tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3–H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N–O fragment donor.


Introduction
Polycyclic structures containing heteroatoms are regarded as important structural motifs in the realm of organic chemistry and pharmaceuticals.They are present in various natural products, agrochemicals, and physiologically active molecules and play a significant role in drug synthesis and discovery [1,2].The benzo oxacyclic ketone skeleton is an important scaffold for multiring structures, such as benzochromones and their derivatives.These structures are found in numerous natural products and pharmaceuticals, playing a pivotal role in the formation of polycyclic systems (Figure 1) [3][4][5][6][7][8].
Isoxazole/isoxazoline, a five-membered heterocyclic ring, is present in numerous biologically significant compounds known for their anti-inflammatory, antifungal, anticancer, and antimicrobial properties.Its ability to interact with the target protein through multiple non-covalent bonds makes it a pivotal drug component in various pharmaceutical formulations [9][10][11][12].
Due to the significant biological activities associated with the benzo oxacyclic ketone and isoxazole/isoxazoline skeletons, the development of efficient methods to merge these two entities is highly significant and desirable in the realms of medicinal and synthetic chemistry.Fusing two or more heterocycles to form a tricyclic or tetracyclic fused heterocycle is of interest to access polycyclic architectures.These polycyclic architectures demonstrate enhanced biological activity [13,14].
Numerous methods have been reported for synthesizing small ring (3-6 membered) and large ring (≥12 membered) compounds, including the Diels Alder reaction, Corey Nicolaou macrocycle esterification reaction, Keck macrocycle esterification reaction, and olefin metathesis reaction.Advancements in transition-metal-catalyzed closed-loop metathesis, olefin reactions, small ring cycloaddition, and hydrogenation acylation have led to progress in synthesizing medium-sized ring (7-11 membered) compounds.The intermolecular cycloaddition reaction is also effective for the formation of medium-sized rings [15].However, predicting the reactivity of these compounds is challenging due to unfavorable cross-ring tension and entropy effects, making their synthesis both difficult and intriguing.Mediumsized rings, particularly seven-and eight-membered ones, pose significant challenges in synthesis [16][17][18][19].Numerous methods have been reported for synthesizing small ring (3-6 membered) and large ring (≥12 membered) compounds, including the Diels Alder reaction, Corey Nicolaou macrocycle esterification reaction, Keck macrocycle esterification reaction, and olefin metathesis reaction.Advancements in transition-metal-catalyzed closed-loop metathesis, olefin reactions, small ring cycloaddition, and hydrogenation acylation have led to progress in synthesizing medium-sized ring (7-11 membered) compounds.The intermolecular cycloaddition reaction is also effective for the formation of medium-sized rings [15].However, predicting the reactivity of these compounds is challenging due to unfavorable cross-ring tension and entropy effects, making their synthesis both difficult and intriguing.Medium-sized rings, particularly seven-and eight-membered ones, pose significant challenges in synthesis [16][17][18][19].
Recently, our group successfully demonstrated an efficient synthetic method to synthesize diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives (Scheme 1c) [35].We gained inspiration from the synthesis of the 3-acyl-isoxazoles and ∆ 2 -isoxazolines series compounds reported by Zhang et al. [34] based on their previous research.Drawing inspiration from these investigations, a metal-free and additive-free method for C sp 3 -H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones to synthesize 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported.This convenient approach enables the simultaneous formation of the isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketone, thereby leading to the formation of the polycyclic architectures using TBN as a non-metallic radical initiator and N−O fragment donor (Scheme 1d).Recently, our group successfully demonstrated an efficient synthetic method to synthesize diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives (Scheme 1c) [35].We gained inspiration from the synthesis of the 3-acyl-isoxazoles and Δ 2isoxazolines series compounds reported by Zhang et al. [34] based on their previous research.Drawing inspiration from these investigations, a metal-free and additive-free method for Csp 3 -H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones to synthesize 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported.This convenient approach enables the simultaneous formation of the isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketone, thereby leading to the formation of the polycyclic architectures using TBN as a non-metallic radical initiator and N−O fragment donor.(Scheme 1d).

Results and Discussion
Firstly, the reaction conditions were optimized, and the results are summarized in Tables S2-S4 (supporting information).The substrate scope of 2 was investigated under optimized conditions.As shown in Figure 2, the method displayed excellent tolerance for structure 1, substituted with electron-donating groups, and can yield the desired products 2b, 2g-2i.A series of substrates with a methyl group at the C4 (1b) and the methoxyl group

Results and Discussion
Firstly, the reaction conditions were optimized, and the results are summarized in Tables S2-S4 (supporting information).The substrate scope of 2 was investigated under optimized conditions.As shown in Figure 2, the method displayed excellent tolerance for structure 1, substituted with electron-donating groups, and can yield the desired products 2b, 2g-2i.A series of substrates with a methyl group at the C4 (1b) and the methoxyl group at the C4 (1i), C5 (1h), and C6 (1g) positions led to the corresponding products with yields ranging from 81% to 91%.On the other hand, structure 1 substituted with electron-withdrawing groups such as Cl, Br, and F at the C4 or C5 position performed the reaction smoothly to give the desired products 2c-2f in good yields (79-88%).The naphthalenyl-substituted substrate 1j was also suitable for this reaction to deliver the desired product 2j with an 86% yield.X-ray single crystal diffraction was employed to determine the crystal structure of product 2a.
ranging from 81% to 91%.On the other hand, structure 1 substituted with electronwithdrawing groups such as Cl, Br, and F at the C4 or C5 position performed the reaction smoothly to give the desired products 2c-2f in good yields (79-88%).The naphthalenylsubstituted substrate 1j was also suitable for this reaction to deliver the desired product 2j with an 86% yield.X-ray single crystal diffraction was employed to determine the crystal structure of product 2a.Moreover, the reaction between various acrylates 3 with TBN was explored.It is evident from Figure 3 that 3a was successfully converted into the expected product 4a with a 95% yield.Surprisingly, different acetophenones 3b-3e with electron-donating substituents (such as 4-Me, 5-Me, 4-OMe, and 5-OMe) reacted analogously, yielding the corresponding products 4b-4e with 82-91% yields.Halogen-halogen atom substrates formed the corresponding products (4f-4h) with 78-83% yields.Furthermore, the side chain ethyl ester was converted to methyl ester and proceeded under standard conditions, yielding the desired products (4j-4q) within 67-92% yields.When the benzene ring of the template substrate 3 became a naphthalene ring, 3i and 3q yielded the corresponding products 4i and 4q in 70% and 67% yields, respectively.We synthesized the raw material O-acetylphenoxybutene (3r).Subsequently, 3r performed the reaction under the optimal conditions to give a polycyclic compound containing an eight-membered ring (4r) with a 78% yield.Moreover, the reaction between various acrylates 3 with TBN was explored.It is evident from Figure 3 that 3a was successfully converted into the expected product 4a with a 95% yield.Surprisingly, different acetophenones 3b-3e with electron-donating substituents (such as 4-Me, 5-Me, 4-OMe, and 5-OMe) reacted analogously, yielding the corresponding products 4b-4e with 82-91% yields.Halogen-halogen atom substrates formed the corresponding products (4f-4h) with 78-83% yields.Furthermore, the side chain ethyl ester was converted to methyl ester and proceeded under standard conditions, yielding the desired products (4j-4q) within 67-92% yields.When the benzene ring of the template substrate 3 became a naphthalene ring, 3i and 3q yielded the corresponding products 4i and 4q in 70% and 67% yields, respectively.We synthesized the raw material O-acetylphenoxybutene (3r).Subsequently, 3r performed the reaction under the optimal conditions to give a polycyclic compound containing an eight-membered ring (4r) with a 78% yield.
Next, substrate 5 was explored to obtain a series of derivatives with an isoxazole structure, and the reaction conditions were further optimized for the synthesis (Table S4).The scope of 6 was studied under the optimal conditions.As shown in Figure 4, substrate 5a was smoothly transformed into the corresponding product with a yield of 82%.A series of 5 with different substitutions (4-Me, 5-Me 4-OMe, and 4-OMe) was investigated.The desired products 6b-6e were obtained with 68%-75% yields.The 1-(2-(prop-2-yn-1-yloxy)phenyl)ethan-1-ones (5f-5h) attached with halogen atoms (e.g., 5-F, 5-Cl, and 5-Br) were also tolerated in the reaction, yielding the corresponding products 6f-6h with 62%-83% yields.Substrate 5i was also found to be suitable for this reaction, giving the desired product 6i with an 85% yield.Next, substrate 5 was explored to obtain a series of derivatives with an isoxazole structure, and the reaction conditions were further optimized for the synthesis (Table S4).The scope of 6 was studied under the optimal conditions.As shown in Figure 4, substrate 5a was smoothly transformed into the corresponding product with a yield of 82%.A series of 5 with different substitutions (4-Me, 5-Me 4-OMe, and 4-OMe) was investigated.The desired products 6b-6e were obtained with 68%-75% yields.The 1-(2-(prop-2-yn-1yloxy)phenyl)ethan-1-ones (5f-5h) attached with halogen atoms (e.g., 5-F, 5-Cl, and 5-Br) were also tolerated in the reaction, yielding the corresponding products 6f-6h with 62%-83% yields.Substrate 5i was also found to be suitable for this reaction, giving the desired product 6i with an 85% yield.
Several control experiments were carried out to investigate the reaction mechanism (Scheme 2) [36][37][38].The reaction was restrained completely and trace amounts of 2a were observed when a 2.0-equivalent radical scavenger 2,2,6,6-tetramethyl-1-piperidinyl (TEMPO) was added to the standard reaction.This result revealed that the reaction proceeded through a radical pathway.Next, 1a and TBN were reacted under standard conditions for 20 min to identify the possible intermediates.However, only 2a was detected by MS (APCI) because the intermediate nitrile oxide E shares the same relative molecular mass as 2a.The result of MS is ambiguous because the masses 2a and E are the same.Alternative approaches were performed to confirm this by subjecting substrates 7 to standard conditions for 20 min to detect 8 nitrile oxides via MS (APCI).A group of intermolecular reactions was used to further explore the reaction mechanism by using 9, 11, and ethyl acrylate.Under the optimal conditions, the desired product 10 was produced with yields of 58% and 50% from 9 and 11.These results disclosed that nitrile oxide was the potential intermediate for this protocol.Several control experiments were carried out to investigate the reaction mechanism (Scheme 2) [36][37][38].The reaction was restrained completely and trace amounts of 2a were observed when a 2.0-equivalent radical scavenger 2,2,6,6-tetramethyl-1-piperidinyl (TEMPO) was added to the standard reaction.This result revealed that the reaction proceeded through a radical pathway.Next, 1a and TBN were reacted under standard conditions for 20 min to identify the possible intermediates.However, only 2a was detected by MS (APCI) because the intermediate nitrile oxide E shares the same relative molecular mass as 2a.The result of MS is ambiguous because the masses 2a and E are the same.Alternative approaches were performed to confirm this by subjecting substrates 7 to standard conditions for 20 min to detect 8 nitrile oxides via MS (APCI).A group of intermolecular reactions was used to further explore the reaction mechanism by using 9, 11, and ethyl acrylate.Under the optimal conditions, the desired product 10 was produced with yields of 58% and 50% from 9 and 11.These results disclosed that nitrile oxide was the potential intermediate for this protocol.

General Information
Analytical thin layer chromatography (TLC) was performed by using pre-coated silica gel HF254 glass plates.Column chromatography was performed by using silica gel (200-300 mesh).The 1 H NMR and 13 C NMR spectra were recorded on a Bruker Advance 500 MHz instrument at 500 MHz ( 1 H NMR) and 126 MHz ( 13 C NMR).We used the residual solvent peak in CDCl3 as an internal reference (δ = 7.26 for 1 H and δ = 77.0 for 13 C{ 1 H}).Chemical shifts (δ) are reported in ppm relative to the internal standard of tetramethylsilane (TMS).The coupling constants (J) are quoted in Hz (hertz).Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), or combinations thereof.High-resolution mass spectra (HRMS) were obtained on Thermo Scientific Q-Exactive (ESI mode, Q-Exactive Orbitrap MS system).The melting points were measured with the SGW X-4 apparatus.Data collection for the crystal structure was Scheme 3. Proposed mechanism.

General Information
Analytical thin layer chromatography (TLC) was performed by using pre-coated silica gel HF254 glass plates.Column chromatography was performed by using silica gel (200-300 mesh).The 1 H NMR and 13 C NMR spectra were recorded on a Bruker Advance 500 MHz instrument at 500 MHz ( 1 H NMR) and 126 MHz ( 13 C NMR).We used the residual solvent peak in CDCl 3 as an internal reference (δ = 7.26 for 1 H and δ = 77.0 for 13 C{ 1 H}).Chemical shifts (δ) are reported in ppm relative to the internal standard of tetramethylsilane (TMS).The coupling constants (J) are quoted in Hz (hertz).Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), or combinations thereof.High-resolution mass spectra (HRMS) were obtained on Thermo Scientific Q-Exactive (ESI mode, Q-Exactive Orbitrap MS system).The melting points were measured with the SGW X-4 apparatus.Data collection for the crystal structure was performed by using Mo Kα radiation on a Bruker Smart APEX CCD area-detector diffractometer.

Synthetic Procedures
Compounds 1a-1j were prepared according to the referenced literature [42].To a solution of 1-(2-hydroxyphenyl)ethan-1-one) (1.0 equiv.)and Cs 2 CO 3 (3.0equiv.) in CH 2 Cl 2 (0.1 M), a solution of 3-bromocyclohex-1-ene (2.0 equiv.) in CH 2 Cl 2 (0.5 M) was added dropwise at room temperature and stirred for 10 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 4).
silica gel HF254 glass plates.Column chromatography was performed by using silica gel (200-300 mesh).The 1 H NMR and 13 C NMR spectra were recorded on a Bruker Advance 500 MHz instrument at 500 MHz ( 1 H NMR) and 126 MHz ( 13 C NMR).We used the residual solvent peak in CDCl3 as an internal reference (δ = 7.26 for 1 H and δ = 77.0 for 13 C{ 1 H}).Chemical shifts (δ) are reported in ppm relative to the internal standard of tetramethylsilane (TMS).The coupling constants (J) are quoted in Hz (hertz).Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), or combinations thereof.High-resolution mass spectra (HRMS) were obtained on Thermo Scientific Q-Exactive (ESI mode, Q-Exactive Orbitrap MS system).The melting points were measured with the SGW X-4 apparatus.Data collection for the crystal structure was performed by using Mo Kα radiation on a Bruker Smart APEX CCD area-detector diffractometer.

Synthetic Procedures
Compounds 1a-1j were prepared according to the referenced literature [42].To a solution of 1-(2-hydroxyphenyl)ethan-1-one) (1.0 equiv.)and Cs2CO3 (3.0 equiv.) in CH2Cl2 (0.1 M), a solution of 3-bromocyclohex-1-ene (2.0 equiv.) in CH2Cl2 (0.5 M) was added dropwise at room temperature and stirred for 10 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 4).Compounds 3a-3q were prepared according to the referenced literature [39,40].To a solution of 1-(2-hydroxyphenyl)ethan-1-one) (1.0 equiv.)and DMAP (0.1 equiv.) in CH2Cl2 (0.1 M), a solution of ethyl acetylenecarboxylate (2.0 equiv.) was added dropwise at room temperature and stirred for 10 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude Compounds 3a-3q were prepared according to the referenced literature [39,40].To a solution of 1-(2-hydroxyphenyl)ethan-1-one) (1.0 equiv.)and DMAP (0.1 equiv.) in CH 2 Cl 2 (0.1 M), a solution of ethyl acetylenecarboxylate (2.0 equiv.) was added dropwise at room temperature and stirred for 10 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 5).
Molecules 2024, 29, x FOR PEER REVIEW 8 of 17 residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 5).Compounds 5a-5i were prepared according to the referenced literature [43][44][45].To a solution of 1-(2-hydroxyphenyl)ethan-1-one) (1.0 equiv.)and K2CO3 (3.0 equiv.) in CH2Cl2 (0.1 M), a solution of 3-bromoprop-1-yne (2.0 equiv.) in CH2Cl2 (0.5 M) was added dropwise at room temperature and stirred for 10 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 6).Compound 3r was prepared according to the referenced literature [46].To a solution of 1-(2-(but-3-en-1-yloxy)phenyl)ethan-1-one (1.0 equiv.)and K2CO3 (1.0 equiv.), a solution of 4-bromo-1-butene (1.2 equiv.) in DMF (4 mL) was added dropwise at 80 °C and stirred for 24 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the Compounds 5a-5i were prepared according to the referenced literature [43][44][45].To a solution of 1-(2-hydroxyphenyl)ethan-1-one) (1.0 equiv.)and K 2 CO 3 (3.0equiv.) in CH 2 Cl 2 (0.1 M), a solution of 3-bromoprop-1-yne (2.0 equiv.) in CH 2 Cl 2 (0.5 M) was added dropwise at room temperature and stirred for 10 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 6).
Compound 3r was prepared according to the referenced literature [46].To a solution of 1-(2-(but-3-en-1-yloxy)phenyl)ethan-1-one (1.0 equiv.)and K2CO3 (1.0 equiv.), a solution of 4-bromo-1-butene (1.2 equiv.) in DMF (4 mL) was added dropwise at 80 °C and stirred for 24 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 7).Compound 10 was prepared according to the referenced literature [28].A mixture of acetophenone (1 equiv.),ethyl acrylate (3 equiv.), and t BuONO (3 equiv.) was dissolved in DMSO (2.0 mL).Then, the mixture was reacted under 80 °C for 4 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with EtOAc 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude residues were purified by column chromatography by using an ethyl acetate/petroleum ether mixture to obtain the desired product (Scheme 8).Scheme 8. General procedure for synthesis of ethyl 3-benzoyl-4,5-dihydroisoxazole-5-carboxylate (10).Compound 10 was prepared according to the referenced literature [28].A mixture of acetophenone (1 equiv.),ethyl acrylate (3 equiv.), and t BuONO (3 equiv.) was dissolved in DMSO (2.0 mL).Then, the mixture was reacted under 80 • C for 4 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with EtOAc 3 times (3 × 50 mL).The extract was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The crude residues were purified by column chromatography by using an ethyl acetate/petroleum ether mixture to obtain the desired product (Scheme 8).Scheme 6.General procedure for synthesis of 1-(2-(prop-2-yn-1-yloxy)phenyl)ethan-1-one 5g-5i.
Compound 3r was prepared according to the referenced literature [46].To a solution of 1-(2-(but-3-en-1-yloxy)phenyl)ethan-1-one (1.0 equiv.)and K2CO3 (1.0 equiv.), a solution of 4-bromo-1-butene (1.2 equiv.) in DMF (4 mL) was added dropwise at 80 °C and stirred for 24 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with DCM 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 7).Compound 10 was prepared according to the referenced literature [28].A mixture of acetophenone (1 equiv.),ethyl acrylate (3 equiv.), and t BuONO (3 equiv.) was dissolved in DMSO (2.0 mL).Then, the mixture was reacted under 80 °C for 4 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with EtOAc 3 times (3 × 50 mL).The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude residues were purified by column chromatography by using an ethyl acetate/petroleum ether mixture to obtain the desired product (Scheme 8).Scheme 8. General procedure for synthesis of ethyl 3-benzoyl-4,5-dihydroisoxazole-5-carboxylate (10).
Compound 11 was prepared according to the referenced literature [36,41].A mixture of acetophenone (1.0 equiv.)and I 2 (1.6 equiv.) was reacted under 110 • C for 10 h.Phenyl glyoxal was afforded without further purification.Then, hydroxylamine hydrochloride (1.0 equiv.) was added to a solution of phenyl glyoxal in THF (40 mL), and the reaction mixture was reacted under 24 • C for 12 h.After the reaction was completed, 50 mL of water was added to the mixture and then extracted with EtOAc 3 times (3 × 50 mL).The extract was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.The crude residues were purified by column chromatography using an ethyl acetate/petroleum ether mixture to obtain the desired product (Scheme 9).

Conclusions
In summary, an effective and metal-free method for the synthesis of 6/7/8-membered ketone-fused isoxazoles/isoxazolines tetra-or tricyclic compounds was developed while employing TBN as a radical initiator and NO source.In this protocol, TBN activated the C sp 3 -H bond of aryl methyl ketones to produce α-carbonyl nitrile oxide intermediates in situ through cascade Hydrogen Atom Transfer (HAT) and the radical coupling process, which then underwent [3 + 2] cycloaddition with alkenyl/alkynyl groups.The present approach overcomes the entropic effects and ring strain associated with the conventional synthesis of densely fused polycyclic compounds.The protocol has a wide substrate scope and diverse possible products, with the additional merits of being metal-catalyst-free and additive-free.

Figure 1 .
Figure 1.Some drugs with pharmacological activity containing benzo[b]oxygenes or isoxazole frameworks.Reactions employing tert-butyl nitrite (TBN) as both a free radical initiator and N-O fragment donor have emerged as an important tool for isoxazole/isoxazoline synthesis over the past few years [20-26].Song et al. developed a new [2 + 1 + 1 + 1] annulation reaction of sulfoxonium ylides with TBN for the first time to synthesize furoxans and isoxazoles[27].Zhang et al. reported the graceful synthesis of isoxazoles from methyl ketones, terminal alkynes, and TBN under catalyst-free conditions[28].Wan, X.-B.et al. reported the graceful cycloaddition reactions for the synthesis of isoxazoles from diazo compounds or N-tosylhydrazones with alkenes or β-keto esters activated by tert-butyl nitrite[29][30][31].These approaches are robust and can deliver fully substituted isoxazoles.In a recent study, Wan, J.-P. et al. reported a refined metal-catalyzed strategy for the synthesis of isomeric isoxazoles through the reactions of enaminones, diazo compounds, and TBN under different Cu-and Ag-catalyzed conditions[32].The synthesis of isoxazoline-fused bicyclic compounds poses challenges, particularly under transition-metal-free conditions.Instead, Wan, X.-B.et al. used intramolecular acyclic nitronate olefin cycloaddition reactions via the in situ generated acyclic nitronates combined with cascade [3 + 2] cycloaddition and tert-butyloxy group elimination to enable the formation of diverse γ-lactone-fused isoxazolines and even tricyclic isoxazolines (Scheme 1a)[33].A metal-free method had already been used to synthesize 3-methyl-1,8-dihydrocycloheptapyrazol-8-one derivatives and isoxazole-fused seven-membered oxacyclic ketones by Imafuku in 1982 (Scheme 1b)[34].Recently, our group successfully demonstrated an efficient synthetic method to synthesize diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives (Scheme 1c)[35].We gained inspiration from the synthesis of the 3-acyl-isoxazoles and ∆ 2 -isoxazolines series compounds reported by Zhang et al.[34] based on their previous research.Drawing inspiration from these investigations, a metal-free and additive-free method for C sp 3 -H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones