3-Bromo-2-fluoropropene - A Fluorinated Building Block. 2-Fluoroallylation of Glycine and Alanine Ester Imines

Abstract

3-Bromo-2-fluoropropene (4) is prepared in a new three-step synthesis from ammonium α -fluoroacrylate (1) in 31% overall yield. Glycine and alanine ester imines are efficiently alkylated by 4 to give, after deprotection, 2-amino-4-fluoropent-4-enoic acid (9) in 63% overall yield, and the α -methylated derivative 13 in 26% overall yield, respectively. Preliminary results indicate that 4 is potentially a new α -carbonyl cation equivalent. Key words: alkylation, amino acid ester imines, β -fluoroallyl bromide, 2-amino-4-fluoropent-4-enoic acid, α -carbonyl cation equivalentThe interest in partially fluorinated organic compounds has grown continuously over the last few years. 1 Nevertheless, the synthesis of highly functionalized molecules containing a limited number of fluorine atoms still remains a significant challenge to synthetic organic chemists.Recently, we reported the syntheses of racemic 2 and optically active 3 γ -and δ -fluoro-α -amino acids using easily accessible fluorinated building blocks. Glycine ester imines have been alkylated with 1-bromo-2-fluoroalkanes 4 in good yields, in spite of the deactivating influence of the fluorine substituent in β -position to the reaction center. 5 We then became interested in the application of 3-bromo-2 -fluoropropene (4) , which should be a more reactive alkylating reagent compared to the saturated β -fluorinated alkyl bromides.Until now β -fluoroallylic compounds have been infrequently used as building blocks. Only a few C-C bond formation reactions of these compounds have been described in the literature. 6 For example, one such compound has been used for the alkylation of Schöllkopf's bislactim ether. 6, 7 However, they have been already shown to participate well in substitution reactions with non-carbon nucleophiles 6 and esters of β -fluoroallylic alcohols have also been used for hetero-Cope rearrangements. 8 3-Bromo-2-fluoropropene (4) , previously prepared in a three-step synthesis from methyl vinyl ether in low overall yield, has been used for O -alkylation by Schlosser et al. 9 We report here a more efficient preparation of 4 and its use for C -alkylation of amino acid ester imines.Attempts to prepare 3-bromo-2-fluoropropene (4) by bromofluorination of allylic bromide followed by dehydrobromination have been thwarted by lack of regioselectivity in the addition step. 10, 11 However, we found that 3-bromo-2-fluoropropene (4) could be efficiently obtained in three steps via 2-fluoroallylic alcohol 3 starting with ammonium α -fluoroacrylate (1) 12 (Scheme 1 ) . The direct reduction of 1 with LiAlH 4 could not be accomplished. However, compound 3 could be synthesized by treatment of 1 with SOCl 2 , followed by reduction of the α -fluoroacrylic acid chloride with LiAlH 4 in diethyl ether at -20 ˚C. Although the reduction step was nearly quantitative, the overall yield of 3 was only 37% in this sequence. The most convenient synthesis of 3 involved the reduction of the benzyl ester 2 with LiAlH 4 in diethyl ether. The ester 2 was prepared under mild conditions by ...

Stereoselective Synthesis of γ-Fluorinated α-Amino Acids Using 2-Hydroxy-3-pinanone as an Auxiliary

“…bromo-2-fluoropropene (7) [11] to the α-alkylation of amino acid derivatives to obtain γ-fluoro α-amino acids. [12,13] Using a Schiff base of (ϩ)-(R)-camphor and glycine esters for diastereoselective synthesis of γ-fluoro α-amino acids, moderate to good diastereomeric excesses have been achieved.…”

Asymmetric Synthesis of γ‐Fluorinated α‐Amino Acid Derivatives

“…[33,38,39] This paper reports the results of our efforts to synthesize enantiopure γ-fluoro-α-amino acid derivatives and the corresponding α-methylated analogues by using enantiopure (S)-Boc-BMI (1a) as a chiral glycine building block. 2-Fluoroallyl tosylate, synthesized [40] in 90% yield from 2-fluoroallyl alcohol [26] and tosyl chloride using NaOH/Et 2 O, was used as the alkylating agent. By using a method similar to that described in the literature, [33] the stereoselective alkylation of 1 was carried out by using LDA as a base in dry THF in the presence of DMPU [41] as co-solvent under argon at -50°C.…”

“…[44] The fluorovinyl group in compounds 2a and 2b was also stable under stronger aqueous basic conditions but hydrolysis to 4-oxonorvalines occurred under stronger aqueous acidic conditions. [24][25][26] Thus, the alkylation reagents, 2-fluoroallylhalogenides and 2-fluoroallyl tosylate, can be seen as acetonyl cation equivalents. 4-Oxo-l-norvaline has been used as an important building block for protease inhibition studies.…”

“…The spectroscopic data for the racemate agree with previously published values. [26] (S)-4-Fluoro-2-(1,3-dioxaisoindolin-2-yl)pent-4-enoic N-Methylamide (6): [46] Phthalic anhydride (3.6 mmol, freshly recrystallized from CHCl 3 ) was added to a solution of N-methylamide (S)-4a (438 mg, 3 mmol in CHCl 3 /MeOH (2:1, 30 mL) at 0°C. After 10 min, oxalyl chloride (4.5 mmol) was added dropwise at 0°C.…”

“…[23] Our group has synthesized several saturated and unsaturated γ-fluorinated amino acids. [24][25][26] Fluoroolefins are well documented as isosteres of peptides (or as peptidomimetics) [27][28][29][30] and are very important, particularly in protein design. [31] The importance and synthesis of fluorinated α-amino acids have been recently reviewed.…”