A Chemo- and Regioselective Tandem [3 + 2]Heteroannulation Strategy for Carbazole Synthesis: Combining Two Mechanistically Distinct Bond-Forming Processes

Abstract

A modular approach to prepare tri- and tetracyclic carbazoles by a sequential [3 + 2]heteroannulation is described. First, optimization of Pd-catalyzed Buchwald–Hartwig amination followed by C/N-arylation in a one-pot process is established. Second, mechanistic analyses identified the origins of chemo- and regioselective sequential control of both bond-forming steps. Finally, the substrate scope is demonstrated by the preparation of a range of tri- and tetracyclic carbazoles, including expedient access to several natural products and anti-cancer agents.

Introduction

Carbazoles are ubiquitous N-heterocycles used throughout medicinal chemistry and material sciences.¹⁻³ From a pharmaceutical perspective, the carbazole core features extensively in drugs and natural products, many of which exhibit potent anti-proliferative activities (Figure 1a).⁴⁻⁹ The breadth of applications has inspired the development of numerous methodologies for their preparation.^2,9,10 Pd-catalyzed processes in particular enable a [3 + 2]heteroannulation via Pd(0)-catalyzed Buchwald–Hartwig amination¹¹ followed by Pd(II)-catalyzed C-arylation at a late stage in a synthetic workflow.¹²⁻²⁵ However, a generalized set of guidelines that control the chemoselectivity of each C–N/C–C bond-forming reaction, and the factors that influence Pd(0)²³ versus Pd(II)¹⁷ catalysis in a one-pot process have not been established. Furthermore, a mechanistic understanding of any regiocontrol underpinning the second C–H activation step for the formation of tetracyclic carbazoles is unknown.

Figure 1.

Generalized approach for the synthesis of tri–/tetracyclic carbazoles by Pd-catalyzed [3 + 2]heteroannulation.

In this manuscript, we establish reaction guidelines to prepare tri- and tetracyclic carbazoles by controlling the chemoselectivity of the first Pd(0)-catalyzed C–N bond-forming step and the regioselectivity of the second Pd(II)-catalyzed C/N-arylation (Figure 1b). Our rationale was to use o-chloroanilines (1) to define the A-ring of a carbazole core and heteroaryl bromides to form the C/D-rings of tricyclic and tetracyclic products. An initial version of this work was deposited in ChemRxiv on the 24th of November 2021.²⁶

Results and Discussion

The motivation for this work was to develop a robust, one-pot synthetic framework that can access both tri- and tetracyclic carbazoles. The synthesis of tetracyclic carbazoles using a heteroaryl bromide substrate such as 3 has potentially two competing C–H activation sites. If the C-arylation proceeded via a Pd(II)-catalyzed intermediate, then we surmised that the more nucleophilic 5-position of an isoquinoline will result in preferential C–H bond activation at this site.²⁷ However, the mechanistic determinants that control the regioselectivity of such Pd(II)-catalyzed C-arylation are not known with respect to a convergent [3 + 2]heteroannulation approach.²⁸⁻³¹

Our studies commenced with optimizing reaction conditions for the Pd(0)-catalyzed C–N bond-forming step using 4-methoxy-2-chloroaniline (1a) and 6-bromoisoquinoline (6a) as exemplar substrates (Scheme 1). An extensive screen (Table S1) identified DavePhos and K₃PO₄ as the optimal ligand/base pairing, which formed 7a in 87% yield.

Scheme 1. Scope (Isolated Yields) of Buchwald–Hartwig Amination.

Using these conditions, secondary anilines 7b–e (56–91%) were obtained using chloroanilines (1b–e) bearing electron-rich and electron-withdrawing substituents when reacted with 6-bromoisoquinoline (6a). The conditions tolerated a range of heteroaryl bromides to form 7g–j, except for 2-bromoquinoxaline (6d). In this case, a mixture of secondary (7i, 27%) and tertiary anilines (8, 25%) was formed. Using 5-bromo-1,3-dihydroisobenzofuran (6e) formed 7j in 18% yield. This process was also compatible with 2-bromonaphthalene-1,4-dione (6f) producing 1,4-napthoquinones³² (7k–p) in 59–82%. Whilst this reaction could conceivably proceed via Michael addition, the reaction afforded the secondary anilines 7k–p in 5–7% in the absence of a Pd catalyst.

With conditions for the Pd(0)-catalyzed C–N bond-forming step established, the optimization of the one-pot process was explored (Table S2). The optimal ligand/base pairing of HPCy₃BF₄ with K₃PO₄ was identified, which formed 9a from 1a and 6a in 82% yield (Scheme 2a). This highlights that the second C–H activation step is regioselective for the 7-position of 6a. To further understand how the nature of the chloroaniline and heteroaryl bromide substrates influenced the chemo- and regioselectivity of both bond-forming steps, a series of test reactions was undertaken. Exchanging 6-bromoisoquinoline (6a) for isoquinoline (10) formed dimethoxyphenazine (11) and the tertiary aniline (12) in 35 and 25% isolated yields, respectively (Scheme 2b). No dihydrophenazine was isolated from the reaction, which suggests that an in situ oxidation occurred.³³ No reaction occurred when isoquinoline (10) was the coupling partner with 1-chloro-3-methoxybenzene (13, Scheme 2c). Only secondary aniline (15) was isolated when para-anisidine (14) was reacted with 6-bromoisoquinoline (6a, Scheme 2d). Taken collectively, these test reactions highlighted the following requirements for the preparation of the tetracyclic core: (i) aryl bromide is essential and prevents dimerization of the o-chloroaniline, (ii) whilst the absence of a bromo substituent in the heteroaryl substrate results in C–H activation at the same site, there is little regiocontrol, (iii) a chloro substituent is essential for C-arylation.

Scheme 2. Mechanistic Studies of the [3 + 2]Heteroannulation.

Reaction conditions: Pd(OAc)₂ (5 mol %), HPCy₃BF₄ (10 mol %), K3PO₄ (3 equiv), 1,4-dioxane; (i) 30 min, 120 °C MW; (ii) 8 h, 160 °C MW; wrt = with respect to.

The influence of the electron-donating aniline lone pair in the direct C-arylation step was then explored (Scheme 2e). We surmised that the acetylated substrate (16) would deactivate the C-ring and render the C-arylation less efficient. This indeed occurred as highlighted by the formation of deacetylated C-arylated regioisomers, 9a and 17, in 27% total yield (1.2:1.0, 9a:17). We assume that deacetylation occurs in situ because of the high temperatures and the presence of a base in the reaction mixture. An unexpected result was the formation of the linear tetracyclic carbazole 17, which arises from C–H activation of the isoquinoline 7-position of 16. The formation of 17 suggests that C–H activation of the 7-position is favored if the acetyl group is present prior to C-arylation. In contrast, if 7a is present, presumably formed by deactylation of 16, C–H activation at the 5-position occurs. DFT calculations confirmed that the 5-position is indeed the more electron-rich site (Scheme 2e and the Supporting Information Section 6). We speculate that the acetyl group (i.e., 16) directs C–H activation at this site via coordination of a Pd(II) species through the amide carbonyl.³⁴⁻³⁶

This series of reactions has guided us to propose that oxidative addition of the C–Cl bond in 7a occurs first and proceeds via a Pd(0) species to form 18 (Scheme 2f). Pd(II)-catalyzed C-arylation forms the palladacycle (20), which could proceed through a concerted metalation–deprotonation pathway via the formation of 19a.¹²

Alternatively, since the efficiency of the reaction is higher with the lone pair of aniline (18) donating into the ring, a Friedel–Crafts-like electrophilic aromatic substitution mechanism proceeding via imine (19b) followed by tautomerization might also be possible to form 20.³⁷ Finally, reductive elimination of 20 produces the C-arylated product (9a). With mechanistic knowledge of the second C–C bond-forming step established, the substrate scope of the process was investigated (Scheme 3).

Scheme 3. Scope and Isolated Yields of the [3 + 2]Heteroannulation^,,,

Addition of PivOH (30 mol %).

Formation of 7e in 79%; traces of 9d detected by LCMS.

Ligand = HPtBu₃BF₄.

Ligand = DavePhos.

The reaction conditions formed 7H-pyrido[3,4-c]carbazole analogues (9a–c). The presence of a nitro group resulted in only trace amounts of 9d formed, with the secondary aniline (7e) isolated in 79% yield. The reaction conditions also tolerated heteroatom changes and saturation in the D-ring of the heteroaryl bromide (9e–j).³⁰ The [3 + 2]heteroannulation strategy was also compatible with the formation of carbazole-1,4-quinones (21a–f).^28,38 Access to N-arylated products is also possible, forming a mixture of fused imidazoles (9k–l) via an N-arylation step, alongside tertiary anilines (22–23). Steric bulk ortho to the aniline substrate is also tolerated, forming 9m in 62%. However, when 3-methyl-2-chloroaniline is used as a substrate, a mixture of regioisomers was formed as an inseparable mixture (see Supporting Information).

The modularity of this strategy is also exemplified by the preparation of natural products glycozoline (9n),³⁹ harmane (9o),⁴⁰ and murrayafoline A (9p).^41,42 In addition, preparation of 9q demonstrates that the reaction conditions tolerate functional groups bearing potential Pd-chelating sites and bulky substituents ortho to the corresponding aryl bromide.

Our [3 + 2]heteroannulation strategy was extended to the targeted synthesis of biologically active tetracyclic carbazoles. Carbazole-1,4-quinones (e.g., 21a–f) have established anti-cancer activity via topoisomerase inhibition or by the production of reactive oxygen species.^38,43 We used 21b as a key intermediate for the targeted synthesis of a deaza analogue of the natural product 9-methoxyellipticine (Scheme 4a), producing 26 in three steps and in an overall yield of 20%.⁴⁴

Scheme 4. Application of the [3 + 2]Heteroannulation Process for the Targeted Synthesis of Biologically Active Tetracyclic Carbazoles.

Yield calculated from the alkylation of 9e; X = iodide for 27 and chloride for 28.

Further exemplification of our strategy was demonstrated by the preparation of alkylated 7H-pyridocarbazoles (e.g., 9a–e), which have well-established anti-cancer activity.^45,46 Previous preparative methods of this series of compounds have involved a six-step linear synthesis affording compound 9e in 28% overall yield.⁴⁷ Our two-step convergent strategy accessed the 7H-pyrido[4,3-c]carbazole core 9e in a single step (83%), followed by alkylation (30–32) to produce mono-N-alkylated examples (27–28) and the potent anti-cancer agent ditercalinium dichloride (29, Scheme 4b).⁴⁸

Conclusions

In summary, we have established a mechanistic framework for the preparation of fused tetracyclic carbazoles. The key to the modularity of this [3 + 2]heteroannulation approach is knowledge of the molecular hallmarks that underpin both the chemo- and regioselectivity of the process. The strategy is amenable for the diversification of tri- and tetracyclic carbazoles and is a scalable method for target-focused synthesis of tetracyclic carbazoles. We envisage that this convergent approach could find application in medicinal chemistry for structure–activity profiling and in broader synthetic applications that require step-efficient access to carbazole scaffolds.

Experimental Section

General Information

All reagents and solvents were obtained from commercial suppliers and were used without further purification unless otherwise stated. Purification was carried out according to standard laboratory methods. Starting materials were purchased from commercial suppliers and used without further purification unless otherwise stated. Dry solvents for reactions were purchased from Sigma-Aldrich and stored under nitrogen. Dichloromethane, chloroform, methanol, ethyl acetate, and petroleum ether (40–60 °C) for purification purposes were used as obtained from suppliers, without further purification. Reactions were carried out using conventional glassware for the preparation of starting materials. Microwave reactions were carried out in capped 2–5 mL microwave vials purchased from Biotage. Microwave reactions were carried out at elevated temperatures using a Biotage Initiator+ equipped with a Robot Eight microwave system. Thin-layer chromatography was carried out using Merck silica plates coated with a fluorescent indicator UV254, and they were analyzed under both 254 and 375 nm UV light or developed using potassium permanganate solution. Normal phase flash chromatography was carried out using 60 Å, 40–63 μm silica gel from Fluorochem. Semi-preparative reversed-phase HPLC purification was carried out on a Kinetex 5 μm, 150 × 21.2 mm XB C18 using a DIONEX 3000 series HPLC system equipped with a VWD3400 variable wavelength detector. Preparative purifications of small molecules were performed using a 30–90% gradient B (solvent A: 0.1% TFA in water, solvent B: 0.1% TFA in acetonitrile), with a flow rate of 12.0 mL/min. The absorbance of the UV-active material was detected at 254 nm. Analytical reversed-phase HPLC (RP-HPLC) was carried out on a Shimadzu Prominence instrument equipped with a PDA detector scanning from 190 to 600 nm using a Thermofisher Hypersil GOLD column 100 × 4.6 mm, with a particle size of 5 μm. The Fourier transform infrared (FTIR) spectra were obtained on a Shimadzu IR Affinity-1 instrument. Only major absorbance bands are reported. The ¹H NMR, ¹³C NMR, and ¹⁹F NMR spectra were obtained on a Bruker AV 400 at 400, 101, and 376 MHz, respectively. Chemical shifts are reported in parts per million (ppm), and coupling constants are reported in hertz with DMSO-d₆ referenced at 2.50 (¹H) and 39.52 ppm (¹³C) and MeOD-d₄ referenced at 3.31 (¹H) and 49.0 ppm (¹³C). Assignment of ¹³C NMR signals is based on HSQC and HMBC experiments. The COSY and NOESY spectra were used to assign unequivocally atom connectivities. The high-resolution mass spectra were recorded on a Bruker microTOF II mass spectrometer at the SIRCAMs facility at the University of Edinburgh or on an LTQ Orbitrap xL at the EPSRC National Facility in Swansea.

General Experimental Procedure for Microwave-Assisted Buchwald–Hartwig Amination

Aryl bromide (0.50 mmol, 1.00 equiv), chloroaniline (0.60 mmol, 1.2 equiv), Pd(OAc)₂ (5 mol %), DavePhos (10 mol %), and K₃PO₄ (1.50 mmol, 3 equiv) were added to a microwave vial (2–5 mL). 1,4-Dioxane (5 mL, 0.1 M) was added and the vial was capped, evacuated and purged with argon three times, and then heated at 120 °C for 30 min under microwave irradiation in a Biotage microwave. The reaction was allowed to cool to rt, diluted with ethyl acetate (50 mL), and the solid was filtered under vacuum. The organic phase was washed with water and brine, dried with Na₂SO₄, filtered, and the solvent was removed in vacuo. The crude compound was purified by silica column chromatography.

N-(2-Chloro-4-methoxyphenyl)isoquinolin-6-amine (7a)

The reaction was carried out according to the general procedure using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 4-methoxy-2-chloroaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (7: 3), to obtain compound 7a in 87% yield (123 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.95 (s, 1H, H¹), 8.29 (s, 1H, NH), 8.20 (d, 1H, J = 4.6 Hz, H³), 7.87 (d, 1H, J = 7.1 Hz, H⁸), 7.41–7.38 (m, 2H, H^6′,4), 7.24 (dd, 1H, J = 7.1, 1.7 Hz, H⁷), 7.18 (d, 1H, J = 2.3 Hz, H^3′), 7.00 (dd, 1H, J = 7.0, 2.3 Hz, H^5′), 6.67 (d, 1H, J = 1.7 Hz, H⁵), 3.81 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 157.1 (C^4′), 151.0 (C¹), 147.9 (C⁶), 143.1 (C³), 137.3 (C^4a), 130.6 (C^2′), 130.3 (C^1′), 128.8 (C⁸), 127.9 (C^6′), 122.9 (C^8a), 119.2 (C⁷), 118.6 (C⁴), 115.2 (C^3′), 114.3 (C^5′), 103.0 (C⁵), 55.7 (−OCH₃).

IR v̅_max (cm^–1): 3230 (N–H stretch), 1618 (C=N stretch), 1476 (C=C stretch), 1284 (C–N stretch), 1212 (C–O stretch), 1039 (C–O stretch), 847 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₄O₁N₂Cl, 285.0789; found, 285.0787.

N-(2-Chloro-4-methylphenyl)isoquinolin-6-amine (7b)

The reaction was carried out according to the general procedure using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 4-methyl-2-chloroaniline (85 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (6:4), to obtain compound 7b in 91% yield (122 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.97 (s, 1H, H¹), 8.35 (s, 1H, NH), 8.23 (d, 1H, J = 5.8 Hz, H³), 7.89 (d, 1H, J = 8.9 Hz, H⁸), 7.45 (d, 1H, J = 5.8 Hz, H⁴), 7.40 (d, 1H, J = 1.4 Hz, H^3′), 7.38 (d, 1H, J = 8.1 Hz, H^6′), 7.32 (dd, 1H, J = 8.9, 2.2 Hz, H⁷), 7.19 (dd, 1H, J = 8.1, 1.5 Hz, H^5′), 6.90 (d, 1H, J = 2.1 Hz, H⁵), 2.32 (s, 3H, −CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): 151.1 (C¹), 146.8 (C⁶), 143.1 (C³), 137.1 (C^4a), 135.3 (C^2′), 135.1 (C^1′), 130.5 (C^3′), 128.8 (C⁸), 128.7 (C^5′), 127.5 (C^4′), 124.9 (C^6′), 123.2 (C^8a), 119.8 (C⁷), 118.8 (C⁴), 104.3 (C⁵), 20.1 (−CH₃).

IR v̅_max (cm^–1): 3234 (N–H stretch), 3031 (C–H stretch), 1608 (C=N stretch), 1474 (C=C stretch), 821 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₄N₂Cl, 269.0840; found, 269.0841.

N-(2-Chlorophenyl)isoquinolin-6-amine (7c)

The reaction was carried out according to the general procedure using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloroaniline (77 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (1:1), to obtain compound 7c in 85% yield (108 mg, green solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.00 (s, 1H, H¹), 8.43 (s, 1H, NH), 8.26 (d, 1H, J = 5.8 Hz, H³), 7.93 (d, 1H, J = 8.9 Hz, H⁸), 7.55 (dd, 1H, J = 8.0, 1.4 Hz, H^3′), 7.51 (dd, 1H, J = 8.0, 1.4 Hz, H⁷), 7.49–7.47 (m, 1H, H^6′), 7.41–7.33 (m, 2H, H^4,5′), 7.18–7.12 (m, 1H, H^4′), 7.06 (d, 1H, J = 2.1 Hz, H⁵). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 151.1 (C¹), 146.1 (C⁶), 143.1 (C³), 138.2 (C^1′), 137.0 (C^4a), 130.3 (C^3′), 128.9 (C⁸), 128.1 (C^5′), 126.7 (C^2′), 124.8 (C^4′), 123.7 (C⁷), 123.5 (C^8a), 120.2 (C⁴), 118.9 (C^6′), 105.5 (C⁵).

IR v̅_max (cm^–1): 3215 (N–H stretch), 3029 (C–H stretch), 1627 (C=N stretch), 1588 (C=C stretch), 1471 (C=C stretch), 737 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₂N₂Cl, 255.0684; found, 255.0688.

N-(2-Chloro-4-(trifluoromethyl)phenyl)isoquinolin-6-amine (7d)

The reaction was carried out according to the general procedure using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-(trifluoromethyl)aniline (117 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (6:4), to obtain compound 7d in 78% yield (116 mg, yellow crystalline solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.12 (s, 1H, H¹), 8.71 (s, 1H, NH), 8.35 (d, 1H, J = 5.7 Hz, H³), 8.03 (d, 1H, J = 8.9 Hz, H⁸), 7.88 (s, 1H, H^5′), 7.64–7.61 (m, 3H, H^{4, 3′, 6′}), 7.55 (dd, 1H, J = 8.8, 2.2 Hz, H⁷), 7.49 (d, 1H, J = 2.0 Hz, H⁵). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 151.4 (C¹), 143.6 (C⁶), 143.3 (C³), 142.9 (C^1′), 136.6 (C^4a), 129.0 (C⁸), 127.2 (q, J = 3.7 Hz, C^5′), 125.2 (q, J = 3.7 Hz, C^3′), 124.4 (C^8a), 123.7 (q, J = 272.9 Hz, −CF₃), 123.6 (C^2′), 122.4 (q, J = 33.2 Hz, C^4′), 121.8 (C⁷), 119.4 (C^4, 6′), 110.3 (C⁵). ¹⁹F NMR ((CD₃)₂SO, 471 MHz): δ −60.20.

IR v̅_max (cm^–1): 3220 (N–H stretch), 1612 (C=N stretch), 1487 (C=C stretch), 823 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₁N₂ClF₃, 323.0557; found, 323.0542.

N-(2-Chloro-4-nitrophenyl)isoquinolin-6-amine (7e)

The reaction was carried out following the general procedure using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 4-nitro-2-chloroaniline (104 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (1:1), to obtain compound 7e in 56% yield (83 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.20 (s, 1H, H¹), 9.07 (s, 1H, NH), 8.42 (d, 1H, J = 5.8 Hz, H³), 8.34 (d, 1H, J = 2.7 Hz, H^3′), 8.12 (d, 1H, J = 8.8 Hz, H⁸), 8.10 (dd, 1H, J = 9.2, 2.7 Hz, H^5′), 7.73 (d, 1H, J = 2.0 Hz, H⁵), 7.71 (d, 1H, J = 5.8 Hz, H⁴), 7.64 (dd, 1H, J = 8.8, 2.0 Hz, H⁷), 7.48 (d, 1H, J = 9.2 Hz, H^6′). ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ 151.7 (C¹), 146.3 (C^4′), 143.4 (C³), 142.1 (C⁶), 139.5 (C^1′), 136.3 (C^8a), 129.2 (C⁸), 125.9 (C^3′), 125.2 (C^4a), 124.3 (C^5′), 123.2 (C⁷), 121.0 (C^2′), 119.7 (C⁴), 115.7 (C^6′), 114.4 (C⁵).

IR v̅_max (cm^–1): 3221 (N–H stretch), 1584 (C=N bend), 1508 (N–O stretch), 1474 (C=C stretch), 1333 (N–O stretch), 821 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₁O₂N₃Cl, 300.0534; found, 300.0538.

N-(2-Chloro-5-fluorophenyl)isoquinolin-6-amine (7f)

The reaction was carried out according to the general procedure using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-5-fluoroaniline (87 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (6:4), to obtain compound 7f in 74% yield (101 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.06 (s, 1H, H¹), 8.51 (s, 1H, NH), 8.31 (d, 1H, J = 5.8 Hz, H³), 7.98 (d, 1H, J = 8.9 Hz, H⁸), 7.58 (d, 1H, J = 5.8 Hz, H⁴), 7.57 (dd, 1H, J = 9.0, 6.0 Hz, H^3′), 7.47 (dd, 1H, J = 8.9, 2.2 Hz, H⁷), 7.33–7.27 (m, 2H, H^5,6′), 6.95 (ddd, 1H, J = 8.8, 8.0, 3.0 Hz, H^4′). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 161.2 (d, J = 244.7 Hz, C^5′), 151.3 (C¹), 144.7 (C^4a), 143.2 (C³), 140.2 (d, J = 10.8 Hz, C^1′) 136.9 (C^8a), 131.5 (d, J = 10.0 Hz, C^3′), 129.0 (C⁸), 124.0 (C⁶), 120.8 (C⁷), 120.5 (d, J = 3.3 Hz, C^2′), 119.2 (C⁴), 110.5 (d, J = 20.9 Hz, C^4′), 108.5 (d, J = 26.0 Hz, C^6′), 107.7 (C⁵). ¹⁹F NMR ((CD₃)₂SO, 376 MHz): δ −113.1.

IR v̅_max (cm^–1): 3221 (N–H stretch), 1592 (C=N stretch), 1474 (C=C stretch), 852 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₁N₂ClF, 273.0589; found, 273.0594.

N-(2-Chloro-4-methoxyphenyl)quinolin-6-amine (7g)

The reaction was carried out according to the general procedure using 6-bromoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 4-methoxy-2-chloroaniline (93 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel chromatography petroleum ether (40–60 °C):EtOAc (7:3), to obtain compound 7g in 59% yield (84 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.56 (dd, J = 4.2, 1.6 Hz, 1H, H²), 8.03–7.97 (m, 2H, NH, H⁴), 7.82 (d, J = 9.1 Hz, 1H, H⁸), 7.40 (dd, J = 9.0, 2.6 Hz, 1H, H⁷), 7.38 (d, J = 8.8 Hz, 1H, H^6′), 7.31 (dd, J = 8.3, 4.2 Hz, 1H, H³), 7.16 (d, J = 2.8 Hz, 1H, H^3′), 6.97 (dd, J = 8.8, 2.8 Hz, 1H, H^5′), 6.85 (d, J = 2.5 Hz, 1H, H⁵), 3.80 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 156.4 (C^4′), 146.3 (C²), 144.1 (C⁶), 143.0 (C^8a), 133.7 (C⁴), 131.6 (C¹), 129.8 (C^4a), 129.3 (C⁸), 129.2 (C^2′), 126.5 (C^6′), 121.8 (C⁷), 121.5 (C³), 115.2 (C^3′), 114.2 (C^5′), 105.6 (C⁵), 55.7 (−OCH₃).

IR v̅_max (cm^–1): 3215 (C–N stretch), 3016 (C–H stretch), 2846 (C–H stretch), 1631 (C=N stretch), 1498 (C=C stretch), 1214 (C–O stretch), 1050 (C–O stretch), 839 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₄O₂N₂Cl, 285.0789; found, 285.0793.

N-(2-Chloro-4-methoxyphenyl)quinoxalin-6-amine (7h)

The reaction was carried out according to the general procedure using 6-bromoquinoxaline (105 mg, 0.50 mmol, 1.0 equiv) and 4-methoxy-2-chloroaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (7:3) to obtain compound 7h in 87% yield (124 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.66 (d, 1H, J = 2.0 Hz, H³), 8.55 (d, 1H, J = 2.0 Hz, H²), 8.42 (s, 1H, NH), 7.87 (d, 1H, J = 9.1 Hz, H⁸), 7.46 (dd, 1H, J = 9.1, 2.6 Hz, H⁷), 7.42 (d, 1H, J = 8.8 Hz, H^6′), 7.20 (d, 1H, J = 2.9 Hz, H^3′), 7.01 (dd, 1H, J = 8.8, 2.9 Hz, H^5′), 6.83 (d, 1H, J = 2.6 Hz, H⁵), 3.82 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 157.2 (C^4′), 147.7 (C⁶), 145.3 (C³), 144.4 (C^4a), 141.0 (C²), 137.4 (C^8a), 130.5 (C^1′), 130.2 (C⁸), 129.8 (C^2′), 127.8 (C^6′), 122.1 (C⁷), 115.3 (C^3′), 114.3 (C^5′), 105.3 (C⁵), 55.7 (−OCH₃).

IR v̅_max (cm^–1): 3301 (N–H stretch), 3068 (C–H stretch), 2837 (C–H stretch), 1618 (C=N stretch), 1504 (C=C stretch), 1221 (C–O stretch), 1037 (C–O stretch), 852 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₃ON₃Cl, 286.0742; found, 286.0740.

N-(2-Chloro-4-methoxyphenyl)quinoxalin-2-amine (7i)

The reaction was carried out according to the general procedure using 2-bromoquinoxaline (105 mg, 0.50 mmol, 1.0 equiv) and 4-methoxy-2-chloroaniline (95 mg, 0.60, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (85:15), to obtain compound 7i in 27% yield (38 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.20 (s, 1H, NH), 8.64 (s, 1H, H³), 7.92 (d, 1H, J = 8.9 Hz, H^6′), 7.84 (dd, 1H, J = 8.2, 1.2 Hz, H⁸), 7.62–7.53 (m, 2H, H^5,6), 7.46–7.41 (m, 1H, H⁷), 7.15 (d, 1H, J = 2.9 Hz, H^3′), 7.00 (dd, 1H, J = 8.9, 2.9 Hz, H^5′), 3.81 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 156.6 (C^4′), 150.5 (C²), 140.8 (C³), 139.8 (C^8a), 137.1 (C^4a), 129.9 (C⁵), 128.9 (C^1′), 128.4 (C⁸), 128.0 (C^2′), 126.9 (C^6′), 126.2 (C⁶), 124.7 (C⁷), 114.6 (C^3′), 113.6 (C^5′), 55.7 (−OCH₃).

IR v̅_max (cm^–1): 3340 (N–H stretch), 2934 (C–H stretch), 1590 (C=N stretch), 1536 (C=N stretch), 1502 (C=C stretch), 1214 (C–O stretch), 1040 (C–O stretch), 841 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₃ON₃Cl, 286.0742; found, 286.0745.

N-(2-Chloro-4-methoxyphenyl)-N-(quinoxalin-2-yl)quinoxalin-2-amine (8)

The reaction was carried out according to the general procedure using 2-bromoquinoxaline (105 mg, 0.50 mmol, 1.0 equiv) and 4-methoxy-2-chloroaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (85:15) to obtained compound 8 in 25% yield (26 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.83 (s, 2H, 2 × H³), 8.06–8.00 (m, 2H, 2 × H⁵), 7.76–7.68 (m, 6H, 2 × H^6/7/8), 7.58 (d, 1H, J = 8.8 Hz, H^6′), 7.32 (d, 1H, J = 2.9 Hz, H^3′), 7.12 (dd, 1H, J = 8.8, 2.9 Hz, H^5′), 3.88 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 159.6 (C^4′), 150.4 (2 × C²), 141.5 (2 × C³), 140.0 (2 × C^8a), 138.8 (2 × C^4a), 133.1 (C^2′), 132.3 (C^6′), 130.9 (C^1′), 130.6 (2 × C⁶ or C⁷ or C⁸), 128.5 (2 × C⁵), 128.0 (2 × C⁶ or C⁷ or C⁸), 127.4 (2 × C⁶ or C⁷ or C⁸), 115.9 (C^3′), 115.0 (C^5′), 55.9 (−OCH₃).

IR v̅_max (cm^–1): 1606 (C=N stretch), 1558 (C=N stretch), 1498 (C=C stretch), 1420 (C=C stretch), 1229 (C–O stretch), 1022 (C–O stretch), 761 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₁₇ON₅Cl, 414.1116; found, 414.1115.

N-(2-Chloro-4-methoxyphenyl)-1,3-dihydroisobenzofuran-5-amine (7j)

The reaction was carried out according to the general procedure using 5-bromo-1,3-dihydroisobenzofuran (100 mg, 0.50 mmol, 1.0 equiv) and 4-methoxy-2-chloroaniline (95 mg, 0.60, 1.2 equiv) as starting materials. The crude residue was purified by reversed-phase semi-preparative HPLC over a 5–95% gradient B, (solvent A: 0.1% TFA in water, solvent B: 0.1% TFA in acetonitrile) to obtain compound 7j in 18% yield (35 mg, white solid) as the TFA salt.

¹H NMR ((CD₃)₂SO, 400 MHz): δ 7.49 (s, 1H, NH), 7.22 (d, 1H, J = 8.9 Hz, H^6′), 7.08 (d, 1H, J = 2.8 Hz, H^3′), 7.07 (d, 1H, J = 8.4 Hz, H⁷), 6.89 (dd, 1H, J = 8.9, 2.8 Hz, H^5′), 6.71 (dd, 1H, J = 8.4, 2.0 Hz, H⁶), 6.66 (d, 1H, J = 2.0 Hz, H⁴), 4.88 (s, 4H, 2 × −CH₂), 3.75 (s, 3H, −OCH₃).

¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 155.4 (C^4′), 144.9 (C^4a), 140.0 (C^3a), 132.8 (C^1′), 128.9 (C^7a), 127.7 (C^2′), 124.7 (C^6′), 121.4 (C⁷), 115.0 (C^3′), 114.8 (C⁶), 114.0 (C^5′), 107.3 (C⁴), 72.5 (C¹ or C³), 72.3 (C¹ or C³), 55.6 (−OCH₃).

IR v̅_max (cm^–1): 3319 (N–H stretch), 2854 (C–H stretch), 1621 (C=C stretch), 1497 (C=C stretch), 1273 (C–O stretch), 1217 (C–O stretch), 1031 (C–O stretch), 821 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₅O₂NCl, 276.0786; found, 276.0792.

2-((2-Chloro-4-methoxyphenyl)amino)naphthalene-1,4-dione (7k)

The reaction was carried out according to the general procedure using 2-bromo-1,4-napthoquinone (119 mg, 0.50 mmol, 1.0 equiv) and 4-methoxy-2-chloroaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc:NEt₃ (100:8:1), to obtain compound 7k in 82% yield (129 mg, dark red solid). mp 155–158 °C.

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.02 (s, 1H, NH), 8.06 (dd, 1H, J = 7.5, 1.0 Hz, H⁵), 7.94 (dd, 1H, J = 8.8, 1.2 Hz, H⁸), 7.86 (ddd, 1H, J = 7.5, 7.5, 1.4 Hz, H⁶), 7.79 (ddd, 1H, J = 7.5, 7.5, 1.4 Hz, H⁷), 7.36 (d, 1H, J = 8.8 Hz, H^6′), 7.22 (d, 1H, J = 2.8 Hz, H^3′), 7.04 (dd, 1H, J = 8.8, 2.8 Hz, H^5′), 5.31 (s, 1H, H³), 3.82 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 182.1 (C¹), 181.3 (C⁴), 158.7 (C^4′), 147.7 (C²), 135.0 (C⁶), 132.6 (C⁷), 131.2 (C^1′), 130.7 (C^8a), 130.3 (C^4a), 129.5 (C^3′), 127.4 (C^2′), 126.0 (C⁵), 125.4 (C⁸), 115.1 (C^6′), 114.4 (C^5′), 102.3 (C³), 55.8 (−OCH₃).

IR v̅_max (cm^–1): 3331 (N–H stretch), 3021 (C–H stretch), 1677 (C=O stretch), 1577 (C=C stretch), 1489 (C=C stretch), 1216 (C–O stretch), 1031 (C–O stretch), 778 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₁₃O₃NCl, 314.0578; found, 314.0577.

2-((2-Chloro-4-methylphenyl)amino)naphthalene-1,4-dione (7l)

The reaction was carried out according to the general procedure using 2-bromo-1,4-napthoquinone (119 mg, 0.50 mmol, 1.0 equiv) and 4-methyl-2-chloroaniline (85 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc:NEt₃ (90:10:1), to obtain compound 7l in 72% yield (107 mg, red solid). mp 150–154 °C.

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.01 (s, 1H, NH), 8.09–8.05 (m, 1H, H⁵), 7.96–7.92 (m, 1H, H⁸), 7.89–7.84 (m, 1H, H⁶), 7.82–7.77 (m, 1H, H⁷), 7.47 (d, 1H, J = 1.1 Hz, H^3′), 7.35 (d, 1H, J = 8.1 Hz, H^6′), 7.27 (dd, 1H, J = 8.1, 1.3 Hz, H^5′), 5.41 (s, 1H, H³), 2.35 (s, 3H, −CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 182.3 (C⁴), 181.2 (C¹), 147.0 (C²), 138.5 (C^1′), 135.0 (C⁶), 132.7 (C^4a), 132.6 (C⁷), 132.1 (C^2′), 130.5 (C^8a), 130.3 (C^3′), 129.6 (C^4′), 129.0 (C^5′), 127.9 (C^6′), 126.1 (C⁵), 125.4 (C⁸), 102.7 (C³), 20.3 (−CH₃).

IR v̅_max (cm^–1): 3342 (N–H stretch), 2927 (C–H stretch), 1675 (C=O stretch), 1599 (C=O stretch), 1526 (C=C stretch), 774 (C–Cl).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₁₃O₂NCl, 298.0629; found, 298.0633.

2-((2-Chlorophenyl)amino)naphthalene-1,4-dione (7m)

The reaction was carried out according to the general procedure using 2-bromo-1,4-napthoquinone (119 mg, 0.50 mmol, 1.0 equiv) and 2-chloroaniline (77 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (9:1) to obtain compound 7m in 64% yield (90 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.08 (s, 1H, NH), 8.08 (dd, 1H, J = 7.7, 0.9 Hz, H⁵), 7.95 (dd, 1H, J = 7.5, 1.1 Hz, H⁸), 7.87 (ddd, 1H, J = 7.4, 7.4, 1.4 Hz, H⁶), 7.80 (ddd, 1H, J = 8.0, 6.5, 2.7 Hz, H⁷), 7.64 (dd, 1H, J = 7.5, 1.1 Hz, H^3′), 7.51–7.44 (m, 2H, H^4′,6′), 7.38 (ddd, 1H, J = 8.0, 6.5, 2.7 Hz, H^5′), 5.47 (s, 1H, H³). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 182.3 (C⁴), 181.2 (C¹), 146.7 (C²), 135.0 (C⁶), 134.2 (C^1′), 132.8 (C⁷), 132.5 (C^4a), 130.3 (C^3′), 129.7 (C^8a), 128.4 (C^2′), 128.3 (C^5′), 128.0 (C^4′, 6′), 126.1 (C⁵), 125.4 (C⁸), 102.9 (C³).

IR v̅_max (cm^–1): 3310 (N–H stretch), 3068 (C–H stretch), 2854 (C–H stretch), 1675 (C=O stretch), 1618 (C=O stretch), 1592 (C=C stretch), 1446 (C=C stretch), 741 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₁O₂NCl, 284.0473; found, 284.0480.

2-((2-Chloro-4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7n)

The reaction was carried out according to the general procedure using 2-bromo-1,4-napthoquinone (119 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-(trifluoromethyl)aniline (117 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (9:1) to obtain compound 7n in 69% yield (122 mg, orange solid). mp 180–183 °C.

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.10 (s, 1H, NH), 8.08 (dd, 1H, J = 7.5, 1.1 Hz, H⁸), 8.06 (d, 1H, J = 1.6 Hz, H^3′), 7.96 (dd, 1H, J = 7.6, 1.2 Hz, H⁵), 7.88 (ddd, 1H, J = 7.5, 7.5, 1.5 Hz, H⁶), 7.85–7.78 (m, 2H, H^5′, 7), 7.75 (d, 1H, J = 8.5 Hz, H^6′), 5.77 (s, 1H, H³).

¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 182.7 (C⁴), 181.0 (C¹), 146.0 (C²), 138.9 (C^1′), 135.1 (C⁶), 133.0 (C⁷), 132.3 (C^4a), 130.2 (C^8a), 129.5 (C^2′), 127.5 (q, J = 32.7 Hz, C^4′), 127. 4 (q, J = 3.8 Hz, C^3′), 127.2 (C^6′), 126.2 (C⁸), 125.5 (C⁵), 125.4 (q, J = 3.8 Hz, C^5′), 123.3 (q, J = 272.9 Hz, −CF₃), 104.6 (C³). ¹⁹F NMR ((CD₃)₂SO, 376 MHz): δ −60.85.

IR v̅_max (cm^–1): 3338 (N–H stretch), 3055 (C–H stretch), 1677 (C=O stretch), 1642 (C=O stretch), 1580 (C=C stretch), 782 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₁₀O₂NClF₃, 352.0347; found, 352.0347.

2-((2-Chloro-5-methoxyphenyl)amino)naphthalene-1,4-dione (7o)

The reaction was carried out according to the general procedure using 2-bromo-1,4-napthoquinone (119 mg, 0.50 mmol, 1.0 equiv) and 5-methoxy-2-chloroaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (85:15), to obtain compound 7o in 59% yield (92 mg, red solid). mp 152–156 °C.

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.05 (s, 1H, NH), 8.07 (dd, 1H, J = 7.6, 1.2 Hz, H⁸), 7.95 (dd, 1H, J = 7.6, 1.2 Hz, H⁵), 7.90–7.84 (m, 1H, H⁶), 7.83–7.77 (m, 1H, H⁷), 7.52 (d, 1H, J = 8.9 Hz, H^3′), 7.03 (d, 1H, J = 3.0 Hz, H^6′), 6.97 (dd, 1H, J = 8.9, 3.0 Hz, H^4′), 5.48 (s, 1H, H³), 3.79 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 182.3 (C⁴=O), 181.2 (C¹=O), 158.8 (C^5′), 146.6 (C²), 135.8 (C^1′), 135.0 (C⁶), 132.8 (C⁷), 132.6 (C^4a), 130.7 (C^3′), 130.3 (C^8a), 126.1 (C⁸), 125.4 (C⁵), 120.9 (C^2′), 114.0 (C^4′), 113.3 (C^6′), 103.3 (C³), 55.7 (−OCH₃).

IR v̅_max (cm^–1): 3299 (N–H stretch), 2843 (C–H stretch), 1675 (C=O stretch), 1647 (C=O stretch), 1579 (C=C stretch), 1541 (C=C stretch), 1219 (C–O stretch), 1067 (C–O stretch), 776 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ cald for C₁₇H₁₃O₃NCl, 314.0578; found, 314.0586.

2-((2-Chloro-5-fluorophenyl)amino)naphthalene-1,4-dione (7p)

The reaction was carried out according to the general procedure using 2-bromo-1,4-napthoquinone (119 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-5-fluoroaniline (87 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (9:1) to obtain compound 7p in 80% yield (120 mg, orange solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.08 (s, 1H, NH), 8.10–8.06 (m, 1H, H⁸), 7.98–7.94 (m, 1H, H⁵), 7.91–7.85 (m, 1H, H⁶), 7.85–7.79 (m, 1H, H⁷), 7.68 (dd, 1H, J = 9.0, 5.7 Hz, H^3′), 7.43 (dd, 1H, J = 9.5, 3.0 Hz, H^6′), 7.26 (ddd, 1H, J = 8.8, 8.1, 3.0 Hz, H^4′), 5.60 (s, 1H, H³).

¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 182.6 (C⁴), 181.0 (C¹), 160.9 (d, J = 246.8 Hz, C^5′), 146.0 (C²), 136.4 (d, J = 10.8 Hz, C^1′), 135.1 (C⁶), 132.9 (C⁷), 132.4 (C^4a), 131.6 (d, J = 9.6 Hz, C^3′), 130.2 (C^8a), 126.2 (C⁸), 125.4 (C⁵), 125.1 (C^2′), 115.2 (d, J = 22.8 Hz, C^4′), 114.8 (d, J = 24.8 Hz, C^6′), 103.9 (C³). ¹⁹F NMR ((CD₃)₂SO, 376 MHz): δ −112.74.

IR v̅_max (cm^–1): 3310 (N–H stretch), 3074 (C–H stretch), 2858 (C–H stretch), 1675 (C=O stretch), 1647 (C=O stretch), 1599 (C=C stretch), 1541 (C=C stretch), 722 (C–Cl stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₀O₂NClF, 302.0379; found, 302.0380.

General Experimental Procedure A for Microwave-Assisted One-Pot Buchwald–Hartwig Amination/Direct Arylation

Aryl bromide (0.50 mmol, 1 equiv), chloroaniline (0.60 mmol, 1.2 equiv), Pd(OAc)₂ (5 mol %), DavePhos (10 mol %), and K₃PO₄ (1.50 mmol, 3 equiv) were added to a microwave vial (2–5 mL). 1,4-Dioxane (5.0 mL, 0.1 M) was added and the vial was capped, evacuated and purged with argon three times, and heated at 120 °C for 30 min followed by 160 °C for 8 h under microwave irradiation in a Biotage microwave. The reaction was allowed to cool to rt, diluted with DCM (50 mL), and the solid was filtered under vacuum. The solvent was removed in vacuo, and the crude sample was dry-loaded onto silica gel without work up. The crude compound was purified by silica column chromatography.

General Experimental Procedure B for Microwave-Assisted One-Pot Buchwald–Hartwig Amination/Direct Arylation

Aryl bromide (0.50 mmol, 1 equiv), chloroaniline (0.60 mmol, 1.2 equiv), Pd(OAc)₂ (5 mol %), P(Cy₃), HBF₄ (10 mol %), and K₃PO₄ (1.50 mmol, 3 equiv) were added to a microwave vial (2–5 mL). 1,4-Dioxane (5.0 mL, 0.1 M) was added, and the vial was capped, evacuated and purged with argon three times, and heated at 120 °C for 30 min followed by 160 °C for 8 h under microwave irradiation in a Biotage microwave. The reaction was allowed to cool to rt and diluted with DCM (50 mL). The solvent was removed in vacuo, and the crude sample dry-loaded onto silica gel without work up. The crude compound was purified by silica column chromatography.

10-Methoxy-7H-pyrido[3,4-c]carbazole (9a)

The reaction was carried out according to the general procedure B using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (1:1), to obtain compound 9a in 82% yield (102 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.94 (s, 1H, −NH), 9.30 (s, 1H, H⁴), 8.63 (d, 1H, J = 5.8 Hz, H²), 8.58 (d, J = 5.8 Hz, 1H, H¹), 8.05–7.99 (m, 2H, H^5,11), 7.85 (d, 1H, J = 8.8 Hz, H⁶), 7.60 (d, 1H, J = 8.8 Hz, H⁸), 7.13 (dd, 1H, J = 8.8, 2.4 Hz, H⁹), 3.96 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 154.1 (C¹⁰), 152.0 (C⁴), 144.1 (C²), 140.0 (C^6a), 133.6 (C^7a), 132.1 (C^11c), 125.9 (C⁵), 123.6 (C^11b), 123.0 (C^11a), 116.4 (C¹), 115.0 (C⁶), 114.3 (C⁹), 112.6 (C⁸), 112.3 (C^4a), 103.9 (C¹¹), 55.8 (−OCH₃).

IR v̅_max (cm^–1): 2830 (C–H stretch), 1616 (C=N stretch), 1458 (C=C stretch), 1229 (C–O stretch), 1031 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃ON₂, 249.1022; found, 249.1021.

10-Methyl-7H-pyrido[3,4-c]carbazole (9b)

The reaction was carried out according to the general procedure B using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methylaniline (85 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (1:1) to obtain compound 9b in 54% yield (63 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.97 (s, 1H, −NH), 9.31 (s, 1H, H⁴), 8.63 (d, 1H, J = 5.7 Hz, H²), 8.58 (d, 1H, J = 5.7 Hz, H¹), 8.41 (s, 1H, H¹¹), 8.04 (d, 1H, J = 8.8 Hz, H⁵), 7.86 (d, 1H, J = 8.8 Hz, H⁶), 7.58 (d, 1H, J = 8.3 Hz, H⁸), 7.30 (dd, 1H, J = 8.3, 1.2 Hz, H⁹), 2.58 (s, 3H, −CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 152.0 (C⁴), 143.9 (C²), 139.7 (C^6a), 137.0 (C^7a), 132.0 (C^11c), 129.0 (C¹⁰), 126.1 (C⁹), 125.8 (C⁵), 123.7 (C^4a), 122.9 (C^11a), 121.3 (C¹¹), 116.4 (C¹), 114.9 (C⁶), 112.2 (C^11b), 111.6 (C⁸), 21.3 (−CH₃).

IR v̅_max (cm^–1): 2917 (C–H stretch), 1616 (C=N stretch), 1474 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃N₂, 233.1073; found, 233.1068.

10-(Trifluoromethyl)-7H-pyrido[3,4-c]carbazole (9c)

The reaction was carried out according to the general procedure B using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-(trifluoromethyl)aniline (117 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (7:2), to obtain compound 9c in 25% yield (35 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.53 (s, 1H, −NH), 9.38 (s, 1H, H⁴), 8.90 (s, 1H, H¹¹), 8.74–8.63 (m, 2H, H^1, 2), 8.17 (d, 1H, J = 8.8 Hz, H⁵), 7.95 (d, 1H, J = 8.8 Hz, H⁶), 7.88 (d, 1H, J = 8.6 Hz, H⁸), 7.78 (d, 1H, J = 8.6 Hz, H⁹). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 152.3 (C⁴), 144.6 (C²), 140.8 (C^7a), 140.5 (C^6a), 131.8 (C^11c), 127.5 (C⁵), 125.4 (q, J = 272.6 Hz, −CF₃), 124.0 (C^4a), 122.2 (C^11a), 121.2 (q, J = 4.0 Hz, C⁹), 120.8 (q, J = 30.8 Hz, C¹⁰), 118.8 (q, J = 4.0 Hz, C¹¹), 116.6 (C¹), 115.0 (C⁶), 112.6 (C⁸), 112.4 (C^11b). ¹⁹F NMR (376 MHz, DMSO-d₆): δ −58.1.

IR v̅_max (cm^–1): 1638 (C=N stretch), 1618 (C=N stretch), 1463 (C=C stretch), 1420 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₀N₂F₃, 287.0791; found, 287.0791.

10-Methoxy-7H-pyrido[4,3-c]carbazole (9e)

The reaction was carried out according to the general procedure B using 7-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (1:1), to obtain compound 9e in 83% yield (103 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.89 (s, 1H, −NH), 10.14 (s, 1H, H¹), 8.53 (d, 1H, J = 5.5 Hz, H³), 8.07 (d, 1H, J = 2.4 Hz, H¹¹), 7.99 (d, 1H, J = 8.8 Hz, H⁶), 7.96 (d, 1H, J = 5.5 Hz, H⁴), 7.91 (d, J = 8.8 Hz, 1H, H⁵), 7.61 (d, J = 8.8 Hz, 1H, H⁸), 7.14 (dd, J = 8.8, 2.4 Hz, 1H, H⁹), 3.98 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 154.0 (C¹⁰), 146.7 (C¹), 140.5 (C³), 138.3 (C^6a), 133.8 (C^7a), 131.0 (C^11b), 124.7 (C^5, 11c), 122.1 (C^11a), 121.6 (C⁴), 118.3 (C⁶), 115.0 (C⁹), 113.0 (C^4a), 112.7 (C⁸), 104.2 (C¹¹), 55.8 (−OCH₃).

IR v̅_max (cm^–1): 2932 (C–H stretch), 1588 (C=N stretch), 1210 (C–O stretch), 1063 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃ON₂, 249.1022; found, 249.1028.

10-Methoxy-7H-pyrazino[2,3-c]carbazole (9f)

The reaction was carried out according to the general procedure B using 6-bromoquinoxaline (105 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (7:2), to obtain compound 9f in 75% yield (93 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.96 (s, 1H, −NH), 9.04 (d, 1H, J = 2.0 Hz, H²), 8.86 (d, 1H, J = 2.0 Hz, H³), 8.29 (d, 1H, J = 2.6 Hz, H¹¹), 8.05 (d, 1H, J = 9.1 Hz, H⁶), 7.98 (d, 1H, J = 9.1 Hz, H⁵), 7.61 (d, 1H, J = 8.8 Hz, H⁸), 7.13 (dd, 1H, J = 8.8, 2.6 Hz, H⁹), 3.91 (s, 3H, −OCH₃).

¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 154.1 (C¹⁰), 144.2 (C²), 141.2 (C³), 140.3 (C^11c), 139.5 (C^6a), 138.7 (C^4a), 133.8 (C^7a), 126.5 (C⁵), 123.3 (C^11a), 118.0 (C⁶), 115.0 (C⁹), 114.5 (C^11b), 112.7 (C⁸), 104.4 (C¹¹), 55.5 (−OCH₃).

IR v̅_max (cm^–1): 3338 (N–H stretch), 2837 (C–H stretch), 1601 (C=N stretch), 1523 (C=C stretch), 1495 (C=C stretch), 1214 (C–O stretch), 1029 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₂ON₃, 250.0975; found, 250.0970.

10-Methoxy-7H-pyrido[2,3-c]carbazole (9g)

The reaction was carried out according to the general procedure B using 6-bromoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (1:1), to obtain compound 9g in 65% yield (80 mg, off-white solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.77 (s, 1H, −NH), 9.17 (d, 1H, J = 8.3 Hz, H¹), 8.82 (dd, 1H, J = 4.2, 1.4 Hz, H³), 8.02 (d, 1H, J = 2.3 Hz, H¹¹), 7.99–7.92 (m, 2H, H^5,6), 7.67 (dd, 1H, J = 8.3, 4.2 Hz, H²), 7.58 (d, 1H, J = 8.8 Hz, H⁸), 7.11 (dd, 1H, J = 8.8, 2.3 Hz, H⁹), 3.95 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 153.8 (C¹⁰), 146.1 (C³), 144.2 (C^4a), 137.4 (C^6a), 133.9 (C^7a), 130.8 (C¹), 127.4 (C⁵), 124.4 (C^11c), 123.1 (C^11a), 121.5 (C²), 116.9 (C⁶), 114.2 (C⁹), 113.3 (C^11b), 112.6 (C⁸), 103.9 (C¹¹), 55.8 (−OCH₃).

IR v̅_max (cm^–1): 3146 (N–H stretch), 2997 (C–H stretch), 1571 (C=N stretch), 1534 (C=C stretch), 1493 (C=C stretch), 1227 (C–O stretch), 1035 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃ON₂, 249.1022; found, 249.1026.

8-Methoxy-11H-pyrido[4,3-a]carbazole (9h)

The reaction was carried out according to the general procedure B using 5-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, hexane:EtOAc (3:7), to obtain compound 9h in 90% yield (111 mg, gray solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.30 (s, 1H, −NH), 9.36 (s, 1H, H⁴), 8.62 (d, 1H, J = 5.7 Hz, H²), 8.38 (d, 1H, J = 8.5 Hz, H⁶), 8.32 (d, J = 5.7 Hz, 1H, H¹), 7.81 (d, 1H, J = 2.3 Hz, H⁷), 7.75 (d, 1H, J = 8.5 Hz, H⁵), 7.60 (d, 1H, J = 8.8 Hz, H¹⁰), 7.13 (dd, 1H, J = 8.8, 2.3, H⁹), 3.89 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 153.7 (C⁸), 152.0 (C⁴), 142.8 (C²), 134.1 (C^10a), 133.7 (C^4a), 126.6 (C^11a), 124.1 (C^11b), 123.0 (C^6b), 121.2 (C⁶), 120.3 (C^6a), 117.4 (C⁵), 115.7 (C⁹), 114.9 (C¹), 112.5 (C¹⁰), 102.3 (C⁷), 55.6 (−OCH₃).

IR v̅_max (cm^–1): 3149 (N–H stretch), 1619 (C=N stretch), 1480 (C=C stretch), 1439 (C=C stretch), 1215 (C–O stretch), 1027 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃ON₂, 249.1022; found, 249.1020.

8-Methoxy-11H-pyrido[3,4-a]carbazole (9i)

The reaction was carried out according to the general procedure B using 8-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, hexane:EtOAc (3:7), to obtain 9i in 94% yield (104 mg, gray solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.39 (s, 1H, −NH), 9.86 (s, 1H, H¹), 8.55 (d, 1H, J = 5.6 Hz, H³), 8.48 (d, 1H, J = 8.5 Hz, H⁶), 7.91 (d, 1H, J = 5.6 Hz, H⁴), 7.79 (d, 1H, J = 2.5 Hz, H⁷), 7.61 (d, 1H, J = 8.5 Hz, H⁵), 7.59 (d, 1H, J = 8.8 Hz, H¹⁰), 7.10 (dd, 1H, J = 8.8, 2.5, H⁹), 3.89 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 153.8 (C⁸), 146.4 (C¹), 142.6 (C³), 134.7 (C^4a), 134.4 (C^11a), 133.7 (C^10a), 124.6 (C⁶), 123.2 (C^6b), 121.1 (C⁴), 118.8 (C^6a), 116.8 (C^11b), 116.6 (C⁵), 114.9 (C⁹), 112.3 (C¹⁰), 102.2 (C⁷), 55.6 (−OCH₃).

IR v̅_max (cm^–1): 3074 (N–H stretch), 2962 (C–H stretch), 1627 (C=N stretch), 1474 (C=C stretch), 1437 (C=C stretch), 1217 (C–O stretch), 1027 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃ON₂, 249.1022; found, 249.1032.

9-Methoxy-3,6-dihydro-1H-furo[3,4-c]carbazole (9j)

The reaction was carried out according to the general procedure A using 5-bromo-1,3-dihydroisobenzofuran (99 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by reversed-phase semi-preparative HPLC over a 5–95% gradient B, (solvent A: 0.1% TFA in water, solvent B: 0.1% TFA in acetonitrile) to obtain compound 9j in 10% yield (35 mg, white solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.15 (s, 1H, −NH), 7.41 (d, 1H, J = 8.8 Hz, H⁷), 7.38 (d, 1H, J = 8.3 Hz, H⁵), 7.30 (d, 1H, J = 2.6 Hz, H¹⁰), 7.29 (d, 1H, J = 8.3 Hz, H⁴), 7.06 (dd, 1H, J = 8.8, 2.6 Hz, H⁸), 5.52 (t, 2H, J = 2.2 Hz, 2 × H¹), 5.14 (t, 2H, J = 2.2 Hz, 2 × H³), 3.84 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 153.1 (C⁹), 140.0 (C^5a), 134.8 (C^6a), 131.5 (C^10c), 128.2 (C^3a), 121.6 (C^10a), 118.0 (C⁴), 116.0 (C^10b), 114.6 (C⁸), 111.6 (C⁷), 110.0 (C⁵), 104.2 (C¹⁰), 72.8 (C³), 72.4 (C¹), 55.7 (−OCH₃).

IR v̅_max (cm^–1): 3246 (N–H stretch), 2867 (C–H stretch), 1478 (C=C stretch), 1439 (C=C stretch), 1214 (C–O stretch), 1014 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₄O₂N, 240.1019; found, 240.1030.

10-Methoxybenzo[4,5]imidazo[1,2-a]quinolone (9k)

The reaction was carried out according to the general procedure B using 2-bromoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, hexane:EtOAc (3:7), to obtain compound 9k in 25% yield (31 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.78 (d, J = 8.5 Hz, 1H, H¹), 8.08 (d, 1H, J = 2.3 Hz, H¹¹), 8.03 (dd, 1H, J = 7.8, 1.5 Hz, H⁴), 7.88–7.82 (m, 3H, H^2,5,8), 7.59 (d, 1H, J = 9.5 Hz, H⁶), 7.59–7.54 (m, 1H, H³), 7.21 (dd, 1H, J = 8.9, 2.3 Hz, H⁹), 4.00 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 156.0 (C¹⁰), 147.1 (C^6a), 138.8 (C^7a), 134.8 (C^12a), 130.7 (C^11a), 130.4 (C⁵), 130.0 (C²), 129.5 (C⁴), 124.4 (C³), 123.0 (C^4a), 120.3 (C⁸), 117.5 (C⁶), 115.6 (C¹), 113.8 (C⁹), 98.3 (C¹¹), 56.1 (−OCH₃).

IR v̅_max (cm^–1): 1636 (C=N stretch), 1608 (C=N stretch), 1487 (C=C stretch), 1448 (C=C stretch), 1219 (C–O stretch), 1026 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃ON₂, 249.1022; found, 249.1026.

N-(2-Chloro-4-methoxyphenyl)-N-(quinolin-2-yl)quinolin-2-amine (22)

The reaction was carried out according to the general procedure B using 2-bromoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, hexane:EtOAc (3:7) to obtain compound 22 in 26% yield (54 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.22 (d, 2H, J = 9.0 Hz, 2 × H⁴), 7.88 (d, 2H, J = 8.0 Hz, 2 × H⁵), 7.66–7.59 (m, 4H, 2 × H^7,8), 7.45 (ddd, 2H, J = 8.1, 5.5, 2.8 Hz, 2 × H⁶), 7.38 (d, 1H, J = 8.8 Hz, H^6′), 7.28 (d, 2H, J = 8.9 Hz, 2 × H³), 7.24 (d, 1H, J = 2.9 Hz, H^3′), 7.07 (dd, 1H, J = 8.8, 2.9 Hz, H^5′), 3.87 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 158.9 (C^4′), 155.3 (2 × C²), 146.4 (2 × C^8a), 137.3 (2 × C⁴), 133.5 (C^1′, 2′), 132.6 (C^6′), 129.7 (2 × C⁷), 127.6 (2 × C⁵), 127.2 (2 × C⁸), 125.2 (2 × C^4a), 124.7 (2 × C⁶), 116.6 (2 × C³), 115.5 (C^3′), 114.6 (C^5′), 55.8 (−OCH₃).

IR v̅_max (cm^–1): 1597 (C=N stretch), 1575 (C=N stretch), 1502 (C=C stretch), 1428 (C=C stretch), 1230 (C–O stretch), 1040 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₅H₁₉ON₃Cl, 412.1211; found, 412.1230.

10-Methoxybenzo[4,5]imidazo[1,2-a]quinoxaline (9l)

The reaction was carried out according to the general procedure B using 2-bromoquinoxaline (105 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, hexane:EtOAc (3:7), to obtain compound 9l in 14% yield (17 mg, white solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 9.23 (s, 1H, H⁶), 8.81 (d, 1H, J = 8.3 Hz, H¹), 8.14 (dd, 1H, J = 9.0, 1.4 Hz, H⁴), 8.10 (d, 1H, J = 2.3 Hz, H¹¹), 8.00 (d, 1H, J = 9.0 Hz, H⁸), 7.87 (ddd, 1H, J = 8.3, 7.6, 1.4 Hz, H²), 7.69 (ddd, 1H, J = 8.0, 7.6, 1.0 Hz, H³), 7.33 (dd, 1H, J = 9.0, 2.3 Hz, H⁹), 4.04 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 157.6 (C¹⁰), 146.1 (C⁶), 140.5 (C^6a), 138.5 (C^7a), 135.2 (C^4a), 130.2 (C⁴), 130.0 (C^2, 11a), 129.1 (C^12a), 125.7 (C³), 122.1 (C⁸), 116.3 (C⁹), 115.9 (C¹), 97.4 (C¹¹), 56.2 (−OCH₃).

IR v̅_max (cm^–1): 2843 (C–H stretch), 1580 (C=N stretch), 1590 (C=N stretch), 1463 (C=C stretch), 1225 (C–O stretch), 1026 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₂ON₃, 250.0975; found, 250.0982.

8-Methyl-7H-pyrido[3,4-c]carbazole (9m)

The reaction was carried out according to the general procedure B using 6-bromoisoquinoline (104 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-6-methylaniline (85 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, DCM:MeOH (0 to 2% MeOH), to obtain compound 9m in 62% yield (72 mg, white solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.01 (s, 1H, −NH), 9.32 (s, 1H, H⁴), 8.63 (d, 1H, J = 5.8 Hz, H²), 8.56 (d, 1H, J = 5.7 Hz, H¹), 8.42 (dd, 1H, J = 7.2, 2.4 H¹¹), 8.06 (d, 1H, J = 8.9 Hz, H⁵), 7.91 (d, 1H, J = 8.9 Hz, H⁶), 7.31–7.24 (m, 2H, H⁹,H¹⁰), 2.65 (s, 3H, −CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 152.2 (C⁴), 144.1 (C²), 139.6 (C^6a), 138.1 (C^7a), 132.0 (C^11c), 125.9 (C⁹), 125.2 (C⁵), 123.9 (C^4a), 122.4 (C^11a), 121.1 (C¹¹), 120.3 (C⁸), 119.1 (C¹⁰), 116.3 (C¹), 114.9 (C⁶), 112.8 (C^11b), 17.5 (−CH₃).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₃N₂, 233.1073; found, 233.1070.

Glycozoline (9n)¹

Preparation 1

The reaction was carried out according to the general procedure A using 4-bromotoluene (85 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (100:6), to obtain compound 9m in 36% yield (38 mg, brown crystalline solid).

Preparation 2

The reaction was carried out according to the general procedure A using 4-bromotoluene (85 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials with the addition of PivOH (15.3 mg, 0.15 mmol, 0.3 equiv). The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (100:6) to obtain compound 9n in 64% yield (66 mg, brown crystalline solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 10.85 (s, 1H, −NH), 7.87 (d, 1H, J = 1.0 Hz, H⁵), 7.61 (d, 1H, J = 2.5 Hz, H⁴), 7.34 (d, 1H, J = 8.8 Hz, H¹), 7.32 (d, 1H, J = 8.3 Hz, H⁸), 7.16 (dd, 1H, J = 8.3, 1.0 Hz, H⁷), 6.98 (dd, 1H, J = 8.8, 2.5 Hz, H²), 3.83 (s, 3H, −OCH₃), 2.45 (s, 3H, −CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 152.8 (C³), 138.6 (C^8a), 134.8 (C^9a), 126.7 (C^6, 7), 126.5 (C^4a), 122.5 (C^4b), 119.9 (C⁵), 114.5 (C²), 111.5 (C¹), 110.6 (C⁸), 102.8 (C⁴), 55.5 (−OCH₃), 21.0 (−CH₃).

IR v̅_max (cm^–1): 3401 (N–H stretch), 3003 (C–H stretch), 2835 (C–H stretch), 1474 (C=C stretch), 1458 (C=C stretch), 1212 (C–O stretch), 1037 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₄H₁₄ON, 212.1070; found, 212.1079.

Harmane (9o)⁴⁸

The reaction was carried out according to the general procedure A using 3-bromo-2-methylpyridine (86 mg, 0.50 mmol, 1.0 equiv) and 2-chloroaniline (77 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, EtOAc (100%), to obtain compound 9o in 45% yield (40 mg, purple solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.53 (s, 1H, NH), 8.20 (d, 1H, J = 5.3 Hz, H³), 8.18 (d, 1H, J = 8.0 Hz, H⁵), 7.92 (d, 1H, J = 5.3 Hz, H⁴), 7.61–7.57 (m, 1H, H⁸), 7.52 (ddd, 1H, J = 8.3, 7.0, 1.2 Hz, H⁷), 7.22 (ddd, 1H, J = 8.0, 7.0, 1.2 Hz, H⁶), 2.76 (s, 3H, −CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 142.1 (C¹), 140.3 (C^8a), 137.5 (C³), 134.4 (C^9a), 127.7 (C⁷), 126.8 (C^4a), 121.7 (C⁵), 121.0 (C^4b), 119.1 (C⁶), 112.6 (C⁴), 111.9 (C⁸), 20.4 (−CH₃).

IR v̅_max (cm^–1): 3062 (N–H stretch), 2954 (C–H stretch), 1627 (C=N stretch), 1571 (C=C stretch), 1506 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₂H₁₁N₂, 183.0917; found, 183.0927.

Murrayafoline A (9p)

The reaction was carried out according to the general procedure A using 2-bromo-5-methylanisole (101 mg, 0.50 mmol, 1.0 equiv) and 2-chloroaniline (77 mg, 0.60 mmol, 1.2 equiv) as starting materials with the addition of PivOH (15.3 mg, 0.15 mmol, 0.3 equiv). The crude residue was purified by silica gel column chromatography, hexane:EtOAc (7:3), to obtain compound 9p in 43% yield (45 mg, brown crystalline solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.12 (s, 1H, −NH), 8.00 (d, 1H, J = 8.0 Hz, H⁵), 7.49–7.46 (m, 1H, H⁴), 7.45–7.41 (m, 1H, H⁸), 7.32 (ddd, 1H, J = 8.3, 7.1, 1.3 Hz, H⁷), 7.09 (ddd, 1H, J = 8.0, 7.1, 1.1 Hz, H⁶), 6.82 (d, 1H, J = 1.1 Hz, H²), 3.96 (s, 3H, −OCH₃), 2.46 (s, 3H, −CH₃).

¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 145.3 (C¹), 139.7 (C^8a), 128.0 (C^9a), 127.8 (C³), 125.0 (C⁷), 123.4 (C^4a/4b), 122.4 (C^4a/4b), 120.0 (C⁵), 118.2 (C⁶), 112.2 (C⁴), 111.2 (C⁸), 107.7 (C²), 55.2 (−OCH₃), 21.5 (−CH₃).

IR v̅_max (cm^–1): 3418 (N–H stretch), 2921 (C–H stretch), 1590 (C=C stretch), 1454 (C=C stretch), 1232 (C–O stretch), 1040 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₄H₁₄ON, 212.1070; found, 212.1070.

2-((5,8-Dimethyl-9H-carbazol-3-yl)oxy)-N,N-dimethylethan-1-amine (9p)

The reaction was carried out according to the general procedure B using 2-bromo-p-xylene (93 mg, 0.50 mmol, 1.0 equiv) and 2-chloro-4-(2-(dimethylamino)ethoxy)aniline (128 mg, 0.60 mmol, 1.2 equiv) as starting materials and HPtBu₃BF₄ (14.5 mg, 10 mol %). The crude residue was purified by silica gel column chromatography, DCM:MeOH (100:3) to obtain compound 9p in 22% yield (31 mg, brown solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 11.04 (s, −NH), 7.67 (d, 1H, J = 2.4 Hz, H⁴), 7.46 (d, 1H, J = 8.7 Hz, H¹), 7.12 (dd, 1H, J = 8.7, 2.4 Hz, H²), 7.06 (d, 1H, J = 7.2 Hz, H⁷), 6.82 (d, 1H, J = 7.2 Hz, H⁶), 4.40 (t, 2H, J = 5.1 Hz, H^2′), 3.44 (t, 2H, J = 5.1 Hz, H^1′), 2.82 (s, 6H, −N(CH₃)₂), 2.77 (s, 3H, C⁵–CH₃), 2.50 (s, 3H, C⁸–CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 151.1 (C³), 139.8 (C^8a), 135.2 (C^9a), 129.6 (C⁵), 125.8 (C⁷), 123.6 (C^4a), 120.3 (C^4b), 119.6 (C⁶), 117.5 (C⁸), 114.1 (C²), 111.4 (C¹), 107.0 (C⁴), 63.7 (C^2′), 56.0 (C^1′), 41.2 ((−NCH₃)₂), 20.2 (C⁵–CH₃), 16.7 (C⁸–CH₃).

IR v̅_max (cm^–1): 3857 (N–H stretch), 2925 (C–H stretch), 1523 (C=C stretch), 1465 (C–H stretch), 1057 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₈H₂₃ON₂, 283.1805; found, 283.1812.

5H-Benzo[b]carbazole-6,11-dione (21a)

The reaction was carried out according to the general procedure A using 2-bromonaphthalene-1,4-dione (119 mg, 0.50 mmol, 1.0 equiv) and 2-chloroaniline (77 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, CHCl₃ (100%), to obtain compound 21a in 73% yield (90 mg, orange solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 13.08 (s, 1H, −NH), 8.22 (d, 2H, J = 8.0 Hz, H¹), 8.12 (ddd, 2H, J = 7.4, 7.4, 1.5 Hz, H^7, 10), 7.87 (ddd, 1H, J = 7.4, 7.4, 1.5 Hz, H⁹), 7.82 (ddd, 1H, J = 7.4, 7.4, 1.5 Hz, H⁸), 7.61 (d, 1H, J = 8.3 Hz, H⁴), 7.46 (ddd, 1H, J = 8.3, 7.0, 1.2 Hz, H³), 7.33–7.41 (m, 1H, H²). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 180.4 (C¹¹), 177.6 (C⁶), 138.2 (C^4a), 137.2 (C^5a), 134.3 (C⁹), 134.1 (C^10a), 133.2 (C⁸), 132.6 (C^6a), 127.0 (C³), 126.1 (C¹⁰), 126.0 (C⁷), 124.0 (C^11b), 123.9 (C²), 122.4 (C¹), 117.4 (C^11a), 113.9 (C⁴).

IR v̅_max (cm^–1): 3263 (N–H stretch), 1649 (C=O stretch), 1590 (C=C stretch), 1474 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₁₀O₂N, 248.0706; found, 248.0703.

2-Methoxy-5H-benzo[b]carbazole-6,11-dione (21b)

The reaction was carried out according to the general procedure A using 2-bromonaphthalene-1,4-dione (119 mg, 0.50 mmol, 1 equiv) and 2-chloro-4-methoxyaniline (94 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc:NEt₃ (70:30:1), to obtain compound 21b in 79% yield (93 mg, orange solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 13.02 (s, 1H, −NH), 8.15–8.08 (m, 2H, H^7,10), 7.86 (dd, 1H, J = 7.5, 1.5 Hz, H⁹), 7.81 (dd, 1H, J = 7.4, 1.7 Hz, H⁸), 7.63 (d, 1H, J = 2.5 Hz, H¹), 7.51 (d, 1H, J = 9.1 Hz, H⁴), 7.10 (dd, 1H, J = 9.0, 2.6 Hz, H³), 3.86 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 180.2 (C¹¹), 177.2 (C⁶), 157.0 (C²), 137.0 (C^5a), 134.2 (C^9, 10a), 133.4 (C^4a), 133.1 (C⁸), 132.7 (C^6a), 126.0 (C^7, 10), 124.8 (C^11b), 118.4 (C³), 117.0 (C^11a), 115.0 (C⁴), 102.1 (C¹), 55.4 (−OCH₃).

IR v̅_max (cm^–1): 3195 (N–H stretch), 1673 (C=O stretch), 1644 (C=O stretch), 1592 (C=C stretch), 1530 (C=O stretch), 1223 (C–O stretch), 1020 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₂ON₃, 278.0812; found, 278.0812.

2-Methyl-5H-benzo[b]carbazole-6,11-dione (21c)

The reaction was carried out according to the general procedure A using 2-bromonaphthalene-1,4-dione (119 mg, 0.50 mmol, 1.0 equiv) and 4-methyl-2-chloroaniline (85 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, CHCl₃ (100%), to obtain compound 21c in 59% yield (77 mg, orange solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.98 (s, 1H, −NH), 8.15–8.06 (m, 2H, H^7,10), 8.01 (s, 1H, H¹), 7.89–7.84 (m, 1H, H⁹), 7.84–7.78 (m, 1H, H⁸), 7.50 (d, 1H, J = 8.5 Hz, H⁴), 7.29 (d, 1H, J = 8.5 Hz, H³), 2.46 (s, 3H, −CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 180.3 (C¹¹), 177.5 (C⁶), 137.1 (C^5a), 136.7 (C^4a), 134.2 (C^10a), 134.1 (C⁹), 133.4 (C²), 133.2 (C⁸), 132.7 (C^6a), 128.9 (C³), 126.1 (C¹⁰), 126.0 (C⁷), 124.2 (C^11b), 121.6 (C¹), 116.9 (C^11a), 113.5 (C⁴), 21.3 (−CH₃).

IR v̅_max (cm^–1): 3174 (N–H stretch), 1670 (C=O stretch), 1642 (C=O stretch), 1595 (C=C stretch), 1538 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₁₂O₂N, 262.0863; found, 262.0861.

2-(Trifluoromethyl)-5H-benzo[b]carbazole-6,11-dione (21d)

The reaction was carried out according to the general procedure A using 2-bromonaphthalene-1,4-dione (119 mg, 0.50 mmol, 1.0 equiv) and 4-trifluoromethyl-2-chloroaniline (117 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc:NEt₃ (100:20:4), to obtain compound 21d in 35% yield (54 mg, orange solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 13.44 (s, 1H, −NH), 8.49–8.45 (m, 1H, H¹), 8.16–8.08 (m, 2H, H^7, 10), 7.91–7.81 (m, 2H, H^8, 9), 7.80–7.71 (m, 2H, H^3, 4). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 180.3 (C¹¹), 177.5 (C⁶), 139.5 (C^4a), 139.0 (C^5a), 134.5 (C⁸), 133.8 (C⁹), 133.5 (C^7a), 132.5 (C^10a), 126.2 (C^7, 10), 124.7 (q, J = 272.9 Hz, −CF₃), 124.3 (q, J = 31.8 Hz, C²), 123.1 (C^11b), 123.0 (q, J = 3.4 Hz, C³), 119.6 (q, J = 4.3 Hz, C¹), 117.6 (C^11a), 115.1 (C⁴). ¹⁹F NMR ((CD₃)₂SO, 376 MHz): δ −59.7.

IR v̅_max (cm^–1): 3234 (N–H stretch), 1655 (C=O stretch), 1631 (C=O stretch), 1586 (C=C stretch), 1541 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₉O₂NF₃, 316.0580; found, 316.0585.

3-Methoxy-5H-benzo[b]carbazole-6,11-dione (21e)

The reaction was carried out according to the general procedure A using 2-bromonaphthalene-1,4-dione (119 mg, 0.5 mmol, 1.0 equiv) and 2-chloro-5-methoxyaniline (95 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc (9:1), to obtain compound 21e in 68% yield (94 mg, red solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.89 (s, 1H, −NH), 8.11–8.03 (m, 3H, H^1, 7, 10), 7.87–7.76 (m, 2H, H^8, 9), 7.00 (dd, 1H, J = 8.8, 2.0 Hz, H²), 6.98 (d, 1H, J = 2.0 Hz, H⁴), 3.85 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 180.5 (C¹¹), 176.8 (C⁶), 159.4 (C³), 139.8 (C^4a), 136.4 (C^5a), 134.0 (C^6a), 133.9 (C⁸), 133.2 (C⁹), 132.7 (C^10a), 126.0 (C^7/10), 125.9 (C^7/10), 123.2 (C¹), 118.0 (C^11a/11b), 117.9 (C^11a/11b), 115.5 (C²), 95.1 (C⁴), 55.4 (−OCH₃).

IR v̅_max (cm^–1): 3189 (N–H stretch), 2927 (C–H stretch), 1664 (C=O stretch), 1629 (C=O stretch), 1532 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₁₂O₃N, 278.0812; found, 278.0809.

3-Fluoro-5H-benzo[b]carbazole-6,11-dione (21f)

The reaction was carried out according to the general procedure A using 2-bromonaphthalene-1,4-dione (119 mg, 0.50 mmol, 1.0 equiv) and 5-fluoro-2-chloroaniline (87 mg, 0.60 mmol, 1.2 equiv) as starting materials. The crude residue was purified by silica gel column chromatography, petroleum ether (40–60 °C):EtOAc:NEt₃ (100:20:4) to obtain compound 21f in 58% yield (76 mg, orange solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 13.12 (s, 1H, −NH), 8.19 (dd, 1H, J = 8.8, 5.5 Hz, H¹), 8.11–8.05 (m, 2H, H^7, 10), 7.87 (m, 2H, H^8, 9), 7.29 (dd, 1H, J = 9.4, 2.2 Hz, H⁴), 7.27–7.20 (m, 1H, H²). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 180.3 (C¹¹), 177.1 (C⁶), 161.5 (d, J = 243.5 Hz, C³), 138.6 (d, J = 13.2 Hz, C^4a), 138.0 (C^5a), 134.2 (C⁸), 133.8 (C^6a), 133.3 (C⁹), 132.5 (C^10a), 126.0 (C^7, 10), 124.1 (d, J = 10.5 Hz, C¹), 120.6 (C^11a/11b), 117.4 (C^11a/11b), 113.1 (d, J = 25.2 Hz, C²), 99.6 (d, J = 26.1 Hz, C⁴). ¹⁹F NMR ((CD₃)₂SO, 376 MHz): δ −113.2.

IR v̅_max (cm^–1): 3230 (N–H stretch), 2928 (C–H stretch), 1647 (C=O stretch), 1588 (C=C stretch), 1472 (C=C stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₉O₂NF, 266.0612; found, 266.0609.

2-Methoxy-5-(4-methoxybenzyl)-5H-benzo[b]carbazole-6,11-dione (24)

2-Methoxy-5H-benzo[b]carbazole-6,11-dione (21b) (74 mg, 0.27 mmol, 1.0 equiv) was stirred in anhydrous DMF (8 mL) and cooled to 0 °C in an ice bath. NaH (16 mg, 0.66 mmol, 2.4 equiv) was added and stirred for 1 h. Next, benzyl bromide (0.078 mL, 0.66 mmol, 2.4 equiv) was added dropwise and the reaction was stirred for 2 h at rt. The reaction mixture was diluted with EtOAc, washed with 5% w/v aqueous solution of LiCl followed by water and brine, dried over Na₂SO₄, and filtered. The filtrate was then concentrated in vacuo and purified by silica gel flash column chromatography (petroleum ether (40–60 °C):EtOAc (10:1)) to afford the desired compound 24 in 83% yield (81 mg, orange solid).

¹H NMR ((CD₃)₂SO, 500 MHz): δ 8.13 (dd, 1H, J = 7.5, 1.1 Hz, H⁷ or H¹⁰), 8.10 (dd, 1H, J = 7.5, 1.2 Hz, H⁷ or H¹⁰), 7.90–7.85 (m, 1H, H⁹), 7.85–7.80 (m, 1H, H⁸), 7.75 (d, 1H, J = 2.5 Hz, H¹), 7.71 (d, 1H, J = 9.2 Hz, H⁴), 7.33–7.28 (m, 2H, 2 × H^2′), 7.27–7.20 (m, 3H, 2 × H^3′and H^4′), 7.15 (dd, 1H, J = 9.2, 2.6 Hz, H³), 6.04 (s, 2H, −CH₂), 3.88 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 125 MHz): δ 180.3 (C¹¹), 177.9 (C⁶), 158.6 (C^4′), 157.5 (C²), 134.6 (C^4a), 134.4 (C^5a), 134.2 (C⁹), 133.5 (C⁸), 133.3 (C^10a), 133.2 (C^6a), 128.6 (2 × C^2′), 127.5 (C^4′), 126.6 (2 × C^3′), 126.3 (C⁷ or C¹⁰), 125.7 (C⁷ or C¹⁰), 124.2 (C^11b), 118.8 (C³), 117.7 (C^11a), 113.8 (C⁴), 102.3 (C¹), 55.5 (Ar–OCH₃), 47.8 (−CH₂).

IR v̅_max (cm^–1): 2926 (C–H stretch), 1647 (C=O stretch), 1489 (C–H bend), 1234 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₁₈O₃N, 368.1281; found, 368.1284.

5-Benzyl-2-methoxy-6,11-dimethyl-5H-benzo[b]carbazole (25)

5-Benzyl-2-methoxy-5H-benzo[b]carbazole-6,11-dione (71 mg, 0.19 mmol, 1.0 equiv) was dissolved in anhydrous THF (7 mL) under an argon atmosphere. The reaction was cooled to −80 °C, and a 1.6 M MeLi in THF solution (0.55 mL, 0.87 mmol) was added dropwise over 5 min. The reaction mixture was stirred at −80 °C for 3 h. Next, the reaction was quenched with water and extracted with CHCl₃. The combined organic phases were washed with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The isolated crude solid was dissolved in anhydrous THF (5 mL) and added to a solution of SnCl₂ (0.37 g, 1.94 mmol) in a mixture of 37% HCl (4.8 mL) and Et₂O (4.8 mL). The reaction mixture was stirred vigorously for 5 h and then extracted with CHCl₃. The combined organic phases were washed with water and brine, dried over Na₂SO₄, and the filtrate was concentrated in vacuo. The crude was purified by silica gel flash column chromatography, petroleum ether (40–60 °C):EtOAc (7:3), to afford the desired compound 25 in 40% yield (28 mg, cream solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 8.36 (dd, 1H, J = 8.8, 0.8 Hz, H¹⁰), 8.15 (dd, 1H, J = 8.9, 0.8 Hz, H⁷), 7.92 (d, 1H, J = 2.5 Hz, H¹), 7.55–7.48 (m, 1H, H⁸), 7.48–7.42 (m, 1H, H⁹), 7.39 (d, 1H, J = 8.8 Hz, H⁴), 7.29 (m, 2H, 2 × H^3′), 7.22 (m, 1H, H^4′), 7.15 (dd, 1H, J = 8.8, 2.5 Hz, H³), 7.08 (m, 2H, 2 × H^2′), 5.83 (s, 2H, −CH₂), 3.90 (s, 3H, −OCH₃), 3.20 (s, 3H, C¹¹–CH₃), 2.84 (s, 3H, C⁶–CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 153.4 (C²), 139.5 (C^4a), 139.2 (C^5a), 139.1 (C^1′), 131.8 (C^6a), 128.7 (2 × C^3′), 126.9 (C^4′,11a), 126.7 (C¹¹), 125.6 (2 × C^2′), 124.8 (C⁸), 124.5 (C¹⁰), 123.7 (C^10a), 123.4 (C^11b), 123.3 (C⁷), 122.2 (C⁹), 114.4 (C³), 109.8 (C⁴), 109.6 (C⁶), 108.2 (C¹), 55.8 (−OCH₃), 49.0 (−CH₂), 15.2 (C¹¹–CH₃), 13.6 (C⁶–CH₃).

IR v̅_max (cm^–1): 2922 (C–H stretch), 1599 (C=C stretch), 1437 (C–H bend), 1204 (C–O stretch).

HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₇H₂₅O₂N, 366.1852; found, 366.1854.

2-Methoxy-6,11-dimethyl-5H-benzo[b]carbazole (26)

The N-debenzylation protocol was based on a literature procedure.⁴⁹ 5-Benzyl-2-methoxy-6,11-dimethyl-5H-benzo[b]carbazole (25) (10 mg, 0.027 mmol, 1 equiv) was dissolved in DMSO (0.5 mL) and added to a flame-dried vial. While stirring the solution at room temperature, KO^tBu (21 mg, 0.19 mmol, 7 equiv) in THF (0.5 mL) was added. An oxygen balloon was then bubbled into the solution for 30 min. After stirring at room temperature for 5 h, the reaction was quenched with a saturated ammonium chloride aqueous solution. The product was extracted three times with EtOAc. The combined organic phases were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography using hexane:EtOAc (7:3) to afford the desired compound 26 in 61% yield (4.5 mg, yellow solid). Characterization of 26 is in agreement with that previously described in the literature.⁵

¹H NMR ((CD₃)₂SO, 400 MHz): δ 10.83 (s, 1H, NH), 8.32 (dd, 1H, J = 8.7, 0.7 Hz, H¹⁰), 8.10 (d, 1H, J = 8.7, 0.7 Hz, H⁷), 7.86 (d, 1H, J = 2.5 Hz, H¹), 7.51 (ddd, 1H, J = 8.7, 6.5, 1.3 Hz, H⁸), 7.45–7.39 (m, 2H, H^9,4), 7.14 (dd, 1H, J = 8.7, 2.5 Hz, H³), 3.89 (s, 3H, Ar–OCH₃), 3.16 (s, 3H, C¹¹–CH₃), 2.80 (s, 3H, C⁶–CH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 152.6 (C²), 138.9 (C^5a), 137.5 (C^4a), 130.6 (C^6a), 126.4 (C^10a), 125.8 (C¹¹), 124.5 (C¹⁰), 124.3 (C⁸), 123.7 (C^11b), 123.1 (C⁷), 122.7 (C^11a), 121.5 (C⁹), 114.6 (C³), 110.7 (C⁴), 108.8 (C¹), 107.7 (C⁶), 55.8 (Ar–OCH₃), 15.1 (C¹¹–CH₃), 12.6 (C⁶–CH₃).

LC-MS (ESI +ve mode): m/z = 276.1. Retention time = 8.19 min.

10-Methoxy-2-methyl-7H-pyrido[4,3-c]carbazol-2-ium (27)

To a solution of 10-methoxy-7H-pyrido[4,3-c]carbazole 9e (80 mg, 0.32 mmol, 1.0 equiv) in DMF (1.3 mL) was added MeI (230 mg, 1.61 mmol, 5.3 equiv). The reaction was stirred for 19 h at 50 °C in a DrySyn heating block. The resulting yellow precipitate was filtered and washed with cold Et₂O. The resulting solid was recrystallized from hot EtOH twice to yield compound 27 in 88% yield (111 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.50 (s, 1H, NH), 10.28 (s, 1H, H¹), 8.71 (dd, 1H, J = 6.7, 1.2 Hz, H³), 8.67 (d, 1H, J = 6.7 Hz, H⁴), 8.44 (d, 1H, J = 8.8 Hz, H⁶), 8.30 (d, 1H, J = 2.3 Hz, H¹¹), 8.24 (d, 1H, J = 8.8 Hz, H⁵), 7.75 (d, 1H, J = 8.9 Hz, H⁸), 7.32 (dd, 1H, J = 8.9, 2.4 Hz, H⁹), 4.67 (s, 3H, −NCH₃), 4.00 (s, 3H, −OCH₃). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 154.7 (C¹⁰), 143.3 (C¹), 139.4 (C^6a), 134.4 (C^7a), 133.5 (C³), 133.1 (C^4a), 126.0 (C⁴), 124.3 (C⁵), 124.2 (C⁶), 123.4 (C^11c), 121.3 (C^11a), 116.1 (C⁹), 113.7 (C^11b), 113.4 (C⁸), 105.5 (C¹¹), 56.3 (−OCH₃), 48.0 (−NCH₃).

IR v̅_max (cm^–1): 3129 (N–H stretch), 1631 (C=N stretch), 1562 (C=C stretch), 1497 (C=C stretch), 1029 (C–O stretch).

HRMS (ESI) m/z: [M]⁺ calcd for C₁₇H₁₅ON₂, 263.1179; found, 263.1179.

10-Methoxy-2-(2-(piperidin-1-yl)ethyl)-7H-pyrido[4,3-c]carbazol-2-ium (28)⁴⁵

To a solution of 10-methoxy-7H-pyrido[4,3-c]carbazole 9e (60 mg, 0.24 mmol, 1.0 equiv) in DMF (0.5 mL) was added a solution of 1-(2-chloroethyl)piperidine hydrochloride (178 mg, 1.0 mmol, 4.0 equiv) in a 1:1 mixture of DMF:water (1 mL). The reaction was stirred for 19 h at 80 °C in a DrySyn heating block. The resulting yellow precipitate was filtered and washed with cold Et₂O. The resulting solid was recrystallized from hot EtOH three times to yield compound 28 in 80% yield (77 mg, yellow solid).

¹H NMR (400 MHz, DMSO-d₆): δ 12.61 (s, 1H, NH), 11.00 (s, 1H, NH), 10.46 (s, 1H, H¹) 8.86 (d, 1H, J = 6.7 Hz, H³), 8.76 (d, 1H, J = 6.7 Hz, H⁴), 8.50 (d, 1H, J = 8.9 Hz, H⁶), 8.41–8.34 (m, 1H, H¹¹), 8.26 (d, 1H, J = 8.9 Hz, H⁵), 7.76 (d, 1H, J = 8.9 Hz, H⁸), 7.34 (dd, 1H, J = 8.9, 1.9 Hz, H⁹), 5.56–5.42 (m, 2H, 2 × H^1″), 4.04 (s, 3H, −OCH₃), 3.95–3.82 (m, 2H, 2 × H^2″), 3.67–3.54 (m, 2H, 2 × H^2′ or H^6′), 3.11–2.94 (m, 2H, 2 × H^2′ or H^6′), 1.90–1.77 (m, 4H, 2 × H^3′,5′), 1.76–1.70 (m, 1H, H^4′), 1.49–1.40 (m, 1H, H^4′). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 154.7 (C¹⁰), 143.8 (C¹), 139.4 (C^6a), 134.5 (C^7a), 133.7 (C^4a), 132.5 (C³), 126.4 (C⁴), 124.8 (C⁶), 124.3 (C⁵), 123.6 (C^11c), 121.3 (C^11a), 116.1 (C⁹), 114.1 (C^11b), 113.5 (C⁸), 105.9 (C¹¹), 56.4 (−OCH₃), 55.0 (C⁵), 54.2 (C^2″), 52.6 (2 × C^2′, 6′), 22.2 (2 × C^3′, 5′), 21.2 (C^4′).

IR v̅_max (cm^–1): 3390 (N–H stretch), 2958 (C–H stretch), 1634 (C=N stretch), 1219 (C–O stretch), 1029 (C–O stretch).

HRMS (ESI) m/z: [M]⁺ calcd for C₂₃H₂₆ON₃, 360.2070; found, 360.2081.

Ditercalinium (29)⁴⁷

10-Methoxy-7H-pyrido[4,3-c]carbazole 9e (100 mg, 0.40 mmol, 1.0 equiv) and 1,1′-bis(2-chloroethyl)-4,4′-bipiperidine (89 mg, 0.24 mmol, 0.6 equiv) were charged to a 2–5 mL microwave vial that was evacuated and purged with argon twice. DMF (4 mL) was added, and the vial was heated to 80 °C in a DrySyn heating block for 22 h. H₂O (0.1 mL) was added to further solubilize the starting materials, and the reaction was heated for a further 24 h at 80 °C. DMF (1 mL) was added to redissolve the formation of a yellow precipitate, and the reaction was heated to 120 °C for a further 24 h. The reaction was cooled, and the precipitate was isolated by filtration. The precipitate was washed with cold Et₂O and then recrystallized from hot EtOH five times to isolate 29 in 33% yield (52 mg, yellow solid).

¹H NMR ((CD₃)₂SO, 400 MHz): δ 12.69 (s, 2H, NH), 11.63 (s, 2H, NH), 10.51 (s (br), 2H, H¹), 9.00–8.78 (s (br), 2H, H³), 8.77–8.67 (d, 2H, J = 5.8 Hz, H⁴), 8.49 (d, 2H, J = 8.8 Hz, H⁶), 8.45–8.29 (s (br), 2H, H¹¹), 8.25 (d, 2H, J = 8.9 Hz, H⁵), 7.75 (d, 2H, J = 8.9 Hz, H⁸), 7.31 (dd, 2H, J = 9.0, 2.2 Hz, H⁹), 5.71–5.26 (m, 4H, H^1″), 4.03, 4.00–3.77 (m, 4H, H^2″), 3.73–3.50 (m, 4H, 4 × H^2′eq or 4 × H^2′ax), 3.11–2.91 (m, 4H, 4 × H^2′eq or 4 × H^2′ax), 2.06–1.51 (m, 8H, 4 × H^3′eq and 4 × H^3′ax), 1.48–1.29 (m, 2H, H^4′). ¹³C{¹H} NMR ((CD₃)₂SO, 101 MHz): δ 154.7 (C¹⁰), 143.7 (C¹), 139.4 (C^6a), 134.4 (C^7a), 133.6 (C^4a), 132.6 (C³), 126.4 (C⁴), 124.8 (C⁶), 124.3 (C⁵), 123.6 (C^11c), 121.3 (C^11a), 116.3 (C⁹), 114.1 (C^11b), 113.4 (C⁸), 105.7 (C¹¹), 56.4 (−OCH₃), 55.3 (C⁵), 54.3 (C^2″), 52.6 (2 × C^2′), 37.3 (2×C^4′), 25.8 (2 × C^3′).

IR v̅_max (cm^–1): 3342 (N–H stretch), 2927 (C–H stretch), 1616 (C=N stretch), 1472 (C=C stretch), 1402 (C=C stretch), 1214 (C–O stretch), 1031 (C–O stretch).

HRMS (ESI) m/z: [M]²⁺ calcd for C₄₆H₅₀O₂N₆, 359.1992; found, 359.1991.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c02943.

• Experimental procedures, characterization data, the ¹H and ¹³C NMR spectra for new compounds, DFT calculations, and crystallographic data (PDF)

Accession Codes

CCDC 2102051–2102053 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author Contributions

^§ E.C. and A.T.S. contributed equally. Conceptualization was done by G.A.B., E.C., A.T.S. and O.I.P.; methodology was performed by E.C., O.I.P., A.T.S, and J.B.; validation was done by E.C. and A.T.S.; formal analysis was done by E.C. and A.T.S.; and manuscript preparation was done by E.C., A.T.S., and G.A.B.

The authors declare no competing financial interest.

Notes

All data underpinning this publication are openly available from the University of Strathclyde KnowledgeBase at https://doi.org/10.15129/f45b6f45-b8f7-435a-b5a3-097e3ff7397c.