α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• use of aldehydes (R′ = H), which are usually less stable than their ketone counterparts; (2) ring expansion (Z, R = cyclic) or contraction (Z, R′ = cyclic) of strained cyclic α-ketols; (3) the use of α-dicarbonyl compounds (R′ = acyl, ester, amide, etc.), which lead to more stable β-dicarbonyl

• rearrangements utilizes asymmetric induction arising from the chiral alcohol. When the ketol’s carbonyl is located at the α position to an amide, as in β-hydroxy-α-ketoamide 21, the difluoroalkoxyborane intermediate 22 that results from BF3-promoted α-ketol rearrangement can be isolated chromatographically

• . Subsequent methanolysis yields α-hydroxy-β-ketoamide 23 (Figure 6). The overall reaction occurs diastereospecifically, with greater than 80% yield across each of 5 distinct amide derivatives [8]. Tandem α-ketol rearrangements Because α-ketol rearrangements can be initiated by simple reagents like a Brønsted

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• ferrocene carboxylic amide 1a with morpholine (2a) using 8-amonoquinoline as directing group [51][52][53][54][55][56]. The ortho-aminated ferrocenylamide 3a was isolated in 11% yield in the presence of CuI, N-methylmorpholine N-oxide (NMO) and K2CO3 in DMF (Table 1, entry 1). When the reaction was conducted

Enantioselective PCCP Brønsted acid-catalyzed aminalization of aldehydes

• Martin Kamlar,
• Robert Reiberger,
• Martin Nigríni,
• Ivana Císařová and
• Jan Veselý

Beilstein J. Org. Chem. 2021, 17, 2433–2440, doi:10.3762/bjoc.17.160

• (Table 2). Apart from model catalyst II, equipped with five (−)-menthol units, also the sterically less demanding amide-type catalyst III and the thiourea derivative IV were tested (Table 2). First, the diamide-type catalyst III was examined (Table 2, entry 4). Although complete conversion of 1a and 2a

Synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and their transformations under superelectrophilic activation conditions

• Andrey I. Puzanov,
• Dmitry S. Ryabukhin,
• Anna S. Zalivatskaya,
• Dmitriy N. Zakusilo,
• Darya S. Mikson,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2417–2424, doi:10.3762/bjoc.17.158

• h), t-BuOK–THF (reflux, 2 h), or LiN(iPr)2–THF (−40 °C, 2 h), afforded complex mixtures of reaction products without desired acetylenyloxadiazoles 3. We succeeded to get compounds 3a–e by the reaction of 2a–e with sodium amide in liquid ammonia [NaNH2–NH3(liq.)] only at low temperature −70 to −60 °C

Isolation and characterization of new phenolic siderophores with antimicrobial properties from Pseudomonas sp. UIAU-6B

• Emmanuel T. Oluwabusola,
• Olusoji O. Adebisi,
• Fernando Reyes,
• Kojo S. Acquah,
• Mercedes De La Cruz,
• Larry L. Mweetwa,
• Joy E. Rajakulendran,
• Digby F. Warner,
• Deng Hai,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2021, 17, 2390–2398, doi:10.3762/bjoc.17.156

• nitrogen stream. The hydrolysates were treated with 1 M NaHCO3 solution (20 µL) and 1% solution of ʟ-FDAA (Marfey's reagent, 1-fluoro-2-4-dinitrophenyl-5-ʟ-alanine amide) in acetone (40 µL). The reaction mixtures were gently heated at 40 °C for 1 h, after which the solutions were neutralized by the

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• nucleophilic attack at the γ-carbon took place. Cyclization of amide derivative 66 induced by Hg(OAc)2 followed by reduction with LiBH4 afforded a mixture of compounds 67A/67B [71]. The formation of endo,trans-product as a major product over the exo,cis-isomer was primarily due to a stereoinduction effect

• oxazolidine derivatives. Cyclization of amide derivatives induced by Hg(OAc)2. Hg(OAc)2/Hg(TFA)2-promoted cyclization of salicylamide-derived amidal auxiliary derivatives. Hg(II)-salt-mediated cyclization to form dihydrobenzopyrans. HgCl2-induced cyclization of acetylenic silyl enol ether derivatives

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• has a remarkable structural feature: the phosphate moiety is located at the benzylic position as well as at the position α to an amide group, which makes it a good leaving group for the design and development of new reactions. Accordingly, diethyl (2-oxoindolin-3-yl) phosphates 2 have been used

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• C1 position. Analogously to the Pictet–Spengler cyclization, the group initially speculated that the thiourea catalyst 6 interacts with the carbonyl function of the amide intermediate I and, thus, a SN2-type mechanism via hydrogen bonding catalysis was proposed. A similar bidentate carbonyl

• performances as nucleophile precursors using a triazolium-amide chiral catalyst 34 [21] (Scheme 8a), as well as by Jacobsen in the desymmetrization of oxetanes 35 using TMSBr and squaramide 37 as catalyst [56] (Scheme 8b). For the latter, a more detailed mechanistic study was recently provided [57]. The

• binding simultaneously to the chloride or through a cooperative 2H abstraction mechanism. These findings proved to be decisive in the development of new and more efficient anion-binding catalysts. By introducing a methyl group (R = Me) into the pyrrolidine moiety of the initial catalyst design, the amide

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

• Luiz Claudio Ferreira Pimentel,
• Lucas Villas Boas Hoelz,
• Henayle Fernandes Canzian,
• Frederico Silva Castelo Branco,
• Andressa Paula de Oliveira,
• Vinicius Rangel Campos,
• Floriano Paes Silva Júnior,
• Rafael Ferreira Dantas,
• Jackson Antônio Lamounier Camargos Resende,
• Anna Claudia Cunha,
• Nubia Boechat and
• Mônica Macedo Bastos

Beilstein J. Org. Chem. 2021, 17, 2260–2269, doi:10.3762/bjoc.17.144

• ) inherent to this type of treatment [25]. In this regard, Arioli and co-workers developed a series of derivatives (from PAPP) containing the 1,2,3-triazole nucleus in place of the amide group (present in the IMT structure) that showed inhibitory activity of recombinant Abl kinase equivalent to the drug of

• reference [26]. In this context, the intent is to replace the amide group present in IMT by the 1,2,3-triazole nucleus, similar to compound 3 described in the literature by Li and co-workers, which showed a good inhibition profile of the myelogenous leukemia K562 cell line [27]. Considering the good

• original work that led to compound 3, and, additionally, they are able to act as acceptors and donors in hydrogen bonds and thus were expected to increase the aqueous solubility of the compounds. Additionally, Kalesh and co-workers demonstrated good results with derivative 4 which contains the amide group

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• available. The authors examined ample scope of alkyl trifluoroacetamides 56 and alkyl bromides 40 to afford the corresponding alkylated products 57 in moderate to good yields (Scheme 30) [94]. As to the modus operandi, the generation of an alkyl radical species through amide directed 1,5-HAT followed by

• substrates 65 and the amide substrates 64. However, the role of the nickel catalyst in this process and the reaction mechanism pathway were not fully established. The photoredox nickel-catalyzed allylation of α-amino C(sp3)–H bonds with trifluoromethylated alkenes 68 has been more recently achieved by Martin

• and co-workers (Scheme 35) [113]. This defluorinative functionalization protocol set the stage for the introduction of gem-difluoroalkene motifs into α-amino C(sp3)–H sites. Interestingly, substrates having a trifluoromethyl group on the amide backbone enabled the functionalization of δ C(sp3)–H bonds

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• )-tryptophan amide 129 (Scheme 17a) [92]. Bis(indol-2-yl)selane 130 was found as a byproduct having very low such bioactivity. The polyselanes formed were separated by treating them with NaBH4, which did not affect the monoselane 130. On the other hand, selenopyrans structurally resemble indolocarbazoles

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• was synthesized by Kumagai et al. and applied in the Michael addition of 4-hydroxycoumarin 1 with α,β-unsaturated ketones 2 [42]. This chiral primary amino amide organocatalyst 32 afforded the desired products 3, including warfarin (3a) in 86% yield, although in moderate enantioselectivity (up to 56

• recently, the strategy via introducing secondary interactions for the design of the bifunctional catalysts achieved wide application in asymmetric reactions [74]. Wu et al. described a Mannich asymmetric addition of cyanocoumarins 39 to isatin imines 112 catalyzed by an amide-phosphonium salt 114. This

• %) providing excellent results, besides the use of only 0.1 mol % of amide-phosphonium salt for the synthesis of coumarin derivatives. Some methodologies have also proven to be highly efficient in one-pot and gram-scale procedures, which turns to be more environmentally benign. Nevertheless, studies are still

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• demonstrated a higher preference for N-1 indazole alkylation under conditions B, when compared with conditions A (Table 2, entries 1, 2, 4–7, and 9). Furthermore, C-3 ketone (22) and amide (23 and 24) substituted indazoles also gave the corresponding N-1 regioisomers with a high degree of N-1 regioselectivity

• ):N-2 (44) = 16:1; Table 2, entry 10) was obtained under conditions A. Notably, under conditions A (NaH in THF), C-3 substituted indazoles 19 (-NO2), 21 (-CHO), 22 (-COMe), 23 (-CONHMe), and tertiary amide 24 all demonstrated a high degree of N-1 regioselectivity (ratio N-1:N-2 = 16:1 (21), 83:1 (19

• , respectively). Similarly, strong amide bases, including NaHMDS, NaNH2, and LDA, also furnished N-1-alkylindazole 10 with excellent regioselectivity (up to > 98%, N-regioisomer), when using THF as the reaction solvent (Table 3, entries 7–9). These latter results indicate that the reaction solvent may play an

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

• can be formed from I and the Cr(III) salt to start the cycle, thereby providing intermediate VI. The latter then undergoes a ligand exchange with I to give the product and the key intermediate II. It is noteworthy that the secondary amide works both as the substrate and the ligand for the metal center

• , so that no additional ligand is required. The method presents a broad scope regarding the amide substrate. It gives moderate to excellent yields for heteroaromatic and aromatic carboxamides bearing electron-donating and electron-withdrawing substituents, whereas substrates with ortho-substituents

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• post-ON synthesis conjugation chemistry. The first method was used to attach 1-piperazinepropionic acid through an amide coupling onto 2’-amino-LNA. This monomer (51) induced high binding affinity towards complementary targets upon incorporation into a 9-mer ON. In DNA, an increase of 7.0 °C and 17.5

• ]. In a follow-up study, after being introduced into bisLNAs, the piperazino-modified 2'-amino-LNA-T nucleotide was compatible with invasion into dsDNA targets in vitro [56]. In further studies utilizing the same amide coupling, nor-spermidine with different group lengths (52 and 53), a glycol-amine

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

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• a neutral and achiral pseudopeptide backbone (Figure 1) [1]. PNA retains the natural DNA nucleobases that are connected to the amide-linked backbone through additional amide linkages. PNA was originally designed as a DNA mimic to improve the properties of triplex-forming oligonucleotides [1][2]. Two

• key considerations were elimination of electrostatic repulsion (neutral backbone) and synthetic accessibility (simple to make achiral amide linkages) [3]. The design was guided by a simple computer model where the natural sugar-phosphodiester backbone of the Hoogsteen strand of a T•A–T DNA triplex was

• amide linkages, to form strong and sequence specific complexes with natural DNA and RNA [3]. As will be discussed below, despite extensive studies [4][5][6], relatively few modifications have improved this simple original design. Since its inception, PNA has become an extremely useful research tool and

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

• unactivated olefins [33][34]. The observed competition between protodemetalation and β-hydride elimination steps was elegantly overcome by Engle and co-workers through the use of olefins tethered to the directing group 8-aminoquinoline (AQ) amide. This amide trapped the carbometalated intermediate generated

• containing a disubstituted olefin carbon were also effective (Scheme 8A, 14e), although they required higher temperatures and long reaction times. Substrates containing a β-ester or a β-amide instead of a β-keto group failed to deliver the cyclization products (Scheme 8A, compounds 14e and 14f), probably

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• origin of this is considered the central puzzle of biology [58]. Hydrogen cyanide is a fundamental prebiotic constituent, and glutarimides are easily formed under prebiotic conditions [58]. Could a Guareschi amide precursor have served as a primordial source of reducing power in prebiotic media en route

Photoinduced post-modification of graphitic carbon nitride-embedded hydrogels: synthesis of 'hydrophobic hydrogels' and pore substructuring

• Cansu Esen and
• Baris Kumru

Beilstein J. Org. Chem. 2021, 17, 1323–1334, doi:10.3762/bjoc.17.92

• were characterized via FTIR analysis to elucidate structural footprints of CM embedding and vTA photographing. The broad peak in the range from 3639 cm−1 to 3136 cm−1 corresponds to the hydrogen bonding between carboxyl and hydroxy groups with amide functionality of the hydrogel backbone. Significant

• primary amide C=O stretching vibration of the amide group. The strong signals at 1558 and 1404 cm−1 are originated from amine N–H bending and scissoring –CH2– vibrations, respectively. At last, the poly(ethylene glycol) methyl ether methacrylate (PEGMEMA)-based network displays O–H stretching from 3106 cm

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

• demonstrates the ease with which highly reactive reagents such as lithium bis(trimethylsilyl)amide can be used to effect sensitive aldol reactions in flow. Another recent example of an aldol reaction on a complex system originates from the group of Gauthier, which details the production of the HIV non

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

• using DMF as solvent. After addition, a subsequent intramolecular cyclization involving the resulting amide and the vicinal carbon with bromine atoms took place. By contrary, when the reaction was carried out in THF, the elimination process was suppressed, leading exclusively to enantiomerically pure α

• process. After addition of the organomagnesium reagent to the imine 79, cyclization involving the magnesium amide and the ester occurred without the need of an extra cyclization step to give, after N-Boc protection, 4-hydroxy-5-substituted pyrrolidin-2-ones 90, with relative trans-configuration (Scheme 24

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• therapeutic tool [15]. The chemical make-up of RNA, i.e., the ribose-phosphate backbone, has inspired countless strategies to chemically modify either the sugar [12][41][42][43][44], or the phosphate (e.g., amide-RNA [45]), or both [46][47]. In addition, the ribose has been replaced with alternative sugar

• arguably the most radical alternative nucleic acid pairing system, peptide nucleic acid (PNA), the sugar-phosphate backbone is replaced by an amide-based, neutral and achiral scaffold that allows cross-pairing with both DNA and RNA as well as formation of double- and triple-stranded species [57]. Despite

• -phosphate backbone relative to native phosphodiester oligomers. This N-type sugar puckering and increased hydration of the sugar phosphate backbone could also account for the triplex-favoring properties of this modification [72]. Amide While many amide backbone oligonucleotide variants exist, the focus of

Manganese/bipyridine-catalyzed non-directed C(sp³)–H bromination using NBS and TMSN₃

• Kumar Sneh,
• Takeru Torigoe and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2021, 17, 885–890, doi:10.3762/bjoc.17.74

• -position of an oxazoline or amide is selectively activated using a copper or palladium catalyst. Manganese is one of the most abundant and nontoxic transition metals found in the earth’s crust and its corresponding complexes and salts are useful in synthetic organic reactions [29][30][31][32][33][34][35

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• solvent to successfully furnish 5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones 89. Similarly, excellent yields were obtained when the thiol was replaced by malononitrile (51) even in the absence of catalyst or any promoter. The malononitrile undergoes hydrolysis forming an amide, thus giving rise

• adduct B. Adduct B then undergoes in situ cyclization through an intramolecular addition of nitrogen on amide which acts as a nucleophile to the nitrile and give intermediate C. The tautomerization of the imino to an amino group and subsequent auto-oxidation followed by aromatization affords the required