<i>tert</i>-Butoxide-Mediated Arylation of Benzene with Aryl Halides in the Presence of a Catalytic 1,10-Phenanthroline Derivative

Shirakawa, Eiji; Itoh, Ken‐ichi; Higashino, Tomohiro; Hayashi, Tamio

doi:10.1021/ja1080822

Cited by 498 publications

(292 citation statements)

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“…[44] There is a growing body of literature in which KOtBu plus associated ligands are capable of promoting transition metal-free cross-coupling reactions between arenes and aryl halides. [45][46][47][48][49][50][51][52][53][54][55][56][57] Computational [58,59] and empirical studies implicate radical intermediates and electron transfer processes. While the findings from these reports may, in part, be applicable to our work, the formation of cine substitution products in the title reaction necessitates that aryne intermediates be considered alongside.…”

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confidence: 99%

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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confidence: 99%

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

Chen

2017

Angewandte Chemie

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“…31 In deuterated benzene, the conversion of 22-d 6 to electron donor 23-d 5 would require that a C−D bond be broken (Scheme 4, inset). But this step of BHAS reactions is routinely not the ratedetermining step, and so no isotope effect is likely to be seen in this step.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Dual Roles for Potassium Hydride in Haloarene Reduction: CS_NAr and Single Electron Transfer Reduction via Organic Electron Donors Formed in Benzene

et al. 2018

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Potassium hydride behaves uniquely and differently than sodium hydride toward aryl halides. Its reactions with a range of haloarenes, including designed 2,6-dialkylhaloarenes, were studied in THF and in benzene. In THF, evidence supports concerted nucleophilic aromatic substitution, CS N Ar, and the mechanism originally proposed by Pierre et al. is now validated through DFT studies. In benzene, besides this pathway, strong evidence for single electron transfer chemistry is reported. Experimental observations and DFT studies lead us to propose organic super electron donor generation to initiate BHAS (base-promoted homolytic aromatic substitution) cycles. Organic donor formation originates from deprotonation of benzene by KH; attack on benzene by the resulting phenylpotassium generates phenylcyclohexadienylpotassium that can undergo (i) deprotonation to form an organic super electron donor or (ii) hydride loss to afford biphenyl. Until now, BHAS reactions have been triggered by reaction of a base, MOtBu (M = K, Na), with many different types of organic additive, all containing heteroatoms (N or O or S) that enhance their acidity and place them within range of MOtBu as a base. This paper shows that with the stronger base, KH, even a hydrocarbon (benzene) can be converted into an electron-donating initiator.

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“…After investigation of better conditions for the coupling in the absence of any transition metals, the system shown in Scheme 3 was found to be effective. 9,10 Thus, the reaction of p-tolyl iodide with benzene (120 equiv) in the presence of NaOt-Bu (2 equiv) and 4,7-diphenyl-1,10-phenanthroline (Ph-phen: 0.1 equiv) at 155°C 11 for 6 h gave 4-methylbiphenyl in 76% yield. Phenyl iodides having an electron-donating or -withdrawing group as well as heteroaryl iodides underwent the coupling in high yields.…”

Section: ç Tert-butoxide-mediated Coupling With Arenesmentioning

confidence: 99%

Transition-metal-free Coupling Reactions of Aryl Halides

2012

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Transition metal catalysis plays a leading role in C(sp 2 )C(sp 2 ) bond formation through substitution reactions. On the other hand, a similar type of substitution reaction has recently been achieved without the aid of transition-metal catalysts. In this review, recent transition-metal-free coupling reactions of aryl halides with arenes, alkenes, or aryl Grignard reagents are summarized in view of S RN 1 reaction. Ç IntroductionAryl halides (ArX), readily available aryl electrophiles, do not undergo S N 2 nor S N 1 reaction. Instead, they are usually activated by reduction to participate in substitution reactions, even though the overall processes are not reduction or oxidation. Transition metal catalysis plays a dominant role to make use of ArX for substitution reactions in such a way.1,2 In particular, palladium is versatile to catalyze the coupling reaction of ArX with nucleophiles such as arenes, alkenes, and aryl Grignard reagents (Scheme 1).3 The generally accepted catalytic cycle consists of oxidative addition of ArX to a Pd(0) complex (i), reaction of the resulting ArPd II X with a nucleophile (ii), and reductive elimination to give the coupling product with regeneration of the Pd(0) complex (iii). ArX is activated by two electron reduction in step i, whereas two electron oxidation takes place in step iii.Single electron reduction also is effective for activation of aryl halides, 4 leading them to the substitution reaction (S RN 1 reaction) with anionic nucleophiles (R ¹ ) (Scheme 2). 5 Radical anion [ArX] •¹ , produced by single electron transfer (SET) from single electron donor Y in the initiation step (a), is converted into an aryl radical (Ar •¹ to ArX gives the coupling product (ArR) and regenerates [ArX] •¹ (e). S RN 1 reaction includes reduction of ArX (steps a and e) and oxidation giving coupling products (step e), as same as the palladium-catalyzed reaction. A major difference between these is the number of electrons involved in the redox processes. S RN 1 reaction features high efficiency that such a small unit as a single electron works as a catalyst, avoiding the use of expensive transition-metal catalysts. Although S RN 1 reaction is expected to have ability to connect the aryl group of aryl halides to sp 2 -carbons as same as transition metal catalysis, 6,7 the scope on anionic nucleophiles has been limited mainly to heteroatom anions and sp 3 -carboanions such as enolates. No reports are available for use of arenes, alkenes, or aryl Grignard reagents as (pro)nucleophiles in S RN 1 reaction.We have recently developed the transition-metal-free coupling reactions of aryl halides with arenes, alkenes, or aryl Grignard reagents (Scheme 1: ac). All the reactions are considered to proceed within the boundary of S RN 1 mechanism. In this Highlight Review, we summarize our work on the transition-metal-free coupling reactions in addition to related reactions reported by others. Ç tert-Butoxide-mediated Coupling with ArenesDuring the course of our studies on the iron-catalyzed coupling r...

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tert-Butoxide-Mediated Arylation of Benzene with Aryl Halides in the Presence of a Catalytic 1,10-Phenanthroline Derivative

Abstract: Sodium tert-butoxide mediates the coupling of aryl halides with benzene derivatives without the aid of transition metal catalysts but with a catalytic 1,10-phenanthroline derivative.

Cited by 498 publications

References 15 publications

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

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

Dual Roles for Potassium Hydride in Haloarene Reduction: CS_NAr and Single Electron Transfer Reduction via Organic Electron Donors Formed in Benzene

Transition-metal-free Coupling Reactions of Aryl Halides

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tert-Butoxide-Mediated Arylation of Benzene with Aryl Halides in the Presence of a Catalytic 1,10-Phenanthroline Derivative

Abstract: Sodium tert-butoxide mediates the coupling of aryl halides with benzene derivatives without the aid of transition metal catalysts but with a catalytic 1,10-phenanthroline derivative.

Cited by 498 publications

References 15 publications

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

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

Dual Roles for Potassium Hydride in Haloarene Reduction: CSNAr and Single Electron Transfer Reduction via Organic Electron Donors Formed in Benzene

Transition-metal-free Coupling Reactions of Aryl Halides

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Dual Roles for Potassium Hydride in Haloarene Reduction: CS_NAr and Single Electron Transfer Reduction via Organic Electron Donors Formed in Benzene