Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane

Abstract

SummaryA large-scale synthesis of meso-2,3-difluoro-1,4-butanediol in 5 steps from (Z)-but-2-enediol is described. Crystallographic analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilylation of the diol is high-yielding but all attempts to achieve chain extension through addition of alkyl Grignard and acetylide nucleophiles failed.

The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

“…As previously reported [ 17 ], epoxide opening of cis- 2 with Olah’s reagent (HF·py) led to an 80% yield of the fluorohydrin after just three hours, however, the product was obtained as a mixture of both the syn- and anti -diastereomers. Whilst no mechanistic studies were conducted, it is possible that competing S N 1 and/or anchimeric assistance by the benzyloxy group occurred.…”

“…While the synthesis of anti- 5 as described in Scheme 1 was high-yielding [ 17 ], two disadvantages were apparent. First, the epoxide opening takes 2.5 days at 115 °C and uses an expensive fluoride source (Landini’s reagent [ 18 ]: Bu 4 NH 2 F 3 ).…”

“…The vicinal -difluoride motif is known to exert conformational control through the fluorine gauche effect [ 14 – 15 ], and so building blocks containing this motif are of interest [ 16 – 17 ]. We have previously reported on the gram-scale synthesis of meso -2,3-difluorobutane-1,4-diol ( anti - 5 ) starting from commercially available cis -but-2-ene-1,4-diol ( Scheme 1 ) [ 17 ].…”

“…The vicinal -difluoride motif is known to exert conformational control through the fluorine gauche effect [ 14 – 15 ], and so building blocks containing this motif are of interest [ 16 – 17 ]. We have previously reported on the gram-scale synthesis of meso -2,3-difluorobutane-1,4-diol ( anti - 5 ) starting from commercially available cis -but-2-ene-1,4-diol ( Scheme 1 ) [ 17 ]. The vicinal -difluoride group was introduced by a two-step sequence, with initial nucleophilic epoxide [ 18 ] opening by a fluoride source [ 19 ], followed by nucleophilic deoxyfluorination [ 9 – 11 ].…”

The preferred all-gauche conformations in 3-fluoro-1,2-propanediol

“…The remaining 28 structures converged to replicates of some 53 energy minima or exhibited imaginary frequencies (transition states). 26 Despite the well known gauche effect along with the 1,2-disubstituted ethane fragment (substituents = electronegative groups), multivicinal substituents in the gauche arrangement have been observed only in a few examples, emerging as candidates for inclusion in the design of performance organic molecules. 2).…”