Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• . Due to the challenges associated with the activation of C(sp3)–H bonds, this kind of activation strategy has received extensive attention. Huang et al. developed a Cu-catalyzed CDC of unactivated C(sp3)–H ethers with simple ketones under the synergistic effect of CuBr2 and pyrrolidine. By this route

• extract a hydrogen from the ether C (sp3)–H bond to form radicals. Subsequently, a single electron transfer (SET) leads to the oxonium species. Then, the enamine generated in situ from methyl aryl ketone and pyrrolidine undergoes a nucleophilic reaction with the oxonium species followed by hydrolysis to

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

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

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• compounds’ true inhibitory activity and selectivity toward these relevant GH38 enzymes remain unknown [29]. In this regard, another promising strategy seems to be a modification of the pyrrolidine core at the C-1 position. For example, attaching an amide moiety directly to C-1 in pyrrolidines possessing the

• after hydrogenolysis and treatment with conc. HCl gave hydrochloride 10 (Scheme 1). The versatile intermediate 3 was further employed in the synthesis of the target compounds 17–20 (Scheme 2) homologated at the C-5 position. The transformation of pyrrolidine 3 to 13 included the replacement of the N

• that 29 and swainsonine bind to GMII in a similar manner. The pyrrolidine ring of 29 interacts with the Zn2+ ion cofactor, amino acid residues Asp92, Asp204 (catalytic nucleophile), Asp341 (catalytic acid), Asp472, and Trp 95. The (R)-1-hydroxyethyl group at the C-5 position of the ring forms hydrogen

An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides

• Shubham Sharma,
• Dharmender Singh,
• Sunit Kumar,
• Vaishali,
• Rahul Jamra,
• Naveen Banyal,
• Deepika,
• Chandi C. Malakar and
• Virender Singh

Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22

• ) in 86% yield. To find out more information about the mechanistic route of the reaction, we performed a control experiment in the presence of TEMPO as a radical scavenger as depicted in Scheme 6. The reaction of pyrazole-3-carbaldehyde 1, pyrrolidine (A) and elemental sulfur in the presence of 1.1

• 1C (1.18 g from 1 g, 86%; Rf 0.19 (hexane/EtOAc 90:10, v/v)). Procedure for the synthesis of (5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanethione (1A) through control experiment: In a dry round-bottomed flask, pyrazole-3-carbaldehyde 1 (0.05 g, 0.19 mmol), pyrrolidine (A, 0.015

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• Center, Togliatti State University, Togliatti 445020, Russian Federation Immanuel Kant Baltic Federal University, Kaliningrad 236016, Russian Federation 10.3762/bjoc.18.177 Abstract A straightforward access to novel spiro[benzofuran-2,3'-pyrrolidine]-2',5'-diones based on the Rh2(esp)2-catalyzed

• [benzofuran-2,3'-pyrrolidine]-2',5'-diones based on Rh2(esp)2-catalyzed insertion of carbenes derived from α-diazosuccinimides (DAS) into the O–H bond of phenols. The initial adducts underwent a thermally promoted Claisen rearrangement followed by a DABCO-catalyzed intramolecular 5-exo-dig Michael addition

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• one-pot reactions were also developed by Zhang using the 4-aminoquinoline synthesis, for example, in amino acids(esters)-based [3 + 2] cycloadditions [38][39][40][41][42][43][44][45][46][47][48] and in the synthesis of pyrrolidine-containing systems [49][50][51][52][53][54][55][56][57][58][59

Experimental and theoretical studies on the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-diones

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Nguyen Ngoc Tri,
• Luc Van Meervelt,
• Nguyen Tien Trung and
• Wim Dehaen

Beilstein J. Org. Chem. 2022, 18, 1140–1153, doi:10.3762/bjoc.18.118

• -Trisubstituted pyrrolidine-2,3-dione derivatives were prepared from the above mentioned 2-pyrrolidinone derivatives and aliphatic amines, which exist in enamine form and are stabilized by an intramolecular hydrogen bond. A possible reaction mechanism between 3-pyrroline-2-one and aliphatic amine (CH3NH2) was

• . Keywords: 4-acetyl-3-hydroxy-3-pyrroline-2-ones; 1,5-dihydro-2H-pyrrol-2-ones; pyrrolidine-2,3-dione; 2-pyrrolidinone derivative; 3-pyrroline-2-one; Introduction 2-Pyrrolidone, also known as γ-lactam, is a five-membered heterocyclic ring containing four carbon and one nitrogen atoms [1]. This γ-lactam

• -acetyl-3-hydroxy-3-pyrroline-2-ones via multicomponent reactions of ethyl 2,4-dioxovalerate with aromatic aldehydes, and aniline in glacial acetic acid. These 2-pyrrolidinone derivatives were then reacted with aliphatic amines in ethanol to obtain a library of 1,4,5-trisubstituted pyrrolidine-2,3-dione

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

• Anas J. Rasras,
• Mohamed El-Naggar,
• Nesreen A. Safwat and
• Raed A. Al-Qawasmeh

Beilstein J. Org. Chem. 2022, 18, 631–638, doi:10.3762/bjoc.18.63

• MCF7) [13]. In 2008, Muhi-eldeen et al, synthesized a hybrid compound with 1,3,4-oxadiazole moiety and pyrrolidine connected with propargylic moiety showed antibacterial activity against Staphylococcus aureus and E. coli [14]. On the other hand, the coupling of piperazine with heterocyclic compounds

• were obtained from piperidine and pyrrolidine, respectively, as secondary cyclic amine component (Figure 2). The structures of the newly synthesized compounds were confirmed on the basis of their spectral data in particular nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. The 1H

• HMQC experiment revealed a correlation between the CH–O protons at 3.37, 3.79, and 3.91 ppm, and the carbon atoms at 72.0, 68.6, and 73.2 ppm, respectively. Moreover, the CH2S proton at 3.99 ppm correlated with carbon at 21.7 ppm. The methylene protons in -CH2-N-pyrrolidine at 3.51 ppm correlated with

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• Yuki Naito Naoki Shida Mahito Atobe Graduate School of Science and Engineering, Yokohama National University, Yokohama, Kanagawa 240-8501, Japan 10.3762/bjoc.18.39 Abstract We have successfully synthesized piperidine and pyrrolidine derivatives by electroreductive cyclization using readily

• . Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour. Keywords: electrochemical synthesis; electrocyclization; flow microreactor; heterocyclic amines; imine; Introduction Heterocycles are a very important class of

• compounds and make up more than half of all known organic chemicals [1]. Among them, heterocyclic amines, particularly pyrrolidine and piperidine derivatives, have attracted considerable attention because these are important structural motifs in a wide variety of applications including pharmaceuticals

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• blocks was developed. Regioisomeric methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates were prepared by the reaction of β-enamino ketoesters (including azetidine, pyrrolidine or piperidine enamines) with hydroxylamine hydrochloride. Unambiguous structural assignments were based on chiral HPLC

• , two negative signals of the same phase at δ 1.44 ppm and δ 1.24 ppm were observed (Figure 4b; Supporting Information File 1 in Figure S53a). Additionally, when the pyrrolidine ring proton 2-H (δ 5.61–5.65 ppm) was irradiated, two negative signals of the same phase at δ 5.51–5.56 ppm and δ 5.61–5.65

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• such as piperidine, tetrahydroisoquinoline derivatives, and pyrrolidine were also tolerated well in this reaction. The use of the non-toxic and inexpensive acetone cyanohydrin makes this method more advantageous compared to the known methods. 2 Cyanation of arenes and heteroarenes 2.1 Cyanation of

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• -isothiocyanato-1-indanones with barbiturate-based olefins have been developed to afford chiral dispiro[indene-pyrrolidine-pyrimidine]s. Through this strategy, the target products could be obtained in good to excellent yields with excellent stereoselectivities. In addition, the synthetic utility was verified

• application value of this asymmetric domino Michael addition/cyclization reaction, a gram-scale experiment was performed under the optimized conditions. As exemplified in Scheme 4, the desired dispiro[indene-pyrrolidine-pyrimidine] 3ah could be obtained in 94% yield with excellent stereoselectivity (>20:1 dr

• , >99% ee), which indicated this strategy shows promising prospects for mass production. Moreover, two different transformations of the product 3ah are shown to validate synthetic utility of the reaction. As demonstrated in Scheme 5, the dispiro[indene-pyrrolidine-pyrimidine] 3ah could be easily

Biological properties and conformational studies of amphiphilic Pd(II) and Ni(II) complexes bearing functionalized aroylaminocarbo-N-thioylpyrrolinate units

• Samet Poyraz,
• Samet Belveren,
• Sabriye Aydınoğlu,
• Mahmut Ulger,
• Abel de Cózar,
• Maria de Gracia Retamosa,
• Jose M. Sansano and
• H. Ali Döndaş

Beilstein J. Org. Chem. 2021, 17, 2812–2821, doi:10.3762/bjoc.17.192

• –125 μg/mL) as reference. The tested complexes showed antituberculosis activity, in the range of 3.90–62,50 μg/mL (Table 1) when compared to reference drugs. It is interestingly important to notice that the L3-Ni complex bearing an indole ring in the pyrrolidine skeleton has the highest activity when

• rotation of the thioketone carbon–N-pyrrolidine bond, are energetically accessible, in agreement with the two set of signals observed by 1H NMR spectroscopy (energy differences between conformers lower than 1 kcal·mol–1 in both cases). However, this equilibrium is strongly affected by the coordination to

• nickel or palladium atoms. As far as the L1-Ni complex was concerned, this fluxional equilibrium disappeared due to metal coordination. In this case, complexes involving conformer B were highly energetic due to steric repulsion between the CO2Me substituents of the pyrrolidine ring. Thus, only one set of

The PIFA-initiated oxidative cyclization of 2-(3-butenyl)quinazolin-4(3H)-ones – an efficient approach to 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones

• Alla I. Vaskevych,
• Nataliia O. Savinchuk,
• Ruslan I. Vaskevych,
• Eduard B. Rusanov,
• Oleksandr O. Grygorenko and
• Mykhailo V. Vovk

Beilstein J. Org. Chem. 2021, 17, 2787–2794, doi:10.3762/bjoc.17.189

• literature to date. One of them is based on the construction of the central pyrimidine ring starting from ortho-disubstituted aromatic compounds 2 bearing a pyrrolidine moiety (see Scheme 1A). Examples include cyclocondensation of (2-pyrrolidin-1-yl)benzaldehyde and aniline occurring in the presence of TsOH

• [13], as well as Ir-catalyzed intramolecular dehydrative cross-coupling of 2-(pyrrolidine-1-yl)benzamide [14]. Another approach to compounds of type 1 that relies on a cascade formation of the pyrimidine and pyrrole rings have found much wider application (see Scheme 1B). One of its variations

• well as by Sm(OTf)3-catalyzed stereoselective [3 + 2] cycloaddition of bis-silyldienediolate and imines, in turn synthesized from anthranylamides and benzaldehydes [32]. A promising approach to the synthesis of 2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-one derivatives substituted at the pyrrolidine

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• Bratislava, Radlinského 9, 81237 Bratislava, Slovak Republic 10.3762/bjoc.17.188 Abstract A new highly diastereoselective synthesis of the polyhydroxylated pyrrolidine alkaloid (±)-codonopsinol B and its N-nor-methyl analogue, starting from achiral materials, is presented. The strategy relies on the trans

• evaluated using several cell line models. Keywords: alkaloids; antiproliferative effect; codonopsinol B; diastereoselectivity; pyrrolidines; Introduction Codonopsinol B (1) is a polyhydroxylated pyrrolidine alkaloid isolated from the roots of the plant Codonopsis pilosula (Figure 1) [1]. This compound was

• mentioned work. Pyrrolidine 2 has been prepared before, however, it was not tested against glycosidases [6]. In addition, a very limited number of related 2-aryl-substituted hydroxylated pyrrolidines with a hydroxymethyl substituent at C-5 have been synthesized [7]. Along with (−)-codonopsinol B, five other

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• , Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia 10.3762/bjoc.17.176 Abstract The synthesis of bifunctional N-sulfinylureas and thioureas with an appended pyrrolidine unit is presented. These organocatalysts were evaluated in

• aldehydes and hydrogen-bond activation of nitroalkenes. Keywords: asymmetric organocatalysis; hydrogen bond; Michael addition; pyrrolidine; thiourea; urea; Introduction Asymmetric organocatalysis became one of the strategic ways for the efficient synthesis of chiral compounds [1]. Bifunctional catalysis

• itself, in which the carboxylic function acts as an ancillary hydrogen-bond donor for the direction of one of the reagents [9]. Amines serve as basic units and nucleophilic components capable of carbonyl compounds activation via enamine or iminium ion formation [10][11]. In particular, pyrrolidine became

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• and enantiomeric excesses. On the other hand, N-heterocyclic carbenes and chiral pyrrolidine derivatives acting through covalent bond formation such as the iminium ions with the substrates have also been included. Wherever possible, a comparison has been made between the efficacies of various

• reactions [34][35]. In 2015, Zhao et al. synthesized spiro[pyrrolidine-3,3'-oxindoles] 29 in single step by asymmetric cascade aza-Michael/Michael addition reaction between 4-tosylaminobut-2-enoates 27 and 3-ylideneoxindoles 26 catalyzed by a chiral bifunctional tertiary amine, squaramide (cat. 28) which

• -2,3-dihydro-4-quinolones 99 were obtained in good yields of up to 95% and good ee (58–72%) (Table 22) [61]. 2. Covalent-bonding organocatalysis of aza-Michael reactions This category of organocatalysts includes N-heterocyclic carbenes and pyrrolidine derivatives. 2.1 Catalysis by N-heterocyclic

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

• , Stellenbosch University, Matieland 7602, Stellenbosch, South Africa 10.3762/bjoc.17.170 Abstract A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones

• geometry was inferred from its NOESY spectrum, which showed a weak but distinct correlation between the vinyl proton singlet (δ 5.66) and the methylene group flanked by nitrogen and the ester (δ 4.06). The E-geometry was also suggested by the chemical shift of the hydrogen atoms at C-3 of the pyrrolidine

• ring (δ 3.43), which showed anisotropic deshielding by the carbonyl group. In similar pyrrolidine-containing (Z)-enaminones these hydrogen atoms appear approximately 0.5–0.7 ppm upfield (ca. δ 2.5–2.7) compared to the chemical shifts of related (E)-enaminones [29][34]. In contrast to the corresponding

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

• [46]. A similar type of reaction methodology was employed for the formation of a bicyclic nucleoside analog. 4'-C-vinylribofuranoside derivative 21 on treatment with Hg(TFA)2 followed by reduction with NaBH4 leads to the formation of bicyclic nucleoside derivative 22 (Scheme 10) [49]. Pyrrolidine and

• piperidine derivatives were also synthesized by Hg(II)-salt-induced cyclization. N-Isopropyl-1-aminohex-4-ene (23) on treatment with 1 equiv HgCl2 followed by reduction with NaBH4 yielded pyrrolidine 24 and piperidine derivative 25 in the ratio of 7:3 [50]. N-Methylaniline derivative 26 undergoes cyclization

• with HgCl2 and gave cis-mercuro chlorides 27 and 28 as isolated products (Scheme 11) [51]. For the synthesis of diastereomeric pyrrolidine derivatives, a Hg(II) salt had been used. When HgCl2 was added to secondary methylamine derivatives 29 and 31 followed by reduction with NaBH4 a mixture of

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

• binding simultaneously to the chloride or through a cooperative 2H abstraction mechanism. These findings proved to be decisive in the development of new and more efficient anion-binding catalysts. By introducing a methyl group (R = Me) into the pyrrolidine moiety of the initial catalyst design, the amide

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• and colleagues proposed an asymmetric [3 + 2] cycloaddition employing a coumarin dipolarophile 43 with azomethine ylides 60 organocatalyzed by quinidine (62) for the formation of fused pyrrolidine compounds through activation of the coumarin substrate by hydrogen bonding [53]. The methodology enabled

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• . Moreover, TMS-substituted alkyne was suitable for this Huisgen reaction to achieve the desired triazole product. Next, some triazene scaffolds, such as dimethylamino-, pyrrolidine-, piperidine-, morpholine-, and piperazine-derived triazenes were screened. Aryl azides containing Br, I, Me, and MeO as well

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