Efficient synthesis of piperazinyl amides of 18β-glycyrrhetinic acid

• Dong Cai,
• ZhiHua Zhang,
• Yufan Meng,
• KaiLi Zhu,
• LiYi Chen,
• ChangXiang Yu,
• ChangWei Yu,
• ZiYi Fu,
• DianShen Yang and
• YiXia Gong

Beilstein J. Org. Chem. 2020, 16, 798–808, doi:10.3762/bjoc.16.73

• with chloroacetic anhydride. Having accessed compound 12, many other new compounds can also be prepared by replacing an amine with the halogen atom. With compounds 12 and 15 in hand, we then tried to synthesize target compound 17 (Scheme 4), which is a novel 18β-glycyrrhetinic acid derivative to

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K₂CO₃/n-Bu₄PBr in water

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati and
• Gregor Schnakenburg

Beilstein J. Org. Chem. 2020, 16, 778–790, doi:10.3762/bjoc.16.71

• broad substrate scope, functional group tolerance, and simple purification technique is highly desired. In our continuous effort of synthesizing indole derivatives [29][30][31], herein, we report an efficient synthesis of multiple halogen-substituted (1H-indol-3-yl)methanol derivatives in the presence

• ketones were investigated, and the results are summarized in Table 2. Trifluoroacetophenones having a halogen substituent at the para-position of the phenyl ring such as p-F (2b), p-Cl (2c), and p-Br (2d) provided the corresponding trifluoro-1-(1H-indol-3-yl)ethan-1-ols 3b, 3c, and 3d in 97, 92 and 89

• scope of ketones was further extended with mixed halogen-substituted, pentafluoro or heptafluoro ketones such as 2-chloro-2,2-difluoro-1-phenylethan-1-one (2m), 2,2,3,3,3-pentafluoro-1-phenylpropan-1-one (2n) and 2,2,3,3,4,4,4-heptafluoro-1-phenylbutan-1-one (2o). All these reactions provided the

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles

• Ming-Xi Bi,
• Shuai Liu,
• Yangen Huang,
• Xiu-Hua Xu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2020, 16, 657–662, doi:10.3762/bjoc.16.62

• and agrochemical industries [3][4][5]. Traditional methods to access these compounds mainly include halogen–fluorine exchange of halomethyl sulfides and trifluoromethylation of sulfur-containing compounds [6][7][8]. Over the last decade, tremendous efforts have been triggered to develop methods for

Rhodium-catalyzed reductive carbonylation of aryl iodides to arylaldehydes with syngas

• Zhenghui Liu,
• Peng Wang,
• Zhenzhong Yan,
• Suqing Chen,
• Dongkun Yu,
• Xinhui Zhao and
• Tiancheng Mu

Beilstein J. Org. Chem. 2020, 16, 645–656, doi:10.3762/bjoc.16.61

• all with halogen anions), but also structural differences (e.g., crystal water, RhCl3 vs RhCl3·3H2O) of analogous Rh salts played an important role in the catalytic synthesis of benzaldehyde. Among all tested rhodium salts, RhCl3·3H2O afforded benzaldehyde in the highest yield and was chosen as the

• catalytic process giving aldehyde 31 with 77% yield. Also substrates comprising two halogen substituents performed well offering access to dihalogenated aldehydes 32–35 with yields between 76–81%. In addition, heterocyclic iodides were also amenable to the reductive carbonylation reaction and the

Asymmetric synthesis of CF₂-functionalized aziridines by combined strong Brønsted acid catalysis

• Xing-Fa Tan,
• Fa-Guang Zhang and
• Jun-An Ma

Beilstein J. Org. Chem. 2020, 16, 638–644, doi:10.3762/bjoc.16.60

• dr values, including alkyl or halogen-substituted phenyl and 2-naphthyl ketones (Scheme 2). Unfortunately, phenylglyoxal monohydrates bearing strong electron-withdrawing groups were not compatible with the current conditions. X-ray analysis of aziridine 4a confirmed the absolute configuration of the

Copper-catalyzed remote C–H arylation of polycyclic aromatic hydrocarbons (PAHs)

• Anping Luo,
• Min Zhang,
• Zhangyi Fu,
• Jingbo Lan,
• Di Wu and
• Jingsong You

Beilstein J. Org. Chem. 2020, 16, 530–536, doi:10.3762/bjoc.16.49

• electronic effects and steric hindrances. Arylating reagents with ortho-substituents led to slightly reduced yields (Scheme 2, 3f and 3i). Aryliodonium salts containing halogen substituents, especially bromo and iodo atoms, could afford the desired products in moderate to good yields (Scheme 2, 3j–n), making

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• (5). First, a Finkelstein halogen exchange reaction and a dehydration reaction were combined to obtain fluoroacetonitrile (7) in 82% yield [36]. The latter then underwent a Claisen condensation with ethyl formate to obtain 8 in 77% yield with a purity of 90%. The product contained about 10% (1H NMR

Synthesis of six-membered silacycles by borane-catalyzed double sila-Friedel–Crafts reaction

• Yafang Dong,
• Masahiko Sakai,
• Kazuto Fuji,
• Kohei Sekine and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2020, 16, 409–414, doi:10.3762/bjoc.16.39

• halogen substituents or sterical hindrance. A gram-scale synthesis of phenoxasilins and transformation of the amino groups in the phenoxasilin product were also achieved. We hope that the developed protocol will prove to be a useful and efficient method to synthesize six-membered silacyclic compounds

Six-fold C–H borylation of hexa-peri-hexabenzocoronene

• Mai Nagase,
• Kenta Kato,
• Akiko Yagi,
• Yasutomo Segawa and
• Kenichiro Itami

Beilstein J. Org. Chem. 2020, 16, 391–397, doi:10.3762/bjoc.16.37

• produces undesired cyclic compounds [14]. To design and synthesize a variety of HBC derivatives, methods for regioselective functionalization of HBC are in strong demand. As for functional groups on the HBC core, the introduction of halogen and boryl groups is an effective way to enable further

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• Preparation of N-heterocyclic phosphines via P–C bond formation Nucleophilic substitution of halogens There are different methods that have been reported for the construction of the P–C bonds. Two approaches are possible using halogenated precursors. The first one is the organometal-halogen-phosphine route

• where the metalated organohalogen compound is reacted with the halogen phosphine. Alternatively, the metal phosphide can be reacted with an organohalogen compound leading to the desired product. The most commonly used trans-metalation reagents are Grignard [54] or organolithium reagents [55] and other

• lithium halogen elimination, halide migration, and ring-opening reactions [56][57]. Butylphosphines are also formed alongside the main product, and in most cases pure phosphine pyridines are obtained using column chromatography followed by extractions adding to the number of synthesis steps. This method

Formal preparation of regioregular and alternating thiophene–thiophene copolymers bearing different substituents

• Atsunori Mori,
• Keisuke Fujita,
• Chihiro Kubota,
• Toyoko Suzuki,
• Kentaro Okano,
• Takuya Matsumoto,
• Takashi Nishino and
• Masaki Horie

Beilstein J. Org. Chem. 2020, 16, 317–324, doi:10.3762/bjoc.16.31

• to afford the regioregular polythiophene in which 2,5-dihalo-3-substituted thiophene 1 is employed as a monomer precursor, converting to the corresponding organometallic monomer by a halogen−magnesium exchange reaction with a Grignard reagent. The employment of 1 leading to polythiophene has been

Synthesis of 3-alkenylindoles through regioselective C–H alkenylation of indoles by a ruthenium nanocatalyst

• Abhijit Paul,
• Debnath Chatterjee,
• Srirupa Banerjee and
• Somnath Yadav

Beilstein J. Org. Chem. 2020, 16, 140–148, doi:10.3762/bjoc.16.16

• different functional groups (Table 2). It was found that the reactions tolerated carboxylic acid, ketone, halogen (Cl, Br, I, and F), aldehyde, amide, primary amine, secondary amine, and phenolic functional groups to a reasonably acceptable extent. Recovery and recyclability of the Ru nanocatalyst The

Halogen-bonding-induced diverse aggregation of 4,5-diiodo-1,2,3-triazolium salts with different anions

• Xingyu Xu,
• Shiqing Huang,
• Zengyu Zhang,
• Lei Cao and
• Xiaoyu Yan

Beilstein J. Org. Chem. 2020, 16, 78–87, doi:10.3762/bjoc.16.10

• triazolium salts show diverse aggregation via halogen bonding between C–I bonds and anions. Triazolium with halide anions exists as a tetramer with saddle conformation. Triazolium tetrafluoroborate exists as a trimer with Chinese lantern shape conformation. Triazolium trifluoroacetate and acetate exist as

• dimers, respectively, while the former shows boat conformation and the latter forms rectangle conformation. Triazolium salts form a linear polymer with polyiodide. Keywords: aggregation; 4,5-diiodo-1,2,3-triazolium salts; halogen bond; non-covalent interaction; Introduction The halogen bond (XB) is a

• reported neutral 4-halo-1,2,3-triazolylidenes C [43], which had a carbene character with σ-donation at the carbon and a σ-hole at the halogen atom. XB is observed by single-crystal X-ray diffraction in their coinage metal complexes. Meanwhile, 4-bromo-1,2,3-triazolylidene can catalyze H/D exchange of

Functionalization of the imidazo[1,2-a]pyridine ring in α-phosphonoacrylates and α-phosphonopropionates via microwave-assisted Mizoroki–Heck reaction

• Damian Kusy,
• Agata Wojciechowska,
• Joanna Małolepsza and
• Katarzyna M. Błażewska

Beilstein J. Org. Chem. 2020, 16, 15–21, doi:10.3762/bjoc.16.3

• halogen substituent in the imidazo[1,2-a]pyridine ring on its reactivity in the Mizoroki–Heck reaction. We confined our studies to the analogs bearing substituents at positions 6, 7, and 8 of the six-membered ring of the imidazo[1,2-a]pyridine (1a–f, in Figure 1) [24]. We found that the reaction occurred

A combinatorial approach to improving the performance of azoarene photoswitches

• Joaquin Calbo,
• Aditya R. Thawani,
• Rosina S. L. Gibson,
• Andrew J. P. White and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2019, 15, 2753–2764, doi:10.3762/bjoc.15.266

• ). The ortho-halogen-substituted photoswitches also present an unexpected behavior, where very large differences in half-lives are predicted depending on the nature of the halogen atom (from 5 days in 4pzH-Cl2 to ca. 4000 days in 4pzH-F2, or from 2 minutes in 4pzMe-Cl2 to 26 days in 4pzMe-F2, Table 1

Synthesis of aryl-substituted thieno[3,2-b]thiophene derivatives and their use for N,S-heterotetracene construction

• Nadezhda S. Demina,
• Nikita A. Kazin,
• Nikolay A. Rasputin,
• Roman A. Irgashev and
• Gennady L. Rusinov

Beilstein J. Org. Chem. 2019, 15, 2678–2683, doi:10.3762/bjoc.15.261

• amino group in the corresponding 3-aminothiophene-2-carboxylates with a halogen atom by the Sandmeyer reaction [20][21]. The former transformation is preferable for large-scale syntheses, but we failed to repeat the reported procedures. For example, our attempt to diazotizate methyl 3-amino-5

Acid-catalyzed rearrangements in arenes: interconversions in the quaterphenyl series

• Sarah L. Skraba-Joiner,
• Carter J. Holt and
• Richard P. Johnson

Beilstein J. Org. Chem. 2019, 15, 2655–2663, doi:10.3762/bjoc.15.258

• Sarah L. Skraba-Joiner Carter J. Holt Richard P. Johnson Department of Chemistry and Materials Science Program, University of New Hampshire, Durham, NH 03824, USA 10.3762/bjoc.15.258 Abstract Arenes undergo rearrangement of phenyl, alkyl, halogen and other groups through the intermediacy of ipso

AgNTf₂-catalyzed formal [3 + 2] cycloaddition of ynamides with unprotected isoxazol-5-amines: efficient access to functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives

• Ziping Cao,
• Jiekun Zhu,
• Li Liu,
• Yuanling Pang,
• Laijin Tian,
• Xuejun Sun and
• Xin Meng

Beilstein J. Org. Chem. 2019, 15, 2623–2630, doi:10.3762/bjoc.15.255

• % yields. For examples, the aromatic motifs of ynamides possessing an electron-donating group such as MeO-, Me- and t-Bu- are well tolerated to afford the desired cycloadducts 10ba–da in 85–99% yields. The ynamide substrates 4e–g with an electron-deficient halogen substituent (F-, Cl- and Br-) on the

A new approach to silicon rhodamines by Suzuki–Miyaura coupling – scope and limitations

• Thines Kanagasundaram,
• Antje Timmermann,
• Carsten S. Kramer and
• Klaus Kopka

Beilstein J. Org. Chem. 2019, 15, 2569–2576, doi:10.3762/bjoc.15.250

• 30b to rhodamine 30c clearly outperforms the addition of lithiated 2-bromothiophene to xanthone 12 since 2-bromothiophene might also undergo lithiation in 5-position in competition to the halogen metal exchange (in general multiple halogenated aryls are problematic nucleophiles for these addition

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

• Xavier Gómez-Santacana,
• Sabrina M. de Munnik,
• Tamara A. M. Mocking,
• Niels J. Hauwert,
• Shanliang Sun,
• Prashanna Vijayachandran,
• Iwan J. P. de Esch,
• Henry F. Vischer,
• Maikel Wijtmans and
• Rob Leurs

Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244

• used to guide the design iterations. Investigations of positional and substituent effects reveal that halogen substituents on the ortho-position of the outer ring are preferred for conferring partial agonism on the cis form of the ligands. This effect could be expanded by an electron-donating group on

• substitution pattern of this biaryl moiety, a broad spectrum of efficacies for CXCR3 can be obtained, i.e., from antagonists to partial agonists and full agonists (Figure 1C) [24]. Meta and para-substitution yields antagonists (exemplified by 1a,b), while ortho-substitution with halogen atoms provides agonists

• , exemplified by partial agonist 1c and equal full agonists 1d and 1e (VUF11418, Figure 2A). A tentative explanation for this efficacy switch includes a variation of the dihedral angle of the biaryl moiety, an increase of the electron density in the biaryl unit and/or a postulated halogen bond of the halogen

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• , while a OMe substituent in this position no product 4e was obtained. On the other hand, no significant effect was observed when the substituents were placed in the meta- or para-position (4f–m) of the amide group. It must be noted that for substrates bearing a halogen (1k–m) in the meta-position of the

• amide, a mixture of the two possible regioisomers of compounds 4k, 4l and 4m was obtained. Fortunately, the major isomers (shown in Scheme 3) could be isolated as pure products corresponding to the less hindered isomer, in which the annulation took place in the para-position of the halogen. When a Me

Synthesis of a dihalogenated pyridinyl silicon rhodamine for mitochondrial imaging by a halogen dance rearrangement

• Jessica Matthias,
• Thines Kanagasundaram,
• Klaus Kopka and
• Carsten S. Kramer

Beilstein J. Org. Chem. 2019, 15, 2333–2343, doi:10.3762/bjoc.15.226

• the use in multimodal (PET/OI) medical imaging of mitochondria in cancerous cells. Results: A dihalogenated fluorinatable pyridinyl rhodamine could be successfully synthesized with the high yield of 85% by application of a halogen dance (HD) rearrangement. The near-infrared dye shows a quantum yield

• optical properties for medical and bioimaging. As a compound with intrinsic mitochondria targeting ability, the radiolabelled analogue can be applied in multimodal (PET/OI) imaging of mitochondria for diagnostic and therapeutic use in, e.g., cancer patients. Keywords: halogen-dance reaction

• also be used for further functionalization. Until now, no silicon rhodamines are known that bear two phenylic halogen substituents (Cl/Cl, Cl/Br, Br/Br nor combinations with F) at the positions adjacent to the xanthene benzene bond. The same holds true for the oxygen counterparts with a dihalogenated

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• –nitrogen double bond [13] (see Figure 2B), further undesired bromo–lithium exchange is possible at C-4. Since halogen substituents at C-4 are further readily substituted by nucleophiles, we considered bulky, non-nucleophilic amide bases as most promising for the metalation at C-5. Inspired by reports of

• equivalents of base, longer reaction times, higher or lower temperatures did not increase the yields. In order to explore additional metalations at other positions than C-5 or imaginable halogen dance reactions [24] during the metalation process, we performed a D2O quenching experiment after the metalation

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

• Sara Peeters,
• Linn Neerbye Berntsen,
• Pål Rongved and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2019, 15, 2156–2160, doi:10.3762/bjoc.15.212

• . These halo-acceptor carbenoids undergo cyclopropanation of N–H indoles with high selectivity, and only traces of C–H or N–H insertion products were observed. The yield of ethyl quinoline-3-carboxylate is dependent on the halogen in X-EDA (Cl: 90%, Br: 84%, I: 70%). The reaction works well for

• of indole substituents on the yields of ethyl quinoline-3-carboxylates [15]. Green = good, orange = medium, red = poor. R = halogen, Me, MeO, NO2. Retrosynthetic outline for the synthesis of quinolone-3-carboxlates from indole derivatives. Synthesis of ethyl 4-quinolone-3-carboxylate (6) and proposed

1,2,3-Triazolium macrocycles in supramolecular chemistry

• Mastaneh Safarnejad Shad,
• Pulikkal Veettil Santhini and
• Wim Dehaen

Beilstein J. Org. Chem. 2019, 15, 2142–2155, doi:10.3762/bjoc.15.211

• -triazole units to more electrophilic 1,2,3-triazolium units by influencing both hydrogen bonding-like and anion–π interactions. Moreover, halogen bond (XB) and chalcogen bond (ChB) interactions (see Figure 1) also been applied for the selective detection of anions by exchanging C5–H protons with halogens

• -position of the triazoles (triazolium), and nucleophilic substitution of halogen can be used to introduce chalcogens (Se, Te). Thus, the corresponding triazolium macrocycles can take advantage respectively of halogen and chalcogen bonding as part of the molecular recognition (vide infra). In this review

• − and Cl− (4.7 × 102 and 4.6 × 102 M−1, respectively) then followed by Br− (2.1 × 102 M−1), N3− (1.9 × 102 M−1) and I− (1.3 × 101 M−1) [47]. Soon after, a mixed halogen and hydrogen bonding hetero[2]catenane 6 (Figure 6) was successfully synthesized by the same group via an anion templated Grubbs’ II