Applications of caged-designed proton sponges in base-catalyzed transformations Dedicated to Professor Milan Kratochvíl for his 90th birthday anniversary.

Article abstract of DOI:10.1016/j.molcata.2014.08.004

Superbasic properties of caged proton sponges (PSs) - substituted diazatetracyclo[4.4.0.1^3,10.1^5,8]dodecanes (DTDs) - were utilized in Knoevenagel and Claisen-Schmidt condensations, the Pudovik reaction, and Michael addition. This investigation covers the influence of the solvent, reaction temperature, catalyst loadings as well as the electronic properties of substituents upon the reaction. Moreover, we provided an activity comparison between our new base and a well-known and commercially available proton sponge (DMAN). The basicity (in MeCN) of our chosen DTD (pKBH_⁺=21.7±0.1) exceeded the prototypal PS - 1,8-bis(dimethylamino)naphthalene (DMAN, pKBH_⁺=18.6), by three orders of magnitude. We proved that DTDs are reasonably active species in monitored reactions, which is a consequence of a hydrogen bridge angle (～130°) between the two nitrogen atoms and the captured proton. We present here syntheses of aminoindolizine, substituted 4H-chromene, and flavanones, and the unexpected formation of a bis-addition product formed after Michael addition, all under mild conditions.

Full text of DOI:10.1016/j.molcata.2014.08.004

Accepted Manuscript
Title: Applications of Caged-Designed Proton Sponges in
Base-Catalyzed Transformations
´ˇ
Author: Juraj Galeta Milan Potacek
PII:
S1381-1169(14)00351-3
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http://dx.doi.org/doi:10.1016/j.molcata.2014.08.004
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2-8-2014
Please cite this article as: J. Galeta, Applications of Caged-Designed Proton Sponges in
Base-Catalyzed Transformations, Journal of Molecular Catalysis A: Chemical (2014),
http://dx.doi.org/10.1016/j.molcata.2014.08.004
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Applications of Caged-Designed Proton Sponges in Base-
Catalyzed Transformations
Juraj Galeta and Milan Potáček*
Department of Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic
jurgal@mail.muni.cz
*Corresponding author: potacek@chemi.muni.cz; Tel: +420 549 496 615; Fax: +420 549 492 688
Abstract. Superbasic properties of caged proton sponges (PSs) – substituted
diazatetracyclo[4.4.0.13,10.15,8]dodecanes (DTDs) – were utilized in Knoevenagel and Claisen-
Schmidt condensations, the Pudovik reaction, and Michael addition. This investigation covers
the influence of the solvent, reaction temperature, catalyst loadings as well as the electronic
properties of substituents upon the reaction. Moreover, we provided an activity comparison
between our new base and a well-known and commercially available proton sponge®
(DMAN). The basicity (in MeCN) of our chosen DTD (pKBH+ = 21.7 ± 0.1) exceeded the
prototypal PS - 1,8-bis(dimethylamino)naphthalene (DMAN, pKBH+ = 18.6), by three orders
of magnitude. We proved that DTDs are reasonably active species in monitored reactions,
which is a consequence of a hydrogen bridge angle (≈130°) between the two nitrogen atoms
and the captured proton. We present here syntheses of aminoindolizine, substituted 4H-
chromene, and flavanones, and the unexpected formation of a bis-addition product formed
after Michael addition, all under mild conditions.
Key Words: proton sponge; base catalyst; Knoevenagel, Claisen-Schmidt and Pudovik
ractions; Michael addition.
1. Introduction
Building a carbon-carbon single bond is one of the most important procedures in synthetic
chemistry and requires accurate information about the possibilities and conditions of such
transformations. Most frequently, base catalysis serves as a tool for the production of both
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fine chemicals and intermediates. Hence, chemists from all research areas try to develop smart
catalytic systems based on organic [1], organometallic [2], or inorganic [3] structures,
sometimes fixed at various carriers [4]. It is not surprising that many of them are "green" and
recyclable and that the development of such chemicals is an area of growing interest. Solid
bases are preferred over liquids because of their economic and environmental impacts
connected with the recoveries of catalysts. All these requirements are fulfilled by our newly
developed generation of PSs – diazatetracyclo[4.4.0.13,10.15,8]dodecanes (DTDs) [5]. They
exhibited very good activity when tested and measured at classical condensation reactions, as
shown in our study. At the same time, their resistance to highly basic and acidic conditions as
well as toward nucleophiles was observed. Neither their decomposition nor transformation
were observed even after one week. It is actually disputable whether we should call them
directly proton sponges or proton-sponge-like compounds. Nevertheless, their
physicochemical properties are in good agreement with established knowledge. In general,
PSs are organic diamines with unusually high basicity where the two basic nitrogen centers
are in close proximity to each other. This orientation allows the uptake of one proton to yield
a structure stabilized by an intramolecular hydrogen bond [6]. The first of them, DMAN, was
reported by Alder in 1968 [7]. This compound has a basicity about 10 million times higher
than other similar organic amines. Two general protocols have been established to raise the
thermodynamic basicity or proton affinity. In one, the naphthalene skeleton is replaced by
another aromatic spacer, thus influencing the basicity by varying the nonbonding N-N
distance. The second approach focuses on the substitution at the nitrogen atoms or their
adjacent environment (buttressing effect) [8]. In this way, several different structures with
superbasic properties can be prepared [9]. In our previous study, we contributed to this area
with a new class of PSs having a rare rigid skeleton [5]. Their preparation was optimized and
we are able to prepare them in 25 – 30 % overall yields in an eight-step synthesis. We can
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change their pKBH+ values by more than three orders of magnitude using different p-
substituted benzyl bromides (Table 1).
Table 1. Proton sponges DTDs and their basicities [5]
X
X
X
X
X
4 steps
NH4ClO4
MeCN
50°C, 3h
C
O
ClO4
N
N
N
N
H
R
R
R
R
DTD-H+
X = morpholinomethyl
DTD
DTD /
pKBH+ (DTD-H+)
R
DTD-H+
(CD3CN)
a
b
c
d
e
f
Me
22.6 ± 0.1
22.4 ± 0.1
21.7 ± 0.1
19.0 ± 0.1
19.4 ± 0.1
20.0 ± 0.1
21.1 ± 0.1
22.1 ± 0.1
22.0 ± 0.1
22.2 ± 0.1
21.6 ± 0.1
allyl
benzyl
p-NO2-benzyl
p-CN-benzyl
p-CF3-benzyl
p-F-benzyl
g
h
i
p-Me-benzyl
p-tBu-benzyl
p-MeO-benzyl
p-MeS-benzyl
j
k
2. Experimental
2.1. General Information
All reagents were purchased from commercial suppliers and redistilled or recrystalyzed.
Solvents were dried and distilled by standard procedures and stored over molecular sieves (3
or 4 Å). All reactions were carried out under a dry argon atmosphere and followed by TLC
(Merck F254 silica gel). Respective model reactions were monitored by dynamic proton NMR
measurements (Bruker Avance 500).
2.2. Knoevenagel Condensation: Final Procedure
Ethyl cyanoacetate – ECA (4 mmol, 426 μl) was mixed with propan-2-ol (2 ml) and aldehyde
(8 mmol). Then, the catalyst was added (0.5 mol%, 12 mg of DTD or 4.3 mg of DMAN,
respectively) and the reaction mixture was stirred at 50°C under an argon atmosphere. The
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conversion was followed by proton NMR. After solvent removal, the residue was washed
with Et2O and the liquid part separated from the insoluble part. The solution consisted of
Knoevenagel product and used aldehyde, which were separated by column chromatography.
The solid part was the DTD catalyst and its regeneration involved washing with 5M aqueous
KOH and extraction with DCM. This procedure was carried out especially when larger scale
reactions were performed, and by this simple method the catalyst was regenerated, usually
with 90 – 95 % effectiveness.
2.3. Claisen-Schmidt Condensation: General Procedure
Substituted benzaldehydes (2 mmol) and 2'-hydroxyacetophenone (2.1 mmol, 253 μL) were
mixed together and the catalyst was added (2 mol%, 25 mg). The reaction mixture was stirred
at 150°C for 3 hours under an argon atmosphere. The reaction was followed by proton NMR.
After the consumption of aldehyde, the condensed intermediate 2`-hydroxychalcone (at lower
temperature) or final flavanone were purified by column chromatography.
2.4. Pudovik Reaction: General Procedure
Diethyl phosphite (1 mmol, 129 μL) in solvent (4 ml) was mixed with aldehyde (1 mmol) and
the catalyst (2 mol% = 12 mg, 4 mol% = 24 mg) and stirred at 50°C. After completion, the
solvent was evaporated and the crude mixture separated by column chromatography. In the
case of rearrangement to phosphate, mobile phase Et2O / DCM = 1 : 5 effectively enabled
separation of the formed products.
2.5. Michael Addition: General Procedure
Methyl acrylate (4 mmol, 360 μL) was added to a mixture of iPrOH (2 mL) and ECA (2
mmol, 213 μl). Then, the catalyst was added (1 mol%, 12 mg) and the reaction mixture was
stirred at 50°C for 2 hours. Subsequently, the solvent was evaporated and the remainder was
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dissolved in Et2O and filtered through a short column of silica gel. After solvent evaporation,
we obtained a pure oily product in an almost quantitative yield (98 %). This reaction works
also under solvent-free conditions.
3. Results and Discussion
In a previous paper [5], we demonstrated considerable structural relaxation upon the
monoprotonation of DTDs by measuring bond angles and nonbonding N-N distances in the
free base and its acid (Figure 1 and 2). Clearly, the shape of the molecule is significantly
changed by the action of the free electron pairs. The high basicity of such a rigid structure is
caused by the release of energy after molecule protonation.
Figure 1. ORTEP representation of DTD shown at the 50% probability level (upside-
down view; hydrogen atoms and methyl and morpholinomethyl groups are omitted for
clarity).
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Figure 2. ORTEP representation of DTD-H+ shown at the 30% probability level (upside-
down view; hydrogen atoms (except for the captured proton), plus chloride anion,
methyl and piperidinomethyl groups are omitted for clarity).
For our study, we selected DTDs with R = benzyl and X = piperidinomethyl groups (Table 1).
Piperidinomethyl group was chosen instead of morpholinomethyl substitution because of its
better solubility. Moreover, as expected, measurements showed the same basicities (21.7 ±
0.1) for both derivatives. We performed several types of base-catalyzed reactions to find
suitable application for these promising molecules. As Knoevenagel condensation is a
classical base-catalyzed reaction, we initiated our investigation in this area and started with
the condensation of benzaldehyde and ethyl cyanoacetate (pKa = 8.6) (Scheme 1). In all cases,
optimized reaction conditions afforded the desired α,β-unsaturated product as E-isomer only.
During the NMR measurements, we clearly recognized the presence of four possible
diastereoisomers as intermediates, which provided the final condensed product after a water
molecule elimination.
DTD
O
COOEt
CN
NC
COOEt
DTD
solvent, up to 50°C
ECA
DTD
-H2O
DTD-H
COOEt
DTD-H
O
aldehyde
COOEt
CN
NC
Scheme 1. Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate using the
DTD catalyst.
A similar study with DMAN has already been published [10] and even the heterogeneous
catalysis of immobilized DMAN on inorganic carriers appeared in literature [11]. We have
conducted numerous experiments with ECA to set up the catalytic limits of DTDs. This
means the determination of the most suitable solvent as well as the reactant molar ratios, the
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catalyst loading, the reaction temperature, and even the concentration of the reaction mixture.
We followed the change in conversion over time by proton NMR at appropriate intervals.
First of all, we carried out several dynamic proton NMR measurements at different
temperatures with a 1 : 1 molar ratio of reactants using 2 mol% of catalyst relative to
aldehyde. The first experiments in CDCl3 and CD3CN showed very low conversions (Figure
3; the lowest two curves, experiments at 50°C). However, CD3OD appeared to be a much
more suitable environment (Figure 3; the three upper curves at three different temperatures).
It was evident that the ion pair formed after the deprotonation step must be highly stabilized
by solvation to be able to react with the submitted aldehyde. Otherwise, it would be
immediately reprotonated as shown in Scheme 1. Thus, methanol with hydrogen bond
donating and accepting abilities is a much more obvious choice, where the nucleophile
formed in situ from ECA is a longer living system which subsequently attacks the carbonyl
group. On the other hand, DTD-H+ is deprotonated and refreshed via a hydrogen bond chain
formed by the solvent.
Figure 3. Dynamic proton NMR measurements of DTD catalytic activity in the
benzaldehyde / ethyl cyanoacetate reaction in CD3OD (the three upper curves) and in
CDCl3 vs. CD3CN (the lowest two curves).
At this point, we were interested in reactions carried out with conventional heating and
stirring. This change was immediately reflected in conversions and results obtained by NMR
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tube experiments. We were able to reduce the reaction time and even the catalyst loading, the
latter four times (0.5 mol%). Aliquots (100 μL) were taken from the reaction mixture at 30-
minute intervals and analyzed by proton NMR. To fix the conversion, we quenched the
reaction with trifluoroacetic acid (5 μL). We observed the considerable influence of the molar
ratio of aldehyde / ECA upon the reaction (Figure 4). After 30 minutes in the presence of 1
mol% of catalyst at 50°C in MeOH, the aldehyde was fully consumed when the concentration
of ECA was two times higher (1 : 2). The same conditions but without a solvent afforded the
same results. However, solvent-free conditions could be used with liquid aldehydes only. This
led us to apply an aldehyde / ECA molar ratio of 1 : 2 in the following reactions and even
reduce the catalyst loading. It is worth noting that we used 2 mL of solvent in each reaction
and that this amount appeared to be suitable on the milligram to four-gram scale.
Figure 4. Effect of benzaldehyde / ethyl cyanoacetate molar ratio on reaction
conversions in MeOH and under solvent-free conditions.
Then, we focused more deeply on the question of the used solvent and found that isopropanol
was even better solvent for such a reaction, increasing the conversions to 96 % after 30 min
with just 0.5 mol% of catalyst at 50°C with a 1 : 2 molar ratio of reactants (Figure 5). We
followed the influence of various solvents and found that ethyl acetate also worked fairly
well. The reaction without any solvent, on the other hand, afforded the worst results. As
mentioned above, previous results were fully confirmed here, and 1,2-dichloroethane (DCE)
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and acetonitrile were shown to be the least efficient solvents. We observed just 60 % of
conversion in MeCN after 30 minutes. We chose DCE instead of CHCl3 because of its higher
boiling point and lower reactivity at higher temperatures.
Figure 5. Effect of solvent on reaction conversion using DTD base and its comparison to
the activity of DMAN catalyst in iPrOH.
Finally, we applied the known proton sponge® (1,8-bis(dimethylamino)naphthalene - DMAN)
at most suitable reaction conditions (50°C, 0.5 mol%, iPrOH, ECA/aldehyde 1 : 2 ratio).
From the beginning it is already clear, that DTD starts the catalyzed reaction very rapidly and
the curve profile is almost flat. However, DMAN works much slower and the initial
conversion (30 min.) is even lower than that for DTD in DCE (Figure 5). But after 60 minutes
it reached the conversion in AcOEt environment and after 1.5 hours the conversion was
already 95 %. These results show the difference in basicities between DMAN and DTD and,
more importantly, they indicate a significantly higher kinetic activity in iPrOH for our base.
However, DMAN’s better solubility was reflected in the results under solvent-free conditions
where even a 1:1 molar ratio of reactants worked well and considerably better than DTD
(Figure 6). The curve profile almost duplicates the process taking place with DTD in iPrOH
with a 1:1 ratio of reactants. In fact, these conditions are for DMAN even better than that used
before. So we can conclude here that DTD works better in solution but DMAN, regarding its
perfect solubility, works much better under solvent-free protocol.
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Figure 6. The results of reactions in iPrOH or at solvent-free conditions with 0.5 mol%
of DTD and a solvent-free reaction using 0.5 mol% of DMAN catalyst and a 1:1 molar
ratio of reactants.
Figure 6 further shows the results of reactions performed in iPrOH and without a solvent.
From this graph, the importance of the solvent and the excess of ECA are evident. We also
observed a rapid decrease in conversion compared to experiments with the 1 mol% of catalyst
used before. After 120 min, we observed just 70% of the desired product against the full
consumption of aldehyde in Figure 4. Then, we took inspiration from green chemistry
principles and carried out the reaction under room temperature conditions (Figure 7). The
result was surprising, because even 0.5 mol% of DTD afforded 91% conversion (after 2.5 h)
and prolongation (≈ 6 h) led to completion of the reaction. Again, we performed the same
reaction with DMAN and it was in a good agreement with our previous findings where DTD
is much faster in the beginning but with time the process became almost equally efficient. But
we must take into account the solubility factors for DTD at room temperature as well.
Hypothetically, solvents like DMF, DMA, DMSO etc. would be just perfect but we wanted to
show how the catalyst works in easily evaporable solvents and 50°C as working temperature
using benign isopropanol are usable conditions for numerous reactions.
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Figure 7. Reactions performed at room temperature in iPrOH.
We then considered whether our catalyst would work in very small amounts. Thus, we
performed the reaction with 0.1 mol% of DTD at 80°C in iPrOH (2 mL). This means that for
4 grams of Knoevenagel product we used only 12 mg of DTD; the reaction was completed
after 180 min. The scope of the method was further tested with several aromatic, aliphatic,
and heteroaromatic aldehydes. We found that reaction times for their full consumption varied
according to their aldehydic character (Figure 8).
O
O
O
O
O
H
Br
N
NO2
Cl
> 80 % for all
O
30 min
O
O
S
NO2
C
O
92 %
OMe
> 90 % for all
90 min
O
N
O
OH
30 min
90 min
COOEt
CN
COOEt
CN
OH
N
A
C
(> 95%)
(91 %)
12 h
3.5 h
EtOOC
NC
COOEt
COOEt
NH2
NH2
N
O
B
D
(89 %)
(87 %)
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Figure 8. Condensation reactions of various aldehydes with ECA in iPrOH and their
reaction times for full conversions with isolated yields including two cyclization
reactions leading to heterocyclic products B and D.
Moreover, after an intramolecular cyclization of the Knoevenagel products A and C, 2-
pyridinecarboxaldehyde and salicylaldehyde afforded aminoindolizine B [12] and 2-amino-
4H-chromene D [13] in quantitative yields. Product D was formed as two diastereoisomers
(ratio 1 : 2), i.e. we used either a 1 : 1 or 1 : 2 molar ratio of reactants. This means that
molecule C reacted immediately with the presented ECA to the final compound D and that the
second half of the starting aldehyde remained unconsumed in the reaction mixture. Further
our attention was devoted to the least acidic activated methylene compound, ethyl malonate
with pKa = 13.3. This significantly less acidic starting material caused much more difficult
deprotonation. Therefore we utilized 5 mol% of catalyst with longer reaction times. All the
other reaction conditions as solvent, temperature and molar ratio of reactants stayed the same.
Moreover, we tested the electronic influence of p-substitution on benzaldehydes upon the
reaction (Figure 9). As expected, the best results afforded the condensation of p-
nitrobenzaldehyde but the conversion has never exceeded 90 % even after 24 hours at 80 °C.
Figure 9. The results of condensations of benzaldehydes with ethyl malonate in iPrOH.
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In order to investigate the scope of our DTD application as a base for further catalyzed
reactions we tried the Claisen-Schmidt condensation reaction [14]. The first experiments in
various solvents were not very successful and produced only negligible conversions to the
desired flavanones (Scheme 2). Later, we performed this reaction at 150°C in a solvent-free
arrangement, which turned out to be an ideal protocol. It highly accelerated the second step –
intramolecular Michael addition at 2'-hydroxychalcones as intermediates. After
chromatographic purification, three different benzaldehydes afforded very good to excellent
yields. Under milder conditions (lower temperature and shorter reaction time) it was also
possible to isolate chalcones, some of them known as biologically active species [15].
O
O
O
DTD
(2 mol%)
solvent-free
150°C
OH Ar
OH
R
3 h
2'-hydroxychalcones
R = MeO (81 %), H (89 %), NO2 (93 %)
O
O
Ar
Flavanones
Scheme 2. Claisen-Schmidt Condensation with Isolated Yields.
We also tested our catalyst DTD in the Pudovik reaction [16], which is a straightforward
powerful method for creating a single C-P bond. It is a reaction involving dialkyl phosphites
(in our case, diethyl phosphite E), which are deprotonated in a basic environment and, after
addition to the submitted aldehyde, afford α-hydroxyphosphonates F (Scheme 3). There is
also an enantioselective version of this reaction [17]. An important aspect here is the possible
rearrangement of the formed phosphonates F to phosphates G. In the Brook rearrangement, an
organosilyl group R changes position with the proton of an hydroxy group, all under the
influence of a base. The reaction product is then a silyl ether [18]. The authors call it a
phospha-Brook rearrangement, and it proceeds when an electron withdrawing group is bound
in α-position to carbonyl functionality [19].
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OH
O
O
Pudovik reaction
solvent, 50°C
O
P
H
P
R
EtO
R
EtO
F (70 - 80 %)
OEt
OEt
E
DTD
R = o-nitrophenyl (4 h, 2 mol%
)
ratio F:G = 10:90)
p-nitrophenyl (8 h, 2 mol% DTD)
phenyl (12 h, 4 mol% DTD)
p-methoxyphenyl (24 h, 4 mol% DTD)
O
P
O
EtO
OEt
G
NO2
(69 %)
Scheme 3. Pudovik reaction and subsequent phospha-Brook rearrangement with
isolated yields.
The first step, the Pudovik reaction itself, proceeds fairly well in different types of solvents,
starting from polar aprotic (DCM, DMF, MeCN) to polar protic ones (EtOH, iPrOH).
However, ethanol appeared to be the most suitable one. In the case of this solvent, after 2
hours at 50°C with 2 mol% DTD, we observed the formation of products F and G in the ratio
20 : 80 %. Prolongation of the reaction to 4 hours led to 90 % of G; however, we never
observed full conversion to phosphate G, even after 24 hours. In acetonitrile, the situation
after 2 hours was exactly the opposite (F : G = 80 : 20 %). We tested four benzaldehydes
(Scheme 3) and the results confirmed that without an electron withdrawing group at the α-
position no rearrangement proceeds. Moreover, even p-nitrobenzaldehyde showed a twice
longer reaction time. Thus, it was not surprising that benzaldehyde and its p-methoxy analog
reacted very slowly. However, with one more equivalent of DTD (4 mol%) both reactions
were completed after 12 and 24 hours, respectively.
DTD
(1 mol%)
MeOOC
COOMe
NC COOEt
COOMe
NC
COOEt
iPrOH
or
solvent-free
ECA
I
H
50°C
Scheme 4. Michael addition of ethyl cyanoacetate and methyl acrylate in quantitative
yield.
14
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The last base-catalyzed reaction investigated in our study was Michael addition, which is one
of the most often used and elegant ways of forming a C-C single bond. We used ethyl
cyanoacetate as a Michael donor, and methyl acrylate H as a Michael acceptor (Scheme 4).
We obtained the same results both in the presence of a solvent and without it. The formed
molecule was not the expected product of the simple addition of a nucleophile prepared in situ
on α,β-unsaturated ester H. Instead, triester I formed from 1 molecule of ECA and two
molecules of ester H was identified [20]. In the case of the reactants having a molar ratio of 1
: 1, one half of ECA was still unconsumed. Enlargement of the molar ratio in favour of
acrylate (1 : 2) led exclusively to unexpected product I of very high purity.
4. Conclusions
Superbasic properties of caged proton sponges (PSs) – substituted
diazatetracyclo[4.4.0.13,10.15,8]dodecanes (DTDs) – were demonstrated in several base-
catalyzed transformations in the role of base. Knoevenagel and Claisen-Schmidt
condensations, the Pudovik reaction, and Michael addition were carried out to investigate
their activity. During the test, the influence of the solvent, reaction temperature, catalyst
loading, and substituents upon the reaction was followed. It was shown that the catalyst was
active in the range of 0.1 – 5mol%. Moreover, a catalytic activity of commercially available
DMAN proton sponge® was compared to DTD in Knoevenagel condensation reaction. We
observed a considerable influence of solvent upon the reaction, where DTD was more active
in solution and, on the other hand, DMAN under a solvent-free arrangement. This was
explained by the significant differences in catalysts solubilities.
Acknowledgements
15
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This work was supported financially by the Grant Agency of the Czech Republic (grant No.
203/09/1345). We are grateful to Lukáš Maier for dynamic proton NMR measurements.
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Pharmacol. 52 (2000) 163-171; c) Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Nakanishi,
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Page 17 of 19

O
NC
COOEt
DTD 0.5 mol%
NC
COOEt
O
alcohols, 50° C, 30 min, 96 %
20o C, 2.5 h, 91 %
20o C, 6 h, 100%
Knoevenagel
N
O
N
O
O
DTD 2 mol%
solvent-free
150°C
O
Ar
R
OH Ar
OH
R
3 h
flavanones
Claisen-Schmidt
2'-hydroxychalcones
OH
R = MeO (81 %), H (89 %), NO2 (93 %)
N
N
O
phospha-Brook
rearrangement
R
O
O
O
DTD 2 mol%
O
P
H
P
Ph
Ph
P
EtO
solvent, 50°C
R = p-nitrophenyl, 8 h
EtO
R
EtO
OEt
OEt
OEt
PROTON SPONGE - DTD CATALYST
pKBH+ = 21.7 0.1
Pudovik reaction
Michael addition
O
O
O
±
O
DTD 1 mol%
NC
COOEt
O
O
iPrOH(or solvent free) 50%
NC COOEt
Graphical abstract
18
Page 18 of 19

Highlights
•
•
•
Superbasic properties of a new proton sponge were tested in base catalysed
reactions.
Activity comparison between new base and proton sponge® (DMAN) was
performed.
The new catalyst was very active in solvents, DMAN in solvent free conditions.
19
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