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

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• in the synthesis of (–)-batzelladine D 61 and (–)-13-epi-batzelladine D 62. The reaction of (SS)-58 with methyl bromoacetate in the presence on Zn and CuCl in THF, left, after removal of the sulfinyl group under acidic conditions, to β-amino ester ammonium chloride 59 in high yield. This compound was

• rhodium catalyst in dioxane, in the presence of 2 equivalents of MeOH, at 65 °C, leading to compounds 65 with high diastereomeric ratio. Crude amides 65 were converted into the corresponding pyrrolidines 66 in high yield by stirring at room temperature for 1 h in presence of 2.0 equivalents of LiHMDS

• -amino ketone derivative 124 in high yield and diastereoselectivity (Scheme 34). A reduction of 124 gave a mixture of diastereomeric alcohols, and the one with (R)-configuration at the benzylic position was isolated in 54% yield. Further treatment of the alcohol with NaH furnished a cyclized product

Nitroalkene reduction in deep eutectic solvents promoted by BH₃NH₃

• Chiara Faverio,
• Monica Fiorenza Boselli,
• Patricia Camarero Gonzalez,
• Alessandra Puglisi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2021, 17, 1041–1047, doi:10.3762/bjoc.17.83

• eutectic mixtures DES D and E, and a ChCl/ʟ-(+)-lactic acid mixture, DES F (Table 2). The reduction worked in all systems, in low yield with DES E (where it was not possible to separate the product from the DES) and DES F, but it proceeded in very high yield and short reaction time in DES D. Based on these

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• guanidine to a carbodiimide was reported by Richter and Ulrich in 1981 (Scheme 38) [78]. The authors prepared an N1,N2,N3,N4,N5-pentaarylbiguanide derivative by reacting an N,N’,N’’-triarylguanidine with diphenylcarbodiimide. The reaction occurred at room temperature in dichloromethane with a high yield

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

• mannosyl fluoride α-1a was achieved and the desired O-mannoside 3a was isolated in a high yield and α-selectivity. Hemiacetal α-4 was isolated as the only side-product formed via glycosyl donor hydrolysis with the water present in commercial SO2 [62]. To note, at lower temperatures (Table 1, entry 1) no

• were not fully consumed. The superior reactivity of glycosyl fluoride α-1a in liquid SO2 compared to other halides was clearly demonstrated when thiol 2c was used as an acceptor (Table 3, entries 4–6). S-Mannoside 3c was isolated from mannosyl fluoride α-1a in twice as high yield as from the

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

• allylic geminal bissilyl alcohol 221 for the construction of THP ring A of (−)-exiguolide via Prins cyclization with an aldehyde in the presence of Lewis acid as a promoter [95]. High yield and excellent diastereoselectivity were obtained under standard silyl-Prins cyclization conditions using TMSOTf as

• the stereoselective construction of the THF ring (Scheme 67) [109]. A series of geminal bishalogen-containing fused THPs was synthesized in high yield (up to 80%) and excellent diastereoselectivity. A Prins cyclization mechanism was proposed for the above transformation in the presence of TiCl4

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

• irradiation (Scheme 61). It was worth mentioning that longer reaction times and increased DIPEA loading were required owing to the inactivity of α-bromoketones, esters, and nonactivated sulfones; however, corresponding products could be given in high yield. When the DIPEA molarity was double that of

Synthesis of dibenzosuberenone-based novel polycyclic π-conjugated dihydropyridazines, pyridazines and pyrroles

• Ramazan Koçak and
• Arif Daştan

Beilstein J. Org. Chem. 2021, 17, 719–729, doi:10.3762/bjoc.17.61

• dihydropyridazine 3e, the intended pyridazine compound could not be obtained. Alternatively, nitrogen monoxide (NO) gas was used as oxidizer and pyridazineamide 4e was obtained in high yield (83%, Scheme 5). In another important part of this study, pyridazines were converted into the corresponding pyrroles via a

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• the convex face of the bicyclic system. Amide 9p with an enantiomerically enriched cyclohex-2-enyl substituent cyclized with exclusive diastereoselectivity and only two diastereomers 12pA differing in the orientation of the hydroxy group were obtained in high yield. The radical coupling with TEMPO

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• involved in C60 reactions with diazo compounds is much wider. In addition, the high yield of the target products and the nearly unlimited variability of substituents in the cyclopropane moiety should be noted as advantages of the latter method. Nevertheless, a drawback that all the [2 + 1] cycloaddition

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• -hydroxyglutarate (84) in a Mitsunobu reaction to generate the γ-phosphonodepsipeptide 79 in a high yield of 66% (Scheme 27) [28]. Synthesis of phosphonodepsipeptides via the multicomponent condensation of amides, aldehydes, and phosphites followed by alcoholysis with hydroxy esters Previously, the Mannich-type

Helicene synthesis by Brønsted acid-catalyzed cycloaromatization in HFIP [(CF₃)₂CHOH]

• Takeshi Fujita,
• Noriaki Shoji,
• Nao Yoshikawa and
• Junji Ichikawa

Beilstein J. Org. Chem. 2021, 17, 396–403, doi:10.3762/bjoc.17.35

• % yield. Similarly, C-shaped double helical helicene 5b was obtained in high yield using m-dibromobenzene 6b with two acetal moieties, prepared from m-xylene (Scheme 5b). We also achieved the synthesis of heterohelicenes, which involve heteroatoms in the helicene frameworks, via a Suzuki–Miyaura coupling

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of β-amino acid

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

• compounds 161 in high yield (Scheme 40, top). The reaction of CF3-substituted 1,3-diketones 165a–d in TfOH was also deeply investigated by Klumpp et al. [101]. The syn-indanes 166a–d could cleanly be generated after successive well-defined arylation reactions via 167 (Scheme 40, bottom). Moreover, the CF3

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• in a high yield of 94%. Accordingly, the synthesis of the chromogenic ferulate 12 was achieved in 32% overall yield in 3 steps from commercial reactants (convergent synthesis using a slight excess of the synthesized vinyl ferulate 2) and without the requirement to perform a final deprotection. As

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• straightforward way to novel fluorinated norbornadienes from β-fluoro-β-nitrostyrenes and CPD. Conclusion In summary, the Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic 1,3-dienes was investigated. A series of novel monofluorinated norbornenes was prepared in high yield up to 97%. A number of novel

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• -2-thione species 6a in a high yield (Scheme 1, route 2). The red color of the reaction mixture belonging to the parent o-quinone rapidly turns into a brown color of o-quinone 6a. o-Quinone 6a was isolated as red-brown crystals by cooling the acetone/ether mixture. It is a structural analogue of o

• manner to give the corresponding 1,3-dithiole derivatives in a high yield. On the other hand, the fact that treatment of 4 with NaH(hfac) and CS2 does not result in substitution of chlorine atoms at the quinone backbone indicates that under such conditions the gem-dithiolate species is not formed

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

• )-monoacetate (S)-80, respectively (Scheme 32). As for the transesterification, a high yield (96.5%) and enantioselectivity (91.3% ee) were obtained using lipase PS in benzene. In the case of the deacetylation, the use of Amano PS lipase in acetone gave a high yield (86.2%), enantioselectivity (91.7% ee), and

• alkenes with the CF3SiMe3–NaI system has been studied (Table 2). Difluorocarbene addition to α-fluorostyrenes enabled the efficient synthesis of trifluorocyclopropanes 34 [41]. The difluorocyclopropanation of protected cyclohexenone yielded cyclopropane 35 [42]. Difluorocyclopropane 36 was formed in high

• yield from the α-bromopyridine-substituted N-Boc-3,4-dehydropiperidine. When the same reaction was attempted on the bromine-free analog, the yield was only 22% [43]. The difluorocyclopropanation of an alkenyl trifluoroborate using the TMSCF3–NaI system afforded the boronate derivative 37 [44]. The

Selective synthesis of α-organylthio esters and α-organylthio ketones from β-keto esters and sodium S-organyl sulfurothioates under basic conditions

• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Thiago Barcellos,
• Claudio C. Silveira and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2021, 17, 234–244, doi:10.3762/bjoc.17.24

• conditions to obtain ethyl 2-(benzylthio)acetate (3a) selectively and in a high yield in hand (Table 1, entry 22), we turned our attention to find an ideal protocol to synthesize 4a. When 0.5 mmol of 1a and 1 mmol of 2a were used in the presence of 2 equivalents of NaOH under air, compound 4a was obtained in

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

• ((cis)-3-aminocyclobutyl)carbamate afforded the undesired regioisomer 28 as the majority product (Scheme 5). As we were unable to exploit intermediate 26, we turned our attention to the pyridine-2-(1H)-one building block 30, easily prepared by hydrolysis of the C-2–F bond in high yield and without the

Insight into functionalized-macrocycles-guided supramolecular photocatalysis

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

Beilstein J. Org. Chem. 2021, 17, 139–155, doi:10.3762/bjoc.17.15

• + and crown ether, leading to the formation of cyclobutane in a high yield. D’Souza et al. constructed a photosynthetic triad 4 to mimic the photosynthetic reaction center [19]. A BODIPY, an ammonium-functionalized fullerene, and a zinc porphyrin functioned as the energy donor, electron acceptor, and

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• was also performed (Table 3). First of all, 3aa was introduced to a t-BuOH solution of 2 equiv of t-BuOK to afford the desired product 4aa in a high yield, and an increase in the amount of this base to 3 equiv led to the complete conversion of the substrate 3aa (Table 3, entries 3 and 4). This trend

• outlined above, the results of which are summarized in Table 6. When the reactions were performed with acetamidine and guanidine, a good to high yield was recorded, while only a lower yield was obtained by the application of formamidine acetate, for which the reaction was not further elucidated at this

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• (−)-79a and (−)-79b, which were oxidized to enone (−)-80. The enone (−)-80 was subjected to ring-closing metathesis with Grubbs second-generation catalyst resulting in cyclic enone (−)-81 in 74% yield. (−)-81 was treated with phenylselenol to generate selenide 82 in high yield. The ozonolysis of 82 was

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

• sterically hindered DICAB, compared to the liquid DIPAB, but that a too high reaction temperature such as 60 °C tends to increase the degradation pathways instead of the formation of the desired compound. However, this effect was not observed when performing the reaction in MTBE. A high yield of 86% was

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

• afforded the desired products smoothly in good to high yield in solvent-free conditions. An extension of this deoxyfluorination strategy to drug-like molecules was demonstrated to show the usefulness of this transformation. The present protocol also expands the utility of FLUOLEAD® in organic synthesis