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The selective introduction of fluorine atoms into drug candidates has long been used as a common strategy in drug discovery. Most methods used for the synthesis of tertiary aliphatic fluorides rely...

Fluorinated motifs are frequently encountered in drugs and agrochemicals. Incorporating fluorine-containing motifs in drug candidates for lead optimization in pharmaceutical research and development has emerged as a powerful tool. The construction of molecules that feature a trifluoromethyl (CF

A photoredox/nickel-catalyzed selective 1,4-arylsulfonation of 1,3-enynes to access structurally diverse sulfone-containing allenes has been established with low catalyst loading.

A synthesis of trifluoromethylated thioethers via Ni-catalyzed reductive C–S coupling has been established, exhibiting broad substrate scope and high efficiency.

An exclusively regioselective hydrocyanation of monofluoroalkenes has been developed, with which a series of aliphatic quaternary α-fluoronitriles were synthesized in a facile and efficient manner. This novel method is featured with mild conditions, good functional groups compatibilities, and high reactivity.

The first example of copper-catalyzed ring-opening, enantioselective arylation of cyclic ketoxime esters to access ω,ω-diaryl alkyl nitriles has been developed in high yield (up to 92% yield) with excellent enantioselectivity (up to 91% ee). Side-arm bis(oxazoline) ligand plays a significant role in this asymmetric catalytic transformation, which provides an efficient route to construct diverse chiral ω,ω-diaryl alkyl nitriles. Synthetic utility has also been demonstrated in the further derivatization of the ω,ω-diaryl alkyl nitrile to the corresponding amide.

Monofluoroalkanes are important in many pharmaceuticals, agrochemicals and functional materials. However, the lack of easily available and transformable monofluoroalkylating reagents that facilitate a broad array of transformations has hampered the application of monofluoroalkylation. Herein, we report a general and efficient method of preparing diverse aliphatic monofluorides with monofluoroalkyl triflate as the synthetic scaffold. Using both nickel-catalyzed hydromonofluoroalkylation of unactivated alkenes and copper-catalyzed C-C bond formation, the general diversification of the monofluoroalkylating scaffold has been exhibited. The broad utility of this monofluoroalkylating reagent is shown by concise conversion into various conventional fluoroalkylating reagents and construction of monofluoro-alkoxy, -alkylamino motifs with commercially available heteroatom-based coupling partners.

Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel-catalyzed monofluoromethylation of unactivated alkyl halides using a low-cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross-coupling of two alkyl halides. Results with 1-bromo-1-fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp3 )-C(sp3 ) cross-coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional-group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first-order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate-determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.

The trifluoromethyl group represents one of the most functional and widely used fluoroalkyl groups in drug design and screening, while the drug candidates containing chiral trifluoromethyl-bearing carbons are still few due to the lack of efficient methods for the asymmetric introduction of trifluoromethyl group into organic molecules. Herein, we described a nickel-catalyzed asymmetric trifluoroalkylation of aryl iodides, for the first time, by utilizing reductive cross-coupling in enantioselective fluoroalkylation. This novel method has demonstrated high efficiency, mild conditions, and excellent functional group tolerance, especially for substrates containing diverse pharmaceutical and bioactive molecules moieties. This strategy provided an efficient and facile way for diversity-oriented synthesis of chiral trifluoromethylated alkanes.

A facile and efficient approach for the synthesis of the CF3-containing dioxodibenzothiazepines has been developed via copper-catalyzed trifluoromethylation/cyclization of alkynes utilizing a radical relay strategy. This method has demonstrated low catalyst loading, high regiocontrol, and broad scope under mild conditions. Good compatibility for the N-protecting group, gram-scale experiment, and further derivation of product prove the versatility of this transformation.

The cross-coupling of C-N bond directly from inert C-H bonds is an ideal approach to synthesize saturated azacycles due to its high efficiency and atom economy. In this article, a copper-catalyzed intramolecular amination via the cross coupling of C(sp3)-H and N-H bonds of secondary amine has been reported, which exhibit excellent chemo- and regioselectivity, extensive substrate scope, and functional group tolerance in good to excellent yield, offering an efficient pathway to build nitrogen-containing heterocycle skeletons.

A novel method by a one-step introduction of axial chirality and sterically hindered group has been developed for facile synthesis of axially chiral styrene-type carboxylic acids. With the palladium-catalyzed C–H arylation and olefination of readily available cinnamic acid established, this transformation demonstrated excellent yield, excellent stereocontrol (up to 99% yield and 99% ee), and broad substrate scope under mild conditions. The axially chiral styrene-type carboxylic acids produced have been successfully applied to Cp*CoIII-catalyzed asymmetric C–H activation reactions, indicating their potential as chiral ligands or catalysts in asymmetric synthesis., Palladium-catalyzed asymmetric C–H functionalization to yield axially chiral styrene-type carboxylic acids is described, in which axial chirality and sterically hindered group were incorporated in one-step.

Circularly polarized light (CPL)-triggered enantioselective thiol–ene reactions, which combine absolute asymmetric synthesis with click reactions, enable facile synthesis of optically active poly(thioether) directly from a racemic monomer. However, the enantioselectivity is low and the challenge of producing highly asymmetrical poly(thioether) with distinct circularly polarized luminescence has not been met to date. Herein, we show that the poor enantioselectivity can be largely attributed to the inevitable racemization of thiyl radicals during the growth cycle, and more importantly, it can be remedied by addition of achiral hydrogen atom donors (HAD). The enhancement in enantioselectivity of CPL-triggered thiol–ene reactions can be experimentally controlled by varying the reaction kinetics without introducing any chiral inducer other than CPL. A maximum excess of enantiomeric units (∼20%) in the final polymer chains could be obtained, and so-formed optically active poly(thioether) exhibited not only clusterization-triggered emission (CTE), but also fascinating circularly polarized luminescence for the first time.

Efficient copper-catalyzed 1,2-difunctionalization of alkenes with commercially available BrCH2Cl as a chloromethylating source was carried out, in which mild conditions, high reactivity, excellent functional-group tolerance, and late-stage modification of a bioactive molecule are demonstrated. This strategy offers a solution for the diverse syntheses of nitrogen-containing terminal alkyl chlorides, a common synthetic handle that is promising for multiple derivatizations. Mechanistic studies indicate that a chloromethyl radical is involved in the catalytic cycle.

Development of visible light-mediated atom transfer radical addition of haloalkanes onto unsaturated hydrocarbons has seen rapid growth in recent years. However, due to its radical chain propagation mechanism, diverse functionality other than the pre-existing (pseudo-)halide on the alkyl halide source cannot be incorporated into target molecules in a one-step, economic fashion. Inspired by the prominent reactivities shown by cytochrome P450 hydroxylase and non-heme iron-dependent oxygenases, we herein report the first modular, dual catalytic difunctionalization of unactivated alkenes via manganese-catalyzed radical ligand transfer (RLT). This RLT elementary step involves a coordinated nucleophile rebounding to a carbon-centered radical to form a new C-X bond in analogy to the radical rebound step in metalloenzymes. The protocol leverages the synergetic cooperation of both a photocatalyst and earth-abundant manganese complex to deliver two radical species in succession to minimally functionalized alkenes, enabling modular diversification of the radical intermediate by a high-valent manganese species capable of delivering various external nucleophiles. A broad scope (97 examples, including drugs/natural product motifs), mild conditions, and excellent chemoselectivity were shown for a variety of substrates and fluoroalkyl fragments. Mechanistic and kinetics studies provide insights into the radical nature of the dual catalytic transformation and support radical ligand transfer (RLT) as a new strategy to deliver diverse functionality selectively to carbon-centered radicals.

A Rh(III)-catalyzed C-H arylation reaction of N-nitrosoanilines has been developed in which arylboronic acids were used as arylation reagents. It provides an efficient strategy for the synthesis of N-nitroso-[1,1'-biphenyl]-2-amine, which is an important starting material for the synthesis of N-hetero biaryl compounds, such as 2-amine-1,1'-biphenyl, carbazole, phenanthridone. This protocol can be applied to various N-alkyl substituted N-nitrosoanilines and N-nitrosoanilines with substituents on the phenyl ring. Arylboronic acids with both electron-donating and electron-withdrawing groups are tolerated.

The first example of the Pd(II)-catalyzed enantioselective amination of aryl C-H bonds is reported. The key to the successful realization of this asymmetric catalytic transformation was the identification of mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands, which promote reactivity under mild conditions and control enantioselectivity. The counteranions in the solvent medium, hexafluoroacetylacetate and acetate, were also found to play key roles in stereocontrol and reactivity enhancement.

The highly efficient copper-catalyzed enantioselective alkynylation of the remote C(sp3)–H bond on linear primary sulfonamides is presented here using a radical relay strategy. The chiral box–coppe...

The first example of a visible light-mediated atom transfer radical addition reaction of (phenylsulfonyl)difluoromethyl iodide to styrenes has been reported. By simply tuning the organic or inorganic bases in the reaction system, both ATRA and heck-type products could be afforded with high selectivity. This method has demonstrated mild conditions, high catalytic reactivity, excellent chemoselectivity and a broad substrate scope. Besides, it offers a new solution for difunctionalization of alkenes to synthesize diverse difluoromethylated molecules after a simple work-up.

With an iron catalyst playing dual roles as a radical initiator and terminator, we report a selective remote C–H functionalization to access δ-azido sulfonamides through a radical relay process. The reaction of N-fluorosulfonamide furnishes the corresponding products in excellent yields with high regioselective control. The key to success is the highly efficient iron-mediated redox azido transfer to the in situ generated carbon radical. The products provide incentives for drug discovery and ligand designs.

As an alternative approach to traditional C–H activation that often involved harsh conditions, and vicinal or primary C–H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp3 C-centered radical to promote selective cleavage of inert C(sp3)–H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido–ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF3-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials.

Stress granules (SGs) form through phase separation of biomacromolecules to assist cells in resisting environmental stresses. Numbers of SG proteins contain Arg-Gly-Gly (RGG) motifs, indicating their RNA binding ability, and providing a substrate platform for asymmetric dimethylation of arginine (ADMA), whose roles in SG assembly remain unclear. Here, we demonstrated that Caprin1-mediated recruitment of PRMT1 asymmetrically dimethylates RGGs to provide multiple binding sites for TDRD3, a typical ADMA reader, which in turn bridges the multivalent interactions between RGG motifs and RNA to promote phase separation. This process was suppressed by a bivalent inhibitor of TDRD3, eventually inhibiting proliferation more effectively than arsenite treatment alone. Our work reveals the role of ADMA in SG assembly and the potential of targeting condensates for cancer therapy.

A nickel-catalysed direct terminal monofluoromethlyation between alkyl tosylates and a low-cost, industrial raw material bromofluoromethane has been developed. This transformation has demonstrated high efficiency, mild conditions, and good functional-group compatibility. The key to success of this transformation lies in the ligand and mild base selection, ensuring the generation of various terminal monofluormethylation products.

Summary: The direct functionalization of C(sp3)-H bonds has led to the development of methods to access molecules or intermediates from basic chemicals in an atom- and step-economic fashion. Nevertheless, achieving high levels of chemo-, regio-, and enantioselectivity in these reactions remains challenging due to the ubiquity and low reactivity of C(sp3)-H bonds. Herein, we report an unprecedented protocol for enantioselective cyanation of remote C(sp3)-H bonds. With chiral Box-Cu complex as the catalyst, the reaction of N-fluorosulfonamide furnishes the corresponding products in excellent yields and high enantiomeric excess (ee) under mild reaction conditions. A radical relay pathway involving 1,5-hydrogen atom transfer (1,5-HAT) of N-center radicals followed by enantioselective cyanation of the in situ-formed benzyl radicals is proposed. This enantioselective copper-catalyzed cyanation thus offers insights into an efficient way for the synthesis of bioactive molecules for drug discovery. : Catalysis; Organic Synthesis; Stereochemistry Subject Areas: Catalysis, Organic Synthesis, Stereochemistry

A palladium-catalyzed C(sp3)–H carbonylation of alkylated aryl triflates or bromides under 1 atm of CO has been developed, in which no directing group or oxidant was required. The essence of this r...

A nickel-catalyzed 1,4-carbofluoroalkylation of 1,3-enynes to access structurally diverse fluoroalkylated allenes has been established. This method has demonstrated high catalytic reactivity, mild reaction conditions, broad substrate scope, and excellent functional-group tolerance. The key to success is the use of a nickel catalyst to generate different fluoroalkyl radicals from readily available and structurally diverse fluoroalkyl halides to access 1,4-difunctionalization of 1,3-enynes by a radical relay. This strategy provides facile synthesis of structurally diverse multisubstituted allenes, and offers a solution for batch production of various fluorinated bioactive molecules for drug discovery by further transformations.

A mild and efficient nickel-catalyzed direct monofluoromethylation of (hetero)aryl bromides by reductive cross-coupling has been developed. This method exhibits good efficiency, wide functional-group compatibility, and suitability for aryl and heteroaryl bromides with abundant industrial raw material BrCH2F. This strategy provides an efficient way to synthesize monofluoromethylated molecules for drug discovery.

A nickel-catalyzed difluoroalkylation of α-C-H bonds of aryl ketones to furnish highly stereo-defined tetrasubstituted monofluoroalkenes or quaternary alkyl difluorides from secondary or tertiary ketones, respectively, has been established. Mechanistic investigations indicated that these C-H fluoroalkylations proceed via a Ni(i)/Ni(iii) catalytic cycle. An obvious fluorine effect was observed in the reaction, and this reaction has demonstrated high stereoselectivity, mild conditions, and broad substrate scopes, thus enabling the late-stage fluoroalkylation of bioactive molecules. This method offers a solution for expedient construction of monofluoroalkenes from readily available materials, and provides an efficient approach for the synthesis of bioactive fluorinated compounds for the discovery of lead compounds in medicinal chemistry.

As an alternative approach to traditional C–H activation that often involved harsh conditions, and vicinal or primary C–H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp3 C-centered radical to promote selective cleavage of inert C(sp3)–H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido–ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF3-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials., Remote functionalization of inert C(sp3)–H bonds is described via iron-catalyzed sp3 C-centered radical relay.

Efficient copper-catalyzed 1,2-difunctionalization of alkenes with commercially available BrCH2Cl as a chloromethylating source was carried out, in which mild conditions, high reactivity, excellent functional-group tolerance, and late-stage modification of a bioactive molecule are demonstrated. This strategy offers a solution for the diverse syntheses of nitrogen-containing terminal alkyl chlorides, a common synthetic handle that is promising for multiple derivatizations. Mechanistic studies indicate that a chloromethyl radical is involved in the catalytic cycle.

Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel-catalyzed monofluoromethylation of unactivated alkyl halides using a low-cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross-coupling of two alkyl halides. Results with 1-bromo-1-fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp

Enantioselective synthesis of tetrahydroisoquinolines bearing an all-carbon quaternary stereogenic center, was achieved via asymmetric C–H activation with high enantioselectivities (up to 93% ee). Fair substrate tolerance was indicated throughout the scope investigation and no evident loss of enantioselectivity was exhibited in late-stage derivatization. This study provides incentives for the construction of diverse chiral isoquinoline derivatives, which are prevalent among pharmaceuticals, natural products, etc.

The first example of the Pd(II)-catalyzed enantioselective amination of aryl C-H bonds is reported. The key to the successful realization of this asymmetric catalytic transformation was the identification of mono

With an iron catalyst playing dual roles as a radical initiator and terminator, we report a selective remote C-H functionalization to access δ-azido sulfonamides through a radical relay process. The reaction of N-fluorosulfonamide furnishes the corresponding products in excellent yields with high regioselective control. The key to success is the highly efficient iron-mediated redox azido transfer to the in situ generated carbon radical. The products provide incentives for drug discovery and ligand designs.

The highly efficient copper-catalyzed enantioselective alkynylation of the remote C(sp

A copper-catalyzed dichloromethylazidation of alkenes using commercially available BrCCl2H as a stoichiometric dichloromethylating reagent has been reported. Mechanistic studies indicated that a dichloromethyl radical was involved in the catalytic cycle. This transformation has demonstrated mild conditions, high reactivity, excellent functional-group tolerance, and a broad substrate scope, and thus it has offered a new solution for difunctionalization of alkenes to make diverse transformable dichloromethylated molecules.

The selective incorporation of gem-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. However, the catalytic C(sp3)-CF2 bond-forming cross-coupling reaction for selective incorporation of difluoromethylene group into diverse alkyl chains, especially more sterically demanding secondary and tertiary functionalized alkanes, still remains as a major challenge. Herein, we describe a cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides, which exhibited high efficiency, broad scope and mild conditions. The synthetic utility of this method is demonstrated by late-stage difluoroalkylation of donepezil, a well-known acetylcholinesterase inhibitor used to treat the Alzheimer’s disease. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle. This cobalt-catalyzed fluoroalkylation thus offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery., The catalytic C(sp3)-CF2 bond formation is of high interest in drug design and discovery. Here, the authors report a cobalt-catalyzed difluoroalkylation of tertiary α-C-H bonds of aryl ketones for facile synthesis of quaternary alkyl difluorides and show the late-stage functionalization of marketed drugs.

A palladium-catalyzed, amine-directed C(sp2)–H carbonylation of α,α-disubstituted benzylamine under 1 atm of CO for the facile synthesis of sterically hindered benzolactam has been developed. The key to success is the use of 2,2,6,6-tetramethyl-1-piperidinyloxy as the crucial sole oxidant. The synthetic utility of this transformation has been demonstrated by the first concise synthesis of the natural product spiropachysin-20-one.