Atom-Economical Transformation of Diaryliodonium Salts: Tandem C–H and N–H Arylation of Indoles

Modha, Sachin G.; Greaney, Michael F.

doi:10.1021/ja5124754

Cited by 200 publications

(81 citation statements)

References 50 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2 Similar concepts of atom economy have been set out by Dauban and co-workers, who demonstrated a sequential oxidant / arylation role for ArI(OAc) 2,3 Muñiz who performed tandem borylation / Suzuki-Miyaura cross-coupling of diaryliodoniums, 4 and Jiang who described diaryl sulfide synthesis from a single iodonium species. 5 , 6 In each case (and, perforce, all intramolecular applications of cyclic diaryliodoniums) 7 the iodonium undergoes functionalization at the two ipso-positions.…”

mentioning

confidence: 79%

Domino N‐/C‐Arylation via In Situ Generation of a Directing Group: Atom‐Efficient Arylation Using Diaryliodonium Salts

et al. 2017

Self Cite

View full text Add to dashboard Cite

Both aryl components of diaryliodonium salts can be used in a domino one-pot reaction via in situ generation of a directing group. A number of heterocycles undergo N-arylation which is followed by ruthenium-catalyzed C-arylation. Notably the reaction extends well to unsymmetrical diaryliodonium salts with a number of highly selective examples shown.Diaryliodonium salts have seen extensive application as arylating agents in recent years, as they possess desirable qualities of high reactivity, ease of use as stable, crystalline solids, and compatibility with a wide variety of metal catalysts. 1Their major drawback, however, is the generation of one equivalent of 'waste' aryl iodide in the vast majority of transformations, an unsustainable feature that limits future exploitation. We recently addressed this issue by capturing the generated aryl iodide in an iodonium arylation through a one-pot, tandem C-/ N-arylation of indole (Scheme 1A).2 Similar concepts of atom economy have been set out by Dauban and co-workers, who demonstrated a sequential oxidant / arylation role for ArI(OAc)2, 3 Muñiz who performed tandem borylation / Suzuki-Miyaura cross-coupling of diaryliodoniums, 4 and Jiang who described diaryl sulfide synthesis from a single iodonium species. 5 , 6 In each case (and, perforce, all intramolecular applications of cyclic diaryliodoniums) 7 the iodonium undergoes functionalization at the two ipso-positions. We were interested in developing alternative pathways to create new arylation patterns from iodoniums while preserving the atom-economic approach. Our plan is set out in Scheme 1B, which proposes a domino reaction whereby an intermediate generated in step one opens up new reactivity to harness the aryl iodide in step two: The Nheterocycle 1 can undergo arylation with 2 to give an N-aryl product 3, where the heterocycle can then act as a directing group for subsequent ortho C-H arylation taking place in situ with the released aryl iodide. Crucially, this second arylation breaks the symmetry of the starting iodonium, creating structures having greater diversity for application as building blocks in the chemical sciences.To develop the proposed sequence we required a heteroarene substrate offering versatile scope with respect to reaction conditions for the two arylations. Pyrazoles were appealing as they are known to react with iodoniums under both metal-catalyzed and metal-free conditions, 8 and functionalized pyrazoles have been extensively employed as privileged motifs in medicinal chemistry. 9 We elected to investigate rutheniumcatalysis for the key C-H arylation step, given the robust literature precedent, 10 the affordability of many Ru catalysts, 11 and our own recent experiences in developing Ru-catalyzed C-H functionalization chemistry. 12Scheme 1. Atom economical use of diaryliodoniums.Preliminary reaction screening of the two steps in isolation established that the first N-arylation step could be performed in a variety of solvents with 1.2 equivalents of diphenyliodonium triflate 2a...

show abstract

mentioning

confidence: 79%

Domino N‐/C‐Arylation via In Situ Generation of a Directing Group: Atom‐Efficient Arylation Using Diaryliodonium Salts

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

2017

Angewandte Chemie

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). ...

show abstract

“…Reaction Couplingpartner/reagentC atalyst References 1a rylation aryl halides Pd [101,102,104,105] 2b enzoic acids Pd [107] 3a rylhydrazines Pd [108] 4c yclohexanones Pd [109] 5d iaryliodonium salts Cu [110] 6N -heterocyclic compounds Pd [111][112][113][114] 7a lkynylation alkynes Au [115] 8b enzylation benzylic alcohols Au [116] 9o lefination alkenes Pd [117,118] 10 acylation benzaldehydes Pd [119] 11 TMEDA Cu [120] 12 nitrilesP d [121] 13 CO and alcohols Rh [122] 14 a-amino carbonyl compounds Cu [123] 15 Pd [124] 16 synthesis of bisindoles alcohols Pd [141,142] 17 aldehydes Ag [143] 18 amines Pd [144] 19 annulation alkenes Pd 21 cyanation CuCN Pd [150] 22 K 4 [Fe(CN) 6 ]P d [151] 23 t-BuNC Pd [152] 24 NH 4 HCO 3 and DMSOP d [153] 25 amidation isocyanides Pd [154] Scheme 44. Pd-catalyzedarylation.…”

Section: Entrymentioning

confidence: 99%

Transition Metal‐Catalyzed CH Activation of Indoles

2015

View full text Add to dashboard Cite

Thel ast decades have seen at remendous expanse in the applicationo fC À Ha ctivation of many different substrate classes,including the invaluable indole scaffold. Following the exciting emergence of C À Ha ctivation as am ulti-faceted platform for functionalization, av ersatile toolb ox has been developed for the preparation of structurally diverse indoles. This review article discussesr ecent advances and strategies for transitionm etal-catalyzed C À Ha ctivationofi ndoles.

show abstract

Atom-Economical Transformation of Diaryliodonium Salts: Tandem C–H and N–H Arylation of Indoles

Cited by 200 publications

References 50 publications

Domino N‐/C‐Arylation via In Situ Generation of a Directing Group: Atom‐Efficient Arylation Using Diaryliodonium Salts

Domino N‐/C‐Arylation via In Situ Generation of a Directing Group: Atom‐Efficient Arylation Using Diaryliodonium Salts

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

Transition Metal‐Catalyzed CH Activation of Indoles

Contact Info

Product

Resources

About