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

• . For example, Liu and colleagues demonstrated the electrochemical oxidation of benzylic C–H bonds to ketones using tert-butyl hydroperoxide as the radical initiator [14]. This method was applied to functionalize bioactive molecules, with celestolide, ibuprofen methyl ester, and papaverine being

• direct activation of C(sp3)–H bonds under mild conditions [17]. The pronounced electron-deficient W2C nanocatalysts greatly facilitate the direct deprotonation process, ensuring the longevity of the electrode by overcoming self-oxidation. The LSF of drug molecules such as ibuprofen methyl ester and

• including ibuprofen, febuxostat, and gemfibrozil, achieving moderate to good yields. The proposed mechanism involves the oxidation and deprotonation of NHPI at the cathode to form phthalimide-N-oxyl (PINO) radicals. These PINO radicals act as HAT reagents, abstracting a hydrogen atom from the Si–H bond of

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

• in this procedure, giving product 3q in 21% yield (see Supporting Information File 1, Figure S1 for other challenging substrates). Finally, ibuprofen-derived olefin 1r underwent aziridination to afford 3r in 31% yield. Overall, these results highlight the efficacy of a simple activation protocol and

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

• showed they were able to scale-up and selectively fluorinate the ibuprofen methyl ester at the methylene group to produce over 2 g of product 12. The utility of the benzyl fluoride products as strategic intermediates for benzylation of electron-rich arenes was demonstrated by the authors (Figure 41B

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• method, we conducted the reaction with ibuprofen on a 3.0 mmol scale and obtained product 3 in 78% isolated yield. More importantly, the extremely mild reaction conditions imparted by the combination of electrochemistry and photochemistry made accessible a broad range of products with functionalities

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

• % 19F NMR yields, respectively. Furthermore, the widely available drug molecules naproxen and ibuprofen could be efficiently converted into their acyl fluoride derivatives 2k and 2l in 97% and quantitative yields, respectively. To improve the practicality of the methodology and to avoid the often

• carboxyl α-position. Finally, to assess the influence of the reaction on the stereochemical integrity of chiral carboxylic acid substrates, the deoxyfluorination was performed on the enantiopure (S)-isomer of ibuprofen (er = 99:1). Pleasingly, efficient conversion to the corresponding amide (S)-5l was

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• . The photo-electro methodology allowed the late-stage functionalization of valuable bioactive molecules, and the structures of a adapalene precursor (65) and ibuprofen derivative (66) were successfully azidated in moderate yields (Scheme 23C). Some silylated compounds like 67 have proven to be

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• , azidated N-protected memantine 13a was successfully generated by employing electricity and visible-light irradiation in the presence of a Mn catalyst. High regioselectivity was observed at tertiary or benzylic positions (see 13a–c). For commercially available drug derivatives, methyl esters of ibuprofen

• molecules bearing unactivated Csp3–H bonds facilitated by electricity (Scheme 5) [43]. Several pharmaceutically active molecules were committed to the external oxidant-free reaction conditions and were shown to undergo chemoselective azidation. Azidation of ibuprofen methyl ester (14a) was selective for the

• secondary benzylic position over the tertiary. Similar regioselectivity pattern of ibuprofen methyl ester (14a) and celestolide (14b) was observed in a study on manganese-catalyzed isocyanation [44]. Moreover, (−)-menthol acetate (14c) was successfully azidated, indicating that azidation favors tertiary C–H

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• products (10–20%) was observed in several cases indicating the competitive attack of the isocyanate by adventitious water followed by the reaction of the resulting amine with a second isocyanate molecule. Consistent with the expectations, substituted phenylacetic acids such as ibuprofen showed an increased

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• ibuprofen, through sequential oxidation of the product with NaBO3·4H2O and Jones reagent. The catalytic cycle includes formation of (L)Cu-O-t-Bu (366) which then reacts with B2R2 (310, B2mpd2) to form (L)Cu–BR (367). The reaction of this species with the olefin 307 afforded a borylcuprated intermediate 368

Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid

• Kaj M. van Vliet,
• Nicole S. van Leeuwen,
• Albert M. Brouwer and
• Bas de Bruin

Beilstein J. Org. Chem. 2020, 16, 398–408, doi:10.3762/bjoc.16.38

• compound, with applications ranging from thickening agents (carboxymethyl cellulose, E466) [1][2], herbicides (2,4-dichlorophenoxyacetic acid), cosmetics (cocamidopropyl betaine), dyes (indigo vat dye) [3], to pharmaceuticals (ibuprofen, glycine, malonates) [4] (see Figure 1). Many reactions with

Selective benzylic C–H monooxygenation mediated by iodine oxides

• Kelsey B. LaMartina,
• Haley K. Kuck,
• Linda S. Oglesbee,
• Asma Al-Odaini and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2019, 15, 602–609, doi:10.3762/bjoc.15.55

• conditions cleanly yielded monooxidized acetate esters 3b and 3c in 70 and 72% yield, respectively. Bibenzyl and 1-ethylnaphthalene were also oxidized in reasonable yield to acetate esters 3i and 3h. The oxidation of the biologically active ibuprofen methyl ester yielded the secondary acetate 3k in 78% yield

Hypervalent iodine(III)-mediated decarboxylative acetoxylation at tertiary and benzylic carbon centers

• Kensuke Kiyokawa,
• Daichi Okumatsu and
• Satoshi Minakata

Beilstein J. Org. Chem. 2018, 14, 1046–1050, doi:10.3762/bjoc.14.92

• example, commercially available arylpropanoic acids, which include ibuprofen (1m) and loxoprofen (1n), underwent decarboxylative acetoxylation in a highly efficient manner. It should be noted that, although benzylic C–H bonds are frequently incompatible with oxidative conditions, no products derived from

Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review

• Vânia André,
• Sílvia Quaresma,
• João Luís Ferreira da Silva and
• M. Teresa Duarte

Beilstein J. Org. Chem. 2017, 13, 2416–2427, doi:10.3762/bjoc.13.239

• biomedical applications [128]. Having in mind the synthesis of BioMOFs involving the excipient magnesium oxide initially proposed by Byrn et al. [129], Chow et al. and Friščić et al. developed new BioMOFs by LAG, grinding together MgO with the non-steroidal anti-inflammatory drugs (NSAIDS) ibuprofen (S and

• -101(Cr) involving heating which was successfully tested for the incorporation of ibuprofen. In this case, mechanochemistry proved once again to be a much faster process than the traditional hydrothermal synthesis that was used to obtain this compound involving solvents and often also hydrofluoric acid

• [140]. The linker used to build MIL-101 is 1,4-benzenedicarboxylic acid. Different applications of MIL-101 have been reported, from which we highlight the delivery of ibuprofen. MIL-101 exhibits a very high capacity of ibuprofen and therefore only very little quantities of MIL-101 are necessary for the

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• representative case studies [11][14] that do not involve any phase separation. Finally, we selected an ibuprofen synthesis protocol as it had an overall residence time significantly less than the conventional approach [60]. Symbols for block diagram and P&ID Translating any chemistry to process at industrial

• : Multistep synthesis for ibuprofen (low overall residence time) In a fascinating approach, recently Sneed and Jamison have reported a multistep synthesis for ibuprofen with a total residence time of the entire process approximately equal to 3 minutes [60] (Scheme 5). The process involves three reaction steps

• and carried further saponification of the ester intermediate in another tubular reactor at 90 °C and 1 min residence time. The entire process is carried out at 200 psi pressure and the yield of the target product ibuprofen is reported to be 83%. This report has been among the most eye-popping works in

Dynamics and interactions of ibuprofen in cyclodextrin nanosponges by solid-state NMR spectroscopy

• Monica Ferro,
• Franca Castiglione,
• Nadia Pastori,
• Carlo Punta,
• Lucio Melone,
• Walter Panzeri,
• Barbara Rossi,
• Francesco Trotta and
• Andrea Mele

Beilstein J. Org. Chem. 2017, 13, 182–194, doi:10.3762/bjoc.13.21

• solutions of ibuprofen sodium salt (IbuNa) affording hydrogels that, after lyophilisation, gave two solid CDNS-drug formulations. 1H fast MAS NMR and 13C CP-MAS NMR spectra showed that IbuNa was converted in situ into its acidic and dimeric form (IbuH) after freeze-drying. 13C CP-MAS NMR spectra also

• reported matched the information from powder X-ray diffraction profiles. Keywords: cross-polarization; cyclodextrin; ibuprofen; nanosponges; solid-state NMR; Introduction In the last ten years cyclodextrin nanosponges (CDNS) polymer materials received great attention as promising new materials in several

• nanoporous polymer structure influences the delivery property of entrapped drugs [8]. In particular the transport properties of ibuprofen sodium salt (IbuNa) entrapped in CDNS polymer gels has been investigated by high resolution magic angle spinning (HR-MAS) NMR technique [9] as a paradigmatic case of an

Stabilization of nanosized titanium dioxide by cyclodextrin polymers and its photocatalytic effect on the degradation of wastewater pollutants

• Tamás Zoltán Agócs,
• István Puskás,
• Erzsébet Varga,
• Mónika Molnár and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2016, 12, 2873–2882, doi:10.3762/bjoc.12.286

• carboxymethyl β-cyclodextrin polymer (CMBCD-P) for stabilization of nanoTiO2 dispersions. The photocatalytic degradation of methylene blue and ibuprofen as model organic pollutants in various media (distilled water, NaCl solution and tap water) has been studied using nanoTiO2 as catalyst stabilized by CMBCD-P

• . CMBCD-P itself showed a catalytic effect on the UV degradation of methylene blue. In addition to enhancing the colloid stability of nanoTiO2 CMBCD-P showed also synergistic effects in catalyzing the photodecomposition process of the dye. On the other hand, ibuprofen as a model pharmaceutical, a

• pollutant of emerging concern (EP), was protected by CMBCD-P against the photocatalytic degradation showing that inclusion complex formation can result in opposite effects depending on the structure of the host–guest complex. Keywords: carboxymethyl β-cyclodextrin polymer; colloid stability; ibuprofen

The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot

• Philip J. Kitson,
• Stefan Glatzel and
• Leroy Cronin

Beilstein J. Org. Chem. 2016, 12, 2776–2783, doi:10.3762/bjoc.12.276

• was used to 3D print reaction vessels (reactionware) of differing internal volumes using polypropylene feedstock via a fused deposition modeling 3D printing approach and subsequently make use of these fabricated vessels to synthesize the nonsteroidal anti-inflammatory drug ibuprofen via a consecutive

• one-pot three-step approach. The synthesis of ibuprofen could be achieved on different scales simply by adjusting the parameters in the robot control software. The software for controlling the synthesis robot was written in the python programming language and hard-coded for the synthesis of ibuprofen

• by the method described, opening possibilities for the sharing of validated synthetic ‘programs’ which can run on similar low cost, user-constructed robotic platforms towards an ‘open-source’ regime in the area of chemical synthesis. Keywords: 3D printing; digitising chemistry; ibuprofen; laboratory

Synthesis of α,β-unsaturated esters via a chemo-enzymatic chain elongation approach by combining carboxylic acid reduction and Wittig reaction

• Yitao Duan,
• Peiyuan Yao,
• Yuncheng Du,
• Jinhui Feng,
• Qiaqing Wu and
• Dunming Zhu

Beilstein J. Org. Chem. 2015, 11, 2245–2251, doi:10.3762/bjoc.11.243

• aromatic and aliphatic carboxylic acids, including ibuprofen. The Mycobacterium CAR catalyzed carboxylic acid reduction to give aldehydes, followed by a Wittig reaction to afford the products α,β-unsaturated esters with extension of two carbon atoms, demonstrating a new chemo-enzymatic method for the

• its saturated counterpart (7a). Interestingly, Mycobacterium CAR could effectively reduce ibuprofen (20a) more effectively than NiCAR and SrCAR, but it was not enantioselective. Rac-13a, rac-14a and rac-15a (5 mM) were almost completely transformed by Mycobacterium CAR (100 µg), suggesting it had no

• new CAR from Mycobacterium sp. was successfully cloned, overexpressed and identified. It exhibited a broad substrate spectrum and was active toward both aliphatic and aromatic carboxylic acids, including ibuprofen. Other functional groups such as keto groups and C=C double bonds remained unaffected

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• step approach towards ibuprofen (16) using microreactor technology [48]. A fully continuous process was aspired to, in which only final purification was to be performed off-line at the end of the sequence. Each of the individual steps were first optimised in flow being mindful of the reagents used in

• ibuprofen (16). Work-up, via acidification and repeated washes with ether, water and brine, followed by filtration, evaporation, treatment with active carbon and finally recrystallisation was performed manually to eventually yield pure ibuprofen product (99%). Overall this pioneering work allowed for the

• synthesis of ibuprofen in only ten minutes residence time albeit in a yield of only 51% equating to a productivity of 9 mg/min. Although this work nicely demonstrates the feasibility of constructing a continuous process it is mainly an academic proof of principle based upon an important well known molecule

Synthesis of modified cyclic and acyclic dextrins and comparison of their complexation ability

• Kata Tuza,
• László Jicsinszky,
• Tamás Sohajda,
• István Puskás and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2014, 10, 2836–2843, doi:10.3762/bjoc.10.301

• ; cyclodextrin; ibuprofen; maltodextrin; maltoheptaose; maltohexaose; maltooctaose; Introduction The complexing ability of amylose to iodine and fatty acids is well known in the literature [1][2][3]. The question is raised whether the maltooligomers containing 6, 7, or 8 glucose units (G6, G7 and G8), derived

• of the tested drugs, ibuprofen and nateglinide showed significant interaction with both the cyclic and acyclic analogs. While the apparent binding constant of the ibuprofen/β-CD system is the highest, all the acyclic derivatives showed significant affinity towards this guest irrespective of the

• number of glucopyranose units. Unlike CDs, the number of the glucose units might not be of primary importance in the case of ibuprofen/acyclodextrin interactions. An even more surprising finding was observed for nateglinide, as the highest interaction affinity was determined with the G6 acyclic dextrin

Anomalous diffusion of Ibuprofen in cyclodextrin nanosponge hydrogels: an HRMAS NMR study

• Monica Ferro,
• Franca Castiglione,
• Carlo Punta,
• Lucio Melone,
• Walter Panzeri,
• Barbara Rossi,
• Francesco Trotta and
• Andrea Mele

Beilstein J. Org. Chem. 2014, 10, 2715–2723, doi:10.3762/bjoc.10.286

• .10.286 Abstract Ibuprofen sodium salt (IP) was encapsulated in cyclodextrin nanosponges (CDNS) obtained by cross-linking of β-cyclodextrin with ethylenediaminetetraacetic acid dianhydride (EDTAn) in two different preparations: CDNSEDTA 1:4 and 1:8, where the 1:n notation indicates the CD to EDTAn molar

• potential use in therapy. In this work we present a study based on HRMAS NMR spectroscopy on the transport properties of Ibuprofen sodium salt (IP) confined in CDNSEDTA nanosponge hydrogels. Here, two different formulation of the nanosponges are investigated, characterized by a different CD/cross linker

• ) giving two different products (Scheme 1). Drug loading and NMR samples preparation The encapsulation of IP in CDNSEDTA 1:4 and CDNSEDTA 1:8 for the preparation of the loaded gels for HRMAS NMR analysis was done in three steps: (1) A 0.27 M stock solution of Ibuprofen sodium salt was prepared by

Improving ITC studies of cyclodextrin inclusion compounds by global analysis of conventional and non-conventional experiments

• Eléonore Bertaut and
• David Landy

Beilstein J. Org. Chem. 2014, 10, 2630–2641, doi:10.3762/bjoc.10.275

• treatment to competitive and non-competitive experiments for 1:1 Ibuprofen (IBU) complexes which are formed with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HPβ-CD) covering temperature ranges from 283 K to 313 K. These experimental studies were used as starting points for theoretical

• thermodynamic data, not only for easily accessible complexes but also when ITC studies approximate their limits of detection. Experimental Materials Ibuprofen (racemic mixture, sodium salt), sodium hydroxide and potassium dihydrogen phosphate were purchased from Acros Organics. β-CD, HPβ-CD (with a mean of 5.6

Electrocarboxylation: towards sustainable and efficient synthesis of valuable carboxylic acids

• Roman Matthessen,
• Jan Fransaer,
• Koen Binnemans and
• Dirk E. De Vos

Beilstein J. Org. Chem. 2014, 10, 2484–2500, doi:10.3762/bjoc.10.260

• ibuprofen. A nafion membrane is used, allowing a selective passage of protons and tetraalkylammonium cations from the anolyte to the catholyte. Cyclohexene is added to the anolyte to scavenge the anodically formed bromine. A current efficiency of up to 90% was reached with a copper cathode and graphite