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

• . Finally, we turned out attention to transition metal-catalyzed formation of phenols from aryl halides [5]. After another round of screening, we successfully applied palladium-catalyzed conditions discovered by the Buchwald group [6], using KOH as the nucleophile and X-Phos as the ligand, to afford 7 in 83

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

• Armin Ariamajd,
• Nils J. Gerwien,
• Benjamin Schwabe,
• Stefan Dix and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8

• of an alkyl electrophile has been reported to date [35]. This process used an umpolung strategy with activation of typically electrophilic perfluoroalkylsulfenamide reagents by iodide, releasing −SC2F5 or −SC3F7 anions in situ, which could then react with a selection of alkyl halides (Scheme 1b). In

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• (rac)-13 in a stereoselective manner, attention was then focused on the development of an analogous strategy towards the (Z,Z,E)- and (Z,E,E)-triene systems present in oxazolomycin A (5a) and oxazolomycin C (5c), respectively. The key steps were i) synthesis of dienyl halides, ii) synthesis of the

• required vinylstannane and iii) Stille coupling between them (Scheme 3) [39]. The required divinyl halides 36 were prepared, starting from phenylacetaldehyde (33), by using the Takai [38] or Wittig procedures [40] as shown in Scheme 3 (68% of a 3.3:1 mixture of (E,E)/(Z,E)-36b and 69% yield of a 8:1

• (Scheme 23). The aldehyde (Z)-(+)-143a was the common intermediate for the synthesis of (E)- or (Z)-selective vinyl boronates or vinyl halides (+)-145 to accomplish total syntheses of all inthomycins A–C ((+)-1, (+)-2 and (–)-3, see Scheme 25 and Scheme 26). With the key intermediate (Z)-(+)-143a in hand

Silver-catalyzed synthesis of β-fluorovinylphosphonates by phosphonofluorination of aromatic alkynes

• Yajing Zhang,
• Qingshan Tian,
• Guozhu Zhang and
• Dayong Zhang

Beilstein J. Org. Chem. 2020, 16, 3086–3092, doi:10.3762/bjoc.16.258

• . Substrates containing a range of functional groups, including halides (F, Cl, and Br), CF3, and even ester groups, were amenable to this transformation. The reaction was also compatible with a CN group to afford the corresponding product 2n in 69% yield. Heteroaromatic alkynes, such as 2-ethynylpyridine and

Amine–borane complex-initiated SF₅Cl radical addition on alkenes and alkynes

• Audrey Gilbert,
• Pauline Langowski,
• Marine Delgado,
• Laurent Chabaud,
• Mathieu Pucheault and
• Jean-François Paquin

Beilstein J. Org. Chem. 2020, 16, 3069–3077, doi:10.3762/bjoc.16.256

• recently, it has been shown that some of these common amine–borane complexes can also be used as radical initiators for atom transfer radical addition of alkyl halides to alkenes [48]. They were also used in the free-radical polymerization of alkene-containing monomers such as methyl methacrylate or

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD^®/Olah’s reagent under solvent-free conditions

• Yumeng Liang,
• Akihito Taya,
• Zhengyu Zhao,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2020, 16, 3052–3058, doi:10.3762/bjoc.16.254

• fluorides. Acyl fluorides, which are one type of acyl halides, show distinct stability in the presence of moisture, indicating their suitable reactivity only in selected conditions [19]. In addition to our direct cross-coupling reaction method, several useful synthetic methods for the formation of acyl

Chiral anion recognition using calix[4]arene-based ureido receptors in a 1,3-alternate conformation

• Tereza Horáčková,
• Jan Budka,
• Vaclav Eigner,
• Wen-Sheng Chung,
• Petra Cuřínová and
• Pavel Lhoták

Beilstein J. Org. Chem. 2020, 16, 2999–3007, doi:10.3762/bjoc.16.249

• fact, irrespective of the base or solvent used, the alkylation with appropriate n-propyl or n-hexyl halides always led to the partial cone conformation as the main product. To overcome this problematic step, we used the conditions described by Böhmer et al. [46] for a similar system bearing propyl

Selective recognition of ATP by multivalent nano-assemblies of bisimidazolium amphiphiles through “turn-on” fluorescence response

• Rakesh Biswas,
• Surya Ghosh,
• Shubhra Kanti Bhaumik and
• Supratim Banerjee

Beilstein J. Org. Chem. 2020, 16, 2728–2738, doi:10.3762/bjoc.16.223

• -imidazol-1-yl)methane (5) was synthesized from imidazole (4) and CH2Br2 following a literature procedure [62][63] with slight modifications. Then, BImNs (N = 4, 10, 12, 14) were synthesized from 5 by mono-alkylation using the corresponding n-alkyl halides in DMF. Finally, PBImNs (N = 4, 10, 12, 14) were

Optical detection of di- and triphosphate anions with mixed monolayer-protected gold nanoparticles containing zinc(II)–dipicolylamine complexes

• Lena Reinke,
• Julia Bartl,
• Marcus Koch and
• Stefan Kubik

Beilstein J. Org. Chem. 2020, 16, 2687–2700, doi:10.3762/bjoc.16.219

• water/methanol 1:2 (v/v). These anions caused the bright red solutions of the nanoparticles to change their color because of nanoparticle aggregation followed by precipitation, whereas halides or oxoanions such as sulfate, nitrate, or carbonate produced no effect. The sensitivity of phosphate sensing

• . AuNP-based probes for inorganic anions, for example, can serve to monitor the water quality [14][15]. An example is the probe for halides that was described by the Sessler group. It comprised AuNPs with immobilized calix[4]pyrrole residues that are known to interact with chloride and fluoride. The

• response was observed to hydrogenphosphate (and hydrogenarsenate). Other oxoanions and halides induced no visible effects and also did not interfere in diphosphate and triphosphate sensing when simultaneously present. It should be noted that other strategies of detecting diphosphate anions by using

Catalytic trifluoromethylation of iodoarenes by use of 2-trifluoromethylated benzimidazoline as trifluoromethylating reagent

• Tatsuhiro Uchikura,
• Nanami Kamiyama,
• Taisuke Ishikawa and
• Takahiko Akiyama

Beilstein J. Org. Chem. 2020, 16, 2442–2447, doi:10.3762/bjoc.16.198

• ; catalysis; copper; fluorine chemistry; trifluoromethylation; Introduction The introduction of a trifluoromethyl group is one of the most attractive reactions in drug discovery [1][2]. In the past decade, trifluoromethylation reactions of aryl halides in the presence of transition-metal complexes were

• reported [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. CuCF3 is a useful species for the trifluoromethylation of aryl halides and there are a number of precursors of CuCF3 for trifluoromethylation reactions. In contrast, the catalytic generation of CuCF3 was less investigated [15

• , hexafluorobenzene was added as an internal standard and the mixture analyzed by 19F NMR spectroscopy for the calculation of the NMR yield. Then, the crude products were purified by preparative TLC to give pure products 3. Trifluoromethylation of aryl halides. Scope of aryl iodides. Yields determined by 19F NMR

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• photocatalysts used for this reaction, it is proposed the excited state of 9 is sufficiently reducing to initiate the chain mechanism through an oxidative quench. Moving away from electronically activated halides, MacMillan et al. investigated a tricatalytic system, utilising enamine, photoredox, and HAT

• ). It is notable that pyridyl ketones do not perform well in this reaction (1 example, 70:30 er). A further extension of this methodology includes the deuteration of 128 and alkyl halides 132 using D2O to afford 133 (18 examples, up to >99:1 er) and 134 (34 examples, up to 98:2 er), respectively (Scheme

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• promising building blocks for further functionalization, including (het)aryl or alkenyl substitution at the N1 atom. However, direct arylation of 1 with aryl halides under Ullmann reaction conditions is a low-efficiency process giving only complex mixtures. It is likely that the harsh thermal conditions

Regiodivergent synthesis of functionalized pyrimidines and imidazoles through phenacyl azides in deep eutectic solvents

• Paola Vitale,
• Luciana Cicco,
• Ilaria Cellamare,
• Filippo M. Perna,
• Antonio Salomone and
• Vito Capriati

Beilstein J. Org. Chem. 2020, 16, 1915–1923, doi:10.3762/bjoc.16.158

• °C) in the presence or absence of bases (Et3N). Keywords: deep eutectic solvents; imidazoles; phenacyl azides; phenacyl halides; pyrimidines; Introduction In a world with dwindling petroleum resources, the setting up of more and more sustainable routes for the preparation of heterocyclic compounds

• (g) heterogeneous “click” cycloaddition reactions [15] using DESs as environmentally responsible and non-innocent reaction media. Telescoped, one-pot transformations of phenacyl halides to symmetrical 2,5-disubstituted pyrazines (A), through phenacyl azides as intermediates, were also found to take

• separation of the organic layer from water, and removal of the volatiles under reduced pressure. To examine the scope and limitation of this transformation, various functionalized phenacyl halides (1c–i) were tested as substrates. As can be seen from the results compiled in Scheme 3, the reaction is amenable

Design, synthesis and application of carbazole macrocycles in anion sensors

• Alo Rüütel,
• Ville Yrjänä,
• Sandip A. Kadam,
• Indrek Saar,
• Mihkel Ilisson,
• Astrid Darnell,
• Kristjan Haav,
• Tõiv Haljasorg,
• Lauri Toom,
• Johan Bobacka and
• Ivo Leito

Beilstein J. Org. Chem. 2020, 16, 1901–1914, doi:10.3762/bjoc.16.157

• synthesis to access up to –[CH2]10– macrocycles or acyl halides to access up to –[CH2]14– macrocycles. Seventy-five receptor–anion complexes were modelled and studied with COSMO-RS, in addition to all free host molecules. In order to predict initial selectivity towards carboxylates, 1H NMR relative

• anions also represented different parts of the Hofmeister series. Chloride and nitrate are also common in real-world samples that such sensors might be used to analyse. Fluoride and iodide represented halides at opposite ends of the Hofmeister series. The selectivity pattern for the control membrane

On the hydrolysis of diethyl 2-(perfluorophenyl)malonate

• Ilya V. Taydakov and
• Mikhail A. Kiskin

Beilstein J. Org. Chem. 2020, 16, 1863–1868, doi:10.3762/bjoc.16.153

• , hydrolysis of the ester with a mixture of HBr and AcOH gave 2-(perfluorophenyl)acetic acid in a good preparative yield of 63%. A significant advantage of this new approach to 2-(perfluorophenyl)acetic acid is that handling toxic substances such as cyanides and perfluorinated benzyl halides is avoided

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• ., the organic Acr–H2 molecule (Figure 23). In this study, 35 examples of the targeted coupling products were afforded in good to excellent yields. Various synthetically relevant functional groups, including halides, esters, amides, ethers, ketones, and aldehydes were compatible with the protocol. This

• very efficient at room temperature while applying blue LED irradiation. Two slightly modified catalytic systems composed of a [Ru(p-cymene)Cl2]2 catalyst and either K2CO3 or KOAc bases promoted the direct meta-selective C(sp2)–H alkylation with secondary and tertiary alkyl halides, delivering the

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• photocatalyst for the reduction of aryl halides [193]. The material could undergo consecutive photoinduced electron transfers (ConPET) in which the material enters an excited state and is reduced by a sacrificial electron donor (NEt3). The resulting Zn-PDI radical anion then undergoes a second photon absorption

• to achieve a superreducing electronic excited state capable of reducing stable aryl halides (Figure 14) [193]. More recently, PDI self-assemblies have been reported as efficient HPCats for the hydrogen evolution reaction [194] and degradation of phenol [192]. Another important material design applied

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• , or disulfonates of alkane-1,3-diols with sodium sulfide. The intramolecular substitution of 3-mercaptoalkyl halides or sulfonates is a similar strategy for the preparation of thietanes [12][13][14]. Alternatively, inter- and intramolecular photochemical [2 + 2] cycloadditions (thia-Paternò–Büchi

Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• combined with a solution-phase reagent, including: (1) copper(I) oxide to produce N-heterocyclic carbene–Cu(I) complexes for use as catalysts [13]; (2) proline to perform proline-based catalytic reactions [14]; (3) zinc powder to produce organozinc halides in tandem with Negishi couplings [15]; (4) zinc

• conversion because the neutralization can alter the aggregation states, producing a significant batch-to-batch variability. The direct insertion of magnesium metal into organic halides is the most common method used to prepare Grignard reagents but present difficulties: (1) sluggish reactions with ordinary

• use a practical system with a broad range of substrates [40][41][42]. The Alcázar group reported the generation and subsequent use of Grignard reagents [40]. In 2018, the Loren group extended the scope of the organozinc reagents made in flow to aryl and tertiary alkyl halides by the in situ formation

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• fragmentation of the reduced intermediates. Due to their availability and their attitude to undergo reductive fragmentations, alkyl halides have been extensively used as C(sp3) radicals sources. Recently, Dell’Amico and co-workers reported a new class of naphthochromenone-based organic dyes, which, due to the

• wide redox window (E = 3.22 eV, +1.65 V/−1.77 V), can be exploited as photocatalysts for various transformations, including the reductive dehalogenation of benzylic halides (Scheme 7) [52]. In this protocol, the excited state photocatalyst OD18 can generate C(sp3) radicals through the reductive

• cleavage of various benzyl halides 7.1 (I, Br, Cl). The radical is then intercepted by an H atom donor (Hantzsch ester), which delivers the corresponding toluene derivative 7.2. Other organic dyes can promote the reductive fragmentation of alkyl halides. For instance, König and Zeitler demonstrated that a

Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones

• Valeria Nori,
• Antonio Arcadi,
• Armando Carlone,
• Fabio Marinelli and
• Marco Chiarini

Beilstein J. Org. Chem. 2020, 16, 1084–1091, doi:10.3762/bjoc.16.95

• -alkynyltrifluoroacetanilides. In all these procedures, the activation of the triple bond was achieved by means of a σ-organyl palladium complex, in turn generated in situ by oxidative addition of a Pd(0) species to suitable organic electrophiles (aryl and vinyl halides or triflates [35][36], alkyl halides [37], alkynyl

• halides [38], α-iodoenones [39], or by transmetalation of a Pd(II) species with boronic acids [33]. In this context, we decided to explore the use of substrates 2 in the reaction with 2-alkynyltrifluoroacetanilides 5 through a sequential cyclocarbopalladation/aminopalladation/reductive elimination process

Synthesis and anticancer activity of bis(2-arylimidazo[1,2-a]pyridin-3-yl) selenides and diselenides: the copper-catalyzed tandem C–H selenation of 2-arylimidazo[1,2-a]pyridine with selenium

• Mio Matsumura,
• Tsutomu Takahashi,
• Hikari Yamauchi,
• Shunsuke Sakuma,
• Yukako Hayashi,
• Tadashi Hyodo,
• Tohru Obata,
• Kentaro Yamaguchi,
• Yasuyuki Fujiwara and
• Shuji Yasuike

Beilstein J. Org. Chem. 2020, 16, 1075–1083, doi:10.3762/bjoc.16.94

• , and aryl halides in the presence of Na2CO3 (2 equiv) using a NiBr2/2,2-bipyridine system [31]. We also developed reactions of imidazopyridines, Se powder, and triarylbismuthanes using a CuI/1,10-phenanthroline catalytic system that did not require a base or an additive [32]. On the other hand, the

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• difluoromethylcopper ones are less stable as demonstrated by the work of Burton in 2007 [37]. Investigations on the in situ synthesis of difluoromethylcopper from a difluoromethylcadmium source at low temperature and the study of its reactivity with various classes of compounds such as allylic halides, propargylic

• halides and tosylates, iodoalkynes and reactive alkyl halides were realized. It was established that CuCF2H readily decompose into 1,1,2,2-tetrafluoroethane and cis-difluoroethylene. From this pioneer work, attention was paid either to the design of new synthetic pathways for the synthesis of a well

• -generated copper-based reagent (19 examples, up to 80% yield, Scheme 7e). With a similar method and in the presence of 1,10-phenanthroline as a ligand, the functionalization of alkenyl halides (8 examples, up to 82% yield), allyl halides (7 examples, up to 99% yield) and benzyl bromides (6 examples, up to

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

• reported herein different methods for their synthesis. 1.1. Negishi cross coupling of aryl halide and organozinc compounds Jackson and co-workers reported the synthesis of a range of phenylalanine derivatives via Negishi cross-coupling reactions of aryl halides and Zn homoenolates of the protected (R

• )-iodoalanine 2. The reaction was activated using Pd(0) as a catalyst. A palladium-catalyzed cross-coupling reaction between an organozinc iodide and aryl halides offers a convenient method for the direct preparation of protected fluorinated Phe analogues 3. Thus, cross coupling of the protected iodoalanine 2

• and 12b afforded ʟ-4-[sulfono(difluoromethyl)]phenylalanine derivatives 13a and 13b, respectively [39] (Scheme 3). 1.2. Alkylations of fluorinated aryl halides with a chiral auxiliary Alternatively, the coupling of the bis(dimethoxybenzyl)-protected sulfonamide 14, instead of the esters 10a and 10b

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

• Quentin Lefebvre,
• Christophe Salomé and
• Thomas C. Fessard

Beilstein J. Org. Chem. 2020, 16, 982–988, doi:10.3762/bjoc.16.87

• halides to get an insight into the specific reactivity of these building blocks. The workflow combined a powerful photoreactor with precise and reproducible conditions control with benchtop analytical tools such as TLC–MS and low-field NMR. This enabled the identification of privileged spirocyclic