2-Azidobenzaldehyde-Enabled Construction of Quinazoline Derivatives: A Review

Abstract

Quinazoline is a privileged heterocyclic scaffold commonly found in numerous pharmaceuticals and bioactive natural products, known for its diverse biological activities. The pursuit of efficient and versatile synthetic methods to produce quinazoline derivatives remains a central focus for organic and medicinal chemists, owing to the therapeutic potential of these compounds. This paper reviews the innovative use of 2-azidobenzaldehyde-enabled annulation strategies for the synthesis of quinazoline derivatives, including quinazolin-4(3H)-one, 2,3-dihydroquinazolin-4(1H)-one, 3,4-dihydroquinazoline, 3,4-dihydroquinazoline-2(1H)-thione, and 1,2,3,4-tetrahydroquinazoline. Emphasizing both the mechanistic insights and practical advantages, this review highlights the efficacy and applicability of these methods in the domain of heterocyclic chemistry, providing an invaluable framework for future drug discovery and development efforts.

1. Introduction

Quinazoline derivatives are an important class of nitrogen-containing heterocycles that have garnered considerable attention in drug discovery and medicinal chemistry [1,2,3]. Their unique chemical structure allows for versatile modifications, leading to a wide array of pharmacological activities [4,5]. The quinazoline scaffold serves as a core structure in numerous therapeutic agents due to its ability to interact with diverse biological targets. Quinazoline derivatives have been pivotal in drug discovery, serving as key components in the development of treatments for various diseases, such as quinazoline-based drugs in the market (Figure 1) [6,7,8]. Their ability to inhibit critical enzymes and receptors has made them attractive candidates for anticancer, antiviral, antibacterial, and anti-inflammatory drugs [9,10,11]. For instance, several quinazoline-based compounds have been developed as epidermal growth factor receptor (EGFR) inhibitors for treating cancers, particularly non-small lung cancer cells, by impeding tumor growth and proliferation [12,13,14,15].

The synthesis of quinazoline derivatives has seen significant advancements with numerous methodologies developed to efficiently construct these biologically important heterocyclic scaffolds [1,16,17,18,19]. A prominent trend in the synthesis of quinazoline derivatives is the use of transition-metal-catalyzed reactions, which have emerged as indispensable tools in organic synthesis due to their ability to streamline complex procedures, increase yields, and reduce reaction times [20]. Advances in synthetic techniques, including microwave-assisted synthesis [21], green chemistry approaches [22,23], and multicomponent reactions [24,25,26,27], have made it possible to produce quinazolines with high yields and purity.

Quinazoline derivatives, a fascinating class of compounds known for their diverse biological activities, are generally categorized into several key types: 3,4-dihydroquinazoline [28,29], 2,3-dihydroquinazolin-4(1H)-one [30,31,32], 4-quinazolinone [33,34,35,36], 3,4-dihydroquinazoline-2(1H)-thione [37,38], and 1,2,3,4-tetrahydroquinazoline [39,40], which are seen in Figure 2. The synthetic innovations associated with these categories have significantly broadened their applicability, allowing for the creation of novel compounds specifically designed to meet various therapeutic needs.

Among these, 2-azidobenzaldehyde stands out as a particularly versatile synthetic intermediate. This material plays a critical role in the construction of various heterocyclic systems, such as quinolines [41], and quinazolines, owing to its reactive azido group and aldehyde functionalities. The exploration of 2-azidobenzaldehyde-enabled synthesis techniques opens new avenues for the development of quinazoline derivatives, as detailed in this article. Through these innovative methodologies, researchers continue to expand the potential applications of quinazoline derivatives in medicinal chemistry and beyond, addressing complex therapeutic challenges with tailored molecular solutions.

2. Synthesis of Quinazoline Derivatives

2.1. Quinazolines

Quinazoline serves as a crucial pharmacophore in drug discovery. Numerous substituted quinazoline derivatives exhibit remarkable bioactivities, with some having received approval from the Food and Drug Administration (FDA) for clinical use (Figure 1) [42]. An example of synthesizing quinazoline 3-oxides 4 can be found in the Pd(II)-catalyzed three-component reaction (3-CR) involving 2-azidobenzaldehyde 1, isocyanide 2, and hydroxylamine hydrochloride 3 in a one-pot procedure reported by the Sawant group (Scheme 1) [43]. This approach offers significant advantages over traditional methods, which typically rely on prefabricated substrates generated through multistep syntheses. Conventional techniques often suffer from drawbacks such as low yields, harsh reaction conditions, limited substrate scope, and the use of expensive starting materials [44,45,46,47]. In contrast, the Pd(II)-catalyzed strategy provides a more efficient and streamlined pathway to quinazoline 3-oxides 4 with 15 examples in the range of 71–91%.

In general, isocyanides are highly versatile chemicals that enable the rapid assembly of complex molecules. However, their characteristic odor and toxicity, as well as their tendency to undergo undesired side reactions under harsh conditions, require careful handling and consideration of such environmental impact, regioselectivity, and scalability in synthetic applications [48]. Thus, for the validation of mechanistic pathways, authors confirmed that 3-CR proceeds predominantly through the generation of compounds 5 and 6, involving the azide–isocyanide denitrogenative coupling/condensation/6-exo-dig cyclization by a series of control experiments, and denied a pathway via compound 7a (Scheme 2). Pd(II)-catalyzed mechanism was proposed in Scheme 3; initially, coordination of 2-azidobenzaldehyde 1a and isocyanide 2a with Pd(OAc)₂ generates intermediate 8 in mild conditions. This intermediate undergoes nitrogen extrusion to form nitrene intermediate 9. Subsequently, intramolecular isocyanide transfer over the nitrene occurs in a concerted manner, yielding carbodiimide 5a. This reactive carbodiimide then enters the second catalytic cycle, coordinating with palladium metal. During this cycle, the aldehydic functional group of 5a condenses with hydroxylamine 3, resulting in the loss of a water molecule that is trapped by 4 Å molecular sieves. This condensation furnishes hydrazone 12, which subsequently undergoes 6-exo-dig cyclization to produce quinazoline-3-oxide 4a.

Quinazoline-derived azomethine imines (QAIs) have emerged as a compelling class of compounds in this field due to their high reactivity. These QAIs, based on the quinazoline scaffold, can effectively serve as 1,3-dipoles in cycloaddition or formal cycloaddition reactions [49]. This enables the construction of diverse quinazoline-fused polycyclic compounds, highlighting their versatility and potential in synthetic chemistry. Compared to traditional methods that rely on a three-step process involving 2-nitrobenzaldehyde for the preparation of functional azomethine imines 15 [50,51,52]. The Sawant group has developed a more practical approach. They reported a Pd-catalyzed three-component reaction (3-CR) protocol using 2-azidobenzaldehyde 1, tert-butyl isocyanide 2, and sulfonyl hydrazide 14 in tetrahydrofuran to synthesize tert-butylamino-substituted azomethine imines 15 in 65–86% yield (Scheme 4) [53]. This 3-CR method via cross-coupling/condensation/condensation/6-exo-dig cyclization is more efficient in terms of operational simplicity and effectiveness, despite the presence of a substituent on the pyrimidine ring.

2.2. 3,4-Dihydroquinazolines

3,4-Dihydroquinazoline-based compounds have garnered significant attention in both natural product chemistry and pharmaceutical research due to their diverse biological activities and therapeutic potential, such Anagrelide, Letermovir, Quazinone, Vasicine, Linagliptin and Deoxyvasicine (Figure 3). The presence of the 3,4-dihydroquinazoline core in natural products and marketed drugs often contributes to their unique mechanisms of action and biological efficacy, making them valuable leads in drug discovery [28,29,54,55].

In contrast to the reported complex and intricate synthetic protocols [56,57,58,59,60], the synthesis of 3,4-dihydroquinazoline derivatives via Ugi-initiated approaches [61,62,63,64], and azomethine imines-promoted one-pot processes [49] is systematic, straightforward, and easy to implement. These methods are associated with detailed and specific mechanistic studies, ensuring good reproducibility and offering potential for further in-depth exploration. By enhancing operational efficiency, these methodologies provide a robust platform for advancing research, leading to deeper levels of understanding and innovation in the field.

Among these efforts, the Sawant group reported a series of innovative syntheses of 3,4-dihydroquinazoline derivatives, enabled by 2-azidobenzaldehyde and executed through a four-component reaction (4-CR). This process involves the generation of azomethine imines 15, followed by a 1,3-dipolar cycloaddition to drive the diversity-oriented synthesis (DOS) [65,66] of 3,4-dihydroquinazoline derivatives, providing the means to explore uncharted chemical and biological spaces, ultimately driving forward the discovery of new and effective therapeutics. Initially, they demonstrated a 4-CR using four versatile privileged synthons: 2-azidobenzaldehyde 1, isocyanide 2, sulfonyl hydrazide 14a, and alkynes 17. This reaction, promoted by the transition metal catalysts Pd(OAc)₂ and AgOTf, yielded pyrazolo[1,5-c]quinazolines 18 (Scheme 5) [67]. The 4-CR process efficiently generates five new chemical bonds, producing diverse compounds 18, with 32 examples yielding between 46 and 97% in a single operation. Moreover, substituting alkynes 17 replaced by electron-deficient alkenes 19, such as acrylates and acrylonitrile, facilitates the one-step synthesis of tetrahydropyrazolo[1,5-c]quinazolines 20. This 4-CR mechanism was validated through a stepwise synthetic process, demonstrating that azomethine imines 15 was formed via the azide–isocyanide denitrogenative coupling, condensation, and 6-exo-dig cyclization, then followed by 1,3-dipolar cycloaddition to yield compounds 18 and 20. These powerful molecules underwent cell viability assays, revealing excellent cytotoxic effects and strong inhibition of EGFR, with docking studies highlighting hydrogen bonding interactions with key amino acid residues, namely Met769, Glu738, and Thr766 [67].

Subsequently, the Sawant group investigated the scalability of 4-CR using 1,3-dipolar cycloadditions of azomethine imines 15, employing various dipolarophiles in a one-pot approach. Authors synthesized azomethine imines 15a from a 3-CR of 2-azidobenzaldehydes 1, isocyanides 2, and tosyl hydrazides 14a. These were then used to produce pyrazolo[1,5-c]quinazolines 22 and 24 by incorporating dipolarophiles like 21 and 23 in the 1,3-dipolar cycloaddition process (Scheme 6) [68]. Furthermore, one-pot two-step reaction conditions were optimized using 1,4-diazabicyclo[2.2.2]octane (DABCO) and DABCO/I₂ under palladium catalysis at 100 °C for 2 h, yielding compounds 22 with 13 examples ranging from 73 to 93%, and compounds 24 with 5 examples, yielding between 65 and 87%.

Additionally, a Pd-catalyzed 4-CR involving 2-azidobenzaldehyde 1, isocyanides 2, sulfonyl hydrazides 14, and 2-(trimethylsilyl)-phenyltriflates 25, the latter serving as an aryne precursor, was explored for the cascade synthesis of fluorescent indazolo[2,3-c]quinazolines 26 (Scheme 7) [69]. This resulted in 16 examples with yields between 63 and 82%. These compounds demonstrated absorption in the visible region, high quantum yield fluorescence, and excellent photostability. This cascade 4-CR encompasses three sequential transformations: (1) palladium-catalyzed formation of azomethine imine; (2) cyclocondensation with hydrazides; and (3) carboamination of aryne [70]. Azomethine imines 15 were synthesized by 3-CR in hand; the Sawant group further explored diverse one-pot 4-componet synthesis by offering nitroolefins 27 and allenoates 29 as dipolarophiles to make 1-nitro-2-aryl-1,2,3,10b-tetrahydropyrazolo[1,5-c]quinazolines 28 and 2-methylpyrazolo[1,5-c]quinazolines 30 in medium yields, respectively (Scheme 8) [53]. This 4-CR was also offered in the DOS of compounds 32 and 34 through using α-halo hydroxamates 31 and cyclic ketones 33 reacting with versatile azomethine imines 15 (Scheme 8).

DOS is a strategic approach in organic synthesis designed to explore novel reaction pathways. It plays a crucial role in drug discovery by generating structurally diverse compounds, thereby identifying potential molecules with a wide range of biological activities [53,65,66]. Zhang group exemplified this approach by using 2-azidobenzaldehyde 1 to promote 1,3-dipolar cycloaddition with amino esters 35 and maleimides 36, resulting in versatile pyrrolidine adducts 37. These adducts contain dual functional NH and N₃ groups, enabling a range of DOS applications through various reaction pathways. Notable pathways include click chemistry, radical reactions, and Staudinger/aza-Wittig reactions, which effectively connect the NH and N₃ groups and expand the diversity of the resulting compounds [71,72]. Recently, Ma and colleagues reported a cascade reaction process through Pd-catalyzed azide–isocyanide coupling/cyclization/lactamization reactions using dual functional intermediates 37 for the synthesis of tricyclic guanidine-containing polyheterocycles 38 with 30 examples in the scale of 47–82% yields (Scheme 9) [73].

In 2010, Ding group reported a stepwise Biginelli/Staudinger/aza-Wittig process to construct 3,4-dihydroquinazoline derivatives, which involves the preparation of dual functional adducts 41 by 3-CR with 2-azidobenzaldehyde 1a, ethyl acetoacetate 39, and urea 40, followed by one-pot Staudinger and aza-Wittig reactions to give carbodiimides 43 without the isolation of iminophosphoranes 42, then cyclized easily to afford pyrimido[1,6-c]quinazolin-4-ones 44 in moderate to good overall yields in the presence of catalytic amount of potassium carbonate in acetonitrile (CH₃CN) at room temperature (Scheme 10) [74]. This strategy was also applied to make compounds 46 with 17 examples in the scale of 61–92% yields by the reaction of iminophosphoranes 42 with acyl chloride.

Ding group reported a second example of 3,4-dihydroquinazoline synthesis using an Ugi/Staudinger/aza-Wittig sequence. This method produced 33 examples of compound 51 with yields ranging from 35% to 93%. Initially, adducts 49 were synthesized with yields of 66% to 92% through a 4-CR (Ugi) involving substrates 1a, 2, 47, and 48. This was followed by a one-pot Staudinger/aza-Wittig process, as depicted in Scheme 11 [64]. Some of the products 51 with dual functional sites prepared by Ugi reaction of 2-bromobenzenamine 48a, cinnamic acids 47, 2-azidobenzaldehyde 1a, and isocyanide 2, could be implemented in an intramolecular Heck cyclization under Pd-catalysis to give tetracyclic 3,4-dihydroquinazolines 52 with four cases in the range of 58–77% yield (Scheme 12) [64].

Furthermore, the Ding group explored the DOS of the Ugi/Staudinger/aza-Wittig sequence using a variety of substrates in a stepwise manner. They reported a third example for the synthesis of indolo[1,2-c]quinazolines 56, achieving 18 examples with yields ranging from 55% to 92% (Scheme 13) [75]. The synthesis utilized 2-acylaniline 53 in an Ugi 4-CR. Under the experimental conditions, benzodiazocine 57 was not detected; instead, indolo[1,2-c]quinazoline 56 was obtained. This outcome is likely attributed to the restricted conformation of iminophosphorane 55, which may be entropically unfavorable for cyclization between the iminophosphorane moiety and the ketone carbonyl group.

Similar to last case for compound 56, authors developed a DOS example by using benzoylformic acid 58 in Ugi reaction to synthesize multi-functional intermediates 59 with 14 examples ranging from 64% to 91%, then followed by a one-pot Staudinger/aza-Wittig approach to produce 2-acylquinazolines 61 (10 examples, 36–92%) and/or 3H-1,4-benzodiazepin-3-ones 62 (6 examples, 36–92%) in Scheme 14 [76].

Additionally, the Ding group reported a synthesis sequence involving Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution reactions to produce 3,4-dihydroquinazolines 70. This sequence begins with the synthesis of azides 64, yielding 8 examples with yields ranging from 75% to 87% via a three-component Passerini reaction. The azides were then reacted with PPh₃ and phenyl isocyanates 66 through Staudinger/aza-Wittig reactions to generate carbodiimides 67. These compounds were subsequently treated with diethylamines 68 to form guanidine intermediates 69. Finally, under reflux in CH₃CN with K₂CO₃, 18 examples of 3,4-dihydroquinazolines 70 were obtained with yields between 42% and 85%, as illustrated in Scheme 15 [77].

Yao and Zhu group reported a novel approach to follow a four-component reaction of Ugi-azide for making intermediates 72 with dual functional sites involving NH and azide groups, then implemented the one-pot synthesis of 3,4-dihydroquinazolines 75 with 17 examples in the range of 56–90% by Pd-catalyzed azide–isocyanide coupling and cyclization (Scheme 16) [63].

2.3. 2,3-Dihydroquinazolin-4(1H)-One and 4-Quinazolinone

2,3-Dihydroquinazolin-4(1H)-one derivatives have garnered significant attention in pharmaceutical research due to their diverse pharmacological activities. These compounds, often derived from natural sources, serve as pivotal scaffolds in medicinal chemistry, contributing to the development of novel therapeutic agents such as Fenquizone, Quinethazone, Evodiaming, Metolazone, and Febrifugine (Figure 4).

The synthesis of 2,3-dihydroquinazolin-4(1H)-one typically involves the condensation of anthranilic acid derivatives with carbonyl compounds such as aldehydes or ketones. This process often utilizes catalysts, which can include Lewis acids or Bronsted acids, to promote the cyclization and formation of the quinazolinone core [78,79,80]. In another approach, isatoic anhydride is reacted with amines in the presence of a suitable reagent to yield the target compound. The synthesis can be adjusted to incorporate various substituents on the quinazolinone scaffold, allowing for the exploration of its diverse chemical space [81,82]. In addition, the Alves group reported a three-component reaction with 2-azidobenzaldehyde 1a, phenylacetylene 76a, and anthranilamide 77a to make triazoyl-2,3-dihydroquinazolinone 78a isolated in 82% yield, which was characterized by high- and low-resolution mass spectrometry, ¹H and ¹³C NMR analysis. This Cu-catalyzed mechanism for making 78a in dimethyl sulfoxide (DMSO) was proposed: click chemistry with 76a and azide group of 2-azidobenzaldehyde 1a was completed to give triazole 82, and followed by an intramolecular cyclization reaction after a nucleophilic attack from the amide nitrogen 82a to the imine carbon 83 (Scheme 17) [83]. They also explored this 3-CR to make heterocycles 85 with 17 examples ranging from 34% to 98% yield, and compounds 87 with 15 examples in the scale of 17–98% through using diamine 84a and thiourea 86a instead of 77a, respectively (Scheme 18) [84,85].

Furthermore, similar to 3,4-dihydroquinazolines in biological interests, the versatility of the 4-quinazolinone scaffold allows for varied structural modifications to enhance efficacy and specificity, contributing to its continued interest and exploration in drug discovery (Figure 5). The construction of 4-quinazolinone typically involves cyclization of anthranilic acid or isatoic anhydride [79,81,86]. Based on the Cu-catalyzed synthesis of 3,4-dihydroquinazolines 78a, the Alves group further offered optimal reaction conditions involving 3-CR of with 2-azidobenzaldehyde 1a, phenylacetylene 76a, and anthranilamide 77a to synthesize 4-quinazolinones 88 with 14 examples ranging from 20% to 67% yield via in situ aromatic oxidation (Scheme 19) [83].

2.4. 3,4-Dihydroquinazoline-2(1H)-Thione

3,4-Dihydroquinazoline-2(1H)-thione is a heterocyclic compound that has garnered interest in drug discovery due to its potential biological activities. Compounds containing the quinazoline scaffold, including 3,4-dihydroquinazoline derivatives, have been studied for their pharmacological properties, such as anticancer, anti-inflammatory, anti-microbial, anti-malarial, and anti-melanogenesis activities, such as bioactive compounds in Figure 6 [4,87,88,89]. The synthetic route for 3,4-dihydroquinazoline-2(1H)-thione typically involves the cyclization of a precursor, such as anthranilic acid or an isatoic anhydride, with a suitable thiourea component [90,91].

Ding and co-workers developed a Biginelli/Staudinger/aza-Wittig sequence to make 3,4-dihydroquinazolines 44 and 46 (Scheme 10) involving a stepwise synthesis of intermediates 42 by Biginelli/Staudinger process. This strategy also facilitates making 3,4-dihydroquinazoline-2(1H)-thiones 90a and 90b with 82% and 86% yield through 42 reacting with carbon disulfide (CS₂) in aza-Wittig reaction, illustrated in Scheme 20 [74].

Similar to one-pot sequential Ugi–azide/Pd-catalyzed azide–isocyanide cross-coupling/cyclization reaction to make 3,4-dihydroquinazolines 75 in Scheme 15, Ding group also developed a sequential Ugi–azide/Staudinger/aza-Wittig/cyclization reaction to accomplish the stepwise synthesis of 3,4-dihydroquinazoline-2(1H)-thiones 91 with 17 examples ranging from 75% to 94% yield. The whole reaction process underwent Ugi–azide 4-CR to give intermediate 72, then followed by Staudinger reaction to provide compounds 92, and aza-Wittig reaction reacting with CS₂ to obtain adducts 93, finally afforded compounds 91 via cyclization (Scheme 21) [92]. Generally, the synthesis of 3,4-dihydroquinazoline-2(1H)-thiones using CS₂ suffers from challenges in toxicity, volatility, flammability, handling, and storage difficulties; it is essential to have an insight into human health and environmental hazard [93].

Furthermore, the Zhang group reported two examples of synthesizing 3,4-dihydroquinazoline-2(1H)-thiones using carbon disulfide (CS₂) through a sequential Staudinger/aza-Wittig/cyclization reaction. The initial example was accomplished via a one-pot process involving a 1,3-dipolar cycloaddition, followed by Staudinger, aza-Wittig, and cyclization reactions. Specifically, intermediate 37 was derived from a three-component [3+2] cycloaddition involving 2-azidobenzaldehyde 1, amino esters 35, and maleimides 36 as substrates. This was subsequently followed by Staudinger/aza-Wittig/cyclization reactions without the need for intermediate purification, successfully yielding the 3,4-dihydroquinazoline-2(1H)-thione 94 across 15 examples, with yields ranging from 42% to 73% (Scheme 22) [94]. Recently, they developed the second case to make 3,4-dihydroquinazoline-2(1H)-thiones 98 with 16 examples in the scale of 70–93% yield via a one-pot reductive amination/ Staudinger/aza-Wittig/cyclization reaction (Scheme 23) [95].

2.5. 1,2,3,4-Tetrahydroquinazoline

The core structure of 1,2,3,4-tetrahydroquinazoline and its derivatives is of significant interest due to their diverse biological activities in drug discovery. 1,2,3,4-Tetrahydroquinazoline is a chemical building block that can be synthesized using a variety of methods, typically involving the condensation of an appropriate carbonyl compound with an amine derivative, often in the presence of catalysts. One common approach involves the use of anthranilic acid derivatives and aldehydes, followed by cyclization and reduction steps to produce the tetrahydroquinazoline framework. Zhang group utilized a three-step synthesis to make 1,2,3,4-Tetrahydroquinazolines 103 with 10 examples ranging from 88% to 93% yield, which underwent a one-pot two-step process to make 15 examples of adducts 101 in the scale of 43–73% involving three-component 1,3-dipolar cycloaddition of 2-azidobenzaldehyde 1, amino esters 35, and maleimides 36, [3+2] cycloaddition and denitrogenation of compounds 37 reacting with the second equivalent of maleimides 36′. Subsequently, 1,2,3,4-Tetrahydroquinazolines 103 were generated by cyclization of adducts 101 reacting with formaldehyde (Scheme 24) [96].

3. Conclusions

This paper presents 2-azidobenzaldehyde-enabled reactions for synthesizing various quinazoline derivatives, including 3,4-dihydroquinazoline, 2,3-dihydroquinazolin-4(1H)-one, 4-quinazolinone, 3,4-dihydroquinazoline-2(1H)-thione, and 1,2,3,4-tetrahydroquinazoline. These biologically significant quinazoline systems are frequently found in natural products and marketed drugs. The 2-azidobenzaldehyde-initiated approach can be developed into one-pot stepwise syntheses or multicomponent reactions for enhancing operational simplicity, process efficiency, step, pot, and atom economy in sustainability and green chemistry integration. Some of the synthetic methods introduced in this paper provide novel pathways for synthesizing quinazolines, which can also be applied to the synthesis of other heterocyclic blocks. The future of 2-azidobenzaldehyde as a versatile precursor lies in sustainable methodologies, computationally guided design, and the creative exploration of new chemical spaces. Addressing these challenges will enhance its value as a synthetic promoter and drive innovation across multiple scientific disciplines.