Over the past few decades, the trifluoromethyl group (CF3) has become one of the most prevalent in applied chemistry, frequently appearing in approved drugs and even more commonly in agrochemicals. However, this widespread use has led to the accumulation of trifluoroacetic acid (TFA) in the environment as a byproduct of metabolic and environmental degradation, prompting legislative actions to restrict certain chemicals and even entire compound classes of so-called "forever chemicals". Hence, this has created a growing demand for alternative motifs that retain the beneficial molecular properties of the trifluoromethyl group but avoid forming trifluoroacetate during degradation. This review summarizes the current state of the application of trifluoromethyl-free, partially fluorinated fluoroalkyl groups in the development of drugs and agrochemicals. We focus on nine moieties that have shown presence in already approved and investigational structures. We also present data on fifteen innovative fragments promising for current and future research. We believe this guide will be valuable for industrial and academic researchers seeking sustainable and ecologically responsible solutions for biomolecular engineering, especially in applications that create risks of environmental pollution.

The incorporation of fluorinated alkyl groups is a powerful strategy to fine-tune the physicochemical and biological properties of organic molecules. In particular, the trifluoroethyl (-CH2CF3) substituent offers a valuable C1-homologated analogue of trifluoromethylated motifs, yet methods for its direct introduction at sp3-hybridized carbon centers remain scarce. Here, we report a general and practical approach for the decarboxylative trifluoroethylation of aliphatic carboxylic acids under near visible-light irradiation. The transformation proceeds via photoinduced generation of a carbon-centered radical that adds to a bench-stable sulfonyl hydrazone reagent derived from trifluoroacetaldehyde, followed by light-driven fragmentation to furnish the desired trifluoroethylated products. The reaction operates under mild conditions, exhibits broad substrate scope, including primary, secondary, and tertiary acids, and tolerates diverse functional groups. Conceptually, the process can be viewed as a C1-homologative trifluoromethylation, offering a distinct retrosynthetic disconnection for the synthesis of trifluoroethyl-containing building blocks. Mechanistic studies combining experimental and computational analysis provide insight into the fragmentation behavior of the key alkylated sulfonyl hydrazide intermediate.

Since 1947, the Balz-Schiemann reaction remains the most popular method for metafluorinated pyridines. It involves dangerous pyridyl diazonium salts, and numerous explosions have been documented in the literature. The last incident was reported only recently, in 2020. Here, we have developed a safe alternative to meta -fluoropyridines with a shelf-stable reagent.

The replacement of aromatic rings with saturated molecular frameworks is a recent development encapsulated by the motto "escape from flatland" and conceptualized through the use of saturated benzene bioisosteres. This Review summarizes the application of the smallest bicyclic and spirocyclic ring systems as saturated scaffolds, focusing on applications in constructing bioactive molecules. We discuss considerations of their molecular strains, their potential to serve as saturated benzene isosteres in terms of both volume and geometry, and structural data derived from small-molecule and protein crystallography. Additionally, we present general approaches to synthesis, examine the current commercial availability of functional building blocks, and present existing examples of applications of bicyclic systems in drug discovery programs. At least eight structures based on the smallest skeletons have advanced to clinical trials, with one, vanzacaftor, recently receiving U.S. FDA approval. Our analysis indicates that small bicyclic fragments are represented exceptionally unevenly. While bicyclo[1.1.1]pentane and spiro[3.3]heptane have become routine and indispensable in medicinal chemistry over the past decade, ladderane and housane remain exotic and unexplored. We highlight knowledge gaps, aiming to stimulate interest in small saturated skeletons for innovative molecular engineering.

Bicyclo[2.1.1]hexanes have generated considerable interest in recent years as bioisosteres of benzene. In this article, a C-H functionalization approach is described to derivatize the bicyclo[2.1.1]hexanes. The approach relies on dirhodium-catalyzed C-H insertion by donor/acceptor carbenes, which proceeds in a highly diastereoselective and enantioselective manner. By the appropriate choice of substrates, the reaction can also be highly site-selective. The bicyclo[2.1.1]hexane is a difficult system for C-H functionalization via carbene intermediates because it is a strained molecule, which causes the C-H bonds to be stronger than in an unstrained system. The only catalyst that performed well in this transformation is the newly developed D4 symmetric catalyst, Rh2(S-megaBNP)4, which contains four (4,4'-dichloro-6,6'-di(3,5-di-tert-butyl)phenyl)binaphthyl phosphate ligands. Computational studies revealed that the donor-acceptor carbene binds in a defined cleft within the bowl-shape of the dirhodium catalyst. Due to the high symmetry of the catalyst, only two orientations of the carbene are possible, and the most stable one has an open face for attack by the substrate. The substrate also needs to approach through a defined cleft causing the reaction to proceed with high levels of diastereoselectivity and enantioselectivity. These studies represent a further example of how the dirhodium catalysts can display many of the characteristics typically associated with enzymes with well-defined secondary interactions between the wall of the catalyst and the approaching substrate controlling the stereochemical outcome.

Reality. Since 1985, scientists have been chasing aliphatic α-fluoroamines. Yet, these structures are unstable due to dehydrofluorination. In this work, we have shown that the minimal structural modification - incorporation of the CH 2 -group - of the elusive α-fluoropiperidine provides a stable α-fluoroamine. This previously nonexistent chemical compound class has been comprehensively studied, characterized, and used in a medicinal chemistry project. Dedicated to the people of Ukraine.

The CFMe2-substituent is a close analogue of the CF3-group. The CF3 for CFMe2 replacement in model compounds mostly does not affect key physicochemical properties: water solubility, lipophilicity, and metabolic stability. Analogous replacement in the anticancer drug Enasidenib, however, provides a biologically active analogue with improved solubility and reduced lipophilicity.

Using the inexpensive, air-stable ruthenium catalyst derived from RuHCl(CO)(PPh3)3 and the achiral ligands Cy-BIPHEP or dCypb, acetylenic bicyclooctyl, azabicycloheptyl, adamantyl, bicyclopentyl and azabicyclooctyl bioisosteres 2a-2f are conjugated to diverse azines and azoles 1a-1t via Csp2-Csp3 bond formation. Using chiral ruthenium catalysts modified by (S)-Cy-SEGPHOS or (R)-Cy-BINAP, high levels of enantioselectivity are obtained in reactions of azines. Late-stage C-H functionalization of the B(Epin) derivative of bortezomib (Velcade) and studies corroborating the reaction mechanism are described.

In 1924, Bruylants reported a reaction between aminonitriles (from ketones) and organomagnesium compounds. During the past 100 years, all possible ketones have been successfully used in this reaction except for one – N-Boc azetidinone. Here we report why that is and how to solve that problem.

In 2019, we hypothesised that bicyclo[2.1.1]hexanes could mimic meta-benzenes in bioactive compounds. In this work, we have proven this hypothesis experimentally.

In this work, we demonstrate that directing group flexibility plays a decisive role in overcoming reactivity barriers in PdII-catalyzed alkene functionalization. Kinetic, organometallic, and DFT studies reveal that employing the rigid 8-aminoquinoline (AQ) auxiliary in α,α-disubstituted substrates leads to high activation barriers for a rate-determining protonation transition state arising from geometric distortion. Guided by these insights, we show that judicious tuning of the directing group can minimize energetic penalties with the use of a flexible 2-pyridylmethylamine (PM) auxiliary. This mechanistically informed approach led to a 115-fold rate increase for the model α,α-dimethyl substrate and broadens the scope to sterically encumbered alkenes, including α-spiro(hetero)cyclic systems, with tolerance for diverse N-H and C-H nucleophiles. Furthermore, we demonstrate that the mechanistic framework developed for hydroamination extends to other difunctionalization reactions such as carboamination and cyclopropanation. This work expands access to structurally complex and lipophilic scaffolds from readily available alkenes.

Systemic toxicity of the local anesthetic bupivacaine can lead to adverse cardiac conditions, creating a significant challenge in clinics. In this study, we examined its analogues with the central piperidine ring replaced with linear spirocyclic scaffolds. The analogues demonstrated an acceptable level of local anesthesia in mice. Notably, the spirocyclic structures exhibited significantly lower toxicity, with increases in the lethal doses of 1.3-, 2.2-, and 5.0-fold for the three tested structures, respectively. Animal studies suggested that this reduced toxicity may be attributed to lower cardiotoxicity, as evidenced by less QRS widening in isolated guinea pig hearts. Pharmacokinetic analysis in mice showed higher relative affinity of the spirocyclic analogues to plasma, while bupivacaine was more affine to the brain and heart. Our results suggest that further exploration of spirocyclic analogues of local anesthetics is warranted and support the use of spirocyclic azetidines as a replacement for the piperidine ring in drugs.

The [3 + 2] cycloaddition between thiocarbonyl ylide CH2═S(+)-CH2(-) and electron-deficient cyclic alkenes provides bicyclic sulfides. The reaction efficiently works on milligram, gram, and even multigram quantities. Standard modifications of the obtained products give fused and spirocyclic sulfones for medicinal chemistry.

Regioselective access to electron-deficient and highly substituted pyrroles from simple building blocks remains challenging. Here we show that O-vinylhydroxylamines enable the de novo construction of pyrroles through an aza-Michael/oxaza-Cope [3,3]-sigmatropic rearrangement/aromatization cascade with activated alkynes. This one-pot transformation proceeds rapidly at room temperature using catalytic amounts of a mild organic base and furnishes dihydropyrrole hemiaminal intermediates that can be directly converted to pyrroles or selectively functionalized. The method accommodates a broad range of O-vinylhydroxylamines and activated alkyne partners and enables access to substitution patterns that previously required harsh conditions or hazardous acetylene-based methods. These results establish O-vinylhydroxylamines as versatile building blocks for the synthesis of highly functionalized pyrroles.

Primary alkylamines are widely used in chemical synthesis, yet their high reactivity at nitrogen has made selective alpha-C-H functionalization almost always dependent on preinstalled protecting or directing groups, compromising atom- and step-economy. Here we report the alpha-C-H heteroarylation of unprotected, non-benzylic primary alkylamines, enabling a direct, catalytic, and scalable synthesis of unprotected alpha-azolyl primary amines, including sterically congested alpha-tertiary motifs. The transformation proceeds via photoredox-catalyzed hydrogen-atom transfer to achieve chemoselective C-H activation and heteroaryl coupling. Notably, a representative case study demonstrates that low-temperature continuous-flow photochemistry enables a reaction with a highly electrophilic azolyl chloride that is impossible under batch conditions, illustrating how flow can kinetically divert reactivity from nitrogen to carbon in unprotected amines.

N-Boc azetidinone smoothly reacts with secondary amines and benzotriazole at room temperature to provide Katritzky benzotriazole adducts. The subsequent addition of Grignard reagents afforded amino azetidines. The reaction is scalable (up to 100 g) and can be used for the preparation of other functionalized small rings: amino oxetanes and cyclobutanes.

ABSTRACT Since 1947, the Balz–Schiemann reaction has remained the most popular method for the synthesis of meta ‐fluoropyridines. The method involves dangerous pyridyl diazonium salts and has led to numerous documented explosions. A safe alternative to meta ‐fluoropyridines has now been developed on the basis of a 1,3‐disconnection strategy.

Piperidines are the most prevalent saturated nitrogen heterocycles in pharmaceuticals, yet efficient and general methods for accessing α-disubstituted and spirocyclic variants have remained a long-standing synthetic challenge. A broadly applicable annulation strategy from unprotected primary alkylamines would represent an important advance, enabling access to privileged piperidine scaffolds from the most accessible nitrogen feedstocks. Here we disclose a general photoredox/hydrogen atom transfer dual catalytic annulation that converts primary amines into α-mono- and α-disubstituted δ-lactams, versatile intermediates that provide streamlined access to diverse piperidines. The method proceeds under mild conditions, can be scaled to ∼100 g in continuous flow, and affords products capable of downstream modification. This work provides a broadly applicable solution to a challenging problem in heterocycle synthesis, expanding the structural space accessible to drug discovery.

3-Oxabicyclo[3.1.1]heptanes were designed as saturated isosteres of meta-benzene. Crystallographic analysis revealed that these structures and meta-benzene have identical geometric properties. Replacement of the central benzene ring in the anticancer drug Sonidegib with 3-oxabicyclo[3.1.1]heptane provided a patent-free analogue with a nanomolar potency, reduced lipophilicity, and improved water solubility (>500%).

Here, we present an approach for the ring-expansion of ketones, enabled by the rare electrophilic activation of [1.1.1]propellane. A broad spectrum of ketones was examined, showcasing excellent compatibility with various functional groups such as ester, amide, and amines. The novel reaction is practical and scalable (up to 56 g). It allows the rapid preparation of mono-, bis-, and tris-spirocyclic scaffolds, which are highly valuable in organic synthesis and drug discovery. Mechanistic insights, supported by control experiments and density functional theory (DFT) calculations, provide a comprehensive understanding of the reaction mechanism.