Reductive Transamination of Pyridinium Salts to N-Aryl Piperidines.

Saturated N-heterocycles are found in numerous bioactive natural products and are prevalent in pharmaceuticals and agrochemicals. While there are many methods for their synthesis, each has its limitations, such as scope and functional group tolerance. Herein, we describe a rhodium-catalyzed transfer hydrogenation of pyridinium salts to access N-(hetero)aryl piperidines. The reaction proceeds via a reductive transamination process, involving the initial formation of a dihydropyridine intermediate via reduction of the pyridinium ion with HCOOH, which is intercepted by water and then hydrolyzed. Subsequent reductive amination with an exogenous (hetero)aryl amine affords an N-(hetero)aryl piperidine. This reductive transamination method thus allows for access of N-(hetero)aryl piperidines from readily available pyridine derivatives, expanding the toolbox of dearomatization and skeletal editing.

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes.

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Palladium-Catalyzed Synthesis of α-Carbonyl-α'-(hetero)aryl Sulfoxonium Ylides: Scope and Insight into the Mechanism.

Despite recent advances, a general method for the synthesis of α-carbonyl-α'-(hetero)aryl sulfoxonium ylides is needed to benefit more greatly from the potential safety advantages offered by these compounds over the parent diazo compounds. Herein, we report the palladium-catalyzed cross-coupling of aryl bromides and triflates with α-carbonyl sulfoxonium ylides. We also report the use of this method for the modification of an active pharmaceutical ingredient and for the synthesis of a key precursor of antagonists of the neurokinin-1 receptor. In addition, the mechanism of the reaction was inferred from several observations. Thus, the oxidative addition complex [(XPhos)PhPdBr] and its dimer were observed by 31P{1H} NMR, and these complexes were shown to be catalytically and kinetically competent. Moreover, a complex resulting from the transmetalation of [(XPhos)ArPdBr] (Ar = p-CF3-C6H4) with a model sulfoxonium ylide was observed by mass spectrometry. Finally, the partial rate law suggests that the transmetalation and the subsequent deprotonation are rate-determining in the catalytic cycle.

Chemospecific Cyclizations of α-Carbonyl Sulfoxonium Ylides on Aryls and Heteroaryls.

The functionalization of aryl and heteroaryls using α-carbonyl sulfoxonium ylides without the help of a directing group has remained so far a neglected area, despite the advantageous safety profile of sulfoxonium ylides. Described herein are the cyclizations of α-carbonyl sulfoxonium ylides onto benzenes, benzofurans and N-p-toluenesulfonyl indoles in the presence of a base in HFIP, whereas pyrroles and N-methyl indoles undergo cyclization in the presence of an iridium catalyst. Significantly, these two sets of conditions are chemospecific for each groups of substrates.

Cross-Coupling of α-Carbonyl Sulfoxonium Ylides with C-H Bonds.

The functionalization of carbon-hydrogen bonds in non-nucleophilic substrates using α-carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross-coupling reactions of sulfoxonium ylides with C(sp2 )-H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C-H activation, migratory insertion of the ylide into the carbon-metal bond, and protodemetalation, the last step being turnover-limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium-catalyzed dehydrative cyclization.

Isomerization of Olefins Triggered by Rhodium-Catalyzed C-H Bond Activation: Control of Endocyclic ß-Hydrogen Elimination.

Five-membered metallacycles are typically reluctant to undergo endocyclic ß-hydrogen elimination. The rhodium-catalyzed isomerization of 4-pentenals into 3-pentenals occurs through this elementary step and cleavage of two C-H bonds, as supported by deuterium-labeling studies. The reaction proceeds without decarbonylation, leads to trans olefins exclusively, and tolerates other olefins normally prone to isomerization. Endocyclic ß-hydrogen elimination can also be controlled in an enantiodivergent reaction on a racemic mixture.

Diastereoselective carbocyclization of 1,6-heptadienes triggered by rhodium-catalyzed activation of an olefinic C-H bond.

The use of α,ω-dienes as functionalization reagents for olefinic carbon-hydrogen bonds has been rarely studied. Reported herein is the rhodium(I)-catalyzed rearrangement of prochiral 1,6-heptadienes into [2,2,1]-cycloheptane derivatives with concomitant creation of at least three stereogenic centers and complete diastereocontrol. Deuterium-labeling studies and the isolation of a key intermediate are consistent with a group-directed C-H bond activation, followed by two consecutive migratory insertions, with only the latter step being diastereoselective.

Regioselective cycloaddition of 3-azetidinones and 3-oxetanones with alkynes through nickel-catalysed carbon-carbon bond activation.

Get in the ring! The first examples of transition-metal-catalysed C-C bond activation of 3-azetidinones and 3-oxetanones are reported. In the presence of a nickel catalyst and alkynes, a regioselective and high-yielding [4+2] cycloaddition occurs, leading to the formation of pyridinones, pyranones and eventually 4,5-disubstituted 3-hydroxypyridines (see scheme).

Synthesis of Sulfur-Substituted Bicyclo[1.1.1]pentanes by Iodo-Sulfenylation of [1.1.1]Propellane.

Thiols easily react with [1.1.1]propellane to give sulfur-substituted bicyclo[1.1.1]pentanes in radical reactions, but this reactivity is not replicated in the case of heterocyclic thiols. Herein, we address this issue by electrophilically activating [1.1.1]propellane to promote its iodo-sulfenylation with 10 classes of heterocyclic thiols in two protocols that can be conducted on a multigram scale without exclusion of air or moisture.

Enantioselective Intramolecular Iridium-Catalyzed Cyclopropanation of α-Carbonyl Sulfoxonium Ylides.

Enantioselective cyclopropanation of α-carbonyl sulfoxonium ylides (SY) has so far been limited to addition/ring closure reactions on electron-poor olefins. Herein, we report the iridium-catalyzed intramolecular cyclopropanation of SY in the presence of a chiral diene in up to 96% yield and 98% enantioselectivity. Moreover, density functional theory calculations suggest that the re face of the olefin preferably attacks an iridium carbene intermediate in an asynchronous concerted step that is independent of the geometry of the olefin.

Regioselective cycloaddition of potassium alkynyltrifluoroborates with 3-azetidinones and 3-oxetanone by nickel-catalysed C-C bond activation.

In the presence of a nickel catalyst, the intermolecular (4+2) cycloaddition of potassium alkynyltrifluoroborates with 3-azetidinones and 3-oxetanone leads to the formation of borylated dihydropyridinones and dihydropyranones without unwanted carbon-boron bond cleavage. The regioselectivity is influenced only by the trifluoroborate group, and only one regioisomer is obtained, whether the other alkyne substituent is an alkyl, vinyl, or (hetero)aryl group.

Palladium-Catalyzed Synthesis of Bis-Substituted Sulfoxonium Ylides.

The lack of general access to bis-substituted sulfoxonium ylides is addressed by developing a palladium-catalyzed C-H cross-coupling of α-ester sulfoxonium ylides with (hetero)aryl iodides, bromides, and triflates. Three different catalysts have been evaluated. This method is amenable to the late-stage functionalization of active pharmaceutical ingredients.

A rhodium-catalyzed C-H activation/cycloisomerization tandem.

A reaction cascade comprising a rhodium-catalyzed C-H activation, a subsequent hydrometalation of an alkylidene cyclopropane in vicinity, regioselective C-C bond activation of the flanking cyclopropane ring, followed by reductive elimination of the resulting metallacycle, opens a new entry into functionalized cycloheptene derivatives. This crossover of C-H activation and higher order cycloaddition has been performed in two different formats, either using alkylidenecyclopropanes with a lateral vinylpyridine moiety or with a pending aldehyde group as the trigger. The reaction tolerates various functional groups, leaves chiral centers alpha to the reacting sites unaffected, and proceeds with excellent stereoselectivity. Labeling experiments support the proposed mechanism explaining the observed net cycloisomerization process.

The synthesis and biological evaluation of a kabiramide C fragment modified with a WH2 consensus actin-binding motif as a potential disruptor of the actin cytoskeleton.

The F-actin depolymerisation potency of a fragment of kabiramide C was increased when modified with a WH2 consensus actin-binding motif LKKV. Despite its low affinity for actin monomers, a shorter analogous fragment not bearing LKKV was identified as a potent inhibitor of actin polymerisation and a promoter of its depolymerisation, resulting in a loss of actin stress fibres in cells.

Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates.

The poor regioselectivity of the [4 + 2] cycloaddition of 3-azetidinones with internal alkynes bearing two alkyl substituents via nickel-catalyzed carbon-carbon activation is addressed using 1,3-enynes as substrates. The judicious choice of substitution on the enyne enables complementary access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines, which are important building blocks in medicinal chemistry endeavors.

Multiple rhodium-catalyzed cleavages of single C-C bonds.

The Rh(I)-catalyzed intramolecular hydroacylation of cis and trans asymmetrically substituted alkylidenecyclobutanes proceeds according to three mechanistic pathways. As shown by deuterium-labeling experiments, the mechanism accounting for the rearrangement of the cis isomers includes the cleavage of three carbon-carbon bonds and a remarkable transannular 3-exo-trig carbometalation.

Facile and chemoselective rhodium-catalysed intramolecular hydroacylation of α,α-disubstituted 4-alkylidenecyclopropanals.

Mild intramolecular hydroacylation of α,α-disubstituted 4-alkylidenecyclopropanals has been developed, avoiding decarbonylation and affording cycloheptenones in good yields. The reaction is chemoselective in favour of the alkylidenecyclopropane moiety when potential alkene or alkyne acceptors are tethered to the substrate.