Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• benzodiazepinones, where the protonation would be exclusively controlled by the chiral amine in the synthesis of 6. Moreover, this proposed mechanism also explains the spontaneous cyclization in the absence of a base when 3-bromopropanamine was used (Scheme 8). Moreover, we envisaged the possibility of obtaining

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• nucleophilic and can lead to the formation of five- or six-membered rings, the authors proposed that the thione group of ii was tautomerized to an iminothiol, from which the sulfur atom attacked the most electrophilic site of the epoxide (which was activated by protonation), producing the spiro-1,3,4

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• promising starting point for pursuing this ring-opening attempt [41]. We hypothesized that this approach would allow the synthesis of 3-amino-1,2-diols, a motif commonly found in pharmaceuticals such as, e.g., β-blockers [42]. Our envisioned one-pot protocol features protonation of the azetidine from

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• interactions [4]. Protonation of 3-fluoropyrrolidine generates the 3-fluoropyrrolidinium cation, and this typically results in a highly favored conformation in both the gas phase and solution where the fluorine and nitrogen atoms are cis, mirroring the behavior observed in analagous 4- and 6-membered ring

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• , the addition of the benzoyl radical to azobenzene results in the generation of a nitrogen-centered radical. This radical is then subjected to reduction by the reduced photocatalyst, producing the nitrogen-centered anion intermediate. Ultimately, the protonation of this anion gives rise to the desired

• breakdown of ethyl vinyl ether and trapping of ethanol, yielding radical 84. To regenerate the photocatalyst, PhSSPh functioned as an oxidant. After protonation upon the β-elimination step, PhS− contributed a hydrogen atom to both 83 and 84, alongside regeneration of the HAT catalyst. Lastly, the acetal

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• alkene 2 to provide alkyl radical species B. Further single-electron reduction by 1,3-DCB•− or at the cathode followed by protonation of B provides hydroarylation product 3. Meanwhile, the sacrificial anode is oxidized to form Al cations. Although the exact role of visible-light irradiation in the

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization. Keywords: atropisomer; Cope

• Ring fusion configuration does not affect protonation-induced cyclization Our initial observation that albireticulene (2) was unstable in chloroform, resulting in two tricyclic isomers gersemienes A (5) and B (6) [7], while benditerpetriene (1) was stable [5], led us to investigate the protonation

• -induced cyclization of the eunicellane skeleton (Figure 2). When 1 and 2 were individually subjected to acidic conditions (i.e., TFA in CHCl3), both cyclized into 6/6/6-tricyclic skeletons via a selective C2–C7 cyclization after protonation at C6 to give trans-BC ring systems (i.e., cis,trans-6/6/6 for 1

Mechanistic investigations of polyaza[7]helicene in photoredox and energy transfer catalysis

• Johannes Rocker,
• Till J. B. Zähringer,
• Matthias Schmitz,
• Till Opatz and
• Christoph Kerzig

Beilstein J. Org. Chem. 2024, 20, 1236–1245, doi:10.3762/bjoc.20.106

• protonation of Aza-H, both in its ground state and in the excited singlet state (see Figure S10 in Supporting Information File 1 and the corresponding section for details). Based on our studies in aqueous ethanol, Aza-H is a weak photobase but protonation is seen to be unimportant in neutral and alkaline

Introduction of peripheral nitrogen atoms to cyclo-meta-phenylenes

• Koki Ikemoto and
• Hiroyuki Isobe

Beilstein J. Org. Chem. 2024, 20, 1207–1212, doi:10.3762/bjoc.20.103

• -doped CMPs. Thus, when trifluoroacetic acid (TFA) was added to a solution of 3a in chloroform, bathochromic shifts in UV spectra were observed, indicating protonation-induced changes in the electronic properties [10]. Because of the weakly acidic nature of pyridinic nitrogen atoms, an excess amount of

• equivalent of TFA at 2 × 105 [13], bathochromic shifts were also observed. However, unlike the case with 3a, gradual absorption shifts were not observed, and the absorption changed from 299 nm to 320 nm with an isosbestic point at 303 nm as shown in Figure 5b. This observation indicated that the protonation

• -induced change of UV spectra for 6 involved two equilibrating states, which most likely originated from single protonation at the centre of the CMP pore. On the other hand, the gradual absorption shifts observed with 3a might thus be ascribed to the presence of multiple protonated species involved in the

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• ]. Furthermore, (R)-(+)-1 germacrene A or hedycaryol can be protonated at C7, leading to cyclization and formation of a 5-7 bicyclic skeleton (I–L), which are precursors to guaiane sesquiterpenes. Alternatively, guaiane precursors can be formed by protonation at C3 resulting in E–H. These carbocations derived

• formation of (6,6) vs (5,7) is rooted in very slight changes in mechanism (protonation at C1 vs C10), it is of interest to understand whether there is a systematic difference in energy. In cases where enzymes use pathways with high-energy intermediates, the enzyme active site must in some way direct the

• relative stability of carbocations resulting from protonation and ring closure of germacrene A and hedycaryol. The ring closures considered were: four molecules containing 6-6 bicyclic rings, four 5-7 bicyclic compounds with the carbocation located on the seven-membered ring and the remaining four 5-7

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• activated by the base, affording the active amido complex Mn1-a which reacts with the alcohol to form the alkoxo-type complex Mn1-b. An intramolecular ligand-assisted mechanism produced the aldehyde and manganese hydride complex Mn1-c after protonation of the intermediate. The aldehyde then underwent aldol

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• observed that the β-anomer of charge-neutral nucleoside Vb exhibited similar inhibition of hCDA as the control dZ (IIc). Presence of a negative charge in nucleoside Va led to lack of inhibition at pH 7.4. We assumed that protonation of Va might result in some inhibition of hCDA. However, the pKa of Va was

• against hCDA (Table 1), which might be a result of protonation of the pyrimidine ring in dZ (IIc). Some inhibition of hCDA by the β-anomer of Va was observed at pH 4.7, with a Ki value of 560 μM. At this pH value, less than 1 in 1,000 molecules of Va might be protonated, which could mean that protonated

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• products) were found to be somehow unstable when concentrated to dryness during work-up. We hypothesize that a possible cause of such instability might consist in the formation of a highly electrophilic iminium ion upon protonation of the hemiaminal ether by silica or glassware acidity and further

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• provide a better overall understanding. The hydrochlorination of alkenes can be categorized into three main classes (Scheme 1; only a terminal alkene is shown as a substrate, although polysubstituted and conjugated alkenes can also serve as substrates). 1) Polar reactions: These involve the protonation of

• alkene reactivity is essential. Two reactivity scales for alkenes are available in the literature, one considering the reactivity of the alkene itself (Mayr scale) [25] and the other the stability of the corresponding cation after protonation (hydride affinities) [26]. In the polar hydrochlorination

• reaction, the protonation of the alkene is the rate-determining step. This process can be viewed as the reaction between a nucleophile (alkene) and an electrophile (proton). According to the Mayr–Patz equation log(k) = s(N + E), the second order reaction rate constant k at 20 °C for a reaction is related

Synthesis of new representatives of A₃B-type carboranylporphyrins based on meso-tetra(pentafluorophenyl)porphyrin transformations

• Victoria M. Alpatova,
• Evgeny G. Rys,
• Elena G. Kononova and
• Valentina A. Ol'shevskaya

Beilstein J. Org. Chem. 2024, 20, 767–776, doi:10.3762/bjoc.20.70

• easily converted into hydrophilic charged entities by the protonation of the unsubstituted amino functionalities in their structure providing improved bioconjugation. Spectroscopic data All porphyrin conjugates were structurally characterized by IR, UV–vis, NMR spectroscopy, and mass spectrometry. The IR

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• meroterpenoids: insuetusin A1 (12) and insuetusin B1 (10), respectively (Figure 2) [9]. Like other Trt1-type enzymes, InsB2 catalyzes the protonation of the epoxide, the formation of two six-membered rings in a chair–chair conformation, but the reaction finishes with the deprotonation of the hydroxy group at C-3

• to produce compound 10. In contrast, InsA7 commonly initiates and terminates the reaction with the protonation of the epoxide and the deprotonation of OH-3, respectively, but it produces product 12 via a boat–chair conformation. Since all of the other Trt1-like cyclases catalyze the reaction with

• cyclization process is initiated by the protonation of the epoxide, leading to the formation of a cation at C-7. A cascade of migrations then occurs to form the final backbone: H-6 migrates to the cation C-7, the methyl group at C-13 shifts to C-6, H-10 migrates to C-11, and finally, deprotonation of the

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• summarized in Scheme 8). The first pathway is realized in the formation of five-membered (in the case of 3-bromopropanol) and six-membered (in the case of 2-(bromomethyl)benzyl alcohol) cycles – the cyclization of the anion is faster than its reverse protonation. The same applies to substrates with activated

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• and drug delivery systems [12]. pH-Responsive molecular tweezers A particular case of coordination-responsive systems is when a proton is used as a stimulus leading to pH-responsive systems with the protonation/deprotonation of the switchable moiety. The conformational switch in these systems is

• signals in the low-range visible/NIR region. Upon protonation of the pyridine, the conformation switch leads to a spatial separation of the active Pt moieties and a release of the guest (Figure 4). Also, the same group demonstrated the induction of chirality and fluorescence with chiral guest molecules

• observed confirming the formation of the host–guest complex. Again, protonation of the pyridine results in a guest release and a loss of the CD signal. Thus, this system provides a peculiar example of the control of chirality by a pH stimulus. A similar moiety employed for acid–base-triggered

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

• concerted attack and protonation [59]) may be being mimicked by the gold-catalyzed processes here, further supporting the viability of a mechanism like that shown in Scheme 2. Finally, at its extreme, increasing nitrogen basicity inhibits gold catalytic activity, but within this low basicity regime, the

• behaves accordingly here [66]. Specific gold–oxygen interactions are typically not invoked in mechanistic discussions, though a gold alcohol complex has been proposed in silyl enol ether protonation [67]. Equilibrium studies by Maier et al. indicate that methanol is more weakly coordinating than alkynes

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• . The difference between the two mechanistic pathways is the nature of activation of the carbonyl group. Protic acids induce the protonation of the carbonyl group of the aldehyde or ketone, enhancing its electrophilic character. Whereas, Lewis acid catalysts bind to the heteroatom of the carbonyl group

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• , protonation, and luminescence, have recently been studied by us in sufficient detail [15], nothing is known so far about the possibility of chemical modification of this molecule. It should be emphasized that the presence of a dimethylene moiety in the peri-positions of the naphthalene system will not only

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles

• Yumei Wang,
• Guangzhu Wang,
• Yanping Zhu and
• Kaiwu Dong

Beilstein J. Org. Chem. 2024, 20, 205–211, doi:10.3762/bjoc.20.20

• mechanism of the CPA-catalyzed transfer hydrogenation reaction was proposed (Figure 2). The activation of 3,3-difluoro-substituted 3H-indole 1 by protonation through the Brønsted acid generates the iminium A. Subsequent hydrogen transfer from the Hantzsch ester gives the chiral amine 2 and pyridinium salt B

Facile access to pyridinium-based bent aromatic amphiphiles: nonionic surface modification of nanocarbons in water

• Lorenzo Catti,
• Shinji Aoyama and
• Michito Yoshizawa

Beilstein J. Org. Chem. 2024, 20, 32–40, doi:10.3762/bjoc.20.5

• through the template effect of the hydrophobic nanocarbon guests (Table 2). Moreover, aromatic micelle (PA-Im)n and its host–guest composite (PA-Im)n·(C60)m were anticipated to provide pH-dependent ZPs via imidazole-based protonation/deprotonation. Micelle (PA-Im)n showed a significantly higher ZP (41.7

• mV) compared to the other derivatives in neutral water, owing to the basic imidazole groups (Table 1). The protonation behavior of the imidazole groups on (PA-Im)n·(C60)m in D2O (0.5 mM based on PA-Im) was monitored by 1H NMR spectroscopy, showing significant down-field shifts of the imidazole ring

Effects of the aldehyde-derived ring substituent on the properties of two new bioinspired trimethoxybenzoylhydrazones: methyl vs nitro groups

• Dayanne Martins,
• Roberta Lamosa,
• Talis Uelisson da Silva,
• Carolina B. P. Ligiero,
• Sérgio de Paula Machado,
• Daphne S. Cukierman and
• Nicolás A. Rey

Beilstein J. Org. Chem. 2023, 19, 1713–1727, doi:10.3762/bjoc.19.125

• azomethine nitrogen N1 as H-acceptor is observed, which originates six-membered cyclic motifs with a graph-set (6) [39]. The hydrogen atom is closer to O1 than to N1, indicating that the preferred protonation site is the former, as can be observed at the Fourier difference maps (Figure S1A and S1B in

• absorptions lose intensity by around 10% along the first 48 hours after dilution in buffer (Figure S13 in Supporting Information File 1). The mechanism associated with the hydrolysis of N-acylhydrazones involves the protonation of the azomethine nitrogen (in this case, N1), followed by the nucleophilic attack

Tying a knot between crown ethers and porphyrins

• Maksym Matviyishyn and
• Bartosz Szyszko

Beilstein J. Org. Chem. 2023, 19, 1630–1650, doi:10.3762/bjoc.19.120

• alternative approach towards crown ether–porphyrin hybrids. They have introduced the crown ether segment by exploiting a dicarbinol 38, which, once subjected to the reaction with pyrrole, formed 39 [68]. The latter reacted with arylaldehydes under acidic conditions yielding 40 (Scheme 11). Protonation of 40