Stereoselective construction of functionalized tetracyclic and pentacyclic coumarinopyranpyrazole/pyrimidinedione/coumarin scaffolds using a solid-state melt reaction

Article abstract of DOI:10.1039/c5ob00442j

An assembly of tetra / pentacyclic hybrid scaffolds have been synthesized for the first time using a solid-state melt reaction in a stereoselective fashion with excellent yields.

Full text of DOI:10.1039/c5ob00442j

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Stereoselective Construction of Functionalized Tetra
and Pentacyclic Coumarinopyranpyrazole
/
Cite this: DOI: 10.1039/x0xx00000x
Pyrimidinedione / Coumarin Scaffolds Using Solid
State Melt Reaction
Received 00th January 2012,
Accepted 00th January 2012
Manickam Bakthadoss,*a,b Damodharan Kannan,b Nagappan Sivakumar,b Palani
Malathib and Vasudevan Manikandanb
DOI: 10.1039/x0xx00000x
www.rsc.org/
synthetic chemists to find newer and more economic protocol to
attain them in a strategically attractive manner.
An assembly of tetra and pentacyclic hybrid scaffolds has
been established using a solid state melt reaction (SSMR)
for the first time. These hybrid heterocyclic entities were
accomplished in a stereoselective fashion in 86ꢀ98% yield
under catalystꢀ, solventꢀ, work upꢀ and column
chromatography free conditions.
Introduction
Heterocyclic frameworks are ubiquitous in nature and found to be an
integral part of vast number of biologically active components.1 In Figure 1. Natural products and bioactive molecules embodying
general, multistep involved to construct complex heterocycles;
the coumarin, pyrazole, pyrimidinedione and chromenopyran
however the number of steps can be intensely reduced while using units
domino / cascade reactions.2 The domino reaction in organic
In continuation of our studies,2c, 2h, 9e-f, 10 we explored the solid
synthesis which enhances the selectivity and efficiency, particularly state melt reaction (SSMR) for the synthesis of novel
for fused heterocyclic architectures. Similarly, the domino
heterocyclic frameworks particularly chromeno / quinolino
Knoevenagel-hetero-Diels-Alder reaction2-3 substantially increase the pyranpyrimidinedione, pyrazoles and coumarins. Furthermore,
molecular complexity and high levels of convergence in synthesis. this novel SSMR was utilized for the construction of benzo-
Indeed, these reactions minimizes the laboratory equipment, heterocyclic frameworks and other useful motifs.10 The
chemical and solvent usage for the synthesis of various heterocyclic
successful outcome of this protocol intrigued us to synthesis
various compounds through the domino transformations via
motifs,4 in which coumarin, pyrazole and pyrimidinedione
containing hybrid pyranochromenone frameworks are important due multiple bond-forming processes. Thus, we have undertaken a
to their key units in many natural products pertaining to their research program for the construction of various hybrid
interesting medicinal properties.
compounds using domino Knoevenagel hetero Diels-Alder
reaction via SSMR strategy.
Consequently, we envisaged that the privileged tetra /
Recently, significant numbers of reports are appearing in the
literature towards the coumarin, pyrazole and pyrimidine fused
heterocyclic derivatives5 due to their aforementioned properties. pentacyclic hybrid pyrazole, pyrimidine and coumarin
Accordingly, the pyrazole centered ring system, in particular the
pyranopyrazole units have shown molluscicidal, antimicrobial, anti-
annulated coumarinopyran frameworks can be effectively
constructed using solid state melt reaction (SSMR) through
inflammatory activities, besides active ingredients in prominent domino Knoevenagel hetero Diels-Alder reaction according to
drugs viz., Viagra®, Celebrex® etc.6a-f Coumarin scaffolds display a the retrosynthetic analysis shown in Scheme 1.
broad range of applications like optical brightening agents, . To execute our idea, initially we treated cinnamoyl chloride
pharmaceuticals, food additives, cosmetics, agrochemicals and
with salicylaldehyde in presence of potassium carbonate in
tunable dye lasers.6g-h In addition, they also possess a broad spectrum acetonitrile as a solvent at room temperature for about 1 h
of biological activities such as anthelmintic, anticoagulants, hypnotic which led to the requisite precursor i.e. 2-formylphenyl
and insecticidal properties.7 Whereas, the pyrimidine moieties cinnamate
(2a) in 74% yield. After obtaining the 2-
exhibiting antiviral and anti-HIV activities.8 Some of the
formylphenyl cinnamate (2a), initially we tried the reaction
representative examples for coumarin, pyrazole, pyrimidinedione, with
and coumarinopyran motif9a-d containing natural products and conditions, however the best result was obtained when the
potential bioactive molecules are shown in Figure 1. The wide ranges substrate 2a was melted with
-dimethyl barbituric acid (3a)
N,N-dimethyl barbituric acid under various reaction
N,
N
of biological applications have intrigued considerable attention of
at 180 °C under solvent- and catalyst- free condition over a
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period of 1 h which successfully provided the complex Encouraged by this result, we have utilized cinnamoyl /
angularly fused tetracyclic coumarinopyranpyrimidinedione crotonyl chlorides with various salicyaldehyde derivatives
(
5a) in excellent yield (98%). Interestingly, this novel reaction under basic condition for the preparation of various 2-
creates coumarin ring and coumarinopyran ring in a highly formylaryl cinnamate and crotonate derivatives (2bꢀg). Further
diastereoselective fashion with the conservation of high atom reaction of the substrates 2bꢀg with -dimethyl barbituric
N,N
economy.
acid (3a) / 5, 5-dimethylcyclohexane-1,3-dione (3b) under
similar condition smoothly led to the tetracyclic
Scheme 1. Retrosynthetic strategy for the synthesis of tetra and coumarinopyran annulated pyrimidinedione / cyclohexenone
pentacyclic frameworks
frameworks (5bꢀh) in excellent yields (90-96%), and the results
are summarized in Table 1. It is important here that reaction is
not only diastereoselective but also chemoselective in nature
which was confirmed by NMR and single crystal X-ray studies.
Table 2. Synthesis of tetra / pentacyclic coumarinopyran
pyrazoles (8aꢀc) / coumarinopyrancoumarins (10aꢀb
formylarylcinnamate / crotonate derivatives (2a, dꢀe
)
a,b using 2-
)
Table 1. Synthesis of tetracyclic coumarinopyranpyrimidine
a,b
diones / dimethylcyclohexanones (5aꢀh
)
using 2-formylaryl
cinnamate / crotonate derivatives (2aꢀg
)
aAll reactions were carried out on 1 mmol scale of 2-formylaryl
cinnamate / crotonate derivatives (2a, dꢀe) with 1 mmol of 1,3-
diphenyl-1
5(4 )-one
condition at 180 ºC for 1 h. bIsolated yields of 8aꢀc and 10aꢀb
H
-pyrazol-5(4
H
)-one (6a) / 3-methyl-1-phenyl-1
H-pyrazol-
H
(6b), 4-hydroxy-2
H
-chromen-2-one 6c under melt
( )
.
To check the generality of the reaction, we have treated various
2-formylaryl cinnamate derivatives (2a, dꢀe) with diverse active
methylenes such as 1,3-diphenyl-1
H
-pyrazol-5(4
-pyrazol-5(4H)-one (6b) and 4-hydroxy-
6c under aforementioned synthetic
H)-one (6a) /
3-methyl-1-phenyl-1
2H-chromen-2-one
H
(
)
procedure which successfully provided the anticipated tetra and
pentacyclic hybrid coumarinopyranpyrazole/coumarin scaffolds
(8 / 10) in 92-97% yields as shown in Table 2. In order to
broaden the scope of this protocol, we have decided to construct
various polycyclic frameworks using similar method with nitro
functionality. Accordingly, on treatment of salicylaldehyde with
several Baylis-Hillman bromides containing nitro functionality
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aAll reactions were carried out on 1 mmol scale of 2-formylaryl
cinnamates (2aꢀg) with 1 mmol of -dimethyl barbituric acid / 5, 5-
dimethylcyclohexane-1,3-dione (3a / 3b) under melt condition at 180 ºC
for 1 h. bIsolated yields of 5aꢀh. cStructures of the molecule were further
confirmed by single-crystal X-ray data.11
N,N
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under basic condition led to the requisite precursors 11 and 14
Furthermore, we have melted the 4-hydroxy-2
6b) with various Baylis-Hillman derivatives (11aꢀe), (14aꢀb
derived from nitro olefins which efficiently led to the (3b) undergo a Knoevenagel condensation with aldehydes (2aꢀg) to
pentacyclic hybrid coumarinopyrancoumarins (13aꢀe 16aꢀb afford the heterodienes 4′aꢀh which in turn may lead to the
possessing nitro functionality at the angular position in very compounds (4aꢀh) with another orientation. The geometrical nature
.
The plausible mechanistic pathway for the formation of 5aꢀh is
H
-chromen-2-one shown in Scheme 2 in which the active methylenes such as N, N-
dimethyl barbituric acid (3a) / 5, 5-dimethylcyclohexane-1,3-dione
(
)
/
)
good yields (86-92%) and the results are presented in Table 3.
and attack of dienophiles are the controlling factors for the
stereochemistry of the tetracyclic frameworks formed in the reaction.
Table 3. Synthesis of pentacyclic coumarinopyrancoumarins The exo transition state leads an adduct with trans fusion in the ring
a,b
(
13aꢀe / 16aꢀb
)
possessing nitro functionality at angular junction. Whereas the endo transition state leads to adducts 5aꢀh
position using
O
-alkylated derivatives (11aꢀe & 14aꢀb
)
with cis fusion in the ring junction. The cis fusion of the ring
junction was further confirmed by coupling constants of Hb and Hc
protons (J = 3.9-5.1 Hz). Furthermore the stereochemistry of the
compounds (5a, 5c & 5g) was established by single crystal X-ray
analysis.11
Conclusions
We have successfully developed a simple and novel protocol
for the facile synthesis of complex angularly substituted tetra
and pentacyclic hybrid molecular frameworks containing a
coumarinopyranpyrazole / pyrimidinedione and coumarin ring
systems using cinnamate, crotonate and
O-allyl derivatives via a
solid-state melt reaction (SSMR) through a domino process.
Noteworthy features include the following: (a) Avoidance of
catalysts and solvents even for solid reactants; (b) the products
are obtained in a high diastereo- and chemoselective fashion;
(c) column chromatography purification is not required to
obtain the pure products; and (d) products are obtained with
excellent yields. Therefore, this method will be highly useful to
organic chemists both in academia as well as industrial sector.
Furthermore, the highly remarkable SSMR strategy is valuable
additional tool box for the production of various complex
hybrid polyheterocyclic scaffolds.
Acknowledgment: We thank DST-SERB, New Delhi for the financial
support. We also thank DST-FIST for the NMR facility. D.K thanks
Council of Scientific and Industrial Research for the award of Senior
Research Fellowship.
aAll reactions were carried out on 1 mmol scale of
compounds (11aꢀe
one (6b) under melt condition at 180 ºC for 1 h. Isolated yields of the
products 13aꢀe 16aꢀb
O
-allylated
Notes and references
aDepartment of Chemistry, Pondicherry University, Pondicherry – 605 014,
&
14aꢀb) with 1 mmol of 4-hydroxy-2H-chromen-2-
b
India.
&
.
bDepartment of Organic Chemistry, University of Madras, Guindy Campus,
Chennai-600025, Tamil Nadu, India.
Scheme 2. A plausible mechanistic pathway for the synthesis of
*Corresponding author. Tel.: (+91)413-2654830; Fax: (+91) 44
22352494. E-mail: bhakthadoss@yahoo.com
5aꢀh
Electronic Supplementary Information (ESI) available: Representative
experimental procedures with all spectral data of 5aꢀh
and 16aꢀb. See DOI: 10.1039/c000000x/
, 8aꢀb, 10aꢀb, 13aꢀf
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