N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• lactams). The second approach, which asserts its universality, frequently displays inadequate yield of target compounds. As such, the endeavour to discover novel approaches for synthesizing N-heterocycle-glutarimide ensembles of type 1 persists as imperative. Aliphatic diazocarbonyl reagents are widely

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• ], trifluorinated α-methylene-γ-lactams [99][100], and β-trifluoromethyl-β-acylhydrazonyl carbonyl compounds [101] (Scheme 15). Among these fluorinated products, the trifluoromethylated homoallylic acylhydrazines were easily transformed to CF3-substituted pyrazolines and 1,6-dihydropyridazines via a cascade

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• ) [82]. In the method, functionalized γ-lactams 102 were produced in aqueous media with high enantioselectivities. However, N-(alkylsulfanyl)succinimides and α-isobutyl containing butyrolactam did not work in this reaction. Another work by Denmark on intramolecular sulfenylation of alkenes 119 with

• basic nature. However, the electron-poor ones exhibited less autocatalysis effect requiring the use of the Lewis base catalyst P. In 2019, Denmark and Panger disclosed a novel method for the preparation of γ‑lactams 133 through the reaction of alkenes 132 with N-thiophthalimides 14 in the presence of

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

• lactams 1, 2b, and 3 (i.e., cleavage of Ar–N bond or removal of >C(CH3)2 or >C=O bridge) leads to secondary α-bromo(phenyl)acetamides 4a and 4b. When α-bromoamide 4a was treated with thiobenzamide without any base (entries 1 and 7 in Table 3), 2,5-diphenyl-1,3-thiazol-4-ol (13) was the only product

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

• /bjoc.19.50 Abstract Phostams, phostones, and phostines are a series of 1,2-azaphosphaheterocycle and 1,2-oxaphosphaheterocycle 2-oxide derivatives. They are phosphorus analogues of lactams and lactones and important biologically active compounds. The strategies for the synthesis of medium and large

• Phostam, phostone, and phostine derivatives are important 1,2-aza/oxaphosphaheterocyclic compounds and phosphorus analogues of lactams and lactones. They show important biological activities. Medium and large phostam, phostone, and phostine derivatives are important biologically active compounds. Several

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• the synthesis of tricyclic α-methylene-γ-lactams 7 as single diastereomers and in good to high yields through the use of a catalytic amount of AgOTf (silver trifluoromethanesulfonate) as an anion-exchange agent (Scheme 1d) [35]. In this transformation, treatment of 3,4-dihydroisoquinolines 5 with acyl

• -heterocycles [39][40][41][42][43][44][45] and specifically α-methylene-γ-lactams as a subset of this compound class, are popular targets in heterocyclic chemistry and drug discovery [46][47][48][49][50][51][52][53][54][55][56]. Against this background, we herein disclose a full account of our studies on the

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• ][72]. A recent achievement of the enantioselective hydroxylation of α‑aryl-δ-lactams by O2 is shown in Scheme 5 [73] as an example of such organocatalyzed reaction type. Triethyl phosphite is added to reduce a hydroperoxide, which is initially formed by the enolate oxidation with O2. In summary

• with amino and nitro groups due to side processes on the electrodes. Cyclic carbamates were oxidized to lactams using ABNO derivatives as electrocatalysts [104] (Scheme 16A). The substrates with easily oxidizable pyrazole and oxazole fragments reacted successfully under these conditions. Under similar

• -hydroxylation of lactams under phase-transfer organocatalysis conditions employing a chiral quaternary ammonium ion salt. Selective CH-oxidation of methylarenes to aldehydes or carboxylic acids. An example of the regioselective CH-amination by a sterically hindered imide-N-oxyl radical precursor. CH-amination

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• which parts are prone to oxidation/metabolization. A remarkable result, using diluted iodine, was actually reported recently [301]. Concerning another class of “old” drugs, and as depicted in Figure 9 with the (few) structures 49–61, the many generations of β-lactams used in human medicine is certainly

• various bacterial β-lactamases but still reactive (and selective) enough to form relatively stable covalent adducts with the bacterial DD-transpeptidases. The carboxylic or sulfonic moieties in these structures are instrumental in this regard. As seen in Figure 9, the rate of new β-lactams approved for

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• China 10.3762/bjoc.18.90 Abstract γ-Phostams include γ-phosphonolactams and γ-phosphinolactams and their fused derivatives, phosphorus analogues of γ-lactams. They are 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides and important biological five-membered azaphosphaheterocycles. They have

• analogues of the corresponding lactams [11][12][13][14]. 1,2-Azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides, also called γ-phosphonolactams and γ-phosphinolactams, and their fused derivatives are important five-membered 1,2-azaphosphaheterocyclic derivatives. They are γ-phostams, phosphorus

• analogues of γ-lactams, showing various biological activities, such as anti-inflammatory [15][16], antioxidant [17][18], and antitumor [18][19][20] (Figure 1). Various synthetic methods of 1,2-azaphospholidine 2-oxide and 1,2-azaphospholine 2-oxide derivatives have been developed to date. Two major

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

• nitrogen atom to nitrenium intermediates occurred initially; further stabilization of these species resulted in the formation of hydroxylated lactams [44][45][46][47][48], azaspirocycles [49][50][51][52][53], or tricyclic nitrogen-containing heterocycles [44][53]. Our study commenced with the synthesis of

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• secondary and tertiary amines, amides/lactams/carbamates, and nitrile. The test reactions were monitored by thin-layer chromatography (TLC) and, where deemed necessary, results were further verified by GC–MS. The reagents employed encompassed tritylium tetrafluoroborate [50], H2O2/HBr [42], ceric ammonium

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• [21], this variation of the reaction draws considerably less attention in comparison to the usage in the synthesis of amides or lactams. As presented in Figure 2, after initial formation of the azidohydrine by addition of hydrazoic acid to the ketone, the reaction can undergo two pathways. In the

• . Intramolecular Schmidt reaction of alkyl azides and ketones, which follows the first pathway in the mechanism, found especially broad application in the synthesis of different lactams [23][24]. Serious drawbacks of the Schmidt reaction for tetrazole synthesis are the need for a large excess of the hazardous

• , employing hydrazoic acid, was used in transformations of some steroidal ketones to the corresponding lactams and tetrazoles. Often in these cases, the yield of the tetrazole was low, and the steroids used as starting material lacked potentially reactive functional groups [36][37][38][39]. Referring to the

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

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

• -alkylarenesulfonamides, N-fluoropyridinium salts and derivatives, N-fluoroquinuclidium salts, N-fluoro-trifluoromethanesulfonimide, N-fluoro-sultams, N-fluoro-benzothiazole dioxides, N-fluoro-lactams, N-fluoro-o-benzenedisulfonimide, N-fluoro-benzenesulfonimide, 1-alkyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane salts, N

• al. allowed these lactams to react with 0.05% 18F2/Ne in a freon and obtained the N-[18F]fluorolactams 12-1 in good yields (Scheme 27, entry 1). The 18F-transfer ability was demonstrated by fluorination reactions with various Grignard reagents in up to 51% yield (Scheme 27, entry 2). In the event the

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

• external Lewis acid and trimethylaluminum as a methyl source (Scheme 7) [61]. The late-stage methylation of simple heterocyclic motifs was initially investigated using (S,S)-Mn(CF3–PDP) (21), providing methylated lactams 22a–e. Notably, methylation site selectivity was observed for the carbon atoms

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

• nucleophiles beyond the usually employed dicarbonyl compounds to cyanoacetates, nitroacetates, fluoroacetates, lactones, lactams, and aromatic and heteroaromatic carbonyl compounds. The reactions were carried out at higher temperatures (120 °C) than used in the previous protocols involving more reactive

• -biphenyl)]Cl as a catalyst (Scheme 8) [41]. Under mild conditions, functionalized five and six-membered lactams 14 were synthetized in excellent yields (90–99%), including those of the lactams in which a quaternary center was constructed. Only exo-trig cyclization products were obtained, and substrates

• (Scheme 8B). An asymmetric version of this reaction was developed in 2014 by the Gandon group [42], who employed the chiral bis(phosphine)digold(I) complex 18 as a pre-catalyst in combination with silver triflate as an activator (Scheme 9). They obtained lactams 17 by cyclization of α-substituted N

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

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• pharmacy as highly biological active compounds. Among this group of nitrogenated heterocycles, β-lactams (azetidin-2-ones) have reached especial attention [78][79][80], being easily accessible from β-aminoesters. A stereoselective synthesis of 1-substituted 2-azaspiro[3.3]heptanes 45 (n = 1) was reported

• the asymmetric synthesis of a variety of aromatic, heteroaromatic, and aliphatic 1-substituted 2,6-diazaspiro[3.3]heptanes 48, with overall yields ranging from 74 to 94% (Scheme 16). Asymmetric synthesis of β–lactams β-Lactam antibiotics are important drug class of antibacterial agents [83] and in the

• successively into β-amino esters 51, and the corresponding β-lactams 52 with high optical purity (Scheme 17) [89]. The absolute configurations of compounds 52 were obtained by the comparison of the signs of specific rotation of 52 with R = Ph(CH2)2, with that of known (R)-4-(2-phenylethyl)azetidin-2-one. A 6/4

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• remedies [4]. β-Lactams (BL) have served as the first line antibiotics since the introduction of penicillin. However, due to existence and continuous increase in β-lactamases [5], multidrug therapy is becoming the new modality of bacterial treatment against multiple-drug resistant (MDR) bacteria. Multidrug

• passing through phase I and phase III clinical trials [6][25] in combination with different types of β-lactams. These multidrug combinations have shown promise for future antibiotic regime and drug development based on non-β-lactam inhibitors. Nonetheless, a partial loss of activity has been reported in

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

• , 12843 Prague 2, Czech Republic 10.3762/bjoc.17.58 Abstract Pyrrolidones are common heterocyclic fragments in various biologically active compounds. Here, a two-step radical-based approach to γ-lactams bearing three to four stereocenters starting from epoxides, N-allylic silylacetamides and TEMPO is

• reactions providing functionalized pyrrolidones in high yields as diastereomeric mixtures. They converge to 3,4-trans-γ-lactams by base-mediated equilibration, which can be easily further diversified. Stereochemical models for both reaction types were developed. Keywords: Brook rearrangement; cyclization

• ; electron transfer; γ-lactams; tandem reactions; Introduction Nitrogen-containing heterocycles are widely distributed in biologically active compounds [1][2][3][4]. Saturated nitrogen heterocycles such as pyrrolidines [5][6][7][8][9], piperidines, pyrrolizidines or indolizidines [10][11][12][13][14][15][16

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

• Zbigniew Malinowski,
• Emilia Fornal,
• Agata Sumara,
• Renata Kontek,
• Karol Bukowski,
• Beata Pasternak,
• Dariusz Sroczyński,
• Joachim Kusz,
• Magdalena Małecka and
• Monika Nowak

Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50

• selectively alkylated on the nitrogen atom [30][36]. For our purposes, the simple alkyl halides (MeI, iPrI), and 2-chloro-N,N-dimethylethylamine hydrochloride and 4-(2-chloroethyl)morpholine hydrochloride, were chosen as the alkylating agents. Thus, the desired N-methyl and N-isopropyl lactams 3a,b (3a R1

• = Me, 85%; 3b R1 = iPr, 84%) were obtained by the direct alkylation of bromophthalazinone 2 with methyl or isopropyl iodide in the presence of K2CO3 in dry acetone as the solvent (conventional heating). In the similar way also the 2-aminoethyl lactams 3c (R1 = CH2CH2NMe2) and 3d (R1 = CH2CH2(morpholin

• 2-chloro-N,N-dimethylethylamine and 4-(2-chloroethyl)morpholine and further palladium-catalyzed amination of lactams 3 with aliphatic, aromatic, benzylic, cyclic amines and polyamines. Furthermore, we have demonstrated that some of the phthalazinone derivatives act as ligands and form stable

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• employment of these methods for modification of lactams is a challenge in its own right – there are hardly any examples of such transformations available in the literature [23]. Our group was the first to surmount this challenge by means of Schwartz’s reagent-mediated reductive functionalization. Since then

• , we have performed a number of different functionalizations of such cyclic systems with various complexity, and with a particular focus on the modification of sugar-derived lactams. As summarized in Scheme 1, this includes simple nucleophile addition to in situ-generated imines [23], the consecutive

• have, however, only reported one example of lactam functionalization which only proceeded with moderate efficiency (1-tert-butylazepan-2-one, 41% yield of the desired product). Unfortunately, this approach cannot be utilized for the functionalization of secondary amides, like sugar-derived lactams, due

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

• Tetsuya Sengoku,
• Koki Makino,
• Ayumi Iijima,
• Toshiyasu Inuzuka and
• Hidemi Yoda

Beilstein J. Org. Chem. 2020, 16, 2769–2775, doi:10.3762/bjoc.16.227

• 501-1193, Japan 10.3762/bjoc.16.227 Abstract New synthetic methods for spirolactams bearing an α-methylene-γ-butyrolactone or its analogous methylene-lactam have been developed. The allylation of γ-phenylthio-functionalized γ-lactams with 2-(acetoxy)methyl acrylamides was accomplished by using 2.5

• methylene-lactams (C) through zinc-catalyzed addition to N-carbonyl imides [13][14][16]. Meanwhile, we also developed an umpolung electrophilic allylation of 3-heterosubstituted oxindole D for the synthesis of lactam analog of A (Scheme 1c) [17]. The oxindole D readily reacted with 2-(acetoxy)methyl

• conditions, 3i–o were predominantly formed in 92–99% yields. Thus, we could obtain a wide variety of 3-phenylthio lactams bearing an amide functionality by electrophilic allylation with 1. Having completed the installation of an acrylamide side chain into 3-phenylthio lactams, we subsequently proceeded to

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• cyclic olefins, such as diesters, imides, and lactams with varied functionalization patterns and different structural architectures is described. The synthetic methodologies were based on electrophilic activation through halonium ions of the ring olefin bonds, followed by nucleophilic fluorination with

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• photocycloaddition of coumarins 202 (Scheme 31) [89]. The proposed mechanism for this reaction is similar to that proposed by Bach and Krische, proceeding via a key hydrogen bonding complex 203. Interestingly, this catalyst allowed for reactivity with lactones, whereas Bach’s catalysts are limited to lactams. Yoon

• the substrate within a hydrogen bonding complex 207 that provides the desired products 208 in excellent yields and good enantioselectivities (13 examples, up to 96:4 er) and a quantum yield of 0.31 [91]. As with Bach’s catalysts, the scope is limited to lactams. Yoon et al. then applied a similar