Silver-Catalyzed Cascade Cyclization of Amino-NH-1,2,3-Triazoles with 2-Alkynylbenzaldehydes: An Access to Pentacyclic Fused Triazoles

An operationally simple Ag(I)-catalyzed approach for the synthesis of isoquinoline and quinazoline fused 1,2,3-triazoles was developed by a condensation and amination cyclization cascade of amino-NH-1,2,3-triazoles with 2-alkynylbenzaldehydes involving three new C-N bond formations in one manipulation, in which the group of -NH of the triazole ring serves as a nucleophile to form the quinazoline skeleton. The efficient protocol can be applied to a variety of substrates containing a range of functional groups, delivering novel pentacyclic fused 1,2,3-triazoles in good-to-excellent yields.


Results and Discussion
At the outset of our studies, the cascade reaction between 2-(1H-1,2,3-triazol-5-yl)aniline 1a and 2-alkynylbenzaldehyde 2a was investigated as a model (Table 1). To our delight, the reaction proceeded very successfully in the presence of 10 mol% AgNO 3 at 80 • C for 1 hour using DMF as a solvent, delivering the product isoquinolino [2,1-a] [1-3] triazolo [1,5-c] quinazoline 3aa with excellent yield (82%) (Entry 1). The structure of 3aa was unambiguously confirmed by X-ray crystallography analysis (CCDC NO: 2133327) (see Supplementary Materials) [80]. The screening of solvents was then performed. Unfortunately, we found that other solvents, including toluene, DCE, MeCN, and DMSO, were less effective than DMF (Entries 2-5). Increasing or decreasing the temperature of the reaction could not lead to any further improvements in the yield (Entries 6-8). Changing the catalyst to AgOTf resulted in a slightly decreased yield, and the desired product 3aa was obtained with 76% yield (Entry 9). However, the reaction proceeded very reluctantly in the presence of other catalysts (Ag 2 O, Ag 2 CO 3 , and AgOAc, without any target molecules detected (Entry 10-12)). When CuSCN or CuI is used instead of AgNO 3 , the yield drops sharply (Entry 13-14). However, the yield of the reaction slightly decreased when different amounts of AgNO 3 catalyst were used (Entry 15-17). After testing different reaction concentrations, 0.2 M DMF was kept as the optimum one (Entry [18][19]. Lastly, when the reaction time was extended to 2 hours, the target product was obtained in excellent 92% yield (Entry 20).
With the optimized reaction conditions in hand (Table 1, entry 18), the substrate scope of the cascade cyclization reaction was investigated with o-alkynyl aldehydes first. To our delight, a variety of o-alkynyl aldehydes with different alkynyl bearing substituted groups (including various aryl, alkyl, and heteroaryl) could work efficiently with 2-(1H-1,2,3-triazol-5-yl)aniline (1a), as shown in Figure 2. Reactions of alkynylbenzaldehydes containing electron-donating (3ab-3af) and electron-withdrawing (3ag-3al) groups on the phenyl ring proceeded smoothly to afford the corresponding products in moderate-to-good yields (37-88%). Generally, electron-donating groups substituted with alkynylbenzaldehyde (3ab-3af) were more successfully converted into target products than those with strong electron-withdrawing groups (3ak-3al). It should be noted that alkynylarylaldehyde with 2-pyridyl (3aq) was also suitable for this reaction, furnishing the corresponding products in satisfactory yield. Unfortunately, to substrates with aliphatic groups. such as pentyl, methoxymethyl, and hydroxymethyl on the 2-position of the alkynyl moiety (3an-3ap), the reaction could not provide the desired product. Surprisingly, when 2-((trimethylsilyl)ethynyl)benzaldehyde 2m was used, the desilylation product (3am) was obtained in a low yield of 16%. Then, the effects of substituents on the core benzene ring linked directly to the formyl group were also studied. It was found that both electron-rich (-Me and -OMe) and -poor (-F, -Cl, and -CF 3 ) groups were well tolerated in the reactions, and good yields were obtained (3ar-3av). Table 1. Optimization of the reaction conditions a .

Entry
Sol groups (including various aryl, alkyl, and heteroaryl) could work efficiently with 2-(1H-1,2,3-triazol-5-yl)aniline (1a), as shown in Figure 2. Reactions of alkynylbenzaldehydes containing electron-donating (3ab-3af) and electron-withdrawing (3ag-3al) groups on the phenyl ring proceeded smoothly to afford the corresponding products in moderateto-good yields (37-88%). Generally, electron-donating groups substituted with alkynylbenzaldehyde (3ab-3af) were more successfully converted into target products than those with strong electron-withdrawing groups (3ak-3al). It should be noted that alkynylarylaldehyde with 2-pyridyl (3aq) was also suitable for this reaction, furnishing the corresponding products in satisfactory yield. Unfortunately, to substrates with aliphatic groups. such as pentyl, methoxymethyl, and hydroxymethyl on the 2-position of the alkynyl moiety (3an-3ap), the reaction could not provide the desired product. Surprisingly, when 2-((trimethylsilyl)ethynyl)benzaldehyde 2m was used, the desilylation product (3am) was obtained in a low yield of 16%. Then, the effects of substituents on the core benzene ring linked directly to the formyl group were also studied. It was found that both electron-rich (-Me and -OMe) and -poor (-F, -Cl, and -CF3) groups were well tolerated in the reactions, and good yields were obtained (3ar-3av). To gain further insight into the reaction, we continued our study by examining the 2-(1H-1,2,3-triazol-5-yl)aniline substrate scope, as shown in Figure 3. Gratifyingly, different electron-withdrawing group (-F, -Cl, -Br, -CN) and electron-donating group of -Me on 4or 5-position of the phenyl ring (3ba-3ja) were perfectly tolerated, with the corresponding products obtained in moderate-to-good yields (60-88%).
To illustrate the synthetic applicability of the protocol, the reaction was conducted on a gram-scale. A reaction of 5 mmol of 1a and 2a in 25 mL of DMF was carried out, and it could proceed smoothly under the optimized conditions to produce the product 3aa in 92% (1.60 g) yield within 2 h (Scheme 2).  To gain further insight into the reaction, we continued our study by examining the 2-(1H-1,2,3-triazol-5-yl)aniline substrate scope, as shown in Figure 3. Gratifyingly, different electron-withdrawing group (-F, -Cl, -Br, -CN) and electron-donating group of -Me on 4-or 5-position of the phenyl ring (3ba-3ja) were perfectly tolerated, with the corresponding products obtained in moderate-to-good yields (60-88%). To illustrate the synthetic applicability of the protocol, the reaction was conducted on a gram-scale. A reaction of 5 mmol of 1a and 2a in 25 mL of DMF was carried out, and it could proceed smoothly under the optimized conditions to produce the product 3aa in 92% (1.60 g) yield within 2 h (Scheme 2).

Scheme 2. Gram scale experiment.
Based on our studies and previous reports [72][73][74][75], a plausible mechanism for the formation of target product 3aa is presented in Scheme 3. The condensation reaction of 2- on 4-or 5-position of the phenyl ring (3ba-3ja) were perfectly tolerated, with the corresponding products obtained in moderate-to-good yields (60-88%). To illustrate the synthetic applicability of the protocol, the reaction was conducted on a gram-scale. A reaction of 5 mmol of 1a and 2a in 25 mL of DMF was carried out, and it could proceed smoothly under the optimized conditions to produce the product 3aa in 92% (1.60 g) yield within 2 h (Scheme 2).

Scheme 2. Gram scale experiment.
Based on our studies and previous reports [72][73][74][75], a plausible mechanism for the formation of target product 3aa is presented in Scheme 3. The condensation reaction of 2- imine carbon center to form intermediate 5 (the first amination). Intramolecular proton transfer then occurred, producing fused tricyclic intermediate 6, which would undergo a second intramolecular nucleophilic attack of the −NH group onto the triple bond, upon the π-activation by AgNO3, to afford 7 (the second (hydro-) amination), then deliver the desired compound 3aa through protonolysis. Alternatively (path B), from the N-nucleophilic attack of the imine to the triple bond activated by AgNO3, imine cation intermediate 5' could be formed initially, followed by intramolecular nucleophilic attack of triazole's N 3 to the carbon center of the formed imine to produce the fused pentacyclic intermediate 6', which would then give the final compound 3aa through the subsequent deprotonation. Scheme 3. Proposed mechanism. [81,82] A 15 mL flask equipped with a magnetic stir bar was charged with 2-iodoaniline S1 (2 mmol), trimethylsilylacetylene S2 (3 mmol), bis(triphenylphosphine)palladium(II) chloride (1 mol%), cuprous iodide (5 mol%), and 5 mL of triethylamine. The solution was stirred at room temperature under argon for 12 h. Upon completion of the reaction, the Scheme 3. Proposed mechanism.
A 15 mL flask equipped with a magnetic stir bar was charged with 2-((trimethylsilyl)eth ynyl)aniline S3 (2 mmol), potassium carbonate (4 mmol), and 5 mL of methanol. The solution was stirred at room temperature for 4 h. Upon completion of the reaction, the mixture was added to H 2 O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (3 × 5 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to afford product S4 (Scheme 4).
Molecules 2022, 27, x FOR PEER REVIEW 8 of 12 solvent was evaporated under vacuum, and the crude product was purified by column chromatography on silica gel (EtOAc:Petrol = 1:50), giving the pure product S3 (Scheme 4).

Scheme 4. Synthesis of substrate 1a.
A 15 mL flask equipped with a magnetic stir bar was charged with 2-((trimethylsilyl)ethynyl)aniline S3 (2 mmol), potassium carbonate (4 mmol), and 5 mL of methanol. The solution was stirred at room temperature for 4 h. Upon completion of the reaction, the mixture was added to H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (3 × 5 mL), dried over Na2SO4, and concentrated under reduced pressure to afford product S4 (Scheme 4).

Scheme 4. Synthesis of substrate 1a.
A 15 mL flask equipped with a magnetic stir bar was charged with 2-((trimethylsilyl)ethynyl)aniline S3 (2 mmol), potassium carbonate (4 mmol), and 5 mL of methanol. The solution was stirred at room temperature for 4 h. Upon completion of the reaction, the mixture was added to H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (3 × 5 mL), dried over Na2SO4, and concentrated under reduced pressure to afford product S4 (Scheme 4).

General Procedure for Synthesis Pentacyclic Fused Triazoles (Take 3aa as An Example)
A 15 mL flask equipped with a magnetic stir bar was charged with 2-(1H-1,2,3-triazol-5-yl)aniline 1a (0.2 mmol), 2-alkynylbenzaldehyde 2a (0.2 mmol), and 1 mL of DMF. The solution was stirred at 80 • C under air for 2 h. Upon completion of the reaction, the mixture was added to H 2 O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (3 × 5 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to afford a crude product. Purification by column chromatography on silica gel (EtOAc:Petrol = 1:3) afforded the desired product 3aa.

Conclusions
In summary, we developed a cascade process of condensation/in-situ generated imine and alkyne aminations of 2-(1H-1,2,3-triazol-5-yl)anilines with 2-alkynylbenzaldehydes catalyzed by AgNO 3 to deliver novel isoquinoline and quinazoline-fused 1,2,3-triazoles in good-to-excellent yields. The methodology mainly features three new C-N bond formations in one convenient manipulation to construct various pentacyclic fused 1,2,3-triazoles, which may possess broad potential applications. Furthermore, the gram-scale reaction, broad substrate scope, excellent functional-group compatibility, and H 2 O as the only by-product, further demonstrate the atomic economy of this method.