Salicylic Acid-catalyzed Three-component Synthesis of 1-Amido/thioamidoalkyl-2-naphthols Under Solvent-free Conditions

A simple, efficient, and green procedure for the solvent-free synthesis of 1-amido/thioamidoalkyl-2-naphthols by one-pot stirring of starting reactants at 100 °C has been introduced. By utilizing salicylic acid (SA) as the catalyst, the reaction of aryl aldehydes, 2-naphthol, and acetamide/benzamide/urea/thiourea were successfully performed, and 1-amido/thioamidoalkyl-2-naphthols were obtained in good to high isolated yields. The notable advantages of this method over some previous methods are the availability of catalyst, atom efficiency, not using any solvent for reaction, relatively green conditions, no need for catalyst synthesis, relatively shorter reaction times, and no specialized equipment (microwave or ultrasound) or purification techniques are needed.


Introduction
The multi-component reactions (MCRs) have been recognized as a class of chemical transformations, which are useable for the construction of various synthetically useful heterocyclic compounds, natural products, complex libraries of biological molecules, and other organic molecules such as 1amido/thioamidoalkyl-2-naphthols and different functionalized organic compounds in atomeconomical ways by generating multiple bonds in a single step.MCRs can reduce the number of steps and present advantages including, low energy consumption, simplicity, ease of processing for isolation and purification, high efficiency, the lower making of chemical byproducts, little to no waste production, bondforming economy, and leading to desired environmentally friendly processes [1][2][3][4][5][6][7].MCRs under solvent-free reaction conditions (SFRCs) are also interesting since they involve the best reaction medium with "no medium" [8].
Salicylic acid (2-hydroxybenzoic acid) is a plant phenolic acid, which found in willow bark, willow leaves, poplar tree and has been used as an analgesic 400 B.C. Salicylic acid (SA) shows anti-bacterial, antifungal, antipyretic, and antiinflammatory properties and also participates in many important activities in plants, including flowering, seed germination, heat production, membrane permeability, defense responses, and response to stress.This natural organoacid is employed as a precursor to the synthesis of aspirin ® .Moreover, SA and its derivatives exist in skin-care products and are used for the treatment of acne [37][38][39][40][41][42][43][44][45][46].

Results and Discussion
Initial experiments were performed using 3nitrobenzaldehyde (1 mmol), benzamide (2a, 1 mmol), and 2-naphthol (3, 1 mmol) as the model reaction.The results are summarized in Table 1.It is disappointing that the reaction gave no desired product (4c) in the absence of a catalyst at refluxing water after 120 min (Table1, entry 1).When the reaction was performed in the presence of SA (5 mol%) at refluxing water, the corresponding product (4c) was obtained in 25% isolated yield (Table 1, entry 2).No better yield was achieved when the reaction was carried out in water in the presence of various amounts of catalyst (Table 1, entries 3 and 4).Implementation of the reaction in other solvents such as ethanol, acetonitrile, and dichloromethane did not achieve good results (Table 1, entries 5-7).The reaction was performed in solvent-free conditions (SFRCs) at 100 °C without any catalyst, and the desired product 4c was observed in minor amounts as well as even after prolonged reaction time a significant amount of starting materials was intact (Table 1, entry 8).When the 5 mol% SA catalyst was added to the reaction mixture at 100 °C under SFRC, the product was obtained with 83% isolated yield after 50 min ( Reaction conditions: the reaction was performed using a mixture of 3-nitrobenzaldehyde (1 mmol), benzamide (2a, 1 mmol), 2-naphthol (3, 1 mmol), and catalyst (x mol%) under SFRCs or solution state.b Solvent free.c Optimized conditions.
In the direction of search the scope of this 3-CR, some substituted benzaldehydes reacted with amides (benzamide, urea, acetamide)/thiourea (2a-d) and 2-naphthol (3) under the optimized reaction conditions, and the results are shown in Table 2.All the corresponding 1-amido/thioamidoalkyl-2naphthols (4a-v) were synthesized in good to excellent isolated yields without any special purification methods, although in some cases the reactions proceeded rather slowly.
The possible reaction mechanism for the formation of 1-amido/thioamidoalkyl-2-naphthols (4a-v) is presented in Scheme 2. Probably the reaction starts through the activation of substituted benzaldehydes by the SA catalyst.In the second step, the ortho-quinone methides (o-QMs) were formed via the reaction of activated aldehydes and 2-naphthol.The Michael addition of compounds 2 into the o-QMs intermediates, and then elimination of water leads to the creation of desired products (4a-v).

Material and Methods
All chemicals were purchased from Alfa Aesar and Aldrich as well as were used without further purification, except 4-methylbenzaldehyde, 4methoxylbenzaldehyde, and benzaldehyde which were distilled before use.All solvents were distilled before use.The products were characterized by comparison of their physical data with those of known samples or by their spectral data.Melting points were measured on a Buchi 510 melting point apparatus.NMR spectra were recorded at ambient temperature on a BRUKER AVANCE DRX-400 MHz using DMSO-d6 as the solvent.FT-IR spectra were recorded on a Perkin-Elmer RXI spectrometer.The development of reactions was monitored by thin layer chromatography (TLC) analysis on Merck pre-coated silica gel 60 F254 aluminum sheets, visualized by UV light.Elemental microanalyses were performed on an Elementar Vario EL III analyzer.All of the targeted products are reported in the literature, and they are shown to be identical with the authentic samples prepared according to our previous works [58,59].
General procedure for the synthesis of 1amido/thioamidoalkyl-2-naphthols (4a-v): A mixture of substituted aldehyde 1 (1 mmol), 2a-d (benzamide, 2a; urea, 2b; acetamide, 2c; thiourea, 2d) or 2-naphthol 3 (1 mmol), and salicylic acid (15 mol%) was stirred at 100 ºC in an oil bath.After completion of the reaction (using TLC analysis), the reaction mixture was allowed to cool to room temperature.Next, hot ethyl acetate was added to the resulting mixture and then cooled to room temperature (rt).The resulting solid product was filtered off, washed with distilled water, and dried to afford the targeted compounds.If further purification was needed, the target compounds could be recrystallized from hot ethanol.Spectral data for compounds 4c and 4t were as follows: N-((2-Hydroxynaphthalen-1-yl) (

Conclusions
In conclusion, an efficient one-pot, threecomponent reaction of aromatic aldehydes, 2naphthol, and amides/urea/thiourea aimed at the synthesis of amido/thioamidoalkyl naphthols under SFRCs has been developed.Easy workup, simplicity, cost-effective, easy purification, ready availability of the catalyst, and no need for special equipment, such as ultrasonic devices are remarkable benefits of this synthetic method

Table 1 .
[13][14][15][16]).The yield was increased to 85% and 92% when 10 and 15 mol% of SA was employed, respectively (Table 1, entries 10 and 11).There was no increase in the reaction yield when 20 mol% of catalyst was used (Table 1, entry 12).Screening various temperatures did not get satisfactory results (Table 1, entries[13][14][15][16].With these interpretations, we conclude that 15 mol% of the catalyst, the temperature of 100 °C and the SFRCs, are the best conditions for the reaction.Optimization of the reaction conditions.a