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The replacement of aryl rings with C(sp3)-rich structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for para-substituted arene rings, appearing in a number of lead pharmaceutical candidates. Due to their medicinal importance, multiple methods have been developed to efficiently synthesize these 1,3-difunctionalized BCPs. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often non-modular sequences. While challenging, direct functionalization of the strong bridge BCP C–H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C–H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogs, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well-suited since the ring strain imparts high bond strength and thus metabolic stability on its C–H bonds. Cubane is the ideal bioisostere since it provides the closest geometric match to benzene. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings. This is due to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the incompatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalyzed valence isomerization. Herein, we disclose expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C–H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C–N, C–C(sp3), C–C(sp2), and C–CF3 cross-coupling protocols. Our research enables facile elaboration of all cubane isomers into drug candidates thus enabling ideal bioisosteric replacement of ortho-, meta-, and para-substituted benzenes.

Methods that functionalize the periphery of azacylic scaffolds have garnered increasing interest in recent years. Herein, we investigate the selectivity of a solid-state Norrish-Yang cyclization (NYC) and subsequent C-C cleavage/cross-coupling reaction of a strained cyclopropane-fused azacyclic system. Surprisingly, the NYC primarily furnished a single lactam constitutional and diastereo-isomer. The regioselectivity of the C-C cleavage of the α-hydroxy-β-lactam moiety could be varied by altering the ligand set used in the coupling chemistry. Experimental and computational observations are discussed.

We report our efforts toward achieving C(sp2)-C(sp3) coupling reactions with 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. By comparing the reactivities of matching pairs of bicyclo[1.1.1]pentane (BCP) and BCP-F2 analogues, we discovered that the Barluenga coupling reaction was the only cross-coupling protocol that translated well between the two structural motifs in contrast to other reported protocols. In this chemistry, a BCP-F2 bearing a tosylhydrazone functional group is cross-coupled with an arylboronic acid. These results further expanded the scope of BCP-F2 building blocks for potential applications in organic chemistry as well as medicinal chemistry.

We describe a photocatalytic system that elicits potent photoreductant activity from conventional photocatalysts by leveraging radical anion intermediates generated in situ. The combination of an isophthalonitrile photocatalyst and sodium formate promotes diverse aryl radical coupling reactions from abundant but difficult to reduce aryl chloride substrates. Mechanistic studies reveal two parallel pathways for substrate reduction both enabled by a key terminal reductant byproduct, carbon dioxide radical anion.

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C─H and C─C bond functionalizations. Inspired by the Norrish–Yang Type II reaction, C─H functionalization of azacycles is achieved by forming α-hydroxy-β-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp(2))─C(sp(3)) bond in α-hydroxy-β-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C─C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-β-lactams under mild, visible light conditions using a Norrish–Yang process to affect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α-hydroxy-β-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.

The Pd-catalyzed cross-coupling of thiols with aromatic electrophiles is a reliable method for the synthesis of aryl thioethers, which are important compounds for pharmaceutical and agricultural applications. Since thiols and thiolates strongly bind late transition metals, previous research has focused on catalysts supported by chelating, bisphosphine ligands, which were considered less likely to be displaced during the course of the reaction. We show that by using monophosphine ligands instead, more effective catalysis can be achieved. Notably, compared to previous methods, this increased reactivity allows for the use of much lower reaction temperature, soluble bases, and base-sensitive substrates. In contrast to conventional wisdom, our mechanistic data suggest that the extent of displacement of phosphine ligands by thiols is, firstly, not correlated with the ligand bulk or thiol nucleophilicity, and secondly, not predictive of the effectiveness of a given ligand in combination with palladium.

We report the first enantioselective addition of pyrazoles to 1,3-dienes. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity. Mechanistic studies support a pathway distinct from previous hydroaminations: a Pd(0)-catalyzed ligand-to?ligand hydrogen transfer (LLHT). This hydroamination tolerates a range of functional groups and provides a breakthrough in hydrofunctionalization of dienes.

Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light-mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.

We report our efforts toward achieving C(sp

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity versus off-target CLK2.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.

The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism. We applied both light and heat activation in a synergistic fashion, achieving gram-scale bridged aza-cycle synthesis.

Carbon dioxide is an attractive reagent for organic synthesis from the standpoint of global sustainability. Its widespread use, however, is hampered by the fact that it is poorly reactive. New catalysts and technologies that enable C-C bond constructions are thus of high intrinsic value. This Minireview describes recent advances in the area of photoredox catalysis as an enabling strategy for promoting carboxylations.

A metal-free, innate, and practical C–H formylation of nitrogen heterocycles using trioxane as a formyl equivalent is reported. This reaction provides a mild and robust method for modifying medicinally relevant heterocycles with an aldehyde handle. The use of an organic soluble oxidant, tetrabutylammonium persulfate, is critical in promoting the desired coupling.

Carbon dioxide is an attractive reagent for organic synthesis from the standpoint of global sustainability. Its widespread use, however, is hampered by the fact that it is poorly reactive. New catalysts and technologies that enable C-C bond constructions are thus of high intrinsic value. This Minireview describes recent advances in the area of photoredox catalysis as an enabling strategy for promoting carboxylations.

Indazoles represent a privileged scaffold in medicinal chemistry. In the presence of strong base, however, N-protected indazoles are prone to an undesirable ring-opening reaction to liberate o-aminobenzonitriles. By employing unprotected indazoles with a free N-H bond, isomerization is averted because the heterocycle is deprotonated in situ. We herein report functional group-tolerant and robust C-S couplings of bromoindazoles with thiols of varying electronic nature in the presence of lithium bis(trimethylsilyl)amide at elevated temperatures.

We report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Brønsted acid. The indole-pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.

Developing more green and sustainable strategies for organic synthesis is an important modern challenge. Although carbon dioxide is an attractive reagent, because of its availability, the low reactivity of this small molecule renders it challenging to use widely in organic synthesis. The discovery of new catalysts thus plays a central role in advancing the science and impact of CO2 utilization. This perspective describes advances in metal-catalyzed carbon dioxide incorporation since Aresta’s report of the first metal-CO2 complex.

Traditional organic synthesis is driven by the need for functional molecules. The development of green chemical methods, however, is an increasingly important challenge in the context of global sustainability. To this end, the direct use of abundant carbon feedstocks in synthesis (such as CO, CO2, methanol, arenes, alkanes, α-olefins, and biological raw materials) aims to minimize waste production and increase efficiency.

The Lewis acidic character of alkyl- and arylplatinum complexes has been investigated within density functional theory with an emphasis on supramolecular structures (e.g., buckybowls, fullerenes, and nanotubes) doped with Pt atoms. By selective substitution of a single atom within a larger carbon framework with a Pt atom, the resulting species demonstrate a strong preference for interaction with small organic molecules, particularly polar substances via a Lewis acid/Lewis base complexation. Coordination with CO and maleic anhydride offers a gauge of comparing the Lewis acidity of these alkyl- and arylplatinum complexes. We have also examined the use of these organometallic species as catalysts for the Diels−Alder reaction and have found that curved π-conjugation and delocalization of electrons offer modest rate enhancements and improvements in selectivity. Preliminary results suggest that extended molecular architectures such as Pt-doped nanotubes may provide selectivities that differ from that of traditi...

We report a Pd-catalyzed ORTHO-arylationof N-aryloxazolidinones under mild conditions.Our oxidative cross-coupling consumes sodium persulfate (Na 2 S 2 O 8 ),a green and environmentally benign reagent, as the terminal oxidant.Trifluoroacetic acid (TFA) is critical for reactivity.

We report a novel strategy for the formal activation of sp3 C–O bonds under Ru catalysis. In this reaction, an O-alkylpyridine undergoes migratory rearrangement to its corresponding N-alkylpyridone via coordination of the Lewis basic N atom. This transformation represents the first generalcatalytic approach to O- to N-alkyl migration in N-containing heterocycles. Extension of this methodology to other heterocycles, including O-alkylpyridazines and O-alkylazoles, was achieved.

The rich chemistry of single-walled carbon nanotubes (SWCNTs) is enhanced by substitutional doping, a process in which a single atom of the nanotube sidewall is replaced by a heteroatom. These so-called heteroatom-substituted SWCNTs (HSWCNTs) exhibit unique chemical and physical properties not observed in their corresponding undoped congeners. Herein, we present theoretical studies of both main group element and transition metal-doped HSWCNTs. Within density functional theory (DFT), we discuss mechanistic details of their proposed synthesis from vacancy-defected SWCNTs and describe their geometric and electronic properties. Additionally, we propose applications for these nanomaterials in nanosensing, nanoelectronics, and nanocatalysis.

The adsorption of small gaseous molecules to the metal center in Pt-doped (5,5) single-walled carbon nanotubes has been explored within density functional theory. A model system consisting of a single Pt atom residing in the middle of a carbon nanotube with capping H atoms is used for our investigation. For all gases studied, the overall process of adsorption was found to be exothermic, where the affinity strongly depended on the orientation of the molecule. By examining the density of states and molecular orbitals of these nanotube−adsorbate complexes in comparison to the bare Pt-doped nanotube, we show that the electronic structure of these materials is strongly influenced by the presence of gases. Hence, we propose an application of Pt-doped single-walled carbon nanotubes as gas sensors and hope to motivate experimental work in this field.

[structure: see text] The synthesis, characterization, and solid-state structures of new salicylaldimines are reported. Bis(N-salicylideneaniline)s (BSANs) and tris(N-salicylideneaniline)s (TSANs) are sterically encumbered compounds featuring a central six-membered ring in the keto-enamine tautomer. When extended with additional functional groups, these molecules may form hydrogen-bonded capsules, clefts, and extended structures. A TSAN with N-(t)()BOC-o-phenylenediamine groups has been structurally investigated. The complementary hydrogen-bonding motif in this molecule leads it to form dimers in solution and in the solid state. A BSAN with N-(t)()BOC-o-phenylenediamine substituents forms a hydrogen-bonded cleft in solution but forms an extended hydrogen-bonded ladder assembly of cofacial dimers in the solid state. When N-(t)()BOC-1,8-naphthalenediamine was utilized to extend the cleft, an unusual perimidine structure was obtained with the central core in the enol tautomer. In addition, ab initio calculations have been used to support the assignment of the keto-enamine or enol-imine tautomers of the BSANs and TSANs and to predict tautomerization in related BSANs and TSANs.

We report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Bronsted acid. The indole–pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.

Highly enantioselective vicinal iodoamination of olefins is accomplished through the iodocyclization of alkenyl trichloroacetimidates catalysed by a new chiral Schiff-base urea derivative. The resulting products are converted readily to a variety of polyfunctional amine-containing chiral building blocks.

Carbon nanotubes (CNTs) have been the subject of intensive research since their discovery by Iijima in the early 1990s (Iijima 1991). Single-walled carbon nanotubes (SWCNTs, Iijima & Ichihashi 1993; Bethune et al. 1993) are of particular interest because the electronic properties of these nanomaterials can vary from semiconducting to metallic depending on its molecular structure. This contrasts multi-walled carbon nanotubes (MWCNTs), which are metallic and exhibit a zero bandgap. Fundamental understanding of these supramolecular carbon allotropes (Tasis et al. 2006; Ajayan 1999) is essential to the development of new nanomaterials for applications in biosystems, sensors (Wang & Yeow 2009; Hu & Hu 2009; Li et al. 2008), optics (Avouris 2008), nanomechanics (Li et al. 2008; Park 2004), nanoelectronics (Park 2004; Fuhrer 2003; Tsukagoshi 2002), and catalysis (Serp 2003, Tian et al. 2006, Yeung et al. 2011). The molecular structure of SWCNTs can be described as a cylindrical roll of an infinite graphene sheet and is characterized by a chiral circumferential vector AB = ma + nb, a linear combination of two unit lattice vectors a and b where m and n are integers (Figure 1-1, Ajayan 1999; Moniruzzaman & Winey 2006). The pair of indices (m,n) for any given nanotube determines its diameter, chirality, and electronic character. For all n = m, the nanotube is termed armchair and is metallic, exhibiting a zero bandgap. For n ≠ m and neither n and m are zero, the nanotube exhibits chirality and supramolecular helicity, having important implications in optical properties. For n = 0 or m = 0, the nanotube is termed zigzag. For n − m = 3p, where p is a non-zero integer, the nanotube is semimetallic with a band gap on the order of meV. For n − m ≠ 3p, where p is a non-zero integer, the nanotube is semiconducting with a band gap on the order of 1 eV; as a general rule of thumb, the observed band gaps are roughly proportional to the reciprocal of the tube radius. Each individual C atom in the sidewall of a CNT exhibits pyramidalization and partial sp3 hybridization as a result of sidewall curvature. This phenomenon leads to a weakening of the overall π-conjugation of the SWCNT and slight misalignment of π-orbitals between adjacent atoms. Curved π-conjugation can be quantified using Haddon’s π-orbital axis vector (POAV) method (Figure 1-2, Haddon & Scott 1986). In this analysis, the pyramidalization angle θp = θσπ − 90o, where θσπ is the angle between the π-orbital and the σ-bond of the C atom of interest. In contrast to planar (i.e., θp = 0o) and pyramidal (i.e.

This oxidative cross-coupling approach for the direct functionalization of N-aryloxazolidinones is conducted by employing unactivated arenes as the coupling partners and sodium persulfate as an environmentally benign and easy to handle stoichiometric oxidant.

A novel and distinct strategy for sp3 etheral C—O bond activation towards the preparation of N-alkylated 2-pyridones and related heterocycles is developed.

Palladium-catalyzed oxidative ortho-arylation with unactivated arenes proceeds smoothly for a range of electron-rich phenylacetamides (I), benzamides (IV) and anilides (VII), (IX) in the system Na2S2O8—TFA.

The present oxidative cross-coupling reaction proceeds by a Pd(0)/Pd(II) catalytic cycle involving C—H bond activation by carbamate-assisted cyclopalladation, C—H bond functionalization by electrophilic metalation, reductive elimination and reoxidation of Pd(0).

By palladium catalysis, the C-H bond functionalization of O-phenylcarbamates with simple arenes has been achieved using sodium persulfate (Na(2)S(2)O(8)), an inexpensive, easy-to-handle, and environmentally friendly oxidant. This oxidative cross-coupling involves two aromatic C-H bonds undergoing concomitant oxidation to furnish a new biaryl C-C linkage. Excellent reaction efficiencies and regioselectivities were observed with a range of electron-rich, electron-neutral, and electron-deficient arenes; minimal homocoupling of either component was observed. When two reactive C-H bonds are present on the O-phenylcarbamate, selective diarylation can be achieved via quadruple C-H bond functionalization. This work represents a rare example of using O-carbamates as directing groups for catalytic C-H bond activation. Additionally, a palladacycle obtained from an O-phenylcarbamate was prepared and fully characterized. This trifluoroacetate-bridged bimetallic Pd complex exhibits clean conversion to the ortho-arylation product upon treatment with simple arenes. The addition of trifluoroacetic acid (TFA) was found to be critical for successful cyclopalladation of O-phenylcarbamates. We propose this oxidative arene cross-coupling occurs via two discrete C-H bond activations, namely cyclopalladation and electrophilic metalation, within a Pd(0/II) catalytic cycle.

Organozinc reagents are widely used in organic synthesis due primarily to their high functional group compatibility. However, under mild conditions, these organometallic reagents do not react directly with CO2, the ideal C1 source for organic synthesis. Herein, we report that both Ni and Pd complexes can catalyze the addition of organozinc reagents to CO2 under mild conditions (1 atm CO2, 0 °C). This transformation represents an important extension of the Negishi cross-coupling and is believed to occur via a novel mechanism involving Aresta’s complex and/or its corresponding Pd analogue.

Organozinc reagents are widely used in organic synthesis due primarily to their high functional group compatibility. However, under mild conditions, these organometallic reagents do not react directly with CO2, the ideal C1 source for organic synthesis. Herein, we report that both Ni and Pd complexes can catalyze the addition of organozinc reagents to CO2 under mild conditions (1 atm CO2, 0 degrees C). This transformation represents an important extension of the Negishi cross-coupling and is believed to occur via a novel mechanism involving Aresta's complex and/or its corresponding Pd analogue.