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Synthesis 2022; 54(21): 4727-4733
DOI: 10.1055/a-1791-7218
special topic
Asymmetric C–H Functionalization

Rhodium-Catalyzed C–H Activation of Indoles for the Construction of Spiroindole Scaffolds

Huiying Wang
a   School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P. R. of China
,
Mengmeng Wang
a   School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P. R. of China
,
Biao Ma∗
b   Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, P. R. of China
,
Hui-Xiong Dai∗
a   School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P. R. of China
b   Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, P. R. of China
c   School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, P. R. of China
› Author Affiliations

We gratefully acknowledge the Shanghai Institute of Materia Medica; the Chinese Academy of Sciences; the National Natural Science Foundation of China (22001258 and 21920102003); the Youth Innovation Promotion Association CAS (nos. 2014229 and 2018293); Institutes for Drug Discovery and Development, the Chinese Academy of Sciences (no. CASIMM0120163006); the Science and Technology Commission of Shanghai Municipality (17JC1405000, 21ZR1475400, and 18431907100); the Program of Shanghai Academic Research Leader (19XD1424600); and the China Postdoctoral Science Foundation (2019M662854) for financial support.
› Further Information
 
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Abstract

Spiroindoles are key scaffolds in a large number of natural products, pharmaceuticals, and agrochemicals. Selective C–H activation has emerged as a powerful synthetic approach to streamline the synthesis of substituted spiroindoles. To date, various 2- and 3-indolyl-tethered aza-spiro-centers have been successfully achieved via C–H activation. However, introduction of spiro-containing systems onto the benzenoid core of indole still remains challenging. Herein, a method of Rh(III)-catalyzed selective C7-H activation/cyclization of indole with maleimide to afford novel spiroindole derivatives is reported, which incorporate both succinimide and spirocycle into indole unit. Gram-scale synthesis demonstrates the utility of this protocol, further modification via click chemistry offered a novel scaffold as a versatile spiro linker.


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Key words

indole - C7-H activation - spirocycle - succinimide - Rh-catalyzed

Spirocycles containing an indole scaffold are widely present in drug research and development exhibiting a broad range of biological activities,[1] owing to their intrinsic complexity, unique rigidity, stability, and three-dimensionality. Therefore, substantial progress has been made in the field for their construction and modification.[2]

In recent years, transition-metal-catalyzed C–H activation has become a key strategy in the field of organic synthesis.[3] Complicated substrates can be obtained easily from simple precursors by this atom economy chemistry. To date, the construction of spiroindole through C–H activation has attracted wide attention of chemists.[4] In 2014, Cui reported a method of Rh(III)-catalyzed C2-H activation/cyclization of indole with diazo compound to afford spiroindole derivatives.[5] More recently, Li developed a palladium-catalyzed C–H bond activation at C2 of indole in water followed by cyclization­ with a transient directing group (DG) to generate spirocyclic indole compounds (Scheme [1]).[6]

Zoom Image
Scheme 1 Selective C7-H activation of indoles

Given the importance of C7-decorated indoles in many bioactive and pharmaceutical compounds,[7] the development of new strategies to directly functionalize the C7-H of indole has become a highly attractive prospect.[8] Nevertheless, selectively introducing the spiro system at C7 position of indole over the highly reactive C2 and C3 positions has remained a challenge.[9] Based on our previous work on selective C7-H functionalization of indole,[10] we envisioned to expand the scope of spiroindole library further by introducing novel and diverse motifs, especially when considering the importance of spiroindole libraries in medicinal chemistry.

Succinimide derivatives are present in many bioactive compounds and natural products.[11] Moreover it can be easily converted into other useful functional groups.[12] Herein, we report a method of Rh(III)-catalyzed selective C7-H activation/annulation of indole with maleimide to afford novel spiroindole derivatives, which incorporate both succinimide and spirocycle into indole units (Scheme [1]).

N-Methoxy-2-methyl-1H-indole-1-carboxamide (1a) and 1-methyl-1H-pyrrole-2,5-dione (2a) were selected as the model substrates. Inspired by previous work,[13] we found that the reaction could be catalyzed by [Cp*RhCl2]2 (5 mol%) and used DABCO (2 equiv) as base in CF3CH2OH (0.5 mL) to give the desired C7 annulation product 3aa in 76% optimal yield (Table [1], entry 1). A set of control experiments were then conducted to understand the role of each reactant. [Cp*RhCl2]2 as catalyst and DABCO as base were essential for this annulation process. Replacing DABCO with inorganic base, such as NaOAc, reduced the yield of 3aa to 62% yield (entry 4). Other solvent, including MeCN, MeOH, and HFIP were investigated in the reaction and the results showed CF3CH2OH was still the optimal solvent (entries 5–7). It is worth noting that neither C2-H nor C7-H activation was observed when C2-Me group was removed, and the starting material was decomposed (entry 8). Finally, higher temperature or shorter reactive time resulted in a low conversion for this transformation (entries 9, 10).

Table 1 Selected Optimization Studiesa

Entry

Changes

Yield (%)

 1

none

76 (64)b

 2

without Rh catalyst

 0

 3

without DABCO

 0

 4

NaOAc as base

62

 5

MeCN as solvent

10

 6

MeOH as solvent

32

 7

HFIP as solvent

30

 8

R = H

 0

 9

100 °C

64

10

8 h

61

a Reaction conditions: 1a (0.1 mmol), 2a (1.5 equiv), [Cp*RhCl2]2 (5 mol%), DABCO (2 equiv), CF3CH2OH (0.5 mL). Yields are determined by 1H NMR analysis using CH2Br2 as an internal standard.

b Isolated yield.

After obtaining the optimized reaction conditions, we next proceeded to investigate the scope of indoles to react with maleimide. As shown in Scheme [2, a] variety of C5 substituted indoles were well applicable to access diverse spiroindole products. For example, indoles bearing fluoro, bromo, chloro, or methyl groups at C5 position realized annulation in mild to excellent yields (Scheme [2], 3ba–da, 3fa). C5-Methoxy-substituted indole could also be tolerated (Scheme [2], 3ea). The low yield may be partially due to the electronic effect. Replacing C2-Me with phenyl or p-methylphenyl groups were compatible, giving moderate yields respectively (Scheme [2], 3ga, 3ha). 2,3-Disubstituted indole could also be converted into the corresponding annulation products in 67% yield (Scheme [2], 3ia). Subsequently, substituted maleimides were also investigated. Besides the methyl moiety, other groups at N atom, such as ethyl, benzyl, or tertiary butyl group, were also suitable for this reaction, providing products in 60–69% yields, respectively (Scheme [2], 3ja–la).

Zoom Image
Scheme 2 Substrate Scope. Reagents and conditions: 1 (0.1 mmol), 2 (1.5 equiv), [Cp*RhCl2]2 (5 mol%), DABCO (2 equiv), CF3CH2OH (0.5 mL). Isolated yields are shown.

The synthetic utility of the annulation system was next demonstrated in a scale-up reaction (Scheme [3]). Thus, gram-scale synthesis was carried out under standard condition, affording the spiroindole product 3aa in 67% yield. Furthermore, the formed spiroindole could be modified via sequential N–H alkylation and click chemistry with oseltamivir derivative, reflecting the feasibility of the scaffold as a versatile spiro linker.

Zoom Image
Scheme 3 Synthetic utility of protocol

Given that the scaffold of spiroindole is chiral, we were motivated to examine the feasibility of realizing an asymmetric version of the annulations. Preliminary studies showed that product 3aa could be achieved in 12% yield with 15% ee using a chiral Rh catalyst, which was first reported by Cramer.[14] Efforts on further improving the reactivity and stereoselectivity are currently ongoing.

To probe the reaction mechanism, we measured the intermolecular kinetic isotope effect (Scheme [4]), which showed C–H activation may not be the rate-limiting step.

Zoom Image
Scheme 4 KIE experiment. Reagents and conditions: 1g (0.1 mmol), 1g-d 4 (0.1 mmol), 2a (0.15 mmol), [Cp*RhCl2]2 (5 mol%), DABCO (0.2 mmol), CF3CH2OH (0.5 mL), 80 °C, 3 h.

In summary, we have developed a strategy of rhodium-catalyzed regioselective C7-H activation/annulation of indoles, which constructed a series of novel spiroindole scaffolds. The protocol showed excellent functional group tolerance. Gram-scale synthesis and further modification demonstrated the utility of this protocol.

All reagents were purchased from commercial suppliers with the highest purity grade and used directly without further purification. 1H and 13C NMR spectra were recorded on Bruker Avance III 400 instruments. 19F NMR spectra were recorded on Bruker Avance III 500 and Bruker Avance NEO 500 instrument and are reported relative to the CFCl3 as the external standard. EI-double focus magnetic-sector high resolution MS (EI-DFS-HRMS) were recorded on a DFS-ThermoFischer instrument at the Center for Mass Spectrometry, Shanghai Institute of Material Medica. HPLC analyzer was carried out at Shanghai Institute of Organic Chemistry by using Agilent Series 1260. Reactions were monitored by TLC using silica gel plates. Column chromatography was performed on silica gel (200–300 mesh) using a mixture of PE/EtOAc acetate as the eluent.


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Indole Substrates 1; General Procedure

To a 100 mL round-bottomed flask charged with a stirring bar was added MeONH2·HCl (20.0 mmol) and THF (5 mL). To the system was then added powdered NaOH (1.5 equiv). The system was then stirred at rt for about 3 h until the system became clear.

To a 100 mL round-bottomed flask charged with a stirring bar was added indole 1 (5.0 mmol, 1.0 equiv), 1,1′-carbonyldiimidazole (CDI, 7.5 mmol, 1.5 equiv), and DMAP (20.0 mol%). Then anhyd MeCN (20 mL) was added to the flask under the protection of N2. The system was refluxed at 85 °C for 10 h. After cooling to rt, the above prepared MeONH2 solution (4 M in THF, 2 equiv) was added and the mixture stirred at 80 °C for 6 h (when most of indole was consumed as detected by TLC). After completion of the reaction, the mixture was extracted with EtOAc and the combined organic layers were dried (MgSO4). The solvent was removed in vacuo and the product 1 was purified by silica gel column chromatography using PE/EtOAc (5:1) as eluent.


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5-Fluoro-N-methoxy-2-methyl-1H-indole-1-carboxamide (1b)

White solid; yield: 30%; mp 98–100 °C; Rf = 0.3 (PE/EtOAc 5:1).

1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.67 (dd, J = 9.0, 4.4 Hz, 1 H), 7.12 (dd, J = 8.9, 2.6 Hz, 1 H), 6.94 (td, J = 9.1, 2.6 Hz, 1 H), 6.32 (s, 1 H), 3.95 (s, 3 H), 2.58 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 159.12 (d, J = 238.5 Hz), 152.88, 138.47, 131.99, 130.32 (d, J = 10.1 Hz), 113.62 (d, J = 9.3 Hz), 110.69 (d, J = 25.4 Hz), 107.01 (d, J = 3.9 Hz), 105.63 (d, J = 23.5 Hz), 64.93, 15.29.

19F NMR (376 MHz, CDCl3): δ = –121.38.

HRMS (EI): m/z [M]+ calcd for C11H11FN2O2: 222.0799; found: 222.0800.


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5-Bromo-N-methoxy-2-methyl-1H-indole-1-carboxamide (1c)

White solid; yield: 64%; mp 160–162 °C; Rf = 0.3 (PE/EtOAc 5:1).

1H NMR (400 MHz, CDCl3): δ = 8.24 (s, 1 H), 7.58 (s, 1 H), 7.56 (d, J = 6.0 Hz, 1 H), 7.28 (dd, J = 8.8, 1.6 Hz, 1 H), 6.27 (s, 1 H), 3.93 (s, 3 H), 2.55 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 152.59, 138.14, 134.34, 131.23, 125.79, 122.90, 115.73, 114.11, 106.42, 65.07, 15.22.

HRMS (EI): m/z [M]+ calcd for C11H11BrN2O2: 281.9998; found: 282.0001.


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5-Chloro-N-methoxy-2-methyl-1H-indole-1-carboxamide (1d)

White solid; yield: 67%; mp 158–160 °C; Rf = 0.3 (PE/EtOAc 5:1).

1H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.15 (dd, J = 8.8, 2.1 Hz, 1 H), 6.27 (s, 1 H), 3.93 (s, 3 H), 2.55 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 152.64, 138.28, 133.97, 130.69, 128.10, 123.13, 119.83, 113.72, 106.56, 65.06, 15.26.

HRMS (EI): m/z [M]+ calcd for C11H11ClN2O2: 238.0504; found: 238.0502.


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N,5-Dimethoxy-2-methyl-1H-indole-1-carboxamide (1e)

White solid; yield: 50%; mp 129–131 °C; Rf = 0.3 (PE/EtOAc 5:1).

1H NMR (400 MHz, CDCl3): δ = 8.35 (s, 1 H), 7.59 (d, J = 9.0 Hz, 1 H), 6.92 (d, J = 2.5 Hz, 1 H), 6.80 (dd, J = 9.1, 2.5 Hz, 1 H), 6.26 (s, 1 H), 3.91 (s, 3 H), 3.83 (s, 3 H), 2.54 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 155.70, 153.25, 137.82, 130.43, 130.14, 113.61, 111.68, 107.11, 102.80, 64.89, 55.77, 15.44.

HRMS (EI): m/z [M]+ calcd for C12H14N2O3: 234.0999; found: 234.0998.


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N-Methoxy-2,5-dimethyl-1H-indole-1-carboxamide (1f)

White solid; yield: 64%; mp 119–121 °C; Rf = 0.3 (PE/EtOAc 5:1).

1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 7.25 (s, 1 H), 7.02 (d, J = 8.3 Hz, 1 H), 6.27 (s, 1 H), 3.95 (s, 3 H), 2.56 (s, 3 H), 2.41 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 153.25, 137.04, 133.62, 131.76, 129.68, 124.14, 120.06, 112.37, 106.67, 64.68, 21.24, 15.16.

HRMS (EI): m/z [M]+ calcd for C12H14N2O2: 218.1015; found: 218.1052.


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N-Methoxy-2,3-dimethyl-1H-indole-1-carboxamide (1i)

White solid; yield: 62%; mp 110–112 °C; Rf = 0.3 (PE/EtOAc 5:1).

1H NMR (400 MHz, CDCl3): δ = 8.75 (s, 1 H), 7.61–7.58 (m, 1 H), 7.37–7.34 (m, 1 H), 7.15–7.12 (m, 2 H), 3.81 (s, 3 H), 2.34 (s, 3 H), 2.10 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 153.28, 134.6, 131.88, 130.48, 122.85, 121.83, 118.25, 113.04, 112.44, 64.58, 12.08, 8.55.

HRMS (EI): m/z [M]+ calcd for C12H14N2O2: 218.1015; found: 218.1052.


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Spiroindoles 3; General Procedure

To a solution of 1 (0.1 mmol), [Cp*RhCl2]2 (3.1 mg, 5 mol%), and DABCO (22.4 mg, 0.2 mmol) in CF3CH2OH (0.5 mL) was added 2 (0.15 mmol). The reaction mixture was stirred at 80 °C for 12 h. After completion of the reaction, the mixture was filtered through Celite washing with EtOAc. The solvent was removed in vacuo and 3 was purified by silica gel column chromatography using PE/EtOAc (2:1) as eluent.


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1,5′-Dimethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3aa)

White solid; yield: 64%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, DMSO-d 6): δ = 8.18 (s, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.7 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.44 (s, 1 H), 3.34 (d, J = 18.4 Hz, 1 H), 3.19 (d, J = 18.4 Hz, 1 H), 2.94 (s, 3 H), 2.62 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 176.36, 173.93, 148.63, 137.55, 132.77, 126.68, 123.82, 119.65, 117.43, 116.33, 106.20, 62.85, 44.97, 25.17, 14.87.

HRMS (EI): m/z [M]+ calcd for C15H13N3O3: 283.0951; found: 283.0951.


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8′-Fluoro-1,5′-dimethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ba)

White solid; yield: 62%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, acetone-d 6): δ = 7.36 (s, 1 H), 7.20 (dd, J = 9.5, 2.1 Hz, 1 H), 6.95 (dd, J = 9.7, 2.2 Hz, 1 H), 6.43 (s, 1H), 3.47 (d, J = 18.6 Hz, 1 H), 3.34 (d, J = 18.6 Hz, 1 H), 2.99 (s, 3 H), 2.67 (s, 3 H).

13C NMR (126 MHz, acetone-d 6): δ = 176.53, 173.86, 161.10 (d, J = 236.7 Hz), 149.27, 140.72, 130.71, 128.85 (d, J = 10.7 Hz), 119.62 (d, J = 9.8 Hz), 106.89 (d, J = 4.0 Hz), 106.27 (d, J = 25.3 Hz), 105.18 (d, J = 28.9 Hz), 64.24, 45.79, 25.51, 15.09.

19F NMR (376 MHz, acetone-d 6): δ = –120.47.

HRMS (EI): m/z [M]+ calcd for C15H12FN3O3: 301.0857; found: 301.0857.


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8′-Bromo-1,5′-dimethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ca)

White solid; yield: 69%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, acetone-d 6): δ = 7.64 (s, 1 H), 7.39 (s, 1 H), 7.26 (s, 1 H), 6.42 (s, 1 H), 3.51 (d, J = 18.6 Hz, 1 H), 3.34 (d, J = 18.6 Hz, 1 H), 2.99 (s, 3 H), 2.68 (s, 3 H).

13C NMR (101 MHz, acetone-d 6): δ = 176.53, 173.86, 149.14, 140.48, 133.12, 129.83, 123.18, 120.48, 119.82, 116.94, 106.29, 64.04, 45.76, 25.54, 15.02.

HRMS (EI): m/z [M]+ calcd for C15H12BrN3O3: 361.0057; found: 361.0051.


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8′-Chloro-1,5′-dimethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3da)

White solid; yield: 53%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, DMSO-d 6): δ = 8.33 (s, 1 H), 7.50 (d, J = 1.7 Hz, 1 H), 7.22 (d, J = 1.7 Hz, 1 H), 6.43 (s, 1 H), 3.40 (d, J = 18.5 Hz, 1 H), 3.14 (d, J = 18.5 Hz, 1 H), 2.93 (s, 3 H), 2.61 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 175.92, 173.78, 148.13, 139.21, 131.59, 128.16, 127.77, 119.31, 118.77, 116.91, 105.72, 62.69, 44.79, 25.30, 14.87.

HRMS (EI): m/z [M]+ calcd for C15H12ClN3O3: 317.0562; found: 317.0563.


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8′-Methoxy-1,5′-dimethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ea)

White solid; yield: 22%; mp 198–200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, acetone-d 6): δ = 7.22 (s, 1 H), 6.99 (d, J = 2.0 Hz, 1 H), 6.64 (d, J = 2.0 Hz, 1 H), 6.34 (s, 1 H), 3.79 (s, 3 H), 3.43 (d, J = 18.4 Hz, 1 H), 3.30 (d, J = 18.4 Hz, 1 H), 2.99 (s, 3 H), 2.64 (s, 3 H).

13C NMR (101 MHz, acetone-d 6): δ = 175.92, 173.20, 157.52, 148.65, 138.41, 127.98, 127.94, 118.29, 106.01, 104.88, 102.80, 63.41, 55.31, 44.92, 24.53, 14.14.

HRMS (EI): m/z [M]+ calcd for C16H15N3O4: 313.1057; found: 313.1057.


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1,5′,8′-Trimethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3fa)

White solid; yield: 76%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, DMSO-d 6): δ = 8.10 (s, 1 H), 7.21 (d, J = 1.1 Hz, 1 H), 6.82 (d, J = 1.2 Hz, 1 H), 6.35 (s, 1 H), 3.32 (d, J = 18.4 Hz, 1 H), 3.15 (d, J = 18.4 Hz, 1 H), 2.93 (s, 3 H), 2.58 (s, 3 H), 2.33 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 176.73, 174.34, 149.00, 137.84, 133.50, 131.43, 127.18, 119.95, 117.61, 117.33, 106.27, 63.13, 45.25, 25.53, 21.68, 15.16.

HRMS (EI): m/z [M]+ calcd for C16H15N3O3: 297.1108; found: 297.1109.


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Methyl-5′-phenylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ga)

White solid; yield: 53%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, acetone-d 6): δ = 7.69–7.66 (m, 2 H), 7.59 (dd, J = 7.8, 0.8 Hz, 1 H), 7.43–7.37 (m, 3 H), 7.32 (s, 1 H), 7.28 (t, J = 7.7 Hz, 1 H), 7.14 (dd, J = 7.5, 0.8 Hz, 1 H), 6.75 (s, 1 H), 3.47 (d, J = 18.4 Hz, 1 H), 3.37 (d, J = 18.4 Hz, 1 H), 3.00 (s, 3 H).

13C NMR (101 MHz, acetone-d 6): δ = 176.92, 174.06, 149.08, 141.92, 135.36, 133.16, 130.38, 129.01, 128.35, 128.25, 124.88, 121.38, 119.77, 118.02, 109.82, 63.95, 45.41, 25.42.

HRMS (EI): m/z [M]+ calcd for C20H15N3O3: 345.1108; found: 345.1107.


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1-Methyl-5′-(p-tolyl)spiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ha)

White solid; yield: 57%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, DMSO-d 6): δ = 8.23 (s, 1 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 2 H), 7.27–7.21 (m, 3 H), 7.12 (d, J = 7.5 Hz, 1 H), 6.73 (s, 1 H), 3.40 (d, J = 18.4 Hz, 1 H), 3.22 (d, J = 18.4 Hz, 1 H), 2.95 (s, 3 H), 2.35 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 176.39, 173.98, 148.15, 140.52, 137.90, 134.05, 129.35, 129.05, 128.36, 126.82, 124.20, 120.52, 118.41, 117.62, 108.76, 62.58, 44.45, 25.25, 21.04.

HRMS (EI): m/z [M]+ calcd for C21H17N3O3: 359.1264; found: 359.1256


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1,5′,6′-Trimethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ia)

White solid; yield: 67%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, DMSO-d 6): δ = 8.05 (s, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 6.97 (d, J = 7.5 Hz, 1 H), 3.31 (d, J = 18.4 Hz, 1 H), 3.16 (d, J = 18.4 Hz, 1 H), 2.92 (s, 3 H), 2.53 (s, 3 H), 2.13 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 176.6, 174.16, 148.88, 132.76, 131.98, 128.13, 123.77, 118.38, 117.34, 116.53, 113.12, 62.71, 45.00, 25.30, 12.25, 8.47.

HRMS (EI): m/z [M]+ calcd for C16H15O3N3: 297.1108; found: 297.1108.


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Ethyl-5′-methylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ja)

White solid; yield: 60%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, acetone-d 6): δ = 7.45 (d, J = 8 Hz, 1 H), 7.33 (s, 1 H), 7.20(t, J = 7.6 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.42 (s, 1 H), 3.56 (q, J = 7.2 Hz, 2 H), 3.40 (d, J = 18.4 Hz, 1 H), 3.34 (d, J = 18.4 Hz, 1 H), 2.68 (s, 3 H), 1.13 (t, J = 7.2 Hz, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 176.09, 173.60, 148.73, 137.62, 132.74, 126.76, 123.92, 119.68, 117.55, 115.94, 106.21, 62.73, 44.87, 33.74, 14.89, 12.62.

HRMS (EI): m/z [M]+ calcd for C16H15N3O3: 297.1108; found: 297.1107.


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Benzyl-5′-methylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3ka)

White solid; yield: 63%; mp >200 °C; Rf = 0.2 (PE/EtOAc 2:1).

1H NMR (400 MHz, DMSO-d 6): δ = 8.34 (s, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.35–7.25 (m, 5 H), 7.14 (t, J = 7.7 Hz, 1 H), 6.87 (d, J = 7.5 Hz, 1 H), 6.44 (s, 1 H), 4.64 (s, 2 H), 3.43 (d, J = 18.4 Hz, 1 H), 3.27 (d, J = 18.4 Hz, 1 H), 2.61 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 176.25, 173.67, 148.87, 137.74, 135.63, 132.79, 128.78, 126.86, 123.92, 119.90, 117.41, 116.03, 106.35, 62.87, 44.50, 42.23, 14.95.

HRMS (EI): m/z [M]+ calcd for C21H17N3O3: 359.1264; found: 359.1267.


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1-(tert-Butyl)-5′-methylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (3la)

White solid; yield: 69%; mp >200 °C; Rf = 0.2 (PE/EtOAc, 2:1).

1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 7.8 Hz, 1 H), 7.19 (t, J = 7.7 Hz, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.58 (s, 1 H), 6.31 (s, 1 H), 3.25 (d, J = 18.0 Hz, 1 H), 3.07 (d, J = 18.0 Hz, 1 H), 2.69 (s, 3 H), 1.58 (s, 9 H).

13C NMR (101 MHz, CDCl3): δ = 176.97, 174.22, 150.53, 138.61, 133.04, 127.90, 124.11, 120.12, 117.50, 114.90, 106.88, 63.16, 59.46, 45.49, 28.26, 15.17.

HRMS (EI): m/z [M]+ calcd for C18H19N3O3: 325.1421; found 325.1421.


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Gram-Scale Synthesis of 3aa

To a solution of 1a (1.0 g, 4.9 mmol), [Cp*RhCl2]2 (151.4 mg, 5 mol%), and DABCO (1.1 g, 9.8 mmol) in CF3CH2OH (24.5 mL) was added 2a (815.8 mg, 7.4 mmol). The reaction mixture was stirred at 80 °C for 12 h. After completion of the reaction, the mixture was filtered through Celite washing with EtOAc. The solvent was removed in vacuo and 3aa was purified by silica gel column chromatography (PE/EtOAc 2:1); yield: 934 mg (67%).


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Asymmetric Experiment

Rh-1 (5 mg, 5 mol%), DABCO (11.2 mg, 0.1 mmol), and benzoyl peroxide (2.4 mg, 0.01 mmol ) were added into CF3CH2OH (0.5 mL). The reaction mixture was stirred for 15min at rt. After that, 1a (10.2 mg, 0.05 mmol) was added into the system which was stirred for another 15 min. Finally, 2a (8.3 mg, 0.075 mmol) was added. The mixture was stirred at 80 °C for 12 h. After completion of the reaction, the mixture was filtered through Celite washing with EtOAc. The solvent was removed in vacuo and the chiral product was obtained by silica gel column chromatography with 15% ee. The ee was determined by HPLC using an IB column [MeOH/i-PrOH (0.1% Et2NH) = 90:10], wavelength: 254 nm) (See specific charts in SI).


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1,5′-Dimethyl-2′-(prop-2-yn-1-yl)spiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazoline]-2,3′,5(2′H)-trione (4)

To a solution of 3aa (141. 5mg, 0.5 mmol) in DMF (2 mL) was added NaH (18 mg, 0.75 mmol). The reaction mixture was stirred at rt for 1 h, Then 3-bromopropyne (71.4 mg, 0.6 mmol) and KI (8.3 mg, 0.05 mmol) were added into the reaction system under N2. The mixture was stirred at 60 °C overnight. After completion of the reaction, the mixture was extracted with EtOAc and the combined extracts were evaporated in vacuo. Finally, it was purified by chromatography (PE/EtOAc 2:1, Rf = 0.5); yield: 35.7 mg (22%); yellow solid; mp 154–156 °C.

1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 7.8 Hz, 1 H), 7.19 (t, J = 7.7 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 6.35 (s, 1 H), 4.87 (dd, J = 18.2, 2.5 Hz, 1 H), 3.99 (d, J = 18.7 Hz, 1 H), 3.72 (dd, J = 18.2, 2.5 Hz, 1 H), 3.24 (d, J = 18.7 Hz, 1 H), 3.21 (s, 3 H), 2.76 (s, 3 H), 2.40 (t, J = 2.5 Hz, 1 H).

13C NMR (151 MHz, CDCl3): δ = 174.72, 173.32, 148.85, 139.40, 131.85, 127.60, 124.21, 120.27, 117.36, 114.95, 106.96, 79.13, 73.79, 69.27, 44.23, 34.71, 25.81, 15.39.

HRMS (EI): m/z [M]+ calcd for C18H15N3O3: 321.1108; found: 321.1102.


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Ethyl (3R,4R,5S)-4-Acetamido-5-{4-[(1,5′-dimethyl-3′-methylene-2,5-dioxospiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinazolin]-2′(3′H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (6)

Compound 4 (16.1 mg, 0.05 mmol), oseltamivir derivative 5 (16.9 mg, 0.05 mmol, prepared according to previous report[15]) and CuI (0.9 mg, 0.005 mmol) were charged into a Schlenk tube, and DMF (1 mL) was added under N2. The reaction mixture was stirred at 60 °C for 14 h. At rt, H2O (2.5 mL) was added and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with H2O (3 × 5 mL), dried (Na2SO4) and the volatiles were evaporated in vacuo. The residue was purified by chromatography (EtOAc/PE 4:1, Rf = 0.3); yield: 9.0 mg (27%); white solid; 1:1 ratio of epimer; mp 132–134 °C.

1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 6.1 Hz, 2 H), 7.38 (d, J = 7.8 Hz, 2 H), 7.15 (t, J = 7.7 Hz, 2 H), 6.88 (s, 2 H), 6.71 (t, J = 7.8 Hz, 2 H), 6.31 (s, 2 H), 5.72 (d, J = 6.8 Hz, 1 H), 5.52–5.37 (m, 3 H), 4.99 (d, J = 15.8 Hz, 1 H), 4.93 (d, J = 9.0 Hz, 1 H), 4.82 (d, J = 8.8 Hz, 1 H), 4.78 (s, 2 H), 4.30 (d, J = 15.8 Hz, 1 H), 4.25–4.19 (m, 5 H), 4.08 (d, J = 18.7 Hz, 1 H), 3.73 (q, J = 8.7 Hz, 1 H), 3.52 (q, J = 8.8 Hz, 1 H), 3.34 (q, J = 5.3 Hz, 2 H), 3.28 (d, J = 18.9 Hz, 1 H), 3.22 (d, J = 18.8 Hz, 1 H), 3.15 (s, 3 H), 3.06 (s, 3 H), 3.04–2.98 (m, 3 H), 2.72 (s, 3 H), 2.70 (s, 3 H), 1.76 (s, 3 H), 1.69 (s, 3 H), 1.55–1.41 (m, 5 H), 1.30–1.25 (m, 10 H), 0.91 (td, J = 7.4, 3.0 Hz, 6 H), 0.83 (dt, J = 11.6, 7.3 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 175.64, 175.04, 173.54, 173.32, 171.80, 171.27, 165.78, 165.70, 149.84, 149.47, 143.43, 143.11, 138.98, 138.42, 138.30, 131.98, 128.28, 128.23, 127.43, 127.35, 125.55, 124.74, 124.09, 120.15, 120.08, 117.57, 117.55, 115.34, 115.25, 106.86, 106.82, 82.30, 82.28, 77.36, 73.29, 72.76, 69.25, 68.38, 61.29, 61.25, 59.41, 58.34, 56.86, 56.71, 44.98, 43.48, 40.92, 39.96, 31.66, 30.54, 29.84,26.49, 26.46, 25.83, 25.80, 25.69, 23.41, 23.13, 15.43, 15.40, 14.33, 9.75, 9.39, 9.34.

HRMS (EI): m/z [M]+ calcd for C34H41N7O7: 659.3062; found: 659.3058.


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KIE Experiment

To a solution of 1g (0.1 mmol), 1g-d 4 (0.1 mmol) (2-phenylindole-d 4 was synthesized according to previous report[16]), [Cp*RhCl2]2 (3.1 mg, 5 mol%), and DABCO (22.4 mg, 0.2 mmol) in CF3CH2OH (0.5 mL) was added 2a (0.15 mmol). The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction, the mixture was filtered through Celite washing with EtOAc. Then, the solvent was removed in vacuo and product was purified by silica gel column chromatography. The distribution of 3ga and 3ga-d 3 was calculated from the integrals of the 1H NMR signals at 7.14 ppm and 7.59 ppm (see SI).


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1791-7218.
  • Supporting Information

Corresponding Authors

Biao Ma
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences
Shanghai 201203
P. R. of China   

Hui-Xiong Dai
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences
Shanghai 201203
P. R. of China   

Publication History

Received: 25 January 2022

Accepted after revision: 08 March 2022

Accepted Manuscript online:
08 March 2022

Article published online:
20 April 2022

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Zoom Image
Scheme 1 Selective C7-H activation of indoles
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Scheme 2 Substrate Scope. Reagents and conditions: 1 (0.1 mmol), 2 (1.5 equiv), [Cp*RhCl2]2 (5 mol%), DABCO (2 equiv), CF3CH2OH (0.5 mL). Isolated yields are shown.
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Scheme 3 Synthetic utility of protocol
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Scheme 4 KIE experiment. Reagents and conditions: 1g (0.1 mmol), 1g-d 4 (0.1 mmol), 2a (0.15 mmol), [Cp*RhCl2]2 (5 mol%), DABCO (0.2 mmol), CF3CH2OH (0.5 mL), 80 °C, 3 h.