Recent advances in metal-free functionalization of 1,4-benzoxazin-2-one scaffolds

Abstract

Transition metal free methodologies have emerged as sustainable alternatives for the functionalization of biologically important heterocylic scaffolds. Among the heterocycles 1,4-benzoxazin-2-one has attracted considerable interest owing to its diverse pharmaceutical and agrochemical applications. In this review, we summarize the recent advances in the transition metal-free functionalization of 1,4-benzoxazin-2-one, highlighting the organocatalytic transformations, main group Lewis acid/base promoted reactions, visible-light mediated and ultrasound assisted multicomponent reactions. Special emphasis is given to methodologies that enable the efficient synthesis of biologically active 1,4-benzoxazin-2-one derivatives. The reaction scope, mechanistic aspect, regio and stereoselectivity, and synthetic applications of these methodologies are critically discussed to provide a comprehensive overview of this rapidly developing area.

Transition metal free methodologies have emerged as sustainable alternatives for the functionalization of 1,4-benzoxazin-2-one scaffolds, providing efficient access to biologically important heterocylic scaffolds.

1. Introduction

Heterocyclic compounds comprise one of the most important classes of molecules in modern organic and medicinal chemistry owing to their broad occurrence in natural products, pharmaceuticals, and functional materials. Among the diverse nitrogen and oxygen-containing heterocycles, 1,4-benzoxazin-2-one and its partially hydrogenated analogue, 3,4-dihydro-1,4-benzoxazin-2-one, have attracted significant interest because of their diverse biological activity and synthetic utility. The benzoxazin-2-one framework is a key structural motif found in numerous naturally occurring and biologically active molecules demonstrating a wide spectrum of pharmacological properties, including antibacterial, antimicrobial, anti-inflammatory, and antitumour properties.¹ In addition, several benzoxazin-2-one has been reported platelet aggregration inhibitors, which further illustrate their importance in drug discovery and medicinal chemistry.² Beyond pharmaceutical applications, the utility of the benzoxazine framework extends to agrochemical research, where several commercially important products, such as flumioxazib, trifludimoxazin, have been sucessfully developed.³

The diverse biological and industrial applications of benzoxazinone-based compounds continued to stimulate the development of efficient synthetic strategies for the functionalization of these valuable heterocyclic frameworks.⁴ Despite the remarkable biological importance of benzoxazinone derivatives, their synthesis has traditionally relied on multistep synthesis starting from pre-functionalized precursors or on reactions requiring harsh reaction conditions, thereby reducing compatibility with diverse functional groups and limiting overall synthetic efficiency.⁵ To overcome these limitations, direct C–H functionalization has emerged as an attractive alternative and straightforward synthetic strategy as it enables the direct introduction of different substituent onto readily available benzoxazinone framework without the need of prior substrate modification.⁶ Early progress in this area of direct fuctionalization of benzoxazinone mainly relied on transition-metal catalyzed methodology which provide efficient access to wide variety of functionalized benzoxazinone derivatives.⁶ However, use of transition metals also presents several practical challenges, particularly in the synthesis of pharmaceutical compounds. Even the trace metal residues in the final products require rigorous purification to meet the regulatory standards, often resulting in the increased solvent consumption, higher production costs, and in most of the cases, reduced product yields. These limitations have motivated the search for cleaner and more sustainable synthetic approaches, making transition metal free C–H functionalization an increasingly attractive alternative for the preparation of structurally diverse benzoxazinone derivatives.

In addition to metal free C–H functionalization, 1,4-benzoxazin-2-one scaffolds have also been explored through other important transformations, including metal free asymmetric hydrogenation reactions and asymmetric/non-asymmetric nucleophilic addition to C N bonds. These approaches provide important opportunities for the construction of functionalized benzoxazinones.

The biological activity of benzoxazinone derivatives is highly influenced by the nature, position, and electronic characteristics of the substituents attached to the heterocyclic core.⁷ Even slight structural modification can significantly affect the molecular recognition behavior and interactions with biological target molecules and thus perturb the overall therapeutic potential of these molecules. Furthermore, the unique intrinsic reactivity of the heterocyclic core makes this heterocycle a privileged molecule for systematic exploration of structure–activity relationship (SAR) studies, thereby facilitating the discovery and development of new bioactive molecules. Fig. 1 shows representative examples of 1,4-benzoxazin-2-one derivatives with different pharmacological activities.⁸

Fig. 1. Representative examples of 1,4-benzoxazin-2-one derivatives with their pharmacological activities.

Beyond the synthetic advantage, the adaptation of transition-metal-free methodologies is environmentally preferable. The advantage of adopting these approaches is to minimize the use of metal-based toxic catalysts, hazardous reagents, and energy-intensive processes, thus favoring environmental and economic sustainability.

To achieve metal-free functionalization on the 1,4-benzoxazin-2-one ring under transition-metal-free conditions, a variety of alternative activation modes have been explored. These include organocatalysis using small chiral organic molecules, including amino acids and squaramide derivatives, which have emerged as an effective approach for enantioselective functionalization of benzoxazinones.^11–17 In parallel, main-group Lewis acid/base catalysis such as tris(pentafluorophenyl)borane-based system combined with chiral phosphoric acids, along with visible-light-driven transformations mediated by non-metallic dyes or electron donor–acceptor (EDA) complexes have substantially broadened the range of synthetic strategy available for the benzoxazin-2-one functionalization.^22,27 Physical activation techniques, such as ultrasound-assisted sonochemical activation, have also provided efficient and sustainable alternatives for promoting these transformations.⁹ Collectively these strategies lower the activation energy barriers for either reduction or addition to C N bond or for the formation of new C–C, C–N, C–O and C–P bonds, thus facilitate the formation of product under mild conditions, reducing energy requirements, and improving reaction selectivity, making them valuable approaches for sustainable functionalization of benzoxazinones.

Several reviews have summarized the synthesis, biological significance, and transition metal catalyzed functionalization of 1,4-benzoxazin-2-one derivatives.¹⁰ However, to the best of our knowledge, a comprehensive review dedicated exclusively to the transition metal free functionalization of this important heterocyclic scaffold has not been reported. Over the past two decades remarkable advances have been made through the development of organocatalysis, main-group catalysis, visible-light mediated, and sonochemical approaches providing efficient, selective and environmentally sustainable alternatives to conventional metal-catalyzed protocols.

This review provides a comprehensive overview of recent advances in transition-metal-free functionalization of 1,4-benzoxazin-2-one derivatives. In the present review, metal-free refers to functionalization strategies that proceed in the absence of transition-metal catalysts or reagents.

Particular emphasis is placed on reaction design, activation strategies, mechanistic insights, substrate scope and chemo-, regio-, and stereoselectivity, together with synthetic application of these methodologies for the preparation of biologically active benzoxazinone derivatives.

2. Metal free asymmetric/non-asymmetric functionalization of the C N bond of 1,4-benzoxazin-2-ones

2.1. Asymmetric reduction of the C N bond

The first report on metal free functionalization of benzoxazinone was reported in 2006 by Magnus Rueping and co-workers,¹¹ where he reported Brønsted acid catalyzed enantioselective hydrogenation of benzoxazines, benzothiazines, and 1,4-benzoxazine-2-one. Initially they optimized the reaction with respect to Brønsted acid catalysts, solvent and temperature for the reduction of benzoxazine.

Under optimized reaction condition for the reduction of benzoxazine, they tried scope of 3-aryl-1,4-benzoxazinone-2-ones for this reduction. For this they took 1.25 equiv. of each 3-aryl-1,4-benzoxazinone-2-ones (1a–g) and Hantzsch dihydropyridine (HEH, 2a), Brønsted acid (A, 1 mol%) in CHCl₃ solvent at 60 °C, gave good to excellent yield of the desired products with good enantioselectivities (Scheme 1, 3a–g). They observed that electron donating or electron withdrawing groups present on aryl ring of 3-aryl-1,4-benzoxazinone-2-ones were tolerated under the reaction conditions and reaction is also compatible with 2-thiophen-2-yl-1,4-benzoxazinone-2-ones (3a–g).

Scheme 1. Scope of 3-aryl-1,4-benzoxazinone-2-ones for Brønsted acid catalyzed enantioselective hydrogenation reactions.

They also proposed possible mechanism for this hydrogenation reaction (Fig. 2). Reaction starts with protonation of aryl-1,4-benzoxazinone-2-ones (1a) through Brønsted acid (A) that generate chiral ion pair (B) which then undergo a hydride transfer addition from Hantzsch dihydropyridine (HEH, 2) to produce desired product dihydro-2H-benzoxazinones (3a) and regenerated Brønsted acid (A).

Fig. 2. Possible mechanism for Brønsted acid catalyzed enantioselective hydrogenation of 3-aryl-1,4-benzoxazinone-2-one (1a).

In 2010, Zhang and coworkers¹² reported Lewis base organocatalyzed, highly enantioselective hydrosilylation of benzoxazinones to afford chiral dihydrobenzoxazinones in good yields. In this process, they have optimized and developed an ephedrine-derived Lewis base organocatalyst 5a, which promoted successful hydrosilylation of 3-phenyl-2H-benzo[b][1,4]oxazin-2-one (4a). Consequently, they optimized solvent, reaction time and other parameters to improve the yield and enantioselectivity of the products. The scope of the reaction was investigated with various 3-substituted benzoxazinones. With the optimized conditions, they synthesized a series of dihydrobenzoxazinones 6a–h in good to excellent yields by carrying out the reaction of different substituted benzoxazinones 4a–h (0.5 equiv.) with trichlorosilane (1.0 equiv.), catalyst 5a (10 mol%) and water (0.12 equiv.) in 2 mL of dichloromethane at 0 °C for the specified time (Scheme 2).

Scheme 2. Scope of substrates for hydrosilylation of benzoxazinones (4a–h).

In case of phenylbenzoxazinones, the para or meta substituents present on phenyl ring did not affect the reactivity, but made a decreasing trend in enantioselectivity regardless of their electron-donating or electron-withdrawing nature. The ortho substituted phenyl ring (4c) led to noticeable decrease in both the yield as well as enantioselectivity, possibly due to steric hindrance. In case of 3-heteroaryl-benzoxazinone (4f), the product 6f obtained smoothly in high yield and good ee value. The absolute stereochemical configuration of 6f was also determined as R. The alkyl substituted benzoxazinones (4g and 4h) afforded the products (6g and 6h) in good yield but with poor ee values. In mechanistic point of view, the author suggeted that part of the trichlorosilane broken down in the presence of water to form HCl, which activated the benzoxazinone leading to increased reactivity and enantioselectivity.

The asymmetric hydrogenation of heterocyclic scaffolds having C N bond, is an emerging research methodology in the field of organic synthesis. In 2015 Zhang et al.¹³ explored an enantioselective transfer hydrogenation of different aryl substituted 1,4-benzoxazines (7) and 3-phenyl-2H-1,4-benzoxazin-2-one (8), catalyzed by 1,1′-spirobiindane-7,7′-diol (SPINOL)-derived chiral phosphoric acid, to get the corresponding dihydro-2H-1,4-benzoxazines (3)/dihydro-2H-1,4-benzoxazin-2-one (12) in good yields and excellent enantioselectivities. Zhang and group started with the model reaction of 1,4-benzoxazine 7 (1 mmol) in the presence of Hantzsch ester 9 (1.3 mmol) as the hydride source and a catalytic amount of SPINOL-derived phosphoric acid catalyst S-(10) (10 mol%) at 60 °C. The SPINOL-derived catalyst S-(10) was found to produce better result with the formation of the expected product 11 in 99% yield with 98% ee. After several trials for optimizing solvent, temperature and catalyst loading, the optimum reaction condition was found to be when catalyst S-(10) (1 mol%) was used in the presence of DCM at room temperature (Scheme 3). With this optimized condition in hand, the substrate scope was investigated with various substituted 1,4-benzoxazines (7) to get the corresponding products in good yields. The author also investigated the enantioselective reduction of 1,4-benzoxazin-2-one (8) in benzene at 60 °C, to get the reduced analogue (12) with 99% yield and 98% ee.

Scheme 3. Asymmetric transfer hydrogenation of 1,4-benzoxazines/1,4-benzoxazin-2-one.

The proposed mechanism for the asymmetric reduction of 1,4-benzoxazines/1,4-benzoxazin-2-one (7/8) suggests that initially, the ion pair C is formed by the protonation of (7/8) by SPINOL-derived chiral phosphoric acid catalyst S-(10). Then, the hydride transfer from Hantzsch ester (9) resulted in formation of corresponding dihydro-2H-1,4-benzoxazines/dihydro-2H-1,4-benzoxazin-2-one (11/12) and pyridinium salts D (Fig. 3).

Fig. 3. Plausible mechanism for the asymmetric reduction of 1,4-benzoxazines/1,4-benzoxazin-2-one.

In 2017, Zhang and group¹⁴ reported the synthesis of a chiral phosphoric acid BiCz-POF-1, a carbazolic framework derived from BINOL. In order to get high enantioselectivity, the authors introduced carbazole at the 3,3′-positions of the BINOL-derived phosphoric acid. BiCz-POF-1 showed very good catalytic activity and enantioselectivity for the asymmetric transfer hydrogenation of 1,4-benzoxazines and 1,4-benzoxazinones. The catalytic action of BiCz-POF-1 was investigated by optimizing transfer hydrogenation of 3-phenyl-2H-1,4-benzoxazine derivative (1.25 equiv.) with the Hantzsch dihydropyridine 9 (1.25 equiv.) in the presence of catalyst BiCz-POF-1 (5 mol%) in THF at rt for 24 h, to get the chiral dihydrobenzoxazine in 95% yield with 94% ee. Further to check the versatility of this catalyst as chiral phosphoric acid, the authors also performed the asymmetric transfer hydrogenation of 3-phenyl-benzoxazinone 13 (1.5 equiv.) by using the optimized conditions with Hantzsch ester 9 (1.5 equiv.) in the presence of catalyst BiCz-POF-1 (5 mol%) in CHCl₃ at 40 °C for 24 h, to get the chiral dihydrobenzoxazinone 14 in 95% yield with 96% ee (Scheme 4).

Scheme 4. Asymmetric transfer hydrogenation of 3-phenyl-benzoxazinone using chiral phosphoric acid catalyst (BiCz-POF-1).

In 2022, Gao et al.¹⁵ carried out a chiral phosphoric acid (CPA) catalyzed, highly enantioselective and metal-free ATH of benzoxazinones to give various dihydrobenzoxazinones. The Lewis acid catalyst, borane 16b facilitates hydrogenation of phenanthridine (PD) to produce back the hydrogen donor dihydrophenanthridine.

Gao and his group initially optimised borane 16b for the hydrogenation of PD (18) to produce dihydrophenanthridine with 87% conversion. Thus, it was found that without PD or CPA, borane 16b was unable to facilitate the hydrogenation of benzoxazinone 15a. Various CPAs were screened for ATH process, and it was found that CPA 17 furnished the desired product dihydrobenzoxazinone 19a with 99% yield and 92% ee. Out of the various solvents screened, toluene was found to be the best one.

The scope of substrates for the reduction of benzoxazinones was studied and revealed that substrates 15a–d having different substituents present on the 3-phenyl ring, were well-suited and yielded the corresponding products 19a–d in very good yield and high enantioselectivity (Scheme 5). Under the optimized reaction conditions, they carried out asymmetric transfer hydrogenation of various benzoxazinones 15 (1 equiv.) using borane 16b (5 mol%), CPA 17 (0.5 mol%), and PD (10 mol%) under H₂ gas atmosphere (40 bar) in toluene at 90 °C for 24 h, to get optically active dihydrobenzoxazinones 19 in good to excellent yields with high enantioselectivity (Scheme 5).

Scheme 5. Asymmetric hydrogenation of benzoxazinones (15).

Substrate 15e having a 2-thienyl substituent at C-3 position of benzoxazinone, was also found to be effective to form the product 19e in 69% yield with71% ee. The ATH of 3-methylbenzoxazinone (15f) also gave product (19f) successfully in 98% yield and 64% ee. Substituents present at the C-7 position of benzoxazinones (15g) was well-tolerated, giving the corresponding desired product (19g) in good yields and high ee values. However, the reduction of benzoxazinone15h containing a C-5 substituent (Me) afforded only traces of product, probably due to steric hindrance. This work will motivate researchers to work in the field of asymmetric hydrogenation catalyzed by frustrated Lewis pairs.

The author proposed a probable mechanism for the above asymmetric hydrogenation of benzoxazinones, which starts with the activation of H₂ by borane 16b and PD (18) to form an intermediate (E), followed by formation of dihydrophenanthridine (F) using hydrogen transfer. This compound F will act as a hydrogen donor to facilitate the ATH of benzoxazinones (15), which was supposed to be catalyzed by CPA 17via a transition state (G), yielding the desired products 19 (Fig. 4).

Fig. 4. Plausible mechanism for the asymmetric reduction of benzoxazinones (15).

2.2. Asymmetric nucleophillic addition to the C N bond

In 2016 Lou et al.¹⁶ explored an enantioselective aza-Friedel–Crafts reaction between 3-trifluoromethyl substituted benzoxazinones and 2-substituted pyrroles, catalyzed by chiral phosphoric acid catalyst to get the corresponding dihydrobenzoxazinones having a trifluoromethylated quaternary stereocenter in good yields and enantioselectivities. Initially, the authors investigated the reaction between benzoxazinone derivative (20a, 1 equiv.) and pyrrole (21a) in the presence of chiral catalyst (R)-23 (Ar′ = Ph) (5 mol%), which yielded 92% of product 22a with 20% ee. After several optimization trials for different chiral phosphoric acid catalysts and solvents, the best result was obtained with the use of (R)-SPINOL-derived (R)-23 catalyst in Toluene, giving the product 22a in 96% yield and 91% ee. The scope of the reaction was investigated with this optimized condition by reaction of various substituted trifluoromethylated benzoxazinones (20) and different substituted pyrroles (21), to get the corresponding products (22) in good yields with better ee (Scheme 6), despite the electron-withdrawing or electron-releasing nature of substituents.

Scheme 6. Asymmetric synthesis of trifluoromethylated dihydrobenzoxazinones.

In 2018, Jung and coworkers,¹⁷ reported a regioselective l-proline-catalyzed Mannich reaction of benzoxazinones with various ketones, offering an efficient route to chiral benzoxazinone derivatives. The initial reaction between benzoxazinone and acetone was carried out in the presence of l-proline (30 mol%) and 4 Å molecular sieves in DMSO at room temperature for 1.5 h, which furnished the corresponding Mannich adduct (26a) in 78% yield with an excellent enantiomeric excess of 99%. After that they thoroughly optimized the reaction conditions by examining the effects of catalyst, temperature, solvent, and reaction time. It was observed that the reaction of benzoxazinone 24a (1 equiv.) with acetone (5 equiv.) in the presence of catalyst l-proline (30 mol%) and chloroform at 50 °C for 1.5 h, yielded the desired product 26a in an excellent yield of 82% while maintaining outstanding enantioselectivity (99% ee). The scope of substrates for this reaction was investigated using a diverse range of ketones (linear, cyclic, and aromatic ketones) and substituted benzoxazinones. For this they performed the reactions of different substituted benzoxazinones (24, 1 equiv.) with various pyrroles (25, 5 equiv.) in the presence of l-proline (30 mol%) and chloroform at 50 °C, to get the 3-substituted chiral benzoxazinones (26) in high yields with excellent enantio- and diastereoselectivity (Scheme 7). These reactions were proved to be solvent dependent as the unsymmetrical ketones afforded linear regioisomer as the major product in the presence of chloroform as the solvent, while DMSO favoured branched isomer as the major one.

Scheme 7. Synthesis of 3-substituted chiral 3,4-dihydrobenzoxazinones (26).

The reactions involving aromatic ketones such as 4-chloroacetophenone, proceeded at a significantly slower rate (72 h) to form only 23% of 26d with 97% ee, as compared to those bearing linear alkyl chain-based ketones. Benzoxazinones bearing electron-donating substituents such as methoxy group at C-6 position, underwent conversion to furnish the corresponding product (26g) in good yield (71%) with excellent enantioselectivity (98% ee). In contrast, benzoxazinone containing a strongly electron-withdrawing nitro substituent was found to be unreactive, indicating the necessity of adequate electrophilicity within the cyclic imine moiety for the formation of products. Overall, the broad substrate tolerance and consistently high enantioselectivities demonstrated the wide applicability and synthetic utility of this l-proline-catalyzed methodology.

The preferential formation of the highly branched Mannich products in DMSO was rationalized on the basis of the mechanistic model previously proposed by Frank Glorius and co-workers¹⁸ (Fig. 5). According to this model, reactions involving unsymmetrical ketones preferentially proceed through the more substituted enamine intermediate, which subsequently reacts via transition state I, ultimately driving the reaction to yield the branched Mannich product rather than the linear one. However, in cases where the imine bears sterically demanding substituents, the steric effect overrides this solvent effect and drives the reaction towards the formation of the linear isomer even in DMSO.

Fig. 5. Proposed mechanism for solvent controlled regioselectivity in the Mannich reaction.

The development of asymmetric transfer hydrogenation (ATH) process by using such hydrogen donors that can be regained by the hydrogenation, is of great interest. The metal-free ATH of various unsaturated molecules with regenerable hydrogen donors, is widely reported to take place by the frustrated Lewis pairs (FLPs) catalysed reactions.¹⁹ The aromatic N-heterocycles are well reported for the hydrogenation of various substrates by FLP catalysis.²⁰

Chiral alkenes are widely synthesized by enantioselective catalytic alkenylation,²¹ but the asymmetric metal-free catalytic alkenylation of simple alkenes remained a challenging task for researchers. In 2024, Liu et al.²² explored an asymmetric alkenylation of benzoxazinones with diarylethylenes by employing a B(C₆F₅)₃/chiral phosphoric acid catalyst system to obtain chiral alkenes in good yields with high enantioselectivity (Scheme 8). To start with their idea, they have taken benzoxazinone (28a) and 1,1-diphenylethylene (29a) as the model substrates and reacted in the presence of chiral phosphoric acid (S)-31a (2 mol%) as catalyst in DCM at an ambient temperature, which yielded only traces of desired product 30a. The yield was further improved to 90% with enantioselectivity of 92 : 8 e.r. by the use of catalyst system B(C₆F₅)₃/(S)-31a. Addition of 5 Å molecular sieves in the reaction mixture helped in the acceleration of reaction rate (8h) and improved the enantioselectivity (94 : 6 e.r.). This enantioselectivity was further improved to 97 : 3 e.r.; by lowering the reaction temperature to −20 °C and increasing the concentration. The absolute configuration of target base compound 30a was determined by X-ray diffraction analysis and found to be (R).

Scheme 8. Scope of substrates for asymmetric alkenylation of benzoxazinones (28).

With the optimized conditions in hand, they performed asymmetric alkenylation by reaction of various substituted benzoxazinones 28 (0.1 mmol) and different substituted diarylethylenes 29 (0.12 mmol) using B(C₆F₅)₃ (2 mol%), (S)-31a (2 mol%) and 5 Å molecular sieves (50 mg) in DCM (0.5 mL) at −20 °C for 48 h, to obtain the desired alkenes (30) in good to excellent yields with high value of enantiomeric ratio (Scheme 8). The benzoxazinones having different substituents of varying electronic nature present at C-6, C-7 and C-8 positions, were tolerated well to yield the corresponding products 30a–e in 48–91% yields with 88 : 12 to 97 : 3 e.r. Variations in the phenyl rings of 1,1-diphenylethylenes (29b–29c) were also examined, which also tolerated well to give the corresponding products (30f–g) in good yields and high enantioselectivity. Monosubstitution in 1,1-diphenylethylene (29c) also afforded the product 30g in 85% yield with moderate Z/E ratio (1 : 1.9) and good enantioselectivity (Z: 95 : 5 e.r.; E: 96 : 4 e.r.).

The mechanistic part of above asymmetric alkenylation was studied by control experiments, nonlinear effect experiment and theoretical calculations. DFT studies revealed that B(C₆F₅)₃ enhanced the acidity of chiral phosphoric acid and also helped in activation of imine by interacting with the substrate.

2.3. Nucleophilic addition to the C N bond

Bernal-Evangelista et al.²³ in the year 2026, reported the phosphonylation of 3-substituted 2H-benzo[b][1,4]oxazin-2-ones with dialkyl phosphites, to get the α-aminophosphonates in good yields under metal-free and solvent-free conditions. The novel compounds isolated in this work represent potential scaffolds for further applications in medicinal and organic chemistry. To start with their ideas, the authors initially synthesized 3-substituted 2H-benzo[b][1,4]oxazin-2-ones by simple condensation-cyclization reaction between 2-aminophenol and ethyl-2-oxopropanoate or ethyl 2-oxobutanoate in ethanol at 90 °C for 18 h, which yielded the required starting substrate 32a (R = Me, 60%) and 32b (R = Et, 63%), respectively. Further, they reacted the corresponding 3-substituted benzoxazinones (32, 1 mmol) with different dialkylphosphites (33, 2 mmol) at 80 °C for 1 h, to obtain the corresponding phosphonylated products (34) in good yields (Scheme 9). In this small range of substrate scope, authors also used diphenyl phosphite (6d, R′ = Phenyl), which proved to be inefficient and the corresponding product was not detected, possibly due to steric hindrance.

Scheme 9. Phosphonylation of 3-substituted benzoxazinones (32).

3. Metal free C-3 C(sp³)–H bond functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones

3.1. Metal free C-3 C(sp³)–H bond oxidation of 3,4-dihydro-1,4-benzoxazin-2-ones

In 2020, Huo and co-workers²⁴ reported a catalyst-free, mild method for the C(sp³)–H peroxidation of 3,4-dihydro-1,4-benzoxazin-2-ones (35) using tert-butyl hydroperoxide (TBHP) as an oxidant and peroxide precursor. They optimized several reaction parameters, and the optimization results revealed that TBHP (2 equiv.), in dichloroethane (DCE) at 70 °C under an argon atmosphere, is the optimal condition, delivering the C3-peroxyl product in optimum yield (37a, 84%). The use of cumene hydroperoxide (CHP) in the reaction also delivered the C3-peroxyl products under the same optimized conditions. Later, they investigated a variety of electronically variable 3,4-dihydro-1,4-benzoxazin-2-ones (35), which smoothly underwent C3-peroxidation in the presence of TBHP or CHP under optimized conditions, delivering the respective products in 67–89% yield (37a–i; Scheme 10). Additionally, quinoxalinone derivatives also worked smoothly in the reaction, demonstrating the versatility of the method. It is important to note that other peroxides, such as tert-butyl peroxide, hydrogen peroxide and dibenzoyl peroxide did not work under the optimized set of reaction conditions. Moreover, several synthetic transformations were performed on the installed peroxide functionality, emphasizing the importance of this peroxyl group, especially in terms of post-modification in medicinal chemistry.

Scheme 10. C3-Peroxidation of 3,4-dihydro-1,4-benzoxazin-2-ones (35) using peroxides (36).

The mechanistic investigation results showed that the use of radical scavengers such as TEMPO, BHT, and diphenylethylene in the optimized condition significantly suppressed the yield of C3-peroxyl product, justifying the involvement of a radical mechanism for this transformation. Additionally, the key intermediate formation in mechanistic pathways was further confirmed by radical-trapping experiments and their subsequent ESI-HRMS analysis. Based on the control experiments, the authors proposed that the thermal decomposition of TBHP (36a) generates hydroxyl and tert-butoxy radicals, which abstract a hydrogen radical from the benzoxazinone, giving the carbon-centered radical, which then undergoes radical addition with tert-butylperoxyl radical to produce the respective product (37a; Fig. 6).

Fig. 6. Proposed mechanism for the C-3 peroxidation of 3,4-dihydro-1,4-benzoxazin-2-ones (18).

3.2. Metal free direct C-3 C(sp³)–H bond amination of 3,4-dihydro-1,4-benzoxazin-2-ones

In 2021, Rostoll-Berenguer et al.²⁵ disclosed a metal and photocatalyst-free direct C(sp³)–H amination of 3,4-dihydrobenzoxazin-2-ones (38) or 3,4-dihydroquinoxalin-2-ones using dialkyl azodicarboxylates (DIAD) (39) under visible-light irradiation. The optimization of reaction conditions using dihydroquinoxalin-2-one substrate revealed that irradiation with the visible light (a single blue HP LED) is not essential for this amination process; however, it just accelerates the reaction significantly, demonstrating a higher conversion in shorter reaction times (99% yield in 2 h). Under the optimized set of reaction conditions (irradiation of an HP single LED (450 nm), in CH₃CN as solvent, at room temperature under argon atmosphere), various dihydrobenzoxazin-2-ones (38) decorated with different benzyl and alkyl groups smoothly reacted with DIAD (39) to produce the corresponding C3-aminated products in 50–89% yield (Scheme 11). The method also works for the C3-amination of dihydroquinoxalin-2-one derivatives, yielding the corresponding products in 15–93% yield. The authors also successfully performed one-pot functionalization of benzyl-substituted 3,4-dihydrobenzoxazin-2-one substrate (38a) with DIAD (39) to achieve the respective C3-phosphonated product in 63% yield (41). Moreover, this methodology was successfully extended for the synthesis of biologically relevant rac-GW420867X (Opaviraline) as an antiviral compound. The mild reaction conditions, broad substrate scope and valuable synthetic transformations make this a versatile method to access biologically useful benzoxazinone heterocycles.

Scheme 11. C(sp³)–H amination of 3,4-dihydrobenzoxazin-2-ones (38) using dialkyl azodicarboxylates (DIAD).

The use of TEMPO as a radical scavenger in the optimized reaction did not influence the yield of the corresponding product, which clearly supports the involvement of a non-radical mechanism for this transformation. The reaction is most likely to proceed through the nucleophilic addition of the amine part of the substrate to DIAD to form the zwitter ionic species (J), which, upon dehydrogenation and subsequent elimination of 1H-DIAD anion, leads to the formation of the iminium ion (G). The formed iminium ion (K) was further captured by an in situ-generated 1H-DIAD anion to give the final aminated product (40a; Fig. 7).

Fig. 7. Proposed mechanism for the C(sp³)–H amination of 3,4-dihydrobenzoxazin-2-ones (38a).

4. Metal free radical/polar C-3 C(sp²)–H bond functionalization of 1,4-benzoxazin-2-ones

In 2021, Kim and their research group²⁶ developed an efficient, transition-metal-free route for the direct C(sp²)–H alkylation and acylation of 2-benzoxazinones (42) using 1,4-dihydropyridines (1,4-DHPs; Hantzsch esters, 43) as readily available radical surrogates, Na₂S₂O₈ as an oxidant, in acetonitrile at 50–80 °C. The method demonstrated a broad substrate scope for both 2-benzoxazinones and 1,4-DHPs. 2-Benzoxazinone derivatives bearing various EDGs (–Me, –OMe and –^tBu) and EWGs (–F, –Br, –CN, and –CO₂Et) reacted smoothly with alkyl- or aroyl-substituted 1,4-DHPs under optimized conditions, delivering the corresponding alkylated and acylated products in 22–96% yield (44a–n; Scheme 12). Importantly, 2-benzoxazinones bearing sensitive functional groups (i.e., OH, OTBS, bromomethyl, epoxide, and sulfonamide) reacted well with C4-isopropylated 1,4-DHP under the optimized conditions to afford the corresponding alkylated products in lower yields (22–53%), thereby underscoring the excellent functional-group compatibility of this method. However, the cyclopropyl acyl-substituted 1,4-DHP failed to afford the desired acylated product. Overall, the metal-free nature, simple reaction conditions, broad substrate scope, and excellent functional group compatibility of this method are notable features of this methodology.

Scheme 12. C(sp²)–H Alkylation and acylation of 2-benzoxazinones (42) using 1,4-dihydropyridines (43).

The authors demonstrated the presence of a radical-mediated mechanism for this transformation. This radical-based mechanism was supported by an experiment using TEMPO as a radical scavenger in the optimized reaction, which resulted in complete inhibition of alkylated product formation. However, the iso-propylated-TEMPO adduct was produced in the reaction, as confirmed by NMR studies. Mechanistically, the reaction proceeds by oxidation of the Hantzsch ester by Na₂S₂O₈ to generate the isopropyl radical, which adds to the C3-position of 2-benzoxazinone, followed by oxidation and deprotonation to furnish the end product (44a; Fig. 8).

Fig. 8. Proposed mechanism for the C(sp²)–H alkylation/acylation of 2-benzoxazinones (42a).

In the same year, Zheng et al.²⁷ reported a direct C-3 amination of 2-benzoxazinones or 2-quinoxalinones using newly synthesized O-perhalopyridin-4-yl hydroxylamines as an important source of amidyl radical precursor. The amination reagent was synthesized from inexpensive pentahalo pyridines and monoprotected HONH₂ under basic conditions. They have optimized a series of reaction conditions using a 2-quinoxalinone substrate and observed that using solvent red 43 as photocatalyst with blue-light LEDs (30 W) in DCM provided the optimum yield (87%) of the respective aminated product. In general, photocatalyst-free conditions also yielded the corresponding products in relatively lower yields; however, some of the substrates also yielded equivalent yields of the products. Under the optimized reaction conditions, 2-benzoxazinones smoothly underwent an amination process with O-perfluoropyridin-4-yl hydroxylamine, yielding the corresponding products in 29–43% yield (47a–c; Scheme 13). Majorly, this method exhibited a broad substrate scope of 2-quinoxalinones, giving the respective aminated products in moderate to very good yields. Overall, this method installed an important amine precursor to the benzoxazinone heterocycles, which may serve as potential synthetic intermediates for structural diversification in medicinal chemistry.

Scheme 13. C-3 Amination of 2-benzoxazinones (45) using O-perfluoropyridin-4-yl hydroxylamine (46).

A detailed mechanistic investigation clearly indicated that initially, the reaction of 2-benzoxazinone reacts with O-perchloropyridin-4-yl hydroxylamine, giving the electron donor–acceptor (EDA) complex (L), which, upon SET process, generates amidyl radical. The in situ-generated amidyl radical was added to the C-3 position of 2-benzoxazinone to give the respective aminated product (47a; Fig. 9).

Fig. 9. Plausible mechanism for the C-3 amination of 2-benzoxazinones (45a).

Recently (2026), S. Adapa et al.⁹ reported the sonochemical synthesis of biologically important 3-indolylbenzoxazin-2-one derivatives using heterogeneous Wang-OSO₃H as a reusable catalyst. These compounds are of significant pharmaceutical interest, particularly due to the selective inhibitory activity towards PDE4B over PDE4D, thereby minimizing PDE4D-associated adverse emetic effects such as responses like nausea and vomiting. The scope of the reaction was examined using different benzoxazinones (48) and various N-substituted indoles (49) bearing alkyl and aryl groups, with good tolerance of both electron-donating and electron-withdrawing substituents (Me, F, Cl and OMe) on the N-phenyl ring as well as indole ring. After several trials and optimization of the reaction with respect to different catalysts, resins, catalyst loading, solvent and temperature, they conducted the reactions between different substituted benzoxazinones (48, 1 mmol) and various indoles (49, 1.05 mmol) in the presence of Wang-OSO₃H (10% w/w) as a catalyst and DMF at 60 °C for 4 h under open air and ultrasound irradiation, to get the desired 3-indolylbenzeoxazin-2-one derivatives (50) in good to moderate yields (65–91%) (Scheme 14).

Scheme 14. Synthesis of 3-indolylbenzoxazin-2-ones (50) assisted by ultrasound.

Indoles bearing strongly electron-withdrawing N-substituents like benzoyl (–COPh) and benzenesulfonyl (–SO₂Ph) groups, failed to afford the desired products, probably due to strong electron-withdrawing resonance effect by these substituents. Overall, this ultrasound-assisted Wang-OSO₃H-catalyzed methodology provides a cost-effective single-step synthesis of 3-indolylbenzoxazin-2-one derivatives.

A mechanistic study for this ultrasound assisted C–C bond forming reaction suggests that the catalytic cycle initiates with the Wang-OSO₃H catalyst, which acts as an acid and is stimulated by the ultrasound irradiation. This effectively activates the substrate 1,4-benzoxazinones (48), turning it into a highly reactive intermediate M. The substrate indole (49) acts as a nucleophile and specifically attacks the C-3 position of the activated M intermediate to produce an adduct called N. Immediately after this nucleophilic attack, the newly formed N undergoes deprotonation to restore the aromatic indole forming the third intermediate called O. This O simply undergoes oxidation from the surrounding open air to yield the desired 3-indolylbenzoxazin-2-one derivative (50) (Fig. 10).

Fig. 10. Plausible reaction mechanism for the synthesis of 3-indolylbenzoxazin-2-ones catalyzed (50) by Wang-OSO₃H.

5. Metal free cycloaddition/cycloannulation reactions of 1,4-benzoxazin-2-one

In the same year (2022), Dahiya et al.²⁸ explored the metal-free cyclization reactions between alkylidene acenaphthylenones with 1,4-benzoxazinone derivatives catalyzed by iodine to access benzopyrrolo-oxazinones with high regio- and stereo-selectivity in good yields. Initially, they have taken compounds 51a and 52a as the model substrates and optimised the reaction conditions by screening with various acidic catalysts such as PTSA.H₂O, FeCl₃ and BF₃·OEt₂ in DCM as solvent, which afforded the product 53a in moderate yields (40–65%). Later, molecular iodine (I₂) as catalyst afforded the product in 71% yield using simple filtration method. The use of different bases (triethyl amine, K₂CO₃, DBU) and solvents (MeOH, EtOH, toluene, THF) gave negative results. Consequently, the yield was improved on using acetonitrile (ACN) as the solvent and varying the temperature and amount of catalyst. Acetonitrile is apolar aprotic solvent which accelerated the rate of reaction and enabled the cyclization of product. Finally, with the optimised conditions, authors conducted reactions between various substituted 1,4-benzoxazinones (51, 0.25 mmol) and different substituted alkylidene acenaphthylenones (52, 0.25 mmol) using I₂ (50 mol%) in ACN (3 mL) at 70 °C for 45 min to get the desired products (53) in good yields (Scheme 15).

Scheme 15. Synthesis of benzopyrrolo-oxazinones (53).

They found that reactions of 1,4-benzoxazinone having electron-withdrawing nitro group led to the formation of products 53b, 53c, 53d in 64–71% yield (Scheme 15). All the other substrates were well tolerated and corresponding products were isolated in 79–92%, irrespective of electronic nature of the substituents.

They proposed the mechanism for the synthesis of above series of benzopyrrolooxazinones (53) which suggested that reaction facilitates with the activation of the carbonyl group of alkylideneacenaphthylenone (52a) by electrophilic molecular iodine. Nucleophilic attack of exocyclic double bond present in benzoxazinone (51a) takes place at the β-carbon of enone functionality present in 52a, leading to formation of enolate intermediate (P). Proton transfer formed the Michael adduct (Q), which upon followed by intramolecular-cyclization led to formation of carbinol intermediate (R). Finally, dehydration of intermediate R resulted in desired product (53a) (Fig. 11).

Fig. 11. Proposed mechanism for the synthesis of benzopyrrolo-oxazinone (53a).

In the same year (2024), Liu et al.²⁹ reported an asymmetric aza-Diels–Alder reactions between benzoxazinones and unactivated dienes by using the catalytic system B(C₆F₅)₃/chiral phosphoric acid to synthesize chiral tetrahydropyridine derivatives. These products were later found to get oxidized and emit light showing photoresponsive luminescence effect used in the anticounterfeiting of QR codes. This luminescence mechanism was studied by performing control reactions, light/dark experiments, and analysis of NMR and HRMS.

The optimization of the reaction conditions revealed that (S)-57a and B(C₆F₅)₃ is only effective when used together as a catalyst system. This catalytic system lowers the LUMO orbital of benzoxazinone to match with the HOMO of diene, for the feasibility of aza-Diels–Alder reaction. After several optimization trials, authors carried out reactions between different substituted benzoxazinones (54, 0.1 mmol) and dienes (55, 0.2 mmol) in the presence of B(C₆F₅)₃ (2 mol%) and (S)-57a (2 mol%) in mesitylene (1.0 mL) at −40 °C for 12 h, to obtain the chiral products (56) in good to excellent yields with high enantioselectivity (Scheme 16). The scope of the reaction was investigated and found that the reactions tolerated well with various benzoxazinones having electron-releasing or electron-withdrawing substituents to get the desired products in very good yields (70–99%) with high enantioselectivities (78–99% ee). Low yield was only reflected in the compound 56c, having a strong electron-releasing group (CH₃O) at C-7 position of benzoxazinone ring.

Scheme 16. Asymmetric aza-Diels–Alder reactions of benzoxazinones (54).

Another significant advancement in the synthesis of medicinally important chiral benzoxazinone derivatives was reported by Wang and coworkers in 2025.³⁰ The authors developed a metal-free organocatalyzed asymmetric [3 + 2] cycloannulation of benzoxazinones with isatin-derived ketimines, providing an efficient access to structurally complex imidazo[5,1-c]oxazinones with excellent stereoselectivities and high yields. After several trials and optimization with respect to catalysts and solvents, the authors with optimized conditions in hand, conducted reactions between various substituted benzoxazinones (58, 0.20 mmol) and isatin derivatives (59, 0.10 mmol) in the presence of squaramide organocatalyst 61a (0.02 mmol) in toluene at 40 °C, to get the desired imidazo[5,1-c]oxazinones (60) in good yields with high enantioselectivities (Scheme 17).

Scheme 17. A metal-free organocatalyzed synthesis of imidazo[5,1-c]oxazinones (60).

The reaction shows a broad substrate tolerance with both electron-donating and electron-withdrawing substituents present on the benzoxinones as well as isatin moieties, furnishing the corresponding imidazo[5,1-c]oxazinone derivatives (60) in moderate to good yields (54–84%) and with consistently high enantioselectivities (80–99% ee). A range of N1-substituents (ethyl, isopropyl, allyl, and benzyl) present on the isatin were also found to be well tolerated, furnishing the corresponding products in good yields (76–84%) with excellent stereocontrol (90–96% ee). Thus, the reactions showed a broad substrate scope and excellent functional group tolerance, and have potential for utilization in other reactions to construct various N-heterocyclic scaffolds.

To rationalize the observed stereochemical outcome, the author proposed a plausible Mannich cascade reaction mechanism for asymmetric [3 + 2] cycloannulation (Fig. 12).The catalytic cycle is initiated by activation of isatin-derived ketimine (59a) through hydrogen bonding interaction with squaramide organocatalyst (S), leading to the formation of intermediate T. Subsequently, the activated ketimine (59a) then undergoes a stereoselective Michael addition with benzoxazinone through the Si face, furnishing intermediate U. This intermediate subsequently undergoes an intramolecular Mannich cyclization via Re-face attack, generating intermediate V, establishing the stereochemical configuration of the newly formed stereocentres. Finally, proton transfer and catalyst release deliver the desired imidazo[5,1-c]oxazinone product (60a), thereby regenerating the squaramide catalyst for the next catalytic cycle. The co-operative hydrogen-bonding interaction and stereodirecting ability of the squarimide catalyst are believed to play a crucial role in controlling both the enantioselectivity and diastereoselectivity of the transformation.

Fig. 12. Proposed reaction mechanism for the metal-free organocatalytic synthesis of chiral imidazo[5,1-c]oxazinone (60a).

6. Conclusion

The transition metal-free functionalization of 1,4-benzoxazin-2-one and its partially hydrogenated analogue, 3,4-dihydro-1,4-benzoxazin-2-one has emerged as an efficient and sustainable strategy in contemporary organic synthesis. The adoption of transition metal free methodology not only enhances the sustainability but also reduces the risk of metal contamination, an important consideration for pharmaceutical synthesis.

In addition, many of the reported metal free methodologies using organocatalysis, exhibit excellent chemo-, regio-, stereoselectivity while providing broad substrate scope under mild conditions. Although significant progress has been achieved, further efforts towards expanding substrate compatibility, improving reaction efficiency, and developing scalable protocols will enhance the practical utility of these approaches. Overall, continued advances in transition metal free functionalization are expected to facilitate the synthesis of pharmaceutically relevant benzoxazinone derivatives and inspire the development of new heterocyclic molecules for applications in medicinal chemistry and related field.

Conflicts of interest

There are no conflicts to declare.

Data availability

Data sharing is not applicable to this article as no new data were generated or analysed during the preparation of this article.