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

• ] In 1996, the Banks group reported perfluoro[N-fluoro-N-(4-pyridyl)acetamide] (21-3) as a carboxamide analogue of perfluoro[N-fluoro-N-(4-pyridyl)methanesulfonamide] (11-2, see section 1-11) [82]. Its precursor, 21-2, was prepared from pentafluoropyridine by either one of two methods (Scheme 46

• ). Precursor 21-2 was treated with neat F2 at 10–20 mmHg pressure in acetonitrile at −35 °C to produce the N-F carboxamide 21-3 in 75% yield but the resulting product was a 79:18 mixture of the desired N-F product 21-3 and the protonated compound 21-1. As a reagent N-F carboxamide 21-2 fluorinated electron

• -rich substrates such as sodium diethyl (phenyl)malonate, 1-morpholinocyclohexene, phenol, and anisole (Scheme 47). The fluorination power of the carboxamide 21-2 was less than that of its N-F sulfonamide analog 11-2. 1-22. N,N’-Difluoro-1,4-diazoniabicyclo[2.2.2]octane salts In 1996, Umemoto and co

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• , 60, Avenue Rockefeller, Bioparc, Bioserra 1 Building, 69008 Lyon, France 10.3762/bjoc.17.16 Abstract In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant

• -azabenzotriazole; hinge-binder; ionic hydrogenation; library; pyridine-2(1H)-one; Introduction During a recent medicinal chemistry program targeting a kinase to treat skin disorders, we identified the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one motif (1) as an interesting starting point. Recently, both

• affording only acceptable yields of pyridine intermediate (9a–c) with the major byproduct arising from the dechlorination of 8. Application of the same conditions with aromatic amides at C-3 (8d,e) failed with only trace quantities of final product observed. We speculated that the aromatic carboxamide NH

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• with aniline (1a) or amantadine in the presence of HATU or EDCI to form the multisubstituted pyrrole-3-carboxamide derivatives 4x and 4y (Scheme 4). These skeletons have been proven to be promising inhibitors for the production of cytokines [47]. A plausible mechanism for the model reaction was

• . Direct synthesis of pyrrole-3-carboxamide derivatives. Plausible mechanism of the three-component reaction. Synthesis of polysubstituted pyrazolo[3,4-b]pyridine derivatives. Optimization of the conditions for the reaction between 1a, 2a, and 3a.a Supporting Information Supporting Information File 500

Three new O-isocrotonyl-3-hydroxybutyric acid congeners produced by a sea anemone-derived marine bacterium of the genus Vibrio

• Dandan Li,
• Enjuro Harunari,
• Tao Zhou,
• Naoya Oku and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1869–1874, doi:10.3762/bjoc.16.154

• three deshielded resonances (H3, H2', and H3') and a pair of mutually coupled doublet-of-doublets resonances (H22), indicating a shared core structure (Table 1, Table 2, and Supporting Information File 1). In fact, the 13C NMR spectra all had signals in common: two carboxy (carboxamide) and two olefinic

Anthelmintic drug discovery: target identification, screening methods and the role of open science

• Frederick A. Partridge,
• Ruth Forman,
• Carole J. R. Bataille,
• Graham M. Wynne,
• Marina Nick,
• Angela J. Russell,
• Kathryn J. Else and
• David B. Sattelle

Beilstein J. Org. Chem. 2020, 16, 1203–1224, doi:10.3762/bjoc.16.105

• . mansoni [161]) and the cestode E. multilocularis [162]. Perhaps the most promising lead from the Pathogen Box so far is tolfenpyrad, a pyrazole-5-carboxamide insecticide, which was first identified as an anthelmintic with activity against exsheathed L3 and L4 parasitic life stages of Haemonchus contortus

• follow-up study identified two additional pyrazole-5-carboxamide compounds with activity against H. contortus, although not improving on the potency of tolfenpyrad [166]. Tolfenpyrad acts in arthropods as an inhibitor of mitochondrial complex I [167]. It will be interesting if a tolfenpyrad derivative

• through systematic alteration of the pyrazole-5-carboxamide and phenoxybenzyloxy moieties within tolfenpyrad 19 (Table 4). The systematic variation of the p-methylphenyl ring within 19 gave rise to a number of aromatic and heteroaromatic analogues with similar levels of potency to tolfenpyrad (Table 4

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• which was immediately hydrolyzed to provide the racemic carboxamide 172. The subsequent removal of the chiral auxiliary by catalytic hydrogenation then afforded the carboxamide 173. Finally, an acid-mediated hydrolysis of the carboxamide 173 to generate the free amino acids ʟ- or ᴅ-168a, was carried out

Copper-catalyzed remote C–H arylation of polycyclic aromatic hydrocarbons (PAHs)

• Anping Luo,
• Min Zhang,
• Zhangyi Fu,
• Jingbo Lan,
• Di Wu and
• Jingsong You

Beilstein J. Org. Chem. 2020, 16, 530–536, doi:10.3762/bjoc.16.49

• groups. Under standard conditions, the remote C–H arylation of other PAHs including phenanthrene-9-carboxamide, pyrene-1-carboxamide and fluoranthene-3-carboxamide has also accomplished, which provides an opportunity for the development of diverse organic optoelectronic materials. Keywords: C–H

• -9-carboxamide, pyrene-1-carboxamide and fluoranthene-3-carboxamide, which provides an opportunity for the development of diverse organic photoelectrical materials. Results and Discussion Our investigation commenced with the reaction between N-(tert-butyl)-1-naphthamide (1a) and mesityl(phenyl

• arylation of PAHs is challenging, and so far, there are no examples on the selective remote C–H arylation of phenanthrene-9-carboxamide, pyrene-1-carboxamide and fluoranthene-3-carboxamide. Gratifyingly, the remote C–H arylation of these PAH substrates occurred smoothly, giving the corresponding arylation

Controlling alkyne reactivity by means of a copper-catalyzed radical reaction system for the synthesis of functionalized quaternary carbons

• Goki Hirata,
• Yu Yamane,
• Naoya Tsubaki,
• Reina Hara and
• Takashi Nishikata

Beilstein J. Org. Chem. 2020, 16, 502–508, doi:10.3762/bjoc.16.45

• . Moreover, the reaction of α-bromocarbonyl compound 2 and an alkyne 4 possessing a carboxamide moiety undergoes tandem alkyl radical addition/C–H coupling to produce indolinone derivative 5. Keywords: copper catalyst; 1,3-enyne; functionalized quaternary carbon; indolinone; tandem alkyl radical addition

• addition at a C–C triple bond followed by Sonogashira coupling to produce 1,3-enyne compounds. On the other hand, the reaction with alkyne possessing a carboxamide moiety underwent tandem alkyl radical addition at the C–C triple bond followed by C–H coupling to produce indolinone derivatives. These results

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

• Panagiotis S. Gritzapis,
• Panayiotis C. Varras,
• Nikolaos-Panagiotis Andreou,
• Katerina R. Katsani,
• Konstantinos Dafnopoulos,
• George Psomas,
• Zisis V. Peitsinis,
• Alexandros E. Koumbis and
• Konstantina C. Fylaktakidou

Beilstein J. Org. Chem. 2020, 16, 337–350, doi:10.3762/bjoc.16.33

• )-one [29] derivatives, various enediyne [30][31][32], proflavine [33], N-nitroso carboxamide [34], naphazoline [35] and triazole [36] derivatives, azido carbonyl compounds [37] and N,O-diacyl-4-benzoyl-N-phenylhydroxylamines [38]. O-Acyl amidoximes, ketoximes and aldoximes (I, II and III, respectively

Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetrahydro-1,3-thiazepines from 4-aminobutanol

• María C. Mollo,
• Natalia B. Kilimciler,
• Juan A. Bisceglia and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2020, 16, 32–38, doi:10.3762/bjoc.16.5

• of the corresponding tetrahydro-1,3-oxazepines. This unexpected reaction path is reasonable considering the relative ease of formation of five-membered rings as compared to the isomeric seven-membered heterocycles together with the relatively poor nucleophilicity of the carboxamide oxygen. An

• alcohols. In both cases, PPSE would activate the OH group for nucleophilic attack, and the plausible reaction mechanism would involve an intramolecular SN2-type displacement. However, the lower reactivity of the carboxamide oxygen (as an O-nucleophile), together with the comparatively high activation

• energy associated to the formation of a seven-membered heterocycle would favour the competitive ring closure leading to the five-membered ring (Scheme 2, reaction a), which would involve attack of the carboxamide nitrogen to the ω-carbon. On the other hand, the higher nucleophilicity of the sulfur in the

AgNTf₂-catalyzed formal [3 + 2] cycloaddition of ynamides with unprotected isoxazol-5-amines: efficient access to functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives

• Ziping Cao,
• Jiekun Zhu,
• Li Liu,
• Yuanling Pang,
• Laijin Tian,
• Xuejun Sun and
• Xin Meng

Beilstein J. Org. Chem. 2019, 15, 2623–2630, doi:10.3762/bjoc.15.255

• Analysis, Qufu 273165, P. R. China 10.3762/bjoc.15.255 Abstract A formal [3 + 2] cycloaddition between ynamides and unprotected isoxazol-5-amines has been developed in the presence of catalytic AgNTf2 in an open flask. By the protocol, a variety of functionalized 5-amino-1H-pyrrole-3-carboxamide

• derivatives can be obtained in up to 99% yield. The reaction mechanism might involve the generation of an unusual α-imino silver carbene intermediate (or a silver-stabilized carbocation) and subsequent cyclization/isomerization to build the significant pyrrole-3-carboxamide motif. The reaction features the

• carbene and subsequent cyclization to pyrroles (Scheme 2b). Herein we want to provide some detailed results on the reaction (Scheme 2b), leading to the synthesis of a variety of functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives in high yields. The reaction features the use of an inexpensive

Synthesis of novel sulfide-based cyclic peptidomimetic analogues to solonamides

• José Brango-Vanegas,
• Luan A. Martinho,
• Lucinda J. Bessa,
• Andreanne G. Vasconcelos,
• Alexandra Plácido,
• Alex L. Pereira,
• José R. S. A. Leite and
• Angelo H. L. Machado

Beilstein J. Org. Chem. 2019, 15, 2544–2551, doi:10.3762/bjoc.15.247

• ), as expected for the C-terminal carboxamide, we observed three ions derived from the breaking of two amide bonds, starting from the opening of the macrocycle by the loss of one, two or three amino acid residues as neutral fragments. This fragmentation pattern agrees with the one expected for cyclic

In search of visible-light photoresponsive peptide nucleic acids (PNAs) for reversible control of DNA hybridization

• Lei Zhang,
• Greta Linden and
• Olalla Vázquez

Beilstein J. Org. Chem. 2019, 15, 2500–2508, doi:10.3762/bjoc.15.243

• base sensitive compounds, which undergo degradation under standard Fmoc deprotection conditions. As it is common for PNAs, our oligomers have an acetylated N-terminus and a C-terminal carboxamide group. After completion of the PNA sequences, the orthogonally protected backbone module [2-(N-Alloc

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• heterocyclic carboxamide moieties, while the N-alkyl substituent of the tetrazole ring also proved to show a wide substrate scope. Overall, the reaction sequence is easy to implement and does not require inert conditions. Based on the experimental results, we believe that not only the amido group but also the

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• added at C-5 of 4-chloro- (9a) and 4-fluorobenzo[c][2,7]naphthyridine (9b) as well as the 4-carboxamide 9c to give 5-substituted-5,6-dihydro derivatives, which were readily aromatized with manganese dioxide [13]. Further functionalization was performed by Stille cross coupling of a 4-chloro intermediate

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

• Christoph W. Grathwol,
• Nathalie Wössner,
• Sören Swyter,
• Adam C. Smith,
• Enrico Tapavicza,
• Robert K. Hofstetter,
• Anja Bodtke,
• Manfred Jung and
• Andreas Link

Beilstein J. Org. Chem. 2019, 15, 2170–2183, doi:10.3762/bjoc.15.214

• selective Sirt1 inhibitor, passed phase II clinical trials as a disease-modifying therapeutic for Huntington’s disease (HD) and was acquainted by AOP Orphan Pharmaceuticals AG for phase III trials in 2017 [9][10]. Its structure comprises a carboxamide moiety, which mimics the amide group of the endogenous

• benzoquinoline carboxamide isomers 8a and b formed by photocyclization and successive oxidation (Scheme 3). Furthermore, small amounts of cycloaddition products in two fractions were found, probably due to the high concentration of 2b in the irradiated solution. In contrast, 2f was remarkably stable to long-term

Characterization of two new degradation products of atorvastatin calcium formed upon treatment with strong acids

• Jürgen Krauß,
• Monika Klimt,
• Markus Luber,
• Peter Mayer and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2085–2091, doi:10.3762/bjoc.15.206

• concentrated sulfuric acid, lactonization/dehydration is accompanied by complete loss of the carboxanilide residue to give pyrrole 7. Complete one-step removal of carboxamide residues from aromatic rings has been observed before in investigations of fragmentations of protonated species in mass spectrometry [21

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• -(4-chlorophenyl)-2-oxoethyl)-6-(4-methoxyphenyl)-3-methyl-N-p-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (11n) according to X-ray diffraction data. Non-hydrogen atoms are presented as thermal ellipsoids with 50% probability. An overview of heterocyclic acids used in the Ugi reaction. Synthesis of

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

• -component reaction, to afford isoindolinones 53 substituted with nitrile or carboxamide groups (Scheme 15, method A) [93]. Trimethylsilylcyanide (52), and benzyl-, alkyl- and allylamines 2 were reacted with 2-formylbenzoic acid (33) in the presence of OSU-6, a mesoporous silica performing as a green Lewis

• acid catalyst for this transformation. At room temperature, the product of this environmentally friendly Strecker reaction is nitrile derivative 53 (R2 = CN, Scheme 15, method A), while at reflux carboxamide 53 (R2 = CONH2, Scheme 15, method A) is obtained. Notoriously, aromatic amines 2 did not work

• heteroaromatic analogues of aldehyde 62, such as 2-bromonicotinaldehyde or 2-bromothiophene-3-carbaldehyde did not produce the desired product. On the other hand, 2-aminoquinoline-3-carboxamide also reacted under these conditions to produce the corresponding isoindoloquinazolinone analogue of 57. Some control

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• . are a source of alkaloids with core structures containing simultaneously pyrrole carboxamide and 2-aminoimidazole moieties such as the simple achiral compound oroidine (V) and spatially organized molecules in a complex manner with a large number of chiral centres like (−)-palau’amine (VI) [3

Diaminoterephthalate–α-lipoic acid conjugates with fluorinated residues

• Leon Buschbeck,
• Aleksandra Markovic,
• Gunther Wittstock and
• Jens Christoffers

Beilstein J. Org. Chem. 2019, 15, 981–991, doi:10.3762/bjoc.15.96

• (compound 2). If the Boc group is replaced by the slightly more electron-withdrawing carboxamide as in compound 3, this bathochromic shift (compared to compound 1) is only ca. 10 nm. Without an N-acceptor moiety, i.e., N-monoalkyl (compounds 4 and 5) or N,N'-dialkyl substitution (compounds 6–8), a stronger

Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

• Pedro N. Batalha,
• Luana da S. M. Forezi,
• Maria Clara R. Freitas,
• Nathalia M. de C. Tolentino,
• Ednilsom Orestes,
• José Walkimar de M. Carneiro,
• Fernanda da C. S. Boechat and
• Maria Cecília B. V. de Souza

Beilstein J. Org. Chem. 2019, 15, 388–400, doi:10.3762/bjoc.15.35

• antibacterial and antiviral. The presence of a carboxamide unit connected to carbon C-3 of the 4-oxoquinoline core has been associated with various biological activities. Experimentally, the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide occurs at the nitrogen of the oxoquinoline

• group, in a regiosselective way. In this work, we employed DFT methods to investigate the regiosselective ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, evaluating its acid/base behavior and possible reaction paths. Keywords: alkylation; carboxamide; oxoquinoline; quinolone

• been explored and were successfully described by researchers around the world [3][4], such as antiviral [5][6], antiplasmoidal [7][8], anticancer [9][10], and trypanocide [11] activities. 4-Oxoquinoline-3-carboxamide derivatives, more specifically, have shown to be a promising structural scaffold for

Thermophilic phosphoribosyltransferases Thermus thermophilus HB27 in nucleotide synthesis

• Ilja V. Fateev,
• Ekaterina V. Sinitsina,
• Aiguzel U. Bikanasova,
• Maria A. Kostromina,
• Elena S. Tuzova,
• Larisa V. Esipova,
• Tatiana I. Muravyova,
• Alexei L. Kayushin,
• Irina D. Konstantinova and
• Roman S. Esipov

Beilstein J. Org. Chem. 2018, 14, 3098–3105, doi:10.3762/bjoc.14.289

• APRT limits the number of possible nucleotides that can be synthesized. Thus, for Thermus thermophilus HB27 APRT (TthAPRT), nucleotide synthesis is limited to the closest structural homologs of adenine (Table 1) [1]. Unfortunately, 1,2,4-triazole-3-carboxamide, its analogues, guanine, hypoxanthine, and

• phosphoribosyltransferase only [2]. Unfortunately, we did not find any product in reactions with compounds based on 1,2,4-triazole-3-carboxamide, which was also observed for E. сoli HPRT [15][16]. However, allopurinol and 8-azaguanine are substrates for TthHPRT, and 2-chloroadenine is a substrate for TthAPRT. For 2

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• protein [79]. Indicated key interactions are π-stacking of Y258 with the phenoxy moiety in the tail region and a hydrogen bond formed between the Q194 side chain and the carboxamide in the linker area. Furthermore the benzimidazole core shows hydrophobic contacts with isoleucins 149 and 236. More

• benzimidazole moiety (compound not shown) [80]. In a follow-up patent they generated PqsR inhibitor 45 as a front-runner compound [81], in which the benzimidazole headgroup was replaced by a substituted naphthalene bearing a carboxamide, in analogy to a fragment 44 of Zender et al. [82] and similar to the

• carboxamide-decorated nitro-quinoline scaffold described by Lu et al. (Figure 20) [73]. Compound 45 was highly potent in inhibiting pyocyanin production (stated IC50 in a range of 50–250 nM) and was furthermore able to suppress PQS and HHQ production (50 nM < IC50 < 250 nM). In a murine thigh infection model