An Aza-Enolate Strategy Enables Iridium-Catalyzed Enantioselective Hydroalkenylations of Minimally Polarized Alkenes en Route to Complex N-Aryl ß2-Amino Acids.

Cationic Ir(I)-complexes modified with homochiral diphosphines promote the hydroalkenylative cross-coupling of ß-(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 ß2-amino acids that possess contiguous stereocenters.

An Aza-Prilezhaev-Based Method Inverts Regioselectivity in Stereospecific Alkene 1,2-Aminohydroxylations.

Under acidic conditions (TFA) and in the presence of water, BocNHOTs promotes stereospecific 1,2-aminohydroxylations of alkenes. The processes involve intermolecular aza-Prilezhaev aziridination followed by stereospecific SN2 opening by water. This reagent combination provides regiochemical outcomes that are opposite to, or more selective than those observed using epoxidation initiated 1,2-aminohydroxylation protocols. Replacement of water by other nucleophiles allows 1,2-amino(thio)etherification, diamination, aminoazidation and aminofluorination reactions. Intramolecular processes are also feasible, including unusual variants that evoke azabicyclobutane-like reactivity.

A Strategy for the Formal C-N Cross-Coupling of Tertiary Amines.

We report a strategy for the C-N cross-coupling of tertiary amines via the in situ generation and displacement of N-acyl ammonium species. Specifically, treatment of diverse tertiary amines with TFAA or choroformates in the presence of NaI leads to the efficient generation of alkyl iodides, which can be engaged directly in Ni-catalyzed cross-couplings. The protocol is applicable to acyclic and cyclic systems, including highly hindered variants. Applications to the late-stage modification of complex heterocycles are presented.

The Synthesis and Reactivity of Naphthoquinonynes.

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.

Iridium-Catalyzed Enantioselective Alkene Hydroalkylation via a Heteroaryl-Directed Enolization-Decarboxylation Sequence.

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 ß-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(sp3)-C(sp3) cross-coupling.

Selective Carbon-Carbon Bond Cleavage of Cyclopropylamine Derivatives.

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.

A Stereospecific Alkene 1,2-Aminofunctionalization Platform for the Assembly of Complex Nitrogen-Containing Ring Systems.

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(sp3 )-rich polyheterocycles of relevance to medicinal chemistry.

Stereospecific Aminative Cyclizations Triggered by Intermolecular Aza-Prilezhaev Alkene Aziridination.

Under acidic reaction conditions (TFA), deprotection of BocNR(OSO2 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 SN 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.

A Hemilabile NHC-Gold Complex and its Application to the Redox Neutral 1,2-Oxyarylation of Feedstock Alkenes.

We describe a AuI 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" AuI /AuIII 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.

Migratory Insertion of CO into a Au-C Bond.

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.

Carbonylative N-Heterocyclization via Nitrogen-Directed C-C Bond Activation of Nonactivated Cyclopropanes.

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.

Cyclopropane-Fused N-Heterocycles via Aza-Heck-Triggered C(sp3)-H Functionalization Cascades.

Unique examples of aza-Heck-based C(sp3)-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(sp3)-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.

An endo-Directing-Group Strategy Unlocks Enantioselective (3+1+2) Carbonylative Cycloadditions of Aminocyclopropanes.

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.

Complex Polyheterocycles and the Stereochemical Reassignment of Pileamartine A via Aza-Heck Triggered Aryl C-H Functionalization Cascades.

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.

Dearomatizing Amination Reactions.

Dearomatization reactions allow the direct synthesis of structurally complex sp3 -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 sp3 -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.

Electrophilic Aminating Agents in Total Synthesis.

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.

A Systematic Study of the Effects of Complex Structure on Aryl Iodide Oxidative Addition at Bipyridyl-Ligated Gold(I) Centers.

A combined theoretical and experimental approach has been used to study the unusual mechanism of oxidative addition of aryl iodides to [bipyAu(C2 H4 )]+ 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) Pd0 and Pt0 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.

Rhodacyclopentanones as Linchpins for the Atom Economical Assembly of Diverse Polyheterocycles.

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.

Carbonylative C-C Bond Activation of Aminocyclopropanes Using a Temporary Directing Group Strategy.

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.

Pseudo-enantiomeric carbohydrate-based N-heterocyclic carbenes as promising chiral ligands for enantiotopic discrimination.

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.