Dibutylamine-catalysed efficient one-pot synthesis of biologically potent pyrans

Article abstract of DOI:10.1016/j.tetlet.2014.12.079

An expedient, eco-friendly and efficient procedure for the preparation of novel pyran derivatives has been developed through a solvent-free, one-pot reaction of various aldehydes, malononitrile and either methylacetoacetate or ethyl benzoylacetate in the presence of dibutylamine (2.5 mol %) at room temperature. This procedure is advantageous because it is mild, environmentally friendly, gives high yields and requires short reaction times. Furthermore, the product did not necessitate separation via extraction and column chromatography.

Full text of DOI:10.1016/j.tetlet.2014.12.079

Accepted Manuscript
Dibutylamine-catalyzed efficient one-pot synthesis of biologically potent pyr-
ans
Reddi Mohan Naidu Kalla, Mi Ri Kim, Il Kim
PII:
S0040-4039(14)02145-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.079
TETL 45603
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 November 2014
9 December 2014
14 December 2014
Please cite this article as: Kalla, R.M.N., Kim, M.R., Kim, I., Dibutylamine-catalyzed efficient one-pot synthesis
of biologically potent pyrans, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.079
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Tetrahedron Letters
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Dibutylamine-catalyzed efficient one-pot synthesis of biologically potent pyrans
Reddi Mohan Naidu Kalla, Mi Ri Kim, Il Kim *
BK21 PLUS Center for Advanced Chemical Technology, Department of Polymer Science and Engineering, Pusan National University, Busan 609-735, Republic
of Korea
Fax: +82-51-5137720; Tel.: +82-51-5102466; E-mail: ilkim@pusan.ac.kr
ARTICLE INFO
ABSTRACT
Article history:
Received
An expedient, eco-friendly, and efficient procedure for the preparation of novel pyran
derivatives have been developed through a solvent-free, one-pot reaction of various
aldehydes, malononitrile, and either methylacetoacetate or ethyl benzoylacetate in the
presence of dibutylamine (2.5 mol%) at room temperature. This procedure is advantageous
because it is mild, environmentally friendly, gives high yields, and requires short reaction
times. Furthermore, the product did not necessitate separation via extraction and column
chromatography.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Heterocyclic compound
Pyran
Organocatalysis
Solvent-free method
been used for the preparation of laser dyes,12cosmetics and
pigments,13 agrochemicals,14 nonlinear optical (NLO)
1. Introduction
properties,15 photo chromic materials,16 and photovoltaic
application.17,18 In addition, they also serve as intermediates for
the synthesis of organic compounds, including lactones,
Sustainable chemistry emphasizes the development of
operationally simple and eco-friendly routes to the synthesis of
biologically potent organic and medicinal compounds, which
are the most significant objective compounds in synthetic
chemistry. Conducting reactions in the absence of a solvent
(i.e., neat conditions) is an important aspect of green
chemistry;1,2 furthermore, the completion of various
transformations via a single process is highly compatible with
the goals of green chemistry. A one-pot reaction in which three
or more reactants combine to form a new compound without
isolation of any intermediate is known as a multi-component
reaction (MCR)3 and is highly attractive because of their ability
to generate two or more C–C, C–N, or C–O bonds in a single
step.
Organocatalysis is presently one of the fastest growing fields
of research in organic chemistry.4 Even though chemical
transformations that use organic catalysts, or organocatalysts,
are currently standard and have been over the last century, the
application of small natural molecules as organocatalysts in
MCRs for diversity-oriented syntheses (DOSs) offers many
advantages; e.g., they do not require moisture-sensitive Lewis
acids, air-sensitive reagents, toxic metals, nor an inert
atmosphere.
imidoesters,19
polyazanaphthalenes,20
pyridin-2-ones,21
pyrano[2]-pyrimidines,22 and pyranopyridinederivatives.23 The
generation of pyrans are of significant interest given their wide
range of applications. A variety of catalytic methods have been
reported for the synthesis of pyrans; these include
heterogeneous catalysis,24–26 ionic liquids,27 and base-promoted
reactions under microwave irradiation20 and thermal heating28.
Chemical reactions under microwave irradiation at high
temperatures in the presence of acids or metal catalysts are
favourable for side reactions such as Knoevenagel condensation
(KC) that form byproducts. Hence, the development of similar
milder and environmentally sustainable procedures for the
preparation of pyrans is needed.
Currently, reactions conducted under neat conditions were
used for the synthesis of various chemicals. Furthermore, the
cost effectiveness and reaction rates of various organic
transformations are also being improved. The most significant
goals of sustainable chemistry are to reduce the use of organic
solvents, toxic reagents, and laborious work-up procedures
associated with the synthesis of compounds. An extensive
survey of the literature revealed that there are, to the best of our
knowledge, no reports on the synthesis of pyrans promoted by a
dibutylamineorganocatalyst. This is a continuation of our
ongoing research interest in the growth of efficient,
inexpensive, and new methodologies.29–34 Herein, we report the
eco-friendly one-pot synthesis of pyrans through a three-
component condensation of aldehyde, malononitrile (MN), and
methylacetoacetate (MAA) or ethyl benzoylacetate (EBA) in
Synthetic heterocyclic compounds are most important in the
fields of organic and medicinal chemistry because these
compounds have
applications. Pyrans are an important class of oxygen
heterocycles that have various biological properties such as
anti-leishmanial,5 anti-HIV,6 antioxidant,7 anti-tumor,8 and
central nervous system (CNS) activities and effects;9 they are
also used for treatment of Alzheimer’s disease10 and
schizophrenia.11 Furthermore, some pyran derivatives have also
a
broad range of pharmacological

2
Tetrahedron
dKnoevenagel condensation.
the presence of a dibutylamineorganocatalyst under neat
conditions at room temperature
2. Results and discussion
The low toxicity, ease of handling, commercial availability, and
economical aspects of DBA (low cost), as well as the ease of its
removal (water washings) from reaction mixtures prompted us
to choose it as a suitable organocatalyst for the synthesis of
pyrans (Scheme 1).
Generally, MCRs require elevated reaction temperatures, long
reaction times, and high catalyst loading to promote the
formation of the desired product. One-pot three-component
reactions of aldehyde, MN, and MAA or EBA (1 mmol each)
were first attempted using various types of catalysts at room
temperature using the solvent-free method (Table 1). First, the
experiments were performed in the absence of catalyst at room
temperature for 14 h using the solvent-free method; however,
no product formed (entry 1). Then, we tried acidic species such
as ZnCl , ZrOCl , ZrOCl2⋅⋅SiO , BF3⋅⋅OEt , BF3⋅⋅SiO , silica-
⋅⋅ ⋅⋅ ⋅⋅
2
2
2
2
2
supported ClSO3H, and trifluoroacetic acid at room temperature
for 6 h of reaction, which proved ineffective, whereas the same
catalysts at 100
℃
product yields (entries 2–8). The addition of metal salts such as
over 6 h of reaction resulted in relatively low
Mg(ClO ) and Y(CF COO)3⋅⋅nH O was also ineffective (entries
⋅⋅
3
4
2
2
9 and 10). On the other hand, with heterogeneous catalysts like
dimethylaminopyridine (DMAP) and diazabicycloundecene
(DBU), a mixture of pyrans and KC products were observed in
all cases based on thin-layer chromatography (TLC) analysis of
the reaction mixture after 5 h. After stirring continuously for an
additional hour, the mixture of products remained and very low
yields of products were obtained (entries 11 and 12). We also
attempted the reaction in the presence of base catalysts such as
piperazine, pyrrolidine, morpholine, dimethylamine, and
dibutylamine (DBA) (entries 13–17) with very similar pKa
values, which were equally efficient at furnishing the desired
product with good yields. Among these basic catalysts,
dibutylamine furnished the product in the highest yield and
shortest reaction time; the results are summarized in Table 1.
Table 1. Effect of various catalysts on the synthesis of
Scheme 1. Synthesis of a series of novel pyrans (1-32).
To determine the optimum catalyst loading of dibutylamine,
model reactions were carried out using 1, 1.5, 2, 2.5, and 3
mol% dibutylamine under neat conditions at room temperature
(rt), which afforded 80%, 85%, 96%, 98%, and 98% product
yields, respectively. Increasing the amount of catalyst beyond
2.5% had no additional effect on the reaction progress. The
results are summarized in Fig. 1.
compound
1
in the absence of solvent at room temperature.a
Catalyst amount
(mol%)
Time
(h)
Entry
Catalyst
Yield (%)b
1
2
Catalyst free
ZnCl2
-
14
3
nrc
30
5
3
4
ZrOCl2
5
5
6
6
25
32
ZrOCl2⋅SiO2
5
BF3O(Et)2
5
5
6
6
42
48
6
BF3⋅SiO2
7
5
6
35
SiO2⋅SO3H
8
TFA
5
6
46
nrc
9
Mg(ClO4)2
5
6
10
11
12
13
14
15
16
17
18
19
20
21
5
6
nrc
Y(CF3COO)3⋅nH2O
DMAP
5
6
KCd (80)
KCd (85)
80
DBU
5
6
Piperazine
5
1
Pyrrolidine
5
1
82
Morpholine
Dimethylamine
Dibutylamine
Dibutylamine
Dibutylamine
Dibutylamine
Dibutylamine
5
1
84
5
1
90
1
0.5
0.5
0.5
0.3
0.3
80
1.5
2
85
94
2.5
3
98
98
Figure 1. Effect of the amount of dibutylamine on the yield of
1.Conditions: benzaldehyde (1 mmol), malononitrile (1 mmol),
methylacetoacetate (1 mmol), dibutylamine (2.5 mol%), neat, rt.
aReaction conditions35: aldehyde (1 mmol), malononitrile (1 mmol),
methylacetoacetate (1 mmol), DBA (2.5 mol%), neat, and r.t.
bIsolated yield measured gravimetrically.
cNo reaction.

Consequently, we then explored the general applicability of
the reaction conditions towards the synthesis of various
substituted pyrans; the results are summarized in the
experimental section. Firstly, reactions were performed between
MAA, MN, and various aromatic aldehydes; aromatic
aldehydes bearing electron-withdrawing as well as electron-
donating groups on the aromatic ring were successfully utilized
in the reaction, and the desired products were obtained in high
yields within a short reaction time. The procedure was extended
towards heteroaromatic and aliphatic aldehydes; in all cases, the
respective pyrans were obtained with good yields within a short
time. Additionally, we replaced MAA with EBA, which also
generated the desired products in good yields. Among all the
observed in the region of 44.1–36.8 ppm, confirming the
formation of pyrans.36 A detailed description of the spectral data
for all compounds (
information.
1–32) is provided in the supporting
3. Conclusion
A straight-forward, efficient, and green procedure for the
synthesis of pyrans using dibutylamine organocatalysts under
solvent-free conditions was described. In this study,
dibutylamine was used as a highly efficient organocatalyst for
the multi-component synthesis of pyrans at room temperature.
The availability of this non-toxic and low-cost catalyst as well
as the resultant high yields, operational simplicity, and simple
work-up make this an eco-friendly alternative to the presently
accessible protocols.
reactions the compounds 11
,
12
,
14 and 32 were are obtained
12 substituted
not pure compounds because the compounds 11
,
with hydroxy groups are less reactivity with MAA when
compared to EBA. Furthermore the compound 14 is
heterocyclic aldehyde is bearing methyl substitution at 5-
position due to progress of the reaction is slow where as in the
case of compound 32 is contains n-hexanaldehyde is aliphatic in
nature and in general aliphatic aldehydes are less reactive than
aromatic and heterocyclic aldehydes.
Acknowledgments
This work was supported by the Basic Science Research
Program through the National Research Foundation of Korea
funded by the Ministry of Education (2012R1A1A2041315),
and by the Fusion Research Program for Green Technologies
through the National Research Foundation of Korea funded by
the Ministry of Knowledge Economy (2012M3C1A1054502).
The authors would also like to thank the BK21 PLUS Program
for partial financial support.
There are numerous advantages of dibutylamine in
comparison with other catalysts used for the synthesis of
pyrans. Recently, Khurana et al.36 reported the use of task-
specific ionic liquids (ILs) at 50–60 oC for the synthesis of
pyrans. In 2011, Banerjee37 established the synthesis of pyrans
promoted by SiO2 nanoparticles in ethanol at room temperature;
however, this method required a long reaction time (2 h).
Valizadehet al.38 reported the synthesis of pyrans using
ZnO/MgO-containing ZnO nanoparticles in the presence of
ionic liquids at rt that required a tedious work-up procedure and
resulted in a yield of 91%. Peng et al.27also reported the
synthesis of pyrans in a 92% yield using amino-functionalized
ILs with microwave irradiation as an additional energy source
for product formation. Compared to the above-reported
catalysts, the dibutylamine organocatalyst was superior for the
synthesis of pyrans with high yields with no need for severe
reaction conditions, additional energy (i.e., microwaves or,
ultrasonication), and laborious work-up procedures; the full
comparison is summarized in Table 2.
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aldehyde (1 mmol), malononitrile (1 mmol) in 25mL reaction flask
equipped with a magnetic stirring bar was added dibutylamine (2.5
mol%); the resulting reaction mixture was stirred at r.t. for the
appropriate time (10–40 min). The progress of the reaction was
monitored by TLC. After completion of the reaction, chilled water (10
mL) was added, and stirring was continued until a free–flowing solid was
obtained. It was filtered and then washed successively with chilled water
(40 mL) after that the products were dried at r.t. The identical
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