Synthesis of Functionalized 3H-pyrrolo-[1,2,3-de] Quinoxalines via Gold-Catalyzed Intramolecular Hydroamination of Alkynes

A gold-catalyzed protocol to obtain functionalized 3H-pyrrolo [1,2,3-de] quinoxalines from suitable substituted N-alkynyl indoles has been proposed. The mild reaction conditions were revealed to be compatible with different functional groups, including halogen, alkoxyl, cyano, ketone, and ester, allowing the isolation of title compounds with yields from good to high. A reaction mechanism has been proposed, and theoretical calculations have been provided to rationalize the final step of the hypothesized reaction mechanism. As quinoxaline-containing polycyclic compounds, this class of molecules may represent a valuable template in medicinal chemistry and material science.


Introduction
Nitrogen-containing heterocycles are a class of compounds of great importance to life science since they are present as scaffolds in several biologically active natural products and synthetic drugs [1]. For this reason, a great deal of attention has been devoted to the development of methods for their preparation and, in particular, to those catalytic protocols that overcome the limitations of traditional C-N bond-forming reactions. In this regard, the transition metal-catalyzed hydroamination assumed great significance [2], with a lot of expedient routes based on gold catalysis [2][3][4][5].
We previously described a domino approach to 4-substituted 1,5-benzodiazepines based on the reactive sequence gold-catalyzed hydroamination/cyclization [6] (Scheme 1a), as well as a stereo and regioselective approach to Z-enamine products via an intermolecular gold-catalyzed reaction of the 2-(arylethynyl)pyridines with anilines [7] (Scheme 1b). Continuing our investigations in this research field, we focused on the intra-molecular gold-catalyzed hydroamination as a tool for the construction of condensed polycyclic structures, envisaging the possibility of obtaining the 3H-pyrrolo-[1,2,3-de] quinoxalines 2 starting from suitable substituted N-alkynyl indoles 1 (Scheme 1c).
To the best of our knowledge, the derivatives of which the synthesis was pursued are unknown compounds with a rather infrequently reported heterocyclic core [8,9]. Extensive state-of-the-art studies revealed a lack of methods to achieve their construction, even though their synthesis might be of interest in medicinal chemistry. Indeed, the tricyclic quinoxaline-containing compounds are widespread in a variety of therapeutic agents such as anti-HIV [10], antiparasitic [11][12][13][14], and antitumoral [15] (Figure 1), and make our new condensed cyclic systems promising candidates for diverse uses. To the best of our knowledge, the derivatives of which the synthesis was pursued are unknown compounds with a rather infrequently reported heterocyclic core [8,9]. Extensive state-of-the-art studies revealed a lack of methods to achieve their construction, even though their synthesis might be of interest in medicinal chemistry. Indeed, the tricyclic quinoxaline-containing compounds are widespread in a variety of therapeutic agents such as anti-HIV [10], antiparasitic [11][12][13][14], and antitumoral [15] (Figure 1), and make our new condensed cyclic systems promising candidates for diverse uses. To the best of our knowledge, the derivatives of which the synthesis was pursued are unknown compounds with a rather infrequently reported heterocyclic core [8,9]. Extensive state-of-the-art studies revealed a lack of methods to achieve their construction, even though their synthesis might be of interest in medicinal chemistry. Indeed, the tricyclic quinoxaline-containing compounds are widespread in a variety of therapeutic agents such as anti-HIV [10], antiparasitic [11][12][13][14], and antitumoral [15] (Figure 1), and make our new condensed cyclic systems promising candidates for diverse uses.  In addition, the 3H-pyrrolo-[1,2,3-de] quinoxalines 2 may be structurally related to a class of compounds with antiapoptotic activity acting as potent inhibitors of the Mcl-1 protein ( Figure 2) [16]. In addition, the 3H-pyrrolo-[1,2,3-de] quinoxalines 2 may be structurally related to a class of compounds with antiapoptotic activity acting as potent inhibitors of the Mcl-1 protein ( Figure 2) [16]. As to industrial applications, substituted quinoxalines and their derivatives are known as metal corrosion inhibitors and are often found as constituents of electroluminescent materials [17].
Given this broad range of applications of quinoxaline derivatives and the gap of synthetic methodology for the 3H-pyrrolo-[1,2,3-de] quinoxalines, we decided to study the cyclization of the indole derivatives 1, which were suitably designed to provide an intramolecular gold-catalyzed hydroamination reaction. The proposed methodology is strongly based on the background of the research group, which has been continuously devoted to the construction and functionalization of indoles.

Results and Discussion
Substrates for our studies have been synthesized according to slightly modified known procedures depicted in the following Scheme 2 (for a detailed description of the procedures, see Materials and Methods (Section 3)).  As to industrial applications, substituted quinoxalines and their derivatives are known as metal corrosion inhibitors and are often found as constituents of electroluminescent materials [17].
Given this broad range of applications of quinoxaline derivatives and the gap of synthetic methodology for the 3H-pyrrolo-[1,2,3-de] quinoxalines, we decided to study the cyclization of the indole derivatives 1, which were suitably designed to provide an intramolecular gold-catalyzed hydroamination reaction. The proposed methodology is strongly based on the background of the research group, which has been continuously devoted to the construction and functionalization of indoles.

Results and Discussion
Substrates for our studies have been synthesized according to slightly modified known procedures depicted in the following Scheme 2 (for a detailed description of the procedures, see Materials and Methods (Section 3)).
Molecules 2023, 28, x FOR PEER REVIEW 3 In addition, the 3H-pyrrolo-[1,2,3-de] quinoxalines 2 may be structurally related class of compounds with antiapoptotic activity acting as potent inhibitors of the M protein ( Figure 2) [16]. As to industrial applications, substituted quinoxalines and their derivative known as metal corrosion inhibitors and are often found as constituent electroluminescent materials [17].
Given this broad range of applications of quinoxaline derivatives and the ga synthetic methodology for the 3H-pyrrolo-[1,2,3-de] quinoxalines, we decided to stud cyclization of the indole derivatives 1, which were suitably designed to provid intramolecular gold-catalyzed hydroamination reaction. The proposed methodolo strongly based on the background of the research group, which has been continuo devoted to the construction and functionalization of indoles.

Results and Discussion
Substrates for our studies have been synthesized according to slightly mod known procedures depicted in the following Scheme 2 (for a detailed description o procedures, see Materials and Methods (Section 3)). Based on the working hypothesis (Scheme 1c), the reaction of substrate 1a was selected as the model system for a series of preliminary experiments aimed at identifying the best reaction conditions. For our first attempt, we decided to perform the reaction under the same condition previously used for the synthesis of 1,5-benzodiazepines [6]. Pleasingly, a smooth gold-catalyzed intramolecular hydroamination of 1a took place, and the 6-exo-dig cyclization product 2a was isolated in almost quantitative yield after 1 h ( Table 1, entry 1). Table 1. Synthesis of 2-benzyl-7-chloro-5-phenyl-3H-pyrrolo [1,2,3-de]quinoxaline 2a from 4-chloro-2phenyl-1-(3-phenylprop-2-yn-1-yl)-1H-indol-7-amine 1a. selected as the model system for a series of preliminary experiments aimed at identifying the best reaction conditions. For our first attempt, we decided to perform the reaction under the same condition previously used for the synthesis of 1,5-benzodiazepines [6]. Pleasingly, a smooth gold-catalyzed intramolecular hydroamination of 1a took place, and the 6-exo-dig cyclization product 2a was isolated in almost quantitative yield after 1 h ( Table 1, entry 1). 1 Reactions were carried out with 0.25 mmol of 1 in 1.0 mL of solvent and in the presence of a catalyst in the reported mmol percentage. 2 Yields are given for isolated products. 3 JP = JohnPhos. 4 A total of 55% of starting material 1 recovered. 5 A total of 14% of starting material 1 recovered. 6 In this condition, a mixture of degradation compounds was obtained.
Given the high reaction rate, we decided to carry out the reaction at room temperature, obtaining similar results in terms of yield even though with a longer reaction time (Table 1, entry 2). A lower yield (42%) was obtained by switching to the PPh3AuCl/AgSbF6 combination (Table 1, entry 3), with a significant amount of starting material (55%) recovered after 24 h. The reaction was also performed in the presence of other transition metal catalysts leading to worse results in terms of efficiency, time, and harsher reaction conditions. Indeed, the use of PtCl2 resulted in a slower and less efficient cyclization at 80 °C (Table 1, entry 4), while, at the same temperature, using PdCl2(CH3CN)2, the final compound 2a was isolated in 36% yield, along with degradation compounds (Table 1, entry 5). Switching to the Brønsted acid catalyst TsOH, poor results were observed in obtaining a 2 h mixture of degradation compounds (Table 1, entry 6). In this case, very likely, the formation of the imine derivative 2a also occurred, but in the acidic reaction conditions, it was rapidly degraded.
Once we established the best reaction conditions, we investigated this method's scope. Variously substituted quinoxaline derivatives were obtained in good to excellent yield both in the presence of electron-donating groups and electron-withdrawing groups ( Reactions were carried out with 0.25 mmol of 1 in 1.0 mL of solvent and in the presence of a catalyst in the reported mmol percentage. 2 Yields are given for isolated products. 3 JP = JohnPhos. 4 A total of 55% of starting material 1 recovered. 5 A total of 14% of starting material 1 recovered. 6 In this condition, a mixture of degradation compounds was obtained. Given the high reaction rate, we decided to carry out the reaction at room temperature, obtaining similar results in terms of yield even though with a longer reaction time (Table 1, entry 2). A lower yield (42%) was obtained by switching to the PPh 3 AuCl/AgSbF 6 combination (Table 1, entry 3), with a significant amount of starting material (55%) recovered after 24 h. The reaction was also performed in the presence of other transition metal catalysts leading to worse results in terms of efficiency, time, and harsher reaction conditions. Indeed, the use of PtCl 2 resulted in a slower and less efficient cyclization at 80 • C ( Table 1, entry  4), while, at the same temperature, using PdCl 2 (CH 3 CN) 2, the final compound 2a was isolated in 36% yield, along with degradation compounds (Table 1, entry 5). Switching to the Brønsted acid catalyst TsOH, poor results were observed in obtaining a 2 h mixture of degradation compounds (Table 1, entry 6). In this case, very likely, the formation of the imine derivative 2a also occurred, but in the acidic reaction conditions, it was rapidly degraded.
Once we established the best reaction conditions, we investigated this method's scope. Variously substituted quinoxaline derivatives were obtained in good to excellent yield both in the presence of electron-donating groups and electron-withdrawing groups (Table 2).
Notably, in all experiments, compound 2 was the only observed product, with no traces of any 7-endo-dig cyclization product (compounds 8 and 8 , Figure 3).  Notably, in all experiments, compound 2 was the only observed product, with no traces of any 7-endo-dig cyclization product (compounds 8 and 8′, Figure 3). The formation of 2 may be rationalized based on the general mechanism of the goldcatalyzed hydroamination [18] through the basic steps shown in Scheme 3. Particularly, the hydroamination intermediate IV is formed by admitting the nucleophilic addition of the amine group towards the triple bond activated by the Au(I) coordination (I) followed by a protodeauration step (Scheme 3).   1e Reactions were carried out on 0.25 mmol of 1 in 1.0 mL of CH2Cl2, in the presence of 0.02 equiv of JPAu(CH3CN)SbF6. 2 Yields are given for isolated products. 3 Degradation compounds. 4 Starting material 1k has been prepared according to the procedure detailed in Supplementary Materials.
Notably, in all experiments, compound 2 was the only observed product, with no traces of any 7-endo-dig cyclization product (compounds 8 and 8′, Figure 3). The formation of 2 may be rationalized based on the general mechanism of the goldcatalyzed hydroamination [18] through the basic steps shown in Scheme 3. Particularly, the hydroamination intermediate IV is formed by admitting the nucleophilic addition of the amine group towards the triple bond activated by the Au(I) coordination (I) followed by a protodeauration step (Scheme 3). The formation of 2 may be rationalized based on the general mechanism of the goldcatalyzed hydroamination [18] through the basic steps shown in Scheme 3. Particularly, the hydroamination intermediate IV is formed by admitting the nucleophilic addition of the amine group towards the triple bond activated by the Au(I) coordination (I) followed by a protodeauration step (Scheme 3).
Then, the isomerization of IV can take place in two different modalities providing, alternatively, the imine-derivative 2 or the enamine-derivative 2 . In the reaction conditions, this step proceeds, providing only compound 2, which is very likely the most stable.
To this regard, HF (6-31G**) calculations performed on the two isomeric compounds 2a and 2 a revealed a higher stability of 2a than 2 a by 5.2 kcal/mol ( Figure 4) [19] and explained the exclusive formation of imine-derivative 2 in the reaction conditions. In addition, similar isomerization modes are described in the literature [20]. Then, the isomerization of IV can take place in two different modalities providing, alternatively, the imine-derivative 2 or the enamine-derivative 2′. In the reaction conditions, this step proceeds, providing only compound 2, which is very likely the most stable.
To this regard, HF (6-31G**) calculations performed on the two isomeric compounds 2a and 2′a revealed a higher stability of 2a than 2′a by 5.2 kcal/mol ( Figure 4) [19] and explained the exclusive formation of imine-derivative 2 in the reaction conditions. In addition, similar isomerization modes are described in the literature [20].   Then, the isomerization of IV can take place in two different modalities providing, alternatively, the imine-derivative 2 or the enamine-derivative 2′. In the reaction conditions, this step proceeds, providing only compound 2, which is very likely the most stable.
To this regard, HF (6-31G**) calculations performed on the two isomeric compounds 2a and 2′a revealed a higher stability of 2a than 2′a by 5.2 kcal/mol ( Figure 4) [19] and explained the exclusive formation of imine-derivative 2 in the reaction conditions. In addition, similar isomerization modes are described in the literature [20].

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 a stationary phase, eluting with nhexane/ethyl acetate mixtures. 1

Conclusions
A protocol for the synthesis of functionalized 3H-pyrrolo-[1,2,3-de] quinoxalines from substituted N-alkynyl indoles has been developed. The reaction proved to be highly selective in promoting the exclusive formation of the 6-exo-dig cyclization product, which, after isomerization, affords the final compound. As to the isomerization mode, theoretical calculations were provided to support the experimental data indicating that differences in terms of stability between the two possible isomers determine the formation of the imine-type product. The mild reaction conditions in which the reaction takes place led to the synthesis of derivatives with useful functional groups, including halogen, alkoxyl, cyano, ketone, and ester, with yields from good to high in all the cases reported.