Rapid and Efficient Microwave-Assisted Amination of Electron-Rich Aryl Halides without a Transition-Metal Catalyst

Shi, Lei; Wang, Min; Fan, Chun-An; Zhang, Fu‐Min; Tu, Yong‐Qiang

doi:10.1021/ol0353868

Cited by 134 publications

(85 citation statements)

References 15 publications

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“…Preliminary mechanistic investigations point towards an unusual hybrid reaction pathway that exhibits features of both radical and aryne intermediates. Although Daugulis and Tu have reported a limited number of basepromoted C2-and N-selective arylation reactions of indoles, [30][31][32] there appear to be very few precedents for C3-selective variants [32,33] and none that proceed by the proposed hybrid radical/aryne mechanism. …”

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confidence: 99%

“…The fact that O 2 leads to greater amounts of N-arylated products is consistent with literature precedent. [30] In contrast, the electron transfer inhibitor p-dinitrobenzene, completely suppresses C3 arylation (Table 4, entry 4), with only minimal amounts of N-arylated product formed. This result strongly implicates the role of electron transfer processes in the reaction mechanism.…”

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Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Chen

2017

Angewandte Chemie

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Herein, we report an unprecedented transition metal-free, coupling of indoles with aryl halides. The reaction is promoted by KOtBu and is regioselective for C3 over nitrogen. The use of degassed solvents devoid of oxygen is necessary for the success of the transformation. Preliminary studies implicate a hybrid mechanism that involves both aryne intermediates and non-propagative radical processes. Electron transfer is also a distinct possibility. These conclusions were substantiated by EPR data, isotopic labeling studies, and the use of radical scavengers and electron transfer inhibitors. Graphical AbstractMetals? What metals? Regioselective transition metal-free cross-coupling of aryl halides with indoles at C3 has been reported. The reaction proceeds through an unusual hybrid radical/aryne mechanism. Keywordsindole; transition metal-free; cross-coupling; radical; aryne Indoles with aromatic substituents at C3 are an important class of compounds, many of which possess potent biological activity. For instance, fluvastatin is an FDA-approved HMG-CoA reductase inhibitor that is used in the clinic for lowering LDL cholesterol. [1] Other C3 arylated indoles exhibit pico-to nanomolar inhibitory actions against a wide range of biological targets and processes such as the progesterone receptor, [2] COX-II enzyme, [3] carbonic anhydrase I and II, [4] and tubulin polymerization, [5] etc.The direct introduction of aromatic groups onto an extant indole nucleus at C3 is typically carried out by transition metal-catalyzed cross-coupling reactions (Figure 1). [2,[6][7][8][9][10][11][12][13][14] Methods utilizing C-H activation have also been reported. [15][16][17][18] While transition metal-free Correspondence to: Jimmy Wu. Supporting information for this article is given via a link at the end of the document. processes are rare, they have been accomplished through the use of hypervalent iodine reagents, [19][20][21] diazonium salts, [22] or by means of electrochemistry. [23][24][25] Our group has a longstanding interest in the reaction of indoles and related heterocycles. [26][27][28][29] Herein, we disclose a new approach for the intermolecular C3 arylation of unprotected indoles with simple aryl halides. The reaction is promoted by KOtBu and does not require the use of transition metal catalysts. Preliminary mechanistic investigations point towards an unusual hybrid reaction pathway that exhibits features of both radical and aryne intermediates. Although Daugulis and Tu have reported a limited number of basepromoted C2-and N-selective arylation reactions of indoles, [30][31][32] there appear to be very few precedents for C3-selective variants [32,33] and none that proceed by the proposed hybrid radical/aryne mechanism. HHS Public AccessOptimization studies were carried out on the reaction between indole (1a) and iodobenzene (Table 1). A brief solvent survey identified DMF and DMSO as the only effective solvents (entries 1-5). A reaction performed in the dark resulted in similar yield and selectivity (entry 7 vs 5). ...

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Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Chen

2017

Angewandte Chemie

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“…This suggested that PEGs acted not only as the solvent but could accelerate the coupling reactions. [14] Looking through the published papers, it can be seen that Tu [19] has reported the rapid and efficient microwave-assisted amination of electron-rich aryl halides without a transition-metal catalyst and Leadbeater [20] also disclosed an example of the transition metal-free Sonogashira-type coupling. Therefore, in this paper we have shown that Suzuki-Miyaura coupling reaction could be carried out without using a transition metal catalyst.…”

Section: Resultsmentioning

confidence: 99%

Iodine‐Catalyzed Suzuki–Miyaura Coupling Performed in Air

Mao¹,

Hua

Xie³

et al. 2009

Adv Synth Catal

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Suzuki-type coupling reactions can be performed directly in air using a catalytic system composed of iodine, potassium carbonate, and polyethylene glycol 400 (I 2 /K 2 CO 3 /PEG-400). Iodine was found to be an effective additive for accelerating these couplings. The methodology is also suitable for the coupling of (E)-b-bromostyene with phenylboronic acid, with retention of the double bond geometry.

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“…N-(3-Hydroxyphenyl)-morpholine [18] (product in Table 1 and Table 2 3-Hydroxy-N-methyl-diphenylamine [19] ( Table 2, 156.7, 150.8, 149.0, 130.3, 129.6, 122.7, 122.6, 111.7, 107.8, 106.2, 40.6. N-(3-Hydroxyphenyl)-piperidine [20] ( Table 2, entries 2 and 27): N-(4-Hydroxyphenyl)-morpholine [6] ( Table 2, 4-Hydroxy-N-methyldiphenylamine [6] ( N-(4-Hydroxyphenyl)-piperidine [21] ( [6] ( 4'-(N-Phenyl-N'-methylamino)-acetophenone [25] ( 3'-(N-Phenyl-N'-methylamino)-acetophenone [6] ( 4-(N-Phenyl-N'-methylamino)-benzamide [28] ( N-tert-Butoxycarbonyl-4-(4-hydroxyphenyl)-piperazine [30] ( …”

Section: General Procedures For the Coupling Of Aryl Halides With Aminesmentioning

confidence: 99%

Palladium/Proazaphosphatrane‐Catalyzed Amination of Aryl Halides Possessing a Phenol, Alcohol, Acetanilide, Amide or an Enolizable Ketone Functional Group: Efficacy of Lithium Bis(trimethylsilyl)amide as the Base

Urgaonkar¹,

Verkade²

2004

Adv Synth Catal

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A commercially available catalyst system comprising Pd(OAc) 2 or Pd 2 (dba) 3 and the proazaphosphatrane ancillary ligand P(i-BuNCH 2 CH 2 ) 3 N (1) for the amination of aryl halides substituted with a phenol, alcohol, acetanilide, amide or ketone group containing an enolizable hydrogen is described. The reaction is performed in the presence of LiN (SiMe 3 ) 2 as the base. Other bases tested were either less effective or completely non-functional.

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Rapid and Efficient Microwave-Assisted Amination of Electron-Rich Aryl Halides without a Transition-Metal Catalyst

Cited by 134 publications

References 15 publications

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Iodine‐Catalyzed Suzuki–Miyaura Coupling Performed in Air

Palladium/Proazaphosphatrane‐Catalyzed Amination of Aryl Halides Possessing a Phenol, Alcohol, Acetanilide, Amide or an Enolizable Ketone Functional Group: Efficacy of Lithium Bis(trimethylsilyl)amide as the Base

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