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.

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.

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.

Regioselective Synthesis of α-Fluorinated Cyclopentenones by Organocatalytic Difluorocyclopropanation and Fluorine-Directed and Fluorine-Activated Nazarov Cyclization.

Silyl dienol ethers, prepared from α,ß-unsaturated ketones, underwent proton sponge-catalyzed difluorocyclopropanation with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in a regioselective manner, leading to 1,1-difluoro-2-siloxy-2-vinylcyclopropanes in good yields. The cyclopropanes thus obtained were in turn subjected to fluoride-ion-catalyzed ring opening to afford 1-fluorovinyl vinyl ketones (i.e., Nazarov precursors). Treatment of the precursors with Me3 Si+ B(OTf)4- regioselectively promoted the Nazarov cyclization, the rate and regioselectivity of which were drastically enhanced by the fluoro substituent, which thus facilitated efficient synthesis of biologically promising α-fluorocyclopentenone derivatives.

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.

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.

Ring-size-selective construction of fluorine-containing carbocycles via intramolecular iodoarylation of 1,1-difluoro-1-alkenes.

1,1-Difluoro-1-alkenes bearing a biaryl-2-yl group effectively underwent site-selective intramolecular iodoarylation by the appropriate cationic iodine species. Iodoarylation of 2-(2-aryl-3,3-difluoroallyl)biaryls proceeded via regioselective carbon-carbon bond formation at the carbon atoms in ß-position to the fluorine substituents, thereby constructing dibenzo-fused six-membered carbocycles bearing a difluoroiodomethyl group. In contrast, 2-(3,3-difluoroallyl)biaryls underwent a similar cyclization at the α-carbon atoms to afford ring-difluorinated seven-membered carbocycles.

Ni-Catalyzed Synthesis of Fluoroarenes via [2+2+2] Cycloaddition Involving α-Fluorine Elimination.

A method for direct synthesis of tetrasubstituted fluoroarenes via nickel-catalyzed [2+2+2] cycloaddition is presented. The reaction combines one molecule of 1,1-difluoroethylene with two molecules of alkynes and involves sequential cleavage of the C-F and C-H bonds in difluoroethylene. The catalytic cycle is established by reduction of the intermediary Ni(II) fluoride with a triethylborane-based borate.

Double C-F bond activation through ß-fluorine elimination: nickel-mediated [3+2] cycloaddition of 2-trifluoromethyl-1-alkenes with alkynes.

The nickel-mediated [3+2] cycloaddition of 2-trifluoromethyl-1-alkenes with alkynes afforded fluorine-containing multi-substituted cyclopentadienes in a regioselective manner. This reaction involves the consecutive two C-F bond cleavage of a trifluoromethyl or a pentafluoroethyl group through ß-fluorine elimination.

Domino synthesis of fluorine-substituted polycyclic aromatic hydrocarbons: 1,1-difluoroallenes as synthetic platforms.

Rather crafty: 1,1-Difluoroallenes bearing an aryl group and a cyclopentene moiety undergo indium(III)-catalyzed Friedel-Crafts-type cyclization with subsequent ring expansion and dehydrogenation to afford fluorinated polycyclic aromatic hydrocarbons in high yields. The introduction of an Ar group was effected by in situ halogenation of the intermediary indium species and a subsequent Suzuki-Miyaura reaction.

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.

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.

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.

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.

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.

Domino Friedel-Crafts-type cyclizations of difluoroalkenes promoted by the α-cation-stabilizing effect of fluorine: an efficient method for synthesizing angular PAHs.

In order to synthesize polycyclic aromatic hydrocarbons with nonlinear arrangements (angular PAHs), acid-promoted domino cyclizations of 1,1-difluoroalk-1-enes and 1,1-difluoroalka-1,3-dienes were studied. 1,1-Difluoroalkenes, each bearing two aryl substituents, were regioselectively protonated with FSO(3)H⋅SbF(5) to generate fluorine-stabilized carbocations, which readily underwent domino Friedel-Crafts-type cyclizations to give carbocycles based on 6/n/m/6 ring systems (n,m=5-7) in good to high yields. Protonation of 1,1-difluoroalka-1,3-dienes took place at their electron-rich methylene (CH(2)) carbon atoms in the presence of milder acids such as camphorsulfonic acid and trifluoromethanesulfonic acid. Domino cyclizations of the resulting fluorine-stabilized allylic carbocations afford carbocycles based on 6/6/6/6 or 6/6/5/6 ring systems in high yields.

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.

[A case of duodenal perforation during mFOLFOX6 treatment for metastatic sigmoid colon cancer].

We present a case of metastatic sigmoid colon cancer causing duodenal perforation during modified FOLFOX6 chemotherapy. The patient was a 68-year-old man who underwent sigmoidectomy for an advanced sigmoid cancer in September 2007. He has been received mFOLFOX6 chemotherapy for multiple liver metastases since January 2009. In March 2010, the patient complained of abdominal pain during the 24th course of chemotherapy, and was admitted to our hospital. On admission, his vital signs were normal, and abdominal findings revealed no peritonitis signs. An abdominal CT scan showed free air and fluid collection on the first day of admission. The patient was diagnosed with gastrointestinal perforation, and underwent emergency operation for abdominal drainage. The leakage of biliary fluids was recognized at the drain to the Winslow postoperatively. It ceased on the 25th admission day, and an upper gastrointestinal examination showed good passage of fluids and no leakage at the duodenum. However, the patient died 36 days after admission from remarkable pleural effusion and respiratory failure.