Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate

• Masahiro Terada,
• Zen Iwasaki,
• Ryohei Yazaki,
• Shigenobu Umemiya and
• Jun Kikuchi

Beilstein J. Org. Chem. 2024, 20, 1973–1980, doi:10.3762/bjoc.20.173

• , initiating further radical reactions through the formation of radical cations B. Nucleophilic arylmethyl radicals C, which are generated from radical cations B by desilylation, undergo an addition reaction with 2-benzopyrylium intermediates A, giving rise to the corresponding radical cation. Catalytic cycle

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• 1,2-difluoroethylene (HFO-1132). The major routes for the preparation of the E- and Z-isomer of HFO-1132 are reviewed, along with the chemistry in radical, nucleophilic, and electrophilic reactions. Keywords: 1,2-difluoroethylene; fluorinated monomers; HFO-1132; hydrofluoroolefins; radical reactions

• transitional metal complexes with 1,2-difluoroethylene as a ligand should be mentioned [109][110][111]. Conclusion In conclusion, our literature analysis demonstrated that radical processes are most typical for 1,2-difluoroethylene, while examples of electrophilic reactions are scarce, and nucleophilic

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• regioselectivity. Additionally, these data show the importance of NCIs in understanding mechanisms where regioselectivity outcomes are unexpected. Lastly, it should be noted that these reactions are likely irreversible due to the ≈50–60 kcal/mol barriers of the reverse reactions and near-absent nucleophilic

A new platform for the synthesis of diketopyrrolopyrrole derivatives via nucleophilic aromatic substitution reactions

• Vitor A. S. Almodovar and
• Augusto C. Tomé

Beilstein J. Org. Chem. 2024, 20, 1933–1939, doi:10.3762/bjoc.20.169

• synthesis of highly fluorescent DPP derivatives through straightforward nucleophilic aromatic substitution reactions with thiols and phenols. These nucleophilic substitutions occur at room temperature and manifest a remarkable selectivity for the 4-position of the pentafluorophenyl groups. Both symmetrical

• (disubstitution) and non-symmetrical (monosubstitution) DPP derivatives are formed in excellent overall yields. The optical properties of the newly synthesized compounds are also discussed. The new platform may be useful for bioorthogonal chemistry. Keywords: diketopyrrolopyrrole; fluorescent dye; nucleophilic

• pentafluorobenzyl bromide, followed by a nucleophilic aromatic substitution (SNAr) with thiols and phenols. This approach is based on the well-established reactivity of perfluoroaromatic compounds in nucleophilic aromatic substitutions [32][33][34][35]. By varying the reaction conditions and the number of

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• for our needs [52][53]. Benzylic bromination followed by nucleophilic substitution offers a general approach for the introduction of the nitrogen atom [54][55][56]. Consequently, the continuous flow Wohl–Ziegler bromination of 2b was attempted [57]. Even though we could observe excellent LCMS

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• then undergoes a proton shift to provide intermediate B. Intermediate B collapses via reductive elimination to give nitrenium ion C, along with the release of iodobenzene and sulfamate. Finally, nucleophilic attack of the olefin moiety of C on the electrophilic nitrogen atom, followed by the

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

• cyclization of perfluorinated phenylpyrilium salts using arylhydrazine [12]; the process is based on the fluorine nucleophilic substitution thus limiting its applicability to a wider range of substrates. Pyridyl-substituted diarylamines may be considered as the possible precursors for N-arylpyridoindazolium

• reported as substrates for nucleophilic substitutions using potassium fluoride [22]. The study is in progress now. Voltammetry characterization of the N-arylpyridoindazolium salts S1–S3 and their precursors, diarylamines A1–A3 The electrochemical investigation of the new salts was performed at a Pt

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• substituent in the exocyclic acyl group by introducing different N-, O-, and S-nucleophilic reagents into the reaction. The reaction of chiral diazotetramic acids leads exclusively to trans-diastereomeric β-lactams. The use of variously substituted diazotetramic acids, including spirocyclic derivatives, as

• the lower stability of the less-substituted β-lactam derivatives under thermolysis conditions. Additional alkyl substituents sterically shield the ring and prevent an unwanted nucleophilic attack leading to product degradation. In reactions with alcohols and mercaptans, the corresponding esters 3k–n,r

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• instead, the authors synthesized a series of 2-amino-protected compound 41 through an aromatic nucleophilic substitution on 2-chloropyrimidin-4-amines. Derivatives 41 were then reacted under the optimized conditions, leading to the formation of a series of GBB adducts 42, finally deprotected with TFA to

• limited to methanol due to solubility problems, and HClO4 was selected because other Brønsted acids caused amine deprotection. The GBB adducts 58 could be further elaborated through a Buchwald intramolecular nucleophilic substitution/cyclization, as it will be described in section 3.3. 3 Novel scaffolds

• formation of linked polyheterocycles 75. The authors then decided to perform the reaction using 3 equiv of aldehyde 70 under acidic conditions (Scheme 25, conditions a). The presence of a nucleophilic indole in the GBB adducts 71 induced further additions towards the excess aldehydes 70. The diols 73

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• product 3a for further transformations. Comparable yield and enantioselectivity were observed relative to those of the smaller-scale reaction (0.1 mmol scale, Scheme 4). The bromomethyl group in 3a readily undergoes nucleophilic substitution reactions, leading to the formation of optically active δ

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

•  2, entry 3) or at 40 °C for 6 hours (Table 2, entry 4). Finally, reducing the amount of Selectfluor to 1.5 equivalents led to an excellent 90% isolated yield and the conclusion that Selectfluor delivered one electrophilic fluorine (from the N–F) and one nucleophilic fluoride (from the

• reported before [26][27][28], we developed a new synthetic route which is shown in Scheme 5. In the first step trifluoromethylketone 17 was prepared by a nucleophilic acyl substitution of methyl 2-iodobenzoate 16 with Ruppert’s reagent. Ketone 17 was then reacted with an excess of Ruppert’s reagent and

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• case of bisamides 5d, 6a, 6c, 7b, 8a, and 8c (Table 2), additional transformation products were also isolated from the reaction mixture. According to 1H and 13C NMR, MS, and X-ray diffraction studies these were the corresponding ketobisamides 12, which are products of a nucleophilic substitution of the

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

• hurdles. Here, we have demonstrated the possibility of using the combination of arylglyoxals and carboxylic acids tethered to nonprotected deactivated amines as a powerful strategy for the synthesis of complex fused heterocycles. The limited nucleophilic character of the amino group of the anthranilic

• protecting groups, as the reduced nucleophilic character of the amino group of the anthranilic acid would prevent its participation in the Ugi reaction. In this way, the Ugi reaction was performed using arylglyoxals 1, anthranilic acid derivatives 2, amines 3 and isocyanides 4 following the most common

• Ugi reaction. The reduced nucleophilic character of the amino group of the anthranilic acid, indole-2-carboxylic acid, pyrrole-2-carboxylic acid or N-phenylglycine allowed the use of these compounds in this multicomponent reaction without triggering competitive reactions. The presence of an additional

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• cation is formed with two resonance structures (not counting further movement into the other aromatic rings destroying the aromaticity of one more ring). Resonance structure A has the cation in a benzylic position and will be the preferred site for nucleophilic attack of methanol compared to resonance

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

• -lactone motif on an estradiol backbone [17]. Beginning with the 7α-alkanamidoestrone derivative 17, a nucleophilic addition by the anion of the THP propargyl ether occurred stereoselectively and provided the alkyne 18 in a 75% yield. Afterwards, the catalytic hydrogenation of the alkyne with a 1:1 mixture

• reactions. To increase the molecular diversity at the morpholine ring, tertiary amines were formed by nucleophilic substitution. A final removal of the cyclic ketal group in aq sulfuric acid provided spiromorpholinone derivatives 134a–e, 136a–e, and 138 (Scheme 37). Spiromorpholinones were evaluated as

• reaction on 16β,17β-epoxypregnenolone (156), synthesized via a four-step process from 16-dehydropregnenolone acetate (155) [65]. Initially, the nucleophilic ring opening of the oxirane with substituted oxamic acid thiohydrazides led to a non-isolated intermediate hydrazone ii. Since both NH and SH are

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

• 73% yield. Mechanistically, we believe that the hemiketal protonates the azetidine before a nucleophilic attack can occur. Therefore, the ring opening is critical to the acidity of the transient hemiacetals and to the basicity of the respective azetidines, explaining the unsuccessful attempts with 3a

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• chains possessed a nucleophilic primary amine. Curiously, the macrocyclizing amide bond was found to exist between a Trp side chain indole nitrogen and the C-terminal carboxylate. To the best of our knowledge, this was the first example of the involvement of a Trp indole in macrolactam formation in

New triazinephosphonate dopants for Nafion proton exchange membranes (PEM)

• Fátima C. Teixeira,
• António P. S. Teixeira and
• C. M. Rangel

Beilstein J. Org. Chem. 2024, 20, 1623–1634, doi:10.3762/bjoc.20.145

• nucleophilic substitution using hydrobromic acid, as a 33% solution in acetic acid, to afford the corresponding bromide derivative 9 [54] (Scheme 2). Subsequently 1-(benzyloxy)-4-(bromomethyl)benzene (9) underwent Michaelis–Arbuzov reaction with triethyl phosphite to afford diethyl [4-(benzyloxy)phenyl

• , purification of the crude product by column chromatography led to the decomposition of compound TP7. Another strategy was devised to obtain the desired triazinephosphonate TP7: The first step was the nucleophilic substitution of the chlorine atoms of triazine 1 by 4-hydroxybenzaldehyde (12), followed by the

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• reduction of A afforded the desired benzylamine (2a). However, nucleophilic attack of 2a on A, followed in situ by reduction, proceeded competitively to form dibenzylamine (3a). We considered that by protonating 2a to form 2a-H+, its nucleophilic nature could be suppressed, thereby inhibiting the formation

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• mechanistic strategies, namely, electrophilic, radical and nucleophilic approaches, and highlighted when emerging technologies, such as photo- and electrochemistry effect the desired transformation [22][27]. Review Electrophilic benzylic C(sp3)–H fluorination Base mediated Electrophilic fluorinating reagents

• of C(sp3)–H activation and fluorination, including on one tertiary and five secondary benzylic substrates (Figure 14) [54]. This work utilised electrochemical oxidation with a nucleophilic source of fluoride, CsF, to regenerate the trisligated copper(III) fluoride complex. In 2016, Silas reported an

• in this section, radical-based approaches enable the fluorination of a diverse range of benzylic substrates, which rely on the use of FAT reagents, such as Selectfluor, NFSI or copper fluoride complexes. Nucleophilic benzylic C(sp3)–H fluorination Nucleophilic fluorine sources can be more economical

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• an ammonium hypoiodite species which first facilitates the α-iodination of the pronucleophile, followed by a phase-transfer-catalyzed nucleophilic substitution by the azide. Furthermore, we also show that an analogous α-nitration by using NaNO2 under otherwise identical conditions is possible as well

• can be accessed by different approaches [6][7][8]. Maybe the most classical way to access organic azides is based on the utilization of pre-functionalized starting materials where a suited leaving group undergoes substitution using nucleophilic azide sources such as NaN3 or TMSN3 [6][7][15]. In

• the starting materials (nucleophilic approach), or rely on more advanced N3-transfer agents (electrophilic approach), over the course of the last years also α-azidations of enolate-type precursors using nucleophilic azide sources under oxidative conditions have been introduced very successfully [24

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• -selective manner with moderate levels of enantioselectivities (up to 83:17 er). Furthermore, the obtained products can be successfully engaged in nucleophilic ring opening reactions, thus giving highly functionalized α-amino acid derivatives. Keywords: allenoates; amino acids; azlactones; organocatalysis

• steric bulk (5p) leads to a somewhat lower enantioselectivity, while the methoxy-substituent does not have a strong impact on the yield. It should, however, be stated that some of the methoxy-containing products, i.e., the α-alkyl-substituted 5j and 5k tend to undergo partial nucleophilic ring opening by

• derivatives by means of nucleophilic azlactone-opening reactions. Gratifyingly primary amines can be easily utilized under reflux conditions to access the amide derivatives 6a and 6b straightforwardly (Scheme 3), thus demonstrating the versatility of compounds 5 to access more complex acyclic α-AA derivatives

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• formation of the 1,2-anhydro sugar through intramolecular attack of the 2-hydroxy group of the DMC-activated β-intermediate, followed by dihydroxyazobenzene attacking the anomeric center in an SN2 manner, or by direct nucleophilic SN2 attack on the DMC-activated α-intermediate, to produce the corresponding

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

• -cyclohexenones with nucleophilic nitrogen sources like ammonia, amines and hydrazine [14]. The reactions were regarded as via simple nucleophilic addition along with Pd-catalyzed dehydrogenative aromatization in these elegant works (Scheme 1, (1)). The Semmler–Wolff reaction is often implemented in the synthesis

• speculate that the solvation effect might be beneficial for stabilizing the condensation intermediate I and avoiding further unwanted conversions, e.g., nucleophilic attack of excessive benzylamine to the intermediate I. The following examination on solvents demonstrated that using ether solvents as the

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• carbon atom of isocyanide has both a lone electron pair and empty orbitals, so it has outstanding electrophilic and nucleophilic reactivity. At the same time, isocyanide also has good coordination ability to coordinate with metals to form diverse metal complexes [1][2][3]. Therefore, isocyanides have

• polycyclic compounds. At first, the nucleophilic addition of alkyl isocyanide to dialkyl but-2-ynedioate afforded the expected Huisgen’s 1,4-dipolar intermediate A. Secondly, the sequential addition of the Huisgen’s 1,4-dipole A to the second molecular dialkyl but-2-ynedioate resulted in a 1,5-dipolar

• -deficient alkynes [59][60][61][62][63]. The in situ generated cyclic intermediate C has a resonance hybrid C’. Then, the further nucleophilic addition of the electron-rich enamino unit to 5-(alkylimino)cyclopenta-1,3-diene intermediate C gave intermediate D. At last, the coupling of the iminium cation with