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

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• stabilize the oxocarbenium ion formed from glycosyl perchlorate that is generated in situ from glycosyl chloride and AgClO4 [56]. Apart from that, SO2 has considerable affinity to the Lewis basic halide ions [57][58][59]. Kuhn et al. [60] and later Eisfield and Regitz [61] have published ab initio studies

• on the stability of halosulfites HalSO2− (Hal = F, Cl, Br or I) that can be formed between halide ions and the SO2 molecule. They disclosed that the formation of fluorosulfite anion (FSO2−) has the highest energy gain and it appears to be stable even in highly polar solvents (ε ≤ 45), while all other

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• -orbital at C4. These orbital stabilizations, along with the lack of 1,3-diaxial interaction experienced by the incoming nucleophile (mostly halide) leads to the preferential equatorial attack over an axial attack by the nucleophile (Scheme 3) to give all-cis-2,4,6-trisubstituted THPs. In the absence of an

• cyclization between homoallyl alcohol 118 (or using the corresponding aldehyde and allylsilyl chloride 119) and an aldehyde 120 in the presence of a catalytic amount of the mild Lewis acid In(OTf)3 and trimethylsilyl halide as an additive to produce cis-4-halo-2,6-disubstituted tetrahydropyran 121 (Scheme 28

• -trimethylsilylalkenyl cation 242 formed by the Grob-type fragmentation (Scheme 57), which was trapped by the subsequent attack of the halide anion, leading to the formation of Prins product 244. On the basis of theoretical calculations, the authors could conclude factors controlling the alkyne Prins cyclization over

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

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• 22 can be afforded easily (Scheme 7). This procedure offers a novel cyclization method with bifunctionalization, causing a multicomponent reaction of vinylaniline, halide, and sulfonylate to give corresponding indole derivatives. Furthermore, a wide variety of applicable substrates and good

• process, the authors supposed that it may facilitate single-electron transfer between biguanidine anion and perfluoroalkyl halide. By constructing two C–N bonds at the same time, the triazine heterocyclic structure that is commonly utilized in medical and material fields was accomplished by [5 + 1

• the EDA complex formed by aryl halide 106 and oxindole 107 under alkaline conditions allowed single-electron transfer under irradiation with light, eventually affording arylated oxidized indole product 108 (Scheme 37). This reaction provides an effective method to construct various 3-arylindoles with

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

• Zbigniew Malinowski,
• Emilia Fornal,
• Agata Sumara,
• Renata Kontek,
• Karol Bukowski,
• Beata Pasternak,
• Dariusz Sroczyński,
• Joachim Kusz,
• Magdalena Małecka and
• Monika Nowak

Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50

• the coordination of the amine takes place after the oxidative addition of the organic halide to the palladium–ligand complex. Based on the analysis of our results we have concluded that in the case of systems 3, the order of reagent addition could have a significant impact on a proper course of the

Deoxygenative C2-heteroarylation of quinoline N-oxides: facile access to α-triazolylquinolines

• Geetanjali S. Sontakke,
• Rahul K. Shukla and
• Chandra M. R. Volla

Beilstein J. Org. Chem. 2021, 17, 485–493, doi:10.3762/bjoc.17.42

• 3i and 3j were isolated in slightly lower yield (81% and 84%, respectively). Triazoles bearing halide substituents (Cl and Br) at the meta- or para-positions were also found to be viable substrates to afford the products 3k and 3l with 85–90% yield. Additionally, the reaction protocol is compatible

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• halodifluoromethanes and alkenes (Scheme 2). The elimination of hydrogen halide from the halodifluoromethane under basic conditions (metal alkoxide or alkyllithium) generated difluorocarbene [14][15]. The low yields of the product have been attributed to the facile addition of the strong bases to difluorocarbene. The

• yields were best in the reactions with electron-rich alkenes and when a low concentration of the base was used to minimize the destruction of difluorocarbene. The use of oxirane or epichlorohydrin as hydrogen halide scavengers avoided the need for a stoichiometric amount of the strong base [16][17]. The

• amounts of halide sources (e.g., tetramethylammonium chloride or tetrabutylammonium bromide). Compared with the difluoromethylenation protocols using TFDA (25), MDFA (30), or TMSCF3 (31), the application of BrCF2SiMe3 has been claimed to be safer and more convenient for large-scale application because of

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

• substitution reactions of this type are synthetically appealing as they avoid pre-generation of an active electrophile such as an alkyl halide. A selection of benzylic alcohols 2 was reacted under the standard conditions with BT-SC2F5 (1.25 equiv) and NEt(iPr)2 (2 equiv) in MeCN at −40 °C, providing the

• alcohols, thus avoiding the pre-formation of an alkyl halide. This straight-forward route should inspire further investigations of perfluoroalkylthio groups in pharmaceutical, agrochemical and materials science. Synthetic routes towards perfluoroalkyl thioethers. Two-step synthesis of BT-SRF reagents from

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

• Vyacheslav I. Supranovich,
• Igor A. Dmitriev and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 3104–3108, doi:10.3762/bjoc.16.260

• photocatalyst and stoichiometric quantities (1.2 equiv) of a reducing system (ascorbic acid/collidine). In this reaction no products were formed with reactant 2a remaining unconsumed (Table 1). To obtain a more reactive fluorinated halide, the bromine atom residing at the fluorinated moiety was exchanged for

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• halide to iodine, taking into account that direct iodination of purines has been claimed being troublesome [26], although not impossible [27]. For C8-iodination of adenosine, first the hydroxy groups at the sugar moiety were protected with tert-butyldimethylsilyl (TBDMS) groups. The silylated nucleoside

Dirhamnolipid ester – formation of reverse wormlike micelles in a binary (primerless) system

• David Liese,
• Hans Henning Wenk,
• Xin Lu,
• Jochen Kleinen and
• Gebhard Haberhauer

Beilstein J. Org. Chem. 2020, 16, 2820–2830, doi:10.3762/bjoc.16.232

• chain length without the production of side products (Scheme 1). Under mild and basic conditions, with this SN2 reaction of the dirhamnolipid and any primary alkyl halide, the desired product was obtained with a high yield ranging from 70–85%. Also, a gemini-like structure 7 was synthesized. Solubility

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• steric hindrance – and 33% unreacted starting material was recovered from the iodofluorination reaction mixture. In order to study the synthetic usefulness of the halofluorinated products, E2 hydrogen halide elimination was attempted. Since bromide and iodide are much better leaving groups than fluoride

• , the selective elimination of the former halogens was expected. Taking into account the stereochemical requirements of the E2 elimination (the halide group and the β-hydrogen atom should be antiperiplanar relative to each other), the limited availability of the compound (rac)-5b, and Bredt’s rule

• upon the intramolecular nucleophilic attack by the alkyl halide (Scheme 16). The reaction of the compound (rac)-6b is less direct. According to the above pathway, the formation of the compound (rac)-T10 would be expected (Scheme 17). In order to generate the final product (rac)-27, a base-catalyzed

Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

• , a microcapillary reactor (1/6” OD, 3.5 mL reactor volume) that was wrapped around a metal halide UV lamp was scaled up by using several strategies together. Rather than splitting up the reaction medium into many photoreactors, the photoreactors were numbered up by adding them in series (Figure 3b

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

• cross-coupling reactions. A 4-fluoro-substituted phenacyl chloride as well as a bromomethyl 2-naphthyl ketone proved to be competent substrates as well, thus furnishing the corresponding imidazoles 3i/3i' and 3j in 67–87% yield. Conversely, a phenacyl halide decorated with an additional phenyl group at

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

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• (Scheme 23) [59]. The authors rationalized the formation of 45 by considering that the inherent weakening of the C—X bond going down the halogen series may favor the generation of radical A with chloride and bromide derivatives, especially given the tertiary position of the halide and the stoichiometric

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• occur via a radical pathway. When iodide 29 was replaced by a superior oxidant in 1,2-dibromoethane, formation of dimer 32 increased (17% isolated yield). This supports the previously reported proposals that dimerisation occurs via single-electron oxidation of the 2-picolyl anion by the halide

• /pseudohalide oxidant followed by recombination of the resulting picolyl radical [28][29][30]. Whilst trace oxygen may be involved, as indicated by the presence of alcohol 31, no dimerisation or alcohol formation was seen in the absence of a halide/pseudohalide-based oxidant, during C-phosphorylation or

Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita–Baylis–Hillman adducts

• Soundararajan Karthikeyan,
• Radha Krishnan Shobana,
• Kamarajapurathu Raju Subimol,
• J. Helen Ratna Monica and
• Ayyanoth Karthik Krishna Kumar

Beilstein J. Org. Chem. 2020, 16, 1579–1587, doi:10.3762/bjoc.16.130

• -lactams [6], quinolin-5-ones [7], spirobisglutarimides [8], indolizines [9], and spiro carbocyclic frameworks [10]. However, most of the reported synthetic transformations utilize either allylic hydroxy-protected or allyl halide-substituted MBH adducts [11][12][13][14][15][16][17][18][19][20][21][22][23

• transformations for complex molecules [29][30][31]. Two individual research groups have reported the multistep pathway to access the cinnamyl-1H-1,2,3-triazole derivatives IX from acetates of MBH adducts (Scheme 2) [32][33]. The other preferable moiety for triazole transformations is the allyl halide of MBH

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

• optimization (Table S4, Supporting Information File 1), solubility issues hindered the formation of a concentrated solution (>0.8 M). The crystallization of iPrMgBr in the collection flask forced us to reduce the initial concentration of the organic halide to 0.9 M, yielding iPrMgBr (0.75 M, 82%, note: the

• yields reported herein refer to the amount of organometallic reagent produced in a steady state; no detectable halide was recovered, and the organometallic reagent purity was high unless otherwise stated, Table S4, entry 3, Supporting Information File 1). The reactivity order of organic halides against

• consistent results over a relatively large amount (≈100 mmol) of organic halide that was converted. We offer two explanations: (1) the higher purity of Mg chips (99.98%) and (2) the higher surface area (SA) of the Mg powder (≈130 mesh, SA ≈ 30 cm2/g) than Mg chips (≈20 mesh, SA ≈ 4 cm2/g). We hypothesize

Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

• Xiaoming Ma,
• Suzhi Meng,
• Xiaofeng Zhang,
• Qiang Zhang,
• Shenghu Yan,
• Yue Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106

• IV which undergoes dissociation to afford product 9a. The hydridopalladium(II) halide is converted to the catalytically active Pd(0) with a base. Conclusion In summary, we have developed an efficient method through a three-component [3 + 2] cycloaddition followed by a one-pot N-allylation and an

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

• the nature of the halide: as a trend, aryl iodides are easier to reduce than aryl bromides and aryl chlorides [67][77]. Under organophotocatalytic conditions, the reduction can be achieved following two main strategies for accessing stronger reduction potentials: (a) tuning the electronics of 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

• 87% yield) was investigated (Scheme 8) [52]. Finally, the Poisson’s group developed a methodology for the Ullman cross-coupling reaction between the in situ-generated CuCF2PO(OEt)2 and aryl iodides containing a coordinating group (e.g., CO2CH3, COCH3, NO2), at the ortho-position of the halide [52

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

• involved a Negishi cross coupling of an aryl halide and the Zn homoenolate of the protected (R)-iodoalanine 2 using a Pd(0) catalyst. This method provided a versatile range of fluorinated phenylalanine products with high enantioselectivities and in acceptable yields. 2. Synthesis of β-fluorophenylalanines