Search

The chemistry of acyclic and heterocyclic perfluoro-N-vinylamines has been investigated extensively for the first time. The reaction of these compounds with electrophiles is equally facile when compared to those with nucleophiles even under very mild conditions. With nitrogen based nucleophiles such as ammonia, methylamine, and 2,2,2-trifluoroethylamine, R f CHFCN and R f CHFCF=NR [R f =CF 2 CF 2 CF 2 CF 2 N or CF 2 CF 2 OCF 2 CF 2 N and R=CH 3 or CH 2 CF 3 ] are obtained, respectively

Cis-2,6-dimethylmorpholine and its derivatives having an ester group were subjected to electrochemical fluorination. The electrochemical fluorination of cis-2,6-dimethylmorpholine afforded only a small quantity of F-(N-fluoro-2,6-dimethyl-morpholine), whereas the N-(methoxycarbonylalkyl)-substituted cis-2,6-dimethyl-morpholines gave the corresponding F-acid fluorides in fair yields. Cis-and trans-isomerization on two methyl substituents of the morpholine ring occurred through electrochemical fluorination of pure cis-2,6-dimethylmorpholine to give a 1:0.25–0.5 mixture of cis- and trans-isomers having a F-2,6-dimethylmorpholino-moiety. The formation of a seven-membered ring expanded product was confirmed as a by-product in the fluorination of methyl cis-2,6-dimethylmorpholino-acetate. Spectroscopic data as well as physical properties of new nitrogen-containing F-carboxylic acids are presented.

Enantiomerically pure α,α-dichloro β-fluoroalkyl γ-p-tolylthio γ-butyrolactones trans-6a–c have been obtained with excellent stereocontrol (> 98:2) and enantiomeric purity (> 98:2) by sulfoxide-directed lactonization (Marino's annu-lation reaction) of β-fluoroalkyl vinyl sulfoxides (R)-(E)-5a–c with dichloroketene. Highly chemoselective dechlorination and desulfurization reactions performed on trans-6c efficiently provided the β-chlorodifluoromethyl γ-butyrolactone (S)-8c, the absolute stereochemistry of which was determined by X-ray diffraction analysis of its γ-p-tolylthio precursor (2R,3S)-7c.

This study present a full account of continuous-flow reaction conditions for biomimetic reductive amination of fluorinated carbonyl compounds to corresponding amines and amino acids of biomedical importance. We demonstrate that simple silica-adsorbed DBU can be used as efficient catalysts for on-column 1,3-proton shift reaction, a key transformation in the biomimetic reductive amination process. This new on-column process features operationally convenient conditions, higher chemical yields, enantioselectivity and purity of the corresponding products as compared with traditional in-flask reactions. Moreover the removal of base-catalyst, the most delicate problem of the in-flask reactions, is not an issue in the on-column process, as the silica-adsorbed DBU or polymer-bound guanidine remains on the column and can be reused. This feature renders the overall process substantially more economical and synthetically efficient, in particular, for large-scale synthesis of the corresponding fluorinated amines and amino acids target.

This paper reviews the synthesis of unnatural chiral β-fluoroalkyl β-amino alcohols, with an emphasis on their biological activity and pharmaceutical applications.

Series of amino alcohols including 2-( N,N -dialkylamino)ethanols, 3-( N,N -dimethylamino)propanol and 4-( N,N -dimethylamino)butanol were subjected to electrochemical fluorination. In the case of 2-( N,N -dialkylamino)ethanols, the F -(2- N,N -dialkylamino)acetyl fluorides were obtained in fair to good yields. Yields of each target compound were strongly dependent on the kind of the dialkylamino group. Cyclic amines having an N -(2-hydroxylethyl) group afforded the corresponding F -[ N -( c -alkylamino)-substituted acetyl fluorides]. Their yields were generally better than those of acyclic analogs. Several 2-( N,N -dialkylamino)ethanols and 3-( N,N -dimethylamino)propanol were converted into the corresponding trimethylsilylethers, aminoalkyl methyl carbonates and bis-aminoalkyl carbonate, respectively, and they were subjected to fluorination for a comparison of the yield with that obtained from that of the parent aminoalcohol.

The reactions of F -(5,6-dihydro-2 H -1,4-oxazine) and F -(3,4-dihydro-2 H -pyrrole) were investigated using two series of reagents: one is the polyfluoroalkylating agent RfOSO 2 CF 3 and the other is the (polyfluoroalkoxy)trimethylsilane RfOSi(CH 3 ) 3 . Systematic study with polyfluoroalkyl groups such as CF 3 CH 2 , C 2 F 5 CH 2 , CHF 2 CH 2 , and (CF 3 ) 2 CH revealed that the regio-chemistry, isomer distribution, product distribution between mono-, di-, and tri-substituted products and even the reaction pathways were subtly changed by the structure of these fluoro substituents as well as by the reagent stoichiometry. A notable substitution effect was found in the reaction of F -(5,6-dihydro-2 H -1,4-oxazine): substitution at the 3-position prevented the N -polyfluoroalkylation by CF 3 CH 2 OSO 2 CF 3 . No particular difference was found between the two different heterocyclic systems in contrast with the reaction of these heterocyclic systems with C 6 F 5 Si(CH 3 ) 3 . The discussion about the reaction mechanisms for both reagents are included.

This study demonstrated that alkylation of chiral glycine Schiff base 3 with chloride 4 can be efficiently conducted in acetonitrile as a solvent using commercial-grade potassium tert -butoxide as a base. High reaction rate (1 h) chemical (>90%) and stereochemical (>95% de) outcomes of the alkylation step render this procedure reliable and operationally convenient for multi-gram synthesis of enantiomerically pure amino acid 1 . Due to the simplicity of experimental procedures and commercial availability all reagents involved, this procedure can be easily reproduced in regular biochemistry laboratories allowing for systematic biological studies and medicinal applications of compound 1 .

This study has demonstrated that conceptually new continuous-flow reaction procedure for biomimetic transamination of perfluoroalkyl-containing ketones is substantially more efficient as compared with conventional in-flask approach, allowing preparation of the target fluorinated amines with generally improved chemical yields and enantioselectivity.

This study presents the first example of continuous-flow reaction conditions for biomimetic reductive amination of fluorinated carbonyl compounds using silica-adsorbed DBU as catalyst for on-column process. This new on-column process features operationally convenient conditions, higher chemical yields and purity of products as compared with traditional in-flask reactions. Furthermore the removal of base-catalyst is not an issue in this process at all, as the catalyst (DBU) remains on the column in the “reaction zone”, the feature which makes the overall process substantially more efficient and inexpensive, in particular, for large-scale synthesis of the target α-perfluoroalkyl amines.

Hybrid compounds R F -X-R H consisting of perfluoro and hydro moieties, R F and R H , which are connected with X functionality, are described. New crystal engineering based on these hybrid compounds is proposed as a rational method for the design of the functional materials. Hexafluoropropene trimers are selected as the fluoro synthons. A systematic investigation on the crystal structures of the hybrid compounds revealed that there are five packing motifs in connection with the topology of the molecules. Topochemical requirements for the solid-state polymerization of diacetylene functionality were satisfied with the precise tuning by tailor-made hybrid synthons. As a result, a black crystalline material with a metallic luster was synthesized. This new fluorine-based crystal engineering will be one of the unique molecular design methods for the material science.

The liquid-phase direct fluorination (LPDF) was overviewed as a tool for the synthesis of perfluoro compounds by focusing on our original LPDF method. The brief history, some general features, scope and limitations, the present and the future were presented.

The enantiopure Davis' N-sulfinylimines were found to be efficient as chiral imine equivalents in the high-temperature Reformatsky-type additions with BrZnCF2COOEt affording an efficient approach to the enantiomerically pure α,α-difluoro-β-amino acids. High chemical and stereochemical yields (drs > 9:1, and as high as 99:1) render this method immediately useful for preparing the target amino acids.

Introduction of a methyl group into hexafluoropropene trimers was achieved by reactions with organometallic carbon nucleophiles. Unusual cyclization and defluorination occurred simultaneously with a formation of methylated polyfluoroolefins: excess methyllithium provided a polyfluorocyclobutene compound, while a polyfluoropentadiene derivative was formed by use of excess methyllithium.

The synthesis of enantiomerically and diastereomerically pure (−)-(1R,2R,5R)- and (−)-(1R,2S,5R)-2-fluoro frontalin (7) starting from (+)-(1S)-menthyl-(R)-toluene-4-sulfinate, methylmagnesium bromide, methyl fluoroacetate, 4-pentenyl bromide and diazomethane is described. The absolute stereochemistry was unambiguously determined by X-ray analysis of (+)-(1S,2R,5S,RS)-5, an intermediate in the synthesis of the enantiomeric (+)-(1S,2R,5S)-2-fluoro frontalin (7).