Palladium-Catalyzed Regiodivergent Three-Component Alkenylamination of 1,3-Dienes with Alkyl and Aryl Amines.

We report a palladium-catalyzed method for 4,3- or 4,1-selective alkenylamination of terminal dienes. Three-component couplings proceed with alkenyl triflates and several amines, giving vicinal carboamination with a Xantphos-supported catalyst and distal difunctionalization with a phosphoramidite ligand. A number of constitutionally different disubstituted dienes also participate in regiodivergent carboaminations. Experimental evidence indicates that selectivity in the Xantphos reactions is largely influenced by the substrate, whereas the phosphoramidite-promoted process is catalyst controlled, orchestrated by a key π-stacking interaction among the ligand, solvent, and substrate.

A Diastereodivergent and Enantioselective Approach to syn- and anti-Diamines: Development of 2-Azatrienes for Cu-Catalyzed Reductive Couplings with Imines That Furnish Allylic Amines.

We introduce a new reagent class, 2-azatrienes, as a platform for catalytic enantioselective synthesis of allylic amines. Herein, we demonstrate their promise by a diastereodivergent synthesis of syn- and anti-1,2-diamines through their Cu-bis(phosphine)-catalyzed reductive couplings with imines. With Ph-BPE as the supporting ligand, anti-diamines are obtained (up to 91% yield, >20:1 dr, and >99:1 er), and with the rarely utilized t-Bu-BDPP, syn-diamines are generated (up to 76% yield, 1:>20 dr, and 97:3 er).

Rational ligand choice extends the SABRE substrate scope.

Here we report on chelating ligands for Signal Amplification By Reversible Exchange (SABRE) catalysts that permit hyperpolarisation on otherwise sterically hindered substrates. We demonstrate 1H enhancements of ∼100-fold over 8.5 T thermal for 2-substituted pyridines, and smaller, yet significant enhancements for provitamin B6 and caffeine. We also show 15N-enhancements of ∼1000-fold and 19F-enhancements of 30-fold.

Enantioselective Construction of Quaternary Stereogenic Centers by the Addition of an Acyl Anion Equivalent to 1,3-Dienes.

We report the enantioselective formation of quaternary stereogenic centers by the intermolecular addition of malononitrile, an acyl anion equivalent, and related pronucleophiles to several 1,3-disubstituted acyclic 1,3-dienes in the presence of a Pd-PHOX catalyst. Products are obtained in up to 88% yield and 99:1 er and in most cases are formed as a single regioisomer. The products' malononitrile unit undergoes oxidative functionalization to afford ß,γ-unsaturated carbonyls bearing internal olefins and α-quaternary stereogenic centers.

Enantio- and Diastereoselective Synthesis of Homoallylic α-Trifluoromethyl Amines by Catalytic Hydroalkylation of Dienes.

We describe a strategy for the enantio- and diastereoselective synthesis of homoallylic α-trifluoromethyl amines by the catalytic hydroalkylation of terminal dienes. Trifluoromethyl-substituted isatin-derived azadienolate nucleophiles undergo γ-selective alkylation with a Pd-DTBM-SEGPHOS catalyst, which additionally promotes regioselective addition to the diene and delivers products in up to 86% yield, 10:1 dr, and 97.5:2.5 er.

Strategies for the Catalytic Enantioselective Synthesis of α-Trifluoromethyl Amines.

The exploitation of the α-trifluoromethylamino group as an amide surrogate in peptidomimetics and drug candidates has been on the rise. In a large number of these cases, this moiety bears stereochemistry with the stereochemical identity having important consequences on numerous molecular properties, such as the potency of the compound. Yet, the majority of stereoselective syntheses of α-CF3 amines rely on diastereoselective couplings with chiral reagents. Concurrent with the rapid expansion of fluorine into pharmaceuticals has been the development of catalytic enantioselective means of preparing α-trifluoromethyl amines. In this work, we outline the strategies that have been employed for accessing these enantioenriched amines, including normal polarity approaches and several recent developments in imine umpolung transformations.

Catalytic Enantio- and Diastereoselective Cyclopropanation of 2-Azadienes for the Synthesis of Aminocyclopropanes Bearing Quaternary Carbon Stereogenic Centers.

We report the catalytic enantio- and diastereoselective preparation of aminocyclopropanes by the cyclopropanation of terminal and (Z)-internal 2-azadienes with donor/acceptor carbenes derived from α-diazoesters. The resulting cyclopropanes bear quaternary carbon stereogenic centers vicinal to the amino-substituted carbon and are formed as a single diastereomer in up to 99:1 er and 97% yield with 0.5 mol % of Rh2(DOSP)4 and only 1.5 equiv of the diazo reagent. Transformations with internal azadienes afford cyclopropanes with three contiguous stereogenic centers.

Brønsted acid and Pd-PHOX dual-catalysed enantioselective addition of activated C-pronucleophiles to internal dienes.

We describe the development of Pd-PHOX-catalysed enantioselective couplings of internal dienes with malononitrile and other activated C-pronucleophiles. Reactions are dramatically accelerated by the addition of Et3N·HBArF 4 as a Brønsted acid co-catalyst, enabling a suite of products bearing a variety of alkyl substituents at the stereogenic carbon to be prepared. A series of mechanism-oriented experiments reveal key aspects of the catalytic cycle and the importance of the non-coordinating BArF 4 counterion in not only promoting reactions of internal dienes but also additions of previously unreactive nucleophiles towards terminal dienes.

Preparation of Chiral Allenes through Pd-Catalyzed Intermolecular Hydroamination of Conjugated Enynes: Enantioselective Synthesis Enabled by Catalyst Design.

In this study, we establish that conjugated enynes undergo selective 1,4-hydroamination under Pd catalysis to deliver chiral allenes with pendant allylic amines. Several primary and secondary aliphatic and aryl-substituted amines couple with a wide range of mono- and disubstituted enynes in a nonenantioselective reaction where DPEphos serves as the ligand for Pd. Benzophenone imine acts as an ammonia surrogate to afford primary amines in a two-step/one-pot process. Examination of chiral catalysts revealed a high degree of reversibility in the C-N bond formation that negatively impacted enantioselectivity. Consequently, an electron-poor ferrocenyl-PHOX ligand was developed to enable efficient and enantioselective enyne hydroamination.

Palladium-Catalyzed Synthesis of α-Trifluoromethyl Benzylic Amines via Fluoroarylation of gem-Difluoro-2-azadienes Enabled by Phosphine-Catalyzed Formation of an Azaallyl-Silver Intermediate.

We report the synthesis of α-trifluoromethyl benzylic amines through the vicinal fluoroarylation of gem-difluoro-2-azadienes. Our studies indicate that XPhos plays an important role as a phase transfer catalyst that promotes the addition of AgF to the difluoroazadiene, generating an α-trifluoromethyl azaallyl-silver intermediate that we have characterized by NMR spectroscopy. This intermediate likely transmetallates to Pd, coupling several aryl iodides to deliver products in up to 90% yield. Modification of the azadiene's activating group facilitates challenging cross-couplings.

2-Azadienes as Enamine Umpolung Synthons for the Preparation of Chiral Amines.

The development of new strategies for the preparation of chiral amines is an important objective in organic synthesis. In this Synpacts, we summarize our approach for catalytically accessing nucleophilic aminoalkyl metal species from 2-azadienes, and its application in generating a number of important but elusive chiral amine scaffolds. Reductive couplings with ketones and imines afford 1,2-amino tertiary alcohols and 1,2-diamines, respectively, whereas fluoroarylations of gem-difluoro-2-azadienes deliver α-trifluoromethylated benzylic amines.

Enantioselective Synthesis of anti-1,2-Diamines by Cu-Catalyzed Reductive Couplings of Azadienes with Aldimines and Ketimines.

Here we report highly efficient and chemoselective azadiene-imine reductive couplings catalyzed by (Ph-BPE)Cu-H that afford anti-1,2-diamines. In all cases, reactions take place with either aldimine or ketimine electrophiles to deliver a single diastereomer of product in >95:5 er. The products' diamines are easily differentiable, facilitating downstream synthesis.

Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of Acyclic 1,3-Dienes with Activated Pronucleophiles.

We report a highly enantioselective Pd-PHOX-catalyzed intermolecular hydroalkylation of acyclic 1,3-dienes. Meldrum's acid derivatives and other activated C-pronucleophiles, such as ß-diketones and malononitriles, react with a variety of aryl- and alkyl-substituted dienes in ≤20 h at room temperature. The coupled products, obtained in up to 96% yield and 97.5:2.5 er, are easily transformed into useful chemical building blocks for downstream synthesis.

2-Azadienes as Reagents for Preparing Chiral Amines: Synthesis of 1,2-Amino Tertiary Alcohols by Cu-Catalyzed Enantioselective Reductive Couplings with Ketones.

We introduce a new strategy for synthesis of chiral amines: couplings of α-aminoalkyl nucleophiles generated by enantioselective migratory insertion of 2-azadienes to a Cu-H. In this report, we demonstrate its application in catalytic reductive coupling of 2-azadienes and ketones to furnish 1,2-amino tertiary alcohols with vicinal stereogenic centers.

Diastereoselective and Enantiospecific Synthesis of 1,3-Diamines via 2-Azaallyl Anion Benzylic Ring-Opening of Aziridines.

The 1,3-diamine motif appears in numerous complex molecules, yet there are few methods for the stereoselective construction of this moiety. Herein, we demonstrate a stereocontrolled synthesis of 1,3-diamines, which bear up to three contiguous stereogenic centers, through benzylic ring-opening of aziridines with 2-azaallyl anion nucleophiles. Reactions proceed efficiently (yield up to 95%), diastereoselectively (dr up to >20:1), site selectively, and enantiospecifically to deliver products with differentiated amino groups.

Diazirines as Potential Molecular Imaging Tags: Probing the Requirements for Efficient and Long-Lived SABRE-Induced Hyperpolarization.

Diazirines are an attractive class of potential molecular tags for magnetic resonance imaging owing to their biocompatibility and ease of incorporation into a large variety of molecules. As recently reported, 15 N2 -diazirine can be hyperpolarized by the SABRE-SHEATH method, sustaining both singlet and magnetization states, thus offering a path to long-lived polarization storage. Herein, we show the generality of this approach by illustrating that the diazirine tag alone is sufficient for achieving excellent signal enhancements with long-lasting polarization. Our investigations reveal the critical role of Lewis basic additives, including water, on achieving SABRE-promoted hyperpolarization. The application of this strategy to a 15 N2 -diazirine-containing choline derivative demonstrates the potential of 15 N2 -diazirines as molecular imaging tags for biomedical applications.

Umpolung Synthesis of 1,3-Amino Alcohols: Stereoselective Addition of 2-Azaallyl Anions to Epoxides.

We report the direct preparation of 1,3-amino alcohols that contain up to three contiguous stereogenic centers by the umpolung coupling of imines and epoxides. Nucleophilic 2-azaallyl anions, generated from imines, are stereoselectively added to epoxides to furnish 1,3-amino alcohols after hydrolysis of the product imine. Transformations afford amino alcohols with >98% site selectivity with respect to both reaction partners and in up to >98% yield and >20:1 dr.

Direct Hyperpolarization of Nitrogen-15 in Aqueous Media with Parahydrogen in Reversible Exchange.

Signal amplification by reversible exchange (SABRE) is an inexpensive, fast, and even continuous hyperpolarization technique that uses para-hydrogen as hyperpolarization source. However, current SABRE faces a number of stumbling blocks for translation to biochemical and clinical settings. Difficulties include inefficient polarization in water, relatively short-lived 1H-polarization, and relatively limited substrate scope. Here we use a water-soluble polarization transfer catalyst to hyperpolarize nitrogen-15 in a variety of molecules with SABRE-SHEATH (SABRE in shield enables alignment transfer to heteronuclei). This strategy works in pure H2O or D2O solutions, on substrates that could not be hyperpolarized in traditional 1H-SABRE experiments, and we record 15N T1 relaxation times of up to 2 min.

Enantioselective Intermolecular Addition of Aliphatic Amines to Acyclic Dienes with a Pd-PHOX Catalyst.

We report a method for the catalytic, enantioselective intermolecular addition of aliphatic amines to acyclic 1,3-dienes. In most cases, reactions proceed efficiently at or below room temperature in the presence of 5 mol % of a Pd catalyst bearing a PHOX ligand, generating allylic amines in up to 97:3 er. The presence of an electron-deficient phosphine within the ligand not only leads to a more active catalyst but also is critical for achieving high site selectivity in the transformation.