Enantioselective Arylative Dearomatization of Indoles via Pd-Catalyzed Intramolecular Reductive Heck Reactions

Shen, Chong; Liu, Renrong; Fan, Ren-Jie; Li, Yinglong; Xu, Tengfei; Gao, Jianrong; Jia, Yi‐Xia

doi:10.1021/jacs.5b01705

Cited by 289 publications

(93 citation statements)

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“…It was proposed that the addition of trialkylammonium salts in ethylene glycol facilitates the halide dissociation through its hydrogen bond donor capacity. Another enantioselective transformation of this class was reported with the asymmetric arylative dearomatization of indoles through palladium‐phosphine‐catalyzed reductive Heck reaction using sodium formate in methanol . To date, the asymmetric reductive Heck reaction is rather limited to intramolecular reactions, which is particularly interesting for the synthesis of natural products .…”

Section: Introductionmentioning

confidence: 99%

“…Another enantioselective transformation of this class was reported with the asymmetric arylative dearomatization of indoles through palladium‐phosphine‐catalyzed reductive Heck reaction using sodium formate in methanol . To date, the asymmetric reductive Heck reaction is rather limited to intramolecular reactions, which is particularly interesting for the synthesis of natural products . To the best of our knowledge, there are no examples that describe the “direct intermolecular” enantioselective reductive Heck reaction with a high ee , most likely because of the challenges involved in the asymmetric induction step.…”

Section: Introductionmentioning

confidence: 99%

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Importance of the Reducing Agent in Direct Reductive Heck Reactions

et al. 2017

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The role of the reductant in the palladium N‐heterocyclic carbene (NHC) catalyzed reductive Heck reaction and its effect on the mechanism of the reaction is reported. For the first time in this type of transformation, the palladium‐NHC‐catalyzed reductive Heck reaction was shown to proceed in the presence of LiOMe and iPrOH even at 10 °C to give the products very efficiently in excellent yields and with exceptional chemoselectivities. This study shows that the reaction proceeds through two distinct mechanisms that depend on the nature of the reducing agent. In the presence of a protic solvent or acidic medium the reaction undergoes protonation to yield the reduced product, whereas in the absence of proton source, it proceeds through the insertion of the reductant followed by reductive elimination. The kinetic data reveal that the oxidative addition is the rate‐determining step in the reaction. The reaction profiles show first‐order kinetics in aryl iodide and Pd and zero‐order kinetics in LiOMe, benzylideneacetone, and the excess amount of NHC ligand. In addition, the reaction progress kinetic analysis shows that neither catalyst decomposition nor product inhibition occurs during the reaction. DFT calculations of the key steps confirm that the oxidative addition step is the rate‐determining step in the reaction. Deuterium‐labeling experiments indicate that the product is formed by the protonation of the Pd−Calkyl bond of the intermediate formed after enone insertion into the Pd−CAr bond. Application of chiral NHC ligands in the asymmetric reductive Heck reaction only results in poor enantioselectivities (enantiomeric excess up to 20 %) and is also substrate specific. DFT calculations suggest that the migration of the aryl group to the alkene of the substrate is the enantioselectivity‐determining step of the reaction. It is further shown that if the steric bulk at the enone is small (a methyl group), the two transition state barriers from [PdII(L2)(ArI)(enone)] species Cre and Csi, which have the re and si face of the enone substrate coordinated to Pd, are very similar, in line with the experimental results. With a slightly larger group (an isopropyl substituent) a significant difference in energy barriers is calculated (2.6 kcal mol−1), and in the experiment this product is formed with a modest enantiomeric excess (up to 20 %).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Importance of the Reducing Agent in Direct Reductive Heck Reactions

et al. 2017

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“…[7] Palladium-catalyzed dearomative Heck arylation of indoles provides ar eliable approach to indolines,w hich are frequently occurring substructures in natural products. [9] Further,t hrough aH eck/benzyl-Pd capture sequence,d iastereoselective indole dearomative difunctionalization reactions were established, as reported by the groups of Lautens and Liang, as well as ourselves.This sequqnce furnishes ar ange of 2,3-disubstituted indolines, bearing vicinal stereocenters,b ya rylcyanation, diarylation, and arylalkynylation reactions. [9] Further,t hrough aH eck/benzyl-Pd capture sequence,d iastereoselective indole dearomative difunctionalization reactions were established, as reported by the groups of Lautens and Liang, as well as ourselves.This sequqnce furnishes ar ange of 2,3-disubstituted indolines, bearing vicinal stereocenters,b ya rylcyanation, diarylation, and arylalkynylation reactions.…”

mentioning

confidence: 85%

“…Subsequent ligand examination revealed that the amino substituent of BINOL-based phosphoramidite ligands significantly influenced the enantioselectivity (entries [5][6][7][8][9][10][11][12][13][14]. Surprisingly,t he addition of CuI (5 mol %) as ac o-catalyst fully suppressed the reaction (entry 2).…”

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confidence: 99%

Enantioselective Dearomative Difunctionalization of Indoles by Palladium‐Catalyzed Heck/Sonogashira Sequence

Liu

Wang

et al. 2017

Angewandte Chemie

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Palladium-catalyzed enantioselective dearomative arylalkynylation of N-substituted indoles,t hrough aH eck/ Sonogashira sequence,w as established using an ew BINOLbased phosphoramidite as the chiral ligand. Aw ide range of 2,3-disubstituted indolines,b earing vicinal quaternary and tertiary stereocenters,w ere efficiently constructed in one step with excellent enantioselectivities (up to 97 %e e) and diastereoselectivities (> 20:1).

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“…取代吲哚底物 1 [6] 和芳基炔酸 2 [14] 的合成均采用文献报道的方法. 138.7, 135.7, 132.8, 132.5, 131.1, 129.1, 128.8, 127.89, 127.87, 126.0, 125.0, 124.6, 123.1, 122.4, 117.6, 87.0, 86.6, 75.3, 43.1, 26.7 8, 149.5, 143.3, 138.9, 135.5, 131.1, 130.2, 129.7, 129.0, 127.9, 126.0, 124.8, 124.4, 123.6, 122.6, 117.6, 86.9, 86.8, 75.0, 43.1, 26.8, 22.0 8, 149.5, 143.3, 138.9, 135.6, 131.2, 130.3, 129.8, 129.0, 127.87, 127.86, 126.0, 124.8, 124.5, 123.6, 122.6, 117.6, 86.9, 86.8, 75.0, 43.2, 26.8, 22 6,166.8,164.8,151.7 (d,J＝9.9 Hz),138.7,135.4,131.2,129.2,128.9,128.1 (d,J＝12.6 Hz),126.8 (d,J＝9.9 Hz),126.1,125.2,122.3,117.6,116.7,116.6,110.7,110.5,87.3,86.2,74.9,43.2,26.7. 8-氟-10b-甲基-11-(苯基乙炔基)-10b,11-二氢-6H-异 160.7, 148.6, 142.3, 140.4, 132.7, 132.2, 131.2, 128.9, 128.8, 128.2, 128.0, 127.9, 127.1, 126.0, 125.0, 124.6, 124.1, 122.5, 111.5, 103.2, 87.5, 87.0, 81.2, 55.7, 44.7 2, 146.0, 143.2, 139.4, 135.5, 132.7, 132.4, 131.2, 129.2, 129.1, 128.0, 127.9, 125.8, 125.3, 124.6, 122.3, 117.5, 110.3, 106.7, 87.7, 85.9, 76.3 6, 149.1, 138.7, 138.0, 135.8, 132.8, 132.4, 131.0, 129.0, 128.7, 128.6, 126.0, 124.9, 124.5, 123.1, 119.4, 117.6, 87.1, 85.9, 75.3, 43.2, 26.7, 21.3 168.3, 149.0, 139.8, 138.5, 136.2, 133.0, 132.6, 131.6, 129.04, 129.02, 128.8, 127.9, 125.9, 125.1, 125.0, 124.7, 123.2, 122.2, 117.6, 90.3, 85.9, 75.1, 43.3, 26.8, 19.9 …”

Section: 基于文献结果我们提出了如下反应机理(Schemementioning

confidence: 99%