Simple procedure for preparation of α-fluoro esters by fluorination of ester enol silyl ethers with perchloryl fluoride

Fujisawa, Hidehito; Takéuchi, Yoshio

doi:10.1016/s0022-1139(02)00185-9

Cited by 15 publications

(15 citation statements)

References 17 publications

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“…α-Fluorine is used to modify the biological activity [1][2][3][4] in the complex drug molecules. To synthesize these α-fluoro carbonyl derivatives, multistep chemical methods are available.…”

Section: Introductionmentioning

confidence: 99%

Electrochemical fluorination of dimethyl glutarate and its characterization

Ilayaraja

Radhakrishnan

Renganathan

2009

Ionics

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Monofluoro dimethyl glutarate has been successfully synthesized for the first time by electrochemical fluorination. It is done in an undivided polypropylene cell with platinum electrodes. Initially at three different current densities, dimethyl glutarate is subjected to electrofluorination. Maximum yield of monofluoro product is obtained at 15 mA cm −2 . Selecting this current density, electrosynthesis is done at three different charges. Maximum yield of 71.5% of the monofluoro product is obtained with a conversion efficiency of 95.2% when the charge of 6 F/mol is passed. The synthesized product is characterized using Fourier transform infrared (FTIR), gas chromatography/mass spectrometry (GC/MS), and nuclear magnetic resonance (NMR). The product purity and composition are ascertained using GC/MS. The attachment of fluorine to methylene group is indicated using FTIR data. From NMR studies, the environment of fluorine in the neighborhood of carbon and hydrogen has been established. Results are discussed in the paper.

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Section: Introductionmentioning

confidence: 99%

Electrochemical fluorination of dimethyl glutarate and its characterization

Ilayaraja

Radhakrishnan

Renganathan

2009

Ionics

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“…13) However, the yields seemed sensitive to the amount and kind of bases employed for the reaction and the results were found not to be reproducible. We then focused on fluorination using diluted FClO 3 , [9][10][11] considering the successful results obtained in the preparation of the structurally similar 2-cyano-2-fluoro-p-tolylacetic acid ethyl ester. 14,15) We first examined bases and temperatures for the fluorination of ibuprofen methyl ester 3a with FClO 3 in order to optimize reaction conditions ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…[9][10][11] A simple and general procedure for optical resolution of the 2-fluoro acids 2 is also described.…”

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confidence: 99%

“…6 A solution of methyl esters 3 or 5 (4.0 mmol) in dry THF (5 ml) was added to a stirred solution of lithium diisopropylamide [1.5 eq, prepared at 0°C from diisopropylamine and butyllithium (1.5 M in hexane) in dry THF (15 ml)] cooled at Ϫ40°C. The stirred solution was maintained at Ϫ40°C for 10 min and diluted FClO 3 gas in nitrogen [9][10][11] was introduced for 1 h. Hexane (10 ml) was added and the resulting mixture was filtered through a short column chromatography on silica gel to remove polar substances. After the solvent was evaporated, the residual oil was purified by column chromatography on silica gel (hexane/AcOEtϭ4/1) or by recrystallization from hexane/AcOEt to give 2-fluorinated esters 4 or 6 in 79-97% yields.…”

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confidence: 99%

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Synthesis and Optical Resolution of 2-Aryl-2-fluoropropionic Acids, Fluorinated Analogues of Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Fujisawa

Fujiwara

Takéuchi

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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2-Arylpropionic acids 1 are used clinically as nonsteroidal anti-inflammatory drugs (NSAIDs) (Fig. 1). The (S)-enantiomers have been considered to be pharmacologically more active than the (R)-enantiomers of these acids. 1)Nonetheless, these agents are normally marketed as racemates. This is possible because it has been shown [1][2][3][4] that an in vivo inversion at the stereogenic center converts the pharmacologically less active (R)-enantiomers into the more active (S )-enantiomers, thereby obviating a prior separation of enantiomers.Owing to this in vivo epimerization, it is difficult to examine and clarify the medicinal actions or metabolism of each enantiomer closely. The replacement of hydrogen with fluorine can produce isosteric analogues (pseudologues) that often mimic the parent with respect to biological behavior. Therefore, to provide tools to study the in vivo behavior of the individual enantiomers of these NSAIDs, we have prepared a series of chiral non-epimerizable 2-fluorinated 2-arylpropionic acids 2 (Fig. 2).Some other groups have reported the synthesis of 2-aryl-2-fluoropropionic acid derivatives 2a, b, and 4a (RϭMe) by nucleophilic fluorination of the corresponding 2-hydroxy acids or 2-aryl epoxides with (diethylamino)sulfur trifluoride (DAST) or Et 3 N · 3HF, respectively (Eqs. 1, 2), 5,6) or electrophilic fluorination of the enol silyl ether of 3a with acetyl hypofluorite (Eq. 3).7) Laurent et al. reported the synthesis of 2-fluorinated ester 4a (RϭEt) by electrochemical oxidation in fluorinating media (Eq. 4).8) However, all of these methods require rather delicate conditions and/or many steps, and therefore, they lack synthetic generality (Chart 1).In this paper, we report an efficient and practical synthesis of 2-aryl-2-fluoropropionic acids 2 by direct fluorination of readily available 2-arylpropionic acid methyl esters 3 with diluted perchloryl fluoride (FClO 3 ), according to the convenient procedure we have reported previously.9-11) A simple and general procedure for optical resolution of the 2-fluoro acids 2 is also described. Results and DiscussionWe first attempted direct fluorination of carbanions derived from methyl ester 3a using selectfluor 12) and N-fluorobenzenesulfonimide.13) However, the yields seemed sensitive to the amount and kind of bases employed for the reaction and the results were found not to be reproducible. We then focused on fluorination using diluted FClO 3 , 9-11) considering the successful results obtained in the preparation of the structurally similar 2-cyano-2-fluoro-p-tolylacetic acid ethyl ester. 14,15) We first examined bases and temperatures for the fluorination of ibuprofen methyl ester 3a with FClO 3 in order to optimize reaction conditions (Table 1). The best result was obtained when a solution of the lithium enolate of 3a in tetrahydrofuran (THF), formed by treatment with lithium diisopropylamide (LDA) by usual procedure, was subjected to slow introduction of diluted FClO 3 , at Ϫ40°C for 1 h, to give a-fluoroibuprofen methyl ester 4a in 93% yield ...

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“…The compounds thus synthesized will have increase of membrane permeability, hydrophobic binding and stability against metabolic oxidation and these are due to the presence of fluorine compounds, being bioactive compounds, are expected to play a vital role in medicinal chemistry. In view of high rate of growth in the medicinal field the synthesis of organo fluorine compounds gains importance [1][2][3][4]. Despite the availability of multi step chemical routes, attempts have been made in this laboratory to synthesize fluorination of amine through single step electrochemical fluorination.…”

Section: Introductionmentioning

confidence: 99%