Selective Synthesis of 2-(1,2,3-Triazoyl) Quinazolinones through Copper-Catalyzed Multicomponent Reaction

Abstract

We describe here our results from the copper-catalyzed three component reaction of 2-azidobenzaldehyde, anthranilamide and terminal alkynes, using Et₃N as base, and DMSO as solvent. Depending on the temperature and amount of Et₃N used in the reactions, 1,2,3-triazolyl-quinazolinones or 1,2,3-triazolyl-dihydroquinazolinone could be obtained. When the reactions were performed at 100 °C using 2 equivalents of Et₃N, 1,2,3-triazolyl-dihydroquinazolinone was formed in 82% yield, whereas reactions carried out at 120 °C using 1 equivalent of Et₃N provided 1,2,3-triazolyl-quinazolinones in moderate-to-good yields.

1. Introduction

Nitrogen heterocyclic compounds are among the most representative chemical architectures, and they are found in several natural products and commercial drugs. Quinazolinones are important members of the N-heterocycles, and they are building blocks in numerous natural products and widely used in the preparation of synthetic bioactive compounds, especially in the pharmaceutical industry [1]. Quinazolinones derivatives exhibit a wide range of pharmacological activities, including antimicrobial and antitubercular [2], anti-inflammatory [3], antiviral [4], anticancer [5], anti-Alzheimer [6], antimalarial [7], among others [8,9] (Figure 1).

Due to the pharmacological importance of the quinazolinone moiety, in recent years the development of new synthetic methods to access this class of compounds has attracted attention in organic synthesis. Generally, the quinazolinones are synthesized by the condensation of o-aminobenzamides with aldehydes [10], phenylacetic acid [11] and alcohols [12,13]. Other important protocols include carbon-supported acid-catalyzed cascade coupling of isatoic anhydrides with amides and aldehydes [14], oxidative annulation of alcohols with o-aminoarylnitriles [15], and Cu-catalyzed oxidative annulation of anilines, alkylamines and aldehydes [16].

Recently, the use of copper catalysis in the synthesis of quinazolinones has received much attention. An example was reported by Akhlaghinia et al. [17], who described an efficient protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones using Cu(I) functionalized with aminated 3-glycidyloxypropyltrimethoxysilane with thiosemicarbazide [SBA-16/GPTMS-TSC-Cu(I)] as a catalyst in the condensation of 2-aminobenzamide and an aldehyde under solvent-free conditions (Figure 2A). In 2020, Suresh et al. [18] reported the copper-catalyzed oxidative synthesis of quinazolinones in the presence of the reusable catalyst based in Cu₃(BTC)₂ (BTC = 1,3,5-benzene tricarboxylate) under mild condition, as shown in Figure 2B. There remains, however, a need for in-depth research on the synthesis of highly functionalized quinazolinones from various substrate combinations.

In this sense, substituted 1,2,3-triazoles are an important and useful class of heterocycles and have received considerable attention because of their application in organic synthesis, medicinal chemistry, and materials science [19,20,21,22,23,24]. For instance, the hybrid molecule containing quinoline and 1,2,3-triazole nucleus, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide (QTC-4-MeOBnE A), exerts therapeutic effect through multiple pathways involved in AD (Figure 1) [25,26]. Other examples are Rufinamide^® [27] and Tazobactam^® [28], that having anticonvulsant and antibiotic activities, respectively (Figure 1). Some 1,2,3-triazole-based compounds have shown antibacterial [29,30,31], anticancer [32], antifungal [33,34], antiviral [35], among others [36,37]. Efficient methods to access highly functionalized 1,2,3-triazoles include the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction [38,39] and the organocatalyzed [3+2] cycloaddition reactions via the generation of enamines, also known as Ramachary-Bressy-Wang organocatalytic azide-ketone [3+2]-cycloaddition (OrgAKC) [40,41,42]. Both CuAAC and OrgAKC are a powerful synthetic tool, due to simple reaction conditions, broader substrate scope and high atom economy.

Hybrid molecules containing the combination of quinazolinones and 1,2,3-triazoles, leads to compounds with promising pharmacological activities, such as antihistaminic [43], anticancer [44] antitubercular [2], antimicrobial [2], antihypertensive [45], and for the treatment of Alzheimer’s disease [46]. Continuing our studies on the synthesis of new functionalized 1,2,3-triazoles, and due to the pharmacological importance of the 1,2,3-triazoyl-quinazolinones scaffold, we describe herein the synthesis of a range of new 2-(1,2,3-triazoyl)quinazolin-4(3H)-ones by a copper-catalyzed multicomponent reaction of 2-azidobenzaldehyde 1, anthranilamide 2 and terminal alkynes 3 (Figure 2C).

2. Results

The original objective of this work was the synthesis of ten-membered heterocycles fused to a triazole ring (4), as a continuation of our previous works on the synthesis of medium-sized rings [47]. Thus, aiming to prepare the bicyclic triazole 4, a mixture of 2-azidobenzaldehyde 1 (0.5 mmol), anthranilamide 2 (0.5 mmol) and phenylacetylene 3a (0.5 mmol) in the presence of CuI (10 mol%) as a catalyst and Et₃N (2 equivalents) as a base, in DMSO (1.5 mL) and under N₂ atmosphere was stirred at 100 °C (Figure 3). However, after 16 h of reaction, the only isolated product was the triazoyl-2,3-dihydroquinazolinone 5a, which was isolated in 82% yield. The structure of 5a was confirmed after fully characterization by high- and low-resolution mass spectrometry, ¹H and ¹³C NMR analysis (data are described in Supplementary Materials).

After confirming the identity of compound 5a, and checking in the literature the importance and versatility of the quinazolinone nucleus, our efforts were aimed at optimizing the reaction described in Figure 3. For this purpose, freshly prepared 2-azidobenzaldehyde 1 (0.5 mmol), anthranilamide 2 (0.5 mmol) and phenylacetylene 3a (0.5 mmol) were used as standard substrates, and different copper(I) and copper(II) salts, as well as a diversity of solvents and temperatures were evaluated (

Table 1. Optimization of the reaction conditions ^a.

Entry	Et3N (mmol)	Catalyst (10 mol%)	Solvent	Temp. (°C)	Yield (%) b	Ratio c 5a:6a
1	1	CuI	DMSO	100	82	1:0
2	1	CuBr	DMSO	100	21	1:0
3	1	CuCl	DMSO	100	27	1:0
4	1	CuBr2	DMSO	100	n.f.	--
5	1	CuCl2	DMSO	100	n.f.	--
6	1	Cu(OAc)2·H2O	DMSO	100	38	1:0
7 d	1	CuI	DMSO	100	81	1:0
8 e	1	CuI	DMSO	100	31	1:0
9	1	CuI	1,4-dioxane	100	36	1:0
10	1	CuI	DMF	100	NF	1:0
11	1	CuI	PEG-400	100	58	1:0
12	1	CuI	Toluene	100	61	1:0
13 f	1	CuI	DMSO	100	65	1:0
14	1	CuI	DMSO	80	60	1:0
15	1	CuI	DMSO	120	88	1:0.5
16	1	CuI	DMSO	140	90	1:0.7
17	0.5	CuI	DMSO	120	87	0:1
18	0.5	CuI	DMSO	100	66	0.2:1
19	0.5	--	DMSO	120	NF	--

^a Reaction using 2-azidobenzaldehyde 1 (0.5 mmol), anthranilamide 2 (0.5 mmol) and phenylacetylene 3a (0.5 mmol) in the presence of copper salt as catalyst, Et₃N as base, in 1.5 mL of solvent fo 16 h. ^b Yield of 5a + 6a. ^c Determined by ¹H NMR. ^d Used 20 mol% of CuI. ^e Used 5 mol% of CuI. ^f Reaction using 2.0 equiv of phenylacetylene 3a. NF = not formed.

).

When the same conditions of Figure 3 (Table 1, entry 1) were performed using other copper(I) salts, such as CuBr and CuCl, it was observed a significant decrease in the yield of product 5a, from 82% to 21% and 27%, respectively (Table 1, entry 1 vs. entries 2–3). When copper(II) salts like CuBr₂, CuCl₂, and Cu(OAc)₂·H₂O were tested, only the latter afforded the expected product 5a, in 38% yield (Table 1, entries 4–6 ). By increasing the amount of the best catalyst (CuI) to 20 mol%, the yield of 5a was the same, whereas when we decrease the catalyst charge to 5 mol%, a decrease in the yield to 31% was observed (Table 1, entry 7–8). By fixing 10 mol% of CuI as catalyst, the following studies were intended to verify which would be the best solvent for the reaction. When 1,4-dioxane was used, the product 5a was obtained in 36% yield (Table 1, entry 9), while no product was observed when N,N-dimethylformamide (DMF) was used as solvent (Table 1, entry 10). Polyethylene glycol (PEG-400) and toluene were also tested, affording the product 5a in 58% and 61% yield, respectively (Table 1, entries 11,12). These outcomes indicate that DMSO is the best solvent for the synthesis of 5a. When a large excess of phenylacetylene 3a was used (2.0 equiv), compound 5a was obtained in 65% yield, a lower yield than that observed using an equivalent amount (Table 1, entry 13 vs. entry 1). A decrease in the reaction performance was observed at 80 °C instead of 100 °C, with product 5a being obtained in 60% yield (Table 1, entry 14). Notably, when higher temperatures were evaluated (120 and 140 °C), the formation of the aromatic quinazolin-4(3H)-one 6a was detected (Table 1, entries 15–16). The overall yield refers to the mixture of compounds 5a and 6a as this cannot be separated by column chromatography. The mixture of products could be observed in the ¹H NMR spectrum of the crude reaction.

Our next aim was then establishing an optimal condition to selectively lead to the formation of the aromatic quinazolinone 6a. Firstly, the amount of base was reduced in order to verify its influence in the oxidation stage; using equivalent amount of Et₃N at 120 °C, the aromatic product 6a was exclusively obtained in 87% yield (Table 1, entry 17). However, both the selectivity and the yield were diminished when the temperature was reduced to 100 °C (66% yield; 5a:6a ratio: 0.2:1) (Table 1, entry 18 vs. entry 17). Finally, the role of the catalyst was verified, the formation of products 5a and 6a was not observed in the absence of CuI (Table 1, entry 19). Compound 6a, once isolated, was characterized by high- and low-resolution mass spectrometry, ¹H and ¹³C NMR, and X-ray diffraction analysis (data are described in Supplementary Materials). Selected bond lengths (Å) and angles (°) for compound 6a are summarized in Table S2 (Supplementary Materials).

Thus, with the best condition to prepare the triazoylquinazolin-4(3H)-one 6a in hand (Table 1, entry 16), this methodology was expanded to the reaction of 2-azidobenzaldehyde 1 and anthranilamide 2 with a variety of alkyl and aryl terminal alkynes 3a-n (Figure 4).

When analyzing the results shown in Figure 4, it is observed that the developed protocol tolerates a range of substituents in the alkynes counterpart. For instance, the variation of the groups at the para-position of the pendent phenyl ring, did not influence in the reactivity, and both electron-donating and electron-withdrawing substituents afforded the expected product 6 in around the same average yield. For instance, the electron-rich compounds 6b (R = 4-Me), 6c (R = 4-Et), 6d (R = 4-^tBu), and 6e (R = 4-OMe) were obtained respectively in 54%, 67%, 51% and 66% yield, while the electron-poor one 6g (R = 4-Cl) was isolated in 60% yield (Figure 4). The presence of an ortho-substituent, however, caused a decrease in the yield, probably due a slightly steric hindrance compared to the para-substituted analogs, and compound 6f (R = 2-OMe) was obtained in 42% yield. A good result was obtained starting from 2-ethynylnaphthalene (3h), with the desired product 6h being obtained in 63% yield, while the aliphatic 1-hexyne (3i) afforded 6i in 57% yield after reaction with 1 and 2. The effect of the presence of different functional groups in the alkyne evaluated. Propagyl alcohols 3j and 3k satisfactorily reacted to afford the respective products 6j and 6k in 41% and 52%, respectively. In the case of 1-ethynylcyclopentanol (3k), an inseparable mixture of aromatic (6j) and non-aromatic (5j) products was obtained. The method was suitable also to ethyl propiolate (3l); however the expected product 5l was obtained in only 20% yield, with the formation of several by-products. Interestingly, alkynyl selenide 3m and alkynyl sulfide 3n could be converted to the respective selenium- and thio- derivatives 5m and 5n in 53% and 55% yield, respectively.

Thus, based on our results, and on studies described in the literature [38,47,48,49,50,51], a plausible mechanism for the multicomponent synthesis of quinazolinones functionalized with 1,2,3-triazoles 6 was proposed (Figure 5). Firstly, the triazole nucleus is formed, through the reaction between the terminal alkyne 3, Et₃N and CuI, generating the copper acetylide intermediate A. Then, intermediate A reacts with 2-azidobenzaldehyde (1), through the complexation of the nucleophilic nitrogen from azide with the metal, forming of intermediate B. The β-vinylidene attack of copper(I) acetylide to the terminal electrophilic nitrogen of the azide occurs, affording the unstable six-membered ring C, which undergoes a ring contraction to give the copper triazoyl D [38]. After a protolysis step, the intermediate E is formed and the copper catalyst is regenerated in the catalytic cycle. In the sequence, a condensation reaction occurs by the nucleophilic attack of the nitrogen atom of the amino group of the anthranilamide (2) to the carbonyl of intermediate E, eliminating a water molecule and affording the intermediate F. Then, an intramolecular cyclization reaction occurs after a nucleophilic attack from the amide nitrogen to the imine carbon, forming the triazoyl-2,3-dihydroquinazolinone 5, which is oxidized in the reaction media [52,53,54] to the more stable aromatic quinazolin-4(3H)-one 6 (Figure 5).

3. Materials and Methods

3.1. General Information

The reactions were monitored by TLC carried out on Merck silica gel (60 F₂₅₄) by using UV light as visualizing agent and 5% vanillin in 10% H₂SO₄ and heat as developing agents. Baker silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Hydrogen nuclear magnetic resonance spectra (¹H NMR) were obtained at 400 MHz on Bruker DPX 400 spectrometer. Spectra were recorded in DMSO-d6 solutions. Chemical shifts are reported in ppm, referenced to tetramethylsilane (TMS) as the external reference. Coupling constants (J) are reported in Hertz. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), quin (quintet), sex (sextet) and m (multiplet). Carbon-13 nuclear magnetic resonance spectra (¹³C NMR) were obtained at 100 MHz on Bruker DPX 400 spectrometer. Chemical shifts are reported in ppm, referenced to the solvent peak of DMSO-d6. Low-resolution mass spectra were obtained with a Shimadzu GC-MS-QP2010 mass spectrometer. High resolution mass spectra (HRMS) were recorded on a Bruker Micro TOF-QII spectrometer 10416. The collection of X-ray diffraction data of compound 6a was performed on a Bruker D8 Quest diffractometer equipped with a Photon 100 detector, Incoatec microfocus Montel optic X-ray tube with Cu-Kα radiation (1.54178 Ǻ). Structure solutions and refinements were done through direct methods, with the SHELX program package [55,56]. Hydrogen atoms were included in the refinement at calculated positions. The graphical representation of the crystal structure was performed using the DIAMOND program (version 4.6.0) [57]. The crystallographic information file (CIF) for the compound 6a was deposited at the Cambridge Crystallographic Data Centre (CCDC) under identification number 2106971. Crystal data and more details of the data collection and refinement of 6a is provided in Table S1 (Supplementary Materials).

3.2. General Procedure for the Synthesis of Triazoylquinazolin-4(3H)-ones 6a–n

In a test tube was added 2-azidobenzaldehyde (1, 0.5 mmol), anthranilamide (2, 0.5 mmol), CuI (10 mol%). Then, DMSO (1.5 mL) was added, followed by triethylamine (0.5 mmol) and the terminal alkyne 3a–n (0.5 mmol). The system was heated to 120 °C under a nitrogen atmosphere and magnetic stirring for 16 h. Afterwards, the organic phase was received in water (20 mL), extracted with dichloromethane (3 × 10 mL), dried with MgSO₄, and concentrated on a rotary evaporator followed by a vacuum pump. Finally, a purification by column chromatography of silica gel as a stationary phase, and a mixture of hexanes/ethyl acetate as eluent (50/50) was performed, providing the desired products 6a–n (20–87%).

4. Conclusions

In this work, an efficient method was developed for the synthesis of a series of unprecedented quinazolinones functionalized with 1,2,3-triazoles in modrate to good yields. The reaction involves a 1,3-dipolar cycloaddition between terminal alkynes and 2-azidobenzaldehyde, to obtain the triazole nucleus, followed by a cyclocondensation with anthranilamide to form the quinazolinone nucleus, which is oxidized in situ to the aromatic product. Fourteen new compounds (6a–n) were obtained in yields from 20 to 87%, presenting in their structure different substituents with a diversity of functional groups, including aryl, naphthyl, alkyl, ester, alcohol, as well as sulfide and selenide.