Difluoromethyl Group Research Articles

Design, Synthesis, and Structure−Activity Relationship, Molecular Modeling, and NMR Studies of a Series of Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors

Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC(50) values. The most potent compounds have IC(50) values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.

Synthesis and Reactions of Trifluorovinylferrocene

AbstractTrifluorovinylferrocene (1) is obtained in high yield by a Stille coupling of iodoferrocene with tributyltrifluorovinylstannane. [2+2] Cycloaddition of 1 yields the cyclobutane derivatives 2a and 2b under mild conditions. At higher temperature a defluoration reaction takes place yielding the cyclobutane derivative 3 under inert conditions whereas in the presence of air and water the cyclobuta‐1,2‐dion derivative 4 is formed presumably by an unusual hydrolysis of an aliphatic difluoromethylene group. Nucleophilic attack of the CF2 group of 1 yields specifically the trans isomer of 1,2‐Diferrocenyl‐1,2‐difluoroethene 5. The crystal and molecular structures of 1, 2a, 2b, 3 and 5 were elucidated by X‐ray diffraction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A New Class of Substrates for Nucleophilic 5‐endo‐trig Cyclization, 2‐Trifluoromethyl‐1‐alkenes: Synthesis of Five‐Membered Hetero‐ and Carbocycles That Bear Fluorinated One‐Carbon Units

Disfavored 5-endo-trig cyclizations were achieved in 2-trifluoromethyl-1-alkenes with a nucleophilic nitrogen, oxygen, sulfur, or carbon atom through 1) intramolecular S(N)2' reaction with loss of a fluoride ion or 2) intramolecular nucleophilic addition to the vinylic group. This reaction manifold provides a versatile method for the synthesis of indolines, indoles, pyrrolidines, tetrahydrofurans, 2,3-dihydrobenzo[b]thiophenes, tetrahydrothiophenes, and cyclopentanes that bear a fluorinated one-carbon unit such as a difluoromethylene, difluoromethyl, or trifluoromethyl group.

ChemInform Abstract: Photochemical Generation of Difluoromethyl Radicals Having Various Functional Groups and Their Highly Regioselective Addition to Olefins and Aromatic Substitution.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of 3,3-Difluoro-2-pyrrolidone Derivatives

Introduction of a difluoromethylene group into organic compounds has been observed to impart them with positive properties, as viewed by a wide range of industries. Here, synthesis of 3,3-difluoro-2-pyrrolidone derivatives (7) was accomplished by the reaction of ethyl 2,2-difluoro-4-iodo-4-(trimethylsilyl) butanolate (4) with primary amines followed by desilylation. The key intermediate (4) was prepared from the addition reaction of trimethylvinylsilane (3) to ethyl difluoroiodoacetate (2) in the presence of Cu(0). Ethyl difluoroiodoacetate (2) was prepared starting from ethyl bromodifluoroacetate (1) via Reformatsky-type reaction.

New preparation of difluoroiodomethylsulfanylbenzenes and their radical addition to unsaturated compounds initiated by sodium dithionite

Difluoroiodomethylsulfanylbenzene ( 3a) and 1-chloro-4-difluoroiodomethylsulfanylbenzene ( 3b) are novel and efficient difluoromethylating reagents via the reaction with unsaturated compounds, such as alkenes, ethynylbenzene, pent-4-en-1-ols, and pent-4-enoic acids initiated by Na 2S 2O 4, to afford the corresponding adducts, tetrahydrofuran derivatives, and γ-butyrolactones containing difluoromethylene group in moderate to good yields.

Sodium Dithionite Initiated Addition of CF2Br2, CF3I and (CF3)2CFI to Allylaromatics. Synthesis and the Reactivity of 4‐Aryl‐1,1‐difluorodienes and 4‐Aryl‐1,1‐bis(trifluoromethyl)dienes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Addition of Difluoromethyl Radicals to Glycals: A New Route to α‐CF2‐D‐Glycosides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Photochemical generation of difluoromethyl radicals having various functional groups and their highly regioselective addition to olefins and aromatic substitution

Difluoromethyl radicals bearing ester, phosphonate, nitrile, cyclic carbonate, and carbamate groups were generated by the photoinitiated S–CF 2 bond cleavage of electrosynthesized α,α-difluorosulfides, and their addition to olefins and aromatic substitution were successfully carried out to provide the regioselective adducts and substitution products in moderate yields. The yields of substitution products increased by the addition of diphenyl diselenide and 2,4,6-trimethylpyridine.

Synthesis and conformational behavior of the difluoromethylene linked C-glycoside analog of β-galactopyranosyl-(1↔1)-α-mannopyranoside

C-Glycosides in which the pseudoglycosidic substituent is a methylene group have been advertised as hydrolytically stable mimetics of their parent O-glycosides. While this substitution assures greater stability, the lower polarity and increased conformational flexibility in the intersaccharide linker brought about by this change may compromise biological mimicry. In this regard, C-glycosides, in which the pseudoanomeric methylene is replaced with a difluoromethylene group, are interesting because the CF2 group is more of an isopolar replacement for oxygen than CH2. In addition, the CF2 residue is expected to instill conformational bias into the intersaccharide torsions. Herein is described the synthesis and conformational behavior of the difluoromethylene linked C-glycoside of β-d-galactopyranosyl-(1↔1)-α-d-mannopyranoside. The synthesis centers on the formation of the galactose residue via an oxocarbenium ion–enol ether cyclization. Conformational analysis, using a combination of molecular mechanics, dynamics, and NMR spectroscopy, suggests that the difluoro-C-glycoside populates the non-exo-Gal/exo-Man conformer to a major extent (ca 50%), with a minor contribution (∼15%) from the exo-Gal/exo-Man conformer that corresponds to the ground sate of the parent O-glycoside.

Addition of Difluoromethyl Radicals to Glycals: A New Route to α-CF2-d-Glycosides

The synthesis of synthetically useful alpha-CF2-glycosides by radical addition of ethyl bromodifluoroacetate onto 2-benzyloxyglycals is described. The methodology provides an access to alpha-O-glycoside mimics and, potentially, to valuable alpha-O-glycoconjugate analogues.

Sodium dithionite initiated addition of CF 2Br 2, CF 3I and (CF 3) 2CFI to allylaromatics : Synthesis and the reactivity of 4-aryl-1,1-difluorodienes and 4-aryl-1,1-bis(trifluoromethyl)dienes

Sodium dithionite initiated addition of CF 2Br 2, CF 3I and (CF 3) 2CFI to the terminal double bond of allylbenzenes and of (CF 3) 2CFI to allylpyridines in a MeCN/H 2O system were investigated. The reactions of CF 2Br 2 with allylbenzenes gave comparable amounts of adducts, 1-(2,4-dibromo-4,4-difluorobutyl)benzenes, debrominated products,1-(4-bromo-4,4-difluorobutyl)benzenes, and dimeric compounds in total yields 40–66%. Treatment of the adducts with DBU resulted in double dehydrohalogenation affording 4-aryl-1,1-difluorobutadienes which undergo Diels–Alder condensation with nitrogen dienophiles to give N-heterocycles with difluoromethylene group in the ring. The reactions of CF 3I and (CF 3) 2CFI with allylbenzenes gave the respective adducts, (4,4,4-trifluoro-2-iodobutyl)benzenes and 1-(4,5,5,5-tetrafluoro-4-(trifluoromethyl)-2-iodopentyl)benzenes as the main products. Dehydrohalogenation of these adducts resulted, respectively, in (4,4,4-trifluoro-but-1-enyl)benzenes and 4-aryl-1,1-bis(trifluoromethyl)butadienes in high yields. (CF 3) 2CFI reacted rapidly with allylpyridines to give mixtures from which, after treatment with DBU, 4-pyridyl-1,1-bis(trifluoromethyl)butadienes were isolated in a ca. 60% yield.

New Electrophilic Difluoromethylating Reagent

A new electrophilic difluoromethylating reagent has been developed. The S-(difluoromethyl)diarylsulfonium tetrafluoroborate has been shown to be effective for the introduction of an electrophilic difluoromethyl group into the following nucleophiles: sulfonic acids, tertiary amines, imidazole derivatives, and phosphines. The reagent failed to transfer the difluoromethyl group to phenols, carbon nucleophiles, and primary and secondary amines.

Palladium‐Catalyzed Cross‐Coupling Reactions in C6 Modifications of Purine Nucleosides

This unit describes the cross-coupling methodology for introduction of diverse C-substituents to position 6 of purine nucleosides. Protected 6-chloropurine nucleosides undergo Pd-catalyzed cross-coupling reactions with trialkylaluminium, alkylzinc halides, aryl(tributyl)stannanes, and arylboronic acids to give the corresponding 6-substituted intermediates, which can be deprotected by treatment with NaOMe. (Acetyloxy)methylzinc iodide is used for introduction of the hydroxymethyl group, which can further be transformed to fluoromethyl and difluoromethyl groups. Most of the title 6-substituted purine ribonucleosides possess cytostatic and/or anti-HCV activity.

Structures and Large NLO Responses of New Electrides: Li-Doped Fluorocarbon Chain

An alkali-metal-doped effect on the nonlinear optical (NLO) property in new electrides is studied. The electrides are formed by doping alkali atom Li into a fluorocarbon chain H-(CF2-CH2)3-H. Six stable structures of the Lin-H-(CF2-CH2)3-H (n = 1, 2) complexes with all real frequencies are obtained at the MP2/6-31+G (d) level. Among these six structures, the largest first static hyperpolarizabilities (beta(0)) are found to be 76,978 au, which is much larger than the beta(0) value of 112 au for H-(CF2-CH2)3-H. Clearly, the Li-atom-doped effect on the first hyperpolarizability is dramatic. Three interesting relationships between the structure and beta(0) value have been observed. (1) For the one-Li-atom-doped systems as well as for the structures with two opposite Li atoms, the shorter the distance between the Li atom and difluoromethyl group, the larger the beta(0) value. (2) The beta(0) values of the two-Li-atom-doped chains are much larger than those of the one-Li-atom-doped systems, except for the case of cis-AB where the Li-Li distance (2.847 Angstrom) is close to the bond length of the Li2 molecule (2.672 Angstrom). (3) For the two-Li-atom-doped chains, the beta(0) value increases as the Li-Li distance increases. These relationships between the structure and beta(0) value may be beneficial to experimentalists for designing electrides with large NLO responses by using the alkali-metal-doped effect.

Introducing difluoromethylene sulfonamide group via nucleophilic addition of difluoromethylene anion with aromatic aldehydes

A new fluorine-containing synthon, R 1COCF 2SO 2R 2 ( 2, R 1, R 2=morpholino, piperidino, etc.), was developed for the introduction of difluoromethylene sulfonamide or difluoromethylene group. Under different conditions, 2 reacted readily with aromatic aldehydes to give the corresponding difluoromethylene-containing alcohols or diols in moderate to good yields in the presence of potassium tert-butoxide. Difluoromethylene sulfonamide group was introduced into organic compounds directly for the first time by this method.

Synthesis of Methylene- and Difluoromethylenephosphonate Analogues of Uridine-4-phosphate and 3-Deazauridine-4-phosphate

Cytidine triphosphate synthetase (CTPS) catalyzes the formation of cytidine triphosphate from glutamine, uridine-5'-triphosphate (UTP), and adenosine-5'-triphosphate. Inhibitors of CTPS are of interest because of their potential as therapeutic agents. One approach to potent enzyme inhibitors is to use analogues of high energy intermediates formed during the reaction. The CTPS reaction proceeds via the high energy intermediate UTP-4-phosphate (UTP-4-P). Four novel analogues of uridine-4-phosphate (U-4-P) and 3-deazauridine-4-phosphate (3-deazaU-4-P) were synthesized in which the labile phosphate ester oxygen was replaced with a methylene and difluoromethylene group. The methylene analogue of U-4-P, compound 1, was prepared by a reaction of the sodium salt of tert-butyl diethylphosphonoacetate with protected, 4-O-activated uridine followed by acetate deprotection and decarboxylation. It was found that this compound undergoes relatively facile dephosphonylation presumably via a metaphosphate intermediate. The difluoromethylene derivative, compound 2, was prepared by electrophilic fluorination of protected 1. This compound was stable and did not undergo dephosphonylation. Synthesis of the methylene analogue of 3-deazaU-4-P, compound 3, was achieved by ribosylation of protected 4-(phosphonomethyl)-2-hydroxypyridine. Electrophilic fluorination was also employed in the preparation of protected 4-(phosphonodifluoromethyl)-2-hydroxypyridine which was used as the key building block in the synthesis of difluoro derivative 4. These compounds represent the first examples of a nucleoside in which the base has been chemically modified with a methylene or difluormethylenephosphonate group.

Divergent Chemical Synthesis of Prolines Bearing Fluorinated One-Carbon Units at the 4-Position via Nucleophilic 5-Endo-Trig Cyclizations

N-[3-(Trifluoromethyl)homoallyl]sulfonamides, prepared via ring opening of (S)-glycidyl ethers or 2-aryloxiranes with 1-(trifluoromethyl)vinyllithium, underwent intramolecular addition or S(N)2'-type reaction in the normally disfavored 5-endo-trig fashion, leading to 2-substituted 4-(trifluoromethyl)- or 4-(difluoromethylene)pyrrolidines. Both alpha- and beta-face-selective hydrogenation of the 4-difluoromethylene group afforded syn- and anti-4-(difluoromethyl)pyrrolidines, respectively. These sequences, followed by the oxidation of a 2-hydroxymethyl or 2-aryl group, successfully provided prolines with a trifluoromethyl, difluoromethylene, or difluoromethyl group at the 4-position, including optically active prolines.

Synthesis, tuberculosis inhibitory activity, and SAR study of N-substituted-phenyl-1,2,3-triazole derivatives

The aim of this work was to describe the synthesis, the in vitro anti- Mycobacterium tuberculosis profile, and the structure–activity relationship (SAR) study of new N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes ( 3a– l). The reactions of aromatic amine hydrochlorides with diazomalonaldehyde ( 1) produced several N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes ( 3a– l) in moderate-to-good yields. In order to investigate the influence of the difluoromethylene group on the anti- Mycobacterium activity of these compounds, fluorination of triazoles with DAST converted the corresponding carbaldehyde compounds into new difluoromethyl derivatives ( 4a– l) in excellent yield. Characterization of all compounds was achieved by spectroscopic means and additional for 1-(4-methylphenyl)-1,2,3-triazole-4-carbaldehyde, 3k by X-ray crystallography. Compounds ( 3a– l) and ( 4a– l) have been screened for the inhibitory activity against Mycobacterium tuberculosis H37Rv strain (ATCC 27294) and all of them were able to inhibit the growth of the bacterium. Interestingly, 3a and 3k exhibited the best inhibition with MIC values of 2.5 μg/mL, similar to pharmaceuticals currently used in the treatment of tuberculosis. Our SAR study indicated the importance of the hydrogen bond acceptor subunit ( 3a– l), the position in the aromatic ring, the planarity of triazole and phenyl rings in these compounds, and a correlation between the uniform HOMO coefficient distribution and the anti-tubercular activity. The significant activity of 3a and 3k pointed them as promising lead molecules for further synthetic and biological exploration.

New Nucleophilic Fluoroalkylation Chemistry

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.