Fluorine-Activated and -Directed Allene Cycloadditions with Nitrile Oxides and Imine Oxides: Synthesis of Ring-Fluorinated Isoxazole Derivatives.

In this study, 1,1-difluoroallenes underwent a regioselective [2+3] cycloaddition with nitrile oxides and imine oxides in the presence of a AuCl catalyst. (E)-4-Alkylidene-5,5-difluoroisoxazolines and -isoxazolidines were obtained in regioselective and diastereoselective manners by employing aurated difluoroallylic cation intermediates. The synthesized 5,5-difluoroisoxazolines were readily aromatized through dehydrofluorination or allylic fluorine substitution to provide 5-fluoroisoxazoles.

Synthesis of 2-Difluoroethylated 2H-1,3-Benzoxazines via Proton-Mediated Ring Opening/Interrupted Ritter Reaction of 1,1-Difluorocyclopropanes.

2-(1,1-Difluoroethyl)-2H-1,3-benzoxazines were synthesized by (i) the regioselective ring opening of 1,1-difluorocyclopropanes bearing an aryloxy group and (ii) the Ritter reaction followed by a Friedel-Crafts-type ring closure. When 2-aryloxy-1,1-difluorocyclopropanes were treated with triflic acid, the C-C bond distal to the CF2 moiety was cleaved regioselectively via protonation to generate the corresponding oxocarbenium ions. These intermediates readily underwent nucleophilic attack by nitriles, followed by a carbocationic cyclization to afford the 2-difluoroethylated benzoxazines.

Generation of difluorocarbenes and introduction of fluorinated one carbon units into carbonyl and related compounds.

Difluorocarbene is a simple and versatile one-carbon unit for synthesizing acyclic and cyclic organofluorine compounds. However, the use of difluorocarbene in organic synthesis has been relatively limited because of the harsh conditions required for its generation, the toxicity of the precursors, and undesired dimerization. This feature article provides an account of (i) the generation of free and metal difluorocarbenes from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) or BrCF2CO2Li/Na and (ii) their application to the facile synthesis of valuable organofluorine compounds. The difluorocarbenes thus generated react with (thio)carbonyl compounds and silyl dienol ethers to provide a wide variety of products such as (a) difluoromethyl (thio)ethers, (b) fluorinated thiophenes, (c) fluorinated thia/oxazoles, (d) fluorinated cyclopentanones and (e) difluoroalkenes.

Two-Step Synthesis of 2-Trifluoromethylated and 2-Difluoromethylated Benzoheteroles Starting from HFO-1224yd(Z) and HFO-1233yd(Z).

An efficient two-step method for synthesizing 2-(trifluoromethyl)- and 2-(difluoromethyl)benzoheteroles bearing various substituents was developed. Commercially available HFO-1224yd(Z) or HFO-1233yd(Z) underwent the Suzuki-Miyaura coupling with arylboronic acids (acid esters) bearing a nucleophilic moiety at the ortho position to yield the corresponding ß-fluoro-ß-(trifluoromethyl)- or ß-fluoro-ß-(difluoromethyl)styrenes, respectively. Treatment of the obtained styrenes with potassium phosphate induced nucleophilic 5-endo-trig cyclization to provide the corresponding 2-trifluoromethylated or 2-difluoromethylated indoles and benzofurans, as well as benzothiophenes.

Nickel-Catalyzed Reductive Allyl-Aryl Cross-Electrophile Coupling via Allylic C-F Bond Activation.

Nickel-catalyzed reductive cross-coupling of allylic difluorides with aryl iodides was achieved via allylic C-F bond activation. Based on this protocol, a series of γ-arylated monofluoroalkenes were synthesized in moderate to high yields with high Z-selectivities. Mechanistic studies suggest that the C-I bonds of the aryl iodides and the C-F bonds of the allylic difluorides were cleaved via oxidative addition and ß-fluorine elimination, respectively, where the oxidative addition of less reactive C-F bonds was avoided to permit their transformation.

Construction of Thienothiophene and Thienofuran Ring Systems via Ring Expansion of Difluorothiiranes Generated from Dithioesters.

The reaction of aryl thiophene-2-carbodithioates or thiophene-3-carbodithioates with difluorocarbene generated from BrCF2CO2Li/molecular sieves 4A produced arylsulfanylated 2,2-difluoro-3-thienylthiiranes. In the presence of lithium ion, the thiirane intermediates underwent ring expansion followed by HF elimination, leading to fluorinated thieno[3,2-b]thiophenes or thieno[2,3-b]thiophenes. The reactions of the oxygen analogues, aryl furancarbodithioates, also proceeded to afford the corresponding thieno[3,2-b]furans. Intramolecular fluorine substitution in the produced arylsulfanyl(fluoro)thienofurans allowed for another thiophene ring construction, leading to the synthesis of fused pentacyclic thienothienofurans.

Acid-mediated intermolecular C-F/C-H cross-coupling of 2-fluorobenzofurans with arenes: synthesis of 2-arylbenzofurans.

Transition-metal-free acid-promoted biaryl construction was achieved via intermolecular C-F/C-H cross-coupling. By treating 2-fluorobenzofurans with arenes in the presence of AlCl3, 2-arylbenzofurans were obtained. This protocol was successfully applied to the short-step orthogonal synthesis of a bioactive 2-arylbenzofuran natural product, which allows independent transformations of C-F and C-Br bonds. Mechanistic studies indicated that α-fluorine-stabilized carbocations, generated via the protonation of 2-fluorobenzofurans, served as key intermediates. The Friedel-Crafts-type C-C bond formation between the α-fluorocarbocations and arenes, followed by hydrogen fluoride elimination, afforded 2-arylbenzofurans.

Helicene synthesis by Brønsted acid-catalyzed cycloaromatization in HFIP [(CF3)2CHOH].

A facile synthesis of carbo- and heterohelicenes was achieved via tandem cycloaromatization of bisacetal precursors, which were readily prepared through C-C bond formation by Suzuki-Miyaura coupling. This cyclization was efficiently realized by a catalytic amount of trifluoromethanesulfonic acid (TfOH) in a cation-stabilizing solvent, 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), which readily allowed gram-scale syntheses of higher-order helicenes, double helical helicenes, and heterohelicenes.

Copper-Catalyzed [3 + 2] Annulation of Azides with a (Difluorovinyl)zinc Complex, Fluoroacetylene Equivalent.

The copper-catalyzed [3 + 2] annulation of organic azides with (2,2-difluorovinyl)zinc chloride-TMEDA was achieved via C-F bond cleavage. Thus, a series of 1-substituted 4-fluorotriazoles was synthesized in high yields. In this reaction, the difluorovinylzinc complex functions as an easy-to-handle equivalent of fluoroacetylene (FC≡CH) to undergo cycloaddition with azides. This work offers a facile and practical method for the use of fluoroacetylene, which has been considered to be highly reactive and difficult to handle and control for synthetic applications.

Synthesis of Ring-Fluorinated Thiophene Derivatives Based on Single C-F Bond Activation of CF3-Cyclopropanes: Sulfanylation and 5-endo-trig Cyclization.

The treatment of CF3-bearing cyclopropanes with Et2AlCl generated stabilized difluorocarbocations, which underwent a nucleophilic addition of thiocarboxylic acids or thiols. The sulfur functionality was introduced at the position δ to the fluorine substituents in a regioselective manner (single activation of CF3-cyclopropanes). The formed 1,1-difluoro-1-alkenes underwent successive deesterification/5-endo-trig cyclization. Intramolecular vinylic substitution proceeded in an aprotic solvent, whereas intramolecular addition proceeded in a protic solvent to afford pharmaceutically and agrochemically promising 2-fluoro-4,5-dihydrothiophene and 2,2-difluorotetrahydrothiophene scaffolds, respectively.

Fluorinated Phenanthrenes as Aryne Precursors: PAH Synthesis Based on Domino Ring Assembly Using 1,1-Difluoroallenes.

On treatment with the catalyst InBr3 , 1,1-difluoroallenes that bear a cyclopentene moiety and an aryl group underwent domino ring assembly in the presence or absence of N-bromosuccinimide or N-iodosuccinimide to afford aryne precursors such as three-ringed ortho-fluoro(halo)phenanthrenes, four-ringed ortho-fluoro(halo)tetraphenes, ortho-fluoro(halo)chrysenes and fluoro[4]helicenes. Metalation of the aryne precursors followed by elimination of the fluoride resulted in the unprecedented systematic generation of arynes bearing π-extended systems. Diels-Alder reactions of these arynes with isobenzofurans afforded the corresponding cycloadducts whose reductive aromatisation in an SnCl2 /HBr system furnished fully aromatised benzotriphenylenes. In addition, oxidative aryl-aryl coupling (the Scholl reaction) of these benzotriphenylenes facilitated the synthesis of 'half HBCs' (hexabenzocoronenes).

Brønsted acid-catalysed hydroarylation of unactivated alkynes in a fluoroalcohol-hydrocarbon biphasic system: construction of phenanthrene frameworks.

Transition metal-free hydroarylation of unactivated alkynes was achieved by combining a Brønsted acid catalyst and a two-phase solvent system consisting of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) and cyclohexane. This protocol is applicable to a wide variety of 2-alkynylbiaryls which leads to the synthesis of substituted phenanthrenes via 6-endo-selective ring closure. The biphasic system achieves highly efficient ring closure by appropriate separation of cationic intermediates from neutral compounds. The vinyl carbocation intermediates are stabilised in the HFIP phase, while the substrates and products are distributed in the cyclohexane phase to suppress intermolecular side reactions.

Synthesis of (difluoromethyl)naphthalenes using the ring construction strategy: C-C bond formation on the central carbon of 1,1-difluoroallenes via Pd-catalyzed insertion.

The insertion of 1,1-difluoroallenes was carried out to form a C-C bond exclusively on their central carbon. o-Bromophenyl-bearing 1,1-difluoroallenes underwent intramolecular insertion in the presence of a palladium catalyst. Regioselective C-C bond formation occurred to form a six-membered carbocycle, leading to pharmaceutically and agrochemically promising difluoromethylated naphthalenes.

Transition-Metal-Mediated and -Catalyzed C-F Bond Activation by Fluorine Elimination.

The activation of carbon-fluorine (C-F) bonds is an important topic in synthetic organic chemistry. Metal-mediated and -catalyzed elimination of ß- or α-fluorine proceeds under milder conditions than oxidative addition to C-F bonds. The ß- or α-fluorine elimination is initiated from organometallic intermediates having fluorine substituents on carbon atoms ß or α to metal centers, respectively. Transformations through these elimination processes (C-F bond cleavage), which are typically preceded by carbon-carbon (or carbon-heteroatom) bond formation, have been increasingly developed in the past five years as C-F bond activation methods. In this Minireview, we summarize the applications of transition-metal-mediated and -catalyzed fluorine elimination to synthetic organic chemistry from a historical perspective with early studies and from a systematic perspective with recent studies.

Single C-F Bond Activation of the CF3 Group with a Lewis Acid: CF3 -Cyclopropanes as Versatile 4,4-Difluorohomoallylating Agents.

The selective activation of one C-F bond (single activation) of the CF3 group on cyclopropanes was achieved for the first time. When (trifluoromethyl)cyclopropanes were treated with arenes, allylsilanes, silyl enol ethers, or hydrosilanes in the presence of Me2 AlCl, fluoride elimination and the subsequent ring opening proceeded to afford 4,4-difluorohomoallylated products. In the absence of external nucleophiles, an alkyl group of AlR3 was effectively introduced to provide the corresponding 1,1-difluoroalkenes.

sp3 carbon-fluorine bond activation in 2,2-difluorohomoallylic alcohols via nucleophilic 5-endo-trig cyclisation: synthesis of 3-fluorinated furan derivatives.

Nucleophilic 5-endo-trig cyclisation was achieved in 2,2-difluorohomoallylic alcohols. Upon treatment with potassium hydride, 2,2-difluorohomoallylic alcohols underwent an intramolecular SN2'-type reaction to afford 3-fluoro-2,5-dihydrofurans in high yields. In addition, the oxidation of these dihydrofurans formed 4-fluorofuran-2(5H)-ones. Thus, ring-fluorinated furan derivatives were efficiently obtained via allylic sp3 carbon-fluorine bond cleavage.

Synthesis of Sulfanylated Difluoroalkenes: Electrophilic Difluoromethylidenation of Dithioesters with Difluorocarbene.

Electrophilic difluoromethylidenation of dithioesters was achieved in high yields via the reaction with difluorocarbene. When aryl or alkyl dithiocarboxylates were treated with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in the presence of 5 mol % of a Proton Sponge catalyst, the in situ generated difluorocarbene reacted with the dithioesters to afford 2-sulfanylated 1,1-difluoro-1-alkenes via difluorothiiranes. This reaction can be considered as an electrophilic counterpart of the Wittig-type difluoromethylidenation of carbonyl compounds with nucleophilic difluoromethylene ylides.

Synthesis of Pinpoint-Fluorinated Polycyclic Aromatic Hydrocarbons: Benzene Ring Extension Cycle Involving Microwave-Assisted SN Ar Reaction.

Fluoroarenes bearing no electron-withdrawing groups (non-activated fluoroarenes) readily underwent nucleophilic aromatic substitution with α-cyanocarbanions under microwave irradiation. The sequence (i) formylalkylation involving the cyanoalkylation of fluoroarenes, (ii) difluorovinylidenation, and (iii) Friedel-Crafts-type cyclization, afforded extended fluoroarenes by one benzene ring per cycle. Furthermore, the performance of multiple cycles successfully provided higher-order pinpoint-fluorinated polycyclic aromatic hydrocarbons (F-PAHs).

Lewis Acid Promoted Single C-F Bond Activation of the CF3 Group: SN 1'-Type 3,3-Difluoroallylation of Arenes with 2-Trifluoromethyl-1-alkenes.

Activation of the sp3 C-F bond in 2-trifluoromethyl-1-alkenes was accomplished through treatment with a Lewis acid. In the presence of an equimolar amount of EtAlCl2 , the (trifluoromethyl)alkenes readily underwent an SN 1'-type reaction with arenes through a Friedel-Crafts-type mechanism via elimination of a fluoride ion to afford 3,3-difluoroallylated arenes in good yields. This selective activation of one C-F bond of the CF3 group provides a synthetic method for accessing biologically and synthetically important 1,1-difluoro-1-alkenes.

Cell-quintupling: Structural phase transition in a molecular crystal, bis(trans-4-butylcyclohexyl)methanol.

A structural phase transition at 151.6 K of the title compound [bis(trans-4-butylcyclohexyl)methanol] is examined by X-ray diffraction crystallography, Fourier-transform infrared spectroscopy, and adiabatic calorimetry. A general consideration on possible superstructures indicates that a single modulation wave is sufficient to drive this cell-quintupling transition. The entropy of transition determined calorimetrically indicates that two conformations are dominant in the room-temperature phase in contrast to the fivefold disorder expected from the structure of the low-temperature phase.