Rh(III)-Catalyzed Double Annulation of 3-Phenyl-1,2,4-oxadiazoles with 2-Diazo-1,3-diketones: Access to Pyran-Fused Isoquinolines

Abstract

Efficient access to pyranoisoquinoline derivatives via rhodium-catalyzed double C-H functionalization of phenyl oxadiazoles and diazo compounds has been developed. Two C-C bonds and one C-O and C-N bond formation was realized by this tandem reaction, along with the formation of two heterocycles, affording diversified pyran-fused isoquinolines in moderate to good yields with broad functional group tolerance under mild reaction conditions.

1. Introduction

As a representative fused heterocyclic scaffold, pyranoisoquinoline derivatives are ubiquitous in bioactive compounds and natural products. For instance (Figure 1), Pranoprofen (I) and Amlexanox (II) are marketed anti-inflammatory drugs [1,2]. Compound III inhibits mitogen-activated protein kinase 2 (MK-2) and suppresses expression of TNFa in U937 cells [3]. Compound IV has potential activity for the treatment of Alzheimer’s disease [4].

Thus, the development of efficient methods for accessing such frameworks has attracted much more attention from the synthetic community. For example, in 2018, Cheng’s group developed a rhodium-catalyzed functionalization of aromatic C-H bonds to obtain a series of pyrano and isoquinoline derivatives with good optical properties [Scheme 1a] [5]. The group also developed an asymmetric double six-membered ring compound of heteroaryl and alkynes [Scheme 1b] [6]. You et al. reported a strategy for the synthesis of bicycles via Rh-catalyzed activation of double C-H bonds of benzamides [Scheme 1c] [7]. Maheswari developed a cascade strategy for the assembly of 3,4-dihydrophenanthridines using high-valent iodonium ylides as a carbene precursor [Scheme 1d] [8]. The yield of pyran-fused isoquinolines obtained via the reported literature methods is low and requires nitrogen protection, leading to the complex synthesis of pyran-fused isoquinolines. In 2022, Shang’s group reported the formation of a pyrano [4,3,2-ij]isoquinoline skeleton using bis-orthorhombic-C-H activation of methyl benzimidazolate and subsequent N,O-bicycloaddition with a-carbonyl diazides. However, AcCl, the raw material for the synthesis of methyl benzimidazolate, is highly toxic. The yields of pyran-fused isoquinolines synthesized by this reaction are generally low and the atom economy is poor [Scheme 1e] [9]. Therefore, it is necessary to further explore the low-toxicity and high-efficiency method to prepare pyran-fused isoquinolines. The unique physicochemical properties of pyranoisoquinolines have inspired more synthetic workers to develop new synthetic strategies and obtain molecules with diverse structures.

Due to their unique structure, oxadiazoles are not only used as the cores of bioactive compounds as well as functional materials but are also applied as directing groups in the field of catalytic C-H bond activation. For example, in 2017, Zhu’s group used cobalt(III) to catalyze the construction of 1-aminoisoquinolines by oxadiazole [Scheme 2a] [10]. Later on, they reported a Rh(III)-catalyzed coupling of alkenyl oxadiazoles with alkynes for the synthesis of 2-acylamino acids and 2-aminopyridines, which are important heterocyclic backbones in a variety of natural products and synthetic drugs with readily reactive functional groups [Scheme 2b] [11]. In 2018, Dong and colleagues developed an efficient Rh(III)-catalyzed one-pot synthesis of indene derivatives from oxadiazole and allyl alcohols [Scheme 2c] [12]. In 2023, Dong’s group developed access to isoquinoline compounds with good chemo- and regioselectivity via Rh(III)-catalyzed [4+2] cycloaddition reactions of oxadiazoles and difluoromethylene alkynes [Scheme 2d] [13]. The reaction type of oxadiazole involved in the above report is a simple ortho-C-H activation reaction, which generally retains the unexpected structure and does not conform to the principle of atomic economy. Herein, we report a Rh-catalyzed double C-H activation of aryl oxadiazoles with diazo compounds. The reaction method is simple, the raw materials are easy to obtain, and it does not require N₂ conditions. The yields of the prepared product are high. This reaction provides efficient access to obtain the pyranoisoquinoline skeleton [Scheme 2e].

2. Results and Discussion

This research was started with 2-diazo-5,5-dimethylcyclohexane-1,3-dione (1a) and 5-methyl-3-phenyl-1,2,4-oxadiazole (2a) as the model substrates (

Table 1. Optimization of the reaction conditions ^a.

Entry	Catalyst	Base	Additive	Solvent	Yield (%) b
1	Rh2(OAc)4	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	nr
2	Pd(OAc)2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	nr
3	Ru(PPh3)3Cl2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	nr
4	[RuCl2(p-cymene)]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	nr
5	[Cp*IrCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	41
6	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	95
7	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgSbF6	1,4-dioxane	25
8	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgOAc	1,4-dioxane	10
9	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgBF4	1,4-dioxane	18
10	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgOTf	1,4-dioxane	15
11	[Cp*RhCl2]2	Cu(OAc)2·H2O	none	1,4-dioxane	nr
12	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	toluene	nr
13	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	MeCN	nr
14	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	DCE	nr
15 c	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	85
16 d	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	92
17 e	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	73
18 f	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	80
19 g	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	77
20 h	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	75
21 i	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	79
22 j	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	82
23	[Cp*RhCl2]2	AgOAc	AgNTf2	1,4-dioxane	39
24	[Cp*RhCl2]2	NaOAc	AgNTf2	1,4-dioxane	nr
25	[Cp*RhCl2]2	KOAc	AgNTf2	1,4-dioxane	nr
26 k	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	46
27 l	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	71
28 m	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	80
29 n	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2	1,4-dioxane	93
30	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2 (10 mol%)	1,4-dioxane	53
31	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2 (20 mol%)	1,4-dioxane	67
32	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2 (30 mol%)	1,4-dioxane	75
33	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2(40 mol%)	1,4-dioxane	82
34	[Cp*RhCl2]2	Cu(OAc)2·H2O	AgNTf2 (60 mol%)	1,4-dioxane	85

^a Reaction conditions: 1a (0.35 mmol), 2a (0.1 mmol), catalyst (5 mol %), additive (50 mol %), and Base (2.0 equiv) in solvent (3 mL) at 100 °C under air atmosphere for 11 h. ^b Isolated yields. nr: no reaction. ^c The catalyst loading was 4 mol %. ^d The catalyst loading was 6 mol %. ^e The additive loading was 40 mol %. ^f The additive loading was 60 mol %. ^g At 90 °C. ^h At 110 °C. ⁱ For 10 h. ^j For 12 h. ^k Cu(OAc)₂·H₂O (0.5 equiv). ^l Cu(OAc)₂·H₂O (1.0 equiv). ^m Cu(OAc)₂·H₂O (1.5 equiv). ⁿ Cu(OAc)₂·H₂O (2.5 equiv).

). A screening of the catalysts was carried out. First, the expected reaction to generate the chromopyridine product 3a could be in [Cp*RhCl₂]₂ (5 mol %) as the catalyst (Table 1, entries 1–6). Other additives, including AgSbF₆, AgOAc, AgBF₄, and AgOTf, failed to promote the reaction, resulting in a significant decrease in reaction yield (Table 1, entries 7–10). Satisfactory yields of 3a can also be obtained by reducing or increasing the content of additives (Table 1, entries 17 and 18). Common solvents such as toluene, acetonitrile, and DCE failed to improve product yields (Table 1, entries 12–14). For reaction temperatures of 90 °C and 110 °C, the isolated yields of product 3a were 77% and 75%, respectively (Table 1, entries 19 and 20). No obvious change was revealed in the reaction after further optimization (Table 1, entries 21 and 22). The reaction yield was 39% when AgOAc was used as a base. The NaOAc and KOAc did not promote the reaction when used as bases (Table 1, entries 23–25). The reaction yield gradually increased with an increasing amount of Cu(OAc)₂·H₂O (Table 1, entries 26–28). The reaction yield was highest when the amount of base reached 2.0 equiv (entry 6), after which the reaction yield remained constant with an increasing amount (entry 29). The reaction yields gradually increased with the amount of AgNTf₂ additive increasing (Table 1, entries 30–33). When the amount of AgNTf₂ reached a certain amount, the reaction yield declined instead of increasing (Table 1, entry 34).

The interaction range of oxadiazole 2 with cyclic diazo compounds was examined under optimal conditions (Scheme 3). Typically, substrate 2 with both electron-donating (Me, Bu, OMe, and SMe) and electron-absorbing groups (F, Cl, and Br) was successfully converted to the desired chromopyridine products 3a–3h in good yields (75–95%). When R³ was CF₃ or Ph, the corresponding yields of products 3i and 3j were 68% and 70%, respectively. In addition, the reaction of oxadiazoles with cyclic diazonium compounds yielded 3k and 3l in 85% and 83% yields when the oxadiazole interstitials were linked to the substituted OMe and F. The reaction of different types of diazonium compounds with oxadiazole 2 also proceeded well, giving the target products 3m–3t in 80–95% yields. Single-crystal characterization determined the structure of 3a [14]. However, 3-phenyl-1,2,4-oxadiazole with other substituents could not give the desired product in this reaction. Due to the steric exclusion of the 3-phenyl-1,2,4-oxadiazole substituent group, the insertion of the diazo compound in the neighboring position was prevented, which is not conducive to the formation of Rh-carbene.

The reaction was scaled up to 4 mmol (scaled up to 40 times) to yield the desired product 3a in 82% yield (Scheme 4). To demonstrate the utility of product 3, its reactivity was then investigated in palladium-catalyzed cross-coupling reactions. As shown in the results in Scheme 5, the generated chromium pyridine compound 3h reacted smoothly with styrene, phenylacetylene, phenylboronic acid, diphenylamine, and bis(pinacolato)diboron to obtain the corresponding products 4, 5, 6, 7, and 8 in 88%, 91%, 93%, 89%, and 89% yields, respectively. The generated chromium pyridine compound 3h could also be reduced by NaBH₄ to obtain product 9 in 95% yields.

Some of the products we prepared are partially similar in structure to those prepared by the previous Shang group, for example, products 3a and 3b [9]. Other products that they did not obtain include 3q, 3r, and 3s. We were able to synthesis pyran-fused isoquinolines using cyclic diazides with different substituents. We report a Rh-catalyzed double C-H activation reaction of an aryl oxadiazole with a diazo compound. Compared with previous reports, our works have the advantages of easy availability of feedstock, no need to be carried out under nitrogen atmosphere, and high yield. Most of the synthesized compounds have bright fluorescence. The fluorescence emission range of these pyran-fused isoquinoline compounds is very wide, which indicates that they have a wide range of applications in biological imaging, organic light-emitting diodes, optoelectronic devices, fluorescent sensors, and biomedical imaging [5,6,9].

Based on the experimental results and literature reports, a possible reaction mechanism was proposed in Scheme 6. Initially, [Cp*RhCl₂]₂ undergoes anion exchange in the presence of AgNTf₂ and Cu(OAc)₂·H₂O to generate a Rh(III)-active catalyst. The active catalyst and substrate 2a were activated by the C-H bond to form a five-membered rhodium ring as intermediate A. Subsequently, the cyclic 2-diazo-1,3-diketone 1a coordinates with intermediate A to form intermediate B by releasing N₂. Then, migratory insertion of carbine into Rh-C bond completes the C-C coupling and affords the six-membered intermediate C, which can be protonated with acetic acid to generate intermediate D and release the Rh(III)-catalyst. Intermediate E is an isomer of intermediate D. Repeating the above steps, intermediate G was obtained. Intermediate F is an isomer of intermediate G. Intermediate G coordinates with the Rh(III)-active substance to generate intermediate H. Intermediate H undergoes an elimination reaction to eliminate H₂O and obtain intermediate I. The Rh remains trivalent throughout and does not undergo a valence state change. Cu does not participate in the reaction in this process. Subsequently, intermediate I undergoes electron transfer to generate intermediate J [11,12,13]. In addition, complex J undergoes reductive elimination to form the C-N bond to generate complex K and generate Rh(I). Rh(I) is reoxidized to Rh(III) in the next catalytic cycle using the N-O bond cleavage as the internal oxidant [10,11,15]. Intermediate K undergoes oxidation by Cu(OAc)₂·H₂O followed by an intramolecular nucleophilic addition reaction to produce the desired product 3a [16].

3. Materials and Methods

3.1. General Methods (Chemistry)

The general methods are described in the Supplementary Materials. The 500 MHz NMR spectrometer (AVANCE IIITM HD 500), the 400 MHz NMR spectrometer (AVANCENEO 400) and the X-ray single crystal diffractometer (D8 VENTURE) are from Bruker, Germany. The company is located in Wurzbach in the Berlin region of eastern Germany. NMR analysis was carried out at 298 K. High Resolution Mass measurement was performed on Agilent QTOF 6520 mass spectrometer with electron spray ionization (ESI or APCI) as the ion source (Agilent Technologies, Santa Clara, CA, USA). The melting points were measured using SGWX-4 melting point apparatus and were not corrected (Zhejiang NADE Scientific Instrument Co., Ltd., Hangzhou, China). The software is ChemBioDraw Ultra (ACS Document 1996) and MestReNova (15.0).

3.2. General Procedures for the Preparation of Compounds 3

A Schlenk tube was equipped with a magnetic stir bar and charged with substituted 2-diazo-1,3-dione 1 (0.35 mmol), 2 (0.1 mmol), [Cp*RhCl₂]₂ (5 mol %), Cu(OAc)₂·H₂O (2.0 equiv), and AgNTf₂ (0.5 equiv.), which were stirred in 1,4-dioxane (3.0 mL) under atmosphere at 100 °C for 11 h. After completion, the reaction mixture was purified by flash chromatography, eluting with ethyl acetate and petroleum ether to give product 3 as a yellow solid.

• 6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3a), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 34.4 mg, yield: 95%; m.p 259–260 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.20 (dd, J = 8.7, 0.9 Hz, 1H), 8.80 (dd, J = 7.7, 0.9 Hz, 1H), 7.86 (dd, J = 8.7, 7.7 Hz, 1H), 3.03 (s, 2H), 2.80 (s, 2H), 2.60 (s, 2H), 2.53 (s, 2H), 1.19 (s, 6H), 1.14 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 199.4, 197.0, 168.0, 161.4, 159.8, 136.9, 136.0, 127.8, 123.5, 120.8, 117.6, 116.2, 112.2, 54.3, 53.1, 47.9, 42.7, 33.0, 32.3, 28.6, 28.5. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₂₄NO₃⁺ 362.1751; found 362.1753.

• 2,6,6,11,11-pentamethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3b), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 31.5 mg, yield: 84%; m.p 256–257 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.03 (s, 1H), 8.65 (s, 1H), 3.04 (s, 2H), 2.78 (s, 2H), 2.59–2.58 (m, 5H), 2.52 (s, 2H), 1.18 (s, 6H), 1.13 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 199.6, 197.1, 168.2, 161.7, 159.7, 147.5, 137.1, 127.6, 123.1, 122.3, 117.2, 114.4, 112.1, 54.3, 53.2, 47.9, 42.7, 32.9, 32.3, 28.6, 28.5, 23.8. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₂₆NO₃⁺ 376.1907; found 376.1906.

• 2-butyl-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3c), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 37.5 mg, yield: 90%; m.p 196–197 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.02 (d, J = 1.5 Hz, 1H), 8.66 (d, J = 1.4 Hz, 1H), 2.99 (s, 2H), 2.86–2.78 (m, 2H), 2.77 (s, 2H), 2.58 (s, 2H), 2.51 (s, 2H), 1.74–1.59 (m, 2H), 1.43–1.35 (m, 2H), 1.18 (s, 6H), 1.13 (s, 6H), 0.93 (t, J = 7.4 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 199.6, 197.2, 168.1, 161.7, 159.7, 152.4, 137.1, 127.6, 122.6, 121.8, 117.3, 114.6, 112.2, 54.3, 53.2, 48.0, 42.7, 37.8, 34.0, 33.0, 32.3, 28.6, 28.5, 23.0, 14.4. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₇H₃₂NO₃⁺ 418.2377; found 418.2368.

• 2-methoxy-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3d), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 34.8 mg, yield: 89%; m.p 260–261 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.70 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 2.98 (s, 2H), 2.77 (s, 2H), 2.58 (s, 2H), 2.51 (s, 2H), 1.18 (s, 6H), 1.12 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 199.6, 196.9, 168.5, 166.1, 162.6, 159.2, 139.3, 129.4, 116.8, 111.7, 111.5, 111.3, 104.0, 56.1, 54.3, 53.0, 48.0, 42.7, 32.9, 32.3, 28.6, 28.5. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₂₆NO₄⁺ 392.1856; found 392.1853.

• 6,6,11,11-tetramethyl-2-(methylthio)-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3e), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 35.1 mg, yield: 86%; m.p 305–306 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.04 (d, J = 1.5 Hz, 1H), 8.72 (d, J = 1.5 Hz, 1H), 3.00 (s, 2H), 2.79 (s, 2H), 2.62 (s, 3H), 2.59 (s, 2H), 2.52 (s, 2H), 1.19 (s, 6H), 1.14 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 199.1, 196.5, 168.3, 162.0, 150.5, 136.6, 127.0, 117.8, 116.6, 115.9, 112.9, 111.1, 53.9, 52.7, 47.6, 42.4, 32.5, 31.9, 28.1, 28.0, 14.7. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₂₆NO₃S⁺ 408.1628; found 408.1625.

• 2-fluoro-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3f), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 32.6 mg, yield: 86%; m.p 235–236 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.94 (dd, J = 11.9, 2.5 Hz, 1H), 8.62 (dd, J = 10.6, 2.5 Hz, 1H), 3.03 (s, 2H), 2.82 (s, 2H), 2.60 (s, 2H), 2.54 (s, 2H), 1.20 (s, 6H), 1.14 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ198.8, 196.2, 168.7 (d, J_C,F = 27.0 Hz), 166.4, 162.3, 138.8, 130.5 (d, J_C,F = 13.7 Hz), 117.1, 113.1, 110.2 (d, J_C,F = 29.4 Hz), 108.7, 108.4, 53.7, 52.5, 47.5, 42.3, 32.6, 32.0, 28.2, 28.1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₂₃FNO₃⁺ 380.1656; found 380.1665.

• 2-chloro-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3g), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 34.4 mg, yield: 87%; m.p 234–235 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.27 (d, J = 1.9 Hz, 1H), 8.84 (d, J = 1.9 Hz, 1H), 3.03 (s, 2H), 2.81 (s, 2H), 2.60 (s, 2H), 2.53 (s, 2H), 1.19 (s, 6H), 1.14 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 199.1, 196.6, 168.8, 162.5, 159.5, 143.6, 137.6, 129.2, 122.9, 121.5, 116.8, 114.4, 111.3, 54.1, 52.9, 47.9, 42.7, 32.9, 32.3, 28.6, 28.5. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₂₃ClNO₃⁺ 396.1361; found 396.1369.

• 2-bromo-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3h), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 32.9 mg, yield: 75%; m.p 259–260 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.43 (s, 1H), 8.97 (s, 1H), 3.03 (s, 2H), 2.81 (s, 2H), 2.60 (s, 2H), 2.53 (s, 2H), 1.19 (s, 6H), 1.14 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 198.7, 196.2, 168.5, 166.3, 162.2, 159.0, 130.4, 117.0, 113.0, 111.2, 110.2, 110.0, 108.7, 108.4, 53.7, 52.5, 47.5, 42.3, 32.5, 31.9, 28.2, 28.1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₂₃BrNO₃⁺ 440.0856; found 440.0853.

• 6,6,11,11-tetramethyl-2-(trifluoromethyl)-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3i), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 29.2 mg, yield: 68%; m.p 240–241 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.56 (dd, J = 1.7, 0.8 Hz, 1H), 9.08 (d, J = 1.6 Hz, 1H), 3.07 (s, 2H), 2.83 (s, 2H), 2.63 (s, 2H), 2.56 (s, 2H), 1.21 (s, 6H), 1.15 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 198.7, 196.1, 168.5, 162.0, 159.0, 136.2, 128.7, 127.8, 120.3 (q, J_C,F = 5.6 Hz), 117.5, 116.5 (q, J_C,F = 3.8 Hz), 111.2, 53.7, 52.5, 47.4, 42.3, 32.6, 31.9, 28.1, 28.0. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₂₃F₃NO₃⁺ 430.1625; found 430.1624.

• 6,6,11,11-tetramethyl-2-phenyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3j), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 30.6 mg, yield: 70%; m.p 280–281 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.51 (d, J = 1.6 Hz, 1H), 9.14 (d, J = 1.6 Hz, 1H), 7.82–7.79 (m, 2H), 7.51–7.47 (m, 2H), 7.44–7.40 (m, 1H), 3.04 (s, 2H), 2.81 (s, 2H), 2.62 (s, 2H), 2.54 (s, 2H), 1.20 (s, 6H), 1.16 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 199.0, 196.6, 167.9, 161.5, 159.3, 148.1, 140.5, 136.9, 128.9, 128.5, 128.0, 127.8, 121.2, 119.6, 117.3, 114.7, 111.8, 53.9, 52.7, 47.6, 42.3, 32.6, 31.9, 28.2, 28.1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₉H₂₈NO₃⁺ 438.2064; found 438.2066.

• 3-methoxy-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3k), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 33.3 mg, yield: 85%; m.p 258–259 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 3.96 (s, 3H), 2.96 (s, 2H), 2.75 (s, 2H), 2.69 (s, 2H), 2.50 (s, 2H), 1.18 (s, 6H), 1.16 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 197.2, 197.0, 166.4, 159.3, 158.2, 153.3, 126.6, 122.0, 121.5, 120.2, 118.1, 115.7, 112.0, 56.5, 54.0, 53.0, 47.4, 42.5, 34.2, 32.4, 29.2, 28.6. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₂₆NO₄⁺ 392.1856; found 392.1857.

• 3-fluoro-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3l), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 31.5 mg, yield: 83%; m.p 234–235 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.43 (s, 1H), 9.97 (s, 1H), 3.03 (s, 2H), 2.81 (s, 2H), 2.60 (s, 2H), 2.53 (s, 2H), 1.19 (s, 6H), 1.14 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 196.8, 196.3, 167.4, 159.5 (d, J_C,F = 58.8 Hz), 156.6, 154.6, 126.2, 124.6 (t, J_C,F = 12.5 Hz), 122.1 (d, J_C,F = 7.8 Hz), 121.5 (d, J_C,F = 22.5 Hz), 119.4, 118.3, 117.6, 111.8, 53.7, 53.0, 47.6, 42.5, 34.0, 32.3, 28.9, 28.6. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₂₃FNO₃⁺ 380.1656; found 380.1658.

• 6,11-dimethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3m), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 29.3 mg, yield: 88%; m.p 241–242 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.19 (d, J = 8.6 Hz, 1H), 8.81 (d, J = 7.4 Hz, 1H), 7.85 (t, J = 8.2 Hz, 1H), 3.27–3.08 (m, 1H), 3.02–2.91 (m, 1H), 2.92–2.77 (m, 2H), 2.76–2.60 (m, 2H), 2.55–2.27 (m, 4H), 1.21–1.18 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 199.4, 197.0, 169.0, 162.4, 159.4, 137.0, 136.0, 127.9, 123.6, 120.9, 118.2, 116.2, 112.8, 48.8, 47.4, 42.3, 37.0, 29.3, 28.0, 21.5, 21.2. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₁H₂₀NO₃⁺ 334.1438; found 334.1447.

• 6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3n), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 25.9 mg, yield: 85%; m.p 239–240 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.19 (d, J = 8.7 Hz, 1H), 8.81 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 8.6, 7.8 Hz, 1H), 3.15 (t, J = 6.2 Hz, 2H), 2.95 (t, J = 6.3 Hz, 2H), 2.83–2.71 (m, 2H), 2.70–2.57 (m, 2H), 2.37–1.99 (m, 4H). ¹³C NMR (125 MHz, CDCl₃) δ 199.4, 197.0, 169.5, 163.0, 159.2, 137.7, 136.0, 128.0, 123.7, 121.1, 118.6, 116.2, 113.2, 40.7, 39.2, 34.1, 29.2, 22.0, 20.4. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₉H₁₆NO₃⁺ 306.1125; found 306.1134.

• 2-methoxy-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3o), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 27.8 mg, yield: 83%; m.p 309–310 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H), 3.12 (t, J = 6.2 Hz, 2H), 2.94 (t, J = 6.3 Hz, 2H), 2.75–2.72 (m, 2H), 2.68–2.64 (m, 2H), 2.21–2.16 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 199.2, 196.5, 169.6, 165.7, 163.8, 158.3, 139.2, 129.2, 117.4, 112.3, 111.4, 111.0, 104.0, 55.7, 40.3, 38.8, 33.9, 28.8, 21.7, 19.9. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₀H₁₈NO₄⁺ 336.1230; found 336.1232.

• 2-methyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3p), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 25.5 mg, yield: 80%; m.p 328–329 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H), 8.63 (s, 1H), 3.12 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.57 (s, 3H), 2.20–2.17 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 199.1, 196.7, 169.2, 162.9, 158.7, 147.0, 136.9, 127.2, 122.8, 122.1, 117.7, 114.0, 112.6, 40.3, 38.9, 33.7, 28.8, 23.4, 21.6, 19.9. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₀H₁₈NO₃⁺ 320.1281; found 320.1286.

• 5,6,9,10-tetrahydrocyclopenta[5,6]pyrano[4,3,2-ij]cyclopenta[c]isoquinoline-4,11-Dione (3q), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 22.2 mg, yield: 80%; m.p 214–215 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.62 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 7.3 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 3.44–3.14 (m, 2H), 3.17–2.90 (m, 2H), 2.85–2.80 (m, 2H), 2.80–2.75 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 204.7, 200.5, 180.9, 174.6, 163.3, 136.0, 134.9, 126.8, 121.7, 121.4, 118.8, 117.0, 115.5, 36.5, 34.9, 29.2, 26.0. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₁₂NO₃⁺ 278.0812; found 278.0816.

• 6,11-diphenyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3r), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 41.1 mg, yield: 90%; m.p 263–264 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.26 (d, J = 8.6 Hz, 1H), 8.88 (d, J = 7.7 Hz, 1H), 7.91 (t, J = 8.2 Hz, 1H), 7.42–7.38 (m, 4H), 7.36–7.29 (m, 6H), 3.59 (d, J = 14.8 Hz, 2H), 3.51–3.28 (m, 2H), 3.19 (d, J = 8.0 Hz, 2H), 3.11–3.02 (m, 1H), 3.02–2.76 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 198.1, 195.7, 168.2, 161.8, 159.2, 142.6, 141.4, 136.6, 135.8, 129.1, 128.9, 127.5, 127.4, 127.1, 126.7, 126.6, 123.4, 120.8, 117.9, 112.6, 47.1, 45.8, 41.0, 39.2, 37.9, 36.0. HRMS (ESI) m/z: [M + H]⁺ calcd for C₃₁H₂₄NO₃⁺ 458.1751; found 458.1744.

• 6,11-bis(4-chlorophenyl)-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3s), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 49.9 mg, yield: 95%; m.p 329–330 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.24 (d, J = 8.7 Hz, 1H), 8.86 (d, J = 7.7 Hz, 1H), 7.90 (t, J = 8.2 Hz, 1H), 7.38–7.34 (m, 4H), 7.27–7.24 (m, 4H), 3.58–3.55 (m, 2H), 3.41–3.33 (m, 2H), 3.16–3.13 (m, 2H), 3.03 (d, J = 13.5 Hz, 1H), 2.96–2.85 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 198.0, 195.6, 168.3, 161.8, 159.5, 141.5, 140.2, 137.0, 136.3, 133.8, 133.2, 129.7, 129.4, 128.5, 128.4, 127.7, 123.8, 121.3, 118.3, 116.3, 113.1, 47.3, 46.0, 41.3, 39.0, 37.7, 36.4. HRMS (ESI) m/z: [M + H]⁺ calcd for C₃₁H₂₂ClNO₃⁺ 526.0971; found 526.0978.

• 2-butyl-6,11-bis(4-chlorophenyl)-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione (3t), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 50.0 mg, yield: 86%; m.p 230–231 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.73 (d, J = 1.4 Hz, 1H), 7.35 (dd, J = 14.3, 8.5 Hz, 4H), 7.26 (s, 1H), 7.25–7.23 (m, 3H), 3.66–3.50 (m, 2H), 3.43–3.24 (m, 2H), 3.21–3.06 (m, 2H), 3.08–2.98 (m, 1H), 2.97–2.73 (m, 5H), 1.74–1.68 (m, 2H), 1.43–1.39 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.8, 195.4, 168.0, 161.6, 159.1, 152.4, 141.2, 139.8, 136.9, 133.4, 132.8, 129.3, 129.0, 128.1, 128.0, 127.1, 122.7, 122.0, 117.6, 114.4, 112.7, 47.0, 45.7, 41.0, 38.7, 37.4, 37.4, 36.0, 33.6, 22.6, 14.0. HRMS (ESI) m/z: [M + H]⁺ calcd for C₃₅H₃₀ClNO₃⁺ 582.1597; found 582.1604.

3.3. General Procedures for the Preparation of Compounds 4

A Schlenk tube was equipped with a magnetic stir bar and charged with 2-bromo-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione 3h (0.1 mmol), styrene (0.1 mmol), Pd(OAc)₂ (4 mol %), K₃PO₄ (3.0 equiv), and DMAc (2 mL). Then, the flask was sealed under Ar and stirred at 110 °C for 12 h. After the reaction was quenched by the addition of water, the mixture was extracted with dichloromethane, and the combined organic layer was dried over sodium sulfate. The concentration in vacuo followed by silica gel column purification with petroleum ether/ethyl acetate eluent gave the desired product 4.

• (E)-6,6,11,11-tetramethyl-2-styryl-6,7,11,12-tetrahydrochromeno[2,3,4-gh] phenanthridine-4,13(5H,10H)-dione (4), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 40.7 mg, yield: 88%; m.p 186–187 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.70 (d, J = 1.2 Hz, 1H), 7.25–7.13 (m, 5H), 6.88–6.71 (m, 2H), 2.99 (s, 2H), 2.75 (s, 2H), 2.55 (s, 2H), 2.44 (s, 2H), 1.15 (s, 6H), 1.12 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 198.6, 195.9, 167.4, 161.2, 159.2, 145.1, 136.6, 136.5, 133.3, 130.2, 129.0, 128.2, 127.5, 127.0, 123.3, 121.2, 117.1, 114.6, 111.7, 53.8, 52.6, 47.5, 42.3, 32.5, 31.8, 28.1, 28.0. HRMS (ESI) m/z: [M + H]⁺ calcd for C₃₁H₃₀NO₃⁺ 464.2220; found 464.2213.

3.4. General Procedures for the Preparation of Compounds 5

A Schlenk tube was equipped with a magnetic stir bar and charged with 2-bromo-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione 3h (0.1 mmol), ethynylbenzene (0.1 mmol), PdCl₂ (5 mol %), PPh₃ (15 mol %), CuI (5 mol %), and Et₃N (2 mL). Then, the flask was sealed under Ar and stirred at 80 °C for 12 h. After the reaction was quenched by the addition of water, the mixture was extracted with dichloromethane, and the combined organic layer was dried over sodium sulfate. The concentration in vacuo followed by silica gel column purification with petroleum ether/ethyl acetate eluent gave the desired product 5.

• 6,6,11,11-tetramethyl-2-(phenylethynyl)-6,7,11,12-tetrahydrochromeno[2,3,4-gh] phenanthridine-4,13(5H,10H)-dione (5), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 41.9 mg, yield: 91%; m.p 222–223 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.40 (s, 1H), 8.94 (s, 1H), 7.74–7.53 (m, 2H), 7.50–7.30 (m, 3H), 3.03 (s, 2H), 2.80 (s, 2H), 2.62 (s, 2H), 2.55 (s, 2H), 1.20 (s, 6H), 1.15 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 198. 8, 196.4, 168.0, 161.7, 159.1, 136.3, 132.0, 130.9, 128.8, 128.4, 127.4, 126.2, 122.9, 122.7, 116.7, 114.7, 111.3, 93.1, 89.8, 53.8, 52.6, 47.5, 42.3, 32.6, 31.9, 28.2, 28.1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₃₁H₂₈NO₃⁺ 462.2064; found 462.2067.

3.5. General Procedures for the Preparation of Compounds 6

A Schlenk tube was equipped with a magnetic stir bar and charged with 2-bromo-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione 3h (0.1 mmol), p-tolylboronic acid (0.1 mmol), Pd(PPh₃)₄ (5 mol %), K₂CO₃ (2.0 equiv), and EtOH:Toluene (V:V = 1:2.5, 3.5 mL). Then, the flask was sealed under Ar and stirred at 100 °C for 3 h. After the reaction was quenched by the addition of water, the mixture was extracted with dichloromethane, and the combined organic layer was dried over sodium sulfate. The concentration in vacuo followed by silica gel column purification with petroleum ether/ethyl acetate eluent gave the desired product 6.

• 6,6,11,11-tetramethyl-2-(p-tolyl)-6,7,11,12-tetrahydrochromeno[2,3,4-gh] phenanthridine-4,13(5H,10H)-dione (6), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 41.9 mg, yield: 93%; m.p 143–144 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.51 (s, 1H), 9.15 (s, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.30 (d, J = 7.5 Hz, 2H), 3.04 (s, 2H), 2.81 (s, 2H), 2.62 (s, 2H), 2.55 (s, 2H), 2.43 (s, 3H), 1.21 (s, 6H), 1.16 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 199.1, 196.6, 167.9, 161.5, 159.4, 148.1, 138.6, 137.5, 137.0, 134.7, 129.6, 127.9, 120.8, 119.5, 117.3, 114.6, 111.9, 53.9, 52.8, 47.6, 42.4, 32.6, 31.9, 28.2, 28.1, 21.2. HRMS (ESI) m/z: [M + H]⁺ calcd for C₃₀H₃₀NO₃⁺ 452.2220; found 452.2227.

3.6. General Procedures for the Preparation of Compounds 7

A Schlenk tube was equipped with a magnetic stir bar and charged with 2-bromo-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione 3h (0.1 mmol), 4-methyl-N-phenylaniline (0.1 mmol), Pd(OAc)₂ (10 mol %), RuPhos (20 mol %), NaO^tBu (1.2 equiv), and 1,4-Dioxane (2 mL). Then, the flask was sealed under Ar and stirred at 110 °C for 12 h. After the reaction was quenched by the addition of water, the mixture was extracted with dichloromethane, and the combined organic layer was dried over sodium sulfate. The concentration in vacuo followed by silica gel column purification with petroleum ether/ethyl acetate eluent gave the desired product 7.

• 6,6,11,11-tetramethyl-2-(phenyl(p-tolyl)amino)-6,7,11,12-tetrahydrochromeno[2,3,4-gh] phenanthridine-4,13(5H,10H)-dione (7), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 48.2 mg, yield: 89%; m.p 199–200 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.68 (s, 1H), 8.46 (s, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.24–7.16 (m, 5H), 7.12 (d, J = 8.0 Hz, 2H), 2.92 (s, 2H), 2.74 (s, 2H), 2.46 (s, 2H), 2.41 (s, 2H), 2.36 (s, 3H), 1.14 (s, 6H), 1.09 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 198.7, 196.5, 167.9, 162.2, 158.7, 154.7, 146.2, 143.4, 138.0, 135.3, 130.4, 129.7, 128.3, 126.6, 125.4, 115.9, 112.9, 111.5, 110.2, 110.0, 53.8, 52.6, 47.7, 42.4, 32.4, 31.9, 28.2, 28.1, 21.1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₃₆H₃₅N₂O₃⁺ 543.2642; found 543.2648.

3.7. General Procedures for the Preparation of Compounds 8

A Schlenk tube was equipped with a magnetic stir bar and charged with 2-bromo-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione 3h (0.1 mmol), (Bpin)₂ (4.0 equiv), Pd₂(dba)₃ (10 mol %), XPhos (40 mol %), KOAc (6.0 equiv), and 1,4-Dioxane (2 mL). Then, the flask was sealed under Ar and stirred at 110 °C for 12 h. After the reaction was quenched by the addition of water, the mixture was extracted with dichloromethane, and the combined organic layer was dried over sodium sulfate. The concentration in vacuo followed by silica gel column purification with petroleum ether/ethyl acetate eluent gave the desired product 8.

• 6,6,11,11-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,11,12-tetrahydrochromeno[2,3,4-gh] phenanthridine-4,13(5H,10H)-dione (8), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 43.3 mg, yield: 89%; m.p 265–266 °C. ¹H NMR (500 MHz, CDCl₃) δ 9.61 (s, 1H), 9.14 (s, 1H), 3.03 (s, 2H), 2.79 (s, 2H), 2.60 (s, 2H), 2.53 (s, 2H), 1.37 (s, 12H), 1.19 (s, 6H), 1.14 (s, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 198.8, 196.3, 167.3, 160.7, 159.5, 135.6, 129.9, 126.3, 125.2, 117.5, 116.9, 112.0, 84.4, 53.8, 52.7, 47.5, 42.3, 32.6, 31.9, 28.2, 28.1, 24.9. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₉H₃₅BNO₅⁺ 488.2603; found 488.2604.

3.8. General Procedures for the Preparation of Compounds 9

A Schlenk tube was equipped with a magnetic stir bar and charged with 2-bromo-6,6,11,11-tetramethyl-6,7,11,12-tetrahydrochromeno[2,3,4-gh]phenanthridine-4,13(5H,10H)-dione 3h (0.1 mmol), NaBH₄ (1.0 equiv), CeCl₃·7H₂O (1.0 equiv), and MeOH (2 mL). Then, the flask was sealed under Ar and stirred at rt for 3 h. After the reaction was quenched by the addition of water, the mixture was extracted with dichloromethane, and the combined organic layer was dried over sodium sulfate. The concentration in vacuo followed by silica gel column purification with petroleum ether/ethyl acetate eluent gave the desired product 9.

• 2-bromo-6,6,11,11-tetramethyl-4,5,6,7,10,11,12,13-octahydrochromeno[2,3,4-gh] phenanthridine-4,13-diol (9), a yellow solid after purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1), 42.1 mg, yield: 95%; m.p 174–175 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.03 (s, 1H), 7.55 (s, 1H), 5.39–4.99 (m, 1H), 4.84–4.82 (m, 1H), 2.78 (d, J = 17.2 Hz, 1H), 2.62 (d, J = 17.3 Hz, 1H), 2.46 (d, J = 17.6 Hz, 1H), 2.35 (d, J = 17.5 Hz, 1H), 2.11 (dd, J = 13.7, 6.1 Hz, 1H), 2.01 (dd, J = 13.9, 5.8 Hz, 1H), 1.82 (dd, J = 13.8, 5.7 Hz, 1H), 1.76 (dd, J = 13.7, 5.2 Hz, 1H), 1.19 (s, 3H), 1.15 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 157.9, 154.3, 150.7, 139.4, 133.3, 128.3, 122.3, 119.1, 114.6, 110.5, 65.6, 65.1, 46.8, 45.9, 45.3, 41.4, 30.4, 30.3, 29.0, 28.6, 28.3. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₂₇BrNO₃⁺ 444.1169; found 444.1171.

4. Conclusions

In conclusion, we have developed an efficient double C-H activation/cyclization reaction for the construction of pyranoisoquinoline derivatives from aryl oxadiazoles and diazo compounds. This reaction features a broad substrate scope and mild conditions. In addition, large-scale preparation and further transformations of the products were carried out, revealing the practicality of the annulation method.