Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• % yield. Compound 4a could be hydrogenated to the corresponding reduction product 12 using Pd/C and ammonium formate conditions (Scheme 6a). Notably, as shown in Scheme 6b, treatment of the unsaturated γ-AA derivative 6a with Pd/C and ammonium formate led to a cyclization reaction, furnishing γ-lactam 13

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

• -unsaturated acyl chlorides to afford substituted α-methylene-γ-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov

• -lactam heterocycles 19 in up to 76% yield and with good to high diastereoselectivities (4.3:1 to 16:1). We have demonstrated the scalability of the reaction with a gram-scale example. The relative stereochemistry of the α-methylene-γ-lactam products 19 has been determined via the single-crystal X-ray

• on the success of the catalytic aza-Nazarov reaction. Keywords: α-methylene-γ-lactam; aza-Nazarov reaction; β-silicon effect; heterocycles; intramolecular cyclization; Introduction The rapid construction of aliphatic heterocycles from acyclic building blocks via cyclization or cycloaddition

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

• . 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

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

• /reagent combinations employed. The reaction of the secondary N-methylamine 2b with CBr4 [22] gave fluorenone (3) in 6% yield (determined by GC–MS), while tertiary amines, amides, and the γ-lactam 2e did not yield any. Formation of fluorenone (3) was also confirmed after applying a modified version of one

• fluorenone (3) in 30% yield (determined by GC–MS). TLC analysis further revealed that fluorenone formation does not occur when treating tertiary amides 2h and 2i, γ-lactam derivative 2e, and carbamate 2j with this reagent (Table 1, entries 5, 8, 9, and 10). The reaction does, however, also work with tertiary

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

• ] are central fragments in various natural products, which are often synthesized from lactams by reduction. This makes them important building blocks in the total syntheses of alkaloids and their non-natural analogs [17][18][19][20][21]. However, the γ-lactam substructure itself is a central fragment of

• γ-lactam scaffold [40][41][42][43][44]. The pyrrolidinone fragment is often synthesized by transition metal- [45][46][47][48][49][50] or Lewis acid-catalyzed cyclization reactions [51][52][53][54]. The Diels–Alder reaction can also be used for the preparation of functionalized γ-lactams in a single

• step [55]. Radical 5-exo or 5-endo cyclizations of substituted N-allyl or N-vinyl α-halo amides VIII [56][57][58][59][60][61] or X [62][63][64][65][66] using atom transfer and other chain reactions, as well as non-chain methods [67][68][69][70][71][72][73] have been used to approach diverse γ-lactam

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

• -lactam structure. The key intermediates were synthesized by electrophilic allylation of γ-phenylthio-functionalized γ-lactam derivatives with 2-(acetoxy)methyl acrylamides in the absence of any metal catalyst and delivered into each type of spirolactams through desulfinative hydroxylation/lactamization

Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: application of ¹J_C,H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial metabolites

• Md. Rokon Ul Karim,
• Enjuro Harunari,
• Amit Raj Sharma,
• Naoya Oku,
• Kazuaki Akasaka,
• Daisuke Urabe,
• Mada Triandala Sibero and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 2719–2727, doi:10.3762/bjoc.16.222

• actinomycete origin. For example, salinosporamide A, an antitumor drug candidate in clinical trials, is a proteasome inhibitor with an unusual γ-lactam-β-lactone bicyclic core produced by marine Salinospora tropica [10]. Abyssomicin, another example of uncommon polycyclic frameworks, is an antibacterial

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

• halofluorination of the trans-imide (rac)-10. Synthesis of the cyclic carbamide (rac)-13. Halofluorination reactions of the γ-lactam (rac)-14. Relevant NOESY interactions are indicated by two-headed arrows. Reactions of the diester 16 with NBS or NIS in the presence or absence of Deoxo-Fluor®. Formation of the

Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

• an ene reaction of β-citronellol and Diels–Alder reactions of α-terpinene and (5-methylfuran-2-yl)methanol [46] as well as the synthesis of cyclopent-2-enones from furans [47] and the synthesis of diverse γ-lactam scaffolds [48]. Conversions larger than 90% were achieved for all reactions [46][47][48

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• was followed by the aziridinium ion opening with cyanide to access compound 64 which was first transformed into diester and later after hydrogenolysis into the γ-lactam (S)-65 [62]. The methoxycarbonyl to acetyl group conversion was accomplished via Weinreb amide to give the pyrrolidin-2-one (S)-66

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• Benzo-fused γ-lactam rings such as isoindolin-2-ones and 2-oxindoles are part of the structure of many pharmaceutically active molecules. They can be often synthesized by means of multicomponent approaches and recent contributions in this field are summarized in this review. Clear advantages of these

• -oxindoles; Introduction Pyrrolidin-2-ones (I, Figure 1) are heterocycles that contain a γ-lactam ring that can be found in many biologically active compounds with natural or synthetic origin [1]. When an aryl group is fused to the 3- and 4-positions of the five-membered heterocycle, isoindolinones (II

• , Figure 1) are generated, while if such fusion takes place between the 4- and 5-positions of the γ-lactam ring, 2-oxindoles (also named as indolin-2-ones III, Figure 1) are formed. The isoindolinone structural motif is a part of the core of many natural products [2]. To cite some examples, cichorine [3

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields. Keywords: amino acid-based isocyanides; levulinic acid

• -tryptophane, DL-leucine and DL-phenylalanine worked very well in this reaction to provide the corresponding pseudo-peptides 4 containing γ-lactam, amide and ester functional groups in a single structure. By starting from DL-amino acids, the corresponding racemic isocyanides were obtained. By using the racemic

• Figure 2 (CCDC 1896942); for details of the crystal structure data and refinement of (R*,S*)-4a see Supporting Information File 1). Conclusion In conclusion, we have synthesized a novel category of pseudo-peptides containing γ-lactam, amide and ester moieties in a single structure via Ugi-4-centre-3

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• . Ring opening proved to be successful with second generation catalysts, yielding the corresponding diolefinated isoxazoline (±)-17 (Scheme 6). Our studies were continued with the ROM reactions of conformationally restricted γ-lactam (±)-18 (Vince’s lactam) as model compound [24]. The ring opening in

• multiple stereogenic centers thus synthesized can be considered interesting scaffolds for further transformations in view of the access of novel three-dimensional functionalized scaffolds through cross-metathesis (CM). An illustrative example is shown on Scheme 7. Divinylated γ-lactam (±)-19 selected as a

• of an ethylene atmosphere for the time indicated in the text (monitored by TLC). After completion of the reaction, the mixture was concentrated under vacuum and purified by column chromatography on silica gel (n-hexane/EtOAc). General procedure for cross-metathesis To a solution of γ-lactam

Methyl isocyanide as a convertible functional group for the synthesis of spirocyclic oxindole γ-lactams via post-Ugi-4CR/transamidation/cyclization in a one-pot, three-step sequence

• Amarendar Reddy Maddirala and
• Peter R. Andreana

Beilstein J. Org. Chem. 2018, 14, 875–883, doi:10.3762/bjoc.14.74

• conclusion, we have investigated and developed an efficient process towards spirocyclic α,β-unsaturated γ-lactam oxindoles and spirocyclic γ-lactams using a one-pot three-step post-Ugi-4CR intramolecular transamidation/cyclization approach. We utilized this strategy for the synthesis of a small library of

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• subsequent 1,2-proton transfer followed by the elimination of triphenylphosphine and ring closure via formation of the new C–N bond gave the final γ-lactam derivatives 80 (Scheme 50) [66]. In 2013 Mohebat et al. used 6-amino-N,N'-dimethyluracil as an NH-acid and precursor of the carbon nucleophile in the

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

Highly reactive, liquid diacrylamides via synergistic combination of spatially arranged curing moieties

• Maximilian Maier,
• Magnus S. Schmidt,
• Markus Ringwald and
• Christoph P. Fik

Beilstein J. Org. Chem. 2017, 13, 372–383, doi:10.3762/bjoc.13.40

• , or 5-membered γ-lactams can be formed. The emerging FTIR signal at ≈1680 cm−1 strongly indicates the formation of γ-lactams as it can be attributed to the stretching vibration of γ-lactam carbonyl groups [28]. However, the corresponding δ-lactam peak could be located below the amide peak at ≈1645 cm

• the curing of 1–6 at 37 °C (* no polymerization heat detected). FTIR spectra of 1–6 before (top) and after (bottom) curing; the arrows indicate emerging, characteristic γ-lactam vibration at ~1680 cm−1 for polymers 1 and 3–5. Flexural strength (FS) and E-modulus of cured crosslinkers 1–6; letters

p-Nitrophenyl carbonate promoted ring-opening reactions of DBU and DBN affording lactam carbamates

• Madhuri Vangala and
• Ganesh P Shinde

Beilstein J. Org. Chem. 2016, 12, 2086–2092, doi:10.3762/bjoc.12.197

• towards highly electrophilic p-nitrophenyl carbonate derivatives with ring opening of the bicyclic ring to form corresponding substituted ε-caprolactam and γ-lactam derived carbamates. This simple method presents a unified strategy to synthesize structurally diverse ε-caprolactam and γ-lactam compounds

• behavior of DBU towards imidazolides providing ε-caprolactam-derived carbamates and amides [17]. Here, in this report we present the results obtained by the reaction of DBU and DBN with highly electrophilic p-nitrophenyl carbonates leading to ε-caprolactam and γ-lactam carbamates. p-Nitrophenyl carbonates

• reaction giving the γ-lactam carbamate 2ab in 56% yield (Table 2). The 1H NMR spectrum of the product 2ab showed a broad singlet at 5.70 ppm assigned to the carbamate NH. The corresponding peaks at 175.6, 156.3 ppm in the 13C NMR spectrum as well as the HRMS and IR data confirmed the ring opening of DBN

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• diazoacetamides (Scheme 8) [61]. He found an important example of a transformation where the ratio of gamma vs beta-lactam formation could be controlled to a significant extent by catalyst choice. In particular, Rh2(4S-MEOX)4 favored the bridged γ-lactam 41 over the fused β-lactam 42 in about a 3:1 ratio. The

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• transformation was regio and stereoselective where the main product was trans-γ-lactam (56). The chiral rhodium complexes (S)-17, (S)-18 and (S)-23 were also evaluated and yielded similar regio- and diastereoselectivity, however, with lower enantioselectivity when compared to the bis(oxazoline)/CuCl2/NaBARF

• C(sp3)–H catalyzed by (S)-23. Asymmetric insertion of copper carbenoids in C(sp3)–H bonds to prepare trans-γ-lactam. Chiral porphyrin iridium complex catalyzes the carbenoid insertion into bis-allylic C(sp3)–H bonds. Chiral porphyrin iridium complex catalyzes the carbenoid insertion into

New synthetic strategies for xanthene-dye-appended cyclodextrins

• Milo Malanga,
• Andras Darcsi,
• Mihaly Balint,
• Gabor Benkovics,
• Tamas Sohajda and
• Szabolcs Beni

Beilstein J. Org. Chem. 2016, 12, 537–548, doi:10.3762/bjoc.12.53

• -B lactone belongs to the carbonyl stretching of the γ-lactone moiety of the dye and this value is very similar to that found in the carbonyl region of the IR spectrum of Rho-β-CD at 1755.4 cm−1. This last frequency is typical for the carbonyl stretching of a γ-lactam ring [27], thus demonstrating

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• sterically hindred 64 (Scheme 20) [61] in a similar MAO-N/MCR combination. In this way, dipeptide mimics 66 were obtained in good yields (75–83%), however, now with very high diastereomeric (>98%) and enantiomeric excesses (>99%). γ-lactams The γ-lactam unit is an important dipeptide pharmacophore since it

• can induce β-turns. A well-known example was described by Freidinger in 1980, who successfully developed a γ-lactam β-turn mimic of the luteinizing hormone-releasing hormone (LHRH) almost nine times more potent than the original hormone [64]. Since then, these “Freidinger lactams” have been used in

• numerous pharmaceutical and biological active compounds. For example, they are found in compounds used for the treatment of epilepsy [65][66], HIV [67][68], and depression [69]. Multicomponent reactions towards γ-lactam peptidomimetics were earlier described by Ugi [70], Mjalli [71] and Harriman [72

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative

• Tomoko Yajima,
• Eriko Yoshida and
• Masako Hamano

Beilstein J. Org. Chem. 2013, 9, 1432–1436, doi:10.3762/bjoc.9.161

• development of stereoselective synthesis of chiral γ-lactams remains a challenge [4][5]. Developing effective and simple synthetic methods is important so that the drug candidates can be screened. A stereoselective addition to a γ-lactam skeleton provides a direct and efficient method for synthesizing various

• γ-lactam derivatives. However, the most commonly used methods for synthesizing chiral γ-lactams are based on the cyclization or cycloaddition of N-containing precursors, which are synthesized stereoselectively, and there are limited studies on the stereoselective additions to γ-lactam skeletons [6

• ][7][8] and no reports on radical addition. We have already investigated diastereoselective alkyl radical additions to α-methylene-γ-phenyl- γ-lactam and reported that the N-unsubstituted lactam yields cis-α,γ-disubstituted lactams using (Me3Si)3SiH under UV irradiation, whereas the reactions of N

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• Comparing with results obtained using dirhodium(II) catalysis, the α-H-analogue of the azepane derivative 5c was prepared in 67% yield by Doyle et al. from 3d [61]. They could also prepare the analogous azocane-derived α-H-β-lactam in 45% yield, accompanied by a 22% yield of the α-H-γ-lactam. Interestingly