1,4-Michael additions of cyclic-β-ketoesters catalyzed by DNA in aqueous media

Article abstract of DOI:10.1016/j.catcom.2013.08.015

In this work, we describe the 1,4-Michael addition of the 1,3-dicarbonyl compounds to activated ethylenes under st-DNA catalysis in water. The reaction of the β-ketoester 4 with nitroolefins and conjugated carbonyls proceeds quite well, whereas other less

Full text of DOI:10.1016/j.catcom.2013.08.015

Catalysis Communications 44 (2014) 10–14
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Catalysis Communications
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Short Communication
1,4-Michael additions of cyclic-β-ketoesters catalyzed by DNA in
aqueous media
⁎
⁎⁎
Cristina Izquierdo, Javier Luis-Barrera, Alberto Fraile , José Alemán
Departamento de Química Orgánica (Módulo 1), Universidad Autónoma de Madrid, 28049 Madrid, España
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2013
Received in revised form 18 July 2013
Accepted 13 August 2013
Available online 28 August 2013
In this work, we describe the 1,4-Michael addition of the 1,3-dicarbonyl compounds to activated ethylenes under
st-DNA catalysis in water. The reaction of the β-ketoester 4 with nitroolefins and conjugated carbonyls proceeds
quite well, whereas other less activated ethylenes exhibit low or null reactivity. The catalyst can be recovered and
reused for several catalytic cycles without significantly diminishing its efficiency. These reactions are similarly
catalyzed by GMP, methyl-adenine and ethyl guanine, which suggests that the catalytic activity of st-DNA
could be associated to the basic nature of their nucleotides' integrants.
Keywords:
Catalysis
© 2013 Elsevier B.V. All rights reserved.
DNA
1,4-Michael-addition
Aqueous medium
1. Introduction
their reaction. The resulting product would be released from the DNA,
which could be incorporated again into the catalytic cycle (Fig. 1). The
The development of sustainable chemical processes is one of the
most important features in modern chemistry. It has become a world-
wide key research area to provide solutions to important societal de-
mands by optimizing the use of natural resources and minimizing
waste and environmental impact. Thus, European society has recently
realized the importance of implementing sustainable chemistry in
our industry by creating the European Technology Platform (ETP) for
Sustainable Chemistry (http://www.suschem.org/). Among the rele-
vant methods toward achieving this goal, catalysis represents a key
and central approach. Both Organocatalysis [1] and Metal Catalysis [2]
have emerged as solutions for the problems originated in this context.
Despite the enormous advances made toward both types of catalysis,
there is still a search for more efficient and general catalysts or methods,
and challenges remain from economic and ecological points of view.
The use of new ligands in metal-catalysis and also new organocatalysts
requires the design and synthesis of complicated structures with a large
sequence of steps, especially for carrying out the asymmetric version of
the chosen reaction [3].
low price of DNA (compared with that of the most widely used
ligands for metal catalysis or organocatalysts), its multiple binding
sites (allowing the reaction to proceed with low catalyst loadings),
and its compatibility with the use of inexpensive “green” solvents
such as water [4] (which in its turn allows reusing it after recovering
them from the aqueous solution) are three features conferring it an ad-
ditional interest in catalysis.
Despite this potential interest, only two papers [5,6] have been re-
ported that concern the use of the DNA as the only catalyst. Both of
them describe 1,2-additions to carbonyl groups and evolve with scarce
stereochemical control [7]. Thus, it would be highly desirable to explore
the DNA catalytic ability in other reactions. In this sense, we fixed our at-
tention in the behavior of double bonds bearing EWG and in this paper
we describe the 1,4-addition of β-ketoesters to different Michael accep-
tors catalyzed by st-DNA [8].
2. Experimental
Nature, our bioinspiration, controls chemical reactivity with differ-
ent approaches, mainly by the use of enzymes which are able to select
between hundreds of reactants in solution at very low concentrations.
Biopolymers such as DNA are potentially interesting as catalysts as far
as it could ideally coordinate two reagents (A and B) through different
non-covalent interactions producing their approach and making easier
2.1. Material and methods
All reagents and chemicals were purchased from commercial
sources (Sigma-Aldrich, U.S.A.) and used without further purifications.
Solvents were purified by standard procedures [9]. NMR spectra were
acquired on a Bruker 300 spectrometer, running at 300, and 75 MHz
for 1H and 13C, respectively. Chemical shifts (δ) are reported in ppm
relative to residual solvent signals (CDCl3, 7.26 ppm for 1H NMR,
CDCl3, 77.0 ppm for 13C NMR). 13C NMR spectra were acquired on a
broad band decoupled mode.
⁎
Corresponding author.
⁎⁎ Corresponding author. Tel./fax: +34 914973875.
E-mail addresses: alberto.fraile@uam.es (A. Fraile), jose.aleman@uam.es (J. Alemán).
1566-7367/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2013.08.015

C. Izquierdo et al. / Catalysis Communications 44 (2014) 10–14
11
2.3. General procedure for the synthesis of compound 6 (Table 2)
To a solution of st-DNA (2.5 mL of a 2.0 mg mL−1 solution of st-DNA
dissolved in 20 mM MOPS buffer, pH 6.5, and prepared 24 h in ad-
vance) were added 0.1 mmol of β-ketoesther 4 and 1.0 mmol of the
corresponding electrophile 2. The reaction was allowed to continue
for the indicated time in Table 2 at rt, while mixing continuously by a
stirring shaker. The product was isolated by extraction with CH2Cl2
(2 × 5.0 mL). After drying (Na2SO4) and removal of the solvent, the
crude product was analyzed by 1H NMR spectroscopy and was purified
by flash chromatography.
2.3.1. Methyl 2-(2-nitro-1-phenylethyl)-1-oxo-2,3-dihydro-1H-indene-2-
carboxylate (6a)
The product was directly obtained following the standard procedure
as colorless oil (87% yield) after flash chromatography (2:1, Hexanes:
AcOEt) as mixture of diastereoisomers (50:50). The product matched
with the previous spectroscopic data described in the literature [11].
1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 7.7 Hz, 1H), 7.80 (d, J =
7.7 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.52–
7.44 (m, 4H), 7.39–7.30 (m, 10H), 5.56 (dd, J = 13.6, 3.7 Hz, 1H), 5.32
(dd, J = 13.4, 10.9 Hz, 2H), 5.19 (dd, J = 13.4, 3.6 Hz, 1H), 4.61 (dd,
J = 11.0, 3.6 Hz, 1 H), 4.34 (dd, J = 10.8, 3.7 Hz, 1 H), 3.87 (s, 3H),
3.82 (s, 3H), 3.77 (d, J = 17.7, 1H), 3.64 (d, J = 17.7 Hz, 1H), 3.34
(d, J = 17.7 Hz, 1H), 3.29 (d, J = 17.7 Hz, 1H).
Fig. 1. Proposed catalytic cycle to be developed in this work.
2.3.2. Methyl 1-oxo-2-(3-oxobutyl)-2,3-dihydro-1H-indene-2-carboxylate
(6b)
The product was directly obtained following the standard procedure
as colorless oil (75% yield) after flash chromatography (3:1, Hexanes:
AcOEt). The product matched with the previous spectroscopic data de-
scribed in the literature [12]. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J =
6.0 Hz, 1H), 7.63 (t, J = 6.0 Hz, 1H), 7.47 (d, J = 6.0 Hz, 1H), 7.41
(t, J = 9.0 Hz, 1H), 3.69 (s, 3H), 3.66 (d, J = 17.4 Hz, 1H), 3.03 (d, J =
17.4 Hz, 1H), 2.62–2.36 (m, 2H), 2.20–2.12 (m, 2H), 2.06 (s, 3H).
2.2. General procedure for the synthesis of compound 3 (Table 1)
2.2.1. 3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (3)
To a solution of st-DNA (5.0 mL of a 2.0 mg mL−1 solution of st-DNA
dissolved in 20 mM MOPS buffer, pH 6.5, and prepared 24 h in ad-
vance) were added 5.0 mmol of pentane-2,4-dione (1) and 0.5 mmol
of nitroalkene 2a. The reaction was allowed to continue for the indicated
time in Table 1 at rt and mixing continuously by a stirring shaker.
The product was isolated by extraction with CH2Cl2 (2 × 5.0 mL).
After drying (Na2SO4) and removal of the solvent, the crude product
was analyzed by 1H NMR spectroscopy and was purified by flash chro-
matography (Hexanes/AcOEt: 2/1) as a yellow oil (yield = 45%). The
product matched with the previous spectroscopic data described in
the literature [10]. 1H NMR (300 MHz, CDCl3) δ 7.33–7.24 (m, 3H),
7.21–7.12 (m, 2H), 4.64–4.57 (m, 2H), 4.32 (d, J = 12.0 Hz, 1H), 4.23–
4.15 (m, 1H), 2.24 (s, 3H), 1.89 (s, 3H).
2.3.3. Methyl 1-oxo-2-(3-oxopropyl)-2,3-dihydro-1H-indene-2-
carboxylate (6c)
The product was directly obtained following the standard procedure
as colorless oil (82% yield) after flash chromatography (3:1, Hexanes:
AcOEt). The product matched with the previous spectroscopic data de-
scribed in the literature [13]. 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H),
7.78 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz,
1H), 7.42 (t, J = 7.5 Hz, 1H), 3.69 (d, J = 15.9 Hz, 1H), 3.67 (s, 3H),
3.04 (d, J = 17.3 Hz, 1H), 2.70–2.47 (m, 2H), 2.40–2.20 (m, 2H).
2.3.4. Methyl 1-oxo-2-(4-oxobutan-2-yl)-2,3-dihydro-1H-indene-2-
carboxylate (6d)
The product was directly obtained following the standard procedure
as colorless oil as a mixture of diastereoisomers (56% yield) after flash
chromatography (2:1, Hexanes:AcOEt). The product matched with the
previous spectroscopic data described in the literature [14]. 1H NMR
(300 MHz, CDCl3) δ 9.76 (s, 1H), 9.67 (s, 1H), 7.78–7.74 (m, 2H),
7.66–7.61 (m, 2H), 7.51 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H),
3.72 (s, 3H), 3.68 (s,3H), 3.80–3.63 (m, 2H), 3.34–3.26 (m, 2H), 3.09
(d, J = 17.0 Hz, 1H), 3.06 (d, J = 17.7 Hz, 1H), 2.67 (d, J = 16.2 Hz,
1H), 2.35–2.13 (m, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz,
3H).
Table 1
Michael addition of 1 to nitroalkene 2a catalyzed by st-DNAa.
Entry Buffer
Time
Note
Conversion(%)
(days)
1
2
3
4
5
6
7
–
1
1
1
1
7
3
3
–
25
22
27
35
75
70
7
CHES(5 mL)
MES (5 mL)
MOPS (5 mL)
MOPS (5 mL)
MOPS(2.5 mL)
–
–
2.3.5. Ethyl 1-oxo-2-(3-oxo-3-(2-oxooxazolidin-3-yl)propyl)-2,3-dihydro-
1H-indene-2-carboxylate (6e)
–
–
The product was directly obtained following the standard procedure
as yellow oil (42% yield) after flash chromatography (3:1, Hexanes:
AcOEt). The product matched with the previous spectroscopic data de-
scribed in the literature [15]. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J =
7.7 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.40
–
10 mol% TBAI
10 mg of st-DNA in 0.5 mL CH2Cl2
a
All the reactions were carried out with 0.5 mmol of 2a, 5.0 mmol of 1 and st-DNA
(2.0 mg mL−1).

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C. Izquierdo et al. / Catalysis Communications 44 (2014) 10–14
Table 2
Reaction of the β-ketoesther 4 to different electrophiles 5a.
Entry
1
Electrophile
Product
Conversion (%)
Time (h)
24
Yield (%)
87b
N99
2
3
N99
N99
24
24
75
82
4
5
80
50
168
72
56b
42
6
7
23
168
168
7
–
–
Nr
8
9
a
–
–
–
–
168
168
Nr
Nr
All the reactions were carried out with 1 mmol of the electrophile, 0.1 mmol of the nucleophile 4, and 2.5 mL of MOPS buffer with 2.0 mg mL−1 of st-DNA.
b
In this case a mixture of diastereoisomers 50:50 was obtained.
(d, J = 7.4 Hz, 1H), 4.39 (t, J = 8.0 Hz, 2H), 4.02–3.96 (m, 2H), 3.72
(d, J = 18.7 Hz, 1H), 3.69 (s, 3H), 3.16 (d, J = 17.4 Hz, 1H), 3.15–30.5
(m, 1H), 2.97–2.87 (m, 1H), 2.56–2.46 (m, 1H), 2.23–2.15 (m, 1H).
found that the addition of a phase transfer catalyst (PTC), increasing
in this manner the contact of the two phase (organic-reagent and
aqueous), led a conversion of 70% (entry 6). Since other authors have
studied the solubility of DNA in organic solvents [20], we also tried the
reaction of DNA in CH2Cl2. However, we observed a very low solubility
of the st-DNA and a quite poor conversion in the reaction (entry 7). Un-
fortunately, in all these reactions we only obtained racemic compounds
(ee ranges between 1 and 4%), indicating that the aqueous media would
be interrupting the plausible chiral pocket for the stereoselective pro-
cesses or would be an inefficiency of DNA to induce asymmetry. After
these initial results, we decided to study other Michael-type additions
(Table 2) in order to increase the scope and also to find new results
2.3.6. Methyl 2-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-indene-2-
carboxylate (6f)
The product was directly obtained following the standard procedure
as colorless oil (7% yield) after flash chromatography (3:1, Hexanes:
AcOEt). The product matched with the previous spectroscopic data
described in the literature [16]. 1H NMR (300 MHz, CDCl3) δ 7.80
(d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H),
7.44 (t, J = 7.6 Hz, 1H), 3.77 (d, J = 17.0 Hz, 1H), 3.70 (s, 3H), 3.16
(d, J = 17.4 Hz, 1H), 2.64–2.55 (m, 2H), 2.44–2.22 (m, 2H).
Table 3
3. Results and discussion
Several catalytic cycles by using st-DNA in the Michael additiona.
We first studied the reaction of 1,3-dicarbonyl compounds with
nitroalkenes. This reaction has been described with good results under
thiourea [17] and squaramide [18] bifunctional catalysis (5–20 mol%
catalytic loading) in toluene or CH2Cl2 and in some cases with lower cat-
alytic loading (up to 0.1 mol%) [19]. The reaction of 1 with 2a did not
work in the absence of DNA, but in its presence the Michael product 3
was obtained in a moderated conversion after 24 h (entry 1, Table 1).
The use of basic or acidic buffers (MES and CHES) did not improve the
previous results (entries 2, and 3, Table 1), which were slightly better
with a neutral buffer (MOPS, entry 4). An increase in the reaction time
to 7 days was beneficial for the reaction, and we found a much better
conversion (entry 5). This result clearly indicates that st-DNA is the
real catalyst of this reaction. In order to increase the conversion, we
Entry
Catalytic cycle
Conversion (%)
Yield (%)
1
2
3
4
5
1
2
3
4
5
N99
N99
N99
N99
N99
86
93
80
78
70
a
All the reactions were carried out with 1 mmol of the electrophile 2b, 0.1 mmol of the
nucleophile 4, and 2.5 mL of MOPS buffer with 2.0 mg mL−1 of st-DNA.

C. Izquierdo et al. / Catalysis Communications 44 (2014) 10–14
13
Table 4
Reaction carried out with GMP, ethylguanine and methyladeninea.
Entry
Catalyst (10 mol%)
Time (h)
24
Conversion (%)
Yield (%)
1
N99
92
2
3
a
24
24
N99
N99
94
68
All the reactions were carried out with 0.5 mmol of the vinyl methyl ketone 2b, 0.05 mmol of 4, and 1.25 mL of MOPS buffer with 20 mol% of the catalyst.
that could give more information about the catalytic activity of the st-
DNA as a catalyst.
that the catalytic activity was due to the basic nature of the DNA (similar
to the result obtained from Et3N [22]).
Due to the low reactivity of the 1,3-dicarbonyl compound 1, we
studied the addition of the more reactive β-cyclic ketoesther 4 to differ-
ent Michael acceptors 2 (Table 2) [21]. Full conversion was observed
after 24 h in the reaction with the nitroalkene 2a, affording 6a in 87%
isolated yield as a 1:1 mixture of diastereoisomers (entry 1). Similar re-
sults were obtained with ketone 2b and aldehyde 2c, which were
completely transformed into 6b (75% yield) and 6c (82% yield) after
24 h (entries 2 and 3, Table 2). The β-substituted aldehyde 2d
required longer reaction times (7 days, entry 4) to afford 6d (56%
yield) as 1:1 mixture of diastereoisomers and the Evans' oxazolidinone
derivative 2e gave 6e in 42% yield after 72 h (50% conversion, entry
5). Reactivity of acrylonitrile (2f) was lower (23% conversion after
7 days), affording 6f in a poor yield (7%, entry 6), and other ethylene
derivatives bearing EWG like esther, sulfoxide or sulfone, did not
react, even increasing the time reaction to one week (entries 7, 8
and 9).
In conclusion, we have found that the 1,4-Michael addition of
1,3-dicarbonyl compounds can be carried out with st-DNA as catalyst.
The reaction proceeds quite well for high activated double bonds and
can be carried out in water. The st-DNA can be recovered and reused
for further catalytic cycles without diminishing its activity. Finally, the
similar or even larger efficiency of some nucleotides or nucleosides
as catalysts of these reactions suggests that the basic nitrogen of the
st-DNA could be responsible of the catalytic activity. Further research
is needed in order to carry out the asymmetric version of this reaction
and also mechanistic studies are in progress and will be reported at a
later date.
References
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(c) B. List, Chem. Commun. 46 (2006) 819;
Then, we focused our attention in recycling the st-DNA (Table 3).
With this aim, we carried out the reaction of β-ketoester 4 and vinyl
methyl ketone 2b. The reaction proceeds quite well after five catalytic
cycles. In all of them we observed full conversion after 24 h and excel-
lent yields.
(d) A. Erkkil, I. Majander, P.M. Pihko, Chem. Rev. 107 (2007) 5416;
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After this initial studies about the 1,4-Michael addition, we studied
which is the plausible cause of the catalytic activity of the st-DNA.
Therefore, we carried out the reaction with a more basic unit of the
DNA (GMP) in MOPS buffer and the same reaction conditions used for
st-DNA. To our surprise, the reaction gave the final product 6b with
20 mol% of the catalyst in 24 h (entry 1, Table 4). Thus, we decided to
eliminate the sugar from GMP, and therefore we carried out the reaction
with methyl-adenine and ethyl-guanine, in both cases with a 20 mol%
(entries 2 and 3). We found exactly the same results, obtaining the
product 6b with excellent yields in 24 h. These results suggest that
the more basic nitrogen (N-7) is acting as a base and the high polarity
of these molecules allows them to perform the reaction in water.
Besides our initial objective was the use of DNA as a catalyst for asym-
metric reactions (instead of complex chiral catalysts), we have found
that only racemic products were obtained and we have demonstrated
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14
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[21] We have carried out the reaction without st-DNA and we did not observe any con-
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For second generation, see e.g.:
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(f) See also,S.K. Silverman, Acc. Chem. Res. 42 (2009) 1521.
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[22] We also carried out the reaction with Et3N in the same reaction conditions,
obtaining full conversion with 89% isolated yield of product 6a.