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Article

One-Pot Synthesis of Isoxazole-Fused Tricyclic Quinazoline Alkaloid Derivatives via Intramolecular Cycloaddition of Propargyl-Substituted Methyl Azaarenes under Metal-Free Conditions

by
Zhuo Wang
1,
Yuhan Zhao
1,
Jiaxin Chen
1,
Mengyao Chen
1,
Xuehan Li
1,
Ting Jiang
1,
Fang Liu
1,
Xi Yang
1,
Yuanyuan Sun
1 and
Yanping Zhu
1,2,*
1
Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai 264005, China
2
Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, China
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(6), 2787; https://doi.org/10.3390/molecules28062787
Submission received: 14 February 2023 / Revised: 14 March 2023 / Accepted: 15 March 2023 / Published: 20 March 2023
(This article belongs to the Special Issue Synthesis and Modification of Nitrogen Heterocyclic Compounds)
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Abstract

:
A practical method was developed for the convenient synthesis of isoxazole-fused tricyclic quinazoline alkaloids. This procedure accesses diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives via intramolecular cycloaddition of methyl azaarenes with tert-butyl nitrite (TBN). In this method, TBN acts as the radical initiator and the source of N–O. Moreover, this protocol forms new C–N, C–C, and C–O bonds via sequence nitration and annulation in a one-pot process with broad substrate scope and functionalization of natural products.

1. Introduction

Quinazolinones are a well-known family of N-heterocyclic compounds with bioactivities [1,2,3,4,5,6] on multiple fronts and occur often in natural products [7,8,9,10]. Recently, a group of special tricyclic quinazoline alkaloids, such as 2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-ones, have attracted increased attention from medicinal chemists and biologists for their bioactivity levels in areas such as antitumor, antibacterial, anti-inflammatory and anti-acetylcholinesterase activities [11,12,13,14,15,16]. Key examples include deoxyvasicinone and vasicinone isolated from the adhatoda vasica medicinal plant, with pronounced anti-inflammatory, antimicrobial, and antidepressant activities (Figure 1) [17,18,19,20]. Luotonin A and evodiamine are promising anticancer natural products that act as topoisomerase I inhibitors [21,22]. Anisulcusine B, isolated from anisotes trisulcus, showed moderate cytotoxic effect against human hepatoma (HuH7) cells [23]. Rutaecarpine is an inhibitor of COX-2 with an IC50 value of 0.28 μM [24].
The ubiquitous nature and importance in pharmaceutical research have led to several reported synthetic methodologies for 2,3-fused quinazoline-4(3H)-ones and their derivatives (Scheme 1a) [25,26,27,28]: (1) N-Cyanamide alkenes react with aldehydes or diketones via intramolecular cyclization difunctionalization [18], [29,30,31]; (2) intramolecular radical cyclization of N3-Alkenyl-tethered quinazolinone [32,33,34,35]; (3) oxidative cyclization of isatins or isatoic anhydrides with cyclic amines by ring opening strategy [36,37]; (4) cyclic amines undergo a dehydrogenation process including intermolecular and intramolecular cyclization [38,39,40,41]; (5) 2-Arylquinazolinones undertake a cyclization reaction via transition metal catalysis [42,43].
Isoxazole is a five-membered heterocycle with two adjacent heteroatoms and a cyclic conjugated system, which could react with target proteins via multiple noncovalent bonds [44,45,46]. This feature of isoxazole makes it a key pharmaceutical fragment in many drugs [47,48,49]. In recent years, tert-butyl nitrite (TBN) has acted as a metal-free radical initiator and source of N-O [50,51,52,53,54,55,56,57,58,59], which has attracted extensive attention in the construction of isoxazoles [60,61,62,63,64,65,66,67,68,69]. Despite these excellent methods, there are few reports on the construction of skeletal cores containing isoxazole and tricyclic quinazoline alkaloids or their derivatives. Recent literature reports have focused primarily on the formation of isoxazole-substituted methyl azaarenes from intermolecular reactions via tert-butyl nitrite. For example, Zhang and co-workers reported a graceful method for the synthesis of 3-quinolinyl-isoxazoles from 2-methyl quinolines, ethyl propiolate, and TBN under metal-free conditions [70]. Yang et al. developed copper-catalyzed 1,3-dipolar cycloaddition of alkylazaarenes with alkynes to synthesize isoxazoles, in which the nitro sources were generated in situ from KNO3 and K2S2O8 [71,72]. Song et al. developed an elegant protocol to synthesize isoxazoles via divergent annulation of sulfoxonium ylides with t-BuONO [73]. To the best of our knowledge, the formation of isoxazole fusing 2,3-dihydropyrrolo[2,1-b]quinazoliones or other tricyclic quinazoline alkaloids remains challenging and difficult, with no synthetic procedures previously reported.
Recently, our group had successfully demonstrated an efficient synthetic method to synthesize furoxans from methyl azaarene and t-BuONO [74]. Inspired by these brilliant works, herein we disclose an efficient and practical method for the synthesis of isoxazole-fused quinazolinones or quinolines from 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-ones and 2-methyl-3-(prop-2-yn-1-yloxy)quinolines with TBN via metal-free conditions in a single reaction (Scheme 1c).

2. Results and Discussion

2.1. Reaction Optimization

We selected 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one (1a) as the model substrate to optimize the reaction conditions and to verify the feasibility of our assumption (Table 1). We initially treated 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one and TBN in DMSO at 80 °C for 6 h, which yielded the desired 4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2a) in a 45% yield (Table 1, entry 1). We varied the solvent (DMF, 1,4-dioxane, and acetonitrile; Table 1, entries 2–4). Acetonitrile afforded the desired product in a 64% yield. Temperature modification (Table 1, entries 4–6) confirmed 100 °C as the optimal reaction temperature. Adding TBN (4.5, 5, 5.5, and 6 eq.) was examined, which resulted in yields of 61%, 65%, 72%, and 70%, respectively, indicating that 5.5 eq. of TBN optimized the yield. Conducting the reaction under argon increased the yield of 2a to 75% (Table 1, entry 8). Adding 0.5 eq. of NCS (N-chlorosuccinimide) increased the yield to 76% (entry 9). We also screened several acids to determine their influence on the annulation reaction. Using trifluoroacetic acid (TFA) decreased the yield of the desired product 2a to 46% (entry 10); however, adding acetic acid increased the yield increased to 80% (entry 11). Aliphatic and aromatic carbonic acids did not promote this reaction effectively (entries 12–17).

2.2. Substrate Scope

After the optimum conditions were established, the substrate scope of 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one for the formation of 4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one 2 was evaluated. As shown in Figure 2, a series of electron-donating groups on the phenyl ring of 1, such as the methyl groups at the C-4, C-4,6, C-5,6 position (1b–1d) and the methoxyl group at the C-5 position (1e), could participate in this reaction to afford the corresponding products in 73–83% yields (2b–2e). To our delight, 1 with a phenyl group in the position of C-5 (1g–1h) gave the corresponding products smoothly in 75% and 50% yields, respectively. However, 1f was not tolerated in the reaction under the optimized conditions, giving the desired product in a very low yield. Meanwhile, electron-drawing groups on the phenyl ring of 1 proceeded well via our protocol, such as the fluoro group at the position C-5, C-4,5 (1i–1j), the chloro and nitro group at the C-4 position (1k–1l), leading to the desired products in good yields (60–76%). To our delight, heteroatom-contained substrate 1m was also suitable for this reaction to afford the desired product 2m in 46% yield. In addition, the substrates of the substituted alkynyl group were also tested; those results showed that alkynyl substituted substrate (1n) was unsuitable for this reaction.
To further investigate the universality of our method, a variety of substituted 2-methyl-3-(prop-2-yn-1-yloxy)quinolines were surveyed. As shown in Figure 3, 2-methyl-3-(prop-2-yn-1-yloxy)quinoline (3a) was smoothly transformed into the corresponding product with a yield of 80%. Substrates of substituted groups on the phenyl ring 3b and 3c were applied to this reaction, which yielded products 4b and 4c in 77% and 24% yields, respectively. Then, ester-substituted substrates in the C-4 position were also screened, and all substrates were transformed smoothly to obtain the desired products in moderate to good yields (4d–4h, 56–79%). Moreover, different amide-substituted substrates on the C-4 position (3i–3j) were tested, processing the corresponding products 4i and 4j in 43% and 51% yields, respectively.
Furthermore, to evaluate the application of the present reaction. Several natural products were modified via our protocol. As shown in Figure 4, 2-methyl-3-(prop-2-yn-1-yloxy)quinoline-4-carboxylic acid reacted with natural alcohols to generate ester derivates 3. The L-menthol and sugar methyl 2,3-O-isopropylideneisopropylidene-β-D-ribofuranoside could be involved in this protocol, giving the desired products (4k–4l) in 22–35% yields. The 3m phytol derivate was smoothly transformed into the corresponding product with a yield of 67%. Two natural steroids, cholesterol and stigmasterol, were also screened, affording the corresponding products (4n–4o) in 29–33% yields.

2.3. Mechanism Experiments

Several control experiments were carried out to explore the reaction mechanism (Scheme 2). The reaction was halted completely with only trace amounts of 2a, when 3.5 equivalent of radical scavenger 2,2,6,6-tetramethyl-1-piperidinyl (TEMPO) was added to the standard reaction. These results indicated that the reaction was conducted possibly through a radical pathway. Then, 2-methyl-3-(prop-2-yn-1-yl)quinazolinone (1a) and TBN were reacted under standard conditions for 20 min to address the possible intermediates. Only 2a 4H,6H-isoxazolo-pyrrolo[2,1-b]quinazolin-6-one was detected by MS (APCI), because the intermediate nitrile oxide F (Scheme 3) shares the same relative molecular mass as 2a. Then, we tried other ways to prove them by conducting substrates 5a 2-methyl-3-phenyl quinazoline-4(3H)-one under standard conditions for 20 min to detect 5ac nitrile oxides via MS (APCI) (see Supplementary Materials). A group of intermolecular reactions was used to explore the reaction mechanism further by using 5a, 5ab, and phenylacetylene. Under optimal conditions, the desired product 6a was afforded in yields of 56% and 65%, respectively. These results disclosed that nitrile oxide was the potential intermediate for this protocol.
Based on the evidence presented above and the related literature [75,76,77], a plausible reaction pathway was proposed (Scheme 3). Firstly, TBN was transformed to NO and t-BuO radicals via thermal homolysis. 2-Methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one (1a) could be transformed into intermediate isomer A via acid promotion, which reacts with TBN to produce intermediate B and releases a tert-butoxy radical. Then, intermediate C from oxidation of intermediate B undergoes tautomerization to generate oxime D, which can be further converted into intermediate E via NCS. Subsequently, the intermediate E can be oxidized to afford the nitrile oxides F, which could be transformed into the desired product 2a through 1,3-dipolar cycloaddition.

3. Materials and Methods

3.1. General Information

Analytical thin layer chromatography (TLC) was performed using pre-coated silica gel HF254 glass plates. Column chromatography was performed using silica gel (200–300 mesh). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Advance 500 MHz spectrometer at ambient temperature using DMSO-d6 or CDCl3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature (1H δ 7.26 ppm and 13C{1H} δ 77.0 ppm for CDCl3; 1H δ 2.50 ppm and 13C{1H} δ 39.5 ppm for DMSO-d6). Chemical shifts (δ) are reported in ppm, relative to the internal standard of tetramethylsilane (TMS). The coupling constants (J) are quoted in hertz (Hz). Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad) or combinations thereof. High-resolution mass spectra were obtained on Thermo Scientific Q-Exactive (ESI mode). Melting points were determined using SGW X-4 apparatus and were not corrected.

3.2. Synthetic Procedures

Compounds 1a–1l were prepared according to the referenced literature (Scheme 4) [78]. To corresponding 2-aminobenzoic acid (1 mmol) was added acetic anhydride (5 mmol), and the mixture was warmed to 120 °C for 3 h with stirring. The mixture was then concentrated in vacuo (50 °C) to remove excess acetic anhydride (bp 138 °C) to give a dry solid. Ammonium hydroxide (28% NH3, 100 mL) was added, and the mixture was heated to 95 °C for 4 h. The mixture was cooled, vacuum filtered and the resultant solid washed with water, saturated with NaHCO3 solution and more water. The 3-bromopropyne (1.5 equiv.) was dropped into the solution of the obtained solid, t-BuOK (1.3 equiv.) and DMF under Argon atmosphere at 0 °C to r.t overnight. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the corresponding products [79].
Compound 1m was prepared according to the referenced literature with some modification (Scheme 5) [80]. A Schlenk flask was charged with a magnetic stirrer, evacuated and backfilled with argon. 2-Chloronicotinic acid (0.5 mmol) and acetamidine hydrochloride (0.75 mmol) in EtOH (3 mL) were added under Argon atmosphere. After 10 min of stirring, Cs2CO3 (1 mmol) was added to the flask. Then, 15 min later, CuI (0.1 mmol) was added to the flask. The mixture was stirred at 80 °C for 12 h. After completion of the reaction, the mixture was filtered, and the solvent of the filtrate was removed with the aid of a rotary evaporator. The residue was purified by column chromatography on silica gel to provide the desired quinazolinone. The 3-Bromopropyne (1.5 equiv.) was dropped into the solution of the obtained solid, t-BuOK (1.3 equiv.), and DMF under argon atmosphere at 0 °C to overnight. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the desired products.
7-Chloro-2-methylquinazolin-4(3H)-one was prepared from the above procedure. A Schlenk flask was charged with a 7-chloro-2-methylquinazolin-4(3H)-one (0.3 mmol), corresponding to phenylboronic acid (0.45 mmol), Pd(OAc)2 (0.05 mmol), Sphos (0.03 mmol) and K3PO4 (2.4 mmol), and was heated in toluene (2 mL) at 80 °C for 24 h. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the corresponding products [81]. The 3-bromopropyne (1.5 equiv.) was dropped into the solution of the obtained solid, t-BuOK (1.3 equiv.), and DMF under argon atmosphere at 0 °C to r.t overnight. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 6).

3.2.1. Typical Procedure (TP 1) for the Synthesis of 2 and 4 Taking 2a as an Example

A sealed tube charged with 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one (1a) (0.2 mmol), TBN (1.1 mmol), NCS (0.1 mmol) and AcOH (0.1mmol) were heated in acetonitrile (2 mL) at 100 °C for 10 h under argon atmosphere. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the corresponding products 2a.
Compound 4a–4c were prepared according to the referenced literature (Scheme 7) [82]. A solution of MeONa (1.5 mmol) in MeOH was added to a stirred solution of the corresponding 2-nitrobenzaldehyde (1.5 mmol) and a chloracetone (1.5 mmol) in MeOH (3.5 mL) at room temperature overnight. After the reaction was completed, the resulting precipitate was filtered off, the mixture was quenched carefully with water (3 × 50 mL) and with saturated NH4Cl (1 × 10 mL), and the product was isolated as a corresponding (2-(2-nitrophenyl)oxiran-1-yl)(aryl)methanone. A solution of Na2S2 O4 (5 mmol) in H2O (65 mL) was added to a solution of (2-(2-nitrophenyl)oxiran-1-yl)(aryl)methanone (1 mmol) in dioxane (65 mL). The reaction mixture was allowed to cool down to room temperature after reflux for 3 h and was poured into water (500 mL). The resulting precipitate was filtered off, washed with water (2 × 50 mL) and dried in air to give the corresponding 2-arylquinolin-3-ols. The 3-bromopropyne (3 equiv.) was dropped into the solution of the obtained solid, K2CO3 (3 equiv.), and acetonitrile under argon atmosphere at 0 °C to r.t overnight. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the desired products [83,84].
To a solution of 3-hydroxy-2-methyl-4-quinolinecarboxylic acid (1.1 equiv.), ROH or secondary amine (1.0 equiv.), DCC (1.1 equiv.) and DMAP (0.1 equiv.) were added in CH2Cl2 overnight to obtain 3-hydroxy-2-methylquinoline-4-carboxylate [85]. The 3-bromopropyne (3 equiv.) was dropped into the solution of the obtained solid, K2CO3 (3 equiv.), and acetonitrile under argon atmosphere at 0 °C to r.t overnight. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the desired products (Scheme 8).
Compound 5ab was prepared according to the referenced literature (Scheme 9) [86,87,88]. A mixture of isatoic anhydride (2 mmol), aniline (2 mmol) and triethyl orthoacetate (2 mmol) was reacted under 120 °C for 4 h. After completion of the reaction, the crude reaction mixture was recrystallized from EtOH to obtain analytically pure product 5a. Then, 5a (0.5 mmol) and SeO2 (6.5 mmol) were stirred at 80 °C in 1,4-dioxane for 3 h to corresponding aldehyde. A solution of the corresponding aldehyde (0.5 mmol) in pyridine (6 mL) was added to the solution of hydroxylamine hydrochloride (0.5 mmol), keeping the reaction mixture overnight. Then, the mixture was filtered and washed water to obtain the 5ab.

3.2.2. Typical Procedure (TP 2) for the Synthesis of 6a

A sealed tube charged with 2-methyl-3-phenyl quinazoline-4(3H)-one (5a) or (E)-4-oxo-3-phenyl-3,4-dihydroquinazoline-2-carbaldehyde oxime (5ab) (0.2 mmol), phenylacetylene (0.22 mmol), TBN (1.1 mmol), NCS (0.1 mmol) and AcOH (0.1mmol) was heated in acetonitrile (2 mL) at 100 °C for 10 h under argon atmosphere. After the reaction was completed, 50 mL 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 using ethyl acetate/petroleum ether mixture to obtain the corresponding products 6a.

3.3. Characterization of Products

4H,6H-Isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2a), 40 mg, brown solid, m.p.: over 280 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.26 (dd, J = 8.0, 1.5 Hz, 1H), 7.93 (td, J = 7.6, 7.0, 1.5 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.69–7.62 (m, 1H), 5.03 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.4, 159.7, 154.7, 150.0, 145.3, 134.7, 127.9, 126.0, 120.8, 119.7, 43.3. HRMS (ESI): m/z [M+H]+ calcd for C12H7N3O2: 226.0611; found: 226.0610.
8-Methyl-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2b), 38 mg, white solid, m.p.: over 280 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.06 (s, 1H), 7.76 (q, J = 8.4 Hz, 2H), 5.02 (s, 2H), 2.50 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 163.3, 159.6, 154.6, 146.0, 144.5, 137.9, 135.9, 127.8, 125.3, 120.6, 119.6, 43.2, 20.9. HRMS (ESI): m/z [M+H]+ calcd for C13H9N3O2: 240.0768; found: 240.0763.
9,10-Dimethyl-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2c), 38 mg, white solid, m.p.: 259–260 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 4.99 (s, 2H), 2.55 (s, 3H), 2.43 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 163.5, 159.9, 154.6, 146.2, 144.1, 143.4, 134.2, 129.5, 122.8, 119.6, 118.7, 43.0, 20.5, 13.1. HRMS (ESI): m/z [M+H]+ calcd for C14H11N3O2: 254.0924; found: 254.0924.
8,10-Dimethyl-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2d), 42 mg, white solid, m.p.: over 280 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 5.03 (s, 2H), 2.60 (s, 3H), 2.46 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 163.4, 159.8, 154.5, 144.5, 143.6, 137.3, 136.5, 135.9, 123.1, 120.7, 119.6, 43.2, 20.9, 17.3. HRMS (ESI): m/z [M+H]+ calcd for C14H11N3O2: 254.0924; found: 254.0924.
9-Methoxy-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2e), 37 mg, white solid, m.p.: over 280 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H), 5.01 (s, 2H), 3.94 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 164.2, 163.4, 159.3, 154.7, 150.3, 145.8, 127.5, 119.8, 117.2, 114.3, 109.2, 55.9, 43.2. HRMS (ESI): m/z [M+H]+ calcd for C13H9N3O3: 256.0717; found:256.0714.
9-(p-Tolyl)-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2g), 47 mg, white solid, m.p.: 271–272 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.94 (dd, J = 8.4, 1.9 Hz, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 5.04 (s, 2H), 2.38 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 163.4, 159.6, 154.7, 148.6, 146.0, 145.6, 138.4, 135.4, 129.8, 127.1, 126.6, 126.2, 124.9, 119.8, 119.4, 43.3, 20.7. HRMS (ESI): m/z [M+H]+ calcd for C19H13N3O2: 316.1081; found:316.1081.
9-(4-Methoxyphenyl)-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2h), 33 mg, yellow solid, m.p.: 252–253 °C. 1H NMR (500 MHz, DMSO-d6) 9.22 (d, J = 1.2 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.94 (dd, J = 8.3, 1.9 Hz, 1H), 7.87–7.81 (m, 2H), 7.12–7.07 (m, 2H), 5.06–5.03 (m, 2H), 3.83. 13C NMR (126 MHz, DMSO-d6) δ 163.4, 160.0, 159.6, 154.7, 148.6, 145.7, 145.6, 130.5, 128.5, 126.6, 125.9, 124.4, 119.8, 119.1, 114.7, 55.3, 43.3. HRMS (ESI): m/z [M+H]+ calcd for C19H13N3O3: 332.1030; found:332.1030.
9-Fluoro-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2i), 36 mg, white solid, m.p.:277–278 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.23 (d, J = 1.3 Hz, 1H), 8.30 (dd, J = 8.9, 6.2 Hz, 1H), 7.69 (dd, J = 10.0, 2.6 Hz, 1H), 7.51 (td, J = 8.7, 2.6 Hz, 1H), 5.02 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ165.7 (d, J = 251.5 Hz), 163.2, 159.1, 154.9, 150.3 (d, J = 13.4 Hz), 146.7, 129.0 (d, J = 11.0 Hz), 119.9, 117.9(d, J = 2.52 Hz), 116.4 (d, J = 23.3 Hz), 113.1 (d, J = 22.1 Hz), 43.5. HRMS (ESI): m/z [M+H]+ calcd for C12H6FN3O2: 244.0517; found: 244.0512.
8,9-Difluoro-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2j), 39 mg, white solid, m.p.:224–226 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.19 (td, J = 9.3, 3.3 Hz, 1H), 8.02 (td, J = 8.7, 7.5, 3.0 Hz, 1H), 5.03 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.2, 158.5, 155.0, 153.9 (dd, J = 251.5, 14.5 Hz), 149.2 (dd, J = 251.5, 16.1 Hz), 146.3, 146.0 (dd, J = 11.1, 2.6 Hz), 119.8, 118.4 (d, J = 7.2 Hz), 116.1 (d, J = 17.9 Hz), 113.7 (d, J = 18.8 Hz), 43.6. HRMS (ESI): m/z [M+H]+ calcd for C12H5F2N3O2: 262.0423; found: 262.0422.
8-Chloro-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2k), 39 mg, white solid, m.p.:248–250 °C, 1H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.94 (dd, J = 8.7, 2.5 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 5.02 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.2, 158.7, 154.9, 146.7, 145.7, 134.8, 132.2, 130.1, 124.9, 122.1, 119.7, 43.5. HRMS (ESI): m/z [M+H]+ calcd for C12H6ClN3O2: 260.0221; found: 260.0220.
8-Nitro-4H,6H-isoxazolo[3′,4′:3,4]pyrrolo[2,1-b]quinazolin-6-one (2l), 32 mg, yellow solid, m.p.: over 280 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.90 (d, J = 2.7 Hz, 1H), 8.64 (dd, J = 8.9, 2.7 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 5.08 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.1, 159.0, 155.3, 152.2, 148.4, 145.7, 129.7, 128.7, 121.9, 121.1, 120.0, 43.9. HRMS (ESI): m/z [M+H]+ calcd for C12H6N4O4: 271.0462; found: 271.0641.
4H,6H-Isoxazolo[3′,4′:3,4]pyrrolo[1,2-a]pyrido[2,3-d]pyrimidin-6-one (2m), 21mg, white solid, m.p.: over 280 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.27 (d, J = 1.6 Hz, 1H), 9.07 (dd, J = 4.5, 2.0 Hz, 1H), 8.66 (dd, J = 7.9, 2.1 Hz, 1H), 7.68 (dd, J = 7.9, 4.6 Hz, 1H), 5.05 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.3, 160.2, 158.1, 156.1, 155.0, 148.3, 135.7, 123.2, 119.8, 116.3, 43.6. HRMS (ESI): m/z [M+H]+ calcd for C11H6N4O2: 227.0564; found:227.0560.
4H-Isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline (4a), 36 mg, brown solid, m.p.: 194–196 °C. 1H NMR (500 MHz, CDCl3) δ 8.40 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.74–7.68 (m, 2H), 7.62 (dd, J = 8.5, 6.7 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 5.35 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 154.1, 152.0, 148.9, 144.6, 137.0, 130.2, 130.0, 128.2, 128.1, 126.7, 120.9, 113.8, 61.5. HRMS (ESI): m/z [M+H]+ calcd for C13H8N2O2: 225.0659; found: 225.0658.
8-Chloro-4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline (4b), 39 mg, White solid, m.p.: 273–274 °C. 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.62 (s, 1H), 7.55 (dd, J = 9.1, 2.3 Hz, 1H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 153.8, 152.2, 149.5, 142.9, 137.2, 134.1, 131.6, 130.8, 129.3, 125.3, 120.0, 113.6, 61.7. HRMS (ESI): m/z [M+H]+ calcd for C13H7ClN2O2: 259.0269; found: 259.0269.
4H-[1,3]Dioxolo[4,5-g]isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline (4c), 13 mg, brown solid, m.p.: over 280 °C. 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 1.3 Hz, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 6.96 (s, 1H), 6.11 (s, 2H), 5.32–5.29 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 154.2, 151.6, 150.1, 149.4, 148.4, 142.7, 134.1, 128.0, 120.8, 113.4, 106.1, 101.9, 101.7, 61.5. HRMS (ESI): m/z [M+H]+ calcd for C14H8N2O4: 269.0557; found: 269.0556.
Methyl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4d), 38 mg, yellow solid, m.p.: 252–254 °C. 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.75 (dd, J = 8.4, 1.5 Hz, 1H), 7.67 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.60 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 5.43 (d, J = 1.3 Hz, 2H), 4.08 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.6, 153.6, 152.4, 145.2, 144.1, 137.0, 130. 6, 129.2, 128.6, 126.1, 124.8, 124.0, 113.4, 62.2, 53.0. HRMS (ESI): m/z [M+H]+ calcd for C15H10N2O4: 283.0713; found: 283.0713.
Ethyl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4e), 44 mg, brown solid. m.p.: 197–198 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.75 (dd, J = 8.4, 1.4 Hz, 1H), 7.66 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.59 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 5.42 (d, J = 1.3 Hz, 2H), 4.56 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.2, 153.6, 152.3, 145.1, 144.1, 137.0, 130.5, 129.1, 128.6, 126.1, 125.2, 123.9, 113.4, 62.2, 62.1, 14.3. HRMS (ESI): m/z [M+H]+ calcd for C16H12N2O4: 297.0870; found: 297.0869.
4-Methoxybenzyl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4f), 44 mg, yellow solid, m.p.: 120–122 °C. 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.68–7.60 (m, 2H), 7.57–7.50 (m, 1H), 7.43 (d, J = 8.7 Hz, 3H), 6.93 (d, J = 8.7 Hz, 3H), 5.46 (s, 4H), 5.38 (s, 2H), 3.82 (s, 5H). 13C NMR (126 MHz, CDCl3) δ 165.1, 159.9, 153.5, 152.3, 145.2, 144.1, 136.9, 130.5, 130.4, 129.1, 128.5, 127.3, 126.1, 124.8, 123.8, 114.0, 113.4, 67.7, 62.0, 55.3. HRMS (ESI): m/z [M+H]+ calcd for C22H16N2O5:389.1132; found:389.1131.
2-Bromobenzyl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4g), 50 mg, yellow solid, m.p.: 166–168 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.69–7.54 (m, 4H), 7.34 (t, J = 7.5 Hz, 1H), 7.23 (td, J = 7.8, 1.7 Hz, 1H), 5.62 (s, 2H), 5.41 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 164.9, 153.5, 152.4, 145.4, 144.1, 137.0, 134.4, 133.0, 130.5, 130.4, 130.2, 129.2, 128.6, 127.6, 126.1, 124.4, 124.00, 123.7, 113.4, 67.4, 62.1. HRMS (ESI): m/z [M+H]+ calcd for C21H13BrN2O4:437.0131; found:437.0133.
Benzyl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4h), 56 mg, white solid, m.p.: 126–128 °C. 1H NMR (500 MHz, CDCl3) δ 8.43 (d, J = 1.5 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.58–7.52 (m, 1H), 7.49 (d, J = 6.8 Hz, 2H), 7.40 (dt, J = 12.3, 6.8 Hz, 3H), 5.54 (s, 2H), 5.39 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 165.1, 153.5, 152.3, 145.2, 144.1, 137.00, 135.1, 130.5, 129.2, 128.7, 128.6, 128.6, 128.5, 126.1, 124.7, 123.9, 113.4, 67.8, 62.1. HRMS (ESI): m/z [M+H]+ calcd for: C21H14N2O4: 359.1026; found:359.1025.
N,N-Dibenzyl-4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxamide (4i), 45 mg, yellow solid, m.p.: 89–91 °C. 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.52–7.42 (m, 4H), 7.39 (t, J = 6.8 Hz, 1H), 7.32–7.21 (m, 4H), 7.07 (d, J = 6.4 Hz, 2H), 5.48 (d, J = 13.7 Hz, 1H), 5.25 (d, J = 13.6 Hz, 1H), 4.98 (d, J = 14.5 Hz, 1H), 4.79 (d, J = 14.5 Hz, 1H), 4.32–4.21 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 177.2, 166.0, 153.5, 152.4, 144.2, 143.9, 136.7, 136.3, 135.2, 130.5, 129.1, 128.7, 128.7, 128.6, 128.6, 127.8, 127.6, 127.5, 126.4, 123.8, 113.3, 61.9, 51.1, 46.7. HRMS (ESI): m/z [M+H]+ calcd for C28H21N3O3:448.1656; found:448.1656.
4H-Isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinolin-6-yl)(morpholino)methanone (4j), 33 mg, yellow solid, m.p.: over 280 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J = 8.9 Hz, 2H), 5.41 (q, J = 13.7 Hz, 2H), 4.03–3.91 (m, 2H), 3.84 (ddt, J = 18.4, 7.8, 5.7 Hz, 2H), 3.62 (ddd, J = 10.1, 6.2, 3.2 Hz, 1H), 3.53 (ddd, J = 11.2, 6.7, 3.2 Hz, 1H), 3.27 (ddd, J = 13.8, 6.7, 3.2 Hz, 1H), 3.19 (ddd, J = 13.6, 6.3, 3.3 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 163.9, 153.6, 152.4, 144.3, 143.9, 136.8, 130.6, 129.2, 128.8, 127.0, 126.2, 123.8, 113.4, 67.0, 66.8, 62.1, 47.0, 42.1. HRMS (ESI): m/z [M+H]+ calcd for C18H15N3O4: 338.1135; found: 338.1132.
(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4k), 18 mg, yellow solid, m.p.:176–178 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.70–7.64 (m, 1H), 7.64–7.57 (m, 1H), 5.40 (q, J = 13.6 Hz, 2H), 5.13 (td, J = 11.0, 4.3 Hz, 1H), 2.34 (d, J = 12.1 Hz, 1H), 2.11 (pd, J = 6.9, 2.7 Hz, 1H), 1.78–1.72 (m, 2H), 1.63 (d, J = 2.9 Hz, 1H), 1.54–1.46 (m, 1H), 1.28–1.11 (m, 2H), 1.00 (d, J = 6.5 Hz, 3H), 0.92 (dd, J = 7.0, 4.0 Hz, 7H). 13C NMR (126 MHz, CDCl3) δ 165.0, 154.6, 152.3, 144.7, 144.2, 137.0, 130.5, 129.1, 128.6, 126.1, 125.8, 123.8, 113.4, 61.9, 46.9, 40.9, 34.1, 31.6, 26.0, 23.2, 22.0, 20.8, 16.0. HRMS (ESI): m/z [M+H]+ calcd for C24H26N2O4:407.1965; found: 407.1960.
((3aS,4S,6S,6aS)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4l), 31 mg, yellow solid, m.p.:139–141 °C. 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.67 (dd, J = 8.4, 7.0 Hz, 2H), 7.64–7.57 (m, 1H), 5.43 (s, 3H), 5.04 (s, 2H), 4.77 (d, J = 5.9 Hz, 2H), 4.66 (d, J = 5.9 Hz, 2H), 4.58–4.52 (m, 3H), 4.51–4.45 (m, 2H), 3.38 (s, 5H), 1.50 (s, 5H), 1.33 (s, 5H). 13C NMR (126 MHz, CDCl3) δ 164.7, 153.5, 152.4, 145.4, 144.1, 137.0, 130.6, 129.3, 128.6, 126.0, 124.4, 123.9, 113.4, 112.7, 109.4, 85.1, 83.9, 81.8, 65.9, 62.1, 55.1, 26.4, 25.0. HRMS (ESI): m/z [M+H]+ calcd for C23H22N2O8:455.1449; found:455.1442.
(7S,11S,E)-3,7,11,15-Tetramethylhexadec-2-en-1-yl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4m), 73 mg, orange oil, 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J = 5.4 Hz, 1H), 8.23 (t, J = 7.3 Hz, 1H), 7.79 (dd, J = 37.8, 8.4 Hz, 1H), 7.65 (q, J = 7.6, 7.0 Hz, 1H), 7.58 (h, J = 8.2, 7.3 Hz, 1H), 5.57–5.48 (m, 1H), 5.41 (s, 2H), 5.00 (t, J = 7.6 Hz, 1H), 4.78–4.68 (m, 1H), 2.25–2.03 (m, 1H), 1.79 (d, J = 8.1 Hz, 2H), 1.51 (dtd, J = 13.2, 6.5, 2.3 Hz, 1H), 1.38–1.18 (m, 4H), 1.15–1.09 (m, 1H), 1.09–1.02 (m, 2H), 0.90–0.76 (m, 12H). 13C NMR (126 MHz, CDCl3) δ 165.2, 153.6, 152.3, 145.0, 144.6, 144.1, 136.9, 130.5, 129.0, 128.5, 126.1, 123.9, 117.9, 117.2, 113.4, 63.0, 62.1, 39.9, 39.3, 37.4, 37.3, 37.2, 36.6, 32.7, 32.6, 27.9, 25.6, 25.1, 24.7, 24.4, 22.7, 22.6, 19.7, 16.5. HRMS (ESI): m/z [M+H]+ calcd for C34H46N2O4:547.3530; found: 547.3528.
(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4n), 42 mg, yellow soild, m.p.: 196–197 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.81–7.74 (m, 1H), 7.70–7.64 (m, 1H), 7.63–7.58 (m, 1H), 5.49 (d, J = 5.4 Hz, 1H), 5.43 (d, J = 5.1 Hz, 2H), 5.09 (td, J = 11.5, 5.6 Hz, 1H), 2.64–2.46 (m, 2H), 2.18–1.92 (m, 2H), 1.85 (ddd, J = 9.8, 5.8, 3.8 Hz, 1H), 1.62–1.59 (m, 5H), 1.50 (qd, J = 11.4, 9.1, 3.8 Hz, 2H), 1.42–1.33 (m, 2H), 1.25 (ddt, J = 19.4, 13.3, 6.0 Hz, 2H), 1.20–1.07 (m, 3H), 1.05 (s, 4H), 0.93 (d, J = 6.3 Hz, 3H), 0.87 (dd, J = 6.6, 2.3 Hz, 8H), 0.70 (d, J = 8.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 164.6, 153.6, 152.3, 144.9, 144.1, 139.2, 137.0, 130.5, 129.1, 128.6, 126.1, 125.5, 123.9, 123.3, 113.5, 76.3, 62.1, 56.7, 56.1, 50.0, 42.3, 39.7, 39.5, 38.1, 37.0, 36.6, 36.2, 35.8, 31.9, 31.8, 28.2, 28.0, 27.9, 24.3, 23.8, 22.8, 22.5, 21.0, 19.3, 18.7, 11.9. HRMS (ESI): m/z [M+H]+ calcd for C41H52N2O4:637.4000; found: 637.4000.
(3S,8S,9S,10R,13R,14S,17R)-17-((2R,5S,E)-5-Ethyl-6-methylhept-3-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 4H-isoxazolo[3′,4′:4,5]pyrano[3,2-b]quinoline-6-carboxylate (4o), 38 mg, yellow solid, m.p.: 213–214 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.4 Hz, 1H), 7.70–7.63 (m, 1H), 7.63–7.57 (m, 1H), 5.49 (d, J = 5.5 Hz, 1H), 5.43 (s, 2H), 5.27–5.09 (m, 1H), 5.07–4.99 (m, 1H), 2.63–2.46 (m, 2H), 2.18–1.93 (m, 3H), 1.81–1.66 (m, 2H), 1.60–1.45 (m, 3H), 1.29–1.14 (m, 2H), 1.04 (d, J = 13.4 Hz, 5H), 0.93 (d, J = 6.2 Hz, 1H), 0.88–0.78 (m, 7H), 0.70 (d, J = 9.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 164.6, 153.6, 152.3, 144.9, 144.1, 139.2, 138.3, 137.0, 130.5, 129.3, 129.1, 128.5, 126.0, 125.5, 123.8, 123.3, 113.4, 76.3, 62.1, 56.8, 55.9, 51.2, 50.0, 45.8, 42.2, 40.5, 39.7, 39.6, 38.1, 37.0, 36.6, 31.9, 31.9, 31.8, 28.9, 27.9, 25.4, 24.3, 21.2, 21.1, 21.0, 19.3, 19.0, 19.0, 12.2, 12.0. HRMS (ESI): m/z [M+H]+ calcd for C43H54N2O4:663.4156; found: 663.4150.
3-Phenyl-2-(5-phenylisoxazol-3-yl)quinazolin-4(3H)-one (6a), 41 mg, yellow soild, m.p.: 120–122 °C. 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 7.92–7.83 (m, 4H), 7.69–7.64 (m, 3H), 7.64–7.58 (m, 1H), 7.52–7.40 (m, 9H), 7.32 (dd, J = 8.0, 1.7 Hz, 3H), 6.51 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 170.1, 161.8, 159.3, 147.1, 145.6, 137.0, 134.9, 130.6, 129.4, 129.0, 128.8, 128.3, 128.2, 127.3, 126.6, 125.9, 121.6. HRMS (ESI): m/z [M+H]+ calcd for C23H15N3O2:366.1237; found: 366.1228.

4. Conclusions

In summary, a facile and practical 1,3-dipolar cycloaddition reaction that accessed a wide variety of isoxazole-fused tricyclic quinazoline alkaloids and their derivatives has been developed under metal-free conditions. In this system, methyl azaarenes were transformed into nitrile oxides in situ by using TBN as the radical initiator and source of N-O without transition metal. This strategy has broad substrate applicability and good functional group tolerance with facile manipulation of readily available starting materials. Natural product modifications confirmed the practical utility of this synthetic method.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28062787/s1, Characterization data for product 2, 4 and 6a, include 1H-NMR, 13C-NMR and high-resolution mass spectrometry (HRMS) spectroscopies are available online.

Author Contributions

Conceptualization, Y.Z. (Yanping Zhu); methodology, Y.Z. (Yanping Zhu); investigation, Z.W. and Y.Z. (Yuhan Zhao); data curation, J.C., M.C., X.L., T.J., F.L., X.Y. and Y.S.; writing—original draft preparation, Z.W., Y.Z. (Yuhan Zhao) and Y.S.; writing—review and editing, Y.Z. (Yanping Zhu); visualization, Z.W.; supervision, Y.Z. (Yanping Zhu); project administration, Y.Z. (Yanping Zhu). All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Science and Technology Innovation Development Plan of Yantai (2020MSGY114), Yantai “Double Hundred Plan” and by the Foundation of Anhui Laboratory of Molecule-Based Materials (fzj22022). The Graduate Innovation Foundation of Yantai University (KGIFYTU2223) is gratefully acknowledged (for Z. Wang).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors also thank the Talent Induction Program for Youth Innovation Teams in Colleges and Universities of Shandong Province.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 2 and 4 are available from the authors.

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Molecules 28 02787 g001 550
Figure 1. Representative molecules containing tricyclic quinazoline.
Figure 1. Representative molecules containing tricyclic quinazoline.
Molecules 28 02787 g001
Molecules 28 02787 sch001 550
Scheme 1. Strategies for the synthesis of 2,3-fused quinazolin-4(3H)-ones. (a) Current methods to synthesize tricyclic quinazoline alkaloid. (b) Our previous work forming 1,3-dipolar nitrile oxide from methyl azaarenes via TBN. (c) Our current work to form 1,3-dipolar nitrile oxide from propargyl-substituted methyl azaarenes via TBN.
Scheme 1. Strategies for the synthesis of 2,3-fused quinazolin-4(3H)-ones. (a) Current methods to synthesize tricyclic quinazoline alkaloid. (b) Our previous work forming 1,3-dipolar nitrile oxide from methyl azaarenes via TBN. (c) Our current work to form 1,3-dipolar nitrile oxide from propargyl-substituted methyl azaarenes via TBN.
Molecules 28 02787 sch001
Molecules 28 02787 g002 550
Figure 2. Scope of 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one a,b. a Reaction conditions: 1 (0.2 mmol), TBN (1.1 mmol), NCS (0.1 mmol), AcOH (0.1 mmol) were stirred in acetonitrile (2 mL) at 100 °C for 6 h under Ar. b Isolated yields. c Not detected.
Figure 2. Scope of 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one a,b. a Reaction conditions: 1 (0.2 mmol), TBN (1.1 mmol), NCS (0.1 mmol), AcOH (0.1 mmol) were stirred in acetonitrile (2 mL) at 100 °C for 6 h under Ar. b Isolated yields. c Not detected.
Molecules 28 02787 g002
Molecules 28 02787 g003 550
Figure 3. Scope of 2-methyl-3-(prop-2-yn-1-yloxy)quinoline a,b. a Reaction conditions: 3 (0.2 mmol), TBN (1.1 mmol), NCS (0.1 mmol), AcOH (0.1 mmol) were stirred in acetonitrile (2 mL) at 100 °C for 6 h under Ar. b Isolated yields.
Figure 3. Scope of 2-methyl-3-(prop-2-yn-1-yloxy)quinoline a,b. a Reaction conditions: 3 (0.2 mmol), TBN (1.1 mmol), NCS (0.1 mmol), AcOH (0.1 mmol) were stirred in acetonitrile (2 mL) at 100 °C for 6 h under Ar. b Isolated yields.
Molecules 28 02787 g003
Molecules 28 02787 g004 550
Figure 4. Modification of natural products a,b. a Reaction conditions: 3 (0.2 mmol), TBN (1.1 mmol), NCS (0.1 mmol), AcOH (0.1 mmol) were stirred in acetonitrile (2 mL) at 100 °C for 6 h under Ar. b Isolated yields.
Figure 4. Modification of natural products a,b. a Reaction conditions: 3 (0.2 mmol), TBN (1.1 mmol), NCS (0.1 mmol), AcOH (0.1 mmol) were stirred in acetonitrile (2 mL) at 100 °C for 6 h under Ar. b Isolated yields.
Molecules 28 02787 g004
Molecules 28 02787 sch002 550
Scheme 2. Control experiments. (a) Radical capture. (b) Formation of intermediate 5ac. (c) Formation of isoxazole 6a via intermolecular cycloaddition under standard conditions. (d) Formation of 6a from intermediate 5ab under standard conditions.
Scheme 2. Control experiments. (a) Radical capture. (b) Formation of intermediate 5ac. (c) Formation of isoxazole 6a via intermolecular cycloaddition under standard conditions. (d) Formation of 6a from intermediate 5ab under standard conditions.
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Molecules 28 02787 sch003 550
Scheme 3. Proposed mechanism.
Scheme 3. Proposed mechanism.
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Molecules 28 02787 sch004 550
Scheme 4. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 1a–1l.
Scheme 4. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 1a–1l.
Molecules 28 02787 sch004
Molecules 28 02787 sch005 550
Scheme 5. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yl)pyrido[2,3-d]pyrimidin-4(3H)-one 1m.
Scheme 5. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yl)pyrido[2,3-d]pyrimidin-4(3H)-one 1m.
Molecules 28 02787 sch005
Molecules 28 02787 sch006 550
Scheme 6. General procedure for synthesis of 2-methyl-7-phenyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 1g–1h.
Scheme 6. General procedure for synthesis of 2-methyl-7-phenyl-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 1g–1h.
Molecules 28 02787 sch006
Molecules 28 02787 sch007 550
Scheme 7. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yloxy)quinoline 4a–4c.
Scheme 7. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yloxy)quinoline 4a–4c.
Molecules 28 02787 sch007
Molecules 28 02787 sch008 550
Scheme 8. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yloxy)quinoline-4-carboxylate 3d–3o.
Scheme 8. General procedure for synthesis of 2-methyl-3-(prop-2-yn-1-yloxy)quinoline-4-carboxylate 3d–3o.
Molecules 28 02787 sch008
Molecules 28 02787 sch009 550
Scheme 9. Procedure for synthesis of (E)-4-oxo-3-phenyl-3,4-dihydroquinazoline-2-carbaldehyde oxime (5ab).
Scheme 9. Procedure for synthesis of (E)-4-oxo-3-phenyl-3,4-dihydroquinazoline-2-carbaldehyde oxime (5ab).
Molecules 28 02787 sch009
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 28 02787 i001
EntrySolventAcidAdditiveTemp
(°C)		Yield b
(%)
1DMSO 8045
2DMF 8062
31,4-Dioxane 8056
4MeCN 8064
5MeCN 6055
6MeCN 10065
7 cMeCN 10072
8 c,dMeCN 10075
9 c,dMeCN NCS10076
10 c,dMeCNTFANCS10046
11 c,dMeCNAcOHNCS10080
12 c,dMeCNPropanoic acidNCS10068
13 c,dMeCNPropanedioic acidNCS10058
14 c,dMeCN4-Nitrobenzoic acidNCS10068
15 c,dMeCN2-Nitrobenzoic acidNCS10073
16 c,dMeCN4-Chlorobenzoic acidNCS10071
17 c,dMeCNPTA eNCS10055
18 c,dMeCNAcOH 10066
19 c,dMeCN4-Chlorobenzoic acid 10042
a Reaction conditions: 1a (0.2 mmol), TBN (1.0 mmol), NCS (0.1 mmol), AcOH (0.1 mmol) were stirred in acetonitrile (2 mL) at 100 °C for 6 h under air. b Isolated yields. c TBN (5.5 equiv.). d under argon. e p-Toluic acid.
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MDPI and ACS Style

Wang, Z.; Zhao, Y.; Chen, J.; Chen, M.; Li, X.; Jiang, T.; Liu, F.; Yang, X.; Sun, Y.; Zhu, Y. One-Pot Synthesis of Isoxazole-Fused Tricyclic Quinazoline Alkaloid Derivatives via Intramolecular Cycloaddition of Propargyl-Substituted Methyl Azaarenes under Metal-Free Conditions. Molecules 2023, 28, 2787. https://doi.org/10.3390/molecules28062787

AMA Style

Wang Z, Zhao Y, Chen J, Chen M, Li X, Jiang T, Liu F, Yang X, Sun Y, Zhu Y. One-Pot Synthesis of Isoxazole-Fused Tricyclic Quinazoline Alkaloid Derivatives via Intramolecular Cycloaddition of Propargyl-Substituted Methyl Azaarenes under Metal-Free Conditions. Molecules. 2023; 28(6):2787. https://doi.org/10.3390/molecules28062787

Chicago/Turabian Style

Wang, Zhuo, Yuhan Zhao, Jiaxin Chen, Mengyao Chen, Xuehan Li, Ting Jiang, Fang Liu, Xi Yang, Yuanyuan Sun, and Yanping Zhu. 2023. "One-Pot Synthesis of Isoxazole-Fused Tricyclic Quinazoline Alkaloid Derivatives via Intramolecular Cycloaddition of Propargyl-Substituted Methyl Azaarenes under Metal-Free Conditions" Molecules 28, no. 6: 2787. https://doi.org/10.3390/molecules28062787

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