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

• reactions with elemental sulfur [23][24][25], resulting in the generation of non-enolizable imidazole-2-thiones. At first, the alkylation of 2-unsubstituted imidazole N-oxides 40 took place in the presence of an equimolar quantity of benzyl bromide in CH2Cl2 at rt providing the (N-benzyloxy)imidazolium

1,4,6,10-Tetraazaadamantanes (TAADs) with N-amino groups: synthesis and formation of boron chelates and host–guest complexes

• Artem N. Semakin,
• Ivan S. Golovanov,
• Yulia V. Nelyubina and
• Alexey Yu. Sukhorukov

Beilstein J. Org. Chem. 2022, 18, 1424–1434, doi:10.3762/bjoc.18.148

• triple alkylation of ammonia with α-halohydrazones 9a–e following a protocol previously developed by us [35] (Scheme 2a). Halohydrazones 9a–e were prepared by condensation of readily available chloroacetone or bromoacetaldehyde (generated from the corresponding diethyl acetal) with hydrazides or

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

• Sanaz Ahmadipour,
• Alice J. C. Wahart,
• Jonathan P. Dolan,
• Laura Beswick,
• Chris S. Hawes,
• Robert A. Field and
• Gavin J. Miller

Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142

• active site thiohemiaminal (amine to imine oxidation) or disulfide formation, respectively. Additionally, C6–Cl derivative 9 could probe cysteine alkylation. Reported herein is our exploration of this synthesis and the evaluation of GDP 6-chloro-6-deoxy-ᴅ-mannose 18 against GMD. Results and Discussion

• the GMD-19 incubation time to overnight, followed by protein-MS analysis, but found no evidence of sugar nucleotide–protein conjugation; by contrast a positive control treating GMD with iodoacetamide showed multiple alkylation of the protein (see Figure S4 in Supporting Information Information File 1

• accepted. Evaluation of GDP 6-chloro-6-deoxy-ᴅ-mannose suggests that the ligand can bind to GMD, but that targeting inhibitive S-alkylation of an sp3-hybridised C6 electrophilic probe is ineffective here. a) Proposed oxidative pathway for provision of GDP-ManA 5 from GDP-Man 1, C6 stereochemistry of 3 is

Ionic multiresonant thermally activated delayed fluorescence emitters for light emitting electrochemical cells

• Merve Karaman,
• Abhishek Kumar Gupta,
• Subeesh Madayanad Suresh,
• Tomas Matulaitis,
• Lorenzo Mardegan,
• Daniel Tordera,
• Henk J. Bolink,
• Sen Wu,
• Stuart Warriner,
• Ifor D. Samuel and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2022, 18, 1311–1321, doi:10.3762/bjoc.18.136

• -dibromobutane in moderate yield, followed by a second alkylation step with 1-methylimidazole in very good yield. DiKTa-OBuIm was isolated as its hexafluorophosphate salt following anion metathesis with NH4PF6. DiKTa-DPA-OBuIm was obtained also in three steps at 35% overall yield from compound 4 using a similar

Ferrocenoyl-adenines: substituent effects on regioselective acylation

• Mateja Toma,
• Gabrijel Zubčić,
• Jasmina Lapić,
• Senka Djaković,
• Davor Šakić and
• Valerije Vrček

Beilstein J. Org. Chem. 2022, 18, 1270–1277, doi:10.3762/bjoc.18.133

• both isomers is, therefore, a competitive process. This confirms that the adenine anion behaves as an ambident nucleophile with two competing reaction centers at the N7- and N9-position [26]. It is known that acylation [25] or alkylation [27][28][29] of adenine is rarely regiospecific, and mixtures of

• N7- and N9-isomers are usually obtained. In some cases, the acylation of adenine may also occur at the exo-amino group (N6) [30][31]. In general, the literature on the regioselectivity of alkylation of adenines/purines is more abundant, includes an array of reaction conditions (base, solvent

• in the alkylation of purines were reported earlier [40]. Now, we demonstrate for the first time that similar effect is operative in the acylation of purines. It is evident from the results in Table 1 that the N9/N7 ratio increases with the increasing size of the substituent at the exocyclic amino

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C–Si bond functionalization

• Sebastien Curpanen,
• Per Reichert,
• Gabriele Lupidi,
• Giovanni Poli,
• Julie Oble and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2022, 18, 1256–1263, doi:10.3762/bjoc.18.131

• details). We also contemplated the use of alkyl iodides as electrophiles. Methylation with methyl iodide was efficient, as shown through the preparation of 28 in 61% yield from 4c. In contrast, higher alkyl iodides, such as ethyl iodide, failed to provide the alkylation product (i.e., 29) and only

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

• the methylation reagents and the reductive amination reactions by using formaldehyde or paraformaldehyde as the “indirect” alkylation reagents [16][17][18][19]. Recently, a variety of promising methylating agents or C1 sources such as formic acid [20][21], methanol [22][23][24][25][26][27][28][29][30

• ][31] and carbon dioxide (CO2) [32][33][34][35][36][37][38][39] have been developed for the N-methylation of amines. However, these N-alkylation methods often require the employment of expensive catalysts, and the N-alkylation of primary amines generally does not stop with monomethylation as expected

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

• -phenylphosphinamide (92a) and chloromethyl N,N’-dimethyl-N,N’-diphenylphosphondiamide (92b) via an intramolecular Friedel–Crafts alkylation. Although they tried several different amide derivatives, only phosphinamide 92a and phosphonic diamide 92b gave the corresponding 1-methyl-1,3-dihydrobenzo[d][1,2]azaphosphole 2

• intramolecular nucleophilic dearomatization and protonation or electrophilic alkylation reactions, affording the corresponding dihydronaphthylene-fused γ-phosphinolactams 135–142. Methanol was used as the electrophile for protonation, while methyl iodide and allyl bromide were used as electrophiles for

• alkylation. A remarkable difference compared with the diphenylphosphinamides is the fact that the current reactions proceeded with excellent regio- and stereoselectivities and yields in THF without the use of the carcinogenic cosolvent HMPA (Scheme 24) [51]. With benzaldehyde as an electrophile, both

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

• Virginija Jakubkiene,
• Gabrielius Ernis Valiulis,
• Markus Schweipert,
• Asta Zubriene,
• Daumantas Matulis,
• Franz-Josef Meyer-Almes and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 837–844, doi:10.3762/bjoc.18.84

• to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate

• both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively. Keywords: alkylation; aminolysis; HDAC inhibitors; hydroxamic acid; pyrimidine; Introduction Histone deacetylases (HDACs) are a family of intracellular proteins responsible for removing acetyl groups in histones

• ][28][29][30]. In this work, the pyrimidine-based hydroxamic acids were synthesized by aminolysis of the corresponding esters. The required esters 3 and 4 were obtained by alkylation of pyrimidinones 1 and 2 with ethyl 2-bromoethanoate in triethylamine in the presence of tetrabutylammonium bromide at

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• . On the other hand, the tetrahydrospiro[carbazole-3,5'-pyrimidine] 4 can be converted to aromatized spiro[carbazole-3,5'-pyrimidine] 3 through the oxidation of DDQ. In the absence of the effective dienophile, the normal Friedel–Crafts alkylation of 2-methylindole with aromatic aldehyde gives the well

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• , the expansion of our previously reported propiophenone family of reagents was envisioned as suitable alternative to produce a bench stable, organic soluble, and iodine-free perfluroalkylation source. In 2017, our group developed a metal-free and redox-neutral protocol for the photoinduced alkylation

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• and warm odor; interestingly, it is also strongly antiseptic [9]. In 2005, Poliakoff and co-workers developed a synthesis of thymol by alkylation of m-cresol (39) in supercritical carbon dioxide (scCO2) using γ-Al2O3 in a packed-bed reactor (Scheme 9) [40]. In the presence of Brønsted-acidic Nafion

• SAC-13, alkylation of m-cresol with isopropanol proceeds via a Friedel–Crafts-type mechanism in much lower selectivity. In contrast, the authors proposed that employing γ-Al2O3 as Lewis acid catalyst, reaction of 39 and isopropanol leads to isopropyl ether 40. This intermediate undergoes a Fries-type

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• 180 °C at 4.5 MPa for 7.5 min. These conditions allowed to suppress the decomposition of the N-alkylation product 78 by using a 1/8“-reactor. The subsequent purification was realized by a clever catch and release protocol based on a silica column, yielding iloperidone (80, 67%). The tricyclic

• included a carboxylation and a Parham cyclization and hence a Grignard alkylation of ketone 82 using reagent 81. The resulting alcohol 83 was subjected to thermolysis that led to water elimination. This step proceeded in just 30 s by employing the inductive heating technique. The crude elimination product

• fixed-bed materials serving as catalysts: A. with copper metal, B. with Au-doped MagSilicaTM, and C. with Pd-doped MagSilicaTM. Two step flow protocol for the preparation of 1,1'-diarylalkanes 77 from ketones and aldehydes 74, respectively, and boronic acids 76. O-Alkylation, the last step in the

Synthesis of sulfur karrikin bioisosteres as potential neuroprotectives

• Martin Pošta,
• Václav Zima,
• Lenka Poštová Slavětínská,
• Marika Matoušová and
• Petr Beier

Beilstein J. Org. Chem. 2022, 18, 549–554, doi:10.3762/bjoc.18.57

• compounds 8, 20 and 21 albeit in low yields. Due to the extremely low isolated yield of compounds 20 and 21, we looked for an alternative more efficient procedure. In 2008 Sun et al. [32] described a method of karrikin alkylation in position 7 via direct metalation with lithium bis(trimethylsilyl)amide

• (LiHMDS), followed by the addition of an alkyl halide. Application of this method to 8 provided the target molecule 21 in good yield (Scheme 4). It has to be mentioned that the metalation proceeds exclusively at C7, and thus cannot be used for the preparation of 20 via alkylation at C5. Our attempt to

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• were coupled with a benzoic acid-based stopper using N,N′-diisopropylcarbodiimide (DIC) and tributylphosphine (26–75% yield). The isolated rotaxanes were then used for subsequent reductive N-alkylation to obtain the tert-amine-type rotaxanes (R)-29a–f in yields of 67–92%. Finally, dimethyldioxirane

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban

• Martin Vrbický,
• Karel Macek,
• Jaroslav Pochobradský,
• Jan Svoboda,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2022, 18, 438–445, doi:10.3762/bjoc.18.46

• utilized, which consisted of alkylation of aniline 3 by methyl bromoacetate, followed by introduction of the Boc group into intermediate Int-17a, and final reduction of Int-17b with DIBAL-H (Scheme 1). For the study of the asymmetric Henry reaction aldehydes 15–20, nitromethane, and highly enantioselective

Tetraphenylethylene-embedded pillar[5]arene-based orthogonal self-assembly for efficient photocatalysis in water

• Zhihang Bai,
• Krishnasamy Velmurugan,
• Xueqi Tian,
• Minzan Zuo,
• Kaiya Wang and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2022, 18, 429–437, doi:10.3762/bjoc.18.45

• supramolecular assembly with a two-step FRET process by the utilization of a metallacycle-tetraphenylethylene (TPE) donor and eosin Y (EsY) and sulforhodamine (SR101) as first and second acceptors, respectively. The resulting supramolecular energy transfer system was applied to the alkylation of C–H bonds via a

Cs₂CO₃-Promoted reaction of tertiary bromopropargylic alcohols and phenols in DMF: a novel approach to α-phenoxyketones

• Ol'ga G. Volostnykh,
• Olesya A. Shemyakina,
• Anton V. Stepanov and
• Igor' A. Ushakov

Beilstein J. Org. Chem. 2022, 18, 420–428, doi:10.3762/bjoc.18.44

• -phenoxyketones, the most common methodologies are base-catalyzed alkylation of the corresponding phenols with halo- [28][29][30] and mesyl [31][32][33] ketones (Scheme 9), the preparation of which are not always selective and high-yielded. The ring opening of ArOCH2-epoxides [34][35], the SmI2-catalyzed

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• maintaining animals’ physiology, by acting on blood clotting and regulating bone calcification [10]. In animals, menadione can be converted in vitamin K2 in the intestinal tract, by intestinal microbiota [10]. In humans, the menadione–vitamin K2 conversion occurs after its alkylation in the liver [11

• useful alkylation approach is the Kochi–Anderson method [76] (or also known as Jacobsen–Torssell method [77][78]), via oxidative decarboxylation, where the quinone reacts with a carboxylic acid in the presence of silver(I) nitrate and ammonium or potassium peroxydisulfate. Nucleophilic free radicals are

• -workers synthetized 10 using a much simpler way (Scheme 1) [80]. These authors reported the methylation and alkylation of 1,4-naphthoquinone (1) in the presence of (NH4)2S2O8 and AgNO3 as catalyst to obtain 10 in 60% yield. Recently, Onuki and co-workers conducted dimerization reactions of 10, exploring

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• [Pd(C3H5)Cl]2 and ligand L1 (Scheme 2) [11]. The reaction, that could also be considered as Friedel–Crafts type, intramolecular allylic alkylation, delivered nine-membered ring bearing 3,4-fused indoles 2 in moderate to good yields. In the asymmetric version of the reaction catalyzed by [Ir(cod)Cl]2

• synthesis of pyrano[2,3-e]indol-3-ols 41 via trifluoroethanol-mediated intramolecular ring-opening cyclization of 4-(2-oxiranylmethoxy)indoles 40 which were prepared by O-alkylation of 4-hydroxyindole 38 using epoxy tosylates 39 as the alkylating agents, followed by (in selected cases) N-tert

• -butyloxycarbonylation and N-alkylation (Scheme 14) [25]. The C5 cyclization regioselectivity and trans-diastereoselectivity were not influenced by the electronic nature of the indole-N-substituent. Conclusion As illustrated by these studies, SEAr-based intramolecular cyclization and annulation reactions of 3,5

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• catalysis relies on the deprotonation of one of the substrates, but basic conditions may limit the applicability of this methodology. A unique base-free variant of chiral phase-transfer catalytic alkylation of 2-oxindoles was developed by Connon and co-workers [23]. Pentacarboxycyclopentadienes are a unique

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• transformations. Organometallics are the most commonly used catalysts to promote C–C bond formation. In addition, other so-called classical reactions are also widely used, such as Friedel–Crafts alkylation and acylation, Wittig and Horner–Emmons reactions, carbonyl addition/substitution, α-alkylation, aldol

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

• Nicolai Wippert,
• Martin Nieger,
• Claudine Herlan,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2021, 17, 2773–2780, doi:10.3762/bjoc.17.187

•  1, the alkylation protocol did not give a selective conversion in favor of one of the generated isomers. The protocol was not changed or adapted to gain a higher selectivity of one of the isomers, as both regioisomers were used in the subsequent syntheses. For the derivatives 12h and 13c, we were

• able to exemplarily determine the molecular structure by X-ray crystallography, proving the regioisomer obtained in the alkylation reaction (Figure 2). While isomer 12 was used for the synthesis of pyrazolo[3,4-d][1,2,3]-3H-triazine derivatives of general structure 5, the isomer 13 was intended to

• -triazine derivatives. Molecular structures of compounds 12h (A) and 13c (B) representing both possible regioisomers of the alkylation reaction (displacement parameters are drawn at the 50% probability level). The X-ray data corroborate the obtained NMR data. Graphical overview about selected pyrazolo[1,2,3

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• values of up to 95% and very good yields (≈99%) in all cases (Table 11) [45]. Guo et al. synthesized a variety of benzoindolizidines (56) from α,β-unsaturated aminoketones 54 through intramolecular domino aza-Michael addition/alkylation reactions. The reactions were carried out in the presence of

• and thioureas were screened for the enantioselective N-alkylation of isoxazolin-5-ones via a 1,6-aza-Michael addition of isoxazolin-5-ones 64 to p-quinone methides (p-QMs) 65 to give isoxazolin-5-ones 67 bearing a chiral diarylmethyl moiety attached to the N atom. The best result in terms of

• aza-Michael/alkylation reaction catalyzed by cinchona alkaloid-derived quaternary ammonium salts. Asymmetric aza-Michael synthesis of isoindolinones. Asymmetric aza-Michael addition reaction catalysed by chiral bifunctional thiourea. Enantioselective 1,6-aza-Michael addition of isoxazolin-5-ones to p