Fluorine-containing Building Blocks Research Articles

Concise synthesis of ω-fluoroalkylated ketoesters. A building block for the synthesis of six-, seven-, and eight-membered fluoroalkyl substituted 1,2-diaza-3-one heterocycles

A concise and general synthetic route toward the small and medium-sized fluoroalkyl substituted 1,2-diaza-3-one heterocyclic ring skeletons via a sequential reaction of condensation and ring-closure reaction of ω-fluoroalkylated ketoesters 4 with hydrazines 5 catalyzed by 10–20 mol % TsOH has been developed. A practical preparation of biologically interested ω-fluoroalkylated ketoesters 4, which were subsequently subjected as a fluorine-containing building block to the synthesis of 1,2-diaza-3-one heterocycles has been optimized. Trifluoromethyl substituted seven- and eight-membered 1,2-diazapinone 8, 1,2-diazocinone 10 were also obtained via this sequential reaction of δ- (or ɛ-) trifluoromethyl ketoesters with hydrazine hydrates in acidic condition. In contrast, the sequential reaction of ω-fluoroalkylated δ- or ɛ-ketoesters with aryl hydrazines under the same conditions did not result in the formation of diazepinones and diazocinones, and instead, the reaction provided a direct access to the biologically important 2-fluoroalkyl-indole-3-carboxylate derivatives via a Fisher indole synthesis.

Regioselective Electrochemical Monofluorination of α-Sulfonyl Sulfides

Highly regioselective monofluorination of α-sulfonyl sulfides was successfully carried out using anodic oxidation to provide the corresponding α-fluorinated products in moderate yields. The fluorinated products would be versatile fluorine-containing building blocks.

Fluoroalkyl substituted ( Z)-dehydro α-amino ester as a building block for the fluorine-containing cyclopropyl α-amino esters and dihydrooxazole

Multi-functionalized β-trifluoromethyl and β-difluoromethyl substituted ( Z)-α,β-dehydro α-amino esters have been successfully prepared from N-protected fluorinated threonine ester. Applications of this new fluorine-containing building block to the synthesis of biologically important fluorinated cylcopropyl α-amino esters and dihydrooxazole ester have also been reported.

Novel Synthetic Methods for the Preparation of Optically Active Fluorine-Containing Building Blocks on the Basis of Sigmatropic Rearrangements

Optically active γ-fluoroalkylated allylic alcohols were prepared via various synthetic protocols such as enzymatic resolution of the racemate, difluorocarbene-mediated reaction, and a novel 1, 3-allylic rearrangement of α-fluoroalkylcarbinols. Thus-obtained allylic alcohols could participate nicely in various sigmatropic rearrangements such as Johnson-, Eshenmoser-, Ireland-Claisen, and [2, 3] -Wittig shifts, to give the corresponding rearranged products with excellent stereoselectivity in good to high yields. The sequential operation of 1, 3-allylic shift and the following Ireland-Claisen rearrangement realized the one-pot synthesis of the multifunctionalized building blocks in high yields from easily accessible α-fluoroalkylated carbinols. The Ireland-Claisen products underwent iodolactonization and osmylation, γ-lactones with four successive chiral centers being afforded in a highly stereoselective manner.

3‐Trifluoromethyl‐ and 3‐Difluoromethyl‐thalidomides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chemo-Enzymatic Synthesis of Chiral Fluorine-Containing Building Blocks

Two complementary strategies for the synthesis of optically active fluorine-containing building blocks have been probed. The first strategy involves either the enzymatic resolution of fluorinated ?,?-disubstituted-?-amino acid amides, or the asymmetric hydrogenation of fluorinated dehydroamino acids. The second strategy involves the transition metal-catalyzed introduction of fluorine-containing substituents onto olefin- or acetylene-containing ?-H-?-amino acids. These amino acids in turn are made optically active by enzymatic resolution of the corresponding amides.

3-Trifluoromethyl- and 3-difluoromethyl-thalidomides

Syntheses of racemic 3-trifluoromethyl- and 3-difluoromethyl-thalidomide starting from 2-( tert-butyloxycarbonylimino)-3,3,3-trifluoropropionate or -3,3-difluoropropionate as fluorine-containing building blocks are described.

Synthesis of Fluoroalkyl Substituted Heterocycles Using Fluorinecontaining Building Blocks

This review deals with recent progress in the synthesis of fluorine-containing heterocyclic compounds using the fluorinated building block method. Several fundamental fluorinated building blocks such as fluorinecontaining multiple bond compounds, fluoroalkyl substituted carbonyl compounds are described in detail, they are readily prepared and easy to scale up from the commercial available starting materials such as RfX, RfCXYZ (X, Y, Z: halogen), (CF3CO)2O etc. Under mild reaction condition, they react with various organic reagents to give a variety fluoroalkyl substituted N, S, O-heterocycles.

Why fluorine has fascinated me for 30 years

The new notion, background, and the first synthesis of the chiral multifunctional carbon compound are described. Fluorine-containing multifunctional carbon compounds have been applied to the development of versatile fluorine-containing building blocks, the new chiral derivatizing agents, CFPA and CFTA, and the novel electrophilic asymmetric fluorinating agent, CMIT-F.

The first alpha-fluoroallenylphosphonate, the synthesis of conjugated fluoroenynes, and the stereoselective synthesis of vinylfluorophosphonates using a new multifunctional fluorine-containing building block

Limitations on current methodologies for the introduction of CF(2) and CFH in complex alpha-fluorophosphonates led to the synthesis of a fluorine-containing building block TIPS-C&tbd1;CCFXP(O)(OEt)(2), where X = H or F. This multifunctional fluorine synthon reacts with carbonyl compounds under WHE conditions to give high yields of fluorinated conjugated enynes and enediyne. When X = F, trapping of the desilylated anion with an electrophile after TIPS removal provided exclusive access to gamma-substituted derivatives of alpha-fluorophosphonates. When X = H, TBAF deprotection of the silyl group yields H(2)C=C=CFP(O)(OEt)(2) through an allenyl-propargyl resonance stabilized anion. The allene moiety has been used as template in the stereoselective synthesis of alpha-fluoro-beta, gamma-diiodopropenyl phosphonate, via electrophilic iodination, and alpha-fluoro-gamma-amino-alpha,beta-unsaturated phosphonates, including unsaturated phosphononucleosides, by nucleophilic displacement of an allylic iodide. Hydroamination of H(2)C=C=CFP(O)(OEt)(2) using secondary amines produced (Z)-alpha-fluoroenaminophosphonates, whereas Diels-Alder cycloaddition with cyclopentadiene provides the corresponding exocyclic vinylfluorophosphonate.

Study of the nucleophilic reaction of 2-mercaptoethanol with 1-fluoroalkyl-2-iodo-alkenes

The stepwise nucleophilic addition of 2-mercaptoethanol ( 2) to 1-fluoroalkyl-2-iodo-alkenes ( 1) was studied. Fluorine-containing building blocks of a new type ( 4) containing a fluorine atom, a fluoroalkyl-substituted double bond and a latent carbonyl group were synthesized in good yield via the intermediate thioethers 3. A reasonable pathway is suggested.

1,1-Difluoro-2-triphenylsiloxybuta-1,3-diene as a potentially useful fluorine-containing building block: preparation and [4 + 2] and [2 + 2] cycloadditions

1,1-Difluoro-2-triphenylsiloxybuta-1,3-diene has been conveniently prepared and undergoes [4 + 2] or [2 + 2] cycloadditions with various olefins.

Trifluoroacetyltriphenylsilane as a potentially useful fluorine-containing building block. Preparation and its transformation into 2,2-difluoro enol silyl ethers

The first example of perfluoroacylsilanes—trifluoroacetyltriphenylsilane was prepared in good yield and it has been converted into a series of 2,2-difluoro enol silyl ethers in almost quantitative yields by treatment with various organolithiums.

Generation and trapping of a stabilised difluorovinyl anion

The generation of the anion is described; this species reacts with a range of electrophiles in good yield, according to the Scheme. ▪ The adducts display synthetic utility; the adduct with chlorodimethylphenylsilane allows stereocontrolled replacement of the fluorine anti-to the silicon with an alkyl group. The adduct with tributyltin chloride serves as a convenient source for the anion under amine-free conditions while the aldehyde adducts, after suitable derivatisation undergo a range of sigmatropic rearrangements leading to interesting difluoromethylene-containing compounds. The anion represents a significant addition to the pool of fluorine-containing building blocks and approaches to fluorine-containing natural product analogues using this chemistry will be described.

Fluorine-containing organozinc reagents - VI. The preparation of α-Trifluoromethyl-α,β-unsaturated carboxylic acid esters

The Reformatzky reaction of the readily available methyl 2,2-dichloro-3,3,3-trifluoropropionate with aldehydes followed by acylation and reductive elimination in situ constitutes a general synthetic scheme for the preparation of methyl α-trifluoromethyl-α,β-unsaturated carboxylates, useful as fluorine-containing building blocks.

Studies on organic fluorine compounds. LIV. Synthesis of 2,2-difluoroarachidonic acid.

2, 2-Difluoroarachidonic acid, characterized by the inductively enhanced acidity of the carboxyl group and its biological stability to β-oxidation, was synthesized using a fluorine-containing building block derived from ethyl bromodifluoroacetate and a carbon-chain extension reaction.