Magnetically recoverable silica catalysed solvent-free domino Knoevenagel-hetero-Diels-Alder reaction to access divergent chromenones

Article abstract of DOI:10.1039/d0ob00284d

A three-component domino Knoevenagel-hetero-Diels-Alder (DKHDA) reaction between 1,3-dicarbonyl, aldehydes/ketones, and alkenes/alkynes leading to the divergent synthesis of chromenones, dihydrochromenones, and spirocyclic chromenones is reported. The reaction was carried out under solvent-free conditions using a magnetically separable silica (Fe₃O₄?SiO₂) catalyst. While two component DKHDA reactions are known, this is the first example of a three component DKHDA reaction involving 1,3-dicarbonyl, ketones, and alkynes producing spirocyclic pyranone derivatives. Twenty-six different highly substituted chromenones were synthesized using this methodology. A wide substrate scope due to the multicomponent nature of the reaction, high atom economy, the use of inexpensive and non-Toxic recyclable silica as the catalyst, and solvent free reaction conditions make it an advantageous process. The catalyst was characterized using different analytical techniques such as XRD, IR, HRTEM, VSM, and TGA. Based on the earlier reports a mechanism has also been proposed.

Full text of DOI:10.1039/d0ob00284d

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Magnetically recoverable silica catalysed solvent-
free domino Knoevenagel-hetero-Diels–Alder
reaction to access divergent chromenones†
Cite this: DOI: 10.1039/d0ob00284d
Received 8th February 2020,
Accepted 3rd March 2020
Mrinaly Suri,a Farhaz Liaquat Hussain,a Chinu Gogoi,a Pankaj Dasb and
a,c
DOI: 10.1039/d0ob00284d
Pallab Pahari
*
rsc.li/obc
A
three-component domino Knoevenagel-hetero-Diels–Alder vitamin essential for blood clotting,4 and trigolutes show
(DKHDA) reaction between 1,3-dicarbonyl, aldehydes/ketones, AChE inhibitory activity.5 Synthetic chromene derivatives also
and alkenes/alkynes leading to the divergent synthesis of show antioxidant,6 anticancer,7 antimicrobial,8 and molluscici-
chromenones, dihydrochromenones, and spirocyclic chromenones dal activities.9
is reported. The reaction was carried out under solvent-free con-
In recent years, the domino Knoevenagel-hetero-Diels–
ditions using a magnetically separable silica (Fe3O4@SiO2) catalyst. Alder (DKHDA) reaction has gained immense interest due to
While two component DKHDA reactions are known, this is the first its application in the construction of synthetic drugs,10
example of a three component DKHDA reaction involving 1,3- natural products11 and poly-heterocyclic compounds12 incor-
dicarbonyl, ketones, and alkynes producing spirocyclic pyranone porating pyran-based frameworks with high atom economy.
derivatives. Twenty-six different highly substituted chromenones Following the pioneering works by Tietze,12a–c several
were synthesized using this methodology. A wide substrate scope methods have been reported in the literature employing the
due to the multicomponent nature of the reaction, high atom DKHDA strategy leading to the construction of a vast array of
economy, the use of inexpensive and non-toxic recyclable silica as highly diverse pyran-fused carbocycles.13 Although intra-
the catalyst, and solvent free reaction conditions make it an advan- molecular or two component DKHDA reactions between
tageous process. The catalyst was characterized using different various aromatic and aliphatic aldehydes and 1,3-dicarbonyl
analytical techniques such as XRD, IR, HRTEM, VSM, and TGA. compounds have been widely reported,10–13 examples of
Based on the earlier reports a mechanism has also been proposed.
intermolecular three component reactions involving 1,3-
dicarbonyl, aldehydes/ketones, and alkenes/alkynes are com-
paratively less.14 Moreover, reactions with non-activated term-
inal alkynes are limited compared to alkenes. To our knowl-
edge there are no reports on DKHDA reactions involving 1,3-
Introduction
The chromene core is exemplified as a privileged moiety in a
variety of natural products such as flavonoids, alkaloids and
anthrocyanins and is known to possess fascinating therapeutic
properties.1 For example, calanolide A and B show prominent
HIV-1 inhibitory activity (Fig. 1).2 Ethuliacoumarion A and its
derivatives show anticancer, molluscicidal and anthelmintic
activities.3 Ferprenin is a specific inhibitor of the enzyme
VKORC1 which is responsible for the recycling of vitamin K, a
aChemical Science and Technology Division, CSIR-North East Institute of Science and
Technology, Jorhat-785006, Assam, India. E-mail: ppahari@gmail.com,
pallab@neist.res.in
bDepartment of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India
cAcademy of Scientific and Innovative Research, CSIR-NEIST Campus, Jorhat-785006,
Assam, India
†Electronic supplementary information (ESI) available: Experimental details,
catalyst characterization and spectra of all new products. See DOI: 10.1039/
d0ob00284d
Fig. 1 Biologically active natural products containing chromenones.
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chromenones/dihydrochromenones/spirochromenones.
For
operational simplicity in recycling, the silica catalyst has been
prepared as a magnetically active catalyst using in situ generated
Fe3O4. Moreover, the reaction has been performed under
solvent free conditions, which meets the recent green chemistry
trends to develop green and sustainable chemical processes.
The Fe3O4@SiO2 catalyst was prepared using a modified lit-
erature procedure17 starting from silicic acid, iron(II) chloride
and iron(III) chloride (see the ESI†).17 Characterization of the
prepared catalyst was carried out using XRD (Fig. S1†), FTIR
(Fig. S2†) and HRTEM (Fig. S3†). The magnetic nature was
studied using a vibrating sample magnetometer (Fig. S4†). The
thermal stability was determined using TGA (Fig. S5†).
To identify the optimal reaction conditions, 1,3-cyclohexa-
nedione (1a), benzaldehyde (2a), and phenylacetylene (3a)
were used as model substrates. The reaction mixture was
refluxed for 3 h using acetonitrile as the solvent and the chro-
menone product was obtained in 50% yield (Table 1, entry 1).
Although the yield could not be improved significantly by
varying the solvents (Table 1, entries 2–5), the reaction pro-
vided a significantly good yield (82%) of the product under
solvent free conditions (Table 1, entry 11). The optimal temp-
erature was found to be 100 °C and the reaction was completed
in 2 h (Table 1, entries 6–11). The ideal catalyst amount was
10 wt% with respect to 1a. The role of the catalyst was con-
firmed by performing the reaction in the absence of the cata-
lyst wherein no product formation could be observed (Table 1,
entry 12). The reaction did not afford any product when per-
formed in the presence of Fe3O4, FeCl2 or FeCl3 (Table 1,
entries 14–16). This observation confirmed the role of the
Scheme 1 The domino Knoevenagel-hetero-Diels–Alder (DKHDA)
reaction.
dicarbonyl, ketones, and alkynes producing spirocyclic pyra-
none derivatives (Scheme 1).
The use of silica as a catalyst for organic reactions is a rela-
tively less explored area.15 Because of its non-toxicity, porous
structure, large specific area, low cost, high stability and wide
availability, there is a wide scope for the utilization of silica as a
recyclable heterogeneous catalyst. In continuation of our work
on the development of recyclable heterogeneous catalyst for
different organic transformations,16 herein, we report a silica
catalyzed three component domino-Knoevenagel-hetero-Diels–
Alder reaction for the efficient synthesis of highly substituted
Table 1 Synthesis of chromenones and optimization of the reaction conditionsa
Temperature
(°C)
Catalyst
amount (wt%)
Yieldb
(%)
Entry
Catalyst
Solvent
1
2
3
4
5
6
7
8
Fe3O4@SiO2
Fe3O4@SiO2
Fe3O4@SiO2
Fe3O4@SiO2
Fe3O4@SiO2
Fe3O4@SiO2
Fe3O4@SiO2
Fe3O4@SiO2
CH3CN
DMSO
H2O
80
110
100
80
110
80
100
120
100
100
100
100
100
100
100
100
20
20
20
20
20
20
20
20
15
5
10
10
10
10
10
10
50
52
38
45
18
73
82
79
82
79
82
0
C2H5OH
Toluene
None
None
None
None
None
None
None
None
None
None
None
9
Fe3O4@SiO2
Fe3O4@SiO2
Fe3O4@SiO2
No catalyst (only silicic acid)
SiO2 without Fe3O4 (prepared using identical conditions)
Fe3O4
FeCl3
FeCl2·H2O
10
11
12
13
14
15
16
82
0
0
0
a All the reactions were carried out using 0.9 mmol each of 1,3-cyclohexanedione (1a), benzaldehyde (2a), and phenylacetylene (3a). b Isolated yield.
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silica as the active catalyst. For further confirmation, a catalyst ponding hexahydro-5H-chromen-5-ones 4q–4s. All the com-
1
was prepared from silicic acid without the addition of iron pounds were characterized with the help of H NMR and 13C
salt. The newly formed silica catalyst showed identical activity NMR spectra. Their molecular formulae were confirmed with
to the original Fe3O4@SiO2 (Table 1, entry 11).
the HRMS data. The melting point data of the reported com-
With the aforementioned optimised reaction conditions in pounds matched with those in the literature.
hand, we further examined the substrate scope by reacting 1,3-
After the successful exploration of Fe3O4@SiO2 towards the
cyclohexanedione with different aromatic aldehydes and term- synthesis of chromenones, we further extended our study
inal alkynes/alkenes (Table 2). It was observed that aldehydes towards cyclic ketones. It was observed that the reaction
and alkynes containing electron withdrawing as well as elec- between 1,3-diketones, alkynes or alkenes and cyclic ketones
tron donating groups performed well to give the corresponding provided the corresponding spirocyclic chromenones 6a–g in
tetrahydro-5H-chromen-5-ones 4a–4s under the given reaction good to excellent yields (Table 3). Both cyclobutanone and
conditions. Not only aromatic aldehydes, but also phenylace- cyclopentanone provided the corresponding spirochromenes
taldehyde under the given optimised conditions provided the in good yields. Unfortunately, cyclohexanone and larger cyclic
desired products 4i and 4l. 4-Allyloxybenzaldehyde reacted well ketones did not participate in the reaction. This fact may be
to give the corresponding tetrahydro-5H-chromen-5-one 4j explained by the difficulty in the formation of the Knoevenagel
without any side reaction. Other 1,3-diones such as cyclopen-
tane-1,3-dione, dimedone, and chromane-2,4-dione were
coupled with aldehydes and alkynes to give the corresponding
chromenones 4k–4p in very good yields. Styrene derivatives
also participated in the same reaction producing the corres-
Table 3 Synthesis of spirochromenones from 1,3-diketones, ketones,
and alkynes or alkenes
Table 2 Synthesis of chromenones from 1,3-diketones, aldehydes, and
alkynes or alkenes
Scheme 2
A plausible mechanism for the Fe3O4@SiO2 catalyzed
Knoevenagel-hetero-Diels–Alder reaction.
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product with cyclohexanone and larger counterparts. Simple
acyclic ketones also didnot participate under the given reaction
conditions. All the prepared compounds were duly character-
ized with the help of NMR and mass spectral data.
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There are no conflicts to declare.
Acknowledgements
This work is financially supported by the SERB, New Delhi,
India (GPP0356) and CSIR, New Delhi, India (OLP2020 and
HCP021). The authors are thankful to the analytical facility,
CSIR-NEIST, for recording all the analytical data.
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