Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• strategic positions in a drug candidate may result in not only an increase in its potency, but also, perhaps more importantly, bring about an enhanced pharmacokinetic profile resulting in a more “drug-like” molecule [4]. Subtle changes in physicochemical properties such as acidity/basicity, lipophilicity

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• using ethyl fluoroacetate as the internal standard. Initially, the effect of Brønsted acidity was explored by varying the amine/HF ratio with mixtures of commercially available NEt3/HF 1:3 and Olah’s reagent (pyr/HF 1:9.23). Lower amine/HF ratios (1:4.5) resulted in poor conversion (9% yield, Table 1

• , entry 1), whereas increasing the Brønsted acidity to 1:7.5 furnished the desired α-fluoroketone 2 in 64% yield (Table 1, entry 2). However, employing Olah’s reagent (1:9.23) had a negative impact on the efficiency (45% yield, Table 1, entry 3) thereby allowing a plateau to be established (vide infra

• ). Having established that an amine/HF ratio of 1:7.5 provides the optimal Brønsted acidity for catalysis, a solvent screen was conducted to assess the effect of the reaction medium. Chlorinated solvents proved to be most effective, with reactions performed in CHCl3 slightly outperforming those in CH2Cl2

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• 143. A proton transfer generated hydroxyalkanethiolates 144 because the acidity of the thiols is higher than that of alcohols, the newly generated thiolates 144 underwent an intramolecularly nucleophilic displacement to give thietane-3-ols 145 [56] (Scheme 28). In a similar approach

Highly selective Diels–Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole

• Carlos H. Escalante,
• Eder I. Martínez-Mora,
• Carlos Espinoza-Hicks,
• Alejandro A. Camacho-Dávila,
• Fernando R. Ramos-Morales,
• Francisco Delgado and
• Joaquín Tamariz

Beilstein J. Org. Chem. 2020, 16, 1320–1334, doi:10.3762/bjoc.16.113

• similar chemoselectivity has been previously observed, being explained as a consequence of the acidity of the C–H bond being cleaved [6][44]. Additional intramolecular cross-coupling reactions were carried out by utilizing dimethyl malonates 8k and 8l, which were prepared through the N-benzylation of 16c

The charge-assisted hydrogen-bonded organic framework (CAHOF) self-assembled from the conjugated acid of tetrakis(4-aminophenyl)methane and 2,6-naphthalenedisulfonate as a new class of recyclable Brønsted acid catalysts

• Svetlana A. Kuznetsova,
• Alexander S. Gak,
• Yulia V. Nelyubina,
• Vladimir A. Larionov,
• Han Li,
• Michael North,
• Vladimir P. Zhereb,
• Alexander F. Smol'yakov,
• Artem O. Dmitrienko,
• Michael G. Medvedev,
• Igor S. Gerasimov,
• Ashot S. Saghyan and
• Yuri N. Belokon

Beilstein J. Org. Chem. 2020, 16, 1124–1134, doi:10.3762/bjoc.16.99

• Supporting Information File 1) to be 4.94, 4.46, 4.04, and 3.79. Thus, the difference in the acidity of the NDS and TAPM components was large enough to ensure a complete salt formation. Solid F-1 was practically insoluble in organic solvents with the exception of DMSO. The analytical data supported its

• . However, the framework F-1 underwent “breathing” in organic solvent solutions (see below), which allowed catalytic sites to become available without the need for a pore structure in the desolvated material. The calculated acidity of the components of F-1 (see above) indicated possible catalytic

• incorporating multitopic tectons with a greater number of negatively charged sulfonate groups mutually rigidly fixed in space. Such arrangement should produce large pores within the framework and further reduce the framework’s solubility in water and organic solvents. Additionally, the acidity of these

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

• size of fluorine, the next in size to hydrogen. However, the high electronegativity of the fluorine leads to low polarizability and a strong covalent bond to carbon [1][2][3][4]. Therefore, the introduction of fluorine into phenylalanine (Phe) can modulate the acidity, basicity, hydrophobicity

• the properties of peptides and proteins [5][6][7], influencing aspects such as protein folding, protein–protein interactions, ribosomal translation, lipophilicity, acidity/basicity, optimal pH, stability, thermal stability, and therapeutic properties [8][9][10]. This extends to metabolic properties of

Efficient synthesis of piperazinyl amides of 18β-glycyrrhetinic acid

• Dong Cai,
• ZhiHua Zhang,
• Yufan Meng,
• KaiLi Zhu,
• LiYi Chen,
• ChangXiang Yu,
• ChangWei Yu,
• ZiYi Fu,
• DianShen Yang and
• YiXia Gong

Beilstein J. Org. Chem. 2020, 16, 798–808, doi:10.3762/bjoc.16.73

• factor is that the acidity of chloroacetic acid (pKa = 2.87) was stronger than that of acetic acid (pKa = 4.76). The procedure for the generation of byproduct 11 was similar to N-Boc-deprotection using trifluoroacetic acid. The effective synthesis of compound 10 was then explored (Table 3). In our

Asymmetric synthesis of CF₂-functionalized aziridines by combined strong Brønsted acid catalysis

• Xing-Fa Tan,
• Fa-Guang Zhang and
• Jun-An Ma

Beilstein J. Org. Chem. 2020, 16, 638–644, doi:10.3762/bjoc.16.60

• no enantioselectivity at all. As arylboronic acids have been harnessed to enhance the Brønsted acidity in asymmetric organocatalysis in combination with chiral diols or chiral aminoalcohols [40][41][42][43][44], we envisioned that the simultaneous use of arylboronic acids and chiral Brønsted acids

• limited Brønsted acidity of chiral phosphoric acids. Bearing this in mind, we then turned our attention to chiral disulfonimides developed by List, which have been established as a unique type of stronger Brønsted acids [45]. Putting it into practice, a range of BINOL-derived disulfonimides was used as

• attributed to the increased Brønsted acidity when the strong electron-withdrawing trifluoromethyl group was placed on the benzene ring of the arylboronic acid. Removing the boronic acid from the reaction system leads to a dramatic decrease in both yield and enantiocontrol (Table 1, entry 16). The challenge

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• , Scheme 23) which could only be obtained by using a strong base such as n-BuLi for proton abstraction, probably due to a reduced acidity induced by the positive inductive effect of the substituents. The use of a weaker base such as triethylamine did not result in the targeted compounds and the authors

Why do thioureas and squaramides slow down the Ireland–Claisen rearrangement?

• Dominika Krištofíková,
• Juraj Filo,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2019, 15, 2948–2957, doi:10.3762/bjoc.15.290

• demanding ones, e.g., C6, C9 or C11. In addition, the acidity of the hydrogen-bond-donating moiety also ranges over a rather large area from pKa (H2O) 1 for phosphoric acid C10 to pKa (DMSO) 28 of diols C7 and C8. However, neither steric factors, nor the acidity of the H-bond-donor moiety seemed to play a

Small anion-assisted electrochemical potential splitting in a new series of bistriarylamine derivatives: organic mixed valency across a urea bridge and zwitterionization

• Keishiro Tahara,
• Tetsufumi Nakakita,
• Alyona A. Starikova,
• Takashi Ikeda,
• Masaaki Abe and
• Jun-ichi Kikuchi

Beilstein J. Org. Chem. 2019, 15, 2277–2286, doi:10.3762/bjoc.15.220

• used for anion recognition [27][28][29]. In the oxidized state, the enhanced acidity of NH protons can increase the strength of H-bonds and give them more dynamic properties, which can be useful for refined designs of supramolecular systems [30] and proton-coupled electron-transfer systems [31][32][33

• oxidation from 1 to 1+ (Supporting Information File 1, Figure S5). The enhanced acidity of the NH protons in 1b+, compared to that in 1b, was well predicted by electrostatic potential maps. The positive regions (blue) were found around the two hydrogen atoms of the urea bridge in the electrostatic potential

• 2.75 Å), primarily reflecting the absence of packing in the former. In the optimized structure of 1a+–PF6−, the N–H···F hydrogen-bonding was comparable to that in 1b+–PF6− with regard to the atomic geometry and the N···F distances. The increased acidity of 1 upon one-electron-oxidation enhances the

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• similar to that of hydrogen atoms. Due to these unique properties, the introduction of fluorine into a molecule can cause dramatic changes, such as the acidity or basicity of neighboring groups, dipole moment, and properties such as lipophilicity, metabolic stability, and bioavailability [1]. Consequently

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

• in the literature in which they bind to the anionic species by utilizing multiple noncovalent interactions based on electrostatics, including hydrogen bonding (HB), anion–π interactions [30], and on Lewis acidity/basicity [31]. 2.1. Bile acid-based 1,2,3-triazolium macrocycles Bile acid-based

• density of the triazolium derivative. Rigid macrocycles 12 display selective complexation with I− because of the complementary size of the cavity of the macrocyclic ring and the iodide ion. In addition, the acidity of the inner protons of 12 is higher than the corresponding neutral analogue which also

• 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

Reactions of 2-carbonyl- and 2-hydroxy(or methoxy)alkyl-substituted benzimidazoles with arenes in the superacid CF₃SO₃H. NMR and DFT studies of dicationic electrophilic species

• Dmitry S. Ryabukhin,
• Alexey N. Turdakov,
• Natalia S. Soldatova,
• Mikhail O. Kompanets,
• Alexander Yu. Ivanov,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2019, 15, 1962–1973, doi:10.3762/bjoc.15.191

• AlCl3 and AlBr3 took longer time (24–27 h, Table 3, entries 1, 2, and 4). In some cases, the use of H2SO4 resulted in the formation of oligomeric reaction products in the reaction of 1 with electron donating p-xylene (Table 3, entry 10). Apart from that, the acidity of H2SO4 was not high enough to

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• performed a Cu(OAc)2-Et3N-mediated coupling reaction of α-azido ketones 115 with pyridinium ylides 114 using oxygen as a green oxidant (Scheme 40). The oxo-functionality present in α-azido ketones increased its acidity thus making it a good organic synthon. Optimization of the reaction conditions revealed

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

Superelectrophilic carbocations: preparation and reactions of a substrate with six ionizable groups

• Sean H. Kennedy,
• Makafui Gasonoo and
• Douglas A. Klumpp

Beilstein J. Org. Chem. 2019, 15, 1515–1520, doi:10.3762/bjoc.15.153

• high degree of delocalization into the neighboring phenyl group. Both the trication 3 and the tetracation 4 were directly observed from FSO3H–SbF5 solution using low temperature NMR. Experimental observations also revealed an exceptionally high acidity of the pyridinium N–H bonds. Here, we describe the

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

• organocatalysts [58][59][60][61]. This was explained by the authors as a result of the high CH acidity of the corresponding Michael adducts. The highest reaction rate with good enantioselectivity is achieved using catalyst 7a (Table 1, entry 1). For this reason, further studies were carried out with catalyst 7a

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• optimal acidity to the reaction medium needed for successful protonation of the intermediate azomethine, formed between the aromatic aldehyde 8 and aniline 9, to the corresponding iminium cation and its further transformation involving carboxylic acid 4 and isocyanide 10. As a result, we developed an

Robust perfluorophenylboronic acid-catalyzed stereoselective synthesis of 2,3-unsaturated O-, C-, N- and S-linked glycosides

• Madhu Babu Tatina,
• Xia Mengxin,
• Rao Peilin and
• Zaher M. A. Judeh

Beilstein J. Org. Chem. 2019, 15, 1275–1280, doi:10.3762/bjoc.15.125

• , entry 1). This is attributed to its low acidity. Gratifyingly, the more acidic perflurophenylboronic acid successfully promoted the reaction to give 4,6-di-O-acetyl-2,3-unsaturated glucoside 3a in CH3CN or CH3NO2 solvents (Table 1, entries 3 and 4). It gave better 92% yield of glucoside 3a in CH3NO2

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

Catalytic asymmetric oxo-Diels–Alder reactions with chiral atropisomeric biphenyl diols

• Chi-Tung Yeung,
• Wesley Ting Kwok Chan,
• Wai-Sum Lo,
• Ga-Lai Law and
• Wing-Tak Wong

Beilstein J. Org. Chem. 2019, 15, 955–962, doi:10.3762/bjoc.15.92

• hydroxy and NH units for hydrogen bonding activation, % ee and yields in oxo-DA reactions were found to be enhanced with increasing NH acidity, leading to stronger hydrogen bonds [32]. So, there is much room for further investigation and improvement with other hydrogen bonding organocatalysts. An earlier

• other biphenyl hybrid diols with different steric bulky substituents were incorporated (3 and 4). Since it is known that the catalyst acidity has significant influence on hydrogen-bond-catalyzed reactions [32], we also incorporated a CF3 group in our molecular scaffold to investigate how it would affect

Tuning the stability of alkoxyisopropyl protection groups

• Zehong Liang,
• Henna Koivikko,
• Mikko Oivanen and
• Petri Heinonen

Beilstein J. Org. Chem. 2019, 15, 746–751, doi:10.3762/bjoc.15.70

• (Scheme 2). Experimental data on the acidity of the 5’- and 3’-hydroxy groups of thymidine are not available, but computed NBO charges suggest that the electronic properties of both hydroxy functions are close to each other [10]. Our DFT level calculations indicated that the 3’-hydroxy function is

• slightly more acidic than the 5’-hydroxy group, but absolute values for the acidity constants could not be reliably determined. The hydrolysis of the acetals is suggested to follow most often the A-1 mechanism via formation of an oxocarbenium ion [11]. Polarity effects and the stability of the formed

• observed rate constants are proportional to the acidity of the alcohol moieties corresponding to the varied stems of the acetal structures: the hydrolysis rate steadily decreases with increasing electron-withdrawing ability of the alkyl group. A comparison of this observation with the results of Salomaa

Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

• Pedro N. Batalha,
• Luana da S. M. Forezi,
• Maria Clara R. Freitas,
• Nathalia M. de C. Tolentino,
• Ednilsom Orestes,
• José Walkimar de M. Carneiro,
• Fernanda da C. S. Boechat and
• Maria Cecília B. V. de Souza

Beilstein J. Org. Chem. 2019, 15, 388–400, doi:10.3762/bjoc.15.35

• one-dimension spectra of compound 7 are available in Supporting Information File 1. Theoretical data Two main approaches were considered to better understand the reactivity of substrate 5 and, consequently, the regioselectivity of the reaction: quantification of the acidity of the N–H units and

• comparative analysis of the possible reaction paths. Acidity of the N–H units A first possibility to rationalize the reactivity of carboxamide 5 was its deprotonation to produce a nucleophilic species which would then attack the bromoethane to produce the derivatives 7 or 11. Therefore, we considered the

• deprotonation of both the oxoquinoline core and the carboxamide N–H sites, followed by the alkylation of the respective anion 8a and 8b, providing two possible products 7 and 11, from which the results obtained could be compared (Scheme 3). The acidity of both carboxamide and oxoquinoline N–H sites were

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• formation of alkylidenecyclopropanes 58a (86%), 58b (60%) and 58c (84%). It is worth mentioning that despite the use of a strong base (KHMDS) and the acidity of the “vinylic” protons of cyclopropenes which is comparable to that of a terminal alkyne [62], cyclopropenylcarbinyl glycolates devoid of

• 60 was converted into glycolate 61 under standard conditions and the latter ester was engaged in the Ireland–Claisen rearrangement. Because the gem-diester substitution at C3 increased the acidity of the proton at C2 in substrate 61 [64], silylation of that position took place under the reaction