A Simple Metal-Free Cyclization for the Synthesis of 4-Methylene-3-Substituted Quinazolinone and Quinazolinthione Derivatives: Experiment and Theory

A new series of 3-substituted 4-methylene-quinazolinthiones and 4-methylene-quinazolinones were synthesized in moderate to excellent yield through a simple reaction of 2-aminoacetophenones with isocyanates or isothiocyanates. The reaction shows good tolerance of many important functional groups in the presence of air and water under metal-free conditions. Only water is produced as a coproduct, rendering this “green” methodology a highly versatile and eco-friendly alternative to the existing methods for the construction of the quinazolinone/quinazolinthione framework. We have interpreted the reaction mechanism by use of quantum chemical calculations on the basis of state-of-the-art computational methods SMD-B3LYP-D3(BJ)/BS1//B3LYP/BS1.


RESULTS AND DISCUSSION
Nucleophilic addition of 2-aminoacetophenones 1 with isothiocyanates 2a results in a formation of 1,3-diarylthiourea 3. In principle, heterocyclization of compound 3 may occur by three different mechanisms (Scheme 2). Firstly, quinazolinthione 4a can result from the nucleophilic attack of N-3 of compound 3 on the carbonyl group of the ketone followed by removal of water (path A). Secondly, compound 3 is transformed to its mesomeric form C and the latter cyclizes through an addition reaction to the carbonyl group of the ketone leading to the formation of benzothiazinimine 4 ′ by the elimination of one molecule of water (path B). Thirdly, compound 3 is first converted to an enol form and the enol of intermediate F attacks the thiocarbonyl group of thiourea followed by a loss of H 2 S to afford quinolinone 4 ′′ (path C).
In an initial experiment, the reaction of 2-aminoacetophenone 1 with phenyl isothiocyanate 2a was undertaken in acetonitrile (MeCN) at room temperature. Not surprisingly, the main nucleophilic addition product 3 was isolated (yield: 50%). Apart from this, a small proportion of a new compound was detected (entry 1, Table 1). 1 H NMR spectra demonstrated that there are two double peaks at 4.82 (one proton) and 3.69 ppm (one proton), respectively, ruling out the existence of product 4 ′′ . To identify the product structure as being either 4a or 4 ′ , single crystals were isolated and the structure characterized by X-ray crystallographic analysis. It was established that the quinazolinthione 4a was the correct structure (CCDC1906269, Figure 1, left, see Supporting Information for details). However, to our surprise, when crystals of the compound were incubated in methanol, an additional methoxy group was attached to 4position of the quinazolinthione ring (CCDC1906268, Figure 1, right), indicating that the methylene group of compound 4a is an active site and performs a further coupling reaction. This observation is currently under investigation.
Consistent with Fukui's theory, LUMO (the lowest unoccupied molecular orbital) and E LUMO (the energy of LUMO) are clear, as is the extent of molecular susceptibility toward attack by external electrons (Dhami et al., 1997;Yan et al., 2019). Thus, the carbon-carbon double bond character of the 4a structure is also represented by strong binding interactions in LUMO and LUMO+1 (Figure 2). This calculation provides a realistic description of the nucleophilic attack on the double bond on 4a.
We optimized the reaction conditions in order to obtain the best yield by screening solvents and temperatures. As shown in Table 1, the yield was improved to 58% when the reaction was increased to 50 • C (entry 2). In parallel, replacement of acetonitrile with ethyl acetate resulted in lower yield, even with an extended time. The reaction was found to occur with high efficiency at a short reaction time in acetonitrile under reflux conditions (entry 4). Replacement of acetonitrile with other solvents such as ethyl acetate, dichloromethane, THF, benzene and dioxane, resulted in lower yields (entries 5-9). Based on these results, the optimal reaction conditions were selected as 1 (1 mmol) and 2 (1.1 mmol) in MeCN (5 mL) under reflux condition for 1.5 h.
With these optimized reaction conditions in hand, the substrate scope of this methodology was explored (Figure 3). We found that both electron-donating groups (EDG) and electron-withdrawing groups (EWG) on the aromatic ring were well-tolerated by the reaction conditions. However, the yields of the products attached with EDG were significantly lower than those with EWG (4b-4d vs. 4e-4g). In addition, the stereochemistry also influenced the yield. For example, using para-and meta-chloro substituted 2 in the reaction provided good yields of 4 whereas ortho-chloro substituted 2 gave the corresponding product in only a moderate yield (4e-g). The yield sequence followed the order: para-> meta-> ortho-.
In similar fashion to mono-substituted analogs, di-substituted isothiocyanates reacted smoothly with 2-aminoacetophenone to furnish the corresponding quinazolinthiones in moderate to high yields (4h-4i). Again, the electronic nature of the aryl moiety on the isothiocyanates had a dramatic effect on the product yield. As a result, 2,4-dichloro substituted 2i gave the corresponding product at 90% yield while the 2-methoxy-5-methyl substituted analog 2h only offered 42% yield of product 4h. To further SCHEME 1 | Previous and present work for the synthesis of 4-methylene-quinazolin-2-ones. expand the substrate scope, two aliphatic isothiocyanates (2j, 2k) were also investigated for this cycloaddition reaction. Benzyl isothiocyanate (2j) was found to be smoothly converted to the corresponding product 4j in a high yield, whereas propyl isothiocyanate (2k) only gave 20% yield of the desired 4k. In addition, diisothiocyanate (2l) was also examined for this conversion, but only one isothiocyanate group was involved in the reaction and a mono-cyclized product 4l was obtained with the second isothiocyanate not involved in the reaction, even in the presence of an excess of 2-aminoacetophenone 1 (>2 equiv.). This interesting result provides an opportunity for further diversification and amplification with the entire isothiocyanate group. In this regard, compound 4l was refluxed with ethylamine, a highly nucleophilic amine, to afford compound 4l * with an excellent yield (Scheme 3).
This success led us to further investigate the reaction generality by replacement of isothiocyanates with isocyanates. Under the optimized reaction conditions, the reaction of isocyanate 5 and 2-aminoacetophenone 1 only resulted in the coupling product 6, even after prolonging the reaction time to 24 h. The annulation compound 7 was not detected (Scheme 4). Pleasingly, compound 6 can undergo an intramolecular cyclization to afford the target 4-methylene-quinazolinone 7 in the presence of NaOH (10 mol%). Encouraged by these results, a subsequent study was undertaken to evaluate a one-pot cascade reaction of isocyanates 5 and 2-aminoacetophenone 1. In the presence of a catalytic amount of aqueous NaOH (10 mol%), the reaction progressed smoothly to yield the annulation product 7 even at room temperature. Consequently we modified the conditions for the reaction of 1 with 2, and achieve a significantly improved yield for the production of 4b (58 vs. 10%, Figure 3).
On the basis of this latter result, the scope of substituted isocyanates was explored (Figure 4). Aromatic isocyanates bearing either an EDG or an EWG group were found to undergo the reaction smoothly and the corresponding 4-methylenequinazolinones were formed in excellent yields (7b-7j). In this case, neither the electronic nature nor position of the functional groups attached to the aromatic ring dramatically influenced the product yield. However, the 2-CF 3 -substituted isocyanate 5k only gave a moderate yield of the expected product 7k. Compared to the mono-substituted analogs, di-substituted aryl isocyanates were converted into the corresponding quinolinones in relatively low yields (7l-7o). In addition, three aliphatic isocyanates (5p-5r) were investigated for this annulation reaction. It was found that benzyl isocyanate was converted smoothly to afford the corresponding product 7p in a high yield, whereas only moderate yields were achieved for 7q and 7r. The diisocyanate (5s) was also investigated for this conversion. In a similar fashion to the SCHEME 2 | Possible main pathways for the addition/cyclization of compounds 1 and 2a. aforementioned reaction with diisothiocyanate (2l), only one isocyanate group was involved in the reaction and an excellent yield of mono-cyclized product 7s was obtained. The scope of substituted 2-aminoacetophenones 1 was also investigated in this novel cyclization process. 2-Aminoacetophenones bearing either an EWG such as chloro group or an EDG such as methyl group on the aromatic ring, progressed in this reaction smoothly with either aromatic isocyanates or benzyl isocyanate to provide the corresponding quinazolinones in moderate to excellent yield (7t-7ab).
In order to demonstrate the suitability of this new synthetic methodology for industrial use, an increased scale preparation of 7a was investigated. Reaction of substrates 1 and 5a in MeCN (20 mmol, 50 mL) was performed in the presence of NaOH (5 M in H 2 O, 10 mol%) at room temperature. The corresponding product 7a was afforded in 90% yield, the yield being similar to that of the small-scale reaction (Scheme 5). Moreover, the workup procedure is simple, as the product precipitated from MeCN on cooling the reaction medium. A pure product was obtained after filtration, without the requirement of further purification.
As indicated in Scheme 2, the heterocyclization of starting materials 1 and 2/5 may in principle lead to at least three different products. To better understand the intramolecular cyclization reaction, we calculated Gibbs free energy of each intermediate and products listed in Scheme 2 by a computational method. Compounds 1 and 2a were selected as the model substrates for this study. The calculation was based on quantum chemical calculations (SMD-B3LYP-D3(BJ)/BS1//B3LYP/BS1). The geometry of transition states (TSs) and compound 3 in Scheme 2 have been fully optimized in vacuum and the TSs were verified to have only one imaginary frequency vibrational mode that connects the reactants and products. The calculated energy values of the intermediates and products, including dispersion interactions are presented in Figure 5. All stationary points were fully optimized and subjected to frequency analyses. The data demonstrates that paths A and C mechanism routes have a negative value of Gibbs free energy for the final product while the path B mechanism route gives a positive value, thus ruling FIGURE 1 | Single crystal X-ray structures of compound 4a and its derivative 4a*. out the path B mechanism. In the route of path A 3 → A → B → 4a (black, Figure 5), there is only one energy barrier at a value of 4.77 kcal/mol. In contrast, there are two high energy barriers (20.53 and 7.19 kcal/mol) in the route of path C 3 → F → G → H → 4 ′′ (blue), rendering the transformation via path C difficult. These results indicate that the route of path A is the most probable pathway for this annulation reaction.

CONCLUSION
In summary, we have presented a novel preparation of 3-substituted 4-methylene-3,4-dihydroquinazoline-2(1H)-thiones/ones from 2-aminoacetophenone and isothiocyanates/isocyanates. The method utilizes commercially available starting materials and is applicable to a large range of compounds. This new synthetic methodology does not require expensive/complicated metal catalysts and the work-up procedure is simple. The novel transformation indicates the feasibility of this pathway in both research and industrial laboratories. Comprehensive quantum chemical calculation studies indicate the probable synthetic route.

Experimental and Computational Details
All chemicals were obtained from Aladdin (China) as reagent grade and were used as received. Column chromatography purifications were performed on silica gel 60 (0.04-0.063 mm). Melting points were determined using an Electrothermal WRS-1B Digital Melting Point Apparatus and are uncorrected. 1 H-NMR spectra were recorded using a Bruker (400/500 MHz) NMR spectrometer. 13 C-NMR spectra were recorded using a Bruker (101/151 MHz) NMR spectrometer. Chemical shifts (δ) are reported in ppm downfield from the internal standard tetramethylsilane (TMS).
Gaussian 09 software (Frisch et al., 2016) packages can implement density functional theory (DFT) conveniently, thus geometry optimizations were carried out with the hybrid B3LYP functional in conjunction with 6-31G++(d,p) basis set for all the atoms of these compounds. Additionally, the geometry optimizations were followed by frequency calculations using the same basis set. Moreover, the effect of dispersion was incorporated using Grimme-D3 approximation during geometry optimizations (Grimme et al., 2010). To further refine the energies, single-point B3LYP calculations including D3 version of Grimme's dispersion with Becke-Johnson damping (D3BJ) FIGURE 3 | Substrate scope of isothiocyanates a,b . SCHEME 3 | Nucleophilic attack of 4l* by an aliphatic amine. (Grimme et al., 2011) were performed with a higher basis set BS1 (BS1 = 6-31++G(d,p) basis set for all atoms). The use of SMD-B3LYP-D3(BJ)/BS1 to calculate compound Gibbs energy was reported in the literature for mechanistic investigation (Markovic et al., 2010;Kleine et al., 2011).

Synthesis of 4a-4l
A mixture of 2-aminoacetophenone 1 (1 mmol) and isothiocyanatobenzene 2 (1.1 mmol) in acetonitrile (5 ml) was stirred at 82 • C for 4 h. After completion, the reaction solvent was reduced to half and upon cooling a white or yellow precipitate was obtained. Recrystallization from ethanol produced white or yellow solid.

Synthesis of 6a and 6r
A mixture of 2-aminoacetophenone (1 mmol) and isocyanatobenzene/isocyanatocyclohexane (1.1 mmol) in acetonitrile (5 ml) was stirred at 82 • C for 4 h. After completion, the reaction solvent was reduced to half and upon cooling a white or yellow precipitate was obtained. Recrystallization from ethanol produced white solid.

Synthesis of 7a-7ab
A mixture of 2-aminoacetophenone 1 (1 mmol), isocyanatobenzene 5 (1.1 mmol) and a drop of aqueous NaOH solution (5 M, 10 mol%) in acetonitrile (5 ml) were stirred at room temperature. After completion, the reaction solvent was reduced to half and upon cooling a white or yellow precipitate was obtained. Recrystallization from ethanol produced white solid.