Synthesis of α,β-unsaturated ketones from alkynes and aldehydes over Hβ zeolite under solvent-free conditions

Abstract

A facile Hβ zeolite-catalyzed strategy has been successfully developed for the synthesis of α,β-unsaturated ketones from alkynes and aldehydes under solvent-free conditions. The reaction proceeds via tandem hydration/condensation of alkynes with aldehydes to afford a range of α,β-unsaturated carbonyls in good to excellent yields.

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Introduction

α,β-Unsaturated carbonyls are important structural motifs found in various bioactive natural products which exhibit diverse pharmaceutical and biological properties, including antimalarial, antitumor, antiviral, anti-tuberculosis, anti-hyperglycaemic and anti-inflammatory activities (Fig. 1).¹ In addition to their biological applications, they have also been utilizing as intermediates in the synthesis of various biologically important heterocyclic compounds² and functional materials.³ Consequently, significant efforts have been made over the years to develop highly efficient synthetic strategies for the preparation of α,β-unsaturated carbonyls including strong base-promoted aldol condensation,⁴ palladium-catalyzed Sonogashira coupling between aryl halides and propargyl alcohols,⁵ carbonylative Heck coupling,⁶ cross-coupling of ketones with arenes or aryl carboxylic acids,⁷ coupling of alkynes with aldehydes⁸ and hydration–condensation reactions of alkynes with aldehydes.⁹ Despite formidable advances, most of the methods suffer from one or more limitations, such as poor substrate scope, limited functional group tolerance, the use of stoichiometric amounts of strong bases or toxic transition metal catalysts and high cost of the catalytic system. Owing to their varied pharmacological activities and synthetic utility, the development of a general, green and environmentally benign synthetic protocol for the synthesis of α,β-unsaturated ketones is highly desirable.

Fig. 1 Representative examples of biological significant α,β-unsaturated carbonyl-containing compounds.

Recently, the development of new processes that minimize pollution in the chemical industry has received considerable attention due to growing environmental concerns. In this path, heterogeneous catalysis has emerged as a useful tool to reduce waste production with regard to the simplicity of the process, lower contamination of the products with the active catalytic species and separation and recycling of the catalysts.¹⁰ In addition, pursuing organic reactions in solvent-free conditions¹¹ is also a vital aim in modern organic synthesis due to some advantages over reactions in organic solvents, as they are not only reducing the burden of organic solvent disposal, but also increase the rate of many organic reactions.

Zeolite materials have wide spread applications both in petroleum and fine chemical industries¹² because of its unique physical and chemical properties, such as uniform channel size, large internal surface area, unique molecular shape selectivity, strong acidity and good thermal/hydrothermal stability. The BEA-type of zeolite consists of an intergrowth of two or more polymorphs comprised of a three dimensional system of 12-membered ring channels.¹³ Zeolite beta has pore diameters of 0.76 × 0.64 nm and 0.55 × 0.55 nm. The BEA framework topology attracts much attention as an alternative and promising candidate for a wide array of different chemical reactions because of the available large micro-pore volume, large-pore channel system and the presence of active sites (Bronsted acid sites in the micropores and on the external surface and Lewis acid sites predominantly at the internal surface due to the local defects) in different concentrations.¹⁴ In continuation of our efforts toward the development of novel and eco-friendly synthetic protocols using zeolites,¹⁵ herein we describe a simple, efficient and environmentally benign approach for the synthesis of α,β-unsaturated ketones from alkynes and aldehydes over Hβ zeolite under solvent-free conditions (Scheme 1).

Scheme 1 Synthesis of α,β-unsaturated ketones from alkynes and aldehydes over Hβ zeolite.

Experimental

General information

Alkynes and aldehydes were purchased from Sigma-Aldrich. Hβ (Si/Al = 15) zeolite was obtained from Alfa Aesar, England. All chemicals used were reagent grade and used as received without further purification. The XRD patterns of the samples were obtained on a Rigaku miniflex X-ray Diffractometer using Ni filtered CuKα radiation at 2θ = 2–80° with a scanning rate of 2° min⁻¹ and the beam voltage and currents of 30 kV and 15 mA, respectively. ¹H NMR spectra were recorded by using Bruker VX NMR FT-300 or Varian Unity 500 and ¹³C NMR spectra were recorded by using Bruker VX NMR FT-75 MHz spectrometers in CDCl₃. The chemical shifts (δ) are reported in ppm units relative to TMS as an internal standard for ¹H NMR and CDCl₃ for ¹³C NMR spectra. Coupling constants (J) are reported in hertz (Hz) and multiplicities are indicated as follows: s (singlet), d (doublet), dd (doublet of doublet), t (triplet), m (multiplet). TLC inspections were performed on Silica gel 60 F₂₅₄ plates. Column chromatography was performed on silica gel (100–200 mesh) using n-hexane–EtOAC as eluent.

General procedure

Hβ zeolite (100 mg) was added to the well stirred solution of alkyne (2 mmol), aldehydes (2 mmol) and H₂O (8 mmol) in a 15 mL of sealed vial and the reaction mixture was allowed to stir at 100 °C. After disappearance of the alkyne (monitored by TLC) or after an appropriate time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The catalyst was separated by filtration and the removal of solvent in vacuo yielded crude. The crude was further purified by column chromatography using silica gel (100–200 mesh) to afford pure products. All the products were identified on the basis of ¹H and ¹³C NMR spectral data.

Results and discussion

In our previous work¹⁶ we found that the Hβ zeolite was efficient to convert alkynes into methyl ketones in presence of over stoichiometric amount of water under solvent-free conditions. From this work, we envisioned that the Hβ zeolite catalyst may transform the alkynes into α,β-unsaturated ketones in presence of stoichiometric amount of aldehydes via Claisen–Schmidt condensation of in situ generated methyl ketones with aldehydes in one-pot.

To test our working hypothesis, we investigated the reaction of phenylacetylene with benzaldehyde using Hβ zeolite as catalyst under solvent free conditions (Table 1). Gratifyingly, the desired chalcone product was obtained in excellent yield over 100 mg of Hβ zeolite after 20 h (Table 1, entry 1). When the amount of catalyst was reduced, the yield of 4a was decreased (Table 1, entry 2). However, the increasing the amount of catalyst did not have any effect on the reaction yield (Table 1, entry 3).

Table 1 Synthesis of chalcone from phenylacetylene (1a) and benzaldehyde (2a)^a,b

Entry	Hβ amount (mg)	Conversion of 1a (%)	Yield (%)
			3a	4a
a Reaction conditions: 1a (2 mmol), 2a (2 mmol), H2O (8 mmol), 100 °C, 20 h.b Isolated yields.
1	100	99	4	95
2	50	99	34	65
3	200	99	4	95

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Next, the generality of the Hβ zeolite-catalyzed strategy was investigated with a variety of aldehydes under similar reaction conditions. Surprisingly, all the aromatic aldehydes used in the reaction were reacted smoothly with phenylacetylene to afford good to excellent yields of the corresponding chalcone products (Table 2). In order to determine the influence of substitution on the aromatic ring of benzaldehyde with this reagent system, we have carried out the reaction of different substituted benzaldehydes with phenylacetylene. It was observed that aromatic aldehydes bearing either activating or halo substituents were successfully converted into the respective chalcone derivatives in relatively excellent yields compared to electron-deficient substrates (Table 2, 4a–4q). It is noteworthy that benzaldehyde bearing the same substituents at different positions on the phenyl ring had little influence on the reaction yield (4b–4c, 4i–4j and 4k–4l). Importantly, heterocyclic aldehydes also reacted smoothly with phenylacetylene and gave the respective products in 88% and 87% yields, respectively (Table 2, 4r and 4s). Unfortunately, the aliphatic aldehydes such as 1-pentanal and 1-heptanal failed to participate in the condensation reaction and only phenylacetylene hydration product 3a was observed in 95% yield.

Table 2 Scope of the tandem hydration/condensation reaction of phenylacetylene with various aldehydes over Hβ zeolite^ab

a Reaction conditions: 1 (2 mmol), 2 (2 mmol), H₂O (8 mmol), Hβ zeolite (100 mg), 100 °C, 20 h.b Isolated yields.

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To further extend the scope of this reaction, a variety of alkynes were employed to react with benzaldehyde under similar conditions to provide the corresponding chalcone products in moderate to excellent yields (Table 3). Highly activating or moderately activating groups present on aromatic ring of phenylacetylene furnished excellent yields of the respective chalcone derivatives (Table 3, 4aa–4ac), whereas highly deactivating groups bearing phenylacetylene afforded the desired products relatively in lower yields than electron-rich phenylacetylenes (Table 3, 4ag–4ai). Remarkably, halo aromatic alkynes participated well in this reaction to afford the desired products in 85–90% yields (Table 3, 4ad–4af). The internal alkyne i.e., 1-phenyl-1-propyne was also reacted smoothly and yielded the corresponding product in 90% yield (Table 3, 4aj). The efficiency of this method was also demonstrated by performing the reaction with aliphatic alkynes and furnished the respective products in good yields (Table 3, 4ak and 4al).

Table 3 Scope of the tandem hydration/condensation reaction of various alkynes with benzaldehyde over Hβ zeolite^ab

a Reaction conditions: 1 (2 mmol), 2 (2 mmol), H₂O (8 mmol), Hβ zeolite (100 mg), 100 °C, 20 h.b Isolated yields.

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The recovery and reusability of the catalyst are the significant properties of heterogeneous catalysts for their industrial applications and environmental considerations. Therefore, we performed the recyclability studies of Hβ zeolite catalyst up to five cycles on the tandem hydration/condensation reaction of phenylacetylene with benzaldehyde under standard conditions. Significantly, the catalyst showed the consistent catalytic activity in all the investigated cycles (Fig. 2). The XRD analysis of reused catalyst matched well with fresh catalyst, thus suggesting that the crystallinity of the reused catalyst is comparable to the original material (Fig. S1, see the ESI†). Further, there was no leaching of aluminium or silicon from Hβ zeolite observed, which was confirmed by elemental analysis.

Fig. 2 Recyclable study of Hβ zeolite on the reaction of phenylacetylene with benzaldehyde.

The plausible reaction mechanism for the formation of α,β-unsaturated ketones from alkynes and aldehydes over Hβ zeolite is illustrated in Scheme 2. Initially, Hβ zeolite converts alkyne 1 into corresponding methyl ketone 3.¹⁶ The resulting ketone 3 undergoes Claisen–Schmidt condensation with aldehyde 2 (adsorbed on the Bronsted acid sites of the zeolite) to provide the corresponding product 4 via formation of β-hydroxy ketone intermediate A. Over all, the formation of α,β-unsaturated ketones 4 proceed via tandem hydration/condensation of alkynes 1 with aldehydes 2.

Scheme 2 The plausible mechanism for the formation of α,β-unsaturated ketones from alkynes and aldehydes over Hβ zeolite.

Conclusions

In summary, we have developed a facile Hβ zeolite-catalyzed tandem hydration/condensation approach for the synthesis of α,β-unsaturated ketone derivatives from alkynes and aldehydes under solvent-free conditions. The attractive features of this procedure are absence of organic solvent, broad substrate scope, excellent functional group compatibility, high atom economy, ready availability of materials, high yields of the desired products and simple work-up procedure.

Acknowledgements

We thank the CSIR Network project CSC-0123 for financial support. M. N. and C. D. acknowledge the financial support from CSIR, India in the form of fellowships. P. S., K. S. and B. R. acknowledge the financial support from UGC, India in the form of fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and NMR spectra (¹H and ¹³C). See DOI: 10.1039/c6ra11593d

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