Methane Sulfonation via a Free-Radical Mechanism by Trifluoroacetylsulfuric Acid.

Using trifluoroacetyl sulfuric acid (TFAOSO3H), we discovered a new methane activation method and revealed its radical pathway under mild conditions. Upon the addition of a radical initiator with methane, the crude solution of TFAOSO3H developed the methyltrifluoroacetylsulfate radical ((TFAO)CH3S(OH)O2•). The resulting (TFAO)CH3S(OH)O2• behaved as a critical radical propagator for carbon-hydrogen bond activation, culminating in successful methane sulfonation. With 9.5 mol % of K2S2O8, TFAOSO3H and methane were selectively converted to methanesulfonic acid in 94 and 86% conversion yields, respectively.

Unexpected, Latent Radical Reaction of Methane Propagated by Trifluoromethyl Radicals.

Thorough mechanistic studies and DFT calculations revealed a background radical pathway latent in metal-catalyzed oxidation reactions of methane at low temperatures. Use of hydrogen peroxide with TFAA generated a trifluoromethyl radical (•CF3), which in turn reacted with methane gas to selectively yield acetic acid. It was found that the methyl carbon of the product was derived from methane, while the carbonyl carbon was derived from TFAA. Computational studies also support these findings, revealing the reaction cycle to be energetically favorable.

H-D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and amino acids.

A method has been developed for one-step ortho-selective ligand-directed H-D exchange, accompanied in some cases by concurrent acid-catalyzed electrophilic deuteration. This method is effective for deuteration of aromatic substrates ranging from ketones to amides and amino acids, including compounds of biological and pharmaceutical interest such as acetaminophen and edaravone. Use of a palladium catalyst featuring an NHC ligand is critical for the observed reactivity. Experimental evidence strongly suggests that palladium facilitates C-H activation of the aromatic substrates, a mechanism seldom observed under strongly acidic conditions. 2015 Elsevier Ltd. All rights reserved.

Hydrogen-deuterium exchange of aromatic amines and amides using deuterated trifluoroacetic acid.

The H-D exchange of aromatic amines and amides, including pharmaceutically relevant compounds such as acetaminophen and diclofenac, was investigated using CF3COOD as both the sole reaction solvent and source of deuterium label. The described method is amenable to efficient deuterium incorporation for a wide variety of substrates possessing both electron-donating and electron-withdrawing substituents. Best results were seen with less basic anilines and highly activated acetanilides, reflecting the likelihood of different mechanistic pathways.

Dual Studies on a Hydrogen-Deuterium Exchange of Resorcinol and the Subsequent Kinetic Isotope Effect.

An efficient laboratory experiment has been developed for undergraduate students to conduct hydrogen-deuterium (H-D) exchange of resorcinol by electrophilic aromatic substitution using D2O and a catalytic amount of H2SO4. The resulting labeled product is characterized by 1H NMR. Students also visualize a significant kinetic isotope effect (kH/kD ≈ 3 to 4) by adding iodine tincture to solutions of unlabeled resorcinol and the H-D exchange product. This method is highly adaptable to fit a target audience and has been successfully implemented in a pedagogical capacity with second-year introductory organic chemistry students as part of their laboratory curriculum. It was also adapted for students at the advanced high school level.

Direct Conversion of Glycerol into Formic Acid via Water Stable Pd(II) Catalyzed Oxidative Carbon-Carbon Bond Cleavage.

Using our tridentate NHC-amidate-alkoxide Pd(II) complex, we developed a catalytic method for oxidative C-C bond cleavage of glycerol. The glycerol was degraded exclusively to formic acid and CO2. Two possible degradation pathways were proposed through 13C labeled studies.

Chemoselective hydroamination of vinyl arenes catalyzed by an NHC-amidate-alkoxide Pd(II) complex and p-TsOH.

The hydroamination of various substituted vinyl arenes with benzenesulfonamide was explored using an NHC-amidate-alkoxide palladium catalyst in conjunction with p-TsOH. Utilizing halide-substituted and electron-rich vinyl arenes, this methodology selectively furnished the cross-coupled hydroamination products in moderate to excellent yields in a Markovnikov fashion while greatly reducing undesired acid-catalyzed homocoupling of the vinyl arenes. Electron-rich vinyl arenes typically required milder conditions than electron-poor ones. While most effective for para-substituted substrates, the catalyst system also furnished the desired products from ortho- and meta-substituted vinyl arenes with high chemoselectivities.

Asymmetric intermolecular boron Heck-type reactions via oxidative palladium(II) catalysis with chiral tridentate NHC-amidate-alkoxide ligands.

Chiral dimeric tridentate NHC-amidate-alkoxide palladium(II) complexes, 3a and 3b, effected oxidative boron Heck-type reactions of aryl boronic acids with both acyclic and cyclic alkenes at room temperature to afford the corresponding coupling products with high enantioselectivities. The high degree of enantioselection, far superior to existing methods, stems from differences in the nonbonding interactions in the proposed transition states, due to the influence from bulky substituents of the alkene substrates and the "counter axial groups" of the palladium(II) catalysts.

Development of the next generation of HIV-1 integrase inhibitors: pyrazolone as a novel inhibitor scaffold.

HIV-1 integrase (IN), one of the essential enzymes in HIV infection, has been validated as a target for HIV treatment. While more than 20 drugs have been approved by the FDA to treat HIV/AIDS, only one drug, Raltegravir (1), was approved as an IN inhibitor. The rapid mutation of the virus, which leads to multidrug resistant HIV strains, presents an urgent need to find potent compounds that can serve as second-generation IN inhibitors. The pyrazolone scaffold, predicted by a computational modeling study using GS-9137(2) as a pharmacophoric model, has shown to inhibit the IN catalytic activities in low micromolar range. We have synthesized various analogs based on the pyrazolone scaffold and performed SAR studies. This paper will showcase the up-to-date result of this scaffold as a promising HIV-1 IN inhibitor.

Oxidative degradation of reducing carbohydrates to ammonium formate with H(2)O(2) and NH(4)OH.

Oxidation of various carbohydrates to ammonium formate was investigated in the presence of hydrogen peroxide and ammonium hydroxide. Most of the examined carbohydrates except nonreducing sugars were efficiently converted into ammonium formate under environment friendly and mild conditions in aqueous media.

Air/Water-Stable Tridentate NHC-Pd Complex; Catalytic C-H Activation of Hydrocarbons via H/D Exchange Process in D(2)O.

While developing novel catalysts for carbon-carbon or carbon-heteroatom coupling (N, O, or F), we were able to introduce tridentate NHC-amidate-alkoxide palladium(II) complexes. In aqueous solution, these NHC-Pd(II) complexes showed high ability for C-H activation of various hydrocarbons (cyclohexane, cyclopentane, dimethyl ether, THF, acetone, and toluene) under mild conditions.

Efficient three-component Strecker reaction of aldehydes/ketones via NHC-amidate palladium(II) complex catalysis.

A simple and efficient one-pot, three-component method has been developed for the synthesis of alpha-aminonitriles. This Strecker reaction is applicable for aldehydes and ketones with aliphatic or aromatic amines and trimethylsilyl cyanide in the presence of a palladium Lewis acid catalyst in dichloromethane solvent at room temperature.

Formal aromatic C-H insertion for stereoselective isoquinolinone synthesis and studies on mechanistic insights into the C-C bond formation.

Formal aromatic C-H insertion of rhodium(II) carbenoid was intensively investigated to develop a new methodology and probe its mechanism. Contrasting with the previously proposed direct C-H insertion, the mechanism was revealed to be electrophilic aromatic substitution, which was supported by substituent effects on the aromatic ring and a secondary deuterium kinetic isotope effect. Various isoquinolinones were synthesized intramolecularly via six-membered ring formation with high regio- and diastereoselectivity, while averting the common Buchner-type reaction. Intermolecularly, dirhodium catalyzed formal aromatic C-H insertion on electron-rich aromatics was also achieved.

Expeditious Enyne Construction from Alkynes via Oxidative Pd(II) Catalyzed Heck-Type Coupling.

The enyne, ubiquitous in natural products, can be a challenge to generate since these moieties require many synthetic transformations to assemble them. We developed a simpler protocol to construct enynes while we found that this oxidative reaction was tolerant in substrate scope. In addition, the utility of this reaction was demonstrated through the attempt in synthesizing antifungal agent Lamisi.

Chemoselective Three-Component Coupling via A Tandem Pd Catalyzed Boron-Heck and Suzuki Reaction.

Reported herein is a new approach to prepare biaryl derivatives via a tandem Pd catalyzed boron-Heck and Suzuki reaction. This one-pot tandem process avoided purification or addition of extra catalyst between steps. The resulting biaryl compounds can be prepared with substrate variability in good to moderate yields.

Asymmetric intermolecular heck-type reaction of acyclic alkenes via oxidative palladium(II) catalysis.

Herein, we report an asymmetric intermolecular Heck-type reaction of acyclic alkenes by using a palladium-pyridinyl oxazoline diacetate complex under oxidative palladium(II) catalysis conditions. A premade palladium-ligand complex afforded higher enantioselectivities than a corresponding premixed palladium-ligand system, while offering enhanced asymmetric induction when compared to known intermolecular Heck-type protocols.

Oxygen-promoted palladium(II) catalysis: facile C(sp2)-C(sp2) bond formation via cross-coupling of alkenylboronic compounds and olefins.

[reaction: see text] Oxygen-promoted Pd(II) catalysis facilitated the synthesis of conjugated dienes by cross-coupling of alkenylboronic compounds and various olefins including highly substituted alkenes and cyclohexenone. Under mild conditions, these versatile reactions were efficient and highly stereoselective.

Oxygen-promoted Pd(II) catalysis for the coupling of organoboron compounds and olefins.

Reported herein is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen was employed to reoxidize the resultant Pd(0) species back to Pd(II) during catalytic cycles. This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded competing Pd(0) catalytic pathways such as Heck or Suzuki couplings. [reaction: see text]

Gamma-lactam synthesis via C-H insertion: elaboration of N-benzyl protecting groups for high regioselectivity toward the total synthesis of rolipram.

By intramolecular C-H insertion of alpha-diazo-alpha-(phenylsulfonyl)acetamides, gamma-lactams such as the antidepressant agent rolipram were efficiently synthesized in a highly regioselective manner. N-Benzyl moieties were elaborated as amide protecting groups to enhance regioselectivity in C-H activation as well as chemoselectivity over addition reactions. [reaction: see text]