A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres.

C(sp3)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes, play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop science. Substituted bicyclo[2.1.1]hexanes (BCHs) are emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Therefore, a general synthetic route to BCHs is needed if their potential as bioisosteres is to be realized. Here we describe a broadly applicable catalytic approach that delivers substituted BCHs by intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2-catalysed process works for a wide range of electron-deficient alkenes and substituted BCB ketones, operates with SmI2 loadings as low as 5 mol% and is underpinned by a radical relay mechanism that is supported by density functional theory calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation and the expedient synthesis of a saturated hydrocarbon analogue of the broad-spectrum antimicrobial, phthalylsulfathiazole.

Recent advances in the chemistry of ketyl radicals.

Ketyl radicals are valuable reactive intermediates for synthesis and are used extensively to construct complex, functionalized products from carbonyl substrates. Single electron transfer (SET) reduction of the C[double bond, length as m-dash]O bond of aldehydes and ketones is the classical approach for the formation of ketyl radicals and metal reductants are the archetypal reagents employed. The past decade has, however, witnessed significant advances in the generation and harnessing of ketyl radicals. This tutorial review highlights recent, exciting developments in the chemistry of ketyl radicals by comparing the varied contemporary - for example, using photoredox catalysts - and more classical approaches for the generation and use of ketyl radicals. The review will focus on different strategies for ketyl radical generation, their creative use in new synthetic protocols, strategies for the control of enantioselectivity, and detailed mechanisms where appropriate.

SmI2-Catalyzed Intermolecular Coupling of Cyclopropyl Ketones and Alkynes: A Link between Ketone Conformation and Reactivity.

The archetypal single electron transfer reductant, samarium(II) diiodide (SmI2, Kagan's reagent), remains one of the most important reducing agents and mediators of radical chemistry after four decades of widespread use in synthesis. While the chemistry of SmI2 is very often unique, and thus the reagent is indispensable, it is almost invariably used in superstoichiometric amounts, thus raising issues of cost and waste. Of the few reports of the use of catalytic SmI2, all require the use of superstoichiometric amounts of a metal coreductant to regenerate Sm(II). Here, we describe a SmI2-catalyzed intermolecular radical coupling of aryl cyclopropyl ketones and alkynes. The process shows broad substrate scope and delivers a library of decorated cyclopentenes with loadings of SmI2 as low as 15 mol %. The radical relay strategy negates the need for a superstoichiometric coreductant and additives to regenerate SmI2. Crucially, our study uncovers an intriguing link between ketone conformation and efficient cross-coupling and thus provides an insight into the mechanism of radical relays involving SmI2. The study lays further groundwork for the future use of the classical reagent SmI2 in contemporary radical catalysis.

Regioselective Synthesis of Fused Furans by Decarboxylative Annulation of α,ß-Alkenyl Carboxylic Acid with Cyclic Ketone: Synthesis of Di-Heteroaryl Derivatives.

α,ß-Alkenyl carboxylic acids undergo CuII -mediated decarboxylative annulation reactions with aliphatic cyclic ketones to provide synthetically valuable di-heterocycles. The annulation process tolerates a variety of aliphatic ketones and heterocyclic alkenyl carboxylic acids, producing substituted fused furan derivatives with complete regioselectivity. The current protocol offers a synthetically applicable pathway to construct a variety of oligo-heterocycles through Cu-mediated single-electron transfer and decarboxylation. Notably, synthesis of relatively inaccessible di-heterocycles has been achieved successfully using this protocol.

Palladium-catalyzed benzofuran and indole synthesis by multiple C-H functionalizations.

Heterocyclic compounds are commonly found in the core structures of several pharmaceuticals, natural products, and agrochemicals, thus spurring intensive research for conducting their synthesis in a mild and simpler way. Over the years, a host of different strategies has been introduced in an effort to synthesize these heterocyles. In this context, significant attention has been gained by methodologies that ensure both step as well as atom efficiency. Synthesis of heterocyclic moieties via multiple C-H activations was found to fulfill these expectations besides guaranteeing the use of starting materials that are easily procurable. This review is focused on the current development in the field of benzofuran and indole synthesis using multiple C-H functionalization strategies.

Rhodium-Catalyzed meta-C-H Functionalization of Arenes.

Rhodium-catalyzed ortho-C-H functionalization is well known in the literature. Described herein is the Xphos-supported rhodium catalysis of meta-C-H olefination of benzylsulfonic acid and phenyl acetic acid frameworks with the assistance of a para-methoxy-substituted cyano phenol as the directing group. Complete mono-selectivity is observed for both scaffolds. A wide range of olefins and functional groups attached to arene are tolerated in this protocol.

Traceless directing group mediated branched selective alkenylation of unbiased arenes.

Owing to the synthetic importance of branched olefinated products, we report palladium catalyzed formation of branched olefins facilitated by a C-H activation based protocol. This involves selective insertion of olefins and subsequent decarboxylation using a completely unbiased benzene ring as the starting precursor. The significance of the protocol has been further highlighted by exhibition of functionality tolerance along with a late-stage modification of the branched olefinated products leading to the formation of other functionalized molecules.

Palladium-Catalyzed Directed para C-H Functionalization of Phenols.

Various practical methods for the selective C-H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C-H functionalization of toluene derivatives, we herein report the first remote para C-H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.

Palladium catalysed meta-C-H functionalization reactions.

The directing group assisted site selective C-H functionalization approach is having a continuous impact in the field of natural product synthesis, drug discovery and material sciences. While ortho-selective C-H functionalization has been studied extensively, meta-selective C-H functionalization has been less explored. Recent studies have highlighted the efficacy of palladium as a catalyst in activating the meta-C-H bond of arenes. Notably, the introduction of a novel palladium catalysed directing template based approach to activate the remote meta-position has created a revolutionary impact towards seeking a solution to this long standing challenge. In this review we summarize recent advances in palladium catalysed meta-C-H functionalization that have helped in creating a new outlook towards modern organic synthesis.

Sequential meta-C-H olefination of synthetically versatile benzyl silanes: effective synthesis of meta-olefinated toluene, benzaldehyde and benzyl alcohols.

Tremendous progress has been made towards ortho-selective C-H functionalization in the last three decades. However, the activation of distal C-H bonds and their functionalization has remained fairly underdeveloped. Herein, we report sequential meta-C-H functionalization by performing selective mono-olefination and bis-olefination with late stage modification of the C-Si as well as Si-O bonds. Temporary silyl connection was found to be advantageous due to its easy installation, easy removal and wide synthetic diversification.

Palladium-Catalyzed Synthesis of 2,3-Disubstituted Benzofurans: An Approach Towards the Synthesis of Deuterium Labeled Compounds.

Palladium-catalyzed oxidative annulations between phenols and alkenylcarboxylic acids produced a library of benzofuran compounds. Depending on the nature of the substitution of the phenol precursor, either 2,3-dialkylbenzofurans or 2-alkyl-3-methylene-2,3-dihydrobenzofurans can be synthesized with excellent regioselectivity. Reactions between conjugated 5-phenylpenta-2,4-dienoic acids and phenol gave 3-alkylidenedihydrobenzofuran alkaloid motifs while biologically active 7-arylbenzofuran derivatives were prepared by starting from 2-phenylphenols. More interestingly, selective incorporation of deuterium from D2O has been discovered, which offers an attractive one-step method to access deuterated compounds.

Nickel-Catalyzed Insertion of Alkynes and Electron-Deficient Olefins into Unactivated sp(3) C-H Bonds.

Insertion of unsaturated systems such as alkynes and olefins into unactivated sp(3) C-H bonds remains an unexplored problem. We herein address this issue by successfully incorporating a wide variety of functionalized alkynes and electron-deficient olefins into the unactivated sp(3) C-H bond of pivalic acid derivatives with excellent syn- and linear- selectivity. A strongly chelating 8-aminoquinoline directing group proved beneficial for these insertion reactions, while an air-stable and inexpensive Ni(II) salt has been employed as the active catalyst.

Orthogonal selectivity with cinnamic acids in 3-substituted benzofuran synthesis through C-H olefination of phenols.

A palladium catalyzed intermolecular annulation of cinnamic acids and phenols has been achieved for the selective synthesis of 3-substituted benzofurans. Isotope labeling, competition experiments, kinetic studies, and intermediate trapping have supported a sequence of C-C bond formation and decarboxylation followed by the C-O cyclization pathway.

Palladium-catalyzed annulation of diarylamines with olefins through C-H activation: direct access to N-arylindoles.

A palladium-catalyzed dehydrogenative coupling between diarylamines and olefins has been discovered for the synthesis of substituted indoles. This intermolecular annulation approach incorporates readily available olefins for the first time and obviates the need of any additional directing group. An ortho palladation, olefin coordination, and ß-migratory insertion sequence has been proposed for the generation of olefinated intermediate, which is found to produce the expected indole moiety.

Nickel-catalyzed hydrogenolysis of unactivated carbon-cyano bonds.

Selective hydrogenolysis of C-CN bonds can allow chemists to take advantage of ortho-directing ability, α-C-H acidity and electron withdrawing ability of the cyano group for synthetic manipulations. We have discovered hydrogenolysis of aryl and aliphatic cyanides under just 1 bar of hydrogen by using a nickel catalyst. This protocol was applied in the aryl cyanide directed functionalization reaction and α-substitution of benzyl cyanides.

Nickel-catalyzed decyanation of inert carbon-cyano bonds.

Nickel catalyzed decyanation of aryl and aliphatic cyanides with hydrosilane as the hydride source has been developed. This method is easy to handle, scalable and can be carried out without a glove box. The method has been applied in the cyanide directed functionalization reaction and α-substitution of benzyl cyanide.

ipso-Nitration of arylboronic acids with bismuth nitrate and perdisulfate.

An efficient and one pot synthetic method of ipso-nitration of arylboronic acids has been developed. The high efficiency, general applicability, and broader substrate scope including heterocycles and functional groups make this method advantageous. Due to its simplicity, we expect to find application of this method in synthesis.