Search

An operationally simple protocol for direct N- and O-difluoromethylation of 2-pyridones, quinolinones, and isoquinolinones using commercially available TMSCF2Br is disclosed. The chemoselectivity is modulated by simple variations in temperature, solvent, and strength of the base. Diverse, synthetically relevant functional groups are tolerated, including functional groups that have reported reactivity with TMSCF2Br. Gram-scale reactions to prepare both N- and O-difluoromethyl compounds are included.

A method for the O-difluoromethylation of carboxylic acids using commercially available TMSCF2Br is disclosed. The devised benchtop reaction system is air-stable and offers mild reaction conditions while using readily available reagents and solvents. The method is applicable to both aliphatic and aromatic carboxylic acids while demonstrating compatibility with a range of commonly encountered functional groups. The difluoromethyl esters of FDA approved drugs and pharmaceutically relevant molecules are also presented, demonstrating the potential for late-stage functionalization.

A variety of long-lived carbocations containing the p-(pentafluorosulfanyl)phenyl and m-(pentafluorosulfanyl)phenyl groups have been characterized by low-temperature NMR spectroscopy. In the case of potential nonclassical carbocations substituted with the p-(pentafluorosulfanyl)phenyl substituent, deviations from linearity when the Hammett parameter (σC+) is plotted versus 13C NMR shifts of the carbocationic center were observed. Plotting the experimentally derived 13C NMR shifts versus σC+ or σ+ of classical 4-phenyl-X substituted carbocations also provides a means to accurately back-calculate the σ+ and σC+ parameters of the -SF5 substituent.

The widespread application of 1,2,3-triazoles in pharmaceuticals has resulted in substantial interest toward developing efficient postmodification methods. Whereas there are many postmodification methods available to obtain N1-substituted 1,2,3-triazoles, developing a selective and convenient protocol to synthesize N2-aryl-1,2,3-triazoles has been challenging. We report a catalyst-free and regioselective method to access N2-aryl-1,2,3-triazoles in good to excellent yields (66–97%). This scalable postmodification protocol is effective for a wide range of substrates.

A method for the first direct insertion of difluorcarbene, generated from TMSCF3, into diselenides and disulfides is disclosed, producing novel difluoromethyl diselenoacetals and difluoromethyl dithioacetals. The reaction conditions tolerate a range of synthetically useful and biologically relevant functional groups. The process is scalable, with two representative compounds prepared at a gram-scale in good yields, and it utilizes cheap and available reagents.

The structures of the elusive cyclobutane dication, (CH2)42+, were investigated at the MP2/cc-pVTZ and CCSD(T)/cc-pVTZ levels. Calculations show that the two-electron four-center (2e-4c) bonded structure 1 involving four carbon atoms is a minimum. The structure contains formally two tetracoordinate and two pentacoordinate carbons. The non-classical σ-delocalized structure can be considered as a prototype for a 2e-4c Woodward–Hoffmann frozen transition state. The planar rectangular shaped structure 2 with a 2e-4c bond was found not to be a minimum.

CO2 adsorbents based on the reaction of pentaethylenehexamine (PEHA) or tetraethylenepentamine (TEPA) with propylene oxide (PO) were easily prepared in "one pot" by impregnation on a silica support in water. The starting materials were readily available and inexpensive, facilitating the production of the adsorbents on a large scale. The prepared polyamine/epoxide adsorbents were efficient in capturing CO2 and could be regenerated under mild conditions (50-85 °C). They displayed a much-improved stability compared with their unmodified amine counterparts, especially under oxidative conditions. Leaching of the active organic amine became minimal or nonexistent after treatment with the epoxide. The adsorption as well as desorption kinetics were also greatly improved. The polyamine/epoxide adsorbents were able to capture CO2 from various sources including ambient air and indoor air with CO2 concentrations of only 400-1000 ppm. The presence of water, far from being detrimental, increased the adsorption capacity. Their use for indoor air quality purposes was explored.

The reagent system comprised of halotrimethylsilane and nitrite or nitrate salts has now been successfully used as an efficient system for a series of versatile synthetic transformations. In recent years, the significance and efficacy of this system for reactions such as nitration of aromatics and olefins, oxidation of thiols to sulfonyl chlorides, ipso-nitrosation/nitration of arylboronic acids, ipso-nitration of α,β-unsaturated carboxylic acids to nitro olefins, etc. have been disclosed. Though the reagent system has not been exploited to its full potential, the reported reactions reveal its advantages as a very safe and convenient system that works under mild conditions. This brief Account reveals various synthetic applications of halotrimethylsilane-nitrite/nitrate salts in organic synthesis hitherto reported.1 Introduction2 Reactions Using a Halotrimethylsilane-Nitrate Salt System2.1 Nitration of Olefins and Aromatics2.2 One-Pot Preparation of gem-Chloronitroso, gem-Chloronitro, and vic-Dichloro Compounds2.3 One-Step Conversion of Anilines into Haloarenes2.4 Deoximation of Aldoximes to Aldehydes and Ketoximes to ­Ketones2.5 One-Pot Synthesis of Cyclic/Noncyclic α-Nitroketones from ­Cyclic/Noncyclic Olefins2.6 ipso-Nitration of Arylboronic Acids2.7 ipso-Nitrosation of Arylboronic Acids2.8 Oxidation of Sulfides and Sulfoxides to Sulfones2.9 Oxidative Chlorination of Thiols and Disulfides to Sulfonyl ­Chlorides2.10 α-Halogenation of Carbonyl Compounds2.11 Decarboxylative ipso-Nitration and Dibromination of Cinnamic Acid3 Conclusion

A method for siladifluoromethylation of dialkyl phosphonates and secondary phosphine oxides with TMSCF3 to produce nucleophilic PV–CF2– transfer reagents is disclosed, with multigram scale reactions included. Condition-dependent divergent reactivity under the established conditions is demonstrated by the formation of trifluoromethylphosphines. Both one-pot transformations are operationally simple and employ inexpensive materials. Mechanistic investigations suggest the divergent reactivity originates from a common intermediate, with Li+ concentration directing the chemoselectivity.

Carbon dioxide capture using tertiary amines in ethylene glycol solvent was performed under ambient conditions. Subsequently, the CO2 captured as alkyl carbonate salts was successfully hydrogenated to methanol, in the presence of H2 gas and Ru-Macho-BH catalyst. A comprehensive series of tertiary amines were selected for the integrated capture and conversion process. While most of these amines were effective for CO2 capture, tetramethylethylenediamine (TMEDA) and tetramethylbutanediamine (TMBDA) provided the best CH3 OH yields. Deactivation of the base due to side reactions was significantly minimized and substantial base regeneration was observed. The proposed system was also highly efficient for CO2 capture from a gas mixture containing 10 % CO2 , as found in flue gases, followed by tandem conversion to CH3 OH. We postulate that such high boiling tertiary amine-glycol systems as dual capture and hydrogenation solvents are promising for the realization of a sustainable and carbon-neutral methanol economy in a scalable process.

Ab initio calculations at the MP2/cc-pVTZ level of theory show that the classical 1-(trifluoromethyl)cyclopentyl cation (11) is substantially destabilized (by 9.8 kcal/mol) as compared to its isomeric μ-hydrido-bridged global minimum structure 16. However, the classical carbocation 11 is relatively more stable than the nonclassical cyclobutylmethyl cations 6 and 7, by 7.9 and 3.6 kcal/mol, respectively. We have also shown involvement of the noncovalent H⋯F bonding interactions in the μ-hydrido bridged structures, 13, 16, 19, and 20. The latter H⋯F bond distances are dependent on the number of fluorines in the fluoroalkyl group, and decrease in the order: 16 (CF3) > 20 (CHF2) > 19 (CH2F), in accordance with the decreased basicity of the fluorine atom across this series.

Reaction of the Ruppert–Prakash reagent (Me3SiCF3) with aromatic aldehydes in the presence of triphenylphosphine, lithium iodide and lithium tetrafluoroborate selectively furnishes gem-difluorinated phosphonium salts. Simple alkaline hydrolysis of these salts results in difluoromethylated products. Thus, one-pot nucleophilic difluoromethylation of aromatic aldehydes using Me3SiCF3 has been accomplished. The protocol tolerates electron withdrawing as well as electron donating substituents.

A direct double functionalization involving both difluorination and hydroxylation of enamides is reported. With the appropriate combination of an electrophilic fluorinating reagent and H2O, the most convenient and ecofriendly hydroxylating agent, the preparation of 3-(difluoroalkyl)-3-hydroxyisoindolin-1-ones was achieved under basic or Bronsted acidic conditions. Suitable conditions for trifluorination as well as C(sp2)–H fluorination were also identified. Subsequent asymmetric functionalization of the obtained gem-difluorinated products has also been demonstrated.

Fluorodecarboxylation of aryloxydifluoroacetic acid (ArOCF2CO2H) and arylmercaptodifluoroacetic acid (ArSCF2CO2H) towards ArXCF3 (X = O, S) using silver (I) salts in the presence of Selectfluor in a biphasic system with trifluoroacetic acid additive is discussed.

Mn(I)-PNP pincer catalyzed sequential one-pot homogeneous CO2 hydrogenation to CH3OH by molecular H2 is demonstrated. The hydrogenation consists of two parts—N-formylation of an amine utilizing CO2 and H2, and subsequent formamide reduction to CH3OH, regenerating the amine in the process. A reported air-stable and well-defined Mn-PNP pincer complex was found active for the catalysis of both steps. CH3OH yields up to 84% and 71% (w.r.t amine) were obtained, when benzylamine and morpholine were used as amines, respectively; and a TON of up to 36 was observed. In our opinion, this study represents an important development in the nascent field of base-metal-catalyzed homogeneous CO2 hydrogenation to CH3OH.

There have been significant developments in the area of perfluoroalkyl group transfer using silicon reagents, specifically in nucleo­philic trifluoromethylation. The mild and versatile activation conditions bestow significant synthetic prowess to the silicon reagents in the area of fluoroalkylations. Owing to the importance of difluoromethylene (CF2) containing compounds in pharmaceuticals, materials, and agrochemicals, several CF2 group transfer methods using related silicon reagents have been developed and studied in detail. This review summarizes the recent developments and trends in this area.1 Introduction2 Trimethyl(trifluoromethyl)silane (Me3SiCF3)3 (Difluoromethyl)trimethylsilane (Me3SiCF2H)3.1 Nucleophilic Addition3.2 Nucleophilic Substitution3.3 Nucleophilic Difluoromethylation of Electron-Deficient Hetero­cycles3.4 Metal-Mediated Cross Coupling3.5 Oxidative Coupling of Terminal Alkynes4 Post-functionalizable Difluoromethyl Transfer Reagents4.1 (Chlorodifluoromethyl)trimethylsilane (Me3SiCF2Cl)4.2 (Bromodifluoromethyl)trimethylsilane (Me3SiCF2Br)4.3 [Difluoro(iodo)methyl]trimethylsilane (Me3SiCF2I)4.4 [Difluoro(phenylthio)methyl]trimethylsilane (Me3SiCF2SPh)4.5 [Difluoro(phenylsulfonyl)methyl]trimethylsilane (Me3SiCF2SO2Ph)4.6 Diethyl [Difluoro(trimethylsilyl)methyl]phosphonate [Me3SiCF2P(O)(OEt)2]4.7 Ethyl Difluoro(trimethylsilyl)acetate (Me3SiCF2CO2Et)4.8 Difluoro(trimethylsilyl)acetamides (Me3SiCF2CONR2)4.9 Difluoro(trimethylsilyl)acetonitrile (Me3SiCF2CN)5 Others6 Conclusions

Further synthetic potential of halotrimethylsilane-nitrate salt mixture is revealed. A mixture of TMSX-Cu(NO3)2.3H2O system is found to be an efficient reagent system for both the decarboxylative nitration (ipso-nitration) when X = Cl, and dibromination of cinnamic acids, with X = Br, under mild conditions. The reactions are safe and simple, affording the corresponding products (E)-β-nitrostyrenes, and anti-2,3-dibromo-3-phenylpropanoic acids in high yields with high selectivity in a relatively short time. Use of hazardous and toxic nitrating systems such acetyl nitrate and brominating agents such as molecular bromine can be avoided.

A selective reductive monodefluorination reaction of trifluoromethyl arenes was developed. Mediated by magnesium metal, various difluoromethylated aromatics were accessed at room temperature in the presence of acetic acid. This protocol shows tolerance to a wide range of functional groups and it was applicable in late-stage hydrodefluorination of complex pharmaceutical compounds, affording the corresponding CF2H analogues and their deuterated (CF2D) counterparts.

Incorporation of fluorinated heterocyclic framework into organic molecules results in profound changes in their physical, chemical and biological properties. Realizing that the fluorinated thiochroman-4-ones are important scaffolds in medicinal chemistry and are rare in the chemical literature, one-pot synthesis of 2-/3-(trifluoromethyl)thiochroman-4-ones was attempted. Direct access to 2-/3-(trifluoromethyl)thiochroman-4-ones was achieved by a tandem alkylation-cyclic acylation process promoted by superelectrophilic activation of 2-/3-(trifluoromethyl)acrylic acid in superacidic trifluoromethanesulfonic acid under microwave-assisted Friedel-Crafts alkylation of benzenethiols followed by cyclization (via intramolecular acylation). Synthesis of a series of 2-/3-(trifluoromethyl)thiochroman-4-ones from protosolvated 2-/3-(trifluoromethyl)acrylic acid intermediates and benzenethiols is described.

A fast and simple method for deoxyfluorination of carboxylic acids is presented. The protocol employs commodity chemicals (PPh3, NBS, fluoride), affording products in excellent yields under mild co...

The structures of the elusive cyclobutane dication, (CH2)4 2+, were investigated at the MP2/cc-pVTZ and CCSD(T)/cc-pVTZ levels. Calculations show that the two-electron four-center (2e-4c) bonded structure 1 involving four carbon atoms is a minimum. The structure contains formally two tetracoordinate and two pentacoordinate carbons. The non-classical σ-delocalized structure can be considered as a prototype for a 2e-4c Woodward–Hoffmann frozen transition state. The planar rectangular shaped structure 2 with a 2e-4c bond was found not to be a minimum.

A deoxygenative difluoromethylenation of carbonyl compounds has been developed by using readily available, inexpensive trifluoromethyltrimethylsilane, LiI, and PPh3. The presence of the Li+ ion prevents the unproductive exhaustion of trifluoromethyltrimethylsilane (TMSCF3) by keeping the soluble free fluoride concentration in the reaction medium under control. The strategy of combining solvents to increase the reactivity and thereby reduce the reaction temperature and time is disclosed.

The synthesis of several chiral α,α,α-trifluoromethylbenzylamines by an environmentally benign exclusively heterogeneous catalytic method is described. The procedure is based on trifluoromethyl acetophenones as starting materials. The commercially available inexpensive K-10 montmorillonite was applied for the synthesis of imines from the α,α,α-trifluoromethyl ketones and chiral α-methylbenzylamines. The diastereoselective hydrogenations of the imines were carried out in the presence of 5 % Pd/BaCO3 catalyst followed by the hydrogenolysis of the benzylic group under acidic conditions to give the respective chiral amines in good yields. The diastereomeric excess achieved in the hydrogenation was further enhanced by a secondary kinetic resolution during the hydrogenolysis step ensuring good to excellent enantioselectivities. The simplicity of this method makes it an alternative synthetic procedure for the preparation of both enantiomers of substituted chiral α,α,α-trifluoromethylbenzylamines.

A simple and expedient method for the synthesis of 3-methylene-isoindolin-1-ones 4 under aqueous phase-transfer conditions has been developed. Starting from 2-iodobenzamides 1 and (silyl) alkynes, the products are obtained in high yields and short reaction times (30 min) with the use of inexpensive CuCl/PPh3 catalyst system in the presence of n-Bu4NBr (TBAB) as a phase-transfer agent. Terminal alkynes are conveniently "unmasked" upon in situ desilylation under the reaction conditions. Alkynes possessing heterocyclic moieties were also found as amenable substrates. Furthermore, a one-pot process starting from 2-iodobenzamides 1, aryl halides (bromides or iodides) and trimethylsilylacetylene (TMSA) as a convenient acetylene surrogate was also shown to be feasible under Pd/Cu catalysis.

Boron trifluoride monohydrate is an excellent Bronsted acid catalyst system for a wide range of reactions. It is a non-oxidizing acid catalyst prepared easily by bubbling BF 3 into water. We have found boron trifluoride monohydrate/sodium azide combination to be an efficient reagent system for aromatic electrophilic amination. The present method avoids the use of expensive superacids such as trifluoromethanesulfonic acid and provides a facile access to aromatic amines directly from aromatics.

An efficient microwave-assisted protocol for the synthesis of 2-/3-methylthiochroman-4-ones by superacid-catalyzed alkylation followed by cyclic acylation (cyclization via intramolecular acylation) is described. Using easily accessible benzenethiols and crotonic acid/methacrylic acid with triflic acid (as catalyst of choice for needed optimal acidity), the reaction was tuned toward the formation of the cyclized products in good selectivity and yield. A mechanism involving the formation of carbenium-carboxonium superelectrophilic species is suggested.

Direct S-difluoromethylation of aryl and aliphatic thiols using the Ruppert–Prakash reagent is demonstrated. The reaction produces trimethylsilyldifluoromethyl sulfides, which upon cleavage with fluoride produces the difluoromethyl sulfides. The key reaction features are the use of relatively inexpensive and commercially available starting materials, shorter reaction times, ambient temperatures, easy reaction procedure, and selective S-difluoromethylation in the presence of OH, NH2 and CO2H functional groups. Furthermore, one-pot arylthiodifluoromethyl transfer to PhCHO is also demonstrated.

Trivalent boron-carbenium ion continuum was extended to include trifluoro-, F 3 BX − (X = H 1a , CH 3 3a , F 5a , CF 3 7a , CN 9a , NO 2 11a , HCC 13a , H 2 CCH 15a ) and trihydridoborate, H 3 BX − (X = H 2a , CH 3 4a , F 6a , CF 3 8a , CN 10a , NO 2 12a , HCC 14a , H 2 CCH 16a ) anions and their corresponding isoelectronic neutral trifluoro-, F 3 CX and trihydridoalkanes, H 3 CX. The 11 B NMR chemical shifts of a series of trifluoro- and trihydridoborate anions and the 13 C NMR chemical shifts of the corresponding isoelectronic neutral trifluoro- and and trihydridoalkanes were calculated by GIAO-CCSD(T) method. The data show good linear correlation between 11 B and 13 C NMR chemical shifts, which indicates that the same factors that determine the chemical shifts of the boron nuclei also govern the chemical shifts of the carbon nuclei within these trifluoro- and trihydrido compounds.

Condensed heterocycles such as quinazolines constitute the framework of many promising drugs. The great impact of the dramatic fluorine effect in pharmaceuticals prompted a great surge in the quest for fluorinated drug design resulting in over 20 % fluorine-containing drugs in the market today. Therefore, finding an efficient and cost-effective method for the direct synthesis of fluorine-tagged quinazoline systems is of great significance in the pharmaceutical arena. For the first time, a one-pot sequential condensation-cyclization reaction to form selectively the difluoro/trifluoromethylated tetrahydroquinazolines from simple components difluoro/trifluoroacetaldehyde hemiacetal and aromatic amines is reported. Our recent studies using difluoro/trifluoroacetaldehyde hemiacetal as simple and elegant difluoro/trifluoromethyl synthons and metal triflates such as gallium triflate as safe and stable Lewis acid catalysts led us to this direct synthesis protocol for the expedient and convenient synthesis of fluorinated quinazolines. DFT calculations at PCM/B3LYP/6-31++G** were carried out for evaluating a possible reaction mechanism for this cyclization. According to the DFT calculations, product stereochemistry is thermodynamically driven, favoring the cis isomer as the major product, which is also confirmed experimentally.

The application of poly(4-vinylpyridine) supported trifluoromethanesulfonic acid (PVP-TfOH, 1:10) as a convenient solid superacid catalyst system in Friedel–Crafts reactions is described. In the presence of PVP-TfOH, one pot solvent-free synthesis of a wide variety of diarylacetic acid derivatives was achieved by Friedel–Crafts hydroxyalkylation reaction of glyoxylic acid with arenes under mild conditions. Acylation of both activated and deactivated aromatic compounds with acetyl chloride was also achieved using PVP-TfOH complex under solvent-free conditions at room temperature. As the polymer supported triflic acid was found to be a very efficient and an easy-to-handle solid acid, it can be a useful addition to environmentally more adaptable strong acid catalyst systems.

Adsorbents based on linear polyethylenimines (LPEIs) supported on fumed silica were prepared and studied for the reversible adsorption of CO2 under mild conditions from various gas mixtures, including dry air with a CO2 concentration of only 400 ppm. While the adsorption kinetics were similar between linear and branched PEI impregnated on fumed silica, the desorption rate was noticeably faster on linear PEI, which is advantageous for fast adsorption/desorption cycling. The enthalpy of CO2 adsorption was also lower on LPEI based adsorbents (−43 to −53 kJ mol−1 CO2). Desorption of the adsorbed CO2 occurred rapidly at relatively low temperatures (50 to 100 °C). The adsorption/desorption process can be repeated for more than one hundred cycles with no noticeable decrease in adsorption capacity even under humid conditions. The stability of the adsorbents under CO2, air, and N2 was also investigated.