KO<i>t</i>Bu: A Privileged Reagent for Electron Transfer Reactions?

Barham, Joshua P.; Coulthard, Graeme; Emery, Katie J.; Doni, Eswararao; Cumine, Florimond; Nocera, Giuseppe; John, Matthew P.; Berlouis, L.E.A.; McGuire, Thomas M.; Tuttle, Tell; Murphy, John A.

doi:10.1021/jacs.6b03282

“…[44] There is a growing body of literature in which KO t Bu plus associated ligands are capable of promoting transition metal-free cross-coupling reactions between arenes and aryl halides. [45–57] 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

¹

,

Wu

²

2017

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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.

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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.…”

mentioning

confidence: 99%

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

Chen

¹

,

Wu

²

2017

View full text Add to dashboard Cite

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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“…As KO( t -Bu) does not have sufficient reducing power to generate ArI •− , it has been proposed that initiation could arise from the reaction of ArI and KO( t -Bu) to form benzyne or that organic electron donors form in situ with suitable additives under the basic conditions of the reaction [58–60]. For example, observation of faster direct arylation in the presence of DMF led to proposals of deprotonated DMF as one electron donor [61] or forming a dibasic -enediol in situ as an electron donor [62]. …”

Section: Resultsmentioning

confidence: 99%