Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• -saving drugs and medicines. Imidazole is one of the pharmacologically important heterocyclic motifs found in widely used and well-known medicines and bioactive molecules. The applications of imidazole derivatives displaying various biological activities, motivated researchers for the development of more

• potent and significant drugs containing imidazole moieties. The formation of imidazole derivatives can be achieved using imidazole N-oxide as starting material. In this review, the scope of substrates and reaction mechanisms of various synthetic approaches using imidazole N-oxides as substrates are

• summarized so that the chemists, researchers, and pharmaceutical industries find its effectiveness in near future for the synthesis of potent, novel, and non-toxic drug molecules. Keywords: functionalization; imidazole N-oxide; mechanistic insights; multicomponent reaction; nucleophilic substitution

Using UHPLC–MS profiling for the discovery of new sponge-derived metabolites and anthelmintic screening of the NatureBank bromotyrosine library

• Sasha Hayes,
• Aya C. Taki,
• Kah Yean Lum,
• Joseph J. Byrne,
• Merrick G. Ekins,
• Robin B. Gasser and
• Rohan A. Davis

Beilstein J. Org. Chem. 2022, 18, 1544–1552, doi:10.3762/bjoc.18.164

• to the purealidin structure class, the majority of which all contain a terminal imidazole system. HMBC data from the one of the methylene protons (δH 2.59) that constituted the -NHCH2CH2- spin system to the imidazole carbons at δC 124.4 and 109.3 linked these fragments, while a strong HMBC

• correlation from the imidazole proton at δH 6.55 to the downfield carbon at δC 146.8 indicated a 2-amino substituted histamine moiety [19]. Finally, the unassigned exchangeable protons at δH 10.11 and 7.36, were assigned to phenol (4-OH) and amino groups (14-NH2), respectively, following comparison of NMR

One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides

• Arisu Koyanagi,
• Yuki Murata,
• Shiori Hayakawa,
• Mio Matsumura and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 1479–1487, doi:10.3762/bjoc.18.155

• benzazoles containing oxazole and imidazole skeletons are the most commonly used scaffolds [1][2][3][4][5]. Therefore, it is crucial for the drug industry to develop methods for their syntheses [1][2][4][6]. For example, conventional benzoxazole synthesis methods involve the condensation of 2-aminophenol

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• Palau’amine (45), a dimeric pyrrole-imidazole-bisguanidine alkaloid, was first isolated from the marine sponge Stylotella aurantium in 1993 [16][17]. It received considerable attention from the synthetic community because of its broad range of biological activities and complex structure. In an early endeavour

From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• -Tosylimidazole releases imidazole as a byproduct during the process. Therefore, we wondered whether imidazole could promote the formation of the target formamide 2. Imidazole, compared to p-tosylimidazole, is a cheaper reagent and makes the final purification process easier. As a matter of fact, by reacting 1.0

• mmol of the model substrate with 2.0 mmol of formic acid and 1.0 mmol of imidazole [23], the product was obtained in better yield and with a higher degree of purity. A control experiment performed by reacting p-methoxyaniline (1.0 mmol) and formic acid (2.0 mmol) provided lower conversion into the

• desired formamide 2 (71% NMR yield, Table S1 in Supporting Information File 1), denoting the input given by imidazole as a promoter of formamide synthesis. Further variation in the ratio of imidazole/formic acid/amine decreases the reaction yield (Table S1 in Supporting Information File 1). These data

A Streptomyces P450 enzyme dimerizes isoflavones from plants

• Run-Zhou Liu,
• Shanchong Chen and
• Lihan Zhang

Beilstein J. Org. Chem. 2022, 18, 1107–1115, doi:10.3762/bjoc.18.113

• removing cell debris by centrifugation, the lysate supernatant was purified by Ni-NTA resin with washing buffer (50 mM NaH2PO4, 150 mM NaCl, 100 mM imidazole, pH 7.5) and elution buffer (50 mM NaH2PO4, 150 mM NaCl, 300 mM imidazole, pH 7.5) and then dialyzed into the storage buffer (50 mM NaH2PO4, 150 mM

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• investigated and the denitrogenative annulation towards imidazoloquinoxalines could be observed as a competing reaction depending on the alkyne concentration and the substitutions at the quinoxaline. Keywords: click reaction; CuAAC; denitrogenative annulation; imidazole; metal complexes; quinoxaline

• imidazole-fused products via denitrogenative annulation leading to 2 is, compared to the ever-present CuAAC, less known and was only shown with one example so far [11]. The study described herein intends to investigate the reactivity of tetrazolo[1,5-a]quinoxalines 1 concerning the competing formation of

• conditions that favor the triazole formation or the imidazole, giving indications for alternative strategies to access imidazo[1,2-a]quinoxalines. Results All tetrazolo[1,5-a]quinoxaline precursors were synthesized in three to five steps from commercially available o-1,2-phenylenediamine (8, Scheme 2

Electrochemical formal homocoupling of sec-alcohols

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masashi Shiota,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2022, 18, 1062–1069, doi:10.3762/bjoc.18.108

• effect of acidic and basic additives on the reaction outcome. While the use of Mg(OTf)2, HCO2H, or 2,6-lutidine resulted in reduced reaction efficiency, imidazole exhibited the positive effect on the product yield, providing 2a in 72% yield (Table 1, entries 8–11). Addition of H2O was crucial to obtain

• (Scheme 5a). The dl:meso ratio of 2a was identical compared with that observed in the reaction using 1a as the starting material. This observation indicated that ketone 3a would be the intermediate in the present transformation. The reaction in the absence of imidazole also proceeded to afford 2a in a

• reaction conditions. While ketone 3a was obtained in a higher yield when the reaction was performed in the absence of imidazole, a lower yield of 3a and a poor mass balance were observed in the reaction without adding water. These results indicate that imidazole may suppress the formation of the ketone

A versatile way for the synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with the NaBH₄/I₂ system

• Lin Chen,
• Xuan Zhou,
• Zhiyong Chen,
• Changxu Wang,
• Shunjie Wang and
• Hanbing Teng

Beilstein J. Org. Chem. 2022, 18, 1032–1039, doi:10.3762/bjoc.18.104

• attacked by a nucleophile the imidazole group readily dissociates. The N-substituted carbonylimidazoles have favorable reactivity and can be widely used in the synthesis of various valuable products such as ureas [63][64][65][66][67][68][69][70], carbamates [66][71][72][73][74], thiocarbamates [66], and

• materials including amines, carboxylic acids and isocyanates under mild and safe reaction conditions. Results and Discussion Initially, N-phenethyl-1H-imidazole-1-carboxamide (1b) was chosen as a model substrate to react with 3.0 equiv of NaBH4 and 1.0 equiv of I2 in THF at reflux temperature, as expected

• for carboxylic acids, the carbon source is the carboxyl group. When carboxylic acids were used, the carboxyl moiety was first converted to an isocyanate via Curtius rearrangement [82][83][84][85], then reacted with imidazole to form the carbonylimidazole, and eventually reduced to the methyl moiety

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544

• Yin Chen,
• Jinqiu Ren,
• Ruimin Yang,
• Jie Li,
• Sheng-Xiong Huang and
• Yijun Yan

Beilstein J. Org. Chem. 2022, 18, 1009–1016, doi:10.3762/bjoc.18.101

• , 20 mM imidazole, pH 8.0). After ultrasonic cell crushing, the cells were centrifuged at 24,000 rpm for 60 min to remove cell fragments. The supernatant was filtered through 0.22 μm of the filter membrane and then loaded into the nickel column of the rebalanced lysate (HisTraqTM FF, GE Healthcare

• ). The eluent was removed with buffer B (50 mM Tris-HCl, 300 mM NaCl, 250 mM imidazole, pH 8.0) at a flow rate of 2 mL/min, starting from the fourth tube of the collection tube and ending at the sixth tube. The outgoing protein was collected and poured into a precooled filter column (Ultracel series 10

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• elsewhere [36]. General procedure for the synthesis of 1-butyl-3-methyl-1H-imidazole-2(3H)-thione Constant current electrolyzes (I = 134 mA) were carried out using a parallel plate divided cell. Anolyte (25 mL) and catholyte (20 mL) were separated through a Nafion® 438 membrane. The anode material was

• -Butyl-3-methyl-1H-imidazole-2(3H)-thione (1a): Spectral data are consistent with those reported in the literature [38]. 1H NMR (CDCl3) δ 6.64 (s, 2H), 3.99 (t, J = 7.4 Hz, 2H), 3.57 (s, 3H), 1.79–1.64 (m, 2H), 1.39–1.28 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (CDCl3) δ 162.3, 117.5, 116.4, 47.8

A trustworthy mechanochemical route to isocyanides

• Francesco Basoccu,
• Federico Cuccu,
• Federico Casti,
• Rita Mocci,
• Claudia Fattuoni and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 732–737, doi:10.3762/bjoc.18.73

• whilst the latter should produce CO2 and imidazole as byproducts. In both cases, the reaction driving force is the production of thermodynamically stable products. However, they did not bring any advantage compared to acetic anhydride. Considering that CDI is activated in an acid environment, adding a

• organic bases like potassium tert-butoxide and imidazole proved to be as effective as triethylamine. Much to our surprise, we observed that the association between only 1 equivalent of triethylamine and 6 equivalents of sodium carbonate brought a good conversion rate of 1f in 2f at a frequency of 36 Hz

DDQ in mechanochemical C–N coupling reactions

• Shyamal Kanti Bera,
• Rosalin Bhanja and
• Prasenjit Mal

Beilstein J. Org. Chem. 2022, 18, 639–646, doi:10.3762/bjoc.18.64

• . Keywords: ball mill; 1H-benzo[d]imidazole; C(sp2)–H amidation; DDQ; mechanochemistry; quinazolin-4(3H)-one; Introduction The reawakening approaches to use solvent-free and environmentally benign conditions in organic synthesis have facilitated new opportunities [1][2][3][4]. The research area of

• ). Results and Discussion Towards the optimization study, (E)-N-(2-((2-bromobenzylidene)amino)phenyl)-4-methylbenzenesulfonamide (1a) was considered as a model substrate for the synthesis of 2-(2-bromophenyl)-1-tosyl-1H-benzo[d]imidazole (2a, Table 1). Initially, with 1.0 equiv of DDQ, product 2a was

• g (92%) of the cyclized product 2-(4-bromophenyl)-1-tosyl-1H-benzo[d]imidazole (2c). Similarly, we also carried out the large-scale synthesis with 4.04 mmol each of anthranilamide and 4-bromobenzaldehyde (4), which produced 1.16 g (95%) of the desired product 2-(4-bromophenyl)quinazolin-4(3H)-one

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• imidazole-based multidentate donors [58]. The conformational asymmetry of the imidazole units opened the venue to nanocages of different shapes and sizes with ease. To take the directional self-assembly to the next level, a three-component self-assembly of the tetra- and tri-imidazole donors 6 and 7

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• . The recombinant protein was separated from cell debris by centrifugation (20,000g, 30 min). The supernatant was loaded to a 5 mL HisTrapTM HP column (GE healthcare) pre-equilibrated with buffer A (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 20 mM imidazole) and purified at 4 °C using an ÄKTA pure FPLC system

• (GE Healthcare). The column was washed with buffer A to remove unbound proteins followed by elution of bound proteins with buffer B (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 500 mM imidazole). Further purification was carried out by gel filtration chromatography (Superdex S200 16/600 column, GE Healthcare

Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions

• José G. Hernández,
• Karen J. Ardila-Fierro,
• Dajana Barišić and
• Hervé Geneste

Beilstein J. Org. Chem. 2022, 18, 182–189, doi:10.3762/bjoc.18.20

• , we reacted a mixture of NFSI and imidazole (3a) by ball milling. Analysis by NMR spectroscopy of the crude reaction mixture showed that 1-(benzenesulfonyl)imidazole (4a) had been formed in 41% yield (Scheme 3a). Complementarily, 19F NMR spectroscopy of the crude reaction mixture evidenced a

• also been reported to act as a transfer of the sulfonyl moiety from NFSI to carbon centers [12][13]. Alternatively, 4a could have been formed from the reaction of imidazole (3a) with the in situ formed PhSO2F. To better understand the formation of PhSO2F during the milling of NFSI with 3a, we reacted

• its N-methylated derivative 3b, a substrate unable to undergo the sulfonylation pathway with NFSI. We hypothesized that PhSO2F could have been generated after an initial reaction of the nitrogen with the lone electron pair in imidazole at the sulfonyl group of the NFSI (Scheme 3c), mimicking the

Synthesis of a novel aminobenzene-containing hemicucurbituril and its fluorescence spectral properties with ions

• Qingkai Zeng,
• Qiumeng Long,
• Jihong Lu,
• Li Wang,
• Yuting You,
• Xiaoting Yuan,
• Qianjun Zhang,
• Qingmei Ge,
• Hang Cong and
• Mao Liu

Beilstein J. Org. Chem. 2021, 17, 2840–2847, doi:10.3762/bjoc.17.195

• heterocalixarenes, which all comprised benzimidazol-2-one and 1,3-phenylene units in an alternate cyclic arrangement. In 2008, Kwit et al. [35] synthesized urea and thiourea derivatives of chiral triangular polyimine macrocycles. The macrocycles above mainly consisted of imidazole analogs and aromatic fragments

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• into a primary alcohol with sodium borohydride affords compound 23. The protection of the hydroxy group of compound 23 was carried out by TBDPSCl in the presence of imidazole and N,N-dimethylformamide (DMF) as solvent, and deprotection of the benzoyl group by ammonolysis provides silylated compound 24

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

• ; c) TBHPaq, 1,2-DCE, 100 °C, 18 h (yields in parentheses). Total synthesis of nobilone (1d). Conditions: a) TBS-Cl, imidazole, DMF, 50 °C, 18 h; b) n-BuLi, B(OiPr)3, THF, −78 °C to rt, 16 h; c) BF3·OEt2, NBS, −20 °C to rt, 24 h; d) Pd(PPh3)4 (5 mol %), Na2CO3, DMF/H2O, 100 °C, 12 h; e) TBS-Cl

• , imidazole, DMF, 50 °C, 18 h; f) LAH, AlCl3, THF, rt, 12 h; g) TBHPaq, DCE, 100 °C, 18 h; h) pyridine, HF·pyridine, EtOAc, rt, 14 h. Proposed mechanism for the oxidative cyclization of amines 2a and 2b to fluorenone (3). Reactivity of different functional groups towards TBHP-mediated cyclization to give

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

• hydration and α-ketol rearrangement to give the corresponding ring-expanded cyclopentanones. IPr = N,N′-bis(2,6-diisopropylphenyl)imidazole-2-ylidene. The diastereospecific α-ketol rearrangement of 32 to 33, part of the total synthesis of periconianone A (31). Two α-ketol rearrangements, one catalyzed by

In-depth characterization of self-healing polymers based on π–π interactions

• Josefine Meurer,
• Julian Hniopek,
• Johannes Ahner,
• Michael Schmitt,
• Jürgen Popp,
• Stefan Zechel,
• Kalina Peneva and
• Martin D. Hager

Beilstein J. Org. Chem. 2021, 17, 2496–2504, doi:10.3762/bjoc.17.166

• ) (PPG3-PEG39-PPG3) featuring also two amine groups as end groups. The molar mass of this reactant was 1900 g/mol. The conversion with perylene-3,4,9,10-tetracarboxylic dianhydride resulted in polymer P2. In both synthesis protocols imidazole was applied as a catalyst in order to obtain higher molar

• . P1: Perylene-3,4,9,10-tetracarboxylic dianhydride (1.02 g, 2.60 mmol), poly(propylene glycol) bis(2-aminopropyl ether) (Mn = 2000 g/mol; 5.2 g, 2.60 mmol) and imidazole (18 g, 264.39 mmol) were mixed in a round bottom flask under nitrogen atmosphere. Afterwards, the reaction mixture was heated to 150

• (propylene glycol) bis(2-aminopropyl ether) (Mn = 1900 g/mol; 4.94 g, 2.60 mmol) and imidazole (18 g, 264.39 mmol) were mixed in a round bottom flask under nitrogen atmosphere. Afterwards, the reaction mixture was heated to 150 °C for 17 h. After cooling to room temperature, water and chloroform were added

Synthesis and antimicrobial activity of 1H-1,2,3-triazole and carboxylate analogues of metronidazole

• Satya Kumar Avula,
• Syed Raza Shah,
• Khdija Al-Hosni,
• Muhammad U. Anwar,
• Rene Csuk,
• Biswanath Das and
• Ahmed Al-Harrasi

Beilstein J. Org. Chem. 2021, 17, 2377–2384, doi:10.3762/bjoc.17.154

• next step, the metronidazole tosylate 2 under treatment with NaN3 in DMF at 70 °C afforded the corresponding metronidazide 3 in 88% yield [18]. The 1H NMR spectrum of metronidazide 3 showed a singlet at δ 7.93 for the 1H-imidazole proton. Two triplet signals at δ 4.40 and δ 3.74 were assigned to four

• methylene protons of –N–CH2-CH2–N3. A singlet peak at δ 2.50 was due to methyl protons on the imidazole ring. The high-resolution mass spectrometric data at 197.0737 (M + H)+ confirmed the structure of metronidazide 3. Single crystals of metroazide compound 3 were grown from slow evaporation of DCM solution

• 1H NMR spectrum of 1H-1,2,3-triazole compound 5c showed two singlet signals at δ 8.13 and 7.99 corresponding to the 1H-imidazole and 1H-1,2,3-triazole protons, respectively. The four aromatic protons appeared in the region of δ 7.67–7.05 ppm. A doublet signal at δ 4.77 is due to the four methylene

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

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• constituent M and G residues and C2/C3 acetylation for one M residue. b) Introduction of bioisosteric carboxylate groups at C6 within a ᴅ-manno thioglycoside donor, P = appropriate protecting group. a) H2N(CH2)2CN, PyBOP, DIPEA, CH2Cl2, 0 °C, 40 min, 47% (+44% 3); b) TBSOTf, imidazole, DMAP, DMF, 24 h, 80%; c

• ) PPh3, DIAD, TMSN3, MeCN, 80 °C, 48 h. a) BzCl, DMAP, pyridine, CH2Cl2, rt, 24 h, 90%; b) TBSOTf, imidazole, DMAP, DMF, 40 °C, 24 h, 78%; c) Na(s), MeOH, THF, 16 h, 90%; d) DMSO, SO3·pyridine, Et3N, rt, 1 h, 98%; e) H2NOH·HCl, THF, H2O, Na2CO3, 24 h, 80%; f) POCl3, MeCN, 65 °C, 40%; g) TBSOTf, imidazole

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide)

• Louis G. Mueller,
• Allen Chao,
• Embarek AlWedi and
• Fraser F. Fleming

Beilstein J. Org. Chem. 2021, 17, 1499–1502, doi:10.3762/bjoc.17.106

• electrophiles to afford imidazoles. In situ cyclization to the imidazole is promoted by the conjugate acid, hexamethyldisilazane, which facilitates the requisite series of proton transfers. The rapid formation of imidazoles and the interchange of the anisylsulfanyl for hydrogen with Raney nickel make the method

• a valuable route to mono- and disubstituted imidazoles. Keywords: Asmic; cyclization; imidazoles; isocyanides; nitriles; Introduction The imidazole core is the seventh most prevalent heterocycle among nitrogen-containing pharmaceuticals [1]. The privileged efficacy of imidazoles emanates from the

• central role of histidine in biological machinery, particularly as a base at enzymatic active sites [2]. As histidine mimics, imidazole-containing pharmaceuticals are often only N-substituted, as in the fungicides ketoconazole and econazole (Figure 1) [3], or disubstituted as illustrated by the anesthetic