An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• by activation with HBTU and then subsequent reaction with the amine 18 (Scheme 4). These amides 17 were designed to have molecular properties (mw, cLogP, tPSA, HBD, pKa) consistent with CNS drug-like space [20]. Although significant Notum inhibition activity could be achieved (IC50 < 100 nM), none of

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• -indanedione (2c), malononitrile (2e), 4-cyanomethyl-2,3,5,6-tetrafluorobenzonitrile (2f) were successfully applied as active methylene compounds; all of them have pKa values between 4.70 (2b, in dioxane/H2O 3:1 [20]) and ≈15.80, reported for 2-(pentafluorophenyl)acetonitrile in DMSO [21], the value for 2f

• was obtained from 1,1,1,5,5,5-hexafluoropropane-2,4-dione (pKa 2.30 in DMSO) and dimedone (pKa 11.42 in DMSO). Figure 1 also shows that 3-aryl- as well as various 3-alkyl-substituted propiolamides 1 furnish betaines 3 in high yields. A separate case was observed for 3-trimethylsilylpropiolamide 1f

1,2,3-Triazolium macrocycles in supramolecular chemistry

• Mastaneh Safarnejad Shad,
• Pulikkal Veettil Santhini and
• Wim Dehaen

Beilstein J. Org. Chem. 2019, 15, 2142–2155, doi:10.3762/bjoc.15.211

• also determined the dissociation constant pKa of this acid−base switchable MIM system by an indicator method which could make a quantitative and precise estimation of its dynamics with environmental acidity change. By combining NMR spectroscopic data and quantum chemistry calculations, a motion

Enantioselective PCCP Brønsted acid-catalyzed aza-Piancatelli rearrangement

• Gabrielle R. Hammersley,
• Meghan F. Nichol,
• Helena C. Steffens,
• Jose M. Delgado,
• Gesine K. Veits and
• Javier Read de Alaniz

Beilstein J. Org. Chem. 2019, 15, 1569–1574, doi:10.3762/bjoc.15.160

• (Figure 1) [38]. First, the pKa values measured in acetonitrile (MeCN) are lower than chiral phosphoric acids (Brønsted acid pKa = 8.85 vs chiral phosphoric acids pKa = 12–14) [38]. Given the enhanced acidity, we reasoned that this type of chiral Brønsted acid catalyst could facilitate the dehydration

Host–guest interactions between p-sulfonatocalix[4]arene and p-sulfonatothiacalix[4]arene and group IA, IIA and f-block metal cations: a DFT/SMD study

• Valya K. Nikolova,
• Cristina V. Kirkova,
• Silvia E. Angelova and
• Todor M. Dudev

Beilstein J. Org. Chem. 2019, 15, 1321–1330, doi:10.3762/bjoc.15.131

• descriptors of the group IA, IIA and f-block metal cations binding to the host calixarene systems have been evaluated and the factors that affect the interactions in the gas phase and in water medium have been unraveled. Available data on the experimental pKa values [31][33][34] imply that in acidic water

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• ) complexes [56]. The above considerations lead to the use of β-ketosulfones in the Ni(II)-catalyzed reaction, since the proposed mechanism [47], that involves the formation of cyclic Ni enolate, and the high CH acidity of ketosulfones (pKa 9.8–10.5 [4]). The formation of the key intermediate can be provided

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• linkers for ODN synthesis [40][41]. Due to the low acidity of H-2 (pKa ≈31) in the Dmoc function, these groups and linkers were expected to be stable under ODN synthesis conditions. However, once the dithioketal in the group is oxidized, the acidity of H-2 (pKa ≈12) is drastically increased [42][43

• ]. Considering that the widely used Fmoc protecting group, of which the H-9 has a pKa of ≈22 [42], can be readily removed with a weak base such as piperidine, we hypothesized that the oxidized Dmoc groups and linkers could be cleaved under weakly basic and non-nucleophilic conditions via β-elimination. Indeed

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

• -methylpyridine (89.7 versus 87.2 kcal/mol, respectively) [56]. Moreover, the electron withdrawing nature of the pyrimidine nitrogen atoms will affect the pKa of the adjacent secondary benzylic C–H bonds. The hydrogen atom abstraction from this position would then be influenced by the pKa of the C–H bond via a

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• +, NMN and NAD+ are readily hydrolyzed to Nam, with their rapid decomposition particularly promoted by heat and basic aqueous solutions (pH ≥ 8). Under non-buffered conditions, the hydrolysis of the glycosidic bond leads to the release of Nam, which possesses a pKa at 3.35 [47]. The release of Nam

Computational characterization of enzyme-bound thiamin diphosphate reveals a surprisingly stable tricyclic state: implications for catalysis

• Ferran Planas,
• Michael J. McLeish and
• Fahmi Himo

Beilstein J. Org. Chem. 2019, 15, 145–159, doi:10.3762/bjoc.15.15

• same manner. Of course, while the relative stability of the TC form may slow down the BFDC reaction, it is conceivable that it may also play a beneficial role. As the pKa of the C2 proton decreases, the activity of the ThDP cofactor increases [62]. However, concomitantly, the thiazolium ring becomes

A convenient and practical synthesis of β-diketones bearing linear perfluorinated alkyl groups and a 2-thienyl moiety

• Ilya V. Taydakov,
• Yuliya M. Kreshchenova and
• Ekaterina P. Dolotova

Beilstein J. Org. Chem. 2018, 14, 3106–3111, doi:10.3762/bjoc.14.290

• developed two new mild protocols for the regeneration of diketones (Scheme 3). A vigorously stirred or shaken two-phase mixture of EtOAc and an aqueous solution of the reagent were used, and a finely ground solid Cu chelate was added to it in small portions. The choice of the reagent depends on the pKa of

1,8-Bis(dimethylamino)naphthyl-2-ketimines: Inside vs outside protonation

• A. S. Antonov,
• A. F. Pozharskii,
• P. M. Tolstoy,
• A. Filarowski and
• O. V. Khoroshilova

Beilstein J. Org. Chem. 2018, 14, 2940–2948, doi:10.3762/bjoc.14.273

• rotation of the NH2+ fragment in dications. Keywords: hydrogen bond; imine; NMR; proton sponge; superbase; Introduction It is well known that the extremely high basicity of 1,8-bis(dimethylamino)naphthalene (1, DMAN; pKa = 12.1 in H2O [1][2], 18.62 in MeCN [3], 7.5 in DMSO [4]) and its derivatives

• sponge moiety: for example, the basicity of benzophenone imine (pKa = 6.82) and even that of cyclohexanone imine (pKa = 9.15) [12] is much lower than that of DMAN (pKa = 12.1) [1][2]. Moreover, as it was already mentioned in the introduction, this is the third known example of a DMAN derivative with a

An overview on recent advances in the synthesis of sulfonated organic materials, sulfonated silica materials, and sulfonated carbon materials and their catalytic applications in chemical processes

• Hashem Sharghi,
• Pezhman Shiri and
• Mahdi Aberi

Beilstein J. Org. Chem. 2018, 14, 2745–2770, doi:10.3762/bjoc.14.253

• commercial strong acids with pKa-values of −1.9 and −2.8, respectively, which are regularly used as simplest and more usable catalysts in chemical reactions. MSA is almost completely ionized at a concentration of 0.1 M in an aqueous solution. The oxidative stability of organic compounds and metal ions in MSA

Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• constant of 14 [11]. It is slightly basic, with a pKa lower than 1 for the Co–H complex [12]. The “supernucleophilic” cob(I)alamin is found in many enzymes such as methionine synthetases, adenosyltransferases, and reductive dehalogenases. In addition, the reactivity of cob(I)alamin has been investigated

Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• pKa values. In both macrocycles the UV maxima are bathochromically shifted (273 to 301 nm) for 4 and 261 to 294 nm for 8 (Supporting Information File 1, Figure S1). Also, the pKa values are affected by the cyclization. In case of dU (9.3) a decrease to 8.7 [35] for 6 and further to 8.2 for cyclic dU 8

• is observed (Supporting Information File 1, Figure S2). This might go back to stacking interactions of the nucleobase and the triazole residue. A similar relationship exists in the dC series with values of 4.2 for dC and 3.0 for 1 [35]. In contrast the pKa for cyclic dC 4 (3.2) did not further

Dynamic light scattering studies of the effects of salts on the diffusivity of cationic and anionic cavitands

• Anthony Wishard and
• Bruce C. Gibb

Beilstein J. Org. Chem. 2018, 14, 2212–2219, doi:10.3762/bjoc.14.195

• titration with various halide salts. The fifteen salts studied were a matrix of the alkali metal cations Li+, Na+, K+, and Cs+ in combination with the halides F− through I−, the one omission being poorly soluble lithium fluoride (maximum solubility = 0.134 g mL−1). Unsurprisingly, given the pKa values of

• -solubilizing group. Although its pKa may not be optimal for deprotonation at neutral or physiological pH, its small size and relatively high free energy of hydration (−373 kJ mol−1) ensure that ion-pairing effects are not strong. This was further confirmed by 1H NMR spectroscopy (Supporting Information File 1

Cobalt-catalyzed nucleophilic addition of the allylic C(sp³)–H bond of simple alkenes to ketones

• Tsuyoshi Mita,
• Masashi Uchiyama,
• Kenichi Michigami and
• Yoshihiro Sato

Beilstein J. Org. Chem. 2018, 14, 2012–2017, doi:10.3762/bjoc.14.176

• species (Figure 1). However, the substrates employed have been restricted to allylarenes and 1,4-enyne, and 1,4-diene derivatives and α-olefins were totally unexplored. Therefore, the next challenge would be to use less reactive α-olefins (pKa value of 1-propene = 43). In this paper, we describe an

• 1-undecene (1a) but also 1-octadecene (1b) and 6-phenyl-1-hexene (1c) were tolerable to afford the corresponding products in around 70% yield with perfect branch selectivity (Figure 3). Although the allylic C(sp3)–H bond of α-olefins is weakly acidic (pKa value of 1-propene = 43), it is noteworthy

Rational design of boron-dipyrromethene (BODIPY) reporter dyes for cucurbit[7]uril

• Mohammad A. Alnajjar,
• Jürgen Bartelmeß,
• Robert Hein,
• Pichandi Ashokkumar,
• Mohamed Nilam,
• Werner M. Nau,
• Knut Rurack and
• Andreas Hennig

Beilstein J. Org. Chem. 2018, 14, 1961–1971, doi:10.3762/bjoc.14.171

• motifs for CB7. The unprotonated dyes show low fluorescence due to photoinduced electron transfer (PET), whereas the protonated dyes are highly fluorescent. Encapsulation of the binding motif inside CB7 positions the aniline nitrogen at the carbonyl rim of CB7, which affects the pKa value, and leads to a

• host-induced protonation and thus to a fluorescence increase. The possibility to tune binding affinities and pKa values is demonstrated and it is shown that, in combination with the beneficial photophysical properties of BODIPYs, several new applications of host–dye reporter pairs can be implemented

• investigate their complexation behaviour with CB7. The goal was to explore the suitability of this approach, the possibility to fine-tune binding constants with different anchor groups and to provide BODIPYs with different absorption and emission wavelengths as well as pKa values of the aniline substituent

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions

• Siva Sankar Murthy Bandaru,
• Darinka Dzubiel,
• Heiko Ihmels,
• Mohebodin Karbasiyoun,
• Mohamed M. A. Mahmoud and
• Carola Schulzke

Beilstein J. Org. Chem. 2018, 14, 1871–1884, doi:10.3762/bjoc.14.161

• initial broad long wavelength absorption (Figure 5A). The emission intensity of derivative 2c increased by a factor of 250 with decreasing pH value (Figure 5B). The pKa value of the protonated amine 2c in water was determined from the titration curve to be 3.1 which is in the same range as the ones of 9

• -(p-amino)phenylacridinium ions (pKa = 2.5–3.5) [49][50] and the dimethylaminophenyl-substituted benzo[b]quinolizinium ion [34] (pKa = 3.8). Photometric and fluorimetric DNA titrations of 9-(arylethynyl)benzo[b]quinolizinium derivatives 2a–d The interactions of the arylethynylbenzoquinolizinium

Design, synthesis and structure of novel G-2 melamine-based dendrimers incorporating 4-(n-octyloxy)aniline as a peripheral unit

• Cristina Morar,
• Pedro Lameiras,
• Attila Bende,
• Gabriel Katona,
• Emese Gál and
• Mircea Darabantu

Beilstein J. Org. Chem. 2018, 14, 1704–1722, doi:10.3762/bjoc.14.145

• amides [64], no such vicinal effect created by a quaternary EWG of type >Nsp3H2+ [63] was detected in the piperazine P-1 linker of compounds 7b, 8 and 9, even in the case of the strongest proton donor, the trimesic acid (pKa = 3.12, 3.89 and 4.70). In addition, only in G-1 amino-dendron D-N

  NH the 1H

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• or secondary alcohols, while the nucleophilic species needs to be acidic [13] with a pKa < 11. Otherwise the azo reagent would compete with the acidic nucleophile and participate in the substitution reaction [14]. Various compounds comply with that condition: carboxylic acids, phenols, hydrazoic acid

• -chloroacetyl-D-glucose (30) as well as its galacto-configured analogue with the carboxylic acids 31–34 to obtain products 35–38 which are related to various pesticide agents (Scheme 6). Their results supported the theory that, along with an effect of the reaction temperature, an increase of the pKa of the

• authors state that the observed pKa effect is either due to the influence of the acidity of the employed acid on the reaction mechanism or results from the proton-catalyzed change of the anomeric ratio of the starting material 30 in solution. Very recently, anomeric phosphorylation via a Mitsunobu

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• substituent (3-quinolinyl nitrogen forming a hydrogen bond with a guanine amino group at the base of the minor groove) and a low pKa tail group. This drug was further selected for the treatment of Gram-positive bacteria Clostridium difficile infections and is currently in the phase II clinical trials

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• pseudorotation has almost exclusively used in mechanistic discussion of RNA cleavage. The stability of the phosphorane intermediate largely depends on its state of protonation. The first pKa value of the acyclic tetraalkoxy monohydroxy phosphorane has been estimated to be 8.6 for an equatorial hydroxy group and

• 13.5 for an apical group [22]. For a cyclic phosphorane derived from ethylene phosphate, the first pKa value is 7.9 and the second 14.3, both values referring to an equatorial hydroxy ligand [23]. Accordingly, both neutral phosphorane and its monoanion are present in significant amount at physiological

• activation free energy, ΔG‡ (or log k), against the change in standard free energy of the reaction, ΔGo (or log Keq). The latter quantity is often difficult, sometimes even impossible, to determine. For this reason, ΔG‡ (or log k) is more frequently plotted as a function of the pKa of the departing (or

An uracil-linked hydroxyflavone probe for the recognition of ATP

• Márton Bojtár,
• Péter Zoltán Janzsó-Berend,
• Dávid Mester,
• Dóra Hessz,
• Mihály Kállay,
• Miklós Kubinyi and
• István Bitter

Beilstein J. Org. Chem. 2018, 14, 747–755, doi:10.3762/bjoc.14.63

• , the spectra of UHF and UHF∙ATP were recorded at different pH values (Figure 4). Since the pKa value of the hydroxy group of the flavones is around 9 [54], no significant deprotonation should occur at pH 7.8. As can be seen in Figure 4, the excitation band of UHF around 400 nm is the same at each pH

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• (kcov/khydr), when reacting with an RNA primer. It will not be trivial to find such a leaving group, as the nucleophilicity of alcohols is quite similar to that of water, so that it is difficult to utilize the chemoselectivity toward reaction partners with different softness, pKa, or other structural