Incredible Role of Glycerol in Multicomponent Synthesis of 2 , 3-Dihydroquinazoline-4 ( 1 H )-ones and 1-Amidoalkyl-2-naphthols

An efficient and green synthesis of 1-amidoalkyl-2-naphthols via one-pot three-component condensation of aromatic aldehydes, acetamide and 2-naphthol in the presence of catalytic amounts of glycerosulfonic acid in glycerol as a green solvent was elaborated. Also a simple method for the one-pot threecomponent synthesis of 2,3-dihydroquinazoline-4(1H)-ones using of isatoic anhydride, aldehydes and ammonium acetate in the presence of glycerol as a green catalyst and solvent was described. In this light we introduced the brilliant and valuable role of glycerol in the synthesis of 2,3-dihydroquinazoline-4(1H)ones and 1-amidoalkyl-2-naphthols.


INTRODUCTION
Multicomponent reactions (MCRs), have elicited increasing interest since they have been performed without the need to isolate any intermediate during their processes, this reduces time and saves both energy and raw materials. 1 This reactions play as an important tool for building diverse and complex organic molecules in a tandem manner. They are also suitable for library synthesis to meet the demands for high-throughput screening in the pharmaceutention from both academic and industrial researchers. 2 Two of these MCRs are the synthesis of 1-amidoalkyl-2-naphthols and 2,3-dihydroquinazoline-4(1H)-ones. Amidoalkyl naphthols are an important group of compounds because they have been found to possess useful biological traits. 3 1-amidoalkyl-2-naphthol derivatives are of significant medical relevance since they can be converted into hypertensive and bradycardia active 1-aminoalkyl-2-naphthols by amid hydrolysis reaction. 4 1-amidoalkyl-2-naphthols can also be converted to 1,3-oxazine derivatives with different biological activities. 5 Also 2,3-Dihydroquinazolinone derivatives are an important class of fused heterocycles that display a wide range of biological, pharmacological, and medicinal properties involving antitumor, antibiotic, antipyretic, analgesic, antihypertonic, diuretic, antihistamine, antidepressant, and vasodilating activities. 6 The preparation of 1-amidoalkyl-2-naphthols can be carried out by the condensation of aryl aldehydes, 2-naphthol and acetonitrile or amide in the presence of Lewis or Brønsted acid catalysts 7 such as K-10 clay, 8 Ce(SO4)2, 9 iodine, 10 K5CoW12O40• 3H2O, 11 p-TSA, 12 sulfamic acid, 13 cation-exchanged resins, 14 silica-sulfuric acid, 15 silica supported dual acidic ionic liquid, 16 MoO3-ZrO2 17 and trityl chloride. 18 Also, 2,3-dihydroquinazoline 4(1H)-ones prepared via one-pot threecomponent reaction of aldehydes, isatoic anhydride and source of ammonia. Therefore various procedures have been developed for preparing this important class of compounds. 19 Other methods including synthesis of 2,3dihydroquinazoline 4(1H)-ones via one-pot threecomponent reaction catalyzed by L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate (supported on silica gel), 20 Cu-CNTs, 21 copper-catalyzed, 22 Ce(CH3SO3)3 • 2H2O, 23 montmorillonite K-10, 24 MCM-41-SO3H, 25 gallium triflate, 26 were also reported. However, most of the synthetic protocols reported so far suffer from drawbacks such as low yields, long reaction times, the use of expensive or toxic metal salts as catalysts, the use of toxic solvents and tedious work-up procedures. Therefore, introducing clean, versatile and eco-friendly processes have been under permanent attention.
It is well known that most organic reactions occur in a liquid phase. 27 Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids known as triglycerides. From the standpoint of green chemistry, glycerol is a valuable solvent for organic synthesis. Like polar solvents such as water, DMSO and DMF, glycerol is able to facilitate the dissolution of inorganic salts, acids, bases, enzymes and many metal transition complexes. Furthermore, it also dissolves organic compounds that are poorly miscible in water, many hydrophobic solvents, such as ethers and hydrocarbons, are immiscible in glycerol. 8 In this context, glycerol has a clear advantage compared with most organic solvents. Indeed, glycerol is a nontoxic, biodegradable and nonflammable solvent for which no special handling precautions or storage is required. It is also a by-product of the production of biodiesel via trans-esterification and co-product of the vegetable oil industry. 28 In this light we introduced the important role of glycerol in the synthesis of 2,3-dihydroquinazoline-4(1H)-ones and 1-amidoalkyl-2-naphthols.

EXPERIMENTAL
All chemicals were purchased from Aldrich and Merck and used without further purification. The known products were characterized by the comparison of their spectral ( 1 H NMR, and 13 C NMR, Bruker NMR spectrometer FX 400Q; MS, mass spectrometer 70 eV) and physical data with those of authentic samples.

General Procedure for the Synthesis of 2,3-Dihydroquinazoline-4(1H)-ones
A mixture of aldehyde 3 (1 mmol), isatoic anhydride 4 (1 mmol) and ammonium acetate 6 (3 mmol) in glycerol 1 (3 ml) was stirred at 80 °C in a boil bath for the appropriate time. After the completion of the reaction, as indicated by TLC, the reaction mixture was cooled, water was added and the mixture was stirred. That glycerol was dissolved in H2O and separated from the mixture. The remained was dissolved in boiling EtOH and stirred. Solvent was evaporated. Finally solid product was recrystallized from ethanol. Some of the synthesized compounds were characterized by 13 CNMR and 1 HNMR analyses, and values were compared with the literature data of known products.

Synthesis of Glycerosulfonic Acid
In order to prepare glycerosulfonic, to glycerol 1 (1 mmol) in diethyl ether, chlorosulfonic acid (3 mmol) was added slowly in ice bath. The mixture was stirred for 1 h. After evaporation of the solvent the product is designated as glycerosulfonic acid (2, Scheme 1). The viscous liquid was then supported on the silica gel (1.424 g).

General Procedure for the Synthesis of 1-Amidoalkyl-2-naphthols
In a typical reaction, to a solution of 2-naphthol 7 (1 mmol), aldehyde 3 (1 mmol) and acetamide 8 (1.5 mmol) in glycerol 1 (0.5 ml), glycerosulfonic acid 2 (0.664 g) was added. Then the reaction mixture was stirred at 80 °C in a boil bath for the appropriate time (see Table 5). Reaction progress was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature, water was added and the mixture was stirred for 10 minutes. That glycerol was dissolved in H2O and separated from the mixture. The residue was dissolved in boiling EtOH and stirred for 10 minutes. Catalyst was filtered and solvent was evaporated under reduced pressure. Finally solid product was recrystallized from ethanol (Scheme 1). Synthesized compounds were characterized by 13 CNMR and 1 HNMR analyses, and values were compared with the literature data of known products.

RESULTS AND DISCUSSION
Here in we investigated glycerol as green media with dual role for the one-pot three-component reaction of isatoic anhydride, aromatic aldehydes, and ammonium acetate for the synthesis of 2,3-dihydroquinazoline derivatives. Also following our current study in the synthesis of 1-amidoalkyl-2-naphthols 29 we would like to report that silica supported glycerosulfonic acid as a solid acid catalyst which has been used in the synthesis of 1-amidoalkyl-2-naphthol derivatives in glycerol as solvent (Scheme 2).

Synthesis of 2,3-Dihydroquinazolines
To find the optimized experimental conditions, the reaction of 4-chlorobenzaldehyde with isatoic anhydride and ammonium acetate in the presence of glycerol as solvent and catalyst, was selected as a model reaction (Table 1). A simple comparison between the entries 4 and 5 Scheme 2. One-pot Synthesis of 2,3-dihydroquinazolines and 1-amidoalkyl-2-naphthols  Yield / % t / °C reveals that apart from isatoic anhydride and ammonium acetate, the amount of glycerol effect on the yield of product. Therefore, we employed the optimized conditions (1 mmol isatoic anhydride, 3 mmol ammonium acetate and 3 mL glycerol) for the synthesis of 2,3dihydroquinazolines (Entry 5, Table 1). Furthermore, the model reaction was studied at different temperatures. As can be seen rising temperatures to 80 °C increased the yield of product. With further increase in temperature, the yield was reduced. Therefore when the reaction was performed at 80 °C, a higher yield was observed (Figure1).
To further establish the scope of optimized reaction conditions, variety of electronically divergent aromatic aldehydes were treated with isatoic anhydride and ammonium acetate in glycerol. The presence of electron-withdrawing and electron-releasing groups on the aromatic rings does not affect the yield of the product. The results of Table 2, clearly indicate the feasibility of three-component reaction. The products were synthesized in excellent yield with simple workup procedure. After completion the reaction, the glycerol was dissolved in water and separated from product. All results are compiled in Table 2. An acceptable proposed mechanism for the synthesis of 2,3-dihydroquinazoline-4(1H)-ones is illustrated in Scheme 3. Ammonium acetate is dissociated to ammonia and acetic acid. In the presence of glycerol as catalyst, the carbonyl group of isatoic anhydride (I) is activated, to form an intermediate (II), then ammonia (III) attacks on the carbonyl unit of an intermediate (II) to produce an intermediate (IV), which in turn affords an intermediate (IV) through decarboxylation reaction and proton transfer. Subsequently, the reaction of aldehyde activated by glycerol with (IV) proceeds to resulting in the formation of the imine intermediate (V), which is followed by cyclization to yield the final product (VI). Generally, glycerol through hydrogen bonds with carbonyl group increased the electrophilicity of both isatoic anhydride and aldehyde carbonyl groups. So they react well with nucleophiles and the desired products achieved.

Synthesis of 1-Amidoalkyl-2-naphthols
In the synthesis of 1-amidoalkyl-2-naphthols, in order to increase the acidic character of glycerol, it was reacted with chlorosulfonic acid and glycerosulfamic acid was synthesized. The structure of synthesized catalyst was examined by Fourier transform infrared spectroscopy (FTIR) analyses were carried on FTIR spectrophotometer (Bruker, Germany) Vertex 70 in the range of 400-4000 cm -1 . FTIR spectroscopy was used to detect the presence of binding groups in glycerol and glycerosulfonic acid (Figure 2). The vibration signals around 3000 cm -1 are typical O-H bands. And signals around 1000-1200 cm -1 are typical SO2 bands.
Mass spectroscopy has been used to identify the mass of glycerosulfonic acid (Figure 3). The peak around 331.0 m/z is typical glycerosulfonic acid.
To select an appropriate solvent, the reaction of 2naphthol (1 mmol), 4-chlorobenzaldehyde (1 mmol) and acetamide (1.5 mmol) was examined as a model reaction (table 3). As mentioned in Table 3 and entry1 nothing happens after 7 h under solvent-free condition. Also in ethanol or H2O the small amount of product produced. Mixing water with glycerol led to more output, but it is not acceptable. It was observed that reaction proceeds more effectively in glycerol as the reaction medium (Table 3, Entry 5).
To further optimize the conditions, we examined the amount of glycerosulfonic acid as catalyst (Table 4). In the absence of any kinds of catalysts, a desirable product was obtained in very low yield (Table 4, Entry 1). Subsequently, the yield of N-[(4-chloro-phenyl)-(2hydroxy-napthalen-1-yl)-methyl]-acetamide gradually increased with increasing the amount of glycerosulfonic acid (Table 4, Entry 2-4). So the best yield was achieved in the presence of 0.664 g of catalyst.
Furthermore, In order to show the effect of temperature on 1-amidoalkyl-2-naphthols synthesis the Scheme 3. Proposed mechanism for the synthesis of 2,3-dihydroquinazolines model reaction was studied at different temperatures. As shown in Figure 4, 80 °C is the best temperature for the reaction and at higher and lower temperatures did not achieve satisfactory results.
To explore the range of suitable substrates for this new catalytic system, the one-pot three component reac-tion of various aromatic aldehydes, 2-naphthol and acetamide catalyzed glycerosulfonic acid was investigated under the optimized conditions, and the results are given in Table 5. In all the reactions, excellent yields were obtained at appropriate reaction times. Clean and complete conversions leading to the corresponding 1amidoalkyl-2-naphthols were observed. Aromatic aldehydes carrying either electron-withdrawing or electrondonating groups were all suitable for the reactions. The synthesis of N-[(4-chloro-phenyl)-(2-hydroxy-naphtalen-1-yl)-methyl]-acetamide was examined in the absence of glycerol or glycerosulfonic acid. As shown in entry 3, the reaction didn't occur in the absence of glycerol. Also without any glycerosulfonic acid just a trace amount of catalyst was achieved (Table 5, entry 4).
On the basis of the previously reported mechanism for the synthesis of 1-amidoalkyl-2-naphthol, the acid catalysis condensation reaction via in situ generation of ortho-quinone methides (o-QMs) is presented. The o-QMs have been reacted with acetamide via conjugate addition to form 1-amidoalkyl-2-naphthols as final products.

CONCLUSIONS
In conclusion, we have developed a green, versatile and easy manner for the synthesis of 2,3-dihydroquinazoline-4(1H)-one and 1-amidoalkyl-2-naphthol derivatives via one-pot three-component condensation reactions in glycerol as a green media at 80 °C. We have reported for the first time the use of glycerosulfonic acid as an efficient and heterogeneous catalyst for the onepot synthesis of a variety of amidoalkylnaphthols in the presence of glycerol as a green solvent. The present protocol enjoys high yields of products, a wide range of substrates, simple workup, use of glycerol as a green solvent and use of glycerosulfonic acid as a new nonmetallic catalyst.