Meglumine-Promoted Eco-Compatible Pseudo-Three-Component Reaction for the Synthesis of 1,1-Dihomoarylmethane Scaffolds and Their Green Credentials.

A simple, straightforward, and energy-efficient greener route for the synthesis of a series of biologically interesting functionalized 1,1-dihomoarylmethane scaffolds has been developed in the presence of meglumine as an efficient and eco-friendly organo-catalyst via one-pot pseudo-three-component reaction at room temperature. Following this protocol, it is possible to synthesize 1,1-dihomoarylmethane scaffolds of an assortment of C-H activated acids such as dimedone, 1,3-cyclohexadione, 4-hydroxy-6-methyl-2-pyrone, 4-hydroxycoumarin, and 1-phenyl-3-methyl-pyrazolone. The salient features of the present green protocol are mild reaction conditions, good to excellent yields, operational simplicity, easy isolation of products, no cumbersome post treatment, high atom economy, and low E-factor. In addition, this chemistry portrays several green advantages including the reusability of reaction media and product scalability, which makes protocol sustainably efficient. Additionally, several control experiments such as protection of catalyst reactive site, D2O exchange, and 1H NMR studies revealed possible pathways for meglumine-promoted reactions. Inspired by the natural physiological environment of 1,1-dihomoarylmethane scaffolds, we reconnoitered the biological profile of our compounds and synthesized compounds that were promising for their antiproliferative and antibacterial activities.

Introduction

1,1-Dihomoarylmethane scaffolds, explicitly 4-hydroxycoumarin, 4-hydroxy-2-pyrone, and pyrazolone represent “privileged” structural motif well distributed in the natural world with a broad spectrum of their intriguing pharmaceutical activities, for instance, anticoagulant,[1−3] urease inhibitors,[4] anticancer,[5,6] anti-HIV,[7−9] antiviral,[10] anti-inflammatory,[11] antibiotic,[12,13] antioxidant,[14,15] antidepressant,[16] antifilarial,[17] and antipyretic.[18]Figure signifies a glimpse of some of the naturally occurring bioactive heterocyclic compounds exhibiting diverse pharmaceutical potentials.[19,20] Among them, pinillidine is a well-known natural product isolated from the medicinal fungi Phellinus pini, which exhibited significant antioxidant activity.[21] Likewise, 5-substituted pyrimidine nucleosides with a bispyranylmethane scaffold exhibited antiviral, anti-inflammatory activities and can be used as an inhibitor for mPGES-1 and 5-LO.[22] Recently, Fu and his co-workers found that this type of strategy was used to remove formaldehyde from water.[23] Furthermore, Chung & his co-workers used 2,2-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-ones) compounds as a highly efficient building block for the construction of a variety of N-heterocycles.[24]Figure indicates some of the marketed drugs bearing 1,1-dihomoarylmethane moieties as a core.

Figure 1

Natural products containing 4-hydroxycoumarin and 4-hydroxy-6-methyl-2-pyrone moieties.

Figure 2

Representative examples of bioactive dihomoarylmethane moiety.[19,20,25]

In the light of the significance of 1,1-dihomoarylmethane derivatives, there have been continuous efforts to develop a practical and efficient approach for the synthesis of this class of compounds (Scheme ).

Scheme 1

Synthetic Approaches for 1,1-Dihomoarylmethane Scaffolds

(26−50)

Although these protocols reported by others find certain merits, still they suffer from several demerits such as extended reaction time, heating, use of metal catalysts, byproduct formation, high catalytic loading, use of toxic organic solvents, highly acidic or basic media, and need of chromatographic techniques. Moreover, this kind of reactions presumably could not conduct well due to limited substrate scope in C–H activated acids, that is, most protocols are working with one or two C–H activated acids. These disadvantages hamper the construction of greener and more sustainable protocols and remain a formidable challenge. Therefore, owing to the environmental perspective, the search for more general, efficient, and feasible routes to this class of derivatives remains a meaningful goal.

Meglumine is an amino sugar derived from sorbitol, and it is an FDA-approved excipient in pharmaceuticals and medicine. It helps to enhance the stability and solubility of active pharmaceutical ingredients in formulation studies. It possesses astonishing physical and chemical properties such as biocompatibility, biodegradability, stability to air and moisture, and water miscibility. Also, it is inexpensive and readily available in the market.[51−53]

As a part of our efforts to develop green synthetic methodologies for useful organic transformations, herein, we wish to unveil a straightforward, efficient, clean, and high-yielding MCR protocol for the one-pot facile synthesis of biologically relevant 1,1-dihomoarylmethane scaffolds from aldehydes and a variety of C–H activated acids in aqueous ethanol at room temperature using meglumine as a sustainable and eco-compatible organo-catalyst. The results are summarized in Tables –9.

Table 1

Optimization of Reaction Conditions for the Synthesis of 1,1-Dihomoarylmethane Scaffoldsa

entry	catalyst (mol %)	solvent	temp.	time	yield (%)b
1	no catalyst	no solvent	rt	24 h	NR
2	no catalyst	EtOH	rt	24 h	NR
3	meglumine (50)	no solvent	rt	24 h	NR
4	meglumine (50)	H2O	rt	2 h	69
5	meglumine (50)	EtOH	rt	30 min	66
6	meglumine (50)	EtOH:H2O (1:1 v/v)	rt	10 min	70
7	meglumine (30)	EtOH:H2O (1:1 v/v)	rt	26 min	72
8	meglumine (10)	EtOH:H2O (1:1 v/v)	rt	7 min	85
9	meglumine (10)	ACN	rt	4 h	53
10	meglumine (10)	MDC	rt	4 h	49
11	meglumine (10)	THF	rt	5 h	41
12	meglumine (10)	DMF	rt	7 h	39
13	meglumine (10)	EtOH:H2O (1:1 v/v)	80 °C	5 min	76
14	p-TSA (10)	EtOH:H2O (1:1 v/v)	rt	19 h	62
15	sulfamic acid (10)	EtOH:H2O (1:1 v/v)	rt	20 h	58
16	piperidine (10)	EtOH:H2O (1:1 v/v)	rt	25 min	54

Reaction conditions: 1c (0.5 mmol) and 2a (1 mmol) stirred under ambient condition.

Isolated yield. NR = no reaction.

Table 9

Reusability Investigation of Model Reaction’s Filtrate for Other Reaction

sr no.	filtrate of the compound	C–H activated acid	aldehyde	time	product	yield (%)
1.	3ac	dimedone	p-fluoro benzaldehyde	10 min	3aa	89
2.	3ac	6-methyl-4-hydroxy pyrone	formaldehyde	3 h	3cl	86

Results and Discussion

We commenced our reaction optimization study for the synthesis of 1,1-dihomoarylmethane scaffold (3) using p-nitrobenzaldehyde (1c) and dimedone (2a) under catalyst- and solvent-free condition as a model reaction. But unfortunately, no product formation was observed even after 24 h of stirring at room temperature (Table , entry 1). Then, the reaction was performed by taking ethanol as a sole solvent, but transformation was not achieved (Table , entry 2). Then, to add extra cooperative chemical activation, we attempted the reaction by employing meglumine as an organo-catalyst. From a sustainability point of view, we continued to examine our model reaction using water as a reaction medium. Fortuitously, when meglumine in water was used, product 3ac was isolated in 69% yield after 2 h (Table , entry 4). These preliminary results encouraged us to systematically investigate different reaction parameters to improve the yield. Attempts to further optimize this process were inspected by switching the solvent from water to ethanol and aq ethanol. Ethanol favored the reaction conversion and reaction was completed within 30 min to give 66% yield (Table , entry 5). In aq ethanol, the reaction time was further reduced to 10 min with 70% yield (Table , entry 6). When the amount of meglumine was decreased to 30%, a slight increase in the isolated yield of 3ac was observed with a longer reaction time (Table , entry 7). Gratifyingly, the amount of meglumine was decreased to 10% and a notable increase in the isolated yield of 3ac was observed with a shorter reaction time (Table , entry 8). These results showed that 10 mol % of meglumine had the highest efficiency in aq ethanol to afford 3ac in 85% yield (Table , entry 8). Furthermore, we investigate the reaction by employing different solvents (Table , entries 9–12). The results demonstrated that a mixture of polar solvents like water and ethanol emerged as the best solvent pair with the highest efficiency. Other solvents [acetonitrile (ACN), methylene dichloride (MDC), tetrahydrofuran (THF), and dimethylformamide (DMF)] also gave the desired product 3ac but in lower yields. We also attempted reaction at different temperature gradients, but the yield of 3ac was not improved (Table , entry 13). Moreover, various catalysts such as p-toluenesulfonic acid (p-TSA), sulfamic acid, and piperidine were screened under similar reaction conditions. In all of these cases, the observed yield was lowered than that of meglumine (Table , entries 14–16). Thus, the optimal reaction condition for the synthesis of 1,1-dihomoarylmethane scaffold was found to be 10 mol % of meglumine at room temperature using 1:1 v/v aq ethanol as a solvent (Table , entry 8).

The substrate scope with various aromatic aldehydes was checked using identical reaction conditions; all of them underwent the reaction smoothly to afford the corresponding products (3aa–ak; Table ) in good to excellent yields at room temperature. Especially, the reaction was in great progress when dimedone reacted with benzaldehyde-bearing electron-withdrawing groups. We wondered that aliphatic aldehydes also reacted with similar efficiency to form corresponding products.

Table 2

Synthesis of 2,2′-(Aryl methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3aa–ak)

Reaction conditions: 1 (0.5 mmol), 2a (1 mmol), and meglumine (10 mol %) in (1:1 v/v) aq ethanol (4 mL), ambient condition.

Isolated yield.

Reaction time.

To check the generality as well as the effectiveness of our newly developed protocol, other C–H activated acids were used. To our delight, the reactions attempted with 1,3-cyclohexadione (2b) also underwent successful condensation to produce the desired 2,2′-(arylmethylene)bis(3-hydroxycyclohex-2-en-1-one) (3ba–bh; Table ) in good to excellent yields. Fortunately, the electronic nature of the substituent on the parent phenyl ring has a slight impact on the reaction.

Table 3

Synthesis of 2,2′-(Aryl methylene)bis(3-hydroxycyclohex-2-en-1-one) (3ba–bh)

Reaction conditions: 1 (0.5 mmol), 2b (1 mmol), and meglumine (10 mol %) in (1:1 v/v) aq ethanol (4 mL), ambient condition.

Isolated yield.

Reaction time.

Encouraged by these results, we attempted to extend the present protocol using 4-hydroxy-6-methyl-2-pyrone (2c) and 4-hydroxycoumarin (2d) as varying C–H activated acids. Also, these C–H activated acids smoothly reacted to give corresponding products under similar reaction conditions (3ca–cm;Table ) and (3da–dj; Table ), respectively.

Table 4

Synthesis of 2,2′-(Aryl methylene)bis(4-hydroxy-6-methyl-2-pyrone) (3ca–cm)

Reaction conditions: 1 (0.5 mmol), 2c (1 mmol), and meglumine (10 mol %) in (1:1 v/v) aq ethanol (4 mL), ambient condition.

Isolated yield.

Reaction time.

Table 5

Synthesis of 2,2′-(Aryl methylene)bis(4-hydroxycoumarin) (3da–dj)

Reaction conditions: 1 (0.5 mmol), 2d (1 mmol), and meglumine (10 mol %) in (1:1 v/v) aq ethanol (4 mL), ambient condition.

Isolated yield.

Reaction time.

Next, we attempted the formation of 1,1-dihomoarylmethane scaffolds by employing 1-phenyl-3-methyl-pyrazolone (2e) as a C–H activated acid. Pleasingly, pyrazolone also underwent a smooth reaction to form title derivatives (3ea–ed; Table ). Aldehydes equipped with aryl and aliphatic groups reacted smoothly to afford the final product with excellent yield in a very short time.

Table 6

Synthesis of 4,4′-(Aryl methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3ea–ed)

Reaction conditions: 1 (0.5 mmol), 2e (1 mmol), and meglumine (10 mol %) in (1:1 v/v) aq ethanol (4 mL), ambient condition.

Isolated yield.

Reaction time.

The scope of the present protocol was further investigated with acyclic C–H activated acidic compounds such as acetylacetone (2f) and ethyl acetoacetate (2g). But unfortunately, both the C–H activated acid recovered intact. So, it concluded that reaction is more suitable for cyclic C–H activated acid (Table ).

Table 7

Synthesis of 2,2′-(Aryl methylene)bis(acetyl acetone) and 2,2′-(Aryl methylene)bis(ethyl acetoacetate)

Reaction conditions: 1 (0.5 mmol), 2f/2g (1 mmol), and meglumine (10 mol %) in (1:1 v/v) aq ethanol (4 mL), ambient condition. NR = no reaction.

After careful observation of the above results, we inferred that rigid systems or comparatively lock systems are proved to be more reactive and transformations occur at a faster rate. i.e., 3a reacts faster than 3b, while 3d reacts faster than 3c under given sets of conditions.

All of the synthesized products were isolated in pure form by washing with water and without the need for any tedious purification process such as recrystallization or chromatographic techniques. The isolated products were characterized by Fourier transform infrared (FT-IR) spectroscopy, 1H NMR, 13C NMR, and mass spectrometry. All of the known compounds had physical and spectroscopic data identical to that of the literature values (Supporting Information, Figures S1–S112).

To measure the selectivity of this method, we carried out some competitive reactions for the preparation of 1,1-dihomoarylmethane scaffolds using aldehydes in the presence of ketones using 10 mol % meglumine as a catalyst in aqueous ethanol at room temperature. These reactions reiterate that the reaction selectively transformed aldehydes than ketones. Aldehydes condense with dimedone (2a) to afford the corresponding product (3a), while ketones were recovered intact (Table , entries 1–3).

Table 8

Effect of Catalyst on Substrate Selectivity

entry	R1	R2	time (min)	3 (% yield)	3′ (% yield)
1	C6H5	C6H5	14	93 (3aa)	0
2	4-NO2 C6H4	C6H5	7	85 (3ac)	0
3	4-NO2 C6H4	CH3	7	85 (3ac)	0

We also examined the feasibility of the present method for a somewhat scale-up (on the gram scale). Experiment with 4-nitrobenzaldehyde (1c; 10.7 mmol) and dimedone (2a; 21.4 mmol) using 10 mol % meglumine at room temperature in ethanol–water (1:1 v/v); the reaction was found to proceed smoothly affording the desired product (3ac) in 84% isolated yield within 9 min. This experiment demonstrated the efficiency of the catalyst for large-scale production as well (Scheme ).

Scheme 2

Gram-Scale Synthesis of 3ac

From the perspective of green chemistry, it is highly necessary and indispensable to investigate recyclability. So, to figure out the potential of whole reaction media, we conducted reusability experiments for model reactions. The miscibility of meglumine in reaction media makes the reusability approach easier (Figure ). The reaction media (residual solvent and catalyst) obtained after removal of product by filtration could be successfully reused for a particular entry up to four times without appreciable loss of catalytic performance. The addition of reactants directly into the reaction media without adding further catalysts resulted in the formation of the expected product without obvious change in the yield at least up to the fourth run. This experiment demonstrated the economical and ecological efficiency of the protocol for large-scale production (Figure ).

Figure 3

Recycle system for reusability of reaction media.

Figure 4

Reusability investigation of reaction media for the model reaction.

To further extend the efficiency of the reaction media for the transformation of other systems, we performed a couple of reactions in the following different ways (Table , entries 1 and 2).

Same C–H activated acid and different aldehyde

Different C–H activated acid and different aldehyde

The reaction of dimedone (2a) with 4-nitrobenzaldehyde (1c) in the presence of meglumine was monitored with 1H NMR at different time intervals (Figure ). After 1 min, a characteristic peak of the −CHO at 10.18 ppm was observed along with a peak at 5.56 ppm that corresponds to the methine proton of the product. Upon further continuation, steady augmentation of the peak at 5.56 ppm, along with the reduction of the peak at 10.18 ppm, indicated the gradual increase in the formation of product. After 7 min, the −CHO peak completely disappeared, indicating the completion of the reaction.

Figure 5

Time-dependent 1H NMR spectra.

The two possible mechanistic itineraries for activation of aldehyde by meglumine are depicted in Scheme . So, to get an insight into the mechanism and to check the more feasible pathway of reaction, we executed some control experiments (Figure ). To elucidate the role of amine in catalyst, we carried out a model reaction with Boc-protected meglumine. To our surprise, the rate of reaction was suppressed and only 69% yield was obtained after 2 h. These results revealed that amine plays an imperative role in the activation of aldehyde. We also screened glucose and fructose (catalyst with only hydroxyl groups) under similar reaction conditions, and relatively lower yields were observed even after prolonged stirring. Also, when we performed a reaction with l-proline (catalyst with amine and carboxylic −OH group), it took 1 h to furnish the desired product. All aforementioned experiments suggested that meglumine had a dual role. So, we inferred that the amine site is crucial to activate the aldehyde by the imine formation and hydroxyl groups are more likely to interact with C–H activated acid to increase its nucleophilicity via H-bond formation.

Scheme 3

Possible Mechanistic Routes for the Activation of Aldehyde by Meglumine Itinerary

Figure 6

Control experiments to get an insight into the mechanism.

To further verify the efficacy of water on the promotion of reaction, we performed experiments by selecting the model reaction in 10 mol % meglumine/(EtOH:D2O) and 10 mol % Boc-meglumine/(EtOH:D2O) (Figure ). As expected, a reduction in yield was observed in EtOH:D2O compared to that obtained in EtOH:H2O. From the above experiment, we inferred that water with ethanol interacts efficiently with substrates and enhances the reactivity of catalyst as well via hydrogen-bond formation. To prove our envision, we intend to apply NMR experiments to investigate the H-bond network of water (Supporting Information, Figure S114). 1H NMR pattern of meglumine and meglumine with D2O revealed that all acidic protons of meglumine were exchanged by deuterium. Thus, we surmised that in the presence of D2O, the hydrogen-bond network vanished and diminishes the catalytical efficiency of meglumine. So, the H-bond network is also played a vital role in the meglumine-promoted transformations in aq ethanol.

Based on the above observations upon monitoring the reaction sequence, we herein proposed a plausible mechanism for the meglumine-promoted one-pot synthesis of functionalized 1,1-dihomoarylmethane scaffolds from the pseudo-three-component reaction of C–H activated acid (2) and various aldehydes (1) in aq ethanol at room temperature (Scheme ). First, we assumed that the meglumine activates aldehyde by the formation of imine intermediate (intermediate-I). This imine intermediate (I) takes part in the Knoevenagel condensation with C–H activated acid (2), which was converted into (3), after the liberation of the catalyst. This intermediate is immediately captured by another molecule of C–H activated acid to give adduct (4), which in turn tautomerizes into the desired product (5). The liberated catalyst was reused for the next cycle and only a stoichiometric amount of water was eliminated in this transformation as a green waste.

Scheme 4

Plausible Reaction Mechanism

Finally, to explore the green chemistry aspects of the reaction, we calculated several green metrics for the reaction using a catalyst and without using a catalyst, i.e., effective mass yield (EMY), atom economy (AE), atom efficiency (AEf), carbon efficiency (CE), reaction mass efficiency (RME), optimum efficiency (OE), process mass intensity (PMI), mass intensity (MI), mass productivity (MP), E-factor, solvent intensity (SI), water intensity (WI), turnover number (TON), and turnover frequency (TOF) for all synthesized compounds (detailed calculations for all of the synthesized compounds are presented in Supporting Information Tables S1–S15). The radar plot represents some of the green parameters of the synthesized compounds 3aa–ak [(Figure ; with catalyst) and (Figure ; without catalyst)]. All green metrics credentials indicate an environmental friendliness of the process.

Figure 7

Radar chart of evaluated green metrics (with catalyst) for the synthesis of 2,2′-(aryl methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3aa–ak).

Figure 8

Radar chart of evaluated green metrics (without catalyst, considering reusability of reaction media) for the synthesis of 2,2′-(aryl methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3aa–ak).

Biological Evaluation

Antimicrobial Activities of Tested Compounds

In the literature, it has been well established that the 4-hydroxyl-6-methyl-2-pyrone-bearing moieties are promisingly biologically active, and encouraged by these results, we tested the antimicrobial properties of a few selective compounds which are described in the following section.

The growth inhibitory property of some compounds was tested against three pathogenic Gram-positive bacteria, namely, Staphylococcus aureus, Bacillus megaterium, and Bacillus subtilis as well as three Gram-negative bacteria, namely, Escherichia coli, Pseudomonas aeruginosa, and Salmonella enterica. The organisms were purchased from MTCC and maintained on nutrient agar media. The minimum inhibitory concentration (MIC) of selected compounds was tested using the broth dilution method. In which, 1.5 mL of Muller Hinton broth was taken in each test tube using tetracycline and dimethyl sulfoxide (DMSO) as positive and negative controls, respectively. MIC values were later determined against the bacterial and fungal members by making a sequential dilution such as 400, 200, and 100 μg/mL of the compounds.[54,55] Loopful test organisms were added with a sterile loop in the media containing organisms and drug, and then incubated at 37 °C overnight, and the absorbance was measured at 600 nm.

In vitro antifungal activity of compounds was tested against Aspergillus niger, Penicillium, and Saccharomyces cerevisiae. Fungi A. niger and Penicillium were cultured in sterile potato dextrose agar media, while S. cerevisiae was cultured in sterile yeast extract agar media.[54,55] The wells were bored using a sterile borer having a 10 mm diameter. After that, the wells were filled with 50 μL of solution in each Petri dish containing cultured organisms. Amphotericin-B and DMSO were used as positive and negative controls, respectively. The solution of compounds was diffused for 30 min, and the agar plates were incubated for 5 days at 25 ± 2 °C for antifungal studies. The antifungal activities were evaluated by observing the growth inhibition of organisms around each well using 400, 200, and 100 μg/mL as various concentrations. The entire process except the incubation was carried out in a laminar flow unit.

Compounds 3, 3, 3, and 3 showed the most prominent activity against Gram-negative bacteria E. coli and P. aeruginosa (Figure ). Residual compounds also inhibited all of these six bacterial strains, but their MIC values were comparatively higher. Most of the compounds showed less inhibition against Gram-negative bacteria S. enterica. Compounds 3 and 3 gave good inhibition toward all three fungal strains, while the remaining compounds showed less potency against all fungal strains (Figure ). In general, we concluded that compounds containing 4-hydroxyl-6-methyl-2-pyrone core displayed admirable antimicrobial activity, especially antibacterial profile.

Figure 9

Representative graph showing antibacterial activity of tested compounds using agar well diffusion method.

Figure 10

Representative graph showing antifungal activity of tested compounds using agar well diffusion method.

Antiproliferative Activities of Tested Compounds

Some selective compounds were also assessed for their antiproliferative profile against MCF-7 (human breast adenocarcinoma) and HEK-293 (kidney cancer cell line) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.[56,57] The growth inhibition of compounds at variable concentrations against MCF-7 has been carried out using bendamustine as the positive control (Figure ). Compounds 3, 3, 3, and 3 displayed prominent growth inhibition toward the MCF-7 cell line. After showing a good potency of the aforementioned compounds against the MCF-7 cell line, we further tested them on HEK-293 to confirm their potential (Figure ). All compounds demonstrated remarkable activity toward the HEK-293 cell line. Especially, 3, 3, 3, 3, and 3 expressed prominent potential against HEK-293. As evident, activities of the synthesized compounds were found to depend upon the nature of substituents on the phenyl ring. After analyzing the structures, we concluded that compounds bearing m-NO2, o-OH, p-OH, and p-F groups were more active against both the cell lines.

Figure 11

Representative graph showing percentage growth inhibition against MCF-7 at different concentrations for tested compounds. Bendamustine (100 μg/mL) was used as a positive control. aValues are the mean of two to three independent experiments.

Figure 12

Representative graph showing percentage growth inhibition against HEK-293 at different concentrations for tested compounds. Bendamustine (100 μg/mL) was used as a positive control. aValues are the mean of two to three independent experiments.

Conclusions

In conclusion, we have developed a simple, energy-efficient, and practical method for easy access to a wide range of 1,1-dihomoarylmethane scaffolds in the presence of meglumine as a green and eco-compatible organo-catalyst. The key advantages of the present protocol are mild reaction condition, good to excellent yields, operational simplicity, no cumbersome post treatment, clean reaction profile, energy efficiency, and high atom economy, as well as the use of an inexpensive and environmentally benign catalyst. Their antiproliferative and antimicrobial properties have been studied. The reusability of the reaction media and scale-up synthesis make the protocol sustainable and economical. Furthermore, acceleration of reaction by meglumine via its amine site can be clear from the Boc-protection studies. The facilitation of reaction by water was proved by D2O exchange studies. Moreover, this protocol shows better agreement with green chemistry metrics. So, we believe that this greener approach provides an alternative route to the existing processes.

Experimental Section

General Information

General Procedures

Commercially available starting materials were purchased from Sigma-Aldrich and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) carried out on silica plates (silica gel 60 F254, Merck) using UV light and iodine for visualization.

Instrumentation

1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 as a solvent on a Bruker AVANCE 400, INOVA Instruments with 400 and 500 MHz frequency spectrometers. The coupling constant (J) is given in hertz. Chemical shifts (δ) were reported in parts per million (ppm) relative to the residual solvent signal (CDCl3 δ = 7.26 for 1H NMR and δ = 77.0 for 13C NMR; DMSO-d6 δ = 2.54 for 1H NMR and δ = 39.52 ppm for 13C NMR). Signal patterns are indicated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded on a Bruker infrared spectrophotometer and are reported as cm–1. Melting points were determined by the open capillary tube method and are uncorrected.

General Procedure for the Synthesis of 1,1-Dihomoarylmethane Scaffolds (3)

An oven-dried round-bottom flask was charged with a magnetic stir bar, aldehyde (1; 0.5 mmol), C–H activated acid (2; 1 mmol) along with meglumine (10 mol % as organo-catalyst), and EtOH:H2O (1:1 v/v; 4 mL) in a sequential manner; the reaction mixture was then stirred at room temperature, and the stirring was continued for an appropriate range of time as indicated in respective tables in the text. The progress of the reaction was monitored by TLC. After completion of the reaction, 10 mL of water was added, and a solid mass precipitated out that was filtered off to obtain the product enough pure for spectral characterization without carrying out column chromatography or crystallization. The filtrate containing residual solvent, catalyst, and substrates obtained upon filtration of the reaction mixture after completion of the reaction could be successfully reused for a particular entry up to four times without appreciable loss of catalytic activity. The structure of each purified scaffold was confirmed by various analytical techniques including 1H NMR, 13C NMR, MS, and FT-IR.

General Procedure of Recycling 10 mol % Meglumine in Aqueous Ethanol Solution

After completion of the reaction, the product was separated by filtration, and the reaction media was directly reused for the next run. To the recycled 10 mol % meglumine solution, C–H activated acid (2) (1 equiv) and aldehyde (1) (0.5 equiv) were added and the reaction was stirred under ambient condition for a stipulated range of time.

Characterization Data of Some Representative Entries

2,2′-((4-Fluorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3aa)

White solid; Rf = 0.78 (30% EtOAc/70% hexane); mp = 180–183 °C (lit. mp = 185–186 °C);[58]1H NMR (CDCl3, 400 MHz): δ 11.9 (br s, 2H), 7.06 (t, J = 5.5 Hz, 2H), 6.96 (t, J = 8.5 Hz, 2H), 5.50 (s, 1H), 2.40 (m, 8H), 1.24 (s, 6H), 1.11 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 190.5, 189.4, 160.0, 133.6, 128.3, 115.5, 114.9, 47.0, 46.6, 32.2, 31.4, 27.4; MS (APCI) m/z: [M + H]+ calcd for C23H28FO4 386, found 387; IR Vmax = 2962, 2877, 1589, 1450, 1234, 1157, 1118, 833 cm–1.

2,2′-((2-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3ab)

White solid; Rf = 0.47 (30% EtOAc/70% hexane); mp = 186–188 °C (lit. mp = 181–183 °C);[58]1H NMR (CDCl3, 400 MHz): δ 11.61 (br s, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 6.05 (s, 1H), 2.39 (m, 8H), 1.16 (s, 6H), 1.03 (s, 6H); 13C NMR (CDCl3, 100 MHz): 190.8, 189.4, 149.7, 132.1, 131.3, 129.5, 127.1, 124.3, 114.6, 46.8, 46.3, 31.8, 29.7 28.1; MS (APCI) m/z: [M + H]+ calcd for C23H28NO6 413, found 414; IR Vmax = 3371, 3063, 2955, 1720, 1612, 1519, 1388, 1342, 1288, 1188, 1141, 848, 748 cm–1.

2,2′-((4-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3ac)

White solid; Rf = 0.57 (30% EtOAc/70% hexane); mp = 186–188 °C (lit. mp = 188–189 °C);[59]1H NMR (CDCl3, 400 MHz): δ 11.32 (br s, 2H), 8.14 (d, 2H), 7.27 (d, 2H), 5.56 (s, 1H), 2.42 (m, 8H), 1.25 (s, 6H), 1.31 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 190.9, 189.5, 146.5, 146.1, 127.6, 123.5, 114.9, 46.9, 46.4, 31.4, 29.5, 27.4; MS (APCI) m/z: [M + H]+ calcd for C23H28NO6 413, found 414; IR Vmax = 2870, 1797, 1581, 1512, 1458, 1373, 1249, 1157, 1118, 856 cm–1.

2,2′-((4-(Trifluoromethyl)phenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3ae)

White solid; Rf = 0.70 (30% EtOAc/70% hexane); mp = 150–153 °C; 1H NMR (CDCl3, 400 MHz): δ 11.82 (br s, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.50 (s, 1H), 2.37 (m, 8H), 1.20 (s, 6H), 1.08 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 190.7, 189.4, 142.5, 128.0, 127.1, 125.2, 123.1, 115.1, 47.0, 32.9, 31.4, 29.5, 27.3; MS (APCI) m/z: [M + H]+ calcd for C24H28F3O4 436, found 437.

2,2′-((2,5-Dimethoxyphenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3af)

Light yellow solid; Rf = 0.57 (30% EtOAc/70% hexane); mp = 178–181 °C; 1H NMR (CDCl3, 400 MHz): δ 11.85 (br s, 2H), 6.80 (s, 1H), 6.67 (s, 2H), 5.53 (s, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 1.08 (s, 12H); 13C NMR (CDCl3, 100 MHz): δ 189.1, 153.0, 151.4, 116.3, 115.8, 111.1, 110.7, 55.7, 55.5, 46.7, 32.8, 32.4, 31.2, 29.4; MS (APCI) m/z: [M + H]+ calcd for C25H33O6 428, found 429; IR Vmax = 3379, 3063, 2947, 2907, 1720, 1604, 1496, 1427, 1219, 1141, 1064, 895, 840, 794, 709, 663 cm–1.

2,2′-((3,4-Dimethoxyphenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3ag)

White solid; Rf = 0.54 (30% EtOAc/70% hexane); mp = 172–175 °C (lit. mp = 175–177 °C);[61]1H NMR (CDCl3, 400 MHz): δ 11.96 (br s, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.60 (d, 2H), 5.49 (s, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.36 (m, 8H), 1.23 (s, 6H), 1.21 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 204.8, 195.5, 148.7, 147.1, 134.1, 118.8, 115.7, 111.6, 54.4, 52.4, 47.1, 31.2, 29.8, 27.0; MS (APCI) m/z: [M + H]+ calcd for C25H33O6 428, found; IR Vmax = 2931, 1720, 1581, 1458, 1242, 1149, 1026, 871, 840, 763, 663 cm–1.

2,2′-Methylenebis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3aj)

White solid; Rf = 0.85 (30% EtOAc/70% hexane); mp = 191–193 °C (lit. mp = 191–193 °C);[60]1H NMR (CDCl3, 400 MHz): δ 11.50 (br s, 2H), 3.10 (s, 2H), 2.23 (s, 8H), 0.99 (s, 12H); 13C NMR (CDCl3, 100 MHz): δ 189.4, 113.4, 45.9, 31.7, 29.4, 27.0, 15.9; MS (APCI) m/z: [M + H]+ calcd for C17H25O4 292, found 293.

2,2′-(Butane-1,1-diyl)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) (3ak)

Shinning white solid; Rf = 0.90 (30% EtOAc/70% hexane); mp = 134–136 °C (lit. mp = 191–193 °C);[59]1H NMR (CDCl3, 400 MHz): δ 12.45 (br s, 2H), 3.90 (t, J = 8.0 Hz, 1H), 2.24 (m, 8H), 1.95 (q, J = 7.6 Hz, 2H), 1.16 (m, 2H), 1.02 (s, 12H), 0.83 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 189.9, 189.5, 116.5, 46.9, 46.1, 31.2, 29.8, 29.3, 26.5, 22.0, 13.8; MS (APCI) m/z: [M + H]+ calcd for C20H31O4 334, found 335.

2,2′-(Phenylmethylene)bis(3-hydroxycyclohex-2-en-1-one) (3ba)

White solid; Rf = 0.28 (30% EtOAc/70% hexane); mp = 206–208 °C (lit. mp = 206–208 °C);[60]1H NMR (CDCl3, 400 MHz): δ 12.37 (br s, 2H), 7.28 (t, J =, 2H), 7.19 (d, J =, 1H), 7.13 (t, J =, 2H); δ 13C NMR (CDCl3, 100 MHz): δ 192.6, 190.6, 131.6, 131.1, 129.6, 127.1, 124.1, 115.4, 33.3, 32.9, 30.4, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H20NO6 357, found 358; IR Vmax = 3379, 3070, 2962, 1712, 1612, 1419, 1157, 856, 740 cm–1

2,2′-((2-Nitrophenyl)methylene)bis(3-hydroxycyclohex-2-en-1-one) (3bb)

Off-white solid; Rf = 0.10 (30% EtOAc/70% hexane); mp = 209–211 °C; 1H NMR (CDCl3, 400 MHz): δ 12.22 (s, 2H), 7.50 (q, J =, 2H), 7.34 (d, J =, 1H), 7.26 (t, J =, 1H), 5.98 (s, 1H), 2.60 (q, 4H), 2.38 (m, 4H), 1.99 (t, 4H); 13C NMR (CDCl3, 100 MHz): δ 192.6, 190.6, 131.6, 131.1, 129.6, 127.1, 124.1, 115.4, 33.3, 32.9, 30.4, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H20NO6 357, found 358; IR Vmax = 3379, 3070, 2962, 1712, 1612, 1419, 1157, 856, 740 cm–1.

2,2′-((3-Nitrophenyl)methylene)bis(3-hydroxycyclohex-2-en-1-one) (3bc)

White solid; Rf = 0.11 (30% EtOAc/70% hexane); mp = 206–207 °C (lit. mp = 205–207 °C);[59]1H NMR (CDCl3, 400 MHz): δ 12.32 (s, 2H), 8.05 (q, J =, 1H), 7.45 (d, J =, 1H), 7.28 (s, 2H), 5.50 (s, 1H), 2.67 (q, 4H), 2.45 (m, 4H), 2.10 (t, 4H); 13C NMR (CDCl3, 100 MHz): δ 192.6, 190.6, 131.6, 131.1, 129.6, 127.1, 124.1, 115.4, 33.3, 32.9, 30.4, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H20NO6 357, found 358; IR Vmax = 3379, 3070, 2962, 1712, 1612, 1419, 1157, 856, 740 cm–1

2,2′-Methylenebis(3-hydroxycyclohex-2-en-1-one) (3bg)

Shinning white solid; Rf = 0.80 (30% EtOAc/70% hexane); mp = 135–138 °C; 1H NMR (CDCl3, 400 MHz): δ 11.89 (s, 2H), 3.06 (s, 2H), 2.29 (s, 4H), 2.40 (s, 4H), 1.85 (s, 4H); 13C NMR (CDCl3, 100 MHz): δ 190.9, 114.6, 36.4, 32.2, 20.3, 16.4; MS (APCI) m/z: [M + H]+ calcd for C13H17O6 236, found 237.

2,2′-(Butane-1,1-diyl)bis(3-hydroxycyclohex-2-en-1-one) (3bh)

White solid; Rf = 0.73 (30% EtOAc/70% hexane); mp = 96–99 °C; 1H NMR (CDCl3, 400 MHz): δ 12.83 (s, 2H), 3.81 (t, 1H), 2.44 (s, 4H), 2.25 (m, 4H), 1.88 (m, 4H), 1.77 (m, 2H), 1.11 (q, 2H), 0.81 (t, 3H); 13C NMR (CDCl3, 100 MHz): δ 191.5, 190.9, 117.7, 32.7, 31.3, 29.8, 29.7, 21.9, 19.9, 13.8; MS (APCI) m/z: [M + H]+ calcd for C16H23O4 278, found 279.

3,3′-(Phenylmethylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3ca)

White solid; Rf = 0.35 (pure EtOAc); mp = 214–217 °C (lit. mp = 210–215 °C);[32−48]1H NMR (CDCl3, 400 MHz): δ 10.91 (br s, 2H), 7.29 (t, J = 7.72 Hz, 2H), 7.21 (d, 7.2 Hz, 1H), 7.14 (d, 8.0 Hz, 2H), 6.04 (d, 2H), 5.73 (s, 1H), 2.27 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 135.3, 128.5, 126.7, 126.4, 103.5, 102.8, 34.7, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H17O6 340, found 341.

3,3′-((2-Nitrophenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3cb)

White solid; Rf = 0.30 (pure EtOAc); mp = 228–231 °C (lit. mp = 224–226 °C);[59]1H NMR (DMSO, 400 MHz): δ 11.72 (br s, 2H), 7.07–7.00 (m, 4H), 6.07 (s, 2H), 5.88 (s, 1H), 2.19 (s, 6H); MS (APCI) m/z: [M + H]+ calcd for C19H16NO8 385, found 386.

3,3′-((3-Nitrophenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3cc)

White solid; Rf = 0.30 (pure EtOAc); mp = 203–206 °C (lit. mp = 202–204 °C);[32]1H NMR (CDCl3, 400 MHz): δ 11.05 (br s, 2H), 8.06 (d, J = 6 Hz, 1H), 7.96 (s, 1H), 7.45 (m, 2H), 6.08 (s, 2H), 5.81 (s, 1H), 2.27 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 169.3, 162.2, 148.6, 138.4, 132.7, 129.4, 121.9, 121.7, 103.3, 34.6, 29.6, 19.7, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H16NO8 385, found 386.

3,3′-((4-Nitrophenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3cd)

Off-white solid; Rf = 0.27 (pure EtOAc); mp = 239–241 °C (lit. mp = 234–236 °C);[32]1H NMR (CDCl3, 400 MHz): δ 10.96 (br s, 2H), 8.14 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.0, 2H), 6.09 (d, 2H), 5.76 (s, 1H), 2.29 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 170.5, 162.6, 162.0, 146.7, 143.6, 127.5, 123.7, 103.6, 103.0, 35.1, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H16NO8 385, found 386.

3,3′-((4-Flourophenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3ce)

White solid; Rf = 0.36 (pure EtOAc); mp = 224–227 °C (lit. mp = 219–221 °C);[32]1H NMR (CDCl3, 400 MHz): δ 10.93 (br s, 2H), 7.10 (t, 2H), 6.98 (t, 2H), 6.05 (s, 2H), 5.70 (s, 1H), 2.28 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 170.2, 162.9, 161.5, 160.4, 143.3, 131.0, 128.2, 103.6, 102.9, 34.3, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H16FO6 358, found; IR Vmax = 3117, 1635, 1450, 1280, 1219, 1095, 1049, 871, 840 cm–1.

3,3′-((4-Hydroxyphenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3cg)

Pale orange solid; Rf = 0.41 (pure EtOAc); mp = 154–157 °C (lit. mp = 202 °C);[32]1H NMR (CDCl3, 400 MHz): δ 10.80 (br s, 2H), 6.96 (d, 2H), 6.71 (d, 2H), 6.03 (s, 1H), 5.66 (s, 1H), 2.25 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 169.4, 161.7, 154.6, 127.7, 126.9, 115.5, 103.3, 91.5, 34.1, 19.7; MS (APCI) m/z: [M + H]+ calcd for C19H17NO7 356, found; IR Vmax = 3618, 1620, 1450, 1280, 1234, 1172, 1057, 871, 833 cm–1.

3,3′-((4-Methoxyphenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3ch)

White solid; Rf = 0.41 (pure EtOAc); mp = 176–179 °C (lit. mp = 173–175 °C);[32]1H NMR (CDCl3, 400 MHz): δ 10.88 (br s, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.03 (s, 2H), 5.67 (s, 1H), 3.76 (s, 3H), 2.26 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 158.2, 127.5, 127.1, 113.8, 103.5, 102.8, 55.2, 34.1, 19.7; MS (APCI) m/z: [M + H]+ calcd for C20H19O7 370, found 371.

3,3′-((4-Hydroxy-3-methoxyphenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3ci)

Off-white solid; Rf = 0.22 (pure EtOAc); mp = 208–210 °C; 1H NMR (CDCl3, 400 MHz): δ 10.89 (br s, 2H), 6.81 (d, J = 8.30 Hz, 1H), 6.61 (t, J = 8.38 Hz, 2H), 6.02 (s, 2H), 5.69 (s, 1H), 3.76 (s, 3H), 2.25 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 161.5, 146.6, 144.4, 127.0, 119.4, 114.3, 109.4, 103.1, 56.0, 56.0, 34.4, 19.6; MS (APCI) m/z: [M + H]+ calcd for C20H19O8 386, found 387; IR Vmax = 3117, 2839, 1681, 1450, 1242, 1203, 1126, 1049, 817, 794, 740, 648 cm–1.

3,3′-((3,4-Dimethoxyphenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3cj)

White solid; Rf = 0.22 (pure EtOAc); mp = 136–139 °C; 1H NMR (CDCl3, 500 MHz): δ 10.91 (br s, 2H), 6.75 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.61 (s, 1H), 6.02 (s, 2H), 5.70 (s, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 2.24 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 169.4, 169.1, 161.6, 148.9, 147.8, 127.8, 118.8, 111.1, 110.4, 110.3, 103.1, 56.0, 34.2, 19.6; MS (APCI) m/z: [M + H]+ calcd for C21H21O8 400, found 401; IR Vmax = 3201, 3070, 1627, 1450, 1257, 1149, 1026, 817, 771, 709, 648 cm–1.

3,3′-((2,5-Dimethoxyphenyl)methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3ck)

White solid; Rf = 0.24 (pure EtOAc); mp = 185–188 °C; 1H NMR (CDCl3, 500 MHz): δ 10.72 (br s, 2H), 6.78 (s, 1H), 6.71 (s, 2H), 6.01 (s, 1H), 5.76 (s, 1H), 3.71 (s, 1H), 3.57 (s, 1H), 2.22 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 169.2, 168.5, 160.8, 153.3, 151.7, 125.7, 115.8, 111.7, 111.3, 104.1, 103.0, 56.1, 55.6, 31.8, 19.5; MS (APCI) m/z: [M + H]+ calcd for C21H21O8 400, found 401; IR Vmax = 3610, 3101, 2955, 2831, 1674, 1450, 1288, 1165, 1057, 1026, 833, 748, 686 cm–1.

3,3′-Methylenebis(4-hydroxy-6-methyl-2H-pyran-2-one) (3cl)

White solid; Rf = 0.41 (pure EtOAc); mp = 254–257 °C; 1H NMR (CDCl3, 400 MHz): δ 10.72 (s, 2H), 5.99 (s, 2H), 3.49 (s, 2H), 2.21 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 170.0, 168.6, 161.3, 102.7, 101.6, 19.8, 18.5; MS (APCI) m/z: [M + H]+ calcd for C13H13O6 264, found.

3,3′-(Butane-1,1-diyl)bis(4-hydroxy-6-methyl-2H-pyran-2-one) (3cm)

White solid; Rf = 0.56 (pure EtOAc); mp = 156–159 °C; 1H NMR (CDCl3, 400 MHz): δ 11.04 (br s, 2H), 5.97 (d, 2H), 4.15 (d, 1H), 2.15–2.21 (m, 8H), 1.25 (m, 2H), 0.88 (d, 3H); 13C NMR (CDCl3, 100 MHz): δ 170.5, 161.4, 160.6, 103.6, 102.8, 31.2, 30.0, 21.8, 19.6, 13.8; MS (APCI) m/z: [M + H]+ calcd for C16H19O6 306, found.

3,3′-((4-Hydroxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3da)

Pale pink solid; Rf = 0.47 (pure EtOAc); mp = 190–193 °C (lit. mp = 222–224 °C);[58]1H NMR (CDCl3, 400 MHz): δ 11.44 (br s, 2H), 7.99 (d, 2H), 7.59 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 8.0 Hz, 4H), 7.02 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.0 (s, 1H), 5.60 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 165.8, 154.6, 152.4, 132.8, 127.7, 126.7, 124.9, 124.3, 116.6, 115.6, 35.4; MS (APCI) m/z: [M + H]+ calcd for C25H17O7 428, found 429; IR Vmax = 3664, 3078, 1820, 1620, 1450, 1219, 1095, 833 cm–1.

3,3′-((3,4-Dimethoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3dc)

Off-white solid; Rf = 0.36 (pure EtOAc); mp = 266–268 °C; 1H NMR (CDCl3, 400 MHz): δ 11.49 (br s, 2H), 8.01 (d, 2H), 7.60 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 8.0 Hz, 4H), 6.78 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.68 (s, 1H), 3.84 (s, 3H), 3.70 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 166.8, 165.6, 164.6, 152.5, 149.1, 148.0, 132.8, 127.5, 124.9, 124.3, 118.9, 116.6, 111.2, 110.3, 104.1, 56.12, 55.9, 35.7; MS (APCI) m/z: [M + H]+ calcd for C27H21O8 472, found; IR Vmax = 3078, 1828, 1612, 1450, 1219, 1141, 1057, 864, 802, 763, 671 cm–1.

3,3′-((2,5-Dimethoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3dd)

Off-white solid; Rf = 0.43 (pure EtOAc); mp = 198–201 °C; 1H NMR (CDCl3, 400 MHz): δ 11.24 (br s, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 2H), 7.33 (q, J = 8.0 Hz, 4H), 6.86 (s, 1H), 6.74 (s, 2H), 6.05 (s, 1H), 3.70 (s, 3H), 3.49 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 168.1, 163.8, 153.4, 152.1, 151.8, 132.4, 125.0, 124.7, 124.2, 116.7, 116.4, 115.9, 111.8, 111.5, 56.1, 55.6, 33.5; MS (APCI) m/z: [M + H]+ calcd for C27H21O8 472, found 473; IR Vmax = 3063, 1620, 1496, 1226, 1180, 1095, 1033, 871, 771, 671 cm–1.

3,3′-((4-Methoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3de)

White solid; Rf = 0.55 (pure EtOAc); mp = 226–229 °C (lit. mp = 228–230 °C);[59]1H NMR (CDCl3, 400 MHz): δ 11.31-11.53 (d, 2H), 8.01–8.11 (m, 2H), 7.62–7.67 (t, J = 7.5 Hz, 2H), 7.42–7.44 (d, J = 8.0 Hz, 4H), 7.14–7.16 (d, J = 8.0 Hz, 2H), 6.86–6.89 (d, J = 8.5 Hz, 2H), 6.07 (s, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 169.2, 166.8, 165.6, 164.5, 158.4, 152.5, 152.2, 132.8, 127.6, 126.9, 124.8, 124.3, 116.6, 114.0, 105.7, 104.2, 55.2, 35.5; MS (APCI) m/z: [M + H]+ calcd for C26H19O7 442, found; IR Vmax = 3634, 3078, 3009, 1828, 1612, 1450, 1257, 1041, 833 cm–1.

3,3′-(Phenylmethylene)bis(4-hydroxy-2H-chromen-2-one) (3df)

White solid; Rf = 0.54 (pure EtOAc); mp = 198–201 °C (lit. mp = 230–232 °C);[59]1H NMR (CDCl3, 400 MHz): δ 11.32-11.55 (d, 2H), 8.02–8.11 (d, 2H), 7.36–7.67 (t, 2H), 7.24–7.45 (m, 9H), 6.13 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 169.3, 166.8, 165.8, 164.6, 152.5, 152.3, 135.2, 132.8, 128.6, 126.8, 126.4, 124.9, 124.4, 116.9, 116.6, 116.4, 105.6, 103.9, 36.1; MS (APCI) m/z: [M + H]+ calcd for C25H17O6 412, found 413; IR Vmax = 3664, 3070, 1805, 1612, 1496, 1188, 1095, 864, 648 cm–1.

3,3′-((4-Nitrophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3dg)

White solid; Rf = 0.6 (pure EtOAc); mp = 233–236 °C (lit. mp = 242–244 °C);[59]1H NMR (CDCl3, 400 MHz): δ 11.40-11.59 (d, 2H), 8.20–8.23 (d, 2H), 8.11–8.13 (d, 1H), 8.02–8.04 (d, 1H), 7.67–7.71 (t, 2H), 7.42–7.48 (m, 6H), 6.14 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 169.1, 167.0, 166.4, 164.8, 152.5, 152.3, 146.9, 143.3, 133.3, 127.5, 125.2, 125.1, 124.5, 124.4, 123.8, 116.8, 116.7, 116.6, 116.2, 104.7, 103.2, 36.5; MS (APCI) m/z: [M + H]+ calcd for C25H16O8 457, found 458; IR Vmax = 3078, 1658, 1612, 1566, 1450, 1342, 1265, 856, 763 cm–1.

4,4′-(Phenylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3ea)

Pale pink solid; Rf = 0.85 (pure EtOAc); mp = 169–171 °C (lit. mp = 170–172 °C);[49,50]1H NMR (CDCl3, 400 MHz): 7.52 (d, J = 7.62 Hz, 4H), 7.15–7.24 (m, 9H), 7.07–7.10 (t, 2H), 4.75 (s, 1H), 2.06 (s, 6H); 13C NMR (CDCl3, 100 MHz): 157.6, 146.4, 140.8, 136.9, 133.6, 128.3, 127.1, 126.3, 126.1, 121.3, 105.6, 33.6, 11.5.

4,4′-((4-Nitrophenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3eb)

Pale yellow solid; Rf = 0.77 (pure EtOAc); mp = 229–230 °C (lit. mp = 228–230 °C);[49]1H NMR (CDCl3, 400 MHz): 8.15 (d, J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 4H), 7.39–7.47 (m, 7H), 7.23–7.26 (t, J = 7 Hz, 2H), 4.99 (s, 1H), 2.36 (s, 6H).

4,4′-((4-Methoxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3ec)

Orange solid; Rf = 0.82 (pure EtOAc); mp = 181–182 °C (lit. mp = 180 °C)62; 1H NMR (CDCl3, 400 MHz): 7.54 (d, J = 7.58 Hz, 4H), 7.23–7.28 (t, J = 7.88 Hz, 4H), 7.07–7.11 (d, 4H), 6.78 (d, J = 8.88 Hz 2H), 4.71 (s, 1H), 3.74 (s, 3H), 2.07 (s, 6H); 13C NMR (CDCl3, 100 MHz): 158.0, 146.4, 137.0, 132.8, 128.8, 128.1, 126.1, 121.3, 118.9, 113.7, 55.2, 32.9, 11,5.

4,4′-(Butane-1,1-diyl)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3ed)

Off-white solid; Rf = 0.88 (pure EtOAc); mp = 114–115 °C; 1H NMR (CDCl3, 400 MHz): 13.33 (s, 2H), 7.55 (d, J = 8.07 Hz, 4H), 7.24–7.27 (t, J = 7.84 Hz, 4H), 7.06–7.09 (t, J = 7.46 Hz, 2H), 3.23–3.26 (t, 1H), 1.95 (s, 8H), 1.15–1.19 (q, 2H), 0.88 (t, 3H); 13C NMR (CDCl3, 100 MHz): 157.7, 145.9, 137.0, 128.8, 126.0, 121.3, 106.7, 33.6, 21.3, 13.7, 11.4.