A pyridine–pyridine coupling reaction has been developed between pyridyl phosphonium salts and cyanopyridines using B2pin2 as an electron‐transfer reagent. Complete regio‐ and cross‐selectivity are ...observed when forming a range of valuable 2,4′‐bipyridines. Phosphonium salts were found to be the only viable radical precursors in this process, and mechanistic studies indicate that the process does not proceed through a Minisci‐type coupling involving a pyridyl radical. Instead, a radical–radical coupling process between a boryl phosphonium pyridyl radical and a boryl‐stabilized cyanopyridine radical explains the C−C bond‐forming step.
Pyridyl phosphonium salts react with cyanopyridines and B2pin2 to form 2,4‐bipyridines with complete regiocontrol. Mechanistic studies support a radical–radical coupling process between two boryl‐stabilized pyridyl radical anions rather than a Minisci‐type pathway, and the process is unique to pyridyl phosphonium salts.
1,2‐Dithio‐1‐alkenes are biologically active compounds widely implemented throughout organic synthesis, functional materials, coordination chemistry, and pharmaceuticals. Traditional methods for ...accessing 1,2‐dithio‐1‐alkenes often demand transition metal catalysts, specialized or air‐sensitive ligands, high temperatures, and disulfides (R2S2). Herein, a general and efficient strategy utilizing ethynylbenziodoxolone (EBX) reagents and thiols is presented that results in the formation of 1,2‐dithio‐1‐alkenes with excellent regioselectivity and stereoselectivity through unprecedented reactivity between the EBX and the thiol. This operationally simple procedure utilizes mild conditions, which result in a broad substrate scope and high functional‐group tolerance. The observed unexpected reactivity has been rationalized through both experimental results and DFT calculations.
Uniquely reactive: Ethynylbenziodoxolone (EBX) reagents react with thiols to form 1,2‐dithio‐1‐alkenes with cis regiocontrol. Experimental results and DFT calculations showed that the cis regioselectivity observed in the final products is due to cis‐selective nucleophilic RSH addition followed by cis‐specific radical RSH addition. This process is unique to EBX reagents.
The 2+2 photocycloaddition is the most valuable and intensively investigated photochemical process. Here we demonstrate that irradiation of N‐acryloyl heterocycles with blue LED light (440 nm) in the ...presence of an IrIII complex leads to efficient and high yielding fused γ‐lactam formation across a range of substituted heterocycles. Quantum calculations show that the reaction proceeds via cyclization in the triplet excited state to yield a 1,4‐diradical; intersystem crossing leads preferentially to the closed shell singlet zwitterion. This is geometrically restricted from undergoing recombination to yield a cyclobutane by the planarity of the amide substituent. A prototropic shift leads to the observed bicyclic products in what can be viewed as an interrupted 2+2 cycloaddition.
Irradiation of N‐acryloyl heterocycles with blue LED light and an IrIII complex leads to fused γ‐lactam formation. The reaction proceeds via cyclization in the triplet excited state to yield a 1,4‐diradical; intersystem crossing leads to a singlet zwitterion that is geometrically restricted from yielding a cyclobutane. Proton transfer leads to the products in an interrupted 2+2 cycloaddition.
Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed ...cross-coupling to make heterobiaryls using contractive phosphorus C-C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C-H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.
Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence almost all metrics associated with their pharmacokinetic and pharmacodynamic profile1-4. Drug candidates ...increasingly contain trifluoromethyl (CF3) and difluoromethyl (CF2H) groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect and plant life5,6. New fluoroalkylation reactions have undoubtedly stimulated this shift; however, methods that directly convert C-H bonds into C-CF2X groups (where X is F or H) in complex drug-like molecules are rare7-13. Pyridines are the most common aromatic heterocycles in pharmaceuticals14, but only one approach-via fluoroalkyl radicals-is viable for achieving pyridyl C-H fluoroalkylation in the elaborate structures encountered during drug development15-17. Here we develop a set of bench-stable fluoroalkylphosphines that directly convert the C-H bonds in pyridine building blocks, drug-like fragments and pharmaceuticals into fluoroalkyl derivatives. No preinstalled functional groups or directing groups are required. The reaction tolerates a variety of sterically and electronically distinct pyridines, and is exclusively selective for the 4-position in most cases. The reaction proceeds through initial formation of phosphonium salts followed by sp2-sp3 coupling of phosphorus ligands-an underdeveloped manifold for forming C-C bonds.
Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C–H precursors are lacking. ...We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. Computational studies indicate that C–halogen bond formation occurs via an S N Ar pathway, and phosphine elimination is the rate-determining step. Steric interactions during C–P bond cleavage account for differences in reactivity between 2- and 3-substituted pyridines.
3+2 cycloadditions of nitroolefins have emerged as a selective and catalyst‐free alternative for the synthesis of 1,2,3‐triazoles from azides. We describe mechanistic studies into the ...cycloaddition/rearomatization reaction sequence. DFT calculations revealed a rate‐limiting cycloaddition step proceeding via an asynchronous TS with high kinetic selectivity for the 1,5‐triazole. Kinetic studies reveal a second‐order rate law, and 13C kinetic isotopic effects at natural abundance were measured with a significant normal effect at the conjugated olefinic centers of 1.0158 and 1.0216 at the α and β‐carbons of β‐nitrostyrene. Distortion/interaction‐activation strain and energy decomposition analyses revealed that the major regioisomeric pathway benefits from an earlier and less‐distorted TS, while intermolecular interaction terms dominate the preference for 1,5‐ over 1,4‐cycloadducts. In addition, the major regioisomer also has more favorable electrostatic and dispersion terms. Additionally, while static DFT calculations suggest a concerted but highly asynchronous Ei‐type HNO2 elimination mechanism, quasiclassical direct‐dynamics calculations reveal the existence of a dynamic intermediate.
A detailed mechanistic study of 3+2 cycloadditions between nitroolefins and azides is described. Combining DFT calculations, kinetic studies, and activation strain analysis, our studies shed new mechanistic insight on the factors controlling reactivity and regioselectivity in this transformation and highlight the role of non‐statistical effects in organocatalyzed and metal‐free dipolar cycloadditions.
Arene regioisomerism in low‐molecular‐weight gelators can be exploited as a tool to modulate the micro‐structures of the corresponding xerogel networks by using the three different possible ...substitution patterns ortho, meta and para. This aromatic regioisomer‐driven strategy has been used with a cholesterol‐based gelator to prepare hollow self‐assembled organic nanotubes (S‐ONTs) with inside and outside diameters of ca. 35 and 140 nm, respectively. Electron microscopy imaging and theoretical calculations were employed to rationalize the formation mechanism of these S‐ONTs. From the three possible regioisomers, only the ortho‐disubstituted cholesteryl‐based gelator showed the optimal angle and distance between substituents to afford the formation of the cyclic assemblies required for nanotube growth by assembling 30–40 units of the gelator. This study opens fascinating opportunities to expand the synthesis of controllable and unique microstructures by modulating geometrical parameters through aromatic regioisomers.
Ortho is important: Self‐assembled organic nanotubes are created in ether‐based solvents from a cholesteryl‐based aromatic low‐molecular‐weight gelator as long as an ortho‐disubstitution pattern is maintained in the aromatic core. The nanotubes have inside and outside diameters of ca. 35 and 140 nm, respectively.
The ability to manipulate C–C bonds for selective chemical transformations is challenging and represents a growing area of research. Here, we report a formal insertion of diazo compounds into the ...“unactivated” C–C bond of benzyl bromide derivatives catalyzed by a simple Lewis acid. The homologation reaction proceeds via the intermediacy of a phenonium ion, and the products contain benzylic quaternary centers and an alkyl bromide amenable to further derivatization. Computational analysis provides critical insight into the reaction mechanism, in particular the key selectivity-determining step.
The first asymmetric catalyzed aza‐Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted β‐nitrohydrazides with ee up ...to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C−C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base‐promoted Henry and aza‐Henry reactions.
A new protocol: The first asymmetric catalyzed aza‐Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize a variety of alkyl substituted β‐nitrohydrazides with up to 94 % ee. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The results revealed a concerted mode of activation in which a C−C bond forming reaction and a protonation occur simultaneously.
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