Daniele Leonori

Dual Catalysis: Combination of Photocatalytic Aerobic Oxidation and Metal Catalyzed Alkynylation Reactions—CC Bond Formation Using Visible Light

A new dual catalytic system for efficient C[BOND]H functionalization was developed. The appropriate choice of two metal catalysts allows the oxidative alkynylation of tertiary amines under mild and sustainable reaction conditions.

Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters

The cross-coupling of boronic acids and related derivatives with sp(2) electrophiles (the Suzuki-Miyaura reaction) is one of the most powerful C-C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.

Visible-Light-Mediated Generation of Nitrogen-Centered Radicals: Metal-Free Hydroimination and Iminohydroxylation Cyclization Reactions.

The formation and use of iminyl radicals in novel and divergent hydroimination and iminohydroxylation cyclization reactions has been accomplished through the design of a new class of reactive O-aryl oximes. Owing to their low reduction potentials, the inexpensive organic dye eosin Y could be used as the photocatalyst of the organocatalytic hydroimination reaction. Furthermore, reaction conditions for a unique iminohydroxylation were identified; visible-light-mediated electron transfer from novel electron donor–acceptor complexes of the oximes and Et3N was proposed as a key step of this process.

Visible-Light-Mediated Synthesis of Amidyl Radicals: Transition-Metal-Free Hydroamination and N-Arylation Reactions

The development of photoredox reactions of aryloxy-amides for the generation of amidyl radicals and their use in hydroamination-cyclization and N-arylation reactions is reported. Owing to the ease of single-electron-transfer reduction of the aryloxy-amides, the organic dye eosin Y was used as the photoredox catalyst, which results in fully transition-metal-free processes. These transformations exhibit a broad scope, are tolerant to several important functionalities, and have been used in the late-stage modification of complex and high-value N-containing molecules.

Stereospecific Couplings of Secondary and Tertiary Boronic Esters

This Minireview highlights advances in the Suzuki-Miyaura cross-coupling of secondary boron reagents for the creation of C-C bonds with control of stereochemistry. It also includes non-transition-metal coupling of secondary and tertiary boronic esters to electron-rich aromatics.

An Experimental and in Situ IR Spectroscopic Study of the Lithiation–Substitution of N-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters

A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be ∼10 h at -78 °C and ∼3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be ∼4 s at -78 °C.

Asymmetric Substitutions of 2‐Lithiated N‐Boc‐piperidine and N‐Boc‐azepine by Dynamic Resolution

Proton abstraction of N-tert-butoxycarbonyl-piperidine (N-Boc-piperidine) with sBuLi and TMEDA provides a racemic organolithium that can be resolved using a chiral ligand. The enantiomeric organolithiums can interconvert so that a dynamic resolution occurs. Two mechanisms for promoting enantioselectivity in the products are possible. Slow addition of an electrophile such as trimethylsilyl chloride allows dynamic resolution under kinetic control (DKR). This process occurs with high enantioselectivity and is successful by catalysis with substoichiometric chiral ligand (catalytic dynamic kinetic resolution). Alternatively, the two enantiomers of this organolithium can be resolved under thermodynamic control with good enantioselectivity (dynamic thermodynamic resolution, DTR). The best ligands found are based on chiral diamino-alkoxides. Using DTR, a variety of electrophiles can be used to provide an asymmetric synthesis of enantiomerically enriched 2-substituted piperidines, including (after Boc deprotection) the alkaloid (+)-beta-conhydrine. The chemistry was extended, albeit with lower yields, to the corresponding 2-substituted seven-membered azepine ring derivatives.

Stereospecific Coupling of Boronic Esters with N-Heteroaromatic Compounds

A protocol for the stereospecific coupling of chiral secondary and tertiary boronic esters with lithiated N-heteroaromatics is described. The process involves initial boronate complex formation followed by addition of Troc-Cl, which activates the nitrogen and induces 1,2-migration. Oxidative workup furnishes the coupled product with >98% es.

Synthesis of 2-Arylpiperidines by Palladium Couplings of Aryl Bromides with Organozinc Species Derived from Deprotonation of N-Boc-Piperidine

The organolithium species derived from proton abstraction of N-Boc-piperidine with s-BuLi and TMEDA can be transmetalated to the organozinc reagent, and this organometallic species can be coupled directly with aryl bromides in a Negishi-type reaction using palladium catalysis with the ligand tri-tert-butylphosphine (t-Bu3P-HBF4). The chemistry was applied to a very short synthesis of the alkaloid anabasine.

Photoinduced Remote Functionalisations by Iminyl Radical Promoted C−C and C−H Bond Cleavage Cascades

Abstract A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp3)−(sp3) and C(sp3)−H bond cleavage gives access to distal carbon radicals that undergo SH2 functionalisations. These mild, visible‐light‐mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules.