Sonochemistry in an organocatalytic domino reaction: an expedient multicomponent access to structurally functionalized dihydropyrano[3,2-b]pyrans, spiro-pyrano[3,2-b]pyrans, and spiro-indenoquinoxaline-pyranopyrans under ambient conditions

A highly convenient and sustainable one-pot approach for the diversely-oriented synthesis of a variety of medicinally privileged amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives on the basis of a domino three-component reaction of readily available carbonyl compounds including aryl aldehydes or isatins, active methylene compounds, and kojic acid as a Michael donor using secondary amine catalyst l-proline under ultrasound irradiation in aqueous ethanolic solution at ambient temperature has been developed. This methodology can involve the assembly of C–C, C 
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Created by potrace 1.16, written by Peter Selinger 2001-2019
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 C, C–O, C–N bonds via a one-pot operation, and following this protocol, a series of novel amino-substituted spiro[indeno[1,2-b]quinoxaline-11,4-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylates have been synthesized. The practical utility of this method was found to be very efficient for scale-up reaction and other useful transformations. The methodology provides significant advantages including mild reaction conditions, energy-efficiency, short reaction time, fast reaction, simple work-up procedure, broad functional group tolerances, utilization of reusable catalyst, green solvent system, being metal-free, ligand-free, waste-free, inexpensive, etc. Excellent chemical yields have been achieved without using column chromatography. To address the issues of green and more sustainable chemistry, several metrics including Atom Economy (AE), Reaction Mass Efficiency (RME), Atom efficiency, E-factor, Process Mass Intensity (PMI), and Carbon Efficiency (CE) have been quantified for the present methodology that indicates the greenness of the present protocol.


Introduction
Over 60% of organic compounds produced by diverse chemical industries in the form of ne chemicals, drugs, optoelectronic materials, and agrochemicals contain heterocycles as the key active ingredients. In particular, the synthesis of novel oxygen and nitrogen-containing heterocycles is of signicant importance on account of their occurrences in natural compounds, medicinally active components, and optoelectronic materials. 1 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one, commonly known as kojic acid is an oxygen-containing natural g-pyrone generated by lamentous fungi and numerous kinds of bacteria including Aspergillus, Penicillium, and Acetobacter, etc. 2 The kojic acid nucleus and its analogs have drawn immense signicance in recent years due to their various application in the medicinal and pharmaceutical industry, 3 food industry, 4 cosmetic and personal care products, 5 agriculture, 6 and chemical industry. 7 By taking into consideration kojic acid's structural characteristics and broad-spectrum activities, a substantial attempt was made not just towards its synthesis but also to using them as an essential constituent for construction and identication of potent structural fragments. 8 In line with this, one of the most important fused heterocycles namely, pyrano [3,2-b]pyrans, was synthesized mostly in the last two decades based on kojic acid. 9 Pyrano [3,2-b]pyrans are found to be the major structural constituent of many natural products (Fig. 1) and they are established as the most important target for total synthesis. Elatenyne (A), a dibrominated natural product extracted from Laurencia elata, belongs to a class of non-isoprenoid, halogenated ethers having an unbranched C 15 backbone and a conjugated enyne terminal in their structure. 10 The compound B, also a halogenated C 15 natural product was derived from Laurencia a School of Applied Material Sciences, Centre for Applied Chemistry, Central University of Gujarat, Sector-30, Gandhinagar-382030, Gujarat, India. E-mail: rchowhan@cug. ac majuscule, a marine red alga. 11 Both compounds A and B have received a lot of attention as potential total synthesis targets due to the presence of the functionalized pyrano [3,2-b]pyran core in their skeleton. Alternatively, the presence of strategically situated halogen atoms on the tetrahydropyran rings of the natural products (3Z)-Dactomelynes (C) and (3E)-Dactomelynes (D) isolated from the digestive glands of the sea hare Aplysia dactylomela make them an important skeleton for laboratory synthesis to evaluate pharmacologically. 12,13 Pyrano[3, pyrans are oen found in the core structure of many nonnatural products, synthetic drug candidates and holds a pivotal position in drug discovery and medicinal chemistry on account of their remarkable biological activities 14 such as antioxidant, antifungal, antibacterial, anti-tumor activity [ Fig. 1

(E)-(I)].
Furthermore, the synthesis of spiro-heterocyclic compounds especially spiro-oxindoles have drawn much more attention not only in synthetic chemistry but also in medicinal chemistry for their outstanding reactivity and prolic therapeutic potential along with their utilization as key intermediates for direct access to natural product types molecules and medicinally privileged heterocycles. 15 Considering these prominent signicances and the broadspectrum pharmacological prole of pyrano[3,2-b]pyran derivatives, the synthesis of these structural motifs becomes extremely demanding. Several synthetic procedures for pyrano [3,2-b]pyrans have been established during the past decades. 9 Although, the previously reported methods offer some advantages, many of them suffer drawbacks, including the use of volatile organic solvents, metal-catalyst, tedious work-up procedure, time-consuming, limited substrate scopes, harsh reaction conditions, and relatively low products yield. Consequently, developing an alternative approach for conducting organic synthesis that avoids or minimizes the use of volatile organic solvents and hazardous reagents by introducing environmentally benign conditions with the main focus to reduce the cost-effectiveness of the chemical transformation is highly desired.
With these perspectives and people's ever-increasing awareness about their living environment to protect from chemical pollution associated with a chemical process, sonochemistry appears to be a promising and alternative eco-friendly activation method for organic synthesis due to attractive features associated with it such as the improved reaction rates and product selectivity under mild condition, low energy requirements, along with an immediate reduction in reaction times. 16 The ability to accomplish or promote chemical reactions by means of sound waves triggered by ultrasound can make the sonochemical-assisted synthetic method much more superior to the conventional method with respect to green and sustainable chemistry. 17 When exposed to a reaction mixture, ultrasound irradiation caused a large number of cavitation bubbles to form once the pressure reached a specic level. These cavitation bubbles will rapidly growing up and then violently collapsed. This repeated dynamic process of oscillation of formation, growing up, and collapses generates the ne emulsion between the reactants and elevated the local temperature of the reaction mixture to cross the activation energy of the reaction. 18 But, again the occurrence of transition-metal-catalyst(s) in chemical processes even at the lowest level oen triggers an undesirable impact on the greenness or sustainability of the transformation. 19 Notwithstanding, transition metal catalyst(s) has been successfully employed in the synthesis of valuable structural building blocks; 20 their occurrences in a chemical process is associated with limitations because of their highly toxic nature, and high cost involved in the preparation of transition metal catalyst alongside the requirement of noncommercial supporting ligands for catalyst preparation. Besides these, the elimination of transition-metal-catalyst(s) from chemical transformation which is predominantly required in the pharmaceutical industry is extremely challenging and oen results in contamination of the target compounds. Consequently, the recent years have witnessed tremendous progress in the use of small organic molecules known as organocatalyst(s) in organic transformations, which has resulted in a revolution in the synthesis of molecular diversity and complexity in asymmetric and non-asymmetric ways using a variety of activation modes and has emerged as a popular research topic on the context of synthetic effectiveness and also from a green and sustainability standpoint. 21 Among other organocatalysts, secondary amine catalyst, Lproline has received immeasurable attention in synthetic chemistry on account of its easy availability, non-toxic, economical nature, and bifunctional mode of reactivity that could be operated simply in chemical transformation and recovered easily from the chemical process. The versatile structural features of L-proline have allowed it to act either as Brønsted acid or Brønsted base or show both the behaviours and it can undergo covalent organocatalysis by generating iminium or enamine intermediates. 22 The effectiveness of L-proline was demonstrated by its applicability in various organic transformations 23 for example Aldol reaction, 23a Mannich reaction, 23b Knoevenagel condensation reaction, 23c Michael reaction, 23d Diels-Alder, 23e Biginelli reaction, 23f and multicomponent reactions. 23g,h Multicomponent reactions (MCRs) have drastically received a spectacular application in organic synthesis owing to their prolic propensity for the synthesis of complex molecular structures in a single operation. The ability to accomplish reaction from simple, cheap, and readily available starting materials through the creation of several bonds in a one-pot with immediate prevention in the isolation and purication of product intermediates makes MCRs a powerful tool for green or sustainable synthesis as compared to the conventional stepwise method which avoids green chemistry principle. 24 By considering these all aspects and in accordance with making a pollution-free environment, the present study reports an ultrasound-assisted supercial organocatalytic one-pot approach for the assembly of a variety of amino-substituted pyrano [3,2-b]pyrans such as dihydropyrano [3,2-b]pyran-3carbonitriles (4a-n), and spiro[indoline-3,4 0 -pyrano[3,2-b] pyran]-3 0 -carbonitrile/carboxylate derivatives (6a-j) from a domino three-component reaction of active methylene compounds 1a-b, kojic acid 2, and substituted aldehydes 3a-n/ isatins 5a-f in aqueous ethanolic solution by employing secondary amine, L-proline as the catalyst at ambient temperature (Scheme 1).
Quinoxaline, a nitrogen-containing bicyclic heterocycle, and its fused derivatives, on the other hand, have been shown to represent attractive structural features in synthetic and medicinal chemistry. 19a They are commonly encountered in many natural products, agrochemicals, synthetic drug candidates and represent a wide variety of therapeutic potential such as antidiabetic, antibacterial, anticancer, anti-inammatory, antituberculosis, anti-HIV, antiprotozoal, etc. These impressive properties of the privileged quinoxaline nucleus have prompted us to synthesize some novel hybrid molecules incorporating both quinoxaline and pyrano [3,2-b]pyran moiety by joining them through C-11 of the spiro-system. In this context, we reported here the synthesis of several novel amino-substituted spiro[indeno [1,2-b]quinoxaline -11,4 0 -pyrano[3,2-b]pyran] derivatives (9a-e) for the rst time via ultrasound-assisted organocatalytic domino four-component reactions of active methylene compound 1, kojic acid 2, ninhydrin 7, and 1,2-diamine 8 under the inuences of L-proline in aqueous ethanolic solution at ambient temperature (Scheme 1).

Result and discussion
We commence our studies with an equimolar amount of malononitrile 1a, kojic acid 2, benzaldehyde 3a, as our model substrates and the reaction was performed under the inuences of various types of catalysts, solvents, along with catalyst-free and solvent-free conditions using ultrasonic irradiation as a green energy source at ambient temperature. Our preliminary investigation was aimed to authenticate the general feasibility of our approach for aromatic aldehydes to provide 2-amino-6- b]pyran-3-carbonitriles 4a-n. A quick investigation of the results outlined in Table 1 revealed that the reaction executed in absence of any catalyst failed to yield the intended product 3a even aer 1 hour (entry 1, Table 1). Then, we turned our focus on examining the effects of different catalysts on the model reaction and the results were summarized in Table 1. Under the inuences of bases such as Et 3 N, K 2 CO 3 , DBU, DABCO; the reaction can require a longer time to complete, and the yield of the product was found to be not satisfactory (entries 2-5, Table  1). Changing the reaction condition from base to acid catalysts such as p-TSA, triuoroacetic acid (TFA), acetic acid, and benzoic acid, seemed to have no effect on the reaction rate or product yield (entries 6-9, Table 1). With the expectation to improve the yield of the product, next, we investigated the model reaction under the inuence of different types of organocatalysts ( Fig. 2) such as Cat-I, Cat-II, Cat-III, Cat-IV, Cat-V, and Cat-VI (entries 10-15, Table 1). The catalysts Cat-I, Cat-II, Cat-III, and Cat-VI are found to be slightly able to catalyze the reaction albeit with lower yields of the product, and catalyst Cat-IV gave good conversion of the starting materials to the nal product with a slight increase in the yield. However, no significant improvement in the yield as compared to other acids and bases were achieved. But surprisingly, the high completion rate of the model reaction with an excellent yield (96% yields for 4a, entry 14, Table 1) of the product has been achieved under the inuence of 20 mol% of Cat-V in only 10 minutes. As a consequence, the exploration of the high catalytic activity of L-proline (Cat-V) was demonstrated as the best optimum catalytic condition for the present study (entry 14, Table 1). To nd out the appropriate reaction medium necessary for the formation of 4a, the representative reaction was then performed in solventfree as well as in a different solvent system such as MeOH, EtOH, H 2 O, H 2 O : EtOH (v/v, 1 : 1), H 2 O : EtOH (v/v, 2 : 1), toluene, DMF, CH 2 Cl 2 , and CH 3 CN in presence of Cat-V in sonication at ambient temperature (entries 1-10, Table 2). Initial observation in solvent-free conditions realizes the unsuccessful completion of the reaction. While insufficient yields of the product were obtained in different solvent systems such as MeOH, toluene, DMF, CH 2 Cl 2 , and CH 3 CN (entry 2, 7, 8, 9, 10; Table 2). Conversely, the reaction performed in presence of ethanol was found to lead to the product in good yield (88% yields, entry 3, Table 2). Then we investigated the reaction using water as the solvent system and noticeably, the preferred product has been achieved in 90% yields (entry 4, Table 2). Furthermore, mixing the solvent system including water and ethanol in a 1 : 1 ratio was found to be very efficient to deliver the product in excellent yields (entry 5, Table 2). However, there was no change in product yield with changing the ratio of the mixing solvent system (entry 6, Table 2). Although the reaction was very compatible with water as the medium, the high yield of the product in aqueous ethanol (1 : 1, v/v) over pure water promoted us to consider L-proline (Cat-V) in aqueous ethanol by employing ultrasound irradiation as the optimum reaction condition for the synthesis of dihydropyrano[3,2-b]pyran-3carbonitrile 4a.
Moreover, the amounts of catalyst required for the conversion of reactant into the desired product were evaluated by varying the loading of catalyst (10 mol%, 15 mol%, 20 mol%, and 25 mol%) in the model reaction (Table 3).
A slight reduction in the rate of complete conversion of reactants was observed when the reaction was performed in presence of 10 mol% of catalyst. Pleasingly, increasing the amounts of catalyst from 10 mol% to 20 mol% leads to the   corresponding products with excellent yield, and no further increase in the product yield was detected with increasing the catalyst loading. Therefore, 20 mol% of Cat-V is sufficient for the maximum conversion of the reactants to the nal product. With this information in hand, then we investigate the model reaction by employing 20 mol% of Cat-V in aqueous ethanol under stirred conditions as well as reux conditions. But no improvements in the reaction rate or product yields have been observed. Consequently, ultrasound irradiation was demonstrated as the efficient condition for this transformation as compared to both traditional conditions in terms of reaction time, energy, work-up procedure, and product yields. Aer ascertaining the optimal conditions, the reaction was performed with various substituted aromatic aldehyde such as 4-urobenzaldehyde (3b)/4-chlorobenzaldehyde (3c)/4bromobenzaldehyde (3d)/4-methylbenzaldehyde (3e)/4methoxybenzaldehyde (3f)/4-nitrobenzaldehyde (3g)/2chlorobenzaldehyde (3h)/2-nitrobenzaldehyde (3i)/2bromobenzaldehyde (3j)/3-uorobenzaldehyde (3k)/4-hydroxy-3-methoxy-benzaldehyde (3m), active methylene compound 1a, and kojic acid 2 by using 20 mol% of L-proline (Cat-V) in H 2 O : EtOH (1 : 1, v/v) under ultrasound irradiation for 8-15 minutes at ambient temperature (Table 4). The electronic effect of substitution on the aryl ring of aldehydes undergoing this domino reaction was rst examined. All halogenated substrates like uoro, chloro, bromo located on C-2, C-3 and C-4 position of the aromatic ring of aldehydes (3b, 3c, 3d, 3h, 3j, and 3k) efficiently worked under this condition and afforded the amino substituted-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile derivatives 4b, 4c, 4d, 4h, 4j, and 4k with excellent yields without any side reaction. It is interesting to note that aldehyde possessing electron-donating groups such as methyl (3e), methoxy (3f) at C-4 and electron-withdrawing groups including nitro group (3g and 3i) at C-2, and C-4 positions successfully give the desired product 4e, 4f, 4g, and 4i in 90%, 92%, 94%, and 94% yields respectively for a time of 10-15 minutes. In addition, di-  substituted groups like hydroxy and methoxy at different positions appeared to be very effective for this reaction (entry 3m). Concurrent to aryl aldehydes, heteroaryl aldehydes such as 2naphthaldehyde (3l) and thiophene-2-carbaldehyde (3n) are also well suited for this transformation to deliver the desired products 4l and 4n, respectively in 94% and 97% yields at 13 and 10 minutes. The utilization of ultrasound as a green activation method for this reaction was found to increases the yield of the products in a very short reaction time as compared to the reaction performed in absence of ultrasonic irradiation. Furthermore, the temperature of the water bath was remained constant during the reaction and not increased even aer the optimized reaction time, which indicates the acceleration of the reaction by irradiation as the energy source not for an increased in the temperature of the reaction. However, aliphatic aldehydes were unable to react under this condition.
To further explore the synthetic potentiality of the current approach, we investigate this domino reaction with isatin 5a by replacing aldehyde 3a. To our delight, the reaction of active methylene compound 1a, kojic acid 2 and isatin 5a successfully worked under the similar reaction condition to deliver the corresponding product 2 0 -amino-6 0 -(hydroxymethyl)-2,8 0 -dioxo- (6a) in excellent yield (97%) within a very short reaction time. Encouraged by these results, we then attempted a series of reactions between several derivatives of isatin 5 such as 5-chloro isatin 5b/5-bromo isatin 5c/N-methyl isatin 5d/N-allyl isatin 5e/ N-benzyl isatin 5f, active methylene compound 1 such as malononitrile 1a/ethyl cyanoacetate 1b, and kojic acid 2 that smoothly providing the corresponding amino-substituted spiro [indoline-3,4 0 -pyrano[3,2-b]pyran]-3 0 -carbonitrile/carboxylate derivatives 6a-j in good to excellent yields (Table 5). Variations in the yields of the obtained products were found to be not greatly inuenced by the substitutions on the isatin ring. Halogen substituted isatins including chloro and bromo, are efficiently worked to provide the desired product 6b, 6c, and 6h in 98%, 97%, and 95% yield respectively within 10-12 minutes. The reaction was found to be very compatible with both Nsubstituted as well as N-unsubstituted isatins. For N-substituted isatin, the corresponding products 6d, 6e, 6f, 6i, and 6j derived from 5d, 5e, and 5f have been achieved in 88-97% yield at 10-15 minutes.
All of the synthesized compounds were isolated pure just by ltering off the precipitate along with continuous washing by water followed by recrystallization from ethanol. Notably, the approach does not necessitate the use of time-consuming column chromatographic techniques. The structure of the synthesized compounds has been determined based on spectroscopic analysis such as FT-IR, 1 H NMR, 13 C NMR, and HRMS (see ESI †).
To further established the effectiveness of this ultrasoundassisted domino 'one-pot' reaction system, we performed a gram-scale reaction for the preparation of pyrano[3,2-b]pyran derivatives 4a, 6a, and 9a on a 10 mmol scale (Scheme 2). With the help of 20 mol% of Cat-V, the reaction between benzaldehyde (3a)/isatin (5a) with malononitrile 1a and kojic acid 2, smoothly furnished 95% and 96% yield of the respective product 4a and 6a at 15 minutes. Similarly, the gram-scale synthesis of 9a was also performed using the standard condition and the corresponding product 9a was achieved in 93% yield. Gratifyingly, the gram-scale reaction is found to be almost similar to the 1 mmol scale protocol in terms of product yield albeit with a slightly longer reaction time.
The synthetic applicability of the present approach was also established by the convergent synthesis of a fused aminosubstituted pyrimidine derivative 11 in 68% yield over a onestep procedure from dihydropyrano [3,2-b]pyran 4h by treating it with formamide 10 (Scheme 3). The successful construction of quinoxaline, as well as pyrimidine derivatives fused with the pyrano[3,2-b]pyran core, marks the most notable aspects of this approach.

Recyclability experiments
Apart from this, the possibility of recyclability and sustainability of the catalyst for the present protocol was examined by employing 2-bromobenzaldehyde 3j, malononitrile 1a, and kojic acid 2 as the reaction partners (Fig. 3). Aer that, the solid reaction mixture was ltered off once the reaction was completed, and the ltrate containing Cat-V was recovered and successfully utilized for further subsequent reactions. From the observations, it has been revealed that there was no considerable change in the yields of the product (95-90% yields for 4j) at the end of the 4 th catalytic cycle which demonstrated the effectiveness and efficiency of the catalyst for the present work.

Plausible mechanism
To demonstrate the mechanism of this domino reaction, we executed some control experiments as shown in Scheme 4. Initially, when ninhydrin 7 was subjected to malononitrile 1a under the standard reaction condition, the reaction was found to be incomplete and failed to yield any product. Treatments of kojic acid 2 with ninhydrin 7 were also unable to form any product. These two results indicated that ninhydrin 7 was not likely to undergo either Knoevenagel condensation or Michael Scheme 2 Preparative scale-up synthesis of 4a, 6a, and 9a.
Scheme 3 Further synthetic applications of the synthesized compounds to more complex-fused compounds 11. Based on these experimental results, we suggest the following plausible mechanistic pathway (Scheme 5) for the ultrasound-assisted synthesis of amino-substituted 8H 0 -spiro [indeno[1,2-b]quinoxaline-11,4 0 -pyrano[3,2-b]pyran]-3 0carbonitrile/carboxylate derivatives 9 from the domino fourcomponent reaction of ninhydrin 7 with 1,2-diamine 8, active methylene 1 and kojic acid 2 under the inuences of secondary amine catalyst, L-proline (Cat-V) in aqueous ethanolic solution at ambient temperature. We assume that initially, the reversible reaction of intermediate Int-1 (generated in situ from ninhydrin 7 and 1,2-diamine 8) with L-proline formed an iminium ion intermediate Int-2 that could facilitate the Knoevenagel condensation with active methylene compound 1 to form the Knoevenagel adduct Int-4 via subsequent elimination of Lproline from Int-3. Thereaer, a Michael addition between the adduct Int-4 and kojic acid 2 took place to form an intermediate Int-5 which is followed by a 6-exo-dig cyclization of -OH group to the -CN moiety to afford the corresponding products 9, aer an imine-enamine tautomerization.

Green chemistry metrics calculation
In order to formulate the actual progress of chemical syntheses and chemical processes in both industry and academia in the move toward more sustainable practices, the assessment of the greenness of different chemical processes is crucial. 26 The quantication of sustainable practices has to lead to the development of a series of metrics to support and reinforce the behavior change of chemical technology with the aim to addressed green and sustainable chemistry. 27 Most importantly used green metrics including Atom Economy (AE), atom efficiency, E-factor, Reaction Mass Efficiency (RME), Process Mass Intensity (PMI), Carbon Efficiency (CE) are calculated for our newly developed methodology towards the synthesis of pyrano [3,2-b]pyran derivatives among which we examined the value of the metrics for compound 4b, 6b and 9b.
Scheme 5 The plausible mechanism for the L-proline catalyzed synthesis of 9 via iminium activation strategy.  Table 7, it was observed that the calculated value of atom economy and atom efficiency for compounds 4b, 6b, and 9b were much closer to the ideal value of atom economy which indicates the presence of all starting material in the nal product. The ideal value of the E-factor is considered zero for a chemical process and the calculated E-factor for compounds 4b, 6b, and 9b was found to be almost similar to the ideal value that points out the avoidance of waste products from the reaction. Similarly, the value of RME ranges from 0-100%, and the greater amount of RME provides the "cleanness" of a chemical reaction. The calculated value of RME for compounds 4b, 6b, and 9b resemble the ideal value which conrms the cleanness of the presented protocol. Also, the value of PMI and CE is matched with the calculated value for compounds 4b, 6b, and 9b. The above results point towards the greenness and sustainability of the present approach.
Further, we had investigated the effectiveness and efficiency of the present protocol by comparing it with the previously reported procedure for the assembly of amino-substituted dihydro-pyrano [3,2-b]pyran derivatives 4 and spiro [indoline-3,4 0pyrano[3,2-b]pyran] derivatives 6. First, we compared the previously published method (entries 1-5) for the synthesis of 4a with the present method (entry 6) and then we compared the previously published method (entries 7-10) for the synthesis of 6a with our method (entry 11). From the results depicted in Table 8, it was observed that the present protocol is undeniably more efficient in terms of reaction time, reaction temperature, energy source, solvent, product yield, and substrate scopes.

Conclusion
In conclusion, we have demonstrated a energy-efficient, environmentally benign, and eco-compatible one-pot domino organocatalytic methodology for the expedient access to a series of medicinally privileged amino-substituted dihydro-pyrano [3,2-b]pyrans 4a-n, spiro[indoline-3,4 0 -pyrano[3,2-b]pyran] (6aj) and novel spiro[indeno [1,2-b]quinoxaline -11,4-pyrano[3,2-b] pyran]-3-carbonitrile/carboxylates (9a-e) by employing the reactivity of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one in aqueous ethanolic solution under ultrasonic irradiation at ambient temperature. Good to excellent yields were obtained and the product could be isolated without using column chromatography techniques. Highly economical bifunctional natural amino acid L-proline was used as a recyclable catalyst with low catalytic loading. The methodology provides a vast array of incredible advantages including utilization of readily available starting material, mild reaction condition, fast reaction rate, cost-effectiveness, easy work-up procedure, short reaction time, metal-free, ligand-free, waste-free, work in an open vessel, high conversion rate, a wide range of substrate scope that makes it more useful synthetic protocol from the perspective of green and sustainable chemistry. The ability to accomplish multiple C-C, C]C, C-N, C-O bonds in a one-pot operation under the metal-free organocatalytic condition in presence of a green solvent system by employing sonochemistry as green energy input features the signicant advantages of this protocol. The synthetic application of the product to more complex-fused compounds points toward another advantage of the present study (Scheme 3). The effectiveness of the methodology was also established by a scale-up reaction and it was observed to be equally efficient in all three cases. Sustainability of the present protocol was studied by using several green metrics such as Atom Economy (AE), Atom efficiency, E-factor, Reaction Mass Efficiency (RME), Process Mass Intensity (PMI), Carbon Efficiency (CE), and the entire three compounds examined were found to be very close with the ideal value that indicates the greenness of the present protocol.

Experimental section
General experimental detail All commercially available chemicals were used without further purication. Thin Layer Chromatography (TLC) was executed utilizing silica gel 60 F 254 (Merck) plates. Proton nuclear magnetic resonance spectra ( 1 H NMR spectra) were obtained on Bruker 500 MHz FT-NMR spectrometers and 400 MHz FT-NMR in CDCl 3 and DMSO solvents. 13 C NMR spectra were recorded at 125 MHz and 100 MHz. Chemical shis are reported in parts per million (ppm) relative to the TMS signal. Multiplicity is indicated as follows: s (singlet); bs (broad singlet); d (doublet); t (triplet); q (quartet); m (multiplet); dd (doublet of doublets), etc. Sonication was performed using an ultrasonic bath cleaner (model: SB-3200DT) with an operating frequency of 40 kHz and nominal power of 180 W. TOF and quadrupole mass analyzer types are used for the HRMS measurements The IR spectra were recorded using an FT-IR spectrometer (Shimadzu) in the range of 400-4000 cm À1 .
General procedure for the synthesis of amino-substituted dihydropyrano[3,2-b]pyran 4 and spiro[indoline-3,4 0 -pyrano [3,2-b]pyran] 6. An oven-dried round bottom ask charged with a mixture of active methylene compounds 1 (1 mmol), kojic acid 2 (1 mmol), carbonyl compound such as aryl aldehydes 3, or substituted isatin 5 and 20 mol% of L-proline (Cat-V) in aqueous ethanolic solution (1 : 1, v/v; 3 mL) was subjected to ultrasonic irradiation (40 kHz, 180 W) at ambient temperature for the indicated time. The progress of the reaction was monitored by TLC (thin layer chromatography); however, the same can be inferred by visualizing the disappearance of the colour of the starting material. Aer the complete consumption of starting material, as indicated by the TLC, the reaction mixture was ltered off by using lter paper and washed with dilute water, and the crude solid product was recrystallized from ethanol to give analytically pure products 4, and 6. All the compounds were fully characterized based on analytical data and detailed spectral studies including FT-IR, 1 H NMR, 13 C NMR, and HRMS.