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

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

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 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

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

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

Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita–Baylis–Hillman adducts

• Soundararajan Karthikeyan,
• Radha Krishnan Shobana,
• Kamarajapurathu Raju Subimol,
• J. Helen Ratna Monica and
• Ayyanoth Karthik Krishna Kumar

Beilstein J. Org. Chem. 2020, 16, 1579–1587, doi:10.3762/bjoc.16.130

• chemists. Accordingly, MBH adducts have been explored as strategic intermediates for the synthesis of interesting molecules, such as carbamates of unsaturated β-amino acids [1], β-phenylsylfenyl-α-cyanohydrocinnamaldhydes [2], 2-alkylcarbonyl-1-indanols [3], dihydropyrazoles [4], tetrahydroacridines [5], γ

• -lactams [6], quinolin-5-ones [7], spirobisglutarimides [8], indolizines [9], and spiro carbocyclic frameworks [10]. However, most of the reported synthetic transformations utilize either allylic hydroxy-protected or allyl halide-substituted MBH adducts [11][12][13][14][15][16][17][18][19][20][21][22][23

Preparation and in situ use of unstable N-alkyl α-diazo-γ-butyrolactams in Rh^II-catalyzed X–H insertion reactions

• Maria Eremeyeva,
• Daniil Zhukovsky,
• Dmitry Dar’in and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2020, 16, 607–610, doi:10.3762/bjoc.16.55

• -ethoxalyl-γ-lactams 6a–c, prepared by oxalylation of the respective γ-lactams as decribed previously [1], underwent a rapid diazo transfer reaction via the conventional protocol [4][5] employing 4-nitrobenzenesulfonyl azide and DBU. A quick filtration through a plug of alumina (in lieu of silica gel, which

• led to decomposition of the diazo compounds 4a–c), and addition of an alcohol, a thiol, or an aromatic amine along with a RhII catalyst resulted in a rapid insertion reaction and the isolation of the desired α-substituted γ-lactams 7a–o in modest yields (Scheme 1). It should be noted that, after some

• substantially expanded, thereby making this approach more useful for potential medicinal chemistry exploration of these disubstituted γ-lactams. Previously reported uses of α-diazo-γ-butyrolactams 1 and 4. Generation and in situ RhII-catalyzed X–H insertion reactions of the diazo compounds 4a–c. Conditions

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

• methods include the efficiency in saving raw materials and working time. However, there is still a need of new catalytic systems to allow the enantioselective preparation of these heterocycles by multicomponent reactions. Keywords: indolin-2-ones; isoindolinones; γ-lactams; multicomponent reactions; 2

• imines 99 to furnish complex spirocyclic γ-lactams 101 (Scheme 29) [107]. These products show a trans orientation of the benzene moiety in the isoindolinone and the substituent in R2, according to NOE experiments and crystal structure analysis. The proposed mechanism involves an initial palladium

• generation of new chiral centres. This drawback needs to be addressed so that new ligands and organocatalysts can be discovered and applied to the synthesis of enantiomerically pure γ-lactams of this type under smooth and environmentally more benign reaction conditions. Another area of improvement is the

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

• functionalized derivatives such as bicyclic lactones, γ-lactams or isoxazolines, derived from various cyclodienes and to evaluate their chemical behavior under Ru-catalyzed ring-opening conditions (Scheme 2). First, the ring opening of racemic bicyclic γ-lactone (±)-3 (derived from cyclodiene 1 via β-lactam

• transformations, cyclic dienes with different ring sizes might be considered to be important starting materials for the generation of structurally diverse molecules. Among the large number of possible transformations, the ring olefinic bond of alicyclic dienes may lead to valuable β-lactams [21][22][23] or γ

• -lactams [24], shown to be highly important precursors for the access of various structures (e.g., amino acids, azido esters, hydroxylated amino esters, fluorinated amino esters, etc.) with various functional groups as well as stereochemical and skeletal diversity [21][22][23]. Results and Discussion

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• introduction of the iodobenzoic acid motif onto the pyrrole ring. 5-Aroyloxy-γ-lactams 4 can be isolated with yields in the 56–96% range, however, the reaction requires 2.5 equivalents of the λ5-iodane reagent, a result that supports its limited efficiency in terms of atom economy (Scheme 3) [31]. λ3-Iodane

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

• spirocyclic oxindole γ-lactams). There have been other groups in the past, including our own research group, who have reported on post-modified Ugi-four-component synthetic strategies (Scheme 1) towards the synthesis of 2-oxindoles and spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-diones and spiro[indoline-3,2

• facile to synthesize. Here within, we document that the reaction sequence for spirocyclic oxindole γ-lactams (Scheme 2) follows a three-step sequential strategy involving: a) an Ugi-4CR, b) an acid-promoted intramolecular transamidation, and c) a base-mediated cyclization giving spiro[indoline-3,2

• 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

• carried out by Yavari and Nourmohammadian in good yields of 80–85% (Scheme 49) [22]. A facile route to N-acylated α,β-unsaturated γ-lactams 80 was reported by Asghari et al. The reaction of acetylenedicarboxylates with triphenylphosphine and N-acetylaminocyanoacetate gave the corresponding ylide 79. The

• -chlorotetrahydrofuran-2,4-dione. Synthesis of N-acylated α,β-unsaturated γ-lactams via resonance-stabilized phosphorus ylides derived from N-acetylaminocyanoacetate. Synthesis of resonance-stabilized phosphorus ylides derived from 6-amino-N,N'-dimethyluracil and their subsequent cyclization to bicyclic compounds

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

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

• . To evaluate the substrate feasibility, one phenol, an allylic alcohol and three sugar alcohols were subjected to the reaction. The 3,4-dimethylphenyl p-nitrophenyl carbonate (9a) and geranyl carbonate 10a gave the corresponding γ-lactams 9b and 10b in 62% and 46% yields, respectively. Similarly, the

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• % yield, 95.5:4.5 to 97:3 er). The resulting nitroalkane adduct 159 could be reduced and cyclized to access α,γ-disubstituted γ-lactams. Ellman and co-workers, in the second example of conjugate addition–enantioselective protonation with nitroalkenes, showed that thioacids 160 could be added in high

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• corresponding halide in the presence of sodium hydride, giving thus access to thioether derivatives of type 68, which can also be converted into γ-lactams such as 69. On the other hand, experiments carried out with pyridyl and quinoylthiazolone substrates reveal that in these cases selectivity is higher than

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• enantioselectivity. Since the publication of these results, many different types of chiral dienes have been used in rhodium-catalyzed ECA reactions [148][149]. In 2011, Lin and co-workers reported the rhodium–diene-catalyzed asymmetric 1,4-arylation of γ-lactams [150]. Though He and co-workers previously reported a

• 1,4-arylation of γ-lactams, they obtained the product in moderate yields and good enantioselectivities [151]. When Lin and co-workers were developing their 1,4-arylation procedure, they decided to use a chiral diene because the literature had shown that these ligands provide higher reactivities and

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

• to determine the biological activity of peptides and peptidomimetics,[50] and research towards such peptidic structures containing proline-analogues has received much attention [48]. In this part, multicomponent reactions to access pyrrolidines and other five-membered derivatives such as γ-lactams

• 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

• ]. However, in the last decade two other groups, independently, published Ugi-MCRs towards these cyclic dipeptide isosteres. Hulme et al. reported an Ugi-Deprotection–Cyclization strategy using resin-bound convertible isonitrile 67 to provide primary and secondary γ-lactams 70 in high purities over five

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

• Tomoko Yajima Eriko Yoshida Masako Hamano Department of Chemistry, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo, 112-8610, Japan 10.3762/bjoc.9.161 Abstract The cis- and trans-stereoselective radical additions to α-methylene-γ-alkyl- γ-lactams were investigated and the scope and limitation of

• acid derivative; radical alkylation; Introduction γ-Lactams exist in many natural products and biologically active compounds and are one of the most important classes of compounds for drug discovery [1][2][3]. Substituted γ-lactams, in particular, have potential application in drug synthesis, but the

• 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

A construction of 4,4-spirocyclic γ-lactams by tandem radical cyclization with carbon monoxide

• Mitsuhiro Ueda,
• Yoshitaka Uenoyama,
• Nozomi Terasoma,
• Shoko Doi,
• Shoji Kobayashi,
• Ilhyong Ryu and
• John A. Murphy

Beilstein J. Org. Chem. 2013, 9, 1340–1345, doi:10.3762/bjoc.9.151

• Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka 535-8585, Japan Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK 10.3762/bjoc.9.151 Abstract A straightforward synthesis of 4,4-spirocyclic indol γ-lactams by tandem radical cyclization of iodoaryl allyl

• azides with CO was achieved. The reaction of iodoaryl allyl azides, TTMSS and AIBN under CO pressure (80 atm) in THF at 80 °C gave the desired 4,4-spirocyclic indoline, benzofuran, and oxindole γ-lactams in moderate to good yields. Keywords: 4,4-spirocyclic indol γ-lactams; carbon monoxide; free radical

• ; iodoaryl allyl azides; tandem radical cyclization; Introduction 4,4-Spirocyclic oxindole γ-lactams containing a quaternary carbon center are key structures for the synthesis of biologically active natural products and the related analogues [1][2][3][4]. Therefore, the development of an efficient synthesis

Automated three-component synthesis of a library of γ-lactams

• Erik Fenster,
• David Hill,
• Oliver Reiser and
• Jeffrey Aubé

Beilstein J. Org. Chem. 2012, 8, 1804–1813, doi:10.3762/bjoc.8.206

• , Germany 10.3762/bjoc.8.206 Abstract A three-component method for the synthesis of γ-lactams from commercially available maleimides, aldehydes, and amines was adapted to parallel library synthesis. Improvements to the chemistry over previous efforts include the optimization of the method to a one-pot

• process, the management of by-products and excess reagents, the development of an automated parallel sequence, and the adaption of the method to permit the preparation of enantiomerically enriched products. These efforts culminated in the preparation of a library of 169 γ-lactams. Keywords: γ-lactam

• been significant in the treatment of epilepsy [6][7], HIV [8][9], neurodegenerative disease and depression [10][11]. Having identified the lactam ring as a target of opportunity in chemical-screening efforts, we previously reported a method to prepare γ-lactams from readily available maleimides

N-Heterocyclic carbene/Brønsted acid cooperative catalysis as a powerful tool in organic synthesis

• Rob De Vreese and
• Matthias D’hooghe

Beilstein J. Org. Chem. 2012, 8, 398–402, doi:10.3762/bjoc.8.43

• functionalized pyrrolidin-2-ones as valuable scaffolds in heterocyclic chemistry. This Commentary will briefly highlight the concept of N-heterocyclic carbene/Brønsted acid cooperative catalysis as a new and powerful methodology in organic chemistry. Keywords: Brønsted acids; cooperative catalysis; γ-lactams; N

• the search for suitable combinations and, if one of both partners is chiral, the development of enantioselective catalytic processes. Selected examples of the successful deployment of cooperative catalysis in organic synthesis comprise the preparation of chiral γ-lactams from N-acyl hydrazones and α,β

• as electrophiles could not be excluded in advance [16]. Application of this methodology indeed enabled the facile and stereoselective synthesis of trans-γ-lactams 16 in a straightforward manner (Scheme 5), which would not have been possible without cooperative catalysis. In a first attempt, this

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• cyclofunctionalization of the allyl moiety by carbopalladation/reductive elimination [22]. It is interesting to note that 3-sulfonylpyrolidin-2-ones (γ-lactams) 48 may also be accessed in high yield as single trans-diastereomers upon simple treatment of N-allyl- or N-methylpyrrolidines with 2-mercaptobenzoic acid in

• boiling MeCN. Acid-promoted formation of a ring-opened iminium salt intermediate 47, followed by hydrolysis and subsequent intramolecular attack of the released secondary amine onto the ester group, would account for the formation of the γ-lactams [23]. This unexpected transformation was observed during

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium–arene complexes

• Yannick Borguet,
• Xavier Sauvage,
• Guillermo Zaragoza,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2010, 6, 1167–1173, doi:10.3762/bjoc.6.133

• generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic γ-lactams and lactones from α,ω-diene substrates bearing trihaloacetamide or

• reactions with homobimetallic ruthenium–indenylidene complex 1 to generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic γ-lactams and lactones