Difluoromethyl Group Research Articles

Late-Stage Difluoromethylation of Aliphatic Carboxylic Acids with Copper Catalysis

Difluoromethyl groups are of great importance to synthetic and pharmaceutical chemistry because of their unique properties that regulate molecular bioactivity. In this article, approaches towards difluoromethylation are discussed and the development of the first aliphatic decarboxylative difluoromethylation reaction is detailed. With a broad scope, the real-world utility of the protocol is demonstrated.

Two Ligands Transfer from Ag to Pd: En Route to (SIPr)Pd(CF2H)(X) and Its Application in One-Pot C-H Borylation/Difluoromethylation.

A process for the concurrent transfer of both the NHC ligand and the difluoromethyl group from [(SIPr)Ag(CF2H)] to PdX2 (X = Cl, OAc, and OPiv) for the preparation of [(SIPr)Pd(CF2H)X] complexes is described. These complexes were air-stable and easily underwent transmetalation with aryl pinacol boronate/reductive elimination to generate ArCF2H in high yields. Based on this discovery, the first one-pot C-H borylation and difluoromethylation process for the preparation of difluoromethylated (hetero)arenes was developed.

Crystal structure of pantoprazole sodium sesquihydrate Form I, C16H14F2N3O4SNa(H2O)1.5

The crystal structure of pantoprazole sodium sesquihydrate has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Pantoprazole sodium sesquihydrate crystallizes in space groupPbca(#61) witha= 33.4862(6),b= 17.29311(10),c= 13.55953(10) Å,V= 7852.06(14) Å3, andZ= 16. The crystal structure is characterized by layers parallel to thebc-plane. One layer contains the Na coordination spheres. The two independent sodium ions are trigonal bipyramidal and octahedral. The NaO3N2and NaO4N2coordination spheres share an edge to form pairs. The sodium bond valence sums are 1.17 and 1.15. The difluoromethyl groups are probably disordered. Two water molecules act as hydrogen bond donors to pyridine nitrogen atoms and sulfoxide oxygen atoms. The third water molecule participates in bifurcated hydrogen bonds, but one of its hydrogen atoms does not participate in hydrogen bonds. The powder pattern is included in the Powder Diffraction File™ as entry 00-065-1424.

The copper(ii)-catalyzed and oxidant-promoted regioselective C-2 difluoromethylation of indoles and pyrroles.

A novel and efficient approach for the highly selective C-2 difluoromethylation of indole derivatives was developed by using sodium difluoromethylsulfinate (HCF2SO2Na) as the source of difluoromethyl groups and a Cu(ii) complex as the catalyst. Various substrates were well tolerated in this transformation and the desired products were obtained in moderate to good yields. Moreover, the late-stage C-2 difluoromethylation of bioactive molecules containing an indole ring was achieved in good yields. Generally, this reaction features excellent functional group compatibility, broad substrate scope and excellent C-2 selectivity.

Photoredox-catalyzed sulfonylation of difluoroenoxysilanes with the insertion of sulfur dioxide.

A photoredox-catalyzed three-component reaction of aryldiazonium tetrafluoroborates with sodium metabisulfite and 2,2-difluoro enol silyl ethers is described. By using sodium metabisulfite as the source of sulfur dioxide, this method provides an elegant access to α,α-difluoro-β-ketosulfones in moderate to good yields under mild conditions, and features a broad substrate scope and wide functional group tolerance. Both of the difluoromethyl group and sulfone moiety can be introduced in a single step. Based on the experimental results, a single-electron transfer pathway is proposed with the insertion of sulfur dioxide.

Photocatalytic Difluoromethylation Reactions of Aromatic Compounds and Aliphatic Multiple C-C Bonds.

Among the realm of visible light photocatalytic transformations, late-stage difluoromethylation reactions (introduction of difluoromethyl groups in the last stages of synthetic protocols) have played relevant roles as the CF2X group substitutions exert positive impacts on the physical properties of organic compounds including solubility, metabolic stability, and lipophilicity, which are tenets of considerable importance in pharmaceutical, agrochemical, and materials science. Visible-light-photocatalyzed difluoromethylation reactions are shown to be accomplished on (hetero)aromatic and carbon–carbon unsaturated aliphatic substrates under mild and environmentally benign conditions.

Copper-Catalyzed, Chloroamide-Directed Benzylic C-H Difluoromethylation.

We report herein the first catalytic strategy to harness amidyl radicals derived from N-chloroamides for C-C bond formation, allowing for the discovery of the first catalytic benzylic C-H difluoromethylation. Under copper-catalyzed conditions, a wide variety of N-chlorocarboxamides and N-chlorocarbamates direct selective benzylic C-H difluoromethylation with a nucleophilic difluoromethyl source at room temperature. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage difluoromethylation of bioactive molecules. This copper-catalyzed, chloroamide-directed strategy has also been extended to benzylic C-H pentafluoroethylation and trifluoromethylation. Mechanistic studies on the difluoromethylation reactions support that the reactions involve the formation of benzylic radicals via intramolecular C-H activation, followed by the copper-mediated transfer of difluoromethyl groups to the benzylic radicals.

Copper-catalyzed aryldifluoromethylenation of N-arylacrylamides to synthesis of the diheterocyclic compounds linked by gem-difluoromethylene moiety

An efficient method of copper-catalyzed aryldifluoromethylenation of N-arylacrylamides is described to step-economic synthesis of the various biologically important biheterocyclic compounds linked by gem-difluoromethylene moiety through addition of benzo-1,3-azolic (oxa- or thia-)difluoromethyl radicals generated in situ to terminal of C–C double bond of N-arylacrylamides then cyclization cascade. This protocol has demonstrated to have broad substrate scope and excellent functional-group tolerance under mild reaction conditions.

Hydrochlorofluoromethylation of unactivated alkenes with chlorofluoroacetic acid

An operationally simple method enabling hydrochlorofluoromethylation of unactivated alkenes under visible light activation is reported. The procedure has various benefits. It uses commercially available and inexpensive chlorofluoroacetic acid and phenyliodine(III) diacetate for the generation of the required chlorofluoromethyl radical, it converts feedstock olefins into attractive 1-chloro-1-fluoroalkanes, and it tolerates a broad variety of functional groups. The chlorofluoromethyl radical has a reactivity profile towards alkenes similar to the nucleophilic difluoromethyl radical.

A Unified Strategy for the Synthesis of Difluoromethyl- and Vinylfluoride-Containing Scaffolds.

Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical, scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl group, this approach provides a valuable tool for late-stage functionalization and drug development.

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups.

Fluorine chemistry plays an increasingly important role in pharmaceutical, agricultural, and materials industries. The incorporation of fluorine-containing groups into organic molecules can improve their chemical and physical properties, which attracts continuous interest in organic synthesis. Among various reported methods, transition-metal-catalyzed fluorination/fluoroalkylation has emerged as a powerful method for the construction of these compounds. This review attempts to describe the major advances in the transition-metal-catalyzed incorporation of fluorine, trifluoromethyl, difluoromethyl, trifluoromethylthio, and trifluoromethoxy groups reported between 2011 and 2019.

Synthesis and biological activity of fluorinated analogues of the DAF-12 receptor antagonist 24-hydroxy-4-cholen-3-one

The DAF-12 receptor is a ligand-activated transcription factor that in its ligand-bound form allows the expression of target genes needed to support the reproductive life cycle of the free-living nematode Caenorhabditis elegans, whereas unbound DAF-12 receptor leads to the developmentally arrested “dauer larvae”, specialized for survival and dispersal. The endogenous ligands of the DAF-12 receptor are 3-keto-cholestenoic acids dubbed dafachronic acids. In a previous publication we reported that oxysterols with a shorter side chain (C24) modulate the DAF-12 receptor activity either as partial agonists or, in the case of the C24 alcohol 24-hydroxy-4-cholen-3-one, as an antagonist both in vitro and in vivo. Preliminary structure-activity relationships suggested that this activity profile could be improved with more lipophilic and less acidic functional groups at the end of the side chain. Thus, we have now synthesized two fluorine containing analogues in which the C-24 hydroxyl was replaced by a difluoromethyl group (regarded as a “lipophilic hydroxyl”) or a difluoromethylidene group with similar lipophilicity but lacking the hydrogen bond donor capacity. Activity was evaluated in vitro using transactivation cell-based assays and in vivo by the effect on the development of wild-type C. elegans. The 24-difluoromethyl analogue retained the antagonist activity in vitro, being completely devoid of agonist activity and exhibited improved activity in vivo. The difluoromethylidene showed a slight antagonist tendency in vitro (statistically not significant), in the concentration range tested and was weakly active in vivo. None of the compounds were toxic, as treated worms recovered to normal development, when transferred to fresh media without added steroids.

Synthesis and evaluation of new tri- and difluoromethyl containing 2,6,9-trioxabicyclo[3.3.1]nonanes

Enones 1, are examples of available and attractive building block which already has the polyfluoroalkyl group in blocks skeleton and their functionalization is an actual and perspective approach for the synthesis of more functionalized molecules. This approach led us to new polyfluoroalkyl containing trioxabicyclo[3.3.1]nona-3,7-diene-4,8-dicarboxylates with four trifluoromethyl or two trifluoromethyl and two difluoromethyl groups in moderate yields (up to 68%). These compounds are perspective as synthetic intermediates for preparation of new polyfluoromethyl containing heterocycles as well as their interaction into macrocycles system like crown ethers.

Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols

The -CHF2 moiety has shown a growing interest in pharmaceutical and agrochemical applications over the last few years. Its introduction is therefore a current research topic for organic chemists. Several groups have reported the synthesis of difluoromethylated compounds. However, the more challenging enantioselective introduction of the difluoromethyl group has been scarcely described yet. We recently developed a new strategy, based on the use of an enantiopure difluoromethyl sulfoxide used as chiral and traceless auxiliary, for the synthesis of highly enantioenriched α-difluoromethyl alcohols. The first method developed in our laboratory aims to access highly stereoenriched α,α-difluoro-β-hydroxysulfoxides through the condensation of the enantiopure difluoromethyl sulfoxide on carbonyl derivatives. It is noteworthy that highly diastereo- and enantioenriched α,α-difluoro-β-hydroxysulfoxides can also be accessed after the diastereoselective reduction of highly enantioenriched α,α-difluoro-β-ketosulfoxides. Finally, the expected difluoromethyl-substituted alcohols can be obtained after removal of the chiral auxiliary with complete retention of stereoenrichment at carbon.

Ligand-Less Iron-Catalyzed Aromatic Cross-Coupling Difluoromethylation of Grignard Reagents with Difluoroiodomethane.

Iron-catalyzed cross-coupling difluoromethylations of the Grignard reagents with difluoroiodomethane provide various aromatic difluoromethyl products in good yields, not employing sterically demanding ligands. Difluoromethylations proceed within 30 min at -20 °C with 2.0 equiv of the Grignard reagents and FeCl3 or Fe(acac)3 (2.5 mol %). Mechanistic investigations clarify difluoromethyl radical intervention; Fe(0) ate is initially generated. Single-electron transfer from Fe(0) ate to difluoroiodomethane takes place. Recombination with aryl groups gives Ar-CF2Hs. The catalyst can be regenerated by the Grignard reagents.

Unexpected Hydrated Electron Source for Preparative Visible-Light Driven Photoredox Catalysis.

The hydrated electron is experiencing a renaissance as a superreductant in lab-scale reductions driven by light, both for the degradation of recalcitrant pollutants and for challenging chemical reactions. However, examples for its sustainable generation under mild conditions are scarce. By combining a water-soluble Ir catalyst with unique photochemical properties and an inexpensive diode laser as light source, we produce hydrated electrons through a two-photon mechanism previously thought to be unimportant for laboratory applications. Adding cheap sacrificial donors turns our new hydrated electron source into a catalytic cycle operating in pure water over a wide pH range. Not only is that catalytic system capable of detoxifying a chlorinated model compound with turnover numbers of up to 200, but it can also be employed for two novel hydrated electron reactions, namely, the decomposition of quaternary ammonium compounds and the conversion of trifluoromethyl to difluoromethyl groups.

Cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides

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.

Palladium-Catalyzed Decarbonylative Difluoromethylation of Acid Chlorides at Room Temperature.

Methods for the direct synthesis of difluoromethylated arenes are sparse, despite the importance of the difluoromethyl group in medical, agro-, and materials chemistry. A palladium-catalyzed decarbonylative cross-coupling reaction of acid chlorides with a difluoromethyl zinc reagent is achieved to access difluoromethylated compounds. The transformation proceeds at room temperature and shows broad functional group tolerance, thus providing a general and efficient method for decarbonylative difluoromethylation of a wide range of aromatic carboxylic acids.

Palladium‐Catalyzed Decarbonylative Difluoromethylation of Acid Chlorides at Room Temperature

AbstractMethods for the direct synthesis of difluoromethylated arenes are sparse, despite the importance of the difluoromethyl group in medical, agro‐, and materials chemistry. A palladium‐catalyzed decarbonylative cross‐coupling reaction of acid chlorides with a difluoromethyl zinc reagent is achieved to access difluoromethylated compounds. The transformation proceeds at room temperature and shows broad functional group tolerance, thus providing a general and efficient method for decarbonylative difluoromethylation of a wide range of aromatic carboxylic acids.

Palladium-Catalyzed Cascade Difluoroalkylation/Cyclization of N-Propargylamides: Synthesis of Oxazoles and Oxazolines.

A palladium-catalyzed process to construct oxazoles and oxazolines with broad functional-group tolerance has been developed, and the method introduces difluoromethyl groups into heterocycles in a one-pot fashion. This system uses a carbonyl oxygen as the acceptor for the addition of a vinylpalladium intermediate to achieve the cyclization. Oxazoline derivatives are generated as the Z-isomer with high stereoselectivity. Additionally, we validated the tentative mechanism of this reaction.