In water, Green and Efficient Multicomponent Synthesis of 4H-Pyran Derivatives catalyzed by LiOH·H 2 O under Ultrasound Irradiation

doi:10.21203/rs.3.rs-4717470/v1

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In water, Green and Efficient Multicomponent Synthesis of 4H-Pyran Derivatives catalyzed by LiOH·H 2 O under Ultrasound Irradiation

https://doi.org/10.21203/rs.3.rs-4717470/v1

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This research work introduce a straightforward and efficient method for synthesizing 4H-pyrans via a multi-component cyclocondensation reaction involving aromatic aldehydes, malononitrile, and ethyl acetoacetate. This environmentally friendly approach utilizes ultrasound and water as the reaction medium, enabling the production of 4H-pyrans with good yields at room temperature. Notably, commercially available LiOH·H₂O serves as a dual-activated catalyst, facilitating the formation of benzylidene intermediates and serving as a mild base for 4H-pyran production. The simplicity of the operational procedure, short reaction times, cleanliness, low cost and ready availability of LiOH·H₂O, high efficiency, and excellent yields collectively render this novel approach highly appealing for 4H-pyran synthesis.

4H-pyrans

Multi-components

Cyclocondensation

Water

LiOH·H2O

Ultrasound

One heterocyclic system that is particularly noteworthy, fascinating, and of significant importance in the medical field is pyran. Many natural compounds possess this highly prevalent key motif [1-3]. Heterocyclic synthesis is crucially important, given that heterocyclic derivatives play a central role in our increasingly technological framework. It is important to synthesize polyfunctionalized 4H-pyrans, as they are essential components in the formation of diverse synthetic and natural heterocyclic compounds.

4H-pyrans are widely distributed in natural and pharmaceutical compounds due to their "privileged" structural motif [4]. As a crucial pharmacophore, pyran exhibits a wide range of significant biological activities, including anti-inflammatory [5], anti-cancer [6], cytotoxic [7], antimicrobial [8], anti-HIV [9], antiallergic [10], antitumor [11], hypolipidemic [12], antibiotic [13], and antimalarial [14]. These compounds have proven effective in combating diseases such as schizophrenia, myoclonus, and Alzheimer's [15]. Additionally, analogous to 1,4-dihydropyridines, 4H-pyrans have been employed as calcium channel blockers. [16].

4H-pyrans are pivotal in synthesizing pharmaceutical compounds with therapeutic potential, notably pyridines, lactones, 1,4-dihydropyridines, pyranopyrazoles, imidoesters, and aminopyrimidines. [6].

Due to their inherent reactivity within the pyran ring, they serve as versatile building blocks for generating a diverse array of heterocycles, including pyranopyridines, polyazanaphthalenes, pyridine-2-ones, pyranopyrazoles, and pyranopyrimidines [17]. Moreover, they are extensively utilized in the composition of pigments, photoactive materials, cosmetics, biodegradable agrochemicals [17], and fluorescent reagents [18].

In recent years, several synthetic methods have emerged for the production of 2-amino-3-cyano-4H-pyrans, tailored for diverse therapeutic applications within the pharmaceutical sector [19-23].

Initially, the synthesis of 2-amino-4H-pyran derivatives involved cyclization reactions of arylidenes malononitriles and β-dicarbonyls catalyzed by piperidine [24] or triethylamine [25]. Indeed, elements of this approach remain relevant today. For instance, F. Auria-Luna et al. have recently presented two innovative methods for synthesizing pyran derivatives with high yields. The first method employs the alkylidene reagents malononitrile and ethyl acetoacetate in an aqueous medium, catalyzed by triethylamine (NEt₃). The second method involves a multi-component approach activated by ultrasound waves, conducted in pure water, which has demonstrated better results [26].

Ultrasonic irradiation is increasingly recognized as an eco-friendly and safe method, offering new avenues for various chemical processes. Its current application has proven particularly advantageous for activating reagents in both organic and inorganic compound synthesis [27]. Recent studies have highlighted the efficacy of ultrasound irradiation as an activation method in organic synthesis [28-31].

In contrast to traditional approaches, ultrasonic irradiation has demonstrated significant benefits in enhancing chemical reactions, whether conducted in homogeneous or heterogeneous environments. Its activation yields several advantages, including reduced reaction times, streamlined processing protocols, high yields, and the generation of pure products under mild conditions [32].

The synthesis of pyran derivatives has garnered widespread attention among researchers owing to their significance, prompting exploration through various methodologies, including microwave [33] and ultrasound irradiation in water [17,26,34] as well as the use of different catalysts under various conditions such as: halide ions [35-36], ionic liquids [37-39], triethylamine (NEt₃) [26], sophisticated organocatalysts potassium-N-oxyl phthalimide [40], heterogeneous catalysts [41], alkalin metallo-organic ([Mg₃(NDC)₃(DMF)₄]-H₂O) [42], magnetic nanoparticles [43], polyethylene glycol (PEG) [44], piperidine [45], NaOH in water [46], 1,8-diazabicyclo [5. 4.0] undec-7-ene (DBU) in water [47], LiBr in water [48], sodium acetate combined with microwave irradiation [33], and CaO/KOH under solvent-free conditions [49].

However, while these methods exhibit varying degrees of success, they also present drawbacks such as elevated temperatures, moderate yields, limited applicability, prolonged reaction times, and reliance on harmful or costly solvents or catalysts. In this regard, green chemistry approaches play a pivotal role in advancing organic chemistry by minimizing the reliance on organic solvents.

The incorporation of water into organic reaction synthesis holds significant importance, heralded as an optimal alternative to organic solvents due to its non-toxic properties, cost-effectiveness, abundant natural availability, and environmental compatibility [50].

Despite extensive study and development of processes in water, its exclusive use as the sole solvent for organic reactions remains uncommon, likely due to the fundamental requirement for adequate solubility of reagents to ensure optimal reactivity [51-52]. The endeavor to develop reactions in pure water persists as a challenge, encompassing various factors including solubility considerations and reaction kinetics.

The Knoevenagel condensation stands as a classic and universally acknowledged reaction in organic chemistry, serving to form a carbon-carbon bond from active methylene compounds and aldehydes. Gouda et al. introduced lithium hydroxide monohydrate (LiOH·H₂O) as a novel 'double activation' catalyst for Knoevenagel condensation, facilitating the reaction between malononitrile or ethyl cyanoacetate and aromatic aldehydes. This innovative approach enables the efficient and facile synthesis of the corresponding arylidenes using ethanol and pure water as solvents at room temperature within a short reaction time [53].

Lithium hydroxide monohydrate is commonly employed as a versatile and eco-friendly catalyst in various reactions, including esterification [54], Knoevenagel [53], Mannich [55], Claisen Schmidt [56], and Aza-Michael, among others. Due to the many advantages it offers as an environmentally friendly element, such as its activation, abundance, lower toxicity, operational simplicity, broad applicability, and cost-effectiveness, making it an appealing choice for environmentally conscious processes.

Motivated by the preceding findings, our study aims to synthesize diverse arylidene malonitriles in an aqueous medium catalyzed by LiOH·H₂O, subsequently utilizing them as reagents in the synthesis of 2-amino-4H-pyrans within the same catalytic system (LiOH·H₂O/H₂O) activated by ultrasonic waves. Notably, the major advantage of this catalytic combined with ultrasonic activation is its use in the multicomponent synthesis of these pyranic derivatives for the first time.

From an ecological perspective in organic synthesis, the necessity persists for the development of a milder, simpler, and more environmentally respectful method for synthesizing pyrans, particularly 2-amino-4H-pyrans.

Multicomponent reactions stand as a pivotal asset for organic chemists, presenting numerous advantages over conventional methods. They enable the streamlined synthesis of complex molecules in a single step, mitigating the formation of side products and saving time [57]. It also offers low pollution, energy and cost savings, high selectivity, and high atomic economy while avoiding tedious purification processes that are useful to industry [58]. However, conducting multi-component organic synthesis in aqueous media presents both a significant challenge and a promising avenue for achieving more structures and enhanced yields [59]. This approach has emerged as a central topic in the formation of diverse essential heterocyclic compounds, notably 4H-pyran derivatives.

In this paper, we introduce a novel synthetic pathway for thoroughly functionalized 4H-pyran derivatives, achieved through a 1,4-Michael addition followed by a cascade cyclization catalyzed by LiOH·H₂O. Notably, this protocol is eco-friendly, as it can be conducted at room temperature in water with minimal catalyst usage. Importantly, the resulting synthesized products are easily purified.

2.1. Materiels

Lithium hydroxide (LiOH) is an inorganic compound available in both anhydrous and hydrated forms, both of which are classified as strong bases. In this study, lithium hydroxide monohydrate (LiOH·H₂O) was utilized as the catalyst, purchased from Sigma-Aldrich (Steinheim). Aryl-aldehydes (≥98%), malononitrile (≥99%), and ethyl acetoacetate (≥99%) were also purchased from Sigma-Aldrich.

2.2. General Protocol for 4H-Pyran Synthesis

The ultrasound probe was immersed directly in the reactor. An ultrasonic generator (Bioblock Scientific 750 W) emits the sound vibration into the reaction mixture. Sonification was achieved at low frequencies of 20 kHz (amplitude of 30%) and the water bath temperature (r.t) was controlled by the addition and remove of water.

Method 1 : The synthesis was carried out using 2 mmol of arylidenemalononitrile with 2 mmol of ethyl acetoacetate, conducted in the presence of lithium hydroxide monohydrate (17 mg, 20% molar) in 5 mL of water. After being irradiated with ultrasound at room temperature, the reaction mixture was monitored by TLC (hexane:ethyl acetate, 7:3) until the consumption of 2-benzylidenemalononitrile was complete.

Method 2 : A suspension of 17 mg of LiOH·H₂O in 5 mL of water and 0.5 mL of ethanol was added to 2 mmol of malononitrile and 2 mmol of arylaldehyde. The resulting mixture was subjected to ultrasound irradiation for 5 minutes. Throughout the process, the reaction progress was monitored via TLC (hexane : acetate 7:3) until complete consumption of the aldehydes. Upon reaction completion, a precipitate of intermediate (3) indicated the reaction endpoint visually. Subsequently, 2.4 mmol of ethyl acetoacetate (312 mg) was introduced into the mixture, followed by an additional 30 minutes of ultrasound irradiation. TLC analysis confirmed the disappearance of all starting materials and intermediates (3). After cooling, the product precipitated spontaneously in the reaction mixture, which was then isolated by filtration and purified through recrystallization using H₂O/EtOH/ (9v/1v).

2.3. Spectroscopic analysis

The IR analysis was performed using a spectrometer type Perkin Elmer Spectrum version 10. The NMR of the isolated products was recorded in solution in CDCl₃ on a Bruker 300 Ultrashield spectrometer (¹H at 300 MHz and ¹³C at 75 MHz). The internal reference was TMS. The spectral data of the isolated compounds, are listed below.

2-benzylidene malononitrile 3a :: yellowish white, crystalline solid.

M.p. 80-82°C (Lit.,^[⁶⁰^]80-82°C); IR [ν, cm^-1] 3034.14 (C=C-H, Ar-H), 2223.43 (CN), 1589.85 (C=C); ¹H NMR [δ, ppm] 7.94 (d, 2H, J_H-H = 7.8Hz), 7.80 (s, 1H), 7.66 (m, 1H), 7.57 (m, 2H); ¹³C NMR [δ, ppm] 159.32, 134.04, 130.49, 130.18, 129.11, 113.14, 111.99, 82.53.

2-(4-methoxybenzylidene) malononitrile 3b :Yellow,crystalline solid.

M.p. 110-112°C (Lit.,^[⁶⁰^]112-114°C); IR [ν, cm^-1] 3030.75 (C=C-H, Ar-H), 2221.00 (CN), 1604.05 (C=C); ¹H NMR [δ, ppm] 7.93 (d, 2H, J_H-H = 8.4Hz), 7.67 (s, 1H), 7.04 (d, 2H, J_H-H = 8.4Hz), 3.94 (s, 3H) ; ¹³C NMR [δ, ppm] 164.35, 158.26, 132.90, 123.58, 114.65, 113.87, 112.80, 78.21, 55.26.

2-(2-chlorobenzylidene) malononitrile 3c :white, crystalline solid.

M.p. 96-98°C (Lit.,^[⁶⁰^]94-96°C); IR [ν, cm^-1] 3050.87 (C=C-H, Ar-H), 2222.41 (CN), 1557.74 (C=C); ¹H NMR [δ, ppm] 8.29 (s, 1H), 8.21 (d, 1H, J_H-H = 7.8Hz), 7.57 (m, 2H), 7.47 (m, 1H); ¹³C NMR [δ, ppm] 155.43, 135.81, 134.45, 130.19, 128.99, 128.62, 127.26, 112.66, 111.36, 85.42.

2-(3,4-dimethoxybenzylidene) malononitrile 3d:Yellow,crystalline solid.

M.p. 146-148°C (Lit.,^[⁶⁰^]142-143°C); IR [ν, cm^-1] 3009.15 (C=C-H, Ar-H), 2221.19 (CN), 1567.40 (C=C); ¹H NMR [δ, ppm] 7.68 (s, 1H), 7.65 (s, 1H), 7.41 (d, 1H, J_H-H = 8.4Hz), 6.97 (d, 1H, J_H-H = 8.4Hz), 3.99 (s,3H), 3.95 (s, 3H) ; ¹³C NMR [δ, ppm] 158.51, 154.47, 149.17, 127.52, 123.83, 113.84, 113.01, 110.71, 110.58, 78.10, 55.77, 55.59.

2-(3,4,5-trimethoxybenzylidene) malononitrile 3e :Yellow,crystalline solid.

M.p. 144-146°C (Lit.,^[⁶⁰^]140-141°C); IR [ν, cm^-1] 2940.03 (C=C-H, Ar-H), 2218.88 (CN), 1568.11 (C=C); ¹H NMR [δ, ppm] 7.66 (s, 1H), 7.21 (s, 2H), 4.00 (s,3H), 3.92 (s, 6H) ; ¹³C NMR [δ, ppm] 158.81, 152.93, 143.74, 125.43, 113.46, 112.67, 108.02, 80.12, 60.66, 55.89.

2-(3-hydroxy-4-methoxybenzylidene) malononitrile 3f :Yellow,crystalline solid.

M.p. 250-252°C (Lit.,^[⁶¹^]250-252°C); IR [ν, cm^-1] 3028.33 (C=C-H, Ar-H), 2230.61 (CN), 1565.23 (C=C), 3393.76 (O-H); ¹H NMR [δ, ppm] 8.11 (s, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.51 (d, 1H, J_H-H = 8.4Hz), 6.99 (d, 1H, J_H-H = 8.4Hz), 4.04 (s, 3H); ¹³C NMR [δ, ppm] 159.16, 149.67, 147.59, 128.53, 125.28, 116.09, 110.73, 108.39, 64.37, 56.67.

2-(4-nitrobenzylidene) malononitrile 3g :Brown, crystalline solid.

M.p. 158-160°C (Lit.,^[⁶⁰^]160-161°C); IR [ν, cm^-1] 3041.08 (C=C-H, Ar-H), 2231.48 (CN), 1580.11 (C=C), 1343.36 (NO₂) ; ¹H NMR [δ, ppm] 8.41 (d, 2H, J_H-H = 8.4Hz), 8.09 (d, 2H, J_H-H = 8.4Hz), 7.90 (s, 1H); ¹³C NMR [δ, ppm] 156.27, 149.75, 135.32, 130.76, 124.10, 112.09, 111.14, 87.12.

2-(4-chlorobenzylidene) malononitrile 3h :yellowish white,crystalline solid.

M.p. 160-162°C (Lit.,^[⁶⁰^]162-163°C); IR [ν, cm^-1] 3034.50 (C=C-H, Ar-H), 2228.72 (CN), 1580.18 (C=C) ; ¹H NMR [δ, ppm] 7.88 (d, 2H, J_H-H = 8.4Hz), 7.75 (s, 1H), 7.55 (d, 2H, J_H-H = 8.4Hz); ¹³C NMR [δ, ppm] 157.67, 140.63, 131.29, 129.56, 128.82, 112.89, 111.79, 82.99.

Ethyle 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate 5a :white, crystalline solid.

M.p. 190-192°C (Lit.,^[⁶²^]192°C) ; R [ν, cm^-1] 3399.60 (NH₂), 3202.07 (C=C-H, Ar-H), 2189.70 (CN), 1689.06 (C=O), 1257.66 (C-O) ; ¹H NMR [δ, ppm] 7.33 (d, 2H, J_H-H = 7.2Hz), 7.26 (m, 3H), 4.52 (s, 2H), 4.50 (s, 1H), 4.10 (q, 2H, J_H-H = 6.9Hz), 2.43 (s, 3H), 1.14 (t, 3H, J_H-H = 6.9Hz); ¹³C NMR [δ, ppm] 165.32, 156.96, 156.19, 143.25, 128.04, 126.98, 126.65, 118.25, 107.57, 62.08, 60.09, 38.32, 17.81, 13.33.

Ethyle 6-amino-5-cyano-4-(4-methoxyphenyl) -2-methyl-4H-pyran-3-carboxylate 5b :white, crystalline solid.

M.p. 129-131°C (Lit.,^[³³^]132-133°C) ; IR [ν, cm^-1] 3399.31 (NH₂), 3203.60 (C=C-H, Ar-H), 2188.52 (CN), 1673.74 (C=C), 1257.13 (C-O) ; ¹H NMR [δ, ppm] 7.12 (d, 2H, J_H-H = 8.4Hz), 6.85 (d, 2H, J_H-H = 8.7Hz), 4.49 (s, 2H), 4.43 (s, 1H), 4.08 (q, 2H, J_H-H = 7.2Hz), 3.80 (s, 3H), 2.37 (s, 3H), 1.14 (t, 3H, J_H-H = 7.2Hz); ¹³C NMR [δ, ppm] 165.43, 158.26, 156.86, 155.73, 135.57, 128.08, 118.36, 113.49, 107.84, 62.27, 60.08, 54.72, 37.54, 17.79, 13.40.

Ethyle 6-amino-4-(4-chlorophenyl) -5-cyano-2-methyl-4H-pyran-3-carboxylate 5c :white, crystalline solid.

M.p. 172-174°C (Lit.,^[³³^]171-172°C) ; IR [ν, cm^-1] 3406.74 (NH₂), 3205.34 (C=C-H, Ar-H), 2193.39 (CN), 1679.42 (C=O), 1265.65 (C-O) ; ¹H NMR [δ, ppm] 7.29 (d, 2H, J_H-H = 8.1Hz), 7.16 (d, 2H, J_H-H = 8.1Hz), 4.57 (s, 2H), 4.45 (s, 1H), 4.07 (q, 2H, J_H-H = 7.2Hz), 2.39 (s, 3H), 1.14 (t, 3H, J_H-H = 6.9Hz); ¹³C NMR [δ, ppm] 165.10, 157.04, 156.49, 141.88, 132.48, 128.39, 128.23, 118.08, 107.18, 61.46, 60.23, 37.86, 17.88, 13.39.

Ethyle 6-amino-4-(2-chlorophenyl) -5-cyano-2-methyl-4H-pyran-3-carboxylate 5d :white, crystalline solid.

M.p.192-194 °C (Lit.,^[³³^]179-181°C) ; IR [ν, cm^-1] 3423.95 (NH₂), 3226.62 (C=C-H, Ar-H), 2194.42 (CN), 1683.03 (C=O), 1261.36 (C-O) ; ¹H NMR [δ, ppm] 7.36 (d, 1H, J_H-H = 7.8Hz), 7.19 (m, 3H), 5.08 (s, 1H), 4.50 (s, 2H), 4.02 (q, 2H, J_H-H = 6.9Hz), 2.42 (s, 3H), 1.07 (t, 3H, J_H-H = 7.2Hz) ; ¹³C NMR [δ, ppm] 165.04, 157.20, 157.09, 140.60, 132.67, 129.30, 127.80, 126.74, 117.82, 106.49, 60.86, 60.12, 35.02, 17.74, 13.19.

Ethyle 6-amino-5-cyano-4-(3,4-dimethoxyphenyl) -2-methyl-4H-pyran-3carboxylate 5e :white, crystalline solid.

M.p. 128-130°C (Lit.,^[⁶³^]138-140°C) ; IR [ν, cm^-1] 3394.67 (NH₂), 3201.97 (C=C-H, Ar-H), 2192.85 (CN), 1673.87 (C=O), 1264.38 (C-O) ; ¹H NMR [δ, ppm] 6.78 (m, 3H), 4.50 (s, 2H), 4.42 (s, 1H), 4.08 (q, 2H, J_H-H = 7.2Hz), 3.88 (s, 3H), 3.86 (s, 3H), 2.37 (s, 3H), 1.14 (t, 3H, J_H-H = 6.9Hz) ; ¹³C NMR [δ, ppm] 165.43, 158.52, 156.87, 149.17, 148.56, 136.08, 127.50, 119.17, 111.04, 110.70, 107.70, 62.13, 60.10, 55.41, 37.91, 17.79, 13.45.

Ethyle 6-amino-5-cyano-2-methyl-4-(3,4,5-trimethoxyphenyl) -4H-pyran-3 carboxylate 5f : white, crystalline solid.

M.p. 184-186°C (Lit.,^[³³^]181-183°C) ; IR [ν, cm^-1] 3340.31 (NH₂), 3199.17 (C=C-H, Ar-H), 2195.06 (CN), 1682.97 (C=O), 1258.68 (C-O) ; ¹H NMR [δ, ppm] 6.43 (s, 2H), 4.51 (s, 2H), 4.43 (s, 1H), 4.09 (q, 2H, J_H-H = 6.9Hz), 3.86 (s, 6H), 3.84 (s, 3H), 2.39 (s, 3H), 1.15 (t, 3H, J_H-H = 7.2Hz) ; ¹³C NMR [δ, ppm] 165.35, 156.95, 155.91, 152.83, 138.84, 136.97, 118.27, 107,50, 104.37, 61.93, 60.23, 60.15, 55.69, 38.52, 17.80, 13.45.

Ethyle 6-amino-5-cyano-2-methyl-4-(4-nitrophenyl) -4H-pyran-3-carboxylate 5g : Brown, crystalline solid.

M.p. 173-175°C (Lit.,^[³³^]175-176°C) ; IR [ν, cm^-1] 3399.65 (NH₂), 3202.43 (C=C-H, Ar-H), 2198.86 (CN), 1679.16 (C=O), 1266.92(C-O) ; ¹H NMR [δ, ppm] 8.20 (d, 2H, J_H-H = 8.4Hz), 7.41 (d, 2H, J_H-H = 8.7Hz), 4.67 (s, 2H), 4.59 (s, 1H), 4.07 (q, 2H, J_H-H = 7.2Hz), 2.43 (s, 3H), 1.13 (t, 3H, J_H-H = 7.2Hz) ; ¹³C NMR [δ, ppm] 164.73, 157.47, 157.25, 150.55, 146.67, 127.90, 123.46, 117.67, 106.38, 60.50, 60.43, 38.38, 18.05, 13.40.

Ethyle 6-amino-5-cyano-4-(3-hydroxy-4-methoxyphenyl) -2-methyl-4H-pyran-3 carboxylate 5h :Yellow,crystalline solid.

M.p. 154-156°C; IR [ν, cm^-1] 3399.11 (NH₂), 3201.19 (C=C-H, Ar-H), 2192.82 (CN), 1677.81 (C=O), 1277.81 (C-O) ; ¹H NMR [δ, ppm] 6.76 (m, 3H), 5.60 (s, 1H), 4.46 (s, 2H), 4.38 (s, 1H), 4.08 (q, 2H, J_H-H = 7.2Hz), 3.88 (s, 3H), 2.37 (s, 3H), 1.17 (t, 3H, J_H-H = 6.9Hz) ; ¹³C NMR [δ, ppm] 165.38, 156.88, 155.87, 145.27, 144.10, 136.74, 122.70, 118.80, 113.14, 110.06, 107.70, 62.26, 60.09, 55.46, 37.77, 17.82, 13.43.

3.1.Synthesis of arylidene malononitrile

The synthesis was performed using 2 mmol of arylaldehyde and 2 mmol of malononitrile in the presence of 10% molar lithium hydroxide monohydrate in 5 mL of water. The reaction mixture was subjected to ultrasonic irradiation for the durations shown in Table 1. The reactor was immersed in a water bath to maintain a temperature between 25 and 30°C.

Table 1 displays the yields of arylidene malononitrile. The results indicate that high yields are obtained and the reactions were generally clean since the isolated compounds were obtained in pure form without requiring further purification after crystallization (confirmed by IR and NMR analyses).

Table 1

Yields of the synthesized arylidene malononitrile.
Entry N^o	(1) R	Product (3)^a	Time (min)	Yield (%)
1	H	3a	1	82.4
2	4-OCH₃	3b	0.5	86.1
3	4-Cl	3c	1	95.9
4	2-Cl	3d	1	87.8
5	3,4-OCH₃	3e	1	70.2
6	3,4,5-OCH₃	3f	0.5	80.2
7	4-NO₂	3g	2	71.8
8	3-OH-4-OCH₃	3h	5	90.0

^a known compounds

In general, aromatic aldehydes featuring electron-withdrawing groups exhibited greater reactivity in comparison to those containing electron-donating groups. This trend is evident when comparing entries 3 and 4 with entries 5 and 6.

Reduced yields were observed in prolonged reactions conducted under environmentally unfavorable conditions, as exemplified in the synthesis of 2-benzylidene malononitrile by M. Hassan et al. They achieved a yield of 55% after 60 minutes at 50°C. Similarly, in the condensation of 4-methoxybenzaldehyde under identical conditions using the same methylene activated, a yield of only 10% was obtained. These reactions utilized a graphene oxide nanocomposite-grafted amino magnetic (Fe₃O₄@DETA@GO) catalyst and THF as the solvent, both activated by microwave [64].

The condensation of benzaldehyde and malononitrile at room temperature in an aqueous medium yielded 35% without any catalyst [65]. A 100% yield was obtained after a 15 hours reaction under toluene reflux with Ni-SiO₂ as the catalyst [66]. Similarly, using metal dioxide terephthalate (M₂dobdc) as the catalyst at 70°C under toluene reflux, yields between 32% and 77% were achieved after 24 hours [67]. In contrast, the current process, employing lithium hydroxide monohydrate as a catalyst, achieved an 82.4% yield within just 5 minutes under ultrasonic irradiation in an aqueous medium.

Using montmorillonite KSF as a catalyst, the condensation of 4-chlorobenzaldehyde with malonitrile resulted in an 84% yield after 24 hours at 160°C [68]. When using CexZn₁-xO₂ under ethanol reflux conditions, a yield of 81% was achieved in 50 to 60 minutes [69]. Remarkably, employing LiOH·H₂O as the catalyst, the process reached an exceptional yield of 95.9% at room temperature within just 5 minutes of ultrasonic irradiation.

3.2.Condensation of ethyl acetoacetate with 2-benzylidene malononitrile (Method 1) :

Preliminary tests of the condensation of 3a (0.30g, 2 mmol) with 4 (0.26g, 2 mmol) in 5 mL of water, in the presence of 20% molar LiOH·H₂O (0.017g), under magnetic stir and ultrasonic irradiation at room temperature, resulted in the formation product (5a) (Scheme 2). The reactor was immersed in a water bath to maintain temperature between 25°C and 30°C. The crude product was then crystallized from H₂O/EtOH (9v/1v).

Initially, we investigated the influence of various catalysts on the yield of the Michael addition involving 2-benzylidene malononitrile and ethyl acetoacetate.

Table 2

Optimization of different catalysts for the 1.4-Michael reaction.
Entry N°	Catalyst	Time	Yield (%)
1	NaOH	24h	74.1
2	KOH	24h	67.8
3	LiOH	24h	68.7
4	LiOH·H₂O	24h	75.9 (69.7^a)
5	LiOH·H₂O	30 min	80.3^b
6	LiOH·H₂O	60 min	81.2^b

^aYield obtained after 6 hours of stir.

^b Yields obtained under ultrasound irradiation.

In an Erlenmeyer flask, a mixture of ethyl acetoacetate and 2-benzylidene malononitrile, when reacted with LiOH·H₂O in water as the solvent, resulted in the formation of product (5a) with a good yield of 75.9%. This reaction proceeded at room temperature over 24 hours of magnetic stir (entry 4).

The results in Table 2 demonstrate the impact of various alkalis on the reaction. It is notable that sodium hydroxide, potassium hydroxide and, lithium hydroxide yielding lower results compared to lithium hydroxide monohydrate (LiOH·H₂O) (Table 2, entry 4). This observation suggests that LiOH·H₂O offers the most favorable conversion of reagents into product (5a) under magnetic stirring. Due to its dual activation capability, LiOH·H₂O effectively promotes the reaction, leading to the desired product.

After selecting the optimal catalyst, we examined the two activation methods : magnetic stir and sonication, over varying reaction times.

The results presented in Table 2 clearly demonstrate the significant impact of ultrasonic activation on reaction kinetics. Compared to magnetic stirring, ultrasonic activation significantly reduces reaction time. For instance, the yield increases from 75.9% with conventional stirring over 24 hours to 80.3% after just 30 minutes of ultrasonic irradiation. The additional times do not seem to have a significant effect on the reaction yield (81.2% after 60 min). In this case, the use of ultrasound as a reaction activation method proved to be essential to obtaining high yields. Additionally, in this protocol, the bath temperature did not increase appreciably even after 30 minutes. Therefore, reactions are expected to be initiated by ultrasound energy rather than by an increase in reaction temperature.

Ultrasound enhances reactions through dual mechanisms: chemically, by creating localized hotspots through cavitation, promoting high-energy conditions for reactions; and mechanically, as an acoustic wave that energizes the reaction medium via cavitation and associated effects. Cavitation, characterized by the formation of vapor bubbles due to pressure drops, plays a pivotal role in intensifying ultrasound's impact on reactions. Ultrasound has been shown to accelerate reaction rates by emulsifying liquid–liquid systems and by causing the erosion, disruption, and dispersion of solid particles. Ultrasound has demonstrated beneficial effects on both homogeneous and heterogeneous reactions, including high yields, simplified work-up procedures, production of pure products under milder conditions, reduced reaction times, and minimized waste generation [70].

The effect of catalyst ratio was investigated by conducting the same reaction model with varying amounts of LiOH·H₂O, conducted at 25–30°C for 30 minutes under ultrasound irradiation. As shown in Fig. 1, increasing the amount of catalyst improves the yield, with the highest yield (85.3%) achieved at a catalyst/reagent ratio of 0.017g/2 mmol. From this ratio the yield remains constant. However, reducing the amount of lithium hydroxide monohydrate led to lower yields. Furthermore, the additional addition of catalyst did not lead to a significant improvement in yields. Additionally, the reaction does not proceed in the absence of the catalyst. These results suggest that a 20% molar ratio of LiOH·H₂O (0.017g) is optimal for catalyzing the 1,4-Michael reaction.

Generalization of the reaction model

To generalize this model reaction, the reactivity of various arylidene malononitriles, and ethyl acetoacetate was tested under the same conditions: T = 25–30°C, LiOH·H₂O ratio = 0.017 g/ 0.02 mol under ultrasound irradiation (Scheme 3).

The results presented in Table 3 indicate that high yields ranging from 62.8–93.3% were obtained after durations varying from 30 to 60 minutes of ultrasonic irradiation.

The condensation of benzylidenemalononitrile with ethyl acetoacetate, catalyzed by triethylamine (Et₃N), yielded a 97% yield in water at room temperature after 24 hours with magnetic stirring and 98% after 2 hours under ultrasonic irradiation [26]. In another instance, a yield of 70% was achieved under solvent-free conditions within 15 minutes, utilizing an aqueous solution of ammonium hydroxide (NH₄OH) as a catalyst under infrared irradiation [71].

Table 3

Yields of the synthesized ethyl 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylate.
Entry N°	(3) Ar	Product (5)^a	Time (min)	Yield (%)
1	C₆H₅	5a	30	85.3
2	4-OCH₃C₆H₄	5b	60	70.9
3	4-ClC₆H₄	5c	60	84.1
4	2-ClC₆H₄	5d	60	86.5
5	3,4-(OCH₃)₂C₆H₃	5e	60	73.5
6	3,4,5-(OCH₃)₃C₆H₂	5f	30	86.5
7	4-NO₂C₆H₄	5g	30	93.3
8	3-OH-4-OCH₃C₆H₃	5h	30	62.8

^a known compounds

However, the process still faces challenges due to its complexity. Indeed, obtaining the final product necessitates conducting consecutive synthesis. Multicomponent synthesis, entailing the concurrent reaction of three or more reactants from the outset, presents numerous benefits. Primarily, it streamlines the experimental process by consolidating multiple reaction steps into one. Furthermore, this approach enhances reaction selectivity and reduces mass loss as the reactants are utilized more efficiently.

3.3. Synthesis of pyrans via multicomponent reaction (Method 2):

Compared to the conventional synthesis methods of 4H-pyran, which typically involve the Michael addition of ethyl acetoacetate with α, β-unsaturated nitriles in the presence of a Lewis acid, the present single-pot synthesis mediated by a base provides an innovative, practical, straightforward, and efficient approach to synthesizing 4H-pyrans. This method circumvents the complexity associated with two-step synthesis routes, which initially necessitate the preparation of α, β-unsaturated nitriles.

After thorough examination of the reaction conditions such as reactant concentration, reaction time, and solvent (refer to Table 4 for details), we explored the applicability of this method for synthesizing highly substituted 4H-pyrans (5).

In pursuit of environmentally friendly methods, two novel approaches utilizing pure water were investigated (Method 1 and Method 2).

The first method entails utilizing the preformed alkylidene malononitrile reagent (following the previously mentioned procedure). Additionally, the exploration of a multicomponent approach employing ultrasound, also conducted in pure water, proved to be particularly intriguing (Scheme 4).

A series of preliminary multicomponent reactions of aromatic aldehyde (2 mmol), malononitrile (2mmol) and ethyl acetoacetate (2,4 mmol) were carried out under variable conditions and ultrasound irradiation.

It's worth noting that the multi-component method conducted in pure water at room temperature (as depicted in Table 4) yielded satisfactory results within short reaction times.

Following Method 1, the final products were obtained in good yields (up to 93%, Table 3) using the optimal reaction conditions of LiOH·H₂O (20 mol%) and H₂O (5 ml) at room temperature. The second method requires the addition of 0.5 mL of ethanol in situations where low yields were obtained, which led to better results. This may be due to the improved solubility of all reactants in the reaction medium.

Table 4

Investigation of the Reaction Parameters for Method 2.
Entry N°	Ethyl acetoacetate (mmol)	Time (min)	Water (mL)	Yield (%)
1	2	30	5	72.3
2	2.4	30	5	73.2
3	2.4	60	5	75.9
4	2.4	30	10	67.8
5	2.4^a	30	5	76.8
6	2.4	30	5^b	80.3
7	2.4	60	5^b	81.2
8	2.4	30	5^c	82.3

^a 2.2 mmol of malononitrile.

^b Adding 0.5 mL of EtOH.

^c Adding 1 mL of EtOH.

To ascertain the reaction's generality, a range of substituted 4H-pyrans was synthesized by altering the aromatic aldehyde within the established reaction system, as mentioned earlier. The obtained results are summarized in Table 5, where the corresponding products 5 (entries 1–8) were obtained in high yields after reaction times ranging from 30 to 60 minutes, respectively.

Table 5

Yields of the synthesized ethyl 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylate via multicomponent reaction.
Entry N°	Ar	Product	Time (min)	Yield (%)
1	C₆H₅	5a	30	80.3 (73.2^a)
2	4-OCH₃C₆H₄	5b	60	66.1 (45.8^a)
3	4-ClC₆H₄	5c	60	82.5
4	2-ClC₆H₄	5d	60	87.3
5	3,4-(OCH₃)₂C₆H₃	5e	60	77.2 (52.2^a)
6	3,4,5-(OCH₃)₃C₆H₂	5f	30	79.7
7	4-NO₂C₆H₄	5g	30	80.0
8	3-OH-4-OCH₃C₆H₃	5h	30	65.1

^a Yields without the addition of EtOH.

To validate this new method and assess the impact of different substituents on the formation of 4H-pyrans, both electron-poor and electron-rich aromatic aldehydes were investigated. Generally, aromatic aldehydes with more reactive carbonyl groups exhibit faster reaction rates. Electron-withdrawing groups on the aromatic ring enhance the reaction rate, whereas electron-donating groups slightly decrease it. This trend is observed when comparing entries 3 and 4 with entries 5 and 6. One of the significant advantages of this protocol is the straightforward isolation and purification of products achieved through simple washing and crystallization of crude products.

During the first step of the reaction, the reaction medium is liquid until the formation of the intermediate (3). The second, slower step continues in a solid-liquid biphasic medium. Ultrasonic irradiation has confirmed its effectiveness in increasing the reaction rate either by emulsifying liquid-liquid systems or by producing disturbances and dispersion of solid particles. Ultrasound can provide excess energy capable of forming new interfaces. Cavitation is the rapid nucleation, oscillation, and final collapse of tiny air bubbles within a liquid. The collapse of cavitation bubbles gives rise to special phenomena, such as localized extremely high temperature and pressure, high-speed microjets, and shock waves.

The following representative examples compared the efficiency of our method with those of some reported procedures.

The condensation reaction of aromatic aldehydes, malononitrile, and ethyl acetoacetate, catalyzed by a 4 Å molecular sieve modified with zinc (II), afforded high yield equal to 95% after 4 hours under ethanol reflux [57]. Using lipase enzyme as the catalyst, a yield of 94% was attained after 4 hours at 50°C [72], and a notable 88% yield was achieved at room temperature in methanol within 60 minutes, employing snail shell (SS) as the catalyst [20]. R. Pagadala et al. achieved an excellent yield of 99% in the synthesis of 4H-pyran derivatives using NaOH as catalyst and water as a solvent at room temperature, with the reaction conducted under magnetic stirring for 4 hours [46]. Additionally, a 98% yield was obtained after 120 minutes at room temperature using triethylamine (NEt₃) in water [26]. In comparison, the present approach yielded 80.3% after just 30 minutes under ultrasonic irradiation.

Khan et al. synthesized pyran analogs using ZnCl₂ as a heterogeneous catalyst. The reaction, conducted in a solvent-free environment at 120°C, achieved a 70% yield within 30 minutes [73]. The condensation of benzaldehyde, malononitrile, and ethyl acetoacetate, catalyzed by silica nanoparticles fixed with stannous chloride (SnCl2@nano SiO2), yielded between 82–96% under ethanol reflux for 25 minutes [74]. Additionally, yields ranged between 88% and 92% for reaction times varying from 10 to 120 minutes at 60°C using CaO/KOH as a catalyst under solvent-free conditions [49].

In the presence of the hybrid magnetic nanocatalyst (Mag-IPS-DES), the condensation of 4-nitrobenzaldehyde, malononitrile, and ethyl acetoacetate in water yielded 75% under reflux after 65 minutes at room temperature [75]. The current method achieved an 80% yield after 30 minutes at room temperature under ultrasonic irradiation.

3.4. Proposed mechanism

Drawing upon the previously obtained results, this paper presents a plausible mechanism proposal. Figure 1 illustrates the dual function of LiOH·H₂O, which involves forming the enolate from malononitrile and activating the aldehyde carbonyl via coordination with Li⁺.

When LiOH·H₂O deprotonates malononitrile, it leads to the formation of lithium dicyanomethanide I. The interaction between the Li⁺ cation and the oxygen of the aldehyde carbonyl leads to the formation of the six-membered cyclic transition state II, thereby increasing the electrophilicity of the aldehyde carbonyl group and making it more reactive to intramolecular nucleophilic attack, thus leading to the formation of the iminolate anion III as mentioned Gouda et al. [53]. Then, the iminolate anion extracts the proton from the water and produces 2-benzylidenemalononitrile. The intermediate 3 formed underwent an in-situ Michael addition with the ethyl acetoacetate anion, thus giving intermediate V. Subsequently, intermediate VI was protonated and intramolecular cyclisation allow to obtain the desired product 5.

In conclusion, this study introduces a novel one-pot method for synthesizing a series of 4H-pyrans using a three-component system with LiOH·H₂O as a catalyst in water under ultrasonic irradiation. Our method offers numerous advantages over existing procedures, including high yields, elimination of organic solvents, cost-effectiveness, an environmentally friendly and safe protocol with simple work-up, utilization of a non-toxic catalyst, and short reaction times.

Our synthesis shows promise and can serve as a valuable guideline for future researchers in this field. It also lays a theoretical foundation for expanding the scope of the investigation. Future work could involve synthesizing new heterocycles, with potential biological activities using the same experimental method. Additionally, further exploration of its biological properties could lead to significant applications in areas like pharmacology.

Author Contribution

Nihel Masmoudi wrote the main manuscript text and Manef Chtourou reviewed the manuscript.

Acknowledgment

The authors are thankful to Ms. Amna Debbabi, assistant at the nuclear magnetic ray laboratory of the Faculty of Sciences of Monastir, Tunisia for her help in the NMR spectroscopic analyses.

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Schemes 1-5 are available in the Supplementary Files section.

No competing interests reported.

GraphicalAbstract.png
SupplementaryInformation.docx
Scheme1.tif
Scheme 1 Synthesis of arylidene malononitrile.
Scheme2.tif
Scheme 2 Synthesis of ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate.
Scheme3.tif
Scheme 3 Synthesis of ethyl 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylate (Method 1).
Scheme4.tif
Scheme 4 Multicomponent Synthesis of 4H-pyran Activated by Ultrasonic Irradiation.
Scheme5.tif
Scheme 5 The proposed reaction mechanism for the synthesis of 4H-pyrans catalyzed by LiOH·H₂O.

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In water, Green and Efficient Multicomponent Synthesis of 4H-Pyran Derivatives catalyzed by LiOH·H 2 O under Ultrasound Irradiation

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Abstract

Figures

1. Introduction

2. Experimental

3. Results and discussion

3.1.Synthesis of arylidene malononitrile

3.2.Condensation of ethyl acetoacetate with 2-benzylidene malononitrile (Method 1) :

3.3. Synthesis of pyrans via multicomponent reaction (Method 2):

3.4. Proposed mechanism

4.Conclusion

Declarations

Author Contribution

Acknowledgment

References

Schemes

Additional Declarations

Supplementary Files

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