New Synthetic Routes to 2‐Fluoro‐2‐phenylalkanoic Acids

Abstract

Triethylamine tris(hydroflu0ride)2-Fluoro-2-phenylalkanoic acids 2 are obtained by oxidation of the corresponding P-fluoro-p-phenyl alcohols 6. These compounds are shown to be accessible by two alternative pathways, either by bromo fluorination of a-alkyl styrenes 3, subsequent bromine-by-acetate replacement in the bromo fluorides 4 and hydrolysis of the acetates 5 or by a BF3 . OEt2 catalyzed ring opening of corresponding styrene oxides 8 with triethylamine tris(hydrof1uoride).Fluorine-containing compounds are widely used in scientific research and industry. Among the carbonyl compounds fluorinated carboxylic acids are used as substrates for biochemical studies and as building blocks for the synthesis of large, selectively fluorinated molecules ['].Utilization of fluorinated acids for analytical purposes became particularly common[2] since Mosher et aI.L3] described the efficiency of 2-methoxy-2-phenyl-2-(trifluoromethy1)acetic acid (MTPA) (1) as a chiral dcrivatizing agent to determine the enantiomeric excess of optically active alcohols and amines by 19F-NMR spectroscopy after esterification or amidation, respectively.However, the applicability of compound 1 is sometimes limited. Shift differences in I9F-NMR spectra in some cases are very due to the distance of the fluorine atoms to the stereogenic centers originating from the alcohol or amine part of the formed esters or amides, respectively. In these cases optically pure carboxylic acids like perfluoro-2-propoxypropionic acidL4] or compounds of general structure 2 bearing the fluorine atom at the stereogenic center in aposition to the carboxylic function were shown to be a significant impro~ement [~-~].The use of 2-fluoro-2-phenylacetic acid (2e) as the simplest representative of this class of compounds increases the shift differences of the diastereomeric esters in 19F-NMR spectra up to ten times in comparison with MTPA l[3b].[*I Present address: Department of Chemistry, State University of New York at Albany, Albany, New York 12222, USA.Replacement of the a-hydrogen in 2e by a methyl group often causes a further enhancement of the shift differences and also prevents the possibility of racemization. Best results with respect to large shift differences were obtained in the case of diastereomeric esters of a-cyano-a-fluorophenylacetic acid (2f) [7]. In spite of these interesting results only two methods for the synthesis of the optically active compound 2a are known. In both cases fluorine is introduced into methyl 2-phenylpropionates either by use of N-fluorocamphorsultame after metalation[*] giving a low enantiomeric excess of the product or by replacement of the amino group in racemic 2-amino-2-phenyl-propionate by fluoride[@. The separation into the enantiomerically pure compounds was accomplished by classical fractional crystallization of phenylethylamino salts. Higher yields (65 or 83%, respectively) of racemic methyl 2-fluoro-2-phenylpropionate were obtained by fluorination of the parent ester using Nfluoro-bissulfonyl imide~ [~]. Results and Discussio...

Beyond the Balz–Schiemann Reaction: The Utility of Tetrafluoroborates and Boron Trifluoride as Nucleophilic Fluoride Sources

“…Within these major categories, examples are organized in a manner that best facilitates ease of discussion, whether that be by substrate or product class, reagent employed, or reaction subtype. Crucially, C–F bond formations featuring BF 3 ·OEt 2 in a catalytic role and not as the stoichiometric source of nucleophilic fluoride are beyond the scope of this Review, even though such reactions may (at least in some cases) involve fluoride transfer from in situ formed BF 4 – ions . Second, reactions involving fluoride transfer to elements other than carbon are not discussed [e.g., the excision of silicon-based protecting groups with BF 3 ·OEt 2 or BF 4 – sources, and the formation of B–F, Si–F, P–F, or M–F bonds (M = metal) by fluoride transfer from BF 3 ·OEt 2 or the BF 4 – ion].…”

Selective Synthesis of Monofluorinated Compounds Applying Amine/HF Reagents

“…When 1‐alkyl‐1‐phenyl oxiranes were reacted with this modified reagent at room temperature for 7 h, moderate yields of the corresponding 2‐fluoro‐2‐phenylalkan‐1‐ols were isolated (Scheme 19). [48] Similarly, an achiral rhodium catalyst was used for regioselective opening of vinyl epoxides with Et 3 N ⋅ 3HF [49] …”

“…When 1-alkyl-1-phenyl oxiranes were reacted with this modified reagent at room temperature for 7 h, moderate yields of the corresponding 2-fluoro-2phenylalkan-1-ols were isolated (Scheme 19). [48] Similarly, an achiral rhodium catalyst was used for regioselective opening of vinyl epoxides with Et 3 N • 3HF. [49] Under the above-mentioned conditions, also p-substituted 2-arylpropene oxides were transformed to the corresponding fluorohydrins, which were oxidized to the 2-fluoro analogues of the "profen" family of nonsteroidal anti-inflammatory agents Ibuprofen and Naproxen (Scheme 20).…”

Regio- and stereoselective synthesis of vicinal fluorohydrins

“…First enantiopure amine-HF-reagents, such as (S)-N,N-dimethyl-phenylethylamineÁ3HF have been applied, but the ee never exceeded 2% [146]. Almost 10 years ago we realized that epoxide ring opening with neat Et 3 NÁ3HF, which needs elevated temperature, can be catalyzed with BF 3 ÁOEt 2 without loss of regio-and diastereoselectivity and then occurred at room temperature [147,148]. Thus, it was obvious to apply chiral Lewis acids in combination with hydrofluorinating reagents for asymmetric ring opening of meso-and racemic epoxides.…”