Enantioselective Palladium‐Catalyzed CH Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

Gao, Xiang; Wu, Bo; Huang, Wen‐Xue; Chen, Mu‐Wang; Zhou, Yuhan

doi:10.1002/anie.201504483

Cited by 129 publications

(48 citation statements)

References 75 publications

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“…[6b] Overall, the proposed mechanism shares similarities with those proposed for related reactions promoted by Rh- [5c] and non-heme Fe-based catalysts [6a] but differs from that reported for indole functionalization with diazo reagents with Cu-complexes. [6b] …”

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confidence: 65%

“…[5] More recently, other catalytic systems have been introduced to enable these reactions. [6] Invariably, however, the scope of these protocols have been limited to the C—H functionalization of indoles in which the N—H group is masked either through alkylation or via a protecting group, [5–6] due to inherently higher reactivity of this functional group toward carbene insertion. The application of these catalysts to unprotected indoles have indeed resulted in mixtures of N—H, C—H, and double N—H/C—H insertion products.…”

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confidence: 99%

“…The application of these catalysts to unprotected indoles have indeed resulted in mixtures of N—H, C—H, and double N—H/C—H insertion products. [5a, 6b, 7] These limitations impose the need of additional protection/deprotection steps for the functionalization of indoles using carbene transfer chemistry ( Scheme 1). …”

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confidence: 99%

“…These TON values are lower than those supported by this variant in other carbene transfer reactions with EDA (1,000–10,000), [8a, 9–10] but they compare favourably (3- to 6-fold higher) with those reported using Pd- or Cu-based catalysts for the C3 functionalization of N-protected indoles. [6c, 6d] From time course experiments, the Mb(H64V,V68A)-catalyzed conversion of indole to 3 was determined to proceed with an initial rate of about 10 turnovers/min and to reach completion in less than 15 minutes (Figure S2). Control reactions confirmed that the ferrous form of Mb(H64V,V68A) is responsible for catalysis.…”

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Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles

et al. 2018

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Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal-catalyzed carbene transfer has provided an attractive route to afford C3-functionalized indoles, these protocols are viable only in the presence of N-protected indoles, owing to competition from the more facile N-H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C-H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α-diazoacetate to give the corresponding C3-functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti-inflammatory drug indomethacin.

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confidence: 65%

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confidence: 99%

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Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles

et al. 2018

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“…[11] Stimulated by the pioneering work, we synthesized two bipyridine ligands, L1 and L3,s tarting from 2-iodopyridin-3-ol and optically active diols of various lengths.T hrough either aM itsunobu reaction or S N 2r eaction, and subsequent Ullmann coupling, these ligands were obtained in moderate yields. [12] Subsequently,westarted to investigate their performance in palladium-catalyzed enantioselective C À Hf unctionalization of indoles.…”

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Enantioselective Palladium‐Catalyzed CH Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

Gao

Huang

et al. 2015

Angewandte Chemie

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Ap alladium-catalyzed enantioselective C À Hf unctionalization of indoles was achieved with an axially chiral 2,2'-bipyridine ligand, thus providing the desired indol-3-acetate derivatives with up to 98 %ee. Moreover,the reaction protocol was also effective for asymmetric OÀHi nsertion reaction of phenols using a-aryl-a-diazoacetates.T his represents the first successful application of bipyridine ligands with axial chirality in palladium-catalyzed carbene migratory insertion reactions.Functionalized indoles are ubiquitous structural motifs in am yriad of biologically active alkaloids and pharmaceuticals.[1] To access these privileged building blocks,t he most straightforward approach is direct functionalization of simple and commercially available indoles.A mong the enormous efforts devoted to this area, transition-metal-catalyzed C À H functionalization by diazo compounds stands out because of its convenience in constructing indol-3-acetate derivatives with high medicinal value.[2] Theg roups of Fox [2c] and Hashimoto [2d] disclosed rhodium-catalyzed direct C À Hf unctionalization of indoles by carbenoids,d erived from a-alkyla-diazo-acetates,w ith excellent enantioselectivity.B ut when a-aryl-a-diazoacetates were used, neither iron [2e] nor rhodium catalysts [2f] gave satisfactory results in terms of enantioselectivity (Scheme 1). An interesting protocol to acquire chiral indol-3-acetate derivatives was developed by the group of Hu through enantioselective trapping of zwitterionic intermediates.[2g,h] Despite the progress made recently,d eveloping an enantioselective method for the direct functionalization of indoles using a-aryl-a-diazoacetates is still challenging and highly desirable.Palladium is an indispensable and versatile catalyst in modern organic synthesis.[3] Palladium-catalyzed carbenetransfer reactions based on migratory insertion have received considerable attention recently, [4,5] but asymmetric versions are underexplored. Thef ew catalytic systems developed by the groups of Hu, [6a] Feng [6b] and Zhou [6c] were successfully applied in palladium-catalyzed asymmetric carbene-transfer reactions,b ut stagnation in the design of efficient ligands impeded development of this area. From these previous works,w es aw an opportunity for realizing the direct palladium-catalyzed enantioselective functionalization of indoles by a-aryl-a-diazoacetates with the aid of ap roper ligand. In this context, we report ahighly efficient palladiumcatalyzed method for the enantioselective CÀHf unctionalization of indoles with an axially chiral 2,2'-bipyridine ligand. In addition, this catalytic system is also effective for asymmetric O À H-insertion reaction of phenols.At the outset, we examined the catalytic performance of the palladium complex, coordinated with the classical diphosphine ligand (R)-Binap,i nt he CÀHf unctionalization of 1,2-dimethylindole (2a)b yb enzyl 2-diazo-2-phenylacetate (1a; Figure 1). Ther eaction was complete in 0.5 hours and delivered the desired product in 82 %yield, albeit ...

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Carbenes and Nitrenes

Gras¹,

Chassaing²

2019

Organic Reaction Mechanisms Series

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Enantioselective Palladium‐Catalyzed CH Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

Cited by 129 publications

References 75 publications

Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles

Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles

Enantioselective Palladium‐Catalyzed CH Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

Carbenes and Nitrenes

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