Microwave-Assisted Three-Component ‘ ‘ Catalyst and Solvent-Free ’ ’ Green Protocol : A Highly Efficient and Clean One-Pot Synthesis of Tetrahydrobenzo [ b ] pyrans

A green and highly efficient method has been developed for the one-pot synthesis of tetrahydrobenzo[b]pyrans via a threecomponent condensation of aldehydes, 1,3-cyclic diketones, and malononitrile under MW irradiation without using any catalyst and solvent. This transformation presumably occurs by a sequential Knoevenagel condensation, Michael addition, and intramolecular cyclization. Operational simplicity, solvent and catalyst-free conditions, the compatibility with various functional groups, nonchromatographic purification technique, and high yields are the notable advantages of this procedure.


Introduction
Development of environmentally benign and clean synthetic procedures has become the goal of organic synthesis in recent times [1][2][3][4][5].The multicomponent reactions (MCRs) are one of the most powerful and efficient tools in organic synthesis for the invention of biologically important scaffolds in the viewpoint of green chemistry [6][7][8][9].One-pot multicomponent reactions (MCRs) have attracted considerable attention from the viewpoint of ideal synthesis by virtue of their efficiency, facile implementation, and generally high yield of the products [10][11][12][13].Indeed, the concept of environmental factor (E-factor) and atom economy have gradually become included into conventional organic synthesis in both industry and academia.Solvents are the main reason for an insufficient E-factor, especially in synthesis of fine chemicals and pharmaceutical industries [14,15].As a result, it has become imperative both in academia and industry to design catalystand solvent-free MCRs, as these processes are rendered green with reduction of waste, time, manpower, and cost [16][17][18][19][20][21].

Materials and Methods
Reactions carried out under scientific microwave reactor (Biotage, Initiator EXP EU 355301).Melting points were determined on a glass disk with an electric hot plate and are uncorrected. 1H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were run in DMSO- 6 and CDCl 3 solutions.IR spectra were taken as KBr plates in a Shimazdu 8400S FTIR.Commercially available substrates were freshly distilled before the reaction.Solvents, reagents, and chemicals were purchased from Aldrich, Fluka, Merck, SRL, Spectrochem and Process Chemicals.

Results and Discussion
As a part of our ongoing research to provide greener methodologies under solvent and catalyst-free conditions [27,29,[68][69][70][71] we have found that the three-component condensation of aldehyde, 1,3-cyclic diketone, and malononitrile under MW irradiation without using any catalyst and solvent produced 4H-benzo[b]pyran derivatives in high yields within short reaction times (Scheme 1).Indeed, to the best of our knowledge, this is the first report of synthesis of 4H-benzo[b]pyran under catalyst and solvent-free conditions.
Initially, we commenced our study taking benzaldehyde, malononitrile, and dimedone as the model substrates at 80 ∘ C (conventional heating) under catalyst and solvent-free conditions for 3 hours; however, a mixture of products was obtained.By increasing the temperature and time, the progress of the reaction was not satisfactory.We, then, turned our attention towards MW irradiation instead of conventional heating.Gratifyingly, the desired product was obtained in 88% in a microwave reactor (Biotage, Initiator EXP EU 355301) after 7 min at 80 ∘ C. By increasing the time and temperature the yield decreased.This may be due to the decomposition of the product at higher temperature.Finally, reaction conditions were optimized using benzaldehyde (1 mmol), malononitrile (1 mmol), and dimedone (1 mmol) at 80 ∘ C under microwave irradiation for 7 min.A wide range of structurally varied aldehydes and 1,3-cyclic diketones were subjected under optimized reaction conditions to provide the corresponding 4H-benzo[b]pyran derivatives as summarized in Scheme 3.
It can be seen that electron-rich and electron-deficient aldehydes reacted efficiently to afford the desired products with good yields.The chloro-and bromo-substituted benzaldehydes gave the corresponding 4ca, 4ja, and 4cb in 84%, 85%, and 88% yields, respectively.Aldehyde containing electron donating -OMe groups on the aromatic ring were welltolerated (4ea and 4ha).3-Hydroxybenzaldehyde afforded the corresponding product (4ga) with good yield.In addition, aldehyde containing two electron donating functional groups (-OH and -OMe) reacted very well (4ha).Heteroaryl aldehydes such as furfural also participated in the multicomponent reaction to produce the desired product in moderate yield without affecting the heterocyclic moiety (4ka).We are delighted to find that the ,-unsaturated aldehyde, such as cinnamaldehyde, was tolerated under our present reaction conditions (4fa).Acid-sensitive substrate, such as piperonal, produced the desired condensation product 4ia in excellent yield.Notable advantage of this method is its efficiency for the synthesis of 4H-benzo[b]pyrans derivative from aliphatic aldehyde with high yields (4la).In addition, 4hydroxycoumarin also afforded the corresponding products (4bc and 4cc).In general the reactions are clean and reaction procedure is very simple.To provide the analytically pure 4H-benzo[b]pyran derivatives, only ethanol was employed for recrystallization.Moreover, we have developed greener reaction conditions bearing lower E-factor [14,15,72] of 0.21 and 0.25 in the cases of synthesizing 4aa and 4ba, respectively.The plausible mechanism for the reaction is exposed in Scheme 2. Based on the literature [61], we assume that Knoevenagel condensation, Michael addition, and intramolecular cyclization are involved subsequently in the synthesis of 4Hbenzo[b]pyran derivatives.In the first step, the aldehyde undergoes a Knoevenagel condensation reaction with malononitrile to afford cyano olefin [A] [61,73]

Conclusions
In summary, we have developed an environmentally benign one-pot strategy for the synthesis of 4H-benzo[b]pyran derivatives in high yields under microwave irradiation using a mixture of aldehydes, malononitrile, and 1,3-cyclic diketones.Operational simplicity, solvent and catalyst-free conditions, compatibility with various functional groups, and nonchromatographic purification technique are notable advantages of this procedure.Lower E-factor values make this protocol better and a more practical alternative to the existing methodologies.The combination of solvent and catalystfree conditions under microwave irradiation makes this procedure truly environmentally benign.
, which endures a Michael addition reaction with the tautomeric enolic form of dimedone [B] to give the intermediate [C].The intermediate C on intramolecular cyclization produces the final product 4.