Search

Cationic Ir(I)-complexes modified with homochiral diphosphines promote the hydroalkenylative cross-coupling of β-(arylamino)acrylates with monosubstituted styrenes and α-olefins. The processes are dependent on the presence of an NH unit, and it is postulated that metalation of this generates an iridium aza-enolate that engages the alkene during the C-C bond forming event. The method offers high branched selectivity and enantioselectivity and occurs with complete atom economy. Diastereocontrolled reduction of the products provides β 2 -amino acids that possess contiguous stereocenters.

Homochiral α-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the α-stereocentre. By contrast, and despite their importance, α-amino acids possessing β-stereocentres are much harder to synthesize. Here we demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give β-substituted α-amino acids with exceptional levels of regio- and stereocontrol. Our method exploits the native directing ability of a glycine-derived N-H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or α-olefin to install two contiguous stereocentres. The process offers very high levels of regio- and stereocontrol and occurs with complete atom economy. In broader terms, our reaction design offers a unique directing-group-controlled strategy for the direct stereocontrolled α-alkylation of carbonyl compounds, and provides a powerful approach for the synthesis of challenging contiguous stereocentres., (© 2024. The Author(s).)

The first systematic exploration of the synthesis and reactivity of naphthoquinonynes is described. Routes to two regioisomeric Kobayashi-type naphthoquinonyne precursors have been developed, and the reactivity of the ensuing 6,7- and 5,6-aryne intermediates has been investigated. Remarkably, these studies have revealed that a broad range of cycloadditions, nucleophile additions and difunctionalizations can be achieved while maintaining the integrity of the highly sensitive quinone unit. The methodologies offer a powerful diversity oriented approach to C6 and C7 functionalized naphthoquinones, which are typically challenging to access. From a reactivity viewpoint, the study is significant because it demonstrates that aryne-based functionalizations can be utilized strategically in the presence of highly reactive and directly competing functionality., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Under acidic reaction conditions (TFA), deprotection of BocNR(OSO 2 R) reagents triggers intermolecular aminative cyclizations of alkenes equipped with pendant nucleophiles. The processes are predicated on a sequence of stereospecific intermolecular aza-Prilezhaev aziridination followed by stereospecific S N 2-like opening by the pendant nucleophile. The method offers broad scope with respect to the nucleophile (N-, O- or C-based), alkene and cyclization mode, allowing the installation of two contiguous stereocenters under operationally simple conditions., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Upon exposure to a cationic Ir(I)-complex modified with the chiral diphosphine DuanPhos, hydroalkylations of styrenes and α-olefins with diverse heteroaryl tert -butyl acetates occur with complete branched selectivity and very high enantioselectivity. The initial adducts undergo acid promoted decarboxylation in situ to provide alkylated heteroarenes possessing defined β-stereocenters. The processes are postulated to proceed via a stereodefined chiral Ir-enolate, which arises upon heteroarene directed enolization of the heteroaryl acetate precursor. The method can be classified as an enantioselective decarboxylative C(sp 3 )-C(sp 3 ) cross-coupling.

We describe a Au I complex of a hemi-labile (C^N) N-heterocyclic carbene ligand that is able to mediate oxidative addition of aryl iodides. Detailed computational and experimental investigations have been undertaken to verify and rationalize the oxidative addition process. Application of this initiation mode has resulted in the first examples of "exogenous oxidant-free" Au I /Au III catalyzed 1,2-oxyarylations of ethylene and propylene. These demanding yet powerful processes establish these commodity chemicals as nucleophilic-electrophilic building blocks in catalytic reaction design., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

TFA promoted deprotection of O-Ts activated N-Boc hydroxylamines triggers aminofunctionalization-based polycyclizations of tethered alkenes. The processes involve intramolecular stereospecific aza-Prilezhaev alkene aziridination in advance of stereospecific C-N cleavage by a pendant nucleophile. Using this approach, a wide range of fully intramolecular alkene anti-1,2-difunctionalizations can be achieved, including diaminations, amino-oxygenations and amino-arylations. Trends associated with the regioselectivity of the C-N cleavage step are outlined. The method provides a broad and predictable platform for accessing diverse C(sp 3 )-rich polyheterocycles of relevance to medicinal chemistry., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

A MeDalPhos-ligated gold(III) metallafluorene complex, generated via C-C oxidative addition of biphenylene, reacts with CO to produce 9-fluorenone. Experimental and computational studies show that this proceeds via a hitherto unknown migratory insertion of CO into a Au(III)-C bond. This process is more energetically challenging compared to other M-C bonds, but once achieved, the product is comparatively stable with respect to retro-carbonylation. Exploiting migratory insertion of CO into Au-C bonds may extend the range of products that are accessible using gold chemistry.

Unique examples of aza-Heck-based C(sp 3 )-H functionalization cascades are described. Under Pd(0)-catalyzed conditions, the aza-Heck-type cyclization of N -(pentafluorobenzoyloxy)carbamates generates alkyl-Pd(II) intermediates that effect C(sp 3 )-H palladation en route to cyclopropanes. Key factors that control the site selectivity of the cyclopropanation process have been elucidated such that selective access to a wide range of ring- or spiro-fused systems can be achieved.

Quaternary benzylic centers are accessed with high atom and step economy by Ir-catalyzed alkene hydroarylation. These studies provide unique examples of the use of non-polarized 1,1-disubstituted alkenes in branch selective Murai-type hydro(hetero)arylations. Detailed mechanistic studies have been undertaken, and these indicate that the first irreversible step is the demanding alkene carbometallation process. Structure-reactivity studies show that the efficiency of this is critically dependent on key structural features of the ligand. Computational studies have been undertaken to rationalize this experimental data, showing how more sterically demanding ligands reduce the reaction barrier via predistortion of the reacting intermediate. The key insight disclosed here will underpin the ongoing development of increasingly sophisticated branch selective Murai hydroarylations., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

An endo-directing group strategy enables enantioselective (3+1+2) cycloadditions that are triggered by carbonylative C-C bond activation of cyclopropanes. These processes are rare examples of cycloadditions where C-C bond oxidative addition is enantiodetermining, and the first where this is achieved within the context of a multicomponent (higher order) reaction design., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Under Rh-catalyzed conditions, secondary amines and anilines function as directing groups to facilitate regioselective C-C bond activation of nonactivated cyclopropanes. The resulting amino-stabilized rhodacycles undergo carbonylative C-N bond formation en route to challenging seven- and eight-membered lactams. The processes represent rare examples where C-C bond oxidative addition of nonactivated cyclopropanes is exploited in reaction design.

Metal catalyzed C-H functionalization offers a versatile platform for methodology development and a wide variety of reactions now exist for the chemo- and site-selective functionalization of organic molecules. Cyclopentadienyl-metal (CpM) complexes of transition metals and their correlative analogues have found widespread application in this area, and herein we highlight several key applications of commonly used transition-metal Cp-type catalysts. In addition, an understanding of transition metal Cp-type catalyst synthesis is important, particularly where modifications to the catalyst structure are required for different applications, and a summary of this aspect is given.

Classical amination methods involve the reaction of a nitrogen nucleophile with an electrophilic carbon center; however, in recent years, umpoled strategies have gained traction where the nitrogen source acts as an electrophile. A wide range of electrophilic aminating agents are now available, and these underpin a range of powerful C-N bond-forming processes. In this Review, we highlight the strategic use of electrophilic aminating agents in total synthesis., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

A combined theoretical and experimental approach has been used to study the unusual mechanism of oxidative addition of aryl iodides to [bipyAu(C 2 H 4 )] + complexes. The modular nature of this system allowed a systematic assessment of the effects of complex structure. Computational comparisons between cationic gold and the isolobal (neutral) Pd 0 and Pt 0 complexes revealed similar mechanistic features, but with oxidative addition being significantly favored for the group 10 metals. Further differences between Au and Pd were seen in experimental studies: studying reaction rates as a function of electronic and steric properties showed that ligands bearing more electron-poor functionality increase the rate of oxidative addition; in a complementary way, electron-rich aryl iodides give faster rates. This divergence in mechanism compared to Pd suggests that Ar-X oxidative addition with Au can underpin a broad range of new or complementary transformations., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Dearomatization reactions allow the direct synthesis of structurally complex sp 3 -rich molecules from readily available "flat" precursors. Established dearomatization processes commonly involve the formation of new C-C bonds, whereas methods that enable the introduction of C-N bonds have received less attention. Because of the privileged position of nitrogen in drug discovery, significant recent methodological efforts have been directed towards addressing this deficiency. Consequently, a variety of new processes are now available that allow the direct preparation of sp 3 -rich amino-containing building blocks and scaffolds. This review gives an overview of C-N bond forming dearomatization reactions, particularly with respect to scaffold assembly processes. The discussion gives historical context, but the main focus is on selected methods that have been reported recently., (© 2021 The Authors. Published by The Chemical Society of Japan & Wiley-VCH GmbH.)

Structurally complex benzo- and spiro-fused N-polyheterocycles can be accessed via intramolecular Pd(0)-catalyzed alkene 1,2-aminoarylation reactions. The method uses N -(pentafluorobenzoyloxy)carbamates as the initiating motif, and this allows aza-Heck-type alkene amino-palladation in advance of C-H palladation of the aromatic component. The chemistry is showcased in the first total synthesis of the complex alkaloid (+)-pileamartine A, which has resulted in the reassignment of its absolute stereochemistry.

This review summarizes synthetic developments reported from 1987 to 2019 that exploit C-C single bond cleavage of cyclopropylamine-based systems. The synthetic and mechanistic aspects of key methodologies are highlighted, and examples where aminocyclopropanes are exploited as key intermediates in multistep synthesis are also discussed. The review encompasses cases where aminocyclopropanes participate in polar reactions, pericyclic processes, radical-based reactions, and C-C bond activations.

Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited, and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF 3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo is essential for the development of a novel, specific and safe derivative, minimizing adverse effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Temporary directing groups (TDGs) underpin a range of C-C bond activation methodologies; however, the use of TDGs for the regiocontrolled activation of cyclopropane C-C bonds is underdeveloped. In this report, we show how an unusual ring contraction process can be harnessed for TDG-based carbonylative C-C bond activations of cyclopropanes. The method involves the transient installation of an isocyanate-derived TDG, rather than relying on carbonyl condensation events as used in previous TDG-enabled C-C bond activations.

Rhodium-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulations and nitroalkene reactions have been employed for the synthesis of 56 quinone-based compounds. These were evaluated against Trypanosoma cruzi, the parasite that causes Chagas disease. The reactions described here are part of a program that aims to utilize modern, versatile and efficient synthetic methods for the one or two step preparation of trypanocidal compounds. We have identified 9 compounds with potent activity against the parasite; 3 of these were 30-fold more potent than benznidazole (Bz), a drug used for the treatment of Chagas disease. This article provides a comprehensive outline of reactions involving over 120 compounds aimed at the discovery of new quinone-based frameworks with activity against T. cruzi., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The practical synthesis of carbohydrate-based NHC-Rh complexes bearing C1 or C3 sterically differentiated positions, accessed by glycosylation or SNAr strategies, is reported. These catalysts exhibit pseudo-enantiomeric behaviour in the hydrosilylation of acetophenone. We show that steric bulk at C1 gives preference for (S)-phenyl-1-ethanol, while bulk at C3 leads to the (R)-enantiomer. These results represent the first example of pseudo-enantiomeric carbohydrate-based NHC ligands leading to enantiotopic discrimination.

The first isolated examples of intermolecular oxidative addition of alkenyl and alkynyl iodides to Au I are reported. Using a 5,5'-difluoro-2,2'-bipyridyl ligated complex, oxidative addition of geometrically defined alkenyl iodides occurs readily, reversibly and stereospecifically to give alkenyl-Au III complexes. Conversely, reversible alkynyl iodide oxidative addition generates bimetallic complexes containing both Au III and Au I centers. Stoichiometric studies show that both new initiation modes can form the basis for the development of C-C bond forming cross-couplings., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We outline a conceptual blueprint that provides direct and atom economical access to a wide range of complex polyheterocycles. Our method capitalizes on the ambiphilic reactivity of rhodacyclopentanones that arise upon exposure of cyclopropanes to Rh(I) catalysts and CO. Using this approach, a wide array of polycyclizations are achieved, including variants that involve powerful dearomatizations and medium ring formations.

The first examples of Rh-catalyzed [2 + 2 + 2] cycloadditions between diynes and benzoquinones are described. The method enables de novo and step-economical access to challenging naphthoquinones that are of relevance to lignan and type II polyketide synthesis. The value of the chemistry is demonstrated by a short total synthesis of justicidone.

Aminocyclopropanes equipped with pendant nucleophiles undergo carbonylative heterocyclization triggered by C-C bond activation to generate eight-membered N-heterocycles. In these processes, intramolecular "capture" of a rhodacyclopentanone intermediate by an aryl or N-based nucleophile is followed by C-C or C-N bond-forming "collapse" to the targets. These studies demonstrate how the combination of cyclopropane strain release and the templating effect of catalytically generated metallacycles can be harnessed to enable otherwise challenging medium ring closures., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pd(0)-systems modified with SPINOL-derived phosphoramidate ligands promote highly enantioselective aza-Heck cyclizations of alkenyl N-(tosyloxy)carbamates. The method provides versatile access to challenging N-heterocycles and represents the broadest scope enantioselective aza-Heck protocol developed to date.

Rh-catalyzed carbonylative C-C bond activation of cyclopropylamides generates configurationally stable rhodacyclopentanones that engage tethered alkenes in (3+1+2) cycloadditions. These studies provide the first examples of multicomponent cycloadditions that proceed through C-C bond activation of "simple" electron poor cyclopropanes., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In situ deprotection (TFA) of O-Ts activated N-Boc hydroxylamines triggers intramolecular aziridination of N-tethered alkenes to provide complex N-heterocyclic ring systems. Synthetic and computational studies corroborate a diastereospecific aza-Prilezhaev-type mechanism. The feasibility of related intermolecular alkene aziridinations is also demonstrated.

An Ir I -system modified with a ferrocene derived bisphosphine ligand promotes α-selective arylation of styrenes by dual C-H functionalization. These studies offer a regioisomeric alternative to the Pd-catalyzed Fujiwara-Moritani reaction., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This review concentrates on recent developments from our laboratory concerning the Rh-catalyzed carbonylative C-C bond activation of cyclopropanes. Specifically, we have found that N-based directing groups are effective at controlling the regioselectivity of C-C bond activation during the formation of rhodacyclopentanone intermediates. These engage tethered π -unsaturated components ( e.g. alkenes) or conventional nucleophiles in cycloaddition and heterocyclization processes, respectively. Using this approach, direct and modular access to a wide range of complex heterocyclic ring systems is achieved. The review summarizes the scope of our methodologies and outlines key mechanistic features.

Tertiary benzylic stereocenters are accessed in high enantioselectivity by Ir-catalyzed branch selective addition of anilide ortho-C-H bonds across styrenes and α-olefins. Mechanistic studies indicate that the stereocenter generating step is reversible.

Ligand-enabled aza-Heck cyclizations and cascades of N-(pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non-biased 6-exo aza-Heck cyclizations. The methodology provides direct and flexible access to carbamate protected pyrrolidines and piperidines., (© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Three-coordinate bipyridyl complexes of gold, [(κ 2 -bipy)Au(η 2 -C 2 H 4 )][NTf 2 ], are readily accessed by direct reaction of 2,2'-bipyridine (bipy), or its derivatives, with the homoleptic gold ethylene complex [Au(C 2 H 4 ) 3 ][NTf 2 ]. The cheap and readily available bipyridyl ligands facilitate oxidative addition of aryl iodides to the Au(I) center to give [(κ 2 -bipy)Au(Ar)I][NTf 2 ], which undergo first aryl-zinc transmetalation and second C-C reductive elimination to produce biaryl products. The products of each distinct step have been characterized. Computational techniques are used to probe the mechanism of the oxidative addition step, offering insight into both the origin of the reversibility of this process and the observation that electron-rich aryl iodides add faster than electron-poor substrates. Thus, for the first time, all steps that are characteristic of a conventional intermolecular Pd(0)-catalyzed biaryl synthesis are demonstrated from a common monometallic Au complex and in the absence of directing groups.

A modular Rh-catalyzed entry to azepines is outlined. Under a CO atmosphere, protecting group directed C-C bond activation of aminocyclopropanes provides rhodacyclopentanones. These intermediates are effective for intramolecular C-H metalation of either an N-aryl or N-vinyl unit en route to azepine ring systems. Thus, byproduct-free heterocyclizations are enabled by sequential C-C activation and C-H functionalization steps.

A C-N bond forming dearomatization protocol with broad scope is outlined. Specifically, bifunctional amino reagents are used for sequential nucleophilic and electrophilic C-N bond formations, with the latter effecting the key dearomatization step. Using this approach, γ-arylated alcohols are converted to a wide range of differentially protected spirocyclic pyrrolidines in just two or three steps., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Nickel-catalyzed coupling of benzyl acrylates with activated ketones and imines provides γ-butyrolactones and lactams, respectively. The benzyl alcohol byproduct released during the lactonization/lactamization event is relayed to the next cycle where it serves as the reductant for C-C bond formation. This strategy represents a conceptually unique approach to transfer-hydrogenative C-C bond formation, thus providing examples of reductive heterocyclizations where hydrogen embedded within an alcohol leaving group facilitates turnover., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

We outline a simple protocol that accesses directly unprotected secondary amines by intramolecular C-N bond forming dearomatization or aryl C-H amination. The method is dependent on the generation of a potent electrophilic aminating agent released by in situ deprotection of O-Ts activated N-Boc hydroxylamines.

Under the conditions of oxidative gold catalysis, exposure of ethylene to aryl silanes and alcohols generates products of 1,2-oxyarylation. This provides a rare example of a process that allows catalytic differential 1,2-difunctionalization of this feedstock chemical.

Thirty four halogen and selenium-containing quinones, synthesized by rhodium-catalyzed C-H bond activation and palladium-catalyzed cross-coupling reactions, were evaluated against bloodstream trypomastigotes of T. cruzi. We have identified fifteen compounds with IC 50 /24 h values of less than 2 μM. Electrochemical studies on A-ring functionalized naphthoquinones were also performed aiming to correlate redox properties with trypanocidal activity. For instance, (E)-5-styryl-1,4-naphthoquinone 59 and 5,8-diiodo-1,4-naphthoquinone 3, which are around fifty fold more active than the standard drug benznidazole, are potential derivatives for further investigation. These compounds represent powerful new agents useful in Chagas disease therapy., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Aza-Heck cyclizations are an emerging method for the construction of chiral N-heterocyclic systems. In these processes, an activated N-O bond replaces the C-X bond (X = halide, OTf) used in conventional Heck reactions, with the associated aza-Pd(ii)-intermediate engaging pendant alkenes in a Heck-like manner. This perspective article commences with an historical overview of the area, which stems from Narasaka's seminal studies using oxime esters as the initiating motif. The scope and mechanism of associated chiral N-heterocyclic methodologies are then outlined, including cascade processes that enable diverse alkene 1,2-carboaminations. The recent emergence of new N-O donors and the realization of highly enantioselective aza-Heck cyclizations are then discussed. Collectively, these studies suggest that the aza-Heck approach can underpin a broad family of redox-neutral and enantioselective C-N bond forming processes.

In this review, synthetic and mechanistic aspects of key methodologies that exploit C-C single-bond cleavage of strained ring systems are highlighted. The focus is on transition-metal-catalyzed processes that are triggered by C-C bond activation and β-carbon elimination, with the review concentrating on developments from mid-2009 to mid-2016.

The first examples of highly enantioselective Narasaka-Heck cyclizations are described. A SPINOL-derived P,N-ligand system enables Pd-catalyzed 5- exo cyclization of a range of oxime esters with sterically diverse trisubstituted alkenes to generate dihydropyrroles containing tetrasubstituted nitrogen-bearing stereocenters in 56 to 86% yield and 90 : 10 to 95 : 5 e.r. These processes are rare examples of reactions that proceed via enantioselective migratory insertion of alkenes into Pd-N bonds, and the first where trisubstituted alkenes are used to generate tetrasubstituted stereocenters with high enantioselectivity.

Under carbonylative conditions, neutral Rh(I)-systems modified with weak donor ligands (AsPh 3 or 1,4-oxathiane) undergo N-Cbz, N-benzoyl, or N-Ts directed insertion into the proximal C-C bond of aminomethylcyclopropanes to generate rhodacyclopentanone intermediates. These are trapped by N-tethered alkenes to provide complex perhydroisoindoles.

Rhodacyclopentanones, an "sp(3)-rich" class of metallacycle, underpin an emerging range of catalytic methodologies for the direct generation of complex scaffolds. This review highlights strategies for accessing rhodacyclopentanones (and related species) by C-C bond activation of cyclobutanones or cyclopropanes. The scope and mechanism of methodologies that exploit these activation modes is outlined.

Under Rh-catalyzed conditions, typically electrophilic 1,4-benzoquinones exhibit nucleophilic reactivity, such that exposure to appropriate electrophiles generates products of C-H iodination, bromination, and phenylselenation. This provides a mild and general method for direct halofunctionalization, and the first method that can achieve direct C-H phenylselenation of this compound class. The scope and limitations of the new protocols are outlined, and representative derivatizations are highlighted.

Rhodacyclopentanones derived from carbonylative C-C activation of cyclopropyl ureas can be "captured" by pendant nucleophiles prior to "collapse" to 1,3-diazepanes. The choice of N-substituent on the cyclopropane unit controls the oxidation level of the product, such that C4-C5 unsaturated or saturated systems can be accessed selectively.

Aza-Heck cyclizations initiated by oxidative addition of Pd(0) -catalysts into the N-O bond of N-(pentafluoro-benzoyloxy)sulfonamides are described. These studies, which encompass only the second class of aza-Heck reaction developed to date, provide direct access to diverse N-heterocyclic ring systems., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Substituted heteroaromatic compounds, especially those based on pyridine, hold a privileged position within drug discovery and medicinal chemistry. However, functionalisation of the C2 position of 6-membered heteroarenes is challenging because of (a) the difficulties of installing a halogen at this site and (b) the instability of C2 heteroaryl-metal reagents. Here we show that C2-alkenylated heteroaromatics can be accessed by simple Brønsted acid catalysed union of diverse heteroarene N-oxides with alkenes. The approach is notable because (a) it is operationally simple, (b) the Brønsted acid catalyst is cheap, non-toxic and sustainable, (c) the N-oxide activator disappears during the reaction, and (d) water is the sole stoichiometric byproduct of the process. The new protocol offers orthogonal functional group tolerance to metal-catalysed methods and can be integrated easily into synthetic sequences to provide polyfunctionalised targets. In broader terms, this study demonstrates how classical organic reactivity can still be used to provide solutions to contemporary synthetic challenges that might otherwise be approached using transition metal catalysis.