Somesh K. Ganesh

Copper-Mediated Difluoromethylation of (Hetero)aryl Iodides and β-Styryl Halides with Tributyl(difluoromethyl)stannane†

Organofluorine compounds have found application in a wide variety of fields. They occur, for example, in pharmaceuticals, agrochemicals, materials, surfactants, and catalysts. The selective introduction of the difluoromethyl group (CF2H) into organic molecules is of interest owing to the special biological properties of this group, such as its enhancement of membrane permeability, binding affinity, and bioavailability. The CF2H functionality is isosteric and isopolar with the hydroxy (OH) group and is reasonably lipophilic. At the same time, the CF2H group is weakly acidic and capable of participating in weak hydrogen-bonding interactions. Because of these properties, the CF2H group is found in various biologically active compounds, such as enzyme inhibitors, sugars, and agrochemicals. Several methods have been developed for the preparation of CF2H-containing compounds, including the deoxofluorination of aldehydes with SF4, N,N-diethylaminosulfur trifluoride (DAST), and derivatives of DAST. The magnesium-metal-mediated reductive difluoromethylation of chlorosilanes with difluoromethyl sulfides, sulfoxides, and sulfones has been reported, as has the nucleophilic introduction of a CF2H group into carbonyl compounds with difluoromethyl phenyl sulfone, (difluoromethyl)dimethylphenylsilane, and (chlorodifluoromethyl)trimethylsilane. 9] The direct transfer of a difluoromethyl group to a heteroarene with zinc difluoromethanesulfinate (DFMS), which is believed to proceed by a radical pathway, was reported by the Baran research group. However, direct access to regiospecifically difluoromethylated arenes has been a challenge until recently. Amii and co-workers reported a CuI-catalyzed three-step approach for the synthesis of difluoromethyl aromatic and heteroaromatic compounds by a C C coupling reaction between an aryl iodide and an a-silyldifluoroacetate, followed by hydrolysis and decarboxylation (Scheme 1). Fier and Hartwig reported a one-step copper-mediated (CuI) nucleophilic difluoromethylation of iodoarenes with TMSCF2H. [12] Although the products were obtained in excellent yields, the latter method requires a significant excess of TMSCF2H, is limited to electron-rich and electron-neutral iodoarenes, and is not compatible with aldehydes and ketones owing to competitive nucleophilic addition at the carbonyl center. Herein we report the synthesis of tributyl(difluoromethyl)stannane and its application in the copper-mediated difluoromethylation of iodoarenes and b-styryl halides. This methodology has been extended to the difluoromethylation of both activated and deactivated iodoarenes (iodoheteroarenes), including those with carbonyl substituents, in moderate to good yields, and the difluoromethylation of b-styryl halides in good to excellent yields. Our research group recently demonstrated that singlet CF2 carbene can be generated from TMSCF3 in the presence Scheme 1. Methods for difluoromethylation. EWG= electron-withdrawing group, TMS= trimethylsilyl.

Synthesis of gem-Difluorinated Cyclopropanes and Cyclopropenes: Trifluoromethyltrimethylsilane as a Difluorocarbene Source

Difluorocyclopropanes and difluorocyclopropenes are becoming an important class of compounds in organofluorine chemistry. Introduction of a fluorine atom onto a cyclopropane ring is known to alter the structure and reactivity of the molecule because of the high electronegativity and small size of the fluorine atom, and consequently the increase in the C F bond polarity. Fluorine substituents also raise the biological activity, the bioavailability, and in some cases the potency of known biologically active molecules. The difluoromethylene group is also considered as a bioisostere for an oxygen atom in biological studies. Recently, a unique application of difluorocyclopropanes to trap the 1,3-diradical formed during the mechanochemical activation of the polybutadiene backbone was reported. Besides biological and polymeric applications, difluorocyclopropanes are synthetically useful substrates for a variety of reactions such as thermal rearrangements, bimolecular reactions, carbocation, carbanion, and radical chemistry. The synthesis of difluorocyclopropanes and difluorocyclopropenes can be achieved in various ways. However, a [2+1] cycloaddition reaction of difluorocarbene to an alkene or an alkyne has proven to be the most efficient method to date. 5] This result has led to considerable efforts in developing reagents that can act as a source of difluorocarbene. Owing to the interaction of the lone pairs of electrons on the fluorine substituents with the carbene center, difluorocarbene is a relatively stabilized carbene species (with a singlet ground state) and is therefore less reactive than other dihalocarbenes. This could be one of the reasons why difluorocarbenes do not react well with electron-poor alkenes. Higher temperatures are often required for the generation as well as efficient reactions of difluorocarbene with alkenes. Some of the reagents used previously include sodium chlorodifluoroacetate (or sodium bromodifluoroacetate), PhHgCF3 [8] and Me3SnCF3 [9] (Seyferth reagents), FSO2CF2CO2SiMe3 (TFDA), and Zn/CF2Br2. [11] However, most of these reagents suffer from disadvantages such as harsh reaction conditions, high toxicity, lack of commercial availability, and/ or low product yields. Recently, Hu and co-workers reported that TMSCF2Cl can act as an efficient difluorocarbene precursor under chloride-ion catalysis at 110 8C. However, TMSCF2Cl is not commercially available and its preparation requires the use of ozone-depleting CBrClF2. [13] For substrates that are thermally unstable, the abovementioned methods and reagents could be a serious limitation, and development of better difluorocarbene precursors that can generate difluorocarbenes at lower temperatures is required. There are only few reports that discuss difluorocarbene generation at room temperature with Ph3P/CF2Br2, [15] or at low temperatures (below 78 8C) with bis(trifluoromethyl) cadmium, which is a highly pyrophoric reagent, as a source. Again, the use of cadmium or phosphines and the lack of commercial availability of these reagents is a severe limitation. Trifluoromethyltrimethylsilane (Me3SiCF3 or TMSCF3), commonly known as the Ruppert–Prakash reagent, is readily available and is the most widely used nucleophilic trifluoromethylating agent for a variety of

N-Difluoromethylation of imidazoles and benzimidazoles using the Ruppert-Prakash reagent under neutral conditions.

Direct N-difluoromethylation of imidazoles and benzimidazoles has been achieved using TMS-CF3 (the Ruppert-Prakash reagent) under neutral conditions. Difluoromethylated products were obtained in good-to-excellent yields. Inexpensive, commercially available starting materials, neutral conditions, and shorter reaction times are advantages of this methodology. Reactions are accessible through conventional as well as microwave irradiation conditions.

Facile Oxy‐Functionalization of a Nucleophilic Metal Alkyl with a cis‐Dioxo Metal Species via a (2+3) Transition State

Selective, low-temperature hydroxylation of alkanes catalyzed by transition-metal complexes is an important area of study, given its possible applications to natural-gas conversion as well as to more efficient production of bulk chemicals and energy. Several promising electrophilic catalysts that couple C–H activation to facile oxy-functionalization of the resulting electrophilically activated M R intermediates have been reported (Figure 1). To address practical challenges with

Mechanism of efficient anti-Markovnikov olefin hydroarylation catalyzed by homogeneous Ir(III) complexes

The mechanism of the hydroarylation reaction between unactivated olefins (ethylene, propylene, and styrene) and benzene catalyzed by [(R)Ir(μ-acac-O,O,C3)-(acac-O,O)2]2 and [R-Ir(acac-O,O)2(L)] (R = acetylacetonato, CH3, CH2CH3, Ph, or CH2CH2Ph, and L = H2O or pyridine) Ir(III) complexes was studied by experimental methods. The system is selective for generating the anti-Markovnikov product of linear alkylarenes (61:39 for benzene + propylene and 98:2 for benzene + styrene). The reaction mechanism was found to follow a rate law with first-order dependence on benzene and catalyst, but a non-linear dependence on olefin. 13C-labelling studies with CH313CH2-Ir-Py showed that reversible β-hydride elimination is facile, but unproductive, giving exclusively saturated alkylarene products. The migration of the 13C-label from the α to β-positions was found to be slower than the C–H activation of benzene (and thus formation of ethane and Ph-d5-Ir-Py). Kinetic analysis under steady state conditions gave a ratio of the rate constants for CH activation and β-hydride elimination (kCH: kβ) of ∼0.5. The comparable magnitude of these rates suggests a common rate determining transition state/intermediate, which has been shown previously with B3LYP density functional theory (DFT) calculations. Overall, the mechanism of hydroarylation proceeds through a series of pre-equilibrium dissociative steps involving rupture of the dinuclear species or the loss of L from Ph-Ir-L to the solvento, 16-electron species, Ph-Ir(acac-O,O)2-Sol (where Sol refers to coordinated solvent). This species then undergoes trans to cisisomerization of the acetylacetonato ligand to yield the pseudo octahedral species cis-Ph-Ir-Sol, which is followed by olefin insertion (the regioselective and rate determining step), and then activation of the C–H bond of an incoming benzene to generate the product and regenerate the catalyst.

Synthesis of Dihydropyrimidinones/Thiopyrimidinones: Nafion-Ga, an Efficient “Green” Lewis Acid Catalyst for the Biginelli Reaction

Biginelli reaction is the most well-known and widely studied multicomponent reaction used for the direct synthesis of many biologically active 3,4-dihydropyrimidinones or thiones and their derivatives by reacting a β-keto ester/1,3-dicarbonyl compound, an aldehyde, and urea/thiourea. A new easily recoverable solid catalyst, Nafion-Ga (Gallium Nafionate, Ga(III) salt of Nafion-H, a solid polymeric perfluoroalkanesulfonic acid) was prepared from Nafion-K by metal exchange. Nafion-Ga is found to be an efficient and environmentally benign catalyst for the Biginelli reaction. A series of 3,4-dihydropyrimidinones and thiones were conveniently prepared by this green protocol using the catalyst under solvent free conditions. The wide scope of the catalyst for many other acid catalyzed organic transformations can be ascertained by further screening studies.Graphical Abstract

Role of intraoperative echocardiography in surgical correction of the superior sinus venosus atrial septal defect.

Superior type of sinus venosus atrial septal defect (SVASD) is invariably associated with the unroofing of right upper pulmonary vein (RUPV). Warden procedure and pericardial patch repair with rerouting of the RUPV are commonly performed operations for the superior SVASD. Both operations involve the risk of obstruction to the flow of superior vena cava or rerouted pulmonary vein in the postoperative period. The sinus venosus defects are well visualized on the transesophageal echocardiography (TEE) because of the proximity of the TEE probe to these structures. We are reporting two cases operated for the superior SVASD with unroofed RUPV, highlighting the intraoperative echocardiographic features before and after the surgery.