Proline Catalyzes Direct C–H Arylations of Unactivated Arenes

Tanimoro, Kouichi; Ueno, Minoru; Takeda, Kazuya; Kirihata, Mitsunori; Tanimori, Shinji

doi:10.1021/jo3008594

Cited by 101 publications

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

Chen

2017

Angewandte Chemie

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“…40 When the reaction was conducted in C 6 D 6 , 51-d 1 and 12-d 10 were now detected (Table 5, entry 2), but in very low yield. No arylation product from coupling of aryl radical 49 to benzene was observed.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

“…Formation of anion 35-d 11 (Scheme 6B) takes place analogously to Scheme 6A; if isotope effects for conversion of 35-d 11 to 48-d 10 are large, then the concentration of 35-d 11 may build up in solution to a level greater than for the nondeuterated counterpart that is present when benzene is the solvent. This means that if a molecule of 48-d 10 forms and executes SET to the haloarene substrate to form an aryl radical, that radical can abstract D from 35-d 11 , thereby forming 36-d 10 , which in turn can donate an electron to another molecule of haloarene to initiate another cycle. The comparison between conditions A (entries 1 and 2) and conditions B (entries 3 and 4) reflects that the higher temperature selectively helps the reaction in C 6 D 6, possibly either by creating a greater concentration of 35-d 11, or by facilitating the conversion to 48-d 10 .…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

“…This means that if a molecule of 48-d 10 forms and executes SET to the haloarene substrate to form an aryl radical, that radical can abstract D from 35-d 11 , thereby forming 36-d 10 , which in turn can donate an electron to another molecule of haloarene to initiate another cycle. The comparison between conditions A (entries 1 and 2) and conditions B (entries 3 and 4) reflects that the higher temperature selectively helps the reaction in C 6 D 6, possibly either by creating a greater concentration of 35-d 11, or by facilitating the conversion to 48-d 10 .…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

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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

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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“…Recently, organo catalysts have been employed in a variety of chemical transformations [26][27][28][29][30] and they dominate the natural world in triggering chemical reactions. Particularly, L-proline has received much attention due to its dual role as a ligand and catalyst [31][32][33][34]. In view of the above perceptions, the development of benign and metal-free transamidation procedures with high yield and selectivity is desirable.…”

Section: Introductionmentioning

confidence: 99%

L-Proline: An Efficient and Selective Catalyst for Transamidation of Thioamides with Amines

Adimurthy¹

2016

J Biomol Res Ther

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Proline Catalyzes Direct C–H Arylations of Unactivated Arenes

Cited by 101 publications

References 41 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

L-Proline: An Efficient and Selective Catalyst for Transamidation of Thioamides with Amines

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Proline Catalyzes Direct C–H Arylations of Unactivated Arenes

Cited by 101 publications

References 41 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

L-Proline: An Efficient and Selective Catalyst for Transamidation of Thioamides with Amines

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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