Dearomative Indole (3 + 2) Reactions with Azaoxyallyl Cations – New Method for the Synthesis of Pyrroloindolines

DiPoto, Maria C.; Hughes, Russell P.; Wu, Jimmy

doi:10.1021/jacs.5b10221

Cited by 172 publications

(68 citation statements)

References 38 publications

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“…Conversion of 10 into the vinyl compound 11 required three steps:1 )deacetylation (95 %), 2) conversion into the bis-(alkyliodide) (92 %), and 3) finally double E 2 elimination (85 %) to give 11 in 74 %yield for the three steps combined. Finally,adouble cross-metathesis with the terminal alkene 12 (excess) using ac atalytic amount of the Hoveyda-Grubbs II catalyst allowed the formation of the symmetrical target nigramide R ( 13). Thes pectroscopic data for this compound was avery good match with that reported in the literature.…”

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confidence: 67%

“…Initially,w e found that aw ide range of standard solvents were not compatible with the reaction at all and only starting material was recovered. We noted that hypervalent iodine reagents are sometimes used in fluorinated solvents [3,13] and therefore we screened hexafluoroisopropanol (HFIPA) for the dimerization. Pleasingly,t he reaction began to work well, and the addition of 10 mol %IBX formed 2a in 39 %yield (entry 1).…”

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confidence: 99%

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Catalytic Hypervalent Iodine Promoters Lead to Styrene Dimerization and the Formation of Tri‐ and Tetrasubstituted Cyclobutanes

2016

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Reported herein is that the use of catalytic quantities of hypervalent iodine reagents (phenyliodine diacetate or Dess-Martin periodinane) allows the rapid and stereoselective formation of cyclobutanes under very mild reaction conditions. The presence of a fluorinated solvent is essential for the success of these reactions which form unsymmetrical tri- and tetrasubstituted cyclobutanes through a heterodimerization process involving two different alkenes.

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confidence: 67%

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confidence: 99%

Catalytic Hypervalent Iodine Promoters Lead to Styrene Dimerization and the Formation of Tri‐ and Tetrasubstituted Cyclobutanes

2016

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“…[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.…”

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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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“…[26–29] Herein, we disclose a new approach for the intermolecular C3 arylation of unprotected indoles with simple aryl halides. The reaction is promoted by KO t Bu and does not require the use of transition metal catalysts.…”

mentioning

confidence: 99%