Asymmetric total synthesis of tricyclic prostaglandin D2 metabolite methyl ester via oxidative radical cyclization

• Miao Xiao,
• Liuyang Pu,
• Qiaoli Shang,
• Lei Zhu and
• Jun Huang

Beilstein J. Org. Chem. 2025, 21, 1964–1972, doi:10.3762/bjoc.21.152

• reaction at 50 °C for 36 h, and extensive decomposition of the starting material β-keto ester 15 occurred (Table 1, entry 1). Solvent screening of EtOH [26], acetic acid [26], and hexafluoroisopropanol (HFIP) [27] demonstrated that HFIP afforded optimal results, delivering cyclopentanone 14 in 63% yield as

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• 4d oxidation (Table 1, entry 1). We found that substrate S-2d can be transformed to ester S-3d in a single step with a reduced amount of HFIP as the only additive (Table 1, entries 2 and 3). Given the high cost of HFIP, we examined if it could be replaced with other proton donors for the cathode

• acetic acid or HFIP the electrochemical oxidation also provided the desired product 3d, although in reduced yield (Table 1, entry 7). An increased amount of acetic acid (1 mL or ≈ 18 equiv) also reduced the yield (Table 1, entry 8). The attempt to use LiOAc as electrolyte instead of LiClO4 was not

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• pathway initiates with ground-state complexation 90 between HRP-12 and HFIP via hydrogen bonding. Following visible-light excitation of 90, intersystem crossing (ISC) from the S1(LE) to T2 state generates the catalytically competent triplet excited state 91. This N-centered radical species subsequently

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• simple single benzannulation of a series of precursors 138a–k (Scheme 19) [95]. The reaction was mediated by MsOH and carried out in hexafluoroisopropanol (HFIP), yielding the final products (139a–k) in 53–93% yield. In general, the absorption spectra of the products show a typical “azulene-like” fine

Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

• oxidation followed by an internal combination of the formed radical to give the corresponding product (Scheme 17). The oxidation reaction was probably ineffective in the absence of HFIP due to the stability of HFIP's radical cation ions. The efficiency of the reaction was dependent on the electrolyte

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• electrode, Pt foil as counter electrode, 0.1 M tetrabutylammonium tetrafluoroborate (TBA-BF4) in HFIP electrolyte and 2 F passed charge at a current density of 10 mA·cm−2) afforded the desired Br(III) product 1a in poor 14% NMR yield (Table 1, entry 1). The cyclic diarylbromonium salt 1a was isolated by

• ) experiments (0.1 M TBA-BF4 in HFIP on a Pt disk electrode) revealed that the reduction current increases almost 4 times upon the addition of 5 mM 1a to the electrolyte (see Supporting Information File 1, Figure S1). At the same time, passing 6.0 F through a solution of 1a in 50 mM TBA-BF4/HFIP at j = 8 mA·cm

• starts with a single-electron oxidation of 4a on the electrode surface to form cation radical A, in which Br(II) is chelation-stabilized by the carboxyl group [21] and the neighbouring Br substituent [24]. Intermediate A rapidly undergoes irreversible chemical reaction by HFIP coordination to transient

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• with key hydrogen bonds between substrates, organocatalyst, and HFIP. Sheng et al. utilized the BINOL-derived organocatalyst C34 in the reaction of benzylindoles 148 and 2-indolylmethanols 149 leading to the bisindoles 150 (Scheme 44) [72]. Very good yields and good to high enantioselectivities were

Hot shape transformation: the role of PSar dehydration in stomatocyte morphogenesis

• Remi Peters,
• Levy A. Charleston,
• Karinan van Eck,
• Teun van Berlo and
• Daniela A. Wilson

Beilstein J. Org. Chem. 2025, 21, 47–54, doi:10.3762/bjoc.21.5

• the PSar-PBLG block copolymers was optimally achieved by dissolving the block copolymers in DMF followed by a solvent-exchange method. Here, Milli-Q water was gradually introduced to form monodisperse polymersomes (Figure 1i, and Supporting Information File 1, Figure S22). Hexafluoroisopropanol (HFIP

• ) emerged as another solvent yielding monodisperse assemblies. HFIP promotes formation of alpha helices in peptides and this property yielded vesicles with different morphologies [30]. The resulting vesicles looked darker compared to those formed in DMF, as observed through TEM (Supporting Information File

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• difference in HVI reagent used. In 2023, Du and co-workers reported a method for synthesizing 3-bromoindoles via a cascade oxidative cyclisation–halogenation encompassing oxidative C−N/C−Br bond formation, and utilising phenyliodine(III) diacetate (PIDA) in combination with LiBr in HFIP (Scheme 35) [54]. The

• also demonstrated the formation of 3-bromoindoles 66 (Scheme 43) [54]. In this instance, KI was used as the iodide source with PIDA in HFIP. The mechanism proposed was the same as that for the bromoindoles (Scheme 35). Oxygen nucleophiles In addition to chloroamidation and chlorolactonization

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• corresponding heteroaryl–aryl compounds 32 in moderate to good yield. The use of blue LEDs (456 nm), nitrogen atmosphere, and HFIP/H2O 4:1 solvent mixture improved the yield of the product by up to 90%. Various substituted azauracils were used to study the reaction and it was observed that different substituted

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• method for the regioselective thiolation of aromatic C–H bonds by activating the thiol rather than the arene [19]. For their developed reaction, Pt electrodes were used in an undivided cell with a mixture of HFIP/DCE 3:1 at room temperature under argon. Late-stage functionalization was demonstrated for

HFIP as a versatile solvent in resorcin[n]arene synthesis

• Hormoz Khosravi,
• Valeria Stevens and
• Raúl Hernández Sánchez

Beilstein J. Org. Chem. 2024, 20, 2469–2475, doi:10.3762/bjoc.20.211

• Hormoz Khosravi Valeria Stevens Raul Hernandez Sanchez Department of Chemistry, Rice University, 6100 Main St., Houston, Texas 77005, USA Rice Advanced Materials Institute, Houston, Texas 77005, USA 10.3762/bjoc.20.211 Abstract Herein, we present 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as an

• tolerated. This method leads to a variety of 2-substituted resorcin[n]arenes in a single synthetic step with isolated yields up to 98%. Keywords: cavitand; cyclization; HFIP; hydroxyalkylation; resorcinarenes; Introduction The acid-catalyzed aldehyde-resorcinol condensation has been studied for more than

• ]; and 3) access to larger macrocycles with n > 4 is not a trivial task usually leading to reaction yields <10% [21][38][42][60]. Herein, we report 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as an efficient solvent to speed up reaction times and also capable of tolerating electron-deficient and halogenated

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• -pyridyl)phenol (23) as an activator, 3 equivalents of HFIP and a slightly different catalyst, 3,3’-bis(3,5-bis(trifluoromethyl)phenyl)-BINOL 21 at 20 mol % loading (Scheme 5). Interestingly, the reaction showed an opposite trend and worked better with Z-geranylboronic acid (14). The scope was tested over

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• general, transition metal catalysts are required to effect efficient NGT to unactivated olefins because iminoiodinanes are insufficiently electrophilic to engage in direct aziridination chemistry. Here, we demonstrate that 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) activates N-arylsulfonamide-derived

• iminoiodinanes for the metal-free aziridination of unactivated olefins. 1H NMR and cyclic voltammetry (CV) studies indicate that hydrogen-bonding between HFIP and the iminoiodinane generates an oxidant capable of direct NGT to unactivated olefins. Stereochemical scrambling during aziridination of 1,2

• described in some group-transfer schemes [23][24][25], and in particular, fluorinated alcohol solvents, such as 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), have been reported to enhance hypervalent iodine reactivity by providing a H-bonding solvent cluster that enhances the electrophilicity of the iodine

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• substrate (1-(diphenylmethylene)-2-(4-nitrophenyl)hydrazine), which displayed three oxidation peaks (0.9, 1.7 and 2.2 V vs Ag+/Ag in HFIP ). The authors assumed that the two first peaks would correspond to the oxidation of 8 to 10 and 11 to 12 and that the oxidation of 10 would be responsible for the final

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• reaction still proceeded well, and the corresponding products 2p,q,r were obtained in 69%, 41%, and 40% yield, respectively. Interestingly, when screening solvents for the synthesis of 4-methylisoquinolinones, we were surprised to discover that when hexafluoro-2-propanol (HFIP) was used as the solvent, 3

• of 3-methylisoquinolinone as follows: reacting 1.1 equivalents of PISA in HFIP (0.1 M of 1a) containing 2.5 equivalents of H2O at room temperature for 20 minutes (Scheme 3). The general applicability of PISA in wet HFIP solvent was studied. When R1 was ethyl, isopropyl, cyclopropyl, or hydrogen

• substrate 1c may act as an electrophilic center, forming a C–O bond with the alkenyl group to give the isochromen-1-one oxime product 2c'. When wet HFIP was used as the solvent, the reaction followed a different pathway. HFIP, a strong hydrogen bonding donor [26][27][28], interacts with the amide moiety of

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• , reported that, by using hexafluoroisopropanol (HFIP) as the solvent, GBB adducts derived from glycal aldehydes could be isolated without additional catalysts in a few hours at 25–50 °C [10]. In this case, however, the role of the solvent as a Brønsted acid cannot be ruled out (this article will be

• also in the work reported by Shankar et al. [10], already mentioned in chapter 1. The authors established a solvent-catalyzed GBB-3CR to synthesize glycosylated imidazo[1,2-a]pyridines 33 starting from 1-formyl glycals 32; using HFIP as the solvent, the addition of any metal catalyst was not needed

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• rearrangement between a barbiturate–furan adduct 4 and compound 3n under ambient conditions in dichloromethane and hexafluoro-2-propanol (HFIP). The synthetic procedures and characterization of all newly synthesized compounds, including DA11, DA7, and DA6, are summarized in Supporting Information File 1

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• , undesired dibenzylamine (3a), was obtained as a major product [53]. To suppress the generation of 3a, we examined the effect of solvent (Table 1, entries 6 and 7). When the reaction was performed in a mixed solvent consisting of CH2Cl2 and 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), the yield of 2a increased

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• optimisation campaign. The fluorinated alcohol HFIP was used to dissolve caesium fluoride allowing for the electrochemical benzylic fluorination by Fuchigami, Inagi and co-workers in 2021 (Figure 40) [98]. The HFIP/CsF system functioned as both a fluoride source and as supporting electrolyte, enabling the

• work of Fuchigami, a more general electrochemical method for the nucleophilic fluorination of secondary and tertiary benzylic C(sp3)–H bonds was reported by Ackermann and co-workers in 2022 (Figure 41) [99]. A solvent mixture of DCE and HFIP (2:1) and 12 equivalents of Et3N·3HF resulted in the highest

• yields, with the authors proposing that HFIP aided in stabilising the electrochemically generated benzylic radical cation intermediates. Secondary and tertiary benzylic substrates bearing halogen, ester, protected amine and alkyl functional groups tolerated the reaction conditions well. The authors

Oxidative hydrolysis of aliphatic bromoalkenes: scope study and reactivity insights

• Amol P. Jadhav and
• Claude Y. Legault

Beilstein J. Org. Chem. 2024, 20, 1286–1291, doi:10.3762/bjoc.20.111

• ’. Unfortunately, while it eliminated the side products, it further limited the yield for α-bromoketone, whereas no reactivity was seen when EtOAc and DMA were used as solvents (Table 1, entries 7–9). The use of HFIP led to complete conversion of 1a, but no observation of the desired product 2a (Table 1, entry 10

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• , entry 1). Decreasing or increasing the concentration did not improve the yield of 4aa (Table 1, entries 2 and 3). The reaction became rather sluggish in different solvents such as HFIP and Et2O (Table 1, entries 4 and 5). By reducing the equivalents of 2a to 3 equiv and 2 equiv, the yield of 4aa dropped

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• that the use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent in the isomerisation reaction changes the obtained ratio in favour of the 1,3-cuneane when compared to their alternative solvent system of H2O/MeOH [72]. Iwabuchi and co-workers demonstrated the suitability of 1,3-cuneanes to

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• no impact on the reaction (Table 1, entry 12), the presence of 1.5 equivalents of HFIP slightly improved the yield (Table 1, entry 13). Increasing the amount of styrene in the reaction had no impact (Table 1, entry 14), highlighting that the issue might come from an inefficient trapping of the C

• reduced yields (Table 3, entry 5). We were pleased to see that running the reaction in DME afforded 36% of 4a (Table 3, entry 6). A mixture of DME with HFIP, known to stabilize carbocationic intermediates [56], slightly increased the yield (Table 3, entry 7). DME was selected for further optimization as

• the increased yield with the addition of HFIP was not significant enough to compensate the downside of having an expensive co-solvent. Next, the stoichiometry of the different reaction components was examined. When styrene (1a) was used as limiting reagent instead of Ts-ABZ (3), a slightly higher

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• slight inhibitory effect that does not change significantly with concentration. Addition of 5 μL hexafluoroisopropanol (HFIP) slows the reaction. Additional HFIP disrupts catalytic reactivity almost completely; none of the expected product 3a was detectable after 1.6 hours in the presence of 55 μL HFIP

• . Acetonitrile is similarly detrimental to reaction rates. As discussed above, decomposition with catalysts supported by Ph3P show a diagnostic peak in the 31P NMR spectrum for (Ph3P)2Au+ (45 ppm). Deactivation with HFIP does not reveal a peak for the bisphosphine complex 7a, so we are uncertain of the mechanism

• uniquely beneficial – no other additives worked as well. Strategies to improve gold catalysis often center on enhancing protodeauration, and in studies of a vinylgold intermediate, HFIP was capable of mediating protodeauration while acetic acid was not [62]. Neutral alcohols are not acidic enough to