Three-component one-pot metal-free synthesis of 2,3-dihydroquinazolin-4(1 H )-ones using Mukaiyama’s reagent

A rapid, effective, without transition metal and column chromatography-free protocol for the synthesis of 2,3-dihydroquinazolinones (DHQ) derivatives via one-pot tri-component reaction using amine, aldehyde (aromatic or aliphatic) and i satoic anhydride in the existence of Mukaiyama’s reagent (CMPI: 2 -chloro-1-methylpyridinium iodide) has been developed with commendable isolated yields. The operation is a high atom economy experimental procedure, with good functional group tolerance, broad substrate scope

Due to the well-known pharmaceutical and physiological activity of DHQ derivatives, several synthetic protocols have been developed for quinazolinone-incorporated organic skeletons during the past decades, [13][14][15][16] various of them have demerits like unfavourable conditions, 13 long reaction times, 14 and the use of high-priced and hazardous acid catalysts. 15,16Therefore, it seemed there is a need to develop simple, efficient, and easy methods to perform synthesis of quinazolinone derivatives under environmentally kind conditions.Eliminating a volatile organic component in organic synthesis is one of the many strategies to accomplish greenness in the processes. 17  The cheap and commercially available Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide: CMPI) is used for triggering between carboxylic acids and alcohols. 19][22][23][24] Recently Mukaiyama's reagent has also been employed in C-N bond formation as in formation of 3alkylquinazolin-4-ones. 25 Multi-component reactions (MCRs) are considered a noteworthy tool in synthetic chemistry and have been used in synthetic transformations where traditional techniques involve several steps.The MCR comes within reach of offering a high yield at a low price in a short time.MCR is eco-friendly and acts as an amenable tool for the creation of carbon-carbon and carbon-heteroatom bonds in pharmaceutically significant chemical entities.To determine the best conditions, isatoic anhydride, 4-methoxybenzaldehyde, and aniline were used as a model substrate.Optimization was focused on the best-suited solvent and amount of catalyst to afford a good yield of product in a minimum time period.
In the process of optimization, the model reaction was conducted with isatoic anhydride with aniline and 4methoxybenzaldehyde in the presence of different equivalents (0, 0.25, 0.5, 0.75 and 1.0) of Mukaiyama's reagent (CMPI) in the solvent MeCN at 110 o C. Without the reagent reaction was very slow and low yielding (Table-1: entry 1), 0.25 equivalent of CMPI is an adequate amount for completion of reaction with 55% isolated yield in 24 h, while with 0.5 equivalent the product was obtaianed in 85% in 18 h, though with 0.75 equivalent the product was obtained with 89% yield in 9 h, further increase of CMPI up to 1.0 equivalent resulted in 91% isolated yield of product in 3 h (       a Molar ratio: isatoic anhydride (5.0 mmol), ammonium salt or aniline or benzyl amine (5.0 mmol), aromatic/aliphatic aldehydes (5.0 mmol), b Yields reported after recrystallization.
To find the best solvent, we screened a range of non-polar to polar solvents (Table -1).In THF, 1,4-dioxane and dimethoxyethane isolated yields were moderately low, as the intermediate was not consumed even after 24 h (Table-1: entry 6, 7 and 8); in the case of ethanol, acetic acid, and dimethylformamide product isolated was lower (entry 9, 10 and 11).In water, poor solubility of reactants results in an isolated yield of up to 35% in 24 h (entry 12).In the case of MeCN, all reactants and reagents were soluble even at room temperature, and as the reaction progressed product started to precipitate out as solid, which made isolation easy by filtration.From the results obtained it was certain that MeCN is a better solvent to get a product with a higher yield in a short time period using 1.0 equivalent of Mukaiyama's reagent (CMPI).
Furthermore, we applied an optimized synthetic procedure on a wide range of aldehydes (aliphatic or aromatic) having substituents with different electronic effects and primary amine with isatoic anhydride for preparation of derivatives of 2,3-dihydroquinazolin-4(1H)-one and study the scope of the three-component reaction method.© AUTHOR(S) Figure 2. Molar ratio: isatoic anhydride (5.0 mmol), ammonium salt or aniline or benzyl amine (5.0 mmol), aromatic/aliphatic aldehydes (5.0 mmol), ACN. a isolated yield.Employment of ammonium chloride as a source of ammonia produced 2-substituted-2,3-dihydro-4(1H)quinazolinones (1a-1k).By using optimized synthetic protocol, along with functionally variable aryl aldehyde including those having electron withdrawing fluoro (1e, 1f), chloro (1g, 1s), bromo (1c, 1f, 1m, 1t), nitro (1d)] and electron-releasing groups methoxy (1b, 1l, 1q), methyl (1g); naphthalene-1-yl-benzaldehyde and naphthalene-2-yl-benzaldehyde were also successfully incorporated into the 2-position of dihydroquinazolinones to obtain (1j) and (1k) with good to excellent yields.There was no significant impact of electronic effect on reaction rate and yield.Aromatic aldehydes having bulky substituens like nitro at the ortho position (1d) had a moderately sluggish rate of reaction.Further, in an attempt to introduce a heterocyclic aldehyde in the 2-position of dihydroquinazolinones, use of furfural was employed, but this led to multiple byproduct formation.Aliphatic aldehydes such as cyclopropanecarboxaldehyde and 3-methylbutanal successfully led to the synthesis of corresponding DHQ derivatives (1h, 1i, 1n and 1o).However, in the case of 3-methylbutanal, isolated yield of the product was comparatively low (1i, 1o), which might be due to the poor stability of aliphatic aldehyde in the reaction mixture.In order to check the scope of primary amine, use of benzyl amine effectively leads to the desired product (1u) formation.In addition, the use of cyclopentanone to synthesize spiro compound (1v) was low-yielding.So there is further scope for optimization in reaction conditions to improve better conversion for some other spiro compounds.
Study of the reaction mechanism was the next subject of investigation (Scheme 3).First, isatoic anhydride 1 is converted into 2-amino-N-substituted benzamide 3 by nucleophilic attack by the amine, with the loss of carbon dioxide.CMPI having a pyridinium nucleus (electron deficient) shows good electron affinity towards Oatom of carbonyl compound, which further promotes attack of NH2 group on the carbonyl carbon to form an imine intermediate (Schiff base) with the generation of halogen acid and N-methylpyridin-2-one.The halogen acid might be helpful in intramolecular cyclisation of Schiff base to afford 2,3-dihydroquinazolin-4(1H)-one as we have already reported (Scheme 1). 26To demonstrate the utility of the developed method, a variety of 2,3disubstituted quinazolinones (1a-1v) were synthesized using aliphatic and aromatic aldehydes.

Scheme 3. Plausible reaction mechanism for the formation of dihydroquinazolinone.
To verify the utility and simplicity of this method, we illustrate (Fig. 3) the physical changes in the reaction mass and pure compound after filtration and washing with diethyl ether.A small-scale reaction was set into a vial with solid isatoic anhydride as starting material, then we added the solvent (ACN) and stirred for a minute followed by the addition of CMPI, ammonium salt or aniline or benzyl amine, aromatic/aliphatic aldehydes.The reaction mixture was heated at 110 o C for 3 to 4 h.The reaction mass was cooled to room temperature, and a solid precipitate was collected by filtration (Figure 3, image I).The solid was washed with cold diethyl ether and then dried under a high vacuum to yield a pure compound.(Figure 3, image II).

Conclusions
In conclusion, Mukaiyama's reagent has been demonstrated to be an efficient reagent for the one-pot threecomponent reaction of isatoic anhydride, aromatic/aliphatic aldehyde, and ammonium salt or aniline or benzyl amine, in MeCN under mild reaction condition.This reaction methodology allows the synthesis of both monoand di-substituted 2,3-dihydroquinazolin-4(1H)-ones in high yield.This method offers several advantages including a nontoxic, clean, and mild reaction conditions, a wide range of substrates, a simple work-up procedure, and isolation without column chromatography.Moreover, the absence of metal, any co-catalyst, and a nonvolatile byproduct make this an environment friendly method.

Experimental Section
General.All chemicals and reagents were purchased from Sigma Aldrich India and Spectrochem Chemical companies in high purity which was used without further purification.All reactions were run in an oven-dried round bottom flask containing a Teflon-coated stir bar and sealed with a septum. 1 H NMR and 13 C spectra were recorded on Brukar Avance II 400 MHz FT-NMR spectrometer (400 and ed in units δ (ppm) relative to tetramethylsilane (Me4Si) as an internal standard.Abbreviations used for NMR signals are s =singlet, d = doublet, t = triplet, and m = multiplet.Melting points were determined in open capillaries using an electrothermal Mk3 apparatus.The progress of the reactions was monitored by TLC (thin layer chromatography) on Merck Kieselgel 60F254 aluminum-backed plates, visualized by UV fluorescence (254 nm), and with KMnO4 and ninhydrin stains.

Figure 3 .
Figure 3. Physical changes in reaction mixture and pure compound after filtration.