nBu4N+[AgI(CF3)2]-: Trifluoromethylated Argentate Derived from Fluoroform and Its Reaction with (Hetero)Aryl Diazonium Salts.

The preparation of a well-defined trifluoromethylated argentate nBu4N+[Ag(CF3)2]- 1 from fluoroform was described. The complex was stable in the solid state and in solution under an inert atmosphere. Treatment of a variety of (hetero)aryl diazonium tetrafluoroborates with nBu4N+[Ag(CF3)2]- 1 generated trifluoromethylated (hetero)arenes in good to excellent yields. Preliminary experiments were conducted, and a reasonable mechanism of the reaction was proposed.

Oxidative addition of an alkyl halide to form a stable Cu(III) product.

The step that cleaves the carbon-halogen bond in copper-catalyzed cross-coupling reactions remains ill defined because of the multiple redox manifolds available to copper and the instability of the high-valent copper product formed. We report the oxidative addition of α-haloacetonitrile to ionic and neutral copper(I) complexes to form previously elusive but here fully characterized copper(III) complexes. The stability of these complexes stems from the strong Cu-CF3 bond and the high barrier for C(CF3)-C(CH2CN) bond-forming reductive elimination. The mechanistic studies we performed suggest that oxidative addition to ionic and neutral copper(I) complexes proceeds by means of two different pathways: an SN2-type substitution to the ionic complex and a halogen-atom transfer to the neutral complex. We observed a pronounced ligand acceleration of the oxidative addition, which correlates with that observed in the copper-catalyzed couplings of azoles, amines, or alkynes with alkyl electrophiles.

[(SIPr)Ag(CF2 H)]: A Shelf-Stable, Versatile Difluoromethylation Reagent.

Due to its unique physical and electrophilic properties, the difluoromethyl group (-CF2 H) has been playing an irreplaceable role in the field of pharmaceutical and agrochemical industry. Methods that could efficiently incorporate the difluoromethyl group into the target molecules are increasing in the recent years. Developing a stable and efficient difluoromethylating reagent is thus highly attractive. In this review, we describe the development of a nucleophilic difluoromethylation reagent [(SIPr)Ag(CF2 H)], including its elemental reaction, difluoromethylation reaction with different types of electrophiles, and its application in the synthesis of a nucleophilic and an electrophilic difluoromethylthiolating reagent.

Diimidazolium Salt HBDIM: An Easily Available, Low-Cost, CageCarbene Precursor with Broad Applications in Transition Metal-Catalyzed Reactions.

The preparation of diimidazolium salt HBDIM 1, a precursor for a di-NHCs ligand, from cheap and easily available agent hexabenzylhexaazaisowurtzitane (HBIW) is reported. Under basic conditions, HBDIM undergoes facile deprotonation to in situ generate CageCarbene, which could efficiently coordinate to transition-metals, such as, Au, Cu or Pd, to give the corresponding bimetallic complexes 2-4. These complexes were isolated and fully characterized, including X-ray diffraction of their single crystals. It was found that the steric hinderance of CageCarbene is similar to that of SIMes but smaller than that of IPr, and electronically, CageCarbene is a strong σ-donator similar to SIMes and a stronger σ-donator than IPr. Further studies showed that complexes 2-4 were highly reactive to catalyze up to 17 reactions. Control experiments utilizing a N-benzyl-substituted monoimidazolium salt showed much lower catalytic reactivity when it was bound to Au or Cu, but exhibited similar reactivity for the Pd complex. Kinetic studies showed that the low reactivity of the monodentate carbene-ligated Au or Cu complex was due to the low stability of the complex under the reaction conditions.

A Toolbox of Reagents for Trifluoromethylthiolation: From Serendipitous Findings to Rational Design.

Two types of electrophilic trifluoromethylthiolating reagents were developed in the past 10 years in our laboratory. The development of the first type of reagent, trifluoromethanesulfenate I, which is highly reactive toward a variety of nucleophiles, was based on an unexpected discovery in the initial design for the development of an electrophilic trifluoromethylthiolating reagent with a hypervalent iodine skeleton. A structure-activity study disclosed that α-cumyl trifluoromethanesulfenate (reagent II) without the iodo substituent is equally effective. Subsequent derivatization let us develop an α-cumyl bromodifluoromethanesulfenate III that could be used for the preparation of [18F]ArSCF3. To remediate the low reactivity of the type I electrophilic trifluoromethylthiolating reagent for Friedel-Crafts trifluoromethylthiolation of electron-rich (hetero)arenes, we designed and prepared N-trifluoromethylthiosaccharin IV, which exhibits broad reactivity toward various nucleophiles, including electron-rich arenes. A comparison of the structure of N-trifluoromethylthiosaccharin IV with that of N-trifluoromethylthiophthalimide showed that the replacement of one carbonyl group in N-trifluoromethylthiophthalimide with a sulfonyl group made N-trifluoromethylthiosaccharin IV much more electrophilic. Thus, the replacement of both carbonyls with two sulfonyl groups would further increase the electrophilicity. Such a rationale prompted us to design and develop the current most electrophilic trifluoromethylthiolating reagent, N-trifluoromethylthiodibenzenesulfonimide V, and its reactivity was much higher than that of N-trifluoromethylthiosaccharin IV. We further developed an optically pure electrophilic trifluoromethylthiolating reagent, (1S)-(-)-N-trifluoromethylthio-2,10-camphorsultam VI, for the preparation of optically active trifluoromethylthio-substituted carbon stereogenic centers. Reagents I-VI now constitute a powerful toolbox for the introduction of the trifluoromethylthio group into the target molecules.

Copper-Catalyzed Trifluoromethylation of (Hetero)aryl Boronic Acid Pinacol Esters with YlideFluor.

A copper-catalyzed trifluoromethylation of (hetero)arylboronic acid pinacol esters with YlideFluor for the preparation of trifluoromethylated (hetero)arenes was described. The reaction conditions are mild and compatible with a broad range of functional groups. Heteroaryl boronic acid pinacol esters could also be trifluoromethylated in high yields. Application of this protocol for trifluoromethylation of drug and OLED molecules was demonstrated.

[Ph4 P]+ [Cu(CF2 H)2 ]- : A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation.

The quest of the active species in copper-mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4 P]+ [Cu(CF2 H)2 ]- 2. Complex 2 was able to difluoromethylate a variety of electrophiles including electron-deficient and electron-rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex 2 reacted with various lithium nbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex 2 could transmetalate the difluoromethyl reagent to other metals such as [Ph4 P]+ [CuCl2 ]- and [(DPPF)PdCl2 ].

Mechanistic Insight into Copper-Mediated Trifluoromethylation of Aryl Halides: The Role of CuI.

The synthesis, characterization, and reactivity of key intermediates [Cu(CF3)(X)]-Q+ (X = CF3 or I, Q = PPh4) in copper-mediated trifluoromethylation of aryl halides were studied. Qualitative and quantitative studies showed [Cu(CF3)2]-Q+ and [Cu(CF3)(I)]-Q+ were not highly reactive. Instead, a much more reactive species, ligandless [CuCF3] or DMF-ligated species [(DMF)CuCF3], was generated in the presence of excess CuI. On the basis of these results, a general mechanistic map for CuI-promoted trifluoromethylation of aryl halides was proposed. Furthermore, on the basis of this mechanistic understanding, a HOAc-promoted protocol for trifluoromethylation of aryl halides with [Ph4P]+[Cu(CF3)2]- was developed.

Difluoromethylthiolator: A Toolbox of Reagents for Difluoromethylthiolation.

Recently, the strategic installation of a fluorine atom or a fluoroalkyl group site-selectively at the specific position of the target molecule has become a routine approach and daily practice for medicinal chemists in their endeavor to fine tune the structure of the lead compound to improve its physicochemical properties such as the cell membrane permeability and metabolic stability. Among many fluoroalkyl groups, the difluoromethylthio group (-SCF2H) has attracted recent intense attention. Largely due to the weak acidity of the proton in the difluoromethylthio group, the difluoromethylthio group is generally considered to be a lipophilic hydrogen-bonding donor and a bioisostere of the hydroxy/thio group that might interact with the heteroatom of the enzyme via a hydrogen bond to improve the binding selectivity of the drug molecule. Besides, the difluoromethylthio group is less lipophilic, less electron-withdrawing, and less stable to the acidic or basic environment than its analogue trifluoromethylthio group (-SCF3), making it easier to regulate the metabolic stability of drug molecules. These beneficial effects render the difluoromethylthio group one of the most favorable functional groups in drug design; consequently, there is an urgent need to develop new strategies for the efficient introduction of the difluoromethylthio group into small molecules under mild conditions. Over the last few decades, several different approaches to the preparation of difluoromethylthiolated compounds have been developed, including the difluoromethylation of thiolated substrates with an electrophilic/nucleophilic difluoromethylating reagent or the insertion of a difluoromethyl carbene into the S-H bond of the thiols. In contrast, we adopt an alternative approach to the preparation of difluoromethylthiolated compounds by late-stage direct difluoromethylthiolation of the specific substrates with a difluoromethylthiolating reagent. With this aim in mind, in the last 6 years we have successfully developed a toolbox of reagents that are capable of the direct introduction of the difluoromethylthio group into the target molecules, including nucleophilic difluoromethylthiolating reagent [(SIPr)AgSCF2H] I, electrophilic difluoromethylthiolating reagent PhthSCF2H II, three optically pure difluoromethylthiolating reagents camphorsultam-SCF2H III, radical difluoromethylthiolating reagent PhSO2SCF2H IV, and reagent PhSO2SCFClH V that could be used for the preparation of 18F-labeled [18F]ArSCF2H. These reagents reacted with a broad range of substrates to get access to difluoromethylthiolated compounds efficiently, thus providing medicinal chemists a powerful weapon for the direct introduction of the difluoromethylthio group into promising molecules during the search for new drugs.

Difluoromethylation of Alkyl Bromides and Iodides with TMSCF2H.

We describe, for the first time, two protocols for direct difluoromethylation of unactivated alkyl bromides and iodides. Reactions of alkyl iodides with TMSCF2H were mediated by a copper catalyst using CsF as the activator, while reactions of less reactive alkyl bromides required a combination of palladium and a stoichiometric amount of CuI as the catalysts. Preliminary mechanistic studies of the synergistic Pd/Cu-catalyzed difluoromethylation of alkyl bromides suggest that it proceeds likely via a Pd(I)/Pd(III) catalytic cycle.

C(sp3)-CF3 Reductive Elimination from a Five-Coordinate Neutral Copper(III) Complex.

The reductive elimination from a high-valent late-transition-metal complex for the formation of a carbon-carbon or carbon-heteroatom bond represents a fundamental product-forming step in a number of catalytic processes. While reductive eliminations from well-defined Pt(IV), Pd(IV), Ni(III)/Ni(IV), and Au(III) complexes have been studied, the analogous reactions from neutral Cu(III) complexes remain largely unexplored. Herein, we report the isolation of a stable, five-coordinate, neutral square pyramidal Cu(III) complex that gives CH3-CF3 in quantitative yield via reductive elimination. Mechanistic studies suggest that the reaction occurs through a synchronous bond-breaking/bond-forming process via a three-membered ring transition state.

Cobalt-Catalyzed Asymmetric Cross-Coupling Reaction of Fluorinated Secondary Benzyl Bromides with Lithium Aryl Boronates/ZnBr2.

A cobalt-catalyzed asymmetric cross-coupling of α-bromo-α-fluorotoluene derivatives with a variety of aryl zincates derived from lithium aryl n-butyl pinacol boronates and ZnBr2 under mild reaction conditions was described. In addition to mild reaction conditions, another advantage includes the compatibility of various common functional groups such as fluoride, chloride, bromide, cyano, or ester groups. Furthermore, this protocol was successfully applied to the enantioselective synthesis of three fluorinated derivatives of biologically active compounds or drug molecules.

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.

Electrophilic fluoroalkylthiolation induced diastereoselective and stereospecific 1,2-metalate migration of alkenylboronate complexes.

A transition metal free process for conjunctive functionalization of alkenylboron ate-complexes with electrophilic fluoroalkylthiolating reagents is described, affording ß-trifluoroalkylthiolated and difluoroalkylthiolated boronic esters in good yield and excellent diastereoselectivity. The potential applicability of the method was demonstrated by the preparation of a difluoromethylthiolated mimic 12 of a potential drug molecule PF-4191834 for the treatment of asthma.

Transition-Metal-Free ipso-Trifluoromethylthiolation of Lithium Aryl Boronates.

A transition-metal-free direct trifluoromethylthiolation of the ipso-carbon of lithium aryl boronates with trifluoromethanesulfenate under mild conditions was described. In addition, late-stage site-selective C-H borylation/trifluoromethylation and C-Cl borylation/trifluoromethylthiolation of biologically active molecules was developed. Initial mechanistic study suggested that the Li+ cation plays a vital role by coordinating to the oxygen atom of an aryl boronate complex and the oxygen of the reagent, thus allowing the aryl group to directly attack the trifluoromethylthio group of the trifluoromethylthiolating reagent.

Facilitating the transmetalation step with aryl-zincates in nickel-catalyzed enantioselective arylation of secondary benzylic halides.

Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers. Yet, the use of aryl Grignard reagents or aryl zinc halides in many reactions typically resulted in low enantioselectivity, mainly due to their slow transmetalation step in the catalytical cycle and consequently the requirement of relatively high temperature. Here we report that the use of lithium aryl zincate [Ph2ZnBr]Li facilitates the transmetalation step of the nickel-catalyzed cross-coupling reaction. Based on this discovery, a highly enantioselective construction of fluoroalkyl-substituted stereogenic center by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of α-bromobenzyl trifluoro-/difluoro-/mono- fluoromethanes with a variety of lithium aryl zincates [Ph2ZnBr]Li that  were in situ generated from the reaction of lithium organoboronate with 1.0 equivalent of ZnBr2 was described.

A Key Intermediate in Copper-Mediated Arene Trifluoromethylation, [nBu4 N][Cu(Ar)(CF3 )3 ]: Synthesis, Characterization, and C(sp2 )-CF3 Reductive Elimination.

The synthesis, characterization, and C(sp2 )-CF3 reductive elimination of stable aryl[tris(trifluoromethyl)]cuprate(III) complexes [nBu4 N][Cu(Ar)(CF3 )3 ] are described. Mechanistic investigations, including kinetic studies, studies of the effect of temperature, solvent, and the para substituent of the aryl group, as well as DFT calculations, suggest that the C(sp2 )-CF3 reductive elimination proceeds through a concerted carbon-carbon bond-forming pathway.

Synthesis and Reactivity of α-Cumyl Bromodifluoromethanesulfenate: Application to the Radiosynthesis of [18 F]ArylSCF3.

A highly reactive electrophilic bromodifluoromethylthiolating reagent, α-cumyl bromodifluoro-methanesulfenate 1, was prepared to allow for direct bromodifluoromethylthiolation of aryl boron reagents. This coupling reaction takes place under copper catalysis, and affords a large range of bromodifluoromethylthiolated arenes. These compounds are amenable to various transformations including halogen exchange with [18 F]KF/K222 , a process giving access to [18 F]arylSCF3 in two steps from the corresponding aryl boronic pinacol esters.

Palladium-Catalyzed Difluoromethylation of Aryl Chlorides and Triflates and Its Applications in the Preparation of Difluoromethylated Derivatives of Drug/Agrochemical Molecules.

A palladium-catalyzed difluoromethylation of a series of aryl chlorides and triflates under mild conditions was described. A variety of common functional groups were tolerated. In addition, by using this protocol, several drug molecules containing an aryl chloride unit were successfully difluoromethylated, thus enabling medicinal chemists to rapidly access novel drug derivatives with potentially improved properties via late-stage functionalization.