S. Hamman

Acide fluoro-2 phenyl-2 acetique: Synthesis, configuration absolute et emploi comme agent chiral de derivation

Abstract 2-Fluoro-2-phenyl acetic acid was synthetized from phenylglycine through a fluorodeamination reaction in a HF : pyridine mixture or from ethylmandelate through fluorodehydroxylation using the reagent fluoroamine (FAR). The specific rotation of S-2-fluoro-2-phenyl acetic acid is [α] 20D = + 153° in chloroform at concentration c = 1,25 g/100 ml. This acid can be used as a derivatizing chiral agent : the enantiomers can be distinguished and the enantiomeric excess of secondary alcohols can be determined by 19F NMR spectra of the corresponding esters.

Fluoro-2 phényl-2 amino-1 éthane: obtention des énantiomères, configuration absolue et emploi comme agent chiral de dérivation

Abstract 2-Fluoro-2-phenyl-1-aminoethane was synthesized from styrene. The enantiomers were separated and their absolute configurations were determined: the specific rotation of the amine with an R configuration is [α] D 20 =37.7° in methanol. This amine can be used as a chiral derivatizing agent: amides prepared with different chiral acids are distinguished by fluorine NMR.

Synthesis of β-fluoroazides: a route to primary β-fluoro amines

Abstract Two ways for the synthesis of β-fluoroazides are presented. The first one uses 1,2,2-trifluoro-2-chloro triethylamine (FAR) as a fluorinating reagent on the corresponding azidoalcohols. It is a smooth reaction at room temperature, but is not stereospecific; it works well for phenyl substituted or primary α-carbon β-fluoroazides. The second route is the substitution of the azide group for bromine on an appropriate fluorobromide in phase transfer conditions. It is stereospecific (except for one case). It works well to give pure diastereoisomers of β-fluoroazides with pseudo primary (with deuterium) or secondary α-carbon atoms.

Synthese et stereochimie de formation d'amines tertiaires β-fluorees par fluoration d'aminoalcools avec la trifluro-1,1,2 chloro-2 N,N-diethyl ethylamine (FAR) et le melange HF - pyridine.

Abstract The fluorination of amino-alcohols giving tertiary β-fluoroamines was studied synthetically and stereochemically. Configuration of initial and final products were assigned using 1H and 19F NMR. The fluorination of amino-alcohols with FAR is a stereospecific reaction with retention of configuration. Isomerically or optically pure compounds can be obtained. The fluorination with HF - pyridine mixture gives preferentially threo fluoroamines.

Selective reduction of β-fluoroazides to β-fluoroamines

Abstract Three methods were tested to reduce chemoselectively β-fluoroazides into β-fluoroamines : catalytic hydrogenation, catalytic transfer hydrogenation, and reduction with triphenyl phosphine. The last was the best.

Fluoroimines from the reaction of fluoroamino acids or fluoroketo acids with the aldehyde or amine form of vitamin B6: Part III. Influence of fluorine on the formation and the reactivity of fluoroimines derived from β-fluoroaspartates or β-fluorooxaloacetate

Abstract The introduction of fluorine at the β-position in aspartate and in oxaloacetate, the typical amino acid-keto acid couple in transamination, induces large effects in their reaction with respectively pyridoxal 5′-phosphate (PLP) ( 1 ) and pyridoxamine 5′-phosphate (PMP) ( 4 ). The formation of imine intermediates through reaction of 1 with erythro or threo -β-fluoroaspartate ( 2e and 2t ) and through reaction of 4 with β-fluorooxaloacetate 5 is highly favored in comparison with that of non-fluoro compounds. The stereoisomers of the imines are unambiguously determined using a reduction reaction. The evolution of these intermediates shows that no transaminatlon is observed and that a dehydrofluorination occurs suggesting that the β-fluoro moiety in the intermediate turns into a good leaving group, changing the model reaction of transamination on α carbon through the aldimine-ketimine tautomerization to an elimination on β carbon.

Hydrofluorination and bromofluorination of halogeno-substituted ethyl cinnamates and related compounds

Abstract We have effected bromofluorination of six olefins (unsubstituted and α or β halogeno-substituted ethyl cinnamates) and ethyl propiolate with N-bromosuccinimide: hydrofluoric acid: pyridine and the hydrofluorination of two β halogeno-ethyl cinnamates and ethyl propiolate with hydrofluoric acid: pyridine. The bromofluorination proceeds with Markovnikov-type and α-halogeno-substituted ethyl cinnamates but faster and not stereospecific for the β-substituted ones and ethyl propiolate. This difference is interpreted for cinnamates as a change in transition state from a bridged bromonium ion to an open-chain ion.

Use of 19F NMR spectroscopy for study of the different steps of transamination model reactions

Abstract The reaction products of pyridoxal-5′-phosphate (PLP) and p-fluorophenyl alanine were observed versus time using 1H noise decoupled 19F NMR signal in the 4–8 pD range, in D2O at room temperature. Several signals were observed whose chemical shifts are pH dependant. Two of them are seen at early times and regularly decreased, then an other signal appears, goes through a maximum and then disappears in the same time that two (one of them being splitted in two for a small pH range) increases and are finally the only signals for long reaction times. This behaviour can be interpreted with the following equations: and where the underlined symbols contains aromatic fluorine. In the cited conditions Ket bas too low a concentration to be observed (it was nevertheless identified from KA and PMP). Equilibrium 1 and 3 are fast at the NMR time scale. From measurements of interesting of signals k2(k - 2 being neglected) and k4 can be measured versus pH. Comparison of k2 values with those obtained from ordinary UV measurements are made. Some more applications of these 19F NMR measurements which are actually in progress will be presented.

Stereochemistry of flourination of alpha-substituted benzylic alcohols using several flourination reagents

Abstract Fluorinations of several benzylic alcohols PhCH(OH) CH(R)X, where C β is a secondary or a tertiary carbon (R = 2 H, Me) and X = −N , NHCH 3 , N 3 , Et, Br and CO 2 Et in HF:pyridine or using FAR, were studied. The structures and the stereochemistry of the fluorocompounds obtained were unambigously determined through 1 H, 19 F and 13 C NMR spectroscopy taking advantage of the chirality of the Cβ carbon. Substitution, transposition, inversion or retention of configuration (on the deuterated compounds for secondary Cβ) were observed. A discussion on the regio and stereoselectivity of these reactions with literature data also will be presented taking into account medium effects (non-ionizing power in the FAR reaction, and the variable acidity and ionizing power of HF:pyridine according the HF:pyridine molar ratio) or structural effects (evolution of the incipient carbenium ion, transposition of the positive charge, occurrence of a bridged structure…).

Influence of the hydrogen fluoride-pyridine molar ratio on the regio- and stereo-selectivity in several fluorination reactions

Abstract We used the hydrogen fluoride-pyridine mixture of different molar ratio as a solvent for different fluorination reactions: 1. (i) bromofluorination of unsubstituted and substituted ethyl cinnamates ZC6H4C(2)XC(1)HCO2Et with N-bromosuccinimide; 2. (ii) fluorodeamination of α-amino-esters RR′C(2)HC(1)H(NH2)CO2Et with sodium nitrite; 3. (iii) fluorodehydroxylation of alkyl-phenyl carbinols Ph C(2)H(OH)C(1)HRR′. The regiochemistry and the stereochemistry of the reaction products were unambiguously established by 13C and 19F NMR spectroscopy. The influence of the HF:pyridine molar ratio on the regio- and stereo-selectivity can be described as the influence of solvation by the solvent mixture of the cationic intermediates in the reactions (bridged or open-chain carbenium ions): hindrance to free rotation of the C(1)C(2) bond in the carbenium ion, mono or bifacial attack of this ion or rearrangement of the carbenium ion (positive charge on carbon C(1) or C(2). The importance of this solvation is depending on the HF:pyridine molar ratio and on the nature of the substituents (Z, X, R or R′).