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3‐Amino‐substituted saturated nitrogen heterocycles are an important subclass of β‐diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox‐mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N−H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks., Medicinally important 3‐amino‐substituted cyclic amines can be accessed in a single step by photoredox‐catalysed hydroamination of cyclic enecarbamates. A diverse range of drug‐relevant amine substituents can be introduced under unified reaction conditions, including primary alkyl amines, ammonia, (hetero)aromatic amines, and N‐heterocycles (see scheme).

A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries.

High throughput experimentation (HTE) has enabled the rapid identification of ligand/precatalyst combinations that facilitate highly enantioselective hydrogenations of prochiral N‐alkyl α‐aryl ketimines containing a furyl moiety. The chiral amines obtained have proven to be modular precursors in the synthesis of novel unnatural mono N‐alkylated arylalanines and related derivatives.

Vinyl acetate is used as an acetylene equivalent in rhodium(III)-catalysed C-H activation/annulation with aryl ketoxime esters. Extension to an aldoxime ester allows for a concise formal synthesis of decumbenine B.

Aryl dialkyl amines, valuable subunits of a wide range of effect chemicals, are accessed by intramolecular amination of aromatic C–H bonds employing UV photolysis of N-chloroamines. The reactions show good functional group tolerance and allow access to a range of fused and bridged polycyclic structures. The homogeneous reaction conditions allow for the one-pot conversion of secondary amines to their arylated derivatives. Experimental and theoretical evidence supports the involvement of electrophilic aminium radicals which react via direct ortho-attack on the arene.

The organocatalytic asymmetric transfer hydrogenation of N-alkyl aryl imino esters for the direct synthesis of N-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity.

Investigation of the use of green organic solvents for the Cu-catalysed arylation of phenols and amides is reported. Alkyl acetates proved to be efficient solvents in the catalytic processes, and therefore excellent alternatives to the typical non-green solvents used for Cu-catalysed arylation reactions. Solvents such as isosorbide dimethyl ether (DMI) and diethyl carbonate also appear to be viable possibilities for the arylation of phenols. Finally, a novel copper catalysed acyl transfer process is reported.

A convenient, one-pot, two-component synthesis of 2-(1-amidoalkyl)pyridines is reported, based upon the substitution of suitably-activated pyridine N-oxides by azlactone nucleophiles, followed by decarboxylative azlactone ring-opening. The synthesis obviates the need for precious metal catalysts to achieve a formal enolate arylation reaction, and constitutes a formally ‘umpoled’ approach to this valuable class of bioactive structures.

A general and efficient method for the synthesis of drug-like fused bicyclic hydantoins is reported. An Ugi–Joullie reaction/cyclisation sequence was exploited as the key complexity-generating process in which trifluoroacetic acid was employed as synthetic equivalent for chloroformic acid. Exemplar diversification of the bicyclic scaffolds was performed to enable subsequent translation to the synthesis of large small molecule libraries, leading to the production of >1000 compounds for addition to the screening collection of the European Lead Factory.

Cu-catalysed arylation reactions devoted to the formation of C-C and C-heteroatom bonds (Ullmann-type couplings) have acquired great importance in the last decade. This review discusses the history and development of coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years. Selected mechanistic investigations are treated more in depth than others. For example, evidence in favour or against radical mechanisms is discussed. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalcohol arylation are discussed. A separate section has been dedicated to the synthesis of heterocyclic rings through intramolecular couplings. Finally, recent developments in green chemistry for these reactions, such as reactions in aqueous media and heterogeneous catalysis, have also been reviewed.

Aryl ethers are prepared by cross-coupling of phenols with aryl iodides in isopropyl acetate as solvent.

A one-pot, three-component synthesis of α-pyridyl, α-substituted amino acid derivatives is described. The key transformation is a direct, precious-metal-free heteroarylation of readily available, amino acid derived azlactones with electrophilically activated pyridine N-oxides. The resulting intermediates can be used directly as efficient acylating agents for a range of nucleophiles, leading to the heteroarylated amino acid derivatives in a single vessel.

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels–Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.

Bicyclic hydantoins are efficiently obtained utilizing a three-component Ugi—Joullie reaction/cyclization sequence as key complexicity-generation process using trifluoroacetic acid as synthetic equivalent for chloroformic acid.

The combination of an air-stable iridium catalyst and the dipolar aprotic solvent dimethyl sulfoxide (DMSO) allowed, for the first time, the systematic exploitation of highly polar, functionalized amines in asymmetric allylic substitutions: low molecular weight, sp 3 -rich chiral building blocks were obtained with physicochemical properties that will be valuable in the synthesis of lead-like small molecules.

The use of [Cp*IrI2]2 as an efficient catalyst for the alkylation of amines by alcohols in either water or ionic liquid is described. Primary amines are converted into secondary amines, and secondary amines into tertiary amines in the absence of base, and the chemistry has been applied to the synthesis of the analgesic fentanyl. The conversion of primary amines into N-heterocycles by the reaction with diols is also described, along with the N-alkylation of sulfonamides.

Benzoxazoles are synthesised directly by oxidative condensation of primary and secondary amines with o-aminophenols under hydrogen transfer catalysis. The optimal system utilises 1 mol % of the Shvo catalyst, with dimethoxybenzoquinone as the hydrogen-accepting terminal oxidant.

Stable silylketenes, prepared by rhodium-catalysed decomposition of silyldiazoketones, undergo addition/cyclocondensation sequences with aminophenols and aminomalonate to give α-silylalkylbenzoxazoles and oxazoles, respectively. The silicon can be retained throughout functional group interconversions or can be removed by protodesilylation under acidic conditions as desired.

A de novo asymmetric synthesis of the octahydroisobenzofuran skeleton contained within the eunicellin family of natural products has been completed. The key transformations involve the convergent assembly of a tetrasubstituted tetrahydrofuran by condensation of a functionalised allylsiloxane with an aldehyde; controlled epimerisation of a C4 aldehyde by intramolecular trapping; installation of the isopropyl substituent by stereoselective Michael addition to a 5,5-bicyclic enone; and ring expansion of the 5,5-system to the target structure by radical-mediated cyclopropane fragmentation.

The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans. With electron-rich aryl and alpha,beta-unsaturated aldehydes as substrates, the stereochemical outcome at C5 can be dictated by appropriate choice of Lewis acid. The reaction has been applied to a concise (nine step) synthesis of (+)-virgatusin (ent-1). [reaction: see text]

The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production.

The behavior of electron-rich alkenes in rhodium-catalyzed C–H activation/annulation reactions is investigated. Vinyl acetate emerges as a convenient acetylene equivalent, facilitating the synthesis of sixteen 3,4-unsubstituted isoquinolones, as well as select heteroaryl-fused pyridones. The complementary regiochemical preferences of enol ethers versus enol esters/enamides is discussed.

Rh-catalysed conjugate additions of 2-aminophenyl boronic acid derivatives were exploited in diastereoselective and asymmetric syntheses of tetrahydroquinolines. In both cases, combinatorial variation of the substitution of the tetrahydroquinoline ring system was possible.

The use of picolinic acid amide derivatives as an effective family of bidentate ligands for copper-catalysed aryl ether synthesis is reported. A fluorine-substituted ligand gave good results in the synthesis of a wide range of aryl ethers. Even bulky phenols, known to be very challenging substrates, were shown to react with aryl iodides with excellent yields using these ligands. At the end of the reaction, the first examples of end-of-life Cu species were isolated and identified as Cu(II) complexes with several of the anionic ligands tested. A preliminary mechanistic investigation is reported that suggests that the substituents on the ligands might have a crucial role in determining the redox properties of the metal centre and, consequently, its efficacy in the coupling process. An understanding of these effects is important for the development of new efficient and tunable ligands for copper-based chemistry.

Vinyl dioxazaborocines 5 with asymmetric centres on the nitrogen bridgehead substituent have been prepared and assayed in nitrile oxide and nitrone cycloadditions, giving asymmetric inductions of up to 70 and 74% ee, respectively.

The epoxidation of a number of cyclic and linear terminal alkenes by an O 2 –O 3 mixture at room temperatures catalysed by Fe(TMP)Cl is reported. It appears that the alkene forms a primary ozonide which rearranges to a secondary ozonide, and it is the latter which, when catalysed by Fe(TMP)Cl, affects the subsequent alkene epoxidation. A number of other metal complexes were also tested as catalysts, but Fe(TMP)Cl was the most effective.

The formation of a phosphine oxide with its strong P=O bond is the driving force for the classical Wittig reaction, but is wasteful and can pose problems during purification. A new development allowing the use of catalytic phosphorus reagents promises to clean up olefination chemistry.

A catalyst screening programme has revealed that a combination of Pd(0) and the N-heterocyclic carbene ligand SIPr forms a particularly robust and efficient catalyst for the formation of important quaternary 3-aminooxindoles via intramolecular enolate arylation. Catalyst loadings of 0.1 mol % give complete conversion in under 4 h.

The first examples of heterocycle synthesis by iminophosphorane formation/intramolecular aza-Wittig cyclizations that are catalytic in the organophosphorus component are reported. The reaction has been demonstrated in the synthesis of both azine (phenanthridine) and azole (benzoxazole) heterocycles. Catalyst loadings down to 1 mol % have been used with little or no loss in reaction efficiency. The intimate involvement of the phosphine oxide in the catalytic cycle has been verified by in situ infrared spectroscopy.

Vinyl dioxazaborocines 1a-c have been subjected to 1,3-dipolar cycloadditions with benzonitrile oxide. The products are enantiomerically enriched 5-substituted Δ 2 -isoxazolines 2a-c .

The rhodium catalysed CH insertion reactions of α-(triethylsilyl)diazoacetates have been studied, facilitating the stereoselective synthesis of α-(triethylsilyl)-γ-lactones. An intriguing and unprecedented inversion of stereoselectivity is observed upon changing from rhodium (II) carboxylates to rhodium (II) acetamide as catalyst for insertion to acyclic esters.

An ozone–oxygen mixture has been used to generate a number of high oxidation-state transition-metal complexes in aqueous solution at room temperature by simple and safe procedures. Species so prepared include the oxo species [OsVIIIO4], [RuVIIIO4], cis-[OsVIIIO4(OH)2]2–, trans-[OsVIO2(OH)4]2–, [RuVIIO4]–, trans-[RuVI(OH)2O3]2–, [VVO4]3– and the new complex [PPh4]2[Ru2O(µ-OCOEt)2Cl6] 1 for which the crystal structure is reported; the polyoxometalates K6[MnIVMo9O32]·10H2O, K8[MnIVW6O24]·6H2O, [NH4]2[MnIVMo6H6O24]·20H2O and Na8[CeIVW10O36]·8H2O; the chloro complexes [MIVCl6]2– (M = Pt, Pd, Ir) and [AuIIICl4]–, and manganic acetate [MnIII(OAc)3]·2H2O. Ozonolytic oxidation of coordinated benzylamine in cis-[RuII(bipy)2(NH2CH2Ph)2][PF6]2 to coordinated benzonitrile in cis-[RuII(bipy)2(NCPh)2][PF6]2 is also reported.

A concise (six-step) synthesis of the indolizidine alkaloid tashiromine (1) has been achieved. Olefin cross-metathesis was used to prepare a key functionalised allylsilane, which subsequently underwent electrophile-induced ring-closure to establish the bicyclic framework with complete control of stereochemistry.

A convergent synthesis of the C22C32 portion of rapamycin has been achieved by way of a Nozaki-Kishi coupling of vinyl iodide 14 with aldehyde 13. This aldehyde is available by the stereoselective addition of organometallic reagents to aldehyde 5, synthesised by either of two selenium mediated electrophilic cyclisations. Optically active starting materials for this synthesis are prepared by an enzymatic acylation of meso-diol 6.

This article reviews the oxidations of a wide range of molecules with tetrapropylammonium perruthenate including examples of both double oxidations and selective oxidations. Mechanistic studies are discussed and general experimental procedures are reported. In addition several interesting developments in the chemistry of this reagent are outlined, that is, heteroatom oxidation, cleavage reactions and also its use in sequential reaction processes. In order to present a complete picture examples of failed reactions have been included

Amines have been formylated using aqueous formaldehyde or paraformaldehyde and the iridium catalyst [Cp∗IrI2]2. Paraformaldehyde acts as both a formylating agent and an oxidant.

This article reviews the oxidations of a wide range of molecules with tetrapropylammonium perruthenate including examples of both double oxidations and selective oxidations. Mechanistic studies are discussed and general experimental procedures are reported. In addition several interesting developments in the chemistry of this reagent are outlined, that is, heteroatom oxidation, cleavage reactions and also its use in sequential reaction processes. In order to present a complete picture examples of failed reactions have been included

Vinyl dioxazaborocines 1a-c have been subjected to 1,3-dipolar cycloadditions with benzonitrile oxide. The products are enantiomerically enriched 5-substituted Δ 2 -isoxazolines 2a-c .

Silylketenes bearing a range of substituents (alkyl, alkenyl, aryl, heteroaryl) are prepared by an unusual rhodium mediated Wolff rearrangement of the corresponding silyl diazo ketones.

Stable silylketenes, prepared by rhodium-catalysed decomposition of silyldiazoketones, undergo addition/cyclocondensation sequences with aminophenols and aminomalonate to give α-silylalkylbenzoxazoles and oxazoles, respectively. The silicon can be retained throughout functional group interconversions or can be removed by protodesilylation under acidic conditions as desired.

The first examples of heterocycle synthesis by iminophosphorane formation/intramolecular aza-Wittig cyclizations that are catalytic in the organophosphorus component are reported. The reaction has been demonstrated in the synthesis of both azine (phenanthridine) and azole (benzoxazole) heterocycles. Catalyst loadings down to 1 mol % have been used with little or no loss in reaction efficiency. The intimate involvement of the phosphine oxide in the catalytic cycle has been verified by in situ infrared spectroscopy.