Indolyne and Aryne Distortions and Nucleophilic Regioselectivites

Cheong, Paul Ha‐Yeon; Paton, Robert S.; Bronner, Sarah M.; Im, G-Yoon Jamie; Garg, Neil K.; Houk, K. N.

doi:10.1021/ja9098643

Cited by 234 publications

(123 citation statements)

References 17 publications

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“…These regioselectivities are consistent with the aryne distortion model espoused by Garg and Houk. [34,35] With the exception of nitro, naphthyl, and benzofuran-derived aryl halides, the reactions were accompanied by various amounts of Narylated products that were readily removed by standard silica flash chromatograph. The reaction carried out on a 1.2 g scale also proceeded as expected (entry 1b).…”

Section: Hhs Public Accessmentioning

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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Section: Hhs Public Accessmentioning

confidence: 99%

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

Chen

2017

Angewandte Chemie

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“…Next, we examined reaction of 1 in the presence of 4g,which normally reacts with predominant meta selectivity. [15] Although 2g was obtained as the major product, as mall amount of 2h was also formed, presumably because of coordination of the nitrogen atom to the countercation (Li + ) of 1. [16] Thep hysicochemical and structural properties of 2 and 6 were next investigated.…”

Section: Angewandte Chemiementioning

confidence: 99%

Access to Air‐Stable 1,3‐Diphosphacyclobutane‐2,4‐diyls by an Arylation Reaction with Arynes

2016

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Tuning of the physicochemical properties of the 1,3-diphosphacyclobutane-2,4-diyl unit is attractive in view of materials applications. The use of arynes is shown to be effective for installing relatively electron rich aryl substituents into the open-shell singlet P-heterocyclic system. Treatment of the sterically encumbered 1,3-diphosphacyclobuten-4-yl anion with ortho-silylated aryl triflates in the presence of fluoride under appropriate conditions afforded the corresponding 1-aryl 1,3-diphosphacyclobutane-2,4-diyls. The air-stable open-shell singlet P-heterocycles exhibit considerable electron-donating character, and the aromatic substituent influences the open-shell character, which is thought to be related to the property of p-type semiconductivity. The P-arylated 1,3-diphosphacyclobutane-2,4-diyl systems can be further utilized as detectors of hydrogen fluoride (HF), which causes a remarkable change in their photoabsorption properties.

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“…26,27 Thus, we had ready access to indolyne precursors 12-14 ( Figure 3). Trapping of the indolyne intermediates with nucleophilic agents and cycloaddition partners provided access to a number of 4-, 5-, 6-, and 7-substituted indoles (e.g., 25-…”

Section: Scheme 3 Synthesis Of Silyltriflate 17mentioning

confidence: 99%

Understanding and Modulating Indolyne Regioselectivities

Bronner¹,

Goetz²,

Garg³

2011

Synlett

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Heterocyclic arynes hold much promise for applications in modern synthetic chemistry. One particular class of hetarynes is those derived from the indole heterocycle (i.e., indolynes). Indolynes can be generated under mild fluoride-based reaction conditions using silyltriflate precursors. Indolyne-trapping experiments provide access to benzenoid-substituted indoles in a controlled manner with synthetically useful yields. Regioselectivities can be predicted prior to experiments using simple calculations, ultimately allowing for the modulation of selectivities by careful design. This strategy has enabled a concise synthesis of indolactam V.

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Indolyne and Aryne Distortions and Nucleophilic Regioselectivites

Cited by 234 publications

References 17 publications

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

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

Access to Air‐Stable 1,3‐Diphosphacyclobutane‐2,4‐diyls by an Arylation Reaction with Arynes

Understanding and Modulating Indolyne Regioselectivities

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