Gerd-Volker Röschenthaler

Recent advances in the synthesis of fluorinated aminophosphonates and aminophosphonic acids

This review article surveys recent achievements in the preparation and biological properties evaluation of fluorinated aminophosphonates and aminophosphonic acids. Recently, in view of various important biological applications of the fluorinated aminophosphonic acid derivatives, the development of suitable synthetic methodologies for their preparation in racemic and in optically pure form has been a topic of great interest. Considerable progress has been made in asymmetric synthesis of fluorinated acyclic aminophosphonates and aminophosphonic acids using catalytic enantioselective reduction of fluorinated α-iminophosphonates, catalytic enantioselective addition of alkyl phosphites to fluorinated imines, and diastereoselective addition of alkyl phosphites to chiral fluorinated imines. A new efficient access to CF3-substituted cyclic α-aminophosphonates has been developed based on metal-catalyzed carbene transfer reactions with diethyl 1-diazo-2,2,2-trifluoroethylphosphonate. New processes, e.g. enantioselective alkynylation and nucleophilic aromatic substitution involving fluorinated substrates are also considered.

Pentakis(trifluoromethyl)phenyl, a sterically crowded and electron-withdrawing group: synthesis and acidity of pentakis(trifluoromethyl)benzene, -toluene, -phenol, and -aniline.

A general route to functionalized pentakis(trifluoromethyl)phenyl (C6(CF3)5) derivatives, promising building blocks for designing novel stable carbenes, radical species, superacids, weakly coordinating anions and other practically and theoretically useful species, is presented. This pertrifluoromethylation route proceeds via conveniently pregenerated (trifluoromethyl)copper (CF3Cu) species in DMF, stabilized by addition of 1,3-dimethyl-2-imidazolidinone (DMI). These species react with hexaiodobenzene at ambient temperature to give the potassium pentakis(trifluoromethyl)phenoxide along with hexakis(trifluoromethyl)benzene and pentakis(trifluoromethyl)benzene in a combined yield of 80%. A possible reaction pathway explaining the formation of pentakis(trifluoromethyl)phenoxide is proposed. Pentakis(trifluoromethyl)phenol gives rise to easily functionalized pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)aniline. Pertrifluoromethylation of pentaiodochlorobenzene and pentaiodotoluene allows straightforward access to pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)toluene, respectively. XRD structures of several C6(CF3)5 derivatives were determined and compared with the calculated structures. Due to the steric crowding the aromatic rings in all C6(CF3)5 derivatives are significantly distorted. The gas-phase acidities (Delta Gacid) and pKa values in different solvents (acetonitrile (AN), DMSO, water) for the title compounds and a number of related compounds have been measured. The origin of the acidifying effect of the C6(CF3)5 group has been explored using the isodesmic reactions approach.

Design, cytotoxic and fluorescent properties of novel N-phosphorylalkyl substituted E,E-3,5-bis(arylidene)piperid-4-ones

A series of E,E-N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones 7a-k was prepared via the condensation of aromatic aldehydes with omega-aminophosphonates 5a-c and 6a,b bearing piperidone or a protected piperidone moiety, respectively. The synthetic routes to the starting aminophosphonates 5a-c and 6a,b varied depending on the number of methylene groups in the alkylene chain and comprised the Kabachnik-Fields reaction (n=1), the aza-Michael reaction (n=2) or alkylation of 4-piperidone hydrochloride with diethyl omega-bromoalkylphosphonates under phase transfer catalysis conditions (n=3,4). Phosphoryl substituted 3,5-bis(arylidene)piperid-4-ones 7b,c,e,f,h,i,k bearing both nitro groups and fluorine atoms in the para-position of the arene rings possess cytotoxicity toward human carcinoma cell lines CaOv3, Scov3, PC3 and A549 in the low micromolar range while their analogues having para-dimethylamino groups had IC(50) values greater than 50 microM. In contrast, only Me(2)N-substituted phosphonates 7g,j (n=3 and 4) and the salts of Me(2)N-substituted phosphonic acids 10c,f (n=2 and 3) display fluorescence.

(NHCMe)SiCl4: a versatile carbene transfer reagent – synthesis from silicochloroform

A new synthetic pathway for the N-heterocyclic carbene adduct (NHCMe)SiCl4 (2) (NHCMe = 1,3-dimethylimidazolidin-2-ylidene) using silicochloroform is presented. Supported by DFT calculations, the energy for dissociation of 2 into the carbene and the SiCl4 fragment was found to be comparable to carbene transfer reagents based on silver(I) chloride. Compound 2 was used to transfer the NHC ligand to three different phosphorus(III) chloro compounds, resulting in the neutral complexes (NHCMe)PCl3 (3a), (NHCMe)PCl2Ph (3b) and (NHCMe)PCl2Me (3c). The sterically non-demanding NHC ligand allowed the phosphorus(III) in complex 3a to be oxidized to phosphorus(V) without loss of the NHC ligand, and afford (NHCMe)PF4H (4). Furthermore, bis-carbene complexes of Ni(II) (5) and Pd(II) (6) were obtained by reacting 2 with the respective metal chlorides.

Simple preparation of difluorophosphoranes using anhydrous zinc and tetramethylammonium fluorides

Abstract Bromophosphonium bromides, R 3 PBr + Br − (R= n Bu, NMe 2 , NEt 2 ) are easily fluorinated using zinc difluoride in pyridine or tetramethylammonium fluoride in methylene chloride to give the corresponding difluorophosphoranes R 3 PF 2 in high yield. A simple procedure for preparing pure tetramethylammonium fluoride is described.

New asymmetric approach to β-trifluoromethyl isoserines

Enantiomerically pure N,O-protected β-trifluoromethyl isoserine derivatives of (2S,3S)- and (2R,3S)-absolute configurations have been easily prepared by diastereoselective addition of the enolates, derived from O-protected α-hydroxyacetates, to (S)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine with high combined yield and good syn/anti stereoselectivity. To explain the unusual stereochemical outcome in these reactions a mechanistic rationale involving the addition of Z-enolates to (S)-imines via open transition states was proposed on the basis of the experimental data. Elaboration of these products via chemoselective manipulation of the protecting groups has been demonstrated.

Synthesis of 2-(trifluoromethyl)-1,2-dihydro-4H-thieno[2,3-c]chromen-4-ones and 2-(trifluoromethyl)-4H-thieno[2,3-c]chromen-4-ones from 2-trifluoromethylchromones and ethyl mercaptoacetate

The redox reaction of 2-trifluoromethylchromones with ethyl mercaptoacetate in the presence of triethylamine results in the formation of 1,2-dihydrothieno[2,3-c]chromen-4-ones and diethyl 3,4-dithiadipate in high yields. Oxidation of the first compounds with nitrogen dioxide gave 1,2-dihydrothieno[2,3-c]chromen-3,4-diones which were converted into thieno[2,3-c]chromen-4-ones.

Complexes of Ge(IV)- and Sn(IV)-fluorides with cyclic and acyclic carbenes: bis(dialkylamino)-difluoromethylenes as carbene sources.

Carbene complexes of Ge(IV)- and Sn(IV)-fluorides have been synthesized by oxidative addition of 2,2-difluoro-1,3-dimethylimidazolidine and bis(dimethylamino)difluoromethane to GeCl(2)•dioxane and SnF(2). Chloride analogs of the Ge(IV) complexes were also isolated. All compounds were characterized in the solid state by single-crystal X-ray diffraction.

Generation of heteroarylium-N-difluoromethylides and heteroaryl-N-difluoromethyl anions and their reactions with electrophiles: heteroaryl- and heteroarylium-N-difluoromethyl trimethylsilanes and a new heteroaryl-N-trifluoromethane

Abstract Reductive debromination of N -bromodifluoromethyl-4-dimethylaminopyridinium bromide, 1-bromodifluoromethyl-imidazole, 1-methyl-3-bromodifluoromethyl-imidazolium bromide and 1-bromodifluoromethyl-2-methyl-benzimidazole using tetrakis(dimethylamino)ethylene (TDAE) or tris(diethylamido)phosphite leads to new fluorinated carbanionic species, namely heteroarylium- N -difluoromethylides and heteroaryl- N -difluoromethyl anions. In the presence of electrophiles such as benzaldehyde, chlorodiphenylphosphine and chlorotrimethylsilane, the corresponding heteroarylium- and heteroaryl- N -difluoromethylated derivatives, imidazole- N -difluoromethyl-phosphines and -silanes, 2-methyl-benzimidazole- N -difluoromethyltrimethyl-carbinols-phosphines and -silanes were obtained. Similar 4-dimethylaminopyridinium derivatives were synthesized.

Facile syntheses of tris(trifluoromethyl)phosphine and difluorotris (trifluoromethyl) phosphorane

Abstract Tris(trifluoromethyl) phosphine is easily available in high yield using the three component system D(NAt)2)3/NF3Ar/(DhI)3D in IIDA. Addition of chlorine and fluorination with zinc difluoride yield difluorotris (trifluoromethyl) phosphorane.