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

Abstract

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...

Cu(OTf)2-Mediated Ionizing Cross-Coupling of N(sp) and N(sp2) with Arylboronic Acids

“…These processes have also been rationalized as direct arylation using the increased electrophilicity of the aryl transfer reagent via Lewis acid activation. 12 More specifically, while Cu(I) has been shown to slightly accelerate aryl transfer with diaryliodoniums, these processes also proceed effectively without Cu(I), 13,14 consistent with observed general reactivity of this class of reagents 15 and related reactive aryl transfer reagents, such as aryldiazonium salts. 16 Here, we report the discovery, mechanistic rationale, example scope, and limitations of a Cu-mediated C-N cross-coupling method that promotes reductive elimination to neutral N-ligands, such as nitriles and N-heterocycles generating reactive cationic products (Scheme 1b).…”

Atom‐Economical Applications of Diaryliodonium Salts

“…In 2017, the Greaney group described another double arylation reactionf rom diaryliodonium salt( Scheme 5). [10] In their one-pot reaction, the N-heterocycle could undergo arylation with diaryliodonium salt to give an N-aryl product, where the heterocycle can then act as ad irecting group for subsequent CÀHa rylationt aking place in situ with the generateda ryl iodide. Ab road range of symmetrical diaryliodoniums alts was well toleratedr egardless of the electronics of the substituents.…”

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

“…An initial N -arylation reaction of 3,5-dimethylpyrazole is performed in the presence of potassium carbonate, in xylene at 70 °C, releasing 1 equivalent of aryl iodide. The latter is then used for a sequential ruthenium-catalyzed ortho -C–H functionalization directed by the pyrazole group ( Scheme 37 ) [ 76 ]. Starting from non-symmetrical diaryl-λ 3 -iodanes, the electron-poorest or more sterically hindered aromatic group is first transferred to the 3,5-dimethylpyrazole.…”