Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• N,S-acetals; β-keto amide; β-keto thioester; dodecylbenzenesulfonic acid; hydrolysis; Introduction In the past decades, the application of easily available and stable α-oxo ketene N,S-acetals as significant synthons has received more and more attention in organic synthesis due to their unique

• form adduct I', which is then transformed into intermediate II' by elimination of ethanethiolate. Subsequently, β-keto amide 3a is obtained when II' releases H+. Conclusion In summary, we have successfully developed an environmentally friendly method for the selective aqueous synthesis of β-keto

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• radical, which induces 5-exo cyclization. The following hydrogen abstraction, intramolecular ionic cyclization, and hydrolysis during chromatography on silica gel affords the cyclic amide in good yield. They further applied this radical cyclization reaction as a key step in the synthesis of (±)-α-kainic

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• deprotonation with sulfamate, gives the 4-substituted isoquinolinone derivative 2a (Scheme 6). Looking into the formation of 2c' from 1c (Scheme 2), two other resonance structures for the initially formed intermediate 1CC, namely 1CC' and 1CC'', are shown in Scheme 7. The oxygen atom in the amide motif of the

• substrate 1c may act as an electrophilic center, forming a C–O bond with the alkenyl group to give the isochromen-1-one oxime product 2c'. When wet HFIP was used as the solvent, the reaction followed a different pathway. HFIP, a strong hydrogen bonding donor [26][27][28], interacts with the amide moiety of

• the substrate, and thus preventing the possible interaction between the amide moiety and PISA, as opposed to CH3CN. The olefin moiety of the complex then interacts with the exposed central iodine(III) atom in PISA [25], forming the intermediate D. Similar cyclic iodonium intermediates were also

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• catalysts. Asymmetric bromolactonizations of model substrate 2a with amide- and urea-type chiral bifunctional sulfides (S)-5 and 6, known to be effective for other asymmetric halocyclizations [32][33][34][35], resulted in δ-valerolactone product 3a with low enantioselectivities (50:50 and 56:44 er

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• difluoroiodanes 7a and 7b containing the amide sidearms would have an even more acute N–I–N bond angle (156.6–156.9 °). Furthermore, the internal chelate NCC bond angle in 7a/b (111.7°) was calculated to be bigger than the corresponding OCC angle (108.3(5)° to 109.2(5)°) in 6 due to the sp2-hybridised carbon in

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• -called convertible isocyanides [27][28][29][30][31][32][33][34][35][36] in Ugi-4CR makes it possible to obtain carboxylic acids or esters after hydrolysis of the secondary amide group in the Ugi products (Scheme 2) [27][28][29][31][32][34][35][36]. Ugi bisamides modified in this way may be subsequently

• which the Z-configuration of the chlorovinyl fragment was detected. Post-Ugi transformations As previously mentioned [32], the introduction of the convertible 2‑bromo-6-isocyanopyridine into the Ugi bisamide structure allows the conversion of the newly formed amide into a carboxylic acid fragment after

• acid hydrolysis. Similar results were obtained by Dömling and co-workers [27], who used 2-nitrobenzyl isocyanide as a universal convertible isocyanide, and the amide group was also converted into a carboxylic acid under the conditions of acid hydrolysis (Scheme 2). Therefore, taking into account the

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• amide substituent in C3 is pseudoaxially oriented in an all-trans conformation, only the unlike attack would be allowed (Scheme 3). On the other hand, when 3-bromopropanamine was used, the formation of the pyrrolobenzodiazepinone system 8 was observed albeit along with benzodiazepinone 5c (Scheme 4). In

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• ). Spiro tetraoxanes were tested for their antimalarial activity. From the biological results, it was observed that compounds with an amide moiety were more active compared to those possessing an ester or a carboxylic group. It was observed that tetraoxanes with a primary amide were more active towards

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• synthesis of the bis-THIQ alkaloid family, Oguri and Oikawa utilized the NRPS module SfmC to construct a highly functionalized scaffold from amino acid derivatives (Scheme 10) [102]. The total synthesis of 5 from original biosynthetic intermediate 93 requires regioselective amide bond cleavage to remove the

• this problem, the research group designed synthetic substrate analogs (96, 101) that mimic the biosynthetic intermediate 88 (Scheme 10A). By replacing an amide linkage in 88 with an ester linkage, the fatty acid side chain could be removed under mild conditions after enzymatic construction of the

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• . Additionally, stereoselectivity can be achieved by using potassium bis(trimethylsilyl)amide for deprotonation and methylation with MeI [33][39]. Any of these routes would yield methylated amino acids that can then be incorporated into an oligopeptide in solid-phase peptide synthesis (SPPS). Additionally, N

• -methylation concurrently to peptide synthesis is also possible. Commonly used methods for SPPS of N-methylated peptides involve activating the amino group with 2-nitrobenzenesulfonamide and methylating agents, such as dimethyl sulphate [40][41][42]. Directly methylating peptides is challenging. Multiple amide

• occur at the N-terminal amide, the peptide backbone, as well as on amino acid side chain amides (Figure 1). While traditional synthesis of N-methylated peptides is challenging and time consuming, installation via RiPP maturases provides an easier, quicker, and greener approach to confer these attributes

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• chains possessed a nucleophilic primary amine. Curiously, the macrocyclizing amide bond was found to exist between a Trp side chain indole nitrogen and the C-terminal carboxylate. To the best of our knowledge, this was the first example of the involvement of a Trp indole in macrolactam formation in

• bacterial natural products, the only other example being the fungal psychrophilins [142][143][144]. It should be noted that the Trp indole nitrogen does participate in amide bond formation in other fungal natural products as well, but not in the context of macrocycle assembly [145]. Compound 27 inhibited

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• yields (7a–e, 7g, and 7h), except for 6f which contained a methyl group at the 4-position. The reaction of 2,3-dimethylquinoline (6i) gave the desired product 7i (cis/trans = 3:1) in 77% yield. Substrates bearing acetyl (6k), ester (6l), and amide (6m) groups were tolerated under these conditions and

• applicable and 2,6-dimethylpiperidine (9g) was obtained in moderate yield. In contrast to quinolines, pyridines bearing an amide group were also applicable and amidylpiperidines 9h and 9i were obtained in high yields. Conclusion We established the electrochemical reduction of cyanoarenes, nitroarenes

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• intramolecular fluorine-atom-transfer (FAT) from an N-fluorinated amide to a pendant carbon-based radical formed from an iron catalyst (Figure 15) [55][56]. This concept of fluorine transfer through a 6-membered transition state was shown to work efficiently from primary, as well as secondary, benzylic radicals

• , non-photochemical, silver-catalysed HAT radical-polar crossover mechanism for nucleophilic benzylic fluorination (Figure 34) [85]. The authors proposed a similar mechanistic pathway to the photochemical methods, citing the use of amide ligands as important for modulating the silver catalyst stability

• benzylic C(sp3)–H fluorination with TBPB HAT reagent. Silver-catalysed, amide-promoted benzylic fluorination via a radical-polar crossover pathway. General mechanism for oxidative electrochemical benzylic C(sp3)–H fluorination. Electrochemical benzylic C(sp3)–H fluorination with HF·amine reagents

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• derivatives by means of nucleophilic azlactone-opening reactions. Gratifyingly primary amines can be easily utilized under reflux conditions to access the amide derivatives 6a and 6b straightforwardly (Scheme 3), thus demonstrating the versatility of compounds 5 to access more complex acyclic α-AA derivatives

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• the amide anion in intermediate D afforded the final product 4 or 6. On the other hand, the final product 4 or 6 might be directly produced by dipolar cycloaddition reaction of 5-(alkylimino)cyclopenta-1,3-diene intermediate C with 5,6-unsaturated dihydropyridine. In consideration of the high

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• ), whose sequential acylation process by iso(thio)cyanates 3a–h gives rise to the asymmetric (thio)urea derivatives (intermediate II). The spontaneous nucleophilic attack of the (thio)amide nitrogen on the terminal methyl ester function at C-4 of the starting azo-ene system provides a regioselective

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• simple lithium salts for hypervalent iodine catalyst activation. The activated hypervalent iodine catalyst allows the intermolecular coupling of soft nucleophiles such as amides onto electronically activated olefins with high regioselectivity. Keywords: amide coupling; hypervalent iodine catalysis

• hypervalent iodine catalyst. The cationic hypervalent iodine catalyst could then activate the olefin to allow the addition of bifunctional nucleophiles such as an amide to achieve an overall olefin oxyamination process. We have previously reported a series of iodide-catalyzed processes, in which the

• bifunctional amide nucleophiles (Scheme 1e). Results and Discussion Our studies here focused on the development of hypervalent iodine-catalyzed amide and alkene coupling reaction [53][54][55]. In this case, we started with styrene (1) and benzamide (2) as the standard substrates. Using iodotoluene A as the

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• , and amide, etc. functionalities. The vast area of synthetic venture highlights the significance of this reaction, as exemplified here, in some of the most recent advances of this reaction during the last two decades. Proper utilization of Lewis acid catalysis, desymmetrization of symmetrically remote

Synthesis of 1,2,3-triazoles containing an allomaltol moiety from substituted pyrano[2,3-d]isoxazolones via base-promoted Boulton–Katritzky rearrangement

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 1334–1340, doi:10.3762/bjoc.20.117

• reaction of hydrazones of 1,2,4-oxadiazoles leads to the corresponding 1,2,3-triazoles containing an amide fragment. Generally, the considered rearrangement proceeds under action of acidic or basic reagents [3][4][5][6][7]. Other options for this process are based on the application of copper salts or

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• in good agreement with those reported for this compound in the literature. In all synthesized compounds, Ha and Hb protons are only in endo conformation and therefore the amide and carboxylic acid functional groups are arranged in exo conformation. The fact that the flexible 2n and 2o compounds in

• reaction, the acylation is followed by an intramolecular Diels–Alder reaction and the amide intermediate (a sample compound has been previously isolated and fully characterized as a result of detailed studies) is in equilibrium with the final product at room temperature in polar solvents such as DMSO

• (Figure 3, path I) [132]. Similarly, Tomberg et al., note that in such reactions, amide is formed rapidly by opening the maleic anhydride ring first, followed by a slower cyclization [133]. On the other hand, according to the results of some DFT calculations, Naguib et al., state that [4 + 2

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• P21/c [49]. It adopts a transoid geometry around the oxamide C–C bond with nearly 180° torsion angle. This provides the molecule with a planar geometry. It shows intermolecular hydrogen bonding between the amide O and NH moieties. (Figure S35, Supporting Information File 1). Oxamide 9 crystallized in

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• , 38200, La Laguna, Spain 10.3762/bjoc.20.104 Abstract Considering early-stage drug discovery programs, the Ugi four-component reaction is a valuable, flexible, and pivotal tool, facilitating the creation of two new amide bonds in a one-pot fashion to effectively yield the desired α-aminoacylamides. Here

• , aliphatic chain on the acid component and small aliphatic chain on the aldehyde component to increase the antiproliferative activity. Also, benzyl isocyanide was favored over the aliphatic one (Scheme 1A) [16]. Considering the value of amide groups in drug discovery [19], the feasibility of running the

• isatin-based Ugi reaction [16][20][21][22][23] and the potential of the bis-amide-oxindole type derivatives as anticancer agents, a second family was synthesized, and screened for their anticancer activities (Scheme 1B). Results and Discussion Synthesis Underlining sustainability and economically favored

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• )phosphine ligand (PN3P) (Mn3) and studied N-methylation reactions in the presence of t-BuOK (20 mol %) at 120 °C for 24 h in toluene [36]. This catalytic system tolerated various functional groups, including nitro, ester, amide, and ketones and gave moderate to good yields (42–98%) of the mono-N-methylated

• Mn23 and t-BuOK (30 mol %) in toluene at 110 °C for 8 h to afford the C3-alkylated oxindoles with up to 85% yield (Scheme 60). However, secondary alcohols substituted with reducible (nitro, amide, aldehyde) groups and −OH, −SH, and –NHMe groups did not provide any expected C-alkylated product. Like the

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• than 90% purity, as determined by 31P NMR. Compound 10 was used in the next step without further purification. A linear amide 11 was obtained in 47% yield by reacting phosphinate 10 with chloroacetamide in the presence of a large excess of HMDS in acetonitrile at 70 °C for two days. A cyclisation of

• the linear amide 11 was performed in DCM using a 10-fold excess of trifluoroacetic acid at room temperature, providing 1,4-azaphosphinine 12 in 68% yield. Various conditions used for the coupling of nucleobase 8, such as using silylated derivatives (HMDS, BSA) or salts obtained by base treatment (NaH