Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• to deliver acyl fluorides via two distinct deoxyfluorination pathways, an efficient process could be achieved using only sub-stoichiometric amounts of the fluorinating reagent. Results and Discussion In an initial test reaction, 4-methylbenzoic acid (1a) was reacted with 1.25 equiv of BT-SCF3 and 2.0

• , we were interested in the reactivity of other BT-SRF reagents developed in our group and tested three longer-chain derivatives under deoxyfluorination conditions. Employing BT-SC4F9 and BT-SC8F17, 19F NMR yields of 2a of 84% and 81% were achieved (Table 1, entries 6 and 7), however, BT-SCF(CF3)2

• starting material was completely converted after only 30 min at rt (Table 1, entry 14). With the optimised conditions in hand, the scope of the reaction was investigated to assess the practical utility of BT-SCF3-mediated deoxyfluorination as a method for preparing diverse acyl fluorides. As shown in

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• of gem-dihalo groups to corresponding CF2 derivatives using silver tetrafluoroborate [5] or mercury(II) fluoride [6], deoxyfluorination of carbonyl derivatives using diethylaminosulfur trifluoride (DAST) or related Deoxo-Fluor and Xtalfluor reagents [7][8]. Alternatively, oxidative

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• introduced to the corresponding α- and β-fluorinated aminophosphonates 4, 6 (Scheme 1) by regioselective deoxyfluorination reactions of α-hydroxy-β-aminophosphonates 2 [24][25][26]. Next, the conditions for the solvolysis were carefully assembled (Scheme 2). The optimized reaction conditions included 8 equiv

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• thioglycosides prepared from deoxyfluorinated 1,6-anhydro-2-azido-β-ᴅ-hexopyranose precursors by ring-opening reaction with phenyl trimethylsilyl sulfide. Nucleophilic deoxyfluorination at C4 and C6 by reaction with DAST, thioglycoside hydrolysis and azide/acetamide transformation completed the synthesis

• . Keywords: amino sugars; deoxyfluorination; fluorinated carbohydrates; hexosamine hemiacetals; thioglycosides; Introduction Fluorinated carbohydrates are versatile carbohydrate mimetics used to probe or manipulate the recognition of carbohydrates by carbohydrate-binding proteins or carbohydrate-processing

• reaction with diethylamino sulfurtrifluoride (DAST) [27]. This reaction was greatly improved by microwave irradiation, especially in the GalNAc series [31][32]. The deoxyfluorination of the secondary hydroxy groups at the 3- and 4-positions was accomplished using a treatment of the C3/4 hydroxy groups with

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD^®/Olah’s reagent under solvent-free conditions

• Yumeng Liang,
• Akihito Taya,
• Zhengyu Zhao,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2020, 16, 3052–3058, doi:10.3762/bjoc.16.254

• the formation of trifluoromethyl compounds from acyl fluorides has been developed. The combination of FLUOLEAD® and Olah’s reagent in solvent-free conditions at 70 °C initiated the significant deoxyfluorination of the acyl fluorides and resulted in the corresponding trifluoromethyl products with high

• trifluoromethyl compounds under the same reaction conditions. A reaction mechanism is proposed. Keywords: acyl fluorides; deoxyfluorination; fluorine; solvent-free; trifluoromethyl group; Introduction Due to an impressively wide effect of fluorine on the biological activity, the insertion of fluorine atoms or

• and not as fluorination of acyl fluorides. Thus, the acyl fluoride moiety is commonly sacrificed as a “leaving group” in reactions. On the other hand, the transformation to CF3 derivatives from carboxylic acids are traditionally examined. In 1960, Engelhardt [27] performed the deoxyfluorination of

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

• Danny Lainé,
• Vincent Denavit,
• Olivier Lessard,
• Laurie Carrier,
• Charles-Émile Fecteau,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2020, 16, 2880–2887, doi:10.3762/bjoc.16.237

• at C4 could contribute to a new fluorine effect in nucleophilic substitution. Finally, with the continuous objective of synthesizing novel multi-vicinal fluorosugars, we prepared one difluorinated and one trifluorinated alditol analogue. Keywords: deoxyfluorination; Et3N·3HF; fluorine effect

• -difluoro-β-ᴅ-hexopyranoses 2–5 were prepared as pivotal intermediates to access compounds 6–9. We initially supposed that C4 deoxyfluorination of intermediates 2–5 could provide the corresponding trifluorinated product with inversion of configuration. Although that holds true for intermediates 2–4 (leading

• to products 6–8 after few synthetic steps), intermediate 5 failed to produce any significant results under various reaction conditions. Surprisingly, depending on the reaction conditions, C4 deoxyfluorination of compound 4 led to either the product with inversion or retention of configuration

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• fluorohydrin 10 suggested that the earlier dihydroxylation reaction had proceeded with 90% ee. The deoxyfluorination of 10 was then attempted using several reagents including DeoxoFluor, DeoxoFluor in combination with TMS-morpholine [29], and PyFluor [30]. The optimal yield of the threo-difluoroalkane 11 was

• moiety throughout (Scheme 3). Thus, the α,β-unsaturated ester 15 [25] was carried through a similar sequence to that previously described, i.e., dihydroxylation, cyclic sulfate formation, ring-opening with TBAF (although note the regioselectivity [31]), deoxyfluorination, and deprotection to deliver the

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• of halogens [19]. Halofluorinaton-related reactions, such as fluorosulfuration, fluoroselenation, nitrofluorination, and nitriminofluorination, in contrast, are much less studied [20]. Deoxyfluorination, that is fluorine introduction accompanied by oxygen removal (subtypes: OH→F exchange, C=O→CF2

• transformation, and COOH→CF3 transformation), is also an important nucleophilic fluorination method [2][3][4][5][10][11][18]. The synthesis of fluorinated compounds via deoxyfluorination [21][22][23][24][25][26][27][28][29][30] or utilizing sulfur fluoride deoxyfluorinating reagents [31][32] is a highlighted

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• high diastereoisomeric purities [74] (Scheme 37). The deoxyfluorination of the enantiopure α-hydroxy-β-amino ester 152a or α-amino-β-hydroxyphenylalanine ester 155 [74][75][76] under the same conditions proceeded via aziridinium ion 156 and generated β-fluoro-α-amino ester 153a in good yield and high

Efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates

• Marcin Kaźmierczak and
• Henryk Koroniak

Beilstein J. Org. Chem. 2020, 16, 756–762, doi:10.3762/bjoc.16.69

• . For example 2-pyridinesulfonyl fluoride (PyFluor, 1) [20][21] or perfluorobutanesulfonyl fluoride (PBSF, 2) [22][23] (Figure 1). On the other hand, Hu just recently presented a novel deoxyfluorination reagent with a similar structure to 1 and 2, containing a sulfonimidoyl instead of sulfonyl group. 4

• worse results in each case. We assume it is associated with a much greater reactivity of this reagent in relation to PyFluor. The mechanism of the PyFluor-mediated deoxyfluorination of the α-hydroxy-β-aminophosphonates 5 was previously proposed. Based on spectroscopic studies (19F,1H-HOESY, 1H,1H-NOESY

• -aminophosphonates 15 was presented. These compounds were prepared in a four-step sequence starting from N,N-dibenzylamino aldehydes 5. Each step of the synthesis has been optimized to provide very good yields (Pudovik, deoxyfluorination and amine–acid coupling reactions). Furthermore, the absolute configuration of

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

• Robert Szpera,
• Nadia Kovalenko,
• Kalaiselvi Natarajan,
• Nina Paillard and
• Bruno Linclau

Beilstein J. Org. Chem. 2017, 13, 2883–2887, doi:10.3762/bjoc.13.280

• substituents is of interest. Here we describe optimisation efforts in the synthesis of anti-2,3-difluorobutane-1,4-diol, as well as the synthesis of the corresponding syn-diastereomer. Both targets were synthesised using an epoxide opening strategy. Keywords: acetal isomerization; deoxyfluorination; epoxide

• -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][10][11]. In

• -difluorobutan-1,4-diol diastereomers is described. The key steps involve epoxide opening and subsequent deoxyfluorination. For the first step, Et3N·3HF was found to be the best reagent, giving an excellent yield with no formation of diastereomeric byproducts. Unfortunately it was found that the subsequent DAST

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• diastereoisomers of this fluorinated δ-amino acid adopt distinct conformations in solution, suggesting that these molecules might have value as shape-controlled building blocks for future applications in peptide science. Keywords: amino acids; conformation; deoxyfluorination; fluorine; stereochemistry

• were not facile, we decided to start the new approach with a full-length carbon chain in the form of piperidinedione 21. We envisaged that a sequence of reactions – two electrophilic fluorinations [29][30][31] followed by reduction and deoxyfluorination – would deliver the target molecule 6

• have previously reported a concise method for synthesising compounds that contain three vicinal C–F bonds [34]; their method commences with an epoxy alcohol, which undergoes three successive nucleophilic substitutions with fluoride (i.e., deoxyfluorination of the alcohol, epoxide ring opening with

Organofluorine chemistry: Difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

• Mathew J. Jones,
• Ricardo Callejo,
• Alexandra M. Z. Slawin,
• Michael Bühl and
• David O'Hagan

Beilstein J. Org. Chem. 2016, 12, 2823–2827, doi:10.3762/bjoc.12.281

• diketones 5a–c was explored with DAST or Deoxo-Fluor® (Scheme 3). When diketones 5a and 5b were treated with DAST or Deoxo-Fluor®, either neat or in DCM as a solvent, only complex and intractable products were obtained. These highly enolisable diketones [27][28] were incompatible with deoxyfluorination. In

Coupling of α,α-difluoro-substituted organozinc reagents with 1-bromoalkynes

• Artem A. Zemtsov,
• Alexander D. Volodin,
• Vitalij V. Levin,
• Marina I. Struchkova and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2015, 11, 2145–2149, doi:10.3762/bjoc.11.231

• , unique stereoelectronic properties of the CF2-unit may be exploited in conformational analysis [3][4][5], carbohydrate and peptide research [6][7], and reaction engineering [8][9]. Typically, the difluoromethylene fragment is created by deoxyfluorination, which requires harsh or hazardous conditions [10

Synthesis and biological evaluation of a novel MUC1 glycopeptide conjugate vaccine candidate comprising a 4’-deoxy-4’-fluoro-Thomsen–Friedenreich epitope

• Manuel Johannes,
• Maximilian Reindl,
• Bastian Gerlitzki,
• Edgar Schmitt and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2015, 11, 155–161, doi:10.3762/bjoc.11.15

• capable of binding to the native MUC1 antigen structures present on MCF-7 human breast cancer cells. Moreover, selective deoxyfluorination at the antigenic carbohydrate determinant might be used to improve the metabolic stability of the saccharide epitope, as was showcased by the enhanced resistance of

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• yield (92%). A three step, one pot sequence consisting of methylation, treatment with phenylhydrazine and subsequent cyclisation furnished the triazolium salt 17 in 76% yield (3 steps). Finally, DAST-mediated TBDMS deprotection/deoxyfluorination completed the synthetic sequence to give 7 in 45% yield

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• been developed in recent years. 6. There are many ways to synthesise stereoselectively fluorinated N-heterocycles 6.1 Deoxyfluorination Because of the ease of synthesis of enantiomerically pure alcohols, and the ever-increasing availability of deoxyfluorination reagents [10], the deoxyfluorination of N

• -protected alcohols is the most obvious strategy for synthesising fluorinated N-heterocycles (Scheme 3). Deoxyfluorination methods have already been extensively reviewed [8], and of course they are not limited in scope to N-heterocyclic systems, so we will not attempt to comprehensively cover this topic here

• . Instead, we will focus on two recent developments in deoxyfluorination methods that are particularly relevant to N-heterocyclic targets. Late stage deoxyfluorination is an attractive method for synthesising multifunctional fluorinated N-heterocycles, but mild and selective reagents are required if this is