Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• . Nonetheless, use of the weaker acids seems to be crucial, since with strong acids the protonation to 20 appears not to be reversible, and direct cyclization of 20 to 19a cannot be occurring (cf. Table 1, entries 6–21). Secondly, the acid is also likely to facilitate enolization of the ester such that 5-exo

• appeared that, even in acetic acid at room temperature, protonation of 25a was virtually instantaneous and irreversible, as evinced by the formation of a baseline spot for the acetate salt. Since the analogous five-membered enaminones 15 form an obvious baseline salt spot only with strong protic acids but

• not with acetic acid, it appears that protonation of the pyrrolidine-based enaminones with this weak acid must be readily reversible. Thus the critical isomerization equilibrium postulated to be essential for pyrrolizine formation (see Scheme 3) appears not to operate to any appreciable extent with

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• standard conditions. The proposed catalytic cycle included aza-Michael addition of arylamines, Lewis acid copper(II)-catalyzed intramolecular 5-endo-dig cyclization, protonation, and oxidation to provide the final products, tetrasubstituted pyrroles 39. The introduction of a trifluoromethyl group into

Synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and their transformations under superelectrophilic activation conditions

• Andrey I. Puzanov,
• Dmitry S. Ryabukhin,
• Anna S. Zalivatskaya,
• Dmitriy N. Zakusilo,
• Darya S. Mikson,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2417–2424, doi:10.3762/bjoc.17.158

• ], it was shown by means of NMR spectroscopy and DFT calculation that the protonation of these oxadiazoles in Brønsted superacids TfOH and FSO3H gave reactive N,C-diprotonated species. The protonation of oxadiazoles 1 takes place at the nitrogen N4 and the α-carbon of the side chain C=C bond. One would

• expect the formation of similar dications at the protonation of acetylenyloxadiazoles 3 in Brønsted superacids (see Table 1). Table 1 contains data on DFT calculations of cations Aa–d (N-protonated forms) and Ba–d (N,C-diprotonated forms) derived at the protonation of oxadiazoles 3a–d. Charge

• delocalization, contribution of atomic orbital into LUMO, global electrophilicity indices ω [26][27], and Gibbs free energies of protonation reactions with hydroxonium ion (H3O+) ΔG298 were calculated. Big negative values of ΔG298 (−86.6 to −79.2 kJ/mol) of the first protonation step show that the formation of N

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• derivative 127. The plausible mechanism for the formation of compound 127 proceeded consecutively with π-complex formation, Friedel–Crafts type addition, deprotonation, and finally protonation of alcohol for the elimination of water to get the final product [92]. A Hg(OTf)2-mediated cyclization was utilized

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• -3-yl) phosphate 2 is activated by protonation with a haloid acid. Subsequently the phosphate leaving group is eliminated to generate the carbocation intermediate III, which is then followed by rapid combination with a nucleophilic halide ion to form a 3-monohalooxindoles 3 or 4. Conclusion In

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• example utilizing this strategy was provided by Jacobsen and co-workers for the desymmetrization of meso-aziridines 29. In their work, the bifunctional phosphinothiourea catalyst 31 promoted the C–N bond cleavage by hydrochloric acid upon initial protonation (Scheme 7) [55]. Subsequently, the catalyst

Chemical syntheses and salient features of azulene-containing homo- and copolymers

• Vijayendra S. Shetti

Beilstein J. Org. Chem. 2021, 17, 2164–2185, doi:10.3762/bjoc.17.139

• -polyazulene 5 (417 nm) compared to azulene (1, 341 nm) supporting the presence of extended conjugation prevailing in the polymer. The absorption and EPR spectral patterns of 1,3-polyazulene 5 recorded in TFA and H2SO4 were contrasting to each other inferring the varied degree of protonation caused by these

• acids on the polymer backbone. The direct current (DC) conductivity of protonated and iodine-doped 1,3-polyazulene 5 (0.74 and 1.22 S/cm respectively) was significantly higher than its neutral form (<10−11 S/cm). The increased conductivity of 1,3-polyazulene 5 upon protonation can be attributed to the

• protonation of 17 and 18 by TFA resulted in a large red-shifted broad absorption band in the 500–900 nm region due to the formation of azulenium cations in the polymer backbone unlike the 1,3-polyazulene 5, which had no significant effect on its absorption spectrum upon protonation. The HOMO–LUMO gap for the

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• effect of the 2-SO3H substituent formed by the protonation of the sulfonate anion in 18-2h. 1-19. 1-Fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane salts (NFTh) In 1995, Poss and Shia disclosed the synthesis and fluorination reactivity of 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis

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

• ). Manganaelectro-catalyzed late-stage azidation of bioactive molecules. Mn-catalyzed late-stage amination of bioactive molecules. a3 Å MS were used. Protonation with HBF4⋅OEt2 (1.1 equiv) in dichloromethane before amination, then deprotonation with 1 M NaOH in dichloromethane after amination. b3.0 equiv of PhI

Electron-rich triarylphosphines as nucleophilic catalysts for oxa-Michael reactions

• Susanne M. Fischer,
• Simon Renner,
• A. Daniel Boese and
• Christian Slugovc

Beilstein J. Org. Chem. 2021, 17, 1689–1697, doi:10.3762/bjoc.17.117

• , in this case, the activity of the catalyst is not rate determining. This observation is rationalized by the occurrence of a non-productive acid–base equilibrium involving the de- and re-protonation of the considerably acidic alkyne proton in d (pKa = 15.61 [20]) [21]. The reaction conditions

• and -donor and the corresponding zwitterion i is believed to be decisive for the efficacy of the subsequent reaction, protonation of i by the alcohol resulting in the formation of ion pair ii (Scheme 1) [40]. In turn, the pKa value of the alcohol is another important parameter for the speed of the

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• -bonding (Figure 6) [94]. A significant bottleneck for triple helix formation is the requirement for cytosine protonation to form the natural C+•G–C triplet. Because of the low pKa of cytosine (≈4.5), formation of the C+•G–C triplet is unfavorable at physiological pH, which severely destabilizes the

• pseudoisocytosine (J, Figure 6) in triplex-forming oligonucleotides, alleviating the problem of unfavorable cytosine protonation [95][96]. Nielsen and co-workers replaced Cs with Js in the Hoogsteen strand of their original design of bis-PNAs in 1995 [34]. While J demonstrated weaker binding than C at pH 5, J

• cationic RNA binding compounds, perhaps, because the protonation event is coupled with the Hoogsteen hydrogen bond formation. As a result, the partially protonated M strengthens the triple helix without compromising the sequence specificity of recognition [28][30][31]. As discussed above, guanidine groups

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• the protonation of a Pd(II) enolate intermediate by a proton source (HCl) generated at the cyclization step. The catalytic cycle begins with the enolic carbon of A attacking the complexed metal–olefin double bond in a turnover-limiting 6-endo-trig cyclization step (Scheme 3). The formed alkylpalladium

• (II) intermediate (B) then undergoes a sequence of reversible hydride β-eliminations [30] until the formation of the Pd(II) enolate (F), which, after protonation, irreversibly furnishes the product 2 and regenerates the Pd(II) catalyst. The lack of the usually kinetically favored 5-exo-trig

• product was also compatible with the reaction conditions. Alkylated phenols 61 were obtained after protonation/isomerization of the generated enolate intermediate (Scheme 24B). In 2018, the same authors continued to explore the synthetic opportunities offered by the enolate generated in MHAT radical

Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes

• Suraj Patel,
• Tyson N. Dais,
• Paul G. Plieger and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2021, 17, 1518–1526, doi:10.3762/bjoc.17.109

• , protonation might not be the key step, and the highly oxidizing nature of nitration conditions that can lead to the formation of a cationic intermediate via a radical cation might control this reaction [68]. A possible mechanism for the formation of 5 and 6 starts with protonation of 1 give the Wheland

• observed (Figure 6). As with the oxidation, we assume that the lower deck blocks approach from one face. Protonation of the adduct also occurs anti to the para ring. We suspect that this second addition favors the trans product over the cis rather than the para ring influencing the approach of the proton

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide)

• Louis G. Mueller,
• Allen Chao,
• Embarek AlWedi and
• Fraser F. Fleming

Beilstein J. Org. Chem. 2021, 17, 1499–1502, doi:10.3762/bjoc.17.106

• in 93% yield (Table 1, entry 6). Presumably the cyclization of 6 is followed by protonation at the former isocyanide carbon by HMDS (the emerging C-2 of the imidazole) with the reformed LiHMDS deprotonating C-4 to form the imidazole ring. Identifying LiHMDS as the optimal base allowed the scope of

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• in determining ring closure either via path a or path b. In path a, the protonation of the imine nitrogen in 7a by the conjugate acid (+ BH) leads to an electrophilic aromatic substitution at the 3-position of the indole unit to form a carbon–carbon bond in the intermediate 8. A further proton

• moderately polar dichloromethane and then highly polar DMSO (Table 2, Figure 3). The fluorescence quenching of 3ac in methanol is attributed to the partial protonation of the carboline unit's nitrogen atoms facilitated by polar-protic solvents [33]. The fluorescence lifetimes were measured by time-correlated

Photoinduced post-modification of graphitic carbon nitride-embedded hydrogels: synthesis of 'hydrophobic hydrogels' and pore substructuring

• Cansu Esen and
• Baris Kumru

Beilstein J. Org. Chem. 2021, 17, 1323–1334, doi:10.3762/bjoc.17.92

• due to amine groups' protonation on the polymer backbone via electrostatic attraction, and it responded to monovalent electrolyte with a higher ESR. With the increased pH, HGCM-PAA eventuated with enhanced ESR results arising from the dissociation of carboxylic acid groups. Swelling in saltwater

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

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• (pKaH = 13.6) [2]. Moreover, due to the stability of the monocation they display significantly lower second dissociation constants (pKa2H ≈ 3.0). X-ray crystallographic studies and modelling studies have shown that the first protonation occurs mainly on the N4 nitrogen atom, weakening substantially the

• intramolecular H-bond character. The second protonation rather takes place on the N3 nitrogen atom, causing planar character disruption and preventing H-bonding (Figure 2) [1]. Biguanide derivatives often display low melting points (mp = 136 °C for simple biguanide). However, above 130 °C, a concomitant thermal

• 1888 it was discovered that heating a mixture of cyanoguanidine and amine hydrochloride in a polar solvent (mainly alcohols) led to the formation of biguanide. Indeed, proton exchanges at high temperatures may lead to the activation of cyanoguanidine by protonation, and the subsequent attack of the

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

•  18). A sequence of reactions involving elimination of a proton from 83, treatment of 84 with an alkoxide, and protonation of the resulting enolate delivered thermodynamically favored equatorial ester 80 and 81. The highly diastereoselective Brønsted superacid-catalyzed Prins cyclization of

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• -proliferative activity against tumor cell lines leading to the discovery of new lead compounds (Scheme 6). A tentative mechanism in Scheme 7 depicts the formation of iminium ion A from the reaction between 19 and 20 after the intramolecular protonation by carboxylic acid. The A conformer stabilized by

• the allene intermediate D. Finally, an intramolecular 6π-electrocyclization and tautomerism results in the desired products 143a. The authors proposed a mechanism for azepinoindoles (Scheme 59) [128] wherein acid-catalyzed protonation of arylglyoxal monohydrate followed by dehydration and addition of

Synthesis of β-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles

• Soumyaranjan Pati,
• Renata G. Almeida,
• Eufrânio N. da Silva Júnior and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2021, 17, 762–770, doi:10.3762/bjoc.17.66

• , triazoles 1b and 1c containing electron donating 4-tolyl and 4-methoxyphenyl groups did not deliver the products 3b and 3c, respectively, even after prolonged reaction time. This is attributable to the greater reactivity of their corresponding triazolyl anion which preferred protonation over Michael

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• equilibrium (Table 4, entries 7 and 11 vs entries 1 and 9). Attempts to influence the diastereomeric ratio of the cyclization products by irreversible stoichiometric deprotonation of the lactams 12d,f,i by LDA at −78 °C and subsequent protonation by methanol did not lead to substantial changes of the initial

Mesoionic tetrazolium-5-aminides: Synthesis, molecular and crystal structures, UV–vis spectra, and DFT calculations

• Vladislav A. Budevich,
• Sergei V. Voitekhovich,
• Alexander V. Zuraev,
• Vadim E. Matulis,
• Vitaly E. Matulis,
• Alexander S. Lyakhov,
• Ludmila S. Ivashkevich and
• Oleg A. Ivashkevich

Beilstein J. Org. Chem. 2021, 17, 385–395, doi:10.3762/bjoc.17.34

• the data for 1,3-di-alkyltetrazolium-5-aminide salts as described in the literature [25][26][28][32][33][34][35]. First of all, it should be mentioned that the formation of the salt from the corresponding mesoionic compound followed by protonation of the endocyclic N atom in all cases presented in

• ), showing that the largest negative charge and the deepest minimum of MESP of 8a are located near the exocyclic atom N5, and hence it is the most preferable protonation site in 8a. The TD-tHCTHhyb/6-311+G(2d,p) calculated UV–vis spectra of compound 8a in n-hexane, THF, chloroform, methanol, and water are

• of a hydrogen bond between the exocyclic N5 atom and the solvent is taken into account (model structure in Figure 4b). For the methanol and water solutions, the agreement between the calculated and experimental spectra is observed only when the protonation of the N5 atom is taken into account (model

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• , and triflate 45f, which was isolated after basic workup of the reaction (59% yield) [63]. Hence, protonation of 44 led to dialkoxysulfonium triflate 47 along with the release of alcohol 9g. The subsequent formation of the excellent sultine leaving group 46 (assumed to be as good of a leaving group as

• , Pittman, et al. investigated the protonation of a variety of trifluoromethyl ketones in a superacid [35][91]. Trifluoromethyl ketone protonation was observed by NMR spectroscopy at −60 °C in a superacidic FSO3H–SbF5–SO2 solution (Scheme 34). The 19F chemical shift variation for the generated oxygen

• ] (Scheme 38). In these reactions, oxygen-stabilized α-(trifluoromethyl)carbenium ions 142 are supposed to be generated by protonation or Lewis acid activation of the starting ketones. Klumpp et al. explored the reactivity of CF3-substituted superelectrophiles (defined as multiply charged cationic

Hydrazides in the reaction with hydroxypyrrolines: less nucleophilicity – more diversity

• Dmitrii A. Shabalin,
• Evgeniya E. Ivanova,
• Igor A. Ushakov,
• Elena Yu. Schmidt and
• Boris A. Trofimov

Beilstein J. Org. Chem. 2021, 17, 319–324, doi:10.3762/bjoc.17.29

• traces of the 1,4-dihydropyridazine 4af were detected following the two-step, one-pot protocol (Scheme 3). Apparently, the basic pyridine nitrogen atoms of intermediate 3af deactivate the acid catalyst, whilst the use of 3.4 equiv of TFA causes the full protonation of the pyridine rings thus making them

• (Scheme 4). A proposed mechanism for the recyclization of hydroxypyrrolines 1 with hydrazides 2 is shown in Scheme 5. The protonation of the starting hydroxypyrroline 1 with TFA leads to the formation of cation A, which reacts with hydrazide 2 to give the pyrrolidine derivative B. The latter undergoes a