Chiral phosphoric acid catalyzed enantioselective N-alkylation of indoles with in situ generated cyclic N-acyl ketimines

Zhang, Lvye; Wu, Binqiang; Chen, Zhangtao; Hu, Jinjin; Zeng, Xiaofei; Zhong, Guofu

doi:10.1039/c8cc05073b

Cited by 40 publications

(21 citation statements)

References 55 publications

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“…To gain the insight of the reaction mechanism, several control experiments were carried out (Scheme ). The N ‐methylated 3‐hydroxyisoindolinone 8 , which is believed unable to undergo dehydration upon treatment with chiral phosphoric acids, was found to be unreactive under the established reaction conditions (Scheme a). This result showed that the formation of cyclic ketimine intermediates is crucial for this reaction.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective Addition of Enamides to Cyclic Ketimines: Access to Chiral 3,3‐Disubstituted Isoindolin‐1‐Ones

Feng

Shen

et al. 2019

Adv Synth Catal

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An enantioselective addition of enamides to cyclic ketimines generated in situ from 3hydroxyisoindolin-1-ones was developed. This reaction takes advantage of readily available substrates, mild reaction conditions, as well as enlarged reaction generality, affording chiral 3,3-disubstituted isoindolin-1-ones with a quaternary stereogenic center in high yields (up to 98%) and enantioselectivities (up to 99% ee). Scheme 1. Synthesis of chiral 3,3-disubstituted isoindolin-1ones. Scheme 2. Substrate scope with respect to 3-hydroxyisoindolinones. [Reaction conditions: 1 a-q (0.2 mmol), 2 a (0.5 mmol), (S)-5 (0.01 mmol) in CH 2 Cl 2 (2 mL) at 25°C.] Scheme 3. Substrate scope with respect to N-acetyl enamines. [Reaction conditions: 1 a (0.2 mmol), 2 a'-o' (0.5 mmol), (S)-5 (0.01 mmol) in CH 2 Cl 2 (2 mL) at 25°C.] Scheme 4. Synthetic transformations of the products. Scheme 5. Control experiments.Scheme 6. Proposed mechanism and transition state model.

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Section: Methodsmentioning

confidence: 99%

Enantioselective Addition of Enamides to Cyclic Ketimines: Access to Chiral 3,3‐Disubstituted Isoindolin‐1‐Ones

Feng

Shen

et al. 2019

Adv Synth Catal

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“…In this context, Zeng and Zhong in 2018 reported an asymmetric N-alkylation of indoles with in situ generated αdiaryl-substituted N-acyl ketimines from 3-aryl-3hydroxyisoindolinones catalyzed by chiral SPINOL derived phosphoric acid 13 b (Scheme 27). [11] The N-alkylated indoles 85 were selectively furnished in moderate to good yields (50-79%) and excellent ee values (up to 98% ee). Control experiment using N-methyl indole gave only the C2-alkylation product with no ee value.…”

Section: Nitrogen-based Nucleophilesmentioning

confidence: 98%

Recent Advances in the Direct Functionalization of Isoindolinones for the Synthesis of 3,3‐Disubstituted Isoindolinones

Chen

Zou

2021

Adv Synth Catal

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The construction of tetrasubstituted carbon centers (especially chiral ones) represents one of the most challenging and demanding topics in the synthesis of natural products and related drugs. The development of isoindolinones with this feature appears to be of great importance, because 3,3disubstituted isoindolinones, which feature all kinds of tetrasubstituted carbon centers, also including spirocyclic and all-carbon or heteroatom-containing centers, show a wide spectrum of biological and pharmaceutical activities. Therefore, the synthetic methodologies for preparing these skeletons have received significant attention during the past decade. In general, these strategies can be classified into two major categories, namely the direct functionalization of parent isoindolinones and lactam-ring-formationinvolved reactions, depending on whether there is a lactam-ring-formation process or not during the production of the final 3,3-disubstituted isoindolinone. Since the second strategy has been well reviewed, this review mainly summarizes the recent progress in the direct functionalization of parent isoindolinones to construct 3,3-disubstituted isoindolinones via three subdivided strategies.

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“…Interestingly, Boc and phenyl N-protected α,β-unsaturated γ-lactams afforded only C3 alkylated products with low ee values. Another example of the application of SPINOL-derived phosphoric acid in the N-alkylation of indoles was demonstrated by Zeng and Zhong [25]. An enantioselective N-addition of indoles to in situ generated cyclic N-acyl imines from hydroxy isoindolinones 23 was efficiently catalyzed by hindered bismesityl-substituted chiral phosphoric acid 25 (Scheme 9).…”

Section: N-selective Additions Of Indoles To Imine/iminium Activated mentioning

confidence: 99%

Enantioselective Catalytic Synthesis of N-alkylated Indoles

Trubitsõn

Kanger

2020

Symmetry

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During the past two decades, the interest in new methodologies for the synthesis of chiral N-functionalized indoles has grown rapidly. The review illustrates efficient applications of organocatalytic and organometallic strategies for the construction of chiral α-N-branched indoles. Both the direct functionalization of the indole core and indirect methods based on asymmetric N-alkylation of indolines, isatins and 4,7-dihydroindoles are discussed.

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Chiral phosphoric acid catalyzed enantioselective N-alkylation of indoles with in situ generated cyclic N-acyl ketimines

Cited by 40 publications

References 55 publications

Enantioselective Addition of Enamides to Cyclic Ketimines: Access to Chiral 3,3‐Disubstituted Isoindolin‐1‐Ones

Enantioselective Addition of Enamides to Cyclic Ketimines: Access to Chiral 3,3‐Disubstituted Isoindolin‐1‐Ones

Recent Advances in the Direct Functionalization of Isoindolinones for the Synthesis of 3,3‐Disubstituted Isoindolinones

Enantioselective Catalytic Synthesis of N-alkylated Indoles

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