Continuous-Flow Photocatalysis for the Direct C-H Trifluoromethylation of Heterocycles with an Organic Photoredox Catalyst

Photocatalysis for direct C−H trifluoromethylation represents an ideal way to synthesize trifluoromethyl-containing chemical compounds, but the conventional batch processes are inefficient with limited light penetration and indispensably irradiated for a long while. Herein, we report a continuous-flow protocol for photocatalytic direct C−H trifluoromethylation of heterocycles in the presence of an organic photoredox catalyst: 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN). In this approach, benefiting from the merger of organic photoredox catalysis and continuous-flow techniques, a variety of trifluoromethylated heterocycles were rapidly synthesized up to 85 % yield with 80 min residence time under metal- and oxidant-free reaction conditions.     

Trifluoromethanesulfonic Anhydride as a Low‐Cost and Versatile Trifluoromethylation Reagent

A large number of reagents have been developed for the synthesis of trifluoromethylated compounds. However, an ongoing challenge in trifluoromethylation reaction is the use of less expensive and practical trifluoromethyl sources. We report herein the unprecedented direct trifluoromethylation of (hetero)arenes using trifluoromethanesulfonic anhydride as a radical trifluoromethylation reagent by merging photoredox catalysis and pyridine activation. Furthermore, introduction of both the CF₃ and OTf groups of the trifluoromethanesulfonic anhydride into internal alkynes to access tetrasubstituted trifluoromethylated alkenes was achieved. Since trifluoromethanesulfonic anhydride is a low‐cost and abundant chemical, this method provides a cost‐efficient and practical route to trifluoromethylated compounds.     

Nickel-Mediated Trifluoromethylation of Phenol Derivatives by Aryl C−O Bond Activation

The increasing pharmaceutical importance of trifluoromethylarenes has stimulated the development of more efficient trifluoromethylation reactions. Tremendous efforts have focused on copper- and palladium-mediated/catalyzed trifluoromethylation of aryl halides. In contrast, no general method exists for the conversion of widely available inert electrophiles, such as phenol derivatives, into the corresponding trifluoromethylated arenes. Reported herein is a practical nickel-mediated trifluoromethylation of phenol derivatives with readily available trimethyl(trifluoromethyl)silane (TMSCF₃). The strategy relies on PMe₃-promoted oxidative addition and transmetalation, and CCl₃CN-induced reductive elimination. The broad utility of this transformation has been demonstrated through the direct incorporation of trifluoromethyl into aromatic and heteroaromatic systems, including biorelevant compounds.     

Quantum-chemical predictions of redox potentials of organic anions in dimethyl sulfoxide and reevaluation of bond dissociation enthalpies measured by the electrochemical methods

A first-principle theoretical protocol was developed that could predict the absolute pK(a) values of over 250 structurally unrelated compounds in DMSO with a precision of 1.4 pK(a) units. On this basis we developed the first theoretical protocol that could predict the standard redox potentials of over 250 structurally unrelated organic anions in DMSO with a precision of 0.11 V. Using the two new protocols we systematically reevaluated the bond dissociation enthalpies (BDEs) measured previously by the electrochemical methods. It was confirmed that for most compounds the empirical equation (BDE = 1.37 pK(HA) + 23.1E(o) + constant) was valid. The constant in this equation was determined to be 74.0 kcal/mol, compared to 73.3 kcal/mol previously reported. Nevertheless, for a few compounds the empirical equation could not be used because the solvation energy changed dramatically during the bond cleavage, which resulted from the extraordinary change of dipole moment during the reaction. In addition, we found 40 compounds (mostly oximes and amides) for which the experimental values were questionable by over 5 kcal/mol. Further analyses revealed that all these questionable BDEs could be explained by one of the three following reasons: (1) the experimental pK(a) value is questionable; (2) the experimental redox potential is questionable; (3) the solvent effect cannot be neglected. Thus, by developing practical theoretical methods and utilizing them to solve realistic problems, we hope to demonstrate that ab initio theoretical methods can now be developed to make not only reliable, but also useful, predictions for solution-phase organic chemistry.     

Nickel‐Mediated Trifluoromethylation of Phenol Derivatives by Aryl C−O Bond Activation

The increasing pharmaceutical importance of trifluoromethylarenes has stimulated the development of more efficient trifluoromethylation reactions. Tremendous efforts have focused on copper‐ and palladium‐mediated/catalyzed trifluoromethylation of aryl halides. In contrast, no general method exists for the conversion of widely available inert electrophiles, such as phenol derivatives, into the corresponding trifluoromethylated arenes. Reported herein is a practical nickel‐mediated trifluoromethylation of phenol derivatives with readily available trimethyl(trifluoromethyl)silane (TMSCF₃). The strategy relies on PMe₃‐promoted oxidative addition and transmetalation, and CCl₃CN‐induced reductive elimination. The broad utility of this transformation has been demonstrated through the direct incorporation of trifluoromethyl into aromatic and heteroaromatic systems, including biorelevant compounds.     

Electrophilic trifluoromethylation of arenes and N-heteroarenes using hypervalent iodine reagents

The reaction of hypervalent iodine trifluoromethylating reagents with a variety of arenes and N-heteroarenes gives access to the corresponding trifluoromethylated compounds. In comparative studies, 1-trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (2) proved to be the superior to 1-trifluoromethyl-1,2-benziodoxol-3-(¹H)-one (1) for the direct aromatic trifluoromethylation. Depending on the individual substrates, additives such as zinc bis(trifluoromethylsulfonyl)imide or tris(trimethylsilyl)silyl chloride proved helpful in promoting the reactions. In the case of nitrogen heterocycles a pronounced tendency for the incorporation of the trifluoromethyl group at the position adjacent to nitrogen was observed.     

Synthesis of Trifluoromethylated Alkenes: Hypervalent Iodine Meets High-Valent Copper

The first trifluoromethylation of vinylbenziodoxolones (VBX) is reported herein. The synthetic method is based on the use of bench-stable, high-valent copper(III) species, and the reaction can be initiated under thermal conditions and/or irradiation (365 nm) giving access to trifluoromethylated alkenes in a stereoselective fashion. Various VBX reagents derived from tyrosine, cysteine, small peptides, thiols and amides can be used as precursors. The obtained alkenes could be further functionalized by reduction or epoxidation of the trifluoromethylated double bond. Furthermore, the method could be applied in a large-scale batch/flow synthesis and could be conducted under visible light irradiation.     

Estimation of dissociation energies of C—H bonds in oxygen-containing compounds from kinetic data for radical abstraction reactions

The C—H bond dissociation energies were calculated on the basis of the parabolic model from the rate constants of free radical reactions for more than 160 oxygen-containing compounds. The enthalpies of formation of free radicals formed from these compounds were calculated. The method was modified taking into account the influence of functional groups on the partial rate constant and for the case when the reference reaction in the reaction series belongs to another class of structurally similar reactions.     

Recent Developments on the Trifluoromethylation of (Hetero)Arenes

Aryl‐CF₃ as an extremely important family of fluorinated organic compounds holds wide applications in pharmaceuticals, agrochemicals, and advanced materials. Traditionally, such trifluoromethylated compounds have been synthesized from the corresponding aryl trichlorides via Cl exchange reactions (Scheme 1 ). This Focus review gives an overview over the recent development of trifluoromethylation of (hetero)arenes.     

O-H bond dissociation enthalpies of oximes: a theoretical assessment and experimental implications

By using a multilayer composite ab initio method ONION-G3B3, we calculated O-H bond dissociation enthalpies (BDEs) of 58 oximes that were measured experimentally. Experimental BDEs derived from thermal decomposition kinetics and calorimetric measurements were found to be consistent with the theory. However, the electrochemical method was found to give questionably high BDEs possibly due to errors in the measurement of pKa's or redox potentials. Subsequently, the performances of a variety of DFT functionals including B3LYP, B3P86, B3PW91, BHandH, BHandHLYP, BMK, PBE1PBE, MPW1KCIS, mPWPW91, MPW1B95, and MPW1K were tested to calculate oxime O-H BDEs, where ROBHandHLYP was found to be the most accurate. By using this method, we calculated O-H BDEs of over 140 oximes in a systematic fashion. All of the calculated O-H BDEs fell in the range from 76.8 to 89.8 kcal/mol. An amino group on the azomethine carbon was found to strengthen the O-H bond, whereas bulky alkyl substituents on oximes decreased O-H BDEs due to their large steric-strain-relieving effects in the process of O-H bond cleavage. Para substituents had little effect on the BDEs of benzaldoximes and phenyl methyl ketoximes. Finally, on the basis of a spin distribution calculation, aryl-, alkyl-, and carbonyl-substituted iminoxyl radicals were found to be sigma-radicals, whereas amino-substituted iminoxyl radicals were of pi-structure.     

Solid-State Radical C−H Trifluoromethylation Reactions Using Ball Milling and Piezoelectric Materials

The application of piezoelectricity for the generation of trifluoromethyl (CF₃) radicals is reported together with the development of a method for the mechanochemical C−H trifluoromethylation of aromatic compounds. As compared to conventional solution-based approaches, this mechanoredox C−H trifluoromethylation enables cleaner and more sustainable access to a wide range of trifluoromethylated N-heterocycles and peptides, which are important structural motifs in modern drug discovery. This study thus represents an important milestone for future applications of mechanoredox systems to medicinal and pharmaceutical science.     

The enthalpies of formation and reorganization of aromatic radicals

The enthalpies of formation of some biphenyl derivatives were determined. A "double difference" method for calculating the enthalpies of formation of aromatic radicals and the bond dissociation energies was proposed. The enthalpies of formation of the radicals biphenyl, diphenyl oxide, and phenyl oxide were determined. The energies of reorganization of these radicals as well as phenyl and 4-, 3-, and 2-pyridyls were calculated. The sums of the energies of the chemical bonds in the molecular moieties transformed into radicals upon the decomposition of chemical compounds were found to be constant for different compounds. The energies of the chemical bonds in arenes were determined.     

Facile synthesis of TMS-protected trifluoromethylated alcohols using trifluoromethyltrimethylsilane (TMSCF3) and various nucleophilic catalysts in DMF

Organofluorine compounds are becoming increasingly important in different fields, such as material science, agro chemistry, and the pharmaceutical industry. Nucleophilic trifluoromethylation is one of the widely used methods to incorporate a trifluoromethyl moiety into organic molecules. We have carried out extensive studies to develop varieties of easily accessible nucleophilic catalysts to promote such reactions. TMS-protected trifluoromethylated alcohols were prepared from both aldehydes and ketones in excellent yields using catalytic amount of amine N-oxide. Carbonate and phosphate salts also showed efficient catalytic activity toward this reaction. These reactions were highly solvent dependent, and DMF was found to be the most suitable one among the various solvents studied. All these reactions proceeded under very mild conditions, giving clean products and avoiding the use of any fluoride initiators or expensive catalysts, and extremely water-free conditions. The mechanism for the reaction is discussed in detail. DFT calculations were performed on the possible reaction intermediates using the Gaussian 03 program at B3LYP/6-311+G* level to support the proposed mechanism.     

Copper-catalyzed C(sp3)-C(sp3) bond formation using a hypervalent iodine reagent: an efficient allylic trifluoromethylation

An efficient copper-catalyzed allylic trifluoromethylation reaction has been developed. This reaction provides a general and straightforward way to synthesize allylic trifluoromethylated compounds under mild conditions.     

A new method for estimation of homolytic C-H bond dissociation enthalpies

In this work we have quantitatively analyzed substituent effects on the homolytic bond dissociation enthalpy of 79 different compounds using a method based on discrete distance dependent atomic contributions to a molecular property. The resulting empirical relationship can be used to predict C-H bond dissociation enthalpies (within +/-10 kJ mol(-1)) for molecules where resonance contributions and captodative stabilization are insignificant. For species where captodative stabilization of the corresponding C-centered radical is possible, the method clearly overestimates the C-H bond dissociation enthalpy.     

Synthesis of α-trifluoromethyl-β-keto phosphonates by electrophilic trifluoromethylation with Togni reagent

A new synthetic method of trifluoromethylated phosphonates was developed via electrophilic trifluoromethylation with Togni reagent. A variety of β-keto phosphonates were converted into the corresponding α-trifluoromethyl-β-keto phosphonates in moderate to good yields. This protocol could also be extended to other fluoroalkylation reactions, such as pentafluoroethylation.     

Development of an ONIOM-G3B3 method to accurately predict C-H and N-H bond dissociation enthalpies of ribonucleosides and deoxyribonucleosides

The roles of ribonucleoside and deoxyribonucleoside radicals in DNA and RNA damage cannot be properly understood in the absence of knowledge of the C-H and N-H bond dissociation enthalpies (BDEs) depicting the energy cost to generate each of these radicals. However, because the nucleoside radicals tend to be extremely short-lived and it is very difficult to separate and identify different nucleoside radicals, experimental BDEs for nucleosides have remained elusive. Herein, we developed an ONIOM-G3B3 method in order to reliably predict the BDEs of nucleosides and we carefully benchmarked this new method against over 60 experimental BDEs of diverse sizable molecules. It was found that the accuracy of the ONIOM-G3B3 method was about 1.4 kcal/mol for BDE calculations. Using the ONIOM-G3B3 method, a full scale of C-H and N-H BDEs were obtained for the first time for ribonucleosides and deoxyribonucleosides with an estimated error bar of +/-1.4 kcal/mol. Discussions were then made about the interesting connections between these BDE values and previously reported experimental observations concerning radical-mediated DNA and RNA lesions. The significance of the work is twofold: (i) Nucleosides represent one of the most important groups of compounds in science. A full scale of reliable bond dissociation enthalpies for nucleosides is of fundamental importance. (ii) This work demonstrates the feasibility to accurately predict the bond strength of various sizable molecules ranging from nanosize molecular devices to biologically significant compounds.     

Thermochemical studies on 3-methyl-quinoxaline-2-carboxamide-1,4-dioxide derivatives: enthalpies of formation and of N-O bond dissociation

The standard molar enthalpies of formation of the 3-methyl-N-R-2-quinoxalinecarboxamide-1,4-dioxides (R = H, phenyl, 2-tolyl) in the gas phase were derived using the values for the enthalpies of combustion of the crystalline compounds, measured by static bomb combustion calorimetry, and for the enthalpies of sublimation, measured by Knudsen effusion, at T = 298.15 K. These values have also been used to calibrate a computational procedure that has been employed to estimate the gas-phase enthalpies of formation of the corresponding 3-methyl-N-R-2-quinoxalinecarboxamides and also to compute the first, second, and mean N-O bond dissociation enthalpies in the gas phase. It is found that the size of the substituent almost does not influence the computed N-O bond dissociation enthalpies; the maximum enthalpic difference is approximately 5 kJ.mol-1.     

TTMPP-catalyzed trifluoromethylation of carbonyl compounds and imines with trifluoromethylsilane

A highly basic phosphine, tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP), catalyzes trifluoromethylation using trifluoromethyltrimethylsilane to give the corresponding trifluoromethylated products in good to high yields, with both carbonyl compounds and imines.     

Copper-catalyzed oxidative trifluoromethylation of terminal alkenes using nucleophilic CF3SiMe3: efficient C(sp3)-CF3 bond formation

An efficient C(sp(3))-CF(3) bond-forming reaction via Cu-catalyzed oxidative trifluoromethylation of terminal alkenes has been developed, which proceeds under mild conditions using readily available, less expensive CF(3)SiMe(3) as the source of the CF(3) group. This method allows access to a variety of trifluoromethylated allylic compounds.