will be a key parameter to achieve high catalytic
activities and selectivities. This mode of activation can also occur with organocatalysts,
[4] as is the case for protonated gem-diamine piperidinomethane piperidium
tetrafluoroborate (A), a molecule with an acid-base pair in close proximity, which has
shown high activity and selectivity for condensation reactions. [5] Along with this, the
combination of the acid and basic sites in the same molecule could make the
organocatalyst behave as an ionic liquid hence facilitating its recovery and reuse. Thus,
the interesting structural and chemical features as well as the good results obtained with
gem diamine A for condensations, led us to explore the ability of this molecule as
organocatalyst to perform multiple transformations in a single pot. Hence we will show
that synthetic strategies involving a Michael reaction coupled with other acid/base
catalyzed reactions in a sequential mode, allow gains of complexity in the synthesis of
cyclic and acyclic organic structures of interest in the fine chemicals industry. [6] For
achieving this, the ability of compound A for catalyzing the conjugated 1,4-addition of
olefins will be studied and the results will be compared with the performance of other
structurally related catalysts. Then, the ability of gem diamine A to couple an aldol
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condensation reaction with a sulfa-Michael addition for forming new sulfur containing
compounds in an expeditious way will be studied (Scheme 1).
INSERT SCHEME 1
It has to be said that a sulfa-Michael addition is an important synthetic tool for forming
carbon sulfur bonds, since other synthetic alternatives such as the aldol reaction
involving thiocarbonyl compounds are of limited synthetic viability. [7, 8] These
limitations come from the fact that thiocarbonyl compounds are generally poor
electrophiles, unstable under the aldol reaction conditions and are difficult to synthesize.
[8,9]
Finally, we have also shown that the above working methodology is successful for
performing two different cascade reactions involving a 1,4-conjugated addition
(Michael reaction) and a cyclocondensation reaction, leading to the synthesis of types
of heterocyclic compounds containing a 2H-chromene (3) and a 2H-quinoline (4) core.
[10, 11]
INSERT SCHEME 2
Chromenes and quinolines are structural motifs that are usually found in natural
products and drug-like compounds. In fact, chromenes have pharmacological activity as
anti HIV, antitumor, antibacterial, fungicidal and insecticidal agents among other things;
[10] whereas the quinoline ring occurs in general in natural products (especially in
alkaloids), as is often involved in the design of synthetic compounds in the areas of
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medicine, food, catalysis, dyes, and electronics. [11] For example, in the area of
pharmacology the activity of quinolines in the treatment of leishmaniasis, malaria, as
antitumor agents, antibiotics and antifungals is well-known. [11]
Due to the wide variety of applications, the synthesis of chromenes and quinolines has
been an attractive goal for most synthetic organic chemists. The non-availability of
many of these substrates and/or the limitations for achieving a specific substitution
pattern as the main incentives for searching alternatives for the synthesis of these
scaffolds by means of green and efficient processes should also be taken into account.
To this respect, synthetic organic chemists have made use of new catalysts and/or
different methodologies to obtain the chromene as well as the quinoline structures. [12-
15]
However, despite many efforts, the catalytic synthesis of 2H-chromenes (3) and 2H-
quinolines (4) has been reported to still proceed with large catalyst to substrate ratios, in
occasions with the intervention of additives and usually with the impossibility of
recovering and recycling the catalyst. [14, 15]
One will see here that is possible to prepare these molecules with high efficiency, while
overcoming many of the above described drawbacks, by using a bifunctional acid-base
catalyst with ionic liquid properties.
2. Experimental
Reagents solvents and basic and neutral Al2O3 were obtained from commercial sources and
were used as received.
1) Synthesis of catalysts A and B. The catalysts were synthesized according to a procedure
described in the literature. [5b]
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Synthesis of catalyst A: A 100 mL round-bottomed flask was charged with
dipiperidinomethane (10 g, 54.85 mmol) and diethyl ether (30 mL). Then equimolar
amounts of tetrafluoroboric acid/diethyl ether were added dropwise into an ice bath. The
mixture was stirred at room temperature for 1 h. A solid was formed which was
recovered by filtration being exhaustively washed with diethyl ether. Then the solid was
dried under vacuum to give the organic salt as a yellow solid (8.1 g, 55%).
Synthesis of catalyst B: 100 mL round-bottomed flask was charged with 1,2-di(N-
piperidine)ethane (5.0 g, 25.47 mmol) and diethyl ether (30 mL). Then equimolar
amounts of tetrafluoroboric acid/diethyl ether were added drop-wise into an ice bath.
The mixture was stirred at room temperature for 1 h. A solid was formed and was
recovered by filtration being washed exhaustively with diethyl ether. Finally it was
dried under vacuum to give the organic salt as a yellow solid (4.25 g, 58.7%).
2) General procedure for the Michael addition reaction: In a typical experiment 0.1
mmol (or 0. 28 mmol) of catalyst and 1.5 mmol (or 2.8 mmol) of nucleophile were
incorporated into a reactor while stirring under inert atmosphere. After temperature
adjustment (80 ºC or 110 ºC), 1 mmol (or 2.8 mmol) of the carbonyl compound were
added the reaction being periodically monitored by GC. The products were
characterized by GC-MS and 1H and 13C-NMR by comparing with spectroscopic data of
authentic samples.
3) General procedure for the condensation/sulfa-Michael one-pot sequence:
In a typical experiment 0.1 mmol of the catalysts were added to a solvent free solution
of acetophenone (1 mmol) while stirring under inert atmosphere. After temperature
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adjustment (100ºC), benzaldehyde (1 mmol) was added the reaction being periodically
monitored by GC. After completing the formation of the condensation product chalcone,
a stoichiometric amount of thiol was incorporated in the reactor and the reaction was
monitored by GC. The products were characterized by GC-MS and 1H and 13C-NMR by
comparing with spectroscopic data of authentic samples.
4) General procedure for the Michael addition/cyclization one-pot sequence
4a) Synthesis of 2H-chromene derivatives
In a typical experiment catalyst A (10% mol) was added to a solution containing a net
solution of salicylaldehyde (1 mmol) and the alkene (1 mmol) while stirring under inert
atmosphere. The temperature was adjusted to 100ºC, and the reaction was periodically
monitored by GC. The products were characterized by GC-MS and 1H and 13C-NMR by
comparing with spectroscopic data of authentic samples.
4b) Synthesis of 2H-quinoline derivatives
In a typical experiment catalyst A (10% mol) was added to a solution containing a
solvent free solution of 2-aminobenzaldehyde (1 mmol) and the alkene (1 mmol) while
stirring under inert atmosphere. After temperature adjustment (80ºC), the reaction was
periodically monitored by GC. The products were characterized by GC-MS and 1H and
13C-NMR by comparing with spectroscopic data of authentic samples.
Experimental techniques: NMR spectra were recorded using a Bruker Avance 300
spectrometer at 300 (1H) and 75 (13C) in deuterated solvents with TMS as an internal
standard.
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Gas Chromatography coupled to Mass Spectrometry (GC-MS) was carried out using an
Agilent 6890N GC /5973 Network model.
Gas chromatography was carried out using a Varian CP8400 equipment.
3. Results and Discussion
Given that previous studies have already shed light on the best conditions to carry out
condensation reactions, [5] we have conducted preliminary experiments on the Michael
addition in order to search a common operational window (temperature and solvent) for
the desired multistep process that involves a condensation and a Michael addition.
Study of the Michael addition
Initially the Michael addition (1,4-conjugated addition) of different nucleophiles to the
α,β-unsaturated carbonyl compounds 1,3-diphenyl-2-propenone and 2-cyclohexen-1-
one were chosen as model reactions, and the activity and selectivity of bifunctional
catalyst A was compared with that of other monofunctional (C, D, E) and bifunctional
B related catalysts depicted below.
INSERT CHART 1
For example, in the acid-base organocatalyst B the separation between both active
centers has been increased with respect to catalyst A, whereas compound C (the basic
catalyst A precursor) is a strong basic catalyst which has shown high activity for aldol
condensations. [4b] Finally, methylpiperidine
D
and N-methylpiperidinium
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tetrafluoroborate E are organocatalysts commonly used for basic and acid catalyzed
reactions respectively. [16]
In the first part of the work, a Michael addition between the nucleophile benzenethiol
and the enone 1,3-diphenyl-2-propenone (chalcone) acting as Michael acceptor was
performed with the organocatalysts depicted in chart 1 and the results are collected in
Table 1 (see entry 1, Table 1).
INSERT TABLE 1
As shown in Table 1, the organocatalyst A exhibited an excellent activity and
selectivity towards the Michael adduct when reacting 1,3-diphenyl-2-propenone
(chalcone) and benzenethiol in the absence of solvent, whereas catalysts B, C and D
were less active and selective than the former (entries 1-4, Table 1). Indeed, the
resulting adduct was obtained at 110ºC with very good yields and in a relative short
period of time with catalyst A (entry 1, Table 1), while no by-products were generated
from 1,2-addition or polymerization or even hydrolytic reactions, under our
experimental conditions.
It is interesting to notice that the activity of the catalyst decreased when the
separation between both active centres was increased in the related organocatalyst B
(see Chart 1 and results in Table 1 when going from catalyst A to catalyst B). This fact
highlights the importance of keeping the appropriate distance between both catalytic
functions to stabilize a given transition state (entries 1-2, Table 1). [5]
The higher activity of catalyst A can be attributed to a cooperative effect in where the
carbonyl group of chalcone interacts with the acid site increasing the electron deficiency
of the β-carbon of the enone in close analogy to previous studies on condensation
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reactions [5], while the lone pair of the nearby N-basic center of A, abstracts the acidic
proton of benzenethiol to generate a sulphur anion. The activation of both reactant
molecules (protonated chalcone and anion) in the transition state complex at the proper
distance facilitates the formation the Michael adduct (Scheme 3).
INSERT SCHEME 3
Just for comparison it is necessary to indicate that the bifunctional amino acid L-
proline has been reported to catalyze the Michael addition between the same
nucleophile /Michael acceptor pair with very good yields albeit working in ionic liquids
as solvents. [17]
Since the Michael reaction can be catalyzed by stronger bases or acids, which will
activate either the nucleophile or the acceptor component of the reaction [18] we have
also used catalysts C and D. The Michael 1,4-adduct was obtained, albeit with
moderated yields, under the same experimental conditions (entries 3-4, Table 1).
In view of these results, the conjugated enone 2-cyclohexen-1-one was selected as
Michael acceptor being reacted with benzenethiol as S-nucleophile in the presence of
the organocatalysts A-D, again in the absence of solvent at moderate temperature. The
results collected in Table 1 show that again the conjugated addition of benzenethiol to a
hexacyclic enone can selectively be conducted in the presence of the bifunctional
catalyst A to afford the corresponding sulfa-Michael adduct with very good conversion
(98%) and selectivity (95%), as compared with the rest of catalysts B-D (entries 5-8,
Table 1).
In this case, it is necessary to indicate that the diphenyldisulfide compound could be
detected as by-product, especially with the more basic catalysts C and D. Indeed,
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disulfides form spontaneously by autooxidation of thiols upon exposure to air. [19]
Since deprotonation of thiol to thiolate is the first step in disulfide formation, this
reaction will be fast under neutral and basic conditions explaining why the more basic
catalysts C and D are less selective towards the formation of the Michael adduct,
whereas less basic conditions or even acidic conditions will stabilize thiols. [19]
It has to be pointed out that the Michael addition of thiols to α,β-unsaturated carbonyl
compounds has been described to also occur without catalyst, albeit using an excess of
thiol. [20] Taking into account this precedent, a blank reaction was carried out in the
absence of catalyst showing that the reaction did not occur under our reaction conditions.
Finally, it is important to remark that the Michael addition is a highly demanding
reaction in basic catalyzed reactions, showing the interest of applying bifunctional
organocatalyst A with acid/base sites.[4] In other words a bifunctional acid-base catalyst
with lower basicity can catalyze reactions that would require stronger basicities with a
monofunctional base catalyst.
In summary, organocatalyst A has shown to be active and selective for the Michael
addition with two different unsaturated carbonyl compounds and thiophenol as sulphur
nucleophile (see Table 1), and we are now really ready to combine a conjugated 1,4-
addition with different condensation reactions in order to prepare a variety of fine
chemicals in one-pot processes.
Two-step reactions catalyzed by organocatalyst A in one-pot
a) Sequential condensation/sulfa-Michael addition for obtaining sulphur-
containing compounds in one-pot process.
We have devised a one-pot sequence in which the formation of 1,3-diphenyl-2-
propenone 1 as Michael acceptor, was followed by the 1,4 conjugated addition with
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different aliphatic and aromatic thiols. The general structure of the resulting Michael
adducts 2a-f as well as the yields obtained by reacting benzaldehyde, acetophenone and
diverse thiols are summarized in Table 2.
INSERT TABLE 2
In an initial approach benzaldehyde and acetophenone reacted in the presence of
bifunctional catalyst A to form chalcone, which reacted in situ with different thiols
acting as nucleophiles, to afford different sulphur containing compounds with very good
yields in a two-step one-pot strategy (Scheme 1 and Table 2).
The combination of these two individual reactions in a single pot requires a change in
the reaction conditions in order to maximize the yield of the final Michael adducts.
Then the first step was carried out at 130ºC and the second one was performed at lower
temperature (100ºC) under solventless conditions (see Table 2).
b) Sequential Michael addition/cyclocondensation reactions for forming 2H-chromenes
and 2H-quinolines in a one-pot process.
The synthesis of important heterocycles such as 2H-chromenes or 2H-benzopyrans and
2H-quinolines was also accomplished in the presence of organocatalyst A. For
achieving this, a tandem reaction comprising a Michael addition followed by an
intramolecular cyclocondensation furnished chromenes and quinolines derivatives in
one-pot. With this objective, different salicylaldehydes were reacted with a variety of α-
functionalized alkenes in presence of catalyst A, resulting in the formation of diverse
2H-benzopyran structures under solventless conditions.
The most important results obtained on this reaction are detailed in Table 3.
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INSERT TABLE 3
From the results collected there, we can conclude that, in general, organocatalyst A
efficiently catalyzes the synthesis of 2H-chromenes starting from salicylaldehyde
derivatives and trans-β-nitrostyrene as electron acceptor (entries 1-7, Table 3).
Moreover, we found that selectivitities toward the corresponding chromene derivatives
were in all cases 100%. A priori, these good results can be explained on the bases of the
strong inductive effect of the nitro group on the double bond that makes the latter more
prone to an electrofilic attack versus other electrowithdrawing groups, vs. a formyl
group (compare entries 1-7 and 8-11 in Table 3). Therefore the utility of this strategy is
evident if we take into account that both the nitro and formyl groups are valuable
precursors for producing a wide variety of target molecules.
In order to complete the scope of the reaction, other selected examples were assessed by
using salicylaldehyde derivatives, as well as differently substituted trans-β-nitrostyrenes.
The most interesting results are collected in Table 4.
INSERT TABLE 4
From results presented in Table 4, other substituent effects were inferred on the
synthesis 2H-chromene derivatives as will be described below. For example, the
resonant effect transmitted by the OCH3 group was differently manifested when this
group moved from the salicylaldehyde derivative to the Michael acceptor. Indeed when
the OCH3 group at the ortho position (of the OH) in the salicylaldehyde moved to the
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para position in the p-methoxy-trans-β-nitrostyrene, the yield of the corresponding
2(H) chromene decreased from 100% to 89% respectively (compare entries 2 in Table 3
and entry 1 in Table 4).
The same effect was observed when p-methoxy-trans-β-nitrostyrene reacted with
different substituted salicylaldehydes, as the yields of chromene derivatives were in
general lower than those obtained when reacting with the unsubstituted alkene trans-β-
nitrostyrene (compare entries 1, 3, 5, 6 in Table 4 and entries 1-4 in Table 5).
Other inductive electrowithdrawing substituents such as the halogen Br and the NO2
groups afforded lower yields of the desired heterocycle when placed at the para and
ortho positions of the alkene respectively (entries 5-7, Table 5).
It is important to indicate that the synthesis of 2H-chromenes has been reported in the
literature [14] to proceed with lower yields, while requiring higher amounts of catalysts
than those reported in the present work. Indeed, the following table shows a collection
of results obtained with different catalysts under different reaction conditions for the
synthesis 3-nitro-2-phenyl-2H-chromene 3a and 3-formyl-2-phenyl-2H-chromene 3h as
model compounds (Table 5).
INSERT TABLE 5
From the results given in Table 5 it follows that, in general, catalyst A is more efficient
than some classical organocatalysts (DABCO, pipecolinic acid, etc), classic solid acid
catalysts such as basic and neutral Al2O3, as well as other structural related catalysts (B,
C and D employed in this study (see Table 5).
Besides this, other advantages of using catalyst A deserve to be highlighted. These are
the lower amount of catalyst required, the no need of using solvent and, as we will see
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later, the possibility of recovering and recycling catalyst A given its characteristics of
ionic liquid.
Finally a library of differently substituted 2H-quinoline derivatives could be easily
prepared from readily available starting reagents such as 2-aminobenzaldehyde [21]
and appropriately substituted electron deficient alkenes in the presence of bifunctional
catalyst A (Table 6).
INSERT TABLE 6
In this series of one-pot reactions, an initial 1,4-Michael addition between 2-
aminobenzaldehyde and an electron deficient alkene, was followed by the formation of
the respective intermediate which underwent cyclocondensation assisted by bifunctional
acid-base catalyst A. The final result is the one-pot synthesis of a variety of quinolines
(Scheme 1).
In general, the reactions were very fast since all of them went to completion in less than
half an hour under solventless conditions. However in contrast to 2H-chromenes, the
catalyst were less selective towards the desired 2H-quinoline. Interestingly the
secondary product that could be detected in all cases was the respective fully aromatic
quinoline derivative 5a-h (see Table 6).
The importance of this route for the synthesis of 2H-quinolines is evident since the
molecules obtained are intermediates for the synthesis of quinolines and 1,2,3,4-
tetrahydroquinolines (both compounds mainly used as a feedstocks in the production of
other specialty chemicals). [11, 13, 22] Again in this case we could find significant
differences between the bifunctional catalyst A and other reported organocatalysts
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(DABCO and pipecolinic acid) for the synthesis of some quinoline derivatives, which
require the use of large catalyst to substrate ratios. [14c, 14f, 15]
Reusability of catalyst A
The reusability of the bifunctional catalyst A for the one-pot preparation of chromene
3a has been shown here. The key point is that due to the ionic liquid characteristics the
catalyst can be efficiently extracted from the reaction media by using the appropriate
solvent. Thus, after extracting the products with diethyl ether, catalyst A was extracted
with dichloromethane from the crude left. After solvent elimination the recovered
catalyst (90%wt recovering) was dried at 50 ºC under vacuum. The catalyst was reused
in successive runs for the synthesis of chromene 3a and the results are depicted in
Figure 1.
INSERT FIGURE 1
As can be deduced from the Figure 1, catalyst A retained its high activity and
1
13
selectivity at least after three reaction cycles, whereas the H and C NMR spectra of
the recovered catalyst A showed that this organocatalyst was stable under the described
reaction and extraction process.
4. Conclusion
We have presented that the use of a bifunctional catalyst piperidinomethane piperidium
tetrafluoroborate (A) in the Michael addition of different nucleophiles to activated α,β-
unsaturated compounds, can afford the corresponding 1,4-adducts in good yields and
selectivities.
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In this case, the bifunctional catalyst A works better than monofunctional basic
catalysts C and D or than bifunctional acid basic catalysts B in where the distance
between the acid and basic site was increased.
This last observation points out to a plausible cooperative effect between the
acid and basic site in the catalyst, leading to the stabilization of the reaction transition
state for different condensation reactions (Knoevenagel and aldol condensation) using
compound A as catalyst. In this case DFT mechanistic studies corroborated the
existence of this cooperative effect and similar computational studies for the Michael
addition are now underway.
The fact that organocatalyst A simultaneously activates electrophiles and
nucleophiles for condensation reactions has been used to design the preparation of more
complex molecules by means of a series of one-pot reactions. In this case, diverse
conjugate systems that are initially formed in situ through a condensation reaction are
further activated by bifunctional catalyst A, and have been used as reactants in a
subsequent Michael addition by reacting with a variety of sulphur nucleophiles.
The application of organocatalyst A in one-pot reactions that strive for atom economy
has been extended to the synthesis of heterocycles, leading into complex molecules that
are of pharmacological and synthetic interest.
Moreover the resulting multi-functionalized compounds would serve as useful
intermediates for further chemical manipulations.
The catalyst can be recovered and reused several times without loss of activity and
selectivity.
Acknowledgments
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Financial support by Consolider-Ingenio 2010 (project MULTICAT), Spanish MICINN
(Projects MAT2011-28009 and CTQ-2011-27550) and Program Severo Ochoa are
gratefully acknowledged.
References
[1] a) S. Huh, H.T. Chen, J.W. Wiench, M. Pruski, V.S.Y. Lin, Angew. Chem. Int. Ed.
44 (2005), 1826-1830; b) R.K. Zeidan, S.J. Hwang, M.E. Davis, Angew. Chem. Int.
Ed. 45 (2006), 6332-6335.
[2] a) C. Kwong, R. Huang, M. Zhang, M. Shi, P. Toy, Chem. Eur. J. 13 (2007), 2369-
2376; b) M. Martin, F. Manea, R. Fiammengo, L. Prins, L. Pasquato, P. Scrimin, J.
Am. Chem. Soc. 129 (2007), 6982-6983.
[3] J.K. Lee, M. C. Kung, H. H. Kung, Top. Catal. 49 (2008), 136-144.
[4] a) T. Weil, M. Kotke, C.M. Kleiner, P.R. Schreiner, Org. Lett. 10 (2008), 1513-1516;
b) M. J. Climent, A. Corma, I. Dominguez, S. Iborra, M. J. Sabater, G. Sastre, J.
Catal. 246 (2007), 136-146.
[5] a) M. Boronat, M.J. Climent, A. Corma, S. Iborra, R. Monton, M. J. Sabater, Chem
Eur. J. 16 (2010), 1221-1231; b) M. Boronat, M.J. Climent, A. Corma, S. Iborra, R.
Montón, M. J. Sabater, PCCP, 13 (2011), 17255-17261.
[6] a) M. J. Climent, A. Corma, S. Iborra, Chem. Rev. 111 (2011), 1072-1133; b) A.
Corma, J. Navas, M. J. Sabater, Chem Eur J. 18 (2012), 14150-14156; c) A.
Corma, T. Ródenas, M. J. Sabater, J. Catal., 279 (2011), 319-327; d) A. Corma, T.
Ródenas, M. J. Sabater, Chem. Eur. J. 16 (2010), 254-260.
[7] a) H. Wynberg, Top. Stereochem. 16 (1986), 16, 87-129; b) A. Kamimura, J.
Synth. Org. Chem. Jpn. 62 (2004), 62, 705-715; c) A. Berkessel, H. Gröger,
Asymmetric Organocatalysis, (2005), Wiley-VCH, Weinheim.
18
Page 18 of 36

19
[8] a) R. Okazaki, Organosulfur Chemistry, (1995), 225, Vol 1; page P., Ed. Academic
Press: London; b) D. Enders, K. Lütgen, A.A. Narine, Synthesis, 7 (2007), 959-980.
[9] O.M. Berner, L.Tesdechi, D. Eriders, J. Org. Chem., (2002), 1877-1894.
[10] a) V.A. Ashwood, R.E. Buckingham, F. Cassidy, J.M. Evans, E.A. Faruk, T.C.
Hamilton, D.J. Nash, J. Med. Chem. 29, (1986), 2194-2201; b) J.N. Kim, K.Y.
Lee, Curr. Org. Chem. 6 (2002), 627-645; c) J.M. Evans, C.S. Fake, T.C.
Hamilton, J. Med. Chem., 26 (1983), 1582-1589; d) G.P. Ellis, G.P. Chromenes,
Chromanones and Chromones, Wiley Interscience, New York, (1977); e) J.D.
Hepworth, In Comprehensive Heterocyclic Chemistry, A. R. Katrizky, C.W. Rees,
A.J. Boulton, A.J., A. McKillop, Eds., Vol. 3, (1984), Pergamon Press, Oxford; e)
B.W. Fravel, N.A. Nedolya, Comprehensive Heterocyclic Chemistry III, A.R.
Katrizky, C.A. Ramsden, E.F.V. Scriven, R.J. K. Taylor, Eds., (2008), Elsevier,
Ltd.,; f) K.Y. Lee, D.H. Nam, C.S. Moon, S.H. Seo, J.Y. Lee, Y.S. Lee, Eur. J.
Med. Chem., 41 (2006), 991-996; g) S. Sang, J.D. Lambert, S. Tian, J. Hong, J.
Hou, J. Ryu, R.E. Stark, R.T. Rosen, M. Huang, C.S. Yang, C. Ho, Bioorg. Med.
Chem., 12 (2004), 459-467; h) M. Sirafianpour, O. Kayser, J. Christensen, M.
Asfa, M.W. Stark, J.W. Jarozewski, J. Nat. Prod., 65 (2002), 1754-1758; i) K.M.
Dawood, T. Fuchigami, J. Org. Chem. 66 (2001), 7691-7695.
[11] a) A Fournet, M E Ferreira, A Rojas De Arias, S. Torres De Ortiz, S. Fuentes, H
Nakayama, A. Schinini, R. Hocquemiller, Antimicrob. Agents Chemother., 40
(1996), 2447-2451; b) M. A. Fakhfakh, A. Fournet, E. Prina, J-F Mouscadet, X.
Franck, B. Figadère, Bioorg. Med. Chem., 11 (2003), 5013-5240; c) M. Henry, S,
Alibert, C. Rogier, J. Barbe, B. Pradines, Curr. Top. Med. Chem., 8 (2008), 563-
578; d) B.Heiniger, G. Gakhar, K. Prasain, D.H. Hua, T.A. Nguyen, Anticancer
Res., 30 (2010), 3927-3932; e) D.A. Marble, J.A. Bosso, Drug Intell. Clin. Pharm.,
19
Page 19 of 36

20
20 (1986), 261-266; f) R. Musiol, M. Serda, S. Hensel-Bielowka, J. Polanski, Curr.
Med. Chem., 17 (2010), 1960-1973; g) O. Bilker, V. Lindo, M. Panico, A.E.
Etiene, T. Paxton, A. Dell, M. Rogers, R.E. Sinden, H. R. Morris, Nature, 392
(1988), 289-292; h) P.A. Winstanley, Parasitol. Today, 16 (2000), 146-153; i) L.Y.
Vargas, M.V. Castelli, V.V: Kouznetsov, J. M. Urbina, S.N. Lopez, M. Sortino,
R.D. Enriz, J.C. Ribas, S. Sacchino, Bioorg. Med. Chem., 11 (2003), 1531-1550;
j) L. Dassonneville, A. Lansiaux, A. Wattelet, N. Wattez, C. Mahieu, S. Van
Miert, L. Pieters, C. Bailly, Eur.J. Pharmacol. 409 (2000), 9-18.
[12] a) Y-L Shi, M. Shi, Org. Biomol. Chem. 5 (2007), 1499-1504; b) G. Sartori, G.
Casiraghi, L. Bolzoni, G. Castani, J. Org. Chem. 44 (1979), 803-805; c) J.J.
Talley, Synthesis, (1983), 845; d) B.A. Chauder, C.C. Lopes, R.S.C. Lopes,
A.J.M. da Silva, V. Snieckus, Synthesis (1998), 279; e) J.Y. Goujon, F.
Zammatio, S. Pagnoncelli, Y. Boursereau, B. Kirschleger, Synthesis, (2002),
322.
[13] a) V.V. Kouznetsov, LY. Vargas Mendez, C.M. Melendez Gómez, Curr. Org,
Chem., 9 (2005), 141-161; b) C.R. Brindaban, H. Alakananda, J. Umasish,
Tetrahedron Letters., 41 (2000), 531-533; c) S. Madapa, Z. Tusi, S. Batra, Curr.
Org. Chem. 12 (2008), 1116-1183; d) J. Wiesner, R. Ortmann, H. Jomaa, M.
Schlitzer, Angew. Chem. Int. Ed., 43 (2003), 5274-5293.
[14] a) M-C.Yan, Y-J. Jang, C-F. Yao, Tetrahedron Lett. 42 (2001), 42, 2717-2721; b)
M-C. Yan, Y-J. Jang, W-Y. Kuo, Z. Tu, K-H. Shen, T-S. Cuo, C-H. Ueng, C-F.
Yao, Heterocycles, 57 (2002), 1033-1048; c) B. C. Das, S. Mohapatra, P. D.
Campbell, S. Nayak,S. M. Mahalingam, T. Evans, Tetrahedron Lett., 51 (2010),
2567-2570; d) S. Bonollo, D. Lanari, T. Angelini, F. Pizzo, A. Marrocchi, L.
Vaccaro, J. Catal., 285 (2012), 216-222; e) R.S. Varma, G.W. Kabalka,
20
Page 20 of 36

21
Heterocycles, 23 (1985), 139-141; f) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri,
Green Chem. 7 (2005), 825-827; g) I. Ibrahem, H. Sundén, R. Rios, G-L. Zhao, A.
Córdova, Chimia, 61 (2007), 219-223.
[15] a) M.C. Yan , Z. Tu, C. Lin, S. Ko, J. Hsu, C.F. Yao. J. Org. Chem. 69 (2004),
1565-1570.
[16] S‐H Zhao, Z‐B Chen, Synth. Commun. 35 (2005), 3045-3053.
[17] P. Kotrusz, Š. Toma, Molecules, 11 (2006), 197-205.
[18] (a) S. Matsubara, M. Yoshioka, K. Utimoto, Chem. Lett. (1994), 827; (b) M.
Pérez, R. Pleixats, Tetrahedron, 51 (1995), 8355-8362; (c) G. Cardillo, L.
Gentilucci, M. Gianotti, P. Perciaccante, A. Tolomelli,; (d) K. Nakama, S. Seki,
S. Kanemasa, Tetrahedron Lett. 42 (2001), 6719-6722; (e) T-P. Loh, L-L.Wei,
Synlett (1998), 975; (f) G. Bartoli, M. Bosco, E. Marcantoni, M. Petrini, L.
Sambri, L., E. Torregiani, J. Org. Chem. 66 (2001), 9052-9055; (g) M.
Kawatsura, J. F. Hartwig, Organometallics 20 (2001), 1960-1964; (h) N.
Srivastava, B.K. Banik, J. Org. Chem. 68 (2003), 2109-2114; h) G. V. M.
Sharma, V. G. Reddy, A. S. Chander, K. R. Reddy, Tetrahedron Asymm.13
(2002), 21-24; i) R. Ballini, G. Bosica, M. V. Gil, E. Roman, J. A. Serrano,
Tetrahedron Asymm. 13 (2002), 1773-1789.
[19] K. Albrecht, M. Moeller, J. Groll, Adv. Polym. Sci, (2010), 69.
[20] B. Movassagh, P. Shaygan, Arkivoc, XII (2006), 130-137.
[21] B.D. Foy, R.A. Smudde, W.F. Wood, J. Chem. Ed., (1993), 70 (4), 322-323.
[22] A. R. Katritzky, S. Rachwal, B. Rachwal, Tetrahedron (1996), 52, 15031-15070.
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22
H
N
H
N
N
N
+
+
-
-
BF4
BF4
A
B
N
N
NCH3
C
D
Chart 1
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23
Aldol condensation/Michael addition
H
N
N
-
+
A
BF4
CH3COPh
HSR
O
O
SR
A
A
CHO
2
1
Scheme 1. Two step aldol condensation/Michael addition sequence catalyzed by A for
the synthesis of S-compounds in one-pot.
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24
Michael addition/Cyclocondensation
H
N
N
+
-
A
BF4
EWG
R2
R2
H
N
O
OH (NH2)
R2
A
or
EWG
EWG
R1
R1
CHO
R1
3
4
Scheme 2. Two step Michael addition/cyclocondensation sequence catalyzed by A for
the synthesis of 2H-chromenes (3) and 2H-quinolines (4) in one-pot.
O
S
H
H
N
N
+
-
BF4
A
Scheme 3 Transition state complex for the Michael addition reaction of chalcone and
benzenethiol
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25
SELECTIVITY (%)
CONVERSION (%)
100
80
60
40
20
0
1
2
3
NUMBER OF USES
Figure 1. Graphic representation of the catalytic parameters obtained with catalyst A
for the synthesis of chromene 3a after successive uses.
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26
Table 1. Results on the Michael addition of α, β-unsaturated compounds (1,3-diphenyl-
2-propenone and 2-cyclohexen-1-one) with benzenethiol with different
catalysts.[a,b]
O
O
O
Nu
Ph
O
Nu
or
or
Ph
Ph
Ph
Nu
Entry Catalyst
Nucleophile
C(%)a
S(%)b
α, β-
Unsaturated
compound
O
PhSH
PhSH
PhSH
PhSH
Ph
Ph
1
2
3
4
Ac
Bc
Cc
Dc
90
69
64
100
O
O
O
Ph
Ph
Ph
Ph
100
100
Ph
Ph
66
98
100
95
O
O
O
O
PhSH
PhSH
PhSH
PhSH
5
6
7
8
Ad
Bd
Cd
Dd
96
92
90
93
78
86
[a] Conversion (%) calculated by GC on the amount of unsaturated compound transformed; [b]
Selectivity (%) calculated by GC towards the Michael adduct; [c] Reaction conditions (Michael addition
of 1,3-diphenyl-2-propenone and benzenethiol): 1,3-diphenyl-2-propenone (1 mmol), benzenethiol (1.5
mmol), 0.1 mmol catalyst, n-dodecane: 0.1 mmol, T 110 ºC, t = 1h; [d] Reaction conditions (Michael
addition of cyclohexenone and benzenethiol): cyclohexenone (2.8 mmol), PhSH (2.8 mmol), 0.28 mmol
catalyst, T 80 ºC; t = 2h.
26
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27
Table 2. Results on the condensation/sulfa-Michael one-pot sequence by reacting
benzaldehyde, acetophenone and diverse thiols catalyzed by A.a
O
O
SR
CHO
a
b
RSH
CH3COPh
2a-f
1
Entry Catalyst Time(h)
Nucleophile
Michael adduct
Yield(%)b
1
95
2a-fc
80
O
SPh
1
2
A
A
4
5
PhSH
Ph
Ph
2a
OCH3
95
78
OCH3
HS
O
S
Ph
Ph
Ph
Ph
2b
2c
A
A
3
4
5
95
95
86
79
SH
O
O
O
S
Cl
4.5
SH
Cl
S
Ph
Ph
2d
5
PhCH2SH
A
A
5
6
95
95
83
76
CH2
S
Ph
Ph
2e
6
SH
6
O
S
Ph
Ph
2f
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28
[a] Reaction conditions: Step a: benzaldedyde (1 mmol); acetophenone (1 mmol), catalyst (0.1 mmol), T
130 ºC; step b: nucleophile (an equimolar amount of nucleophile was added on the amount of
condensation product formed; T 100 ºC; [b] yield was calculated by GC; [c]: isolated yield.
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29
Table 3. Results on the synthesis of 2H-chromene derivatives from salicylaldehydes
and the electron deficient alkenes trans-β-nitrostyrene and cinnamaldehyde
catalyzed by A under solventless conditions.[a]
R1
R1
R2
R3
OH
NO2
R2
R3
O
A
(10%mol)
+
100ºC
CHO
NO2
3a-g
Entry
1
R1
R2
R3
H
Product
Time
(h)
24
Yield[b,c]
(%)
H
OCH3
H
H
94
O
NO2
3a
2
3
4
5
6
7
H
H
H
24
48
24
24
24
24
100
56
90
89
68
62
OCH3
O
NO2
3b
OCH3
H3CO
O
NO2
3c
H
F
H
F
O
NO2
3d
H
H
Cl
O
Cl
NO2
3e
H
H
NO2
CH3
O
O2N
H3C
NO2
3f
H
H
O
NO2
3g
29
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