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

Abstract

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). ...

Regiospecificity in Ligand-Free Pd-Catalyzed C–H Arylation of Indoles: LiHMDS as Base and Transient Directing Group

“…Using LiHMDS, solvents other than toluene and mesitylene, such as tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethylacetamide (DMAc) and DMSO, gave essentially N-arylation or no reaction at all (see SI, Table S7). In contrast to the work of Chen and Wu who noticed a change in selectivity towards N-arylation in the presence of oxygen, 33 here the standard reaction with bromobenzene and a metal loading as low as 0.05 mol% did not require an anhydrous or deoxygenated solvent but could be performed in technical grade toluene without affecting neither yield nor regiospecificity (Table S7).…”

“…[25][26][27][28][29][30][31][32] Yields of up to 76% for the C-3 arylated product (after 35 hours) were obtained via a transition metal-free system developed by Chen and Wu using four equivalents of potassium tert-butoxide and an excess of indole. 33 However, this system led to mixtures of regioisomers. Another metal-free system for the arylation of indoles was described by Ackermann et al using substituted diaryliodonium salts as reagents without any catalyst.…”

“…Lithium and potassium tert-butoxide did not allow the arylation to proceed in toluene, in contrast to the activity reported by Chen and Wu in dimethylsulfoxide (DMSO). 33 Scheme 2. The Pd(OAc)2/LiHMDS catalytic system for efficient C-3 arylation of 1H-indole and overview of screened parameters.…”

“…Noteworthy, the Pd(OAc)2/LiHMDS system allowed preparing 3-(o-tolyl)indole, which cannot be obtained using the previously reported transition metal-free system, since the latter operates via a benzyne intermediate. 33 The scope of applicable functionalized indoles is presented in Scheme 4. The C-3 arylation efficiently proceeded with both phenyl iodide and bromide in most cases.…”

Dual Palladium/Scandium Catalysis toward Rotationally Hindered C3‐Naphthylated Indoles from β‐Alkynyl Ketones and o‐Alkynyl Anilines

“…The range of methods available for the fabrication of such scaffolds includes transition metal‐catalyzed cross‐coupling reactions of indoles and their derivatives (Scheme 1a), [ 14‐20 ] Au‐catalyzed annulation of o ‐azidoarylalkynes with anisole (Scheme 1b), [ 21 ] Pd‐catalyzed oxidative cyclization of 2‐alkynyl trifluoroacetanilides and arylboronic acids (Scheme 1c) [ 22 ] and other methods. [ 23‐27 ] Despite the advances made in this field, a number of crucial issues have remained unsolved, including the prefunctionalization of starting materials, the combination of transition metal catalysts with phosphine ligands and unsatisfactory atomic utilization and regioselectivity. Consequently, the development of a simple and efficient protocol for installing rotationally hindered C3‐arylated indoles, while overcoming these challenges is highly desired.…”