Uncatalysed Production of Coumarin-3-carboxylic Acids : A Green Approach

1Departamento de Ciencias Quı́micas, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, 54740 Cuautitlán Izcalli, MEX, Mexico 2Facultad de Ciencias Quı́micas, Posgrado en Ciencias en Ingenieŕıa Quı́mica, Universidad Autónoma de San Luis Potośı, 78210 San Luis Potośı, SLP, Mexico 3Instituto de Quı́mica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 Ciudad de México, Mexico 4Laboratorio de Espectrometŕıa de Masas, Centro de Quı́mica ICUAP, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, PUE, Mexico 5Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Casco de Santo Tomas, 11340 Ciudad de México, Mexico

On the other hand 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) has attracted considerable attention due to its high acidity and rigid cyclic structure [14].This versatile molecule is an important substrate for many interesting organic transformations such as the preparation of pyridones [15], pyrimidines, and azoloazines in tandem reactions [16] and the synthesis of natural products [17] and, of particular interest for this work, as a condensation partner to generate coumarins [18][19][20][21].
Owing to the value of these molecules, a search for new and more convenient methods of preparation is desirable, mainly if the novel offered procedure diminished pollution; in other words, with proper green approach, the adoption of novel cleaner methods must be an urgent priority.Some efforts, with occurrence in the Green Chemistry Protocol, have been explored to prepare coumarins derivatives, many of them using green approaches, for example, zeolites [23], clays [22], cation exchange resins [24], solventless [25] and solidphase [26] conditions, reflux in water [18], microwave irradiation [19], oxidative cyclocarbonylation [27], using mixtures of PEG400/H 2 O or PEG400/EtOH as solvents [28], ultrasound [29], and room temperature [30].However, many of these procedures involve long time reactions and the presence of a solvent or catalyst or both.
As a part of our ongoing research program, we are very interested in the development of green procedures for the production of different heterocycles with interesting pharmacological properties.Consequently, the goal of the present work was to create a green approach [31] for the production of several coumarins using Meldrum's acid as a reagent, offering an insightful study by comparison of five different modes to activate the reaction: microwave (MW) and near-infrared (NIR) irradiations, ultrasound (US), and mechanical milling (MM) versus the typical mantle heating (MH).Some of experiments were carried out in ethanol, a green solvent, according to the TRI-EPA [32].It is also worth noting that a careful search of the literature revealed that this is the first report wherein near-infrared irradiation [33] and mechanical milling or tribochemistry [34] have been employed to carry out reaction successfully.In general, in this work an acute procedure for the green synthesis of various coumarin-3-carboxylic acids in moderate yields and in short reaction times is provided.

Materials and Methods
General.Starting materials salicylaldehyde (1a), 2-hydroxy-5methylbenzaldehyde (1b), 2-hydroxy-3-methylbenzaldehyde (1c), 2-hydroxy-4-methoxybenzaldehyde (1d), 2-hydroxy-1naphthaldehyde (1e), and solvents were purchased from Sigma Aldrich Chemical and used without further purification.Meldrum's acid was prepared according to a literature procedure [35]. 1 H and 13 C NMR (DMSO- 6 ) spectra were recorded using a Varian Mercury-300 spectrometer at 300 MHz and 75 MHz for hydrogen and carbon, respectively.The multiplicities are reported as singlet (s), doublet (d), triplet (t), doublet of doublet (dd), and triplet doublet (td).The EIMS (70 eV) were determined using a JEOL JMS-700 MStation mass spectrometer.The HRMS-DART + data were obtained using a JEOL AccuTOF (Direct Analysis in Real Time) mass spectrometer.The measurements were performed using a DART experiment with PEG (polyethylene glycol) 400 as internal reference at 6000 resolutions and triplet helium as carrier gas at 350 ∘ C. In the first orifice, the temperature and voltage were 120 ∘ C and 15 V, respectively, and the voltage in the second orifice was 5 V. Elemental composition was calculated within a mass range of ±10 ppm from the measured mass.Melting points were determined using a Fisher-Johns apparatus and are uncorrected.Microwave-assisted synthesis of the target compounds was performed using a CEM Focused Microwave6 Synthesis System.Near-infrared irradiation was generated using a commercial "Flavor-Wave5" (1300 W/110 V/120 V-60 Hz|220 V/240 V-60 Hz) device [33].Ultrasound-assisted synthesis was performed using a Transonic 460/H Elma ultrasound bath (35 kHz).Mechanical milling was conducted using a Ball Mill PM 100 Retch, using25 carbon steel balls (weight 11,050 mg, 3/16  diameter).It was not possible to determine temperature and pressure in this device.In the NIR and ultrasound experiments, the temperature was measured using an infrared thermometer (Infrared + Type K Thermometer, Extech Instruments, Sigma Aldrich 2509388-1 EA) with the laser pointer directed to the center of reaction.The progress of the reactions was monitored by TLC using silica gel 60-F 254 coated aluminum sheets (n-hexane-ethyl acetate 6 : 4) visualized using a UV light at 254 nm.

Method A (with Solvent).
A mixture of aldehyde 1a (120 mg, 0.9833 mmol), 1b (140 mg, 1.0290 mmol), 1c (140 mg, 1.0290 mmol), 1d (140 mg, 0.9865 mmol) or 1e (140 mg, 0.9881 mmol), Meldrum's acid 2 (150 mg, 1.0408 mmol), and EtOH (5 mL for US and NIR, 2 mL for MW and 0.5 mL for MM) was placed in an appropriate Erlenmeyer flask, bottom flask, or steel container.The mixtures were treated using different activation modes: near-infrared irradiation for 20 min at 70 ∘ C with vigorous magnetic stirring, placing the magnetic agitator under Flavor-Wave, microwave irradiation for 1 min at 70 ∘ C (run time), and then 5 min at 70 ∘ C (hold time) with medium level stirring and 100 W power; ultrasound bath for 30 min at 70 ∘ C; mechanical milling for 25 min with 400 rpm and 27% power.All reactions were conducted in open vessels and monitored by TLC (silica gel, n-hexaneethyl acetate 6 : 4).After cooling, ice-water was added to the flask to precipitate the product, and the solid collected to give the corresponding pure coumarin-3-carboxylic acid.

Results and Discussion
3.1.Synthesis.In order to minimize the energy requirements of a given process, various attempts were made to make the energy input as efficient as possible for the production of the 3-carboxycoumarins (3a-e).Five salicylaldehydes (1a-e) were treated with Meldrum's acid (2) under four nonconventional activating methods (MW, NIR, US, and MM) and with mantle heating (MH) under solventless conditions or in ethanol without a catalyst (Scheme 1).In general, these onepot processes occur via a typical Knoevenagel condensation according to the literature [17].The results are summarized in Table 1.
The performance of US-assistance may be due to ultrasonic acceleration effects on the liquid system, explained by cavitation-collapse promoting low-energy chemical reactions [29].With regard to the low yields for MM, it is known that various tribophysical phenomena exist [37]: it is possible that the formation of electrons and positive ions to produce the required plasma was not generated in an appropriate quantity, reducing the production of triboplasma, leading to poor lubrication of the tribosystem and consequently affording low yields.The yields obtained with NIR and MW were similar due to the fact that both must be directly absorbed by the solvent and the reagents, resulting in a rapid temperature rise in the system and consequently increasing reactivity [38].
All of these methods fit appropriately with the sixth principle of the Green Chemistry Protocol, that is, decreasing energy consumption.The solvent, ethanol, has a high tan  value (0.941), a measure of its ability to convert electromagnetic energy into heat [39], also favoring efficient energy absorption.It is also important to take into account that it is a green solvent because of its low toxicity and good degradability [31,32,40] in accordance with the fifth principle of the green protocol; moreover, the use of ethanol instead of pyridine or piperidine as solvent supports the third and twelfth green chemistry principles.The use of sodium azide, lithium bromide, ammonium acetate, potassium carbonate, palladium, and other catalyst, several of which considered as toxic by TRI-EPA, was avoided in agreement with the third and twelfth green chemistry principles.The byproducts generated are water, green molecule, and ketone, all classified as nontoxic (TRI-EPA), favoring the first and third principles.
In addition, the atom economy is in the order of 71.43%, a value considered as a good approach to the second principle.Consequently, the best processes were developed employing EtOH as solvent, offering higher yields in comparison with solventless conditions.From these strategies, the MW and NIR irradiations are the best alternatives because they offer, in general, the same yields, but the microwaves' use in obtaining the title molecules is well known; however, NIR irradiation is offered as clean energy source to activate reactions, being easily controllable and with the quality of a fast responding heat source [33].
The structural identification of products 3a-e was made on the basis of their corresponding spectral data.The compounds 3a, 3b, 3d, and 3e were consistent with authentic ones in literature [21,22].Since compound 3c is a novel molecule, the corresponding spectroscopic data is discussed.

Spectroscopic Attribution.
The 1 H NMR exhibited the expected singlet for the allylic proton (H4) at  8.68; also two double signals were assigned at  7.69 (J = 7.95 Hz) and at 7.56 (J = 7.05 Hz) to H5 and H7, respectively; a triplet at  7.26 (J = 7.65 Hz) was assigned to H6; finally, the hydrogens of the methyl group (H9) were unequivocally assigned to a singlet at  2.34; the proton of CO 2 H was not observable, probably because the concentration of nuclei which produce the signal was poor or because of fast dissociation [36]; in addition, the exchange with the deuterated solvent or water from solvent itself can occur.The 13 C NMR spectrum contained four signals at  164.1, 156.8, 148.7, and 125.1, which were appropriately assigned to CO 2 H, C2 (C=O), C4, and C8, respectively; the patterns for aryl and methyl groups were also observed in the experimental data, and these signals were corroborated by a HMBC experiment (three bonds distance): H4 correlated with C8a at  152.8, with C5 at  127.9, with C2 (C=O) at  156.8, and with CO 2 H at  164.1.
The hydrogen of the methyl group correlated with C7 at  135.3, and H5 correlated with C8a at  152.

Conclusions
In conclusion, coumarin-3-carboxylic acids 3a-e have been prepared using a one-pot procedure, where the best synthetic strategy was obtained in solution conditions.Different activating energy sources were employed, providing several environmental benefits: less energy consumption, product isolation by simple filtration, and use of ethanol as a green solvent, without catalyst and very good atom economy.In other words, the overall process occurs with a good incidence in the Green Chemistry Protocol (the twelve principles).The NIR irradiation is proposed as a new alternative and as a clean energy to produce this kind of molecules.

Table 1 :
Formation of coumarins using five activating modes.