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Original article
2021
:14;
202106
doi:
10.1016/j.arabjc.2021.103155

Palladium-catalyzed intramolecular tandem dearomatization of indoles for the synthesis of tetracyclic indolines

, , , , , , ,
a School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China

⁎Corresponding authors. 2019070@hebut.edu.cn (Ya-Ping Han), yczhang@hebut.edu.cn (Yuecheng Zhang), liangym@lzu.edu.cn (Yong-Min Liang)

Received: , Accepted: ,
© The Author(s) 2021
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

A highly diastereoselective, atom-economical, and palladium-catalyzed Heck protocol for the assembly of structurally diverse indoline scaffolds with vicinal tertiary as well as quaternary stereocenters is described, starting from readily available N-halobenzoyl o-haloaniline derivatives and phenylboronic acids. This cascade annulation reaction, which is scalable and conducts under an ambient atmosphere, provides the valuable tetracyclic indoline derivatives in an efficient and straightforward way.

Keywords

Tetracyclic indoline derivatives
Palladium-catalyzed
Aryl halides
Phenylboronic acids
Heck reaction
1

1 Introduction

Transition-metal-catalyzed diastereoselective dearomatization of arenes has become a powerful strategy for the selective synthesis of a wide array of complex carbocycles, heterocycles, and condensed molecules bearing key scaffolds of biologically active natural products, medicinal molecules, agrochemicals, and functional materials (Chen et al., 2013; Ding et al., 2014; Du et al., 2015; Huang and Yin, 2019; Meng and Szostak, 2015; Ortiz et al., 2007; Roche and Porco, 2011; Sun et al., 2016; Wang et al., 2012; Wu et al., 2016; Yang et al., 2015; Zhuo et al., 2014, 2012). Among the compounds, indolines, specifically those possessing tertiary and quaternary carbon centers at C2 and C3 positions, represent an important class of heterocyclic moieties with many pharmacological and biological activities, and act as critical precursors in the field of drug discovery and functional material science (Bananezhad et al., 2019; Dalpozzo et al., 2012; Douki et al., 2016; Du et al., 2017; Ghonchepour et al., 2019; Islami et al., 2004; Leggans et al., 2013; Pillaiyar et al., 2017; Ruiz-Sanchis et al., 2011; Zhang et al., 2008). For instance, 6H-isoindolo[2,1-a]indol-6-ones, containing a tetracyclic unit, are of significant interest owing to their inherent potential activities and advanced applications, such as anticancer, antioxidant, antitumor, antibacterial, and antifungal activities (Čarný et al., 2019; Crawford et al., 2008; Guo et al., 2016; Han et al., 2016; Huang et al., 2016; Liu et al., 2018; Tang et al., 2014; Yoo et al., 2016). Compound A1, which is a quinone reductase-2 enzyme, has shown no affinity towards the melatonin MT3 receptors and could be further used as synthetic intermediate for other pharmaceuticals such as inhibitor of 3a-hydroxysteroid dehydrogenase (Boussard et al., 2006; Komoda et al., 2003). Compound B1, which incorporates fused four-membered rings system, was found to be the most potent pump inhibitor of bacterium Staphylococcus aureus and applied as a versatile precursor in organic synthesis (Ambrus et al., 2008; Laha et al., 2015; Samosorn et al., 2006). Compound C1 and compound D1 exhibit DNA binding abilities and are believed to hold therapeutic promise anti the human HT-29 colon carcinoma cell lines and the murine L1210 Fig. 1.

Representative examples with the 1,2-dihydropyridine-3-carbonitrile skeleton.
Fig. 1 Representative examples with the 1,2-dihydropyridine-3-carbonitrile skeleton.

leukaemia (Guillaumel et al., 2006; Kadam and Tilve, 2013; Paquin et al., 2015). Compound E1, a novel 2-aryl indole human neurokinin-1 receptor ligand in the central nervous system, displays therapeutic activities in a wide range of pathological conditions and indications, ranging from inflammation, anxiety, depression to chemotherapy-induced emesis (Dinnell et al., 2001; Leroy et al., 2000).

Due to the significance and valuable utility of such scaffolds in synthetic and medicinal chemistry, diverse approaches that may expediently access to 6H-isoindolo[2,1-a]indol-6-one core have been the focus of an important subject of current research (Liang et al., 2019; Marchese et al., 2019; Petrone et al., 2016; Wang et al., 2020). In 2012, Yao, Wu and their colleagues reported an concise Pd-promoted intramolecular Heck reaction of 2,3-disubstituted indoles that delivered fused indolines with wide functional group compatibility (Scheme 1a) (Zhao et al., 2012). In 2015 and 2017, Jia group and Zhou group respectively disclosed protocols for the synthesis of indoline derivatives through the Pd and Ni catalyzed asymmetric reductive Heck reactions of aryl bromides and aryl chlorides (Scheme 1b) (Qin et al., 2017; Shen et al., 2015). Recently, Lautens, Jia, and Liang et al. achieved Pd-promoted synthesis of substituted indolines using N-(2-bromobenzoyl)indoles with a series of nucleophiles such as B2pin2, heterocycles, cyanides, alkynes, H-phosphonates, and alkynyl carboxylic acids (Scheme 1c) (Chen et al., 2016; Liu et al., 2017; Paquin et al., 2015; Petrone et al., 2015; Shen et al., 2019; Zeidan et al., 2018). In 2019, three-component reactions of N-(2-

Summary of reported works and our novel anticipation to the 6H-isoindolo[2,1-a]indol-6-one scaffold.
Scheme 1 Summary of reported works and our novel anticipation to the 6H-isoindolo[2,1-a]indol-6-one scaffold.

bromobenzoyl)indoles with anilines and alcohols as nucleophiles under CO atmosphere for the straightforward assembly of various fused indoline amides and esters using commercially available Pd(OAc)2 as catalyst were reported by the Wu group (Scheme 1d) (Wang and Wu, 2019). Inspired by these intriguing discoveries, as well as our current interest in the transformations of novel approaches to indoline derivatives, herein, we report this palladium-promoted dearomative Heck protocol using aryl chlorides, aryl bromides, and phenylboronic acids as the substrates, delivering various indoline scaffolds with vicinal tertiary and quaternary chiral centers in moderate to good yields with excellent diastereoselectivities.

2

2 Materials and methods

2.1

2.1 Material

The starting materials and reagents were provided by Innochem or Energy Chemicals, and used directly. Solvents were purified and dried as the standard procedures described in “Purification of Laboratory Chemicals book”.

2.2

2.2 Pd(0)-promoted dearomative of indoles

A strictly dried Schlenk tube was charged with N-benzoylindoles (0.2 mmol), boric acid (0.4 mmol), Pd catalyst (0.02 mmol), Cu2O (2.8 mg, 0.02 mmol), PPh3 (10.5 mg, 0.04 mmol), Cs2CO3 (130.4 mg, 0.4 mmol) and solvent (4.0 mL) successively. Then, the reaction was run under air atmosphere at 100 °C for 14.0 h, and monitored by TLC. After reaction, the reaction mixture was cooled down to ambient temperature. Then, the solvent was evaporated under vacuum. The residue was purified by chromatography on silica gel to give the anticipated product.

3

3 Results and discussion

The initial exploration for our anticipation was optimized with compound 1a and phenylboronic acid 2a as the model substrates. As exhibited in Table 1, the expected product 3a was isolated in 38% yield under the conditions of XPhos (20 mol %), Pd(OAc)2 (10 mol %), Cs2CO3 (2.0 equiv) in toluene (2.0 mL) at 100 °C for 14 h under air atmosphere (Table 1, entry 1). The configuration of 3a was identified by NMR spectrum and X-ray crystallographic analysis. A subsequent investigation of various phosphine ligands including dppb, dppe, dppp, and PPh3 revealed that PPh3 exhibited the best result and the anticipated product was generated in 65% yield (entries 2–5). Different palladium catalysts were tested in this transformation, however, no better results were observed (entries 6–10). With the aim of further increasing the yield of product 3a, several inorganic bases such as Na2CO3, K2CO3, and tBuONa were then evaluated, but all of them led to poor yields (entries 11–13). Besides, organic bases such as Et3N and DIPEA were also ineffective and did not lead to any improvement in the yield (entries 14, 15). Next, some representative solvents such as THF, CH3CN, DCE, DMSO, and cyclohexane were evaluated in the reaction, and cyclohexane proved to be the best effective and furnished the target product 3a in 71% yield (entries 16–20). Delightedly, the yield of product 3a could be further increased to 85% by adding 10 mol % of Cu2O (entry 21). Finally, the optimal conditions for the synthesis of 3a were determined to be: (2-bromophenyl)(2-methyl-1H-indol-1-yl)methanone 1a (0.1 mmol), boronic acid 2a (2.0 equiv), Pd(OAc)2 (10 mol %), Cu2O (10 mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv) in 2.0 mL of cyclohexane at 100 °C for 14 h. It is noteworthy that all of the desired products were obtained with excellent diastereoselectivities (>20:1) in this transformation.

Table 1 Screening of Reaction Conditions of 1a with boronic acida,b,c.
entry catalyst ligand base solvent yieldb
1 Pd(OAc)2 XPhos Cs2CO3 toluene 38%
2 Pd(OAc)2 dppb Cs2CO3 toluene 25%
3 Pd(OAc)2 dppe Cs2CO3 toluene 19%
4 Pd(OAc)2 dppp Cs2CO3 toluene 50%
5 Pd(OAc)2 PPh3 Cs2CO3 toluene 65%
6 Pd(MeCN)2Cl2 PPh3 Cs2CO3 toluene 31%
7 PdCl2 PPh3 Cs2CO3 toluene 49%
8 Pd(PPh3)2Cl2 PPh3 Cs2CO3 toluene 37%
9 Pd(TFA)2 PPh3 Cs2CO3 toluene 18%
10 Pd(PPh2Me)2Cl2 PPh3 Cs2CO3 toluene 46%
11 Pd(OAc)2 PPh3 Na2CO3 toluene 49%
12 Pd(OAc)2 PPh3 K2CO3 toluene 44%
13 Pd(OAc)2 PPh3 tBuONa toluene 35%
14 Pd(OAc)2 PPh3 Et3N toluene 12%
15 Pd(OAc)2 PPh3 DIPEA toluene 9%
16 Pd(OAc)2 PPh3 Cs2CO3 THF 11%
17 Pd(OAc)2 PPh3 Cs2CO3 MeCN 27%
18 Pd(OAc)2 PPh3 Cs2CO3 DCE 56%
19 Pd(OAc)2 PPh3 Cs2CO3 DMSO 18%
20 Pd(OAc)2 PPh3 Cs2CO3 cyclohexane 71%
21c Pd(OAc)2 PPh3 Cs2CO3 cyclohexane 85%
a Unless otherwise noted, all reactions were conducted with 1a (0.1 mmol), phenylboronic acid 2a (2.0 equiv), ligand (20 mol%), catalyst (10 mol%), and base (2.0 equiv) in solvent (2.0 mL) for 14 h at 100 °C. b Isolated yields. c Cu2O (10 mol %) in the reaction.

With the optimal reaction conditions in hand, the substrate scope of this palladium-promoted dearomative Heck protocol was then evaluated, and the results were shown in Scheme 2. Delightedly, a wide variety of aryl bromides were tolerated and all the transformations worked smoothly to generate the corresponding products in moderate to good yields with excellent diastereoselectivities (3o − 3u). Both electron donating (Me; 3b) and electron withdrawing groups (F and Cl; 3c and 3d), at the 5-position of the indol ring (R3), were compatible with this reaction and gave the desired products 3b − 3d with yields ranging from 31% to 62%. The substrate with an electron-withdrawing chlorine meta to the bromide group afforded the corresponding product in a moderate yield of 62% with > 20:1 d.r (3e). In the cases of an aromatic ring attaching at the 2-position (R2), the substrates with both electron-donating and electron-withdrawing substituents such as OMe, F, and Cl on the 5- or 6-positions to the indol ring, were well coupled with the phenylboronic acid, delivering the desired products 3f − 3j in 64–71% yields. Furthermore, indole derivatives with big steric bulk (4-methoxyphenyl, 4-isopropyl phenyl, 4-fluorophenyl, and 4-chlorophenyl) at the 2-position were well compatible in the transformation and afforded the corresponding products 3 k − 3 t in moderate to good yields. Indole bearing an ester group at C2 position reacted smoothly with 2a to generate the target product 3u in 54% yield. It is noteworthy that the reaction could tolerate halide substituents (3d, 3e, 3i, 3j, 3 m, 3o, 3p, 3 s, and 3 t), which might provide a potential means for further structural elaborations via metal-catalyzed cross-coupling reactions. However, some limitations of this protocol were noted. When the substrates with 2-methyl-5-hydroxy-indole and 2,3-dimethy-indole motifs were subjected to the reaction, no expected products were observed, instead, the starting materials decomposed.

Scope of the aryl bromides a, b. a Unless otherwise noted, all reactions were run with 1 (0.1 mmol) and 2a (2.0 equiv) under the conditions of Pd(OAc)2 (10 mol %), Cu2O (10 mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv) in 2.0 mL of cyclohexane at 100 °C for 14 h. b Isolated yield. c drs were determined by 1H NMR analysis of the crude reaction mixtures.
Scheme 2 Scope of the aryl bromides a, b. a Unless otherwise noted, all reactions were run with 1 (0.1 mmol) and 2a (2.0 equiv) under the conditions of Pd(OAc)2 (10 mol %), Cu2O (10 mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv) in 2.0 mL of cyclohexane at 100 °C for 14 h. b Isolated yield. c drs were determined by 1H NMR analysis of the crude reaction mixtures.

To further evaluate the scalability of this transformation, we turned our attention to the scope of aryl iodides, and the results are summarized in Scheme 3. Electron-rich substituents and halogens at the 5-position of indole ring were tolerated, affording the corresponding products with high yields and excellent diastereoselectivities (5a − 5d). The substrates with a buck phenyl at the 2-position of the indole also reacted well with phenylboronic acid to afforded the desired products in moderate to good yields with > 20:1 d.r. (5e − 5 g). It seemed that a halogen group (Cl) at the 6-position of indole had a negative effect on the reaction (5 g). Higher yields ranging from 80% to 95% were received in the cases of the substrates bearing substituents with different electronic properties (OMe, CH(CH3)2, F, and Cl) at the 2-position and 5-position of indole moiety (5 h − 5 k).

Scope of the aryl iodides a, b. a Unless otherwise noted, all reactions were run with 4 (0.1 mmol) and 2a (2.0 equiv) under the conditions of Pd(MeCN)2Cl2 (10 mol %), Cu2O (10 mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv) in 2.0 mL of DCE at 100 °C for 14 h. b Isolated yields. c drs were determined by 1H NMR analysis of the crude reaction mixtures.
Scheme 3 Scope of the aryl iodides a, b. a Unless otherwise noted, all reactions were run with 4 (0.1 mmol) and 2a (2.0 equiv) under the conditions of Pd(MeCN)2Cl2 (10 mol %), Cu2O (10 mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv) in 2.0 mL of DCE at 100 °C for 14 h. b Isolated yields. c drs were determined by 1H NMR analysis of the crude reaction mixtures.

Subsequently, the substrate scope of phenylboronic acids 2 was examined by the reactions with aryl iodide (Scheme 4). Substrates with various para-substituents on the benzene ring, including both electron-rich (Me, OMe, and Et; 6a–6c) and electron-deficient (COOMe; 6 g) groups, as well as halogen groups (F, Cl, and Br; 6d–6f), were compatible with the optimized conditions and provided the anticipated products in yields of 56% to 83%. It is noteworthy that the cyclopent-1-en-1-ylboronic acid (2 h) was tolerated, albeit in a lower yield of 55%. Gratifyingly, phenylboronic acids bearing methoxyl and F on the meta-position of the aryl group reacted efficiently with 4a, leading to the target products 6i and 6j in 71% and 58% yields, respectively. Phenylboronic acids substituted with electron-donating (Me) and electron-drawing (Cl) groups at the ortho-position were easily converted to the anticipated products 6 k and 6 l in moderate yields. To our gratification, the reactions of 3,5-diMe-substituted and naphthyl-based substrates could survive the reaction conditions, which led to the desired products 6 m and 6n in yields of 75% and 81%, respectively. Regrettably, thiophen-2-ylboronic acid as a substrate could not react with 4a under the optimal conditions, and no expected product was achieved.

Scope of the boric acids a, b. a Unless otherwise noted, all reactions were run with 4a (0.1 mmol) and 2 (2.0 equiv) under the conditions of Pd(MeCN)2Cl2 (10 mol %), Cu2O (10 mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv) in 2.0 mL of DCE at 100 °C for 14 h. b Isolated yields. c drs were determined by 1H NMR analysis of the crude reaction mixtures.
Scheme 4 Scope of the boric acids a, b. a Unless otherwise noted, all reactions were run with 4a (0.1 mmol) and 2 (2.0 equiv) under the conditions of Pd(MeCN)2Cl2 (10 mol %), Cu2O (10 mol %), PPh3 (20 mol %), Cs2CO3 (2.0 equiv) in 2.0 mL of DCE at 100 °C for 14 h. b Isolated yields. c drs were determined by 1H NMR analysis of the crude reaction mixtures.

To showcase scalability of the developed reaction system, a gram-scale reaction of substituted indole 1a with phenylboronic acid 2a was conducted under the standard conditions, which afforded the desired product 3a in 71% yield with > 20:1 d.r, portraying the potentials of the reaction in the synthetic industry (Scheme 5). To further demonstrate the synthetic utility of this palladium-catalyzed Heck reaction, some transformations of the 2,3-disubstituted indoline derivatives were then carried out. A reduction of substrate 3a led to amine 7 as a single isomer in moderate yield using LiAlH4 as the reducing agent in refluxing THF for 12 h, providing an efficient pathway of accessing to valuable tetracyclic indoline products in high diastereoselectivities. The nucleophilic attack of inorganolithium reagent such as LiAlH4 onto the C − O double bond of 3a appeared to be quite general, which could be further converted into product 8 in 37% yield and > 20:1 d.r. by the reaction with indole under acidic conditions through the release of a molecule of water over two steps. The Suzuki reaction of product 6f with a bromide group at the para-position of the benzene ring was established, which could generate the coupling product 9 in 87% yield.

Derivatization of Products. Gram-scale reaction and derivatization studies of 3: [a] LiAlH4 (5.0 equiv), in THF at 90 °C for 12 h; [b] LiAlH4 (5.0 equiv), in THF at 90 °C at RT for 6 h, then indole (1.0 equiv), TFA (10 mol %), in CH2Cl2 at RT for 6 h; [c] Pd(PPd3)4 (8 mol %), K2CO3 (2.5 equiv), PhB(OH)2 (1.2 equiv), in THF/H2O at 65 °C for 12 h.
Scheme 5 Derivatization of Products. Gram-scale reaction and derivatization studies of 3: [a] LiAlH4 (5.0 equiv), in THF at 90 °C for 12 h; [b] LiAlH4 (5.0 equiv), in THF at 90 °C at RT for 6 h, then indole (1.0 equiv), TFA (10 mol %), in CH2Cl2 at RT for 6 h; [c] Pd(PPd3)4 (8 mol %), K2CO3 (2.5 equiv), PhB(OH)2 (1.2 equiv), in THF/H2O at 65 °C for 12 h.

Based on above observations and published results (Gao et al., 2020; Li et al., 2018; Liang et al., 2019b, 2019a; , Liu et al., 2017; Paquin et al., 2015; Xu et al., 2017), a tentative mechanism for the palladium-promoted dearomative Heck reaction is depicted in Scheme 6. The Pd(0) species, formed in situ from Pd(OAc)2 in the presence of PPh3, undergoes oxidative addition of C(sp2)-Br bond of arylbromide 1 and affords the intermediate A. The intramolecular syn-insertion into the olefin of indole to provide benzylic Pd(II) intermediate B, which is further transformed into intermediate C through transmetalation. Then the palladium intermediate D is formed by coordination and insertion of the phenylboronic acid with the release of a molecule of Br-B(OH)2. Finally, the target product 3 is generated via reductive elimination of intermediate D in the presence of base with the regeneration of Pd(0) to accomplish the catalytic cycle.

Proposed Mechanism for the Formation of 6H-isoindolo[2,1-a]indol-6-ones.
Scheme 6 Proposed Mechanism for the Formation of 6H-isoindolo[2,1-a]indol-6-ones.

4

4 Conclusion

In conclusion, we have established a distinct and efficient Pd-promoted dearomative of indoles, using phenylboronic acids as coupling partners, thereby to afford the 2,3-disubstituted indoline derivatives bearing vicinal tertiary and quaternary chiral centers in moderate to good yields with excellent diastereoselectivities (>20:1). The novel methodology presented here provides versatile, straightforward, and efficient method of accessing 6H-isoindolo[2,1-a]indol-6-one motif, featuring wide functional group tolerance and highly efficient catalytic system.

Acknowledgment

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21776056), the Natural Science Foundation of Hebei Province (CN) (Grant No. B2020202010, B2018202253).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Appendix A

Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2021.103155.

Appendix A

Supplementary data

The following are the Supplementary data to this article:

Supplementary data 1


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