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Article

Construction of 1,2,3-Triazole-Embedded Polyheterocyclic Compounds via CuAAC and C–H Activation Strategies

by
Antonia Iazzetti
1,2,
Dario Allevi
1,
Giancarlo Fabrizi
3,*,
Yuri Gazzilli
3,
Antonella Goggiamani
3,
Federico Marrone
3,
Francesco Stipa
3,
Karim Ullah
3,† and
Roberta Zoppoli
3
1
Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, L.go Francesco Vito 1, 00168 Rome, Italy
2
Policlinico Universitario ‘A. Gemelli’ Foundation-IRCCS, 00168 Rome, Italy
3
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma, P. le A. Moro 5, 00185 Rome, Italy
*
Author to whom correspondence should be addressed.
†
Current address: Department of Chemistry, Sustainable Chemistry for Metals and Molecules (SCM2), KU Leuven, Celestijnenlaan 200F—Box 2404, B-3001 Leuven, Belgium.
Molecules 2025, 30(12), 2588; https://doi.org/10.3390/molecules30122588
Submission received: 21 May 2025 / Revised: 10 June 2025 / Accepted: 12 June 2025 / Published: 13 June 2025
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Versions Notes

Abstract

Over the past two decades, the copper(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC), commonly known as click chemistry, and C–H bond activation have gained significant attention and have emerged as key synthetic methodologies. In our efforts to synthesize fused nitrogen-containing heterocycles, we developed a palladium-catalyzed protocol for the synthesis of functionalized 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolines and 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indoles from suitable bromo-substituted N-propargyl-indoles. The reaction conditions demonstrate broad functional group compatibility including halogen, alkoxyl, cyano, ketone, and ester, affording the target compounds in good to high yields.

Graphical Abstract

1. Introduction

The strategic incorporation of multiple pharmacophores, particularly heterocycles, into single molecular frameworks is a powerful approach in designing novel therapeutic agents. This strategy often yields hybrid molecules with enhanced biological properties. Among these, triazole-fused polycyclic heterocycles have attracted significant interest due to their broad spectrum of pharmacological activities, including anticancer, antibacterial, anti-HIV, antifungal, and anti-inflammatory effects [1,2,3,4,5,6,7]. The triazole unit is particularly valuable for its metabolic stability, hydrogen-bonding capabilities, and function as a non-classical amide isostere [8]. The widespread relevance of triazole-fused polycyclic heterocycles in medicinal chemistry and interdisciplinary research has spurred efforts to develop efficient and sustainable synthetic methodologies [9,10,11].
Transition metal-catalyzed strategies have emerged as indispensable tools for constructing complex architectures, offering advantages such as broad functional group tolerance, operational simplicity, and high efficiency. In particular, the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC), a hallmark of click chemistry, has become the method of choice for triazole formation due to its regioselectivity, modularity, high efficiency, and facile nature [12,13,14,15]. Triazole derivatives have found diverse applications in organic chemistry, medicinal chemistry, and functional materials, with numerous reports highlighting their versatility [16,17,18,19,20,21]. The C–H bond activation is an attractive alternative to “classical” cross-coupling reactions because it is a process capable of forming carbon–carbon, carbon–nitrogen, or carbon–oxygen bonds via the direct functionalization of a carbon–hydrogen bond with transition metal catalysis, avoiding the preparation and use of organometallic reagents [22,23].
According to our background in the construction of heterocycles [24,25,26,27], here we report an efficient process providing ready access to hybrid molecules incorporating key pharmacophores (Figure 1), including pyrroloquinoline [28,29,30] and azepino[1,2-a]indole [31,32,33] cores linked to triazole moieties by combining CuAAC and palladium-catalyzed C–H bond activation. Furthermore, the pyrroloquinoline moiety has also demonstrated potential in material chemistry as red-emitting dopants (DCQTB) for organic light-emitting diodes [34].
Notably, by designing opportunely the starting materials, we successfully synthesized 10-substituted-1, 5,10-disubstituted-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolines 2 (Scheme 1a) and 5-substituted-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indoles 3 (Scheme 1b).

2. Results and Discussion

We selected 1-((1-substituted-1H-1,2,3-triazol-4-yl)methyl)-1H-indoles 4, 5, and 6 as the starting materials for the palladium-catalyzed annulation. The synthesis of the triazole core in precursors of types 4, 5, and 6 was carried out via a copper-catalyzed azide–alkyne cycloaddition (CuAAC) on functionalized halo N-propargyl indoles, specifically designed for this purpose, under reaction conditions previously optimized by our group for structurally related substrates (Scheme 2) [26]. The desired products were obtained in good yields (see Supplementary Materials).
To evaluate our working hypothesis, we initiated our investigation with the cyclization of 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a into 10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a as a model system to optimize reaction conditions. It is worth noting that 4a was readily synthesized in two steps from commercially available 7-bromo-1H-indole 10 via N-propargylation, followed by a CuAAC reaction with benzyl azide (Scheme 3).
Different reaction parameters were screened, including transition metal catalysts, ligands, solvents, and temperatures (Table 1). For our initial attempt, we employed conditions previously developed in our copper-catalyzed synthesis of heterocycles [35], expecting that copper catalysis could enable a domino or one-pot transformation of 7a to 1a [CuAAC/C–H activation]. However, despite testing various Cu catalysts, solvents, and bases (Table 1, entries 1–5), no reaction occurred (Table 1, entries 1–5). Consequently, we switched to palladium catalysis for the intramolecular C–H activation. Using Pd(OAc)2 as the palladium source, DavePhos as the ligand, and CsOAc as the base in dry DMF at 120 °C, the desired annulation product 1a was obtained in 14% yield, while the major product was the hydrodebromination derivative 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1H-indole, isolated in 42% yield (Table 1, entry 6) [36,37,38]. Interestingly, replacing the ligand with PPh3 significantly improved the reaction outcome, affording 10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a in 68% yield. Encouraged by this result, we systematically optimized the reaction parameters (Table 1, entries 8–13). Notably, the combination of Pd(OAc)2, PPh3, and CsOAc in dry DMSO provided the best outcome, affording 1a in excellent 80% yield (Table 1, entry 8). Lowering the temperature (Table 1, entries 9–10) or replacing DMSO with MeCN or 1,4-dioxane led to decreased yields. Furthermore, reducing the palladium catalyst load resulted in less efficient cyclization (Table 1, entry 13).
Once the optimal reaction conditions were established, we investigated the scope and generality of this method. Initially, we modified only the N-substitution on the triazole ring in 4, introducing aryl groups with electron-donating and electron-withdrawing substituents (4b–g). The required starting materials were prepared according to Scheme 3, employing various aryl azides instead of benzyl azide. The resulting 10-aryl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline derivatives 1b–g were obtained in good to excellent yields (Table 2, 70–91% yields). Subsequently, the newly designed reaction procedure was tested on the gram scale to determine its synthetic scalability, producing 1a in 69% yield.
We further investigated a domino strategy involving the simultaneous addition of all reagents and catalysts at the beginning of the reaction. However, this approach proved inefficient, resulting in a complex reaction mixture. Consequently, a sequential protocol was adopted: the CuAAC reaction was first performed in DMSO, and, without intermediate workup, the catalyst required for C–H activation was subsequently introduced. This protocol afforded the final compound 1a in 45% yield, along with the recovery of the starting triazole derivative 4a in 25% yield after 24 h. Finally, a one-pot strategy incorporating an intermediate workup following the CuAAC reaction was implemented, which enabled the isolation of the desired product 1a in a good yield of 65%.
With these encouraging results in hand, we envisioned increasing molecular complexity by introducing different substituents on 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline nucleus. Our approach to assembling the required substrates 5 involves a one-pot, chemoselective Sonogashira cross-coupling of substituted 2-bromo-6-iodoanilines 15 with aryl acetylenes 17, followed by an endo-dig cyclization of the resulting 2-alkynylanilines 13. The ensuing indole derivatives 11 are then subjected to N-propargylation to afford 8, which subsequently undergo a Cu-catalyzed azide–alkyne cycloaddition (CuAAC) to yield the desired starting materials (5a–k) (Scheme 4).
Further details on the preparation of the starting materials, based on slightly modified known procedures, are provided in Supplementary Materials [39].
As shown in Table 3, good to excellent results were usually obtained with a variety of 7-bromo-1-((1-substituted-1H-1,2,3-triazol-4-yl)methyl)-2-phenyl-1H-indoles 5 containing different functionalities such as ether, ester, benzyl, and halogens both in indole and triazole cores (Table 3, 2a–k, 52–99%).
The potential of the reported strategy for the synthesis of polyfused N-heterocycles containing triazole was further demonstrated by the ready construction of the 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole skeleton, albeit through a slight modification in the starting 1-((1H-1,2,3-triazol-4-yl)methyl)-1H-indole. In particular, we envisaged that 2-((2-bromoaryl)ethynyl)-4-substituted aniline 14 might represent suitable building blocks for the synthesis of this core through a process that involves the assembly of the indole ring followed by N-propargylation/CuAAC/palladium-catalyzed intramolecular C–H bond activation. (Scheme 3)
We selected 2-(2-bromophenyl)-1-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-indole 6a as the model substrate for obtaining the corresponding 5-(4-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3a. Fortunately, under the optimized reaction condition [Pd(OAc)2 (2 mol %), PPh3 (4 mol %), and CsOAc (2.0 equiv.) in DMSO at 120 °C], we successfully isolated 3a in 83% yield after one hour (Scheme 5) and on the gram scale in 71% yield.
To demonstrate the versatility of intramolecular C–H annulation, we prepared several 2-(2-bromoaryl)-1-((1-substituted-1H-1,2,3-triazol-4-yl)methyl)-1H-indole 6. All the tested starting materials (6b–n) were converted into the corresponding functionalized 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole derivative 3 in good to excellent yield (Table 4, 3b–q, 55–96%), regardless of the electronic effect of the substituents.
It is worth noting that the developed protocol tolerates a–Cl substituent in the indole (Table 3, 2a–d; Table 4, 3o, 3p) and/or triazole framework (Scheme 5, 3a; Table 2, 1e; Table 4, 3f, 3g, 3k, 3o) of hybrid heterocycles 1, 2, and 3, which may serve as a useful handle for introducing other functional groups through cross-coupling reactions. For example, we performed post-synthetic modification of 1e and 3a via palladium-catalyzed Suzuki–Miyaura coupling and Buchwald–Hartwig C-N bond-forming reactions. As shown in Scheme 6, compounds 1e and 3a were successfully treated with different aryl and heteroaryl boronic acids under reaction conditions previously reported by us [Pd2dba3, Sphos, K3PO4, 1,4-dioxane, 100 °C] (Scheme 6, path a; 21a, 23a–c, 71–98%) [40].
Furthermore, the Buchwald–Hartwig amination reactions were carried out in the presence of Pd2(dba)3, Xphos, and tBuOK in toluene, leading to the desired N-derivatives 22a and 24a in a yield of 72% and 92%, respectively (Scheme 6, path b).
Based on the literature reports highlighting the role of the acetate ion in promoting the cyclization process [41], the mechanism of palladium-catalyzed C–H functionalization/C-C bond formation can be rationalized, as depicted in Scheme 7, for the formation of the final product 1 (ligands omitted for clarity). Following the in situ reduction of Pd(II) to Pd(0), oxidative addition of substrate 4 to Pd(0) generates the aryl palladium complex A. In the presence of the acetate ion, a rapid ligand exchange occurs, affording the palladium(II)-acetate complex B. This intermediate undergoes cyclopalladation via transition state C, forming the seven-member palladacycle D. The transition state likely involves a concerted metalation–deprotonation (CMD) process, where the Pd–C bond formation and C–H bond cleavage occur simultaneously, facilitated by the acetate ligand acting as base. Finally, reductive elimination regenerates the active Pd(0) species and delivers the triazole-fused heterocycle 1.
However, the involvement of an electrophilic mechanism reported for direct Pd-catalyzed arylation of 1,2,3-triazoles cannot be definitively ruled out [42].

3. Materials and Methods

3.1. General Information

All of the commercially available reagents, catalysts, bases, and solvents were used as purchased, without further purification. Starting materials and reaction products were purified by flash chromatography using SiO2 as the stationary phase, eluting with n-hexane/ethyl acetate (EtOAc) mixtures. 1H NMR (400.13 MHz), 13C NMR (100.6 MHz), and 19F spectra (376.5 MHz) were recorded with a Bruker Avance 400 spectrometer equipped with a Nanobay console and Cryoprobe Prodigy probe (Bruker, Billerica, MA, USA). Splitting patterns are designed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or bs (broad singlet). IR spectra were recorded with a Jasco FT/IR-430 spectrometer (JASCO Corporation, Tokyo, Japan). HRMS were recorded with an Orbitrap Exactive Mass spectrometer with ESI source (Thermo Fisher, Waltham, MA, USA). Melting points were determined with a Büchi B-545 apparatus and are uncorrected.

3.2. General Experimental Procedures

3.2.1. Synthetic Procedures for Starting Materials

General Procedure for the Preparation of 1-((1-Substituted)-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4
  • Typical procedure for the preparation of 1-((1-benzyl)-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a
  • STEP 1: Synthesis of 7-bromo-1-(prop-2-yn-1-yl)-1H-indole 7a
A flame-dried 100 mL three-necked round-bottom flask, equipped with a magnetic stirring bar, was charged under argon with NaH (60% dispersion in mineral oil, 240.0 mg, 6.00 mmol, 1.2 equiv.). The solid was washed three times with n-hexane and then suspended in anhydrous DMF (15.0 mL). The suspension was cooled to 0 °C, and a solution of 7-bromo-1H-indole 10 (980.0 mg, 5.00 mmol, 1.0 equiv.) in DMF (15.0 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 5 min. After cooling again to 0 °C, propargyl bromide (solution 80 wt % in toluene) (808 μL, 7.50 mmol, 1.5 equiv.) was added dropwise. The mixture was subsequently warmed to room temperature and stirred for 30 min. Upon completion, the reaction was quenched with water, diluted with diethyl ether, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 (25–40 μm), followed by eluting with a 90/10 (v/v) n-hexane-AcOEt mixture (Rf = 0.25) to obtain 7-bromo-1-(prop-2-yn-1-yl)-1H-indole 7a (1.111 g, 95% yield).
7-bromo-1-(prop-2-yn-1-yl)-1H-indole 7a: 95% yield; white solid; mp: 65–67 °C; IR (neat): 3267, 1303, 917, 779, 710 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.46 (dd, J = 7.8, 1.0 Hz, 1H), 7.28 (dd, J = 7.6, 1.0 Hz, 1H), 7.15 (s, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.45 (d, J = 3.3 Hz, 1H), 5.29 (d, J = 2.5 Hz, 2H), 2.35 (d, J = 2.5 Hz, 1H); 13C NMR (100.6 MHz) (CDCl3): δ 132.4 (C), 132.2 (C), 130.1 (CH), 127.2 (CH), 121.2 (CH), 120.6 (CH), 103.6 (C), 102.8 (CH), 78.8 (C), 74.2 (CH), 38.1 (CH2). HRMS: m/z [M + H]+ calcd for C11H9BrN: 233.9913; found: 233.9926.
  • STEP 2: synthesis of 1-((1-benzyl)-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a
In a 50 mL Radley’s Discovery Technology Carousel reactor equipped with a magnetic stirrer (Radley, London, UK), 7-bromo-1-(prop-2-yn-1-yl)-1H-indole 7a (1.0 g, 4.27 mmol, 1.0 equiv.) was dissolved in 4 mL of 1,4-dioxane. Then, CuI (162.3 mg, 0.85 mmol, 0.20 equiv.) and benzyl azide (624.7 mg, 4.70 mmol, 1.1 equiv.) were sequentially added, the vial was sealed, and the reaction mixture was stirred at 80 °C overnight. Upon completion, the mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography on SiO2 (25–40 μm), eluting with an 80/20 (v/v) n-hexane-AcOEt mixture (Rf = 0.25) to afford 1-((1-benzyl)-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a (1.489 g, 95% yield).
1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a: 95% yield; off-white solid; mp: 85–87 °C; IR (neat): 3067, 1554, 1313, 912, 709 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.46–7.36 (m, 1H), 7.25–7.15 (m, 4H), 7.15–7.09 (m, 2H), 7.04 (dd, J1 = 6.7, J2 = 2.9 Hz, 2H), 6.80 (t, J = 7.7 Hz, 1H), 6.39 (d, J = 3.3 Hz, 1H), 5.75 (s, 2H), 5.26 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 146.1 (C), 134.6 (C), 132.1 (C), 132.1 (C), 131.1 (CH), 129.1 (CH), 128.7 (CH), 127.8 (CH), 127.2 (CH), 122.1 (CH), 120.9 (CH), 120.7 (CH), 103.5 (C), 102.9 (CH), 54.1 (CH2), 43.6 (CH2); HRMS: m/z [M + H]+ calcd for C18H16BrN4: 367.0553; found: 367.0561.
One-Pot Protocol for the Preparation of 1-((1-Substituted)-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4 Starting from 10
Starting materials 4a–e were prepared through a one-pot, two-steps protocol omitting the isolation of 7a–e.
Starting materials 5a–5k and 6a–6q were prepared according to slightly modified literature procedures described in the Supplementary Materials [43] through the retrosynthesis depicted in Scheme 3.

3.2.2. Synthetic Procedures for Final Products

Typical Procedure for the Preparation of Functionalized 10-Substituted 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1 and 2: Synthesis of 10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a
In a 50 mL Carousel Tube Reactor (Radley, London, UK), equipped with a magnetic stirrer, Pd(OAc)2 (3.4 mg, 0.015 mmol, 0.05 equiv.) and PPh3 (7.9 mg, 0.03 mmol, 0.10 equiv.) were dissolved in anhydrous DMSO (2 mL) under an argon atmosphere at room temperature. To this solution, 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a (110.2 mg, 0.30 mmol, 1.0 equiv.) and Cs(OAc) (114.6 mg, 0.60 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at 120 °C and monitored by TLC (n-hexane/EtOAc, 80/20) for the conversion of 4a into 10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a. Upon completion, the mixture was diluted with diethyl ether, washed with saturated NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (25–40 μm), eluting with an 80/20 (v/v) n-hexane–AcOEt mixture (Rf = 0.20) to afford 1a (68.6 mg, 80% yield).
Gram-Scale Synthesis of 10-Benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a
In a 50 mL Carousel Tube Reactor (Radley, London, UK), equipped with a magnetic stirrer, Pd(OAc)2 (10.2 mg, 0.045 mmol, 0.05 equiv.) and PPh3 (23.7 mg, 0.09 mmol, 0.10 equiv.) were dissolved in anhydrous DMSO (6.0 mL) under an argon atmosphere at room temperature. To this solution, 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a (1.10 g, 3.00 mmol, 1.0 equiv.) and CsOAc (343.8 mg, 1.8 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at 120 °C and monitored by TLC (n-hexane/EtOAc, 80/20) for the conversion of 4a into 10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a. Upon completion, the mixture was diluted with diethyl ether, washed with saturated NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (25–40 μm), eluting with an 80/20 (v/v) n-hexane–AcOEt mixture (Rf = 0.20) to afford 1a (592.7 mg, 69% yield).
10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a: white solid; mp: 246–248 °C; IR (neat): 3156, 1309, 1230, 684, 599 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.37 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.29–7.09 (m, 5H), 7.03 (d, J = 3.1 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 3.2 Hz, 1H), 5.73 (s, 2H), 5.57 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 139.9 (C), 134.6 (C), 133.4 (C), 129.1 (CH), 128.3 (CH), 126.84 (CH), 126.82 (C), 126.6 (CH), 125.9 (C), 122.4 (CH), 120.1 (CH), 114.5 (CH), 109.1 (C), 103.6 (CH), 53.3 (CH2), 44.6 (CH2); HRMS: m/z [M + H]+ calcd for C18H15N4: 287.1291; found: 287.1287.
Typical Procedure for the Preparation of Functionalized 5-Substituted-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3: 5-(4-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3a
In a 50 mL Carousel Tube Reactor (Radley, London, UK), equipped with a magnetic stirrer, Pd(OAc)2 (3.4 mg, 0.015 mmol, 0.05 equiv.) and PPh3 (7.9 mg, 0.03 mmol, 0.10 equiv.) were dissolved in anhydrous DMSO (2 mL) under argon. Then, 2-(2-bromophenyl)-1-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-indole 6a (139.1 mg, 0.3 mmol, 1 equiv.) and CsOAc (114.6 mg, 0.6 mmol, 2.0 equiv.) were added, and the reaction mixture was stirred at 120 °C and monitored by TLC. Upon completion, the mixture was diluted with diethyl ether, washed with saturated NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 (25–40 μm), eluting with an 70/30 (v/v) n-hexane-AcOEt mixture (Rf = 0.19) to afford 3a (95.3 mg, 83% yield).
5-(4-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3a: 83% yield; yellow solid; IR (neat): 1600, 1459, 1053, 786, 765 cm−1; mp: 232–234 °C; 1H NMR (400.13 MHz) (CDCl3): δ 7.90 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.50–7.44 (m, 3H), 7.39–7.37 (m, 2H), 7.31 (td, J1 = 8.3 Hz, J2 = 1.2 Hz, 1H), 7.25 (td, J1 = 8.6 Hz, J2= 1.2 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.86 (s, 1H), 5.44 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 145.0 (C),138.4 (C), 137.0 (C), 135.7 (C), 135.2 (C), 133.8 (C), 132.5 (C), 131.9 (CH), 129.9 (CH), 129.8 (CH), 128.6 (CH), 127.9 (C), 127.8 (CH), 126.3 (CH), 122.7 (CH), 122.6 (C), 121.0 (CH), 120.2 (CH), 109.3 (CH), 104.0 (CH), 39.4 (CH2). HRMS: m/z [M + H]+ calcd for C23H16ClN4: 383.1058; found: 383.1066.

3.2.3. Synthetic Procedures for Post-Synthetic Derivatives Compounds 21a, 23a–c, 22a, and 24a

Typical Procedure for the Suzuki Cross-Coupling: Synthesis of 10-([1,1′-Biphenyl]-4-yl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolone 21a
A Carousel Tube Reactor (Radley, London, UK), equipped with a magnetic stirrer, was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 0.02 equiv.), Sphos (4.1 mg, 0.010 mmol, 0.04 equiv.), and dry dioxane (2.0 mL). After solubilization of this precatalyst system at room temperature under an argon atmosphere, compound 1e (76.7 mg, 0.25 mmol, 1.0 equiv.), phenyl boronic acid (45.7 mg, 0.375 mmol, 1.5 equiv.), and K3PO4 (0.159 g, 0.750 mmol, 3.0 equiv.) were added. The resulting mixture was heated at 100 °C and stirred for 2 h. Afterwards, the mixture was cooled, added with ethyl acetate, and washed with brine. The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 (25–40 μm), (90:10 n-hexane/EtOAc) to obtain 21a (82.6 mg, 95% yield).
10-([1,1′-biphenyl]-4-yl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 21a: 95% yield; red solid; mp: 220–222 °C; IR (neat): 3152, 1333, 1248, 1068, 708 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.77 (d, J = 8.30 Hz, 2H), 7.65–7.60 (m, 5H), 7.46–7.41 (m, 3H), 7.14 (d, J = 3.00 Hz, 1H), 6.80–6.70 (m, 2H), 6.5 (d, J = 3.00 Hz, 1H), 5.73 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 143.4 (C), 139.6 (C), 136.0 (C), 133.7 (C), 129.9 (C), 129.1 (CH), 128.4 (C), 128.3 (CH), 128.2 (CH), 127.3 (C), 126.9 (CH), 126.3 (CH), 126.0 (C), 122.7 (CH), 120.0 (CH), 114.4 (CH), 109.2 (C), 103.8 (CH), 44.6 (CH2). HRMS: m/z [M + H]+ calcd for C23H17N4: 349.1448; found: 349.1432.
Typical Procedure for the Buchwald–Hartwig N-Arylation: Synthesis of 4-(4-(Benzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indol-5(8H)-yl)phenyl)morpholine 24a
In a 50 mL Carousel Tube Reactor (Radley, London, UK) containing a magnetic stirring bar, Pd2(dba)3 (4.6 mg, 0.0053 mmol, 0.02 equiv.) and Xphos ligand (4.8 mg, 0.01 mmol, 0.04 equiv.) were dissolved at room temperature with 2.0 mL of toluene under argon. Then, 5-(4-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3a (95.7 mg, 0.25 mmol, 1.0 equiv.), morpholine (33 μL, 0.375 mmol, 1.5 equiv.), and tBuOK (56.1 mg, 0.50 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 3 h at 100 °C. Afterwards, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with a saturated NaCl solution. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2 25–40 μm, n-hexane/EtOAc 70/30) to afford 4-(4-(benzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indol-5(8H)-yl)phenyl)morpholine 24a (92% yield, 43.2 mg).
4-(4-(benzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indol-5(8H)-yl)phenyl)morpholine 24a: 92% yield; brown solid; mp: 238–240 °C; IR (neat): 3115, 2980, 1365, 911, 709 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.80 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.23–7.09 (m, 4H), 7.05 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 5.35 (s, 2H), 3.79 (t, J = 4.8 Hz, 4H), 3.14 (t, J = 4.8 Hz, 4H).; 13C NMR (100.6 MHz) (CDCl3): δ 151.7 (C), 144.5 (C), 138.7 (C), 136.9 (C), 133.6 (C), 132.3 (C), 131.6 (CH), 129.3 (CH), 128.5 (CH), 127.8 (C), 127.6 (CH), 126.0 (CH), 123.19 (C), 123.18 (C), 122.5 (CH), 120.9 (CH), 120.1 (CH), 115.5 (CH), 109.3 (CH), 103.8 (CH), 66.7 (CH2), 48.6 (CH2), 39.5 (CH2). HRMS: m/z [M + H]+ calcd for C27H24N5O: 434.1974; found: 434.1988.

3.3. Characterization Data of Synthesized Compounds

Characterization data for the starting materials 4b–e, 5a–k, and 6a–q, with their precursors reported in the Supplementary Materials.

3.3.1. Characterization Data of Final Compounds 1b–g and 2a–k

10-(4-methoxyphenyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1b: 81% yield; brown solid; mp: 238–240 °C; IR (neat): 3115, 2980, 1365, 911, 709 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.45 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 3.1 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.76 (t, J = 7.7 Hz, 1H), 6.59 (d, J = 7.3 Hz, 1H), 6.48 (d, J = 3.1 Hz, 1H), 5.69 (s, 2H), 3.85 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 161.0 (C), 139.1 (C), 133.6 (C), 129.9 (C), 129.8 (C), 127.4 (CH), 126.8 (CH), 125.9 (C), 122.5 (CH), 119.9 (CH), 114.8 (CH), 114.2 (CH), 109.3 (C), 103.7 (CH), 55.7 (CH3), 44.6 (CH2). HRMS: m/z [M + H]+ calcd for C18H15N4O: 303.1240; found: 303.1233.
10-(3,4,5-trimethoxyphenyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1c: 91% yield; yellow solid; mp: 240–242 °C; IR (neat): 3109, 2991, 1344, 924, 715 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.40 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 2.9 Hz, 1H), 6.84–6.72 (m, 4H), 6.46 (d, J = 2.9 Hz, 1H), 5.63 (s, 2H), 3.88 (s, 3H), 3.80 (s, 6H); 13C NMR (100.6 MHz) (CDCl3): δ 153.8 (C), 139.4 (C), 139.2 (C), 133.6 (C), 132.3 (C), 129.8 (C), 126.9 (CH), 126.0 (C), 122.7 (CH), 120.0 (CH), 114.4 (CH), 109.1 (C), 103.7 (CH), 103.6 (CH), 61.2 (CH3), 56.5 (CH3), 44.5 (CH2). HRMS: m/z [M + H]+ calcd for C20H19N4O3: 363.1452; found: 363.1466.
10-(2-fluoro-4-methylphenyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1d: 70% yield; brown solid; mp: 270–272 °C; IR (neat): 2877, 1537, 1194, 820, 722 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.46–7.36 (m, 2H), 7.21–7.10 (m, 3H), 6.77 (t, J = 7.7 Hz, 1H), 6.52–6.45 (m, 2H), 5.73 (s, 2H), 2.46 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 156.6 (d, JC-F = 253.0 Hz, C), 143.8 (d, JC-F = 7.7 Hz, C), 138.9 (C), 133.6 (C), 131.0 (C), 128.3 (CH), 126.8 (CH), 125.9 (C), 125.79 (d, JC-F = 3.8 Hz, CH), 122.7 (CH), 122.4 (d, JC-F = 12.4 Hz, C), 120.1 (CH), 117.6 (d, JC-F = 18.6 Hz, CH), 113.7 (CH), 109.0 (C), 103.7 (CH), 44.6 (CH2), 21.6 (CH3); 19F NMR (376.5 MHz) (CDCl3): δ −121.29 (m). HRMS: m/z [M + H]+ calcd for C18H14FN4: 305.1197; found: 305.1181.
10-(4-chlorophenyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1e: 85% yield; yellow solid; mp: 230–232 °C; IR (neat): 3059, 1508, 1198, 1087, 717 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.59–7.47 (m, 4H), 7.41 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 3.2 Hz, 1H), 6.77 (t, J = 7.7 Hz, 1H), 6.61 (d, J = 7.3 Hz, 1H), 6.49 (d, J = 3.2 Hz, 1H), 5.68 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 139.4 (C), 136.5 (C), 135.5 (C), 133.6 (C), 130.0 (C), 129.8 (CH), 127.3 (CH), 126.9 (CH), 126.1 (C), 122.9 (CH), 120.0 (CH), 114.2 (CH), 108.9 (C), 103.8 (CH), 44.5 (CH2). HRMS: m/z [M + H]+ calcd for C17H12ClN4: 307.0745; found: 307.0730.
10-(4-nitrophenyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1f: 89% yield; yellow solid; mp: 246–248 °C; IR (neat): 3102, 1486, 1092, 815 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.51 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 3.0 Hz, 1H), 6.87 (t, J = 7.7 Hz, 1H), 6.75 (d, J = 7.1 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 5.80 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 148.8 (C), 142.1 (C), 140.3 (C), 133.9 (C), 130.2 (C), 127.3 (CH), 127.0 (CH), 126.6 (C), 125.4 (CH), 123.6 (CH), 120.3 (CH), 114.6 (CH), 108.7 (C), 104.3 (CH), 44.8 (CH2). HRMS: m/z [M + H]+ calcd for C17H12N5O2: 318.0985; found: 318.0973.
4-(pyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolin-10(7H)-yl)benzonitrile 1g: 83% yield; yellow solid; mp: 232–234 °C; IR (neat): 3048, 1517, 1185, 1076, 678 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.96 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H), 6.90 (t, J = 7.7 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.61 (d, J = 3.2 Hz, 1H), 5.79 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 140.5 (C), 140.0 (C), 133.8 (CH), 133.7 (C), 129.9 (C), 127.1 (CH), 126.7 (CH), 126.3 (C), 123.4 (CH), 120.0 (CH), 117.6 (C), 114.4 (C), 114.3 (CH) 108.6 (C), 104.0 (CH), 44.6 (CH2). HRMS: m/z [M + H]+ calcd for C18H12N5: 298.1087; found: 298.1099.
10-benzyl-2-chloro-5-phenyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2a: 80% yield; white solid; mp: 240–242 °C; IR (neat): 3014, 1489, 1347, 1015, 985 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.63–7.21 (m, 10H), 7.16 (s, 1H), 6.91 (s, 1H), 6.43 (s, 1H), 5.77 (s, 2H), 5.54 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 142.0 (C), 140.8 (C), 134.2 (C), 132.9 (C), 131.4 (C), 129.2 (CH), 129.0 (CH), 128.8 (CH), 128.6 (CH), 128.5 (CH), 128.0 (C), 127.1 (C), 126.8 (CH), 126.0 (C), 121.0 (CH), 114.7 (CH), 110.3 (C), 102.9 (CH), 53.5 (CH2), 44.2 (CH2). HRMS: m/z [M + H]+ calcd for C24H18ClN4: 397.1214; found: 397.1225.
2-chloro-5-phenyl-10-(3,4,5-trimethoxyphenyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2b: 74% yield; brown solid; mp: 250–252 °C; IR (neat): 2924, 1596, 1414, 1228, 1127 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.53–7.48 (m, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.42–7.39 (m, 2H), 6.83 (s, 1H), 6.80 (s, 2H), 6.49 (s, 1H), 5.62 (s, 2H), 3.91 (s, 3H), 3.85 (s, 6H); 13C NMR (100.6 MHz) (CDCl3): δ 153.9 (C), 142.1 (C), 139.6 (C), 133.3 (C), 131.9 (C), 131.4 (C), 129.4 (C), 129.0 (CH), 128.9 (CH), 128.6 (CH), 127.9 (C), 127.3 (C), 125.9 (C), 121.4 (CH), 114.7 (CH), 110.4 (C), 103.3 (CH), 103.1 (CH), 61.2 (CH3), 56.5 (2CH3), 44.1(CH2); HRMS: m/z [M + H]+ calcd for C26H22ClN4O3: 473.1375; found: 473.1383.
2-chloro-10-(3,5-dimethylphenyl)-5-phenyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2c: 87% yield; white solid; mp: 258–260 °C; IR (neat): 3179, 1380, 1259, 1170, 999 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.53–7.34 (m, 6H), 7.21–7.13 (m, 3H), 6.65 (d, J = 1.8 Hz, 1H), 6.46 (s, 1H), 5.60 (s, 2H), 2.38 (s, 6H); 13C NMR (100.6 MHz) (CDCl3): δ 142.0 (C), 140.0 (C), 139.8 (C), 136.4 (C), 133.2 (C), 132.2 (CH), 131.4 (C), 129.0 (CH), 128.8 (CH), 128.6 (CH), 128.4 (C), 127.2 (C), 125.8 (C), 123.4 (CH), 121.1 (CH), 114.6 (CH), 110.5 (C), 103.0 (CH), 44.1 (CH2), 21.3 (CH3); HRMS: m/z [M + H]+ calcd for C25H20ClN4: 411.1371; found: 411.1389.
1-(3-(2-chloro-5-phenylpyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolin-10(7H)-yl)phenyl)ethan-1-one 2d: 52% yield; yellow solid; mp: 250–252 °C; IR (neat): 3185, 1734, 1495, 1107, 662 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.24–8.14 (m, 2H), 7.81–7.70 (m, 2H), 7.52–7.38 (m, 6H), 6.56 (d, J = 1.8 Hz, 1H), 6.48 (s, 1H), 5.62 (s, 2H), 2.61 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 196.2 (C), 142.2 (C), 140.4 (C), 138.6 (C), 137.0 (C), 133.2 (C), 131.3 (C), 130.3 (CH), 130.2 (CH), 129.9 (CH), 129.0 (CH), 128.9 (CH), 128.7 (C), 128.59 (C), 128.56 (CH), 127.4 (C), 125.8 (C), 125.7 (CH), 121.6 (CH), 114.3 (CH), 110.1 (C), 103.1 (CH), 44.1 (CH2), 26.8 (CH3); HRMS: m/z [M + H]+ calcd for C25H18ClN4O: 425.1164; found: 425.1152.
10-(9H-fluoren-2-yl)-5-phenyl-2-(trifluoromethyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2e: 76% yield; brown solid; mp: 280–282 °C; IR (neat): 2921, 1487, 1294, 1109, 735 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.94 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.77–7.70 (m, 2H), 7.61–7.50 (m, 4H), 7.48–7.30 (m, 5H), 7.00 (s, 1H), 6.62 (s, 1H), 5.67 (s, 2H), 3.97 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 144.8 (C), 144.1 (C), 143.8 (C), 142.6 (C), 140.2 (C), 140.1 (C), 136.0 (C), 134.7 (C), 131.2 (C), 129.1 (CH), 128.64 (CH), 128.55 (C), 127.9 (CH), 127.2 (CH), 125.7 (C), 125.35 (CH), 125.34 (CH), 124.4 (CH), 124.7 (q, JC-F = 273.0 Hz, C), 122.9 (q, JC-F = 31.3 Hz, C), 122.5 (CH), 120.72 (CH), 120.68 (CH), 119.7 (q, JC-F = 4.4 Hz, CH), 110.8 (q, JC-F = 4.4 Hz, CH), 110.0 (C), 104.2 (CH), 44.2 (CH2), 37.0 (CH2); 19F NMR (376.5 MHz) (CDCl3): δ −60.92 (s); HRMS: m/z [M + H]+ calcd for C31H20F3N4: 505.1635; found: 505.1647.
4-(5-phenyl-2-(trifluoromethyl)pyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolin-10(7H)-yl)benzonitrile 2f: 80% yield; white solid; mp: 224–226 °C; IR (neat): 3176, 2284, 1240, 789, 655 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.84 (s, 1H), 7.67–7.52 (m, 9H), 7.00 (s, 1H), 6.73 (s, 1H), 5.75 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): 142.7 (C), 140.3 (C), 136.9 (C), 135.9 (C), 135.0 (C), 131.1 (C), 130.1 (CH), 129.1 (CH), 129.1 (CH), 128.6 (CH), 127.0 (CH), 125.8 (C), 124.5 (q, JC-F = 273.0 Hz, C), 122.9 (q, JC-F = 31.8 Hz, C), 120.0 (q, JC-F = 4.3 Hz, CH), 110.6 (q, JC-F = 4.3 Hz, CH), 109.6 (C), 104.3 (CH), 44.2 (CH2); 19F NMR (376.5 MHz) (CDCl3): δ −60.93 (s); HRMS: m/z [M + H]+ calcd for C25H15F3N5: 442.1274; found: 442.1283.
5-phenyl-2-(trifluoromethyl)-10-(3,4,5-trimethoxyphenyl)-7,10-dihydropyrrolo[3,2,1ij][1,2,3]triazolo[4,5-c]quinoline 2g: 99% yield; white solid; mp: 212–214 °C; IR (neat): 3125, 1602, 1336, 1126, 816 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.91 (s, 1H), 7.65 (s, 1H), 7.49 (s, 4H), 7.40 (s, 1H), 6.83 (s, 2H), 6.74 (s, 1H), 5.99 (s, 2H), 3.91 (s, 6H), 3.87 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 153.9 (C), 146.7 (C), 145.8 (C), 138.4 (C), 135.2 (C), 132.7 (C), 131.3 (C), 131.1 (C), 129.8 (CH), 129.2 (CH), 128.8 (CH), 124.0 (CH), 124.0 (q, JC-F = 273.0 Hz, C), 124.1 (q, JC-F = 31.8 Hz, C), 124.0 (q, JC-F = 3.6 Hz, CH), 119.9 (CH), 117.7 (q, JC-F = 3.6 Hz, CH), 105.0 (CH), 104.2 (C), 98.5 (CH), 61.0 (CH3), 56.4 (CH3), 41.5 (CH2); 19F NMR (376.5 MHz) (CDCl3): δ −60.78 (s); HRMS: m/z [M + H]+ calcd for C27H22F3N4O3: 507.1638; found: 507.1645.
10-(4-(tert-butyl)phenyl)-5-phenyl-2-(trifluoromethyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2h: 84% yield; orange solid; mp: 230–232 °C; IR (neat): 3152, 2978, 1325, 1254, 595 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.91 (s, 1H), 7.65 (s, 1H), 7.57–7.52 (m, 2H), 7.51–7.46 (m, 6H), 7.37 (s, 1H), 6.73 (s, 1H), 6.00 (s, 2H), 1.35 (s, 9H); 13C NMR (100.6 MHz) (CDCl3): δ 154.4 (C), 142.5 (C), 139.9 (C), 136.0 (C), 133.8 (C), 131.2 (C), 129.1 (CH), 128.71 (C), 128.62 (CH), 126.8 (CH), 125.67 (C), 125.45 (CH), 124.7 (q, JC-F = 273.2 Hz, C) 122.8 (q, JC-F = 31.5 Hz, C), 120.5 (d, JC-F = 4.0 Hz, C), 119.6 (q, JC-F = 3.7 Hz, CH), 110.6 (q, JC-F = 3.7 Hz, CH), 109.8 (C), 104.1 (CH), 44.2 (CH2), 35.1 (C), 31.3 (CH3); 19F NMR (376.5 MHz) (CDCl3): δ −60.93 (s); HRMS: m/z [M + H]+ calcd for C28H24F3N4: 473.1948; found: 473.1961.
methyl 10-benzyl-5-phenyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline-2-carboxylate 2i: 78% yield; white solid; mp: 242–244 °C; IR (neat): 3042, 1768, 1225, 1015, 966 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.15 (s, 1H), 7.74 (s, 1H), 7.50–7.34 (m, 5H), 7.33–7.16 (m, 5H), 6.56 (s, 1H), 5.83 (s, 2H), 5.56 (s, 2H), 3.85 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 167.4 (C), 161.4 (C), 142.1 (C), 140.4 (C), 136.8 (C), 134.3 (C), 131.3 (C), 129.1 (CH), 129.0 (CH), 128.9 (CH), 128.6 (CH), 128.5 (CH), 127.1 (CH), 125.7 (C), 124.8 (CH), 122.6 (C), 115.5 (CH), 109.1 (C), 104.6 (CH), 53.6 (CH2), 52.1 (CH3), 44.3 (CH2); HRMS: m/z [M + H]+ calcd for C26H21N4O2: 421.1659; found: 421.1677.
methyl 5-phenyl-10-(3,4,5-trimethoxyphenyl)-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo [4,5-c]quinoline-2-carboxylate 2j: 68% yield; white solid; mp: 242–244 °C; IR (neat): 3108, 2897, 1759, 1047, 987 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.34 (s, 1H), 8.12 (s, 1H), 7.48 (s, 4H), 7.42 (s, 1H), 6.83 (s, 2H), 6.74 (s, 1H), 5.99 (s, 2H), 3.96 (s, 3H), 3.90 (s, 6H), 3.87 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 166.7 (C), 153.9 (C), 147.0 (C), 145.2 (C), 138.4 (C), 136.2 (C), 132.7 (C), 131.4 (C), 131.2 (C), 129.8 (CH), 129.1 (CH), 128.8 (CH), 128.6 (CH), 123.8 (C), 122.7 (CH), 119.9 (CH), 105.5 (CH), 103.7 (C), 98.5 (CH), 61.1 (CH3), 56.5 (CH3), 52.2 (CH3), 41.6 (CH2); HRMS: m/z [M + H]+ calcd for C28H25N4O5: 497.1819; found: 497.1826.
10-benzyl-2-methyl-5-phenyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2k: 67% yield; white solid; mp: 250–252 °C; IR (neat): 3314, 3111, 1487, 1019, 971 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.65–7.42 (m, 5H), 7.42–7.22 (m, 6H), 6.91 (s, 1H), 6.53 (s, 1H), 5.91 (s, 2H), 5.67 (s, 2H), 2.37 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 140.9 (C), 140.5 (C), 134.7 (C), 133.3 (C), 132.0 (C), 129.7 (C), 129.1 (CH), 129.0 (CH), 128.9 (CH), 128.5 (CH), 128.41 (CH), 128.36 (CH), 126.8 (CH), 126.6 (C), 121.5 (CH), 116.0 (CH), 109.1 (C), 102.8 (CH), 53.4 (CH2), 44.1 (CH2), 21.7 (CH3); HRMS: m/z [M + H]+ calcd for C25H21N4: 377.1761; found: 377.1749.

3.3.2. Characterization Data of Final Compounds 3b–k

5-(3,4,5-trimethoxyphenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 3b: 92% yield; yellow solid; mp: 192–194 °C; IR (neat): 1506, 1460, 1230, 1032, 748 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.81 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22–7.15 (m, 2H), 7.05–6.99 (m, 2H), 6.77 (s, 1H), 6.53 (s, 2H), 5.33 (s, 2H), 3.80 (s, 3H), 3.65 (s, 6H); 13C NMR (100.6 MHz) (CDCl3): δ 153.8 (C), 144.6 (C), 138.9 (C), 138.5 (C), 136.9 (C), 133.7 (C), 132.2 (C), 132.1 (C), 131.6 (CH), 129.62 (CH), 128.6 (CH), 127.7 (CH), 127.6 (C), 122.7 (C), 122.6 (CH), 120.8 (CH), 120.2 (CH), 109.3 (CH), 103.9 (CH), 102.82 (CH), 61.10 (CH3), 56.40 (CH3), 39.4 (CH2). HRMS: m/z [M + H]+ calcd for C26H23N4O3: 439.1765; found: 439.1774.
5-(4-fluorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 3c: 87% yield; white solid; mp: 243–245 °C; IR (neat): 1596, 1457, 1237, 1032, 762, 669 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.80 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.34 Hz, 1H), 7.38–7.30 (m, 3H), 7.21 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.1 Hz, 1H), 7.10–7.03 (m, 3H), 6.87 (d, J = 7.8 Hz, 1H), 6.76 (s, 1H), 5.34 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 162.9 (d, JC-F = 254 Hz, C), 144.8 (C), 138.5 (C), 137.0 (C), 133.9 (C), 132.8 (d, JC-F = 3.1 Hz, C), 132.5 (C), 131.8 (CH), 129.7 (CH), 128.5 (CH), 127.8 (C), 127.7 (CH), 127.1 (d, JC-F = 8.7 Hz, CH), 122.7 (C), 122.7 (CH), 121.0 (CH), 120.2 (CH), 116.8 (d, JC-F = 22.6 Hz, CH), 109.3 (CH), 104.0 (CH), 39.5 (CH2); 19F NMR (376.5 MHz) (CDCl3): δ −110.36 (m). HRMS: m/z [M + H]+ calcd for C28H25N4O5: 497.1819; found: 497.1827.
5-(2-fluoro-4-methylphenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 3d: 83% yield; orange solid; mp: 255–257 °C; IR (neat): 1506, 1456, 1230, 1019, 989 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.78 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.34–7.26 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.10 (td, J1 = 7.9 Hz, J2 = 0.8 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.92–6.89 (m, 2H), 6.74 (s, 1H), 5.34 (s, 2H), 2.32 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 155.6 (d, JC-F = 254 Hz, C), 143.8 (C), 143.1 (d, JC-F = 7.41 Hz, C), 138.6 (C), 137.0 (C), 135.3 (C), 132.2 (C), 131.7 (CH), 129.7 (CH), 127.9 (C), 127.8 (d, JC-F = 8.1 Hz, CH), 126.9 (CH), 125.9 (d, JC-F = 3.54 Hz, CH), 122.9 (C), 122.5 (CH), 122.2 (d, JC-F = 12.56 Hz, C), 120.9 (CH), 120.1 (CH), 117.6 (d, JC-F = 18.30Hz, CH), 109.3 (CH), 104.0 (CH), 39.4 (CH2), 21.5 (CH3); 19F NMR (376.5 MHz) (CDCl3): δ −121.03 (bs). HRMS: m/z [M + H]+ calcd for C24H18FN4: 381.1510; found: 381.1531.
5-(4-methoxyphenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3e: 96% yield; white solid; mp: 211–213 °C; IR (neat): 1509, 1458, 1250, 1032, 832 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.81 (d, J1 = 8.2 Hz, J2 = 0.6 Hz 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.36 (td, J1 = 7.7 Hz, J2 = 0.7 Hz, 1H), 7.27–7.20 (m, 3H), 7.13 (td, J1 = 7.5 Hz, J2 = 1.1 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.93–6.87 (m, 3H), 6.76 (s, 1H), 5.36 (s, 2H), 3.78 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): 160.4 (C), 144.6 (C), 138.7 (C), 137.0 (C), 133.8 (C), 132.4 (C), 131.7 (CH), 129.7 (C), 129. (CH), 128.5 (CH), 127.9 (C), 127.7 (CH), 126.6 (CH), 123.1 (C), 122.6 (CH), 120.9 (CH), 120.2 (CH), 114.8 (CH), 109.4 (CH), 103.9 (CH), 55.7 (CH3), 39.5 (CH2). HRMS: m/z [M + H]+ calcd for C24H19N4O: 379.1553; found: 379.1565.
5-(2-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3f: 55% yield; white solid; mp: 210–212 °C; IR (neat): 1508, 1457, 1125, 1037, 764 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.83 (dd, J1= 7.85 Hz, J2= 0.54 Hz, 1H), 7.60 (d, J = 7.86 Hz, 1H), 7.54 (d, J = 8.40 Hz, 1H), 7.50–7.35 (m, 5H), 7.25 (td, J1= 15.39 Hz, J2= 7.67 Hz, J3= 0.92 Hz, 1H), 7.13–7.06 (m, 2H), 6.82 (dd, J1= 8.05 Hz, J2= 0.53 Hz, 1H), 6.77 (s, 1H), 5.49–5.34 (m, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 14.72 (C), 138.64 (C), 137.13 (C), 135.56 (C), 134.78 (C), 132.36 (C), 131.81 (CH), 131.71 (CH), 131.61 (C), 131.05 (CH), 129.78 (CH), 129.21 (CH), 128.22 (CH), 127.97 (C), 127.95 (CH), 127.02 (CH), 122.96 (C), 122.65 (CH), 121.04 (CH), 120.20 (CH), 109.43 (CH), 104.13 (CH), 39.54 (CH2). HRMS: m/z [M + H]+ calcd for C23H16ClN4: 383.1058; found: 383.1073.
5-(4-chlorophenyl)-3-methyl-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 3g: 86% yield; yellow solid; mp: 281–283 °C; IR (neat): 1501, 1460, 1228, 989, 750 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.63 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.37–7.35 (m, 2H), 7.29–7.27 (m, 2H), 7.23–7.19 (m, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.97 (dd, J1 = 7.9 Hz, J2 = 0.9 Hz, 1H), 6.76 (d, J = 7.8 Hz, 2H), 5.33 (s, 2H), 2.36 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 144.7 (C), 140.0 (C), 138.6 (C), 136.9 (C), 135.6 (C), 135.3 (C), 133.9 (C), 132.4 (C), 132.3 (CH), 129.9 (CH), 128.8 (CH), 128.5 (CH), 127.8 (C), 126.3 (CH), 122.6 (CH), 120.9 (CH), 120.2 (CH), 119.9 (C), 109.3 (CH), 103.8 (CH), 39.4 (CH2), 21.5 (CH3). HRMS: m/z [M + H]+ calcd for C24H18ClN4: 397.1214; found: 397.1203.
5-(4-methoxyphenyl)-3-methyl-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 3h: 88% yield; yellow solid; mp: 237–238 °C; IR (neat): 1513, 1555, 1034, 742, 670 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.63 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.26–7.20 (m, 3H), 7.05 (t, J = 7.4, 1H), 6.95 (dd, J1 = 7.9 Hz, J2 = 1.1 Hz, 1H), 6.91–6.87 (m, 2H), 6.80 (d, J = 8.05 Hz, 1H), 6.76 (s, 1H), 5.33 (s, 2H), 3.78 (s, 3H), 2.35 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 160.4 (C), 144.2 (C), 139.7 (C), 138.9 (C), 136.9 (C), 133.9 (C), 132.3 (C), 132.1 (CH), 129.8 (C), 128.7 (CH), 128.4 (CH), 127.9 (C), 126.5 (CH), 122.5 (CH), 120.9 (CH), 120.4 (C), 120.1 (CH), 114.8 (CH), 109.4 (CH), 103.7 (CH), 55.7 (CH3), 39.6 (CH2), 21.5 (CH3). HRMS: m/z [M + H]+ calcd for C25H21N4O: 393.1710; found: 393.1722.
5-benzyl-12-methyl-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a] indole 3i: 90% yield; white solid; mp: 163–165 °C; IR (neat): 1510, 1452, 1032, 762, 738 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.80 (d, J = 7.9 Hz, 1H), 7.43–7.37 (m, 2H), 7.33 (s, 1H), 7.3–7.24 (m, 5H), 7.14–7.12 (m, 2H), 7.03 (dd, J1 = 8.5 Hz, J2 = 1.3 Hz, 1H), 6.61 (s, 1H), 5.59 (s, 2H), 5.29 (s, 2H), 2.37 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 144.3 (C), 138.4 (C), 135.5 (C), 134.6 (C), 132.7 (C), 131.9 (CH), 129.8 (CH), 129.3 (C), 129.2 (CH), 128.4 (CH), 128.1 (C), 128.0 (CH), 127.7 (CH), 126.8 (CH), 124.3 (CH), 122.9 (C), 120.5 (CH), 109.1 (CH), 103.3 (CH), 52.5 (CH2), 39.6 (CH2), 21.5 (CH3). HRMS: m/z [M + H]+ calcd for C25H21N4: 377.1761; found: 377.1778.
12-methyl-5-(3,4,5-trimethoxyphenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6] azepino[1,2-a]indole 3j: 95% yield; white solid; mp: 234–236 °C; IR (neat): 1596, 1450, 1224, 1024, 1031 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ (dd, J1 =7.9 Hz, J2 = 0.78 Hz, 1H), 7.51–7.46 (m, 3H), 7.29–7.25 (m, 1H), 7.16 (dd, J1 = 8.5 Hz, J2 = 1.2 Hz, 1H), 7.10 (dd, J1 = 7.9 Hz, J2 = 0.8 Hz, 1H), 6.81 (s, 1H), 6.65 (s, 2H), 5.44 (s, 2H), 3.93 (s, 3H), 3.78 (s, 6H), 2.49 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ153.8 (C), 144.7 (C), 138.9 (C), 138.6 (C), 135.5 (C), 133.8 (C), 132.4 (C), 132.3 (C), 131.6 (CH), 129.6 (C), 129.5 (CH), 128.7 (CH), 128.1 (C), 127.5 (CH), 124.5 (CH), 122.7 (C), 120.4 (CH), 109.1 (CH), 103.4 (CH), 102.9 (CH), 61.2 (CH3), 56.5 (CH3), 39.6 (CH2), 21.5 (CH3). HRMS: m/z [M + H]+ calcd for C27H25N4O3: 453.1921; found: 453.1907.
5-(4-chlorophenyl)-12-methyl-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6] azepino [1,2-a]indole 3k: 95% yield; white solid; mp: 215–217 °C; IR (neat): 1499, 1456, 1120, 1041, 789 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ (dd, J1 = 7.9 Hz, J2 = 0.7 Hz, 1H), 7.39–7.36 (m, 5H), 7.30–7.28 (m, 2H), 7.17–7.13 (m, 1H), 7.05 (dd, J1= 8.5 Hz, J2 = 1.1 Hz, 1H), 6.88 (dd, J1 = 7.8 Hz, J2 = 0.8 Hz, 1H), 6.68 (s, 1H), 5.32 (s, 2H), 2.37 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 145.1 (C), 138.4 (C), 135.7 (C), 135.6 (C), 135.3 (C), 133.8 (C), 132.6 (C), 131.8 (CH), 130.0 (CH), 129.8 (CH), 129.5 (C), 128.6 (CH), 128.1 (C), 127.7 (CH), 126.4 (CH), 124.5 (CH), 122.6 (C), 120.5 (CH), 109.0 (CH), 103.5 (CH), 39.6 (CH2), 21.5 (CH3). HRMS: m/z [M + H]+ calcd for C24H18ClN4: 397.1214; found: 397.1228.
5-(2-fluoro-4-methylphenyl)-12-methyl-5,8-dihydrobenzo[3,4][1,2,3]triazolo [4′,5′:5,6]azepino[1,2-a]indole 3l: 90% yield; white solid; mp: 231–233 °C; IR (neat): 1499, 1448, 1338, 1053, 767 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.78 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 7.39–7.27 (m, 4H), 7.12–7.08 (m, 1H), 7.05–6.99 (m, 2H), 6.94–6.89 (m, 2H), 6.66 (s, 1H), 5.33 (s, 2H), 2.36 (s, 3H), 2.34 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 155.7 (JC-F = 253.0 Hz, C), 143.9 (C), 143.14 (JC-F = 7.5 Hz, C), 138.6 (C), 135.5 (C), 135.3 (C), 132.i4 (C), 131.7 (CH), 129.6 (CH), 129.4 (C), 128.2 (C), 127.8 (JC-F = 10.2 Hz, CH), 126.9 (CH), 125.9 (JC-F = 3.16 Hz, CH), 124.3 (CH), 122.9 (C), 122.3 (JC-F = 12.5 Hz, C), 120.5 (CH), 117.6 (JC-F = 18.8 Hz, CH), 109.0 (CH), 103.5 (CH3), 39.5 (CH2), 21.5 (CH3); 19F NMR (376.5 MHz) (CDCl3): δ −121.01 (bs). HRMS: m/z [M + H]+ calcd for C25H20FN4: 395.1666; found: 395.1681.
5-benzyl-3-(trifluoromethyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 3m: 85% yield; gray solid; mp: 227–229 °C; IR (neat): 1455, 1338, 1124, 1031, 738 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.90 (d, J = 8.2 Hz, 1H), 7.62 (dd, J1 = 8.3 Hz, J2 = 1.2 Hz, 1H), 7.57 (d, J = 8.06 Hz, 1H), 7.54–7.47 (m, 2H), 7.33–7.23 (m, 4H), 7.21 (m, 2H), 7.09–7.05 (m, 1H), 6.67 (s, 1H), 5.58 (s, 2H), 5.33 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 144.6 (C), 137.4 (C), 137.0 (C), 135.6 (C), 134.8 (C), 133.4 (C), 132.3 (CH), 131.2 (C), 130.0 (JC-F = 33.0 Hz) (C), 129.4 (CH), 128.8 (CH), 127.7 (C), 127.1 (CH), 126.2 (JC-F = 3.5 Hz, CH), 125.1 (JC-F = 3.6 Hz, CH), 123.8 (JC-F = 272.0 Hz, C), 123.4 (CH), 121.3 (CH), 120.5 (CH), 109.5 (CH), 105.2 (CH), 53.1 (CH2), 39.5 (CH2); 19F NMR (376.5 MHz) (CDCl3): δ −62.64 (s). HRMS: m/z [M + H]+ calcd for C25H18F3N4: 431.1478; found: 431.1485.
5-(4-methoxyphenyl)-3-(trifluoromethyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo [4′,5′:5,6]azepino[1,2-a]indole 3n: 84% yield; yellow solid; mp: 260–262 °C; IR (neat): 1513, 1336, 1296, 1251, 1123 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.93 (d, J = 8.3 Hz, 1H), 7.62–7.57 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.29–7.22 (m, 3H), 7.14–7.07 (m, 2H), 6.95–6.90 (m, 2H), 6.85 (s, 1H), 5.40 (s, 2H), 3.79 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 160.8 (C), 144.8 (C), 137.4 (C), 137.2 (C), 135.5 (C), 132.76 (C), 132.0 (CH), 129.6 (q, JC-F = 33.0 Hz, C), 129.1 (C), 127.8 (C), 126.6 (CH), 125.8 (q, JC-F = 3.5 Hz, CH), 125.5 (q, JC-F = 3.8 Hz, CH), 123.5 (C), 123.4 (CH), 123.2 (q, JC-F = 270.3 Hz), 121.3 (CH), 120.6 (CH), 115.09 (CH), 109.53 (CH), 105.41 (CH), 55.8 (CH3), 39.6 (CH2); 19F NMR (376.5 MHz) (CDCl3): δ −62.24 (s). HRMS: m/z [M + H]+ calcd for C25H18F3N4O: 447.1427; found: 447.1411.
12-chloro-5-(4-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 3o: 93% yield; yellow solid; mp: 273–275 °C; IR (neat): 1497, 1333, 992, 760, 539 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.81 (d, J1 = 7.9 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.43–7.38 (m, 4H), 7.4–7.28 (m, 2H), 7.20–7.16 (m, 2H), 6.91 (dd, J1 = 7.9 Hz, J2 = 0.9 Hz, 1H), 6.71 (s, 1H), 5.33 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 144.8 (C), 139.7 (C), 135.8 (C), 135.4 (C), 135.1 (C), 133.8 (C), 132.0 (C), 131.9 (CH), 130.0 (CH), 129.9 (CH), 128.7 (C), 128.6 (CH), 128.2 (CH), 126.3 (CH), 125.9 (C), 123.0 (CH), 122.7 (C), 120.3 (CH), 110.4 (CH), 103.5 (CH), 39.8 (CH3). HRMS: m/z [M + H]+ calcd for C23H15Cl2N4: 417.0668; found: 417.0653.
12-chloro-5-(3,4,5-trimethoxyphenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6] azepino[1,2-a]indole 3p: 92% yield; yellow solid; mp: 232–234 °C; IR (neat): 1605, 1461, 1125, 826, 774 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.81 (dd, J1 = 7.9 Hz, J2 = 0.7 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.43–7.38 (m, 2H); 7.24–7.14 (m, 2H); 7.02 (dd, J1 = 7.9 Hz, J2 = 0.7 Hz; 1H), 6.72 (s, 1H), 6.56 (s, 2H), 5.33 (s, 2H), 3.83 (s, 3H), 3.68 (s, 6H); 13C NMR (100.6 MHz) (CDCl3): δ 153.9 (C), 144.4 (C), 139.9 (C), 139.0 (C), 135.3 (C), 133.7 (C), 132.1 (C), 131.8 (C), 131.7 (CH), 129.8 (CH), 128.7 (CH), 128.7 (C), 128.0 (CH), 125.8 (C), 122.9 (CH), 122.8 (C), 120.2 (CH), 110.4 (CH), 103.4 (CH), 102.9 (CH), 61.2 (CH3), 56.5 (CH3), 39.8 (CH2). HRMS: m/z [M + H]+ calcd for C26H22ClN4O3: 473.1375; found: 473.1389.
methyl 5-(4-methoxyphenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6] azepino[1,2-a]indole-12-carboxylate 3q: 94% yield; white solid; mp: 200–202 °C; IR (neat): 1703, 1508, 1243, 1053, 1032 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 8.34 (d, J = 1.1 Hz, 1H), 7.90 (dd, J1 = 8.8 Hz, J2 = 1.4 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.35 (dt, J1 = 8.0 Hz, J2 = 1.1 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.15 (dt, J1 = 8.0 Hz, J2 = 1.1 Hz, 1H), 6.93–6.87 (m, 3H), 6.82 (s, 1H), 5.35 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ 168.0 (C), 160.5 (C), 144.1 (C), 140.2 (C), 139.2 (C), 133.7 (C), 131.8 (CH), 131.7 (C), 129.6 (CH), 129.5 (C), 128.5 (CH), 128.1 (CH), 127.4 (C), 126.5 (CH), 124.1 (CH), 123.7 (CH), 123.2 (C), 122.1 (C), 114.8 (CH), 109.0 (CH), 105.1 (CH), 55.7 (CH3), 51.9 (CH3), 39.9 (CH2). HRMS: m/z [M + H]+ calcd for C26H21N4O3: 437.1608; found: 437.1621.

3.3.3. Characterization Data of Post-Synthetic Derivatives Compounds 22a and 23a–c

4-(4-(pyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolin-10(7H)-yl)phenyl)morpholine 22a: 72% yield; yellow solid; mp: 190–192 °C; IR (neat): 2876, 1582, 1236, 1132, 991 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.63–7.53 (m, 1H), 7.51–7.30 (m, 5H), 7.10 (d, J = 3.2 Hz, 1H), 7.02–6.94 (m, 2H), 6.75 (t, J = 7.6 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 6.47 (d, J = 3.2 Hz, 1H), 5.68 (s, 2H), 3.83 (t, J = 4.8 Hz, 4H), 3.22 (dd, J = 6.1, 3.6 Hz, 4H); 13C NMR (100.6 MHz) (CDCl3): δ 152.4 (C), 139.0 (C), 133.6 (C), 132.9 (C), 132.2 (CH), 132.1 (CH), 132.0 (CH), 131.9 (CH), 129.9 (C), 128.6 (CH), 128.5 (CH), 128.4 (C), 126.9 (CH), 126.8 (CH), 125.9 (C), 122.5 (CH), 119.9 (CH), 115.3 (CH), 114.3 (CH), 109.4 (C), 103.6 (CH), 66.7 (CH2), 48.5 (CH2), 44.6 (CH2). HRMS: m/z [M + H]+ calcd for C21H20N5O: 358.1662; found: 358.1654.
5-(4′-methoxy-[1,1′-biphenyl]-4-yl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6] azepino[1,2-a]indole 23a: 96% yield; yellow solid; mp: 248–250 °C; IR (neat): 1460, 1340, 1058, 763, 740 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.84 (d, J = 7.7 Hz, 1H), 7.61–7.57 (m, 3H), 7.53 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.40–7.38 (m, 3H), 7.24 (td, J1 = 8.2 Hz, J3 = 0.8 Hz, 1H), 7.18 -7.16 (m, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.00 (dd, J1 = 7.9 Hz, J2 = 0.9 Hz, 1H), 6.93 (d, J = 7.7 Hz, 2H), 6.79 (s, 1H), 5.39 (s, 2H), 3.79 (s, 3H);13C NMR (100.6 MHz) (CDCl3): δ 159.9 (C), 144.9 (C), 142.2 (C), 138.7 (C), 137.0 (C), 135.2 (C), 133.8 (C), 131.4 (C), 132.0 (C), 131.8 (CH), 129.6 (CH), 128.7 (CH), 128.3 (CH), 127.8 (CH), 125.4 (CH), 123.1 (C), 122.7 (CH), 121.0 (CH), 120.2 (CH), 114.6 (CH), 109.4 (CH), 103.9 (CH), 55.5 (CH3), 39.6 (CH2). HRMS: m/z [M + H]+ calcd for C30H23N4O: 455.1866; found: 455.1879.
5-([1,1′-biphenyl]-4-yl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 23b: 98% yield; white solid; mp: 220–222 °C; IR (neat): 1439, 1160, 1054, 995, 767 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.84 (d, J = 7.9 Hz, 1H), 7.63–7.59 (m, 3H), 7.55–7.51 (m, 3H), 7.43–7.37 (m, 5H), 7.33 (m, 1H), 7.23 (td, J1 = 7.7 Hz, J2 = 0.8 Hz, 1H), 7.18–7.14 (m, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.00 (dd, J1 = 7.9 Hz, J2 = 0.6 Hz, 1H), 6.80 (s, 1H), 5.38 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 144.8 (C), 142.5 (C), 139.5 (C), 138.6 (C), 136.9 (C), 135.7 (C), 133.7 (C), 132.4 (C), 131.7 (CH), 129.6 (CH), 129.0 (CH), 128.7 (CH), 128.2 (CH), 128.1 (CH), 127.8 (C), 127.7 (CH), 127.2 (CH), 125.3 (CH), 122.9 (C), 122.6 (CH), 120.9 (CH), 120.1 (CH), 109.3 (CH), 103.8 (CH), 39.5 (CH2). HRMS: m/z [M + H]+ calcd for C29H21N4: 425.1766; found: 425.1753.
5-(4-(thiophen-2-yl)phenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino [1,2-a]indole 23c: 71% yield; gray solid; mp: 218–220 °C; IR (neat): 1458, 1319, 1032, 994, 728 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ 7.83 (d, J = 8.0 Hz, 1H), 7.62–7.59 (m, 3H), 7.52 (d, J = 8.3, 1H), 7.46–7.44 (m, 1H), 7.39–7.32 (m, 5H), 7.23 (dt, J1 = 6.9 Hz, J2 = 0.8 Hz, 1H), 7.17–7.12 (m, 1H), 7.07 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 7.86 Hz, 1H), 6.79 (s, 1H), 5.33 (s, 2H); 13C NMR (100.6 MHz) (CDCl3): δ 144.9 (C), 140.8 (C), 138.6 (C), 137.2 (C), 137.0 (C), 135.4 (C), 133.8 (C), 132.4 (C), 131.8 (CH), 129.6 (CH), 128.7 (CH), 127.9 (C), 127.8 (CH), 127.5 (CH), 127.0 (CH), 126.2 (CH), 126.0 (C),125.5 (CH), 122.7 (CH), 121.6 (CH), 121.0 (CH), 120.2 (CH), 109.4 (CH), 103.9 (CH), 39.6 (CH2). HRMS: m/z [M + H]+ calcd for C27H19N4S: 431.1330; found: 431.1346.

4. Conclusions

We have developed an efficient protocol for the synthesis of polysubstituted 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline and 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole from bromo-substituted N-propargyl-indoles. The reaction conditions exhibit broad functional group tolerance, accommodating halogens, alkoxy, cyano, ketone, and ester functionalities, with yields from good to high. Notably, their compatibility with chloro substituent provides a valuable handle for further molecular diversification through transition metal-catalyzed transformations, expanding the synthetic utility of this methodology.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30122588/s1. References [39,43,44] are cited in Supplementary Materials.

Author Contributions

Conceptualization, G.F. and A.I.; methodology, A.I. and A.G.; formal analysis, G.F. and A.G.; investigation, D.A., Y.G., F.M., F.S., R.Z. and K.U.; writing—original draft preparation, G.F. and A.G.; writing—review and editing, A.I.; supervision, G.F. and A.I.; project administration, G.F.; funding acquisition, G.F. All authors have read and agreed to the published version of the manuscript.

Funding

This work is part of the activities of the National Center for Gene Therapy and Drugs Based on RNA Technology, funded in the framework of the National Recovery and Resilience Plan (NRRP), Mission 4 “Education and Research”, Component 2 “From Research to Business”, Investment 1.4 “Strengthening research structures for supporting the creation of National Centers, national R&D leaders on some Key Enabling Technologies”, funded by the European Union—Next Generation EU, Project CN00000041, CUP B93D21010860004, Spoke 2.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article or Supplementary Materials.

Acknowledgments

We gratefully acknowledge the Sapienza University of Rome and Catholic University of Sacred Heart, Rome. Some of the experimental data presented in this manuscript are derived from the PhD theses of Allevi and Ullah, carried out, respectively, under the supervision of Iazzetti at Università Cattolica del Sacro Cuore and Fabrizi at Sapienza.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 02588 g001
Figure 1. Natural products, biologically active compounds, and red-emitting dopants containing 5,6-dihydro-4H-pyrrolo [3,2,1-ij]quinoline and azepino[1,2-a]indole scaffold.
Figure 1. Natural products, biologically active compounds, and red-emitting dopants containing 5,6-dihydro-4H-pyrrolo [3,2,1-ij]quinoline and azepino[1,2-a]indole scaffold.
Molecules 30 02588 g001
Molecules 30 02588 sch001
Scheme 1. This work. (a): construction of 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline nucleus; (b): construction of 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole nucleus.
Scheme 1. This work. (a): construction of 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline nucleus; (b): construction of 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole nucleus.
Molecules 30 02588 sch001
Molecules 30 02588 sch002
Scheme 2. CuAAC with functionalized halo N-propargyl indoles 7, 8, and 9.
Scheme 2. CuAAC with functionalized halo N-propargyl indoles 7, 8, and 9.
Molecules 30 02588 sch002
Molecules 30 02588 sch003
Scheme 3. Preparation of 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a.
Scheme 3. Preparation of 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a.
Molecules 30 02588 sch003
Molecules 30 02588 sch004
Scheme 4. Retrosynthetic approach for assembly of 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolines 2 and 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indoles 3 derivatives.
Scheme 4. Retrosynthetic approach for assembly of 7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinolines 2 and 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indoles 3 derivatives.
Molecules 30 02588 sch004
Molecules 30 02588 sch005
Scheme 5. Synthesis of 5-(4-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3a from 2-(2-bromophenyl)-1-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-indole 6a on a 0.30 mmol scale and a gram scale.
Scheme 5. Synthesis of 5-(4-chlorophenyl)-5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3a from 2-(2-bromophenyl)-1-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-indole 6a on a 0.30 mmol scale and a gram scale.
Molecules 30 02588 sch005
Molecules 30 02588 sch006
Scheme 6. Post-synthetic modification of 1e and 3a. Path (a): reactions were carried out on a 0.25 mmol scale using 1.0 equiv. of 1e or 3a, 1.5 equiv. of boronic acid derivatives, 0.02 equiv. of Pd2(dba)3, 0.04 equiv. of Sphos, and 3.0 equiv. of K3PO4 in 2.0 mL of dry 1,4-dioxane under argon at 100 °C. Path (b): reaction was carried out on a 0.25 mmol scale using 1.0 equiv. of 1e or 3a, 1.5 equiv. of morpholine, 0.02 equiv. of Pd2(dba)3, 0.04 equiv of Xphos, and 2.0 equiv. of tBuOK in 2.0 mL of dry toluene under argon at 100 °C.
Scheme 6. Post-synthetic modification of 1e and 3a. Path (a): reactions were carried out on a 0.25 mmol scale using 1.0 equiv. of 1e or 3a, 1.5 equiv. of boronic acid derivatives, 0.02 equiv. of Pd2(dba)3, 0.04 equiv. of Sphos, and 3.0 equiv. of K3PO4 in 2.0 mL of dry 1,4-dioxane under argon at 100 °C. Path (b): reaction was carried out on a 0.25 mmol scale using 1.0 equiv. of 1e or 3a, 1.5 equiv. of morpholine, 0.02 equiv. of Pd2(dba)3, 0.04 equiv of Xphos, and 2.0 equiv. of tBuOK in 2.0 mL of dry toluene under argon at 100 °C.
Molecules 30 02588 sch006
Molecules 30 02588 sch007
Scheme 7. Proposed reaction mechanism.
Scheme 7. Proposed reaction mechanism.
Molecules 30 02588 sch007
Table 1. Optimization studies for the synthesis of 10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a from 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a a.
Table 1. Optimization studies for the synthesis of 10-benzyl-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1a from 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-7-bromo-1H-indole 4a a.
Molecules 30 02588 i001
EntryCatalystLigandBaseSolventT (°C)Time (h)Yield (%) b
1 cCuI1,10-PhenLi2CO3DMF12048-
2 cCuI1,10-PhenK2CO3DMSO12048-
3 cCuIDMEDACs2CO3DMF12048-
4 cCuOAc1,10-PhenK2CO3DMF12048-
5 cCuBr1,10-PhenK2CO3DMF12048-
6Pd(OAc)2DavePhosCs(OAc)DMF120214 d
7Pd(OAc)2PPh3Cs(OAc)DMF120168
8Pd(OAc)2PPh3Cs(OAc)DMSO120180
9Pd(OAc)2PPh3Cs(OAc)DMSO100269
10Pd(OAc)2PPh3Cs(OAc)DMSO80458
11Pd(OAc)2PPh3Cs(OAc)1,4-dioxane10024-
12Pd(OAc)2PPh3Cs(OAc)MeCN100225
13 ePd(OAc)2PPh3Cs(OAc)DMSO120160
a Unless otherwise stated, reactions were carried out on a 0.30 mmol scale under an argon atmosphere using 0.05 equiv. of catalyst, 0.20 equiv. of ligand, 2.0 equiv. of base in 2.0 mL of solvent. b Yields are given for isolated products. c 0.10 equiv. of ligand. d 1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1H-indole was isolated in 42%. e The reaction was carried out using 0.02 equiv. of catalyst, 0.08 equiv. of ligand, and 2 equiv. of base.
Table 2. Synthesis of 10-substituted-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1 from 4 through a palladium-catalyzed C–H activation a,b.
Table 2. Synthesis of 10-substituted-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 1 from 4 through a palladium-catalyzed C–H activation a,b.
Molecules 30 02588 i002
Molecules 30 02588 i003
a Unless otherwise stated, reactions were carried out on a 0.30 mmol scale under an argon atmosphere using 0.05 equiv. of Pd(OAc)2, 0.20 equiv. of PPh3, 2.0 equiv. of CsOAc in 2.0 mL of anhydrous DMSO at 120 °C. b Yields are given for isolated products.
Table 3. Synthesis of functionalized 2,5,10-trisubstituted-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2 from 5 through a palladium-catalyzed C–H activation a,b.
Table 3. Synthesis of functionalized 2,5,10-trisubstituted-7,10-dihydropyrrolo[3,2,1-ij][1,2,3]triazolo[4,5-c]quinoline 2 from 5 through a palladium-catalyzed C–H activation a,b.
Molecules 30 02588 i004
Molecules 30 02588 i005
a Unless otherwise stated, reactions were carried out on a 0.30 mmol scale under an argon atmosphere using 0.05 equiv. of Pd(OAc)2, 0.20 equiv. of PPh3, and 2.0 equiv. of CsOAc in 2.0 mL of anhydrous DMSO at 120 °C. b Yields are given for isolated products.
Table 4. Synthesis of polysubstituted 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3 from 6 through a palladium-catalyzed C–H activation a,b.
Table 4. Synthesis of polysubstituted 5,8-dihydrobenzo[3,4][1,2,3]triazolo[4′,5′:5,6]azepino[1,2-a]indole 3 from 6 through a palladium-catalyzed C–H activation a,b.
Molecules 30 02588 i006
Molecules 30 02588 i007
a Unless otherwise stated, reactions were carried out on a 0.30 mmol scale under an argon atmosphere using 0.05 equiv. of Pd(OAc)2, 0.20 equiv of PPh3, and 2.0 equiv. of CsOAc in 2.0 mL of anhydrous DMSO at 120 °C. b Yields are given for isolated products.
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Iazzetti, A.; Allevi, D.; Fabrizi, G.; Gazzilli, Y.; Goggiamani, A.; Marrone, F.; Stipa, F.; Ullah, K.; Zoppoli, R. Construction of 1,2,3-Triazole-Embedded Polyheterocyclic Compounds via CuAAC and C–H Activation Strategies. Molecules 2025, 30, 2588. https://doi.org/10.3390/molecules30122588

AMA Style

Iazzetti A, Allevi D, Fabrizi G, Gazzilli Y, Goggiamani A, Marrone F, Stipa F, Ullah K, Zoppoli R. Construction of 1,2,3-Triazole-Embedded Polyheterocyclic Compounds via CuAAC and C–H Activation Strategies. Molecules. 2025; 30(12):2588. https://doi.org/10.3390/molecules30122588

Chicago/Turabian Style

Iazzetti, Antonia, Dario Allevi, Giancarlo Fabrizi, Yuri Gazzilli, Antonella Goggiamani, Federico Marrone, Francesco Stipa, Karim Ullah, and Roberta Zoppoli. 2025. "Construction of 1,2,3-Triazole-Embedded Polyheterocyclic Compounds via CuAAC and C–H Activation Strategies" Molecules 30, no. 12: 2588. https://doi.org/10.3390/molecules30122588

APA Style

Iazzetti, A., Allevi, D., Fabrizi, G., Gazzilli, Y., Goggiamani, A., Marrone, F., Stipa, F., Ullah, K., & Zoppoli, R. (2025). Construction of 1,2,3-Triazole-Embedded Polyheterocyclic Compounds via CuAAC and C–H Activation Strategies. Molecules, 30(12), 2588. https://doi.org/10.3390/molecules30122588

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