The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition

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

Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73

• gives the well-known Huisgen 1,4-dipole A. Secondly, Michael addition of the 1,4-dipole A to 5,6-unsubstituted 1,4-dihydropyridine gives the adduct intermediate B. At last, the intramolecular coupling of the negative and the positive charges in intermediate B directly affords isoquinolino[1,2-f][1,6

• an intramolecular Michael addition process. Conclusion In summary, we have investigated the three-component reaction of isoquinoline, dialkyl acetylenedicarboxylate and 5,6-unsubstituted 1,4-dihydropyridines. This reaction successfully provided an efficient protocol for the synthesis of

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

•  7b) [31]. In 2018, Ishihara and co-workers developed a novel C2 and C1-symmetric bisphosphoric acid-catalyzed asymmetric aza-Friedel–Crafts reaction. Both catalysts showed intramolecular H-bonding causing a sharp increase in Brønsted acidity of free OH groups and prevention of catalyst dimerization

• , the authors were able to obtain X-ray crystallographic data of the pyridine–catalyst complex which showed two intramolecular H-bonding interactions in the molecular framework of the catalyst where two free OH groups were engaged in interactions with the pyridine. This data clearly indicates the

• of the Boc-protecting group with the Teoc group then gave phenol 136. Compound 136 was then subjected to a highly diastereoselective oxidative phenolic coupling giving fused tetracyclic architecture 137. Follow-up acid-mediated intramolecular aza-Michael addition and subsequent alkene reduction

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• hydrolysis of 2,5-DMTHF (2), which provide intermediate C after the removal of methanol in the presence of CuCl2. In the next steps, nucleophilic addition reaction of amines 34 with intermediate C, dehydration, and intramolecular aromatization affords N-substituted pyrroles 35. In 2018, Patil and Kumar [70

• shown in Scheme 20b. In this mechanism, calcium nitrate first activates the decomposition process of 2,5-DMTHF (2) from A to B. Further, a nucleophilic attack of amines 42 on B generates imine intermediate C. Finally, intramolecular nucleophilic attack by enamine D on the aldehyde group, dehydration and

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• intramolecular decarboxylative cyclization with the formation of the 3,4-fused indole carbocycle rings (Figure 1b,c). In detail, the photocatalytic strategy for accessing the two C(sp3) radicals of DMAT derivatives envision the formation of a relatively stabilized allylic-benzylic carbon-centered radical by

• the importance of steric effects [99]. Indeed, while the addition of the nucleophilic α-amino radical to the α-styrenyl position affords the 6-membered ring (kinetic product via intramolecular 6-exo-trig ring closure) [100] the resulting radical is unstabilized, the 7-membered ring (obtained via

• intramolecular 7-endo-trig ring closure) may well be the thermodynamic product based on the more stabilized benzylic radical that is produced [101]. As largely reported in the literature [102][103], radicals generated next to alcohols do not normally undergo β-elimination to give alkene/carbon–carbon double-bond

First synthesis of acylated nitrocyclopropanes

• Kento Iwai,
• Rikiya Kamidate,
• Khimiya Wada,
• Haruyasu Asahara and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2023, 19, 892–900, doi:10.3762/bjoc.19.67

• through an intramolecular aza-Wittig reaction, yielding cyclopropane-fused 2-quinolones [2]. A nitro group not only activates substrates and stabilizes the α-anion as an electron-withdrawing group but also acts as a nucleophile, electrophile, and leaving group, exhibiting diverse reactivities [3]. For

• ) halogenation, and 3) ring closure (Scheme 2). β-Nitrostyrene 2 serves as an appropriate acceptor for conjugate addition by diethyl malonate (3a) to afford adduct 4a, in which the methine group flanked by two carbonyl groups is readily halogenated, and the subsequent intramolecular nucleophilic substitution by

• , but a dihydrofuran, so the cyclopropane 1b’ reported in the literature [12][13][19] is presumably incorrect [22]. In the cases of donor–acceptor cyclopropanes possessing an electron-donating group such as an alkoxy or amino group, ring expansion caused by an intramolecular attack of nitro oxygen

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• reactions are very scarcely reported which specifically include the intramolecular C–H alkylation of pyridine with alkenes at the C3 or C4 positions. Hence, very recently in 2022, Shi and co-workers [64] adopted an intermolecular process and reported the enantioselective para-alkylation of pyridines with

• . These annulations can be either intermolecular or intramolecular and various substrates have been studied resulting in diverse products. Pyridine has been also reported for the construction of pyridine-fused heterocycles via C(sp2)–H functionalization and further annulation. In this aspect, considering

• biological activities. Hence, looking at the importance of azaindolines in drug discovery a protocol of rare earth metal-catalyzed intramolecular insertion of the pyridine C–H bond into unactivated vinyl C–H bonds has been developed by Chen and co-workers [108] (Scheme 38). Using this protocol azaindolines

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• Y: alkyl, aryl). This reaction pathway represents the well-known Hantzsch thiazole synthesis [13][14][15][16][17][18][19][20][21]. If the imidothioate IV is further deprotonated [10][11][12] at nitrogen using a strong base (e.g., NaOH/H2O or EtONa/DMF are strong enough), then another intramolecular

• where triethylamine behaves as a much stronger base. A much weaker base – solid KHCO3 – is probably still strong enough to generate free imidothioates 6a,b''' which undergo parallel base-catalyzed elimination (minor route to nitriles) and intramolecular proton-transfer between the carbon and nitrogen to

• ) level of theory. Quantum calculations (Figure 2) have shown that the reaction pathway that involves an intramolecular proton transfer between the α-carbon and imine nitrogen through TS1 is much more favorable for imidothioate derived from 4-bromoisoquinoline-1,3(2H,4H)-dione (3) and 3-bromooxindole (1

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

• Ksenia Malkova,
• Andrey Bubyrev,
• Stanislav Kalinin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 800–807, doi:10.3762/bjoc.19.60

• including the following steps: the formation of iminophosphorane 3 from o-azidobenzaldehyde (1) and PPh3 followed by the base-mediated Knoevenagel condensation results in compound 4; a subsequent intramolecular aza-Wittig reaction leads to the desired product 5 (Scheme 1). Starting from the reaction

Synthesis of substituted 8H-benzo[h]pyrano[2,3-f]quinazolin-8-ones via photochemical 6π-electrocyclization of pyrimidines containing an allomaltol fragment

• Constantine V. Milyutin,
• Andrey N. Komogortsev,
• Boris V. Lichitsky,
• Mikhail E. Minyaev and
• Valeriya G. Melekhina

Beilstein J. Org. Chem. 2023, 19, 778–788, doi:10.3762/bjoc.19.58

• pyranone ring leading to the formation of α-hydroxy-1,2-diketones. This phototransformation is initiated by an excited state intramolecular proton transfer (ESIPT) process. In most cases the resulting α-hydroxy-1,2-diketones are unstable and their further reactions open access to various original products

• guanidine C. Finally, the intramolecular cyclization of the guanidine moiety and the carbonyl group leads to the target pyrimidine 9. After the general synthetic method for pyrimidines containing the allomaltol fragment had been established, the photochemical behavior of the obtained compounds 9 was

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

• Joydev K. Laha,
• Pankaj Gupta and
• Amitava Hazra

Beilstein J. Org. Chem. 2023, 19, 771–777, doi:10.3762/bjoc.19.57

• deliver N-arylsulfonylimines under mild reaction conditions is highly desirable. Previously, we reported a tandem oxidative intramolecular cyclization of N-aryl(benzyl)amines, having an internal nucleophile substituted at the ortho-position in the aniline ring, to nitrogen heterocycles using potassium

• persulfate (K2S2O8) as the exclusive reagent [14]. The mechanistic study revealed that an initial oxidation to an iminium ion could be the key intermediate in the intramolecular cyclization step. In sharp contrast, when N-aryl(benzyl)amines that do not have an ortho-substituted nucleophile in aniline ring

• corresponding N-heterocycles 4c–f were obtained in good to moderate yield. However, the reaction with 2-aminophenol did not give the corresponding cyclized product 4g. This could be possibly due to the poor nucleophilicity of the ortho-OH group in 2-aminophenol thereby restricting the intramolecular

Construction of hexabenzocoronene-based chiral nanographenes

• Ranran Li,
• Di Wang,
• Shengtao Li and
• Peng An

Beilstein J. Org. Chem. 2023, 19, 736–751, doi:10.3762/bjoc.19.54

• Müllen [29], HBC was simply constructed through the Scholl-type oxidative intramolecular cyclodehydrogenation of hexaphenylbenzene. Accordingly, in the current cases in this review, the HBC-based chiral NGs were all established through oxidative cyclodehydrogenation by employing different oligophenylene

• , functionalized COT-Ph reacted with compound 50 through Sonogashira cross-coupling reaction affording compound 119 in a 73% yield. Then Diels–Alder reaction between 119 and 2 gave structure 120 as NG precursor. Compound 120 underwent intramolecular cyclodehydrogenation mediated by FeCl3, affording the final NG

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• modular access to arylglycines from three readily available building blocks [10][11][12]. The Petasis borono-Mannich reaction usually proceeds in the absence of any external catalyst via zwitterionic intermediates and an intramolecular transfer of the aryl residue form the activated boronate to the

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• authors postulated an intramolecular electrophilic substitution via a carbocation intermediate 42 (Scheme 9). Elliott et al. [47] investigated several methods to synthesise substituted dibenzo[b,f]azepines, which included the ring expansion of N-arylindoles 41 to synthesise 43 and the rearrangements of 9

• . Among these, Heck reaction conditions allowed for the coupling of aryl acrylates 50 to aryl halides 48 and 49, followed by intramolecular Pd-catalysed amination or etherification to give C-10 carboxylates of dibenzo[b,f]azepine 55 and dibenz[b,f]oxepine 54 in good yield (Scheme 11). However, no ring

• -substituted derivatives were reported. The authors used alpha-substituted acrylates to reduce the effect of poor endo/exo regioselectivity in the intramolecular Heck reaction (cf. Scheme 19). Božinović et al. [52] reported the synthesis of symmetrical 5H-dipyridoazepines 60a and unsymmetrical 5H

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• -methylphenyl)benzothiophene-fused 2-hydroxy-1-oxa-2-phosphacycloundecane 2-oxide 36 in 83% yield (Scheme 7) [22]. 1.1.2 Synthesis via other C–C bond formations: The palladium-catalyzed intramolecular Heck arylation of 2-bromophenylmethyl alk-1-enylphosphinates 37 provides access to 4-alkylidene-1,4

• refluxing toluene under argon atmosphere (Scheme 9) [21]. In addition, the intramolecular coupling reaction of diphenyl pyren-1-ylphosphonate (47) accomplished the synthesis of 3-phenoxybenzo[f]pyreno[1,10-cd][1,2]oxaphosphepine 3-oxide (48) in 35% yield in the presence of largely excessive amounts of AlCl3

• palladium-catalyzed intramolecular arylation of 3-(2-bromophenyl)propyl alkylphosphinates 61 approached the synthesis of 3,4,5-trihydrobenzo[c][1,2]oxaphosphepine 1-oxides 62 in moderate 39–45% yields in the presence of triethylamine in dry toluene at 100 °C [33]. When the substrates were extended to 5

Synthesis, structure, and properties of switchable cross-conjugated 1,4-diaryl-1,3-butadiynes based on 1,8-bis(dimethylamino)naphthalene

• Semyon V. Tsybulin,
• Ekaterina A. Filatova,
• Alexander F. Pozharskii,
• Valery A. Ozeryanskii and
• Anna V. Gulevskaya

Beilstein J. Org. Chem. 2023, 19, 674–686, doi:10.3762/bjoc.19.49

• proposed for D–π–A systems. This parameter is a good indication for intramolecular charge transfer from the donor to the acceptor moiety in the ground state. In benzene, the qr value is equal to 0. In a fully quinoid ring, the qr was found to be equal to 0.10–0.12. Calculations based on the bond lengths in

• donor p-amino and an acceptor p’-nitro terminus, it was shown that upon protonation the band associated with the intramolecular charge-transfer transition emanating from the lone pair on the NH2 nitrogen and terminating in an empty π* orbital on the NO2 group, disappears [38]. The high-energy absorption

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• moieties in several bioactive pharmaceuticals and natural products [1][2][3][4]. Moreover, due to their susceptibility towards 'exited-state intramolecular proton transfer' phenomena, IPs are also effective in optoelectronics and materials sciences [5][6]. C-3-functionalized imidazo[1,2-a]pyridines are

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• to the PBTA scaffold is an annulation of benzothiazoles with a pyrrole moiety (Scheme 1). It includes intramolecular cyclizations of benzothiazoles bearing a 3'-chloro substituent at C2 position (Scheme 1, entries 1 and 2) [5][6][7], intramolecular catalytic carbene cascade reactions of propargyl 1,3

• ) [32]. The third group of approaches to the PBTA scaffold includes only one example, the intramolecular radical substitution reaction in 1-(2-bromophenyl)-5-(butylsulfanyl)pyrrolidin-2-one (Scheme 3, entry 13) [8]. The fourth group of approaches to the PBTA scaffold is the intramolecular cyclization of

• 1-(2-thiophenyl)pyrroles (Scheme 4). It includes intramolecular cationic π-cyclizations in 3-hydroxy-2-(2-sulfanylphenyl)-2,3-dihydro-1H-isoindol-1-ones (Scheme 4, entry 14) [9] and intramolecular cyclizations of 1-(2-(methylsulfinyl)phenyl)-1H-pyrroles under «interrupted Pummerer rearrangement

pH-Responsive fluorescent supramolecular nanoparticles based on tetraphenylethylene-labelled chitosan and a six-fold carboxylated tribenzotriquinacene

• Nan Yang,
• Yi-Yan Zhu,
• Wei-Xiu Lin,
• Yi-Long Lu and
• Wen-Rong Xu

Beilstein J. Org. Chem. 2023, 19, 635–645, doi:10.3762/bjoc.19.45

• illumination in the solid state due to powerful self-quenching effects in the aggregates [25]. Strong emission is observed at approximately 485 nm for all CS-TPE bioconjugates in the solid state (Figure 2b). A major reason for the emission behavior is the restriction in intramolecular rotation (RIR) of

• structures. As shown in Figure 7b, the emission of all CS-TPE in a solution at pH 5.3 was enhanced after the addition of the host TBTQ-C6. This effect can be attributed to the further inhibition of the intramolecular rotation of the phenyl rings of TPE after binding with the host molecule [31]. The

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• ) [34]. Encouraged by this, they have also attempted an intramolecular tandem conjugate addition/Michael reaction sequence, which has resulted in the expected cyclization product 30 in a diastereopure form (Scheme 7B). Zinc enolates readily react with allyl iodides 31 or the structurally similar Stork

• addition with Grignard reagents Feringa and co-workers realized the tandem conjugate addition of Grignard reagents to 4-chlorocrotonates 46 [42]. The enolate 47, which was formed in this process, underwent an intramolecular nucleophilic substitution to form cyclopropane derivatives. Thioesters, esters as

• asymmetric conjugate addition. The magnesium enolates 56 then participated in a copper(II)-mediated intramolecular oxidative coupling to afford benzofused spirocyclic cycloalkanones 57 (Scheme 14) [45]. Our team became interested in domino reactions of metal enolates generated by Cu-catalyzed asymmetric

Direct C2–H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes

• Martina Mamone,
• Giuseppe Gentile,
• Jacopo Dosso,
• Maurizio Prato and
• Giacomo Filippini

Beilstein J. Org. Chem. 2023, 19, 575–581, doi:10.3762/bjoc.19.42

• charge transfer state which results in a bathochromic shift of the absorption towards the visible range [19][20]. Upon light irradiation, the EDA complex may undergo an intramolecular single-electron-transfer (SET) process to produce a radical ion pair (D•+, A•−). To avoid the occurrence of a back

Phenanthridine–pyrene conjugates as fluorescent probes for DNA/RNA and an inactive mutant of dipeptidyl peptidase enzyme

• Josipa Matić,
• Tana Tandarić,
• Marijana Radić Stojković,
• Filip Šupljika,
• Zrinka Karačić,
• Ana Tomašić Paić,
• Lucija Horvat,
• Robert Vianello and
• Lidija-Marija Tumir

Beilstein J. Org. Chem. 2023, 19, 550–565, doi:10.3762/bjoc.19.40

• ]. Excimers are formed when pyrene moieties form supramolecular complexes by intermolecular or intramolecular π–π interactions, causing a significant shift of single pyrene bands to longer wavelengths. Pyrenes are often used as a sensor part of receptor molecules, so their excimer bands switch on/off to

• solvents, including water. The exciplex was formed by the intramolecular interaction of guanine and pyrene, linked by a flexible methylene chain [10]. Our lab has conducted considerable research on phenanthridine derivatives, and earlier research has demonstrated that two phenanthridine units can also

• ), differing only in the linker length between the aromatic units, have been prepared by condensation of two different pyrenecarboxylic acids with phenanthridine-labelled amino acid (Scheme 2). The influence of the linker length on the molecule flexibility, intramolecular conformation, spectroscopic properties

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• undergoing reductive elimination to afford to [2 + 2] adduct, β-oxygen elimination followed by E/Z isomerization and intramolecular lactonization generates the annulated coumarin scaffold. In 2003, the Cheng lab extended on this Ni-catalyzed ring-opening strategy [31]. It was noted the addition of 1.5

• solely observed (Scheme 1). This unprecedented lactone is presumed to be generated through the expected reductive coupling to generate the ring-opened intermediate 5 which undergoes subsequent intramolecular lactonization with the distal ester group. In the same year, Cheng and co-workers observed the

• the bicyclic alkene followed by migratory insertion affords intermediate 12 which undergoes β-oxygen elimination to form 13. Rearrangement of 13 via β-hydride elimination and enolization generates a 1-naphthol species which undergoes intramolecular cyclization with the ester to form the final product

Computational studies of Brønsted acid-catalyzed transannular cycloadditions of cycloalkenone hydrazones

• Manuel Pedrón,
• Jana Sendra,
• Irene Ginés,
• Tomás Tejero,
• Jose L. Vicario and
• Pedro Merino

Beilstein J. Org. Chem. 2023, 19, 477–486, doi:10.3762/bjoc.19.37

• the reaction. To investigate further the origin of the observed lack of reactivity for medium- and long-size tethers we applied the Houk’s distortion model [30] to our substrates using the modified model [9] that allows the analysis of intramolecular reactions. According to that modified model, the

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• with nucleophilic deoxyfluorinating reagents often does not lead to the expected products with a fluorine atom in place of the –OH group. They usually undergo rearrangement, and intramolecular cyclization leading to products that are constitutional isomers [15]. The solvolysis reaction of phosphonates

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• /acceptor (route A), while the other corresponds to the intramolecular Ar–O–Ar coupling from the former ester (route B). Both synthetic routes have their advantages and disadvantages. The formation of the Ar–O–Ar bond can be accomplished using different methodologies [20] such as SNAr [21], Ullmann [22], or

• under different conditions [30] did not lead to the desired macrolide 2, but only the formation of the diolide was observed (Scheme 4). Once the first synthetic pathway did not furnish the desired compound, the authors carried out the formation of the macrocycle using an intramolecular Ullmann-type

• 97% yield. Subsequent intramolecular Ullmann-type reaction using CuMe under high dilution conditions [31] gave macrolide 28 in low yield. Finally, demethylation using boron triiodide [32] led to the formation of combretastatin D-2 (2, Scheme 5). Using this strategy, Boger succeeded to synthesize