Palladium-catalyzed aziridination of alkenes using N,N-dichloro-p-toluenesulfonamide as nitrogen source

N,N-Dichloro-p-toluenesulfonamide (TsNCl₂) was found to be an efficient nitrogen source for the aziridination of unfunctionalized alkenes using palladium catalysts. Among the palladium salts, palladium acetate was the most effective catalyst for this reaction. A variety of alkenes were reacted at room temperature with TsNCl₂ to form the desired aziridines in moderate to good yields. This method can complement our previous protocol which is limited to the use of electron-deficient α,β-unsaturated alkenes.     

Reaction of CBrF2-CBrF2 with hydrazones of aromatic aldehydes: Novel efficient synthesis of fluorocontaining alkanes, alkenes and alkynes

An olefination of hydrazones of aromatic aldehydes by CBrF₂-CBrF₂ under copper catalysis was investigated. In situ prepared aldehydes hydrazones were converted to (3-bromo-2,2,3,3-tetrafluoropropyl)arenes by reaction with CBrF₂-CBrF₂ in the presence of CuCl. Subsequent elimination of HF by sodium hydroxide resulted in stereospecific formation of fluorocontaining alkenes. Elimination proceeds stereoselectively, only Z-isomers of alkenes are formed. Elimination of two molecules of HF from (3-bromo-2,2,3,3-tetrafluoropropyl)arenes by treatment with potassium tert-butoxide leads to formation of (bromodifluoromethyl)alkynes. As a result a simple and efficient transformation of aromatic aldehydes to range of various fluorinated alkanes, alkenes and alkynes was elaborated.     

Intermolecular Palladium‐Catalyzed Oxidative Fluorocarbonylation of Unactivated Alkenes: Efficient Access to β‐Fluorocarboxylic Esters

A novel palladium‐catalyzed intermolecular oxidative fluorocarbonylation of alkenes has been developed, in which employment of a cooperative process with electrophilic ArIF₂‐meidated alkenes activation and palladium‐catalyzed carbonylation is crucial for the successful catalytic transformation. The current transformation presents the first convenient method to generate β‐fluorinated carboxylic acid derivatives under mild reaction conditions from simple alkenes with excellent regioselectivity.     

Ligand‐Promoted Iron(III)‐Catalyzed Hydrofluorination of Alkenes

An iron‐catalyzed hydrofluorination of unactivated alkenes has been developed. The use of a multidentate ligand and the fluorination reagent N‐fluorobenzenesulfonimide (NFSI) proved to be critical for this reaction, which afforded various fluorinated compounds in up to 94 % yield.     

Selective mono-fluorination of diols via a cyclic acetal of N,N-diethyl-4-methoxybenzamide

Selective mono-fluorination of 1,2- and 1,3-diols was achieved using N,N-diethyl-4-methoxybenzamide diethyl acetal and Et₃N-3HF. The reaction proceeds through a cyclic acetal of the benzamide, and only one hydroxy group was fluorinated and another one was acylated.     

Organocatalyzed regio- and stereoselective diamination of functionalized alkenes

The first organocatalyzed diamination reaction of alkenes with N,N-dichlorotoluenesulfonamide (TsNCl₂) and acetonitrile as nitrogen sources was reported. The catalytic diamination reaction was convenient to carry out, resulting in imidazoline products with good yields and excellent regio- and stereoselectivities. Several other organic molecules were also tried as catalyst for this reaction and good results were achieved. A new one-pot synthesis of vicinal diamines via the current PPh₃-catalyzed diamination and the hydrolysis of resulting imidazoline products with SnCl₄ as promoter was also established.     

Regioselective reactions of β-aminovinyl trifluoromethyl ketones with tosyl isocyanate

The NH- and α-CH-insertion reactions of tosyl isocyanate with N-monosubstituted and N,N-disubstituted trifluoromethyl-containing enaminones have been studied. The regioselectivity of N-tosylcarbomoylation of N-monosubstituted β-aminovinyl trifluoromethyl ketones depends on the structure of enaminones, the reaction temperature, the nature of solvent and catalyst. The Z configuration of fluorinated vinylogous sulphonylurea 3e was deduced from X-ray analysis. The reaction of N,N-disubstituted enaminone 5a with tosyl isocyanate gave the product mixture of electrophilic attack on either the α-CH- or the oxygen atom of COCF₃ group—vinylog of sulfonylurea 6a and tosylamide 7a, correspondingly.     

N-(Benzoyloxy)amines: an investigation of their thermal stability, synthesis, and incorporation into novel peptide constructs

A series of N-benzoyloxyamines were pyrolyzed and their decomposition temperatures correlated well with the amine architecture's ability to stabilize a N-centered radical. A variety of amine substrates were treated with a biphasic mixture of benzoyl peroxide (BPO), CH₂Cl₂ and an aqueous carbonate buffer (at pH 10.5). Primary and secondary amines were successfully N-benzoyloxylated in good yield. Tertiary amines and BPO gave low yields of the corresponding N-oxide and complex product mixtures, presumably via radical decomposition. Electron deficient amines (such as fluorinated aliphatic amines, α-aminoacids, α-aminoesters, and α-aminoamides) were not N-benzoyloxylated under these conditions. Instead, N-benzoylation was observed with the fluorinated amines and the reaction was sensitive to temperature and the pH of the aqueous medium. A one-pot-two-step synthesis of N^α-FMOC-l-Leu-N^β-(benzoyloxy)-β-alanine ethyl ester, a peptide containing both an α- and a novel β-amino acid framework, was also developed.     

A simple route to side-chain fluorinated β-lactams from ring-fluorinated aziridines

β-Lactams bearing a Ph₂CF substituent at the C(4)-atom were synthesized from N-alkyl-2-fluoro-3,3-diphenylaziridines. The transformation was realized using SbF₃-mediated isomerization of the monofluoroaziridines to fluorinated aldimines, followed by Staudinger reaction with ketenes. It was shown that this reaction sequence can be performed as a one-pot procedure.     

Highly Regioselective Radical Amination of Allenes: Direct Synthesis of Allenamides and Tetrasubstituted Alkenes

The first controllable, regioselective radical amination of allenes with N‐fluoroarylsulfonimide is described to proceed under very mild reaction conditions. With this methodology, a general and straightforward route for the synthesis of both allenamides and fluorinated tetrasubstituted alkenes was realized from a wide range of terminal and internal allenes.     

A facile one-pot synthesis of 2-fluoroalkyl 1,3-imidazolines and 1,3-oxazolines through imidoyl halide intermediates

A facile one-pot procedure has been developed for the synthesis of 1,3-imidazolines and 1,3-oxazolines bearing fluorinated alkyl groups at the 2-position. The reaction involves the condensation of N-monosubstituted ethane-1,2-diamines or 2-aminoethanols with a fluorinated carboxylic acid in the presence of PPh₃/CX₄. The proposed mechanism is that the amide intermediates were initially formed, and then converted to the imidoyl halide intermediates in the presence of PPh₃/CX₄, followed by rapid intramolecular cyclization to 1,3-diazoline products. This protocol allows for the synthesis of 2-bromodifluoromethyl-1,3-imidazoline, a useful CF₂Br-heterocyclic building block, which can be used for the synthesis of gem-difluoromethylene linked compounds.     

trans-Selective Aryldifluoroalkylation of Endocyclic Enecarbamates and Enamides by Nickel Catalysis

Efficient methods for the dicarbofuntionalization of the cyclic alkenes 2-pyrroline and 2-azetine are limited. Particularly, the dicarbofunctionalization of endocyclic enecarbamates to achieve fluorinated compounds remains an unsolved issue. Reported here is a nickel-catalyzed trans-selective dicarbofunctionalization of N-Boc-2-pyrroline and N-Boc-2-azetine, a class of endocyclic enecarbamates previously unexplored for transition metal catalyzed dicarbofunctionalization. The reaction can be extended to six- and seven-membered endocyclic enamides. A variety of arylzinc reagents and bromodifluoroacetate, and its derivatives, undergo the reaction, providing straightforward and efficient access to an array of pyrrolidine- and azetidine-containing fluorinated amino acids and oligopeptides, which may have applications in the life sciences.     

Substituent-controlled domino-Knoevenagel-hetero Diels-Alder reaction—a one-pot synthesis of polycyclic heterocycles

The reaction of 2-(N-alkenyl-N-aryl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde with dimedone/Meldrum’s acid/4-hydroxycoumarin by heating in ethanol in the presence of pyridine produces polycyclic heterocycles bearing pyridine and pyran rings in a one-pot reaction. The effect of substituents on N-atom of the amino function controls the mode of reaction. Terminal alkenes prefer intramolecular Michael type reaction, but non-terminal alkenes favour Diels-Alder reaction, whereas, under similar condition, 2-(N-alkyl-N-allyl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde undergoes domino-Knoevenagel-hetero Diels-Alder reaction.     

γ-Fluorophenyl-GABA derivatives from fluorobenzonitriles in high diastereomeric and enantiomeric excess

An enantioselective synthesis of α-fluoroaryl homoallylic amines in 52-71% yields and 76-93% enantioselectivities has been achieved via the allylboration of the corresponding fluorinated N-aluminobenzaldimines with B-allyldiisopinocampheylborane in the presence of methanol, followed by alkaline hydrogen peroxide workup. Crotylboration of these aluminobenzaldimines with potassium B-methoxy B-E- or -Z-crotyldiisopinocampheylborinate provided the corresponding β-anti- or -syn-methyl α-fluoroarylhomoallylamines, respectively in high de and ee. Similarly, alkoxyallylboration with lithium B-methoxy B-γ-OMEMallyldiisopinocampheylborinate provided the corresponding β-syn-alkoxyhomoallylamines in excellent de and ee. Representatives of these amino alkenes were converted to the corresponding optically active N-Boc-protected fluorinated amino alcohols via hydroboration-oxidation. Further chromium-mediated oxidation provided N-Boc-protected γ-fluorophenyl-γ-aminobutyric acids, which upon deprotection provided the corresponding γ-lactams.     

Synthesis, properties, and hepatic metabolism of strongly fluorescent fluorodipyrrinones

From non-fluorescent 8-H fluorophenyldipyrrinones, highly fluorescent (?_F 0.4-0.6) analogs have been synthesized by reaction with 1,1′-carbonyldiimidazole to bridge the dipyrrinone nitrogens and form an N,N′-carbonyldipyrrinone (3H,5H-dipyrrolo[1,2-c:2′,1′-f]pyrimidine-3,5-dione). Amphiphilic, water-soluble 8-sulfonic acid derivatives are then obtained by reaction with concd H₂SO₄. The resulting fluorinated and sulfonated N,N′-carbonyl-bridged dipyrrinones, isolated as their sodium salts, are potential cholephilic fluorescence and ¹⁹F MRI imaging agents for use in probing liver and biliary metabolism. After intravenous injection in the rat they were excreted rapidly and largely unchanged in bile. ¹⁹F NMR spectroscopy of a pentafluorophenyl-tosylpyrrolinone synthetic precursor exhibited rarely seen diastereotopicity.     

Heterosubstituted cyclopropanation of alkenes with organochromium reagents derived from heterosubstituted dihalomethanes,CrCl2, and tetraalkylethylenediamine

Iodocyclopropanes of trans configuration are produced stereoselectively from terminal alkenes by treatment with a reagent derived from iodoform, chromium(II) chloride, and TEEDA (N,N,N′,N′-tetraethylethylenediamine) in THF. Similarly, cyclopropylsilanes and cyclopropylboronic esters are obtained by using R₃SiCHI₂, and a combination of Cl₂CHB(OR)₂ and LiI instead of iodoform, respectively. The heterocyclopropanation occurs selectively at terminal double bonds, and di- and trisubstituted double bonds in the same molecules remain unchanged. Such functional groups as alcohol, ether, silyl ether, ester, tertiary amine, and amide groups are compatible with the reaction conditions.     

An evidence of contact ion pair in β-(acyloxy)alkyl radical heterolysis during copper(I)-mediated synthesis of trisubstituted alkenes

The first evidence for a unified mechanism of heterolysis in β-(acyloxy)alkyl radical involving contact ion pair (CIP) is presented for both fragmentation and rearrangement of the acyloxy group in the reaction of 1-alkoxy-2,2,2-trichloroethyl acetate with 2 mol equiv each of CuCl and bpy in refluxing DCE under a N₂ atmosphere and availed this reaction for the synthesis of Z-stereoselective trisubstituted alkenes. The stereochemistry of the trisubstituted alkenes was assigned by the uniform pattern of the chemical shift values of some relevant signals in ¹H and ¹³C NMR spectra. This assignment was further supported by the X-ray diffraction spectroscopy of Z-1-chloro-2-(4-nitrobenzyloxy)vinyl acetates.     

Recent Progress toward the Introduction of Functionalized Difluoromethylated Building Blocks onto C(sp2) and C(sp) Centers

Fluorine chemistry is a field undergoing tremendous expansion. Although much attention has been paid to the introduction of the fluorine atom and the CF₃ group, less interest has been devoted to the introduction of functionalized fluorinated building blocks, in sharp contrast with the high versatility of the fluorinated products. In this Minireview, the most relevant methods for the introduction of difluoromethylated building blocks are summarized. Access to difluoromethylated arenes, alkenes, and alkynes is highlighted and special attention is paid to explanation of the reaction mechanism.     

Recent advances in the synthetic and mechanistic aspects of the ruthenium-catalyzed carbon-heteroatom bond forming reactions of alkenes and alkynes

The group’s recent advances in catalytic carbon-to-heteroatom bond forming reactions of alkenes and alkynes are described. For the C-O bond formation reaction, a well-defined bifunctional ruthenium-amido catalyst has been successfully employed for the conjugate addition of alcohols to acrylic compounds. The ruthenium-hydride complex (PCy₃)₂(CO)RuHCl was found to be a highly effective catalyst for the regioselective alkyne-to-carboxylic acid coupling reaction in yielding synthetically useful enol ester products. Cationic ruthenium-hydride catalyst generated in-situ from (PCy₃)₂(CO)RuHCl/HBF₄·OEt₂ was successfully utilized for both the hydroamination and related C-N bond forming reactions of alkenes. For the C-Si bond formation reaction, regio- and stereoselective dehydrosilylation of alkenes and hydrosilylation of alkynes have been developed by using a well-defined ruthenium-hydride catalyst. Scope and mechanistic aspects of these carbon-to-heteroatom bond forming reactions are discussed.     

Solubilization and applications of single-walled carbon nanotubes into aqueous and organic media by the use of nanometer size-controlled fluoroalkyl end-capped oligomeric aggregates

We have studied on the solubilization of single-walled carbon nanotubes (SW-CNTs) into aqueous and organic media by the use of a variety of nanometer size-controlled fluorinated self-assemblies, which were formed by the aggregations of end-capped fluoroalkyl segments in fluoroalkyl end-capped acrylic acid oligomers [R_F-(ACA)_n-R_F], N,N-dimethylacrylamide oligomers [R_F-(DMAA)_n-R_F], acryloylmorpholine oligomers [R_F-(ACMO)_n-R_F], and N-(1,1-dimethyl-3-oxobutyl)acrylamide oligomers [R_F-(DOBAA)_n-R_F]. Fluorinated self assemblies formed in organic media (colorless solutions) could solubilize SW-CNTs into organic media to afford the transparent pale yellow solutions. The dynamic light scattering measurements showed that the size of fluorinated self-assemblies increased after the solubilization of SW-CNTs into organic media. It was suggested that the solubilization of SW-CNTs into organic media is due to the encapsulation of SW-CNTs into fluorinated assemblies. Fluorinated assemblies were also able to solubilize SW-CNTs into water to give the transparent gray solutions. Among a variety of fluorinated assemblies, fluorinated assemblies formed by R_F-(ACMO)_n-R_F [R_F = CF(CF₃)OC₆F₁₃] oligomer was more effective for the solubilization of SW-CNTs into both aqueous and organic media. Contact angle measurements of dodecane and the fluorescence spectra for poly(methyl methacrylate) cast film modified by fluorinated self-assemblies—SW-CNTs complexes showed that SW-CNTs are dispersed above the PMMA surface.