Fluorination Step Research Articles

Investigation of the Fluorination Step in the Biosynthesis of Nucleocidin

Natural products (NPs) are secondary metabolite compounds produced by living organisms like bacteria and fungi. NPs and their derivatives commonly have biological activity and contribute to the development of pharmaceuticals, particularly antibiotics. NPs are encoded by biosynthetic gene clusters, which are sets of genes that when collectively expressed, lead to the production of these compounds. Nucleocidin is an NP derived from adenosine and is produced by Streptomyces species. Its 4’-fluoro and 5’-O-sulfamoyl groups make nucleocidin of particular interest, as it is one of the few natural products known to contain fluorine. Additionally, the incorporation of fluorine at the 4’ position of the adenosine ring requires novel fluorine chemistry, since previously characterized fluorinases have only been known to substitute fluorine at the 5’ position. Previously, three candidate fluorinase genes from the nucleocidin biosynthetic gene cluster, ORF2, 3, and -3, were identified using a genome mining approach and cloned for gene expression in E. coli. In-vitro assays were performed with the purified fluorinase enzymes, but the results were inconclusive regarding enzymatic characterization and association with the fluorination of nucleocidin. This project builds on previous experimentation to prove the fluorination activity of these enzymes through an in-vivo system. The three candidate fluorinase genes, along with a glucosyltransferase essential to the fluorination process, were cloned into a duet-vector system and expressed in a medium supplemented with fluorine. The extracted compounds were analyzed using UPLC-MS, but the results were inconclusive. Further steps will include screening media conditions for nucleocidin production in a heterologous system, and optimizing the in-vivo expression of the potential fluorinase genes. Ultimately, further characterization will be necessary to reveal the specific role each of these candidate fluorinase enzymes plays in the biosynthesis of nucleocidin. Future exploration into the fluorination of nucleocidin offers novel insights into increasing the production efficiency of nucleocidin and its derivatives for pharmaceutical development, along with providing potential avenues for bio-catalytically introducing fluorine into new pharmaceuticals.

Hypervalent Iodine-Catalyzed Fluorination of Diene-Containing Compounds: A Computational Study.

Studies have shown that the incorporation of fluorine into materials can improve their properties, but C-F bonds are not readily formed in nature. Although some researchers have studied the reaction of fluorinating alkenes catalyzed by hypervalent iodine, far too little attention has been paid to its reaction mechanism. This study aimed to explore the mechanism of the hypervalent iodine-catalyzed 1,4-difluorination of dienes. We found that the catalyst is favorable for the activation of C1=C2 double bonds through halogen bonds, and then two HFs interact with one F atom in the catalyst via hydrogen bonds, resulting in the cleavage of I-F bonds and the formation of [F-H∙∙∙F]-. Subsequently, the catalyst interacts with C1, and the roaming [F-H···F]- attacks C4 from the opposite side of the catalyst. After the fluorination step is completed, the nucleophile F- substitutes the catalyst via the SN2 mechanism. Our calculations demonstrated that the interaction between HF and F- is favorable for the stabilization of the transition state within the fluorination process for which the presence of two HFs in the reaction is the best. We also observed that [F-H∙∙∙F]- attacking C4 from the opposite side of the catalyst is more advantageous than attacking from the same side. This study therefore offers a novel perspective on the mechanism of the hypervalent iodine-catalyzed fluoridation of dienes.

Hydrothiolation of Triisopropylsilyl Acetylene Sulfur Pentafluoride - Charting the Chemical Space of β-SF5 Vinyl Sulfides.

Recently, we suggested liquid and high-boiling TIPS-CC-SF5 (TASP) as a versatile reagent to access so far elusive SF5-containing building blocks by less specialized laboratories under bench-top conditions. The synthesis of non-aromatic SF5 building blocks generally requires on-site fluorination or pentafluorosulfanylation steps employing toxic and/or gaseous reagents. Herein, we underline the versatility of this reagent by reporting a benign bench-top protocol for the synthesis of Z-configured β-pentafluorosulfanylated vinyl sulfides in good to excellent yields (up to 99 %) with exclusive (Z)-diasteroselectivity and broad functional group tolerance. This method exploits an in-situ protodesilylation-hydrothiolation sequence. This so far uncharted class of compounds was characterized by means of NMR-spectroscopy as well as SC-XRD. Furthermore, we suggest the reaction to proceed via a kinetically controlled closed-shell reaction pathway, corroborated by in-silico experiments.

Co-Catalyzed Hydrofluorination of Alkenes: Photocatalytic Method Development and Electroanalytical Mechanistic Investigation.

The hydrofluorination of alkenes represents an attractive strategy for the synthesis of aliphatic fluorides. This approach provides a direct means to form C(sp3)-F bonds selectively from readily available alkenes. Nonetheless, conducting hydrofluorination using nucleophilic fluorine sources poses significant challenges due to the low acidity and high toxicity associated with HF and the poor nucleophilicity of fluoride. In this study, we present a new Co(salen)-catalyzed hydrofluorination of simple alkenes utilizing Et3N·3HF as the sole source of both hydrogen and fluorine. This process operates via a photoredox-mediated polar-radical-polar crossover mechanism. We also demonstrated the versatility of this method by effectively converting a diverse array of simple and activated alkenes with varying degrees of substitution into hydrofluorinated products. Furthermore, we successfully applied this methodology to 18F-hydrofluorination reactions, enabling the introduction of 18F into potential radiopharmaceuticals. Our mechanistic investigations, conducted using rotating disk electrode voltammetry and DFT calculations, unveiled the involvement of both carbocation and CoIV-alkyl species as viable intermediates during the fluorination step, and the contribution of each pathway depends on the structure of the starting alkene.

Catalytic HF Shuttling between Fluoroalkanes and Alkynes.

In this paper, we report BF3 ⋅ OEt2 as a catalyst to shuttle equivalents of HF from a fluoroalkane to an alkyne. Reactions of terminal and internal aliphatic alkynes led to formation of difluoroalkane products, while diarylalkynes can be selectively converted into fluoroalkenes. The method tolerates numerous sensitive functional groups including halogen, protected amine, ester and thiophene substituents. Mechanistic studies (DFT, probe experiments) suggest the catalyst is involved in both the defluorination and fluorination steps, with BF3 acting as a Lewis acid and OEt2 a weak Lewis base that mediates proton transfer. In certain cases, the interconversion of fluoroalkene and difluoroalkane products was found to be reversible. The new catalytic system was applied to demonstrate proof-of-concept recycling of poly(vinylidene difluoride).

Catalytic HF Shuttling between Fluoroalkanes and Alkynes**

AbstractIn this paper, we report BF3 ⋅ OEt2 as a catalyst to shuttle equivalents of HF from a fluoroalkane to an alkyne. Reactions of terminal and internal aliphatic alkynes led to formation of difluoroalkane products, while diarylalkynes can be selectively converted into fluoroalkenes. The method tolerates numerous sensitive functional groups including halogen, protected amine, ester and thiophene substituents. Mechanistic studies (DFT, probe experiments) suggest the catalyst is involved in both the defluorination and fluorination steps, with BF3 acting as a Lewis acid and OEt2 a weak Lewis base that mediates proton transfer. In certain cases, the interconversion of fluoroalkene and difluoroalkane products was found to be reversible. The new catalytic system was applied to demonstrate proof‐of‐concept recycling of poly(vinylidene difluoride).

Robust omniphobic ceramic hollow fibre membrane with leaf-like copper oxide hierarchical structure by membrane distillation

Omniphobic membranes have recently shown promising performance in water desalination using MD due to their ability to repel all liquid drop types and keep the membrane surface dry. This study successfully modified the surface of robust hydrophilic mullite-stainless steel hollow fibre membranes (M-SS HFMs) to omniphobic properties. The omniphobic layer was achieved through surface grafting with copper oxide (CuO) rough layer by a hydrothermal technique at different hydrothermal reaction times of 1, 2, 3, 4 and 5 h, followed by fluorination step using 1H,1H,2H,2H-perfluorode-cyltriethoxysilane (C8, 97 %). Next, the omniphobic membranes were characterized in terms of membrane morphology, roughness, mechanical strength, pore size/distribution, liquid entry pressure, contact angle and fouling accumulation. The prepared omniphobic M-SS HFMs were also tested through the DCMD system at 80 °C using a feed solution containing 35 g/L of NaCl and 10 mg/L of humic acid as a foulant agent. The results indicated that M-SS HFMs subjected to a 4 h hydrothermal reaction time, resulting in a leaf-like surface structure, exhibited superior characteristics compared to other omniphobic HFMs reported in the literature that used titania (SiO2), zinc oxide (ZnO), and cobalt (Co3O4) as roughing material. These superior features included higher roughness of 0.798 μm, liquid entry pressure of 5.40 bar, and enhanced liquid repellence and contact angles towards DI water of 167°, olive oil of 152°, and ethanol of 145°. Additionally, the M-SS HFMs at 4 h hydrothermal demonstrated remarkable performance in terms of rejection performance (99.99 %) and vapour flux stability of about 29 kg/m2.h in DCMD operations, surpassing the performance of omniphobic HFMs fabricated using mullite-ball clay, mullite-kaolinite, and alumina (Al2O3). Notably, no fouling/wetting on the membrane surface and elements leaching was observed throughout the MD operation. These findings highlight the potential of this omniphobic HFM for seawater desalination using DCMD systems, even in the presence of organic contaminants.

Electrochemical behavior of iodide ions in molten fluoride salts

The electrochemical behavior of iodide ions has been studied in the ternary fluoride salt, LiF-NaF-KF and in the binary salts, LiF-CaF2 and LiF-ThF4. The electrochemical study demonstrated that iodide ions are oxidized to produce gaseous species in the three molten fluoride salts. However, the stability of iodide ions was observed to be influenced by the fluroacidity of the molten salt. The efficiency of the extraction of iodide ions was examined in LiF-NaF-KF and LiF-ThF4. UV-visible spectroscopy was used to quantify the amount of iodide ions oxidized after the execution of several coulometries at applied potential, these coulometries simulated the fluorination step in the reprocessing unit designed for the MSFR. The efficiency of extraction determined in LiF-ThF4 is higher than 95 % while it is close to 64 % in LiF-NaF-KF at 650°C.

Surface reaction modelling of thermal atomic layer etching on blanket hafnium oxide and its application on high aspect ratio structures

Thermal atomic layer etching is rapidly becoming an important complementary processing technology in the manufacturing of 5 and 3 nm devices in the semiconductor industry. Critically, architectures such as 3D NAND and 3D DRAM require conformal isotropic etching to remove material such as HfO2 in hard-to-reach locations with aspect ratios that can be greater than 50:1. To achieve repeatable device performance throughout a 3D stack, the removal rate (etch per cycle) of the etched material during an etch process needs to be controlled such that the overall etch amount is the same from top to bottom of the device stack. In this work, the reaction kinetics of reactants and byproducts during a cyclical ligand exchange-based atomic layer etching (ALE) process have been modelled. This ALE process consists of two steps: a fluorination step followed by a fluorine-to-chlorine ligand exchange-based removal step. Modeling was performed for each of those steps separately. Experimental data revealed that the fluorine dosing during the fluorination step was predominantly responsible for controlling the etch rate of the ALE process but had only a minimal impact on the etch profile inside high aspect ratio holes. The ligand exchange dosing, on the other hand, predominantly controlled the etch profile (depth loading) with equal etch rates from top-to-bottom, obtained when the step was operated close to saturation. The model predicts that the chemical reaction rate of dimethylaluminum chloride (DMAC) on a fluorinated surface during the ligand exchange step is 9.1 s−1, about 46 times greater than the reaction rate of hydrogen fluoride (HF) on the hafnium oxide surface during the fluorination step (only 0.2 s−1). Furthermore, modeling results revealed that the sticking coefficient for DMAC on a hafnium fluoride surface far exceeded that of HF on a hafnium oxide surface in the conditions modelled (0.94 s−1 for DMAC vs 0.0058 s−1 for HF). With these modeling results, the different roles fluorination and ligand exchange steps have regarding the control of etch rate per cycle and profile inside high aspect ratio holes can be explained.

(Invited) Transport and Reaction Kinetics of Thermal ALE in High Aspect Ratio Hafnium Oxide Structures

Thermal atomic layer etching is rapidly becoming an important complementary processing technology in manufacturing 5 and 3 nm devices in the semiconductor industry. Critically, stacked chip architectures such as 3D NAND and 3D DRAM require conformal isotropic etching to remove material such as HfO2 in hard-to-reach locations with aspect ratios that can be >50. To achieve repeatable device performance throughout a 3D stack, the removal rate (etch per cycle) of the etched material during an etch process need to be controlled such that the overall etch is the same from top to bottom of the device stack. In this work, we have modelled the reaction kinetics and transport processes of reactants and by-products during a cyclical ligand exchange-based ALE process. This ALE process consists of two steps: a fluorination step, followed by a fluorine-to-chlorine ligand exchange-based removal step. Experimental data revealed that the fluorine dosing during the fluorination step was predominantly responsible for controlling the etch rate of the ALE process but had only a minimal impact on the etch profile inside these holes. The ligand exchange dosing, on the other hand, predominantly controlled the etch profile (depth loading) with equal etch rates top-to-bottom obtained when the step was operated close to saturation. Our model predicts, in agreement with the experiment, that adsorption and reaction rates during fluorination on HfO2 surfaces are significantly slower than transport times inside these deep holes leading to essentially flat fluorination profiles even if the fluorination step is not operated in saturation mode. In contrast, transport rates with the ligand exchange molecule are slow in comparison but adsorption and ligand exchange rates with the fluorinated hafnium appear to be significantly higher than for fluorine during the fluorination step. Slow transport in combination with high surface reaction rates for the ligand exchange step led to an etch rate that was dependent on aspect ratio (feature depth) in processes that used sub-saturation exposures.

Interventions to the Spontaneous Fabrication of Hierarchical ZSM-5 Zeolites by Fluorination-Alkaline Treatment

The sequential fluorination-alkaline treatment protocol has been applied for the tailoring of siliceous ZSM-5 zeolite. The original spontaneous growth of mesoporosity in alkaline medium is altered due to the antecedent fluorination step. The outcome is demonstrated by the apparent delay in the mesoporosity growth, whose essential duration for the well-defined mesoporosity is therefore extended from 30 min to 60 min. A low fluorination level decelerates the mesoporosity growth, whereas a high fluorination level enables the achievement of the mesoporosity. These impacts are closely linked with the alteration to the states of Al sites as the function of fluorination level. Compared to the states of Al sites in the pristine and steamed zeolites, the electronic and steric consequences on the environment of Al species by fluorination is proposed for the interplay with the alkaline medium for the mesoporosity growth.

Transition metal-free fluorocyclization of unsaturated N-methoxyamides gives cyclic N-methoxyimidates

A new class of fluorinated, cyclic N-methoxyimidates was prepared by the intramolecular fluorocyclization of unsaturated N-methoxyamides. The reaction combined unsaturated amides, a monofluoroiodane, and HFIP as the activator, and this induced an intramolecular fluorocyclization expeditiously at room temperature, giving the products in up to 81% yield in a single step. Two product isomers were chemoselectively produced, depending on whether or not an α-arene substituent was present, in which case the typical reaction sequence was interrupted by a 1,2-phenyl shift prior to the final fluorination step.

Behavior and distribution of nuclides in the fluoride volatility process of uranium containing molten salt fuel

The recovery of uranium from FLiBe-ZrF4 (LiF-BeF2-ZrF4: 65–30–5 mol%) molten-salt containing irradiated UF4 and ThF4 by the fluoride volatility process (FVP) was carried out. Gamma radiography was applied for in-situ monitoring of the fluorination and desorption steps successfully. The results confirmed that it was feasible to monitor the FVP by detecting the changes of the γ activities of key nuclides in the molten salt and the NaF adsorber. The behavior and distribution of actinides and fission products in each unit of the FVP were investigated by the determination of their activities with the γ-ray spectroscopy. The results indicated the conversion and volatilization rate of UF4 was greater than 99.8%. And the recovery yield of uranium was approximately 80% in two cold traps. A small amount of uranium remained in the molten salt, others was found in the NaF trap and the NaF adsorber. In addition, small amounts of uranium were also found in the off-gas, in the desorption step. As for 95Zr, 140La, 140Ba, 141Ce, 143Ce and 233Pa, existing as nonvolatile fluorides, remained in the fluorinated salt with the overall process gamma (γ) decontamination factors (DFs) in the UF6 product greater than 105∼106. Meanwhile, 99Mo, 131I and 239Np existing as volatile fluorides, were found in the UF6 product, NaF absorber and off-gas with the overall process γ DFs in the UF6 product less than 10. In the case of 103Ru and 132Te also existing as volatile fluorides, the overall process γ DFs in the UF6 product still reached approximately 105∼106 due to their separation from the UF6 product by the NaF adsorber.

Platinum-Catalyzed Hydrofluorination of Alkynes: Hydrogen Bonding to Indolylphosphine Ligands to Provide Fluoride Reactivity.

The reaction of the Pt complexes cis‐[Pt(CH3)2{R2P(Ind)}2] (Ind=2‐(3‐methyl)indolyl, R=Ph (1 a), 4‐FC6H4 (1 b), 4‐CF3C6H4 (1 c)) with HF afforded the fluorido complexes trans‐[Pt(F(HF)2)(CH3){R2P(Ind)}2] 2 a–c, which can be converted into trans‐[Pt(F)(CH3){R2P(Ind)}2] (3 a–c) by treatment with CsF. Addition of 3‐hexyne to 2 a–c gave alkyne complexes trans‐[Pt(C,C‐η2 ‐C2H5 C≡CC2H5)(CH3){R2P(Ind)}2{F(HF)2}] (4 a–c) at which a fluoride is stabilised as polyfluoride in the coordination sphere by hydrogen bonding to the indolyl‐substituted phosphine ligands. Subsequent heating of a solution of 4 a in the presence of PVPHF led to fluoroalkene formation. Selective catalytic hydrofluorination of alkynes to yield (Z)‐fluoroalkenes were developed. The ability of hydrogen bonding to polyfluoride favours the fluorination step as demonstrated by studies with complexes bearing no indolyl groups at the phosphine ligands.

Novel approach to surface functionalization of mullite-kaolinite hollow fiber membrane using organosilane-functionalized Co3O4 spider web-like layer deposition for desalination using direct contact membrane distillation

This work investigated a novel omniphobic mullite ceramic hollow fiber membrane (MCHFM) with low fouling and wetting propensity for use in direct contact of membrane desalination (MD) processes. The MCHFM was surface-coated with a spider web-like (SWL) cobalt oxide (Co3O4) rough layer via hydrothermal method at different reaction time (10, 13, 16, and 19 h) before a fluorination step using 1H,1H,2H,2H-perfluorodecyltriethoxysilane (97%) (FAS-17). After surface modification, the synthesized super hydrophilic membrane became highly repellent to water and other low surface tension liquids such as olive oil and engine oil with 32 and 31 mN/m of force, respectively. The surface-modified omniphobic membrane showed super-omniphobic properties towards engine oil at 154°, deionized water at 165°, and near superomniphobicity at 142.1° towards olive oil. The hydrothermal reaction time of the omniphobic membranes was studied using the DCMD test at 60 °C, while utilizing 30 g/L of NaCl and 8 mg/L of humic acid as feed. It was found that the hydrothermal reaction time at 16 h/FAS (Hy-16h/FAS) achieved a long-term stability as the rejection rate and water flux values were relatively constant (99.99%) and 22.8 kg/m2.h for about 4.3 h of the MD process. SEM analysis showed no fouling on the surface modified membrane. This was attributed to the Co3O4 spider web-like particles, which achieved superior anti-fouling properties. This implied the suitability of the fabricated omniphobic MCHFM with a SWL structure for DCMD and seawater desalination, in spite of organic contaminants.

Atomic layer etching of Al2O3 with NF3 plasma fluorination and trimethylaluminum ligand exchange

In this study, a cyclic isotropic plasma atomic layer etching (ALE) process was developed for aluminum oxide that involves fluorination with NF3 plasma and ligand exchange with trimethylaluminum (TMA). The isotropic plasma ALE consists of two steps: fluorination and removal. During the fluorination step, the Al2O3 surface was fluorinated to AlOFx with NF3 plasma at 100 °C. The formation of the AlOFx layer was confirmed by x-ray photoelectron spectroscopy analysis, and the atomic fraction of fluorine on the surface was saturated at 25% after 50 s of plasma fluorination. The depths of the fluorinated layers were in the range of 0.79–1.14 nm at different plasma powers. In the removal step, the fluorinated layer was removed by a ligand exchange reaction with TMA at an elevated temperature range of 250–480 °C. The etch per cycle (EPC) was 0.20–0.30 nm/cycle and saturated after 30 s in the temperature range of 290–330 °C. No etching was observed below 250 °C, and the EPC increased in the temperature range of 250–300 °C during the removal step with the ligand exchange reaction and reached the maximum at 300 °C. Then, the EPC was significantly reduced at high temperatures, possibly due to TMA decomposition. The fluorine atomic fraction on the surface was reduced to 14% after the removal. In conclusion, Al2O3 was successfully etched at the atomic scale by the cyclic plasma ALE process. The average surface roughness of Al2O3 was reduced from 8.6 to 5.3 Å after 20 cycles of etching.

Au(I) Catalyzed HF Transfer: Tandem Alkyne Hydrofluorination and Perfluoroarene Functionalization.

HF transfer reactions between organic substrates are potentially useful transformations. Such reactions require the development of catalytic systems that can promote both defluorination and fluorination steps in a single reaction sequence. Herein, we report a catalytic protocol in which an equivalent of HF is generated from a perfluoroarene | nucleophile pair and transferred directly to an alkyne. The reaction is catalyzed by [Au(IPr)NiPr2] (IPr = N,N′-1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). HF transfer generates two useful products in the form of functionalized fluoroarenes and fluoroalkenes. Mechanistic studies (rate laws, KIEs, density functional theory (DFT) calculations, competition experiments) are consistent with the Au(I) catalyst facilitating a catalytic network involving both concerted SNAr and hydrofluorination steps. The nature of the nucleophile impacts the turnover-limiting step. The cSNAr step is turnover-limiting for phenol-based nucleophiles, while protodeuaration likely becomes turnover-limiting for aniline-based nucleophiles. The approach removes the need for direct handling of HF reagents in hydrofluorination and offers possibilities to manipulate the fluorine content of organic molecules through catalysis.

Plasma atomic layer etching for titanium nitride at low temperatures

Isotropic plasma atomic layer etching (ALE) was developed for titanium nitride (TiN) through a three-step process: plasma oxidation, plasma fluorination, and thermal removal at low temperatures. In the plasma oxidation step, TiN was oxidized to form a titanium oxide (TiO2) layer with O radicals generated from O2 plasma at 100 °C. The TiO2 thickness was found to be saturated with plasma after an exposure time of 300 s, and the saturated thickness increased from 0.29 to 1.23 nm with increasing temperature and RF power. In the plasma fluorination step, the TiO2 layer was converted to titanium oxyfluoride (TiO2−xFx) with F radicals generated in the CF4 plasma at 100 °C. The F atomic fraction on the surface was found to be saturated at 12%, with RF powers below 15 W in the fluorination step. The process temperature was increased during the removal step, and the TiO2−xFx formed by plasma fluorination was completely removed above 150 °C. The removal rates of TiN ranged from 0.24 to 1.71 nm/cycle by controlling the thickness of the TiO2 layer determined earlier. The average surface roughness of TiN decreased from 1.27 to 0.26 nm after 50 cycles of the ALE process. This work demonstrated that plasma oxidation and fluorination with thermal removal can remove TiN at the atomic scale at low temperatures for atomic-scale three-dimensional devices.

Facile Preparation of Hydrophobic PET Surfaces by Solvent Induced Crystallization

In this work, Polyethylene terephthalate (PET), one of the most widely consumed polymers, has been used as starting material for the development of non-stick surfaces through a fast, simple and scalable method based on solvent-induced crystallization to generate roughness, followed by a fluorination step. Several solvents were tested, among which dichloromethane was chosen because it gives rise to the formation of a particulate layer with rough topography. This particulate layer was covered by a polymer thin and smooth skin that must be removed to leave the rough layer as surface. The skin has been successfully removed by two strategies based on mechanical and chemical removal, each strategy producing different surface properties. A final treatment with a diluted solution of a fluorinated silane showed that it is possible to obtain PET surfaces with a water contact angle higher than 150° and low water adhesion. The reason behind this behavior is the development of a hierarchical rough profile during the induced polymer crystallization process. These surfaces were characterized by XRD, FTIR and DSC to monitor solvent induced crystallization. Topography was studied by SEM and optical profilometry. Wetting behavior was studied by measuring the contact angles and hysteresis.

Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow

This article describes two routes toward the synthesis of cis or trans C2,3,5,7-tetrasubstituted dihydrobenzofurans as potent and selective bromodomain and extra-terminal BD2 inhibitors, followed by the optimization of the synthesis of the lead molecule GSK973 to support pre-clinical efficacy and safety studies. The use of flow chemistry for a Claisen rearrangement, extensive optimization of the fluorination step, and high-yielding aminocarbonylation were key to generate the required 50 g of material. The identified new route also represents a robust starting point for further optimization.