Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• enamides contain an N-acyl group in place of the original alkyl group. The electron-withdrawing effect of the amide group delocalizes the nitrogen lone pair, thereby reducing the electron density and nucleophilicity of the enamide double bond. These features significantly diminish the reactivity of

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

Molecular diversity of the reactions of MBH carbonates of isatins and various nucleophiles

• Zi-Ying Xiao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2025, 21, 286–295, doi:10.3762/bjoc.21.21

• reactions of isatins with alkyl acrylates, acrylonitrile, and other activated alkenes [26][27][28][29]. Due to the stronger electron-withdrawing effect of the oxindole motif, MBH carbonates of isatins showed higher reactivity than that of the normal MBH carbonates of normal ketones [30][31][32][33][34][35

Synthesis of fluorinated acid-functionalized, electron-rich nickel porphyrins

• Mike Brockmann,
• Jonas Lobbel,
• Lara Unterriker and
• Rainer Herges

Beilstein J. Org. Chem. 2024, 20, 2954–2958, doi:10.3762/bjoc.20.248

• carboxylic acids [10]. It was therefore obvious to use a perfluoroalkyl chain as a tether. However, a perfluoroalkyl chain as a substituent on the porphyrin has an electron-withdrawing effect and thus a negative influence on the oxidation potential. We have therefore inserted an O–CH2 group between the

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• , leading to the formation of products 12a–d as illustrated in Scheme 3. This outcome suggests a significant role of the fluorine atom at the alpha position, where its electron-withdrawing effect likely influenced the feasibility of the following Michael addition for compounds 9a–d (Scheme 2). Interestingly

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• coupling reactions of the obtained compounds 2. It should be emphasized that amino-1,2,5-oxadiazoles correspond to very weak nucleophiles due to the highly electron-withdrawing effect of the heterocycle. Our previous efforts achieved a certain result indicating that (1,2,5-oxadiazolyl)diazonium salts

• , whether isolated or generated in situ, may undergo various controlled transformations [42]. However, previously, we failed to introduce amino-1,2,5-oxadiazoles bearing an amide functionality into the diazotization protocol, arguably due to an increased electron-withdrawing effect and elevated instability

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• contained some other compounds, which have not been identified. Among the amines studied, amine A3 is less prone to oxidation (due to the electron-withdrawing effect of the trifluoromethyl group) and is the less basic; the presence of a lutidine base even more fastens deprotonation of the radical cation

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• electron-withdrawing effect made the fluoroiodane precursors more resistant to oxidation. Consequently, higher temperatures, longer reaction times and more equivalents of Selectfluor were required to prepare trifluoroiodanes 21 and 22. Trifluoro(aryl)-λ5-iodane 22 was also prepared directly from its iodine

• across the series of monocyclic trifluoroiodanes 20 to 22, the I–O bond length increases slightly due to the electron-withdrawing effect of the trifluoromethyl groups in the sidearms and consequently, the synergistic effect of the 3-centre-4-electron bond causes the I–F’ bond length to decrease slightly

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• of 3-cyclohexanones caused by the strong electron-withdrawing effect, which made 3a as a base rather than a nucleophile under such conditions. The location of substituents was found to affect the product yield greatly, considering that the reactions worked better with 3-cyclohexenones bearing a para

Synthesis and physical properties of tunable aryl alkyl ionic liquids based on 1-aryl-4,5-dimethylimidazolium cations

• Stefan Fritsch and
• Thomas Strassner

Beilstein J. Org. Chem. 2024, 20, 1278–1285, doi:10.3762/bjoc.20.110

• unsubstituted aryl moiety. The viscosities of the 4-CF3 and 2,4-F2 TAAILs with butyl chains are very similar, since the viscosity is influenced by π–π and dispersion effects facilitated by the electron-withdrawing effect of the fluorine atoms [46][47]. The 4-OCF3 substituted TAAIL with a butyl chain, however

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• on the electron-donating effect of the methyl groups. Good yields were obtained for parent 3-formylchromone (10a) and for chlorine-substituted chromones, because of the higher electrophilicity of the chromone based on the electron-withdrawing effect of the methyl groups. 1,3-Bis(silyloxy)-1,3

• of the carbonyl group adjacent to the ester, due to the electron-withdrawing effect of the latter. The yields were generally good to very good and no trend was observed depending on the structure of the chromones. 1,3-Diphenylacetone Similarly, reaction of 1,3-diphenylacetone (4) with 11a,d afforded

Synthesis and properties of 6-alkynyl-5-aryluracils

• Ruben Manuel Figueira de Abreu,
• Till Brockmann,
• Alexander Villinger,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 898–911, doi:10.3762/bjoc.20.80

• functional groups adjacent to them, due to withdrawing effects. Chlorine has a stronger electron-withdrawing effect than bromine, so the electrophilic character of the 6-position should be higher than that of the 5-position. However, it is unlikely to be the only reason for the formation of just one

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups

• Ita Hajdin,
• Romana Pajkert,
• Mira Keßler,
• Jianlin Han,
• Haibo Mei and
• Gerd-Volker Röschenthaler

Beilstein J. Org. Chem. 2023, 19, 541–549, doi:10.3762/bjoc.19.39

• . Phosphonates containing CF2 groups can sterically and electronically mimic oxygen, enabling the second dissociation constant, pKa2, to closer mirror those of the phosphates due to the electron-withdrawing effect of fluorine [39]. As a result, improved lipophilicity, metabolic stability or bioavailability of

A study of the DIBAL-promoted selective debenzylation of α-cyclodextrin protected with two different benzyl groups

• Naser-Abdul Yousefi,
• Morten L. Zimmermann and
• Mikael Bols

Beilstein J. Org. Chem. 2022, 18, 1553–1559, doi:10.3762/bjoc.18.165

• pattern. The reason for this behavior is probably due to the collective electron-withdrawing effect of the chlorine atoms making the glucose residues of the fully DCB-protected compound more electron deficient at the ring oxygen. This means that the Lewis acidic aluminum reagent has more difficulty

Mechanochemical synthesis of unsymmetrical salens for the preparation of Co–salen complexes and their evaluation as catalysts for the synthesis of α-aryloxy alcohols via asymmetric phenolic kinetic resolution of terminal epoxides

• Shengli Zuo,
• Shuxiang Zheng,
• Jianjun Liu and
• Ang Zuo

Beilstein J. Org. Chem. 2022, 18, 1416–1423, doi:10.3762/bjoc.18.147

• due to the strong electron-withdrawing effect of bromine, enhancing the electrophilic property of bromo-substituted salicylaldehyde. Because of the poor solubility in the eluent, the yield of dichloro-containing 1c (88%) was lower than 1a after isolating by column chromatography. This was also found

Syntheses of novel pyridine-based low-molecular-weight luminogens possessing aggregation-induced emission enhancement (AIEE) properties

• Masayori Hagimori,
• Tatsusada Yoshida,
• Yasuhisa Nishimura,
• Yukiko Ogawa and
• Keitaro Tanaka

Beilstein J. Org. Chem. 2022, 18, 580–587, doi:10.3762/bjoc.18.60

• containing two acceptor (maleimide and pyridine) and one donor (secondary amine) moieties in 72% yield (Scheme 1). Due to the electron-withdrawing effect of the bromo substituent at position 5 of the pyridine ring, the cyclization reaction did not occur. The structure of product 4a was confirmed by 1H and

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

• Rodolfo H. V. Nishimura,
• Thiago dos Santos,
• Valter E. Murie,
• Luciana C. Furtado,
• Leticia V. Costa-Lotufo and
• Giuliano C. Clososki

Beilstein J. Org. Chem. 2021, 17, 2968–2975, doi:10.3762/bjoc.17.206

• and 9h, respectively) allowed us to isolate the expected derivatives 10m–p in yields ranging from 70 to 84% (Table 1, entries 13–16). The electron-withdrawing effect of the fluoro substituent appeared to affect the reactivity of amine 9g in those reactions drastically, so a longer reaction time (40

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

• enaminone 15r, which was prepared in situ prior to cyclization. The pyrrolizine 19r was obtained within 90 seconds of microwave heating, and in 99% yield over the two steps. The rapidity of the condensation probably reflects both the inductive electron-withdrawing effect of fluorine and the minimal steric

Synthesis of new substituted 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids containing a tetracyclic tetrahydroisoquinoline core structure

• Agnieszka Grajewska,
• Maria Chrzanowska and
• Wiktoria Adamska

Beilstein J. Org. Chem. 2021, 17, 2511–2519, doi:10.3762/bjoc.17.168

• compound 16; the next step involves the formation of the iminium ion 17, which is then hydrolyzed to compound 8 and hydroxyacetaldehyde in the last step. Thus, the unexpected reactivity of 6a with diluted HCl may be explained by the electron-withdrawing effect exerted by the adjacent COOH group which

Synthesis and investigation on optical and electrochemical properties of 2,4-diaryl-9-chloro-5,6,7,8-tetrahydroacridines

• Najeh Tka,
• Mohamed Adnene Hadj Ayed,
• Mourad Ben Braiek,
• Mahjoub Jabli and
• Peter Langer

Beilstein J. Org. Chem. 2021, 17, 2450–2461, doi:10.3762/bjoc.17.162

• atom and at the two external phenyl groups, show the electron abundance (low electrostatic potential). The trifluoromethoxy group for 4c resulted in a decrease of electron density in the tetrahydroacridine core. In addition, this strong electron-withdrawing effect induced the appearance of blue

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

• Hg(TFA)2 then five- and six-membered rings 64 and 65 were formed with a 1:4 ratio (Scheme 22) [70]. The greater yield of the six-membered product was primarily due to the electron-withdrawing effect of ethereal oxygen which in turn destabilizes the carbocation at the β-carbon and hence 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

• was ≈30 h without the additive (entry 1, Scheme 41), 1 equiv of TfOH shortened this to less than 1 h (entry 2). Therefore, it would appear that this additive acted as a catalyst. With 0.1 equiv of TfOH, the reaction time was 5.5 h (entry 3) which can be attributed to the strong electron-withdrawing

• 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

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• , while the remaining C–H bond in Flp acquires an enhanced positive charge due to the electron-withdrawing effect of fluorine. Based on these considerations, a fluoroproline–aromatic-system interaction has been previously utilized in the engineering of a few peptide therapeutics [44][45]. 2.3

• biochemical settings [54]. The process becomes slightly faster when proline is replaced by fluorinated analogues. The acceleration occurs due to the electron-withdrawing effect of the fluorine atoms. According to the data for the model compounds in water [16][19], the cis-to-trans rotation velocity increases

• folding kinetic pathways can also lead to aggregation and misfolding issues, affecting the protein production. 2.7 Other properties The acid–base transitions also appear altered in fluoroprolines primarily due to the electron-withdrawing effect of the fluorine atoms (Table 2) [16][19][55][57][58]. This

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

• downfield shifts for the carbon atoms C2 and C6, suggesting a highly delocalized positive charge in the heteroaromatic ring as depicted below. α-(Trifluoromethyl)allylcarbenium ions In 1976, Poulter et al. exploited the powerful electron-withdrawing effect of the CF3 group to elucidate the prenyltransferase

• of dicationic superelectrophile 160. Again, due to charge repulsions as well as due to the strong electron-withdrawing effect of the CF3 group, the positive charge adjacent to the CF3 group is highly delocalized within the phenyl ring, and arylation occurs regioselectively at the para-position

• of this strategy was the installation of a CF3 group in the α-position of the N2 moiety. This strategy relies on the high electron-withdrawing effect of the CF3 group, which greatly destabilizes nearby positive charges. As a result, the dissociation rate for the generation of molecular nitrogen was

Ultrasound-assisted Strecker synthesis of novel 2-(hetero)aryl-2-(arylamino)acetonitrile derivatives

• Emese Gal,
• Luiza Gaina,
• Hermina Petkes,
• Alexandra Pop,
• Castelia Cristea,
• Gabriel Barta,
• Dan Cristian Vodnar and
• Luminiţa Silaghi-Dumitrescu

Beilstein J. Org. Chem. 2020, 16, 2929–2936, doi:10.3762/bjoc.16.242

• 10-methylphenothiazine which was reported to be 143.7° [29], thus revealing a negligible electron-withdrawing effect of the substituent. The aromatic plane situated on the edge of the phenothiazine and the plane of the aromatic unit attached to the amino substituent appear twisted with a dihedral