Synthesis of a Hominal Bis(difluoromethyl) Fragment

Abstract

This paper describes the synthesis of a discrete unit of hominal bis( gem -CF 2 ). The controlled introduction of fluorine atoms is a powerful synthetic tool to introduce dipole moments with minimal impact to sterics. Poly(vinylidene difluoride) is a striking example of the influence of fluorine atoms, which impart ferroelectric behavior from the alignment of the dipole moments of CF 2 units; however, it is prepared via direct polymerization of vinylidene difluoride. Thus, a different synthetic pathway is required to produce synthons containing discrete numbers of CF 2 groups in a hominal relation to each other. We found out that, in the case of short chains, the consecutive deoxofluorination of sequentially introduced keto groups is inefficient, as it requires harsh conditions and decreasing yields at each step. To solve this problem, we combined the selective desulfurative fluorination of dithiolanes with pyridinium fluoride and the deoxofluorination of keto groups with morpholinosulfur trifluoride. This strategy is highly reproducible and scalable, allowing the synthesis of the hominal bis( gem -CF 2 ) fragment as a shelf-stable tosylate, which can be used to install discrete chains of hominal bis( gem -CF 2 ) on a variety of synthons and monomers.

FDA-Approved Fluorinated Heterocyclic Drugs from 2016 to 2022

“…2023, 24, 7728 3 of 36 Some of the main processes used for the introduction of F atoms are summarized in Figure 2. The introduction of C-F or CF 2 groups is achieved through the nucleophilic fluorination of electrophiles; some examples involving dithiane or sulphonate formation are reported in Figure 2a,b [20,21].…”

Skipped Fluorination Motifs: Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs

“…This was subsequently converted to the skipped 1,3-tetrafluoro compound 23 with Morph-DAST. 50 In this contribution, we report on a systematic investigation to compare internal vicinal fluorination motifs with their (internal) skipped counterparts, using the 1,4-butanediol and 1,5-pentanediol scaffolds C and H, respectively (Figure 3). For this investigation, we opted to have a constant structural feature at the molecule termini, with the structural change focused on the extension of the two-carbon vicinal motif with the three-carbon skipped motif without any additional influence caused by fluorination motifs being at different distances from a polar functional group or aliphatic chain terminus.…”

“…In a related approach, the Chiechi group directly fluorinated β-dithiolane 21 , obtained from the corresponding propargylic ketone 20 , using HF-pyridine, to obtain 22 . This was subsequently converted to the skipped 1,3-tetrafluoro compound 23 with Morph-DAST …”